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Hematology
Kaushansky_FM_pi_xxii.indd 1 9/21/15 4:40 PM

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Williams
Hematology Ninth Edition
Kenneth Kaushansky, MD, MACP Marshall A. Lichtman, MD
Senior Vice President for Health Sciences Professor of Medicine and of Biochemistry and Biophysics
Dean, School of Medicine University of Rochester Medical Center
SUNY Distinguished Professor Rochester, New York
Stony Brook University
Stony Brook, New York Marcel Levi, MD, PhD
Professor of Medicine
Josef T. Prchal, MD Dean, Faculty of Medicine
Professor of Medicine, Pathology, and Genetics Academic Medical Center
Hematology Division University of Amsterdam
University of Utah Amsterdam, The Netherlands
Salt Lake City, Utah
Department of Pathophysiology Linda J. Burns, MD
First Faculty of Medicine Professor of Medicine
Charles University in Prague Division of Hematology, Oncology and Transplantation
Prague, Czech Republic University of Minnesota
Minneapolis, Minnesota
Oliver W. Press, MD, PhD
Acting Director, Clinical Research Division Michael A. Caligiuri, MD
Dr. Penny E. Peterson Memorial Chair for Lymphoma Director, Comprehensive Cancer Center
Research CEO, James Cancer Hospital and Solove Research Institute
Fred Hutchinson Cancer Research Center Professor of Medicine
Professor of Medicine and Bioengineering The Ohio State University
University of Washington Columbus, Ohio
Seattle, Washington
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Milan New Delhi Singapore Sydney Toronto

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vv
CONTENTS
Contributors . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . ix 16. Cell-Cycle Regulation and Hematologic Disorders . . . . . . . . . 213
Preface . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . xxi Yun Dai, Prithviraj Bose, and Steven Grant
17. Signal Transduction Pathways . . . . . . . . . . . . . . . . . . . . . . . . . . . 247
Kenneth Kaushansky
PART I
18. Hematopoietic Stem Cells, Progenitors, and Cytokines . . . . . . 257
Clinical Evaluation of the Patient
Kenneth Kaushansky
1. Initial Approach to the Patient: History and Physical
19. The Inflammatory Response . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 279
Examination . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 3
Jeffrey S. Warren and Peter A. Ward
Marshall A. Lichtman and Linda J. Burns
20. Innate Immunity . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 293
2. Examination of Blood Cells . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 11 Bruce Beutler
Daniel H. Ryan
21. Dendritic Cells and Adaptive Immunity . . . . . . . . . . . . . . . . . . 307
3. Examination of The Marrow . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 27 Madhav Dhodapkar, Crystal L. Mackall, and Ralph M. Steinman
Daniel H. Ryan
4. Consultative Hematology . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 41
PART V
Rondeep S. Brar and Stanley L. Schrier
Therapeutic Principles
PART II 22. Pharmacology and Toxicity of Antineoplastic Drugs . . . . . . . . 315
Benjamin Izar, Dustin Dzube, James M. Cleary, Constantine
The Organization of the Lymphohematopoietic Tissues S. Mitsiades, Paul G. Richardson, Jeffrey A. Barnes, and
5. Structure of the Marrow and the Hematopoietic Bruce A. Chabner
Microenvironment . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 53 23. Hematopoietic Cell Transplantation . . . . . . . . . . . . . . . . . . . . . . 353
Utpal P. Davé and Mark J. Koury Andrew R. Rezvani, Robert Lowsky, and Robert S. Negrin
6. The Organization and Structure of Lymphoid Tissues . . . . . . . . 85 24. Treatment of Infections in The Immunocompromised
Aharon G. Freud and Michael A. Caligiuri Host . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 383
Lisa Beutler and Jennifer Babik
PART III 25. Antithrombotic Therapy . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 393
Epochal Hematology Gregory C. Connolly and Charles W. Francis
7. Hematology of the Fetus and Newborn . . . . . . . . . . . . . . . . . . . . 99 26. Immune Cell Therapy . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 409
James Palis and George B. Segel Carolina Berger and Stanley R. Riddell
8. Hematology during Pregnancy . . . . . . . . . . . . . . . . . . . . . . . . . . 119 27. Vaccine Therapy . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 421

Martha P. Mims Katayoun Rezvani and Jeffrey J. Molldrem
9. Hematology in Older Persons . . . . . . . . . . . . . . . . . . . . . . . . . . . 129 28. Th

erapeutic Apheresis: Indications, Efficacy, and
William B. Ershler, Andrew S. Artz, and Bindu Kanapuru Complications . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 427
Robert Weinstein
29. Gene Therapy for Hematologic Diseases . . . . . . . . . . . . . . . . . . 437
PART IV
Hua Fung and Stanton Gerson
Molecular and Cellular Hematology
30. Regenerative Medicine: Multipotential Cell Therapy for
10. Genetic Principles and Molecular Biology . . . . . . . . . . . . . . . . . 145 Tissue Repair . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 447
Lynn B. Jorde Jakub Tolar, Mark J Osborn, Randy Daughters, Anannya Banga, and
11. Genomics . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 155 John Wagner
Lukas D. Wartman and Elaine R. Mardis
12. Epigenetics . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 165 PART VI
Bradley R. Cairns The Erythrocyte
13. Cytogenetics and Genetic Abnormalities . . . . . . . . . . . . . . . . . . 173 31. Structure and Composition of the Erythrocyte . . . . . . . . . . . . 461
Lucy A. Godley, Madina Sukhanova, Gordana Raca, and Narla Mohandas
Michelle M. Le Beau
32. Erythropoiesis . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 479
14. Metabolism of Hematologic Neoplastic Cells . . . . . . . . . . . . . . 191
Josef T. Prchal and Perumal Thiagarajan
Zandra E. Walton, Annie L. Hsieh, and Chi V. Dang
33. Erythrocyte Turnover . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 495
15. Apoptosis Mechanisms: Relevance to the Hematopoietic
Perumal Thiagarajan and Josef Prchal
System . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 203
John C. Reed 34. Clinical Manifestations and Classification of Erythrocyte
Disorders . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 503
Josef T. Prchal

vi Contents
35. Aplastic Anemia: Acquired and Inherited . . . . . . . . . . . . . . . . . 513

PART VII
George B. Segel and Marshall A. Lichtman
Neutrophils, Eosinophils, Basophils, and Mast Cells
36. Pure Red Cell Aplasia . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 539
Neal S. Young 60. Structure and Composition of Neutrophils,
Eosinophils, and Basophils . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 925
37. Anemia of Chronic Disease . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 549
C. Wayne Smith
Tomas Ganz
61. Production, Distribution, and Fate of Neutrophils . . . . . . . . . . 939
38. Erythropoietic Effects of Endocrine Disorders . . . . . . . . . . . . . 559
C. Wayne Smith
Xylina T. Gregg
62. Eosinophils and Related Disorders . . . . . . . . . . . . . . . . . . . . . . . 947
39. The Congenital Dyserythropoietic Anemias . . . . . . . . . . . . . . . 563
Andrew J. Wardlaw
Achille Iolascon
63. Basophils, Mast Cells, and Related Disorders . . . . . . . . . . . . . . 965
40. Paroxysmal Nocturnal Hemoglobinuria . . . . . . . . . . . . . . . . . . . 571
Stephen J. Galli, Dean D. Metcalfe, Daniel A. Arber, and Ann M. Dvorak
Charles J. Parker
64. Classification and Clinical Manifestations of
41. Folate, Cobalamin, and Megaloblastic Anemias . . . . . . . . . . . . 583
Neutrophil Disorders . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 983
Ralph Green
Marshall A. Lichtman
42. Iron Metabolism . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 617
65. Neutropenia and Neutrophilia . . . . . . . . . . . . . . . . . . . . . . . . . . . 991
Tomas Ganz
David C. Dale and Karl Welte
43. Iron Deficiency and Overload . . . . . . . . . . . . . . . . . . . . . . . . . . . 627
66. Disorders of Neutrophil Function . . . . . . . . . . . . . . . . . . . . . . . 1005
Tomas Ganz
Niels Borregaard
44. Anemia Resulting from Other Nutritional Deficiencies . . . . . 651
Ralph Green
PART VIII
45. Anemia Associated with Marrow Infiltration . . . . . . . . . . . . . . 657
Monocytes and Macrophages
Vishnu VB Reddy and Josef T. Prchal
67. Structure, Receptors, and Functions of Monocytes and
46. Erythrocyte Membrane Disorders . . . . . . . . . . . . . . . . . . . . . . . . 661
Macrophages . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1045
Theresa L Coetzer
Steven D. Douglas and Anne G. Douglas
47. Erythrocyte Enzyme Disorders . . . . . . . . . . . . . . . . . . . . . . . . . . 689
68. Production, Distribution, and Activation of Monocytes and
Wouter W. van Solinge and Richard van Wijk
Macrophages . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1075
48. The Thalassemias: Disorders of Globin Synthesis . . . . . . . . . . . 725 Steven D. Douglas and Anne G. Douglas
David J. Weatherall
69. Classification and Clinical Manifestations of Disorders
49. Disorders of Hemoglobin Structure: Sickle Cell of Monocytes and Macrophages . . . . . . . . . . . . . . . . . . . . . . . . 1089
Anemia and Related Abnormalities . . . . . . . . . . . . . . . . . . . . . . 759 Marshall A. Lichtman
Kavita Natrajan and Abdullah Kutlar
70. Monocytosis and Monocytopenia . . . . . . . . . . . . . . . . . . . . . . . 1095
50. Methemoglobinemia and Other Dyshemoglobinemias . . . . . . 789 Marshall A. Lichtman
Archana M. Agarwal and Josef T. Prchal
71. Inflammatory and Malignant Histiocytosis . . . . . . . . . . . . . . . 1101
51. Fragmentation Hemolytic Anemia . . . . . . . . . . . . . . . . . . . . . . . 801 Kenneth L. McClain and Carl E. Allen
Kelty R. Baker and Joel Moake
72. Gaucher Disease and Related Lysosomal Storage Diseases . . 1121
52. Erythrocyte Disorders as a Result of Chemical Ari Zimran and Deborah Elstein
and Physical Agents . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 809
Paul C. Herrmann
PART IX
53. Hemolytic Anemia Resulting from Infections
with Microorganisms . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 815 Lymphocytes and Plasma Cells
Marshall A. Lichtman 73. The Structure of Lymphocytes and Plasma Cells . . . . . . . . . . . 1137
54. Hemolytic Anemia Resulting from Immune Injury . . . . . . . . . 823 Natarajan Muthusamy and Michael A. Caligiuri
Charles H. Packman 74. Lymphopoiesis . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1149
55. Alloimmune Hemolytic Disease of the Fetus Christopher S. Seet and Gay M. Crooks
and Newborn . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 847 75. Functions of B Lymphocytes and Plasma Cells in
Ross M. Fasano, Jeanne E. Hendrickson, and Naomi L. C. Luban Immunoglobulin Production . . . . . . . . . . . . . . . . . . . . . . . . . . . 1159
56. Hypersplenism and Hyposplenism . . . . . . . . . . . . . . . . . . . . . . . 863 Thomas J. Kipps
Jaime Caro and Srikanth Nagalla 76. Functions of T Lymphocytes: T-Cell Receptors
57. Primary and Secondary Erythrocytoses . . . . . . . . . . . . . . . . . . . 871 for Antigen . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1175
Josef T. Prchal Fabienne McClanahan and John Gribben
58. The Porphyrias . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 889 77. Functions of Natural Killer Cells . . . . . . . . . . . . . . . . . . . . . . . . 1189
John D. Phillips and Karl E. Anderson Giorgio Trinchieri, Richard W. Childs, and Lewis L. Lanier
59. Polyclonal and Hereditary Sideroblastic Anemias . . . . . . . . . . 915 78. Classification and Clinical Manifestations of
Prem Ponka and Josef T. Prchal Lymphocyte and Plasma Cell Disorders . . . . . . . . . . . . . . . . . . 1195
Yvonne A. Efebera and Michael A. Caligiuri

Contents vii
79. Lymphocytosis and Lymphocytopenia . . . . . . . . . . . . . . . . . . 1199 101. Marginal Zone B-Cell Lymphomas . . . . . . . . . . . . . . . . . . . . . . 1663
Sumithira Vasu and Michael A. Caligiuri Pier Luigi Zinzani and Alessandro Broccoli
80. Immunodeficiency Diseases . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1211 102. Burkitt Lymphoma . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1671
Hans D. Ochs and Luigi D. Notarangelo Andrew G. Evans and Jonathan W. Friedberg
81. Hematologic Manifestations of Acquired Immunodeficiency 103. Cutaneous T-Cell Lymphoma (Mycosis Fungoides
Syndrome . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1239 and Sézary Syndrome) . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1679
Virginia C. Broudy, Robert D. Harrington Larisa J. Geskin
82. Mononucleosis Syndromes . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1261 104. Mature T-Cell and Natural Killer Cell Lymphomas . . . . . . . . 1693
Robert F. Betts Neha Mehta, Alison Moskowitz, and Steven Horwitz
105. Plasma Cell Neoplasms: General Considerations . . . . . . . . . . 1707
PART X Guido Tricot, Siegfried Janz, Kalyan Nadiminti, Erik Wendlandt, and
Fenghuang Zhan
Malignant Myeloid Diseases
106. Essential Monoclonal Gammopathy . . . . . . . . . . . . . . . . . . . . . 1721
83. Classification and Clinical Manifestations of the
Marshall A. Lichtman
Clonal Myeloid Disorders . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1275
Marshall A. Lichtman 107. Myeloma . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1733
Elizabeth O’Donnell, Francesca Cottini, Noopur Raje, and
84. Polycythemia Vera . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1291 Kenneth Anderson
Jaroslav F. Prchal and Josef T. Prchal
108. Immunoglobulin Light-Chain Amyloidosis . . . . . . . . . . . . . . . 1773
85. Essential Thrombocythemia . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1307 Morie A. Gertz, Taimur Sher, Angela Dispenzieri, and
Philip A. Beer and Anthony R. Green Francis K. Buadi
86. Primary Myelofibrosis . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1319 109. Macroglobulinemia . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1785
Marshall A. Lichtman and Josef T. Prchal Steven P. Treon, Jorge J. Castillo, Zachary R. Hunter, and
Giampaolo Merlini
87. Myelodysplastic Syndromes . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1341
Rafael Bejar and David P. Steensma 110. Heavy-Chain Disease . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1803
Dietlind L. Wahner-Roedler and Robert A. Kyle
88. Acute Myelogenous Leukemia . . . . . . . . . . . . . . . . . . . . . . . . . . 1373
Jane L. Liesveld and Marshall A. Lichtman
89. Chronic Myelogenous Leukemia and Related Disorders . . . . 1437 PART XII
Jane L. Liesveld and Marshall A. Lichtman Hemostasis and Thrombosis
111. Megakaryopoiesis and Thrombopoiesis . . . . . . . . . . . . . . . . . . 1815
PART XI Kenneth Kaushansky
Malignant Lymphoid Diseases 112. Platelet Morphology, Biochemistry, and Function . . . . . . . . . 1829
Susan S. Smyth, Sidney Whiteheart, Joseph E. Italiano Jr.,
90. Classification of Malignant Lymphoid Disorders . . . . . . . . . . 1493
Paul Bray, and Barry S. Coller
Robert A. Baiocchi
113. Molecular Biology and Biochemistry of the
91. Acute Lymphoblastic Leukemia . . . . . . . . . . . . . . . . . . . . . . . . . 1505
Coagulation Factors and Pathways of Hemostasis . . . . . . . . . 1915
Richard A. Larson Mettine H. A. Bos, Cornelis van ‘t Veer, and Pieter H. Reitsma
92. Chronic Lymphocytic Leukemia . . . . . . . . . . . . . . . . . . . . . . . . 1527 114. Control of Coagulation Reactions . . . . . . . . . . . . . . . . . . . . . . . 1949
Farrukh T. Awan and John C. Byrd Laurent O. Mosnier and John H. Griffin
93. Hairy Cell Leukemia . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1553 115. Vascular Function in Hemostasis . . . . . . . . . . . . . . . . . . . . . . . 1967
Michael R. Grever and Gerard Lozanski Katherine A. Hajjar, Aaron J. Marcus, and
94. Large Granular Lymphocytic Leukemia . . . . . . . . . . . . . . . . . . 1563 William Muller
Pierluigi Porcu and Aharon G. Freud 116. Classification, Clinical Manifestations, and
95. General Considerations for Lymphomas: Epidemiology, Evaluation of Disorders of Hemostasis . . . . . . . . . . . . . . . . . . . 1985
Etiology, Heterogeneity, and Primary Extranodal Disease . . 1569 Marcel Levi, Uri Seligsohn, and Kenneth Kaushansky
Oliver W. Press and Marshall A. Lichtman 117. Thrombocytopenia . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1993
96. Pathology of Lymphomas . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1587 Reyhan Diz-Küçükkaya and José A. López
Randy D. Gascoyne and Brian F. Skinnider 118. Heparin-Induced Thrombocytopenia . . . . . . . . . . . . . . . . . . . . 2025
97. Hodgkin Lymphoma . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1603 Adam Cuker and Mortimer Poncz
Oliver W. Press 119. Reactive Thrombocytosis . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 2035
98. Diffuse Large B-Cell Lymphoma and Related Diseases . . . . . 1625 Kenneth Kaushansky
Stephen D. Smith and Oliver W. Press 120. Hereditary Qualitative Platelet Disorders . . . . . . . . . . . . . . . . . 2039
99. Follicular Lymphoma . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1641 A. Koneti Rao and Barry S. Coller
Oliver W. Press 121. Acquired Qualitative Platelet Disorders . . . . . . . . . . . . . . . . . . 2073
100. Mantle Cell Lymphoma . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1653 Charles S. Abrams, Sanford J. Shattil, and Joel S. Bennett
Martin Dreyling 122. The Vascular Purpuras . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 2097
Doru T. Alexandrescu and Marcel Levi

viii Contents
123. Hemophilia A and Hemophilia B . . . . . . . . . . . . . . . . . . . . . . . 2113 133. Venous Thrombosis . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 2267

Miguel A. Escobar and Nigel S. Key Gary E. Raskob, Russell D. Hull, and Harry R. Buller
124. Inherited Deficiencies of Coagulation Factors II, V, 134. Atherothrombosis: Disease Initiation, Progression,
V+VIII, VII, X, XI, and XIII . . . . . . . . . . . . . . . . . . . . . . . . . . . 2133 and Treatment . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 2281
Flora Peyvandi and Marzia Menegatti Emile R. Mohler III and Andrew I. Schafer
125. Hereditary Fibrinogen Abnormalities . . . . . . . . . . . . . . . . . . . . 2151 135. Fibrinolysis and Thrombolysis . . . . . . . . . . . . . . . . . . . . . . . . . . 2303
Marguerite Neerman-Arbez and Philippe de Moerloose Katherine A. Hajjar and Jia Ruan
126. von Willebrand Disease . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 2163
Jill Johnsen and David Ginsburg PART XIII
127. Antibody-Mediated Coagulation Factor Deficiencies . . . . . . 2183 Transfusion Medicine
Sean R. Stowell, John S. (Pete) Lollar, and Shannon L. Meeks 136. Erythrocyte Antigens and Antibodies . . . . . . . . . . . . . . . . . . . . 2329
128. Hemostatic Alterations in Liver Disease and Liver Marion E. Reid and Christine Lomas-Francis
Transplantation . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 2191 137. Human Leukocyte and Platelet Antigens . . . . . . . . . . . . . . . . . 2353
Frank W.G. Leebeek and Ton Lisman Myra Coppage, David Stroncek, Janice McFarland, and Neil Blumberg
129. Disseminated Intravascular Coagulation . . . . . . . . . . . . . . . . . 2199 138. Blood Procurement and Red Cell Transfusion . . . . . . . . . . . . 2365
Marcel Levi and Uri Seligsohn Jeffrey McCullough, Majed A. Refaai, and Claudia S. Cohn
130. Hereditary Thrombophilia . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 2221 139. Preservation and Clinical Use of Platelets . . . . . . . . . . . . . . . . 2381
Saskia Middeldorp and Michiel Coppens
Terry Gernsheimer and Sherrill Slichter
131. The Antiphospholipid Syndrome . . . . . . . . . . . . . . . . . . . . . . . . 2233
Index . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 2393
Jacob H. Rand and Lucia Wolgast
132. Thrombotic Microangiopathies . . . . . . . . . . . . . . . . . . . . . . . . . 2253
J. Evan Sadler

ix
ix
CONTRIBUTORS
Charles S. Abrams, MD [121] Jennifer Babik, MD, PhD [24]
Professor of Medicine, Pathology and Laboratory Medicine Division of Infectious Diseases
Vice Chair for Research & Chief Scientific Officer Department of Medicine
Department of Medicine University of California
University of Pennsylvania School of Medicine San Francisco, California
Philadelphia, Pennsylvania
Robert A. Baiocchi, MD, PhD [90]
Archana M. Agarwal, MD [50] Associate Professor of Medicine
Department of Pathology Division of Hematology
University of Utah/ARUP Laboratories Department of Internal Medicine
Salt Lake City, Utah The Ohio State University
Columbus, Ohio
Doru T. Alexandrescu, MD [122]
Department of Medicine Kelty R. Baker, MD [51]
Division of Dermatology Clinical Assistant Professor
University of California, San Diego Baylor College of Medicine
VA San Diego Health Care System Houston, Texas
San Diego, California
Anannya Banga, PhD, [30]
Carl E. Allen, MD, PhD [71] Assistant Professor
Associate Professor of Pediatrics Department of Genetics
Texas Children’s Cancer Center/Hematology Cell Biology, and Development, Stem Cell Institute
Baylor College of Medicine University of Minnesota
Houston, Texas Minneapolis, Minnesota
Karl E. Anderson, MD, FACP [58] Jeffrey A. Barnes [22]

Professor, Departments of Preventative Medicine and Community Instructor in Medicine
Health, Internal Medicine, and Pharmacology and Toxicology Dana-Farber Cancer Institute
University of Texas Medical Branch Harvard Medical School
Galveston, Texas Boston, Massachusetts
Kenneth Anderson, MD [107] Philip A. Beer, MRCP, FRCPath, PhD [85]

