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Williams Hematology, 8 th edition (2010)

Marshall A. Lichtman, Thomas J. Kipps, Uri Seligsohn, Kenneth Kaushansky, Josef T. Prchal ---------------------------------------------------------------------------------------------------------------------------- Hecho por Od Mortales para El Estigma del Dr. Vaporeso. Material dispuesto libremente en formato CHM, extrado desde la red para su divulgacin, pasado a pdf de Acrobat. De ningn modo pretendo violar dere-chos de autor (copyright), solamente publico en otro formato a partir de material asequible en lnea para todos los usuarios de Internet. El mero hecho de cambiar el formato ya representa un cambio, pero no es mi intencin alterar lo expuesto por el autor del presente e book, ste formato pdf es porttil, puede ser aca-rreado a otros ordenadores que no estn conectados a Internet, dando la posibilidad a aquellos que no estn conectados de acceder a este material de divulgacin cientfica. Adems, pdf es ms fcil de imprimir que el CHM. Insto a los lectores a que compren los libros ya que EL PLACER DE TENER Y LEER UN LIBRO EN SUS MANOS NO TIENE PARANGN. Http: www.landsteiner.blogspot.com. Done by Od Mortales for El Estigma del Dr. Vaporeso. Material ready freely in CHM format, extracted from the internet for its disclosure, transformed to Acrobat PDF. In any way I intend violating copyright, only public in another format from material affordable on line for all Internet users. The mere fact to change the format already represents a change, but it is not my intention alter the above by the author of the present e book, this PDF format is portable, can be brought to other computers that are not connected to the Internet, giving the possibility to those who are not connected to accede to this material science popularization. In addition, pdf is easier to print the CHM. I urge readers to buy the books since THE PLEASURE OF HAVING AND READ A BOOK IN YOUR HANDS IS UNIQUE. Http: www.landsteiner.blogspot.com. No profits with this book.

Od Mortales, Chepes (La Rioja), Argentina, The best country in the World

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Table of contents (TOC) Preface Copyright Contributors Part I. Clinical Evaluation of the Patient Chapter 1 Initial Approach to the Patient: History & Physical Examination Chapter 2 Examination of Blood Cells Chapter 3 Examination of the Marrow Part II. The Organization of the Lymphohematopoietic Tissues Chapter 4 Structure of the Marrow & the Hematopoietic Microenvironment Chapter 5 The Organization & Structure of Lymphoid Tissues Part III. Epochal Hematology Chapter 6 Hematology of the Fetus & Newborn Chapter 7 Hematology during Pregnancy Chapter 8 Hematology in Older Persons Part IV. Molecular & Cellular Hematology Chapter 9 Genetic Principles & Molecular Biology Chapter 10 Genomics & Epigenetics

Es el deseo de quien hace este trabajo:

Od Mortales. Is the desire of one who

makes this work.

Ayudando a ayudar. Haciendo de este mundo un lugar mejor. Por el libre acceso a la informacin y el libre intercambio de material de aprendizaje para el avance de los pueblos, mejoramos la salud de sus

habitantes. Favoreciendo el crecimiento de los pases en vas de desarrollo.

Helping to help. Doing this world a better place. By the free access to information

and the free exchange of learning material for the advancement of peoples, improve the health of its inhabitants. Favoring the

growth of developing countries.

Williams Hematology 8TH Ed. (2010) 3

Chapter 11 Cytogenetics & Molecular Abnormalities Chapter 12 Apoptosis Chapter 13 Cell-Cycle Regulation & Hematologic Disorders Chapter 14 Signal Transduction Pathways Chapter 15 The Cluster of Differentiation Antigens Chapter 16 Hematopoietic Stem Cells, Progenitors & Cytokines Chapter 17 The Inflammatory Response Chapter 18 Innate Immunity Chapter 19 Dendritic Cells & the Control of Innate & Adaptive Immunity Part V. Therapeutic Principles Chapter 20 Pharmacology & Toxicity of Antineoplastic Drugs Chapter 21 Principles of Hematopoietic Cell Transplantation Chapter 22 Treatment of Infections in the Immunocompromised Host Chapter 23 Principles of Antithrombotic Therapy Chapter 24 Principles of Immune Cell Therapy Chapter 25 Principles of Vaccine Therapy Chapter 26 Principles of Therapeutic Apheresis: Indications, Efficacy & Complications Chapter 27 Principles of Gene Transfer for Therapy Chapter 28 Regenerative Medicine: Principles of Multipotential Cell Therapy for Tissue Replacement Part VI. The Erythrocyte Chapter 29 Morphology of the Erythron Chapter 30 Composition of the Erythrocyte Chapter 31 Production of Erythrocytes Chapter 32 Destruction of Erythrocytes Chapter 33 Clinical Manifestations & Classification of Erythrocyte Disorders Chapter 34 Aplastic Anemia: Acquired & Inherited Chapter 35 Pure Red Cell Aplasia Chapter 36 Anemia of Chronic Renal Disease Chapter 37 Anemia of Chronic Disease Chapter 38 Anemia of Endocrine Disorders Chapter 39 The Congenital Dyserythropoietic Anemias Chapter 40 Paroxysmal Nocturnal Hemoglobinuria Chapter 41 Folate, Cobalamin & Megaloblastic Anemias Chapter 42 Disorders of Iron Metabolism Chapter 43 Anemia Resulting from Other Nutritional Deficiencies Chapter 44 Anemia Associated with Marrow Infiltration Chapter 45 The Red Blood Cell Membrane & Its Disorders: Hereditary Spherocytosis, Elliptocytosis & Related Diseases Chapter 46 Disorders of Red Cells Resulting from Enzyme Abnormalities Chapter 47 The Thalassemias: Disorders of Globin Synthesis Chapter 48 Disorders of Hemoglobin Structure: Sickle Cell Anemia & Related Abnormalities Chapter 49 Methemoglobinemia & Other Dyshemoglobinemias Chapter 50 Hemolytic Anemia Resulting from Physical Injury to Red Cells Chapter 51 Hemolytic Anemia Resulting from Chemical & Physical Agents Chapter 52 Hemolytic Anemia Resulting from Infections with Microorganisms Chapter 53 Hemolytic Anemia Resulting from Immune Injury Chapter 54 Alloimmune Hemolytic Disease of the Fetus & Newborn Chapter 55 Hypersplenism & Hyposplenism Chapter 56 Primary & Secondary Polycythemias (Erythrocytosis) Chapter 57 The Porphyrias Chapter 58 Hereditary & Acquired Sideroblastic Anemias Part VII. Neutrophils, Eosinophils, Basophils & Mast Cells Chapter 59 Morphology of Neutrophils, Eosinophils & Basophils Chapter 60 Composition of Neutrophils Chapter 61 Production, Distribution & Fate of Neutrophils Chapter 62 Eosinophils & Their Disorders Chapter 63 Basophils & Mast Cells & Their Disorders Chapter 64 Classification & Clinical Manifestations of Neutrophil Disorders Chapter 65 Neutropenia & Neutrophilia Chapter 66 Disorders of Neutrophil Function Part VIII. Monocytes & Macrophages Chapter 67 Morphology of Monocytes & Macrophages Chapter 68 Biochemistry & Functions of Monocytes & Macrophages Chapter 69 Production, Distribution & Fate of Monocytes & Macrophages Chapter 70 Classification & Clinical Manifestations of Disorders of Monocytes & Macrophages Chapter 71 Monocytosis & Monocytopenia Chapter 72 Inflammatory & Malignant Histiocytosis Chapter 73 Lipid Storage Diseases

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Part IX. Lymphocytes & Plasma Cells Chapter 74 Morphology of Lymphocytes & Plasma Cells Chapter 75 Composition & Biochemistry of Lymphocytes & Plasma Cells Chapter 76 Lymphopoiesis Chapter 77 Functions of B Lymphocytes & Plasma Cells in Immunoglobulin Production Chapter 78 Functions of T Lymphocytes: T-Cell Receptors for Antigen Chapter 79 Functions of Natural Killer Cells Chapter 80 Classification & Clinical Manifestations of Lymphocyte & Plasma Cell Disorders Chapter 81 Lymphocytosis & Lymphocytopenia Chapter 82 Immunodeficiency Diseases Chapter 83 Hematologic Manifestations of Acquired Immunodeficiency Syndrome Chapter 84 Mononucleosis Syndromes Part X. Neoplastic Myeloid Diseases Chapter 85 Classification & Clinical Manifestations of the Clonal Myeloid Disorders Chapter 86 Polycythemia Vera Chapter 87 Essential Thrombocythemia Chapter 88 Myelodysplastic Syndromes (Clonal Cytopenias & Oligoblastic Myelogenous Leukemia) Chapter 89 Acute Myelogenous Leukemia Chapter 90 Chronic Myelogenous Leukemia & Related Disorders Chapter 91 Primary Myelofibrosis Part XI. Neoplastic Lymphoid Diseases Chapter 92 Classification of Malignant Lymphoid Disorders Chapter 93 Acute Lymphoblastic Leukemia Chapter 94 Chronic Lymphocytic Leukemia & Related Diseases Chapter 95 Hairy Cell Leukemia Chapter 96 Large Granular Lymphocytic Leukemia Chapter 97 General Considerations of Lymphoma: Epidemiology, Etiology, Heterogeneity & Primary Extranodal Disease Chapter 98 Pathology of Malignant Lymphomas Chapter 99 Hodgkin Lymphoma Chapter 100 Diffuse Large B-Cell Lymphoma Chapter 101 Follicular Lymphoma Chapter 102 Mantle Cell Lymphoma Chapter 103 Marginal Zone B-Cell Lymphomas Chapter 104 Burkitt Lymphoma Chapter 105 Cutaneous T-Cell Lymphoma (Mycosis Fungoides & Szary Syndrome) Chapter 106 Mature T-Cell & Natural Killer Cell Lymphomas Chapter 107 Plasma Cell Neoplasms: General Considerations Chapter 108 Essential Monoclonal Gammopathy Chapter 109 Myeloma Chapter 110 The Amyloidoses Chapter 111 Macroglobulinemia Chapter 112 Heavy-Chain Disease Part XII. Hemostasis & Thrombosis Chapter 113 Megakaryopoiesis & Thrombopoiesis Chapter 114 Platelet Morphology, Biochemistry & Function Chapter 115 Molecular Biology & Biochemistry of the Coagulation Factors & Pathways of Hemostasis Chapter 116 Control of Coagulation Reactions Chapter 117 Vascular Function in Hemostasis Chapter 118 Classification, Clinical Manifestations & Evaluation of Disorders of Hemostasis Chapter 119 Thrombocytopenia Chapter 120 Reactive Thrombocytosis Chapter 121 Hereditary Qualitative Platelet Disorders Chapter 122 Acquired Qualitative Platelet Disorders Chapter 123 The Vascular Purpuras Chapter 124 Hemophilia A & Hemophilia B Chapter 125 Inherited Deficiencies of Coagulation Factors II, V, VII, X, XI & XIII & Combined Defi-ciencies of Factors V & VIII & of the Vitamin K-Dependent Factors Chapter 126 Hereditary Fibrinogen Abnormalities Chapter 127 von Willebrand Disease Chapter 128 Antibody-Mediated Coagulation Factor Deficiencies Chapter 129 Hemostatic Dysfunction Related to Liver Diseases & Liver Transplantation Chapter 130 Disseminated Intravascular Coagulation Chapter 131 Hereditary Thrombophilia Chapter 132 The Antiphospholipid Syndrome Chapter 133 Antibody-Mediated Thrombotic Disorders: Thrombotic Thrombocytopenic Purpura & Heparin-Induced Thrombocytopenia Chapter 134 Venous Thrombosis Chapter 135 Atherothrombosis: Disease Initiation, Progression & Treatment Chapter 136 Fibrinolysis & Thrombolysis

