Concise Guide to Hematology (eBook)

Hillard M. Lazarus, MD, FACPProfessor of MedicineCase Western Reserve University School of MedicineDepartment of MedicineCleveland, OHUSAAlvin H. Schmaier, MDRobert W. Kellermeyer Professor of Hematology and OncologyUniversity Hospital Cleveland Medical CenterDepartment of MedicineCleveland, OHUSA 

Preface 6
Contents 7
Contributors 10
1: Introduction to Hematology 14
Introduction 14
Origins of Hematopoietic Cells 14
The Myeloid System 15
Mononuclear Phagocytic System 16
Lymphocyte System 16
The Physical States of Blood 16
2: Hematopoiesis 17
Introduction 17
Hematopoietic Ontogeny 17
Primitive Hematopoiesis 17
Definitive Hematopoiesis 17
Adult Hematopoiesis 17
Clinical Implications of Hematopoietic Ontogeny 18
Hemoglobin Switches During Embryonic Development and Its Role in Sickle Cell Disease 18
Myelophthisis (Displacement of Hematopoietic Bone Marrow: Phthisis – Shrinkage or Atrophy) and Extramedullary Hematopoiesis 18
Hierarchical Organization (Fig. 2.1) 18
Hematopoietic Stem Cells 18
Hematopoietic Progenitor Compartment (HPCs) 20
The Precursor Compartment 20
Mature Blood Cells 20
Regulation of Hematopoiesis 21
Bone Marrow Niches 21
Growth Factors and Extracellular Matrix 21
Abnormal Hematopoiesis 22
Leukopenia 22
Anemia 23
Thrombocytopenia 23
Multilineage Cytopenias 23
Increased Production of Hematopoietic Cells 23
Clonal Hematopoiesis of Undetermined Potential (CHIP) 24
Conclusions 24
References 24
3: Red Blood Cell Biochemistry and Physiology 26
Red Blood Cell Development 26
Hemoglobin: Structure and Function 27
Red Blood Cell Membrane 29
Metabolic Pathways in Red Blood Cells 29
Summary 31
References 31
4: Anemia: Clinical Approach 32
Definition of Anemia 32
Acute Blood Loss 32
Inadequate Production 32
Destruction 33
Symptoms and Signs of Anemia 35
Laboratory Diagnosis 35
Reticulocyte Count 35
Peripheral Blood Smear 36
Integration of Information from the CBC, Reticulocyte Count, and Peripheral Smear 36
Summary 38
References 38
5: Iron Deficiency 39
Introduction 39
Iron Metabolism 39
Iron Depletion and Iron Deficiency 41
Prevalence of Iron Deficiency 41
Causes of Iron Deficiency 41
Clinical Manifestations 43
Laboratory Diagnosis of Iron Deficiency 43
Treatment of Iron Deficiency 44
The Anemia of Inflammation (Anemia of Chronic Disease) 45
Other Microcytic Conditions (Box 5.3) 46
Summary 46
References 46
6: Vitamin B12 (Cobalamin) and Folate Deficiency 47
General Considerations 47
Epidemiology 47
Vitamin B12 Nutrition 47
Folates Nutrition 47
Vitamin B12 Physiology 49
Normal Absorption and Transport 49
Normal Cellular Processing 49
Pathogenesis of Vitamin B12 Deficiency (Table 6.3) 50
Folate Physiology 52
Pathogenesis of Folate Deficiency (Key Points) (Table 6.3) 53
Nutritional Causes (Decreased Intake or Increased Requirements) 53
Pregnancy and Infancy 53
Tropical and Nontropical (Celiac) Sprue 54
Drugs 54
Clinical Presentations of Folate/Vitamin B12 Deficiency (see Table 6.1) 54
Spectrum of Clinical Presentations of Folate/Vitamin B12 Deficiency (Tables 6.1 and 6.2) 54
Diagnostic Approach to the Patient 55
Laboratory Tests (Fig. 6.1 and Table 6.4) 55
Megaloblastosis 55
Peripheral Smear (Fig. 6.1) 55
Vitamin B12 and Folate Levels (Table 6.4) 55
Metabolite Levels: Serum Homocysteine and Methylmalonic Acid (MMA) (Table 6.4) 56
Bone Marrow Examination for Rapid Diagnosis (1 h) of Megaloblastosis 56
Determining the Cause of Vitamin Deficiency 57
Treatment 57
Drug Dosage 57
Prognosis 57
Causes of Incomplete Response 57
Prophylaxis of Vitamin B12 and Folate Deficiency 57
Further Reading 57
7: Sickle Cell Disease and the Hemoglobinopathies 59
Overview 59
Qualitative Abnormalities in Hemoglobin 59
Quantitative Abnormalities in Hemoglobin 64
?-Thalassemia 64
?-Thalassemia 67
Suggested Reading 68
8: Congenital Hemolytic Anemias 69
Introduction 69
General Diagnostic Approach to Congenital Hemolytic Anemias 69
Laboratory Studies 69
Red Blood Cell Membrane Disorders (See Fig. 8.1) 69
Hereditary Spherocytosis 69
Hereditary Elliptocytosis and Hereditary Pyropoikilocytosis 71
Hemolytic Enzyme Disorders 71
Glucose-6-Phosphase Dehydrogenase Deficiency 72
Pyruvate Kinase Deficiency 73