Dana-Farber Cancer Institute Wellcome Trust Sanger Institute
Boston, Massachusetts Wellcome Trust Genome Campus, Hinxton
Cambridge, United Kingdom
Daniel A. Arber, MD [63]
Ronald F. Dorfman, MBBch, FRCPath Professor in Hematopathology Rafael Bejar, MD, PhD [87]
Professor of Pathology Division of Hematology and Oncology
Stanford University School of Medicine Moores Cancer Center
Stanford University Medical Center University of California San Diego
Stanford, California La Jolla, California
Andrew S. Artz, MD, MS [9] Joel S. Bennett, MD [121]

Associate Professor of Medicine Professor of Medicine
University of Chicago Division of Hematology-Oncology
Chicago, Illinois University of Pennsylvania School of Medicine
Farrukh T. Awan, MD [92]
Associate Professor of Internal Medicine Carolina Berger, MD [26]
Division of Hematology Fred Hutchinson Cancer Research Center
Department of internal Medicine Seattle, Washington
The Ohio State University Comprehensive Cancer Center
Columbus, Ohio

x Contributors
Robert F. Betts, MD [82] Francis K. Buadi, MD [108]

Professor of Medicine, Emeritus Division of Hematology
Division of Infectious Diseases Mayo Clinic
University of Rochester Medical Center Rochester, Minnesota
Rochester, New York
Harry R. Buller, MD [133]
Bruce Beutler, MD [20] Professor of Medicine,
Regental Professor and Director Department of Vascular Medicine
Center for the Genetics of Host Defense Academic Medical Center
Raymond and Ellen Willie Distinguished Chair in Cancer Research in Amsterdam, The Netherlands
Honor of Laverne and Raymond Willie Sr.
University of Texas Southwestern Medical Center Linda J. Burns, MD [1]
Dallas, Texas National Marrow Donor Program/Be The Match
Vice President and Medical Director
Lisa Beutler, MD, PhD [24] Health Services Research
Department of Medicine Minneapolis, Minnosata
UCSF School of Medicine
San Francisco, California John C. Byrd, MD [92]
D. Warren Brown Chair of Leukemia Research
Neil Blumberg, MD [137] Professor of Medicine, Medicinal Chemistry, and Veterinary
Professor and Director, Clinical Laboratories and Transfusion Biosciences
Medicine Director, Division of Hematology
Department of Pathology and Laboratory Medicine Department of Medicine
University of Rochester The Ohio State University
Rochester, New York Columbus, Ohio
Niels Borregaard, MD, PhD [66] Bradley R. Cairns, PhD [12]

Professor of Hematology Howard Hughes Medical Institute
Department of Hematology Professor and Chair
University of Copenhagen Department of Oncological Sciences
Copenhagen, Denmark Huntsman Cancer Institute
University of Utah School of Medicine
Prithviraj Bose, MD [16] Salt Lake City, Utah
Assistant Professor
Department of Leukemia Michael A. Caligiuri, MD [6, 73, 78, 79]
University of Texas MD Anderson Cancer Center Professor and Director, The Ohio State University Comprehensive
Houston, Texas Cancer Center
CEO, James Cancer Hospital and Solove Research Institute
Rondeep S. Brar, MD [4] The Ohio State University
Clinical Assistant Professor of Medicine (Hematology and Oncology) Columbus, Ohio
Stanford University School of Medicine
Stanford, California Jaime Caro, MD [56]
Paul Bray, MD [112] Department of Medicine
Professor Thomas Jefferson University
Director, Division of Hematology Cardeza Foundation for Hematologic Research
Jefferson University Philadelphia, Pennsylvania
Jorge J. Castillo, MD [109]
Alessandro Broccoli, MD [101] Assistant Professor of Medicine
Institute of Hematology “L. e A. Seràgnoli” Dana-Farber Cancer Institute
University of Bologna Harvard Medical School
Bologna, Italy Boston, Massachusetts
Virginia C. Broudy, MD [81] Bruce A. Chabner, MD [22]

Professor of Medicine Professor of Medicine
Scripps Professor of Hematology Massachusetts General Hospital Cancer Center
University of Washington Harvard Medical School
Seattle, Washington Boston, Massachusetts

Contributors xi
Richard W. Childs, MD [77] Adam Cuker, MD, MS [118]

Clinical Director, NHLBI Assistant Professor of Medicine & of Pathology and Laboratory
Chief, Section of Transplantation Immunotherapy Medicine
National Heart, Lung, and Blood Institute, NIH Perelman School of Medicine at the University of Pennsylvania
Bethesda, Maryland Philadelphia, Pennsylvania
James M. Cleary, MD, PhD [22] Yun Dai, MD [16]

Instructor in Medicine Associate Professor of Medicine
Dana-Farber Cancer Institute Department of Medicine
Harvard Medical School Massey Cancer Center
Boston, Massachusetts Virginia Commonwealth University
Richmond, Virginia
Theresa L Coetzer, MD [46]
Head: Red Cell Membrane Unit David C. Dale, MD [65]
Department of Molecular Medicine and Haematology Professor of Medicine
National Health Laboratory Service Department of Medicine
University of the Witwatersrand University of Washington
Wits Medical School Seattle, Washington
Johannesburg, South Africa
Chi V. Dang, MD, PhD [14]
Claudia S. Cohn, MD [138] Professor and Director
Assistant Professor, Laboratory Medicine and Pathology Abramson Cancer Center
University of Minnesota University of Pennsylvania
Minneapolis, Minnesota Philadelphia, Pennsylvania
Barry S. Coller, MD [112, 120] Utpal P. Davé, MD [5]

Head Division of Hematology/Oncology
Allen and Frances Adler Laboratory of Blood and Vascular Biology Department of Medicine
Physician-in-Chief Vanderbilt University Medical Center
Vice President for Medical Affairs Nashville, Tennessee
The Rockefeller University
New York, New York Randy Daughters, PhD [30]
Assistant Professor
Gregory C. Connolly, MD [25] Department of Genetics
Department of Medicine Cell Biology, and Development, Stem Cell Institute
Lipson Cancer Center University of Minnesota
Rochester Regional Health System Minneapolis, Minnesota
Rochester, New York
Philippe de Moerloose, MD [125]
Myra Coppage [137] Professor
Associate Professor of Laboratory Medicine Division of Angiology and Haemostasis
Department of Pathology and Laboratory Medicine University of Geneva Faculty of Medicine
University of Rochester Geneva, Switzerland
Rochester, New York
Madhav Dhodapkar, MBBS [21]
Michiel Coppens, MD, PhD [130] Arthur H. and Isabel Bunker Professor of Medicine (Hematology) and
Department of Vascular Medicine Professor of Immunobiology
Academic Medical Center Chief, Section of Hematology, Department of Internal Medicine
Amsterdam, The Netherlands Clinical Research Program Leader, Hematology Program
Yale Cancer Center
Francesca Cottini, MD [107] New Haven, Connecticut
Dana-Farber Cancer Institute
Boston, Massachusetts Angela Dispenzieri, MD [108]
Division of Hematology
Gay M. Crooks, MB, BS, FRACP [74] Mayo Clinic
Professor Rochester, Minnesota
Departments of Pathology & Laboratory Medicine and Pediatrics
David Geffen School of Medicine
University of California, Los Angeles
Los Angeles, California

xii Contributors
Reyhan Diz-Küçükkaya, MD [117] Andrew G. Evans, MD, PhD [102]

Associate Professor Assistant Professor
Department of Internal Medicine Department of Pathology and Laboratory Medicine
Division of Hematology University of Rochester Medical Center
Istanbul University Rochester, New York
Istanbul Faculty of Medicine
Istanbul, Turkey Ross M. Fasano, MD [55]
Assistant Professor
Anne G. Douglas, BA [67, 68] Emory University School of Medicine
Student, Perelman School of Medicine Departments of Pathology and Pediatric Hematology
University of Pennsylvania (Class of 2017) Assistant Director, Children’s Healthcare of Atlanta Transfusion
Philadelphia, Pennsylvania Services
Associate Director, Grady Health System Transfusion Service
Steven D. Douglas, MD [67, 68] Atlanta, Georgia
Professor and Associate Chair
Department of Pediatrics Charles W. Francis, MD [25]
Perelman School of Medicine Hematology/Oncology Division
University of Pennsylvania University of Rochester Medical Center
Children’s Hospital of Philadelphia Rochester, New York
Aharon G. Freud, MD, PhD [6, 94]
Martin Dreyling, MD [100] Assistant Professor
Department of Internal Medicine III Department of Pathology
Medical Center of the University of Munich The Ohio State University
Munich, Germany Columbus, Ohio
Ann M. Dvorak, MD [63] Jonathan W. Friedberg, MD [102]

Senior Pathologist, Professor of Pathology Samuel Durand Professor of Medicine
Department of Pathology Director, Wilmot Cancer Institute
Beth Israel Deaconess Medical Center University of Rochester Medical Center
Harvard Medical School Rochester, New York
Boston, Massachusetts
Hua Fung, MD [29]
Dustin Dzube, MD [22] Case Western Reserve University
Resident Physician University Hospital of Cleveland
Massachusetts General Hospital Cleveland, Ohio
Harvard Medical School
Boston, Massachusetts Stephen J. Galli, MD [63]
Mary Hewitt Loveless, MD, Professor
Yvonne A. Efebera, MD, MPH [78] Professor of Pathology and of Microbiology and Immunology
Associate Professor of Internal Medicine Chair, Department of Pathology
Division of Hematology Stanford University School of Medicine
Department of Internal Medicine Stanford University Medical Center
The Ohio State University Stanford, California
Columbus, Ohio
Tomas Ganz, MD, PhD [37, 42, 43]
Deborah Elstein, PhD [72] Departments of Medicine and Pathology, David Geffen School of
Gaucher Clinic Medicine
Shaare Zedek Medical Center University of California, Los Angeles
Jerusalem, Israel Los Angeles, California
William B. Ershler, MD [9] Randy D. Gascoyne, MD, FRCPC [96]

Scientific Director Clinical Professor of Pathology
Institute for Advanced Studies in Aging and Geriatrics Research Director, Centre for Lymphoid Cancers
Falls Church, Virginia Departments of Pathology and Advanced Therapeutics British
Columbia Cancer Agency, the BC Centre Research Center and
Miguel A. Escobar, MD [123] University of British Columbia
Professor of Medicine and Pediatrics Vancouver, British Columbia, Canada
Division of Hematology
University of Texas Health Science Center at Houston
Director, Gulf States Hemophilia and Thrombophilia Center
Houston, Texas

Contributors xiii
Terry B. Gernsheimer, MD [139] Xylina T. Gregg, MD [38]

Professor of Medicine Director of Laboratory Services
Department of Medicine, Division of Hematology Utah Cancer Specialists
University of Washington School of Medicine Salt Lake City, Utah
Seattle Cancer Care Alliance
Seattle, Washington Michael R. Grever, MD [93]
Chair and Professor
Stanton Gerson, MD [29] Department of Internal Medicine
Director, Case Comprehensive Cancer, Seidman Cancer Center Bertha Bouroncle MD and Andrew Pereny Chair in Medicine
& National Center for Regenerative Medicine The Ohio State University
Distinguished University Professor Columbus, Ohio
Case Western Reserve University
University Hospital of Cleveland John Gribben, MD, DSc, FRCP, FRCPath, FMedSci [76]
Cleveland, Ohio Chair of Medical Oncology
Barts Cancer Institute
Morie A. Gertz, MD, MACP [108] Centre for Haemato-Oncology
Division of Hematology Queen Mary University of London
Mayo Clinic London, United Kingdom
Rochester, Minnesota
John H. Griffin, PhD [114]
Larisa J. Geskin, MD, FAAD [103, 105] Professor
Associate Professor of Dermatology and Medicine Department of Molecular and Experimental Medicine
Director, Division of Cutaneous Oncology and Comprehensive Skin The Scripps Research Institute
Cancer Center La Jolla, California
Department of Dermatology
Columbia University Katherine A. Hajjar, MD [115, 135]
New York, New York Professor of Pediatrics
Brine Family Professor, Department of Cell and Developmental
David Ginsburg, MD [126] Biology
Professor, Department of Internal Medicine, Human Genetics and Professor of Medicine
Pediatrics Well Cornell Medical College
Investigator, Howard Hughes Medical Institute Attending Pediatrician
Life Sciences Institute New York Presbyterian Hospital
University of Michigan New York, New York
Ann Arbor, Michigan
Robert D. Harrington, MD [81]
Lucy A. Godley, MD, PhD [13] Professor of Medicine
Section of Hematology/Oncology University of Washington
Department of Medicine and The University of Chicago Seattle, Washington
Comprehensive Cancer Center
The University of Chicago Jeanne E. Hendrickson, MD [55]
Chicago, Illinois Associate Professor
Departments of Laboratory Medicine and Pediatrics
Steven Grant, MD [16] Yale University School of Medicine
Professor of Medicine and Biochemistry New Haven, Connecticut
Shirley and Sture Gordon Olsson Professor of Oncology
Associate Director Paul C. Herrmann, MD, PhD [52]
Translational Research, Massey Cancer Center Associate Professor and Chair
Virginia Commonwealth University Health Sciences Center Department of Pathology and Human Anatomy
Richmond, Virginia Loma Linda University School of Medicine
Loma Linda, California
Anthony R. Green, PhD, FRCP, FRCPath, FMedSci [85]
Professor of Haematology Steven Horwitz, MD [104]
Cambridge Institute for Medical Research and Stem Cell Institute Department of Medicine
University of Cambridge Memorial Sloan Kettering Cancer Center
Cambridge, United Kingdom New York, New York
Ralph Green, MD, PhD, FRCPath [41, 44] Annie L. Hsieh, MD [14]
Professor of Pathology and Medicine Department of Pathology
University of California Davis Medical Center Johns Hopkins University, School of Medicine
Sacramento, California Baltimore, Maryland

xiv Contributors
Zachary R. Hunter, PhD [109] Kenneth Kaushansky, MD, MACP [17, 18, 111, 116, 119]
Bing Center for Waldenstrom’s Macroglobulinemia Senior Vice President, Health Sciences
Dana-Farber Cancer Institute Dean, School of Medicine
Instructor of Medicine, Harvard Medical School SUNY Distinguished Professor
Boston, Massachusetts Stony Brook Medicine
State University of New York
Russell D. Hull, MD [133] Stony Brook, New York
Professor
Department of Medicine Nigel S. Key, MB, ChB, FRCP [123]
University of Calgary Harold R. Roberts Distinguished Professor of Medicine
Active Staff Director, University of North Carolina Hemophilia and Thrombosis
Department of Internal Medicine Center
Foothills Hospital Chapel Hill, North Carolina
Calgary, Alberta, Canada
Thomas J. Kipps, MD, PhD [75]
Achille Iolascon, MD, PhD [39] Evelyn and Edwin Tasch Chair in Cancer Research
Professor of Medical Genetics Professor of Medicine
Dept. of Molecular Medicine and Medical Biotechnologies Division of Hematology/Oncology
University Federico II of Naples Deputy Director for Research Operations
Naples, Italy Moores UCSD Cancer Center
University of California, San Diego
Joseph E. Italiano Jr., PhD [112] La Jolla, California
Associate Professor of Medicine
Brigham and Women’s Hospital Mark J. Koury, MD [5]
Harvard Medical School Division of Hematology/Oncology
Boston, Massachusetts Department of Medicine
Vanderbilt University Medical Center
Benjamin Izar, MD, PhD [22] Nashville, Tennessee
Post-doctoral Scientist
Dana-Farber Cancer Institute and Broad Institute Abdullah Kutlar, MD [49]
Associate Physician, Brigham and Women’s Hospital Professor of Medicine
Harvard Medical School Georgia Sickle Cell Center
Boston, Massachusetts Medical College of Georgia
Sickle Cell Center
Siegfried Janz, MD, DSc [105] Augusta, Georgia
Division of Hematology/Oncology & Blood and Marrow Transplantation
Department of Pathology, Carver College of Medicine Robert A. Kyle, MD [110,]
University of Iowa Health Care Professor of Medicine
Iowa City, Iowa Laboratory Medicine and Pathology
Mayo Clinic
Jill M. Johnsen, MD [126] Rochester, Minnesota
Assistant Member, Research Institute
Bloodworks Northwest Lewis L. Lanier, PhD [77]
Puget Sound Blood Center Professor
Assistant Professor, Division of Hematology Department of Microbiology and Immunology
Department of Medicine University of California, San Francisco
University of Washington San Francisco, California
Seattle, Washington
Richard A. Larson, MD [91]
Lynn B. Jorde, PhD [10] Section of Hematology/Oncology
H. A. and Edna Benning Presidential Professor Department of Medicine and the Comprehensive Cancer Center
Department of Human Genetics University of Chicago
University of Utah School of Medicine Chicago, Illinois
Salt Lake City, Utah
Michelle M. Le Beau, PhD [13]
Bindu Kanapuru, MD [9] Section of Hematology/Oncology
Institute for Advanced Studies in Aging and Geriatrics Department of Medicine and the Center Research Center
Falls Church, Virginia University of Chicago
Chicago, Illinois

Contributors xv
Frank W.G. Leebeek, MD, PhD [128] Naomi L. C. Luban, MD [55]

Professor of Hematology Professor, Pediatrics and Pathology
Department of Hematology George Washington University Medical Center
Erasmus University Medical Center Division Chief, Laboratory Medicine
Rotterdam, The Netherlands Director, Transfusion Medicine/Donor Center
Children’s National Medical Center
Marcel Levi, MD, PhD [116, 122, 129 ] Washington, D.C.
Department of Medicine/Vascular Medicine
Academic Medical Center
Crystal L. Mackall, MH [21]
University of Amsterdam
Head, Immunology Section and
Amsterdam, The Netherlands
Chief, Pediatric Oncology Branch
Marshall A. Lichtman, MD [1, 35, 53, 64, 69, 70, 83, 86, 88, 89, National Cancer Institute
95, 106] Bethesda, Maryland
Professor of Medicine and of Biochemistry and Biophysics
University of Rochester Medical Center Aaron J. Marcus, MD* [115]
Rochester, New York Professor of Medicine
Weill Cornell Medical College
Jane L. Liesveld, MD [88, 89] Attending Physician
Professor of Medicine (Hematology-Oncology) New York Harbor Healthcare System
James P. Wilmot Cancer Institute New York, New York
University of Rochester Medical Center
Rochester, New York Elaine R. Mardis, PhD [11]
Ton Lisman, PhD [128] Robert E. and Louise F. Dunn Distinguished Professor of Medicine
Professor of Experimental Surgery Co-director, The Genome Institute, Division of Genomics and
Surgical Research Laboratory and Section of Hepatobiliary Surgery Bioinformatics, Department of Medicine, Washington University
and Liver Transplantation School of Medicine
Department of Surgery Siteman Cancer Center, Washington University School of Medicine
University Medical Center, Groningen Saint Louis, Missouri
Groningen, The Netherlands
Fabienne McClanahan, MD, PhD [76]
John S. (Pete) Lollar III, MD [127] Barts Cancer Institute
Aflac Cancer Center and Blood Disorders Services Centre for Haemato-Oncology
Department of Pediatrics Queen Mary University of London
Emory University London, United Kingdom
Atlanta, Georgia
Christine Lomas-Francis, MSc, FIBMS [136] Kenneth L. McClain, MD, PhD [71]
Technical Director Professor of Pediatrics
Laboratory of Immunohematology and Genomics Texas Children’s Cancer Center/Hematology
New York Blood center Baylor College of Medicine
New York, New York Houston, Texas
José A. Lópéz, MD [117] Jeffrey McCullough, MD [138]

Chief Scientific Officer Professor
Bloodworks Northwest Department of Laboratory Medicine and Pathology
Professor of Medicine and Biochemistry American Red Cross Professor, Transfusion Medicine
University of Washington University of Minnesota Medical School
Seattle, Washington Minneapolis, Minnesota
Robert Lowsky, MD [23]
Division of Blood and Marrow Transplantation Janice McFarland, MD [137]
Stanford University Blood Center of Southeast Wisconsin
Stanford, California Milwaukee, Wisconsin
Gerard Lozanski, MD [93] Shannon L. Meeks, MD [127]

Director, Hematopathology Aflac Cancer Center and Blood Disorders Services
Medical Director Department of Pediatrics
Flow Cytometry Laboratory Emory University
Associate Professor—Clinical Atlanta, Georgia
Department of Pathology
The Ohio State University
Columbus, Ohio
*
Deceased

xvi Contributors
Neha Mehta, MD [104] Emile R. Mohler III, MD [134]

Department of Medicine Director, Vascular Medicine
Memorial Sloan Kettering Cancer Center Professor of Medicine
New York, New York Division of Cardiovascular Medicine
Perelman School of Medicine at the University of Pennsylvania
Marzia Menegatti, MD [124] Philadelphia, Pennsylvania
Angelo Bianchi Bonomi Hemophilia and Thrombosis Center
Fondazione IRCCS Ca’ Granda Ospedale Maggiore Policlinico Jeffrey J. Molldrem, MD [27]
University of Milan Professor of Medicine
Milan, Italy Stem Cell Transplantation and Cellular Therapy,
MD Anderson Cancer Center
Giampaolo Merlini, MD [109] Houston, Texas
Director, Center for Research and Treatment of Systematic
Amyloidoses Alison Moskowitz, MD [104]
University Hospital Policlinico San Matteo Department of Medicine
Professor, Department of Medicine Memorial Sloan Kettering Cancer Center
University of Pavia New York, New York
Pavia, Italy
Laurent O. Mosnier, PhD [114]
Dean D. Metcalfe, MD [63] Associate Professor
Chief, Laboratory of Allergic Diseases Department of Molecular and Experimental Medicine
Chief, MCBS/LAD The Scripps Research Institute
NAID/National Institute of Health La Jolla, California
Bethesda, Maryland
William A. Muller, MD, PhD [115]
H. A. Mettine Bos, HA, PhD [113] Magerstadt Professor and Chair
Assistant Professor Department of Pathology
Division of Thrombosis and Hemostasis Feinberg School of Medicine
Einthoven Laboratory for Experimental Vascular Medicine Northwestern University
Leiden University Medical Center Chicago, Illinois
Leiden, The Netherlands
Natarajan Muthusamy, DVM, PhD [73]
Saskia Middeldorp, MD, PhD [130] Professor of Medicine
Department of Vascular Medicine Division of Hematology
Academic Medical Center Department of Internal Medicine
Amsterdam, The Netherlands The Ohio State University
Columbus, Ohio
Martha P. Mims, MD, PhD [8]
Professor of Medicine Kalyan Nadiminti, MD [105]
Section Chief, Section of Hematology/Oncology Division of Hematology/Oncology & Blood and Marrow Transplantation
Baylor College of Medicine Department of Pathology, Carver College of Medicine
Houston, Texas University of Iowa Health Care
Iowa City, Iowa
Constantine S. Mitsiades, MD, PhD [22]
Assistant Professor of Medicine Srikanth Nagalla, MBBS, MS [56]
Dana-Farber Cancer Institute Assistant Professor of Medicine
Harvard Medical School Division of Hematology
Boston, Massachusetts Cardeza Foundation for Hematologic Research
Thomas Jefferson University
Joel Moake, MD [51] Philadelphia, Pennsylvania
Senior Research Scientist and Associate Director
Biomedical Engineering Laboratory Kavita Natrajan, MBBS [49]
Rice University Associate Professor of Medicine
Houston, Texas Division of Hematology/Oncology
Georgia Regents University
Narla Mohandas, D.Sc [31] Augusta, Georgia
Red Cell Physiology Laboratory
New York Blood Center Marguerite Neerman-Arbez, PhD [125]
New York, New York Professor
Department of Genetic Medicine and Development
University of Geneva Faculty of Medicine
Geneva, Switzerland