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Part XIII. Transfusion Medicine Chapter 137 Erythrocyte Antigens & Antibodies Chapter 138 Human Leukocyte & Platelet Antigens Chapter 139 Blood Procurement & Screening Chapter 140 Red Cell Transfusion Chapter 141 Preservation & Clinical Use of Platelets

Contributors Editors Kenneth Kaushansky, MD Helen M. Ranney Professor and Chair Department of Medicine University of California, San Diego La Jolla, California Ernest Beutler, MD* Professor and Chairman Department of Molecular and Experimental Medicine The Scripps Research Institute La Jolla, California Senior Consultant Division of Hematology Oncology Scripps Clinic Medical Group, Inc. Clinical Professor of Medicine University of California, San Diego La Jolla, California Uri Seligsohn, MD Professor and Director Amalia Biron Research Institute of Thrombosis and Hemostasis Department of Hematology Chaim Sheba Medical Center Tel-Hashomer and Sackler Faculty of Medicine Tel Aviv University Tel Aviv, Israel Marshall A. Lichtman, MD Professor of Medicine and of Biochemistry and Biophysics University of Rochester Medical Center Rochester, New York Thomas J. Kipps, MD, PhD Evelyn and Edwin Tasch Chair in Cancer Research Professor of Medicine Division of Hematology/Oncology Deputy Director for Research Operations Moores UCSD Cancer Center University of California, San Diego La Jolla, California Josef T. Prchal, MD Professor of Medicine, Pathology, and Genetics Hematology Division University of Utah Salt Lake City, Utah Department of Pathophysiology First Faculty of Medicine Charles University in Prague Czech Republic Contributors Charles S. Abrams, MD [122] Professor of Medicine Division of Hematology-Oncology University of Pennsylvania School of Medicine Philadelphia, Pennsylvania Archana M. Agarwal, MD [44] Department of Pathology, University of Utah Salt Lake City, Utah Neeraj Agarwal, MD [49] Assistant Professor of Medicine Department of Internal Medicine University of Utah Salt Lake City, Utah Doru T. Alexandrescu, MD [123] Department of Medicine Division of Dermatology University of California, San Diego VA San Diego Health Care System San Diego, California

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Carl E. Allen, MD, PhD [72] Texas Children's Cancer Center/Hematology Baylor College of Medicine Houston, Texas Elias Anaissie, MD [109] Myeloma Institute for Research and Therapy University of Arkansas for Medical Sciences Little Rock, Arkansas Karl E. Anderson, MD, FACP [57] Professor, Departments of Preventative Medicine and Community Health, Internal Medicine, and Pharmacology and Toxicology University of Texas Medical Branch Galveston, Texas Edgardo Angtuaco [109] Myeloma Institute for Research and Therapy University of Arkansas for Medical Sciences Little Rock, Arkansas Daniel A. Arber, MD [63] Director of Clinical Hematology Clinical Laboratories Stanford University Medical Center Stanford, California Kelty R. Baker, MD [50] Clinical Assistant Professor Baylor College of Medicine Houston, Texas Bart Barlogie, MD, PhD [109] Myeloma Institute for Research and Therapy University of Arkansas for Medical Sciences Little Rock, Arkansas Jeffery Barnes [20] Massachusetts General Hospital Cancer Center Boston, Massachusetts Twyla Bartel [109] Myeloma Institute for Research and Therapy University of Arkansas for Medical Sciences Little Rock, Arkansas Philip A. Beer, MD [87] Department of Haematology University of Cambridge Cambridge Institute for Medical Research Cambridge, United Kingdom Joel S. Bennett, MD [122] Professor of Medicine and Pharmacology Division of Hematology-Oncology University of Pennsylvania School of Medicine Philadelphia, Pennsylvania Carolina Berger, MD [24] Fred Hutchinson Cancer Research Center Seattle, Washington Robert F. Betts, MD [84] University of Rochester Medical Center Rochester, New York Bruce Beutler, MD [18] Professor and Chairman Department of Genetics The Scripps Research Institute La Jolla, California Ernest Beutler, MD [1, 9, 30, 32, 42]* Professor and Chairman Department of Molecular and Experimental Medicine The Scripps Research Institute La Jolla, California Senior Consultant Division of Hematology Oncology Scripps Clinic Medical Group, Inc. Clinical Professor of Medicine University of California, San Diego La Jolla, California Lisa Beutler [22] Genome Sciences University of Washington Seattle, Washington Steven Beutler, MD [22] Redlands Community Hospital Redlands, California Neil Blumberg, MD [138, 140]

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Professor and Director, Clinical Laboratories and Transfusion Medicine Department of Pathology and Laboratory Medicine University of Rochester Rochester, New York Niels Borregaard, MD, PhD [66] Professor of Internal Medicine and Hematology Department of Hematology Copenhagen, Denmark Laurence A. Boxer, MD [66] Henry and Mala Dorfman Professorship of Pediatric Hematology/Oncology Professor of Pediatric Hematology/Oncology University of Michigan Ann Arbor, Michigan Michael Boyiadzis [100] Division of Hematology-Oncology University of Pittsburgh Cancer Institute University of Pittsburgh School of Medicine Pittsburgh, Pennsylvania H. Elizabeth Broome [74, 107] Clinical Professor of Medicine University of California, San Diego Department of Pathology Moores Cancer Center La Jolla, California Brian S. Bull, MD [29, 51] Professor and Chair Department of Pathology and Human Anatomy Loma Linda University Medical Center Loma Linda, California Joel N. Buxbaum, MD [110] The Scripps Research Institute La Jolla, California Jamie Caro, MD [36, 55] Professor of Medicine Department of Medicine Thomas Jefferson University Cardeza Foundation for Hematologic Research Philadelphia, Pennsylvania Dennis A. Carson, MD [13] Professor of Medicine Director, Moores CSD Cancer Center La Jolla, California Januario E. Castro, MD [27] Associate Professor of Medicine University of California, San Diego Moores Cancer Center La Jolla, California Bruce A. Chabner, MD [20] Massachusetts General Hospital Cancer Center Boston, Massachusetts Junmei Chen [119] Research Scientist Puget Sound Blood Center Seattle, Washington James Cleary [20] Massachusetts General Hospital Cancer Center Boston, Massachusetts Barry S. Coller, M.D. [114, 121] Professor Laboratory of Blood and Vascular Medicine Physician-in-Chief Vice President for Medical Affairs Hospital Medical Affairs The Rockefeller University New York, New York Myra Coppage [138] Department of Pathology and Laboratory Medicine University of Rochester Rochester, New York Gay M. Crooks, MB, BS, FRACP [76] Professor of Medicine Department of Pathology and Laboratory Medicine David Geffen School of Medicine University of California, Los Angeles Los Angeles, California Mark Crowther, MD, MSC, FRCPC [23] Professor of Medicine and Pathology and Molecular Medicine

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McMaster University Hamilton, Ontario, Canada David C. Dale, MD [65] Professor of Medicine Department of Medicine University of Washington Seattle, Washington Nam H. Dang, MD, PhD [106] Department of Hematologic Malignancies Nevada Cancer Institute Las Vegas, Nevada Philip G. De Groot, PhD [129] Department of Clinical Chemistry and Hematology University Medical Center Utrecht Utrecht, The Netherlands Jean Delaunay, MD, PhD [39] Professor of Genetics INSERUM U 779 Secteur Paul-Broca 78 rue du Gnral-Leclerc Hpital de Bictre 94275 Le Kremlin-Bictre France Philippe de Moerloose, MD [126] Haemostasis Unit University Hospital of Geneva and University of Geneva Faculty of Medicine Geneva, Switzerland Madhav Dhodapkar, MD [19] Bunker Professor of Medicine Chief, Section of Hematology Yale University New Haven, Connecticut Reyhan Diz-Kucukkaya, MD [119] Associate Professor Department of Internal Medicine Division of Hematology Istanbul University Istanbul Faculty of Medicine Istanbul, Turkey Steven D. Douglas, MD [67] Professor and Associate Chair Pediatrics Chief Section of Immunology and Director of Clinical Immunology Laboratories Children's Hospital of Philadelphia Philadelphia, Pennsylvania Ann M. Dvorak, MD [63] Director, Electron Microscopy Unit Senior Pathologist, Professor of Pathology Department of Pathology Beth Israel Deaconess Medical Center Harvard Medical School Boston, Massachusetts Deborah Elstein, PhD [73] Gaucher Clinic Shaare Zedek Medical Center Jerusalem, Israel Joshua Epstein, DSC [109] Myeloma Institute for Research and Therapy University of Arkansas for Medical Sciences Little Rock, Arkansas William B. Ershler, MD [8] Senior Investigator Deputy Clinical Director Intramural Research Program National Institute on Aging National Institute of Health Baltimore, Maryland Miguel A. Escobar, MD [124] Associate Professor of Medicine and Pediatrics Division of Hematology University of Texas Health Science Center at Houston Houston, Texas Kenneth A. Foon, MD [97, 100] Nevada Cancer Institute Department of Hematological Malignancies Las Vegas, Nevada Charles W. Francis, MD [23] Hematology/Oncology Division

