Hematology: Basic Principles and Practice

✍ Scribed by Ronald Hoffman (editor), Edward J. Benz (editor), Leslie E. Silberstein (editor), Helen Heslop editor), Jeffrey Weitz (editor), Mohamed E. Salama (editor), Syed Ali Abutalib (editor)

• Publisher: Elsevier
• Year: 2022
• Tongue: English
• Leaves: 2787
• Edition: 8
• Category: Library

✦ Table of Contents

HEMATOLOGY
Basic Principles and Practice​
Copyright
CONTENTS​
PART I MOLECULAR AND CELLULAR BASIS OF HEMATOLOGY.pdf
1
Anatomy and Physiology of the Gene
The Genetic View of the Biosphere: The Central Dogma of Molecular Biology
The Anatomy and Physiology of THE Gene
DNA and RNA Structure
Storage of Genetic Information in the Nucleotide Sequences of DNA
Transmission of Genetic Information to the Next Generation
The Expression of Genetic Information Via Translation Into Proteins Using the Genetic Code
Regulation of Gene Expression
Chromatin and the Epigenetic Regulation of Gene Expression
Regulatory Sequence Motifs in or Near Genes: Enhancers, Promoters, and Silencers
Transcription Factors
Regulation at the Level of Pre-mRNA and mRNA Metabolism
Pre-mRNA Splicing
Modification of the Ends of the mRNA Molecule
5' and 3' Untranslated Sequences Within mRNAs That Modulate Stability and Translatability
Transport of mRNA From Nucleus to Cytoplasm: mRNP Particles
Regulation of mRNA Processing and Stability
Regulation at the Level of mRNA Translation
Heterogeneity of rRNAs and tRNAs
Roles of Small Interfering RNAs, Micro RNAs, Short Hairpin RNAs, and Long Noncoding RNAs in Regulating Gene Expression
Some Illustrative Structural Features of the Genome Relevant to Hematology
Polymorphism and Single Nucleotide Polymorphisms
Repeated Sequence Motifs
Molecular Genetic Methodologies Allowing the Isolation, Analysis, and Manipulation of Genes
The Polymerase Chain Reaction
High-Throughput DNA and RNA Sequencing
Gene Cloning
Use of Transgenic and Knockout/Knockin Organisms to Model Gene Function
DNA- and RNA-Based Therapeutics
Gene Therapy and Gene Editing
RNA Therapeutics
Future Directions
Suggested Readings
2
Epigenomics in Hematology
Functional Chromatin Domains
Dna Methylation
Histones And Histone Variants
Covalent Histone Modifications
Transcription Factors
Chromatin Remodelers
Experimental Approaches in Epigenetics
Mechanisms of Disease
Epigenetic Therapies
Future Directions
Suggested Readings
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3
Genomic Approaches to Hematology
Introduction
General Principles of Genomic Testing
Genomic Analysis
The Importance of Sample Quality
Analytical Considerations
Next-Generation Sequencing Technology
RNA Profiling
Noncoding RNA
Mutation Detection Strategies
Germline Versus Somatic Variants
Point Mutations or Single Nucleotide Variants
Structural Variation
Copy Number Abnormalities
Chromosomal Rearrangements
Epigenomics
The Clinical Utility of Genomics in Hematologic Malignancies
Diagnosis
Precision Medicine and Molecularly Targeted Therapies
Risk-Stratified Therapy
Response-Adapted Therapy and Minimal Residual Disease Monitoring
Pharmacogenomics
The Clinical Utility of Genomics in Benign Hematology
The Hemoglobinopathies
Clotting Disorders
Disease with Rare Penetrant Variants Involving Multiple Loci
Common Low Penetrance Risk Variants
Approaches to the Development of Molecular Testing
Suggested Readings
References
4
Regulation of Gene Expression in Hematology
Introduction
Regulation of Transcription
RNA Polymerase Binding and Regulation by Transcription Factors
Regulation of Transcription by Chromatin
Regulation of Transcription by DNA Modification
RNA Proofreading
Regulation of RNA Processing: Capping, Splicing, and Polyadenylation
Nuclear Export of RNA
RNA Heterogeneity
Regulation of RNA Metabolism: Stability and Localization
Regulation of RNA Stability by 5' and 3' UTR Sequences and Structures
Nonsense-Mediated Decay
RNA Modifications: The Epitranscriptome
RNA Interference
RNA Granules and Membraneless Organelles
Protein Synthesis
The Process of Translation
Ribosome Disorders
Protein Sorting
Targeting of Nuclear Proteins
Cotranslational Protein Translocation Into the Endoplasmic Reticulum
Intra-Golgi Transport and Protein Processing
Sorting Into Lysosomes
Targeting of Mitochondrial Proteins
Targeting of Peroxisomal Proteins
Sorting into Regulated Secretory Granules
Protein Folding and Posttranslational Modifications
Protein Folding
Protein Modifications
Protein Folding and Modifications in the Endoplasmic Reticulum
Protein Degradation
Endoplasmic Reticulum-Associated Degradation and the Unfolded Protein Response
Protein Degradation by the Proteasome
Conclusions
Suggested Readings
References
5
Genome Editing
Double-Stranded Dna Breaks: The Basis of Nuclease-Based Genome Editing
Base Editing
Other Genome Editing Systems
Using Engineered Nucleases to Initiate the Genome Editing Process
Genome Editing Using Only a Nuclease And Nonhomologous End-Joining Repair
A Broad Range of Genomic Changes by Homologous Recombination–Mediated Genome Editing
Genotoxicity Through Potential Off-Target Nuclease-Induced Double-Strand Breaks
Genome Editing As a Research Tool
Genome Editing As a Therapeutic Strategy
Ex Vivo Manufacturing of Therapeutic Cells
Therapeutic Genome Editing for Hematologic Diseases
Sickle Cell Disease
Fetal Hemoglobin Derepression
Direct Gene Correction
β-Thalassemia
Fetal Hemoglobin Derepression
Knocking HBB into HBA1
Primary Immunodeficiency Diseases
Using the Blood System to Treat Nonhematologic Diseases (Metabolic Diseases)
Genome Editing of Immune Effector Cells for Safer and More Potent Cancer Therapies (CAR-T Cells)
Off-the-Shelf CAR-T Cells
Increasing Potency
Opportunities for Genome Editing in Vivo
Challenges to in Vivo Editing of Hematopoietic Stem Cells
Delivery
Immunogenicity
Heritable Genome Editing
Suggested Readings
References
6
Signaling Transduction and Metabolomics
Signaling Transduction
Receptor Tyrosine Kinases, Phosphoinosite-3-Kinase, and Mitogen-Activated Protein Kinase Pathways
Receptor Tyrosine Kinases