Contributors xvii
Robert S. Negrin, MD [23] Mortimer Poncz, MD [118]

Division of Blood and Marrow Transplantation Jane Fishman Grinberg Professor of Pediatrics
Stanford University Perelman School of Medicine at the University of Pennsylvania
Stanford, California Children’s Hospital of Philadelphia
Luigi D. Notarangelo, MD [80]
Professor of Pediatrics and Pathology Prem Ponka, MD [59]
Harvard Medical School Professor of Physiology and Medicine
Jeffrey Modell Chair of Pediatric Immunology Research Lady Davis Institute
Division of Immunology, Children’s Hospital Boston McGill University
Boston, Massachusetts Montreal, Quebec, Canada
Hans D. Ochs, MD [80] Pierluigi Porcu, MD [94]

Professor of Pediatrics Professor of Internal Medicine
Jeffrey Modell Chair of Pediatric Immunology Research Division of Hematology, and Comprehensive Cancer Center
Division of Immunology The Ohio State University
Seattle Children’s Research Hospital Columbus, Ohio
Department of Pediatrics
University of Washington Jaroslav F. Prchal, MD [84]
Seattle, Washington Director, Department of Oncology
St. Mary’s Hospital
Elizabeth O’Donnell, MD [107] Montreal, Quebec, Canada
Massachusetts General Hospital
Boston, Massachusetts Josef T. Prchal, MD [ 32, 33, 34, 45, 50, 57, 59, 84, 86]
The Charles A. Nugent, M.D., and Margaret Nugent Professor
Mark J. Osborn, PhD [30] Division of Hematology, Pathology, and Genetics
Assistant Professor University of Utah
Pediatrics Salt Lake City, Utah
Blood and Marrow Transplantation, Stem Cell Institute Department of Pathophysiology
University of Minnesota First Faculty of Medicine
Minneapolis, Minnesota Charles University
Prague, Czech Republic
Charles H. Packman, MD [54]
Professor of Medicine Oliver W. Press, MD, PhD [ 95, 97, 98, 99]
University of North Carolina School of Medicine Acting Senior Vice President, Fred Hutchinson Cancer Research
Levine Cancer Institute, Hematologic Oncology and Blood Disorders Center
Charlotte, North Carolina Acting Director, Clinical Research Division, FHCRC
Recipient, Dr. Penny E. Peterson Memorial Chair for Lymphoma
James Palis, MD [7] Research
Professor of Pediatrics Professor of Medicine and Bioengineering
University of Rochester Medical Center University of Washington
Rochester, New York Seattle, Washington
Charles J. Parker, MD [40] Gordana Raca, MD, PhD [13]

Professor of Medicine Section of Hematology/Oncology
Division of Hematology and Bone Marrow Transplantation Department of Medicine and The University of Chicago Comprehensive
University of Utah School of Medicine Cancer Center
Salt Lake City, Utah University of Chicago
Chicago, Illinois
Flora Peyvandi, MD [124]
Angelo Bianchi Bonomi Hemophilia and Thrombosis Center Noopur Raje, MD [107]
Fondazione IRCCS Ca’ Granda Ospedale Maggiore Policlinico Massachusetts General Hospital
University of Milan Boston, Massachusetts
Milan, Italy
Jacob H. Rand, MD [131]
John D. Phillips, PhD [58] Professor of Pathology and Medicine
Associate Professor of Medicine Director of Hematology Laboratory
Division of Hematology Montefiore Medical Center
University of Utah School of Medicine The University Hospital for the Albert Einstein College of Medicine
Salt Lake City, Utah Bronx, New York

xviii Contributors
A. Koneti Rao, MD [120] Jia Ruan, MD, PhD [135]

Sol Sherry Professor of Medicine Associate Professor
Director of Benign Hematology, Hemostasis and Thrombosis Department of Medicine
Co-Director, Sol Sherry Thrombosis Research Center Weill Cornell Medical College
Temple University School of Medicine Associate Attending Physician
Philadelphia, Pennsylvania New York Presbyterian Hospital
New York, New York
Gary E. Raskob, PhD [133]
Dean, College of Public Health Daniel H. Ryan, MD [2, 3]
Regents Professor, Epidemiology and Medicine Professor Emeritus
The University of Oklahoma Health Science Center Department of Pathology and Laboratory Medicine
Oklahoma City, Oklahoma University of Rochester Medical Center
Rochester, New York
Vishnu VB Reddy, MD [45]
Department of Pathology, J. Evan Sadler, MD, PhD [132]
University of Alabama in Birmingham, Ira M. Lang Professor of Medicine
Birmingham, Alabama Washington University School of Medicine
St. Louis, Missouri
John C. Reed, MD, PhD [15]
Pharmaceutical Research & Early Development Andrew I. Schafer, MD [134]
Roche Innovation Center-Basel Professor of Medicine,
Basel, Switzerland Director, The Richard T. Silver Center for Myeloproliferative
Neoplasms,
Majed A. Refaai, MD [138] Weill Cornell Medical College
Associate Professor New York, New York
Department of Pathology and Laboratory Medicine
University of Rochester Medical Center Stanley L. Schrier, MD [4]
Rochester, New York Professor of Medicine (Hematology)
Active emeritus
Marion E. Reid, PhD, DSc (Hon.) [136] Division of Hematology
(Retired) Stanford University School of Medicine
New York Blood Center Stanford, California
New York, New York
Christopher S. Seet, MD [74]
Pieter H. Reitsma, PhD [113] Department of Medicine
Professor in Experimental Molecular Medicine Division of Hematology/Oncology
Division of Thrombosis and Hemostasis David Geffen School of Medicine
Einthoven Laboratory for Experimental Vascular Medicine University of California
Leiden University Medical Center Los Angeles, California
Leiden, The Netherlands
George B. Segel, MD [7, 35]
Andrew R. Rezvani, MD [23] Professor of Pediatrics, Emeritus
Division of Blood and Marrow Transplantation Professor of Medicine
Stanford University University of Rochester Medical Center
Stanford, California Rochester, New York
Katayoun Rezvani, MD [27] Uri Seligsohn, MD [116, 129]

Professor of Medicine Professor of Hematology and Director
Stem Cell Transplantation and Cellular Therapy Amalia Biron Research Institute of Thrombosis and Hemostasis
MD Anderson Cancer Center Sheba Medical Center
Houston, Texas Tel-Hashomer and Sackler Faculty of Medicine
Tel Aviv University
Paul G. Richardson, MD [22] Tel Aviv, Israel
Dana-Farber Cancer Institute Sanford J. Shattil, MD [121]
Harvard Medical School Professor and Chief, Division of Hematology-Oncology
Boston, Massachusetts Department of Medicine
University of California, San Diego
Stanley R. Riddell, MD [26] Adjunct Professor of Molecular and Experimental Medicine
Member, Clinical Research Division The Scripps Research Institute
Fred Hutchinson Cancer Research Center La Jolla, California
Seattle, Washington

Contributors xix
Taimur Sher, MD [108] Perumal Thiagarajan, MD [32, 33]

Division of Hematology/Oncology Professor of Medicine and Pathology
Mayo Clinic Baylor College of Medicine
Jacksonville, Florida Director, Blood Bank and Hematology Laboratory
Michael E. DeBakey VA Medical Center
Brian F. Skinnider, MD [96] Houston, Texas
Clinical Associate Professor
Department of Pathology Jakub Tolar, MD, PhD [30]
Vancouver General Hospital, British Columbia Cancer Agency, and Professor, Department of Pediatrics
University of British Columbia Blood and Marrow Transplantation, Stem Cell Institute
Vancouver, British Columbia, Canada University of Minnesota
Minneapolis, Minnesota
Sherrill J. Slichter, MD [139]
Professor of Medicine Steven P. Treon [109]
Department of Medicine, Division of Hematology Director, Bing Center for Waldenstrom’s Macroglobulinemia
University of Washington School of Medicine Dana-Farber Cancer Institute
Bloodworks Northwest Associate Professor, Harvard Medical School
Seattle, Washington Boston, Massachusetts
C. Wayne Smith, MD [60, 61] Guido Tricot, MD, PhD [105]

Professor and Head, Section of Leukocyte Biology Division of Hematology/Oncology & Blood and Marrow
Department of Pediatrics Transplantation
Baylor College of Medicine Department of Pathology, Carver College of Medicine
Houston, Texas University of Iowa Health Care
Iowa City, Iowa
Stephen D. Smith, MD [98]
Associate Professor, Internal Medicine Division of Medical Oncology Giorgio Trinchieri, MD [77]
University of Washington Director, Cancer and Inflammation Program
Seattle, Washington Chief, Laboratory of Experimental Immunology
Center for Cancer Research, NCI, NIH
Susan S. Smyth, MD, PhD [112] Bethesda, Maryland
Jeff Gill Professor of Cardiology
Chief, Division of Cardiovascular Medicine Wouter W. van Solinge, PhD [47]
Medical Director, Gill Heart Institute Professor of Laboratory Medicine
University of Kentucky Head of Department
Lexington, Kentucky Chair and Medical Director Division Laboratories and Pharmacy
Department of Clinical Chemistry and Haematology
David P. Steensma, MD [87] University Medical Center Utrecht
Department of Medical Oncology Utrecht, The Netherlands
Division of Hematological Malignancies
Dana-Farber Cancer Institute Cornelis van ‘t Veer, PhD [113]
Boston, Massachusetts Associate Professor
Center for Experimental and Molecular Medicine
Sean R. Stowell, MD, PhD [127] Academic Medical Center
Department of Pathology and Laboratory Medicine Amsterdam, The Netherlands
Emory University
Atlanta, Georgia Richard van Wijk, PhD [47]
Associate professor
David Stroncek [137] Department of Clinical Chemistry and Haematology
Department of Transfusion Medicine Division Laboratories and Pharmacy
National Institutes of Health University Medical Center Utrecht
Bethesda, Maryland Utrecht, The Netherlands
Madina Sukhanova, PhD [13] Sumithira Vasu, MBBS [79]

Section of Hematology/Oncology Assistant Professor
Department of Medicine and the Center Research Center Medical Director, Cell Therapy Lab
University of Chicago Blood and Marrow Transplantation Section
Chicago, Illinois Division of Hematology
The Ohio State University
Columbus, Ohio

xx Contributors
John Wagner, MD [30] Karl Welte, MD [65]

Professor, Department of Pediatrics Senior-Professor
Blood and Marrow Transplantation, Stem Cell Institute Department of Pediatrics
University of Minnesota University of Tübingen
Minneapolis, Minnesota Tübingen, Germany
Dietlind L. Wahner-Roedler, MD [110] Erik Wendlandt, PhD [105]

Professor of Medicine Division of Hematology/Oncology & Blood and Marrow
Mayo Clinic Transplantation
Rochester, Minnesota Department of Pathology, Carver College of Medicine
University of Iowa Health Care
Zandra E. Walton [14] Iowa City, Iowa
Abramson Family Cancer Research Institute
Perelman School of Medicine Sidney Whiteheart, PhD [112]
University of Pennsylvania Professor
Philadelphia, Pennsylvania Molecular and Cellular Biochemistry
University of Kentucky College of Medicine
Peter A. Ward, MD [19] Lexington, Kentucky
Godfrey D. Stobbe Professor of Pathology
Department of Pathology Lucia Wolgast, MD [131]
University of Michigan Medical School Assistant Professor of Pathology (Clinical)
Ann Arbor, Michigan Director, Clinical Laboratories, Moses Division
Associate Director, Hematology Laboratories
Andrew J. Wardlaw, MD, PhD [62] Montefiore Medical Center/Albert Einstein College of Medicine
Institute for Lung Health Department of Pathology
Department of Infection Bronx, New York
Immunity and Inflammation
Leicester University Medical School Neal S. Young, MD [36]
Leicester, United Kingdom Hematology Branch
National Heart, Lung, and Blood
Jeffrey S. Warren, MD [19] National Institutes of Health
Aldred S. Warthin Professor of Pathology Bethesda, Maryland
Department of Pathology
University of Michigan Medical School Fenghuang Zhan, MD, PhD [105]
Ann Arbor, Michigan Division of Hematology/Oncology & Blood and Marrow
Transplantation
Lukas D. Wartman, MD [11] Department of Pathology, Carver College of Medicine
Assistant Professor, Section of Stem Cell Biology University of Iowa Health Care
Division of Oncology, Department of Medicine, Washington Iowa City, Iowa
University School of Medicine
Siteman Cancer Center, Washington University School of Medicine Ari Zimran, MD [72]
Assistant Director, Section of Cancer Genomics Gaucher Clinic
The Genome Institute, Washington University School of Medicine Shaare Zedek Medical Center
St. Louis, Missouri Jerusalem, Israel
Sir David J. Weatherall, MD [48] Pier Luigi Zinzani, MD, PhD [101]
Professor Professor
Weatherall Institute of Molecular Medicine Institute of Hematology “L. e A. Seràgnoli”
John Radcliffe Hospital University of Bologna
Headington, Oxford, United Kingdom Bologna, Italy
Robert Weinstein, MD [28]

Professor of Medicine and Pathology
University of Massachusetts Medical School
Chief, Division of Transfusion Medicine
UMass Memorial Medical Center
Worcester, Massachusetts

xxi
xxi
PREFACE
The first edition of Williams Hematology (né Hematology) was published of Williams Hematology also includes PubMed links to journal articles
in 1972. This, our 9th edition, will represent our continued efforts over cited in the references.
nearly one-half century to provide the most current concepts of the In addition, Williams Manual of Hematology will be revised to
pathophysiology and treatment of hematologic diseases. reflect the diagnostic and therapeutic advances incorporated in the
The rate of growth in our understanding of diseases of blood cells 9th edition of Williams Hematology. The convenient Manual features
and coagulation pathways provides a challenge for editors of a com- the most clinically salient content from the parent text, and is useful
prehensive textbook of hematology. The sequencing of individual ge- in time-restricted clinical situations. The Manual will be available for
nomes, analysis of the “dark DNA” and noncoding RNAs, advances in iPhone™ and other mobile formats.
knowledge in proteomics, metabolomics, and other “-omics” fields, as The readers of the 9th edition of Williams Hematology will note a
applied to hematologic disorders, have accelerated the understanding “changing of (some of) the guard” of our editorial group; Drs. Marcel
of the pathogenesis of the diseases of our interest. The rate at which Levi (a member of the 8th edition of Williams Manual of Hematology
basic knowledge in molecular and cellular biology and immunology editorial group), Oliver Press, Linda Burns, and Michael Caligiuri have
has been translated into improved diagnostic and therapeutic methods joined continuing editors Drs. Kenneth Kaushansky, Marshall Licht-
is equally impressive. Specific molecular targets for therapy in several man, and Josef Prchal in the 9th edition.
hematologic disorders have become reality, and it is not hyperbole to The production of this book required the timely cooperation of
state that hematology is the poster child for the rational design of ther- 101 contributors for the production of 139 chapters. We are grateful for
apeutics applicable to other fields of medicine. their work in providing this comprehensive and up-to-date text. Despite
This edition of Williams Hematology includes changes designed to the growth of both basic and clinical knowledge and the passion that
facilitate ease of access to information, both within the book and its as- each of our contributors brings to the topic of their chapter, we have
sociated links, and has been modestly reorganized to reflect our greater been able to maintain the text in a single volume through scrupulous
understanding of the origins of hematologic disorders. Each chapter attention to chapter length.
has been revised or rewritten to provide current information. Four new Each editor has had expert administrative assistance in the man-
chapters have been added and other notable changes have been made. agement of the manuscripts for which they were primarily responsible.
Chapter 4 “Consultative Hematology” is new to this edition. The chap- We thank Susan Madden in Salt Lake City, Utah; Nancy Press and Deb-
ter “Epigenetics and Genomics” has been divided into separate chap- orah Lemon in Seattle, Washington; and Annie Thompson, Rebecca
ters to reflect the growth of knowledge in those disciplines. Chapter 14, Posey, and Kimberly Morley in Columbus, Ohio for their very helpful
“Metabolism of Hematologic Neoplastic Cells” is new, as this topic has participation in the production of the book. Special thanks go to Susan
become the basis of multiple potential drug targets for hematologic dis- Daley in Rochester, New York, and Marie Brito in Stony Brook, New
ease. A section on “Autophagy” has been added to Chap 15 “Apoptosis York, who were responsible for coordinating the management of 139
Mechanisms: Relevance to the Hematopoietic System,” as the topic is chapters, including many new figures and tables, and managing other
becoming increasingly important for understanding of the physiology administrative matters, a challenging task that Ms. Daley and Ms. Brito
of blood cell development; and an independent chapter “Heparin-In- performed with skill and good humor. The editors also acknowledge the
duced Thrombocytopenia” (Chap 118) has been created to reflect both interest and support of our colleagues at McGraw-Hill, including James
its pathophysiologic and clinical importance. Recognizing that at the F. Shanahan, Publisher, Medical Publishing; Karen Edmonson, Senior
heart of diagnostic hematology is blood and marrow cell morphology, Editor for Williams Hematology; and Harriet Lebowitz, Senior Project
we have continued our incorporation of informative color images of the Development Editor for Williams Hematology.
relevant disease topics in each chapter, allowing easy access to illustra-
tions of cell morphology important to diagnosis. Kenneth Kaushansky
The 9th edition of Williams Hematology is also available online, Marshall A. Lichtman
as part of the excellent www.accessmedicine.com website. With direct Joseph T. Prchal
links to a comprehensive drug therapy database and to other impor- Marcel Levi
tant medical texts, including Harrison’s Principles of Internal Medicine Oliver W. Press
and Goodman and Gilman’s The Pharmacological Basis of Therapeutics, Linda J. Burns
Williams Hematology Online is part of a powerful resource covering all Michael A. Caligiuri
disciplines within medical education and practice. The online edition

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Part I Clinical Evaluation of the
Patient
1. Initial Approach to the Patient: History and 3. Examination of the Marrow . . . . . . . . . . . . . 27
Physical Examination . . . . . . . . . . . . . . . . . . . 3 4. Consultative Hematology . . . . . . . . . . . . . . . 41
2. Examination of Blood Cells . . . . . . . . . . . . . . 11
Kaushansky_chapter 01_p0001-0010.indd 1 17/09/15 5:32 pm

3
CHAPTER 1 In each discussion of specific diseases in subsequent chapters, the signs
INITIAL APPROACH TO THE and symptoms that accompany the particular disorder are presented, and the
clinical findings are covered in detail. In this chapter, a more general system-
atic approach is taken.
PATIENT: HISTORY AND
PHYSICAL EXAMINATION THE HEMATOLOGY CONSULTATION
Table 1–1 lists the major abnormalities that result in the evaluation of
Marshall A. Lichtman and Linda J. Burns the patient by the hematologist. The signs indicated in Table 1–1 may
reflect a primary or secondary hematologic problem. For example,
immature granulocytes in the blood may be signs of myeloid diseases
SUMMARY such as myelogenous leukemia, or, depending on the frequency of these
cells and the level of immaturity, the dislodgment of cells resulting from
The care of a patient with a suspected hematologic abnormality begins with marrow metastases of a carcinoma. Nucleated red cells in the blood
a systematic attempt to determine the nature of the illness by eliciting an may reflect the breakdown in the marrow–blood interface seen in pri-
in-depth medical history and performing a thorough physical examination. mary myelofibrosis or the hypoxia of congestive heart failure. Certain
The physician should identify the patient’s symptoms systematically and obtain disorders have a propensity for secondary hematologic abnormalities;
as much relevant information as possible about their origin and evolution and renal, liver, and connective tissue diseases are prominent among such
abnormalities. Chronic alcoholism, nutritional fetishes, and the use of
about the general health of the patient by appropriate questions designed
certain medications may be causal factors in blood cell or coagulation
to explore the patient’s recent and remote experience. Reviewing previous protein disorders. Pregnant women and persons of older age are prone
records may add important data for understanding the onset or progression to certain hematologic disorders: anemia, thrombocytopenia, or intra-
of illness. Hereditary and environmental factors should be carefully sought and vascular coagulation in the former case, and hematologic malignancies,
evaluated. The use of drugs and medications, nutritional patterns, and sexual pernicious anemia and the anemia of aging in the latter. The history and
behavior should be considered. The physician follows the medical history with physical examination can provide vital clues to the possible diagnosis
a physical examination to obtain evidence for tissue and organ abnormalities and also to the rationale choice of laboratory tests.
that can be assessed through bedside observation to permit a careful search
for signs of the illnesses suggested by the history. Skin changes and hepatic,
splenic, or lymph nodal enlargement are a few findings that may be of consid-
THE HISTORY
erable help in pointing toward a diagnosis. Additional history is obtained dur- In today’s technology- and procedure-driven medical environment, the
ing the physical examination, as findings suggest an additional or alternative importance of carefully gathering information from patient inquiry and
consideration. Thus, the history and physical examination should be considered examination is at risk of losing its primacy. The history (and physical
as a unit, providing the basic information with which further diagnostic infor- examination) remains the vital starting point for the evaluation of any
mation is integrated: blood and marrow studies, imaging studies, and biopsies. clinical problem.1–3
Primary hematologic diseases are common in the aggregate, but hemato-
logic manifestations secondary to other diseases occur even more frequently. GENERAL SYMPTOMS AND SIGNS
For example, the signs and symptoms of anemia and the presence of enlarged Performance status (PS) is used to establish semiquantitatively the extent
lymph nodes are common clinical findings that may be related to a hemato- of a patient’s disability. This status is important in evaluating patient
logic disease but occur frequently as secondary manifestations of disorders comparability in clinical trials, in determining the likely tolerance to
not considered primarily hematologic. A wide variety of diseases may produce cytotoxic therapy, and in evaluating the effects of therapy. Table 1–2
signs or symptoms of hematologic illness. Thus, in patients with a connective presents a well-founded set of criteria for measuring PS.4 An abbrevi-
ated version sometimes is used, as proposed by the Eastern Cooperative
tissue disease, all the signs and symptoms of anemia may be elicited and
Oncology Group (Table 1–3).5
lymphadenopathy may be notable, but additional findings are usually present
Weight loss is a frequent accompaniment of many serious diseases,
that indicate primary involvement of some system besides the hematopoietic including primary hematologic malignancies, but it is not a prominent
(marrow) or lymphopoietic (lymph nodes or other lymphatic sites). In this dis- accompaniment of most hematologic diseases. Many “wasting” dis-
cussion, emphasis is placed on the clinical findings resulting from either pri- eases, such as disseminated carcinoma and tuberculosis, cause anemia,
mary hematologic disease or the complications of hematologic disorders so as and pronounced emaciation should suggest one of these diseases rather
to avoid presenting an extensive catalog of signs and symptoms encountered than anemia as the primary disorder.
in general clinical medicine. Fever is a common early manifestation of the aggressive lympho-
mas or acute leukemias as a result of pyrogenic cytokines (e.g., interleu-
kin [IL]-1, IL-6, and IL-8) released as a reflection of the disease itself.
After chemotherapy-induced cytopenias or in the face of accompanying
immunodeficiency, infection is usually the cause of fever. In patients
Acronyms and Abbreviations: Ig, immunoglobulin; IL, interleukin; POEMS, with “fever of unknown origin,” lymphoma, particularly Hodgkin lym-
polyneuropathy, organomegaly, endocrinopathy, monoclonal gammopathy, and skin phoma, should be considered. Occasionally, primary myelofibrosis,
changes; PS, performance status. acute leukemia, advanced myelodysplastic syndrome, and other lym-
phomas may also cause fever. In rare patients with severe pernicious

