BOOK
SPEC - Hematology E- Book 12 Month Subscription
Leslie E. Silberstein | John Anastasi | Ronald Hoffman | Edward J. Benz | Helen Heslop | Jeffrey Weitz
(2012)
Additional Information
Book Details
Abstract
Hematology, 6th Edition encompasses all of the latest scientific knowledge and clinical solutions in the field, equipping you with the expert answers you need to offer your patients the best possible outcomes. Ronald Hoffman, MD, Edward J. Benz, Jr., MD, Leslie E. Silberstein, MD, Helen Heslop, MD, Jeffrey Weitz, MD, John Anastasi, MD, and a host of world-class contributors present the expert, evidence-based guidance you need to make optimal use of the newest diagnostic and therapeutic options.
- Consult this title on your favorite e-reader with intuitive search tools and adjustable font sizes. Elsevier eBooks provide instant portable access to your entire library, no matter what device you're using or where you're located.
- Make confident, effective clinical decisions by consulting the world's most trusted hematology reference.
- Access the complete contents online at www.expertconsult.com, with a downloadable image collection, regular updates, case studies, patient information sheets, and more.
- Apply all the latest knowledge on regulation of gene expression, transcription splicing, and RNA metabolism; pediatric transfusion therapy; principles of cell-based gene therapy; allogeneic hematopoietic stem cell transplantation for acute myeloid leukemia and myelodysplastic syndrome in adults; hematology in aging; and much more, thanks to 27 brand-new chapters plus sweeping updates throughout.
- Find the information you need quickly and easily thanks to a completely reworked organization that better reflects today’s clinical practice.
- Visualize clinical problems more clearly with new and updated images that reflect the pivotal role of hematopathology in modern practice.
- Benefit from the experience and fresh perspective of new editor Dr. Jeffrey Weitz, Professor of Medicine at McMaster University School of Medicine and Executive Director of the Thrombosis and Atherosclerosis Research Institute in Ontario.
Table of Contents
| Section Title | Page | Action | Price |
|---|---|---|---|
| Front cover | cover | ||
| Expert consult page | FMii | ||
| Hematology, 6/e | i | ||
| Copyright page | iv | ||
| Dedication | v | ||
| Contributors | vii | ||
| Preface | xxiii | ||
| Table of Contents | xxv | ||
| I Molecular and Cellular Basis of Hematology | 1 | ||
| 1 Anatomy and Physiology of the Gene | 2 | ||
| The Genetic View of the Biosphere: the Central Dogma of Molecular Biology | 2 | ||
| Anatomy and Physiology of Genes | 2 | ||
| DNA Structure | 2 | ||
| Storage and Transmission of Genetic Information | 4 | ||
| Expression of Genetic Information Through the Genetic Code and Protein Synthesis | 4 | ||
| mRNA Metabolism | 6 | ||
| mRNA Splicing | 6 | ||
| Modification of the Ends of the mRNA Molecule | 7 | ||
| 5′ and 3′ Untranslated Sequences | 8 | ||
| Transport of mRNA from Nucleus to Cytoplasm: mRNP Particles | 8 | ||
| Gene Regulation | 8 | ||
| Epigenetic Regulation of Gene Expression | 8 | ||
| Enhancers, Promoters, and Silencers | 9 | ||
| Transcription Factors | 9 | ||
| Regulation of mRNA Splicing, Stability, and Translation (Posttranscriptional Regulation) | 9 | ||
| Small Interfering RNA and Micro RNA | 10 | ||
| Additional Structural Features of Genomic DNA | 10 | ||
| Key Methods for Gene Analysis | 12 | ||
| Restriction Endonucleases | 12 | ||
| DNA, RNA, and Protein Blotting | 12 | ||
| Polymerase Chain Reaction | 13 | ||
| Use of Transgenic and Knockout Mice to Define Gene Function | 13 | ||
| DNA-Based Therapies | 14 | ||
| Gene Therapy | 14 | ||
| Antisense Therapy | 14 | ||
| FUTURE DIRECTIONS | 14 | ||
| Suggested Readings | 15 | ||
| 2 Genomic Approaches to Hematology | 16 | ||
| Principles of Genomic Approaches | 16 | ||
| Hypothesis-Generating Versus Hypothesis-Testing | 16 | ||
| Systematic and Comprehensive Measurements and Perturbations | 16 | ||
| Importance of Sample Acquisition | 17 | ||
| Analytical Considerations | 17 | ||
| Unsupervised Learning Approaches | 17 | ||
| Supervised Learning Approaches | 17 | ||
| Challenges of High-Dimensional Data | 17 | ||
| Robustness of Pattern Recognition Algorithms | 18 | ||
| Next-Generation Sequencing Technology | 18 | ||
| Distinguishing Features Compared With Sanger Sequencing | 18 | ||
| Error Rates and Coverage | 19 | ||
| Future of Sequencing Technologies | 19 | ||
| DNA-Level Characterization | 19 | ||
| Somatic Versus Germline Events | 19 | ||
| Point Mutations | 19 | ||
| Copy Number | 19 | ||
| Rearrangements | 20 | ||
| Methylation | 21 | ||
| RNA-Level Characterization | 21 | ||
| mRNA Profiling | 21 | ||
| Noncoding RNA Profiling | 22 | ||
| Protein-Level Characterization | 22 | ||
| Mass Spectrometry | 22 | ||
| Reverse Phase Lysates | 23 | ||
| Bead-Based Profiling | 23 | ||
| Metabolite-Level Characterization | 23 | ||
| Functional Genomics | 23 | ||
| Pharmacogenomics | 24 | ||
| Clinical Use of Genomics | 25 | ||
| Expression-Based Diagnostics | 25 | ||
| Sequencing-Based Diagnostics | 25 | ||
| FUTURE DIRECTIONS | 25 | ||
| References | 25 | ||
| 3 Regulation of Gene Expression, Transcription, Splicing, and Rna Metabolism | 27 | ||
| How Genes are Organized in DNA | 27 | ||
| Transcription of Genes | 28 | ||
| RNA Splicing | 30 | ||
| Nuclear Export of RNA | 31 | ||
| RNA Metabolism | 31 | ||
| Micro-RNA | 33 | ||
| FUTURE DIRECTIONS | 34 | ||
| Suggested Readings | 34 | ||
| 4 Protein Synthesis, Processing, and Trafficking | 35 | ||
| Key Words | 47.e1 | ||
| Protein Synthesis | 35 | ||
| Regulation of mRNA Translation | 35 | ||
| Protein Folding | 36 | ||
| Protein Degradation | 36 | ||
| Sorting From the Cytosol Into Other Compartments | 36 | ||
| Targeting of Nuclear Proteins | 36 | ||
| Targeting of Mitochondrial Proteins | 38 | ||
| Targeting of Peroxisomal Proteins | 39 | ||
| Cotranslational Protein Translocation in the Endoplasmic Reticulum | 39 | ||
| Protein Trafficking Within the Secretory Pathway | 40 | ||
| Processing of Proteins in the Endoplasmic Reticulum | 41 | ||
| Protein Folding in the Lumen of the ER | 41 | ||
| Protein Modifications in the ER | 41 | ||
| Destruction of Misfolded or Misassembled Proteins: ER-Associated Degradation | 42 | ||
| The Unfolded Protein Response | 42 | ||
| Control of Exit From the Endoplasmic Reticulum | 42 | ||
| Intra-Golgi Transport and Protein Processing | 44 | ||
| Organization of the Golgi Apparatus | 44 | ||
| Retention of Resident Golgi Proteins | 44 | ||
| Protein Trafficking to and Through the Golgi Apparatus | 44 | ||
| Sorting Events at the Trans-Golgi Network | 44 | ||
| Overview | 44 | ||
| Sorting Into Lysosomes | 44 | ||
| Autophagy: A Lysosomal Degradation Pathway | 44 | ||
| Sorting Into Regulated Secretory Granules | 45 | ||
| Endocytic Traffic | 45 | ||
| Overview | 45 | ||
| Phagocytosis | 45 | ||
| Pinocytosis | 46 | ||
| Receptor-Mediated Endocytosis | 46 | ||
| Specificity of Vesicular Targeting | 46 | ||
| FUTURE DIRECTIONS | 46 | ||
| Suggested Readings | 47 | ||
| 5 Protein Architecture: | 48 | ||
| Amino Acids and the Peptide Bond | 48 | ||
| Protein Secondary Structure | 48 | ||
| Disulfide Bonds and Posttranslational Modifications | 49 | ||
| The Domain Structure of Proteins | 50 | ||
| The Immunoglobulin Domain and Variations | 51 | ||
| The Protein Kinase Domain | 52 | ||
| Molecular Interactions and Regulation of Gene Expression | 53 | ||
| SUGGESTED READINGS | 54 | ||
| References | 54.e1 | ||
| 6 Signaling Transduction and Regulation of Cell Metabolism | 55 | ||
| Signaling Transduction | 55 | ||
| Receptor Tyrosine Kinases, Phosphoinosite-3-Kinase, and Mitogen-Activated Protein Kinase Pathways | 55 | ||
| Receptor Tyrosine Kinases | 55 | ||
| Phosphatidylinositol-3-Kinase Pathway | 55 | ||
| MAPK/ERK Pathway | 57 | ||
| Transforming Growth Factor-β Pathway | 57 | ||
| Signaling Through Receptors Associated With Protein-Tyrosine Kinases | 57 | ||
| Cytokine Receptors and JAK Signaling | 57 | ||
| Multichain Immune Recognition Receptors | 58 | ||
| Integrin Signaling | 58 | ||
| Tumor Necrosis Factor Receptors and Signaling | 58 | ||
| Toll-like Receptors and Signaling | 58 | ||
| Wnt Signaling | 59 | ||
| Notch Signaling | 59 | ||
| Nuclear Hormone Receptor Superfamily | 59 | ||
| G Protein–Coupled Receptor and Chemokine Signaling | 59 | ||
| GPCR Signaling | 59 | ||
| Chemokine Signaling | 59 | ||
| Regulation of Cell Metabolism | 60 | ||
| Glucose Metabolism | 60 | ||
| Glycolysis | 60 | ||
| Pentose Phosphate Pathway | 61 | ||
| Tricarboxylic Acid or Krebs Cycle | 61 | ||
| Oxidative Phosphorylation | 61 | ||
| Reactive Oxygen Species Metabolism | 61 | ||
| Lipid Metabolism | 62 | ||
| Fatty Acid Synthesis | 62 | ||
| Fatty Acid Oxidation | 62 | ||
| Cholesterol | 62 | ||
| Amino Acid Metabolism | 62 | ||
| Biosynthesis of the Non-Essential Amino Acids | 62 | ||
| Amino Acid Catabolism | 63 | ||
| Nucleotide Metabolism | 63 | ||
| Nucleotide Synthesis | 63 | ||
| Nucleotide Degradation | 63 | ||
| FUTURE DIRECTIONS | 63 | ||
| SUGGESTED READINGS | 63 | ||
| 7 Pharmacogenomics and Hematologic Diseases | 65 | ||
| Key Words | 76.e1 | ||
| Variation in the Human Genome | 65 | ||
| Single-Nucleotide Polymorphisms | 65 | ||
| Single-Nucleotide Polymorphisms and Phenotypes | 65 | ||
| Haplotypes, Linkage Disequilibrium, and Hapmap | 66 | ||
| Structural Genomic Variants | 66 | ||
| Somatic Genomic Variants | 66 | ||
| Catalogues of Genomic Variants, Genotyping Platforms, and Genome-Wide Association Studies | 66 | ||
| Genetic Variations Influencing Drug Response: Pharmacogenetics–Pharmacogenomics | 67 | ||
| Optimization of Drug Therapy | 67 | ||
| Genetic Variations that Influence Drug Disposition | 67 | ||
| Drug Metabolism | 67 | ||
| Thiopurine S-Methyltransferase and Thiopurines | 67 | ||
| Cytochrome P450 Enzymes | 69 | ||
| CYP2C19 and Clopidogrel | 69 | ||
| CYP2C9, VKORC1, and Warfarin | 70 | ||
| Drug Transporters | 72 | ||
| Adenosine Triphosphate-Binding Cassette Transporters | 72 | ||
| Organic Anion-Transporting Polypeptide 1B1 (OAT1B1) and Methotrexate | 72 | ||
| Genetic Variations Influencing Drug Targets | 72 | ||
| BCR-ABL and Tyrosine Kinase Inhibitors | 72 | ||
| C-KIT and Tyrosine Kinase Inhibitors | 73 | ||
| Adverse Drug Effects Presenting as Hematologic Disorders | 73 | ||
| Drug Development | 73 | ||
| Connectivity Map and Steroid Resistance | 73 | ||
| FMS-Like Tyrosine Kinase-3 (FLT3) and FLT3 Inhibitors | 74 | ||
| Janus Kinases (JAKs) and JAK Inhibitors | 75 | ||
| Future Directions | 75 | ||
| References | 75 | ||
| II Cellular Basis of Hematology | 77 | ||
| 8 Hematopoietic Stem Cell Biology | 78 | ||
| Embryonic Origin of Hematopoietic Stem Cells | 78 | ||
| Definition of Hematopoietic Stem Cells | 78 | ||
| Phenotype | 78 | ||
| Murine Hematopoietic Stem Cells | 78 | ||
| Human Hematopoietic Stem Cells | 79 | ||
| CD49f+ Human Hematopoietic Stem Cells | 79 | ||
| Functional Assays | 80 | ||
| In Vitro Assays | 80 | ||
| In Vivo Assays | 81 | ||
| Colony-Forming Unit–Spleen Assay | 81 | ||
| Competitive Repopulation Assay | 81 | ||
| Regulation of Hematopoietic Stem Cell Fate | 81 | ||
| Intrinsic Pathways | 81 | ||
| Transcription Factors | 81 | ||
| HOX PROTEINS | 81 | ||
| Epigenetic Regulation of Hematopoietic Stem Cells Self-Renewal | 82 | ||
| MicroRNA Regulation | 82 | ||
| Extrinsic Regulation | 82 | ||
| Notch Signaling | 83 | ||
| Wnt Signaling | 83 | ||
| Smad Signaling Pathway | 84 | ||
| Novel Growth Factors for Hematopoietic Stem Cells | 84 | ||
| Methods for Hematopoietic Stem Cell Expansion in Clinical Testing | 85 | ||
| Hematopoietic Stem Cell Regeneration | 85 | ||
| Generating Hematopoietic Stem Cells from Embryonic Stem Cells and Induced Pluripotent Stem Cells | 86 | ||
| Suggested Readings | 86 | ||
| References | 87.e1 | ||
| 9 Hematopoietic Microenvironment | 88 | ||
| Evolution of the Niche Concept | 88 | ||
| Hematopoieitic Microenvironment during Development | 88 | ||
| Adult Bone Marrow Microenvironment | 89 | ||
| Hematopoietic Stem Cell Niches | 89 | ||
| Osteolineage Cells | 90 | ||
| Endothelial Cells | 91 | ||
| Adipocytes | 91 | ||
| Osteoclasts | 91 | ||
| Nestin-Positive Cells | 92 | ||
| CXCL12-Abundant Reticular Cells | 92 | ||
| Bone Marrow Macrophages | 92 | ||
| Extrinsic Regulation of the Hematopoietic Stem Cell Niche | 92 | ||
| Innervation | 92 | ||
| Hypoxia | 92 | ||
| Lymphoid Niches | 92 | ||
| Erythroid Niches | 93 | ||
| Megakaryocytic Niches | 93 | ||
| Human Bone Marrow Microenvironment | 93 | ||
| Hematopoieitic Microenvironment in Acute Leukemia and Myelodysplasia | 94 | ||
| Endothelial Cells | 95 | ||
| Osteolineage Cells | 95 | ||
| Macrophages | 95 | ||
| Hypoxia | 95 | ||
| FUTURE DIRECTIONS | 95 | ||
| Suggested Readings | 96 | ||
| References | 96.e1 | ||
| 10 Cell Adhesion | 97 | ||
| Key Words | 104.e1 | ||
| Adhesion Molecules | 97 | ||
| Extracellular Matrix Proteins | 97 | ||
| Integrins | 97 | ||
| Immunoglobulin-Like Receptors | 98 | ||
| Other Adhesion Receptors That Mediate Protein–protein Interactions | 98 | ||
| Lectin Adhesion Receptors | 100 | ||
| Ligand Binding Versus Cell Adhesion | 101 | ||
| Regulation of Adhesion Receptors | 101 | ||
| Regulation of Synthesis | 101 | ||
| Regulation of Surface Expression | 101 | ||
| Regulation of Binding Affinity | 101 | ||
| Cell Signaling Through Adhesion Molecules | 102 | ||
| Cooperative Interactions Between Signaling and Adhesion Molecules | 102 | ||
| Platelet Adhesion and Aggregation | 102 | ||
| Neutrophil Rolling, Spreading, and Migration | 102 | ||
| Adhesion of T Cells to Antigen-Presenting Cells | 103 | ||
| Altered Expression of Adhesion Molecules | 104 | ||
| Genetic Deficiencies in Adhesion Molecules | 104 | ||
| Dysregulated Expression of Adhesion Molecules | 104 | ||
| Suggested Readings | 104 | ||
| 11 Hematopoietic Cell Trafficking and Chemokines | 105 | ||
| Chemokines in Control of Leukocyte Trafficking | 105 | ||
| Nomenclature and Structure of Chemokines | 105 | ||
| Chemokine Signaling Through G-Protein–Coupled Receptors | 105 | ||
| Termination of Chemokine Signaling | 105 | ||
| Fine Tuning of Chemokine Signaling by Chemokine Cleavage and Inactivation | 109 | ||
| Leukocyte Entry into Tissues | 109 | ||
| Tethering and Rolling of Leukocytes | 109 | ||
| Firm Adhesion of Leukocytes | 110 | ||
| Postadhesional Leukocyte Crawling | 111 | ||
| Leukocyte Transendothelial Migration | 111 | ||
| Interstitial Leukocyte Migration | 111 | ||
| Chemokine Control of Lymphocyte Homing to Secondary Lymphoid Organs | 111 | ||
| Homing of T and B Lymphocytes in High Endothelial Venules of Lymph Nodes | 111 | ||
| Homing in the High Endothelial Venules of the Peyer Patches | 112 | ||
| Trafficking of Leukocytes from Blood into Nonlymphoid Tissues | 112 | ||
| General Principles of Leukocyte Trafficking to Nonlymphoid Tissues | 112 | ||
| Mechanisms of Tissue-Tropic Lymphocyte Trafficking | 112 | ||
| Migration of Hematopoietic Stem Cells to the Bone Marrow | 113 | ||
| Role of Adhesion Molecules for Hematopoietic Stem Cell Trafficking | 113 | ||
| Role of Chemokines for Homing and Retention of Hematopoietic Stem Cells and Hematopoietic Progenitor Cells in the Bone Marrow | 113 | ||
| Regulation of Hematopoietic Stem Cell and Hematopoietic Progenitor Cell Homing in the Bone Marrow by the Nervous System | 113 | ||
| Leukocyte Migration within Tissues | 114 | ||
| Trafficking Patterns of Lymphocytes | 114 | ||
| Migration of T Cells to T Zones within Secondary Lymphoid Organs | 114 | ||
| Positioning of B Cells within Secondary Lymphoid Organs | 114 | ||
| Leukocyte Exit from Tissues | 114 | ||
| Reprogramming Dendritic Cells to Exit Tissues Toward Secondary Lymphoid Organs | 114 | ||
| Egress of Lymphocytes from Secondary Lymphoid Organs | 115 | ||
| Egress of Hematopoietic Stem Cells and Hematopoietic Progenitor Cells from Non-Marrow Tissues | 115 | ||
| FUTURE DIRECTIONS | 115 | ||
| Suggested Readings | 115 | ||
| References | 116.e1 | ||
| 12 Dynamic Interactions Between Hematopoietic Stem and Progenitor Cells and the Bone Marrow: | 117 | ||
| Hematopoietic Stem and Progenitor Cell Homing | 117 | ||
| Studying Human Hematopoietic Stem and Progenitor Cell Homing: Use of Preclinical Immunodeficient Mice Models | 117 | ||
| Homing: Essential Role of the SDF-1–CXCR4 Axis | 117 | ||
| Retention of Hematopoietic Stem and Progenitor Cells in the Bone Marrow | 118 | ||
| Hematopoietic Stem and Progenitor Cell Mobilization | 119 | ||
| Stress Signals and Extensive Hematopoietic Stem and Progenitor Cell Recruitment | 119 | ||
| Stem Cell Trafficking is Coordinated by the Brain–Bone–Blood Triad | 120 | ||
| Proteolytic Enzymes and Hematopoietic Stem and Progenitor Cell Mobilization | 121 | ||
| Additional Control of Hematopoietic Stem and Progenitor Cell Mobilization | 121 | ||
| FUTURE DIRECTIONS | 123 | ||
| Suggested Readings | 124 | ||
| References | 125.e1 | ||
| 13 Vascular Growth in Health and Disease | 126 | ||
| Hemostatic, Hematopoietic, and Vascular Systems As A Functional Continuum | 126 | ||
| Constituents of the Vascular System | 126 | ||
| Cells Involved in Vascular Growth | 126 | ||
| Molecular Regulators of Vascular Responses | 126 | ||
| Vascular Endothelial Growth Factors | 126 | ||
| Platelet-Derived Growth Factors | 127 | ||
| Prokineticins | 127 | ||
| Angiopoietins and Tie Receptors | 127 | ||
| Notch Pathway | 127 | ||
| Ephrins and Eph Receptors | 128 | ||