Phosphatidylinositol 3-Kinase Pathway
MAPK/ERK Pathway
The Transforming Growth Factor-β Pathway
Signaling Through Receptors Associated With Protein-Tyrosine Kinases
Cytokine Receptors and Janus-Activated Kinase Signaling
Multichain Immune Recognition Receptors
Integrin Signaling
Tumor Necrosis Factor Receptors and Signaling
Toll-Like Receptors and Signaling
Wnt Signaling
Notch Signaling
Hedgehog Signaling
Nuclear Hormone Receptor Superfamily
G Protein–Coupled Receptor and Chemokine Signaling
G Protein–Coupled Receptor Signaling
Chemokine Signaling
cGAS–cGAMP–STING Signaling Pathway
Endoplasmic Reticulum Stress Signaling Pathways
Heme Signaling Transduction
Hypoxia Signaling Transduction
Metabolomics and Control of Hematopoietic Cell Metabolism
Glucose Metabolism
Glycolysis
Pentose Phosphate Pathway
Tricarboxylic Acid or Krebs Cycle
Oxidative Phosphorylation
Reactive Oxygen Species Metabolism
Lipid Metabolism
Fatty Acid Synthesis
Fatty Acid Oxidation
Cholesterol
Phospholipids
Amino Acid Metabolism
Biosynthesis of Nonessential Amino Acids
Amino Acid Catabolism
Nucleotide Metabolism
Nucleotide Synthesis
Nucleotide Degradation
Introduction to Metabolomics
Metabolomics of Glucose Metabolism
Metabolomics of Lipid Metabolism
Metabolomics of Nucleotide Metabolism
Metabolomics of Amino Acid Metabolism
Summary and Perspectives
Suggested Readings
7
Protein Architecture: Relationship of Form and Function
Amino Acids And The Peptide Bond
Protein Secondary Structure
Posttranslational Modifications
The Domain Structure of Proteins
The Immunoglobulin Domain and Variations
The Protein Kinase Domain
Membrane Proteins
Future Directions
Suggested Readings
References
8
Pharmacogenomics and Hematologic Diseases
Variation in the Human Genome
Single-Nucleotide Polymorphisms
Single-Nucleotide Polymorphisms and Phenotypes
Structural Genomic Variants
Somatic Genomic Variants
Catalogs of Genomic Variants, Genotyping Platforms, and Genome-Wide Association Studies
Variation in the Human Epigenome
Genetic Variations Influencing Drug Response: Pharmacogenetics–Pharmacogenomics–Pharmacoepigenomics
Optimization of Drug Therapy
Genetic Variations That Influence Drug Disposition and Effects
Drug Metabolism and Effects
Pharmacogenomics of Thiopurines in Childhood Leukemia
MP Dosage Adjustment According to the CPIC Guidelines Based on TPMT and NUDT15 Genotypes in Acute Lymphoblastic Leukemia
Relapse of Acute Lymphoblastic Leukemia, Thiopurine Resistance, and Somatic Variants in NT5C2 and PRPS1
Glucocorticoid Pharmacogenomics in Childhood Acute Lymphoblastic Leukemia
Inherited Genome Variants in Cytochrome P450 Enzymes
Pharmacogenomics of Warfarin
Drug Transporters
SLCO1B1 and Methotrexate
Genetic Variations Influencing Drug Targets
BCR-ABL1 and Tyrosine Kinase Inhibitors in Chronic Myeloid Leukemia
Adverse Drug Effects Presenting as Hematologic Disorders
Glucose-6-Phosphate Dehydrogenase Deficiency and Rasburicase
Drug Development
Drug Development in Pediatric High-Risk B-Cell Acute Lymphoblastic Leukemia
Identification of Novel Therapies for KMT2A-Rearranged Infant ALL
Identification of Novel Therapies for “BCR-ABL1–Like” ALL
Future Directions
Suggested Reading
References
PART II CELLULAR BASIS OF HEMATOLOGY.pdf
Chapter
9
Hematopoietic Stem Cell Biology
Embryonic Origin of Hematopoietic Stem Cells
Definition and Characterization of Hematopoietic Stem Cells
Phenotype
Murine Hematopoietic Stem Cells
Human Hematopoietic Stem Cells
CD49f+ Human Hematopoietic Stem Cells
Functional Characterization
In Vitro Assays
In Vivo Assays
Colony-Forming Unit–Spleen Assays
Competitive Repopulation Assays
Clonal Dynamics of Hematopoietic Stem Cells
Regulation of Hematopoietic Stem Cell Fate
Extrinsic Regulation
NOTCH Signaling
WNT Signaling
Transforming Growth Factor-β and Hedgehog Signaling
CXCL12–CXCR4 Signaling
Intrinsic Pathways
Transcription Factors
Transcription Factors Required for the Specification of Hematopoietic Stem Cells
Transcription Factors Required for Hematopoietic Stem Cell Homeostasis
The Homeobox Cluster in Hematopoietic Stem Cell Self-Renewal
Transcription Factor Networks
Epigenetic Regulation of Hematopoietic Stem Cell Self-Renewal
Regulation of Hematopoietic Stem Cells by Noncoding RNAs
Hematopoietic Stem Cell Metabolism
Novel Growth Factors For Expanding Hematopoietic Stem Cells and Clinical Testing
Generating Hematopoietic Stem Cells From Pluripotent Stem Cells and by Reprogramming of Somatic Cells
Hematopoietic Stem Cell Regeneration
Hematopoietic Stem Cells and Malignancy (See Chapters 13 and 59)
Suggested Readings
References
10
Mitochondria and Hematopoiesis
Mitochondrial Structure and Function
Mitochondrial Diseases
Mitochondrial Regulation of Hematopoietic Stem Cell Fates
The Mitochondrial Unfolded Protein Response Mechanism
The Mitochondrial Oxidative Self-Defense Response Mechanism
Mitochondrial Dynamics Controls the Self-Renewing Potential of Hematopoietic Stem Cells
Mitophagy as a Gatekeeper of Hematopoietic Stem Cells Fate Decisions
Mitochondrial Metabolic Regulation of the Epigenetic Landscape of Hematopoietic Stem Cells
Interaction Of Mitochondrial Network With The Bone Marrow Milieu Regulates Hematopoietic Stem Cell Fates
Mitochondrial And Bone Marrow Roles In Leukemic Stem Cells And Aged Hematopoietic Stem Cells
Mitochondrial and Epigenome Control Reprogramming Of Hematopoietic Stem Cells
Concluding Remarks
References
11
Cytokines, Chemokines, Other Growth Factors, and Their Receptors
Introduction
Cytokines And Their Modifying Influences
Specifics Of Growth-Modulating Factors
Colony-Stimulating Factors
Interleukins
Chemokines and Chemokine Receptors
Role of Nuclear Factor-κB in Cytokine and Chemokine Gene Regulation, Inflammation, Immunity, and Cancer
Engineered Cytokines and Role of Cytokines and Other Reagents for Preclinical and Clinical Ex Vivo Expansion of Hematopoiet ...
Other Growth Modulating Proteins/Factors
Iron-Binding Proteins
Transforming Growth Factor-β, Associated-Inhibin Family Members, Bone Morphogenic Protein, Tumor Necrosis Factor-α, and Int ...
