2 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 -------------------------------------------------------------------------------------------------------------- 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 4 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 Williams Hematology 8TH Ed. (2010) 5 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 Contri butors 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 6 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] Williams Hematology 8TH Ed. (2010) 7 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 8 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 Williams Hematology 8TH Ed. (2010) 9 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 10 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] Williams Hematology 8TH Ed. (2010) 11 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 12 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 Williams Hematology 8TH Ed. (2010) 13 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 14 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 Williams Hematology 8TH Ed. (2010) 15 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 16 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 18 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) Copyri ght I nformati on Wi lli ams Hematology, Ei ghth Edi ti on 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 ---------------------------------------------------------------------------------------------------------------------------- PAB7 l. CLlRlCAL VALUA7l0R 0f 7B PA7lR7 CHAPTER 1 . I NI TI AL APPROACH TO THE PATI ENT: HI STORY AND PHYSI CAL EXAMI NATI ON 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 20 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 5 x 109/L was reduced from 14 days with mar-row to 11 days with PBPCs (p = 0.005).77 The time to platelet recovery of >20 x 109/L was 23 days for patients who received marrow compared to 16 days in the PBPC group (p = 0.02). Patients who received PBPC also required fewer red blood cell and platelet transfusions and spent less time in the hospital. Overall survival was similar in the two groups. On the basis of these and other results, most transplantation centers use mobilized PBPCs and have adopted a CD34 cell minimum of >1 x 106 CD34+ cells/kg with a preferred content of >2 x 106 CD34+ cells/kg. An absolute minimum CD34+ cell dose below which autologous HCT would not be recommended has not been defined, and it is the opinion of the authors that marrow harvesting to supplement the PBPC graft be considered for patients with a CD34+ cell dose below 1 x 106 cells/kg. In the allogeneic setting, the situation is considerably more complex. The approximately 10-fold greater number of T cells contained in PBPC grafts led to the concern that higher number of T cells may result in increased incidence and severity of graft-versus-host disease (GVHD). In the initial phase II studies the incidence and severity of GVHD were similar among patients who received G-CSF mobilized PBPCs compared to historical cohorts of patients who received mar-row.80,81 In a series of prospective studies, most reported no clear difference in the incidence of acute GVHD (grades II to IV).7982 The observation that the infusion of 10-fold greater number of T cells did not increase the risk of acute GVHD may in part be related to findings that G-CSF can induce functional immune tolerance in vivo in healthy individuals. Purified T cells from G-CSFmobilized PBPC donors were analyzed by gene-expression profiling and immunophenotyping that showed a predominantly immune-tolerant profile with upregulation of genes related to T- 394 cell helper type 2 (Th2) and T-regulatory (Treg) cells, and downregulation of genes associated with Th1 cells, cytotoxicity, antigen presentation, and GVHD.86 Similar to the autologous setting, hematopoietic reconstitution was significantly more rapid in patients who received allogeneic mobilized PBPCs compared to allogeneic marrow.7982 These studies were largely performed with patients who had histocompatibility locus antigen (HLA)-compatible siblings, and there are relatively few data yet in the unrelated donor setting, al-though a large randomized clinical trial through the Marrow Transplantation Clinical Trials Net-work is ongoing. The risk of chronic GVHD (limited and extensive) is more controversial. Some studies have not shown a significant difference, including a randomized collaborative study from the Fred Hut-chinson Cancer Research Center, the City of Hope National Medical Center, and Stanford Uni-versity.87 In this study, the incidence of chronic GVHD for patients who received mobilized blood was 46 percent compared to 35 percent in the patients receiving marrow (p = 