CLINICAL' HEMATOLOGY.
DACOSTA.
II.
THE LEUCOCYTES.
(WRIGHT'S STAIN.)
I. Normal erythrocytes.
II. Large and small lymphocytes and transitional forms.
III. Polynuclear neutrophiles.
IV. Blood plaques.
V. Eosinophiles
VI. Myelocytes.
VII. Mast cells.
(E. F. Faber, fee.)
III.
CLINICAL
HEMATOLOGY
A PRACTICAL GUIDE TO THE
EXAMINATION OF THE BLOOD
WITH REFERENCE TO DIAGNOSIS
BY
JOHN C. DACOSTA, JR., M.D.
DEMONSTRATOR OF CLINICAL MEDICINE, JEFFERSON MF.DICAL COLLEGE; CHIEF OF MEDICAL
CLINIC AND ASSISTANT VISITING PHYSICIAN, JBPFERSON MEDICAL COLLEGE HOSPITAL;
HEMATOLOGIST, GERMAN HOSPITAL; ASSISTANT VISITING PHYSICIAN, PHILADEL-
PHIA GENERAL HOSPITAL; FELLOW OF THE COLLEGE OF PHYSICIANS
OF PHILADELPHIA
Secon£> Edition, IRevfsefc anfc
CONTAINING NINE FULL-PAGE COLORED PLATES, THREE CHARTS,
AND SIXTY-FOUR OTHER ILLUSTRATIONS
PHILADELPHIA
P. BLAKISTON'S SON & CO.
1012 WALNUT STREET
1907
COPYRIGHT, 1904, BY P. BLAKISTON'S SON & Co.
REGISTERED AT STATIONERS' HAI.L, LONDON, ENGLAND
PHILADCLPHIA
TO
MY FATHER,
C. 2>aCosta, flD.H).,
THESE PAGES ARE
AFFECTIONATELY DEDICATED.
PREFACE TO THE SECOND EDITION.
Three noteworthy lines of advance have developed from recent
work in hematology: the identification of new clinical entities,
the correlation of blood pictures with a number of diseases hitherto
unstudied or imperfectly investigated hematologically, and the
proof of the septic nature of many of the specific infections. The
first has established upon a clinical basis trypanosomiasis, kala-azar,
spotted (Montana) fever, and cyanotic polycythemia ; the second
has shown in detail the blood changes incident to chloroma, hydatid
infection, multiple periostitis, pancreatitis, variola, arthritis defor-
mans, sprue, leukanemia, burns, and x-ray therapy; and the last
has proved the bacteriemic character of enteric fever, Malta fever,
pneumonia, scarlet fever, and, possibly, rheumatic fever. Prog-
ress of great practical Value has been made in the technic of
blood examinations, notably in staining methods, in serum diag-
nosis, and in blood culturing. These advances, all made during
the past two years, have been incorporated in this edition, together
with much other new material, gleaned by the consultation of
more than nine hundred late references to hematological literature.
The original data of the book are based upon the records of
about ten thousand blood examinations, made chiefly at the Ger-
man, the Jefferson, and the Philadelphia General Hospitals. This
new matter relates more especially to the primary anemias, malig-
nant disease, cholelithiasis, icterus, pancreatitis, gastric ulcer, pneu-
monia, septicemia, and suppurative lesions. For the sake of clear-
ness, tabulations have been avoided as far as possible, and the
data analyzed and presented as summaries. Among the improve-
ments in technic described are Wright's stain, Milian's method
of estimating the coagulation time, Reudiger's serum test, medico-
legal tests for blood, and cryoscopy. A brief account is given of
Ehrlich's side-chain theory and its relation to immunity and to
hemolysis. The detailed revision of the text has been supple-
mented by the addition of a new- colored plate and numerous other
illustrations.
In this revision the plan of the first edition has been adhered
to — the interpretation of the blood report as a rational aid to
Vlll PREFACE TO THE SECOND EDITION.
diagnosis. The author has profited by the views of his critics
whenever they could be consistently adopted, and he begs to
acknowledge his appreciation of the many suggestions from this
source.
1022 SPRUCE STREET, PHILADELPHIA,
November i, 1904.
PREFACE TO THE FIRST EDITION.
This book, designed as a practical guide to the examination of
the blood by methods adapted to routine clinical work, represents
an endeavor to recount the salient facts of hematology as they are
understood at the present time, to correlate certain of these facts
with familiar pictures of disease, and to apply them to medical
and surgical diagnosis. The purpose has been to interpret the
blood report according to its true value as a clinical sign, neither
exploiting it as a panacea for every diagnostic ill, nor belittling it
because of its failure consistently to give the sought-for clue in
every instance.
A minimum amount of theoretical discussion has been intro-
duced in the sections dealing with the physiology and pathology of
the whole blood and of the cellular elements — only sufficient, in the
author's judgment, to add clearness to the number of the mooted
points of this science, which in its present transitional stage must
still be regarded as one from which more or less hypothesis and
conjecture are inseparable. Intimate familiarity with technic
being an essential qualification for the comprehensive study of the
blood, a somewhat lengthy consideration of this subject is given.
The methods of examination likely to prove useful in everyday
practice have been described in detail, perhaps somewhat at the
risk of prolixity, in the hope of thus simplifying for the novice the
minutiae of blood counting, staining, and other means of investi-
gation. In the discussion of the primary anemias and of the
anemias peculiar to infancy, prominent clinical features other than
those referable to the blood have been briefly mentioned, in order
to add clearness to the differential diagnosis. For convenience in
reference, the various diseases included in the section on general
hematology are arranged alphabetically, rather than grouped
according to a traditional classification.
The greater part of the original data referred to in the text is
taken from the records of the Pathological Institute of the German
Hospital, where a systematic account of all blood examinations has
been kept for the past six years. The remaining data represent
the writer's personal examinations in hospital and private practice
and in the Army Medical Service, these sources of statistics
together including about four thousand blood reports in various
pathological conditions.
X PREFACE TO THE FIRST EDITION.
Hematological literature has been freely consulted in the prepa-
ration of this volume, special acknowledgment being due to
Hayem, Ehrlich and Lazarus, von Limbeck, Rieder, Lowit, Turk,
Grawitz, Cabot, Stengel, Thayer, Ewing, Taylor, and Coles for
the profitable information gleaned from their writings. Due
credit in the text has been given to these as well as to the other
authors of whose labors use has been made.
The colored plates and other histological illustrations, the origi-
nals of which were made by Mr. E. F. Faber from fresh and stained
specimens, bear evidence of the artist's technical skill and faithful
attention to structural detail. Mr. S. Trenner has kindly furnished
the engravings of several of the special instruments.
The author takes pleasure in acknowledging the assistance of his
wife and critic in revising the proofs of these pages; in crediting
Dr. G. P. Miiller for collecting and verifying much statistical
matter relating to hospital cases; and in thanking Dr. J. Chalmers
Da Costa and Dr. T. G. Ashton for helpful suggestions.
313 SOUTH THIRTEENTH STREET, PHILADELPHIA,
November 1901
TABLE OF CONTENTS.
INTRODUCTION, xxxi
SECTION I.
EXAMINATION OF THE BLOOD BY CLINICAL METHODS.
PAGE
GENERAL SCHEMA, 33
I. MICROSCOPICAL EXAMINATION OF THE FRESH BLOOD, 33
Obtaining the Specimen, 33
Preparing the Slide, 35
Microscopical Examination, 37
Changes Affecting the Erythrocytes, 37
Changes Affecting the Leucocytes, 37
Increase in Fibrin, Blood Plaques, and Hemoconia, 38
Blood Parasites, 39
Foreign Bodies, 39
II. ESTIMATION OF THE PERCENTAGE OF HEMOGLOBIN, 39
Dare's Hemoglobinometer, 41
Von Fleischl's Hemometer, 43
Oliver's Hemoglobinometer, 49
Gowers' Hemoglobinometer, 52
Haldane's Hemoglobinometer, 53
Tallquist's Method, 54
Haig's Blood Decimal Card, 55
III. COUNTING THE ERYTHROCYTES AND THE LEUCOCYTES, 55
Methods, 55
Diluting Fluids, 56
The Thoma-Zeiss Hemocytometer, 57
Counting the Erythrocytes, .- 60
Counting the Leucocytes, 64
Cleaning the Pipette, 67
Durham's Hemocytometer, 68
Gowers' Hemocytometer, 69
Oliver's Hemocytometer, ' 71
Dry Film Method, 73
IV. MICROSCOPICAL EXAMINATION OF THE STAINED SPECIMEN 75
Objects of Staining, 75
The Anilin Dyes, 76
Preparing the Films, 76
Fixation Methods, 79
Methods of Staining, 8r
Wright's Stain, 82
Ehrlich's Triacid Stain, 83
Prince's Stain 85
Staining with Eosin and Methylene-blue, 86
Staining with Eosin and Hematoxvlin, 87
Staining with Thionin 87
Staining with Polychrome Methylene-blue, 88
Differential Counting, 89
xi
xii TABLE OF CONTENTS.
PACK
V. COUNTING THE BLOOD PLAQUES, 90
Determann's Method, 90
VI. ESTIMATION OF THE RELATIVE VOLUMES OF CORPUSCLES AND PLASMA, . 9 r
Daland's Heraatocrit, 91
Limitations of the Hematocrit, 93
VII. ESTIMATION OF THE SPECIFIC GRAVITY, 94
Hammerschlag's Method, 94
VIII. ESTIMATION OF THE ALKALINITY, 96
Engel's Alkalimeter, 96
Dare's Hemo-alkalimeter, 98
IX. DETERMINATION OF THE RAPIDITY OF COAGULATION, 100
Glass Slide Method, 100
Wright's Coagulometer, 101
X. CRYOSCOPICAI. EXAMINATION, 102
Cryoscopy in Pathological Conditions, 102
Fontaine's Cryoscope, 104
XI. ESTIMATION OF THE RESISTANCE OF THE ERYTHROCYTES, 106
Hamburger's Method, 106
XII. SPECTROSCOPICAL EXAMINATION, % 107
The Sorby-Beck Microspectroscope, 107
XIII. BACTERIOLOGICAL EXAMINATION, 109
Value of Positive Findings, 109
Methods, 109
Blood Cultures, 109
Staining Methods, in
XIV. DETERMINATION OF THE SERUM REACTION, 112
WidaPsTest, 112
The Serum Reaction in Specific Infections 113
XV. MEDICO-LEGAL TESTS FOR BLOOD, 114
Methods, 114
Microscopical Examination, 114
Spectroscopy, 115
Teichmann's Hemin Test, 115
The Guaiacum Test, 116
The Biological Test, 117
Hanging Drop Test, 122
OTHER METHODS OF BLOOD EXAMINATION, 122
SECTION H.
THE BLOOD AS A WHOLE.
I. GENERAL COMPOSITION, 125
Plasma, Serum, and Cells, 125
Salts, 126
Extractives, 126
Gases, 126
II. COLOR, 126
Normal Variations, 126
Density and Opacity, 126
Pathological Variations, 127
III. ODOR AND VISCOSITY, 127
TABLE OF CONTENTS. Xlll
PACE
IV. REACTION, 128
Reaction in Health, 128
Table of Normal Blood Alkalinity, 129
Physiological Variations, 1 29
Pathological Variations, 130
V. SPECIFIC GRAVITY, 132
Normal Range, 132
Pathological Variations, 132
Relation of Specific Gravity to Hemoglobin, 133
Table of Hemoglobin Equivalents, 133
VI. FIBRIN AND COAGULATION 134
Relation of Fibrin to Coagulation, 134
Appearance of Fibrin in Fresh Blood, 135
Hyperinosis and Hypinosis, 135
Pathological Variations in Amount of Fibrin, 136
VII. OLIGEMIA, 138
Definition, 138
Occurrence, 138
Vin.jF-LETHORA, .' 138
Definition, 138
Permanent and Transient Polyemia, 139
Serous Plethora, 139
Cellular Plethora, 139
IX. HYDREMIA, 139
Definition, 139
Causes, 140
Occurrence, 140
|X. ANHYDREMIA, 140
Definition, 140
Causes, . .• 141
Occurrence, 141
XI. LIPEMIA, 141
Amount of Fat in Normal Blood, 141
Definition, 141
Physiological arid Pathological Lipemia, 142
Tests for Fat, 142
XII. MELANEMIA, 142
Definition, 142
Occurrence, 142
XIII. GLYCEMIA, 143
Amount of Sugar in Normal Blood, 143
Hyperglycemia, 143
Test for Sugar, 143
XIV. URICACIDEMIA, 144
Definition, 144
Occurrence, 144
Test for Uric Acid, 144
XV. CHOLEMIA 145
Definition, 145
Occurrence, 145
Test for Bile, 145
XIV TABLE OF CONTENTS.
PAGE
XVI. ACETONEMIA AND LlPACIDEMIA, 145
Definition, 145
Occurrence, 145
Tests for Acetone and Fatty Acids, 145
XVII. BACTERIEMIA, 146
Occurrence, 146
Latent Infection, 146
Blood Cultures, 147
Bacteria Found in the Blood, 148
XVIII. ANEMIA, 148
Definition, 148
Pseudo-anemia, 149
Classification, 150
Pathogenesis, 151
XIX. HEMOLYSIS, 151
Ehrlich's Side-chain Theory, 151
Hemolysis, 154
Antihemolysis, 155
Agglutination and Precipitation, 156
SECTION III.
HEMOGLOBIN, ERYTHROCYTES, BLOOD PLAQUES,
AND HEMOKONIA.
I. HEMOGLOBIN, 161
General Properties, 161
Origin, 162
Variations in Amount, 163
Absolute Amount, 165
Color Index, 165
Hemoglobinemia, 166
Methemoglobinemia, 167
Carbon Mono.xid Hemoglobin, 168
II. THE ERYTHROCYTES, 169
Appearance in Fresh Blood, 169
Histological Structure, 170
Origin and Life History, 171
Size, 172
Normal Number, 173
Volume Index, 173
III. INFLUENCE OF PHYSIOLOGICAL FACTORS ON THE ERYTHROCYTES, . 174
Age and Sex, ^ 174
Pregnancy, Menstruation, and Lactation, 175
Constitution and Nutrition, 176
Muscular Exercise, 176
Fatigue, 176
Digestion and Food, 177
High Altitudes, 178
Climate, 180
IV. PATHOLOGICAL CHANGES IN THE ERYTHROCYTES, 180
Ameboid Motility, 180
Alterations in Isotonicity, 180
Hyperviscosity, 181
TABLE OF CONTENTS. XV
PAGE
Deformities of Shape and Size, 182
Megalocytes, 182
Microcytes, 182
Poikilocytes, 183
Endoglobular Degeneration, 184
Total Necrosis, 185
Atypical Staining Reaction, 186
Nucleation, 187
Normoblasts, 187
Megaloblasts, 189
Microblasts, 192
Atypical Erythroblasts, 192
Ring Bodies, 194
Granular Basophilia, 194
Schiiff ner's Granules, 196
Oligocy themia, 196
Polycythemia, 197
V. BLOOD PLAQUES, 198
Appearance in Fresh Blood, 198
Histological Structure, 199
Origin, 199
Normal Number, 200
Pathological Variations, 200
VI. HEMOKONIA, 200
Appearance in Fresh Blood, 200
Histological Characteristics, 200
Occurrence, 201
SECTION IV.
THE LEUCOCYTES.
I. GENERAL CHARACTERISTICS, 205
Appearance in Fresh Blood, : 205
Ameboid Movement, 206
Cell Granules, 207
Normal Number, 209
II. CLASSIFICATION, 209
Number and Percentage of Different Varieties, 209
Small Lymphocytes, 210
Large Lymphocytes, 211
Transitional Forms, ". 213
Polynuclear Neutrophiles, 214
Eosinophiles, 216
Basophiles, 217
Myelocytes, 217
Mast Cells, 219
Mononuclear Neutrophiles, 222
Neutrophilic Pseudolymphocytes, 222
Reizungsformen, 222
Differential Table of the Leucocytes, 223
Origin and Development, 224
lodin Reaction, 226
Perinuclear Basophilia, 228
XVi TABLE OF CONTENTS.
PAGE
III. LEUCOCYTOSIS, 228
Definition, 228
Classification of the Leucocytoses, 229
Physiological Leucocytosis, 230
Character, 230
Causal Factors, 230
Leucocytosis of the New-born, 230
Digestion Leucocytosis, 231
Leucocytosis of Pregnancy and Parturition 233
Leucocytosis Due to Thermal and Mechanical Influences, 234
Terminal Leucocytosis, 235
Pathological Leucocytosis, 236
Occurrence, 236
Degree of Increase, 236
Differential Changes, 237
Causal Factors, 237
Functions, 238
Hypoleucocytosis and Hyperleucocytosis, 239
Leucocytolysis, 240
Changes in the Bone Marrow, 241
Inflammatory and Infectious Leucocytosis, 242
Post-operative Leucocytosis, 244
Leucocytosis of Malignant Disease, 245
Post-hemorrhagic Leucocytosis, 246
Toxic Leucocytosis, 247
Ether Leucocytosis, 248
Chloroform Leucocytosis, 249
Experimental Leucocytosis, 249
IV. LYMPHOCYTOSIS, 252
Definition, 252
Differential Changes, 252
Causal Factors, 253
Physiological Lymphocytosis, 253
Pathological Lymphocytosis, 254
Experimental Lymphocytosis, 254
Clinical Significance, 254
V. EOSINOPHILIA, 255
Definition, 255
Causal Factors, 256
Physiological Eosinophilia, 256
Pathological Eosinophilia, 256
Experimental Eosinophilia, 257
Diminution in the Number of Eosinophiles, 257
Clinical Significance, 258
VI. BASOPHILIA, 258
VII. MYELEMIA, 259
Definition, 259
Occurrence, 259
Causal Factors, 260
VIII. LEUCOPENIA, 260
Definition, 260
Differential Changes, 261
Physiological Leucopenia, 261
Pathological Leucopenia, 262
Experimental Leucopenia, 262
TABLE OF CONTENTS. XVJi
SECTION V.
DISEASES OF THE BLOOD.
PAGE
I. CHLOROSIS, 267
Volume, Oxygen Capacity, and Albumin, 267
Appearance of the Fresh Blood, 267
Coagulation, 268
Specific Gravity, 268
Alkalinity, 268
Hemoglobin and Erythrocytes, 269
Color Index, 269
Deformed and Nucleated Erythrocytes, 271
Leucocytes, 272
Differential Changes, 272
Blood Plaques, 274
Diagnosis, 274
Clinical Features, 275
II. PERNICIOUS ANEMIA, 276
Volume, Oxygen Capacity, and Albumin, 276
Appearance of the Fresh Blood, 276
Coagulation, 277
Specific Gravity, 278
Alkalinity, 278
Hemoglobin and Erythrocytes, 278
Color Index, 279
The Blood During Remissions, 280
Megalocytosis, 281
Poikilocytosis, 281
Prevalence of Megaloblasts, 282
Polychromatophilia, 285
Granular Basophilia, 285
Leucocytes, 285
Differential Changes, 286
Blood Plaques, 287
Diagnosis, 287
Clinical Features, 288
Pernicious Anemia and Severe Secondary Anemia, 289
Pernicious Anemia and Chlorosis, 289
Pernicious Anemia and Bothriocephalus Anemia, 290
Pernicious Anemia and Nitrobenzene Poisoning, 290
Conversion of Pernicious Anemia into Leukemia, 290
Leukanemia, 290
III. SPLENIC ANEMIA, 291
Appearance of the Fresh Blood, 291
Hemoglobin and Erythrocytes, 291
Color Index, 291
Deformed and Nucleated Erythrocytes, 292
Leucocytes, 292
Blood Plaques, 293
Diagnosis, 293
Clinical Features, 294
Splenic Anemia and Myelogenous Leukemia, 295
Splenic Anemia and Pernicious Anemia, 295
Splenic Anemia and Hodgkin's Disease, 295
Splenic Anemia and Splenic Tumors, 295
IV. SECONDARY ANEMIA, 296
Appearance of the Fresh Blood, 296
XV111 TABLE OF CONTENTS.
PAGE
Coagulation, 296
Specific Gravity, 296
Alkalinity 296
Hemoglobin and Erythrocytes, 296
Color Index, 297
Deformed and Nucleated Erythrocytes, 297
Leucocytes, 298
Differential Changes, 298
Blood Plaques, 298
Diagnosis, 298
V. POST-HEMORRHAGIC ANEMIA, 299
Etiology, 299
Immediate Effects of Hemorrhage, 299
Secondary Effects of Hemorrhage, 300
Degree of Blood Loss Compatible with Life, 300
Regeneration of the Blood, 301
Blood Crises, 302
DIFFERENTIAL TABLE OF THE ANEMIAS, 303
VI. LEUKEMIA, 302
Varieties, 302
Conversion of Leukemia into Pernicious Anemia, 304
Parasitology, 305
Myelogenous Leukemia, 306
Appearance of the Fresh Blood, 306
Coagulation, 307
Alkalinity, 307
Specific Gravity, 307
Hemoglobin and Erythrocytes, 308
Color Index, 308
Relation of Erythrocyte and Leucocyte Counts, 308
Erythroblasts, 309
Leucocytes, 310
Influence of Arsenic on the Leucocyte Count, 311
The Blood During Remissions, 311
Influence of Rontgen-ray Treatment, 312
Differential Changes, 312
Blood Plaques, 317
Lymphatic Leukemia, *. 317
Appearance of the Fresh Blood, 317
Hemoglobin and Erythrocytes, 317
Deformeci and Nucleated Erythrocytes, 318
Differential Changes, 319
Blood Plaques 321
Acute Leukemia, 321
Influence of Intercurrent Infections, 322
Diagnosis, 323
Myelogenous and Lymphatic Leukemia, 325
Leukemia and Pathological Leucocytosis, 325
Leukemia and Lymphocytosis, 325
Leukemia and Hodgkin's Disease, • 326
Leukemia and Chloroma, 326
Leukemia and Multiple Periostitis, 326
Leukemia and Still's Disease, 326
Leukemia and Tumors of the Spleen, Kidney, and Pancreas, 327
Leukemia and Lymphatic Hyperplasia, 327
VII. HODGKIN'S DISEASE, 327
Appearance of the Fresh Blood, 327
TABLE OF CONTENTS. xix
PAGE
Hemoglobin and Erythrocytes, 327
Color Index, 328
Nucleated and Deformed Erythrocytes, 328
Leucocytes, 328
Differential Changes, 328
Conversion of Hodgkin's Disease into Leukemia, 329
Diagnosis, 330
Clinical Features, 331
Influence of Rontgen-ray Treatment, 331
Hodgkin's Disease and Tuberculous Adenitis, 331
Hodgkin's Disease and Syphilitic Adenitis, 332
Hodgkin's Disease and Local Lymphoma, 332
Hodgkin's Disease and Lymphatic Sarcoma, 332
Hodgkin's Disease and Lymphatic Carcinoma, 333
VIII. THE EFFECT ON THE BLOOD OF SPLENECTOMY, 333
Hemoglobin and Erythrocytes, 333
Leucocytes, 335
Differential Changes, 336
Factors of the Blood Changes Following Splenectomy, 336
DIFFERENTIAL TABLE OF LEUKEMIA, HODGKIN'S DISEASE, LEUCOCYTOSIS,
AND LYMPHOCYTOSIS 337
SECTION VI.
THE ANEMIAS OF INFANCY AND CHILDHOOD.
I. CHARACTERISTICS OF THE BLOOD IN CHILDREN, 341
Fetal Blood, 341
The Blood at Birth, 342
II. ANEMIA IN CHILDREN, 345
Frequency, 345
General Characteristics, 345
Classification, 346
Primary Anemia, 347
Pernicious Anemia, 347
Splenic Anemia, 347
Leukemia, 348
Secondary Anemia, 351
Mild Anemia, . . -. 35 1
Severe Anemia, 351
Anemias with Leucocytosis, 352
Etiology of Secondary Anemia, 352
Anemia Due to Syphilis, 352
Anemia Due to Rachitis, 353
Anemia Due to Tuberculosis, 353
Anemia Due to Gastro-intestinal Diseases, 353
Post-typhoid Anemia, 354
Anemia Infantum Pseudoleukemica, 354
Bacteriemia, 35^
SECTION VII.
GENERAL HEMATOLOGY.
I. ABSCESS, 3or
Coagulation, Fibrin, and lodin Reaction, 361
Hemoglobin and Erythrocytes 301
Factors of the Anemia in Abscess, 3or
Cell Deformity and Nucleation, 36z
xx TABLE OF CONTENTS.
PAGE
Leucocytes 3°2
Relation of the Leucocyte Count to the Local Lesion, 362
Range of the Leucocyte Count in Different Forms of Abscess, . 363
Differential Changes, 3^3
Diagnosis, 3°3
II. ACROMEGALY, 3^4
III. ACTINOMYCOSIS, 364
IV. ACUTE YELLOW ATROPHY OF THE LIVER, 365
V. ADDISON'S DISEASE, 3^5
VI. ANTHRAX, 3°<?
VII. APPENDICITIS, 366
Factors of the Anemia, 3°6
Grade of Anemia in Catarrhal and Suppurative Cases, 366
Hemoglobin and Erythrocytes, 3^6
Cell Deformity and Nucleation, 367
Leucocytes • - 3°^
Range of the Leucocyte Count in Different Forms of Appendi-
citis, 369
Differential Changes, 369
lodin Reaction, 37°
Diagnosis, 37°
Clinical Value of the Blood Examination, 371
VIII. ARTHRITIS DEFORMANS, 371
IX. ASIATIC CHOLERA, 372
X . ASTHMA AND EMPHYSEMA, 374
XI. BRONCHITIS, 375
XII. BUBONIC PLAGUE, 376
Coagulation, 376
Bacteriology, 376
Serum Reaction, 377
Hemoglobin and Erythrocytes, 377
Leucocytes, 377
Blood Plaques, 378
XIII. BURNS, 378
XIV. CHLOROMA 379
XV. CHOLELITHIASIS, 380
Fibrin and Coagulation, 380
Bacteriology, 380
Hemoglobin and Erythrocytes, 380
Leucocytes, 381
Diagnosis, 381
XVI. CYANOTIC POLYCYTHEMIA, 381
XVII. DENGUE, 382
XVIII.VDiABETES MELLITUS, 383
Alkalinity, Lipemia, Lipacidemia, and Glycemia, 383
Williamson's Test, 383
Bremer's Test, 384
Hemoglobin and Erythrocytes, 385
Leucocytes, 386
Digestion Leucocytosis, 386
lodin Reaction, 386
Diagnosis, 386
TABLE OF CONTENTS. XXI
PAGE
XIX. DIPHTHERIA, 386
Hemoglobin and Erythrocytes, 386
Leucocytes, 387
Course of the Leucocytosis, 388
Influence of Antitoxin on the Leucocyte Count, 388
Differential Changes, 388
Affinity of the Leucocytes for Basic Dyes, 389
Diagnosis, 390
XX. ENTERITIS, 390
Enteritis, Diarrhea, and Gastro-enteritis, 390
Dysentery and Ulcerative Enteritis, 391
Effect of Purges, 392
XXI. ENTERIC FEVER, 393
Alkalinity and Coagulation, 393
Bacteriology, 393
Blood Cultures, 393
Spot Cultures, 395
Serum Reaction, 396
Dried Blood Method, 398
Fluid Blood Method, 399
Macroscopical Method, . . . ..." 400
The Test with Dead Cultures, 401
The Choice of a Method, 401
Value of the Serum Test, 402
Positive Reactions in Non-typhoid Conditions, 403
Hemoglobin and Erythrocytes, 404
Cell Deformity and Nucleation, 406
Leucocytes, 406
Differential Changes, 408
Effect of Complications, 408
Blood Plaques, 409
Diagnosis, 409
XXII. ERYSIPELAS, .- 410
XXIII. EXOPHTHALMIC GOITER, 411
XXIV. FEVER, 411
Factors of the Blood Changes, 412
Pyrexial Polycythemia and Post-febrne Anemia, 412
Coagulation, Fibrin, and Alkalinity, 412
The Leucocytes, — 412
XXV. FILARIASIS, 413
Occurrence, 413
Parasitology, 413
The Filaria Nocturna, 414
Technic of Examination, 418
Staining the Filariae, 4*9
Hemoglobin and Erythrocytes, 419
Leucocytes, 420
Diagnosis, 421
XXVI. FRACTURES 421
XXVII. GASTRITIS, 421
Acute and Chronic Forms, 421
Hyperchlorhydria, Hypochlorhydria, Gastric Achylia, Gastric
Dilatation, Gastric Neurasthenia, 422
Diagnosis, 423
\\VIII. GASTRIC ULCER, 423
Hemoglobin and Erythrocytes, 423
xxii TABLE OF CONTENTS.
PAGE
Effect of Hemorrhage and Emesis, 423
Leucocytes, 424
Diagnosis, 425
XXIX. GLANDERS, 425
XXX. GONORRHEA, 426
XXXI. GOUT, 426
Alkalinity, Fibrin, and Uric Acid, 426
Cellular Elements, 427
Perinuclear Basophilia, 427
XXXII. HEMORRHAGIC DISEASES, 427
Specific Gravity, 427
Bacteriology, 427
Alkalinity, 428
Coagulation, 428
Hemoglobin and Erythrocytes, 429
Leucocytes, 429
Blood Plaques, 430
XXXIII. HEPATIC CIRRHOSIS, 43°
Anemia in Atrophic Cirrhosis, 430
Effect of Ascites, 431
Anemia in Hypertrophic Cirrhosis, 431
Leucocytes in Atrophic and Hypertrophic Cirrhoses, 432
Diagnosis, 433
XXXIV. HYDATID DISEASE, 433
XXXV. HERPES ZOSTER, 434
XXXVI. ICTERUS, 434
Fibrin, Coagulation, Specific Gravity, and Alkalinity, 434
Hemoglobin and Erythrocytes, 435
Leucocytes, 436
Diagnosis, 436
XXXVII. INFLUENZA, 436
XXXVIII. INSOLATION, 437
XXXIX. INTESTINAL HELMINTHIASIS, 438
Parasites Causing Anemia, 438
Factors of the Blood Changes, 439
Hemoglobin and Erythrocytes, 439
Bothriocephalus Anemia, 439
Ankylostomiasis Anemia, 440
Leucocytes, 440
XL. INTESTINAL OBSTRUCTION, 441
XLI. KALA-AZAR, 44 1
Parasitology, 44 1
Leishman-Donovan Bodies, 442
Hemoglobin and Erythrocytes, 443
Leucocytes, 44 ^
Diagnosis, 443
XLII. LEPROSY, 444
XLIII. MALARIAL FEVER, 44^
Parasitology, 44^
Developmental Cycle of the Malarial Parasite in Man, 445
Developmental Cycle of the Malarial Parasite in the Mosquito. 446
Varieties of the Malarial Parasite, 447
TABLE OF CONTENTS. XX111
PAGE
The Parasite of Tertian Fever, "448
Infections with Single and Multiple Groups, 448
Anticipation of the Paroxysm, 449
Intracellular Hyaline Forms, 449
Intracellular Pigmented Forms, 450
Segmenting Forms, 45 1
Extracellular Pigmented Forms, 452
Flagellate Forms, 453
Degenerate Forms, 454
The Parasite of Quartan Fever, 454
Infections with Single and Multiple Groups, 454
Intracellular Hyaline Forms, 454
Intracellular Pigmented Forms, 455
Segmenting Forms, 456
Extracellular Pigmented Forms, 456
Flagellate Forms, 45 7
Degenerate Forms, 45 7
The Parasite of Estivo-autumnal Fever, 45 7
Irregularities in Time of Developmental Cycle, 457
Disc- and Ring-shaped Forms, 458
Pigmented Forms, 458
Segmenting Forms, 459
Erythropyknosis, 459
Spherical, Ovoid, and Crescentic Forms, 460
Flagellate Forms, 461
Degenerate Forms, 461
Pigmented Leucocytes and Phagocytosis, 462
Differential Table of the Malarial Parasites, 463
Technic of Examination, 464
Artefacts in Fresh Blood Specimens, 465
Hemoglobin and Erythrocytes, 466
Causes of Malarial Anemia, 466
Anemia in the Regularly Intermittent Fevers, 466
Anemia in Estivo-autumnal Fever, 467
Anemia in Malarial Cachexia, 468
Nucleated and Deformed Erythrocytes, 468
Types of Post-malarial Anemia, 469
Leucocytes 469
Differential Changes, : 47°
Blood Plaques, 471
Diagnosis 471
XLIV. MALIGNANT DISEASE, 472
Carcinoma, 472
Fibrin, Coagulation, Specific Gravity, and Alkalinity, 472
Glycemia, 472
Parasitology, 473
Hemoglobin and Erythrocytes, 473
Regeneration of the Blood after Operation, 474
The Oligocythemia and Polycythemia of Gastric Cancer, . . 474
Deformed and Nucleated Cells, 475
Leucocytes, 475
Frequency of Cancer Leucocytosis, 475
Causes of Cancer Leucocytosis, 47°
Range of the Leucocytes in Different Forms of Cancer, . . 476
Digestion Leucocytosis in Gastric Cancer, 477
Differential Changes, 477
Sarcoma, 47^
General Features of the Blood 47**
Cytology, 478
TABLE OF CONTENTS.
PAGE
Hemoglobin and Erythrocytes, 478
Leucocytes, 479
Diagnosis, 479
XLV. MALIGNANT ENDOCARDITIS, 482
Bacteriology, 482
Hemoglobin and Erythrocytes, 482
Leucocytes .' 483
Diagnosis, 483
XLVI. MALTA FEVER, 484
XLVII. MEASLES, 485
XLVIII. MENINGITIS, 486
XLIX. MYXEDEMA, 488
L. NEPHRITIS, 489
Factors of the Blood Changes, 489
The Edema of Anemia, 489
Specific Gravity, Fibrin, Coagulation, and Alkalinity, 490
Bacteriology, 490
Hemoglobin and Erythrocytes, 490
Anemia in Acute and Chronic Parenchymatous Nephritis, 490
Polycythemia, 491
Anemia in Chronic Interstitial Nephritis, 491
Leucocytes, 491
Uremia, 492
Diagnosis, 492
LI. NERVOUS AND MENTAL DISEASES, 492
Neuritis, Beri-beri, Neuralgia, Akatama, and Erythromelalgia, 492
Brain Tumor, 493
Neurasthenia, Hypochondriasis, and Hysteria, 493
General Paresis, Dementia, Melancholia, and Mania, 494
Convulsions, Apoplectiform Attacks, and Acute Delirium, . . . 495
Epilepsy, Chorea, and Tetany, 497
LIT. OBESITY, 498
LIII. OSTEOMALACIA, 498
LIV. PANCREATITIS, 499
LV. PERICARDIAI. EFFUSION, 500
LVI. PERITONITIS, 500
LVII. PERTUSSIS, 502
LVIII. PLEURISY, 503
Serous Pleurisy, 503
Purulent Pleurisy, 504
Diagnosis, 505
LIX. PNEUMONIA, 505
General Features of the Blood, 505
Bacteriology, 505
Hemoglobin and Erythrocytes, 507
Leucocytes, 507
Relation of Leucocytosis to Intensity of Infection, 507
Frequency and Extent of Leucocytosis, 508
Effect of Induced Leucocytosis, 509
Effect of Antipyresis, 510
Differential Changes, 510
TABLE OF CONTENTS. XXV
PAGE
Blood Plaques, 510
Diagnosis, 511
LX. POISONING, 511
LXI. RABIES, 513
LXII. RELAPSING FEVER, 514
Parasitology, 514
LowenthaPs Reaction, 516
Hemoglobin and Erythrocytes, 516
Leucocytes, 516
Diagnosis, 517
LXIII. RHEUMATIC FEVER, 518
Coagulation, Fibrin, and Alkalinity, 518
Bacteriology, 5 18
Hemoglobin and Erythrocytes, 519
Leucocytes, 520
Diagnosis, 520
LXIV. SCARLET FEVER, 521
Coagulation, Fibrin, and Specific •Gravity, 521
Bacteriology, 521
Hemoglobin and Erythrocytes, 522
Leucocytes, 523
Blood Plaques, 524
Diagnosis, 525
LXV. SEPTICEMIA AND PYEMIA, 525
General Features of the Blood, 525
Serum Reaction, 525
Bacteriology, 526
Hemoglobin and Erythrocytes, 527
Deformed and Nucleated Erythrocytes, 528
Leucocytes, 529
Differential Changes, 529
Diagnosis, 530
LXVI. SPOTTED FEVER OF MONTANA, 531
LXVII. SYPHILIS, , 532
Bacteriology, 532
Hemoglobin and Erythrocytes, 532
Syphilitic Chlorosis and Pernicious Anemia, 532
Effect of Mercury and Iodides on the Blood, 533
Justus' Test, 533
Leucocytes, 534
Diagnosis, 535
Blood Plaques, 535
LXVIII. TETANUS, 535
LXIX. TONSILLITIS, 535
LXX. TRICHINIASIS, 536
LXXI. TRYPANOSOMIASIS, 538
Parasitology, 538
Cellular Elements, 54*
Diagnosis, 541
LXXII. TUBERCULOSIS, 54*
General Features of the Blood, 541
Bacteriology, 542
Serum Reaction, 542
X.xvi TABLE OF CONTENTS.
PAGE
Hemoglobin and Erythrocytes, 544
Anemia in Pulmonary Tuberculosis, 545
Anemia in Bone Tuberculosis, 546
Anemia in Tuberculous Adenitis, Meningitis, Pericarditis,
Pleurisy, and Peritonitis, and in Genito-urinary Tubercu-
losis 546
Leucocytes, 546
Differential Changes, 547
Range of the Leucocytes in Pulmonary Tuberculosis, 547
Range of the Leucocytes in Bone Tuberculosis, 548
Range of the Leucocytes in Acute Miliary Tuberculosis, Tuber-
culous Adenitis, Pleurisy, Peritonitis, Pericarditis, and Men-
ingitis, and in Genito-urinary Tuberculosis, 549
Effect of Secondary Septic Infections, 549
Diagnosis, 550
LXXIII. TYPHUS FEVER, 550
Parasitology, 550
Hemoglobin and Erythrocytes, 551
Leucocytes, 551
Diagnosis, 551
LXXIV. VACCINATION, 552
LXXV. VALVULAR HEART DISEASE, 552
Stage of Compensation, 552
Acute Rupture of Compensation, 552
Effect of Stasis, 553
LXXVI. VARICELLA, 554
LXXVII. VARIOLA, 555
Parasitology, 555
Hemoglobin and Erythrocytes, 556
Leucocytes, 556
Blood Plaques, 557
Diagnosis, 557
LXXVIII. YELLOW FEVER, 558
Fibrin and Coagulation, 558
Bacteriology, 558
Hemoglobin and Erythrocytes, 559
Degenerative Changes, 560
Leucocytes, 560
Diagnosis, 560
LIST OF ILLUSTRATIONS, xxvii
INDEX OF AUTHORS 561
INDEX OF SUBJECTS, i
LIST OF ILLUSTRATIONS.
The Leucocytes, Frontispiece.
PLATE PAGE
I. The Erythrocytes, 161
II. The Leucocytes, 205
III. Leucocytosis, 228
IV. Myelogenous Leukemia, ; 306
V. Lymphatic Leukemia, 317
VI. The Tertian Malarial Parasite, 449
VII. The Quartan Malarial Parasite, 455
VIII. The Estivo-autumnal Malarial Parasite, 459
CHART
I . Pernicious Anemia, 279
II. Myelogenous Leukemia, 311
III. Multiple Infections in Malarial Fever, 447
FIGURE
1 . Blood Lancet, 34
2. Proper Distribution of Cells in a Blood Film, 36
3. Zones of Rouleaux and of Isolated Cells in a Fresh Blood Film, 36
4. Dare's Hemoglobinometer, , 40
5. Horizontal Section of Dare's Hemoglobinometer, 41
6. Method of Filling Blood Chamber, 43
7. Von FleischFs Hemometer, 43
8. Tinted Wedge of von Fleischl's Hemometer, .: 43
9. Capillary Pipette of von Fleischl's Hemometer, 43
10. Method of Using von Fleischl's Hemometer, 46
1 1 . Light-proof Box for von Fleischl's Hemometer, 48
12. Method of Using Oliver's Hemoglobinometer, 51
13. Gowers' Hemoglobinometer, 52
14. Thoma-Zeiss Hemocytometer, 57
15. Thoma-Zeiss Counting Chamber, 58
1 6. Ruled Area of Thoma-Zeiss Counting Chamber, 59
17. Ruled Area of Zappert's Counting Chamber, 60
18. Method of Filling the Hemocytometer, 61
i() . Plan of Counting the Erythrocytes, 63
20. Ocular Diaphragm, 65
2 1 . Expelling Contents of the Erythrocytometer, 67
22. Cross-section of Durham's Blood Pipette, 68
23. Method of Using Oliver's Hemocytometer, 72
24. Superimposing the Charged Cover-glass, 77
25. Drawing Apart the Cover-glasses, 77
26. The Cover-glasses after Separation, jS
27. Spreading a Film with Two Glass Slides, 78
28. Spreading a Film with Cigarette Paper, 78
29. Oven for Fixing Blood Films, 79
xxrii
XXV111 LIST OF ILLUSTRATIONS.
FIGURE PACE
30. Daland's Hematokrit, 92
31. Engel's Alkalimeter, 97
32. Dare's Hemo-alkalimeter, 99
33. Milian's Coagulation Test, 100
34. Wright's Coagulometer, 101
35 . Fontaine's Cryoscope, 105
36. Sorby-Beck Microspectroscope, 107
37. Sorby Tubular Cell, 108
38. Aspirating Tube for Blood Culturing, no
39. Rouleaux Formation and Fibrin in Normal Blood, 136
40. Hyperinosis, 137
41. Mechanism of Toxin-cell Union, 152
42. Elaboration and Action of Antitoxin, 153
43. Mechanism of Hemolysis, 155
44. Mechanism of Antihemolysis, 156
45. Blood Spectra, 168
46. Deformities of Size and Shape of the Erythrocytes. 182
47. Degenerative Changes in the Erythrocytes, 184
48. Megaloblasts, 190
49. Atypical Forms of Erythroblasts, 193
50. Granular Basophilia, 159
5 1 . Changes in the Erythrocytes in Chlorosis, 269
52. Changes in the Erythrocytes in Pernicious Anemia, 280
53. Atypical Myelocytes in Myelogenous Leukemia, 313
54. Atypical Polynuclear Neutrophiles in Myelogenous Leukemia, 315
55. Atypical Lymphocytes in Lymphatic Leukemia, 320
56. Positive Serum Reaction in Enteric Fever, 396
57. Pseudo-reaction in Enteric Fever, 396
58. Bacillus Typhi Abdominalis, 397
59. Filaria Nocturna in Fresh Blood, 414
60. Filaria Nocturna, showing Granular Degeneration, 416
61 . Filaria Nocturna, showing Changes in Shape, 418
62 . Leishman-Donovan Bodies, 442
63 . Spirilla of Relapsing Fever 480
64. Trypanosoma Gambiensc, 540
INTRODUCTION.
The rapid growth and development of hematology during
recent years and the practical application of many of its teachings
to the diagnosis of various diseases have made this science one
which no progressive medical man can afford to disregard. Ex-
amination of the blood gives definite clinical information which
may be profitable both to the practitioner of internal medicine
and to the surgeon, and the procedure is capable of throwing light
upon the diagnosis in so wide a range of pathological conditions
that it is difficult to single out any disease in which it may not
be of some utility, either as positive or as negative evidence.
In the light of our present knowledge of the subject, clinical
information of two kinds may be derived from hematology,
namely, findings which are pathognomonic of certain diseases;
and auxiliary data which, if considered in connection with other
clinical manifestations, may prove either essential or helpful in
establishing the precise nature of a disease.
The list of diseases in which pathognomonic blood findings
are met with includes leukemia, the malarial fevers, relapsing
fever, filariasis, trypanosomiasis, and piroplasmiasis. In per-
nicious anemia a typical picture is also found, if two conditions
capable of exciting identical. blood changes are excepted, the pro-
found secondary anemias due to certain intestinal parasites and to
nitrobenzene poisoning.
The blood examination affords data which, although not
pathognomonic, are nevertheless essential for the diagnosis of
chlorosis, Hodgkin's disease, splenic anemia, chloroma, Osier's
disease, multiple periostitis, kala-azar, and secondary anemias
dependent upon various causes. For example, in chlorosis a
definite group of blood changes must exist in order to justify
an unconditional diagnosis, although the occurrence of these
changes, unassociated with other equally definite clinical signs,
is insufficient evidence of this disease. In Hodgkin's disease,
a condition indistinguishable from leukemia by an ordinary
physical examination, the absence of a leukemic state of the
blood at once excludes the latter disease. In the secondary
anemias, it is obvious that the blood count alone can give the
XXX INTRODUCTION.
exact clue to the condition, by determining the degree and char-
acter of the blood impoverishment, and by tracing from time to
time its progress. In this connection it is important to remember
that pallor may go hand in hand with a normal hemoglobin per-
centage and erythrocyte count, and that, on the other hand, a high
color by no means invariably signifies that the individual is not
anemic. In addition to the diseases just named, hematology gives
information which is often of great assistance in, although not
essential for, the diagnosis of such conditions as enteric fever,
sepsis, pneumonia, pertussis, appendicitis, diabetes, rabies, syph-
ilis, gastric ulcer, malignant disease, helminthiasis, the exanthe-
mata, the hemorrhagic diseases, and suppurative processes.
Clinical experience has repeatedly illustrated the value of the
serum reaction in enteric and Malta fevers and in dysentery; of
Williamson's test in diabetes mellitus; of eosinophilia in trichini-
asis, in echinococcus disease, and in other forms of helminthiasis ;
of mononucleosis in variola and in pertussis ; and of leucocytosis
and iodophilia in sepsis, in suppurative lesions, and in many of
the acute infections. The forensic use of Bordet's test for the
identification of blood stains, and the application of cryoscopy to
the diagnosis of renal disease are also of practical utility.
Negative results from a blood examination also possess diag-
nostic value within certain limits, but too great reliance upon
evidence of this sort more often proves delusive than helpful. In
a patient whose waxy, yellowish facies suggests with equal force
pernicious anemia, chronic nephritis, and, perhaps, liver cirrhosis,
the absence of characteristic blood changes is sufficient to exclude
the first-named condition. But failure to detect the malarial
parasite does not necessarily exclude malarial fever; a negative
serum test does not absolutely rule out enteric fever; and an
absence of leucocytosis cannot be regarded as an infallible sign
that a suppurative focus does not exist, nor does it always indicate
the benignity of a neoplasm. Negative evidence, then, is usually
to be considered merely suggestive, the real pertinence of the hint
thus obtained depending upon its correlation with other physical
signs and symptoms.
The significance of positive findings in bacteriological investi-
gations of the blood is patent, and recent improvements in technic
have made this means of research simple, dependable, and certain.
Blood cultures furnish conclusive information in general septi-
cemia, pneumonia, enteric fever, Malta fever, plague, scarlet
fever, malignant endocarditis, and similar conditions in which
bacteria invade the blood stream.
At the present time the most useful information furnished by
INTRODUCTION. XXXI
hematology has been derived from study of the cellular elements
of the blood, but closer familiarity with the chemistry of this tissue,
still an undeveloped science, will undoubtedly in the near future
afford not only more tangible clues to the etiology and pathology
of the blood diseases, but also will bring to light additional facts
which may be applied to the diagnosis of these and other maladies.
The study of the coagulation time of the blood is of practical
utility in the study of purpura, hemophilia, jaundice, and other
conditions characterized by slow clotting and by a tendency
toward hemorrhage.
The technic of blood examinations, such as described in the
following pages, is neither elaborate nor difficult to master. Nec-
essarily, it must be rigidly exact, but no more so than any other
branch of physical diagnosis, if the worker is content only with the
best results. To acquire a good working knowledge of hema-
tology takes but a fraction of the time and application that one
must spend in familiarizing one's self with the most common heart
murmurs or chest signs, and the time thus spent equips the physi-
cian with an additional diagnostic agent of the greatest value. If
the newly graduated physician would provide himself with a
microscope and a set of blood instruments, and systematically
study the blood in the various general diseases which he encounters
in practice, many a slip-shod diagnosis might be avoided, and a
great stride forward made in popularizing this practical branch
of clinical diagnosis.
" L'avenir appartient a I'hematologie. C'est elle qui nous apportera la solu-
tion des grands problemes nosologiques. Elle doit nous apparaltre comme une
vaste science puisant ses materiaux dans toutes les branches des connaissances
biologiques et recueillant les di-verses notions de Vhumorisme ancien pour les
rajeunir et les cojnplettr a la lumiere des decouvertes modernes en anatomic, en
physiologic, en chimie biologique el en pathologic"
GEORGES HAYEM.
SECTION I.
EXAMINATION OF THE BLOOD BY
CLINICAL METHODS.
SECTION I.
EXAMINATION OF THE BLOOD BY CLINICAL
METHODS.
P A systematic examination of the blood by
Sen MA clinical methods of established utility includes
the following different processes:
I. Microscopical examination of the fresh blood.
II. Estimation of the percentage of hemoglobin.
III. Counting the erythrocytes and the leucocytes.
IV. Microscopical examination of the stained specimen.
These four procedures, which should invariably be included in
every clinical blood report, furnish the most important informa-
tion to be derived from hematological study, and are sufficient
for routine clinical work. In certain instances in which more de-
tailed investigation of special points is sought, it may be thought
advisable to supplement the above plan by employing one or
more of these remaining procedures:
V. Counting the blood plaques.
VI. Estimation of the relative volumes of corpuscles and
plasma.
VII. Estimation of the specific gravity/
VIII. Estimation of the alkalinity.
IX. Determination of the rapidity of coagulation.
X. Cryoscopical examination.
XI. Estimation of the resistance of the erythrocytes.
XII. Spectroscopical examination.
XIII. Bacteriological examination.
XIV. Determination of the serum reaction.
XV. Medico-legal tests for blood.
I. MICROSCOPICAL EXAMINATION OF THE FRESH
BLOOD.
The finger-tip or the lobe of the ear is the part
OBTAINING THE usually selected from which to obtain the blood,
SPECIMEN. by puncture, for examination. The former site
is preferable in most instances, owing to its con-
3 33
34 EXAMINATION OF THE BLOOD BY CLINICAL METHODS.
vcnient situation and ease of manipulation; but in nervous indi-
viduals and in children the ear-lobe may be chosen, because of its
limited sensibility and on account of the patient's inability to
watch the operation.
The puncture may be made with one of the special blood
lancets devised for this purpose, or, in lieu of such an instrument,
a Hagedorn or spear-pointed surgical needle or a new sharp-
pointed steel pen from which one nib has been' twisted off, will
answer the purpose equally as well. The author is accustomed
to use a small steel trocar blade, mounted on a metal shaft which
screws into an outer barrel by means of a thread. By the use
of a threaded locking-nut, any desired length of the trocar may
be exposed, so that the depth of the wound may be controlled
at will, irrespective of the force used to drive the point of the
instrument through the skin. It is not necessary to sterilize the
puncture-needle: wiping it with a towel wet with alcohol is all
that is required in ordinary examinations. Of course, should
the patient happen to be syphilitic or septic, it is safer to pass
the blade through an alcohol flame after having used it.
Having chosen, say, the patient's
middle or ring-finger, the part is first
thoroughly cleansed with alcohol or
ether and then with water, and wiped
FIG. i. -BLOOD LANCET. perfectly dry with a clean, lint-free
towel, which may then be folded into
a pad and slipped behind the finger to isolate it from the
neighboring digits, and to serve as a cushion for the back
of the hand. The operator, holding the patient's hand in a
firm, steady position, makes the puncture \vith a rapid motion
of the wrist, such as one is accustomed to use in percussing
the thorax, the depth of the wound being just sufficient to
cause a free flow of blood in good-sized drops, unaided by
the slightest pressure on the finger other than that necessary to
start the initial oozing. The needle should be aimed so as to
strike a point in the center of the flexor surface of the finger, just
back of the extreme tip. The blood drop to be used for the ex-
amination should under no circumstance be squeezed from the
finger, for blood secured in this manner is certain to be more or
less highly diluted with lymph from the surrounding tissues — a
condition which will lead to erroneous results, especially to lower
hemoglobin, specific gravity, and corpuscular estimations than
actually exist. In severe anemias, especially in those of the
pernicious type, the bloodless condition of the superficial ves-
sels is sometimes so marked that it may be impossible to obtain
MICROSCOPICAL EXAMINATION OF THE FRESH BLOOD. 35
enough blood for the examination by an ordinary puncture, even
from the ear-lobe, which, as a rule, is highly vascular. Relatively
deep incisions are unavoidable in such instances. On the con-
trary, in most cases of leukemia, unless the coexisting anemia
is of striking intensity, the blood usually flows very freely, and
may even spurt from the wound in a fine jet several inches in
height.
Most writers on hematology utter an emphatic warning against
hemophilics, in whom the slightest prick of a needle may cause
troublesome bleeding. The writer has never had the misfortune
to meet with this accident, but recognizes the wisdom of observ-
ing the precaution to question every patient concerning an
abnormal tendency toward hemorrhage.
The observer's attention should be directed to the color and
the density of the blood drop as it flows frpm the puncture, and
a note taken of the various macroscopical changes which may
occur, such as the pale, hydremic condition of the blood found
in severe anemias, the deep blue color in cyanosis, and the milky
appearance in leukemia and in diabetes. These and other altera-
tions in the naked-eye appearance of the fresh blood have been
discussed in another section.
The first few drops of blood which follow the
PREPARING puncture are wiped away, and the site of the in-
THE cision freed from every trace of moisture, after
SLIDE. which a perfectly clean cover-glass, held edge-
wise between the thumb and forefinger, is lightly
touched to the summit of the next drop as it oozes from the punc-
ture, and is then immediately placed, blood side downward,
upon the surface of a clean glass slide. If the cover-glass and
the slide are perfectly clean and dry, and if the drop is of the
proper size, the blood will at once spread out in a thin film con-
sisting of a single layer of corpuscles (Fig. 2), surrounded by an
outer zone in which the cells are heaped up in masses and rouleaux ;
this thicker area of the specimen is unsuited for examination
(Fig. 3). Gently heating the slide over an alcohol flame just
before use will insure a thin, even spread. If prolonged study
of the specimen is intended, it is advisable to exclude air from
the film, by ringing the margins of the cover-glass with a thin
layer of cedar oil or vaselin, but ordinarily this precaution is
unnecessary. In order to prevent distortion of the corpuscles,
pressure must be avoided while adjusting the cover-glass. If
the blood does not spread of itself, without the aid of pressure,
it is usually owing to the presence of particles of dust or grease
between the opposed surfaces of the slide and cover-glass.
EXAMINATION OF THE BLOOD BY CLINICAL METHODS.
Absolute cleanliness of the covers and slides is an essential
detail to which too great attention cannot be paid, for neglect of
this precaution is responsible for the majority of failures to secure
good specimens. Perhaps the most useful cleansing agent is the
FIG. 2. — PROPER DISTRIBUTION OF THE CORPUSCLES IN A FRESH BLOOD FILM PREPARED FOR
MICROSCOPICAL EXAMINATION.
solution popularly known as "acid alcohol" (hydrochloric acid,
i part; absolute alcohol, 29 parts; water, 70 parts), which quickly
-and effectually removes all traces of grease and dirt from the glasses,
so that their preliminary soaking in soap-suds^ or in a strong
mineral acid, as some
recommend, may be dis-
pensed with. The slides
and covers may be con-
veniently kept in closed
glass receptacles contain-
ing this solution, from
which they are removed
as the occasion demands,
being then dried and
polished with a bit of
clean linen or with tissue-
paper. Ordinary soft
"toilet-paper" is excellent for this purpose. Oblong cover-glasses,
measuring £ X i£ inches and of "No. i" thickness, are more
easily handled without forceps than smaller square or circular slips,
and also have a much larger surface than the latter, which is often
decidedly advantageous.
FIG. 3. — ZONES OF ROULEAUX (A) AND OF ISOLATED
CELLS (B) IN A FRESH BLOOD FILM.
MICROSCOPICAL EXAMINATION OF THE FRESH BLOOD. 37
The use of forceps is unnecessary if care is observed to hold
the cover-glass in the manner already directed, so that only its
edges come in contact with the thumb and finger.
The specimen, prepared in the manner just
MICROSCOPICAL described, is examined under the microscope
EXAMINATION, with both low and high powers, a ^ or ^ inch
dry, and a y1^ inch oil-immersion, objective being
the most satisfactory lenses for the purpose. The substage con-
denser and diaphragm should be adjusted so that the field is but
moderately illuminated, rather than flooded with a glare of white
light. Microscopical examination of the fresh blood film furnishes
information about the following points:
Changes Affecting the Erythrocytes. — With a little practice one
soon becomes able to detect, with a tolerable degree of accuracy,
any conspicuous decrease in the number of erythrocytes, by the
relatively small number of cells in the field in comparison with
their number in a similar field of normal blood. With less con-
fidence it is also possible to decide whether or not the number
of erythrocytes is much in excess of the normal standard.
Deficiency in hemoglobin produces unmistakable changes in
the appearance of the cells, those in which this change is well
defined appearing as pale, washed-out bodies which stand in
striking contrast to the darker, yellowish-green color of the normal
erythrocytes.
Abnormal viscosity of the erythrocytes, their tendency toward
rouleaux formation, the presence of deformities of size and of
shape, and the occurrence of structural degenerative changes
may also be distinguished in the fresh, unstained blood film.
Nucleated erythrocytes are not demonstrable in the fresh
specimen.
Changes Affecting the Leucocytes. — A glance is usually suffi-
cient to determine whether or not the number of leucocytes is
markedly in excess of normal, but too great dependence should not
be placed on such a method of detecting the presence or absence
of a leucocyte increase, since it is at the best approximate, and
sometimes erroneous. As will be explained elsewhere, any
marked decrease in the number of erythrocytes, the leucocytes
remaining normal, may so increase the ratio of the latter to the
former, that the leucocytes may be apparently increased.
Having tentatively determined that an increase in the total
number of leucocytes is present, it is furthermore possible for
one familiar with the morphology of the unstained leucocyte to
make a fairly accurate differential count of these cells, and thus
to decide whether the increase is due to a pure leucocytosis
38 EXAMINATION OF THE BLOOD BY CLINICAL METHODS.
or to some form of leukemia. This distinction is not at all diffi-
cult in most instances, when one recalls the characteristics of
the several forms of leucocytes in the fresh blood, viz.: small
lymphocytes, large lymphocytes, and transitional forms, appear-
ing as cells having a single spherical or indented nucleus, and a
clear, shining, non-granular protoplasm ; polynuclear neutrophiles,
as cells with polymorphous or multiple nuclei, and a protoplasm
crowded with very fine, moderately refractive granules; eosino-
philes, as cells with a single polymorphous nucleus or multiple
nuclei, and a protoplasm containing coarse, spherical, highly re-
fractive, fat-like granules; and myelocytes, as cells with a single
spherical or ovoid nucleus, and a protoplasm crowded with very
fine, moderately refractive granules. It is, of course, obviously
impossible to distinguish basophile cells in the fresh blood, as
well as some of the cells containing fine eosinophile granules,
but the characteristics noted above are sufficiently plain to justify
at least a provisional diagnosis of either of the conditions in ques-
tion, which, in every instance, should be verified by a careful
examination of the stained specimen.
While most of the degenerative changes which affect the leuco-
cytes are clearly demonstrable only in the stained specimen, it is
still possible to recognize some of the grosser examples of such a
process by a study of the fresh film. Vacuolation of both nucleus
and protoplasm, extrusion of portions of the cell substance, and
the various stages of nuclear disintegration and of apparent solu-
tion of the protoplasm are the alterations most commonly ob-
served. In certain specimens "fractured" leucocytes are seen
with more or less frequency, a cell thus affected being drawn out
into a diffuse, irregularly shaped body with indistinct and ragged
margins, about which the cell granules, which have escaped from
the protoplasm, are scattered in the form of a nebulous mass.
The eosinophile leucocytes seem especially prone to undergo
this disintegration. The exact significance of this phenomenon
is not clear, but it probably represents a degenerative change in
which the cells have become abnormally vulnerable, and thus
highly susceptible to mechanical injury from the pressure of the
cover-glass.
Ameboid activity of the leucocytes and pigmentation of these
cells are among the other changes to be observed in a histolog-
ical examination of the unstained blood film.
Increase in Fibrin, Blood Plaques, and Hemokonia. — The den-
sity of the fibrin network and the rapidity with which it forms
may be studied as coagulation of the blood film progresses. Un-
less the blood plaques are very greatly increased in number,
ESTIMATION OF THE PERCENTAGE OF HEMOGLOBIN. 39
they are not usually noticeable in the specimen prepared in the
ordinary manner. The presence of hemokonia, or "blood dust,"
is at once rendered conspicuous by the rapid and incessant molec-
ular motion with which these bodies are endowed.
Blood Parasites. — The hematozoa of the malarial fevers, the
spirilla of relapsing fever, the organisms of trypanosomiasis,
and the embryonic forms of the parasite of filarial disease should
be studied in the fresh blood whenever this is possible, rather
than in the fixed and stained film, since in the latter the charac-
teristic morphology of these parasites is greatly altered and their
motility lost. The stained specimen is more useful in studying
the finer structure of these organisms than for diagnostic examina-
tions.
The distoma of bilharzia disease, although, strictly speaking,
a blood parasite, is not found in the general 'circulation, since this
worm resides solely in the portal vein and branches, the vena cava,
and certain veins of the lower pelvis. Leishman-Donovan
bodies are obtained by puncture of the spleen, but they do not
enter the peripheral blood.
Foreign bodies, such as free fat droplets, collections of extra-
cellular pigment, and, very rarely, the crystalline bodies of Char-
cot may also be observed in the fresh specimen during the course
of certain diseases.
Microscopical examination of the fresh specimen should form
the initial step taken in every systematic examination of the
blood, since it may be the means of determining whether or not
a more elaborate investigation is necessary. By this simple pro-
cedure an immediate diagnosis may be made in a number of in-
stances, while in others the findings, although not pathogno-
monic, are of distinct clinical value. Close familiarity with the
normal histology of the blood is, of course, essential for the ap-
preciation of the various pathological changes which have been
outlined above. Fuller reference to these changes has been
made in other parts of this book. (See Sections III and IV.)
II. ESTIMATION OF THE PERCENTAGE OF HEMO-
GLOBIN.
No fewer than half a dozen different hemoglo-
METHODS. binometers, or instruments for estimating the
amount of hemoglobin in the blood, are in vogue
at the present time, of which the most reliable for general clinical
use are those devised by Dare, by von Fleischl, by Oliver, and by
Gowers. The hemometer of von Fleischl has been the general
4O EXAMINATION OF THE BLOOD BY CLINICAL METHODS.
DARE'S
HEMOGLOBIN-
OMETER.
favorite for a number of years, both in this country and on the
Continent, but in America, at least, Dare's hemoglobinometer
is rapidly supplanting it; in England it has been supplanted to
some extent, first by Gowers' hemoglobinometer, and in recent
years by the hemoglobinometer lately invented by Oliver. The
instruments of von Fleischl, Gowers, and Oliver are based upon
a similar principle, that of measuring the depth of color of the
diluted blood by a standard color scale of varying intensity, the
gradations of which correspond to different hemoglobin values;
that of Dare uses undiluted blood.
With this instrument a thin film of undiluted
blood is brought into direct comparison with a
standard semicircular wedge of tinted glass
ranging in color from a claret red at the thickest
part to a pale pink at the thinnest. The in-
strument consists of the following parts: (i) A capillary blood
chamber, constructed of
two rectangular plates of
polished glass, the op-
posed surfaces of which
are so ground that, when
clamped together in a
metal bracket, a shallow
compartment holding a
thin film of blood is
formed. One plate is
made of transparent, the
other of opaque, glass,
the latter being next to
the source of light, in
order to soften its glare,
when the instrument is in
use. The metal bracket
of the blood chamber is
adjusted to the stage of
the instrument in such a
blood chamber adjusted to stage of instrument, the slip manner that the blood
of opaque glass, W, being nearest to the source of light; £1__ £«._
Y, detachable candle-holder; Z, rectangular slot through Him tltS OVCr an aperture
Sto dfehSS*"" scale indicated °n the "m °f communicating with a
camera tube screwed to
the opposite side of the rubber case. (2) A graduated color standard
made of a semicircle of glass tinted with Cassius' ''golden pur-
ple," and thinning out like a wedge with various depths of color
corresponding to the tints of fresh blood containing different
FIG. 4. — DARE'S HEMOGLOBINOMETER.
R, Milled wheel acting by a friction bearing on the
rim of the color disc; S, case inclosing color disc, and
provided with a stage to which the blood chamber is
fitted; T, movable wing which is swung outward during
the observation, to serve as a screen for the observer's
eyes, and which acts as a cover to inclose the color disc
when the instrument is not in use; U, telescoping camera
tube, in position for examination; V, aperture admitting
light for illumination of the color disc; X, capillary
blc
ESTIMATION OF THE PERCENTAGE OF HEMOGLOBIN.
percentages of hemoglobin. It is mounted upon a disc adjusted
in the frame of the instrument, so that it may be revolved to
bring various portions of its surface over an aperture directly
alongside of the one through which the blood film is visible.
A scale, read from the outside of the instrument, indicates in
units the hemoglobin percentages from 10 to 120. (3) A hard
rubber case incloses the color standard when the instrument is
in use, the disc upon which the standard is mounted being re-
volved by turning a small milled wheel acting upon the rim of
the disc by a friction bearing. To one side of the case a telescopic
camera tube, fitted with an eye-piece, is attached, while on the
opposite side a stage furnishes support for the blood chamber,
back of which a candle, held between a pair of spring clips, is
adjusted. Two apertures of equal di-
ameter, placed side by side on the same
level, transmit the light of the candle
through the blood film and the color
standard to the field of vision inclosed
by the camera tube. By reference to
the accompanying diagram (Fig. 5) it
will be seen that the light of the can-
dle, J, equally illuminates the blood
film inclosed between the two rect-
angular glass plates, O and P, and the
edge of the color standard, L, mounted
upon the glass disc, K. The differences
in the two colors are visible through
the two apertures, M and M', commu-
nicating with the camera tube, X.
By revolving the disc the tint of the
color standard may be altered until it matches that of the blood
film.
Method 0} Use. — The instrument is prepared for use by first
swinging outward the movable screen which serves as a cover for
the case. The two apertures overlying the blood film and the
color scale are thus brought into view, the direct light from the
candle being shaded from the observer's eyes by the intervening
screen. The camera tube and the candle-holder are then fitted
to their attachments on opposite sides of the instrument, and a
candle adjusted so that the surface of its "wick end" is just on
a level with the top of the spring clips.
The blood chamber is filled by touching its edge to the side of
a rather large drop of blood as the latter flows from the punc-
ture, so that the blood at once flows into and fills, by capillary
force, the shallow compartment between the pair of glass plates.
FIG. 5. — HORIZONTAL SECTION OF
DARE'S HEMOGLOBINOMETER.
42 EXAMINATION OF THE BLOOD BY CLINICAL METHODS.
As soon as this occurs, any excess of fluid which may have adhered
to the outer surface of the blood chamber is carefully wiped
away, and the latter is slipped into the tongue, which holds it
in position on the stage of the instrument.
The candle having been lighted, the observer holds the instru-
ment as a field glass, and compares with one eye the colors of
the blood film and the standard disc which are seen side by side
in the field of vision limited by the camera tube. The disc is
made to revolve by making short, quick turns with the milled
wheel until the two colors are identical, and the hemoglobin per-
centage indicated by the scale is then noted.
The color comparisons need not be made in a darkened room,
although the observer should avoid facing the direct sunlight,
and, in order to exclude reflected light, should hold the instru-
ment against a dark surface, such as a black coat-sleeve. When
the observation is
completed, the twro
glass plates of the
blood chamber are
removed from the
bracket by loosening
the screw which holds
them in position.
They are then cleaned
with water and with
acid alcohol, dried,
polished, and replaced
in the bracket. The
various parts of the instrument, when detached, fit into a small
leather carrying-case.
The chief advantage of Dare's instrument lies in the fact that
dilution of the blood is not required, and therefore errors due to
incorrect measuring and dilution of the blood, which must be care-
fully guarded against in the older hemoglobinometers, are entirely
eliminated. A film of whole blood also gives a relatively deep
and definite color, which may be judged with greater ease and
accuracy than the paler and more indefinite tint of a blood solu-
tion. It is also obvious that errors due to the turbidity of an
aqueous solution of leukemic blood are avoidable by the use of
an undiluted film. Coagulation of the film does not occur with
sufficient rapidity to constitute a source of error, since the test
may be completed within a few seconds after the blood has been
drawn.
Three years' constant use of this hemoglobinometer in the
FIG. 6. — MANNER OF FILLING BLOOD CHAMBER.
ESTIMATION OF THE PERCENTAGE OF HEMOGLOBIN.
43
Jefferson Medical Clinic has proved it the most accurate, sim-
ple, and convenient instrument for clinical purposes. Its read-
ings closely correspond to those of Oliver's hemoglobinometer,
and average somewhat higher than those of the von';Fleischl
instrument. The color standard of Dare's apparatus, being
wedge-shaped and therefore gradually blending the tints, is open
to the same criticisms w^hich have
been urged against the scale of
the hemometer.
With this in-
strument the
color of a fixed
volume of blood
VON
FLEISCHL'S
HEMOMETER.
in an aqueous
solution of a definite strength is
compared with the color of a
movable glass wedge, tinted with
Cassius' "golden purple." The
hemometer consists of the follow-
ing parts:
(i) A tinted glass wedge, the
thickest portion of which is of a
deep pink color, and the thinnest portion almost colorless, with
every intermediate color gradation between the two extremes.
It is mounted in a metal frame provided with a scale, graduated
at every five degrees from o to 120, the former corresponding to
the thinnest, and the latter to the thickest, part of the wedge.
The metal frame is grooved so that it fits beneath (2) a small
FIG. 7. — VON FLEISCHL'S HEMOMETER.
FIG. 8. — TINTED GLASS WEDGE OF THE VON FLEISCHL
HEMOMETER.
FIG. 9. — CAPILLARY PIPETTE OF
VON FLEISCHL'S HEMOMETER.
stage, in which it may be moved backward and forward by turn-
ing a milled wheel. In the center of this stage there is a circu-
lar opening through which the light of a candle is reflected by a
disc of calcium sulphate, mounted on the pillar supporting the
stage, like the mirror of a microscope. Back of this opening there
is a small oval slot through which the scale of the underlying
44 EXAMINATION OF THE BLOOD BY CLINICAL METHODS.
tinted wedge is visible, when the latter is adjusted to the stage.
(3) A mixing chamber, consisting of a short metal tube closed
at the bottom by a disc of glass and divided into two equal com-
partments by a vertical partition, fits accurately over the circular
opening in the stage. When properly adjusted to the latter, the
vertical partition exactly coincides with the upper edge of the
underlying tinted wedge, so that the upper compartment of the
chamber is illuminated by the dull white light from the reflector,
while the lower compartment receives the color of the tinted
wedge. (4) A capillary pipette mounted in a short metal handle,
used for making the blood dilution. A single pipetteful of normal
blood mixed with sufficient distilled water to fill exactly one of
the compartments of the mixing chamber gives a solution which
matches the color of the tinted wedge opposite the mark 100.
(5) A small, fine-pointed glass dropper, used for filling the com-
partments with water.
Method of Use. — As a preliminary step, each compartment of
the mixing chamber is filled about one-quarter full of distilled
water by means of the glass dropper, to one end of which a rubber
cap has been fitted. A puncture having been made, as previously
directed, a measured volume of blood is collected by bringing one
end of the capillary pipette lightly in contact with the blood drop
as it oozes from the wound, so that the tube is instantly filled
with blood, by capillary force. No difficulty will be experienced
in quickly filling the tube if it is applied horizontally to the side
of the blood drop, rather than vertically to its summit, care being
observed not to immerse the end too deeply. It is needless
to add that the interior of the tube must be absolutely clean
and dry, to insure which a very fine needle and thread may be
passed through it just before using. As soon as the pipette is
filled, every trace of blood must be removed from its outer surface
and the precaution taken to see that the column of blood is exactly
flush with the ends of the tube, being neither bulged out nor de-
pressed. The blood is then washed into one of the compartments
of the mixing chamber, by forcing a stream of distilled water
through the pipette by means of the glass dropper, this rinsing
being repeated until it is certain that every trace of blood has been
removed. The preceding steps must be carried out quickly, in
order to avoid errors arising from coagulation of the blood. The
blood and water in the compartment are now thoroughly mixed
by stirring with the handle of the pipette until the color of the
solution is diffused uniformly, after which water is added, drop
by drop, to each compartment until they are both filled exactly
to their brims. In doing this, no water must be spilled on the
ESTIMATION OF THE PERCENTAGE OF HEMOGLOBIN. 45
thin edge of the vertical partition, for should this occur, it may
cause an overflow of the liquid from one compartment to the
other, and thus alter the strength of the blood solution. If the
latter should appear turbid or muddy, as it sometimes does with
leukemic blood, a few drops of a weak aqueous solution of potas-
sium hydrate may be added to the diluent as a preventive of
this change. The addition of a little ether will clear the solu-
tion if the turbidity is due to the presence of fat.
Having carried out the preceding steps, the mixing chamber is
adjusted over the circular opening in the stage of the instrument,
so that the compartment containing the blood solution is upper-
most, overlying the semicircle illuminated by the clear white
light ; while the compartment filled with water fits over the semi-
circle, which receives the tint of the underlying glass wedge.
The remainder of the test, the comparison of the color of the
two compartments, must be completed by artificial light, prefer-
ably by candle-light. Moderately bright illumination is better
than a strong glare, for the latter interferes seriously with the
accurate determination of delicate color differences. By means
of the milled wheel the tinted glass wedge is moved backward
and forward until its color precisely corresponds to that of the
diluted blood. When this occurs, the percentage of hemoglobin
is read off from the scale visible through the oval slot in the stage
of the instrument.
While making the color comparison the observer should stand
facing one end of the glass wedge (not the milled wheel), so that
the partition between the two compartments of the mixing cham-
ber is on a line with the vertical axis of his eye's, the distance from
the latter to the top of the stage of the instrument being about
ten or twelve inches. Gross errors may be avoided if the observa-
tion is made with one eye and if the same eye is habitually used,
since the two eyes may differ radically in their sensitiveness to
color impressions. It is important to decide the color differences
as quickly as possible, for prolonged examination rapidly dulls
one's color perception, and creates uncertainty as to the proper
reading. It is a good plan first to bring into the field of vision
the darkest portions of the wedge between the figures 100 and
120 of the scale, and then, by short, sudden turns of the milled
wheel, to produce abrupt color contrasts of from 5 to 10 degrees
at each turn, until the two tints approximately correspond.1
When this point is reached, the eye should be rested for a few
1 It is important to bear in mind the fact that the judgment of color differences
is much easier if marked contrasts in color value are made, than if a gradual blend-
ing of the two tints is attempted, by slowly moving the wedge past the visual field.
46 EXAMINATION OF THE BLOOD BY CLINICAL METHODS.
moments, and then, by a succession of shorter turns, .the wedge
is again swept to and fro until the colors appear identical. In
the average instance an error of about 5 degrees must be antici-
pated in spite of every precaution to insure accuracy.
FIG. 10. — METHOD OF USING THE VON FLEISCHL HEMOMETER.
Note that the septum between the two halves of the blood compartment is at right angles to
the horizontal axis of the observer's eyes. A cylinder of paper may be fitted over the blood com-
partment, to serve as a camera tube.
In cases in which low hemoglobin percentages (30 per cent,
or less) are suspected, it is essential to use two or three pipette-
fuls of blood in making the dilution, dividing the percentage indi-
cated by the instrument by two or three, as the case may be.
ESTIMATION OF THE PERCENTAGE OF HEMOGLOBIN. 47
This precaution effectually removes the objection which has been
urged against this instrument on account of its inaccuracies in
the determination of low hemoglobin percentages. Another
criticism of the von Fleischl instrument has been made on the
ground that, since the length of the tinted wedge visible through
the compartment of the mixing chamber includes a color range
of 20 per cent., it is impossible for one to select a single point in
the center of this color for comparison with the even, diffuse tint
of the blood solution. This objection may be overcome to a
great extent by using a metal diaphragm, provided with a slit
one-eighth of an inch in width, which is placed over the glass
disc at the bottom of the compartments, to limit the field of
vision. Adjusted so that the slit crosses at right angles the par-
tition separating the two colors, the use of this device cuts down
the field of observation to a portion of. the glass wedge corre-
sponding to about 2.5 degrees on the scale.
The hemoglobin percentages indicated by this instrument
appear to be low for the blood of the average healthy American,
since it is more common to obtain readings of from 90 to 95 than
of the arbitrary standard 100, in persons in whom there is no
good reason to suspect subnormal hemoglobin values. In in-
struments of recent manufacture, however, this fault is largely
corrected.
In order to exclude the light of the candle from the field of
vision while making the color comparison, it is customary to
use a tube of cardboard or stiff paper, which is slipped over the
mixing chamber and rests upon the platform of the instrument.
This sort of a device answers very well when the examination is
made in a darkened room, as, for example, at a patient's residence.
In hospital work, however, the inconvenience, sometimes con-
siderable, of being compelled to carry the diluted blood some
distance from the bedside to a dark room may be avoided by the
use of a light-proof box, which may be conveniently carried from
ward to ward, so that the test may be completed at the bedside
(Fig. n). A box of this kind should measure sixteen inches
in height by twelve inches in length and in width, being fitted
with a hinged door which may be fastened by a simple catch,
and provided with a circular opening through which the milled
wheel of the hemometer projects when the door is closed. A
metal camera tube, flanged at the upper extremity for the obser-
ver's eye, pierces the top of the box and communicates inside
with the mixing chamber of the hemometer. The tube fits
loosely in a circular opening in the top of the box, so that it may
readily be raised and lowered; its diameter is a trifle greater
48 EXAMINATION OF THE BLOOD BY CLINICAL METHODS.
than that of the mixing chamber, around which it should fit
snugly when lowered into position; and its length is governed
by a fixed collar outside the box, which prevents it from slipping
and jarring the instrument. Wooden guides, such as are used
for securing a microscope in its box, are provided to receive the
FIG. ii. — LIGHT-PROOF Box FOR THE VON FLEISCHL HEMOMETER.
The door of the box is closed and the color comparison made through the camera tube.
Xote. — Reichert, at the suggestion of Miescher, has introduced a modification
of the original von Fleischl hemometer, designed to increase the accuracy of the
test, by making it possible, by definite dilution of the blood, to select that part
of the tinted wedge which is best adapted for the examination of any particular
sample. This innovation was prompted by the discovery that the intermediate
portions of the wedge are better adapted for obtaining accurate readings than the
terminal parts. The principal modification of the new hemometer consists in
the substitution, for the original capillary blood pipette, of a special mixing pipette,
similar to a mclangeur, graduated so that the blood may be diluted i : 200, i : 300,
and i : 400 times. A table supplied with the instrument translates the combined
results of the dilutions and the figures indicated by the scale on the wedge into
absolute hemoglobin percentages. The instrument is also supplied with mixing
chambers of different depths, and with a diaphragm designed to limit the field of
vision. The writer has had no practical experience with the Miescher-Fleischl hem-
ometer, but an examination of the instrument justifies the belief that its elaborate-
ness renders it undesirable for general clinical work. Its cost ($50.00) is also a
bar to many.
horseshoe base of the hemometer, holding it firmly in such a
position that when the camera tube is lowered into place the
milled wheel of the instrument projects through the opening in
the closed door. The interior of the tube and of the box is painted
a dull black. A candle is placed in position on the floor of the
ESTIMATION OF THE PERCENTAGE OF HEMOGLOBIN. 49
box, on a line with the "mirror" of the instrument. In using
this device first the candle within the box is lighted, and the
hemometer base is slipped into place between the wooden guides.
The blood dilution having been made in the usual manner,
the mixing chamber is then set upon the platform of the instru-
ment, and the camera tube, which has been raised to allow this
to be done, is lowered until it telescopes around the mixing cham-
ber and rests firmly upon its collar. The door of the box is
now closed, and the two compartments are brought into their
proper positions over the glass wedge by turning the camera
tube from the outside of the box, the observer meanwhile noting
the result by looking through the flanged extremity of the tube.
This accomplished, the projecting wheel of the instrument is
turned to and fro until the colors of the two compartments are
the same, when the door is opened and the percentage read off
from the scale of the hemometer. Care must be observed to
see that the exterior of the mixing chamber is perfectly dry,
for if any moisture collects between its outer surface and the
inner surface of the camera tube, the contents of the compart-
ments may be disturbed and serious errors result. As the open-
ing in the door of the box is covered by the hand with which
the milled wheel is turned, sufficient light to interfere with the
test cannot leak in at this situation.
With a light-proof box of this sort it is possible accurately
to carry on hemoglobin estimations in the brightest daylight,
which may be entirely excluded from the instrument, while the
observer's field of vision is limited to the two semicircles illumi-
nated by the candle burning within the box.
With this instrument the principles of Lovi-
OLIVER'S bond's tintometer are applied to the quantitative
HEMOGLOBIN- estimation of hemoglobin, the color of- a blood
OMETER. solution of a definite strength being compared,
by light reflected from a dead white surface, with
a series of tinted glass standards which constitute a progressive
color scale. Thus, a series of fixed, definite tints is provided,
each of which accurately corresponds to the specific color curve
of progressive dilutions of normal blood, this having been de-
termined individually by means of the tintometer. Two sets
of color standards have been devised: one for daylight readings
and one for observations by candle-light, the latter being prefer-
able on account of the greater delicacy of its readings. Oliver's
complete apparatus consists of : (i) A capillary blood measure,
made of heavy glass tubing, and having a capacity of 5 c.mm.
The end to be presented to the blood drop, in filling the
50 EXAMINATION OF THE BLOOD BY CLINICAL METHODS.
measure, is tapered to a blunt point and highly polished. (2)
A mixing pipette, provided with a short rubber tube which fits
over the tapered end of the blood measure, while rinsing out
the blood from the latter into the (3) standard blood cell, which,
when filled exactly to the brim with distilled water in which one
measureful of blood has been dissolved, yields a blood solution
of approximately one per cent. When filled, the cell is covered
with a glass slip provided for this purpose. (4) A standard color
scale, consisting of 12 tinted glass discs, mounted in two series,
and corresponding to hemoglobin percentages ranging from 10
to 1 20. (5) A set of riders, or squares of tinted glass, used for
determining the intermediate degrees of color between the deci-
mals indicated by the fixed tints of the scale. For ordinary clin-
ical work two riders are sufficient, which, when laid over the discs
of the standard scale, read 2.5 and 5 degrees respectively on its
upper half, but double this amount on the lower half. For physi-
ological observations requiring readings in units a set of nine
riders is supplied. (6) A collapsible camera tube through which
the color comparisons are made.
Method of Use. — In making hemoglobin estimations with
Oliver's apparatus, first the capillary measure is filled with blood
by the method directed for filling the pipette of the von Fleischl
instrument. The rubber nozle of the mixing pipette, previously
filled with distilled water, is then adjusted over the polished end of
the blood measure, and the blood washed into the standard cell by
forcing through the water, drop by drop. As soon as all the
blood contained in the bore of the measure has been thus washed
out into the cell, the rubber nozle of the pipette is removed, and
the handle of the measure used as a stirrer to mix the blood
solution, more water being added in single drops, from time
to time, until the cell is accurately filled. The blue cover-glass
is then adjusted, with the result that, if the cell has not been
overfilled, a small air-bubble forms on the surface of the liquid.
The blood cell, filled in this manner with a blood solution of
definite strength, is now placed by the side of the standard scale,
opposite the tinted disc to which it corresponds most closely,
the eye readily recognizing its approximate position. More accu-
rate matching of the two colors is made with the aid of the
camera-tube, the cell being moved from disc to disc in an
endeavor to match exactly the color of the blood solution by one
of the standard tints of the scale. If this is successful, the hemo-
globin percentage indicated by the disc is read off, and the obser-
vation is completed. But if it happens that the tint of the blood
solution is obviously deeper than a certain disc, but paler than the
ESTIMATION OF THE PERCENTAGE OF HEMOGLOBIN.
51
one immediately above, the cell is kept alongside the lower of the
two, over which a rider is adjusted in order to deepen its color,
while the square of white glass is placed over the cell, so as to
compensate for the thickness of the rider. If, now, the colors
correspond, the final reading is ascertained by taking the percent-
age of the disc plus the value of the superimposed rider. If the
color of the blood solution is darker than that of any one of the
standard discs, but paler than the disc plus a rider, the mean
average of the two is taken as the final reading; similarly, if the
FIG. 12. — METHOD OF USING OLIVER'S HEMOGLOBINOJIETER.
color of the blood solution is darker than a certain disc plus a
rider, but paler than the disc immediately above, the values of
the two must be averaged. An error of two per cent, is un-
avoidable, even in the hands of a skilful observer.
During the observation the candle should be placed three or
four inches from the end of the color scale, being adjusted so that
the flame is on a line with the opposed sides of the cell and of the
scale, thus illuminating both with equal intensity. The positions
of the candle and of the apparatus are shown in the accompanying
illustration (Fig. 12). Small-sized candles, such as are used
52
EXAMINATION OF THE BLOOD BY CLINICAL METHODS.
for decorating Christmas trees, furnish a flame of the proper de-
gree of brilliancy, the candle of ordinary size giving too intense a
light. Total exclusion of daylight is not necessary, so that the
observation may be made in the corner of a partly darkened
room, as, for example, behind a closet door or some other similar
shield against direct rays of light.
Oliver's hemoglobinometer is a trial to the patience of one
who has habitually used the Dare or the von Fleischl, and it
takes some time to become accustomed to it after having worked
with the comparatively simple color comparisons of other instru-
ments. Its accuracy is undeniable, although for clinical work
a simpler apparatus is to be preferred.
This instrument, which for
GOWERS' many years has been popular
HEMOGLOBIN- in England and is used to
OMETER. some extent in this country,
consists essentially of two small
flattened tubes of equal diameter, which, when
in use, are fixed upright and parallel to each
other in a small wooden support furnished for
this purpose. One tube contains glycerin jelly
colored with picrocarmin to correspond to the
tint of a i : 100 solution of normal blood (or
20 c.mm. of blood in 2 c.c. of water), this
being taken as the standard with which the
blood solution contained in the second tube
is compared. The second tube is provided
with a scale graduated in units from 5 to 120, each degree of
which equals the volume of blood required for the test. Twenty
c.mm. of normal blood, dissolved in sufficient distilled water to
fill this tube to the 100 mark on the scale, give a solution which
corresponds to the tint of the standard tube. The special capil-
lary pipette used for measuring the blood is graduated at 10 and
at 20 c.mm., and fitted with a bit of rubber tubing and mouth-
piece for filling it by suction.
Method of Use. — The technic of hemoglobin estimations with
Gowers' apparatus is extremely simple. Having made the punc-
ture in the usual manner, the blood is sucked up the caliber of
the capillary pipette until the mark 20 is reached, and then im-
mediately blown out into the graduated tube, into which a few
drops of distilled water have previously been placed, in order to
insure instantaneous solution of the measured amount of blood.
All traces of blood which may have adhered to the bore of the
capillary pipette are removed by filling it several times with water,
ESTIMATION OF THE PERCENTAGE OF HEMOGLOBIN. 53
the rinsings being added to the mixture of blood and water in the
tube. During the preceding steps the usual precautions must be
observed to wipe all surplus blood from the outside of the pipette
before expelling its contents, and to measure the blood rapidly, so
as to guard against errors arising from rapid clotting. Distilled
water is now added, drop by drop, to the mixture in the tube
until the color of the blood solution exactly corresponds to that
of the picrocarmin standard, the contents of the tube being mixed
between each addition by rapidly reversing it two or three times,
writh its open end closed by the thumb. The drop or two of
liquid adhering to the thumb should be wiped off against the wall
of the tube, so that it may drain back into the liquid. When the
tints of both tubes are precisely similar, the division of the scale
to which the diluted blood reaches is read off, to express the per-
centage of hemoglobin in the specimen under consideration.
In comparing the colors, which is done by daylight, the tubes
should be held against a sheet of white paper, or, as suggested
by Gowers, between the eye and a window, and viewed at such
an angle that their adjoining edges appear to overlap, thus cutting
off the vertical streak of white light visible between them should
this precaution be neglected. Owing to the diagonal position in
which the two tubes are adjusted in their support, the proper
angle to produce this effect may readily be determined.
The chief drawback to the use of this instrument is the likeli-
hood of overdiluting the blood after it has been mixed in the
graduated tube, the occurrence of this accident necessitating, of
course, a repetition of the entire operation. It is not always
easy to decide just when sufficient water has been added to the
blood to bring its color down to that of the standard tint, since
one must depend solely upon a gradual weakening of the tint of
the blood solution, and this is much more difficult than to com-
pare a definite blood color with a sliding scale or with a series
of discs. The instrument may be regarded as accurate within
two or three per cent, for hemoglobin percentages above ten,
below which figure it is impossible to distinguish a difference
between the tints of the two tubes. This source of error, how-
ever, is too remote a possibility to detract from the instrument's
practical value. A real source of error in Gowers' instrument is
the deterioration with age of the picrocarmin color standard,
with a consequent change in its tint.1
1 Haldane (Jour. Physiol., 1901, vol. xxvi, p. 497) has modified Gowers'
instrument by substituting for the picrocarmin jelly a one per cent, solution of
carbonic oxid hemoglobin, which remains stable indefinitely. Using Gowers'
technic, the blood is first partly diluted and then charged with illuminating gas,
54 EXAMINATION OF THE BLOOD BY CLINICAL METHODS.
A simple method of approximately determin-
TALLQUIST'S ing hemoglobin percentages without the aid of
METHOD. a special instrument has recently been devised
by Tallquist,1 the procedure consisting, in brief,
in allowing a drop of blood to soak into a bit of filter-paper and
comparing with the naked eye the color strength of the stain
with a series of printed standard tints of known value. The lat-
ter are arranged as a scale of ten different colors, corresponding
to the colors of stains produced by bloods having hemoglobin
values ranging from 10 to 100 per cent., the latter being regarded
as the normal. 'A lithographed copy of the color standard ac-
companies Tallquist's original article. Dealers in laboratory
supplies also furnish a small book containing the color scale and
a supply of standard absorbent paper. The test is made in the
following manner: A drop of blood, large enough to make a
stain about 5 or 6 mm. in diameter, is caught in the center of a
piece of white filter-paper, care being taken in collecting it to
apply the paper to the exuding drop in such a manner that the
blood soaks in very slowly, and thus produces a stain which is
evenly colored throughout. Perfectly white filter-paper, having
a smooth surface and of a thickness corresponding to about 55
leaves to the centimeter, should be used for the test. The blood
stain thus made is pressed lightly against a pad of filter-paper,
and then compared, by direct daylight, with the series of standard
tints, the figure opposite to the tint which the stain most accurately
matches being read off, to indicate the percentage of hemoglobin
in the specimen under examination. The comparison must be
made immediately after the stain loses its humid gloss, since
blood soon changes its color after exposure to the air.
This direct method of hemoglobin testing is, of course, only
approximate, at the best, and cannot be expected to furnish re-
sults comparable in point of accuracy with those to be obtained
by any of the instruments just described. It may, however, be
employed to excellent advantage when a hemoglobinometer is
by means of a special fitting to be attached to a gas-burner. The oxyhemoglobin
of the blood is thus converted into carbonic oxid hemoglobin, the color of which
is comparable to that of the standard solution. After having been charged with
gas, the blood is mixed by repeatedly inverting the tube, the open end of which
is closed by the thumb, after which the dilution is proceeded with until the colors
match, when the final reading is made. The inventor's claims for the accuracy
of his instrument have been substantiated by Horder (Lancet, 1903, vol. i,
p. 1305). In ten estimates by different observers it was determined that the
possible errors with Haldane's instrument averaged 1.9 per cent., and with the
hemometer, 4.25 per cent. Haldane's device, despite its accuracy, obviously is
better adapted to physiological research work than to clinical hematology.
1 St. Paul Med. Jour., 1900, vol. ii, p. 291.
COUNTING THE ERYTHROCYTES AND LEUCOCYTES. 55
not at hand, or in certain cases in which only a rough estimate of
the amount of coloring matter of the blood is sought. Tall-
quist, who has tested his method, under the control of the he-
mometer, in his clinic at Helsingfors, claims that the limit of error
generally does not exceed ten per cent.
Here may be mentioned Haig's blood decimal card, devised
for roughly estimating the color index of the blood. It consists
of a series of four different colors, scaled 0.80, 0.60, 0.40, and
0.20, respectively. By matching one of these colors with the
color of the patient's gums or tongue an approximate idea of the
individual's color index is obtained. Haig's device may serve
for a hurried examination, but it is obviously too crude to give
accurate results.
III. COUNTING THE ERYTHROCYTES AND THE
LEUCOCYTES.
Of the various instruments used for count-
METHODS. ing the blood corpuscles, the hemocytometers de-
vised by Thoma and by Gowers are most gener-
ally employed at the present time, the former being used almost
to the exclusion of the latter everywhere except in England,
where Gowers' apparatus has many firm adherents. Durham,
by adapting and modifying a number of the details of the older
instruments, has succeeded in devising an improved form of hemo-
cytometer which possesses many advantages over the original
models, being of simple construction, accurate, and comparatively
inexpensive. The method of making the estimate, which is es-
sentially the same with all three of these instruments, consists,
briefly, in first diluting the fresh blood in definite proportions with
some indifferent preservative flifid, and in then counting, under
the microscope, the number of corpuscles in a drop of the diluted
blood, the latter being contained in a small glass cell on the floor
of which is ruled a series of micrometer squares of certain dimen-
sions. The cubic contents of the cell and the degree of the blood
dilution being known, the number of corpuscles counted in any
given number of these squares may be taken as a basis for cal-
culating the total count of corpuscles to the cubic millimeter
of blood.
Strong and Seligmann dispense with a special counting cham-
ber, and enumerate the cells in a measured quantity of blood
diluted in definite proportions with a diluent-stain and mounted
as a permanent dry specimen.
Oliver has devised an instrument with which the number of
56 EXAMINATION OF THE BLOOD BY CLINICAL METHODS.
erythrocytes may be estimated by means of their optical effect,
without the use of the microscope.
Diluting fluids for use with the hemocytom-
DILUTING eters of Thoma, Gowers, and Durham should
FLUIDS. be of such a composition that when mixed with
the fresh blood they preserve unaltered the form
of the corpuscles. This requirement being met, the examiner
may choose from the numerous formulas in current use the one
which best suits his individual preference. Among the most sat-
isfactory solutions used for this purpose the following may be
mentioned :
TOISSON'S SOLUTION.
Methyl-violet, 5 B 0.025
Sodium chlorid i .o
Sodium sulphate 8.0
Neutral glycerin .* 30.0
Distilled water 160.0
SHERRINGTON'S SOLUTION.
Methylene-blue o.i
Sodium chlorid 1.2
Neutral potassium oxalate 1.2
Distilled water 300.0
For general clinical work no better formulas have ever been
suggested than the preceding two. Both solutions act as excel-
lent preservative fluids, and each contains just sufficient quantity
of a basic anilin dye to stain the leucocytes with great distinct-
ness, so that they may readily be differentiated from the erythro-
cytes, which remain uncolored.
HAYEM'S SOLUTION.
Mercuric chlorid 0.25
Sodium chlorid 0.5
Sodium sulphate 2.5
Distilled water 100.0
Oliver specifies this solution as the diluent invariably to be
employed with his instrument, but it may be used also with the
other forms of hemocytometers, although with less satisfaction
than the formulas first mentioned.
Among the simpler diluting fluids, all of which are depend-
able, are solutions in distilled water of common salt (0.7 per cent.),
of potassium bichromate (2.5 per cent.), and of sodium sulphate
(5 per cent.), to any of which about 0.5 per cent, of an alcoholic
solution of methyl-violet may be added, in order to stain the
leucocytes, and thus to facilitate the counting.
COUNTING THE ERYTHROCYTES AND LEUCOCYTES.
57
An aqueous solution of acetic acid, varying in strength from
0.3 to 0.5 per cent., which destroys the erythrocytes and at the
same time renders more conspicuous the leucocytes, has been
recommended by Thoma as a diluent in counting the latter cells,
by means of his special pipette.
Turk recommends the use of a one per cent, solution of acetic
acid containing one per cent, of gentian-violet,
in order to recognize the different forms of leu-
cocytes, as well as to count their total number.
This method is, however, only approximate, and
should not replace the examination of the dried
stained film. (See p. 75.)
As spores are liable to develop and precipi-
tates to form in all the above-mentioned solu-
tions, they should always be filtered before
using and kept in tightly corked bottles.
The Thoma-Zeiss hemo-
THE THOMA- cytometer, which is to-day re-
ZEISS HEMO- garded as the standard instru-
CYTOMETER. ment for blood counting, con-
sists of two graduated capil-
lary pipettes for diluting and mixing the blood,
and a counting chamber in which a measured
volume of diluted blood is placed for the pur-
pose of counting the corpuscles under the
microscope. One of the pipettes is intended
for counting the erythrocytes, and, for con-
venience sake, may be termed the erythrocy-
tometer; while the other pipette, which is used
for counting the leucocytes, may be called the
leucocytometer. It is not, however, necessary
to purchase both pipettes, as supplied with the
complete apparatus, since both erythrocytes and
leucocytes may be counted accurately with the
erythrocytometer.
The erythrocytometer consists of a heavy
glass capillary tube, the lumen of which is ex-
panded near the upper end into a bulb contain-
ing a small cubical glass bead, which serves as a stirrer. The
lower end of the tube is ground to a blunt point, and to the upper
end is fitted a short bit of rubber tubing capped by a bone mouth-
piece for filling the tube by suction. A scale is enameled into
the glass wall of the pipette, the three main divisions of which
are indicated by the figures 0.5, i, and 101, the first two grada-
B
FIG. 14. — THE
THOUA-ZEISS HEMOCY-
TOMETER. A, ERYTHRO-
CYTOMETER; B, LEUCO-
CYTOMETER.
58 EXAMINATION OF THE BLOOD BY CLINICAL METHODS.
tions being below, and the latter one above, the bulb; the lower
portion of the tube is further graduated in tenths, by cross lines,
from o.i to i. If blood is drawn up in the pipette to the mark
i, and the diluent added until the mark 101 is reached, the blood
is thus diluted one hundred times; or if the blood is drawn up
only to the mark 0.5, and the diluent added as before, a two-
hundred-fold dilution is obtained.
The leucocytometer is a capillary tube similar to the former,
but having a larger lumen, so that lower dilutions are obtained
with it. If blood is drawn up to the mark i, and the diluent
added until the mixture reaches the mark n, the blood is diluted
ten times; or if the blood column reaches the mark 0.5, with
the same addition of diluent, the dilution thus made is twenty-
fold. In the latest model of this pipette the lower end tapers
to a fine point, the diameter of the lumen thus gradually decreas-
ing as the extreme tip is approached. The chief object of this
FIG. is- — THOMA-ZEISS COUNTING CHAMBER.
modification is to prevent accidental leaking out of the column
of blood when the tube is held vertically, while sucking up the
diluting fluid — an accident difficult to avoid with the old-style
pipette having a large lumen from tip to bulb.
The counting chamber (Fig. 15) consists of a heavy glass slide
in the center of which is cemented a square glass plate provided
with a circular opening which fits around a ruled disc ; the diameter
of the latter being slightly less than that of the opening in the
surrounding plate, a shallow, narrow gutter is thus formed be-
tween the two. The surface of the ruled disc is exactly y1^ mm.
below the level of the glass plate by which it is inclosed, so that
a chamber of this depth is formed when both are superimposed
by a cover-glass having an absolutely plane surface, two such
covers being furnished with each instrument. An ordinary cover-
glass should never be used, for, owing to the unevenness of its
surface, a deviation from the standard in the depth of the under-
COUNTING THE ERYTHROCYTES AND LEUCOCYTES. 59
lying chamber must necessarily result. When an objective having
an extremely close "working distance" is employed, the special
hollow cell cover-glass made by Zeiss will prove useful.
The central part of the disc's surface is divided, by micro-
scopical diamond-rulings, into 400 small squares, each of which
has an area of T^7 sq. mm., these small squares being grouped
into sets of sixteen by a series of vertical and horizontal double
rulings bisecting each fifth column of squares (Fig. 16). The
cubic contents of each small square, when the cover-glass is
adjusted, is j-^nrg- c.mm., since they measure individually y1^
by -^ by -^ mm. In Zappert's modified ruling of the Thoma-
Zeiss counting chamber extra lines have been added so as to
FIG. 16. — RULED AREA OF THE THOMA-ZEISS COUNTING CHAMBER (ORDINARY RULING).
increase the ruled area of the disc to nine times its original size.
As illustrated in the accompanying diagram (Fig. 17), the
surface of the disc is thus divided, by heavy cross-rulings, into
nine large squares, each equal in area to the central group of 400
small squares, the whole ruled surface therefore equaling an area
covered by 3600 of the latter. To simplify the counting, the
peripheral squares are subdivided into four, each of the latter
being of the same area as 100 of the small central squares. This
improved form of counting chamber is an invaluable convenience
in leucocyte counting, and should be chosen in preference to
the older model.1
1 Other counting chambers, ruled so as to provide a larger number of squares
in the field, have been devised by Turk, Breuer, Elzholz, and others, but none
of them possesses any real advantages over Zappert's slide.
60 EXAMINATION OF THE BLOOD BY CLINICAL METHODS.
If any difficulty should be experienced in distinguishing the
ruled lines under the microscope, they may be made more con-
spicuous by blackening them with a little soft lead-pencil dust
placed on the surface of the disc and thoroughly rubbed in with
the ball of the finger, the excess being wiped off and the disc
polished with a bit of lens-paper or a soft handkerchief.
Counting the Erythrocytes. — Having made the puncture, as
already described, the point of the erythrocytometer is plunged
into the blood drop as it flows from the wound, and, by making
gentle, uniform suction, a column of blood is drawn up the capil-
lary tube exactly to the mark 0.5. The point of the instrument
is then wiped perfectly dry, and immediately dipped into the dilut-
FIG. 17. — ZAPPERT'S MODIFIED RULING or THE THOMA-ZEISS COUNTING CHAMBER.
ing fluid, which is drawn up the tube in the same manner until
the mixture of blood and diluent reaches the mark 101 above the
bulb. While adding the diluent, the pipette should be twisted to
and fro between the thumb and forefinger, in order that the blood
and diluent may be mixed, by the whipping about of the glass
bead, as they fill the bulb; if this precaution is neglected, a por-
tion of the blood will rise in a distinct layer above the diluent as
the latter flows into the bulb, and may be drawn, unmixed, into
the capillary constriction beyond. A more thorough mixture of
the blood and diluent is now made, the rubber tubing being
slipped from the instrument, which is then grasped so that its
ends are closed by the thumb and middle finger, and rapidly
COUNTING THE ERYTHROCYTES AND LEUCOCYTES.
6l
shaken for about half a minute. By the above steps a mixture
is made in which the proportion of blood to diluent is i : 200, a
degree of dilution with which it is most convenient to work in
the great majority of instances. For two reasons a i : 200, rather
than a i : 100, dilution is to be preferred in routine work: (i)
If, as not infrequently happens, the blood column is accidentally
drawn up -the tube beyond the mark 0.5 in an attempt exactly
to reach this gradation, it is a simple matter to correct the error
by gently blowing or shaking the blood column down to the
FIG. 18. — METHOD OF FILLING THE CAPILLARY TUBE OF THE THOMA-ZEISS HEMOCYTOMETER
WITH BLOOD.
proper level; whereas, in attempting to make a i : 100 dilution,
should the mark i be exceeded, the blood column will almost
surely escape into the bulb, whence it cannot be blown back again
into the capillary tube, thus necessitating a repetition of the
whole operation with a fresh drop after having cleaned and dried
the erythrocytometer. (2) It is easy to count the corpuscles
in a i : 200 dilution, since the surface of each ruled square of the
counting chamber is, as a rule, occupied by not more than half
a dozen cells; on the contrary, in a i : 100 dilution, except in
an occasional instance in which there is a striking paucity of cells,
62 EXAMINATION OF THE BLOOD BY CLINICAL METHODS.
the field may be so overcrowded with corpuscles that their enu-
meration is difficult and often inaccurate.
The next step is to place a drop of the diluted blood in the
counting chamber, preparatory to counting the corpuscles under
the microscope. The unmixed diluting fluid in the lower portion
of the capillary tube is first expelled, by blowing out four or five
drops, after which the point of the pipette is dried with a soft
cloth and a small drop of the blood mixture is allowed to fall,
by force of gravity, exactly in the center of the surface of the
ruled disc. The cover-glass is then immediately placed in posi-
tion, and the slide left undisturbed for several minutes, so that
the corpuscles may settle. The drop placed on the disc should
be of sufficient size to occupy only its central portion, the object
being to use just enough of the blood mixture to cover the ruled
area and exactly to fill in the vertical space between the surfaces
of the disc and cover-glass when the latter is placed in position.
If the drop contains air-bubbles, or if it is so large that it over-
flows into the gutter and perhaps finds its way between the cover-
glass and the glass plate beneath, errors will result, so that in the
event of either of these accidents the procedure must be repeated
with another drop, after having cleaned and dried the cover-glass
and the counting chamber. Water, and not alcohol or xylol, is
to be used for this purpose, since the repeated use of chemicals
will soon dissolve the cement which fixes the disc to the counting
chamber. In repeating the operation the original technic must
be rigidly followed — i. e., the erythrocytometer must be briskly
shaken for half a minute or so, and the contents of its capillary
stem blown out, before placing the new drop in the counting
chamber.
In a properly prepared slide concentric rings of color — New-
ton's rings — may be seen at the points of contact between the
cover-glass and the underlying glass plate. If these rings are in-
visible, or if they do not appear when pressure is made upon the
cover-glass, it is a sign that the contact between the two glass
surfaces is not true, this being due to the presence of particles of
dust or of moisture beneath the cover-glass. Inasmuch as this
may seriously affect the correctness of the count, it is a safe rule
invariably to reject a slide in which these color rings are not visible.
As soon as sufficient time has elapsed for the corpuscles to sink
to the bottom of the counting chamber — about five minutes — the
slide is transferred to the stage of the microscope, which should not
be inclined, for fear of disturbing the uniform distribution of the
cells. The field is first brought into focus with a low-power objec-
tive (a No. 3 objective of Leitz, for example), and the slide moved
COUNTING THE ERYTHROCYTES AND LEUCOCYTES. 63
across the stage until the extreme upper left-hand corner of the
group of small ruled squares is brought into view, when a higher
power, to be used in counting, is substituted. For this purpose
the writer is accustomed to use a Leitz No. 6 objective and No. 4
ocular, which lenses, with a tube length of 155 mm., cut off a
field occupied by a block of 25 small squares.
As a basis for the final calculation, the erythrocytes in 400
small squares, or the entire ruled surface of the old-style disc,
should be counted, preferably by going over two groups of 200
squares each in two different drops, rather than by taking the en-
tire 400 squares in a single specimen. By following this plan the
FIG. 19. — PLAN OF COUNTING THE ERYTHROCYTES.
The small squares are examined in the order indicated by the arrow, successive blocks of 25
squares being covered until the required number of cells has been counted.
count of one drop may be controlled by the count of the other,
and any discrepancy between the two discovered, for if the dif-
ference in the counts is striking, a third group of 200 squares
must be examined in an additional drop, and an average taken
of the two counts which most closely correspond.
In order to simplify the process of counting, some routine
method of examining the ruled area, such as the following, should
be adopted : Beginning at the upper left-hand corner of the ruled
disc, the corpuscles in the first 100 small squares are counted,
the slide being moved from above downward, preferably by the
aid of a mechanical stage, as the successive groups of squares are
64 EXAMINATION OF THE BLOOD BY CLINICAL METHODS.
covered. By employing the magnification to which reference has
just been made, three shifts of the slide are sufficient to bring
into the field the requisite number of squares in blocks of 25
each. Examining each small square in succession, proceed from
left to right along one row of five, then drop to the next row and
count from right to left, and continue in the manner illustrated
by the diagram (Fig. 19) until all the erythrocytes in the first
group of 100 squares have been counted, the totals of each block
of 25 squares being noted as they are completed. To avoid repe-
tition in counting it is necessary to include in the total all the cor-
puscles which touch the upper and left boundary lines, and to
disregard those which touch the lower and right boundaries. A
second group of 100 squares, not immediately adjacent to the
first, is then inspected in a similar manner, after which the cover-
glass and counting chamber are washed with water and dried, and
the operation repeated with a second drop. Thus the 400 squares
are covered by examining 16 blocks of 25 squares each — 8 in the
first and 8 in the second drop of diluted blood. In a i : 200
dilution of normal blood this involves the counting of approxi-
mately from 2400 to 2800 erythrocytes, and gives results which
are accurate within one and one-half per cent.
To calculate the number of erythrocytes to the cubic milli-
meter of blood the following formula is employed:
A ir»u* num-
ber of erythro-
cytes per c.tnm.
Number of eryth- ., Degree of dilu- Cubic contents of each Total
rocytes counted tion (200) square (4000) _ oer Ot
Number of squares counted (400) cytes
For example, supposing that in the 400 squares of a i : 200
blood dilution a total of 2500 erythrocytes is counted, the cal-
culation is made thus :
.- -. 2500 X 200 X 4000 .,
(a) -=? — — = 5,000,000 erythrocytes per c.mm.
400
(6) 2500X2000 = 5,000,000 erythrocytes per c.mm.
Counting the Leucocytes. — The leucocytes may be counted by
two different methods: (a) With the erythrocytometer, in the
same drop of diluted blood in which the erythrocytes are esti-
mated ; or (6) with the special leucocytometer, as a separate pro-
cedure. Of the two methods, the former is greatly to be preferred,
since it is fully as accurate and much more convenient and time-
saving than the latter. Furthermore, there is an undoubted ad-
vantage in counting both the red and the white corpuscles in the
same drop of the blood dilution.
(a) If the leucocytes are counted with the erythrocytometer,
the same technic is followed as in determining the number of
COUNTING THE ERYTHROCYTES AND LEUCOCYTES.
erythrocytes, except that a much larger area of the counting
chamber must be examined, owing to the comparatively small
number of leucocytes contained in the i : 200 blood mixture.
It is necessary, for the sake of accuracy, to count the leucocytes
in the entire space inclosed by Zappert's ruling, and to repeat the
count in a second drop, making an area equal to eighteen times
the ruled space of the old-style counting chamber to be examined.
If the totals of both counts are approximately the same, their
combined figures, representing the corpuscles found in a space
corresponding to 7200 of the small ruled squares, are taken as a
basis for the final estimate; but if these totals differ widely, a
third drop is to be examined in the same manner, and, as in
counting the erythrocytes, an average taken of the two totals
which are nearest alike. Since in normal blood, in a i : 200
dilution, each block of 400 small squares contains from 3 to 6
leucocytes, the examination of the above-mentioned area of the
counting chamber involves the counting of approximately from
54 to 108 of these cells — an operation which, practically, is not
nearly so laborious as it appears from the description, being
easily completed within ten or fifteen minutes in most cases.1
As an example of the method of calculating the final estimate,
supposing that 90 leucocytes have been counted in the area equal
to 7200 small squares, the blood dilution being i : 200, this for-
mula is employed:
90 X 200 X 4000 -s- 7200 = 10,000 leucocytes per c.mm.
If the old-style counting chamber is used, the leucocytes in the
unruled portion of the disc outside of the central block of 400
squares may be counted with the aid of an eye-
piece diaphragm, which, when adjusted inside
the tube of the ocular, cuts off a field exactly
the size of 100 small squares (Fig. 20). A
black metal or cardboard disc having a central
aperture of the proper size will answer just as
well for this purpose as the more expensive
and elaborate mechanical eye-piece devised by
Ehrlich, which is provided with a diaphragm
having a square opening the size of which is
regulated by a small lever. Having first counted all the leuco-
cytes in the 400 small squares, the cells are then counted in
32 of the diaphragm-fields outside the latter, in order to cover
Should the leucocytes be decidedly increased, it is unnecessary to cover so
•arce a number of squares. One hundred cells taken as a basis for the calculation
will give an accurate estimate.
Fie. 20. — OCULAR
DIAPHRAGM.
66 EXAMINATION OF THE BLOOD BY CLINICAL METHODS.
an area of the disc corresponding to the entire ruled surface of the
Zappert counting chamber. This operation having been repeated
in a second drop, the totals of both counts are taken as the basis
for the final calculation, which is made in the manner already
described.
If one happens to have neither an eye-piece diaphragm nor
a Zappert counting chamber, the following method of calculat-
ing the cubic contents of the portions of the disc outside the
ruled area may be adopted, as advised by Stengel.1 Using, for
example, a i-inch objective and a i-inch ocular, the ruled lines
are brought into focus, and the tube of the microscope drawn
out until one of the parallel lines of the ruled disc exactly coin-
cides with either boundary of the field of vision. Assuming that 8
of these parallel columns, each -^ mm. in width, are included
in the visual field, the diameter of the latter is therefore T87, or -|
mm., and the radius one-half of this figure, T87, or i mm. The
area of the field may then be readily determined by multiplying
the square of its radius by 3.1416. Its cubic contents are
obtained by also multiplying by y1^ mm., the formula being:
i X 3 X t o X 3-1416 = 0.0125664, cubic contents of the visual field.
Having in this manner ascertained the cubic contents of each
field of vision, the final calculation of the number of leucocytes
to the c.mm. of undiluted blood is made by multiplying the total
number of these cells found in a definite number of fields (for in-
stance, 50) by the degree of dilution (usually i : 200), and then by
dividing the cubic contents of each field (0.0125664) multiplied
by the number of fields examined. The formula for this calcula-
tion is:
Total number of leucocytes counted X Degree of dilution -=-
Cubic contents of visual field X Number of fields examined =
Total number of leucocytes per c.mm.
For example, in a i : 200 blood dilution a total of 30 leucocytes
is noted in fifty fields, each having a cubic contents of 0.0125664,
since they individually include 8 parallel columns of the ruled disc :
(30 X 200) -f- (0.0125664 X 50) = 9550 leucocytes per c.mm.
(b) If the special leucocytometer is used for counting the leu-
cocytes, a 0.3 per cent, aqueous solution of glacial acetic acid
must be employed as a diluent, in order to render invisible the
erythrocytes and at the same time to make the leucocytes appear
1 "Twentieth Century Practice of Medicine," New York, 1896, vol. vii, p. 271.
COUNTING THE ERYTHROCYTES AND LEUCOCYTES. 67
more conspicuously in the field. A i : 10 dilution is made by
drawing the blood up the capillary tube of the instrument until
the mark i is reached, and by then adding the diluent until the
mixture reaches the mark n. The leucocytes are then counted
in an area of the counting chamber equal to 8co of the small
squares (preferably by examining 400 squares in two separate
drops), and the calculation made according to the method pre-
viously described. For instance, if in a given case 130 leucocytes
were counted in 800 squares, the estimate would be made as
follows :
130 X 4000 X 10 -4- 800 = 6500 leucocytes per c.mm.
The chief objection to this method of leucocyte counting lies
in the difficulty in distinguishing the cells, owing to the unavoid-
FIG. 21. — EXPELLING CONTENTS OF ERYTHROCYTOMETER.
By twisting the rubber suction tube into a tight spiral rope the fluid in the bore of the pipette may
be forcibly expelled in a tine jet.
able presence in the field of masses of granular debris resulting
from the action of the acetic acid solution upon the erythrocytes.
For this reason, if for no other, it seems advisable to dispense
with the leucocytometer, and to make the count of both red and
white corpuscles with the erythrocytometer in the same drop.
Cleaning the Pipette, — As soon as the count has been finished,
the pipette should be carefully cleaned and dried. Having first
expelled what remains of the blood dilution, the instrument is
rinsed out, first with distilled water and then with a mixture of
equal parts of absolute alcohol and ether, the latter being used to
remove all traces of the dye, in case either Toisson's or Sherring-
ton's solution has been employed as a diluent, as well as to dry
the interior of the tube. The pipette, while it may be filled with
a fluid by suction, should not be emptied by blowing through it,
for if this is done, a certain amount of moisture from the breath
unavoidably becomes deposited in its lumen. Its contents may be
68 EXAMINATION OF THE BLOOD BY CLINICAL METHODS.
expelled in the form of a fine jet, simply by twisting the rubber suc-
tion tube into a tight spiral rope, as shown in the illustration (Fig.
21). When the interior of the instrument is perfectly clean, it
is dried by forcing through it a current of air by means of a
rubber atomizer bulb, or an ordinary bicycle-pump, until the glass
bead no longer clings to the wall of the bulbous expansion, as it
will as long as the slightest trace of moisture remains.1
A new form of hemocytometer has been
DURHAM'S HEM- recently designed by Durham, who has em-
OCYTOMETER. bodied in this device the principles of the older
instruments, together with the substitution of a
self-measuring pipette designed to overcome the sources of error
which may occur in making blood dilutions with a suction pipette.
Durham's instrument, which appears to be a valuable improve-
ment over other forms of blood-counting apparatus, consists of
the following parts:
i. Several capillary pipettes of the Oliver type, each mounted
FIG. 22. — CROSS-SECTION OF DURHAM'S BLOOD PIPETTE.
T, Glass tube; N, rubber nipple; p, lateral perforation in nipple; c, cork in which a capillary pipette
is fitted.
in a glass tube, provided with a rubber nipple having a lateral
perforation. The capacity of the pipettes is 5 and 10 c.mm.
2. A number of mixing vessels, each consisting of a small glass
test-tube, graduated from i and for 0.5 c.c. of fluid. The tubes
holding i c.c. measure 2f x yV m-> an(^ those holding 0.5 c.c.,
2f X f in. One or more glass beads are shaken about in the
tube to mix the blood and the diluting fluid.
3. A number of graduated pipettes for measuring the diluting
fluid, of i and 0.5 c.c. capacity, marked at 995 and 990 c.mm.
and at 495 and 490 c.mm., respectively. Used with the appro-
priate capillary pipette, dilutions of i : 200, i : 100, and i : 50
may be obtained.
4. A counting chamber of the Thoma-Zeiss pattern.
Method o] Use. — Having placed in one of the mixing vessels
some of the diluting fluid, the quantity of which is measured with
1 A o.i per cent, solution of pepsin in one per cent, hydrochloric acid is useful
for removing any bits of clotted blood which may adhere to the caliber of the
instrument.
COUNTING THE ERYTHROCYTES AND LEUCOCYTES. 69
one of the graduated pipettes according to the dilution desired, the
capillary pipette is filled with blood by touching it lightly to the
blood drop as it flows from the puncture. All traces of blood are
then removed from the outside of the pipette, the contents of which
are now expelled into the fluid contained in the mixing vessel.
This is accomplished by inserting the pipette into the latter, keep-
ing its point about half an inch above the level of the diluting fluid,
and by then rotating it between the thumb and forefinger so that
the lateral perforation is brought under the ball of the thumb;
the nipple is now squeezed gently, and, continuing the pressure,
the pipette is rotated back so that the perforation is free again.
In this manner the blood is forced from the pipette but is not
sucked back. The blood remaining in the pipette is now com-
pletely washed away by thrusting its point into the diluting fluid,
this at once filling its caliber, by capillarity. Withdrawing the
pipette from the fluid, the rotation and pressure of the nipple are
repeated, the capillary tube being thus rinsed out several times in
order to remove completely all the blood clinging to its interior.
The blood and the diluting fluid are now mixed by briskly ro-
tating the mixing vessel between the opposed hands, so that the
tumbling about of the glass beads in the vessel may thoroughly
distribute the cellular elements through the fluid. When the
mixing is completed, a drop of the fluid is transferred to the
counting chamber, and the corpuscles counted under the micro-
scope in the usual manner.
Durham's device makes it possible for the unskilled to measure
accurately the desired volumes of blood and diluting fluid, and
largely eliminates the errors which are likely to occur in sucking
up the blood and the diluent with either the Thoma-Zeiss or
the Gowers hemocytometer. The ease and thoroughness with
which the capillary blood pipette may be cleaned are also ad-
vantages, this being done by passing through its caliber a piece of
darning-cotton, dry or soaked in ether, by means of a needle.
Comparative observations made with the Thoma-Zeiss hemocy-
tometer have shown that the readings of the two instruments are
practically identical.
In this form of hemocytometer the blood and
GOWERS' HEM- the diluting fluid are each measured in a separate
OCYTOMETER. pipette, and deposited in a small receptacle, in
which they are mixed, a small portion of the mix-
ture then being placed in a counting chamber and the number of
corpuscles counted under the microscope. Gowers prefers to use
as a diluent an aqueous solution of sodium sulphate having a
specific gravity of 1.025, DUt Toisson's solution, or any of the
70 EXAMINATION OF THE BLOOD BY CLINICAL METHODS.
other diluting fluids previously mentioned, will prove satisfactory.
The instrument comprises five working parts, as follows :
1. A pipette, graduated to hold a volume of 995 c.mm., for
measuring the diluting fluid.
2. A capillary pipette, graduated to hold a volume of 5 c.mm.,
for measuring the blood.
3. A small glass mixing jar, in which the dilution of the blood
is made.
4. A glass stirring rod, for mixing the blood and the diluent
in the jar.
5. A counting chamber, consisting of a glass slide mounted on
a brass plate, and containing a cell ^ mm. in depth, the floor of
the cell being divided by cross-rulings into squares the sides of
which measure y^ mm. When a cover-glass is fitted over this
cell, being retained in position by means of a pair of clips attached
to either end of the brass plate, the cubic contents of the space
overlying each square measure ^-^ c.mm.
Method of Use. — In using the instrument 995 c.mm. of the
diluting solution are first measured by means of the larger pip-
ette and blown out into the mixing jar. The latter must be
perfectly clean and absolutely free from moisture before it is
used, in order to avoid errors in the count. Now, using the
capillary blood pipette, 5 c.mm. of blood are secured from the
puncture, and immediately added to the diluent contained in the
jar. The blood and the diluent are then thoroughly mixed, by
rapidly stirring the solution with the glass rod. The dilution thus
made is in the proportion of i : 200 of blood to diluent. As
soon as the mixture is completed, a small drop of the solution is
transferred to the center of the cell in the middle of the counting
chamber, the small end of the glass rod being used for this pur-
pose, after which the cover-glass is gently placed in position, and
the clips adjusted so as to hold it in place. The counting cham-
ber may then be placed upon the stage of the microscope, and
the corpuscles overlying the ruled portion of the cell brought
into focus with a low-power objective.
It is necessary to use a small drop of the diluted blood, and
to place it exactly in the center of the block of ruled squares,
otherwise the fluid may flow toward the walls of the cell, alter-
ing its volume and making it necessary to reject the specimen
and to prepare a new drop, after thoroughly cleaning and drying
the cell, and again stirring the blood solution.
The corpuscles having settled to the bottom of the cell, their
number in a given number of squares is noted, and the final cal-
culation made according to the formula:
COUNTING THE ERYTHROCYTES AND LEUCOCYTES. 7 1
Number of Number of ~, . ,
corpuscles X 200 X 5oo + squares = To'al ™mb*r °/ """
counted counted puscles per c.mm.
In counting the erythrocytes at least 20 squares of the count-
ing chamber should be inspected, in different drops, a procedure
involving the enumeration of about 1000 cells, in normal blood.
Except in high leucocytoses, the number of leucocytes is usually
estimated indirectly, by determining their ratio to the erythro-
cytes, and basing their actual number upon this figure. This
plan (the necessity for which is a serious drawback to the use of
this instrument) is followed so as to dispense with the tedious
filling and refilling of the counting chamber, in an endeavor to
find a sufficient number of leucocytes to serve as a basis for the
calculation, should the latter be direct. Ordinarily, not more
than two of these cells are contained in an area including 20
squares. Gowers * claims that the limit of error with his instru-
ment is less than 3 per cent.
After use, the different parts of the instrument are to be thor-
oughly cleaned and dried, in the manner already described.
For making rapid numerical estimates of the
OLIVER'S HEM- erythrocytes Oliver has designed an instrument
OCYTOMETER. based upon the following principles: When a
candle-flame is viewed through a flat glass test-
tube filled with water, a bright transverse line is visible, com-
posed of densely packed, minute images of the flame produced
by the longitudinal corrugations of the glass. If lor the water a
mixture of blood and Hayem's solution2 is substituted, a more or
less opaque fluid results, so that, in low dilutions, this illuminated
line is invisible, reappearing only when a definite degree of higher
dilution is reached, by the gradual addition of the diluent; when
this point has been obtained, the line is again detected as a bright,
delicate streak horizontally crossing the tube. Experiments having
proved that the development of such a line, by gradual dilution
of the blood with Hayem's fluid, is an accurate gage of the per-
centage of erythrocytes in the specimen tested, it remained for
Oliver to devise a hemocytometer consisting of the following
essential parts:
1. A capillary pipette for measuring the blood.
2. A glass dropper, one end of which is capped by a rubber
nipple, the other by a short rubber nozle which fits over the blunt
end of the pipette.
3. A standard graduated tube, in which the blood and the
diluent are mixed.
1 Lancet, 1877, vol. ii, p. 797. 2 For formula see page 56.
EXAMINATION OF THE BLOOD BY CLINICAL METHODS.
The four walls of the tube are flattened so that it is rectangular
on cross-section, one wall being provided with an etched scale
indicating units from 10 to 120. Each of these divisions is equiv-
alent to 50,000 erythrocytes, the point marked ico degrees repre-
senting the arbitrary normal number, 5,000,000.
Small-sized wax candles, known as "Christmas candles," are
to be preferred for the illumination, as they give the small flame
requisite to obtain a sharply denned line, but the flame from a
gas-jet turned low may also be used with satisfaction.
Method o] Use. — In making the observation the pipette, which
has been previously cleaned and dried, is filled with blood in the
usual manner, and any excess of blood on the outside carefully
removed. The rubber
nozle of the dropper,
filled with Hayem's
fluid, is then slipped
over the blunt end of
the pipette, and the
blood washed out into
the graduated tube by
squeezing the nipple.
This preliminary dilu-
tion is continued until
the column in the tube
rises to within 10 or 15
degrees below the fig-
ure for the hemoglobin
percentage of the same
blood, this having been
previously determined.
For instance, if the
hemoglobin percentage was found to be 70, the diluting fluid is added
in large quantities until the mixture in the tube reaches to about the
mark 60, after which it is added more cautiously and in smaller
quantities at a time, careful search for the bright line being made
after each addition. In cases of chlorosis and of pernicious anemia,
in which parallelism between the hemoglobin and corpuscular loss
is lacking, it is, of course, impossible to depend upon the hemo-
globin percentage as an index to the amount of diluent required,
so that in instances of this kind the line must be developed more
slowly, by making a. smaller primary dilution and by adding the
requisite volume of liquid more deliberately.
After the first dropperful of diluent has been added to the con-
tents of the tube, the latter are mixed by inverting the tube a
FIG. 23. — METHOD or USING OLIVER'S HEMOCYTOMETER.
Showing manner in which the blood is washed from the capil-
lary pipette into the tube containing Hayem's solution.
COUNTING THE ERYTHROCYTES AND LEUCOCYTES. 73
number of times with the thumb held over its mouth, the precau-
tion being taken also to remove the thumb by drawing it over the
mouth of the tube, in order to restore to its contents any liquid
which may have adhered to the skin. The tube should be inverted
thus after each addition of the diluting fluid.
The steps of the observation succeeding the measuring of the
blood and its primary dilution are to be made in a dark room,
free from cross lights, the candle being placed about ten feet dis-
tant from the observer. In order to shut out the diffused light
of the candle the tube should be held vertically in the concavity
formed between the thumb and forefinger, being kept close to
the eye while searching for the bright line. Oliver states that the
earliest indications of this line are obtained by turning the tube
on its axis, when it will become visible at the sides.
Apart from the "personal equation," the serious drawback
to this test is its failure to indicate the number of leucocytes,
this fact alone being sufficient to curtail its use for routine clinical
work. It is also apparent that in cases of marked leucocytosis
and of leukemia the optical principles of the test must necessarily
fail because of the enormous number of leucocytes in the blood.
Furthermore, the instrument gives false results with blood in
which conspicuous deformities of the erythrocytes exist, for the
reason that the standard tube is corrected for normally shaped
corpuscles, so that blood composed largely of microcytes, megalo-
cytes, or poikilocytes will give different readings from blood in
which the cells are of unaltered biconcave shape and of normal
size. The discrepancies between the Oliver and the Thoma-
Zeiss instruments have been carefully worked out by Emerson l
and by Baumgarten.2
This method, devised by Strong and Selig-
DRY FILM mann,3 aims to eliminate errors due to variations
METHOD. in the depth of the Thoma-Zeiss counting chamber,
and at the same time to furnish permanent speci-
mens which may be examined at any subsequent time. It is
practically a simplification of the method suggested by Einhorn
and Laporte.4 The principle involved consists in diluting a
measured volume of fresh blood with a measured volume of a
diluent with which a suitable differential stain is combined, a
definite quantity of the mixture then being spread upon a glass
slide, allowed to evaporate, mounted in the ordinary manner, and
examined microscopically.
1 Johns Hopkins Hosp. Bull., 1903, vol. xiv, p. 9.
1 Ibid., 1902, vol. xiii, "p. 176.
8 Brit. Med. Jour., 1903, vol. ii, p. 74. 4Med. News, 1902, vol. Ixxx, p. 741.
74 EXAMINATION OF THE BLOOD BY CLINICAL METHODS.
Two different diluting fluids are used, one for the leucocytes
and one for the erythrocytes. Tabloids (made by Parke, Davis
and Company) containing 0.25 gm. of sodium chlorid combined
with 0.004 gm. of methyl- violet (for leucocytes) and with 0.0025
gm. of eosin (for erythrocytes) are employed for making the dil-
uents, instead of stock solutions, which become unstable after a
short time. To prepare the diluents one of each of these tabloids
is dissolved in 30 c.c. of distilled water to which 0.5 c.c. of
formalin is added, the mixture then being filtered.
Counting the Leucocytes. — Five c.mm. of blood are sucked up
into a graduated pipette, and then blown out into a small vessel
containing 495 c.mm. of the methyl-violet diluent. After stirring,
5 c.mm. of this i : 100 mixture are drawn up in a pipette and
deposited upon the surface of a glass slide so as to form a film
about 10 or 12 mm. in diameter. The film thus made is allowed
to evaporate and then mounted with balsam and a cover-glass.
The count is made by going over the entire area of the film with
a £-inch dry objective, and noting the number of violet-stained
cells. In order to facilitate this procedure, either a square or an
oblong ocular diaphragm, made of black paper or of metal,
should be used, together with a mechanical stage. The blood dilu-
tion being i : 100 and the volume of this mixture spread upon
the slide being 5 c.mm., the number of leucocytes per c.mm.
of undiluted blood is therefore 100-^-5, or 20 times the total
number counted in the entire film. For example, having noted
400 leucocytes in the latter, the simple formula 400 X 20 = 8000
leucocytes per c.mm., gives the final calculation. An error of 50
cells in the count alters the final result by only 1000 cells — a trivial
matter.
Counting the Erythrocytes. — In this instance a i : 20,000 dilu-
tion is made, by mixing 5 c.mm. of the above i : 100 blood and
methyl-violet diluent with 995 c.mm. of the eosin diluent. After
allowing the erythrocytes to stain for a few minutes, 5 c.mm. of
this mixture are spread over a slide, as described above, similarly
mounted, and examined microscopically, the erythrocytes being
recognized by their rose-red color. The number of erythrocytes
per c.mm. of undiluted blood is 4000 times the number counted
in the dry eosined film, since 5 c.mm. of a i : 20,000 dilution of
the blood has been used ; thus, 20,000 H- 5 = 4000. For instance,
having counted 1200 erythrocytes in the 5 c.mm. film, the formula
1 200 X 4000 = 4,800,000 erythrocytes per c.mm., gives the final
result.
The originators of the dry film method of blood counting
insist that its results are more accurate than are possible with a
MICROSCOPICAL EXAMINATION OF STAINED SPECIMEN. 75
hemocytometer. In three Thoma-Zeiss instruments, three years
old, they found figures consistently ten per cent, higher than those
obtained by new instruments of the same design and make, an
error which could be explained by an increase of o.oi mm. in
the depth of the counting chamber. Counts made by the dry
method averaged i.i per cent, lower than those in which the hemo-
cytometer was used. Several sources of error, however, must be
guarded against. For example, in making the dilutions, unless
every trace of the measured 5 c.mm. of whole blood is blown
from the pipette into the diluting fluid, the dilution will be too
high ; and if, in making the film, the diluted blood is blown out
too forcibly, the film will be scattered and ragged and stippled with
air-bubbles. The erythrocytes may stain violet instead of rose
should the diluting solution not be perfectly fresh. The leuco-
cytes, which may stain violet, usually take the color of eosin, with
the eosin dilution for erythrocytes. Thus, the former are un-
consciously counted with the latter, but under ordinary circum-
stances this is an unimportant error, since the number of leuco-
cytes is comparatively too small appreciably to affect the erythro-
cyte count. In leukemia, however, the error may be suffi-
ciently great to need correction. In this disease, therefore, all
the blood cells, red and white, should be counted, multiplied by
4000, and from this total is to be subtracted the total leuco-
cyte estimate previously determined, the result being obviously
the total number of erythrocytes per c.mm. Unfortunately,
the specimens prepared by Strong and Seligmann's technic are
marred by deposits of salt crystals and by masses of amorphous
eosin, both at the edges of the film and scattered throughout it.
This defect, if it does not render an accurate count impossible,
may at least make it difficult and tedious. In a passably good
specimen the counts of erythrocytes and leucocytes together should
not take longer than half an hour.
IV. MICROSCOPICAL EXAMINATION OF THE
STAINED SPECIMEN.
The microscopical study of the dried and
OBJECTS OF stained blood film, which should supplement the
STAINING. methods of investigation just described, is for
many reasons the most important step in the
clinical examination, of the blood. By means of this method
of "color analysis" it is possible to differentiate easily and with
absolute certainty the various forms of leucocytes, and, by differ-
ential counting, to calculate the relative percentages of each
76 EXAMINATION OF THE BLOOD BY CLINICAL METHODS.
variety of these cells; to distinguish the several structural de-
generative changes affecting chiefly the erythrocytes, and to a
less extent the leucocytes; and to recognize and classify accord-
ing to their histological character the nucleated forms of the eryth-
rocytes. To sum up, in the words of Ehrlich,1 to whom we
owe this rational means of investigation :" Everything that is
to be seen in the fresh specimens — apart from the quite unim-
portant rouleaux formation and ameboid movements — can be
seen equally well, and indeed much better, in a stained prepara-
tion; and there are several important details which are made
visible only in the latter, and never in wet preparations."
According to the classification introduced
THE ANILIN many years ago by Ehrlich,2 the anilin dyes
DYES. are divided into three different groups: acid,
basic, and neutral. Acid dyes, or compounds in
which the coloring principle acts or exists as an acid, possess a
special affinity for cell protoplasm, and, therefore, are generally
employed as plasma stains; in hematological work acid fuchsin,
eosin, and orange G are the principal dyes used for this purpose.
Basic dyes, or compounds in which the coloring principle exists
chemically as a base in combination with a colorless acid, are
especially useful as nuclear stains, since they exhibit a special
affinity for chromatin structures; members of this group of
dyes commonly used in blood staining are methylene-blue, tol-
uidin-bluej methyl-green, methyl-violet, thionin, and hema-
toxylin. Neutral dyes are the coloring principles which result
from the mixture of solutions of an acid and a basic dye; they
are used for the demonstration of the so-called neutrophile
granules of the leucocytes, for which they show a selective
affinity.
Cover-glass Films. — For the preparation of
PREPARING the dried blood films it is advisable to have at
THE FILMS, hand at least half a dozen perfectly clean, polished
cover-glasses, which may be arranged in pairs
on a sheet of white paper within convenient reach of the examiner.
After having wiped away the blood which immediately follows the
puncture, a minute portion of the next drop is collected, by lightly
touching the center of one of the cover-glasses to its summit, care
being taken to avoid bringing the polished surface of the glass in
contact with the skin of the patient's finger. The charged cover-
glass is then at once dropped, blood side downward, upon the
1 Ehrlich and Lazarus, "Die Anaemic," Vienna, 1900 (Nothnagel's "Spec.
Path. u. Therap.," vol. viii, No. 2).
2 Zeitschr. f. klin. Med., 1880, vol. i, p. 555.
MICROSCOPICAL EXAMINATION OF STAINED SPECIMEN.
77
FIG. 24. — SUPERIMPOSING THE CHARGED COVER-
GLASS.
surface of the second glass (Fig. 24), with the result that the
blood quickly spreads out in a thin film between the two, and ex-
tends to their peripheries, provided that the proper quantity of
blood has been used (Fig. 25). As soon as the film has reached
the margins of both cover-glasses, they are rapidly drawn apart
in a horizontal direction, so that the surface of each, when thus
separated, is covered with a thin layer of blood (Fig. 26), which
should be rapidly dried, either by blowing briskly upon its sur-
face or by holding the glass for
a few seconds high over the
flame of an alcohol lamp. If
care is taken to use but a very
small drop of blood, to avoid
pressure in opposing the sur-
faces of the two cover-glasses,
and to separate them in their
true horizontal planes, the
films will consist of a single
layer of corpuscles, most of
which will be sufficiently isolated to allow the study of their
individual morphology and other characteristics. The beginner
should persistently practise the technic of film-making until he
is able to obtain a satisfactory percentage of good specimens from
every batch of spreads. Thick, uneven spreads, in which the
corpuscles are heaped up and glued together in dense masses,
are of no value for histologi-
cal study of the cells, al-
though they are often useful
when searching for parasites
in blood containing very
few organisms. In such
instances Ross1 advises
smearing the blood thickly
on the slide, and, after it
has dried, washing out the
hemoglobin with water.
The film thus dehemoglobinized, unfixed, and still wet, is then
stained with aqueous solutions of eosin and methylene-blue, washed
with water, and mounted. The parasites stain the color of the basic
dye, but the erythrocytes, since they contain no hemoglobin, are
practically colorless. This method, while, of course, unsuitable for
differential counting, may be of value in certain cases of malarial
fever, filariasis, and trypanosomiasis.
1 Thompson Yates and Johnston, Lab. Rep., 1903, vol. v, p. 117.
FIG. 25. — DRAWING APART THE COVER-GLASSES.
EXAMINATION OF THE BLOOD BY CLINICAL METHODS.
The films, after having been dried, may be placed in a pill box
and labeled, to await fixation and staining at the examiner's con-
venience. Dried specimens will keep for an indefinite period if
not exposed to dust or to moisture. Unfixed cover-glass specimens
of leukemic blood have
been "triple-stained" by
the writer, with perfect
results, more than three
years after they were
spread. With the Rom-
anowsky method, how-
ever, the fresher the
specimen, the sharper the
stained film.
Many histologists recommend the use of special forceps for
holding the cover-glasses while making the spreads, claiming thus
to avoid the injurious effects upon the blood corpuscles which may
be caused by the moisture of the fingers if they come in con-
FIG. 26. — THE COVER-GLASSES AFTER SEPARATION.
FIG. 27.— SPREADING A FILM WITH Two GLASS SLIDES.
tact with the films. The careful worker need have no fear on this
score, for if the covers are held in the manner shown in the illus-
trations, this accident will not occur. A pair of light thumb
forceps is useful for picking up the cover-glasses •
from a flat surface, but the employment of spe-
cial spreading forceps is quite unnecessary.
Glass Slide Films. — Some prefer to make the
spread upon an ordinary glass slide, but this
method rarely yields as thin and even a film
as the one just described, though it is easier
to learn. A small-sized drop of blood is dis-
tributed along the edge of a glass slide,1 which is then held
at an angle of 45 degrees against the surface of another slide,
1 Waldstein's smearing slip (Med. Rec., 1896, vol. 1, p. 385), made of crown
glass, with its " spreading edge " ground smooth and round, answers much better
than an ordinarv slide.
FIG. 28. — SPREADING A
FILM WITH CIGAR-
ETTE PAPER.
MICROSCOPICAL EXAMINATION OF STAINED SPECIMEN.
79
over which it is rapidly drawn, with moderate pressure, thus
depositing a thin film of blood upon the surface of the latter
(Fig. 27). Instead of a glass slide, a leaf of cigarette paper
or a slip of thin tissue-paper, trimmed to a narrower width
than that of the slide, may be used as a spreader (Fig. 28). A
fair spread may also be made by depositing a drop of blood upon
a slide, near one end, and then distributing it by means of a needle
or a glass rod, the shaft of which is applied to the drop with even
pressure. The film thus made is
immediately dried in air and treated
as a cover-glass spread.
As a step pre-
FIXATION liminary to stain-
METHODS. ing, the albuminoid
principles of the
blood must be fixed, by exposing
the dried film either to a high de-
gree of dry heat or to various chemi-
cal hardening agents, the choice be-
tween these two methods being de-
termined by the character of the
staining solution to be used subse-
quently.
Heat Fixation. — This method
may be employed with any of the
stains described in the following
pages, except with Wright's solu-
tion; it must be used with Ehrlich's triple stain, in preference to
fixation by chemicals, in order to obtain crisp, clean-cut pictures.,
The author is accustomed to use an oven, such as is illustrated
above (Fig. 29), consisting of a copper box with a heavy bottom
and hinged cover, mounted on an ordinary iron burette stand, by
means of a thumb-screw. A small "baby" Bunsen lamp placed
underneath the box furnishes the requisite degree of heat, the
temperature being indicated by a thermometer mounted at one end
and resting upon the floor of the oven. By sliding the latter up and
down the vertical rod to which it is attached the desired degree of
temperature may be obtained at will. The blood films are inclosed
in the copper box, and the latter fixed at a point eight inches above
the summit of the burner, after which the gas is lighted and allowed
to burn until the temperature, as indicated by the thermometer, has
gradually crept up to 160° C. As soon as this degree of heat has
been reached the gas is extinguished, the cover of the oven thrown
back, and, after the temperature has fallen to 30° C., the films
FIG, 29. — OVEN FOR FIXING BLOOD FILMS.
80 EXAMINATION OF THE BLOOD BY CLINICAL METHODS.
removed, being now thoroughly fixed and ready for staining.
Fifteen minutes suffice for the whole operation, from the time the
gas is lighted until the films have been removed and cooled, for
staining.
A less satisfactory method of heat fixation is by the use of a
copper plate upon which the films are kept at a temperature of
from 100° to 110° C. for from one-half to one hour. The ap-
paratus used for this purpose consists of a rectangular plate of
sheet copper, about fifteen inches long by four inches wide by
one-sixth of an inch thick. An alcohol or a Bunsen lamp burns
under one end of the plate, which is elevated about six inches
above the flame by four metal legs. After having heated the
plate for ten or fifteen minutes, until a relatively constant tem-
perature becomes established, water is dropped upon its surface,
beginning with the end farthest from the flame, until a point is
reached at which the water boils. This part of the plate is con-
sidered to have a temperature of 100° C., and at this point the
blood films are placed, " spread" side downward, and heated for
the required time. No one with much blood staining to do will
choose this method of prolonged heating at a relatively low, ap-
proximate temperature in preference to brief heating at a high,
definite temperature in an oven. The use of the latter, aside
from its convenience as a time-saver, insures constant and cer-
tain results, for overheating and underheating of the blood film may
be avoided, since the degree of heat is exactly indicated and easily
controllable. In triple-stained specimens the blood cells are much
more brilliantly colored and sharply differentiated when the films
are fixed at a temperature of 160° C. than at a lower degree.
Should nothing but a Bunsen or an alcohol lamp be available,
the cover-glass film, held with a pair of forceps, may be fixed by
passing it rapidly through the flame thirty or forty times and then
holding it twelve or fifteen inches above the flame for a minute
or so. This makeshift method, which is often sufficient for a hur-
ried clinical examination, usually gives fair, and sometimes very
good, results, but the fixation is generally uneven, and the speci-
men is frequently scorched in some places and underfixed in
others.
Chemical Fixation. — Immersion of the dried films in ether, in
absolute alcohol, or in a mixture of equal parts of the two (Niki-
foroff's method) gives satisfactory results with specimens stained
by any of the single basic dyes, or with the simpler double stains,
such as eosin and methylene-blue or hematoxylin. The time of
fixation varies from five to fifteen minutes with any of these agents,
the specimen then being dried without using heat and stained
MICROSCOPICAL EXAMINATION OF STAINED SPECIMEN. 8 1
without previously washing. If time is an object, the specimens
may be boiled for one minute in a test-tube containing absolute
alcohol, as advised by Ehrlich.1 Some workers employ one
minute's fixation by a one per cent, alcoholic solution of forma-
lin (Benario's method), while others prefer to expose the films to
the vapors of this chemical for the same length of time. Five
to ten minutes' immersion in a concentrated aqueous solution of
mercuric chlorid is one of the older, but useful, methods of fixation.
Solley 2 has recently suggested that the film be flooded with a two per
cent, aqueous solution of chromic acid, which is washed off after
exactly thirty seconds, the specimen being then stained while still
wet ; he recommends this procedure as a substitute for heat in fixing
specimens for triple staining, but the method, while fairly good,
cannot be regarded as entirely satisfactory. In the author's hands
both Merck's methyl alcohol (five minutes) a'nd a two per cent,
aqueous solution of osmic acid (half a minute) have been found to
be fair substitutes for heat fixation.
In hematological as in other histological work
METHODS OF the choice of a staining method is determined by
STAINING the character of the investigation to be undertaken.
For general clinical purposes it is advantageous
habitually to employ some routine method by means of which
the greatest possible number of elements may be demonstrated
in a single blood film, this procedure being known as panoptic
staining. Thus, by using a solution containing several of the
anilin dyes, the stroma of the erythrocytes, the cell granules, the
cell nuclei, and the various blood parasites may be simultaneously
stained each in a characteristic manner, owing to the selective
affinity displayed by the different coloring principles of the mix-
ture toward these several histological elements. The most useful
solutions which have been devised for this purpose are Wright's
alkaline eosinate of methylene-blue 3 and Ehrlich's triacid mixture.4
Practically all the information that it is possible to derive from
the study of the stained dry blood film may be obtained with the
aid of these two solutions.
Simple combinations of an acid and a basic dye, such as eosin
and methylene-blue, eosin and hematoxylin, and orange and hema-
toxylin, are used by many investigators, chiefly for the purpose
of staining the cell stroma and the nuclear structures; but, as a
general rule, such mixtures are not adapted for clinical work,
1 Loc. cit.
2 Med. and Surg. Reports of the Presbyterian Hospital, New York, 1900, vol.
iv, p. 169.
3 Jour. Med. Research, 1902, vol. vii, p. 138. 4 Loc. cit.
6
82 EXAMINATION OF THE BLOOD BY CLINICAL METHODS.
since with none of them is it possible to differentiate the neutro-
phile granules. Solutions of a single dye are but seldom used
except for the demonstration of special elements, such, for in-
stance, as the staining of the malarial parasite by thionin, the
mast cells by dahlia, and certain bacteria by the basic dyes, such
as methylene-blue and gentian-violet. Since by this method of
staining only the particular elements toward which the dye reacts
are differentiated, the employment of single stains is inadequate
for the study of the general morphology of the blood cells.
The following formulas will be found sufficient for all purposes
of clinical investigation:
WRIGHT'S STAIN. — This excellent stain is an improvement on
Leishman's modification1 of the late Louis Jenner's solution,2 and
is so prepared that its basic constituent (methylene-blue) acquires
the polychromatic properties of the Romano wsky stain,3 so valuable
in differentiating chromatin and cytoplasm. Wright's stain gives
sharp pictures of cell protoplasm, chromatin, and nuclei, and is
especially useful in studying the lymphocytes, the mast cells, the
blood plaques, and the finer structure of the malarial parasite.
It is prepared according to the following somewhat complicated
formula :
1. To a 0.5 per cent, aqueous solution of sodium bicarbonate
contained in an Erlenmeyer flask add one per cent, of Griibler's
methylene-blue (''medicinal"), and steam the mixture in a
sterilizer for one hour, counting from the time "steam is up."*
This step not only serves to develop the polychromatic property of
the alkaline methylene-blue, but increases its power as a nuclear
and granular stain.
2. Cool the bicarbonized methylene-blue solution after steam-
ing, and then, without filtering, add to it, meanwhile stirring with a
glass rod, sufficient of a i : 1000 aqueous solution of Griibler's
yellowish eosin ("water soluble") to change the color of the
solution from blue to purple, with a surface scum of a yellowish,
metallic luster. About 500 c.c. of the methylene-blue solution to
100 c.c. of the eosin solution are required to produce this change.
1 Brit. Med. Jour., 1901, vol. ii, p. 757. 2 Lancet, 1899, vol. i, p. 370.
8 Centralbl. f. Bakt., 1899, vol. xxv, p. 764.
4 When a steam sterilizer is not available, polychrome blue may be developed
by heating the methylene-blue solution with freshly precipitated silver oxid. Dan-
iels ("Studies in Laboratory Work," London, 1903, p. 63) directs that a solution
of sodium hydrate be added to one of silver nitrate until no more precipitate forms,
the precipitate, silver oxid, being then washed until the washings are neutral to
litmus-paper. This neutral precipitate is added to the methylene-blue solution
and allowed to stand for twenty-four hours, whan the supernatant fluid is decanted
off from the sediment and filtered before using. Polychrome blue thus prepared
is treated according to the above directions for making Wright's solution.
MICROSCOPICAL EXAMINATION OF STAINED SPECIMEN. 83
3. Collect, by filtration, this scum (which consists of a granular
black precipitate), and dry, without washing. When dry, make
of it a saturated solution in methyl alcohol. Three-tenths of a
gram of the dry precipitate saturates 100 c.c. of methyl alcohol.
4. Filter the alcoholic solution of the precipitate and add to the
filtrate 25 per cent, of methyl alcohol. For 80 c.c. of the filtrate, the
amount usually available, 20 c.c. of methyl alcohol are required.
This alcoholic solution is used for staining. It does not deteriorate
with age if kept in a well-corked bottle, and is sufficiently dilute
to prevent precipitation during staining, an accident which was
the chief drawback to Jenner's original stain.
Technic of Staining. — Owing to the methyl alcohol which it
contains, Wright's solution fixes and stains the blood film simul-
taneously, so that preliminary fixation may be omitted.
The unfixed film is stained for one minute, as much of the
solution being used as the cover-glass will hold without spilling.
Next, to the staining fluid upon the specimen are added, drop by
drop, eight or ten drops of distilled water — sufficient to develop
a reddish tint at the margins of the cover-glass and a semitrans-
lucency in the stain, with a metallic scum on the surface. The
stain, thus diluted, is allowed to act for two or three minutes, when
it is rinsed off with water, showing that the film has become
stained deep blue or purplish. The final step in the process is the
decolorization of the overstained specimen and the differentiation
of its histological elements. This is accomplished by washing
with water until the color of the film changes to yellowish or pink.
From one to three minutes' washing, depending upon the intensity
of the staining, is required to reach the desired tint. The specimen
is then dried between filter-paper (never by heat), and mounted
in balsam.
Wright's stain gives the following results : erythrocytes, orange
or pink; nuclei of the leucocytes, blue or dark lilac; neutrophile
granules, lilac; eosinophile granules, pink; fine basophile granules,
deep blue; and coarse, mast cell granules, deep royal purple.
The nuclei of the erythroblasts and bacteria stain various shades
of blue, and the blood plaques purplish, flecked with red.
The body of the malarial parasite stains blue, and its chromatin
varies from lilac to red to almost black.
Aside from its obvious value as a panoptic staining fluid, this
solution will often prove of great convenience for the reason that
it does not require special fixation of the blood film.
EHRLICH'S TRIACID STAIN. — This "triple stain," containing
one basic and two acid dyes (methyl-green, orange G, and acid
fuchsin), is peculiar in that a chemical combination is formed by
84 EXAMINATION OF THE BLOOD BY CLINICAL METHODS.
its acid and basic components, which may be regarded as a neutral
coloring principle, serving the purpose of selectively staining the
so-called neutrophile elements for which the primary components
of the mixture have no affinity. With this stain histological
structures having an affinity for the acid dyes are stained the color
of one of its acid constituents, basic structures the color of its
basic dye, and structures having an equal affinity for acid and
basic dyes the color of the neutral compound.
Saturated aqueous solutions of the three dyes are first pre-
pared, and allowed to stand for several days until they have be-
come thoroughly cleared. It is essential that the anilin dyes used
for making these "stock" solutions should be chemically pure, to
insure which the products of Grubler or of the Berlin Anilin Dye
Company should invariably be chosen. From these saturated
solutions the following mixture is made:
Acid fuchsin solution 6-7 c.c.
Orange G solution 13-14 c.c.
Distilled water 15 c.c.
Absolute alcohol 15 c.c.
Mix the above thoroughly and add, drop by drop, with con-
tinuous agitation, in the following order :
Methyl-green solution 12.5 c.c.
Absolute alcohol 10.0 c.c.
Glycerin 10.0 c.c.
The mixture should under no circumstance be filtered, but
allowed to stand for about twenty-four hours in order that a slight
precipitate may form. As soon as this occurs the stain is ready
for use, the necessary quantity being pipetted from the super-
natant fluid without disturbing the precipitate.
Technic of Staining. — The heat-fixed film, held preferably
with a pair of Stewart's staining forceps, is flooded with the stain,
which is washed off in running water after the lapse of from five
to eight minutes, the specimen then being dried by gentle heat
and mounted in xylol balsam or in cedar oil.
In the specimen thus prepared the stroma of the erythrocytes is
stained orange, the nuclei of the leucocytes greenish-blue, the neu-
trophile granules violet or lavender, and the eosinophile granules
copper red. The nuclei of the erythroblasts react with varying
degrees of intensity toward the basic component of the mixture,
those of the normoblasts staining deep purple or black, and those
of the megaloblasts pale green or greenish-blue. The basophile
granules remain unstained, appearing as dull white, coarse,
stippled areas in the cell protoplasm — "negative staining." In
order to stain these granules, as well as the basic protoplasm of
MICROSCOPICAL EXAMINATION OF STAINED SPECIMEN. 85
the lymphocytes, Hewes 1 suggests that the triple-stained film,
after having been washed, be subjected for from one-half second
to ten seconds to Loffler's 2 methylene-blue solution, after which it
is again washed, and mounted as above directed. This modifica-
tion is of undoubted value, chiefly because it usually enables one
to differentiate the larger forms of lymphocytes from the large
mononuclear leucocytes. Malarial and other parasites are also
distinctly stained by this method.
Unsatisfactory results with the triple stain, provided that the
latter is properly made, can almost always be attributed to faulty
fixation. As already remarked, heat is the only method of fixa-
tion which will insure faultless differentiation in the specimen
stained with this mixture. The perfect specimen is of a deep,
rich orange tint to the naked eye; if underheated, the film reacts
too strongly toward the acid fuchsin of the mixture, and, conse-
quently, is the color of this dye; if overheated, the plasma stain,
orange G, is but feebly displayed, so that the color of the film is
pale lemon yellow.3 As a stain for general clinical work Ehrlich's
is inferior to Wright's. Although a sharper neutrophile stain, it
reacts feebly toward basophile structures, and requires careful
and skilful heat fixation of the films.
PRINCE'S STAIN. — This mixture, which consists of an aqueous
solution of one basic and two acid dyes, is an excellent stain for
the differentiation of both nuclei and granules, and may be em-
ployed as a fair substitute for either of the two preceding solutions.
It should be made in this manner:
Saturated aqueous solution of toluidin blue 24 c.c.
Saturated aqueous solution of acid fuchsin i c.c.
Two per cent, aqueous solution of eosin 2 c.c.
These solutions are mixed in the order named, and shaken
briskly for several minutes, so as to secure complete precipitation
of the basic toluidin blue by the acid dyes. The solution, which
should not be filtered, is ready for use as soon as made. Only
the supernatant fluid should be employed, care being taken not
to disturb the sediment.
Technic of Staining. — If a newly made solution is used, the
films are stained for from one-half to one minute, after which they
are rinsed in water, dried in air, and mounted; but if the solution
has stood for several weeks, its basic constituent becomes less
1 Boston Med. and Surg. Jour., 1899, vol. cxli, p. 39.
'Saturated alcoholic solution of methylene-blue, 30 c.c.; i: 10,000 aqueous
solution of potassium hydrate, 100 c.c.
* A reliable triacid stain, made according to Ehrlich's formula, is sold by
Messrs. Shinn and Kirk, Philadelphia.
86 EXAMINATION OF THE BLOOD BY CLINICAL METHODS.
active, so that the specimen requires to be stained for from five to
ten minutes. Either chemical or heat fixation of the blood film
may be used with this stain, both methods giving equally sharp dif-
ferentiation. Prince's solution colors the erythrocytes rose-red, the
nuclei of the leucocytes and erythroblasts blue, the neutrophile
granules pink, the eosinophile granules maroon, and the fine and
coarse basophile granules blue. Blood parasites are also stained
the color of the basic dye.
DOUBLE STAINING WITH EOSIN AND METHYLENE-BLUE. —
Crisp, clear pictures of nuclear and stroma structures, of the ma-
larial parasites, and of the basophile granules may be obtained
by the use of these two dyes, and to investigations of this nature
should this staining method be restricted. It is impossible, for
example, accurately to distinguish a large lymphocyte from a
myelocyte in a specimen stained in this manner, so that for differ-
ential counting a more elaborate stain is essential. In films stained
by this method the stroma of the erythrocytes and the eosinophile
granules react toward the acid dye, staining the color of eosin;
while the nuclei of the leucocytes and erythrocytes, the basophile
granules, and all blood parasites show an affinity for the basic
dye, being colored various shades of blue. The protoplasm of
the polynuclear neutrophiles is either colorless or tinged a deli-
cate pink, the granules of these cells remaining unstained.
The author has always found the following simple formula de-
pendable :
Eosin (aqueous), to which sufficient water has been added
for solution 0.5 gm.
Absolute alcohol 0.5 c.c.
Saturated aqueous solution of methylene-blue 96.0 c.c.
Technic of Staining. — Films are fixed by immersion for ten
minutes in absolute alcohol or in equal parts of absolute alcohol
and ether. The cover-glass is flooded with the stain, gently
heated for one minute over a Bunsen flame, allowed to stain
without heat for two or three minutes longer, and then thoroughly
washed in running water, dried in air, and mounted.
Another method of staining with eosin and methylene-blue,
slower than the above, but as a rule giving sharper differentiation,
is to stain without heat for five minutes with a 0.5 per cent, solu-
tion of eosin in absolute alcohol to which an equal quantity of
water is added. Then, after having washed off the eosin solution
and dried the film in air, the specimen is counterstained for one
minute or less with a saturated aqueous solution of methylene-
blue, after which it is rinsed again in water, dried in air, and
mounted.
MICROSCOPICAL EXAMINATION OF STAINED SPECIMEN. 87
Among the many other methods of staining with eosin and
methylene-blue those suggested by Chenzinsky,1 by Plehn,2 by
Holmes,3 by Laporte,4 and by Hastings5 will be found the most
useful.
DOUBLE STAINING WITH EOSIN AND HEMATOXYLIN. — By the
employment of these two dyes the erythrocytes and the eosinophile
granules are stained the color of eosin, and all nuclei and parasites,
the color of hematoxylin. This method, which is decidedly in-
ferior to staining with the eosin and methylene-blue mixtures just
described, is useful for little else than the study of nuclear struc-
tures. It should not be used for differential counting, since in
films stained in this manner the neutrophile granules are invisible.
Ehrlich6 recommends this formula:
Eosin (cryst.) .- 0.5 gm.
Hematoxylin 2.0 gm.
Absolute alcohol 100.0 c.c.
Distilled water 100.0 c.c.
Glycerin 100.0 c.c.
Glacial acetic acid 10.0 c.c.
Alum in excess.
This mixture must "age" for several weeks before it can be used for staining.
Technic 0} Staining. — Specimens, fixed either chemically or
by heat, are stained for from one-half hour to two hours, thor-
oughly washed in water, dried, and mounted. In order to obtain
the best results, it is advisable to filter the solution before using,
and to wash the films very thoroughly after staining.
If time is an object, the following rapid method may be substi-
tuted for the above : The film is first stained for about five minutes
with a 0.5 per cent, solution of aqueous eosin in 50 per cent,
alcohol, washed, and dried in air; it is then counterstained for
about one-half minute with Delafield's hematoxylin,7 washed
a second time, and mounted in the usual manner.
STAINING WITH THIONIN. — Thionin (also known as the "violet
of Hoyer" and the "violet of Lauth") is an excellent stain for
1 Zeitschr. f. wiss. Mik., 1894, vol. xi, p. 260.
2 "Aetiologischeundklinische Malaria Studien," Berlin, 1890.
3 Jour. Amer. Med. Assoc., 1898, vol. xxx, p. 303.
* Med. Rec., 1903, vol. Ixiii, p. 1017.
s Johns Hopkins Hosp. Bull., 1904, vol. xv, p. 122. 8 Loc. cit.
7 This solution is made by first adding 4 gm. of hematoxylin crystals, dis-
solved in 25 c.c. of alcohol, to 400 c.c. of a saturated aqueous solution of ammonia-
alum. The mixture is left exposed to the sunlight and air in an uncorked bottle
for four days, at the end of which time it is filtered, and mixed with 100 c.c. each
of methyl alcohol and glycerin. This solution is allowed to stand until it becomes
dark colored, when it is filtered and placed in a tightly corked bottle to "age"
for at least two months before it can be used successfully for staining. Owing to
the complicated manner in which Delafield's hematoxylin must be prepared, it is
usually preferable to purchase it ready-made, from a dealer in microscopical sup-
plies, Griibler's make being entirely reliable.
88 EXAMINATION OF THE BLOOD BY CLINICAL METHODS.
blood parasites in general, being especially useful for the demon-
stration of the malarial parasites and the filarial embryos. Thionin
should not be used as a stain for films in which the general mor-
phology of the blood cells is to be studied, since the basophile
granules and the nuclei are the only histological elements for which
it displays any decided affinity. Structures reacting toward the
dye are stained violet of varying degrees of intensity. The follow-
ing recipe, suggested by Futcher and Lazear,1 will prove satis-
factory :
Thionin 0.3 gm.
Absolute alcohol 10.0 c.c.
One per cent, solution of carbolic acid q. s. ad 100.0 c.c.
Technic of Staining. — Films which have been fixed either
chemically or by heat are stained in the above solution for from
one to three minutes, being then washed in water, dried, and
mounted as usual. The best results are obtained by using the
French thionin, made by Cogit et Cie, of Paris.
STAINING WITH POLYCHROME METHYLENE-BLUE. — Goldhorn's
solution of methylene-blue and lithium carbonate affords a rapidly
acting stain, excellent for the demonstration of the finer structure
of the malarial parasite in every phase of its development. In
addition to giving crisp, clear-cut pictures of the chromatin of this
organism, the solution also brings out distinctly the granular
degeneration of the erythrocytes, the nuclear characteristics of
the erythroblasts and leucocytes, the basophile granules, and all
ordinary bacteria.