Pyrimidine 5? Nucleotidase Deficiency 73
Other Hemolytic RBC Enzyme Deficiencies 73
Hemolytic Hemoglobinopathies 74
Thalassemias 74
Alpha-Thalassemias 74
?-Thalassemias 74
Sickle Cell Disease 75
Treatment of Sickle Cell Disease 75
Unstable Hemoglobins 76
Congenital Dyserythropoietic Anemias (CDAs) 76
Congenital Predisposition to Acute Microangiopathic Hemolytic Anemias 76
Summary 76
Suggested Reading 76
9: Acquired Hemolytic Anemias 77
Definitions 77
Clinical and Laboratory Evaluation 77
Clinical Characteristics 77
Laboratory Evaluation 78
Basic Tests to Evaluate Hemolytic Anemias 78
Special Tests to Explore the Cause of Hemolytic Anemia 79
Causes of Acquired Hemolytic Anemias 80
Outline per Disease Process 81
Immune-Mediated Hemolytic Anemia 81
Traumatic Hemolytic Anemia 85
Hypersplenism 87
Hemolytic Anemia due to Toxic Effects on the Membrane 87
Paroxysmal Nocturnal Hemoglobinuria (PNH) 88
Suggested Reading 89
10: Physiology of Hemostasis 90
The Hemostatic System 90
Coagulation Protein System 91
The Fibrinolytic System 94
The Anticoagulation System 95
Cohesive Hypotheses for the Initiation of the Hemostatic System 96
References 97
Suggested Reading 97
General Reviews 97
11: Approach to the Bleeding Patient 98
Introduction 98
Pathogenesis of Bleeding Disorders 98
Clinical Presentation of Bleeding Disorders 98
Coagulation Cascade Hypothesis 98
Screening Tests for Bleeding Disorders 99
Interpretation of Screening Tests of the Proteins in the Coagulation System 99
Differential Diagnosis of an Isolated Prolonged Activated Partial Thromboplastin Time 100
Differential Diagnosis of a Prolonged Prothrombin Time Only 100
Differential Diagnosis of a Prolonged Activated Partial Thromboplastin Time and Prothrombin Time 100
Use of the Activated Partial Thromboplastin Time and Prothrombin Time to Monitor Anticoagulation 101
Differential Diagnosis of a Prolonged Bleeding Time and a Normal Platelet Count 101
Prolonged Bleeding Time as a Result of Platelet Defects 101
Differential Diagnosis of a Bleeding State that Is Not Associated with an Abnormality in the Screening Tests 101
Summary 102
Suggested Reading 102
12: Congenital Bleeding Disorders 103
Overview 103
Hemophilia 103
Role of FVIII and FIX in Hemostasis 103
Epidemiology 103
Genetics 104
Clinical Classification 104
Bleeding Manifestations 104
Overview 104
Hemarthrosis and Hemophilic Arthropathy 105
Muscle and Soft Tissue Bleeds 105
Life-Threatening Bleeds 105
Diagnosis of Hemophilia 106
Special Coagulation Tests 106
Genetic Testing 106
Special Considerations in Newborns 106
Prenatal Testing 106
Principles of Management of Hemophilia 106
Factor Replacement Therapies [5] 106
Substitution and Hemostatic Rebalancing Therapies 107
Adjuvant Therapies 108
Inhibitors of Coagulation Factor VIII and Factor IX 108
Gene Therapy for Hemophilia A and B 109
von Willebrand Disease 109
Overview 109
Structure and Function of vWF 110
Genetics of vWD 110
Clinical Presentation 110
Diagnosis of vWD 110
Clinical Subtypes of vWD 112
Treatment of vWD 113
Acquired Abnormalities of vWF 114
Rare Bleeding Disorders 114
Overview 114
Epidemiology 114
Bleeding Manifestations 114
Diagnosis of RBDs 115
Management of RBDs 115
Miscellaneous Bleeding Disorders: Deficiencies of Inhibitors of Fibrinolytic Pathway 115
References 118
13: Acquired Bleeding Disorders 119
Introduction 119
Diagnosis 119
Medical History and Bleeding History 119
Physical Examination 119
Laboratory Tests 119
Acquired Platelet Disorders: Impairment of Primary Hemostasis 121
Quantitative Defects in Primary Hemostasis: Thrombocytopenia 121
Qualitative Defects in Primary Hemostasis 122
Acquired Impaired Fibrin Formation 123
Acquired Coagulation Factor Deficiency 123
Coagulation Factor Inhibitors 123
Bleeding Due to Anticoagulants 124
Consumption Coagulopathy 126
References 128
14: Platelet Function in Hemostasis and Inherited Disorders of Platelet Number and Function 130
Platelet Structure 130
Platelet Function in Hemostasis 130
Platelet Activation Mechanisms 132
Regulation of Platelet Number 132
Inherited Disorders of Platelets 132
Evaluation of Platelet Number and Function 132
Inherited Thrombocytopenias 133
Autosomal Dominant Thrombocytopenias 133