| Vascular Integrins, Cadherins, and Cell Adhesion Molecules | 128 | ||
| Proteases | 129 | ||
| Angiogenesis Stimulators and Inhibitors | 130 | ||
| Processes Involved in Blood Vessel Formation | 130 | ||
| Vasculogenesis and Vascular Repair | 130 | ||
| Angiogenesis | 130 | ||
| Vascular Maturation | 130 | ||
| Lymphangiogenesis | 131 | ||
| Vasculogenic Mimicry | 132 | ||
| Vascular Cooption | 132 | ||
| Mechanisms Triggering Angiogenesis | 132 | ||
| Therapeutic Implications of Angiogenesis in Hematology | 132 | ||
| Therapeutic Inhibition and Stimulation of Angiogenesis | 132 | ||
| Tumor Angiogenesis and Antiangiogenesis | 132 | ||
| Angiogenesis and Antiangiogenesis in Hematopoietic Malignancies | 133 | ||
| Hematologic Complications Associated With Blood Vessel–Directed Agents | 134 | ||
| FUTURE DIRECTIONS | 134 | ||
| References | 134 | ||
| 14 Principles of Cytokine Signaling | 136 | ||
| Cytokine and Receptor Families and Signal Transduction | 136 | ||
| Models of Ligand-Receptor Binding and Activation | 136 | ||
| Janus Kinases | 137 | ||
| Janus Kinase 1 | 137 | ||
| Janus Kinase 2 | 137 | ||
| Janus Kinase 3 | 137 | ||
| Tyrosine Kinase 2 | 138 | ||
| Signal Transducers and Activators of Transcription | 139 | ||
| Signal Transducer and Activator of Transcription 1 | 141 | ||
| Signal Transducer and Activator of Transcription 2 | 142 | ||
| Signal Transducer and Activator of Transcription 3 | 142 | ||
| Signal Transducer and Activator of Transcription 4 | 143 | ||
| Signal Transducer and Activator of Transcription 6 | 143 | ||
| Signal Transducer and Activator of Transcription 5 | 143 | ||
| Negative Regulators of Cytokine Signaling | 143 | ||
| Src-Homology 2 Containing Phosphatase 1 | 143 | ||
| Src-Homology 2 Containing Phosphatase 2 | 144 | ||
| CD45, PTP1B, TC-PTP, PTPRT, and PTP-BL | 144 | ||
| Protein Inhibitor of Activated STAT | 144 | ||
| Suppressor of Cytokine Signaling | 145 | ||
| FUTURE DIRECTIONS | 145 | ||
| References | 145 | ||
| 15 Control of Cell Division | 147 | ||
| Signal Transduction and Cell Proliferation | 147 | ||
| The Cell Division Cycle | 149 | ||
| S Phase | 149 | ||
| M Phase | 149 | ||
| G1 and G2 Phases | 149 | ||
| G0 Phase | 150 | ||
| Rb and Transcriptional Regulation of the Cell Division Cycle | 150 | ||
| Cyclins, Cyclin-Dependent Kinases, and Cell Cycle Regulation | 152 | ||
| Entry Into S Phase | 152 | ||
| Entry Into M Phase | 153 | ||
| Inhibitors of Cyclin-Dependent Kinases | 154 | ||
| Cell Cycle Checkpoints | 155 | ||
| Cell Cycle Alterations with Differentiation | 156 | ||
| Withdrawal From and Entry Into the Cell Cycle and Cell Differentiation | 156 | ||
| Coupling of Mandatory Cell Cycle Progression and Cell Differentiation | 157 | ||
| Specialized Cell Cycle: Endoreplication and Differentiation | 157 | ||
| Suggested Readings | 157 | ||
| References | 157.e1 | ||
| 16 Cell Death | 158 | ||
| Physiologic Cell Turnover | 158 | ||
| Embryogenesis and Sculpting | 158 | ||
| Executioners of Apoptosis | 158 | ||
| Caspases | 158 | ||
| Activation of Procaspases | 159 | ||
| Discs, Apoptosomes, Inflammasomes, and Piddosomes | 161 | ||
| Non-Apoptotic Roles for Caspases | 161 | ||
| Inhibitor of Apoptosis Proteins | 161 | ||
| Inhibitor of Apoptosis Protein Antagonists | 163 | ||
| Core Apoptosis Pathways | 163 | ||
| BCL-2 Family Proteins and the Intrinsic Pathway of Apoptosis | 163 | ||
| BAX and BAK and the Mitochondrial Gateway to Apoptosis | 163 | ||
| BH3-Only Proteins | 164 | ||
| BCL-2 Family Protein and the Endoplasmic Reticulum Gateway to Apoptosis | 165 | ||
| Nonapoptotic Roles for BCL-2 Family Proteins | 166 | ||
| Death Receptor Signaling and the Extrinsic Pathway of Apoptosis | 166 | ||
| Specific Apoptotic Pathways | 167 | ||
| Unfolded Protein Response | 167 | ||
| Oncogene-Induced Apoptosis | 167 | ||
| Autophagy | 167 | ||
| Clinical Applications | 168 | ||
| FUTURE DIRECTIONS | 168 | ||
| References | 168 | ||
| III Immunologic Basis of Hematology | 171 | ||
| 17 Overview and Compartmentalization of the Immune System | 172 | ||
| Key Words | 181.e1 | ||
| The Innate Immune System | 172 | ||
| Pathogen Recognition Receptors and Pathogen-Associated Molecular Patterns | 172 | ||
| Consequences of PRR–PAMP Ligation: Phagocytosis, the Cytokine Response, and Priming the Adaptive Immune Response | 172 | ||
| Immune Deficiency Conditions Caused by Mutations in the Innate Immune System | 173 | ||
| Innate Immunity and Tissue Homeostasis | 173 | ||
| Adaptive Immune Response | 173 | ||
| Cells of the Innate and Adaptive Immune Systems | 173 | ||
| Lymphocytes | 173 | ||
| Monocytes, Macrophages, and Dendritic Cells | 175 | ||
| Granulocytes | 175 | ||
| Non–Bone Marrow–Derived Cells Involved in Immune Function | 176 | ||
| Anatomy of the Immune System | 176 | ||
| Immune Cell Development: Primary and Secondary Lymphoid Organs | 176 | ||
| T-Cell Maturation | 176 | ||
| B-Cell Maturation | 177 | ||
| Encounters with Antigen: the Inflammatory Response | 177 | ||
| Systemwide Surveillance: the Role of Lymphatic Circulation | 178 | ||
| Secondary Lymphoid Tissue: Common and Unique Anatomy and Functions | 179 | ||
| Suggested Readings | 181 | ||
| References | 181.e1 | ||
| 18 B-Cell Development | 182 | ||
| The Hematopoietic Hierarchy and Stages of B-Cell Development | 182 | ||
| Transcriptional Regulation of B-Cell Development | 182 | ||
| Developmental Checkpoints During B-Cell Differentiation | 183 | ||
| The Pro-B to Pre-B Cell Transition | 183 | ||
| Sterile Transcripts | 184 | ||
| Immunoglobulin Heavy Chain Gene Rearrangement and Expression | 185 | ||
| Allelic Exclusion | 185 | ||
| Expression of the Pre-B Cell Receptor | 185 | ||
| The Pre-B to B-Cell Transition | 186 | ||
| Immunoglobulin Class Switching | 187 | ||
| The B-Cell Receptor | 187 | ||
| Generation and Selection of the Primary B-Cell Repertoire | 187 | ||
| Regulation of Primary B-Cell Development | 188 | ||
| Cell–Cell Interactions | 188 | ||
| Cytokines | 188 | ||
| Systemic Factors | 189 | ||
| B-1 B Cells | 189 | ||
| Fetal B-Cell Development | 189 | ||
| Secondary Lymphoid Compartments | 190 | ||
| T-Independent B-Cell Responses | 191 | ||
| T-Dependent Responses | 191 | ||
| Affinity Maturation and Lymphomagenesis | 191 | ||
| Aging and B-Cell Development | 191 | ||
| References | 192 | ||
| 19 T-Cell Immunity | 193 | ||
| T-Cell Activation | 193 | ||
| Antigen Presentation: Creating the Ligand for the T-Cell Receptor | 193 | ||
| The T-Cell Receptor Complex | 194 | ||
| T-Cell Receptor Signal Transduction | 196 | ||
| Spatial Coordination of T-Cell Receptor Signal Transduction: The Immunologic Synapse | 197 | ||
| T-Cell Proliferation | 198 | ||
| T-Cell Development | 198 | ||
| T-Cell Function | 200 | ||
| Th1 Cells | 200 | ||
| Th2 Cells | 201 | ||
| Th17 Cells | 201 | ||
| Tfh Cells | 202 | ||
| CD8+ Cytotoxic T Cells | 202 | ||
| Maturation of T Cell–mediated Immunity | 203 | ||
| T-Cell Memory | 203 | ||
| T-Cell Exhaustion: An Aborted T-Cell Response | 204 | ||
| Inhibition of T Cell–mediated Immunity | 204 | ||
| Prevention of Inappropriate Initiation of T-Cell Responses | 204 | ||
| Anergy | 204 | ||
| Regulatory T Cells | 204 | ||
| Limiting T-Cell Responses After Stimulation by Foreign Antigen | 205 | ||
| Limitation of T-Cell Activity From Cell-Intrinsic Components | 205 | ||
| Protein Tyrosine Phosphatases | 205 | ||
| CTLA-4 | 206 | ||
| E3 Ubiquitin Ligases | 206 | ||
| Diacylglycerol Kinases | 206 | ||
| Limitation of T-Cell Activity From Cell-Extrinsic Components | 206 | ||
| Terminating Immune Responses After Pathogen Clearance | 206 | ||
| Therapeutic Manipulation of T Cell–mediated Immunity | 207 | ||
| Suggested Readings | 209 | ||
| 20 Natural Killer Cell Immunity | 210 | ||
| Fundamental Biology | 210 | ||
| Natural Killer Subsets | 210 | ||
| CD56dim Natural Killer Cells | 210 | ||
| CD56bright Natural Killer Cells | 210 | ||
| Natural Killer Cell Development | 210 | ||
| Natural Killer Cell Receptors | 211 | ||
| Killer Immunoglobulin-Like Receptors | 211 | ||
| C-Type Lectin Receptors | 212 | ||
| Other Activating Natural Killer Receptors | 212 | ||
| Adaptive Immune Properties of Natural Killer Cells | 212 | ||
| Natural Killer Cell Education | 212 | ||
| Natural Killer Cell Memory | 213 | ||
| The Role of Natural Killer Cells in Human Disease | 213 | ||
| Natural Killer Deficiency Syndromes Linked to Increased Infectious Risks | 213 | ||
| The Role of Natural Killer Cells in Autoimmunity | 213 | ||
| The Therapeutic Potential of Natural Killer Cells | 213 | ||
| FUTURE DIRECTIONS | 215 | ||
| Suggested Readings | 215 | ||
| References | 216.e1 | ||
| 21 Dendritic Cell Biology | 217 | ||
| Dendritic Cell Subsets and Development | 217 | ||
| The Concept of Maturation | 218 | ||
| Antigen Acquisition and Dendritic Cell Activation | 219 | ||
| Antigen Processing | 220 | ||
| Major Histocompatibility Complex Class I Antigen Presentation (Endogenous Route) | 220 | ||
| Major Histocompatibility Class II Antigen Presentation (Exogenous Route) | 221 | ||
| T-Cell Activation | 222 | ||
| B-Cell Activation | 223 | ||
| Natural Killer Cell Activation | 223 | ||
| Activation of Other Elements of the Immune System | 223 | ||
| Tolerance and Autoimmunity | 224 | ||
| Subversion of Dendritic Cell Function by Pathogens and Tumors | 225 | ||
| Immunotherapeutic Strategies and Clinical Trials | 226 | ||
| FUTURE DIRECTIONS | 227 | ||
| Suggested Readings | 227 | ||
| References | 227.e1 | ||
| 22 Complement and Immunoglobulin Biology | 228 | ||
| The Complement System: an Overview | 228 | ||
| Classical Pathway | 228 | ||
| Lectin Pathway | 229 | ||
| Alternative Pathway | 229 | ||
| C3, C5, and the Membrane Attack Complex | 231 | ||
| Complement Receptors and Their Role in Immune Complex Clearance and Activation | 232 | ||
| Biologic Activity of C3a and C5a | 232 | ||
| Regulation of Complement Activation | 232 | ||
| Biologic Consequences of Complement Cascade Deficiencies | 233 | ||
| Biologic Consequences of Complement Regulatory Protein Deficiencies | 233 | ||
| Autoimmunity and Complement Deficiencies | 234 | ||
| Natural Antibody | 235 | ||
| Complement Links Innate and Adaptive Immune Responses | 235 | ||
| Soluble Complement Mediators of Antibody Responses | 235 | ||
| Complement Receptors and Antibody Responses | 236 | ||
| B-Lymphocyte Coreceptors | 236 | ||
| Focusing Antigen on Follicular Dendritic Cells | 236 | ||
| Complement and T-Cell Immunity | 238 | ||
| Conclusion | 239 | ||
| Immunoglobulins | 239 | ||
| Properties and Structure | 239 | ||
| Therapeutic Use | 243 | ||
| Adverse Events Related to Intravenous Immunoglobulin Infusion | 243 | ||
| Early Systemic Events | 243 | ||
| Infectious Disease Transfer | 244 | ||
| High-Dose Treatment-Related Adverse Events | 244 | ||
| Monoclonal Antibody Therapy | 244 | ||
| Suggested Readings | 245 | ||
| References | 246.e1 | ||
| 23 Tolerance and Autoimmunity | 247 | ||
| Self-Reactive Lymphocytes: Origin and Control | 247 | ||
| Origins | 247 | ||
| Regulation: Central Tolerance | 247 | ||
| Clonal Deletion | 247 | ||
| Clonal Anergy | 247 | ||
| Tolerance of Memory B Cells | 248 | ||
| T Cells | 248 | ||
| Limitations of Central Tolerance | 249 | ||
| Persistence of Self-Reactive Lymphocytes | 249 | ||
| Control of Self-Reactive Lymphocytes: Preventing Activation | 250 | ||
| Absence of Self-Antigen | 250 | ||
| Costimulation | 250 | ||
| Control of Self-Reactive Lymphocytes: Downregulation | 251 | ||
| Control of Self-Reactive Lymphocytes: Channeling the Type of Effector Response | 252 | ||
| Breakdown of Self-Tolerance in Autoimmune Diseases | 252 | ||
| Genetic and Environmental Factors | 253 | ||
| Genetic Factors | 253 | ||
| Environmental Factors | 254 | ||
| Examples in Hematology: Epitope Spreading in Posttransfusion Purpura | 254 | ||
| Implications and Therapy | 254 | ||
| Suggested Readings | 255 | ||
| References | 255.e1 | ||
| IV Disorders of Hematopoietic Cell Development | 257 | ||
| 24 Biology of Erythropoiesis, Erythroid Differentiation, and Maturation | 258 | ||
| Erythroid Progenitor Cell Compartment | 258 | ||
| Erythroid Morphologically Recognizable Precursor Cell Compartment | 261 | ||
| Erythropoietin and Epor | 265 | ||
| Signal Transduction by Epor | 266 | ||
| Alterations in Epor and Its Signaling in Disorders of Erythropoiesis | 268 | ||
| Hematopoietic Microenvironment | 269 | ||
| Ontogeny of Erythropoiesis | 271 | ||
| Transcription Factors in Erythropoiesis | 274 | ||
| Transcriptional and Posttranscriptional Impairment in Disorders of Erythropoiesis | 276 | ||
| Cellular Dynamics in Erythropoiesis | 278 | ||
| Suggested Readings | 279 | ||
| References | 279.e1 | ||
| 25 Granulocytopoiesis and Monocytopoiesis | 280 | ||
| Granulocytopoiesis | 280 | ||
| Granulocyte Ontogeny | 280 | ||
| Stages of Neutrophil Differentiation | 280 | ||
| Markers of Granulocytic Maturation | 280 | ||
| Neutrophil Granules and Their Content Proteins | 280 | ||
| Control of Granulopoiesis | 282 | ||
| Cytokine Regulation of Myeloid Proliferation and Differentiation | 282 | ||
| Transcriptional Regulation of Myeloid Differentiation | 283 | ||
| Transcription Factors Regulating Myeloid Differentiation and Myeloid-Specific Gene Expression | 284 | ||
| Runx1 | 284 | ||
| CCAAT Enhancer–Binding Protein Family of Transcription Factors | 285 | ||
| C/EBPα | 285 | ||
| C/EBPβ | 285 | ||
| C/EBPγ | 285 | ||
| C/EBPδ | 285 | ||
| C/EBPε | 286 | ||
| C/EBPζ | 286 | ||
| PU.1 | 286 | ||
| Growth Factor Independence-1 | 286 | ||
| CCAAT Displacement Protein | 286 | ||
| Role of Developmentally Important Neutrophil-Specific Genes in Disease | 287 | ||
| Role of microRNAs in Controlling Gene Expression in Granulopoiesis | 287 | ||
| Eosinophil Production | 288 | ||
| Basophil and Mast Cell Production | 289 | ||
| Monocytopoiesis | 289 | ||
| Monocyte Ontogeny | 289 | ||
| Stages of Monocyte Differentiation | 289 | ||
| Markers of Monocyte Maturation | 289 | ||
| Control of Monocytopoiesis | 290 | ||
| Cytokine Regulation of Monocyte Proliferation and Differentiation | 290 | ||
| Transcriptional Regulation of Monocyte Differentiation | 290 | ||
| c-Jun | 290 | ||
| Other Transcription Factors Modulating Monocyte Development | 290 | ||
| Egr-1. | 290 | ||
| C/EBPβ. | 290 | ||
| MafB and c-Maf. | 290 | ||
| References | 291 | ||
| 26 Thrombocytopoiesis | 292 | ||
| Megakaryocyte Biology | 292 | ||
| Megakaryocyte Development | 292 | ||
| Megakaryocyte Progenitors | 292 | ||
| Immature Megakaryocytes: Promegakaryoblasts | 292 | ||
| Mature Megakaryocytes | 293 | ||
| Prospective Isolation of Megakaryocyte Progenitor Cells | 293 | ||
| Structure of Mature Megakaryocytes | 293 | ||
| Ontogeny of Megakaryopoiesis | 295 | ||
| Platelet Biogenesis | 295 | ||
| Bone Marrow Spatial Cues and Megakaryocyte Maturation | 295 | ||
| Cytokine Regulation of Thrombocytopoiesis | 296 | ||
| Thrombopoietin Signaling | 296 | ||
| Thrombopoietin | 296 | ||
| Thrombopoietin Receptor (c-Mpl) | 296 | ||
| TPO Receptor Downstream Signaling Pathways | 297 | ||
| Negative Regulation of TPO Signaling | 297 | ||
| TPO Signaling in Hematopoietic Stem Cells | 297 | ||
| Congenital Amegakaryocytic Thrombocytopenia | 297 | ||
| Essential Thrombocythemia | 297 | ||
| Regulation of Platelet Mass by Thrombopoietin | 297 | ||
| Additional Cytokines Involved in Megakaryocytopoiesis | 298 | ||
| Therapeutic Cytokine Stimulation of Megakaryocytopoiesis | 298 | ||
| Endomitosis | 299 | ||
| The Endomitotic Cell Cycle | 299 | ||
| Role of Endomitosis in Thrombocytopoiesis | 300 | ||
| Mechanisms of Endomitosis in Megakaryocytes | 300 | ||
| Cyclins and Cyclin-Dependent Kinases | 300 | ||
| Other Mitotic Kinases | 300 | ||
| The Spindle Checkpoint | 300 | ||
| Microtubule Regulation | 300 | ||
| Contractile Ring Activity | 301 | ||
| Transcriptional Control of Megakaryocytopoiesis | 301 | ||
| GATA Family Transcription Factors | 301 | ||
| GATA1 | 301 | ||
| Friend of GATA (FOG-1) | 301 | ||
| X-Linked Dyserythropoietic Anemia and Thrombocytopenia Due to GATA1 Mutations | 301 | ||
| X-Linked Thrombocytopenia and β-Thalassemia Due to GATA1 Mutations | 302 | ||
| X-Linked Gray Platelet-Like Syndrome | 302 | ||
| GATA1 Mutations in Down Syndrome Transient Myeloproliferative Disorders and Acute Megakaryoblastic Leukemia | 302 | ||
| ETS Family Transcription Factors | 303 | ||
| Fli-1 | 303 | ||
| TEL (ETV6) | 304 | ||
| RUNX1 | 304 | ||
| NF-E2 p45 | 304 | ||
| SCL (TAL1) | 304 | ||
| Other Transcription Factors | 305 | ||
| Megakaryocyte Enhancesome Complex | 305 | ||
| Micrornas in Megakaryocytopoiesis | 305 | ||
| FUTURE DIRECTIONS | 305 | ||
| References | 305 | ||
| 27 Inherited Forms of Bone Marrow Failure | 307 | ||
| Bi-Lineage and Tri-Lineage Cytopenias | 307 | ||
| Fanconi Anemia | 307 | ||
| Background | 307 | ||
| Epidemiology | 307 | ||
| Etiology and Genetics | 307 | ||
| Complementation Subtyping | 307 | ||
| Fanconi Anemia Genes | 309 | ||
| Murine Models | 310 | ||
| Function of FANC Proteins | 310 | ||
| Genotype–Phenotype Correlations | 310 | ||
| Pathophysiology | 310 | ||
| Hematopoietic Dysfunction | 311 | ||
| Clinical Features | 311 | ||
| History and Physical Examination | 311 | ||
| Laboratory Manifestations | 312 | ||
| Peripheral Blood and Bone Marrow Findings | 312 | ||
| Abnormal Chromosome Fragility. | 312 | ||
| Somatic Mosaicism. | 312 | ||
| Immunoblotting for FANCD2. | 312 | ||
| Other Findings. | 312 | ||
| Predisposition to Malignancy | 313 | ||
| Heterozygote Phenotype | 313 | ||
| Differential Diagnosis | 313 | ||