Transforming Growth Factor-β
Inhibins (Activin and Inhibin)
Bone Morphogenetic Protein
Tumor Necrosis Factor
Interferons
Additional Growth Modulating Factors
Prostaglandin E
Enzymes, Matrix Metalloproteinases, and Dipeptidylpeptidase 4, as Modifiers of Cytokine/Chemokine Biologic Activities
Microenvironmental Niche and Role of Oxygen Tension in Hematopoiesis
Exosomes/Extracellular Vesicles
Aging in Context of Cell Regulation
Radiation Effects on Hematopoiesis
Concluding Thoughts
Suggested Readings
References
12
Role of Chemokines in Leukocyte Trafficking​
Chemokines
Signaling by Chemokine Receptors
Atypical Chemokine Receptors
Chemokine Interaction With Glycosaminoglycans
Leukocyte Entry Into Tissues
Chemokine Control of Lymphocyte Homing to Secondary Lymphoid Organs
Trafficking of Leukocytes From Blood Into Nonlymphoid Tissues
Migration of Hematopoietic Stem Cells to the Bone Marrow and Mobilization in the Niche
Leukocyte Migration Within Tissues
Trafficking Patterns of Lymphocytes
Migration of T Cells to T Zones Within Secondary Lymphoid Organs
Positioning of B Cells Within Secondary Lymphoid Organs
Leukocyte Exit From Tissues
Reprogramming Dendritic Cells to Exit Tissues Toward Secondary Lymphoid Organs
Egress of Lymphocytes From Secondary Lymphoid Organs
Summary
References
Suggested Readings
13
Stem Cell Model of Hematologic Diseases
Cell-Of-Origin Studies In Hematologic Malignancies
Acute Myeloid Leukemia
Myelodysplastic Syndromes
Myeloproliferative Neoplasms
Acute Lymphoblastic Leukemia
Mature B-Cell Malignancies
Chronic Lymphocytic Leukemia
Hairy Cell Leukemia
Diffuse Large B-Cell Lymphoma
Follicular Lymphoma
Conclusion
References
14
Hematopoietic Microenvironment
Evolution of The Niche Concept
Hematopoietic Microenvironment During Development
Adult Bone Marrow Microenvironment
Hematopoietic Stem Cell Niches
Location of the Hematopoietic Stem/Progenitor Cell Niche
Cellular Components of the Hematopoietic Stem/Progenitor Cell Niche
Osteolineage Cells
Endothelial Cells
Perivascular Cells
Adipocytes
Osteoclasts
Bone Marrow Macrophages
Megakaryocytes
Extrinsic Regulation of the Hematopoietic Stem Cell Niche
Sympathetic Innervation
Hypoxia
Niche Contribution to Leukemia Development
Niche Alterations by Leukemia
Therapeutic Targeting of Leukemic Niche
Lymphoid Niches
Erythroid Niches
Megakaryocytic Niches
Human Bone Marrow Microenvironment
Hematopoietic Microenvironment in Acute Leukemia and Myelodysplasia
Future Directions
References
15
Cell Adhesion
Adhesion Molecules
Extracellular Matrix Proteins
Integrins
Immunoglobulin-Like Receptors
Other Adhesion Receptors that Mediate Protein–Protein Interactions
Lectin Adhesion Receptors
Ligand Binding Versus Cell Adhesion
Regulation of Adhesion Receptors
Regulation of Synthesis
Regulation of Surface Expression
Regulation of Binding Affinity
Cell Signaling Through Adhesion Molecules
Cooperative Interactions Between Signaling and Adhesion Molecules
Platelet Adhesion, Aggregation, and Hemostasis
Leukocyte Rolling, Spreading, and Migration Across Vascular Endothelium During Inflammation
Adhesion of T Cells to Antigen-Presenting Cells during Antigen Priming
Genetic Deficiencies in Adhesion Molecules
Dysregulated Expression of Adhesion Molecules
Suggested Readings
16
Current Biology of Stem Cell Homing and Mobilization: Dynamic Interactions Between Hematopoietic Stem and Progenitor Ce ...
Introduction
Lessons from Steady-State Homeostatic Regulation of Hematopoietic Stem and Progenitor Cells
Daily Light- and Darkness-Onset Induced Signals Maintain Blood Replenishment Together With Self-Renewal of Long-Term Repopu ...
Mechanisms of Long-term Repopulating Stem Cell Chemotherapy Resistance via Anchorage to Their Supportive Bone Marrow Niches ...
Hematopoietic Stem and Progenitor Cell Regulation via Dynamic Interactions With the Blood-BM Endothelial Barrier and the St ...
Medical Approaches Originating from Understanding Mechanisms that Regulate Physiological Hspc Trafficking, for the Sake of ...
Establishment of Functional Preclinical Immune-Deficient Mice Models to Study Human Hematopoietic Stem Cell Trafficking and ...
Hematopoietic Stem and Progenitor Cell Homing
The Essential Role of the CXCL12/CXCR4 AXIS in the Regulation of Hematopoietic Stem and Progenitor Cell Homing
Hematopoietic Stem and Progenitor Cell Mobilization: A Dynamic Multi-Facet Process
The CXCL12/CXCR4 Axis as a Driving Force Leading to Hematopoietic Stem and Progenitor Cell Mobilization
Dynamics of the Hematopoietic Stem and Progenitor Cell Niches and the Bone Marrow Microenvironment During Mobilization
Concluding Remarks
Acknowledgments
References
17
Control of Cell Division
The Cell Division Cycle
Quiescence and Differentiation
G1 Phase
S Phase
G2 Phase
M Phase
Signaling
T-Cell Receptor
B-Cell Receptor
Macrophage Colony-Stimulating Factor Receptor
RAS Pathway to Cyclin D
Cyclins and Cyclin-Dependent Kinases
Cyclin-Dependent Kinase Inhibitors
Transcriptional Regulation: MYC, RB-E2F, And Dream/Muvb
Ubiquitination
Deoxyribonucleic Acid Replication
Mitosis
Cell Cycle Checkpoints
Competence
Restriction Point
G1/S Checkpoint
S Phase Checkpoint
G2/M Checkpoint
Senescence
Spindle Assembly Checkpoint
Special Hematology Cell Cycle Features
Hematopoietic Stem Cells
Endoreplication
References
18
Cell Death
Core Apoptosis Pathways
The Intrinsic Apoptotic Pathway
Nonapoptotic Roles Of Bcl-2 Family Proteins
The Death Receptor (Extrinsic) Pathway Of Apoptosis
Nonapoptotic Forms Of Cell Death
Necroptosis
Ferroptosis
Pyroptosis
Cell Survival And Cell Death Pathways And Adaptive Responses To Stress
Autophagy
Unfolded Protein Response
Clinical Applications
Preclinical Activity Of Bcl2 Antisense And Bh3-Mimetics In Myeloid Malignancies
Preclinical Activity of Oblimersen in Acute Myeloid Leukemia
Preclinical Activity of Obatoclax in Acute Myeloid Leukemia
Preclinical Activity of Navitoclax and ABT-737 in Acute Myeloid Leukemia
Preclinical Activity of Single-Agent Venetoclax in Acute Myeloid Leukemia
Combination Strategies to Boost Venetoclax Activity and Overcome Venetoclax Resistance
Novel Venetoclax-Based Combinations
Clinical Development Of Bh3-Mimetics For Myeloid Malignancies
Clinical Development of Oblimersen for Acute Myeloid Leukemia
Clinical Development of Obatoclax for Acute Myeloid Leukemia
Clinical Development of Venetoclax for Acute Myeloid Leukemia
Rationale For Use Of Bh-3 Mimetics In Chronic Lymphocytic Leukemia
Clinical Development Of Venetoclax For Chronic Lymphocytic Leukemia
Mechanisms Of Resistance To Venetoclax In Chronic Lymphocytic Leukemia
Summary
Suggested Readings
References
19
Aging and Hematopoiesis
Aging
Hematopoietic Stem Cell Potential Declines With Aging
Clinical Manifestations
Anemia
Immunosenescence
Myelodysplastic Syndromes
Leukemia
Clonal Hematopoiesis, Clonal Hematopoiesis Of Indeterminate Potential, And Age-Related Clonal Hematopoiesis
Mechanisms Of Hematopoietic Stem Cell Aging
Intrinsic Factors
DNA Damage
Autophagy and Reactive Oxygen Species
Epigenetic Modifications
Chromatin Architecture and Polarity
Extrinsic Factors
Bone Marrow Microenvironment
Senescence
Inflammation
Future Perspectives
References
PART III IMMUNOLOGIC BASIS OF HEMATOLOGY.pdf
20
Dendritic Cell Biology
Dendritic Cell Subsets And Development
Conventional Dendritic Cells
Plasmacytoid Dendritic Cells
Inflammatory Dendritic Cells
Langerhans Cells
New Developments in Dendritic Cell Classification
Dendritic Cell Maturation
Antigen Processing And Presentation
MHC Class I Antigen Presentation (Endogenous Route)
MHC Class II Antigen Presentation (Exogenous Route)
Cross-Presentation
