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Williams
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
New York Chicago San Francisco Athens London Madrid Mexico City
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

6 Part I: Clinical Evaluation of the Patient
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

Chapter 1: Initial Approach to the Patient: History and Physical Examination 7
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.

Another random document with
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á esplicar la situació de la casa, pera veure si s’emportava alguna
criatura ó ausiliava á la mare, pero ahir al vespre, que jo hi vaig
tornar, encara no s’hi havia acostat… Sort dels vehins que essent casi
tan pobres com ells, fan més de lo que poden pera cuydar á l’ávia y á
la partera.
—¡Ay dels pobres, si no fossin los pobres! —esclamá tristament la

Presidenta. Y tot seguit digué dirigintse al sacerdot:
—¿No li apar que’s podria fer una solicitut á la Beneficencia de la

Parroquia? ¿vosté ja ho recomanará, veritat?
—Si, si; que la fassin avans del dissapte. Y si l’home fa llit, també’s
podria cercar la cooperació de la Caritat Cristiana.
—¿Vosté se’n podrá encarregar senyora Guerra de fer aquestas

diligencias?
—Jo tinch al meu marit un xich delicat y no sé si podré sortir aquesta

tarde; pero ja havém quedat ab la meua companya que si jo no hi
podia anar, ella faria las diligencias necessarias per aquesta pobre
familia. Si alguna senyora te robeta petita, llensols vells, camisas, en
fí, lo que sía, que fassa la caritat d’enviarho pensant que en aquella
casa tot hi fa falta. ¡Allí si que serian precisos á més dels bonos de pá,
los que’s poguessen donar pera caldo, mentres se corra pe’ls demes
ausilis!
—¡Válgans Deu! ¡com més déficit més necessitats! —esclamá la

Presidenta; y dirigintse á la Tresorera digué:
—Pósili sis bonos de carn.

—Y ¿vosté, senyora Prats?
—Jo crech que aquesta setmana quedará llest lo dels orfanets

Campins. Nostre Senyor nos ha ajudat y com la superiora del
Albergue de Sant Antoni en la providencia d’aquesta barriada, hem
quedat que si surt alguna almoyna pera pagar la mesada de la nena li
donarém y sino será lo mateix: ella se la queda. Y pe’l noy malalt
també s’ha pogut alcansar una plassa gratuhita al Asilo de noys
escrofulosos de Sant Joan de Deu. Lo Padre superior apesar de no
tenir cap vacant, l’ha admés. S’ ha fet cárrech de la desgracia
d’aquestas pobras criaturas…
La Presidenta continuá preguntant ab la mateixa forma á cada una

de las senyoras allí reunidas y al acabar digué:
—Ara m’es precís á mi exposar la situació de la familia Dominguez,

aquella pobra senyora andalussa, viuda de un empleat ab quatre
noyas, que quan nosaltres anarem á visitarlas per primera vegada, ja
li havian fugit de casa las duas grans… La infelis está esparverada ab
las que li quedan, tement que’l mal exemple de las altras y la miseria
que passan…
—¿Qué no treballan? —interrumpí’l sacerdot.
—¡Treballar! Fan calsotets, que’ls ne donan noranta céntims per

cusirne una dotzena!; y encara tenen que posarhi’l fil y pagar catorse
rals cada setmana per la máquina de cusir que las ha fet tornar mitj
tísicas á totas duas! Y aixó no es tot. La Emilia, tenia promés. Ja feya
tres mesos que entrava á la casa, quan la mare ha sapigut que era un
trampós, un home de mala conducta. La pobra dona desatinada l’ha
tret; pero com segons sembla es dels que va armat á las casas de joch,
ha dit que si no’l tornan á admetre, allá ahont las trobi las matará. La
pobra dona vá venir á casa esglayadísima y me digué que si ella
tingués diners pera anársen á Bilbao, ahont hi té un germá que
sembla que está arregladet y las vol, marxaria immediatament, aixís
per fugir del promés de la noya, com per tenir un apoyo…
—Pero’l viatje d’aquí á Bilbao…
—La senyora Sanmartí, ja ho ha gestionat y la Companyia del

ferrocarril del Nort ha fet la caritat de donarlos mitj pasatje franch…
Las dificultats son per l’altre mitj… Ja hi há recullida alguna cosa,
pero no basta…
Lo sacerdot parlá de baix en baix, algunas pocas paraulas ab la