| Natural History and Prognosis | 314 | ||
| Therapy | 314 | ||
| Hematopoietic Stem Cell Transplantation | 314 | ||
| Hematopoietic Growth Factors | 315 | ||
| Androgens | 315 | ||
| Future Directions | 316 | ||
| Shwachman-Diamond Syndrome | 316 | ||
| Epidemiology | 316 | ||
| Pathobiology | 316 | ||
| Clinical Features | 317 | ||
| Laboratory Findings | 318 | ||
| Peripheral Blood and Bone Marrow Findings. | 318 | ||
| Immune Dysfunction. | 318 | ||
| Exocrine Pancreatic Tests. | 318 | ||
| Skeletal Imaging. | 319 | ||
| Imaging of the Brain. | 319 | ||
| Leukemia Predisposition. | 319 | ||
| Differential Diagnosis | 320 | ||
| Prognosis | 320 | ||
| Therapy | 320 | ||
| G-CSF | 320 | ||
| Steroids and Androgens | 320 | ||
| Blood Products and Other Supportive Care | 320 | ||
| Hematopoietic Stem Cell Transplantation | 320 | ||
| Future Directions | 321 | ||
| Dyskeratosis Congenita | 321 | ||
| Background | 321 | ||
| Epidemiology | 321 | ||
| Pathobiology | 321 | ||
| Clinical Features | 322 | ||
| Laboratory Findings | 322 | ||
| Peripheral Blood, Bone Marrow, and Immunologic Findings | 322 | ||
| Cancer Predisposition | 323 | ||
| Differential Diagnosis | 323 | ||
| Natural History and Prognosis | 324 | ||
| Therapy | 324 | ||
| Androgens | 324 | ||
| G-CSF | 324 | ||
| Hematopoietic Stem Cell Transplantation | 324 | ||
| Future Directions | 324 | ||
| Congenital Amegakaryocytic Thrombocytopenia | 324 | ||
| Background | 324 | ||
| Epidemiology | 324 | ||
| Pathobiology | 325 | ||
| Type 1 | 325 | ||
| Type II | 325 | ||
| Clinical Features | 325 | ||
| Laboratory Findings | 326 | ||
| Predisposition to Leukemia | 326 | ||
| Differential Diagnosis | 326 | ||
| Therapy and Prognosis | 326 | ||
| Future Directions | 327 | ||
| Other Inherited Syndromes With Associated Pancytopenia | 327 | ||
| Down Syndrome | 327 | ||
| Dubowitz Syndrome | 327 | ||
| Seckel Syndrome | 327 | ||
| Reticular Dysgenesia (Dysgenesis) | 327 | ||
| Schimke Immunoosseous Dysplasia | 328 | ||
| Noonan Syndrome | 328 | ||
| Cartilage-Hair Hypoplasia | 328 | ||
| Pearson Syndrome | 328 | ||
| Other Unclassified Inherited Forms of Bone Marrow Failure | 328 | ||
| Treatment of Unclassified Familial Forms of Bone Marrow Failure | 328 | ||
| Unilineage Cytopenias | 328 | ||
| Diamond-Blackfan Anemia | 328 | ||
| Background | 328 | ||
| Epidemiology | 329 | ||
| Etiology, Genetics, and Pathophysiology | 329 | ||
| Clinical Features | 330 | ||
| Laboratory Findings | 331 | ||
| Peripheral Blood and Bone Marrow. | 331 | ||
| Erythrocyte Findings. | 331 | ||
| Miscellaneous Findings. | 332 | ||
| Imaging Studies. | 332 | ||
| Differential Diagnosis | 332 | ||
| Predisposition to Malignancy | 333 | ||
| Natural History and Prognosis | 334 | ||
| Therapy | 334 | ||
| Transfusions for Patients With Diamond-Blackfan Anemia | 334 | ||
| Corticosteroids | 334 | ||
| High-Dose Methylprednisolone. | 335 | ||
| Cytokine Therapy | 335 | ||
| Hematopoietic Stem Cell Transplantation | 335 | ||
| Other Therapeutic Options | 335 | ||
| Future Directions | 335 | ||
| Kostmann Syndrome and Severe Congenital Neutropenia | 335 | ||
| Background | 335 | ||
| Epidemiology | 336 | ||
| Etiology, Genetics, and Pathophysiology | 336 | ||
| Clinical Features | 337 | ||
| Laboratory Findings | 337 | ||
| Peripheral Blood and Bone Marrow | 337 | ||
| Predisposition to Leukemia and Myelodysplastic Syndrome | 337 | ||
| Differential Diagnosis | 338 | ||
| Therapy and Prognosis | 338 | ||
| Cytokine Therapy | 338 | ||
| Hematopoietic Stem Cell Transplantation | 339 | ||
| Bisphosphonates for Osteoporosis | 340 | ||
| Future Directions | 340 | ||
| Other Inherited Neutropenia Syndromes | 340 | ||
| Barth Syndrome | 340 | ||
| Glycogen Storage Disease Type 1b | 340 | ||
| Cyclic Neutropenia | 341 | ||
| Myelokathexis and WHIM Syndrome | 341 | ||
| Dursun Syndrome | 341 | ||
| Other Inherited Neutropenias | 341 | ||
| Thrombocytopenia With Absent Radii Syndrome | 341 | ||
| Background | 341 | ||
| Etiology and Pathophysiology | 341 | ||
| Clinical Features | 342 | ||
| History and Physical Examination | 342 | ||
| Laboratory Findings | 342 | ||
| Differential Diagnosis | 342 | ||
| Therapy and Prognosis | 342 | ||
| Platelet Transfusions | 343 | ||
| Other Therapies | 343 | ||
| Congenital Dyserythropoietic Anemias | 343 | ||
| Background | 343 | ||
| Etiology, Genetics, Pathophysiology, and Clinical Features | 344 | ||
| CDA Type I | 344 | ||
| Laboratory Abnormalities. | 344 | ||
| CDA Type II (HEMPAS) | 344 | ||
| Laboratory Abnormalities. | 345 | ||
| CDA Type III | 346 | ||
| Laboratory Abnormalities. | 347 | ||
| Other CDAs: Classifiable and Nonclassifiable Variants | 347 | ||
| CDA Group IV. | 347 | ||
| CDA Group V. | 347 | ||
| CDA Group VI. | 347 | ||
| CDA Group VII. | 347 | ||
| Variant CDAs Associated With Specific Gene Mutations | 347 | ||
| Differential Diagnosis | 347 | ||
| Therapy and Prognosis | 347 | ||
| Future Directions | 348 | ||
| Suggested Readings | 348 | ||
| General | 348 | ||
| Fanconi Anemia | 348 | ||
| Shwachman-Diamond Syndrome | 348 | ||
| Dyskeratosis Congenita | 348 | ||
| Congenital Amegakaryocytic Thrombocytopenia | 348 | ||
| Diamond-Blackfan Anemia | 348 | ||
| Kostmann or Severe Congenital Neutropenia | 348 | ||
| Congenital Dyserythropoietic Anemias | 349 | ||
| 28 Aplastic Anemia | 350 | ||
| History | 350 | ||
| Classification | 350 | ||
| Epidemiology | 350 | ||
| Incidence and Geographic and Age Distribution | 350 | ||
| Epidemiologic Clues to Causality | 350 | ||
| Genetic Aspects | 350 | ||
| Etiology and Pathogenesis | 352 | ||
| Hematopoiesis in Bone Marrow Failure | 352 | ||
| Stem Cells | 352 | ||
| Telomeres and Bone Marrow Failure | 352 | ||
| Stromal and Hematopoietic Growth Factors | 353 | ||
| Pathophysiologic Pathways Leading to Aplastic Anemia | 353 | ||
| Direct Hematopoietic Injury | 353 | ||
| Immune-Mediated Bone Marrow Failure | 354 | ||
| Radiation | 354 | ||
| Drugs and Chemicals | 355 | ||
| Benzene | 356 | ||
| Aromatic Hydrocarbons | 357 | ||
| Chloramphenicol | 357 | ||
| Nonsteroidal Antiinflammatory Drugs | 357 | ||
| Neuroleptics and Psychotropic Drugs | 357 | ||
| Gold and Heavy Metals | 357 | ||
| Typical and Atypical Presentations | 357 | ||
| Clinical Associations | 359 | ||
| Posttransfusion Graft-Versus-Host Disease | 359 | ||
| Pregnancy | 359 | ||
| Post-Hepatitis AA | 359 | ||
| Postmononucleosis Aplastic Anemia | 359 | ||
| Hemophagocytic Syndrome | 359 | ||
| Paroxysmal Nocturnal Hemoglobinuria and Aplastic Anemia | 360 | ||
| Collagen Vascular Diseases | 360 | ||
| Laboratory Evaluation | 360 | ||
| Peripheral Blood | 360 | ||
| Diagnosis of Aplastic Anemia | 360 | ||
| Bone Marrow | 360 | ||
| Radiographic Measures of Bone Marrow Function | 362 | ||
| Differential Diagnosis of Pancytopenia | 362 | ||
| Treatment | 362 | ||
| Supportive Management | 363 | ||
| Bleeding | 363 | ||
| Anemia | 364 | ||
| Infection | 364 | ||
| Definitive Therapy | 364 | ||
| Hematopoietic Stem Cell Transplantation | 364 | ||
| Therapy for Aplastic Anemia | 365 | ||
| Matched Sibling Donor (Hematopoietic Stem Cell Transplantation [see Table 28-8]) | 367 | ||
| Matched Unrelated and Nonhistocompatible Family Donors (see Table 28-9) | 367 | ||
| Late Complications of Bone Marrow Transplantation | 368 | ||
| Immunosuppression | 368 | ||
| Antithymocyte Globulins | 368 | ||
| Cyclosporine | 369 | ||
| Combined or Intensive Immunosuppressive Therapy | 369 | ||
| Cyclophosphamide | 370 | ||
| Corticosteroids | 370 | ||
| Late Complications of Immunosuppressive Therapy | 370 | ||
| Immunosuppression Versus Bone Marrow Transplantation | 370 | ||
| Androgens | 370 | ||
| Hematopoietic Growth Factors | 371 | ||
| Prognosis | 372 | ||
| Suggested Readings | 372 | ||
| References | 372.e1 | ||
| 29 Paroxysmal Nocturnal Hemoglobinuria | 373 | ||
| Pathophysiology | 373 | ||
| The Glycosylphosphatidylinositol Anchor | 373 | ||
| PIGA Gene | 374 | ||
| Paroxysmal Nocturnal Hemoglobinuria Stem Cell | 374 | ||
| Paroxysmal Nocturnal Hemoglobinuria Red Blood Cells | 375 | ||
| Clinical Features | 375 | ||
| Hemolytic Anemia and Hemoglobinuria | 375 | ||
| Smooth Muscle Dystonia and Nitric Oxide | 376 | ||
| Renal Manifestations | 376 | ||
| Thrombosis and Paroxysmal Nocturnal Hemoglobinuria | 376 | ||
| Liver | 377 | ||
| Other Abdominal Veins | 377 | ||
| Cerebral Veins | 377 | ||
| Other Sites | 377 | ||
| Clonality and Bone Marrow Failure | 377 | ||
| PIGA Mutations in Aplastic Anemia and Myelodysplastic Syndrome | 377 | ||
| PIGA Mutations in Healthy Controls | 377 | ||
| Clonal Transformation | 378 | ||
| Natural History | 378 | ||
| Laboratory Evaluation | 378 | ||
| Blood | 378 | ||
| Bone Marrow | 378 | ||
| Diagnosis | 378 | ||
| Complement-Based Assays | 378 | ||
| GPI Anchor-Based Assays | 378 | ||
| Aerolysin Assays | 379 | ||
| Therapy | 379 | ||
| Immunosuppressive Therapy | 379 | ||
| Management of Anemia | 379 | ||
| Eculizumab | 379 | ||
| Indications for Therapy | 380 | ||
| Monitoring Patients on Eculizumab | 380 | ||
| Thrombosis | 380 | ||
| Bone Marrow Transplantation | 380 | ||
| Approach to Treatment | 381 | ||
| Hypoplastic Paroxysmal Nocturnal Hemoglobinuria | 381 | ||
| Classical Paroxysmal Nocturnal Hemoglobinuria | 381 | ||
| Anemia | 381 | ||
| Thrombosis | 381 | ||
| References | 382 | ||
| 30 Acquired Disorders of Red Cell, White Cell, and Platelet Production | 383 | ||
| Acquired PURE RED CELL APLASIA | 383 | ||
| Etiology and Classification | 383 | ||
| Pathogenesis | 383 | ||
| Primary Pure Red Cell Aplasia | 383 | ||
| Secondary Forms of Pure Red Cell Aplasia | 384 | ||
| Clinical Associations | 384 | ||
| B-Cell Chronic Lymphocytic Leukemia–Associated PRCA | 384 | ||
| T-Cell Large Granular Lymphocyte–Associated PRCA | 384 | ||
| Thymoma-Associated PRCA | 384 | ||
| Pregnancy-Associated PRCA | 384 | ||
| Parvovirus B19 and Other Viral-Induced PRCAs | 384 | ||
| Connective Tissue Disease–-Associated PRCA | 385 | ||
| Drug-Induced PRCA | 385 | ||
| Erythropoietin Antibody–Associated PRCA | 385 | ||
| PRCA Postallogeneic Stem Cell Transplantation | 386 | ||
| PRCA Postradiation Therapy | 386 | ||
| PRCA Associated With Immune Dysregulation, Polyendocrinopathy, Enteropathy, X-Linked Syndrome | 386 | ||
| Laboratory Evaluation | 386 | ||
| Differential Diagnosis | 387 | ||
| Therapy | 387 | ||
| Surgery or Radiation | 387 | ||
| Medical | 387 | ||
| Supportive | 387 | ||
| Immunosuppression | 387 | ||
| Hematopoietic Stem Cell Transplantation | 388 | ||
| Prognosis | 388 | ||
| Acquired White Blood Cell Production Disorder | 389 | ||
| Classification of Acquired Neutropenias | 389 | ||
| Primary Neutropenia | 389 | ||
| Chronic Idiopathic Neutropenia in Adults | 389 | ||
| Chronic Benign Neutropenia of Infancy and Childhood | 390 | ||
| Secondary Forms of Neutropenias | 390 | ||
| Clinical Associations | 390 | ||
| Drug-Induced Neutropenia/Agranulocytosis | 390 | ||
| Neutropenia as a Manifestation of Systemic Diseases | 391 | ||
| Postinfectious Neutropenia | 391 | ||
| Neutropenia in Nutritional Deficiency and Nutritional Excess | 391 | ||
| Neutropenia Associated With Metabolic Disorders | 391 | ||
| Acquired Neonatal Neutropenias | 391 | ||
| Neutropenia and Hypersplenism | 392 | ||
| Pure White Cell Aplasia | 392 | ||
| Neutropenia Associated With Immunologic Abnormalities | 392 | ||
| Other Iatrogenic Forms of Neutropenia | 392 | ||
| Laboratory Evaluation | 392 | ||
| Differential Diagnosis | 393 | ||
| Therapy | 393 | ||
| Large Granular Lymphocyte Leukemia | 393 | ||
| Pathogenesis | 393 | ||
| Inciting Events | 393 | ||
| Clonal Transformation | 394 | ||
| Extreme Clonal Expansion and the Nonrandom Nature of the T-Cell Large Granular Lymphocyte Leukemia Clone | 394 | ||
| Putative Viral Culprits | 394 | ||
| New Insights Into the Pathogenesis of Large Granular Lymphocyte Leukemia and Potential Therapeutic Targets | 395 | ||
| Clinical Presentation and Physical Features | 395 | ||
| Clinical Overlap and Associations | 395 | ||
| Laboratory Diagnosis | 395 | ||
| Differential Diagnosis | 397 | ||
| Therapy | 397 | ||
| Prognosis | 398 | ||
| Acquired Platelet Production Disorder | 398 | ||
| Selective Megakaryocyte Aplasia | 400 | ||
| Infection | 401 | ||
| Chemotherapy and Irradiation | 401 | ||
| Nutritional Deficiencies | 402 | ||
| Iron Deficiency | 402 | ||
| Marrow Infiltration | 402 | ||
| Ethanol-Related Disorders | 402 | ||
| Other Drug-Related Disorders | 403 | ||
| Paroxysmal Nocturnal Hemoglobinuria | 403 | ||
| Refractory Thrombocytopenia Due to Myelodysplasia | 403 | ||
| Cyclic Thrombocytopenia | 403 | ||
| Suggested Readings | 404 | ||
| References | 404.e1 | ||
| V Red Blood Cells | 405 | ||
| 31 Pathobiology of the Human Erythrocyte and Its Hemoglobins | 406 | ||
| Essential Features of Red Blood Cell Homeostasis | 406 | ||
| Major Features of the Red Blood Cell Membrane | 407 | ||
| Enzymes of Red Blood Cell Intermediary | 407 | ||
| Metabolism | 407 | ||
| Red Blood Cell Senescence and Destruction | 408 | ||
| Hemoglobin Synthesis, Structure, and Function | 408 | ||
| Basic Features | 408 | ||
| Hemoglobin Structure | 408 | ||
| Hemoglobin Function | 410 | ||
| Globin Gene Clusters | 412 | ||
| Ontogeny of Hemoglobin | 413 | ||
| Hemoglobin Biosynthesis and Its Regulation | 414 | ||
| Transcriptional Regulation of Globin Gene Expression | 415 | ||
| Posttranscriptional, Translational, and Posttranslational Mechanisms | 415 | ||
| Nosology of Hemoglobinopathies | 416 | ||
| Suggested Readings | 416 | ||
| 32 Approach to Anemia in the Adult and Child | 418 | ||
| Overview of Erythropoiesis | 418 | ||
| Definition of Anemia | 418 | ||
| Mechanisms of Anemia | 418 | ||
| Hypoproliferative Anemia | 418 | ||
| Hemolytic Anemia | 419 | ||
| Comparison of Etiologies of Anemia in Adults and Children | 419 | ||
| Anemia in Children | 419 | ||
| Anemia in Adults | 420 | ||
| Systematic Approach to Anemia | 421 | ||
| History and Physical Examination | 421 | ||
| Reticulocyte Count | 423 | ||
| Mean Corpuscular Volume and Red Blood Cell Distribution Width from the Complete Blood Count | 423 | ||
| Examination of the Peripheral Blood Smear | 423 | ||
| Bone Marrow Examination | 423 | ||
| FUTURE DIRECTIONS | 426 | ||
| References | 426 | ||
| 33 Pathophysiology of Iron Homeostasis | 427 | ||
| Regulation of Cellular and Systemic Iron Homeostasis | 427 | ||
| Utilization of Iron for Erythropoiesis | 428 | ||
| Recycling of Erythrocyte Iron by Macrophages | 431 | ||
| Liver Iron Storage and Regulation of Systemic Iron Homeostasis | 432 | ||
| Iron Regulation of Hepcidin Expression | 433 | ||
| Erythropoietic Regulation of Hepcidin Expression | 434 | ||
| Inflammatory and Endoplasmic Reticulum Stress–Related Regulation of Hepcidin Expression | 435 | ||
| Intestinal Iron Absorption | 435 | ||
| Future Directions | 435 | ||
| References | 435 | ||
| 34 Disorders of Iron Homeostasis: | 437 | ||
| Laboratory Evaluation of Iron Status | 437 | ||
| Direct Measures | 437 | ||
| Indirect Measures | 437 | ||
| Iron Deficiency | 439 | ||
| Epidemiology | 439 | ||
| Etiology and Pathogenesis | 440 | ||
| Clinical Presentation | 440 | ||
| Laboratory Evaluation | 441 | ||
| Differential Diagnosis | 441 | ||
| Therapy | 442 | ||
| Prognosis | 443 | ||
| Iron Overload | 443 | ||
| Epidemiology | 443 | ||
| Genetic Aspects | 443 | ||
| Etiology and Pathogenesis | 444 | ||
| Hereditary Iron Overload | 444 | ||
| Acquired Iron Overload | 446 | ||
| Clinical Presentation | 446 | ||
| Laboratory Evaluation | 447 | ||
| Differential Diagnosis | 447 | ||
| Therapy | 448 | ||
| Prognosis | 448 | ||
| References | 449 | ||
| 35 Anemia of Chronic Diseases | 450 | ||
| Description and Epidemiology | 450 | ||
| Etiology and Pathogenesis | 450 | ||
| Biology and Molecular Aspects | 451 | ||
| Cytokine-Induced Decreases in Red Blood Cell Survival | 451 | ||
| Cytokine-Induced Abnormalities in Iron Metabolism | 452 | ||
| Cytokines Leading to Direct Inhibition of Hematopoiesis | 452 | ||
| Cytokines Leading to Decreased Erythropoietin Secretion | 452 | ||
| Diagnosis | 453 | ||
| Treatment | 454 | ||
| Summary and Future Directions | 455 | ||
| Suggested Readings | 456 | ||
| References | 456.e1 | ||
| 36 Heme Biosynthesis and Its Disorders: | 457 | ||
| Heme Biosynthesis | 457 | ||
| Biosynthetic Pathways | 457 | ||
| Control of Heme Biosynthesis | 457 | ||
| Porphyrias | 459 | ||
| Biologic and Molecular Aspects | 459 | ||
| Genetic Aspects | 460 | ||
| Acute Intermittent Porphyria | 461 | ||
| Clinical and Laboratory Manifestations | 461 | ||
| Other Acute Porphyrias | 462 | ||
| Hereditary Coproporphyria | 462 | ||
| Variegate Porphyria | 463 | ||
| ALA Dehydratase–Deficiency Porphyria | 463 | ||
| Concurrent Porphyrias | 463 | ||
| Nonacute or Cutaneous Porphyrias | 463 | ||
| Porphyria Cutanea Tarda or Cutaneous Hepatic Porphyria | 463 | ||
| Biologic and Molecular Aspects | 463 | ||
| Genetics | 464 | ||
| Clinical Features | 464 | ||
| Precipitating Factors | 464 | ||
| VI Non-Malignant Leukocytes | 639 | ||
| 46 Neutrophilic Leukocytosis, Neutropenia, Monocytosis, and Monocytopenia | 640 | ||
| Neutrophilic Leukocytosis (Neutrophilia) | 640 | ||
| Leukemoid Reaction Versus Chronic Leukemia | 641 | ||
| Infection | 641 | ||
| Inflammation and Stress | 641 | ||
| Hereditary and Congenital Neutrophilias | 641 | ||
| Smoking | 642 | ||
| Drugs | 642 | ||
| Malignancy | 642 | ||
| Asplenia | 642 | ||
| Obesity | 642 | ||
| Neutropenia (and Agranulocytosis) | 642 | ||