Dendritic Cell-Mediated Immune Responses
T Cells
B Cells
Innate Lymphoid Cells
Other Elements of the Immune System
Dendritic Cells In Disease
Dendritic Cells and Autoimmunity
Dendritic Cells and Immunodeficiency
Dendritic Cells and Pathogens
Dendritic Cells And Cancers
Immunotherapeutic Strategies And Clinical Trials
Future Directions
Suggested Readings
References
21
Natural Killer Cell Immunity AND THERAPY
Natural Killer Cell Fundamental Biology
Natural Killer Cell Subsets
CD56dim Natural Killer Cells
CD56bright Natural Killer Cells
Natural Killer Cell Development
Natural Killer Cell Receptors
Killer-Cell Immunoglobulin-Like Receptors
C-Type Lectin Receptors
Natural Cytotoxicity Receptors
Other Activating Receptors
Adaptive Immune Properties Of Natural Killer Cells
Natural Killer Cell Education
Natural Killer Cell Memory
The Role Of Natural Killer Cells In Human Disease
Natural Killer Deficiency Syndromes Linked to Increased Infectious Risks
The Role of Natural Killer Cells in Autoimmunity
The Therapeutic Potential Of Natural Killer Cells
Natural Killer Cells and Hematopoietic Cell Transplantation
Infusion of Autologous Natural Killer Cells
Infusion of Allogeneic Natural Killer Cells
Expansion of Natural Killer Cells In Vivo via Cytokine Administration
Killer-Cell Immunoglobulin-Like Receptors Blockade
Natural Killer Cell Checkpoint Blockade
Natural Killer Cell Antibody-Dependent Cytotoxicity
Genetic Engineering of Natural Killer Cells
Future Directions
Suggested Readings
References
22
B-Cell Development
Stages of B-Cell Development
Murine B-Cell Development
Human B-Cell Development
B Lineage Specification and Commitment
Transcriptional Regulation of B-Cell Development
MicroRNAs
Immunoglobulin Gene Rearrangement
Heavy Chain Gene Rearrangement
Light Chain Gene Rearrangement
The Immunoglobulin Recombinatorial Machinery
Generation and Selection of the Primary B-Cell Repertoire
The Pro-B- and Pre-B-Cell Checkpoints
The Pro-B- to Pre-B-Cell Transition
The Pre-B to B-Cell Transition
The B-Cell Receptor
The Hematopoietic Microenvironment
Fetal B-Cell Development
B-1 B Cells
Secondary Lymphoid Tissues
Anatomic Organization of Secondary Lymphoid Tissues
Transitional B Cells
Immune Responses in Secondary Lymphoid Tissues
Germinal Centers
Immunoglobulin Class Switching and Affinity Maturation
Effects of Aging on B-Cell Development and Function
References
23
Complement And Immunoglobulin Biology Leading To Clinical Translation​
The Complement System: An Overview
Classical Pathway
Lectin Pathway
Alternative Pathway
C3, C5, and the Membrane Attack Complex
Complement Receptors and Their Role in Immune Complex Clearance and Activation
Biologic Activity of C3a and C5a
Regulation of Complement Activation
Biologic Consequences of Complement Cascade Deficiencies
Biologic Consequences of Complement Regulatory Protein Deficiencies and Function-Affecting Mutations
Autoimmunity and Complement Deficiencies
Natural Antibody
Complement Links Innate and Adaptive Immune Responses
Soluble Complement Mediators of Antibody Responses
Complement Receptors and Antibody Responses
B-Lymphocyte Coreceptors
Focusing Antigen on Follicular Dendritic Cells
Complement and T-Cell Immunity
Complement and Cancer
Complement and Coagulation
Conclusion
Immunoglobulins
Properties and Structure
Therapeutic Use Of Immunoglobulin
Intravenous Immunoglobulin
Adverse Events Related to Intravenous Immunoglobulin Infusion
Early Systemic Events
Infectious Disease Transfer
High-Dose Treatment–Related Adverse Events
Therapeutic Passive Immunization and Monoclonal Antibody Therapy
Drugs Targeting The Complement System
Eculizumab
Ravulizumab
New Anticomplement Drugs: Pegcetacoplan and Beyond
References
Suggested Readings
24
T-Cell Immunity
T-Cell Activation
Antigen Presentation: Creating the Ligand for the T-Cell Receptor
The T-Cell Receptor Complex
T-Cell Receptor Signal Transduction
Co-Stimulation
Spatial Coordination of T-Cell Receptor Signal Transduction: The Immunologic Synapse
T-Cell Proliferation
T-Cell Development
Early T-Cell Development
Positive Selection
CD4 and CD8 Lineage Commitment
Negative Selection
T-Cell Function
Th1 Cells
Th2 Cells
Th17 Cells
Tfh Cells
CD4+ Th Plasticity
CD8+ Cytotoxic T Cells
Maturation Of T-Cell-Mediated Immunity
T-Cell Memory
T-Cell Exhaustion: Impaired Response after Chronic Antigen Exposure
Inhibition Of T Cell-Mediated Immunity
Prevention of Inappropriate Initiation of T-Cell Responses
Anergy
Regulatory T Cells
Limiting T-Cell Responses After Stimulation by Foreign Antigen
Limitation of T-Cell Activity from Cell-Intrinsic Components
Protein Tyrosine Phosphatases
Cytotoxic T Lymphocyte Antigen-4
E3 Ubiquitin Ligases
Diacylglycerol Kinases
Limitation of T-Cell Activity From Cell-Extrinsic Components
Terminating Immune Responses After Pathogen Clearance
Therapeutic Manipulation Of T-Cell-Mediated Immunity
Modulating T Cells to Permit Allograft Transplantation
Manipulating T Cells to Improve Activity Against Malignancy
Suggested Readings
References
25
Unmodified Ex Vivo Expanded T Cells
Adoptive Immunotherapy of Viral Infections with Virus-Specific T Cells
Methods to Generate Virus-Specific T Cells
Rapid Selection
Ex Vivo Expansion
Off-the-Shelf T-Cell Banks
Adoptive Immunotherapy Of Cancer
Adoptive Immunotherapy of Virus-Associated Malignancies
Adoptive Immunotherapy of Virus-Independent Malignancies
Neoantigens
Mismatched Histocompatibility Antigens
Non-Histocompatibility, Germline Antigens
Future Directions
Suggested Readings
References
26
Treatment of Hematologic Malignancies With Genetically Modified T Cells
Types of Cellular Immunotherapy
Adoptive Cell Therapy With T Lymphocytes
Allogeneic Donor Lymphocyte Infusion
Infusion of Activated T Lymphocytes
Genetic Modification of T Cells
Artificial αβT-Cell Receptors
Chimeric Antigen Receptors
Clinical Results of Chimeric Antigen Receptor T Cells in Hematologic Malignancies
CD19
B-Cell Maturation Antigen
CD30
Acute Myeloid Leukemia Targets
T-Cell Antigens
Factors Affecting Response
Toxicities of Chimeric Antigen Receptor T Cells
Allogeneic Banked Cells
Optimizing T-Cell Trafficking and Overcoming Tumor Immune Evasion
T Lymphocytes, Transfer of Safety Genes, and Strategies to Improve Tumor Cell Specificity
Future Applications and Implementation of Cell Therapies for Cancer
ACKNOWLEDGMENT
References
PART IV DISORDERS OF HEMATOPOIETIC CELL DEVELOPMENT.pdf
27
Biology Of Erythropoiesis, Erythroid Differentiation, And Maturation
Erythroid Cell Compartments
Phenotypic and Functional Properties of Erythroid Progenitor Cells
The Morphologically Recognizable Erythroid Precursor Cell Compartment
Plasma Membrane and Cytoskeleton Reorganization
Mitophagy and Ribosome and Mitochondria Clearance
Nuclear Condensation and Enucleation
Intrinsic Control of Erythropoiesis
Extrinsic Control of the Erythropoiesis
Erythropoietin
Hematopoietic Microenvironment
Erythropoiesis and Iron Regulation
Cellular Dynamics in Erythropoiesis: Steady State and Stress Erythropoiesis
Ontogeny of Erythropoiesis
Erythroid Cells from in Vitro Generated Sources
Suggested Readings
References
28
Granulocytopoiesis and Monocytopoiesis
Granulocytopoiesis
Granulocyte Ontogeny
Stages of Neutrophil Differentiation
Markers of Granulocytic Maturation
Neutrophil Granules and Their Content Proteins
Control of Granulopoiesis
Cytokine Regulation of Myeloid Proliferation and Differentiation
Transcriptional Regulation of Myeloid Differentiation
Transcription Factors Regulating Myeloid Differentiation and Myeloid-Specific Gene Expression
Runx1
CCAAT Enhancer-Binding Protein Family of Transcription Factors.
