Preface xi 1 Molecular Biology of the Cell 1 Compartmentalization of the Cell 1 Gene Transcription and Messenger RNA Translation: The Production and Journey of mRNA 3 DNA Mutations can Alter Protein Synthesis by a Number of Mechanisms 6 Transcriptional Control of Gene Expression 6 Transcription Factors, Control of Gene Expression, and Lineage Commitment 14 MicroRNAs 16 Regulatory Noncoding RNAs 16 DNA Replication and Telomeres 16 Mutations and How They Result in Disease 17 Cell Cycle 19 Apoptosis 20 Organelles in Cells 21 Link Between Metabolism and Gene Expression 22 Removal Of Circulating and Cellular Debris by Lysosomes 26 Protein Ubiquitination 26 2 Hematopoiesis 27 Sites of Hematopoiesis 27 Road Maps of Hematopoiesis 27 Transcriptional Control of Hematopoiesis 32 The Hematopoietic Niche 33 3 Growth Factor Signaling 37 Signaling at Different Stages of Hematopoiesis 37 Cytokine Receptors 38 Signaling Pathways Downstream of Receptors 39 Mutations in Signaling Components Leading to Clonal Hematologic Disorders 46 4 Erythropoiesis and Examination of the Peripheral Blood and One Marrow 47 Erythropoiesis 47 Examination of Peripheral Blood and the Bone Marrow 49 Erythroid Cells in the Bone Marrow and Peripheral Blood 49 5 Hypochromic Anemias 53 Iron Metabolism 53 Iron Absorption 55 Hepcidin 55 Iron Homeostasis 55 IronDeficiency Anemia 55 Sideroblastic Anemia 62 Alcohol 67 Lead Poisoning 67 Differential Diagnosis of Hypochromic Microcytic Anemias 68 6 The Porphyrias and Iron Overload 69 Congenital Erythropoietic Porphyria 69 Congenital Erythropoietic Protoporphyria 71 Iron Overload 71 7 Megaloblastic Anemias 76 Clinical Features 77 Bone Marrow Appearances 81 Causes of Megaloblastic Anemia 81 8 Hemolytic Anemias 89 Hereditary Hemolytic Anemia 91 Acquired Hemolytic Anemia 99 9 Genetic Disorders of Hemoglobin 106 Thalassemia 106 αThalassemia 118 Structural Hemoglobin Variants 122 10 Benign Disorders of Phagocytes 130 Granulopoiesis and Monocyte Production 130 Neutrophils (Polymorphs) 131 Mononuclear Phagocytic System 133 Reticuloendothelial System 133 Hereditary Variation in White Cell Morphology 137 Disorders of Phagocytic Function 140 Leukocytosis 142 Leukoerythroblastic Reaction 145 Neutropenia 146 Myelokathexis 149 Lysosomal Storage Diseases 150 11 Benign Disorders of Lymphocytes and Plasma Cells 155 T Cells 155 B Cells, 157 Natural Killer Cells 160 Lymphocyte Proliferation and Differentiation 162 Somatic Hypermutation In Normal B Cells 164 Lymphocyte Circulation 164 Complement 165 Lymphocytosis 165 Lymphadenopathy 167 Primary Immunodeficiency Disorders 168 12 Aplastic and Dyserythropoietic Anemias 185 Aplastic Anemia 185 Red Cell Aplasia 193 Congenital Dyserythropoietic Anemias 195 13 The Hematologic Neoplasms:Laboratory Techniques And Acute Myeloid Leukemia 198 Diagnostic Techniques 198 Acute Myeloid Leukemia 208 14 Acute Lymphoblastic Leukemia 241 Classification 241 Clinical Features 242 Microscopic Appearances 244 Immunology 246 Cytogenetics 247 Fluorescence in Situ Hybridization 248 Molecular Findings 248 Minimal Residual Disease 250 15 Myelodysplastic Syndromes 256 Clinical Features 256 Molecular Genetics 263 Mirage Syndrome 268 Clonal Hematopoiesis of Indeterminate Potential 269 16 Myeloproliferative Neoplasms 271 Chronic Myeloid Leukemia, BCR ABL1 + 271 Chronic Neutrophilic Leukemia 277 The Nonleukemic Myeloproliferative Diseases 277 Leukemic Transformation of Polycythemia Vera and Myelofibrosis 295 Chronic Eosinophilic Leukemia, Not Otherwise Specified 300 Myeloproliferative Disorder Unclassifiable 300 17 Mastocytosis, Myeloid/Lymphoid Neoplasms With Eosinophilia and Specific Cytogenetic Rearrangements, Myelodysplastic/Myeloproliferative Neoplasms 302 Mastocytosis 302 Paraneoplastic Pemphigu 309 Myeloid/Lymphoid