| Severe Congenital Neutropenias | 643 | ||
| Benign Ethnic Neutropenia | 643 | ||
| Autoimmune Neutropenia (Primary and Secondary) | 643 | ||
| Large Granular Lymphocyte Syndrome and Natural Killer Cell Proliferations | 643 | ||
| Neutropenia With Infectious Diseases | 643 | ||
| Hypersplenism | 644 | ||
| Chemotherapy-Induced Neutropenia | 644 | ||
| Drug-Induced Neutropenia | 644 | ||
| MONOCYTOSIS | 644 | ||
| Infectious Diseases | 645 | ||
| Connective Tissue Disorder | 645 | ||
| Hematopoietic Malignancies | 645 | ||
| MONOCYTOPENIA | 645 | ||
| Hairy Cell Leukemia | 645 | ||
| MonoMAC Syndrome | 645 | ||
| Suggested Readings | 645 | ||
| 47 Lymphocytosis, Lymphocytopenia, Hypergammaglobulinemia, and Hypogammaglobulinemia | 647 | ||
| Quantitative Disorders of Lymphocytes | 647 | ||
| Lymphocytosis | 647 | ||
| Clonal Disorders | 647 | ||
| Infectious Causes | 647 | ||
| Physiologic Stress | 648 | ||
| Drug Reactions | 648 | ||
| Polyclonal B-Cell Lymphocytosis | 648 | ||
| Lymphocytopenia | 649 | ||
| Inherited Disorders | 649 | ||
| Infections | 649 | ||
| Collagen Vascular Disorders | 649 | ||
| Malignancies | 649 | ||
| Systemic Disorders | 650 | ||
| Drug Effects | 650 | ||
| Quantitative Disorders of Immunoglobulins | 650 | ||
| Hypogammaglobulinemia | 650 | ||
| Secondary Causes | 650 | ||
| Primary Immunodeficiencies | 650 | ||
| Hypergammaglobulinemia | 652 | ||
| Disorders Producing Polyclonal Gammopathy | 652 | ||
| Disorders Producing Monoclonal Gammopathy | 654 | ||
| References | 654 | ||
| 48 Disorders of Phagocyte Function | 655 | ||
| Approach to Diagnosis of Phagocyte Function Disorders | 655 | ||
| Disorders of the Respiratory Burst Pathway | 655 | ||
| Chronic Granulomatous Disease | 656 | ||
| Molecular Genetics of Chronic Granulomatous Disease | 657 | ||
| Clinical Manifestations | 659 | ||
| Diagnosis | 662 | ||
| Prognosis and Treatment | 663 | ||
| Neutrophil Glucose-6-Phosphate Dehydrogenase Deficiency | 664 | ||
| Disorders of Glutathione Metabolism | 664 | ||
| Myeloperoxidase Deficiency | 665 | ||
| Disorders of Phagocyte Adhesion and Chemotaxis | 665 | ||
| Leukocyte Adhesion Deficiency Type I | 666 | ||
| Molecular Genetics of Leukocyte Adhesion Deficiency Type I | 666 | ||
| Clinical Features | 666 | ||
| Diagnosis | 667 | ||
| Prognosis and Treatment | 667 | ||
| Leukocyte Adhesion Deficiency Types II and III | 667 | ||
| Hyperimmunoglobulin E Syndrome | 667 | ||
| Clinical Manifestations | 668 | ||
| Diagnosis | 669 | ||
| Therapy | 669 | ||
| Miscellaneous Chemotactic Disorders | 669 | ||
| Defects in the Structure and Function of Lysosomal Granules | 669 | ||
| Chédiak-Higashi Syndrome | 670 | ||
| Molecular Genetics | 670 | ||
| Clinical Manifestations | 670 | ||
| Diagnosis | 670 | ||
| Therapy | 671 | ||
| Specific Granule Deficiency | 671 | ||
| Miscellaneous Inherited and Aquired Disorders of Phagocyte Function | 671 | ||
| Acknowledgment | 672 | ||
| References | 672 | ||
| 49 Congenital Disorders of Lymphocyte Function | 674 | ||
| Defects of Thymus Organogenesis | 674 | ||
| DiGeorge Syndrome | 674 | ||
| FOXN1 Deficiency | 674 | ||
| Severe Combined Immunodeficiency Caused by Early Defects in T-Lymphocyte Development | 674 | ||
| Pathobiology and Genetics | 675 | ||
| Cytokine Receptor Signaling Defects | 675 | ||
| Defects in Lymphocyte Survival | 675 | ||
| Defects of Expression and Signaling Through the Pre–T-Cell Receptor and the T-Cell Receptor | 675 | ||
| Clinical Manifestations | 676 | ||
| Diagnostic Approach and Laboratory Manifestations | 676 | ||
| Prognosis, Therapy, and Future Directions | 677 | ||
| Supportive Management | 677 | ||
| General Principles of Hematopoietic Cell Transplantation for Severe Combined Immunodeficiency | 677 | ||
| Survival and Long-Term Outcome After Hematopoietic Cell Transplantation for Severe Combined Immunodeficiency | 678 | ||
| Gene Therapy for Severe Combined Immunodeficiency | 678 | ||
| Late Defects in T-Cell Development | 679 | ||
| ZAP-70 Deficiency | 679 | ||
| Human Leukocyte Antigen Class II Deficiency | 679 | ||
| Human Leukocyte Antigen Class I Deficiency | 679 | ||
| Other Combined Immunodeficiencies | 679 | ||
| CD40LG Deficiency | 679 | ||
| CD40 Deficiency | 679 | ||
| Wiskott-Aldrich Syndrome | 679 | ||
| NEMO Deficiency | 680 | ||
| Disorders with T Cell-Mediated Immune Dysregulation | 680 | ||
| Autoimmune Polyendocrinopathy Candidiasis Ectodermal Dystrophy Syndrome | 680 | ||
| Immune Dysregulation Polyendocrinopathy Enteropathy X-linked Syndrome | 681 | ||
| CD25 Deficiency | 681 | ||
| Autoimmune Lymphoproliferative Syndrome | 681 | ||
| Defects of Cell-Mediated Cytotoxicity | 681 | ||
| Chédiak-Higashi Syndrome | 681 | ||
| X-Linked Lymphoproliferative Disease | 682 | ||
| Defects of B-Cell Development and Function | 682 | ||
| X-linked Agammaglobulinemia | 682 | ||
| Autosomal Recessive Agammaglobulinemia | 682 | ||
| Common Variable Immunodeficiency | 683 | ||
| Genetic Variants Associated With Common Variable Immunodeficiency | 684 | ||
| B-Cell–intrinsic Defects of Class Switch Recombination: Defects of Activation-Induced Cytidine Deaminase and Uracil-N-Glycosylase | 684 | ||
| Key Words | 685.e1 | ||
| Suggested Readings | 685 | ||
| 50 Histiocytic Disorders | 686 | ||
| Langerhans Cell Histiocytosis | 686 | ||
| Epidemiology | 686 | ||
| Pathobiology | 686 | ||
| Clinical Manifestations | 687 | ||
| Bony Involvement | 687 | ||
| Cutaneous Involvement | 688 | ||
| Involvement of Other Organ Systems | 689 | ||
| Other Clinical Features | 689 | ||
| Laboratory Manifestations | 690 | ||
| Differential Diagnosis | 690 | ||
| Prognosis | 691 | ||
| Therapy | 691 | ||
| Surgery and Radiotherapy | 691 | ||
| Chemotherapy | 692 | ||
| Long-Term Follow-Up | 692 | ||
| Future Directions | 692 | ||
| Juvenile Xanthogranulomatous Disease | 692 | ||
| Erdheim-Chester Disease | 693 | ||
| Hemophagocytic Lymphohistiocytosis | 693 | ||
| Epidemiology | 693 | ||
| Pathobiology | 694 | ||
| Clinical Manifestations | 695 | ||
| Prolonged Fever | 695 | ||
| Liver Disease and Coagulopathy | 695 | ||
| Bone Marrow Failure | 695 | ||
| Skin Manifestations | 695 | ||
| Pulmonary Dysfunction | 695 | ||
| Brain, Ophthalmic, and Neuromuscular Symptoms | 695 | ||
| Laboratory Manifestations | 696 | ||
| Differential Diagnosis of Hemophagocytic Lymphohistiocytosis | 697 | ||
| Diagnosis | 697 | ||
| Therapy | 697 | ||
| Induction Therapy | 697 | ||
| Central Nervous System Disease | 697 | ||
| Supportive Care | 698 | ||
| Continuation Therapy | 698 | ||
| Salvage Therapy | 698 | ||
| Hematopoietic Cell Transplantation | 698 | ||
| Prognosis | 698 | ||
| Macrophage Activation Syndrome | 699 | ||
| Diagnosis and Treatment | 699 | ||
| Future Directions | 699 | ||
| Sinus Histiocytosis with Massive Lymphadenopathy or Rosai-Dorfman Disease | 699 | ||
| Suggested Readings | 700 | ||
| 51 Lysosomal Storage Diseases: | 701 | ||
| Key Words | 707.e1 | ||
| Pathobiology of Lysosomal Storage Diseases | 701 | ||
| Biology of the Lysosome and Lysosomal Enzymes: Basic Principles | 701 | ||
| Pathogenesis of Lysosomal Storage Diseases: General Concepts | 702 | ||
| Genetics and Diagnosis of Lysosomal Storage Diseases | 703 | ||
| Therapy of Lysosomal Storage Diseases: An Overview | 704 | ||
| Hematologic Manifestations of Lysosomal Storage Diseases | 705 | ||
| Gaucher Disease: β-Glucosidase Deficiency | 705 | ||
| Types A and B Niemann-Pick Disease: Acid Sphingomyelinase Deficiency | 706 | ||
| Fabry Disease: α-Galactosidase Deficiency | 706 | ||
| Sea Blue Histiocytosis and Lysosomal Storage Diseases | 707 | ||
| Conclusions and Future Directions | 707 | ||
| References | 707 | ||
| 52 Infectious Mononucleosis and Other Epstein-Barr Virus–Associated Diseases | 708 | ||
| Biology of EBV | 708 | ||
| Primary EBV Infection | 708 | ||
| Latent EBV Infection | 709 | ||
| Immune Response to EBV | 710 | ||
| Humoral Immune Responses | 710 | ||
| Heterophile Antibodies | 710 | ||
| EBV-Specific Antibodies | 710 | ||
| Cellular Immune Responses | 711 | ||
| EBV Vaccine Development | 711 | ||
| Infectious Mononucleosis | 711 | ||
| Epidemiology | 711 | ||
| Clinical Manifestations | 712 | ||
| Complications of Primary EBV Infections | 712 | ||
| Hematologic Complications | 712 | ||
| Anemia | 712 | ||
| Neutropenia | 712 | ||
| Thrombocytopenia | 712 | ||
| Splenic Rupture | 713 | ||
| Neurologic Complications | 713 | ||
| Other Organ Involvement | 713 | ||
| Diagnosis | 713 | ||
| Differential Diagnosis | 713 | ||
| Treatment | 713 | ||
| Other EBV-Associated Diseases | 714 | ||
| Hemophagocytic Lymphohistiocytosis | 714 | ||
| X-Linked Lymphoproliferative Diseases | 714 | ||
| XLP1 | 714 | ||
| XLP2 | 714 | ||
| CAEBV | 714 | ||
| Oral Hairy Leukoplakia | 715 | ||
| EBV-Associated Malignancies | 715 | ||
| Lymphoproliferative Disease | 715 | ||
| Treatment of Lymphoproliferative Disease | 716 | ||
| Monoclonal Antibody Therapy | 716 | ||
| T-Cell Therapies | 717 | ||
| EBV-Positive Hodgkin Disease and Non-Hodgkin Lymphomas | 718 | ||
| Hodgkin Disease | 718 | ||
| Non-Hodgkin Lymphomas | 718 | ||
| Adoptive Immunotherapy for EBV-Positive Hodgkin Disease and Non-Hodgkin Lymphomas in Immunocompetent Individuals | 718 | ||
| EBV-Associated Non-Hodgkin Lymphoma in HIV Patients | 718 | ||
| Burkitt Lymphoma | 719 | ||
| Nasopharyngeal Carcinoma | 719 | ||
| FUTURE DIRECTIONS | 719 | ||
| References | 719 | ||
| VII Hematologic Malignancies | 721 | ||
| 53 Progress in the Classification of Myeloid Neoplasms: | 722 | ||
| The Myeloproliferative Neoplasms | 722 | ||
| The Acute Myeloid Leukemias | 724 | ||
| The Myelodysplastic Syndromes | 725 | ||
| The Overlap Myelodysplastic/Myeloproliferative Neoplasms | 726 | ||
| References | 726 | ||
| 54 Conventional and Molecular Cytogenetic Basis of Hematologic Malignancies | 728 | ||
| Methods | 728 | ||
| Cytogenetic Analysis | 728 | ||
| Fluorescence In Situ Hybridization | 728 | ||
| Clonal Origin of Leukemia | 735 | ||
| Chronic Myeloproliferative Neoplasms | 738 | ||
| Chronic Myelogenous Leukemia | 738 | ||
| Ph-Negative Chronic Myeloproliferative Neoplasms | 741 | ||
| Myelodysplastic Syndromes | 744 | ||
| Acute Myeloid Leukemia | 749 | ||
| Acute Lymphoblastic Leukemia | 758 | ||
| B-Cell Chronic Lymphocytic Leukemia | 763 | ||
| Multiple Myeloma | 765 | ||
| Lymphoma | 771 | ||
| T-Cell Lymphoproliferative Diseases | 775 | ||
| Allogeneic Hematopoietic Cell Transplantation | 778 | ||
| Future Directions | 779 | ||
| References | 780 | ||
| 55 Pharmacology and Molecular Mechanisms of Antineoplastic Agents for Hematologic Malignancies | 781 | ||
| Cell Kinetics, the Cell Cycle, and Tumor Growth | 781 | ||
| Tumor Cell Heterogeneity of Hematologic Malignancies | 782 | ||
| Development of Chemotherapeutic Agents | 783 | ||
| Screening for Antitumor Activity Among Chemotherapeutic Agents | 784 | ||
| Phase I Clinical Trial Design | 784 | ||
| Phase II Drug Development | 784 | ||
| Pharmacology of Chemotherapeutic Agents | 785 | ||
| Alkylating Agents | 785 | ||
| Nitrogen Mustard | 786 | ||
| Nitrosoureas | 787 | ||
| Methylating Agents | 787 | ||
| Bendamustine | 788 | ||
| Alkylating Agent–Induced Leukemias | 788 | ||
| Antimicrotubule Agents | 788 | ||
| Antimetabolites | 789 | ||
| Inhibitors of DNA Topoisomerase I and II | 789 | ||
| DNA Topoisomerase I | 789 | ||
| DNA Topoisomerase II | 789 | ||
| DNA Topoisomerase I Inhibitors | 790 | ||
| DNA Topoisomerase II Inhibitors | 791 | ||
| Drug Resistance to Topoisomerase Inhibitors | 791 | ||
| Platinum Analogs | 792 | ||
| Miscellaneous Agents | 792 | ||
| Targeted Agents | 792 | ||
| Imatinib Mesylate and Other BCR/ABL Kinase Inhibitors | 792 | ||
| Dasatinib | 792 | ||
| Nilotinib | 792 | ||
| Bruton Tyrosine Kinase Inhibitors | 793 | ||
| PI3K/AKT Inhibitors | 793 | ||
| PI3K Inhibitors | 793 | ||
| AKT Inhibitors | 793 | ||
| Janus Kinase 2 Inhibitors | 793 | ||
| Other JAK2 Inhibitors | 794 | ||
| Hypomethylating Agents | 794 | ||
| Ubiquitin–Proteasome Inhibitors | 794 | ||
| Proteosome Targeted Agents (Bortezomib) | 795 | ||
| Preclinical Studies With Bortezomib. | 795 | ||
| Pharmacology of Bortezomib. | 796 | ||
| Clinical Studies With Bortezomib. | 796 | ||
| Newer Proteasome Inhibitors | 796 | ||
| Immunomodulatory Agents | 796 | ||
| Thalidomide and Lenalidomide | 796 | ||
| Agents in Development | 797 | ||
| Targeting Apoptosis Signaling in Hematologic Malignancies | 797 | ||
| Proapoptotic Targets of Anticancer Agents | 797 | ||
| Death Receptor–Initiated Apoptotic Signaling | 797 | ||
| Mitochondria-Initiated Apoptotic Signaling | 798 | ||
| Selective Antitumor Agents or Strategies | 799 | ||
| BCL2 Family of Proteins as Targets for Anticancer Drug Design | 799 | ||
| Bcl-2 Antisense | 799 | ||
| BH3 Peptide/Mimetics or Bcl-2/Bcl-xL Small Molecule Antagonists | 799 | ||
| Cyclin-Dependent Kinase Inhibitors as Therapeutic Targets | 800 | ||
| Flavopiridol | 800 | ||
| SNS032 | 800 | ||
| Farnesyltransferase Inhibitors: Zarnestra | 801 | ||
| Inhibitors of the RAF1/Mek/ERK Pathway | 801 | ||
| Sorafenib | 801 | ||
| Inhibitors of the Mammalian Target of Rapamycin | 802 | ||
| Histone Deacetylase Inhibitors | 802 | ||
| Posttranslational Histone and Nonhistone Protein Modifications and Gene Transcription | 802 | ||
| Aberrant Histone Acetyl Transferase and Histone Deacetylase Activity in Hematologic Malignancies | 803 | ||
| Mechanisms of Anticancer Activity of Histone Deacetylase Inhibitors | 803 | ||
| Classes of Histone Deacetylase Inhibitors | 804 | ||
| Short-Chain Fatty Acid Histone Deacetylase Inhibitors | 804 | ||
| Vorinostat and Other Hydroxamic Acid Derivative Histone Deacetylase Inhibitors | 804 | ||
| Synthetic Benzamide Derivative Histone Deacetylase Inhibitors | 805 | ||
| Cyclic Tetrapeptide Histone Deacetylase Inhibitors | 805 | ||
| Combinations of Histone Deacetylase Inhibitors With Other Agents | 805 | ||
| Histone Deacetylase Inhibitors With Cell Cycle and Cell-Signaling Modulators | 805 | ||
| Heat Shock Protein Inhibitors | 805 | ||
| Benzoquinone Ansamycins (Herbamycin A, Geldanamycin, and Tanespimycin) | 806 | ||
| Preclinical Studies of Tanespimycin | 806 | ||
| Metabolism of Tanespimycin | 807 | ||
| Clinical Investigation With Tanespimycin | 807 | ||
| Clinical Investigation With IPI-504 | 807 | ||
| Clinical Investigation With Alvespimycin (KOS-1022) | 807 | ||
| 17-DMAG | 807 | ||
| Other HSP90 Inhibitors | 807 | ||
| Radicicol | 807 | ||
| Novobiocin | 807 | ||
| Bryostatin 1 | 807 | ||
| Drug Resistance to Chemotherapeutic Agents or Multidrug Resistance | 808 | ||
| P-Glycoprotein (ABC-B1 Transporter) | 808 | ||
| Structure and Function | 808 | ||
| Methods of Detection | 809 | ||
| P-Glycoprotein Expression in Normal Human Tissue | 809 | ||
| P-Glycoprotein Expression in Human Malignancies | 809 | ||
| Acute Myeloid Leukemia | 809 | ||
| Impact of P-Glycoprotein in Other Hematologic Malignancies | 810 | ||
| Clinical Studies With Modulators of P-Glycoprotein | 810 | ||
| Multidrug Resistance–Associated Protein (ABC G2 Transporter) | 810 | ||
| Structure and Function | 810 | ||
| Multidrug Resistance Protein Expression in Hematologic Malignancies | 811 | ||
| DNA Repair Pathway Mechanisms of Drug Resistance | 811 | ||
| O6-Alkylguanine-DNA Alkyltransferase (MGMT) | 811 | ||
| Mismatch Repair | 812 | ||
| Major Molecular Response Mutations and Methylating Agent Resistance | 812 | ||
| Base Excision Repair | 812 | ||
| Drug Resistance to Antimetabolites | 812 | ||
| Future DIRECTIONS | 813 | ||
| References | 813 | ||
| Appendix 55-1 Clinical Pharmacology of Alkylating Agents | 815 | ||
| Mechlorethamine (Mustargen) | 815 | ||
| VIII Comprehensive Care of Patients with Hematologic Malignancies | 1375 | ||
| 88 Clinical Approach to Infections in the Compromised Host | 1376 | ||
| Hematologic Conditions Predisposing to Infection | 1376 | ||
| Malignant Hematologic Disorders | 1376 | ||
| Antineoplastic Therapy | 1376 | ||
| Acute Leukemias | 1376 | ||
| Chronic Leukemias | 1376 | ||
| Lymphomas | 1376 | ||
| Myelodysplastic Syndrome | 1376 | ||
| Multiple Myeloma | 1377 | ||
| Uncommon Malignancies | 1377 | ||
| Nonmalignant Hematologic Disorders | 1377 | ||
| Aplastic Anemia | 1377 | ||
| Paroxysmal Nocturnal Hemoglobinuria | 1377 | ||
| Granulocytic Phagocyte Disorders | 1377 | ||
| Erythrocyte Disorders | 1378 | ||
| Hemoglobin Gene Variants | 1378 | ||
| Coagulation Disorders | 1379 | ||
| Blood Groups | 1379 | ||
| Host Defense Impairment and Associated Infection Issues | 1379 | ||
| Neutropenia | 1379 | ||
| Defects in Cell-Mediated Immunity | 1379 | ||
| Defects in the Humoral Immune System | 1379 | ||
| Abnormalities in Splenic Function | 1380 | ||
| Anatomic Alterations in Host Defense | 1380 | ||
| Infection in Patients With Acute Neutropenia or Lymphopenia Following Chemotherapy or Transplantation | 1380 | ||
| Fever | 1380 | ||
| Pulmonary Infiltrates | 1382 | ||
| Bacteria | 1383 | ||
| Viruses | 1384 | ||
| Fungi | 1385 | ||
| Malignancy-Associated Fever and Drug Fever | 1385 | ||
| Infection Management in the Hematopoietic STEM Cell Transplant Recipient: A Model of Severe Immune Deficiency | 1386 | ||
| Pretransplantation Prophylactic Techniques in Hematopoietic Stem Cell Transplant Recipients | 1386 | ||
| Assessment of Pretransplantation Serostatus | 1386 | ||
| Herpes Simplex Virus | 1387 | ||
| Cytomegalovirus | 1387 | ||
| Varicella, Human Herpes Virus Type 6, and Epstein-Barr Virus | 1387 | ||
| Hepatitis B and C | 1387 | ||
| Human Immunodeficiency Virus | 1387 | ||