C/EBPα
C/EBPβ
C/EBPβ in Emergency Granulopoiesis
Transcriptional Networks in Emergency Granulopoiesis
C/EBPγ
C/EBPδ
C/EBPε
C/EBPζ
PU.1
Growth Factor Independence-1
CCAAT Displacement Protein
Role of Developmentally Important Neutrophil-Specific Genes In Disease
Severe Congenital Neutropenia and the Unfolded Protein Response
Role of MicroRNAs in Controlling Gene Expression in Granulopoiesis
Eosinophil Production
Basophil and Mast Cell Production
Monocytopoiesis
Monocyte Ontogeny
Stages of Monocyte Differentiation
Markers of Monocyte Maturation
Control of Monocytopoiesis
Cytokine Regulation of Monocyte Proliferation and Differentiation
Transcriptional Regulation of Monocyte Differentiation
c-Jun
Other Transcription Factors Modulating Monocyte Development
Egr-1.
C/EBPβ.
MafB and c-Maf.
Suggested Readings
References
29
Thrombocytopoiesis
Megakaryocyte Biology
Megakaryocytopoiesis
Cellular Hierarchy of Megakaryocyte Development
Relationship Between Megakaryocytes and Hematopoietic Stem Cells
Unique Features Of Megakaryocytes
Endomitosis and Polyploidization
The Endomitotic Cell Cycle
Role of Endomitosis in Thrombocytopoiesis
Mechanisms of Endomitosis in Megakaryocytes
Cyclins and Cyclin-Dependent Kinases
Other Mitotic Kinases
Microtubules and the Mitotic Spindle
The Spindle Checkpoint.
Contractile Ring Activity
Platelet Biogenesis
Megakaryocytopoiesis in Ontogeny
Tissue Distribution and Spatial Cues During Megakaryocytopoiesis
Therapeutic Applications of Ex Vivo Megakaryocytopoiesis
Cytokine Regulation Of Thrombocytopoiesis
Thrombopoietin Signaling
Thrombopoietin
Thrombopoietin Receptor (c-Mpl)
Thrombopoietin Receptor Downstream Signaling Pathways
Negative Regulation of Thrombopoietin Signaling
Regulation of Platelet Mass by Thrombopoietin
Thrombopoietin Signaling in Disease Conditions
Congenital Amegakaryocytic Thrombocytopenia (Chapter 30)
Essential Thrombocythemia (Chapter 71)
Additional Cytokines Involved in Megakaryocytopoiesis
Therapeutic Cytokine Stimulation of Megakaryocytopoiesis
Transcriptional Control Of Megakaryocytopoiesis
GATA Family Transcription Factors
GATA1
Friend of GATA (ZFPM1)
X-Linked Dyserythropoietic Anemia and Thrombocytopenia Caused by GATA1 Mutations
X-Linked Thrombocytopenia and Thalassemia Caused by GATA1 Mutations
X-Linked Gray Platelet–Like Syndrome
GATA1 Mutations in Down Syndrome Transient Myeloproliferative Disorders and Acute Megakaryoblastic Leukemia
E26 Transformation Specific Family Transcription Factors
Fli-1
ETS-Related Gene
ETV6 (TEL)
Other Transcription Factors
RUNX1
NF-E2 p45
SCL (TAL1)
Gfi-1b
HOX-Related Genes
MECOM (MDS1-EVI1)
c-Myb
Hypoxia-Inducible Factor 1-Alpha
Micro Rnas In Megakaryocytopoiesis
Future Directions
Suggested References
References
30
Inherited Bone Marrow Failure Syndromes
Introduction
Inherited Bone Marrow Failure Syndrome With Multi-Lineage Cytopenias
Fanconi Anemia
Background
Epidemiology
Genetics
Pathophysiology
Fanconi Anemia Genes and DNA Damage Repair
Fanconi Anemia Genes, Cell Survival, and Balancing Oxidative Stress
Pathogenesis of Bone Marrow Failure
Mouse Models
Clinical Features
Laboratory Findings
Peripheral Blood and Bone Marrow Findings
Abnormal Chromosome Fragility.
Immunoblotting for FANCD2.
Imaging Studies.
Predisposition to Malignancy
Heterozygote Phenotype
Genotype–Phenotype Correlations
Differential Diagnosis
Natural History and Prognosis
Therapy
Androgens
Hematopoietic Growth Factors
Hematopoietic Stem Cell Transplantation
Genetic Counseling
Future Directions
Shwachman-Diamond Syndrome
Epidemiology
Genetic Basis
Pathobiology
Shwachman-Diamond Syndrome Genes and Bone Marrow Failure
Clinical Features
Laboratory Findings
Peripheral Blood and Bone Marrow Findings.
Immune Dysfunction.
Exocrine Pancreatic Tests.
Imaging Studies.
Cancer Predisposition.
Genotype Phenotype Correlation
Differential Diagnosis
Prognosis
Therapy
G-CSF
Androgens and Other Medications
Blood Products and Other Supportive Care
Hematopoietic Stem Cell Transplantation
Future Directions
Dyskeratosis Congenita
Background
Epidemiology
Genetics
Pathobiology
Clinical Features
Laboratory Findings
Peripheral Blood, Bone Marrow, and Immunologic Findings.
Cancer Predisposition
Differential Diagnosis
Natural History and Prognosis
Therapy
Androgens
G-CSF
Hematopoietic Stem Cell Transplantation
Future Directions
Congenital Amegakaryocytic Thrombocytopenia
Background
Epidemiology
Genetics and Pathobiology
Type 1
Type II
Clinical Features
Laboratory Findings
Predisposition to Leukemia
Differential Diagnosis
Therapy and Prognosis
Future Directions
Other Inherited Syndromes With Associated Pancytopenia
Dubowitz Syndrome
Seckel Syndrome
Reticular Dysgenesis
Schimke Immunoosseous Dysplasia
Cartilage-Hair Hypoplasia
Pearson Syndrome
Unclassified Inherited Forms of Bone Marrow Failure
Treatment of Unclassified Familial Forms of Bone Marrow Failure
Inherited Bone Marrow Failure Syndromes Predominantly with Anemia
Diamond-Blackfan Anemia
Background
Epidemiology
Genetics
Pathophysiology
Clinical Features
Laboratory Findings
Peripheral Blood and Bone Marrow.
Erythrocyte Findings.
Miscellaneous Findings.
Imaging Studies.
Predisposition to Malignancy
Genotype-Phenotype Correlation
Differential Diagnosis
Natural History and Prognosis
Therapy
Transfusions for Patients With Diamond-Blackfan Anemia
Corticosteroids
Cytokine Therapy
Hematopoietic Stem Cell Transplantation
Other Therapeutic Options
Future Directions
Congenital Dyserythropoietic Anemias
Etiology, Genetics, Pathophysiology, and Clinical Features
CDA Type I
CDA Type II (HEMPAS)
CDA Type III
CDA Group IV.
Other CDAs.