Presidenta y aquesta digué:
—¡Deu li pagui! Aixís me sembla que aquest assumpto quedará

arreglat y aqueixa pobra familia podrá sortirse de tan trista situació.
Ara aném á la familia Saleta. Ab la senyora Marsal varem anar á casa
de don Melcior Ferrer, qui s’ha portat nobilíssimament ab la
Conferencia; donchs á més de donarme una almoyna per aqueixa
desventurada familia, m’ha promés que apesar de sas moltas
ocupacions s’encarregaria del assumpto d’aquest pobre home, que
ben ignocentament lo poden portar á un presiri.
—¿Y la familia? —preguntá ab interés lo Director.
—La seua dona fa molta llástima. La desgracia li ha vingut tant de

nou, que no hi há pas manera de que s’hi conformi. Las criaturas
apesar de sos pochs anys, sembla que comprenen la terrible
pedregada que’ls ha caygut á sobre. Allá no hi há recursos de cap
mena, puig lo que s’ha pogut recullir jo’ls hi guardo per si es possible
que ell se’n vaji á Fransa, fins á esperar l’éxit de las gestions del
advocat, que com es de primera talla, hi ha molt que confiar.— Y
girantse seguidament envers la Tresorera digué:
—Reparteixi’ls bonos.
La Secretaria aná cridant una per una, á totas las senyoras allí
reunidas, afegint al nom de la sócia, lo del pobre que li corresponia,
pera ferli entrega dels bonos de pá, arrós, carn, llet y patatas, que
estavan destinats á la familia que visitava.
Acabat lo repartiment, lo sacerdot ab tó persuassiu y elegant dicció,

feu una breu y sentida plática plena d’evangélica caritat, que fou
atentament escoltada y tot seguit la Tresorera passá una grossa bossa
de felpa blava, en la que cada senyora hi ficá la má, depositanthi la
seua almoyna.
Acabada la col·lecta aquesta se vuydá dessobre la taula. Las sócias

reunidas eran vinticinch y en la cantitat recullida s’hi trobaren divuyt
pessetas en monedas de cuatre rals, una de vuyt, dos duros y cinch
mitjas pessetas.
La Tresorera recullí la cantitat; la Secretaria l’apuntá en lo llibre

d’actas y la Presidenta agenollantse seguida de las sócias, resá unas
curtíssimas oracions que donaren per acabada la sessió,
qu’escassament havia durat una hora, portantse ab un órdre y
rectitut verament monástica. Mes tan bon punt s’hagué fet la senyal
de la creu y s’aixecaren las senyoras, paresqué qu’en la cambra
s’acabava d’obrir la resclosa d’un riu impetuós. Com esbart d’aucellas
que l’esparver destria, quedá trencada en vint parts la simétrica
renglera de cadiras; y las senyoras aplegantse en rotllos de tres, de
cinch, de cuatre, segons s’esqueya, romperen en animada conversa
que contrastava ab la severa rigidés fins aquell instant
escrupulosament observada.
Aquella cambra pareixía una miniatura del saló de conferencias del

Congrés, tant per l’animació y efervescencia que hi regnava, com per
sentirse que en un rotllo se demanavan recomanacions; en l’altre
feyna de roba blanca; en altre mitjas á fer; en aquell se combinava
dia y hora pera fer alguna diligencia relativa á tal ó qual pobre ó
sensillament pera ferli la visita de la setmana; en tant que en lo de
més enllá se tractava la manera de pagar un didatje ó gestionar la
entrada en las Hermanitas dels pobres d’algun vell desamparat. En la
taula’l rotllo era molt més nombrós: totas las sócias tenian quelcom
que ultimar ó recomenar al Director ó á las quatre senyoras que
formavan la junta de la Conferencia y que á totas las sócias rebian ab
fraternal afecte.
La Montserrat contemplá ab creixent interés l’animada escena que’s