Technic of Staining. — The films are fixed for fifteen seconds
in methyl alcohol, rinsed in water, and then stained, unheated,
for from one to two minutes, after which they are thoroughly
washed in running water, dried without the use of heat, and
mounted in balsam. Preliminary staining for ten or fifteen sec-
onds with a o.i per cent, aqueous solution of eosin, followed by
washing, gives a picture in which the contrast between the plasma
and the basic elements of the cells is clearly differentiated. Poly-
chrome methylene-blue, prepared according to Goldhorn's for-
mula,2 is sold by dealers in laboratory supplies, or it may be made
in this manner:
Two grams of methylene-blue are dissolved in 300 c.c. of
warm water and 4 gm. of lithium carbonate are added, with
constant agitation. The mixture is poured into an uncovered por-
celain capsule, which is heated over a shallow water-bath for ten or
1 Johns Hopkins Hosp. Bull., 1899, vol. x, p. 70.
1 Ibid., 1899, vol. x, p. 70; also N. Y. Univ. Bull, of Med. Sci., 1901, vol. i,
P-57-
MICROSCOPICAL EXAMINATION OF STAINED SPECIMEN. 89
fifteen minutes, being frequently stirred with a glass rod. After
removal from the water-bath the fluid is bottled, without filtering,
and set aside for several days, after which its reaction is cor-
rected by the cautious addition of a 5 per cent, acetic acid solu-
tion until the dye is but very faintly alkaline. Should the solution
become too alkaline after having been kept for some time, its reac-
tion may be corrected by adding a small quantity of acetic acid,
as in the preparation of the original mixture.
A differential count of the leucocytes consists
DIFFERENTIAL in determining, by microscopical examination of
COUNTING, the stained specimen, the relative percentages of
the different varieties of these cells, the estimate
being based upon a count of several hundred cells, which are
classified according to the several forms described in a following
section (Section IV). This procedure, by means of which quali-
tative changes affecting the leucocytes may be detected, is ob-
viously a most important step in every blood examination, and
one which should not be regarded as of secondary importance to
the numerical estimate with the hemocytometer.
The technic of differential counting consists simply in exam-
ining successive microscopical fields until at least 500 leucocytes
have been counted, the cells in each field of vision being identified
as they appear, and jotted down on a piece of paper by the ob-
server under their appropriate class. As soon as the requisite
number of cells has been counted, the percentages of the different
forms are calculated, to express the final result. For the exami-
nation a TVinch oil-immersion objective is practically indispen-
sable, for to any but the skilled worker it is difficult, if not some-
times impossible, to distinguish the various forms of leucocytes
with a lower magnification than this lens provides. In order to
be certain that each field is taken in accurate succession to its
neighbor, the slide should be moved across the visual field by the
aid of a mechanical stage; systematic examination of any given
area of the specimen is well-nigh an impossibility if the slide is
simply laid on, or clipped to, the stage of the microscope, and
pushed across it with the fingers alone.
If nucleated erythrocytes are found in the specimen, it is
equally important to include them also in the differential count,
classifying them into two histological divisions, normoblasts and
megaloblasts. In calculating the number of these cells, it is
obviously impossible to employ any direct method, so that the
estimate must of necessity be more or less approximate, since it
is based upon the ratio of erythroblasts to a given number of
leucocytes. Having first counted the latter with the hemocytom-
90 EXAMINATION OF THE BLOOD BY CLINICAL METHODS.
eter, the number of nucleated erythrocytes is noted in an area
of the stained specimen in which a fixed number of leucocytes
is contained, and having ascertained these data, the estimate is
made according to the formula:
Number of erythroblasts _ Number oj leucocytes
counted in the stained film per c.mm. Number of erythro-
Number of leucocytes counted in the stained film blasts per c.mm.
For example, in a case of pernicious anemia in which the leu-
cocytes number 4000 per c.mm., and a total of 35 erythroblasts
is noted while counting 1000 leucocytes in the stained film, the
calculation is as follows :
35 X 4000 -5- 1000 = 140 erythroblasts per c.mm.
Whenever erythroblasts are found, it is important to determine
their number to the c.mm. of blood, and should normoblasts and
megaloblasts both occur, to estimate the ratio between these two
types of cells.
V. COUNTING THE BLOOD PLAQUES.
Determann's method * of indirectly estimating the number of
plaques to the c.mm. of blood is both simple and accurate. It
consists, briefly, in first determining the ratio of these elements to
the erythrocytes, which are then counted, to furnish the basis for
the final calculation.
In obtaining the blood, a drop of the diluting fluid is placed
upon the patient's finger and the puncture made through it, in
order that the blood, as it flows from the puncture, will instantly
mix with the diluent without coming in contact with the air.
The blood and diluent are then thoroughly mixed for a few mo-
ments by the aid of a cover-glass, after which a small portion of
the mixture is transferred to a Thoma-Zeiss counting chamber,
and the ratio of plaques to erythrocytes determined under the
microscope. In the healthy adult this ratio, according to Deter-
mann, ranges from i to 18 to i to 30, averaging about i to 22.
With another drop of blood the erythrocyte count is then made
by the usual method, and the actual number of plaques to the
c.mm. of undiluted blood calculated from the figure thus obtained.
For example, in a given specimen of blood in which the ratio of
plaques to erythrocytes is found to be i to 25, the count of the
latter cells being 5,000,000, the actual number of plaques is there-
fore 200,000 per c.mm.
1 Deutsch. Arch. f. klin. Med., 1899, vol. Ixi, p. 365.
ESTIMATION OF CORPUSCLES AND PLASMA. QI
The diluents for which Determann expresses a preference are
either a 9 per cent, aqueous solution of sodium chlorid to which
a little methyl- violet has been added, or an aqueous solution con-
taining one per cent, of sodium chlorid and 5 per cent, of po-
tassium bichromate. Brodie and Russell1 recommend equal
parts of dahlia-glycerin and a two per cent, aqueous solution of
sodium chlorid.
Any of the diluting fluids already mentioned are also suit-
able for the purpose.
VI. ESTIMATION OF THE RELATIVE VOLUMES OF
CORPUSCLES AND PLASMA.
The use of centrifugal force for the purpose of determining the
relative volumes of blood corpuscles and plasma was first applied
in a practical manner by Hedin,2 who embodied the earlier ideas
of Blix in an instrument known as the hematocrit. More re-
cently Daland,3 by improving the mechanical construction of the
original instrument and by simplifying the technic of using it,
has made centrifugalization of the blood a method of investigation
adapted to general clinical work. By the use of the hematocrit
a pair of capillary glass tubes filled with undiluted blood are ro-
tated in their horizontal axes at a high rate of speed until, as the
result of the centrifugal force thus applied, the corpuscular and
liquid portions of the blood become separated, the former being
distinguishable in the lumen of the tube as a column the length
of which is dependent upon the volume which the corpuscles con-
stitute in relation to the rest of the blood mass.
This instrument (Fig. 30) is composed of a
DALAND'S set of cog-wheels inclosed in a metal box and
HEMATOCRIT. geared in such a manner as to cause 10,000
revolutions a minute of a vertical spindle, by
turning a handle at a definite, uniform rate of speed. A metal
frame, which may be securely fastened to the spindle by a modi-
fied bayonet-lock, carries a pair of capillary glass tubes, each
of which fits into two cup-like, rubber- lined depressions, and
is adjusted and held in place by a spring. Each tube measures
50 mm. in length with a lumen of 0.5 mm., and has engraved upon
its outer surface a scale representing 160 equal divisions, the glass
1 Jour. Physiol., 1897, vol. xxi, p. 390.
2 Skandinavisch. Arch. f. Physiol., 1890, vol. ii, p. 134.
3 University Med. Mag., 1891, vol. iv, p. 85; also Edwards' supplement to
Keating's " Cyclopedia of the Diseases of Children," Philadelphia, 1899, vol. v,
P- 537-
92 EXAMINATION OF THE BLOOD BY CLINICAL METHODS.
immediately above the scale being molded so as to form a lens-
front, to magnify the column of blood and to facilitate the reading
of the divisions. A bit of rubber tubing fitted with a mouthpiece
is used for rilling the capillary tube, in the same manner in which
the blood is measured with the hemocytometer. While in use,
the instrument is securely attached to the projecting edge of a
table or shelf by means of a clamp operated by a thumb-screw.
Method o] Use. — Having cleaned and punctured the patient's
finger in the usual manner, the beveled end of one of the capil-
lary tubes is immersed in the drop of blood, which is sucked up
the lumen of the tube until it is exactly filled. The forefinger,
smeared with a little vaselin, is then
applied to the beveled end of the tube,
while the rubber suction tube is care-
fully removed by twisting it free — not
by forcibly pulling it off, since this may
accidentally cause removal of a portion
of the blood column by suction. The
tube thus charged with blood is at once
adjusted to one arm of the frame, and
the empty tube similarly fixed in the
other arm, to equalize the balance, this
step being completed as rapidly as pos-
sible, in order to anticipate coagulation.
When the tubes have been- thus ad-
justed, and the frame securely locked
in the spindle, the handle of the in-
strument is turned for three minutes1 at
the rate of 77 revolutions a minute, this
rate of speed securing 10,000 rotations
a minute of the frame, since the latter
revolves 130 times with each complete turn of the handle. The
centrifugalization having been finished, the charged tube is care-
fully removed from the frame, and held against a piece of dull
white paper, so that the height of the blood column may be easily
determined. In order to make the reading with accuracy, it is
sometimes necessary to use a small magnifying glass, for the
divisions on the scale of the tube are but 0.5 mm. apart — a
distance too small to judge easily with the naked eye. On ex-
amination, three distinct divisions of the lumen of the tube
containing the centrifugalized blood may be distinguished : first,
1 In a recent personal communication Dr. Daland advises that, in order to
insure the most accurate results with his instrument, the centrifugalization be con-
tinued for three, instead of for two, minutes, as he formerly recommended.
FIG. -30. — D ALAND'S HEMATOCRIT.
ESTIMATION OF CORPUSCLES AND PLASMA. 93
a dark-colored column consisting of erythrocytes, reaching, in
normal blood, to a point between the divisions marked 50 and 51 ;
second, a thin layer of leucocytes, showing, in blood in which
these cells are not largely increased, as an indistinct, milky stratum
overlying the erythrocytes ; and, third, a layer of clear plasma
occupying the remainder of the lumen. The normal volume of
erythrocytes being arbitrarily regarded as 100 per cent., to com-
pute this result the figure of the scale to which these cells rise is
multiplied by two. Unless the leucocytes are greatly increased
in number, the layer formed by these cells is too delicate and too
dully defined to be read with any degree of accuracy ; but in
cases of high leucocytosis and of leukemia it is quite possible to es-
timate roughly the relative proportions of leucocytes to erythro-
cytes.
The capillary tube which has been filled with blood should be
cleaned as soon after use as possible, water, followed by alcohol
and ether, being used for this purpose. A fine wire should be
passed through its lumen, to dislodge any obstruction which may
result from drying of the column of closely packed corpuscles.
The hematocrit, if its clinical application is limited to the de-
termination simply of the relative volumes of the blood corpus-
cles and plasma, may be relied upon to furnish, on the whole,
dependable information, the necessary errors attending its use
probably being within two per cent. It is also useful in the study
of hemoglobinemia, cholemia, and lipemia. If employed in the
role of a hemocytometer, however, its results must needs be highly
inaccurate, just, in those instances in which exact methods of
investigation are all important. It is true that in normal blood,
in which the size of the corpuscles ranges within the physiologi-
cal limits, it is correct to consider each percentage volume as
representing approximately a count of 100,000 erythrocytes per
c.mm. In blood characterized by any considerable deformity
in the size and shape of these cells, as in high-grade anemia
or in leukemia, it is perfectly obvious that no such corres-
pondence between the count and the percentage volume can be
expected — blood in which microcytosis is pronounced is certain
to show a lower percentage volume of erythrocytes than blood in
which megalocytosis prevails, or than blood containing normal-
sized cells, although the counts of all three may be identical. Simi-
larly, a given number of lymphocytes should indicate a lower per-
centage volume than an equal number of myelocytes, or even
polynuclear neutrophiles. On account of these sources of fallacy,
if for no other reason, the hematocrit estimate should never be
taken as a basis for calculating the count in pathological condi-
94 EXAMINATION OF THE BLOOD BY CLINICAL METHODS.
tions, in lieu of the more accurate, if more laborious, method of
counting the corpuscles.
Capps1 considers that the hematocrit may be used to advan-
tage in conjunction with the hemocytometer, in determining the
actual size or volume of the individual erythrocyte, and he regards
this method as far more reliable than the use of the micrometer,
since with the latter only the transverse diameter of the cells, and
not their depth, can be measured. The formula for calculating
this " volume index " has been given elsewhere. (See p. 173.)
VII. ESTIMATION OF THE SPECIFIC GRAVITY.
This method of investigation is used as an indirect means of
computing the percentage of hemoglobin, owing to the more or
less constant parallelism maintained between it and the specific
gravity of the whole blood. The correspondence between the two,
together with the sources of error inseparable from the test, has
been pointed out in another section. (See p. 133.)
Hammerschlag's modification2 of Roy's
HAMMER- method3 of determining the specific gravity of
SCHLAG'S the blood best serves the purpose of those who
METHOD. choose this roundabout means of approximating
the hemoglobin percentage. It consists in first
making a mixture of benzol and chloroform of such a specific
gravity that a small drop of blood deposited in the liquid remains
suspended, after which the specific gravity of the mixture is de-
termined with a hydrometer, the figure thus obtained representing
the density of the blood used in the test. The hemoglobin per-
centage corresponding to this figure is then selected from a table
giving the various degrees of blood densities and the percentages
of hemoglobin to which they are equivalent.
The apparatus required for making the test includes a hy-
drometer provided with a scale graduated to 1.070, a hydrometer
jar having a wide, substantial base, a glass capillary tube, and a
glass stirring rod. An ordinary urinometer may be used instead
of a special hydrometer, since specific gravities in excess of 1.060
(the highest gradation on the scale of most urinometers) are not
often encountered. More accurate results, however, are possible
with a standardized instrument. Levy4 has shown that with an
1 Jour. Amer. Med. Assoc., 1900, vol. xxxvi, p. 464.
2 Zeitschr. f. klin. Med., 1892, vol. xx, p. 444.
3 Cited by Devoto, Zeitschr. f. Heilk., 1889, vol. xi, p. 175.
4 Lancet, 1903, vol. i, p. 1302
ESTIMATION OF THE SPECIFIC GRAVITY. 95
ordinary hydrometer an excessive reading, ranging from 3 to 10
degrees, always occurs, owing to the disturbing effect upon the in-
strument of the low surface tension of the chloroform-benzol mix-
ture. To obtain accurate figures it is necessary to use a hydrome-
ter which has been standardized to these reagents. Either a
Thoma-Zeiss leucocytometer or a medicine dropper, the free end
of which should be heated in a flame and bent into an obtuse
angle, will serve as a capillary pipette.
Benzol and chloroform are mixed together in the hydrometer
jar in such proportions that the specific gravity of the liquid is
approximately equal to that of normal blood, 1.060. This mix-
ture having been made and its specific gravity taken, the point of
the capillary pipette, charged with blood, is plunged beneath the
surface of the liquid and a small bead of blood gently expelled.
If the blood drop rises to the surface of the mixture, a few drops
of benzol are added, while if it sinks to the bottom of the jar,
chloroform is used, the addition of the appropriate reagent being
continued until the drop neither rises nor sinks, but remains sta-
tionary, suspended in the mixture. When this point has been
determined, the specific gravity of the liquid is taken by means of
the hydrometer, this figure obviously representing the specific
gravity of the blood drop itself. To convert the specific gravity
into its hemoglobin equivalent the figure obtained by the above
procedure is compared with one of the tables given on page 133.
After each addition of benzol or of chloroform the contents of the
jar must be thoroughly mixed by stirring with the glass rod, in
order to secure uniformity in the density of the liquid. The latter,
if it is filtered free from blood and preserved in a tightly stop-
pered bottle, may be used again in subsequent tests.
In spite of the enthusiasm evinced by certain authors for this
method of obtaining hemoglobin values, considerable experi-
ence with the test has convinced the writer that it is both crude
and untrustworthy — it is useful, no doubt, when a hemometer
cannot be obtained, but in no sense is it an efficient substitute for
colorimetric methods. The liability of the blood drop to split
up into numerous fine particles, to adhere to the inside of the
jar, and to become altered in composition from the influence of the
reagents, as well as the tedious attempts which must usually be
made to add just the proper quantities of benzol and chloroform
to secure a mixture in which the drop neither sinks nor rises, are
a few of the drawbacks which must make the test unpopular with
busy clinicians. For a critical review of the clinical value of
Hammerschlag's test Baumann's article1 should be consulted.
1 Brit. Med. Jour., 1904, vol. i, p. 473.
96 EXAMINATION OF THE BLOOD BY CLINICAL METHODS.
VIII. ESTIMATION OF THE ALKALINITY.
A convenient clinical method of deter-
ENGEL'S mining the alkalinity of the blood is by the use
ALKALIMETER. of Engel's alkalimeter (Fig. 31). By means
of this instrument a measured quantity of fresh
blood is diluted with distilled water in the proportion of one to
ten, and then titrated with a -j-% normal solution of tartaric acid
until the mixture reacts with lacmoid paper, the total alkalinity
being calculated from the amount of the tartaric acid used. The
methods of alkalinity estimation devised by Landois,1 by Lieb-
reich,2 by Haycraft and Williamson,3 by Wright,4 and by Kraus5
are not well adapted to routine blood work, being either too com-
plicated and elaborate for such a purpose or too inaccurate.
The apparatus which Engel has devised consists of the follow-
ing parts: a diluting and mixing pipette, resembling a large-sized
Thoma-Zeiss erythrocytometer; a graduated burette by means of
which the amount of tartaric acid solution used in the test is meas-
ured; a glass cylinder in which the titration is made; and a glass
stirring rod. The mixing pipette is graduated in three principal
divisions marked 0.025, °-°5> and 5-o respectively, the first two
divisions being further scaled in tenths by fine horizontal mark-
ings; otherwise the instrument is modeled like a blood-counting
pipette. The burette has a capacity of 5 c.c., and is provided with
a scale indicating 100 equal divisions; when in use, it is clamped up-
right, by means of a special attachment, to a vertical brass support
which screws into a fitting in the box containing the apparatus.
Method of Use. — The technic of using the alkalimeter is simple
and time saving in comparison with that required by other well-
known methods of alkalinity testing. Finger-blood, obtained by a
rather deep puncture, so as to afford a good-sized drop, is sucked
up in the pipette until it reaches the mark 0.05, immediately after
which distilled water is similarly drawn up the lumen of the tube
until the mixture of blood and water fills the bulbous expansion
and reaches the mark 5.0 in the constricted portion beyond.
While sucking up the water the pipette should be rapidly twisted
to and fro between the thumb and forefinger, to insure thorough
mixing of the blood and water as they together fill the expanded
portion of the instrument. As soon as the dilution has been
made, the pipette should be shaken for a minute or so, until the
1 Real-Encyclop., 1885, vol. iii, p. 161.
2 Berichte d. deutsch. chem. Gesellsch., 1868, vol. i, p. 48.
3 Proc. Roy. Soc., Edinburgh, June 18, 1888.
4 Lancet, 1897, vol. ii, p. 719. 5 Zeitschr. f. Heilk., 1889, vol. x, p. 106.
ESTIMATION OF THE ALKALINITY.
97
mixture becomes of a uniform "laky" tint, which indicates that
all the hemoglobin has been dissolved from the corpuscular
stroma. The contents of the pipette are blown out into the glass
cylinder, which is placed beneath the faucet of the burette, the
latter having been previously filled to the mark o with a 7V nor-
mal solution of tartaric acid. By turning the stop-cock of the
burette the test solution is now added, drop by drop, stirring be-
tween each addition, to the measured amount of diluted blood
in the cylinder. From time to time a drop of the mixture is re-
FIG. 31. — ENGEL'S ALKALIMETER.
moved by means of the glass rod and tested with the lacmoid
paper, the titration being continued until the reaction, recognized
as a bright-red halo which forms around the edge of the drop, is
obtained. The titration is then stopped, and a note made of the
number of drops of the test solution which have been used. In
normal blood the writer finds that from 9 to u drops are re-
quired to give the reaction. The estimate of the total alkalin-
ity of the blood is made by multiplying by the figure 53.3 the
number of drops of the tartaric acid solution used, according to
7
EXAMINATION OF THE BLOOD BY CLINICAL METHODS.
the formula, 10 : a :: 533.0 :.r, a representing the drops of the
reagent.1 The result thus obtained is expressed in milligrams of
NaOH per 100 c.c. of blood. The following table may be useful
for reference in determining the various degrees of alkalinity:
If 6 drops of the solution are used, the alkalinity equals 319 mgm. NaOH
9
1C
II
12
13
M
373
436
479
533
586
639
692
746
After use the pipette should be thoroughly washed out with
water, alcohol, and ether, and then dried, in the manner already
directed for cleaning the Thoma-Zeiss instrument.
This ingenious instrument2 is used in con-
DARE'S nection with a spectroscope, its principle depend-
HEMO-ALKALIM- ing upon the dissipation of the absorption bands
ETER. of oxyhemoglobin when exact neutralization of
the blood ensues, after the addition of a 2^V¥nor'
mal solution of tartaric acid. The working parts of the apparatus
are explained by the accompanying illustration (Fig. 32). The test
solution to be employed is made up as follows:
Acid, tartaric. (Merck's reagent) .................... gr. j (0.075
Alcohol .......................................... Z v (20 c.c.) .
Aqua destil ................................... q. s. 3 vj (200 c.c.).
Method of Use. — The alkalimeter tube (Fig. 32, A), fitted with
its blood pipette, B, is held horizontally, and the pipette filled
with blood by presenting its exposed end to the drop as it flows
from the puncture. With an ordinary medicine dropper containing
distilled water and coupled to the blood pipette by a bit of rubber
tubing, the measured blood is washed into the. alkalimeter tube
until the point o is reached. Now, with the thumb closing the
opening, C, in its bulb, the alkalimeter tube is inverted several times,
in order to mix the blood and water. The reagent pipette, D, is
filled with the test solution, connected by tubing with the free end
1 Assuming that 0.5 c.c. of tartaric acid is used to neutralize 0.05 c.c. of blood,
therefore for every 100 c.c. of blood 1000 c.c., or one liter, of a -^ normal solution of
tartaric acid are required. As the alkalinity of the blood is not expressed by the
amount of acid necessary to saturate it, but in milligrams of an alkali, sodium hy-
drate, the calculation is made thus: as the equivalent weight of tartaric acid is 75,
and that of sodium hydrate 40, one liter of water dissolving 75 gm. of the former
saturates 40 gm. of the latter — that is, one liter of a 7V normal tartaric acid solution
saturates if gm., or, in other words, 533 mgm., of sodium hydrate, this figure
being taken by Engel as the degree of normal alkalinity of the blood.
2 Phila. Med. Jour., 1903, vol. xi, p. 137.
ESTIMATION OF THE ALKALINITY.
99
of the blood pipette, and compressed so as to force the reagent
into the diluted blood within the alkalimeter tube. In doing this
it is necessary to thumb the opening in the bulb of the latter, to
avoid the mixture of the blood and reagent. The tube and reagent
pipette, still connected, are now grasped and inverted, to mix thor-
oughly the contents of the former, after which a preliminary
observation is made by adjusting the lower part of the tube
(below the mark o) to the cleft of a Browning pocket spectroscope.
If the oxyhemoglobin absorption bands per-
sist, more of the reagent is added, drop by
drop, inverting the tube between, and exam-
ining with the spectroscope after, each drop.
When the bands disappear, the figure to which
the neutralized blood solution reaches is noted,
and compared with the table of equivalents given
below, to obtain the final result, which is ex-
pressed in milligrams of NaOH per 100 c.c.
of blood. The figure for normal blood with
this instrument is 266.
TABLE OF EQUIVALENTS.
CUBIC CENTIMETERS OF MGII. OF NAOH TO
REAGENT. 100 c.c. OF BLOOD.
2-6 345-0
2.4 3I9-°
2.2 292.0
2 .0 ". 266.O
1.8 239.0
1.6 2I2.O
1 .4 1 76.0
1.2 I59-O
1-0 I33-0
0.8 96.0
0.6 79.0
0.4 53.0
0.2 26.6 FIG
32. — DARE'S HEMO-
AI.KAI.IMETER.
Alkalimeter tube; B,
automatic blood pi-
pette; C. opening for
the admission of air:
D, reagent pipette.
While, up to the present time, it cannot be
claimed that information of any real diagnostic
pertinence has been obtained from the study of
the alkalinity of the blood, this procedure should
prove of value in the systematic investigation of many cases,
especially those of high-grade anemia. As elsewhere mentioned,
the degree of normal blood alkalinity varies greatly according to
the particular method by which this figure is ascertained, so that
it follows that the results obtained by means of one apparatus
cannot be compared with those based upon investigation with
another instrument of different design.
100 EXAMINATION OF THE BLOOD BY CLINICAL METHODS.
IX. DETERMINATION OF THE RAPIDITY OF
COAGULATION.
This procedure is useful in the study of such conditions as
icterus, purpura, hemophilia, scurvy, various specific infections,
and other diseases characterized by abnormalities in the clotting
time of the blood. Knowledge of how long it takes a given blood
to clot not only adds completeness to the clinical history, but
allows the physician to judge of the effect of remedies administered
with a view to promoting coagulation. No careful surgeon to-
day neglects to test the patient's blood coagulability before operat-
ing for the relief of obstructive lesions of the biliary passages. No
physician should omit to make repeated
coagulation tests in treating one of the
hemorrhagic diatheses or a primary ane-
mia.
The coagulation time
GLASS SLIDE may be determined ap-
L METHOD. proximately by collecting
I & several individual drops
^ I of blood of the same size upon the surface
£ of a perfectly clean, slightly warmed glass
slide. At regular intervals of about one
minute a straw of a whisk-broom is lightly
trailed through each drop in succession,
until sooner or later a delicate thread of
fibrin may be observed clinging to the
straw. The period which has elapsed
between the deposit of the blood on the
slide and the appearance of this indica-
cinvex dropTC CoAGCLATION- tion of clotting is expressed in minutes,
to represent the coagulation time of the
specimen under investigation. Normal blood thus treated coagu-
lates in from two and one-half to five minutes.
The method described by Milian1 is perhaps even simpler. A
rather large drop of blood is collected upon the center of a clean,
dry glass slide, which, after the lapse of a minute or so, is carefully
tilted to a vertical plane. With the slide held in this position the
profile of the coagulated drop forms a symmetrical, mound-like
convexity, while that of the incompletely clotted drop is tear-
shaped (Fig. 33). The time elapsing between the collection of
the blood drop and the first-named change is considered the coagu-
lation time. Five minutes is the average period for normal blood.
1 Presse med., 1904, vol. i, p. 202.
DETERMINATION OF THE RAPIDITY OF COAGULATION. IOI
The latest model of this instrument1 consists
WRIGHT'S of a tin reservoir fitted with a removable rack
COAGULOMETER. holding a thermometer and a set of twelve
calibrated glass coagulation tubes. For filling
the latter an aspirator tube with a rubber connection is employed.
The thermometer indicates degrees of the Centigrade scale, and is
FIG. 34. — WRIGHT'S COAGULOMETER.
also graduated at 18.5° and at 37°, the temperature of "half blood
heat" and of "blood heat," respectively. The coagulation tubes,
made of stout glass, are furnished with tight rubber caps, used to
seal their blunt ends when immersed; they have an internal di-
ameter of 0.25 mm., and are marked to indicate a blood column
of 5 c.c. Each tube is numbered to correspond with its appropriate
place in the rack of the reservoir.
1 Lancet, 1902, vol. ii, p. 15.
102 EXAMINATION OF THE BLOOD BY CLINICAL METHODS.
Method oj Use. — The reservoir is filled with water having a
temperature of 18.5° C.,1 and the tubes, each fitted with a rubber
cap, are placed in the rack, sealed end downward, wrhere they are
allowed to remain immersed for a few minutes until they acquire
approximately the same temperature as that of the water. They
are then removed, dried, and stripped of their rubber caps.
Having then pricked the patient's finger, 5 c.c. of blood
are sucked up each tube, at successive intervals of one min-
ute, a tube as soon as filled being returned to its appropriate
place in the reservoir. It is not necessary to replace the caps —
the tubes are simply placed point downward in the water, the
temperature of which is from time to time readjusted to the stand-
ard by adding hot water to the reservoir as its contents cool.
After the lapse of an appropriate interval the tube first filled is re-
moved from the reservoir and tested by attempting to blow out its
contents upon the surface of a piece of white filter or blotting paper.
The other tubes are similarly tested in rotation, at intervals of one
minute or less, until, after having thus tried a variable number
one is found from which the blood cannot be expelled.
Coagulation may then be considered to have occurred, the
time required for this process being expressed by the number of
minutes elapsing between the filling of the tube in question and
the evidence of clotting thus demonstrated. With normal blood
the coagulation time, as determined by this instrument, gener-
ally ranges from about three to six minutes. In rare instances
Wright 2 found that in the healthy male adult clotting may be pro-
longed for fifteen minutes.
After use, a fine wire should be forced through the lumen of
the tubes to dislodge the clots, after which the remaining traces of
blood are to be removed by thorough washing with distilled water,
alcohol, and ether, in the order named.
X. CRYOSCOPICAL EXAMINATION.
Cryoscopy is the method' of determining the
CRYOSCOPY. freezing-point of a given liquid and the com-
parison of this figure with the freezing-point of
distilled water. This method of investigation is based upon the
principle that the freezing-point of any liquid is proportionate to the
number of its contained molecules. The greater the molecular
concentration, the lower the point at which the fluid freezes.
1 In slowly coagulating bloods the temperature should be about that of blood
heat, 37° C.
2 Brit. Med. Jour., 1902, vol. ii, p. 1706.
CRYOSCOPICAL EXAMINATION. 103
Cryoscopy of the blood and urine was first applied to clin-
ical medicine by von Koranyi,1 who thus was able to determine
the status of the renal function. The average freezing-point of
normal blood is — 0.57° C., ranging between — 0.56° and — 0.58°
C. Urine in the healthy individual freezes between — 0.9° and
— 2° C. Venous blood freezes at a slightly lower temperature
than arterial. In renal disease with decided insufficiency of the
kidneys it is found that the freezing-point of the blood is lowered,
while that of the urine is correspondingly raised, owing to the
retention in the blood of matter which the crippled kidneys are
unable to excrete. Excision of one kidney does not disturb the
normal freezing-points of the blood and urine, but double neph-
rectomy promptly lowers that of the former and raises that of the
latter.
A freezing-point of — 0.6° C. or lower for blood and of i° C.
or higher for urine indicates a sufficient degree of renal impair-
ment to contraindicate surgical interference in lesions of the kid-
neys. This dictum was first expressed by Kummel,2 who bases it
upon an experience of 170 cases of renal surgery in which cryos-
copy was practised, including chronic nephritis, nephrolithiasis,
tuberculosis, cysts, neoplasms, pyonephrosis, hydronephrosis, and
post-operative anuria. Rumpel's extensive researches3 in 300
similar cases showed that in normal individuals and in those
with unilateral renal lesions the blood freezing-point did not vary
from the figures given above (: — 0.56° to — 0.58° C.), while in
bilateral lesions of the kidneys it ranged between — 0.55° and
— 0.81° C. In renal disease unaccompanied by uremia, Linde-
mann4 found no variations from the normal freezing-point, but
with the onset of this complication the blood froze at a point as low
as —0.7° C.
Koeppe's data3 in conditions other than those involving the
kidneys are of interest. He found, in a series of cases including
functional neuroses, carcinoma, diabetes, pleurisy, and pneumonia,
a blood freezing-point varying from — 0.5° to — 0.63° C. Similar
figures, of theoretical rather than practical interest, have also been
determined in various general diseases by Ogston,6 Tinker,7 Tieken,3
1 Zeitschr. f. klin. Med., 1897, vol. xxxiii, p. .45; ibid., 1899, vol. xxxiv, p. i;
Berlin, klin. Wochenschr. , 1901, vol. xxxviii, p. 424.
2 Centralbl. f. Chir., 1902, vol. xxix, p. 121.
3 Munch, med. Wochenschr., 1903, vol. 1, pp. 19, 67, and 117.
4 Deutsch. Arch. f. klin. Med., 1899, vol. Ixv, p. i.
5 Cited by Cattell, Internat. Clinics, 1904, vol. i, p. 6.
8 Lancet, 1901, vol. ii, p. 1253.
7 Johns Hopkins Hosp. Bull., 1903, vol. xiv, p. 162.
8 Med. News, 1904, vol. Ixxxiv, p. 416.
104 EXAMINATION OF THE BLOOD BY CLINICAL METHODS.
Ceconi,1 Sollmann,2 and others.3 It is of interest to note that the
pregnant woman's blood freezes at a higher temperature than nor-
mal, but that the latter figure is reached after delivery, as the
molecular concentration of her blood rises. In diabetes mellitus
the freezing-point is low, but in pernicious anemia and in various
forms of hydremia it is high. Inhalations of oxygen lower the
figure, but in conditions of cyanosis with an excess of carbonic
acid in the blood the freezing-point rises. It is of value also to
observe that cystitis and pyelitis do not affect the blood's freezing-
points.
Carrara4 and Revenstorf 5 found that in cases of drowning the
resulting dilution of the blood causes radical deviations from
the normal freezing-point, which rises in the case of drowning
in fresh water and falls after death by submersion in salt water.
In this connection the general statement applies, that the freezing-
point of the diluted blood approaches that of the fluid with which
the body is waterlogged. Whether the deviation be plus or minus,
it is generally more marked in the blood of the left than of the
right heart, because of the greater dilution of the venous blood,
owing to the water drawn into the lungs and entering the pulmon-
ary capillaries. Exceptionally this difference between the halves
of the heart is not apparent, as in the case of bodies remaining
submerged for a long period and in those in which the circulation
persists for a few moments after the blood dilution, in either of
which instances the entire blood mass tends to become equally
diluted. The utility of cryoscopy as a forensic test of death by
drowning is obvious from these experiments, although its value
is to some extent restricted by the fact that advanced putrefaction
and prolonged submersion interfere with its reliability.
Cryoscopy of the blood and urine is of value in determining
the condition of renal adequacy, but it should be supplemented by
other laboratory tests devised for this purpose. Forensically, the
test may yield reliable evidence not only in cases of death by
drowning, but possibly also in the identification of blood stains
from various sources.
The cryoscope made by Fontaine, of Paris
FONTAINE'S (Fig. 35), is simply constructed, durable, and
CRYOSCOPE. thoroughly satisfactory for clinical use. It con-
sists of a stout glass freezing-jar, A, provided with
a large test-tube, B, passing to its center and kept in position by a
1 Rif. med., 1901, vol. iii, p. 109. 2 Amer. Med., 1902, vol. iii, p. 656.
3 For an excellent resum£ of cryoscopy in all its phases see Cattell, Proc. Phila.
Path. Soc., 1904, vol. vi, p. 244.
4 Arch. Ital. de Biol., 1901, vol. xxxv, p. 349.
8 Munch, med. Wochenschr., 1902, vol. xlix, p. 1880.
CRYOSCOPICAL EXAMINATION.
metal support, C. At the base of the jar there is a drain, D, for
the liquid which accumulates as the ice-salt mixture melts. A
small test-tube, E, having a lateral vent, F, fits within the larger
tube, being adjusted by means of a rubber collar, G,1 so that be-
tween the two tubes an air chamber is formed. A thermometer,
H, encircled by a metal spiral stirrer, I, is let down into the
smaller test-tube and adjusted so that it touches neither the walls
nor the bottom of the latter, being kept in this position by means
of a vertical standard fitted with an adjustable horizontal arm.
The thermometer registers from — 3° C. to +3° C., being gradu-
ated in Tj-J-g- of a degree, and is provided with a pear-shaped bulb
at the top, to allow for the expansion of
the mercury column. The thermometer
is an extremely delicate and expensive
bit of apparatus, and must be handled
with care, for fear of breakage. It
should be tested with distilled water,
so that any deviation may be taken into
account in subsequent observations.
Method of Use. — The freezing- jar,
with its large test-tube adjusted, is filled
to the brim with a mixture of cracked
ice and rock-salt, packed in alternate
layers, the whole being covered, at the
level of the mouth of the jar, with a
layer of salt an inch in depth. The size
of the bits of ice should be large enough
to insure gradual thawing, for finely
crushed ice rapidly turns to slush. Ten
c.c. of the blood or urine 2 are placed in
the small test-tube, which is laid against
a block of ice, to cool, while the freez-
ing-jar is being packed. By the time
this is accomplished (about five minutes) the fluid to be tested
will have cooled sufficiently, and the next step in the test may
1 In the original model of the instrument this collar, as well as the metal band
supporting the large test-tube, interferes with the reading of the thermometer
scale, but this defect may be easily remedied by cutting in each a small window,
so as to allow a clear view of the mercury column. The apparatus is made by
G. Fontaine, 16, Rue Monsieur le Prince, Paris; it costs, duty free, 90 francs. The
'A. H. Thomas Company, Philadelphia, makes an excellent cryoscope of the Fon-
taine model, the cost of which is considerably less than that of the French instru-
ment.
2 The patient's blood and urine should be collected at the same time: the
former by aspirating a superficial vein, the latter by catheterizing each ureter if
the test involves a determination of the integrity of each kidney.
FIG. 35. — FONTAINE'S CRYOSCOPE.
I06 EXAMINATION OF THE BLOOD BY CLINICAL METHODS.
proceed. Great care must be taken that both the test-tubes
and the thermometer are absolutely dry, for the slightest trace
of moisture so alters the freezing-point that gross inaccuracies
in the final reading may result. The small test-tube is now
fitted within the larger one, after which the thermometer, with
the stirrer in place, is carefully lowered into position, rest-
ing free from contact with the walls and bottom of the tube,
with its mercury bulb immersed in the test fluid. The ther-
mometer, when correctly adjusted, is hung from the arm of the
standard, placed alongside the freezing-jar. The handle of the
stirrer is now constantly moved up and down, so as to equalize the
temperature of the test fluid as it congeals, and this mixing is to be
continued intermittently during the rest of the observation. After
a wait of about five minutes the column of mercury begins to fall,
first very slowly, then rapidly, to approximately two degrees
below zero, at which point it remains for a few moments, and then,
because of the heat evolved, rises to the true freezing-point, where
it remains stationary for about two minutes, after which it falls to
the temperature of the outside mixture of ice and salt. When the
point of stability is attained, the degree registered by the mercury
column is noted to obtain the freezing-point of the specimen. In
making this end-observation the eyes should be on a level with the
top of the mercury column. It may be hastened somewhat by the
insertion of a pellet of ice in the vent of the small test-tube just
before the freezing-point is reached.
XI. ESTIMATION OF THE RESISTANCE OF THE
ERYTHROCYTES.
This method of examination is of more than mere theoretical
value in the study of diseases associated with hemoglobinemia,
in which conditions it indicates, and with great accuracy, the vul-
nerability of the erythrocytes, as expressed by their resistance to the
action of salt solutions of different strengths. Among the patho-
logical conditions in which the method is useful may be named the
severe anemias, the specific infections, such as malarial fever,
yellow fever, and sepsis, all forms of icterus, the different cachectic
states, paroxysmal hemoglobinemia, and toxemias due to snake
venom and to other hemolytic agents.
Hamburger's method, as modified by von Lim-
HAMBURGER'S beck,1 requires the use of twelve small glass recep-
METHOD. tacles, about the size of a Gowers' hemocytometer
mixing cell, each of which contains a small glass
1 "Einer klinische Pathologic des Blutes," 26. ed., Jena, 1896 ; also New Sy-
denham Soc. trans, by Arthur Latham, London, 1901.
SPECTROSCOPICAL EXAMINATION.
107
bead. Into these vessels is placed i c.c. of salt solutions of dif-
ferent strengths, each differing by 0.02 per cent., the minimum
being 0.3 per cent., the next 0.32 per cent, (or 0.02 per cent,
stronger), and so on. A drop of blood as it drips from the puncture
is allowed to fall into each of the vessels, which are then shaken
briskly for a minute or so, in order to cause defibrination by the
whipping about of the glass beads. When this is accomplished,
the blood-charged solutions are allowed to stand for six hours,
when it will be noted that some of them are tinged with hemoglobin,
while others remain clear. The first tube showing no solution of
hemoglobin indicates the isotonicity of the cells under examination.
For normal blood this index ranges between 0.46 and 0.48 NaCl.
XII. SPECTROSCOPICAL EXAMINATION.
For clinical work the Sorby-Beck microspectroscope, to be used
in connection with the microscope, is an excellent instrument,
being both accurate and, comparatively
speaking, easy to manipulate. Other
very perfect instruments for the spec-
troscopical examination of the blood,
differing but little from the original
Sorby model, are also made by Zeiss,
by Leitz, and by Browning.
This instrument
THE (Fig. 36) when in use
SORBY-BECK fits into the tube of
MICROSPEC- the microscope like an
TROSCOPE. ordinary ocular, for
which it is substituted.
Its essential part consists of a tube, A ,
in which a series of five prisms, two of
flint and three of crown glass, is ar-
ranged in such a manner that the emer-
gent rays, which are separated by dispersion, leave the prisms in
practically the same direction as that taken by the entering im-
mergent ray. At one side of the tube is fixed a right-angle
reflecting prism, so that the spectrum of a solution of normal
blood may be thrown alongside that of the specimen under
investigation, the two spectra thus being comparable. The ad-
justment of the spectra is effected by means of the two small
screws, B, B' . The receptacle containing the control solution
of blood is clamped to the stage, C, by a spring clip, D, light being
reflected through the liquid and into the rectangular aperture, £,
FIG. 36. — SORBY-BECK MICROSPEC-
TROSCOPE.
108 EXAMINATION OF THE BLOOD BY CLINICAL METHODS.
by the swinging mirror, F. The width of this aperture is controlled
by the screw, G. The receptacle containing the blood solution to
be examined is placed upon the stage of the microscope, being
brought into focus with a low-power (f or i inch) dry objective.
Beneath the tube inclosing the series of prisms is mounted an
achromatic ocular, below which a narrow, slit-like diaphragm is
situated, the vertical size of this opening being regulated by a
milled screw, not shown in the illustration, and its breadth by the
two small levers, /, /'. Both ocular and prisms may be moved
simultaneously toward and away from the diaphragm, by a rack-
and-pinion mechanism controlled by the wheel, /, so that any part
of the spectrum may be brought into focus.
The liquids to be examined should be placed in Sorby's tubular
cells, and cover-glasses superimposed. These cells (Fig. 37) are
narrow-lumened glass receptacles made of barometer tubing, both
ends of which are accurately ground to parallel surfaces, one end
being cemented to a small polished glass plate.
Method of Examination. — The specimen of blood, obtained in
the usual manner, by puncture, is first diluted
• with distilled water 100 times by means of the
Thoma-Zeiss erythrocytometer, and sufficient
of this laked blood dropped into a Sorby cell
FIG. 37.— SORBY TUBU- to fill it exactly to the brim. A cover-glass is
then carefully laid over the open end of the
cell, the precaution being taken to prevent the
formation of air-bubbles upon the surface of the column of liquid
thus inclosed. A second cell, to be used as the control, is filled
with normal blood, similarly diluted, and both are then adjusted
in their respective positions, as already explained.
In making the examination a ray of artificial light (that from
a Welsbach incandescent burner being most suitable) is projected
by the microscope mirror through the lumen of the cell contain-
ing the suspected blood, and the surface of the liquid focused
with an ordinary ocular. The latter is' then removed from the
microscope tube and replaced by the spectroscope ocular, and
the second spectrum, that of the normal blood, is brought into
proper position alongside that of the first, so that any differences
between the two may be contrasted by the observer.
The appearance of the spectra of normal and of pathological
blood, together with the circumstances under which the latter
occur, has been described in another section. (See p. 168.)
BACTERIOLOGICAL EXAMINATION. 1 09
XIII. BACTERIOLOGICAL EXAMINATION.
The demonstration of bacteria in the circulating blood, pro-
vided that faultless technic is employed, furnishes in some in-
stances a diagnostic sign of the greatest importance. The patho-
logical significance of such a finding is much greater than that
of a similar result obtained postmortem, since with the latter
there is no means of determining whether the bacterial invasion
of the blood current took place during the active stages of the
disease, or whether it occurred as either a preagonal or a postag-
onal process.
Cultural methods with blood aspirated directly
METHODS, from a superficial vein should invariably be used
whenever such a procedure is practicable, for
blood obtained simply by pricking the skin is most likely to be
contaminated with various bacteria which have their normal hab-
itat in the epidermis and its appendages, notably by the Staphyl-
ococcus epidermidis albus. Welch,1 who first drew attention to
this source of error, emphasizes the fact that no diagnostic sig-
nificance should be attached to the demonstration of this bac-
terium in blood obtained by puncture of the skin.
Direct examination of stained cover-glass specimens prepared •
from finger blood gives either negative or erroneous results in the
great majority of instances. In certain overwhelming infections,
notably in some of the severer forms of bubonic plague, it may
often be possible to detect the specific micro-organism in the
stained film, but the method must be regarded as too crude -and
unreliable to furnish accurate findings in the average case.
Blood Cultures. — In order to secure the most reliable informa-
tion from blood culturing, the systematic observance of three pre-
cautions is essential. First, contamination by the skin bacteria
above referred to must be carefully avoided, by the thorough ster-
ilization of the patient's skin at and adjacent to the site from
which the blood is aspirated. Second, not less than 0.5 c.c.
of blood should be used for each culture, since only in rare in-
stances are bacteria so numerous in the peripheral circulation as
to be demonstrable in a single drop of blood. Third, -fluid, rather
than solid, culture media should be used, in sufficiently large
quantities to dilute the blood freely, — about 100 parts of me-
dium to each part of blood, — the object of this precaution being
to secure attenuation of the bactericidal properties of the blood,
which otherwise might prove strong enough to prevent all bac-
terial development.
'Dennis' "System of Surgery," Philadelphia, 1895, vol. i, p. 251.
110 EXAMINATION OF THE BLOOD BY CLINICAL METHODS.
For aspirating the blood the author prefers to use a tube of
about 10 c.c. capacity, like that illustrated below (Fig. 38).
One end of the tube is ground to fit a No. 42 hypodermic
needle, while over the other end (plugged with a small bit of
cotton) is slipped a piece of rubber tubing for aspirating. The
apparatus, minus the rubber tubing, is inclosed in a larger glass
tube, both open ends of which are also plugged with cotton, and
sterilized by dry heat, the aspirating tube being adjusted at the
time the blood is to be collected. This instrument is far superior
to an antitoxin or a hypodermic syringe for the purpose intended,
being simple, inexpensive, easily sterilized, and readily cleaned
after use. It is especially well adapted for making cultures at a
distance from a laboratory, where the sterilization of an ordinary
piston-syringe is difficult, if not impossible.
At least one hour before the aspiration of the blood the skin
of the patient's arm at and for some distance on all sides of the
bend of the elbow should be scrubbed thoroughly for several
FIG. 38. — ASPIRATING TUBE FOR BLOOD CULTURING.
minutes either with a strong ethereal soap or with tincture of
green soap, after which the part is well rinsed with hot sterile
water, and finally washed with alcohol and ether. A moist hot
i : 500 bichlorid compress is then applied over the site thus cleaned,
being left in place until the time of the withdrawal of the blood.
As a preliminary to this operation the dressing is removed, and
the part freely douched and scrubbed with hot sterile water, in
order to remove every trace of the bichlorid. A rubber drain-
age tube, previously sterilized, is twisted tightly around the pa-
tient's arm above the bend of the elbow, so as to cause disten-
tion of the superficial veins in this situation, and the point of the
needle is then thrust obliquely into the most prominent of these
vessels, with the result that the blood immediately begins to flow
into the bore of the instrument. If, for any reason, the force of
t^e blood flow should fail to fill the caliber of the tube, sufficient
blood may easily be obtained by making gentle suction through
the rubber tubing. While introducing the needle it should be held
almost parallel to the long axis of the vein, for should it be simply
BACTERIOLOGICAL EXAMINATION. Ill
plunged into the vessel at right angles, there is danger that the
point will pass completely through the vessel from wall to wall
and penetrate the surrounding tissues — an accident which may
explain the cause of many a "dry tap." The site of the aspira-
tion may be made anesthetic by preliminary freezing with a spray
of ethyl chlorid, but to most patients the operation is not painful
enough to necessitate this.
Having thus collected, say, 10 c.c. of blood, the con-
tents of the tube are divided equally among five Pasteur flasks,
each containing at least 200 c.c. of broth or other suitable
fluid culture medium. The flasks are . then shaken for a few
moments, in order to mix the blood and medium and to dilute
thoroughly the former, after which they are placed in an in-
cubator. The identity of the growths, should any occur, remains
to be determined by secondary culturing and microscopical ex-
amination, for descriptions of which the student should consult
text-books on bacteriology. Cultures made by this technic,
suggested by Adami,1 are much more favorable to the growth
of any bacteria which may be in the blood stream than the older
methods of using solid media, except under special circumstances,
such as the cultivation of the gonococcus, the influenza bacillus, and
other germs which grow most luxuriantly on special forms of
media.
Staining Methods. — In the limited number of instances to which
such methods are applicable the technic described below will be
found useful.
An attempt should be made to sterilize the skin of the finger
from which the blood is obtained by thoroughly scrubbing the
part first with ethereal or green soap, and then with a i : 500
bichlorid solution, alcohol, and ether, in the order named, this
being followed by sponging with sterile water. A deep punc-
ture having been made with a needle which has been sterilized
by the naked flame, and the first few drops of blood escaping
from the wound allowed to drip away, one of the succeeding
drops is transferred by means of a sterile platinum needle to the
surface of a cover-glass upon which a second cover-glass is at
once laid, the two being drawn apart, in order to secure a pair
of spreads. The latter are immediately dried by gentle heat
and then passed several times through a Bunsen flame. It is
needless to add that the cover-glasses used for making the films
must be sterilized by heat, and handled by means of a pair of
sterile forceps. Films thus prepared may be stained with any of
the basic anilin dyes (thionin, methylene-blue, and methyl- or
1 Jour. Amer. Med. Assoc., 1899, vol. xxxiii, p. 1514.
112 EXAMINATION OF THE BLOOD BY CLINICAL METHODS.
gentian- violet being most useful for this purpose), after which
they are washed in water, dried, and mounted in Canada balsam
or in cedar oil. Should a double-stained specimen be desired,
one of the eosin and methylene-blue solutions referred to previously
may be depended upon to give satisfactory results.
Giinther's method l will be found useful if the object is to de-
stroy the color of the erythrocytes, so as to leave a freer field of
vision for any bacteria which may be present in the film. Ac-
cording to this method, the specimen is first immersed for ten
seconds in a 5 per cent, aqueous solution of acetic acid, until
the tint of the hemoglobin has entirely faded away, after which
the reagent is removed by briskly blowing upon the surface of
the cover-glass; the latter is then held, face downward, over the
open mouth of a bottle containing strong ammonia water, so as
to neutralize all remaining traces of the acid. The film is now
stained for twenty-four hours with the Ehrlich-Weigert fluid
(contained in a covered staining dish), at the end of which time
it will be found to be colored a deep blue. It is then decolorized
by a few seconds' immersion in a i : 14 aqueous solution of nitric
acid, until the color fades to a light green; rinsed in alcohol; dried
in air; and mounted in balsam.
The Ehrlich-Weigert fluid is prepared by adding from 10 to
15 drops of anilin oil to 6 c.c. of distilled water, held in a test-
tube. The fluid is thoroughly mixed by shaking, and then filtered.
To the filtrate a few drops of a concentrated alcoholic solution
of methyl- or gentian-violet are added — just sufficient of the dye
to produce a slight turbidity of the liquid, which clears up in a
few minutes. The mixture prepared in this manner is employed
as the staining agent.
XIV. DETERMINATION OF THE SERUM REACTION.
In 1894 Pfeiffer2 noticed that the vibrios of
WIDAL'S Asiatic cholera, if injected into the peritoneal
TEST. cavity of a guinea-pig immunized against this
disease, rapidly lost their characteristic motility,
and tended to become granular, broken up, and dissolved, while
in the healthy, non-immune animal they developed normally and
abundantly, and failed to show any such changes in their mor-
phology. He claimed that this reaction, known as "Pfeiffer's
1 Fortschr. d. Med., 1885, vol. iii, p. 775.
1 Zeitschr. f. Hyg., 1894, vol. xviii, p. i; ibid., 1895, vol. xix, p. 75; also
Centralbl. f. Bakt. u. Parasitenk., 1896, vol. xix, p. 191; also Deutsch. med.
Wochenschr., 1896, vol. xxii, p. 97.
DETERMINATION OF THE SERUM REACTION. 113
phenomenon," was specific, and emphasized its value as a means
of laboratory differentiation. Two years later Pfeiffer and Kolle1
found that the same changes occurred in experiments with the
bacillus of Eberth and animals rendered immune to enteric fever,
and, furthermore, discovered that the test could be conducted in
vitro, by mixing in a test-tube typhoid cultures and immune serum.
It is of interest to note that results somewhat analogous to those of
Pfeiffer had been observed in 1891 by Metschnikoff,2 and in 1889
by Bordet,3 and by Charrin and Roger,4 although none of these
workers appeared to recognize the significance of their observa-
tions.
In 1896 Griiber and Durham5 applied the principles of Pfeif-
fer's phenomenon to many other motile as well as non-motile
bacteria, deduced new facts regarding its utility as a means of
differentiating various species of germs, improved the technic
of the test, and made the important announcement that aggluti-
nation and immobility of typhoid bacillus cultures were pro-
duced by the action of blood serum from a patient having re-
cently recovered from an attack of enteric fever. It remained,
however, for Widal,8 in 1896, first to apply the reaction clinically,
and to announce that enteric fever could be diagnosed by noting
the clumping and immobilization of the typhoid bacillus when
mixed in definite proportions with blood serum from a patient
suffering from typhoid. This reaction, Widal insisted, was one of
infection, and was demonstrable not only during convalescence,
but during the incipiency and the height of the disease.
The serum reaction is to-day recognized as an important sign
in the diagnosis not only of enteric fever, but also of Asiatic
cholera, Malta fever, relapsing fever, paracolon infections, and
bacillary dysentery, while its value still remains less certainly
established in many other conditions, such as, for example, lep-
rosy, tuberculosis, bubonic plague, sepsis, and pneumococcus in-
fections. The technic of the test and its diagnostic significance
under various circumstances will be described under the headings"
of the diseases in which it occurs. (See Section VII, " General
Hematology.")
1 Zeitschr. f. Hyg., 1896, vol. xxi, p. 203; also Deutsch. med. Wochenschr., 1896,
vol.xxii, p. 735.
J Annal. de 1'Institut Pasteur, 1891, vol. v, p. 473; ibid., 1894, vol. viii, p. 714;
ibid., 1895, vol. ix, p. 433.
3 Ibid., 1895, vol. ix, p. 462; ibid., 1896, vol. x, p. 191.
4 Compt. rend. Soc. biol., Paris, 1889, vol. i, p. 667.
6 Munch, med. Wochenschr., 1896, vol. xliii, p. 285.
' Bull, meld., 1896, vol. x, pp. 618 and 766; Sem. m<?d., 1896, vol. xvi,
p. 259; ibid., 1897, vol. xvii, p. 69; Lancet, 1896, vol. ii, p. 1371; Munch,
med. Wochenschr., 1897, vol. xliv, p. 202.
114 EXAMINATION OF THE BLOOD BY CLINICAL METHODS.
XV. MEDICO-LEGAL TESTS FOR BLOOD.
The examination of suspected blood stains for forensic pur-
poses includes microscopical search for blood corpuscles, spec-
troscopy, the hemin and guaiacum tests, and the biological serum
test of Bordet. The first three of these procedures are used
merely to determine whether a given stain is or is not composed
of blood, but they failed conclusively to prove the source of the
latter. By the biological reaction it is possible to supplement
these tests by proving the precise origin of the blood, whether
human or derived from one of the lower animals. It need scarcely
be added that in medico-legal work it is essential to use all four
tests in the investigation of the material submitted for study.
In undertaking the demonstration of eryth-
MICROSCOPICAL rocytes in a dried clot, the latter must be
EXAMINATION, treated with an agent which will macerate and
dissolve the cells without laking them and
thus removing their hemoglobin and altering their shape. Vir-
chow's fluid — a 30 per cent, aqueous solution of potassium hydrate
— is suitable for this purpose ; or Ranvier's solution — a saturated
aqueous solution of iodin containing 2 per cent, of potassium iodid
— may be used ; this stains various starchy cells which might other-
wise counterfeit blood cells. The solution having been effected,
a minute portion of the dissolved stain is either mounted as a wet
specimen or spread as a dry film between cover-glasses, subse-
quently stained with appropriate dyes, and mounted in balsam
as a permanent specimen. For the microscopical examination
a y^-inch oil-immersion objective is essential, and, if measurements
are to be attempted, an ocular micrometer.
If corpuscles resembling those of blood are detected in the
specimen, especial attention should be directed to their average
size, their shape, and to the presence or absence of nuclei. The
.diameter of the normal human erythrocyte (agoff inO i§ almost
equaled by that of the dog's corpuscles, which averages approxi-
mately -g-jVir in. If the cells are disc-shaped and measure ^in^r
in. or less in diameter, it is safe to consider them non-human,
and belonging to some one of the common domestic animals,
such as the cat, horse, cow, ox, pig, sheep, or goat. If the cor-
puscles are of oval shape and nucleated, they are certainly not
mammalian, but are derived from a fowl, a fish, or a reptile. A
possible, though highly improbable, contradiction to these general
premises must be recalled, namely, the structural alterations of
human erythrocytes occurring in anemic bloods — particularly
the tendency toward microcytosis in chlorosis, and toward megalo-
MEDICO-LEGAL TESTS FOR BLOOD. 115
cytosis, poikilocytosis (often of oval character), and nucleation in
intense anemia, such as that of the primary pernicious type.
Leukemic blood, however, is characteristically hall-marked. Here
may be noted Dresbach's case,1 unique of its kind, of a healthy
young mulatto 90 per cent, of whose erythrocytes were of oval
or elliptical shape.
In a considerable proportion of cases microscopical examina-
tion of a dried blood clot avails nothing, owing to the destructive
changes which have taken place in the cells. Even under the
most favorable conditions all one can usually accomplish with the
aid of microscopy is to hazard an opinion that a given specimen
of blood is either mammalian or derived from a fowl, a fish, or a
reptile. For the medico-legal aspects of such examinations,
together with the rigid technical precautions demanded, the
reader is referred to the standard works on forensic medicine.2
This method of examination has already been
SPECTROS- described. (See p. 107.) It is to be employed
COPY. whenever a sufficient quantity of a blood solu-
tion is available, the purpose being to deter-
mine the presence or absence of blood pigment, and further to
identify its particular variety. If the blood clot is tolerably fresh,
it may yield, in aqueous solution, the absorption bands of oxy-
hemoglobin, which, on the addition of ammonium sulphid, charac-
teristically change to the spectrum of reduced hemoglobin. Old
stains, especially those whose hemoglobin has been altered by
exposure to the air and sunlight, show a spectrum of methemo-
globin, while blood which has undergone putrefaction, in addition
to yielding this spectrum, shows that of hematin. Recent stains
can usually be dissolved in distilled water, but old clots require
a more active solvent, such as acetic acid or sodium hydroxid.
When such reagents are used, the spectra either of acid hematin
or of alkaline hematin result,* according to the reaction of the
solvent employed. If the stain has been subjected to a high de-
gree of heat, with the consequent formation of hematoporphyrin,
it should be dissolved with concentrated sulphuric acid, the re-
sulting solution producing the spectrum of hematoporphyrin in
acid solution.
If positive, Teichmann's hemin test is certain
TEICHMANN'S proof of blood, although it does not, of course,
HEMIN TEST, indicate its source. The test is of extreme deli-
cacy, and may be relied upon to show the
presence of the slightest trace of blood in the material examined,
1 Jour. Amer. Med. Assoc., 1904, vol. xlii, p. 837.
2 Peterson and Haines, "Text-book of Legal Medicine and Toxicology,"
Philadelphia, 1904; Tidy, "Legal Medicine," London, 1882.
Il6 EXAMINATION OF THE BLOOD BY CLINICAL METHODS.
provided that the composition of the blood is not too materially
altered. Negative results are therefore not conclusive, since the
reaction may fail in stains exposed to a high temperature or to the
prolonged action of the* sun's rays, and in those contaminated by
certain substances, such as naphtha, iron rust, lime, lead, and
animal charcoal.
The hemin test is carried out as follows : A small particle
of the suspected material, reduced to a fine powder, is mixed with a
drop of normal salt solution upon the surface of a glass slide, the
mixture then being evaporated slowly by moderate heat until a
dry film forms. Care should be observed not to use too great heat
in the evaporation, for fear of spoiling the reaction by causing
decomposition of the hematin. The dry film is now covered with
a cover-glass, under which a drop of glacial acetic acid is allowed
to flow, after which the slide is again heated until minute bubbles
begin to form. At this instant the heating should cease, and the
preparation be allowed to cool. Active boiling at this stage of
the test may drive off all the free hydrochloric acid evolved by the
addition of acetic acid, and thus prevent the formation of the
sought-for crystals. When cool, the specimen is examined micro-
scopically with a low power (^ inch) dry objective, which shows,
if the material contained blood, distinctive crystals of hemin or
hematin hydrochlorid, consisting of yellow or brown rtiombo-
hedral plates, lying singly and arranged as crosses or as stellate
designs.
Van Deen's guaiacum test is sufficiently deli-
THE GUAIACUM cate to show the presence of blood pigment in
TEST. a solution as dilute as i : 5000, but unfortunately
it responds to so many other substances that its
only value is as a negative sign. A bit of the suspected clot or a
shred of the stained fabric is moistened with distilled water, in
order to dissolve the blood pigment, and to this solution are added
a few drops of freshly prepared tincture of guaiacum. To this a
drop or two of hydrogen peroxid is added, with the result that a
blue color immediately develops in the presence of even minute
traces of blood. Or the test may be carried out just as satis-
factorily simply by pressing against the dry stain a piece of wet
filter-paper, and then adding to the moist daub thus made the
guaiacum and peroxid. According to Peterson and Haines,1 the
following substances produce the same reaction with this test as
given by blood pigment : potato skin, casein, glue, iron and copper
compounds, the double chlorid of gold and sodium, manganese
dioxid, potassium permanganate, and indigo; all of which means
1 Loc. cit.
MEDICO-LEGAL TESTS FOR BLOOD. 117
that a positive reaction indicates absolutely nothing definite,
although, on the other hand, a negative result proves with great
certainty the absence of blood pigment in the material examined.
Originally Bordet,1 later Uhlenhuth and
THE BIOLOG- Tchistovitch,2 Wassermann and Schutze,3 and
ICAL TEST others demonstrated the important fact that the
FOR BLOOD, blood serum of an animal into which has been
injected the blood of another animal of different
species develops the property of agglutinating and dissolving
erythrocytes similar to those injected, but has no such effect upon
blood derived from another source. The principle of this biologi-
cal reaction is well expressed by Valee's law: If an animal, A, be
inoculated repeatedly with an albuminoid material from an animal
of a different species, B, the blood serum of A acquires the specific
property of precipitating in vitro albuminoid fluids derived from
animals belonging to the species B. Thus, in the blood of the
inoculated animal are developed antibodies selectively hostile to
the toxic principles of substances identical with those injected,
and the serum containing such antibodies is known as an anti-
serum. Lysins, which dissolve ; precipitins, which precipitate ; and
agglutinins, which clump, the poisonous substances and antidote
their toxicity, are examples of the antibodies evolved in this
•aanner. On this principle it is possible to produce antisera not
only for homologous bloods, but also for different animal albumin-
ous fluids and cells and for vegetable albumins. For instance,
such sera have been developed which react specifically with cow's
milk, with horse-meat, with semen, with various epithelial cells,
and with a number of other substances homologous to those
injected.
In the case of antisera for various bloods, while the test is
specific with homologous blood, it is also true that feeble reactions
may occur with the blood of closely related species. Thus,
rabbits treated with human blood yield a serum reacting not
only with the blood of man, but also with that of certain species
of monkeys. Nuttall and Dinkelspiel4 and Grimbaum5 showed
that it is the blood of the anthropoid apes (Simiada), especially
the gorilla, the chimpanzee, and the . orang, which reacts most
1 Annal. de PInstitut Pasteur, 1898, vol. xii, p. 688; ibid, 1899, vol. xiii,
p. 273.
* Deutsch. med. Wochenschr., 1901, vol. xxvii, p. 82; ibid., 1902, vol. xxviii,
pp. 659 and 679.
s Berlin, klin. Wochenschr., 1901, vol. xxxviii, p. 187; also Wassermann,
"Immune Sera " (Eng. trans, by Chas. Bolduan), New York, 1904.
4 Brit. Med. Jour., 1901, vol. i, p. 1141; also Nuttall, "Blood Immunity and
Blood Relationship," Cambridge, 1904.
4 Lancet, 1902, vol. i, p. 143.
Il8 EXAMINATION OF THE BLOOD BY CLINICAL METHODS.
decidedly with human antiserum; while the lower orders of
monkeys, represented by the Hapalida, the Cercopithecida, and
the CebidcB, give less positive results. Practically, this startling
biological confirmation of Darwin's views is scarcely a source of
error, since in high dilutions (500 or more) human antiserum does
not show a precipitate even with the highest order of primates'
blood (Layton1).
Antisera for horses, cattle, sheep, pigs, dogs, birds, and other
animals and fowls all react typically with homologous bloods,
but also sometimes, although always atypically, with alien bloods.
Pig antiserum, for example, reacts faintly with the blood of the
wild boar; horse antiserum with donkeys' blood; fox antiserum
with wolves' and dogs' blood; and sheep antiserum with goats'
blood. It is a notable fact that these are reactions between
biologically related species of animals, and that they are feeble
and atypical, in comparison with the reactions occurring between
homologous antisera and bloods. It is also true that the more
remote the biological relation of the animal from the one whose
blood activates the antiserum, the feebler the reaction becomes.
As explained subsequently, these pseudo-reactions do not occur
if the blood to be tested is adequately diluted before examination.
TECHNIC. — Preparation 0} the Antiserum. — The antiserum is
prepared by injecting healthy rabbits with from 5 to 10 c.c. of
human defibrinated blood, at intervals of about four days, until a
total of between 50 and 80 c.c. has been administered. One or
two weeks after the last injection the animal is bled, and the serum
obtained is collected in sterile test-tubes, which are sealed and
stored for future use. Belgian hares are excellent antiserum
producers, and are preferable to ordinary rabbits, being more
resistant to the toxic effects of the injections, and yielding highly
potent antiserum. Goats, sheep, and dogs have also been used,
but not with wholly satisfactory results. Ewing2 obtained ex-
cellent antiserum from a hen, which, being biologically far re-
moved from man, should theoretically furnish a highly selective
human antiserum.
The blood used for the immunization may be conveniently
secured from the placenta and umbilical cord. It is collected in a
sterile flask containing several small glass beads, which defibrinate
the blood when the flask is agitated for a few minutes. The blood
thus defibrinated may be injected immediately into the animal,
or placed in a refrigerator for subsequent use. The fresher the
blood injected, however, the more powerful the antiserum which it
produces. The injections may be subcutaneous, intravenous, or
1 Amer. Med., 1903, vol. v, p. 913. 2 Med. News, 1903, vol. Ixxxiii, p. 925.
MEDICO-LEGAL TESTS FOR BLOOD. 119
intraperitoneal, the last being the simplest and least dangerous
to the animal if properly carried out. One-half of the rabbit's
lower abdomen having been shaved and disinfected with a sub-
limate solution, the needle of the syringe is firmly thrust through
the tissues at a point within the prepared area, and .the injection
made when the abdominal cavity is entered. Experience will
determine the amount of pressure and manipulation necessary to
penetrate the abdomen to a sufficient depth and to avoid wounding
the gut. While making the injection an assistant should hold the
animal in such a position that its abdominal wall is kept tense.
Since the injection of human blood not infrequently causes toxic
symptoms in the treated animals, they should be kept in the best
possible hygienic surroundings, with ample runways, an abundance
of air and light, and plenty of food and water. It is a good plan
temporarily to discontinue the injections in animals which show
marked loss of weight and other evidences of severe reaction.
The blood of the animal under treatment should be tested
from time to time, and when found to be sufficiently potent with
human blood, the injections are stopped. A week or two later the
antiserum will be sufficiently powerful, and it is then collected by
bleeding the rabbit either from an ear vein or from the carotid
artery. In neither instance is it necessary to exsanguinate the
animal. The blood is collected, under aseptic precautions, in
a dish, from which the serum, after coagulation has occurred,
is pipetted into small sterile test-tubes measuring 10 cm. in
height by 0.5 cm. in diameter. The filled tubes are then
plugged with cotton and set upright in a refrigerator until re-
quired for the test. As a preservative a few drops of chloroform
may be added to each tubeful of antiserum. If this is done,
however, the antiserum must be incubated for half an hour before
being used, in order to remove, by volatilization, all traces of the
chloroform, which otherwise might cause a pseudo-reaction with
alien blood. Other preservatives, such as lysol, lysoform, carbolic
acid, and thymol, may also cause clouding of antiserum, and
therefore should not be used. Solutions of mercuric chlorid
strong enough to be antiseptic destroy the antiserum.
The test antiserum may be preserved in dry form by pouring
it into Petri dishes and drying in a cool place, the film thus ob-
tained being powdered and kept in a tightly stoppered bottle until
required for use. To prepare the antiserum, this powder is simply
dissolved in normal salt solution in definite proportions.
Testing the Suspected Stain. — In all cases the suspected stain
must be proved to be blood by the hemin crystal test, the spectro-
scope, and the other older methods described above. This is
120 EXAMINATION OF THE BLOOD BY CLINICAL METHODS.
highly essential in forensic work, because body albumins other than
blood (sputum, saliva, pus, feces, exudates, and albuminous urine)
are capable of giving positive reactions with human antiserum.
Contamination by such materials is, however, readily detectable
by other tests.
The stain to be examined is dissolved with a few drops of a 0.6
per cent, aqueous solution of chemically pure sodium chlorid,1 and
the resulting cloudy mixture cleared by nitration through either
asbestos or Schleicher's "blue ribbon" filter-paper, or by centrif-
ugalization. The solution of the stain thus rendered perfectly
clear is then added to the antiserum in the proportion of at least
100 to i, and the mixture incubated at 37° C. If the test be posi-
tive, a distinctly flocculent precipitate will form in the test-tube
within three hours, this reaction being preceded by the formation
of a more or less marked turbidity immediately or very shortly
after having mixed the antiserum and the blood solution. Slight
turbidities do not constitute positive reactions — they may occur
with heterologous bloods in dilutions less than the above. Several
controls are also to be prepared and incubated simultaneously:
one of the salt solution used as a solvent; a second of the pure
dissolved and cleared stain; a third of the pure test antiserum;
a fourth of human blood and normal rabbit's serum; and a fifth
of human blood and the test antiserum. All but the last of these
controls should remain clear.
Sources of Error. — Aside from pseudo-reactions due to under-
dilution of the antiserum, accidental clouding and precipitation
may arise from the following group of factors:
1. Bacterial Growths. — Antiserum clouded by bacterial con-
tamination may be rendered clear by filtration through a Pasteur-
Chamberland filter or by centrifugalization. Clouding from this
cause does not occur within the arbitrary three-hour time limit of
the test.
2. Preservatives and Solvents. — As stated above, various chemi-
cals used for preserving the antiserum and for dissolving the sus-
pected stains may lead to wrong inferences.
3. Hyperacidity and Hyper alkalinity. — The solution of the
stain should be neutral in reaction, feebly acid, or feebly alkaline.
1 In the case of old, difficultly soluble stains Uhlenhuth uses a one per cent,
aqueous solution of sodium hydrate, while Ziemke prefers a concentrated solution
of potassium cyanid, with subsequent neutralization with tartaric acid. These
chemicals, though active solvents for old blood stains, are not dependable, because
of their likelihood to cause false reactions with various antisera. Graham-Smith
and Sanger obtained precipitates with solutions of potassium cyanid (one per cent.),
tartaric acid (o.i percent.), and sodium hydrate (o.i per cent.). In medico-legal
work it is safe to be guided by Nuttall's advice, and refuse to submit to the test
bloods which are insoluble in normal salt solution
MEDICO-LEGAL TESTS FOR BLOOD. 121
If too highly acid or alkaline, positive reactions may occur with
unrelated blood.
4. Contamination of the Specimen. — Human albumins and
various chemicals may be mixed with the suspected blood stain or
may resemble it, and in forensic work their presence must be ab-
solutely excluded by appropriate tests. Nuttall 1 found that tannin
especially causes decided clouding even in i : 1000 dilutions, and
that solutions contaminated with yellow polished leather acted
similarly. He found that human blood mixed with shoe polish,
and blood allowed to dry upon black leather, wall-paper, various
dress fabrics, rubber, oil-cloth, silver and copper coins, coal, wood,
and other substances, reacted typically with human antiserum.
The clouding due to the admixture of earth (referable to the
presence of lime salts) Nuttall obviates by saturating with carbon
dioxid and subsequent nitration.
Old blood stains, except that they develop the precipitate
slowly, react like fresh blood. Ziemke2 examined stains known to
be twenty-five years old and obtained positive findings. Accord-
ing to J. Meyer,3 even solutions of the muscular tissues of five-
thousand-year-old .mummies react positively! Uhlenhuth4 found
that specimens could be frozen for two weeks at a temperature of
— ro° C. without in any manner affecting the sensitiveness of
the reaction,, and that blood mixed with soapy water, menstrual
urine, and other contaminating fluids responds typically and
promptly. Nuttall and Dinkelspiel5 demonstrated that human
blood mixed with the blood of different animals (sheep, oxen,
horses, and dogs) reacts characteristically with human antiserum.
Dried blood crusts subjected to an hour's heating at 130° C. do
not respond to the test.
Value of the Test. — The Bordet reaction has already figured in
three murder trials in this country,6 and in these cases it has been
accepted by the Court as valid evidence. In order to insure in-
fallibility, faultless technic, bred only of long and intelligent
experience, is one of the first essentials. This acquired, the ex-
aminer must exclude every source of error outlined above, and
consider as positive only those reactions which, with proper dilution,
afford a turbidity and distinct precipitate within the prescribed
time limit, the behavior of the several controls being consistent
with that of the main test. Under these conditions a solution
1 Loc. cit.
2 Deutsch. med. Wochenschr., 1901, vol. xxvii, pp. 424 and 731.
3 Munch, med. Wochenschr., 1904, vol. li, p. 663.
4 Loc. cit. 6 Brit. Med. Jour., 1901, vol. i, p. 1141-
8 1901, State of Maine vs. Lambert (Whittier); 1903, State of Del. vs. Collins
(Robin); 1903, Commonwealth of Penna. vs. Bechtel (Lear).
122 EXAMINATION OF THE BLOOD BY CLINICAL METHODS.
proved to be blood which reacts typically with human antiserum
may surely be pronounced of human origin.
The agglutination of human erythrocytes after
HANGING- their admixture with alien serum and the absence
DROP TEST, of this change on the addition of homologous
serum may be observed under the microscope.
This fact was first noted by Marx and Ehrnrooth,1 who use the
principle as the basis for the following simple test for identifying
blood stains.
The suspected blood stain is dissolved with a small quantity
of normal salt solution mixed with an equal amount of fresh
human blood, and of this solution a hanging-drop preparation is
made and examined under the microscope with a i-inch objective.
If the stain tested is human blood, the erythrocytes of the added
fresh blood remain unclumped at the end of fifteen minutes' time,
while if it is alien blood, they become distinctly agglutinated within
this period. Monkeys' blood, although it fails to clump the
erythrocytes, causes them to shrink and to become polygonal in
shape. The writer can confirm this test, so far as human blood is
concerned, but its medico-legal value must remain undetermined
until further studies have been made. The reaction should be
controlled by Bordet's test, for which it is in no sense a substitute.
OTHER METHODS OF BLOOD EXAMINATION.
Numerous methods of blood analysis other than those de-
scribed in this section have also been devised, more especially
for scientific investigation than for clinical use. Their detailed
description not being germane to the plan of this book, the reader
is referred to the original articles for exact data. Among these
non-clinical methods of research are included the estimations of
the total volume of blood (Haldane and Smith2); of the amount of
solids (Stintzing3); of the percentage of blood iron (Jolles4); of the
quantity of fat and fatty acids in the blood (Engelhardt 5) ; of the
blood viscosity (Hirsch and Beck8) ; of the osmotic tension of the
plasma (Hamburger7; de Vries8); and of the resistance of the
erythrocytes to the action of electricity, heat, and mechanical
injury (Laker9 ; Maragliano 10).
1 Munch, med. Wochenschr., 1904, vol. li, p. 293.
1 Jour. Physiol., 1900, vol. xxv, p. 311.
3 Verhandl. d. XII. Cong. f. inn. Med., 1893.
4 Arch. f. med. Exp., vol. xiv, p. 73.
8 Deutsch. Arch. f. klin. Med., 1901, vol. Ixx, p. 182.
8 Ibid., 1901, vol. Ixix, p. 503. 7 Centralbl. f. Physiol., 1893, vol. vii, p. 656.
8 Jahrb. f. w. Botanik, 1884, vol. xiv, p. 427.
* Wien. med. Presse, 1890, vol. xxxi, p. 1375.
10 Berlin, klin. Wochenschr., 1887, vol. xxiv, p. 797.
SECTION II.
THE BLOOD AS A WHOLE,
SECTION II.
THE BLOOD AS A WHOLE.
I. GENERAL COMPOSITION.
Blood is a tissue consisting of fluid and cor-
PLASMA, SERUM, puscular elements, the former constituting about
AND CELLS, three-fifths, and the latter two-fifths, of its total
volume. It has been approximated that the total
quantity of blood in the normal individual is from one-twelfth to
one-fourteenth of the body-weight, the proportion being somewhat
less in the infant than in the adult. Much lower proportions
than these were determined by Haldane and Smith,1 who found
that in health the bulk of blood ranged from one-thirtieth to one-
sixteenth of the body- weight (3.34 to 6.27 per cent.), these figures
having been calculated by a method based upon the capacity of
the blood to absorb CO 2 • The fluid element of the blood, known
as the plasma or liquor sanguinis, is an alkaline, yellowish liquid,
of a specific gravity ranging from about 1.026 to 1.030, and
containing approximately 10 per cent, of solid matter, of
which three-fourths are proteids, consisting of fibrinogen, serum
albumin, and serum globulin. Coagulation of the blood results
in its separation into a densely reticulated, somewhat granular
substance, fibrin, and into a clear, straw-colored, alkaline fluid,
serum. Fibrin is a sparingly soluble, highly elastic, proteid body,
which incloses and imprisons within its multitude of delicate
fibrils the corpuscular elements, the whole forming the blood clot
or crassamentum. Serum is a clear, straw-colored, alkaline fluid,
having a specific gravity of about 1.026 and containing practically
the same amount of solids and relative proportion of proteids as are
found in the plasma ; its proteid constituents are fibrin ferment,
which replaces the fibrinogen of the plasma, serum albumin,
and serum globulin.
The corpuscular elements of the blood are free cellular bodies
suspended in the plasma. They are of two varieties : the eryth-
rocytes or red corpuscles, and the leucocytes or white corpuscles.
1 Jour. Physiol., 1900, vol. xxv, p. 33.
"5
126 THE BLOOD AS A WHOLE.
In addition to these cells, two other elements are also found,
namely, the blood plaques and the hemokonia, although these
bodies, while they may be conveniently grouped with the red and
white cells, are not to be regarded as definite corpuscular entities.
The salts of the blood include sodium chlorid, potassium
chlorid, sodium carbonate, sodium phosphate, magnesium phos-
phate, calcium phosphate, and sulphates ; of these salts, sodium
chlorid is the most abundant, constituting from 60 to 90 per
cent, of the total amount of mineral matter.
Certain extractives are also found, among which are urea and
uric acid, creatin, creatinin, xanthin, hypoxanthin, sugar, fats,
soaps, and cholesterin.
The gases of the blood consist of oxygen, nitrogen, and carbon
dioxid, the oxygen existing chiefly in combination with hem-
oglobin in the erythrocytes, and the carbon dioxid as carbonates ;
the nitrogen is held in simple solution. About 60 volumes of gas
are contained in each 100 volumes of blood. Arterial blood con-
tains roughly 20 volumes of oxygen and 40 of carbon dioxid,
while venous blood contains less than 10 volumes of oxygen and
almost 50 of carbon dioxid ; the quantity of nitrogen in both
arterial and venous blood is from i to 2 volumes.
II. COLOR.
The distinctive color of the blood is due to
NORMAL the presence of the hemoglobin contained in the
VARIATIONS, erythrocytes, and alterations in the chemical com-
position of this pigment produce corresponding
changes in the color of these cells, and, consequently, in the
naked-eye appearance of the whole blood. The color of arte-
rial blood is bright scarlet, inasmuch as it contains a large amount
of oxygen in chemical combination with the hemoglobin ; while
venous blood, on the other hand, is of a dark, purplish-blue tint,
owing to its deficiency in oxygen and to the presence of more or
less uneliminated carbon dioxid. This difference in color is so
obvious that a cursory glance suffices to distinguish arterial and
venous bloods.
The presence of immense numbers of hemo-
DENSITY globin-containing elements accounts for the vary-
AND ing degree of density and opacity which the
OPACITY. blood possesses, distinguishing it from a mere
transparent, colored fluid. If, for any reason, the
hemoglobin escapes from the erythrocytes into the surrounding
plasma, this characteristic opacity is quickly lost, and the blood
ODOR AND VISCOSITY. 127
becomes transparent and of a " laky " color. The cells are laked
by the influence of heat, water, fat solvents, and hydrogen and
hydroxyl ions, all of which act upon the outer semipermeable layer
of the cells' stroma and thus favor hemoglobin dissolution. The
density and the opacity, and, consequently, the color, of the blood
increase and diminish according to the fluctuations which occur
in the relative amounts of plasma and erythrocytes, and also
according to the cells' richness in hemoglobin, irrespective of their
numerical variation.
In anemic conditions the blood is usually
PATHOLOGICAL pale in color, somewhat transparent, and thin
VARIATIONS, and watery-looking. This is the case particu-
larly in primary pernicious anemia, in chlorosis,
and in leukemia; in [the first- named disease it is sometimes difficult
to believe that the watery, pale fluid which flows from the puncture
is anything but pure serum ; in leukemia the blood drop may have
a peculiar light, mottled, streaked appearance, or a uniform milky-
white tint may predominate over the normal red hue. In cases
of dyspnea, arterial blood, because of its inadequate oxygenation,
may be dark blue, closely resembling blood from the veins. This
similarity has also been noted in cases of poisoning by sulphur-
etted hydrogen, in which condition the blood may even be changed
to a dark greenish tint. In some cases of diabetes mellitus the
presence of large quantities of free fat in the circulation seem-
ingly divides the blood drop into two distinct layers — an upper,
light-colored portion, containing supernatant fat droplets, and a
lower, darker layer of pure blood ; at first glance diabetic blood
may be somewhat pinkish or salmon-colored.
In poisoning by anilin, nitrobenzol, hydrocyanic acid, and potas-
sium chlorate the blood is chocolate- or dun-colored ; and in
poisoning by carbon monoxid, bright cherry-red. In severe
icterus a yellowish- red tint of the blood has been observed.
III. ODOR AND VISCOSITY.
Owing to the presence of certain volatile fatty acids blood
possesses a peculiar and characteristic odor or halitus, which may
be intensified by the addition of concentrated sulphuric acid, and
which rapidly disappears after the withdrawal of the blood from
the body. The slippery, greasy feeling of freshly drawn blood is
quickly lost after its exposure to the atmosphere, and is replaced by
a viscosity, or stickiness, as coagulation progresses. The viscosity
of the whole blood is apparently influenced to a large extent by
the cellular elements, chiefly by the erythrocytes, although the
128 THE BLOOD AS A WHOLE.
viscosity of the serum must also be regarded as a determining
factor of more or less importance.
Hirsch and Beck1 have determined that the "viscosity value,"
as they term it, of human blood is about five times that of distilled
water — i. e., the viscosity of blood having a specific gravity rang-
ing between 1.045 and 1-055 is expressed by the figure 5.1, in
comparison with that of water, which equals i, the temperature
of both fluids being the same, 38° C. Although no close relation-
ship can be distinguished between the degree of viscosity and the
specific gravity of the blood, these experimenters have apparently
proved that the lower the density of the blood, the less marked
its adhesiveness. This quality is exaggerated in individuals living
upon a largely nitrogenous diet, and it is greatly modified by star-
vation. S. Weir Mitchell2 has observed that hyperviscosity
develops when blood is subjected to the direct action of snake
venom, while Stengel3 has noted a similar condition resulting
from contaminating fresh blood with the serum of patients suffer-
ing from chlorosis, pernicious anemia, and leukemia. Any one
who has done much blood work is familiar with the marked
fluidity of the fresh specimen in the high-grade anemias, and
with the diminished viscosity of the erythrocytes and their dis-
inclination to form rouleaux under such circumstances.
IV. REACTION.
Under normal conditions the reaction of the
REACTION blood is alkaline, owing chiefly to the presence
IN HEALTH, of sodium carbonate and disodium phosphate.
Clinically, the degree of alkalinity is determined
by ascertaining the amount of sodium hydroxid which is exactly
neutralized by 100 c.c. of blood, the result being usually expressed
in milligrams of NaOH per 100 c.c. of blood. The figures given
by different investigators as representing the normal alkalinity
range within the widest limits, chiefly in consequence of the many
different methods by which such data were obtained. In view
of these marked discrepancies the alkalinity figures of different
workers are in no sense comparable unless they are based upon
precisely similar methods of investigation pursued with identical
technic. The following table, compiled from reliable data, illus-
1 Deutsch. Arch. f. klin. Med., 1901, vol. bdx, p. 503.
2 Mitchell and Stewart, "A Contribution to the Study of the Effect of the
Venom of Crotalus adamanteus upon the Blood," Washington, 1898.
3 "Twentieth Century Practice of Medicine," New York, 1896.
REACTION.
129
trates the range of the normal blood alkalinity as estimated by
various observers:
OBSERVER. DECREE OF ALKALINITY.
Kraus 162-232 mgm. NaOH per 100 c.c. of blood.
Burmin 182—218
Rumpff 182-218
Jeffries 200
Freudberg 200-240
Lepine 203
Canard 203-276
Drouin 206
Von Limbeck 218
Zuntz and Lehmann 240
Orlowsky 240-267
Von Jaksch 260—300
Schultz-Schultzenstein 260-300
Dare 266
Strauss 300-350
Brandenburg 33°~37°
Lowy 449
Berend 450-500
Engel 479-533
Mya and Tassinari 616
With the titration method, now generally admitted to furnish
fairly accurate results, appreciably higher figures are obtained
with laked whole blood than with serum alone, since by the
former method the alkalinity of all the plasma and cellular ele-
ments is estimated, while by the latter the influence of the cor-
puscles is entirely eliminated.
The alkalinity of the blood is slightly higher,
PHYSIOLOGICAL as a general rule, in men than in women and
VARIATIONS, children, and is somewhat influenced by the time
of day, being at its minimum during the early
morning hours, gradually rising during the afternoon, and falling
again during the evening. Some observers maintain that it is
increased during the period of digestion, but this fact is disputed
by others. It is temporarily diminished by the effects of mus-
cular exercise and by a diet deficient in nitrogenous substances;
on the contrary, richly nitrogenous }ood eaten during the per-
formance of muscular work overcomes the effect of such exertion
in lowering the alkalinity. The effects of cold baths are said to
increase the alkalinity of the blood. Orlowsky,1 from a study
of 63 cases of various maladies, concludes that the degree of
blood alkalinity is proportional to the erythrocyte count, but that
it bears no relation to the number of leucocytes.
In health, by the perfect mechanism of the emunctory organs
of the body, the normal balance of blood alkalinity is constantly
1 Deutsch. med. Wochenschr., 1903, vol. xxix, p. 601.
9
130 THE BLOOD AS A WHOLE.
maintained, in spite of the entrance of acids into the blood,
whether by the ingestion of acid substances or by their produc-
tion within the system, for the hyperacidity from such causes
is promptly removed from the blood by the action of the kidneys,
the skin, and the lungs. Thus, the ingestion of acids is quickly
followed by increased acidity of the urine and sweat, while at the
same time an increased quantity of carbon dioxid is given off by
the lungs. It is probable that the tendency to acidity is partly
neutralized by the ammonium salts generated from proteid foods,
and also by the action of the liver. The blood alkalinity may
be transiently increased by administering an alkali internally or
by enema, the latter method having the more pronounced effect,
according to Orlowsky.1
Increased alkalinity goes hand in hand with increased antidotal
action 0} the blood against bacterial infection, as experiments have
shown that animals whose blood had been artificially rendered
highly alkaline by the administration of sodium salts, showed
much greater resistance to the effects of virulent micro-organisms
than untreated animals. Therefore, it is believed that the power
of immunity against infections may, to a certain degree, be meas-
ured by the alkalinity of the blood, for, in animal experimenta-
tion, the fact is evident that the greatest degree of blood alka-
linity is found in animals whose immunity is absolute. The rat,
which is naturally immune to anthrax, has excessively alkaline
blood and other body fluids. This hyperalkalinity, however, does
not protect this rodent against plague. An excess of alkali in the
blood is probably antidotal to invading bacteria, not per se, but
rather because of its power to dissolve and liberate cell nucleins,
which, as alexins, are directly bactericidal.
Unfortunately, the question of alteration in the
PATHOLOGICAL alkalinity of the blood in various pathological
VARIATIONS, conditions is at the present time one about which
the opinions of different observers conflict, so
that conclusions concerning this subject must be accepted with
more or less reserve.
It is of interest, however, to note that most observers agree
that, as a rule, the alkalinity of the blood is perceptibly lowered
in those diseases associated with a febrile movement, but no defi-
nite relation between the intensity of the pyrexia and the degree
of lessened alkalinity has been established. Auerbach,2 having
noted that a temperature of 108° F. renders alkaline culture media
bactericidal, argues that in acute infections the pyrexia, although
it diminishes the alkalinity of the blood, at the same time may be
1 Loc. cit. 2 Abst. in Jour. Amer. Med. Assoc., 1903, vol. xli, p. 1122.
REACTION. 131
beneficial, in that it also increases its bactericidal action. Sub-
normal alkalinity figures have also been met with in the primary
and secondary anemias, with the exception of chlorosis, in which
condition the blood alkalinity usually is either normal or perhaps
slightly increased. Desevres1 has drawn attention to the fact
that in the early stages of acute diseases the alkalinity is either
normal or somewhat increased, and in the majority of instances
it becomes perceptibly diminished during convalescence. In
chronic diseases it is usually decreased if the duration of the dis-
ease has been of long standing.
Drouin2 found a lessened alkalinity of the blood in enteric
fever, pneumonia, malarial fever, diphtheria, rheumatic fever, ery-
sipelas, appendicitis, and in many other acute infections. Can-
tani3 maintains that in the algid stage of Asiatic cholera the
reaction of the blood during life in some cases may be even
acid, and that the alkalinity is always markedly reduced. Von
Jaksch,4 Peiper,5 Kraus,6 and others state that the alkalinity
is generally diminished in uremia, diabetes, osteomalacia, organic
diseases of the liver, and in poisoning by carbon monoxid and
by phosphorus, especially by the latter. Decreased alkalin-
ity has also been noted in cholemia, Addison's disease, Hodg-
kin's disease, poisoning by mineral acids, the late stages
of malignant neoplasms, and in various long-standing cachectic
conditions. Thomas7 found the alkalinity reduced in acute
alcoholism and as the result of chloroform narcosis. TchlenorfT8
found a diminished alkalinity in a wide variety of skin diseases,
among which are named psoriasis, eczema, pemphigus, purpura
hcsmorrhagica, erythema multiforme, lichen rubra, and elephantiasis.
Since it was also found that the administration of arsenic failed
to increase the blood alkalinity, the action of this drug upon
dermatoses is evidently not due to its influence upon the blood.
In organic diseases of the heart unassociated with pyrexia and
in nervous diseases the alkalinity of the blood has been found to
be increased. In chronic rheumatism and in renal lesions unac-
companied by uremic symptoms the reaction of the blood is usu-
ally found to be unaltered.
1 These de Lyon, 1897-98.
2 " Hemo-alcalimetrie et Hemo-acidimetrie," These de Paris, 1892, No. 83.
3 Centralbl. f. d. med. Wissensch., 1884, vol. xxii, p. 785.
4 Deutsch. med. Wochenschr., 1893, vol. xix, p. 10.
5 Arch. f. pathol. Anat., 1889, vol. cxvi, p. 337.
8 Zeitschr. f. Heilk., 1889, vol. x, p. 106.
7 Arch. f. exper. Pathol. u. Pharm., 1898, vol. xli, p. i.
8 Russkiy Vrach, 1898, vol. xix, p. 248; abst. in Jour. Cutan. and Genito-
Urin. Dis., 1898, vol. xvi, p. 544.
132 THE BLOOD AS A WHOLE.
V. SPECIFIC GRAVITY.
In the majority of healthy male adults the
NORMAL specific gravity of the blood varies from 1-055 to
RANGE. 1-065, the average being in the neighborhood of
i .060. In women the average is somewhat less —
about 1.056; in children it is about 1.051; and in new-born infants
i. 066 is considered normal. Diurnal variations in the specific
gravity have been noted, but these fluctuations are slight and
unimportant. The blood density of habitual dwellers in high alti-
tudes is distinctly increased. Lloyd Jones1 and Schmaltz2 found
that muscular exercise, if moderate, lowers the blood density, but
if prolonged and attended by free sweating, distinctly increases it.
Venous blood is said to be of slightly higher specific gravity than
arterial. The average specific gravity of the blood of the two
sexes, as determined by the principal observers, is as follows:
AUTHORITY. MALES. FEMALES.
Askanazy 1060. i 1056.4
Schmidt 1060.0 1050.0
Hammerschlag 1061.5 IO57-5
Lloyd Jones 1058.5 105 1 .5
Landois IO57-5 1056.0
Becker 1057.0 1056.5
Schmaltz 105 7.0 1056.0
Peiper 1055.0 1053.0
From a clinical standpoint the specific gravity
PATHOLOGICAL of the blood may be regarded, within certain
VARIATIONS, limits, as a tolerably accurate index to the
corpuscular richness of this tissue and to the
hemoglobin equivalent of the erythrocytes, since fluctuations in
these constituents immediately give rise to corresponding altera-
tions in the density of the blood mass. It follows, then, that in
the various conditions of anemia, characterized by corpuscular
and hemoglobin losses, low specific gravities are encountered;
on the other hand, it is also obvious that in conditions of polycy-
themia the cellular increase and the high hemoglobin equivalent
are mirrored by the corresponding rise in the density of the
blood. An increase promptly follows any sudden drain upon
the fluids of the system sufficient to cause inspissation of the
blood, such as may result from copious diarrhea, free sweating,
or hyperemesis; while the density is at once lowered as the re-
sult of sudden dilution of the blood, following, for example, the
injection of a large quantity of saline solution or even the inges-
1 Jour. Physiol., 1887, vol. viii, p. i.
2 Deutsch. Arch. f. klin. Med., 1890, vol. xlvii, p. 145.
SPECIFIC GRAVITY.
133
tion of a large volume of liquid. Fluctuations in the specific
gravity of the blood under such circumstances, which are purely
physiological in character, are invariably of transient duration,
for the normal relation between the relative volumes of corpuscles
and plasma becomes quickly reestablished by means of the liquid
interchange between the tissues and the blood vessels.
Owing to the fact that in most instances a close relationship
exists between the amount of hemoglobin and the specific gravity,
some investigators are accustomed to take this parallelism as a
basis for calculating the percentage of hemoglobin in the blood.
Thus, by determining the specific gravity and by comparing the
figure thus obtained with a table giving the hemoglobin equiva-
lents corresponding to varying degrees of blood density, fairly
accurate results have been obtained. The following hemoglobin
equivalents of different specific gravities of the blood have been
determined by Hammerschlag 1 and by Lichty.2
LICHTY.
Specific gravity. Hemoglobin equivalent.
1035-1038
25-30 pe
1038-1043
30-40
I 043-1 045
40-45
1045-1047
45-5°
1047-1049
50-55
1049-1052
55-65
1052-1054
65-70
1054-1056
70-75
1056—1060
75-85
1060-1063
85-95
1063-1065
: 95-100
HAMMERSCHLAG.
Specific gravity. Hemoglobin equivalent.
1033-I035 25-30 Per cent-
1035-1038 3°-35
1038-1040 35-4°
1040-1045 40-45
1045-1048 45-55
1048-1050 55-65
1050-1053 65-70
io53-I055 70-75
i°55-I057 75-85
1057-1060 85-95
It will be noted that in both these tables the variations in
density are somewhat greater in high than in low hemoglobin
percentages. It has been stated by Diabella3 that, on the aver-
age, a difference of 10 per cent, in hemoglobin corresponds to
4.46 parts per thousand in specific gravity, and that differences
amounting to from 3 to 5 parts per thousand in the specific grav-
ity may arise from the influence of the stroma of the erythrocytes,
in blood characterized by a striking disturbance in the parallelism
which normally exists between these cells and the hemoglobin.
In the clinical application of this indirect method of computing
hemoglobin percentages several conditions, in which factors other
than the presence of hemoglobin in the erythrocytes influence the
specific gravity, must be excluded. In leukemia, for example, it
will be found that hemoglobin percentages based on the above
tables are much higher than actually exist, the cause of this fal-
1 Loc. cit. * Phila. Med. Jour., 1898, vol. ii, p. 242.
8 Deutsch. Arch. f. klin. Med., 1896, vol. Ivii, p. 302.
134 THE BLOOD AS A WHOLE.
lacy being the presence of enormous numbers of leucocytes in the
blood; in pernicious anemia the hemoglobin is frequently higher
than the specific gravity indicates, for in this disease the individual
corpuscles are much richer in hemoglobin than normally; and
in conditions associated with extensive dropsy the hemoglobin
percentage does not parallel the specific gravity, owing to the
abnormally high proportion of fluids in the blood mass.
These three sources of error, aside from the rather trying tech-
nic by which one must first determine the specific gravity of the
blood drop (see p. 94), are sufficient to make most workers
reluctant to adopt this method as a substitute for the hemometer.
VI. FIBRIN AND COAGULATION.
The essential factor of coagulation of the blood is the forma-
tion of fibrin, a proteid substance, produced in the plasma after
the withdrawal of the blood from the body, by complex chemical
changes occurring between the soluble calcium salts and the
nucleoproteids of the blood, with the consequent production of a
fibrin ferment. The theories regarding coagulation are numer-
ous, conflicting, and unsatisfactory, and must necessarily remain
disputed points until our present uncertain knowledge of the
chemistry of the blood proteids becomes fuller and more definite.1
Coagulation is delayed and imperfect in hemoglobinemia, in as-
phyxia, in jaundice, in conditions of general dropsy, and in in-
dividuals who are prone to bleed freely from trivial wounds. A
similar effect is produced by the administration of alcohol. Lamb2
has found that the venom of certain poisonous snakes conspicu-
ously affects clotting. Cobra venom diminishes coagulation to a
marked degree, and in some instances may even wholly prevent it.
Intoxication with daboia poison (the venom of Russell's viper) acts
variously, according to the quantity injected. In small doses it
hinders coagulation and causes the formation of soft, loose clots;
but in large doses this venom so increases the coagulability of
the blood as to lead to fatal intravascular clotting. Small doses
of the calcium salts, especially the chlorid, promote coagulation,
but the opposite effect ensues if the dose is too large. The
administration of gelatin usually acts in the same manner, be-
cause, so Gley 3 and others of the French school believe, of the fact
1 Schafer's "Text Book of Physiology," vol. i, Edinburgh and London, 1898,
contains a complete exposition of the various theories of coagulation of the blood
existing up to the present time.
2 Glasgow Med. Jour., 1903, vol. lix, p. 80.
3 Sem. m&L, 1903, vol. xxiii, p. 113.
FIBRIN AND COAGULATION.
135
that it always contains from 2 to 5 per cent, of calcium chlorid.
Brat 1 explains the therapeutic action of gelatin in promoting in-
travascular clotting by assuming that it contains substances which
favor the deposit of plastic material, presumably derived from the
blood cells, at the site of the clot. The studies of Boggs2 show that
gelatin is a much less active clotting agent than calcium chlorid,
and that it may entirely fail to act in some cases. Blood coagu-
lability as a factor of intestinal hemorrhage and of venous throm-
bosis in enteric fever is referred to elsewhere. (See Section VII.)
Carstairs Douglas3 found the following coagulation figures in
healthy women and in normal and complicated pregnancies:
AVERAGE
GROUP.
COAGULATION
TIME IN
MINIMUM.
MAXIMUM.
MINUTES.
Albuminurics (16 cases):
(a) Pregnant
s.6o
4.70
7.c
(b) Puerperal
7.OO
?.6o
IO.O
Eclampsias (22 cases):
(a) Pregnant
7.40
4.^0
Q.O
(&) Puerperal
7.OO
4.50
Q.C
Healthy pregnant women ( 7 cases) ....
7.40
5.00
9.0
Healthy non-pregnant women (7 cases)
7-75
5.00
IO.O
From these findings Douglas concludes that the thrombi
found in various organs in fatal cases of eclampsia are not due
to increased intravascular clotting.
In the microscopical examination of a slide of fresh blood
fibrin appears as extremely delicate, straight, filamentous lines
which cross and recross the field in every direction. It forms
a network of fine, interlacing, fibrillary bands, in the clear areas
of the serum intervening between the masses of corpuscles, some
of the fibrin threads apparently radiating from centers consisting
of small irregular masses of blood plaques. The relation of these
islands of blood plaques to coagulation and fibrin formation, if,
indeed, any exists, is undetermined.
In normal blood the formation of the fibrin
HYPERINOSIS network becomes apparent within two or three
AND minutes after exposure of the blood to the air,
HYPINOSIS. and the process is completed within about six
minutes. * In certain pathological conditions,
however, both the length of time required for its formation
1 Berlin, klin. Wochenschr., 1902, vol. xxxix, pp. 1146 and 1170.
1 Med.News, 1904, vol. Ixxxiv., p. 182. 3 Brit. Med. Jour., 1904, vol. i, p. 709.
136
THE BLOOD AS A WHOLE.
and the density of the network vary. An increase in the amount
of the fibrin network is spoken of as hyperinosis, while a decrease
in .fibrin is termed hypinosis.
In general terms it may be stated that fibrin
PATHOLOGICAL is increased in acute inflammatory and infectious
VARIATIONS, diseases, especially in those attended by an ac-
tive febrile movement and by exudative proc-
esses, the amount of fibrin roughly corresponding to the intensity
of the process. This statement is made with certain reserva-
tions, for the rule does not hold true in all such instances, as is
FIG. 39. — NORMAL BLOOD.
Showing rouleaux formation and fibrin network.
noted below. All febrile states do not imply a fibrin increase,
for none is found in the fevers associated with grave cases of
chlorosis and of pernicious anemia. Hayem 1 suggests that the
density of the fibrin network may be taken as an indication
of the individual's resisting powers against disease, inasmuch
as it appears to be more marked in the blood of the vigorous than
of the feeble. In acute inflammations accompanied by serous
and purulent exudates a dense fibrin reticulum is observed, the
extent of the exudation being in a degree measured by the density
1 "Du Sang," Paris, 1889.
FIBRIN AND COAGULATION.
137
of the network. Fibrin is increased to a slighter extent in par-
enchymatous inflammations, in inflammations of the mucous
membranes and skin, and in the febrile stages of chronic sup-
purations. Among the diseases which are associated with an
increase in fibrin are the following: abscess, pneumonia, rheumatic
fever, erysipelas, acute gout, severe angina, bronchitis, influenza,
diphtheria, pleurisy, peritonitis, pericarditis, hepatitis, meningitis,
acute gastritis, enteritis, cystitis, vaginitis, pustular stage of variola,
and suppurating tuberculous cavities. Fibrin is not increased
in malignant neoplasms, enteric fever, malarial lever, tubercu-
losis, pernicious anemia, leukemia, chlorosis, and purpura. In
FIG. 40. — HYPERINOSIS.
Showing marked increase in the density of the fibrin network.
parenchymatous nephritis it is but slightly, if at all, increased,
while in interstitial nephritis the increase may be notable.
Pfeiffer1 declares, as the result of his investigations, that in
all diseases in which an increase of fibrin exists inflammatory
leucocytosis is also present, and that he has never been able to
demonstrate hyperinosis without coexisting increase in the number
of leucocytes. But leucocytosis does not invariably imply hyper-
inosis, although the two conditions almost always go hand in
hand. Leucocytosis may occur in purpura and in malignant
disease unattended by fibrin increase; on the other hand, in in-
1 Zeitschr. f. klin. Med., 1897, vol. xxxiii, p. 215.
138 THE BLOOD AS A WHOLE.
fluenza the fibrin network is denser than normal, while the number
of leucocvtes is not increased.
VII. OLIGEMIA.
The term oligemia signifies a reduction in the total volume of
the blood, involving a diminution of both the liquid and the cel-
lular portions. It occurs most conspicuously after hemorrhage,
and probably after this accident only. Sometimes, the hemorrhage
having been profuse, the oligemia proves rapidly fatal; but in
other instances, where the hemorrhage has been less extensive,
the decreased volume of blood is slowly made up, first by a rapid
osmosis of serum into the depleted capillaries from the neighbor-
ing lymph spaces, and later by a slower numerical increase of
the cellular elements, the products of an actual manufacture of
erythrocytes by the blood-making organs.
In some of the advanced cachectic states, in which profound
adynamia and poor nourishment of the body are prominent clin-
ical manifestations, there is seemingly good reason for believing
in the existence of a true oligemia; but in the absence of con-
firmatory evidence, reduction of the blood volume in this class of
cases must remain rather a suspicion than an accepted fact. The
term oligemia is, therefore, in the light of our present understand-
ing, applicable only to blood losses resulting from hemorrhage.
VIII. PLETHORA.
The term plethora is currently used to express a condition
characterized by an actual excess in the total volume of the blood,
affecting both the liquid and the cellular elements. According
to the views of many of the older and a few of the modern path-
ologists, a true polyemia, or an increase in the blood volume, un-
accompanied by any qualitative changes, is thought to exist in
certain individuals whose mode of life and luxurious habits are
supposed to predispose and give rise to excessive blood-forma-
tion. The compatibility between a real full-bloodedness and
a "high-liver" was formerly much more generally credited than
at the present time, and the association of such signs as a rich,
ruddy complexion, enlargement of the superficial blood vessels,
and a full, bounding pulse was depended upon for the recognition
of this condition. Of late, however, the drift of opinion is against
the probability of any such permanent increase in blood volume,
but until an accurate method of estimating the total quantity of
HYDREMIA. 139
blood in the body has been devised, the presence or absence of a
real plethora must obviously remain conjectural.
True plethora may occur as a transitory condition, as the re-
sult of the direct transfusion of blood, or the mechanical forcing
back into the general circulation of a quantity of blood from a
part to be removed from the body, as by the use of an Esmarch
rubber bandage previous to the amputation of a limb ; in a similar
manner a new-born infant may become temporarily plethoric by
a complete emptying of the placenta before tying the umbilical
cord. Plethora resulting from any of these influences is invari-
ably of a transient character, for the physiological balance of the
organism rapidly disposes of the surplus amount of blood by de-
struction of the excess of cellular elements and by the elimination
of the liquid portions.
Serous plethora may be defined as an increase in the volume of
blood due to excessive quantities of its liquid and saline con-
stituents, without augmentation in the number of its cellular
elements. A condition of this sort may be dependent upon the
ingestion of large amounts of liquids, upon the transfusion of saline
solutions, or upon vasomotor dilatation, whereby the transfer
of an unduly large amount of liquids from the tissues to the blood
vessels is promoted. In organic lesions of the kidneys and of the
heart, with diminished elimination of water from the system, a
serous plethora of more or less chronicity may develop. The
condition, however, is usually of transient duration, as the surplus
liquids in the circulatory system are quickly disposed of and the
blood volume reduced to normal by intracapillary transudation.
J. L. Smith1 believes that in chlorosis a true excess in the volume
of blood exists, though Lloyd Jones2 maintains that the condition is
one of hydremia (see below) rather than of actual serous plethora.
Cellular plethora is a term which may appropriately be applied
to the condition, also known as polycythemia, consisting in an in-
crease in excess of the normal standard in the number of erythro-
cytes. The circumstances under which this change occurs will
be discussed later. (See p. 197.)
IX. HYDREMIA.
A relative increase in the quantity of the liquid constituents of
the blood is known as hydremia. This condition must not be
confused with serous plethora, which is characterized by both a
relative and an absolute increase in the liquids of the blood. The
1 Jour. Physiol., 1900, vol. xxv, p. 6. 2 "Chlorosis," London, 1897.
140 THE BLOOD AS A WHOLE.
specific gravity of the blood is observed to fall in relation to the
degree to which the change develops.
Hydremia may be produced by any factors which disturb the
normal relations between the cellular and the liquid elements of
the blood, so that the latter are unduly increased. In other
words, the blood is diluted, in consequence of which a given drop
of such blood shows an apparent decrease in the number of cel-
lular elements, although the latter are in reality unaffected by the
change. Hydremia is observed after extensive hemorrhages, in
which the primary effect of the oligemia is the taking up by the
capillaries of an excess of tissue fluids to replace the blood loss;
later, as blood formation gradually makes up for the cellular
deficiency, the normal ratio between the corpuscles and the plasma
is reestablished. In the acute febrile infections hydremia may
develop in consequence of excessive destruction of the blood
albumins by the pyrexia. Hydremia may also occur as the result
of the ingestion of large amounts of liquids, after the injection of
normal saline solution, and as a consequence of vasomotor dila-
tation. The watery constituents of the blood are relatively in-
creased in certain of the severe anemias, owing to the deficiency of
corpuscular elements, which is compensated by fluids derived from
the tissues. In some dropsical conditions, notably those associated
with renal and cardiac lesions, hydremia may also be said to
exist, either with or without anemia. Hydremia, while it does not
necessarily imply the coexistence of anemia, is naturally often an
accompaniment of the latter condition.
Hydremia dependent upon such physiological factors as inges-
tion of fluids and vasomotor dilatation is a transient condition,
for the excess of fluid is promptly eliminated, and the normal
relations restored. In other conditions the duration of the change
obviously depends upon the nature and permanency of the etiolog-
ical factor or factors.
X. ANHYDREMIA.
Anhydremia is a condition in which a relative diminution in
the liquid constituents of the blood occurs, as the result of rapid
osmosis from the capillaries into the surrounding tissues. Inas-
much as the cellular elements do not share in this draining-away,
their number is necessarily increased in a given drop of such con-
centrated blood. The specific gravity of the blood increases in
relation to the extent of the fluid drain.
Conditions which cause the sudden dissipation of large quanti-
ties of liquids from the body, in consequence of hyperactivity of
LIPEMIA. 141
the mucous and serous surfaces, are the most prominent factors
in producing anhydremia. Thus, after profuse diarrheas, urinary
crises, free sweating, excessive vomiting, and sudden and exten-
sive pleural and peritoneal effusions the blood becomes concen-
trated from a temporary loss of its fluid elements, which pass
from the vessels into the tissues to replace the liquids lost in
consequence of the drain. Ewing1 illustrates this principle of
anhydremia by his observations on patients in whom a pro-
longed attack of malarial fever with severe anemia was followed
by enteric fever or by acute dysentery. In such instances the
thin, watery blood of the malarial infection promptly became
thicker and darker in color as the inspissating effects of the com-
plicating illness supervened.
Oliver 2 has shown also that a moderate degree of anhydremia
may arise as the result of various influences ' which cause an in-
crease in arterial tension and a consequent acceleration in the
transfer of water from the vessels into the tissues. For example,
the change has been brought about by the influence of local and
general exercise, faradism, massage, cold bathing, and the admin-
istration of suprarenal extract.
From the nature of the drain, which is rapidly compensated by
the constant interchange which goes on between the vessel and
the tissue fluids, anhydremia is a temporary condition. A per-
fect physiological balance limits its duration to brief periods of
time. (See " Polycythemia," p. 197.)
XI. LIPEMIA.
Fat is present in normal blood in the form of an exceedingly
fine emulsion, the amount varying in man from i.co to 3.25 parts
per thousand of blood, the mean amount being 1.6, according .to the
analyses of Becquerel and Rodier.3
By the term lipemia is meant the presence of an excess of free
fat in the circulating blood, a phenomenon which is observed in a
number of conditions, both physiological and pathological. In
addition to fat globules, the blood in lipemia may also contain
fine granular particles failing to respond to the usual tests for
fat. The nature of these granules is still in dispute, but it is
generally believed that they are either a proteid substance pre-
cipitated in the presence of free fat, or that they represent the
1 "Clinical Pathology of the Blood," ad ed., Philadelphia and New York, 1903.
2Croonian Lectures, Lancet, 1896, vol. i, pp. 1541, 1621, 1699, and 1778.
3 Cited by Futcher, Jour. Amer. Med. Assoc., 1899, vol. xxxiii, p. 1006.
142 THE BLOOD AS A WHOLE.
albuminous envelop surrounding certain of the fat globules.1
During the period of digestion, especially after a meal rich in
fats, the blood may contain a sufficient amount of fat to give rise
to temporary lipemia; the condition may also be met with in the
breasl-jed infant, in the pregnant woman, and in the obese.
Menstrual suppression is also capable of overloading the blood
with fat.
The existence of lipemia is of little clinical importance, for it
has been observed in a number of diseases, so that it cannot be
considered characteristic of any particular lesion. It has been
noted in the following conditions: arteriosclerosis, chronic alcohol-
ism, diabetes mellitus, gout, certain diseases of the liver, heart, and
pancreas, chronic nephritis, tuberculosis, splenitis, malarial fei'er,
typhus fever, Asiatic cholera, peritonitis, pneumonia, and poison-
ing by phosphorus and by carbon monoxid. Lipemia commonly
occurs as the result of lacerated "wounds of the blood vessels situated
in fatty tissues, and after fractures of the long bones involving injury
of the fatty marrow.
The degree of lipemia may be so marked that the macroscop-
ical appearance of the fresh blood is altered, the presence of large
quantities of free fat rendering it salmon-colored, turbid, and
milky. This is especially conspicuous in the specimen of blood
serum obtained by centrifugalization, which has a distinct grayish,
opaque appearance, not unlike that of chyle.
Macroscopically, the presence of lipemia may be determined
by mixing with ether in a test-tube a portion of the turbid blood
serum, the excess of fat promptly dissolving, so that the serum
becomes clear. Hey I,2 W. Hale White,3 and others have been
able to distinguish lipemic blood in the retinal vessels by means
of the ophthalmoscope.
Microscopically, lipemia may be recognized by the presence
of large numbers of glistening fat droplets, about 0.5 to 2 f* in
diameter, which lie in the plasma between the groups of cor-
puscles, often exhibiting very lively Brownian movements. These
droplets respond to the usual tests for fat, dissolving in ether,
and staining black with osmic acid and brick-red with Sudan III.
XII. MELANEMIA.
The occurrence in the circulating blood of minute particles of
melanin or pigment, derived usually from the hemoglobin of the
1 See Futcher, loc. cit.; also Cole (cited by White), Lancet, 1903, vol. ii, p.
1007.
2 Trans. Amer. Ophthal. Soc., 1880, p. 54. 3 Lancet, 1903, vol. ii, p. 1007.
GLYCEMIA. 143
erythrocytes destroyed by blood parasites, is known as melan-
emia. These melanin particles appear as fine bits of granu-
lar matter, black or of a reddish-yellow color, either lying free in
the blood plasma or embedded in the protoplasm of the leuco-
cytes. In some instances the granules are extremely small-sized
and few in number, and again the amount may be considerable,
large numbers of pigment particles being apparently fused into
masses.
Melanemia is frequently present in malarial jever, especially
of the severer types, both in the form of free pigment and as
pigmented leucocytes. Particles of pigment in the bodies of the
leucocytes have also been seen in cases of insolation, in relapsing
fever, in melanotic sarcoma, and in Addison's disease.
XIII. GLYCEMIA.
Glycemia, or the presence of grape-sugar in the blood, occurs
in perfectly normal blood to a very slight degree, the quantity of
sugar found under physiological circumstances not exceeding 1.5
parts per thousand.1 The presence of sugar in excess of this fig-
ure, which may be termed hyperglycemia, is met with in diabetes
mellitus, in which disease as high as 9 parts per thousand have
been detected.2 The investigations of Freund3 and of Trinkler4
apparently show that the blood in carcinoma, especially of vis-
ceral involvement, contains an excess of some reducing agent, to
all intents and purposes identical with sugar. Tire former author,
in consequence of this fact, lays stress on the finding as a means
of differentiating between carcinoma and sarcoma, since no such
increase has been observed as an accompaniment of the latter
type of neoplasm. Lepine5 finds that the sugar content of the
blood appreciably increases after extirpation of the pancreas,
a hyperglycemia developing within twenty-four hours after the
ablation of this organ. He also finds hyperglycemia after liga-
tion of the duct of Wirsung*
The most accurate method of detecting small quantities of
sugar in the blood is by the phenylhydrazin hydrochlorid test,
conducted by von Jaksch7 as follows: A small amount of blood,
1 The term "potential sugar" (Lepine) is applied to the sugar produced in
normal blood after having been kept outside the body for half an hour, at a tem-
perature of 58° C. This sugar is believed to be evolved from one or more carbo-
hydrate molecules of the blood proteids.
1 Hoppe-Seyler, Virchow's Arch., 1858, vol. xiii, p. 104.
8 Wien. med. Blatter, 1885, vol. vii, pp. 268 and 873.
4 Centralbl. f. d. med. Wissensch., 1890, vol. xxviii, p. 498.
5 Cited by Flexner, Univ. of Penna. Med. Bull., 1902, vol. xiv, p. 391.
* Sem. me*d., 1903, vol. xxiii, p. 385. 7 Zeitschr. f. klin. Med., 1886, vol. xi, p. 20.
144 THE BLOOD AS A WHOLE.
obtained by wet-cupping, is first freed from proteids by adding
an equivalent weight of sodium sulphate and then boiling and
filtering, the filtrate thus obtained being used for the test. A
solution is now made in a test-tube, by mixing 2 parts of phenyl-
hydrazin hydrochlorid and 4 parts of sodium acetate with about
6 c.c. of water, and gently heating the fluid, if necessary, to
effect solution. Five c.c. of the proteid-free filtrate, while still
warm, are added to an equal volume of the test solution. This
mixture is then placed in a test-tube half filled with water, heated
for half an hour in a water-bath, and allowed to stand until cool.
When cooling of the mixture has occurred, it shows under the
microscope the presence of the characteristic yellowish crystals
of phenyl-glucosazon, either detached or in clusters, together with
colorless crystals of sodium sulphate.
XIV. URICACIDEMIA.
The presence in the blood of a demonstrable amount of uric
acid has been designated as uricacidemia. The blood of the
normal individual does not contain this substance in amounts
sufficiently large to be detected by ordinary clinical tests, but it is
found in appreciable quantities in a number of pathological condi-
tions. Garrod,1 many years ago, recognized that excessive accumu-
lation of uric acid in the blood was associated with gout, and he at-
tached to this sign much diagnostic significance. Later investiga-
tions, however, have proved the utter unreliability of this finding
as a pathognomonic sign of this disease, for in recent years a large
number of other conditions has been found to be more or less
constantly accompanied by relatively large amounts of uric acid
in the circulating blood. Notable examples of such diseases are
pneumonia, hepatic cirrhosis, acute and chronic nephritis, uremia,
chronic gastritis, leukemia, severe anemia, and those conditions in
which deficient blood aeration constitutes a prominent clinical
symptom, such as organic cardiac disease, exudative pleurisy, and
emphysema. Uric acid is not found in the blood hi enteric fever nor
in rheumatic fever. Pyrexia, of itself, evidently has no influence
in producing uricacidemia, nor is it at all probable that this con-
dition goes hand in hand with an excessive elimination of uric acid
in the urine.
Garrod's test is well adapted clinically for detecting the pres-
ence of appreciable quantities of uric acid in the blood. Slightly
modified, it may be applied in the following manner: Two
1 Med. and Chirurg. Trans., 1854, vol. xxxvii, p. 49; ibid., 1848, vol. xxxi, p. 183.
ACETONEMIA AND LIPACIDEMIA. 145
and one-half c.c. of blood serum, obtained by blistering, are
placed in a shallow watch-glass and acidulated by the addi-
tion of about 4 drops of a 30 per cent, aqueous solution of acetic
acid. A linen thread is then immersed in the acidulated blood,
which is slowly evaporated at a temperature not exceeding 70°
F. At the expiration of from twrenty-four to forty-eight hours,
if the sample of blood contains uric acid, characteristic crystals
of this substance are deposited upon the thread, their identity
being readily detected by microscopical examination and by the
murexid test.
XV. CHOLEMIA.
The presence in the blood of bile or bile-pigments has been
termed cholemia, a condition which accompanies various forms
of icterus. Bilious blood may have, as already stated, a yellow-
ish-red color, and may yield, on agitation, an abundant foam,
tinged with yellow. Hypertonicity of the serum and a tendency
toward hemoglobin dissociation are characteristic of cholemic
blood. (See " Icterus.") Bilirubin may be detected in the blood
even when urine tests for this substance have proved negative,
according to von Jaksch,1 who employs this procedure to demon-
strate its presence: About 10 c.c. of blood, obtained by wet
cupping, are allowed to clot, after which the serum is pipetted
off, filtered through asbestos, and coagulated at a temperature of
80° C. Thus treated, the presence of bilirubin is betrayed by a
greenish discoloration of the serum, which, if bile-free, remains
a pale straw color. Should a brownish color develop by this
test, the presence of hemoglobin in the serum is indicated.
XVI. ACETONEMIA AND LIPACIDEMIA.
The occurrence in the blood of demonstrable amounts of ace-
tone and of fatty acids is referred to as acetonemia and lipac-
idemia, respectively. Acetonemia has been found in associa-
tion with numerous pathological conditions, chiefly in those
characterized by pyrexia, while fatty acids in the blood have been
detected in diabetic coma, in malignant jaundice, in leukemia,
and in various acute infections.
For the recognition of acetone Simon2 recommends Den-
ige's test, to be applied as follows: About 3 c.c. of blood are
treated with 30 c.c. of Denige's reagent (20 gin. of concentrated
sulphuric acid mixed with 100 c.c. of distilled water, to which 5
1 Loc. cit. 2 "Clinical Diagnosis," 5th ed., Philadelphia, 1904.
10
146 THE BLOOD AS A WHOLE.
gm. of yellow oxid of mercury are then added), and allowed to
stand until a dark-brown precipitate has formed, after which the
supernatant fluid is filtered off and treated with more of the
reagent, so as to effect complete precipitation. It is then acidi-
fied by the addition of about 3 c.c. of a 30 per cent, solution of
sulphuric acid, and boiled for one or two minutes. The appear-
ance of a white precipitate on boiling indicates the presence
of acetone. This precipitate may be almost wholly dissolved
by the addition of hydrochloric acid in excess.
Fatty acids may be detected by boiling equal parts, by weight,
of blood and sodium sulphate, filtering, evaporating the filtrate
to dryness, and then extracting the residue with absolute alcohol.
Microscopical examination of the residue will reveal crystals of
fatty acids if lipacidemia exists.
XVII. BACTERIEMIA.
Bacteriemia, or the presence of bacteria in the
OCCURRENCE, circulating blood, is a condition associated with
a number of infectious diseases, in which instances
it is frequently, but by no means constantly, possible to dis-
cover the specific micro-organism of the disease in question by
careful bacteriological examination of the blood. The demon-
stration in the blood of such bacteria as pyogenic cocci in gen-
eral septicemia, of the Streptococcus pyogenes and other pyogenic
organisms in malignant endocarditis, of the bacillus of Eberth
in enteric fever, of the gonococcus in gonorrheal arthritis, of
the pneumococcus in pneumonia, and of the Bacillus tuberculosis
in severe cases of acute miliary tuberculosis, is sufficient proof,
without citing other instances, of the diagnostic value of bacterio-
logical blood examinations. Such examinations are warranted
in every case of severe infection the nature of which appears
doubtful, since by their aid alone it is often possible to derive
diagnostic clues of the greatest practical value.
From the clinician's viewpoint, normal blood
LATENT is absolutely sterile, since no cultural method has
INFECTION, yet been devised by which it is possible to demon-
strate the presence of bacteria in the circulation
of the healthy individual. From the pathologist's standpoint,
however, such a statement must be accepted guardedly, in the
light of recent investigations. Adami,1 in a comprehensive resume
of the whole field of bacterial infection, cites a series of apparently
1 Jour. Amer. Med. Assoc., 1899, vol. xxxiii, pp. 1509 and 1572; also Ford,
Jour, of Hygiene, 1901, vol. i, p. 277.
BACTERIEMIA. 147
conclusive experiments by his assistants, Nicholls and Ford, who
found that the kidneys and livers of healthy animals, removed
aseptically immediately after death and placed in agar-agar kept
at the temperature of the body, showed, after a few days, a rela-
tively abundant growth of bacteria. This observer concludes
that under normal conditions the leucocytes pass out through
the mucosa on to the free surface of, more especially, the alimen-
tary tract, some of these cells then undergoing destruction, while
others, now laden with various foreign matters, including bacteria,
pass back again into the submucosa and find their way either
into the lymphatic channels or into the portal venules. In both
of these sites there exists a decided tendency toward bacterial
disintegration and destruction. Such isolated bacteria as may
have escaped leucocytal destruction, or removal by the lymphatic
glands or by the endothelium of the portal system, may pass
either through the thoracic duct or through the liver, and enter
the systemic circulation, from which they are eliminated chiefly
by the kidneys. Such a condition as this, known as "latent in-
fection" or "latent microbism," appears to be compatible with
perfect health, for the number of bacteria which thus gain access
to the blood stream and tissues is so small that unless their
virulence is especially striking and the susceptibility of the indi-
vidual peculiarly marked, the resisting powers of the tissues re-
main sufficiently strong to prevent bacterial proliferation. It is
also obvious that the presence in the blood of so limited a num-
ber of bacteria cannot be demonstrated by culturing.
If, on the other hand, the conditions are such
BLOOD that bacteria multiply in the blood to any decided
CULTURES, extent, then their development in artificial media
outside the body may be successfully obtained in
many instances, provided that proper technic is employed. That
this has not been more successfully accomplished is no doubt
due to the powerful bactericidal action of the shed blood, whereas
this influence in the circulating blood is but trifling. As Adami
remarks, "Because certain observers have failed to discover
bacteria in the blood from cases of infectious diseases, it by no
means follows that the blood when shed has been free from bac-
teria." In modern methods of examination precautions are
taken to attenuate the bactericidal properties of the shed blood
by freely diluting it with a large quantity of fluid media, instead
of using relatively small amounts of solid culture, as has been
done largely in the past, and as the result of this improved technic
blood culturing now yields a much higher percentage of positive
148 THE BLOOD AS A WHOLE.
findings, and gives more uniform results than were formerly
obtained. (See " Bacteriological Examination," p. 109.)
Among the various bacteria which different
BACTERIA observers have succeeded in isolating from the
FOUND IN circulating blood are included many micro-organ-
THE BLOOD, isms, the identity of which, as etiological factors
of disease, is generally recognized, and also a
number to which pathogenicity cannot be convincingly attributed.
The following list gives the most important examples of the
former class :
B. aerogenes capsulatus. B. tetani.
B. anthracis. B. tuberculosis.
B. coli communis. B. typhosus.
B. influenza. Diplococcus intracellularis menin-
B. leprcB. gitidis.
B. mallei. Gonococcus.
B. cedematis maligni. Micrococcus tetragenus.
B. pestis bubonica. Pneumococcus.
B. pneumonia. Pyo genie staphylococci.
B. proteus vulgaris. Pyogenic streptococci.
In addition to this list, a certain amount of interest attaches to
the discovery in the blood of certain bacilli (Achalme), micrococci
(Walker), and diplococci (Triboulet) in rheumatic fever; of
peculiar bacilli (Afanasiew) in relapsing fever, in addition to the
specific spirillum of this infection; of diplobacilli (Craig) in
mumps; and of diplococci (Class) in scarlet fever and in typhus
fever (Balfour and Potter). The presence of the Bacillus icte-
roides (Sanarelli) in the blood of yellow fever patients is now
known to mirror a secondary infection.
The conditions in which the above-named bacteria occur in the
blood will be discussed in a later section, under the diseases in
question. (See " General Hematology," Section VII.)
XVIII. ANEMIA.
In a clinical sense the term anemia refers to
DEFINITION, any deterioration in the quality of the blood, af-
fecting the erythrocytes, the hemoglobin, or
both of these elements. Thus, in pernicious anemia the most
conspicuous deterioration in the quality of the blood is a diminu-
tion in the number of erythrocytes, or an oligocythemia; in chlo-
rosis the most marked change is usually a loss of hemoglobin,
ANEMIA. 149
or an oligochromemia; while in many other anemic conditions the
erythrocytes and hemoglobin are decreased more or less propor-
tionately. While it is true that, strictly speaking, the word anemia
may also be used to designate a reduction in the blood volume,
this condition is better denned by the use of the term oligemia.
Ischemia is a form of local anemia resulting from some mechani-
cal interference with the blood supply of the affected area.
In certain individuals with such decided pallor
PSEUDO- of the skin and mucous membranes that their
ANEMIA. appearance at once leads one to infer that they
are suffering from a well-defined anemia, no signs
of this condition can be discovered, for even after the most careful
examination of the blood the number of erythrocytes and the per-
centage of hemoglobin may be. found to be normal. Such instances
of apparent blood deterioration have been called pseudo-anemia;
they are often explained by hereditary peculiarities, by vaso-
motor disturbances affecting the superficial capillaries, and by
deficiencies in the pigment and in the development of the capillary
network of the skin. In pseudo- chlorosis the patient shows the
typical objective signs of chlorosis, yet her hemoglobin and cor-
puscular values are normal. (See "Chlorosis.") Vermehren1
has described, under the term angiospastic pseudo-anemia, the
transient periods of almost cadaveric pallor which occur in some
individuals with normal blood, as the result of vasomotor spasm
provoked by cold, fatigue, emotion, and like influences. Dwellers
in tropical countries are especially prone to a spurious form of
anemia, to which the misnomer tropical anemia is occasionally
applied. Every medical clinic can furnish patients suffering from
neurasthenia, tuberculosis, and advanced Bright's disease, whose
pallid countenances are a striking contrast to their normal blood
counts. "Prison pallor" suggests lack of fresh air and sunshine
rather than severe blood deterioration. It does not follow, therefore,
that pallor of the skin and mucous membranes is invariably an indi-
cation of anemia, although this sign is not misleading in the ma-
jority of instances. On the other hand, it should not be forgotten
that persons of good color and robust appearance sometimes suf-
fer from decided anemias without the fact becoming evident at
first glance. In chlorosis florida, for example, red cheeks are not
incompatible with a low hemoglobin percentage. In view of these
sources of error, in order to diagnose anemia with absolute accu-
racy, an examination of the blood is essential, for no matter how
valuable other clinical signs may appear, the changes in the blood
are often the real key to the situation.
1 Sem. med., 1903, vol. xxiii, p. 167.
150 THE BLOOD AS A WHOLE.
An entirely satisfactory classification of the
CLASSIFI- various forms of anemia still remains to be de-
CATION. vised, in spite of the numerous attempts which
not a few eminent authorities have made to
group these conditions according to sound pathological consid-
erations. Therefore, largely for the sake of convenience, all
anemias may be broadly grouped into two theoretical classes:
primary and secondary.
According to this tentative classification, primary anemias may
be considered those in which a lesion of the hematopoietic organs
is essentially accountable for the production of the disease. In
anemias of this sort, the etiological factors are either entirely un-
discoverable, or, if they are to be detected, too trivial to explain the
intensity of the disease. Here the predominant clinical manifesta-
tions are to be found in the changes occurring in the composition
of the blood, the other symptoms being considered secondary to,
and dependent upon, these alterations.
Under the term secondary anemia are included those cases
of anemia which are apparently secondary to, and symptomatic
of, certain definite pathological lesions not primarily affecting
the blood-making organs, such as, for example, enteric fever,
syphilis, septicemia, malignant disease, malarial fever, and hemor-
rhage. In such anemias the other clinical symptoms are, as a
rule, much more conspicuous than the blood changes, which
are thought to be secondary. An exception to this general rule
must be taken, however, in regard to the anemia caused by the
presence of the Bothriocephalus latus in the intestinal canal, for
in this infection the blood picture is by all odds the most striking
clinical manifestation. It is, furthermore, true that in some
instances a secondary anemia may apparently merge into one of
the primary type, should the protracted duration of the former
in course of time cause such profound systemic effects that finally
the blood-making organs become exhausted, and refuse ade-
quately to supply the constant demand for corpuscles, with the
result that the most prominent clinical signs are now found in
the blood, and not in the original symptoms of the disease in
question. The high grade anemia which sometimes follows
enteric fever, becoming of such intensity that it counterfeits a
primary anemia, may be cited as an example of this change.
Until further progress has been made in the study of the physi-
ology and pathology of the blood-making organs the following
provisional classification of the anemias may be used for clinical
purposes :
I. PRIMARY ANEMIA. — Chlorosis, pernicious anemia, splenic
HEMOLYSIS. 151
anemia, lymphatic leukemia, myelogenous leukemia, Hodgkin's
disease.
II. SECONDARY ANEMIA. — Dependent upon causes such as
hemorrhage, intestinal parasites, prolonged lactation, unfavorable
hygiene, metal poisoning, malignant disease, acute infections, and
chronic diseases producing long-standing drains on the albumin
of the blood.
Excluding the effects of hemorrhage, deficient
PATHOGENESIS. blood formation, excessive blood destruction,
and a combination of these two processes are
generally regarded as the three possible essential factors in the pro-
duction of anemia. Deficient hemogenesis is to be attributed to a
large number of different causes, among the most prominent of
which may be mentioned the influence of unhygienic surroundings
and insufficient nourishment from improper food and from in-
adequate powers of assimilation. It is also probable that con-
genital and acquired failure of the blood-making organs and the
presence of growths which intercept the material for blood forma-
tion are to be considered as the origin of defective hemogenesis in
some instances.1 Excessive blood destruction may be due to
acute febrile and infectious conditions, or to the presence in the
blood of certain toxins which destroy the corpuscles. It is char-
acterized during life by an excess of urobilin and iron in the urine,
and by the development of hematogenous jaundice.
XIX. HEMOLYSIS.
In order to understand the process of hemol-
EHRLICH'S ysis it is necessary briefly to refer to Ehr-
SIDE-CHAIN lich's side-chain theory of immunity,2 the hy-
THEORY. pothesis which furnishes the best explanation
of the organism's reaction against bacteria,
toxins, and other noxious agencies. According to this theory, it
is assumed that the body cell consists of a central group of mole-
cules by virtue of which the inherent characteristics of the cell are
determined and maintained, and a second, subsidiary molecular
group, which, by means of its unsatisfied affinities, is capable of
combining with nutrient materials, toxins, and other substances,
which are thus brought into intimate relationship with the cell
1 Mackenzie, Lancet, 1891, vol. i, p. 73.
2 Proc. Roy. Soc., London, 1900, vol. Ixvi, p. 424; Nothnagel's "Spec. Path,
u. Ther.," 1901, vol. viii, p. i; Klin. Jahrb., 1898, vol. vi, p. 299; also Ehr-
lich and Morgenroth, Berlin, klin. Wochenschr., 1899, vol. xxxvi, pp. 6 and 481;
ibid., 1900, vol. xxxvii, pp. 453 and 681; ibid., 1901, vol. xxxviii, pp. 251, 569,
and 598.
1^2 THE BLOOD AS A WHOLE.
structure. These subsidiary molecules, known as side-chains or
receptors, are simply links between assimilable substances and the
cell, which can neither be nourished nor poisoned except by the
intermediation of its receptors. Just as receptors possess specific
affinities for linking with certain food stuffs and with no others,
so there is believed to be a congenial reaction between receptors
and toxins, certain varieties of receptors combining with one kind
of toxin and other varieties with another. The receptor and the
toxin, therefore, must be homologous before the two can combine.
The receptors concerned in the process of toxin immunity belong
to Ehrlich's "first order"; they have but a single uniting bond for
combining with the toxin, and for this reason are also termed
uniceptors.
Receptors.
~ Tcocophore.
• Haptophore.
Body cell.
FIG. 41. — ILLUSTRATING THE MECHANISM OF THE TOXIN-CELL UNION BY THE INTERMEDIA-
TION OF RECEPTORS
A toxin molecule consists of two atomic groups, each with dif-
ferent affinities and with separate functions. One, termed the
haptophore group, serves to combine the toxin unit with the cell
receptor for which it has a selective affinity; the second, known as
toxophore group, serves to injure the cell when the haptophore-
receptor combination is formed. The mechanism of this anchoring
of the toxin to the vulnerable cell may be represented by the above
diagram (Fig. 41).
The union of toxin and cell leaves the latter more or less crippled,
either so severely that it dies, or but slightly, so that it still lives.
If the latter be the case, the cell commences to elaborate more re-
ceptors in its combat against the toxin — elaborates them in great
excess of its needs, so that in spite of the fact that many of these
new-born receptors are promptly seized by other toxin molecules,
HEMOLYSIS. 153
some of them are thrown off by the cell and float off free in the
blood and other body fluids. These liberated receptors, or hap-
tins, constitute antitoxin. In their free state they can combine
with homologous toxin molecules just as readily as when still at-
tached to the cell, and such a combination obviously renders inert
the toxin, since its haptophore group is thus satisfied and cannot
now become anchored to the cell. According to Welch's hypoth-
esis, these antidotal substances may act not only in their primary
function as toxin neutralizers, but, under certain conditions, may
irritate the invading bacteria to elaborate similar substance for
their own protection. In other words, this theory of reciprocity
in infection assumes that if bacteria irritate the body cells, the latter
in turn similarly affect the bacteria.
Toxins deprived of their toxophore groups, but retaining their
haptophore group, are designated toxoids, and such bodies, though
capable of becoming attached to the cells by their haptophore
group, are inert, because they contain no toxic element.
Toxoids can also unite with antitoxin (free receptors or hap-
tins) by means of their haptophore link. Toxins incompletely
combined with antitoxins, and therefore still capable of causing
modified poisonous effects, are known as toxones. The following
diagram illustrates the production of antitoxin and the union of
toxins and toxoids with the cell and its liberated receptors :
—vi Toxins united
,/\ with cell.
Free recep-
tors; haptin; <-
antitoxin. '.•/X
Toxins united with
antitoxin.
Body cell.
FIG. 42. — ILLUSTRATING THE ELABORATION AND ACTION OF ANTITOXIN.
The injection into animals of bacteria, various
HEMOLYSIS. body cells, and the products of these substances
in time gives rise to the development of specific
"antibodies" in the blood serum of the treated animal, as it ac-
154 THE BLOOD AS A WHOLE.
quires immunity. When the latter is complete, the animal's blood
will be found to have acquired a lytic or destructive action upon
cells similar to those injected. For example, the injection of ery-
throcytes gives rise to hemolytic serum; of bacteria, to bacterio-
lytic serum for the specific organism introduced; of bone marrow
and lymphatic tissue, to leucolytic serum ; of spermatozoa, hepatic
cells, and epithelial cells, to spermolytic, hepatolytic, and epi-
theliolytic sera, respectively. The adaptive changes thus pro-
duced in the animal injected are absolutely specific — the injection
of erythrocytes produces a serum acting only upon the erythro-
cytes, not upon the leucocytes, bacteria, or body cells.1
Isolysis is a term used to denote a hemolytic action due to the
injection of one animal with cells from another animal of the same
species, the active factors of this process being known as isolysins.
The destructive influence of a normal individual's blood upon the
erythrocytes of another person illustrates this phase of hemolysis.
Autolysis should result, theoretically at least, by the immunization
of an animal against injections of his own cells, with the conse-
quent evolvement of substances termed autolysins. The occurrence
of hemolysis in icterus, in Winckel's disease, and after internal
hemorrhage is suggestive of autolysis.
The lytic property of the blood Ehrlich attributes to the inter-
dependent action of two distinct elements of the plasma, the com-
bined influences of which are essential to produce the change. In
the process of hemolysis the receptors of the erythrocytes serve
to connect these cells, by the interposition of an intermediary
body, or amboceptor, with a complementary toxic body, or com-
plement, which, when thus united to the cells, exerts its destructive
influence. The receptors concerned in hemolysis are said to be-
long to the "third order"; they are provided with two haptophore
groups, one for combining with the vulnerable cell and the other
with the complement, which then can act upon the cell attached to
the first haptophore group.
The amboceptor is formed within the body, as the result of a
cellular hyperactivity excited by the organism's adaptation to
alien blood or to other irritant and toxic material. Amboceptors
are thought to represent liberated "third order" receptors, evolved
and cast off by the cells during the process of adaptation. They
are stable substances, capable of progressive increase, and act as con-
necting links between the complement and the cell. This function
1 For a complete account of these reactions see: (i) Vaughan and Novy,
"Cellular Toxins," Philadelphia, 1902; (2) Welch, Huxley Lecture, Lancet, 1902,
vol. ii, p. 977; (3) Prudden, Med. Rec., 1903, vol. Ixiii, p. 241; (4) Aschoff, Zeitschr.
f. allg. Physiol., 1902, vol. i, p. 69; (5) Wassermann, " Immune Sera," Eng. transl.
by Chas. Bolduan, New York, 1904.
HEMOLYSIS.
155
of anchoring the complement to the cell is performed by means of
two groups of atoms (hence the term, amboceptor), one with an
affinity for the corpuscle (cytophilic group), and the other with
an affinity for the complement (complementophilic group}. The
complement, which acts upon the erythrocyte partly as an enzyme
and partly as a toxin, is normally present in the blood, being
probably derived largely from the leucocytes. It is provided
with a haptophore group of atoms, which link it to the ambo-
ceptor, and with a zymophore group (corresponding to a toxin's
toxophore group) upon the action of which depends the cellular
destruction. The complement is of unstable nature, being de-
stroyed at a temperature of 55° C., and possesses many of the
characteristics of the enzyme. Its toxic action upon the erythro-
cytes is exhibited only when it is anchored, to them by the inter-
vention of the amboceptor, so that unless this link is formed, the
complement can exert no deleterious effect upon these cells. The
accompanying diagram (Fig. 43) shows the mechanism by which
an erythrocyte succumbs to the zymotoxic action of the comple-
ment:
Union of comple-
ment, amboceptor,
and cell.
'Zymophore.
— Haptophore.
Complement.
J- — Complemento-
phile.
" Cytophile.
Amboceptor.
Erythrocyte.
FIG. 43. — ILLUSTRATING THE MECHANISM OF HEUOLYSIS.
Resistance of the erythrocytes to hemolysis
ANTI- is attributed to the protective influences of sub-
HEMOLYSIS. stances known as antihemolysins, which in their
action correspond to antitoxins. Antihemolysins
are formed within the blood plasma after inoculation with hem-
olysins, and are of two kinds: anticomplements and antiamboceptors.
The former combine with the haptophore group of the complement,
156
THE BLOOD AS A WHOLE.
and the latter unite with the cytophilic group of the amboceptor —
combinations which in either instance break the continuity of the
complement-amboceptor-erythrocyte chain essential for the cell's
destruction. The action of these two forms of antihemolysins may
be illustrated thus:
Erythrocyte.
Antiamhoceptor. Anticomplement.
FIG. 44. — ILLUSTRATING THE MECHANISM OF ANTIHEMOLYSIS.
A. Interference of anticomplement with complement-amboceptor union. B. Interference of
antiamboceptor with amboceptor-cell union. C. Antiamboceptor-amboceptor union. D. Anti-
complement-complement union.
Hemolysis, although generally associated with
AGGLUTINA- more or less agglutination and precipitation of the
TION AND PRE- erythrocytes, is not always part and parcel of
CIPITATION. these phenomena. Serum may clump and pre-
cipitate the cells without exerting the slightest
hemolytic effect, while, on the other hand, dissolution of the cells
may progress without their becoming clumped or precipitated.
The principles of agglutination and precipitation have been applied
clinically in the diagnosis of enteric fever and other specific in-
fections, and in the biological test for the detection of human
blood (q. v.).
The injection of bacteria, alien erythrocytes, and other foreign
cells produces in the blood serum of the animal thus treated the
property of agglutinating and precipitating, in vitro, the bacteria or
cells injected. These phenomena are attributed to the presence,
in the animal's serum, of substances known as agglutinins and
precipitins, developed during the process of adaptation or im-
HEMOLYSIS. 157
munization. According to Ehrlich's theory, agglutinins are
liberated receptors elaborated by the body cells concerned in
the process, such receptors having a haptophore group with which
the bacterium or cell, as it may be, combines, and a zymophore or
agglutinophore group, which, when this link is formed, exhibits
its clumping properties. It will be noted that agglutination, unlike
hemolysis and bacteriolysis, does not involve the action of a com-
plementary toxic body — the receptor at once anchors and clumps
the homologous cell or bacterium through the combined offices
of its haptophore and zymophore atomic groups. Receptors
of this sort belong to Ehrlich's "second order." An agglutinoid
is the term used to designate a receptor deprived of its zymophore,
agglutinating group, but retaining its haptophore, combining group.
It is analogous to a toxoid, and, like this substance, is developed
by heat.
Precipitins are elaborated by the injection of albuminous
body fluids, such as defibrinated blood, into certain animals whose
blood serum, in consequence, acquires the property of precipitating,
in vitro, the albumins against which the adaptation is directed.
The serum of a rabbit adapted to human blood precipitates the
blood of man but none other, except, in low dilutions, the blood
of certain monkeys! (See p. 117.) Similarly, the injection of
milk from one animal develops in the serum of the animal treated
a precipitin which is specific for the milk used in the adaptation,
but for milk of no other species. " Antisera," as they are termed,
can also be prepared for various warm- and cold-blooded animals,
and such fluids precipitate only the blood of the animals for which
adaptation is sought, save in the case of closely related species,
in which a partial, incomplete reaction may occur in a low dilution.
Other albuminous body fluids (pus, albuminous urine, inflam-
matory exudates, and saliva) are capable of evolving, after injec-
tion, sera which precipitate the blood of the species from which
they were derived. The mechanism of precipitation is analogous
to that of agglutination, the precipitins consisting of liberated
"second order" receptors provided with a haptophore, combining
group, and a zymophore, precipitating group of atoms which
together act upon the susceptible cell.
SECTION III.
HEMOGLOBIN, ERYTHROCYTES, BLOOD
PLAQUES, AND HEMOKONIA.
PLATE I.
FIG. 1.
,
o
3
FIG. 3.
0
13
10
FIG. 4.
12
1
e
FIG. 5.
THE ERYTHROCYTHS.
(Figs. 1,3,3, and 4, Triacid Stain ; Fig. 5, Eosin and Methylene-blue. )
(E. F.
(Triacid Stain.)
Fig. 1. Normal Erythrocytes.
Fig. 2. Erythroblasts.
1. Microblast. Note the dense, glistening nucleus, and the scanty, ragged zone of proto-
plasm.
2, 3. 4. 5. 6. Normoblasts. The process of partial nuclear textrusion is apparently shown
in 3 and 5; in the latter cell the basic affinity of the nucleus is singularly slight. The
cell, 6, while as large as many megaloblasts, retains the nuclear characteristics of the
normoblast, of which it represents perhaps a hydropic form. Some writers regard
such erythroblasts as megaloblasts, on account of their large size.
7, 8, 9, 10, n, 12, 13. Megaloblasts. In 7 the nucleus, while normoblastic in size, is
megaloblastic in structure and in staining affinity. Note the variation in the size of
these cells, their delicate nuclear chromatin, and their decided tendency toward
polychromatophilia. In all the nucleus and protoplasm are separated by a conspicu-
ous hyaline ring.
Pig. 3. Erythroblasts with Multiple Nuclei.
1. Cell with a constricted, convoluted nucleus, apparently undergoing solution in the
protoplasm.
2. Normoblast with three nuclei arranged somewhat in the form of a clover-leaf.
3. Cell with two large nuclei, each apparently in an early stage of extrusion. Note the
affinity for fuchsin displayed by the protoplasm and by the upper nucleus, and the
distinct hyaline zone encircling the lower one.
4. 5. Normoblasts in karyokinesis.
Pig. 4. Erythrocytes Deformed in Shape and Size,
i, 2. Microcytes.
3. Megalocyte.
• 4. 5i 6. 7. 8, 9, 10, ii, 12, 13. Poikilocytes. Many of these cells are highly polychromato-
philic, especially n, 12, and 13.
(Eosin and Methylene-blue.)
Fig. 5. Erythrocytes Showing Degenerative Stroma Changes.
Granular basophilia is shown by i and 2 ; extreme decolorization by 3, 4, and 5. The other
cells represent various stages of hemoglobin loss and protoplasmic degeneration.
SECTION III.
HEMOGLOBIN, ERYTHROCYTES, BLOOD PLAQUES,
AND HEMOKONIA.
I. HEMOGLOBIN.
Hemoglobin, which occurs in the circulating
GENERAL blood in chemical union with oxygen as oxyhem-
PROPERTIES. oglobin, is an extremely complex ferruginous and
albuminoid substance contained within the stroma
of the erythrocytes. It constitutes approximately nine-tenths of
their total bulk, and a trifle less than 14 per cent, of the whole
blood. Hemoglobin displays a striking avidity for combining
with oxygen to form a peculiarly unstable, but definite, chemical
compound, and a similar tendency to yield up to the tissues
much of its oxygen during its passage through the capillary
circulation. Under the influence of deoxidizing agents oxyhemo-
globin may be deprived of its loosely combined oxygen molecule,
the resulting oxygen- free constituent being known as reduced
hemoglobin. Rhombic crystals of oxyhemoglobin, scarlet or
reddish-green in color, are rapidly formed if, for any reason,
separation of this substance from the corpuscular stroma takes
place. These crystals may be easily demonstrated by Reichert's
method l of laking a small quantity of blood with ether and then
adding from one to five per cent, of ammonium oxalate. Met-
hemoglobin is an oxygen compound of hemoglobin containing the
same quantity of combined oxygen as the latter, but differing from
it in holding its oxygen constituent in. a more intimate union.
The dingy brown color which develops in a solution of • oxyhemo-
globin after prolonged exposure to the atmosphere evidences the
production of this variety of blood pigment. (See " Methemo-
globinemia," p. 167.)
The amount of iron (in the form of hemochromogen) which
hemoglobin contains is considerable — somewhat in excess of
four per cent. It has been shown, clinically, by estimates made
with the ferrometer and the hemometer, that no fixed parallelism
1 Amer. Jour. Physiol., 1903, vol. ix, p. 97.
ii 161
1 62 ERYTHROCYTES, BLOOD PLAQUES, AND HEMOKONIA.
is maintained between the percentage of hemoglobin and the iron
contained in the blood.1
Under the action of acids, strong alkalis, or heat, hemoglobin
may be readily decomposed into two constituents: hematin, or
an iron-containing principle; and an albuminous residue of un-
known character, but somewhat resembling globulin. In combi-
nation with hydrochloric acid hematin forms a crystalline hydro-
chlorid of hematin termed hemin, or Teichmanri's crystals. Under
the microscope these crystals appear as black or dark brown,
elongated, rhombic prisms belonging to the triclinic system, which
are insoluble in water, alcohol, ether, chloroform, and dilute
acids. They may be demonstrated by preparing a slide of blood
(or of any dried substance containing blood pigment) to which a
small quantity of common salt has been added; a drop of glacial
acetic acid is then run beneath the cover-glass, so that it mixes
with the blood and salt, and the specimen thus prepared is heated
to just below the boiling point over a Bunsen flame. On cooling,
Teichmann's crystals may be seen under the microscope with a
low-power dry objective. (See p. 116.)
Iron-free hematin, or hematoporphyrin, may be derived from
blood by the admixture of concentrated sulphuric acid. This
substance is closely related chemically to urobilin, and occurs oc-
casionally as a pigment in nature and in normal and pathological
urines. Hematoidin, which is also free from iron, occurs in the
form of reddish, rhombohedral crystals, only in old clots resulting
from blood extravasations, such as cerebral hemorrhages and
splenic infarcts. It is derived from hematin, and is probably
identical with bilirubin.
The chief source of hemoglobin is the iron
ORIGIN. contained in various food products, about 10
mgm. daily representing the amount of this
metal ingested in an ordinary diet, according to the analyses
of Stockman.2 In the event of a stoppage of this source of an
iron supply, the formation of hemoglobin may proceed from the
supply of iron stored up in the various organs of the body, notably
in the liver. Bunge 3 has shown that in the young infant, whose
natural food, milk, contains but a slight trace of iron, this source
of hemoglobin manufacture is most potent. '
The recent experiments of Aporti 4 regarding the origin of
hemoglobin and the erythrocytes have shown that animals sub-
1 Rosin and Jellinek, Zeitschr. f. klin. Med., 1900, vol. xxxix, p. 109.
2 Jour. Physiol., 1897, vol. xxi, p. 55; ibid., 1895, vol. xviii, p. 484.
3 Zeitschr. f. physiol. Chem., 1892, vol. xvi, p. 177.
4 Centralbl. f. inn. Med., 1900, vol. xxi, p. 41.
HEMOGLOBIN. 163
jected to repeated bleedings and kept on an iron-free diet are able,
up to a certain point, to utilize the supply of body iron for hemo-
globin manufacture; but that when such a demand became so
great that this supply was exhausted, the red corpuscles became
progressively paler and paler, and the animal finally died. During
the course of these experiments, if the animal received injections
of iron, a prompt and striking increase in hemoglobin occurred,
the gain ranging from 50 to 95 per cent, within a week's time.
The injection of arsenic, on the contrary, produced no effect upon
the hemoglobin percentage, although it caused an increase in the
number of erythrocytes. The investigations of Stockman and
Charteris1 show that arsenic does not stimulate hemogenesis in
the bone marrow, and that its favorable action in malarial fever
and diseases of this class is probably due to its parasiticidal effect.
In animals injected with small doses of arsenic the marrow changes
consisted of hyperemia, decrease in the number of giant cells and
fat cells, increase in the leucoblasts, and slight, if any, prolifera-
tion of erythroblasts.
Baumann,2 studying the effects of iron carbonate, iron albumin-
ate, and arsenic upon regeneration of the blood in dogs after hem-
orrhage, arrived at these conclusions : that the administration of
either Blaud's pill or an albuminate of iron causes a rapid gain in
hemoglobin, even to a higher figure than that originally found
before the blood loss, the effects of each of these preparations of
iron being similar; that arsenic and iron combined, although
stimulating hemoglobin formation less than the above drugs,
are better general hemogenetic agents, so far as regeneration of
the corpuscles, proteids, and plasma is concerned; and that
arsenic, when given alone, is but an indifferent blood-builder.
The practical import of these experiments is patent.
Diminution in the amount of hemoglobin, as
VARIATIONS indicated by the hemometer, is known as oligo-
IN AMOUNT, chromemia, or achroiocythemia. It is a condition
usually, but not invariably, associated with a cor-
responding decrease in the number of erythrocytes. An ap-
parent increase in the hemoglobin percentage may result from the
concentration of the blood caused by a reduction in the quantity
of blood plasma consequent to excessive drains upon the liquids
of the body. By a similar physical mechanism factors produc-
ing a dilution of the blood are capable of causing an apparent
diminution in the hemoglobin. Marked oligochromemia is com-
monly observed in chlorosis, pernicious anemia, and leukemia;
1 Jour. Path, and Bacteriol., 1903, vol. viii, p. 443.
2 Jour. Physiol., 1903, vol. xxix, p. 18.
164 ERYTHROCYTES, BLOOD PLAQUES, AND HEMOKONIA.
and in the secondary anemias dependent upon such factors as
hemorrhage, mineral poisoning, acute and chronic infections,
malignant neoplasms, and constitutional diseases. The behavior
of the hemoglobin under such conditions is more fully alluded to
in connection with the lesions in question. Poggi,1 from a series
of experiments upon normal women, has shown that the hemo-
globin is slightly lowered (10 or 15 per cent.) for a few days before
menstruation, but with the establishment of the flow the oligo-
chromemia soon disappears. The primary loss he attributes to
retarded hemogenesis consequent to the lessened consumption of
albumin occurring in menstruating women, while the subsequent
gain he explains by the increased functional activity of the hemato-
poietic organs. Double oophorectomy in sexually active bitches
is followed by a distinct oligochromemia and by a less marked
oligocythemia, persisting for from two to six weeks, but in old
dogs the operation has no such effect. This experimental evi-
dence is advanced by Breuer and von Seiller2 in corroboration
of the ovarian theory of chlorosis.
In passing, it may be of interest to compare the degree of
hemoglobin loss in the various forms of anemia, as illustrated by
the following averages determined by the writer:
Average of 50 estimates in pernicious anemia 25.5 per cent.
" chlorosis 43.2 "
' leukemia - 39.4
" secondary anemia 55.2
Bierfreund's investigations3 in Mikulicz's clinic have led to the
current impression among surgeons that it is highly dangerous to
give a general anesthetic to a patient 'whose hemoglobin percent-
age is below 30; some operators regard 40 per cent, as the
lowest limit of safety, and refuse to employ any but a local anes-
thetic in cases with an oligochromemia exceeding this figure,
except under circumstances of imperative necessity. Any one,
however, who has attempted to verify the correctness of this gen-
eral belief must accept it with a shrug of the shoulders. The
writer knows of numerous patients whose hemoglobin percentages
all were below 30 in whom operations under general anesthesia with
ether were followed by uneventful recovery; in one instance (a
pan-hysterectomy lasting more than an hour and a half) the
hemoglobin was but 21 per cent., yet no ill effects were observed.
Patients with hemoglobin percentages of from 15 to 30 have
1 Policlin. Roma, 1899, vol. vi, p. i.
2 Wien. klin. Wochenschr., 1903, vol. xvi, p. 869.
3 Langenbeck's Arch., 1890-91, vol. xli, p. i.
HEMOGLOBIN. 165
been successfully operated by Girvin, Shober, Le Conte, Noble,
Baldy, J. C. Da Costa and others.1
Assuming that in the normal adult 14 gm.
ABSOLUTE represent the average amount of hemoglobin in
AMOUNT. 100 gm. of blood, the absolute amount of
hemoglobin may be readily calculated thus:
Hemoglobin percentage X 14 -r- 100 = Grams of hemoglobin in 100 gm. of
blood.
For example, in blood in which the percentage of hemoglobin,
as determined by the hemometer, is found to be 40, the calcula-
tion (40 X 0.14) gives the absolute amount of hemoglobin as
5.6 gm.
The proportionate amount of hemoglobin con-
COLOR tained in each erythrocyte, or its corpuscular
INDEX. richness in hemoglobin, is known as the color
index, or blood quotient, or valeur globulaire.
In normal blood the color index is theoretically expressed by the
figure i, although, practically, it varies from 0.95 to 1.05 in men,
and from 0.9 to i in women.2
In those anemias in which the decrease in the amount of
hemoglobin in the blood is coincident with a proportionate de-
crease in the number of erythrocytes, the color index remains
practically at the normal figure. If, however, the cellular de-
crease happens to be relatively greater than the hemoglobin
loss, then the index will naturally be found to rise above normal ;
thus, in pernicious anemia, in which condition the loss of cells
is proportionately much greater than the loss of hemoglobin,
high color indices, approaching or even exceeding 1.25, are fre-
quently observed. On the contrary, if the hemoglobin loss is rela-
tively more excessive than the corpuscular decrease, the color
index falls below normal; for example, in chlorosis, in which, as
a rule, the decrease affects the hemoglobin much more strikingly
than the erythrocytes, low indices, such as 0.50 or less, are common.
To calculate the color index, the percentage of hemoglobin is
divided by the percentage of erythrocytes, the "result being ex-
pressed in decimals. In order to Simplify this procedure 5,000,-
ooo erythrocytes per c.mm. must be arbitrarily considered as
normal, or 100 per cent. To obtain the percentage of cor-
puscles the actual number counted in one c.mm. of blood is
simply multiplied by two, and two or three decimals pointed off
from the left, depending upon whether the count is below or
1 Trans. Coll. of Phys. of Phila. (Sect, on Gynecology), 1902, vol. viii, p. 26;
also Amer. Jour. Obstet., 1902, vol. xlv, pp. 666 and 701.
2 Oliver, loc. cit.
1 66 ERYTHROCYTES, BLOOD PLAQUES, AND HEMOKONIA.
above the normal 5,000,000. The following examples serve to
illustrate the calculation in several conditions:
Normal Adult.
Erythrocytes : 5,000,000 per c. mm. (100 per cent.).
Hemoglobin: 100 per cent.
100 -e- loo = i : Color index.
Secondary Anemia.
Erythrocytes: 2,650,000 per c.mm. (53 per cent).
Hemoglobin: 40 per cent.
4° ~5~ 53 — °-75 : Color index.
Pernicious Anemia.
Erythrocytes: 840,000 per c.mm. (16.8 per cent.).
Hemoglobin: 18 per cent.
18 -4- 16.8 = 1.07: Color index.
Chlorosis.
Erythrocytes: 4,100,000 per c.mm. (82 per cent.).
Hemoglobin: 32 per cent.
32 -4- 82 = 0.39: Color index.
These examples, of course, refer only to the usual blood find-
ings, for the color index is by no means always high in pernicious
anemia, nor always low in chlorosis. The color index shows
simply the relative relations of the hemoglobin and the corpus-
cular percentages. It is only suggestive, not diagnostic, of a
specific blood disease.
The term hemoglobinemia is used to designate
HEMOGLO- a condition in which the hemoglobin is dissolved
BINEMIA. from the corpuscular stroma as the result of
some pathological factor, and is held in solution
by the blood plasma. In extreme instances this condition is
sooner or later succeeded by hemoglobinuria.
Among the most potent causal factors of hemoglobinemia are
certain drugs which act as blood poisons when administered in
toxic doses, of which the following are examples: arseniuretted
hydrogen, sulphuretted hydrogen, potassium chlorate, carbolic acid,
hydrochloric acid, sulphuric acid, pyrogallic acid, nitrobenzol, anti-
mony sulphid, iodin, naphthol, and many of the coal-tar deriva-
tives, such as acetanilid, antipyrin, and phenacetin. A similar
liberation of the hemoglobin may be observed as the result of
poisoning by certain varieties of mushrooms, by some snake-
venoms, by the bite of scorpions, and by a number of vegetable
glucosids. Sunstroke, extensive burns, and exposure to excessive
cold are also capable of giving rise to hemoglobinemia. Experi-
mentally, hemoglobinemia may be produced by the transfusion
oj blood from one animal into the circulation of another belonging
to a different species.