Differential Diagnosis
Therapy and Prognosis
Future Directions
Inherited Bone Marrow Failure Syndromes with Predominantly Neutropenia
Severe Congenital Neutropenia
Background
Epidemiology
Genetics
Pathophysiology
Clinical Features
Laboratory Findings
Predisposition to Leukemia and Myelodysplastic Syndrome
Genotype-Phenotype Correlations
Differential Diagnosis
Therapy and Prognosis
Cytokine Therapy
Hematopoietic Stem Cell Transplantation
Bisphosphonates for Osteoporosis
Future Directions
Cyclic Neutropenia
Myelokathexis and WHIM Syndrome
G6PC3-Associated SCN (Dursun Syndrome)
Barth Syndrome
Glycogen Storage Disease Type 1b
Other Inherited Neutropenias
Inherited Bone Marrow Failure Syndromes With Predominantly Thrombocytopenia
Thrombocytopenia With Absent Radii Syndrome
Background
Genetics
Pathophysiology
Clinical Features
Laboratory Findings
Cancer Predisposition
Differential Diagnosis
Therapy and Prognosis
Platelet Transfusions
Other Therapies
Suggested Readings
31
Aplastic Anemia
History
Classification
Epidemiology
Incidence, Geographic and Age Distribution
Epidemiologic Clues to Causality
Genetic Aspects
Etiology And Pathogenesis
Hematopoiesis in Bone Marrow Failure
Stem Cells
Telomeres and Bone Marrow Failure
Stromal and Hematopoietic Growth Factors
Pathophysiologic Pathways Leading To Aplastic Anemia
Direct Hematopoietic Injury
Immune-Mediated Bone Marrow Failure
Radiation
Drugs and Chemicals
Benzene
Aromatic Hydrocarbons
Chloramphenicol
Nonsteroidal Antiinflammatory Drugs
Neuroleptics and Psychotropic Drugs
Typical And Atypical Presentations
Clinical Associations
Posttransfusion and Post Solid Organ Transplant Associated Graft-Versus-Host Disease
Pregnancy
Hepatitis
Postmononucleosis Aplastic Anemia
Hemophagocytic Syndrome
Paroxysmal Nocturnal Hemoglobinuria and Aplastic Anemia
Rheumatologic Diseases
Laboratory Evaluation
Peripheral Blood
Diagnosis Of Aplastic Anemia
Bone Marrow
Differential Diagnosis Of Pancytopenia
Treatment
Supportive Management
Bleeding
Anemia
Infection
Definitive Therapy
Hematopoietic Stem Cell Transplantation
Matched Sibling Donor Hematopoietic Stem Cell Transplantation
Transplant From Alternative Donors
Late Complications of Stem Cell Transplantation
Immunosuppression
Antithymocyte Globulins
Cyclosporine
Combined or Intensive Immunosuppressive Therapy
Cyclophosphamide
Corticosteroids
Late Complications of Immunosuppressive Therapy
Immunosuppression Versus Bone Marrow Transplantation
Hematopoietic Growth Factors
Androgens
Prognosis
Suggested Readings
References
32
Paroxysmal Nocturnal Hemoglobinuria
Introduction and History
Epidemiology And Classification
Clinical Manifestations
Pathophysiology
The Glycosylphosphatidylinositol Anchor
PIGA Gene Mutations
Loss of Glycosylphosphatidylinositol in Blood Cells Due to Mutations in Genes Other Than PIGA
Glycosylphosphatidylinositol Anchored Proteins and Complement-Mediated Hemolysis
Clonal Expansion of Glycosylphosphatidylinositol-Negative Populations in Paroxysmal Nocturnal Hemoglobinuria
Thrombosis
Diagnosis And Differential Diagnosis
Evaluation OF Newly Diagnosed Patients
Treatment
Supportive Care
Prevention and Treatment of Thrombosis
Treatment of Marrow Failure
Anticomplement Therapy
Transplant
Transformation to MDS/AML
Pregnancy
Monitoring/Follow-Up of Patients
Suggested Readings
References
33
Acquired Disorders of Red Cell, White Cell, and Platelet Production
Etiology and Classification
Pathogenesis
Primary Pure Red Cell Aplasia
Secondary Forms of Pure Red Cell Aplasia
Clinical Associations
B-Cell Chronic Lymphocytic Leukemia–Associated Pure Red Cell Aplasia
T-Cell Large Granular Lymphocyte–Associated Pure Red Cell Aplasia
Thymoma-Associated Pure Red Cell Aplasia
Pregnancy-Associated Pure Red Cell Aplasia
Parvovirus B19 and Other Viral-Induced Pure Red Cell Aplasias
Connective Tissue Disease–Associated Pure Red Cell Aplasia
Drug-Induced Pure Red Cell Aplasia
Erythropoietin Antibody–Associated Pure Red Cell Aplasia
Pure Red Cell Aplasia Following Allogeneic Stem Cell Transplantation
Pure Red Cell Aplasia Associated With Immune Dysregulation, Polyendocrinopathy, Enteropathy, X-Linked Syndrome
Laboratory Evaluation
Differential Diagnosis
Therapy
Surgery or Radiation
Medical
Supportive
Immunosuppression
Hematopoietic Stem Cell Transplantation
Prognosis
Acquired White Blood Cell Production Disorders
Classification of Acquired Neutropenias
Primary Neutropenia
Chronic Idiopathic Neutropenia in Adults
Chronic Benign Neutropenia of Infancy and Childhood
Secondary Forms of Neutropenias
Clinical Associations
Drug-Induced Neutropenia/Agranulocytosis
Neutropenia as a Manifestation of Systemic Diseases
Postinfectious Neutropenia
Neutropenia Association With Nutritional Deficiency and Nutritional Excess
Neutropenia Associated With Metabolic Disorders
Acquired Neonatal Neutropenias
Neutropenia and Hypersplenism
Pure White Cell Aplasia
Neutropenia Associated With Immunologic Abnormalities
Laboratory Evaluation
Differential Diagnosis
Therapy
Large Granular Lymphocyte Leukemia
Pathogenesis
Inciting Events
Clonal Transformation
Extreme Clonal Expansion and the Nonrandom Nature of the T-Cell Large Granular Lymphocyte
Genetic Alterations in Large Granular Lymphocyte
Clinical Presentation and Physical Features
Clinical Overlap and Associations
Laboratory Diagnosis
Differential Diagnosis
Therapy
Prognosis
Acquired Platelet Production Disorder
Selective Megakaryocyte Aplasia
Infection
Chemotherapy and Irradiation
Nutritional Deficiencies
Marrow Infiltration
Ethanol-Related Disorders
Other Drug-Related Disorders
Paroxysmal Nocturnal Hemoglobinuria
Refractory Thrombocytopenia Caused by Myelodysplasia
Suggested Readings
References
PART V RED BLOOD CELLS.pdf
34
Pathobiology of the Human Erythrocyte and Its Hemoglobins
Essential Features of Red Blood Cell Homeostasis
Major Features of the Red Blood Cell Membrane
Enzymes of Red Blood Cell Intermediary Metabolism
Red Blood Cell Senescence and Destruction
Hemoglobin Synthesis, Structure, and Function
Basic Features
Hemoglobin Structure
Hemoglobin Function
Globin Gene Clusters
Ontogeny of Hemoglobin
Hemoglobin Biosynthesis and Its Regulation
Transcriptional Regulation of Globin Gene Expression
Posttranscriptional, Translational, and Posttranslational Mechanisms
Nosology of Hemoglobinopathies
Suggested Readings
35
Approach to Anemia in the Adult and Child
Overview of Erythropoiesis
Definition, PhysioloGic Consequences and Symptoms of Anemia
Mechanisms of Anemia
Blood Loss Anemia
Hypoproliferative Anemia
Hemolytic Anemia
Comparison of Etiologies of Anemia in Adults and Children
Anemia in Children
Anemia in Adults
Systemic Approach to Anemia
History and Physical Examination
Reticulocyte Count
Mean Corpuscular Volume and Red Blood Cell Distribution Width From the Complete Blood Count