| Syphilis | 1387 | ||
| Toxoplasma | 1387 | ||
| Review of Commonsense Measures to Prevent Infection | 1387 | ||
| Environmental Measures to Prevent Infection | 1388 | ||
| Infection in the Hematopoietic Stem Cell Transplant Recipient Preengraftment | 1388 | ||
| Infection in the Hematopoietic Stem Cell Transplant Recipient After Engraftment | 1388 | ||
| Cytomegalovirus | 1388 | ||
| Varicella-Zoster Virus | 1389 | ||
| Epstein-Barr Virus | 1389 | ||
| Invasive Mold Infections | 1389 | ||
| Pneumocystis | 1389 | ||
| Parasitic Infections | 1389 | ||
| Infection Issues in the Late Posttransplantation Period | 1389 | ||
| Encapsulated Organism Prophylaxis | 1389 | ||
| Vaccination | 1389 | ||
| References | 1389 | ||
| 89 Indwelling Access Devices | 1391 | ||
| Indwelling Central Venous Access Devices | 1391 | ||
| Device Types | 1391 | ||
| Catheters | 1391 | ||
| Implantable Central Venous Devices (Ports) | 1391 | ||
| Device Choice | 1392 | ||
| Patient Characteristics and Preference | 1392 | ||
| Duration of Use | 1393 | ||
| Purpose for Which the Device Is Required | 1393 | ||
| Relative Complication Rates | 1394 | ||
| Device Insertion | 1394 | ||
| Catheters | 1394 | ||
| IX Cell-Based Therapies | 1469 | ||
| 95 Overview and Historical Perspective of Current Cell-Based Therapies | 1470 | ||
| References | 1471 | ||
| 96 Practical Aspects of Hematologic Stem Cell Harvesting and Mobilization | 1472 | ||
| Selection and Evaluation of the Stem Cell Donor | 1472 | ||
| Selection of the Stem Cell Donor | 1472 | ||
| Evaluation of HSC Donors | 1472 | ||
| Specific Evaluation of Bone Marrow Donors | 1474 | ||
| Specific Evaluation of Peripheral Blood Stem Cell Donors | 1474 | ||
| Specific Evaluation of Umbilical Cord Blood Donors | 1474 | ||
| Collection of Bone Marrow for Transplantation | 1474 | ||
| Bone Marrow Collection Techniques | 1474 | ||
| Toxicity of Bone Marrow Collection | 1475 | ||
| Collection of Umbilical Cord Blood Stem Cells for Transplantation | 1475 | ||
| Cord Blood Collection Techniques | 1475 | ||
| Collection of Peripheral Blood Stem Cells for Transplantation | 1476 | ||
| Background | 1476 | ||
| Mobilization of Hematopoietic Stem Cells into Peripheral Blood | 1477 | ||
| Cytokine Mobilization | 1477 | ||
| Granulocyte Colony-Stimulating Factor | 1477 | ||
| Mobilization of Hematopoietic Stem Cells Using Granulocyte Colony-Stimulating Factor | 1477 | ||
| Toxicity and Complications of Granulocyte Colony-Stimulating Factor | 1478 | ||
| Granulocyte-Macrophage Colony-Stimulating Factor | 1478 | ||
| Other Hematopoietic Cytokines | 1478 | ||
| Chemotherapy Plus Cytokine Mobilization | 1478 | ||
| Chemokines | 1479 | ||
| Plerixafor | 1479 | ||
| Strategies for the Patient Who Is Difficult to Mobilize | 1479 | ||
| Timing of Apheresis | 1479 | ||
| Timing of Apheresis Using Plerixafor | 1480 | ||
| Collection of PBSC by Apheresis | 1480 | ||
| Apheresis Technology | 1481 | ||
| Venous Access | 1481 | ||
| Anticoagulation for PBSC Collection | 1481 | ||
| Large-Volume Leukapheresis | 1481 | ||
| Pediatric Donors and Patients | 1482 | ||
| Quality Control of HSC Products | 1482 | ||
| Quantity of Bone Marrow Cells for Transplantation | 1482 | ||
| Definition of Adequate PBSC Component(s) | 1483 | ||
| Management of Donor-Recipient Red Blood Cell Incompatibility | 1483 | ||
| Tumor Cell Contamination | 1483 | ||
| Microbial Contamination of Hematopoietic Stem Cell Components | 1484 | ||
| Quantitation of CD34+ Cells | 1484 | ||
| Progenitor Cell Cultures | 1484 | ||
| Suggested Readings | 1485 | ||
| References | 1485.e1 | ||
| 97 Preclinical Process of Cell-Based Therapies | 1486 | ||
| Key Words | 1491.e1 | ||
| Overview of the Cell Therapy Product | 1486 | ||
| Challenges for Cell Therapy Product and Manufacturing Development | 1486 | ||
| Biologic Variability | 1486 | ||
| Characterization | 1486 | ||
| Raw Materials | 1487 | ||
| Adventitious Agents | 1487 | ||
| Aseptic Processing | 1487 | ||
| Target Cell Population | 1487 | ||
| Autologous Versus Allogeneic Products | 1487 | ||
| The Regulation of Cell Therapy Products: the Center for Biologics Evaluation and Research | 1488 | ||
| The Investigational New Drug Process | 1488 | ||
| Investigational New Drug Sponsor and Investigator | 1488 | ||
| Requesting a Meeting | 1488 | ||
| Pre–Investigational New Drug Meeting | 1488 | ||
| Investigational New Drug Submission | 1489 | ||
| Chemistry, Manufacturing, and Control Section | 1489 | ||
| Pharmacology/Toxicology Section | 1489 | ||
| Cross-Referencing | 1489 | ||
| An Investigational New Drug Hold | 1489 | ||
| Investigational New Drug Maintenance | 1490 | ||
| When Is a Cell Therapy Product Ready to be Tested in a Clinical Trial? | 1490 | ||
| Trial Design Considerations | 1490 | ||
| Operational Issues | 1490 | ||
| Shipping and Administration of Cellular Products | 1490 | ||
| Quality Control and Quality Assurance | 1490 | ||
| Data and Adverse Event Monitoring | 1490 | ||
| Future Directions | 1491 | ||
| Suggested Readings | 1491 | ||
| References | 1491 | ||
| 98 Graft Engineering and Cell Processing | 1492 | ||
| Key Words | 1502.e1 | ||
| Regulatory Issues with Cell Processing | 1492 | ||
| Professional Standards | 1493 | ||
| Manipulation of Hematopoietic Stem Cell Transplantation Products | 1493 | ||
| Routine Minimal Manipulation for Volume Reduction or ABO Incompatibility | 1493 | ||
| Purging of Autologous Grafts | 1494 | ||
| T-Cell Depletion of Allogeneic Products | 1494 | ||
| Evaluation of Manipulated Grafts | 1495 | ||
| Flow Cytometry | 1495 | ||
| Tetramer Analysis | 1495 | ||
| Functional Assays | 1496 | ||
| Cellular Therapy Products | 1496 | ||
| Donor Leukocyte Infusions | 1497 | ||
| Nonspecifically Activated Autologous T Cells | 1498 | ||
| Tumor-Infiltrating Lymphocytes | 1498 | ||
| Allodepleted Cells | 1498 | ||
| Suicide Gene Transduced Lymphocytes | 1499 | ||
| Antigen-Specific Cytotoxic T Lymphocytes | 1499 | ||
| Natural Killer Cells | 1499 | ||
| Dendritic Cells | 1499 | ||
| Mesenchymal Stromal Cells | 1500 | ||
| Genetically Modified Cell Therapy Products | 1500 | ||
| Gene-Modified Tumor Vaccines | 1500 | ||
| Future Directions | 1501 | ||
| Suggested Readings | 1501 | ||
| Professional Standards for Cellular Therapy | 1501 | ||
| FDA Regulations: cGMP and cGTP | 1501 | ||
| FDA Guidances on Cellular and Gene Therapy | 1501 | ||
| GMP Facilities and Product Manufacturing | 1501 | ||
| Specific Cell Types: Current Reviews | 1501 | ||
| Mesenchymal Stromal Cells | 1501 | ||
| Dendritic Cells | 1501 | ||
| Natural Killer Cells | 1501 | ||
| Tumor-Infiltrating Lymphocyte Cells | 1501 | ||
| T Cells | 1501 | ||
| Donor Leukocyte Infusions and Suicide Genes | 1502 | ||
| Tumor Vaccines | 1502 | ||
| 99 Principles of Cell-Based Genetic Therapies | 1503 | ||
| Keywords | 1512.e1 | ||
| Hematologic Diseases, Cellular Targets, and the Basis for Genetic Therapies | 1503 | ||
| Vector Systems | 1503 | ||
| Retrovirus Vectors | 1504 | ||
| Lentivirus Vectors | 1505 | ||
| Foamy Virus Vectors | 1505 | ||
| Alpharetroviruses | 1505 | ||
| Experience in Hematologic Clinical Trials to Date | 1505 | ||
| X-Linked Severe Combined Immunodeficiency | 1505 | ||
| Adenosine Deaminase Deficiency | 1507 | ||
| Chronic Granulomatous Disease | 1507 | ||
| Wiskott-Aldrich Syndrome | 1508 | ||
| Childhood Cerebral X-Linked Adrenoleukodystrophy | 1508 | ||
| β-Thalassemia | 1509 | ||
| Insertional Mutagenesis | 1509 | ||
| Recent Modifications of Vector Systems Based on Clinical Experience | 1510 | ||
| New Cell Targets in Genetic Engineering | 1510 | ||
| Site-Directed Homologous Recombination to Correct Gene Mutations | 1511 | ||
| FUTURE DIRECTIONS | 1511 | ||
| Acknowledgements | 1511 | ||
| Suggested Readings | 1511 | ||
| References | 1512.e2 | ||
| 100 Mesenchymal Stromal Cells | 1513 | ||
| Nomenclature and the Defining Phenotype | 1513 | ||
| Identification and Physiologic Role of Mesenchymal Stem Cells | 1513 | ||
| Cell biology of Ex Vivo–Expanded Mesenchymal Stromal Cells for Clinical Cell Therapy | 1515 | ||
| Source | 1515 | ||
| Isolation | 1515 | ||
| Expansion | 1515 | ||
| Phenotype | 1515 | ||
| Secretome | 1515 | ||
| Homing and Migration | 1516 | ||
| Life Span of Mesenchymal Stromal Cells | 1516 | ||
| Immunobiology of Ex Vivo–Expanded Mesenchymal Stromal Cells | 1516 | ||
| T Lymphocytes | 1516 | ||
| B Lymphocytes | 1517 | ||
| NK Cells | 1517 | ||
| Dendritic Cells | 1517 | ||
| Immune Privilege | 1517 | ||
| Risks of Mesenchymal Stromal Cells as Cell Therapy | 1517 | ||
| Malignant Transformation | 1517 | ||
| Ectopic Tissue Formation After Systemic Infusion | 1517 | ||
| Opportunistic Infections | 1517 | ||
| Mesenchymal Stromal Cells in Hematopoiesis | 1518 | ||
| Hematopoietic Cell Transplantation | 1518 | ||
| Clinical Studies | 1518 | ||
| Future Applications | 1519 | ||
| Mesenchymal Stromal Cells for the Treatment of Graft-Versus-Host Disease | 1519 | ||
| Future DIRECTIONS | 1520 | ||
| Suggested Readings | 1520 | ||
| References | 1520.e1 | ||
| 101 T-Cell Therapy of Hematologic Diseases | 1521 | ||
| Types of Cellular Immunotherapy | 1521 | ||
| Adoptive Cell Therapy With T Lymphocytes | 1521 | ||
| Donor Lymphocyte Infusion | 1521 | ||
| Infusion of Activated T Lymphocytes | 1522 | ||
| Adoptive Immunotherapy With Virus-Specific Cytotoxic T Lymphocytes | 1522 | ||
| Donor-Derived Virus-Specific Cytotoxic T Lymphocytes | 1522 | ||
| Third-Party Allogeneic Virus-Specific Cytotoxic T Lymphocytes | 1522 | ||
| Adoptive Immunotherapy of Viral-Related Malignancies | 1522 | ||
| Adoptive Immunotherapy of Non–Viral- Mediated Malignancies | 1522 | ||
| Genetic Modifications of T Cells | 1523 | ||
| T Lymphocytes and Gene-Marking Studies | 1523 | ||
| Artificial αβ-T-Cell Receptors | 1523 | ||
| Chimeric Antigen Receptors | 1524 | ||
| Engineering T Cells to Overcome Immune Evasion Strategies | 1524 | ||
| T Lymphocytes and Transfer of Safety Genes | 1525 | ||
| Future DIRECTIONS | 1525 | ||
| References | 1525 | ||
| 102 Natural Killer Cell-Based Therapies | 1527 | ||
| Natural Killer Cell Biology | 1527 | ||
| Natural Killer Cell Functions | 1527 | ||
| Natural Killer Cell Receptors | 1527 | ||
| Killer Immunoglobulin-like Receptors | 1527 | ||
| Additional Natural Killer Cell Receptors | 1528 | ||
| Natural Killer Cell Education—The Acquisition of Function, Self-Tolerance and Alloreactivity | 1528 | ||
| Natural Killer Cell Recognition of Tumors | 1529 | ||
| Interleukin-22–Producing Tissue Resident Natural Killer Cells | 1529 | ||
| Clinical Applications of Natural Killer Cells | 1529 | ||
| Determination of Donor Natural Killer Cell Alloreactivity | 1529 | ||
| The Role of Natural Killer Cells in Hematopoietic Cell Transplantation | 1529 | ||
| Natural Killer Cell Function After Hematopoietic Cell Transplantation | 1530 | ||
| Donor Selection Based on Killer Immunoglobulin-like Receptor Genotype | 1530 | ||
| Manipulation of Natural Killer Cell Alloreactivity | 1530 | ||
| Control of Viral Infection | 1530 | ||
| Adoptive Transfer of Natural Killer Cells | 1530 | ||
| X Transplantation | 1541 | ||
| 104 Overview of Hematopoietic Stem Cell Transplantation | 1542 | ||
| Allogeneic Transplantation | 1542 | ||
| Autologous Transplantation | 1542 | ||
| Source of Hematopoietic Stem Cells | 1543 | ||
| Autologous Donors | 1543 | ||
| Allogeneic Donors | 1543 | ||
| Umbilical Cord Blood | 1544 | ||
| Conditioning Regimens | 1544 | ||
| Complications after Stem Cell Transplantation | 1544 | ||
| Acute Graft-Versus-Host Disease | 1544 | ||
| Graft Failure | 1544 | ||
| Infections | 1544 | ||
| Regimen-Related Toxicity | 1544 | ||
| Secondary Malignancies | 1544 | ||
| Treatment of Relapse | 1544 | ||
| FUTURE DIRECTIONS | 1545 | ||
| References | 1545 | ||
| 105 Indications and Outcome of Allogeneic Hematopoietic Cell Transplantation for Hematologic Malignancies in Adults | 1546 | ||
| Key Words | 1556.e1 | ||
| Patient Population | 1546 | ||
| Conditioning Regimens | 1546 | ||
| Graft Sources | 1548 | ||
| Alternative Donor Transplants | 1549 | ||
| Graft Versus Malignancy Effects | 1549 | ||
| Prognostic Factors | 1550 | ||
| Donor Factors | 1550 | ||
| Timing of Transplantation | 1551 | ||
| Patient- and Disease-Related Factors | 1551 | ||
| Clinical Research in Allogeneic Transplantation | 1551 | ||
| Long-Term Survival after Allogeneic Transplantation | 1553 | ||
| Disease-Specific Indications for Allogeneic Transplantation | 1553 | ||
| Acute Myeloid Leukemia | 1553 | ||
| Acute Lymphoblastic Leukemia | 1553 | ||
| Chronic Myeloid Leukemia | 1553 | ||
| Chronic Lymphocytic Leukemia | 1554 | ||
| Diffuse Large B-Cell Lymphoma | 1555 | ||
| Follicular Lymphoma | 1555 | ||
| Mantle Cell Lymphoma | 1555 | ||
| T-Cell Lymphoma | 1555 | ||
| Hodgkin Lymphoma | 1555 | ||
| Multiple Myeloma | 1555 | ||
| References | 1555 | ||
| 106 Unrelated Donor Hematopoietic Cell Transplantation | 1557 | ||
| Volunteer Registries | 1557 | ||
| Donor Evaluation and Selection | 1557 | ||
| Process of Identifying A Suitable Unrelated Donor | 1558 | ||
| Human Leukocyte Antigen Typing and Donor Matching in the DNA Era: Genetics of the Human Leukocyte Antigen Complex | 1558 | ||
| Human Leukocyte Antigen Typing Methods | 1559 | ||
| Serology and Cellular Assays | 1559 | ||
| DNA Methods | 1559 | ||
| Assessment of the Vector of Mismatching | 1560 | ||
| Assessment of Human Leukocyte Antigen Haplotypes | 1561 | ||
| Clinical Importance of Donor HLA Matching in Cases of Unrelated Donor HCT | 1561 | ||
| Human Leukocyte Antigen–matched Unrelated Donor Hematopoietic Cell Transplantation | 1562 | ||
| Single-Locus Mismatched Unrelated Hematopoietic Cell Transplantation | 1562 | ||
| Human Leukocyte Antigen C: Discovery of a Classical Transplantation Antigen | 1562 | ||
| Models for Understanding Alloreactivity | 1563 | ||
| Does Mismatch for Alleles or Antigens Pose the Same Risks? | 1564 | ||
| Multilocus Mismatched Unrelated Donor Hematopoietic Cell Transplantation | 1564 | ||
| Importance of Major Histocompatibility Complex Haplotypes and Major Histocompatibility Complex Resident Variation | 1564 | ||
| KIR Receptors | 1565 | ||
| Ligands | 1566 | ||
| Alleles and Haplotypes | 1566 | ||
| FUTURE DIRECTIONS | 1567 | ||
| Suggested Readings | 1567 | ||
| References | 1568.e1 | ||
| 107 Haploidentical Hematopoietic Cell Transplantation | 1569 | ||
| Principles and Rationale | 1569 | ||
| Complications of Haploidentical Hematopoietic Cell Transplantation | 1569 | ||
| Graft-Versus-Host Disease | 1569 | ||
| Graft Rejection | 1570 | ||
| Prolonged Immunodeficiency | 1570 | ||
| Historical Clinical Experience of Haploidentical Hematopoietic Cell Transplantation | 1571 | ||
| Recent Haploidentical Hematopoietic Cell Transplantation Approaches | 1571 | ||
| Myeloablative Haploidentical Hematopoietic Cell Transplantation: Ex Vivo T-Cell Depletion | 1571 | ||
| Ex Vivo T-Cell Anergization | 1572 | ||
| Myeloablative Haploidentical Hematopoietic Cell Transplantation With In Vivo T-Cell Depletion | 1573 | ||
| Nonmyeloablative Conditioning for Haploidentical Hematopoietic Cell Transplantation | 1573 | ||
| Nonmyeloablative Haploidentical Hematopoietic Cell Transplantation Strategies Using in Vivo T-Cell Depletion | 1574 | ||
| Nonmyeloablative Haploidentical Hematopoietic Cell Transplantation With Posttransplant High-Dose Cyclophosphamide | 1574 | ||
| Selective Allodepletion | 1574 | ||
| Choice of Donors for Haploidentical Hematopoietic Cell Transplantation: Special Considerations | 1575 | ||
| Exploiting KIR Ligand Mismatching in the Graft-Versus-Host Direction | 1575 | ||
| Fetomaternal Microchimerism | 1575 | ||
| Immune Reconstitution Following Haploidentical Hematopoietic Cell Transplantation | 1575 | ||
| Cytokines and Chemokines | 1576 | ||
| Enhancement of Antigen-Specific Immune Responses | 1576 | ||
| Optimization of Graft-Versus-Tumor Effect: Adoptive Cellular Therapy Via DLI | 1576 | ||
| Haploidentical Hematopoietic Cell Transplantation: New Applications | 1577 | ||
| Combining Haploidentical Peripheral Blood Stem Cells With Umbilical Cord Blood for Facilitation of Engraftment | 1577 | ||
| Specific Tolerance Induction | 1577 | ||
| Future Directions | 1577 | ||
| Suggested Readings | 1578 | ||
| References | 1579.e1 | ||
| 108 Unrelated Donor Cord Blood Transplantation for Hematologic Malignancies | 1580 | ||
| Single Unit Cord Blood Transplantation | 1580 | ||
| Engraftment | 1580 | ||
| Graft-Versus-Host Disease | 1580 | ||
| Relapse | 1581 | ||
| Transplant-Related Mortality and Survival | 1581 | ||
| Comparison of Single-Unit Cord Blood Transplantation and Adult Donor Allografts | 1582 | ||
| Double-Unit Cord Blood Transplantation | 1582 | ||
| Determinants of Unit Dominance | 1582 | ||
| Host Factors as Determinants of Unit Dominance | 1582 | ||
| Hematopoietic Potency as a Determinant of Unit Dominance | 1583 | ||
| Immune Factors as Determinants of Unit Dominance | 1583 | ||
| Determinants of Speed and Success of Engraftment After Double-Unit Cord Blood Transplantation | 1585 | ||
| Graft-Versus-Host Disease After Double-Unit Cord Blood Transplantation | 1586 | ||
| Relapse | 1586 | ||
| Transplant-Related Mortality and Survival | 1587 | ||
| Comparison of Double-Unit Cord Blood Transplantation With Adult Donor Allografts | 1587 | ||
| Cord Blood Unit Selection | 1587 | ||
| Novel Strategies to Enhance Engraftment | 1588 | ||
| Adoptive Immunotherapy | 1590 | ||
| Future Directions | 1590 | ||
| Disclaimer | 1590 | ||
| Acknowledgment | 1590 | ||