HEMOGLOBIN. 167
i
Hemoglobinemia is observed with more or less constancy in a
number of acute infectious diseases, such as grave cases of septice-
mia, diphtheria, malignant jaundice, syphilis, malarial fever, enteric
fever, scarlet fever, yellow fever, typhus fever, and variola. It also
may occur in scurvy and in Raynaud's disease, and is a prominent
blood rinding in those two obscure conditions known as epidemic
hemoglobinuria of the new-born and paroxysmal hemoglobinuria.
Hemoglobinemia may be readily detected by the following
method, recommended by von Jaksch : 1 A small amount of blood,
drawn from the patient by means of a cupping-glass, is imme-
diately placed in a refrigerator, in which it is allowed to remain
for twenty-four hours. In normal blood the serum which separates
at the expiration of this period is of a perfectly clear straw-color,
whereas if hemoglobinemia exists, the serum is colored a beautiful
ruby-red. If this hemoglobinemic serum is examined with the
spectroscope, the two characteristic absorption bands of oxy-
hemoglobin may be observed. If it is coagulated by heat, a
deep brown color is imparted to the coagulum.
Methemoglobinemia, or the presence in the
METHEMOGLO- circulating erythrocytes of methemoglobin, is
BINEMIA. produced by the action of a number of toxic
substances, which, if given in sufficiently massive
doses, may seriously or fatally cripple the oxygenating functions
of the blood. Among the agencies which cause this conversion
of oxyhemoglobin into methemoglobin are potassium chlorate,
anilin, iodin, bromin, ether, turpentine, acetanilid, potassium per-
manganate, hydrochinon, kairin, thallin, and pyrocatechin. The
inhalation of amyl nitrite and the intravenous injection of sodium
nitrite also act in a similar manner. Henri and Mayer2 found that
methemoglobinemia could be produced by the influence of radium
rays.
Spectroscopical examination of the blood is essential for the
detection of methemoglobinemia. The spectrum of methemo-
globin in alkaline solution shows three absorption bands: one
well-marked band between C and D of Fraunhofer's lines and
two others of much less distinct appearance, lying between D
and E, each immediately adjacent to the lines. In acid and neu-
tral solutions the spectrum of methemoglobin shows four absorp-
tion bands: a decided one between C and D, two between D and
E, and one closely adjacent to F. This spectrum, it is true, is
identical with that produced by an acid solution of hematin, but
it may be easily distinguished from the latter by the fact that
1 "Clinical Diagnosis," 3d ed., London, 1807, p. 75.
J Sem. med., 1904, vol. xxiv, p. 68.
1 68 ERYTHROCYTES, BLOOD PLAQUES, AND HEMOKOXIA.
the spectrum of methemoglobin, when acted upon by ammonium
sulphid, changes first to that of oxyhemoglobin, and later to
that of reduced hemoglobin, while when hematin is thus treated,
a spectrum which shows two bands between D and E is pro-
duced.
Aside from the bright, cherry-red color of the
CARBON MON- blood in coal-gas poisoning the presence of car-
OXID HEMO- ban monoxid hemoglobin may be determined by
GLOBIN. spectroscopical examination and by a number of
distinctive chemical reactions.
Recalling the characteristic spectrum of oxyhemoglobin (two
distinct absorption bands between D and E, the one nearest D
Oxyhemoglobin .
Methemoglobin .
Reduced Hemo-
globin.
CO Hemoglobin.
FIG. 45. — PRINCIPAL BLOOD SPECTRA.
being darker, narrower, and more sharply defined), it is found that
in the spectrum of carbon monoxid hemoglobin these bands
are replaced by two others, also between £> and E, but nearer
together, and somewhat closer to the violet end of the spectrum.
This distinction, which may be so slight as to appear confusing,
is at once emphasized by the fact that the addition of ammo-
nium sulphid has absolutely no effect upon the carbon mon-
oxid spectrum, while it transforms the spectrum of oxyhemoglo-
bin into that of reduced hemoglobin.
Carbon monoxid hemoglobin in the blood is also demonstra-
THE ERYTHROCYTES. 169
ble by the following simple test devised by Hoppe-Seyler * : A
small quantity of blood, removed from the patient by means of
a wet-cup, is mixed with twice its volume of a 10 per cent, solu-
tion of potassium hydrate. Thus treated, blood containing car-
bon monoxid hemoglobin changes the color of the mixture to a
rich cinnabar-red, while with normal blood the solution turns
brownish-green.
II. THE ERYTHROCYTES.
The erythrocytes or red corpuscles are thin,
APPEARANCE flattened, biconcave discs, of sharply denned,
IN regular outline and of smooth, even surface.
FRESH BLOOD. That they are neither bell-shaped nor globular,
as is also maintained, is obvious on careful
microscopical examination. In the blood of the normal indi-
vidual the erythrocyte does not possess a nucleus. When the
corpuscle is examined microscopically as it rests upon its flat sur-
face, its central concavity is plainly indicated by a dark central
area surrounded by a narrower, lighter rim as the periphery of the
cell is brought into sharp focus, changing to a pale, white center
encircled by a darker periphery as the objective is brought closer
to the corpuscle. When viewed in profile, it is shaped somewhat
like a slim dumb-bell, with regularly rounded poles tapering
from either end toward a shallow central concavity on either
surface. The color of the cells, when examined singly under the
microscope, is a pale greenish-yellow, but when they are col-
lected in masses, a more or less marked reddish tint becomes ap-
parent. The erythrocytes possess a peculiar tendency of collect-
ing and adhering in more or less regularly arranged piles, like
rolls of coins stacked up face to face, this being known as rouleaux
formation.
After withdrawal of the blood from the body various structural
changes in the erythrocytes, commonly known as crenation, may
be observed. In normal blood the .rapidity with which these
changes progress depends upon the quantity of air which leaks
in between the slide and the cover-glass, and thus causes de-
generation of the corpuscular stroma. The development of one
or more small, bright, highly refractive spots in the body of the
corpuscle, and a slight indentation of the cell's periphery are the
the most conspicuous indications of beginning crenation. As the
process goes on, more and more of these hyaline points develop,
1 Loc. cit.
I JO ERYTHROCYTES, BLOOD PLAQUES, AND HEMOKONIA.
until finally the whole surface of the corpuscle becomes thickly
studded with glistening, bead-like spines. As the stroma be-
comes drier and drier, its typical biconcavity and sharply-cut out-
line are lost, contracting strands of the stroma are seen to extend
from point to point among the beaded projections, the periphery
of the cell changes to a cogged rim, and finally the cell becomes
shrunken and shriveled up into a small, many-starred asterisk.
Some of the erythrocytes become fragmented, and small bits of
their stroma are observed to break off and float through the plasma.
Others become progressively paler and paler as the hemoglobin
is dissolved out, until complete decoloration occurs. Still others
become distorted into designs of every conceivable shape, so
that their resemblance to the normal cell becomes most remote.
These changes, which never occur in normal blood until the cells
have been exposed to prolonged atmospheric influence, must
not be confused with similar alterations in the structure of the
erythrocytes occurring as the result of pathological states of the
blood. The latter changes are described more fully in another
place. (See p. 184.)
The finer structure of the erythrocyte is still
HISTOLOGICAL a moot point among different histologists, the
STRUCTURE, view most generally accepted regarding it as a
homogeneous cell composed of an insoluble
spongy network, the stroma of Rollet, in the interstices or trabec-
ulas of which is embedded a soluble, finely granular substance,
the hemoglobin, existing probably as a compound with some un-
known constituent of the cell. In lieu of a distinct limiting
membrane the portions of the stroma nearest to the surface of
the corpuscle are condensed, to protect it from injury during its
movement through the blood stream. This outer layer, accord-
ing to Peskind,1 is composed of a proteid substance, lecithin,
and cholesterin, but contains no hemoglobin. The corpuscles are
highly elastic and contractile, to permit of the rapid and marked
temporary distortions of shape which they constantly undergo in
the circulating blood.
Other authorities, notably Schafer,2 disagree with Rollet's view,
inclining rather to consider the erythrocytes as vesicular masses,
consisting of an external envelop inclosing a fluid contents.
Thus, Schafer believes that the cell consists of two distinct por-
tions, a colored and a colorless, the former being a solution of
hemoglobin, while the latter, or so-called stroma, consists chiefly
of lecithin and cholesterin, together with a small amount of cell
1 Amer. Jour. Physiol., 1903, vol. viii, p. 404.
2 Quain's "Anatomy," Philadelphia, 1891, pt. 2, p. 210.
THE ERYTHROCYTES. 171
globulin. Without attempting to discuss the correctness of either
of these two views, a single tangible reason for regarding the
corpuscle according to Rollet's opinion may be stated, viz.: the
fact that exposure of blood to destructive temperatures results in
fragmentation of the corpuscles into numerous minute portions,
each one of which consists of a bit of hemoglobin-containing
stroma. This obviously seems to disprove the existence of a
limiting membrane, without further investigation.
In the human body an active manufacture of
ORIGIN AND erythrocytes constantly goes on during health,
LIFE HISTORY, in order to compensate for the continuous
drain on their number by the destruction of those
cells which have become incapable of function and useless, their
life cycle being run. That this reproduction is the direct answer
to a call for new cells is proved by the prompt and rapid increase
of corpuscles following the loss of blood from hemorrhage. That
such a manufacture is attempted in severe pathological conditions,
although the attempts are sometimes abortive, is evinced by the
large numbers of immature and misshapen erythrocytes which
appear in the blood in certain of the grave anemias.
In the adult it is generally conceded that the erythrocytes
are reproduced in the red bone marrow, being developed from
their direct antecedents, the nucleated erythrocytes or erythro-
blasts, which exist in this tissue in large numbers. The erythro-
blasts appear to multiply in the thin-walled capillaries and veins
of the red marrow, and, having lost their nuclei, become trans-
formed into normally developed erythrocytes, which pass from the
blood channels of the marrow into the general circulation. Some
authorities have attributed to the spleen and lymphatic glands a
share in the formation of the red cells, while others have main-
tained that they may be transformed from the leucocytes in the
circulating blood, but none of these theories has been associated
with convincing evidence, so that it is fair to consider the red
bone marrow the chief, if not the only, seat of production, in
the light of our present knowledge of. the subject. Hayem's
ingenious theory, that the erythrocytes arise from the hematoblasts,
does not enjoy the confidence of modern investigators.
When finally the erythrocyte, after having executed its function
for a certain length of time, becomes useless in its primary office
as an oxygen carrier, its death ensues, the destruction of the
cell probably taking place largely in the liver and to a less degree
in the spleen. Bain1 has shown that this hemolytic power re-
sides in both of these viscera, the liver acting chiefly upon the
1 Jour. Physiol., 1903, vol. xxix, p. 352.
172 ERYTHROCYTES, BLOOD PLAQUES, AND HEMOKONIA.
erythrocytes and the spleen affecting mainly the leucocytes.
After the passage of blood through the liver it was proved that
the hemoglobin-deficient cells were most prone to destruction,
that the hemoglobin content of the invulnerable cells was dis-
tinctly increased, and that the perfusion appreciably augmented
the quantity of iron in the liver and was accompanied by a consid-
erable output of highly pigmented bile. The perfused spleen was
also found to contain an increase in the amount of iron, indicative
of a relatively slighter destruction of erythrocytes. Splenectomy
in animals does not to any great extent interfere with erythro-
cytic destruction (Lapicque).1 Warthin's2 studies show that de-
struction of the erythrocytes also occurs in the splenolymph
glands, minute vascular sinuses situated chiefly in the retroperi-
toneal and mediastinal tissues, and in the thyroid and thymus
regions. The possibility that certain of the partly degenerate
cells also undergo a certain form of repair, first in the spleen and
then in the liver, rendering them still capable of function, is an
interesting but obviously unproved conjecture.
The average diameter of the erythrocyte is
SIZE. about 7.5 //,3 its average thickness being about
1.8 p. According to Gram,4 the diameter appears
to vary somewhat with the geographical and climatic conditions
surrounding the individual, being considerably larger in inhabi-
tants of northern countries than in southerners, as the following
average measurements of this observer attest :
COUNTRY. AVERAGE DIAMETER.
Italy 7 to 7.5 p
France , 7.5 to 7.6 /*
Germany 7.8 fi
Norway 8.5 p
Hayem5 distinguishes three different sizes: large, averaging
8-5// in diameter; medium, averaging 7.5," in diameter; and
small, averaging 6.5 // in diameter. Of these three classes, ap-
proximately 75 per cent, are of the medium size, while 12.5 per
cent, each are large and small. The diameter varies within some-
what wider limits in the infant and in the young child than in the
adult. It is, however, not materially influenced by sex. The
pathological increase and decrease in the diameter of the erythro-
cytes occurring in certain anemias are discussed in another place.
1 Med. News, 1903, vol. Ixxxii, p. 311.
2 Jour. Boston Soc. Med. Sci., 1901, vol. v, p. 414.
3 The Greek letter fi is used to represent a micromillimeter, or T^Vu °f a
millimeter, which is a standard unit of measurement used in microscopy.
4 Fortschr. d. Med., 1884, vol. ii, p. 33. 5 Loc. cit.
THE ERYTHROCYTES. 173
The normal number of erythrocytes in the
NORMAL healthy male adult may be approximated at
NUMBER. 5,000,000 to the c.mm. of blood. Higher counts
than this are frequently observed, however,
especially in healthy, well-developed men, so that this figure
should be taken to represent a rather low average, subject to an
upward fluctuation of half a million cells, and occasionally even
more. In females a count of about 4,500,000 erythrocytes per
c.mm. may be regarded as normal.
Arterial and venous blood contain practically the same number
of corpuscles, the apparent slight increase in favor of the latter,
mentioned by some observers, being within the limits of technical
error. For a like reason, under normal conditions, peripheral
blood may be taken as representative of the blood of the entire
body. Blood derived from dependent parts of the body contains
a diminished proportion of corpuscular elements. Oliver's1
studies of this question have shown that blood from the finger
invariably gives a higher count of erythrocytes than blood from
the toe, this disparity being explained by the fact that the larger
quantity of lymph gravitating to the more dependent parts of the
body causes a dilution of the blood in these areas.
This term has been applied by Capps 2 to the
VOLUME figure representing the percentage volume of the
INDEX. individual erythrocyte, in contradistinction to the
color index, which expresses the amount of hemo-
globin in the single cell. It is calculated by dividing the percent-
age volume of the erythrocytes as a whole, obtained by centrifu-
galization of the blood, by the percentage number of erythrocytes,
as determined by the actual count with the hemocytbmeter, the
normal volume index being taken as i.co. For example, the
erythrocyte column, after centrifugalization with the hematokrit,
reaches to the mark 40 on the capillary tube, indicating a total
volume of 80 per cent.; while the count with the hemocytometer
gives 3,000,000 cells per c.mm., or 60 per cent, of the normal num-
ber. Then, 80-^-60, or 1.33, equals the volume index, a figure
which in this instance shows an increase of 33 per cent, in the
volume of each corpuscle. As a general rule, it may be. stated that
the volume index and the color index, rise and fall together,
although the parallelism between the two is not always closely
maintained. The volume index is generally lowered in chlorosis,
in leukemia, and in most of the secondary anemias, while in
pernicious anemia it tends to rise above the normal standard.
1 Loc. cit.
7 Jour. Amer. Med. Assoc., 1900, vol. xxxvi, p. 464; also Jour. Med. Re-
search, 1903, vol. v, p. 367.
174 ERYTHROCYTES, BLOOD PLAQUES, AND HEMOKONIA.
The cell's volume is influenced mainly by factors affecting cell
degeneration, and is altered but slightly by osmotic influences.
During blood regeneration the volume of the cell is restored before
the color becomes normal.
III. INFLUENCE OF PHYSIOLOGICAL FACTORS ON
THE ERYTHROCYTES.
Polycythemia, associated with a proportion-
AGE AND SEX. ately high percentage of hemoglobin, is found
in the blood of the new-born infant immediately
after birth, the maximum counts being observed some time during
the first twenty-four hours of life, after which period they progres-
sively diminish until, at the end of eight or ten days, about
1,000,000 cells per c.mm. have been lost. Each period of nursing
is generally followed by a prompt temporary decrease in the
count, and a similar change has been observed as the. effect' of
premature ligation of the cord at birth. Hayem1 found an aver-
age of 5,368,000 erythrocytes per c.mm. in 17 infants at birth,
the highest count being 6,362,000, and the lowest, 4,340,000.
Fehrsen2 regards 6,000,000 per c.mm. as the average count at
birth. The cause of this polycythemia is attributed to concentra-
tion of the blood from the abstraction of water by the tissues to
replace the fluids of the body lost during the first few days of life.
As soon as this loss is made up by the i-ngestion of a sufficient
amount of liquids by the child, the normal relation between the
liquid and the solid portions of the blood is reestablished, so
that the polycythemia disappears.
During the growth of the adult the average number of erythro-
cytes continues to rise, until the maximum number is attained at
some time between the third and fifth decades, after which a de-
crease is observed, usually becoming more marked as the decline
of life progresses. Schwinge3 and others have shown that during
the period of sexual activity the counts in females are generally
lower than in males, but that after the climacteric the number of
cells in the two sexes is practically identical.
The influence of age and sex upon the number of erythrocytes
is well illustrated in the following table prepared by Sorensen4 :
AGE. MALES. AGE. FEMALES.
SJtoJS days 5,769,500 i to 14 days . . . .5,560,800
5jyears 4,950,000 2 to 20 years. . . .5,120,000
19.5 to 22 years 5,600,000 15 to 28 years .4,820,000
25 to 30 years 5,340,000 41 to 61 years 5,010,000
50 to 52 years 5,137,000
82 years 4,174,700
1 Loc. cit. 2 Jour. Physiol., 1903, vol. xxx, p. 322.
3 Pfluger's Arch., 1898, vol. Ixxiii, p. 299. 4 Cited by von Limbeck, loc. cit.
INFLUENCE OF PHYSIOLOGICAL FACTORS. 175
There are no conspicuous changes in the num-
PREGNANCY, her of erythrocytes in any of these conditions.
MENSTRUATION, In primiparae there is often a slight decrease in
AND the number of corpuscles, particularly in the later
LACTATION, months of pregnancy, but in multiparae this
change is rarely observed. Distinct anemia dur-
ing gestation is invariably pathological, although a moderate de-
gree of hydremia may be physiological. J. Henderson1 found
an average hemoglobin percentage of 68.2 in 38 cases at term,
and an average erythrocyte count of 3,975,348; by the eleventh
day after delivery these values increased to 74 and 4,020,0x30,
respectively. Postpartum oligocythemia commonly develops, the
intensity of which depends largely upon the amount of blood
lost and upon the general health of the woman; this loss of cells
is gradually made up, and unless convalescence is delayed, reaches
the normal by the second or third week after delivery. Bar and
Daunay 2 have determined that the density of the blood progres-
sively declines toward the end of pregnancy, but rapidly increases
after delivery.
During menstruation there may be a trifling reduction, caused
by the physiological hemorrhage of the phenomenon, but the
loss is rapidly made up in a few days' time. Sfameni3 found that
a transient polycythemia usually occurs shortly before the estab-
lishment of the menstrual flow, and that the average loss of hemo-
globin and corpuscles during the flow does not exceed 4.5 per cent.,
the decrease being in direct proportion to the actual volume of
blood lost.
In healthy, robust women lactation is accompanied by a
normal count, but in weak, young girl-mothers, particularly
those of the "chlorotic age," a moderate reduction is sometimes
observed.
Here may be noted O. Schaffer's observation,4 thus far uncon-
firmed, that pregnancy can be detected by an increased affinity
of the erythrocytes for iodin in blood obtained by puncture of the
cervix. Using a reagent containing i gm. of iodin, 2 gin. of potas-
sium iodid, and 300 c.c. of water, Schaffer found that the number
of iodin-stained erythrocytes began to increase immediately after
conception, until just before delivery they became at least twenty
times more numerous than the unstained cells, which in the non-
pregnant woman they outnumber only between two and five to one.
1 Amer. Jour. Obstet., 1902, vol. xlv, p. 745.
2 Sem. med., 1904, vol. xxiv, p. 28.
8 Centralbl. f. Gynakol., 1899, vol. xxiii, p. 1311.
4 Ibid., igoi, vol. xxv, p. 1375.
176 ERYTHROCYTES, BLOOD PLAQUES, AND HEMOKONIA.
Well-developed, robust individuals average a
CONSTITUTION larger percentage of erythrocytes than the poorly
AND nourished and weakly. In the former, counts
NUTRITION, much in excess of 5,000,000, and in the latter
counts of less than 5,000,000, are the rule.
Fasting, inasmuch as it causes a drain upon the liquid elements
of the vascular system, may rapidly bring about an apparent
polycythemia due to concentration of the blood, this increase in
cells being in direct relation to the length of abstinence from food.
Hayem1 states that a twenty-four hours' fast will cause a gain of
between 400,000 and 500,000 cells; while the experiments of Reyne2
on a dog, starved to death after a twenty-four days' fast, showed
an increase of 2,500,000 corpuscles at the expiration of this period.
Active muscular exercise (gymnasium work,
MUSCULAR walking, running, swimming, and so forth) pro-
EXERCISE. vokes transient increase in the peripheral eryth-
rocyte count, due primarily to increased blood
pressure, which not only inspissates the blood, but also disseminates
peripherally many cells which hitherto lay inactive in the deeper
circulation. From the studies of Willebrand3 and of Zuntz and
Schumberg4 it seems that the duration of this increase stands in
inverse ratio to the length of the period of exercise. Hawke5
found that the average gain in erythrocytes was 21 per cent, after
swimming, 16.6 per cent, after sprinting, 12.8 per cent, after walk-
ing, and 12 per cent, after bicycling.
Physical labor prolonged to the point of fatigue
FATIGUE. appreciably diminishes the number of erythro-
cytes. Cadet's8 investigations of the blood of a
number of peasants, examined after two months of hard field
labor during the summer, showed a moderate oligocythemia — in
one instance a loss of over 1,000,000 cells, and in the others dimi-
nutions averaging about one-half of this figure. Cadet believes
that this anemia is referable to a true blood destruction, and notes
as a rather mythical support of this view that the blood plaques
were increased in these cases.
Among other factors increasing the erythrocyte count may be
noted cold tubbing (Winternitz ;7 Thayer8), warm baths (Knopfel-
macher9), and general massage (J. K. Mitchell10).
1 Loc. tit. 3 Cited by Hayem, loc. cit.
3 Skandin. Arch. f. Physiol., 1903, vol. xiv, p. 176.
4 " Studien zu einer Physiologic des Marsches," Berlin, 1901.
5 Amer. Jour. Physiol., 1904, vol. x, p. 384.
* Cited by Hayem, loc. cit. 1 Centralbl. f. klin. Med., 1893, vol. xiv, p. 177.
8 Johns Hopkins Hosp. Bull., 1893, vol. iv, p. 37.
* Wien. klin. Wochenschr., 1893, vol. vi, p. 810.
10 Amer. Jour. Med. Sci., 1894, vol. cvii, p. 502.
INFLUENCE OF PHYSIOLOGICAL FACTORS. 177
Within an hour after a meal there is a slight,
DIGESTION, transitory increase in the number of erythro-
FOOD. cytes, amounting on the average to a gain of one-
quarter of a million cells to the c.mm. This acme
is soon followed by a gradual decline, corresponding to the period
of digestion, the normal i standard being regained within two or
three hours after the preliminary rise began. Corresponding fluc-
tuations in the hemoglobin and in the density of the blood also
occur.
Oliver * states that these variations are not affected by the taking
of liquids with meals, for he has noticed that they were quite
as pronounced when water was withheld. The same observer has
shown2 that these fluctuations correspond accurately to what he
terms the "digestive lymph wave," or the to-and-fro intermediary
circulation between the capillaries and the lymph spaces excited by
the ingestion of food. Immediately after a meal this wave begins
to rise, and coincidentally with this leakage of fluid from the blood
into the tissues the hemoglobin and erythrocyte values begin to
rise, as the blood thus becomes more and more concentrated. The
acme is reached within an hour, and at this time the blood count
and the percentage of lymph in the tissues are at their maximum.
The wave then begins to decline slowly, and as the effused fluid
gradually is restored to the blood vessels, the hemoglobin and cor-
puscle figures correspondingly decline, until they reach normal,
after the lapse of two or three hours after their initial rise. The
following table, from von Limbeck,3 illustrates the variations in the
red and white cells caused by taking food.
TIME. ERYTHBOCYTES. LEUCOCYTES. ' HEMOGLOBIN.
11 15 A. M. 5>553>°°° 7,666 98 per cent.
12 M. Dinner of meat and farinaceous food.
15 p. M. 5,320,000 6,166
15 P. M. 5,480,000 8,500
15 P. M. 4,733,000 12,000
15 P. M. 4,872,000 14,000 89 per cent.
15 P. M. 4,720,000 10,830
Hayem 4 believes that meat eaters average a higher percentage of
erythrocytes than vegetarians, on account of the more nitrogenous
character of their food, and that a diet of fats and albuminoids is
most favorable for the increase of the cellular elements of the
blood.
1 Loc. cit. * Lancet, 1903, vol. ii, p. 940.
3 Loc. cit. 4 Loc. cit.
178 ERYTHROCYTES, BLOOD PLAQUES, AND HEMOKONIA.
The habitual polycythemia of individuals liv-
HIGH ing in high altitudes is an interesting and inade-
ALTITUDES. quately explained fact in hematology. Viault,1
Wolff and Koeppe,2 Egger,3 and other observers
have shown the invariable occurrence of this polycythemia both
in inhabitants of elevated districts and in the occasional visitor.
In the case of the latter, as the individual ascends from the sea-
level to the mountainous district, a rapid increase in corpuscles
and in hemoglobin develops, this increase bearing a certain rela-
tion to the height ascended, and becoming apparent usually
within twenty-four or forty-eight hours after his arrival in the
highland. Campbell and Hoagland4 computed the increase at
the rate of 50,0x20 cells to the c.mm. per 1000 feet of elevation.
Ten hours' stay in a balloon, at a height of over 15,000 feet, pro-
duced no morphological changes in the blood of two aeronauts,
Schroetter and Zuntz,5 who undertook this experiment. Viault
counted 8,000,000 erythrocytes to the c.mm. in the residents of the
Cordilleras, at an elevation of 14,274 feet above the sea-level;
Cazeaux6 found 7,100,000, at a height of 5904 feet. Egger
counted 7,000,000 at Arosa, at a height of 6100 feet; and Wolff
and Koeppe found an average of 5,970,000 in dwellers at Reibolds-
griin,,at a height of 2257 feet. Oliver7 relates the interesting ex-
perience of finding in his own blood, during a stay at Davos Platz,
at an elevation of 5200 feet, an increase of corpuscles within
twenty-four hours after his arrival, the maximum count, 5,550,000,
being attained within seven days, and the number declining within
five days after his return to London.
The following table, by Marie,8 illustrates the fact that the
higher the altitude the higher is the count of erythrocytes :
HEIGHT ABOVE COUNT OF
PLACE. SEA-LEVEL. ERYTHROCYTES. AUTHOR.
Christiania o 4,974,000 Laache.
Gottingen 148 meters. 5,225,000 Schafer.
Tubingen 314
Zurich 414
Auerbach 425
Reiboldsgriin 700
Arosa 1,800
The Cordilleras. . . .4,392
5,322,000 Reinert.
5,752,000 Stierlin.
5,748,000 Koeppe.
5,900,000 Koeppe.
7,000,000 Egger.
8,000,000 Viault.
1 Compt. rend. Soc. biol., Paris, 1890, vol. iii, p. 917.
2 Munch, med. Wochenschr., 1893, vol. xl, p. 904.
3 XII. Cong. f. inn. Med., Wiesbaden, 1893.
4 Amer. Jour. Med. Sci., 1901, vol. cxxii, p. 654.
5 Pfluger's Arch., 1902, vol. xcii, p. 615.
* Cited by Tissier, Cohen's "System of Physiological Therapeutics," Philadel-
phia, 1903, vol. x, p. 182.
7 Loc. cii. 8 "Lecons de Clinique Medicale," Paris, 1896, p. 237.
INFLUENCE OF PHYSIOLOGICAL FACTORS. 179
Foa1 reports that animals taken to a height of 10,000 feet
develop polycythemia within eight hours after their arrival, and
that the increase disappears within thirty-six hours after their
return to a normal level. On the contrary, Armand-Delille and
Meyer2 were unable to detect any definite changes either in the
peripheral and heart blood or in the hematopoietic organs of ani-
mals kept for from two to seven weeks at an altitude of 6000 feet.'
The hemoglobin changes which accompany these cellular
alterations are never so marked as the latter, both the rise and
the fall being less rapid ; consequently it is common to find a low
color index at first, whereas later, inasmuch as the rapidity of
the cellular loss is greater than the fall in hemoglobin, a high
color index is likely to persist for some time after return to the low-
land. Curry3 could determine no consistent changes in hemo-
globin, the volume of the cells, or the specific gravity of the whole
blood at an elevation of 6000 feet. The blood changes, as a rule, are
more conspicuous in normal than in anemic persons. In phthisics
living in high altitudes, Meissner and Schroder4 found that the
hemoglobin value rose and fell in relation to the patient's im-
provement and decline in health. Kemp 5 calls attention to the
fact that the morning erythrocyte count is always higher by from
500,000 to 1,000,000 than the evening estimate. He also noted
that a large increase in the number of blood plaques developed
as the patient ascended to a high elevation.
Concentration of the blood doubtless explains the polycythe-
mia of high altitudes, this change being due largely to the great
loss of body fluids (Grawitz), and partly to the increased arterial
tension (Oliver) arising from a rarefied atmosphere. 'Koeppe's
ingenious theory that the process mirrors an actual manufacture
of new cells is scarcely tenable, for although this observer has
found numerous microcytes and poikilocytes coincidentally with
the appearance of the polycythemia, normoblasts were not de-
tected, as an evidence of rapid hemogenesis, nor did such signs
of excessive blood destruction as icterus and hemoglobirruria de-
velop, as the increased count rapidly declined on the individual's
descent to a lower level.
It has been recently urged that in high elevations the effect
upon the hemocytometer of atmospheric pressure and tempera-
ture may be the real secret of the cellular increase, but how such
influences act, if, indeed, they are active, is unknown.
1 Brit. Med. Jour., 1904, vol. i, p. 1097.
1 Sem. me'd., 1903, vol. xxiii, p. 371. s Amer. Med., 1902, vol. iv, p. 367.
4 Cohen's "System of Physiological Therapeutics," Phila., 1903, vol. x, p. 191.
4 Med. News, 1904, vol. Ixxxiv, p. 383; also Johns Hopkins Hosp. Bull., 1904,
vol. xv, p. 177.
l8o ERYTHROCYTES, BLOOD PLAQUES, AND HEMOKONIA.
A sea climate apparently causes a moderate
CLIMATE. increase in the number and hemoglobin value of
the erythrocytes. Marestang's studies1 of the
blood of several sailors during a sea voyage are the only available
proof of this change.
A tropical climate of itself probably does not affect the blood,
although it offers fruitful factors of anemia in predisposing to such
infections as the malarial fevers, ankylostomiasis, and filariasis.
So-called tropical anemia is more often apparent than actual.
IV. PATHOLOGICAL CHANGES IN THE ERYTHRO-
CYTES.
True ameboid movements of the erythrocytes
AMEBOID are sometimes observed, as the result of the effect
MOTILITY. of globulicidal agents, or of some pathological
state of the blood, such as a severe, high-grade
anemia. The inherent elastic and contractile qualities shown by
the cells, by virtue of which they undergo various changes in
shape while floating about in the plasma, must not be confounded
with the actual ameboid motility which they exhibit in disease.
The oscillatory dancing movements of bits of fragmental cor-
puscles, and the characteristic motility of the intracellular hyaline
malarial parasite, also must be distinguished from the progres-
sive, deliberate characteristics of the truly ameboid red blood cell.
Within the body the hemoglobin and other
ALTERATIONS constituents of the erythrocytes are preserved
IN intact within the corpuscular stroma by the com-
ISOTONICITY. position of the blood plasma, which is such that
a perfect osmotic balance is constantly main-
tained. Outside of the body, if this relationship is disturbed by the
addition of distilled water to a specimen of blood, thus lowering
the concentration of the plasma, the corpuscles swell, and a rapid
discharge of hemoglobin into the surrounding tissue ensues, but the
addition of saline solutions of a definite strength prevent such a
change. Solutions of salts of just sufficient concentration to pre-
serve the corpuscles and to prevent removal of their elements
are known as isotonic, solutions of greater strength are termed
hypertonic, and those of lesser strength, hypotonic. In normal
blood it has been determined that the isotonicity of the erythro-
cyte usually ranges from about 0.48 to 0.46 per cent. NaCl; that
is, salt solutions of this concentration are just sufficient to prevent
1 Cited by von Limbeck, loc. cit.
PATHOLOGICAL CHANGES IN THE ERYTHROCYTES. l8l
the discharge of hemoglobin by the cell, although it may swell by
taking up water. A 0.9 per cent, or "normal" salt solution not
only preserves the hemoglobin within the cell, but also prevents
alterations in its size and contour. Hamburger1 and others have
shown that alterations in isotonicity depend not only upon changes
in the plasma, but also upon the constitution of the erythrocytes
themselves. Fluctuations in the amount of the cells' diffusible
albumins, chlorids, and phosphates are attended by corresponding
osmotic variations.
Owing to the conflicting results obtained by different in-
vestigators, the isotonicity of the erythrocytes in different dis-
eases is of little clinical value. Stengel2 found the percentage
0.52 and 0.6 in two cases of pernicious anemia, yet in other
cases the figures were normal; in other diseases marked by ane-
mia, such as carcinoma, hepatic cirrhosis, renal disease, and
tuberculosis, he found that the variations were trivial. Von Lim-
beck3 found that the isotonicity was usually, but not invariably,
increased in high-grade secondary anemias, in leukemia, and in
many of the acute injections, while it was decreased in chlorosis
and in calarrhal icterus. A decidedly increased isotonicity was
found by Vicarelli 4 in pregnant and nursing women. As a gen-
eral rule, it is believed that degenerative changes in the erythro-
cytes, whatever their nature, predispose to dissociation of hemo-
globin from the stroma, and that in such instances the isotonic
percentages are higher than normal.
In the fresh specimen of blood, exaggeration
HYPERVIS- of the adhesive properties of the erythrocytes
COSITY. may be observed in a number of conditions, but
up to the present time no special clinical signifi-
cance has been assigned to the phenomenon. It occurs to some
extent in most inflammatory diseases, and, according. to Hayem,5
is often seen in the anemias associated with marked cachexia.
Striking examples of hyperviscosity result when .the erythrocytes
are subjected to the action of various poisons, notably snake-venom,
and of heterogeneous pathological blood serum. (See p. 128.)
From the effect of such influences the erythrocytes, instead of
forming normal rouleaux, tend to adhere in large, irregular
masses in which the distinctive characteristics of the cells are
masked or lost. The individual cells, unattached to such a mass,
may exhibit every possible variety of distortion, losing their typi-
cal biconcavity and regular disc-like appearance, and "becoming
1 Arch. f. Anat. u. Physiol., 1886, p. 476; ibid., 1887, p. 31.
2 Loc. cit. 3 Loc. cit.
4 Cited by von Limbeck, he. cit 8 Loc. cit.
1 82 ERYTHROCYTES, BLOOD PLAQUES, AND HEMOKONIA.
DEFORMITIES
OF
SHAPE AND
SIZE.
converted into elongated, misshapen bodies. It frequently happens
that the cell is provided with one or more long, delicate processes
several times the length of its diameter, this being due to the ad-
hesion of a bit of the stroma to the cover-glass while preparing the
specimen; in the spread film it will be noted that these processes
all point in the same direction.
Changes in the shape and size of the eryth-
rocytes are common in all anemias which reach
a severe grade, the degree of such deformities
corresponding closely to the intensity of the
anemic process. The diameter of the cells may
be more or less uniformly increased or decreased,
and such pronounced alterations in their shape may occur that
many of them bear but
slight resemblance to the
typical discs of normal blood
(Plate I; also Fig. 46). Ab-
normal inequality in the
size of the erythrocytes is
expressed by the term aniso-
cytosis.
When the corpuscle be-
comes greatly enlarged in
diameter it is known as a
megalocyte or macrocyte, the
presence of large numbers
of such cells being known
as megalocytosis or macrocy-
tosis. The diameter of a
megalocyte generally varies
from 9 to 12 ,«, but some-
times much larger forms are
seen, measuring as much as 20 p. They are present in the severer
anemias, especially in the pernicious form, in which they constantly
occur in large numbers. The megalocyte found in this disease is
usually characterized by an excess of hemoglobin, while in the
secondary anemias such cells are generally deficient in their hemo-
globin content.
The smaller forms, the microcyles, illustrate the extreme de-
crease in size of the red cell under pathological conditions. The
microcyte is an extremely small globular body, measuring from
about 3 to 5 /J. in diameter. It is found in all the varieties of ane-
mia, but is most commonly associated with chlorosis and with
the moderately developed second forms. An abundance of
microcytes in the blood is known as microcytosis.
FIG. 46. — DEFORMITIES OF SHAPE AND SIZE.
Illustrating various grades of cell deformity
associated with severe anemia. The large nu-
cleated erythrocyte is a typical megaloblast. (Ehr-
lich's triacid stain.)
PATHOLOGICAL CHANGES IN THE ERYTHROCYTES. 183
Eichhorsfs corpuscles are deeply colored, highly refractive mi-
crocytes, about 3 f* in diameter, and usually of regularly spherical
shape. They were once regarded as pathognomonic of pernicious
anemia, but are now considered diagnostic of no especial condi-
tion, being frequently found in severe anemias of any type, and
often being absent in pernicious anemia.
It seems reasonable to infer that deformities in the size of the
erythrocyte are referable chiefly to two different factors: to faulty
hemogenesis and to degenerative changes of the corpuscle which
lead to alterations in its histological structure. Megalocytes, for
example, may in some instances represent an actual giantism of
the cell, bred in the marrow from correspondingly large-sized
nucleated antecedents; in other instances (of which those exceed-
ingly pale, "washed-out" forms are examples) their abnormal
size may be attributed to hydropic enlargement, resulting from
their imbibition of fluids from the surrounding plasma. Micro-
cytes may enter the circulating blood as such, or, as is frequently
the case, they may be the products of corpuscular budding and
fragmentation.
In severe forms of anemia, characterized by excessive cellular
loss, there appears also to be a tendency toward a compensatory
hypertrophy of many of the erythrocytes, in order thus to in-
crease the oxygen-carrying capacity of the blood, which, were it
not for these numerous megalocytes, might in some instances be
too limited to sustain life.
Poikilocytes are erythrocytes deformed in shape as the result
of some pathological condition of the blood. Poikilocytosis, the
name by which this condition is designated, is .akin to crenation
in so far as in both conditions the cells may be similarly distorted
and misshapen. But it is unlike crenation for the reason that
poikilocytosis is a pathological condition, and demonstrable the
moment the blood is withdrawn from the body; while crenation
is a physiological phenomenon depending upon external influences
for its production, and never occurring until the blood has re-
mained exposed to the air for some time. Poikilocytes may be
of large or small size, the varieties of deformities being infinite,
and the degree marked or slight in relation to the nature of the
blood disease. Some of the cells may resemble the shape of a
gourd or a horseshoe ; others may be drawn out at both ends until
they form a spindle-shaped or oval body, while others appear
sharply beaked at one or more points, or shaped like a dagger or
the blade of a tomahawk. Occasionally very minute, rapidly
oscillating, rod-shaped forms are .seen, morphologically not unlike
large, unstained bacilli — pseudo-bacilli of Hayem. These rod-
184 ERYTHROCYTES, BLOOD PLAQUES, AND HEMOKONIA.
shaped forms are products of corpuscular fragmentation, and
indicate lowered vitality and feeble powers of resistance to the
pathological influences affecting the cells.
Poikilocytosis is not characteristic of any single disease of the
blood, but it is generally most marked in the grave forms of
primary anemia, such as leukemia and pernicious anemia. Oval-
shaped red cells are considered by Cabot l as particularly abundant
in the latter disease.
The conditions of deformity affecting the shape and size of the
erythrocytes are nearly always associated. As a general rule, it
may be stated that in the milder types of anemia small-sized,
slightly deformed poikilocytes and microcytes are most common;
and that in the severe forms, large-sized, conspicuously distorted
poikilocytes and megalocytes
predominate.
Loss of
ENDOGLOBULAR color by the
DEGENERATION, erythrocytes,
which pro-
gresses hand in hand with
alterations in their size and
shape and other structural
changes, is regarded as a de-
generative process of purely
endoglobular nature. It is
observed in the fresh specimen
FIG. 47.-DEGENERAT.vE CHANGES m THE ERY- of blood in many severe ane-
THROCYTES. (FRESH BLOOD FILM.) mjc conditions, especially in
the anemias associated with
infectious diseases, such as variola, typhus fever, and grave septi-
cemia and pyemia (Fig. 47).
The decoloration may commence in one or more spots, or it
may equally involve the whole surface of the corpuscle, beginning
at its center and spreading progressively toward its periphery.
Clear, hyaline areas of oval, round, or elongated shape appear
within the stroma, in some instances sharply contrasting with the
relatively dark color of the hemoglobin, but in other instances
imperceptibly blending with the tint of the surrounding cell body.
The active motility of these decolorized spots must be carefully
distinguished from the ameboid movements of the young malarial
parasite. Complete decoloration transforms the cell into a mere
colorless shell or "phantom," which would be practically invisible
1<(A Guide to the Clinical Examination of the Blood," 5th ed., New
York, 1904, p. 131.
PATHOLOGICAL CHANGES IN THE ERYTHROCYTES. 185
were it not for its faintly colored periphery. Such cells are known
as Ponfick's shadow corpuscles or as Hayeni's achromacytes.
Maragliano and Castellino 1 have minutely described this proc-
ess of decoloration, along with certain other alterations in the
structure of the erythrocyte, which they have termed endoglobu-
lar necrosis. This process first becomes apparent by a visible
enlargement of the central concavity of the corpuscle, together
with a simultaneous fading away of the hemoglobin in this situ-
ation. This central area of pallor gradually spreads toward the
periphery of the cell, until finally the latter alone shows evidence
of containing coloring matter. Such a corpuscle, when examined
on cross-section, appears to be shaped like the figure 8. Frag-
mentation of this delicate rim of coloring matter may occur, in
the event of which numerous independent, rod-like bits of stroma
are formed. The decolorized area is not always symmetrical, so
that frequently various strikingly bizarre designs, widely differing
in shape and appearance, may be observed, It has been deter-
mined that in the dried blood film these areas of decoloration show
a decided affinity for basic stains, such as methylene-blue and
thionin.
Total cellular necrosis, also described by the
TOTAL authors mentioned above, represents a phase
NECROSIS. of structural degeneration in the erythrocyte
of more advanced development than the endo-
globular changes. This process begins with the development of
several small elevations or corrugations in the stroma of the cor-
puscle, which gradually multiply, increase in size, and change in
shape until the larger portion of the cell's surface is thus de-
formed. Ameboid movements are seen to begin, as if the entire
cell as a whole were involved, the final stage of the process re-
sulting in the formation of a poikilocyte, from which body points
and small fragments are observed to break off and to float free
in the plasma. Decoloration, starting usually from a single point
and in time affecting the whole stroma, also accompanies this
necrotic alteration. On cross-section the cell appears as an
elongated, thin rod with rounded poles. This fragmentation of the
cells is spoken of as schistocytosis. The erythrocytes are much
more resistant than the leucocytes, which succumb much more
readily to necrobiotic influences.
Endoglobular degeneration and total necrosis of the erythro-
cytes may be observed both in normal and in pathological blood.
In normal blood they occur as the result of prolonged contact
with the air, the endoglobular phase becoming first apparent
1 XI. Cong. f. inn. Med., Leipsic, 1892.
1 86 ERYTHROCYTES, BLOOD PLAQUES, AND HEMOKONIA.
within from thirty to seventy minutes, and the total necrosis in
from three to four hours, after the preparation of the specimen.
In pathological blood the changes are thought to be due chiefly
to increased globulicidal properties of the plasma, whereby intra-
vascular necrosis is excited, and partly to decreased resistance
of the erythrocytes, in consequence of which their degeneration is
abnormally hastened by contact with normal plasma and by
exposure to extraneous influences. In disease it follows that
they are demonstrable immediately or very shortly after the blood
has been withdrawn, and that the development of the changes
occurs with much greater rapidity than in normal blood. The
endoglobular changes are regarded as a more favorable prog-
nostic sign than the total necrosis, being usually associated with
anemias of less severe character than those in which the latter
process prevails.
The normal erythrocyte, when fixed and
ATYPICAL stained with anilin dyes, according to one of
STAINING RE- the methods described in another section, pos-
ACTION. sesses a strong affinity for a single, acid stain;
it is therefore termed monochromatophilic. When
solutions are used containing both acid and basic dyes, such
as eosin and methylene-blue or eosin and hematoxylin, the nor-
mal erythrocyte is always stained by the eosin; and with Ehr-
lich's triple mixture, which is so formulated that acid, basic, or
so-called neutral principle may be selected by the elements sub-
jected to its action, according to their affinities, the erythrocyte
invariably is colored by the orange G of the mixture (Plate I).
In certain morbid conditions some, of the corpuscles lose their
affinity for the acid stain, and with mixtures of both acid and
basic dyes are stained atypically by either or both elements.
Such corpuscles are said to be polychromatophilic. Thus, when
stained with an eosin and methylene-blue mixture, they are
tinged a dirty grayish-purple or violet, instead of the rose color
of eosin; and with the triple mixture they may be stained pur-
ple, reddish-brown, or pale yellowish-pink, flecked here and
there with shadings of a darker red (Plate I).
In polychromatophilic corpuscles the staining is likely to be
very unevenly shaded, often being quite dark in spots, especially
around the periphery of the cell and the margin of the nucleus,
if the cell be nucleated. These color changes affect not only
the protoplasm, but the nucleus as well, and are strongly em-
phasized in megaloblasts, the nuclei of which may show every sort
of color combination. The more deficient the corpuscle in hemo-
globin, the more decided its polychromatophilic tendency; and
PATHOLOGICAL CHANGES IN THE ERYTHROCYTES. 187
the more strikingly the latter is developed, the more intense the
cell's affinity toward the basic element of the stain.
Polychromatophilia may occur in severe forms of anemia due
to any cause, and it is especially noted in two of the primary
varieties — pernicious anemia and myelogenous leukemia — in
both of which conditions the process is a prominent character-
istic of the blood picture. Corpuscles of Poggi, or erythrocytes
which stain with basic dyes in the fresh, unfixed specimen, are also
found in various anemias. They probably represent immature
elements whose presence in the circulating blood reflects stimulated
hemogenesis.
Nucleated erythrocytes, or erythroblasts, are
NUCLEATION. found in the blood of the adult only during the
existence of pathological conditions, but occur
in large numbers in the blood of the fetus, and occasionally in
the infant during the first few days of life. Being invisible in the
fresh blood, they must be studied in the dried, stained specimen.
In such preparations the finer structure of their nucleus, which
bears a special affinity for the basic anilin dyes, may be beauti-
fully illustrated by the use of solutions containing methylene-
blue, methyl-green, and hematoxylin.
According to their size and nuclear characteristics the ery-
throblasts are designated as normoblasts, megaloblasts, and mi-
croblasts. Certain intermediate forms are also common, some-
times termed mesoblasts, such cells being atypical, and sharing
characteristics of both the normoblast and the megaloblast. .
Normoblasts (Plate I). — The normoblast is a nucleated ery-
throcyte of about the general size and shape of the normal erythro-
cyte. In the typical mature cell the nucleus is round or ovoid in
shape, very deeply stained, and situated rather toward the periph-
ery of the cell than in the exact center, its diameter approximating
more than one-half that of the corpuscle which it occupies. In the
normoblast of an earlier developmental stage the nucleus, is rela-
tively larger and is composed of delicate, faintly basic chromatin
— hall-marks of histological youth. In some of the typical cells
the nucleus appears to have become partly or completely extruded
from the protoplasm, lying either somewhat over the periphery of
the cell or, being completely detached from it, free in the plasma
(Fig. 49, III). The nucleus may be single, or partly divided by
constricting bands of chromatin into a figure like a dumb-bell or
a clover-leaf, or completely divided into several small, round
sections. More rarely, karyokinesis may be observed, the diaster
and early convolution stages, with an intact but plainly con-
stricted cell body, being the phases ordinarily found. (Plate I,
1 88 ERYTHROCYTES, BLOOD PLAQUES, AND HEMOKONIA.
Fig. 3; also Fig. 49, II.) In carefully stained films it will be
noted that the nuclear framework of the typical normoblast
consists of a rather sharply defined network of chromatin hav-
ing relatively wide intervening open spaces, so that the general
appearance of the nucleus is not unlike that of a coarse net.
The protoplasm of this cell is usually of regular outline along
the periphery, stains somewhat more intensely than that of the
normal erythrocyte, and may show distinct evidences of poly-
chromatophilia, this characteristic being especially marked in forms
with dividing nuclei.
The normoblast is regarded as the immediate antecedent of the
normal erythrocyte or normocyte, into which it becomes trans-
formed by the loss of its nuclear structure. The exact manner
in which the nucleus is disposed of has long been a bone of con-
tention among histologists, and even at the present time views on
this question should be held but tentatively, notwithstanding many
exhaustive investigations, especially those of the German school.
According to the views of Rindfleisch,1 it is lost by extrusion
from the cell body, which thus becomes a normal erythrocyte,
while the free nucleus, to which a small fringe of protoplasm still
remains adherent, collects from the plasma material by virtue of
which it ultimately develops into a new erythroblast. Ehrlich2
believes that in blood rich in normoblasts a series of connected
pictures may be observed, showing that the normoblast becomes
transformed into the erythrocyte by the extrusion or emigration
of the nucleus. The later investigations of Neumann and Kol-
liker,3 however, tend to prove that the nucleus is disposed of by
its destruction and absorption within the cell, and that its ap-
parent extrusion from the stroma is simply the result of mechan-
ical influences. Pappenheim and Israel4 also believe that the
normoblast's nucleus disappears by decay and solution within the
body of the corpuscle, and that the apparently extruded nuclei
are to be taken as an evidence of plasmolysis, or a solution of
the protoplasm of the cells once containing nuclei. To attempt
a reconciliation of these diametrically opposed views is a task for
future workers to undertake. Meanwhile, the general trend of
opinion inclines toward the theory of nuclear solution within
the corpuscle, and regards the so-called free nuclei of the normo-
blasts simply as artefacts (Fig. 49, I and III).
Normoblasts exist in the red bone marrow of the normal indi-
1 Arch. f. mik. Anat., 1880, vol. xvii, p. i.
2 Loc. cit. 3 Zeitschr. f. klin. Med., 1881, vol. iii, p. 411.
4 Virchow's Arch., 1896, vol. cxlv, p. 587; also Pappenheim, Inaug. Dis-
sert., Berlin, 1895.
PATHOLOGICAL CHANGES IN THE ERYTHROCYTES. 189
•
vidual, but are found in the circulating blood only when the
marrow, in consequence of pressing demands made upon it for
the rapid manufacture of new erythrocytes, becomes unable to
furnish an adequate supply of perfectly developed cells, so that
some of these immature, nucleated forms prematurely leave their
birthplace in the marrow, and pass into the blood stream in com-
pany with large numbers of mature, non-nucleated discs. Normo-
blasts are associated with lesions in which active hemogenesis
of the normal type is stimulated, being the prevailing type of
erythroblast in the anemias resulting from hemorrhage and in
other severe anemias of a secondary type. They sometimes ap-
pear in the blood in successive crops of large numbers during the
course of certain severe anemias, this phenomenon having been
termed by von Noorden1 a blood crisis. Blood crises, which are
of abrupt onset and of brief duration, lasting but a few hours,
are usually the direct precursors of an increase in the erythro-
cyte count and in the hemoglobin percentage, being therefore
a favorable sign, indicating regeneration of the blood. They occur
with especial frequency after loss of blood from hemorrhage and
in chlorosis, and are not uncommon in long-standing cases of
myelogenous leukemia and primary pernicious anemia, in which
diseases periods of temporary improvement are likely to take place
from time to time.
Megaloblasts (Plate I; also Fig. 48). — The typical megaloblast
is much larger in size than the normoblast, and contains a single,
large, pale-staining nucleus which occupies the greater part of the
cell body. Both cell and nucleus are round or ovoid in sljape, the
diameter of the former being from about u to 20 fi, and that of the
latter from 6 to 10 /A The greatest extremes of these' measurements
apply to those forms which are seen with relative infrequency, for
the megaloblast most commonly observed does not usually measure
more than 12 // in diameter, with a nucleus of proportionate size.
The nucleus, which may be situated either in or 'away from the
center of the cell, is composed of a chromatin network • having
relatively small intervening open spaces, so that the nuclear
structure is decidedly more delicate and less well-defined than that
of the normoblast. With the triacid solution and with the Roman-
owsky stain it is tinted pale green or blue, or it may show every sort
of irregular tinctorial reaction to the anilin dyes, certain portions
being deeply stained, while other parts are but faintly cojored; the
undertone of green or blue is frequently stippled with fine dots of
purple or of brilliant crimson, especially about the periphery; or
it may be mottled and splotched here and there with areas of purple
1 Charit£-Annalen, 1891, vol. xvi, p. 217.
IQO ERYTHROCYTES, BLOOD PLAQUES, AND HEMOKONIA.
or of dark blue. The nucleus, in the triple-stained film, usually
is sharply differentiated from the body of the cell by a distinct
white margin which encircles it and is thrown out in bold relief by
the deep staining of the nuclear and cell bodies on either side.
Occasionally a megaloblast shows a coarse, small nucleus of very
basic affinity, resembling that of the normoblast — characteristics of
nuclear senility.
The protoplasm of the megaloblast often seems swollen and
enlarged, and appears to contain areas of depression and elevation
at different points; it is sometimes quite round or oval in contour,
and sometimes more or less deformed. It is usually polychro-
matophilic, and, like the nucleus, may show the greatest variety
of color combinations. Some
cells stain, with the triacid mix-
ture, a dull brownish-yellow
color with deeper shadings of
a burnt-sienna tint in the
neighborhood of the nucleus
and of the periphery; others
have an undertone of crimson,
as if the stain contained an
excess of fuchsin, and are
strea'ked and dotted with yel-
low and tan-colored patches;
still others stain a diffuse pur-
ple, blending in spots into a
light pink. With Wright's
stain the color varies from
greenish-blue to purple to dull
yellow. Mitotic megaloblasts,
with figures similar to those
exhibited by normoblasts thus
dividing, are met with occasionally in anemias of great severity.
(Plate I, Fig. 3; also Fig. 49, II.)
The megaloblast is an element of the bone marrow of the young
fetus, and is totally foreign both to the marrow and to the blood of
the normal adult. According to the views -of Ehrlich, it repre-
sents the immediate antecedent of the megalocyte, into which it
develops by the absorption of its nucleus. Apparent extrusion
of megaloblastic nuclei is never observed. Megaloblasts are
found in the circulating blood only under conditions in which the
blood-making organs have reverted more or less to the fetal type,
so that their presence in the circulation is considered to indicate that
a sluggish hemogenesis of embryonal character exists. The
FIG. 48. — MEGALOBLASTS.
Common types of megaloblasts, showing va-
riations in size and shape and peculiarities of the
nuclear structure. (Ehrlich's triacid stain.)
PATHOLOGICAL CHANGES IN THE ERYTHROCYTES. 191
significance of megaloblasts, therefore, is diametrically opposed
to that of normoblasts, for, while the latter are regarded as an
expression of blood regeneration and are considered to be of
favorable prognostic significance, the former must be looked on
as an evidence of degeneration of the hematopoietic organs, and,
consequently, are of grave prognosis.
In the following table the principal points of distinction between
the typical normoblast and the megaloblast are emphasized:
\ORiIOBLAST.
MEGALOBLAST.
Size.
7.5 to 10 n.
II tO 20 /I.
Nucleus.
Sharply defined.
Intensely basic. '
Coarsely meshed.
Occupies about one-half of
cell body.
Dully defined.
Feebly basic.
Delicately meshed.
Occupies greater part of cell body.
Protoplasm.
Sometimes very scanty
and of ragged outline.
Occasionally polychro-
matophilic.
Frequently appears swollen; out-
line fairly regular, but surface
undulating in many cells.
Striking tendency toward poly-
chromatophilia .
Hislological
Significance.
Typical of active, adult
hemogenesis.
Typical of sluggish, embryonal
hemogenesis.
Occurrence.
Prevailing type of ery-
throblast in anemias
with active blood re-
generation.
Prevailing type of erythroblast in
anemias with megaloblastic de-
generation of the bone marrow.
Megaloblasts are found in the blood, almost in variably in as-
sociation with normoblasts, in various anemias of marked severity,
but in only three conditions, viz., primary pernicious anemia,
certain cases of anemia due to Bothriocephalus latus infection,
and nitrobenzol poisoning, have these cells been found to con-
stitute the prevailing type of erythroblast.
In pernicious anemia the prevalence of megaloblasts is. gener-
ally admitted to be a sign that in this disease the bone marrow,
in consequence of its reversion to a fetal type, throws into the
blood stream large numbers of these blood cells of embryonal
character, these degenerative changes, the presence of megalo-
blasts, overshadowing the regenerative changes, or the presence
of normoblasts. In bothriocephalus anemia, in which also the
megaloblasts may outnumber the normoblasts, it is believed that
the toxins produced by the parasite cause changes in the hema-
topoietic organs precisely similar to those found in pernicious
anemia. Rosenquist's 1 elaborate studies show that the excessive
1 Berlin, klin. Wochenschr., 1901, vol. xxxviii, p. 666.
IQ2 ERYTHROCYTES, BLOOD PLAQUES, AND HEMOKONIA.
albumin disintegration caused by the bothriocephalus toxin is
essentially like that occurring in typical pernicious anemia. In
a single case of nitrobenzol poisoning, reported by Ehrlich and
Lindenthal,1 large numbers of erythroblasts were noted; normo-
blasts predominated at first, but in the later stages of the intoxica-
tion they were outnumbered by megaloblasts. In other grave
anemias, notably in leukemia, the regenerative signs appear to
be more active than the degenerative, for, while in these condi-
tions megaloblasts are frequently found, they are never so numer-
ous as the normoblasts.
Microblasts. — The microblast, which is the rarest form of nu-
cleated erythrocyte, is a cell usually not larger than 5 or 6 p in
diameter, and often of smaller size. It consists of a deeply stained,
round nucleus like that of the normoblast, encircled by a frag-
ment of ragged protoplasm of a dull brownish-yellow tint, in films
stained with the triacid solution. Wright's stain frequently
colors this stroma blue. Microblasts are thought to be simply
forms of the normoblast in a more or less advanced stage of
protoplasm degeneration, this process accounting for the char-
acteristic scantiness and frayed-out appearance of their cell body.
Their clinical significance, naturally, is identical with that of the
normoblast.
From what has been stated, it may be concluded that nor-
moblasts and megaloblasts constitute two distinct classes of
nucleated erythrocytes, each evidencing a separate type of blood-
formation, and each carrying a different clinical meaning. Nor-
moblasts, being an adult type of cell, have sharply defined, dense,
deeply stained nuclei; megaloblasts, being an embryonal type of
cell, have poorly defined, delicate, feebly stained nuclei.
Atypical Erythroblasts. — In some of the severer anemias,
notably in myelogenous leukemia and in pernicious anemia,
various atypical erythroblasts are frequently found, corresponding
partly to one and partly to the other of the first two species of cells
described above. These so-called " mesoblasts," which may be re-
garded either as normoblasts with immature nuclei or as megalo-
blasts with mature nuclei, are in some instances almost as numerous
as the typical forms of erythroblasts. It is sometimes impossible
accurately to determine to which type such cells belong, but
usually they may be classified by taking size as a criterion for
differentiation. Those approximating the normocyte in size may
safely be classed as normoblasts; those of larger size, as megalo-
blasts— regardless of their nuclear peculiarities. The two fol-
1 Zeitschr. f. klin. Med., 1896, vol. xxx, p. 427.
PATHOLOGICAL CHANGES IN THE ERYTHROCYTES. 193
lowing commoner forms of atypical erythroblasts may be rec-
ognized :
i. Corpuscles about 8 or 10 // in diameter, containing a rela-
tively large, round or ovoid nucleus, composed of a finely meshed
chromatin framework. The nucleus is pale, and is often filled with
m
FIG. 49. — ATYPICAL FORMS OF ERYTHROBLASTS.'
/, Megaloblasts and normoblasts showing nuclear solution; the two cells (a) show, early, and
the three (o) late, stages of karyolysis. Five of the six cells (c) contain nuclear remains consisting
of both coarse and delicate chromatin masses. Note the granular basophilia in the groups of cells
at /, //, ///, and IV. II, Erythroblasts with multiple and dividing nuclei; the megaloblast (a)
represents the wreath-shaped (monaster) stage of karyokinesis, the megaloblast (fr) the double star-
shaped (diaster) stage, and the megaloblast (c) the convolution (daughter cell) stage. The other
cells jllustrate the kinds of erythroblasts with convoluted and multiple nuclei ordinarily found
in high-grade anemias. ///, Erythroblasts showing so-called nuclear extrusion. IV, Erythro-
cytes containing ring bodies. V, Normal erythrocytes. (Wright's stain.)
finely stippled areas of acid affinity. The cell body is usually of
regular outline, and, as a rule, is decidedly polychromatophilic.
Such cells may be regarded as immature forms of normoblasts,
with which they may properly be classed in the differential count
(Plate I; also Fig. 48).
13
194 ERYTHROCYTES, BLOOD PLAQUES, AND HEMOKONIA.
2. Corpuscles about 12 to 15 /* in diameter, having a small,
coarsely meshed nucleus not exceeding 2 or 3 ,« in diameter, and,
as a rule, situated eccentrically. The nucleus stains very basically,
and may or may not be separated from the protoplasm by a color-
less zone. The body of the cell is round or ovoid, and stains
faintly. This form of cell appears to carry the same clinical
significance as the megaloblast, of which it is probably a late
developmental phase (Plate I; also Fig. 48).
Ring Bodies. — In severe anemia Wright's stain often brings out
peculiar intra- and extra-cellular ring-shaped bodies whose outlines
resemble those of the nuclear figures of erythroblasts (Fig. 49,
IV). Cabot,1 who described these bodies, suggests that they may
represent nuclear remnants, or portions of the erythrocytes' nuclei
which are especially resistant to whatever forces ultimately destroy
the cells and their nuclei. Basic (blue) ring bodies within the
erythrocytes were described and pictured, in 1901, by Strauss
and Rohnstein,2 who interpreted them as a variety of granular
basophilia. The bodies have been found, in association with
frankly nucleated erythrocytes, polychromatophiles, and basically
stippled cells, in lead poisoning, in pernicious anemia, and in
lymphatic leukemia. The writer has noted them in high-grade
anemia secondary to sepsis. With Wright's solution the ring-
shaped bodies stain red and, rarely, blue; they are variously
shaped — circles, rude rosettes, clover leaves, figures-of-eight, and
forms with twisted threads and with netted structures. These
designs, it will be noted, correspond accurately to the nuclear
figures of various erythroblasts.
In certain of the severe anemias, staining with
GRANULAR methylene-blue shows a peculiar granular condi-
BASOPHILIA. tion of the protoplasm in some of the erythro-
cytes, attention first having been called to this
fact by von Noorden,3 who demonstrated the basophilic charac-
ters of such granules, and described their occurrence in vari-
ous pathological states. Many of the corpuscles thus affected
are of the nucleated form, but non-nucleated cells may be simi-
larly granulated; as a rule, such corpuscles are also strikingly
polychromatophilic.
The granules appear either as fine or as coarse, stippled areas,
staining intensely with the basic stain, and distributed through
the body of the cell either quite uniformly or in localized patches
1 Jour. Med. Research, 1903, vol. iv, p. 15.
"Die Blutzusammensetzung bei den verschiedenen Anamienen," Berlin,
1901, p. 224.
3 Charite-Annalen, 1892, vol. xvii, p. 202.
PATHOLOGICAL CHANGES IN THE ERYTHROCYTES.
195
at one or at several points. In some cells they are exceedingly
fine and closely packed together, so that at first glance the whole
protoplasm appears to be a homogeneous mass of purplish dis-
coloration; in others the protoplasm is dotted here and there
with coarse granules, not more than five or six being found
in the whole cell; still others may contain both fine and coarse
granules irregularly sprinkled over the surface (Plate I; also
Figs. 49 and 50).
The occurrence of somewhat similar granulations in the eryth-
rocytes of the embryo has been noted by Engel,1 Pappenheim,2
and others, who regard them as nuclear debris, the product of
nuclear disintegration. Such an origin in embryonic blood is
FIG. 50. — GRANULAR BASOPHELIA.
Erythrocytes showing various degrees of basophilia, with fine, coarse, spherical, ovoid, and spicu-
late, granules. Note the basophilic normoblast. (Wright's stain.)
probably physiological. In post-uterine life, however, this proc-
ess is to be regarded as a sign of stroma degeneration, arising
in all likelihood through the influence of various blood' poisons.
In some instances the change precedes all other recognizable alter-
ations in the blood, and appears as the first, and, indeed, some-
times the only, distinct sign of anemia.
Granular basophilia of the erythrocytes has been^ noted with
more or less constancy in these conditions: pernicious anemia,
leukemia, Hodgkin's disease, so-called tropical anemia, bothrio-
cephalus anemia, malarial fever, sepsis, carcinoma, long-standing
suppurati-ve lesions, and chronic lead poisoning. In chlorosis, if
1 Verhandl. d. Vereins f. inn. Med. z. Berlin, 1898-99, vol. xviii, p. 216.
2 Loc. cit.
196 ERYTHROCYTES, BLOOD PLAQUES, AND HEMOKONIA.
uncomplicated by symptoms of intestinal auto-intoxication, the
erythrocytes do not exhibit this alteration; granule cells are also
absent in syphilis, in acute infectious diseases, in chronic lesions
oj the kidney and the liver, and in diabetes, according to Grawitz.1
Regarding the occurrence of this change in pernicious anemia,
Ehrlich 2 believes that the number of granule cells in the blood
bears a certain relation to the severity of the disease, stating that
they decrease and often disappear during the periods of remission,
reappearing as the other blood changes again become evident.
On the other hand, Litten,3 who asserts that he has found these
basophilic granulations in one-tenth of all cases of anemia, has
been unable to determine their clinical significance from either
a diagnostic or a prognostic point of view. The studies of
Grawitz and Hamel4 show that granular degeneration of the
erythrocytes occurs with great regularity in saturnism, both
in obscure and in well-marked cases, and these authors attach
considerable diagnostic value to this fact, concluding that the sign
is important in the diagnosis of lead poisoning in patients in whom
the intoxication is merely suspected, being evidenced by no other
definite symptoms. Experimentally, basophilia has been produced
by the administration of lead salts, tin chlorid, copper, pyrodin,
atropin, toluylendiamin, and phenylhydrazin. A dose of any of
the proprietary preparations of hemoglobin may also promptly
excite the change, as may the ingestion of whole blood —
facts which lead Grawitz5 to assume that blood in the gastro-
intestinal canal elaborates toxic substances the absorption of which
acts deleteriously upon the erythrocytes. This and other phases
of basophilia have been reviewed at length by the writer elsewhere.6
Here may be mentioned certain areas of reddish stippling
(Schiifiner's granules) demonstrated by polychrome methylene-
blue in the erythrocytes of tertian malarial fever (q. v.).
' Oligocythemia, or diminution in the number of
OLIGOCY- erythrocytes below the normal standard, is pres-
THEMIA. ent to a more or less marked degree in all forms
of anemia, being associated, naturally, with an
oligochromemia, or diminution in the percentage of hemoglobin,
but not necessarily with an oligemia, or reduction in the volume
of the blood mass.
The loss of corpuscles may be slight or it may be marked, ac-
cording to the nature of the anemia of which it is symptomatic.
1 Amer. Jour. Med. Sci., 1900, vol. cxx, p. 277.
2 Loc. cii. 3 Deutsch. med. Wochenschr., 1899, vol. xxv, p. 717.
4 Deutsch. Arch. f. klin. Med., 1900, vol. Ixvii, p. 357.
5 Deutsch. med. Wochenschr., 1901, vol. xxvii, p. 908.
* Amer. Med., 1903, vol. v, p. 571.
PATHOLOGICAL CHANGES IN THE ERYTHROCYTES. 197
The most striking examples of oligocythemia are encountered
after hemorrhages involving the loss of a large amount of blood
and in pernicious anemia; while in chlorosis and in the majority
of the secondary anemias the decrease is relatively less marked.
The following summary of the averages of fifty consecutive counts
each in cases of primary and secondary anemia illustrates the
various degrees of cellular loss which ordinarily accompany these
conditions :
AVERAGE or 50 COUNTS. ERYTHROCYTES PER c.ioi.
In pernicious anemia 1,152,470
" leukemia 2,729,763
" secondary anemia 3,642,900
" chlorosis 4, 1 11,000
It is impossible to designate the degree of oligocythemia which
may exist without a fatal outcome, although a number of author-
ities have attempted to set fixed limits beyond which reduction
in the number of erythrocytes is supposed to cause death. The
effects of a blood loss are so diverse in different individuals that
all such arbitrary rules must, of necessity, prove practically
valueless. It should be remembered that while in some persons
a comparatively moderate decrease may prove fatal, in others a
most astonishing loss is compatible with life. It may be stated
in general terms that few individuals recover in whom a count of
less than 500,0x20 erythrocytes to the c.mm. is found, although
occasional exceptions to this rule have been reported.
Whether or not an actual, permanent polycy-
POLYCYTHEMIA. themia, or an increase in the number of erythro-
cytes above the normal standard, exists is still
an unsettled question, but the majority of authorities maintain
that such a condition is due merely to some physical change
producing concentration of the blood, or unequal Distribution of
the corpuscles, in favor of the peripheral blood vessels. .In health,
it would not seem unreasonable to suppose that a moderate de-
gree of polycythemia may be habitual in the strong, overdevel-
oped adult, whose blood-making organs are possibly developed
proportionately to the other parts of his system. In pathological
conditions there is nothing tangible upon which to base the belief
that an actual and permanent overproduction of the erythro-
cytes ever takes place, the polycythemia associated with certain
diseases being satisfactorily accounted for by coexisting physical
conditions, in no way peculiar to the lesion in question. While
it is true that in some conditions it is not always possible to ex-
plain the increase by purely physical causes, still there is no posi-
198 ERYTHROCYTES, BLOOD PLAQUES, AND HEMOKONIA.
tive proof, in these instances, that the change is pathological.
There seems, therefore, no evidence to warrant an arbitrary clas-
sification of polycythemia into two divisions, actual and relative,
as some authors have suggested.
The cause of polycythemia, then, may be attributed to physio-
logical factors such as concentration of the blood, increased blood
pressure, peripheral stasis, increased viscidity of the erythrocytes,
and their unequal distribution through the circulatory system.
The polycythemia associated with various physiological and
pathological conditions will be considered under their appropriate
headings. Briefly, an increase of erythrocytes over the normal
number is found in the following conditions:
1. In the new-born.
2. After taking food.
3. In starvation.
4. During residence in high altitudes.
5. From the effect of cold and hot baths, muscular exercise,
massage, and electricity.
6. From the administration of lymphagogues, emetics, pur-
gatives, and thyroid extract.
7. During active blood regeneration. '
8. During reformation of an exudate after aspiration.
9. After urinary crises, diaphoresis, emesis.
10. In poisoning by illuminating gas and by phosphorus.
11. In Asiatic cholera, dysentery, and diarrhea.
12. In acute yellow atrophy of the liver and myxedema.
13. In conditions of cyanosis and peripheral stasis, for example,
uncompensated organic heart disease, emphysema, asphyxia, and
Osier's disease.
14. After the transfusion of blood.
V. BLOOD PLAQUES.
If a drop of fresh blood is examined microscopically imme-
diately after it has been taken from the body,' a few pale, some-
what spherical bodies, much smaller in size than the erythrocytes,
may usually be observed. These bodies are known as the blood
plaques or blood platelets. They are of homogeneous structure,
either almost colorless or of a pale yellowish tint, spherical or
irregularly ovoid in shape, and measure from i to 3 or 4 tl in
diameter. They are non-nucleated, and react toward both basic
and acid anilin dyes, having an amphophilic affinity. Deetjen1 has
1 Virchow's Arch., 1901, vol. clxiv, p. 239.
BLOOD PLAQUES. 1 99
shown that the plaques exhibit definite ameboid movement — a
property denied these bodies by the earlier investigators — and
that they are apparently nucleated.
The plaques exist as free bodies in the general circulation, but
directly after the withdrawal of the blood from the vessels they show
a remarkable degree of viscosity, by virtue of which they tend to
adhere in racemose masses, the occurrence of which at or near the
radiating points of the fibrin network has already been described.
Zeri and Amalgia1 found that in malarial fever this agglutination
of the plaques did not occur, although it was regularly observed
in other infections, such as pneumonia, pleurisy, tuberculosis,
enteric fever, and the exanthemata.
The belief of Bizzozero2 and of Hayem,3 that the plaques repre-
sented a so-called " third corpuscle " of the blood, is not justified, for
it has been proved that these bodies are not distinct cellular entities,
but rather de'bris, derived either from the blood corpuscles or from
the plasma. It is evident, from the work of Arnold,4 Engel,5
Klebs,6 and others, that at least a large proportion of the plaques
are simply bits of globular matter extruded from the erythrocytes,
and in eosin-methylene-blue films the apparent eruption of plaques
from the stroma of the erythrocytes can be readily demonstrated.
It is possible that some of the plaques are derived by the disintegra-
tion of the nuclei of the leucocytes (Lilienfeld ;7 Howell ;8 Gibson9) ;
and that still others are masses of precipitated globulin (Lowit10).
Heim11 believes that the plaques are nuclear formations of the
erythrocytes, and claims that regeneration of the latter and in-
crease in the number of blood plaques progress pdri passu.
Ducchesi's method of macroscopically demonstrating the
plaques is of clinical interest : A few drops of blood are collected
in a watch-glass, which is gently rocked from side to side for a few
minutes, and then held up to the light, showing the plaques as
groups of delicate white granules in the stratum of blood next to
the glass. These granular masses appear within from forty seconds
to two minutes after withdrawal of the blood, and disappear as
coagulation commences.
1 II Policlin., 1903, vol. ix, p. 485. 2 Virchow's Arch., 1882, vol. xc, p. 261.
3 Compt. rend. Soc. biol., Paris, 1877, vol. ii, p. 85.
4 Centralbl. f. allg. Path., 1897, vol. viii, p. 289.
s " Leitfaden zur klinischen Untersuchung des Blutes," 2d ed., Berlin, 1902,
P-SI-
8 Ziegler's Beitr., 1889, vol. iv, p. 528.
7 Zeitschr. f. physiol. Chem., 1895, vol. xx, p. 155.
8 Jour. Morph., 1891, vol. iv, p. 57.
' Jour. Anat. and Physiol., 1886, vol. xx, p. 100.
10 Arch. f. mik. Anat., 1891, vol. Iviii, p. 598.
11 Deutsch. med. Wochenschr., 1903, vol. xxix, p. 588.
200 ERYTHROCYTES, BLOOD PLAQUES, AND HEMOKONIA.
Exposure to the air appears to cause an almost immediate dis-
appearance of the plaques from the blood, and, therefore, they are
but seldom noticed in the blood film prepared by the ordinary
methods. With Wright's stain, however, they are readily demon-
strable in the dry film. In studying the plaques in their fresh
state the blood may be drawn directly through a drop of Hayem's
solution or a weak solution of osmic acid, the mixture of the blood
and fixative being then placed upon a slide and examined in the
usual manner. (See p. 90.)
The number of plaques in normal blood varies within wide
limits, according to the statements of different authorities, but
about 300,000 to the c.mm. is generally considered the normal
average, and from 180,000 to 500,000 the range under physio-
logical circumstances.
The plaques generally are increased in pernicious anemia,
severe secondary anemias, leukemia, pneumonia, arthritis de-
formans, myelitis, tuberculosis, bubonic plague, and as the effect of
residence in high altitudes. They are diminished in hemophilia,
purpura, and acute febrile diseases, such as erysipelas, typhus
fever, and the malarial fevers.
VI. HEMOKONIA.
Muller 1 has called attention to the constant presence in normal
and pathological blood of small, colorless, refractive bodies, of
spheroidal or dumb-bell shape, not larger than i // in diameter.
These bodies, to which the terms hemokonia and blood dust have
been applied, are highly refractive, and possess active, limited
molecular motility, but not true ameboid motion. They have
been compared in appearance to fine fat droplets, to micrococci,
and to granules derived from the protoplasm of the leucocytes.
Nothing is known of their histological character and significance
beyond the facts that they are not concerned in the process of
fibrin formation, and that they are not fatty bodies, since they are
neither stained by osmic acid nor dissolved by ether. Both
Stokes and Wegefarth,2 and Nicholls3 regard them as free granules
of the neutrophile and eosinophile leucocytes, and believe that
they are probably concerned in the protective properties of the
blood in immunity. Stengel4 suggests that they may be simply
the products of fragmentation of the erythrocytes, such as may
1 Centralbl. f. Path. u. Bakteriol., 1896, vol. xxv, p. 529.
2 Johns Hopkins Hosp. Bull., 1897, vol. viii, p. 246.
8 Phila. Med. Jour., 1898, vol. i, p. 387. g
4 "Text-book of Pathology," 4th ed., Philadelphia, 1903, p. 335.
HEMOKONIA.
2OI
be produced by heating fresh blood to destructive temperatures,
when bits of the corpuscles are seen to bud out, break off, and
float free in the plasma, endowed with pseudo-ameboid motility.
Miiller found large numbers of hemokonia in a case of Addi-
son's disease, but these bodies were very scanty in a number of
markedly cachectic conditions. Their occurrence in the blood
appears to carry no definite clinical significance.
SECTION IV.
THE LEUCOCYTES
PLATE ll.
*• - .. ?••" ;'.-".
• :•.•: t}£: * 13
17 18
oc
THE LEUCOCYTES.
(1-16, Triacid Stain; \~,-tf>t Eosin and Methylene-blue.)
(E. F. FABER,/<T.)
( Triacid Stain.)
i, 2, 3, 4. Small Lymphocytes.
Contrast the faintly colored protoplasm of these cells in the triple stained specimen
with their intensely basic protoplasm in the film stained with eosin and methylene-
blue, 17 and 18. The cell body of i is invisible. Note the kidney-shaped nucleus in 4.
5, 6. Large Lymphocytes.
With this stain the nucleus reacts more strongly than the protoplasm ; with eosin and
methylene-blue (19, 20), on the contrary, the protoplasm is so deeply stained that the
nucleus appears pale by contrast. This peculiarity is also observed in the smaller
forms of lymphocytes.
7, 8. Transitional Forms.
Note the moderately basic and indented nucleus, and the almost hyaline non-granular
protoplasm. Compare 8 with the myelocyte, 7, Plate IV, these cells differing chiefly
in that the myelocyte contains neutrophile granules.
9, 10, ii. Polynuclear Neutrophiles.
These cells are characterized by a polymorphous or polynuclear nucleus, surrounded
by a cell body filled with fine neutrophile granules. In n the nuclear structure is
obviously separated into four parts; in 9 it is moderately, and in 10 markedly, poly-
morphous.
12, 13. Eosinophiles.
The nuclei are not unlike those of the polynuclear neutrophile, except that they are
somewhat less convoluted, and poorer in chromatin, staining less intensely. The pro-
toplasm is filled with coarse eosinophile granules, the characteristics of which are
clearly illustrated by 13, a " fractured " eosinophile.
14. Eosinophilic Myelocyte.
Compare with 15.
15, 16. Myelocytes. (Neutrophilic.)
These cells are morphologically similar to 14, except that they contain neutrophile
instead of eosinophile granules. Note that the granules of the myelocyte are identical
with those of the polynuclear neutrophile. A dwarf form of myelocyte is represented
by 16.
(Eosin and Methylene-blue.)
17, 18. Small Lymphocytes.
Note the narrow rim of pseudo-granular basic protoplasm surrounding the nucleus,
and the pale appearance of the latter.
19, 20. Large Lymphocytes.
Budding of the basic zone of protoplasm is represented by 20. Both of these cells
belong to the same type as 5 and 6.
21, 22. Large Mononuclear Leucocytes.
Compared with 19 and 20, these cells have a decidedly less basic protoplasm, but a
somewhat more basic nucleus. In the triple stained film these differences cannot be
detected, so that they must be classed as large lymphocytes.
23. Transitional Form.
The distinction between this cell and 24 is not marked ; the nucleus of the latter
simply being somewhat more basic and convoluted.
24, 25, 26, 27. Polynuclear Neutrophiles.
With this stain these cells show a feebly acid protoplasm, and lack granules. Note
that the more twisted the nucleus the deeper it is stained. Compare wuh 9, io,and n.
28, 29. Eosinophiles.
Compare with 12 and 13.
30. Eosinophilic Myelocyte.
Compare with 14.
31. Basophile. (Finely granular.)
This cell is characterized by the presence ol exceedingly fine 6-granules, staining the
pure color of the basic dye. The nucleus is markedly convoluted and deficient in
chromatin. The cell here shown was found in normal blood.
32. 33, 34, 35, 36. Mast Cells.
The granules take a modified basic color, as shown by their royal-purple tint in this
illustration. Note their unusually large size and ovoid shape in 35, their peculiar
distribution in 35 and 36, and their irregularity in size in 32 and 36. With the triacid
mixture these granules, as well as those of the finely granular basophile, 31, remain
unstained, showing as dull-white stippled areas in the cell body. The nuclear chro-
matin of the mast cell is so delicate and so feebly stained that it is barely visible.
These cells were found in the blood of a case of spleno-medullary leukemia.
SECTION IV.
THE LEUCOCYTES.
I. GENERAL CHARACTERISTICS.
In the fresh, unstained blood film the leuco-
APPEARANCE cytes are recognized as pale nucleated cells, the
IN majority of which are larger in size than the
FRESH BLOOD, erythrocytes, by which they are greatly outnum-
bered, the proportion of the former to the latter
ranging approximately between i : 450 and i : 1200 in normal
blood. The size of the normal white corpuscles varies from
about 7 // to 10 or 12 />« in diameter, and their shape, while in
the resting stage, is irregularly round or oval.
' By careful examination four different varieties of these cells
may be distinguished, the distinction between these forms being
made more striking by the addition of a small quantity of a one
per cent, acetic acid solution to the fresh film. These varieties,
which are essentially the same as those first described by Schultze,
in 1865, 1 are as follows: (i) Non-ameboid cells about the size
of the normal erythrocyte, consisting of a pale, compact, spher-
ical nucleus encircled by a narrow zone of homogeneous proto-
plasm. (2) Ameboid cells almost twice the size of the erythro-
cyte, consisting of a rather coarsely meshed nucleus, spherical,
ovoid, or indented in form, surrounded by a relatively large
amount of clear protoplasm. The latter is highly opaque, for
although it forms an exceedingly thin layer when spread out flat,
it effectually obscures the outlines of objects over which it lies —
as an explanation for which characteristic Kanthack and Hardy2
presume that the cell matter is composed of a colorless basis
embedding immense numbers of minute vacuoles filled with a
substance of a different refractive index. (3) Ameboid cells of
slightly smaller size than the second variety, consisting of a single
twisted nucleus, or of two or more separate round or ovoid nuclei,
embedded in a body of protoplasm crowded with exceedingly
delicate, moderately refractive granules. The nuclear network is
1 Arch. f. mik. Anat., 1865, vol. i, p. i. * Jour. Physiol., 1894-95, vol. xvii, p. 81.
205
206 THE LEUCOCYTES.
composed of chromatin threads closely united to form a compact,
lobulated structure, and the protoplasm appears 'to consist of a
transparent substance, of gelatinous character, having a refractive
index but slightly below that of the granules which it contains.
(4) Ameboid cells containing a convoluted nucleus, or several
spherical nuclei, embedded in a protoplasm filled with coarse,
highly refractive, fat-like granules. The nuclear structure con-
sists of a coarsely meshed, knotted network, and the protoplasm
is much less refractive than its granules, being clear and struc-
tureless in appearance.
Spontaneous changes in the shape of the larger
AMEBOID varieties of leucocytes may be observed if the slide
MOVEMENT, is placed upon a warm stage having a temper-
ature of about 98.5° F. During these ameboid
movements the shape of the cells constantly undergoes alteration
by the alternate contraction and expansion of the protoplasm.
Tentacular processes reach out from various portions of the
cell body, while at other points its surface becomes retracted,
so that it may appear as an irregular nucleated mass provided
with one or more long, snake-like arms projecting from a central
body. These ameboid cells are chiefly concerned in the process
of phagocytosis, or the engulfing and destruction of micro-organ-
isms and other foreign matter which may gain entrance into
the circulating blood, and to leucocytes which exert this function
the term phagocyte has been applied. The well-known experi-
ments of Metschnikoff l have shown their propensity for seizing
upon and devouring pathogenic bacteria, such as the anthrax
bacillus and the erysipelas streptococcus, and further proof of
such phagocytic action may frequently be found in the fragments
of other foreign matter, such as bits of old blood clots, malarial
pigment, and fat droplets inclosed in their protoplasm.
It has also been suggested by Gabritschewsky 2 that it may be
possible under some circumstances that phagocytes are capable
not only of engulfing solid bodies, but that they may also imbibe
liquid substances, which are thus rendered harmless to the
organism, and to this property the term pinocytosis has been
given by this author. Drugs injected hypodermically are taken
up by phagocytic cells, which, according to Labbe",3 not only
absorb and assimilate medicaments, but perhaps carry them, by
election, to a specific lesion of the organism — mercury to a syphil-
itic nidus, for instance. Iron, iodin, arsenic, mercury, iodoform,
1 "L' Inflammation," Paris, 1892.
2 Annal. de 1'Instituf Pasteur, 1894, vol. viii, p. 673.
3 Presse me'd., 1903, vol. ii, p. 725.
GENERAL CHARACTERISTICS. 207
and the salicylates are among the drugs dealt with in this
manner.
The ameboid property of the leucocytes is also responsible for
the ease with which these cells escape from the blood vessels into
the perivascular tissues in inflammatory lesions, and to a less ex-
tent in health. This well-known process of diapedesis is facili-
tated by virtue of the leucocyte's ability to elongate and flatten
out so that it may readily emigrate through the spaces between
the endothelial cells of the vessel wall.
The identification of the various forms of
CELL leucocytes depends largely upon the presence or
GRANULES, absence of granules in their protoplasm, and upon
the distinctive manner in which these granules
react toward the acid, basic, and so-called neutral solutions of
the anilin dyes. By means of this method of "color analysis"
Ehrlich has provided a rational means by which the study of the
leucocytes may be undertaken.
Five varieties of granules, which are designated by the use of
the Greek letters «, /9, ^, d, and e, may be recognized in the cell
bodies of the leucocytes, as follows :
1. a- granules (eosinophile, oxyphile, or coarse oxyphile gran-
ules): Coarse, spherical or ovoid, highly refractive granules of
a peculiar fat-like appearance, showing a striking affinity for acid
stains, especially for eosin. In normal blood they occur only in
leucocytes with polynuclear or polymorphous nuclei, but in cer-
tain pathological conditions they may be found in that variety of
the leucocyte known as the eosinophilic myelocyte.
2. p- granules (amphophile granules): Fine granules which
are capable of reacting toward both acid and basic dyes, inva-
riably staining with the former and sometimes with the latter, if
the stains are used singly, while in a mixture of the two they
always react toward the acid dye. These granules never occur
in normal blood, but in some pathological conditions a varying
proportion of the leucocytes may exhibit amphophilic reactions
on the part of some of their granules.
3. y-granules (mast cell or coarse basophile granules): Very
coarse granules, measuring from 0.2 to 0.4 // in diameter, and pos-
sessing an intense affinity for basic dyes. If stained with car-
boltoluidin-blue, with thionin, or with alkaline methylene-blue,
they are colored a distinctive deep purplish-red. These granules
occur in a form of leucocyte known as the mast cell, which is
abundant in myelogenous leukemia, and is met with occasionally
in other diseases.
4. ^-granules (fine basophile granules): Fine granules, stain-
208 THE LEUCOCYTES.
ing with basic dyes, and occurring under normal conditions in
leucocytes having polymorphous nuclei. They are most clearly
demonstrated with such basic dyes as thionin or methylene-blue,
by which they are stained a deep blue color.
5. e- granules (neutrophile or fine oxyphile granules) : Exceed-
ingly fine granules, formerly thought to have a selective affinity
for the neutral element of a solution composed of acid and basic
dyes, but now known to have, in reality, a feeble oxyphilic ten-
dency. They occur abundantly in the normal polynuclear
neutrophile cells, and also in several pathological forms of leuco-
cytes : the myelocyte, the small mononuclear neutrophile, and
the "small neutrophilic pseudolymphocyte."
But little is known of the real nature and function of the leuco-
cyte granules, in spite of their elaborate study by different in-
vestigators. Two leading views, which excite much controversy,
to-day command attention: the hypothesis of Ehrlich1 and the
bioblastic theory of Altmann.2 Ehrlich regards them as an
evidence of a specific secretory function on the part of the cells,
which under normal conditions contain but a single variety of
granules. They are to be considered as products of cellular
metabolic activity, and are destined to be given off in the vicinity
of the cells, this elimination perhaps constituting one of the most
important functions of the latter. Far from representing mere
waste-products, as some authors contend, they are in reality ele-
ments of decided, although obscurely defined, value to the or-
ganism. Altmann, in his bioblastic theory, considers cell granules
as definite biological entities, and believes that they "serve as a
basis for the explanation of the many phenomena of organic metab-
olism." In summing up their functions he remarks that "they
effect through oxygen-transmission both reductions and oxygena-
tion, and in this manner accomplish the disunions and the syn-
theses of the economy without sacrificing their own individuality."
As a rule, the cell granules are thought to be relatively simple
bodies, although their exact composition is as yet undetermined.
It has been proved by Weiss3 and others that they are of albu-
minous character. The eosinophile granules, in which iron has
been demonstrated by Barker 4 and other observers, are more com-
plex than the other varieties. They are of a higher histological
structure, consisting of an external limiting portion which may
1 Loc. cit.
2"Ueber die Elementarorganismen und ihre Beziehungen zu den Zellen,"
2d ed., Leipsic, 1894.
3 "Hematologische Untersuchungen," Vienna, 1896.
4 Johns Hopkins Hosp. Bull., vol. v, p. 93.
CLASSIFICATION.
209
be clearly differentiated from the central area. Hankin and
Kanthack1 have determined the fact that increased bactericidal
power of the blood is closely correlated with the discharge of
both eosinophile and neutrophile granules into the plasma, and
the former observer 2 has furthermore shown that in experimental
infections there is at the point of the infection an accumulation of
cells containing eosinophile granules, together with a discharge
of such granules during the conflict of the cells with the invading
micro-organisms.
In the normal adult the number of leucocytes
NORMAL NUM- in the peripheral circulation averages from about
BER. 5000 to 10,000 to the c.mm. of blood. In the
majority of instances, in which the influences of
physical factors are excluded, a count of 7500 leucocytes per c.mm.
may be regarded as the mean normal average. Variations of several
thousand cells per c.mm. above and below this number are within
physiological limits, and frequently occur because of the extreme
susceptibility of the leucocytes to agencies causing such transient
fluctuations. The following table, compiled from data given by
Hayem,3 Grawitz,4 and von Limbeck,5 shows the average number
of leucocytes determined by various authorities :
Thoma 8687 per c.mm.
Von Limbeck 8500
Rieder 7680
Boeckman; Halla 7533
Graeber; Reinecke 7242
Tumas 6200
Hayem 6000
Average 7406 "
II. CLASSIFICATION.
Six distinct varieties of leucocytes may be recognized in the
healthy adult's blood stained by the Romanowsky methocl or by
Ehrlich's stain, according to the methods described in a previous
section. These varieties, together with their normal relative per-
centages and absolute number to the c.mm. of blood, are as fol-
lows:
VARIETY. PER CENT. NUMBER PER C.MM.
Small lymphocytes 20-30 1000-3000
Large lymphocytes and transitional forms 4-8 200-800
Polynuclear neutrophiles 60—75 3000-7500
Eosinophiles °-5~5 25-500
Basophiles, as high as 0.5 25
1 Centraibl. f. Bakt. u. Parasit., 1892, vol. xii, p. 777; ibid., 1893, vol. xiv, p. 852.
2 Jour. Physiol., 1894-95, vol. xvii, p. 81. * Loc. cit.
4 "Klinische Pathologic des Blutes," Berlin, 1896. ' Loc. cit.
210 THE LEUCOCYTES.
With the decline of life the proportion of polynuclear neutro-
philes rises, the lymphocytic forms becoming correspondingly less
numerous. This reversal of the youthful blood picture is, accord-
ing to Dobrovici's researches,1 most conspicuous after the sixtieth
year of age.
The variations in these numbers and percentages, which de-
pend upon different physiological and pathological influences, are
referred to in other sections.
The lymphocytes, or small lymphocytes, as
SMALL they are commonly designated in contradistinc-
LYMPHOCYTES. tion to the large mononuclear forms, are non-
granular cells which measure from about 5 to
io// in diameter, their average size being that of the normal
erythrocyte, or 7.5 p in diameter. The typical cell of this class
consists of a single round, deeply staining nucleus surrounded by
a narrow zone of protoplasm, and sometimes provided with one
or two pseudo-nucleoli, situated eccentrically upon the nuclear
surface. The nucleus is so relatively large that it almost com-
pletely fills the cell, being its most conspicuous part, while the rim
of protoplasm is usually so narrow and poorly defined that at first
glance it may escape notice. These characteristics — a relatively
large nucleus and a relatively scanty amount of protoplasm — are
more conspicuously exhibited in the smaller than in the larger
forms of these cells. (Frontispiece, II, and Plate II, Figs. 1-4, 17,
and 1 8.)
By Romanowsky's method the nucleus stains purple, in which
a red tone prevails, and the protoplasm pure sky-blue. Occa-
sionally the protoplasm is stippled with a few rather coarse purple
or red granules.
In films stained with simple eosin and methylene-blue solu-
tions the nucleus shows a decided affinity for the basic dye, usually
staining dark blue, or, more rarely, pale green. The protoplasm
shows as a relatively narrow encircling area of deep blue color,
which has been likened in appearance to the surface of ground
glass; it is much more intensely basic than the nucleus, which
looks pale by contrast. With Ehrlich's triple stain the nucleus,
being rich in chromatin, is colored deep blue or purple, and the
protoplasm is either entirely unstained, appearing as a narrow
hyaline halo surrounding the nucleus, or it is tinged a delicate
shade of pink if it happens to react toward the acid fuchsin of the
mixture.
Occasionally small lymphocytes are encountered in which the
nucleus is atypical both in morphology and in staining properties.
1 Sem. med., 1904, vol. xxxiv, p. 198.
CLASSIFICATION. 211
Thus, some cells contain a pale, almost hyaline nucleus, composed
of an exceedingly scanty chromatin structure which reacts very
feebly to the basic dyes ; others contain a deeply stained, indented
or kidney-shaped nucleus, similar in shape to that of the so-called
"transitional" forms; while still others are provided with a
nucleus which has evidently become completely divided, so that
such a cell really contains two distinct hemispherical nuclei, rich
in chromatin, deeply stained, and situated toward the poles of
the cell body. These irregular forms of lymphocytes occur both
in normal and in pathological blood, but with much greater fre-
quency in the latter, especially in both forms of leukemia.
The small lymphocyte appears to possess greater powers of
resistance than any other variety of leucocyte. In his studies
of necrobiosis of the blood corpuscles Bodou1 determined that
the degenerative changes first involved the large mononuclear
hyaline cells regarded as myelogenous in type; next, the transi-
tional forms; next, the large lymphocytes of lymphatic origin;
next, the polynuclear neutrophiles ; and last of all the small lym-
phocytes.
Under this term it is convenient to include
LARGE both the larger forms of the true lymphocyte —
LYMPHOCYTES, those measuring 1 1 p. or more in diameter — and
also that variety of hyaline cell known as the
large mononuclear leucocyte. These two forms of cells, although
they are generally considered as distinct histological species, one
being a true lymphocyte and the other probably a marrow-bred
element, may, for practical purposes, be classed together, since it
is impracticable to differentiate one from the other in the speci-
men prepared for an ordinary clinical examination.2 (Frontis-
piece, II, and Plate II, Figs. 5, 6, and 19-22.)
Cells of this type may range in size from n to 15 p. or even
larger in diameter, and are usually of round or ovoid shape, ex-
cept in an occasional cell, where, in consequence of the injury
received during the preparation of the blood film, the outline
may be exceedingly irregular and deformed. The nucleus, which
1 Virchow's Arch., 1903, vol. clxxiii, p. 485.
2 Some authors, Ehrlich himself among them, maintain that a distinction be-
tween these two forms of cells may invariably be made in the stained specimen.
Thus, in the film stained with methylene-blue, it is held that the true lymphocyte,
no matter what its size, always possesses a strongly basic protoplasm and nucleus,
the latter staining less deeply than the former; while the large mononuclear leuco-
cyte has a feebly basic protoplasm and nucleus, the latter staining more intensely
than the former. These points of difference, although they may be distinguished
in specimens stained by special methods, seem to be too finely drawn to justify
their acceptance as reliable criteria for the identification of these two groups of
cells in films prepared by the technic adapted to routine clinical work.
212 THE LEUCOCYTES.
is round, ovoid, or somewhat elongated, is generally situated to-
ward the periphery of the cell body. In most of the cells the
amount of protoplasm is relatively greater than that of the small
lymphocyte, but occasionally this peculiarity cannot be distin-
guished.
With Wright's stain this cell stains fainter than, but in other
respects like, the small lymphocyte, save that it occasionally shows
a number of coarse and fine red granules scattered through its
protoplasm.
With simple mixtures of a strong acid and basic dye, such as
eosin and methylene-blue, the nuclear chromatin stains a diffuse
sky-blue tint, and the protoplasm exhibits a more or less decided
affinity for the basic element of the staining fluid. This tendency
is very marked in some cells, the protoplasm of which contains
an intensely basic pseudo-granular zone staining much deeper
blue than the rest of the cell body, paralleling the extreme periph-
ery of the cell, and often apparently separated from the nucleus
by a distinct unstained area. In other cells this basic affinity is
not so conspicuous, their protoplasm staining a diffuse purplish
shade in which a rose-red tone prevails.
The nucleus, being poor in chromatin, stains pale blue with the
triple stain, and is usually so delicately tinted that it is almost
invisible ; the protoplasm is faintly tinged with pink or with gray-
ish-blue, or it may remain practically colorless, showing merely
as an indefinite hyaline area surrounding the nucleus.
Apparent extrusion of portions of the cell body is not uncom-
monly observed, this phenomenon producing a peculiar "frayed-
out," ragged appearance around the periphery of the lympho-
cyte, due to the partial detachment of small bits of the peripheral
seam of basic protoplasm, which loosely adhere to the outer
margin of the cell. Occasionally these small basic masses be-
come entirely detached, and may be seen lying free in the plasma,
alongside the cell of which they were once a part.
Typical forms of the large and small lymphocyte, such as are
seen in the great majority of stained blood films, may be dis-
tinguished without difficulty, but in some diseases, notably in the"
lymphatic variety of leukemia, irregular forms of these cells are
found, the size and nuclear characteristics of which are so confus-
ingly atypical that it is sometimes futile to attempt the classification
of such hybrids into two arbitrary groups, large and small. Thus
one may meet with cells the size of the small lymphocyte, but hav-
ing a feebly basic, eccentric nucleus and a relatively large amount
of protoplasm; and with cells identical with the large lymphocyte
except that they possess a small, spherical, strongly basic nucleus.
CLASSIFICATION. 213
The reddish protoplasmic granules of the large lymphocyte, shown
by the Romanowsky stain, serve here as valuable criteria, but these
granules, unfortunately, are not always demonstrable in irregular
cells. In attempting to differentiate these atypical forms in the
triple stained specimen it is safe to be guided by the suggestions
given by Thayer,1 who is inclined to place more emphasis upon the
character of the nucleus than upon the size of the cell body as a
whole. Thus, in a doubtful mononuclear, non-granular cell in
which the nucleus is similar in size and shape to that of the small
lymphocyte, regardless of its affinity for the basic element of the
stain, the cell is classed as a small lymphocyte, until the size of
such a cell exceeds that of the polynuclear neutrophile. Some
cells no larger than the smallest lymphocyte may be classed as
large lymphocytes if their nuclei are decidedly ovoid in shape
and pale in color. In spite of every precaution, however, it
must be admitted that in some instances differential counts of
these two types of cells must be more or less inaccurate, for the
obvious reason that so much depends upon the personal equation.
The so-called transitional forms are cells
TRANSITIONAL which closely resemble the large lymphocyte in
FORMS. shape and in size, but which differ from the latter
variety of cell chiefly in having a nucleus which,
instead of being ovoid in shape, is indented and drawn out into the
form of a crescent with rounded poles, the concave aspect of the
nuclear figure lying toward the center of the cell. 'In other forms
the nucleus may have become molded into a figure resembling
an hour-glass, which occupies the central portion of the' cell body,
not lying in contact with its periphery at any point. (Frontispiece,
II, and Plate II, Figs. 7, 8, and 23.)
With eosin and methylene-blue the nucleus shows a moder-
ately strong affinity for the basic dye, being colored much darker
blue than the nucleus of the large, but distinctly paler ^han that
of the small, lymphocyte ; the protoplasm is stained • a diffuse
pale blue, in which the pink tinge of the eosin conspicuously
prevails. With the triple stain the nucleus of this cell -is usually
stained somewhat darker blue than that of the large lymphocyte,
and the protoplasm is either quite colorless or, perhaps, slightly
tinged a grayish-blue.
Inasmuch as the clinical significance of the transitional forms
is identical with that of the large lymphocytes, it is customary to
class both forms together under a single heading in the percentage
table of the different forms of leucocytes.
1 Johns Hopkins Hosp. Reports, 1894, vol. iv, p. 103.
214 THE LEUCOCYTES.
Polynuclear neutrophiles are cells which, as a
POLYNUCLEAR general rule, measure about from 10 to 12 // in
NEUTROPHILES. diameter, although their size may vary within
wide limits, some being not much larger than
the small lymphocytes, while others are nearly twice this size.
(Frontispiece, III, and Plate II, Figs. 9-11 and 24-27.) The
distinguishing characteristics of these cells are the twisted,
polymorphous nature of the nuclei and the so-called "neutro-
philic" reaction of the granules embedded in the protoplasm.
The nucleus may be of almost any shape — elongated, wreathed,
lobulated, horseshoe-shaped, or twisted into designs resembling
various letters of the alphabet, such as S, Z, U, or E. It
usually consists of several apparently separate masses of ir-
regular shape, connected with each other by delicate filamentous
strands of chromatin, which dip beneath the surface of the pro-
toplasm, and, owing to the density of the overlying granules, are
invisible or but dimly defined in the triple stained specimen.
By the use of the simpler double stains, such as eosin and
methylene-blue, the presence of these" connecting chromatin
threads may be demonstrated with great clearness. Less com-
monly, a cell contains several small oval or round nuclei, which
are actually separated from each other, complete division at the
points of constriction having resulted in the production of two or
three, and in rarer instances even six or seven, distinct nuclei.
The nuclear structure is rich in chromatin, which forms a dense,
unevenly staining network possessing a marked affinity for the
various basic dyes. It stains dark blue or greenish-blue with the
triple stain, and still more intensely blue with eosin and methyl-
ene-blue solutions.
The fact that the single, twisted type of nucleus predominates
in these cells has led to the current use of the adjective "poly-
morphonuclear " as a substitute for " polynuclear," but it is per-
fectly obvious that both terms may be used synonymously, the
latter perhaps being preferable, because of its brevity, and of its
established vogue. The irregularity of the nucleus is regarded
as a sign of the ameboid activity of the cell, as first suggested by
Arnold,1 $nd not as an indication of degeneration, as 'formerly
believed. It has been effectually demonstrated by Sherrington2
that if such cells are allowed to quiet down before they are killed,
their nuclei usually return to a spheroidal form.
The protoplasm of the polynuclear neutrophile is densely packed
with exceedingly fine, so-called neutrophile granules, which stain
1 Arch. f. mik. Anat., 1887, vol. xxx, p. 226.
2 Proc. Internal. Congress of Physiologists, Liege, 1892.
CLASSIFICATION. 21$
lavender or purple, or, rarely, pink, with Ehrlich's triacid mix-
ture, but which are not stained by simple solutions of eosin and
methylene-blue. With Wright's stain these granules are colored
reddish-lilac or pink. Kanthack and Hardy1 have shown that
these granules have "a minimal attraction for acid dyes, or,
briefly, a minimal oxyphile reaction," and, furthermore, that
Ehrlich's neutral mixture, by which they are intensely stained,
is not, chemically speaking, a neutral stain, but, on the contrary,
a powerful and exceedingly differential acid dye, intensely staining
oxyphile granules of all varieties.2 Thus, having proved that
the granules of the polynuclear " neutrophile " cell of Ehrlich
display a distinct, although feeble, affinity for acid dyes, and that
they are unstained by basic and neutral dyes, the term "finely
granular oxyphile cell" has been adopted by these authors for
this variety of leucocyte, the granules being known as "finely
granular oxyphile" granules. It is doubtful, however, if the use
of these unwieldy terms will receive general approval, except by
certain of the British school. To designate a polynuclear leuco-
cyte as a "finely granular oxyphile cell" is even more glaringly
inappropriate than the use of Ehrlich's term, "neutrophile," for
other varieties of leucocytes — i.e., myelocytes and " neutrophilic
pseudolymphocytes " — may be just as fittingly described by the
former phrase.
The granules are of very small size and of irregular wedge-
or spike-shape, never being spherical or ovoid in contour. They
are usually most densely distributed about the periphery of the
cell, whence they gradually shade off toward the nucleus, which
is frequently found to be encircled by a perfectly hyaline, non-
granular zone. The granules are not always confined to the cell
protoplasm, being scattered over the nucleus, portions of which
may be partly obscured by the overlying granular film.
The jelly-like substance of the protoplasm in which the granules
are embedded appears to show a slight affinity for acid -dyes, the
intensity of this affinity varying greatly in different cells. With
the triple stain this reaction is evidenced by the variable depth
of fuchsin-colored undertone which may be detected beneath the
1 Jour. Physiol., 1894, vol. xvii, p. 61.
2 Reasoning upon the basis that eosin stains with most striking intensity in an
aqueous solution, less decidedly in a glycerin solution, and even less strongly when
dissolved in strong alcohol, these investigators distinguish three classes of oxyphile
granules, according to the intensity of their affinity for acid dyes, thus: (i) Those
which stain with eosin only in aqueous solutions or in alcoholic solutions of a per-
centage below 60; (2) those which stain in both aqueous and glycerin solutions,
but not in a strong alcoholic solution (90 to 95 per cent.) of the dye; and (3) those
which stain with aqueous, glycerin, and strong alcoholic solutions. They include
in the first class the neutrophile and the amphophile granules of Ehrlich.
2l6 THE LEUCOCYTES.
purplish color of the granules; while in the specimen stained
with eosin and methylene-blue the protoplasm is tinted evenly
the color of eosin.
These cells are the most conspicuous of all the
EOSINOPHILES. leucocytes, and may be at once identified by the
presence of a more or less polymorphous nucleus
embedded in a protoplasm studded with coarse, highly refractive
granules which have a strong affinity for acid dyes, such as eosin
and acid fuchsin. (Frontispiece, V, and Plate II, Figs. 12, 13,
28, and 29.) Owing to the large size of their granules and
to their striking oxyphilic reaction, these cells are also known by
the term "coarsely granular oxyphile cells," in contradistinction
to the "finely granular oxyphile cells" or polynuclear neutrophiles
(Kanthack and Hardy). The size of the eosinophile varies very
greatly, but most of them approximate the size of the polynuclear
neutrophile, or are, perhaps, a trifle smaller. Their diameter
commonly ranges from 8 to 1 1 ,«, although occasionally forms
not larger than the normal erythrocyte are to be observed. Their
shape is usually that of an irregular sphere or oval.
The nucleus may be kidney- or horseshoe-shaped, or twisted
and drawn out into an irregular mass, but it is rarely as con-
stricted and deformed as that of the polynuclear neutrophile. It
is nearly always situated eccentrically, cells of this variety with
centrally placed nuclei being very uncommonly seen. Occasion-
ally the eosinophile contains multiple nuclei, consisting of sev-
eral oval or round masses between which no connecting chro-
matin threads can be distinguished, but usually such portions
of the nucleus are joined together by extensions of chromatin
running beneath the protoplasm. The nucleus stains faintly, in
comparison with that of the polynuclear neutrophile, although
more intensely than that of the large mononuclear cell; it is col-
ored pale blue or greenish-blue by the triple stain, and dark blue
by eosin and methylene-blue mixtures.
The granules, which are relatively large in size and quite regu-
larly spherical in shape (in contrast to the delicate, irregularly
shaped granules of the polynuclear neutrophile), react strongly
toward the acid elements of the triple stain; some are stained
a brilliant fuchsin color, some deep red, while others are brown-
ish-yellow or copper color, or even almost black; with mixtures
of eosin and methylene-blue they take the brilliant color of eosin.
There appears to be a marked tendency on the part of the gran-
ules to overrun the nucleus, so that its morphology in some cells
is almost indistinguishable. The granules are also prone to be-
come readily detached from the protoplasm, which doubtless ac-
CLASSIFICATION. 217
counts for their uneven, blotchy distribution in many cells, in
which densely packed granular areas alternate with open spaces
merely punctuated here and there with an occasional granule.
Eosinophiles appear to offer but feeble powers of resistance
against external influences, so that it is common to find these
cells so injured by the process of making the film that the nu-
cleus has escaped from the cell body, and the granules, lying
free in the plasma, are scattered about it in a cloud. This insta-
bility or "explosive" character of the eosinophile is one of its
most striking attributes, for, while observed now and then in a
polynuclear neutrophile, it occurs with much greater frequency
in eosinophiles than in the latter type of leucocyte.
The protoplasm of the cell may or may not show an affinity for
the anilin dyes; usually it does not, so that the granules appear
to be embedded in a perfectly hyaline substance; occasionally
the protoplasm is faintly stained by fuchsin or by eosin. With
Wright's stain it frequently takes the color of the basic dye,
methylene-blue.
BASOPHILE Finely granular basophile cells, containing
CELLS. Ehrlich's 5-granules, are occasionally encountered
in normal blood, but with such rarity that their
real significance is not understood. (Plate II, Fig. 31.)
In general morphology and size these cells resemble the poly-
nuclear neutrophiles. The nucleus is invariably twisted, and usu-
ally consists of two or three distinct lobes joined, by thin chro-
matin bands ; in the stained specimen it is never of round or oval
shape, but always shows evidences of polymorphism. The nuclear
structure is composed of a delicate, scanty network of chromatin,
and has a moderate affinity for basic dyes, staining dull blue with
the triple stain and pale sea-green with eosin and methylene-blue
mixtures.
The protoplasm of the cell is closely packed with fine, irregu-
larly shaped granules having an intensely basic reaction-; they
stain deep blue with solutions containing methylene-blue, but are
not colored by the triple stain, showing in films stained with
this mixture as groups of dull white spots scattered through the
cell body. Wright's stain is most useful in bringing out the char-
acteristics of these granules.
Myelocytes, or marrow cells, are relatively
MYELOCYTES. large round or oval cells, ranging from 10 to 20 [*
or even more in diameter, their average size
being somewhat larger than that of the large lymphocyte, which
they resemble in general morphology. (Frontispiece, V and VI,
and Plate II, Figs. 14-16 and 30.) The nucleus of the typ-
2l8 THE LEUCOCYTES.
ical myelocyte is of spherical or ovoid shape, and is situated
eccentrically, lying distinctly toward one side of the cell, so that
the peripheries of both cell and nucleus are often closely adjacent
for some little distance — usually for from one-third to one-half
of their course. The nucleus reacts feebly toward the basic
element of the triple stain, being colored a pale, delicate sky-
blue with this solution ; it stains a moderately deep blue or purple
with eosin and methylene-blue mixtures, and appears to be more
coarsely netted and deeply stained than in films prepared by the
preceding method.
In the smaller forms of myelocytes the nucleus is frequently
found to occupy the center of the cell body, so that it is surrounded
on all sides by a protoplasmic zone of even width. In some of
the larger forms the nucleus may be indented and molded along
one margin of the cell body like that of the so-called "transitional"
leucocyte. In rare instances actual division of the nucleus appears
to have occurred, so that two separate nuclei, each shaped like a
flattened hemisphere and situated at an extreme pole of the cell,
may be found. Such cells are often mistaken at first glance for
polynuclear neutrophiles, inasmuch as both forms of cells contain
multiple nuclei and neutrophile granules; but the nucleus of the
polynuclear neutrophile is always more or less twisted and of un-
dulating surface, relatively rich in chromatin and stained with
decided intensity, and rarely situated at the poles of the cell, while
the nuclear halves of this type of the myelocyte are of regular out-
line and uniformly close to the surface of the cell, relatively poor
in chromatin and faintly stained, and invariably occupy the extreme
poles of the cell body.
The protoplasm of the myelocyte is filled with fine neutrophile
granules, such as occur in the polynuclear neutrophile; they are
most densely distributed at the periphery, and grow appreciably
less abundant as they approach the nucleus, which they may
overrun, spreading over its surface like a thin veil, so that its
structure is more or less hidden.
This one characteristic — the presence of neutrophile granules
in the protoplasm — at once serves to distinguish the myelocyte
from the large lymphocyte, which it may exactly resemble in
size, shape, and nuclear structure; the importance of using a
selective neutrophile stain to differentiate these granules in speci-
mens used for differential counting is therefore patent.
With Ehrlich's triple stain the granules stain purple or lavender,
exactly like those of the polynuclear neutrophile. With Wright's
solution the protoplasm has an undertone of light purple, broken
here and there by indistinct, darker granular areas of the same
CLASSIFICATION. 2 19
color, indicating the presence of basophile granules, in addition to
those of neutrophile reaction, which show as a delicate lilac or
pink stippling.
In certain pathological conditions, notably in myelogenous
leukemia, an occasional myelocyte may be observed which con-
tains both fine neutrophile and very coarse basophile granules,
the latter being precisely identical in size, shape, and tinctorial
qualities with Ehrlich's y or mast cell granules. They are
situated both in the protoplasm of the cell and over the nucleus,
and are, in the author's experience, seen most clearly in specimens
stained in solutions containing polychrome methylene-blue. The
basic granules show in such preparations as a coarse, brilliant,
purple stippling, contrasting vividly with the paler, eosin-colored
neutrophile granules which fill the body of the cell, and with the
greenish-blue color of the nucleus.
Eosinophilic myelocytes^ or myelocytes with a protoplasm filled
with coarse eosinophile instead of neutrophile granules, are
common to several pathological conditions, but occur with es-
pecial frequency in the myelogenous variety of leukemia and
also in. pernicious anemia, to some extent. Such cells are iden-
tical in size and morphology of cell body and nucleus with the
commoner neutrophilic myelocytes, from which they differ only
in containing eosinophile granules. (Frontispiece, V, and Plate
II, Figs. 14 and 30.)
The normal habitat of the myelocyte is in the red bone mar-
row, and its presence in the circulating blood must always be re-
garded as pathological. At one time regarded as practically
pathognomonic of leukemia, the myelocyte is now known to occur
in many other conditions, especially those characterized by pro-
found cachexia, by marked anemia, and by increase in the num-
ber of leucocytes. The occurrence of myelocytes in the blood
in various diseases and the clinical significance of these cells are
discussed in another place. (See " Myelemia," p. 259.)
Cells containing Ehrlich's ^-granules, known
MAST CELLS, by the term mast cells, or mastzellen, #re oc-
casionally present in the peripheral circulation,
as the result of certain pathological influences, but are totally
foreign to the normal blood of man. (Frontispiece, VII, and Plate
II, Figs. 32-36.) They are very constantly found, generally in
considerable numbers, in the myelogenous type of leukemia, and
also occur, in small percentages, in many cases of pernicious
anemia and in other grave blood disorders.
The cells are of spherical or ovoid shape, and are characterized
by a relatively large, structureless nucleus inclosed in an almost
220 THE LEUCOCYTES.
indefinable protoplasm, and by the presence of coarse basophile
granules scattered irregularly over the surface of the cell — marks
of identification which remain unchanged whatever the size of
the cell may be. No variety of cell found in the blood exhibits
wider ranges in size. The forms most commonly observed meas-
ure approximately from 9 to 12 n in diameter; some have a di-
ameter of fully 20 or even 22 /./, but cells of this extremely large
size are the exception rather than the rule; others are scarcely
larger than the small lymphocyte, being but 7 or 8 p. in diameter,
and these very small' forms are also uncommon.
The nucleus is round, oval, or somewhat lobulated, and occu-
pies the greater part of the cell body, in which it is usually situ-
ated eccentrically. Owing to the similarity in the appearance of
the nucleus and the protoplasm it is frequently impossible to de-
termine the precise point at which the former structure begins
and the latter ends, so that, in the stained specimen, many cells
are met with which appear to consist simply of irregular groups
of granules clinging to a pale nucleus, every definite trace of the
cell body being lost. (Plate II, Figs. 35 and 36.) In films stained
with Wright's solution (which is, by far, the most satisfactory stain
for illustrating the finer morphology of these cells) the nucleus is
colored a beautiful, iridescent greenish-blue, the tint of which
is so extremely delicate that in many cell,s it is barely perceptible.
The staining, though faint, is even and clear, indicating a structure
almost totally devoid of chromatin.
The granules are generally large and coarse, and vary greatly
in size and in shape. Some are smaller than the granules of the
eosinophile cell, while others approach or even slightly exceed
0.5 ft in diameter. They may be spherical, egg-shaped, or roughly
cuboid, the latter form of granule being exceedingly common.
A single type of granules is not always found to the exclusion of
the others, for one cell often contains granules of every possible
variety of shape and size; this peculiarity is especially striking
in some of the smaller forms of cells in which extremely coarse
egg-shaped and smaller spherical granules may be distinguished
clinging to the periphery of the nucleus, about which no evidence
of protoplasm is demonstrable. (Plate II, Fig. 36, and Frontis-
piece, VII.) In other forms, both large and small, the large
spherical or ovoid granules may prevail almost exclusively.
(Plate II, Figs. 33, 34, and 35, and Frontispiece, VII.) The
distribution of the granules through the cell follows no constant
rule, but it is evident that a more or less decided tendency exists
toward their collection near the periphery. They are always
most densely distributed at this point, sometimes extending in-
CLASSIFICATION. 221
ward over the nucleus, which is thus partly hidden, and some-
times crowded into a limited zone, which coincides with the outer
boundary of the cell for the greater part of its extent.
The granules of the mast cell show an intense affinity for basic
anilin dyes, toward which they react metachromatically in a
highly characteristic manner. With Wright's solution they are
stained a deep royal purple color in which the red tone is dis-
tinctly evident, thus differing from the granules of other basophile
cells, which are stained a pure blue with this mixture. Dr. H. F.
Harris has called the writer's attention to another distinctive
method of identifying these granules, by first staining with carbol-
toluidin-blue or with thionin, and then by differentiating with
Unna's glycerin-ether mixture. In specimens thus treated the
mast cell granules are of a dark red color, while other basophile
granules stain blue, so that the former must be regarded as hav-
ing a modified basic reaction. They are stained reddish-violet
with Ehrlich's acid dahlia solution, and deep blue with aqueous
solution of methylene-blue. They are not stained by the tri-
acid mixture, and appear as coarse, dull white spots through
the cell body in films stained with this solution. The distinc-
tive manner in which they react toward selective stains for
mucin has been discovered by Harris,1 who, in view of this
fact, suggests that the term mucinoblast be applied to the mast
ceU.
The author questions the identity of these coarsely granular
basophilic blood cells with the well-known mast cell of the tissues,
although most hematologists consider them identical. Both,
it is true, contain granules which tinctorially and morpholog-
ically are identical, but it is obviously impossible to determine
cell identity by criteria such as these. The mast cell of the
tissues differs from that of the blood in having a nucleus which is
smaller in relation to the size of the cell body, .more centrally
situated, and richer in chromatin, hence being more deepjy and
more unevenly stained. The "explosive" nature of the tissue
mast cell is also usually more striking, for while cells with this
tendency are met with not infrequently in the blood, they seem
to be the rule rather than the exception in the tissues, large
numbers of them consisting of a nuclear structure surrounded by
dense clusters of granules, which are frequently drawn out in
long tentacular extensions. In view of these differences it may be
well to be more specific, by designating the mast cell found in the
blood as the hemic mast cell.
1 Phila. Med. Jour., 1900, vol. v, p. 757.
222 THE LEUCOCYTES.
This term has been applied by Capps1 to a
MONONUCLEAR form of leucocyte which he found in certain cases
NEUTRO- of general paralysis of the insane, its appearance
PHILES. in the blood having been noted after apoplecti-
form attacks and preceding death. This cell is
as large as, or larger than, the polynuclear neutrophile, contains a
round or ovoid nucleus which is deeply stained by basic dyes,
and has a protoplasm thickly sprinkled with fine neutrophile
granules. Capps suggests that the cell may be a form of leuco-
cyte of slightly more mature development than the large lympho-
cyte, one in which the development of the granules has preceded
the nuclear changes. The close resemblance of these cells to
the smaller forms of myelocytes, however, makes it reasonable
to class them as such.
Ehrlich has described2 as a "small neutro-
NEUTROPHILIC philic pseudolymphocyte " a cell of the same
PSEUDOLYM- size as that of the small lymphocyte, and char-
PHOCYTES. acterized by a relatively large, round, intensely
basic nucleus, surrounded by a narrow zone of
protoplasm filled with neutrophile granules. This cell, it is
maintained, is of very rare occurrence, having been found in the
blood only in a case of hemorrhagic small-pox and in the exudate
of a recent pleural effusion. Ehrlich differentiates it from a myelo-
cyte by its small size, deeply staining nucleus, and scanty amount
of protoplasm, but these points of distinction do not appear con-
clusive, for many of the smaller, "dwarf" forms of myelocytes
have similar characteristics. It does not appear unreasonable,
therefore, to regard this cell as an exceedingly small form of
myelocyte, in which the nucleus is relatively larger and richer in
chromatin than is the rule in the larger, more typical varieties.
These cells, first described by Tiirk3 as "Rei-
REIZUNGS- zungsformen " (or, literally, " stimulation forms "),
FORMEN. are said to occur in the same pathological condi-
tions in which myelocytes are found, but as yet
their exact significance is undetermined. They may be found in
any condition provoking decided anemia or leucocytosis and thus
causing active stimulation of the bone marrow. The writer has
seen such cells in the blood of the post-typhoid anemias of infancy,
always in association with lymphocytosis. The size of the cell is
usually midway between that of the small and large lymphocyte,
more often approximating the size of the former. The cell con-
tains a round nucleus, deficient in chromatin, often eccentrically
1 Amer. Jour. Med. Sci., 1896, vol. cxi, p. 650.
3 Loc. cit. 3 " Klinische Hamatologie," Vienna and Leipzig, 1904, p. 368.
CLASSIFICATION.
223
placed in the cell body, and reacting with moderate intensity to-
ward the basic dyes. The protoplasm is non-granular, and stains
purple with Wright's stain and intense brown with the triacid
mixture. Ehrlich suggests that this cell may possibly represent
an early stage of the erythroblast, but reasons for such an inference
do not seem clear.
The chief points of distinction between the different forms of
leucocytes, as recognized in specimens stained with Wright's
Romanowsky mixture, are tabulated below:
FORK OF CELL.
SIZE.
NUCLEUS.
PROTOPLASM.
Small lymphocyte.
6 to 9 ft.
Single.
Relatively small amount.
Round.
Occasionally granular.
Relatively large.
Pale sky-blue.
Dark blue or purple .
Large mononuclear
10 to 15 ft.
Single.
Relatively large amount.
leucocyte or large
Round or ovoid.
Often granular.
lymphocyte.
Relatively small.
Pale blue.
Very pale blue.
Transitional leuco-
10 to 15 p.
Single.
Relatively large amount.
cyte.
Indented, kidney-
Often granular.
shaped, or cres-
Pale blue.
centic.
Relatively small.
Pale blue.
Polynuclear neutro-
7.5 to 12 p..
Polymorphous or
Relatively large amount.
phile.
polynuclear.
Contains fine lilac or pink
Relatively small.
neutrophile granules.
Moderately dark
Relatively large amount.
blue.
%
Eosinophile.
7.5 to 12 //.
Polymorphous or
Contains coarse rose-col-
polynuclear.
ored eosinophile gran-
Relatively small.
ules.
Pale blue.
Basophile.
7-5 tO 12 p.
Polymorphous.
Relatively large amount.
Relatively small.
Contains fine blue baso-
Dull blue.
phile granules.
Myelocyte.
10 to 20 /'.
Single.
Relatively large. or small
Round or ovoid.
amount.
Relatively large or
Contains fine lilac or pink
small.
neutrophile granules.
Very pale blue.
Mast cell.
7 tO 22 ft.
Single.
Relatively small amount.
Round, ovoid, or
Contains coarse royal
slightly lobulated.
purple basophile gran-
Relatively large.
ules.
Very pale blue.
Reizungsform.
6 to 15 ft.
Single.
Relatively large amount.
Round.
Non-granular.
Relatively small.
Intense lilac or purple.
Deep blue.
224 "THE LEUCOCYTES.
Two different views are current at the present
ORIGIN AND time regarding the origin and development of the
DEVELOP- leucocytes, the first being that of Ehrlich1 and
MENT. his followers, and the second that maintained by
the Russian school, led by Uskow2 and his pupils.
According to Ehrlich's teachings, the small lymphocyte and
its mother-cell, the large lymphocyte, are developed in the lym-
phatic tissues in the various parts of the body, wherever such
structures exist. The large mononuclear leucocytes and transi-
tional forms are considered probably of myelogenous origin.
The polynuclear neutrophiles are thought to develop exclusively
in the bone marrow, the great majority being evolved from the
neutrophilic myelocytes of this tissue, while a very limited num-
ber perhaps arise from the non-granular large mononuclear cells.
The eosinophiles develop from the eosinophilic myelocytes in the
bone marrow, while the basophilic leucocytes similarly have their
origin in basophilic marrow antecedents. Thus, it is maintained
that all varieties of leucocytes may .be classed in two distinct
groups which have separate origins, functions, and relations.
The first group consists of the lymphocytes, large and small,
which are produced solely by the lymphatic tissues; and the
second group includes the mononuclear leucocytes and transi-
tional forms, the polynuclear neutrophiles, the eosinophiles, and
the basophiles, all of which cells are produced exclusively by the
marrow.3 Cellular reproduction, except in rare instances, does
not take place in the circulating blood stream. Labbe 4 considers
that no such distinction between lymphoid and myeloid cells is
possible in early life, at which period he believes that all blood-
forming tissues are capable of producing both hyaline and granular
cells. But as adult life approaches the origin of the lymphocytes
may be traced to the lymphatic tissue, and the birthplace of the
granular leucocytes to the bone marrow.
The scheme devised by the Russian school contends for the
continuous evolution of the leucocyte from its earliest to its most
mature stages. Accordingly, all varieties of the leucocyte, except
the basophilic cells, of which no account apparently is taken, are
but different developmental stages of one and the same cell.
The youngest form of leucocyte, the small lymphocyte, originates
1 Loc. cit.
2 "The Blood as a Tissue," 1890 (Russian); also series of articles by Uskow's
pupils in Arch. d. Soc. biol., St. Petersburg, 1893-97.
8 Muir's article on the relations of the bone marrow to leucocyte formation
(Jour. Path, and Bacteriol., 1901, vol. vii, p. 161) admirably discusses the natal
differences of the lymphoid and myeloid cells of the blood.
4 "Le Sang," Paris, 1902.
CLASSIFICATION. 225
in the lymph glands, the lymphocytic bone marrow, and the
spleen, from which sources of origin it reaches the circulation.
The small lymphocyte enlarges until it becomes identical in
appearance with the cell recognized as the large lymphocyte, its
nucleus at this period of its growth having become somewhat
less intensely basic, although the basic affinity shown by the cell
protoplasm is unaltered. The large lymphocyte in turn under-
goes a simple increase in size, its nucleus meanwhile becoming
progressively paler and its protoplasm more feebly basic, until
it develops into the large mononuclear form. The nucleus of
the latter now becomes indented and molded into a roughly
crescentic figure, its nuclear and protoplasmic characteristics re-
maining unchanged, and the so-called transitional form thus origi-
nates— a type of cell which is regarded as the immediate ante-
cedent of the polynuclear neutrophile. During the next stage of
development the size of the transitional cell decreases and the
whole cell becomes ameboid; the nucleus becomes denser, more
basic, and polymorphous or polynuclear; while the protoplasm
loses the last trace of its basic tendency and becomes sprinkled
with fine neutrophile granules, until finally the mature form of
leucocyte, the polynuclear neutrophile, is fully developed. The
final, or "over-ripe," stage of the leucocyte is represented by the
eosinophile, which is thought to be derived from the polynuclear
form by a transformation of the latter's neutrophile into
eosinophile granules. It is maintained that these, transitions
from one form of cell to the other occur partly in the circulat-
ing blood and partly in the blood-forming tissues — most largely
in the latter.
It is beyond the province of this book to discuss the merits
and demerits of these two opposing views, but it may be remarked
that Uskow's theory, which up to the advent of Ehrlich's observa-
tions commanded general attention among hematologists, has
been generally supplanted by the latter. The investigations of
Ehrlich in this direction constitute the only dependable' means
by which many of the pathological changes in the leucocytes
may be explained, and his views may be accepted, on the whole,
as accurate.
Disintegration of the leucocytes occurs chiefly in the spleen
and to a less extent in the liver. Bain's perfusion experiments,1
of repeatedly passing blood through these organs, indicate that
the hemolytic action of the spleen is directed mainly toward the
leucocytes and especially toward the polynuclear neutrophile
cells. From Lewis' studies2 it is to be inferred that the hemo-
1 Jour. Physiol., 1903, vol. xxix, p. 352. * Ibid., 1902, vol. xxviii, p. 8.
IS
226 THE LEUCOCYTES.
lymph glands have a similar function, by virtue of their phago-
cytic endothelium.
In a number of diseases associated with
IODIN anemia and with bacterial or chemical toxemia
REACTION, the protoplasm of the polynuclear neutrophile
leucocytes, and rarely of the myelocytes and baso-
philes, shows a more or less marked affinity for iodin, as shown by
staining with a weak solution of this metal. Extracellular iodin-
stained masses also are found in both normal and pathological
blood, but they are without significance unless in association with
leucocytes showing a similar reaction. Some of these extracellular
iodophile masses are doubtless bits of protoplasm torn from the
leucocytes; others may be blood plaques, while some are but
artefacts.
Goldberger and Weiss1 recommend the following reagent for'
demonstrating the iodin reaction :
Iodin i
Potassium iodid 3
Distilled water 100
Mix and add sufficient gum arabic (about 50 parts) to make a
syrupy mixture.
With a camel's-hair brush a layer of this solution is painted
over the surface of the dried, unfixed blood film, upon which it
is allowed to act for from one to five minutes. The excess is
then removed by blotting with a bit of filter-paper, and the speci-
men is mounted in cedar oil. Or, as Wolff 2 advises, Zollikofer's
method may be used: placing the fresh film for a few minutes
in a stoppered bottle containing crystals of pure iodin.
In films thus treated the iodin reaction is recognized by a
slight or intense, diffuse brown coloring of the entire protoplasm,
or by the presence throughout the protoplasm of numerous in-
tensely stained, reddish-brown granules, the latter change being
the more common. In normal blood the protoplasm of the leu-
cocytes is stained a pale yellow and the nuclei remain almost
colorless.
The above reaction, known as iodophilia, is constant in all
purulent conditions, persisting as long as the suppurative focus
exists, its intensity appearing to bear no parallelism to the extent
of the pus collection. It signifies simply a general toxemia severe
enough to cause a form of leucocyte degeneration, and, like
its corollary, leucocytosis, is merely a symptomatic sign. Kaminer3
believes that the reaction depends upon three factors for its pro-
1 Wien. klin. Wochenschr., 1897, vol. x, p. 601.
2 Zeitschr. f. klin. Med., 1904, vol. li, p. 407.
3 Deutsch. med. Wochenschr., 1899, vol. xxv, p. 235; also Berlin, klin.
Wochenschr., 1899, vol. xxxvi, p. 119.
CLASSIFICATION. 227
duction, — pyrexia, leucocytosis, and toxemia, — and that it is
caused by the action of some unknown chemotactic substance.
He groups the iodophile cells, according to their grade of reac-
tion, into three stages: diffuse brownish staining, circumscribed
granulation, and complete metamorphosis.
The reaction is absent in pure tuberculous abscesses. It is
present with great constancy in puerperal sepsis and in other
forms of septicemia, frequently in pneumonia, pulmonary tuber-
culosis, and malignant disease, and occasionally in marked cachexias.
Hofbauer l found iodophile granules in the leucocytes in all cases of
pernicious anemia, their number being greatest in the gravest cases ;
they were also present in severe forms of secondary anemia and
in leukemia, but were absent in chlorosis and in pseudoleukemia.
This author also observed numerous iodin-stained extracellular
masses in a case of purpura hamorrhagica. Dunn,2 study-
ing the iodin reaction in children, found it invariably present in
croupous and catarrhal pneumonia, influenza, cerebrospinal men-
ingitis, empyema, and miscellaneous purulent conditions; the reac-
tion was generally present in enteric fever and in acute miliary
tuberculosis. Cabot and Locke3 obtained uniformly positive
reactions in septicemia, pneumonia, empyema, and suppurative
appendicitis; in serous pleural effusions and in catarrhal appendi-
citis the test was negative. In about one-half of the cases of
enteric jever examined by these writers the test was positive,
usually only in those complicated by hemorrhage, perforation,
furunculosis, or lung lesions. These studies have been recently
substantiated by Gulland.4
Experimentally, iodophilia has been caused by Spezia5 by the
subcutaneous injection of peptone, glucose, and olive oil, and the
sign has also been noted by him during the digestive leucocytosis
following a hearty meal. Kaminer6 produced iodophilia in ani-
mals by injecting cultures and toxins of the pneumococcus, the
Klebs-Loffler bacillus, the typhoid bacillus, and various pyogefiic
bacteria; he failed to cause it by injecting tetanus toxin.
The practical value of this test is considerable if it is properly
interpreted merely as a symptom. Its constancy in purulent condi-
tions, however slight in extent the focus of pus, is useful in diagnos-
ing a deep-seated abscess, if other causes which also may give rise
to the reaction can be ruled out. The sign is also a valuable aid in
1 Centralbl. f. inn. Med., 1900, vol. xxi, p. 153.
2 Boston Med. and Surg. Jour., 1903, vol. cxlix, p. 511.
8 Jour. Med. Research, 1902, vol. vii, p. 43.
4 Brit. Med. Jour., '1904, vol. i, p. 880.
5 Lancet, 1903, vol. i, pp. 655 and 1444.
* Brit. Med. Jour., 1902, vol. i, p. 1049.
228 THE LEUCOCYTES.
differentiating serous from purulent effusions and inflammations —
serous pleurisy and empyema; catarrhal appendicitis and appendic-
ular abscess. It is also useful, according to Sorochowitsch,1 in dif-
ferentiating gonorrheal and rheumatic arthritis, since positive reac-
tions occur in the former and negative in the latter. The absence of
the iodin reaction in pure tuberculous abscess and its presence in all
other forms of abscess may aid in distinguishing between the two, and
of ascertaining whether a mixed infection exists. The persistence
of iodophilia for forty- eight hours or so after a pneumonia crisis
and after the incision of a pus cavity suggests, in the first instance,
delayed resolution or some other post-pneumonic complication,
and, in the second, imperfect drainage. Although the writer has
followed out rather at length the suggestion made by Hofbauer,
that the intensity of the reaction serves as an index to the severity
of an anemia, the results from this study have not shown the relia-
bility of such a presumption.
Neusser,2 in 1894, described certain basic
PERINUCLEAR granules about the nuclei of the leucocytes which
BASOPHILIA. he regarded as pathognomonic of the uric acid
diathesis, asserting that this so-called "perinu-
clear basophilia" could be demonstrated constantly in gout,
lithiasis, rheumatism, leukemia, and a number of other diseases.
These statements were soon corroborated by Kolisch,3 and for a
time enjoyed more or less general credence. The later researches
of Futcher4 and of Simon,5 however, have entirely disproved the
claims of Neusser and his school, for these investigators, working
independently, have proved that perinuclear basophilia is not
only quite uncharacteristic of the uric acid diathesis, but that it
can be constantly demonstrated in every sort of blood, whether
from healthy or from diseased persons. It is now clear that
Neusser's granules are simply artefacts, due to some slip in the
technic of staining. Ehrlich6 believes that their presence is but
rarely noted if perfectly pure crystalline dyes are used in pre-
paring the stain.
III. LEUCOCYTOSIS.
Leucocytosis may be described as an increase above the normal
standard in the number of leucocytes in the peripheral blood, this
1Zeitschr. f. klin. Med., 1904, vol. li, p. 245.
2 Wien. klin. Wochenschr., 1894, vol. vii, p. 71.
3 Ibid., 1895, vol. viii, p. 797.
4 Johns Hopkins Hosp. Bull., 1897, vol. viii, p. 85.
5 Amer. Jour. Med. Sci., 1899, vol. cxvii, p. 139. 8 Loc. cil
PLATE III.
LEUCOCYTOSIS.
( Triacid Stain.)
The blood field from a case of croupous pneumonia. The leucocytes are all of the polynuclear
neutrophile type. The erythrocytes show no deformity, and stain a normal orange
color.
Contrast this illustration with leukemia, Plates IV and V.
(E. F. FABER,/«fC.)
LEUCOCYTOSIS. 22Q
change either — (a) involving both an absolute and a relative increase
in the polynuclear neutrophile cells with a consequent relative dimi-
nution in the proportion of mononuclear non-granular forms, or (6)
affecting all varieties of leucocytes alike.
A leucocytosis of the first kind, also termed a polynuclear neu-
trophile leucocytosis, is by far the more common of the two types :
it may be symptomatic either of pathological or of physiological
conditions, being found almost invariably in the former and fre-
quently in the latter. A leucocytosis of the second kind, or a
general increase unattended by any disturbance in the normal
relative proportions of the different forms of cells, is compara-
tively rare: it is more frequently dependent for its production
upon physiological than upon pathological factors, but it may
occur under either of these circumstances.
From these facts it is obvious that simply an increase in the
total number of leucocytes, without regard to the differential
changes involved, does not of necessity constitute a leucocytosis.
Nor is it possible to recognize the condition with certainty by
any such criterion as a deviation from the ratio of red to white
cells maintained in health. To state that a patient's blood con-
tains, say, 50,000 leucocytes to the c.mm. suggests both leuco-
cytosis and leukemia, but to add to such a statement the fact
that of these 50,000 leucocytes 90 per cent, are of the polynuclear
neutrophile variety, at once stamps the condition as a genuine leu-
cocytosis. In order, therefore, to distinguish leucocytosis with
absolute certainty the character of the leucocytes involved in the
increase must be determined by a differential count of the s'tained
specimen of blood. (Plate III.)
Leucocytosis may be of a more or less transient character, or
may persist for a long period, its duration being dependent upon
the nature of the underlying cause. In acute diseases it is usually
a temporary condition, but in long-continued affections it is .pro-
longed in relation to the chronicity of the lesion by which the
increase is excited.
For clinical purposes all forms of leucocytosis may be classed
under two main groups, physiological and pathological, these be-
ing further divided as follows:
Physiological Leucocytosis.
1. Leucocytosis of the new-born.
2. Digestion leucocytosis.
3. Leucocytosis of pregnancy and parturition.
4. Leucocytosis due to thermal and mechanical influences.
5. Terminal leucocytosis.
230 THE LEUCOCYTES.
Pathological Leucocytosis.
1. Inflammatory and infectious leucocytosis.
2. Leucocytosis of malignant disease.
3. Post-hemorrhagic leucocytosis.
4. Toxic leucocytosis.
5. Experimental leucocytosis.
PHYSIOLOGICAL LEUCOCYTOSIS.
The leucocytoses associated with a number of
CHARACTER, purely physiological conditions are generally of
brief duration, and, as a rule, involve a moderate
increase in the white corpuscles, the gain in many instances being
trifling and never excessive. As noted in a preceding paragraph,
the increase sometimes affects equally all forms of leucocytes, so
that, although the total number of cells is higher than the normal
standard, the relative percentages of the different varieties remain
in the ratio observed in normal blood. In other instances the
gain is due to an absolute and relative increase in the polynuclear
neutrophiles, with a consequent decrease in the percentage of
non-granular, mononuclear forms.
The increase of leucocytes under such condi-
CAUSAL tions is to be regarded usually as a physical
FACTORS. phenomenon depending upon temporary concen-
tration of the blood or upon an unequal distri-
bution of the cells in favor of the peripheral vessels. Evidence
is wholly lacking to show that it is caused by an actual overpro-
duction of leucocytes by the blood-forming organs, thus produc-
ing a general increase through all parts of the body. It is, there-
fore, reasonable to believe that the high leucocyte counts may
be accounted for by such factors as decrease in the total volume
of blood plasma, and the transference of cells from the vessels
of the deeper tissues to those of the superficial parts of the body,
i. Leucocytosis of the New-born. — The blood of the infant at
birth contains two or three times the number of leucocytes found
in the normal adult, the count usually ranging from 15,000 to
20,000 or higher during the first forty-eight hours of life. After
this time the number of cells gradually decreases until, by the
end of the first or second week, it has fallen to an average of from
10,000 to 15,000, which figures may be considered normal for
children under one year of age. In ten babies examined by War-
field1 these averages were found: first day, 26,090; third day,
1 Amer. Med., 1902, vol. iv, p. 457.
PHYSIOLOGICAL LEUCOCYTOSIS. ' 231
13,270; and eleventh day, 15,740 leucocytes' per c.mm. In all
of these cases it was found that the younger the infant, the
higher the count, which during the first five hours after birth
commonly ranged between 28,000 and 34,000. Gundobin1 and
Carstan jen 2 have determined, by a series of differential counts, that
the increase is due chiefly to an excessive gain in the polynuclear
neutrophiles, the proportion of these cells during the first ten days
after birth averaging from 60 to 70 per cent, of all forms of leu-
cocytes. The extent of this increase becomes apparent when one
recalls the fact that in the infant the relative proportion of these
cells to the other varieties is usually not more than 40 per cent.
Japha3 considers 42 per cent, the average of the polynuclear neutro-
philes in infants from several weeks to twelve months of age.
By the tenth day this polynuclear increase usually subsides, and
the percentage of mononuclear forms rises to the figure normal
at this period of life. (See Section VI.) In prematurely-born
infants a similar increase in the number of leucocytes is present,
but the mononuclear forms rise to their normal percentage more
rapidly than in the full-term baby; thus, in the case of an eight-
months' child, examined by Whitney and Wentworth,4 the large
and small lymphocytes, which averaged together but 26 per cent,
at birth, rose to 80 per cent, by the fourth day, remaining at practi-
cally this figure through subsequent counts.
The leucocytosis of the new-born is probably attributable
partly to concentration of the blood by venous stasis 'and by the
drain on the body-fluids incident to the early days of life, and partly
to the influence of digestion leucocytosis, which is especially active
at this period. Schiff 5 first noted the influence of the latter factor,
and particularly drew attention to the marked gain in cells after
the baby's initial feeding.
2. Digestion Leucocytosis. — Within an hour after taking food
an appreciable increase in the number of leucocytes may be ob-
served in the great majority of healthy individuals, the/count
reaching its maximum within from two to four hours after the
meal, and then gradually declining. Rieder6 estimates the aver-
age increase at about 33 per cent, in excess of the normal figure.
Meals rich in albuminoids are followed by a more marked increase
than those consisting chiefly of vegetable articles of diet. In in-
dividuals whose process of digestion is slow from any cause the
appearance of the leucocytosis is also delayed. The following two
1 Jahrb. f. Kinderheilk., 1893, vol. xxxv, p. 187.
1 Ibid., 1900, vol. Hi, p. 333. 3 Ibid., 1901, vol. liii, p. 179.
4 Cited by Rotch, "Pediatrics," Philadelphia, 1896, p. 348.
s Zeitschr. f. Heilk., 1890, vol. xi, p. 30.
* " Beitrage zur Kenntniss der Leukocytose," Leipsic, 1892.
232
THE LEUCOCYTES.
instances, taken from von Limbeck,1 illustrate the development of
the leucocytosis in the normal adult:
TIME.
COUNT OF LEUCOCYTES.
TIME.
COUNT OF LEUCOCYTES.
11.15 A- M-2
7,600
11.30 A. M.2
5,800
12.15 p- M-
6,000
12.30 P. M.
10,600
1.15 P. M.
8,500
1.30 P. M.
10,600
3.15 P. M.
12,000
2.30 P. M.
9,600
5. 15 P.M.
I4,OOO
3.30 P. M.
6,800
7.15 P.M.
IO,OOO
6.00 P. M.
6,600
The gain is due usually to a predominance of polynuclear neu-
trophile forms, with a consequent relative diminution in large and
small lymphocytes; but in some instances the differential count
remains normal, all forms of cells sharing equally in the increase.
Digestion leucocytosis is not invariably present even in those
who apparently enjoy perfect health, its absence in such instances
remaining entirely unexplained. It is also absent occasionally in
chronic constipation, frequently in chronic gastric catarrh and
anemia, and is found in only a small proportion of cases of gastric
carcinoma. Other lesions of the gastro-intestinal tract and dis-
eases characterized by high-grade anemia and by marked de-
bility may greatly delay or even entirely prevent the increase.
Rieder3 is authority for the statement that digestion leucocytosis
does not occur during pregnancy, and Bohland 4 finds that it fails
to develop during the administration of tannic acid. Digestion
leucocytosis ordinarily does not occur when the leucocytes are
already increased by some pathological factor.
In children, especially in young breast-fed infants, the increase
is very decided; in the new-born counts of from 30,000 to 35,000
may follow the first few feedings. (See Section VI.) The leucocy-
tosis is also marked after fasting and in diabetics.
The factors of digestive leucocytosis are, theoretically, two-
fold : the chemotactic action of the absorbed albumins, which calls
from the bone marrow an excess of polynuclear neutrophiles ;
and the increased lymph flow from the thoracic duct, which
accounts for the lymphocyte gain. The older writers, notably Poll
and Hofmeister,5 thought the latter due to hyperactivity of the
gastro-intestinal lymphatic tissue, but this view has been con-
troverted by the careful work of Goodall, Gulland, and Paton,6 who
failed to find the slightest sign of adenoid proliferation in the walls
1 Loc. cit. * Meal of nitrogenous and farinaceous food.
3 Loc. cit. 4 Centralbl. f. inn. Med., 1899, vol. xx, p. 361.
8 Cited by von Limbeck, loc. cit.
8 Jour. Physiol., 1903, vol. xxx, p. i.
PHYSIOLOGICAL LEUCOCYTOSIS. 233
of the gut, and who, furthermore, found the quantitative and
qualitative count of leucocytes identical in the mesenteric veins and
arteries and in the general circulation. These investigators also
found that in animals digestion leucocytosis is unaffected by
removal of the spleen.
3. Leucocytosis of Pregnancy and Parturition. — In the majority
of primiparae a moderate leucocytosis, not usually involving an in-
crease in excess of double the normal count, is observed during
the later months of pregnancy. The increase is less constant
and much less marked in multipart, occurring in a smaller per-
centage of the latter, and amounting to a cellular gain of about
one-sixth the original count on the average. The maximum
number of cells is usually found immediately before and after de-
livery, at which time the number of leucocytes commonly rises
to about 15,000 per c.mm. During convalescence the leucocytosis
gradually declines, and disappears before the end of the first week
after delivery, in uncomplicated cases. As a general rule, in both
primiparae and in multiparae the degree of increase is more decided
in young women than in those of middle age. It is also marked
in the late rather than in the early stages of gestation and of labor.
The leucocytosis of pregnancy is best explained by the unusually
active metabolism of this physiological period and by the hyper-
activity of the pelvic lymph glands.
The careful blood studies by Hibbard and White1 in 55 preg-
nant women (33 primiparae and 22 multiparae) furnish the most
reliable data concerning the leucocytosis of this condition. These
authors found that leucocytosis occurred before delivery in 84
per cent, of primiparae and in 75 per cent, of multiparae, the aver-
age counts in 32 of the former being 15,021 (50 per cent, above
normal) and in 20 of the latter 11,700 (17 per cent, above nor-
mal). In normal labor the number of leucocytes fell rapidly after
delivery, gradually reached the normal standard by the fourth or
fifth day, and then again slowly rose until the seventh day, when
a decline to normal was again observed. In 37 cases at full term
(including both primiparae and multiparae) examined by J. Hen-
derson2 the leucocyte count averaged 21,365, falling by the tenth
day after labor to an average of 12,327.
After version, forceps application, and other operations the
leucocytosis persists for a longer period. Post-partum hemorrhage
and lacerations of the genital tract may also prolong the leucocy-
tosis. Zangmeister and Wagner3 found that post-partum pyrexia
1 Jour. Exper. Med., 1898, vol. iii, p. 639.
2 Amer. Jour. Obstet., 1902, vol. xlv, p. 745.
8 Deutsch. med. Wochenschr., 1903, vol. xxviii, p. 549.
234 THE LEUCOCYTES.
with fetid lochia is not a factor of any decided leucocytosis, such
as that supervening in genuine sepsis. Pray1 found in the blood
of a woman delivered by Cesarean section the same leucocyte
changes which accompany a normal labor.
Differential counts in 19 cases of Hubbard and White's series
showed that the leucocytosis was of the polynuclear neutrophile
type, a marked relative and absolute increase in these cells being
constantly present; as a rule, their percentage was from 85 to 95 of
all forms of leucocytes, usually being higher the higher the leu-
cocytosis. Henderson's counts showed similar differential changes.
These results are unlike those obtained by Rieder2 and by Bjork-
man,3 the former having stated that the various forms of cells
remain practically normal, while the latter attributes the increase
to a predominance of mononuclear elements.
Lactation of itself has no appreciable effect upon the leuco-
cytes, so that a leucocytosis occurring in a nursing woman should
be attributed to inflammatory conditions of the breast or nipple —
even a mild mastitis or a slight irritation of the nipple may be
capable of causing a prompt leucocytosis.
The number of leucocytes is somewhat in excess of normal
for a few days preceding and during menstruation in the majority
of healthy women, according to the investigations of Sfameni,4
but the increase scarcely ever reaches a degree which may be
regarded as a genuine leucocytosis.
4. Leucocytosis Due to Thermal and Mechanical Influences. — A
transient increase in the number of leucocytes of the peripheral
blood, not involving a disturbance of the normal ratio between the
different forms of cells, is produced by active local or general
muscular exercise;* by brief exposure to atmospheric cold;6 by
cold baths, either local or general;7 and by the application of
electricity* and of massage? The number of leucocytes is also
increased by the effect of prolonged dry or moist heat.9 Hot
tubbing likewise causes considerable leucocytosis,10 as does free
sweating, whether natural or induced. It occurred in 24 of 29
instances studied by Hannes,11 the increase amounting to between
1 Amer. Gyn., 1902, vol. i, p. 337. 2 Loc. cit.
3 Amer. Medico-Surg. Bull., 1894, vol. vii, pp. 17 and 79. * Loc. cit.
s Oliver, loc. cit.; Larrabee, Jour. Med. Research, 1902, vol. ii, p. 76; Schultz,
Deutsch. Arch. f. klin. Med., 1893, vol. li, p. 234; Willebrand, Skandin. Arch.
f. klin. Med., 1903, vol. xiv, p. 176. 'Oliver, loc. cit.
7 Winternitz, Centralbl. f. klin. Med., 1893, vol. xiv, p. 1017; Thayer,
Johns Hopkins Hosp. Bull., 1893, vol. iv, p. 37.
8 J. K. Mitchell, Amer. Jour. Med. Sci., 1894, vol. cvii, p. 502; Ekgren,
Deutsch. med. Wochenschr., 1902, vol. xxviii, p. 519.
9 Friedlander, Cong. f. inn. Med., Berlin, 1897.
10 Knapfelmacher, Wien. klin. Wochenschr., 1893, vol. vi, p. 810.
11 Centralbl. f. inn. Med., 1901, vol. xxii, p. 823.
PHYSIOLOGICAL LEUCOCYTOSIS. 235
3000 and 5000 cells per c.mm. Checking the perspiration resulted
in a fall of the leucocytes to normal within about half an hour.
The increase under these circumstances is generally attributed
to blood concentration due to the influence of increased vaso-
motor tension, whereby the liquid elements of the blood arc tem-
porarily decreased, and, in addition, many of the cells lodged in
the deeper tissues of the body are swept into the peripheral cir-
culation. As a rule, all varieties of leucocytes share equally in
the process, no single form being unduly increased at the ex-
pense of the others. In the case of long-distance runners, how-
ever, a very decided polynuclear neutrophile increase has been
found.1
5. Terminal Leucocytosis. — Terminal or preagonal leucocyto-
sis is the term applied to an increase in the number of leucocytes
of the peripheral circulation frequently observed just before death.
It occurs during the terminal stages of a number of different
diseases, and is especially marked in those conditions in which
death comes slowly, being ushered in by a more or less mori-
bund state of the patient, lasting for a considerable length of time.
The increase is usually moderate, and the counts do not often
exceed 20,000 or 30,000 per c.mm., except in those cases in
which decided circulatory embarrassment has existed for some
time. Most commonly the blood picture is one of ordinary
polynuclear neutrophile leucocytosis, although occasionally the
large and small lymphocytes show disproportionately high per-
centages, and still more rarely all forms of cells may be in-
creased equally. The presence of myelocytes, in small* numbers
is also common, especially when the leucocyte count is high.
In pernicious anemia the increase may be so great as to simu-
late lymphatic leukemia, according to Cabot,2 who found the fol-
lowing blood changes on the day of death in this disease : ratio of
white to red corpuscles, i to 15; and a differential count of 91.7
per cent, of lymphocytes, 7.7 per cent, of polynuclear "neutro-
philes, and 0.5 per cent, of eosinophiles. Four megalobiasts to
TOCO leucocytes were also found.
The following data were obtained by the writer in a case of
pernicious anemia eighteen hours before death: hemoglobin, 12
percent.; erythrocytes, 622, 500 per c.mm.; leucocytes, 18,600 per
c.mm. The differential count of 1000 leucocytes showed: lymph-
ocytes, 46 per cent.; polynuclear neutrophiles, 49.7 per cent.;
eosinophiles, 2.3 per cent.; myelocytes, 1.6 per cent.; and mast
cells, 0.4 per cent. Megalobiasts outnumbered normoblasts 3 to i,
1 Cabot, Blake, and Hubbard, Annals of Surg., 1901, vol. xxxiv, p. 372.
' Loc. tit.
236 THE LEUCOCYTES.
24 of the former being found in the count of 1000 leucocytes.
The number of leucocytes in four previous counts having ranged
from looo to 2400 per c.mm., and the proportion of lymphocytes
from 42 to 48 per cent., this case illustrates the occurrence of a
terminal leucocytosis without a notable change in the relative
percentage of different forms peculiar to the case in question.
The principal cause of this form of leucocytosis is thought to
be peripheral stasis dependent upon failure of circulatory com-
pensation, but in many instances there is good reason to believe
that terminal infections also act as the causal factors.
PATHOLOGICAL LEUCOCYTOSIS.
Increase in the number of leucocytes, involving
OCCURRENCE, chiefly the polynuclear neutrophile cells in the
great majority of instances, is associated with a
wide variety of pathological conditions, mainly inflammatory, in-
fectious, and toxic in character, and in such conditions the under-
lying cause of the phenomenon is radically different from that
which determines the increase in physiological leucocytosis.
Prominent examples of pathological lesions in which leucocytoses
of this character are observed are pneumonia, diphtheria, scar-
let fever, erysipelas, rheumatic fever, variola, and various septic
processes. Enteric fever, paratyphoid fever, tuberculosis, typhus
fever, Malta fever, the malarial fevers, influenza, measles, and
rotheln are notable exceptions, for in these infections leucocy-
tosis occurs only as the result of some complication.
The extent of the leucocytosis, inasmuch as it
DEGREE OF depends both upon the nature of the exciting cause
INCREASE, and upon the individual's reactive powers, varies
within wide limits in different cases. It is safe to
state, however, that in the great majority of instances the number of
leucocytes is rather below than above 20,000 to the c.mm., counts
in excess of this figure being noted in only about one-fourth of
the cases in which the leucocytes exceed the normal limits of
health. A count of 25,000 cells per c.mm. may be regarded as
a decided leucocytosis, while an increase of from 40,000 to 50,000
is of extremely rare occurrence. In an analysis of 100 consecu-
tive counts made by the writer in pathological conditions, in which
the number of leucocytes reached or exceeded 10,000 per c.mm.,
it was determined that the counts were below 20,000 in 65 per
cent, of cases, and between 20,000 and 30,000 in 28 per cent.; in
4 per cent, the increase was between 30,000 and 40,000; in 2 per
cent., between 40,000 and 50,000; and in only one per cent, did it
PATHOLOGICAL LEUCOCYTOSIS. 237
exceed 50,000. Judging from these figures, which, it should be
remembered, are applicable only to the average case, it appears to
be the rule that in most leucocytoses the increase amounts to
about double the maximum normal number.
With rare exceptions the increase affects
DIFFERENTIAL chiefly the polynuclear neutrophile cells, which
CHANGES. commonly constitute at least 85 per cent, of the
different forms of leucocytes. In many instances
the percentage is much higher, as, for example, in a case of sup-
purative meningitis, reported by Stengel,1 in which a differential
count showed 99.5 per cent, of this variety of cells. The excep-
tional cases in which these disproportionately high percentages of
polynuclear neutrophiles are sometimes wanting are encountered
in the leucocytoses of malignant disease, after hemorrhage, in the
moribund, and in children. The relative lymphocytosis which is
occasionally observed under these circumstances is considered in
connection with these conditions. Coincidentally with the increase
in polynuclear forms there is a marked decrease in the relative
percentages of large and small lymphocytes and of eosinophiles,
the latter variety of cells sometimes entirely disappearing from
the blood. In cases in which the increase is marked, small num-
bers of myelocytes usually may be observed, together with an
occasional cell whose characteristics at once suggest a stage of
development intermediate between that of the myelocyte and the
typical polynuclear neutrophile.
Several times the writer has found in typical infectious leuco-
cytoses practically normal differential counts, notwithstanding
the high total estimates. Still rarer are those instances in which
an inflammatory or infectious lesion excites a high polynuclear
neutrophile percentage with no total increase in the leucocytes.
The latter blood change has been, on insufficient grounds, in-
terpreted in the same light as a frank general increase.
The exact manner in which pathological leu-
CAUSAL cocytosis arises is a question about which many
FACTORS. conflicting views are held by different authorities,
but the general trend of opinion at the present
time attributes the increase chiefly to the influence of chemotaxis.
According to the chemotactic theory of leucocytosis, the pres-
ence in the blood of certain chemical substances, produced by in-
fective principles, is capable of exerting both an attractive and a
repellent influence upon the ameboid leucocytes. If the collec-
tions of cells are attracted by such substances, the phenomenon is
known as positive chemotaxis, but if, on the other hand, they are
1 Loc. cit.
238 THE LEUCOCYTES. .
repelled, the condition is termed negative chemotaxis. This mass-
ing and repulsion of the leucocytes may be caused by various
agents — by thermal and mechanical irritants, by bits of necrotic
tissue which have gained entrance to the circulation, and espe-
cially by the presence in the blood of bacteria or of their meta-
bolic products. Thermotaxis, or attraction by heat, may also
attract the leucocytes to an inflamed area. Mendelson1 has shown
that a local temperature of 39° C. is most active in provoking such
a massing of the cells. In the light of our present knowledge it
appears that the different varieties of ameboid leucocytes respond
to different kinds of chemotactic influences, as an instance of which
the behavior of the neutrophiles and eosinophiles to this sort of
stimulus may be cited. Certain substances, which for one of
these groups of cells are either positively or negatively chemo-
tactic, are, as a rule, indifferent to the other group, and some-
times even antagonistic, for substances which serve to attract one
group either fail to influence or in fact repel the other. Clin-
ically, this theory seems to find corroboration, for in the great
majority of instances an increase in either variety of these cells is
associated with a constant decrease in the other. In infections with
certain animal parasites this general rule does not apply — notably in
trichiniasis, in ankylostomiasis, and in filariasis, in which it is appar-
ent that substances chemotactically active for both neutrophile and
eosinophile cells are at work. Ehrlich2 has shown that the mast cells
are wholly uninfluenced by those substances which exert a strong
chemotactic influence upon the neutrophiles and eosinophiles.
The intense cellular activity excited by the en-
FUNCTIONS. trance of bacteria into the organism indicates an
attempt on the part of the leucocytes to destroy
the invading principle and to counteract its noxious influences.
In this endeavor it is probable that in a restricted sense Metsch-
nikoff's hypothesis holds true, and that the immense numbers of
phagocytic leucocytes which crowd the blood stream mechan-
ically engulf and destroy many of the invading micro-organisms.
But of still greater significance is the faculty which the leuco-
cytes possess of producing, both by secretion and by cellular
disintegration, certain chemical substances (alexins) acting either
as directly bactericidal or as antitoxic agents. The researches of
Buchner,3 Lowy and Richter,4 Goldscheider and Jacob,5 and others
1 Russkiy Vrach, 1903, vol. ii, p. 4; abst. in Phila. Med. Jour., 1903, vol. xi,
P- 78S-
2 Loc. cit. 3 Arch. f. Hyg., 1890, vol. xvii, p. 112.
4 Deutsch. med. Wochenschr., 1895, vol. xxix, p. 240; also Virchow's Arch.,
1898, vol. cli, p. 220.
5 Zeitschr. f. klin. Med., 1894, vol. xxv, p. 373.
PATHOLOGICAL LEUCOCYTOSIS. 239
tend to show that such substances either actually destroy the in-
fecting micro-organisms, or at least antidote and render innocuous
their poisonous products. This joint process of phagocytosis and
bactericidal action is most intensely developed at the period of
maximum leucocytosis, according to the statements of Gabri-
tschewsky.1
Alexin is an unstable nucleo-proteid, acting as an enzyme and
corresponding to the complement of Ehrlich. It is, according to
Metschnikoff, a product of the leucocytes, and does not exist free
in the blood plasma. In the process of bacteriolysis the alexin's
activity depends upon the intermediation of the amboceptor or
immune body, according to the hypothesis of immunity elaborated
by Ehrlich (p. 151). The French school holds that phagocy-
tosis is excited by the action of the amboceptor, the chief source
of which is also the leucocytes. Metschnikoff believes that the
functions of the different phagocytic cells in immunity are dis-
tinctly dissimilar, the action of the polynuclear cells (or micro-
phages) being simply bacteriolytic, while that of the large lympho-
cytes (or macro phages) is solely hemolytic.