Examination of the Peripheral Blood Smear
Bone Marrow Examination
Future Directions
References
36
Iron Homeostasis and Its Disorders
Regulation of Cellular and Systemic Iron Homeostasis
Use of Iron for Erythropoiesis
Recycling of Erythrocyte Iron by Macrophages
Liver Regulation of Systemic Iron Homeostasis and Iron Storage
Iron Regulation of Hepcidin Expression
Erythropoietic Regulation of Hepcidin Expression
Inflammatory and Endoplasmic Reticulum Stress-Related Regulation of Hepcidin Expression
Intestinal Iron Absorption
Future Directions
References
37
Disorders of Iron Homeostasis: Iron Deficiency and Overload
Iron Deficiency
Introduction
Epidemiology
Etiology
Pathobiology
Clinical Manifestations
Laboratory Manifestations
Differential Diagnosis
Prognosis
Therapy
Oral Iron Therapy
Intravenous Iron Therapy
Prevention Strategies
Future Directions
Iron Overload
Introduction
Epidemiology
Genetic Aspects
Pathobiology of Hemochromatosis
Pathobiology of Acquired Iron Overload
Clinical Manifestations
Laboratory Manifestations
Differential Diagnosis
Prognosis
Therapy
Future Directions
Iron Challenge to Test Iron Absorption
Intravenous Iron Treatment: How to Calculate the Correct Dose
How to Manage Hypersensitivity Reactions to Intravenous Iron
Acute Mild Reactions
Acute Moderate Reactions
Acute Severe Reactions
Delayed Reactions
Re-challenge
Examples
References
Cases From Real Life
Case 1
History
Making the Diagnosis
Treatment
Patient Follow-Up
Conclusion
Case 2
History
Making the Diagnosis
Treatment
Patient Monitoring During Phlebotomy Treatment
Patient Follow-Up
Conclusion
References
38
Anemia of Chronic Inflammation
Clinical Overview of Anemia of Chronic Inflammation
Etiology and Pathophysiology of Anemia of Chronic Inflammation
Cytokine-Induced Decreases in Red Blood Cell Life Span
Cytokines Leading to Direct and Indirect Inhibition of Erythropoiesis
Cytokines Leading to Decreased Erythropoietin Secretion
Cytokine-Induced Changes in Iron Metabolism
Pathophysiology of Iron Sequestration
The Rationale and Methodology for Hepcidin-Lowering Agents
Via the Inflammatory Signal
Via the Iron Signal
Via Erythropoietic Signal
Direct Hepcidin Inhibition
Conclusion
References
39
Heme Biosynthesis and Its Disorders: Porphyrias and Sideroblastic Anemias
Heme Biosynthesis
Biosynthetic Pathways
Control of Heme Biosynthesis
Porphyrias
Biologic and Molecular Aspects
Genetic Aspects
Acute Intermittent Porphyria
Clinical and Laboratory Manifestations
Other Acute Porphyrias
Hereditary Coproporphyria
Variegate Porphyria
5-Aminolevulinate Dehydratase Deficiency Porphyria
Concurrent Porphyrias
Nonacute or Cutaneous Porphyrias
Porphyria Cutanea Tarda
Biologic and Molecular Aspects
Genetics
Clinical Features
Precipitating Factors
Differential Diagnosis
Erythropoietic Protoporphyria and X-Linked Protoporphyria
Biologic and Molecular Aspects
Genetics
Clinical Features
Differential Diagnosis
Congenital Erythropoietic Porphyria (Günther Disease)
Biologic and Molecular Aspects
Clinical Features
Differential Diagnosis
Sideroblastic Anemias
Hereditary Sideroblastic Anemia
X-Linked Sideroblastic Anemia
Biologic and Molecular Aspects
Genetic Aspects
Clinical and Laboratory Evaluation.
Differential Diagnosis
Other Nonsyndromic and Syndromic Hereditary Sideroblastic Anemias
Acquired Sideroblastic Anemia
Biologic and Molecular Aspects
Etiology
Differential Diagnosis
Prognosis
Sideroblastic Anemia and Porphyrinuria Caused By Drugs
Alcohol
Isoniazid
Chloramphenicol
Other Drugs
Presentations Associated with Sideroblastic Anemia or Porphyrinuria
Copper Deficiency or Zinc Overload
Iron Deficiency Anemia
Hypothermia
Other Conditions
Environmental Intolerances
References
Suggested Readings
40
Megaloblastic Anemias
Cobalamin
Nutrition
Absorption
Transport
Cellular Processing
Folates
Nutrition
Absorption
Plasma Transport and Enterohepatic Circulation
Cellular Folate Uptake
Folate Receptors
Folate Receptor Regulation and Cellular Folate Homeostasis
Folate Receptors and Placental Folate Transport
Folate Receptors in Embryonic and Fetal Development
Folate Receptors and Proton-Coupled Folate Transporter in Cerebral Folate Transport Across the Choroid Plexus
Renal Retention of Folates (and Cobalamin)
Intracellular One-Carbon Metabolism And Cobalamin–Folate Relationships
Cellular Folate Retention and One-Carbon Metabolism
Compartmentalization and Channeling of Folate Metabolism
Methylation
Consequences of Perturbed One-Carbon Metabolism
Methyl-Folate Trapping
Thymidylate Deficiency and Perturbed DNA Synthesis
Chromosome and Cell Cycle Defects
Morphologic Expression Of Megaloblastosis
Neurologic Dysfunction With Cobalamin Deficiency
Other Effects Of Cobalamin And Folate Deficiency
Spectrum Of Clinical Presentations With Cobalamin Deficiency
Biochemical Indicators Of Evolving Deficiency
Biochemical Evaluation Of Cobalamin And Folate Deficiencies
Total Serum Homocysteine and Methylmalonic Acid Levels
Serum Cobalamin Levels
Serum Folate Levels
Other Tests
Pathogenesis Of Cobalamin Deficiency
Nutritional Cobalamin Deficiency
Intragastric Events Leading to Cobalamin Malabsorption
Inadequate Dissociation of Cobalamin From Food Protein
Congenital Intrinsic Factor Deficiency163
Loss or Atrophy of Gastric Oxyntic Mucosa
Absent Intrinsic Factor Secretion and Pernicious Anemia
Abnormal Events in the Small Bowel Lumen
Insufficient Pancreatic Protease
Inactivation of Pancreatic Protease
Usurpation of Luminal Cobalamin
Disorders of Ileal Intrinsic Factor–Cobalamin Receptors or Mucosa
Absence of Intrinsic Factor–Cobalamin Receptors
Defective Intrinsic Factor–Cobalamin Receptors or Post-Intrinsic Factor–Cobalamin Receptor Defects
Drug-Induced Defects
Disorders of Plasma Cobalamin Transport
Disorders of Intracellular Cobalamin Use
Congenital Metabolic Defects of Cobalamin Metabolism: Cobalamin Mutants A to J
Functional Cobalamin Deficiency After Nitrous Oxide Exposure
Pathogenesis Of Folate Deficiency
Nutritional Causes of Folate Deficiency
Pregnancy and Infancy
Folates and Neurodevelopment
Folates and Intrinsic Hematologic Disease
Folate Malabsorption With Normal Intestinal Mucosa
Hereditary Folate Malabsorption
Folate Malabsorption With Intestinal Mucosal Abnormalities
Tropical Sprue
Nontropical Sprue
Regional Enteritis and Other Small Intestinal Disorders
Cerebral Folate Deficiency
Polymorphisms and Inborn Errors of Folate Metabolism
Megaloblastic Anemia Not Caused By Folate Or Cobalamin Deficiency
Therapy
Response to Replenishment
Follow-Up
Routine Supplementation Of Cobalamin And Folate
Homocysteine-Lowering Trials and Primary Versus Secondary Prevention
Future Directions
Suggested Readings
References
41
Thalassemia Syndromes​
Definitions And Nomenclature
Epidemiology