4 Part I: Clinical Evaluation of the Patient
TABLE 1–1. Findings That May Lead to a Hematology TABLE 1–3. Eastern Cooperative Oncology Group
Consultation Performance Status5
Decreased hemoglobin concentration (anemia) Grade Activity
Increased hemoglobin concentration (polycythemia) 0 Fully active, able to carry on all predisease perfor-
Elevated serum ferritin level mance without restriction
Leukopenia or neutropenia 1 Restricted in physically strenuous activity but ambula-
Immature granulocytes or nucleated red cells in the blood tory and able to carry out work of a light or sedentary
Pancytopenia nature, e.g., light housework, office work
Granulocytosis: neutrophilia, eosinophilia, basophilia, or 2 Ambulatory and capable of all self-care but unable to
mastocytosis carry out any work activities; up and about more than
Monocytosis 50% of waking hours
Lymphocytosis 3 Capable of only limited self-care, confined to bed or
Lymphadenopathy chair more than 50% of waking hours
Splenomegaly 4 Completely disabled; cannot carry on any self-care;
totally confined to bed or chair
Hypergammaglobulinemia: monoclonal or polyclonal
Purpura 5 Dead
Thrombocytopenia Oken MM, Creech RH, Tormey DC, et al: Toxicity and response criteria
Thrombocytosis of the Eastern Cooperative Oncology Group. Am J Clin Oncol.
Exaggerated bleeding: spontaneous or trauma related
Prolonged partial thromboplastin or prothrombin coagulation times anemia or hemolytic anemia, fever may be present. Chills may accom-
Venous thromboembolism pany severe hemolytic processes and the bacteremia that may compli-
Thrombophilia cate the immunocompromised or neutropenic patient. Night sweats
Obstetrical adverse events (e.g., recurrent fetal loss, stillbirth, and suggest the presence of low-grade fever and may occur in patients with
HELLP syndrome) lymphoma or leukemia.
Fatigue, malaise, and lassitude are such common accompaniments
HELLP, hemolytic anemia, elevated liver enzymes, and low platelet of both physical and emotional disorders that their evaluation is complex
count. and often difficult. In patients with serious disease, these symptoms may
be readily explained by fever, muscle wasting, or other associated findings.
TABLE 1–2. Criteria of Performance Status (Karnofsky Patients with moderate or severe anemia frequently complain of fatigue,
Scale)4 malaise, or lassitude and these symptoms may accompany the hematologic
Able to carry on normal activity; no special care is needed. malignancies. Fatigue or lassitude may occur also with iron deficiency
even in the absence of sufficient anemia to account for the symptom.
100% Normal; no complaints, no evidence of disease In slowly developing chronic anemias, the patient may not recognize
90% Able to carry on normal activity; minor signs or reduced exercise tolerance, or other loss of physical capabilities except in
symptoms of disease retrospect, after a remission or a cure has been induced by appropriate
80% Normal activity with effort; some signs or therapy. Anemia may be responsible for more symptoms than has been
symptoms of disease traditionally recognized, as suggested by the remarkable improvement in
Unable to work; able to live at home, care for most personal quality of life of most uremic patients treated with erythropoietin.
needs; a varying amount of assistance is needed. Weakness may accompany anemia or the wasting of malignant
70% Cares for self; unable to carry on normal activity processes, in which cases it is manifest as a general loss of strength or
or to do active work reduced capacity for exercise. The weakness may be localized as a result
60% Requires occasional assistance but is able to care of neurologic complications of hematologic disease. In vitamin B12 defi-
for most personal needs ciency (e.g., pernicious anemia), there may be weakness of the lower
50% Requires considerable assistance and frequent extremities, accompanied by numbness, tingling, and unsteadiness of
medical care gait. Peripheral neuropathy also occurs with monoclonal immunoglob-
Unable to care for self; requires equivalent of institutional or ulinemias. Weakness of one or more extremities in patients with leuke-
hospital care; disease may be progressing rapidly. mia, myeloma, or lymphoma may signify central or peripheral nervous
40% Disabled; requires special care and assistance system invasion or compression as a result of vertebral collapse, a para-
neoplastic syndrome (e.g., encephalitis), or brain or meningeal involve-
30% Severely disabled; hospitalization is indicated
ment. Myopathy secondary to malignancy occurs with the hematologic
though death not imminent
malignancies and is usually manifest as weakness of proximal muscle
20% Very sick; hospitalization necessary; active groups. Foot drop or wrist drop may occur in lead poisoning, amyloi-
supportive treatment necessary
dosis, systemic autoimmune diseases, or as a complication of vincristine
10% Moribund; fatal processes progressing rapidly therapy. Paralysis may occur in acute intermittent porphyria.
0% Dead
SPECIFIC SYMPTOMS OR SIGNS
Adapted with permission from Mor V, Laliberte L, Morris JN, Wiemann
M: The Karnofsky performance status scale: An examination of Nervous System
its reliability and validity in a research setting Cancer 1984 May 1; Headache may be the result of a number of causes related to hematologic
53(9):2002–2007. diseases. Anemia or polycythemia may cause mild to severe headache.

Chapter 1: Initial Approach to the Patient: History and Physical Examination 5
Invasion or compression of the brain by leukemia or lymphoma, or lymph nodes of lymphomas may be tender or painful because of sec-
opportunistic infection of the central nervous system by Cryptococcus ondary infection or rapid growth. Painful or tender lymphadenopathy
or Mycobacterium species, may also cause headache in patients with is usually associated with inflammatory reactions, such as infectious
hematologic malignancies. Hemorrhage into the brain or subarachnoid mononucleosis or suppurative adenitis. Diffuse swelling of the neck and
space in patients with thrombocytopenia or other bleeding disorders face may occur with obstruction of the superior vena cava due to lym-
may cause sudden, severe headache. phomatous compression.
Paresthesias may occur because of peripheral neuropathy in perni-
cious anemia or secondary to hematologic malignancy or amyloidosis. Chest and Heart
They may also result from therapy with vincristine. Both dyspnea and palpitations, usually on effort but occasionally at
Confusion may accompany malignant or infectious processes rest, may occur because of anemia or pulmonary embolism. Congestive
involving the brain, sometimes as a result of the accompanying fever. heart failure may supervene, and angina pectoris may become manifest
Confusion may also occur with severe anemia, hypercalcemia (e.g., in anemic patients. The impact of anemia on the circulatory system
myeloma), thrombotic thrombocytopenic purpura, or high-dose glu- depends in part on the rapidity with which it develops, and chronic
cocorticoid therapy. Confusion or apparent senility may be a mani- anemia may become severe without producing major symptoms; with
festation of pernicious anemia. Frank psychosis may develop in acute severe acute blood loss, the patient may develop shock with a nearly
intermittent porphyria or with high-dose glucocorticoid therapy. normal hemoglobin level, prior to compensatory hemodilution. Cough
Impairment of consciousness may be a result of increased intracra- may result from enlarged mediastinal nodes compressing the trachea
nial pressure secondary to hemorrhage or leukemia or lymphoma in or bronchi. Chest pain may arise from involvement of the ribs or ster-
the central nervous system. It may also accompany severe anemia, poly- num with lymphoma or multiple myeloma, nerve-root invasion or com-
cythemia, hyperviscosity secondary, usually, to an immunoglobulin (Ig) pression, or herpes zoster; the pain of herpes zoster usually precedes
M monoclonal protein (uncommonly IgA or IgG) in the plasma, or a the skin lesions by several days. Chest pain with inspiration suggests a
leukemic hyperleukocytosis syndrome, especially in chronic myeloge- pulmonary infarct, as does hemoptysis. Tenderness of the sternum may
nous leukemia. be quite pronounced in chronic myelogenous or acute leukemia, and
occasionally in primary myelofibrosis, or if intramedullary lymphoma
Eyes or myeloma proliferation is rapidly progressive.
Conjunctival plethora is a feature of polycythemia and pallor a result of
anemia. Occasionally blindness may result from retinal hemorrhages Gastrointestinal System
secondary to severe anemia and thrombocytopenia or blurred vision Dysphagia has already been mentioned under “Nasopharynx, Orophar-
resulting from severe hyperviscosity resulting from macroglobulinemia ynx, and Oral Cavity” above. Anorexia frequently occurs but usually has
or extreme hyperleukocytosis of leukemia. Partial or complete visual no specific diagnostic significance. Hypercalcemia and azotemia cause
loss can stem from retinal vein or artery thrombosis. Diplopia or distur- anorexia, nausea, and vomiting. A variety of ill-defined gastrointestinal
bances of ocular movement may occur with orbital tumors or paralysis complaints grouped under the heading “indigestion” may occur with
of the third, fourth, or sixth cranial nerves because of compression by hematologic diseases. Abdominal fullness, premature satiety, belching,
tumor, especially extranodal lymphoma, extramedullary myeloma, or or discomfort may occur because of a greatly enlarged spleen, but such
myeloid (granulocytic) sarcoma. splenomegaly may also be entirely asymptomatic. Abdominal pain may
arise from intestinal obstruction by lymphoma, retroperitoneal bleed-
Ears ing, lead poisoning, ileus secondary to therapy with the vinca alkaloids,
Vertigo, tinnitus, and “roaring” in the ears may occur with marked
acute hemolysis, allergic purpura, the abdominal crises of sickle cell dis-
anemia, polycythemia, hyperleukocytic leukemia, or macroglobuline-
ease, or acute intermittent porphyria. Diarrhea may occur in pernicious
mia-induced hyperviscosity. Ménière disease was first described in a
anemia. It also may be prominent in the various forms of intestinal
patient with acute leukemia and inner ear hemorrhage.
malabsorption, although significant malabsorption may occur without
Nasopharynx, Oropharynx, and Oral Cavity diarrhea. In small-bowel malabsorption, steatorrhea may be a notable
Epistaxis may occur in patients with thrombocytopenia, acquired or feature. Malabsorption may be a manifestation of small-bowel lym-
inherited platelet function disorders, and von Willebrand disease. phoma. Gastrointestinal bleeding related to thrombocytopenia or other
Anosmia or olfactory hallucinations occur in pernicious anemia. The bleeding disorder may be occult but often is manifest as hematemesis
nasopharynx may be invaded by a granulocytic sarcoma or extranodal or melena. Hematochezia can occur if a bleeding disorder is associated
lymphoma; the symptoms are dependent on the structures invaded. The with a colonic lesion. Constipation may occur in the patient with hyper-
paranasal sinuses may be involved by opportunistic organisms, such as calcemia or in one receiving treatment with the vinca alkaloids.
fungus in patients with severe, prolonged neutropenia. Pain or tingling
in the tongue occurs in pernicious anemia and may accompany severe Genitourinary and Reproductive Systems
iron deficiency or vitamin deficiencies. Macroglossia occurs in amyloi- Impotence or bladder dysfunction may occur with spinal cord or periph-
dosis. Bleeding gums may occur with bleeding disorders. Infiltration of eral nerve damage caused by one of the hematologic malignancies or
the gingiva with leukemic cells occurs notably in acute monocytic leu- with pernicious anemia. Priapism may occur in hyperleukocytic leu-
kemia. Ulceration of the tongue or oral mucosa may be severe in the kemia, essential thrombocythemia, or sickle cell disease. Hematuria
acute leukemias or in patients with severe neutropenia. Dryness of the may be a manifestation of hemophilia A or B. Red urine may also occur
mouth may be caused by hypercalcemia, secondary, for example, to with intravascular hemolysis (hemoglobinuria), myoglobinuria, or
myeloma. Dysphagia may be seen in patients with severe mucous mem- porphyrinuria. Injection of anthracycline drugs or ingestion of drugs
brane atrophy associated with chronic iron-deficiency anemia. such as phenazopyridine (Pyridium) regularly causes the urine to turn
red. The use of deferoxamine mesylate (Desferal) may result in rust col-
Neck ored urine. Amenorrhea may also be induced by certain drugs, such as
Painless swelling in the neck is characteristic of lymphoma but may be antimetabolites or alkylating agents. Menorrhagia is a common cause
caused by a number of other diseases as well. Occasionally, the enlarged of iron deficiency, and care must be taken to obtain a history of the

number of prior pregnancies and an accurate assessment of the extent with methemoglobinemia, either hereditary or acquired; sulfhemoglo-
of menstrual blood loss. Semiquantification can be obtained from esti- binemia; abnormal hemoglobins with low oxygen affinity; and primary
mates of the number of days of heavy bleeding (usually <3), the num- and secondary polycythemia. Cyanosis of the ears or the fingertips may
ber of days of any bleeding (usually <7), number of tampons or pads occur after exposure to cold in individuals with cryoglobulins or cold
used (requirement for double pads suggests excessive bleeding), degree agglutinins.
of blood soaking, and clots formed, and inquiries such as, “Have you Itching may occur in the absence of any visible skin lesions in
experienced a gush of blood when a tampon is removed?” However, an Hodgkin lymphoma and may be extreme. Mycosis fungoides or other
objective distinction between menorrhagia (loss of more than 80 mL lymphomas with skin involvement may also present as itching. A sig-
blood per period) and normal blood loss can best be made by a visual nificant number of patients with polycythemia vera will complain of
assessment technique using pictorial charts of towels or tampons.6 Men- itching after bathing.
orrhagia may occur in patients with bleeding disorders. Petechiae and ecchymoses are most often seen in the extremities in
patients with thrombocytopenia, nonthrombocytopenic purpura, or
Back and Extremities acquired or inherited platelet function abnormalities and von Wille-
Back pain may accompany acute hemolytic reactions or be a result brand disease. Unless secondary to trauma, these lesions usually are
of involvement of bone or the nervous system in acute leukemia or painless; the lesions of psychogenic purpura and erythema nodosum are
aggressive lymphoma. It is one of the most common manifestations of painful. Easy bruising is a common complaint, especially among women,
myeloma. and when no other hemorrhagic symptoms are present, usually no
Arthritis or arthralgia may occur with gout secondary to increased abnormalities are found after detailed study. This symptom may, how-
uric acid production in patients with hematologic malignancies, espe- ever, indicate a mild hereditary bleeding disorder, such as von Wille-
cially acute lymphocytic leukemia in childhood, myelofibrosis, myel- brand disease or one of the platelet disorders. Infiltrative lesions may
odysplastic syndrome, and hemolytic anemia. They also occur in the occur in the leukemias (leukemia cutis) and lymphomas (lymphoma
plasma cell dyscrasias, acute leukemias, and sickle cell disease without cutis) and are sometimes the presenting complaint. Monocytic leukemia
evidence of gout, and in allergic purpura. Arthritis may accompany has a higher frequency of skin infiltration than other forms of leukemia.
hemochromatosis, although the association has not been carefully Necrotic lesions may occur with intravascular coagulation, purpura ful-
established. In the latter case the arthritis starts typically in the small minans, and warfarin-induced skin necrosis, or rarely with exposure to
joints of the hand (second and third metacarpal joints), and episodes cold in patients with circulating cryoproteins or cold agglutinins.
of acute synovitis may be related to deposition of calcium pyrophos- Leg ulcers are a common complaint in sickle cell anemia and occur
phate dehydrate crystals. Hemarthroses in patients with severe bleeding rarely in other hereditary anemias.
disorders cause marked joint pain. Autoimmune diseases may present
as anemia and/or thrombocytopenia, and arthritis appears as a later
manifestation. Shoulder pain on the left may be a result of infarction DRUGS AND CHEMICALS
of the spleen and on the right of gall bladder disease associated with Drugs
chronic hemolytic anemia such as hereditary spherocytosis. Bone pain Drug therapy, either self-prescribed or ordered by a physician, is
may occur with bone involvement by the hematologic malignancies; extremely common in our society. Drugs often induce or aggravate
it is common in the congenital hemolytic anemias, such as sickle cell hematologic disease, and it is therefore essential that a careful history
anemia, and may occur in myelofibrosis. In patients with Hodgkin lym- of drug ingestion, including beneficial and adverse reactions, should
phoma, ingestion of alcohol may induce pain at the site of any lesion, be obtained from all patients. Drugs taken regularly, including nonpre-
including those in bone. Edema of the lower extremities, sometimes scription medications, often become a part of the patient’s way of life
unilateral, may occur because of obstruction to veins or lymphatics by and are forgotten or are not recognized as “drugs.”
lymphomatous masses or from deep venous thrombosis. The latter can Agents such as aspirin, laxatives, tranquilizers, medicinal iron,
also cause edema of the upper extremities. vitamins, other nutritional supplements, and sedatives belong to this
category. Furthermore, drugs may be ingested in unrecognized form,
Skin such as antibiotics in food or quinine in tonic water. Specific, persis-
Skin manifestations of hematologic disease may be of great importance; tent questioning, often on several occasions, may be necessary before a
they include changes in texture or color, itching, and the presence of complete history of drug use is obtained. It is very important to obtain
specific or nonspecific lesions. The skin in iron-deficient patients may detailed information on alcohol consumption from every patient. The
become dry, the hair dry and fine, and the nails brittle. In hypothy- four “CAGE” questions—about needing to cut down, being annoyed
roidism, which may cause anemia, the skin is dry, coarse, and scaly. by criticism, having guilt feelings, and requiring a drink as a morning
Jaundice may be apparent with pernicious anemia or congenital or eye-opener—provide an effective approach to the history of alcohol use.
acquired hemolytic anemia. The skin of patients with pernicious anemia Patients should also be asked about the use of recreational drugs. The
is said to be “lemon yellow” because of the simultaneous appearance of use of “alternative medicines” and herbal medicines is common, and
jaundice and pallor. Jaundice may also occur in patients with hemato- many patients will not consider these medications or may actively with-
logic malignancies, especially lymphomas, as a result of liver involve- hold information about their use. Nonjudgmental questioning may be
ment or biliary tract obstruction. Pallor is a common accompaniment successful in identifying agents in this category that the patient is tak-
of anemia, although some severely anemic patients may not appear pale. ing. Some patients equate the term “drugs,” as opposed to “medicines,”
Erythromelalgia may be a troublesome complication of polycythemia with illicit drugs. Establishing that the examiner is interested in all
vera. Patchy plaques or widespread erythroderma occur in cutaneous forms of ingestants—prescribed drugs, self-remedies, alternative reme-
T-cell lymphoma (especially Sézary syndrome) and in some cases of dies, etcetera—is important to ensure getting the information required.
chronic lymphocytic leukemia or lymphocytic lymphoma. The skin is
often involved, sometimes severely, in graft-versus-host disease follow- Chemicals
ing hematopoietic cell transplantation. Patients with hemochromatosis In addition to drugs, most people are exposed regularly to a variety of
may have bronze or grayish pigmentation of the skin. Cyanosis occurs chemicals in the environment, some of which may be potentially harmful