Neoplasms with Eosinophilia and Abnormalities of PDGFRA,PDGFRB or FGFR1 , or with PCM1 JAK2 309 Myelodysplastic/Myeloproliferative Neoplasms With Ring Sideroblasts and Thrombocytosis,312 Juvenile Myelomonocytic Leukemia 314 18 Chronic Lymphocytic Leukemia and Other Mature B and T Cell Leukemias 317 Mature BCell Leukemias 317 Mature C-Cell Leukemias 328 19 Small B Cell Lymphomas 335 Epidemiology 336 Etiologic Factors 336 Genetic and Molecular Abnormalities 337 Clinical Features and Diagnosis 337 Imaging 341 Diagnosis 342 Lymphoplasmacytic Lymphoma/Waldenstrom Macroglobulinemia 345 Monoclonal Gammopathy of Undetermined Significance IgM+ 346 Heavy Chain Diseases 346 Splenic Marginal Zone Lymphoma 348 Extranodal Marginal Zone Lymphoma of MucosaAssociated Lymphoid Tissue (Malt Lymphoma) 349 Nodal Marginal Zone BCell Lymphoma 351 Follicular Lymphoma 352 Mantle Cell Lymphoma 356 20 Aggressive Mature B Cell Neoplasms 361 Diffuse Large BCell Lymphoma, Nos 361 T Cell/HistiocyticRich Large BCell Lymphoma 365 Primary Cutaneous Diffuse Large BCell Lymphoma, Leg Type 365 Lymphomatoid Granulomatosis, 365 Primary Mediastinal (Thymic) Large BCell Lymphoma 365 Intravascular Large BCell Lymphoma 366 ALKPositive Diffuse Large BCell Lymphoma, 366 Plasmablastic Lymphoma 370 Primary Effusion Lymphoma and Other HHV8Related Disorders, 370 Burkitt Lymphoma 371 High Grade BCell Lymphoma 372 21 Myeloma and Related Neoplasms 376 Multiple (Plasma Cell) Myeloma 376 Other Plasma Cell Tumors 383 Hyperviscosity Syndrome 384 Other Causes of Serum MProteins 384 Amyloidosis 389 22 Peripheral T and Nk Cell Neoplasms 399 Mature T and NKCell Neoplasm 399 Epstein- Barr Virus Positive TCell Lymphoproliferative Diseases of Childhood 399 Extranodal NK/TCell Lymphoma, Nasal Type 400 EnteropathyAssociated TCell Lymphoma 401 Hepatosplenic TCell Lymphoma 402 Primary Cutaneous TCell Lymphomas 404 Subcutaneous PanniculitisLike TCell Lymphoma 404 Mycosis Fungoides 405 Sezary Syndrome 407 Primary Cutaneous CD30+ TCell Lymphoproliferative Disorders 408 Primary Cutaneous γδ TCell Lymphoma 410 Primary Cutaneous Aggressive Epidermotrophic CD8+ TCell Lymphoma (Provisional Category) 410 Primary Cutaneous Small/Medium CD4+TCell Lymphoproliferative Disorder (Provisional Category) 411 Peripheral TCell Lymphoma, Not Otherwise Specified 411 Angioimmunoblastic TCell Lymphoma 412 Anaplastic Large Cell Lymphoma, ALK Positive 413 Anaplastic Large Cell Lymphoma, ALK Negative 414 23 Hodgkin Lymphoma 418 Presentation and Evolution 418 Histology 418 Classification of Hodgkin Lymphoma 421 Staging Techniques 424 Prognostic Factors 432 24 Histiocytic Disorders 434 Hemophagocytic Lymphohistiocytosis (Hemophagocytic Syndrome) 434 Xanthogranuloma 435 Rosai-Dorfman Disease 435 Histiocytic and Dendritic Cell Neoplasms 439 Histiocytic Sarcoma 439 Langerhans Cell Histiocytosis 439 Langerhans Cell Sarcoma 444 Indeterminate Dendritic Cell Tumor 444 Interdigitating Dendritic Cell Sarcoma 444 Follicular Dendritic Cell Sarcoma 446 Fibroblastic Reticular Cell Tumor 447 Disseminated Juvenile Xanthogranuloma 447 Erdheim-Chester Disease 447 Blastic Plasmacytoid Dendritic Cell Neoplasm 448 25 Stem Cell Transplantation 451 Human Leukocyte Antigen System 451 Other Human Leukocyte Antigens 452 Stem Cell Transplantation 452 26 Normal Hemostasis,Platelet Production and Function 468 The Coagulation Cascade 470 Regulation of Coagulation 470 Megakaryocyte and Platelet Production 472 Platelet and Von Willebrand Factor Function 475 27 Vascular and Platelet Bleeding Disorders 479 Vascular Bleeding Disorders 479 Platelet Bleeding Disorders 480 28 Inherited and Acquired Coagulation Disorders 494 Hereditary Coagulation Disorders 494 Acquired Coagulation Disorders 504 29 Thrombosis and Antithrombotic Thera.