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University of Rochester Medical Center Rochester, New York Deborah L. French, PhD [121] Assistant Professor Department of Medicine Mount Sinai School of Medicine New York, New York Jonathan W. Friedberg, MD [104] Chief, Hematology/Oncology Division James P. Wilmot Cancer Center Associate Professor of Medicine University of Rochester Medical Center Rochester, New York Patrick G. Gallagher, MD [45] Professor Department of Pediatrics and Genetics Yale University School of Medicine New Haven, Connecticut Stephen J. Galli, MD [63] Mary Hewitt Loveless, MD, Professor Professor of Pathology and Microbiology and Immunology Chair, Department of Pathology Stanford University School of Medicine Stanford University Medical Center Stanford, California Richard L. Gallo, MD, PhD [123] Department of Medicine Division of Dermatology University of California, San Diego VA San Diego Health Care System San Diego, California Tomas Ganz, MD, PhD [37] Departments of Medicine and Pathology, David Geffen School of Medicine University of California, Los Angeles Los Angeles, California Randy D. Gascoyne, MD, FRCPC [98] Clinical Professor of Pathology Research Director, Centre for Lymphoid Cancers Departments of Pathology and Advanced Therapeutics British Columbia Cancer Agency, the BC Centre Research Center and University of British Columbia Vancouver, BC, Canada Amy Geddis, MD, PhD [119] Associate Professor Department of Pediatrics Division of Hematology/Oncology Univeristy of California School of Medicine University of California San Diego, California Larisa J. Geskin, MD, FAAD [105] Director, Cutaneous Oncology Center University of Pittsburgh Medical Center Pittsburgh, Pennsylvania David Ginsburg, MD [127] Professor, Department of Internal Medicine and Human Genetics Investigator, Howard Hughes Medical Institute University of Michigan Ann Arbor, Michigan Lucy A. Godley, MD, PhD [11] Section of Hematology/Oncology Department of Medicine and the Center Research Center University of Chicago Chicago, Illinois Oscar B. Goodman Jr. [106] Departments of Clinical Oncology Nevada Cancer Institute Las Vegas, Nevada Siamon Gordon, MD, ChB, PhD [68, 69] Sir William Dunn School of Pathology University of Oxford Oxford, United Kingdom Roberta A. Gottlieb, MD [12] San Diego State University San Diego, California Anthony R. Green, PhD, FRCP, FRCPath, FMedSci [87] Professor Department of Haematology University of Cambridge

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Cambridge Institute for Medical Research Cambridge, United Kingdom Ralph Green, MD, PhD, FRCPath [41, 43] Professor of Pathology and Medicine University of California Medical Center Sacramento, California Xylina T. Gregg, MD [38] Utah Cancer Specialists Salt Lake City, Utah John H. Griffin, PhD [116] Professor Department of Molecular and Experimental Medicine The Scripps Research Institute La Jolla, California Katherine A. Hajjar, MD [117, 136] Brine Family Professor and Chair Department of Cell and Developmental Biology Weill Cornell Medical College Professor of Pediatrics New York Presbyterian Hospital New York, New York Paul C. Herrmann, MD, PhD [29, 51] Associate Professor Department of Pathology and Human Anatomy Loma Linda University Medical Center Loma Linda, California Maureane Hoffman, MD, PhD [115] Professor of Pathology Duke University Medical Center and Durham Veterans Affairs Medical Center Durham, North Carolina Sandra J. Horning, MD [99] Emeritus Professor of Medicine/Oncology Stanford University Medical Center Sr. VP, Global Head, Clinical Hematology/Oncology Genentech, Inc. Stanford Cancer Center Stanford, California Russell D. Hull, MD [134] Professor Department of Medicine University of Calgary Active Staff Department of Internal Medicine Foothills Hospital Calgary, Alberta, Canada Joseph E. Italiano Jr., PhD [114] Assistant Professor of Medicine Brigham and Women's Hospital Harvard Medical School Boston, Massachusetts Daniel R. Jacobson, MD [110] A Boston Health Care System Boston, Massachusetts Jill M. Johnsen, MD [127] Assistant Member, Research Division Puget Sound Blood Center Assistant Professor, Division of Hematology Department of Medicine University of Washington Seattle, Washington Lynn B. Jorde, PhD [10] H. A. and Edna Benning Presidential Professor Department of Human Genetics University of Utah School of Medicine Salt Lake City, Utah Marshall E. Kadin, MD [96] Associate Professor of Pathology, Harvard Medical School Professor of Dermatology Boston University School of Medicine Director, Cutaneous Lymphoma Program Providence, Rhode Island Kenneth Kaushansky, MD [14, 16, 113, 118, 120] Helen M. Ranney Professor and Chair Department of Medicine University of California, San Diego La Jolla, California Armand Keating, MD [28]

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Princess Margaret Hospital Institute of Biomaterials and Biomedical Engineering Department of Medicine University of Toronto Toronto, Ontario, Canada Nigel S. Key, MB, FRCP [124] Harold R. Roberts Distinguished Professor of Medicine Division of Hematology/Oncology Department of Medicine University of North Carolina Chapel Hill, North Carolina Thomas J. Kipps, MD, PhD [5, 15, 27, 75, 77, 78, 80, 81, 92, 94] Evelyn and Edwin Tasch Chair in Cancer Research Professor of Medicine Division of Hematology/Oncology Deputy Director for Research Operations Moores UCSD Cancer Center University of California, San Diego La Jolla, California Mark J. Koury, MD [4] Vanderbilt University Medical Center Nashville, Tennessee Abdullah Kutlar, MD [48] Professor of Medicine Georgia Sickle Cell Center Medical College of Georgia Sickle Cell Center Augusta, Georgia Larry W. Kwak, MD, PhD [25] Chairman, Department of Lymphoma and Myeloma Justin Distinguished Chair in Leukemia Research Associate Director, Center for Cancer Immunology Research Division of Cancer Medicine The University of Texas M. D. Anderson Cancer Center Houston, Texas Robert A. Kyle, MD [112] Consultant Division of Hematology Mayo Clinic Professor of Medicine Laboratory of Medicine and Pathology Mayo Clinic, College of Medicine Rochester, Minnesota Andrew Lane [20] Dana-Farber Cancer Institute Boston, Massachusetts Lewis L. Lanier, PhD [79] Professor Department of Microbiology and Immunology University of California, San Francisco San Francisco, California Michelle M. Le Beau, PhD [11] Section of Hematology/Oncology Department of Medicine and the Center Research Center University of Chicago Chicago, Illinois Norma B. Lerner, MD, MPH [140] St. Christopher's Hospital for Children Philadelphia, Pennsylvania Marcel Levi, MD, PhD [130] Department of Medicine/Vascular Medicine Academic Medical Center University of Amsterdam Amsterdam, The Netherlands Marshall A. Lichtman, MD [1, 4, 34, 52, 64, 70, 71, 85, 88, 89, 90, 91, 97, 108] Professor of Medicine and of Biochemistry and Biophysics University of Rochester Medical Center Rochester, New York Jane L. Liesveld, MD [88, 89, 90] James P. Wilmot Cancer Center University of Rochester Medical Center Rochester, New York Ton Lisman, PhD [129] Associate Professor of Experimental Surgery Surgical Research Laboratory and Section of Hepatobiliary Surgery and Liver Transplantation Department of Surgery University Medical Center, Groningen

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Groningen, The Netherlands John S. (Pete) Lollar III, MD [128] Aflac Cancer Center and Blood Disorders Services Department of Pediatrics Emory University Emory Children's Center Atlanta, Georgia Dan L. Longo, MD [8] Senior Investigator Scientific Director Intramural Research Program National Institute on Aging National Institute of Health Baltimore, Maryland Jose A. Lopez, MD [119] Professor of Medicine and Molecular and Human Genetics Scientific Director, Thrombosis Research Section Vice Chairman of Medicine for Research Baylor College of Medicine Houston, Texas Thomas P. Loughran, MD [96] Director, Penn State Hershey Cancer Institute Professor of Medicine Penn State College of Medicine Hershey, Pennsylvania Robert Lowsky, MD [21] Stanford University Division of Blood and Marrow Transplantation Stanford, California Naomi L.C. Luban, MD [54] Professor, Pediatrics and Pathology George Washington University Medical Center Division Chief, Laboratory Medicine Director, Transfusion Medicine/Donor Center Children's National Medical Center Washington, D.C. Aaron Lubetsky, MD [131] Institute of Thrombosis and Hemostasis and National Hemophilia Center Sheba Medical Center Tel Hashomer, Israel Aaron J. Marcus, MD [117] Professor of Medicine and of Pathology and Laboratory Medicine Weill Cornell Medical College Chief of Hematology-Oncology VA New York Harbor Healthcare System New York, New York Kenneth L. McClain, MD, PhD [72] Professor of Pediatrics Texas Children's Cancer Center/Hematology Baylor College of Medicine Houston, Texas Jeffery McCullough, MD [139] Professor Department of Laboratory Medicine and Pathology Director, Division of Laboratory Medicine and Section of Transfusion Medicine University of Minnesota Medical School Minneapolis, Minnesota Janice McFarland, MD [138] Blood Center of Southeast Wisconsin Milwaukee, Wisconsin Peter W. McLaughlin, MD [102] Department of Lymphoma/Myeloma University of Texas Houston, Texas Bruce C. McLeod, MD [26] Rush University Medical Center Chicago, Illinois Giampaolo Merlini [111] Director, Center for Research and Treatment of Systematic Amyloidoses University Hospital Policlinico San Matteo Professor, Department of Medicine University of Pavia Pavia, Italy Dean D. Metcalfe, MD [63] Chief, Laboratory of Allergic Diseases NAID/National Institute of Health Bethesda, Maryland