agents and result in a deleterious hematologic effect, such as anemia or manifest. Prophylactic therapy, as for example in avoiding venous sta-
leukopenia. An occupational history should explore exposure to poten- sis in patients heterozygous for protein C deficiency or administering
tially harmful chemicals. This information should be supplemented prophylactic heparin at the time of major surgery, is a more immediate
by inquiries about hobbies and other interests that result in work with aspect of prevention because it depends on the physician’s intervention.
chemicals, such as glues and solvents. When a toxin is suspected, the Hematologists may also prevent disease by reinforcing community
patient’s daily activities and environment should be carefully reviewed, medicine efforts. Examples include fostering the elimination of sources
as significant exposure to toxic chemicals may occur incidentally. of environmental lead that may result in childhood anemia. Prenatal
diagnosis can provide information to families as to whether a fetus is
VACCINATION affected with a hematologic disorder.
Vaccinations can be complicated by acute immune thrombocytopenia.
In infants, this is most notable after measles, mumps, rubella (MMR) PHYSICAL EXAMINATION
vaccine. This occurrence is approximately 1 in 25,000 children vac-
cinated, occurs within 6 weeks of vaccination, and in the majority of A detailed physical examination should be performed on every patient,
occurrences is self-limited. There is no evidence that children with with sufficient attention paid to all systems so as to obtain a full evalua-
antecedent immune thrombocytopenia are at risk of recurrence after tion of the general health of the individual. The skin, eyes, tongue, lymph
MMR vaccination.7 Analysis, thus far, shows rare cases in following nodes, skeleton, spleen and liver, and nervous system are especially per-
administration of other vaccines (hepatitis A, diphtheria-pertussis- tinent to hematologic disease and therefore deserve special attention.
tetanus, or varicella) administered to older children and adolescents
and significant risk has not been ascertained.8 SKIN
Pallor and Flushing
NUTRITION The color of the skin is a result of the pigment contained therein and to
Children who are breastfed without iron supplementation may develop the blood flowing through the skin capillaries. The component of skin
iron-deficiency anemia. Nutritional information can be useful in deduc- color related to the blood may be a useful guide to anemia or polycythe-
ing the possible role of dietary deficiency in anemia. The avoidance of cer- mia, as pallor may result when the hemoglobin level is reduced, and
tain food groups, as might be the case with vegetarians, or the ingestion of redness when the hemoglobin level is increased. The amount of pig-
uncooked fish can be clues to the pathogenesis of megaloblastic anemia. ment in the skin modifies skin color and can mislead the clinician, as in
individuals with pallor resulting from decreased pigment, or make skin
FAMILY HISTORY color useless as a guide because of the intense pigmentation present.
Alterations in blood flow and in hemoglobin content may change
A carefully obtained family history may be of great importance in the skin color; this, too, can mislead the clinician. Thus emotion may cause
study of patients with hematologic disease (Chap. 10). In the case of either pallor or blushing. Exposure of the skin to cold or heat may sim-
hemolytic disorders, questions should be asked regarding jaundice, ane- ilarly cause pallor or blushing. Chronic exposure to wind or sun may
mia, and gallstones in relatives. In patients with disorders of hemostasis lead to permanent redness of the skin, and chronic ingestion of alcohol
or venous thrombosis, particular attention must be given to bleeding to a flushed face. The degree of erythema of the skin can be evaluated by
manifestations or venous thromboembolism in family members. In the pressing the thumb firmly against the skin, as on the forehead, so that the
case of autosomal recessive disorders such as pyruvate kinase deficiency, capillaries are emptied, and then comparing the color of the compressed
the parents are usually not affected, but a similar clinical syndrome may spot with the surrounding skin immediately after the thumb is removed.
have occurred in siblings. It is particularly important to inquire about The mucous membranes and nail beds are usually more reliable
siblings who may have died in infancy, as these may be forgotten, espe- guides to anemia or polycythemia than the skin. The conjunctivae and
cially by older patients. When sex-linked inheritance is suspected, it is gums may be inflamed, however, and therefore not reflect the hemoglo-
necessary to inquire about symptoms in the maternal grandfather, mater- bin level, or the gums may appear pale because of pressure from the lips.
nal uncles, male siblings, and nephews. In patients with disorders with The gums and the nail beds may also be pigmented and the capillaries
dominant inheritance, such as hereditary spherocytosis, one may expect correspondingly obscured. In some individuals, the color of the capil-
to find that one parent and possibly siblings and children of the patient laries does not become fully visible through the nails unless pressure is
have stigmata of the disease. Ethnic background may be important in the applied to the fingertip, either laterally or on the end of the nail.
consideration of certain diseases such as α- and β-thalassemia, sickle cell The palmar creases are useful guides to the hemoglobin level and
anemia, glucose-6-phosphate dehydrogenase deficiency, hemoglobin E, appear pink in the fully opened hand unless the hemoglobin is 7 g/dL
and other inherited disorders that are prevalent in specific geographic or less. Liver disease may induce flushing of the thenar and hypothenar
areas, such as the Mediterranean basin or Southeast Asia. eminences of the palm, even in patients with anemia.
SEXUAL HISTORY Cyanosis

Because of the frequency of infections with the human immunodefi- The detection of cyanosis, like the detection of pallor, may be made dif-
ciency viruses, it is important to ascertain the sexual behavior of the ficult by skin pigmentation. Cyanosis is a function of the total amount of
patient, especially risk factors for transmission of HIV. reduced hemoglobin, methemoglobin, or sulfhemoglobin present. The
minimum amounts of these pigments that cause detectable cyanosis are
approximately 5 g/dL blood of reduced hemoglobin, 1.5 to 2.0 g/dL of
PREVENTIVE HEMATOLOGY methemoglobin, and 0.5 g/dL of sulfhemoglobin.
Ideally, the physician’s goal is to prevent illness, and opportunities exist
for hematologists to prevent the development of hematologic disor- Jaundice
ders. These opportunities include identification of individual genetic Jaundice may be observed in the skin of individuals who are not oth-
risk factors and avoidance of situations that may make a latent disorder erwise deeply pigmented or in the sclerae or the mucous membranes.

The patient should be examined in daylight rather than under incan- papillary atrophy, presumably on a mechanical basis. The tongue may
descent or fluorescent light, because the yellow color of the latter masks be smooth and red in patients with nutritional deficiencies. This may be
the yellow color of the patient. Jaundice is a result of actual staining accompanied by fissuring at the corners of the mouth, but fissuring may
of the skin by bile pigment, and bilirubin glucuronide (direct-reacting also be caused by ill-fitting dentures. An enlarged tongue, abnormally
or conjugated bilirubin) stains the skin more readily than the unconju- firm to palpation, may indicate the presence of primary amyloidosis.
gated form. Jaundice of the skin may not be visible if the bilirubin level
is below 2 to 3 mg/dL. Yellow pigmentation of the skin may also occur Lymph Nodes
with carotenemia, especially in young children. Lymph nodes are widely distributed in the body, and in disease, any
node or group of nodes may be involved. The major concern on physical
Petechiae and Ecchymoses examination is the detection of enlarged or tender nodes in the cervical,
Petechiae are small (1 to 2 mm), round, red or brown lesions resulting supraclavicular, axillary, epitrochlear, inguinal, or iliofemoral regions.
from hemorrhage into the skin and are present primarily in areas with Under normal conditions in adults, the only readily palpable lymph
high venous pressure, such as the lower extremities. These lesions do not nodes are in the inguinal region, where several firm nodes 0.5 to 2.0
blanch on pressure, and this can be readily demonstrated by compress- cm long are normally attached to the dense fascia below the inguinal
ing the skin with a glass microscope slide or magnifying lens. Petechiae ligament and in the femoral triangle. In children, multiple small (0.5 to
may occasionally be elevated slightly, that is, palpable; this finding sug- 1.0 cm) nodes may be palpated in the cervical region as well. Supraclavi-
gests vasculitis. Ecchymoses may be of various sizes and shapes and may cular nodes may sometimes be palpable only when the patient performs
be red, purple, blue, or yellowish green, depending on the intensity of the Valsalva maneuver.
the skin hemorrhage and its age. They may be flat or elevated; some are Enlarged lymph nodes are ordinarily detected in the superficial
painful and tender. The lesions of hereditary hemorrhagic telangiectasia areas by palpation, although they are sometimes large enough to be
are small, flat, nonpulsatile, and violaceous. They blanch with pressure. seen. Palpation should be gentle and is best performed with a circu-
lar motion of the fingertips, using slowly increasing pressure. Tender
Excoriation lymph nodes usually indicate an inflammatory etiology, although rap-
Itching may be intense in some hematologic disorders, such as Hodg- idly proliferative lymphoma may be tender to palpation.
kin lymphoma, even in the absence of skin lesions. Excoriation of the Nodes too deep to palpate may be detected by specific imaging
skin from scratching is the only physical manifestation of this severe procedures, including computerized tomography, magnetic resonance
symptom. imaging, ultrasound studies, gallium scintography, and positron emis-
sion tomography.9,10
Leg Ulcers
Open ulcers or scars from healed ulcers are often found in the region of Chest
the internal or external malleoli in patients with sickle cell anemia, and, Increased rib or sternal tenderness is an important physical sign often
rarely, in other hereditary anemias. ignored. Increased bone pain may be generalized, as in leukemia, or
spotty, as in plasma cell myeloma or in metastatic tumors. The super-
Nails ficial surfaces of all bones should be examined thoroughly by applying
Detection of pallor or rubor by examining the nails was discussed ear- intermittent firm pressure with the fingertips to locate potential areas
lier. The fingernails in chronic, severe iron-deficiency anemia may be of disease.
ridged longitudinally and flattened or concave rather than convex. The
latter change is referred to as koilonychia and is uncommon in present Spleen
practice. The normal adult spleen is usually not palpable on physical examina-
tion, but occasionally the tip may be felt.11 Palpability of the normal
Eyes spleen may be related to body habitus, but there is disagreement on this
Jaundice, pallor, or plethora may be detected from examination of the point. Percussion, palpation, or a combination of these two methods
eyes. Jaundice is usually more readily detected in the sclerae than in may detect enlarged spleens.12 Some enlarged spleens may be visible by
the skin. Ophthalmoscopic examination is also essential in patients protrusion of the abdominal wall.
with hematologic disease. Retinal hemorrhages and exudates occur in The normal spleen weighs approximately 150 g and lies in the peri-
patients with severe anemia and thrombocytopenia. These hemorrhages toneal cavity against the diaphragm and the posterolateral abdominal
are usually the typical “flame-shaped” hemorrhages, but they may be wall at the level of the lower three ribs. As it enlarges it remains close to
quite large and elevate the retina so that they may appear as a darkly the abdominal wall, while the lower pole moves downward, anteriorly,
colored tumor. Round hemorrhages with white centers are also often and to the right. Spleens enlarged only 40 percent above normal may be
seen. Dilatation of the veins may be seen in polycythemia; in patients palpable, but significant splenic enlargement may occur and the organ
with macroglobulinemia, the veins are engorged and segmented, resem- still not be felt on physical examination. A good but imperfect correla-
bling link sausages. tion has been reported between spleen size estimated from radioisotope
scanning or ultrasonography and spleen weight determined after sple-
Mouth nectomy or at autopsy.13 Although it is common to fail to palpate an
Pallor of the mucosa has already been discussed (see “Pallor and Flush- enlarged spleen on physical examination, palpation of a normal-sized
ing” above). Ulceration of the oral mucosa occurs commonly in neutro- spleen is unusual, and therefore a palpable spleen is usually a significant
penic patients. In leukemia there may also be infiltration of the gums physical finding.
with swelling, redness, and bleeding. Bleeding from the mucosa may An enlarged spleen lies just beneath the abdominal wall and can be
occur with a hemorrhagic disease. A dark line of lead sulfide may be identified by its movement during respiration. The splenic notch may
deposited in the gums at the base of the teeth in lead poisoning. The be evident if the organ is moderately enlarged. During the examination
tongue may be completely smooth in pernicious anemia and iron- the patient lies in a relaxed, supine position. The examiner, standing
deficiency anemia. Patients with an upper dental prosthesis may also have on the patient’s right, lightly palpates the left upper abdomen with the

right hand while exerting pressure forward with the palm of the left and motor neuropathies. Polyneuropathy is a feature of POEMS, a
hand placed over the lower ribs posterolaterally. This action permits the syndrome marked by polyneuropathy, organomegaly, endocrinopathy,
spleen to descend and be felt by the examiner’s fingers. If nothing is monoclonal gammopathy, and skin changes.
felt, the palpation should be performed repeatedly, moving the examin-
ing hand approximately 2 cm toward the inguinal ligament each time. Joints
It is often advantageous to carry out the examination initially with the Deformities of the knees, elbows, ankles, shoulders, wrists, or hips may
patient lying on the right side with left knee flexed and to repeat it with be the result of repeated hemorrhage in patients with hemophilia A,
the patient supine. hemophilia B, or severe factor VII deficiency. Often, a target joint is
It is not always possible to be sure that a left upper quadrant mass prominently affected.
is spleen; masses in the stomach, colon, kidney, or pancreas may mimic
splenomegaly on physical examination. When there is uncertainty
regarding the nature of a mass in the left upper quadrant, imaging pro-
cedures will usually permit accurate diagnosis.13–15
REFERENCES
1. Bickley LS: Bates Guide to Physical Examination and History Taking, 11th ed. Lippincott
Williams & Wilkins, Philadelphia, 2012.
Liver 2. Sackett DL: A primer on the precision and accuracy of the clinical examination. JAMA
Palpation of the edge of the liver in the right upper quadrant of the 267:2638, 1992.
abdomen is commonly used to detect hepatic enlargement, although 3. Williams ME: Geriatric Physical Diagnosis: A Guide to Observation and Assessment.
McFarland & Company, Jefferson, NC, 2008.
the inaccuracies of this method have been demonstrated. It is necessary
4. Mor V, Laliberte L, Morris JN, Wiemann M: The Karnofsky performance status scale:
to determine both the upper and lower borders of the liver by percus- An examination of its reliability and validity in a research setting. Cancer 53:2002, 1984.
sion in order to properly assess liver size.16,17 The normal liver may be 5. Oken MM, Creech RH, Tormey DC, et al: Toxicity and response criteria of the Eastern
palpable as much as 4 to 5 cm below the right costal margin but is usu- Cooperative Oncology Group. Am J Clin Oncol 5:649, 1982.
6. Janssen CAH, Scholten PC, Heintz APM: A simple visual assessment technique to
ally not palpable in the epigastrium. The height of liver dullness is best discriminate between menorrhagia and normal menstrual blood loss. Obstet Gynecol
measured in a specific line 8, 10, or 12 cm to the right of the midline. 85:977, 1995.
Techniques should be standardized so that serial measurements can be 7. Black C, Kaye JA, Jick H: MMR vaccine and idiopathic thrombocytopaenic purpura. Br
J Clin Pharmacol 55:107, 2003.
made. The vertical span of the normal liver determined in this manner 8. O’Leary ST, Glanz JM, McClure DL, et al: The risk of immune thrombocytopenic pur-
will range approximately 10 cm in an average-size man and approxi- pura after vaccination in children and adolescents. Pediatrics 129:248, 2012.
mately 2 cm smaller in a woman. Because of variations introduced by 9. Grubnic S, Vinnicombe SJ, Norman AR, Husband JE: MR evaluation of normal retro-
technique, each physician should determine the normal area of liver peritoneal and pelvic lymph nodes. Clin Radiol 57:193, 2002.
10. Atula TS, Varpula MJ, Kurki TJI, et al: Assessment of cervical lymph node status in head
dullness by the physician’s own procedure. Correlation of radioisotope and neck cancer patients: Palpation, computed tomography and low-field magnetic
imaging data with results from routine physical examinations indicates resonance imaging compared with ultrasound-guided fine needle aspiration cytology.
that often a liver of normal size is considered enlarged on physical Eur J Radiol 25:152, 1997.
11. Arkles LB, Gill GD, Nolan MP: A palpable spleen is not necessarily enlarged or patho-
examination and an enlarged liver is considered normal. Ultrasonogra- logical. Med J Aust 145:15, 1986.
phy and computed tomography measurements are useful in determin- 12. Barkun AN, Camus M, Green L, et al: The bedside assessment of splenic enlargement.
ing size and demonstrating localized infiltrative lesions.18–20 Am J Med 91:512, 1991.
13. Benter T, Klühs L, Teichgräber U. Sonography of the spleen. J Ultrasound Med 30:1281,
2011.
Nervous System 14. Lamb PM, Lund A, Kanagasbay RR, et al: Spleen size: How well do linear ultrasound
A thorough evaluation of neurologic function is necessary in many measurements correlate with three-dimensional CT volume assessments? Br J Radiol
patients with hematologic disease. Vitamin B12 deficiency impairs cere- 75:573, 2002.
15. Palas J, Matos AP, Ramalho M. The spleen revisited: An overview on magnetic reso-
bral, olfactory, spinal cord, and peripheral nerve function, and severe nance imaging. Radiol Res Pract 2013:219297, 2013.
chronic deficiency may lead to irreversible neurologic degeneration. 16. Castell DO, O’Brien KD, Muench H, Chalmers TC: Estimation of liver size by percus-
Leukemic meningitis is often manifested by headache, visual impair- sion in normal individuals. Ann Intern Med 70:1183, 1969.
17. Tucker WN, Saab S, Rickman LS, Mathews WC: The scratch test is unreliable for detect-
ment, or cranial nerve dysfunction. Tumor growth in the brain or spinal ing the liver edge. J Clin Gastroenterol 25:410, 1997.
cord compression may be caused by malignant lymphoma or plasma cell 18. Bennett WF, Dova JG: Review of hepatic imaging and a problem-oriented approach to
myeloma. A variety of neurologic abnormalities may develop in patients liver masses. Hepatology 12:761, 1990.
with leukemias, lymphomas, and myeloma as a consequence of tumor 19. Barloon TJ, Brown BP, Abu-Yousef MM, et al: Teaching physical examination of the
adult liver with the use of real-time sonography. Acad Radiol 5:101, 1998.
infiltration, bleeding, infection, or a paraneoplastic syndrome. Essen- 20. Elstein D, Hadas-Halpern I, Azuri Y, et al: Accuracy of ultrasonography in assessing
tial monoclonal gammopathy is associated with several types of sensory spleen and liver. J Ultrasound Med 16:209, 1997.

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11
CHAPTER 2 The complete blood count is a necessary part of the diagnostic

evaluation in a broad variety of clinical conditions. Similarly, the leu-
EXAMINATION OF kocyte differential count and examination of the blood film, in spite of
limitations as a screening test for occult disease, is important in initial
consideration of the differential diagnosis in most ill patients. Although
BLOOD CELLS quantitative and qualitative (morphologic) examination of the cells

of the blood are considered separately in this chapter, the distinction
between these two is not absolute, and measures once considered “qual-
itative” become quantitative as technology advances.
Daniel H. Ryan
QUANTITATIVE MEASURES OF CELLS IN

SUMMARY THE BLOOD
Determining a patient’s blood cell counts and examining the appearance of
PRINCIPLES OF AUTOMATED BLOOD CELL
cells on a blood film is central to the diagnosis of blood cell diseases and can
give important information about numerous other degenerative, inflamma- ANALYSIS
tory, and neoplastic diseases that are reflected in quantitative or qualitative Automated blood cell analysis is the cornerstone of the modern hema-
changes of blood cells. The quantity and quality of blood cells reflects the tology laboratory, allowing rapid, cost-effective, and accurate analysis
aggregate function of the major blood forming tissue, the marrow, and is thus of the cells of the blood, including new parameters with diagnostic util-
ity. The morphologic and functional complexity of blood cells requires
an essential component of diagnosis and followup of primary hematological
direct microscopic examination of a stained blood film by a trained
disorders. The decision to perform a marrow examination, and the types of
observer. However, it is possible to use automated techniques to analyze
special studies required, follow from a careful analysis of blood cells. Currently and report on the majority of samples, using defined criteria (“flags”)
available automated blood cell analyzers continue to evolve and are the main- to select those that need further microscopic review. Automated hema-
stay of blood cell counting, providing an increasing array of novel quantitative tology analyzers typically incorporate multiple proprietary software
parameters, and flagging of abnormal samples that need manual microscopic flags based on acceptability criteria related to pattern recognition in the
review. The blood provides a unique example of a tissue that can be readily multiparameter displays or comparison of different detection modes for
analyzed with a degree of quantitative detail unavailable in any other organ the same cell type. These are frequently updated in software or when
system. new models are introduced to improve sensitivity and specificity. In this
way, instruments identify samples that contain cells or abnormalities the
instrument cannot definitively identify, so that a skilled morphologist
can visually evaluate that specimen. Some of these flags can be adjusted
or suppressed by the user to achieve an appropriate balance that mini-
INTRODUCTION mizes both false positives and false negatives. The optimum balance is
dependent on the patient population examined. Guidelines for manual
The blood is examined so as to answer these questions: Is the marrow smear review based on comparative data have been published, based
producing appropriate numbers of mature cells in the major hemato- on instruments then in common use.1 Protocols for evaluating and
poietic lineages? Is the development of each hematopoietic lineage adjusting flagging criteria within an individual laboratory have been
qualitatively normal? Are there abnormal (e.g., leukemia or lymphoma) described.2 Manual review may consist of a scan of the blood film, a
cells in the blood? Quantitative measures available from automated more detailed blood film examination including leukocyte differential
cell counters are reliable and provide a rapid and cost-effective way to count, or a physician’s review, based on laboratory defined criteria.3 The
screen for primary or secondary disturbances of hematopoiesis. Light proportion of samples requiring manual blood film review differs among
microscopic observation of the blood film is essential to confirm certain instruments and the type of patient population tested. Studies show a
quantitative results and to investigate qualitatively abnormal differenti- 10 to 30 percent manual review rate,4–6 with a false negative rate (i.e.,
ation of the hematopoietic lineages. Based on examination of the blood, abnormal samples that were not flagged for review) varying from
the physician is directed toward a more focused assessment of marrow approximately 3 percent1 to 10–14 percent.4 Most of the false nega-
function or to systemic disorders that secondarily involve the hemato- tives with current instrumentation are related to red cell and platelet
poietic system. morphology with relatively limited diagnostic significance.4 Contin-
ued improvement in methodology and increased sophistication of data
analysis will result in further reduction of unnecessary manual smear
reviews. Depending on workload and space considerations, laboratories
Acronyms and Abbreviations: CHr, reticulocyte-specific hemoglobin content; may choose to link automated hematology analyzers with automated
EDTA, ethylenediaminetetraacetic acid; fl, femtoliter; FRC, fragmented red cell blood film preparation and automated image analyzers to facilitate man-
counts; Hct, hematocrit; HYPO%, percentages of red cells falling below a cutoff for ual morphologic review of cells by traditional light microscopy or online
hemoglobin concentration; %HypoHe, percentages of red cells falling below a cutoff review of digitized images.7 These instruments can provide a provisional
for hemoglobin content; Ig, immunoglobulin; MCH, mean cell hemoglobin; MCHC, differential count with good accuracy,8 although typically final classifi-
mean cell hemoglobin concentration; MCV, mean cell volume; MPV, mean platelet cation of problematic cells is performed by a technologist or physician.
volume; NHANES, National Health and Nutrition Examination Survey; NK, natural The characteristics of automated hematology analyzer systems
killer; PDW, platelet volume distribution width; RBC, red blood cell; RDW, red cell have been reviewed.9 A detailed description of individual instruments
distribution width; RET-He, reticulocyte-specific hemoglobin content. is beyond the scope of this chapter, but the general principles employed
by state-of-the-art instrumentation are summarized below. The major

analytical challenges are the frequency of the different cell types, which as basophils and immature granulocytic cells, from the major normal
vary over many orders of magnitude, from red cells (millions per μL) to blood cell types. In addition, nucleic-acid-binding fluorescent dyes incor-
basophils (dozens per μL), and the complexity of the structure of normal porated into the lysis buffer measure total RNA plus DNA in the cells and
and abnormal blood cells. Over the past several decades, instruments are used in some analyzers to help differentiate leukocyte types. Fluores-
have become increasingly sophisticated with the use of multiple param- cence measurements after staining with RNA binding dyes are commonly
eters to produce more precise results in the great majority of patient used to detect and subclassify reticulocytes and platelets. Light absorp-
samples. In a typical automated hematology analyzer, the blood sample tion is the principle used for hemoglobin measurement and in some
is aspirated and separated into different fluidic streams. The streams instruments for identifying peroxidase-positive granulocytes. Instru-
are mixed with various buffers that accomplish specific purposes in ments rely on a combination of techniques for accuracy and precision11
the analysis, for instance, using differential lysis to distinguish subsets (Fig. 2–1). Complex algorithms are invoked to determine whether the
of leukocytes, reagents to measure hemoglobin or detect myeloperoxi- distribution of variables for a specific result or for the specimen as a whole
dase containing leukocytes, and various fluorescent dyes. Measurements fit sufficiently within an expected variable space so that the results can
of each fluidic stream are made in flow as the sample passes through be reported with high confidence, or whether the specimen should be
a series of detectors in what are essentially modified flow cytometers “flagged” for further analysis or manual blood film review (Fig. 2–2). There
(Chap. 3). Commonly used principles include light scatter at various is significant overlap in methodology between automated hematology
angles, electrical impedance and conductivity, and fluorescence or light analyzers and flow cytometers (flow cytometers are discussed in Chap. 3).
absorption of cells stained in flow. Light scatter yields information about The latter are distinguished by extensive use of fluorochrome tagged anti-
cell size (using scatter at low-incident angles), nuclear lobulation, and bodies to identify cell subtypes. These instruments have replaced labori-
cytoplasmic granularity (using high-angle light scatter) and refractive ous manual work, but also demand increasing interpretation skills on the
index, with polarization of the scattered light as an additional param- part of laboratory technologists. Automated blood analyzers have been
eter. If red cells are converted to spherocytes by the buffer solution to adapted to accurately count the smaller numbers of blood cells typically
eliminate the variability of cell shape, light scatter at different angles found in body fluids,12 but accurate differential counts13 and detection of
can provide information about hemoglobin content, as well as size of blast cells in fluids of patients14 remains a challenge.
individual red cells. Cell size is also estimated by measuring change in Point of care “bedside” testing is far more challenging in hematol-
electrical resistance, which is proportional to cell size as cells enter a ogy than for typical clinical chemistry analytes for many of the reasons
narrow orifice through which a direct current is maintained, the orig- described above. Instruments have been described for bedside measure-
inal Coulter principle, named for Wallace Coulter who developed the ment of hemoglobin, total leukocytes, three-part leukocyte differential
electronic particle counter.10 Radiofrequency capacitance measurement count, malaria parasitemia, and CD4+ T-cell count, mainly targeting
yields additional intracellular structural information that complements clinical settings with limited access to standard laboratory testing. More
the direct current measurement. Differential lysis with detergents of work remains to be done to demonstrate the reliability and clinical
varying strength or pH is used to separate certain leukocyte types, such impact of such testing strategies.15
Diff channel WBC/baso channel Figure 2–1. Schematic of multiparameter cell discrimi-
Fluorescence (total nucleic acids)
nation in an automated hematology analyzer. The Sysmex