| Suggested Readings | 1590 | ||
| References | 1591.e1 | ||
| 109 Graft-Versus-Host Disease and Graft-Versus-Leukemia Responses | 1592 | ||
| Graft-Versus-Host Disease: Clinical and Pathologic Aspects | 1592 | ||
| Acute Graft-Versus-Host Disease | 1592 | ||
| Clinical Features of Acute GVHD | 1593 | ||
| Other Organs | 1594 | ||
| Differential Diagnosis | 1594 | ||
| Genetic Basis of Graft-Versus-Host Disease | 1594 | ||
| HLA Matching | 1595 | ||
| Minor Histocompatibility Antigens | 1595 | ||
| Other Non-HLA Genes | 1595 | ||
| Pathophysiology of Acute Graft-Versus-Host Disease | 1595 | ||
| Phase 1: Activation of Antigen-Presenting Cells | 1596 | ||
| Phase 2: Donor-T-Cell Activation, Differentiation, and Migration | 1597 | ||
| Costimulation | 1597 | ||
| T-Cell Subsets | 1597 | ||
| CD4+ and CD8+ Cells | 1597 | ||
| Naive and Memory Subsets | 1598 | ||
| Regulatory T Cells | 1598 | ||
| T-Cell Apoptosis | 1598 | ||
| Cytokines and T-Cell Differentiation | 1598 | ||
| CD4+ and CD8+ T Cells | 1599 | ||
| Naive and Memory T Cells | 1599 | ||
| Leukocyte Migration | 1599 | ||
| Phase 3: Effector Phase | 1599 | ||
| Cellular Effectors | 1600 | ||
| Inflammatory Effectors | 1600 | ||
| Biomarkers of Graft-Versus-Host Disease | 1601 | ||
| Prevention of Acute Graft-Versus-Host Disease | 1602 | ||
| Therapy for Acute Graft-Versus-Host Disease | 1603 | ||
| Other Supportive Approaches | 1603 | ||
| Chronic Graft-Versus-Host Disease | 1603 | ||
| Clinical Manifestations of Chronic Graft-Versus-Host Disease | 1604 | ||
| Dermatologic | 1604 | ||
| Ocular | 1604 | ||
| Oral | 1604 | ||
| Gastrointestinal | 1604 | ||
| Hepatic | 1604 | ||
| Pulmonary | 1604 | ||
| Hematopoietic | 1604 | ||
| Immunologic | 1605 | ||
| Musculoskeletal | 1605 | ||
| Differential Diagnosis | 1605 | ||
| Chronic Graft-Versus-Host Disease: Pathophysiology | 1605 | ||
| Therapy for Chronic Graft-Versus-Host Disease | 1605 | ||
| Syngeneic Graft-Versus-Host Disease | 1606 | ||
| Transfusion-Associated Graft-Versus-Host Disease | 1606 | ||
| Graft-Versus-Leukemia Responses | 1606 | ||
| Clinical Features | 1606 | ||
| Genetic Basis | 1607 | ||
| KIR Polymorphisms | 1607 | ||
| Immunobiology of Graft-Versus-Leukemia Responses | 1607 | ||
| Phase 1: Activation of APCs | 1607 | ||
| Phase 2: Donor T Cell Activation | 1608 | ||
| T-Cell Subsets | 1608 | ||
| T-Cell Migration | 1609 | ||
| Phase 3: Effector Phase of GVL | 1609 | ||
| Donor Leukocyte Infusions | 1609 | ||
| Complications of Donor Leukocyte Infusions | 1609 | ||
| Future Directions | 1610 | ||
| Suggested Readings | 1610 | ||
| References | 1611.e1 | ||
| 110 Complications After Hematopoietic Stem Cell Transplantation | 1612 | ||
| Infections | 1612 | ||
| Febrile Neutropenia | 1612 | ||
| Cytomegalovirus Infection | 1613 | ||
| Epidemiology and Risk Factors | 1613 | ||
| Clinical Presentation and Diagnosis | 1615 | ||
| Prevention and Treatment | 1616 | ||
| Other Viral Infections | 1617 | ||
| Fungal Infections | 1617 | ||
| Candida Infections | 1617 | ||
| Aspergillus Infections | 1617 | ||
| Early Noninfectious Complications | 1618 | ||
| Graft Failure | 1618 | ||
| Sinusoidal Obstruction Syndrome | 1619 | ||
| Interstitial Pneumonitis | 1620 | ||
| Infectious Causes of Interstitial Pneumonitis | 1620 | ||
| Noninfectious Causes of Interstitial Pneumonitis | 1620 | ||
| Idiopathic Interstitial Pneumonitis | 1620 | ||
| Diffuse Alveolar Hemorrhage | 1621 | ||
| Late Noninfectious Complications | 1621 | ||
| Organ-Specific Late Effects | 1622 | ||
| Second Cancers | 1622 | ||
| Quality of Life After Transplantation | 1623 | ||
| Graft-Versus-Host Disease | 1623 | ||
| Acute Graft-Versus-Host Disease | 1623 | ||
| Risk Factors and Clinical Features | 1623 | ||
| Prophylaxis of Graft-Versus-Host Disease | 1624 | ||
| Treatment of Acute Graft-Versus-Host Disease | 1624 | ||
| Chronic Graft-Versus-Host Disease | 1624 | ||
| Risk Factors and Clinical Features | 1624 | ||
| Treatment of Chronic Graft-Versus-Host Disease | 1625 | ||
| Future Directions | 1625 | ||
| Suggested Readings | 1625 | ||
| References | 1626.e1 | ||
| XI Transfusion Medicine | 1627 | ||
| 111 Human Blood Group Antigens and Antibodies | 1628 | ||
| Erythrocyte Blood Group Antigens | 1628 | ||
| Terminology | 1628 | ||
| DNA-Based Typing for Blood Group Antigens | 1628 | ||
| Blood Group Antibodies | 1628 | ||
| Compatibility Procedures and Location of Antigen-Negative Blood | 1632 | ||
| ABO | 1632 | ||
| Rh | 1633 | ||
| Antibody Screening | 1633 | ||
| Compatibility Testing | 1633 | ||
| Prevention of Alloimmunization | 1634 | ||
| Blood Group Disease Association | 1634 | ||
| Blood Group Systems | 1634 | ||
| Carbohydrate Blood Groups | 1634 | ||
| ABO and H | 1634 | ||
| Antigens and Their Synthesis. | 1634 | ||
| Inherited and Acquired ABH variants. | 1635 | ||
| Genes and Enzymes. | 1636 | ||
| ABO and Transplantation. | 1636 | ||
| Antibodies. | 1636 | ||
| Other Carbohydrate Blood Group Systems | 1636 | ||
| Protein Blood Groups | 1636 | ||
| Rh, RhAG, and LW Blood Group Systems | 1636 | ||
| Genes, Proteins, Antigens, and Phenotypes. | 1637 | ||
| Antibodies. | 1637 | ||
| RHAG Blood Group System | 1638 | ||
| LW Blood Group System | 1638 | ||
| Kell and Kx Systems | 1638 | ||
| McLeod Syndrome. | 1638 | ||
| Duffy Blood Group System | 1638 | ||
| Antigens. | 1638 | ||
| XII Hemostasis and Thrombosis | 1773 | ||
| 124 Overview of Hemostasis and Thrombosis | 1774 | ||
| Hemostatic System | 1774 | ||
| Vascular Endothelium | 1774 | ||
| Platelet Inhibition | 1774 | ||
| Anticoagulant Activity | 1775 | ||
| Fibrinolytic Activity | 1775 | ||
| Vascular Tone and Permeability | 1775 | ||
| Platelets | 1775 | ||
| Adhesion | 1775 | ||
| Activation and Secretion | 1776 | ||
| Aggregation | 1776 | ||
| Coagulation | 1777 | ||
| Extrinsic Tenase | 1777 | ||
| Intrinsic Tenase | 1777 | ||
| Prothrombinase | 1777 | ||
| Fibrin Formation | 1777 | ||
| Contact Pathway | 1778 | ||
| Fibrinolytic System | 1778 | ||
| Mechanism of Action of Tissue Plasminogen Activator | 1779 | ||
| Mechanism of Action of Urokinase-Type Plasminogen Activator | 1780 | ||
| Mechanism of Action of TAFI | 1780 | ||
| Disorders of Hemostasis or Thrombosis | 1780 | ||
| Hemostatic Disorders | 1780 | ||
| Disorders of Primary Hemostasis | 1780 | ||
| Disorders of Secondary Hemostasis | 1781 | ||
| Disorders of Tertiary Hemostasis | 1782 | ||
| Thrombotic Disorders | 1782 | ||
| Arterial Thrombosis | 1782 | ||
| Intracardiac Thrombosis | 1782 | ||
| Venous Thrombosis | 1782 | ||
| References | 1782 | ||
| 125 The Blood Vessel Wall | 1784 | ||
| Structure of the Vessel Wall | 1784 | ||
| Macrovasculature | 1784 | ||
| Microvasculature | 1784 | ||
| Endothelial Structure and Function | 1784 | ||
| Endothelial Heterogeneity | 1785 | ||
| High Endothelial Venules | 1785 | ||
| Bone Marrow Sinuses | 1786 | ||
| Vascular Development and Differentiation | 1786 | ||
| Vasculogenesis | 1786 | ||
| Vasculogenesis in the Adult | 1786 | ||
| Angiogenesis | 1786 | ||
| Recruitment of Periendothelial Cells | 1787 | ||
| Extracellular Matrix | 1787 | ||
| Cell Adhesion Molecules | 1787 | ||
| Guidance Molecules | 1787 | ||
| Remodeling, Regression, and Apoptosis | 1787 | ||
| Role of Ligand–Receptor Interactions | 1788 | ||
| Inducers of Angiogenesis | 1788 | ||
| Fibroblast Growth Factors | 1788 | ||
| Vascular Endothelial Growth Factors | 1788 | ||
| Angiopoietins | 1789 | ||
| Platelet-Derived Growth Factors | 1789 | ||
| Transforming Growth Factors β | 1789 | ||
| Notch | 1789 | ||
| Coagulation Factors | 1789 | ||
| Other Factors | 1790 | ||
| Inhibitors of Angiogenesis | 1790 | ||
| Arteriogenesis | 1790 | ||
| Lymphangiogenesis | 1790 | ||
| Relationship Between Vascular Development and Hematopoiesis | 1791 | ||
| Physiologic Functions of the Endothelium | 1791 | ||
| The Endothelium as a Barrier | 1791 | ||
| The Endothelium as a Nonthrombogenic Surface | 1791 | ||
| Control of Vascular Tone | 1793 | ||
| Interaction of Blood Cells With the Vessel Wall | 1793 | ||
| Leukocytes | 1793 | ||
| Platelets | 1795 | ||
| Red Blood Cells | 1795 | ||
| Endothelial Cell Activation and Dysfunction | 1796 | ||
| Suggested Readings | 1796 | ||
| References | 1796.e1 | ||
| 126 Megakaryocyte and Platelet Structure | 1797 | ||
| Key Words | 1808.e1 | ||
| Megakaryocyte Development | 1797 | ||
| Endomitosis | 1797 | ||
| Cytoplasmic Maturation | 1797 | ||
| Regulation of Megakaryocyte Development | 1799 | ||
| Platelet Formation | 1800 | ||
| Proplatelets and the Cytoskeletal Mechanics of Platelet Formation | 1800 | ||
| Platelet Maturation at the Proplatelet Tip | 1803 | ||
| Release of Mature Platelets | 1803 | ||
| Location of Platelet Release | 1803 | ||
| Transcriptional Regulation of Platelet Formation | 1803 | ||
| Platelets | 1804 | ||
| Structure of the Resting Platelet | 1804 | ||
| Cytoskeleton of the Resting Platelet | 1804 | ||
| References | 1807 | ||
| 127 Molecular Basis for Platelet Function | 1809 | ||
| Molecular Basis of Platelet Adhesion | 1809 | ||
| Substrates for Platelet Attachment and Spreading | 1809 | ||
| Platelet Adhesion Receptors | 1810 | ||
| The Integrin Family of Adhesion Receptors | 1811 | ||
| Role of Glycoprotein Ib-V-IX in Platelet Adhesion | 1811 | ||
| Collagen Receptors | 1811 | ||
| CLEC2 Adhesion Receptor | 1812 | ||
| Reorganization of the Actin Cytoskeleton | 1812 | ||
| Platelet Secretion | 1813 | ||
| Dense Granules | 1813 | ||
| α Granules | 1813 | ||
| Lysosomal Granules and The Platelet Cytosol | 1815 | ||
| Secretion | 1815 | ||
| Granule Exocytosis | 1815 | ||
| Eicosanoids and Arachidonate | 1815 | ||
| Molecular Basis of Platelet Aggregation | 1815 | ||
| Aggregation Response of Platelets | 1815 | ||
| Molecular Mechanisms Involved in Platelet Aggregation | 1816 | ||
| αIIbβ3: Structure–Function Relationships | 1816 | ||
| Activation of αIIbβ3 | 1817 | ||
| Recognition Specificity and Antagonism of αIIbβ3 | 1818 | ||
| Suggested Readings | 1819 | ||
| References | 1820.e1 | ||
| 128 Molecular Basis of Blood Coagulation | 1821 | ||
| Inventory: Procoagulant, Anticoagulant and Fibrinolytic Proteins, Inhibitors and Receptors | 1821 | ||
| The Vitamin K–Dependent Protein Family | 1822 | ||
| Cofactor Proteins | 1825 | ||
| Cell-Bound Cofactors | 1825 | ||
| Tissue Factor | 1825 | ||
| Thrombomodulin | 1827 | ||
| Soluble Plasma Procofactors | 1827 | ||
| Factor V | 1827 | ||
| Factor VIII | 1827 | ||
| Von Willebrand factor | 1827 | ||
| The Intrinsic Accessory Pathway Proteins | 1827 | ||
| Proteinase inhibitors | 1828 | ||
| Antithrombin | 1828 | ||
| Tissue Factor Pathway Inhibitor | 1829 | ||
| Heparin Cofactor II | 1830 | ||
| Protein C Inhibitor | 1830 | ||
| α2-Macroglobulin | 1830 | ||
| Endothelium | 1830 | ||
| Platelets | 1831 | ||
| Clot Proteins | 1832 | ||
| Fibrinolysis Proteins | 1834 | ||
| Inhibitors of the Fibrinolytic System | 1834 | ||
| Connectivity and Dynamics in Hemostasis | 1834 | ||
| Initiation | 1835 | ||
| Propagation | 1838 | ||
| Termination | 1838 | ||
| Elimination and Fibrinolysis | 1840 | ||
| FUTURE DIRECTIONS | 1840 | ||
| Acknowledgements | 1840 | ||
| Suggested Readings | 1840 | ||
| References | 1841.e1 | ||
| 129 Regulatory Mechanisms in Hemostasis | 1842 | ||
| Key Words | 1846.e1 | ||
| Key Events in the Promotion of Coagulation | 1842 | ||
| Inhibition of Coagulation by Natural Anticoagulants | 1842 | ||
| Tissue Factor Pathway Inhibitor | 1842 | ||
| Antithrombin | 1842 | ||
| The Protein C Anticoagulant Pathway | 1844 | ||
| Regulation of the Protein C Pathway | 1844 | ||
| Disease Modulation by Activated Protein C | 1845 | ||
| Protein S | 1845 | ||
| Protein Z and Protein Z–Dependent Protease Inhibitor | 1845 | ||
| Regulation of Fibrinolysis | 1845 | ||
| Suggested Readings | 1846 | ||
| References | 1846.e1 | ||
| 130 Clinical Approach to the Patient With Bleeding or Bruising | 1847 | ||
| Key Words | 1856.e1 | ||
| Epidemiology | 1847 | ||
| Pathobiology | 1849 | ||
| Clinical Manifestations | 1849 | ||
| Age of Presentation and Extent of Symptoms | 1849 | ||
| Family History and Syndromic Disorders | 1850 | ||
| Bruising, Petechiae, and Other Skin Changes | 1850 | ||
| Epistaxis | 1850 | ||
| Gum Bleeding and Bleeding With Loss of Primary Teeth | 1850 | ||
| Gastrointestinal Bleeding | 1850 | ||
| Challenge-Related Bleeding | 1850 | ||
| Bleeding Symptoms Restricted to Women | 1851 | ||
| Anemia Related to Bleeding | 1851 | ||
| Joint Bleeds and Muscle Bleeds | 1851 | ||
| Subdural and Intracranial Hemorrhage | 1852 | ||
| Hematuria | 1852 | ||
| Bleeding at Birth, Age-Related Changes in Bleeding, and Very Rare Bleeding Symptoms | 1852 | ||
| Laboratory Manifestations | 1852 | ||
| Differential Diagnosis of Bruising and Bleeding | 1853 | ||
| Prognosis | 1853 | ||
| Therapy | 1854 | ||
| Future Directions | 1854 | ||
| References | 1855 | ||
| 131 Laboratory Evaluation of Hemostatic and Thrombotic Disorders | 1857 | ||
| Clinical Screening Assays in Hemostatic Testing to Detect Coagulation Protein Defects | 1858 | ||
| Interpretation of Screening Tests of the Coagulation System | 1860 | ||
| Factor-Specific Coagulation Protein Testing | 1862 | ||
| Practical Approach to the Bleeding Patient with A Coagulation Protein Defect | 1863 | ||
| Screening Tests Used to Recognize Patients with Disorders of Platelet Number or Function | 1864 | ||
| Interpretation of Screening Tests of Platelet Function | 1864 | ||
| Bleeding Disorders Not Recognized by Screening Tests for Coagulation Proteins or Platelets | 1865 | ||
| Other Activities for Hemostasis Laboratories | 1865 | ||
| Thrombosis Evaluation | 1865 | ||
| Monitoring Acute Hemostatic and Thrombotic Conditions | 1865 | ||
| Suggested Readings | 1865 | ||
| References | 1866.e1 | ||
| 132 Acquired Disorders of Platelet Function | 1867 | ||
| Drugs, Foods, and Additives that Affect Platelet Function | 1867 | ||
| Antiplatelet Drugs | 1867 | ||
| Aspirin | 1867 | ||
| Assays of Aspirin Effect on Platelets | 1868 | ||
| Adenosine Diphosphate Receptor Antagonists | 1870 | ||
| Clopidogrel | 1870 | ||
| Prasugrel | 1870 | ||
| Ticagrelor | 1870 | ||
| Platelet αIIbβ3 (Glycoprotein IIb/IIIa) Inhibitors | 1870 | ||
| Abciximab | 1871 | ||
| Eptifibatide | 1871 | ||
| Tirofiban | 1871 | ||
| Phosphodiesterase Inhibitors | 1872 | ||
| Nonselective Phosphodiesterase Inhibitors | 1872 | ||
| PDE5 Inhibitors | 1872 | ||
| Adenyl Cyclase Stimulators or Prostacyclin Analogues | 1872 | ||
| Perioperative Management of Patients Receiving Antiplatelet Therapy | 1872 | ||
| Other Drugs that Adversely Affect Platelet Function | 1873 | ||
| Nonsteroidal Antiinflammatory Drugs | 1873 | ||
| Cardiovascular Drugs | 1873 | ||
| Antibiotics | 1873 | ||
| Psychiatric Drugs | 1874 | ||
| Oncologic Drugs | 1874 | ||
| Anesthetics | 1874 | ||
| Plasma Expanders | 1874 | ||
| Heparins and Thrombolytic Agents | 1874 | ||
| Miscellaneous | 1874 | ||
| Foods and Food Additives | 1875 | ||
| Clonal Disorders | 1875 | ||
| Hematological Clonal Disorders | 1875 | ||
| Myeloproliferative Neoplasms | 1875 | ||
| Management | 1876 | ||
| Paroxysmal Nocturnal Hemoglobinuria | 1877 | ||
| Paraproteinemias | 1877 | ||
| Leukemias and Myelodysplastic Syndromes | 1877 | ||
| Solid Tumors | 1878 | ||
| Systemic Metabolic Disorders | 1878 | ||
| End-Stage Renal Disease | 1878 | ||
| Management of Uremic Bleeding | 1879 | ||
| Liver Disease | 1880 | ||
| Platelet Dysfunction Related with Extracorporeal Circuits | 1880 | ||
| Miscellaneous | 1881 | ||
| Hypothermia | 1881 | ||
| Disseminated Intravascular Coagulation | 1881 | ||
| Antiplatelet Antibodies | 1881 | ||
| Suggested Readings | 1882 | ||
| References | 1882.e1 | ||
| 133 Diseases of Platelet Number: | 1883 | ||
| Immune Thrombocytopenia | 1883 | ||
| Epidemiology | 1883 | ||
| Incidence and Prevalence of Childhood Immune Thrombocytopenia | 1883 | ||
| Adult Immune Thrombocytopenia | 1883 | ||
| Pregnancy | 1884 | ||
| Pathophysiology | 1884 | ||
| Clinical and Laboratory Features | 1885 | ||
| Thrombocytopenia | 1885 | ||
| Clinical Outcomes: Mortality, Bleeding, and Quality of Life | 1885 | ||
| Investigations of Patients With Suspected Immune Thrombocytopenia | 1886 | ||
| Treatment | 1886 | ||
| Observation | 1886 | ||
| Corticosteroids | 1887 | ||
| Intravenous Immunoglobulin and Anti-D | 1887 | ||
| Second-Line Therapy | 1887 | ||
| Splenectomy | 1887 | ||
| Rituximab | 1888 | ||
| Thrombopoietin Receptor Agonists | 1888 | ||
| Treatment of Refractory Immune Thrombocytopenia | 1889 | ||
| Neonatal Alloimmune Thrombocytopenia | 1889 | ||
| Clinical Presentation | 1889 | ||
| Pathophysiology | 1890 | ||
| Laboratory Investigation of Suspected Neonatal Alloimmune Thrombocytopenia | 1890 | ||
| Management | 1891 | ||
| Management of Infants After Delivery | 1891 | ||
| Antenatal Management of the Mother | 1891 | ||
| Fetal Monitoring During Pregnancy | 1891 | ||
| Mode of Delivery | 1891 | ||
| Population Screening for Neonatal Alloimmune Thrombocytopenia | 1891 | ||
| Posttransfusion Purpura | 1892 | ||
| Epidemiology | 1892 | ||
| Clinical Presentation | 1892 | ||
| Diagnosis | 1892 | ||
| Pathophysiology | 1892 | ||
| Management | 1893 | ||
| References | 1893 | ||
| 134 Thrombocytopenia Caused by Platelet Destruction, Hypersplenism, or Hemodilution | 1895 | ||
| Approach to Patients with Thrombocytopenia | 1895 | ||
| History and Physical Examination | 1895 | ||
| Timing of Onset and Severity of Thrombocytopenia | 1895 | ||
| Laboratory Evaluation | 1896 | ||
| Therapy | 1896 | ||