It has been suggested by Wright and Douglas2 that phago-
cytosis is materially aided by the body fluids, which may so influ-
ence invading bacteria as to make them easy prey for the phago-
cytic leucocytes. They attribute this effect to the presence in the
blood serum of an unknown body, "opsonin," which is thought
to develop as immunity is established. In a number* of patients
suffering from furunculosis Wright succeeded, by treating them
with a sterile antistaphylococcus vaccine, in increasing .the phago-
cytic power of the blood which before this treatment was dis-
tinctly below the normal.
In experimental leucocytosis, caused by the
HYPOLEUCOCY- injection of such irritants as bacteria and bacterial
TOSIS AND HY- products, organic extracts, various albumins, and
PERLEUCOCY- even by simple trauma, it has been found that the
TOSIS. first effect of the irritant is to cause a rapid, tran-
sitory diminution in the number of leucocytes in
the peripheral blood, known as hypoleucocytosis, this decrease
being succeeded in turn by an increase of these cells in excess of
the normal standard, termed hyperleucocytosis. Frequently in
simple traumatic leucocytoses after the disappearance of the stage
of hyperleucocytosis, the duration of which is variable, Sher-
rington3 was able to distinguish a secondary stage of hypoleuco-
1 Centralbl. f. Bakt. u. Parasit., 1898, vol. xxiii, p. 365.
1 Prpc. Roy. Soc., London, 1903, vol. Ixxii, p. 357.
3 Ibid., London, 1893, vol. Iv, p. 161.
240 THE LEUCOCYTES.
cytosis during which the leucocyte count again fell below the
normal.
Within certain limits the extent of this preliminary decrease
and of the subsequent increase varies directly in accordance with
the intensity of the irritant. If the irritant is slight, the repellent
influence is feeble, and the consequent cellular increase is in-
conspicuous— in fact, it is the opinion of many that in such in-
stances there may be merely a local accumulation of leucocytes
at the site of the injection, without any real increase in the whole
mass of cells. If the effects of the irritant are severe, both the
repellent and the attractive stages are promptly excited and
markedly developed, and a general increase in the number of
leucocytes through the whole circulatory system promptly re-
sults. If, on the contrary, the effects of the irritant prove to be
too intense, the organism suffers a depression so profound that
reaction is stifled, and leucocytosis docs not develop. It some-
times happens that the attractive influences of the chemotactic
principle predominate over its repellent action, in which case the
stage of hyperlcucocytosis may develop without the initial stage
of hypolcucocytosis. Clinically, the preliminary decrease is prac-
tically never observed, perhaps partly for the reason last given,
but also in a large measure because the repellent action of the
irritant has passed off by the time the disease has developed into
a clinical picture. In artificially excited leucocytoses, however,
its appearance is quite constant, for under such circumstances the
irritant is introduced into the organism suddenly and in a rela-
tively massive dose, thus producing a decidedly repellent in-
fluence.
The initial stage of decrease was termed the leucopenic phase
by Lowit,1 who attributed the change to an actual destruction of
the leucocytes, or a leucocytolysis. The subsequent increase he
spoke of as the leucocytic phase, maintaining that for the produc-
tion of the latter the preliminary development of the former was
in some unexplained manner essential. The work of Goldschei-
der and Jacob2 definitely proved the error of Lowit's leucocyto-
lytic hypothesis, and demonstrated the fact that the leucopenia
was dependent purely upon an altered distribution of the cells
in favor of the vessels of the deeper circulation. Extensive
investigations carried on by these authors showed that at the
time a decided diminution occurred in the number of leucocytes
of the peripheral blood there was a simultaneous increase of
these cells in the capillaries of the lungs and other internal organs.
Furthermore, it was also shown that in some instances a marked
1 "Studien z. Physiol. u. Pathol. d. Blutes," Jena, 1892. 2 Loc. cit.
PATHOLOGICAL LEUCOCYTOSIS. 241
leucocytosis may occur without the initial decrease, this being
the case after the injection of such substances as the glycerin
extract of spleen. From these experiments it seems reasonable
to attribute the initial stage of decrease to a repellent action of
the irritant, and to infer that the stage of hyperleucocytosis is
due to an active stimulation of the hemogenic organs which results
certainly in an increased cellular output from, and probably in
an increased cellular proliferation in, this situation. Muir's
investigations1 tend to strengthen this belief, and to throw
additional light on the phenomenon of pathological leucocytosis.
This author found that in experimental leucocytosis in animals,
produced by the injection of pathogenic bacteria, changes occurred
in the bone marrow, consisting of absorption of the marrow fat,
together with a corresponding hyperplasia of the cells from which
he believes the leucocytes originate, many of these cells under-
going rapid multiplication by mitosis. In inflammatory leuco-
cytosis Muir found the following suggestive changes : first, a local
increase in the polynuclear neutrophile cells; second, an increase
of the same variety of cells in the circulating blood; and third,
a marked increase in the marrow of their direct antecedents. Opie2
found in experimental bacterial infections an accumulation of
eosinophiles at the point of inoculation, where these cells undergo
nuclear fragmentation and other degenerative changes and thereby
probably repel infection, although, unlike the polynuclear neutro-
philes and large mononuclear leucocytes, they rarely if ever act
as phagocytes. Coincident with this massing of eosinophiles at
the site of the infection these cells are exceedingly scanty in the
peripheral blood, but collect in large numbers in the spleen. Ac-
cording to Ehrlich's latest views,3 leucocytosis involving mainly an
increase of the polynuclear neutrophiles (" polynuclear neutrophile
leucocytosis") is the expression of an independent chemotactic
reaction on the part of these cells, caused by the remote influence
of dissolved substances upon the bone marrow, whereby this, tissue
throws into the blood current excessive numbers of these elements.
Schultz 4 and others, on the contrary, attribute leucocytosis en-
tirely to changes in the distribution of the cells, maintaining that
increase in the number of leucocytes in the peripheral vessels
goes hand in hand with a decrease in their number in the vessels
of the internal organs, and vice versa. This view, however, has
been shown to be untenable.
1 Brit. Med. Jour., 1898, vol. ii, p. 604; also Trans. Path. Soc., London, 1902,
vol. liii, p. 379.
2 Amer. Jour. Med. Sci., 1904, vol. cxxvii, p. 988. * Loc. cit.
4 Tagebl. der Naturforsch. Vers., Heidelberg, 1889, p. 405.
16
242 THE LEUCOCYTES.
In summing up the various experimental and clinical data bear-
ing upon the nature of the leucocytoses associated with patho-
logical conditions, the evidence tends to confirm the view that the
process is, in all instances, save perhaps those of trivial local in-
fections, a general one throughout the entire circulatory system,
and that it is symptomatic of an excessive output and rapid de-
velopment of leucocytes by the bone marrow, due to the influence
of chemotactic principles. It must be remembered that this view
is in part based upon hypotheses, but it nevertheless represents
the belief current at the present time.
i. Inflammatory and Infectious Leucocytosis. — In this class are
included the leucocytoses occurring during the course of a num-
ber of diseases of inflammatory and infectious character, in which
the increase may be attributed either to simple inflammation or to
bacterial infection, or to both. The presence of such a leucocy-
tosis is to be regarded as symptomatic of an attempt on the part
of the organism to overcome the noxious invading principle, what-
ever its nature may be, through the protective action of the white
corpuscles. Bearing in mind this construction of the phenom-
enon, it is possible in many instances to derive valuable clinical
information from the presence or absence of a cellular increase.
A genuine inflammatory or infectious leucocytosis is a much
more potent defensive agent than a leucocytosis excited artificially
by the injection of nuclein, for example. (See p. 251.) Accord-
ing to Labbe,1 an induced leucocytosis, while hypothetically an
antidote to disease, practically is of trivial value as a means of
defense against a definitely established infection. As a preventive
measure, however, an artificially provoked leucocyte increase
may confer a certain degree of protection.2 Bezancon and Labbe3
maintain that a polynuclear neutrophile leucocytosis follows
active, rapid infections, and confers simply a transitory immunity,
while an increase affecting chiefly the mononuclear cells attends
slow infections and generally gives permanent protection.
The view expressed by von Limbeck,4 that the height of the
leucocytosis is dependent upon the extent of the inflammatory ex-
udate, is not tenable, for processes characterized by insignificant
exudates are capable of causing as great an increase as those in
which this outpouring is extensive. As a rule, leucocytoses as-
sociated with purulent exudates are much more marked than
those due to serous effusions. The essential factor in determining
1 Presse med., 1903, vol. ii, p. 725.
2 For an account of the practical value of induced leucocytosis in wound in-
fections (reviewing the studies of Lowy, Richter, Jacob, Hahn, Goldscheider, Hof-
bauer, Salieri, and Miyake) see Mikulicz-Radecki, Lancet, 1904, vol. ii, p. i.
3 Presse m^d., 1902, vol. ii, p. 1071; also "Traite d'Hematologie", Paris, 1904.
4 Loc. cit.
PATHOLOGICAL LEUCOCYTOSIS. 243
the degree of the increase is not the extent of the exudate nor,
in all cases, its character, but rather the systemic reaction to which
it gives rise.
The degree of leucocytosis may be considered a general index
to the intensity of the infection and to the strength of the indi-
vidual's resisting powers in reacting against it. It follows,
therefore, that intense infections occurring in individuals whose
resisting powers are strong produce a decided increase; but
the presence of an infection of like intensity in one whose re-
sisting powers are greatly crippled fails to cause leucocytosis, for
in such an instance the organism is s<5 overpowered by the effects of
the morbid process that it is incapable of reacting. The increase is
either absent or slight when a trifling infection is associated with
vigorous resisting powers, and moderate when a moderately intense
infection is linked to fairly well-developed resisting powers.
The clinical inferences to be drawn from these facts are of
value chiefly as corroborative of other wrell-known physical signs,
but are obviously untrustworthy when considered apart from the
latter. A marked leucocytosis indicates simply an intense in-
fection in a person whose resisting powers are normally developed
and actively exerted against the disease, but it is of no prognos-
tic value in itself, for it conveys no idea of the final outcome of
the conflict 'between the disease and the organism. Absence of
leucocytosis or a slight increase may be either of veryvfavorable
or of very grave significance, inasmuch as these signs occur both
in trivial and in overwhelming infections. If the absence is asso-
ciated with clinical manifestations which point to a severe"infec-
tion, the sign may be depended upon as being of grave prognosis.
The clinical significance of the leucocytoses associated with
various inflammatory and infectious processes will be discussed
in Section VII. A more or less decided increase in the num-
ber of leucocytes occurs with great constancy in the following
groups of diseases of this nature :
I. General Infectious Diseases.
Actinomycosis. Pneumonia.
Asiatic cholera. Pyemia.
Bubonic plague. Relapsing fever.
Cerebrospinal meningitis. Rheumatic fever.
Diphtheria. Scarlet fever.
Dysentery. Septicemia.
Erysipelas. Spotted fever (Montana). .
Filariasis. Syphilis (secondary).
Glanders. Trichiniasis.
Malignant endocarditis. Vaccinia.
Multiple neuritis. Varicella.
Osteomyelitis. Variola.
Pertussis. Yellow fever.
244 THE LEUCOCYTES.
II. Simple and Infective Local Inflammations.
Acute yellow atrophy of the liver. Pellagra.
Appendicitis, catarrhal. Pemphigus.
Arthritis, serous. Pericarditis.
Bronchitis, acute. Peritonitis.
Burns. Prurigo.
Cholangitis. Purulent lesions:
Cholecystitis. Appendicular abscess.
Cystitis. Cerebral abscess.
Conjunctivitis, acute. Hepatic abscess.
Dermatitis. Ischio-rectal abscess
Eczema. Ovarian abscess.
Endocarditis. Pancreatic abscess.
Endometritis. Pelvic abscess.
Enteritis. Perinephritic abscess.
Epididymitis. Prostatic abscess.
Gangrene: Pulmonary abscess.
Appendicular. Retropharyngeal abscess.
Cancrum oris Splenic abscess.
Hepatic. Superficial abscess.
Pancreatic. Arthritis, suppurative.
Pulmonary. Carbuncle.
Gastritis, acute. Empyema.
Gastro-enteritis, acute. Felon.
Herpes zoster. Furuncle.
Hydatid disease. Gonorrhea.
Infected wounds. Otitis media, suppurative.
Mastitis. Phlebitis.
Meningitis. Pyelonephritis.
Nephritis, acute. Pyonephrosis.
Orchitis. Pyosalpinx.
Ovaritis. Quinsy.
Pancreatitis. Splenitis.
Under this heading it is convenient to include post-operative
leucocytosis, or the increase commonly occurring after a surgical
operation, as a symptom of the normal process of wound repair.
The reparative process, however, is not always the sole factor of
the leucocytosis, since the effects of the anesthetic and of hemor-
rhage also must be taken into account. In non-septic uncom-
plicated cases the increase amounts to between 5000 and 10,000
cells per c.mm. in excess of the pre-operative count. The maxi-
mum increase, which is transitory, is generally attained within
from twelve to twenty-four hours, and the normal standard is
again reached, by a progressive decline in the leucocyte count,
within two or three, or at the latest four, days. In uncomplicated
cases the count falls to normal within twenty-four hours in Blood-
good's experience1; within thirty-six hours in Cabot's2; within
eighty-four hours in Frazier's3; and within five days in C. Y.
White's.4 Persistence of a post-operative leucocytosis is signifi-
1 Med. News, 1901, vol. Ixxix, p. 321.
2 Annals of Surg., 1901, vol. xxxiv, p. 361.
3 Univ. of Pa. Med. Bull., 1901, vol. xiv, p. 363.
4 Univ. Med. Mag., 1900, vol. xiii, p. 260.
PATHOLOGICAL LEUCOCYTOSIS. 245
cant of some such complication as defective drainage, infection,
hemorrhage, or extensive inflammation.
King1 could determine no relation, in non-septic cases, be-
tween the height of the leucocytosis and the ranges of the pulse
and temperature. Frazier and Holloway2 believe that the in-
crease corresponds in general with the extent of the operation,
but that it is uninfluenced by the degree of the temperature
and by the anesthesia.
2. Leucocytosis of Malignant Disease. — A moderate leucocy-
tosis is commonly, but by no means constantly, associated with
the various forms of carcinomata and sarcomata, but the cases in
which no increase is observed are even more numerous than those
in which it occurs. It is more common and the increase is usually
regarded as more marked in sarcoma than in carcinoma, but in
neither condition are excessively high leucocytoses met with fre-
quently. In the writer's experience the increase, when it does
occur, is generally moderate in most forms of malignant disease,
counts of less than 20,000 leucocytes per c.mm. being the general
rule. Cases in which the number of cells exceeds this figure
are comparatively rare, but are distinctly more common in sar-
coma than in carcinoma; it is especially in rapidly growing
neoplasms of the lung, liver, and kidney that the cells rise to 30,000,
40,000, or even 50,000 or more. In a series of 68 consecutive
cases of malignant disease in the German and Jefferson hospitals
less than one-half were accompanied by a leucocyte ' count of
10,000 or more, this figure being reached or exceeded in approx-
imately 45 per cent, of cases of carcinoma, while in sarcpma such
an increase was noted in almost 65 per cent. Five per cent, of
all cases showed a high leucocytosis — that is, counts ranging
between 30,000 and 50,000. (For further data concerning the
leucocytosis of these conditions see "Malignant Disease," Section
VII.)
The behavior of the leucocytes in malignant disease app'ears
less contradictory when we inquire into the actual influence which
these growths exert in provoking leucocytosis. It is the cur-
rent belief that malignant disease per se has little if any influ-
ence of this sort, and that the increase, if any occurs, is attribu-
table to local inflammatory complications and to secondary septic
infections, rather than to the specific toxic effects of the neoplasm
itself. In some instances it is reasonable to suppose that the
profoundly cachectic state of the patient also is an important de-
termining factor. Clinically, it is observed that tumors of rapid
1 Amer. Jour. Med. Sci., 1902, vol. cxxiv, p. 450.
2 Univ. of Pa. Med. Bull., 1901, vol. xiv, p. 363.
246 THE LEUCOCYTES.
development, involving a large area of tissue and complicated by
extensive metastases, cause decided, often high, leucocytoses; while
localized tumors, of small size and of slow growth, give rise to
trifling, if any, increase. Variations from this general rule are
the result of differences in the resisting powers of different indi-
viduals, for the effects of this factor in causing leucocytosis are
potent in this as in other pathological conditions.
Qualitatively, the leucocytes usually show a marked absolute
and relative increase in the polynuclear neutrophiles, with a con-
sequent diminution of the mononuclear forms. But in some in-
stances, both of carcinoma and of sarcoma, the polynuclear forms
are relatively below the normal percentage, and the lymphocytes
increased, so that the blood picture is not one of leucocytosis, but
rather one of relative lymphocy tosis ; such a change seems es-
pecially prone to occur in sarcoma of the lymphatic system, in
which it may be so marked that it suggests lymphatic leukemia.
There are certain cases of malignant disease in which the propor-
tion of polynuclear neutrophiles rises, although the total number
of leucocytes is not increased; the polynuclear gain is less than
is usually found with high leucocyte counts, and is not
to be regarded as of the same significance as a frank leu-
cocytosis involving an increase in the total number of cells. (See
P- 237-)
The eosinophiles are variously affected in different cases : some-
times they are greatly diminished, if not, indeed, entirely absent,
as in most leucocytoses; sometimes they are normal; and some-
times they are largely increased in number. The increase may
be pronounced in sarcoma, this being due probably to involve-
ment of the bone marrow by the growth, either directly or by
metastasis.
Small numbers of myelocytes — 0.5 to i or 2 per cent. — are ex-
ceedingly common, being found with great constancy in cases
with marked cachexia, especially in carcinoma. In malignant
disease involving the bone marrow the percentage of this variety
of cells is much higher.
3. Post-hemorrhagic Leucocytosis. — A leucocytosis of moderate
grade commonly occurs as the result of hemorrhage due to trau-
matism or to other causes. It has been found that in animals
the stage of increase is preceded by a well-defined leucopenia,
which develops immediately after the loss of blood. This initial
leucopenia, however, has not yet been demonstrated in man,
although it probably occurs. In an extensive traumatic hemor-
rhage the increase sometimes may be recognized in the periph-
eral blood within an hour after the accident, but usually it is
PATHOLOGICAL LEUCOCYTOSIS. 247
not distinguishable until after the lapse of a longer period — from
five to ten hours, as nearly as can be ascertained. In hemor-
rhage accompanying various pathological conditions, such, for
example, as gastric ulcer, lung tuberculosis, or uterine disease,
the appearance of the leucocytosis is less prompt than in hemor-
rhage from trauma. The maximum increase is usually within
moderate limits — approximately two or three times the normal
standard. The injection of a salt solution decidedly aggravates
the leucocytosis. As an illustration of the degree of leucocytosis
which is commonly encountered, Rieder1 noted in four cases
(hematemesis from gastric ulcer, fatal hemophilia, and uterine
hemorrhage) an average count of 22,625, tne maximum being
32,600, and the minimum, 15,100. Inasmuch as the height of
the increase is thought to correspond to the strength of the organ-
ism's reaction in compensating the blood loss, it varies in different
cases. In two individuals of equally strong regenerative powers
a severe hemorrhage will produce a greater leucocytosis than a
slight one. The duration of the increase also varies with the
individual case, for it depends upon a similar factor; but in the
majority of instances it does not last for more than three or four
days, according to the investigations of Lyon.2 Leucocytoses
excited by traumatic hemorrhage are prone to persist longer than
those due to other causes, and the long-persisting increases which
are sometimes associated with other pathological lesions should
be attributed to factors other than the actual loss of .blood. In
an instance of leucocytosis following venesection Rieder3 found
that the increase persisted for twelve days. Head4 found that
in dogs the leucocytosis following extensive hemorrh'age lasted
for at least seven days.
Usually the qualitative changes involve chiefly the polynu-
clear neutrophiles, which are greatly increased at the expense of the
other forms of cells, but in an occasional instance it will be found
that the mononuclear varieties are greatly in excess of their normal
percentages, so that a lymphocytosis is observed. Myelocytes
may also be found in considerable numbers in many cases.
4. Toxic Leucocytosis. — Typical examples of toxic leucocytosis
are found in poisoning by ptomains and by coal-gas, in both of
which conditions the predominant influence of a toxic agency in
producing the increase is self-evident. For the same reasonjthe
leucocytoses occurring as the result of ether and chloroform nar-
cosis, and in convulsions and acute delirium, are included in this
classification. In certain diseases, notably in the uric acid diath-
1 Loc. cit. * VirchoVs Arch., 1881, vol. Ixxxiv, p. 207.
3 Loc. cit. 4 Jour. Amer. Med. Assoc., 1901, vol. xxxvii, p. 501.
248 THE LEUCOCYTES.
esis, in cholemia, and in uremia, the presence in the blood of
toxic principles is thought to be the underlying factor of the in-
crease; the same probably is true of a number of other diseases,
which, for obvious reasons, have been classed with the infectious
and inflammatory leucocytoses.
The effect of gas-poisoning is well illustrated by the blood
examination of a patient admitted to the German Hospital,
fatally poisoned by illuminating-gas. The leucocytes were in-
creased to 32,000 per c.mm., the gain being due to an excessive
predominance of polynuclear neutrophiles, as determined by the
following differential count: small lymphocytes, 3.5 per cent.;
large lymphocytes, 2.5 per cent.; polynuclear neutrophiles, 92
per cent.; eosinophiles, 0.5 per cent.; and myelocytes, 1.5 per
cent. To what extent this increase depended upon the actual
toxic effects of the gas and to what extent it was attributable
to peripheral stasis (which was marked in this^patient) are con-
jectural.
The leucocytosis caused by ether narcosis has been exhaus-
tively studied by von Lerber1 and by Chadbourne.2 The inves-
tigations of von Lerber included 101 cases, of which number leu-
cocytosis was found in more than 95 per cent., the increase fre-
quently amounting to two or three times the original count; in
the majority of instances the maximum count was observed sev-
eral hours after the anesthesia was produced. Chadbourne has
carefully studied 21 cases, all of which showed a more or less
decided leucocytosis, the minimum gain being 6 per cent., the
maximum 73 per cent., and the average 37.3 per cent. He found
that the leucocytosis developed most rapidly during the early
part of the etherization, and that only exceptionally did it persist
for more than twenty-four hours. Differential counts in five
cases showed that all forms of cells were proportionately in-
creased. This author attributes the increase to the irritating
effects of the ether vapor upon the mucous membrane of the
respiratory tract. J. Chalmers Da Costa and Kalteyer,3 in 50
cases, found an average leucocytosis of about 5000 per c.mm.
Results similar to the above also have been obtained by Ewing4
and by Ames,5 in the experimental etherization of animals.
Ether also causes moderate polycythemia, but this is due in
partjto inspissation of the blood by the preparatory treatment of
1 "Ueber die Einwirkung der Aethernarkose auf Blut u. Urin," Inaug. Dis-
sert., Berlin, 1896.
a Phila. Med. Jour., 1899, vol. iii, p. 390.
8 Annals of Surg., 1901, vol. xxxiv, p. 329.
4 N. Y. Med. Jour., 1895, vol. Ixi, p. 257.
5 Jour. Amer. Med. Assoc., 1897, vol. xxix, p. 472.
PATHOLOGICAL LEUCOCYTOSIS. 249
the patient. A slight diminution in hemoglobin is commonly,
but not invariably, found.
The effects of chloroform are similar to those of ether, but
are 'more marked and persist longer. Solimei1 found that the
leucocytosis induced by chloroform narcosis, while sometimes dis-
appearing within a few hours, often continues for several days,
the duration of the increase being related to the amount of the
anesthetic used and to the rate of its elimination from the system.
This observer also detected a loss of hemoglobin and erythrocytes
with moderate poikilocytosis, and, after protracted narcosis, de-
layed coagulability, the presence of a methemoglobin spectrum,
and an increase in the carbon dioxid of the blood, with a corre-
sponding diminution of oxygen. Holman2 warns the operator
against the danger from hemolysis by chloroform in patients
whose hemoglobin percentages arc law.
The leucocytosis associated with acute delirium and with con-
vulsive seizures, due to a variety of causes, has been studied in
detail by Capps3 and by Burrows.4 Under such circumstances the
increase is usually marked, and the height of the count in a gen-
eral way is dependent upon the severity of the attack. The
polynuclear neutfophiles are chiefly concerned in the increase,
with a consequent decline in the proportion of mononuclear
forms. The leucocytosis of this class of diseases is discussed
more fully in Section VII.
5. Experimental Leucocytosis. — Leucocytoses not, differing es-
sentially from those associated with various local and general
infections may be caused by the administration of many drugs,
chemicals, organic principles, bacteria, bacterial proteins, and by
the application of intense irritants and revulsives to the surface
of the body. No doubt many of these leucocytoses should be
classed either as inflammatory or as toxic, owing to the character
of their exciting causes, but for the sake of convenience they may
be grouped under this heading. „ v
Leucocytoses resulting from the administration, subcutaneously
and by the mouth, of various drugs and other substances have
been studied chiefly by the Continental investigators, to whom we
are indebted for most of our present knowledge of this subject.
The manner in which such agencies act in causing the increase is
not at all clear in many instances, but, as a rule, the change is
thought to be dependent upon chemotactic influences, as in in-
1 Gaz. degli Ospedali e. d. Clin., 1902, vol. xxiii, p. 108.
2 St. Paul Med. Jour., 1902, vol. iv, p. 618.
3 Amer. Jour. Med. Sci., 1896, vol. cxl, p. 650.
4 Ibid., 1899, vol. cxvii, p. 503.
250 THE LEUCOCYTES.-
flammatory and infectious leucocytoses,. as well as upon concen-
tration of the blood from vasomotor changes.
Lowit1 determined that a preliminary leucopenia succeeded by
a more or less decided leucocytosis followed the subcutaneous in-
jection of the following substances : hemialbumose, pepsin, nuclein,
nucleic acid, curare, leech extract, tuberculin, filtered yeast cultures,
pyocyanin, sodium urate, and uric acid. This change was not ob-
served, however, after the injection of urea.
Goldscheider and Jacob,2 conducting a large number of experi-
ments with various organic animal extracts, obtained results simi-
lar to Lowit's from the injection of the extracts of spleen, thymus,
and bone marrow, but found negative results from the use of the
extracts of thyroid, pancreas, and liver.
Winternitz 3 studied the effects resulting from the subcutaneous
injection of substances causing both transient inflammatory edema
and aseptic abscess formation at the site of the injection. In the
former class, which includes neutral salts and dilute acids and
alkalis, an increase in the number of leucocytes, amounting to
from 40 to 75 per cent, of the original count, was noted; and it
was furthermore found that even although a local necrosis was
produced by the injection of an irritating salt, the increase still
did not become excessive. In the second class of more active
irritants which produced local abscesses — turpentine, oil of
mustard, carbolic acid, croton oil, sapotoxin, digitoxin, silver
nitrate, cupric sulphate, and salts of mercury and of antimony — the
leucocytosis was much more decided and of less transient dura-
tion. As a rule, in these experiments the height of the leucocy-
tosis ran parallel to the intensity of the local irritation provoked.
Pohl4 noted a moderate leucocytosis following both the inges-
tion and the injection of absinthe, acetic ether, extract of gentian,
peppermint, piperin, the oils of anise and fennel, egg albumin,
and sodium albuminate. With the last two substances he deter-
mined that the increase was greater when they were given by the
mouth than when administered subcutaneously ; the gain usually
ranged from about 5 to 50 per cent, of the normal count. This
investigator also found that quinin, caffein, calomel, sodium bicar-
bonate, ethyl alcohol, and hydrochloric acid did not cause a leucocy-
tosis, while bismuth subnitrate and oxid of iron produced irregular
results. Many of the above experiments have been substantiated
by the later work of von Limbeck.5 Memmi6 produced a moderate
1 Loc. cit. 2 Loc. cit.
3 Arch. f. exp. Pathol. u. Pharmak., 1895, vol. xxxv, p. 77.
4 Ibid., 1889, vol. xxv, p. 51.
5 Loc. cit. * Gaz. degli Ospedali e. d. Clin., 1903, vol. xxiv, p. 995.
PATHOLOGICAL LEUCOCYTOSIS. 251
persistent leucocytosis by the daily intravenous injection of mer-
curic bichlorid, in ordinary doses, the increase first becoming ap-
parent a few days after beginning the treatment and continuing as
long as the drug was given. A single injection generally caused
no increase unless the dose was excessive. In such an instance the
maximum increase occurred within six hours, and the normal count
of cells was reached within twenty-four hours after the injection.
The intravenous injection of lecithin was found by Stassano1 to
increase the number of leucocytes, especially those of the mononu-
clear variety, the leucocytosis thus produced lasting four or five
days.
Wilkinson2 observed leucocytosis, preceded by leucopenia,
after the injection of potassium iodid, camphor, quinin, antipyrin,
salicin, salicylic acid, nuclein, and pilocarpin; by the repeated
administration of the latter drug it was found that the -granules
of the polynuclear neutrophiles disappeared, although no effect
was produced upon the granules of the eosinophile cells. Von
Jaksch3 also studied the effects of the injection of pilocarpin, and
of the administration by the mouth of nuclein, and found that
by either procedure a temporary and sometimes very marked
leucocytosis resulted. Borini4 found a similar effect was pro-
duced by aleuron, but that with digitalis a more prolonged leuco-
cytosis occurred. The leucocytosis caused by the ingestion of
salicylic acid, according to Schreiber and Zandy,5 gradually dis-
appears after the drug has been given for a few days.
The effects of the ingestion of the essential oils of peppermint,
turpentine, and cinnamon have been studied by Meyer,6 while
Hirt 7 has investigated the influences of the simple oitters and
drugs, such as the tincture 0} myrrh. Such drugs were found to
cause a moderate but easily recognized leucocytosis. Krus-
man,8 by the injection of spermin and of protalbumose, and Bes-
redka,9 by a similar use of carmin and of arsenic trisulphate, have
obtained varying degrees of increase in the number of leucocytes.
A marked increase is produced, according to Bohland;10 by the
injection of morphin, Dover's powder, sodium salicylate, pilocar-
pin, antipyrin, phenacetin, and antifebrin.
Shaw11 finds that a marked polynuclear neutrophile leucocytosis
I Me"d. mod:, 1902, vol. xiii, p. 63. 2 Brit. Med. Jour., 1896, vol. ii, p. 836.
3 Centralbl. f. inn. Med., 1892, vol. xiii, p. 81.
4 Centralbl. f. Bakt. u. Parasit., 1902, vol. xxxii, p. 207.
5 Deutsch. Arch. f. klin. Med., 1899, vol. Ixii, p. 242.
* Cited by von Limbeck, loc. cit.
''Ibid. 'These de St. Petersbourg, 1898.
8 Annal. de 1'Institut Pasteur, 1899, vol. xiii, p. 49.
10 Centralbl. f. inn. Med., 1899, vol. xx, p. 361.
II Jour. Path, and Bacteriol., 1902, vol. viii, p. 70.
252 THE LEUCOCYTES.
develops after the administration of sodium cinnamate. The
favorable action of this drug in tuberculosis is attributed partly to
its ability to excite and to maintain leucocytosis.
In addition to the substances already mentioned, the leucocy-
tosis-producing effect of various purgative drugs,1 of the transfusion
of blood and of normal salt solution? of the subcutaneous use of
fibrin ferment,3 of hemoglobin* and of bacterial cultures,5 bacterial
extracts,6 and protein1 has also been demonstrated.
Thymectomy in animals is followed by a well-marked leuco-
cytosis, associated with an increase in the bactericidal properties
of the blood. In a number of experiments upon dogs Cazin8
determined that after contusions of the abdomen the number of
leucocytes was tripled or even quadrupled within three or four hours
after the injury; the height of the count and the rapidity of the
onset of the leucocytosis corresponded in these experiments to the
severity of the visceral injuries inflicted. The same author found
but a trifling leucocytosis after bullet wounds of the abdomen with
intestinal perforation.
IV. LYMPHOCYTOSIS.
An increase, whether relative or absolute, in the lymphocytes
above the number normal in health is known as lymphocytosis.
The word mononucleosis also is used to denote this change. Rela-
tive lymphocytosis involves simply a gain in the percentage of
lymphocytes without a coincident increase in the total leucocyte
count. Absolute lymphocytosis, on the other hand, is character-
ized by an increase above normal both in the percentage of lympho-
cytes and in the total number of leucocytes. Barring lymphatic
leukemia, in which the lymphocytes are both relatively and abso-
lutely in excess, lymphocytosis is almost always a relative condi-
tion, or at least it is not accompanied by a decided rise in the
total leucocyte count.
The increase in the proportion of lymphocytes is moderate in
most instances, the greater number of differential counts showing
percentages of these cells ranging from 50 to 70, in comparison
with the maximum normal percentage, about 30. These figures,
of course, refer to the blood of adults, for in children the increase
1 De Rienzi and Boeni, Gaz. degli Ospedali e. d. Clin., 1898, vol. xix, p. 1570.
2 Hand, N. Y. Med. Jour., 1900, vol. Ixxi, p. 556.
3 Birk, "Das Fibrin-Ferment im lebenden Organismus," Dorpat, 1880.
4 Bojanus, "Exp. Beitrage z. Physiol. u. Pathol. d. Blutes," Dorpat, 1881.
5 Hankin and Kanthack, Centralbl. f. Bakt. u. Parasit, 1892, vol. xvii, p. 782.
* Buchner, Arch. f. Hyg., 1890, vol. x, p. 84. 7 Ibid.
8Sem. med., 1903, vol. xxiii, p. 351.
LYMPHOCYTOSIS. 253
is generally greater, owing to the higher proportion of lympho-
cytes normally found at this period of life. A differential count,
which shows, for instance, 60 per cent, of lymphocytes, means a
decided lymphocytosis in the adult, but is entirely within the
normal limits in the young infant. Either type of cells, large or
small, may predominate, or the change may not involve any con-
spicuous deviation from the normal ratio of one form to the other.
Frequently it happens that the two varieties possess such similar
characteristics that it is impossible to determine which prevails.
Occasionally the lymphocytosis depends largely upon unusually
large percentages of the so-called "transitional" forms, while in
other instances, notably in the lymphocytosis of von Jaksch's
anemia, rickets, syphilis, variola, and scarlatina, the increase
chiefly involves Ehrlich's large mononuclear forms, reputed to
originate in the marrow.
Lymphocytosis may be due either to changes in the distribu-
tion of the cells through the circulatory system, or to their in-
creased production and output by the lymphatic tissues. Ehr-
lich1 attributes lymphocytosis to the local irritation of certain
areas of lymphatic glands which produces an increased circulatory
activity in these situations, in consequence of which large numbers
of lymph elements are swept mechanically from the lymphatics
and enter the general circulation. He does not regard the change
as an expression of an active chemotactic reaction, to which the
lymphocytes are insensible. It also appears reasonable to pre-
sume that the lymphocytosis which often accompanies leucopenia
may be traced to still another factor, that of negative chemotaxis,
which diminishes the number of polynuclear neutrophiles and
thus brings about a relative increase in the lymphatic elements,
upon which the repellent action is not exerted.
Lymphocytosis has been observed in a number of pathological
conditions, but its presence may be considered physiological in
but a single instance — in the blood of infants and young, ctiildren,
in whom such a change is entirely normal. During the decline
of life, on the other hand, the lymphocytes are relatively dimin-
ished. This tendency toward a lymphocytic increase in infantile
life, which becomes less notable as the child matures, is prone to
become markedly exaggerated in many of the forms of secondary
anemia from which children suffer, especially the anemias second-
ary to syphilis, tuberculosis, rachitis, gastro-enteritis, and scurvy;
less commonly, it has been observed in the acute infections.
Lactation, conditions of cachexia, and great debility in the
adult are in many instances accompanied by abnormally high per-
1 Loc. cit.
254 THE LEUCOCYTES.
centages of lymphocytes in the blood. It is a well-known fact
that differential counts show a higher percentage of mononuclear
non-granular elements in the blood of the enfeebled and poorly
nourished than in that of the active and vigorous individual.
Similar changes are frequently associated with the terminal
stages 0} a number 0} diseases, and may be found ajter hemorrhage
from various causes — trauma, hemophilia, purpura, and following
splenectomy.
Lymphocytosis, sometimes decidedly marked, is common in
certain of the severe anemias, especially in chlorosis, pernicious
anemia, Addison's disease, and in syphilitic and tuberculous
secondary anemias; it may be observed in certain of the injections,
such as enteric fever, malarial fever, Malta fever, scarlet fever,
measles, diphtheria, pertussis, variola, phthisis, pneumonia,
plague, and trypanosomiasis. A high degree of lymphocytosis
has been reported by Labbe and Bernard1 in tropical hemato-
chyluria resulting from filariasis. Roger's contention,2 that in-
fections characterized by lymphocytosis are of protozoan type,
is scarcely tenable, in view of the occurrence of this change in
enteric fever, in Malta fever, and in tuberculosis, to name but
three bacterial infections in which the lymphocytes are increased.
Diseases involving the spleen and lymphatic glands are often the
cause of a varying degree of increase in the lymphocytes, common
examples of such conditions being chronic malarial splenic tumors ;
kala-azar; simple, syphilitic, and tuberculous adenitis; and ma-
lignant neoplasms, especially sarcoma, of the lymph glands. On
the contrary, extreme decrease in the lymphocytes develops in
consequence of obliteration of the lymph channels by malignant
tumors. Enlargement of the thyroid gland relatively increases the
lymphocytes, as does that systemic taint known as the constitutio
lymphatica. Chloroma may provoke high absolute lymphocytosis.
Distinct lymphocytosis has been observed by Wilkinson3 after
the injection of quinin hydrochlorate; and by Perry4 and Lepine5
as the result of the administration of thyroid extract. It also follows
the injection of tuberculin, pilocarpin, and emulsion of cancerous
tissue.
From a clinical viewpoint lymphocytosis is of value chiefly in
the diagnosis of lymphatic leukemia. Marked absolute increase
in the number of lymphocytes, associated with enlargement of the
lymphatic glands, forms a pathognomonic picture of this disease.
1 Sem. me"d., 1902, vol. xxii, p. 433.
J "Infectious Diseases," Eng. trans, by Gabriel, New York and Philadelphia,
1903.
1 Loc. cit. 4 Med. Record, 1896, vol. 1, p. 289.
8 Sem. med., 1902, vol. xxii, p. 409.
EOSINOPHILIA. 255
The recognition of a doubtful case of syphilis may be facilitated
by the occurrence of lymphocytosis plus eosinophilia.
V. EOSINOPHILIA.
The term eosinophilia is used to denote an increase above the
normal standard in the number of eosinophiles in the circulating
blood, this change usually, but not necessarily, being associated
with a coincident increase in the relative percentage of these cells
to the other forms of leucocytes. Thus interpreted, eosinophilia
is a condition of absolute increase, in contradistinction to a purely
relative gain in percentage, to which the term is not strictly appli-
cable.
For the sake of uniformity it is customary to speak of the per-
centage of eosinophiles rather than of their actual number, but
in order to determine accurately the presence or absence of eosino-
philia it is also essential in every instance to calculate the number
of eosinophiles to the c.mm. of blood from data obtained by a
numerical estimate and a differential count of the leucocytes,
thus:
Total number oj leu- .. Percentage of eosinophiles to Total number of eosin-
cocytes per c.mm. other forms of leucocytes. ophiles per c.mm.
The necessity for such a calculation is forcibly illustrated in
myelogenous leukemia, since in this condition the ' relative per-
centage of eosinophiles is often well within the normal limits,
and yet a striking degree of eosinophilia may exist. Eor example,
in a given case of this form of leukemia, the blood count shows
300,000 leucocytes per c.mm. with 5 per cent, of eosinophiles.
This percentage, interpreted into the actual number of cells,
means an eosinophilia of 15,000 per c.mm., or an increase of
thirty-fold in excess of the highest normal figure.
On the basis of a variation in the normal number of leucocytes
of from 5000 .to 10,000 per c.mm., the absolute number of eosino-
philes may range from 25 to 500 per c.mm. in the blood of the
healthy adult. An increase in excess of this maximum standard,
regardless 0} the percentage indicated by the differential count, con-
stitutes eosinophilia.
Granting the accuracy of the current view that the hemic
eosinophiles are purely myelogenous elements, their increase in
the blood may be attributed to the influence of chemotaxis, prob-
ably of a specific and selective character. Under the influence of
such a stimulus the eosinophiles are attracted from, and perhaps
overproduced by, the bone marrow, and are thrown into the gen-
256 THE LEUCOCYTES.
eral circulation in large numbers. It is also possible that to a
slight extent their proliferation from like cells may occur in the
blood stream as well.
Increase in the number of eosinophiles occurs as a physiolog-
ical change in young infants, in women during the menstrual period,
and after coitus. With these three exceptions the presence of
eosinophilia is always to be regarded as an evidence of some
pathological condition.
Once believed to be a pathognomonic sign of leukemia, in the
light of more recent investigations eosinophilia is now known to
be associated with diseases of almost every conceivable nature;
in fact, it has been reported in so large a number of conditions
of such widely dissimilar pathogenesis that its value as a clinical
sign must be largely restricted. Inasmuch as many of these re-
ported instances of eosinophile increase lack verification, it can
only prove confusing to give here a list of the many pathological
states in which the change is reputed to have been observed.
The following list, based upon the work of Cannon,1 Zappert,2
Gollasch,3 T. R. Brown,4 von Noorden,5 and others, includes only
those diseases in which eosinophilia is observed with a great de-
gree of constancy. Such conditions are:
I. Diseases of the Skin.
Dermatitis herpetiformis. Pellagra.
Eczema. Pemphigus.
Erythema multiforme. Prurigo.
Herpes zoster. Psoriasis.
Leprosy. Scleroderma.
Lupus. Urticaria.
II. Helminthiasis.
Ankylostomiasis. Oxyuridiasis.
Ascariasis. Strongyloides intestinalis infection.
Bilharziasis. Teniasis.
Filariasis. Trichiniasis.
Hydatid disease.
III. Diseases of the Bones.
Hypertrophy. Multiple periostitis.
Malignant neoplasms. Osteomalacia.
1 Deutsch. med. Wochenschr., 1892, vol. xviii, p. 206.
2 Zeitschr. f. klin. Med., 1893, vol. xxiii, p. 227; also Wien. k!in. Wochenschr.,
1892, vol. v, p. 347.
3 Fortschr. d. Med., 1889, vol. vii, p. 361.
4 Johns Hopkins Hosp. Bull., 1897, vol. viii, p. 79.
5 Zeitschr. f. klin. Med., 1892, vol. xx, p. 98.
EOSINOPHILIA. 257
IV. Post-febrile.
Malarial fever. Scarlet fever.
Pneumonia. Septicemia.
Rheumatic fever. Varicella.
V. Bronchial Asthma.
VI. Myelogenous Leukemia.
In addition to the conditions listed above, eosinophilia also
occurs, but with less constancy, in some forms of the high-grade
secondary anemia of childhood, purpura, hemorrhagic effusions,
gonorrhea, syphilis, malignant disease, and in fibrinous bron-
chitis. It is also seen in many cases of splenomegaly and after
splenectomy, its development under the latter circumstance
being regarded as a compensatory condition. An increase in
the percentage of eosinophiles has also been noted in conditions of
starvation. In scarlet fever the eosinophiles usually persist, in
spite of the coexisting polynuclear leucocytosis, and the same
peculiarity may often be found in trichiniasis, filariasis, hydatid
disease, and infection with intestinal parasites.
Eosinophilia may be produced experimentally by the injection
of a number of medicaments, such as antipyrin, camphor, nu-
clein, phosphorus, pilocarpin, tuberculin, and many of the iron
salts. T. R. Brown1 found high eosinophilia (12 per cent, in a
leucocyte count of 30,000) in acetanilid poisoning. The writer
detected eosinophilia in 3 cases of poisoning by nitrites. >
Neusser2 and his school have contended that eosinophilia is
symptomatic of an extensive group of diseases, chiefly . those in-
volving the sympathetic nervous system, the sexual organs, and a
long list of disorders which they attributed to the "xanthin dia-
thesis." Most of these views have been unsubstantiated, many
are misleading, and a few can be shown to be fanciful. .TRose
who are inclined to investigate some of the remarkable claims
made by Neusser as to the diagnostic and prognostic value of
eosinophilia are referred to his original communication on the
subject.
Diminution in the number of eosinophiles occurs as a physiolog-
ical process during digestion and after active muscular exercise.
It is observed usually in lymphatic leukemia, tuberculosis, during
the febrile stages of diphtheria, influenza, pneumonia, enteric fever,
and septicemia, frequently after hemorrhage, and in the terminal
1 Md. Med. Jour., 1902, vol. xlv, p. 307.
2 Wien. klin. Wochenschr., 1894, vol. vii, p. 737.
17
258 THE LEUCOCYTES.
stages of many diseases. The number of eosinophiles is said to be
diminished ajter castration. The writer has found a decrease or
even absence of eosinophiles in the majority of cases of chlorosis
and pernicious anemia.
The chief clinical value attached to eosinophilia relates to its
presence in trichiniasis, in filariasis, in intestinal helminthiasis,
and in hydatid disease, in which infections it has been shown to
be a sign of great reliability. It may, however, be absent in the
later stages of these infections.
In the diagnosis of an exanthema which is suggestive either of
scarlet fever or -of measles, eosinophilia points to the former dis-
ease, for it does not occur in the latter.
The association of eosinophilia and lymphocytosis constitutes a
blood change which may be helpful in the recognition of an ob-
scure case of syphilis.
High percentages of eosinophiles in chlorosis, in pernicious
anemia, and after hemorrhage are generally regarded as an evi-
dence of good regenerative powers of the hemogenic organs, and
are therefore of favorable import (Rieder).1
VI. BASOPHILIA.
Increase in the number of basophiles in the circulating blood
is of rare occurrence, having been observed in but few diseases
except the myelogenous variety of leukemia, in which this change
is quite constant, and sometimes most striking; the basophiles in
this disease may constitute 10, 20, or even 30 per cent, of all
forms of leucocytes. The increase may involve the finely
granular or the coarsely granular (mast cell) forms, or both.
Until recently but little attention has been paid by hematolo-
gists to the general circulatory form of basophilia, although the
local increase of the basophiles under various conditions has been
well investigated. Canon2 has reported an increase of the mast
cells in a case of chlorosis and in various skin diseases. Sherring-
ton3 has observed a similar blood change in patients dying in the
reaction stage of Asiatic cholera. A. E. Taylor4 states that he has
seen a notable circulatory basophilia in a case of carcinoma, with
marked cachexia, but without bone metastases; in a case of
gonorrhea; in a case of mycosis fungoides; and in two cases of
septic bone disease. Basophilia has also been observed in variola,
1 Loc. cit. * Deutsch. med. Wochenschr., 1892, vol. xviii, p. 206.
3 Proc. Roy. Soc., London, 1894, vol. Iv, p. 189.
4 "Contributions from the William Pepper Laboratory of Clinical Medicine,"
Philadelphia, 1900, p. 148.
MYELEMIA. 259
splenic anemia, Hanoi's cirrhosis, and in hydatid disease and other
forms of helminthiasis. The writer found a mast cell basophilia
of 2 per cent., with a leucocytosis of 13,0x20, in a case of plumbism,
and has noted large numbers of mast cells in suppurative appen-
dicitis, pernicious anemia, filariasis, and trichiniasis.
Owing to our imperfect understanding of this condition no
theory regarding the production of basophilia is as yet generally
acceptable. It is possibly due to the influence of a specific chemo-
tactic substance, in response to which the basophiles are attracted
from the bone marrow and enter the general circulation.
VII. MYELEMIA.
The presence in the circulating blood of myelocytes, in small
or in large numbers, is known as myelemia. As previously re-
marked, this condition is invariably to be regarded as patholog-
ical, since myelocytes are never found in the blood of the normal
individual.
The most striking example of myelemia is to be found in
the myelogenous form of leukemia, in which condition this
change constitutes one of the most conspicuous features of the
blood picture. Myelocytes occur in the blood in this disease in
greater absolute and relative numbers and with greater constancy
than in any other condition — a fact which is of the greatest diag-
nostic value. The degree of increase may be enormous, as illus-
trated by a case of the author's, in which the actual .number of
myelocytes was found to be 192,738 per c.mm., or 27.3 per cent,
of all forms of cells in a total leucocyte count of 706,000. In
instances of splenomegaly with anemia and moderate leucocytosis
small numbers of myelocytes have been reported as a constant
finding by Emile Weil and Clerc.1 Kurpjuweit,2 in malignant dis-
ease with bone metastases, found as high as 17 per cent, of mye-
locytes, and he regards this myelemia as a sign of gravely altered
hemogenesis. (See " Malignant Disease.") Von Jaksch3 noted
marked myelemia in his symptom-complex, termed multiple peri-
ostitis with myelocythemia.
Less frequently myelocytes are observed in lymphatic leu-
kemia and in Hodgkin's disease, but in these conditions their
occurrence is inconstant and their increase trivial. Small num-
bers of myelocytes (from 0.5 to 2 or 3 per cent.) are found in
1 Arch. gen. de Med., 1902, vol. cxc, p. 560.
2 Deutsch. Arch. f. klin. Med., 1903, vol. Ixxvii, p. 553.
3 Zeitschr. f. Heilk., 1901, vol. xxii, p. 259.
200 THE LEUCOCYTES.
almost every case of primary pernicious anemia, and are not un-
common in marked cases of chlorosis and in many of the severe
forms of secondary anemia due to various causes. They are fre-
quently met with in such conditions as pneumonia, septicemia,
diphtheria, syphilis, malignant disease, rachitis, tuberculosis, osteo-
myelitis, osteomalacia, Addison's disease, and the malarial fevers.
The writer has found them also in the following conditions: car-
bon monoxid poisoning, hepatic cirrhosis, acute gout, malignant
endocarditis, exophthalmic goiter, as well as in the above-named
affections. One is forcibly impressed with the almost constant
presence of myelocytes in the estivo-autumnal type of malarial
fever, in severe septic infections, and in enteric fever in childhood,
both in the early stages of the disease and during the later, post-
febrile anemic period. Small numbers of myelocytes have been
reported also in many other conditions, chiefly those associated
with leucocytosis, with anemia, or with both.
Increased activity of the bone marrow, whereby the myelocytes
are forced into the blood stream, is in all probability responsible
for the production of myelemia. In response to an increased
demand for leucocytes the marrow becomes so overstimulated
that many immature forms of leucocytes, or myelocytes, acciden-
tally find their way into the general circulation, their passage from
the marrow no doubt being accomplished largely by emigration.
It is furthermore now believed that substances which are posi-
tively chemotactic for the polynuclear neutrophiles also exert a
similar attractive influence upon their immediate precursors, the
myelocytes, stimulating their increased proliferation in the bone
marrow and exciting their emigration from this tissue into the
blood stream.
VIII. LEUCOPENIA.
Decrease below the normal standard in the number of leuco-
cytes in the peripheral blood is known as leucopenia or hypoleuco-
cytosis. Such a condition, like its antithesis, leucocytosis, may be
the result of either physiological or pathological causes. Owing
to the variation in the normal number of leucocytes in different
individuals, it is difficult to determine arbitrarily just what degree
of decrease may be considered as a leucopenia, but it is safe to
apply the term to any leucocyte count decidedly below 5000 cells
to the c.mm. The number of leucocytes is rarely reduced to
less than 3000, except in certain of the essential anemias, in
which their decline to one-tenth the maximum normal figure
or even less is occasionally to be observed. The most extreme
LEUCOPENIA. 26l
instance of leucopenia on record has been reported by Koblanck,1
who found but a single leucocyte in a careful search through
twenty stained cover-glass preparations of blood from a man of
twenty-five years, suffering from epilepsy; the exact numerical
estimate of the leucocytes in this case is not given in detail.
The decrease may be accompanied by no deviation from the
normal percentages of the different varieties of leucocytes, or it
may involve a more or less decided gain in the lymphocytes, the
latter being the more common change of the two.
According to the nature of its underlying causes, leucopenia may
be considered clinically as either physiological or pathological.
PHYSIOLOGICAL LEUCOPENIA.
The decrease in the number of leucocytes observed in several
physiological states is generally attributed to vasomotor influ-
ences which produce changes in the distribution of the leucocytes
throughout the system. Such changes occur from the effect of
prolonged cold, and brief hot, baths.2 Decastelle3 has found that
a temporary leucopenia may be produced experimentally, by stim-
ulation of sensory nerves, this procedure causing a reflex con-
traction of the abdominal vessels and a consequent retention of
large numbers of circulating leucocytes in this part of the vascu-
lar system. The variations in the number of cells range from
20 to 30 per cent, of the original count; the maximum decrease
occurs usually within three or four minutes, and in most instances
does not persist longer than ten or fifteen minutes. Reduction
of blood pressure is promptly followed by a very transient* diminu-
tion in the leucocytes of the peripheral blood.
Malnutrition and starvation are also potent factors in the pro-
duction of leucopenia, the decrease dependent upon such causes
frequently being most pronounced. The much-cited case of the
faster, Succi, is a good example of the effects produced upon the
leucocytes by abstinence from food. Luciani4 found in the blood
of this individual a decrease in the number of leucocytes from
14,530 to 861 per c.mm. after a seven days' fast; on the eighth
day an increase to 1530 occurred, this being the average count
noted during the remaining twenty-one days of the fast. The
subnormal leucocyte counts which are often met with in many
of the infirm and the greatly enfeebled can be traced to the effects
of faulty nutrition and to the malassimilation of food.
1 Inaug. Dissert., Berlin, 1889. l Winternitz, loc. cit.
3 Wien. klin. Wochenschr., 1899, vol. xii, p. 395.
4 " Das Hungern" (German translation by O. Frankel), Hamburg and Leipsic,
1890.
262 THE LEUCOCYTES.
PATHOLOGICAL LEUCOPENIA.
Leucopenia, or at least an absence of leucocytosis, occurs dur-
ing the course of a number of general infectious diseases, promi-
nent among which are the following: enteric fever, paratyphoid
fever, measles, rotheln, influenza, leprosy, Malta fever, the malarial
fevers, trypanosomiasis, and non-septic tuberculosis. In acute
infections which are ordinarily accompanied by leucocytosis the
combined influences of an intense infection and feeble resisting
powers on the part of the individual may produce a distinct
leucopenia, or may prevent the development of the characteristic
increase. This is well illustrated by the low counts which some-
times are found in severe cases of pneumonia and of appendicitis.
Leucopenia, often pronounced, is not uncommon in chlorosis
and in pernicious anemia, being much more frequent and more
decided in the latter disease. A well-marked leucopenia may be
expected in about one-fourth of all cases of chlorosis, and in
quite three-fourths of cases of pernicious anemia. It is also often
met with in some high-grade secondary anemias, notably in those
due to syphilis and to rachitis, and in splenic anemia.
D'Orlandi1 has called attention to the frequency with which
leucopenia is observed in certain of the severer forms of chronic
gastro-enteritis in young infants. In a fatal case of primary
infectious pharyngitis reported by P. K. Brown,2 the leucocytes
never numbered more than 400 to the c.mm.
In the anemias accompanied by a decrease in the leucocytes,,
especially in primary pernicious anemia, the rule holds good that
the more intense the oligocythemia and oligochromemia, the
greater the degree of leucopenia. Ehrlich3 attributes the de-
crease in such cases to a lessened proliferative function of the
bone marrow, in consequence of which there is a diminution in
the output of leucocytes by this organ.
In leukemia an acute intercurrent infection may produce an
abrupt and marked fall in the number of leucocytes, as in Cabot's
remarkable case of lymphatic leukemia,4 in which, as the conse-
quence of a fatal septicemia, the leucocytes fell in three weeks
from 40,000 to 419 per c.mm.
Decrease in the number of leucocytes may be caused experi-
mentally by the administration of various drugs and other sub-
stances. Bohland5 found that it followed the injection of ergoty
sulphonal, tannic acid, camphoric acid, atropin, agaricin, and
1 Rev. mensuelle des malad. de PEnfance, 1899, vol. xvii, p. 300.
1 Amer. Med., 1902, vol. iii, p. 649. 3 Loc. cit.
4 Loc. cit. 5 Loc. cit.
LEUCOPENIA. 263
picrotoxin. DelezeneV investigations showed that a marked
decrease results from the injection of various anticoagulant sub-
stances, such as peptone, diastase, and eel serum; he attributes
the leucopenia thus produced to two factors — actual destruction
in the circulation of some of the leucocytes and dilatation of the
blood vessels, in which the undestroyed cells tend to accumulate.
The transient leucopenia which precedes an increase in the
leucocytes has been discussed elsewhere. (See p. 239.)
O. K. Williamson2 has shown that an increased destruction
of leucocytes is attended by an increased excretion of uric acid in
the urine. His studies apparently prove that in cases in which
a rise in the phosphoric acid curve follows a fall in the leucocyte
curve and in the number of granular cells especially, this rise
corresponds with a rise in the uric acid curve.
1 Nouveaux Montpel. med., 1898, vol. vii, pp. 694, 733, 765, and 789.
3 Lancet, 1903, vol. i, p. 657.
SECTION V.
DISEASES OF THE BLOOD.
SECTION V.
DISEASES OF THE BLOOD.
I. CHLOROSIS.
Lorrain Smith,1 by his carbonic oxid method,
GENERAL estimates that the total volume of blood is greatly
FEATURES, increased in chlorosis, this excess being due to an
increase in the bulk of normal plasma, and being
more marked the severer the case. Taking the normal blood
volume as 3240 c.c., Smith found in 21 chlorotics an average of
4883 c.c. Although the oxygen capacity of a blood unit is dimin-
ished about one-half, the total oxygen capacity of the blood remains
approximately normal — 95 per cent. Lloyd Jones 2 also believes
in a plasma increase in chlorosis, but further confirmation of the
above experimental work is needed before this presumption can
be registered as a fact.
The proportion of dry residue of the whole blood is-subnormal,
approximating in the severe case between one-half and one-third
the normal amount, with a corresponding increase in water.
There is a decided loss of blood albumin, mainly referable to
the oligochromemia, but, as Biernacki 3 has pointed out, also due,
at least in severe cases, to a deficiency in the amount of serum
albumin. In high-grade chlorosis this author found that the
dry residue of the whole blood might contain a normal iron con-
tent, the inference being that in such instances the albumin .loss
was not always confined to the hemoglobin.
The blood drop is exceedingly pale and
APPEARANCE watery-looking, and flows so abundantly from the
OF THE puncture that it actually seems as if the whole
FRESH BLOOD, mass of blood in the body must be increased; a
large -sized drop usually follows the slightest prick
of the needle, in spite of the obviously anemic appearance of the
patient — a marked contrast to the difficulty commonly experi-
enced in pernicious anemia of obtaining enough blood for the
1 Jour. Physiol., 1900, vol. xxv, p. 6. 2 "Chlorosis," London, 1897, p. 24.
3 Zeitschr. f. klin. Med., 1894, vol. xxiv, p. 500.
267
268 DISEASES OF THE BLOOD.
examination. The blood spread out in a film over the finger is
transparent rather than opaque, and its fluidity is most striking.
Microscopical examination of the fresh film shows excessive
pallor of most of the erythrocytes, together with the presence of
a variable number of cells of smaller diameter than normal, in
the average case, and of cells decidedly deformed in shape, in
severe cases. The resistance of the erythrocytes, as shown by
their hypotonicity,1 is increased. The practised observer can
determine at first glance that the number of erythrocytes is not
greatly decreased, except in an occasional case in which the
oligocythemia may be so marked as to lead him to infer that he is
dealing with a well-defined secondary anemia.
Coagulation of the blood drop, in spite of the
COAGULATION, fact that hyperinosis is absent, is generally very
rapid in chlorosis — often so rapid as to interfere
with the technic of the examination, if one delays during this
procedure.
The specific gravity of the whole blood is more
SPECIFIC or less diminished, the degree of decrease being
GRAVITY, closely parallel with the loss of hemoglobin.
Lloyd Jones,2 who has made elaborate researches
concerning this subject, believes that chlorotic blood exhibits an
exaggeration of the fall in specific gravity which occurs in healthy
girls at about the age of puberty. In the 36 cases studied by
this author the specific gravity ranged from 1.030 to 1.049, these
figures corresponding to 17 and 58 per cent, of hemoglobin, re-
spectively, as estimated by the von Fleischl hemometer. In 30
cases Hammerschlag 3 found that the density of the whole blood
averaged 1.045, and of the serum, 1.030.
Most observers maintain that in this dis-
ALKALINITY. ease the alkalinity of the whole blood generally
remains normal, or suffers but a trifling diminu-
tion, this being in direct contrast to the condition found in other
forms of anemia, in which the fall in the alkalinity figure is usually
pronounced. Burmin,4 in 18 examinations of 9 cases, found that
it ranged between 128 and 200 mgm. NaOH, the normal figures
of this investigator being 182 to 218 mgm. In 6 of these cases
the administration of iron was followed by a marked increase in
the alkalinity of the blood, closely paralleling the gain in hemo-
globin and erythrocytes. On the other hand, Graeber 5 states that
1 Von Limbeck, loc. cit.
2 Loc. cit. 3 Wien. med. Presse, 1894, vol. xliv, p. 1068.
4 Zeitschr. f. klin. Med., 1900, vol. xxxix, p. 365.
6 "Zur klin. Diag. d. Blutkrankheit.," Leipsic, 1890, p. 289.
CHLOROSIS.
269
in many cases he discovered abnormally high alkalinity figures,
so constantly, indeed, that he regarded them as "specific for this
condition." Funke's studies, reported by Dare,1 show that the
alkalinity is diminished, and that it closely corresponds to the
color index.
The decrease in the percentage of hemoglobin
HEMOGLOBIN is usually excessive in comparison with the re-
AND duction in the number of erythrocytes, this dis-
ERYTHROCYTES. proportionate oligochromemia being the most
conspicuous and most constant feature of the
changes affecting chlorotic blood. Naturally, such a change
gives rise to very low color indices. This statement applies only
to the majority of cases, for a low
color index, while it is the rule
in chlorosis, and is, diagnostic-
ally, a most important feature of
the blood picture, is by no means
invariably found — no more in-
variably than a high color index
in pernicious anemia. To illus-
trate this point, of 106 consecu-
tive cases of chlorosis studied by
the author, 49, or more than 46
per cent., showed an index below
0.50, the average for the series
being 0.51, the maximum i.oi,
and the minimum 0.22.
The average loss of hemo-
globin, as evidenced by the 155
cases tabulated below, amounts
to about 53 per cent., in contrast
to which stands the mean average erythrocyte decrease, which is
equivalent to about 23 per cent., the hemoglobin loss thus averag-
ing about two-and-one-half times that of the corpuscles. Indi'
vidually, the hemoglobin percentage ranged in these cases from
12 to 87, averaging 46.8, and the count of erythrocytes from
1,720,000 to 5,600,000, averaging 3,816,486. On account of
their rather close correspondence, it is interesting to compare
with these figures the results obtained by Cabot 2 in 109 cases
and those of Thayer3 for 63 cases. Cabot's cases gave the
following mean averages: hemoglobin, 41.2 per cent.; erythro-
1 Johns Hopkins Hosp. Bull., 1903, vol. xiv, p. 179. * Loc. cit.
3 Cited by Osier, "American Text-book of Theory and Practice of Medicine,"
Philadelphia, 1894, vol. ii, p. 196.
FIG. 51. — CHANGES IN THE ERYTHROCYTES
IN CHLOROSIS (TRIAQID STAIN).
Showing a general decrease in the diam-
eter of the corpuscles, striking decolorization.
and moderate poikilocytosis. The nucleated
cell near the center of the. field is a normo-
blast.
270 DISEASES OF THE BLOOD.
cytes, 4,112,000, with individual counts ranging from 1,932,000
to 7,100,000. In Thayer's series the hemoglobin averaged 42.3
per cent, and the erythrocyte count 4,096,544. Somewhat lower
figures are given by Bramwell,1 who found the following averages
in a series of 80 cases : hemoglobin, 34 per cent., or from 10 to 60
per cent.; erythrocytes, 3,437,300, or from 1,425,000 to 5,200,000
per c.mm.; and color index, 0.49, or from 0.20 to 0.96.
While numerous examples may be found of typical cases of
chlorosis in which the hemoglobin estimate and erythrocyte count
resemble those commonly occurring in pernicious anemia or in
the secondary anemias, nothing is more characteristic of chlorosis
than the averages above mentioned. The great difference is
between chlorosis and pernicious anemia, the index usually being
high and the corpuscular loss extreme in the latter disease. As
compared with the secondary anemias, the difference is too slight
and its occurrence too inconstant to enable one to regard it with
any degree of certainty from a clinical standpoint. Theoretically,
in secondary anemia the hemoglobin loss is fairly proportionate
to the erythrocyte decrease, thus producing color indices at or
somewhat below the normal, but cases of secondary anemia having
a so-called "chlorotic" type of blood are far too common to render
any information reliable gained by a simple inquiry into the
changes affecting the erythrocytes and their hemoglobin content.
TABLE I.— HEMOGLOBIN AND ERYTHROCYTES IN 155 CASES OF
CHLOROSIS.
HEMOGLOBIN NUMBER OF ERYTHROCYTES NUMBER OF
PERCENTAGE. CASES. PER C.MM. CASES.
From 80-90 5 Above 5,000,000 13
7°~°° IJ From 4,000,000-5,000,000 63
00-70 17
50_6o ' 3,000,000-4,000,000 49
40-50 '.'.'.'.'.'.'.'.'.'.'.'.'.'.'. 24 " 2,000,000-3,000,000 28
30-40 25 " I,OOO,000-2,OOO,OOO 2
20-30 28
IO-2O IO
Average, 46.8 per cent. Average, 3,816,486 per c.mm.
Maximum, 87.0 " " Maximum, 5,600,000 " "
Minimum, 12.0 " " Minimum, 1,720,000 " "
The most conspicuous change to be observed in the stained
film of chlorotic blood is the presence of large numbers of under-
sized, pale erythrocytes, such cells usually being so numerous
that one is forcibly impressed with the fact that there must be a
general decrease in the average diameter of all the erythrocytes
in the field. As a rule, this decrease in size involves a large
number of corpuscles moderately, rather than a few to an ex.
1 "Anemia," London, 1899, p. 35.
CHLOROSIS. 271
treme degree, and therefore, except in severe cases associated
with marked oligocythemia, striking examples of microcytosis are
wanting. This alteration is just the opposite of what is generally
found in pernicious anemia, for in this disease a tendency to-
ward an increase in the average diameter of the erythrocytes,
frequently in association with the presence of many extremely
small microcytes, is the rule. If well denned, this feature of the
blood changes carries a certain amount of diagnostic significance,
although it cannot be distinguished in every case of chlorosis,
since in some the diameter of the erythrocytes appears to be un-
altered, while in others the deformities of size may so affect the cells
that the blood picture resembles that of a severe secondary anemia.
The pallor of the erythrocytes, shown by their feeble reaction
toward the plasma stain, is at once apparent. The great majority
of the cells are affected alike, being pale, often quite colorless in
the center, and gradually becoming of darker color toward the
periphery, in which a certain amount of hemoglobin still remains.
This portion of the cell is usually well stained, so that the cor-
puscles frequently appear as hoops or rings; some, however, do
not show even this narrow hemoglobin-filled zone, being practi-
cally decolorized throughout. Stroma degeneration, as shown by
the changes described by Maragliano, is not demonstrable in the
average case of moderate severity, but this process has been ob-
served in occasional cases of high grade. Polychromatophilia,
except in cases of the latter class, does not occur.
Basophilie granulations in the erythrocytes are not present in
this condition, according to Grawitz,1 a finding which 'the author
has substantiated.2 Stengel,3 on the contrary, found them in u of
1 8 chlorotics.
Deformities of shape are not noticeable, as a rule, except in
the severer types of the disorder. In such cases, in which both
the hemoglobin and the cellular losses are excessive, ppikilo-
cytosis may be very striking — as great, in fact, as in any blood
disease, not excepting pernicious anemia. Poikilocytes, should
they occur, are almost invariably of small size.
Nucleated erythrocytes are very rare. In the average case
they are usually sought for in vain, and even in the severer forms
of chlorosis these cells are not numerous. Erythroblasts con-
forming to the normoblastic type are found almost exclusively;
megaloblasts, although they are seen now and then, are extremely
uncommon, and have never been found in a large relative or
absolute proportion to the other form of nucleated erythrocytes.
1 Loc. cit. * Amer. Med., 1903, vol. v, p. 571.
3 Amer. Jour. Med. Sci., 1902, vol. cxxii, p. 873.
272 DISEASES OF THE BLOOD.
TABLE II.— NUMBER OF LEUCOCYTES IN 155 CASES OF
CHLOROSIS.
LEUCOCYTES NUMBER OF
PER C.MM. CASES.
Above 20,000 i
From 15,000-20,000 3
" 10,000-15,000 14
" 5,000-10,000 104
Below 5,000 33
Average, 6,457 per c. mm.
Maximum, 21,000 " "
Minimum, 800 " "
The number of leucocytes per c.mm. is,
LEUCOCYTES, as a rule, normal in the typical case of chloro-
sis. If leucocytosis occurs, as it does occasion-
ally, it should be attributed to some hidden or frank complication ;
if leucopenia exists, as it sometimes does, it may nearly always
be regarded as a sign of the severity of the disease, since it is
rarely met with except in cases in which the hemoglobin and ery-
throcyte losses are decidedly marked. The mean average number
of leucocytes in the 155 cases of chlorosis to which reference has
already been made (Table II) is 6457 per c.mm., or approximately
the same as the average count of these cells in normal blood.
Counts as low as 800 and as high as 21,000 were made in this series ;
and in 18 of the cases (or n.6 per cent.) the increase was suf-
ficiently in excess of the normal standard to justify the application
of the term leucocytosis — that is, it was in excess of 10,000. These
figures do not differ materially from those of Cabot and of Thayer,
alluded to above, Cabot's counts in 104 cases averaging 7400, and
Thayer's estimates in 63 cases being but slightly higher — 7485.
Relative lymphocytosis, usually marked in relation to the se-
verity of the case, is a common, but not a constant, qualitative
change. It occurs in both mild and severe cases, but is much
more common in the latter. In the author's experience this in-
crease involves chiefly the larger forms of these cells, both the
non-granular mononuclear cells with spherical nuclei and the so-
called "transitional" forms with indented nuclei; striking in-
crease in the last-named variety of cells was a notable differential
change in a large proportion of the 37 cases listed in Table III.
In many of the cases in this series the large and small lympho-
cytes together made up from 45 to as high as 67.5 per cent, of
all varieties of leucocytes, the percentage of large forms being
repeatedly estimated at 20 or 30, and even 40, in one instance.
Deviations from normal in the relative percentage of polynu-
clear neutrophiles are governed by the behavior of the lympho-
cytes, low differential counts of the former type of cells accom-
CHLOROSIS.
273
panying high percentages of the latter, and vice versa. Should
leucocytosis exist, it is of the pure polynuclear neutrophile type.
The eosinophiles are notably decreased, both absolutely and
relatively. The author has never found an increase of these cells
in chlorosis, although considerable pains were taken to verify the
statements made by some writers that this variety of leucocytes
is occasionally observed to be greatly above normal in this con-
dition. Eosinophiles were absent entirely in more than seven-
tenths of all the cases collected in Table III, and were never found
to exceed two per cent, of all the forms of leucocytes.
TABLE III.— QUALITATIVE CHANGES IN THE LEUCOCYTES IN
37 CASES OF CHLOROSIS AT THE FIRST EXAMINATION.
CASE No.
SMALL LYMPHO-
CYTES.
LARGE LYMPHO-
CYTES.
POLYNUCLEAR
NEUTROPHILES.
EOSINOPHILES.
MYEL-
OCYTES.
i
16.0
6.0
76.0
2.0
0
2
n. o 3.0
85-5
0-5
o
3
20.0 3.5
75-o
1-5
o
4
25.0 3.0
72.0
o.o
0
5
19.5 20.5
60.0
o.o
o
6
22.5 15.0
62.5
0.0
o
7
20.5 19.0
60.5
o.o
0
8
32.2 17.8
50-0
o.o
0
9
25.5 16.0
57-5
I.O
0
10
18.5 12.0
69-5
o.o
o
ii
18.0 10.0
72.0
0.0
0
12
17.0 21.5
61.5
0.0
0
I3
19.5 17.0
63.0
°-5
o
M
22.0 14.5
63-5
o.o
0
15
7-5 12.4
80. i
0.0
0
16
19.3 21. I
59-6
o.o *
'' 0
i?
18.5 16.0
65-5
o.o
o
18
18.0 16.0
65.0
I.O
o
19
18.3 19.0
61.0
i-7
0
20
15-5 24.5
60.0
0.0
o
21
26.O 21. O
53-o
o.o
0
22
12.0 3O.O
58.0
o.o
o
23
13-5 12.5
73-5
o-5 o .
24
14.0 15.9
70.1
0.0 . O
25
17-5
14.0
68.5
o.o
0
26
15-0
17.0
68.0
O.O 0
27 20.5
ii-5
68 . o o . o o
28
20-3
12.7
67.0 o.o o
29
31.0
9-o
60.0
O.O 0
3°
35-9
6.0
58.0
O.I O
3i
24.0
2.O
74-o
o.o o
32
27-5
4O.O
32.0
o-5
o
33
26.0
15-0
56.0
I.O 2
34
24.0
26.O
50.0
O.O 0
35
22. 0
6.0
72.0
o.o o
36
24-5
14-5
61.0
0.0 0
37
6.0
32.0
59-o
o.o
3
Average: 20.1
IS-S
64.0
0.31
0.13
18
274
DISEASES OF THE BLOOD.
Color.
Coagulation.
Specific gravity.
Hemoglobin.
Erythrocytes.
Exceptionally, small percentages of myelocytes may be en-
countered, as a rule only in cases of a severe character. These
cells are ordinarily present in not more than six per cent, of all
cases, and their relative proportion to the other forms of leuco-
cytes is always trifling, being rarely over one or two per cent.
In the great majority of cases it has been gen-
BLOOD erally observed that the number of plaques is
PLAQUES. considerably in excess of normal. It appears
that these elements are especially numerous in
blood which clots rapidly.
The changes in the blood associated with the
DIAGNOSIS, well-defined case of chlorosis may be summarized
as follows :
Pale and watery.
Usually rapid.
Decreased.
Marked absolute decrease, in most instances
relatively greater than the loss of erythrocytes,
thus producing a low color index.
Moderately decreased, ordinarily to about
4,000,000 per c.mm. Counts of 3,000,000
or lower are common in severe cases. Ery-
throblasts very rare; if present, cells of the
normoblastic type invariably predominate.
General decrease in the average diameter of
the erythrocytes. In severe cases microcy-
tosis may be marked.
Poikilocytes not numerous, except in severe
cases.
Polychromatophilia rare.
Usually normal in number.
Relative lymphocytosis common.
Small percentages of myelocytes, only in severe
cases.
Eosinophiles notably decreased.
Increased in number.
He who attempts the diagnosis of chlorosis solely by the blood
examination is indeed a rash clinician. This point cannot be
emphasized too strongly, that there is no blood picture peculiar
to this condition, since changes precisely similar to those seen in
many a case of typical chlorosis are often observed in the secondary
anemias, especially in those dependent upon such factors as syph-
ilis, septicemia, malignant disease, and chronic renal lesions.
Futhermore, rare cases of chlorosis with typical symptoms
Leucocytes.
Plaques.
CHLOROSIS. 275
have been reported in which no alterations in the blood were
discoverable by ordinary clinical methods. In these cases, mis-
termed "pseudo-chlorosis," a diminished volume of plasma may
mask the blood impoverishment (Lloyd Jones1), or this oligo-
plasmia may be combined with both plasma and cellular hy-
dremia (Biernacki2), the dropsical erythrocytes being actually
deficient in hemoglobin, although the hemoglobin and erythrocyte
estimates of the whole blood remain normal.
The blood changes enumerated above (especially such features
as a low color index, the general decrease in the diameter of the
erythrocytes, the absence or scantiness of erythroblasts, and the
normal number of leucocytes associated with relative lymphocytosis
and a decrease of the eosinophiles) are not then, pathognomonic, but
simply highly suggestive of the disease under discussion, in view of
which fact it becomes essential to seek for other clinical signs
and to consider them carefully in connection with the blood find-
ings. One of the most important points which should be borne
in mind is the fact that chlorosis is practically confined to females,
usually those in early womanhood, at or near the period of puberty.
Chlorosis is about as compatible with the male sex as is pregnancy
— the so-called "male chlorosis" is nothing more than a diagnostic
myth. Osier3 remarks that in girls in whom the disease occurs
early in their teens precocity and almost premature appearance of
the menses are likely to exist. A large proportion of those in
whom the disease develops later in life complain of scantiness or
total suppression of the menstrual flow and of dysmenorrhea, these
symptoms being especially common in chlorotics in. the early
twenties or thereabouts.
The question of heredity also is of some diagnostic value, for
it has been frequently noted that the disease exists, for instance,
in two or more sisters, the statement being elicited upon further
inquiry that their mother suffered from chlorosis at an earlier
period. Thus, Allbutt 4 speaks of meeting in his consulting-room
the chlorotic daughters of women whom years before he had
treated for the same disorder.
Among the other manifestations of the disease to which atten-
tion should be paid the following are the more important : a pecu-
liar greenish-yellow color of the complexion and blanching of the
mucous membranes (except in those rare instances of chlorosis
florida, in which the color is high); the occurrence of various
gastro-intestinal disturbances, of edema of the face and lower
1 Loc. dt..
2 Zeitschr. f. klin. Med., 1894, vol. xxiv, p. 500. * Loc. cit.
4 "System of Medicine," London and New York, 1898, vol. vi, p. 483.
276 DISEASES OF THE BLOOD.
limbs, of vertiginous attacks, and of dyspnea upon physical exer-
tion; and the presence of systolic basic heart murmurs and a
venous hum most distinctly audible over the great vessels of the
neck. Slight enlargement of the thyroid gland, frequently asso-
ciated with Joffroy's sign (absence of horizontal wrinkling of the
skin of the forehead and of upward curving of the eyebrows when
the patient glances suddenly at the ceiling without elevating her
head), is a physical sign which should always make one suspicious
of chlorosis.
The distinctions between chlorosis and pernicious anemia, as
shown by the blood examination, will be described under the
latter disease. (See p. 289.)
II. PERNICIOUS ANEMIA.
Lorrain Smith's experiments1 argue a de-
GENERAL crease, averaging 48 per cent., in the total oxygen
FEATURES, capacity of the blood, and also show that the
blood -volume fluctuates greatly in different cases.
Any decided increase, however, is at variance with both the clini-
cal and the postmortem findings.
Diminution in the albumin of the whole blood, due chiefly to
the cellular poverty, is a conspicuous change, the dry residue in
extreme instances amounting to but one-half of the normal figure.2
The albumin of the blood serum is also diminished,3 but not greatly
— a point of difference between Addisonian and secondary anemia,
since in severe types of the latter the serum albumin is strikingly
subnormal.
In marked cases of pernicious anemia it is
APPEARANCE sometimes almost impossible to obtain from a
OF THE puncture of the finger-tip a sufficient quantity of
FRESH BLOOD, blood for an ordinary clinical examination, owing
to the bloodlessness of the superficial vessels.
This fact naturally prompts the query, Does an actual reduction
in blood volume or oligemia exist in such an instance, or can the
dryness of the superficial tissues be attributed to vasomotor dis-
turbances causing an unequal distribution of the blood mass, in
favor of the internal viscera and deeper circulation ? In a patient
in whom puncture of the finger fails to give the requisite amount
of blood, the lobe of the ear will generally be found to yield a
drop of sufficient size. But even this very vascular part of the
1 Loc. cit.
2 Gumprecht and Stintzing, Deutsch. Arch. f. klin. Med., 1894, vol. liii, p. 265.
3 Diabella, ibid., 1806, vol. Ivii, p. 302.
PERNICIOUS ANEMIA. 277
body may in extreme cases seem practically bloodless. The
writer recalls a case of fatal anemia in which, in order to secure
a drop of blood large enough to fill the lumen of an erythrocy-
tometer only to the 0.5 graduation, it was necessary to open a
small superficial vessel of the scalp, repeated deep punctures of
the ringers, toes, and ear-lobes having given negative results.
The drop as it emerges from the puncture wound is exceed-
ingly pale, thin, and hydremic, lacking the characteristic opac-
ity of healthy blood, and being of a fluidity and general color
which have been likened to those of meat-washings. In an oc-
casional instance the color of the blood may be practically normal,
or, rarely, of a brownish-red or chocolate tint; but, as a rule, it
resembles a watery, pinkish fluid, deficient both in depth of color
and in density. It has been frequently observed that, after having
stood for a short length of time, the drop shows a tendency to
separate into two more or less distinct parts, consisting of a dark
stratum of corpuscles and a clear, watery-looking layer of plasma;
or it may be irregularly mottled at different points, as if the cor-
puscles had become concentrated in isolated, compact groups in
various parts of the plasma, thus producing the effect of alternating
dark and light areas distributed through the drop.
Microscopical examination of the fresh film shows a great re-
duction in the number of the erythrocytes, together with the pres-
ence of many forms of these cells which exhibit every possible
variation in size and in shape. The color of the individual eryth-
rocyte varies, some being normally dark and well colored, while
others appear as mere washed-out rings or " phantoms. " In
some of the cells the hemoglobin appears to be quite evenly dis-
tributed throughout the stroma, so that their typical biconcav-
ity is obliterated. The endoglobular degenerative changes and
those structural alterations denoting total necrosis of the eryth-
rocytes, previously described, may be demonstrated with great
clearness in this condition. Rouleaux formation is either entirely
absent, or incomplete and atypical.
The erythrocytes are abnormally vulnerable, as shown by their
increased isotonicity1 and by the readiness with which their con-
tained hemoglobin crystallizes.2 Von Jaksch's analyses 3 point to
a decided relative excess of cellular albumin.
Owing to the extreme oligocythemia common in pernicious
anemia, it is advisable in making the films to use a somewhat
larger drop of blood than is chosen for making ordinary spreads,
1 Von Limbeck, loc. cit.
2 Copeman, Brit. Med. Jour., 1901, vol. i, p. 161.
3 Zeitschr. f. klin. Med., 1893, vol. xxiii, p. 187.
278 DISEASES OF THE BLOOD.
so that the field will not contain such a pronounced scarcity of
cellular elements.
The obvious fluidity of the blood, the defici-
COAGULATION. ency of the fibrin network, and the slowness with
which coagulation occurs are marked features of
this disease. In fact, in some cases coagulation may be said not to
occur at all, according to the experiments of Hayem1 and others
of the French school, as in the case quoted by Lenoble,2 in which
no clotting of a sample of arterial blood was observed even after
a lapse of seventy-two hours after its withdrawal from the vessels.
Many authors attribute considerable diagnostic value to this
absence of clotting, and others go so far as to state that it ren-
ders a patient suffering with pernicious anemia especially prone
to troublesome hemorrhages, even from a slight finger-prick — an
accident which must be extremely rare, however, for it practically
never complicates an ordinary clinical examination.
The density of the whole blood is much
SPECIFIC below the normal standard, specific gravities as
GRAVITY. low as 1.027 having been reported. It is to
be recalled that in cases with a high color index
erroneous results may occur from attempting to estimate the
hemoglobin percentage by Hammerschlag's table of equivalents,
since the hemoglobin, in reality, is somewhat higher than the
percentages corresponding to the specific gravity figures. (See
P- I33-)
Up to the present time the reaction of the
ALKALINITY, blood in pernicious anemia has not been very
thoroughly studied, but the work already accom-
plished is sufficient to show that the alkalinity is much diminished,
as in other severe anemias. That it may be strikingly below
normal is shown by a case reported by Waldvogel,3 who in one
case estimated the alkalinity figure at 40 mgm., using Salkowski's
method. This author has determined that the normal alkalinity
for men ranges from 350 to 400 mgm., and for women from 300
to 350 mgm.
Both the percentage of hemoglobin and the
HEMOGLOBIN number of erythrocytes are greatly diminished,
AND the former, as a general rule, relatively less so
ERYTHROCYTES. than the latter. Thus, inasmuch as the individual
corpuscles contain often a normal or even an ex-
cessive amount of hemoglobin, it follows that high color indices
are common — common but by no means constant, as seems to be
1 Loc. cit. 2 "Charact. s6m£iol. du caillot et du serum," Paris, 1898.
3 Deutsch. med. Wochenschr., 1900, vol. xxvi, p. 685.
PKK-
CENT
MONTH.
SEPTEMBER.
OCTOBER.
CHART I.
NOVEMBER.
DAY.
100
5,000,
000
Vo
nial
ihrocytes.
90
80
4,000,
000
70
3,000
000
50
40
2,000,
000
30
\J
VI
20
19
18
IT
850,(
10
13
750.0C
13
12
r i
"550J
Ttr^h
11
10
10,
8,000
Let
S
A
\
Red, Hemoglobin.
PERNICIOUS ANEMIA.
Black, Erythrocytes.
Blue, Leucocytes.
PERNICIOUS ANEMIA. 279
the current impression among many students, for although it is
true that while the average color index is about i .00 in pernicious
anemia cases, the same statement cannot always be applied to
the individual case. The author's series of 81 cases (Table
IV) showed, at the first examination, hemoglobin percentages
varying from a minimum of 10 to a maximum of 70, with a mean
average of 27.1; the color index of these cases averaged 0.99.
During remissions, as the erythrocytes increase, it is common to
find low indices, this peculiarity being especially conspicuous
should the improvement in the patient's condition be rapid,
since in such instances the corpuscular increase is relatively much
more rapid than the gain in hemoglobin. In cases in which im-
provement takes place more slowly, the color index is likely to
remain higher, for here the corpuscles and the hemoglobin are
more prone to increase proportionately along parallel lines.
TABLE IV.— HEMOGLOBIN AND ERYTHROCYTES IN 81 CASES
OF PERNICIOUS ANEMIA.
HEMOGLOBIN NUMBER OF ERYTHROCYTES NUMBER OF
PERCENTAGE CASES. PER C.MM. CASES.
From 60-70 i Above 3,000,000 2
50-60 2 From 2,000,000—3,000,000 13
1 40-50 4 1,000,000-2,000,000 41
' 30-40 16 " 500,000-1,000,000 23
' 20-30 30 Below 500,000 2
' 10-20 28
Average, 27.1 per cent. Average, 1,361,777 per c.mm.
Maximum, 70.0 " " Maximum, 3,240,000- "• "
Minimum, 10.0 " Minimum, 450,000 " "
The oligocythemia is most striking, counts of from r,ooo,ooo
to 2,000,000 erythrocytes per c.mm. being not uncommon when
the patient first comes under observation, the number of cells
frequently diminishing to about 750,000 or even 500,000 later
during the course of the disease. In Quincke's often-quoted
case the remarkable count of 143,000 per c.mm. was observed
just before the death of the patient, an instance which is -almost
paralleled by a case recorded by Hills,1 in which the erythrocyte
count fell to 155,760 one day before death. In the series just
mentioned (Table IV) the count of erythrocytes per c.mm.
averaged 1,361,777, ranging between 450,000 and 3,240,000;
this represents an average loss in corpuscular matter of some-
what less than 75 per cent., the greatest decrease amounting to
91 per cent, of normal — a much more striking oligocythemia than
is found in any other form of anemia. Thirty per cent, of the
cases showed a count of 1,000,000 or lowrer.
1 Boston Med. and Surg. Jour., 1898, vol. cxxxix, p. 542.
280
DISEASES OF THE BLOOD.
Periods of temporary increase in the hemoglobin and erythro-
cytes, followed sooner or later by relapses, are commonly observed,
the gain during such periods sometimes being very pronounced.
Thus, in one of the cases tabulated above a gain of more than
2,500,000 erythrocytes to the c.mm. was noted during six weeks'
time with a subsequent loss of over 1,000,000 cells in the fol-
lowing eight days, the color index during this time ranging from
1.25 to 0.74. Such stages of remission may or may not follow
vigorous treatment by arsenic or other medicaments. Elder,1
by the use of antistreptococcic serum, caused a gain of 4,000,000
cells per c.mm., while DeWitt,1 by the same means, caused an in-
crease in hemoglobin
from 30 to 90 per cent,
and in erythrocytes
fr°m 1,000,000 to
4,960,000 in three
weeks' time.
These periods of
improvement in the
condition of the blood
are generally associ-
ated with an amelio-
ration of the other
clinical manifestations
of the disease, the pa-
tient's general condi-
tion improving so sub-
stantially that he be-
gins to consider him-
self on the high road
to recovery, but in the
course of time the old
symptoms return, and
the characteristic blood picture again becomes evident. In most
cases death is preceded by extreme oligochromemia and oligo-
cythemia, the hemoglobin often falling to 15 or 20 per cent, of
normal and the erythrocyte count declining to 750,000 or less; in
some cases, however, these losses are not so marked, and the count
does not fall below 1,500,000 during the whole course of the disease.
A prominent characteristic of the blood in pernicious anemia
is the wide dissimilarity in the size of the erythrocytes, due to the
presence of large numbers of megalocytes and microcytes; so
1 Cited by Packard and Willson, Amer. Jour. Med. Sci., 1902, vol. cxxiv,
p. 1015.
FIG. 52. — CHANGES IN THE ERYTHROCYTES IN PERNICIOUS
ANEMIA (EHRLICH'S TRIACID STAIN).
Showing a general increase in the diameter of the cor-
puscles, and marked poikilocytosis. The nucleated cell in
the right of the field is a megaloblast.
PERNICIOUS ANEMIA. 281
striking may this feature of the blood picture be that it is some-
times difficult to find any two cells in the same field of the micro-
scope which are of the same diameter. In the great majority of
cases it will be found that the megalocytes distinctly outnumber
the microcytes, to such an extent and in so large a proportion
of cases that some writers consider this change an almost con-
stant blood finding in this disease. Large erythrocytes, measur-
ing slightly below or above 10 ,« in diameter, are very common,
while those measuring in the neighborhood of 15 [J- or even 20 «
are met with more rarely. Undersized erythrocytes, about 3 or
4 // in diameter, are also numerous, but, as remarked above,
much less so than those of larger size. The presence of small,
dark-colored, spherical microcytes of this size (the so-called
"Eichhorst's corpuscles"), once regarded as pathognomonic of
pernicious anemia, is neither constant nor diagnostic of this dis-
ease, since they are found in many other anemic conditions, and
are absent in a large proportion of cases of true pernicious anemia.
The fact that, of these alterations in the size of the erythrocytes,
megalocytosis predominates, constitutes a sign of valuable diag-
nostic significance.
Poikilocytosis, to a more or less marked degree, is constantly
observed, the conspicuousness of the deformities being in some
cases extreme, while in others the change is a less notable feature.
While marked poikilocytosis usually goes hand in hand with
excessive diminution in the number of erythrocytes and in the
amount of hemoglobin, the association of these three changes
cannot be invariably counted upon, for in some cases, in spite of
the fact that both oligocythemia and oligochromemia are marked,
deformities in the shape of the corpuscles are but trifling. All
varieties of erythrocytes, small, large, nucleated, and non-nu-
cleated, may be deformed, so that the size of the poikilocytes
varies from that of the smallest microcyte to that of the largest
megalocyte. The kinds of deformity are of infinite variety, but
it is still possible to designate certain well-defined forms which
are especially common in this disease, these being the horseshoe
form (Litten) and the oval form (Cabot), both of which varieties,
while by no means peculiar to this condition, are found so fre-
quently and in such abundance in pernicious anemia that their
presence in the blood is at least highly suggestive. Of these
two forms, the elongated, oval erythrocyte is found more con-
stantly, and has been described in but a few other conditions.
The author has been struck with the predominance of cells of
this sort in three consecutive cases of purpura haemorrhagica,
in one of which the deformitv was so marked that scarcelv a
282 DISEASES OF THE BLOOD.
single normally shaped erythrocyte could be found in certain
fields of the microscope. Cabot1 cites Greene as noticing the
same change in the blood of two patients in whom the tentative
diagnosis of epidemic dropsy had been made. In addition to
these well-defined varieties, many cells of other shapes, also met
with in other severe anemias, are observed, notably those resemb-
ling the form of a sausage, a spindle, or a club. (See Fig. 52,
p. 280.)
In the stained specimen the principal point of interest is the
presence of nucleated erythrocytes, upon the character of which
the diagnosis of pernicious anemia must depend. Erythroblasts
are always to be found in this disease at some stage of its course.2
During remissions, however, they may temporarily disappear.
Megaloblasts are of much greater clinical significance than nor-
moblasts, and by a differential count will be found always to out-
number them in every genuine case of pernicious anemia at
some stage of the disease. This blood picture, which indicates
a megaloblastic degeneration of the bone marrow, due in all proba-
bility to the influence of some unknown but specific toxic agency,
is associated with only two other conditions, namely, nitrobenzol
poisoning and some cases of high-grade anemia due to Bothrio-
cephalus latus infection. The predominance of megaloblasts
over normoblasts in pernicious anemia is well illustrated by Table
V, which shows that at the first examination the former type of
cells outnumbered the latter in 26 of the 29 cases here collected.
The average proportion of megaloblasts to normoblasts in this
series is somewhat more than 2 to i, and in some cases the
former were the only kind of erythroblast discovered. The
total number of erythroblasts of all varieties averaged 220 per
c.mm. of blood, ranging from as low as 3 to as high as 924.
Regarding this last statement, it should be remembered that it
is not the actual number of nucleated erythrocytes, but their
character, which is all important in the diagnosis of this disease.
In 52 additional cases of pernicious anemia a predominance of
megaloblasts was found in 50, either at the first or by later examin-
ation, a total of 76 megaloblastic bloods in the 81 cases studied.
Of 139 cases reported by Cabot, megaloblasts predominated in
109 at the first examination, and in all but 3 of the remaining 30
cases at a subsequent period.
1 Loc. cit.
2 In Ehrlich's "aplastic anemia," a fatal type with profound oligocythemia,
leucopenia, and purpura, the marrow so utterly fails to compensate the blood loss
that erythroblasts of all varieties are wanting. Such cases are obviously not typical
pernicious anemia.
PERNICIOUS ANEMIA.
283
TABLE V.— APPROXIMATE NUMBER OF NUCLEATED ERYTHRO-
CYTES PER C.MM. IN 29 CASES OF PERNICIOUS ANEMIA
AT THE FIRST EXAMINATION.
NUMBER.
TOTAL. MEGALOBLASTS.
NOKMOBLASTS.
MICROS LASTS.
I
924 693
210
21
2
840 616
I4O
84
3
544 512
16
16
4
47° 32°
15°
0
5
368 207
46
"5
6
336 240
90
6
7
328
0
328
o
8
260
20
240
0
9
256
144 •
80
32
10
250 180
70
0
" 235 i?5
60
o
12 224 168
56
0
13 204 148
56
o
14 200 160
40
o
15 192 180
12
0
16
1 60 96
64
o
17
IOI
80
21
o
18
IOO
0
IOO
0
iQ
96
73
23
o
20
67
47
13
7
21
60
40
20
0
22
48
32
16
0
23
48
37
7
4
24
32
24
8
o
25
20
20
0
0
26
15
IS
o
o
27
IO
8
0
2
28
6
6
o'
0
29
3
3
o
0
Average: 220 4-
146 +
64 +.
. 10
Microblasts are rare in comparison to the other forms of nu-
cleated erythrocytes ; in some cases they may be relatively nu-
merous, but in the majority they are absent. They were noted
in but 9 of the 29 cases tabulated above (Table V), their average
number for the series being 10 to the c.mm. In the differential
count of nucleated erythrocytes microblasts should be totaled
with normoblasts, of which they are simply degenerate forms,
more or less stripped of their protoplasm, and hence irregular
and ragged in outline.
In addition to the foregoing types of erythroblasts, cells pos-
sessing the characteristics of both the normoblast and the meg-
aloblast may be observed in many instances. These atypical
forms and their clinical significance have been described in a
previous section. (See p. 192.) In certain corpuscles, both of the
normoblastic and of the megaloblastic types, division of the nu-
284
DISEASES OF THE BLOOD.
cleus into several parts may have occurred, and in rare instances
evidences of true karyokinesis may be seen. Normoblasts show-
ing complete or partial nuclear extrusion and separation of the
nucleus into a clover-leaf design are not uncommon, although
pictures of this sort are found much more frequently in leukemia.
In many cases of pernicious anemia one cannot but be struck
with the fact that the majority of these atypical forms appear as
cells with a megaloblastic protoplasm and a normoblastic nucleus ;
they are, in the author's experience, much more numerous in this
disease than cells having a normoblastic protoplasm and a meg-
aloblastic nucleus, the latter being more common in leukemia.
TABLE VI.— QUALITATIVE CHANGES IN THE LEUCOCYTES IN
31 CASES OF PERNICIOUS ANEMIA AT THE
FIRST EXAMINATION.
PERCENTAGE OF DIFFERENT FORMS.
No.
1 .EUCOC YTES
PER C.MM.
SMALL
LYMPHO-
CYTES.
LARGE
LYMPHO-
CYTES.
POLYNUCLEAR
NEUTROPHILES.
EOSINOPHILES.
MYELO-
'CYTES.
I
13,000
43-2
2.8
49.6
2.8
1.6
2
8,20O
7-7
2.0
86.2
1.6
2-5
3
7,000
14.4
1.6
81.6
2.O
0.4
• 4
7,000
13-6
5-2
77.6
2.8 0.8
5
6,400
34-o
4.0
60.0
I.O
I.O
6
6,000
I I.O
2.0
84-0
I.O
2.0
7
5,800
14.0
3-°
73-o
o.o
IO.O
8
5>4°o
22.1
7-5
67.4
2.O
I.O
9
5,000
32.8
3-6
55-6
5-2
2.8
10
4,600
56.5
6.0
34.5 o.o
ii
4,100
53-o
6.4
39.6 o.o
I.O
12
4,000
30.0
14-5
52.4
2.O
I.I
13
4,000
26.8
15-5
56.8
0-9
o.o
14
4,000
23.0
16.6
58.2
1.2
I.O
is
4,000
15.0
5-°
77-S o-S
2.O
16
4,000
34-o
9.0
45.0 8.0
4.0
i7
4,000
16.3
8.1
72.6 2.O
I.O
18
3,100
19.7
23.0
54.0 i.o
2-3
19
3,000
10.8
2O.O
60.O 7-2
2 O
20
2,500
45-°
I2.O
40.0 i.o
2.O
21
2,300
22.1
16.1
60.8 o.o
I.O
22
2,100
32.1
21.3
40.7
1.6
4-3
23
2,080
45-° J4-7
38.3 1.0
I.O
24
2,000
65.0
2O.O
14.1
0.0
0.9
25
2,000 14.5
14-5
69-5
I.O
°-5
26
1,500
25.0
I4.O
61.0
o.o o.o
27
I,IOO
19.1
12. 1
67.7
0.3
0.8
28
1,000
17.0
2I.O
58.0
2.0
2.O
29
1,000
13.0
II.O
72.0
I.O
3-°
3°
1,000
2O.O
9.0
70.0
°-5
°-5
3i
500
37-5
I8.S
40.8
2-3
0.9
Average: 3,925 +
26 +
10 +
58 +
1 +
i +
PERNICIOUS ANEMIA. 285
Fluctuations in the total number of erythroblasts occur from
time to time during the progress of the disease, these changes
sometimes taking place with great abruptness, being of wide
range and often carrying not the slightest clinical import. A
marked increase usually but not invariably precedes and accom-
panies a gain in the number of erythrocytes and in the percentage
of hemoglobin; and a similar increase, usually associated with
extreme diminution in the erythrocyte count, is commonly met
with as a preagonal sign.
Marked evidences of •polychromatophilia are found in many of
the erythrocytes, both of the nucleated and of the non-nucleated
varieties. Such cells, when stained with Ehrlich's triacid mix-
ture, instead of taking the normal orange color of the solution,
stain some bastard tint, such as slate color, dull purple, or dirty
gray. Others may show a peculiar, streaked appearance, and
irregular, pale, unstained areas, while others are scarcely stained at
all, the greater part of the protoplasm remaining an indefinite shade
of dead white. Granular degeneration of the protoplasm is distinctly
evidenced in some of the cells, this process being betrayed by the
appearance through the stroma of granular areas showing a striking
affinity for a basic stain, such as methylene-blue. These basophilic
granules, which have already been described, are not peculiar to
pernicious anemia, since they have been found in a large number
of secondary anemias of severe type due to various causes. (See
p. 194.)
The same remarks apply to the presence of erythrocytes con-
taining the "ring bodies" of Cabot. This author1 reports having
found them in 9 of 14 cases of pernicious anemia examined during
the active stages, but he failed to detect them in 4 cases in the
stages of remission.
TABLE VII.— NUMBER OF LEUCOCYTES IN 81 CASES* OF
PERNICIOUS ANEMIA
LEUCOCYTES NUMBF.R OF
PER I'.MM. CASES.
From 10,000-15,000 3
" 5,000-10,000 25
Below 5,000 53
Average, 4527 per c.mm.
Maximum, 15,000 " "
Minimum, 500 " "
Leucopenia may be counted on in considerably
LEUCOCYTES, more than one-half of all cases of pernicious
anemia, a fact which stands in direct contrast to
the anemias of secondary type, in which an increase in the number
1 Boston Med. and Surg. Jour., 1904, vol. cl, p. 321.
•81 DISEASES OF THE BLOOD.
of leucocytes is more common. In an occasional case, especially
in one in which the other blood changes are inconspicuous, the
number of leucocytes is found to be normal; and, rarely, a mod-
erate leucocytosis, attributable to some complication, exists. In
the average case, however, these cells are distinctly below the nor-
mal standard, and the degree of kucopenia is sometimes extreme,
the number of cells occasionally falling to below 1000 to the
cjnm.; in rare instances they may apparently be entirely absent,
none being found after prolonged search through both the count-
ing chamber and the stained film. In the 81 cases collected in
Table VII the number of leucocytes averaged about the mean low
normal count 4527 being the exact figure), and ranged, in the
individual case, from 500 to as high as 15,000 to the c-mm. It is
interesting to note, in connection with the preceding remarks, that
feucopenia was found in 53 or 65.4 per cent, of these cases.
The leucocyte count, except in the event of complications,
roughly parallels that of the erythrocytes, falling cointidentally
with the oligocythemia and rising again as the erythrocytes in-
crease. (See chart, p. 279.) An exception to this general rule
is found in the terminal leucocytosis which not uncommonly
develops just before the death of the patient.
Relative lymphocytosis is a common, but not a constant, find-
ing in the differential count of the stained film. It seems to be
more frequently associated with low than with high counts,
although no hard-and-fast rule can be laid down regarding this
point. In extremely leucopenic blood a noteworthy finding is
the abnormally high percentage of large mononuclear non-gran-
ular cells, a change which does not ordinarily take place in con-
nection with leucocyte counts approaching the normal average.
The combined percentage of both large and small forms of
lymphocytes in Table VI averaged 37.8, individual counts vary-
ing from 9.7 to 85 per cent. The writer has noted the
frequent occurrence of small lymphocytes containing coarse
basic granules. Such cells appear to be especially common hi
this form of anemia. Preagonal rises in die leucocyte count
are sometimes lymphocytic in character, resembling the blood
changes seen in lymphatic leukemia, and sometimes purely poly-
nuclear in type. The relative percentage of potynudear neutro-
philes averages low (58.6 per cent, in the above series), but iso-
lated counts show a considerable range; their relative proportion
to the other forms of leucocytes is largely determined by the
fluctuations in the percentage of lymphocytes. The eosinophilcs
are almost invariably decreased, and not infrequently they are
wholly wanting, a circumstance which was made note of in more
PERNICIOUS ANEMIA. 287
than 1 8 per cent, of the cases in the present series, in which the
average percentage of these cells was 1.68. In an occasional
case their percentage is above normal, as in cases 9, 16, and 19
in Table VI.
In no other disease save the myelogenous form of leukemia
are myelocytes so constantly found, but almost always in relatively
small percentages. In the cases under consideration these cells
were absent in only two instances, the average figure for the 31
cases being 1.82 per cent. In a single case (number 7) the re-
markably high estimate (for this disease) of 10 per cent, of myelo-
cytes was made, for in the other cases in which myelocytes oc-
curred their percentage ranged from 0.4 to 4.3.
In the stained specimen it is common to find that the leuco-
cytes, particularly the polynuclear neutrophiles and the myelo-
cytes, are of smaller size and more deeply stained than they ap-
pear in normal blood. This peculiarity seems to be more con-
stant and more striking in pernicious anemia than in any other
disease.
The number of blood plaques is exceedingly
BLOOD variable, so that it is impossible to make definite
PLAQUES. statements regarding either the increase or the
decrease of these bodies. In some cases they
apparently are greatly increased, as evidenced by the groups of
agglutinated masses of these cells which are. sometimes seen
(von Limbeck1), but in other cases it is evident that their number
is appreciably diminished (Hay em2). Van Emden3 supports the
latter view. In one case this observer estimated tKeir* number at
between 32,000 and 64,000 per c.mm.
In a typical case of pernicious anemia the
DIAGNOSIS, blood picture upon which the diagnosis rests is
as follows:
Hemoglobin. Marked absolute decrease, but of relatively higher
percentage than that of the erythrocytes, this
giving rise to a high color index. Striking de-
Erythrocytes. crease, commonly to 1,000,000 or less per c.mm.
Counts of about 500,000 are not uncommon
during the later stages of the disease. Erythro-
blasts constant, cells of the megaloblastic type
predominating.
Megalocytes and microcytes, the former prevailing.
Poikilocytes, usually numerous and conspicuous.
Polychromatophilia.
1 Loc. cit. * " Lemons sur Ics Maladies du Sang," Paris, 1900.
3 "Bijd. t. d. ken. v. h. bloed," Leyden, 1896.
288 DISEASES OF THE BLOOD.
Basophilic stroma degeneration striking in severe
cases.
Leucocytes. Usually decreased; decided leucopenia common.
Relative lymphocytosis in the majority of cases.
Small numbers of myelocytes almost invariably
• present.
Eosinophiles few, sometimes absent.
Plaques. Variable.
Usually the diagnosis of pernicious anemia presents no difficul-
ties, and may be made by the examination of the blood alone,
the association of marked oligocythemia, a high color index, leu-
copenia, and erythroblasts, chiefly of the megaloblastic variety,
constituting a typical group of blood changes the significance of
which is unmistakable.
It should be borne in mind, however, that these changes are
not always present in every case when the patient first comes
under observation, so that repeated and careful examinations of
the blood are sometimes necessary before a diagnosis is possible.
Of the above-named changes, the most important, from a clinical
viewpoint, is the prevalence of nucleated erythrocytes conforming
to the megaloblastic type. With the two exceptions already noted
(bothriocephalus anemia and nitrobenzol poisoning) this "mega-
loblastic blood picture " is seen only in pernicious anemia, and,
what is more important, it occurs in every true case of this dis-
ease sooner or later during its course. Inability to detect this
important characteristic should be regarded rather as a reflection
upon the thoroughness of the examiner's technic than as a con-
tradiction of the truth of this statement. Erythroblasts are not
always numerous in pernicious anemia, and painstaking and pro-
longed study of several stained films may be necessary before
this important feature is distinguishable.
In those cases of doubtful nature in which the typical blood
changes are not at once evident a tentative diagnosis may be
made by taking into careful consideration certain other physical
signs and symptoms which the patient presents. In such in-
stances attention should be directed to such suspicious points in
the clinical history as the existence of a severe anemia arising
either idiopathically or without adequate cause, and pursuing a
progressively unfavorable course, uninfluenced permanently by
treatment; the presence of a light lemon-yellow tint of the skin,
of retinal hemorrhages, of a peculiarly soft, smooth, flabby condi-
tion of the skin, and sometimes of moderate febrile paroxysms
and gastric disturbances; and the remarkable preservation of the
patient's general nutrition and body- weight in comparison with
the severity of the illness.
PERNICIOUS ANEMIA. 289
The severe secondary anemias due to hemorrhage, to advanced
syphilis, and to malignant disease, especially of the stomach,
sometimes give rise to clinical symptoms which so exactly simu-
late pernicious anemia that the diagnosis must rest upon the re-
sult of the blood findings, which are usually well enough marked
to differentiate the conditions. It is true that in these conditions
ample proof of sufficient etiological factors for the production of
the anemia is generally at hand, and this fact should have im-
portant bearing in ruling out anemia of the pernicious type, but
it is also equally true that in malignant disease it is sometimes
impossible to demonstrate the lesion, and that in syphilis the
clinical history may be obscure, so that the blood examination
must, after all, often be depended upon for an accurate diag-
nosis. In secondary anemia from the above causes the oligo-
cythemia is seldom so excessive as it is in pernicious anemia, the
erythrocytes rarely falling as low as 1,000,000 per c.mm.; the
oligochromemia is likely to be relatively greater than the oligo-
cythemia, so that a lower color index results; leucocytosis is
not uncommon; and while deformities of shape and size and
nucleation of the erythrocytes are frequently present, in some
instances to as great an extent as in pernicious anemia, megalo-
cytes do not predominate, nor do megaloblasts ever outnumber
normoblasts.
From chlorosis, which sometimes possesses many clinical mani-
festations in common with pernicious anemia, the diagnosis may
usually be readily made by the blood examination, which shows
decided differences between the two diseases. In a typical case
of chlorosis the deterioration in the quality of the blood affects
chiefly the hemoglobin content of the erythrocytes and not the
cells themselves. Hence it is common to find in this disease
extreme oligochromemia out of all comparison with the more
moderate oligocythemia, and consequently a low color index —
just the reverse of the condition found in pernicious, "anemia.
Deformities in the shape and size of the erythrocytes are not
uncommon in chlorosis, but they are not likely to be con-
spicuous; the prevalent change affecting their shape is micro-
cytosis of a moderate grade, so that a general decrease in the
diameter of these cells is commonly observed. The most im-
portant information derived from the blood is, however, of a
negative character, consisting in the fact that nucleated erythro-
cytes, should they be present, are chiefly normoblasts. While
it is true that an occasional megaloblast may be encountered in
rare instances, no chlorotic bloo.d has ever been known to show
a predominance of this type of cells. The behavior of the leuco-
19
290 DISEASES OF THE BLOOD.
cytes in chlorosis is of no aid in the differentiation of this condi-
tion from pernicious anemia, for in both diseases the count is
usually low and relative lymphocytosis common; in the former,
however, the pronounced leucopenia of the latter condition is not
often found. Myelocytes, while they may occur in both diseases,
are much less common in chlorosis.
In bothriocephalus anemia the expulsion of the parasite by the
administration of an appropriate vermifuge is soon followed by a
radical change in the blood picture and other symptoms, the meg-
aloblasts disappearing, the hemoglobin and erythrocytes quickly
rising to the normal standard, and the patient's health becoming
entirely restored. The history of a patient suffering from anemia
due to nitrobenzol poisoning is sufficiently characteristic to exclude
true pernicious anemia. The differential diagnosis between this
disease and splenic anemia is considered in another place. (See
p. 295.)
Several reputed instances of the conversion of pernicious
anemia into leukemia have been reported by Leube and Fleischer,1
Waldstein,2 and Litten.3 Some such cases probably belong,
as also do many cases of acute leukemia, to Leube's symptom-
complex, " leukanemia " — high-grade anemia plus either myelemia
or lymphocytosis, with fever, hemorrhage, stomatitis, and hyper-
plasia of the spleen and lymphatics. That pernicious anemia is
ever converted into leukemia is questionable, and it seems reason-
able to regard such a change as apparent rather than real. For
example, in a case of leukemia, transient disappearance of the
myelemia, with persistence of the anemia, such as may occur either
spontaneously or from treatment, gives a blood picture not
unlike that of true pernicious anemia, and a case of this sort may
appear to become converted into leukemia, as the temporarily
suppressed leukemic blood changes redevelop in course of time.
A marked leucocytosis engrafted upon pernicious anemia may
also be mistaken for the transformation of this disease into leu-
kemia, but it is obvious that this counterfeit can be detected by
a differential count of the leucocytes.
1 Virchow's Arch., 1881, vol. Ixxxiii, p. 124. 2 Ibid., 1883, vol. xci, p. 12.
3 Berlin, klin. Wochenschr., 1877, vol. xiv, p. 256.
4 Munch, med. Wochenschr., 1900, vol. xlvii, p. 1121. See also Arneth, Deutsch.
Arch. f. klin. Med., 1901, vol. Ixix, p. 331; Luce, ibid., 1903, vol. Ixxvii, p. 215;
F. B. Weber, Brit. Med. Jour., 1904, vol. i, p. 1416; Kormoczi, Deutsch. med.
Wochenschr., 1899, vol. xxv, pp. 238 and 775; Hitschman, Zeitschr. f. Heilk.,
1903, vol. xxiv, p. 190.
SPLENIC ANEMIA. 2QI
III. SPLENIC ANEMIA.
There is nothing distinctive about the appear-
APPEARANCE ance of the drop of freshly drawn blood, the
OF THE color and density of which vary with the inten-
FRESH BLOOD, sity of the anemia present. The author has
notes of a case of splenic anemia in which it was
remarked that, from its color and general appearance, the blood
drop resembled precisely that obtained from a typical case of
high-grade pernicious anemia; in a second case the color and
opacity were but slightly below normal.
No reliable observations have thus far been made regarding
such minor points as the rate of coagulation, the specific gravity,
and the reaction of the blood in this form of anemia.
Decided, often extreme, anemia is the general
HEMOGLOBIN rule in this disease. In the early stages the
AND hemoglobin loss is relatively excessive as com-
ERYTHROCYTES. pared to the decrease in erythrocytes, so that
the color index is consequently low — usually ap-
proximating the figures found in many cases of high-grade sec-
ondary anemia, but not averaging so low as in chlorosis. As the
disease increases in severity, however, the color index tends to
rise, as in pernicious anemia, this change being illustrated by the
counts tabulated below.
In a series of 15 cases reported by Osier1 the following re-
sults were obtained: the hemoglobin in 13 cases averaged 47
per cent., the lowest estimate being 23 and the highest 60 per
cent.; 42 erythrocyte counts averaged 3,336,357 per c.mm., with
extremes of 2,000,000 and 5,200,000. These figures are very
closely approximated by the averages of 35 cases collected by
Lichty2: hemoglobin, 47 per cent.; erythrocytes, 3,293,000; and
leucocytes, 5594. Similar changes were found in series of cases
reported by Rolleston 3 and by Frederick Taylor.4
In a case of splenic anemia in Professor Hare's ward at the
Jefferson Hospital the writer found the following changes in five
consecutive counts:
ERYTHROCYTES
DATE. HEMOGLOBIN. COLOR INDEX. PER C.MM.
March 7,1898 45 per cent. 0.82 2,750,000
March 14, 1898 40 " " 0.73 2,725,000
March 22, 1898 43 " " 0.76 2,812,000
March 29, 1898 45 " " 0.69 3,275,000
April u, 1898 40 " " i.oo 2,000,000
1 Amer. Jour. Med. Sci., 1900, vol. cxix, p. 54; ibid., 1902, vol. cxxiv, p. 781.
1 Jour. Amer. Med. Assoc., 1904, vol. xlii, p. 528.
1 "Splenic Anemia," London, 1902.
4 Lancet, 1904, vol. i, pp. 1477, 1554, and 1636.
292 DISEASES OF THE BLOOD.
Deformities affecting the size of the erythrocytes, sometimes
tending toward striking megalocytosis, may be met with in cases
characterized by great oligocythemia, such an alteration being also
associated with a greater or less degree of poikilocytosis, and with
signs of stroma degeneration. Nucleated erythrocytes, although
they occur infrequently, may be present in enormous numbers
in severe cases, creating a blood picture which is distinguishable
from that of true pernicious anemia only by the fact that normo-
blasts predominate. Thus, in one of McCrae's counts in a case
of Osle'r's, in which the hemoglobin was reduced to 20 and the
erythrocytes to 27.6 per cent., no fewer than 75 erythroblasts
(of which 21 were normoblasts, 19 megaloblasts, and 35 "inter-
mediate" forms) were seen while counting 400 leucocytes. In
the case above summarized the average number of erythroblasts
per 1000 leucocytes was estimated as 67 (the maximum and
minimum being 128 and 9, respectively) for the five examinations,
41 of these cells being normoblasts and 26 megaloblasts. The
presence of nucleated erythrocytes in such large numbers as were
found in these two instances must, however, be regarded as most
exceptional. Polychromatophilia of many of the erythrocytes
may be a striking feature in advanced cases, but in those of a
milder grade the phenomenon is absent. Absence of basophilic
granular degeneration of the cells has been noted by Cohn.1
The transition of splenic anemia into lymphatic leukemia has
been recorded twice in medical literature, according to Zypkin,2
who himself encountered such a change.
Leucopenia, sometimes pronounced, is the
LEUCOCYTES, characteristic finding, counts of from 2000 to
4000 cells to the c.mm. being common; as in
pernicious anemia, the lowest leucocyte counts are generally
associated with those cases in which the anemia is most intense.
In the adult leucocytosis occurs only as the effect of some compli-
cation, and therefore is but occasionally encountered. In Osier's
series, above referred to, the number of leucocytes, determined in
14 cases, averaged 4520 per c.mm., ranging from 2000 to 12,497,
the latter estimate being the only one exceeding 10,000; in 9 of the
cases the count fell below 5000. In the writer's case the five
counts averaged 2400, varying from 1000 to 4000. In children,
also, leucopenia .is the rule, in spite of a child's tendency to
develop leucocytosis upon the slightest provocation. (See p.
347-)
1 Munch, med. Wochenschr., 1900, vol. xlvii, p. 618.
3 Wien. klin. Wochenschr., 1903, vol. xvi, p. 577.
SPLENIC ANEMIA. 293
No constant differential changes have been observed, but rela-
tive lymphocytosis is not infrequent, sometimes involving chiefly
the large, and sometimes the small, forms of these cells. The pro-
portion of both combined may be as high as 50 or 60 per cent.,
an increase of this kind bringing about a consequent fall in the
relative percentage of polynudear neutrophiles. Small numbers
of myelocytes, rarely in excess of a fraction of one per cent., are
to be expected in cases with decided oligocythemia. The eosin-
ophiles remain at about the normal standard. Typical coarsely
granular mast cells are sometimes found in relatively large numbers
— as high as 5 or 6 per cent, of all forms of leucocytes.
No special observations concerning the behavior of the blood
plaques in this disease have been recorded up to the present time.
It is evident, however, that they are not notably increased in
number.
To recapitulate, the blood changes which have
DIAGNOSIS, been most frequently found in splenic anemia
may be tabulated as follows:
Hemoglobin. Marked diminution; color index variable.
Erythrocytes. Usually reduced moderately, sometimes exces-
sively. Counts between 3,000,000 and 4,000,000
cells per c.mm. are most common.
Deformities of shape, especially megalocytosis,
and poikilocytosis common in advanced cases.
Erythroblasts rare, except in cases with decided
oligocythemia. Normoblasts invariably predom-
inate.
Polychromatophilia in severe cases.
Leucocytes. Leucopenia the general rule.
Relative lymphocytosis common.
Small numbers of myelocytes in advanced cases.
Relatively large percentages of mast cells *not
uncommon.
Eosinophiles normal.
Plaques. Not increased.
Many writers still hesitate to assign to splenic anemia the r61e
of a definite clinical entity, choosing to regard the condition
either as a splenic form of Hodgkin's disease or as high-grade
secondary anemia with marked splenic hyperplasia. But of late
the majority of observers lean toward at least a tentative recognition
of the condition as a distinct although an obscure disease.1 Osier,2
1 For a critical re'sume" of the literature on splenic anemia, Sippy's article in
the American Journal of the Medical Sciences, 1899, vol. cxviii, p. 570, should be
consulted. 2 Loc. cit.
294 DISEASES OF THE BLOOD.
well expresses the consensus of opinion when he remarks that
"provisionally, until we have further knowledge, it is useful to
group together . . . cases of idiopathic enlargement of the spleen
with anemia without lymphatic involvement, and to label the
condition splenic anemia." Band's disease, or the terminal stage
of splenic anemia, is characterized by hypertrophic liver cirrhosis
with jaundice and by ascites.
It is quite obvious, from a glance at the above synopsis of the
blood condition, that splenic anemia presents no characteristic
blood picture by which the diagnosis can be made, so that in
order to differentiate it from a number of other diseases which it
more or less closely simulates, careful study of other clinical
features is essential.
The onset of splenic anemia is gradual and insidious, its course
is prolonged often for a number of years, and its termination is
ultimately fatal. The principal clinical features are the leuco-
penic anemia, the great splenic tumor, and the absence of en-
largement of the superficial lymphatics. In some instances the
anemia develops in advance of the splenic tumor, but it is more
often the case that the enlargement of the spleen is the earliest
demonstrable lesion. The anemia is responsible for such symp-
toms as dyspnea, vertigo, cardiac palpitation, loss of strength
and appetite, and the occurrence of unexplained, irregular periods
of fever; and for such signs as hemic heart murmurs, pallor,
lemon-yellow discoloration of the skin and mucous membranes,
and sometimes pigmentation of the skin. The enlarged spleen
may extend as far down as the umbilicus, and sometimes far be-
low this point, even to the iliac crests; the surface of the organ
is smooth and free from nodules, its consistence is firm, and its
shape is unaltered. It may give rise to no symptoms, but occa-
sionally it is the cause of great pain and of hematemesis, the latter
being due to simple mechanical congestion. Epistaxis, purpura,
and hematuria have also been observed. Ascites sometimes de-
velops, as the result either of the splenic enlargement or of the
anemia. Enlargement of the liver, usually associated with de-
cided icterus, occurs as a terminal symptom, and such gastro-
intestinal disturbances as anorexia, nausea, vomiting, and both
constipation and diarrhea are extremely common. Splenic anemia
may prove fatal within six months after the onset of the initial
symptoms, or it may drag along for as many years, but as a
general rule its duration does not exceed two or three years.
In one of Osier's cases the condition probably lasted for at least
twelve years, and in a case recently treated in the Jefferson
Hospital the splenic tumor and the anemia existed for six years,
SPLENIC ANEMIA. 295
if not longer. As in pernicious anemia, periods of remission dur-
ing which the leading symptoms disappear and the quality of the
blood improves are commonly observed in this condition.
The myelogenous form of leukemia, pernicious anemia, and
Hodgkin's disease with splenic enlargement all present clinical
features counterfeiting more or less faithfully splenic anemia, but
the differential diagnosis between these conditions does not in-
volve any great difficulty. The result of the blood examination
gives the clue to the two diseases first named, the myelocytic
type of blood in leukemia and the predominance of megaloblasts
in pernicious anemia being sufficient to fix the identity of these
conditions. In Hodgkin's disease with enlargement of the spleen
there is more or less marked enlargement of the superficial lym-
phatic glands, and the splenic tumor rarely attains the size to
which it grows in splenic anemia; the blood picture of the two
conditions, it must be recalled, may be identical.
Enlargements of the spleen due to such factors as chronic ma-
larial injection, amyloid disease, malignant growths, echinococcus
cysts, and hepatic cirrhosis also occasionally require differentiation
from splenic anemia. A history of previous attacks of malarial
fever and the detection of the specific parasite or of pigment in
the blood will serve to distinguish tumors of the spleen of malarial
nature. In amyloid disease a history of long-standing suppura-
tion, of tuberculosis, or of syphilis, and the presence of signs in-
dicating amyloid involvement of other organs, nota'bly the liver,
kidneys, and intestines, are the chief differentiating features. In
malignant disease of the spleen the tumor is uneven, .irregular,
and nodular, evidences elsewhere of malignant lesions generally
exist, and a well-defined leucocytosis is common. Echino-
coccus disease of the spleen pursues a protracted course unac-
companied by signs of anemia, but generally shows decided
eosinophilia, and, unless secondary infection takes place, is unas-
sociated with rises in temperature; fluctuation of the tumor can
frequently be detected, and hooklets can be recognized in the
fluid obtained from the organ by aspiration. In splenic enlarge-
ments associated with the different varieties of hepatic cirrho-
sis, the previous history and the cachexia of the patient, the
relatively moderate size of the tumor, the signs of portal con-
gestion, the condition of the liver, and the course of the disease
should be taken into account.
296 DISEASES OF THE BLOOD.
IV. SECONDARY ANEMIA.
An approximate idea of the intensity of the
APPEARANCE anemia may usually be formed by noting the
OF THE gross appearance of the fresh blood drop, but it
FRESH BLOOD, must be remembered that it is only when the
process has reached a comparatively high grade
of development that the fact is betrayed by any marked devia-
tion from normal in the color and density of the blood. In the
average. case of well-marked secondary anemia the color of the
drop is but slightly paler than normal, if, indeed, it is visibly al-
tered; but if the anemia is of decided severity, it may resemble a
thin, serum-colored liquid streaked with crimson, similar to the
watery blood drop of typical pernicious anemia. In such cases
microscopical examination of the fresh film shows that there is
little or no tendency toward rouleaux formation.
In general terms it may be stated that the
COAGULATION, rapidity of coagulation bears a direct relation
to the grade of the anemia, since it has been
determined that the greater the oligochromemia and oligocy-
themia, the more rapid the process of clotting. In secondary
anemias with erythrocyte counts under 1,000,000 Lenoble1 found
that coagulation was, as a rule, at least twice as rapid as normal.
The specific gravity of the whole blood is re-
SPECIFIC duced, a change which is dependent chiefly upon
GRAVITY. the loss of hemoglobin. Sufficient reference has
already been made to this subject in a previous
section. (See p. 132.) »
The majority of authors maintain that the al-
ALKALINITY. kalinity of the blood is decreased in relation to
the degree of the anemia, and a large number of
experiments in anemias due to various factors apparently justify
this general belief. But several careful investigators, notable
among whom is Low}',2 have contradicted these reports, having
found the alkalinity normal or even above normal in numerous
cases. The author quoted, for example, calculated the alkalinity
in various cases of secondary anemia at from 360 to 675 mgm.
NaOH, as compared with his normal standard, 447 to 508 mgm.
Taking the ordinarily well-developed case of
HEMOGLOBIN secondary anemia as an example, it is found that
AND the hemoglobin percentage and number of ery-
ERYTHROCYTES. throcytes are both decidedly, though not strikingly,
diminished. As the former usually shows a dis-
1 Loc. cit. 2 Centralbl. f. d. med. Wissensch., 1894, vol. xxxii, p. 785.
SECONDARY ANEMIA. 297
proportionately greater loss than the latter, subnormal color in-
dices are the rule, ranging, say, from about 0.75 to 0.85. In
anemias of severer type, such as those due to gastric cancer and
to enteric fever, the losses frequently are much more exaggerated,
and, in so far as the purely quantitative changes in the erythro-
cytes and their hemoglobin equivalent are concerned, the blood-
picture of true pernicious anemia may be counterfeited. In the
anemias of syphilis, of tuberculosis, and of malignant disease in
general the disproportionate hemoglobin loss may be so decided
that the blood changes cannot be distinguished from those of
chlorosis, and to this condition the much-abused term "chloro-
anemia" has been applied.
The fact must be emphasized that simply the hemoglobin esti-
mate and erythrocyte count alone are absolutely uncharacter-
istic in secondary anemias, for they may range in the individual
case from slightly subnormal figures to an extreme degree of
oligochromemia and oligocythemia. In a patient studied by
von Limbeck,1 for example, at one time the erythrocytes num-
bered only 306,000 per c.mm., but ultimately perfect recovery
ensued and the count rose to 4,280,000. But if averages are used
as a basis for conclusions, it becomes evident that the hemoglobin
diminution is less marked than in any other blood disease, and
that the erythrocyte loss is also less than in any other form of
anemia except chlorosis. Data based upon 200 examinations of
various types of anemia by the writer give the following results
regarding these points:
DISEASE.
AVERAGE PERCENTAGE OF
HEMOGLOBIN Loss IN
50 CONSECUTIVE
ESTIMATES.
AVERAGE PERCENTAGE OF
ERYTHROCYTE Loss IN
50 CONSECUTIVE
COUNTS.
Secondary anemia
44.8 per cent-.
27.1 per cent.*
Chlorosis
14.8 " "
17.8 " "
Leukemia
60.6 " "
4X.4 " * "
Pernicious anemia
74."? " "
76.0 "' "
Examination of the stained specimen shows a variable degree
of alteration in the shape, size, and general structure of the cells.
In mild cases simple pallor of the erythrocytes and perhaps a
few microcytes and moderately misshapen poikilocytes are the
only changes to be observed, erythroblasts, polychromatophiles,
and cells with basophilic stroma degeneration being entirely
wanting. In severe cases, with excessive oligocythemia, a large
proportion of the cells are either under- or over-sized, the latter
1 Loc. cit.
298 DISEASES OF THE BLOOD.
forms appearing to prevail in relation to the intensity of the ane-
mic process; poikilocytosis and polychromatophilia are sometimes
extreme, and evidences of Grawitz's stroma degeneration are
found, together with a more or less abundance of nucleated eryth-
rocytes, the majority of which conform to the normoblastic type.
In most instances normoblasts only are present, but rarely an
occasional megaloblast, implying a slight tendency toward a fetal
type of hemogenesis, is also seen. The significance of erythro-
blasts in anemia and the circumstances under which they are
found have been discussed in a preceding section. (See p. 187.)
Typical polynuclear neutrophile leucocytosis
LEUCOCYTES, is common, but by no means constant, in the sec-
ondary anemias, independent of their grade, for
the cellular increase is provoked by a stimulation of the functional
activities of the marrow, which vary according to the individual
and to the nature of the exciting cause. The differential changes
associated with such a leucocytosis (low percentages of lympho-
cytes and eosinophiles, with, perhaps, a few myelocytes) have
already been referred to in a preceding section. A moderate
leucocytosis is especially common in the anemias of children,
and in those symptomatic of inflammatory and suppurative condi-
tions and of malignant diseases. While in other anemias, espe-
cially those of chronic type, a normal leucocyte count or even
leucopenia may be found, often in association with a relative
lymphocytosis, as is frequently the case in the anemias of enteric
fever and of tertiary syphilis.
The plaques are usually increased, but appa-
BLOOD rently without any constant relationship to the
PLAQUES. degree of hemoglobin and erythrocyte loss. In
some cases these bodies may number more than
double the maximum normal standard, as in a case of anemia in
a child with a tumor of the spleen, noted by von Emden,1 in which
an estimate of 829,000 to the c.mm. was made.
^ The principal blood changes found in second-
UIAGNOSIS. . p 11
ary anemia are as follows:
Hemoglobin. Variable decrease, usually somewhat more marked
than the erythrocyte loss; color index subnormal.
Erythrocytes. Variable decrease.
Erythroblasts, in severe cases; normoblasts out-
numbering megaloblasts, which are rare.
Deformities of shape and size, polychromato-
philia, and basic staining of the stroma in severe
cases.
1 Loc. cit.
POST-HEMORRHAGIC ANEMIA. 299
Leucocytes. Commonly increased; rarely leucopenia.
Polynuclear neutrophiles usually increased, and
lymphocytes and eosinophiles relatively dimin-
ished.
Lymphocytosis in some cases, usually those of
severe type and chronic course.
Small numbers of myelocytes sometimes found.
Plaques. Usually increased.
V. POST-HEMORRHAGIC ANEMIA.
Among the many underlying causes of acute
ETIOLOGY, post-hemorrhagic anemias may be mentioned
trauma, abortion, post-partum hemorrhage, epis-
taxis, pulmonary tuberculosis, peptic ulcer, enteric jever, visceral
carcinoma, hemorrhagic pancreatitis, and the rupture of an aneu-
rysm, of a Fallopian tube during ectopic pregnancy, and of a mass
of extensively varicose veins. Chronic hemorrhages, such as those
resulting from diseases belonging to the hemorrhagic diathesis,
from hemorrhoids, or from uterine diseases usually give rise to a
much less decided blood loss than the first-named conditions, but
in some instances these factors, if persistent, may be sufficient
eventually to provoke anemia of great intensity.
Reduction in the total volume of blood, or.
EFFECT UPON oligemia, ensues as the immediate effect of an
THE BLOOD, acute hemorrhage, and a count made* immedi-
ately after the blood loss may show no reduction
in the hemoglobin and corpuscular value, since the oligemia af-
fects the liquid and cellular elements proportionately. As reac-
tion sets in the system attempts to compensate for the loss of
blood by the rapid absorption by the capillaries of large amounts
of liquids from the tissues, so that the blood soon becomes highly
diluted, or hydremic. This is evidenced by a proportionate dimi-
nution in the hemoglobin percentage and erythrocyte count, the
degree of this decrease depending upon the extent of the hem-
orrhage. It is thought that in many instances this fluid transfer
from tissue to vessel is inaugurated immediately after or even
during the hemorrhage, and that the original volume of blood is
restored within a few hours. A further diminution in hemo-
globin and erythrocytes occurs after the normal volume of blood
has been reestablished, so that the minimum decrease is not ob-
served until some little time has elapsed after the hemorrhage.
As a rule, the minimum count is seen at some period during the
300 DISEASES OF THE BLOOD.
first week after the blood loss — as early as the first or second day
in some instances, but as late as the tenth or eleventh day in
others. This secondary fall is thought to depend upon the in-
troduction into the circulation of large numbers of immature,
feebly resistant erythrocytes, which suffer rapid and premature
destruction, and thus bring about a disturbance in the equilibrium
between the rate of blood production and blood destruction in
favor of the latter. As soon as the marrow is able to meet the
drain in an adequate manner, by the increased production of more
resistant 'cells, the anemia ceases, and the hemoglobin and eryth-
rocyte estimates begin to rise.
Other changes consequent to hemorrhage are a diminution in
the corpuscular volume in the dry residue of the whole blood,
and in the proteids of the serum. The serum solids and fibrin-
forming elements are apparently increased. Despite the loss of
albumin, Haesslin1 found a constant fall in the freezing-point of the
blood.
Authorities differ as to the degree of blood loss which man is
capable of surviving, a difference which is but natural when it is
remembered that factors other than the actual amount of blood
lost, conspicuous among which are the age, sex, and resisting
powers of the patient, are all important in determining the fatality
of the hemorrhage. According to Immermann,2 hemorrhages in-
volving a loss of one-half of the total bulk of blood in the body
invariably prove fatal. Hayem3 is authority for the statement
that, as a general rule, recovery is possible when the total volume
of blood lost does not exceed one-eighteenth of the individual's
body- weight. This author has reported the most astonishing
example on record of post-hemorrhagic cellular decrease, in
which he observed a diminution in the erythrocytes to n per
cent, of normal in a case of post-partum hemorrhage, with sub-
sequent recovery of the patient. Behier 4 has described a case
of metrorrhagia in which recovery occurred in spite of a reduc-
tion in the erythrocytes to 19 per cent, of normal. Laache5 has
recorded a number of instances in which the corpuscular esti-
mates fell below 50 per cent, of normal — in one case to 32 per cent.
These last three examples are sufficient to disprove the former
belief that death inevitably ensues when the corpuscular loss, as
the result of hemorrhage, falls as low as 50 per cent, of normal.
Increase in the number of leucocytes, usually of moderate de-
gree, promptly develops in the great majority of cases and per-
1 Deutsch. Arch. f. klin. Med., 1902, vol. Ixxiv, p. 577.
2 Cited by Rieder, loc. cit. 8 Loc. cit.
* Cited by Laache, loc. cit. 6 "Die Anamie," Christiania, 1888.
POST-HEMORRHAGIC ANEMIA. 301
sists for several days. It usually involves an absolute and rela-
tive gain in the polynuclear neutrophile cells, with a consequent
decrease in the mononuclear forms, but, rarely, the reverse may
be noted. In fatal cases this increase may not occur; nor, ac-
cording to Baumann,1 does it occur after hemorrhage during the
adminstration of arsenic, the leucocytes in such instances diminish-
ing. This investigator also found that the giving of arsenic and
inorganic iron to animals experimentally bled resulted in slighter
blood deterioration than when either drug was used alone.
The maximum count is commonly attained within a few hours
after the onset of the leucocytosis, the normal being regained
within a week or less. (See p. 246.)
The blood plaques are strikingly increased after hemorrhage.
The coagulability of the blood is abnormally quick, being more
rapid in profuse than in moderate hemorrhages.
Following the reestablishment of the normal
REGENERA- blood volume, regeneration of the erythrocytes
TION. and hemoglobin and a consequent dissipation of
the hydremia ensue. The time necessary for
the completion of this process varies greatly in different individ-
uals, as the rapidity with which blood regeneration occurs depends
upon different factors, such as the extent of the original hemor-
rhage and the age and natural regenerative powers of the patient.
The latter are at their maximum during the thircl and fourth
decades of life, at their minimum during infancy and old age, and
are regarded as more active in women than in men. The exist-
ence of a well-developed cachexia or an infectious disease, as
well as the neglect of proper treatment of the hemorrhage, are
obstacles which retard the regeneration of the blood to its normal
composition. The process appears to be more active if trans-
fusion of a normal saline solution has been practised than in un-
treated cases, the rapidity of the gain being especially striking
during the latter half of the regeneration period. The transfusion
of blood hastens regeneration even more decidedly. Otto 2 and
Hall and Eubank3 have shown experimentally in animals, bled
and given transfusions of artificial serum, that regeneration once
stimulated into activity may carry the blood, quantitatively, con-
siderably beyond the established normal standard.
In uncomplicated cases, according to Bierfreund,4 regeneration
is effected within four weeks if the hemorrhage produces a hemo-
1 Jour. Physiol., 1903, vol. xxix, p. 18.
2 Pfliiger's Arch., 1885, vol. xxxv, p. 57.
3 Jour. Exper. Med., 1896, vol. i, p. 656.
4 Langenbeck's Arch., 1890-91, vol. xli, p. i.
3<D2 DISEASES OF THE BLOOD.
globin loss of 25 per cent., and in about three weeks if the loss
does not exceed 20 per cent. The latter period may be regarded
as the average regeneration time in the great majority of instances.
As regeneration proceeds the hemoglobin and corpuscular
deficiencies gradually become less conspicuous, but the increase
in these two constituents does not occur along parallel lines.
The increase in the number of erythrocytes is much more rapid
than the gain in the hemoglobin percentage, which usually
remains subnormal for some time after the normal number of
corpuscles has been reestablished. Owing to this lagging behind
of the hemoglobin low color indices are the rule. Faulty hemo-
genesis, owing to which the great majority of the erythrocytes
are deficient in hemoglobin and many of them of abnormally small
size, serves best to explain this slow restitution of the hemoglobin
value.
The appearance in the blood of normoblasts is common after
hemorrhage, and in rare instances an occasional megaloblast and
atypical erythroblast may be observed. According to Ehrlich,1
if thorough and systematic search is made, normoblasts may
be constantly found after the second or third day following the
blood loss until the regeneration of the blood is complete. The
transient appearance of large numbers of normoblasts, known
as "blood crises," has been already described. (See p. 189.)
Dawson,2 who has carefully studied the effects of venous hemor-
rhage in dogs, found no evidence of any close relation between
the number of erythroblasts and the rapidity and character of
the regeneration of the hemoglobin and erythrocytes. In severe
cases polychromatophilia of the erythrocytes may be noted, this
sign first becoming apparent as early as the first day after the
hemorrhage, and gradually disappearing as regeneration is effected.
Deformities in the size and shape of the erythrocytes are not
uncommon, of which microcytes constitute the most frequent
example. Large hydropic megalocytes and poikilocytes are met
with more rarely.
VI. LEUKEMIA.
According to the classification in general vogue
VARIETIES, at the present time two clinical varieties of leu-
kemia, the myelogenous or spleno-medullary and
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is almost invariably a chronic process, is associated with a
1 Loc. cit. 2 Amer. Jour. Physiol., 1900, vol. iv, p. 2.
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CHLOROSIS.
Marked decrease, averag-
ing to about 50 per cent.
Relatively low to erythro-
cyte loss.
Moderate decrease, counts
averaging about 4,000,000.
Pallor conspicuous.
Poikilocytosis rarely
marked.
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blasts predominating.
Polychromatophilia rare;
basophilic stroma degenera-
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creased; often absent.
Myelocytes very rare.
Basophiles not increased.
Increased.
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303
304 DISEASES OF THE BLOOD.
marked proliferation of myeloid tissue, and is characterized by
a striking myelemia and generally by conspicuous enlargement
of the spleen, with little or no involvement of the lymphatic glands.
The lymphatic form, which may run either an acute or a chronic
course, more commonly the latter, is a process associated with
a proliferation of lymphoid tissue, and is characterized by a
blood picture known as lymphemia, and in the great majority
of cases by marked enlargement of the lymphatic glands, with
moderate involvement of the spleen. But these two clinical pic-
tures, in so far as they relate to the splenic and lymphatic hyper-
trophy, are by no means constant, for, although cases of mye-
logenous leukemia always have enlarged spleens, exceptionally
they may also have decided lymphatic hyperplasia. Furthermore,
cases of lymphatic leukemia are occasionally encountered in which
there is a marked splenic tumor without demonstrable signs of
lymphatic enlargement, as well as those in which the bone marrow
alone is involved without implication of either the spleen or the
lymphatic glands. To this group belong the acute leukemias
with myelogenous lesions described by Miiller,1 Walz,2 Pappen-
heim,3 Michalis,4 Dorothy Reed,5 A. O. J. Kelly,6 and others —
studies wThich tend to upset. Ehrlich's theory that lymphatic leu-
kemia is essentially a lesion of the lymph glands. Because of
such atypical examples, the gross appearance of the spleen and
lymphatics must be regarded as a sign of distinctly secondary
importance to the blood picture, which is alone the tangible diag-
nostic clue.
Gerhardt,7 Fleischer and Penzoldt,8 and Wey 9 report cases of
the apparent transition of myelogenous into lymphatic leukemia
and into pernicious anemia. These so-called conversions of type
may really represent merely the superposition of a leucocytosis
sufficiently great temporarily to dominate the blood picture. If
such were the case, it is obvious that with the disappearance of the
leucocytosis the true character of the blood changes will become
apparent — in the first instance, a lymphocytosis, and in the second,
a megaloblastic anemia.
Of the two forms of the disease, the myelogenous is much the
commoner. In the series of 42 cases of leukemia which the
1 Centralbl. f. allg. Path. u. path. Anat.. 1894, vol. v, pp. 553 and 601.
2 Ibid., 1901, vol. xii, p. 967.
3 Virchow's Arch., 1899, vol. clvii, p. 19; ibid., 1900, vol. clix, p. 40; ibid.,
1901, vol. clxi, p. 424.
4 Deutsch. med. Wochenschr., 1901, vol. xxvii, p. 651.
5 Amer. Jour. Med. Sci., 1902, vol. cxxiv, p. 653.
6 Trans. Assoc. Amer. Phys., 1903, vol. xviii, p. 481.
7 Deutsch. Arch. f. klin. Med., 1880, vol. xxvi, p. 368.
8 Ibid., 1896, vol. Ixvii, p. 300. 8 XV. Cong. f. inn. Med., 1897.
LEUKEMIA. 305
writer has had the opportunity of studying, 29 were of the myelog-
enous and 13 of the lymphatic form; while of Cabot's 66
cases,1 49 were myelogenous and 17 lymphatic — a proportion
of almost three of the former to one of the latter, for the combined
series of 108 cases.
In the present state of our knowledge it is
PARASITOLOGY. not possible to regard leukemia as a disease of in-
fectious origin, notwithstanding the suggestive-
ness of the symptoms shown by many of those cases which run
an acute course. Within the past few years several investigators,
notably Delbert,2 Kelsch and Vaillard,3 Pallowski,4 and Lowit5
have attempted to ascribe to various micro-organisms specific
etiological relationship with the condition, but these attempts
have thus far been unconvincing. Lowit's researches, however,
are worthy of special attention, if for no other reason than for
the elaborate and painstaking study which they represent. This
author believes that two distinct forms of parasites may be dem-
onstrated in leukemia : the Hcemamceba leukemia magna, thought
to be the specific cause of the myelogenous form of the disease,
and the Hcemamceba leukemia parva, which he claims is the
definite infective principle of the lymphatic form. These so-called
"specific bodies," which are found both in the blood of the
peripheral vessels and in the hematopoietic organs,. have either
a granular or an ameboid appearance, and bear a more or less
close resemblance to the basophile granules of the leucocytes;
navicular, segmenting, and vacuolated forms are also. said to
occur. They are either attached to or lie within the leucocytes,
especially the small lymphocytes, and more rarely the other varie-
ties of normal leucocytes and the myelocytes; in an occasional
instance they are said to be found lying free in the plasma. Al-
though it is claimed that a leucocytic infection has been produced
in animals by the injection of blood presumably containing these
micro-organisms, all attempts to cultivate them on artificial media
have proved futile. Lowit's amebae are demonstrated only in heat-
fixed specimens, stained preferably with a steaming hot solution
of Loffler's methylene-blue, after which they are washed, differ-
entiated with a 0.3 per cent, solution of hydrochloric acid alcohol,
again washed, and mounted. In specimens thus treated they stain
metachromatically, and, if the acid alcohol differentiation has
been properly effected, are the only elements except the basophile
1 Loc. cit. t Bull, et me"m. Soc. de chir.. Paris, 1895, vol. xxi, p. 788.
3 Annal. de 1'Institut Pasteur, 1890, vol. iv, p. 276.
4 Deutsch. med. Wochenschr., 1892, vol. xviii, p. 641.
s "Die Leukamie als Protozoeninfektion," Wiesbaden, 1900*
20
306 DISEASES OF THE BLOOD.
leucocyte granules which retain the color of the dye. Turk,1 who
has followed out Lowit's technic precisely, in investigating this
author's claims has come to the conclusion that these "specific
bodies" are in no sense of parasitic nature, but merely artefacts
resulting from the action of an aqueous solution of a basic dye
upon the mast cell granules, which causes the partial solution of
the latter elements and deforms them. Turk claims, furthermore,
that these so-called amebae can be produced both in the normal
blood of. man and in the blood of rabbits.
MYELOGENOUS LEUKEMIA.
„ The drop as it flows from the puncture is, in
APPEARANCE most instances, of a bright scarlet color, and
OF THE often has a peculiar and misleading appearance
FRESH BLOOD, of density. After brief exposure to the air,
it may become resolved into a serous, scarlet
fluid, in which are suspended many minute, whitish, fat-like
masses; the former appears to consist of serum and erythro-
cytes, and the latter of adhering masses of leucocytes. It was
probably this striking appearance of the leukemic blood drop
that led Hughes Bennett erroneously to describe the condition
as a "suppuration of the blood" before he proposed the more
suitable term leucocythemia. In some cases the drop is simply
much darker than normal, but it is difficult to believe that it ever
resembles the chocolate-brown shade mentioned by some authors
as occurring in this disease. The blood usually flows very freely
from the wound, often by fine jets and spurts, especially if slight
pressure is applied above the site of the puncture.
Microscopically, the field is found to contain an enormous
number of leucocytes, the proportion of these cells to the ery-
throcytes being, by actual count, as great as i to 8 or 6, or even
greater. Many different varieties of leucocytes may be distin-
guished in the fresh specimen, the most striking being the large,
mononuclear, finely granular cells of round or ovoid shape. These
are the myelocytes which are present in enormous numbers in
this form of leukemia, of which they form a characteristic blood
picture. "Fractured" leucocytes, usually eosinophiles, with a
cloud of escaped granules free in the plasma in the neighborhood
of the disrupted cell body, may also be observed in variable num-
bers, although such cells are more numerous in the dried, stained
film. (See Figs. 54 and 55.)
The erythrocytes vary in number and in appearance according
1 XVIII. Cong. f. inn. Med., Wiesbaden, 1900.
PLATE IV.
SPLENO-MEDULLARY LEUKEMIA.
( Triacid Stain.)
1. Small Lymphocyte. »
2. Large Lymphocyte.
Contrast this cell with the myelocytes, 10, n, and 12, noting the presence of neutro-
phile granules in the latter, and their absence in the lymphocyte. The size and
nuclear characteristics of all these cells are practically the same.
3. 4. Pol.ynuclear Neutrophiles.
5. Eosinophile.
In this "dwarf" eosinophile, ruptured during the preparation of the specimen, the
granules are peculiarly arranged about the nucleus; no signs of protoplasm are dis-
tinguishable.
6. Eosinophilic Myelocyte.
Note the irregularity with which the granules are stained.
7. 8, 9, 10, ii, 12, 13, 14, 15. Myelocytes. (Neulrophilic.)
These cells vary greatly in size (compare 8 with 9), hut they all have similar distinc-
tive characteristics — a large opalescent nucleus containing a scanty chroinatin net-
work embedded in a cell body crowded with delicate neutrophile granules, precisely
like those found in the polynuclear neutrophiles, 3 and 4. The nucleus of 7 is dis-
tinctly indented and somewhat denser than that of the other myelocytes. This cell
probably represents a developmental phase of the myelocyte just short of its, transi-
tion into a typical polynuclear neutrophile.
16. Normoblast.
The erythrocytes (stained orange) show many evidences of deformity, an occasional
megalocyte, many microcytes, and a few poikilocytes being present. Polychromato-
philia is absent.
(E. F. FABBR, fee.)
LEUKEMIA. 307
to the severity of the coexisting anemia; in some instances large
numbers of poikilocytes, megalocytes, and microcytes, with
marked pallor of the corpuscles, may be seen, while in others
the changes affecting the erythrocytes appear to be but trifling.
In fresh films which have been allowed to dry for some time
Charcot-Leyden crystals may sometimes be detected. They ap-
pear as colorless, refractive crystals, shaped like octahedra, having
long, pointed, sharp angles, and occurring either singly or in
twos or threes, superimposed at right angles or as collections
of radiating, crystalline masses. These crystals are not observed
in the freshly drawn blood, being demonstrable only in films
which have stood exposed to the air for at least twenty-four hours,
and only occasionally even under this circumstance.
On account of the presence in the blood of such large numbers
of leucocytes a very small drop should be used for making the
cover-glass spreads for staining, since it is advisable to avoid
overcrowding the field with these cells. No difficulty will be ex-
perienced in obtaining thin, evenly distributed spreads if this pre-
caution is observed, especially if the cover-glasses are slightly
warmed just before they are used.
The coagulation of the blood and the for-
COAGULATION. mation of the fibrin network must be regarded as
variable. In some cases, especially Jhose with
great loss of hemoglobin and erythrocytes, both processes are de-
layed and imperfect, as evidenced by the formation of the "rasp-
berry-jelly" clots referred to by the German writers. But in
other cases the coagulation time is unaltered, and the fibrin net-
work is perfectly normal.
The alkalinity of the blood is usually de-
ALKALINITY. creased, and, as in chlorosis, it increases after the *
patient is given iron, in parallelism with the gain
in hemoglobin and erythrocytes. In 3 cases studied by Burmin1
an average alkalinity equivalent to 146 mgm. was found, Landois'
method being employed in the investigations. Taylor l found an
average of 380 mgm. in three tested by the von Limbeck method.
In cases with severe anemia the density of the
SPECIFIC blood may fall as low as 1.035 or 1.040. Gra-
GRAVITY. witz1 has reported a case in which the figure was
1.023. The fallacies in leukemia of Hammer-
schlag's tables of specific gravities and their hemoglobin equiva-
lents have already been pointed out. (See p. 133.)
1 Loc. dt.
308 DISEASES OF THE BLOOD.
Decided hemoglobin and erythrocyte loss is
HEMOGLOBIN the invariable rule sooner or later during the
AND course of the disease, the anemia usually being
ERYTHROCYTES. well denned at the time the patient first comes
under observation, and becoming acutely marked
as the termination of the illness approaches. It is generally the
case that the hemoglobin loss is disproportionately greater than
the decrease in the erythrocytes, thus producing a moderately
low color index, but in some cases just the opposite of this is ob-
served.1 In the writer's 29 cases, grouped in Table VIII, the
color index averaged about 0.86. The hemoglobin percentage
ranged between 24 and 70, averaging 48.6, and the number of
erythrocytes was as low as 572,000 and as high as 4,200,000 per
c.mm., the mean average being 2,814,000; the count of these
cells was diminished to one-half of the normal standard, or below
this figure, in n of the cases examined. An analysis of Cabot's
series of 42 cases of myelogenous leukemia2 shows these average
findings: hemoglobin, 43 per cent.; erythrocytes, 3,123,000 per
c.mm.; and color index, about 0.68.
TABLE VIII.— HEMOGLOBIN AND ERYTHROCYTES IN 29 CASES
OF MYELOGENOUS LEUKEMIA.
HEMOGLOBIN NUMBER or ERYTHROCYTES NUMBER OF
PERCENTAGE. CASES. PER C.MM. CASES.
From 60-70 7 From 4,000,000-5,000,000 i
" 50-60 5 " 3,000,000-4,000,000 15
" 40-50 5 2,000,000—3,000,000 8
" 30-40 10 " 1,000,000-2,000,000 4
" 20-30 2 Below 1,000,000 i
Average, 48.6 per cent. Average, 2,814,000 per c.mm.
Maximum 70.0 " Maximum, 4,200,000 "
Minimum, 24.0 " " Minimum, 572,000 " "
Fluctuations in the hemoglobin percentage and in the number of
erythrocytes may or may not accompany variations in the leuco-
cyte count. Sometimes, as the leucocytes rise, the erythrocytes
fall, but again they remain practically stationary; or, the leuco-
cytes may progressively fall to a comparatively moderate count,
coincidentally with an apparent improvement in the patient's gen-
eral condition, and yet the erythrocytes do not materially gain in
numbers. Taylor 3 refers to two such instances which have come
1 It is to be remembered that hemoglobin estimates in leukemia may be unreli-
able (except when Dare's instrument is used), for correct readings are sometimes
impossible, owing to the milkiness of the diluted blood from the presence of such
immense numbers of leucocytes. About one-half of the hemoglobin figures in the
accompanying table (Table VIII) were obtained by means of von Fleischl's hem-
ometer, the remainder being based upon examinations with Oliver's and with
Dare's instruments.
2 Loc. cit. s Loc. cit.
LEUKEMIA.
309
under his observation, in both of which the blood picture at cer-
tain brief intervals resembled that of pernicious anemia, for under
the influence of energetic arsenical treatment the leucocytes were
reduced to normal, while the oligocythemia stubbornly persisted.
In a case studied for a protracted period it is possible to distin-
guish a general decrease in the erythrocyte count as the leuco-
cytes increase, although the reverse may not be true. (See Chart
II, p. 311.)
Examination of the stained specimen shows the presence of
nucleated erythrocytes in practically every case of myelogenous leu-
kemia, these cells often being many times more numerous than
in grave cases of pernicious anemia. Normoblasts prevail,
always being more numerous than megaloblasts ; in some cases
they are the only type of erythroblast to be observed; in others
they are associated with a relatively moderate number of typical
megaloblasts, or, more commonly, with large numbers of atypical
forms, sharing the characteristics of the typical adult and em-
bryonic nucleated erythrocytes. In the 9 cases of this variety of
leukemia in which the writer has made differential erythrocyte
counts the following estimates were obtained at the first exami-
nations :
NUMBER.
TOTAL NUMBER OF
ERYTHROBLASTS PER C.MM.
NORMOBLASTS
PF.R C.MM.
MEGALOBLASTS
PER C.MM.
I
12,913
8376
4537
2
9,178
9I78
o
3
8,626
7264
1362
4
8,064
6048
*20l6
5
5.694
35°4
2190
6
3.234
1848
1386
7
2,940
2940
0
8
1,980
1980
o
9
748
748
0 >
Average: 5,931
4654
1277
Comparison of the above summary with the table giving the
number and forms of erythroblasts in pernicious anemia (Table
V, p. 283) illustrates two striking facts concerning these cells
in myelogenous leukemia: the immense numbers in which they
occur and the predominance of normoblasts over megaloblasts.
Periods of temporary improvement in the patient's general health
are often heralded by a notable increase in the normoblasts,
but it is a noteworthy fact that during these remissions, while the
leucocytes may fall decidedly, the normoblasts tend to persist
in greater or less numbers.
Examples of so-called nuclear extrusion, of multinucleation,
310 DISEASES OF THE BLOOD.
of clover-leaf, dumb-bell, or other irregularly formed nuclei, and
even, in rare instances, of karyokinesis are observed in many of the
normoblasts. (See Fig. 49, p. 193.) Such alterations may be more
conspicuous in highly developed cases of myelogenous leukemia
than in any other disease of the blood. In an occasional normoblast
the contracted, glistening, intensely basic nucleus is highly sugges-
tive of pyknosis. No one who has done much blood work can
fail to be struck with the obvious avidity displayed by the stroma
of the erythroblasts for the acid fuchsin of the triple stain, a
peculiarity which is exhibited in spite of good technic and the
use of a reliable staining solution.
Deformities affecting the size and the shape of the erythrocytes
may be trivial or decided, depending upon the degree of hemo-
globin and erythrocyte loss present. Polychromatophilia, alone
or associated with basophilic stroma degeneration, is very com-
mon in cases with great anemia, these changes affecting both
the nucleated and the non-nucleated cells.
TABLE IX.— NUMBER OF LEUCOCYTES IN 29 CASES OF MYE-
LOGENOUS LEUKEMIA.
LEUCOCYTES NUMBER OF
PER C.MM. CASES.
Above 1,000,000 i
From 500,000—1,000,000 5
400,000— 500,000 4
300,000- 400,000 4
200,000- 300,000 6
100,000— 200,000 6
50,000— 100,000 2
Below 50,000 i
Average, 355,119 per c.mm.
Maximum, 1,046,000 "
Minimum, 44,000 " "
Striking increase in the number of leucocytes
LEUCOCYTES, is found even during the early stages of the dis-
ease. Counts in excess of 100,000 are generally
expected, while in fully 70 per cent, of cases they exceed 300,000
and in about 20 per cent., 500,000 or higher. In rare instances
the number of leucocytes may be as high as 1,000,000 per c.mm.
One case of the writer's had 1,046,000 leucocytes. The leucocyte
count may, very infrequently, equal or even exceed that of the
erythrocytes, and it is easy to see that such a condition is possible,
should the accompanying oligocythemia be intense. In a patient
recently admitted to the Jefferson Hospital the leucocytes numbered
650,000 and the erythrocytes 572,000. In the estimates given
in Table IX, showing the number of leucocytes at the time the
patient first applied for treatment, the average count was 355,119
per c.mm., the highest being 1,046,000 and the lowest 44,000.
CHART II.
SPLENO-MEDULLARY LEUKEMIA.
Red, Hemoglobin. Black, Erythrocytes. Blue, Leucocytes.
LEUKEMIA. 311
The number of leucocytes may fluctuate enormously at various
times during the progress of the disease, a gain or a loss of some
200,000 cells to the c.mm. from week to week being a matter of
common occurrence. Sometimes they are temporarily dimin-
ished as the result of the administration of arsenic to the point
of tolerance, or of the vigorous employment of other therapeu-
tical measures; sometimes the decrease takes place independ-
ently of the influence of remedial agencies, so far as can be deter-
mined. When arsenic is withheld, the number of leucocytes
promptly increases, and in spite of its use they ultimately increase
as the disease runs its fatal course. The relations of the leuco-
cytes' fluctuations to the number of erythrocytes have already
been mentioned. Hayek1 has drawn attention to the fact that in
the leukemic individual the morning leucocyte count may be
greater by more than 100,000 cells per c.mm. than the estimate
made during the afternoon, and vice versa. In a case in Pro-
fessor Wilson's wards at the Jefferson Hospital the writer has
been able to verify this statement, the counts being as follows:
ii A.M., 144,000; 6 P.M., 256,000 — a difference of 112,000 cells
within a period of seven hours. The influences of digestion
and other sources of error were, of course, excluded in making
this observation. The occurrence of this enormous diurnal
fluctuation emphasizes the importance of making the blood ex-
amination of leukemic patients at precisely the same hour each
day in cases studied for a long period.
TABLE X.— QUALITATIVE CHANGES IN THE LEUCOCYTES IN
29 CASES OF MYELOGENOUS LEUKEMIA. v
AVERAGE. MAXIMUM. MINIMUM.
Small lymphocytes 4.1 12.0 . . 0.7
Large lymphocytes 9.5 28.4 0.3
Polynuclear neutrophiles 54.3 77.0 34.1 >
Eosinophiles 5.4 28.7 1.2
Myelocytes 20.6 44.0 7.0
Mast cells2 9.0 28.0 i.o
The possibility of encountering a case of leukemia during a
period of remission, when the typical blood changes are absent,
must be borne in mind, for such instances are observed from time
to time, although they are very rare. For example, McCrae3
reports a case, treated by arsenic, in which twice during a period
of ten months the blood and general symptoms of the patient
were typical of myelogenous leukemia, and twice were abso-
lutely normal. When first examined, this patient's leucocytes
numbered 584,000 per c.mm., three months later they had
1 Wien. klin. Wochenschr., 1897, vol. x, p. 475.
2 Estimates in 19 cases. 3 Brit. Med. Jour., 1900, vol. i, p. 760.
312
DISEASES OF THE BLOOD.
fallen to 9250, two months after this they had risen to 178,000,
and after a lapse of another five months they again fell to 5000.
These fluctuations did not depend upon the influence of any in-
tercurrent infection (see below), and the case is peculiar in that
the leucocytes, as well as the erythrocytes, not only were normal
in number, but also normal qualitatively, and in that the patient's
splenic tumor entirely disappeared during the periods of remis-
sion. A similar case (myelogenous) is reported by Simon and
Campbell,1 in which the leucocytes, after vigorous arsenical treat-
ment for three weeks, fell from 350,000 to 4000, with disappearance
of the myelemic blood picture and of the splenic tumor. Twelve
months later the blood (save for the persistence of mast cells) and
spleen were still normal. Other cases have been recorded showing
brief periods of temporary decline to normal in the number of
leucocytes, but with the persistence of myelocytes, or of the splenic
enlargement, or of both.
Here may be noted the astonishing results of Rontgen-ray
therapy, alone and in conjunction with arsenic, in the treatment
of myelogenous leukemia. Senn,2 E. J. Brown,3 C. H. Weber,4
Grosh and Stone,5 Bryant and Crane,6 and Aubertin and Beau-
jard 7 have reported cases thus treated, in which the blood picture
became normal and the splenic tumor disappeared. Time alone
can determine whether such cures are symptomatic or radical.
The following summary illustrates the good effects of arsenic,
and, in the patient in question, the indifferent results of #-ray
therapy in myelogenous leukemia, observed in the Jefferson Hos-
pital :
ON ADMISSION.
Hemoglobin , 60 per cent.
Erythrocytes 3,520,000
Leucocytes 341,000
Small lymphocytes 3 per cent.
Large lymphocytes i
Polynuclear neutrophiles. .50
Eosinophiles 3
Myelocytes 15
Mast cells 28
The presence of myelocytes in large numbers is the hinge upon
which the diagnosis of myelogenous leukemia must turn, for in
1 Johns Hopkins Hosp. Bull., 1904, vol. xv, p. 181; also Med. News, 1904, vol.
Ixxxiv, p. 431.
2 Med. Rec., 1903, vol. Ixiv, p. 281.
3 Jour. Amer. Med. Assoc., 1904, vol. xlii, p. 827.
4 Amer. Med., 1904, vol. vii, p. 824.
5 Jour. Amer. Med. Assoc., 1904, vol. xliii, p. 18.
* Med. Rec., 1904, vol. Ixv, p. 574. Presse med., 1904, vol. i, p. 399.