Atyp lymph XE-2100 is used as an example, in which leukocytes are dis-
criminated by (A) DNA/RNA fluorescence using a polyme-
Forward scatter
Imm gran Basos thine dye versus high-angle (side) light scatter in lysed blood;
Mono
(B) side scatter versus low-angle (forward) light scatter after
acidic lysis in a separate aliquot that preserves basophil struc-
ture; and (C) direct current (DC) impedance versus radio fre-
quency (RF) capacitance of cells subjected to a lysis reagent
Lymph Leukocytes
that relatively preserves immature cells with lower mem-
Neut + baso other than basos
brane lipid content. Nucleated red blood cells (NRBC) are
Cell ghost distinguished (D) in a lysed sample stained with nucleic acid
Eos Cell ghost dye where leukocyte nuclei have detectably higher DNA/
Side scatter Side scatter RNA content than red cell nuclei. Atyp Lymph, atypical lym-
A B phocytes; Baso, basophils; Blasts, blast cells; Diff Channel, dif-
ferential count channel; Eos, eosinophils; HPC, hematopoietic
Immature myeloid channel NRBC channel progenitor cells; Imm Gran, immature granulocytes; Lymph,
lymphocytes; Mono, monocytes; Neut + Baso, neutrophils
Pit clumps + basophils; Plt Clumps, platelet clumps; WBC, white blood
cells.
RF capacitance
Forward scatter
Imm gran
NRBC
Cell ghost
Leukocytes
Blasts
HPC Cell ghost
DC impedance Fluorescence (total nucleic acids)
C D

Chapter 2: Examination of Blood Cells 13
Figure 2–2. Examples of how samples containing various

abnormal findings are flagged for manual review. A. Nor-
mal sample showing how the major variables and results are
displayed. B. Immature granulocytes appearing on the DIFF
Basophils (leukocyte differential count) and IMI (immature myeloid) his-
tograms, as well as a dimorphic red cell population. C. Multiple
flags, including cells in the area of atypical lymphocytes, and
platelet clumps with abnormal platelet volume distribution.
D. Appearance of nucleated red blood cells (NRBCs), reticulo-
cytes, and reticulated platelets on a different set of parameters.
This figure is not intended as a comprehensive illustration of
the technical details, but serves to demonstrate that differ-
ential lysing reactions coupled with multiparameter light-
scatter, impedance, capacitance, and fluorescence measure-
ments are used to analyze blood cells in current high-through-
A put instruments.
B C
Immature reticulocyte fraction

Reticulocytes
NRBCs RNA containing platelets

Platelets
(detected by light scatter)
Platelets
(detected by impedance)
AUTOMATED ANALYSIS OF RED CELLS The hematocrit may also be determined by subjecting the blood to
sufficient centrifugal force to pack the cells while minimizing trapped
Some red cell parameters (for instance, mean cell volume [MCV], red
extracellular fluid. This approach was traditionally done in capillary
cell number, hemoglobin concentration, red cell distribution width
tubes filled with blood and centrifuged at very high speed in a small
[RDW]) are directly measured, while others (for instance, hematocrit,
tabletop centrifuge, and the technique was referred to as the “microhe-
mean cell hemoglobin [MCH], mean cell hemoglobin concentration
matocrit” or informally as a “spun crit.” Before standardized methods
[MCHC]) are derived from these primary measurements.
for hemoglobin quantification were available, the hematocrit was the
simplest and most accurate method for determining the fractional vol-
Measurement of the Red Cell Count and Hematocrit ume of red cells in blood and by inference the hemoglobin. However,
In electronic instruments, the hematocrit (Hct; fractional volume of this is a manual procedure not well adapted to routine processing in a
blood occupied by erythrocytes) is calculated from the product of direct high-volume clinical laboratory, and is affected by varying amounts of
measurements of the erythrocyte count and the MCV: (Hct [μL/100 μL] = plasma trapped between red cells in the packed cell volume,16 typically
RBC [× 10−6 /μL] × MCV [fl]/10). Falsely elevated MCV and decreased about 2 to 3 percent of the packed volume.17 The hematocrit from poly-
red cell counts can be observed when red cell autoantibodies are present cythemic samples or blood containing abnormal erythrocytes (sickle
and retain binding capability at room temperature (cold agglutinins and cells, thalassemic red cells, iron-deficient red cells, spherocytes, mac-
some cases of autoimmune hemolytic anemia). This causes red cells to rocytes) is increased because of enhanced plasma trapping associated
clump and affects the accuracy of both the red blood cell (RBC) count with increased red cell rigidity.17 Therefore, although automated hemat-
and MCV, as well as the resultant hematocrit. ocrit values are adjusted to be equivalent to spun hematocrit for normal

samples, in abnormal samples, the spun hematocrit may be spuriously although because this parameter is affected by both hypochromia
elevated (up to 6 percent in microcytosis).18 The hemoglobin determina- and microcytosis, it is as least sensitive as the MCV in detecting iron-
tion now is preferred to the hematocrit, because it is measured directly deficiency states.32 Another advantage of the MCH is the consistency
and is the best indicator of the oxygen-carrying capacity of the blood. across different analyzer types, as it is derived from two of the most
accurately measured parameters: hemoglobin and red cell count.33 The
Measurement of Hemoglobin MCHC is not used much diagnostically, and is primarily useful for quality
Hemoglobin is intensely colored, and this property has been used in control purposes, such as detecting sample turbidity. These red cell indi-
methods for estimating its concentration in blood. Erythrocytes con- ces are average quantities and, therefore, may not detect abnormalities
tain a mixture of hemoglobin, oxyhemoglobin, carboxyhemoglobin, in blood with mixed-cell populations. In situations such as sideroblas-
methemoglobin, and minor amounts of other forms of hemoglobin. To tic anemia, recently transfused patients, patients with severe pernicious
determine hemoglobin concentration in the blood, red cells are lysed anemia with red cell fragmentation, and folate plus iron deficiency, both
and hemoglobin variants are converted to the stable compound cyan- large and small red cells are present, diminishing the value of the MCV.
methemoglobin for quantification by absorption at 540 nm. All forms of Red Cell Distribution Width The RDW is an estimate of the vari-
hemoglobin are readily converted to cyanmethemoglobin except sulfhe- ance in volume within the population of red cells, expressed as 1 SD of
moglobin, which is rarely present in significant amounts. In automated red cell volume measurements divided by the MCV. Instrument man-
blood cell counters, hemoglobin is usually measured by a modified ufacturers calculate RDW using different algorithms, so that reference
cyanmethemoglobin or an alternate lauryl sulphate method. In prac- ranges vary according to analyzer model. The RDW can be used in
tice, the major interference with this measurement is chylomicronemia, the laboratory as a flag to select those samples that should have man-
but newer instruments identify and minimize this interference. Nonin- ual review of blood films for red cell morphology. More significantly, a
vasive transcutaneous monitoring of total hemoglobin concentration, large literature has now developed around the evidence that the RDW
as well as methemoglobin and carboxyhemoglobin, using multiwave- is a biomarker predicting morbidity and mortality in a broad variety
length pulse oximetry has become available.19 Although these instru- of clinical settings,34 such as angina/myocardial infarction,35 heart fail-
ments offer the opportunity to track hemoglobin concentration trends ure, trauma, pneumonia, sepsis, intensive care treatment, renal and
in patients subject to blood loss and fluid shifts,20 it is not yet clear that liver disease, and in the general population.36 Most of these studies
they have sufficient precision to guide transfusion decisions.21,22 Such are retrospective, observational, or cohort-based studies, often using
hemoglobin measurements may be unreliable under conditions of databases of routinely collected data gathered for other purposes, but
peripheral circulatory hypoperfusion. prospectively designed studies have arrived at similar conclusions.37,38
The hemoglobin level varies with age (Table 2–1). Chapter 7 dis- The RDW retains its association with poor clinical outcomes whether
cusses changes in hemoglobin in the neonatal period. After the first or not anemia is present,39 and it adds predictive power to more estab-
week or two of extrauterine life, the hemoglobin falls from levels of lished predictive risk models.40 RDW may be a surrogate for systemic
approximately 17 g/dL to levels of approximately 12 g/dL by 2 months of inflammation41 and/or oxidative stress, but the predictive value of RDW
age. Thereafter, the levels remain relatively constant throughout the first is independent of other inflammatory markers,40 suggesting that this
year of life. Any child with a hemoglobin level below 11 g/dL should be biomarker is tracking other mechanistic processes as well. Identification
considered anemic.23 Chapter 8 discusses changes in hemoglobin con- of physiologic mechanisms linking RDW to adverse clinical outcomes
centration with pregnancy and Chap. 9 discusses changes in hemoglo- will be important in using this predictive biomarker to inform thera-
bin levels in older persons. peutic decisions.34
Standard Red Cell Indices Reticulocyte Count and RNA Content

The size and hemoglobin content of erythrocytes (red cell indices), The reticulocyte is a newly released anucleate red cell that enters the
based on population averages, have traditionally been used to assist in blood with residual detectable amounts of RNA (Chaps. 31 and 32).
the differential diagnosis of anemia.24 A variety of newer indices based The number of reticulocytes in a volume of blood permits an estimate
on size and hemoglobinization characteristics of red cell subpopulations of marrow erythrocyte production and is thus useful in evaluating the
are discussed in the section “Novel Red Cell and Reticulocyte Indices”. pathogenesis of anemia by distinguishing inadequate production from
Mean Cell Volume Automated blood counters measure the MCV accelerated destruction (Chap. 32). The manual method for enumerat-
directly by either electrical impedance or light scatter measurements ing reticulocytes by placing a sample of blood in a tube containing new
of individual red cells. The MCV has been used to guide the diagnos- methylene blue and preparing a blood film to enumerate the propor-
tic workup in patients with anemia; for example, testing patients with tion of cells that show blue beaded precipitates (residual ribosomes) has
microcytic anemia for iron deficiency or thalassemia, and those with largely been replaced by automated methods, which are incorporated
macrocytic anemia for folate or vitamin B12 deficiency. This approach into high-volume hematology analyzers.42 Reticulocytes are identified
has practical value, but also limitations25; for instance, MCV may be by direct fluorescence measurement after staining with RNA-binding
normal in some older patients with pernicious anemia,26 or in advanced dyes or light scatter measurements to detect staining if nonfluorescent
pernicious anemia with severe red cell fragmentation,27 while one-third RNA-binding dyes are used. Various proprietary combinations of light
of older patients have an elevated MCV without an evident cause.28 scatter and other parameters are used to minimize interferences such
Mathematical manipulations of various red cell indices take advantage as nucleated red cells, nuclear remnants (Howell-Jolly bodies), malaria
of the trend toward relatively more severe microcytosis than hypochro- parasites, or platelet clumps.
mia in thalassemia trait versus iron-deficiency anemia to assist in Automated reticulocyte counts are typically reported in absolute
the differential diagnosis of these disorders,29 particularly in high- numbers (reticulocytes per μL or per L of blood), obviating the need to
prevalence populations where laboratory resources are limited,30 but correct for a reduced red cell count (anemia), if present. However, one
their usefulness has been questioned.31 may still consider the effect of elevated erythropoietin levels secondary
Mean Cell Hemoglobin The MCH, the amount of hemoglobin to severe anemia, which results in premature release of reticulocytes
per red cell, increases or decreases in parallel with the red cell volume persisting in the circulation for more than the usual 1 day, correspond-
(i.e., MCV) and generally provides similar diagnostic information, ingly inflating estimates of daily marrow reticulocyte production based

Kaushansky_chapter 02_p0011-0026.indd 15
TABLE 2–1. Reference Ranges for Leukocyte Count, Differential Count, and Hemoglobin Concentration in Children*
Neutrophils
Leukocytes Hemoglobin g/dL
Age Total (× 103/μL) Total Band Segmented Eosinophils Basophils Lymphocytes Monocytes Blood
12 mo 11.4(6.0–17.5) 3.5(1.5–8.5) 0.35(0–1.0) 3.2(1.0–8.5) 0.30(0.05–0.70) 0.05(0–0.20) 7.0(4.0–10.5) 0.55(0.05–1.1) 12.6(11.1–14.1)
31 3.1 28 2.6 0.4 61 4.8
4 yr 9.1(5.5–15.5) 3.8(1.5–8.5) 0.27(0–1.0) 3.5(1.5–7.5) 0.25(0.02–0.65) 0.05(0–0.2) 4.5(2.0–8.0) 0.45(0–0.8) 12.7(11.2–14.3)
42 3.0 39 2.8 0.6 50 5.0
6 yr 8.5(5.0–14.5) 4.3(1.5–8.0) 0.25(0–1.0) 4.0(1.5–7.0) 0.23(0–0.65) 0.05(0–0.2) 3.5(1.5–7.0) 0.40(0–0.8) 13.0(11.4–14.5)
51 3.0 48 2.7 0.6 42 4.7
Chapter 2: Examination of Blood Cells

10 yr 8.1(4.5–13.5) 4.4(1.8–8.0) 0.24(0–1.0) 4.2(1.8–7.0) 0.20(0–0.60) 0.04(0–0.2) 3.1(1.5–6.5) 0.35(0–0.8) 13.4(11.8–15.0)
54 3.0 51 2.4 0.5 38 4.3
21 yr 7.4(4.5–11.0) 4.4(1.8–7.7) 0.22(0–0.7) 4.2(1.8–7.0) 0.20(0–0.45) 0.04(0–0.2) 2.5(1.0–4.8) 0.30(0–0.8) M: 15.5(13.5–17.5)
59 3.0 56 2.7 0.5 34 4.0 F: 13.8(12.0–15.6)
*The means and ranges are in thousands of cells per mL. This table is provided as a guide. Normal ranges should be validated by the clinical laboratory for the specific methods in use.
The number in italic is mean percentage of total leukocytes.
For leukocyte and differential count, see Altman PL, Dittmer DS (eds): Blood and Other Body Fluids. Federation of American Societies for Experimental Biology, Washington, DC, 1961.
For hemoglobin concentration, see Rudolph AM, Hoffman JI (eds): Pediatrics, 18th ed, pp 1011, 1012. Appleton and Lange, Norwalk, CT, 1987.
17/09/15 5:34 pm
15
on the reticulocyte count (Chap. 32). The correlation between manual These parameters have the advantage of ready access in the context
and automated methods of reticulocyte enumeration is good, but refer- of an automated blood count, but the availability of differently derived
ence ranges differ slightly among the methods, given the different dyes and calculated parameters from various instrument makers is a chal-
and conditions used and the continuous nature of the variables separat- lenge to remember and compare across laboratories.
ing reticulocytes from mature red cells.
Many hematology analyzers now report some quantitative mea- Other Red Cell Findings
sure of reticulocyte RNA content. Increase in the immature (highest Nucleated Red Cells Nucleated red cells are present in newborns,
RNA content) reticulocyte fraction is an early sign of marrow recovery particularly if physiologically stressed, and in a variety of disorders,
from cytotoxic therapy43 or treatment for nutritional anemias, usually including hypoxic states (congestive heart failure), severe hemolytic
preceding the rise in total reticulocyte count. A limitation at present anemia, primary myelofibrosis, and infiltrative disease of the marrow
is that the methods lack standardization and reference ranges for these (Chap. 45). Most modern automated hematology analyzers are capable
parameters are instrument dependent.44 of detecting and quantitating nucleated red blood cells, which were a
source of spuriously elevated leukocyte counts in earlier instruments, at
Additional Red Cell and Reticulocyte Indices a level of 1 to 2 nucleated red cells per 100 leukocytes.
Current high-end automated cell counters measure unique properties of Malarial Parasites Malarial parasites can also be detected by some
mature red cells and reticulocytes on a cell-by-cell basis, not just as pop- current analyzers, based on detecting parasite infected red cells or neu-
ulation averages. The result is a plethora of new indices that are in many trophils containing ingested hemozoin in regions of the multiparam-
cases specific to an instrument manufacturer, presenting new diagnostic eter display that are not characteristically populated in normal blood
opportunities but also a confusing nomenclature and a potential lack (sometimes causing spurious eosinophilia57). Some reports indicate
of comparability. Some examples of parameters that have been studied high sensitivity and specificity with certain instrumentation,58 a useful
include %HypoHe, %MicroR, RET-He (available on Sysmex instru- consideration in endemic areas where access to technologists with mor-
ments), CHr, HYPO% (Siemens), RSf, LHD% (Beckman-Coulter), and phologic expertise may not be consistent. Careful attention to instru-
FRC (fragmented red cells; Sysmex and Siemens). ment characteristics and limitations as well as the relative prevalence
New formulas for distinguishing causes of microcytosis based on of disorders causing instrument flags in the laboratory’s patient pop-
several novel red cell indices function about as well45 or somewhat bet- ulation is essential in fine tuning instrument review criteria to provide
ter46 than traditional formulas for differentiating iron deficiency from reasonable sensitivity and specificity.
thalassemia trait. More sophisticated mathematical modeling of individ- Other Abnormalities Not Detected by Automation Some disor-
ual cell-based volume and hemoglobin content data available in current ders, such as immune and hereditary spherocytosis (Chaps. 46 and 54),
analyzers has been used in a systems biology approach to demonstrate hemoglobin C disease (Chap. 49), elliptocytosis (Chap. 46), inherited
latent iron deficiency and to distinguish causes of microcytosis.47,48 The granule abnormalities (Chap. 66), and malaria and other parasitic dis-
ability of new automated analyzers to measure parameters specifically eases (Chap. 53), may not be reliably detected by the various flagging
in reticulocytes on a cell-by-cell basis also opens up the possibility of strategies on automated analyzers, and morphologic findings such as
reticulocyte-specific indices. The theoretical advantage is that acute basophilic stippling (Chap. 31), toxic granulation (Chap. 60), sidero-
changes in red cell function would be detected more rapidly and reliably cytes (Chap. 31), and pathologic rouleaux (Chap. 109) are only detect-
in the reticulocyte fraction as opposed to the total red cell population. able by microscopic examination of the blood film.
Estimates of reticulocyte-specific hemoglobin content (CHr and
RET-He, which are comparable) by light-scatter measurements of
reticulocytes are closely related to adequacy of iron availability to ery- AUTOMATED ANALYSIS OF LEUKOCYTES
throid precursors during the preceding 24 to 48 hours, and have been Leukocyte Count
described as diagnostically useful in detecting functional iron deficiency Leukocyte counts are performed by automated cell counters on blood
in complex clinical settings, such as chronic inflammation49 and chronic samples appropriately diluted with a solution that lyses the erythrocytes
renal disease.50 The increase in serum ferritin as an acute phase reactant (e.g., an acid or a detergent), but preserves leukocyte integrity. Man-
combined with the physiologic variation of serum iron and iron-bind- ual counting of leukocytes is used only when the instrument reports a
ing capacity limits the value of conventional parameters in these set- potential interference or the count is beyond instrument linearity lim-
tings. The CHr may be a better predictor of depleted marrow iron stores its. Manual counts are subject to much greater technical variation than
than traditional serum iron parameters in nonmacrocytic patients,51 automated counts because of technical and statistical factors, and with
and is a more sensitive predictor of iron deficiency than hemoglobin modern instrumentation, need to be done infrequently. Instruments
for screening infants52 and adolescents for iron deficiency. Estimates that perform an automated 5-part differential can measure absolute
of percentages of red cells falling below a cutoff for hemoglobin con- neutrophil counts accurately down to 100/μL.59 Automated leukocyte
centration (HYPO%) or hemoglobin content (%HypoHe) may provide counts may be falsely elevated as a result of cryoglobulins or cryofibrin-
greater sensitivity than the corresponding mean values averaged over all ogen, clumped platelets or fibrin from an inadequately anticoagulated
red cells, for instance with respect to iron deficiency in renal disease.53 or mixed sample, ethylenediaminetetraacetic acid (EDTA)–induced
Four of the newer parameters (HYPO%, %HypoHe, CHr, RetHe) sim- platelet aggregation, nucleated red blood cells, or nonlysed red cells,
ilarly outperformed transferrin saturation and ferritin in hemodialysis and falsely decreased because of EDTA-induced neutrophil aggregation.
patients54 for diagnosis of iron deficiency. However, both the CHr and This potential interference is instrument dependent, and current analyz-
RET-He are less effective than the MCH in screening elderly patients ers use a variety of algorithms to minimize their effect and flag those rare
for iron-deficiency anemia.55 The RSf (square root of MCV times MRV samples on which accurate automated analysis cannot be performed.
[mean reticulocyte volume]) and LHD% (a mathematical transforma-
tion of the MCHC) have similar diagnostic utility as RET-He.56 Frag- Leukocyte Differential
mented red cell (FRC) counts by automated analyzers, based on better Leukocytes in the blood serve different functions and arise from dif-
methods of separating small red cells from platelets, appear to lack spec- ferent hematopoietic lineages, so it is important to evaluate each of the
ificity and their clinical role is not yet defined. major leukocyte types separately. Modern automated instruments use