desplegava devant de sos ulls. Ni en visitas, ni en passeigs, havia vist
á senyoras de tan diversas edats y condicions, impregnadas per un
igual d’aquella atmósfera de goig, de benestar, que resplandia en la
cara de las que veya entorn seu. Ni una expressió d’enuig, ni un gesto
de desdeny, ni una sombra d’ergull, ni un signe de cansanci… ¿Era
que totas tenían lo dó de la felicitat, ó mellor dit, de la perfecció
moral? Sens dubte que, subjectes com tots los éssers creats á la
ineludible lley de las debilitats humanas, cada una tenia sos defectes,
y ab sos més ó menos graus de felicitat, sas penas ó sos rosechs; pero
era que en aquells moments gosavan en comunitat de la més
hermosa y més consoladora de las virtuts: s’oblidavan de si mateixas,
per endolsir y socorre infortunis, que aixís per sa magnitut, com per
ésser vistos per sos propis ulls, los feyan agrahir més l’afavoriment
de la seua posició ó ab més facilitat conformarse ab las propias
penas; era que’s desenrotllava davant seu la transformació del cent
per hú, de la hermosa promesa de Jesucrist; la petita almoyna, que
individualment no hauria bastat pera res, ajuntada al fondo comú
operava lo miracle dels peixos y pans del Evangeli; y la probabilitat
del éxit, la interna satisfacció de servir d’instrument de la Divina
Providencia, la emulació del bé, la comunió de las bonas obras, com
tots los goigs dels plahers místichs, enlayrantse envers lo cel,
apartavan lluny de sí las engrunadas petitesas de la terra…
Mes eix raig de celístia del paradís durá poca estona: la porta s’obrí,
donant pas á las senyoras que anaren sortint de la cambra; y la veu
de donya Balbina indicant á la Montserrat son desitj de presentarla á
la Presidenta, tragué á la noya del ensimismament en que l’havia
sotmesa l’interés y novedat de la sessió á que acabava de assistir.
Atansantse á la taula pogué veure d’aprop á la persona que anava á

saludar. Era aquesta una senyora d’uns cuaranta anys, de distingidas
maneras, d’atractiva fesomía, de cabell castany graciosament
ondejat, de mirada dolsa y penetrant á la vegada, de escayenta y
baixeta figura, que encara que sensillament vestida ab lo trajo negre,
que pareixía ésser lo preferit per la Associació, deixava veure la
elegancia de la dama de societat.
Donya Balbina li feu la presentació de la Montserrat y la Presidenta li
allargá la má dihentli afectuosament:
—¿No tindrém lo plaher d’haverli fet entrar desitj d’ésser germana

nostra?
—¡Ay! senyora —feu la Montserrat ab la vehemencia de la impresió

de lo que acabava de presenciar— los desitjos no’m mancan, pero vist
lo que vostés fan, no’m reconech ab suficients qualitats pera tenir
aquesta honra. Jo coneixía de nom las Conferencias de Sant Vicens
de Paul, pero li confesso francament, que no tenia idea de lo que son.
Me creya, per haverho sentit explicar, que era una Associació que
ajuntava las almoynas que recullía pera comprar comestibles que
donava á las familias pobres y… res més. Cregui que no sé tornar en
mí de l’admiració que m’ha causat lo que he sentit… Aixó es una cosa
tan grandiosa com nova; una Associació de Caritat, ahont apar que’ls
diners son lo de menos… perque verdaderament al pobre que se li
col·locan los fills, que en sas malaltías se li cercan ausilis, que se li
busca feyna ó medis pera guanyarse la vida, se li fá un bé cent
vegadas més gran que donantli un, ni tres, ni quatre duros…
—¡Oh filla, filla, aixó no ho alcansém sempre ni molt menos! —

interrumpí somrihent la Presidenta.— ¡Tant de bó que ho logréssim
tan sols la meytat de las vegadas que ho solicitém!
—Pero vostés ho intentan, ho treballan y’s veu que moltas voltas

l’éxit corona los seus esforsos. Cregui que tot aixó m’ha cautivat
sobre manera, pero reconech que per pertanyer á aquesta Associació
es precís á més de poguer disposar de medis pecuniaris, un talent, un
tacte…
—¡Cá! No ho cregui. Per ésser de las Conferencias no’s necessitan
més que las tres cosas que recomana Sant Vicens de Paul. Caritat,
Caritat y Caritat.
Com vosté pot compendre, entre quaranta duas sócias que avuy
compta la nostra Conferencia, n’hi ha de moltas intel·ligencias y
posicions, y no n’hi ha una sola que deixi de ferhi lo seu bon servey.
Es com un ram de flors en lo que aixís hi dona la seva fragancia la
aristocrática gardenia, com la humil maría-lluísa; aixó deixant de
banda que la forsa de la caritat es prodigiosa: senyora hi há, que si
vosté hi enrahonava, li semblaría que es una intel·ligencia que no
arriva á mitjana, y si jo li comptava las cosas que ha lograt per los
seus pobres y la sutilitat de la seua diplomacia, per reconciliar lo
marit ab la muller, los fills ab los pares y fins lo fadrí despedit ab
l’amo enutjat, se’n faria creus. Caritat de cor, d’ánima ¡res més que
Caritat! Miri, hi há sócias que la Conferencia se’n refía pe’ls diners,
altras per las influencias, altras pe’l temps que poden dedicarshi,
altras per la bona voluntat; y de tots aquestos elements que
disgregats se pot assegurar que foran molt poca cosa,
cooperativament, gracias á la ajuda de Deu, á la emulació y á la forsa
imitativa del exemple, naix aquest tot que á vosté li apar tan
admirable. Y vaig á dirli una cosa de la que’n tinch plena convicció:
un dels elements que més bé podrian fer á la nostra obra, es lo de las
senyoretas solteras que passan dels trenta anys y las viudas sense
fills. La dona deslligada de las obligacions més íntimas de la familia,
que arrossega entre la efervescencia del mon la buydor y lo aislament
del seu estat, seria una adquisició per las Conferencias, á las que hi
podrian fer un gran bé, consagranthi la forsa de la seua joventut, de
la seua inteligencia y dels seus sentiments, fent de pas la felicitat de
son cor ab una hermosa manera d’omplir la buydor de la seua vida.
—Vosté te molt talent y molta amabilitat, senyora —interrumpí la