AFTER TWELVE
WEEKS' ARSENIC
TREATMENT.
AFTER Six WEEKS'
ARSENIC TREATMENT
WITH X-RAY.
80 per cent.
4,860,000
32,000
2.5 per cent.
70 per cent.
3,090,000
147,600
3.0 per cent.
1.5
1.4
74-S
2.O
16.0
74-9
3-6
IO.O
•
3-5
7-1 '
LEUKEMIA.
313
no other disease are these cells so numerous or so constantly
present. A high percentage of myelocytes, irrespective of the
degree of increase in the total number of leucocytes of all forms,
is as essential for the diagnosis of this variety of leukemia as is a
predominance of megaloblasts for the recognition of pernicious
anemia. In most cases they constitute at least 20 per cent, of
the different forms of leucocytes, and occasionally as high as 50
per cent, or more. In the 29 cases of the present series (Table
X) the myelocytes, at the first counts, averaged 20.6 per cent.,
with 7 and 44 per cent, as the minimum and maximum esti-
mates, respectively. It is the fact, not that myelocytes simply
occur in this disease, but that they occur in such enormous
numbers, that is of prime value in the diagnosis, since in no other
condition in which this type of marrow leucocyte is found in the
blood are they present in such striking abundance. For example,
12 3 456
FIG. S3- — ATYPICAL FORMS OF MYELOCYTES IN MYELOGENOUS LE'UKEMIA.
i, 2, Dwarf forms, with relatively large and deeply stained nuclei situated in a relatively small
amount of cell body containing neutrophile eranules. 3, "Fractured" myelocyte. 4, Extremely
large form, with kidney-shaped nucleus. 5, Eosinophilic myelocyte with deeply constricted nucleus.
6, Myelocyte with an hour-glass constriction of the nucleus. (Ehrlich's triacid stainj
although myelocytes are very constant in pernicious anemia, they
are only about one-twentieth as numerous in this disease, on the
average, as they are in myelogenous leukemia.
Many of the myelocytes are of very large size, some being
quite 22 IJL in diameter and occasionally of somewhat larger di-
mensions; others are dwarfed to no larger than the diameter of
a small lymphocyte. The nuclei of these larger forms stain
with relatively less intensity than those of the smaller. In-
dentation, apparent division, and hour-glass constriction of the
myelocytes' nuclei are also frequently noted. A very common
form of this cell in myelogenous leukemia is characterized by
its large size and its pale, kidney-shaped nucleus, the regularly
convex border of which lies in intimate contact with fully one-
half the periphery of the cell body. These and other atypical
forms of myelocytes are shown in the accompanying illustra-
tion (Fig. 53). The abnormalities affecting the granules of this
314 DISEASES OF THE BLOOD.
type of cells, as well as certain degenerative changes, do not differ
from those which are found in the polynuclear neutrophiles
described below.
The relative percentage of polynuclear neutrophiles is low, but
not especially so, although, of course, the absolute number of
this type of cells is greatly in excess of the normal standard, as
may be demonstrated by taking into consideration the high total
leucocyte count. For instance, in a case having 300,000 leuco-
cytes per c.mm., with, say, 50 per cent, of them polynuclear
neutrophiles, the actual number of the latter is 150,000 to the
c.mm., or fifteen times the maximum normal number. The
cases listed in Table X averaged 54.3 per cent, for this variety
of leucocytes, with a range between 34.1 and 77.0 per cent, in the
individual case, but other authors, with more extended series
of cases as a basis for their statistics, give lower figures than these.
A feature which at once attracts attention in the examination
of the stained specimen is the deviation from the normal size of
a large proportion of these neutrophilic cells. Dwarfed cells,
often not more than 5 or 6 /i in diameter, and large forms, some
of them measuring 15 fjt or even more in diameter, are common,
the nuclei of the former usually staining much more sharply than
those of the latter, which may exhibit a very feeble reaction to-
ward the basic dye, and show a more diffuse and delicate chro-
matin structure than is the rule in normal blood. The nuclei
tend to exhibit extreme polymorphism and variations in their
relative size to that of the cell body, and many of the cells are
deformed in shape, being drawn out into various oblong and
elliptical designs or into irregular elongated masses. " Frac-
tured" cells, from which the granules have escaped, are very
commonly seen. It seems reasonable to attribute the free neu-
trophile granules sometimes seen in the blood in this disease to
the rupture of a neutrophilic leucocyte, although the particular
cell to which they belonged may be difficult to identify; the view
expressed by some authors that such granules may preexist in
the plasma is scarcely to be thought of seriously. All these
deformities are doubtless the result of injuries to the cells in the
preparation of the cover-glass spreads, and they suggest a lowered
resistance on the part of the leucocytes.
The number of granules in the polynuclear neutrophiles varies
greatly in the individual cells: in some they are densely crowded
throughout the protoplasm and overrun portions of the nucleus;
in others they are confined to certain areas of the cell body, es-
pecially in the neighborhood of the nucleus; while in still others
they are distributed singly or in twos and threes through the
LEUKEMIA. 315
protoplasm. Occasionally a cell wholly devoid of granules is
observed, and, very rarely, one containing both neutrophile and
a few isolated eosinophile or basophile granules. The neutro-
phile granules themselves vary greatly in size, being in some
cells so extremely delicate and fine that they can barely be dis-
tinguished, while in others they almost equal the size of the
smaller eosinophile granules.
Fine and coarse vacuolation of the nucleus and protoplasm, a
fissured and cracked appearance of the nuclear chromatin, and an
apparent solution of the protoplasm, with freeing of the nu-
cleus, are the most prominent degenerative changes affecting the
polynuclear neutrophiles, as well as the other varieties of leuco-
cytes, in this disease.
The relative percentage of lymphocytes, small and large to-
gether, is decidedly lower than normal, although their total num-
I 2 3
FIG. 54. — ATYPICAL FORMS OF POLYNUCLEAR NEUTROPHILES IN MYELOGENOUS LEUKEMIA.
i, Cell containing both neutrophile and moderately coarse basophile granules. 2, Polynuclear
cell with two ovoid nuclei and neutrophile granules, probably representing a later developmental
stage than 6, Fig. 53. 3, "Fractured" polynuclear neutrophile. (No. i stained with Jenner's
eosinate of methylene-blue, 2 and 3 with Ehrlich's triacid stain.) *
ber to the c.mm. of blood is greatly increased. As shown by
the cases in Table X, these cells average approximately 14 per
cent, of all varieties of leucocytes, which represents a diminution
to about one-half of the proportion found in normal blood. It
is the small lymphocytes which suffer the greater loss, for their
proportion in the differential count is sometimes not more than
a fraction of one per cent., and always greatly below normal;
the large lymphocytes and "transitional" forms, on the contrary,
average about normal, and, indeed, may be greatly increased
in the individual case. Turk's stimulation forms are also met
with, but these cells, as a rule, are not numerous.
Atypical forms of lymphocytes are not so common in this form
of leukemia as they are in the lymphatic variety. Such cells are
described under the latter disease. (See p. 319.)
Eosinophilia, as indicated by an increase in the total number of
eosinophiles, is almost invariably found, and an increase above
316 DISEASES OF THE BLOOD.
normal in the relative percentage of these cells sometimes, but not
always, exists.1 Thus, in the above-mentioned series the eosino-
philes, which normally do not exceed 500 per c.mm., ranged
from 780 to 129,150 and averaged 14,204 per c.mm., these figures
corresponding to percentages of 1.2, 28.7, and 5.4, respectively.
Ehrlich's original statement regarding an increase of the eosino-
philes in this form of leukemia has been contradicted by several
writers, notably by von Limbeck 2 and by Mtiller and Rieder3 ;
but these contradictions are based upon a misconception of Ehr-
lich's remarks, for he never claimed that an abnormally high
percentage of eosinophiles was associated with this disease, but
said simply that their absolute number was increased.
Marked variation in the size of many of the eosinophiles is com-
monly observed, dwarf forms, 5 or 6 p in diameter, with densely
crowded and deeply stained granules, being especially striking
and apparently more numerous than the larger forms. Eosino-
philic myelocytes, differing from ordinary 'neutrophilic myelocytes
only in that they are studded with eosinophile granules, are very
numerous, and are among the largest forms of the myelocyte
found in this disease. "Fractured" eosinophiles are common,
being usually more abundant than neutrophilic cells which have
thus traumatically suffered. In some of the eosinophiles the
granules are scanty, and in many their size varies greatly. Un-
usually large-sized granules are often found, especially in the
dwarf cells and in the extremely large forms.
Mast cells with coarse, metachromatic granules are found
with great constancy, being absent in but a small proportion of
cases. This cell is especially suggestive of leukemia of this
variety, since in no other disease does it occur in such large num-
bers. In 19 cases of the above series the mast cells averaged
9 per cent, in the differential leucocyte counts. In some
leukemic bloods the mast cells attain an enormous size, being
quite the largest cellular elements found in the specimen. They
may be easily identified by their characteristic reaction toward
the basic dyes, described in a previous section. (See p. 221.)
From the above remarks it may be concluded that myelocytes
and mast cells are present in the circulating blood at 'the expense
of all the normal varieties of leucocytes except the eosinophiles,
and that the brunt of this decrease is sustained by the mono-
nuclear, non-granular forms, chiefly by the small lymphocytes.
1 Simon's case, in which 13 differential counts were made, consistently showed
an absence of eosinophiles. (Amer. Jour. Med. Sci., 1903, vol. cxxv, p. 984.)
J Loc. cit. , f Deutsch. Arch. f. klin. Med., 1891, vol. xlviii, p. 96.
PLATE V.
LYMPHATIC LEUKEMIA.
( Triacid Stain.)
•uuac uwffiji VIIAII LUC lai^ci ,
7, 8, 9, 10, ii. Large Lymphocytes.
Except in 10, which shows a delicate rim of fuchsin-stained protoplasm, these lympho-
cytes appear simply as pale chromatin-deficient nuclear structures, lacking cell bodies.
Compare these cells with the myelocytes, Plate IV.
12. Transitional Form.
The upper edge of the nucleus is somewhat indented and the protoplasm is distin-
guishable; otherwise this cell resembles a large lymphocyte.
(E. F. FABKR,/<»C.)
LEUKEMIA. 317
These bodies are greatly increased in number
BLOOD in most cases of this form of leukemia, and may
PLAQUES. frequently be recognized in the fresh specimen
and in the diluted blood in the counting chamber
of the hemocytometer. They are very constantly observed in the
stained film prepared by the Romano wsky method.
LYMPHATIC LEUKEMIA.
In most cases the blood drop is watery-looking,
APPEARANCE pale, and thin, for in this variety of leukemia the
OF THE anemia is usually very marked. The milky ap-
FRESH BLOOD, pearance of the drop, frequently observed in the
myelogenous form of the disease, is not often
noticed in the lymphatic variety.
The alterations in the coagulability, alkalinity, and specific
gravity of the whole blood are similar to those met with in mye-
logenous leukemia.
Microscopically, the field is crowded with large numbers of leu-
cocytes, the vast majority of which are mononuclear cells encir-
cled by a perfectly hyaline, non-granular protoplasm. They may
be quite uniformly either of small or of large size, or so many inter-
mediate sizes may be present that it is impossible to distinguish
any single predominating type. It is apparent that the leuco-
cytes do not seem so numerous as in myelogenous leukemia,
nor are their characteristics so striking, at first glance, because of
the lack of granulations in their protoplasm. The difference
between these hyaline cells and the granular leucocytes of the
last-named disease, even although they may not happen to differ
greatly in size and shape, is at once patent to the practised eye.
The changes affecting the size, color, and shape of the eryth-
rocytes vary with the degree of oligochromemia and oligocy-
themia present; they are generally quite decided, as in any high-
grade anemia.
Marked anemia, characterized by a dispropor-
HEMOGLOBIN tionate diminution in hemoglobin, is the general
AND rule in this variety of leukemia, the decrease in
ERYTHROCYTES. both hemoglobin and erythrocytes, especially in
the former, being frequently greater than in the
myelogenous form. In a -series of 13 cases the following figures,
referring to the initial examinations, were obtained :
318 DISEASES OF THE BLOOD.
TABLE XI.— HEMOGLOBIN AND ERYTHROCYTES IN 13 CASES
OF LYMPHATIC LEUKEMIA.
HEMOGLOBIN NUMBER OF ERYTHROCYTES NUMBER OF
PERCENTAGE. CASES. PER C.MM. CASES.
From 40-50 i From 3,000,000-4,000,000 3
" 30-40 4 2,000,000-3,000,000 4
" 20-30 4 " 1,000,000-2,000,000 6
" 10— 20 4
.Average, 38.1 per cent. Average, 3,032,211 per c.mm.
Maximum, 47.0 " Maximum, 3,590,000 "
Minimum, 14.0 " " Minimum, 1,152,000 " "
In rare instances the number of erythrocytes falls below
1,000,000, and the hemoglobin so low that it is impossible to
estimate the percentage at all accurately. Rapidly developing
and extremely pronounced anemia is generally observed in cases
which pursue an acute course.
Nucleated erythrocytes, chiefly of the normoblastic type, are
commonly found in moderate numbers, but never, except in rare
instances, usually occurring in children, are they as numerous
as in the myelogenous form of the disease. As a rule, when
both normoblasts and mcgaloblasts are present, the former vastly
outnumber the latter, although occasionally one meets with a
case in which this predominance of adult-type erythroblasts is
less pronounced. Thus, in one of the writer's cases the total
number of erythroblasts was calculated at 10,678 per c.mm., of
which 8512 were normoblasts and 2166 megaloblasts ; such a
blood picture as this, however, is but seldom found. In general
terms it may be said that the more acute the form of the disease,
the more decided the oligochromemia and oligocythemia, and the
more abundant the erythroblasts, the number and character of
which appear to depend upon the grade of the anemia present.
It should not be forgotten that in some cases of typical lymphatic
leukemia nucleated erythrocytes are so scanty that they are detected
only after repeated examinations.
Deformities of size and shape and atypical staining of the eryth-
rocytes are marked in direct relation to the severity of the anemia.
The number of leucocytes is largely increased,
LEUCOCYTES, but usually much less strikingly so than in
myelogenous leukemia. Counts of 500,000 or
even of 1,000,000 cells have, it is true, -been reported by a few
observers, but only as rare examples of the extreme increase which
it is possible for the leucocytes to attain in this condition. The
cases in Table XII illustrate the range of the leucocytes in this
variety of leukemia.
LEUKEMIA. 319
TABLE XII.— NUMBER OF LEUCOCYTES IN 13 CASES OF LYM-
PHATIC LEUKEMIA.
LEUCOCYTES PER C.MM. NUMBER OF CASES.
Above 300,000 2
From 200,000-300,000 i
" 150,000-200,000 o
" 100,000—150,000 4
" 50,000-100,000 3
Below 50,000 3
Average, 270,822 per c.mm.
Maximum, 958,000 " "
Minimum, 38,000 " "
By examination of the stained film the identity of the leuco-
cytes responsible for the high count is more clearly distinguish-
able, and it is found that the increase is due to a large absolute
gain in the lymphocytes, the relative percentage of these cells to
the other varieties of leucocytes generally being 90, 95, or even
higher. In the series below summarized (Table XIII) these
non-granular cells averaged 89.8 per cent, of the leucocytes, and
equaled or exceeded 90 per cent, in three-fourths of the cases
examined. In some instances the small lymphocytes are found
to be in excess, and the field is dotted with small, deeply stained
cells ranging from about 5 to -10 /* in diameter; in other instances
the larger forms prevail, so that large, feebly stained cells, from
about 10 to 15 /* or even larger, are in excess; while in still other
cases the sizes and staining properties of the cells are so variable
and atypical that it is impracticable to class them in two definite
groups, large and small. It is generally- believed that small
lymphocytes are associated with the more chronic forms of the dis-
ease, and that the larger varieties are found in excess in the acute
cases. Many of the larger forms, which possess a relatively large
nucleus deficient in chromatin and a faintly basic non-granular
protoplasm, are regarded as the mother-cells of the typical small
lymphocytes. They are identical with the " lymphogonien " of
Benda and the " leukoblasts " of Lb'wit, cells resident in the ger-
minal nests of the lymphatic tissues.
TABLE XIII.— QUALITATIVE CHANGES IN THE LEUCOCYTES IN
13 CASES OF LYMPHATIC LEUKEMIA.
AVERAGE. MAXIMUM. MINIMUM.
Total lymphocytes ...89.8 97.7 53.0
Small lymphocytes 5 1 .4 94.0 21.1
Large lymphocytes 38.4 76.2 i .o
Polynuclear neutrophiles 7.6 45.0 1.6
Eosinophiles 0.6 5.0 o.i
Myelocytes i .4 4.9 0.3
Mast cells ' o. i i .o o.o
1 Estimates in 6 cases.
320 DISEASES OF THE BLOOD.
Various atypical forms of lymphocytes, the commonest of
which are pictured below (Fig. 55), are often numerous. With
basic stains, such as methylene-blue, a ragged, torn condition
of the basic seam of protoplasm, with so-called "budding," is
frequently demonstrable, as well as nucleolation of some cells,
especially of those of large size. Nuclear indentation and division
and forms characterized by a small lymphocyte's nucleus within
a large lymphocyte's cell body are also common.
The relative proportion of polynuclear neutrophiles is markedly
diminished, commonly to from about 5 or 10 per cent, of the
total number of leucocytes, and sometimes even to below one per
cent. These cells do not usually display the abnormal staining,
the nuclear peculiarities, and the irregularities in size and shape
that are so often seen in myelogenous leukemia.
Myelocytes are present in the great majority of cases, but al-
ways in trifling numbers, as in pernicious anemia; their propor-
tion rarely exceeds one or two per cent, of all forms of leucocytes.
I 2 3456
FIG. 55. — ATYPICAL FORMS OF LYMPHOCYTES IN LYMPHATIC LEUKEMIA.
i, Large lymphocyte with ragged protoplasm. Two small bits of protoplasm, the product of
"budding," lie free in the plasma beside the cell, a, Large lymphocyte showing a nucleolus. 3,
Large lymphocyte containing two nuclei. 4, Small lymphocyte containing an indented nucleus. 5,
Small lymphocyte containing two nuclei. 6, Cell the size of a large lymphocyte with the nucleus of
a small lymphocyte, (i and 2 are stained with eosin and methylene-blue; 3, 4, 5, and 6 with
Ehrlich's triacid stain.)
The percentage of eosinophiles is diminished, usually to a frac-
tion of one per cent., and in a certain proportion of cases these cells
are absent from the peripheral blood. It must be remembered,
however, that even with a low relative percentage figure for the
eosinophiles true eosinophilia may exist, although usually not to
so marked a degree as in the myelogenous form of the disease.
One per cent, of eosinophiles in a leucocyte count of 100,000 means
looo eosinophiles per c.mm. of blood, or twice the maximum num-
ber found in the normal individual. Eosinophilic myelocytes are
rare, but they occur in small numbers iri an occasional case.
Increase in the number of basophiles does not occur with great
frequency, and both the finely granular basophilic leucocytes and
the typical mast cells are generally conspicuous by their absence,
in contrast to their abundance in the myelogenous variety of this
disease.
LEUKEMIA. 321
From the above it is evident that in lymphatic leukemia the
increase in the total number of leucocytes is dependent upon a
marked absolute gain in the lymphocytes, and that in conse-
quence of this enormous influx of mononuclear hyaline forms,
the relative percentages of the other leucocytes, especially of the
polynuclear neutrophiles, are correspondingly diminished.
As in the myelogenous form, the number of blood plaques is
usually much increased.
This term has been applied to a form of leu-
ACUTE kemia which pursues a rapid course suggestive
LEUKEMIA, of an acute infectious process, and ends fatally
within a few weeks after the onset of the acute
symptoms. Rapid, progressive enlargement of the lymphatic
glands and a relatively small splenic tumor, associated with such
clinical features as rigors and irregular pyrexia, bone pains, ulcer-
ative stomatitis, and a decided tendency to purpura and to hemor-
rhages from the mucous membranes, serve to identify most cases
of this rapidly fatal disease. But, as already stated, there may
be no evidences of lymphatic or splenic involvement, the lesions
in such cases being confined to the bone marrow or to the deep
lymph nodes. Some authors limit the duration of acute leukemia
to six weeks, but the time limit proposed by Fraenkel,1 four months,
is generally accepted as being more appropriate.
The disease is a rare one, for probably less than 100 authentic
cases have been recorded up to the present time, although many
more reputed instances have been published. Ebstein \ collected
17 cases in 1889; Fraenkel3 published the statistics of 10 in 1895;
Bradford and Shaw4 described, in 1898, 5 cases coming under their
observation; and Fussell, Jopson and Taylor,5 in the same year,
published a collective report, embracing the statistics of- 57 cases
selected as representing all the true examples of acute leukemia
reported during the past twenty-one years. Since this report
about 30 additional cases have been described by various observers.6
Beyond stating that lymphemia is the type of blood character-
istic of acute leukemia, no special description of the condition of
the blood is necessary. In the majority of cases the leucocyte
increase may be attributed to a marked gain in the large lympho-
1 Deutsch. med. Wochenschr., 1895, vol. xxi, p. 639, et seq.
2 Deutsch. Arch. f. klin. Med., 1889, vol. xliv, p. 343. s Loc. cit.
4 Medico-Chirurg. Trans., London, 1898, vol. Ixxxf, p. 343.
5 Trans. Assoc. Amer. Phys., Philadelphia, 1898, vol. xiii, p. 124.
* For a review of the literature of acute leukemia see (i) Hamman, Amer. Med.,
1904, vol. vii, p. 138; (2) Kelly, Univ. of Penna. Bull., 1903, vol. xvi, p. 270; (3)
Miller and Hess, Amer. Med., 1904, vol. vii, p. 389; (4) Mixa, Wien. klin. Rund-
schau, 1901, vol. xv, pp. 655 and 671; (5) Billings and Capps, Amer. Jour. Med.
Sci., 1903, vol. cxxvi, p. 375.
322 DISEASES OF THE BLOOD.
cytes, which greatly predominate over the small forms, while the
polynuclear neutrophiles, myelocytes, and eosinophiles are rela-
tively few in number. As a rule, the more acute the case, the
more decided the predominance of the large lymphocytes, which
usually show well-marked evidences of nuclear and protoplasmic
degenerative changes. The loss of hemoglobin and erythrocytes
is generally more marked and the erythroblasts are more numer-
ous, than in the commoner forms of chronic lymphatic leukemia.
The blood may coagulate very imperfectly and the plaques are
often greatly diminished in number. In a case reported by
Bensaude,1 total absence of clotting and of serum transudation
was noted after the expiration of twenty-four hours.
Acute leukemia may begin as such, or either the chronic lym-
phatic or the myelogenous form may develop acute symptoms,
with a coincident change in the condition of the blood, but this
change in the myelogenous variety is extremely rare. Only nine
cases of acute myelogenous leukemia are on record.2
The development of an acute infectious proc-
INFLUENCE OF ess in a leukemic individual commonly provokes
ACUTE INTER- striking changes in the behavior of the leucocytes,
CURRENT IN- consisting in most instances in a decrease of their
FECTIONS. total number to the c.mm. of blood, associated
sometimes with an increase in the polynuclear
variety of cells and a relative diminution in the number of myel-
ocytes. At other times there is practically no alteration in the
relative proportions of the different forms as they existed in the
leukemic blood prior to the onset of the complicating infection.
Among the infectious conditions acting in this manner on the
leucocytes are abscess, sepsis, pneumonia, influenza, tuberculosis,
and erysipelas, but it seems that rheumatic fever has no such effect.
Weil,3 who has studied the effects of colon, pneumococcus, and
streptococcus infections in both forms of leukemia, comes to the
conclusion that the most powerful influence upon the blood pic-
ture is exerted by streptococcus infections. Malignant disease
is also capable of bringing about a leucocyte decrease characterized
by a relative gain in polynuclear neutrophiles at the expense of
the lymphocytes, but the loss does not appear to be so decided as
that excited by a specific infectious process.
In rare instances the occurrence of an, infectious disease fails to
cause a decrease ift the leucocytes, and thus to destroy the leu-
kemic picture, but, on the contrary, increases them, by superim-
1 Sem. med., 1903, vol. xxiii, p. 57.
J Billings and Capps, loc. cit.
3 Gaz. hebdom. de med. et de chir., 1900, vol. v, p. 829.
LEUKEMIA. 323
posing a typical polynuclear neutrophile leucocytosis, which re-
mains during the existence of the complicating infection the
conspicuous feature of the blood. The writer has observed a
typical illustration of such a change in a case of myelogenous
leukemia, in which, within ten days after the onset of a complicat-
ing peritonitis, the leucocyte count rose from 245,000 to 400,000,
and the proportion of polynuclear neutrophiles from 44.5 to 79
per cent., while the percentage of myelocytes fell from 20.5
to 8.
Dock1 has collected 50 cases of leukemia complicated by
various intercurrent infections, which in 27 instances were tuber-
culous and in 23 non-tuberculous. In leukemia plus tuberculosis
the virulence of the complicating infection appears to govern the
behavior of the leucocytes, which are not decidedly influenced
in chronic forms of the disease, but which usually are greatly
diminished in the acute miliary type. In the 23 cases of inter-
current infections other than tuberculosis Dock's analysis shows
that a marked leucocyte decrease occurred in n, a relatively
slight decrease in 9, and either an increase or no change in the
remaining 3. Of qualitative changes in these cases there was
noted a general tendency of the leucocytic blood picture to dis-
appear, with a decided increase, both absolutely and relatively,
in the polynuclear neutrophiles. Dock's masterly monograph
should be consulted for a complete account of this complicated
topic, which does not lend itself to text-book discussion.
Coincidentally with the improvement in the condition of the
blood there is frequently a decrease in the size of the patient's en-
larged spleen and lymphatics, the period during which the leukemic
condition is thus bettered, and, so to speak, held in abeyance,
corresponding to the duration of the complicating infection, for
the blood gradually regains its leukemic type and the glandular
and splenic tumors reappear as recovery from the intercurrent
disease takes place.
D NO The following blood picture is characteristic
of the myelogenous variety of leukemia:
Hemoglobin. Decided loss, averaging about 50 per cent. Color
index subnormal, or high.
Erythrocytes. Counts average about 3,000,000 per c.mm.
Erythroblasts very numerous, cells of the normo-
blastic type predominating.
Deformities of size and shape, polychromato-
philia, and basophilic stroma degeneration marked
in cases with severe anemia.
1 Amer. Jour Med. Sci., 1904, vol. cxxvii, p. 563.
324 DISEASES OF THE BLOOD.
Leucocytes. Increased to about 350,000 per c.mm.
Myelocytes constitute about 20 per cent, of all
forms.
Relative percentage of polynuclear neutrophiles
low.
Relative percentage of lymphocytes very low.
Eosinophiles .absolutely, sometimes relatively, in-
creased.
Mast cells average about 10 per cent, of all forms.
Atypical forms of neutrophiles numerous.
Plaques. Increased.
In lymphatic leukemia the blood changes may be briefly ex-
pressed thus:
Hemoglobin. Marked loss, averaging about 60 per cent. Color
index low.
Erythrocytes. Counts average about 3,000,000 per c.mm.
Erythroblasts usually scanty, cells of the normo-
blastic type predominating.
Deformities of size and shape and atypical stain-
ing reaction marked in relation to the degree of
anemia present.
Leucocytes. Increased to about 250,000 per c.mm., counts
above this figure being rare.
Lymphocytes constitute about 90 per cent, of all
forms.
Relative percentage of polynuclear neutrophiles
strikingly low.
Relative percentage of eosinophiles diminished;
rarely, an absolute increase.
Small numbers of myelocytes frequent.
Basophiles usually not increased.
Atypical forms of lymphocytes numerous.
Plaques. Increased.
In dealing with the differential diagnosis of leukemia it is nec-
essary to distinguish the myelogenous from the lymphatic form,
and also to differentiate both forms of the disease from a number
of other conditions wrhich may present either somewhat similar
blood findings or which, apart from the condition of the blood,
may have closely similar clinical manifestations. Thus, on the
one hand, leucocytosis and lymphocytosis require differentiation
because they produce changes in the blood which may be con-
fused with leukemia; while, on the other hand, one must dis-
tinguish between leukemia and Hodgkin's disease, splenic anemia,
and a number of conditions causing enlargement of the spleen,
LEUKEMIA. 325
neighboring organs, and lymphatic glands, because of the resem-
blance, even the identity in some instances, of the other clinical
signs.
Myelogenous and lymphatic leukemia can be distinguished
only by examination of the blood, for the distinction between
these two forms of the disease cannot be based with any degree
of certainty upon the gross clinical appearance of the spleen and
lymphatics. Nothing can be more marked than the contrast be-
tween the two blood pictures. In the myelogenous form the
leucocyte count is usually much higher, and is associated with the
presence of immense numbers of myelocytes, and with an increase
in the eosinophiles and mast cells; the oligocythemia is not so
marked, but erythroblasts are exceedingly numerous, and, strangely,
tend to persist independently of any increase in the erythrocytes
which may occur from time to time. In the lymphatic form
the relatively moderate leucocyte increase depends upon an
excessive gain in the ungranulated cells, or lymphocytes, myelo-
cytes being either absent or present in trifling numbers, and
decided increase in the eosinophiles and mast cells being most
unusual; the oligocythemia is usually decided, but erythroblasts
are scanty, and stand in relationship to the degree of anemia
existing. The important points of difference are, therefore, the
presence of a myelocytic blood in the myelogenous form, .and of
a lymphocytic blood in the lymphatic variety.
Pathological leucocytosis may occasionally involve an increase
in the total number of leucocytes equal to that found in either
form of leukemia, especially in those cases in whicti a period
of temporary improvement with a fall in the leucocyte count
exists. But, aside from the more or less temporary character of
the increase in leucocytes, the differential count at once shows
that, unlike leukemia, the gain depends upon a large absolute and
relative increase in the polynuclear neutrophiles, which constitute
ordinarily 85 per cent, or more of the several forms of leucocytes.
Lymphocytosis, which is usually a relative condition, may in
rare instances become absolute, so that, in addition to the increase in
the relative percentage of lymphocytes, the total number of leu-
cocytes in the blood is also decidedly increased. In marked in-
stances of this sort it is obviously impossible to distinguish the
blood change from that of lymphatic leukemia, and the aid of
other clinical symptoms must be invoked to make the diagnosis
clear. Thus, both an absolute and a relative lymphocytosis,
closely simulating the lymphatic form of leukemia, have been
observed in severe cases of chlorosis, in pertussis, in sarcoma of the
lymphatic structures, and in acute inflammatory processes oc-
326 DISEASES OF THE BLOOD.
curring in young children. The author recalls an instance of
marked absolute lymphocytosis in a case of pernicious anemia
which seemed to justify the tentative diagnosis of lymphatic leu-
kemia, an error which was later corrected, when the megaloblastic
blood picture became apparent. In such instances, which are,
fortunately, of very rare occurrence, it is true that neither the perr
centage of lymphocytes nor" the count of leucocytes is likely to
average so high as in lymphatic leukemia, but still the blood
changes are sometimes very misleading, and should not be relied
upon to the exclusion of other equally important symptoms.
The glandular and splenic enlargements of Hodgkin's disease
form a clinical picture identical with either the myelogenous or
the lymphatic variety of leukemia, so that these conditions are
distinguishable only by the result of the blood examination. But
by this means the diagnosis is made extremely simple, by finding
in Hodgkin's disease either entirely normal blood or a variable
degree of anemia. • The number of leucocytes is usually nor-
mal, except in cases in which some complicating inflammatory
or infectious process causes a moderate increase, typical of a
polynuclear neutrophile leucocytosis.
In chloroma the blood changes may be practically those of
an acute lymphatic leukemia — progressive anemia with absolute
lymphocytosis. In chloroma, however, the clinical picture is
made up of exophthalmos, deafness, orbital pain, elastic swellings
of the orbital and temporal regions, and a tendency toward met-
astases of the "green tumors" in periosteal structures.
Von Jaksch's multiple periostitis is a symptom-complex
resembling myelogenous leukemia, in that a myelocytic anemia
with splenic enlargement and a tendency toward hemorrhage are
symptoms common to both conditions. In the early stages of the
disease described by von Jaksch, fever, drenching sweats, painful
and swollen joints, and thickening of the distal extremities of the
radius and ulna are observed, these distinctive symptoms being
succeeded by a preagonal stage marked by a cessation of the bone
pains and sweating and by an aggravation of the" already marked
anemia, splenomegaly, and hemorrhagic tendency.
Still's disease, because of the splenic and lymph-node enlarge-
ments, may superficially resemble leukemia, but in this form of
infantile arthritis, besides an aleukemic blood picture, one finds
multiple arthritis,- especially of the periarticular structures, and
usually a clear history of rickets.
The rather close resemblance which certain cases of splenic
anemia bear to leukemia, together with the points of difference
between them, have already been described. (See p. 295.)
HODGKIN'S DISEASE. 327
Enlargements of the spleen, left kidney, and pancreas may lead
to the belief that leukemia exists. Thus, splenic tumors due
to chronic malarial infection, to amyloid disease, to cysts, and to
malignant neoplasms; enlargements of the left kidney, such as
can be caused by hydronephrosis, by cysts, and by malignant
disease; as well as cystic tumors of the pancreas and malignant
disease of the retroperitoneal glands all may, on physical exami-
nation, simulate more or less faithfully the leukemic spleen. The
negative character of the blood findings will at once exclude leu-
kemia, should one of the above-named conditions be the cause
of the physical signs suggesting this disease.
Lymphatic hyperplasia, due to tuberculosis, to syphilis, and to
malignant disease, may also be mistaken for the glandular in-
volvement of leukemia, for such enlargements sometimes show
nothing distinctive. In tuberculous adenitis the blood is either
normal or anemic, if the cachectic state of the patient is marked;
or, should there happen to be a secondary infection of the glands
plus the tuberculous lesions, a simple polynuclear leucocytosis
is found. In syphilitic adenitis there is often anemia with a mod-
erate polynuclear leucocytosis, and sometimes with a relative
lymphocytosis, especially in children. In malignant disease of
the lymphatics increase in the number of leucocytes may also be
noted in association with a high-grade anemia; in carcinoma the
increase involves chiefly the polynuclear neutrophiles, but in sar-
coma the lymphocytes may be unduly increased, though not to
the extent found in lymphatic leukemia.
VII. HODGKIN'S DISEASE.
Nothing characteristic is observed either., in
APPEARANCE the gross appearance of the fresh blood drop or in
OF THE the unstained film, microscopically. The blood
FRESH BLOOD, may appear normal, or it may show changes
common to any secondary anemia.
The alkalinity and specific gravity of the whole blood are di-
minished in relation to the degree of anemia which exists. Coag-
ulation may take place slowly, and even be as incomplete as it
is in some cases of leukemia; or it may occur within the normal
time limit.
Both the hemoglobin percentage and the
HEMOGLOBIN number of erythrocytes are normal in the early
AND stages of the disease, and in slowly progressive
ERYTHROCYTES. cases the blood may remain unaffected for a long
period. But sooner or later, as the disease pro-
328 DISEASES OF THE BLOOD.
gresses and a cachectic condition of the patient develops, anemia
appears, gradually where the course of the disorder is slow, and
rapidly in the more acute forms. Counts made when the patient
first comes under observation usually average 4,000,000 or 5,000,-
ooo cells per c.mm., but in the later stages the number frequently
falls to one-half this figure pr even less. The loss of hemoglobin
begins earlier, and in most instances is proportionately somewhat
greater, than the erythrocyte decrease, so that subnormal color
indices rule — not decidedly low, but yet twenty points or so below
the normal standard. In cases which develop excessive oligocy-
themia the index figures may be quite as high as in pernicious
anemia.
In the series of 21 cases summarized in Table XIV, the hemo-
globin averaged about 55 per cent., ranging between 30 and 81
per cent.; the erythrocyte count ' averaged 3,591,423 per c.mm.,
the minimum being 1,300,000 and the maximum 5,225,000, with
more than one-third of the cases having 4,000,000 cells or more.
TABLE XIV.— HEMOGLOBIN AND ERYTHROCYTES IN 21 CASES
OF HODGKIN'S DISEASE.
HEMOGLOBIN. NUMBER OF ERYTHROCYTES NUMBER OF
PERCENTAGE. CASES. PER C.MM. CASES. -
From 80-90 3 Above 5,000,000 2
70-80 3 From 4,000,000-5,000,000 6
60—70 i 3,000,000-4,000,000 10
50—60 6 2,000,000-3,000,000 i
40-50 4 " 1,000,000—2,000,000 2
30-40 4
Average, 55.3 per cent. Average, 3,591,423 per c.mm.
Maximum, 81.0 " " Maximum, 5,225,000 " "
Minimum, 30.0 " " Minimum, 1,300,000 " "
Qualitative changes affecting the corpuscles occur in relation
to the intensity of the anemic process, deformities of shape and
size and atypical staining reaction of the cells being associated
with cases in which notable hemoglobin and erythrocyte losses
exist, and being absent when the anemia is moderate. Nucle-
ated erythrocytes are not common, nor are they numerous when
present. Usually they are wanting, except in connection with a
high-grade anemia, under which circumstance a few normoblasts
may be detected, and in rare instances an occasional megaloblast.
In the average case the leucocytes are normal,
LEUCOCYTES, both in number and in the relative percentage of
different varieties. More rarely, relative lym-
phocytosis occurs, involving a decrease in the percentage of poly-
nuclear neutrophiles, but not increasing the total number of
leucocytes. An instance of this kind has been observed by the
HODGKIN'S DISEASE. 329
writer, in which the relative proportion of lymphocytes to other
forms of leucocytes habitually remained for some months between
70 and 85 per cent., this change affecting chiefly the large lym-
phocytes, while the total leucocyte count never exceeded normal.
TABLE XV.— NUMBER OF LEUCOCYTES IN 21 CASES OF HODG-
KIN'S DISEASE.
LEUCOCYTES PER C.MM. NUMBER OF CASES.
Above 20,000 1
From 15,000—20,000 3
" 10,000—15,000 4
" 5,000—10,000 7
Below 5,000 6
Average, 8,819 Per c.mm.
Maximum, 21,000 "
Minimum, 1,000 " "
If secondary infection takes place, it soon becomes evident by
an increase in the leucocytes to about 20,000 or more, principally
involving the polynuclear neutrophile cells, at the expense of the
lymphocytes — a picture of typical leucocytosis. In some in-
stances, however, without any apparent signs of a secondary in-
fection or of a glandular inflammation, the total count may ex-
ceed the normal standard by several thousand cells, and yet show
a normal or even somewhat decreased proportion of neutrophiles.
These changes in the blood picture must be distinguished from
those indicating the conversion of Hodgkin's disease into true
lymphatic leukemia. This transition, although exceedingly rare,
probably sometimes occurs, as shown by Wende/ Posselt,2
Senator,3 Hosier,4 Fleischer and Penzoldt,5 and others. Should
the anemia be very marked, pronounced leucopenia is commonly
associated with it. In the present series (Table XV) about one-
fourth of the cases showed frank leucocytosis, the highest estimate
being 21,000, the lowest 1000, and the -average 8819.
TABLE XVI.— QUALITATIVE CHANGES IN THE LEUCOCYTES IN
21 CASES OF HODGKIN'S DISEASE.
, AVERAGE. MAXIMUM. MINIMUM.
Small lymphocytes 16.5 49.0 i.o
Large lymphocytes 10.8 21.0 0.5
Polynuclear neutrophiles ...69.6 88.0 46.2
Eosinophiles 2.2 10.0 o.o
Myelocytes ._ 0.5 3.0 o.o
• Mast cells * .' .' 0.9 i . r o.o •
1 Amer. Jour. Med. Sci., 1901, vol. cxxii, p. 836.
2 Wien. klin. Wochenschr., 1895, vol. viii, p. 407.
3 Berlin, klin. Wochenschr., 1882, vol. xix, p. 533.
4 Virchow's Arch., 1888, vol. cxiv, p. 461.
5 Deutsch. Arch. f. klin. Med., 1896, vol. Ixvii, p. 300.
* Estimates in n cases.
33°
DISEASES OF THE BLOOD.
Small numbers of myelocytes are not uncommon in the ad-
vanced anemia of Hodgkin's disease, but they are never more
numerous than in any other condition accompanied by a similar
deterioration of the blood. These cells were found in 8 of the 21
cases under consideration.
Small numbers and low percentages of eosinophiles are the
rule, in cases both with and without leucocytosis ; it is most un-
usual for these cells to attain the maximum normal figure, and
they are sometimes wholly absent.
Neither the finely granular basophiles nor the typical mast cells
are increased in this disease. The author found the latter in but
a single case of n examined.
As in both forms of leukemia, the number of blood plaques in
Hodgkin's disease is usually increased. ,
Although no characteristic blood changes
DIAGNOSIS, occur in this condition, the alterations most com-
monly observed may be briefly summed up as
follows :
Hemoglobin. Normal in the early stages of the disease; later, a
moderate decrease, estimates averaging about 55
per cent. Color index commonly subnormal,
rarely high.
Erythrocytes. Normal in the early stages ; later, a variable degree
of oligocythemia, counts averaging about 3,500,-
ooo per c.mm.
Erythroblasts uncommon and scanty when pres-
ent.
Normoblasts prevail almost exclusively, megalo-
blasts being very rare.
Deformities of size and shape, polychromato-
philia, and basic stroma degeneration only in cases
with high-grade anemia.
Leucocytes. Normal or moderately increased.
Either polynuclear neutrophiles pr lymphocytes
may be relatively increased, more commonly the
former.
Small numbers of myelocytes in very anemic
cases.
Eosinophiles not increased.
Basophiles not increased.
Plaques. Usually increased.
The absence of characteristic blood changes in Hodgkin's
disease at once distinguishes the condition from its clinical coun-
terfeit, leukemia, but, aside from this single disease, the blood ex-
HODG KIN'S DISEASE. 331
amination is valueless in the differentiation of other conditions
having somewhat similar involvement of the glandular structures.
These conditions, tuberculous and syphilitic adenitis, local lympho-
matous tumors, and malignant neoplasms of the lymphatics, must
therefore be distinguished from Hodgkin's disease by other clin-
ical methods, for all may provoke identical blood changes.
In reviewing the clinical history of a case of suspected Hodg-
kin's disease the following symptoms should be given special
consideration: the gradual onset of a widespread hyperplasia of
the lymphatic structures, occurring most commonly in males
under middle age; the progressive character and chronicity in
most cases of the disorder; the tendency in some cases toward
the occurrence of unexplained febrile periods, sometimes coincid-
ing with a rapid and marked increase in the size of the affected
glands which- disappears as the fever subsides; the cachexia,
asthenia, and emaciation of the patient, frequently associated with
gastro-intestinal and circulatory disturbances and with a tendency
to hemorrhages, such as epistaxis and purpura; the presence of
pressure symptoms, such as cough, dysphagia, dyspnea, edema,
and pleural and peritoneal effusions; and the development of
bronzing of the skin in an occasional case.
In typical cases the glandular enlargement forms a series of
distinct, painless, hard tumors, each freely separable from its
neighbor, and rarely caseating or suppurating. Due weight
should also be given to the fact that in the majority of cases the
lesion originates in the superficial lymphatic glands of the cervical
region, beginning either in the occipital or in the inferior carotid
triangle. The spleen is moderately enlarged in the majority of
cases, and in others the liver, kidneys, suprarenals, tonsils, thymus,
thyroid, and sexual organs may be involved in the lymphoid
growths.
As in leukemia, remarkable improvement in the blood and
other clinical features of Hodgkin's disease is reported by Senn,1
by Steinwald,2 by Childs,3 and by Pusey4 as the result of #-ray
treatment.
Tuberculous adenitis usually first involves a group of glands in
the submaxillary triangle, and tends to produce inflammatory
adhesions between the tissues and the glandular structure, with
softening, fusing; caseation, and suppuration of the glands. It is
of sluggish development, often occurs in the very young, and is
1 N. Y. Med. Jour., 1903, vol. Ixxvii, p. 665.
2 Medicine, 1904, vol. x, p. 438.
SN. Y. Med. Jour., 1904, vol. Ixxx, p. 13.
4 Jour. Amer. Med. Assoc., 1902, vol. xxxviii, p. 911.
332 DISEASES OF THE BLOOD.
almost always confined to a single group of glands. Evidences
of tuberculous lesions in the lungs or in other parts of the body,
especially of dental caries, cutaneous lesions of the face, and ade-
noid pharyngeal growths, and the discovery of tubercle bacilli in
the glandular tissue are valuable evidences of the tuberculous
nature of the disease, yet they do not positively exclude Hodg-
kin's disease, since the coexistence of the two conditions in the
same individual is possible beyond a doubt. Steinberg's belief1
that Hodgkin's disease is essentially tuberculosis is still supported
by Musser2 and Sailer,3 although the recent brilliant work of
Dorothy Reed,4 of Longcope,5 and of Simmons 6 is convincing proof
that the disease is a distinct clinical entity, in no way related
pathologically to the tubercle bacillus.
In syphilitic adenitis of the neck the post-cervical groups are
first affected, the glands being of cartilaginous hardness, painless,
freely movable, and of small or moderate size. The glandu-
lar enlargement is often more or less general, but the affected
groups do not attain a large size. A history of an initial lesion
in the vicinity of the primary glandular swellings, or of the ap-
pearance of secondary symptoms, the disappearance of the glan-
dular tumors after the administration of mercury, and the pres-
ence of Justus' test will suffice to prove the specific character of
the hyperplasia.
A local lymphoma is limited strictly to a single group of glands,
forming a painless, dense mass, free from inflammatory adhesions,
caseation, and suppuration. It commonly involves the submaxil-
lary glands, may attain a large size, and is unassociated with con-
stitutional symptoms. Such a local lymphatic tumor cannot be
distinguished from the early stage of Hodgkin's disease, for in
some cases of the latter the general lymphoid hyperplasia is pre-
ceded by a period during which the only sign of the condition is
a localized enlargement of a single group of glands. If, accord-
ing to Osier,7 a local tumor of this kind persists^ for over a year
or eighteen months without involving the glands of the opposite
side or of the axilla, it is almost certainly a non-malignant
lymphoma.
Sarcoma of the lymphatic tissue forms an immovable tumor,
early complicated by inflammatory processes which cause inter-
glandular adhesions and adhesions between the glands and the
1 Zeitschr. f. Heilk., 1898, vol. xix, p. 21. 2 Amer. Med., 1902, vol. iii, p. 13.
3 Phila. Med. Jour., 1902, vol. x, pp. 615 and 669.
4 Johns Hopkins Hosp. Rep., 1902, vol. x, p. 133.
5 Bull. Ayer Clin. Lab.? Penna. Hosp., 1903, vol. i, p. 4.
8 Jour. Med. Research, 1903, vol. ix, p. 378.
7 Cited by Bramwell, "Anemia," Philadelphia, 1899, p. 203.
THE EFFECT ON THE BLOOD OF SPLENECTOMY. 333
surrounding tissues. The swelling is often red and inflamed, pits
upon pressure, and resembles an abscess, while the skin over the
site of the lesion is frequently marked by a maze of tortuous,
congested, cutaneous veins, and is prone to ulcerate. If nerves
are entangled in the growth, the tumor is exquisitely painful.
The adjacent tissues become densely infiltrated by the sarcomatous
growth, and involvement of distant organs by metastasis is likely
to occur. If such be the case, microscopical search for sarcoma
cells in the fresh specimen may give a definite clue. (See " Sar-
coma," Section VII.) Sarcoma of the lymphatic glands may
occur at any period of life.
Carcinoma of the lymphatic glands is secondary to an initial
growth in some other part of the body, so that in the region of
the neck search should be made for a primary cancerous lesion
in the mouth and upper air-passages. The disease is most com-
monly found during the decline of life.
Finally, as Tyson so pertinently remarks,1 it should not be for-
gotten that all the conditions named as possible to be mistaken
for Hodgkin's disease are limited to a single group of glands,
while Hodgkin's disease always extends, and the fact of such
limitation is of itself sufficient to exclude the disease. This pro-
gressive involvement of the lymphatic glands, group after group,
must, after all, be the mainstay in the diagnosis of doubtful- cases.
VIII. THE EFFECT ON THE BLOOD OF SPLENEC-
TOMY.
Excision of the spleen in man is followed by a
HEMOGLOBIN diminution in the hemoglobin and erythrocytes,
AND the degree of which is generally believed to be
ERYTHROCYTES. more, pronounced than can be accounted for by
the simple factor of hemorrhage incident to the
operation. Blood regeneration is slow, especially the restoration
of the 'hemoglobin, which is prone to increase much less rapidly
than is the rule in an ordinary secondary anemia. In uncompli-
cated cases from one to three months' time usually elapses be-
fore the normal percentages of hemoglobin and erythrocytes are
attained; in unfavorable cases persistence of the anemia for a
much longer period is to be observed. Splenectomies attended
by great loss of blood may excite, in addition to an extreme cel-
lular decrease, striking qualitative changes, and in such instances
the blood picture is characterized by the presence of many normo-
1 "Practice of Medicine," Philadelphia, 1898, p. 606.
334
DISEASES OF THE BLOOD.
blasts, achromacytes, and corpuscles deformed in shape and size.
Conspicuous post-operative anemia is especially common in pa-
tients to whom saline intravenous injections have been admin-
istered.
TABLE XVII.— THE EFFECT ON THE BLOOD OF SPLENECTOMY
NUUBEK.
EMOGI.OBIN.
0
H
I
EUCOCYTES.
a £
^|
ARGE LYM-
'HOCYTES.
If
SINOPHILES.
NOTES.
H
i
,3
CJ3
i-4
O
W
fc
W
i1
65
5,200,000
2,2OO
22
5
70
3
Before operation.
Megaloblasts and nor-
moblasts found.
65
5,000,000
24,OOO
3-6
3-2
93
O.2
2 days after operation.
2I,4OO
3
23,800
4
l8,OOO
5
l8,000
8
45
3,256,000
24,000
7-9
8-5
8!
2.6
n ' "
Myelocytes and mast
cells found. No eryth-
roblasts.
l6,400
1 6 days after operation.
45
4,496,000
I7,OOO
7-8
9
76.8
6.2
21 "
Myelocytes, 0.2 per cent.
40
3,984,000
2O,OOO
9
7-4
82.2
1-4
27 days after operation.
No erythroblasts.
40
4,000,000
I5,OOO
5-8
7-4
82.8
4
37 days after operation.
52.5
4,672,000
2I,6OO
15.8
8.8
73-4
2
56 " "
Myelocytes found; no
erythroblasts.
l6,OOO
5-6
IO.2
79-8
3-5
99 days after operation.
Erythrocytes normal.
2Z
108
4,850,000
30,000
8
8
83
i
Before operation.
IOO
4,700,000
39,000
5
4
o
7 days after operation.
105
3,630,000
18,000
15
6
78
I
60 " "
63
2,750,000
20,000
5
10
84
I
3 years " "
3s
45
1,634,000
12,000
16
20
61
3
14 days "
87
2,460,000
20,000
18
32
49
i
27 ," "
no
4,530,000
27,000
18
15
66
i
33 " "
IOO
3,977,000
8,000
21
n
62
6
2 years and six months
after operation.
4T
63
4,570,000
8,000
Before operation.
64
4,970,000
30,000
3 days after operation.
77
5,180,000
65,000
6 "
66
4,800,000
17,500
48 " "
85
4,353-000
11,700
4 m'ths "
85
3,300,000
1 1, 600
5 years "
1 Warren, Annals of Surgery, 1901, vol. xxxiii, p. 513.
2 Hartmann and Vaquez, Compt. rend Soc. biol., Paris, 1897, vol. iv, p. 126.
3 Ibid. 4 Czerny, cited by Vulpius, Beitrage z. klin. Chir., 1894, vol. xi, p. 633
THE EFFECT ON THE BLOOD OF SPLENECTOMY.
335
TABLE XVII. — THE EFFECT ON THE BLOOD OF SPLENECTOMY. — (Continued.')
S1
•
•
H
jj
it
s
O
u
Hlg
o
a
o
o
a
o
J o
K
i
H
1
60
4,300,000
22,000
14
72
4,408,000
13,000 13
77
4,420,000
II,20O
12
83
3,280,000
22,000
3,980,000
26,000
85
4,480,000
24,OOO
33
82
4,280,000
l8,OOO
86
4,300,000
12,000
90
4,220,000
IO,OOO
27
92
4,630,000
I2,OOO
40
4,100,000
6o,OOO
6
So
4,370,000
46,000
4,300,000
38,000
11.4
26,000
17,000
4,500,000
25,OOO
7.1
75
4,480,000
IO,4OO
14-3
24
12
15
19
16
101
4,700,000
5.700
59-i
in
5,600,000
12,300
42.9
91
4,500,000
15,000
18.0
73
3,900,000
11,300
30.5
85
3,500,000
IO,OOO
26.7
93
4,000,000
8,OOO
32-9
102
5,300,000
7.500
35-9
W O
0 O
18.1
8.6
30.1
1-9
2.2
1.8
2-7
POLYNUCLEAR
NEUTROPHILES.
EOSINOPHILES.
NOTES.
77
66.5
65.2
2
i-5
2
6 days after operation.
19 ""
26 " "
Normoblasts found.
53
63
IO
3
4 days after operation.
8 ;; ;: i
14
18 "
25 « «
30 " "
52 ' " "
81.6
78.9
60. i
61.9
°-3
i.i
2-3
6.7
7 days after operation.
15 " "
19 " "
38 " "
46 " "
2 m'ths "
5 " "
67
77
80
7i
72
2
3
I
3
4
Before operation.
7 days after operation.
30 " " • «
45 " " - "
90 " «
59-i
52.1
78.6
65.6
67.9
58-8
58.5
4.2
3-2
1.4
i-5
3-5
5-5
•3-7
60 days after operation.
91 "
128 "
138 " "
161 "
212 "
13 m'ths " " *
Mast cells ranged from
0.15 to 0.3 per cent.
• Post-operative leucocytosis of the polynuclear
LEUCOCYTES, neutrophile type develops promptly, and persists
in most instances for from four to six weeks, ac-
cording to Hartmann and Vaquez,6 but occasionally for a longer
period. Counts of between 15,000 and 30,000 represent the grade
1 Tieken, Jour. Amer. Med. Assoc., 1903, vol. xl, p. 887.
2 Ballance, Practitioner, 1898, vol. Ix, p. 347.
3 Heaton, Brit. Med. Jour., 1899, vol. ii, p. 476.
4 Hartmann and Vaquez, cited by Bordet, "Des modifications du sang apres
la splenectomie," These, Paris, 1897.
s Staehelin, Deutsch. Arch. f. klin. Med., 1903, vol. Ixxvi, p. 364.
* Compt. rend. Soc. biol., Paris, 1897, vol. iv, p. 126.
336 DISEASES OF THE BLOOD.
of leucocytosis ordinarily found, although occasionally the increase
is far greater — 70,000 in a case cited by Czerny,1 and 75,000 in
one reported by Hartley.2 After a number of months, even as
late as the second or third year after the operation, there is a
moderate increase in the number of eosinophiles. Small-celled
lymphocytosis is a frequent but inconstant change, the develop-
ment and duration of which vary greatly. It is supposed to reflect
hyperactivity of the lymphatic glands. Eosinophilia commonly
develops within a few months, as in a case studied by Rauten-
berg,3 in which the eosinophiles increased to six times the normal
percentage by the fourth week' after the operation. In splen-
ectomized guinea-pigs Kurloff4 found during the first year after
the operation a marked lymphocytosis, as high as 60 per cent,
in some animals, together with a corresponding decrease in the
number of granular cells, but with no alteration in the num-
ber of large monoriuclear leucocytes. Eosinophilia became ap-
parent during the second year, and coincidentally with this change
a decrease in the lymphocytes to their normal percentage took
place. In splenectomized dogs Nicholas and Dumoulin5 noted
post-operative leucopenia, succeeded by eosinophilia and by
lymphocytosis, which, after several months, was followed by a
gradual, progressive lymphocyte decrease. The polynuclear neu-
trophiles showed relatively high percentages, but were not de-
cidedly increased.
The above remarks concerning the differential changes affect-
ing the leucocytes after splenectomy must be regarded as tenta-
tive, in view of the fact that sufficient data bearing upon this
question have not yet accumulated to justify more definite con-
clusions. Enlargement of the lymph glands, bone pains, and a
marked susceptibility to various infections are frequent post-
operative phenomena in splenectomized individuals.
The table on page 334 shows the condition of the blood in the
few recorded cases in which thorough blood examinations have
been carried out. Reports of other cases may be ^ound in Staehe-
lin's monograph, referred to above.
It is to be remembered that, aside from the character of the
splenic lesion, these important factors also determine the degree
of the post-operative anemia and leucocytosis in this procedure:
the grade of the preexisting anemia, the amount of hemorrhage
during the following operation, and the patient's recuperative
powers. All things being equal, the anemia is least marked and
1 Loc. cit. 2 Med. News, 1898, vol. Ixxii, p. 417.
3 Deutsch. Zeitschr. f. Chir., 1902, vol. Ixiv, p. 352. 4 Cited by Ehrlich, loc. cit.
5 Journ. de phys. et de path, gen., 1903, vol. v, p. 1073.
8u6
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HODGKIN'S DISEASE.
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Normal or moderate decre
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Poikilocytosis usually abseni
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Normal or slightly increa
counts averaging about io,oc
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Myelocytes rare.
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Basophiles not increased.
Usually increased.
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338 DISEASES OF THE BLOOD.
the blood regeneration most prompt in simple wandering spleen
and in ague cake, while blood deterioration is more marked and
regeneration slower in rupture of this organ. Splenectomy for
myelogenous leukemia is almost invariably followed by a pro-
gressive anemia and leucocytosis, and in nearly all cases by death.
But five recoveries after removal of the spleen in this disease
have been reported,1 the operation having been performed in
forty-two cases.
1Hage'n, Arch. f. klin. Chir., 1900, vol. v, p. 188; also Richardson, cited by
Warren, loc. cit.
SECTION VI.
THE ANEMIAS OF INFANCY AND
CHILDHOOD.
SECTION VI.
THE ANEMIAS OF INFANCY AND CHILDHOOD.
I. CHARACTERISTICS OF THE BLOOD IN CHILDREN.
As a preliminary essential to the intelligent
FETAL BLOOD, study of the various pathological conditions of
the blood in children it is necessary briefly to
refer to certain points of difference in the composition of this tis-
sue in the child and in the adult. In general terms it may be
stated that the younger the child, the more unformed are the
different elements of the blood and the nearer its composition
resembles the blood of the fetus.
In fetal blood the specific gravity, both of the whole blood and
of the serum, is lower than in the adult, and coagulation is very
slow and imperfect. The erythrocytes vary greatly in size and in
shape, and are deficient in hemoglobin, which is loosely attached
to these cells and hence becomes readily dissolved out. Zang-
meister and Meissl1 conclude that, in comparison with maternal
blood, fetal blood is poorer in albumin and nitrogen ahd is less
active in agglutinative, bactericidal, and immunizing powers.
Until about the seventh month of intra-uterine life normo-
blasts constitute the predominating variety of erythrocytes, after
which period they rapidly diminish in number, until at full term
few, if any, nucleated red corpuscles are found in the blood. Of
the different varieties of leucocytes, the mononuclear forms are
present. in a proportion relatively excessive to the other varieties;
before the seventh month this lymphocytosis is due to a high
relative percentage of large lymphocytes, but after this period
the proportion of small lymphocytes increases, until finally
they predominate. The percentage of eosinophiles reaches its
maximum at the seventh month, gradually becoming less and less
as the end of the intra-uterine life approaches.
We find, therefore, that in the fetus the blood is characterized
chiefly by the presence of large numbers of normoblasts, by a
high relative proportion of mononuclear leucocytes, by a deficiency
1 Munch, med. Wochenschr., 1903, vol. 1, p. 673.
34i
342 THE ANEMIAS OF INFANCY AND CHILDHOOD.
of hemoglobin, and by a feeble activity of the serum. The closer
an infant's blood resembles this picture, the "younger" in point
of development is such blood considered, and the more strongly is
it said to revert to a "young" or " embryonal" type. The deficient
defensive potency of the Blood of the young baby may account for
the proneness of infants toward infections in general.
At birth the blood of the full-term infant is of
THE BLOOD higher specific gravity and richer in hemoglobin
AT BIRTH, and in corpuscular elements than that of the older
child or of the adult.
The specific gravity of the blood of the average healthy infant
at the time of birth and during the first few weeks of life is, ap-
proximately, i. 066. For normal children the average, which is
reached by the beginning of the second year, varies from 1.050 to
1.058, being slightly higher in boys than in girls.
The maximum amount of hemoglobin is found at birth, the
percentage at this time ranging from 100 to 104, according to
the investigations of Hammerschlag.1 After birth the amount of
hemoglobin immediately begins to diminish, the minimum, which
may be as low as 55 or 60 per cent., being attained by the end
of the third week of life. It remains at or about this minimum
for a variable period of time — sometimes for as long as six months
— and then gradually begins to increase.
At birth the number of erythrocytes in the peripheral blood is
decidedly higher than normal, counts of between 5,500,000 and
6,000,000 cells per c.mm. being found at this time, the highest
figures being observed in those cases in which ligation of the
umbilical cord has been delayed. During the first twenty-
four hours of extra-uterine life this polycythemia becomes still
more marked, so that the number of corpuscles per c.mm. may
reach a maximum of from 7,000,000 to 8,000,000, and sometimes
higher, by the end of the first day. Beginning with the second day,
a gradual diminution in the number of these"1 cells is noticed, and
the normal 5,000,000 per c.mm. is reached by the end of the first
week or ten days. Hayem2 emphasizes the fact that the fluctua-
tions in the number of erythrocytes during the early days of life
stand in inverse ratio to the variations* in the weight of the child,
the maximum number being found at the time of the infant's
minimum weight, while as the child begins to gain in weight the
count decreases. .Scruff 3 is inclined to attribute these fluctuations
to the amount of liquids in the body, the result of feeding, showing
1 Centralbl. f. klin. Med., 1891, vol. xii, p. 825.
3 "Du Sang," etc., Paris, 1889.
8 Zeitschr. f. Heilk., 1890, vol. xi, p. 17.
CHARACTERISTICS OF THE BLOOD IN CHILDREN. 343
that in fasting children the counts are always higher than in those
fed at frequent intervals.
Whatever may be the exact manner of their production, it is
evident that these fluctuations are to be regarded as purely physio-
logical in character, depending upon concentration and dilution
of the blood, rather than as an expression of involvement of the
blood-making organs.
The erythrocytes vary greatly in size during the first few days
of post-natal life, the diameter of some cells being as small as
3.25 ft and of others as large as 10.25 //. Many observers have
noticed that the small-sized cells, as a rule, predominate. Such a
microcytosis in the adult would mean well-defined anemia.
Nucleated, erythrocytes of the normoblastic type may or may
not be present in the blood of new-born infants; they are com-
monly found in large numbers in the prematurely-born child, and
also occur less numerously in many fully developed babies, not-
withstanding views to the contrary expressed by some observers,
notably by Hayem1 and by Fischl.2 In most cases normoblasts
disappear from the blood after the first few days of life, and their
presence after the sixth month should always be regarded as
pathological.
The number of leucocytes at birth averages about 20,000 per
c.mm., the normal average for young infants, 15,000 per c.mm., be-
ing reached by the end of the first week, after numerical fluctua-
tions similar to those affecting the erythrocytes. From the second
or third week until the sixth month a count from 10,000 to 14,000
may be regarded as normal, while for the child of one year of age
the average is about 10,000. By the sixth year the number of
leucocytes falls to the number normal for the adult, 7500 per
c.mm. The following excellent table from Rotch3 shows these
average counts of erytKrocytes and leucocytes in children from
birth until the sixth year of age:
AGE. ERYTHROCYTES. LEUCOCYTES. .
At birth 5,900,000 21,000 (26,000 to 36,000
after first feeding).
End of i st day •. . . . 7,600,000 to 8,000,000 24,000
2d " Generally increased. . 30,000
4th ' 6,000,000 20,000
" yth " 5,000,000 15,000
loth day 10,000 to 14,000
i2th to iSth day 12,000
ist year .... 10,000
6th year and upward . 7»5°°
1 Loc. cit.
2 Zeitschr. f. Heilk., 1892, vol. xiii, p. 277.
3 "Pediatrics," Philadelphia, 1896, p. 342.
344 THE ANEMIAS OF INFANCY AND CHILDHOOD.
The influence of the initial feeding in infants produces a
marked leucocytosis, the increase amounting to from 5000 to
15,000 per c.mm., as shown by the above table. It is probable
that the habitual leucocytosis of early childhood is largely refer-
able to a more or less continuous digestion leucocytosis. (For a
further discussion of this question see " Digestion Leucocytosis,"
p. 231.)
The blood of infants and of young children differs greatly from
that of the adult in the relative proportions of the different forms
of leucocytes, these qualitative differences becoming less and less
apparent as the child grows older, and not usually persisting
beyond the tenth year. In' general terms it may be said that
these dissimilarities are striking in relation to the youth of the
child. Compared to the adult, a differential count of the leuco-
cytes in the child shows that the relative percentage of lympho-
cytes is more than twice as great, and of polynuclear neutrophiles
one-half as great, while the proportion of eosinophiles is frequently
much higher. In the following table, based upon data given by
Gundobin,1 these points of difference are contrasted:
FORMS OF LEUCOCYTES. INFANTS. ADULTS.
Small lymphocytes . .50 to 70 per cent. 20 to 30 per cent.
Large lymphocytes
and transitional
forms 6 " 14 " " 4 " 8 "
Polynuclear neutro-
philes 28 " 40 " " 60 " 75 " "
Eosinophiles 0.5 " 10 " " 0.5 " 5 " "
It is important to take into account these differences in mak-
ing blood examinations in children, in whom one must expect to
find percentages of lymphocytes which in the adult would be
regarded as abnormally high.
Many of the lymphocytes differ from corresponding cells in the
adult, chiefly in being of larger size, in exhibiting a greater variety
of nuclear figures, and in having a more basic tendency. Karnizki2
also professes to find an occasional myelocyte in the blood of the
healthy child, and to trace a decided morphological resemblance
between the lymphocytes, the transitional forms, and the neu-
trophiles. While it is true that myelocytes appear in the infant's
blood upon slight provocation, one can scarcely regard them as
normal elements; nor can a relationship between the lymphatic
and the myelogenous leucocytes be established more clearly in
the child than in the adult.
Leucocytosis in children is of extremely common occurrence,
1 Jahrb. f. Kinderheilk., 1893, vol. xxxv, p. 187.
2 Arch. f. Kinderheilk., 1903, vol. xxxvi, p. 42.
ANEMIA IN CHILDREN. 345
often arising from causes of the most trivial character, and de-
veloping to a greater degree and with much more rapidity than
in the adult. It is therefore to be regarded with less significance
than when it occurs in the mature. Usually the polynuclear cells
are chiefly involved in the increase, but the inclination of the
blood of children to revert to the embryonic type appears to
cause, in many cases, a disproportionate increase of lymphocytes
in relation to the other forms, this peculiarity being especially
true of the various pathological leucocytoses. Physiological leu-
cocytosis in children usually affects chiefly the polynuclear neu-
trophile cells.
II. ANEMIA IN CHILDREN.
Children, as a class, are peculiarly susceptible
FREQUENCY, to anemia, for they appear to lack resisting pow-
ers against the influence of causes tending to pro-
duce pathological alterations in the blood. Thus, it is found that
the same factors which in the adult have little or no effect upon
the blood, are capable of producing profound alterations in its
composition in the child. Severe anemias may arise in children
from apparently the most trivial causes; slight hemorrhage from
the navel, for instance, may light up an anemia of an intensity out
of all proportion to the actual amount of the blood loss, while
minor lesions of the gastro-intestinal tract are commonly asso-
ciated with blood deterioration of a severe type.
It is a notable fact that in anemic children a
GENERAL predominant tendency exists toward a reversion
CHARACTER- of the blood to a less mature histological type,
ISTICS. such as that found in the blood of the fetus.
Thus in children anemia of a type which in the
adult is unattended by qualitative changes in the corpuscles is
commonly associated with the presence of large numbers of
nucleated erythrocytes, these cells being far more numerous than
the severity of the anemia would seem to warrant. Megaloblasts
are not of the same significance in infancy as in adult life. They
may occur in anemias of but moderate intensity — in fact, they may
predominate, as Morse has shown,1 without necessarily constituting
a sign of fatal blood disease. In Riviere's experience2 megalo-
blasts, in ordinary well-marked infantile anemias, may constitute
between 20 and 50 per cent, of the erythroblasts, the ratio of
megaloblastic forms apparently standing in no definite parallelism
1 Boston Med. and Surg. Jour., 1903, vol. cxlviii, p. 573.
2 Lancet, 1903, vol. ii, p. 1419.
346 THE ANEMIAS OF INFANCY AND CHILDHOOD.
to the severity of the anemia of which they are symptomatic.
Poikilocytosis and deformities in the size of the corpuscles also
occur with far greater frequency than in the adult. Regeneration
of the blood takes place slpwly. The oligochromemia is relatively
greater than the oligocythemia in most anemias of children, this
being due probably to the fact that the hemoglobin is peculiarly
prone to separate from the corpuscular stroma. Owing to this fact
low color indices, as in chlorosis, are common, irrespective of the
degree of corpuscular diminution.
Myelo'cytes are commonly found in the blood in all the anemias
of children ; they are present .in larger relative percentages and in
less severe pathological conditions than in the adult. The writer
has noted the frequency, almost the constancy, with which typical
mast cells and the fine basophiles occur in the specific infections in
children, notably in enteric fever and in tuberculosis.
Leucocytosis, often lymphocytosis, and enlargement of the
spleen are frequently associated with all forms of anemia in the
young ; and although these conditions are likely to coexist, this is by
no means the invariable rule. Splenic enlargement is especially
common in the anemias due to syphilis, rachitis, tuberculosis,
gastro-intestinal disease, malaria, and septic infection.
To epitomize, in the anemias of infancy and childhood the
following prominent features of the blood are found: (a) The
frequency of a low color index; (ft) the common occurrence of
erythroblasts and of deformities affecting the shape and size of
the erythrocytes ; (c) a tendency toward leucocytosis and splenic
enlargement, and (d) the frequency of myelocytes and mast cells.
It is owing to these peculiarities that the clas-
CLASSIFICA- sification of the anemias of children is such a dif-
TION. ficult matter. The older classifications, based
upon the nature of the causal factors of the an-
emia and upon the presence or absence of enlargement of the
spleen, have failed in many respects to prove adequate, so that it
becomes necessary to adopt a simpler and more comprehensive
division from which no exceptions need be made in the individual
case. Such a classification has been suggested by Morse.1 This
author assuming, and rightly so, that* chlorosis is a condition
wholly foreign to infantile life, and that the disease described
by von Jaksch as "anemia infantum pseudoleukemica " does not
represent a distinct clinical condition, proposes this excellent
classification, slightly modified from that of Monti:
Primary Anemia. Pernicious anemia.
Leukemia.
1 Arch. Pediat., 1898, vol. xv, p. 815.
ANEMIA IN CHILDREN. 347
Secondary Anemia. Mild anemia.
Mild anemia with leucocytosis.
Severe anemia.
Severe anemia with leucocytosis.
Pernicious anemia is rare in the young, and
PRIMARY likely to be mistaken for other forms of severe an-
ANEMIA. emia secondary to various conditions. It is prob-
able that many of the reported cases of Biermer's
anemia in infants were in reality examples of severe secondary
anemia. Hutchinson,1 in his Goulstonian lectures, gives the
data of ii authentic cases, the total number recorded up to the
present time. The apparent tendency of pernicious anemia in
children to become transformed into leukemia is doubtless more
fanciful than real, a remark which is equally true of those few
reported instances of the conversion of leukemia into pernicious
anemia. In the first case the erroneous impression may arise from
such evidence as marked enlargement of the spleen associated with
a high leucocytosis; in the second, a temporary disappearance of
the myelogenous blood-picture plus an aggravation of the exist-
ing anemia may be sufficient to convey the false impression. It
must be admitted that these atypical blood changes, so common
in young children, are highly confusing and difficult to interpret
without the closest observation and the correlation of other clin-
ical signs. (See " Leukanemia," p. 290.)
Infantile pernicious anemia is characterized by the same blood
changes that are found in the adult, in so far as striking oligocy-
themia and deformities of the erythrocytes are concerned, but
the blood often fails to show a high color index. A prevalence
of megaloblasts and 'of megalocytes is not pathognomonic, as
it is in the adult.
Splenic anemia, which is none too certain an entity in the adult,
can rarely be identified in the child. The splenic enlargement
in most reputed instances of this condition in early life must be
regarded as symptomatic of nutritive disturbance, rather than as
a distinctive factor of anemia. Hutchinson2 uses the terms in-
fantile splenic anemia 'and infantile pseudoleukemic anemia
synonymously, and believes that the former is entirely distinct
from splenic anemia of the adult. It must be admitted, however,
that rarely the adult type of the disease is met with in children, as
shown by the cases reported by Williamson,3 Hunt,4 Rolleston,5
1 Lancet, 1904, vol. i, pp. 1253 and 1325, and 1402.
2 Loc. cil. * Med. Chronicle, 1893, vol. xviii, p. 103.
4 Trans. Path. Soc. London, 1899, vol. 1, p. 209.
6 Clin. Jour., 1902, vol. xix, p. 401.
348 THE ANEMIAS OF INFANCY AND CHILDHOOD.
Hamill,1 and others. Such cases show the same type of anemia,
leucopenia, and lymphocytosis found in the blood of the adult
suffering from this disease.
Leukemia in children js uncommon, but instances have been
reported during all stages of infancy and childhood, even in the
new-born. Acute forms of the disease are most frequently met
with, the great majority of cases, according to Holt,2 proving
fatal within a year from the appearance of the first symptoms,
while in many the disease runs its course in a few weeks. Lym-
phatic leukemia is about five times as common in children as
myelogenous. Male children are more commonly leukemic than
female. Conditions such as rachitis, syphilis, and malarial fever
have been regarded by some authors as possessing a certain
amount of importance as etiological factors, but in the vast ma-
jority of cases the cause of the disease is entirely obscure.
Of the several collected reports of leukemia in children, the
two articles of Morse, giving a total of 27 cases, are by far the
most valuable. In his first communication3 20 cases were re-
corded, including one of his own, tabulated below, but of this
series the diagnosis, in the great majority of instances being based
either upon clinical symptoms or upon inadequate examination
of the blood, the reporter is led to remark that "it is highly probable
that not more than half, perhaps not more than a third, of these
were really cases of leukemia." In Morse's second article,4
which deals with the acute form of the disease, seven cases, again
including one of his own, also recorded below, are reported.
Although the literature of pediatrics is fairly rich in alleged
examples of leukemia in children, the cases, with but a few ex-
ceptions, are reported in so unsatisfactory a manner that they
cannot be regarded without reserve as typical. Those reported
prior to the publication of Morse's first article — in 1894 — must all
be open to criticism, owing to the general disregard for differen-
tial counts shown by the various authors, and, strangely enough,
this criticism must hold true for many cases recorded during the
past ten years. The author has been able to collect 21 cases
(Table XVIII), in all of which the differential count of leuco-
cytes leaves no doubt as to the precise character of the disease.
In addition to the above cases several others have been reported
in which the differential count of leucocytes has been either faultily
made or entirely neglected. Thus, Pollman5 believes that he has
1 Arch. Pediat., 1902, vol. xix, p. 641.
2 "The Diseases of Infancy and Childhood," New York, 1897, p. 806.
3 Boston Med. and Surg. Jour., 1894, vol. cxxxi, p. 133.
4 Arch. Pediat., 1898, vol. xv, p. 330.
5 Munch, med. Wochenschr., 1898, vol. xlv, p. 44.
id
H
Lymphatic.
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HISTOLOGICAL CHANGES IN THE
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35°
ANEMIA IN CHILDREN. 351
seen a case of myelogenous leukemia in a new-born infant, the
count on the fourteenth day after birth being 2,500,000 erythro-
cytes and 312,500 leucocytes per c.mm. The latter consisted
chiefly of "large mononucleated cells, with large, distinct nuclei
and an abundance of protoplasm." Nucleated forms of ery-
throcytes were not found. Cassel,1 in addition to his own case,
tabulated above, has collected four others occurring in children
under fourteen years of age.
Theodor2 has collected from German literature six cases of
acute leukemia in children between the ages of two and one-half
and eight years of age, and also reports one of his own, apparently
of the lymphatic form, in a boy of four years. No actual numer-
ical estimates of the corpuscles are given, but the proportion of
leucocytes to erythrocytes is stated to vary from i : 9 to i 13. The
differential count of leucocytes is also very inexact. The greater
percentage apparently consisted of lymphocytes; myelocytes were
fairly numerous, many of them containing mitotic figures, and
normoblasts and megaloblasts were present in large numbers.
Gilbert and Weil,3 in 1899, published data of five acute lymphatic
cases in children between the first and tenth years. Charon and
Gratea4 report a case of myelogenous leukemia in a child of eight
years, the percentage of hemoglobin being 39, the erythrocyte
count 880,000, and the leucocyte count 305,000. Instances of
acute lymphatic leukemia in children have also been reported,
with more or less accuracy, by Bradford and Shaw,5 by Guinon
and Jolly,8 by Haushalter and Richon,7 and by Bloch and
Hirschfeld.8 '
In the above classification of the secondary
SECONDARY anemias, under the heading of mild anemia are
ANEMIA. included those cases characterized by trifling re-
duction in the 'hemoglobin percentage and num-
ber of erythrocytes, and by an absence of histological alterations
in these cells. The color index in these cases is usually i.oo, or
slightly- below, uncommonly falling to a low figure.
The term severe anemia includes cases having marked diminu-
tion of hemoglobin and erythrocytes, associated with deformities
of shape and of size and nucleation of these cells. The hemo-
1 Berlin, klin. Wochenschr., 1898, vol. xxxv, p. 76.
2 Arch. f. Kinderheilk., 1897, vol. xxii, p. 47.
8 Arch, de med. exper., 1899, vol. ii, p. 157.
4 Bull. Soc. roy. sc. me'd. et nat., Brussels, 1896, vol. liv, p. 63.
* Trans. Roy. Med.-chir. Soc., 1898, vol. Ixxxi, p. 343.
8 Rev. mens. des mal. de 1'Enf., 1899, vol. i, p. 262.
7 Arch, de me'd. des Enf., 1899, vol. ii, p.. 356.
8 Zeitschr. f. klin. Med., 1900, vol. xxxix, p. 32.
352 THE ANEMIAS OF INFANCY AND CHILDHOOD.
globin loss is especially marked, often being only one- quarter or
one-third of normal, and the color index is low.
Anemias with leucocytosis, whether of mild or of severe type,
are generally marked by a greater degree of hemoglobin and
corpuscular decrease than anemias without leucocytosis. The
leucocytosis is moderate in the milder forms, but in severe cases
the increase in the number of leucocytes often appears to be pro-
gressive, and the relative number of leucocytes to erythrocytes
occasionally attains the proportion of i to 100.
Histological changes in the erythrocytes are more striking in
grave anemias with leucocytosis than in grave anemias pure and
simple. This is especially true of the changes relating to nuclea-
tion of the cells, normoblasts and atypical forms being very nu-
merous in the former class. As already stated, megaloblasts do
not necessarily mean a fatal nor even an especially intense anemia.
Regarding the etiological factors of these secondary anemias,
the following groups of causes are given by Monti 1 :
1. CONGENITAL Syphilis, tuberculosis, and other infections.
Hemorrhagic. From navel, from circumcision, etc.
Purpuric diseases.
Malnutrition, improper hygiene, etc. ,
Syphilis, rachitis, and tuberculosis.
2. ACQUIRED Gastro-intestinal diseases.
Visceral diseases.
General. Febrile diseases.
Septic infections.
Nephritides.
Malignant growths.
Syphilis, either congenital or acquired, is responsible for a
large proportion of the cases of anemia in children, especially those
of a severe type, associated with enlargement of the spleen, and
often also with enlargement of the lymphatic glands. The hemo-
globin loss is in most instances disproportionately greater than the
corpuscular decrease, so that low color indices are especially
common in this disease — the misnamed "chlorosis" of syphilis.
Deformities and nucleation of the .erythrocytes are common in
the severer types, and in such forms polychromatophilic changes
and excessive decrease in the number of erythrocytes are usually
present. A leucocyte increase is present in the secondary stage,
and is usually associated with the grave anemia of this disease;
the relative percentage of lymphocytes is increased, and of poly-
morphous forms decreased; and small numbers of myelocytes
are common. From the writer's experience, in the average case,
of moderate severity the percentage of hemoglobin varies from
1 Wien. med. Wochenschr., 1894, vol. xliv, pp. 401, 464, 516, 560, and 613.
ANEMIA IN CHILDREN. 353
about 40 to 50, the erythrocytes are reduced to about 3,000,000 to
3,500,000 per c.mm., and the leucocyte count is in the neighbor-
hood of 20,000; but in severe cases the erythrocytes may be re-
duced to 1,000,000, and the leucocytes increased to 50,000 or
more. As in the adult, Justus' test proves of value in the diagnosis
of many anomalous cases. Labbe and Armand Delille 1 insist that
in congenital syphilis the blood picture may precisely resemble
that of von Jaksch's disease (q. v.}, but that the blood promptly
returns to normal after energetic mercurialization.
In rachitis there is usually well-marked anemia, accompanied
by decided enlargement of the spleen, such cases having most
decided blood changes. The hemoglobin percentage tends to
range lower than the percentage of corpuscles, so that low color
indices prevail; but in the individual case neither the oligo-
chromemia nor the oligocythemia is generally as marked as in
syphilis. In severe cases, deformed and nucleated erythrocytes
and a small percentage of myelocytes are commonly found. The
number of leucocytes is, as a rule, moderately increased, and
relatively high percentages of lymphocytes are common.
Uncomplicated tuberculosis, due to pure infections with the
tubercle bacillus, produces an anemia which varies in degree
with the severity of the constitutional effects of the disease. The
hemoglobin and erythrocytes are usually but slightly decreased,
the former suffering a relatively greater loss, and the number of
leucocytes does not rise above normal. If to the tuberculous
process a septic infection is superadded, the anemia becomes
severer, and leucocytosis,, involving the polymorphous forms of
cells, occurs. Splenic enlargement is common and sometimes
marked. The anemia of tuberculosis is in no way referable to %
the infection itself, but depends upon the drain on the albumins
of the blood due to the presence of a long- continued cachexia
and upon secondary infections.
Gastro-intestinal diseases, especially those of chronic character,
cause most marked anemia. Chronic inflammations of the intes-
tines strikingly affect the blood, the percentage of hemoglobin
frequently falling to one-quarter of normal or even lower, and the
number of erythrocytes being decreased to one-half of normal or
lower. Deformities affecting the shape and size of the erythrocytes
and nucleation of these cells are of frequent occurrence. A leu-
cocyte increase, involving in many instances the lymphocytes,
is usually present, and small percentages of myelocytes have
been observed. Splenic enlargement is frequently a conspicu-
ous clinical sign. It should be remembered that in acute forms
1 Sem. med., 1963, vol. xxiii, p. 50.
23
354 THE ANEMIAS OF INFANCY AND CHILDHOOD.
of gastro-intestinal disorders, in which profuse diarrhea and vom-
iting occur, concentration of the blood takes place, causing tem-
porary polycythemia Avhich may for a time hide the real degree
of the blood deterioration. The anemias found in this class of
diseases are apparently to a large extent autointoxicative in char-
acter, depending to a less degree upon insufficient nutrition.
In enteric fever the blood picture does not differ essentially
from that seen in the adult suffering from this affection, absence
of leucocytosis or leucopenia with progressive anemia being
found with great constancy. The difference is simply one of
degree, the changes developing more rapidly but persisting for a
shorter period in the child than in the adult. Churchill's studies l
show that the leucopenia is most decided during the second week
of the fever; and that the anemia is especially apparent during the
first three weeks, after which the hemoglobin and erythrocytes
begin steadily to increase, reaching normal by about the fifth
week. In 12 cases studied by Stengel and White 2 the hemoglobin
ranged from 68 to 83 per cent., the erythrocytes from 3,320,000 to
5,200,000, and the leucocytes (in uncomplicated cases) from 3800
to 12,320. Polynuclear leucocytosis was observed in 3 cases as the
result of inflammatory complications. Two uncomplicated cases
showed fractional percentages of myelocytes, but there were no
other differential changes of any consequence. Head 3 believes that
in uncomplicated cases the leucocytes never number more than
10,000 per c.mm. The writer has found that the alkalinity of the
blood varies within wide limits in infantile typhoid, tests by
Engel's method in 6 consecutive cases showing a range of from
373 to 692 mgm. NaOH. The rapidity of coagulation also was
found to vary greatly, clotting taking place in as short a time as
thirty-seven seconds in one instance, and not occurring for four
minutes and thirty-five seconds in anotlier. Morse 4 concludes
that the serum test appears earlier, is less marked, and persists for
a shorter period in children than in adults. In a nursling it
should be remembered that a positive reaction may be of uncertain
value, for the reason that the agglutinating power may be trans-
mitted from mother to child through the milk, both during the
active stages of the disease and also during and after convales-
cence.
Under the title "anemia infantum pseudoleukemica" von
Jaksch5 has described a condition which he regards as a form of
1 Boston Med. and Surg. Jour., 1903, vol. clviii, p. 692.
2 Arch. Pediat., 1901, vol. xviii, pp. 241 and 321.
3 Ibid., 1902, vol. xix, p. 253. 4 Ibid., igoi, vol. xviii, p. 338.
s Wien. klin. Wochenschr., 1889, vol. ii, p. 435.
ANEMIA IN CHILDREN. 355
primary anemia peculiar to the young child. The blood changes,
which are not characteristic of the disease in question, as this
author admits, consist of (a) marked oligocythemia and oligo-
chromemia; (6) extensive and persistent leucocyte increase; and
(c) striking structural alterations in the erythrocytes. Associated
with these changes in the blood, and of equal importance in diag-
nosing the disease, constant enlargement of the spleen and, less
commonly, enlargement of the liver are found.
The number of erythrocytes is greatly decreased, usually to
from 2,000,000 to 3,000,000 per c.mm., but sometimes falling
to 1,000,000 or even to a lower figure, as in one of von Jaksch's
cases, in which the count was only 820,000. The hemoglobin
loss is also great — relatively more so than the corpuscular decrease.
The leucocyte gain is decided, averaging, in the majority of
cases, from 30,000 to 50,000 corpuscles per c.mm., and in some
instances exceeding 100,000. In some cases the increase involves
principally the polynuclear neutrophiles, while in others the lym-
phocytes are the cells chiefly affected. The cells show a most
striking dissimilarity of form and of size, and a highly confusing
variety of forms atypical in size, shape, and nuclear morphology
is encountered. This "polymorphous" state of the leucocytes
is a point insisted upon by von Jaksch in his description of the
condition. The number of eosinophiles varies within wide
limits, the percentage of these cells being normal, decreased, or
increased. Small percentages of myelocytes have been observed.
The histological changes affecting the erythrocytes consist in
marked poikilocytosis, deformities of size, loss of color, and nu-
cleation. Poikilocytes, megalocytes, and microcytes occur in
large numbers, and the pallor of most of the corpuscles is ex-
treme. Normoblasts are the most common form of erythro-
blasts observed, but occasionally the occurrence of atypical forms,
small and large, and- of megaloblasts has been noted. Karyokin-
etic changes in these cells are not uncommonly seen, and poly-
chromatophilia is of frequent occurrence.
The spleen 'is enlarged in all cases, sometimes moderately, but
often very greatly, so that the organ extends far below the cos-
tal margin, and occupies the entire upper left part of the abdomi-
nal cavity. The spleen is extremely indurated, and may show
capsular thickening from perisplenitis. The increase in the size
of the organ is due to a hyperplasia. Enlargement of the liver
is not constant in all cases, and when present does not reach a
size corresponding to that of the spleen, as is the case in leukemia ;
the lower border of the liver is not rounded, but distinctly sharp.
In a certain proportion of cases' the lymphatic glands are slightly
356 THE ANEMIAS OF INFANCY AND CHILDHOOD.
enlarged, but never to any notable extent. Changes in the bone
marrow, common to any severe anemia, have been observed in
some cases.,
The disease occurs most frequently in infants between the ages
of seven and twelve months, and is rarely met with in children
over four years old. By some writers it is supposed to be slightly
more common in children of the male sex.
In many cases a previous history of rachitis, syphilis, or long-
standing gastro-intestinal disease is obtained, although von
Jaksch denies the existence of these etiological factors in his cases.
The onset of the symptoms is slow and insidious, and the pal-
lor of the skin, blanching of the mucous membranes, and other
signs of anemia slowly develop, with the gradual enlargement of
the spleen, until these clinical manifestations become marked.
In all cases there is excessive loss of strength, and in a great
many a high degree of emaciation.
Von Jaksch's disease, if untreated, tends to pursue a progres-
sively grave course, ending fatally; but, under suitable treatment,
the splenic tumor decreases in size, the leucocytosis disappears
and the hemoglobin and erythrocytes return to normal.
Pseudoleukemic anemia of infants is not generally considered
as a separate clinical entity, but is regarded rather as a form of
severe secondary anemia associated with marked leucocytosis and
splenic enlargement. It may be due to a number of different
causes, the most prominent among which are syphilis, rachitis,
and chronic gastro-intestinal disease. The conflicting reports of
different authors concerning this disease, and the incompleteness
with which the leucocytes have been studied in many instances,
render it probable that in some of the reported cases pernicious
anemia and leukemia have masqueraded, as typical examples of
the condition described by von Jaksch.
Bacleriemia, generally referable to preagonal infections,
appears to occur with great frequency in the young child during
the course of many acute diseases. Delestre's careful studies * of
general blood infections in children tend to show that infants born
before full term are peculiarly susceptible to this condition. Using
careful technic, this author examined 40 children, ranging in age
from a few days to four years, all of whom were believed to be
suffering from infections which bade fair to end fatally within a
few days, at the latest. Of the 32 fatal cases of this series, bacteria
were found in the blood during life in 14, while of the 8 who re-
covered, but one gave a positive result. The bacterium found
with greatest frequency was the streptococcus, while staphylococci,
1 Annal. de gynecol. et .d'obstet., 1901, vol. Iv, p. 51.
ANEMIA IN CHILDREN. 357
pneumococci, colon bacilli, and influenza bacilli were isolated more
rarely. It was furthermore shown that premature babies seemed
especially susceptible to streptococcus and colon infections, and
that nursing infants several months old were more prone to suffer
from the effects of the staphylococcus.
The blood changes occurring in pertussis, pneumonia, diph-
theria, scarlet lever, measles, varicella, and other infectious diseases
of childhood are considered in Section VII.
SECTION VII.
GENERAL HEMATOLOGY.
SECTION VII.
GENERAL HEMATOLOGY.
I. ABSCESS.
The rate of coagulation is, as a rule, somewhat
GENERAL slower than normal. Hyperinosis is conspicuous,
FEATURES, and under the microscope the fibrin network ap-
pears abnormally dense and thick. The iodin
reaction may be detected in the dried blood film by the method
described in a previous section. (See p. 226.) These remarks,
as well as those which follow, do not apply to purely tuberculous or
"cold" abscesses, the effects of which are referred to elsewhere.
If the absorption of toxic material from an ab-
HEMOGLOBIN scess is great enough to produce a systemic effect
AND upon the patient, anemia of an intensity parallel
ERYTHROCYTES. to the severity of the poisoning sooner or later
develops. This fact is sufficient to explain why
the grades of anemia in .purulent conditions vary within such wide
limits. The size and the site of the abscess do not appear pri-
marily to determine the degree of the associated blood changes,
although, other circumstances being equal, a large, deep-seated
collection of pus is likely to have a more harmful effect than one
of small size and superficial situation. Chronicity of the lesion
seems to go hand 'in hand with an increase in the blood deterio-
ration— few persons harboring pus for a protracted period fail to
show decided signs of anemia.
In many cases, especially the acute, the only noticeable change
is a moderate oligochromemia, but in chronic cases different de-
grees of ordinary secondary anemia are commonly encountered,
amounting in an exceptional instance to a reduction of hemo-
globin to as low as 20 or 30 per cent, of the normal standard, and
to an erythrocyte decrease to between 2,000,000 and 3,000,000
cells to the c.mm. Such profound losses are, of course, unusual,
for in the majority of patients with anemia the hemoglobin is
above 50, and the corpuscles above 60, per cent, of normal. The
average color index for 134 German Hospital cases, listed below,
361
362 GENERAL HEMATOLOGY.
was 0.77. The condition of the hemoglobin and erythrocytes
in these patients is shown by the following summary:
<
HEMOGLOBIN NUMBER OF ERYTHROCYTES NUMBER OF
PERCENTAGE. CASES. PER C.MM. CASES.
From 90-100 in ..... 4 Above 5,000,000 in..io
80-90 ' ..... 15 From 4,000,000-5,000,000 ". .41
70-80 < . ...-27 „ 3,000,000-4,000,000 "..68
" 60-70 " ..... 23 ..
« ..... 23 2,000,000-3,000,000".. 9
" .22 1,000,000-2,000,000".. 6
" 30-40 " ..... 13
!•" " 20-30 " ..... 7
Average, 59 per cent. Average, 3,797,470 per c.mm.
Maximum, 95 " Maximum, 5,970,000 " "
Minimum, 20 Minimum, 1,320,000 "
If marked anemia exists, a variable grade of cell deformity,
atypical staining, and nucleation is also to be observed. If the
latter change is evident, it will be found that the great majority, if
not all, of the nucleated corpuscles belong to the normoblastic class.
Practically the same influences governing the
LEUCOCYTES, behavior of the leucocytes in most other infec-
tions also determine their increase and decrease
in abscess. Thus, in both trivial and in extensive pus foci the
number of leucocytes may be normal or even subnormal; in the
former instance because systemic reaction is not provoked, and
in the latter because it is overpowered. Leucocytosis may also
be absent in case toxic absorption is impossible, owing to the com-
plete walling-off of the abscess. In all other instances save these
a definite and usually well-marked leucocyfosis occurs, amount-
ing on the average to a count of about twice the mean normal
standard, but often greatly exceeding this figure in the individual
case. The size of the primary abscess cannot be estimated by
the height of the leucocytosis, but a tendency of the pus to extend
is almost always accompanied by a distinct increase in the number
of cells in excess of the figure originally estimated. Complete evac-
uation of the abscess is soon followed by a disappearance of the
leucocytosis and iodophilia, but so long as the pus remains inef-
fectually drained, these signs persist.
Analysis of the "first counts" in 258 cases of various forms of
abscess (excluding appendicitis) shows that in 184, or 71.3 per
cent., the leucocyte count was in excess of 10,000. The general
range of the leucocytes in abscess is illustrated by the following
table:
ABSCESS. 363
LEUCOCYTES PER C.MM. NUMBER OF CASES.
40,000-50,000 2
30,000-40,000 5
20,000-30,000 28
15,000-20,000 59
10,000-15,000 90
5,OOO-IO,OOO 70
Below 5000 4
Average, 13,931 per c.mm.
Highest, 42,000 "
Lowest, 550 "
A more detailed study of these cases, directed toward the
number of the leucocytes in relation to the site of the abscess, may
be expressed thus in tabular form:
H
.
O
(/3
H
SITE OF ABSCESS. $
<
H
H
n
w CASES WITH LEUCOCYTOSIS.
C/3
W
o
o
u
^
n
HJ
Pelvic
164
13837
42,000
107 or
66
Q
per cent.
Kidney
30
13,924
33,600
6.000
26 "
86
6
Superficial
26
I3,l68
24,000 4,800 19 "
73
n
»
Empyema
IO
I7,l8o
31,800 11,200 10 "
TOO
0
a
Lung. .
8
12,128
17,6^0 8,200 6 "
7C
n
it
Liver
8
14,022
23,400 0,300" " 6 "
O
u
Gall-bladder ... 6
15^50
21/200 9,500 5 '
83
•3
u
Brain
6
13,406
18,560 6,800
5 '
83
•3
a
A polynuclear neutrophile gain generally accounts for the
increase when leucocytosis is present, and, rarely, this differential
change .may be found without any increase in the total number of
cells. In some instances, and these are not so uncommon as
is generally believed, the increase affects all forms of cells pro-
portionately. A few myelocytes are not uncommon in cases having
a decided anemia or a high leucocytosis.
The presence of leucocytosis, especially if
DIAGNOSIS, associated with hyperinosis and a positive iodin
reaction, is suggestive of abscess rather than of
other lesions, such as aneurisms, gummata, hematomata, and
benign neoplasms. An absence of one or all of these signs, on the
other hand, is not sufficient to exclude pus. The distinctions, as
364 GENERAL HEMATOLOGY.
shown by the blood, between pyogenic and tuberculous abscesses
and malignant disease are considered under the last-named con-
ditions. «
II. ACROMEGALY.
The following counts illustrate the blood changes found in two
cases of this disease, the first showing practically normal blood,
except for a moderate relative lymphocytosis and an absence of
eosinophiles, and the second simply a well-marked secondary
anemia with a high color index.
CASE I. CASE II.
Hemoglobin 86 per cent. 60 per cent.
Color index 0.93 i .04
Erythrocytes 4,620,000 per 2,880,000 per
c.mm. c.mm.
Leucocytes 8,000 per 4,890 per
c.mm. c.mm.
Small lymphocytes 31.7 per cent. 21.0 per cent.
Large lymphocytes 2.1 " 7.0 "
Polynuclear neutrophiles 66.2 " 71.0 "
Eosinophiles o.o " i .o "
Basophiles o.o " o.o "
Myelocytes o.o " o.o "
The erythrocytes showed moderate deformities of size and
shape in the anemic case, but no signs of nucleation nor of baso-
philic stroma degeneration were observed. Coagulation, fibrin
formation, and the number of plaques were apparently normal.
III. ACTINOMYCOSIS.
Anemia, marked by a disproportionately great hemoglobin de-
crease, is sometimes found, and leucocytosis appears to be an
almost constant change, judging from the small number of reports
available. In a case of actinomycosis of the arm the writer found
55 per cent, of hemoglobin, with 4,985,000 erythrocytes and 12,000
leucocytes per c.mm. The number of blood plaques was greatly
increased and the erythrocytes were pale, but not deformed,
nucleated, nor basophilic. The percentages of the leucocytes
were: small lymphocytes, 25.5; large lymphocytes, 7.3; polynuclear
neutrophiles, 60.0; eosinophiles, 2.4; myelocytes, 3.2; basophiles
(finely granular), i.o; and mast cells, 0.6.
ADDISON'S DISEASE. 365
Erving1 reports 4 cases with leucocyte counts of 10,000, 12,000,
21,000, and 36,200; Ewing's case2 gave 21,500; and Cabot's two2
showed leucocytoses of from 20,000 to 31,700. As a rule, actin-
omycosis excites a higher leucocytosis when deep organs (liver,
lungs) are involved than when the lesion is situated in superficial
parts of the body (jaw, elbow, abdominal wall) where free drainage
is favored. It is probable that the grade of both the anemia and
the leucocytosis depends largely upon the amount of septic ab-
sorption originating from the lesion.
IV. ACUTE YELLOW ATROPHY OF THE LIVER.
Malignant jaundice appears to be associated with a moderate
polycythemia, so far as can be determined by the limited number
of blood counts made in this disease up to the present time. The
leucocytes are moderately increased in number, but show no
peculiar differential changes. In two cases, reported by Grawitz 3
and by Cabot,4 respectively, the counts of erythrocytes were
5,150,000 and 5,520,000, and the number of leucocytes 12,000
and 16,000 per c.mm. Bacteriological examination of the blood
has thrown no definite light upon the nature of this apparently
infectious process. In many cases hemoglobinemia and lipaci-
demia have been detected.
V. ADDISON'S DISEASE.
Moderate anemia is commonly, and decided
HEMOGLOBIN anemia occasionally, associated with this condi-
AND tion, although the prime importance of this
ERYTHROCYTES. symptom insisted upon by Addison himself ap
pears to be somewhat exaggerated, in the light
of our .more accurate methods of blood study. The "anemiated
eye" of Addison does not always mean anemia. In advanced
cases the blood picture may be characterized by marked hemo-
globin and erythrocyte losses, by the presence of numerous poikil-
ocytes and microcytes, and by small numbers of normoblasts;
the hemoglobin readings in such instances range between 20 and
40 per cent., and the erythrocyte counts between 2,000,000 and
3,000,000 per c.mm., or even less. Tschirkoff 5 reports cases in
which, notwithstanding the coexistence of a notable oligocythe-
1 Johns Hopkins Hosp. Bull., 1962, vol. xiii, p. 261.
2 Loc. cit. •' Loc. cit.
4 Loc. cit. s Zcitschr. f. klin. Med., 1890, vol. xix, p. 87.
366 GENERAL HEMATOLOGY.
mia, the hemoglobin percentage remained normal or above nor-
mal, and this peculiar condition he referred to an increase in the
amount of corpuscular reduced hemoglobin. This author also
detected the presence of methemoglobin and melanin in the blood
of patients suffering from Addison's disease. The polycythemia
which is sometimes .met with in this condition is doubtless to
be attributed to such factors as vasomotor changes and blood
inspissation from emesis. Treatment with suprarenal extract
tends to. improve the anemia, but to what extent and how per-
manently is undetermined.
The number of leucocytes is usually normal
LEUCOCYTES, or below normal, and extreme leucopenia has
been repeatedly noted. Relative lymphocytosis
and sometimes a moderate increase in the number of eosinophiles
are the most familiar differential changes, together, in some in-
stances, with the presence of a few myelocytes and basophiles.
VI. ANTHRAX.
'Nothing definite is known of the behavior of the hemoglobin
and corpuscles in this infection. Only occasionally can the anthrax
bacillus be isolated from the peripheral blood, since general inva-
sion of the circulation by this organism is rare. Blumer and
Young 1 succeeded in finding the organism in the blood of a single
case of anthrax septicemia, both in ordinary cover-glass speci-
mens as well as by culturing.
VII. APPENDICITIS.
Fully three-fourths of all cases of appen-
HEMOGLOBIN dicitis, whatever their character, show a loss of
AND at least 30 per cent, of hemoglobin, while in
ERYTHROCYTES. about one case in five the erythrocytes are di-
minished 1,000,000 or more to the c.mm. From
an analysis, of the cases tabulated below it appears that the average
hemoglobin loss amounts to about 25 per cent., and the average
decrease in erythrocytes to about 15 per cent, of the normal
standard. The. anemia, which may usually be attributed to the
effects of septicemia, is most frequent and most marked in long-
standing cases of appendicular abscess, in which type of the dis-
ease the hemoglobin may fall to between 30 and 40 per cent.,
and the corpuscles to between 2,000,000 and 3,000,000 per c.mm.
1 Johns Hopkins Hosp. Bull. 1895, vol. vi, p. 127.
APPENDICITIS.
367
In such instances the risk, actual or reputed, of operating upon a
patient having so low a percentage of hemoglobin must be re-
called by the surgeon. (See p. 164.) Anemia, usually of a more
moderate grade, is also frequently found in catarrhal cases, and
in the individual instance it may reach as high a grade as in the
purulent form of the disease. The blood impoverishment in such
instances depends probably upon the debilitated state of the pa-
tient, apart from the appendix inflammation.
The following table illustrates the range of the hemoglobin and
erythrocytes, as shown by the initial examinations of 139 cases l
in Dr. J. B. Deaver's wards at the German Hospital:
NUMBER OF CASES.
Purulent, Perfora-
tive, and Gan-
HEMOGLOBIN PERCENTAGE. Non-purulent. grenous.
Above 100 i o
From 90-100 i 4
" 80-90 9 20
" 7o-8o 13 31
60-70 13 23
" 50-60 6 7
" 40-50 2 6
" 30-40 o .3
Highest 102 per cent. 100 per cent.
Lowest 45 38
Average -69.5 " 72.^ "
ERYTHROCYTES PER C.MM.
Above 5,000,000 • .- 6 14
From 4,000,000-5,000,000 27 60
" 3,000,000-4,000,000 ii 15
" 2,000,000-3,000,000 i . 5
Highestt 5,660,000 per 5,710,000 per
c.mm. c.mm.
Lowest 2,050,000 per 2,100,000 per
c.mm. c.mm.
Average 4,295,955 per 4,381,234 per
c.mm. c.mm.
Qualitative changes in the erythrocytes are neither common
nor important, occurring only in cases with decided anemia, and
consisting simply in deformities of shape and of size. Erythro-
1 Similar figures were found in the examination of more than 700 additional
rases not here recorded.
368 GENERAL HEMATOLOGY.
blasts apparently do not occur, although there is no reason why
they should not, if the anemia happens to be of a type of sufficient
severity to provoke marrow changes.
In simple appendicular inflammation uncom-
LEUCOCYTES. plicated by pus, gangrene, or peritonitis there is,
as -a rule, little or no increase in the number of
leucocytes, although in an exceptional case the leucocytosis is
fairly well denned. Thus, of the 45 cases of this form of the disease
below referred to, less than 9 per cent, were accompanied by a
count in excess of 15,000, the maximum estimate being 17,100, and
the average 8987 per c.mm. A relatively high count in this
variety of appendicitis may usually be attributed to a limited
periappendicular peritonitis. In some instances it is possible that
the increase may be due to blood inspissation from vomiting and
purging, or that it may simply represent a blood finding of the
associated anemia.
In cases with abscess, gangrene, or general peritonitis a well-
marked leucocytosis is- the general rule. Few cases of appen-
dicular abscess fail to increase the leucocyte count to at least
15,000 or 20,000 to the c.mm., although it is to be remembered
that should the purulent focus happen to be so effectually walled
off that absorption of toxic material is practically prevented, so
decided an increase does not develop. A trivial increase, or,
indeed, an absence of leucocytosis, is also met with in an occa-
sional grave case (such, for instance, as one complicated by a
general purulent peritonitis), owing to the prostration of the
patient from the systemic poison of the infection. As shown
below, the average count in purulent and gangrenous appendicitis
is higher than the maximum count in the* catarrhal form of the
affection.
A high leucocytosis suggests either a localized abscess or a
general peritonitis, for the differentiation of which other clinical
data are absolutely essential. The belief is current that if a
marked leucocytosis occurs early in the attack, peritonitis is prob-
able, and if it occurs after the first week, a local accumulation of pus
is suggested. While this is undoubtedly true in many instances,
in many others the condition of the appendicular lesion may be
wrongly interpreted if too great reliance is placed on the behavior
of the leucocytes in connection with the period of the attack.
Increase in the purulent focus and extension of peritonitis are
betrayed by an increase in the leucocyte count, provided that the
patient's powers of reaction are not too greatly crippled. In
operative cases thorough evacuation of the abscess is followed
within a few days by a decline to normal in the number of leuco-
APPENDICITIS. 369
cytes. Persistence of the leucocytosis after the third or fourth
day following the operation may usually be attributed to undrained
pus pockets or to a general peritonitis.
In non-operative cases with abscess the leucocytosis, which
becomes well developed by the fourth or fifth day of the attack,
persists but does not tend to increase if the lesion remains local-
ized; it gradually decreases as the pus collection disappears;
and it suddenly increases if the process extends.
To sum up, absence of or slight leucocytosis suggests (a)
simple catarrhal appendicitis; (6) fulminant appendicitis; or (c)
a localized pus focus from which no absorption occurs. Well-
marked leucocytosis indicates (a) a local abscess from which
absorption of toxins occurs; (b) general peritonitis; or (c) gangrene.
The following table shows the range of the leucocytes in the
German Hospital cases to which reference has been made:
NUMBER OF CASES.
LEUCOCYTES PER C.MM. Non-purulent. Purulent, Perforative, and
Gangrenous.
Above 50,000 o i
From 40,000—50,000 o o
" 35,000-40,000 o 2
" 30,000—35,000 o o
" 25,000-30,000 " o 6
" 20,000-25,000 o 16
" 15,000-20,000 .4 . ' 38 >
" 10,000—15,000 10 24
5,000-10,000 25 7
Below 5000 : • 6 o
Highest 1 7,100 per c.mm. 58,500 per c.mm.
Lowest i ,600 " " 6,000 " "
Average 8,987 " " . 17,955 "
The qualitative changes found in high leucocyte counts are
those typical of an ordinary polynuclear neutrophile leucocytosis
— a large absolute and relative gain in polynuclear forms at the
expense of the hyaline mononuclear cells.
Findings essentially like the above have been reported by
Cabot,1 Richardson,2 Bloodgood,3 and Joy and Wright,4 in America;
by Longridge,5 Gulland,8 and French,7 in Great Britain; by
1 Loc. cit. * Amer. Jour. Med. Sci., 1899, vol. cxviii, p. 635.
3 Prog. Med., 1901, vol. iv, p. 216. 4 Med. News, 1902, vol. Ixxx, p. 628.
5 Brit. Med. Jour., 1902, vol. ii, p. 1511; also Lancet, 1902, vol. ii, p. 74.
* Scottish Med. and Surg. Jour., 1903, vol. xii, p. 157.
7 Brit. Med. Jour., 1904, vol. i, p. 1136.
24
370 GENERAL HEMATOLOGY.
Curschmann,1 Wassermann,2 Dutzmann,3 Federmann,4 Gern-
gross,5 Coste,6 Kuhn,7 and Stadler,8 in Germany; and by Cazin
and Gros,9 in France.
The detection of iodophilia is a great diagnostic aid. Like
leucocytosis, it measures the intensity of the toxemia, but it also
develops in greatly anemic patients, irrespective of their systemic
reaction to an appendicular lesion. Iodophilia is most marked
in cases with abscess, gangrene, and local or general peritonitis ;
in pus cases the reaction persists so long as the pus remains
pent up, but it rapidly disappears after adequate drainage is
established — usually, in the author's cases, within thirty-six hours
or so. Thus it appears that the iodin reaction has much the
same meaning as leucocytosis, but it is even a more sensitive sign
than the latter, since it frequently betrays a sepsis too slight to
excite, or so grave as to stifle, a leucocyte increase. Locke,10
from a study of 61 cases of appendicitis, lays stress on iodophilia
as a negative sign; rarely, if ever, does it fail to develop when
sepsis is present.
The conditions which may more or less
DIAGNOSIS, closely simulate an acute attack of appendicitis
are numerous, and unfortunately it happens that
just those lesions in which the resemblance is closest often produce
blood changes identical with those of appendicitis. Thus, leuco-
cytosis is the rule in pyosalpinx, ovarian abscess, ectopic pregnancy,
Pyonephrosis, perinephritic abscess, hepatic abscess, empyema of the
gall-bladder, mesenteric thrombosis, and malignant disease 0} the
cecum, all of which may be confused with an appendicular abscess.
Iodophilia also occurs in these conditions, save perhaps in ectopic
gestation.
Such a large proportion of cases of hepatic and renal colic are
accompanied with acute inflammatory complications, giving rise
to leucocytosis, that these conditions cannot be differentiated
with any degree of confidence from appendicitis simply by an
examination of the blood. The same is true of dysmenorrhea,
in which inflammatory changes in the uterus may constitute the
factor of a leucocyte increase. Acute gastritis is sometimes ac-
companied by a well-marked leucocytosis, and sometimes by
1 Miinch.-med. Wochenschr., 1901, vol. xlviii, pp. 1907 and 1962.
2 Arch. f. klin. Chir., 1903, vol. Ixix, p. 392.
3 Sem. med., 1903, vol. xxiii, p. 324.
4 XXII. Cong. f. Chir., Berlin, 1903; also Sem. med., 1904, vol. xxiv, p. 206.
5 Munch, med. Wochenschr., 1903, vol. 1, p. 1586.
8 Ibid., 1902, vol. xlix, p. 2038. 7 Ibid., 1902, vol. xlix, pp. 2033 and 2085.
8 Jour. Amer. Med. Assoc., 1903, vol. xli, p. 216.
9 Sem. med., 1903, vol. xxiii, p. 141.
10 Boston Med. and Surg. Jour., 1902, vol. cxlvii, p. 289.
ARTHRITIS DEFORM ANS. 371
none at all, so that the blood count cannot be relied upon as a
clue in distinguishing this disease from appendicitis.
Simple enteralgia, gastralgia, and ovarian neuralgia may be
ruled out if a leucocyte increase is present, as also may be intestinal
obstruction, provided that the latter is not 'complicated by inflam-
matory changes, by gangrene, or by malignant disease. In
lead colic there is often a pronounced leucocytosis, especially in
patients with acutely toxic symptoms; but granular basophilia of
the erythrocytes can be detected even in the earliest stages of
plumbism, while in appendicitis this change is found only in
highly anemic subjects.
The presence of a leucocytosis is sufficient to exclude a non-
inflammatory ovarian cyst and a movable kidney, and the same
sign is of no little value in ruling out enteric fever if no leuco-
cyte-raising complications are apparent.
The simple fact of the presence or absence of a leucocytosis is
more often misleading than useful in the diagnosis of appendicitis,
for this sign, to be of any real value, must invariably be corre-
lated with other more clinical manifestations. Appendicitis
should never be ruled out because leucocytosis is absent, nor
should a moderate leucocyte count be considered an indication
of the benignancy of the lesion. A count in excess of 20,000,
particularly if it persists or increases, may be relied upon 'as a
certain sign of pus or its consequences, and is sufficient to
warrant operative interference if the symptoms point to the
appendix as the seat of the trouble. Counts of less than
20,000 cannot be depended upon to reflect the character of the
local lesion, since an increase to practically this figure may be
found occasionally in mild catarrhal cases, as well as in those with
purulent foci. In the writer's experience the behavior of the
leucocytes throws a much clearer light upon the progress of the
disease in both operative and non-operative- cases than it does
upon the. initial diagnosis, which should be determined chiefly by
other clinical methods.
The absence of iodophilia is a dependable sign that no active
inflammation of the appendix exists, although its presence does
not necessarily mean appendicitis, as remarked above.
VIII. ARTHRITIS DEFORMANS.
In spite of their pallor, sufferers from arthritis deformans
seldom have decided anemia. Recent hematological work in this
disease shows that most cases have normal hemoglobin and erythro-
372 GENERAL HEMATOLOGY.
cyte values, and that anemia, when it does develop, is generally
moderate and traceable to causes other than the joint lesions.
McCrae's report1 shows an average hemoglobin percentage of 70.6
in 33 cases, and an average erythrocyte count of 4,468,000 per
c.mm. in 29. Erving's counts 2 in 40 cases show an average
hemoglobin percentage of 94, with a range between 80 and 100,
and an erythrocyte count averaging 5,112,000, with a range
between 4,148,000 and 5,980,000. These figures evidence a much
less marked anemia than that detailed by earlier writers, for ex-
ample by Bannatyne,3 who found that the hemoglobin commonly
ranged between 40 and 80 per cent., and the erythrocytes between
3,000,000 and 4,000,000. Histological changes in the erythrocytes
are conspicuous by their absence.
Leucocytosis rarely accompanies arthritis deformans, and when
present, can generally be referred to some complicating lesion.
Of McCrae's 33 cases, but 9 showed definite leucocytosis, the
average count being 7600; in Erving's 40 cases the leucocytes
exceeded 10,000 per c.mm. in but 5 instances, and averaged 8885.
Differential changes are trifling and do not occur in all cases.
They consist in nothing more than a moderate diminution in the
polynuclear neutrophiles with a proportionate lymphocyte in-
crease.
IX. ASIATIC CHOLERA.
In many cases there is great difficulty in
GENERAL obtaining a sufficient quantity of blood for clin-
FEATURES. ical examination, even from a deep puncture.
This peculiarity, which has been attributed to
excessive dryness of the tissues from drains upon the body fluids,
is most pronounced in the algid stage of the disease.
The great decrease in the alkalinity of the blood in Asiatic
cholera, sometimes spoken of as an acid reaction, was first de-
termined by C. A. Schmidt4 by a series of elaborate analyses
made in 1850, since which time similar findings have been noted
by Cantani,5 Straus,8 and others.
The density of the blood mass is found to be increased, es-
pecially in those cases in which the blood is highly inspissated;
in such instances the specific gravity may rise to as high as 1.073.
The agglutination of cholera vibrios by the blood serum of
1 Jour. Amer. Med. Assoc., 1904, vol. xlii, p. i.
2 Amer. Med., 1903, vol. vi, p. 440. 3 Lancet, 1896, vol. ii, p. 1510.
4 " Charakteristik der epidemischen Cholera gegeniiber venvandten Transsuda-
tionsanomilien," Leipsic, 1850.
* Centralbl. f. d. med. Wissenschaft, 1894, vol. xxii, p. 785.
* Compt. rend. Soc. biol., Paris. 1883, vol. iv, p. 569.
ASIATIC CHOLERA. 373
cholera patients was first applied as a clinical test by Achard
and Bensaude,1 these investigators finding that the reaction may
occur as early as the reputed first day of the illness and as late
as the fourth week after recovery. Clinically, the test may be
made either with dried blood or with serum.
The studies of Biernacki 2 and of Okladnych,3
HEMOGLOBIN which together include the investigation of 62
AND cases, furnish the most complete data con-
ERYTHROCYTES. cerning the changes affecting these elements.
Both of these observers found a more or less
marked polycythemia with a proportionate increase in the hemo-
globin percentage, the erythrocyte count in many cases being
between 6,500,000 and 7,500,000, and in one case reaching a
maximum of 8,000,000. The increase may often be observed
within a few hours after the onset of the infection. Concentra-
tion of the blood is to be considered as the cause of these high
counts, which are, as a rule, highest in cases characterized by
pronounced emesis and purging. No constant relation between
the degree of polycythemia and the gravity of the infection can
be distinguished.
The above-quoted authors found high-grade
LEUCOCYTES, leucocytosis to be the almost invariable rule,
the increase in leucocytes being not parallel
with, but rather relatively greater than, the accompanying in-
crease in erythrocytes. It occurs both in mild and in severe
cases, as early as within twelve hours after the onset of the dis-
ease, and as late as the third, fourth, or sixth day. It may be
present both in the algid stage and in the stage of reaction, but is
likely to be more decided in the former. The degree of leucocy-
tosis may range from a minimum count of 14,000 to a maximum
of 60,000 cells per c.mm., the case of average severity showing
an increase to about 25,000 or 30,000. Preagonal leucocytosis
may be pronounced, counts of 50,000 being not uncommon.
Biernacki 'states that "all cases which in the algid stage show
a leucocytosis of 40,000 to 60,000 soon prove fatal." On the
contrary, an absence of leucocytosis cannot be regarded as a
surety that the patient will recover. In a trivial infection distinct
leucopenia has been observed, but this is rare. Rogers,4 who in-
variably found leucocytosis in 23 cases, also believes that the
higher the count, the worse the prognosis. Of 9 of his patients
with counts of less than 20,000, 4 died; of 14 with counts ranging
1 Presse med., 1896, vol. xvi, p. 504.
2 Deutsch. med. Wochenschr., 1895, vol. xxi, p. 795.
5 Cited by Biernacki, loc. cit. * Lancet, 1902 vol. ii, p. 659.
GENERAL HEMATOLOGY.
between 20,000 and 46,000, n died. Concentration of the blood
does not altogether account for the leucocytosis of cholera, for
the influence of the specific infection as a factor is thought to be
most active.
The leucocytosis involves chiefly the polynuclear neutrophiles,
but not so conspicuously as in most other infections, since the per-
centage of these cells in cholera seldom exceeds 80. Rogers first
described this peculiarity, and also drew attention to the behavior
of the lymphocytes. The small lymphocytes, he found, are
usually outnumbered to the extent of two to one by the large
mononuclear forms, the latter's increase becoming more marked
as the disease progresses, and being especially so in fatal cases.
He finds that an excessive increase in this form of cell is of bad
prognosis: of 18 cases with counts exceeding 2000 large lym-
phocytes per.cjnm., 14 died; while of 5 in which these cells num-
bered less than 2000 but a single patient died. The eosinophiles
rarely numbered more than a fraction of one per cent. Sherring-
ton l has found the mast cells notably increased in some instances.
Leucocytosis is more constant and tends to
DIAGNOSIS, reach, a higher degree in Asiatic cholera than in
any other non-choleraic disease with similar
symptoms. In acute dysentery and in ptomain poisoning, however,
the counts may be identical with those of cholera, but the character-
istic lymphocyte formula of the latter is wanting. From the
viewpoint of prognosis this differential change and the height of
the total leucocyte count are obviously helpful signs.
X. ASTHMA AND EMPHYSEMA.
In long-standing cases moderate secondary anemia involving
chiefly a hemoglobin loss may be found, for in many instances
the general debility of the patient or the presence of lesions of
other organs is quite adequate to give rise to such a change.
In cyanotic patients the anemia may be hidden by the polycy-
themia arising from circulatory disturbances, this deceptive blood
concentration being most conspicuous during an asthmatic par-
oxysm.
Little or no increase above the normal standard in the number
of leucocytes is the usual condition, although these cells may show
a considerable increase in cases associated with acute bronchitis,
and also during an asthmatic attack. Gabritschewrsky,2 Fink,3 von
1 Proc. of the Roy. Soc., London, 1894, vol. Iv, p. 189.
2 Arch. f. exp. Path. u. Pharm., 1890, vol. xxviii, p. 83
3 Inaug. Diss., Bonn, 1890.
BRONCHITIS. 375
Noorden,1 Billings,2 and others have called attention to the pres-
ence of an eosinophile increase in both asthma and emphysema.
From 10 to 20 per cent, of this type of cells is not an unusual
proportion, both in cases with and in those without leucocytosis,
while in one case Billings has reported three consecutive counts
of 33.9, 38.2, and 53.6 per cent, respectively, with correspond-
ing total leucocyte estimates of 7600, 7500, and 8300 per c.mm.
In true bronchial asthma the eosinophile increase develops shortly
before the paroxysm, and persists during and for a short time after
it, disappearing in the interval between the seizures. This sign
is regarded of value in differentiating true bronchial asthma from
the dyspnea due to renal and cardiac lesions, since in the latter
the eosinophiles are never increased, and it is also considered
of some clinical utility in heralding an impending asthmatic
paroxysm.
XI. BRONCHITIS.
With the exception of a slight oligochromemia, which is fre-
quently present in severe cases with high temperatures, the
erythrocytes and their hemoglobin content remain practically
normal in all forms of- bronchial inflammation.
A cute catarrhal bronchitis of the larger tubes is ordinarily un-
attejided by leucocytosis, but, unfortunately for diagnostic pur-
poses, an occasional case shows a marked increase. Thus, in four
of Cabot's seventeen cases3 the counts were 17,600, 23,500, 26,000,
and 41,000 respectively, while in eleven the leucocytes numbered
more than 10,000 per c.mm. In chronic bronchitis leucocytosis
rarely if ever occurs. . Extension of the inflammation to the finer
tubules and vesicular structure causes a leucocytosis identical
with that of crpupous pneumonia (q. v.).
Inflammation of the tracheobronchial glands, according to
Carriere,4 sets up a decided mononucleosis. Lichtwitz and
Sabrazes °t found this change in the blood of children with naso-
pharyngeal adenoids, the mononuclear increase in such cases dis-
appearing after removal of the growths.
1 Zeitschr. f. klin. Med., 1892, vol. xx, p. 98.
2 N. Y. Med. Jour., 1897, vol. Ixv, p. 691.
3 Loc. cit. 4 Sem. med., 1902, vol. xxii, p. 44.
5 Arch, de me*d. des Enf., 1901, vol. iv, p. 120.
376 GENERAL HEMATOLOGY.
, XII. BUBONIC PLAGUE.
Slow, imperfect coagulation of the blood has
GENERAL been found, and, in virulent cases, absolute non-
FEATURES. coagulability. This was noted by Alice M.
Corthorn * in 10 of 12 fatal cases of pest, whose
blood, kept sealed in Wright's tubes for three weeks and longer,
showed no sign of clot formation, but resembled simply a dark-
red, treacle-like fluid. Jennings 2 found that rouleaux formation
is but feebly exhibited.
Since 1894, when Kitasato and Yersin, working independently,
simultaneously discovered the Bacillus pestis bubonicce in the
circulating blood of patients infected with plague, this organism
has been repeatedly isolated from the blood by many different ob-
servers. In a careful bacteriological study of 27 cases Ogata £
also frequently found in the blood, especially in severe infections,
a micro-organism morphologically similar to FrankePs pneu-
mococcus, the significance of this unidentified organism being
undetermined. The same observer calls attention to the fact that
blood from patients convalescent from nineteen to sixty-five days,
although giving negative results by cultural methods, when in-
jected into mice proves rapidly fatal to these animals, in whose
tissues the plague bacillus may be recovered in pure culture. The
relatively large number of positive results to be obtained from
bacteriological blood examinations in this disease, especially in its
septicemic form, attaches to the procedure no small diagnostic
value. The German Plague Commission's results4 — 43 positive
findings in a series of 124 cases examined — are probably represen-
tative of the value of blood culturing in this infection. Powell's
studies5 show but 15 positive cultures in 117 cases. Cultural
methods with blood drawn directly from a vein give, of course,
the most favorable results, but the bacilli may be often detected
in the stained cover-glass specimen of finger blood, in which they
appear as short rods, tending to group together in chains or in
pairs, exhibiting bipolar staining and decolorizing by Gram's
method. In view of the fact that the peripheral blood contains
but small numbers of the bacilli, Rees6 advises making large
films on -slides rather than cover-glass specimens, should direct
examination of the stained film be attempted.
1 Brit. Med. Jour., 1902, vol. i, p. 1143. 2 "Manual of Plague," London, 1903.
3 Centralbl. f. Bakt. u. Parasit., 1897, vol. xxi, p. 769.
4 Cited by Now, Amer. Jour. Med. Sci., 1901, vol. cxxii, p. 416.
5 Indian Med. Gaz., 1904, vol. xxxix, p. 41.
8 Brit. Med Jour., 1900, vol. ii, p. 1236.
BUBONIC PLAGUE. 377
The agglutination of the plague bacillus by the blood serum
from plague subjects has been noted by a number of different
investigators, but thus far no clinical application of the reaction
has been made. The inconstancy with which the reaction occurs —
for it may frequently be absent in both the mildest and the most
severe cases — and the variable degrees of serum dilution neces-
sary for its production appear to bar the acceptance of the test as
a reliable diagnostic sign. The British Indian Plague Commis-
sion 1 concludes that "no practical value attaches to the method of
serum diagnosis in the case of plague."
The striking bactericidal action of plague serum upon the Bacil-
lus pestis has been taken by Row 2 as the basis of a clinical test. A
drop of blood serum from a plague patient is mixed with a loopful
of a saline emulsion of the Bacillus pestis, and from this mixture
a hanging-drop culture is made and placed in the dark for twenty-
four hours at laboratory temperature. The cover-glass is then
fixed, stained with thionin, and examined microscopically. If the
serum used in the test is from a person infected with plague, the
twTenty-four-hour-old culture shows either no growth of the bacillus
or, at the most, a very few distorted and atypical organisms. In
control cases, witfr normal serum, the growth is abundant. Row
considers this test of real value in estimating the protective effects
of Haffkinization. Its usefulness as a clinical means of diagnosing
plague is restricted by the time required (twenty-four hours") for
the completion of the reaction, though in suspected cases with
poorly developed symptoms the test may prove of value.
According to Aoyoma's- studies,3 the hemo-
HEMOGLOBIN globin and the erythrocytes are both decidedly
AND increased above normal in the majority of cases.
ERYTHROCYTES. Of the six cases examined by this writer, five
showed marked polycythemia, the highest count
being 8,190,000, and the average 6,976,666. Septic cases may
develop secondary anemia of variable intensity. Qualitative
changes hi the erythrocytes, it is to be presumed, are not. con-
spicuous, since no mention of such alterations is made.
In two-thirds of the cases just quoted marked
LEUCOCYTES, increase in the number of leucocytes was found,
the gain being greater than is ordinarily met with
in any condition except leukemia; the count exceeded 100,000
in four instances, and averaged for the six 96,666. In fulminant
1 Brit. Med. Jour., 1903, vol. i, pp. 1093, 1155, 1220, 1279.
2 Ibid., 1902, vol. ii, p. 1895.
3 Mittheilungen aus d. Mod. Fac. d. Kaiserlich-Japanischen Univcrsitat, Tokio,
1895, vol. iii, p. 115.
378 GENERAL HEMATOLOGY.
types of plague extreme leucopenia, due to the overpowering
toxemia, is not unusual, and in very mild cases the number of
leucocytes may be normal. The increase was due usually to a
•disproportionately large percentage of poly nuclear neutrophiles,
but in some cases " large and small mononuclear white cells"
were observed. -The eosinophiles were, as a rule, conspicuous
by their absence. Rogers,1 whose leucocyte counts varied from
20,000 to 60,000, also observed a lymphocytosis, and emphasizes
the fact that in most cases the polynuclear neutrophiles show little
or no relative increase. Contrary to Aoyoma's findings, Zinno 2
has noted, in an occasional case, a great abundance of eosinophiles
of the myelocytic type, of the ordinary polynuclear variety, and of a
form transitional between the two; in one of his cases the eosino-
philic myelocytes numbered 13 per cent, of the total leucocyte
count.
The blood plaques are in most cases notably increased in
number.
XIII. BURNS.
Rapidly developing and marked polycythemia, equally striking
leucocytosis, and a plaque increase are the features of clinical
interest in the blood picture of the severely burned. To the naked
eye the blood has a deep purplish color and flows very sluggishly.
Locke's studies3 of ten cases of severe burns show that within
a few hours after the accident a marked increase in the number
of erythrocytes takes place, amounting in favorable cases to be-
tween 1,000,000 and 2,000,000 cells to the c.mm., and in fatal cases
to between 2,000,000 and 4,000,000. This polycythemia may be
explained chiefly by venous stasis and partly by loss of the blood
plasma. Structural changes in the erythrocytes are not con-
spicuous. The leucocytes rapidly increase, reaching a count of
from 30,000 to 40,000 per c.mm. in non-fatal burns, and of 50,000
or more in patients who die. The percentage of polynuclear
neutrophiles increases, although not to so high a figure as is
commonly found in ordinary inflammatory leucocytosis. De-
generative changes, especially of their protoplasm, involve many
of these cells, as well as the other granular leucocytes, and are
marked in parallelism to the severity of the lesion. Myelocytes
occur in small numbers, particularly in cases having a high
leucocytosis. The blood plaques are greatly increased in practi-
cally every instance.
1 Lancet, 1902, vol. ii, p. 660.
2 Centralbl. f. allg. Path. u. path. Anat., 1902, vol. xiii, p. 410.
3 Boston Med. and Surg. Jour., 1902, vol. cxlvii, p. 480.
CHLOROMA. 379
XIV. CHLOROMA.
The blood changes in this rare disease closely resemble those
of lymphatic leukemia, namely, marked anemia with absolute
lymphocytosis. The hemoglobin and erythrocytes progressively
diminish as the disease runs its course, and eventually may sink
quite as low as in pernicious anemia. In a case reported by
Dunlop * the hemoglobin fell from 32 to 12 per cent., and the ery-
throcytes from 1,800,000 to 850,000 per c.mm. during a period of
but four weeks. Estimates not dissimilar from these have been
recorded by a number of other writers, notably by Rosenblath
and Risel,2 by Gumbel,3 and by Weinberger.4 Misshapen and
otherwise degenerate erythrocytes, together with a variable number
of normoblasts, make their appearance as the anemia increases
in degree.
High leucocyte counts, involving absolute lymphocytosis
(small celled), are the rule in the cases thus far reported. Ex-
ceptionally there is simply lymphocytosis of the relative form, as in
a case reported by B ram well5 with 95 per cent, of lymphocytes and
a leucocyte count of 8000. Early in the disease the total count is
not excessive, — 20,000 or 30,000, — but after a few weeks it may
attain much higher figures — 75,000 to 100,000 or more. Dunlop's
case at one time showed a leucocyte count of 245,000 per c,rnm.
Differentially, the count in chloroma differs but slightly from that
of lymphatic leukemia. The percentage of lymphocytes is rarely
so high as in the latter, and mast cells are not so numerous, but
myelocytes are more abundant. Eosinophiles, both pofynuclear
and myelocytic, were numerous in a case studied by Dock.8 These,
however, are minor differences, and do not serve as reliable
criteria of differentiation.
Chloroma has a superficial resemblance to exophthalmic
goiter, and very closely counterfeits acute lymphatic leukemia.
Indeed, o.ne is strongly tempted to agree with Dock in considering
it a malignant form of leukemia, from which it differs chiefly in
being more violently neoplastic and in forming greenish infiltrations
and metastases. Graves' disease is readily differentiated by the
blood picture. The clinical differences between chloroma and
leukemia are dealt with under the latter disease. (See p. 326.)
1 Brit. Med. Jour., 1902, vol. i, p. 1072.
2 Deutsch. Arch. f. klin. Med., 1902, vol. Ixxii, p. i.
3 Virchow's Arch., 1903, vol. clxxi, p. 504.
4 Zeitschr. f. klin. Med., 1903, vol. 1, p. 383.
5 Lancet, 1902, vol. i, pp. 451 and 520, * Med. News,
1904, vol. Ixxxiv, p. 955.
380 GENERAL HEMATOLOGY.
, XV. CHOLELITHIASIS.
In impacted calculi with jaundice, coagulation
GENERAL is frequently but not invariably delayed, but in
FEATURES, gall-stone complicated by phlegmonous cholan-
gitis or other purulent sequelae, hyperinosis is
observed, and coagulation is generally more rapid than normal.
In 28 cases of cholelithiasis the writer found that clotting occurred
in less, than five minutes in 7, in from five to ten minutes in 16,
and in longer than ten minutes in 5. In 60 per cent, clotting was
delayed, the coagulation time for these cases averaging eight and
one-half minutes. The general effects of bile upon the blood,
elsewhere noted, may also be detected when marked jaundice
develops. (See "Cholemia" and "Icterus.")
Positive results from bacteriological examination of the blood
have frequently been obtained in cholelithiasis, streptococci having
been isolated by Netter,1 staphylococci and colon bacilli by Sitt-
mann,2 streptococci and pneumococci by Canon,3 and various
bacteria of unknown identity by other investigators.
HEMOGLOBIN NUMBER OF ERYTHROCYTES NUMBER OF
PERCENTAGE. CASES. PER C.MM. CASES.
From 90-100 12 Above 5,000,000 13
23 From 4,000,000-5,000,000.58
« 43 " 3,000,000-4,000,000.34
" 50-60" ' 8 " 2,000,000-3,000,000.10
« 40-50. " " 1,000,000-2,000,000 . i
" 30-40 i
" 20-3° 3
Below 20 i
Average, 73.5 per cent. Average, 4,080,1 17 per c.mm.
Maximum, 98.0 Maximum, 5,390,000 " "
Minimum, 15.0 Minimum, 1,040,000 " "
Moderate oligochromemia is found in the
HEMOGLOBIN greater proportion of cases, but a decided loss
AND either of hemoglobin or of erythrocytes is com-
ERYTHROCYTES. paratively rare. In general terms it may be
conservatively stated that the hemoglobin loss
on the average amounts to about 30 per cent., and that the cel-
1 Progres med., 1886, vol. xiv, p. 992.
2 Deutsch. Arch. f. klin. Med., 1894, vol. liii, p. 323.
8 Deutsch. med. Wochenschr., 1893, vol. xix, p. 1038.
CYANOTIC POLYCYTHEMIA. 381
lular decrease approximates 15 per cent, of the normal standard.
In occasional instances, notably those in which suppuration or
sepsis coexists, the anemia is of a more intense grade, and may
be associated with various changes indicative of cellular degen-
eration. In 116 cases of cholelithiasis the foregoing estimates of
the hemoglobin and erythrocytes were obtained at the initial
examinations.
Simple gall-stone does not of itself excite the
LEUCOCYTES, slightest increase in the number of leucocytes,
but nevertheless leucocytosis, typically polynu-
clear in type, is a rather common feature of the blood picture in
this disease, owing to the fact that such a large percentage of
cases is complicated by acute inflammatory changes. Thirty-three
of the 116 cases just mentioned had a count of more than 10,000
cells to the c.mm. The following resume of the examinations
illustrates the range of leucocytes in the series:
LEUCOCYTES NUMBER OF
PER C.MM. . CASES.
From 20,000-30,000 6
" 15,000-20,060 8
" 10,000-15,000 ,. 19
5,000-10,000 74 \
Below 5,000 9
Average, 9,623 per c.rrim.
Maximum, 26,000 " "
Minimum, 4,500 ' " "
The presence of a leucocytosis excludes simple
DIAGNOSIS, biliary colic, and indicates as the cause of the in-
crease some other lesion, such, for example, as
phlegmonous cholangitis or cholecystitis, hepatic abscess, peritonitis,
or malignant disease. Hepatic and renal colics cannot be differ-
entiated by the blood count.
The surgeon should remember that cases with delayed coagu-
lation may bleed freely, even fatally, when the knife is used, and
that to such patients remedies which promote clotting should be
given before operating.
XVI. CYANOTIC POLYCYTHEMIA.
In this new clinical entity, first described by Saunby and Rus-
sell,1 the hemoglobin and erythrocyte values attain extraordinarily
1 Lancet, 1902, vol. i, p. 515.
382 GENERAL HEMATOLOGY.
high figures. O^ler,1 who has studied the condition in detail,
reports one case with a hemoglobin percentage of 165 and an
erythrocyte count of 10,200,000 per c.mm., while in a case exam-
ined by J. N. Hall2 the hemoglobin was 200 per cent, (making
it necessary to dilute the blood doubly in order to make the test
with the von Fleischl hemometer), and the erythrocyte count
reached 9,949,600. Estimates not differing greatly from these
have also been reported by Cabot,3 Saunby and Russell,4 C. G.
Stockton,5 Tiirk,6 Vaquez and Quiserne,7 and others. The
blood is thick and tarry, flows sluggishly from the puncture,
and coagulates with great rapidity. The cause of the enor-
mous polycythemia is a moot point. Osier8 proposes as a
factor hyperviscosity of the blood, in consequence of which the
intracapillary flow is impeded. Gibson9 attributes it to peripheral
stasis dependent upon myocardial weakness.
Osier's disease, as it may be fittingly termed, occurs in middle
age, and, aside from the blood findings, is characterized by idio-
pathic and permanent cyanosis, by splenic and sometimes hepatic
enlargement, and almost invariably by albuminuria. In the cases
thus far studied no clinically demonstrable lesion of the heart or
lungs has accounted for the cyanosis, nor has autopsy revealed
tuberculosis of the spleen, which in its primary form is associated
with cyanosis and polycythemia of a moderate degree.
The leucocytes are usually not increased, although in an occa-
sional instance they have been found to number about double the
maximum normal standard. Differentially they are also normal.
. XVII. DENGUE.
Graham,10 of Beyrouth, recently announced that dengue is due
to a protozoon resembling in some respects the malarial parasite.
He believes that such an organism is constantly present in the dis-
ease, and that it undergoes an evolution within the erythrocytes at
their expense. Furthermore, it is held that the parasite is harbored
and conveyed by a species of mosquito, the Culex fatigans.
Graham's work still lacks confirmation, and hence cannot be
1 Amer. Jour. Med. Sci., 1903, vol. cxxvi, p. 187.
7 Amer. Med., 1903, vol. v, p. 1026.
3 Boston Med. and Surg. Jour., 1899, vol. cxli, p. 574; ibid., 1900, vol. cxlii,
P-275-
4 Loc. cit. 5 Medical News, 1903, vol. Ix.xxii, p. 948.
' Cited by Osier, loc. cit. 7 Sem. med., 1902, vol. xxii, p. 235.
8 Brit. Med. Jour., 1904, vol. i, p. 121.
9 Lancet, 1903, vol. ii, p. 1560. • 10 Med. Rec., 1902, vol. Ixi, p. 204.
DIABETES MELLITUS. 383
considered conclusive. Study of the corpuscles in this disease
seems to have been generally neglected.
XVIII. DIABETES MELLITUS.
The alkalinity of the blood, according to the
GENERAL investigations of Minkowski,1 is appreciably
FEATURES, diminished, especially in cases in which coma
either impends or exists. The change, however,
cannot be regarded as constant, since in none of the five cases
lately studied by Golla2 did the alkalinity figures differ materially
from normal.
Orlowsky3 in two cases of diabetes mellitus appreciably in-
creased the blood alkalinity by giving warm alkaline enemata,
the change thus effected being more decided and persisting longer
than when caused by the administration of similar drugs by the
mouth. He believes in treating diabetic coma in this manner,
the alkali being given for some time after urgent symptoms have
disappeared. Lipemia is not uncommon, the amount of fat in
some instances being so large as to produce a milky appearance
of the blood drop, evident to the naked eye, although in most
instances the condition is recognizable only by the detection of
fat globules under the microscope.' Not infrequently diabetic
blood has a peculiar salmon color. Neisser and Berlin4 report a
case of diabetes which showed 20 per cent. ( !) of fat ii\ the in-
spissated blood obtained by venesection. Lipacidemia may
be detected in diabetic coma. Glyccmia is present, and can be
demonstrated by the detection of grape-sugar in relatively large
amounts, even as great as 5.7 parts per thousand, according
to Grawitz,5 or 9 per thousand, according to Hoppe-Seyler.6 (See
p. 141.)
Williamson's Test. — This reaction, devised by Williamson7 in
1896, depends upon the fact that a warm alkaline solution of
methylene-blue is decolorized when mixed with a minute quantity
of glucose. Twenty c.mm. of the suspected blood, obtained
by puncturing the finger, are measured by means of Gower's
hemocytometer pipette, and blown out into 40 c.mm. of distilled
water contained in a small test-tube. To this mixture are then
1 Mitth. a. der med. Klinik. z. Konigsberg, 1888.
2 Lancet, 1903, vol. i, p. 1230.
3 Russkiy Vrach, 1901, vol. xxii, pp. 1190 and 1222.
4 Zeitschr. f. klin. Med., 1904, vol. li, p. 428.
5 Jj)c. cit. • * Virchow's Arch., 1858, vol. xiii, p. 104.
7 Brit. Med. Jour., 1896, vol. ii, p. 730; also Lancet, 1900, vol. ii, p. 320.
384 GENERAL HEMATOLOGY.
added, in the order given, i c.c. of a i : 6000 aqueous solution of
methylene-blue and 40 c.mm. of a six per cent, aqueous solution of
potassium hydrate. In a second test-tube the same proportions of
normal blood and reagents are mixed, to be used as a control.
The color of both mixtures is precisely the same — moderately deep
bluish-green. Both tubes are placed in a beaker filled with boil-
ing water, in which they are allowed to remain for four minutes,
at the end of which time the test fluid containing the diabetic
blood 'will have turned a dingy yellow color, while the color of
the control mixture remains unchanged. Care must be taken to
use not more than 20 c.mm. of blood, since a positive reaction
may be more or less closely counterfeited with non-diabetic blood
should three or four times this quantity be employed. It is
essential, therefore, to measure the blood accurately, and not to
trust to the approximate method used by some, of simply taking
two drops of blood as the equivalent of the required 20 c.mm.
Williamson's reaction is presumably due solely to the action of
the grape-sugar contained in diabetic blood, and if this proves
true, it is not unreasonable to predict that the principle of the test
may be elaborated into a method for estimating the percentage
of sugar in the blood. Positive reactions occur constantly in
diabetes, sometimes even after the disappearance of every trace
of sugar from the urine, and, so far as investigations up to the
present time have shown, negative results are invariably met with
in other diseases.
Brewer's Test, — Bremer,1 having noticed in diabetes mellitus
peculiar affinities of the erythrocytes for various anilin dyes, has
devised upon this basis an ingenious test for the recognition of
diabetic blood. Several thick films from a suspected case, con-
trolled by the same number of preparations made from normal
blood, are prepared, preferably on slides, and heated in an oven
to a temperature of 135° C., after which they are set aside to
cool. Both sets of films are then stained for about two minutes
with a one per cent, aqueous solution of Congo-red (mixed freshly
just before using), thoroughly washed in running water, and
dried between bits of filter-paper. Thus treated, diabetic blood
is either colored pale greenish-yellow or is entirely unstained,
while normal blood stains typically the red color of the dye.
Using the same method of heat fixation, other anilin dyes may
be employed to demonstrate this peculiar behavior of diabetic
blood. For example, with a one per cent, aqueous solution of
methylene-blue the diabetic specimen stains yellowish-green and
1 N. Y. Med. Jour., 1896, vol. Ixiii, p. 301 (Lit.}; also Med. Record, 1897,
vol. xii, p. 495.
DIABETES MELLITUS. 385
the normal film blue. Diabetic blood, on the contrary, treated
with a one per cent, aqueous solution of biebrich-scarlet, takes
the color of the dye in a typical manner, while normal blood re-
mains practically uncolored. Ehrlich's triacid stain, as well as
mixtures of methylene-blue and eosin and methyl-green and
eosin, have also been used to demonstrate the reaction. The
cause of Bremer's reaction is unknown, but apparently it is not
due to the effect of glucose; many authors are inclined to attrib-
ute it to excessive acidity of the blood. Positive results with
this test cannot be regarded as pathognomonic of diabetes mel-
litus, since they have been reported with the blood of persons suf-
fering from exophthalmic goiter, multiple neuritis, leukemia, and
Hodgkin's disease.
There are no constant changes to be found
HEMOGLOBIN in these elements. Normal hemoglobin percent-
AND ages and erythrocyte counts are observed in
ERYTHROCYTES. most cases, while in others in which the cachexia
is pronounced a well-marked secondary anemia
may exist. James,1 in a study of 13 cases, found the number
of erythrocytes over 6,000,000 in 5; 5,000,000 plus in 5; 4,000,-
ooo plus in 2; and 3,000,000 plus in i. The hemoglobin per-
centage was over 100 in 3 cases; 60—70 in 8; and 50—60 in 2. The
alterations in the hemoglobin and erythrocytes in diabetes have
been attributed by the older writers 2 chiefly to the effects of blood
concentration and dilution. Thus, it was believed that in cases
with excessive polyuria the blood became inspissated ajid the
count thus increased, while in cases with pronounced glycemia
the blood became diluted and the count lowered as a consequence
of the fluid transfer from the tissues into the capillaries provoked
by the presence in the blood of a large percentage of sugar. It
is obvious that these influences, if active, are sufficient to render
the blood count in diabetes of little or no practical value, since,
on the one -hand, perfectly normal blood, if diluted, may appear
anemic, while, on the other hand, anemic blood, if concentrated,
may seem normal. James3 contends, however, that the poly-
cythemia is real, and is not dependent upon inspissation, for
were the increase merely relative, it would naturally be accom-
panied by an increase in the density of the blood, and this in his
experience never occurred, the specific gravity figure for his
series ranging between 1.054 and 1.060.
1 Edinburgh Med. Jour., 1896, vol. xlii, p. 193.
2 Lit. cited by Leichtenstern, " Unters. iiber d. Hg-Gehalt d. Blutcs," Leipsic,
1878.
3 Loc. cit.
25
386 GENERAL HEMATOLOGY.
High digestion leucocytosis is the most con-
LEUCOCYTES. stant change affecting these cells, but this is not
found in every case. Isolated examples of leu-
cocytosis, apparently independent of this influence, have been re-
ported, but in1 the great majority of diabetics the leucocyte count
is normal. The presence of small numbers of myelocytes in
cachectic patients is the only qualitative change to which atten-
tion has been directed. Mahogany-colored granules, either within
the leucocytes or extracellular, may usually be demonstrated by
the iodin method. No numerical change in the blood plaques has
been reported.
Williamson's reaction is of real value, es-
DIAGNOSIS. pecially in the recognition of cases with temporary
disappearance of sugar from the urine and in
diabetic coma. Bremer's test and the iodin reaction are to be
regarded as symptomatic, not necessarily of diabetes. The other
blood findings are without diagnostic value.
XIX. DIPHTHERIA.
Usually the changes in the hemoglobin and
HEMOGLOBIN erythrocytes are, at the most, trifling, for in
AND about two-thirds of all cases these elements are
ERYTHROCYTES. practically normal, while in the other one-third
moderate anemia, more marked in severe than
in mild cases, is found. The anemia does not develop until
about the middle of the first week of the disease, and is, as a
rule, characterized by a diminution of hemoglobin roughly pro-
portionate to the corpuscular loss. Degenerative changes are rare,
consisting usually of nothing more than occasional polychromato-
philia; nucleation and deformities of size and of shape are absent.
Regeneration of the blood takes place slowly, and, as the loss of
hemoglobin is made up less rapidly than that of the corpuscles,
the color index, which is approximately normal early in the dis-
ease, later falls considerably.
The loss of hemoglobin does not often exceed 15 per cent.,
nor is the decrease of erythrocytes usually greater than from
500,000 to 750,000 cells to the c.mm. Concentration of the
blood, which frequently occurs during the febrile period, may
cause striking temporary polycythemia.
Morse,1 in single examinations of 30 cases treated without
antitoxin, found the count of erythrocytes above 5,000,000 in
1 Boston Med. and Surg. Jour., 1895, vol. cxxxii, pp. 228 and 252.
DIPHTHERIA. 387
21, and below 4,000,000 in but a single instance, a woman with
chronic anemia; several of his counts were in the neighborhood
of 6,000,000. From this author's monograph1 the following
counts reported by other investigators are taken: Bouchut
and Dubroisay,2 4,305,000 as the mean average of 93 counts in
84 cases; Gilbert,3 an average of 4,500,000 in 58 counts in 22
cases; Carter,4 an average of 4,253,000 in 13 cases; and File,5 an
average of 4,588,000 in 18 counts in 10 cases, some of which had
received antitoxin. Billings,6 in a painstaking study of 7 cases
untreated with antitoxin, in which 36 counts were made, found a
moderate but distinct decrease in hemoglobin and erythrocytes
in 5 cases, the loss first becoming apparent by the third or fourth
day, and being proportionate to the severity of the infection.
This author's first counts, all made during the first week of the
disease, ranged from 5,200,000 to 6,122,000, the average being
5,611,285, the hemoglobin for the same period ranging from 70
to 98 per cent, and averaging 90 per cent. Subsequent counts
in this series showed that the greatest loss of hemoglobin averaged
12 per cent., ranging from i to 30 per cent., and that the maximum
corpuscular loss averaged 878,500, varying from 227,000 to 2,040,-
ooo.
It is generally observed that in cases treated with antitoxin
the anemia is decidedly less than in those treated by other
methods, and, in fact, a majority of cases thus treated suffer no
decrease at all.
Well-marked leucocytosis, beginning probably
LEUCOCYTES, within a few hours after the infection first occurs,
characterizes the average case of diphtheria of
moderate severity. An analysis of the statistics derived from 276
counts made by reliable investigators7 shows that over 90 per
cent, of all cases are accompanied by a more or less marked
increase in the number of leucocytes.
In the majority of cases the number of leucocytes is not in-
creased above 30,000 per c.mm., but a much greater leucocytosis
is sometimes encountered. Thus, the maximum counts of several
authors are as follows: Felsenthal, 148,229"; Ewing, 72,000°;
T ' Med. and Surg. Reports of the Boston City Hospital 1899, tenth series,
p. 138.
1 Compt. rend. Soc. biol., Paris, 1877, vol. Ixxxv, p. 158.
3 Traite" de Me"d. Charcot-Bouchard, vol. ii, p. 485.
4 Univ. Med. Mag., 1894-95, vol. vii, pp. 17, 81, and 158.
8 Lo Sperimentale, 1896, vol. 1, p. 284. • Med. Record, 1896, vol. xlix, p. 577.
7 Ewing, Morse, Billings, Carter, Schlesinger, File, Gabritschewsky, Bouchut
and Dubroisay, Rieder, Felsenthal, and Gilbert.
8 Arch. f. Kinderheilk., 1893, vol. xv, p.»78.
* N. Y. Med. Jour., 1893, vol: Iviii, p. 713.
388 GENERAL HEMATOLOGY.
Gabritschewsky^ijOoo1; Morse, 48,ooo2; Carter, 48,28o3; Billings,
38,600*; and Gilbert, 3i,ooo.5
This increase is to be regarded as a rough gage of the reac-
tion of the individual against the effects of the toxic products of
the disease; it is, therefore, absent in very mild cases, where little
or no reaction is excited, and in severe cases in which the patient's
resisting powers are overwhelmed by the intoxication.
In favorable cases the maximum leucocytosis is reached coin-
cidentally with the height of the disease, and the increase gradually
fades away during convalescence, having in most cases entirely
ceased by the time the membrane has disappeared, but occa-
sionally persisting after the subsidence of all local and systemic
manifestations of the illness. In unfavorable cases high leucocyte
counts persist until death, or "in somewhat prolonged cases,
with much septic absorption, there may be an uninterrupted
decrease of leucocytes continuing up to the fatal termination"
(Ewing). No constant relation has been determined between the
leucocytosis and the extent of the local lesion, the degree of ton-
sillar and glandular swellings, or the height of the fever, although
in individual cases some authors have suggested that such relation-
ship may be distinguished.
The effects of antitoxin upon the leucocytes are well illustrated
by the conclusions of Ewing,6 based upon 228 counts made in 53
cases before and after the injection of the serum. As the result
of these investigations this author concludes that antitoxin, within
thirty minutes after its injection, causes a hypoleucocytosis. In
favorable cases, after the injection, the original height of the
leucocytosis is not again attained, but in severe and less favor-
able cases the dose of antitoxin is followed in a few hours by
a hyperleucocytosis exceeding that found in the primary count.
In malignant cases the administration of antitoxin may be fol-
lowed immediately either by rapid hyperleucocytosis or by ex-
treme hypoleucocytosis and death. Bize7 finds that in some
cases the initial serum injection may not affect the leucocytes be-
cause of the insufficiency of the dose, and that repeated injections
are sometimes required to modify the count. This investigator
has also called attention to the pronounced leucocytoses which
accompany eruptions due to antitoxin.
The leucocytosis of diphtheria, as a rule, involves the polynu-
clear neutrophile cells, most cases showing about 80 per cent,
of this variety, but in an occasional instance there may be a
1 Annal. de PInstitut Pasteur, 1894, vol. viii, p. 673. 2 Loc. cit.
3 Loc. cit. . 4 Loc. cit. 5 Loc. cit.
8 Loc. cit. 1 Arch, de med. des Enf., 1901, vol. iv, p. 102.
DIPHTHERIA. 389
well-marked increase in the mononuclear forms, considerably in
excess of the percentage found in health. Relative lymphocy-
tosis has been observed both during convalescence and in fatal
cases with leucopenia, and absolute lymphocytosis may occur at
the height of the disease in cases with high total leucocyte counts.
In two of Ewing's cases l the estimates showed 60 per cent, of
lymphocytes in a count of 72,000 leucocytes, and 62 per cent, of
these cells in a count of 22,500.
Besredka2 believes that marked polynuclear leucocytosis is a
good prognostic sign, especially if this form of cells shows a
strong tendency to increase after injection of antitoxin. On the
contrary, cases which fail to show such a change he regards as
grave, usually as fatal. This characteristic of high percentages
of polynuclear neutrophiles is also regarded by many other authors
as a favorable clinical sign, and a low percentage as unfavorable.
Ewing,3 by staining the leucocytes with gentian-violet (50 c.c.
of normal salt solution to which one drop of a saturated alcoholic
solution of gentian- violet is a.dded), has deduced certain conclu-
sions from the reaction of the leucocytes to this dye, to which he
is inclined to attribute great prognostic value. He believes that
the numbers and percentages of poorly 'stained leucocytes, and
usually of ameboid figures, invariably increase in unfavorable
cases, without relation to the total -number of cells found in the
blood. In his experience any considerable increase of poorly
stained leucocytes, especially if associated with a decrease of the
well-stained cells, was invariably the forerunner of a grave or
fatal change in the patient's condition. In favorable cases, after
treatment with antitoxin, he noted that the polymorphous forms
show a decidedly increased affinity for gentian-violet, this char-
acteristic often being observed within twelve hours after the in-
jection of the serum. Failure of this peculiarity to develop he
regards as* a very unfavorable prognostic sign.
The proportion of eosinophiles is exceedingly variable, these
cells sometimes being absent, and at other times found in large
numbers — four or five per cent. Kucharzewski 4 concludes, from
experimental work with animals, that a high percentage of eosino-
philes is of favorable prognosis and that a low percentage is unfavor-
able.
Engel5 found variable percentages of myelocytes in both favor-
1 "Clinical Pathology of the Blood," 2d ed., New York and Philadelphia, 1904.
2 Annal. de PInstitut Pasteur, 1898, vol. xii, p. 305.
3 N. Y. Med. Jour., 1893, vol. Iviii, p. 713.
4 XIV. Internal. Med. Congress, Madrid, Apr. 23-30, 1903; abst., Jour. Amer.
Med. Assoc., 1903, vol. xl, p. 1673.
8 Deutsch. med. Wochenschr., 1897, vol. xxiii, pp. 118 and 137.
390 GENERAL HEMATOLOGY.
able and unfavorable cases, especially in the latter, and he con-
siders their presence in relatively high percentages (2 per cent,
or higher) as an unfavorable prognostic indication. In 7 of
Engel's fatal cases the percentage of myelocytes ranged from 3.6
to 14.6, but they never exceeded 1.5 per cent, in patients who
recovered. An absence of myelemia, however, is no guarantee
of recovery, for this sign is absent in about one out of every four
fatal cases.
Examination of the blood in diphtheria gives
DIAGNOSIS, no information which is not clearly shown
by other clinical signs, and it must be regarded
as of no value as an aid to diagnosis. The leucocytosis in this
disease, if the very benign and the very severe cases are excluded,
is, as a rule, proportionate to the intensity of the infection.
From a prognostic point of view it appears that, as in pneu-
monia, an absence of leucocytosis occurring in obviously severe
infections is an unfavorable indication. The presence of a large
percentage of myelocytes has a similar meaning. Pronounced
lymphocytosis is also regarded as an unfavorable prognostic
sign.
XX. ENTERITIS.
In acute catarrhal enteritis the same changes
ENTERITIS occur that are found in acute gastritis, namely,
AND little or no alteration in the hemoglobin and
DIARRHEA, erythrocytes, and an inconstant, moderate leuco-
cytosis. Profuse watery dejecta lead, of course,
to more or less blood concentration, by depletion of the body-
fluids, and hence polycythemia may be a transient sign. In the
summer diarrheas oj infants Knox and Warfield1 found that the
leucocyte count, although usually increased, varies so widely that
the mere presence of a high or a low count is of practically no
definite diagnostic importance. An increase in the relative per-
centage of polynuclear neutrophiles, even with a normal number
of leucocytes, suggests the onset of inflammatory intestinal com-
plications. These findings Zahorsky has fully corroborated.2 In
chronic' enteritis and in gastro-enteritis the interference with the
patient's nutrition plus a drain upon the albuminoids may in
course of time give rise to a decided anemia. Leucocytosis is not
a characteristic of such cases.
1 Johns Hopkins Hosp. Bull., 1902, vol. xiii, p. 167.
2 N. Y. Med. Jour., 1903, vol. Ixxviii, p. 505.
ENTERITIS. 391
In dysentery and in ulcerative and phlegmon-
DYSENTERY. ous enteritis acute forms of secondary anemia are
frequently met with, especially in patients who
pass much blood by the bowel. Leucocytosis, often of high
degree, is also common in these lesions.
In 38 cases of uncomplicated amebic dysentery Futcher1 found
that the hemoglobin averaged 63 per cent, and the erythrocytes
4,802,000 per c.mm., while in 43 cases the leucocytes averaged
10,600. In 15 cases complicated by amebic abscess of the liver the
hemoglobin averaged 66 per cent., the erythrocytes 4,250,000, and
the leucocytes 18,350. Doubtless in both series the high erythro-
cyte values may be referred to blood concentration. The value of
the leucocyte count in the diagnosis of amebic hepatic abscess is
doubtful. In most abscess cases, such as in the n reported by
Schlayer,2 the leucocytosis is high (averaging in this series 25,000
and ranging between 18,000 and 62,000); but in other cases low
counts (6000, 9000, and 11,000 in Osier's series3) are not incom-
patible with pus. In Rogers' experience4 the count is higher in
small, deeply seated abscesses than in those superficially situated.
In differentiating malarial fever from the intermittent pyrexia of
hepatic abscess the presence of leucocytosis practically excludes the
former.
As a means of differentiating amebic from bacillary dysentery
the serum test is of value, for the Bacillus dysenteric is clumped
by the blood of persons suffering from bacillary (Shiga5) dysentery,
but not by the blood of those infected with the amebic form of the
disease. Rogers6 has used the test extensively in India with great
success.
On similar grounds it may be presumed, until proof to the
contrary is shown, that Shiga's organism is unaffected by the
blood of those infected with so-called dysentery due to the bacilli
of Ogata, of Lessage, and of Roger, and to the "Balantidium coli.
Shiga's claim,7 that the Bacillus dysenterm is never clumped
by the blood of non-dysenteric diseases, needs revision, in the
light of the researches of Park,* Pilsbury,9 and Strong.10
These observers have found that dysentery bacilli of the
Shiga, the Flexner, and the Kruse strains occasionally clumped
with the blood of persons suffering from such diseases as alcoholic
1 Jour. Amer. Med. Assoc., 1903, vol. xli, p. 480.
2 Munch, med. Wochenschr., 1903, vol. 1, p. 1372.
3 Med. News, 1902, vol. Ixxx, p. 673: 4 Brit. Med. Jour., 1902, vol. ii, p. 850.
5 Centralbl. f. Bakt. u. Parasit, 1898, vol. xxiii, p. 599.
8 Brit. Med. Jour., 1903, vol. i, p. 1315.
7 Loc. cit. 8 jour. Med. Research, 1903, vol. ix, p. 180.
9 Med. News, 1903, vol. Ixxxiii, p. 1078. 10 Rep. Surg.-Gcn., U. S. A., 1900.
392 GENERAL HEMATOLOGY.
enteritis, tuberculosis, enteric fever, appendicitis, pernicious
anemia, and pleurisy — even in dilutions as high as i : 30, i : 50,
and 1:100. Still, it is safe to regard a positive reaction with the
Bacillus dysenterm as the most valuable single clinical sign of
acute bacillary dysentery in adults in whom a recent chronic in-
flammation of 'the intestine can be ruled out. The test, to be
dependable, should be made with at least a 1:20 dilution, the
time-limit being not more than two hours. Pilsbury found
that false positive reactions do not occur with the blood of non-
dysenteric children under one year of age.
Attempts to isolate organisms by bacteriologi-
SPRUE. cal examination of the blood were unsuccessful
in Goadby's hands,1 although the most careful
methods were employed.
The hemoglobin and erythrocytes are markedly reduced, and
in a remarkably short time after the onset of the acute symptoms
the cellular loss becomes so severe as to simulate that of true
pernicious anemia. Counts of between 1,000,000 and 2,000,000
were found to be the rule by Bassett-Smith,2 with correspondingly
low hemoglobin values. There are also decided structural changes
in the erythrocytes, many of which are deformed in shape and
size (especially microcytes) and show unnatural pallor. A few
normoblasts, but no megaloblasts, may be encountered. The
blood plaques are scanty.