multiple parameters to identify and enumerate the five major morpho- count because of the small size, tendency to aggregate, and potential
logic leukocyte types in blood: neutrophils, basophils, eosinophils, lym- overlap of platelets with more numerous smaller red cells and cellular
phocytes, and monocytes, as well as indicate the possible presence of debris. Current instruments typically construct a platelet volume his-
immature or abnormal cell. Customarily, both absolute (cells per μL) togram based on platelet size within a reliably measured platelet vol-
and relative (percent of leukocytes) counts are reported in the leuko- ume window and mathematically extrapolate this histogram to account
cyte differential. It is the absolute values that relate to pathologic states, for platelets whose size overlaps with debris (smaller) or small red cells
and percentages are sometimes misleading (e.g., absolute neutropenia (larger). This works because platelet volumes in health or disease fol-
appearing as a relative lymphocytosis) if the absolute values are not care- low a log-normal distribution. Some analyzers compare platelet counts
fully examined. Some have proposed to eliminate the reporting of dif- determined by different methods (e.g., impedance, light scatter, or fluo-
ferential count percentages entirely for this reason.60 “Band” neutrophils rescence staining) to improve accuracy, especially useful for low platelet
cannot be identified as such by automated analyzers, although they counts. Based on analysis of volume-distribution histograms of platelets
will usually trigger a manual review flag if present in increased num- and red cells and comparison of optical and impedance-based platelet
bers. Current high-throughput instruments can perform an accurate counts, suspect samples are flagged for microscopic review. Automated
automated “five-part” differential count with a false-positive rate (i.e., platelet counting by current instrumentation is accurate and far more
unnecessarily flagged for review) of 2 to 15 percent in samples from a precise than manual methods. At very low platelet counts (less than
medical center patient population.61 Eosinophils are accurately counted 20 × 109/L), results are less precise70 and there is a method-dependent
by current state-of-the-art instruments, but automated basophil counts tendency to overestimate platelet counts.71 Conversely, platelet activa-
remain imprecise.11 Small numbers of abnormal cells can escape detection in disorders such as disseminated intravascular coagulation (DIC)
tion by either automated or manual methods. The false-negative rate and acute leukemia may result in systematic slight undercounting of
for detection of abnormal cells varies from 1 to 20 percent, depending platelets.72 Advances in instrumentation, such as fluorescent dyes to
on the instrument, type of abnormal cell examined, and the detection more specifically identify platelets in thrombocytopenic73 and micro-
limit desired (1–5 percent abnormal cells).62–64 Careful attention to use cytic74 samples, should improve accuracy. When reviewing the blood
of flagging criteria designed to prompt manual review, which are linked film, platelet count may be roughly estimated as 2000 times the number
to instrument-specific methodology, is essential to insure that optimum of platelets in 10 consecutive oil immersion (1000×) fields.75
workflow strategies are used to detect samples containing abnormal Falsely Decreased Platelet Counts Causes of falsely decreased
cells with a manageable rate of manual review. Many instruments have platelet counts include incomplete anticoagulation of the sample (some-
“blast” flags designed to pick up leukemic blasts, but the sensitivity of times accompanied by small clots in the specimen or fibrin strands on
such flags alone varied from 65 to 94 percent in a recent study,11 and is the stained film) and platelet clumping (pseudothrombocytopenia) or
lower in leukopenic patients.65 One must rely not only on the specifi- “satellitism” (adherence of platelets to neutrophils), caused by aggrega-
cally designed “blast” flags, but also on other abnormalities identified tion induced by nonpathogenic antibodies recognizing platelet adhesion
in the automated blood count, including other flags, to select samples molecule epitopes exposed as a result of chelation of divalent cations in
for manual morphologic smear review. Lymphoma cells and reactive the anticoagulated sample.69 Platelet clumping occurs in approximately
lymphocytes are the most difficult for both automated instruments and 0.1 percent of hospitalized patients.76 The same phenomenon may occur
the human observer to identify. If one needs to search for infrequent to a lesser degree in citrate, which is often used to obtain platelet count
abnormal cells or evaluate leukocyte morphology, there is still no sub- in such cases. Magnesium EDTA, as compared to sodium EDTA, anti-
stitute for microscopic examination of a properly stained blood film by a coagulant is reported to more effectively inhibit platelet aggregation in
trained observer. The variability of morphologic quantification of band these patients and provide an accurate platelet count.77 Classical causes
neutrophils is so high that some have advocated ceasing quantitative of falsely elevated platelet count include severe microcytosis, cryoglob-
reporting of band cells.66 In spite of instrumentation that permits auto- ulins, and leukocyte cytoplasmic fragmentation.69 Infrequently, it may
mated analysis of a majority of clinical samples, the leukocyte differen- be necessary to confirm automated results by a microscopic (phase con-
tial count is still labor intensive relative to other high-volume laboratory trast) platelet count or platelet estimate from the blood film, bearing in
tests, and its value as a cause-finding tool in screening of asymptomatic mind that these methods are imprecise.
patients has been questioned.67 Mean Platelet Volume The mean platelet volume (MPV) has been
The normal differential leukocyte count varies with age. As proposed as a useful clinical tool in the differential diagnosis of throm-
described in Chap. 7, polymorphonuclear neutrophils are predominant bocytopenias, and is associated with cardiovascular risk, stroke, and
in the first few days after birth, but thereafter lymphocytes account for metabolic disease. Increased MPV may be related in a complex way to
the majority of leukocytes. This pattern persists up to approximately 4 to thrombopoietic stimuli that affect megakaryocyte ploidy, and not plate-
5 years of age, when the polymorphonuclear leukocyte again becomes let age per se. A platelet volume distribution width (PDW) can be calcu-
the predominant cell and remains so throughout the rest of childhood lated just as the RDW, and is correlated with platelet count and MPV.78
and adult life. Chapter 9 discusses the leukocyte count in older persons. However, platelet size parameters are difficult to accurately quantify and
The leukocyte count may decrease slightly in older subjects because of use diagnostically because of the wide physiologic variation of the MPV
a fall in the lymphocyte count with age. Neutrophil counts are lower in in normal subjects, lack of standardization of automated measurement
individuals of African descent, and in some Middle Eastern populations techniques and instability of platelet size parameters in the presence of
than in persons of European descent.68 commonly used anticoagulants.79
Newly Released (Reticulated) Platelets Newly released platelets
contain RNA, as do newly released red cells, and are functionally more
AUTOMATED ANALYSIS OF PLATELETS active, with enhanced expression of adhesion molecules and bound
Platelet Count coagulation factors.80 The number of platelets with high RNA content
Platelets are usually counted electronically by enumerating particles in (sometimes termed reticulated platelets or immature platelet fraction,
the unlysed sample within a specified volume window (e.g., 2–20 fl), measured by flow cytometry with RNA-binding fluorescent dyes, or
where volume may be measured by electrical impedance or light scat- by certain automated analyzers81) is a marker of marrow megakary-
ter.69 The platelet count was more difficult to automate than the red cell ocytopoiesis and is proposed as a way of differentiating decreased

production of platelets from circulatory destruction or removal as a The platelet and absolute neutrophil counts are lower in individuals of
cause of thrombocytopenia, in an analogous fashion to the use of the African ethnic origin.68 American men and women of African descent
reticulocyte count. The percentage of reticulated platelets is increased in have lower hemoglobin concentrations than do men and women of
destructive thrombocytopenias, but remains within the reference range European descent, a difference that is reduced by half, but still signifi-
in hypoproductive states.82 Reticulated platelet number or RNA content cant, when subjects with iron deficiency, thalassemia, sickle trait, and
correlates with imminent platelet recovery after chemotherapy.83 Retic- renal disease are excluded.90 Important clinical consequences may
ulated platelet number is correlated with risk of death in patients with result from these differences; for instance, reduced neutrophil counts
acute coronary syndrome84 and DIC,85 and with hyporesponsiveness to in Americans of African descent result in lower-dose intensity of treat-
platelet function inhibitors86 or aspirin.87 ment in early stage breast cancer, which may be related to survival out-
come disparities.91 Beutler and West90 summarize the situation well:
“The problem cannot be solved by simply establishing different ranges
REFERENCE RANGES for different ethnic groups, especially since all represent some degree of
The use of reference ranges for quantitative hematology measurements admixture. Thus, it is basically information that the physician must pos-
deserves some additional comment. The physiologic variation of certain sess that becomes one of the many factors that we designate as clinical
blood cell counts is notably higher than usually found in blood chemistry judgment.” With these caveats in mind, reference ranges for children,
analytes. This is a reflection of the adaptive responsiveness of the mar- and African American, Hispanic, and white adults are presented in
row and other tissues to cytokine and hormonal signaling. For instance, Tables 2–1 and 2–2. As with all laboratory parameters, clinical interpre-
the leukocyte and differential counts are affected by stress, diurnal varia- tation of patient results should be based on laboratory specific reference
tion, tobacco smoking, and ethnic origin. With increasing globalization ranges. Therefore, these tables are not presented to guide interpreta-
of clinical research and therapy, ethnic characterization of populations tion of specific laboratory results, but to indicate the challenges facing
used for reference ranges is critical to data interpretation of clinical laboratories and physicians in constructing and interpreting reference
studies.88 Platelet count and MPV show substantial ethnic variation.89 ranges of even standard and traditional assays.
TABLE 2–2. Published Reference Ranges for Key Blood Variables

NORIP107 Wakeman92 Cheng93 Bain106
Date 2003 2004 1994 1994 1994 1996 1996
Ethnicity Nordic U.K. U.S. European U.S. African U.S. Mexican U.K. European U.K. African
descent descent descent descent descent
No. 1800 250 3125 1712 1735 200 115
Hgb (g/dL) (M) 13.4–17.0 13.7–17.2 13.2–16.9 12.0–16.2 13.1–16.7 NA NA
(F) 11.7–15.3 12.0–15.2 10.7–15.1 10.2–14.4 11.4–15.0
Hct (%) (M) 40–50 40–50 39–50 36–48 39–50 NA NA
(F) 35–46 37–46 34–45 32–43 33–45
MCV (fl) 82–98 83–98 (M) 79–97 (M) 75–97 (M) 83–96 (M) NA NA
85–98 (F) 77–97 (F) 75–97 (F) 81–98 (F)
WBC (× 109/L) 3.5–8.8 3.6–9.2 4.1–11.7 (M) 3.5–9.5 (M) 4.6–10.6 (M) 3.6–9.2 (M) 2.8–7.2 (M)
4.3–12.0 (F) 3.4–10.5 (F) 4.3–11.3 (F) 3.5–10.8 (F) 3.2–7.8 (F)
Neutrophils NA 1.7–6.2 2.7–8.1 (M) 1.5–7.4 (M) 2.2–6.6 (M) 1.7–6.1 (M) 0.9–4.2 (M)
(× 109/L)
2.5–6.9 (F) 1.5–8.4 (F) 2.5–7.9 (F) 1.7–7.5 (F) 1.3–4.2 (F)
Lymphocytes NA 1.0–3.4 1.1–3.7 (M) 1.1–3.6 (M) 1.3–3.4 (M) 1.0–2.9 (M) 1.0–3.2 (M)
(× 109/L)
1.2–3.7 (F) 1.3–3.9 (F) 1.3–3.9 (F) 1.0–3.5 (F) 1.1–3.6 (F)
Monocytes NA 0.2–0.8 0.13–0.86 (M) 0.11–0.72 (M) 0.14–0.70 (M) 0.18–0.62 (M) 0.15–0.58 (M)
(× 109/L)
0.11–0.78 (F) 0.12–0.83 (F) 0.12–0.79 (F) 0.14–0.61 (F) 0.15–0.39 (F)
Platelets 145–348 140–320 161–385 161–381 166–388 143–332 115–290
(× 109/L) (M)
(F) 165–387 180–380 178–434 178–452 171–411 169–358 125–342
F, female; Hct, hematocrit; Hgb, hemoglobin; M, male; MCV, mean cell; NORIP, Nordic Reference Interval Project; U.K., United Kingdom; U.S.,
United States; WBC, white blood cell count; NA, measurement not available.
*Ranges calculated from adult (>18 years) data, assuming equal contribution of subjects from each of multiple adult age groups, derived from
the National Health and Nutrition Examination Survey (NHANES) III.
This table is provided as a guide. Normal ranges should be validated by the clinical laboratory for the specific methods in use.

Men
Subject no.
12
13
Women
24
1.0 3.0 5.0 7.0 12 14 16 18 80 90 100 110 100 200 300 400 500
Granulocytes (109/L) Hemoglobin (g/dL) MCV (fL) Platelets (109/L)
Figure 2–3. Absolute neutrophil count, hemoglobin, mean cell volume (MCV), and platelet count determined repeatedly by automated hematol-
ogy analyzer on 24 healthy elderly subjects. Fasting (7–9 am) blood samples were obtained 9 to 10 times at 14-day intervals from seated elderly sub-
jects with minimal stasis by the same phlebotomist and performed in duplicate on the morning specimen collection. Subjects had no chronic medical
conditions requiring therapy and were not taking drugs. The mean and range for each patient is shown separately for each assay. This is an illustration
of the relatively narrow range within which most variables are maintained in an individual, whereas there are striking differences in both mean and
variance between subjects. Reference ranges need to encompass at least 95% of values from all healthy individuals, placing limits on diagnostic
sensitivity in detecting progressive change in a hematologic variable, previously maintained in a homeostatic range. (Adapted with permission from
Fraser CG, Wilkinson SP, Neville RG, et al: Biologic variation of common hematologic laboratory quantities in the elderly. Am J Clin Pathol 92(4):465–470. 1989.)
Note the variation in reference ranges obtained from different Most hematologic variables show more stability within an individ-
studies. The major variability is likely population selection, especially ual than between individuals, illustrating one reason for the lack of sen-
the degree to which chronic illness or asymptomatic iron deficiency are sitivity and specificity of any test “cutoff,” which is typically designed for
excluded, and physiologic factors, such as diurnal variation, are consid- a population rather than for an individual person. A study of repeated
ered. For example, the Wakeman study92 exclusively used early morn- analyses of blood variables from older subjects98 graphically demon-
ing samples, hence the upper limit of leukocyte count is lower because strates this phenomenon. Some normal subjects have a normal steady-
of diurnal physiologic variation. The National Health and Nutritional state platelet count between 170 × 109/L and 200 × 109/L, whereas others
Examination Surveys (NHANES) III national database has the advan- have one between 280 × 109/L and 310 × 109/L (Fig. 2–3). For the latter
tage of being a very large broad nationwide sampling, which, as used group, a progressive fall in platelet count because of marrow failure may
by Cheng and colleagues,93 excluded any subjects with history of smok- not be detected as quickly as the former group. The same observations
ing, alcohol consumption, contraceptive use, and a variety of chronic are shown for absolute neutrophil count, hemoglobin, and MCV, among
diseases (excluding 60 percent of the tested subjects). However, those others. In normal subjects, the ratio of between subject to within subject
with asymptomatic iron deficiency were not excluded, so hemoglobin variation ranges from about two times for absolute neutrophil count99
tends to be lower than in studies that may have been weighted toward to four to six times for hemoglobin, platelet count, absolute reticulocyte
groups of individuals in which undiagnosed iron deficiency and other count, and MCV.100 Data from a large clinical trial’s central laboratory
asymptomatic disorders are less common. α- and β-thalassemia traits show similar findings for hemoglobin in study subjects with various
are also quite common in healthy individuals of certain ethnic groups, disease states. In this report bayesian methods were used to construct
and inclusion of subjects with these disorders will also affect reference a (narrower) personalized reference range using progressive accumu-
ranges. Normal lower limits for hemoglobin have been determined in lation of baseline measurements to achieve greater sensitivity to per-
U.S. subjects of different ethnic backgrounds carefully screened for turbations following treatment.101 Circadian variations in hematologic
occult disease.94 Such considerations also affect determination of the laboratory values, including hematocrit, total leukocyte count, serum
upper (97.5th percentile) limit of normal hematocrit and hemoglobin iron, and serum folate have been described.102 Some have proposed to
in relation to a possible diagnosis of polycythemia, where one has to customize reference ranges for time of sample collection, so that ref-
carefully weigh the likelihood that a “normal-range” study has ade- erence ranges aren’t inflated by the need to accommodate circadian
quately excluded iron-deficient subjects.95,96 Biomedical parameters variation.103 Genetic loci affect quantitative hematologic traits (such
are also subject to historical trends, such as the observed improvement as hemoglobin, MCH, platelet count, leukocyte count, etc.) in normal
in hemoglobin levels in the post–folic-acid-fortification era.97 Finally, subjects of European, African, and South Asian ancestry.104,105 The loci
when one observes significant changes in reference ranges based on age contain many candidate genes known to be involved in hematopoiesis,
(e.g., glomerular filtration rate, lipid parameters, hemoglobin), there is but known genetic influences identified in such studies only explain a
the question of whether this is physiologic or a result of increased prev- small proportion (4–9 percent) of the observed phenotypic heterogene-
alence of undiagnosed occult disease. ity of these variables.

film interpretation. For example, leukemic blasts may appear dense

MORPHOLOGIC EXAMINATION and rounded and lose their characteristic features when viewed in the
OF THE BLOOD thick part of the film. For specific purposes, the thick portion or side
and “feathered” edges of the film are of interest (for instance, to detect
Microscopic examination of the blood spread on a glass slide or cover-
microfilariae and malarial parasites or to search for large abnormal cells
slip yields useful information regarding all the cells of the blood. The
and platelet clumps).
process of preparing a thin blood film causes mechanical trauma to the
The blood film is first scanned at low magnification (×200) to confirm
cells, introducing artifacts that can be minimized by good technique.
reasonably even distribution of leukocytes and to check for abnormally
The optimal part of the stained blood film to use for morphologic
large or immature cells in the side and feathered edges of the film. The
examination of the blood cells should be sufficiently thin that a small
feathered edge is examined for platelet clumps. Abnormal cells, red cell
proportion of erythrocytes in a ×1000 magnification field touch each
aggregation or rouleaux, background bluish staining consistent with para-
other, but not so thin that no red cells are touching. Figure 2–4 is a
proteinemia, and parasites are all findings that can be suggested by medium
composite image taken from the optimal portion of the film showing
magnification examination (×400). The optimal portion of the film is then
the five major leukocyte types, normal red cells, and platelets. Selection
examined at high magnification (×1000, oil immersion) to systematically
of a portion of the blood film for analysis that is too thick or too thin
assess the size, shape, and morphology of the major cell lineages.
for proper morphologic evaluation is the most common error in blood
A B C
D E F
Figure 2–4. Images from a normal blood film showing major leukocyte types. The red cells are normocytic (normal size) and normochromic (nor-
mal hemoglobin content) with normal shape. The scattered platelets are normal in frequency and morphology. A. A platelet caught sitting in the
biconcavity of the red cell in the preparation of the blood film. This normal finding should not be mistaken for a red cell inclusion. Images are taken
from the optimal portion of the blood film for morphologic analysis. Image shows a (A) segmented (polymorphonuclear) neutrophil and in the inset
a band neutrophil; (B) monocyte; (C) small lymphocyte; (D) large granular lymphocyte, note larger size than lymphocyte in (C) and increased amount
of cytoplasm containing scattered eosinophilic granules; and (E) eosinophil. Virtually all normal blood eosinophils are bilobed and filled with relatively
large (compared to the neutrophil) eosinophilic granules. F. Basophil and in inset a basophil that was less degranulated during film preparation,
showing relatively large basophilic granules. The eosinophilic and basophilic granules are readily resolvable by light microscopy (×1000), whereas the
neutrophilic granule is not resolvable but in the aggregate imparts a faint tan coloration to the neutrophil cytoplasm, quite distinctly different from
the blue-gray cytoplasmic coloring of the monocyte and lymphocyte.