Montserrat— y tinch por de que no li costaria de convéncem…
—Pero jo tampoch desitjo catequisarla de moment. M’ estimo més

que primer ho vegi sobre’l terreno, que fassi la práctica de lo que
acaba de sentir —digué la Presidenta; y girantse envers la germana
del doctor Valls li preguntá:
—Vosté Balbina ¿ab quí visita?
—Ab la senyora Agulló.
—Perfectament. Fassin las visitas juntas, y si en lo camp práctich li

agrada tant la nostra obra, com en la sessió que ha presenciat avuy,
tindré molt gust en proposarla la vinenta setmana.
Pochs minuts després la Montserrat caminava carrer d’Aragó amunt,

entre donya Balbina Valls y la senyora Agulló, que apesar de las
escusas de la neófita s’empenyaren en portarla al mitg de totas duas.
Al arribar al carrer del Bruch la senyora Agulló, preguntá á la sua
companya.— ¿Visitém á la Treno primer, ó á la Roca?
—Casi si á vosté li venia be, preferia anar primer á la meua —digué

donya Balbina,— perque dins del manguito porto una camiseta de
llana del meu germá pe’l noy de la Roca y no’m deixa ficar be las
mans; y com lo fret se deixa sentir…
—Com vulgui; com vulgui —repetí la senyora Agulló. Ho deya, per
dirigirnos cap á la dreta ó cap á l’esquerra; donchs crech que la seua
pobre está molt per munt.
—¿Vosté no l’ha visitada may?
—No; sols la conech per lo que he sentit parlar d’ella en la

Conferencia á vosté y á la senyora Santmartí.
—¡Y tant que convé que vosté la vegi á aquesta familia! —feu la
senyora Valls.
—¡Jo!
—Vosté, vosté. Es una pobre que interessa sobre manera y jo estich

segura, que una volta l’hagi visitada, vosté fará lo que ha fet per
tantas altres.
La senyora Agulló semblá compendre perfectament lo que’s volia

d’ella y digué:
—Per lo mateix que ho he fet per tantas, ja no sé com lograrho per

cap més. Tinch por d’abusar massa… y més que tot, me consta que lo
que aquestos senyors, comensaren per una cantitat ja molt crescuda,
ha arribat á triplicarse y quintuplicarse, y que per lo tant costa
moltíssim de que acceptin cap pobre nou.
—Ja’n sé alguna cosa d’aixó; pero en fí vosté veurá á aquesta pobre

viuda y estich certa que hi fará lo que pugui y Nostre Senyor se
cuydará de lo demés. Miri, ja hi havém arribat —feu donya Balbina,
dirigintse á una casa de pobre apariencia de las últimas edificadas en
lo carrer del Bruch.
—¿Saben que mirant l’ensanxe de pas, ningú diria que hi visquessin

pobres tant necessitats, ni que entre mitj de tanta llum y de tanta
esplendidesa, hi hagin aquestas escalas tan foscas, tan encofornadas
y brutas? —saltá la Montserrat fixantse que després del primer tram
d’esgrahons, la escala que pujavan á més d’anarse estrenyent fins á
uns vuytanta centímetres, estava plena de pols, papers, encenalls y
altres immundicias per l’estil.
—Vaja, ja conech que será bona observadora —digué donya Balbina