Other Inherited Autosomal Dominant Thrombocytopenias 135
Autosomal Recessive Thrombocytopenias 135
X-Linked Disorders 135
Inherited Disorders of Platelet Function 135
General Features 135
Disorders of Platelet Adhesion 135
Bernard-Soulier Syndrome (BSS) 136
Disorders of Platelet Aggregation 136
Glanzmann Thrombasthenia 136
Inherited Afibrinogenemia 136
Disorders of Platelet Granules, Secretion, and Activation 137
Deficiency of Granule Stores (Storage Pool Deficiency) 137
Defects in Platelet Activation/Signal Transduction Mechanisms 139
Disorders of Platelet Procoagulant Activities 139
Other Abnormalities 139
Management of Inherited Platelet Function Defects 139
Summary 139
References 140
15: Acquired Thrombocytopenia 142
Introduction 142
Definition 142
Clinical Features of Thrombocytopenia 142
Classification of Thrombocytopenia 143
Decreased Platelet Production 143
Hemodilution 145
Sequestration (Hypersplenism) 145
Increased Platelet Consumption 146
Increased Platelet Destruction 148
Pseudothrombocytopenia 153
References 154
16: Thrombosis 156
Overview 156
Key Concepts 156
Pathogenetic Features 156
Red (Fibrin) Versus White (Platelet) Clots 157
Venous Thrombosis 158
Introduction 158
Pathogenesis 158
Risk Factors 159
Inherited Risk Factors for Venous Thrombosis 159
Acquired Risk Factors for Venous Thrombosis (Table 16.2) 161
Age 161
Trauma, Surgery, and Immobilization 161
Cardiac Disease 161
Obesity/Metabolic Syndrome 161
Inflammatory Bowel Disease (IBD) 161
Cancer 162
Oral Contraceptives 162
Pregnancy 162
Arterial Thrombosis 162
Overview 162
Etiology 162
Pathogenesis 162
Risk Factors 162
Elevated Homocysteine 162
C-Reactive Protein (CRP) 164
Lipoprotein (a) 164
Special Situations: Combined Venous and Arterial Thrombosis 164
Antiphospholipid Syndrome 164
Paroxysmal Nocturnal Hemoglobinuria (PNH) 165
Thrombotic Microangiopathies (TMAs) 165
Heparin-Induced Thrombocytopenia and Thrombosis (HITT) 165
Immunothrombosis 165
Myeloproliferative Neoplasms (MPNs) 165
Molecular Regulators of Arterial and Venous Thrombosis 166
Summary 167
References 167
17: Anticoagulants and Treatment of Venous Thromboembolism 169
Parenteral Anticoagulants 169
Indirect Thrombin and/or Xa Inhibitors 169
Overview 169
Key Concepts 169
Unfractionated Heparin 169
Pharmacology 169
Mechanism of Action 169
Pharmacokinetics/Pharmacodynamics 169
Clinical Indications 170
Clinical Dosing and Management 171
Initiation of Therapy 171
Maintenance Dosing and Titration 174
Frequency of Monitoring 174
Managing Invasive Procedures 174
Managing Bleeding and Reversal 174
Adverse Events 174
Immune-Mediated Heparin-Induced Thrombocytopenia (HIT) 174
Osteoporosis 175
Abnormal Liver Function Tests 175
Transitioning Between Anticoagulants 175
Transitioning to UFH 175
Transitioning from UFH 175
Low-Molecular-Weight Heparin (LMWH) 175
Pharmacology 175
Mechanism of Action 175
Pharmacokinetics/Pharmacodynamics 175
Clinical Indications 176
Clinical Dosing and Management 176
Dosing 176
Administration 176
Monitoring 176
Managing Invasive Procedures 177
Managing Bleeding and Reversal 177
Adverse Effects 177
Heparin-Induced Thrombocytopenia 177
Transitioning Between Anticoagulants 177
Transitioning from LMWH 177
Transitioning to LMWH 177
Fondaparinux 177
Pharmacology 177
Mechanism of Action 177
Pharmacokinetics/Pharmacodynamics 178
Clinical Indications 178
Clinical Dosing and Management 178
Dosing 178
Administration 178
Monitoring 178
Managing Invasive Procedures 178
Managing Bleeding and Reversal 179
Adverse Effects 179
Transitioning Between Anticoagulants 179
Transitioning from Fondaparinux 179
Transitioning to Fondaparinux 179
Direct Thrombin Inhibitors (Argatroban and Bivalirudin) 179
Overview 179
Key Concepts 179
Pharmacology 179
Mechanism of Action 179
Pharmacokinetics/Pharmacodynamics 179
Clinical Indications 180
Heparin-Induced Thrombocytopenia 180
Clinical Dosing and Management 180
Initiation of Therapy 180
Maintenance Dosing and Titration 180
Frequency of Monitoring 181
Managing Invasive Procedures 181
Transitioning Between Anticoagulants 181
Transitioning to a Parenteral DTI 181
Transitioning from a Parenteral DTI 181
Argatroban 181
Bivalirudin 181