RED CELL MORPHOLOGY densely stained and appear smaller because of their rounded shape, and
show decreased or absent central pallor. A red cell with a spot or disc
Normal erythrocytes on dried films are nearly uniform in size, with a
of hemoglobin within the central pale area is a target cell, in reality a
mean diameter of approximately 7.5 μm (normal and abnormal red cells
cup-shaped cell that distorts as it is flattened on the glass slide. These
are described in more detail in Chap. 31). The normal-sized erythrocyte
cells are typically found in disorders of hemoglobin synthesis (e.g., tha-
is about the diameter of the nucleus of a small lymphocyte. The MCV is
lassemia), liver disease, and postsplenectomy where the cell-surface-to-
a more sensitive measure of red cell volume than the red cell diameter;
cell-volume ratio is high. Chapter 31 describes the inclusions that may
however, an experienced observer should be able to recognize abnor-
be observed in erythrocytes on blood films.
malities in average red cell size when the MCV is significantly elevated
Erythrocytes are usually distributed evenly throughout the blood
or decreased. Anisocytosis is the term that describes variation in ery-
film. In some cases the cells become aligned in overlapping stacks,
throcyte size, and is the morphologic correlate of the RDW. Macrocytes
referred to as rouleaux (Chap. 109), resembling overlapping rows of
and microcytes are red cells larger or smaller than normal, and their
coins. Rouleaux are normal in the thick part of the film, but when found
presence consistent with the measured MCV suggests certain diagnos-
in the optimal viewing portion of the film, suggest a pathologic increase
tic possibilities. Early (“shift” or “stress”) reticulocytes (i.e., those with
in immunoglobulin (Ig), particularly IgM-macroglobulinemia. Occa-
the most residual RNA) appear in stained films as large, slightly blu-
sionally, high concentrations of IgA or IgG in patients with myeloma
ish cells, referred to as polychromatophilic cells (Chap. 32). These cells
may also produce rouleaux.
are roughly the morphologic counterpart of the immature reticulocyte
The blood film is also useful to identify red cells with basophilic
fraction identified by automated instruments.
stippling (evidence of dyserythropoiesis), siderotic granules (evidence
The normal erythrocyte on a blood film is circular with central
of sideroblastic erythropoiesis), Heinz bodies (evidence of unstable
pallor. Poikilocytosis is a term used to describe variations in the shape
hemoglobins), and Howell-Jolly bodies (nuclear remnants). Microor-
of erythrocytes. The predominant appearance of a specific abnormality
ganisms other than malaria parasites also may be found in or attached
in red cell shape can be an important diagnostic clue in patients with
to red cells (Chap. 53).
anemia (Fig. 2–5). Erythrocytes with evenly spaced spikes (echinocytes
or crenated cells) can be an artifact caused by prolonged storage, or may
reflect metabolic erythrocyte abnormalities. PLATELET MORPHOLOGY
The normal erythrocyte appears as a disc with a rim of hemoglobin Platelets appear in normal stained blood film as small blue or colorless
and a clear central area, which normally occupies less than one-half the bodies with red or purple granules (see Fig. 2–4). Normal platelets aver-
cell diameter. Increased central pallor (hypochromia) is associated with age approximately 1 to 2 μm in diameter, but show wide variation in
disorders characterized by diminished hemoglobin synthesis, such as shape, from round to elongated, cigar-shaped forms. In improperly pre-
iron deficiency (Chap. 42). Evaluation of red cell hemoglobin content, pared films, platelets may form large aggregates in some areas and appear
as well as red cell size, is dependent on examining the proper part of to be diminished or absent in others. The frequent occurrence of giant
the blood film. Cells at the far “feathered edge” will always be large and platelets or platelet masses may indicate a myeloproliferative neoplasm
lack central pallor, whereas cells in the thick part of the film will look or improper collection of the blood specimen. The latter circumstance
small and rounded and will also lack central pallor. A sharp refractile can occur when venipuncture technique is faulty and platelets become
border demarcating the central area of pallor is an artifact secondary activated before the blood sample is thoroughly mixed with anticoag-
to inadequate drying of the film before staining (associated with high ulant. These platelet masses are apparent typically in the thin “feath-
humidity, and more common in anemic samples). Spherocytes are more ered edge” of the film, with corresponding fewer platelets elsewhere.
Figure 2–5. Disorders associated with certain red cell

Name Characteristic of Also seen in morphologic changes. Poikilocytosis is a general term used
Spherocyte Hereditary spherocytosis, Clostridial perfringens to indicate the presence of abnormally shaped red cells,
(Chaps. 31, 46, immune hemolytic septicemia, Wilson such as dacryocytes (teardrop-shaped red cells), schisto-
54) anemia disease cytes (fragmented red cells), and elliptocytes, as is found
Iron deficiency, megaloblastic in the most extreme form in hereditary pyropoikilocytosis
Elliptocyte Hereditary elliptocytosis
anemia, thalassemia, (Chap. 46). MDS, myelodysplastic syndromes (Chap. 87).
(Chaps. 31, 46) (HE)
myelofibrosis, MDS
Dacryocyte Severe iron deficiency,
(teardrop) Myelofibrosis megaloblastic anemia,
(Chaps. 31, 86) thalassemia, MDS
Schistocyte Microangiopathic, Occasional schistocytes are
(Chaps. 31, 51, mechanical hemolytic seen in many disorders
129, 132) anemia affecting red cells.
Echinocyte Renal failure, Common in vitro artifact
(Chaps. 31, 37) malnutrition after storage
Acanthocyte Spur cell anemia,

Postsplenectomy
(Chaps. 31, 56) abetalipoproteinemia
Target cell Cholestasis, Hgb C Iron deficiency,

(Chaps. 31, 48) disease thalassemia
Stomatocyte Hereditary
Alcoholism
(Chaps. 31, 46) stomatocytosis

A B C
D E F
G H
Figure 2–6. Blood films. A. Toxic granules in neutrophils. In inflammatory states the neutrophil may develop overt purplish granules as shown in
this example of reactive neutrophilia. B. Chédiak-Higashi disease. Note the giant eosinophilic granule in the monocyte and the numerous enlarged
granules in the lymphocyte (Chap. 66). C. Hurler syndrome. Note characteristic prominent dense cytoplasmic inclusions in the mononuclear cell.
These inclusions are accumulations of glycosaminoglycans resulting from a deficiency of α-l-iduronidase in leukocytes and other tissues. D. Examples
of apoptosis of two neutrophils in normal anticoagulated blood during standing at room temperature. Nuclear condensation and fragmentation
are evident. A normal neutrophil is also present. E. Döhle bodies. These RNA remnants of rough endoplasmic reticulum appear as blue rod-shaped
structures (arrow points to one) in neutrophils involved in inflammatory reactions. F. May-Hegglin disease. The large blue-gray inclusions (arrow)
represent precipitates of nonmuscle myosin heavy chain type IIA. Note also the two macrothrombocytes (the size of red cells) characteristic of
this disorder (Chap. 120). The neutrophil inclusions stain with fluorescent antibodies to nonmuscle myosin heavy chain type IIA. G. Marrow film. A
strand of endothelial cells derived from vascular tissue caught on the biopsy needle. Individual endothelial cells may be found, rarely in a blood film.
H. Platelet satellitism. Three neutrophils surrounded by adherent platelets. This blood film was prepared from an EDTA-anticoagulated sample. (Repro-
duced with permission from Lichtman’s Atlas of Hematology, www.accessmedicine.com.)
Platelet clumping throughout the blood film, or platelet “satellitism” (see Fig. 2–4). Neutrophils are round cells ranging from 10 to 14 μm
(adherence of platelets to neutrophils), may be a result of platelet agglu- in diameter on a blood film. The nucleus is lobulated, with two to four
tinins (Fig. 2–6). A platelet will occasionally overlie an erythrocyte, lobes connected by a thin chromatin thread. The defining feature of
where it may be mistaken for an inclusion body or a parasite. The dif- the mature neutrophil is the round lobes with condensed chromatin,
ferentiation depends on the observation of a halo around the platelet, because the chromatin thread may overlie the nucleus and not be visi-
determination that it lies above the plane of the erythrocyte, and obser- ble. The chromatin stains purple and is coarse and arranged in clumps.
vation of the characteristics of a normal platelet in the “inclusion.” The nucleus of 1 to 16 percent of the neutrophils from females may have
an appendage that is shaped like a drumstick and is attached to one lobe
by a strand of chromatin. It represents the inactive X chromosome of
LEUKOCYTE MORPHOLOGY the pair. The cytoplasm is diffusely pale pink and contains many small,
The cells normally found in blood are mature neutrophils, lymphocytes, tan to pink granules distributed evenly throughout the cell. Bands are
and monocytes, with smaller numbers of eosinophils and basophils identical in appearance to mature neutrophils except that the nucleus

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Astronomen und Mathematiker Apollonios von Perge Ε[83], typische
Schulspitznamen, wie sie wohl heute noch auf jedem Gymnasium
vorkommen. Sie haben meist eine ganz gleichgültige zufällige
Entstehungsursache, die bald vergessen wird. Später werden dann
irgendwelche Gründe hinzugedichtet. Die unwahrscheinlichen
Anlässe, die Ptolemaeus Hephaestion u. a. überliefern, hat Lehrs a.
a. O. widerlegt. Aber wenn er nun alles auf körperliche Ähnlichkeit
der Benannten mit den betreffenden Buchstaben zurückführen will,
so ist das wieder einseitig. Wir werden uns da etwas bescheiden
müssen.
Bloße Numerierung ist es, wenn Martial II 57 und V 26 einen
Freund alpha paenulatorum und sich selber beta togatorum tituliert.
Anth. Palat. XI 15 ist ein Scherz an einen Arzt, der verschiedene
Leute, deren Namen mit A anfängt, totkuriert hatte. Da der Arzt
demnach anscheinend in alphabetischer Reihenfolge vorzugehen
gedenkt, will der Dichter Ὠριγένης heißen.
Das Sprichwort liebt die Häufung in symmetrischer Form. Da
entwickelt sich entweder die Priamel
Beispiel: Ὑγιαίνειν μὲν ἄριστον ἀνδρὶ ϑνατῷ
δεύτερον δὲ φυὰν ϰαλὸν γενέσϑαι usw.[84]
oder das Zahlensprichwort, das der Orientale so liebt. Beispiel:
Vier Tiere dürfen mit der Halfter angetrieben werden: das Pferd, das
Maultier, das Kamel und der Esel. — Sechs Dinge dienen dem
Menschen, drei sind in seiner Gewalt und drei sind nicht in seiner
Gewalt: das Auge, das Ohr und die Nase sind nicht in seiner Gewalt.
Der Mund, die Hand und der Fuß sind in seiner Gewalt (Talmud.)[85]
Diesen Formen ist nahe verwandt die Spielerei mit mehreren
Worten, die gleiche Anfangsbuchstaben haben. In dem Stabreim,
der so entsteht, kommt der sich wiederholende Buchstabe
besonders zu Ehren und wird als das Wichtigste hervorgehoben.
Etwa: τρία ϰάππα ϰάϰιστα, nämlich Kreter, Kilikier, Kappadokier
(Suidas s. v. ϰάππα); lateinisch: Cornelius Sulla, Cornelius Cinna,
Cornelius Lentulus: Schneidewin-Leutsch, Paroemiogr. II S. 369 (aus
Augustinus, de grammat.). Friedensburg, Die Symbolik der
Mittelaltermünzen I, Berlin 1913 S. 90 verweist auf Gesta
Romanorum Kap. 13, 42, 125 und Anhang Kap. 3 der Grässeschen
Ausgabe und gibt als Beispiel: „Vier P soll jeder ehren: patriam,
parentes, praeceptorem, praetorem“ und die drei Regierungsmittel
des Rè Bomba Ferdinand II. von Neapel: farina, forca, festa. Dazu
kämen noch die „drei bösen Weh“, die unter König Friedrich I. das
Land Preußen plagten: Wartenberg, Wittgenstein, Wartensleben.
[61] Johannes Lydus, De mens. II 8 p. 28 Wünsch: οἱ
Πυϑαγορεῖοι τριάδα μὲν ἐν ἀριϑμοῖς ἔν τε σχήμασι τὸ ὀρϑογώνιον
τρίγωνον ὑποτίϑενται στοιχεῖον τῆς τῶν ὅλων γενέσεως, dazu
Lobeck, Aglaophamus 1345. Delatte, BCH 37 (1913) S. 263 ff.
Deltoton als Sternbild bei Aratos 233 und an vielen anderen
Stellen; danach heißt es in einem byzantinischen Gesprächbuch:
Δέλτα ἀπὸ τοῦ δελτωτοῦ ἐξ ἀστέρων συγϰειμένου. Heinrici,
Abhandl. d. sächs. Ges. philos.-histor. Kl. 28 (1911) S. 90, 18.
Wortlaut gebessert von Stählin, Byzantin. Zeitschr. 21 (1913) S.
508.
[62] Zu diesem Ausdruck s. unten in dem Abschnitt über
Onomatomantie.
[63] Es folgt dann dort eine Deutung der einzelnen
Buchstaben auf die Etappen der Schöpfung. Von Π ab gehen die
Zeichen auf Christus (p. 271 ff.). Auf S. 114 steht eine Abbildung,
wo das Delta-Dreieck als Bild des Kosmos in mehrere
Stockwerke eingeteilt ist, die den obersten Himmel, die Wasser
des Himmels, das Firmament, die Erde bezeichnen. Zu diesen
Stockwerken gibt es nach einer Mitteilung von Dr. C. Jaeger-
Straßburg auch äthiopische Belege. In einer Handschrift des
Britischen Museums Orient 503 fol. 1 b steht eine Abhandlung
über die Schönheit der Schöpfung, worin folgende fünf
Stockwerke festgestellt werden: Himmel des Lichtes, das obere
Wasser, der Plafond, das untere Wasser, die Erde. Die
Einzeichnung in ein Dreieck findet sich dort nicht.
[64] Vgl. Lobeck, Aglaophamus 1341.
[65] Friedensburg, Berliner Münzblätter N. F. 4 S. 25. Martial
VII 37, 2.
[66] Friedensburg, Symbolik der Mittelaltermünzen I, Berlin
1913 S. 69 ff.
[67] Albrecht Dieterich, Nekyia S. 182, Kleine Schriften S.
472. Wünsch, Sethianische Verfluchungstafeln S. 98.
[68] Persius III 56 mit Scholien. Lactant. instit. div. VI 3, 6.
Servius zu Aen. 6, 136. Ausonius technop. 12. 13 p. 138 Schenkl;
Maximinus in Anthol. lat. 632 Riese; Martian. Cap. II § 102;
Hieronymus in Eccl. Migne, PL 23, 1091; vgl. Lobeck,
Aglaophamus S. 1341, 1344; Dieterich, Nekyia (1893) S. 192;
Pascal in den Miscellanea Ceriani (1910) p. 64; Wolfgang
Schultz, Philologus 68 (1909) S. 488 ff.
[69] Steinthal, Geschichte der Sprachwissenschaft der
Griechen und Römer² II (1891) S. 366.
[70] Ἐτυμολογία τοῦ ἀλφαβήτου Etym. Gud. Anhang p. 595
Sturz.
[71] Heinrici, Die griechisch-byzantinischen Gesprächbücher,
Abhandl. d. Kgl. sächs. Gesellschaft d. Wissenschaften, histor.-
philol. Klasse, Bd. 28 (1911) S. 90, 14; Nachträgliches zu den
griechisch-byzantinischen Gesprächbüchern, Berichte der Kgl.
sächs. Gesellschaft, histor.-philol. Kl. Bd. 64 (1912) 8. 179 f.: ein
cento grammaticus codex Marcianus VII 38. In der ersten
Heinricischen Abhandlung S. 87, 27, stehen einige Zeilen über
Buchstaben als σφραγῖδες. Ganz Ähnliches findet sich in einer
Handschrift des Briefes Jesu an König Abgar von Edessa, der im
Mittelalter als Palladium diente, s. Dobschütz, Zeitschrift für
wissenschaftliche Theologie 43 (1900) S. 443.
[72] Hrsg. von R. Foerster, Index lectionum Vratislaviensium
1891.
[73] So empfindet noch heute der Orient. Hohes Alter ist das
erste, was man von der Überlieferung verlangt. Und gegen die
Tradition vermögen moderne Errungenschaften nur schwer
aufzukommen.
[74] Dasselbe steht praep. ev. XI 6 p. 519.
[75] Zur Zeitbestimmung J. B. Kellner, Der hl. Ambrosius als
Erklärer des AT, Regensburg 1893 S. 153. Ambrosius versteht es
dabei, einen Zusammenhang der Anfangsbuchstaben mit dem
Inhalt der damit begonnenen Verse nachzuweisen. Der
Buchstabe des Akrostichons erscheint so als Titel. Als Beispiel
diene Vers 4: Daleth bedeutet entweder „Furcht“ oder „Geburt“
(Ambrosius kann kein Hebräisch). Beides paßt; denn die Geburt
ist etwas Materielles und Hinfälliges, deshalb nicht frei von
Furcht. Vortrefflich bestätigt dies die erste Zeile: „Am Staube hing
meine Seele“; denn Staub ist Erde, und die Erde ist etwas
Materielles.
[76] Iren. adv. haeres. I 20. Kindheitsevangelium des Thomas
cap. 6. Dazu Hennecke, Handbuch zu den neutestamentlichen
Apokryphen, Tübingen 1904, 8. 136 ff., bes. S. 142 eine indische
Parallele: jeder Buchstabe ist der Anfang eines Spruches. Auch
den Muslim hat die Geschichte von dem Jesusknaben gefallen,
vgl. Schanawânî Bl. 16 (s. oben S. 5 Anm. 5) bei Goldziher,
Zeitschrift d. deutschen morgenl. Gesellschaft 26 (1872) S. 784.
[77] Von deren Existenz wir zudem gar nichts wissen. D. H.
Müllers Ergebnisse abgelehnt auch von Franz Wutz, Onomastica
sacra, Texte und Untersuchungen 41, 1 (1914) S. 216–231.
[78] Dazu Goebel, Ethnica, de Graecorum civitatum
proprietatibus proverbio notatis, Diss. Breslau 1915 S. 80 f.
[79] Der Schulmeister Eunus, ein fellator, der alle Sexualia in
seinem Schuljargon wiedergibt, sieht das membrum muliebre für
ein Rechteck an. Das hat den Vorteil, daß, wenn die eine Seite
zusammengezogen wird, der Buchstabe Δέλτα herauskommt, der
gewöhnliche Name für das γυναιϰεῖον αἰδοῖον s. oben S. 20 f. Die
Rückansicht der Menschen erklärt er für ein Ψ (gebildet von den
drei Linien: Grenze zwischen den Beinen und untere Grenze der
beiden nates). Ubi si Eunus ligurrit, anus patet sicut Λ. Φ litera
Ausonius aut πορδήν imitari mihi videtur, quae paedogogo
ligurrienti sentienda est, aut figuram, quae natibus pueri et lingua
istius paedagogi efficitur. Im letzten Vers wird ihm die Strafe den
Θ(άνατος) gewünscht (s. oben S. 22). Die Verse 10–12 verstehe
ich nicht.
[80] Preisendanz RM 68 (1913) S. 640.
[81] Herodot V 92.
[82] Marcian. Heracl. epit. peripl. Menippei 2.
[83] Phot. bibl. p. 151, 21; Lehrs, Quaestiones epicae,
Königsberg 1837 p. 19 ff.
[84] Euling, Die Priamel bis Hans Rosenplüt, Germanist.
Abhandlungen hrsg. v. Voigt Bd. 25, Breslau 1905.
[85] Wünsche, Die Zahlensprüche im Talmud und Midrasch,
ZDMG 65 (1911) und 66 (1912).
LEBENSLAUF
Ich, Franz Dornseiff, geboren zu Gießen am 20. März 1888, bin
ein Sohn des Landsgerichtsdirektors Karl Dornseiff und seiner
verstorbenen Frau Käthe geb. Baltzer. Ich besuchte zuerst das
Gymnasium zu Gießen, seit 1904 das Neue Gymnasium zu
Darmstadt, das ich Ostern 1906 verließ, um mich dem Studium der
klassischen Philologie und Germanistik zu widmen. Ich war 3
Semester in Heidelberg, 1 in München, 5 in Berlin.
An diesen Universitäten hörte ich Vorlesungen und besuchte
Übungen bei den Herren Professoren: Boll, Brandt, Dieterich † , v.
Domaszewski, v. Duhn, Elsenhans, Petsch, F. A. Schmid, Schoell,
Uhlig †, Windelband † (Heidelberg); Crusius, von der Leyen, Vollmer
(München); Cassirer, Dessau, Diels, von Harnack, Helm, Meister,
Eduard Meyer, Norden, Riehl, Roethe, Sieglin, Simmel, Vahlen † ,
Wentzel, v. Wilamowitz-Moellendorff, Woelfflin (Berlin).
Ihnen allen schulde ich herzlichen Dank. In besonderem Maß
bin ich Herrn Geh. Hofrat Prof. Dr. Boll verpflichtet, der mich zu
dieser Arbeit angeregt und sie ständig mit fördernder Teilnahme
begleitet hat. Er hat mich dadurch zu wirklicher Forschung geführt
und meine Neigung besonders zu dieser Materie vertieft.
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8. Hematology during Pregnancy . . . . . . . . . . . . . . . . . . . . . . . . . . 119 27. Vaccine Therapy . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 421

9. Hematology in Older Persons . . . . . . . . . . . . . . . . . . . . . . . . . . . 129 28. Th

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35. Aplastic Anemia: Acquired and Inherited . . . . . . . . . . . . . . . . . 513

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123. Hemophilia A and Hemophilia B . . . . . . . . . . . . . . . . . . . . . . . 2113 133. Venous Thrombosis . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 2267

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Robert F. Betts, MD [82] Francis K. Buadi, MD [108]

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José A. Lópéz, MD [117] Jeffrey McCullough, MD [138]

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Robert S. Negrin, MD [23] Mortimer Poncz, MD [118]

Hans D. Ochs, MD [80] Pierluigi Porcu, MD [94]

Charles J. Parker, MD [40] Gordana Raca, MD, PhD [13]

Kaushansky_FM_pi_xxii.indd 17 9/21/15 4:40 PM

A. Koneti Rao, MD [120] Jia Ruan, MD, PhD [135]

Katayoun Rezvani, MD [27] Uri Seligsohn, MD [116, 129]

Kaushansky_FM_pi_xxii.indd 18 9/21/15 4:41 PM

Taimur Sher, MD [108] Perumal Thiagarajan, MD [32, 33]

C. Wayne Smith, MD [60, 61] Guido Tricot, MD, PhD [105]

Madina Sukhanova, PhD [13] Sumithira Vasu, MBBS [79]

Kaushansky_FM_pi_xxii.indd 19 9/21/15 4:41 PM

John Wagner, MD [30] Karl Welte, MD [65]

Dietlind L. Wahner-Roedler, MD [110] Erik Wendlandt, PhD [105]

Robert Weinstein, MD [28]

Kaushansky_FM_pi_xxii.indd 20 9/21/15 4:41 PM

Kaushansky_FM_pi_xxii.indd 21 9/21/15 4:41 PM

123. Hemophilia A and Hemophilia B . . . . . . . . . . . . . . . . . . . . . . . 2113 133. Venous Thrombosis . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 2267

QUANTITATIVE MEASURES OF CELLS IN