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Martha P. Mims, MD, PhD [7] Associate Professor, Department of Medicine Section Chief, Section of Hematology/Oncology Baylor College of Medicine Houston, Texas Constantine Mitsiades [20] Dana-Farber Cancer Institute Boston, Massachusetts Joel Moake, MD [50] Senior Research Scientist and Associate Director Biomedical Engineering Laboratory Rice University Houston, Texas Emile R. Mohler III, MD [135] Director, Vascular Medicine Director, Vascular Diagnostic Center Division of Cardiovascular Medicine University of Pennsylvania School of Medicine Director, Vascular Medicine Program Presbyterian Medical Center Philadelphia, Pennsylvania Dougald M. Monroe III, PhD [115] Professor of Medicine Division of Hematology University of North Carolina School of Medicine Chapel Hill, North Carolina William A. Muller, MD, PhD [117] Magerstadt Professor and Chairman Department of Pathology Feinberg School of Medicine Northwestern University Chicago, Illinois Mike Murphy [141] Professor of Blood Transfusion Medicine University of Oxford Consultant Haematologist, National Blood Service and Oxford Radcliffe Hospitals Oxford, United Kingdom Bijay Nair [109] Myeloma Institute for Research and Therapy University of Arkansas for Medical Sciences Little Rock, Arkansas Kavita Natarajan, MBBS [48] Assistant Professor of Medicine Medical College of Georgia Division of Hematology/Oncology Augusta, Georgia Sattva S. Neelapu, MD [25] Department of Lymphoma and Myeloma Division of Center Medicine The University of Texas M. D. Anderson Cancer Center Houston, Texas Marguerite Neerman-Arbez, PhD [126] Department of Genetic Medicine and Development University of Geneva Faculty of Medicine Geneva, Switzerland Robert S. Negrin, MD [21] Stanford University Stanford, California Luigi D. Notarangelo, MD [82] Division of Immunology Children's Hospital Harvard Medical School Boston, Massachusetts Hans D. Ochs, MD [82] Professor of Pediatrics Jeffrey Modell Chair of Pediatric Immunology Research Division of Immunology Seattle Children's Research Hospital Department of Pediatrics University of Washington Seattle, Washington Ubaldo Martinez Outschoorn, MD [36, 55] Assistant Professor Department of Medical Oncology Cardeza Foundation for Hematologic Research Thomas Jefferson University

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Philadelphia, Pennsylvania Charles H. Packman, MD [53] Clinical Professor of Medicine University of North Carolina School of Medicine Chapel Hill, North Carolina Chief, Hematology-Oncology Section Department of Internal Medicine and Blumenthal Cancer Center Carolinas Medical Center Charlotte, North Carolina James Palis, MD [6] Department of Pediatrics University of Rochester Medical Center Rochester, New York Charles J. Parker, MD [40] Professor of Medicine Division of Hematology and Bone Marrow Transplantation University of Utah School of Medicine Salt Lake City, Utah Archibald S. Perkins, MD [104] Professor Department of Pathology and Lab Medicine University of Rochester Medical Center Rochester, New York John D. Phillips, PhD [57] Associate Professor of Medicine Division of Hematology University of Utah School of Medicine Salt Lake City, Utah Graham F. Pineo, MD [134] Professor of Medicine Department of Medicine and Oncology University of Calgary Department of Medicine Foothills Hospital Calgary, Alberta, Canada Annette Pluddemann [68, 69] Department of Primary Health Care University of Oxford Oxford, United Kingdom Mortimer Poncz, MD [133] Professor of Pediatrics University of Pennsylvania School of Medicine Children's Hospital of Philadelphia Philadelphia, Pennsylvania Prem Ponka, MD [58] Professor of Physiology and Medicine Lady Davis Institute McGill University Montreal, Quebec, Canada Jaroslav F. Prchal, MD [86] Associate Professor of Medicine and Oncology McGill University St. Mary's Hospital Montreal, Quebec, Canada Josef T. Prchal, MD [7, 31, 33, 38, 44, 49, 56, 58, 86] Professor of Medicine, Pathology, and Genetics Division of Hematology University of Utah Salt Lake City, Utah Department of Pathophysiology First Faculty of Medicine Charles University Prague, Czech Republic Oliver W. Press, MD, PhD [101] Member, Fred Hutchinson Cancer Research Center Professor of Medicine/Oncology University of Washington Director of Hematology/Hematologic Malignancies Seattle Cancer Care Alliance Seattle, Washington Ching-Hon Pui, MD [93] Chair American Cancer Society Professor, Department of Oncology St. Jude Children's Research Hospital Professor of Pediatrics University of Tennessee Health Science Center

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Memphis, Tennessee Jayashree Ramasethu, MD, FAAP [54] Associate Professor of Clinical Pediatrics Director, Neonatal Perinatal Medicine Fellowship Program Georgetown University Hospital Division of Neonatology Washington, D.C. Jacob H. Rand, M.D. [132] Professor of Pathology and Medicine Director of Hematology Laboratory Montefiore Medical Center The University Hospital for the Albert Einstein College of Medicine Bronx, New York A. Koneti Rao, MD [121] Assistant Professor of Pathology and Laboratory Medicine Assistant Director, Transfusion Medicine/Blood Bank Strong Memorial Hospital University of Rochester Medical Center Rochester, New York Gary E. Raskob, PhD [134] Dean, College of Public Health Professor, Epidemiology and Medicine The University of Oklahoma Health Science Center Oklahoma City, Oklahoma Majed A. Refaai, MD [140] Department of Pathology and Laboratory Medicine University of Rochester Medical Center Rochester, New York Erin Gourley Reid, MD [83] Associate Professor of Medicine Vice Chair, Lymphoma Working Group AIDS Malignancy Consortium University of California, San Diego Moores Cancer Center La Jolla, California Marion E. Reid, PhD [137] New York Blood Center New York, New York Paul Richardson, MD [20] Dana-Farber Cancer Institute Boston, Massachusetts Stanley R. Riddell, MD [24] Fred Hutchinson Cancer Research Center Seattle, Washington Harold R. Roberts, MD [115, 124] Sarah Graham Kenan Distinguished Professor of Medicine and Pathology Division of Hematology/Oncology Department of Medicine University of North Carolina School of Medicine Chapel Hill, North Carolina Department of Pathology Duke University School of Medicine Durham, North Carolina Jorge E. Romaguera, MD [102] Professor Department of Lymphoma Myeloma The University of Texas M. D. Anderson Cancer Center Houston, Texas Jia Ruan, MD, PhD [136] Assistant Professor of Medicine Department of Medicine Weill Cornell Medical College Assistant Attending Physician New York Presbyterian Hospital New York, New York Daniel H. Ryan, MD [2, 3] University of Rochester Medical Center Rochester, New York J. Evan Sadler, MD, PhD [133] Professor and Director Division of Hematology Department of Medicine Washington University School of Medicine St. Louis, Missouri Ophira Salomon, MD [125] Amalia Biron Research Institute of Thrombosis and Hemostasis Department of Hematology

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Sheba Medical Center Tel Hashomer and Sackler Faculty of Medicine Tel Aviv University Tel Aviv, Israel Vaishali Sanchorawala, MD [110] Associate Professor of Medicine Amyloid Research and Treatment Program and Sections of Hematology-Oncology Boston University School of Medicine and Boston Medical Center Boston, Massachusetts Alan Saven, MD [95] Head, Division of Hematology/Oncology Scripps Clinic Medical Group La Jolla, California Andrew I. Schafer, MD [135] Frank Wister Thomas Professor of Medicine Chairman, Department of Medicine University of Pennsylvania School of Medicine Philadelphia, Pennsylvania Mathias Schmid, MD [13] Assistant Professor University Hospital Ulm Ulm, Germany David C. Seldin, MD, PhD [110] Chief, Hematology-Oncology Section and Director Amyloid Treatment and Research Program Boston University School of Medicine and Boston Medical Center Boston, Massachusetts George B. Segel, MD [6, 34] Department of Pediatrics University of Rochester Medical Center Rochester, New York Uri Seligsohn, MD [118, 125, 130, 131] Professor of Hematology and Director Amalia Biron Research Institute of Thrombosis and Hemostasis Sheba Medical Center Tel-Hashomer and Sackler Faculty of Medicine Tel Aviv University Tel Aviv, Israel Sanford J. Shattil, MD [122] Professor and Chief, Division of Hematology-Oncology Department of Medicine University of California, San Diego Adjunct Professor of Molecular and Experimental Medicine The Scripps Research Institute La Jolla, California John Shaughnessy, PhD [109] Myeloma Institute for Research and Therapy University of Arkansas for Medical Sciences Little Rock, Arkansas Darren Sigal, MD [95] Division of Hematology/Oncology Scripps Clinic Medical Group La Jolla, California Brian F. Skinnider, MD [98] Department of Pathology British Columbia Cancer Agency and University of British Columbia Vancouver, British Columbia, Canada C. Wayne Smith, MD [59, 60, 61] Professor and Head, Section of Leukocyte Biology Department of Pediatrics Baylor College of Medicine Houston, Texas Susan S. Smyth, MD, PhD [114] Research Assistant Professor of Medicine Carolina Center for Cardiovascular Biology Center for Thrombosis and Hemostasis University of North Carolina School of Medicine Chapel Hill, North Carolina Ralph M. Steinman, MD [19] Henry G. Kunkle Professor Head, Laboratory of Cellular Physiology and Immunology Rockefeller University New York, New York David Stroncek [138] Department of Transfusion Medicine National Institutes of Health Bethesda, Maryland

Williams Hematology 8TH Ed. (2010) 17

Ayalew Tefferi, MD [91] Mayo Clinic Rochester, Minnesota Tim M. Townes, PhD [48] Professor and Chair Department of Biochemistry and Molecular Genetics University of Alabama at Birmingham Birmingham, Alabama Steven P. Treon [111] Director, Bing Center for Waldenstrom's Macroglobulinemia Dana-Farber Cancer Institute Associate Professor, Harvard Medical School Boston, Massachusetts Giorgio Trinchieri, MD [79] Director, Cancer and Inflammation Program Chief, Laboratory of Experimental Immunology Center for Cancer Research, NCI, NIH Frederick, Maryland Florin Tuluc, MD, PhD [67] Research Assistant Professor of Pediatrics University of Pennsylvania School of Medicine Joseph Stokes Jr. Research Institute The Children's Hospital of Philadelphia Philadelphia, Pennsylvania Frits van Rhee, MD, PhD, MRCP (UK), FRCPath [109] Professor of Medicine Director of Clinical Research Myeloma Institute for Research and Therapy University of Arkansas for Medical Sciences Little Rock, Arkansas Wouter W. van Solinge, PhD [46] Professor of Laboratory Medicine Head of Department Medical Director Division Laboratories and Pharmacy Department of Clinical Chemistry and Haematology University Medical Center Utrecht Utrecht, The Netherlands Richard van Wijk, PhD [46] Associate Professor Department of Clinical Chemistry and Haematology University Medical Center Utrecht Utrecht, The Netherlands Ralph Vassallo Jr., MD [141] Medical Director American Red Cross Services Penn-Jersey Region Philadelphia, Pennsylvania Dietlind L. Wahner-Roedler, MD [112] Consultant Division of General Internal Medicine Mayo Clinic Associate Professor of Medicine Mayo Clinic College of Medicine Mayo Clinic Rochester, Minnesota Huan-You Wang, MD, PhD [92] Associate Clinical Professor of Pathology Co-Director of Hematopathology Department of Pathology University of California, San Diego La Jolla, California Peter A. Ward, MD [17] Department of Pathology University of Michigan Medical School Ann Arbor, Michigan Andrew J. Wardlaw, MD, PhD [62] Institute for Lung Health Department of Infection Immunity and Inflammation Leicester University Medical School Leicester, United Kingdom Jeffery S. Warren, MD [17] Department of Pathology University of Michigan Medical School Ann Arbor, Michigan Sir David J. Weatherall, MD [47] Professor