Managing Bleeding and Reversal 182
Adverse Events 182
Oral Anticoagulants 182
Vitamin K Antagonists 182
Overview 182
Key Concepts 182
Pharmacology 182
Mechanism of Action 182
Pharmacokinetics/Pharmacodynamics 183
Clinical Indications 184
Clinical Dosing and Management 184
Initiation of Therapy 184
Maintenance Dosing 184
Frequency of Monitoring 185
Managing Out-of-Range INRs 185
Managing Drug Interactions 186
Managing Invasive Procedures 186
Adverse Events: Managing Bleeding and Reversal of Therapy 187
Cessation of Therapy or Transition to Other Oral Anticoagulants 188
Systems of Anticoagulation Management 188
Direct Oral Anticoagulants 188
Overview 188
Key Concepts 188
Pharmacology 189
Mechanism of Action/Pharmacokinetics/Pharmacodynamics 189
Clinical Indications 189
Dabigatran Etexilate 189
Rivaroxaban 189
Apixaban 189
Edoxaban 190
Clinical Dosing and Management 190
Dosing for VTE, AF, Orthopedic Surgery 190
Monitoring Therapy and Coagulation Assays 190
Managing Invasive Procedures 191
Managing Drug Interactions 192
Adverse Events: Managing Bleeding and Reversal of Therapy 192
Managing Transitions of Care 193
Advantages/Disadvantages Compared with Warfarin 193
Treatment of VTE 193
Special Populations/Considerations 193
Pregnancy and Breastfeeding 193
Cancer 194
Thrombophilias 194
Extremes of Weight 194
Renal Impairment 194
Pediatrics 195
IVC Filter Indications 195
Duration of VTE Therapy 196
References 197
18: Antiplatelet Therapy in Cardiovascular Disease 200
Role of Platelets in the Pathophysiology of Cardiovascular Disease 200
Platelets Are Key Mediators in Atherosclerotic Vascular Disease 200
Platelets in Venous Thrombosis 201
Pharmacologic Targets of Antiplatelet Drugs 201
Aspirin 201
Mechanism of Action 201
Pharmacokinetics and Pharmacodynamics 202
Efficacy and Safety 202
Dosing 202
Indications 202
Aspirin “Resistance” 203
P2Y12 Antagonists and Dual Antiplatelet Therapy 203
Mechanism of Action 203
Ticlopidine 203
Clopidogrel 204
Pharmacokinetics and Pharmacodynamics 204
Efficacy and Safety 204
Clopidogrel Resistance 205
Prasugrel 205
Pharmacokinetics and Pharmacodynamics 205
Efficacy and Safety 205
Ticagrelor 205
Mechanism of Action, Pharmacokinetics, and Pharmacodynamics 205
Efficacy and Safety 206
Cangrelor 206
Pharmacokinetics/Pharmacodynamics 206
Efficacy and Use 206
Dual Antiplatelet Therapy (DAPT) 207
Duration 207
Use with Anticoagulation 207
Glycoprotein IIb/IIIa Inhibitors 208
Mechanism of Action, Pharmacokinetics and Pharacodynamics 208
Efficacy and Use 209
Protease-Activated Receptor 1 (PAR-1) Antagonists 209
Vorapaxar 209
Mechanism of Action, Pharmacokinetics, and Pharmacodynamics 209
Efficacy and Safety 209
Dipyridamole 209
Mechanism of Action, Pharmacokinetics, and Pharmacodynamics 209
Efficacy and Safety 209
Cilostazol 210
Mechanism of Action, Pharmacokinetics, and Pharmacodynamics 210
Efficacy and Safety 210
Conclusion 210
References 210
Suggested Reading 212
19: Physiological Roles of Leukocytes and Disorders 213
Myeloid Cells 213
Subsets of Myeloid Cells 213
Neutrophils 213
Production 213
Bone Marrow Homing and Peripheral Functions 214
Elimination 216
Disorders of Neutrophils 216
Quantitative Neutrophil Defects (Disorders that Affect Neutrophil Number) 216
Neutrophil Production Defects 216
Disorders that Increase Neutrophil Destruction and Clearance 219
Neutrophilia 219
Primary/Clonal Neutrophilia 219
Secondary Neutrophilia 219
Qualitative Neutrophil Defects (Disorders that Affect Neutrophil Function) 219
Eosinophils 220
Diseases that Affect Eosinophil Number 221
Disorders of Abnormal Eosinophil Function 221
Basophils and Mast Cells 221
Monocytes 221
Lymphocytes 222
Natural Killer Cells 222
Ontogeny of NK Cells 222
NK Cell Functions 222
Disorders Mediated by Abnormal NK Cell Number 222
Disorders Mediated by Abnormal NK Cell Function 223
B-Cell Lymphocytes 223
Ontogeny of B Cell 223
Disorders of B-Cell Number and Function 224
T Cells 224
Ontogeny of T Cell 224
Disorders of Abnormal T-Cell Quantity 225
Disorders that Affect T-Cell Functions 225
Summary 225
References 225
20: Pediatric Hematology 229
Introduction 229
Development of Hematopoiesis 229
Hemoglobin Synthesis in the Fetus and the Newborn 230