The leucocytes, according to the last-named writer, are not
increased, and in some instances fall to between 1000 and 2000
per c.mm. Relative lymphocytosis, small-celled in type, relative
eosinophilia (in the exceptional case), and fractional percentages
of myelocytes are the other leucocyte findings in this grave form
of enteric disease.
The effects upon the blood of saline purges were
EFFECTS OF first determined by Brouardel,3 and later studied
PURGES. by Grawitz4 and by Hay.5 The investigations of
these authors have shown that the administration
of a purgative dose of Epsom or Glauber salts is followed within
about thirty minutes by an appreciable increase in the number of
erythrocytes, and that within an hour the count of these cells is
fully 1,500,000 more than before the purge was given; three hours
after this maximum is reached the count is again normal. When
a certain degree of concentration is obtained by these means, con-
tinued administration of the salt produces neither additional con-
1 Brit. Med. Jour., 1903, vol. ii, p. 644.
1 Ibid., 1903, vol. ii, p. 641. 3 Union med., 1897, vol. xxii, p. 405.
4 Loc. cit. 5 Jour. Anat. and Physiol., 1882, vol. xvi, p. 435.
ENTERIC FEVER. 393
centration nor further purgation. Common table salt is also a
most energetic factor of blood density, even more so than either
Epsom or Glauber salts. Purgative doses of jalap, croton oil,
and other drugs of this class are also followed by more or less
polycythemia.
XXI. ENTERIC FEVER.
The alkalinity of the blood is generally de-
GENERAL creased, a change which may be due partly to the
FEATURES, effect of the pyrexia and toxemia and partly to
the anemia. Dare and Funke1 found subnormal
alkalinity figures in 20 of 23 cases of enteric fever, but were unable
to determine the relationship of this change to the other clinical
manifestations. Drouin2 also found similar alkalinity values in
this infection.
The coagulation time of the blood is appreciably diminished
in the early stages of typhoid, sometimes to such a degree as to
favor intestinal hemorrhage. During convalescence the rapidity
of clotting is decidedly increased, and this tendency may be re-
garded as a possible factor of thrombosis. Wright and Knapp3
suggest that the increased coagulability is due to the excessive
amount of calcium salts present' in. the blood at the time of con-
valescence, and that this excess depends chiefly upon the- large
quantity of lime salts ingested by a patient kept on a milk diet.
These authors advise, as a preventive measure against thrombo-
sis, partial decalcification of the milk by the addition of sodium
citrate (20 to 40 gr. to the pint) as soon as the danger of intestinal
hemorrhage is over.
Enteric fever is practically always a specific
BACTERIOLOGY, bacteriemia, and the Bacillus typhosus can be
cultured from the circulating blood in more than
75 per cent, of all cases. From 200 to 300 c.c. of nutrient broth
sown with 2 or 3 c.c. of blood gives satisfactory results, although
some investigators, notably Schottmuller,4 prefer to mix the blood
directly with melted agar, at a temperature of 45° C., and to
plate the inoculation, so as to get some idea of the number of
colonies grown.
The typhoid bacteriemia usually develops early in the disease,
and therefore frequently may be demonstrated some days before
the appearance of the serum reaction. Cultures made during the
'Johns Hopkins Ho?p. Bull., 1903, vol. xiv, p. 175.
2 " Herno-alcalime'trie ct Hemo-acidime'trie," These de Paris, 1892, No. 83
3 Brit. Med. Jour., 1902, vol. ii, p. 1706; also Lancet, 1902, vol. ii, p. 1531.
4 Munch, med. Wochenschr., 1902, vol. xlix, p. 1562.
394
GENERAL HEMATOLOGY.
first week of the fever yield a higher percentage of positive results
than those made during the second and third weeks. With def-
ervescence the bacilli disappear from the blood, but they reappear
with a relapse, although not with a simple recrudescence of the
fever — a significant fact when the question arises of determining
the presence of 'a true reinfection. It is the general experience that
the severer the type of the infection, the more abundant the
bacteria in the blood. The following tabulation illustrates the
frequency of positive results in cases examined by modern methods :
AUTHORITY.
Schottmiiller : 212
Hewlett2 125
Courmont; Lesieur3 .. 57
Harris; Kerr * 56
Busquet 6 43
Warfield • 43
Kuhnau 7 41
Lesieur 8 36
Reudiger * 27
Cole10 15
Castellani u 14
Orlovsky 12 12
Auerbach; Unger 13 — 10
Courmont w 9
Total: TOO
POSITIVE RESULTS.
182
90
54
43
33
ii
36
20
II
12
10
7
9
PERCENTAGE OF
POSITIVE RESULTS.
86 per cent.
72
95
55
100
76-5
27
100
74
73
86
83
70
100
549 Average: 78.4 per cent.
Coleman and Buxton's analysis15 of 453 collected cases shows
the following results of blood culturing during the first four weeks
of the fever:
WEEK OF FEVER XL-MBER OF CASES PER CENT.
CASES. POSITIVE. POSITIVE.
First 85 79 93 per cent.
Second 198 151 76 " "
Third « 115 65 56 " "
Fourth 55 18 33 " "
During recent years numerous instances of paracolon (para-
typhoid) infection, clinically counterfeiting typical enteric fever,
1 Munch, med. Wochenschr., 1902, vol. xlix, p. 1562.
2 Med. Rec., 1901, vol. Lx, p. 849. * Sem. me
4 Jour. Amer. Med. Assoc., 1902, vol. xxxix, p. 1000.
5 Presse med., 1902, vol. 1, p. 593.
* Bull. Ayer Clin. Lab., Penna. Hosp., 1903, vol. i, p. 77.
7 Zeitschr. f. Hyg. u. Infectionskr., 1897, vol. xxv, p. 492.
8 Gaz. hebd. de med. et chir., 1902, vol. xlix, p. 1128.
* Medicine, 1903, vol. ix, p. 258.
10 Johns Hopkins Hosp. Bull., 1901, vol. xii, p. 203.
11 Centralbl. f. Bakt. u. Parasit., 1902, vol. xxxi, p. 477.
12 Phila. Med. Jour., 1903, vol. xi, p. 959.
13 Deutsch. med. Wochenschr., 1900, vol. xxvi, p. 796.
14 Jour, de physiol. et de path, gen., 1902, vol. iv, p. 154.
15 Med. News, 1904, vol. Ixxxiv, p. 1046.
med., 1902, vol. xx, p. 408.
ENTERIC FEVER. 395
have been reported, in which a paracolon bacillus has been
isolated from the blood during life. Among those reporting
such cases may be mentioned Gwyn,1 Longcope,2 H. W. Allen,3
Hewlett,4 Johnston,5 and Libman.6 Of 60 cases clinically typhoid
studied by Coleman and Buxton,7 2 yielded blood cultures of the
Bacillus coli communis. In the late stages of the disease pyo-
genic bacteria have been found in the blood.
Examination 0} the Rose Spots. — Formerly the cultivation of
typhoid bacilli from the rose spots was attended by indifferent
success, but the favorable results with this procedure recently
announced by a number of authors must stamp it as a distinct aid
to the diagnosis of typhoid. Neufeld,8 basing his experiments
upon the belief that the bacteria lodge and multiply in the spots
protected from the bactericidal action of the blood, examined
these lesions in 14 cases and obtained positive results in 13. His
findings have been corroborated by the work of Curschmann,9
who found the bacilli in 14 of 20 cases; of Richardson,10 whose
results were positive in 5 of 6 cases; of Kozarinoff,11 who found
positive results in 12 of 17 cases; of Seemann,12 who reports posi-
tive findings in 32 of 34 cases; and of Scholz and Krause,13 who
found bacilli in the spots in 14 of 16 cases examined. The latter
investigators emphasize the statement that the bacilli are prone to
disappear from the spots after from three to five days, and that,
to insure the best results, the examinations must be made as' soon
as possible after the appearance of the roseola. The most favor-
able results from spot culturing yet reported are those of Pollaco
and Gemelli14 — invariably positive findings in 50 consecutive
cases. All investigators agree that, in the great majority of in-
stances, spot cultures give positive results several days before the
appearance of the serum test. The chief disadvantages to this
method of diagnosis appear to be the absence of the roseola in
some cases, its late development in others, and the possibility
of not always being able to distinguish typhoid spots from other
eruptions.
The technic used by Richardson15 is simple, and, judging
1 Johns Hopkins Hosp. Bull., 1898, vol. ix, p. 54.
1 Amer. Jour. Med. Sci., 1902, vol. cxxiv, p. 209.
3 Ibid., 1903, vol. cxxv, p. 96. 4 Ibid., 1902, vol. cxxiv, p. 200.
5 Ibid., 1902, vol. cxxiv, p. 187. 8 Jour. Med. Research, 1902, vol. viii, p. I.
7 Loc. cit. 8 Zeitschr. f. Hyg. u. Infectionskr., 1899, vol. xxx, p. 498.
• Munch, med. Wochenschr., 1899, vol. xlvi, p. 1597
10 Phila. Med. Jour , 1900, vol. v, p. 514.
11 N. Y. Med. Jour., 1903, vol. Ixxviii, p. 196.
12 Wien. klin. Wochenschr., 1902, vol. xv, p. 580.
u Zeitschr. f. klin.Med., 1900, vol. xli, p. 405.
14 Centralbl. f. inn. Med., 1902, vol. xxiii, p. 121. u Loc. cit.
396
GENERAL HEMATOLOGY.
from his results, trustworthy. After having washed the skin of
the part with Alcohol and ether, the spot is frozen with an ethyl-
chlorid spray, after which it is crucially incised. Its substance
is then removed by scraping with a small skin-curette, and trans-
ferred to a tube of nutrient bouillon. A second tubs is inoculated
with the blood which collects as soon as the effects of freezing
have worn off, both cultures being then incubated and examined
in the usual manner. At least five or six spots should be thus
treated in each case, and two tubes, one for the scrapings, the
other for the blood inoculation, used for each spot.
If blood serum from a case of enteric fever is
SERUM TEST, mixed with a broth culture of the Bacillus typho-
sus and a small drop of this mixture placed upon
a slide and examined under the microscope, it will be observed
FIG. 56. — A POSITIVE REACTION..
Large clumps o? motionless bacilli sep-
arated by open spaces. The few bacteria out-
side of the clumps are devoid of motility.
FIG. 57- — A PSEUDO-REACTION.
A few small clumps of bacilli having
impaired motility. Persistent motility of the
bacteria in other parts of the field.
that the bacilli, instead of continuing to dart actively to and fro
across the field, as they do in the pure culture, are attracted to
each other, lose their power of propulsion, and become grouped
together in large agglutinated clumps of irregular outline, which,
after the lapse of a variable length of time, become more and
more compact and homogeneous. In the typical positive reaction
the field of the microscope shows islands of clumped bacilli,
separated from each other by large open spaces, containing per-
haps a few isolated organisms the motility of which is decidedly
inhibited at first, and finally entirely lost. If the clumps are of
very large size, they produce a peculiar grayish mottling of the
specimen visible to the naked eye, a point to which attention
ENTERIC FEVER.
397
was first directed by Greene.1 In a small proportion of cases
the clumps undergo a granular change, and then become entirely
destroyed; in some instances they remain unaltered for several
days; and in still others they may break up after a few hours,
the field then becoming refilled with isolated, actively motile
bacteria.
In a certain percentage of instances the agglutinated, motion-
less masses of bacilli may be observed as soon as the specimen is
brought into focus, so that the reaction may be said to have taken
place immediately. In other instances some little time elapses
before the character of the test can be determined, and in such
reactions the formation of the clumps, from their inception' out
of two or three bacteria to their
completion, when they consist
of several hundred organisms
tightly glued together into a
densely crowded mass, may be
studied advantageously. In
these slower reactions, while
early clumping may progress
to some extent, many isolated
bacteria are seen, the motility
of which persists for a variable
period, gradually growing less
and less, until finally, with
more or less crippled powers
of propulsion, the organisms
are attracted to the clump
centers with which they are
ultimately incorporated, either
becoming adherent at first approach, or, as is usually the case
with the more active bacilli, circling around the edges of the
clump for some little time before becoming attached to it. Still
other reactions are characterized by an almost immediate cessa-
tion of motility, followed by tardy agglutination, and usually by
the formation of clumps of smaller size than those noted in a
prompt and immediate reaction.
If the reaction is negative, the motility of the bacilli persists
and the formation of clumps is not observed, regardless of the
time during which the specimen is watched. Not unless aggluti-
nation is marked and entire loss of motility occurs may a reaction
be considered positive ; and pseudo-reactions resulting in the for-
mation of small masses of more or less motile organisms, together
1 Med. Record, 1896, vol. 1, pp. 697 and 805.
FIG. 58. — BACILLUS TYPHI ABDOMINALIS.
The bacilli are actively motile throughout the
field.
398 GENERAL HEMATOLOGY.
with persistent motility of many unclumped bacteria in other parts
of the field, cannot be regarded as typical in any sense. Clumping of
small numbers of bacteria sometimes occurs in the pure culture
during its growth, and this source of error must be eliminated by
habitually examining the culture before each test or series of tests.
Technic. — In order to exclude all sources of error, such as
may arise from the clumping of the typhoid bacillus by non-
typhoid serum, provided that the latter is sufficiently concentrated
and is allowed enough time to exert its agglutinative powers, the
reaction can be considered of diagnostic value only under the
following two conditions: first, that the blood to be tested must
always be diluted with at least twenty volumes of the culture; and,
second, that loss of motility and clump formation must occur
within an arbitrary time limit of ten minutes. Under these condi-
tions it has been shown that agglutination of the typhoid bacillus
is produced only by the blood from a patient who is or who
has been infected with enteric fever, save in exceptional cases.
(See p. 403.) In some cases of typhoid the reaction occurs in
much higher dilutions, frequently with dilutions of i : 50, or
i : 100, or even higher. Some habitually work with higher
dilutions than i : 20, but they extend the time limit of the reaction
proportionately to the degree of the dilution used.
Cultures from twelve to twenty-four hours old, grown in
neutral peptone bouillon from a stock agar-agar culture, are best
adapted for the test. It is advisable to keep all the cultures at
room temperature, and to transplant the stock agar growths not
oftener than once a month, since cultures " forced" by incubation
and by frequent transplanting may give rise to false reactions
with non-typhoid blood. The cultures should, of course, be ab-
solutely uncontaminated, and must respond typically to the
recognized tests for their identification.
The test may be conducted either microscopically, by the dried
blood method, or by the use of fluid blood or fluid serum; or
macroscopically, the method preferred by Widal.1
The dried blood method, perfected and popularized by Wyatt
Johnston,2 is to be chosen whenever it is necessary to send the
blood sample any distance for examination, and where the ex-
aminer finds it convenient to carry with him to the patient's
bedside the test-tubes required for the methods next to be de-
scribed. Johnston's method is especially adapted for use by
health boards, by which bodies it is now extensively employed
in nearly all the large cities in this country.
1 Bull. m<?d., 1896, vol. x, pp. 618 and 766.
2 N. Y. Med. Jour., 1896, vol. Ixiv, p. 573.
ENTERIC fEVER. 399
The technic of collecting the blood specimens is exceedingly
simple. After having punctured the finger or ear in the usual
manner, several separate drops of blood are collected upon the
surface of some non-absorbent material, preferably glass, then
dried, placed in an envelop or other protective covering, and
tested at the examiner's convenience. Glass slides or slips of
non-absorbent Bristol board or paper are most commonly used
for collecting the blood samples, and specimens thus obtained
may be kept for several months without aseptic precautions and
still retain their agglutinative powers.
If the specimen has been collected on glass, one of the crusts
is moistened with a drop of sterile water and worked up into a
thin paste with a platinum loop, after which complete solution
and proper dilution of the blood are effected by adding twenty
drops of typhoid bouillon and mixing thoroughly. If the sample
has been dried on a paper or cardb.oard surface, the blood crust
may be cut out with a pair of scissors and placed to soak, face
downward, in a watch-glass containing twenty drops of the culture.
From one of these mixtures of blood and typhoid culture a
minute portion is transferred to the center of a clean cover-glass,
which is at once inverted over a " concave slide," sealed with
cedar oil, and examined as a hanging-drop with a £-inch dry
objective, using dim illumination. A plain glass slip is used by
many workers instead of a "hollow slide," but either will prove
satisfactory.
If the fluid blood method is used, the dilution is made at the
patient's bedside, by adding one drop of the whole blood as it
flows from the puncture to twenty drops of typhoid bouillon con-
tained in a small test-tube. The mouth of the tube is then closed
by a cotton plug, and its contents are thoroughly mixed by vigorous
snaking. At the time of the test, which must not be delayed
more than a few hours after the dilution is made, a small drop of
the mixture is removed from the tube and examined microscopic-
ally in the usual manner. In order to insure accurate dilutions,
a graduated pipette is needed for measuring the blood and the
culture, for the drops of both liquids must be of exactly the same
size. Either the special pipettes devised for serum testing or the
Thoma-Zeiss leucocytometer will prove satisfactory for this pur-
pose. In lieu of either of these instruments a graduated pipette
may readily be made from a bit of glass tubing or an ordinary
medicine dropper.
If the liquid serum method is chosen, fifteen or twenty drops of
blood, drawn by making a rather deep puncture, are allowed to
flow into a narrow-calibered test-tube, and set aside for a few
400 GENERAL HEMATOLOGY.
minutes until coagulation has taken place. As soon as the clot
has formed the nose of the graduated pipette is thrust into the
test-tube, and one drop of the fluid serum sucked up and diluted
with twenty drops of typhoid bouillon contained in a second test-
tube. The preparation for microscopical examination is then
made from this dilution. If the requisite apparatus is at hand,
the serum may be obtained by centrifugalization.
If the macroscopical method is employed, the whole procedure
must be carried out under the strictest aseptic precautions, for
otherwise the growth of contaminating bacteria may interfere with
the reaction, owing to the length of time required for the comple-
tion of the experiment.
The blood from which the serum is obtained is aspirated from
one of the superficial veins of the arm, according to the technic
employed in bacteriological examinations, and then immediately
expelled into a sterile test-tube, which is plugged with cotton and
set aside until clotting occurs. If it is desired to send the speci-
men any distance, the blood may be drawn up into a glass bulb,
previously 'sterilized by heat, and then sealed at both ends. Blood
collected in this manner will preserve its agglutinative properties
and remain sterile indefinitely.
Having thus obtained the serum from the whole blood, the
test is carried out by adding the serum in definite dilutions to
either a twenty-four-hour-old bouillon culture of the typhoid
bacillus or to sterile bouillon inoculated with a typhoid culture
at the time of the test.
In the first instance, a i : 20 dilution of serum and twenty-four-
hour typhoid bouillon is made in a sterile test-tube, which is then
plugged and placed in an incubator, where it remains for about
twelve hours at a temperature of 37° C. At the expiration of
this time a positive reaction may be recognized by the presence
of dense, whitish, flaky masses (composed of large clumps of
agglutinated bacteria), forming in the typical positive reaction a
thick precipitate at the bottom of the test-tube, which contrasts
with the perfectly clear appearance of the supernatant bouillon.
If the reaction is negative, the tube shows simply the uniform
cloudiness of an ordinary typhoid bouillon culture.
In the second instance a i : 20 dilution of serum and sterile
neutral peptone bouillon is made, the mixture then being inocu-
lated with a small loopful of typhoid bacilli derived from either a
bouillon or an agar culture. The contents of the test-tube are
then thoroughly mixed, and the preparation incubated at 37° C.
for twenty-four hours. A positive reaction is characterized after
this length of time by the formation of a similar grayish-white
ENTERIC FEVER. 40 1
precipitate at the bottom of the tube, underlying an unclouded
layer of fluid. In negative reactions the typical cloudiness of the
typhoid growth is diffused throughout the bouillon.
In both of these macroscopical methods control tubes of normal
serum and typhoid bouillon should invariably be prepared, and
incubated side by side with the specimen of serum to be tested.
Both tests may be carried out at ordinary room temperature,
but more certain and more typical results are obtained when the
tubes are incubated at a temperature of 37° C.
The Test with Dead Cultures. — Reudiger,1 modifying Picker's
technic,2 has devised a very satisfactory serum test with a solution
of dead Eberth bacilli, made by adding i c.c. of formalin to 100 c.c.
of typhoid bouillon. Four drops of the suspected blood are mixed
with 2 c.c. of a i : 50x3 aqueous solution of formalin, and, after
laking has occurred, i c.c. of this blood solution is mixed in a
small test-tube with 4 c.c. of the dead culture. This gives ap-
proximately a 30 : i dilution of the blood. The test-tube is then
set aside in a vertical position, with the result that, if the reaction
is positive, a flocculent precipitate will appear within an hour
or two, falling to the bottom of the tube as a granular sediment,
with clearing of the supernatant bouillon within from twelve to
twenty-four hours. By microscopical examination this sediment
is found to consist of tightly clumped masses of bacilli.
In his clinic at the Jefferson Hospital the writer uses this test,
in connection with the more rapid hanging-drop method with live
bacilli, in all suspected enterics, and regards it as quite as accurate
as the older method, although, of course, much slower. Dried
blood as well as fresh may be employed, if the precaution is taken
to powder it finely before adding it to the formalin solution.
Reudiger obtained positive results with test cultures killed a year
previously.
The Choice oj a Method. — The choice between the methods
of serum testing described above must depend largely upon the
circumstances under which the test is to be made.
The dried blood method, as already remarked, is best adapted
to health board necessities, where samples of blood are collected
by the general practitioner and sent by mail to the laboratory.
The chief objection to this method is the impossibility in many
cases of making accurate dilutions, since usually it can only be
assumed that a given crust of blood represents the same volume
in its liquid state as the drop of culture with which it is diluted.
If the examiner collects the specimens himself, quite accurate dilu-
1 Jour. Infect. Dis., 1904, vol. i. p. 236.
2 Berlin, klin. Wochenschr., 1903, vol. xl, p. 1021.
26
402 GENERAL HEMATOLOGY.
tions may be obtained if a graduated pipette or a platinum loop
of fixed size is used to measure both the blood and the culture.
Another drawback is the fact that more or less typical agglutina-
tion occasionally occurs with non-typhoid blood, although John-
ston believes that this source of error may always be eliminated
by using cultures of sufficient attenuation.
In hospital work either the fluid blood or fluid serum should
be chosen, for exact dilutions may be made by these methods, and
if the test is made within a reasonable length of time after the
dilution, bacterial contamination need not be feared. The writer,
a warm advocate of Johnston's method in the early days of serum
testing, has now discarded it wherever possible in favor of the
more accurate and equally simple test performed with the fluid
whole blood or serum.
The macroscopical method with fluid serum is too slow, and
requires too elaborate bacteriological apparatus ever to be adopted
for general clinical use. Reudiger's method is obviously of
great value to the practitioner who has not access to a laboratory.1
Value of the Serum Test. — Fully 95 per cent, of all typhoids give
a positive reaction at some period of the disease, usually as early
as the eighth day, as nearly as it is possible to compute this period.
An error of about three per cent, must be allowed for, on account
of the occurrence of positive or misleading results with non-typhoid
blood. The statistics of the Philadelphia Bureau of Health2 are
of interest in demonstrating the usefulness of the test in routine
public health work. These data, covering a period of six years
(1897-1902), show that, of 22,521 tests by the dried blood method,
in 19,080 cases diagnosed as enteric fever, the discrepancy between
the laboratory , and the clinical diagnosis ranged between 3.9 and
8.3 per cent. Rosenberger's collection3 of 17,280 cases from
other sources show's 16,352 positive results, or 94.6 per cent.
In some instances repeated negative results are found until con-
valescence is well established, and, rarely, cases are encountered
1 A. J. Wolff (Amer. Jour. Med. Sci., 1903, vol. cxxv, p. 661) has devised a
clever method of serum testing with the patient's blood and feces. Bouillon
cultures of the patient's feces are incubated for twelve hours, mixed, in definite
dilution, with his blood, and examined microscopically. If Eberth bacilli exist
in the culture thus made, they become clumped and immobilized, while the motility
of the colon organisms also present is unimpaired. If no reaction occurs, the
patient's blood should be tested in the usual manner as a control. Wolff reports
uniformly positive results in 35 cases of enteric fever with this modification of the
Widal test, and claims that reactions occur from the fourth to the seventh day — •
in spite of the general impression that the stools in typhoid do not contain the
Eberth bacillus before the tenth or eleventh day of the disease.
2 A. C. Abbott, Annual Report of the Division of Bacteriology, Pathology, and
Disinfection of the Philadelphia Bureau of Health, 1903, p. 112.
3 Proc. Path. Soc. Phila., 1904, vol. vii, p. 97. •
ENTERIC FEVER. 403
in which the reaction never occurs at any time during the entire
course of the illness. The blood may lose its clumping powers
at about the time of defervescence, or, on the other hand, this
peculiarity may persist for months or even years after the attack.
This last source of error in the test may be due to the presence
of unsuspected foci containing typhoid bacilli, but sometimes it
is apparently independent of such factors. Before pronouncing
upon the value of a positive reaction in the individual case the
occurrence of a previous attack of typhoid and the presence of
lesions which may be due to the Eberth bacillus (osteomyelitis,
cystitis, arthritis, cholecystitis, etc.) must be excluded.
The reaction may be positive on one day of the disease or for
a series of days, and negative on the next day or succeeding days.
Its character is apparently uninfluenced by the intensity of the
infection, for although, as a rule, the reaction is usually prompt
and marked in severe infections, it may be just as marked in mild
cases. A certain relationship seems to exist between the height
of the fever and the intensity of the reaction, for the latter is
usually most decided at the period of maximum pyrexia.
Positive Reactions in Non-typhoid Conditions. — In a number
of conditions other than enteric fever the blood may acquire a
more or less decided agglutinative action toward the Eberth
bacillus, but, with rare exceptions, such reactions are attributable
to low dilutions, to a prolonged time limit, and, perhaps, to a
previous attack of typhoid. Typhus fever, malarial fever, sepsis,
pneumonia, tuberculosis, acute osteomyelitis, and influenza are
among the most important diseases thus simulating a true
typhoid reaction, and a positive test in any of these conditions
must, to be conclusive, occur in a high dilution — i : 50, i : 60,
or higher. In Weil's disease positive reactions are common, even
in high dilutions, and this fact tends to corroborate Weil's original
suggestion, that this disease in reality is nothing more than
typhoid aborted by the supervention of jaundice. Or, as
Lubowski and Steinberg suggest,1 the reaction may sometimes be
due to. a Bacillus proteus infection, since immune proteus serum
may agglutinate the Eberth bacillus, in very high dilutions. The
blood of patients suffering from other forms of jaundice also has
a moderately strong agglutinative effe.ct upon the typhoid bacillus,
although bile itself has no such action. With proper technic,
however, the blood of jaundice cases need not be a source of
error, for Libman,2 in a study of 35 such instances, failed to
find in any one of them greater agglutinative effect than is often
1 Deutsch. Arch. f. klin. Mcd., 1904, vol. Ixxix, p 396.
2 Med. News, 1904, vol. Ixxxiv, p. 204.
404 GENERAL HEMATOLOGY.
seen in normal, blood. Errors of technic and latent or previous
typhoid infection are the probable explanation of most of the
positive results with bilious blood and typhoid cultures, reported
by Koenigstein, Kochler, Greenbaum, and other earlier students
of this question.
In paratyphoid fever the blood serum usually does not clump
the Eberth organism, although in an occasional instance it does
so, even in high dilutions. In doubtful cases, therefore, the ag-
glutination reaction with the typhoid bacillus should always be
supplemented by similar tests with paratyphoid cultures, as well
as by bacteriological examination of the blood for the isolation
of a specific bacterium.
In the light of our present knowledge of the serum test its
value appears to be less than its first enthusiastic advocates were
inclined to urge. A positive reaction, obtained by a skilled
worker whose technic as to dilution, time limit, and culture has
been exact, is the most valuable single sign of enteric fever, al-
though it cannot be regarded as absolutely pathognomonic. On
the other hand, a negative result with the test is no proof of the
absence of the disease.
Anemia develops shortly after the beginning
HEMOGLOBIN of the fever, slowly and progressively increasing
AND in intensity throughout the course of the disease,
ERYTHROCYTES. and persisting during the early weeks of defer-
vescence. During the first week there is little or
no decrease in the number of erythrocytes, although the hemo-
globin loss appears to begin coincidentally with the first manifes-
tations of the infection. Normal erythrocyte counts are the rule
during the first seven days, but there are few cases of typhoid
which fail to show a hemoglobin loss amounting to at least 15
or 20 per cent, during this period. Whether this early oligo-
chromemia is due to the influence of the fever, or whether it rep-
resents the actual prefebrile state of the patient's blood, is difficult
to decide. By the second week the corpuscular decrease becomes
evident and steadily grows more and more marked as the disease
progresses, reaching its maximum at about the end of deferves-
cence.. Thayer 1 distinguishes a slight accentuation of the oligo-
cythemia between the third and fourth weeks, the decrease con-
tinuing until the seventh, when a still more decided fall occurs,
followed in the eighth week by a considerable rise. A slow rise
in the erythrocyte curve is observed after defervescence, and,
indeed, sometimes before the end of the febrile stage, until by the
end of the fourth or fifth week of convalescence the count is again
1 Johns Hopkins Hosp. Reports, 1900, vol. viii, p. 487.
ENTERIC FEVER.
405
normal. The hemoglobin after the first week follows the same
general course as the erythrocytes, but its decrease during the
early weeks is relatively greater and its regeneration slower during
the post-febrile period. These data, as well as those relating to
the leucocytes, have been confirmed by W. A. Winter.1
Thayer's analysis 2 of the blood examinations in enteric fever,
made in the Johns Hopkins Hospital during a period of eleven
years, furnishes a striking illustration of the development of the
anemia during the progress of the disease. Arranged according
to the week of the fever, the following hemoglobin and ery-
throcyte averages in uncomplicated cases are shown :
HEMOGLOBIN.
(165 estimates.)
ist week,
21 estimates
.76.1 per cent.
6th week, 6 estimates
.62.1 per cent.
2d "
5i "
.72.8 " "
7th " 4
-50-5 " "
3d "
34
.66.2 " "
8th " 3
.56.9 « «
4th "
20
.60.5 " "
..9th 4
.47-7 " "
5th »
2O "
-57-8 " "
10th 2 "
.66.5 " "
ERYTHROCYTES.
(265 counts.)
ist week,
32 counts
. .4, QI3, 312
7th week, 8 counts
. . 3,3OQ,I2s
2d
86
4,692,428
8th " 7 "
7, 6^2, 28«;
*d
CO
. .4, 42Q,2O8
9th " 6 "
31 coo. 066
.
4th
16
. 4,222,2?6
loth " i "
3 .020.000
5th
22
. .4,Il8,C.OO
nth " i "
. . 2,100,3*3
O
6th
7
. .4,028,428
Seventy-four typhoid patients, both with and without compli-
cations, examined in the German and the Jefferson Hospitals
showed the following averages, the first estimates being taken in
all cases in which multiple examinations were made :
WEEK. HEMOGLOBIN.
ist week, 14 cases 77.4 per cent.
2d
3d
4th
5th
6th
7th
8th
30
13
6
6
2
2
I
.66.5
.58.8
.49.6
•53-1
•47-5
•47-5
.40.0
ERYTHROCYTES.
4,789,285 per c.mm.
4,161,233 "
3,555,000 '
3,490,833 "
2,445,000 '
3,165,000 "
3,335,000 '
2,790,000 '
As a rule, the degree of a typhoid anemia is parallel to the
severity of the attack, but this is not invariably true, since a mild
case may be associated with a most intense anemia. In the series
1 Dublin Jour. Med. Sci., 1901, vol. cxii p. 249. 2 Loc. cit.
406 GENERAL HEMATOLOGY.
included in t^e last tabulation the most marked instances of
anemia showed hemoglobin and erythrocyte estimates of 40 per
cent, and 1,720,000; 40 per cent, and 1,850,000; and 50 per cent,
and i ,800,000, respectively. The most striking example of oligo-
chromemia showed a hemoglobin percentage of 20, with a cor-
responding erythrocyte count of 2,470,000. Considerably lower
estimates than these have been reported by a number of other
observers, but they are uncommon.
The effects of the cold tub and of excessive diarrhea and
sweating may cause a temporary polycythemia from concentration
of the blood, and these sources of high counts must be excluded
in making examinations during the early weeks of the disease.
In four cases examined by the writer to determine the effects of
the cold plunge it was found that the average erythrocyte increase
after the bath amounted to 813,000 corpuscles per c.mm., and
the hemoglobin gain to 8 per cent. Hemorrhages, if severe, may
cause an abrupt fall in the erythrocyte count, often succeeded by
a more or less successful attempt at regeneration, in an effort to
compensate for the blood loss.
Qualitatively, the cells show no peculiar changes, poikilocytosis,
irregular staining affinities, and deformities of size occurring in
relation to the intensity of the anemia. Erythroblasts are com-
paratively rare, being absent or few in number in the average case.
Normoblasts may be found in cases with high-grade anemia and
as a sequel to hemorrhage. Megaloblasts are very rare, an occa-
sional cell of this type being observed now and then only in severe
cases.
A steady, slow decrease in the number of leu-
LEUCOCYTES. cocytes becomes evident after the first week of
the fever, the lowest counts being found during
the fifth or sixth week, after which an increase, which may be
either permanent or transient and followed by a still more decided
leucopenia, is observed. It appears that the latter change accom-
panies cases with severe post-febrile anemia, although sufficient
data are lacking to justify absolutely positive conclusions on this
point. In uncomplicated cases the normal count becomes re-
established by about the fourth week of convalescence. The
leucopenia of typhoid corresponds in a general way to the severity
of the attack, and although not marked in the average, in the
individual case it may be striking, counts of from 2000 to 3000
being not at all uncommon.
Kast and Gutig,1 in 105 cases, found the leucocytes below
7000 in 97, between 7000 and 9000 in 6, and 9000 or higher in 2
1 Deutsch. Arch. f. klin. Med., 1904, vol. l.xxx, p. 104.
ENTERIC FEVER.
407
cases. Contrary to the experience of others (see below), these
authors found little or no leucocytosis as the effect of non-typhoid
complications, which in their cases generally caused simply a
polynuclear increase with no disturbance of the leucopenia.
Thayer's report of 832 counts in uncomplicated cases shows
the following range of the leucocytes, according to the week of
the disease :
ist week, 119 counts 6442 8th week, 14 counts 6614
2d
3d
4th
5th
6th
7th
258
200
117
70
25
14
6251
....5528
5431
----551°
....5690
6132
9th
loth
nth
1 2th
1 3th
---•5057
5000
-•-•5333
5000
. . 8000
The leucocyte estimates of the 74 hospital typhoids referred to
above averaged:
ist week, 14 cases 8026 leucocytes per c.mm.
2d
3d
4th
5th
6th
7th
8th
3°
6
6
2
2
I
•6713
.7076
.4400
.5766
.6250
.4500
.8000
Disregarding the week of the fever, the number of leucocytes
in these cases ranged as follows:
Above 10,000 in 7 cases.
From 9,000-10,000 in 3
8,000- 9,000 8
7,000— 8,000 14
6,000- 7,000
. 10
I !
5,000- 6,000
4,000- 5,000
3,000— 4,000
2,000— 3,000
1,000- 2,000
Highest, 16,000 per c.mm.
Lowest, 1,333
Average, 6,706
It appears from these figures that counts in excess of 10,000
per c.mm. may be looked for in more than ten per cent of all
cases, such an increase being due either to the effects of blood
concentration from diarrhea, sweating, vomiting, or cold tubbing,
or to some hidden or frank complication. In four of the seven
relatively high counts above noted the cause was plain — croupous
pneumonia in two, cholecystitis in one, and furunculosis in one.
408 GENERAL HEMATOLOGY.
In the other three, all of which were made in patients whose fever
had not yet run seven days, the factors of the increase were unde-
termined; possibly it was due to physiological blood inspissation.
Inflammatory complications, such as otitis, abscess, pneumonia,
severe bronchitis, peritonitis, cystitis, periostitis, and phlebitis, give
rise to a prompt leucocytosis in patients whose vital powers are
sufficiently strong to react against the process. Intestinal hemor-
rhage is usually followed by an increase reaching its maximum
within twenty-four hours after the blood loss, and disappearing
within a week. Intestinal perforation may promptly be followed
by a leucocytosis, the increase developing within a few hours.
Thayer has observed that in some instances the increase in the
number of leucocytes succeeding the perforation may tend to
diminish and disappear with the aggravation of the symptoms,
and that not infrequently there is a complete absence of leucocy-
tosis and sometimes a diminution in the number of leucocytes
after this accident. He also considers that the prospect of relief
by surgical interference is best in those cases with a leucocytosis,
the absence or disappearance of this sign following a perforation
being an indication of the malignancy of the infection or the pros-
tration of the patient.
Qualitative changes are absent or inconspicuous during the
first two weeks of the fever, but during the third week a slow,
progressive decrease in the relative percentage of polynuclear
neutrophiles with a consequent increase in the mononuclear un-
granulated forms, begins, this change becoming most marked at
about the end of defervescence. In 23 of the writer's cases the
percentage of polynuclears averaged, according to the week of
the disease, 75.0 per cent, for 8 cases in the first week; 70.9 per
cent, for 7 in the second week; 50.2 for 4 in the third week; 60.0
per cent, for 2 in the fourth week; and 64.0 and 68.0 per cent,
for a single case in the fifth and sixth weeks, respectively. Higley *
finds that the polynuclear neutrophiles decrease much earlier in
the disease, 9 of his cases examined during the first week showing
an average of 59.4 per cent, for these cells.
Thayer has found that the mononuclear cells which are most
markedly increased are "elements containing nuclei not much
larger than those of lymphocytes, and often presenting the general
appearance of a lymphocyte nucleus, with the exception of the
slight affinity for coloring matters. The size of these cells is
usually about that, or but little larger than that, of the ordinary
polymorphonuclear neutrophile." The typical small lymphocyte
and the transitional forms undergo little or no increase.
1 Med. News, 1903, vol. Ixxxiii, p. 1140.
ENTERIC FEVER.
409
The eosinophiles are almost invariably decreased, both abso-
lutely and relatively, and are often absent during the active
febrile stages. The relative percentages of these cells in the
above cases averaged 0.87, rising as high as 5 per cent, in only
2 cases, and being entirely absent inn.
Myelocytes in small numbers may be found in severe forms
of post-typhoid anemia, but they are absent during the active
period of the infection. Turk's "stimulation forms" are met
with under the same conditions.
Thayer's elaborate report of the Johns Hopkins Hospital cases
includes the following averages of the differential leucocyte counts :
WEEK.
SMALL MONO-
NUCLEAR.
LARGE MONO-
NUCLEAR.
POLYNUCLEAR
NEUTROPHILE.
EOSINOPHILE.
ist week, 12 counts
12.9 per cent.
12.4 per cent.
74.0 per cent.
0.5 per cent.
2d
39
14.6
13-4 '
70.9
0.8
3d
34
21.5
| n.6 '
66.3
°-3
4th
19
20. i
14.4
65.0
0.4
5th
8
18.2
19.7
61.7
0-3
6th
4
22.6
13-5
57-7
6.0
7th
i
23-7
34-4
37-3
4.6
8th
i
24.2
1 6.8
56-9
2.1
According to Hayem,1 the number of blood plaques is markedly
decreased during the febrile period of the fever, as in any other
condition characterized by pyrexia. '
The blood examination furnishes four clinical
DIAGNOSIS, signs of positive value in the diagnosis of enteric
fever: the serum reaction; a subnormal leuco-
cyte count or at least an absence of leucocytosis ; bacteriemia;
and in cases with roseola the detection of the Eb'erth bacillus by
spot culturing. The influence of complications upon the behavior
of the leucocytes must, however, always be borne in mind.
Acute miliary tuberculosis, cerebrospinal meningitis, malarial
fever, certain atypical cases of pneumonia and influenza, and
septicemic and pyemic processes, such as ulcerative endocarditis,
are the diseases most frequently confounded with typhoid, and in
their differentiation the blood report often gives just the essential
clue.
Acute miliary tuberculosis, if a pure infection, shows a similar
absence of a leucocyte increase, and in excluding this disease
reliance must be placed on the Widal test and upon blood cul-
turing. Influenza is not characterized by leucocytosis, and must
be differentiated from typhoid by the aid of the same methods of
1 "Du Sang," etc. Paris, 1889.
410 GENERAL HEMATOLOGY.
examination. jCerebrospinal meningitis, pneumonia, and septic
and pyemic conditions may be differentiated by their association
with a more or less well-marked leucocytosis. In the last-named
processes bacteriological examination of the blood not infrequently
gives conclusive results. Paratyphoid fever, often clinically identi-
cal with genuine enteric fever, shows also a similar anemia and
leucocyte range. As a rule, paratyphoid blood does not agglutin-
ate cultures of the Eberth bacillus; if it does so, the reaction is
less marked than with cultures of the paratyphoid organism.
Blood culturing is the court of final appeal in distinguishing these
two closely related infections. The differentiation of malarial
fever is referred to under this disease. (See p. 472.)
XXII. ERYSIPELAS.
In severe infections 'Turk1 has noted a de-
GENERAL cided increase in the quantity of fibrin and in the
FEATURES, number of blood plaques, but in the case of average
severity these changes are not to be observed.
Drouin2 has found that the alkalinity of the blood is greatly de-
creased. Negative results from bacteriological examination of the
blood are the rule, although streptococci (Fehleisen), diplococci
(Pfahler), and other pyogenic bacteria invade the blood at and
near the erysipelatous lesions.
Moderate anemia, characterized by a some-
HEHOGLOBIN what disproportionate hemoglobin loss, is com-
AND mon in the severer forms of the disease, but not
ERYTHROCYTES. in mild cases. The decreases are not notable,
amounting on the average to a loss of -not more
than 10 or 20 per cent, of corpuscles and of about 30 per cent,
of hemoglobin. Maragliano's degenerative changes of corpus-
cular structure have occasionally been found.
Leucocytosis of the polynuclear neutrophile
LEUCOCYTES, type is the usual finding, but mild cases fre-
quently run their course without provoking the
slightest increase. Except in isolated instances, the leucocytosis
is not -high, the counts usually being about 15,000, and rarely
more than 20,000, cells to the c.mm. Von Limbeck 8 and Chante-
messe and Rey4 have shown that the leucocyte and temperature
curves maintain a definite parallelism in the majority of cases,
and that the diminution in the leucocytosis, as a rule, anticipates
the fall in temperature. There is, however, no apparent rela-
1 Loc. cit. 2 Thfcse de Paris, 1892, No. 83, p. 108.
3 Loc. cit. 4 Presse m£d., 1899, vol. vi, p. 316.
FEVER. 411
tionship between the height of the count and the degree of
pyrexia, for moderate leucocytoses are not incompatible with
strikingly high temperatures. It is generally agreed that the
highest counts are found in the severest cases, provided that the
patient's resisting powers are acting normally. An extension
of the lesion is generally accompanied by an increase in the
leucocytosis.
With the onset of convalescence, as the leucocytosis disappears,
the normal percentages of the different forms of corpuscles, dis-
turbed during the febrile period, are reestablished by a rapid
increase in the small lymphocytes and eosinophiles, and a decrease
in the polynuclear neutrophiles ; the percentage of large lympho-
cytes remains stationary, and the eosinophiles are absent during
the height of the attack, according to Chantemesse and Rey.
Small percentages of myelocytes and an occasional "stimulation
form" are commonly found during the active stages of the leuco-
cytosis.
XXIII. EXOPHTHALMIC GOITER.
There are no characteristic changes in the hemoglobin and
erythrocytes, although an anemia indistinguishable from typical
chlorosis is not an infrequent feature. Such cases must be dis-
tinguished from so-called "thyroid chlorosis," or chlorosis with
thyroid hypertrophy, by means of other clinical symptoms. In
nine cases of which the writer has notes the hemoglobin averaged
78.6 per cent., and the erythrocytes 4,715,571 per c'.mm. It
seems likely that in cases of Graves' disease characterized by
excessive diaphoresis, emesis, and diarrhea, the blood concen-
tration thus produced may be sufficient more or- less effectually
to obscure the real grade of anemia existing.
The leucocytes are not increased in number, and leucopenia of
a decided degree is frequently observed. Of the above cases, the
leucocyte average was 4698 per c.mm., none of the counts exceeding
10,000. Relative lymphocytosis is a common change, and moderate
increase in the percentage of eosinophiles an occasional finding.
XXIV. FEVER.
It is a well-recognized fact that more or less hemoglobin and
erythrocyte losses follow pyrexia maintained for any length of
time, but an attempt to demonstrate the exact cause or group of
causes of this anemia involves the analysis of a most complex
problem in physiology, about which the most skilled investigators
412 GENERAL HEMATOLOGY.
express diametrically opposite opinions. Some maintain that suffi-
cient actual destruction of the corpuscles occurs as the result of
fever to account for their decrease in number, while others attrib-
ute the loss largely, if not wholly, to the influence of vasomotor
changes. Maragliano l has shown that capillary contraction ac-
companies the period of active pyrexia, while Reinert2 suggests
that the blood is diminished in volume by the excessive drain
upon the body fluids occurring at this time. In septic fevers,
furthermore, additional inspissation of the blood is produced by
the influence of bacteria and their products. These factors, tend-
ing to inspissate the blood, favor the1 production of polycythemia,
which change is to be observed during the stage of active fever.
But as defervescence sets in the conditions are reversed, for the
capillaries then dilate, the draining away of the fluid elements of
the blood ceases, and, consequently, dilution of the blood now
occurs. Anemia, therefore, develops coincidentally with the dis-
appearance of the fever. It is undetermined whether this post-
febrile anemia is the result purely of these physical causes or of
these causes plus a certain amount of real hematocytolysis due
to high temperature. It seems reasonable to regard both factors
as active.
Coagulation and fibrin behave so erratically that no definite
statements regarding them are justified. In the incipient stage
of septic fevers coagulation is much delayed, according to Schmidt,3
but during the later stage it occurs more rapidly than normal.
The leucocytes in this class of fevers are generally increased in
number.
The alkalinity of the blood undergoes wide* variations in differ-
ent febrile states, but it cannot be said that these changes, which
are probably due to complex chemical processes rather than to
the primary effect of the fever, are constantly parallel, either to
the degree of pyrexia or to the behavior of the leucocytes. Lb'wy
and Richter4 state that increased alkalinity occurs coincidentally
with the stage of hypoleucocytosis — a statement which Strauss,5
Lowit,6 and others have verified. Fodor and Rigler's experi-
ments7 have proved that the pyrexia following infection with
pathogenic bacteria ultimately effects a diminution in the alkalinity
of the blood, and that this change is sometimes preceded by a dis-
1 Berlin, klin. Wochenschr., 1887, vol. xxiv, p. 797.
2 "Die Zahlung der rothen Blutkorperchen," Leipsic, 1891.
3 Pfliiger's Arch., 1875, vol. xi, pp. 291 and 515.
4 Deutsch. med. Wochenschr., 1895, vol. xxi, p. 526.
5 Zeitschr. f. klin. Med., 1896, vol. xxx, p. 315.
8 "Die Lehre v. Fieber," Jena, 1897.
7 Centralbl. f. Bakt. u. Parasit., 1897, vol. xxi, p. 134.
FILARIASIS. 413
tinct primary increase. The conclusions voiced by von Jaksch,1
Krause,2 and other earlier writers, that decreased alkalinity is a
constant accompaniment of febrile processes, cannot be unreserv-
edly accepted, if von Limbeck's3 later statements to the contrary
are to be believed.
XXV. FILARIASIS.
Filariasis, the pathological condition depend-
OCCURRENCE. ing upon the presence in the body of the parental
and embryonic forms of the Filaria sanguinis
hominis, is of wide-spread distribution throughout the tropics and
subtropics, being prevalent in various districts of Africa, India,
Australia, China, Japan, South America, and the islands of the
South Pacific and the West Indies, and, as mentioned below, hav-
ing been found to a limited extent in North America.
Six distinct species of embryo blood worms,
PARASITOLOGY. the parental forms of which do not .enter the cir-
culation, have been demonstrated in the periph-
eral blood of man, these parasites being known by the general
term Filaria sanguinis hominis. These different filariae, according
to the nomenclature suggested by Manson,4 are distinguished by
the names Filaria nocturna,5 Filaria diurna, Filaria perstansf Fila-
ria demarquaii, Filaria ozzardi, and Filaria magalhdesi. To but a
single member of this group, the Filaria nocturna, has an undis-
puted pathological role been assigned, this parasite being regarded
as the cause of various forms of ulcer, lymphangitis, lymph varices,
lymph scrotum, tropical elephantiasis Arabum, endemic chyluria,
chylous ascites, and other tropical diseases of more or less obscure
nature. The Filaria Persians, Manson conjectures, may possibly
be the cause of that peculiar tropical disease known as African
kra-kra, or "craw-craw." Christy6 couples this worm etiologically
with the "tick fever" of Uganda, and has shown that a variety
of tick (known locally as the Bibo) acts as its intermediary host.
Bastian7 suggests that the embryonic forms of the Filaria Persians
are in reality embryos of a species of Tylenchus, which infests the
roots of the banana. By eating the fruit thus contaminated it is
1 Zeitschr. f. klin. Med., 1887, vol. xiii, p. 380.
* Zeitschr. f. Heilk., 1889, vol. x, p. 106.
3 Centralbl. f. inn. Med., 1895, vol. xvi, p. 649.
4 "Tropical Diseases," 3d ed., New York, 1903.
* The author is greatly indebted to Dr. F. P. Henry and to Dr. J. H. Gibbon
for the opportunity of making repeated blood examinations in two cases of Filaria
nocturna infection occurring in their respective hospital services.
8 Thompson Yates and Johnston Lab. Rep., 1903, vol. v, p. 187.
7 Lancet, 1904, vol. i, p. 286.
414
GENERAL HEMATOLOGY.
possible that s6me of the worms ingested may bore through the
gut and reach the mesentery, where they rest and develop, and
whence they later pass into the general circulation via the lymph
stream. Low,1 on the contrary, has pointed out that the distribu-
tion of the Filaria perstans does not always correspond to that
of banana cultivation, and contends that this organism is in no
way related to the genus Tylenchus. This investigator2 has dis-
proved the belief, once held, that the Filaria perstans is the
specific cause of " sleeping sickness." The other filariae (diurna,
demarquaii, ozzardi, and magalhaesi] possess no interest from
a diagnostic standpoint,
since their life history and
pathological significance
are still obscure.3
This
THE FILARIA is by far
NOCTURNA. the most
import-
ant member of the above-
named class of blood
worms, being the one
most familiarly known
of all, as well as the one
of greatest clinical in-
terest, because of the
interesting pathological
lesions which it is cap-
able of exciting. In this
country cases of filariasis
due to the Filaria noc-
tnrna have been reported by a number of different observers, Gui-
teras,4 de Saussure,5 Mastin,6 Slaughter,7 F. P. Henry,8 Dunn,9 and
Lothrop and Pratt 10 having met with the disease. A few of these
cases have been regarded by their reporters as indigenous, but the
great majority of them, it is safe to state, were directly imported
from the tropics. To the writer's knowledge, at least five cases
have been diagnosed in Philadelphia during the last six years.
1 Lancet, 1904, vol. i, p. 420. J Brit. Med. Jour., 1903, vol. i, p. 722.
3 For a complete description of filariasis and of the various forms of the filariae
the reader should consult Manson's text-book, above mentioned. Davidson's
" Hygiene and Diseases of Warm Climates " (Edinburgh, 1893) contains an excellent
account of the histological structure of filariae.
4 Med. News, 1886, vol. xlvii, p. 399. 6 Ibid., 1890, vol. Ivi, p. 704.
* Annals of Surg., 1888, vol. viii, p. 321. 7 Med. News, 1891, vol. ii, p. 649.
8 Ibid., 1896, vol. xviii, p. 477. • Trans. Coll. Phys. Phila., 1898, p. 80.
10 Amer. Jour. Med. Sci., 1900, vol. cxx, p. 525.
FIG. 59. — THE FILARIA XOCTURNA.
From a photomicrograph of the parasite in a fresh blood
film.
FILARIASIS. 415
As may be inferred from the name, the embryos of the Filaria
nocturna are found in the peripheral blood most abundantly at
night, the vast majority of the parasites retiring into the deeper
circulation during the daytime. From late in the afternoon until
about midnight they make their way into the peripheral vessels
in progressively increasing numbers, with more or less fluctuation,
the maximum number being found at the latter time, after which
they begin to grow less and less numerous, until, by about eight
o'clock in the morning, they have practically all disappeared
from the superficial circulation and reentered the deeper vessels,
in which they remain until the close of the day. This peculiar
periodicity is well illustrated by a recent series of investigations
made by Lothrop and Pratt,1 who have charted the phenomenon
in one case, showing the approximate number of parasites to the
c.mm. of blood as follows: 4 p. M., 100; 6 p. M., 275; 8 P. M., 1300;
10 P. M., QOO; 12 M., 1500; 2 A. M., 700; 4 A. M., 900; 6 A. M., 125;
8 A. M., 125; and 10 A. M., 100. The highest number ever ob-
served by these authors was 2100 embryos per c.mm., "the specimen
in which this count was made having been taken at midnight.
This characteristic periodicity, it should also be remarked, is com-
pletely reversed if the individual harboring the parasite reverses
his habits of life, sleeping during the day and moving about at
night. If such should be the case, the worms will appear in the
peripheral blood during the daytime, the patient's period of rest,
and seek the deeper circulation at night, the patient's period
of activity. :*
The painstaking studies of Manson 2 and Low 3 have shown that
mosquitos (Culex fatigans and several of the genus Anopheles) are
the intermediate hosts of this parasite, which may be found alive
in the stomachs of these insects after they have fed upon a filarious
individual. Ecdysis takes place in this organ, and the embryos,
after having cast their sheaths, manage eventually to penetrate the
thoracic muscles of their host, in which situation they undergo a
developmental phase. This lasts about eighteen days, after which
the larvae thus evolved escape from the thorax and ultimately
reach the insect's labium and proboscis, whence they are directly
introduced in the blood of man by the bite of the infected mosquito.
The parasites having been inoculated into a human being in this
manner, make their way to some part of the lymphatic system, in
which they lodge, sexually mature, fecundate, and beget the
innumerable embryo forms which, via the lymph stream, find
their way into the circulating blood.
Appearance in Fresh Blood. — In the unstained blood film the
1 Loc. cit. 2 Loc. cit. 3 Brit. Med. Jour., 1902, vol. i, p. 1472.
4i6
GENERAL HEMATOLOGY.
0
parasite appears under the microscope as a long, slender, graceful
worm possessing a most remarkable degree of activity. It measures
about -gJ-0- of an inch in length and ^n77r °f an mch m diameter,
and is of a pearly-gray color, with perhaps the faintest suggestion
of a yellowish tone in certain lights. Its general appearance
conveys to one, at first glance, the impression of a thin, transparent
tube, through which a rapidly flowing stream of liquid is con-
stantly circulating. The head (cephalic end) is gracefully rounded,
while the tail (caudal end) gradually tapers for about one-sixth
the entire length of the animal, and ends in a fine-pointed ex-
tremity. The worm is cylin-
drical in shape, of regular out-
line, and consists of a central
body enveloped in a distinct,
loosely fitting, hyaline, struc-
tureless sheath, which is about
as much too large for the body
as the thumb of an adult's
glove would be for the little
finger of a child. Thus, that
part of the sheath temporarily
unoccupied by the body is
prone to collapse, folding upon
itself and trailing after the
worm at either or both ex-
tremities as a twisted, whip-
like ribbon. The greater part
of the body appears to be of a
homogeneous structure when
examined in the freshly pre-
pared slide, but after the speci-
men has been kept for several
hours, coarse granulations begin to stipple its surface, first develop-
ing in the center and gradually spreading toward the periphery.
(See Fig. 60.) A series of fine striations, like the milling on a
coin, may be observed running along both edges of the body at
right "angles to its long axis. A viscus, appearing as a mass of
granular material, occupies a part of the central third of the worm's
body, running parallel to its long axis. Upon careful examination
with an oil-immersion objective rhythmical dimpling or puckering
movements may generally be observed at the tip of the cephalic
end of the embryo; these movements, which occur with more or
less regularity at the rate of from twenty-five to forty times a
minute, have been attributed to the act of respiration. As the
FlG. 60. FttARIA NOCTURNA.
Showing beginning granular degeneration of the
body of the parasite in a fresh blood film.
FILARIASIS. 417
wriggling of the worm becomes less active close observation will
show that these pouting movements are caused by the alternate
covering and uncovering of the cephalic end by a delicate, six-
lipped prepuce. The sudden projection and the equally rapid
retraction of a filamentous fang or tongue-like organ from the
worm's uncovered head may also be noted in some instances, but
this characteristic is so difficult to make out that it may usually
be looked for in vain. At a point about one-fifth of the entire
length of the worm posterior to the head it is possible to make
out a triangular, slightly luminous patch, shaped like the letter V,
this spot being known as the V-shaped patch, regarded by Man-
son as a rudimentary generative organ. A second spot, some-
what similar to it in appearance but smaller in size, may occasion-
ally be seen at a point just above the tail of the parasite; this
spot Manson is inclined to regard as the rudimentary anus.
The movements of the worm arev rapid and violent in the ex-
treme; so much that they are followed with difficulty with any
but a low-power dry objective. The parasite is never at rest:
one moment it may be curled up into a tight bunch, like a coil
of rope; the next moment it may suddenly straighten out and
become rigid for an instant, only to resume its incessant con-
tortions and twistings, which throw it into every conceivable
shape. If particular attention is paid to the point, it will be
noticed that, however rapid and complicated may be its move-
ments, the parasite is never seen to turn completely over laterally.
The accompanying series of sketches of the Filaria nocturna in
a fresh blood slide illustrate a few of the different forms which
this parasite may assume (Fig. 61). The worm seems to move
about among the blood corpuscles with graceful and quick un-
dulations of its body and abrupt whip-like strokes of its tail,
butting its head against the more resisting masses of cells or else
seeking a less difficult passage around them, always in motion,
but never, it appears, with any definite aim to its exertions. Con-
trary to the views expressed by most observers, that the movements
of the Filaria nocturna are not truly propulsive in character, the
writer has repeatedly noticed that this worm sometimes travels
several times the distance of the diameter of the microscope field
(&-inch objective, one-inch ocular, and 160 mm. tube-length),
although in most cases its excursions were limited to a measured
area not exceeding half a dozen square microns. It cannot be denied
that these apparently progressive movements of the worm may pos-
sibly be due to the currents in the blood plasma, but they certainly
seem to have every characteristic of a true locomotive force.
After -the slide has been kept for a few hours, the movements
27
41 8 GENERAL HEMATOLOGY.
of the worm,' at first so confusingly rapid, gradually become
slower and slower, and these torpid, more deliberate turnings and
twistings may be accurately followed under an immersion-lens.
If the parasite happens to become confined in a little pool of
plasma surrounded by rouleaux of half-dried erythrocytes, an
accident which often happens when the drying of the film has
spread inward some little distance from the edges of the cover-
glass^ its finer structure and characteristics may be studied with
great ease and accuracy.
9.*6 9 -fd 9 -SO
954 956 9.58 /OOO
/ooa
/Q./O /O./2
-2*
FIG. 61. — SHOWING THE CHANGES IN THE SHAPE OF THE FILARIA NOCTURNA DURING THE
PERIOD OF HALF AN HOUR.
The sketches, made at two-minute intervals, all represent the same parasite.
The phenomenon of ecdysis, or shedding of the worm's sheath,
with 'the consequent escape of its naked body into the plasma,
occurs when slides containing the live filariae are kept for some
hours in a cold (not freezing) place. It commonly happens that
just before the death of the parasite an occasional erythrocyte or
leucocyte becomes tightly adherent to the sheath, swinging to
and fro with the now lazy, torpid movements of the animal.
Technic of Examination. — A rather large drop of finger
blood, taken from the patient late in the evening, preferably
FILARIASIS. 419
toward midnight, is placed between a slightly warmed slide and
cover-glass, the edges of which are immediately sealed with
cedar oil or with vaselin. The parasite should be searched for
with a low-power dry objective, a f-inch lens being most useful
for this purpose, and the attention of the examiner directed
especially to portions of the field which may show any unnatural
agitation of the blood cells. In specimens prepared in this man-
ner the filariae will usually remain active for several days, gener-
ally for at least forty-eight hours, and sometimes for a longer
period, as in Henry's1 experience, this author having kept them
alive for ten days in a cold room.
Staining the Filarm. — Films fixed for fifteen minutes in equal
parts of absolute alcohol and ether and stained with thionin
give the clearest-cut pictures, the multitude of small nuclei which
crowd the body of the filariae being sharply differentiated by the
use of this dye. Fixation by heat or by formalin cannot be em-
ployed without risk of injuring the finer structure of the embryo.
Fair results may also be obtained by staining with methylene-
blue or with Jenner's or Wright's stain, but the definition is not
nearly so satisfactory with these solutions as it is with thionin.
The technic suggested by Manson2 (washing out the hemoglobin of
the erythrocytes with water, drying, fixing in alcohol, and staining
with methylene-blue or with hematoxylin) has proved unreliable
in the writer's hands. The same comment may be made re-
garding attempts to demonstrate the structure of the worm by
staining with fuchsin, as has also been recommended.
The presence in the circulation of the Filaria
HEMOGLOBIN nocturna does not appear of itself to be a factor
AND of any conspicuous changes in the erythrocytes
ERYTHROCYTES. and their hemoglobin content. The high-
grade anemia sometimes associated with filariasis,
mentioned by the Bancrofts3 and by Ehrlich and Lazarus,4 is due,
no doubt, to such complications as hematuria, severe chyluria, and
chronic diarrhea. In two cases the writer found hemoglobin
percentages of 85 and 88, and erythrpcyte counts of 4,200,000
and 4,876,000 per c.mm., respectively. These figures may be
taken as representative for the average case, judging from the
limited data available.
Neither structural changes, nor irregular staining affinities of
the cells and the occurrence of nucleated erythrocytes have been
reported in connection with the disease.
1 Loc. cit. 2 Loc. at.
3 Australasian Med. Gaz., 1894, vol. xiii, p. 6. *Loc. cit
420 GENERAL HEMATOLOGY.
In the early stages of filariasis a distinct
LEUCOCYTES, leucocytosis is generally found, but as the disease
progresses the number of leucocytes gradually
diminishes, and in cases of long standing the count does not exceed
the physiological limits of health, except as the result of some
complication. Thus, in the first case quoted above the leucocyte
count was found to be 41,000 per c.mm., but this increase was re-
garded purely as a post-operative rise, the patient having been
operated upon for a supposed varicocele less than twenty-four
hours before the blood examination was made. The count in the
second case, one of several years' duration, was 8000.
The relative percentage of mononuclear non-granular leuco-
cytes is somewhat higher than normal, with a consequent decrease
in the proportion of polynuclear neutrophiles. The eosinophiles
either remain at a maximum normal percentage or may be dis-
tinctly in excess of this figure. This statement, made by the writer
in 1901, has since been verified by several observers, notably by
Calvert,1 Gulland,2 Coles,3 Vaquez,4 Sicard,5 and Clerc.8 Calvert
has shown that the eosinophilia, like the leucocytosis, diminishes
as the infection becomes chronic, and that its development is
cyclical, in that it follows by a few hours the periodicity of the
embryo worms in the peripheral blood. In the author's two cases
the percentage of eosinophiles ranged from 3.4 to 9.5; in Gulland's
case, from 3.0 to 12.0; in Calvert's three cases, from 6.0 to 22.0;
and in Coles' two cases, from 15.0 to 17.0. The three French
authors mentioned above report eosinophilia varying from 7.5 to
12 per cent. It may be noted here that the Filaria loa, found in
the subconjunctival tissues, may also excite eosinophilia — 53 per
cent, in a case reported by Wuntz and Clerc7; and that in patients
harboring the guinea-worm a similar eosinophile increase de-
velops— as high as 36.6 per cent, in cases studied by Balfour.8
In six cases of guinea- worm infection Powell9 found eosinophile
percentages of 4.7, 5.5, 7.5, 7.5, 8, and 12.2, respectively. The
lymphocytes frequently appear as cells having a deeply stained
eccentric nucleus surrounded by an abnormally large area of
protoplasm, the general appearance of these cells being similar
to those in the illustration shown on page 320, Fig. 55. Typical
coarsely granular mast cells may be found in small numbers
or they may be entirely absent, as may also be the finely gran-
1 Johns Hopkins Hosp. Bull., 1902, vol. xiii, pp. 23 and 133; also Jour. Amer.
Med. Assoc., 1902, vol. xxxix, p. 1523.
2 Brit. Med. Jour., 1902, vol. i, p. 831. 3 Ibid., 1902, vol. i, p. 1137.
4 Sem. me'd., 1902, vol. xxii, p. 418. 5 Loc. cit.
8 Loc. cit. 7 Sem. med., 1903, vol. xxiii, p. 420.
8 Lancet, 1903, vol. ii, p. 1649. 9 Brit. Med. Jour., 1904, vol. i, p. 73.
GASTRITIS. 421
ular forms of basophiles. The presence of myelocytes has not
been noted.
The detection of the Filaria nocturna in the
DIAGNOSIS, blood serves at once to differentiate idiopathic
from parasitic chyluria, hydrocele from lymph
scrotum, hernia and other tumors of the groin from parasitic
inguinal varicosities (Bancroft's "helminthoma elastica"), and
filarial orchitis from other inflammatory conditions of the testes.
N on- parasitic lymphedema, affecting, for example, the legs, can
but rarely be distinguished by the blood findings from true elephan-
tiasis Arabum, since in the latter disease it is exceptional to find
filariae in the general circulation.
XXVI. FRACTURES.
Blake, Hubbard, and Cabot1 conclude, from a study of 38
cases, that in simple uncomplicated fractures the number of leu-
cocytes is seldom increased to any extent, a statement which applies
also to complicated fractures in the great majority of instances.
Of 23 simple fractures examined by these authors, in but 10 was
the count higher than 10,50x3 per c.mm., and of these, only 6
exceeded 12,000. The highest estimate was 15,400, in a fracture
of the pelvis, and the next highest, 14,800, in a broken leg. Of
15 complicated fractures, but 2 showed any decided increase
in the number of leucocytes, namely, a fracture of the tibia and
fibula, with symptoms suggestive of fat embolism, in which the
count was 15,600; and a case of fractured ribs with injury of the
lung, in which the leucocytes numbered 14,900 two days after
the accident. An estimate of 5400 cells was made in a compound
fracture of the leg two hours after the accident.
Lipemia is occasionally met with in fractures of the long bones
involving injury of the fatty marrow.
XXVII. GASTRITIS.
In the acute form there is no deviation from
HEMOGLOBIN normal in the number and hemoglobin value of
AND the erythrocytes, except in the event of hyper-
ERYTHROCYTES. emesis, which, through concentration of the blood,
may cause a transient polycythemia. In the
chronic form secondary anemia frequently develops, and occasion-
ally reaches an extreme grade, should the gastric lesion be suffi-
1 Annals of Surg., 1901, vol. xxxiv, p. 361.
422
GENERAL HEMATOLOGY.
cient to interfere radically with the digestion and absorption of
food. In instances of this sort the quantitative changes may
simulate those of true pernicious anemia, but the qualitative
changes typical of this disease are invariably wanting. In pass-
ing, it seems pertinent to recall the reputed etiological relationship,
distinguished by some authorities, between gastric tubule atrophy
and pernicious anemia. Well-defined secondary anemia (without
erythroblasts) was found by Einhorn1 in but 4 of 15 cases of gastric
achylia, but in none were the qualitative blood changes of perni-
cious anemia detected. In cases associated with gastrectasis
and hyperacidity, blood inspissation from emesis is a common
change.
A synopsis of J. A. Lichty's studies2 of the hemoglobin and
erythrocytes in 98 cases of various gastric disorders shows the
following average values:
CONDITION.
NUMBER OF
CASES.
HEMOGLOBIN
PERCENTAGE.
ERYTHROCYTES
PER C.MM.
Hyperchlorhydria . . 39
90.9
5,556,000
Hypochlorhydria 13
83-5
5,431,000
Gastric achylia .... 6
92.1
5,680,000
Gastric dilatation . . 1 1
85.6
=5,623,000
Gastric neurasthenia
t$
87.2
=5,274,000
Chronic gastritis. . . .
14
91.0 5,498,000
From other investigations, Lichty also determined that in the
above-named diseases there is no definite relationship between
the condition of the blood, the urine, and the gastric contents.
In gastroptosis the blood remains normal in the great majority
of patients; in small proportion either a mild secondary anemia
or a chlorotic blood picture develops. Francine3 found the latter
change in 3 of 100 cases. Of 55 patients studied by Steele
and Francine,4 the color index averaged 0.95 in 24, 0.9 in 20, and
fell as low as 0.50 in but a single instance. The theory of Meinert,5
that chlorosis is a factor of gastroptosis, has no foundation in fact.
.: In acute gastritis leucocytosis of the poly-
LEUCOCYTES. nuclear neutrophile type is common, although
not constant; the increase is most notable in the
severest cases, but even in these the count seldom exceeds 15,000
or 20,000. Hyperinosis also usually exists. In chronic cases
1 Med. Rec., 1903, vol. Ixiii, p. 321. 2 Phila. Med. Jour., 1899, vol. iii, p. 326.
3 Proc. Phila. Co. Med. Soc., 1902, vol. xxiii, p. 447.
4 Jour. Amer. Med. Assoc., 1902, vol. xxxix, p. 1173.
5 "Zur Aetiologie der Chlorose," Wiesbaden, 1894.
GASTRIC ULCER. 423
an absence of leucocytosis is the rule, while leucopenia, resulting
from defective absorption, is an occasional finding. Relative
lymphocytosis is commonly associated with leucopenia and
sometimes with normal leucocyte counts. In a small proportion
of cases digestion leucocytosis is either delayed or absent.
The presence of a leucocytosis is a valuable
DIAGNOSIS, sign in ruling out enteric fever, should the diag-
nosis lie between this disease and acute febrile
gastritis. This sign, however, cannot be employed to differentiate
other acute infections, such, for instance, as appendicitis.
The blood furnishes no sure means of differentiating chronic
gastritis from gastric cancer, although a persistent leucocytosis is
very suggestive of the latter; unfortunately, digestion leucocytosis
is neither constantly absent in cancer nor invariably present in gas-
tritis.
Certain cases of chronic gastric catarrh, with atrophy of the
stomach tubules, in course of time "develop a clinical picture very
like that of true pernicious anemia, since they present not only a
similar cachexia, but also a very striking diminution in hemo-
globin and erythrocytes. But pernicious anemia is characterized
by the presence of nucleated erythrocytes the majority of which
are megaloblasts, while in the secondary anemia of gastric catarrh
erythroblasts are uncommon, and if present, show a predominance
of cells of the normoblastic type.
XXVIII. GASTRIC ULCER.
The average case shows a loss of approxi-
HEMOGLOBIN mately 40 per cent, of hemoglobin and of
AND 1,250,00x3 erythrocytes to the c.mm., and, owing
ERYTHROCYTES. to this prevalence of a disproportionately large
oligochromemia, low color indices are the rule.
The individual case may show a much greater degree of anemia,
but no matter how marked the cellular decrease, it is always far
outstripped by the diminution in the percentage of hemoglobin.
In fact, in some instances the latter alone is subnormal, the blood
condition of chlorosis being thus faithfully counterfeited. The
average index for the cases tabulated below was 0.75.
Profuse hemorrhage may provoke a very marked anemia, while
protracted emesis tends to concentrate the blood, thus masking
its real condition.
The several degenerative changes affecting the erythrocytes
common to any severe anemia may be present if the blood de-
424 GENERAL HEMATOLOGY.
terioration is sufficiently profound. After a severe hemorrhage
a few normoblasts not infrequently appear in the blood tempo-
rarily, and an occasional cell of this type may be found at other
times in cases with marked cachexia.
The following summary illustrates the hemoglobin and eryth-
rocyte ranges in 33 cases:
HEMOGLOBIN NUMBER OF ERYTHROCYTES NUMBER OF
PERCENTAGE. CASES. PER C.MM. CASES.
From 80-90 5 Above 5,000,0000 2
" 70-80 5 From 4,000,000-5,000,000. . . 16
" 60-70 7 " 3,000,000-4,000,000... 7
" 50-60 i " 2,000,000-3,000,000 7
" 40-50 6 " 1,000,000-2,000,000... i
" 3°-4o 5
20-30 4
Average, 57 per cent. Average, 3,798,000 per c.mm.
Maximum, 89 " " Maximum, 5,200,000 " "
Minimum, 20 " " Minimum, 1,090,000 " "
Futcher l gives the following data of 82 cases : the hemoglobin
percentage in 42 cases averaged 58, ranging from 12 to 105;
the erythrocyte count in 44 cases averaged 4,071,000, or from
1,012,000 to 4,071,000; and the leucocyte count in 45 cases
averaged 7500, varying from noo to 40,000.
Greenough and Joslin2 report hemoglobin estimates in 73 cases,
of which 34 were below 50 per cent, and 64 below 80 per cent.
Of their 43 erythrocyte counts, 24 were below 4,000,000 per
c.mm., the color index for this series averaging 0.67, and ranging
from 0.35 to 1.41.
Absence of leucocytosis is the rule, for an
LEUCOCYTES, increase occurs only after taking food or in the
event of some complication, such as hemor-
rhage or perforation. But the fact must be recalled that hemor-
rhage by no means invariably raises the count; for example, hem-
atemesis is a symptom in fully 50 per cent, of patients suffering
from ulcer of the stomach, yet in not more than 30 per cent, of
all cases, both those with and those without this symptom, does
the number of leucocytes exceed 10,000 to the c.mm. Perforation
always excites leucocytosis, except when the patient is over-
whelmingly toxic.
1 Amer. Med., 1904, vol. viii, p. 53.
2 Amer. Jour. Med. Sci., 1899, vol. cxviii, p. 167.
GLANDERS. 425
The behavior of the leucocytes in the above-mentioned series
of cases may be expressed thus:
LEUCOCYTES PER C.MM. NUMBER OF CASES.
Above 20,000 2
From 15,000-20,000 2
" 10,000-15,000 6
" 5,000-10,000 18
Below 5,000 5
Average, 8,778 per c.mm.
Maximum, 29,400 "
Minimum, 2,400 "
In cases with leucocytosis the increase affects chiefly the poly-
nuclear neutrophiles ; in those without leucocytosis minimum nor-
mal or distinctly subnormal percentages of these cells are not
uncommon, and a total absence of eosinophiles is th6 general rule,
these changes being counterbalanced by a proportionate increase
in the small lymphocytes.
Hematology gives no aid in distinguishing gas-
DIAGNOSIS. trie ulcer from gastf algid, duodenal ulcer, and
simple gall-stone colic, in all of which leucocytosis
is absent. A well-defined leucocytosis points to acute gastritis
rather than to ulcer. The differences in the blood pictures of
gastric ulcer and cancer are referred to under the latter disease.
(See " Malignant Disease.") >
XXIX. GLANDERS.
Data are wanting regarding the condition of the hemoglobin and
erythrocytes in human glanders, but it is known that leucocytosis is
the rule. The Bacillus mallei has been obtained by antemortem
blood culturing and by Duval1 and by von Jaksch.2 Heanley3
claims that, with a dilution of i 12500 and a time limit of twelve
hours, a specific serum reaction occurs with the bacillus of glan-
ders and glanders blood serum. In lower dilutions similar results
may be obtained with the serum of patients suffering from variola
and scarlatina.
1 Arch, de m<5d. exper., 1896, vol. viii, p. 361.
1 "Clinical Diagnosis," 4th ed., London, 1899.
8 Lancet, 1904, vol. i, p. 364.
426 GENERAL HEHATOLOGY.
XXX. GONORRHEA.
The hemoglobin and erythrocytes are unaltered, but the acute
febrile stage of specific urethritis is usually accompanied by a
moderate polynuclear leucocytosis, which, in the event of any of
the inflammatory complications of clap, may be much aggravated.
Sabraze*s 1 found that the increase usually does not exceed double
the mean average normal count. Giorgi,2 contrary to general
opinion, found an absence of leucocytosis, sometimes leucopenia,
the rule, together with a relative mononucleosis, at the expense
of the polynuclear neutrophiles. Some authors formerly claimed
that circulatory eosinophilia was a feature of this disease, but the
investigations of Vorbach3 have shown that such a change, while
occurring sometimes, is by no means constant; he found in 20
cases that the percentage of eosinophiles ranged from as low as
0.05 to as high as 11.5. Bettmann4 believes that eosinophilia is
especially frequent in posterior urethritis, an observation which
thus far is unique.
In gonorrheal endocarditis and in gonorrheal arthritis the
gonococcus has been repeatedly cultured from the blood during
life. In distinguishing gonorrheal arthritis from rheumatic fever a
positive iodin reaction is suggestive of the former.
XXXI. GOUT.
Garrod's 5 earlier teachings regarding the lowered alkalinity of
the blood in acute gout have been contradicted, apparently with
ample proof, by the later researches of Levy,6 who failed to find
a diminution in any of the 17 cases which he investigated by the
most approved methods. Still more recently Levy's conclusions
have been corroborated by Watson.7 During an acute gouty
seizure hyperinosis is an almost invariable finding.
It is questionable whether or not the amount of uric acid in the
blood is greater during the acute stages than in the interval be-
tween them, but it is nevertheless a fact that in many gouty persons
uric acid crystals can be demonstrated in the blood by the " thread-
test" — a reaction by no means peculiar to this disease, as already
pointed out. (Seep. 144.)
1 Sem. med., 1902, vol. xxii, p. 435.
2 Ibid., 1904, vol. xxiv, p. 39. 3 Inaug. Dissert., Wurzburg, 1895.
4 Arch. f. Dermat. u. Syph., 1899, vol. xxxix, p. 227.
1 "Gout and Rheumatic Gout," London, 1876, p. 80.
8 Zeitschr. f. klin. Med., 1898, vol. xxxvi, p. 336.
7 Brit. Med. Jour., 1900, vol. i, p. 10.
HEMORRHAGIC DISEASES. 427
The cellular elements show no characteristic alterations, and
are normal, except in long-standing cases, in which an ordinary
secondary anemia may develop in the course of time. During
the acute attack a moderate increase in the number of leucocytes,
affecting chiefly the polynuclear neutrophiles, may or may not be
found. A relative increase in the eosinophiles is also sometimes
encountered, in cases both with and without an increase in the
leucocyte count. In one case of the writer's the blood examined
during the height of a severe paroxysm showed 100 per cent, of
hemoglobin, 7,125,000 erythrocytes, and 14,000 leucocytes per
c.mm., the only peculiar differential change being the presence of
myelocytes in the proportion of 0.4 per cent. The occurrence of
these cells in gout has also been mentioned by Watson,1 who
found them in small numbers both during and between the acute
seizures.
The same observer also states that he found ..(apparently in
increased numbers) cells resembling blood plaques as large as 4 («
in diameter, often forming "very irregular, torn-looking masses."
The worthlessness of Neusser's so-called perinuclear basophilic
granules as a diagnostic sign of gout has been alluded to in a
previous section (p. 228).
XXXII. HEMORRHAGIC DISEASES.
From a hematological standpoint scurvy, hem-
GENERAL ophilia, and the various forms of purpura may
FEATURES, conveniently be considered together, since the
blood changes in all of these conditions are simi-
lar, and in none are characteristic.
The specific gravity of the blood varies with the degree of
anemia present, but only in exceptional instances does it fall to an
excessively low figure. Aiello2 estimated it as low as 1.043 m
a case of purpura haemorrhagica in which the erythrocyte loss
ranged between 50 and 60 per cent. The same investigator also
detected, by spectroscopical examination, methemoglobin in the
blood in this form of purpura, which he attributes directly to auto-
intoxication from the absorption of the products of decomposition
occurring within the intestinal canal. Immerman3 believed that
in the late stages of hemophilia an increase in the total quantity
of the blood, or a true plethora, exists, but this view is not enter-
tained at the present time.
Various bacteria, especially streptococci, staphylococci, and
1 Loc. cit. 2 Rif. med., 1894, vol. ii, p. 103.
3 Ziemssen's Handb. spec. Pathol. u. Ther., 1879, vol. xiii, p. 2.
428 GENERAL HEMATOLOGY.
bacilli, have been found in the circulating blood by a number of
observers, both in scurvy and in those forms of purpura due to
infectious diseases. No special clinical significance, however, can
be attached to these findings. The specific properties claimed by
Letzerich l for his Bacillus purpura are not generally credited.
The alkalinity of the blood, according to the studies of Cantani 2
and others, is generally decreased in the hemorrhagic diatheses,
although more recent investigators have disputed this fact, having
found it higher than normal. Wright,3 judging from his studies
of the blood alkalinity in 7 cases of scurvy, believes the disease
to be a condition of acid intoxication. He found in 3 of these cases
that the alkalinity corresponded to the figure N. 100, and to N. 200,
N. 150, N. no, and N. 80, respectively, in the remaining 4. As
determined by this author's method, the alkalinity of normal blood
is expressed by the formula N. 35, which means, in other words,
that the degree of alkalinity is such that a mixture of one volume
of a thirty- five-fold diluted normal acid with an equal volume
of blood serum is just sufficient to prevent the latter from
reacting with sensitive blue litmus-paper. Opposed to Wright's
views are the results obtained by Lamb,4 who, in a study of n
cases of scurvy, found no diminution in the alkalinity of the
blood. His cases were investigated by Wright's method, and
showed alkalinity values ranging between N. 30 and N. 35.
The coagulation of the fresh blood drop is, as a rule, slow, and
sometimes incomplete, these characteristics being observed with
especial frequency in hemophilics. In such subjects Wright5
determined that clotting may fail to occur until after the lapse of
over an hour after the withdrawal of the blood from the vessels,
while in other iristances the coagulation time ranged from nine
to fourteen minutes. In 8 cases of scurvy Lamb6 found that
the coagulation time ranged from one and one-quarter to four
minutes, and averaged about three and one-half. An average
clotting time of four and one-third minutes was found by Hutchin-
son in 5 cases of infantile scurvy.7 Of 5 cases of purpura
studied by Sicard,8 but one showed clot retraction with exudation
of serum. Grawitz9 has called attention to the fact that in cases
with long-continued hemorrhage the clotting may be abnormally
rapid, as is the case with normal blood after this accident. This,
however, must be an exception to the general rule, for, unlike
1 Zeitschr. f. klin. Med., 1890, vol. xviii, p. 517.
! "Spec. Pathol. u. Ther. der Stoffwechselkrankh.," Leipsic, 1884.
3 Lancet, 1900, vol. ii, p. 1556.
4 Ibid., 1902, vol. i, p. 10. 5 Brit. Med. Jour., 1893, vol. i, p. 223.
* I.oc. cit. 7 Lancet, 1904, vol. i, p. 1261.
8 Amer. Jour. Med. Sci., 1899, vol. cxviii, p.. 466. * Loc. cit.
HEMORRHAGIC DISEASES. 429
normal blood, that of hemophilias generally clots more and more
imperfectly as the amount of the hemorrhage increases. This is
also true of Werlhoff's purpura, according to Roncagliolo.1
There are no characteristic changes affecting
HEMOGLOBIN the erythrocytes and hemoglobin, the blood pic-
AND ture being that of secondary anemia of variable
ERYTHROCYTES. intensity. In the majority of well-marked cases
the erythrocytes do not suffer a loss of more than
1,000,000 or 2,000,000 to the c.mm., but the hemoglobin tends
toward a proportionately greater decrease, making a low color
index the rule. This is particularly noticeable in scurvy, in which
condition the hemoglobin loss is often twice as great as that of the
cells; in fact, some cases show simply oligochromemia, with a
normal number of erythrocytes. In seven cases of infantile scurvy
examined by the writer the hemoglobin percentage ranged between
35 and 65, averaging 43.8, and ..the erythrocyte count between
2,950,000 and 5,100,000 per c.mm., the average being 3,527,071.
In three of these cases, with counts of 5,100,000, 4,900,000, and
4,814,000, respectively, the corresponding hemoglobin estimates
were 52, 50, and 65 per cent. In severe cases, for example, of
scurvy and purpura haemorrhagica the count may fall to less than
1,000,000 and the hemoglobin to 20 per cent, or lower, these
changes being accompanied by all the qualitative alterations
typical of a profound secondary anemia which sooner or later
may prove fatal. Muir2 reports a case of purpura in which the
hemoglobin was only n per cent., and the erythrocyte's 800,000
per c.mm. Still more remarkable is the anemia reported by
Talley3 in a case of scurvy — 17 per cent, of hemoglobin and
370,000 erythrocytes per c.mm. In mild cases the blood may
be absolutely normal in every respect. Regeneration is rapid in
cases which pursue a favorable course. It is well known that
hemophilics appear to be less susceptible to the ill effects of
hemorrhage than other individuals, and that in this condition
recovery from blood losses is usually rapid and uneventful, in
spite of their number, extent, and chronicity.
The leucocytes are usually increased both in
LEUCOCYTES, purpura and in scurvy, but in hemophilia a de-
cided leucopenia may develop in spite of the ex-
isting hemorrhages. The increase is typically polynuclear in
most instances, although a relative excess of lymphocytes may
occur. Stengel* found this change most striking in two cases of
'Sem. me"d., 1903, vol. xxiii, p. 368. * Brit. Med. Jour., 1900, vol. ii, p. 909.
8 Jour. Amer. Med. Assoc., 1902, vol. xxxix, p. 1086.
4 "Twentieth Century Practice of Medicine," New York 1896, vol. vii, p. 485.
430 GENERAL HEMATOLOGY.
purpura hsemorrnagica, and the writer has noticed an exaggeration
of the lymphocytic tendency of children's blood in a number of
cases of infantile scurvy. In 4 of the 7 cases of this condition
referred to in the preceding paragraph, the total percentage of
lymphocytes was between 60 and 66; in 3 the percentage of
polynuclear neutrophiles was from 27 to 35; the eosinophiles aver-
aged a low normal figure, and in all but a single case myelocytes
were f9und, ranging in percentage from a minimum of i to a
maximum of 6, and averaging 2.5 per cent. The actual number
of leucocytes varied between 8000 and 25,000, and averaged
15,557 per c.mm., all but a single case having a decided increase.
Denys1 has called attention to the presence of large numbers of
leucocytes in the different stages of degeneration, both in scurvy
and in the infectious form of purpura.
In all the hemorrhagic conditions above men-
BLOOD tioned the blood plaques are usually much di-
PLAQUES. minished in number and sometimes are absent.
Especially is this the case in grave forms of
scurvy and of purpura haemorrhagica. Hayem2 believes that a
marked diminution in the number of plaques plus a deficiency in
clotting is a pathognomonic sign of the latter disease. Lenoble3
considers that in all cases of true purpura the plaques are increased
in size but diminished in number, and that (as in malarial fever)
they lose their characteristic viscidity and consequently their race-
mose grouping. These peculiarities, plus the presence of normo-
blasts and the failure of the blood clot to retract, this author
believes to be the specific hematological formula of this disease,
whatever may be its clinical variety.
XXXIII. HEPATIC CIRRHOSIS.
In the early stages of atrophic cirrhosis, so long
HEMOGLOBIN as the patient's general health is maintained, the
AND blood remains practically normal, or shows, per-
ERYTHROCYTES. haps, only a moderate diminution in hemoglobin.
.; But as the disease progresses and the patient
suffers from gastro-intestinal catarrh, hemorrhages, and circulatory
embarrassment, an ordinary secondary anemia sooner or later
becomes apparent, the intensity of this change depending upon
the severity of the primary disease and its associated lesions.
Most advanced cases show a loss of from 2,000,000 to 3,000,000
1 Centralbl. f. allg. Pathol. u. path. Anat., 1893, vol. iv, p. 174.
2 Compt. rend. 1'Acad. sc., Paris, 1896, vol. cxxiii, p. 894.
3 Sem. med., 1902, vol. xxii, p. 355.
HEPATIC CIRRHOSIS. 431
cells to the c.mm., and a few, an even greater oligocythemia.
Hemorrhages, either repeated and small or single and profuse,
constitute the factor of a profound anemia in many instances.
The average case of Laennec's cirrhosis loses about 40 per cent,
of hemoglobin and 30 per cent, of erythrocytes, while in the
individual case the count may fall to between 1,50x3,000 and
2,000,000. The color index, as a rule, is moderately reduced; it
averaged 0.86 for a series of 40 well-advanced cases examined at
the German Hospital, a synopsis of which shows these hemoglobin
and erythrocyte values :
HEMOGLOBIN NUMBER OF ERYTHROCYTES NUMBER OF
PERCENTAGE. CASES. PER C.MM. CASES.
From 90-100 i From 4,000,000-5,000,000. . . 10
" 80-90 6 " 3,000,000-4,000,000 ..18
70-80 8 " 2,000,000-3,000,000. . . 10
60-70 5 "1,000,000-2,000,000... 2
" 50-60 8
40-50 7
30-40 5
Average, 60.4 per cent. Average-,' -3, 526, 825 per c.mm.
Maximum, 98.0 " " Maximum, 4,970,000 " "
Minimum, 30.0 " " Minimum, 1,800,000 " "' .
The effects of ascites upon the blood are probably twofold and
diametrically opposed. Primarily it is thought to cause' more or
less anemia by reason of the steady drain exerted upon the albu-
min of the blood, but this deterioration may >be effectually
masked by a polycythemia due either to peripheral stasis or to
inspissation of the blood caused by the rapid transudation of
liquids from the vessels. This last factor is no doubt the cause
of the polycythemia noted by von Limbeck 1 in cases after para-
centesis. On the other hand, Grawitz-2 has demonstrated . that a
decrease in the hemoglobin and erythrocyte values may follow
this operation, in cases in which the presence of a large ascitic
exudate interferes with the circulation sufficiently to produce
capillary stagnation and a consequent polycythemia, which the
tapping dispels.
Anemia is apparently more striking and more common in
hypertrophic cirrhosis than in ordinary gin-liver. Judging from
a rather limited experience in 16 cases, the writer finds a
greater tendency toward corpuscular than toward hemoglobin loss,
and consequently toward higher color indices. The index for
1 Loc. cit. 2 Loc. cit-
432 GENERAL HEMATOLOGY.
these cases averaged 0.91, and in two it reached the figures 1.02
and i.oo, respectively. For the series the hemoglobin averaged
52.9 per cent., the minimum being 20 and the maximum 85 per
cent. The average erythrocyte count was 2,895,324, and ranged
from as low as 1,100,000 to as high as 4,290,000 per c.mm.
The usual degenerative and other qualitative changes accom-
panying any severe secondary anemia may be found in the anemias
of liver cirrhoses; and, in addition, Hayem1 has observed that in
the hypertrophic variety there seems to be a marked tendency
toward megalocytosis. It may here be noted that in Hanot's
disease Netter2 has detected staphylococci and Kirikow3 diplo-
cocci in the peripheral blood during life. The effect of bile upon
the blood is also apparent in many cases of Hanot's cirrhosis.
(See "Icterus," p. 434.)
In the great majority of atrophic cirrhoses the
LEUCOCYTES, number of leucocytes either remains normal or is
distinctly decreased, while a few show a moderate
degree of intermittent leucocytosis, to be regarded in all proba-
bility as a post-hemorrhagic change. It is questionable whether
or not the jaundice present in some cases accounts for a leucocyte
increase, although some authorities profess this belief. The leu-
cocytes in the 40 cases tabulated above ranged thus :
LEUCOCYTES PER C.MM. NUMBER OF CASES.
From 10,000-15,000 in 4
5,000-10,000 " 26
Below 5,000 " 10
Average, 6,921 per c.mm.
Maximum, 12,000 " "
Minimum, 3,000 " "
In the 1 6 cases of hypertrophic cirrhosis the leucocytes
averaged 9385 per c.mm., the lowest count being 4100, and the
highest 21,600. Seven of the estimates were above, and nine
below,. 10,000 cells to the c.mm. Much higher counts than these,
however, have been reported by others. While it must be ad-
mitted that leucocytosis is more frequent in this than in the
atrophic variety, Hanot and Meunier's4 claim that it is a constant
symptom of hypertrophic cirrhosis is by no means justified.
The leucocytoses of both these forms of the disease depend
1 " Du Sang," Paris, 1889. 2 Progres med., 1886 vol. xiv, p. 992.
8 St. Petersburg med. Wochenschr., 1900, vol. xvii, p. 353.
4 Compt. rend. Soc. biol., Paris, 1895, vol. ii, p. 49.
HYDATID DISEASE. 433
upon an absolute and relative increase in the polynuclear neutro-
philes, at the expense of the other forms of cells.
The blood examination fails to provide any
DIAGNOSIS, dependable signs by which cirrhosis is distin-
guishable from other lesions of the liver, but a
good idea of the inroads made by the disease upon the patient's
health may be gained by determining from time to time the grade
of the anemia present.
XXXIV. HYDATID DISEASE.
In the reported blood studies of this condition
HEMOGLOBIN the hemoglobin and erythrocytes have varied so
AND greatly that it seems fair to regard the presence
ERYTHROCYTES. of an anemia as due to factors other than the
echinococcus infection. Some cases show per-
fectly normal values, or, at the most, trifling hemoglobin losses,
while in others a rather severe type of secondary anemia develops.
Low color indices rule.
Leucocytosis with qosinophilia is the impor-
LEUCOCYTES. tant feature of the blood picture. In Seligmann
and Dudgeon's case,1 the first to be reported, the
leucocytes numbered as high as 17,000 per c.mm., and the eosino-
philes reached 57 per cent., the actual count of these cells being,
therefore, 9690 to the c.mm., or nearly twenty times the maximum
normal number. Longridge's case2 had 9 per cent, of eosino-
philes in a leucocyte count of 18,400, and the reports of others,
notably Launois and Weil,3 Turner and Milian,4 Archard and
Clerc,5 Darguin and Tribondeau,6 attest that this form of leuco-
cyte increase is constant in hydatid disease, no matter in what
region of the body the cysts are situated. As in other forms of
helminthiasis, the eosinophilia of hydatid disease may disappear
in cases of great chronicity. The polynuclear neutrophiles are
greatly diminished, the lymphocytes remain about normal, and
the basophiles are distinctly increased. After evacuation of the
cysts the leucocytosis and eosinophilia promptly disappear, and the
other forms of cells again attain their normal proportions. Memmi 7
has produced eosinophilia experimentally by the injection of
hydatid fluid.
1 Lancet, 1902, vol. i, p. 1764. 2 Ibid., 1902, vol. ii, p. 44.
3 Sem. med., 1902, vol. xxii, p. 378. 4 Ibid., 1902, vol. xxii, p. 75.
5 Arch. ge"n. de me'd., 1902, vol. clxxxix, p. 743.
6 Presse med., 1902, vol. viii, p. 142.
' Riv. crit. di clin. med., 1901, vol. ii, p. 233
28
434 GENERAL HEMATOLOGY.
In hydatids versus abscess or solid tumor the
DIAGNOSIS, presence of eosinophilia is strongly in favor of
the former, other eosinophile-increasing causes
being, of course, eliminated.
XXXV. HERPES ZOSTER.
The blood changes in shingles have been studied by Sabrazes
and Mathias,1 who found no appreciable diminution in the
hemoglobin and erythrocytes and no structural changes affecting
the latter. Leucocytosis develops as early as the first day of the
eruption, and progressively increases until about the third day,
after which it gradually diminishes until, by the fifth day, the
count again' reaches the normal figure. A secondary leucocytosis
accompanies the period of desiccation and desquamation. A gain
in the polynuclear neutrophiles and eosinophiles is accountable
for the leucocytosis, which in some instances is associated with a
few myelocytes.
XXXVI. ICTERUS.
Simple catarrhal jaundice per se produces little
GENERAL or no effect upon the blood, except in the most
FEATURES, pronounced cases. The most conspicuous change
consists in a greenish-yellow discoloration of the
serum, due to the presence of bile. In patients suffering from
obstructive jaundice — due, for instance, to gall-stones — a surgical
operation may.be complicated by dangerous, even fatal, hemor-
rhage, owing to the slow and imperfect coagulation of the blood.
The coagulation time of the blood in this form of obstructive
jaundice is referred to elsewhere. (See " Cholelithiasis," p. 380.)
In the Jefferson Hospital within three years four patients with
jaundice due to malignant disease of the biliary apparatus have
bled to death after operation. The quantity of fibrin is not in-
creased. The specific gravity of the whole blood increases in
relation to the intensity of the icterus, but the density of the serum
is unaffected. In severe cases de Rienzi 2 found that the alkalinity
of the blood was decidedly reduced. The blood serum of patients
affected with icterus, especially Weil's disease, may exhibit a
moderate agglutinative action upon the Eberth bacillus, the colon
bacillus, the cholera spirillum, and other bacteria. Koehler3
1 Rev. de sc. med., 1901, vol. xxi, p. 251.
2 Virchow's Arch., 1885, vol. cii, p. 218.
3 Cited by Libman, Med. News, 1904, vol. Ixxxiv, p. 204.
ICTERUS. 435
attributes this clumping power to the taurochoiic acid constituent
of the bile. (See "Enteric Fever," p. 403.)
In mild cases the hemoglobin and erythrocytes
HEMOGLOBIN remain unaltered, but in severe jaundice a mod-
AND erate anemia is not uncommon, characterized by
ERYTHROCYTES. an absence of rouleaux formation and by evi-
dences of endoglobular degeneration marked out
of all proportion to the grade of the cellular decrease. This
association of a moderate oligocythemia with striking degenera-
tive changes in the corpuscles appears to be peculiar to this affec-
tion. In cases with symptoms of cholemia these degenerative
changes are even more notable, but here the hemoglobin and
erythrocyte losses also are more pronounced.
The effects produced upon the hemoglobin and erythrocytes
by catarrhal jaundice are illustrated by this table of examinations
in 40 cases : ..
HEMOGLOBIN NUMBER OF ERYTHROCYTES NUMBER OF
PERCENTAGE. CASES. PER C.MM. CASES.
From 90-100 4 Above 5,000,000 4
80-90 10 From 4,000,000-5,000,000 . . 19
" 70-80 13 " 3,000,000-4,000,000 .. 8
60-70 4 " 2,000,000-3,000,000 .. 7
50-60 2 " 1,000,000-2,000,000 .'. 2
40-50 3
30-40 2
20-30 2
Average, 72.0 per cent. Average, 3,956,000 per c.mm.
Maximum, 97.0 Maximum, 5,344,000 '
Minimum, 28.0 " Minimum, 1,500,000 "
Von Limbeck * has observed that the volume of the individual
erythrocyte is markedly increased. The cells' diameters, accord-
ing to Vaquez,2 average 8 or 9 //, and 'not infrequently are as large
as 12 ii. Originally von Limbeck,3 and later Lang4 and Vaquez
and Ribierre*,5 also noted that in jaundice the erythrocytes are
highly resistant to the action of hypotonic sodium chlorid solu-
tions and of distilled water. This change probably is preceded
by a period of susceptibility on the part of the erythrocytes to the
action of circulating biliary poisons, and its development suggests
that in time the cells acquire a tolerance against the very toxins
which primarily acted deleteriously upon them. It is possible
1 Loc. cit. * Sem. me"d., 1902, vol%xxiii, p. 245.
3 Loc. cit, * Zeitschr. f. klin. Med.,' 1902, vol. xlvii, p. 153.
6 Sem. me'd., 1902, vol. xxiii, p. 246.
436 GENERAL HEMATOLOGY.
that in some instances the anemia is actually greater than the
blood count indicates, for polycythemia, according to Becquerel
and Rodier,1 may develop by reason of inspissation of the blood
from the action of bile.
Most observers report that no leucocytosis
LEUCOCYTES, occurs in simple catarrhal jaundice, but Grawitz,2
on the contrary, states that he finds a constant
increase in "uncomplicated cases of icterus," the count ranging
in some instances as high as from 30,0x30 to 40,000 to the c.mm.
This author's report, however, does not represent the general
consensus of opinion. In the writer's experience, about one-fifth
of all cases of catarrhal jaundice show a leucocyte count higher
than 10,000 to the c.mm. The following estimates in 40 cases
are the basis for this statement :
LEUCOCYTES NUMBER OF
PER C.MM. CASES.
From 20,000-30,000 4
" 15,000-20,000 o
" 10,000-15,000 4
5,000-10,000 29
Below 5,000 3
Average, 9,361 per c.mm.
Maximum, 26,000 "
Minimum, 3,600 "
Severe cases with cholemia may and usually do give rise to a
well-developed leucocytosis. In experimental cholemia in animals,
caused by the injection of bile and of biliary salts and pigments,
Gilbert and Herscher3 invariably noted a decided leucocytosis,
the extent and persistence of which indexed the animals' defensive
powers against the toxin.
The association of icterus with leucocytosis,
DIAGNOSIS, except in obviously cholemic patients, suggests
some purulent lesion or malignant disease as the
factor of jaundice, rather than uncomplicated angiocholitis.
XXXVII. INFLUENZA.
General invasion of the circulation by the influenza bacillus
occurs very rarely, and the positive results from bacteriological
examination of the blood claimed by Canon,4 Klein,5 and their
1 Arch, de Physiol. norm, et path., 1874, vol. i, p. 509.
2 Loc. cit. 3 Sem. m6d., 1902, vol. xxii, p. 197.
4 Virchow's Arch., 1893, vol. cxxxi, p. 401.
5 Baumgarten's Jahresb., 1893, vol. ix, p. 206.
INSOLATION. 437
contemporaries must be regarded as unsubstantiated, in the light of
the large number of negative findings by Pfeiffer1 and by Kiihnau.*
Slawyk3 has recently succeeded in cultivating this organism from
the blood of a patient whose predominant symptoms suggested
epidemic meningitis. Castellani4 was able to detect pneumo-
cocci, but not Pfeiffer's bacilli, in the blood of patients having
influenza complicated by catarrhal and croupous pneumonia.
Jehle,5 although he admits the rare occurrence of the influenza
bacillus in the blood of uncomplicated influenza, claims to have
obtained many positive blood cultures of this organism in diph-
theria, in pertussis, and in several of the exanthemata — measles,
scarlet fever, and varicella. He attributes these findings to the
fact that these diseases predispose to a secondary infection, espe-
cially to an influenzal bacteriemia.
The hemoglobin and erythrocytes are normal in the great ma-
jority of cases, a moderate diminution in these eiements having
been found only occasionally.
Uncomplicated influenza is one of the few examples of an acute
infection unaccompanied by a leuc.ocytosis, although in some in-
stances hyperinosis may be observed in the early stages of the
attack. Rieder6 states that a complicating catarrhal pneumonia
causes either a moderate increase in the number of leucocytes or
none at all, but that in a post-influenzal croupous pneumonia the
leucocytosis of this condition develops typically.
It is unfortunate that an absence of leucocytosis is common to
both enteric fever and influenza, for these two diseases a-re not in-
frequently confused. The serum test, however, generally is con-
clusive if typhoid exists, and blood cultures are even more definite.
Should a frank leucocytosis be present, croupous pneumonia,
rather than influenza, is suggested.
XXXVIII. INSOLATION.
In the acute stages of thermic fever the hemoglobin and ery-
throcyte values are unduly high, owing to the concentration of
the blood from the excessive loss of body fluids by the lungs and
the skin. Lambert,7 for example, has observed a hemoglobin
percentage of 125 in a sunstroke patient, while Vincent8 states
1 Deutsch. mcd. Wochenschr., 1893, vol. xix, p. 816. 8 Loc. cil.
3 Zeitschr. f. Hyg. u. Infectionskr., 1890, vol. xxxii, p. 443.
4 Fortsch. d. Med., 1901, vol. xix, p. 781.
8 Zeitschr. f. Hcilk., 1901, vol. xxii, p. 190.
9 Munch, med. Wochenschr., 1892, vol. xxxix, p. 511.
7 Loomis-Thompson, "A System of Practical Medicine," New York, 1898,
vol. Hi, p. 877. 8 These d. Bordeaux, 1887-88, No. 8, p. 7.
438 GENERAL HEMATOLOGY.
that the erythroc'ytes may number as high as 300,000 per c.mm.
in excess of the normal average count. A more or less pronounced
destruction of the erythrocytes also occurs both during and after
the acute stages of insolation, and this factor is responsible for
the anemia, sometimes decided, which subsequently develops.
Owing to the coexistence of these two conflicting factors the real
extent of the hemolysis cannot be determined until after the
disappearance of the symptoms leading to blood concentration.
This hemolysis is thought to depend upon the presence in the
blood of some toxic element, since the hyperpyrexia itself is in-
sufficient to cause disorganization of the cells. Schultze and Ran-
vier's 1 experiments have proved that such changes begin only
when an animal is subjected to a temperature of from 54° to 56°
C. (129.2° to 132.8° F.). Levene and Van Gieson2 have shown
that the blood serum of sunstruck patients is a highly active blood
poison to animals when injected intravenously.
Some investigators have found an increased number of leuco-
cytes, but others have been unable to detect any such change, so
that leucocytosis must be regarded as an inconstant sign, depend-
ing, perhaps, more upon the degree of blood condensation than
upon any specific influence of the heat-stroke. Pigmented leuco-
cytes have been observed in cases in which there existed marked
signs of blood destruction.
Wood3 found that a decreased alkalinity or even an acidity of
the blood was a conspicuous postmortem change, but evidence
is lacking to show that the reaction of the blood is altered during
life.
XXXIX. INTESTINAL HELMINTHIASIS.
The presence in the intestinal canal of
GENERAL certain parasites, notably the Bothriocephalus
FEATURES, latus and the Ankylostomum duodenale, is cap-
able of provoking anemia of marked inten-
sity in the individual harboring them. The Ascaris lum-
bricoides also may be held responsible for anemia in some in-
stances, but the blood changes attributable to this parasite are,
as a rule, much less marked than those commonly met with in
the two preceding forms of helminthiasis. Ostrovosky4 has
called attention to a case, unique of its kind, of fatal progressive
anemia attributable to the presence in the intestine of the long
threadworm, Trichocephalus dispar. Severe secondary anemia,
1 Cited by Vincent, loc. cit. 2 Cited by Lambert, loc. cit.
"Thermic Eever or Sun-stroke" (Boylston Prize Essay), Philadelphia, 1872.
4 Russkiy Vrach Sept. 30, 1900; abst., N. Y. Med. Jour., IQOO, vol. Ixxii, p. 826.
INTESTINAL HELMINTHIASIS. 439
not approaching the true pernicious type, has been found in this
infection by E. Becker.1 The cause of these anemias is generally
attributed to two factors : interference with absorption of food from
the intestinal canal due to the catarrhal inflammation therein
existing, and the systemic effects on the host of certain soluble
and absorbable toxic products eliminated by the parasites. That
such poisons are produced, and that they undoubtedly can act in
this deleterious manner, has been abundantly proved by many
different investigators, among whom Hubner,2 Reyner,3 Schau-
mann,4 Askanazy,5 and Lussana6 may be named as authorities
whom the student should consult for more detailed information
on this topic. It is probable that in ankylostomiasis the anemia
is also kept up partly by the constant drain on the system caused
by the direct abstraction of blood by the parasite, and partly by
the so-called " plasmotropic " action of the blood derivatives ab-
sorbed from the gut. Grawitz 7 .explains this form of blood de-
struction by assuming that the presence of blood in the intestine
is attended by the elaboration of certain toxic substances which,
when absorbed, influence the bone marrow, liver, and spleen so
as to provoke increased hemocytolysis. The details of this type
of blood destruction have been described by the writer elsewhere.8
The blood changes due to Bothriocephalus
HEMOGLOBIN latus infection are by far the most interesting,
AND from the clinician's standpoint, since the anemia
ERYTHROCYTES. caused by this "worm may in some individuals
exactly simulate primary pernicious anemia. The
blood pictures of the two conditions may be identical, both being
characterized by marked and disproportionate oligocythemia, and
consequently by a high color index and by the presence of nucleated
erythrocytes, the majority of which conform to the megaloblastic
type. Megalocytes and erythrocytes stippled with basophilic
areas also are usually numerous. This so-called bothriocephalus
anemia has been aptly described by Ehrlich9 as "a pernicious
anemia, with a known and removable cause." It is distinguishable
from true pernicious anemia solely by the fact that after the expul-
sion of the worm by the administration of appropriate vermifuges
the megaloblastic type of blood and the anemia rapidly disappear,
and the patient makes an uneventful recovery.
1 Deutsch. med. Wochenschr.. 1002, vol. xxviii, p. 468.
2 Deutsch. Arch. f. klin. Med., 1870, vol. vii, p. 7.
3 Ibid., 1886, vol. xxxix, p. 31. * " Bothriocephalus-Anamie," Berlin, 1894.
s Zeitschr. f. klin. Med., 1893, vol. xxiii, p. 80; ibid., 1895, vol. xxvii, p. 492.
* Rivista clin., 1889, vol. iv, p. 750.
7 Deutsch. med. Wochenschr., 1901, vol. xxvii, p. 908.
8 Amer. Med., 1902, vol. v, p. 571. * Loc. tit.
44O GENERAL HEMATOLOGY.
The anemia 'of ankylostomiasis (uncinariasis), while it may
reach a very high grade of development, still does not counterfeit
pernicious anemia. Griesinger's Egyptian chlorosis, the brick-
makers' anemia of the Germans and the miners' anemia of the
Italians, as well as many forms of tropical anemia, are all due
to the effects of this nematode. The hemoglobin and erythrocyte
loss may individually be as great as is seen in Biermer's disease,
but low color indices rule. The erythrocytes are commonly found
in a state of marked deformity, as to both shape and size, poly-
chromatophilia may be noted, and erythroblasts are often seen,
but never, so far as our present knowledge indicates, is there a
prevalence of megaloblasts, as there is both in bothriocephalus
and in pernicious anemias.
Save in ankylostomiasis, leucocytosis does not
LEUCOCYTES, accompany any of the above-named forms of
helminthiasis, except as the effect of some com-
plication. In ankylostomiasis it is more frequent the earlier the
stage of the disease, and usually disappears by the time the
anemia is well denned. Boycott and Haldane's 34 cases * ranged
between 3800 and 56,000 per c.mm., the 4 highest (averaging
36,250) being in patients ill not longer than six months, and the
4 lowest (averaging 5875) occurring in cases of from two to four
years' standing. Rogers2 found an average count of 5338 in 12
cases, and Ashford3 an average of 7000 in 19 cases. These cases
were probably of considerable' chronicity. Sandwith4 noted,
contrary to the general rule, that the number of leucocytes in-
creases as the patient convalesces.
As already pointed out (see p. 256), a conspicuous feature of
the blood is the frequent, but not constant, occurrence of both a
relative and an absolute increase in the percentage of eosinophiles.
This change is especially well marked soon after the infection
occurs, but may disappear in time, even though the worm is not
expelled — a fact first proved by Boycott and Haldane,5 and one
to which may be attributed the inconstancy of eosinophilia in
helminthiasis of various types. The individual's age and resisting
powers are, of course, contributing factors. The eosinophilia may
be moderate or it may be enormous — in one case of ankylos-
tomiasis reported by Ashford,6 40 per cent., and in another,
53.5 per cent.;7 72 per cent, in a case of the same disease and
34 per cent, in a patient harboring the Tania mediocanellata,
1 Jour. Hyg., 1903, vol. iii, p. 121. 2 Brit. Med. Jour., 1900, vol. ii, p. 544.
1 N. Y. Med. Jour., 1900, vol. Ixxi, p. 552. 4 Lancet, 1894, vol. i, p. 1365.
s Loc. cit. ' Loc. cit.
7 Amer. Med., 1903, vol. vi, p. 301.
INTESTINAL OBSTRUCTION. 44!
these instances having been reported by Leichtenstern.1 In
bilharziasis high eosinophile figures have also been reported, for
example, 47.6 per cent. (Boycott2); 33.6 per cent. (Russell3);
33 per cent, in one case, and an average of 16.4 per cent, for
50 cases (Douglas and Hardy4); 20 per cent. (Coles5); and
18.4 per cent. (Balfour8). Even the Oxyuris vermicularis,
although it is not considered to be a factor of anemia, may
cause a well-marked increase in the percentage of eosinophiles,
these cells sometimes constituting from 10 to 15 per cent, of all
forms of leucocytes. In three cases of Strongyloides intestinalis
infection, reported by Price,7 eosinophilia was absent.
Relatively high percentages of mononuclear forms, especially
the large, and of basophiles are other differential changes occa-
sionally observed.
XL. INTESTINAL ' OBSTRUCTION.
The hemoglobin and erythrocytes are unaffected, except in ob-
struction due to malignant disease or associated with hemorrhage,
in which there may be a moderate secondary anemia.
Leucocytosis is a frequent, though not a constant, accompani-
ment of all forms of ileus, even those with comparatively slight
symptoms. The increase is most constant in obstruction de-
pending upon malignant disease or complicated by gangrene and
peritonitis, and in this class of cases it tends to reach the highest
figures, except in the event of grave intoxication. Bloodgood8
regards the presence of a high leucocytosis (20,000 to 30,000) on
the third or fourth day after the onset of symptoms as a favorable
indication for operative interference, but he considers that low
counts (below 10,000) under the same circumstances indicate
extensive gangrene-peritonitis, or that the patient will be so de-
pressed that reaction cannot follow -relief of the obstruction.
XLI. KALA-AZAR.
In many cases malarial parasites are detected
PARASITOLOGY. in the blood of individuals suffering from kala-
azar, a finding which points to a coincident ma-
larial infection. Bentley,8 by splenic puncture, demonstrated in
1 Cited by Ehrlich, loc. cit. 2 Brit. Med. Jour., 1903, vol. ii, p. 1267.
3 Lancet, 1902, vol. ii, p. 1540. * Ibid., 1903, vol. ii, p. 1009.
6 Brit. Med. Jour., 1902, vol. i, p. 1137. * Lancet, 1903, vol. ii, p. 1649.
7 Jour. Amer. Med., Assoc., 1903, vol. xli, p. 651.
8 Amer. Med., 1901, vol. i, p. 306.
* Cited by Ross, Brit. Med. Jour., 1904, vol. i, p. 160.
442 GENERAL HEMATOLOGY.
•
kala-azar the newly described Leishmania donovani, an observa-
tion subsequently confirmed by Rogers,1 who found these bodies
in 6 of 7 cases of this disease, as well as in 15 of 30 other febrile
conditions associated with splenomegaly and striking cachexia.
Leishman-Donovan bodies were first found intra vitam by Leish-
man 3 in blood aspirated from the enlarged spleen of a patient
affected with so-called "dum-dum fever," and they were first
demonstrated post-mortem by Donovan 3 in smears from the spleens
in cases of obscure Indian fevers. Marchand and Ledingham4
have similarly detected these organisms in a patient dead of an ir-
regular pyrexia, with anemia and splenomegaly, and Manson and
Low,5 Neave,6 and Swan7 found them in cases of tropical spleno-
megaly. Manson, Low, and Christophers8 detected Leishman-
Donovan bodies in intestinal ulcers.
The parasites are found but rarely in the peripheral blood,
and only when the patient's fever is high, 103° or 104° F.
The organisms in question appear, singly and in clusters, as oval
or spherical bodies, 2 or 3 ft in diameter, and consisting of a limit-
ing membrane inclosing two dis-
tinct masses of chromatin: one
relatively large and of circular or
ring-shaped contour, the other
much smaller, rod-shaped, and,
as a rule, situated perpendicularly
to the circumference of the larger
mass (Fig. 62). The precise
significance of these organisms
is unsettled. Leishman9 suggests
FIG. 62— LEISHMAN-DONOVAN BODIES. that they may be simply evolu-
tion forms of trypanosomata or
of a closely related flagellate organism, and the statements of
Marchand and Ledingham4 carry a similar inference. More
recently Leishman 10 pointed out the resemblance of his bodies
to the Helcosoma tropicum, found by J. H. Wright11 in the
pus of that form of tropical ulcer known as Delhi sore. It is
possible that they are identical with the so-called plasmodia
found in Delhi sore by Cunningham 12 in 1885. Laveran18 and
1 Cited by Ross, Brit. Med. Journ., 1904, vol. i, p. 160.
2 Ibid., 1903, vol. i, p. 1252. 3 Ibid., 1903, vol. ii, p. 79.
4 Lancet, 1904, vol. i, p. 149. 6 Brit. Med. Jour., 1904, vol. i, p. 183.
8 Ibid., 1904, vol. i, p. 1252. ''Ibid., 1904, vol. i, p. 1487.
1 Brit. Med. Jour., 1904, vol. ii, p. n • Loc. cit.
10 Brit. Med. Jour., 1904, vol. i, p. 303.
11 Jour. Med. Research, 1903, vol. v, p. 472.
1 " Scientific Memoirs by Medical Officers of the Army of India," Calcutta, 1885.
1S Bull, de PAcad. de m6d., Paris, 1903, vol. 1, p. 238.
KALA-AZAR. 443
Donovan1 believe that the organisms belong to the genus piro-
plasma, while Ross2 is strongly inclined to the view that they
represent a novel organism, possibly of the genus cercomonas.'
Rogers' 3 success in developing trypanosomata from cultures of
Leishman- Donovan bodies is of the highest importance, if confirmed.
Well-defined secondary anemia sooner or
HEMOGLOBIN later develops, due in part, to the extreme mal-
AND nutrition of the subject and in part to the effect
ERYTHROCYTES. of a coincident ankylostomiasis, for, as Bentley4
has shown, this type of helminthiasis is almost
universally prevalent in natives stricken with kala-azar. Rogers5
found about 3,500,000 per c.mm. as the average number of ery-
throcytes in his series of cases. With the persistence of such an
anemia structural changes are to be expected — poikilocytosis, de-
formities of size, polychromatophilia, and sometimes a few normo-
blasts. .
The leucocyte count is subnormal in the
LEUCOCYTES, majority of cases, and extreme leucopenia may
supervene. Relative lymphocytosis, involving es-
pecially the large cells, with a consequent decrease in the propor-
tion of polynuclear neutrophiles, is the general rule. Neave8
found ii per cent, of small, and 67 per cent, of large, lympho-
cytes in one case. In 10 cases Donovan1 found that the -mono-
nuclear forms averaged 32.8 per cent., of which 23.6 per cent,
were large lymphocytes; and a still more decided mononucleosis
was found by Rogers 7 in 22 cases. Because of the concomitant
ankylostomiasis, an eosinophile increase is common, the percent-
age of these cells frequently rising to 10 or 12. Five per cent, of
mast cells were found in a case studied by Swan.8
The blood plaques, according to Bentley,9 are generally very
abundant, even in the pyrexial stage of the disease, and appear
to exhibit multiple areas, staining more, deeply than the surround-
ing body of the cell.
Hematologically, kala-azar closely simulates
DIAGNOSIS, malarial fever, save in two particulars — the ab-
sence, in uncomplicated cases, of the malarial
parasite and of pigment and the great increase in the number of
plaques. The presence or absence of eosinophilia is naturally
1 Lancet, 1904, vol. ii, p. 613.
2 Brit. Med. Jour., 1903, vol. ii, p. 1261; also ibid., 1904, vol. ii, p. 98.
3 Ibid., 1904, vol. ii, p. 29; also Lancet, 1904, vol. ii, p. 215.
4 Brit. Med. Jour., 1902, vol. ii, p. 872.
6 Ibid., 1904, vol. ii, p. 647. 8 Ibid., 1904, vol. i, p. 1252.
7 Ibid., 1904, vol. ii, p. 647.
8 Loc. cit. * Loc. cit.
444 GENERAL HEMATOLOGY.
of no diagnostic* significance. The blood pictures of kala-azar
and of Malta fever are very similar, aside from the parasitology of
the blood. Although the blood of kala-azar patients clumps
Bruce's micrococcus in low dilutions, no such reaction occurs in
high dilutions — i in 80 or higher.
XLIL LEPROSY.
The studies of Winiarski1 and of P. K. Brown2 show that in
the early stages of this disease neither the hemoglobin nor the
erythrocytes suffer any deterioration, but that in advanced leprosy,
especially in cases with extensive ulcerative lesions, the anemia
may be striking — quite as marked, in fact, as in a moderately
severe case of true Biermer's anemia. In such instances there is
a conspicuous oligocythemia in comparison to the oligochro-
memia, and the counts may fall to below 2,000,000 to the c.mm.
A tendency toward megalocytosis and high color indices has
been observed, the index in some counts being as high as 1.7.
Normoblasts may occur alone or in association with a few megalo-
blasts, but the latter never predominate. Polycythemia, resulting
from peripheral stagnation, may be a feature of some cases. The
number of leucocytes is not increased, but a relative lymphocytosis
is a commonly observed differential change affecting these cells.
An eosinophilia of 8.7 per cent, was present in a leper examined
by Boston.3
Brown,4 Streker,5 and Boston 6 have succeeded in demon-
strating the Bacillus leprce in the circulating blood during life.
These organisms, as a rule, were found to be inclosed in the leuco-
cytes, and, more rarely, lay free in the plasma. On the other hand,
Bibb7 failed in 30 cases to find the bacillus by blood culturing,
although he obtained positive results constantly with blood as-
pirated from the leprous tubercles.
The serum diagnosis of leprosy has not yet come into general
clinical use, although positive clump reactions with cultures of
the leprosy bacillus and the serum of lepers have been observed.
1 St. 'Petersburg med. Wochenschr., 1892, vol. ix, p. 365.
2 Trans. California State Med. Soc., 1897, vol. xxvii, p. 168.
3 Proc. Phila. Co. Med. Soc., 1903, vol. xxiv, p. 6.
4 Loc. cit. 5 Miinch. med. Wochenschr., 1897, vol. xliv, p. 1103.
* Loc. cit. 7 Amer. Jour. Med. Sci., 1894, vol. cviii, p. 539.
MALARIAL FEVER. 44 ^
XLIII. MALARIAL FEVER.
The specific cause of malarial fever is a form
PARASITOLOGY. of blood parasite generally known as the Plas-
modium malaria. or the Hamamceba malaria, an
organism classified among the Sporozoa, according to Metschni-
koff.1 First accurately described in 1880 by Laveran,2 a medical
officer of the French army stationed in Algeria, our knowledge
of the parasite and its relation to the malarial fevers have been
furthered chiefly by the researches of Richard,3 also a French
army surgeon; of Grassi and Filetti,4 in Sicily; of Mannaberg,5
in Austria; of Marchiafava and Celli,6 Bastianelli and Bignami,7
and Golgi,8 of the Italian school; of Manson9 and Ross,10 in
England ; and of Councilman and Abbott,11 Sternberg,12 Osier,13
Dock,14 Thayer and Hewetson,15 and Craig,18 in -America. In
addition to these principal investigators, numerous workers in
other parts of the world have materially advanced our knowledge
of the subject.17
Developmental Cycle in Man. — The malarial organism gains
entrance to the erythrocyte of man, in' which it pursues a definite
cycle of development at the expense of its corpuscular host.
Existing in its earliest stages as a hyaline, ameboid body within
the substance of the corpuscle, the parasite increases in size, and
1 Centralbl. f. Bakt. u. Parasit., 1887, vol. i, p. 624.
2 "Nature parasitaire des accidents de I'impaludisme," Paris, 1881. %
3 Gaz. med. d. Paris, 1882, vol. iv, p. 252.
4 Centralbl. f. Bakt. u. Parasit., 1890, vol. vii, pp. 396 and 430; ibid., 1891
vol. ix, pp. 403, 429, and 461; ibid., 1891, vol. x, p. 449.
5 "The Malarial Parasites," New Sydenham Soc. Trans., London, 1894, vol.
cl, p. 241.
8 Fortsch. d. Med., 1885, vol. iii, p. 787; ibid., 1888, vol. vi, p. 450; also
Festschr. z. Virchow's 70. Geburtstag, 1891, vol. iii, p. 187.
7 Riforma med., 1890, vol. vi, pp. 860, 866, and 872; also Lancet, 1898, vol.
ii, p. 1461.
8 Arch, per le sc. me'd., 1886, vol. x, p. 109.
"Lancet, 1896, vol. i, pp. 695, 751, and 831; also Brit. Med. Jour., 1894,
vol. ii, p. 1306.
10 "Report on the Cultivation of Proteosoma (Labhe) in Gray Mosquitoes,"
Calcutta, 1898.
11 Amer. Jour. Med. Sci., 1885, vol. Ixxxix, p. 416; also Med. News, 1887,
vol. i, p. 59.
12 Med. Record, 1886, vol. xxix, pp. 489 and 517.
13 Phila. Med. Times, 1886, vol. xvii, p. 126.
14 Med. News, 1890, vol. Ivii, p. 59; ibid., 1891, vol. Iviii, pp. 602 and 628.
16 Johns Hopkins Hosp. Reports, 1895, vol. v, p. 3.
" Estivo-autumnal Malarial Fevers," New York, 1901.
17 For an exhaustive bibliography the reader should consult Thayer's admirable
monograph, "Lectures on the Malarial Fevers," New York, 1897. An authorita-
tive account of the malarial fevers in all their phases is given in Celli's book,
"Malaria According to the New Researches," English translation by J. J. Eyre,
London and New York, 1900. The estivo-autumnal fevers are well dealt with in
Craig's book above noted.
446 GENERAL HEMATOLOGY.
derives fine pigment granules from the hemoglobin of its host,
which it ultimately destroys at the time its full maturity is attained.
Full development of the parasite having been reached, it divides
into a number of segments, which, by the rupture of the blood
cell, are set free to enter fresh, uninvaded erythrocytes and there
to initiate a new developmental cycle of similar characteristics.
Segmentation or sporulation of a group of parasites is accompa-
nied by a paroxysm, which in all probability is due to the influence
of certain toxic material liberated at this time.
The favorable effect of quinin in malaria King1 attributes to
the fluorescence of the drug, whereby violet rays flood the blood
and thus deprive the parasites of the light requisite for their
sporulation. This ingenious theory is based upon the fact that
light is essential for fluorescence, and upon the hypothesis that
the malarial parasite must have light in order to segment. It
explains why quinin cures the paroxysms of tertian and quartan
fevers, and also why it fails materially to influence those due to
estivo-autumnal crescents. In the first two infections the organ-
isms circulate freely in the peripheral blood, where there is enough
light to develop fluorescence, while in the latter the organisms are
largely confined to the deep circulation, where, because of dark-
ness, no fluorescence occurs. In addition to quinin, fraxin and
aesculin possess fluorescent properties and are also therapeutically
active in paludism.
In order to complete its full life cycle, the malarial parasite
must also pass through a developmental phase within the bodies
of certain mosquitos, for it has been shown that these insects not
only act as the intermediate hosts of the parasite, but also carry
the infection by means of their bite. These important discoveries
were first made by Ross,2 whose conclusions were shortly con-
firmed by Grassi, Bignami, Bastianelli, 3 and by others of the
Italian school.
Developmental Cycle in the Mosquito. — While in the human
body the malarial parasite pursues an asexual cycle, terminating
in segmentation, in the body of mosquitos of the genus Anopheles
it follows out a true sexual cycle. In the blood of man certain
of the parasites which do not undergo segmentation constitute
sexual forms of the organism, known as gametes, which, after
having been imbibed by the mosquito while biting a malarious
1 Amer. Jour. Med. Sci., 1902, vol. cxxiii, p. 1025.
2 Loc. cit.
3 Reale Accademia dei Lincei. Estratto dal, vol. vii, 2° sem., ser. tja., fasc. TI°.
Seduta del 4 dicembre, 1898; abst. in Progressive Med., Philadelphia, 1899, vol.
I, p. 287; also Bignami, Lancet, 1898, vol. ii, pp. 1461 and 1541; also Grassi, II
Policlinico. 1898, vol. v, p. 469.
SINGLE TERTIAN INFECTION.
Paroxysm every third day.
CHART III.
s
P.
i
I I
f
P. P.
* *
Day. 1
2
v
3
4
V V"
5 6 7 S
9 10
V v
11 12 13
P.
P.
*
P.
*
DOUBLE TERTIAN INFECTION.
Daily paroxysm.
P. P. P. P. P. P. P.
* * * * * * *
P. P.
* *
\ j
\/ \/
\/
\ /
Day. 1
/
2
V
3
v
4
v v v v
5678
v v
9 10
11 12
P.
*
SINGLE QUARTAN INFECTION.
Paroxysm every fourth day.
p. P: P.
* * *
P.
*
Day. 1
2
3
V
4
v
5678
v
9 10
11 12 13
P.
*
P.
*
DOUBLE QUARTAN INFECTION.
Paroxysm on two successive days with one day's intermission.
P. P. P. P. P. P. P.
# # * * * * *
p.
*
\ / \ /
\ /
\ /
Day. 1
/
2
3
V
4
~~v
5678
v
9 10
V V
11 12 13
V
14
P.
P.
*
/
P.
*
TRIPLE QUARTAN INFECTION.
Daily paroxysm.
P. P. P. P. P. P. P.
*******
P. P,
•/ —
~v — \7 \r~
~\7
— \ / — VT*
Day. 1
2
/
3
V
4
V V v V
5678
V v
9 10
v v
11 12
CHART ILLUSTRATING THE DIFFERENT TYPES OF FEVER
RESULTING FROM INFECTION WITH SINGLE AND WITH
MULTIPLE GROUPS OF MALARIAL PARASITES.
The duration of the parasites' cycle of development
is expressed by colored lines, thus:
Black: First group of parasites.
Red: Second " " •' "
Blue: Third " " " "
P: Paroxysm.
MALARIAL FEVER. 447
individual, develop into impregnated bodies by reason of the
fecundation of the female sexual elements, or macro gametes, by the
free flagella, or microgametes, which have become detached from
the male sexual elements, or micro gametocytes. The resultant
fertilized bodies develop into motile pseudo-vermicules, which,
having penetrated the muscular wall of the mosquito's stomach,
lodge and become encysted in this situation and are now known
as zygotes. From the latter are derived large numbers of delicate
spindle-shaped cells, or sporoblasts, which, by the rupture of the
zygote's capsule, are set free, and, as sporozoids, make their way
into the salivary gland of their host, whence they pass by way of
the salivary duct into the proboscis of the insect, and consequently
into the circulating blood of the individual stung by the infected
mosquito. The sporozoids thus inoculated into the blood of man
penetrate his erythrocytes, in which, as the young hyaline forms
of the malarial parasite, they pursue the typical developmental
cycle to be described below.
Thus, it has been definitely shown that mosquitos of the genus
Anopheles are capable of transmitting malarial infection from man
to man, and it is now generally believed that this, the only proved
method of malaria transmission, is probably the sole means by
which the disease is spread. The ordinary house-mosquito, of
the genus Culex, is not concerned in the transmission of malaria,
since it has been shown that the parasites do not follow out a
developmental cycle within the body of this insect.
For a complete review of the "mosquito theory" of 'malaria,
embracing the work of Ross, Manson, MacCallum, and the
Italian school, the reader should consult Thayer's "Recent
Advances in our Knowledge Concerning the ^Etiology of Malarial
Fever,"1 Futcher's "A Critical Summary of Recent Literature
Concerning the Mosquito as an Agent in the Transmission of
Malaria," 2 and Howard's "Mosquitoes."
Varieties of the Malarial Parasite. — Three distinct varieties of
the parasite are recognized, each of which has been found con-
stantly associated with a specific type of malarial infection. These
three varieties are :
1. The parasite of tertian fever, associated with a regularly
intermittent type of fever, with paroxysms every third day.
2. The parasite of quartan fever, associated with a regularly
intermittent type of fever, with paroxysms every- fourth day.
3. The parasite of estiva-autumnal fever, associated with the
more irregular types of fever.
1 Proc. Phila. Co. Med. Soc., 1900, vol. xxi, p. 211.
1 Amer. Jour. Med. Sci., 1899, vol. cxviii, p. 318.
448 GENERAL HEMATOLOGY.
The parasites of tertian and of quartan fever exist in the blood
of the infected individual in great groups, consisting of immense
numbers of organisms, all of which are approximately at the same
stage of development, and therefore undergo sporulation at about
the same period. This fact serves to explain the regularity of
the tertian and quartan paroxysms. On the other hand, in estivo-
autumnal infections this regular grouping of the parasites is often
wanting, and large numbers of this organism commonly exist in
the blood in different stages of development. Sporulation thus
taking place at irregular intervals, irregularity in the occurrence
of the estivo-autumnal paroxysms is extremely common.
As the development of these three types of the malarial parasite
progresses, certain forms are evolved which possess more or less
common characteristics, so that it is convenient to speak of these
forms, which represent the maturing phases of the organism, as
follows :
(a) The intracellular hyaline forms.
(&) The intracellular pigmented forms.
(c) The extracellular pigmented forms.
(d) The segmenting forms.
(e) The flagellate forms.
Furthermore, in parasites of the estivo-autumnal type addi-
tional forms — those of the crescent group — are met with, these
varieties being peculiar to this type of infection and never occurring
in tertian and quartan fevers.
Tertian infections constitute the prevailing type of malarial
fever in almost all countries in which the disease exists. Quartan
fevers are relatively uncommon, except in certain limited districts
— parts of Sicily, for example ? — in which a large proportion of the
cases conform to this type. Estivo-autumnal fevers are especially
common in the tropics, but this type of the disease is by no means
incompatible with temperate regions. In Philadelphia and its
environs tertian infections are about five times as common as those
of the estivo-autumnal type, while quartan malaria is practically
unknown. The writer has seen but a single instance of quartan
infection in this vicinity, and this case was without doubt imported.
The Parasite of Tertian Fever (Plate VI}. — The tertian parasite
attains its full development in about forty-eight hours, segmenta-
tion of a single group of organisms at this interval producing the
characteristic paroxysms every third day. Infection with two dis-
tinct groups of parasites, each maturing on successive days, gives
rise to a quotidian type of fever, characterized by the occurrence of
daily paroxysms. (See Chart III, p. 447.) Infection with more
PLATE VI.
14
12
13
15 /
16
THE TERTIAN PARASITE.
1. Normal erythrocvte.
2, 3, 4. 5- Intracellular hyaline forms.
6, 7. young pigmented intracellular forms. In 6 two distinct parasites inhabit the ery-
throcyte, the larger one being actively ameboid, as evidenced by the long tentacular
process trailing from the main body of the organism. This ameboid tendency is
still better illustrated in 7, by the ribbon-like design formed by the parasite. Note
the delicacy of the pigment granules, and their tendency toward peripheral arrange-
ment in 6, 7, and 8.
8. Later developmental stage of 7. In 7, 8, and 9 enlargement and pallor of the infected
erythrocyte become conspicuous.
9. Mature intracellular pigmented parasite.
10. ii, 12. Segmenting forms. In 10 is shown the early stage of sporulation — the develop-
ment of radial striations and peripheral indentations coincidentally with the swarm-
ing of the pigment toward the center of the parasite. The completion of this process
is illustrated bv n and 12.
13. Large swollen extracellular form. Note the coarse fused blocks of pigment. (Com-
pare size with that of normal erythrocyte, I.)
14. Flagellate form.
i.S. Shrunken and fragmenting extracellular forms.
16. Vacuolation of an extracellular form.
NOTE. — The original water-color drawings were made from fresh blood specimens, a
Leitz j'j-inch oil-immersion objective and 4 ocular, with a Zeiss camera-lucida, being used.
(E. F. FABKR, /<•£.)
MALARIAL FEVER. 449
than two groups is extremely rare, and produces an atypical and
irregular type of fever.
Anticipation of the paroxysm, which is especially frequent in
tertian fever, may be explained by a precocity displayed by a
group of parasites, by virtue of which their development is so
rapid that the stage of sporulation is reached before the expira-
tion of forty-eight hours. On the contrary, should the develop-
ment of a group happen to be slower, requiring more than forty-
eight hours for its full maturity and sporulation, then the paroxysm
is retarded.
If a specimen of fresh, unstained blood from a case of tertian
fever is examined during the period immediately or shortly fol-
lowing the malarial paroxysm, it will be observed that many of
the erythrocytes contain small, pale, transparent foreign bodies,
dim of outline, more or less markedly ameboid in character, and
of a peculiar dirty, grayish-pearl tint. These bodies, known as
the intracellular hyaline forms, or amebultz, represent the youngest
forms of this organism, being derived from the sporulation of the
immediately preceding group of parasites. They may occasionally
be found in the peripheral blood toward the latter part of the
paroxysm, and for a short time after the occurrence of this
phenomenon.
The ameboid movements of these hyaline bodies form one of
their most striking features, and in consequence of this trait their
shape is constantly altered. At one moment the parasite appears
as a flattened spherical or oval disc, measuring 2 or 3 /^ in diameter;
the next instant it may change to the shape of a jack-stone, or
become a stellate design or take the form of an anvil. The suc-
cession of figures which the organism may resemble is limitless.
As the parasite increases in size long pseudopodia, like the delicate
tendrils of a vine, are alternately thrown out and retracted, reaching
here and there through the corpuscular substance with uncertain
but sudden motility. In the active parasite these pseudopodia
appear as long, delicate, gracefully curved branchings of the pro-
toplasm, usually terminating in a spherical, knob-like extremity,
and measuring 4 or 5 /* in length in many instances. Occasionally
the parasite seems to have formed a perfect ring, either because
of the thinning out of its central portion, or, rarely, by reason
of the fusion of two short pseudopodia between which a small
portion of the corpuscle becomes imprisoned. The outline and
color of the hyaline body are quite characteristic, at least to the
eye of the practised observer. Usually described as quite color-
less, the parasite rather possesses a distinctive pearly tint, overlaid
in patches by strata of corpuscular substance of varying depth,
29
450 GENERAL HEMATOLOGY.
so that in certain lights the yellowish-green color of the erythrocyte
predominates and obscures the true color of the organism to some
extent. Usually but a single hyaline body, situated somewhat
eccentrically, 'is found in the corpuscle; less commonly, two or
more are harbored.
The next stage in the development of the organism, the col-
lection of pigment granules derived from the hemoglobin of the
erythrocyte, is reached toward the latter part of the first twenty-
four hours following the paroxysm. By this time the size of the
parasite has increased to about half that of its corpuscular host,
and it is now known as an intracellular p-igmented form.
The pigment appears as a collection of exceedingly fine, yel-
lowish-brown granules, which are usually most densely distributed
near the peripheral rather than the central portion of the parasite.
In the large spherical forms of the latter most of the pigment is
arranged in a series of irregular clumps, loosely strung together
by delicate, wavy connecting lines consisting of individual gran-
ules; or the rim of the parasite may be paralleled for the greater
part of its extent by a pigment design not unlike a wreath or a
hoop. The individual granules are observed to be in active, in-
cessant motion, their violent oscillations hither and thither form-
ing a picture that at once arrests the attention of the observer.
In many of the ameboid figures a polar distribution of the pig-
ment is noticeable, the greater part of the granules being situated,
in fine clumps, in the knob-like extremities of the several pseudo-
podia; and even in these situations the typical tendency of the
pigment to arrange itself eccentrically is striking.
As the parasite matures it becomes of still larger size, more
and more pigmented and less and less ameboid, the latter char-
acteristic becoming quite or almost entirely lost by the time it
attains its full growth. The pigment, fine, of yellowish-brown
color, and eccentrically distributed in the earlier forms, is at this
period of the organism's growth much coarser, darker in color,
and more scattered throughout the protoplasm. Some of the
granules are fused into minute, dark-colored spikes and rods, in
contrast to the discrete, dot-like granules of the younger parasites.
Coincidentally with these changes striking alterations are ap-
parent hi the invaded erythrocytes. These cells become pro-
gressively paler and more swollen as the development of the para-
site goes on, until at the time of the latter 's full maturity (attained
after a growth of about forty hours' duration) the corpuscles have
become almost entirely decolorized, and appear now as hyaline
or pale yellowish rims encircling the parasite, the size of which is
now approximately equal to that of a normal erythrocyte.
MALARIAL FEVER. 451
Just before and during the next paroxysm, or from about forty
to forty-eight hours after the preceding chill, the parasite attains
its full maturity and the stage of sporulation occurs. Coinci-
dentally with this, segmenting forms of the parasite, also known
as sporocytes, begin to appear in the blood. In tertian infections
segmentation occurs to a greater extent in the deep than in the
peripheral circulation, but if finger blood is obtained two or three
hours before the chill, a few "segmenters" will almost always be
found if the search for them is careful and thorough. In cases
in which the number of parasites has been scanty during the pre-
ceding days of the attack it may be impossible to detect these
forms in spite of careful, skilled observation.
Segmentation is heralded by a tendency of the pigment gran-
ules, to collect in or near the center of the parasite in one large
or in several smaller compact clumps or fused masses. This
having taken place, a number of minute, somewhat refractive
points may be seen with more or less distinctness, the majority
of these spots being confined to the peripheral portion of the
organism, which by this time has lost a great deal of its earlier
clear, hyaline appearance, and has become dully opaque and
somewhat granular. Following the development of these refrac-
tive points, indistinct parallel linear shadings, usually fifteen or
twenty in number, extending from the periphery of the parasite
toward the central collection of pigment, may be discerned; and
coincidentally with this change the rim of the parasite becomes
wrinkled, then distinctly corrugated, each corrugation capping a
pair of these radiating shadings. The latter finally, become the
dividing lines of fifteen or twenty spores or segments, of somewhat
round or ovoid shape, radiating in an irregular figure toward the
central pigment mass. By careful focusing each segment is found
to contain a central refractive spot, the whole collection being
surrounded and held together by the shell of the erythrocyte, now
so decolorized that it is scarcely visible.
Finally, when segmentation is completed, the spores — for as
such these segmenting bodies must now be considered — are freed
from the body of the corpuscle which has served until this time
as their limiting capsule. The latter having apparently ruptured,
the spores escape, either by gradually emerging several at a time,
or by the simultaneous and extremely abrupt exit of their whole
number. The spores, which now lie free in the blood plasma,
surround the remains of the central pigment mass in an irregular
group which has been likened in appearance to a bunch of grapes.
Sooner or later they wander off through the plasma and disappear
from view, the inference being that they invade fresh erythrocytes
452 GENERAL HEMATOLOGY.
and thus initiate a new cycle of development of another forty-
eight hours' duration. Although visual proof of this invasion is
lacking, the fact that hyaline bodies, biologically similar to these
free spores, are found in the erythrocytes at or shortly after the
time of segmentation, must be regarded as sufficiently strong
evidence of the truth of this inference.1 Most of the liberated
pigment is carried off through the blood, to be deposited in various
organs, while some of it is taken up by phagocytes. These cells
probably also engulf any free spores which fail to penetrate the
erythrocytes.
The preceding remarks refer to the typical circle of the par-
asite's development, from the smallest hyaline intracellular body
to the full-grown pigmented segmenting variety, from which the
former is derived. But all the parasites of one group do not
pursue this routine, some escaping prematurely from the eryth-
rocyte at an early period of their life history, others continuing
to develop further, and losing their corpuscular capsule just prior
to the time segmentation begins in the other parasites of the
same group. In consequence of the latter change another distinct
class of tertian parasites, the extracellular pigmented forms, or
gametes, is produced, and it is the varieties of this class that we
now have to consider.
In the first instance, the young, slightly pigmented parasite
escapes from its corpuscular host through an apparent breach in
the surface of the latter. The immediate effect of its contact
with the blood plasma is to convert it into a deformed, dwarfed
body of protoplasm, which sooner or later becomes wholly devoid
of ameboid mbtion. It is often fragmented and divided into two
or more small rounded masses, each containing an amount of
pigment seemingly disproportionate to its size, compared to the
quantity found in the intracellular forms. Sometimes two of these
pigmented spheres are joined to each other by a filmy connecting
thread of protoplasm, from 3 to 5 p. in length, forming a design
which may be compared to a miniature chain-shot. After the
lapse of a short length of time the outlines of these bastard forms
of the. parasite become almost indistinguishable. The erythrocytes
from which they have escaped become completely decolorized and
invisible shortly after this accident has occurred.
In the second instance, in which the parasite loses its corpus-
cular envelop just before the time of segmentation, the resulting
spherical extracellular body is usually of large size, often 9 to
1 Christy's drawings (Brit. Med. Jour., 1903, vol. ii, p. 645), showing free
"hyaline organisms adhering to and apparently entering the erythrocytes, are of
interest in connection with this question.
.MALARIAL FEVER. 453
12 // in its greatest diameter, or, in the smaller forms, about
the size of the normal erythrocyte. It is filled with actively
moving pigment granules, wreathed in the center of the parasite,
arranged peripherally, or scattered throughout its body, and
standing out in bold relief against the background formed by the
pale surface of the parasite. The granules in this form of the
organism are usually quite dark in color, some of them being
welded and fused into minute spiculate figures, while others remain
free and distinct. As a rule, male gametes contain pigment in
the form of a more or less compact central mass, while in female
gametes the pigment is arranged in the form of a loose loop or
wreath in the center of the organism.
These extracellular pigmented bodies are of especial interest,
for the reason that from them develop those most striking varieties
of the malarial parasite, the flagellate jorms. The earliest evidence
of the process of flagellation is seen in the strikingly increased
activity of the pigment, the oscillations of the granules growing
more and more violent with the approach of the phenomenon.
Then, one or more long, almost transparent tentacular processes
are observed suddenly to burst from the periphery of the parasite,
their violent and incessant whipping about in the plasma causing
more or less disturbance of the blood corpuscles in their vicinity.
The pigment granules, meanwhile, have swarmed together into a
loose mass at or near the center of the main body. The length of
the flagella varies from 4 to 5 to 20 /* or longer, their average
breadth being somewhat less than 0.5 }i. They frequently possess
one or more bulbous swellings, usually at their distal extremity,
occasionally at their proximal end, and also at other points along
their course intermediate to these situations. They may or may
not contain a few fine and active dotlets of- pigment situated in
the swollen extremity, or sprinkled as fine stipplings along their
course.
The ultimate disposition of the flagella occurs in one of two
ways: they either become detached from the large spherical
parasite, and, as free flagella, wander off through the plasma,
propelled by their own ameboid movements, which finally cease,
after which they soon disappear from view; or, remaining attached
to the large body, they are observed to disappear by apparently
reentering the large parasite and becoming reincorporated with
its protoplasm. Flagellate forms do not occur in the circulating
blood, and are not found in the fresh specimen until some little
time, usually from ten to twenty minutes, has elapsed after the
withdrawal of the blood from the body They are most easily
found in blood which has been taken from the patient just before
454 GENERAL HEMATOLOGY.
the onset of a paroxysm. The nature and functions of these
flagellate bodies were first clearly determined by MacCallum,1
who proved that the flagella are true male sexual organs, actively
concerned in 'the process of fertilization, to which reference has
already been made. (See p. 446.) The parasites from which
they develop are obviously male gamete forms, or microgameto-
cytes.
Some of the gamete forms, failing to develop flagella, undergo
vacuolization, often become exceedingly misshapen, and sometimes
fragmented, these changes being regarded as degenerative in
character. A parasite thus affected loses its regularly spherical
outline, and may so alter in appearance that it resembles .a gourd
or a partly inflated balloon. Constrictions at one or more points
may appear, and in the little knobs thus cut off from the main
body of the organism a few actively motile pigment granules are
usually imprisoned. Small portions of the original body, contain-
ing active pigment, may become extruded and float off through
the plasma, but sooner or later the pigment in these fragmented
bits loses its motility and the bodies themselves become deformed
and so indistinct of outline that they are lost to view. These
degenerative forms closely resemble those derived from prema-
turely escaped intracellular parasites, except that the latter, as
a rule, contain finer and less abundant pigment.
2. The Parasite 0} Quartan Fever (Plate VII). — The quartan
parasite completes its cycle of development in about seventy-two
hours, thus producing a paroxysm every fourth day. Infection
with two separate groups of parasites is marked clinically by a
paroxysm occurring on each of two successive days, separated by
one day of intermission. Infection with three groups of parasites
produces daily paroxysms, the resulting quotidian type of fever
being similar to that due to double tertian infections. (See Chart
III, p. 447.)
Ordinarily, the quartan parasite's cycle of development is ex-
tremely regular, the period required for its maturation seldom
deviating from seventy-two hours. It is owing to this that antici-
pation and retardation of the paroxysm, so common in tertian
infections, are rare in the quartan types of fever.
The young hyaline forms of the quartan parasite closely re-
semble those of the tertian organism: they have the same hyaline
appearance, the same indistinct outline, and the same sort of
ameboid movement. While the quartan hyaline body is usually
described as being of smaller size and less ameboid than the
'Jour. Exper. Med., 181)8, vol. iii, p. 117; also Johns Hopkins Hosp. Bull.,
1897 vol. viii, p. 236.
PLATE VII.
A * *
8 9 10 11
,-f>Y
« £.•'*"* v^
•**; :/ 13 \$
THH QUARTAN PARASITE.
1. Normal ervthrocvte.
2. Intracelhilar hyaline form.
3. Xtf«».f pigmented intracellular form. Note the coarseness, dark color, and scantiness
of the pigment granules.
4. 5. 6, 7. Later developmental stages of 3. Note the peripheral distribution of the pigment
in all the parasites from 3 to 8. (Compare size and color of the erythrocytes in 5, 6,
and 7 with 7. 8, and 9, Plate VI.)
8. Mature intracellular form. Note that the stroma of the erythrocyte is no longer
demonstrable.
9, 10, it, Segmenting forms. In 9 are shown the characteristic radiating lines of pigment.
(Compare with 10, n, and 12, Plate VI, and with 10, ir, and 12, Plate VIII.)
12. Large swollen extracellular form. (Compare with 13, Plate VI.)
>3- Flagellate form. (Compare with 14, Plate VI.)
14. Vacuolaiion of an extracellular form.
(E. F. FABER,/«T.)
• MALARIAL FEVER. 455
similar tertian form, these differences are not well enough marked
to be of practical application. At this stage of its life history
the organism of quartan fever possesses no distinctive characteris-
tics by which it may be differentiated from the tertian variety of
a similar period of growth. It is not until it has matured to
the stage of pigmentation that it is possible to discern points
of distinction by which its identity may be fixed — characteristics
which become more and more striking as development of the
parasite progresses, and which relate to its color, outline, pigment,
and ameboid powers, as well as to changes affecting its corpus-
cular host.
The outline of the intracellular pigmented form is much more
distinct than that of the tertian, its margins contrasting rather
than blending with the color of the surrounding erythrocyte.
The appearance of its protoplasm is also quite different, being ap-
parently denser in consistence, more highly refractive,, and unob-
scured by the color of the overlying corpuscular substance.
Thayer1 has happily compared this difference in refraction and
distinctness of outline between the tertiafi and quartan parasites
to the difference between a pale hyaline and a waxy cast in the
urine — a comparison which precisely expresses these points of
dissimilarity.
The pigment granules, fine, yellowish-brown, and violently
motile in the tertian variety, are coarse, dark brown or almost
black, and sluggishly motile in the quartan form. They early
tend to form little spicula and rods, intensely dark in color,- and
compactly arranged, being frequently grouped together in masses
like coffee-grounds in one corner of the parasite.
By the time the organism reaches about one-half or two-thirds
the size of the corpuscle in which it is contained, it may be ob-
served that its ameboid movements, which in the earlier stages of
its existence were quite active, have now become sluggish, slow,
and inconspicuous. In consequence of this limited motility the
long tentacular shoots of protoplasm, so familiar in the tertian
form, are not seen, the quartan parasite inclining to form resting
figures, oval, round, or somewhat elongated in outline. The
pigment does not oscillate violently, but moves about a more
limited area with a sort of deliberate, tugging motion. It is dis-
tributed about the periphery, which it parallels for only a short
distance, not tending to produce the wreathed designs commonly
observed in the tertian organism at a corresponding stage of its
maturity.
As the parasite matures its ameboid powers progressively di-
1 "Lectures on the Malarial Fevers," New York, 1897.
456 GENERAL HEMATOLOGY.
.
minish, until at a period usually after the forty-eighth hour fol-
lowing the last paroxysm little or no motility either of protoplasm
or of pigment is distinguishable.
The corpuscular host meanwhile undergoes striking changes
in comparison to the erythrocyte invaded by the tertian organism.
Instead of becoming swollen and pale, as in the latter instance,
it becomes, on the contrary, shrunken, darker colored, and some-
times ."brassy." It is not until segmentation is imminent, or from
about ten to twelve hours before the impending paroxysm, that
decolorization of the blood corpuscle becomes marked. At this
period of its cycle the parasite measures about 7 or 8 ft in diameter,
and is apparently, although not actually, unconfined by a cor-
puscular envelop, the latter now having become rapidly decolor-
ized and finally quite invisible.
As segmentation approaches the pigment collects in the center
of the sporocyte, which now becomes more opaque and develops
a number of refractive dots, which later become the nuclei of
from six to twelve segments, developed by a progressive deepening
of parallel radial striations extending from the periphery to the
center of the parasite. The segmenting quartan parasite forms
a perfect rosette, the individual spores being of equal size and of
the same shape, and the collected mass of spores being very
symmetrically arranged. Coincidentally with segmentation a new
group of young hyaline parasites may be found in the hitherto
uninvaded erythrocytes, indicating the beginning of another cycle
of the parasite's development, which, if unchecked, persists for
seventy-two hours.
Thayer1 mentions a star-like arrangement of the pigment in
the early stages of the segmenting quartan organism, as if the
granules had flowed inward in distinct streams during the process
of collection, and this picture he is inclined to consider character-
istic. The author is able to verify Thayer's observation, having,
in a limited experience with the quartan parasite, never failed to
find this peculiarity, its absence having been equally conspicuous
in malarial organisms of other types.
The quartan parasite completes every phase of its development
in the circulating blood, so that all stages of its cycle, from the
earliest hyaline forms to the segmenting and flagellate bodies, may
be studied in the peripheral blood.
Extracellular pigmented forms, which have parted with all
traces of their corpuscular capsule without having undergone
segmentation, may also be observed. These gametes average less
in diameter than similar forms of the tertian parasite, the largest
1 Loc. cit.
MALARIAL FEVER. 457
of the quartan forms being about equal in size to the smallest
of the tertian. Their pigment granules are coarse, very dark
colored, and situated chiefly toward the periphery, with a greater
or less drifting inward of individual pigment clumps apparently
composed of two or three agglutinated coarse granules. The
difference in the distribution of the pigment in the male and female
quartan gametes is more difficult to appreciate than in correspond-
ing tertian bodies.
Flagellate bodies, smaller in size and containing coarser gran-
ules than corresponding tertian forms, develop from these swollen
extracellular parasites, the onset of flagellation being portended
by increased activity and centralization of the pigment in direct
anticipation of the appearance of the flagellate appendages.
Degenerate forms of the parasite, vacuolized, fragmented, and
otherwise deformed, may also be observed, but with less frequency
than in tertian fever, probably for the reason that extracellular
forms of the quartan parasite are not so numerous as those of the
tertian organism. The writer has ^especially noticed the infre-
quency of fragmentation and other deformity of those organisms
which have prematurely emerged from their corpuscular host,
atypical varieties of the more mature free bodies being compara-
tively much commoner.
3. The Parasite of Estivo-autumnal Fever (Plate VIII). — The
developmental cycle of the estivo-autumnal parasite exhibits
marked irregularity as to the length of time required for its com-
pletion, in contrast to the routine forty-eight- and seventy-two-
hour cycles in which the tertian and quartan organisms round out
their life histories. In some instances the cycle of the estivo-
autumnal parasite is of only twenty-four hours' duration, while in
others it is quite forty-eight hours, or perhaps longer. This in-
constancy of type is thought to depend upon some peculiarity of
the organism, by virtue of which the time required for its matu-
ration may widely fluctuate under different conditions of quite
obscure character. It is not generally believed that the common
types of fever, quotidian and tertian, respectively, depend upon
infection with two special forms of the estivo-autumnal parasite,
although this view is held by some authors, notably by Mannaberg *
and by Marchiafava and Bignami,2 all of whom recognize both
a quotidian and a tertian variety of the organism; the former,
furthermore * describes a pigmented and an unpigmented form of
the quotidian variety.
Certain phases of the young hyaline jorms of the estivo-
1 Nothnagel's "Spec. Path. u. Ther.," Vienna, 1899, vol. ii, p. 68.
2 New Sydenham Soc. Transl., London, 1894, vol. cl, p. i.
458 GENERAL HEMATOLOGY.
autumnal parasite bear a striking resemblance to similar forms of
the tertian and quartan organisms, but other phases are, on the
contrary, just as strikingly dissimilar. As a rule, the estivo-
autumnal amebula is much smaller than those just described,
its margins are more sharply defined from the corpuscular sub-
stance, and it appears to possess a greater degree of refraction.
But these are minor points of difference, the chief distinction
relating to the peculiar morphological changes to be observed in
these immature parasites. At one moment they may appear as
pale, rounded or somewhat oval bodies, situated rather toward
the periphery of the corpuscle than in its center, and usually
possessing active ameboid movements which produce various
stellate and forked designs. On closer observation certain other
striking changes may be noted in these round forms. These
changes consist in the formation of the so-called ring-shaped
bodies, due to the development of a more or less marked bicon-
cavity of the hitherto flattened hyaline body, either in its center,
in event of which the parasite appears as a true ring or hoop, or
more toward its periphery, in which instance a figure resembling
a signet-ring is produced. These figures remain visible for a
variable length of time, the parasite meanwhile being apparently
in a resting stage, but sooner or later its ameboid powers are
reasserted, with the result that the biconcavity abruptly disappears,
converting the ring-shaped body into its original form of an
ameboid, flattened disc. This successive alteration in shape, from
disc to ring to disc, regardless of the other changes in shape,
is highly characteristic of the estivo-autumnal organism, and is
fully as valuable a diagnostic sign as the more striking pictures of
the maturer forms, to be considered later. The size of the ring-
shaped parasites varies from less than 2 /./ in diameter to about
3 IJL. They are rarely situated in the exact center of the corpuscles,
more commonly being found lying midway between the center
and the periphery, or, indeed, quite upon the latter.
As the parasite matures, pigment, in the form of a few ex-
ceedingly fine, scattered granules, begins to appear. The gran-
ules are very few in number, dark brown in color, and are usually
situated toward the edge of the organism. They may or may not
be motile, usually not. Strikingly pigmented forms of the estivo-
autumnal parasite are never observed, in marked contrast to the
abundant fine pigment of the tertian forms and to the«coarse gran-
ules typical of the quartan varieties.
The development of the parasite up to this stage can be studied
in the peripheral blood, but the older forms of the pigmented
bodies, and their final division into spores, by segmentation, occur
PLATE VIII.
*• »
10 11
12 13 14
*
15
16
-4
23
24
I
25
26
THE ESTIVO-AUTUMNAI, PARASITE.
1. Normal erythrocyte.
2, 3. Young hyaline ring-forms.
4, 5, 6. Intracellular hyaline forms. In 4 the parasite appears as an irregularly shaped disc
with a thinned-out central area. In s and 6 its ameboid properties are obvious.
7. Young pigmented intracellular form. Note the extreme delicacy and small number of
the pigment granules. (Compare with 6, Plate VI, and with 3, Plate VII.)
8, 9. Later developmental stages of 7.
10, II, 12. Segmenting forms.
13, 14. Crescentic forms at early stages of their development.
15, 16, 17, 18, 19. Crescentic forms. In 15 and 19 a distinct "bib" of the erythrocyte is visible.
Vacuolation of a crescetit is shown in 18, and polar arrangement of the pigment in 17.
20. Oval form.
21,22. Spherical forms.
23. Flagellate form.
24. Vacuolation and deformitv of a spherical form.
25. Vacnolated leucocyte apparently enclosing a dwarfed and shrunken crescent.
26. Remains of a shrunken spherical form.
(E. F. FABER,/«:.)
MALARIAL FEVER. 459
almost exclusively in the deeper circulation, and must be followed
out in blood obtained from one of the internal organs, such as
the spleen, which may be aspirated for this purpose, although
the procedure is not without risk to the patient. In the finger
blood the writer has never seen presegmenting forms more mature
than those represented by the young, slightly pigmented parasite,
and has never had the good fortune to meet with segmenting
bodies except in specimens derived from the spleen. The general
rule is to find in the peripheral blood nothing more than hyaline,
ameboid, and ring-shaped bodies, or, perhaps, a few organisms
containing two or three minute granules of pigment.
If, now, a drop of blood, aspirated from the spleen, is examined,
the remainder of the parasite's cycle may be traced with fair
accuracy. As it approaches the stage of segmentation, the parasite
develops into a spherical body, measuring from about 2 to 6 //
in diameter, and having a distinct outline which limits it
from the surrounding substance of the erythrocyte, which it
only partly fills. The pigment granules, which by this time are
moderately but never strikingly increased in number, show a
marked tendency to become concentrated near the center of the
organism. They here exist as a tightly clumped, compact mass,
in which the identity of the individual granules is completely lost,
as they have now become fused into a single distinct, dark-colored,
round or somewhat elongated mass.
As segmentation commences the parasite becomes -opaque,
minute refractive areas paralleling the periphery develop, and
radial shadings, which later divide the body usually into from
eighteen to twenty spores, become apparent. The segmenting
body is smaller than that of the tertian and «quartan parasites, but
it usually resembles the former as to the arrangement and number
of the individual segments.
A marked characteristic of the estivo-autumnal infections is
the early occurrence of degenerative changes in the invaded
erythrocytes. These changes, the "erythropyknosis" of the Italian
school, consist in the development of a pronounced "brassy"
appearance of the blood cell, together, in many instances, with
distinct crenation along its periphery and in various portions of
its flat surface. Occasionally there appears to be a distinct con-
centration of the hemoglobin about the parasite, leaving portions
of the corpuscle quite colorless. This corpuscular degeneration
occurs early, even in those cells occupied by the youngest hyaline
bodies, and grows more and more marked, as a rule, as the parasite
matures. Simple decolorization of the erythrocyte appears to
follow no fixed rule, for segmenting bodies have been observed
460 GENERAL HEMATOLOGY.
«
both in perfectly hyaline and in apparently unchanged corpuscles.
In Thayer's experience the rim of the blood cell surrounding the
parasite has usually been entirely devoid of color.
After the infection has existed for a week or more examination
of the peripheral blood, which until now has contained perhaps
only ring-shaped organisms, reveals the presence of other highly
characteristic forms of the estivo-autumnal parasite, the round,
ovoid, and crescentic bodies, all belonging to the crescent group,
representing the gamete forms of the organism. These forms,
which are never present in the circulation during the first days
of the fever, are prone to persist in the blood for a long period
after the disappearance of the earlier forms of the parasite, and
even after all the clinical manifestations of the attack have van-
ished. Unlike other forms of the malarial parasite, those of the
crescent group are peculiarly resistant to the effects of the ad-
ministration of quinin, large doses of this drug having in many
instances no appreciable effect in causing their disappearance
from the peripheral circulation.
Crescents are of intracellular origin, being transformed stages
of the full-grown, pigmented, intracellular spherical bodies which
have not been involved in the process of segmentation. These
gamete forms continue their development within the corpuscle,
from which they derive more and more pigment, thus causing
progressive decolorization of their host, until finally all that re-
mains of the corpuscle is a thin shell surrounding the crescent.
As its growth progresses the parasite first loses its regular spheri-
cal contour, and then becomes drawn out into a long, narrow,
spindle-shaped body, which finally becomes bent in the shape
of a crescent, the convexity of which lies next to, and for some
distance parallels, one margin of the now almost colorless eryth-
rocyte.