0.54). In other studies, the risk of chronic GVHD was significantly increased in patients who received G-CSFmobilized PBPCs.85 Additional followup of these patients is important to help resolve this issue. There may be specific reasons to use mobilized PBPCs. For example, in patients with high-risk disease, more rapid hematopoietic reconstitution following PBPC transplantation could result in improved outcomes. Bensinger and colleagues published that patients with high-risk disease (acute myelogenous leukemia [AML] beyond first complete remission [CR1] or after first chronic phase of chronic myelogenous leukemia [CML]) had improved overall survival if they received PBPCs compared to patients with advanced disease characteristics who received mar-row.83 Patients with standard risk (AML in CR1 or first chronic phase of CML) disease had similar outcomes with PBPC and marrow. Consequently, some centers have used an approach where patients with high-risk disease receive mobilized PBPC, whereas those with standard-risk dis-ease continue to receive marrow. In the unrelated donor setting, several randomized clinical trials are ongoing in an effort to address this important question. UMBILICAL CORD BLOOD Umbilical cord blood (UCB) collected from the umbilical vessels in the placenta at the time of delivery is a rich source of HSCs. Because these cells are immunologically relatively nave, re-cipients may have satisfactory outcomes, even when crossing major histocompatibility barriers, thus extending the donor pool to individuals for whom finding allele-matched adult donors can be difficult if not impossible.89 Registries have been established that can be searched for histo-compatible cord blood units. A significant advantage of UCB is that the cells are fully typed be-fore cryopreservation and, therefore, are available, avoiding long search times. A major limita-tion has been the relatively small number of cells available in the cord blood unit, which has made transplantation feasible mainly for pediatric patients.9093 A limited number of studies have been performed in adults and most confirmed prolonged engraftment times.92,94,95 An analysis of approximately 100 UCB transplants showed that recipients who received 20 years during the period 19982004. Figure 212. Progression-free survival curve of 48 patients who had negative positron emission tomography (PET) scans compared with 24 patients who had positive pretransplantation PET scans (PET+). HISTOCOMPATIBLE DONORS Over the years the increased precision in HLA typing has resulted in clinically notable im-provements in outcome as accurate matching at the MHC is considered essential to minimize GVHD and graft failure.217 Comparing studies that evaluated the impact of HLA compatibility with the risk of GVHD and other transplantation outcomes is challenging. The main reason re-lates to the difficulty in assessing the true degree of incompatibility in the earlier studies; when newer molecular-based typing methods were applied to archived specimens, allele disparities were uncovered among phenotypically identical individuals, and these allele disparities were reportedly functionally relevant.218,219 Siblings are the preferred donor source. However, patients who do not have siblings, or who do not have a match following HLA analysis, should be considered for an unrelated donor search. Because finding a suitably matched unrelated donor may require 3 to 6 months, early searching is critical in avoiding unnecessary delays in pursuing an allogeneic transplant. An alternative approach in selected patients has been to perform transplantation using cells from a half-matched or haploidentical donor. Cord blood transplantation is another option, especially for children who do not have HLA-matched sibling donors (see section on Umbilical Cord Blood above). AGE Among adult and pediatric patients, older age at the time of transplantation is an important de-terminant that adversely affects NRM following autologous and full-dose allogeneic transplant conditioning.220226 In a study of 52 highly selected patients between 60 and 68 years of age, the 1-year NRM following full-dose allogeneic HCT approached 40 percent,220 a number considera-bly higher than the NRM reported in younger transplant recipients. In a single-institution evaluation of 500 autologous transplant recipients, age 50 years or older was associated was a fourfold increase in the 100-day NRM compared to younger patients.224 Yet older age does not appear to negatively impact NRM following allogeneic HCT using RIC.227 For these reasons, full-dose allogeneic HCT is generally offered to patients younger than 50 to 55 years of age, whereas older allotransplantation patients are considered for RIC, which is 402 better tolerated