Erythropoiesis After Birth 230
Myelopoiesis in Infancy and Childhood 231
Platelets in Infancy and Childhood 231
Coagulation System in Infancy and Childhood 231
Disorders of Fetomaternal Unit Causing Hematologic Manifestations in the Neonate 232
Further Reading 235
21: Bone Marrow Structure and Marrow Aspiration, Biopsy, and Collection for Therapeutic Intent Procedures 236
Bone Marrow Structure 236
Bone Marrow Diagnostic Testing 239
References 254
22: Flow Cytometry in Hematology 256
Flow Cytometry 256
Summary 277
Literature Cited 277
Web Resources 278
Flow Cytometry Overview 278
23: Genetics in Hematologic Disorders: Implications of Recurring Chromosome Abnormalities and Gene Mutations 279
Introduction 279
Techniques 279
Chromosomal Analysis (Karyotyping) 279
Fluorescence In Situ Hybridization (FISH) Testing 280
Genomic Microarray Testing 280
Next-Generation Sequencing (NGS) Techniques 280
Selection of Karyotyping, FISH, and/or Microarray Tests in Clinical Diagnostics 280
Significance of Detection of Cytogenetic Abnormalities 281
Understanding the Cytogenetic Report 281
Chronic Myeloid Leukemia (CML) and t(9 22)/Philadelphia Chromosome
Acute Myeloid Leukemia (AML) 283
CBF Leukemia with t(8 21)or inv(16)/t(16
APL with t(15 17)
t(9 11) and Other KMT2A(MLL)11q23 Translocations
inv(3)/t(3 3)/MECOM/EVI1 Fusion
t(6 9)/DEK/NUP214 Fusion
t(1 22)/RBM15/MKL1 Fusion
Features of Massive Chromosomal Imbalances, Complex Karyotype, and Clonal Heterogeneity in AML 286
Myelodysplastic Syndrome (MDS) 288
Del(5q) and 5q- Syndrome 289
?7/del(7q) 289
Gene Mutations in AML and MDS, Particularly with Normal Karyotypes 289
Features of Chromosome Abnormalities in Therapy-Related Myeloid Neoplasia (t-AML/MDS) 290
Clonal Hematopoiesis of Indeterminate Potential (CHIP) 290
Acute Lymphoblastic Leukemia (ALL) 290
B-Cell ALL 290
t(12 21)/ETV6/RUNX1 Fusion
t(8 14)/MYC/IGH Fusion
t(4 11)/AFF1/KMT2A Fusion and Other KMT2A/MLL Translocations
t(9 22)/BCR/ABL1 Fusion
t(1 19)/E2A/TCF3 Fusion
iAMP21 291
Hyperdiploidy 291
Hypodiploidy 291
BCR-ABL1 (Ph)-Like B-Cell ALL 292
T-ALL 292
TCR Gene-Related Translocations and Rearrangements 292
Mature B- and T-Cell Non-Hodgkin Lymphoma (NHL) and Hodgkin Lymphoma 292
Non-Hodgkin Lymphoma 294
t(14 18)/IGH/BCL2 Fusion in Follicular Lymphoma and DLBCL
t(8 14)/IGH/MYC Fusion in Burkitt Lymphoma and DLBCL
t(11 14)/IGH/CCND1 Fusion in Mantle Cell Lymphoma
t(11 18)/API1/MALT1 Fusion and Other MALT1 Fusion in Mucosa-Associated Lymphoid Tissue (MALT) Lymphoma
inv(14)/t(14 14)/TRAD/TCL1 Fusion in T-Cell PLL
i(7q) in Hepatosplenic T-Cell Lymphoma 294
t(2 5)/ALK/NPM1 Fusion in Anaplastic Large T-Cell Lymphoma (ALTCL)
Hodgkin Lymphoma (HL) 295
Chronic Lymphocytic Leukemia (CLL) 295
Multiple Myeloma and Other Plasma Cell Neoplasms 296
Summary 297
References 297
General 297
CML 297
AML 297
MDS 298
CHIP 298
B-ALL 298
T-ALL 298
NHL 298
cHL 298
CLL 299
MM 299
24: Understanding Molecular Testing in Patients Affected by Hematologic Disorders 300
Starting Material for Molecular Assays 300
Molecular Techniques 300
Polymerase Chain Reaction (PCR) 300
PCR-Based Technologies 301
Reverse Transcription PCR (RT-PCR) 301
Quantitative PCR (qPCR) 302
Multiplex PCR 302
Allele-Specific Oligonucleotide PCR or Amplification Refractory Mutation System (ARMS) 302
Post-PCR Fragment Analysis or Sizing Assay (Capillary Electrophoresis) 303
PCR-Restriction Fragment Length Polymorphism (RFLP) 303
High Resolution Melting Analysis 303
Short Tandem Repeat (STR) Analysis 304
Gap-PCR 304
Inverse Shifting-PCR (IS-PCR) 304
Multiplex Ligation-Dependent Probe Amplification (MLPA) 304
Digital PCR 305
Chromosomal Analysis (Karyotype) 305
Fluorescent In Situ Hybridization 307
Array 308
Sequencing 309
Sanger Sequencing 310
Next-Generation Sequencing (NGS) 310
Conclusions 312
References 312
25: Chronic Myeloid Leukemia (CML) 314
Definition 314
Pathophysiology 314
Diagnosis 314
Prognosis 315
Treatment of CML in Chronic Phase 315
Treatment of CML in Accelerated Phase (AP)/Blast Crisis(BC) 318
Medications 319
Summary 321
References 322
26: Myeloproliferative Neoplasms 324
Introduction 324
Erythrocytosis and Polycythaemia Vera 325
Presentation and Investigation 325