que á causa de patir d’ofech, tenia que reposar una estoneta á cada
replá— sens que ningú’n fassi esment, sembla estrany com lo visitar
pobres predisposa á la observació y á fer filosofías. Apesar de que la
nostra feyna es sempre pe’ls voltans de las Salesas, com també nos
donan lo seu que fer las porterías y quints pisos dels extréms del
carrer de Lauria, Bruch, Girona, Concell de Cent y Valencia, y entre
ells hi há també las seuas casas de luxo y fins los seus palaus, quan
un baixa de veure tantas miserias, involuntariament se li ocorren
ideas, que estich segura es impossible las concebeixi qui no s’hagi
dedicat á la tasca de visitar pobres. ¡Quants miracles se podrian
realisar ab lo concurs de tots los que tenen cor y possibles per
ferho!… En fí ja li he dit que aquest terreno —feu la senyora Valls
arrivant al replá del quint pis y trucant en la última de las quatre
portas que hi havia arrengleradas— fá acudir á la imaginació moltas
ideas que la gent que no veuhen més pobres, que’ls que corran pe’ls
carrers ne diuhen utópias ó follías…
Ab lo mohiment de trucar, la porta que sols estava ajustada se mitj
obrí, y una noyeta d’uns quatre anys flaca y esgroguehida, tragué’l
cap per la escletja y després de deixarla oberta de bat á bat, se ficá
endintre cridant ab tó d’alegria.
—¡Mare! ¡Mare! ¡Las senyoras de la setmana entrant!
—Aquesta criatura com que al despedirnos dihem sempre: “Fins á la

setmana entrant” nos ho ha deixat per nom —feu donya Balbina tot
ficantse per un estret corredor que acabava ab una petita sala ab
arcoba.
Unas cortinas de indiana ratlladas de blanch y vermell que tapavan

lo llit; una taula de fusta pintada, sis ó set cadiras, de diferentas
formas y edats, segons se veya per ésser unas bastant més vellas que
las altres; un bagul y un mitj armari, que’s coneixia devia haver
tingut en son temps lo seu corresponent sócol y al que á més
d’aquest, hi mancava mitja porta, constituhía lo moblatje del quarto,
que rebia llum per un petit balcó, obstruhit en aquells moments, per
una corda plena de roba á mitg assecar, que una dona d’uns trenta
set á trenta vuyt anys, anava girant á fí d’aixugarla més prompte.
Tan aviat entraren las senyoras, la dona tancá com pogué’l balcó y
s’apressá á donarlos cadiras, cercant las més novas y reforsadas.
—No s’amohini, Juliana; en qualsevulla estarém be —digué

carinyosament donya Balbina, deixant á las seuas companyas que
feyan festas á la criatura, las duas més bonas, y assentantse ella en
una de mitjaneta, foradada del assiento.
—Pero ¡Si hi estará malament! —feu la dona.
—¿Qué creu que s’hi pot caure?
—¡Tant com aixó!…
—Donchs no s’amohini, y díguins com está desde dilluns passat…
—Tant malament com vulgui —respongué secament la dona,

assentantse entre mitj de las senyoras y creuhant las mans sobre la
falda.
—¿Y aixó? ¿Qué hi ha de nou?
—Desde’l dimecres que tinch lo noy al llit…
—¡En Quimet! y donchs ¿qué té? ¿Qué no ha anat á cercar al metje?
—Lo divendres veyent que li havia donat sal de Madrit y que encara
estava de la mateixa manera, vaig anar á cercar al metje de la
Conferencia.
—Ben fet ¿Y qué li ha dit?
—Li va receptar una medicina, la prengué y’l dijous lo trobá més

aliviat y me va dir que li fes caldo, y que li donés com més bó mellor.
¡Figuris quin caldo li puch donar jo! Vosté sab com estich de diners y
del dolor reuma, que la major part dels dias me té ab un crit etern,
sens deixarme bellugar… La setmana passada, de tres pessetas que’m
guanya’l noy, com que estigué malalt y no hi aná més que al principi,
l’amo no me’n doná més que una… Jo ab los dias que m’he trobat
menos malament, entre la setmana passada y aquesta, he guanyat
cinch rals al safreig ¡y ab tot aixó compri quan menos pa!… ¡Y’l
procurador ha vingut avuy, dihent que l’amo no vol esperar un dia
més! ¡que si no pago me treurá al carrer!… ¡Y jo casi voldria que ho
fes! Si á la nit nos troban al mitj de la via, pot esser que’ns recullin
y’ns portin á un lloch ó altre… Dech tres mesos de lloguer de casa ¡y
jo no sé pas de que pagar, ni aquets, ni’ls altres que vingan!…
—Vaja, vaja, Juliana, ja veig que estém fins al cap de amunt…

Paciencia! ¡paciencia y Deu provehirá!
—Ja fa molt temps, que Deu no se’n recorda de mí…
—Vaja que aixó no es pas veritat —feu afectuosament donya Balbina.