and has been successfully performed in patients into their seventh decade of life. Careful screening for comorbid medical conditions, such as heart, lung, kidney, and liver disease, remains important for all patients being considered for HCT. COMORBID MEDICAL CONDITIONS Comorbid medical conditions can have a significant impact on transplantation outcomes. Rou-tine screening of heart and lung function to detect occult abnormalities is of critical importance, especially in older patients. Evaluation of liver and kidney function, as well as exposures to po-tential pathogens such as cytomegalovirus, hepatitis B and hepatitis C, herpes viruses, and HIV are routine and should be performed in all patients. A new pre-HCT evaluation system, the Charlson Comorbidity Index, was reported and clinically tested to evaluate the influence of comorbidities on HCT outcomes.228 Although not yet widely used, this tool will likely become valuable in the risk assessment of transplant candidates. Another major factor impacting outcome following transplantation is the nutritional status of the patient, as extremes such as cachexia or obesity require special considerations. Malnourished patients may require pretransplantation enteral or parenteral nutrition to improve their general condition and patients with excessive obesity (body mass index >35) may be advised to reduce their body weight under the guidance of a dietician. A large clinical study of 2238 patients at the Fred Hutchison Cancer Research Center demonstrated that pretransplantation body weight significantly impacted NRM following allogeneic HCT.229 Patients, whose actual body weight ranged between 95 and 145 percent of ideal, experienced comparable NRM, whereas patients who weighed less than 95 percent or greater than 145 percent had decreased survival. A similar study of 473 patients undergoing autologous HCT reported that patients who were malnour-ished and those who were excessively obese fared the worst.230 Every effort should be made to encourage potential patients to maintain good health practices, including discontinuation of alcohol and smoking, and avoiding illicit drug use permanently. Attention to the medical evaluation and management of pretransplantation conditions and com-plications will help improve outcomes after HCT. DISEASES TREATED WITH TRANSPLANTATION Table 214 presents an extensive list of the diseases treated with HCT. The results obtained with transplantation are reviewed in detail in the disease-specific chapters in this book. Table 214. List of Diseases Treated by Hematopoietic Cell Transplantation Disease/Condition Allogeneic HCT Autologous HCT Malignant disease Acute myelogenous leukemia + + Acute lymphoblastic leukemia + Chronic myelogenous leukemia + + Chronic lymphocytic leukemia + + Myelodysplastic syndromes + Myeloproliferative syndromes + Non-Hodgkin lymphoma + + Hodgkin lymphoma + + Myeloma + + Amyloidosis + Waldenstrm macroglobulinemia + + Hairy cell leukemia + Selected solid tumors (testicular cancer, pediatric tumors) + Neuroblastoma + Nonmalignant diseases Acquired aplastic anemia + Congenital pure red cell aplasia + Fanconi anemia + Thalassemia + Sickle cell anemia + Paroxysmal nocturnal hemoglobinuria + Severe combined immunodeficiency + Wiskott-Aldrich + Congenital leukocyte dysfunction + Osteopetrosis + Familial erythrophagocytic lymphohistiocytosis + Glanzmann disease + Hereditary storage diseases + Williams Hematology 8TH Ed. (2010) 403 Selected autoimmune diseases + + The choice of performing autologous versus allogeneic HCT in patients with hematolymphoid malignancies depends, in part, on the disease being treated, its response to conventional-dose chemotherapy, and the availability of a histocompatible donor. In general terms, autologous transplantation is recommended for patients whose malignancy exhibits chemosensitivity to conventional dose therapy and does not extensively involve the marrow; included are many of the histologic subtypes of lymphoma including HL, germ cell tumors, and other selected pediat-ric tumors. In these instances tumor eradication is a result of dose escalation of cytotoxic ther-apy in the transplant regimen, and the autograft serves as hematopoietic cell rescue. In contrast, allogeneic transplantation is generally pursued for hematologic malignancies and disorders that primarily originate in the marrow, such as acute and chronic leukemia, aplastic anemia, and the myelodysplastic and myeloproliferative syndromes. For some diseases with extensive mar-row tumor involvement, such as the low-grade lymphomas and myeloma, the decision to pursue autologous or allogeneic HCT is more complex. In general terms, in these settings allogeneic transplantation has been more successful in controlling disease