Management 325
Thrombocytosis and Essential Thrombocythaemia 326
Presentation and Investigation 326
Management 327
Primary Myelofibrosis 327
Presentation 327
Diagnosis 328
Prognosis 328
Management 328
Allogeneic Hematopoietic Cell Transplantation 328
Splenomegaly 328
Constitutional Symptoms 329
Cytopenias 329
Blast Phase 329
Eosinophilia 329
Presentation and Differential Diagnosis 329
Investigation 330
Management 330
Mastocytosis 331
Presentation 331
Diagnosis 331
Management 331
Mediator-Release Symptoms 332
Reducing Mast Cell Burden 332
Conclusions 332
Suggested Reading 333
27: Myelodysplastic Syndromes (MDS) 334
Introduction and Pathogenesis 334
Epidemiology 334
Clinical Presentation 334
Evaluation and Differential Diagnosis 335
Pathologic Features of MDS 335
Classification of Myelodysplastic Syndromes 335
French-American-British (FAB) Classification 335
World Health Organization (WHO) Classification 335
Cytogenetic and Molecular Characteristics 336
International Prognostic Scoring Systems (IPSS and Revised IPSS) 336
Treatment of Myelodysplastic Syndromes 339
Treatment of Lower Risk MDS 339
Treatment of Higher Risk MDS 340
Summary 341
References 341
28: Acute Leukemia 343
Acute Myeloid Leukemia 343
Clinical Features, Workup, and Diagnosis 343
Classification 345
Risk Stratification 345
Treatment 346
Induction 346
Consolidation 347
CNS Disease 347
Response Criteria 347
Minimal Residual Disease 347
Acute Promyelocytic Leukemia 348
Acute Lymphoblastic Leukemia 348
Clinical Features, Workup, and Diagnosis 348
Immunophenotypic Characterization 349
Chromosomal and Molecular Changes 349
Risk Stratification 351
Children, Adolescents, and Young Adult Patients (up to 21 Years of Age) 351
Adults 351
Treatment 351
Induction 351
Consolidation 351
CNS Prophylaxis 351
Maintenance 351
Tyrosine Kinase Inhibitor Therapy 352
Anti-CD20 Therapy 352
Other Targeted Therapies 352
Cellular Therapy 352
Supportive Care 352
Leukostasis 352
Tumor Lysis Syndrome 352
Coagulopathy 352
Blood Product Support 353
Opportunistic Infections and Neutropenic Fever 353
Fertility and Suppression of Menses 353
Summary 353
Further Reading 353
29: Classification of Lymphomas 355
Historic Approaches to Classification 355
Diagnosis 356
Mature B Cell Neoplasms (See Table 29.2) 356
Mantle Cell 356
Chronic Lymphocytic Leukemia 356
Monoclonal B Cell Lymphocytosis 357
Follicular Lymphoma 358
Marginal Zone/MALT 358
Lymphoplasmacytic Lymphoma/Waldenström Macroglobulinemia 359
Hairy Cell Leukemia 359
DLBCL 359
Mature T and NK Cell Neoplasms 360
Diagnosis 360
Nodal T Cell Lymphoma 360
Peripheral T Cell Lymphoma Not Otherwise Specified 360
Anaplastic Large Cell Lymphoma 361
Breast Implant Anaplastic Large Cell Lymphoma (BIA-ALCL) 361
Angioimmunoblastic T Cell Lymphoma 361
Extranodal T Cell Lymphoma 361
Leukemic T Cell Lymphoma 362
Cutaneous T Cell Lymphomas 362
Sezary Syndrome/Mycosis Fungoides 362
PTCL Treatment and Prognosis (Table 29.3) 362
Hodgkin Lymphoma 363
Classical Hodgkin Lymphoma (CHL) 363
Prognostic Factors 364
Nodular Lymphocyte-Predominant HL 364
Posttransplant Lymphoproliferative Disorder 365
Monomorphic PTLD 366
Polymorphic PTLD 366
Classical Hodgkin PTLD 366
Plasmacytic Hyperplasia PTLD 366
Infectious Mononucleosis PTLD 366
Florid Follicular Hyperplasia PTLD 366
Histiocytic and Dendritic Cell Neoplasms 366
Langerhans Cell Histiocytosis 366
Langerhans Cell Sarcoma 367
Histiocytic Sarcoma 367
Interdigitating Dendritic Cell Sarcomas 367
Indeterminate Dendritic Cell Tumor/Sarcoma 367
Follicular Dendritic Cell Sarcoma 367
Fibroblastic Reticular Cell Tumor 367
Disseminated Juvenile Xanthogranuloma 367
Erdheim-Chester Disease 368
Summary 368
References 368
30: Clinical Evaluation and Management of Hodgkin Lymphoma 371
Introduction 371
Epidemiology and Pathology of Hodgkin Lymphoma 371
Clinical Evaluation and Staging of Hodgkin Lymphoma 373
Treatment of Hodgkin Lymphoma 374
Summary 377
Suggested Reading 377
31: Indolent Lymphomas 379
Introduction 379
Distinctions Among the Indolent Lymphomas (Table 31.1) 379
Treatment 380
Summary 385
Suggested Reading 385
32: Aggressive Lymphoma 387
Introduction 387
Epidemiology and Classification 387
Clinical Presentation 387