Y girantse envers las seuas duas companyas, que no s’havian atrevit á
bestreure en la conversa, la senyora Agulló per desconeixer la
situació de la pobre, que per primera volta visitava, y la Montserrat
perque la emoció la tenia corpresa, las digué:
—Ab la pobra Juliana, fa molt temps que Nostre Senyor hi pensa; y

ella es molt bona, y s’ho pren ab resignació; pero de tant en tant,
s’exalta y ella mateixa s’engrandeix las cosas, y encara es pitjor.
Perque vaja, ab quatre anys que fá que es viuda y quatre anys que la
Conferencia l’ajuda, es veritat que ha passat moltas penas, perque
una pobra dona ab tres fills, (dos y un que se li morí l’any passat),
pera pujarlos no més que ab lo seu guany, li costa molts fatichs, pero
lo cert es que’l noy que tenia nou anys, ja’n te tretse; y ja es aprenent
y guanya alguna coseta y cada dia guanyará més; y com Deu l’ha
protegida per passar aquestos quatre anys, la protegirá d’aquí
endavant si ella no’s desespera…
—Jo ja ho voldria no desesperarme —feu la dona, bon xich aplacada,
per las rahons de la senyora Valls,— pero quan me veig que á sobre
de totas las meuas penas, ara se m’hi afegeix la poca salut del noy,
me desespero y’m surto de tino y no sé lo que’m dich ni lo que’m
passa pe’l enteniment. ¿Cóm vol que ho pensi, que’l noy guanyará
més, si’l veig tan poca cosa y que’ls remeys que’l metje’m diu que
necessita per reforsarse, jo no’ls hi puch comprar? ¡Tenir un fill
malalt, y no poguerli donar lo que necessita per curarse, per viure, es
horrorós! —afegí la pobra dona, rompent en un mar de plors.
—En los grans mals Deu ajuda —digué la senyora Agulló prenent per
primera volta la paraula, tot aixugant duas llágrimas que li
humitejavan los ulls.
—¡Ay, á mí no m’ajuda ningú! —feu altra volta la dona plorant

sempre— jo ja sé de molts pobres que tenen uns senyors que los hi
pagan lo lloguer del pis. ¡Ay Deu meu! ¡Lo lloguer, que es lo que mata
als pobres! pero á mí ja ho sab donya Balbina, llevat de vostés y la
Beneficencia de la Parroquia, ¡ningú, ningú m’aussilia en res!
—L’ aussilia Nostre Senyor que no l’ha deixada, ni la deixará may:

que de totas aquestas llágrimas, n’hi fá en lo cel una corona, que tal
volta no tindrém nosaltres, y que vosté si sufreix las seuas penas ab
resignació, la disfrutará al costat del fill que ja hi té y d’aquestos dos
si sap criarlos com Deu mana. ¡Vaja, no s’afligeixi més! que d’aixó
sols se’n treu ferse malbé’ls ulls y esverar aquestas pobras criaturas,
que necessitan que vosté las animi.
—¡Ay Deu meu! ¿Cóm volen que m’animi si ara á falta de penas, se
m’hi ha afegit la d’aquesta criatura que está morta de necessitat, que
li tinch de fer caldo? y ¡mirin! ¡mirin! —repetí la Juliana altra volta
bon tros exaltada, girant dessobre de sa falda la butxaca de las
faldillas de la que’n caygueren vuyt ó deu céntims.— ¡Es tot lo que
tinch á casa!
—Aixó ray, aixó ray —feu donya Balbina tot aixecantse. Y dirigintse á
una porta del costat de l’arcoba preguntá:— ¿Es aquí en Quimet?
—No senyora —respongué la pobra, seguint darrera d’ella y apartant

las cortinas de indiana.— He tingut de posarlo en lo meu llit, perque
á lo menos, aquí hi tinch márfega, que en lo seu catre no hi ha més
que la tela…
—Pero dona, dona, ¿perqué no m’havia dit qu’en Quimet no tenia

márfega? —esclamá donya Balbina, atansantse al capsal del llit del
noy.— De la mateixa manera que la Conferencia li doná la de vosté, li
hauria donat la d’en Quimet…
—Com sempre tinch de demanar tantas cosas, ¡me fá pena, amohinar