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Weatherall Institute of Molecular Medicine John Radcliffe Hospital Headington, Oxford, United Kingdom Sidney Whiteheart, PhD [114] Professor Molecular and Cellular Biochemistry University of Kentucky College of Medicine Lexington, Kentucky Shmuel Yaccoby [109] Myeloma Institute for Research and Therapy University of Arkansas for Medical Sciences Little Rock, Arkansas Neal S. Young, MD [35] Hematology Branch National Heart, Lung, and Blood National Institutes of Health Bethesda, Maryland Ari Zimran, MD [73] Gaucher Clinic Shaare Zedek Medical Center Jerusalem, Israel Ariella Zivelin, PhD [125] Laboratory Manager Institute of Thrombosis and Hemostasis Sheba Medical Center Tel Hashomer, Israel Emanuele Zucca, MD [103] IOSI-Oncology Institute of Southern Switzerland Ospedale San Giovanni Bellinzona, Switzerland *Deceased (5 October 2008)

Copyright Information Williams

Hematology, Eighth Edition Copyright 2010, by The McGraw-Hill Companies, Inc. All rights reserved. Printed in China. Electronic version of this book converted from CHM to acrobat PDF without using converters made in Argentina entirely by hand. Note: This copy of chm to acrobat pdf was carried out by a need without benefit of profit. With the permission of the authors for joy of readers. Printable in many ways.

Set ISBN 978-0-07-162151-9; MHID 0-07-162151-2 Book ISBN 978-0-07-162144-1 MHID 0-07-162144-X CD ISBN 978-0-07-162145-8; MHID 0-07-162145-8

NOTICE Medicine is an ever-changing science. As new research and clinical experience broaden our knowledge, changes in treatment and drug therapy are required. The authors and the publisher of this work have checked with sources believed to be reliable in their efforts to provide information that is complete and generally in accord with the standards accepted at the time of publication. However, in view of the possibility of human error or changes in medical sciences, neither the authors nor the publisher nor any other party who has been involved in the prepara-tion or publication of this work warrants that the information contained herein is in every respect accurate or complete, and they disclaim all responsibility for any errors or omissions or for the results obtained from use of the information contained in this work. Readers are encouraged to confirm the information contained herein with other sources. For example and in particular, readers are advised to check the product information sheet included in the package of each drug they plan to administer to be certain that the information contained in this work is accurate and that changes have not been made in the recommended dose or in the contraindications for admini-stration. This recommendation is of particular importance in connection with new or infrequently used drugs. ----------------------------------------------------------------------------------------------------------------------------

Preface The rate of growth in our understanding of diseases of blood cells and coagulation proteins pro-vides a challenge for the editors of a comprehensive textbook of hematology. The sequencing of individual genomes and the acquisition of knowledge in proteomics, metabolomics, and all the other burgeoning "-omics" fields as applied to hematologic disorders have accelerated the understanding of the pathogenesis of the diseases of our interest. The rate at which basic knowledge in molecular and cell biology and molecular immunology has been translated into improved diagnostic and therapeutic methods is equally impressive. Specific molecular targets for therapy in a myriad of hematological disorders have become reality, and it is not hyperbole to state that hematology has become the poster child for the rational design of therapeutics throughout all of medicine. This edition of Williams Hematology includes many changes, we believe, for the better. Each chapter has been extensively revised or rewritten to provide the most current information available. Two new chapters have been added, Chapter 10 entitled Epigenetics and Genomics, to reflect the growing importance of this basic science in hematol-ogy, and Chapter 28 entitled Principles of Multipotential Cell Therapy for Tissue Replacement. In addition, several chapters have been divided, most notably the single chapter on non-Hodgkin lymphoma has been split into its constituent diseases and the chapters on erythrocyto-sis and thrombocytosis have been divided into the myeloproliferative and reactive forms, to

Williams Hematology 8TH Ed. (2010) 19

reflect our growing understanding of the pathophysiology of these disorders and more targeted approaches to their therapy. Recognizing that at the heart of hematology is blood and marrow cell morphology, we have incorporated most of the collection of 274 images that appeared in a separate section of color plates in the 7th edition (as well as additional images) into the relevant topics in each chapter, allowing far easier access to highly informative illustrations and cellular morphology. Apropos the age of information, the new edition of Williams Hematology is also available online, as part of the popular www.accessmedicine.com website. With direct links to a comprehensive drug therapy database and to other important medical texts, including Harri-son's Principles of Internal Medicine and Goodman and Gilman's The Pharmacological Basis of Therapeutics, Williams Hematology Online is part of a powerful resource covering all disciplines within medical education and practice. The online edition of Williams Hematology also includes PubMed links to journal articles cited in the references in our new edition. For the first time, a CD accompanies the Williams Hematology book. The CD features a large selection of mor-phologies, illustrations, and drawings, from this new edition of Williams Hematology; these can be easily transported into PowerPoint format for use in lectures and presentations. Finally, the Williams Manual of Hematology will once again be revised. The convenient Manual features the most clinically salient content from the parent text, and is perfect for use in time-restricted clini-cal situations. The Manual will be available for iPhone and other mobile formats. The readers of the 8th edition of Williams Hematology will note the passing of a legend in hematology, Dr. Ernest Beutler. Ernie was a founding editor and the lead editor of Hematology for the 5th and 6th editions, continued to contribute as an editor for the 7th edition, and passed away in October 2008, while the 8th edition's revised and new chapters were being compiled. Ernie's thumbprint continues to permeate the 8th edition, including F1 and F2 generations of the Beutler pedigree, and it is to Ernie that we dedicate this edition. The production of this book required the timely cooperation of 191 contributors. We are grateful for their work in providing this comprehensive and up-to-date text. Despite the growth of both basic and clinical knowledge and the passion that each of our contributors brings to the topic of their chapter, we have been able to maintain the text in a single volume through scrupulous attention to chapter length. Each editor has had expert administrative assistance in the management of the manuscripts for which they were primarily responsible. We thank Carolina Bump in La Jolla, California; Susan Madden in Salt Lake City, Utah; and Orly Katz in Tel Aviv, Israel, for their very helpful participation in the pro-duction of the book. Special thanks go to Susan Daley in Rochester, New York, and Monica Gudea in La Jolla, California, who were responsible for coordinating the management of 141 chapters, including many new figures and tables, and managing other administrative matters, a challenging task that Ms. Daley and Ms. Gudea performed with skill and good humor. The edi-tors also acknowledge the interest and support of our colleagues from McGraw-Hill, including James F. Shanahan, Editor-in-Chief, Internal Medicine; Harriet Lebowitz, Senior Project Devel-opment Editor for Williams Hematology; and Sylvia Rebert, Project Manager for Williams Hema-tology.

Kenneth Kaushansky Marshall A. Lichtman

Thomas J. Kipps Uri Seligsohn Josef T. Prchal

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CHAPTER 1 . INITIAL APPROACH TO THE PATIENT:

HISTORY AND PHYSICAL EXAMINATION SUMMARY

he care of a patient with a suspected hematologic abnormality begins with a systematic attempt to determine the nature of the illness by eliciting an in-depth medical history and performing a physical examination. The physician should identify the patient's symptoms

systematically and obtain as much relevant information as possible about their origin and evolu-tion and about the general health of the patient by appropriate questions designed to explore the patient's recent and remote experience. Reviewing previous records may add important data for understanding the onset or progression of illness. Hereditary and environmental factors should be carefully sought and evaluated. The use of drugs and medications, nutritional pat-terns, and sexual behavior should be considered. The physician follows the medical history with a physical examination to obtain evidence for tissue and organ abnormalities that can be accessed through bedside observation to permit a careful search for signs of the illnesses sug-gested by the history. Skin changes and hepatic, splenic, or lymph nodal enlargement are a few findings that may be of considerable help in pointing toward a diagnosis. Additional history is obtained during the physical examination, as findings suggest an additional or alternative con-sideration. Thus, the history and physical examination should be considered as a unit, providing

T

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the basic information with which further diagnostic information is integrated: blood and marrow studies and imaging studies and biopsies. Primary hematologic diseases are common in the aggregate, but hematologic manifestations secondary to other diseases occur even more frequently. For example, the signs and symptoms of anemia and the presence of enlarged lymph nodes are common clinical findings that may be related to a hematologic disease but occur frequently as secondary manifestations of disorders not considered primarily hematologic. A wide variety of diseases may produce signs or symp-toms of hematologic illness. Thus, in patients with a connective tissue disease, all the signs and symptoms of anemia may be elicited and lymphadenopathy may be notable, but additional find-ings are usually present that indicate primary involvement of some system besides the hemato-poietic (marrow) or lymphopoietic (lymph nodes or other lymphatic sites). In this discussion, emphasis is placed on the clinical findings resulting from either primary hematologic disease or the complications of hematologic disorders so as to avoid presenting an extensive catalog of signs and symptoms encountered in general clinical medicine. In each discussion of specific diseases in subsequent chapters, the signs and symptoms that accompany the particular disorder are presented, and the clinical findings are covered in de-tail. In this chapter a more general systematic approach is taken. ACRONYMS AND ABBREVIATIONS Acronyms and abbreviations that appear in this chapter include: HELLP syndrome, hemolytic anemia, elevated liver enzymes, and low platelet count; Ig, immunoglobulin; IL, interleukin; POEMS, polyneuropathy, organomegaly, endocrinopathy, monoclonal gammopathy, and skin changes; PS, performance status. The Hematology Consultation Table 11 lists the major abnormalities that result in the evaluation of the patient by the hema-tologist. The signs indicated in Table 11 may reflect a primary or secondary hematologic prob-lem. For example, immature granulocytes in the blood may be signs of myeloid diseases such as myelogenous leukemia, or, depending on the frequency of these cells and the level of imma-turity, the dislodgment of cells resulting from bone marrow metastases of a carcinoma. Nucle-ated red cells in the blood may reflect the breakdown in the marrowblood interface seen in primary myelofibrosis or the hypoxia of congestive heart failure. Certain disorders have a pro-pensity for secondary hematologic abnormalities; renal, liver, and connective tissue diseases are prominent among such abnormalities. Chronic alcoholism, nutritional fetishes, use of certain medications may be causal factors in blood cell or coagulation protein disorders. Pregnant women and persons of older age are prone to certain hematologic disorders: anemia, thrombo-cytopenia, or disseminated coagulation in the former case, and hematologic malignancies and pernicious anemia in the latter. The history and physical examination can provide vital clues to the possible diagnosis and also to the rationale choice of laboratory tests.