Diagnosis 388
Initial Workup and Staging 388
Aggressive B-Cell Lymphoma Subtypes 389
Diffuse Large B-Cell Lymphoma (DLBCL) 389
Diagnostic Considerations 389
Prognostic Factors 390
Treatment 390
First-Line Therapy 390
Limited Stage (Stage I, II) Disease 390
Advanced Stage (Stage III, IV) Disease 390
Relapsed and Refractory Disease 390
Double-Hit Lymphoma 392
Mantle Cell Lymphoma (MCL) 393
Diagnostic Considerations 393
Prognostic Factors 393
Treatment 393
Frontline 393
Relapsed/Refractory MCL 394
Burkitt Lymphoma 394
Diagnostic Considerations 394
Prognostic Factors 394
Treatment 395
First-Line 395
Relapsed/Refractory 395
Transformed Lymphoma 395
Introduction 395
Epidemiology 395
Clinical Presentation 395
Diagnosis 395
Treatment 395
Aggressive Mature Peripheral T-Cell Lymphomas 396
Peripheral T-Cell Lymphoma, Not Otherwise Specified 396
Diagnostic Considerations 396
Prognostic Factors 396
Anaplastic Large Cell Lymphoma 396
Diagnostic Considerations 396
Prognostic Factors 396
Angioimmunoblastic T-Cell Lymphoma 396
Diagnostic Considerations 396
Prognostic Factors 397
Treatment of Mature Peripheral T-Cell Lymphomas 397
First Line 397
Relapsed and Refractory Disease 397
Special Considerations (for All Aggressive NHLs) 397
CNS Treatment and Prophylaxis 397
Investigational/Emerging Therapies 397
Conclusions 398
References 398
33: Clinical Evaluation and Management of Chronic Lymphocytic Leukemia 400
Introduction 400
Epidemiology 400
Biology 400
Clinical Features 401
Laboratory Features and Diagnosis 401
Prognosis 401
Treatment 401
Indications for Treatment 401
Initial Treatment 401
Purine Analogues and Alkylating Agents 401
Monoclonal Antibodies 402
Chemoimmunotherapy 402
Minimal Residual Disease (MRD) 403
First-Line Therapy by Patient and Disease Status 403
Novel Targeted Therapies 403
BCL-2 Inhibitor 404
Lenalidomide 404
Chimeric Antigen Receptor (CAR) T Cell Therapy 404
Hematopoietic Cell Transplantion 405
Autoimmune Complications of CLL 405
Hypogammaglobulinemia 405
Richter Transformation 405
Summary 405
References 405
34: Plasma Cell Disorders 409
Introduction 409
Monoclonal Gammopathy of Undetermined Significance (MGUS) 409
Multiple Myeloma 412
Epidemiology 412
Pathophysiology 413
Clinical Manifestations and Workup 414
Treatment of Multiple Myeloma 414
Waldenstrom Macroglobulinemia 417
Immunoglobulin Light Chain Amyloidosis 418
Other Plasma Cell Disorders 419
References 419
35: Neoplastic Hematologic Disorders in Children and Adolescents 421
Cancer in Children and Adolescents 422
General Information 422
Epidemiology 422
Causes of Pediatric Neoplasia 422
Therapy 423
Induction Phase 423
Consolidation Phase 423
Re-induction Phase 423
Central Nervous System (CNS) Prophylaxis for Hematologic Diseases 423
Maintenance Therapy 423
Radiotherapy 423
CNS Radiotherapy During Hematologic Diseases 423
Prophylactic CNS Radiotherapy 423
Therapeutic CNS Radiotherapy 424
Side Effects of CNS Radiotherapy 424
Long-Term Effects of CNS Radiotherapy 424
Supportive Care 424
Antiemetic Prophylaxis and Therapy 424
Prophylaxis and Therapy of Mucositis 424
Prophylaxis of Infectious Complications 425
Pneumocystis jirovecii Prophylaxis 425
Antifungal Prophylaxis 425
Antiviral Prophylaxis 425
Varicella Zoster Virus Postexposure Prophylaxis 425
Substitution of Blood Components 425
Acute Complications During Chemotherapy 425
Metabolic Complications 425
Tumor Lysis Syndrome 425
Organ-Specific Complications 426
Peripheral Neuropathy 426
Coagulation Disorders 426
Disseminated Intravascular Coagulation (DIC) 426
Thrombophilia 426
Targeted Therapy 426
Tyrosine Kinase Inhibitors (TKI) 426
BCR-ABL Inhibitors 427
Jak1/2 Inhibitors 427
Side Effects 427
Monoclonal Antibodies 427
CAR T Cell Therapy 428
Acute Lymphoblastic Leukemia (ALL) 428
Definition 428
Prevalence 428
Pathogenesis 429
Prognosis 429
Diagnosis 429
Typing 430
Cytology 430
Morphology 430
Cytochemistry 430
Immune Phenotyping 430
Clinical Symptoms 431
Bone Marrow Involvement 431
CNS Involvement 431
Testicular Involvement 432
Clinical and Laboratory: Chemical Diagnosis 432
Bone Marrow Involvement 432
CNS Involvement 432
Testicular Involvement 432
Therapy 432
Initial Patient Admission 432
Chemotherapy 433