tant!… Y ja sap que la meua, si no hagués estat per la malaltia de la
noya tampoch l’hauria demanada…
—Mal fet; mal fet; —digué la senyora Agulló, que junt ab la nevoda de
mossen Jaume, s’havian atansat als peus del llit— vosté, tot lo que
necessiti ho demana; nosaltres, no’ns amohinem, sino de no poguer
donar tot lo que voldriam. Pero si no’s pot fer tot, á voltas se fa una
mica… y val més una mica, que res. Márfegas, llensols, flassadas, la
Conferencia no’n te tantas com ne voldria; pero per una necessitat
forta, ¡sempre n’hi ha alguna de mal desada!…
—Y donchs, Quimet ¿cóm te trobas? —preguntá donya Balbina al
noy, qui al veure á las senyoras s’havia enfonsat en lo llit, cubrintse
ab la manta, fins més amunt dels ulls.
—¡Home! ¡Quimet! Respon —feu la mare, apurada, al veure que’l seu

fill, en lloch de respondre, havia acabat per taparse tot lo cap.
—¡Déixil estar, que deu dormir! Un altre dia, quan estará més bo, ja
coneixerá que lo que está fent, quan hi ha senyoras que l’estiman y
que s’interessan per ell, no está gayre be ¡y no ho fará més! —digué
somrihent donya Balbina. Y sortint de la arcoba y girantse envers á
sa mare afegí:
—Avuy nosaltres anirém á avisar á la Caritat Cristiana, que li donará

bonos de carn y gallina; mes com aixó ja no ho tindrá fins demá y al
noy li convé’l caldo, d’aquí á una hora, arribis fins á casa ab una olla
mitjaneta y n’hi donaré per avuy. Demá ¡Deu provehirá! Y quan
aquest noy estiga bo, s’haurá de veure si’l pot seguir ó no l’ofici de
manyá… A mi’m sembla que te poca robustesa per aquest treball; y
allavors n’hi haurém de cercar un altre…
—¡Ay! ¡prou fa temps que’l metje m’ho diu aixó! ¿Pero com ho haig
de fer pobra de mí? Si ab las tres pessetas que’m porta cada setmana,
me trobo ab aquestos apuros ¿cóm ho faré sense cap? Perque d’aquí
á que ab un altre ofici me las guanyi… ¿y’l lloguer? ¿Y’l pá, que se
me’n menjan un y mitj cada dia? ¡No hi ha remey, ha de fer com jo
que estich plena de dolor y haig de rentar! Ell ha de seguir ab l’ofici
¡no hi ha més! y encara que’l vegi que se’m mor ¡jo, jo mateixa tinch
que caragolarli’l dogal! —esclamá la dona tornant ab major forsa á
abandonarse al seu sentiment.
—Vaja ¡que Nostre Senyor, no vol que la gent se desesperi d’aquest
modo! —feu la senyora Agulló bon tros afectada, passant
carinyosament la má per la espatlla de la pobre. Demanin al Sagrat
Cor de Jesús y á Sant Joseph que es lo protector dels pobres y tinga
confiansa, que quan Deu tanca una porta, diu que Maria Santíssima
n’obra una altra. Y ¡també la obrirá per vosté! Entretant digui al
procurador, que una volta que tants dias s’ha esperat, que prenga
paciencia fins á la setmana entrant, que nosaltres demanarém á la
Conferencia que li pagui algún lloguer atrassat; y després se fará lo
que’s puga per veure si’s pot alcansar per via del bon Almoyner
d’aquestos senyors, que vosté diu que sab que fan tant be als pobres,
que li donguin alguna coseta per ajudarli á pagar lo lloguer de la
casa…
—¡Ay, si Deu ho volia! ¡Si María Santissima me fes aquesta gracia!

¡Lo lloguer! ¡Lo lloguer que es lo que mata als pobres! —esclamá la
dona plena d’alegria ab aquell raig d’esperansa.
Donya Balbina contentíssima interiorment, de las paraulas de la seua

companya, en las que hi veya realisarse lo seu generós intent, doná’ls
bonos á la pobre, dos borregos á la criatura y’s despedí tot fentlos la
promesa de tornar l’endemá á veure’l noy.
La Montserrat que havia sortit de casa, no portant més que duas