Table 11. Findings That May Lead to a Hematology Consultation Decreased hemoglobin concentration (anemia)

Increased hemoglobin concentration (polycythemia)

Elevated serum ferritin level

Accelerated sedimentation rate

Leukopenia or neutropenia

Immature granulocytes or nucleated red cells in the blood

Pancytopenia

Granulocytosis: neutrophilia, eosinophilia, basophilia, or mastocytosis

Monocytosis

Lymphocytosis

Lymphadenopathy

Splenomegaly

Hypergammaglobulinemia: monoclonal or polyclonal

Purpura

Thrombocytopenia

Thrombocytosis

Exaggerated bleeding: spontaneous or trauma related

Prolonged partial thromboplastin or prothrombin coagulation times

Venous thromboembolism

Thrombophilia

Obstetrical adverse events (e.g., recurrent fetal loss, stillbirth, and HELLP* syndrome) *Hemolytic anemia, elevated liver enzymes, and low platelet count. THE HISTORY In today's technology- and procedure-driven medical environment, the importance of carefully gathering information from patient inquiry and examination is at risk of losing its primacy. The

Williams Hematology 8TH Ed. (2010) 21

history (and physical examination) remains the vital starting point for the evaluation of any clini-cal problem.13 GENERAL SYMPTOMS AND SIGNS Performance status (PS) is used to establish semiquantitatively the extent of a patient's disability. This status is important in evaluating patient comparability in clinical trials, in determining the likely tolerance to cytotoxic therapy, and in evaluating the effects of therapy. A well-founded set of criteria for measuring performance status is presented in Table 12.4 An abbreviated version sometimes is used, as proposed by the Eastern Cooperative Oncology Group (Table 13).5

Table 12. Criteria of Performance Status (Karnovsky Scale)4 Able to carry on normal activity; no special care is needed.

100% Normal; no complaints, no evidence of disease

90% Able to carry on normal activity; minor signs or symptoms of disease

80% Normal activity with effort; some signs or symptoms of disease

Unable to work; able to live at home, care for most personal needs; a varying amount of assistance is needed.

70% Cares for self; unable to carry on normal activity or to do active work

60% Requires occasional assistance but is able to care for most personal needs

50% Requires considerable assistance and frequent medical care

Unable to care for self; requires equivalent of institutional or hospital care; disease may be progressing rapidly.

40% Disabled; requires special care and assistance

30% Severely disabled; hospitalization is indicated though death not imminent

20% Very sick; hospitalization necessary; active supportive treatment necessary

10% Moribund; fatal processes progressing rapidly

0% Dead

Table 13. Eastern Cooperative Oncology Group Performance Status5 Grade Activity

0 Fully active, able to carry on all predisease performance without restriction

1 Restricted in physically strenuous activity but ambulatory and able to carry out work of a light or seden-tary nature, e.g., light housework, office work

2 Ambulatory and capable of all self-care but unable to carry out any work activities; up and about more than 50% of waking hours

3 Capable of only limited self-care, confined to bed or chair more than 50% of waking hours

4 Completely disabled; cannot carry on any self-care; totally confined to bed or chair

5 Dead Weight loss is a frequent accompaniment of many serious diseases, including primary hema-tologic entities, but it is not a prominent accompaniment of most hematologic disease. Many "wasting" diseases, such as disseminated carcinoma and tuberculosis, cause anemia, and pro-nounced emaciation should suggest one of these diseases rather than anemia as the primary disorder. Fever is a common early manifestation of the aggressive lymphomas or acute leukemias as a result of pyrogenic cytokines (e.g., interleukin (IL)-1, IL-6, IL-8 and others) released as a reflec-tion of the disease itself. After chemotherapy-induced cytopenias or in the face of accompany-ing immunodeficiency, infection is usually the cause of fever. In patients with "fever of unknown origin," lymphoma, particularly Hodgkin lymphoma, should be considered. Occasionally, pri-mary myelofibrosis, acute leukemia, advanced myelodysplastic syndrome, and other lympho-mas may also cause fever. In rare patients with severe pernicious anemia or hemolytic anemia, fever may be present. Chills may accompany severe hemolytic processes and the bacteremia that may complicate the immunocompromised or neutropenic patient. Night sweats suggest the presence of low-grade fever and may occur in patients with lymphoma or leukemia. Fatigue, malaise, and lassitude are such common accompaniments of both physical and emo-tional disorders that their evaluation is complex and often difficult. In patients with serious dis-ease, these symptoms may be readily explained by fever, muscle wasting, or other associated findings. Patients with moderate or severe anemia frequently complain of fatigue, malaise, or lassitude and these symptoms may accompany the hematologic malignancies. Fatigue or lassi-tude may occur also with iron deficiency even in the absence of sufficient anemia to account for the symptom. In slowly developing chronic anemias, the patient may not recognize reduced exercise tolerance, or other loss of physical capabilities except in retrospect, after a remission has been induced by appropriate therapy. Anemia may be responsible for more symptoms than has been traditionally recognized, as suggested by the remarkable improvement in quality of life of most uremic patients treated with erythropoietin. Weakness may accompany anemia or the wasting of malignant processes, in which cases it is manifest as a general loss of strength or reduced capacity for exercise. The weakness may be

22

localized as a result of neurologic complications of hematologic disease. In vitamin B12 defi-ciency (e.g., pernicious anemia), there may be weakness of the lower extremities, accompa-nied by numbness, tingling, and unsteadiness of gait. Peripheral neuropathy also occurs with monoclonal immunoglobulinemias. Weakness of one or more extremities in patients with leu-kemia, myeloma, or lymphoma may signify central or peripheral nervous system invasion or compression as a result of vertebral collapse, a paraneoplastic syndrome (e.g. encephalitis), or brain or meningeal involvement. Myopathy secondary to malignancy occurs with the hema-tologic malignancies and is usually manifest as weakness of proximal muscle groups. Foot drop or wrist drop may occur in lead poisoning, amyloidosis, systemic autoimmune diseases, or as a complication of vincristine therapy. Paralysis may occur in acute intermittent porphyria. SPECIFIC SYMPTOMS OR SIGNS NERVOUS SYSTEM Headache may be the result of a number of causes related to hematologic diseases. Anemia or polycythemia may cause mild to severe headache. Invasion or compression of the brain by leu-kemia or lymphoma, or opportunistic infection of the central nervous system by Cryptococcus or Mycobacterium species, may also cause headache in patients with hematologic malignancies. Hemorrhage into the brain or subarachnoid space in patients with thrombocytopenia or other bleeding disorders may cause sudden, severe headache. Paresthesias may occur because of peripheral neuropathy in pernicious anemia or secondary to hematologic malignancy or amyloidosis. They may also result from therapy with vincristine. Confusion may accompany malignant or infectious processes involving the brain, sometimes as a result of the accompanying fever. Confusion may also occur with severe anemia, hypercalce-mia (e.g., myeloma), or high-dose glucocorticoid therapy. Confusion or apparent senility may be a manifestation of pernicious anemia. Frank psychosis may develop in acute intermittent porphyria or with high-dose glucocorticoid therapy. Impairment of consciousness may be a result of increased intracranial pressure secondary to hemorrhage or leukemia or lymphoma in the central nervous system. It may also accompany severe anemia, polycythemia, hyperviscosity secondary, usually, to an immunoglobulin (Ig) M monoclonal protein (uncommonly IgA or IgG) in the plasma, or a leukemic hyperleukocytosis syndrome, especially in chronic myelogenous leukemia. EYES Conjunctival plethora is a feature of polycythemia and pallor a result of anemia. Occasionally blindness may result from retinal hemorrhages secondary to severe anemia and thrombocyto-penia or blurred vision resulting from severe hyperviscosity resulting from macroglobulinemia or extreme hyperleukocytosis of leukemia. Partial or complete visual loss can stem from retinal vein or artery thrombosis. Diplopia or disturbances of ocular movement may occur with orbital tumors or paralysis of the third, fourth, or sixth cranial nerves because of compression by tu-mor, especially extranodal lymphoma, extramedullary myeloma, or myeloid (granulocytic) sarcoma. EARS Vertigo, tinnitus, and "roaring" in the ears may occur with marked anemia, polycythemia, hy-perleukocytic leukemia, or macroglobulinemia-induced hyperviscosity. Mnire disease was first described in a patient with acute leukemia and inner ear hemorrhage. Nasopharynx, Oropharynx, and Oral Cavity Epistaxis may occur in patients with thrombocytopenia, acquired or inherited platelet function disorders and von Willebrand disease. Anosmia or olfactory hallucinations occur in pernicious anemia. The nasopharynx may be invaded by a granulocytic sarcoma or extranodal lymphoma; the symptoms are dependent on the structures invaded. The paranasal sinuses may be involved by opportunistic organisms, such as fungus in patients with severe, prolonged neutropenia. Pain or tingling in the tongue occurs in pernicious anemia and may accompany severe iron defi-ciency or vitamin deficiencies. Macroglossia occurs in amyloidosis. Bleeding gums may occur with bleeding disorders. Infiltration of the gingiva with leukemic cells occurs notably in acute monocytic leukemia. Ulceration of the tongue or oral mucosa may be severe in the acute leuke-mias or in patients with severe neutropenia. Dryness of the mouth may be caused by hypercal-cemia, secondary, for example, to myeloma. Dysphagia may be seen in patients with severe mucous membrane atrophy associated with chronic iron-deficiency anemia. NECK Painless swelling in the neck is characteristic of lymphoma but may be caused by a number of other diseases as well. Occasionally, the enlarged lymph nodes of lymphomas may be tender or painful because of secondary infection or rapid growth. Painful or tender lymphadenopathy is usually associated with inflammatory reactions, such as infectious mononucleosis or suppurative adenitis. Diffuse swelling of the neck and face may occur with obstruction of the superior vena cava due to lymphomatous compression. CHEST AND HEART Both dyspnea and palpitations, usually on effort but occasionally at rest, may occur because of anemia or pulmonary embolism. Congestive heart failure may supervene, and angina pectoris may become manifest in anemic patients. The impact of anemia on the circulatory system de-pends in part on the rapidity with which it develops, and chronic anemia may become severe without producing major symptoms; with severe acute blood loss, the patient may develop shock with a nearly normal hemoglobin level, prior to compensatory hemodilution. Cough may result from enlarged mediastinal nodes compressing the trachea or bronchi. Chest pain may arise from involvement of the ribs or sternum with lymphoma or multiple myeloma, nerve-root invasion or compression, or herpes zoster; the pain of herpes zoster usually precedes the skin