| Anatomy and Physiology | 1897 | ||
| The Spleen: Anatomy and Function | 1897 | ||
| Physiologic Platelet Sequestration | 1898 | ||
| Pathologic Platelet Sequestration: Hypersplenism | 1899 | ||
| Definition | 1899 | ||
| Pathogenesis | 1899 | ||
| Diagnosis | 1899 | ||
| Therapy | 1900 | ||
| Drug-Induced Thrombocytopenic Syndromes | 1900 | ||
| Drug-Induced Immune Thrombocytopenia | 1901 | ||
| Pathogenesis | 1901 | ||
| Clinical Features | 1902 | ||
| Diagnosis | 1904 | ||
| Management | 1904 | ||
| Gold-Induced Thrombocytopenia | 1904 | ||
| Drug-Induced Autoimmune Thrombocytopenia | 1904 | ||
| Drug-Induced Immune Thrombocytopenia of Rapid Onset | 1904 | ||
| Thrombocytopenia Caused by Glycoprotein IIb/IIIa Receptor Antagonists | 1906 | ||
| Miscellaneous Drug-Induced Thrombocytopenic Syndromes | 1906 | ||
| Drug-Induced Thrombotic Microangiopathy | 1906 | ||
| Drug-Induced Disseminated Intravascular Coagulation | 1907 | ||
| Nonidiosyncratic Drug-Induced Thrombocytopenia | 1907 | ||
| Rapid Nonimmune Drug-Induced Thrombocytopenia | 1907 | ||
| Drug Hypersensitivity Reactions | 1907 | ||
| Thrombocytopenia Secondary to Biologic Response Modifiers | 1907 | ||
| Other Causes of Destructive Thrombocytopenia | 1907 | ||
| Incidental Thrombocytopenia of Pregnancy | 1907 | ||
| Preeclampsia and Eclampsia | 1908 | ||
| Infection | 1908 | ||
| Systemic Lupus Erythematosus | 1908 | ||
| Antiphospholipid Syndrome | 1909 | ||
| Malignancy | 1909 | ||
| Macrophage Activation (Hemophagocytic) Syndrome | 1910 | ||
| Solid Organ and Bone Marrow Transplantation | 1910 | ||
| Cardiopulmonary Bypass Surgery | 1910 | ||
| Thrombocytopenia Associated with Cardiovascular Disease | 1910 | ||
| Congenital Cyanotic Heart Disease | 1910 | ||
| Valvular Heart Disease | 1911 | ||
| Pulmonary Vascular Disorders | 1911 | ||
| Hemodilution and Platelet Consumption after Surgery | 1911 | ||
| References | 1912 | ||
| 135 Heparin-Induced Thrombocytopenia | 1913 | ||
| Epidemiology | 1913 | ||
| Pathobiology | 1913 | ||
| Clinical and Laboratory Manifestations | 1914 | ||
| Differential Diagnosis | 1916 | ||
| Clinical Scoring Systems | 1916 | ||
| Laboratory Diagnosis | 1917 | ||
| Prognosis | 1917 | ||
| Therapy | 1917 | ||
| Indirect Factor Xa Inhibitors: Danaparoid and Fondaparinux | 1918 | ||
| Direct Thrombin Inhibitors: Recombinant Hirudin (Lepirudin, Desirudin), Bivalirudin, Argatroban | 1919 | ||
| Caveats in Treatment of Heparin-Induced Thrombocytopenia | 1920 | ||
| Prevention | 1921 | ||
| Anticoagulation and Previous Heparin-Induced Thrombocytopenia | 1921 | ||
| References | 1923 | ||
| 136 Thrombotic Thrombocytopenic Purpura and the Hemolytic Uremic Syndrome | 1925 | ||
| Epidemiology | 1925 | ||
| Thrombotic Thrombocytopenic Purpura | 1925 | ||
| Hemolytic Uremic Syndrome | 1925 | ||
| Stx-HUS | 1925 | ||
| Atypical HUS (aHUS) | 1926 | ||
| Pathobiology | 1926 | ||
| TTP | 1926 | ||
| Inherited ADAMTS13 Deficiency | 1926 | ||
| Acquired ADAMTS13 Deficiency | 1927 | ||
| Other Mechanisms of Potential Relevance to TTP | 1927 | ||
| Stx-HUS | 1928 | ||
| Atypical Hemolytic Uremic Syndrome | 1928 | ||
| Clinical Manifestations of Thrombotic Microangiopathies | 1929 | ||
| TTP | 1929 | ||
| Stx-HUS | 1929 | ||
| Atypical HUS | 1931 | ||
| Laboratory Manifestations of Thrombotic Microangiopathies | 1931 | ||
| TTP | 1931 | ||
| Stx-HUS | 1932 | ||
| Atypical HUS | 1932 | ||
| Differential Diagnosis | 1933 | ||
| Posttransplantation and Cyclosporine | 1933 | ||
| Cyclosporine A | 1933 | ||
| Renal Transplantation | 1933 | ||
| Hematopoietic Stem Cell Transplantation | 1934 | ||
| Cancer and Chemotherapy-Associated Thrombotic Microangiopathy | 1934 | ||
| Streptococcus Pneumonia and Disorders of Cobalamin Metabolism | 1934 | ||
| Miscellaneous Drug-Associated Thrombotic Microangiopathy | 1934 | ||
| HIV-Associated Thrombotic Microangiopathy | 1935 | ||
| Pregnancy-Associated Thrombotic Microangiopathy | 1935 | ||
| Prognosis | 1935 | ||
| Therapy | 1936 | ||
| TTP | 1936 | ||
| Plasma Therapy | 1936 | ||
| Rituximab | 1937 | ||
| Corticosteroids | 1937 | ||
| Splenectomy | 1937 | ||
| Other Modalities | 1937 | ||
| Stx-HUS | 1937 | ||
| Atypical HUS | 1938 | ||
| Future Directions | 1938 | ||
| Suggested Readings | 1938 | ||
| 137 Hemophilia A and B | 1940 | ||
| Epidemiology | 1940 | ||
| Factor VIII (FVIII) Biology: Genetics, Structure, Function, and Pathophysiology | 1940 | ||
| The Factor VIII Gene | 1940 | ||
| Factor VIII Expression | 1940 | ||
| The Biosynthesis of Factor VIII | 1940 | ||
| The Factor VIII Protein Structure | 1941 | ||
| Storage, Secretion, and Circulation of Factor VIII | 1941 | ||
| Activation and Coagulant Function of Factor VIII | 1942 | ||
| Pathophysiology of Hemophilia A | 1942 | ||
| Factor IX Biology: Genetics, Structure, Function, and Pathophysiology | 1943 | ||
| Factor IX Gene and Factor IX Expression | 1943 | ||
| Factor IX Protein | 1943 | ||
| Hemophilia B Molecular Pathology | 1944 | ||
| Hemophilia Diagnosis | 1945 | ||
| Phenotypic Diagnosis of Hemophilia | 1945 | ||
| Genetic Diagnosis of Hemophilia | 1945 | ||
| Diagnosis of the Carrier State in Hemophilia | 1946 | ||
| Differential Diagnosis of Hemophilia | 1946 | ||
| Clinical Features of Hemophilia | 1947 | ||
| Hemophilia in Newborns | 1947 | ||
| Intracranial Hemorrhage in Newborns | 1947 | ||
| Circumcision in Newborns | 1948 | ||
| Other Bleeding Manifestations in Hemophilia | 1948 | ||
| Soft Tissue Hemorrhages and Muscle Bleeds | 1948 | ||
| Hemarthrosis | 1949 | ||
| Mucous Membrane Bleeding | 1950 | ||
| Hematuria | 1950 | ||
| Gastrointestinal Bleeding | 1950 | ||
| Neurologic Bleeding | 1950 | ||
| Surgery and Bleeding | 1951 | ||
| Clinical Management of Hemophilia | 1951 | ||
| Preventive Therapy | 1951 | ||
| Vaccinations | 1951 | ||
| Avoidance of Aspirin and Other Medications | 1952 | ||
| Treatment of Bleeds | 1952 | ||
| Coagulation Factor Concentrates | 1952 | ||
| Adjunctive Treatments | 1953 | ||
| Desmopressin | 1953 | ||
| Antifibrinolytic Agents | 1953 | ||
| Fibrin Sealants | 1953 | ||
| Adjunctive and Alternative Management Strategies for Joint Bleeds | 1954 | ||
| Surgical Management of Joint Disease | 1954 | ||
| Prophylactic Clotting Factor Replacement | 1954 | ||
| Considerations for Treatment of Hemophilic Bleeding in Adults | 1955 | ||
| Gene Therapy for Hemophilia | 1955 | ||
| Modes of Transgene Delivery | 1955 | ||
| Clinical Trials of Hemophilia Gene Therapy | 1956 | ||
| Complications of Treatment | 1956 | ||
| Other Comorbidities in Patients With Hemophilia | 1956 | ||
| Current Limitations to Treatment for Hemophilia | 1957 | ||
| Immune Responses to Exogenous Factor VIII and Factor IX | 1957 | ||
| Anaphylactic Reactions | 1957 | ||
| Inhibitory Antibody Development | 1957 | ||
| Factor VIII Inhibitors: Pathophysiology | 1957 | ||
| Transient Inhibitors | 1958 | ||
| Catalytic Antibodies | 1958 | ||
| Factor IX Inhibitors: Pathophysiology | 1958 | ||
| Detection of Inhibitors and Inhibitor Titers | 1959 | ||
| FUTURE DIRECTIONS | 1959 | ||
| References | 1960 | ||
| 138 Inhibitors in Hemophilia A and B | 1961 | ||
| Hemophilia A | 1961 | ||
| Epidemiology | 1961 | ||
| Genetic Factors | 1961 | ||
| Environmental Factors | 1962 | ||
| Mild Hemophilia | 1963 | ||
| Venous Access | 1963 | ||
| Other Factors | 1963 | ||
| Pathobiology of FVIII Alloantibody Inhibitor Formation | 1963 | ||
| Clinical Manifestations | 1964 | ||
| Laboratory Diagnosis | 1964 | ||
| Treatment | 1965 | ||
| Minor Bleeding Episodes | 1965 | ||
| Severe Bleeding Episodes | 1966 | ||
| Surgery | 1967 | ||
| Prothrombin Complex Concentrates | 1967 | ||
| Activated Prothrombin Complex Concentrates and FVIIa | 1967 | ||
| Parallel-Sequential Use of APCC and FVIIa Concentrates | 1967 | ||
| Prophylaxis With APCC and FVIIa | 1968 | ||
| Fibrinolytic Inhibitors | 1968 | ||
| Immune Tolerance Therapy | 1968 | ||
| Hemophilia B | 1969 | ||
| Epidemiology | 1969 | ||
| Diagnosis | 1969 | ||
| Treatment | 1969 | ||
| Suggested Readings | 1969 | ||
| References | 1970.e1 | ||
| 139 Rare Coagulation Factor Deficiencies | 1971 | ||
| Key Words | 1986.e1 | ||
| Fibrinogen Deficiency (OMIM 202400) | 1971 | ||
| Dysfibrinogenemia (OMIM 134820 Aα-Chain, 134830 Bβ-Chain, and 134850 γ-Chain) | 1975 | ||
| Prothrombin Deficiency (OMIM 176930) | 1976 | ||
| Factor V Deficiency (OMIM 227400) | 1977 | ||
| Factor VII Deficiency (OMIM 227500) | 1978 | ||
| Factor X Deficiency (OMIM 227600) | 1979 | ||
| Factor XI Deficiency (OMIM 264900) | 1980 | ||
| Deficiencies of the Contact Factors: Factor XII, Prekallikrein, and High-Molecular-Weight Kininogen | 1981 | ||
| Factor XII Deficiency (OMIM 234000) | 1981 | ||
| Prekallikrein Deficiency (OMIM 229000) | 1982 | ||
| High-Molecular-Weight Kininogen Deficiency (OMIM 228960) | 1983 | ||
| Factor XIII Deficiency (OMIM 134570 [A Subunit] and 134580 [B Subunit]) | 1983 | ||
| Congenital Deficiencies Involving Multiple Coagulation Factors | 1984 | ||
| Combined Factor V and Factor VIII Deficiency (OMIM 227300) | 1984 | ||
| Combined Deficiency of Vitamin K–Dependent Proteins (OMIM 277450 and 607473) | 1984 | ||
| References | 1985 | ||
| 140 Structure, Biology, and Genetics of von Willebrand Factor | 1987 | ||
| Key Words | 2000.e1 | ||
| Functions of vWF | 1987 | ||
| Platelet Adhesion | 1987 | ||
| FVIII Stabilization | 1987 | ||
| Basal vWF Levels | 1987 | ||
| vWF Gene | 1988 | ||
| Domain Structure | 1989 | ||
| Biosynthesis | 1989 | ||
| Storage and Secretion | 1990 | ||
| ADAMTS13 | 1990 | ||
| Clearance | 1991 | ||
| ABO Blood Groups | 1991 | ||
| Areas of Ongoing Investigation | 1991 | ||
| Von Willebrand Disease | 1991 | ||
| Epidemiology | 1991 | ||
| Classification and Pathophysiology | 1992 | ||
| vWD Type 1 | 1992 | ||
| vWD Type 2 | 1992 | ||
| Type 2A | 1993 | ||
| Type 2B | 1993 | ||
| Type 2M | 1993 | ||
| Type 2N | 1993 | ||
| Type 3 vWD | 1994 | ||
| Clinical Manifestations | 1994 | ||
| Penetrance | 1994 | ||
| Laboratory Investigations | 1994 | ||
| Screening Tests | 1995 | ||
| Confirming a Diagnosis of vWD | 1995 | ||
| vWF : Ag | 1995 | ||
| vWF : RCo | 1995 | ||
| Factor VIII : C level | 1995 | ||
| Discriminating Tests to Identify vWD Subtype | 1995 | ||
| vWF Multimer Analysis | 1995 | ||
| Ristocetin-Induced Platelet Aggregation | 1996 | ||
| Binding of FVIII by vWF (vWF : FVIIIB) | 1996 | ||
| Collagen Binding Assay (vWF : CB) | 1996 | ||
| vWF Propeptide/Antigen Ratio (vWFpp/vWF : Ag) | 1996 | ||
| Desmopressin (DDAVP) Responsiveness | 1996 | ||
| Genotyping | 1996 | ||
| Differential Diagnosis | 1996 | ||
| Hemophilia A | 1996 | ||
| Platelet-Type vWD | 1997 | ||
| Acquired von Willebrand syndrome (AvWS) | 1997 | ||
| Management of vWD | 1997 | ||
| Evaluations Following Initial Diagnosis | 1997 | ||
| Treatment of vWD | 1998 | ||
| Localized Measures | 1998 | ||
| Indirect Therapies | 1998 | ||
| Desmopressin | 1998 | ||
| vWF/FVIII Concentrates | 1999 | ||
| Prophylaxis | 1999 | ||
| Pediatric Issues | 1999 | ||
| Suggested Readings | 2000 | ||
| References | 2000.e2 | ||
| 141 Disseminated Intravascular Coagulation | 2001 | ||
| Epidemiology | 2001 | ||
| Pathobiology | 2001 | ||
| Tissue Factor–Factor VII(a) Pathway | 2002 | ||
| The Intrinsic Pathway | 2002 | ||
| Cytokines and Other Amplification Pathways | 2002 | ||
| Cross-Talk Among Coagulation Proteases Results in Proinflammatory Effects | 2003 | ||
| Endogenous Anticoagulant Pathways in Disseminated Intravascular Coagulation | 2003 | ||
| Fibrinolysis | 2004 | ||
| Clinical Manifestations | 2004 | ||
| Disseminated Intravascular Coagulation in Infectious Disease | 2005 | ||
| Disseminated Intravascular Coagulation in Trauma, Brain Injury, Burns, and Heatstroke | 2005 | ||
| Disseminated Intravascular Coagulation in Obstetric Complications | 2006 | ||
| Disseminated Intravascular Coagulation in Malignancy | 2006 | ||
| Disseminated Intravascular Coagulation With Vascular Disorders | 2006 | ||
| Disseminated Intravascular Coagulation With Liver Disease | 2007 | ||
| Disseminated Intravascular Coagulation With Toxic Reactions or Snake Bites | 2007 | ||
| Laboratory Manifestations | 2007 | ||
| Markers of Fibrin Generation and Degradation | 2007 | ||
| Endogenous Coagulation Inhibitors | 2008 | ||
| Fibrinolytic Markers | 2008 | ||
| Point-of-Care Tests | 2008 | ||
| Diagnostic Algorithm for Disseminated Intravascular Coagulation | 2008 | ||
| Differential Diagnosis | 2009 | ||
| Therapy | 2010 | ||
| Platelet and Plasma Transfusion | 2010 | ||
| Anticoagulant Treatment | 2011 | ||
| Physiological Anticoagulant Factor Concentrates | 2011 | ||
| Fibrinolytic Inhibitors | 2011 | ||
| References | 2012 | ||
| 142 Hypercoagulable States | 2013 | ||
| Key Words | 2024.e1 | ||
| Inherited Hypercoagulable States | 2013 | ||
| Loss of Function of Endogenous Anticoagulants | 2013 | ||
| Antithrombin Deficiency | 2013 | ||
| Protein C Deficiency | 2015 | ||
| Protein S Deficiency | 2016 | ||
| Gain of Function Mutations | 2016 | ||
| Factor VLeiden | 2016 | ||
| FIIG20210A Mutation | 2017 | ||
| Elevated Levels of Procoagulant Proteins | 2017 | ||
| Other Hereditary Disorders | 2017 | ||
| Acquired Hypercoagulable States | 2017 | ||
| Lupus Anticoagulants and the Antiphospholipid Syndrome | 2017 | ||
| Heparin-Induced Thrombocytopenia | 2018 | ||
| Cancer and Its Treatment | 2018 | ||
| Myeloproliferative Disorders | 2019 | ||
| Paroxysmal Nocturnal Hemoglobinuria | 2019 | ||
| Pregnancy | 2020 | ||
| Assisted Conception and Ovarian Hyperstimulation Syndrome | 2020 | ||
| Hormonal Therapy | 2020 | ||
| Prior History of Venous Thromboembolism | 2021 | ||
| Combined Inherited and Acquired Hypercoagulable States | 2021 | ||
| Clinical Evaluation of Patients with Hypercoagulable States | 2021 | ||
| Thrombophilia Screening | 2021 | ||
| Laboratory Evaluation of Thrombophilia | 2022 | ||
| Management of Thrombosis in Patients with Hypercoagulable States | 2022 | ||
| Initial Treatment | 2022 | ||
| Extended Therapy | 2022 | ||
| Duration of Treatment | 2023 | ||
| Treatment and Prevention of Thrombosis During Pregnancy | 2023 | ||
| Thrombophilia and Fetal Loss | 2023 | ||
| Conclusions and Future Directions | 2023 | ||
| Suggested Readings | 2024 | ||
| References | 2024.e2 | ||
| 143 Antiphospholipid Syndrome | 2025 | ||
| Definition and Diagnostic Categories | 2025 | ||
| Antigenic Specificities of Antiphospholipid Antibodies | 2025 | ||
| β2Glycoprotein I | 2025 | ||
| Additional Antigenic Targets | 2026 | ||
| Pathogenic Mechanisms | 2026 | ||
| Pathogenic Effects of Anti-β2GPI Antibodies on Endothelial Cells | 2026 | ||
| Activation of Platelets by aPL Antibodies | 2028 | ||
| Inhibition of Endogenous Anticoagulant and Fibrinolytic Mechanism | 2028 | ||
| Antiphospholipid-Mediated Activation of Complement | 2028 | ||
| Genetic, Genomic, and Proteomic Studies in Antiphospholipid Syndrome | 2029 | ||
| Laboratory Assays | 2029 | ||
| Development Paths | 2029 | ||
| Lupus Anticoagulant Tests | 2029 | ||
| Overview | 2029 | ||
| Indications for Testing | 2029 | ||
| Dilute Russell Viper Venom Time | 2030 | ||
| Activated Partial Thromboplastin Time | 2030 | ||
| Antiphospholipid Immunoassays | 2030 | ||
| Anticardiolipin Antibody Assays | 2030 | ||
| Anti-β2GPI Antibody Assay | 2030 | ||
| Multipositivity for Antiphospholipid Tests and Clinical Risk | 2030 | ||
| “Noncriteria” Antiphospholipid Assays | 2031 | ||
| IgA Antibodies to Cardiolipin and β2-Glycoprotein I | 2031 | ||
| Annexin A5 Resistance Assay | 2032 | ||
| Anti–Domain I of β2GPI Assay | 2032 | ||
| Antiprothrombin Antibody Assay | 2032 | ||
| Antiphosphatidylserine Antibody Assay | 2032 | ||
| Assays for Antibodies Against Other Phospholipids | 2032 | ||
| Clinical Manifestations of Antiphospholipid Syndrome | 2033 | ||
| Criteria Manifestations of Antiphospholipid Syndrome | 2033 | ||
| Systemic Vascular Thrombosis | 2033 | ||
| Reproductive Manifestations | 2033 | ||
| Neurologic Manifestations | 2033 | ||
| Cardiovascular Manifestations | 2034 | ||
| Hepatic and Gastrointestinal Manifestations | 2034 | ||
| Renal Abnormalities | 2034 | ||
| Retinal Abnormalities | 2034 | ||
| Other Organ Manifestations | 2034 | ||
| Catastrophic Antiphospholipid Syndrome | 2034 | ||
| Pediatric Antiphospholipid Syndrome | 2035 | ||
| “Noncriteria” Clinical Manifestations Associated With Antiphospholipid Antibodies and Antiphospholipid Syndrome | 2035 | ||
| “Noncriteria” Cardiovascular Manifestations | 2035 | ||
| Cardiac Valve Abnormalities | 2035 | ||
| Coronary Artery Disease in the Absence of Thrombotic Occlusion | 2035 | ||
| Peripheral Arterial Disease | 2035 | ||
| “Noncriteria” Neurologic Manifestations | 2035 | ||
| “Noncriteria” Pulmonary Manifestations | 2035 | ||
| “Noncriteria” Gastrointestinal Manifestations | 2035 | ||
| “Noncriteria” Renal Manifestations | 2035 | ||
| “Noncriteria” Dermatologic Manifestations | 2036 | ||
| Other “Noncriteria” Hematologic Abnormalities | 2036 | ||
| Thrombocytopenia | 2036 | ||
| Bleeding | 2036 | ||
| Treatment of Patients with Antiphospholipid Syndrome | 2036 | ||
| Thrombosis | 2036 | ||
| Stroke | 2037 | ||
| Pregnancy Complications | 2037 | ||
| Catastrophic Antiphospholipid Syndrome | 2037 | ||
| Asymptomatic Antiphospholipid Antibody–Positive Patients | 2037 | ||
| Suggested Readings | 2037 | ||
| 144 Venous Thromboembolism | 2039 | ||
| Pathogenesis of Venous Thromboembolism and Clinical Risk Factors | 2039 | ||
| Thrombogenic Factors | 2039 | ||
| Activation of Blood Coagulation | 2039 | ||
| Venous Stasis | 2040 | ||