Owing to the fact that the early development of the crescents
occurs almost exclusively in the deeper circulation, only the later
phases of their evolution are ordinarily observed in the peripheral
blood. In fresh blood they appear as highly refractive, crescent-
shaped-bodies, measuring about 6 or 8 /* from pole to pole, and
possessing a distinct double outline, as if they consisted of a central
darker body inclosed in a lighter colored membranous envelop.
Adhering to the concave surface of the crescent a more or less
distinct "bib," the remnant of the corpuscular host, may usually
be observed. It varies in color from pale yellow to an almost
indistinguishable shade of light lemon, yet it always, on close
observation, retains sufficient of the corpuscular color to distin-
guish it from the parasite to which it is attached. The "bib"
MALARIAL FEVER. 461
completely bounds the concavity of the crescent in some instances,
extending from pole to pole; in other instances — and this is of
commoner occurrence — it is of smaller size, extending over only
the central portion of the concavity. Occasionally crescentic
bodies totally devoid of all traces of their corpuscular host are
found, but these forms are rare. The pigment is usually arranged
in a moderately compact clump or wreath-like design, in the
center of the crescent; less commonly the granules are scattered
along the long axis; and very rarely a distinct polar grouping of
the pigment at both ends of the crescent is seen. The pigment
granules may or may not show active motility. In the fresh
specimen -it will be noted that in the male crescents the pigment
tends to collect centrally in an irregular mass, while ia the female
crescents it is generally arranged in the form of a wreath.
The ovoid bodies, which are simply transitional forms of the
crescents, are of symmetrically oval shape, and show the same
refractive protoplasm and apparently double outline observed in
the latter. The pigment, which is. generally motionless, is ar-
ranged in an elongated clump in the center of the ovoid, and a
partly decolorized, bib-like corpuscular attachment apparently
clings to one side of the body. The long diameter of the ovoid
body measures approximately 5 or 6 ,« and its short axis is. about
2 or 3 // across.
The round forms, derived from the crescentic and ovoid bodies,
are the direct antecedents of the flagellate organisms. They
appear as perfect spheres, 4 or 5 ft in diameter, either attached
to a more or less yellowish remnant of the erythrocyte or lying
entirely free. Their pigment is prone to form a central wreathed
or ringed design, or to be massed centrally..
The approach of flagellation is preceded by unusual activity of
the central pigment mass, coincidentally with which indications
of motility about the periphery of the parasite become apparent.
The flagella, which are finally seen to reach out from different
points on the periphery of the body, are similar in appearance to
those of the tertian and quartan organisms. Their size, however,
is about midway between that of these forms. Rarely, a free
flagellum may be seen to penetrate and fertilize a female gamete
(represented by one of the round non-flagellate forms), which
in consequence becomes actively motile, loses its spherical con-
tour, and exhibits violent agitation of its contained pigment.
Degenerative changes of the crescentic, ovoid, and round bodies
occur, being evidenced by the development of vacuoles and occa-
sionally by apparent fragmentation.
462 GENERAL HEMATOLOGY.
Pigmented leucocytes are found in the blood
PIGMENTED LEU- of all types of malarial infection, and this fact
COCYTES AND alone, irrespective of the presence of the parasites
PHAGOCYTOSIS, themselves, is an extremely valuable diagnostic
clue to the condition.
In tertian and quartan infections the large mononuclears and
polynuclear neutrophiles are the pigment-bearing cells, the gran-
ules being found scattered either in fine masses or in fused angular
blocks throughout the bodies of the leucocytes. Although both of
these forms of leucocytes show this evidence of having acted the
role of phagocytes, actual visual proof of the performance of this
function by the mononuclear forms is wanting. The phenomenon
of the phagocytosis by the polynuclear leucocytes may, however,
be watched in the fresh specimen, and these cells may be seen
to engulf bits of free pigment, flagellate bodies, bastard forms of
extracellular parasites, and even, rarely, true segmenting bodies.
Distinct periodicity characterizes the performance of phagocytosis
in tertian and quartan infections, this process being most con-
spicuous at the time of segmentation, during and shortly after
the paroxysm, when the extracellular forms of the organism are
present in the blood in greatest number. Phagocytosis is some-
times seen during the interparoxysmal interval, when only the
extracellular forms of parasites which have prematurely escaped
from their corpuscular host are attacked.
In estivo-autumnal infections macrophages, derived from the
spleen, bone marrow, liver, and blood vessel endothelium, act as
phagocytes, as well as the mononuclear and polynuclear cells,
which alone exercise this function in the regularly intermittent
fevers. Phagocytosis is much less periodical than in tertian and
quartan infections, for while it is true that pigmented leucocytes
are most numerous in the blood at the time of segmentation, it is
also true that they may be observed in great numbers during
the interval — a fact which is explained chiefly by the practically
continuous segmentation which goes on in these infections because
of the presence in the blood of multiple groups of the parasite.
Phagocytosis in estivo-autumnal fever differs from that of tertian
and quartan infections in that in the former inclusion of both
parasite and corpuscular host may occasionally be observed — a
phenomenon which does not occur in the latter. Thus, in addi-
tion to free pigment and extracellular, segmenting, and flagellate
forms, the phagocytic leucocytes are found also to contain whole
or portions of necrobiotic erythrocytes, some of the latter, perhaps,
inclosing parasites. Osier * has observed the phagocytosis of
^rit. Med. Jour., 1887, vol. i, p. 556.
MALARIAL FEVER.
463
V
crescentic forms, and the writer believes that he has seen the
result of this phenomenon in a single instance. (See Plate VIII,
Fig- 25.)
DIFFERENTIAL TABLE OF THE MALARIAL PARASITES.
TERTIAN PARASITE.
Cycle, Forty-eight Hours.
QUARTAN PARASITE.
ESTIVO-AUTUMNAL PARASITE.
Cycle, Seventy-two Hours.
Cycle, Twenty-four to Forty-
eight Hours or Longer.
Hyaline body larger than
that of quartan and esti-
vo-autumnal organisms;
outline indistinct; ame-
boid movements exceed-
ingly active; long pseu-
dopodia common.
Pigment granules fine,
very active, and of yel-
lowish brown color;
more or less peripher-
ally arranged.
Mature parasite about 7 //
in diameter.
Segmenting body consists
of from 15 to 30 seg-
ments, arranged in an
irregular racemose fig-
ure about one or more
central pigment clumps.
Hyaline body smaller than
that of tertian, but usu-
ally larger than that of
estivo-autumnal organ-
ism; outline distinct;
ameboid movements
slow, except in early
forms; marked pseudo-
podial branching un-
common.
Pigment granules coarse,
sluggish, and of - dark-
brown color; peripheral
arrangement striking.
Mature parasite about 5 fi
in diameter.
Segmenting body consists
of from 6 to 12 seg-
ments, arranged in regu-
lar rosette form about a
single, compact, centra]
pigment mass, the latter
often being radially
grouped in the early
stages of sporulation.
Hyaline body smaller
than that of tertian and
quartan organisms; out-
line very sharp and dis-
tinct; ameboid move-
ments active in early
stages; ring- and disc-
shaped forms.
Pigment granules ex-
ceedingly fine and
scanty; may be either
motionless or motile;
peripheral arrangement
often marked. '
Mature parasite from
1.5 to 7 ft in diameter.
Segmenting body consists
of from 1 8 to 20 or
more segments, ar-
ranged either as a
regular rosette or irreg-
ularly about a single
compactly fused cen-
tral pigment clump.*
Preflagellate form consists
of swollen, spherical
pigmented body as large
as 10 to 12 11 in diame-
ter.
Flagellate form larger than
that of quartan and
estivo-autumnal para-
site.
Preflagellate form consists
of swollen, spherical
pigmented body as large
as 6 to 8 n in diameter.
Flagellate form smaller
than that of tertian and
estivo - autumnal para-
site.
Erythrocyte becomes very Erythrocyte becomes dark
pale and swollen. and contracted.
Preflagellate form con-
sists of spherical pig-
mented body, 5 to 6 p
in diameter, and de-
rived from crescentic
and ovoid forms, with
which they are asso-
ciated.
Flagellate form smaller
than that of tertian,
but larger than that of
quartan, parasite.
Erythrocyte becomes
brassy and crenated.
464 < GENERAL HEMATOLOGY.
Technic of the Blood Examination. — For diagnostic purposes
the fresh, unstained blood film should be invariably preferred to
the dried, stained specimen, for in the latter not only are the ame-
boid movements of the parasite and the dancing of the pigment
necessarily lost, but much of the morphology and the finer struc-
ture of the organism is also greatly altered. The blood is obtained
in the usual manner, and a drop used which is small enough to
insure an exceedingly thin film, consisting of a single layer of
corpuscles, each lying edge to edge, so that every portion of their
flat surfaces may be readily searched for foreign bodies. Thick,
dehemoglobinized films are useful for the diagnostic examination
of blood in which the parasites are very scanty, but they are
unsuitable for accurate histological study. (See p. 77.) If the
examination is likely to be prolonged, it is advisable to ring the
cover-glass with cedar oil or with vaselin, to prevent crenation of
the corpuscles.
Dried blood films, prepared in the usual way, may be used in
case the specimens must be sent some distance for examination.
Such specimens must be stained with various anilin dyes, as already
directed. Polychrome methylene-blue, in the form of Wright's
or Goldhorn's solutions, gives the sharpest differentiation of the
parasite's histological structure, but solutions of thionin and of
eosin and methylene-blue also will prove useful. (See pp. 82
and 88.)
No magnification can be too great in studying the finer points
of the malarial parasite, so that a y^-inch oil-immersion objective,
with at least a i^-inch ocular, should be habitually employed for
the microscopical examination. While it is frequently convenient
to search for individual parasites with a ^~ or a £-inch lens, one
cannot well dispense with an immersion objective in distinguishing
their finer characteristics. The substage condenser and iris
diaphragm should be so adjusted that the field is dimly illuminated,
and not drowned in a flood of white light. When the ameboid
movements of the parasite are to be studied at length, a warm
stage is useful, but not essential, if the temperature of the room
is not too low.
The best time for the examination is a few hours before the
onset of the expected paroxysm, at which period it is common to
find full-grown pigmented organisms and often an occasional
segmenting form, if the specimen is from a tertian or quartan
infection. In estivo-autumnal fever relatively large ring- and
disc-shaped bodies, containing exceedingly delicate pigment gran-
ules, are usually abundant at this time. Intracellular hyaline
forms are most numerous in the blood a few hours subsequent to
the paroxysm in all three forms of the infection.
MALARIAL FEVER. 465
The writer would urge the beginner systematically to study the
development of a group of parasites by examining the blood of a
single case of malarial fever at frequent intervals between the
paroxysms. For example, the life history of the tertian parasite,
from the youngest hyaline amebula to the segmenter and the
flagellate body, may be traced in most cases of tertian fever if
the blood is examined every three or four hours, day and night,
for a period ~of forty-eight hours. Such a collated series of ob-
servations, although they entail close and tiresome application for
the time, will prove more profitable to the student in his compre-
hension of the organism's developmental cycle than dozens of
haphazard examinations made in many different cases at odd
times. ..
To the unpractised eye a number of artefacts occurring in
fresh blood specimens may for a time be confused with the malarial
parasite, but careful observation linked to an increased familiarity
with the appearance of the organism and of its counterfeits will
eliminate such sources of error. The fallowing are the principal
objects which" require to be differentiated from the malarial par-
asite: (i) The central biconcavity of the- normal erythrocytes ;
(2) morphological changes in the erythrocytes, and (3) hemokoniae.
1. At first glance the pale central biconcavity of the erythro-
cyte somewhat resembles the young hyaline tertian parasite, for
each has an indistinct outline which merges with the surrounding
corpuscular substance. But the parasite is rarely in the center of
the blood cell, it is actively ameboid, and it possesses a character-
istic pearly-gray appearance. On the other hand, the pale area
of the corpuscle is in the center of the normally shaped blood cell,
it never exhibits ameboid powers, and its appearance is clean
white or yellowish- white. It is, of course, uncolored in the stained
specimen.
2. The morphological changes in the erythrocyte, which may
be mistaken for malarial organisms, are those produced by vac-
uolization, crenation, and fragmentation of these cells. Vacuoles
appear as highly refractive, clean-cut, spherical bodies which
possess more or less oscillating, rotary motility, in contrast to the
dimmer, more vaguely outlined, truly ameboid forms of the hya-
line malarial parasite. The spicula of crenated red cells may
in a very dim illumination of the object appear at first glance
somewhat like the coarse granules of the mature pigmented par-
asite, but a change of focus and a wider-open diaphragm imme-
diately dispels the illusion. Fragmentation of the erythrocytes,
as the result of thermic influences, may produce a most bizarre
and peculiar variety of designs, the most confusing of which is a
3°
466 , GENERAL HEMATOLOGY.
sort of flagellate appendage which appears to originate in a frag-
mented sphere of corpuscular substance, to which it is attached.
The size of this body, however, is far too small to be mistaken
seriously for a true malarial flagellate body, for its spherical
portion, which is unpigmented and tinged with hemoglobin,
measures only about 2 p in diameter; while the flagellate ap-
pendage, usually single, is represented by a colorless, thin line
not often longer than 3 or 4 /.*, and tremulously motile, not ame-
boid like the flagellum of the malarial body. This sort of a
flagellate figure is very commonly seen in blood slides which have
become chilled.
3. Hemokonice are readily distinguished by their very small
size, spherical contour, and glistening, fat-like appearance. It
sometimes happens that one of these granules of "blood dust,"
in its Brownian excursion across the field of the microscope, lies
over the flat surface of an erythrocyte, simulating for the moment
a small, hyaline, intracellular parasite. It seems probable, also,
that one of these granules, observed just at the instant it crosses
the rim of the blood cell, has been mistaken for a hyaline spore
in the act of invading an erythrocyte, by those who believe that
they have witnessed this remarkable phenomenon. (See p. 452.)
Well-marked anemia, developing early during
HEMOGLOBIN the course of the disease, and proportionate in
AND degree to the severity of the attack, is a con-
ERYTHROCYTES. spicuous clinical sign in the malarial fevers.
Dionisi,1 Thayer,2 and other authors have ob-
served that a loss of hemoglobin and a diminution in the number
of erythrocytes occur after every paroxysm, this being due largely
to the destruction of immense numbers of parasite-containing cor-
puscles by the maturation of the organisms, and in part to the
presence in the blood of other substances destructive to the un-
invaded red cells. The loss is especially marked after the early
paroxysms, being of slighter degree after, those occurring later in
the course of the disease. On the other hand, during the paroxysm
a tendency on the part of the erythrocytes to increase in number
has" been noted.
The loss is more moderate in the regularly intermittent tertian
and quartan types of malaria than in the estivo-autumnal form.
In the former types, the regenerative powers of the blood are
usually prompt and vigorous, so that the normal number of cells
is almost restored by the onset of the succeeding paroxysm. It
is owing to this fact that repeated paroxysms must occur before
the anemia becomes striking.
1 Lo Sperimentale, 1891, f. iii and iv, p. 284. 2 Loc. cit.
MALARIAL FEVER. 467
In the estivo-autumnal form the loss is far greater, a decrease
of 500,000 or more corpuscles per c.mm. sometimes occurring
after a single paroxysm, so marked a loss as this being associated
especially with cases in which excessive numbers of parasites are
present in the blood. Even in non-febrile cases of larval malarial
fever Marchiafava and Bignami l have observed more or less
anemia. Organisms of the crescent group appear to exert no
influence in causing diminution in the number of erythrocytes.
Regeneration of the blood is slow in the estivo-autumnal fever,
so that the loss of hemoglobin and of corpuscles is not made up
during an interparoxysmal interval, in consequence of which more
marked and graver anemias are commoner than in the tertian
and quartan fevers. If the anemia is markedly developed during
the early stages of the infection, the corpuscular decfease is ag-
gravated slightly, if at all, by the following paroxysms.
In malarial hemoglobinuria an enormous destruction of cor-
puscles occurs, "a destruction," in the words of Thayer,2 "too
great, probably, to be dependent wholly on the disintegration of
parasitiferous elements. We are compelled ... to suppose
the existence of some condition which . renders the uninjected red
blood corpuscles unusually vulnerable, possibly some change in
the blood serum by which its isotonicity is markedly disturbed."
Usually the hemoglobin loss is relatively less than the cor-
puscular decrease, fairly high color indices being the general rule,
but in some cases both are parallel. In estimates made by the
author in 45 cases of malarial fever, nearly all of the tertian type,
the hemoglobin averaged 67 per cent, of normal, ranging, in the
individual case, from 19 to 97 per cent.
The variations in hemoglobin were as follows:
HEMOGLOBIN PERCENTAGE. NUMBER OF CASES.
From 90-100 2
80-90 12
70-80 ii
60-70 7
50-60 4
40-50 5
30-40 2
20-30 i
IO-2O I
Average, 67 per cent.
Maximum, 97
Minimum, 19
1 Loc. cit. 2 Loc. cit.
468 . GENERAL HEMATOLOGY.
The loss of corpuscles varies within wide limits, being most
marked in severe and in long-standing cases. Counts as low as
500,000 per c.mm. have been reported,1 and the number falls to
from 1,000,000 to 2,000,000 in a considerable proportion of cases.
In the above series the average of the 45 counts snowed 2,585,688
erythrocytes per c.mm., individual cases varying from 1,410,000 to
5,250,000. The range of the counts is shown thus, in tabular
arrangement :
ERYTHROCYTES PER C.MM. NUMBER OF CASES.
Above 5,000,000 2
From 4,000,000-5,000,000 22
3,000,000-4,000,000 8
2,000,000-3,000,000 8
1,000,000-2,000,000 5
Average, 2,585,688 per c.mm.
Maximum, 5,250,000 " "
Minimum, 1,410,000 "
In 7 cases clinically designated as "malarial cachexia," in
which parasites were not found in the circulating blood, the fol-
lowing results were obtained: hemoglobin ranged from 40 to 52
per cent., the average being 45.5; color index, from 0.41 to 1.13,
averaging 0.66; and erythrocytes, from 2,300,000 to 4,861,000
per c.mm., with an average of 3,406,250.
As regeneration of the blood, which is generally slow, takes
place, the normal percentage of hemoglobin is reached more
slowly that that of the corpuscles — in fact, in some instances of
post-malarial anemia subnormal hemoglobin percentages persist
for indefinite periods after convalescence has been established.
Histological changes in the erythrocytes are marked in relation
to the severity of the anemia. Pallor of the corpuscles is often
conspicuous, and poikilocytosis and deformities of size are present
in severe cases. In such instances small percentages of normo-
blasts and of atypical nucleated forms are not infrequently found,
sometimes in association with an occasional megaloblast. In
severe cases both polychromatophilia and basic granular degenera-
tion of the erythrocytes are familiar findings.
The peculiar "brassy" appearance of the erythrocytes (" globuli
rossi attonati" of the Italians) invaded by the estivo- autumnal
parasite has already been noted (p. 459).
In tertian fever, and only in this type of malaria, the infected
erythrocytes, when stained by Romanowsky's method, show
Schiiffner's granules, recognized as a reddish mottling of portions
of the cells not occupied by the parasites.
1 Kelsch, Arch. Physiol., 1875, vol. ii, p. 690; ibid., 1876, vol. iii, p. 490.
MALARIAL FEVER. 469
In estivo-autumnal fever the infected cells, when similarly
stained, show minute clefts and cracks and coarse, irregular areas
reacting basically. Stephens and Christophers x demonstrate these
signs of necrobiosis by staining chloroform-fixed films by the
Romanowsky method for one hour, and differentiate them from
the familiar basic stippling and the reddish Schiiffner's granules
of erythrocytes harboring the tertian parasite.
The following four types of post-malarial anemia are distin-
guished by Bignami and Dionisi.2
1. Anemias in which examination of the blood shows altera-
tions similar to those observed in secondary anemias, from which
they differ 'only in that the leucocytes are diminished in number.
The greater part of these cases go on to recovery; a few, without
any further change in the hematological condition, pursue a fatal
course.
2. Anemias in which the examination of the blood shows altera-
tions similar to those seen in pernicious anemia — prevalence of
megaloblasts. These cases end fatally.'
3. Anemias which are progressive as a result of the lack of
compensation by the marrow for losses brought about by the
infection. At autopsy the marrow of the long bones is found to
be wholly yellow, while the marrow of the flat bones is also, poor
in nucleated erythrocytes.
4. Chronic anemias of the cachectic, which differ from the
above-mentioned types by clinical and anatomical characteristics
in that the special symptoms of malarial cachexia prevail, while
one observes, postmortem, a sort of sclerosis of the bone marrow.
The marrow of the long bones is red and of an increased con-
sistency ; the giant cells are very numerous and many are necrotic ;
the nucleated erythrocytes are very rare, and the colorless poly-
nuclear corpuscles are present in small numbers.
Distinct leucopenia, or at least an absence
LEUCOCYTES, of leucocytosis, is almost invariably found in the
uncomplicated cases of malarial fever, the excep-
tions to this general rule occurring during the grave paroxysms
of the pernicious type of fever.
The subnormal range of the leucocytes in malarial fever was
early noted by Kelsch,3 and has been repeatedly confirmed by
other investigators since the former's statement of the fact. Bill-
ings,4 in particular, has carefully studied this question, and his
1 Brit. Med. Jour., 1903, vol. i, p. 730.
1 Centralbl. f. allg. Path. u. path. Anat., 1894, vol. v, p. 422. (Cited by Thayer
and Hewetson, "The Malarial Fevers of Baltimore," Baltimore, 1895, p. 58.)
3 Loc. cit. 4 Johns Hopkins Hosp. Bull., 1894, vol. v, p. 89.
4/0 GENERAL HEMATOLOC,Y.
examinations, 100 in number, show that the number of leucocytes
averaged 4323 per c.mm., or a decrease of about 38 per cent,
below normal. In 71 counts made by this reporter in 16 cases,
to determine the effects of the malarial paroxysms on these
cells, it was found that during the early part of the paroxysm their
number gradually increased, the maximum being reached, as a
rule,- two or three hours after the chill. Following this maximum
increase the number steadily and progressively decreased, hour by
hour, until the minimum was reached during the period of sub-
normal temperature, at the end of the paroxysm. During the
afebrile interval the number of leucocytes is distinctly subnormal,
but it rises slightly again just before the onset of the following chill,
so that the average count is slightly higher immediately before the
chill than during the rest of the interval.
In the author's series, above referred to, the average of 45
counts showed 5622 leucocytes per c.mm., the lowest count being
2000, and the highest 12,800. All these counts were made during
the interval between the paroxysms, in uncomplicated cases, so
far as it was possible to determine.
The counts ranged as follows:
LEUCOCYTES PER C.MM. NUMBER OF CASES.
Above 10,000 3
Between 8,000-10,000 9
" 6,000-7 8,000 9
4,000- 6,000 10
2,000- 4,000 14
Average, 5,622 per c.mm.
. Maximum, 12,800 " "
Minimum, 2,000 " "
In the 7 cases of "malarial cachexia" the number of leucocytes
to the c.mm. ranged from 4500 to 44,000, the average being 16,971.
Five of these cases had distinct leucocytosis, a condition believed
by Thayer to occur in some of the post-malarial anemias, usually
those following short-lived infections.
Relative lymphocytosis, sufficiently decided to become a striking
characteristic of the condition, is practically a constant qualitative
change. As a rule, the increase affects chiefly the large lympho-
cytes. Christophers and Stephens,1 in a study of "blackwater
fever," found that this type of cells often constituted 20 per cent.,
30 per cent., or even 50 per cent, of the total number of leucocytes;
furthermore, they state that this relative increase bears an inverse
relation to the temperature curve, being least marked during the
1 Lancet, 1901, vol. i, p. 848.
MALARIAL FEVER. 471
pyrexia and greatest during the periods of apyrexia. This feature
of the blood picture, which is of considerable importance, has
also been noted by Delarly,1 by Rogers,2 and by Daniels.3 The
percentage of eosinophiles is, as a rule, subnormal, and this variety
of cells K frequently absent ; more rarely they are slightly increased,
especially in some of the post-malarial anemias. Myelocytes in
small numbers are very commonly found, in the writer's experience,
especially in estivo-autumnal infections and in cases with pro-
nounced anemia. In 9 differential counts, made in cases of the
series above referred to, the relative percentages of the different
forms of leucocytes averaged as follows:
Small lymphocytes !5-33 per cent.
Large lymphocytes and transitional :*
forms J5-94 "
Polynuclear neutrophiles *. 67.00 "
Eosinophiles 0.83 "
Myelocytes % 0.51 "
Practically the same figures were obtained from the similar ex-
amination of 5 cases of anemia associated with malarial cachectic
conditions.
The blood plaques are greatly decreased in number, as in other
febrile conditions. They fail to agglutinate in both tertain and
quartan fevers, according to Zeri and Almazia,4 unless cinchoni-
zation is pushed sufficiently to antidote the infection. In. normal
blood and in the blood of various non- malarial fevers the plaques
clump together in masses just before and during the process of
clotting. Ducchesi's method may be used to show this phenom-
enon macroscopically. (See p. 199.)
The detection of the specific parasite in the
DIAGNOSIS, circulating blood is proof positive of malarial
fever, the exact type of which may be determined
by close study of the organism's peculiarities. Even if nothing
more definite than pigmented leucocytes is found, the evidence
is strongly in favor of some form of paludism. The progressive
anemia and the leucopenia involving a relative decrease in the
polynuclear neutrophiles are also valuable side-lights on the
diagnosis. An obscure intermittent fever which shows leucocy-
tosis is almost certainly not malarious.
The chills and pyrexia of sepsis and of tuberculosis are not in-
1 Brit. Med. Jour., 1903, vol. i, p. 725.
2 Ibid., 1902, vol. i, p. 827; also Lancet, 1903, vol. i, p. 1500.
3 Cited by Manson, Lancet, 1902, vol. i, p. 1377.
4 II Policlin., 1903, vol. ix, p. 485.
472 < GENERAL HEMATOLOGY.
frequently misinterpreted as symptoms of malarial fever. In
septicemia leucocytosis is usually found, but even should the
leucocytes not be increased in number, they fail to show the
relative lymphocytosis of malarial blood. In pure tuberculosis
the blood picture of malaria may be counterfeited, in so far as the
quantitative and qualitative leucocyte changes are concerned, and
in such instances the parasite must be demonstrated to settle the
diagnosis.
Enteric fever, like malaria, shows anemia, an absence of leuco-
cytosis, and relative mononucleosis. But in typhoid the small
lymphocytes are increased, while in malaria the large mononuclear
forms are in excess. Minor points of difference are the more
rapid onset of the anemia, the greater frequency of decided leuco-
penia, and the tendency toward higher percentages of myelocytes
in malaria. The pertinence of positive examinations for the
specific parasite and for the serum reaction is obvious. It may be
added that in those rare instances of coincident typhoid and malaria
•the blood of the same individual may contain malarial parasites
and give a positive serum reaction with the Eberth bacillus. In
such cases blood cultures prove the presence of the typhoid in-
fection.
XLIV. MALIGNANT DISEASE.
CARCINOMA.
There is no deviation from normal in the
GENERAL coagulability and the amount of fibrin, except in
FEATURES. * the event of ulcerative and inflammatory changes
affecting the tumor, but, should these conditions
be present, coagulation may occur with abnormal rapidity, and
the density of the fibrin network almost invariably increases.
The specific gravity may or may not be subnormal, according to
whether or not the percentage of hemoglobin, which it parallels,
is reduced. The alkalinity of the blood is almost always decreased
in gastric cancer, according to Krokiewicz.1
Relatively large amounts of sugar (as high as 3 parts per
1000) have been found in the blood of patients suffering from
various forms of carcinoma, especially visceral cancer, in contra-
distinction to more superficial growths, involving, for example, the
skin and mucous membranes. In no other disease except diabetes
has more than one-third of the above-named quantity of sugar been
detected in the blood, according to the analyses made by Trinkler.2
1 Arch. f. Verdauungskr., 1900, vol. vi, p. 25.
2 Centralbl. f. d. med. Wissensch., 1890, vol.
xxviii, p. 498.
MALIGNANT DISEASE. 473
Examination of the blood for the detection of a specific parasite
of cancer has thus far proved unconvincing, although much care-
ful work has been done with this purpose in view. None of the
many bacteria exploited as the cause of cancer has fulfilled Koch's
law, and many of them have been shown to be artefacts. The
protozoan theory of cancer, defended chiefly by Ruffner,1 Gaylord,2
and Feinberg,3 has been criticized on the grounds that the so-called
protozoa found in the neoplasms are nothing more than cell in-
clusions and degenerations. The same stricture has been urged
against the theory advocated by Russell,4 Sanfelice,5 and Plimmer,6
who interpret the factor of cancer as a yeast fungus. The careful
studies of 33 cases of cancer by Maragliano7 have apparently dis-
proved the statements of a number of authors, who claimed to have
cultivated blastomycetes from the circulating blood in' this disease.
During its incipiency carcinoma gives rise to
HEMOGLOBIN practically no changes in the erythrocytes or their
AND hemoglobin content, or, at the most, causes simply
ERYTHROCYTES. a moderate diminution in the latter. As the
disease progresses' and extends, and as the
cachexia of the patient becomes more pronounced, a secondary
anemia develops, attaining but a moderate degree in some
instances, but in others becoming so extreme as to simulate in
some particulars true pernicious anemia. The anemia of- cancer
differs from other forms of secondary anemia in stubbornly
persisting, or at the most improving but slightly, under treatment.
Since the hemoglobin loss usually anticipates the cellular decrease,
the blood picture of early cancer not infrequently .resembles that
of chlorosis. Later, however, these conditions may be reversed,
so that the index rises. In the author's experience, the average
hemoglobin loss has amounted to about 33 per cent., and the
erythrocyte decrease to about 22 per cent., of normal. The color
index tends to range moderately below normal, usually from
20 to 30 points below the standard of health. It averaged 0.86 for
the 145 cases grouped below. As just intimated, it is generally
lower in the early than in the late stages of the disease. In oper-
ative cases of carcinoma it has been observed that the regeneration
time of the hemoglobin averages at least two-thirds longer than in
1 "Sur les Parasites des Tumeurs Epithe"liales Malignes," 1896.
2 Amer. Jour. Med. Sci., 1901, vol. cxxi, p. 503.
1 " Das Gewebe und die Ursache der Krebsgeschwiilste," 1903.
4 Brit. Med. Jour., 1900, vol. ii, p. 1356.
5 Zeitschr. f. Hyg. u. Infektionskr., 1898, vol. xxix, p. 463.
8 Practitioner, 1899, vol. bcvii, p. 430.
7 Gaz. degli Ospedali e. d. Clin., 1900, vol. xxi, p. 1538; also Sem. me"d., 1901,
vol. xxi, p. 63.
474 < GENERAL HEMATOLOGY.
other diseases treated surgically, and that the loss of hemoglobin
after operation is usually not less than 15 per cent. Bierfreund1
finds that the percentage of hemoglobin after the removal of the
tumor never equals that found before the operation.
The oligocythemia is occasionally most striking, for in some
cases the counts may range as low as between 1,000,000 and
2,000,000, such a degree of decrease apparently being most com-
monly found in septic cases and in gastric cancer. F. P. Henry's
statement2 that he has never seen a case of the latter disease in
which the erythrocytes fell below 1,500,000 to the c.mm. has been
generally corroborated, although counts below this figure have been
occasionally reported. In one of the cases of cancer of the stomach
included in the table given below the count was 1,001,000 per
c.mm., and the hemoglobin percentage 50; in another case the
count was 1,240,000 and the hemoglobin 56 per cent.
Polycythemia may occur as a temporary condition in gastric
and esophageal cancer, as the result of blood concentration due
to vomiting, to diarrhea, or to lack of ingested fluids. In such
instances the number of erythrocytes not uncommonly exceeds
6,000,000 or 7,000,000 per c.mm., and, exceptionally, even a
higher figure.
The following table illustrates the alterations in the amount
of hemoglobin and number of erythrocytes, as determined by
the examination of 145 cases of various forms of carcinoma:
HEMOGLOBIN NUMBER OF ERYTHROCYTES NUMBER OF
PERCENTAGE. CASES. PER C.MM. CASES.
From 90-100 5 Above 5,000,000 13
" 80- 90 30 From 4,000,000-5,000,000 ..66
" 70- 80 32 " 3,000,000-4,000,000 ..39
" 60- 70 29 " 2,000,000-3,000,000 ..18
" 50- 60 21 " 1,000,000-2,000,000 .. 9
" 40- 50 12
" 30- 40. . . .10
" 20-30 4
" IO- 2O 2
Average, 67.0 per cent. Average, 3,897,923 per c.mm.
Maximum, 94.0 " " Maximum, 5,900,000 " "
Minimum, 12.0 " " Minimum, 1,001,000 " "
In gastric cancer Osier and McCrae3 report an average of 49.9
per cent, of hemoglobin in 52 cases, and an average erythrocyte
1 Langenbeck's Arch., 1890-91, vol. xli, p. i.
2 Arch. f. Verdauungskr., 1898, vol. iv, p. i.
3 "Cancer of the Stomach," London and Philadelphia, 1900, p. 115.
MALIGNANT DISEASE. 475
count of 3,712,186 in 59 cases. In two cases the count was less
than 1,500,000. An average color index of 0.63 was found in
this series. The author, in a series of 46 cases, found the anemia
less decided, as shown by these averages: hemoglobin, 67.5 per
cent; erythrocytes, 4,020,978; color index, 0.84. Lang1 finds that
the isotonicity of the erythrocytes is increased in this disease,
and this change he attributes to the organism's attempt to
combat some obscure hemolytic agent peculiar to the cancerous
process.
Deformities of shape and of size are marked in relation to the
grade of the anemia which exists. Poikilocytes may be quite as
numerous- and as striking as in true pernicious anemia, while the
alterations affecting simply the size of the cells tend toward micro-
cytosis rather than megalocytosis. Polychromatophih'a and baso-
philic degenerative changes are frequently to be seen in grave
cases with marked cachexia.
Erythroblasts are very common, especially in cancer with
decided cachexia and high-grade anemia, but their occurrence is
by no means limited to such cases, as they may also be found in
blood which shows but trifling quantitative deterioration. It may
be stated as an accepted fact that nucleated erythrocytes occur in
cancer more frequently than in any other variety of secondary
anemia, except that accompanying sarcoma.
Normoblasts are generally found to the exclusion of other
forms, although in an exceptionally grave case an occasional
megaloblast and atypical "mesoblast" may be encountered. The
important point to be remembered is that cells of the adult, normo-
blastic type invariably predominate, since megaloblasts, when
present, are never so numerous as normoblasts.
Leucocytosis is a frequent but not a constant
LEUCOCYTES, feature of the blood picture in carcinosis, for
more cases are encountered in which the number
of leucocytes is normal than those in which an increase prevails.
Judging from the statistics of patients treated in the German Hos-
pital, leucocytosis is present in less than one-third of all forms
of cancer, or in 31 per cent. In general terms, it may be said
that tumors characterized by active inflammatory changes, by
hemorrhage, by rapid growth, or by extensive metastases are
accompanied by a well-marked leucocyte increase, while non-
inflammatory, slowly developing, localized tumors do not raise
the count. Thus, a large carcinoma of the liver or kidney, for
instance, may cause a leucocytosis of 30,000 or 40,000 to the c.mm.,
while a small, limited skin cancer may exist without provoking
1 Zeitschr. f. klin. Med., 1902, vol. xlvii, p. 153.
476
GENERAL HEMATOLOGY.
the slightest increase. Thorough extirpation of the growth is
followed by a decline in the leucocytosis, the normal count being
reached by the time the wound has entirely healed. Hayem1 is
the authority for the statement that in mammary cancer recurrence
of the growth after its removal may be detected by a reappearance
of the leucocytosis, which antedates ah1 other physical signs. The
constancy of this change, as well as the question of its occurrence
in cancer involving other structures, still remains to be investigated.
It seems reasonable to attribute the origin of cancer leucocy-
tosis chiefly to the presence of inflammatory changes and to hemor-
rhage in the tissues in the neighborhood of the growth, although
in some instances it seems possible that positive chemotaxis may
be excited by the absorption of toxins derived from the breaking
down of the neoplasm itself. . The strength of the patient's powers
of resistance as a determining factor of the increase must also be
taken into account in this as in other diseases.
In the writer's experience, leucocytosis is most constant and
most striking in cancer of the liver, least frequent in cancer of
the uterus, and least conspicuous in cancer of the stomach. In
cancer of the esophagus absence of leucocytosis is the rule, while
in many cases a decided leucopenia may exist. Skin cancers,
unless ulcerated and inflamed, do not raise the count.
The 145 cases on the study of which the above observations
are based may be summarized as follows :
ri w
W .
s
s .
SEAT OP
pq t/3
NUMBER AND PERCENTAGE
||
P H
S z
a z
GROWTH.
Is
OF CASES WITH LEUCOCYTOSIS.
fa
< °
Stomach .
69
17 or 24.6 per cent.
7,858
23,400
I, COO
Uterus . .
22
3 " 13-6 " 11,225
24,000
3,200
Rectum .
15
4 " 26.6 "
9*650
16,000
6,000
Breast . .
18
6 " 33.3 " 10,163
31,500
5,200
Liver . . .
IO
8 " 80.0 "
17*549
40,800
8,000
Bowel -. .
7
5 " 71-4 "
11,185
16,300
7,000
Pancreas
4
2 " 50.0 " 10,850
18,200
6,660
As compared with the above, this summary of Cunliffe's 71
cases2 shows a decidedly higher leucocyte average and range :
1 Loc. tit. 2 Med. Chronicle, 1903, vol. xxxviii, p. 333.
MALIGNANT DISEASE.
477
SEAT OF GROWTH.
NUMBER OF
CASES.
AVERAGE
COUNT.
MAXIMUM
COCNT.
MINIMUM
COUNT.
Stomach
10
17,280
36 800
s, 200
Uterus. . -
8
22,800
£.0,200
7 ooo
Rectum
10
12 780
20,200
6,800
Breast ,
18
11,400
24,800
7,800
Esophagus
IT,
13,700
3Q,8oo
10,000
Tongue
12
13,400
24,800
7 800
In cancer of the stomach digestion leucocytosis is usually,
though by no means invariably, absent. The frequency with
which this -phenomenon is absent is shown by the following com-
pilation of the data of various authorities who have studied this
question :
AUTHOR.
NUMBER
OF CASES.
ABSENT.
PRESENT.
»
Hoffman
24
21
7
Osier and McCrae
22
12
IO
Cabot : .
2O
IO
i
Schnever
18
18
o
Capps
17
1C
2
Krokiewicz
17
i^
4
Douglas
II
6
e
Hartung
IO
IO
o
Muller
5
o
144
119 :•
25
These figures, referring to 144 cases, show that digestion leu-
cocytosis is absent in 82.6 per cent, of gastric carcinomata. But
the presence of the phenomenon in practically one case out of
five is sufficient to weaken materially the former belief that ab-
sence of digestion leucocytosis is a diagnostic sign of this disease.
Furthermore, it has also been shown by Hoffman 1 and others
that the sign may be absent in a number of other diseases of the
stomach, as well as in some apparently healthy individuals.
Rencki,2 from an investigation of 15 cases, concludes that the
digestion leucocytosis of gastric cancer, when present, averages
an increase of 3500 cells, and that this acme is reached the third
or fourth hour after taking food.
Differential counts usually show percentages of polynuclear
neutrophiles ranging between 80 and 90, with a corresponding
decrease in the large and small lymphocytes, in cases with leu-
cocytosis, and not infrequently also in those without. This
1 Zeitschr. f. klin. Med., 1898, vol. xxxiii, p. 460.
1 Arch. f. Verdauungskr., 1901, vol. vii, pp. 234 and 392.
478 * GENERAL HEMATOLOGY.
change is not to be considered constant, since relatively high
percentages of lymphocytes, especially of the large variety, have
occasionally been observed. The eosinophiles are usually de-
creased, or, indeed, they may be absent in cases with pronounced
leucocytosis; in a certain proportion of cases, in spite of the ab-
normally high leucocyte count, their relative percentage remains
within the limits of health. Myelocytes are extremely common,
small 'numbers of these cells (usually not higher than a fraction
of one per cent.) occurring in at least a majority of all cases of
cancer. In cancer with bone metastases these cells are much
more abundant. (See p. 259.) The presence of a few basophiles
is sometimes to be noted, particularly often in association with
conspicuously high leucocytoses.
SARCOMA.
The changes affecting the fibrin, the rate of
GENERAL coagulation, and the specific gravity of the blood
FEATURES, are similar to those prevailing in cancer, and
therefore require no further mention.
In contrast to the hyperglycemia of carcinoma, the researches
of Trinkler, previously referred to, tend to show that in sarcoma
no increase above normal in the amount of sugar in the blood can
be detected. Bacteriological examinations of the blood have thus
far given no definite results.
Loeper and Louste * report having found sarcoma cells in the
blood of three cases of sarcoma, one affecting the neck, one the
shoulder, and one being a general sarcomatosis. These observers
centrifugalized a mixture of 20 drops of finger blood and 15 c.c.
of a one per cent, aqueous solution of acetic acid, and detected
in the resulting sediment cells precisely similar in morphology and
other biological characteristics to those of the neoplasms in ques-
tion. In carcinoma, on the contrary, specific cytological findings
in the blood were absent. These experiments, if substantiated,
should be of signal value in the diagnosis of deep-seated sarcomata.
They -tend also to corroborate the belief that sarcoma, but not
cancer, spreads by the blood stream.
The changes in the hemoglobin and erythro-
HEMOGLOBIN cytes are not materially different from those found
AND in cancer, for the genesis of the blood deteriora-
ERYTHROCYTES. tion is doubtless similar in all forms of malignant
disease. Some authors believe that the anemia
tends to reach a higher degree in sarcoma than in carcinoma,
but the truth of this contention certainly does not appear to be
1 Sem. med., 1904. vol. xxiv, p. 36.
MALIGNANT DISEASE. 479
indisputably established. In the writer's experience, the intensity
of the anemia is practically similar in both these forms of neo-
plasms, or, if anything, somewhat more striking in cancer, both
individually and on the average. In a series of 34 cases of sarcoma
the following data were obtained:
HEMOGLOBIN NUMBER OF ERYTHROCYTES NUMBER OF
PERCENTAGE. CASES. PER C.MM. CASES.
Above 100 i Above 5,000,000 5
From 90-100 i From 4,000,000-5,000,000. . 13
" 80-90 8 " 3,000,000-4,000,000. .12
" 70-80 6 " 2,000,000-3,000,000.. 3
" 6o-L7o 6 " 1,000,000-2,000,000.. i
" 50-60 6
40-50 4
30-40 i
20-30 i
Average, 65.5 per cent. Average, 3,962,705 per c.mm.
Maximum, 101 Maximum, 5,400,000 "
Minimum, 25 Minimum, 1,400,000 "
Poikilocytes, microcytes, megalocytes and atypically stained
cells are common in cases with pronounced anemia, and in such
instances erythroblasts, the majority of which are always hormo-
blasts, are also to be looked for.
Leucocytosis, while inconstant in sarcoma, is
LEUCOCYTES, without doubt more frequently associated with
this lesion than with carcinoma. -Statistics have
also been advanced to demonstrate that the counts range higher
than in cancer, but the cases on record ^are still far too few to
warrant this conclusion. The behavior of the leucocytes in both
forms of malignant disease is probably influenced by the same
group of factors. In the cases summarized in this series, leuco-
cytosis was found in 45 of the 145 carcinomata, or in 31 per
cent., and in 20 of the 34 sarcomata, or in 58.8 per cent. In the
latter the counts varied as follows :
LEUCOCYTES PER C.MM. NUMBER OF CASES.
From 30,000-40,000 i
" 20,000-30,000 2
" 15,000-20,000 5
10,000-1 5,000 13
5,000-10,000 13
Average, 12,282 per c.mm.
Maximum, 40,000 "
Minimum, 5,000 "
480 GENERAL HEMATOLOGY.
The increase usually involves a large absolute and relative
gain in the polynuclear neutrophiles at the expense of the lympho-
cytes, although in an occasional instance the latter reach a dispro-
portionately high percentage, while the former decline to a sub-
normal figure. It may be added that either of these differential
changes may also occur in the absence of an increase in the total
number of leucocytes. The percentage of eosinophiles is usually
subnormal, and not infrequently these cells may be searched for
in vain. Rarely, marked eosinophilia has been reported in sar-
comata with bone metastases, but such findings are by no means
constant. Decided myelemia (as high as 10 or 15 per cent.),
according to Kurpjuweit,1 may develop as the result of the altered
hemogenesis excited by invasion of the bone marrow by malignant
tumors. In all forms of sarcoma small numbers of myelocytes are
to be observed as frequently as not, these cells being about as
common and as numerous as they are in cancer — a remark which
is also true of basophiles.
The clinical resemblance between certain
DIAGNOSIS, forms of malignant disease (especially those in
which the lesion remains obscure or undemon-
strable) and pernicious anemia is often very close, on account of
the striking degree of cachexia apparent in both. But the blood
changes found in these two conditions, although similar in some
respects, are sufficiently characteristic to afford the necessary
diagnostic clue. These differences, already referred to in a pre-
ceding section, may, for the sake of emphasis, be expressed as
follows :
Malignant Disease. Pernicious Anemia.
Color index usually moderately Color index almost always
low. high.
Oligocythemia usually marked. Oligocythemia invariably ex-
treme.
Tendency toward microcytosis. Tendency toward megalocy-
tosis.
Erythroblasts common, normo- Erythroblasts constant, mega-
blasts always predominating. loblasts always predominat-
ing.
Leucocytosis common. Leucocytosis rare.
Lymphocytosis rare. Lymphocytosis common.
It is to be noted that of the above changes, but one is charac-
teristic— the invariable predominance of megaloblastic cells in
1 Deutsch. Arch. f. klin. Med., 1903, vol. Ixxvii, p. 553.
MALIGNANT DISEASE. 481
•
pernicious anemia and their minority or absence in those cases of
malignant disease in which nucleated erythrocytes are found.
Should a doubt arise as to whether a tumor is benign or malig-
nant in character, the fact is to be remembered that the presence
of a persistent leucocytosis, especially if accompanied by anemia,
is decidedly in favor of its malignancy. Should it be necessary
to distinguish between a malignant growth and an obscure pus
focus with sepsis, the blood examination, aside from culturing, is
useless, since both leucocytosis and hyperinosis may or may not
exist in either condition; if, however, bacteriological findings are
positive, the existence of a septicemia is obvious.
As a means of differentiating carcinomata and sarcomata, the
chemical examination of the blood for sugar should pr.ove of the
greatest clinical value, if further research substantiates the claims
made that hyperglycemia is constant in the first, and absent in
the second, type of neoplasms.
As a means of distinguishing gastric cancer from gastric ulcer
the blood count is, unfortunately, of doubtful utility. The pres-
ence of a persistent, well-marked leucocytosis is a very significant
sign of cancer, since in ulcer the count- is not increased except
as the result of hemorrhage, perforation, or digestion. On the
other hand, an absence of leucocytosis is of no value in determin-
ing which condition is present, owing to the fact that no increase
occurs in a large proportion of stomach cancers. Tuffier,1 who
found that tumors of epithelial origin cause mononucleosis, con-
tends that it is possible by this sign to differentiate gastric cancer
and ulcer. This observation was not confirmed by Monisset and
Tolot,2 whose studies show that it is impossible to take the differ-
ential count as a criterion of diagnosis. Recent investigations
have fully corroborated Lowit's view that the absence of diges-
tion leucocytosis in gastric cancer has about the same diagnostic
value as the absence of hydrochloric acid and the presence of lactic
acid.
The chief points of distinction in the blood pictures associated
with the two diseases in question are illustrated by this table :
Gastric Cancer. Gastric Ulcer.
Anemia usually marked. Anemia usually moderate, ex-
Erythroblasts common. cept after hemorrhage.
Leucocytosis common. Erythroblasts rare.
Absence of digestion leucocy- Leucocytosis rare.
tosis the rule. Absence of digestion leucocy-
tosis the exception.
1 Presse med., 1901, vol. viii, p. 246. 2 Rev. de med., 1902, vol. xxii, p. 844.
482 GENERAL HEMATOLOGY.
If the diagnosis lies between carcinoma, amyloid disease, and
gumma of the liver, the presence of a leucocytosis suggests the
first; should' it lie between cancer and hypertrophic cirrhosis of
the liver, high leucocytosis (30,000 or more) is strongly in favor
of the first, since although the leucocytes may be increased moder-
ately in this variety of cirrhosis, they do not reach a strikingly
high -figure. In an instance of cancer versus echinococcus cyst of
the liver a high eosinophilia strongly argues the latter condition.
Hyperinosis, if present, is also a sign suggestive of cancer, rather
than of these other liver diseases.
XLV. MALIGNANT ENDOCARDITIS.
The blood changes in malignant or ulcerative
GENERAL endocarditis are essentially those- of a grave sep-
FEATURES. ticemia, described elsewhere, and do not, there-
fore, require extended consideration in this place.
According to the studies of Grawitz,1 Kraus,2 Sittman,3 Kiih-
nau,4 James and Tuttle,5 Thayer and Lazear,8 and others, the
chances of securing definite results from bacteriological examina-
tion of the blood are good in this disease. An analysis of these
authors' work shows that various micro-organisms, notably pneu-
mococci, gonococci, streptococci, and staphylococci, are demon-
strable by culture of the peripheral blood with great frequency.
The loss of hemoglobin and erythrocytes is
HEMOGLOBIN likely to be marked, and, in acute cases, ex-
AND * tremely rapid and often most excessive — some-
ERYTHROCYTES. times as great as in typical pernicious anemia.
Structural degenerative changes are common, as
in any severe anemia, and in many acute cases hemoglobinemia
may be observed. As a rule, the loss of hemoglobin and eryth-
rocytes is not markedly disproportionate, so that moderately
subnormal color indices are commonest.
The following counts, by Dr. Uhle, of a profoundly septic
patient at the German Hospital, illustrate the striking degree of
anemia, as well as the intermittent and moderate leucocytosis
which may develop in a grave case:
1 Charite-Annal., 1894, vol. xix, p. 154.
2 Zeitschr. f. Heilk., 1896, vol. xvii, p. 117.
3 Deutsch. Arch. f. klin. Med., 1894, vol. liii, p. 323.
4 Zeitschr. f. Hyg. u. Infektionskr., 1897, vol. xxv, p. 492.
6 Med. and Surg. Report of the Presbyterian Hosp., New York, 1898, vol. iii,
p. 44.
8 Jour. Exper. Med., 1899, vol. iv, p. 81.
MALIGNANT ENDOCARDITIS.
483
DATE.
HEMOGLOBIN
PERCENTAGE.
ERYTHROCYTES.
PER C.1CM.
LEUCOCYTES
PER C.IfM.
1 1— 4— OO
7O
I.CQO.OOO
8,000
II— 8-QQ...
26
I 243,000
8,400
II— II— QQ...
3O
2,010,000
12,800
II—l6—QO...
28
1,810,000
8,000
II— 2O— QQ.. .
IQ
2,130,000
14,000
II— 2?— QQ--.
24.
2,170,000
12,800
12— I— OQ...
2C
1,710,000
9,600
12— C,— QQ...
je
2,7?O,OOO
16,000
12— 16— QQ.. .
4.1
7,? 10,000
7.2OO
1 2—2 7— OO . . .
76
2.75O.OOO
4.800
I— C.— OO. .
CO
3.7.CO.OOO
8,000
I— II-OO ."
^8
2,760,000
4,000
An increase in the number of leucocytes, more
LEUCOCYTES." commonly moderate than marked, and character-
ized by a high percentage of polynuclear neutro-
philes, is the usual finding, except in profoundly septic patients,
in whom the count may be normal or subnormal during the
greater part of the illness, as shown 'by the above table. Ab-
sence of leucocytosis is not infrequent in this disease, doubtless
because in a large proportion of cases the depressant effe.cts of
the poison predominate. In no other infection is a better illus-
tration offered of the relationship between the behavior of the
leucocytes, the intensity of the disease, and the patient's powers
of reaction. Occasionally, a striking preagonal increase develops,
or, on the contrary, death may be ushered in by a decided leuco-
penia.
In many instances the diagnosis of malignant
DIAGNOSIS, endocarditis is materially facilitated by the blood
examination, and in some it can be made only
by this means. A positive result from blood culturing at once
gives a definite clue to the real character of the disease, and this
procedure should be undertaken in every doubtful case. Malig-
nant endocarditis with marked constitutional symptoms is perhaps
most frequently confused with enteric fever and occasionally with
malarial jever. Both of these infections may be excluded if a
leucocytosis exists, unless, of course, this sign is obviously due
to some complication. It should also be remembered that in
malignant endocarditis the anemia develops early and tends to
attain a marked degree with great rapidity, while in the other two
fevers it does not become striking until the post-febrile stage of
the disease is reached. No comment is necessary on the value
of obtaining a positive serum reaction or of detecting the malarial
parasite as a means of distinguishing this trinity of infections.
484 GENERAL HEMATOLOGY.
XL VI. MALTA FEVER.
Most cases are accompanied by a moderate, progressive second-
ary anemia, becoming most marked at about the end of the febrile
period, and involving, according to Bruce,1 an average loss of
about 1,500,000 erythrocytes to the c.mm. The most severe
anemia is found in cases complicated by profuse epistaxis and by
hemorrhage from the bowel, but those in which these symptoms
are absent may show simply a slight oligochromemia, as demon-
strated by a case studied by Musser and Sailer.2 Bassett-Smith3
found that the average erythrocyte loss ranges between 20 and 40
per cent, below the normal standard, and that the hemoglobin
deficiency is relatively greater. In severely cachectic patients he
noted a decided increase in the number of plaques, together with
poikilocytosis, a tendency toward microcytosis, but never nucleated
erythrocytes. This observer also has determined that the pha-
gocytic powers of the leucocytes are diminished and the bactericidal
properties of the blood lowered in this infection. Frank leucocy-
tosis does not develop, except as the result of hemorrhage, but
occasionally the number of leucocytes is slightly increased —
to about 12,000 or 13,000 per c.mm. Charles4 states that during
the acute stages of the infection he has found a notable relative
increase in the large lymphocytes. In Bassett- Smith's cases the
percentage of mononuclear leucocytes ranged from 26 to 76, the
polynuclear neutrophiles being relatively diminished. Counts
higher than 6600 were not found.
Bassett- Smkh 5 cultured the Micrococcus melitensis from the
peripheral blood in all cases during the early stages and in severe
pyrexial relapses, thus confirming the earlier findings of Gilmour,
Shaw, and Zammit.6 In the finger blood of a case clinically
identical with Malta fever Manson7 found spirilla similar to, yet
differing somewhat from, the Spirillum obermeieri. Wright and
Smith8 found that the blood serum of patients suffering from
Malta fever clumps Bruce's micrococcus but produces no aggluti-
nation of the Bacillus typhosus. The diagnostic value of this
serum test in differentiating Malta and enteric fevers has since
been corroborated by the reports of Aldridge,9 Musser and
1 Brit. Med. Jour., 1889, vol. i, p. 1101.
2 Phila. Med. Jour., 1898, vol. ii, p. 1408.
3 Brit. Med. Jour., 1902, vol. ii, p. 861.
4 Ibid., 1898, vol. ii, p. 607.
4 Ibid., 1904, vol. ii, p. 325.
"Cited by Bruce, ibid., 1904, vol. ii, p. 323.
7 Ibid., 1904, vol. i, p. 538.
8 Lancet, 1897, vol. i, p. 656. 3 Ibid., 1898, vol. i, p. 1394-
MEASLES. 485
Sailer,1 Kretz,2 Cox,3 Bassett-Smith,4 Craig,5 and others. A
i : 50 dilution with a thirty-minute time limit appears to give the
most satisfactory results, but in many instances prompt reactions
occur with dilutions of from i : 100 to i : 250. (See p. 444.)
XL VII. MEASLES.
The amount of fibrin is either normal or de-
GENERAL creased, except in the event of a marked inflam-
FEATURES. matory complication, which may produce hyper-
inosis. The blood plaques are decreased in num-
ber during the febrile period.
A peculiar bacillus has been isolated from the blood of 6 cases
of measles by Arsamaskoff,8 but specificity is not unreservedly
claimed for it. Zlatogoroff7 has -also cultured a novel bacillus
from the blood in 1 7 of 24 cases, the organism in question closely
resembling that isolated from the secretions of the eye and nose.
Protozoa of undetermined character, have been detected in the
blood by Weber.8
The hemoglobin and erythrocytes are prac-
HEMOGLOBIN tically unchanged in typical cases. When a de-
AND crease does occur, it is trifling, amounting .at the
ERYTHROCYTES. most to a loss of from 250,000 to 500,000 cor-
puscles, and of about 15 or 20 per cent, of hemo-
globin. The great majority of cases have counts of 5,000,000
cells to the c.mm. Qualitative changes in the erythrocytes are
absent.
In the uncomplicated case of measles the
LEUCOCYTES, number of leucocytes is .either normal or sub-
normal. The latter change is very common, the
decrease of leucocytes being most marked at the height of the fever
during the stage of eruption, and their number again reaching nor-
mal coincidentally with the fading of the eruption and the begin-
ning of desquamation. The count may fall to 3000 or 4000 per
c.mm. during the period of maximum temperature. Combe9
believes that leucopenia is constant in all uncomplicated cases,
and that the diminution in the number of cells amounts to at
1 Loc. cit. 2 Lancet, 1898, vol. i, p. 221.
3 Phila. Med. Jour., 1899, vol. iv, p. 491. 4 Loc. cit.
6 Amer. Jour. Med. Sci., 1903, vol. cxxv, p. 105.
8 Amer. Year-book of Med. and Surg., 1900, p. 317.
7 N. Y. Med. Jour., 1904, vol. Ixxx, p. 419.
8 Centralbl. f. Bakt. u. Parasit., 1897, vol. xxi, p. 286.
* Arch, de med. des Enf., 1899, vol. ii, p. 345.
486 GENERAL HEMATOLOGY.
least one-half the normal number; he finds that the decrease begins
during the last two days of the invasion period, and persists
through the stage of exanthem. The first two days of the invasion
period, however, are characterized by a moderate leucocytosis,
chiefly involving, according to Renaud,1 the polynuclear neu-
trophiles. This author, as well as Combe, also found a striking
degree of relative lymphocytosis, first developing during the early
days of the eruption. All cases, however, do not show this in-
crease in mononuclear forms, for in some the relative percentages
of the different varieties of leucocytes remain as in health. Cases
with decided adenitis and those with persistent diarrhea most
frequently show this lymphocyte increase. The eosinophiles are
usually either diminished or else entirely absent during the feb-
rile'period of the disease; occasionally they reach a high normal
standard, but are not increased, as in scarlet fever. Reckzeh2
found that, as a rule, the eosinophiles do not reach their normal
value until the end of the second week after invasion.
Should leucocytosis develop, it should be attributed to some
acute inflammatory complication, such as bronchopneumonia,
croupous pneumonia, or severe bronchitis.
In cases with anomalous symptoms the exist-
DIAGNOSIS. ence of scarlet fever may often be excluded by
the absence of leucocytosis. Absence of increase
in fibrin and eosinophiles is also suggestive in ruling out this
infection. If the diagnosis lies between measles and syphilitic
roseola, the absence of leucocytosis points to the former. The
initial stage of variola has been mistaken for measles, but the
blood examination is of no aid in differentiating these two condi-
tions, as leucocytosis is not found in small-pox at this stage of
its development. Rotheln does not give rise to blood changes
distinguishable from those of true measles. This was true of nine
cases examined by Plantenga.3 Tchistovitch 4 found, in four cases,
either normal blood or a very slight neutrophile increase.
XLVIII. MENINGITIS.
The condition of the hemoglobin and erythro-
HEMOGLOBIN cytes has not been extensively studied in this
AND disease, but so far as the data at present avail-
ERYTHROCYTES. able show, the only notable change to be observed
consists of a moderate oligochromemia. This
1 Arch, de med. des Enf., 1901, vol. iv, p. 22.
2Zeitschr. f. klin. Med., 1902, vol. xlv, p. 107.
s Arch, de med. des Enf., 1903, vol. vi, p. 129.
4 Russkiy Vrach, 1904; abst., Jour. Amer. Med. Assoc., 1904, vol. xlii, p. 809.
MENINGITIS. 487
change, however, is inconstant, for, as a rule, both the number of
corpuscles and their hemoglobin value are normal, or, perhaps,
somewhat above normal.
These statements, as well as those relating to the leucocytes,
apply to the various non-tuberculous inflammations of the cerebral
and spinal pia-arachnoid and dura mater, acute leptomeningitis
and pachymeningitis, and epidemic cerebrospinal meningitis.
The blood changes associated with tuberculous meningitis are
described elsewhere. (See pp. 546 and 549.)
Well-defined leucocytosis is found in the great
LEUCOCYTES, majority of instances, the counts usually ranging
in excess of 20,000 to the c.mm., and tending to
attain highest figures in purulent meningitides.
Forty-seven cases of various non-tuberculous metiingeal in-
flammations have been observed by Williams and by Cabot,1 in
all but two of which the leucocytes at the first examinations
numbered more than 10,000 to the c.mm., and in the individual
case as high as 40,000 and 50,000. The two instances in which
the first counts failed to show leucocytosis were cases of epidemic
cerebrospinal meningitis, 36 of which were included in the entire
series. In 37 cases of cerebrospinal fever Koplik2 found leucocy-
tosis a constant sign, the counts ranging from 12,000 to 55,000, and
exceeding 25,000 in 55 per cent, of the cases. The highest leucocy-
toses were found in fatal cases, in which lumbar puncture showed
a thick, turbid, pus-like fluid.
The myth, still entertained to some extent, that tuberculous
and non-tuberculous meningitis differ in that the former does not
cause leucocytosis, should have been dispelled long ago. Thus,
while Turk3 found this sign in 32 out of 35 (or 91.4 per cent.)
counts in non-tuberculous cases, he also noted it in 4 out of 8
counts in the tuberculous form, the maximum estimate in the
latter being 20,800 cells per c.mm. Rieder4 has reported a count
of 14,400 in one case of tuberculous meningitis, and in another,
7800 and 5900 cells; leucocytosis was constant in this author's
10 counts in non-tuberculous cases, the maximum being 29,300.
Examples of this sort could be still further multiplied to demon-
strate that leucocytosis occurs with great frequency in tuberculous
meningitis.
The most common differential change consists in an absolute
and relative increase in the polynuclear neutrophiles, this alteration
tending to become most striking when the total leucocyte count
is excessively high. In cases with a normal count, or with only
1 Loc. cit. 2 Med. News, 1904, vol. Ixxxiv, p. 1065.
3 Loc. cit. 4 Loc. cit.
GENERAL HEMATOLOGY.
a moderate increase, Turk observed a relatively high percentage
of large lymphocytes and transitional forms, and he has further
called attention to the fact that the eosinophiles are either absent
or decreased to a small fraction of one per cent, in practically
every count, irrespective of the presence or absence of an increase
in the total number of leucocytes.
Between tuberculous and non-tuberculous men-
DIAGNOSIS. ingitis an absence of leucocytosis strongly sug-
gests the former, although the presence of a
leucocytosis does not of necessity exclude it.
Epidemic cerebrospinal meningitis sometimes resembles such
infections as enteric fever, typhus fever, pneumonia, and malignant
forms of variola. In attempting these diagnoses, the presence of
a leucocytosis almost invariably excludes typhoid, but the be-
havior of the leucocytes is of no avail as a means of differentiating
pneumonia. In variola the early development of a large-celled
mononucleosis, often with myelemia, proves a helpful sign. Most
cases of typhus show a normal or subnormal number of leucocytes,
but some with moderate leucocytosis have been reported.
Acute meningitis cannot be distinguished by the blood examina-
tion from cerebral hemorrliage and abscess, since in all these condi-
tions high counts are the rule. Cabot 1 believes that hysteria, lead
encephalopathy, diabetic coma, sunstroke, and narcotic or alcoholic
intoxication can be excluded by the presence of a leucocytosis,
and that, should the diagnosis lie between meningitis, on the one
hand, and uremia and post-epileptic coma, on the other, an absence
of leucocytosis is sufficient to exclude meningitis, although its
presence is of no diagnostic value. It is possible that bacterio-
logical examination of the blood may furnish definite information,
for Gwyn 2 has succeeded in repeatedly cultivating the Diplococcus
meningitidis intracellularis from the blood of a case of epidemic
cerebrospinal fever. Several investigators have found pneumo-
cocci in the blood in cases of acute meningitis.
XLIX. MYXEDEMA.
Anemia, involving chiefly the hemoglobin, is a finding in per-
haps four- fifths of all cases, judging from Murray's3 and Bram-
well's4 records of 56 patients. More rarely, high grade anemia
is found in this condition, as in a case examined by Le Breton,5 in
1 Loc. cit. 2 Johns Hopkins Hosp. Bull., 1899, vol. x, p. 112.
3 "Twentieth Century Practice of Medicine," New York, 1895, vol. iv, p. 710.
4 "Anemia," London, 1899, p. 309.
8 Bull. soc. med. des hop. de Paris, 1895, vol. xii, p. 22.
NEPHRITIS. 489
which the loss of hemoglobin amounted to 45, and the loss of
erythrocytes to 66, per cent, of the normal standard, with a color
index of 1.91. This author, as well as Kraepelin,1 in several
instances has observed a general increase in the diameter of the
erythrocytes and the presence of erythroblasts, but such changes
are not ordinarily encountered.
The leucocytes are moderately increased in a small proportion
of patients, but never reach notably high figures; in fully three-
fourths of cases their number does not exceed the maximum
normal limit. In a case published by Putnam,2 a small number
of myelocytes was found, but no other differential changes of
special interest have been reported.
A prompt increase in the hemoglobin and erythrocytes follows
the administration of thyroid extract in appropriate doses, but, on
the other hand, excessive thyroidization rapidly aggravates the
anemia, according to Bramwell.3
L. NEPHRITIS.
Important contributing factors of the blood
GENERAL changes in this condition are albuminuria, hemor-
FEATURES. rhage, circulatory disturbances, and the character
of the disease with which the renal lesion may be
associated. The fact that so many other circumstances are ca-
pable of playing active etiological roles serves to explain the great
dissimilarity of the blood pictures in different nephritides and at
different stages of the same nephritis.
Marked albuminuria produces in course of time a notable drain
upon the serum proteids and a less conspicuous deterioration of
the corpuscles, especially affecting their volume. By this agency,
therefore, the specific gravity of the whole blood is diminished, in
close relationship with the extent of the drain produced. It is
still a disputed question whether or not edema may also be held
responsible for this change. The investigations by Houston,* of
the edema of anemia, tend to prove that in renal disease practically
no direct relationship exists between the condition of the blood
and the extent of the dropsy. At least there is no demonstrable
relationship in cases with gradually developing edema, owing
doubtless to the promptness with which the blood mass corrects
any tendency to dilution. In cases with hematuria as a promi-
nent symptom the familiar picture of a post-hemorrhagic anemia
1 Deutsch. Arch. f. klin. Med., 1892, vol. xlix, p. 587.
2 Amer. Jour. Med. Sci., 1893, vol. cvi, p. 125.
3 Loc. tit. 4 Brit. Med. Jour., 1902, vol. i, p. 1464.
490 GENERAL HEMATOLOGY.
may be encountered, and in kidney inflammations which ac-
company an acute infectious process the effects of the latter upon
the blood are to be remembered.
The amount of fibrin may be found to be increased, especially
in contracted kidney; the rate of coagulation is, so far as has been
determined, exceedingly inconstant.
Von Jaksch,1 von Limbeck,2 and others have drawn attention
to diminished alkalinity of the blood as a sign anticipating and ac-
companying uremic attacks.
Bacteriological examination of the blood proves negative, except
in the terminal stages of nephritis, when evidences of a general
circulatory invasion by micro-organisms may sometimes be de-
tected. Thus, excluding this factor, James and Tuttle 3 failed to
demonstrate pathogenic bacteria in the blood of six successive
chronic cases; while, on the other hand, White4 obtained growths of
streptococci in three consecutive cases of chronic parenchymatous
nephritis, on the second, third, and fourth days before death,
respectively, these positive findings being attributed to terminal
septicemia.
In acute parenchymatous nephritis the hemo-
HEMOGLOBIN globin and erythrocyte values may remain per-
AND fectly normal, or, as is more usual, a moderate
ERYTHROCYTES. secondary anemia develops, of which a greatly
disproportionate oligochromemia is a notable fea-
ture. The grade of the anemia is highest in cases with marked
albuminuria and hematuria, but only exceptionally is a loss of
more than 2,000,000 per c. mm. cells noted. Laache 5 estimates
the average loss in hemoglobin at 26 per cent, and in erythro-
cytes at 19 per cent., and considers that the decrease is much
greater in acute than in chronic cases. Hayem6 is authority
for the statement that striking anemia develops only in cases
with hematuria.
In chronic parenchymatous nephritis most observers state that
moderate hemoglobin and erythrocyte decreases are the most
notable findings, but some report severe anemia the grade of
which -is likely to be most intense in cases with marked, persistent
albuminuria and with associated lesions of other organs. Sor-
ensen7 found that the count of erythrocytes in this form of renal
disease averaged 4,700,000 to the c.mm., but in the writer's ex-
perience a much more pronounced loss has been observed — an
average hemoglobin percentage of 57.1 and an average ery-
1 Zeitschr. f. klin. Med., 1887, vol. xiii, p. 350. 2 Loc. cit. 3 Loc. ciL
4 Loc. cit. 5 "Die Anamie," Christiania, 1883.
8 Loc. cit. 1 Cited by Grawitz, loc. cit.
NEPHRITIS. 491
throcyte count of 3,971,206 per c.mm., in a series of 15 cases. A
synopsis of the examinations in these cases shows the following
data: Hemoglobin percentage : 80-90 in i; 70-80 in 2; 60-70 in 4;
50-60 in 3 ; 40-50 in 2 ; and 30-40 in 3. Erythrocyte counts : above
5,000,006 in 2; 4,000,000-5,000,000 in 4; 3,000,000-4,000,000 in 8;
2,000,000-3,000,000 in i. The maximum hemoglobin estimate in
this series was 82, and the minimum 30, per cent.; the maximum
number of erythrocytes per c.mm. was 5,520,000, and the minimum
2,270,000. The average color index was 0.71.
Polycythemia, masking the real condition of the blood, is not
at all uncommon; it may arise from some such cause as cyanosis
or the sudden development of an extensive edema. Every clinician
must have been repeatedly struck by the evident discrepancy
between the blood report and the pinched, waxy,' nephritic
facies.
In chronic interstitial nephritis, so long as circulatory disturb-
ances do not exist, the condition of the blood remains practically
normal, but as soon as the compensatory hypertrophy of the left
ventricle becomes inadequate, the blood changes identified with
uncompensated valvular heart disease . develop, and various de-
grees of apparent anemia and polycythemia become evident from
time to time. These factors, the importance of which is insisted
upon by Grawitz,1 no doubt serve to explain most of the blood
changes found in sclerotic kidney, but it seems obvious that
neither the malnutrition of the patient nor the considerable hem-
orrhages from which he often suffers should be disregarded as
possible causes of blood deterioration.
All the structural changes affecting the erythrocytes in sec-
ondary anemia may occur in association with any of the preced-
ing varieties of nephritis, should the accompanying anemia be
sufficiently striking.
In acute parenchymatous nephritis leucocytosis
LEUCOCYTES, may develop in the early stages of the disease,
and persist for some time after convalescence is
established. Cabot,2 who attributes the increase to the effects
of hemorrhage and of uremia, found it present in about 80 per
cent, of his 50 cases, the maximum count being 50,000 per c.mm.
Of 12 cases in which these two factors were excluded the writer
found that the number of leucocytes was above 10,000 per c.mm.
in 9.
In the 15 cases of chronic parenchymatous nephritis above
mentioned, the number of leucocytes averaged 8626 per c.mm.,
the maximum being 16,000 and the minimum 4000. Four of
1 Loc. cit. 2 Loc. cit.
492 GENERAL HEMATOLOGY.
the counts were in excess of 10,000; 9 from 5ooo-io,-ooo; and 2
below 5000.
Chronic interstitial nephritis does not of itself influence the
number of leucocytes.
Uremia may or may not be associated with leucocytosis ;
the change is to be noted in the majority of nephritides in which
this complication supervenes, but it is by no means constant.
Dopter and Gourand1 have shown that in rabbits the removal of one
kidney is followed by a transient, doubtless post-operative, leuco-
cytosis, but that after a double nephrectomy the consequent
uremic intoxication provokes a leucocytosis which persists until the
animal's death.
In all the above forms of kidney inflammation the leucocy-
tosis, if present, is of the polynuclear neutrophile type.
The blood count is of no diagnostic value in
DIAGNOSIS, nephritis, nor can it always be relied upon to in-
dicate accurately the richness of the blood in cel-
lular elements, owing to the frequent prevalence of factors which
cause dilution and inspissation.
LI. NERVOUS AND MENTAL DISEASES.
In a single case of febrile multiple neuritis
NEURITIS, Cabot2 found a moderate degree of secondary
BERI-BERI, anemia, with leucocytosis, the counts, 8 in num-
NEURALGIA, ber, ranging from 16,000 to 28,700 per c.mm.,
BRAIN TUMOR v and the latter figure being reached during the
post- febrile period of the attack. This author
also noted a moderate anemia and leucocytosis in 4 of 6 cases
of alcoholic neuritis, but found the number of leucocytes normal
in 25 cases of plumbic neuritis.
Beri-beri, according to Spencer,3 is usually associated with a
well-defined secondary anemia, in some instances characterized
by striking qualitative changes affecting the size and shape of the
erythrocytes. The leucocytes, both in number and in the rela-
tive percentages of their different varieties, remain normal, ex-
cept in the acute stages of the infection, when an increase in the
eosinophiles may develop. Fajardo4 has detected a spore- form-
ing, pigment-producing hematozoon, and Rost 5 a diplobacillus,
in the blood of beri-beri patients, each of which organisms has
1 Sem. me"d., 1903, vol. xxiii, p. 14.
2 Loc. cit. 3 Lancet, 1897, vol. i, p. 32.
4 Centralbl. f. Bakt. u. Parasit., 1900, vol. xxvii, p. 249.
6 Lancet, 1901, vol. i, p. 66.
NERVOUS AND MENTAL DISEASES. 493
been regarded by their respective discoverer as the specific cause
of the disease. Other investigators, notably Affleck,1 have ob-
tained negative results from bacteriological blood examinations.
In the blood of negroes suffering from akatama, a form of peripheral
neuritis endemic in Central Africa, Wellman 2 has found the para-
sites of both tertian malarial fever and of filariasis; he concludes,
however, that neither of these parasites has any etiological bearing
on akatama, for they are frequently harbored by natives exempt
from this disease.
Neuralgia, whatever its seat, is capable of exciting neither
anemia nor leucocytosis. Excessive polycythemia (9,000,000 ery-
throcytes per c.mm., with 125 per cent, of hemoglobin) was found
by F. P. Weber 3 in a case of erythromdalgia.
The blood in brain tumor usually deviates in no manner from
the normal, although rarely a moderate leucocytosis has been
observed. In five cases the writer found that the hemoglobin
averaged 72.2 per cent, (ranging from 70 to 79), and the ery-
throcyte count 3,800,000, the maximum being 4,270,000 and the
minimum 2,860,000 per c.mm. None of the cases showed leucocy-
tosis, the average count of leucocytes being 7320. This is a
distinct contrast to cerebral abscess and hemorrhage, in both of which
conditions leucocytosis is the general rule. The condition of the
blood in meningitis has already been described. (See p. 486.)
Neurasthenia, hypochondriasis, and hysteria,
FUNCTIONAL while they do not primarily serve as factors of
NEUROSES, blood deterioration, are in some instances associ-
ated with other conditions which lead to moderate
secondary anemia, usually involving chiefly the hemoglobin, and
but rarely causing any appreciable diminution in the number of
erythrocytes. But, as a rule, functional neurotics have normal
blood in spite of their anemic appearance. Luxemberg,4 in a
study of 40 cases of hysteria and neurasthenia, found that poly-
cythemia was common, having repeatedly noted erythrocyte
counts as high as 6,000,000, and even in one instance 7,300,000,
per c.mm.; he attributes this to vasomotor changes, possibly
due in large part to the effect of the examination itself. Reinert,5
examining 74 cases of these two forms of neurosis, found a moder-
ate hemoglobin diminution in many cases of hysteria, but normal
blood in neurasthenia. In sexual neurasthenia, however, anemia
is not at all uncommon, in the writer's experience. MacPhail8
1 Edinburgh Med. Jour., 1900, vol. viii, p. 33.
2 Jour. Trop. Med., 1903, vol. vi, p. 267.
3 Brit. Med. Jour., 1904, vol. i, p. 1017.
4 Centralbl. f. inn. Mod., 1899, vol. xx, p. 533.
4 Munch, med. Wochenschr., 1895, vol. xlii, p. 305.
8 Jour. Mental Sci., 1884, vol. xxx, pp. 378 and ^88.
494 GENERAL HEMATOLOGY.
speaks of the marked anemia usually found in insane masturbators,
and every clinician who has made many routine blood counts must
have been struck with the fact that the pallid, pasty face of the con-
firmed masturbator but seldom falsely reflects the state of the
sufferer's blood.
The functional neuroses are not accompanied by leucocytosis,
but, -on the other hand, in many cases a decided leucopenia is
present. In all a relatively increased proportion of lympho-
cytes may frequently be observed, while in hysteria the num-
ber of eosinophiles may be relatively in excess of the normal
standard.
MacPhail,1 in a prize essay submitted to the
GENERAL Medico- Psychological Association of Great
PARESIS, Britain in 1884, concludes that these mental dis-
DEMENTIA, eases are in many instances closely associated
MELANCHOLIA, with a more or less decided anemia, although in
MANIA. no sense can blood deterioration be regarded as a
factor of insanity. In general paresis this ob-
server found subnormal hemoglobin values, averaging about 67 per
cent., on the patient's first admission to the hospital, but later, as
the patient profited by the improved hygienic environment, this
value rose, only again to fall to an average of 52 per cent, in the
terminal stages of the affection. The oligocythemia steadily in-
creased as the disease progressed, and occasionally reached in the
individual case a minimum count of between 3,000,000 and 4,000,-
ooo erythrocytes per c.mm. ; it was more striking during the active
and completely paretic stages than during the intervening periods
of quiescence. ^A well-defined leucocytosis was constant, and
many of the counts made shortly before death reached high
figures. Diefendorf,2 in n paretics, also noted a progressive
anemia, generally of the so-called "chlorotic" type, together with
a steady gain in the polynuclear neutrophile leucocytes, which
attained its acme during the terminal stage. At this time there
developed a distinct leucocytosis, as well as an increase in the
hemoglobin and erythrocyte figures. Paralytic seizures were
accompanied by moderate leucocytosis, usually not exceeding a
count of 20,000. Capps,3 in a study of 19 cases, found that the
hemoglobin averaged 85 per cent, and the erythrocytes 4,789,900
per c.mm. — figures which may be compared with Smyth's average
estimates4 in 40 cases: hemoglobin, 68.7 per cent., and erythro-
cytes, 4,700,000. Capps states that the majority of cases show
a moderate leucocytosis, averaging an increase of 22 per cent, in
1 Loc. cit. 2 Amer. Jour. Med. Sci., 1903, vol. cxxvi, p. 1047.
3 Ibid., 1896, vol. cxi, p. 650. 4 Jour. Mental Sci., 1890, vol. xxxvi, p. 504.
NERVOUS AND MENTAL DISEASES. 495
excess of the normal standard, but that in the incipient stages of the
disease the number of leucocytes usually is not increased. An
average count of 8800 was noted by Somers * in 5 cases. Relatively
high percentages of polynuclear neutrophiles, with a diminution in
the small lymphocytes, are common differential changes, while the
relative numbers of large lymphocytes and eosinophiles may be
higher than normal. The eosinophiles were found, by Roncoroni,2
to be regularly increased in paretic excitement — sometimes as
high as 20 or 25 per cent. Kippel and Lefas,3 in 22 cases,
invariably found from i to 4 per cent, of basophiles; early in the
disease a polynuclear neutrophile increase was the rule, but in
the later stages it declined until finally lymphocytosis, usually but
relative, supervened.
Convulsions and apoplectiform attacks tend to produce blood
concentration, and therefore temporarily increase the hemo-
globin and erythrocyte values. During and following such
seizures an abrupt rise in the leucocyte curve, characterized by
a striking absolute and relative gain in the large lymphocytes,
and, rarely, by the appearance of rhyelocytes, was observed by
Capps, who has also described a small mononuclear neutro-
philic leucocyte, resembling a dwarf myelocyte, as peculiar to
the condition in question. (See p. 222.) Burrows4 believes that
the leucocytosis associated with convulsions, not only in general
paralysis, but in other conditions, bears a definite relation to
the severity of the fit, and that the increase is in part the result
of the muscular contractions attending the convulsion, and in part
represents an actual pathological leucocytosis. In 23 cases of
general paresis a lowered blood alkalinity was constantly found
by Pugh,5 the diminution being most notable in the acuter forms
of the disease and in connection with convulsive seizures. Acute
delirium from any cause also provokes leucocytosis.
In dementia, according to Smyth,8 both the hemoglobin and the
erythrocytes are decidedly lower than in the preceding condition,
his averages for this disease being 53.7 per cent, of hemoglobin
and a count of 4,070,000 erythrocytes in a series of 12 cases.
In 10 cases of melancholia he found that the hemoglobin averaged
69.7 per cent, and the erythrocytes 4,684,000, while Steel,7 in
35 cases of this disease, estimated the average hemoglobin value
at 75 per cent, and the average erythrocyte count at 3,000,000.
1 Bull. N. Y. State Hosp., 1896.
2 Arch. d. Psychiat. Sc., 1894, vol. xv, p. 293.
* Sem. med., 1902, vol. xxii, p. 393.
4 Amer. Jour. Med. Sci., 1899, vol. cxvii, p. 503.
5 Jour. Mental Sci., 1903, vol. xlix, p. 71.
8 Loc. cit. 7 Amer. Jour. Insanity, 1892, vol. xlix, p. 604.
496
GENERAL HEMATOLOGY.
In acute mania anemia of the so-called "chlorptic" type usually
may be observed; this blood change becomes aggravated by each
acute maniacal outbreak, but after recovery from these attacks
the deficiency is rapidly restored. In acute continuous mania
Bruce1 believes that the number of leucocytes stands in direct
relation to the improvement of the patient, convalescents showing
a progressive leucocytosis with a high percentage of polynuclear
neutrophiles, which persists after recovery, but which rapidly
diminishes should a relapse occur. This investigator2 also
cultured from the blood a diplobacillus, indifferently agglutinable
by the serum of patients suffering from mania, and non-patho-
genic for laboratory animals. Bruce interprets his findings as
evidence that some cases of mania, at least, are true infections.
Opposed to the above leucocyte formula of acute mania are the
observations of Johnson and Goodall,3 who found the count
highest during the acute stages and lowest during states of remis-
sion and recovery. These investigators have also shown that in
60 per cent, of all cases of mania, paresis, and other forms of
insanity the patient's blood clumps the colon bacillus. This
suggests that in these diseases the normal inhibition of this or-
ganism's growth in the gut is interfered with, and in consequence
its proliferation is excessive enough to excite toxemia. Somers'4
leucocyte counts in 19 dements averaged 10,743, in 19 melancholies
7947, and in 19 maniacs 8315. The alkalinity of the blood re-
mains normal, except in patients with great motor restlessness, in
whom subnormal figures are the rule. The following table of
averages by Wherry 5 relates to the blood changes in 95 cases of
dementia, melancholia, and mania:
FORM OF INSANITY.
HEMOGLOBIN.
ERYTHROCYTES.
LEUCOCYTES.
Mania, acute, men
84 per cent.
3,780 ooo
7 800
Mania, acute, women
68
•?,?s4,4OO
7,600
Melancholia, acute, men
78
4,OsI,2OO
6,400
Melancholia, acute, women
77
3, 7Q3,6oO
7,400
Mania, chronic, men
82
3.7o8,4OO
7.IOO
Mania, 'chronic, women
71
7,7o8,OOO
8,200
Melancholia, chronic, men
77
•? 624,OOO
6,700
Melancholia, chronic, women
77
"1,764,800
7,200
Dementia, men
71
3,518,400
7,600
Dementia, women
7-2
2,O76.OOO
0,200
1 Jour. Mental Sci., 1903, vol. xlix, p. 441.
2 Ibid., 1903, vol. xlix, p. 219.
4 Loc. cit.
3 Lancet, 1903, vol. ii, p. 470.
5 Amer. Med., 1901, vol. ii, p. 70.
NERVOUS AND MENTAL DISEASES. 497
In family periodic paralysis J. K. Mitchell * finds that the
hemoglobin and corpuscular figures and the differential leucocyte
counts do not deviate from normal. High blood alkalinity was
detected, both during the paralytic attacks and in the intervals
between them.
In epilepsy a moderate anemia appears to be
EPILEPSY, the general rule. Smyth's studies2 of 50 cases
CHOREA. show an average of 62.8 per cent, of hemoglobin,
TETANY. and 4,520,000 erythrocytes per c.mm. Mac-
Phail3 asserts that prolonged attacks of excite-
ment notably increase the anemia, but that the habitual admin-
istration of bromids seems in no manner to produce -deleterious
effects upon the blood. Furthermore, this author observed that
a close relationship can be distinguished between the patient's gain
in weight, the decrease in the anemia, and the mental improve-
ment, and that in patients who recovered, the regeneration of the
blood became practically complete. Distinct leucocytosis seldom
occurs in epilepsy, except as the result of a convulsion. Kuhl-
mann,4 for example, found the leucocytes in excess of normal but
once in a study of 16 cases. In a series of 7 cases, Pearce and
Boston5 found well-marked chloro-anefnia and usually a moderate
leucocyte increase. Differentially, the most conspicuous changes
were a reduction in the polynuclear neutrophiles and the inconstant
presence of small numbers of myelocytes.
Pugh's studies6 of 40 epileptics tend to show that the alkalinity of
the blood is subnormal during the period between epileptic attacks,
that it decidedly falls immediately before a fit, and that a further
fall occurs soon after a fit is over. Pugh attributes the lowered
alkalinity partly to an accumulation of acid toxins in the blood and
partly to an output of sarcolactic and carbonic acids as the result
of the violent convulsive attacks. The administration of strontium
bromid and potassium bicarbonate for a time restores the normal
blood alkalinity and apparently diminishes the number of fits — but
only for a brief period, since it is impossible permanently to in-
fluence the reaction of the blood by drug giving. Bra and Chausse* 7
describe a "neurococcus" in the blood during epileptic fits, and
claim to have cultured the alleged germ and to have produced
convulsions in animals by its injection. Bra's claim for his
neurococcus as the cause of idiopathic epilepsy has been con-
1 Brain, 1902, vol. xxv, p. 109; also Trans. Assoc. Amer. Phys., 1899, vol.
»v,P. 345-
2 Loc. cit. 8 Loc. cit.
4 Bull. N. Y. State Hosp., 1897. 6 Medicine, 1904, vol. x, p. 123.
• Loc. cit. ' Rev. Neuroli. and Psychiat., 1903, vol. i, p. 689
32
498 GENERAL HEMATOLOGY.
troverted by Tirelli and Brossa,1 who obtained uniformly negative
bacteriological blood findings in this condition.
In chorea slight anemia, usually of the "chlorotic" type, occurs
with frequency, but not with constancy, for many cases habitually
show normal hemoglobin and erythrocyte values. It seems
scarcely necessary to remark that the belief once entertained, that
blood deterioration was a causal factor of this disease, is obviously
erroneous. Burr,2 in a study of the hemoglobin and erythrocytes
in 36 cases, concludes that a moderate diminution in both of these
elements is the general finding, and that a high grade of anemia
occurs only as the result of some complication. The oligocy-
themia usually does not exceed a loss of more than 1,000,000
cells per c.mm. in uncomplicated cases. The leucocytes are not
increased, but differential counts may detect a relatively large
percentage of eosinophiles, according to the reports of Zappert 3
and others. Tetany is not of itself a cause of blood impoverishment.
LIL OBESITY.
From Kisch's studies 4 it is evident that the hemoglobin values
are notably high in most corpulent individuals, and in some ex-
cessively increased. In 79 of 100 cases of obesity examined by
this author the hemoglobin percentage exceeded 100, while in
the remaining 21 moderate oligochromemia wras found. The
maximum reading in this series was 120 and the minimum 55
per cent. Actual anemia, however, is not incompatible with this
class of patients, as demonstrated by Leichtenstern5 and by
Oertel.6 The latter also maintains that in some instances true
plethora exists, and furthermore professes to recognize two dis-
tinct forms of obesity, an anemic and a plethoric. Data regarding
the leucocytes in this condition are wanting.
LIIL OSTEOMALACIA.
The hemoglobin and erythrocytes do not exhibit any marked
deviations, being in most instances normal, or but moderately di-
minished. The anemia, when present, is characterized by a
hemoglobin loss relatively exceeding that of the corpuscles.
1 Rif. Med., 1903, vol. xix, p. 934.
J Univ. Med. Mag., 1896, vol. ix, p. 188.
3 Zeitschr. f . klin. Med., 1893, vol. xxiii, p. 227. * Ibid., 1887, vol. xii, p. 357.
' "Untersuch. u. d. Hg-Gehalt d. Blutes," Leipsic, 1878. •
"'Allgem. Ther. d. Kreislaufsstor.," Leipsic, 1884; also Deutsch. Arch. f.
klin. Med., 1892, vol. i, p. 293.
PANCREATITIS. 499
The leucocytes also remain approximately normal in number,
slight fluctuations above and below this standard being the only
numerical change thus far noted. Relative lymphocytosis has
been found by Ritchie 1 and by Tschistowitch,2 while Neusser 3
and others have observed in many cases a moderate increase in
the eosinophiles, and the presence of small numbers of myelo-
cytes. None of these differential changes, however, is to be
considered constant in this condition. According to von Lim-
beck,4 the alkalinity of the blood remains practically unaltered,
although von Jaksch5 formerly maintained that it was considerably
diminished.
LIV. PANCREATITIS.
In interpreting the blood picture of pancreatitis due attention
should be paid to the influence of possible attendant lesions,
especially those such as cholangitis, peritonitis, icterus, and dia-
betes. Acute hemorrhagic pancreatitis is so frequently part and
parcel of abscess, gangrene, and sepsis that more or less anemia is
to be expected. As a rule, the hemoglobin and erythrocyte losses
are moderate, although exceptionally the values approximate but
25 or 30 per cent, of normal. The dual factors, hemorrhage and
acute inflammation, not to mention infection and necrosis, are
ideal theoretical reasons for a leucocytosis, and, practically, it is
found that these factors are active. Seven examinations in four
cases of acute pancreatic inflammation in the German Hospital
gave these averages: hemoglobin, 57.1 per cent., ranging between
26 and 88; erythrocytes, 3,205,714 per c.mm., ranging between
1,550,000 and 4,460,000; and leucocytes, 19,292 per c.mm.,
ranging between 11,600 and 32,000. The histological changes are
those attending secondary anemia and a polynuclear neutrophile
leucocytosis.
Chronic pancreatitis, being a slow sclerosis, has little or no
effect upon the blood. Nine estimates in three German Hospital
cases averaged 80.2 per cent, of hemoglobin, with extremes of 54
and 99; 4,700,000 erythrocytes per c.mm., or a range of from 3,600,-
ooo to 5,900,000; and 7188 leucocytes per c.mm., ranging be-
tween 4000 and 11,300. In non-inflammatory pancreatic cyst a
similar blood picture is found, while if the cyst is actively
inflamed, a varying degree of leucocytosis generally develops.
In pancreatk lithiasis the blood changes may be those of acute
1 Edinburgh Med. Jour., 1896, vol. xlii, p. 208.
2 Berlin, klin. Wochenschr., 1893, vol. xxx, p. 919.
3 Wien. klin. Wochenschr., 1892, vol. v, p. 41.
4 Loc. cit. s Zeitschr. f. klin. Med., 1887, vol. xiii, p. 350.
500 GENERAL HEMATOLOGY.
or chronic pancreatitis or of malignant disease, depending upon the
effects of the stones. The blood in pancreatic malignant neoplasm
has already been considered. (See "Malignant Disease," p. 472.)
Aside from the facts that anemia and leucocytosis attend acute
rather than latent inflammations of the pancreas, and that a
leucocytosis argues the malignancy of a tumor of this organ, the
blood examination is of no definite value in recognizing pancreatic
lesions.
LV. PERICARDIAL EFFUSION.
The hemoglobin and erythrocytes remain normal, or, if anemia
is found, it may be referred to other coexisting conditions.
Leucocytosis of the polynuclear neutrophile type is practically
a constant change in the non-tuberculous forms, but in tuber-
culous pericarditis the leucocytes apparently do not increase.
From a diagnostic viewpoint the presence of a leucocytosis is of
real value in excluding the latter condition, as well as cardiac
dilatation; this sign is also strong evidence against the existence
of a serous pleural effusion, which, if left-sided, may simulate
pericarditis.
LVI. PERITONITIS.
Anemia is frequently found, the degree of
HEMOGLOBIN which largely depends upon the character and
AND the chronicity of the inflammation. In general
ERYTHROCYTES. purulent peritonitis, especially in cases of com-
v paratively long standing, the hemoglobin and
erythrocyte diminution may be excessive — to between 20 and 30
per cent, for the former, and to between 2,000,000 and 3,000,000
per c.mm« for the latter. With such an anemia as this the ery-
throcyte loss is commonly very disproportionate to that of the
hemoglobin, so that high color indices rule; for example, in three
of the cases summarized below, the indices were 1.12, i.oi, and
i.oo respectively. The several qualitative changes accompanying
any severe secondary anemia are also commonly to be observed.
Serous peritonitis has but little effect in provoking a cellular
decrease, although it usually causes a slight but definite oli-
gochromemia, so that in such cases the color indices are moderately
subnormal. On the average, it may be stated that peritonitis
involves a loss of about 30 per cent, of hemoglobin and of 25 per
cent, of erythrocytes.
The following summary of 54 cases, none of which was ap-
pendicular, shows the grade of anemia prevailing in this disease:
PERITONITIS. 501
HEMOGLOBIN NUMBER OF ERYTHROCYTES NUMBER OF
PERCENTAGE. CASES. PER C.MM. CASES.
From 90-100 2 Above 5,000,000 5
" 80- 90. ...15 From 4,000,000-5,000,000. .. .23
" 70-80 10 " 3,000,000-4,000,000 14
" 60- 70 9 " 2,000,000-3,000,000 7
" 50- 60.... 6 1,000,000-2,000,000 5
" 40-5° 7
30-40 3
20- 30 2
Average, 68.4 per cent. Average, 3,756,035 per c.mm.
Maximum, 93.0 Maximum, 5,670,000 " "
Minimum,- 20.0 Minimum, 1,290,000 • " "
Provided that the patient's resisting powers
LEUCOCYTES, react normally, septic peritonitis constantly causes
a typical leucocytosis of the polynuclear neutro-
phile variety. Generally speaking, 80 per cent, of cases show a
leucocyte count of 10,000 or higher. It cannot be stated with
certainty that the increase is greater" in purulent than in serous
inflammations, for any variety of peritonitis, except the tubercu-
lous, may provoke a striking leucocytosis. As already remarked
in the discussion of appendicitis, extension of the process is heralded
by an abrupt rise in the leucocyte curve. As in other infections,
leucocytosis may be absent, or leucopenia may exist, in cases of a
profound, crippling character. The number of leucocytes in the
preceding 54 cases ranged as follows :
LEUCOCYTES NUMBER OF
PER C.MM. CASES.
Above 45,000 i
From 35,000-45,000 ' 2
25,000-35,000 2
" 20,000-25,000 5
" 15,000-20,000 12
" 10,000-15,000 19
5,OOO-IO,OOO 12
Below 5,000 i
Average, 15,526 per c.mm.
Maximum, 46,000 " "
Minimum, 4,400 " "
The presence of leucocytosis is sufficient evi-
DIAGNOSIS. dence for the exclusion of tuberculous peritonitis,
so-called hysterical peritonitis, and rheumatism of
the abdominal muscles. This sign, however, cannot safely be
502 GENERAL HEM ATO LOGY.
employed to differentiate between peritonitis and acute enteritis,
certain forms of intestinal obstruction, and rupture of a tubal
pregnancy or of an abdominal aneurism, all of which may cause
more or less leucocyte increase. (See "Appendicitis," p. 370.)
Cabot1 regards the association of marked leucocytosis with
hyperinosis as strongly in favor of a peritoneal inflammation
rather than of such conditions as non-malignant bowel obstruction,
malignant disease, hysteria, and phantom tumors.
LVII. PERTUSSIS.
lodophilia was detected by Crisafi2 in 16 of 20 cases examined,
but no relationship could be traced between this sign and the
presence of glycosuria, which developed in 4 of the patients. In
so far as can be learned from the scanty literature at present
available, the hemoglobin and erythrocyte values remain nor-
mal in this disease. Lymphocytosis, generally relative, but
sometimes absolute, is a characteristic finding in whooping-
cough. As a consequence of this change there is a coincident
diminution in the polynuclear neutrophiles and eosinophiles.
Frohlich and Meunier,3 who originally determined this fact, found
in 30 cases an average of 27,800 leucocytes per c.mm., the in-
dividual counts ranging from a minimum of 15,500 to a maximum
of 51,150. De Amicis and Pacchioni4 have corroborated this
observation, although they consider that the increase is some-
what less, having found an average count of 17,943 for their cases.
Wanstall,5 in 15 cases, and Stengel and White,8 in 4, obtained
even lower total leucocyte values (no increase being noted in
many instances), but found a lymphocyte increase the rule. The
lymphocytosis develops during the early stages of the disease,
before the cough begins, and usually persists for some time after,
convalescence is established. As a general rule, it may be stated
that the younger the child, the more notable the increase. Such
complications as bronchitis, catarrhal pneumonia, and otitis do
not appear appreciably to exaggerate it. According to Ehrlich,7
it is to be attributed to the stimulation and swelling of the tracheo-
bronchial lymphatic glands.
The fact that a marked lymphocyte increase occurs in the early
catarrhal stages of the disease, antedating the development of the
1 Loc. cit. 2 Brit. Med. Jour. Epit., 1904, vol. i, p. 49.
5 Compt. rend. Soc. biol., Paris, 1898, vol. v, p. 103.
4 Clinica Medica, 1899, vol. iv, p. 103.
6 Amer. Med., 1903, vol. v, p. 62.
8 Arch. Pediat., 1901, vol. xviii, pp. 241 and 321. 7 Loc. cit.
PLEURISY. 503
typical cough, is of diagnostic value, as is also the presence of
iodophilia.
LVIII. PLEURISY.
>
SEROUS PLEURISY.
In acute cases it is customary to find normal
HEMOGLOBIN hemoglobin and erythrocyte values, or, at the
AND most, simply a moderate oligochromemia ; in
ERYTHROCYTES. those of longer standing, with decided debility of
the patient, anemia, sometimes of a considerable
degree, is not an uncommon finding. Thus, in an instance of this
sort the writer found but 38 per cent, of hemoglobin and 3,300,-
ooo erythrocytes per c.mm., together with the corpuscular de-
generative changes to be expected in an anemia of this intensity.
It is to be remembered that a rapidly developing pleural effusion
may so concentrate the blood as to cause a temporary polycy-
themia, disguising the actual quantitative changes.
Absence of leucocylosis is the general rule,
LEUCOCYTES, probably for the reason that almost all serous
pleurisies are of tuberculous origin. Exception-
ally a moderate, intermittent increase is found, chiefly affecting
the polynuclear neutrophiles, and due possibly to the influence of
some intercurrent process, such as a secondary pneumococcus in-
fection. A notable increase in the eosinophiles may often be found
in hemorrhagic pleural effusions. In children a leucocytosis
sometimes occurs, apparently independent of secondary infections.
It is quite evident that the behavior of the leucocytes cannot be
used as a means of differentiating tuberculous from non-tubercu-
lous effusions.
Morse,1 in a study of 224 examinations made in 20 cases,
comes to the conclusion that there is no definite relation between
the leucocyte count and the duration of the disease, the degree
of pyrexia, the amount of the effusion, and its increase and dim-
inution. Neither could he determine that the contamination of
the fluid by blood and by microscopical pus produced the slightest
effect upon the number of cells. In Morse's counts the number
of leucocytes exceeded 10,000 to the c.mm. in 5.8 per cent., while
in Cabot's 99 cases2 this figure was exceeded in 14.1 per cent.,
the average count for the latter being 6130.
1 Amer. Jour. Med. Sci., 1900, vol. cxx, p. 658. 7 Loc. cit.
GENERAL HEMATOLOGY.
PURULENT PLEURISY.
The changes in the hemoglobin and erythro-
HEMOGLOBIN cytes do not differ conspicuously from those pre-
AND vailing in primary serous pleurisy, although evi-
ERYTHROCYTES. dences of a decided anemia are to be observed
somewhat more frequently.
In 8 of the writer's 10 cases of empyema the hemoglobin loss
exceeded 50 per cent, of the normal, 38 per cent, being the min-
imum, 73 per cent, the maximum, and 46 per cent, the average,
estimate. The erythrocytes were below 2,000,000 to the c.mm.
in 2 instances, averaging 3,500,000, with 1,540,000 as the minimum
and 4,600,000 as the maximum, counts.
Leucocytosis, ordinarily of a high grade, ac-
LEUCOCYTES. companies the great majority of cases, the increase
involving mainly the polynuclear neutrophile cells
at the expense of the lymphocytes. It is more usual to find the
count above than below 20,000 to the c.mm., and in an exceptional
instance it may even exceed 50,000. Aspiration of the pus is
followed by a decline, and its reaccumulation by a rise, in the
leucocyte curve. The extent of the primary purulent accumula-
tion cannot be gaged with any accuracy by the degree of the
leucocyte increase.
The following counts in a case of empyema examined at the
German Hospital will serve to illustrate the high leucocytosis
sometimes seen in this condition:
DATE.
HEMOGLOBIN
PERCENTAGE.
ERYTHROCYTES
PER C.MM.
LEUCOCYTES
PER C.MM.
Jan. 16, 1900 . .
84
4,460,000
23,200
" 17, 1900 . .
88
5,380,000
42,400
" 18, 1900 . .
82
4,320,000
45,000
" 19, 1900 . .
82 4,430,000
40,800
" 20, 1900 . .
83
4,383,000
23,320
" 21, I9OO . .
82
4,410,000
44,300
" 22, 1900 ..
81
4,330,000
40,600
" 23, 1900 . .
7i
3,985,000
37>3°°
" 24, I9OO . .
67
4,360,000
53>5°°
" 26, 1900 ..
83
4,240,000
47,100
" 27, 1900 .. 71
3,480,000
48,100
In TO other cases above noted a leucocyte increase was in-
PNEUMONIA. 505
variably found, the counts averaging 17,180 and ranging from
11,200 to 31,800 per c.mm.
The presence of a well-developed leucocytosis
DIAGNOSIS, points to pneumonia or empyema, rather than to
simple serous pleurisy, but it does not differentiate
between these first two conditions. On the other hand, an ab-
sence of leucocytosis does not surely exclude pneumonia and
empyema, although it is extremely suggestive that neither exists.
Malignant neoplasms of the lungs and pleura also cause a decided
leucocyte increase, as does actinomycosis.
LIX. PNEUMONIA.
In the case of average severity, coagulation is
GENERAL exceedingly rapid,, and the amount of fibrin
FEATURES, greatly increased, the network being dense,
coarse, and formed with great rapidity. The
hyperinosis tends to persist for some time after the disappearance
of the pyrexia and the signs of lung involvement. In severe in-
fections, occurring in individuals of good resisting powers, the
change is especially striking, but in fatal cases, overwhelmed by the
disease, a fibrin increase is not observed. High temperature and
extensive infiltration of the lungs are associated with marked
hyperinosis. In children the specific gravity of the blood is usually
high during the febrile period, falling to normal as resolution
takes place; in cases with marked cyanosis the concentration of
the blood also raises its density. Attempts to apply -the serum test
in this disease have generally been disappointing, most reports
having shown that pneumococci are either unaffected by the serum
of pneumonia patients or, at the most, agglutinate slowly and
atypically. (See p. 526.) Rosenow,1 however, reports positive
findings' in 77 of 83 cases examined, and Huber 2 has applied the test
in 10 cases, claiming uniformly positive results, the reaction ap-
pearing as early as the fifth day of the disease, increasing in inten-
sity toward crisis, and slowly disappearing by about the tenth day.
Pneumonia, like enteric fever, is an example
BACTERIOLOGY, of an acute infection which in the great majority
of instances must be classed as a true bacteriemia,
even in its early stages. With modern technic it is now possible
to culture the pneumococcus from the circulating blood in about
70 per cent, of all cases of acute pneumonia, although until within
recent years positive bacteriological findings were the exception
1 Medicine, 1903, vol. ix, p. 435.
2 Centralbl. f. inn. Med., 1902, vol. xxiii, p. 417.
506 GEkERAL HEMATOLOGY.
rather than the rule. Since 1900 the following statistics have been
recorded: Prochaska,1 50 cases, all positive, with 12 deaths; Rose-
now,2 83 cases, 74 positive, mortality, 45 per cent.; Silvestrini
and Sertoli,3 16 cases, 15 positive; Pieracinni,4 28 cases, n positive;
Landi and Cionini,5 27 cases,* 25 positive; Kinsey,6 25 cases, 19
positive,7 of which 31 per cent, died; and Cole,8 30 cases, 9 positive,
all of which were fatal. In contrast with these figures the results of
the earlier investigators should be compared. Of 49 cases studied
by Beco,9 7 were positive, with 5 deaths. Sello,10 in 48 cases,
found 12 positive results, of which 10 ended fatally. Kraus11 ex-
amined 21 cases, with but 2 positive findings, both in fatal cases.
Franklin W. White,12 in 19 carefully studied cases of pneumonia,
obtained positive results in 3 patients, all of whom died; of the 16
negative cases, 7 proved fatal. Sittmann 13 found the pneumo-
coccus in 6 of 16 cases examined by him, in 4 cases by cul-
tural methods, and in 2 in stained cover-slip preparations of the
blood; of these 6 positive cases, 4 died, and of the 10 negative
cases but a single one ended fatally. Kohn14 examined 32 cases,
obtaining positive results in 9, of which number 7 cases were
fatal, while the other 2 finally recovered after a grave infection ;
of this author's 23 negative cases recovery took place in 8. James
and Tuttle,15 in their studies of 12 cases, 2 of which were fatal,
failed in every instance to obtain positive findings.
Analysis of the above data affords a total of 159 positive findings
in which the outcome of the disease is definitely stated by the ob-
server, and of these 159, 96 ended fatally — a mortality of 60.7
per cent. It is obvious, from these figures, that pneumococcemia,
although it means a well-marked infection, is by no means a
hopeless sign, as was once believed.
1 Centralbl. f. inn. Med., 1900, vol. xxi, p. 1145; also Deutsch. Arch. f. klin.
Med., 1901, vol. Ixx, p 559.
2 Loc. cit. 3 Centralbl. f. allg. Path. u. pathol. Anat., 1900, vol. xi, p. 447.
4 Ibid., 1900, vol. xi, p. 460.
5 Deutsch. med. Wochenschr., 1901, vol. xxxvii, p. 296.
8 Jour. Amer. Med. Assoc., 1904, vol. xlii, p. 759.
7 The proportion of bouillon to blood in this series was 15 or 20 to i. In
another.series of 25 cases, with a 6 : i dilution, only 3, or 12 per cent., of the cultures
were positive.
8 Johns Hopkins Hosp. Bull., 1902, vol. xiii, p. 136.
8 Rev. de med., 1899, vol. xix, pp. 385 and 461.
10 Zeitschr. f klin Med , 1898, vol. xxxvi, p 112.
11 Zeitschr. f. Heilk., 1896, vol. xvii, pp. 117 and 138.
12 Jour. Exper. Med., 1899, vol. iv, p. 425.
13 Deutsch. Arch. f. klin. Med., 1894, vol. liii, p. 323.
14 Deutsch. med. Wochenschr., 1897, vol. xxiii, p. 136.
15 Med. and Surg. Rep. of the Presbyterian Hosp., New York, 1898, vol. iii,
p. 46.
PNEUMONIA.
507
During the active stages of the fever the hemo-
HEMOGLOBIN globin and erythrocytes are either normal or
AND very slightly diminished. But polycythemia also
ERYTHROCYTES. may occur, as the result of the fever's influence
in causing contraction of the peripheral vessels,
or from cyanosis. During the post-febrile period moderately
low counts are usually found, being due possibly to the hemo-
cytolytic effects of the fever, and to a dilution of the blood caused
by the decreased arterial tension which occurs at this stage of
the illness. The loss, in the writer's experience, amounts in the
average case to about 20 per cent, of the normal number of cells,
with a slightly greater hemoglobin decrease — approximately 25
per cent. Poikilocytosis and other structural changes in the cells
are to be noted only in severe cases. In 109 hospital cases of
croupous pneumonia the hemoglobin and erythrocyte values were
within the following limits:
HEMOGLOBIN
PERCENTAGE
NUMBER
OF CASES.
NUMBER
OF CASES.
From 90-100. ... 8
" 80- 90 38
" 70- 80 29
" 60- 70 14
" 50- 60 12
40-50 7
30-40 i
Average, 75.0 per cent.
Maximum, 98.0
Minimum, 26.0
ERYTHROCYTES
PER C.MM. .
Above 5,000,000 3
From 4,000,000-5,000,000 60
3,000,000-4,000,000. . . .41
" 2,000,000-3,000,000. ... 4
" 1,000,000-2,000,000 i
Average, 4,048,833 per c.mni.
Maximum, 5,070,000 " • "
Minimum, 1,880,000 " "
In pneumonia, as in other acute infections, the
LEUCOCYTES, severity of the infective process and the intensity
of the reaction on the part of the organism are
the factors which determine the behavior of the leucocytes, In
the great majority of cases a well-marked leucocytosis develops
at or soon after the time of the initial chill, and persists until
shortly after the temperature has fallen to normal.
A high leucocytosis indicates a severe infection in an indi-
vidual of strong resisting powers. A moderate increase indicates
either a slight infection coupled with good resistance, or an in-
tense infection with an inadequate reaction. Little or no leuco-
cyte increase also suggests one of two diametrically opposite con-
ditions : either an infection too trivial to excite reaction, or one so
severe as to overpower the organism, stifling reaction. Ewing1
*N. Y. Med. Jour., 1893, vol. Iviii p. 715.
508 GENERAL HEM ATO LOGY.
has found that, as a rule, the increase is greater in cases with
extensive lung involvement than in those with limited lesions, but
this parallelism between the degree of leucocytosis and the extent
of the pneumonic process is approximate, and does not always
hold good. In a general sense it applies only to cases which
react well toward the disease. There is no relationship between
the degree of increase and the degree of fever during the active
stages of pneumonia.
In the average well-marked case the number of leucocytes
usually ranges between 20,000 and 30,000 per c.mm., the latter
figure being only rarely exceeded, as, for example, in severe sthenic
cases, in which the count may rise to 40,000 or 50,000, or even
higher. To illustrate the constancy of leucocytosis in pneumonia
the table given below shows that this sign developed in about two-
thirds of the 153 cases examined. Summing up a total of 470 cases
reported by various observers, it is found that the average "first
count" of the leucocytes, during the febrile stage of the disease, was
22,693, this figure applying to all cases, both with and without
leucocytosis. In the writer's experience the average has been
distinctly lower — 16,066 per c.mm. Absence of leucocytosis is of
unfavorable prognosis, except in patients in whom the clinical
type of the infection is obviously mild. The occurrence of a high
leucocytosis is of no definite prognostic value, since it indicates
simply a marked infection and good resisting powers.
The following table shows the range of the leucocytes in 153
hospital cases of pneumonia :
LEUCOCYTES PER C.MM. NUMBER OF CASES.
Above 50,000 i
From 40,000-50,000 4
" 30,000-40,000 2
2O,OOO-3O,OOO 24
15,000-20,000 35
10,000-15,000 34
5,000-10,000 49
Below 5,000 4
Average, 16,066 per c.mm.
Maximum, 83,600 " "
Minimum, 3,200 " "
To these figures may be added the counts made in 10 cases
of catarrhal pneumonia, which ranged between 8000 and 40,000,
and averaged 15,210 per c.mm. Seven of the cases showed definite
leucocytosis — namely, a count exceeding 10,000.
In cases terminating by crisis the leucocytes begin to diminish
PNEUMONIA. 509
either a short time before or after the temperature commences
to decline, the normal number being reached, in most cases, within
twenty-four or forty-eight hours after crisis occurs, although in a
small proportion of cases the decrease is much slower, the count
sometimes not reaching normal until a week after the tempera-
ture has dropped. False crises, although they may cause a striking
drop in the temperature, do not cause a decline of the leucocyte
curve.
In cases ending by lysis the decrease in the number of leucocytes
and the decline in the temperature begin simultaneously, but
the latter reaches normal much more rapidly than the former; the
leucocyte decrease progresses more gradually than in the cases
ending by crisis, and the normal count is often not reached until
a week or ten days after the temperature has fallen to t'he normai
figure. At the beginning of lysis a correspondence may be
distinguished between the diurnal fluctuations of the temperature
and leucocyte curves, although no such relation is apparent during
the febrile period of the disease.
It is an interesting fact that in about half of all cases, whether
ending by crisis or by lysis, the maximum count of leucocytes is
attained during the period of temperature decline.
Von Jaksch's 1 idea of injecting substances to cause leuco-
cytosis in pneumonia where this phenomenon was absent, hoping
thereby to benefit the patient, has not been attended by the favor-
able results which he anticipated. Leucocytosis is as promptly
induced in the pneumonic as in the healthy individual,- by the
injection of nuclein, for example, but without beneficial effect
upon the patient's condition, a fact which must be regarded as
evidently signifying that an absence of leucocytosis in fatal cases
is not the cause of death, as Billings 2 remarks. Borini 3 injected
digitalis and aleuron into rabbits inoculated with virulent pneu-
mococci, and found that the animals treated with digitalis sur-
vived the infection longer than those to which aleuron was given.
Both substances caused leucocytosis, but that excited by aleuron
was transient, while that caused by digitalis persisted for some
time — a fact to which Borini believes the beneficial effects of
digitalis in the treatment of pneumonia are largely due. In a series
of German Hospital cases reported by J. C. Wilson 4 the injec-
tion of antipneumococcus serum was followed by a marked increase
in the number of leucocytes, though his method of treatment did
not perceptibly lower the mortality.
1 Cited by Cabot, loc. cit. J Johns Hopkins Hosp. Bull., 1894, vol. v, p. 112.
* Centralbl. f. Bakt. u. Parasit, 1902, vol. xxxii, p. 207.
4 Jour. Amer. Med. Assoc., 1900, vol. xxxv, p. 595.
510 GENERAL HEMATOLOGY.
Hare * has drawn attention to the fact that while leucocytosis
is checked by antipyretics, it is not arrested by cold sponging, an
observation which prompts Cabot 2 to declare in favor of the latter
method of reducing temperature in pneumonia.
The leucocytosis of pneumonia is of the typical variety — that is,
it is due to a large absolute and relative increase in the poly-
nuclear neutrophiles, with a consequent relative decrease in lym-
phocytes. The proportion of eosinophiles is much reduced, and
frequently these cells are entirely wanting. This is regarded as
an unfavorable sign by Becker,3 who states that he has never
found eosinophiles in fatal cases. It is of interest to contrast with
this circulatory poverty in eosinophiles the great abundance of these
cells in serous blister fluid of pneumonia patients, as determined by
Audibert.4 In 27 cases of various diseases this observer found the
highest percentages of eosinophiles in pneumonia — much higher,
for example, than in pleurisy, phthisis, influenza, rheumatic fever,
or erysipelas. With the decline of the temperature and the
fading away of the leucocytosis, the percentage of polymorphous
cells rapidly falls to normal or subnormal, and the lymphocytes
and eosinophiles increase until they regain their normal percen-
tages. The latter cells usually begin to reappear in the circulation
a day or two before defervescence, and in some instances a striking
post-febrile eosinophilia develops. In 20 cases showing marked
leucocytosis, Billings found the following averages : lymphocytes,
9.6 per cent. ; polynuclear neutrophiles, 91.2 per cent. ; eosinophiles,
0.2 per cent. Heim 5 found a similar degree of polynuclear neutro-
phile increase in 19 cases. In 3 of Billings' counts in fatal cases
showing no leucocytosis it was found that the various forms of
leucocytes remained in their normal relative proportions. The
leucocytes usually respond to the iodin reaction, most strikingly in
cases with high leucocytosis. In such instances myelocytes are
generally numerous.
In the pneumonias of children the possibility of lymphocytosis
should be remembered, for although a true lymphocytosis is rare,
it sometimes occurs, giving rise to false impressions if clinical
signs 'other than the examination of the blood are neglected. (See
P- 253-)
During the period of fever the blood plaques are markedly de-
creased in number, and often, indeed, altogether disappear from
the blood, but after the crisis they reappear in great abundance,
1 Therapeutic Gaz., 1898, vol. xii, p. 153.
2 Loc. cit. 3 Deutsch. med. Wochenschr., 1900, vol. xxvi, p. 558.
4 Presse me"d , 1902, vol. xv, p. 1256.
5 Arch, de me"d. des Enf., 1901, vol. iv, p. 21.
POISONING. 511
the fresh specimen taken at this time often being flooded with
these bodies.
In atypical cases the presence of a well-
DIAGNOSIS. marked leucocytosis is a helpful sign in exclud-
ing such conditions as serous pleurisy, enteric
fever, typhus fever, malarial fever, and influenza. In the differ-
entiation of croupous from catarrhal pneumonia, empyema, and
acute meningitis the leucocyte count furnishes no tangible clue,
since it is high in all these conditions; the same is true of some
cases of acute bronchitis. An acute apical pneumonia, if associ-
ated with leucocytosis, is almost invariably to be considered non-
tuberculous. ,
As previously stated, absence of leucocytosis in a case with well-
defined chest signs is of a grave prognosis, but the presence of a
leucocytosis is by no means always of good augury. Persistence
of a high leucocyte count is suggestive of delayed resolution,
empyema, or gangrene, and a sudden reestablishment of the
leucocytosis, after its disappearance at the ttime of crisis, points to a
recurrent attack of the disease. Reappearance of the eosinophiles
and disappearance of the iodin reaction . indicate the termination
of the acute phase of the illness. Post-critical iodophilia is most
suggestive of delayed resolution or of a more serious pulmonary
sequela.
Detection of the pneumococcus in the peripheral circulation
indicates a severe infection, but it is not per se a grave prognostic
sign.
LX. POISONING.
A synopsis of the blood changes produced by various toxic
substances is given in the following table, these changes consist-
ing chiefly in hemocytolysis, methemoglobinemia, anemia, poly-
cythemia, and leucocytosis.
NAME OF POISON. EFFECTS UPON THE BLOOD.
Alcohol Anemia; often leucocytosis.1
Amyl nitrite Methemoglobinemia.2
Acetanilid Marked anemia, with many erythro-
blasts and stroma degeneration; leu-
cocytosis ; increase of plaques ;s eosino-
philia ;4 methemoglobinemia.5
1 Cabot, loc. cit. * Grawitz, loc. cit.
3 Stengel and White, Univ. of Penna. Med. Bull., 1903, vol. xv, p. 462.
4 Leredde and Pautrier, Sem. me"d., 1903, vol. xxx, p. 224.
5 Miiller, Deutsch. med. Wochenschr., 1887, vol. xiii, p. 27.
512 GENERAL HEMATOLOGY.
NAME OF POISON. EFFECTS UPON THE BLOOD.
Ammonia ' Leucocytosis.1
Antipyrin Methemoglobinemia.2
Arseniuretted hydrogen. . .Hemoglobinemia.3
Aspidium Hemocytolysis.4
Bromin Methemoglobinemia.5
Carbon monoxid Methemoglobinemia; diminution of
oxygen content;6 polycythemia; leu-
cocytosis; carbonyl hemoglobin.7
Chloral Leucocytosis.1
Chloroform Oligochromemia; leucocytosis ; 8 oligo-
cythemia; 9 diminished alkalinity.10
Chromic acid .Methemoglobinemia.3
Corrosive metallic salts Anemia; leucocytosis.1
Ether Oligochromemia; leucocytosis.11
Fusel oil Hemocy tolysis ; methemoglobinemia.12
Guaiacol Hemocy tolysis ; j leucocytosis; relative
lymphocytosis.13
Hydrocyanic acid Methemoglobinemia.14
lodin Methemoglobinemia.5
Lead Anemia; granular basophilia; often
leucocytosis.15
Nitrobenzene Methemoglobinemia ; megaloblastic an-
emia;16 eosinophile leucocytosis.17
Nitroglycerin Methemoglobinemia.3
Opium Occasionally leucocytosis.1
Phenacetin Methemoglobinemia.18
Phosphorus Polycythemia; occasionally leucocyto-
sis;19 slow coagulability.20
Potassium chlorate Methemoglobinemia; anemia; leucocy-
tosis.21
1 Cabot, loc. cil. * Miiller, loc. cit. 3 Grawitz, loc. cit.
4 Georgiewsky, Beitr. z. path. Anat. u. z. allg. Path., 1898, vol. xxiv, p. i.
6 Hayem, Compt. rend. Soc. biol., Paris, 1886, vol. cii, p. 698.
' Lacassagne, Martin, and Nicloux, Sem. med., 1903, vol. xxiii, p. 25.
7 Yarrow, Amer. Med., 1904, vol. iv, p. 338.
8 Holman, Jour. Amer. Med. Assoc., 1902, vol. xxxix, p. 939.
'• Loewy and Paris, Compt. rend. Soc. biol., Paris, 1902, vol. h'v, p. 188.
10 Baccarani, Gaz. degli Osped. e. d. Clin., 1900, vol. xlii, p. 445.
11 DaCosta and Kalteyer, Annals of Surg., 1901, vol. xxxiv, p. 329.
12 Futcher, Amer. Med., 1901, vol. ii, p. 210.
1J Wyss, Deutsch. med. Wochenschr., 1894, vol. xx, p. 296.
14 Robert, "Lehrb. d. Intoxicationen," Stuttgart, 1893.
15 Grawitz and Hamel Deutsch. Arch. f. klin. Med., 1900, vol. Ixvii, p. 357
18 Ehrlich and Lindenthal, Zeitschr. f. klin. Med., 1896, vol. xxx, p. 427.
17 Personal observation.
18 Kronig, Berlin, kh'n. Wochenschr., 1898, vol. xxxii, p. 998.
19 Von Jaksch, Deutsch. med. Wochenschr., 1893, vol. xix, p. 10.
20Cevidalli, Phila. Med. Jour., 1903, vol. xi, p. 248.
21 Bradenburg, Berlin, klin. Wochenschr., 1895, vol. xxxii, p. 583.
RABIES. 513
NAME OF POISON. EFFECTS UPON THE BLOOD
Potassium permanganate . Methemoglobinemia. 1
Ptomains Leucocytosis.2
Pyrodin Hemocytolysis.3
Pyrogallol Methemoglobinemia.4
Snake and'scorpion venom. Hemoglobinemia ; 5 agglutination of
erythrocytes;6 diminished coagula-
lation;7 leucocytosis.8
Sodium nitrite Methemoglobinemia.4
Tansy Leucocytosis.2
Toadstools Hemoglobinemia.9
Toluene Hemoglobinemia.10
Toluyldndiamin Marked anemia; hemocytolysis ; eosino-
phile leucocytosis; increase of
plaques.11
Turpentine Methemoglobinemia.12
LXI. RABIES..
Courmont and Lesieur13 have determined that an exces-
sive increase in the number of polyriuelear neutrophiles is a
constant change in the blood of patients suffering from hydro-
phobia, and that analogous findings are met with experimentally
in rabid dogs, guinea-pigs, and rabbits. The polynuclear gain is
frequently, but not invariably, associated with an increase in the
total number of leucocytes. It may amount to as much as 98
per cent., and first develops during the period of incubation, be-
coming emphasized with the appearance of the clinical symptoms
of the affection, and reaching a maximum just before death.
The authors referred to believe that an absence of polynucleosis
is sufficient to rule out rabies in a suspected case, although its
presence cannot be regarded as pathognomonic of the disease.
I Hayem, loc. cit. 2 Cabot, loc. oil.
8 Tallquist, "Exper. Blut-gift Anamie," Berlin, 1900. 4 Grawitz, loc. cit.
•Mitchell and Stewart, "A Contribution to the Study of the Effect of the
Venom of Crotalus adamanteus upon the Blood," Washington, 1898; also Rogers,
Lancet, 1904, vol. i, p. 349. (As a rule, colubrine venoms causes slighter blood
destruction than those of the viperine type. According to Elliot [Lancet, 1904,
vol. ii, p. 143], the venom of the common krait causes neither hemolysis nor ab-
normal clotting.)
8 Flexner and Noguchi, Proc. Phila. Path. Soc., 1903, vol. vi, p. 88.
7 Lamb, Glasgow Med. Jour., 1903, vol. lix, p. 80.
8 Auche" and Vaillant, Jour, de Me"d. de Bordeaux, 1901, vol. xxxi, p. 29.
• Robert, loc. cit. 10 Vast, Thfcse de Paris, 1889.
II Schwalbe and Solley, Virchow's Arch., 1902, vol. clxviii, p. 399.
12 Hayem, loc. cit. a Sem. me"d., 1901, vol. xxi, p. 61.
33
GENERAL HEMATOLOGY.
LXII. RELAPSING FEVER.
The specific cause of relapsing fever, a spiril-
PARASITOLOGY. him discovered by Obermeier in I868,1 may be
found in the peripheral blood of patients suffer-
ing from this disease, only during and shortly before the febrile
paroxysm, the organism disappearing from the general circulation
during the interparoxysmal afebrile period. The number. of para-
sites found in a blood film varies within wide limits, and does not
generally stand in any definite parallelism to the severity of the
infection or to the degree of pyrexia.
Microscopically, the spirilla of Obermeier appear in the fresh
FIG. 63. — SPIRILLA OF RELAPSING FEVER.
blood as delicate, homogeneous, thread-like bodies twisted into
the form of spirals, occurring singly or in groups of several or-
ganisms, radiating from a common center (Fig. 63). The length
of the parasites varies from 1 6 to 40 ,«, or approximately from two
to six times the size of the normal erythrocyte. They possess an
active vibratile motility, exerted in the direction of their long axes,
by 'virtue of which they are propelled and constantly altered in
shape. Owing to this characteristic motility the presence of the
pa*rasites is usually first betrayed to the examiner by the whipping
about of the blood corpuscles in their immediate proximity. The
spirilla remain alive for only a short time after the withdrawal
of the blood, and are so extremely sensitive to external influences
that the addition even of distilled water causes them rapidly to
1 Centralbl. f. d. med. Wissensch.. 1873, vol. xi, p. 145.
RELAPSING FEVER. 515
disappear. Since nothing is known of their life history, the cause
of their disappearance from the peripheral circulation during the
intermissions of the disease is not known.
Both Sarnow1 and von Jaksch2 have called attention to the
presence of certain refractive bodies, similar to diplococci, which
may be found in the blood during the intermission, provided that
another paroxysm is impending. The last-named authority be-
lieves that he has observed the metatnorphosis of these bodies
into short thick rods from which the typical spirilla eventually
are evolved, and he tentatively regards them as spores of the
latter. The views of this investigator have not, however, been
generally accepted up to the present time.
Afanassiew3 has described, in addition to the specific spirilla,
peculiar bacteria which he found in the blood during the parox-
ysm. The organisms in question resemble bacilli with rounded
poles, and appear to be invested by non-staining, hyaline sheaths.
Some of them measure not more than -5 or 6 /./ in length, while
others appear as filamentous threads fully 10, 12, or 14 // long,
this increase in size being demonstrable in the fresh specimen
watched for some time under the microscope. Afanassiew asserts
that, unlike Obermeier's spirilla, the bodies may be cultivated on
bouillon, gelatin, agar, and blood serum; he further claims that,
in three patients inoculated with a twenty-four-hour-old bouillon
culture of the organism, periods of pyrexia, recurring at ten-day
intervals, were produced, and that in the blood of one of the
patients thus treated numerous bacillary and filamentous forms
were discovered. These investigations, as yet unconfirmed by
other workers, are to be regarded only in the light of an interesting
observation.
Melanin granules, either free or within the protoplasm of the
leucocytes, are frequently seen in the blood, especially just after
a paroxysm, and phagocytes containing engulfed spirilla may also
be found at this time.
Technic of Examination. — Fresh specimens of blood, taken
during the paroxysm, from the patient's finger or ear, are most
suitable for microscopical examination. The motility and finer
structure of the spirilla are seen most clearly with a y^-inch oil-
immersion objective, but for making the preliminary search a lower
power, dry lens is more convenient, a |- or J-inch objective being
useful for this purpose.
Dried films, fixed by one of the chemical methods of fixation
1 Inaug. Dissert., Leipsic, 1882.
J "Clinical Diagnosis," 30*. ed., London and Philadelphia, 1897, p. 50.
8 Centralbl. f. Bakt. u. Parasit., 1899, vol. xxv, p. 273.
516 GENERAL HEMATOLOGY.
already described (p. 80), may be stained preferably by fuchsin,
or the method of Giinther (p. 112) may be used. For diagnostic
purposes stained specimens are never to be preferred to the fresh
blood film.
Lowenthal's Reaction. — The ingenious blood test devised by
Lowenthal * furnishes a means of recognizing relapsing fever dur-
ing- the afebrile period, when the spirilla cannot be detected in the
blood. It is conducted in the following manner: A drop of
blood from a suspected case is mixed with a drop containing
motile spirilla, the latter being taken from a patient during the
paroxysmal stage of the disease. The mixture thus made is
sealed between a slide and cover-glass, and incubated at body
temperature for half an hour, at the end of which time it is ex-
amined under the microscope. If the suspected case is one of
relapsing fever, the spirilla will have become quite motionless and
collected together in regular masses, while if the case is one of
some other disease, the motility of the parasites remains unim-
paired. A control specimen, prepared from normal and spirilla-
containing blood, must always be similarly incubated and ex-
amined with each test. If no such reaction as that described
occurs within a time limit of two hours and one-half at the most,
it is safe to regard the suspicious case as one not of relapsing
fever. In 35 cases of this disease Lowenthal obtained about 85
per cent, of positive results, while in 14 cases of fever due to other
causes the reaction was uniformly absent.
The reaction, which takes place in abortive and mild cases as
well as in the severer forms of the disease, is thought to be de-
pendent upon the presence in the blood of specific bactericidal
products.
Von Limbeck,2 quoting von Bockmann, states
HEMOGLOBIN that there is a decrease in the number of erythro-
AND cytes and in the hemoglobin value in cases of re-
ERYTHROCYTES. lapsing fever, but neither the mode of production
of such an anemia nor the exact morphological
changes by which it is characterized has been carefully investi-
gated, so far as can be ascertained. The losses are observed to
occur during and for a few days after each paroxysm, but they
are partly compensated during the interparoxysmal period.
A variable degree of increase in the number of
LEUCOCYTES, leucocytes, often of high grade, has been described
by Laptschinski3 as associated with the paroxys-
mal stage of the disease, this observer having noted that the poly-
1 Deutsch. med. Wochenschr., 1897, vol. xxiii, p. 560.
1 Loc. cit. 8 Centralbl. f. d. med. Wissensch., 1875 vol. xiii, p. 36.
RELAPSING FEVER. 517
nuclear neutrophiles were especially involved, and that the relative
number of leucocytes to erythrocytes was in some instances as
high as i to 37. During the period of intermission this leucocytosis
disappears. This author, as well as von Bockmann1 and Heiden-
reich,2 also noted that the period of maximum leucocytosis was
reached just after the crisis. Melkich,3 in 14 cases of spirillum
fever, noted that the highest counts were attained twenty-four
hours before the crisis, after which the leucocytosis persisted for
a day or two and then rapidly declined, the effect of each succeeding
relapse being to accentuate this post-critical hypoleucocytosis.
The same worker, in collaboration with Kalyapin,4 also de-
termined that in this infection no direct relation exists between
the leucocyte count and the richness of the blood in alexins.
These substances, which are found most abundantly during the
initial paroxysm, begin to diminish just before the crises, still
further decrease during the afebrile periods, and again increase
with the febrile recurrences. With convalescence the alexins rise
to high figures and remain so until recovery takes place.
Phagocytosis occurs with great constancy in the peripheral
blood. Ivanoff,5 who first demonstrated this fact, has shown that
phagocytic leucocytes containing fragments of spirilla are almost
invariably present in the finger-blood of this infection. Espe-
cially is this the case in immunized monkeys, in whose blood
intracellular spirilla are the rule and extracellular spirilla the
exception.
The detection of the spirillum in the blood
DIAGNOSIS, immediately differentiates relapsing fever from
typhus fever, the onset and initial symptoms of
which not infrequently prove confusing, and it may also be added
that in such instances the absence of this organism during the stage
of pyrexia is strong evidence for excluding the first-named disease.
During the afebrile period, when the symptoms may suggest, for
example, malarial fever, Lowenthal's reaction should be attempted,
and the malarial parasite searched for. Melanemia, it must be
recalled, may be encountered in each of these infections.
1 Loc. cit. 2 "Untersuch. u d. Par. d. Ruckfallstyphus," Berlin, 1877.
3 Russkiy Vrach, 1903; abst., Med. News, 1903, vol. Ixxxiii, p. 1031.
* Ibid. 8 Centralbl. f. Bakt. u. Parasit., 1897, vol. xxii, p. 117.
518 GENERAL HEMATOLOGY.
LXIII. RHEUMATIC FEVER.
Coagulation of the blood takes place within the
GENERAL normal time limit, or it may be delayed consider-
FEATURES. ably. The amount of fibrin is markedly in-
creased, especially during the most acute stages of
the illness. Contradictory reports have been made by different
authors concerning the alkalinity, some having found it dimin-
ished, and others having been unable to detect any such altera-
tion. According to Hutchinson,1 the general consensus of opinion
is against any notable disturbance of the normal figure. In chronic
articular rheumatism with coexisting anemia a slight diminution
of the alkalinity is occasionally observed.
The bacteriology of the blood in this disease has for many years
been the object of much careful study, but thus far specific
properties have not been generally conceded to any definite
organism, although many different bacilli, streptococci, staphylo-
cocci, and diplococci have been cultivated from the circulating
blood during life. Most suggestive are the investigations of
Paine and Poynton,2 who discovered a micrococcus, growing in
streptococcal chains, in the blood of 18 cases of rheumatic fever.
This organism is closely allied to, if not identical with, that
previously described by Wasserman,3 Triboulet,4 and others. The
same micrococcus has been cultured by Beaton and Walker5 in
15 cases — 8 of acute rheumatic fever, 4 of rheumatic endocarditis,
and 3 of chorea. Rabbits inoculated with this organism die
after developing fever, arthritides, endocarditis, pericarditis, and
sepsis, and from their cadavers the micrococcus can be recovered
in pure culture. Shaw,6 who recently confirmed the above find-
ings, succeeded in carrying out two successful inoculation experi-
ments with monkeys. These investigators claim to have differen-
tiated this "Micrococcus rheumaticus" from the ordinary Strepto-
coccus pyo genes (which Singer 7 believes to be the germ described)
by Marmorek's method of culturing it upon filtered streptococcus -
bouillon in which streptococci of human origin fail to develop.
1 Lancet, 1896, vol. i, p. 615.
2 Brit. Med. Jour., 1900, vol. ii, pp. 861 and 932; also ibid., 1901, vol. ii,
P- 779-
8 Berlin, klin. Wochenschr., 1899, vol. xxxvi, p. 638.
4 Rev. de med., Paris, 1888, vol. xviii, pp. 189 and 329; also Triboulet, Coyon,
and Zadoc, Bull. Soc. me"d. des hop. de Paris, 1897, vol. xiv, p. 1343; also
"Le Rheumatisme articulaire aigu en bacteriologie," Triboulet et Coyon, Paris,
1900.
s Brit. Med. Jour., 1903.. vol. i, p. 237; also Walker, Practitioner, 1903, vol.
Ixx, p. 185.
8 Jour. Path, and Bact., 1903, vol. be, p. 158. 7 Ibid., 1901, vol. ii, p. 780.
RHEUMATIC FEVER. 519
Additional proof of the specificity of this organism, together with
a study of the toxic specificity of rheumatic fever and of the mode
of infection, is necessary before the organism in question can
be universally credited as the exciting factor of the disease.
Few cases of acute rheumatic fever are unac-
HEMOGLOBIN companied by anemia, the intensity of which
AND generally bears a fairly close relation to the se-
ERYTHROCYTES. verity and the duration of the illness. In acute
attacks of short duration the hemoglobin falls to
about 70 or 80 per cent, and the erythrocytes to 4,000,000, but
in cases of longer standing the losses are likely to be more pro-
nounced, the count often being not more than 3,000,000 or there-
abouts. The color index usually is moderately subnormal, and
may tend to remain so after the attack, even though the rise nor-
malward of the erythrocyte count may have become well estab-
lished. In the exceptional case, however, it may be quite as high
as in pernicious anemia; in 4 of 32 cases noted below the index
was above i.oo. In chronic rheumatism a moderate oligo-
chromemia is usually the only evidenca of anemia that can be
detected, unless the patient happens to be decidedly cachectic.
In the writer's experience, the erythrocytes fall below 3,000,000
in about one case in every five; in an occasional case the anemia
may be intense, as in two of those tabulated below, with hemo-
globin figures of 26 and 30 per cent, and counts of 1,242,000 and
1,590,000, respectively. In the following table of 32 cases it will
be noted that the anemia averages greater than most authors
report :
HEMOGLOBIN NUMBER ERYTHROCYTES NUMBER
PERCENTAGE. OF CASES. PER C.MM. OF CASES.
From 90-100. . . .3 From 4,000,000-5,000,000 16
" 80-90 5 " 3,000,000-4,000,000 9
" 70-80 7 " 2,000,000-3,000,000 5
60-70 3 " 1,000,000-2,000,000 2
" 50-60 8
40-50 2
30-40 o
20-30 4
Average, 63 per cent. Average, 3,686,648 per c.mm.
Maximum, 92 Maximum, 4,980,000 '
Minimum, 26 " Minimum, 1,242,000 "
The average hemoglobin percentage in 33 cases studied by
McCrae l was 73.4, and the average erythrocyte count, 4,636,000.
1 Amer. Med., 1903, vol. vi, p. 22.
520 GENERAL HEMATOLOGY.
Cabot's 43 cases 1 averaged 67 per cent, of hemoglobin and 4,400,-
ooo erythrocytes per c.mm.
Should the cellular loss reach a high grade, deformities of
shape and size, polychromatophilia, and, rarely, nucleated erythro-
cytes of the normoblastic type, may be observed.
Leucocytosis of the typical polynuclear neutro-
LEUCOCYTES. phile type is almost always present during the
acute stages, but it is found only exceptionally in
the subacute form of rheumatism, and practically never exists in
the chronic variety. The count does not often exceed twice the
maximum number of cells found normally, but occasionally it
reaches a figure as high as 30,000 or 40,000 per c.mm. It is in
cases with intense pyrexia, with endocarditis or pericarditis, and
with pulmonary complications that high leucocytoses are most
commonly found.
In 32 cases the leucocyte counts ranged as follows:
LEUCOCYTES PER C.MM. NUMBER OF CASES.
Above 20,000 2
From 15,000-20,000 9
" 10,000-15,000 8
5,000-10,000 ii
Below 5,000 2
Average, 12,218 per c.mm.
Maximum, 31,200 "
Minimum, 4,800 "
McCrae's leucocyte figures in 36 cases averaged 12,370, and
in but 9 was the count below 10,000 at the first examination.
In Cabot's cases, above referred to, the number of leucocytes
averaged 16,800, and ranged from 4700 to 39,000.
Turk 2 has noticed that in many instances well-marked post-
febrile eosinophilia develops, and that in favorable cases a relatively
high percentage of eosinophiles persists during the acute stage of
pyrexia. Both Korowicki 3 and Patella 4 describe a mononucleosis
in cases with endocarditis, but the writer has been unable to verify
this finding.
The blood changes are uncharacteristic, and
DIAGNOSIS, do not serve as a means of differentiating this con-
dition from other lesions in which the joint in
volvement and the constitutional manifestations are more or less
1 Loc. cit. * Loc. cit.
8 Deutsch. Aerzte-Zeitung, 1903, vol. i, p. 241.
4 Sem. m€d., 1903, vol. xxiii, p. 368.
SCARLET FEVER. 521
similar. Thus, in acute gout, in multiple secondary arthritis, and
in septic arthritis due to pyemia the same grade of anemia, leuco-
cytosis, and hyperinosis may be observed. In the latter condition
blood culturing may be helpful.1 lodophilia means gonorrheal
arthritis rather than rheumatic fever. (See p. 228.)
LXIV. SCARLET FEVER.
In cases associated with pronounced anginal
GENERAL symptoms and with marked leucocytosis coagu-
FEATURES. lation of the fresh blood drop is rapid and the
amount of fibrin decidedly in excess of normal.
In many cases a slight increase of fibrin is observed at the period
of beginning desquamation.
The specific gravity is unchanged in the average case, but in
those complicated by acute parenchymatous nephritis, in conse-
quence of the drain on the albumins of the blood thus pro-
duced, it may fall to a very low figure — to i .030, according to
Peiper and Hammerschlag.2 In 12 "cases studied by van den
Berg,8 the specific gravity ranged from 1.931 in complicated cases
to i .060 in uncomplicated cases of the average severity.
The specific micro-organism of scarlet fever has not yet been
isolated, either from the blood or other tissues, although in re-
cent years many different bacteria have been described as
causative factors. Class4 claims to have discovered in the blood
and throats of scarlet fever patients a diplococcus, named by him
the Diplococcus scarlatinas, which he considers specific, and this
claim has received the support of a number of other investigators,
Gradwohl,5 Jaques,6 and Page7 being among those who found the
bacterium in question. Baginsky and Sommerfeld 8 conclude, as
have some earlier writers, that the clinical features of scarlet fever
are due to a general streptococcus infection, having found this
organism in the blood of 42 fatal cases. Class," in a later communi-
cation, hints that his diplococcus and Baginsky and Sommerf eld's
streptococcus are identical, since the former often develops strep-
1 See articles on Pneumococcus Arthritis by Herrick (Amer. Jour. Med. Sci.
1902, vol. cxxiv, p. 12) and by Cole (Amer. Med., 1902, vol. iii, p. 905).
z Centralbl. f. klin. Med., 1891, vol. xii, pp. 217 and 825.
3 Arch. f. Kinderheilk., 1898, vol. xxv, p. 321.
4 Med. Rec., 1899, vol. Ivi, p. 330.
5 Phila. Med. Jour., 1900, vol. iv, p. 688.
8 Ibid., p. 552. 7 Jour. Bost. Soc. Med. Sci., 1899, vol. iii, p. 344.
8 Berlin, klin. Wochenschr., vol. xxxvii, p. 588.
9 Jour. Amer. Med. Assoc., 1900, vol. xxxv, p. 799.
522 GENERAL HEMATOLOGY.
tococcus forms in young cultures made from the blood. Any one
who has read Class' description of his organism must be struck
with its resemblance to the diplococcus found in scarlet fever
blood by Crajkowski,1 in 1895. Both Hektoen2 and Jochmann 3
have isolated the streptococcus during life in a large series
of scarlet fever patients, the former in 12 per cent, and the
latter in 15.5 per cent, of cases examined. Hektoen's findings
suggest no definite relationship between the severity of the
disease and the presence of a bacteriemia, for the latter may
develop in mild, uncomplicated cases, and may not occur in
fatal ones; as a rule, however, more colonies grow in cul-
tures made from severe types of the disease. Jochmann de-
cides that the presence of a streptococcemia does not modify
the symptomatology of scarlet fever; excluding those dying of
nephritis, one-half of his fatal cases gave cultures of the strep-
tococcus. Mackie 4 found streptococci and staphylococci in 3 of 6
cases by blood culturing during life. From the findings just stated
it is clear that streptococci in scarlet fever play the r61e not of a
specific factor, but rather of a secondary infection, the relationship
of which to the primary infective agent remains obscure. The
streptococci found in scarlet fever cannot be differentiated from
ordinary forms of this organism; and the immunity conferred by
an attack of scarlet fever protects only against this exanthema,
and not against ordinary streptococcus infections.
, , Jehle5 states that he has repeatedly isolated the influenza
bacillus from the blood of young children ill with scarlet fever.
It may be added that Mallory's protozoa,6 found in the skin of
scarlet fever patients, have not been demonstrated in the circula-
ting blood.
Most observers agree that the scarlatinal infec-
HEMOGLOBIN tion, unless complicated, produces but trifling
AND changes in the hemoglobin and erythrocytes,
ERYTHROCYTES. moderate anemia characterized by a dispropor-
tionate diminution of hemoglobin being the gen-
eral rule in the cases in which any changes are noted.
W-idowitz 7 found that the percentage of hemoglobin, normal
at the beginning of the illness, slowly diminished during the fe-
brile period, in a degree commensurate to the intensity of infec-
1 Centralbl. f. Bakt. u. Parasit., 1895, vol. xviii, p. 116.
1 Jour. Amer. Med. Assoc., 1903, vol. xl, p. 685.
s Deutsch. Arch. f. klin. Med., 1903, vol. Ixxviii, p. 209.
4 Lancet, 1904, vol. i, p. 494. B Zeitschr. f. Heilk., 1901, vol. xxii, p. 190.
* Boston Soc. Med. Sci., Dec. 15, 1903; also Jour. Amer. Med. Assoc., 1904,
vol. xlii, pp. 31 et seq.
1 Jahrb. f. Kinderheilk., 1888, vol. xxvii, p. 380; vol. xxviii, p. 25.
SCARLET FEVER. 523
tion, and gradually returned to normal during convalescence.
Pe"e 1 noticed in severe cases a pronounced "chloro-anemia,"
characterized by notable pallor and variations in the size of the
corpuscles. Hemoglobinemia has also been occasionally observed.
The number of erythrocytes is generally between 4,000,000
and 5,000,000 per c.mm. in the case of average severity, the
minimum count being reached at about the time of the decline
of the temperature; but in complicated cases the anemia is more
marked, and histological degenerative changes of the corpuscles
have been noted during the period of desquamation. Van den
Berg's examinations of 12 cases2 show that the count is usually
above 4,000,000 per c.mm., except in severe cases complicated
by acute nephritis or endocarditis, in the event of which a rapid
and striking anemia is produced, the hemoglobin sometimes being
as low as 25 per cent., and the corpuscles diminishing to as low
as 2,000,000 per c.mm. In addition to these complications severe
streptococcus septicemia may account for a high grade of scarla-
tinal anemia. From an analysis of the cases reported by Zappert,8
Felsenthal,4 Widowitz,5 Hayem,6 and. others the average loss of
erythrocytes in all cases amounts to about 1,000,000 cells to the
c.mm., but Kotschetkoff 7 notes a more decided average reduction,
this author stating that they progressively decrease to about
3,000,000, and that regeneration is slow and gradual, not being
completed for a period of six weeks.
A well-marked leucocytosis, the count usually
LEUCOCYTES, ranging between 20,000 and 30,000 per c.mm.,
occurs in the majority of cases, often 'first ap-
pearing several days in advance of the cutaneous eruption, and
persisting in some cases long after convalescence has been estab-
lished. Its duration varies widely in different instances : in some
cases, not necessarily of a severe type, the leucocytosis persists for
ten, or even thirty, days; while in others, usually of a mild type,
it disappears before the temperature has fallen to normal. The
maximum degree of increase is reached from four to six days after
the onset of the illness.
In asthenic cases the number of leucocytes is increased but
slightly, or not at all; but in the well-nourished child the degree
of leucocytosis may be regarded as a rough gage of the intensity
of the infection, being usually greater in severe than in mild cases.
The increase appears to bear no fixed relationship either to the
1 Inaug. Dissert., Berlin, 1890. 2 Loc. cii.
* Zeitschr. f. klin. Med., 1893, vol. xiii, p. 292.
4 Arch. f. Kinderheilk., 1892, vol. xv, p. 82. ' Loc. cii.
8 St. Petersburg, med. Wochenschr., 1892, vol. i, p. 914.
7 Russkiy Vracn, 1891, vol. xii, p. 919.
524 GENERAL HEMATOLOGY.
anginal infection or to the glandular involvement, for marked leu-
cocytosis has been observed in cases with mild angina unac-
companied by swelling of the glands. Neither can any clear re-
lation be established between the leucocytosis and the character
of the temperature, the period of desquamation, and the inflam-
matory complications of the ear and kidneys.
In all of van den Berg's cases the number of leucocytes was
in excess of normal, the "first counts" averaging slightly more
than 17,000 per c.mm., and the leucocytosis being higher than
30,000 in only 2 cases. The investigations of the other authors
above referred to give practically the same results, although
somewhat higher counts have been made in some instances.
Mackie1 found leucocytosis constant in 25 cases, and in one
patient with severe anginal symptoms the count rose to 93,300.
He failed to observe any signs of a leucocyte increase until twenty-
four hours after the appearance of the rash.
The leucocytosis is generally due to an increase in the poly-
nuclear neutrophiles, these ceUs ranging from 85 to 90 per cent.;
but in some instances the increase is more evenly divided between
the polymorphous and mononuclear forms, so that from 70 to
80 per cent, of the former and from 15 to 30 per cent, of the
latter may be found. The writer has noticed the presence of
large numbers of the so-called transitional mononuclear leu-
cocytes and of an occasional myelocyte. Van den Berg has noted
the presence of small numbers of myelocytes in grave cases.
Contrary to the rule which holds good in most febrile conditions,
the number of eosinophiles in favorable cases of scarlet fever
remains normal, or, indeed, may be decidedly increased. In the
majority of favorable cases the eosinophile increase begins after the
patient has been ill two or three days, and attains a maximum during
the second or third week, after which it progressively diminishes,
the percentage reaching normal by about the sixth week. In
very grave cases a decrease or absence of these cells is usually
found. In cases with nephritic complications their increase is
thought to be favorable. The proportion of eosinophiles is
usually from 4 to 5 per cent, of the other forms, sometimes even
10 or 15 per cent., especially during the post-febrile period of
the disease. Bowie,2 from a study of 167 cases, concludes that
normal or subnormal eosinophile values after the first forty-
eight hours mean a severe infection, and that the graver the case,
the longer the persistence of these low figures.
The blood plaques are normal at the beginning of the attack,
1 Lancet, 1901, vol. ii, p. 525.
2 Jour. Path, and Bacteriol., 1902, vol. viii, p. 82.
SEPTICEMIA AND PYEMIA. 525
but a large increase in their number is said to occur during the
period of desquamation.
The presence of leucocytosis and persistence
DIAGNOSIS, of the eosinophiles are suggestive signs in distin-
guishing scarlet fever from measles, since in un-
complicated cases of the latter disease these changes are absent.
Disappearance of the eosinophiles is regarded as a bad prognos-
tic sign.
LXV. SEPTICEMIA AND PYEMIA.
The blood changes found in those conditions
GENERAL due to the presence in the circulating blood of
FEATURES, septic bacteria or their toxins, general septicemia,
sapremia, and pyemia, are similar, and' therefore
may be considered together under the above heading. An ap-
parently trivial infected wound may give rise to just as severe
blood changes as an intense pyemia with wide-spread metastatic
abscesses, since these alterations depend upon the virulence
of the infection and the reaction which it provokes, rather than
upon the character of the exciting lesion. and the specific nature of
the offending organisms. Clinically, these blood changes may be
associated with such conditions as infected wounds, osteomyelitis,
malignant endocarditis, puerperal fever, septic joints, and many
other lesions for which various septic micro-organisms are held
responsible.
The amount of fibrin is often appreciably increased in cases in
which the reaction against the infection is well marked, especially
in the early stages of the illness. A decrease in fibrin is com-
mon in patients with pronounced anemia and in those who
readily succumb without reaction against the infection.
Thus far the serum test has given no reliable clinical informa-
tion in this class of diseases, although several clinicians of the
French school claim occasionally to have observed typical clump-
ing of streptococcus bouillon cultures with the serum of patients
suffering from streptococcus infections, such as streptococcus in-
fected wounds, sepsis, puerperal fever, and erysipelas; but nega-
tive results were obtained in testing bouillon cultures of the
staphylococcus with the serum of staphylococcus septicemia.
The evidence brought forward to show that the serum of patients
suffering from colon infections clumps cultures of the colon
bacillus is by no means conclusive; for many races of the colon
bacillus, it may be recalled, clump spontaneously and are agglu-
tinated by normal serum.
526 GENERAL HEMATOLOGY.
If a test-tube containing blood serum of a patient suffering
from pneumococcus septicemia is inoculated with a pure culture
of the pneumococcus, it will be found that, after twenty-four
hours' incubation, the serum still remains free from turbidity,
and shows simply a slight sediment composed of pneumococci,
capsuleless and glued together in tenacious clumps or in serpen-
tine, trailing designs. Pneumococci grown in normal serum
cloud the liquid, and develop a new growth, consisting of encap-
sulated, isolated organisms. Favorable results have been reported
by several Continental writers who have used this test clinically,
but its diagnostic value must still be regarded as questionable.
For a review of the literature of serum diagnosis in sepsis and
in other conditions the reader should consult Rosenberger's com-
prehensive article.1
Blood cultures in sepsis are more frequently
BACTERIOLOGY, sterile than productive, but negative results
neither exclude the existence of a septic process
nor necessarily indicate a favorable prognosis. On the other
hand, positive results are often of the greatest value in the
diagnosis of obscure cases of sepsis, in which the clinical mani-
festations are more or less vague. As pointed out by Welch,2
blood cultures in which the Staphylococcus pyogenes albus is dem-
onstrated have little significance in the prognosis of the case,
whereas the presence in the blood of the other pyogenic cocci
is a sign of intense infection.
The results obtained by different investigators in the bacterio-
logical examination of the blood in septicemia vary within wide
limits, these variations being explained partly by the differences
in the technical methods used by each reporter and partly per-
haps by the nature of the infection. Petruschky3 obtained 17
positive results in the examination of 59 cases of sepsis, strepto-
cocci being found in 15 and staphylococci in 2 instances. Sitt-
man4 examined 53 cases of septicemia, and succeeded in iso-
lating streptococci in 4, staphylococci in u, and pneumococci
in 6. CzernieVski5 in 37 cases of puerperal sepsis obtained
positive results in 10, pure cultures of streptococci being found
in all the grave infections. Symes6 obtained positive cultures
in 9 of 31 cases of sepsis, the Staphylococcus, the streptococcus,
the pneumococcus, and the Micrococcus tetragenus having been the
1 Proc. Path. Soc. of Phila., 1904, vol. vii, p. 97.
2 Dennis' "System of Surgery," Philadelphia, 1895, vol. i, p. 251.
3 Zeitschr. f. Hyg. u. Infektionskr., 1894, vol. xvii, p. 59.
4 Deutsch. Arch. f. klin. Med., 1894, vol. liii, p. 323.
8 Arch. f. Gynakol., 1888, vol. xxxiii, p. 73.
* Brit. Med. Jour., 1901, vol. ii, p. 709.
SEPTICEMIA AND PYEMIA. 527
organisms identified. Kiihnau's investigations1 show a much
lower percentage of positive findings than are commonly re-
ported, for this author, in 23 cases of septicopyemia, obtained
growths in only 3 instances, while but a single positive finding
resulted from the examinations of 12 cases of ulcerative endo-
carditis. " Krauss,2 who has had a very large experience in the
bacteriology of the blood in various infectious diseases, re-
ports 7 positive results in a series of 22 cases of septicemia,
ulcerative endocarditis, and erysipelas. White,3 in 18 severe
cases of sepsis, all of which were fatal, obtained positive
findings in 4: the Streptococcus pyogenes 3 times, and the Staphy-
lococcus pyogenes aureus once. Canon* obtained n positive
results in the examination of 17 cases of septicemia, pyemia,
and osteomyelitis. Hirschlaff5 obtained the streptococcus or
staphylococcus 7 times in cultures made from 8 cases of sepsis.
James and Tuttle,8 in 6 severe septic infections, succeeded in
finding the streptococcus m 2 instances. Brieger7 obtained
uniformly negative findings in the examination of 6 cases of
puerperal sepsis. Similar results have also been reported by
Neumann,8 who obtained negative "findings in blood cultures
from 5 cases of pyemia. Grawitz9 cultured pyogenic cocci only
once in his examination of 7 cases of malignant endocarditis.
Consideration of these figures, together with the statistics of a
number of other reporters of smaller series of cases, furnishes a
total of 316 cases of sepsis in which it is reasonable to presume
that the bacteriological examination of the blood has been made
by dependable methods. Of these 316 cases, positive results
were obtained in 107, while the remaining 209 proved negative — a
percentage of 33.8 for the former. This analysis, however, is not
to be regarded as equivalent to the statement that bacteriological
examination of the blood gives positive diagnostic information in
one-third of all cases, for the results of a single reliable observer,
rather than the aggregate figures of several, are to be considered
in order to arrive at a true estimate of the value of this procedure.
Anemia, of a grade proportionate to the inten-
HEMOGLOBIN sity of the infection, is the rule in septic cases,
AND regardless of the specific nature of the infective
ERYTHROCYTES. process. In very acute cases the diminution of
hemoglobin and erythrocytes may be so excessive
1 Zeitschr. f. Hyg. u. Infektionskr., 1897, vol. xxv, p. 492.
* Zeitschr. f. Heilk., 1896, vol. xvii, p. 117.
3 Jour. Exper. Med., 1899, vol. iv, p. 425.
4 Deutsch. Zeitschr. f. Chirurg., 1893, vol. xxxvii, p. 571.
5 Deutsch. med. Wochenschr., 1897, vol. xxiii, p. 766.
* Loc. cit. 7 Charite'-Annal., 1888, vol. xiii, p. 198.
8 Berlin, klin. Wochenschr., 1888, vol. xxv, p. 143.
9 Charite'-Anna]., 1894, vol. xix, p. 154.
528 GENERAL HEMATOLOGY.
and so rapid that an abrupt downward curve in the erythrocyte
line of the 'blood chart may be detected from day to day, even
from morning until night, in some instances. This rapidly de-
veloping type of anemia is associated especially with fulminant
cases of puerperal septicemia, in which counts of less than 1,000,-
ooo cells per c.mm. have been frequently reported. In a case of
this 'sort the writer found the hemoglobin reduced to 20 per cent,
and the erythrocytes to 730,000 per c.mm.
In less severe cases the development of the anemia is slower
and of a more moderate grade, the hemoglobin being reduced to
40 or 50 per cent., and the erythrocytes to about 2,500,000 or
3,500,000 per c.mm.
The following estimates show the blood changes found in a
case of puerperal sepsis during a period of four months :
HEMOGLOBIN ERYTHROCYTES LEUCOCYTES
DATE. PERCENTAGE. PER C.MM. PER C.MM.
April 29, 1901 57 3,380,000 17,200
May 16, 1901 52 3,390,000 14,200
June 2,1901 38 2,640,000 29,400
" 9,1901 22 2,000,000 33>ioo
" 12, 1901 25 1,600,000 19,000
" 16,1901 30 1,850,000 16,800
" 21, 1901 25 1,902,250 27,200
" 27,1901 35 2,339,000 19,200
July 5,1901 30 2,050,000 8,600
" 22,1901 30 2,300,000 6,000
Aug. 6,1901 35 3,150,000 15,000
i5i I9°I : 39 3>787>000 10,500
22,1901 48 3,637,000 9,200
" 25,1901 52 3,899,000 9,000
The color index is diminished moderately, but not excessively,
save in an occasional instance; it averaged 0.85 for the series on
page 529. Hemoglobinemia is found in occasional instances of
grave character. Most writers lay stress on the excessively
watery condition of the serum, particularly in those cases in which
the development of anemia is early, marked, and rapid.
Deformities of shape and size and atypical staining phenomena
are marked in relation to the degree of the anemia; they are
rarely conspicuous, except in long-standing cases. The same re-
marks apply to the presence of nucleated erythrocytes. Granular
basophilia is found with more or less constancy in severe cases.
SEPTICEMIA AND PYEMIA. 529
In 79 hospital cases of septicemia and pyemia the hemo-
globin and erythrocyte values were as follows :
HEMOGLOBIN NUMBER ERYTHROCYTES NUMBER
PERCENTAGE. OF CASES. PER C.MM. OF CASES.
From 90-100 i Above 5,000,000 4
" 80-90 14 From 4,000,000-5,000,000 21
" 70-80 9 " 3,000,000-4,000,000 29
" 60-70 14 " 2,000,000-3,000,000 17
" 50-60 13 " 1,000,000-2,000,000 7
" 40-50 15 Below 1,000,000 i
" 3°-40 6
" 20-30..' 6
Below 20 i
Average, 58.9 per cent. Average, 3,430,687 per c.mrii.
Maximum, 92.0 " Maximum, 5,970,000 " "
Minimum, 19.0 " Minimum, 730,000 " "
Leucocytosis is always present in those cases
LEUCOCYTES, in which the infection, either moderate or marked,
occurs in a patient whose powers of resistance are
sufficiently strong to react against the poison. The increase in
the number of leucocytes is usually moderate, counts of from 15,000
to 25,000 being commonest. In trifling infections, not sufficiently
marked to produce activity of the leucocyte-forming organs,
and in lethal cases, in which the system is overwhelmed by the
toxins, not only does leucocytosis fail to develop, but sometimes
distinct leucopenia may be observed. These facts -render the
occurrence of leucocytosis in septicemia an inconstant sign, for
it is no uncommon experience to examine case after case of un-
doubted sepsis without encountering any increase in the leucocytes
above normal. In the series tabulated below frank leucocytosis
was found in 92 instances, or in approximately 70 per cent., while
in ii cases, or about 8 per cent., there was distinct leucopenia, the
count in one being only 2000 per c.mm. All the cases not showing
leucocytosis were either very mild or very severe infections.
The increase affects chiefly the polynuclear neutrophiles, which
are both relatively and absolutely increased at the expense of the
mononuclear forms. Mast cells and myelocytes in small numbers,
are common. In a profoundly anemic case of sepsis Kline 1
found striking eosinophilia — 40 per cent ; a decided diminution of
these cells is, however, the common finding. In all forms of
sepsis, and especially in puerperal fever, the iodin reaction occurs
1 Centralbl. f. inn. Med., 1899, vol. xx, p. 97.
34
530 GENERAL HEMATOLOGY.
with great constancy. lodophilia is a more dependable sign of
sepsis than the behavior of the leucocytes, since it is present in
many cases so toxic as to stifle leucocytosis.
One hundred and thirty-five cases in which leucocyte counts
were made showed the following averages:
LEUCOCYTES PER C.MM NUMBER or CASES.
Above 40,000 i
From 30,000-40,000 1 6
" 20,000-30,000 14
" 15,000-20,000 27
" 10,000-15,000 44
" 5,000-10,000 32
Below 5,000 ii
Average, 15,040 per c.mm.