Williams Hematology 8TH Ed. (2010) 23

lesions by several days. Chest pain with inspiration suggests a pulmonary infarct, as does hemoptysis. Tenderness of the sternum may be quite pronounced in chronic myelogenous or acute leukemia, and occasionally in primary myelofibrosis, or if intramedullary lymphoma or myeloma proliferation is explosive. GASTROINTESTINAL SYSTEM Dysphagia has already been mentioned under "Nasopharynx, Oropharynx, and Oral Cavity." Anorexia frequently occurs but usually has no specific diagnostic significance. Hypercalcemia and azotemia cause anorexia, nausea, and vomiting. A variety of ill-defined gastrointestinal complaints grouped under the heading "indigestion" may occur with hematologic diseases. Abdominal fullness, premature satiety, belching, or discomfort may occur because of a greatly enlarged spleen, but such splenomegaly may also be entirely asymptomatic. Abdominal pain may arise from intestinal obstruction by lymphoma, retroperitoneal bleeding, lead poisoning, ileus secondary to therapy with the Vinca alkaloids, acute hemolysis, allergic purpura, the ab-dominal crises of sickle cell disease, or acute intermittent porphyria. Diarrhea may occur in pernicious anemia. It also may be prominent in the various forms of intestinal malabsorption, although significant malabsorption may occur without diarrhea. In small-bowel malabsorption, steatorrhea may be a notable feature. Malabsorption may be a manifestation of small-bowel lymphoma. Gastrointestinal bleeding related to thrombocytopenia or other bleeding disorder may be occult but often is manifest as hematemesis or melena. Hematochezia can occur if a bleeding disorder is associated with a colonic lesion. Constipation may occur in the patient with hypercalcemia or in one receiving treatment with the Vinca alkaloids. GENITOURINARY AND REPRODUCTIVE SYSTEMS Impotence or bladder dysfunction may occur with spinal cord or peripheral nerve damage due to one of the hematologic malignancies or with pernicious anemia. Priapism may occur in hy-perleukocytic leukemia, essential thrombocythemia, or sickle cell disease. Hematuria may be a manifestation of hemophilia A or B. Red urine may also occur with intravascular hemolysis (he-moglobinuria), myoglobinuria, or porphyrinuria. Injection of anthracycline drugs or ingestion of drugs such as phenazopyridine (Pyridium) regularly causes the urine to turn red. The use of deferoxamine mesylate (Desferal) may result in a rust color of the urine. Beeturia, a benign, possibly genetic trait, affecting approximately 4 percent of individuals, causes pinkish-red urine (and feces) as a result of exaggerated excretion of the beetroot pigments betacyanins. Amenorrhea may also be induced by certain drugs, such as antimetabolites or alkylating agents. Menorrhagia is a common cause of iron deficiency, and care must be taken to obtain an accurate history of the extent of menstrual blood loss. Semiquantification can be obtained from estimates of the number of days of heavy bleeding (usually

24

lalgia may be a troublesome complication of polycythemia Vera. Patchy plaques or widespread erythroderma occur in cutaneous T-cell lymphoma (especially Szary syndrome) and in some cases of chronic lymphocytic leukemia or lymphocytic lymphoma. The skin is often involved, sometimes severely, in graft-versus-host disease following marrow transplantation. Patients with hemochromatosis may have bronze or grayish pigmentation of the skin. Cyanosis occurs with methemoglobinemia, either hereditary or acquired; sulfhemoglobinemia; abnormal he-moglobins with low oxygen affinity; and primary and secondary polycythemia. Cyanosis of the ears or the fingertips may occur after exposure to cold in individuals with cryoglobulins or cold agglutinins. Itching may occur in the absence of any visible skin lesions in Hodgkin lymphoma and may be extreme. Mycosis fungoides or other lymphomas with skin involvement may also present as itching. A significant number of patients with polycythemia Vera will complain of itching after bathing. Petechiae and ecchymoses are most often seen in the extremities in patients with thrombocyto-penia, nonthrombocytopenic purpura, or acquired or inherited platelet function abnormalities and von Willebrand disease. Unless secondary to trauma, these lesions usually are painless; the lesions of psychogenic purpura and erythema nodosum are painful. Easy bruising is a common complaint, especially among women, and when no other hemorrhagic symptoms are present, usually no abnormalities are found after detailed study. This symptom may, however, indicate a mild hereditary bleeding disorder, such as von Willebrand disease or one of the platelet disor-ders. Infiltrative lesions may occur in the leukemias (leukemia cutis) and lymphomas (lymphoma cutis) and are sometimes the presenting complaint. Monocytic leukemia has a higher frequency of skin infiltration than other forms of leukemia. Necrotic lesions may occur with intravascular co-agulation, purpura fulminans, and warfarin-induced skin necrosis, or rarely with exposure to cold in patients with circulating cryoproteins or cold agglutinins. Leg ulcers are a common complaint in sickle cell anemia and occur rarely in other hereditary anemias. DRUGS AND CHEMICALS DRUGS Drug therapy, either self-prescribed or ordered by a physician, is extremely common in our society. Drugs often induce or aggravate hematologic disease, and it is therefore essential that a careful history of drug ingestion, including beneficial and adverse reactions, should be ob-tained from all patients. Drugs taken regularly often become a part of the patient's way of life and are often forgotten or are not recognized as "drugs." Agents such as aspirin, laxatives, tran-quilizers, medicinal iron, vitamins, other nutritional supplements, and sedatives belong to this category. Furthermore, drugs may be ingested in unrecognized form, such as antibiotics in food or quinine in tonic water. Specific, persistent questioning, often on several occasions, may be necessary before a complete history of drug use is obtained. It is very important to obtain de-tailed information on alcohol consumption from every patient. The four "CAGE" questionsabout cutting down, being annoyed by criticism, having guilt feelings, and needing an eye-openerprovide an effective approach to the history of alcohol use. Patients should also be asked about the use of recreational drugs. The use of "alternative medicines" and herbal medi-cines is common, and many patients will not consider these medications or may actively with-hold information about their use. Nonjudgmental questioning may be successful in identifying agents in this category that the patient is taking. Some patients equate the term "drugs," as op-posed to "medicines," with illicit drugs. Establishing that the examiner is interested in all forms of ingestantsprescribed drugs, self-remedies, alternative remedies, etceterais important to ensure getting the information required. CHEMICALS In addition to drugs, most people are exposed regularly to a variety of chemicals in the envi-ronment, some of which may be potentially harmful agents in hematologic disease. Similarly, occupational exposure to chemicals must be considered. When a toxin is suspected, the pa-tient's daily activities and environment must be carefully reviewed, since significant exposure to toxic chemicals may occur incidentally. VACCINATION Vaccinations can exacerbate immune thrombocytopenia. NUTRITION Children who are breast-fed without iron supplementation may develop iron-deficiency ane-mia. Nutritional information can be useful in deducing the possible role of dietary deficiency in anemia. The avoidance of certain food groups, as might be the case with vegans, or the inges-tion of uncooked fish can be clues to the pathogenesis of megaloblastic anemia. FAMILY HISTORY A carefully obtained family history may be of great importance in the study of patients with he-matologic disease (see Chap. 9). In the case of hemolytic disorders, questions should be asked regarding jaundice, anemia, and gallstones in relatives. In patients with disorders of hemostasis or venous thrombosis, particular attention must be given to bleeding manifestations or venous thromboembolism in family members. In the case of autosomal recessive disorders such as pyruvate kinase deficiency, the parents are usually not affected, but a similar clinical syndrome may have occurred in siblings. It is particularly important to inquire about siblings who may have died in infancy, as these may be forgotten, especially by older patients. When sex-linked inheritance is suspected, it is necessary to inquire about symptoms in the maternal grandfather, maternal uncles, male siblings, and nephews. In patients with disorders with dominant inheri-