| Immobility | 2040 | ||
| Venous Obstruction and Increased Venous Pressure | 2040 | ||
| Increased Blood Viscosity and Venous Dilation | 2040 | ||
| Vessel Wall Damage | 2040 | ||
| Protective Mechanisms | 2040 | ||
| Endothelial Protective Mechanisms | 2040 | ||
| Inhibitors of Blood Coagulation | 2040 | ||
| Hypercoagulable States | 2040 | ||
| Natural History of Venous Thromboembolism | 2040 | ||
| Prognosis of Venous Thromboembolism | 2041 | ||
| Postthrombotic Syndrome | 2041 | ||
| Diagnosis of Venous Thromboembolism | 2041 | ||
| Deep Venous Thrombosis | 2041 | ||
| Clinical Manifestations | 2041 | ||
| Differential Diagnosis | 2041 | ||
| Objective Diagnostic Tests for Deep Venous Thrombosis | 2041 | ||
| Venography | 2041 | ||
| Venous Compression Ultrasonography | 2042 | ||
| D-Dimer Assays | 2042 | ||
| Diagnostic Strategies for Deep Venous Thrombosis | 2042 | ||
| Pulmonary Embolism | 2043 | ||
| Clinical Manifestations | 2043 | ||
| Differential Diagnosis | 2043 | ||
| Diagnosis | 2043 | ||
| Objective Diagnostic Tests for Pulmonary Embolism | 2043 | ||
| Pulmonary Angiography | 2043 | ||
| Helical Computed Tomography Scanning | 2043 | ||
| Ventilation/Perfusion Lung Scan | 2043 | ||
| Diagnostic Strategy for Pulmonary Embolism | 2044 | ||
| Diagnosis of Acute Recurrent Venous Thromboembolism | 2044 | ||
| Diagnosis of the Postthrombotic Syndrome | 2045 | ||
| Prophylaxis of Venous Thromboembolism | 2045 | ||
| Low-Molecular-Weight Heparins and Fondaparinux | 2045 | ||
| Low-Dose Unfractionated Heparin | 2045 | ||
| Vitamin K Antagonists | 2045 | ||
| Oral Direct Factor Xa or Thrombin Inhibitors for Orthopedic Thromboprophylaxis | 2045 | ||
| Intermittent Pneumatic Compression | 2045 | ||
| Graduated Compression Stockings | 2045 | ||
| Treatment of Venous Thromboembolism | 2046 | ||
| Anticoagulant Therapy for Treatment of Acute Venous Thromboembolism | 2046 | ||
| Inferior Vena Cava Filter | 2046 | ||
| Thrombolytic Therapy for Massive Pulmonary Embolism | 2046 | ||
| Thromboendarterectomy for Pulmonary Embolism | 2047 | ||
| Key Words | 2047.e1 | ||
| Suggested Readings | 2047 | ||
| References | 2047.e2 | ||
| 145 Mechanical Interventions in Arterial and Venous Thrombosis | 2048 | ||
| Overview of Catheter-Based Thrombolytic Interventions | 2048 | ||
| Catheter-Directed Intrathrombus Thrombolysis | 2048 | ||
| Variation on a Theme—Percutaneous Mechanical Thrombectomy | 2049 | ||
| Variations on a Theme—Pharmacomechanical Catheter-Directed Thrombolysis | 2049 | ||
| Mechanical Interventions in Peripheral Arterial Occlusion | 2050 | ||
| Rationale, Benefits, and Risks Associated With CDT for PAO | 2050 | ||
| Randomized Trials—CDT Versus Surgery for Arterial Thrombosis | 2051 | ||
| PMT, PCDT, and Ultrasound-Assisted CDT for Arterial Thrombosis | 2051 | ||
| Summary: Indications and Contraindications for Thrombolytic Therapy in PAO | 2051 | ||
| Mechanical Interventions in Deep Vein Thrombosis | 2052 | ||
| Rationale, Benefits, and Risks Associated With CDT for DVT | 2052 | ||
| Acute Iliofemoral DVT as a High-Risk Condition | 2053 | ||
| Summary: Indications and Contraindications for CDT in DVT | 2053 | ||
| Treatment of Established Postthrombotic Syndrome | 2053 | ||
| Inferior Vena Cava Filters | 2054 | ||
| FUTURE DIRECTIONS | 2054 | ||
| References | 2055 | ||
| 146 Atherothrombosis | 2057 | ||
| Pathobiology | 2057 | ||
| Lipoprotein Homeostasis and the “Cholesterol Hypothesis” | 2057 | ||
| Foam Cell Formation and the Fatty Streak | 2059 | ||
| Lesion Evolution: Remodeling and the Vulnerable Plaque | 2061 | ||
| Plaque Rupture and Acute Arterial Thrombosis | 2063 | ||
| Hyperlipidemia, Atherosclerosis, and a Systemic Prothrombotic State | 2064 | ||
| Cross Talk Between Coagulation and Inflammation Systems Impact Atherogenesis | 2065 | ||
| Plaque Regression and Future Directions | 2065 | ||
| References | 2065 | ||
| 147 Stroke | 2067 | ||
| Definition | 2067 | ||
| Epidemiology | 2067 | ||
| Frequency | 2067 | ||
| Traditional Risk Factors for Stroke | 2067 | ||
| Pathobiology | 2067 | ||
| Etiologic Classification of Ischemic Stroke | 2067 | ||
| Large-Artery Stroke | 2067 | ||
| Cardioembolism | 2068 | ||
| Precardiac. | 2068 | ||
| Intracardiac. | 2068 | ||
| Postcardiac. | 2069 | ||
| Small-Artery Occlusion | 2069 | ||
| Ischemic Stroke of Other Determined Etiology | 2069 | ||
| Cerebral Venous Sinus Thrombosis. | 2069 | ||
| Intracerebral Hemorrhage. | 2069 | ||
| Subarachnoid Hemorrhage. | 2069 | ||
| Stroke of Undetermined Etiology | 2069 | ||
| Covert Stroke | 2069 | ||
| Hematologic Disorders and Ischemic Stroke | 2070 | ||
| Inherited Thrombophilias | 2070 | ||
| Antiphospholipid Syndrome | 2070 | ||
| Sickle Cell Disease | 2070 | ||
| Myeloproliferative Disorders | 2070 | ||
| Thrombotic Thrombocytopenic Purpura | 2070 | ||
| Paraproteinemias | 2070 | ||
| Genetic Risk Factors | 2070 | ||
| Clinical Manifestations | 2070 | ||
| Clinical Presentation | 2070 | ||
| Ischemic Stroke Versus Intracerebral Hemorrhage | 2070 | ||
| Measuring Severity of Stroke | 2071 | ||
| Risk for Stroke After Transient Ischemic Attack | 2071 | ||
| Investigations | 2071 | ||
| CT of the Brain | 2071 | ||
| Magnetic Resonance Imaging | 2071 | ||
| Neurovascular Imaging | 2071 | ||
| Cardiac Workup | 2071 | ||
| Therapy | 2071 | ||
| Reperfusion Therapy for Acute Ischemic Stroke | 2071 | ||
| Thrombolysis for Acute Ischemic Stroke | 2071 | ||
| Intraarterial Thrombolysis | 2071 | ||
| Mechanical Clot Retrieval | 2072 | ||
| Acute Stroke Unit | 2072 | ||
| Blood Pressure in Acute Stroke | 2072 | ||
| Antithrombotic Therapy in Acute Ischemic Stroke | 2072 | ||
| Carotid Endarterectomy and Stenting | 2072 | ||
| Intracranial Stenting | 2072 | ||
| Prevention of Venous Thromboembolism | 2072 | ||
| Acute Management of Intracerebral Hemorrhage | 2073 | ||
| Stroke Rehabilitation | 2073 | ||
| Chronic Secondary Prevention of Ischemic Stroke | 2073 | ||
| Case Study | 2073 | ||
| Antithrombotic Therapy | 2073 | ||
| Lipid Modification | 2073 | ||
| Blood Pressure | 2073 | ||
| Patent Foramen Ovale Closure | 2074 | ||
| Lifestyle Modification | 2074 | ||
| Prognosis | 2074 | ||
| Future Directions | 2074 | ||
| Suggested Readings | 2074 | ||
| 148 Acute Coronary Syndromes | 2076 | ||
| Key Words | 2085.e1 | ||
| Classification | 2076 | ||
| Pathophysiology | 2076 | ||
| Antithrombotic Management | 2076 | ||
| Reperfusion Therapy for ST-Segment Elevation Myocardial Infarction | 2076 | ||
| Primary Percutaneous Coronary Intervention | 2076 | ||
| Fibrinolytic Therapy | 2076 | ||
| Streptokinase | 2077 | ||
| Alteplase | 2077 | ||
| Reteplase | 2077 | ||
| Tenecteplase | 2077 | ||
| Adjunctive Antithrombotic Therapy in Patients Receiving Fibrinolytic Drugs | 2078 | ||
| Intracranial Bleeding | 2078 | ||
| Antiplatelet Therapy | 2078 | ||
| Oral Antiplatelet Drugs | 2078 | ||
| Aspirin | 2078 | ||
| Clopidogrel | 2080 | ||
| Prasugrel | 2080 | ||
| Ticagrelor | 2080 | ||
| Intravenous Antiplatelet Drugs | 2080 | ||
| Glycoprotein IIb/IIIa Inhibitors | 2080 | ||
| Anticoagulant Therapy | 2081 | ||
| Heparin | 2081 | ||
| Low-Molecular-Weight Heparin | 2083 | ||
| Fondaparinux | 2083 | ||
| Bivalirudin | 2083 | ||
| Oral Anticoagulation | 2084 | ||
| Conclusions and Future Directions | 2084 | ||
| References | 2085 | ||
| References | 2085.e2 | ||
| 149 Atrial Fibrillation | 2086 | ||
| Epidemiology | 2086 | ||
| Pathophysiology: A Brief Overview | 2086 | ||
| Genesis and Preservation of Atrial Fibrillation | 2086 | ||
| Thrombosis and Embolism | 2086 | ||
| Clinical Manifestation and Diagnosis | 2087 | ||
| History and Physical Examination | 2087 | ||
| Additional Testing and Cardiac Imaging | 2087 | ||
| Differential Diagnosis | 2088 | ||
| Prognosis | 2088 | ||
| Therapy | 2089 | ||
| General Considerations | 2089 | ||
| Rhythm or Rate Control | 2089 | ||
| General Approaches to Pharmacologic Antiarrhythmic Therapy | 2089 | ||
| Nonpharmacologic Approaches | 2089 | ||
| Device Therapies—Atrial Pacing and Defibrillation | 2090 | ||
| Catheter Ablation | 2090 | ||
| Prevention of Thromboembolism | 2090 | ||
| Cardioversion and Thromboembolism Prevention | 2090 | ||
| Long-Term Primary and Secondary Prevention of Thromboembolism | 2090 | ||
| Risk Stratification | 2090 | ||
| Warfarin for Stroke Prevention in Atrial Fibrillation | 2091 | ||
| New Oral Anticoagulants for Stroke Prevention in Atrial Fibrillation | 2091 | ||
| Antiplatelet Drugs for Stroke Prevention in Atrial Fibrillation | 2092 | ||
| Practical Considerations | 2092 | ||
| Nonpharmacologic Approaches to Prevention of Thromboembolism | 2092 | ||
| Future Directions | 2093 | ||
| References | 2093 | ||
| 150 Peripheral Artery Disease | 2094 | ||
| Epidemiology | 2094 | ||
| Prevalence and Incidence | 2094 | ||
| Risk Factors | 2094 | ||
| Pathobiology | 2095 | ||
| Clinical Manifestations | 2095 | ||
| Diagnosis | 2096 | ||
| Ankle-Brachial Index | 2096 | ||
| Noninvasive Imaging for Diagnosis | 2096 | ||
| Prognosis | 2096 | ||
| Therapy | 2098 | ||
| Dyslipidemia | 2098 | ||
| Hypertension | 2098 | ||
| Diabetes | 2098 | ||
| Antiplatelet Therapy | 2099 | ||
| Treatment of Lower Extremity Symptoms | 2099 | ||
| Exercise Therapy | 2099 | ||
| Pharmacologic Therapies | 2099 | ||
| Revascularization | 2099 | ||
| Therapeutic Angiogenesis | 2100 | ||
| Future Directions | 2100 | ||
| Suggested Readings | 2100 | ||
| Comprehensive Guidelines for the Management of Patients With Atherosclerotic Vascular Disease, Including Epidemiology, Pathophysiology, and Management of Peripheral Artery Disease | 2100 | ||
| Prevalence, Incidence, and Risk Factors for Peripheral Artery Disease | 2101 | ||
| Prognosis and Outcomes in Peripheral Artery Disease | 2101 | ||
| Therapy for Patients With Peripheral Artery Disease | 2101 | ||
| References | 2101.e1 | ||
| 151 Antithrombotic Drugs | 2102 | ||
| Antiplatelet Drugs | 2102 | ||
| Role of Platelets in Arterial Thrombosis | 2102 | ||
| Aspirin | 2102 | ||
| Mechanism of Action | 2102 | ||
| Indications | 2103 | ||
| Dosages | 2103 | ||
| Side Effects | 2103 | ||
| Aspirin Resistance | 2103 | ||
| Thienopyridines | 2103 | ||
| Mechanism of Action | 2103 | ||
| XIII Consultative Hematology | 2131 | ||
| 153 Hematologic Changes in Pregnancy | 2132 | ||
| Anemia in Pregnancy | 2132 | ||
| Iron-Deficiency Anemia | 2132 | ||
| Other Nutritional Deficiencies | 2132 | ||
| Hemoglobinopathies and Pregnancy | 2133 | ||
| Sickle Cell Disease | 2133 | ||
| Thalassemias | 2133 | ||
| Other Hemolytic Anemias | 2134 | ||
| Hereditary Spherocytosis | 2134 | ||
| Glucose 6-Phosphate Dehydrogenase Deficiency | 2134 | ||
| Paroxysmal Nocturnal Hemoglobinuria | 2134 | ||
| Autoimmune Hemolytic Anemia | 2134 | ||
| Thrombocytopenia | 2134 | ||
| Gestational Thrombocytopenia | 2134 | ||
| Immune Thrombocytopenia | 2134 | ||
| Preeclampsia and HELLP Syndrome | 2135 | ||
| Thrombotic Thrombocytopenic Purpura–Hemolytic Uremic Syndrome | 2136 | ||
| Disseminated Intravascular Coagulation | 2137 | ||
| Leukemia and Lymphoma | 2137 | ||
| Hodgkin Lymphoma | 2137 | ||
| Acute and Chronic Leukemias | 2138 | ||
| The Myeloproliferative Neoplasms: Essential Thrombocythemia, Polycythemia Vera, and Myelofibrosis | 2138 | ||
| Bleeding Disorders | 2139 | ||
| von Willebrand Disease | 2139 | ||
| Hemophilias | 2139 | ||
| Venous Thromboembolic Disease and Pregnancy | 2140 | ||
| Prophylactic Anticoagulation during Pregnancy | 2141 | ||
| Thrombophilia and Pregnancy | 2141 | ||
| Antiphospholipid Antibody Syndrome | 2142 | ||
| Future Directions | 2142 | ||
| Suggested Readings | 2142 | ||
| References | 2143.e1 | ||
| 154 Hematologic Manifestations of Childhood Illness | 2144 | ||
| Key Words | 2166.e1 | ||
| Infectious Disease | 2144 | ||
| Changes in Red Blood Cells | 2144 | ||
| Anemia of Acute Infections | 2144 | ||
| Acute Hemolytic Anemia | 2144 | ||
| Aplastic Crisis | 2145 | ||
| Changes in White Blood Cells | 2145 | ||
| Neutropenia | 2146 | ||
| Eosinophilia | 2146 | ||
| Changes in Platelets or Coagulation | 2146 | ||
| Thrombocytosis | 2146 | ||
| Thrombocytopenia | 2146 | ||
| Disseminated Intravascular Coagulation and Purpura Fulminans | 2146 | ||
| Coagulation Inhibitors | 2147 | ||
| Pancytopenia | 2147 | ||
| Human Immunodeficiency Virus Infection in Children and Adolescents | 2147 | ||
| Collagen Vascular Disease and Acute Vasculitis | 2148 | ||
| Juvenile Idiopathic Arthritis | 2148 | ||
| Macrophage Activation Syndrome | 2149 | ||
| Kawasaki Syndrome | 2150 | ||
| Henoch-Schönlein Purpura | 2150 | ||
| Cardiopulmonary Disease | 2151 | ||
| Congenital Heart Disease | 2151 | ||
| Cystic Fibrosis | 2152 | ||
| Hematologic Manifestations of Childhood Gastrointestinal Disease | 2152 | ||
| Milk Protein–Induced Enteropathy and Heiner Syndrome | 2152 | ||
| Celiac Disease | 2153 | ||
| Inflammatory Bowel Disease | 2153 | ||
| Other Gastrointestinal Disorders | 2154 | ||
| Endocrine Disease | 2154 | ||
| Hematologic Manifestations of Thyroid Disorders | 2154 | ||
| Anorexia Nervosa | 2154 | ||
| Thromboembolic Complications in Childhood Illness | 2155 | ||
| Thromboembolism in Pediatric Cancer | 2155 | ||
| Thromboembolism in Congenital Heart Disease | 2155 | ||
| Thromboembolism in Nephrotic Syndrome | 2156 | ||
| Thromboembolism in Systemic Lupus Erythematosus and Antiphospholipid Syndrome | 2156 | ||
| Thromboprophylaxis During Childhood Illness | 2157 | ||
| Hematologic Complications of Solid Organ Transplantation in Children | 2157 | ||
| Red Blood Cells | 2158 | ||
| Early Posttransplant Anemia | 2158 | ||
| Passenger Lymphocyte Syndrome | 2158 | ||
| Hemolytic Uremic Syndrome/Microangiopathic Hemolytic Anemia | 2158 | ||
| Late Posttransplant Anemia | 2158 | ||
| Immunosuppressant Drugs | 2159 | ||
| Pure Red Blood Cell Aplasia Associated With Parvovirus B19 | 2159 | ||
| Platelets | 2159 | ||
| Immediate Thrombocytopenia After Liver Transplantation | 2159 | ||
| Delayed Posttransplantation Thrombocytopenia | 2160 | ||
| Immune-Mediated Thrombocytopenia Posttransplantation | 2160 | ||
| Infection-Associated Thrombocytopenia Posttransplantation | 2161 | ||
| White Blood Cells | 2161 | ||
| Pancytopenia | 2161 | ||
| Hematologic Aspects of Poisoning | 2161 | ||
| Lead Poisoning | 2162 | ||
| Hematologic Aspects of Metabolic Diseases | 2162 | ||
| Splenomegaly in Children | 2162 | ||
| Suggested Readings | 2165 | ||
| General | 2165 | ||
| Infectious Disease | 2165 | ||
| Collagen Vascular Disease and Acute Vasculitis | 2165 | ||
| Cardiopulmonary Disease | 2166 | ||
| Gastrointestinal Disease | 2166 | ||
| Thromboembolic Complications in Childhood Illness | 2166 | ||
| Hematologic Complications of Solid Organ Transplantation in Children | 2166 | ||
| Hematologic Aspects of Poisoning | 2166 | ||
| References | 2166.e2 | ||
| 155 Hematologic Manifestations of Liver Disease | 2167 | ||
| Key Words | 2172.e1 | ||
| Red Blood Cell Abnormalities | 2167 | ||
| Morphologic Abnormalities | 2167 | ||
| Anemia | 2167 | ||
| White Blood Cell Abnormalities | 2167 | ||
| Leukopenia | 2167 | ||
| Platelet Abnormalities | 2167 | ||
| Thrombocytopenia | 2167 | ||
| Platelet Dysfunction | 2168 | ||
| Coagulation and Liver Disease | 2168 | ||
| Treatment of Liver Disease–related Bleeding | 2169 | ||
| Hypercoagulability and Thrombosis in Patients with Liver Disease | 2170 | ||
| FUTURE DIRECTIONS | 2171 | ||
| References | 2171 | ||
| 156 Hematologic Manifestations of Systemic Disease: | 2173 | ||
| Management of Hypoproliferative Anemia | 2173 | ||
| Hemostatic Agents for Use in Uremia | 2174 | ||
| Management of Hemolytic Uremic Syndrome and Thrombotic Thrombocytopenic Purpura | 2175 | ||
| FUTURE DIRECTIONS | 2175 | ||
| Suggested Readings | 2175 | ||
| References | 2175.e1 | ||
| 157 Hematologic Manifestations of Cancer | 2176 | ||
| Cytopenias and Cancer | 2176 | ||
| Anemia | 2176 | ||
| Thrombocytopenia | 2176 | ||
| Multiple Cytopenias Due to Bone Marrow Metastases | 2176 | ||
| Other Cytopenias in Cancer | 2177 | ||
| Evaluation of Cancer-Associated Cytopenias | 2177 | ||
| Treatment of Cytopenias Due to Cancer | 2178 | ||
| Thrombosis and Cancer | 2179 | ||
| Relationship of Cancer and Thrombosis | 2179 | ||
| Diagnosis of Coagulopathies in Cancer Patients | 2179 | ||
| Management of Thrombosis in Patients With Cancer | 2179 | ||
| Biologic Mechanisms Underlying Thrombosis in Cancer | 2180 | ||
| Tumor-Derived Tissue Factor | 2180 | ||
| Coagulation’s Role in Tumor Progression | 2180 | ||
| Platelets and Cancer | 2181 | ||
| Future Directions | 2181 | ||
| Suggested Readings | 2181 | ||
| References | 2182.e1 | ||
| 158 Integrative Therapies in Patients With Hematologic Diseases | 2183 | ||
| Integrative Therapy Domains and Their Use | 2183 | ||
| Research Techniques of Integrative Therapies | 2184 | ||
| Review of Results of Integrative Therapies in Hematology/Oncology Patients | 2184 | ||
| Literature on Outcomes: Science, Safety, and Efficacy | 2184 | ||
| Individual Integrative Therapy Modalities | 2185 | ||
| Mind–Body Therapies | 2185 | ||
| Acupuncture | 2185 | ||
| Overview and Definitions | 2185 | ||
| INDEX | 2271 | ||
| A | 2271 | ||
| B | 2279 | ||
| C | 2282 | ||
| D | 2289 | ||
| E | 2292 | ||
| F | 2295 | ||
| G | 2298 | ||
| H | 2300 | ||
| I | 2308 | ||
| J | 2311 | ||
| K | 2312 | ||
| L | 2312 | ||
| M | 2314 | ||
| N | 2319 | ||
| O | 2322 | ||
| P | 2322 | ||
| Q | 2329 | ||
| R | 2329 | ||
| S | 2331 | ||
| T | 2336 | ||
| U | 2340 | ||
| V | 2341 | ||
| W | 2342 | ||
| X | 2343 | ||
| Y | 2343 | ||
| Z | 2343 |