Relapse 433
Diagnosis of Minimal Residual Disease (MRD) 433
Long-Term Effects and Follow-Up Care 434
Acute Myeloid Leukemia (AML) 434
Definition 434
Incidence 434
Prognosis 434
Pathogenesis 435
Diagnosis 435
Differential Diagnosis 435
Typing 435
Morphology and Cytochemistry 435
Immune Phenotyping 436
Cytogenetic Typing 438
Clinical Symptoms 441
Hyperleukocytosis and Leukostasis 442
Bleeding 442
Infections 442
Therapy 442
Allogeneic Hematopoietic Cell Transplantation 443
Relapse 443
Long-Term Side Effects and Follow-Up (FU) 443
Myelodysplastic Syndromes (MDS) 443
Definition 443
Incidence 444
Prognosis 444
Pathogenesis 444
Diagnosis 444
Differential Diagnosis 444
Classification 444
Typing 445
Morphology and Cytochemistry 445
Immune Phenotyping 446
Cytogenetic Typing 446
Clinical Symptoms 446
Therapy 446
Hematopoietic Stem Cell Transplantation 447
Relapse 448
Long-Term Effects and Follow-Up 448
Juvenile Myelomonocytic Leukemia (JMML) 448
Definition 448
Incidence 448
Prognosis 448
Pathogenesis 448
Diagnosis 448
Differential Diagnosis 448
Typing 449
Morphology and Cytochemistry 449
Immune Phenotyping 449
Cytogenetic Typing 449
Clinical Symptoms 449
Therapy 449
Relapse 450
Long-Term Effects and Follow-Up 450
Chronic Myeloproliferative Diseases 450
Chronic Myeloid Leukemia 450
Definition 450
Incidence 450
Prognosis 450
Pathogenesis 450
Diagnosis 451
Differential Diagnosis 451
Typing 451
Morphology and Cytochemistry 451
Immune Phenotyping 451
Cytogenetic Typing 451
Clinical Symptoms 451
Therapy 451
Relapse 451
Long-Term Effects and Follow-Up 452
Essential Thrombocythemia (ET) 452
Definition 452
Prognosis 452
Pathogenesis 452
Diagnosis 453
Differential Diagnosis 453
Typing 453
Morphology and Cytochemistry 453
Cytogenetic Typing 453
Therapy 453
Long-Term Effects and Follow-Up 454
Primary Myelofibrosis (PMF) 454
Definition 454
Incidence 454
Prognosis 454
Pathogenesis 454
Diagnosis 454
Differential Diagnosis 454
Typing 454
Morphology and Cytochemistry 454
Cytogenetic Typing 454
Clinical Symptoms 454
Therapy 455
Long-Term Effects and Follow-Up 455
Polycythemia Vera (PV) 456
Definition 456
Incidence 456
Prognosis 456
Pathogenesis 456
Diagnosis 456
Differential Diagnosis 456
Typing 456
Morphology and Cytochemistry 456
Cytogenetic Typing 457
Clinical Symptoms 457
Therapy 458
Long-Term Effects and Follow-Up 458
Summary 458
References 458
36: Transfusion Medicine 460
Introduction 460
Donors 460
Blood Bank Policies and Procedures 461
Pretransfusion Testing 461
Transfusion Administration and Monitoring 461
Blood Utilization/Transfusion Committees 462
Whole Blood and Blood Components 462
Whole Blood (WB) 462
Red Blood Cells 463
Plasma Components 465
Cryoprecipitated Components 466
Platelet Components 467
Granulocyte Components 468
Further Processing 468
Alternatives to Transfusion/Mitigation Measures 469
Specific Populations 470
Adverse Events and Side Effects of Transfusion 471
Transfusion-Transmitted Infection (Table 36.5) 476
New Safety Considerations 478
Patient Hemovigilance 479
Risk-Based Decision-Making 479
Health Economics and Cost-Effectiveness 479
Summary 480
References 480
37: Hematopoietic Cell Transplantation 484
Introduction 484
Hematopoietic Cell Transplantation (HCT) 484
Definitions for Graft Sources 484
Frequently Used Abbreviations in Hematopoietic Cell Transplantation 485
Autologous Hematopoietic Cell Transplantation 485
Overview 485
Phases of Autologous HCT 486
Outcomes of Autologous Hematopoietic Cell Transplantation 488
Advantages and Disadvantages of Autologous HCT 489
Allogeneic Hematopoietic Cell Transplantation 489
Overview 489
Indications for Allogeneic HCT 490
Immunologic Aspects of Allogeneic HCT 491
Phases of Allogeneic Hematopoietic Cell Transplantation 496
Outcomes of Allogeneic Hematopoietic Cell Transplantation 498
Summary 498
References 498
Suggested Reading 498
38: Infections in Hematology Patients 500
Introduction 500
Prevention of Infections 500
Neutropenic Fever 500
Pneumonia 502
Cather-Related Bloodstream Infection (CRBSI) 505
Typhlitis (Neutropenic Enterocolitis) 505
Fungal Infections 506
Viral Infections 511
Summary 514
References 514
Correction to: Concise Guide to Hematology 516
Index 517