Highest, 41,600 " "
Lowest, 2,000 " "
The value of the blood examination as an aid
DIAGNOSIS, to the diagnosis of septic conditions must be re-
garded as more or less uncertain. In cases with
clinical manifestations suggesting at once enteric I ever, malarial
fever, and septicemia the presence of leucocytosis is highly sugges-
tive of the latter condition, for in typhoid and in malaria leucocy-
tosis rarely exists, except in the event of some complication. The
early development of a rapidly increasing anemia would also point
to sepsis rather than to typhoid or malaria, for in the latter fevers
the anemia, although it begins early, does not reach a high grade
until comparatively late in the course of the illness. The pres-
ence of a positive serum reaction, or the discovery of malarial
parasites in the blood, will, of course, at once determine the
diagnosis. If the diagnosis lies between sepsis and miliary tuber-
culosis, increase in the number of leucocytes points to the former.
The iodin reaction may be present in all the conditions noted
above.
.In cases without leucocytosis but with marked iodophilia a bad
prognosis is justified, for the reason stated above.
SPOTTED FEVER OF MONTANA. 531
LXVI. SPOTTED FEVER OF MONTANA.
Ovoid bodies, presumably hematozoa, have
PARASITOLOGY. been found first by Wilson and Chowning 1 and
later by Anderson2 and by Cobb 3 in the circulating
blood of those ill with the disease known as spotted fever, or tick
fever, prevailing in the Bitter Root Valley in Montana. The former
investigators have labeled their discovery the Piroplasma hominis.
The ovoid bodies in question remind one of both the Texas
fever and the malarial parasite, though they differ from the
former in being larger and in possessing ameboid motility, and
from the common forms of the latter in being unpigmented. In
the fresh blood three forms of the piroplasma, each ovoid in
shape, were found within the erythrocytes : a small jion-motile
form, i to 2 (i in length by i // in width ; a larger, actively ame-
boid form, 3 to 5 fJ- in length by i to 1.5 // in width, and snowing
a dark granular spot at one end; and a twin form, consisting of
two pear-shaped bodies lying with their tapered ends approaching,
and bearing a granular spot at each end. • Extracellular diplococci-
like forms, 0.5 to i />« in size, and not endowed with motion, were
also identified. In the dry film the bodies are stained best by
one of the basic dyes, such as methylene-blue or thionin. The
theory is tempting that the infection of spotted fever is conveyed
by a variety of tick known as the Dermacentor reticulatus.
Moderate anemia, usually with a low color
HEMOGLOBIN index, is the rule. The hemoglobin percentage
AND may fall as low as 50 or 60, but the erythrocyte
ERYTHROCYTES. count remains at about 4,000,000 cells per c.mm.
The effect of high altitude in masking an ane-
mia must, however, be taken into consideration, for the counts
in all the reported cases of spotted fever were made at an eleva-
tion of 3500 feet above the sea-level. No structural changes in
the erythrocytes have been noted.
The leucocytes are slightly increased — 4o 12,-
LEUCOCYTES. ooo or 13,000 per c.mm. — and show, differen-
tially, nothing abnormal save, perhaps, a mod-
erate increase in the large lymphocytes at the expense of the small
hyaline cells.
The specificity of the ameboid bodies found
DIAGNOSIS, in this disease seems to be well established, and
their detection in the blood should prove a
1 Jour. Amer. Med. Assoc., 1902, vol. xxxix, p. 131.
J Amer. Med., 1903, vol. vi, p. 506.
3 Public Health Rep., 1902, vol. xvii, p. 1868.
532 GENERAL HEMATOLOGY.
means of excluding malarial and enteric fevers. From the latter
the absence of a serum reaction and the presence of a moderate
leucocyte increase are additional points of differentiation.
LXVIL SYPHILIS.
Micrococci (Hallin; Martineau), pleomorph-
BACTERIOLOGY. ous bacilli (van Niessen), cocci-bacilli (Klebs),
bacteria resembling the Klebs-Loffler organism
(Joseph and Piorkowski), and spore-like bodies (Klotzsch;
Lostorfer) are some of the prominent "organisms" which, during
the last three decades, have been found in the circulating blood
of syphilitics and have been exploited as the exciting cause of the
disease. The vogue of these findings, as well as that of those
relating to the presence of a syphilitic organism in various tissues,
has been ephemeral. Lustgarten's bacillus, regarded by many
as specific, has thus far resisted artificial cultivation. De Lisle
and Jullien, in 1901, claimed to have cultured a bacillus from the
blood of syphilitics, and to this microbe they ascribe specific
properties. The bacillus in question is said to occur constantly in
the blood during the secondary manifestations of the infection,
and to excite indurated ulcer, adenitis, and other luetic signs when
inoculated into animals. It possesses peculiar cultural traits,
for an account of which the reader is referred to De Lisle's
original article.1
During the early stages of the infection, in the
HEMOGLOBIN interval between the appearance of the initial
AND lesion and the development of secondary symp-
ERYTHROCYTES. toms, the blood changes closely counterfeit those
of typical chlorosis, a fact which has led to the
use of the term "syphilitic chlorosis" to describe the blood picture
of early lues. The hemoglobin progressively falls until the loss
approximates 20 or 30 per cent., while the number of erythrocytes
remains normal or is but slightly diminished, in consequence of
which the color index is low. As secondary symptoms appear
oligocythemia usually develops, and in some instances reaches
a high grade. There is a close relationship between the intensity
of the infection and the intensity of the anemia. In the tertiary
and hereditary forms of the disease if treatment is neglected,
the count may fall to approximately 1,000,000 cells, and the hemo-
globin to 20 per cent, or even less, while extreme poikilocytosis,
megalocytosis, and microcytosis may be present, together with
1 Amer. Med., 1903, vol. vi, p. 474.
SYPHILIS. 533
numerous normoblasts and, perhaps, a few megaloblasts —
the so-called "syphilitic pernicious anemia." But the anemia
seldom reaches this grade, since most syphilitics receive adequate
treatment early in the course of the disease. Lowenbach and
Oppenheim,1 from a recent study of 36 cases, have shown that a
diminution of the hemoglobin and iron content, with trifling
oligocythemia, is the usual finding in the tertiary stage.
After the administration of mercury both the hemoglobin and
the erythrocytes begin to increase, the former more slowly than the
latter, until treatment has been continued for about two or three
weeks, but should this drug be given for longer than this period,
just the opposite effect is produced — first a diminution in the
hemoglobin percentage, followed later by oligocythemia. Ossen-
dowski2 found that the initial increase is more rapid after in-
tramuscular injections of mercury than after its administration
by inunction or by the mouth. He also determined that the effects
of potassium iodid as a regenerator of the hemoglobin content
are more decided than those of mercurials.
Buffa3 concludes, from a study of 21 cases, that the hemogenesis
excited by mercury is temporary, owing chiefly to the feeble
resistance of the newly bred cells, many, of which perish prema-
turely. The ultimate effect of this drug, therefore, is hemolytic,
although it may antidote the poison of the disease. Extreme
hemoglobin loss in patients undergoing mercurialization is re-
garded as prognostic of severe tertiary manifestations as the in-
fection matures. The intravenous injection of mercuric chlorid
rapidly causes hemoglobinemia in syphilitics. It is ' a well-
recognized clinical fact that the blood changes provoked by
syphilis are likely to be more marked in women than in men,
other things being equal.
Justus' Test. — This reaction, described by Justus,4 depends
upon the presumption that in untreated cases of congenital,
secondary, and tertiary syphilis, a single dose of mercury, ad-
ministered either by inunction or by subcutaneous or intravenous
injection, causes a hemoglobin loss of from 10 to 20 per cent, within
about twenty-four hours, this abrupt decline being followed
within a few days by a rise in the hemoglobin value to a some-
what higher figure than that first observed before the drug was
given. In Justus' last communication,5 relating to over 500 cases,
data are given which show that the test is positive in from 70 to 80
1 Deutsch. Arch. f. klin. Med., 1903, vol. Ixxv, p. 22.
2 Inaug. Dissert., Dorpat, 1903. * Sem. me'd., 1903, vol. xxiii, p. 75.
4 Virchow's Arch., 1894, vol. cxl, pp. 91 and 533.
5 Deutsch. Arch. f. klin. Med., 1903, vol. Ixxv, p. i.
534 GENERAL HEMATOLOGY.
per cent, of all cases of florid syphilis, and that it disappears with
the involution of the specific lesions and reappears with their recur-
rence. It is further claimed that negative findings are constant in
healthy persons and in those suffering from non-syphilitic diseases.
Failures to obtain good results Justus attributes to faulty diagnosis
and to wrong technic — at least 3 gm. of blue ointment for an adult
or I'gm. for a child must be used for the inunction, the final hemo-
globin estimate being made the following morning. Cabot and
Mertins 1 obtained positive results in 7 syphilitics, and also in one
case of chlorosis and in one of tertian malarial fever, but in their
hands the test proved negative in 32 control cases of other diseases.
Regarding the exceptional non-syphilitic diseases in which the
reaction may prove positive, Brown and Dale2 state that such
cases are characterized by striking oligochromemia. A thor-
ough study of the test has been made by Jones,3 who examined
53 cases, of which number 35 were syphilis, and 18 cases of other
diseases. Of the former, 17 were active syphilis untreated, and of
these the test was positive in 13 and negative in 4; 15 cases of
chancre yielded but 7 positive results, these occurring most fre-
quently in chancre with adenitis; in two cases of latent syphilis and
in one of active syphilis under treatment the test failed. Tucker,4
Huger,5 Christian and Foerster,6 and Oppenheimer and Lowen-
bach7 have also reported similar inaccuracies in the test. From
the statistics of these investigators (121 cases) E wing's analysis8
credits the test with positive findings in 62 per cent, of cases of
active syphilis, in 30 per cent, of chancre, and in 67 per cent, of
chancroid. In the writer's experience, limited to 9 cases, the
success of the test has been uniform.
The diagnostic value of Justus' test is greatly restricted by its
frequent failure in early initial lesions and in latent syphilis, and
its occasional failure in the early part of the secondary stage,
periods when a pathognomonic test would prove of the greatest
aid. The fact that positive reactions may occur in non-syphilitic
diseases, in which hypersensitiveness to the action of mercury
is to be presumed, obviously is against the test's specificity.
The number of leucocytes, which remains ap-
LEUCOCYTES. proximately normal during the preemptive stage
of the disease, usually increases moderately with
1 Boston Med. and Surg. Jour., 1899, vol. cxl, p. 323.
2 Cincinnati Lancet-Clinic, 1900, vol. xliv, p. 261.
3 N. Y. Med. Jour., 1900, vol. Lxxi, p. 513.
4 Phila. Med. Jour., 1902, vol. ix, p. 846.
6 Ibid., p. 849. * Univ. Med. Mag., 1900, vol. xiii, p. 634.
7 Deutsch. Arch. f. klin. Med., 1901, vol. Lxxi, p. 425.
8 " Clinical Pathology of the Blood," 2d ed., New York and Philadelphia,
1903, p. 342.
TONSILLITIS. 535
the appearance of the secondary symptoms. Their total number
rarely equals twice the maximum normal standard, and the gain
is due, in the great majority of instances, to an increase in the
non-granular hyaline forms, the percentage of polynuclear neutro-
philes being relatively low. Many authors maintain that the
eosinophiles are increased, but Peter,1 who has especially investi-
gated this question, emphatically states that in no form and at no
stage of syphilis has he observed eosinophilia. In the leucocyte
increase frequently found in the high-grade anemia of tertiary
syphilis the lymphocytosis is especially striking, and the presence
of small numbers of myelocytes is common. Under the influence
of mercurial or iodid treatment the leucocyte count diminishes,
the lymphocytes decrease, and the polynuclear neutrophiles grow
more numerous.
The writer has found iodophilia in severe syphilitic anemia.
In patients whose blood is approximately normal no numerical
changes in the blood plaques occur. " In severe syphilitic anemia
the plaques are increased — a change for which Vorner2 blames
the anemia, not the syphilis.
But slight diagnostic Value can be attached to
DIAGNOSIS, the changes in the blood in this disease. The
association of a low color index and a leucocyte
increase chiefly of the lymphocytes is suggestive, but nothing
more. Justus' test, if positive, strengthens the pertinence of the
preceding signs, provided that all sources of fallacy can be ex-
cluded; absence of the reaction by no means excludes syphilis.
The distinctions between tertiary syphilitic anemia and true per-
nicious anemia have already been discussed. (See p. 289.)
LXVIII. TETANUS,
In a fatal case treated with antitoxin Cabot3 found 70 per
cent, of hemoglobin and 11,900 leucocytes per c.mm., with no de-
crease in the number of eosinophiles, as is usual in most febrile
states. In two other cases, also fatal and treated with antitoxin,
he found leucocytoses of 19,600 and 18,200, respectively.
LXIX. TONSILLITIS.
As a general rule, no appreciable changes are found in the
hemoglobin and erythrocytes, although in severe cases the former
is sometimes diminished. Leucocytosis of a moderate grade may
or may not develop, depending largely upon the character of the
1 Dermatolog. Zeitschr., 1897, vol. iv, p. 669.
2 Deutsch. med. Wochenschr., 1902, vol. xxviii, p. 897. 3 Loc. cit.
536 GENERAL HEMATOLOGY.
tonsillar inflammation. When present, the increase involves prin-
cipally the polynuclear neutrophiles, and the total leucocyte count
rarely exceeds 15,000 cells to the c.mm. Leucocytosis is less
common and less decided in follicular tonsillitis than in quinsy.
In the latter P6e,1 Rieder,2 and others have observed counts in
excess of 20,000.
- The leucocyte count is of no aid in differentiating tonsillitis,
diphtheria, and streptococcus inflammations of the throat.
LXX. TRICHINIASIS.
It is generally agreed that there are no changes
HEMOGLOBIN in the hemoglobin and erythrocytes attributable
AND to the influence of this infection, high counts and
ERYTHROCYTES. hemoglobin estimates, often polycythemia, being
the rule. Rarely, well-marked anemia may be
found, due to some other cause, as in a case reported by Kerr,8 in
which the erythrocytes numbered between 3,300,000 and 3,340,-
ooo per c.mm.
T. R. Brown4 first made the important an-
LEUCOCYTES. nouncement that acute cases of trichiniasis are
accompanied by a well-marked increase in the
number of leucocytes, characterized by an absolute and relative
gain in the eosinophiles. This observation has since been corrob-
orated by a number of other workers whose results are tabulated
below.
Unfortunately, eosinophilia cannot be regarded as constant in
this condition, as shown by the following count made by the writer
in a typical case of trichiniasis occurring in J. Chalmers Da Costa's
surgical service at St. Joseph's Hospital:
Hemoglobin 80 per cent.
Erythrocytes 4,400,000 per c.mm
Leucocytes 12,000 " "
Small lymphocytes 36.7 per cent.
Large lymphocytes and transitional forms ... 6.5 "
Polynuclear neutrophiles 56.1 "
Eosinophiles 0.5 "
Myelocytes 0.2 "
Basophiles o.o "
Repeated examinations by others showed practically these
figures, the eosinophiles at no time being increased. The lesions
1 Inaug. Dissert., Berlin, 1890. * Loc. tit.
3 Phila. Med. Jour., 1900, vol. vi, p. 346.
4 Johns Hopkins Hosp. Bull., 1897, vol. iii, p. 79; also Jour. Exper. Med., 1898,
vol. iii, p. 315.
TRICHINIASIS.
537
in this patient were most striking, as they involved the greater
part of the right lower extremity, from calf to thigh. Excised
bits of muscles from the affected parts were found to be swarm-
ing with trichinae and rich in eosinophile cells. It is possible
that in such instances as this the absence of eosinophilia may be
attributed to the overwhelming nature of the toxins, which, by
their repellant action, stifle eosinophile proliferation in the marrow.
This, indeed, has been proved by Opie,1 who found that in dogs
mortally infected with trichinae the circulatory eosinophiles
rapidly diminished, and at the same time those of the marrow,
mesenteric glands, and intestinal mucosa showed marked degenera-
tive changes. In other (milder) cases, as the disease becomes
chronic, the eosinophilia of the early stages tends to disappear,
as is the rule in other forms of helminthiasis. Howard2 failed
to find an eosinophile increase in a single case, although large
numbers of these cells were detected in the muscle lesions, and
Drake3 and Schleip4 also report trichiniasis without eosinophilia.
LEUCOCYTE COUNT AND PERCENTAGE OF EOSINOPHILES IN
84 CASES OF TRICHINIASIS.
NAME OF REPORTER.
NUMBER
OF CASES.
•
TOTAL NUMBER OF
LEUCOCYTES
PER C.MM.
RELATIVE PERCENTAGE
OF EOSINOPHILES TO
OTHER FORMS OF
LEUCOCYTES.
T. R. Brown5
8,OOO—35,OOO
8-68.2
Gwyn *
i
I7,OOO
Kerr 7
2
IO,OOO—25,OOO
18.1-86.6
Blumer and Neuman 8 . . .
Stump * ...
9
6,OOO-24,OOO
8-50.4
Cabot10
A
I,4IO—25,OOO
' 7-8-^7
Atkinson n
I
28,OOO
• 3*>~~^o.^
Gordinier 12
2
Q— 77
H. Brooks IS
I
l8,OOO-
IS-83
Patek "
I
Gould 15
I
O,8OO
23 7—3O.6
Cheney18
I
12,000—15,000
IO-I7
Schleip "
5,3OO—22,6OO
1.2—62.2.
57
1 Amer. Jour. Med. Sci., 1904, vol. cxxvi, p. 477.
2 Phila. Med. Jour., 1899, vol. iv, p. 1085.
8 Jour. Med. Research, 1902, vol. iii, p. 255.
4 "Die Homberger Trichinosisepidemie und die fur Trichinosis pathognomo-
nische Eosinophilie," Leipsic, 1904.
5 Loc. cit. • Centralbl. f. Bakt. u. Parasit., 1899, vol. xxv, p. 746. 1 Loc. cit.
8 Amer. Jour. Med. Sci., 1900, vol. cxix, p. 14.
* Phila. Med. Jour., 1899, vol. iii, p. 1318.
10 Boston Med. and Surg. Jour., 1897, vol. cxxxvii, p. 676; also " Clinical Ex-
amination of the Blood," 5th ed., New York, 1904.
11 Phila. Med. Jour., 1899, vol. iii, p. 1243.
12 Med. News, 1900, vol. Ixxvii, p. 965. " Med. Rec., 1900, vol. Iviii, p. 885.
14 Amer. Med., 1901, vol. i, p. 513. 15 Ibid., 1903, vol. vi, p. 515.
18 Amer. Med., 1903, vol. vi, p. 985. 1T Loc. cit.
538 GENERAL HEMATOLOGY.
The other differential changes, which are unimportant, consist
in a corresponding relative decrease in the polynuclear neutro-
philes, and occasionally, in the early stages of some cases, in a
similar diminution in the lymphocytes. Mast cells and myelocytes,
in small numbers, have also been observed, although not con-
stantly.
Blumer and Neuman's studies of 9 cases of epidemic trichini-
asis * lead them to conclude that the degree of leucocyte increase
corresponds in a general way to the severity of the attack, rela-
tively severe cases being attended with a higher and more per-
sistent increase than the milder attacks; on the other hand, the
intensity of the infection does not necessarily correspond to the
degree of cosinophilia. The latter may persist for months after
the disappearance of the leucocytosis and the apparent convales-
cence of the patient, but just how long it does last is as yet un-
determined.
The presence of an eosinophile leucocytosis r
DIAGNOSIS, usually of a high grade, may be the only indica-
tion of trichiniasis in obscure cases in which the
characteristic symptoms of the infection are wanting, and in such
instances the change is to be regarded as a most valuable aid to
diagnosis. Absence of this sign, however, does not definitely ex-
clude the disease.
LXXI. TRYPANOSOMIASIS.
Nepveii,2 in 1898, published his observations
PARASITOLOGY. on finding, eight years previously, trypanosomata
•in the circulating blood of man, but not until the
discoveries of Forde,3 Button,4 Manson,5 and Daniels6 were pub-
lished did human trypanosomiasis become recognized as a dis-
tinct entity in tropical medicine. To Forde and to Dutton is
due the credit of first adequately describing the organism.
Since the pioneer labors of these investigators our knowledge
of the condition has been extended by the studies of Castellani,7
Bruce,8 Baker,9 Todd,10 Leishman,11 Nabarro,12 Sambon,13 Lave-
1 Loc. cit. 2 Compt. rend.-Soc. biol., Paris, 1898, vol. v, p. 1172.
3 Jour. Trop. Med., 1902, vol. v, p. 261.
4 Brit. Med. Jour., 1902, vol. ii, p. 881; 1904, vol. ii, p. 369; also Dutton and
Todd, "First Report of the Trypanosomiasis Expedition to the Senegambia (1902)
of the Liverpool School of Tropical Medicine and Medical Parasitology," Lancet,
1903, vol. ii, p. 1727.
6 Brit. Med. Jour., 1903, vol. i, pp. 720 and 1249; vol. ii, p. 645.
8 Ibid., 1903, vol. i, p. 1249. 7 Ibid., 1903, vol. i, p. 1431.
8 Ibid., 1903, vol. ii, p. 1343. * Ibid., 1903, vol. i, p. 1254.
10 Ibid., 1903, vol. ii, p. 645. " Ibid., 1903, vol. i, p. 1252.
u Lancet, 1904, vol. i, p. 229. 13 Ibid-, 1904, vol. i, p. 228.
TRYPANOSOMIASIS. 539
ran,1 and others. Aside from the blood findings, human trypano-
somiasis is characterized by progressive asthenia, wasting, edema,
splenic tumor, accelerated pulse and respirations, and irregular
fever of a relapsing type. The disease runs an exceedingly
chronic course, and has received the name "trypanosoma fever."
Castellani2 was the first to demonstrate the presence of trypano-
somata in the blood and cerebrospinal fluid of persons suffering
from African "sleeping sickness," and later Bruce,3 having con-
firmed these results, repeated the original suggestion of Maxwell
Adams that many, if not all, of the cases of so-called trypanosoma
fever in reality represent early stages of sleeping sickness. The
presence of Castellani's streptococcus, and of Bettencourt's diplo-
streptococcus (probably the same organism) in the cerebrospinal
fluid of patients infected with this disease is thought to mean a con-
comitant infection. These conclusions have recently been voiced
by the Royal Society's Sleeping Sickness Commission.4 Singularly
enough, the Portuguese Commission,5 headed by Bettencourt,
did not find trypanosomata hi sleeping sickness, which they
attribute to a variety of streptococcus. .
There is possibly a relationship (although such is still unproved)
between the parasite of trypanosomiasis and certain obscure trop-
ical maladies, such as kala-azar, dum-dum fever, tropical spleno-
megaly, and the undetermined hyperpyrexias of West Africa.
The organism found in man, tentatively named Trypanosoma
gambiense, is regarded as a form of trypanosoma distinct from those
responsible for tsetse-fly disease, surra, dourain, and mal de cad-
eras, in the lower animals. The parasites multiply by fission, but
evidences of this process are rarely, if ever, found in the circulating
blood of the periphery. They are conveyed by a species of tsetse-
fly, Glossina palpalis, which acts simply as a mechanical carrier
of the parasite, and not as a host for the' evolution of a sexual
cycle. Laveran8 has shown that the administration of arsenic
to animals infected with the trypanosoma causes a rapid disap-
pearance of the parasites from the general circulation, and it has
long been recognized that this drug has a favorable action in the
treatment of trypanosoma disease in the lower animals. Ehrlich
1 Compt. rend. Acad. d. sc., Paris, 1904, vol. cxxxviii, p. 841.
2 Brit. Med. Jour., 1903, vol. i, pp. 1218 and 1431.
3 Ibid.,i<)O3, vol. ii, pp. 1008 and 1291 ; 1904, vol. ii, p. 367.
4 Bruce, Nabarro, and Greig, " Report of the Sleeping Sickness Commission
of the Royal Society of London," Brit. Med. Jour., 1903, vol. ii, p. 1343; also
Button, Todd, and Christy, "First Progress Report of the Expedition of the Liver-
pool School of Tropical Medicine and Medical Parasitology to the Congo, 1903,"
ibid., 1904, vol. i, p. 186; ibid., 1904, vol. ii, p. 369.
5 " Doenga do Somno," Lisbon, 1902. * Sem. me"d., 1904, vol. xxiv, p. 68.
54°
GENERAL HEMATOLOGY.
and Shiga1 effected permanent cures in trypanosomatous mice by
the use of trypan red (a dye belonging to the benzopurpurin series), •
given hypodermically and by the mouth. They also succeeded in
establishing, by the use of this drug, a transient immunity against
the infection.
In the fresh specimen of blood the parasite appears as a minute,
worm-like organism which glides about, with undulatory motility,
between the collections of blood corpuscles (Fig. 64). It is
readily recognized as a flagellated protozoon, one end of which
is bluntly conical, and the other drawn out into a whip-like
flagellum (rarely two flagella occur), while a transparent, flange-
like process or undulatory membrane is attached along one side
FIG. 64. — TRYPANOSOMA GAMBIENSE.
From a stained specimen furnished by Dr. J. E. Button.
of the body. The latter is a rather short, granular structure,
provided with a highly refractile spot, or nucleus, near the blunt
end. The movements of the worm, both forward and backward,
are effected by a sort of screw-like motility, beginning in the flagel-
lated process and shared by the undulatory membrane and by the
body protoplasm. In the fresh specimen the trypanosomata perish
within from one to three hours after the blood is drawn. In the
stained film Button2 found that the parasites measured from 18
to 25 ft in length and from 2 to 2.8// in width, and that they
bear, just posterior to the nucleus, a centrosome or micronucleus.
With Wright's or Irishman's polychrome methylcne-bluc stains
1 Berlin, klin. Wochenschr., 1904, vol. xli, pp. 329 and 362. 2 Loc. cit.
TUBERCULOSIS. 54!
the protoplasm is colored pale blue, and the nucleus, centrosome,
and flagellum red. The organisms stain better with carbolfuchsin
than with the weaker basic dyes, such as hematoxylin.
In the cases of trypanosomiasis thus far
HEMOGLOBIN studied there has been found well-defined, al-
AND though not excessive, anemia. In no instance
ERYTHROCYTES. has the hemoglobin fallen below 36 per cent.,
nor the erythrocytes below 2,825,000 per c.mm.,
and in most cases the loss amounted to about 20 or 25 per cent.,
affecting both elements proportionately. The erythrocytes deviate
but little from their normal size and shape, and normoblasts (found
only occasionally, in small numbers) are the only form of nucleated
erythrocytes • encountered.
The leucocyte counts, absolute and differential,
LEUCOCYTES, are not unlike those of the malarial fevers,
showing either a normal or a subnormal total es-
timate and a decided relative lymphocytosis affecting the large
lymphocytes. These cells are increased to twice or thrice their
normal percentage, at the expense of the polynuclear neutrophiles,
without appreciable alteration in the proportion of small lympho-
cytes and eosinophiles. Mast cells (£ to ^ per cent.), as well as
indeterminate hyaline cells, resembling those found in myelogenous
leukemia, were also noted in the cases examined by Duncan,
Daniels, and Low.1 Daniels2 pictures these cells as having a
relatively large nucleus, staining, by the Romanowsky method, a
delicate pink splotched with purple, encircled by a narrow zone
of blue non-granular protoplasm. > ;
The detection of trypanosomata.in the blood
DIAGNOSIS, is obviously the key to the diagnosis, but in cases
in which no organisms can be found, a well-
defined anemia with a low leucocyte count, characterized by an
excess of large lymphoid cells and by moderate basophilia, gives
a very suggestive blood picture.
LXXII. TUBERCULOSIS.
A pure infection with Koch's bacillus of tuber-
GENERAL culosis is capable of producing comparatively
FEATURES, slight alteration in the composition of the blood,
such changes as may be associated with tuber-
culous processes, whatever organs they involve, being due chiefly
to secondary infection with other bacteria, usually of pyogenic
1 Cited by Manson and Daniels, Brit. Med. Jour., 1903, vol. i, p. 1249.
2 "Studies in Laboratory Work," London, 1903, p. 68.
542 GENERAL HEMATOLOGY.
type, and not to the disease per se. The prolonged ill effects of
tuberculosis upon body nutrition must also in time cause more
or less blood impoverishment, but it is a well-recognized clinical
fact that the changes are, as a rule, trivial in comparison with the
gravity of the disease and the apparent degree of cachexia. The
above facts are sufficient to explain the reason for the varied
blo'od pictures found in tuberculosis — pictures ranging from those
of practically normal blood to those of most intense anemia, and
from leucopenia to frank leucocytosis.
In a limited number of cases of acute miliary
BACTERIOLOGY, tuberculosis the specific bacillus has been isolated
from the blood during life by culturing and by
intraperitoneal inoculation in animals; but in this as well as in
the other forms of the disease this procedure generally results nega-
tively so far as the detection of the tubercle bacillus is concerned.
Nattan-Larrier's method1 of examining fluids for tubercle bacilli
is worthy of trial. An injection of 2 or 3 c.c. of blood is made into
a guinea-pig's mammary gland, in which the organisms rapidly
multiply. A sample of milk expressed from the inoculated gland
is examined, after the lapse of a few days, by the technic used in
sputum staining, with the result that in positive cases tubercle
bacilli are found, generally within from five to ten days after the
injection. In advanced septic cases of pulmonary tuberculosis,
streptococci, staphylococci, blastomycetes, and other micro-organ-
isms have been found in the blood, but only rarely, for the septic
process tends to remain localized in the lungs, rather than to in-
vade the general circulation.
Serum Test. — Arloing and Courmont2 have succeeded in pre-
paring cultures with which they claim that the serum diagnosis
of tuberculosis can be carried out. Glycerin peptone bouil-
lon, inoculated with an old, attenuated culture of the tubercle
bacillus and thoroughly agitated each day to insure homoge-
neity of the culture, finally develops a growth in which the bacilli
are uniformly disseminated and actively motile. Blood serum
from the suspected case is mixed in small test-tubes with the
culture thus prepared, in proportions of i to 5, i to 10, and i to 20,
and the tubes inclined at an angle of 45 degrees, being examined
at intervals of two, ten, and twenty-four hours. A positive reaction
is indicated by a clarification of the mixture and the deposition
of small flakes or granules in the bottom of the tube, while microscop-
ically it may be seen that the bacilli are clumped and motionless.
With this technic, reactions occurring after the lapse of twenty-
1 Presse m&L, 1903, vol. ii, p. 838.
J Congrfes pour PEtude de la Tuberculose, 1898.
TUBERCULOSIS. 543
four hours are without clinical significance. Or Koch's method1 of
using a solution of sterile "tubercle powder" may be employed.
A test solution is made by dissolving pulverized sterile tubercle
cultures in normal salt solution, and then centrifugalizing the
fluid, so. as to obtain a clear, opalescent liquid free from bacilli.
The test fluid thus prepared is mixed with the suspected blood
serum, sedimentation occurring after twenty-four hours in positive
reactions. With normal serum in a dilution of i to 5 positive re-
actions do not occur, and they occur but rarely with tuberculous
serum in a dilution higher than i to 20. A peculiarity about
this test is that it takes place in an inverse ratio to the intensity
of the infection, and hence it fails in advanced and virulent cases in
which presumably there is already an excessive auto-intoxication
with tuberculin. Excluding such cases, Arloing and Courmont
found that positive reactions were constant in all tuberculous
patients, but, unfortunately, they. also found similar results in
some normal individuals and in various non-tuberculous diseases.
Bendix2 found the test successful in 34 of 36 cases of tubercu-
losis, the two failures being in instances of overwhelming infections ;
he also claims that normal blood and the blood from other dis-
eases give negative results. Nine cases of pulmonary tubercu-
losis, 4 of pleurisy, and 17 of various non-tuberculous affections
were examined by Mongour and Buard.3 All the phthisis cases
and 3 of the 4 pleurisies, which were tuberculous, were positive,
the case not reacting proving to be non-tuberculous. In 15 of 17
other diseases the results of the test corresponded with the clinical
diagnosis and the autopsy findings. Similar results in tuberculous
pleurisy were obtained by P. Courmont,4 who found positive
reactions in 10 of u cases clinically tuberculous, while of 9 cases
clinically non-tuberculous 4 were positive and 5 negative. In
12 cases of ascites, 7 due to hepatic cirrhosis failed to react, but
the other 5, all clinically tuberculous, gave positive results. Re-
sults distinctly less favorable than those reported by other in-
vestigators are published by Beck and Rabinowitch,5 but it is
not at all improbable that these discrepancies may be attributed,
at least in part, to the use of unsuitable cultures. According
to these authors' experiments, only 6 of 17 cases of incipient
lung tuberculosis were positive, and but 4 of 16 advanced cases.
Of 5 suspected cases that reacted to tuberculin injections, but
one gave a positive serum reaction. They furthermore found
1 Deutsch. med. Wochenschr., 1901, vol. xxvii, p. 829.
1 Ibid., 1900, vol. xxvi, p. 224.
3 Compt. rend. Soc. biol., Paris, 1898, vol. v, p. 1142; also Buard, Jour, de
phys. et path. ge"n., 1900, vol. ii, p. 797.
4 Congres pour PEtude de la Tuberculose, 1898.
5 Deutsch. med. Wochenschr., 1900, vol. xxvi, p. 400.
544 GENERAL HEMATOLOGY.
that positive reactions may occur in healthy persons, and in
rheumatic fever, bronchitis, hepatic cirrhosis, and croupous pneu-
monia. Von Gebhardt and Torday,1 using Arloing's homo-
geneous cultures, found that in 56 of 75 tuberculous patients and
35 of 96 non-tuberculous diseases the test was positive, and that
a similar result occurred in 3 of 5 healthy persons examined.
Rumpf and Guinard2 obtained positive results in 90 of 107 cases.
Kazarinoff,3 who examined 73 tuberculous and 10 normal persons,
found the test uniformly positive in the former and negative in all
the latter except one. Ivanov4 obtained the reaction in 14 of 21
cases tested. Romberg5 has determined that the serum of more
than 50 per cent, of persons who fail to show clinical evidences of
tuberculosis possesses a more or less agglutinative property.
The serum test in tuberculosis, as at present elaborated,
must be considered of questionable diagnostic value, since it has
been shown that it may occur in normal individuals and in non-
tuberculous diseases, and that it may often be negative in affec-
tions undoubtedly tuberculous. The reaction appears to be-
come less and less marked as the disease advances, and to be
more striking in mild than in severe lesions. Marchetti and
Stefanelli,6 for example, in a study of 73 cases of pulmonary and
abdominal tuberculosis, found that 88 per cent, of early, mild
cases and but 42 per cent, of late, grave cases reacted positively to
the test. Romberg,7 in 105 cases, found that the reaction occurred
in 80 per cent, of cases in the first stage of phthisis, in 66 per cent,
in the second stage, and in 57 per cent, in the third stage. Wright8
values the test chiefly as an index to the organism's ability to
elaborate antibactcricidal substances, as shown by the development
of the reaction m the blood of patients subjected to therapeutic
inoculations of tubercle vaccine. As compared with Widal's ty-
phoid reaction, the test of Arloing and Courmont is crude and
untrustworthy.
The change most frequently observed is a
HEMOGLOBIN moderate loss of hemoglobin, with little or no
AND decrease in the number of erythrocytes, and a
ERYTHROCYTES. low color index, resembling somewhat the blood
picture of chlorosis. In such instances poorly
colored, small-sized corpuscles may be numerous, but poikilocytes
and other structural alterations in the cells are absent. In cases in
1 Munch, med. Wochenschr., 1902, vol. xlix, p. 1171.
2 Deutsch. med. Wochenschr., 1902, vol. xxviii, p. 131.
3 Jour. Amer. Med. Assoc., 1902, vol. xxxviii, p. 362.
4 Sem. me"d., 1902, vol. xxii, p. 207.
* Deutsch. med. Wochenschr., 1901, vol. xxvii, p. 292.
8 Riv. Crit. d. Clin. Med. Fir., 1903, vol. iv, pp. 657, 673, and 689.
7 Munch, med. Wochenschr., 1902, vol. xlix, p. 89.
8 Lancet, 1903, vol. i, p. 1299.
TUBERCULOSIS. 545
which the effects of a complicating septicemic process are active
the above changes may be aggravated, and a secondary anemia of
variable intensity is thus developed. The oligocythemia becomes
marked and more proportionate to the oligochromemia, the color
index consequently rising; deformities of shape and size and
degenerative stroma changes become evident; and in severe cases
an occasional normoblast may stray into the circulation, especially
after the occurrence of a hemorrhage. But these qualitative
changes, even in advanced cases with marked cachexia, are com-
paratively uncommon, and, when present, are usually not striking
in spite of the gravity of the disease.
Appelbaum1 points out that in a group of phthisis cases char-
acterized by the alar chest, by underweight, and often by a scrofu-
lous history, a decided anemia is likely to develop long before
physical and bacteriological signs become manifest. Both Baum-
holtz 2 and Gozdzicki 3 have determined, in a large series of cases,
that the resistance of the erythrocytes is lowered proportionately
to the intensity of the systemic infection.
Finally, in a large proportion of tuberculous patients, neither
the hemoglobin nor the erythrocytes fall "below the normal stand-
ard, this being the rule both in incipient cases and in those which,
although of greater chronicity, have escaped mixed infection or
have successfully withstood the ill effects of the constitutional drain.
Incipient cases may even show polycythemia with excessive hemo-
globin figures.
In 25 hospital cases of pulmonary tuberculosis in various stages
the writer found the hemoglobin percentage from 20 to 30 in i ;
from 30 to 40 in 4; from 40 to 50 in 4; from 50 to 60 in 5; from
60 to 70 in 4; from 70 to 80 in 6; and from 80 to 90 in i. The
lowest estimate was 20, and the highest 83, per cent. The ery-
throcytes were in excess of 5,000,000 in 3 cases; from 4,000,-
ooo to 5,000,000 in 10; from 3,000,000 to 4,000,000 in n, and
from 2,000,000 to 3,000,000 in i. The minimum count was
2,660,000, and the maximum 5,500,000, cells per c.mm. M. L.
Stevens 4 found these averages in 100 cases of phthisis : Males —
hemoglobin, 76.7; erythrocytes, 5,039,000; color index, 0.76;
leucocytes, 14,060; specific gravity, 1.056. Females — hemo-
globin, 72; erythrocytes, 4,373,000; color index, 0.73; leucocytes,
12,666; specific gravity, 1.054. These estimates were made in
Asheville, at an altitude of 2300 feet above sea-level, and there-
fore are doubtless too high for the average patient.
1 Berlin, klin. Wochenschr., 1901, vol. xxxix, p. 7.
2 Sem. m&i., 1900, vol. xx, p. 319. J Ibid., 1903, vol. xxiii, p 131.
4 Med. Rec., 1902, vol. Ixii, p. 133.
35
546 GENERAL HEMATOLOGY.
From a study of 43 cases of coxalgia, vertebral tuberculosis,
and tuberculous osteomyelitis, Dane 1 concludes that most cases of
tuberculous disease of the bones and joints do not cause a de-
crease in the number of erythrocytes, although they do, however,
affect the percentage of hemoglobin, giving rise to a mild degree
of "chloro-anemia," so-called. An analysis of his series shows
that the hemoglobin percentage ranged from 80 to 90 in 2 cases ;
from 70 to 80 in ii ; from 60 to 70 in 24; from 50 to 60 in 4; and
from 40 to 50 in 2. The erythrocytes numbered 5,000,000 or
more in 24 cases, ranging between 6,000,000 and 7,000,000 plus
in 6; from 4,000,000 to 5,000,000 in 15 ; from 3,060,000 to 4,000,000
in 3; and from 2,000,000 to 3,000,000 in i. According to P. K.
Brown's investigations of 73 cases of bone tuberculosis,2 the
erythrocytes decrease only in long-continued and extensive lesions
occurring in young children, and in secondary septic infections, while
the hemoglobin is diminished practically in all cases, the loss de-
pending upon the same factors which influence the erythrocytes.
He also observed that the patient's return to health is indicated by
a tendency of the blood to return to the normal standard. In
about 15 per cent, of this author's cases there was an erythrocyte
loss of 1,000,000 or more cells per c.mm., and in all but some half
dozen the hemoglobin was diminished, in one case to as low as 1 5
per cent.
In cases with secondary septic infection the anemia disappears
as the patient's recuperative powers become active, but should the
system be overwhelmed by the intensity of the pyogenic process,
the anemia either remains stationary or grows more marked.
In other forms of the disease — tuberculous adenitis, meningitis,
pericarditis, pleurisy, peritonitis, and lesions of the genito-urinary
system — the changes affecting the erythrocytes and their hemo-
globin content do not differ from those already described. Well-
developed secondary anemia is not uncommon in the two last-
named forms of tuberculosis, while in the glandular variety dis-
proportionately low hemoglobin values are frequently found. It
is to be recalled that apparent polycythemia may be encountered
in both tuberculous peritonitis and pleurisy, due in the former in-
stance to the inspissating effect of the purging and in the latter
to the same effect produced by the sudden accumulation of an
extensive exudate.
Much the same factors which influence the
LEUCOCYTES, erythrocytes also determine the behavior of the
leucocytes in the different forms of tuberculo-
1 Boston Med. and Surg. Jour., 1896, vol. cxxxiv, pp. 529, 559, and 589.
2 Trans. Med. Soc. of State of California, 1897, vol. xxvii, p. 168.
TUBERCULOSIS. 547
sis. In cases of unmixed infection these cells do not rise above
the normal limits of health, but the moment the tuberculous
lesion becomes complicated by a secondary infectious process,
such as a septicemia, the accident is heralded by a prompt in-
crease in their number. For example, in a simple tubercu-
lous adenitis the count is normal, but should the glands ulcer-
ate, fistulate, and become septic, a leucocytosis at once develops.
As a rule, the qualitative changes are inconspicuous, although
in some forms of the disease, as will be shown below, there
is a tendency toward lymphocytosis. Increase in the number
of leucocytes, characterized by a relative gain in the lymphocytes
and eosinophiles, usually develops during the reactionary fever
following tl^e injection of tuberculin.
The theory that Neusser's "perinuclear basophilic granules"
are a favorable prognostic sign in tuberculosis has been effectu-
ally exploded, since later research has proved that these so-called
granules are simply artefacts. (See p. 228.) lodinophile cells
are generally found in septic cases, but not in pure tuberculosis.
In pulmonary tuberculosis leucocytosis may be symptomatic
of cavities, of rapidly spreading bronchdpneumonia, and of acute
pleurisy. It also usually follows hemorrhage of any considerable
extent, and may develop as the effect of a tuberculous diarrhea.
No definite relationship apparently exists between the degree of
pyrexia and the leucocyte count. Incipient cases of simple tu-
berculous infiltration and pure lung cirrhosis are not accompanied
by an increase. Of the 25 cases above referred to, about one-
half showed a moderate leucocytosis, in 12 the count being 10,000
or higher; in 6 between 9000 and 10,000; in 2 between 8000 and
9000; and in 2 between 3000 and 8000 per c.mm. ' The highest
estimate was 22,000, and the lowest, 3152. Differential counts
in ii of the cases having an increase of 10,000 or more revealed
no qualitative changes other than those typical of an ordinary
polynuclear neutrophile leucocytosis. It may be added that in 6
of these 11 counts the eosinophiles were entirely absent. Mye-
locytes, in fractions of one per cent., were found in cases with
high-grade anemia.
Swan,1 from a careful study of 25 cases of phthisis, concludes
that an absence of eosinophiles is an unfavorable prognostic
sign, but that an increase of these cells while the patient is under
treatment indicates that the progress of the disease has a tendency
to become arrested. Pesel2 regards basophilia as an index to
the progress of phthisis, having found a basophile increase in cases
improving under bettered hygiene and a diet rich in nitrogen.
1 Jour. Amer. Med. Assoc., 1904, vol. xlii, p. 696.
1 Med. Press and Circular, 1903, vol. bcxvi, p. 474
GENERAL HEMATOLOGY.
A. M. Holmes * believes that it is possible to estimate not only
the degree, of the tuberculous process, but the degree of the in-
dividual's recuperative powers, by a careful study of the leuco-
cytes, using a special technic of staining with acid and basic
dyes. Briefly, he considers that the pretuberculous stage is char-
acterized by an absence of leucocytosis, a slight decrease in the
lymphocytes, little or no increase in the polynuclear neutro-
philes, more or less abundant debris from cell disintegration, and
feeble differentiating powers of the cells. In the stage of early
incipiency he finds that there may or may not be leucocytosis,
accompanied by a gain in the polynuclear neutrophiles at the ex-
pense of the lymphocytes as the disease advances, together with
well-marked signs of cell disintegration and impaired differentia-
tion. In the advanced stage, with cavity formation and extensive
distribution of the lesions through the lungs, the preceding signs
are thought to be still more strongly emphasized, especially those
relating to the quantity of debris derived from cells undergoing
dissolution. While it is true that the above changes in the leu-
cocytes may be found in many cases of pulmonary tuberculosis,
they by no means occur in all, nor can they be regarded as char-
acteristic of this disease. Any septic or purulent process may
cause a similar polynuclear neutrophile increase, while the pres-
ence of degenerating forms of cells is not at all uncommon in
such conditions.
The numerical variations in the leucocytes in coxalgia, Pott's
disease, and other forms of joint and bone tuberculosis are well
illustrated by the following analysis of the large number of counts
made by Brown 2 and by Dane 3 in these conditions.
LEUCOCYTES PER C.MM.
BROWN'S 122 COUNTS.
DANE'S 51 COUNTS.
Al
Ft
M
M
ove 30,000 i
Dm 20,000 t
18,000
16,000
14,000
12,000
% 10,000
9,000
8,000
7,000
6,000
5,000
iximum
i
i
8
4
0
22
18
19
9
8
8
4
$X»*5«
5,100
4
12
I
2
4
12
7
3
i
i
4
0
41.369
6,063
D 30,000 i
20 ooo
18,000
16,000
14,000
12,000
10,000
9,000
8,000
7,000
6,000
n
nimum
1 Jour. Amer. Med. Assoc. 1897, vol. xxix, p. 828.
2 Loc. cit. 3 Loc. cit.
TUBERCULOSIS. 549
In the great majority of instances the high counts picture a
polynuclear neutrophile leucocytosis, but this is not invariably
the rule, since in an occasional case the gain depends chiefly
upon an increase in the lymphocytes. Low counts may also
be characterized by a relative lymphocytosis, this change being
most common and most marked in young children and in the
profoundly cachectic.
From the results of the studies made by the above-men-
tioned writers it may be concluded that in these forms of
bone tuberculosis high leucocyte counts generally signify that
an abscess either exists or impends, although, on the contrary,
low counts .do not necessarily preclude the presence of an ab-
scess. High counts, especially those of rapid development,
point to a secondary pyogenic infection, while slowly de-
veloping, moderate leucocytoses appear to be compatible with
simply a sudden increase in the activity of the tuberculous proc-
ess. In the presence of an abscess low counts usually indicate
a pure tuberculous pus collection. Cases in which, at the first
operation, the pus was proved sterile- show an increased leuco-
cyte count when the wound becomes infected with pyogenic bac-
teria. In these post-operative leucocytoses due to secondary
infection the count persists very high for a few days, and then
gradually falls unless the sepsis is so acute as to threaten life, in
the event of which it may still remain high until a crisis is reached.
Should the pyogenic infection be so severe as to overcome the
patient's resisting powers, the leucocytosis either fails to develop
or else disappears, if it is already present. As in pulmonary
tuberculosis, the leucocyte count and the degree of " pyrexia ap-
parently stand in no parallelism.
Absence of a leucocyte increase is the rule in uncomplicated
acute 'miliary tuberculosis, tuberculous adenitis, pleurisy, and peri-
carditis, whereas in tuberculosis of the genito-urinary apparatus
high counts are not uncommon, owing to the frequency of
secondary infections in such lesions. In tuberculous peritonitis,
especially in early life, the count may also be high, probably
always as the result of coexisting inflammatory processes. In
Rotch's1 23 cases in young children the leucocytes averaged 16,435,
and ranged between 5400 and 44,000 per c.mm. Such high counts
as these rarely occur in the adult. In tuberculous meningitis,
unlike other forms of tuberculosis, leucocytosis is the rule. It oc-
curred in 75 per cent, of Cabot's2 43 cases, the counts in some
cases ranging as high as 40,000 to 50,000. Of 26 cases of tubercu-
1 Jour. Amer. Med. Assoc., 1903, vol. xl, p. 69. * Loc. cit.
550 GENERAL HEMATOLOGY.
lous meningitis in children studied by Koplik,1 40 per cent, showed
a count of 20,000 to 25,000, results corresponding to those found
by Osier2 in the adult.
The presence of a leucocytosis in a lesion ob-
DIAGNOSIS. viously tuberculous, whatever its seat, is usually
to be interpreted as a sign of some complicating
secondary infection, the chief exceptions to this general rule being
those infrequent cases in which the sudden extension of a purely
tuberculous bone disease may cause a moderate, progressive rise
in the count. A positive iodin reaction also points to a mixed
infection. In pulmonary tuberculosis, if the influences of broncho-
pneumonia and hemorrhage can be ruled out, leucocytosis almost
invariably indicates the presence of cavity formation, and in bone
tuberculosis the superposition of a pyogenic process. In perito-
neal, pleural, and pericardial effusions low counts suggest an un-
mixed tuberculous affection unless the leucopenic influences of a
virulent infection are to be found. The diagnosis between acute
miliary tuberculosis and enteric fever has been referred to under
the latter disease. (See p. 409.) Blood cultures should be
made in every case of doubtful miliary tuberculosis, for posi-
tive results, although rare, are conclusive when present. The
leucocyte count may be quite as high in tuberculous as it is in
non-tuberculous meningitis.
LXXIII. TYPHUS FEVER.
Lewaschew3 claims to have found, in the
PARASITOLOGY. finger blood of a large number of typhus patients,
a micrococcus, occurring both singly and in
pairs, which he characterizes as the Micrococcus exanthemati-
cus, and regards as the pathological agent of infection. A
diplococcus has been isolated by Balfour and Porter,4 from
blood obtained by puncture of the thumb, in 36 of 43
cases of typhus examined by these authors. In a large num-
ber of control cases, including measles, scarlet fever, and en-
teric fever, the organism in question was uniformly absent, except
in the last-named disease, in which it was discovered in 40 of the
46 cases studied. Cultures of this parasite when injected intrave-
nously into rabbits produced a rapidly fatal septicemia in these
1 Med. News, 1904. vol. Ixxxiv, p. 1065.
1 "Principles and Practice of Medicine,"4th ed., New York, 1901.
8 Russkiy Vrach, 1894, Nos. 2 and 3; abst. in Sajous' Annual, 1895, sec. H,
P-45-
4 Edinburgh Med. Jour., 1899, vol. vi, p. 522.
TYPHUS FEVER. 551
animals. In .6 cases of typhus Gotschlich1 reports having found
protozoan bodies resembling Smith's Piroplasma bigeminum
of Texas fever. The organisms in question were observed in
three different developmental stages — intracellular forms, extra-
cellular ovoids and spheres, and free flagellated bodies. These
investigations, while interesting as pathological studies, throw no
definite light upon the etiology of typhus fever.
From the limited data at present available it
HEMOGLOBIN appears that at the beginning of the attack the
AND amount of hemoglobin and the number of eryth-
ERYTHROCYTES. rocytes remain unchanged, but that later a mod-
erate degree of anemia appears, being most marked
during the period of apyrexia. Tumas' careful studies2 of two
cases, in which altogether 25 examinations were made, showed a
hemoglobin range of from 50 to 94 per cent., with from 3,450,000
to 5,360,000 erythrocytes per c.mm., the minimum figures for both
being observed during the second week of the infection. The
presence of structural degenerative changes and of erythroblasts
has not been recorded. In the acutest forms of the disease hemo-
globinemia has been noted.
Absence of leucocytosis, with occasional counts
LEUCOCYTES, showing a decided leucopenia, is the rule, as in
enteric fever, according to conclusions of the
most careful investigators of this question. Even the coexis-
tence of another infection, alone sufficient to give rise to leu-
cocytosis, seems to have no effect in provoking an increase, as
evidenced by one of Tumas' cases, complicated by diphtheria, in
which the number of leucocytes never exceeded 9600 per c.mm.;
in his other case they once rose to 17,000 after a prof use sweat, but
with this exception the counts all ranged between 1600 and 9600.
Ewing3 found a maximum count of 9000 in a study of 4 cases,
2 of which were fatal. It has not yet been determined whether or
not specific qualitative changes affect the leucocytes in this disease.
In differentiating typhus fever from epidemic
DIAGNOSIS, cerebrospinal meningitis the presence of a frank
leucocytosis should be regarded as highly symp-
tomatic of the latter. The behavior of the leucocytes fails to be
of service in distinguishing typhus from typhoid, since in neither
of these infections are these cells increased in number; here, how-
ever, the serum test and blood culturing prove of signal utility.
1 Sem. me"d., 1903, vol. xxiii, p. 298.
2 Deutsch. Arch. f. klin. Med., 1887, vol. xli, p. 323.
3 " Clinical Pathology of the Blood," 2d ed., Philadelphia and New York, 1904.
552 GENERAL HEMATOLOGY.
Absence of leucocytosis is also associated with malignant measles,
the early stages of which may remind one of typhus fever.
LXXIV. VACCINATION.
•Billings * who has carefully studied the effects of vacci-
nation on the blood, finds that no changes are produced in the
hemoglobin and erythrocytes by this procedure. Pallor, with other
signs of anemia, developing in young children after vaccination
has been described as " post-vaccinal anemia" by Bellotti,2 who
attributes the change, if such it be, to the hemolytic effect of the
vaccine virus. Bellotti's conclusions, since they are not fortified
by blood counts, must be accepted with doubt.
Moderate but definite leucocytosis, the counts averaging about
15,000 per c.mm., is characteristic. The leucocytosis is of the
inflammatory type, and reaches its maximum coincidentally with
the height of maturation of the vaccine pustule, fading away as
the latter desiccates. Sobotka3 has observed a secondary leuco-
cytosis, beginning about the tenth or twelfth day, and often per-
sisting for as long as six days, the height of the count correspond-
ing in a general way to the severity of the local lesion and to the
activity of the virus.
LXXV. VALVULAR HEART DISEASE.
In well-compensated valvular lesions of the
STAGE OF . heart, irrespective of their character, the blood
COMPENSATION, shows no deviation from its normal composition,
for such lesions of themselves are incapable of
giving rise to blood changes. If the latter are observed in cases
of this kind, they should be attributed to other factors rather
than to the heart disease.
In cases associated with acute failure of com-
ACUTE RUP- pensation changes in the blood picture, the in-
TURE OF tensity of which runs parallel to the severity
COMPENSATION, of the circulatory disturbances, sooner or later be-
come manifest. These changes, consisting in the
production of a so-called serous plethora, depend chiefly upon a re-
duction in blood pressure, in consequence of which the blood mass
becomes diluted by transudation into the vessels of fluids from the
1 Med. News, 1898, vol. Ixxiii, p. 301.
2 Gaz. degli Ospedali e. d. Clin., 1903, vol. xxiv, p. 587.
f Zeitschr. f. Heilk., 1893, vol. xiv, p. 349.
VALVULAR HEART DISEASE. 553
surrounding lymph spaces. It is also highly probable that this
surcharging of the blood mass with liquids is aggravated by the
disturbances in the functions of the heart and kidneys whereby
the elimination of the superfluous watery constituents of the blood
is hindered. Oertel * remarks that it seems not unlikely that an-
other factor in the production of this hydremia may be found in
the increased consumption of liquids, which he has noted in many
patients suffering from valvular disease. Examination of the
blood at this stage of the disease shows that there is a diminution
in the albuminoid constituents and in the specific gravity of the
blood, that the percentage of hemoglobin falls, and that oligo-
cythemia proportionate to the latter develops; the leucocytes, un-
like the erythrocytes, do not decrease, but their number remains
within normal limits. The observer must be careful not to mis-
take the blood picture of hydremia for that of a true anemia, from
which it is distinguishable only by taking into consideration other
clinical signs and symptoms.
In chronic valvular lesions, myocarditis, and dilatation, Schott 2
found, as the result of his treatment by baths and gymnastics, a
decided hemoglobin increase. In the average case it amounted to
a gain of about 20 per cent., and usually was associated with a
blood pressure rise ranging from 20 to 30 mm. of mercury.
In cases of chronic valvular disease with
EFFECTS OF stasis, dyspnea, and cyanosis, a very different
STASIS. picture from that just described presents itself.
The hydremia gives way to a concentration of the
blood mass, this change being due mainly to the increased outflow
of plasma from the vessels into the neighboring tissues, and per-
haps to the excessive loss of water, especially through the lungs,
as Grawitz3 has suggested. Stengel4 offers as an explanation of
this inspissation of the blood two other factors: the lagging of
the erythrocytes in the peripheral arterioles and venules, and the
increase in the viscosity of the blood. Calabresse 5 argues that in
some instances the polycythemia may be absolute, being a sign
of hematopoietic hyperactivity excited by an excess of carbonic
acid in the blood. Other signs of active hemogenesis, such as
the presence of normoblasts, are required, however, to make this
view reasonable.
At this period of valvular disease the specific gravity and
the proportion of albuminoid principles of the blood rise,
1 Deutsch. Arch. f. klin. Med., 1892, vol. xxxi, p. 293.
2 Brit. Med. Jour., 1904, vol. i, p. 536. s Loc. cit.
4 Proc. Path. Soc. of Phila., 1898, vol. i, p. 137.
1 Sem. me"d., 1903, vol. xxiii, p. 388.
554 GENERAL HEMATOLOGY.
and high hemoglobin values with more or less decided polycy-
themia are found, the erythrocyte count commonly being in the
neighborhood of 6,ooo,coo per c.mm., or, in some instances, nota-
bly those of congenital heart disease, as high as from 7,000,000
to 8,000,000. It is common to find many megalocytes, and, as
Labbe" 1 has shown, a great increase in the proportion of reduced
hemoglobin in the blood. The polycythemia, it should be remem-
bered, may be sufficient completely to mask a coexisting anemia;
in fact, it must be admitted that no reliable data concerning the
true condition of the blood are obtainable in valvular disease of
the heart, except during the stage of perfect compensation.
The behavior of the leucocytes is variable : their number may
be normal, or, on the other hand, a decided, but not an ex-
cessive, leucocytosis may be present. Should this be the case,
the increase will be found to involve principally the polynuclear
neutrophile cells at the expense of the other forms.
Grawitz2 has drawn attention to the fact that a form of
stroma degeneration is frequently met with in valvular dis-
ease, being evidenced by the unnatural readiness with which
the hemoglobin tends to become diffused in the plasma within a
short time after the removal of the blood from the body. This,
while it cannot be termed a true hemoglobinemia, at least appears
to demonstrate that the stroma and its hemoglobin are less firmly
combined than they are in perfectly normal blood.
The efforts made by some authors to associate certain blood
conditions with definite valvular lesions seem to the writer far-
fetched. The changes just described are thought by some to be
especially prone to occur in affections of the mitral segments,
and other authors even go so far as to state that disease of these
valves is more often associated with transient apparent anemia or
with chronic polycythemia than lesions of the aortic valves, the
blood in the latter conditions being usually normal or but slightly
impoverished. After all, the general disturbances dependent upon
the lesion, and not the lesion per se, account for the alterations of
the normal blood picture which have been observed in heart
disease of this type.
LXXVI. VARICELLA.
Thomson and Brownlee 3 report having found small spherical
hyaline bodies in the blood of persons suffering from chicken-pox,
both in the prodromal stage and during the first week of the disease,
1 Sem. m6d., 1903, vol. xxiii, p. 33. 2 Loc. cit.
3 Brit. Med. Jour., 1903, vol. i, p. 241.
VARIOLA. 555
Uncomplicated chicken-pox produces no alteration in the
hemoglobin and erythrocytes, but in cases complicated by ex-
tensive necrotic processes ("varicella escharotica") or by hem-
orrhage ("varicella haemorrhagica") a variable degree of sympto-
matic anemia may be encountered.
The leucocytes behave erratically both as to number and as to
kind. In about one-third of the reported cases the stage of active
pustulation was associated with a moderate neutrophile increase,
ranging from 1000 to 4500 cells above normal. In Engel's case,1
the first on record, this was accompanied by a disappearance of the
eosinophiles, which, after the pustules healed, rose to 16 per cent.
Practically similar quantitative changes were found by Nobecourt
and Merkleri2 in their series of 15 cases, but in one-half the large
lymphocytes were in excess and myelocytes were noted in one
third. In contrast to these findings, Weil and Descos,3 while
meeting with polynuclear neutrophile leucocytosis in about one
case in three, deny that either lymphocytosis or myelocytosis is
found in varicella, and emphasize the value of this negative
finding as a sign for differentiating this condition from small-pox.
Stengel and White4 report normal leucocyte counts in uncom-
plicated cases.
It is obvious that the contradictory reports of various obser-
vers must be reconciled by further investigation before the blood
examination in varicella can have any dependable clinical bearing.
LXXVII. VARIOLA.
During the first few days of the attack the
GENERAL fibrin network is normal, but as the stage of PUS-
FEATURES, tular eruption is reached, -a decided hyperinosis
develops. Streptococci have been found in the
blood repeatedly by Widal and Benzacon,5 and also by Waele and
Sugg.6 The streptococcus found by the last-named authors is
clumped by variolous blood serum and by that of successfully vac-
cinated subjects, but not by the serum of unvaccinated persons nor
by ordinary antistreptococcus serum. Pfeiffer7 has attached spe-
cific properties to apparently ameboid bodies which he discovered
in small-pox patients' blood, and to this view a number of other
1 XV. Cong. f. inn. Med., 1897.
7 Jour, de physiol. et de path. g£n., 1901, vol. iii, p. 439.
3 Ibid., 1902, vol. iv, p. 504.
4 Univ. of Penna. Med. Bull., 1901, vol. xiv, p. 310.
5 Centralbl. f. allg. Path., 1896. vol. vii, p. 569.
* Brit. Med. Jour. Epit., 1904, vol. i, p. 8.
7 "Handb. d. spec. Therap.," 1894, vol. i, p. 229.
556 GENERAL HEMATOLOGY.
workers, nptably Guarnieri1 and Wasielewski,2 also subscribe.
Other amebse have been found under similar circumstances by
Reed,3 Weber,4 Ishigami,5 Thomson and Brownlee,6 and others.
None of these discoveries has elucidated the etiology of variola.
A protozoan body (Cytoryctes variola} has been found in the
skin epithelium and once in the blood of small-pox patients by
Councilman, Magrath, and Brinckerhoff,7 who consider this or-
ganism the specific cause of the disease. This claim, although
based upon convincing experimental work, has still to endure
the test of corroborative research.
Post-febrile anemia, first becoming apparent
HEMOGLOBIN when defervescence is established, is the rule,
AND the decrease in hemoglobin and corpuscles being
ERYTHROCYTES. usually decided, and not infrequently excessive.
This is especially true in hemorrhagic and con-
fluent variola, in which conditions a loss of 2,000,000 or 3,000,-
ooo cells per c.mm. may occur with great rapidity. The loss
of hemoglobin begins slightly earlier than that of the corpuscles,
but later both elements are usually diminished proportionately.
During the febrile period of the disease the number of erythro-
cytes is approximately normal, or even increased, in case the
blood becomes concentrated by the influence of the temperature.
Qualitative changes in the erythrocytes are not marked, except
in cases with severe anemia, in which nucleation, poikilocytosis,
and deformities of size may be noted. In such instances hemo-
globinemia may also occasionally be detected. Regeneration of
the blood is said to be exceedingly slow.
In the majority of cases a moderate but
LEUCOCYTES, distinct leucocyte increase develops, first becom-
ing apparent in the early stages of the dis-
ease, reaching its maximum during pustulation, and gradu-
ally declining during desiccation of the pocks, unless prolonged
by some complication. In the uncomplicated case the normal
count is regained by the end of the second or the early part of
the third week. The count usually ranges between 10,000 and
20,000, although such factors as hemorrhage, confluence, and
secondary infection tend to exaggerate these figures. In a series
1 Arch, per le sci. med., 1897, vol. xvi, p. 403.
2 Zeitschr. f. Hyg. u. Infectionskr., 1901, vol. xxxviii, p. 212.
3 Jour. Exper. Med., 1897, vol. ii, p. 515.
4 Centralbl. f Bakt. u. Parasit., 1897, vol. xxi, p. 286.
5 Ibid., 1902, vol. xxxi, p. 794. * Brit. Med. Jour., 1903, vol. i, p. 241
7 Jour. Med. Research, 1903, vol. iv, p. 372; ibid., 1904, vol xi, p. 12; also
Calkins, ibid., p. 136.
VARIOLA. 557
of 36 cases studied by Roger1 the count ranged from 6000 to
15,000 in 19; from 15,000 to 20,000 in 12; from 20,000 to 30,000
in 3; and from 30,000 to 35,000 in 2. The count is likely to be
higher in the unvaccinated than in the vaccinated, and may rapidly
diminish under the influence of serum therapy, and, in some fatal
cases, just before death.
The behavior of the leucocytes in small-pox is probably due to
the action of the specific variolous toxin, which, if sufficiently active,
provokes an increase of these cells. This change develops too
early in the disease to be dependent solely upon the effects of
secondary infection of the pocks, which accident the older writers —
Pick,2 Halla,2 Brouardel,2 and others — maintained was the real
determining , factor. Furthermore, the increase involves chiefly
the large lymphocytes, which cells, according to Courmont and
Montgard,3 are in excess even when there is extensive stroptococcic
pustulation of the lesions; when, however, genuine secondary
furunculosis and abscesses complicate the variolous process, a
neutrophile leucocytosis promptly supervenes. These findings,
which have been corroborated by Weil,4 by Ewing,5 and by
Roger,6 strongly suggest that pustulati6n is a specific change,
and not merely the expression of a secondary contamination of
the pocks with pyogenic bacteria, as was the former belief. Myelo-
cytes, sometimes in considerable numbers, are also found with
great constancy, and are especially abundant in the severer types
of the infection. The eosinophiles may be greatly increased in
hemorrhagic small-pox, and small percentages of mast cells are
to be noted in cases with high leucocyte counts.
The blood plaques are decreased in number during the period
of fever, being sometimes absent from the blood at "this stage of
the disease.
Varioloid, unless associated with suppuration, does not give rise
to anemia nor to leucocytosis.
The presence of a definite mononucleosis, in-
DIAGNOSIS. volving principally the large lymphocytes and the
myelocytes, is highly suggestive. Such a blood
picture is sufficient evidence to exclude measles, for which the
prepustular stage of variola has been mistaken, and to suggest
true, rather than modified, small- pox. In pustular syphilide and
in the purpuric type of cerebrospinal meningitis, which may coun-
terfeit variola, the blood shows a typical polynuclear neutrophile
1 "Infectious Diseases," Eng. trans, by Gabriel, New York and Philadelphia,
1903, p. 260. 2 Cited by von Limbeck, loc. cit
8 Province med., 1900, vol. xv, p. 481. 4 Sem. med., 1900, vol. xx, p. 222.
5 "Clinical Pathology of the Blood," New York and Philadelphia, 2d ed.
1904, p. 296. * Loc. cit.
558 GENERAL HEMATOLOGY.
leucocytosis. Owing to the current conflicting views (see p. 555)
it is impossible at present to base the differentiation of variola
and varicella upon the state of the blood.
LXXVIII. YELLOW FEVER.
Slow coagulation and deficiency or even com-
GENERAL plete absence of the fibrin network are common,
FEATURES, these peculiarities being observable often in the
earliest stages of the disease, apparently beginning
coincidentally with the introduction of the infecting principle.
The identity of the specific cause of this diseas^ is still un-
known. Sanarelli's claim,1 that his Bacillus icteroides is to be
found in the circulating blood of yellow fever patients during life,
has been very generally disproved. Reed and Carroll2 have shown
that this bacterium is identical, morphologically and biologically,
with the hog-cholera bacillus, and Agramonte 3 and the members
of the United States Yellow Fever Commission4 (Reed, Carroll,
Agramonte, and Lazear) report uniform failures to isolate Sana-
relli's bacillus either by antemortem blood cultures or by post-
mortem examinations of the blood and organs of persons
dead of yellow fever. In passing, it may be of interest to
add that Finlay's theory,5 that yellow fever is transmitted by
means of the mosquito's bite, has been confirmed beyond question
by the experiments of this Commission, which has identified the
Stegomyia fasciata as the offending insect. The French Yellow
Fever Commission6 has fully corroborated these findings. The
character of the infective principle thus harbored by the mosquito
is unknown — possibly it belongs to that class of invisible (ultra-
microscopic) organisms now believed to excite certain specific
infections. Finlay7 suggests that it may be a protozoon similar
to the malarial plasmodium, which undergoes one developmental
cycle in the human body and another in the mosquito, the former
being an asexual reproduction accompanied by the elaboration of
powerful toxins to which the fever is to be attributed. J. C.
1 Annal. de Hnstitut Pasteur, 1897, vol. xi, p. 433; also Brit. Med. Jour.,
1897, vol. ii, p. 7; also Med. Record, 1897, vol. bdi, p. 117.
2 Jour. Exper. Med., 1900, vol. v, p. 216; also Carroll, N. Y. Med. Jour.,
1904, vol. Ixxix, p. 241. 3 Med. News, 1900, vol. Ixxvi, p. 249.
4 Phila. Med. Jour., 1900, vol. vi, p. 790; also Jour. Amer. Med. Assoc., 1901,
vol. xxxvi, p. 431.
5 Jour. Amer. Med. Assoc., 1901, vol. xxxvi, p. 1040.
* Jour. Amer. Med. Assoc., 1904, vol. xlii, p. 1369.
7 Lancet, 1903, vol. i, p. 1711.
YELLOW FEVER. 559
Smith1 and Parker, Beyer, and Pothier2 have discovered what
they regard as a protozoan parasite, called by them the Myxococ-
cidium stegomyia, in the bodies of Stegomyia jasdata fed upon
the blood of yellow fever patients, but in no others. The inference
from their announcement, that these bodies represent the specific
cause of -yellow fever undergoing its mosquito phase, has been
weakened considerably by Carroll's later and apparently convinc-
ing demonstration3 that the so-called protozoon is merely a
yeast fungus such as is commonly found in the mosquito fed upon
overripe bananas to which yeast has been added.
In a series of 23 cases Tombleson4 claims to have found in
finger blood peculiar polymorphous organisms, appearing as
short oval bacilli, as bacilli with rounded ends, and as long beaded
rods.
Pothier's studies of 154 cases at .the New
HEMOGLOBIN Orleans Isolation Hospital, in iSQy,5 show that a
AND more or less decided loss of hemoglobin com-
ERYTHROCYTES. monly occurs during the active stages of the in-
fection, and that the normal percentage is slowly
regained during and after convalescence;- during the febrile period
the hemoglobin ranged from 50 to 90 per cent., and during con-
valescence from 64 to 80 per cent. He found that the erythro-
cyte count never fell below 4,280,000 per c.mm., and that even
in a fatal case it might be normal. Lack of parallelism between
the hemoglobin percentage and the specific gravity of the blood
is a peculiarity to which Albertim6 has drawn attention, this
investigator having repeatedly noted a considerable fall in the
blood density without a corresponding loss of hemoglobin.' Stern-
berg7 has noted the absence of quantitative changes -affecting the
erythrocytes in this disease, stating that, "although there is no
general destruction of the red corpuscles, it is probable that a con-
siderable number of these elements perish, for the serum contains
free hemoglobin, which gives it a yellow color even as early as the
third or fourth day." This hemoglobinemia is common in all
cases, but especially so in fatal cases just before death. The re-
sults of these investigations by Pothier and by Sternberg are con-
tradictory to the views expressed by earlier writers, who have been
1 Science, 1903, vol. xviii, p. 530.
2 Report of Working Party No. i, Yellow Fever Institute, P. H. and M. H. S.,
Washington, 1903.
3 Jour. Amer. Med. Assoc., 1903, vol. xli, p. 1341.
4 Lancet, 1903, vol. ii, pp. 594 and 1781.
s Jour. Amer. Med. Assoc., 1898, vol. xxx, p. 885.
6 Rev. de Me"d. Trop., 1903, vol. iv, p. 73
7 U. S. M. H. Service Report on the Etiology and Prevention of Yellow Fever,
Washington, 1890.
560 GENERAL HEMATOLOGY.
accustomed to describe the cellular elements of the blood in yellow
fever as profoundly altered.
Decided degenerative changes in the erythrocytes have not been
observed, although it has been asserted by Jones1 that these cells
"present under the microscope certain peculiar appearances which
are referable to the action of certain extraneous excretory matters
in the blood." A few nucleated cells of the normoblastic type are
reported to have been found occasionally.
The behavior of the leucocytes in yellow fever
LEUCOCYTES, is extremely variable, their number being sub-
normal in some cases, and decidedly, but not
strikingly, increased in others. In the series of Pothier, just quoted,
the counts ranged between 4660 and 20,000 per c.mm. In five
counts by John Guiteras2 the leucocytes ranged from 3200 to
11,400 per c.mm., averaging 5400. The increase, when present,
involves chiefly the polynuclear neutrophiles, the relative propor-
tion of these cells usually being in excess of 85 or 90 per cent. Small
numbers of myelocytes were found occasionally by Cabot3 in dif-
ferential counts of 12 films of yellow fever blood.
Sternberg4 has described certain relatively large, highly refrac-
tive, spherical granules in the protoplasm of the leucocytes, which
he is inclined to regard as an evidence of fatty degeneration of
these cells; these granules were especially abundant in severe
cases, nearly every leucocyte containing some of them. They are
not, however, peculiar to yellow fever, since they have been found
in the blood of patients suffering from beri-beri, and even in the
blood of normal individuals, residents of the tropics.
Until the cause of yellow fever is discovered,
DIAGNOSIS. « the blood examination can afford little or no aid
in the recognition of this infection. The fre-
quency of hemoglobinemia in yellow fever, and its absence, so far
as is known, in dengue, may serve as a hint of some importance
in differentiating these two fevers. In differentiating malarial
fever, the examination of the blood for the malarial parasite will
usually give definite information, and the occasional presence of
a well-developed polynuclear leucocytosis in yellow fever should
not be forgotten. The lack of relationship between the specific
gravity and the hemoglobin value of the blood in the latter is also
significant.
1 Jour. Amer. Med. Assoc., 1895, vol. xxiv, p. 403.
3 Brit. Med. Jour., 1902, vol. i, p. 366. 3 Loc. cit. * Loc. cit.
INDEX OF AUTHORS.
ABBOTT, 402> 445
Achalme, 148
Achard, 373
Adami, in, 14°
Adams, 539
Addison, 365
Afanassiew, 148, 5r5
Affleck, 493
Agramonte, 558
Aiello, 427
Albertini, 559
Aldridge, 484
Allbutt, 275
Allen, 395
Almazia, 47 l
Altmann, 208
Amalgia, 199
Ames, 248
Anderson, 531
Aoyoma, 377
Aporti, 162
Appelbaum, 545
Archard, 433
Arloing, 542
Armand-Delille, 179. 353
Arneth, 290
Arnold, 199, 214
Arsamaskoff, 485
Aschoff, 154
Ashford, 440
Askanazy, 132, 439
Atkinson, 537
Aubertin, 312
Auche, 513
Audibert, 510
Auerbach, 130, 394
BACCARANI, 512
Baginsky, 349. 521
Bain, 171, 225
Baker, 538
Baldy, 165
Balfour, 148, 420, 44L 33
Ballance, 335
Bancroft, 4I{>
Bannatyne, 372
Barker, 208
Bassett-Smith, 392, 4»4
36
Bastian, 413
Bastianelli, 445
Baumann, 95. l63. 3O1
Baumgarten, 73
Baumholtz, 545
Beaton, 518
Beaujard, 312
Beck, 122, 128, 543
Becker, 132. 5 IO
Becker, E., 439
Beco, 506
Becquerel, 141. 43°
Behier, 300
Bellotti, 552
Benario,. 81
Benda, 319
Bendix, 543
Bennett, 306
Bensaude, 322, 373
Bentley, 44*> 443
Benzacon, 242, 555
Berend, 129
Bernard, 254
Besredka, 251, 38 7
Bettencourt, 539
Bettman, 426
Beyer, 559
Bibb, 444
Bierfreund, 164, 301, 474
Biernacki, 267, 275, 373
Birk, 252
Bize, 387
Bizzozero, 199
Bjorkman, 234
Blake, 235,421
Blix, 91
Bloch, 351
Bloodgood, 244, 309> 44
Blumer, 366, 537
Boeckman, 209
Boeni, 252
Boggs, 135
Bohland, 232, 251, 262
Bojanus, 252
Bordet, 113. IJ7
Borini, 251
562
INDEX OF AUTHORS.
Boston, 444, 497
Bouchut, 387
Boudou, 211
Bowie, 524
Boycott, 440
Bra, 497
Bradford, 321, 350
Bradley, 350
Bramwell, 270, 379, 488
Brahdenberg, 129, 512
Brat, 135
Bremer, 384
Breuer, 164
Brieger, 527
Brinckerhoff, 556
Brodie, 91
Brooks, 537
Brossa, 498
Brouardel, 392, 557
Brown, E. J., 312
Brown, P. K., 262, 444, 546, 548
Brown, T. R., 256, 257, 536
Brownlee, 554, 556
Bruce, 484, 496, 538
Bryant, 312
Buard, 543
Buchner, 238, 252
Buffa, 533
Bunge, 162
Burmin, 129, 268, 307
Burr, 498
Burrows, 249, 495
Busquet, 394
Buxtdn, 394
CABOT, 184, 194, 227, 235, 244, 262,
269, 282, 285, 305, 308, 365, 369, 382,
421, 487, 491, 502, 512, 520, 534, 537,
549. 56°
Cadet, 1 76
Calabresse, 553
Calvert, 420
Campbell, 178
Canard, 129
Canon, 256, 258, 380, 436, 527
Cantani, 131, 372, 428
Capps, 173, 222, 249, 321, 322, 494
Carpenter, 350
Carrara, 104
Carriere, 375
Carroll, 558
Carstanjen, 231
Carter, 387
Cassel, 350
Castellani, 394, 437, 539
Castellino, 185
Cattell, 104
Cazeaux, 178
-Cazin, 252, 370
Ceconi, 104
Celli, 445
Cevidalli, 512
Chadbourne, 248
Chantemesse, 410
Charcot, 39
Charles, 484
Charon, 350
Charrin, 113
Charteris, 163
Chausse, 497
Cheney, 537
Chenzinsky, 87
Childs, 331
Chowning, 531
Christian, 534
Christophers, 442, 469, 470
Christy, 413, 452
Churchill, 354
Cionini, 506
Class, 148, 521
Clerc, 259, 420, 433
Cobb, 531
Cohn, 292
Cole, 394, 506
Coleman, 394
Coles, 420, 441
Combe, 485
Copeman, 277
Corthorn, 376
Coste, 370
Councilman, 445, 556
Courmont, 394, 513, 542, 557
Cox, 485
Coyon, 518
Craig, 148, 445, 485
Crajkovvski, 522
Crane, 312
Crisafi, 502
Cunliffe, 476
Cunningham, 442
Curry, 179
Curschmann, 370, 395
Czerniewski, 526
Czerny, 334, 336
DA COSTA, 165, 248
Daland, 91
Dale, 534
Dane, 546, 548
Daniels, 82, 471, 538, 541
Dare, 40, 98
Darguin, 433
Darwin, 118
Daunay, 175
Davidson, 414
Dawson, 302
De Amicis, 502
Decastelle, 261
INDEX OF AUTHORS.
563
Deetjen, 198
Delafield, 87
Delany, 471
Delbert, 305
Delestre, 356
Delezene, 263
De Lisle, 532
Denige, 145
Denys, 430
Berlin, 383
De Rienzi, 252, 434
De Saussure, 414
Descos, 555
Desevres, 131
Determann, 90
Devlin, 383
De Vries, 122
De Witt, 280 '
Diabella, 133, 276
Diefendorf, 494
Dinkelspiel, 117, 121
Dionisi, 466, 469
Dobrovici, 210
Dock, 323, 379, 445
Donovan, 442
D'Orlandi, 262
Douglas, 239, 441
Douglas, Carstairs, 135
Drake, 537
Drouin, 129, 131, 393, 410
Dubroisay, 387
Ducchesi, 199
Dudgeon, 433
Dumoulin, 336
Duncan, 541
Dunlop, 379
Dunn, 277,414
Durham, 68, 113
Dutton, 538, 540
Diitzmann, 370
Duval, 425
EBSTEIN, 321
Egger, 178
Ehrlich, 76, 81, 83, 87, 151, 188, 192,
196, 2O8, 222, 224, 228, 238, 241,
253, 262, 282, 302, 316, 419, 439, 502,
Si2
Ehrnrooth, 122
Eichhorst, 183
Einhorn, 73, 350, 422
Ekgren, 234
Elder, 280
Elliott, 513
Emerson, 73
Engel, 96, 129, 195, 199, 389, 555
Engelhardt, 122
Erving, 365, 372
Eubank, 301
Ewing, 118, 141, 248, 365, 387, 389, 506,
534,551.557
FAJARDO, 492
Federmann, 370
Fehleisen, 410
Fehrsen, 174
Feinberg, 473
Felsenthal, 387, 523
Ficker, 401
File, 387
Filetti, 445
Fink, 374
Finlay, 558
Fischl, 343
Fleischer, 290, 304
Flexner, 391, 313
Foa, 179
Fodor, 412 ."-,
Foerster, 534
Ford, 147
Forde, 538
Fraenkel, 321
Francine, 422
Frazier, 244, 245
French, 369
Freudberg, 129
Freund,- 143
Friedlander, 234
Frohlich, 502
Funke, 269, 393
Fussell, 321
Futcher, 88, 142, 228, 391, 424, 447, 512
GABRITSCHEWSKY, 238, 374, 387
Garrod, 144, 426
Gaylord, 473
Geissler, 350
Gemelli, 395
Georgiewsky, 512
Gerhardt, 304
Gerngross, 370
Gibson, 199, 382
Gilbert, 350, 387, 436
Gilmour, 484
Giorgi, 426
Girvin, 165
Gley, 134
Goadby, 392
Goldberger, 226
Goldhorn, 88
Goldscheider, 238, 240, 250
Golgi, 445
Golla, 383
Gollasch, 256
Goodall, 232, 496
Gordinier, 537
Gotschlich, 551
INDEX OF AUTHORS.
Gould, 537
Gowers, 52, 69
Gozdzicki, 545
Gradwohl, 521
Graeber, 268
Graham, 382
Graham-Smith, 120
Gram, 172
Gra^si, 445
Gratea, 350
Grawitz, 179, 196, 209, 271, 307, 365,
383, 392, 428, 431, 436, 439, 482, 491,
511, 512, 513, 527, 553, 554
Greenbaum, 404
Greene, 282, 397
Greenough, 424
Griesinger, 440
Gros, 370
Grosch, 312
Griiber, 113
Griinbaum, 117
Guarnieri, 556
Guinard, 544
Guinon, 350, 351
Guiteras, 414, 560
Gulland, 227, 232, 369, 420
Giimbel, 379
Gumprecht, 276
Gundobin, 231, 344
Giinther, 112
Gutig, 406
Gwyn, 395, 488, 537
HAESSLIN, 300
Hagen, 338
Haig, 55
Haines, 115
Haldane, 53, 122, .125, 440
Hall, 301, 382
Halla, 209, 557
Hallin, 532
Hamburger, 106, 122, 181
Hamel, 196, 512
Hamill, 348
Hamman, 321
Hammerschlag, 94, 133, 268, 342, 521
Hand, 252
Hankin, 209, 252
Hannes, 234
Hanot, 432
Hardy, 215, 441
Hare, 510
Harris, 221, 394
Hartley, 336
Hartmann, 334, 335
Hartung, 477
Hastings, 87
Haushalter, 351
Hawke, 176
Hay, 392
Haycraft, 96
Hayem, 56, 136, 171, 172, 174, 176, 177,
181, 183, 199, 209, 278, 287, 300, 342,
343, 409, 430, 432, 476, 490, 512, 513,
523
Head, 247, 354
Heanley, 425
Heaton, 335
Hedin, 91
Heidenreich, 517
Heim, 199, 510
Hektoen, 522
Henderson. 175, 233
Henri, 167
Henry, 414, 419, 474
Herrick, 521
Herscher, 436
Hess, 321
Hewes, 85
Hewetson, 445
Hewlett, 394
Heyl, 142
Hibbard, 233
Higley, 408
Hills, 279
Hirsch, 122, 128
Hirschfeld, 351
Hirschlaff, 527
Hirt, 251
Hitschmann, 290
Hoagland, 178
Hofbauer, 227
Hoffman, 477
Hofmeister, 232
Holloway, 245
Holman, 249, 512
Holmes, 87, 548
Holt, 348
Hoppe-Seyler, 143, 169, 383
Horder, 54
Houston, 489
Howard, 447, 537
Howell, 199
Hubbard, 235, 421
Hubner, 439, 505
Huger, 534
Hunt, 347
Hutchinson, 347, 350, 428, 518
IMMERMAN, 300, 427
Ishigami, 556
Israel, 188
Ivanoff, 517, 544
JACOB, 238, 240, 250
Jacques, 385, 521
James, 482, 490, 506, 527
INDEX OF AUTHORS.
565
Japha, 231, 350
Jeffries, 129
Jehle, 437, 5 22
Jellinek, 162
Jenner, 82
Jennings, 376
Jochmann, 522
Joffroy, 276
Johnson, 496
Johnston, 395, 398
Jolles, 122
Jolly, 35°. 35 1
Jones, Lloyd, 132, 139, 267, 268, 275
Jopson, 321
Joseph, 532
Joslin, 424
Joy, 369
Justus, 533
KALTEYER, 248
Kalyapin, 517
Kaminer, 226, 227
Kanthack, 205, 209, 215, 252
Karnizki, 344
Kast, 406
Kazarinoff, 395, 544
Kelly, 304, 321
Kelsch, 305, 468, 469
Kemp, 179
Kerr, 394, 536
King, 245, 446
Kinsey, 506
Kippel, 495
Kirikow, 432
Kisch, 498
Kitasato, 376
Klebs, 199, 532
Klein, 436
Kline, 539
Klotzsch, 532
Knapp, 393
Knopfelmacher, 176, 234
Knox, 390
Kobert, 512
Koblanck, 261
Koch, 543
Kochler, 404
Koehler, 434
Koenigstein, 404
Koeppe, 103, 178, 179
Kohn, 506
Kolisch, 228
Kolle, 113
Kolliker, 188
Koplik, 487, 550
Kordnyi, 103
Kormoczi, 290
Korowicki, 520
Kotchetkoff, 523
Kraepelin, 488
Kraus, 96, 131, 482, 506
Krause, 395, 413
Krauss, 527
Kretz, 485
Krokiewicz, 472
Kronig, 512
Kruse, 391
Krusman, 251
Kucharzewski, 389
Kuhlman, 497
Kuhn, 370
Kiihnau, 394, 437, 482, 527
Kiimmel, 103
Kurloff, 336
Kurpjuweit, 259, 480
LAACHE, 300, 490
Labbe, 206, 224, 242, 253, 353, 554
Lacassagne, 512
Laker, 122
Lamb, 134, 428, 513
Lambert, 121, 437
Landi, 506
LandoiSj 96
Lang, 435, 475
Lapique, 172
Laporte, .73, 87
Laptschinski, 516
Larrabee, 234
Latham, 349
Launois, 433
Laveran, 443, 445, 539
Layton, 118
Lazarus, 76, 419
Lazear, 88, 482, 558 •
Lear, 121
Le Breton, 488
Le Conte, 165
Ledingham, 442
Lefas, 495 .
Lehmann, 129
Leichtenstern, 441, 498
Leishman, 82, 442, 538
Le noble, 278, 296, 430
Lupine, 129, 143, 254
Leredde, 511
Lesieur, 394
Lessage, 391
Letzerich, 428
Leube, 290
Levene, 438
Levy, 94, 426
Lewaschew, 550
Lewis, 225
Libman, 395, 403
Lichtwitz, 375
Lichty, 133, 291, 422
Liebreich, 96
566
INDEX OF AUTHORS.
Lilienfeld, 199
Lindenthal, 192, 512
Litten, 196, 281, 290
Locke, 227, 370, 378
Loeper, 478
Loffler, 85
Longcope, 332, 395
Longridge, 369, 433
Lostorfer, 532
Lothrop, 414
Louste, 478
Lovibond, 49
Low, 414, 442, 541
Lowenbach, 533
Lowenthal, 516
Lowit, 199, 240, 250, 305, 481
Lowy, 129, 238, 296, 412, 512
Lubowski, 403
Luce, 290
Luciani, 261
Lussana, 439
Lustgarten, 532
Luxemberg, 493
Lyon, 247
MACCALLUM, 447, 454
MacPhail, 494, 497
Mackenzie, 151
Mackie, 522, 524
Magrath, 556
Mallory, 522
Mannaberg, 445, 457
Manson, 413, 415, 419, 442, 445, 484,
538
Maragliano, 122, 185, 412, 473
Marchand, 442
Marchetti, 544
Marchiafava, 445, 457, 467
Marestang, 180
Marie, 178
Martin, 512
Martineau, 532
Marx, 122
Mastin, 414
Mathias, 434
Mayer, 167
McCaw, 350
McCrae, 311, 350, 372, 474, 519
Meinert, 482
Meissl, 341
Meissner, 179
Melkich, 517
Memmi, 250, 433
Mendelson, 238
Merklen, 555
Mertins, 534
Metschnikoff, 113, 206, 239, 445
Meunier, 432, 502
Meyer, 121, 179, 251
Miescher, 48
Mikulicz, 164, 242
Milian, 250, 433
Miller, 321
Minkowski, 383
Mitchell, J. K., 176, 234, 497
Mitchell, S.W., 128, 513
Mixa, 321
Mongour, 543
Monisset, 481
Montagard, 557
Monti, 352
Morse, 345, 346, 348, 349, 354, 386, 503
Mosler, 329
Muir, 224, 241, 429
Miiller, 200, 304, 316, 349, 511
Murray, 488
Musser, 332, 484
Mya, 129
NATTAN-LARRIER, 542
Neave, 442
Nebarro, 538
Neisser, 383
Nepveu, 538
Netter, 380, 432
Neufeld, 395
Neuman, 537
Neumann, 188, 527
Neusser, 228, 257, 498
Nicholas, 335
Nicholls, 147, 200
Nicloux, 512
Nikiforoff, 80
Nobecourt, 555
Noble, 165
Nouguchi, 513
Novy, 154, 376
Nuttall, 117, 120, 121
OBERMEIER, 514
Oertel, 498, 553
Ogata, 376, 391
Ogston, 103
Okladnych, 373
Oliver, 49, 71, 141, 165, 173, 177, 178,
i79> 234
Opie, 241, 537
Oppenheim, 533
Oppenheimer, 534
Orlowski, 129, 130, 383, 394
Osier, 275, 291, 293, 332, 382, 391, 445,
462, 474, 550
Ossendowski, 533
Ostrovosky, 438
Otto, 301
INDEX OF AUTHORS.
567
PACCHIONI, 502
Page, 521
Paine, 518
Pallowski, 305
Pappenheim, 188, 195, 304
Paris, 512
Park, 391
Parker, 559
Patek, 537
Patella, 520 •
Paton, 232
Pautrier, 511
Pearce, 497
Pee, 523, 536
Peiper, 129, 521
Penzoldt, 304, 329
Perry, 254
Pesel, 547
Peskind, 170
Peter, 535
Peterson, 116
Petruschky, 526
Pfahler, 410
Pfeiffer, 112, 137, 437, 555
Pick, 557
Pieraccini, 506
Pilsbury, 391
Piorkowski, 532
Plantenga, 486
Plehn, 87
Plimmer, 473
Poggi, 164, 187
Ponl, 250
Poll, 232
Pollaco, 395
Pollman, 348
Ponfick, 185
Posselt, 329
Pothier, 559
Potter, 148, 550
Powell, 376, 420
Poynton, 518
Pratt, 414
Pray, 234
Price, 441
Prince, 85
Prochaska, 506
Prudden, 154
Pugh, 495, 497
Pusey, 331
Putnam, 488
QuiNCKE, 279
Quiserne, 382
RABINOWITCH, 543
Ranvier, 114, 438
Rautenberg, 336
Reckzeh, 486
Reed, D., 304, 332
Reed, W., 556, 558
Rees, 376
Reichert, 161
Reinert, 410, 493
Renaud, 486
Rencki, 477
Reudiger, 394, 401
Revenstorf, 104
Rey, 410
Reyne, 176
Reyner, 439
Ribierre, 435
Richard, 445
Richardson, 369, 395
Richon, 351
Richter, 238, 412
Rieder, 231, 232, 234, 247, 258, 316,
387, 437, 487, 536
Rigler, 412
Rindfleisch, 188
Risel, 379
Ritchie, 498
Riviere, 345
Rodier, 141, 436
Roger, ii3, 254, 391, 557
Rogers, 373, 378, 391, 440, 442, 443, 471
Rohnstein, 194
Rolleston, 291, 347, 349
Rollet, 170
Romanowsky, 82
Romberg, 544
Roncagliolo, 429
Rosenberger, 402, 526
Rosenblath, 379
Rosenow, 505
Rosenquist, 191
Rosin, 162
Ross, 77, 443, 445
Rost, 492
Rotch, 343, 549
Row, 377
Roy, 94
Ruffner, 473
Rumpel, 103
Rumpf, 544
Rumpff, 129
Russell, 91, 381, 441, 473
SABRAZES, 375
Sailer, 332, 484
Sambon, 538
Sanarelli, 148, 558
Sandwith, 440
Sanfelice, 473
Sanger, 120
Sarnow, 515
Saunby, 381
568
INDEX OF AUTHORS.
Schafer, 134, 170
Schaffer, 175 '
Schaumann, 439
Schiff, 231, 342
Schlayer, 391
Schleip, 537
Schlesinger, 387
Schmaltz, 132
Schmidt, 372, 410
Schneyer, 388
Scholz, 395
Schott, 553
Schottmiiller, 393
Schreiber, 251
Schroder, 179
Schroetter, 178
Schiiffner, 196
Schultz, 234, 241
Schultz-Schultzenstein, 129
Schultze, 205, 438
Schumberg, 176
Schutze, 117
Schwalbe, 513
Schwinge, 174
Scott, 350
Seemann, 395
Seligmann, 73, 433
Sello, 506
Senator, 329
Senn, 312, 331
Sertoli, 506
Sfameni, 175, 234
Shaw, 251
Sherrington,-56, 214, 239, 258, 374
Shiga,.39i, 540
Shober, 165
Sicard, 420, 428
Silvestrini, 506
Simmons, 332
Simon, 145, 228, 316
Singer, 518
Sippy, 293
Sittmann, 380, 482, 506, 526
Slaughter, 414
Slawyk, 437
•™J"» to/
Smith, J. C., 559
"— ith, T. L., 122, 125, 139, 267, 276
Vth, 4Q4. 4Qi?
Smith,
Smyth, 494, .
Sobotka, 552
Solimei, 249
Solley, 81, 513
Sollmann, 104
Somers, 495
Sommerfield, 521
Sorby, 107
Sorensen, 174, 490
Sorochowitsch, 228
Spencer, 492
Spezia, 227
Stadler, 370
Staehelin, 335
Stassano, 251
Steel, 495
Steele, 422
Stefanelli, 544
Steinberg, 403
Steinwald, 331
Stengel, 66, 128, 181, 200, 237, 271, 354,
429, 5°2>5IO> 553. 555
Stephens, 469, 470
Sternberg, 332, 445, 559, 560
Stevens, 545
Stewart, 84, 513
Stintzing^ 122, 276
: Stockman, 162
Stockton, 382
Stokes, 200
Stone, 312
. Straus, 372
Strauss, 129
Streker, 444
Strong, 55, 391
Stump, 537
Sugg, 555
Swan, 442, 547
Symes, 526
TALLEY, 429
Tallquist, 54, 513
Tassinari, 129
Taylor, A. E., 258, 307, 308, 321
Taylor, F., 291
Tchlenorff, 131
Teichmann, 115, 162
Thayer, 176, 213, 234, 269, 349, 404,
445. 455. 466, 482
Theodor, 351
Thoma, 57
Thomas, 131
Thompson, 554, 556
Tieken, 103, 335
Tinker, 103
Tirelli, 498
Todd,538
Toisson, 56
Tolot, 481
Tombleson, 559
Torday, 544
Tribondeau, 433
Triboulet, 148, 518
Trinkler, 143, 472
Tschirkoff, 365
Tschistovitch, 117, 486, 498
Tucker, 534
Tuffier, 433, 481
Tumas, 551
Turk, 222, 306, 382, 410, 487, 520
Tuttle, 482, 490, 506, 527
Tyson, 333
IMM.X 01 ATTHOKS.
569
UHLEXHUTH, 117, 120, 121
Unger, 394
Uskow, 224
VAILLANT, 513
Vaillard, 305
Val£e, 117
Van Deen, 116 '
Van den Berg, 521, 523
Van Emden, 287, 298
Van Gieson, 438
Van Niessen, 532
Vaquez, 435
Vasquez, 334, 335, 382, 420
Vast, 513
Vaughan, 154
Vermehren, 149
Viault, 178
Vicarelli, 181
Vincent, 437
Von Bockmann, 516
Von Fleischl; 43
Von Gebhardt, 544
Vonjaksch, 129, 131, 143,145,167,251,
259> 277, 354, 4i3' 425, 49°, 49$, 5°9,
5"
Von Lerber, 248 ?
Von Limbeck, 106, 129, 177, 181, 209,
232, 242, 250, 268, 277, 287, 297, 316,
410, 413, 431, 435, 490, 498, 515
VonNoorden, 189, 194, 256, 374
Von Seiller, 164
Vorbach, 426
Vorner, 535
Vulpius, 334
WAELE, 555
Wagner, 233
Waldstein, 78, 290
Waldvogel, 278
Walker, 148, 518
Walz, 304
Wanstall, 502
Warfield, 230, 390, 394
Warren, 334
Warthin, 172
Wasielewski, 556
Wassermann, 117, 154, 370, 518
Watson, 426
Weber, 485, 556
Weber, C. H., 312
Weber, F. B., 290, 493
Wegefarth, 200
Weigert, 112
Weil, 322, 350, 555, 557
Weil, E., 258, 433
Weinberger, 379
Weiss, 208, 226
Welch, 109, 153, 154,526
Wellman, 493
Wende, 329
Wentworth, 231
Wey, 304
Wherry, 496
White, C. Y., 244, 354, 502, 510, 555
White, F. K., 233, 490, 506, 527
White, W. H., 142
Whitney, 231
Whittier, 121 .
Widal, 113, 398, 555
Widowitz, 522
Wilkinson, 251, 254
Willebrand, 176, 234
Williams, 487
Williamson, 96, 263, 347, 383
Wilson, J. C., 509
Wilson, L. B., 531
Winiarski, 444
Winter, 405
Wintejnitz, 176, 234, 250, 261
Wolff, 178, 226
Wolff, A. J., 402
Wood, 438
Wright, A. E., 96, 101, 239, 393, 428,
484, 544
Wright, J. H., 82, 442
Wuntz, 420
Wyss, 512
YARROW, 512
Yersin, 376
Young, 366
ZADOC, 518
Zahorsky, 390
Zammit, 484
Zandy, 251
Zangmeister, 233, 341
Zappert, 60, 256, 498, 523
Zeri, 199, 471
Ziemke, 121
Zinno, 378
Zlatogoroff, 485
Zollikofer, 226
Zuntz, 129, 176, 178
Zypkin, 292
INDEX OF SUBJECTS.
ABSCESS, 361
appendicular, 368
cerebral, 488, 493
coagulation, 361
color index, 361
diagnosis, 363
erythrocytes, 361
fibrin, 361
gall-bladder, 363, 370, 380
hemoglobin, 361
hepatic, 363, 391
iodophilia, 361
leucocytes, 362
normoblasts, 362
ovarian, 370
pancreatic, 499
pelvic, 363
perinephritic, 370
pleural, 504
pulmonary, 363
renal, 363
superficial, 363
tonsillar, 536
tuberculous, 546, 548
Absence of leucocytosis, 262
in acute infections, 262
in chlorosis, 272
in enteric fever, 406
in helminthiasis, 440
in influenza, 436
in kala-azar, 443
in leprosy, 444
in malarial fever, 469
in Malta fever, 484
in measles, 485
in paratyphoid fever, 262
in pernicious anemia, 285
in rotheln, 486
in serous pleurisy, 503
in splenic anemia, 292
in trypanosomiasis, 541
in tuberculosis, 547
in typhus fever, 55 1
in yellow fever, 560
significance of, 240
Acetanilid poisoning, 511
Acetone, test for, 145
Acetonemia, 145
Achroiocythemia, 163
Achromacytes, 185
Acid dyes, 76
Acidity of blood in Asiatic cholera, 372
in insolation, 438
Acromegaly, 364
Actinomycosis, 364
Acute yellow atrophy of the liver, 365
Addison's disease, 365
Adenitis, 254, 331
Afanassiew's bacillus, 515
Agglutinins, 156
Agglutinoids, 157
Ague cake, 338
Akatama, 493
Albuminuria, 135
Alcohol and ether fixation, 80
fixation, 80
poisoning, 511
Alcoholic neuritis, 492
Alcoholism, 511
Alexins, 238
in relapsing fever, 517'
Alkalimeter, Engel's, 96
Alkalinity, 96, 128
estimation of, 96
in Asiatic cholera, 372 .
in chlorosis, 268
in diabetes mellitus, 383
in epilepsy, 497
in erysipelas, 410
in fevej, 412
in gastric carcinoma, 472
in gout, 426
in hemorrhagic diseases, 428
in Hodgkin's disease, 327
in icterus, 344
in infantile enteric fever, 354
in insolation, 438
in lymphatic leukemia, 317
in mental diseases, 496
in myelogenous leukemia, 307
in nephritis, 490
in osteomalacia, 499
in pernicious anemia, 278
in rheumatic fever, 518
in scurvy, 428
in secondary anemia, 296
in uremia, 490
Altitude, effect on blood, 1 78
572
INDEX OF SUBJECTS.
Altmann's bioblastic theory, 208
Amboceptoiy 154
Amebic dysentery, 391
Amebula, 449
Ammonia poisoning, 512
Amphophile granules, 207
Amyl nitrite poisoning, 511
Amyloid disease, 482
Analysis, centrifugal, 91
Anemia, 148
angiospastic pseudo-, 149
bothriocephalus, 439
brick-makers', 440
classification of, 150
edema of, 489
following splenectomy, 233
from ankylostomiasis, 438
from Ascaris lumbricoides, 438
from gastric tubule atrophy, 422
from helminthiasis, 438
from threadworms, 438
from thyroidization, 489
in Addison's disease, 365
in appendicitis, 366
in carcinoma, 473
in children, 345
in gastric carcinoma, 474
in hemorrhagic diseases, 479
in hepatic cirrhosis, 430
in icterus, 435
in kala-azar, 443
in malignant disease, 273, 478
endocarditis, 482
in nephritis, 490
in rheumatic fever, 5 19
in sarcoma, 478
in sepsis, 527
in syphilis, 532
in trypanosomiasis, 541
in tuberculosis,* 544
in typhus fever, 551
in variola, 556
in yellow fever, 559
infantum pseudo-leukemica, 354
miners', 440
pathogenesis, 151
pernicious, 276
post-hemorrhagic, 299
post-malarial, 466
post-typhoid, 404
primary, 150
pseudo-, 149
secondary, 296
splenic, 291 I
syphilitic, 533
toxic, 511
tropical, 149
Von Jaksch's, 354
Anemias of infancy and childhood, 341
bacteriemia, 356
classification, 346
Anemias of infancy and childhood,
erythroblasts, 345
frequency, 345
gastro-intestinal, 353
general characteristics,
345
leukemia, 348
megaloblasts, 345
mild, 351
pernicious, 347
post-typhoid, 354
primary, 347
rachitic, 353
.secondary, 351
severe, 531
splenic, 347
splenic enlargement, 346
syphilitic, 352
tuberculous, 353
with leucocytosis, 352
Aneurism, 363
Anhydremia, 140
Anilin dyes, 76
Anisocytosis, 182
Ankylostomiasis anemia, 438
Anopheles, 415, 447
Anthrax, 366
Antipyrin poisoning, 512
Antiamboceptors, 155
Antibodies, 153
Anticomplements, 155
Antihemolysis, 155
Antipyretics, effect on erythrocytes, 166
leucocytes, 510
Antisera, 117
Antitoxin, 153
Aortic lesions, 447
Apoplectiform attacks, 495
Appendicitis, 366
anemia, 366
diagnosis, 370
iodophilia, 370
leucocytosis, 368
Arloing and Courmont's reaction, 542
Arsenic, effect on blood, 163
effect on trypanosomata, 539
Arseniuretted hydrogen poisoning, 512
Arthritis deformans, 371
gonorrheal, 521
septic, 525
Ascaris lumbricoides, 438
Ascites, 431
chylous, 421
effect on blood, 43 1
Asiatic cholera, 372
Aspidium poisoning, 512
Asthma, 374
Atmospheric cold, effect on blood, 234
Atrophic hepatic cirrhosis, 430
Atypical erythroblasts, 192
Autolysis, 154
INDEX OF SUBJECTS.
573
BACTERICIDAL action of blood, 130, 238
Bacteriemia, 146
in acute mania, 496
in anthrax, 366
in beri-beri, 492
in bubonic plague, 376
in cerebro-spinal fever, 488
in cholelithiasis, 380
in enteric fever, 393
in epilepsy, 497
in glanders, 425
in hepatic cirrhosis, 432
in infants, 356
in influenza, 436
in gonorrheal infection, 426
in leprosy, 444
in leukemia, 305
in malignant disease, 473
in malignant endocarditis, 482
in Malta fever, 484
in measles, 485
in meningitis, 488
in nephritis, 490
in paratyphoid fever, 395
in pneumonia, 505
in purpura, 428
in relapsing fever, 514
in rheumatic fever, 518
in scarlet fever, 521
in scurvy, 427
in sepsis, 526
in syphilis, 532
in tuberculosis, 542
in typhus fever, 550
in variola, 555
in yellow fever, 559
Bacteriological examination, 109
Band's disease, 294
Barlow's disease, 427
Basedow's disease, 411
Basic dyes, 76
Basophile granules, 207
Basophiles, 217. See Mast Cells.
Basophilia, 258
granular, 194
perinuclear, 228
Baths, effect on blood, 176
Benario's method, 81
Beri-beri, 492
Biermer's disease, 276
Bile in the blood, 145
test for, 145
Bilharziasis, 441
Biliary colic, 381
Bioblastic theory-, Altmann's, 208
Blackwater fever, 470
Blastomycetes in carcinoma, 473
in tuberculosis, 542
Bleeders, 35
Blood, arterial and venous, 126
Blood at birth, 342
bactericidal action, 130, 238
biological test, 117
carbonic acid, 126
color, 126
concentration, 197
crisis, 189 '
cryoscopy, 102
crystals, 161
cultures, 109, 147
dust, 200
extractives, 126
fats, 126
fetal, 341
filaria, 413
films, methods of preparing, 76
freezing point, 103
gases, 126
general composition, 125
laked, 127
lancet, 34
lytic action, 154
• medico-legal tests, 1 14
odor, 127
oxygen, 126
parasites, 39
Blood plaques, 198
counting the, 90
Ducchesi's method of demon-
• strating, 199
in bubonic plague, 378
in burns, 378
in chlorosis, 274
in diabetes mellitus, 386
in enteric fever, 409
in erysipelas, 410
in hemorrhagic diseases, 430
in Hodgkin's disease, 330
in kala-azar, 443
in lymphatic leukemia, 321
in malarial fever, 471
in measles, 485
in myelogenous leukemia, 317
in pernicious anemia, 287
in pneumonia, 510
in post-hemorrhagic anemia,
301
in scarlet fever, 524 .
in secondary anemia, 298
in splenic anemia, 293
in syphilis, 535
in variola, 557
nature, 199
normal number, 200
pathological variations, 200
plasma, 125
plasmotropic action, 439
proteids, 125
quantity, 125
quotient, 165
574
INDEX OF SUBJECTS.
Blood, reaction, 128
regeneration, 301
after splenectomy, 333
after surgical operations, 473
after the Schott treatment, 533
after treatment with iron and
arsenic, 163
after treatment with mercury,
533
after treatment with supra-
renal extract, 366
in anemias of children, 346
in bothriocephalus anemia, 290
in carcinoma, 473
in diphtheria, 386
in enteric fever, 404
in malarial fever, 468
in pernicious anemia, 280
in post-hemorrhagic anemia,
301
in scarlet fever, 523
in syphilis, 533
in tuberculosis, 546
in variola, 556
salts, 126
serum, 125
specific test for, 117
spectra, 168
viscosity, 127
viscosity value, 128
Bodies, Leishman-Donovan, 442
Bone marrow, 171
in leucocytosis, 241
in malignant disease, 480
Bordet's reaction, 117
Bothriocephalus anemia, 439
Brain, abscess, 363
hemorrhage, 493
tumor, 493
Bra's neurococcus, 497
Breast, carcinoma of, 476
Bremer's test, 384
Bright's disease, 489
Bromin poisoning, 512
Bronchitis, 375
Bubonic plague, 376
Budding of protoplasm of lymphocytes,
320
Bullet wounds, effect on blood, 252
Burns, 378
CACHEXIA, malarial, 468
Calcium salts, effect on blood, 134
Capillary bronchitis, 508
Carbon monoxid hemoglobin, 168
poisoning, 512
spectrum, 168
test for, 169
Carbuncle, 244
Carcinoma, 472
alkalinity, 472
coagulation, 472
color index, 473
deformed erythrocytes, 475
diagnosis, 480
digestion leucocytosis, 477
erythroblasts, 475
erythrocytes, 473
esophageal, 477
fibrin, 472
gastric, 474, 477
hemoglobin, 473
hepatic, 476
intestinal, 476
leucocytes, 475
lingual, 477
mammary, 476
metastases, 475, 480
pancreatic, 476
polycythemia, 474
protozoa, 473
pulmonary, 505
rectal, 476
regeneration, 473
renal, 476
specific gravity, 472
sugar, 472
uterine, 476
Castration, effect on blood, 258
Catarrhal pneumonia, 508
Cecum, malignant disease, 370
. Cellular elements of blood, 125
plethora, 139
Centrifugal analysis, 91
Cerebro-spinal meningitis, 487
Charcot-Leyden crystals in leukemia,
3°7
Chemical fixation, 80
Chemo taxis, 237
Chicken-pox, 554
Chloral poisoning, 512
Chloro-anemia, 270
Chloroform narcosis, 249
Chloroma, 379
Chlorosis, 267
alkalinity, 268
appearance of fresh blood, 267
blood plaques, 274
blood volume, 267
coagulation, 268
color index, 269
diagnosis, 274
dry residue, 267
Egyptian, 440
eosinophiles, 273
erythroblasts, 271
erythrocytes, 269
florida, 275
granular basophilia, 271
INDEX OF SUBJECTS.
575
Chlorosis, hemoglobin, 269
heredity, 275
leucocytes, 272
male, 275
microcytosis, 270
myelocytes, 274
oxygen capacity, 267
pallor of e'rythrocytes, 271
poikilocytosis, 271
polychromatophilia, 271
polynuclear neutrophiles, 272
pseudo-, 149
relative lymphocytosis, 272
sex, 275
specific gravity, 268
symptoms, 275
syphilitic, 532
transitional forms, 272
without blood changes, 274
Cholangitis, 381
Cholecystitis, 381
Cholelithiasis, 380
Cholemia, 145
Cholera, Asiatic, 372
Chorea, 498
Chromic acid fixation, 81
poisoning, 512
Chyluria, parasitic, 421
Cirrhosis of the liver, 430
Clap, 426
Class' diplococcus, 521
Coagulation, 134. See Fibrin.
in abscess, 361
in acromegaly, 364
in albuminuria, 135
in bubonic plague, 376
in carcinoma, 472
in chlorosis, 268
in cholelithiasis, 380
in cobra poisoning, 134
in cyanosis, 382
in daboia poisoning, 134
in eclampsia, 135
in enteric fever, 393
in fever, 412
in hemophilia, 428
in hemorrhagic diseases, 428
in Hodgkin's disease, 327
in icterus, 434
in infantile enteric fever, 354
in lymphatic leukemia, 317
in myelogenous leukemia, 307
in nephritis, 490
in obstructive jaundice, 434
in pernicious anemia, 278
in pneumonia, 505
in pregnancy, 135
in rheumatic fever, 518
in sarcoma, 478
in scarlet fever, 521
Coagulation in scurvy, 428
in secondary anemia, 296
in snake poisoning, 513
in splenic anemia, 291
in yellow fever, 558
relation to intestinal hemorrhage,
393
time, estimation of, 100
Coagulometer, Wright's, 101
Cobra poisoning, 134 *
Colic, biliary, 381
Color index, 165
of the blood, 126
in anilin poisoning, 127
in carbon monoxid poisoning,
1 68
in chlorosis, 267
in cyanosis, 382
in diabetes mellitus, 383
in dyspnea, 127
in Hodgkin's disease, 327
in hydrocyanic acid poisoning,
127
in icterus, 434
in lymphatic leukemia, 317
in myelogenous leukemia, 306
.in nitrobenzene poisoning, 127
in pernicious anemia, 277
in potassium chlorate poison-
' . ing, 127
in secondary anemia, 296
in splenic anemia, 291
in sulphuretted hydrogen poi-
soning, 127
normal variations, 126.
pathological variations, 127
Coma, diabetic, 383
Complement, 154 .
Complementophiles, 155
Concentration of the blood, 197
Constitutio lymphatica, 254
Contusions, effect on blood, 252
Convulsions, 495
Corpuscles, Eichhorst's, 183
phantom, 184
Poggi's, 185
Ponfick's, 184
Corrosive metallic salts, poisoning by,
5"
Counting chamber, Thoma-Zeiss, 58
Zappert, 59
differential, 89
dry film method, 73
the blood plaques, 90
the erythrocytes, 60, 69, 71, 72, 74
the leucocytes, 64, 69, 71, 74
Cover-glasses, cleaning the, 36
Coxalgia, 346, 348
Crenation, 169, 465
Crisis, blood, 189
576
INDEX OF SUBJECTS.
Cryoscope, Fontaine's, 104
Cryoscopy,. 102
Crystals, Charcot-Leyden, 307
hematoidin, 162
oxy hemoglobin, 161
Teichmann's, 162
Culex fatigans, 382, 415, 447
Cultures, blood, 109, 147
Cyanosis, effect on blood, 381, 553
Cyanotic polycythemia, 381
Cyst, ovarian, 303
pancreatic, 499
Cystitis, 189
Cytophiles, 155
Cytoryctes variolae, 556
DABOIA poisoning, 134
Daland's hematokrit, 91
Dare's hemo-alkalimeter, 98
hemoglobinometer, 40
Degeneration, endoglobular, 184
Delafield's hematoxylin, 87
Delhi sore, 442
Delirium, 495
Dementia, 495
Dengue, 382
Denige's solution, 145
Density and opacity of blood, 126
Dermacentor reticulatus, 531
Dermatitis herpetifonnis, 256
Diabetes mellitus, 383
alkalinity, 383
blood plaques, 386
Bremer's test, 384
diagnosis, 386
erythrocytes, 385
glycemia, 383
hemoglobin, 385
iodophilia, 226
leucocytes, 386
lipacidemia, 383
lipemia, 383
specific gravity, 385
Williamson's test, 383
Diapedesis, 207
Diaphragm, ocular, 65
Diarrhea, 390
Differential counting, 89
table of anemias, 303
of gastric cancer and ulcer, 481
of leucocytosis, lymphocytosis,
and leukemia, 337
of malignant disease and per-
nicious anemia, 480
of normoblasts and megalo-
blasts, 191
of the leucocytes, 223
of the malarial parasites, 463
Digestion leucocytosis, 231
in diabetes mellitus, 386
in gastric carcinoma, 477
in gastric ulcer, 424
in gastritis, 423
in infants, 344
Digestive lymph wave, 177
Dilatation of stomach, 422
Diluting fluids, 56
Diphtheria, 386
diagnosis, 390
effects of antitoxin, 386, 388
eosinpphilia, 389
erythrocytes, 386
hemoglobin, 386
leucocytes, 387
Disease, Addison's, 365
Banti's, 294
Barlow's, 427
Basedow's, 411
Biermer's, 276
Bright's, 489
Duhring's, 256
Graves', 411
Griesinger's, 440
Hodgkin's, 327
hydatid, 433
Laennec's, 431
malignant, 472
Neisser's, 426
Osier's, 381
Pott's, 546, 548
Still's, 326
Von jaksch's, 354
Werlhoff's, 429
Diseases, hemorrhagic, 427
Drowning, freezing point of blood, 104
Drug eosinophilia, 257
leucocytosis, 249
leucopenia, 262
lymphocytosis, 254
Duodenal ulcer, 425
Durham's hemocytometer, 68
Dwarf myelocytes, 222
Dyes, anilin, 76
Dysentery, 391
ECHINOCOCCUS, 433
Ectopic pregnancy, 370, 502
Eczema, 256
Edema of anemia, 489
Effusion, pericardial, 500
peritoneal, 500
pleural, 503
Egyptian chlorosis, 440
Ehrlich's hypothesis, 208
side -chain theory, 151
triacid stain, 83
Ehrlich-Weigert fluid, 112
INDEX OF SUBJECTS.
577
Eichhorst's corpuscles, 183
Electricity, effect on blood, 234
Elephantiasis Arabum, 421
Emphysema, 374
Empyema of gall-bladder, 380
of thorax, 504
Endocarditis, malignant, 482
Endoglobular degeneration, 184
Engel's alkalimeter, 96
Enteralgia, 371
Enteric fever, 393
bacteriology, 393
coagulation, 393
diagnosis, 409
erythrocytes, 404
Ficker-Reudiger test, 401
hemoglobin, 404
leucocytes, 406
serum test, 396
spot cultures, 395
Wolff's test, 402
Enteritis, 390
Eosin and hematoxylin stain, 87
and methylene-blue stain, 86
Eosinophile granules, 208
Eosinophiles, 216
diminution of, after castration, 258
after hemorrhage, 258
during digestion, 257
in acute febrile diseases, 258
in bubonic plague, 378
in carcinoma, 478
in chlorosis, 273
in diphtheria, 389
in enteric fever, 409
in erysipelas, 411
in gastric ulcer, 425
in Hodgkin's disease, 330
in hydatid disease, 433
in influenza, 257
in lymphatic leukemia, 320
in malarial fever, 471
in measles, 486
in meningitis, 488
in pernicious anemia, 286
in pertussis, 502
in phthisis, 547
in pneumonia, 510
in sarcoma, 480
in sepsis, 529
in varicella, 555
physiological, 257
terminal, 257
Eosinophilia, 255
after coitus, 256
after splenectomy, 336
definition, 255
during menstruation, 256
experimental, 257
factors, 255
Eosinophilia, in ankylostomiasis, 440
in asthma, 375
in bilharziasis, 441
in chloroma, 379
in chorea, 498
in diseases of the bones, 256
of the sexual organs, 257
of the sympathetic nervous
system, 257
in filariasis, 420
in gonorrhea, 426
in guinea-worm infection, 420
in helminthiasis, 440
in hemorrhagic effusions, 503
in herpes zoster, 434
in hydatid disease, 433
in hysteria, 494
in infancy, 344
in kala-azar, 443
in myelogenous leukemia, 315
in osteosarcoma, 480
in oxyuris vermicularis infection,
44"o
in paresis, 495
in rheumatic fever, 520
in scarlet fever, 524
in septice'mia, 529
in skin diseases, 256
in splenic tumors, 257
in starvation, 257
in syphilis, 535
in Taenia mediocanellata infection,
440
in trichiniasis, 536
in variola, 557
in xanthin diatheses, 257
physiological, 257 .
post-febrile, 257
Eosinophilic myelocytes, 219-
Epilepsy, 497
Erysipelas, 410
Erythroblasts, 187
atypical forms, 192
differential count of, 89
Erythrocytes, 169
after fasting, 176
ameboid motility, 180
appearance in fresh blood, 169
atypical staining, 186
averages in anemia, 197
color, 169
counting the, 60, 68, 70, 72, 73
crenation, 169
deformities of size and shape, 182
destruction, 171
development, 171
dry film method of counting, 73
endoglobular degeneration, 184
granular basophilia, 194
histological structure, 170
37
578
INDEX OF SUBJECTS.
Erythrocytes, hyperviscosity, 181
influenpe of age and sex, 174
of climate, 180
of constitution and nutrition,
176
of digestion, 177
of fatigue, 176
of high altitudes, 1 78
of muscular exercise, 176
of physical factors, 174
of pregnancy, menstruation,
and lactation, 175
isotonicity, 180
methods of counting, 55
monochromatophilia, 186
necrosis, 185
normal number, 209
nucleation, 187
origin and life history, 171
oval-shaped, 115, 184
pathological changes, i8c
physiological changes, 1 74
polychromatophilia, 186
resistance, 106
rouleaux formation, 169
shape, 169
size, 172
stroma, 170
volume, 173
Erythrocytometer, 57
Erythromelalgia, 493
Erythropyknosis, 459
Estimation of alkalinity, 96
of coagulation time, 100
glass slide method, 100
Wright's method, 101
of hemoglobin percentage, 39
of resistance of erythrocytes, 106
of specific gravity, 94
of volume « of corpuscles and
plasma, 91
Ether leucocytosis, 248
narcosis, 512
Examination of the stained specimen, 75
of the unstained specimen, 33
Exercise, effect on blood, 176
Exophthalmic goiter, 411
Experimental eosinophilia, 257
leucocytosis, 249
lymphocytosis, 254
Extractives of blood, 94
FAMILY periodic paralysis, 497
Fat in the blood, 141
tests for, 142
Fatty acids in the blood, 145
test for, 146
Felon, 244
Fetal blood, 341
Fever, dum-dum, 539
effect on blood, 4 1 j
enteric, 393
gastric, 421
malarial, 445
Malta, 484
paratyphoid, 394, 404
puerperal, 529
relapsing, 514
rheumatic, 518
scarlet, 521
spotted (Montana), 531
spotted (typhus), 550
thermic, 437
tick, 531
trypanosoma, 539
typhus, 550
yellow, 558
Fibrin, 134. See Coagulation.
in abscess, 361
in acromegaly, 364
in carcinoma, 472
in chlorosis, 268
in cholelithiasis, 380
in erysipelas, 410
in fever, 412
in gout, 426
in Hodgkin's disease, 327
in influenza, 437
in lymphatic leukemia, 317
in measles, 485
in myelogenous leukemia, 307
in nephritis, 490
in pernicious anemia, 278
in pneumonia, 505
in rheumatic fever, 518
in sarcoma, 478
in scarlet fever, 521
in sepsis, 525
in splenic anemia, 291
in variola, 555
in yellow fever, 558
pathological variations, 136
relation to leucocytosis, 137
Filariasis, 413
diagnosis, 421
erythrocytes, 419
Filaria nucturna, 414
hemoglobin, 419
leucocytes, 420
occurrence, 413
parasitology, 413
Films, preparing the, 76
staining the, 81
Fixation methods, 79
chemical, 80
heat, 79
Floating kidney, 371
Fluids, diluting, 56
Fluorescence of quinin, 446
INDEX OF SUBJECTS.
579
Fontaine's cryoscope, 104
Formalin fixation, 81
Fractures, 421
Freezing point of blood, 102
Fresh blood, microscopical examination
of, 33
Functional neuroses, 493
Furuncle, 244
Fusel oil poisoning, 512
GALL-STONE, 380
Gametes, 446
Gangrene, 244
appendicular, 369
Garrod's thread test, 144
Gases of blood, 126
Gastrectasis, 422
Gastric achylia, 422
carcinoma, 476, 481
dilatation, 422
neurasthenia, 422
tubule atrophy, 422
ulcer, 423
Gastritis, 421
Gastro-enteritis, 390
Gastroptosis, 422
Gelatin, effect on blood, 134
Genito-urinary tuberculosis, 546, 549
German measles, 486
Glanders, 425
Globuli rossi attonati, 468
Globulin, 171
Glossina palpalis, 539
Glycemia, 143
after pancreatectomy, 143
in carcinoma, 472
in diabetes mellitus, 383
Goiter, exophthalmic, 411
Goldhorn's stain, 88
Gonorrhea, 426
Gonorrhea! arthritis, 521
Gout, 426
Gowers' hemocytometer, 69
hemoglobinometer, 52
Granular basophilia, 194
in carcinoma, 475
in lead poisoning, 196
in lymphatic leukemia, 195
in malarial fever, 468
in myelogenous leukemia, 310
in pernicious anemia, 285
in secondary anemia, 297
in sepsis, 528
in tropical anemia, 195
Granules, leucocyte, 207
Neusser's, 228
Schiiffner's, 196
Graves' disease, 411
Grippe, 436
Guaiacol poisoning, 512
Guinea worm, 420
Gumma, 363
Gunther's method, 112
HAIG'S blood decimal card, 55
Haldane's hemoglobinometer, 53
Halitus of blood, 127
Hamburger's method, 106
Hammerschlag's method, 94
Hanging-drop test, 122
Haptins, 153
Haptophores, 152
Hayem's achromacytes, 185
pseudo-bacilli, 183
solution, 56
Heart, chronic valvular disease, s<;2
• j-i •
dilatation, 500
ulcerative endocarditis, 482
Heat exhaustion, 437
fixation, 79
Helminthiasis, intestinal, 438
Helminthoma elastica, 421
Hemamceba leukemiae, 305
malariae, 445
Hematin, 162
Hematoidin, 162
Hematokrit, Daland's, 91
Hematoma, 363
Hematoporphyrin, 162
Hematoxylin, Delafield's, 87
Hematuria, malarial, 470
Hemin, 162
Teichmann's test, 115
Hemo-alkalimeter, Dare's, 98
Hemochromogen, 161
Hemocytolysis, 151, 153, 511'
in ankylostomiasis, 439
in aspidium poisoning, 512
in fever, 412
in fusel oil poisoning, 512
in guaiacol poisoning, 512
in insolation, 438
in malarial fever, 467
in pyrodin poisoning, 513
in toluylendiamin poisoning, 313
in yellow fever, 559
Hemocytometer, Durham's, 68
Gowers', 69
Oliver's, 71
Thoma-Zeiss, 57
Hemogenesis, 171
adult, 1 88
deficient, 151
embryonal, 190
Hemoglobin, 161
absolute amount, 165
after anesthesia, 249
averages in anemia, 164
INDEX OF SUBJECTS.
Hemoglobin, carbon mono.xid, 168
chemistry of, 161
during menstruation, 164, 175
estimation of, 40, 43, 49, 52, 54
influence of arsenic on, 163
of iron on, 163
of mercury and iodids on, 533
origin, 162
reduced, 161
' tests in surgical operations, 164
Hemoglobinemia, 166
from burns, 166
from drugs, 166
from exposure to cold, 166
from heterogeneous blood trans-
fusion, 1 66
in acute vellow atrophv of the liver,
365
in enteric fever, 124
in epidemic hemoglobinuria, 167
in insolation, 438
in malarial fever, 467
in paroxysmal hemoglobinuria, 167
in poisoning, 511
in Raynaud's disease, 167
in scarlet fever, 523
in scurvy, 167
in sepsis, 528
in syphilis, 533
in typhus fever, 551
in variola, 556
in WinckePs disease, 154
in yellow fever, 559
spectrum of, 168
test for, 167
Hemoglobinometer, Dare's, 40
Gowers', 52
Haldane's, 53
Oliver's, 49
Tallquist's, 54
Hemokonia, 200, 466
Hemolymph glands, 225
Hemolysis, 151. See Hemocytolysis.
Hemometer, von Fleischl's, 43
Hemophilia, 427
Hemophilics, danger of hemorrhage in,
35
Hemorrhage, cerebral, 493
effect on blood, 299
gastric, 423
intestinal, 408
pancreatic, 499
post-operative, 245, 336
pulmonary, 545, 547
regeneration after, 301
renal, 470, 490
treatment by transfusion, 301
Hemorrhagic diseases, 427
Hepatic abscess, 363
carcinoma, 476
Hepatic cirrhosis, 430
colic, 381
Herpes zoster, 434
Hewes' stain, 85
Hodgkin's disease, 327
alkalinity, 327
appearance of fresh blood, 327
basophiles, 330
blood plaques, 330
coagulation, 327
color index, 328
deformed erythrocytes, 328
diagnosis, 330
eosinophiles, 330
erythroblasts, 328
erythrocytes, 327
hemoglobin, 327
influence of ;c-rays, 33 1
leucocytes, 328
mast cells, 330
myelocytes, 330
polychromatophilia, 328
poly nuclear neutrophiles, 329
relative lymphocytosis, 328
specific gravity, 327
symptoms, 331
transformation into lymphatic
leukemia, 329
Hydatid disease, 433
Hydremia, 139
in fever, 412
in nephritis, 489
in valvular heart disease, 553
in yellow fever, 559
Hydrocyanic acid poisoning, 512
Hydroperitoneum, 431
Hydrophobia, 513
Hyperchlorhydria, 422
Hyperinosis, 135
Hyperleucocytosis, 239
Hyperplasia, lymphatic, 327
Hypertonicity, 180
Hypertrophic hepatic cirrhosis, 431
Hyperviscosity, 181
Hypinosis, 135
Hypochlorhydria, 422
Hypochondriasis, 493
Hypoleucocytosis, 239
Hypothesis, Ehrlich's, 208
Welch's, 153
Hysteria, 493
ICTERUS, 434
Ileus, 441
Illuminating gas poisoning, 248, 512
Immune body, 154
Immunity, 130
side-chain theory of, 151
Index, color, 165
INDEX OF SUBJECTS.
Index, volume, 94, 173
Infantile scurvy, 429
Infants, summer diarrheas of, 390
Infected wounds, 525
Infection, latent, 147
Influenza, 436
Initial feeding, effect on blood, 232, 344
Insolation, 437
Interstitial nephritis, 491
Intestinal carcinoma, 441
gangrene, 441
helminthiasis, 438
hemorrhage, 408
inflammation, 390
obstruction, 441
perforation, 408
lodin poisoning, 512
lodophilia, 226
experimental, 227
in abscess, 361
in anemia, 227
in appendicitis, 370
in cachexias, 227
in diabetes mellitus, 386
in enteric fever, 227
in gonorrheal arthritis, 426
in pertussis, 502
in pneumonia, 510-
in pregnancy, 175
in puerperal fever, 529
in purpura haemorrhagica, 227
in purulent lesions, 226
in septicemia, 529
in syphilis, 535
in tuberculosis, 547
Iron, effect on blood, 163
in blood, 161
in eosinophiles, 208
Irritants, effect on blood, 249
Irritation forms, 222
Ischemia, 149
Isolysis, 154
Isotonicity, 180
JAUNDICE, 434
Jenner's stain, 82
Jeffrey's sign, 276
Justus' test, 533
KALA-AZAR, 441
Kidney, abscess, 363
carcinoma, 475
cyst, 327
inflammation, 489
stone, 381
Kra-kra, 413
LACTATION, effect on blood, 1 75
Laennec's cirrhosis, 43 1
Laked blood, 126
Large mononuclear leucocytes, 211
Latent infection, 147
Lead basophilia, 196
colic, 371
poisoning, 512
Leishman-Donovan bodies, 442
Leprosy, 444
Leptomeningitis, 487
Leucocytes, 205
ameboid properties, 206
appearance in fresh blood, 205
classification, 209
counting the, 64, 68, 71, 74
degeneration, 211
differential count of, 89
table of, 223
fatty degeneration, 569
fractured, 38
granules, 207
iodin reaction, 226
methods of counting, 55
necrobiosis, 211
normal number in adults, 209
in children, 343
normal percentages in adults, 209
in children, 344
origin and development, 224
perinuclear basophilia, 228
phagocytes, 206
pigmented, 38, 438, 462, 515
size, 205
vacuolated, 38
varieties, 209
Leucocytolysis, 240
Leucocytometer, 58
Leucocytosis, 228
after thymectomy, 252
after splenectomy, 335
average increase, 236
chloroform, 294
definition, 228
differential changes, 237
digestion, 231
drug, 250
ether, 248
experimental, 249
factors, 238
from mechanical and thermal influ-
ences, 234
functions, 238
general, 242
in general infectious diseases, 243
in malignant disease, 245
in simple and infective local inflam-
mations, 244
induced, 242
inflammatory and infectious, 242
582
1NDKX OF SUBJECTS.
Leucocytosis, influence of chemotaxis,
237
leucecytic phase, 240
leucopenic phase, 240
local, 242
marrow changes, 241
of pregnancy and parturition, 233
of the new-born, 229
- pathological, 236
physiological, 230
post-hemorrhagic, 246
post-operative, 244
terminal, 235
toxic, 247
traumatic, 239, 252
Leucopenia, 260
experimental, 261
in chlorosis, 272
in diphtheria, 388
in enteric fever, 406
in epilepsy, 261
in gastritis, 423
in gastro-enteritis of infancy, 262
in hemorrhagic diseases, 429
in hepatic cirrhosis, 432
in Hodgkin's disease, 328
in infectious pharyngitis, 262
in kala-azar, 443
in leukemia, 262
in malarial fever, 469
in malignant endocarditis, 483
in measles, 485
in paratyphoid fever, 410
in peritonitis, 501
in pernicious anemia, 285
in pneumonia, 507
in rotheln, 486
in secondary anemia, 298
in sepsis, 529"
in splenic anemia, 292
in sprue, 392
in trypanosomiasis, 541
in tuberculous abscess, 549
in typhus fever, 551
in yellow fever, 560 ,
pathological 262
physiological, 261
Leucopenic phase, 186
Leukanemia, 290
Leukemia, 302
acute, 321
blood picture, 321
clinical features, 321
duration, 321
in children, 35 1
statistics, 321
transition from chronic forms,
322
with myelogenous lesions, 304
frequency of different forms, 304
Leukemia in children, 348
influence of intercurrent infections,
322
lymphatic, 317
alkalinity, 317
appearance of fresh blood, 317
atypical lymphocytes, 320
atypically stained erythrocytes,
3i8
basophiles, 320
blood plaques, 321
coagulation, 317
color index, 317
deformed erythrocytes, 318
diagnosis, 324
eosinophiles, 320
erythroblasts, 318
erythrocytes, 317
hemoglobin, 317
leucocytes, 318
leukoblasts, 319
lymphocytosis, 319
lymphogonien, 319
mast cells, 320
myelocytes, 320
polynuclear neutrophiles, 320
specific gravity, 317
myelogenous, 306
alkalinity, 307
appearance of fresh blood, 306
atypical myelocytes, 313
polynuclear neutrophiles,
3i4
basophiles, 316
blood plaques, 317
Charcot-Leyden crystals, 307
coagulation, 307
color index, 308
deformed erythrocytes, 310
degenerate forms of leucocytes,
3i4
diagnosis, 323
dwarf myelocytes, 313
neutrophiles, 314
eosinophilia, 315
eosinophilic myelocytes, 316
erythroblasts, 309
erythrocytes, 308
fibrin, 307
fluctuations in hemoglobin and
erythrocytes, 308
in number of leucocytes,
3"
fractured leucocytes, 314
granular basophilia, 310
hemoglobin, 308
influence of arsenic, 311
of x-rays, 312
karyokinesis, 310
leucocytes, 310
INDEX OF SUBJECTS.
583
Leukemia, myelogenous, lymphocytes,
315
mast cells, 316*
megalobLosts, 309
myelocytes, 312
nuclear extrusion, 309
polychromatophilia, 310
polynuclear neutrophiles, 314
predominance of normoblasts,
3°9
pyknosis, 310
relation of erythrocyte and leu-
cocyte counts, 308
remissions, 311
specific gravity, 307
stimulation forms, 315
J O J
parasitology, 305
splenectomy in, 338
transformation into pernicious ane-
mia, 304
transformations of type, 304
varieties, 302
Leukoblasts, 319
Light-proof hemometer box, 48
Lipacidemia, 145
in acute yellow atrophy of the liver,
. 365
in diabetes mellitus, 383
Lipemia, 141
in diabetes mellitus, 383
in fractures, 421
pathological 142
physiological, 141
Liquor sanguinis, 93
Lithiasis, pancreatic, 499
Liver, abscess, 363
acute yellow atrophy, 365
carcinoma, 476
cirrhosis, 430
Lock-jaw, 535
Lowenthal's reaction, 516
Lowit's ameba, 305
Lungs, malignant neoplasms of, 505
Lupus, 256
Lymph scrotum, 421
Lymphangitis, 421
Lymphemia, 321. See Lymphocylosis.
Lymphocytes, large, 210
small, 211
Lymphocytosis, 252
absolute, 252
after splenectomy, 336
cachectic, 253
definition, 252
differential changes, 252
drug, 254
factors, 253
in acromegaly, 364
in actinomycosis, 364
in acute infections, 254
Lymphocytosis in acute leukemia, 321
in anemia infantum pseudoleu-
kemica, 355
in Addison's disease, 366
in adenitis, 254
in adenoids, 375
in Asiatic cholera, 374
in beri-beri, 492
in bronchitis, 375
in bubonic plague, 378
in carcinoma, 478, 481
in children, 344
in chloroma, 379
in chlorosis, 272
in constitutio lymphatica, 254
in convulsions, 495
in diphtheria, 389
in enteric fever, 408
in epithelial neoplasms, 481
in exophthalmic goitre, 411
in filariasis, 420
in gastritis, 423
• in gastro-enteritis, 353
in Hodgkin's disease, 328
in kala-azar, 443
in lymphatic leukemia, 319
jn 'malarial fever, 470
in malignant disease, 478, 480
in. Malta fever, 484
in measles, 486
in meningitis, 488
in osteomalacia, 499
in paresis, 495
in pernicious anemia, 286 '
in pertussis, 502
in pneumonia, 510
in protozoan infections, 254
in purpura, 430
in rachitis, 353
in rheumatic fever, 520
in rotheln, 486
in sarcoma, 480
in scarlet fever, 524
in scurvy, 430
in secondary anemia, 298
in splenic anemia, 293
tumors, 254
in sprue, 392
in syphilis, 535
in thyroid tumors, 254
in tracheobronchial adenitis, 375
in tropical hematochyluria, 254
in trypanosomiasis, 541
in tuberculosis, 547
in varicella, 555
in variola, 557
of infancy, 344 .
post-hemorrhagic, 301
relative, 252
terminal, 254
INDEX OF SUBJECTS.
Lymphogonien, 319
Lymphoma, 332
MACROCYTES, 182
Macrophages, 239
Making the puncture, 34
Malarial anemia, 469
cachexia, 468
' fever, 445
action of quinin, 446
amebula, 449
anemia, 466
blood plaques, 471
diagnosis, 471
erythrocytes, 466
hemoglobin, 466
incidence, 448
leucocytes, 469
parasite, 445
crescentic forms, 460
degenerate forms, 452,
457> 46i
development in man, 445
in mosquito, 446
differential table, 463
disc forms, 458
estivo-autumnal, 457
extracellular pigmented
forms, 452, 456, 460
flagellate forms, 453, 457,
461
gamete forms, 452, 456,
461
infection with multiple
groups, 448, 454
intracellular hyaline
forms, 449, 454, 457
intracellular pigmented
forms, 450, 455, 458
leucocytes, 462
ovoid bodies, 460
quartan, 454
ring forms, 458
segmenting forms, .451,
456, 459
spherical bodies, 460
sporocytes, 451
staining, 464
tertian, 448
vacuolized forms, 454,
457. 46i
phagocytosis, 462
technic of examination, 464
hematuria, 467, 470
spleen, 338
Male chlorosis, 275
Malignant disease, 472
endocarditis, 482
jaundice, 365
Mallory's protozoon, ,^j
Malta fever, 484
Mania, 496 •
Maragliane's necrosis, 176
Marmorek's method, 518
Massage, effect on blood, 176
Mast cell granules, 207
cells, 219
in Addison's disease, 366
in appendicitis, 259
in Asiatic cholera, 374
in carcinoma, 478
in chlorosis, 258
in filariasis, 420
in gonorrhea, 258
in infantile anemias, 346
in lymphatic leukemia, 320
in mycosis fungoides, 258
in myelogenous leukemia, 318
in plumbism, 259
in septic bone disease, 258
in skin diseases, 258
in splenic anemia, 293
in trichiniasis, 538
in trypanosomiasis, 541
Mastitis, 244
Masturbation, 494
Measles, 485
Megaloblastic blood picture, 282
Megaloblasts, 189
Megalocytes, 182
Melancholia, 494
Melanemia, 107
in Addison's disease, 366
in insolation, 438
in malarial fever, 462
in relapsing fever, 515
Meningitis, 486
cerebro-spinal, 488
tuberculous, 487
Menstruation, effect on blood, 164,
175
Mental diseases, 492
Mercury, effect on blood, 533, 535
Mesoblasts, 192
Methemoglobin, 161
spectrum of, 168
tests for, 167
Methemoglobinemia, 167
from drugs, 167
from influence of radium rays, 167
in Addison's disease, 366
in chloroform narcosis, 249
in poisoning, 511
in purpura haemorrhagica, 427
Methods, fixation, 79
non-clinical, 122
of examination, 33
of staining, 81
MetschnikofF s theory, 239
INDEX OF SUBJECTS.
Microblasts, 192
Microcytes, 182
Microphages, 239
Microspectroscope, Sorby-Beck, 107
Mikulicz's dictum, 164
Milian's method, 100
Mitral lesions, 447
Monochromatophilia, 186
Mononuclear neutrophiles, 222
Mononucleosis, 252. See Lymphocy-
tosis.
Mosquito, dengue, 382
development of Filaria nocturna
in, 415
of malarial parasite in, 446
yellow fever, 559
Mucinoblasts, 221
Multiple neuritis, 492
periostitis, 326
Muscular exercise, effect on blood, 176,
234
Myelemia, 259
Myelocytes, 217
atypical forms in leukemia, 313
dwarf, 222
eosinophilic, 219
in abscess, 363
in actinomycosis, 344
in Addison's disease, 366
in anemia of children, 346
infantum pseudo-leukemica,
355
in bubonic plague, 378
in burns, 378
in carcinoma, 478
in chloroma, 379
in chlorosis, 274
in convulsions, 495
in diabetes melh'tus, 386
in diphtheria, 389
in enteric fever, 409
in epilepsy, 497
in erysipelas, 411
in gastro-enteritis, 353
in gout, 427
in herpes zoster, 434
in Hodgkin's disease, 330
in infantile enteric fever, 354
scurvy, 430
syphilis, 352
tuberculosis, 353
in lymphatic leukemia, 320
in malarial fever, 471
in myelogenous leukemia, 312
in myxedema, 489
in osteomalacia, 499
in osteosarcoma, 480
in pernicious anemia, 274
in phthisis, 547
in pneumonia, 510
Myelocytes in post-hemorrhagic leuco-
cytosis, 248
in rachitis, 353
in sarcoma, 480
in scarlet fever, 524
in secondary anemia, 298
in sepsis, 529
in splenic anemia, 293
in sprue, 392
in syphilis, 535
in trichiniasis, 536
in tuberculosis, 547
in varicella, 555
in variola, 557
in von Jaksch's periostitis, 259
in yellow fever, 560
Myxedema, 488
Myxococcidium stegomyiae, 559
NECROBIOSIS, 211
Necrosis, Maragliano's, 185
Needle for blood culturing, no
Negro lethargy, 539
Nephrectomy, 492
Nephritis, 489
Nervous* diseases, 492
Neuralgia, 492
ovarian, 371
Neurasthenia, 493
gastric, 422
sexual, 494
Neuritis, 492
Neuroses, functional, 493
Neutral dyes, 76
Neutrophile granules, 208
Neutrophiles, mo no nuclear, 222
poly nuclear, 214
Neutrophilic pseudo-lymphocytes, 222
Newton's rings, 62
Nikiforoff's method of fixation, 80
Nitrobenzene poisoning, 512
Nitroglycerin poisoning, 512
Normoblasts, 187
Nuclear stains, 76
Nucleated erythrocytes, 187
Nucleolation of lymphocytes, 320
OBERMEIER'S spirillum, 514
Obesity, 498
Objects of staining, 75
Obstruction, intestinal, 441
Obstructive jaundice, coagulation in,
38o» 434
Ocular diaphragm, 65
Odor and viscosity of blood, 127
Oligemia, 140
Oligochromemia, 163
Oligocythemia, 148
586
INDKX OF SUBJECTS.
Oliver's hemocytometer, 71
hemoglobinometer, 49
Opium poisoning, 512
Opsonin, 239
Osmic acid fixation, 81
Osteomalacia, 498
Osteomyelitis, 525
tuberculous, 546
Osteosarcoma, 259, 480
Otitis media, 244
Oval-shaped erythrocytes, 115, 184
in epidemic dropsy, 282
in pernicious anemia, 281
in purpura haemorrhagica, 281
Ovarian abscess, 370
cyst, 371
neuralgia, 371
Ovaritis, 244
Oven for fixation, 79
Oxyhemoglobin, 161
spectrum of, 168
Oxyuris vermicularis, 441
PACHYMEXIXGITIS, 487
Pancreatitis, 499
Panoptic staining, 81
Paralysis, family periodic, 497
Paratyphoid fever, 394, 404
Parenchymatous nephritis, 490
Paresis, 494
Pathological basophilia, 258
eosinophilia, 256
leucocytosis, 236
leucopenia, 262
lymphocytosis, 254
Pellagra, 244
Pelvic abscess, 370
Pemphigus, 244 «
Pericardial effusion, 500
Perinuclear basophilia, 228
Periostitis, multiple, 326
Peritonitis, 500
appendicular, 368
hysterical, 501
septic, 500
serous, 500
tuberculous, 546, 549
Pernicious anemia, 276
alkalinity, 278
appearance of fresh blood, 276
blood plaques, 287
blood volume, 276
coagulation, 278
color index, 279
diagnosis, 288
dry residue, 276
Eichhorst's corpuscles, 281
eosinophiles, 286
erythroblasts, 282
Pernicious anemia, erythrocytes, 278
fibrin, 278
fluctuations in number of
erythrocytes, 280
granular basophilia, 285
hemoglobin, 278
horseshoe-shaped cells, 281
in children, 347
isotonicity, 181
leucocytes, 285
megaloblasts, 282
megalocytes, 280
mesoblasts, 283
microblasts, 285
myelocytes, 287
nuclear extrusion, 284
oligemia, 276
oval-shaped cells, 281
phantom corpuscles, 277
poikilocytosis, 281
polychromatophilia, 285
polynuclear neutrophiles, 286
predominance of megaloblasts,
282
relative lymphocytosis, 286
rouleaux formation, 277
specific gravity, 278
symptoms, 288
syphilitic, 533
transformation into leukemia,
290
Pertussis, 502
Pfeiffer's phenomenon, 112
Phagocytosis, 206, 238
in malarial fever, 462
in relapsing fever, 517
Phantom corpuscles, 184
tumor, 502
Phenacetin poisoning, 512
Phlebitis, 244
Phosphorus poisoning, 512
Physiological eosinophilia, 256
leucocytosis, 230
leucopenia, 261
lymphocytosis, 253
Pigmented leucocytes in insolation, 438
in malarial fever, 462
in relapsing fever, 515
Pinocytosis, 206
Pipette, Durham's, 68
Gowers', 52
Oliver's, 50
Thoma-Zeiss, 57
Von FleischPs, 43
Piroplasma, 443, 531, 551
Plague, bubonic, 376
Plasma stains, 76
Plasmodium malariae, 445
Plasmotrophic action, 439
Plethora, 138
INDEX OF SUBJECTS.
Plethora in chlorosis, 267
in hemophilia, 427
in obesity, 498
in valvular heart disease, 553
Pleura, malignant neoplasms of, 505
Pleurisy, purulent, 504
serous, 503
Plimmer's bodies, 473
Plumbic neuritis, 492
Plumbism, acute, 196, 512
Pneumonia, catarrhal, 508
croupous, 505
bacteriology, 505
blood plaques, 510
diagnosis, 51.1
effect of aleuron and digitalis,
5°9
antipneumococcus serum,
5°9
antipyretics and cold, 510
erythrocytes, 507
hemoglobin, 507
hyperinosis, 505
induced leucocytosis, 509
iodin reaction, 510
leucocytes, 507
lymphocytosis, 510
serum test, 505
specific gravity, 505
Poggi's corpuscles, 185
Poikilocytes, 183
Poisoning, 511
Polychromatophilia, 186
Polycythemia, 197
after burns, 378
after exercise, 176
after purgation, 392
after transfusion, 301
after urinary crises, 198
cyanotic, 381
during blood regeneration, 301
digestion, 177
menstruation, 175
from administration of lympho-
gogues and emetics, 198
from physiological causes, 198
in acute yellow atrophy of the
liver, 365
in ascites, 431
in Asiatic cholera, 373
in asthma, 374
in bubonic plague, 377
in convulsions, 495
in diabetes mellitus, 385
in diarrhea, 390
in diphtheria, 387
in emphysema, 374
in erythromelalgia, 493
in fever, 412
in gastric and esophageal carci-
noma, 474
Polycythemiu in gastric and esophageal
ulcer, 423
in gastritis, 421
in gout, 427
in hepatic cirrhosis, 431
in icterus, 436
in illuminating-gas poisoning, 512
in insolation, 437
in leprosy, 444
in malarial fever, 466
in nephritis, 491
in Osier's disease, 381
in phosphorus poisoning, 512
in pleural effusion, 503
in pneumonia, 507
in the new-born, 174
in trichiniasis, 536
in tuberculosis, 545
in valvular heart disease, 553
in variola, 556
of high altitudes, 1 78
Polyemia, 138
Polynuclear neutrophiles, 214
Ponfick's corpuscles, 185
Post-hemorrhagic anemia, 299
, blood crises, 302
plaques, 301
color index, 302
• erythroblasts, 302
erythrocytes, 299
etiology, 299
fatality, 300
hemoglobin, 240, 299
hydropic erythrocytes,. 302
immediate effects of blood loss,
299
leucocytes, 300
leucocytosis, 246
lymphocytosis, 247
microcytes, 302
oligemia, 299
polychromatophilia, 302
polycythemia, 302
rapidity of hemoglobin gain,
302
regeneration, 301
saline solution, effect of, 301
Post-operative leucocytosis, 244
Potassium chlorate poisoning, 512
permanganate poisoning, 513
Pott's disease, 546, 548
Preagonal leucocytosis, 235
Precipitins, 157
Pregnancy, 131, 135
ectopic, 370
Preparing the films, 76
the slide, 35
Prince's stain, 85
Prison pallor, 149
Protozoa in beri-beri, 492
in carcinoma, 473
588
INDEX OF SUBJECTS.
Protozoa in dengue, 382
in kala-azar, 441
in leukemia, 305
in measles, 485
in scarlet fever, 522
in spotted fever, 531
in trypanosomiasis, 538
in varicella, 554
. in variola, 555
in yellow fever, 558
Prurigo, 256
Pseudo-anemia, 149
bacilli, 183
chlorosis, 199
lymphocytes, neutrophilic, 222
Psoriasis, 256
Ptomain poisoning, 513
Puerperal fever, 525
Purges, effects on blood, 392
Purpura, 427
Purulent lesions, 361
Pyelonephritis, 244
Pyemia, 525
Pyknosis, 310
Pyonephrosis, 244
Pyosalpinx, 370
Pyrodin poisoning, 513
Pyrogallol poisoning, 513
QUANTITY of blood, 125
Quinsy, 536
Quotient, blood, 165
RABIES, 513
Radium rays, effect on blood, 167
Ranvier's solution, 1 14
Raspberry-jelly clots, 307,
Ratio of erythrocytes to leucocytes, 205
to plaques, 90.
Reaction. See Test. Arloing and Cour-
mont's, 542
Bordet's, 117
LowenthaFs, 516
of blood, 128
pathological variations, 130
physiological variations, 129
tests for, 96
Pfeiffer's, 112
Widal's, 112
Receptors, 152
Rectum, carcinoma of, 476
Red blood corpuscles, 169. See Eryth-
rocytes.
Reichert's method, 161
Reizungsformen, 222
Relapsing fever, 514
diagnosis, 517
erythrocytes, 516
hemoglobin, 516
Relapsing fever, leucocytes, 516
. LowenthaPs reaction, 516
melanin, 515
parasitology, 514
phagocytosis, 517
Remissions in myelogenous leukemia ,
311
in pernicious anemia, 280
Renal colic, 381
disease, freezing point of blood, 103
Revulsives, effect on blood, 249
Rheumatic fever, 518
alkalinity, 518
bacteriology, 518
coagulation, 518
color index, 519
diagnosis, 520
erythrocytes, 519
fibrin, 518
hemoglobin, 519
leucocytes, 520
Rheumatism, chronic, 519
muscular, 501
Ring bodies, 194
Rollet, stroma of, 1 70
Ross' method, 77
Rotheln, 169
Rouleaux formation, 169
Row's test, 377
Rupture of the spleen, 338
Russell's bodies, 473
SALINE purges, effect on blood, 392
Salts of blood, 126
Sanarelli's bacillus, 558
Sapremia, 525
Sarcoma, 478
coagulation, 478
cytodiagnosis, 478
deformed erythrocytes, 479
diagnosis, 480
erythroblasts, 479
erythrocytes, 478
fibrin, 478
hemoglobin, 478
leucocytes, 479
specific gravity, 478
Scarlet fever, 521
bacteriology, 522
blood plaques, 524
coagulation, 521
diagnosis, 525
erythrocytes, 522
fibrin, 521
hemoglobin, 522
leucocytes, 523
protozoa, 522
specific gravity, 521
Schistocytosis, 185
Schuffner's granules, 196
INDEX OF SUBJECTS.
589
Scleroderma, 256
Scorpion poisoning, 513
Scrofula, 545
Scrotum, lymph, 421
Scurvy, 427
infantile, 429
Secondary anemia, 296
alkalinity, 296
appearance of fresh blood, 296
average hemoglobin and eryth-
rocyte losses, 297
blood plaques, 298
coagulation, 296
color index, 297
deformed erythrocytes, 297
diagnosis, 298
eosinophiles, 298
erythroblasts, 298
erythrocytes, 296
granular basophilia, 298
hemoglobin, 296
leucocytes, 298
myelocytes, 298
pallor of erythrocytes, 297
poikilocytosis, 297
poly chroma tophilia, 297
polynuclear neutrophiles, 298
relative lymphocytosis, 298
specific gravity, 296
Septic arthritis, 525
Septicemia and pyemia, 525
bacteriology, 526
color index, 528
diagnosis, 530
erythrocytes, 527
fibrin, 525
hemoglobin, 527
leucocytes, 529
serum reaction, 525
Serous plethora, 139. See Hydremia.
Serum reaction, determination of, 112
in Asiatic cholera, 372
in bubonic plague, 377
in children, 354
in colon infections, 496, 525
in dysentery, 391
in enteric fever, 396
in glanders, 425
in icterus, 403
in kala-azar, 444
in leprosy, 444
in Malta fever, 484
in non-typhoid conditions, 403
in paratyphoid fever, 404
in pneumococcus infections,
526
in pneumonia, 505
in relapsing fever, 511
in septicemia, 525
in streptococcus infections, 525
Serum reaction in tuberculosis, 542
in Weil's disease, 403
Sexual neurasthenia, 494
Shadow corpuscles, 184
Sherrington's solution, 56
Shiga's bacillus, 391
Shingles, 434
Side-chain theory, Ehrlich's, 151
Sign, Jeffrey's, 217
Sleeping sickness, 539
Slide, preparing the, 315
Small lymphocytes, 210
Small-pox, 555
Snake poisoning, 513
Sodium nitrite poisoning, 513
Solution, Brodie and Russell's, 91
Denige's, 145
Determann's, 91
Hayem's, 56
isotonic, 180
Ranvier's, 114
saline, after hemorrhage, 301
•Sherrington's, 56
Toisson's, 56
Sorby-Beck microspectroscope, 107
Sorby's tubular cell, 108
Specific gravity, 132
estimation of, 94
. in Asiatic cholera, 372
in carcinoma, 472
in children, 342
in chlorosis, 268
in diabetes mellitus, 385
in Hodgkin's disease, 327
in icterus, 434
in lymphatic leukemia, 317
in myelogenous leukemia, 307
in nephritis, 489
in pernicious anemia, 278
in phthisis, 545
in pneumonia, 505
in purpura haemorrhagica, 427
in Sarcoma, 478
in scarlet fever, 521
in secondary' anemia, 296
in the fetus, 341
in the new-born, 342
in valvular heart disease, 553
in yellow fever, 559
normal range, 132
pathological variations, 132
table of hemoglobin equiva-
lents, 133
Spectra, blood, 168
Spectroscopical examination, 107
Spirilla in Malta fever, 484
Spirillum of Obermeier, 514
Spleen, hemolytic action, 225
inflammation, 244
malarial, 338
59°
INDEX OF SUBJECTS.
Spleen, neoplasms, 327
rupture, 338
tropical, 442
wandering, 338
Splenectomy, 333
Splenic anemia, 291
appearance of fresh blood, 291
blood plaques, 293
color index, 291
diagnosis, 293
eosinophiles, 293
erythroblasts, 292
erythrocytes, 291
hemoglobin, 291
leucocytes, 292
mast cells, 293
megaloblasts, 292
megalocytosis, 292
myelocytes, 293
poikilocytosis, 292
polychromatophilia, 292
polynuclear neutrophiles, 293
. relative lymphocytosis, 293
symptoms, 294
Splenitis, 244
Splenolymph glands, 172
Splenomegaly, 295
tropical, 442
Sporoblasts, 447
Sporozoids, 447
Spot culturing, 395
Spotted (Montana) fever, 531
(typhus) fever, 550
Sprue, 392
Stain, Delafield's, 87
Ehrlich's triacid, 83
Ehrlich-Weigert, 112
eosin and hematoxylin, 87
methylene-blue, 86
Goldberger and, Weiss', 226
Goldhorn's, 88
Hewes', 85
Jenner's, 82
Leishman's, 82
Loffler's, 85
polychrome methylene-blue, 88
Prince's, 85
Romano wsky, 82
thionin, 87
Wright's, 82
Stained specimen, examination of the, 75
Staining, methods of, 81
bacteria, 1 1 1
basophilic erythrocytes, 194
cellular elements, 82
diabetic blood, 385
double, 87
filaria, 419
Hemamceba leukemia', 305
Hemamceba malariae, 464
Staining iodophile cells, 175, 226
Neusser's granules, 228
objects of, 75
panoptic, -81
ring bodies, 194 '
Schuffner's granules, 469
Spirillum obermeieri, 515
triple, 83
trypanosoma, 540
Stasis, effect on blood, 553
Stegomyia'fasciata, 558
Still's disease, 326
Stimulation forms, 222
Stomach, carcinoma, 476, 481
dilatation, 422
inflammation, 421
ulcer, 423
Stroma of Rollet, 1 70
Strong and Seligmann's method, 73
Strongyloides intestinalis, 441
Sugar in the blood, 143
after pancreatectomy, 143
in carcinoma, 472
in diabetes mellitus, 383
test for, 143
Sunstroke, 437
Sweating, effect on blood, 198, 234
Syphilis, 532
bacteriology, 532
diagnosis, 535
effect of treatment, 533
erythrocytes, 532
hemoglobin, 532
Justus' test, 533
leucocytes, 534
TALLQTJIST'S hemoglobinometer, 54
Tansy poisoning, 513
Tape worms, 440
Teichmann's crystals, 162
test, 115
Terminal leucocytosis, 235
Test, biological, 117. See Reaction.
Bordet's, 117
Bremer's, 384
Ficker-Reudiger, 401
for acetone, 145
for alkalinity, 96
for bile, 145
for carbon monoxid hemoglobin, 169
for fat, 142
for fatty acids, 146
for glycogen, 226
for hemin, 115
for hemoglobin, 40
for hemoglobinemia, 167
for human blood, 114
for methemoglobin, 167
for sugar, 108, 143
for uric acid, 144
INDEX OF SUBJECTS.
591
Test Garrod's, 144
guaiacum, 116
hanging-drop, 122
Justus', 533
Lowenthal'S) 516
Marx and Ehrnrooth's, 122
medico-legal, 114
Row's, 377
Schaffer's, 175
Teichmann's, 115
Van Deen's, 116
Widal's, 112
Williamson's, 383
Wolff's, 402
Tetanus, 535
Tetany, 498
Theory, side-chain, 151
Thermotaxis, 238
Thionin stain, 87
Thoma-Zeiss hemocytometer, 57
Thrombosis, 393
Thymectomy, leucocytosis after, 252
Thyroidization, 489
Tick fever, 531
Toadstool poisoning, 513
Toisson's solution, 56
Toluene poisoning, 513
Toluylendiamin poisoning, 513
Tonsillitis, 535
Total necrosis, 185
Toxic leucocytosis, 247
Toxins 152
Toxoids, 153
Toxones, 153
Toxophores, 152
Transitional forms, 213
Triacid stain, 83
Trichiniasis, 536
Trichocephalus dispar, 438
Tropical anemia, 149
splenomegaly, 442
Trypanosoma gambiense, 539
Trypanosomiasis, 538
Tsetse-fly, 539
Tuberculosis, 541
bacteriology, 542
diagnosis, 550
erythrocytes, 544
forms of anemia, 545
genito-urinary, 546, 549
glandular, 546, 549
hemoglobin, 544
hip-joint, 546, 548
iodophilia, 547
leucocytes, 546
meningeal, 546, 549
osseous, 546, 548
peritoneal, 546, 549
pleural, 546, 5.}.)
polycythemia, 545
Tuberculosis, pulmonary, 545, 547
secondary infections, 545, 547
serum reaction, 542
vertebral, 546, 548
Tuberculous meningitis, 487
Tubular cell, Sorby's, 108
Tumor, brain, 493
phantom, 502
Turpentine poisoning, 513
Typhoid fever, 393. See Enteric Fever.
Typhus fever, 550
ULCER, duodenal, 425
gastric, 423
Uncinariasis, 440
Uniceptors, 152
Uremia, 492
freezing point of blood, 103
Uric acid in gout, 426
relation to leucocytolysis, 263
test for, 144
Uricacidemia, 144
Urinary crises, effects on blood, 198
Urticaria, 256
Uskow's theory, 224
Uterus, carcinoma of, 476
VACCINATION, 552
Valee's law, 117
Valeur globulaire, 165
Valvular. heart disease, 552
Varicella, 554
Variola, 555
Varioloid, 557
Vegetarians, 177
Violet of Hoyer, 87
Viscosity of blood, 127
value, 128
Volume index, 94, 173
of corpuscles and plasma, estima-
tion of , 9 1
Vomiting, effect on blood, 198
Von FleischPs hemometer, 43
Von Jaksch's anemia, 354
WALDSTEIN'S smearing slip, 78
Wandering spleen, 338
Welch's hypothesis, 153
White blood corpuscles, 205 . See Leuco-
cytes.
Whooping-cough, 502
Widal's test, 112
Williamson's test, 383
Wright's coagulometer, 101
stain, 82
YELLOW fever, 558
ZAPPERT counting chamber, 59
Zolliktfer's method, 226
Zygotes, 447
Zymophores, 155
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