recurrence and has been asso-ciated with a significant reduction in disease relapse risk. However, the risks associated with allogeneic transplantation, which include GVHD, increased infections, and regimen toxicities are significant and negatively impact the overall survival of patients. Thus, the decision to pur-sue an allogeneic or autologous HCT for patients with these diseases depends on the combina-tion of patient characteristics such as comorbidities and age, availability of a suitable donor, disease-specific characteristics, and often patient preference. Also, for diseases where there the GVT effects are considered more powerful, allogeneic transplantation is favored. Examples include patients with CML, AML, and ALL, and multiply recurrent low-grade lymphoma.231 For some hematologic conditions, such as the myelodysplastic and myeloproliferative disorders, only allogeneic transplants can be considered. In addition, patients with selected solid tumors, such as testicular cancer, neuroblastomas, and other pediatric tumors, have had successful outcomes with autologous HCT.232234 Studies in women with breast and ovarian carcinoma, and limited studies in patients with renal cell carci-noma and small-cell lung cancer failed to demonstrate a role for HCT.235237 A variety of acquired nonmalignant and congenital disorders can be successfully treated with HCT. Most notable is allogeneic HCT for patients with severe aplastic anemia where outstanding results have been achieved for those individuals who have an HLA-matched sibling donor; up-wards of 80 to 90 percent of these patients enjoy long-term disease-free control and complete hematologic remissions.238,239 Hematopoietic cell transplantation for patients with clinically sig-nificant hemoglobin disorders, such as thalassemia major, has been very successful, especially in patients without significant liver disease.240,241 Likewise, allogeneic HCT is considered a treatment option for young patients with severe forms of sickle cell disease.242 In patients with hemoglobin disorders, transplantation serves as a form of gene therapy that uses allogeneic hematopoietic cells as vectors for genes essential for normal hematopoiesis. Eventually the vec-tor may well be autologous stem cells transformed by the insertion of normal genes, yet there is no indication that this will occur in the near future.243 For patients with severe combined immunodeficiency syndrome and other congenital lymphoid immunodeficiencies, allogeneic HCT remains the treatment of choice.244,245 The role of alloge-neic HCT for patients with storage diseases, a diverse group of disorders that typically involve a single gene defect in a lysosomal hydrolytic enzyme or peroxisomal function, is evolving and it appears that subsets of selected mucopolysaccharidoses derive the most benefit.246,247 Autolo-gous and allogeneic HCT is currently being evaluated in clinical trials for some autoimmune diseases in which patients have had life-threatening events or critical organ damage. SELECTED RESULTS OF HEMATOPOIETIC CELL TRANSPLANTATION A comprehensive discussion of transplantation outcomes is beyond the scope of this chapter. Please refer to other disease-focused chapters of this text for more complete information. A brief overview of transplantation-related outcomes in a number of diseases is presented. ACUTE MYELOGENOUS LEUKEMIA Hematopoietic cell transplantation has a significant role in the treatment of AML patients. Many studies have consistently demonstrated that relapse rates are markedly impacted by allogenic HCT. With improved prognosis afforded by cytogenetic and genetic analysis of the leukemic cells, patients with higher risk of disease recurrence can be better selected for transplantation-based therapies. INDUCTION FAILURE/REFRACTORY RELAPSE The likelihood for long-term survival is very low in AML patients whose disease fails to achieve remission following induction therapy (primary induction failure), or whose disease initially responds yet subsequently relapses and remains refractory to reinduction therapy (refractory relapse). Studies in younger (i.e., 75 percent) despite the use of high-dose steroids. Alveolar hemorrhage can be from infectious and noninfectious causes.314 Another subset of patients with idiopathic pulmo-nary syndrome develop periengraftment respiratory distress, clinically characterized by symp-toms that are identical to alveolar hemorrhage, yet bronchoscopy fails to identify blood.315 Periengraftment respiratory distress, by definition, occurs within 1 week of neutrophil engraft-ment. In the autologous setting, the symptoms respond promptly to steroids, whereas in the allogeneic setting, patients respond less well, indicating that perhaps some cases may be com-plicated by GVH