pessetas que havia tirat á la bossa, al ferse la col·lecta de la
Conferencia, visiblement emocionada per la escena que acabava de
presenciar y per haberse vist en la impossibilitat de socórrela, al
tornar á pendre lloch en lo carrer entre sas duas companyas
d’escursió esclamá ab la habitual impetuositat de son carácter:
—Conech que jo ¡no serviria pas per sócia de las Conferencias! Aixó
tant sols se pot fer portant una butxaca ben plena, per remediar
aquestos horrors socials…
—Lo mateix vaig dir jo la primera vegada que vaig fer visitas de
Conferencia —feu calmosament donya Balbina.
—Y jo —afegí ab lo mateix ayre la senyora Agulló.
—A totas las senyoras que visitan per primera vegada se’ls hi acut lo
que acaba de dir vosté; pero quan se convencen que aixó, com la
major part de las cosas d’aquest mon, qui las fá casi sempre es qui
menos condicions materials té per ferlas, cambian de pensament.
—Perque estarán en altres condicions que jo; perque á falta de diners

sabrán trobar com vostés mateixas paraulas de consol, que á mi
encara que se m’haguessen acudit, no hauria pogut dirlas, perque jo
á n’aquesta dona com una tonta, no li he sapigut obrir la boca. Crega
que lo únich que hauria pogut fer era plorar ab ella.
—Lo que proba que vosté está en possessió de la primera qualitat

que’s necessita pera visitar pobres, que te cor; y que per lo tant,
pensaria que val més fer bonament lo que’s pot que no fer res;
perque, veu, nosaltres en aquesta visita de primer moment sembla
que havem fet molt poca cosa, pero anantho reflexionant ja’s troba
que no es tan poch; puig que la caritat com te sempre l’ajuda de Deu,
molt sovint fa miracles. Aqueixa dona demá tindrá carn y gallina y la
senyora Agulló que ha presenciat l’apremiant necessitat d’aquesta
infelis mare, jo ja sé que posará tota la seua influencia per alcansarli
una de las almoynas que mensualment reparteix la caritativa familia
de qui ella nos ha parlat; y si lo que no es probable, no li fos possible
lograrho, ella y jo y vosté també, cercariam manera de obtenirla de
qualsevulla persona, de las que la experiencia en l’exercici de la
caritat nos diu que se las troba quan se las té de menester; y en ultim
cás l’assistiríam nosaltres; si no podia ésser ab vuyt, fora en cinch ó
en tres, pero sempre ab la seguretat de que la nostra conciencia nos
diría que havém obrat molt mellor ajudantla ab la nostra petitísima
cooperació, que abandonantla en lo seu desespero. Perque aixó que
diuhen molts, de que no volen visitar pobres, perque no están en
condicions de tréurels de la miseria, es posarse al nivell del metje que
deixés morir al malalt pera no véurel patir. ¡Ah Montserrat!, cregui
que es molt diferent sapiguer una necessitat ó véurela ab los propis
ulls y estiga certa de que no hi há res tant ingeniós com la caritat, ni
cosa tant súptil en escusas com l’egoisme ó l’indiferencia…
Enfront de la realitat y de la claríssima manera d’expressarla, la noya

Gil bon xich més reposada de la seua emoció, trobá que donya
Balbina parlava maravellosament, y deixantse portar d’aquella falda
de cabells blanchs y mantellina de manto, l’acompanyá la tarde del
mateix dia á la casa del encarregat de la Caritat Cristiana del barri y á
la visita d’altras duas familias de pobres de la Conferencia, deixant
pera l’endemá l’anar á cercar una fé de baptisme á la parroquia de
Santa Madrona y gestionar ab una bona senyora la manera de
desempenyar un farcell de roba d’abrich al Montepío de la Mare de
Deu de la Esperansa.
A dos quarts de nou del vespre la Montserrat, plé’l cor de la impresió

de las visitas que havia fet aquell dia, y de la idea de que la seua
existencia, anava desde aquell moment á tenir també sa noble utilitat

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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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Karl E. Anderson, MD, FACP [58] Jeffrey A. Barnes [22]

Kenneth Anderson, MD [107] Philip A. Beer, MRCP, FRCPath, PhD [85]

Andrew S. Artz, MD, MS [9] Joel S. Bennett, MD [121]

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

Niels Borregaard, MD, PhD [66] Bradley R. Cairns, PhD [12]

Virginia C. Broudy, MD [81] Bruce A. Chabner, MD [22]

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

James M. Cleary, MD, PhD [22] Yun Dai, MD [16]

Barry S. Coller, MD [112, 120] Utpal P. Davé, MD [5]

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

Ann M. Dvorak, MD [63] Jonathan W. Friedberg, MD [102]

William B. Ershler, MD [9] Randy D. Gascoyne, MD, FRCPC [96]

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

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

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

Gerard Lozanski, MD [93] Shannon L. Meeks, MD [127]

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

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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]

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

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

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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]

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

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

Robert Weinstein, MD [28]

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