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tance, such as hereditary spherocytosis, one may expect to find that one of the parents and pos-sibly siblings and children of the patient have stigmata of the disease. Ethnic background may be important in the consideration of certain diseases such as - and -thalassemia, sickle cell anemia, glucose-6-phosphate dehydrogenase deficiency, hemoglobin E, and other inherited disorders that are prevalent in specific geographic areas, such as the Mediterranean basin or Southeast Asia. SEXUAL HISTORY Because of the frequency of infections with the human immunodeficiency viruses, it is important to ascertain the sexual behavior of the patient, especially risk factors for transmission of HIV. PREVENTIVE HEMATOLOGY Ideally, the physician's goal is to prevent illness, and opportunities exist for hematologists to prevent the development of hematologic disorders. These opportunities include identification of individual genetic risk factors and avoidance of situations that may make a latent disorder manifest. Prophylactic therapy, as for example in avoiding venous stasis in patients heterozy-gous for protein C deficiency or administering prophylactic heparin at the time of major sur-gery, is a more immediate aspect of prevention because it depends on the physician's interven-tion. Hematologists may also prevent disease by reinforcing community medicine efforts. Ex-amples include fostering the elimination of sources of environmental lead that may result in childhood anemia and fostering the careful regulation of environmental toxins, such as benzene, organochlorine and organophosphate pesticides, and phenoxyherbicides that may increase the risk of lymphohematopoietic malignancies. Prenatal diagnosis can provide information to fami-lies as to whether a fetus is affected with a hematologic disorder. PHYSICAL EXAMINATION A detailed physical examination should be performed on every patient, with sufficient attention paid to all systems to obtain a full evaluation of the general health of the individual. Certain body areas are especially pertinent to hematologic disease and therefore deserve special at-tention. These are the skin, eyes, tongue, lymph nodes, skeleton, spleen and liver, and nervous system. SKIN PALLOR AND FLUSHING The color of the skin is a result of the pigment contained therein and to the blood flowing through the skin capillaries. The component of skin color related to the blood may be a useful guide to anemia or polycythemia, as pallor may result when the hemoglobin level is reduced, and redness when the hemoglobin level is increased. The amount of pigment in the skin modi-fies skin color and can mislead the clinician, as in individuals with pallor due to decreased pig-ment, or make skin color useless as a guide because of the intense pigmentation present. Alterations in blood flow and in hemoglobin content may change skin color; this too can mislead the clinician. Thus emotion may cause either pallor or blushing. Exposure of the skin to cold or heat may similarly cause pallor or blushing. Chronic exposure to wind or sun may lead to per-manent redness of the skin, and chronic ingestion of alcohol to a flushed face. The degree of erythema of the skin can be evaluated by pressing the thumb firmly against the skin, as on the forehead, so that the capillaries are emptied, and then comparing the color of the compressed spot with the surrounding skin immediately after the thumb is removed. The mucous membranes and nail beds are usually more reliable guides to anemia or poly-cythemia than the skin. The conjunctivae and gums may be inflamed, however, and therefore not reflect the hemoglobin level, or the gums may appear pale because of pressure from the lips. The gums and the nail beds may also be pigmented and the capillaries correspondingly obscured. In some individuals, the color of the capillaries does not become fully visible through the nails unless pressure is applied to the fingertip, either laterally or on the end of the nail. The palmar creases are useful guides to the hemoglobin level and appear pink in the fully opened hand unless the hemoglobin is 7 g/dL or less. Liver disease may induce flushing of the thenar and hypothenar eminences of the palm, even in patients with anemia. CYANOSIS The detection of cyanosis, like the detection of pallor, may be made difficult by skin pigmenta-tion. Cyanosis is a function of the total amount of reduced hemoglobin, methemoglobin, or sulf-hemoglobin 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 methemoglobin, and 0.5 g/dL of sulfhemoglobin. JAUNDICE Jaundice may be observed in the skin of individuals who are not otherwise deeply pigmented or in the sclerae or the mucous membranes. The patient should be examined in daylight rather than under incandescent or fluorescent light, because the yellow color of the latter masks the yellow color of the patient. Jaundice is a result of actual staining of the skin by bile pigment, and bilirubin glucuronide (direct-reacting or conjugated bilirubin) stains the skin more readily than the unconjugated form. Jaundice of the skin may not be visible if the bilirubin level is below 2 to 3 mg/dL. Yellow pigmentation of the skin may also occur with carotenemia, especially in young children. PETECHIAE AND ECCHYMOSES Petechiae are small (1 to 2 mm), round, red or brown lesions resulting from hemorrhage into the skin and are present primarily in areas with high venous pressure, such as the lower ex-tremities. These lesions do not blanch on pressure, and this can be demonstrated most readily by compressing the skin with a glass microscope slide or magnifying lens. Petechiae may occa-sionally be elevated slightly, that is, palpable; this finding suggests vasculitis. Ecchymoses may

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be of various sizes and shapes and may be red, purple, blue, or yellowish green, depending on the intensity of the skin hemorrhage and its age. They may be flat or elevated; some are painful and tender. The lesions of hereditary hemorrhagic telangiectasia are small, flat, nonpulsatile, and violaceous. They blanch with pressure. EXCORIATION Itching may be intense in some hematologic disorders such as Hodgkin lymphoma, even in the absence of skin lesions. Excoriation of the skin from scratching is the only physical manifesta-tion of this severe symptom. LEG ULCERS Open ulcers or scars from healed ulcers are often found in the region of the internal or external malleoli in patients with sickle cell anemia, and, rarely, in other hereditary anemias. NAILS Detection of pallor or rubor by examining the nails was discussed earlier. The fingernails in chronic, severe iron-deficiency anemia may be ridged longitudinally and flattened or concave rather than convex. The latter change is referred to as koilonychia and is uncommon in present practice. EYES Jaundice, pallor, or plethora may be detected from examination of the eyes. Jaundice is usually more readily detected in the sclerae than in the skin. Ophthalmoscopic examination is also es-sential in patients with hematologic disease. Retinal hemorrhages and exudates occur in patients with severe anemia and thrombocytopenia. These hemorrhages are usually the typical "flame-shaped" hemorrhages, but they may be quite large and elevate the retina so that they may ap-pear as a darkly colored tumor. Round hemorrhages with white centers are also often seen. Dilatation of the veins may be seen in polycythemia; in patients with macroglobulinemia, the veins are engorged and segmented, resembling link sausages. MOUTH Pallor of the mucosa has already been discussed. Ulceration of the oral mucosa occurs com-monly in neutropenic patients. In leukemia there may also be infiltration of the gums with swell-ing, redness, and bleeding. Bleeding from the mucosa may occur with a hemorrhagic disease. A dark line of lead sulfide may be deposited in the gums at the base of the teeth in lead poisoning. The tongue may be completely smooth in pernicious anemia and iron-deficiency anemia. Pa-tients with an upper dental prosthesis may also have papillary atrophy, presumably on a me-chanical basis. The tongue may be smooth and red in patients with nutritional deficiencies. This may be accompanied by fissuring at the corners of the mouth, but fissuring may also be due to ill-fitting dentures. An enlarged tongue, abnormally firm to palpation, may indicate the pres-ence of primary amyloidosis. LYMPH NODES Lymph nodes are widely distributed in the body, and in disease any node or group of nodes may be involved. The major concern on physical examination is the detection of enlarged or tender nodes in the cervical, supraclavicular, axillary, epitrochlear, inguinal, or iliofemoral re-gions. Under normal conditions in adults, the only readily palpable lymph nodes are in the in-guinal region, where several firm nodes 0.5 to 2.0 cm long are normally attached to the dense fascia below the inguinal ligament and in the femoral triangle. In children, multiple small (0.5 to 1.0 cm) nodes may be palpated in the cervical region as well. Supraclavicular nodes may some-times be palpable only when the patient performs the Valsalva maneuver. Enlarged lymph nodes are ordinarily detected in the superficial areas by palpation, although they are sometimes large enough to be seen. Palpation should be gentle and is best performed with a circular motion of the fingertips, using slowly increasing pressure. Tender lymph nodes usually indicate an inflammatory etiology, although rapidly proliferative lymphoma may be tender to palpation. Nodes too deep to palpate may be detected by specific imaging procedures, including com-puterized tomography, magnetic resonance imaging, ultrasound studies, gallium scintography, and positron emission tomography.7,8 CHEST Increased rib or sternal tenderness is an important physical sign often ignored. Increased bone pain may be generalized, as in leukemia, or spotty, as in plasma cell myeloma or in metastatic tumors. The superficial surfaces of all bones should be examined thoroughly by applying in-termittent firm pressure with the fingertips to locate potential areas of disease. SPLEEN The normal adult spleen is usually not palpable on physical examination but occasionally the tip may be felt.9 Palpability of the normal spleen may be related to body habitus, but there is dis-agreement on this point. Percussion, palpation, or a combination of these two methods may de-tect enlarged spleens.10 Some enlarged spleens may be visible by protrusion of the abdominal wall. The normal spleen weighs approximately 150 g and lies in the peritoneal cavity against the dia-phragm and the posterolateral abdominal wall at the level of the lower three ribs. As it enlarges it remains close to the abdominal wall, while the lower pole moves downward, anteriorly, and to the right. Spleens enlarged only 40 percent above normal may be palpable, but significant splenic enlargement may occur and the organ still not be felt on physical examination. A good but imperfect correlation has been reported between spleen size estimated from radioisotope scanning or ultrasonography and spleen weight determined after splenectomy or at autopsy.11 Although it is common to fail to palpate an enlarged spleen on physical examination, palpation

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of a normal-sized spleen is unusual, and therefore a palpable spleen is usually a significant physical finding. An enlarged spleen lies just beneath the abdominal wall and can be identified by its movement during respiration. The splenic notch may be evident if the organ is moderately enlarged. Dur-ing the examination the patient lies in a relaxed, supine position. The examiner, standing on the patient's right, lightly palpates the left upper abdomen with the right hand while exerting pres-sure forward with the palm of the left hand placed over the lower ribs posterolaterally. This ac-tion permits the spleen to descend and be felt by the examiner's fingers. If nothing is felt, the palpation should be performed repeatedly, moving the examining hand approximately 2 cm toward the inguinal ligament each time. It is often advantageous to carry out the examination initially with the patient lying on the right side with left knee flexed and to repeat it with the pa-tient supine. It is not always possible to be sure that a left upper quadrant mass is spleen; masses in the stomach, colon, kidney, or pancreas may mimic splenomegaly on physical examination. When there is uncertainty regarding the nature of a mass in the left upper quadrant, imaging proce-dures will usually permit accurate diagnosis.1113 Figure 11 is an example of splenic enlarge-ment as seen by computerized tomography of the abdomen and Figure 12 as seen by ultra-sonography.

Figure 11. A three-way composite of abdominal computerized tomography. A. Normal spleen size. B. Enlarged spleen. C. Massively enlarged spleen at the level of mid-kidney. Normally the spleen would either not be visualized or only a small lower pole would be evident at the latter level. (White arrow in the three images mark edge of splenic silhouette.) (Images kindly provided by Deborah Rubens, MD, The University of Rochester Medical Center.)

Figure 12. A two-way composite of ultrasonographic examination for spleen size. Patient's head is to the left side of the longitudinal image. A. Image of echo indicating normal spleen size with cranial to caudal longitudinal dimension of 10.3 cm.