Pathophysiology: General Principles
BETA-Thalassemia Syndromes
Nomenclature
Molecular Pathology
Processing
Translation
Other Sites
Relationship Between Specific Mutations and Clinical Severity
Pathophysiology
Clinical Manifestations
Beta-Thalassemia Major
Beta-Thalassemia Intermedia
Beta-Thalassemia Minor
Laboratory Findings
Homozygous β0 Thalassemia
Homozygous or Compound Heterozygous β+ Thalassemia
Heterozygous β-Thalassemia
β-Thalassemia With Normal A2 Level
Dominant β-Thalassemia
Other Laboratory Findings
Treatment
Transfusion Therapy
Iron Toxicity
Assessment of Iron Stores
Chelation Therapy
Benefits of Iron Chelation Therapy
Deferoxamine
Deferasirox
Deferiprone
Combination Chelation Therapy
Complications of Thalassemia and Their Management
Complications Related to Ineffective Erythropoiesis
Skeletal Changes
Endocrinopathies
Liver and Gallbladder
Heart
Lungs
Kidneys
Spleen and Splenectomy
Survival in Patients With Thalassemia Major
Chronic Care of the Adult Patient With Thalassemia
Hematopoietic Stem Cell Transplantation
Novel Therapeutic Approaches
ALPHA-Thalassemia Syndromes
Genetics
Molecular Pathology and Pathophysiology
Clinical Manifestations and Diagnosis
Silent Carrier (α+-Thalassemia Trait)
α0-Thalassemia Trait (α-Thalassemia Trait)
Hemoglobin H Disease
Hydrops Fetalis With Hb Bart
Therapy
Novel Therapies
De Novo and Acquired Forms of α-Thalassemia
α-Thalassemia Associated With Mental Retardation
Acquired HbH Disease Associated With Myelodysplastic Syndrome (ATMDS)
Thalassemic Structural Variants
Hemoglobin Lepore
Hemoglobin E
Hemoglobin Constant Spring
Extraordinarily Unstable Hemoglobins
References
Suggested Readings
42
Pathobiology of Sickle Cell Disease​
Early Years of Sickle Cell Disease Research
Genetic Considerations
Molecular Context
Origin, Selection, and Dispersion of the Sickle Gene
Abnormal Molecular Behaviors of Sickle Hemoglobin
Hemoglobin S Charge and Tetramer Assembly
Hemoglobin S Stability and Oxidant Formation
Hemoglobin S and Polymerization
Polymer Structure
HbS Solubility
Equilibrium and Polymerization
Kinetics and Polymerization
Polymerization Under Physiologic Conditions
HbF and Its Protective Effect
Alternative Ligands: CO and NO
Abnormalities of Sickle Red Blood Cells
Membrane Iron and Oxidant Generation
Cation Homeostasis and Dehydrated Cells
Deformability, Fragility, and Vesiculation
Membrane Proteins and Lipids
Irreversibly Sickled Cells
Endothelial Adhesivity
Macrophage Interaction
Disease Pathogenesis
Vascular Occlusion
RBC Deformability
Adhesive RBC
Adhesive WBC
Hemolytic Anemia
The Unique Systems Biology of Sickle Cell Anemia
Ischemia-Reperfusion Physiology
Hemolysis
Concept of Hyperhemolysis
Inflammation
Endothelial Activation and Dysfunction
Aberrant Vasoregulation
Coagulation Activation
Genesis of Clinical Disease
Pain Syndromes
Chronic Vasculopathy
Thrombosis
Stroke and Cerebrovascular Disease
Pulmonary Disease
Kidney Disease
Mortality and Sudden Death
Basis of Phenotypic Diversity
Level of Hemoglobin F
α-Thalassemia
β-Globin Alleles
Unexplained Phenotypic Diversity
References
43
Clinical Aspects of Sickle​ Cell Disease​
Genetic Epidemiology of the Sickle Gene
Variant Sickle Cell Syndromes
Prevalence
Clinical Laboratory Features and Diagnosis
Solubility Tests and Hemoglobin Electrophoresis
Newborn Screening
Clinical Presentation and Management
Natural History and Life Expectancy
Predictors of Disease Severity
Principles of Clinical Management
Baseline Evaluations
Basic Management and Disease Modification
Nutritional Supplementation
Vaccination and Penicillin Prophylaxis
Hydroxyurea and Fetal Hemoglobin Reactivation
Alternatives to Hydroxyurea for Fetal Hemoglobin Induction
Voxelotor
Crizanlizumab
L-Glutamine
Stem Cell Transplantation
Transfusion Therapy
Phlebotomy
Erythropoietin or Darbepoetin
Iron Chelation
Anticoagulation or Antiplatelet Therapy
Experimental Therapies
Specific Complications and Their Management
Pain Crisis
Acute Pain Episode or Crisis
Chronic Pain
Chronic Anemia
Exacerbations of Anemia
Aplastic Crises
Sequestration Crisis (Spleen or Liver)
Delayed Hemolytic Transfusion Reaction and Autoimmune Hemolytic Anemia
Hyperhemolytic Crisis
Hypothyroidism
Infections
Immune Deficit
Evaluation
Streptococcus pneumoniae, Haemophilus influenzae, Atypical Mycobacteria, and Acute Febrile Illness
Meningitis
Salmonella and Osteomyelitis
Parvovirus B19
Urinary Tract Infections
Neurologic Complications
Cerebrovascular Accidents, Pathophysiology, Incidence, Risk Factors, and Presentation250
Primary Prevention of Cerebrovascular Accidents
Evaluation and Management of Acute Cerebrovascular Accidents
Secondary Prevention of Cerebrovascular Accidents
Seizures
Pulmonary Complications
Pneumonia
Acute Chest Syndrome
Pulmonary Hypertension
Other Pulmonary Complications
Hepatobiliary Complications
Cholelithiasis and Cholecystitis
Acute Hepatic Cell Crisis
Acute Hepatic Sequestration Crisis
Intrahepatic Cholestasis
Hepatitis C Infection
Obstetric and Gynecologic Issues
Pregnancy
Prenatal Diagnosis
Reproductive Health
Renal Complications
Renal Endocrine (Erythropoietin) Deficiency
Gross Hematuria
Papillary Necrosis
Proteinuria
Hyposthenuria and Other Abnormalities of Tubular Function
Enuresis
Urinary Tract Infections
Renal Medullary Carcinoma
Priapism
Ocular Complications342
Bone Complications
Dermatologic Complications
Cardiac Complications
Multiorgan Failure
Psychosocial Issues
Growth and Development
Sickle Cell Trait
HbSC Disease
Sickle Cell–β-Thalassemia
Sickle Cell–Hemoglobin Lepore Disease
Sickle Cell–Hemoglobin D Disease384
Sickle Cell–Hemoglobin O Arab Disease385
Sickle Cell–Hemoglobin E Disease1
Coinherited Hemoglobin Abnormalities That Interact With Sickle Cell Disease: Hereditary Persistence of Fetal Hemoglobin and ...
Sickle Cell–Hereditary Persistence of Fetal Hemoglobin
Sickle Cell Anemia with Coexistent α-Thalassemia
Suggested Readings
References
44
Hemoglobin Variants Associated With Hemolytic Anemia, Altered Oxygen Affinity, and Methemoglobinemias
Unstable Hemoglobins
Pathophysiology of Unstable Hemoglobin Disorders
Patterns of Inheritance and Clinical Manifestations
Diagnosis
Management
Hemoglobins With Increased Oxygen Affinity
Pathogenesis and Pathophysiology
Diagnosis
Management
Hemoglobins with Decreased Oxygen Affinity
Pathogenesis
Diagnosis
Management
Methemoglobinemias
Pathogenesis and Clinical Manifestations
Diagnosis
Management
Hemoglobin Variants That Modify the Clinical Phenotypes of Thalassemia and Sickle Cell Anemia
Suggested Readings
45
Red Blood Cell Enzymopathies
Metabolic Pathways
Enzymopathies Associated with Hemolytic Anemia
Glucose-6-Phosphate Dehydrogenase Deficiency
Introduction
Epidemiology
Pathobiology
Clinical Manifestations
Acute Hemolysis
Favism
Chronic Hemolysis
Neonatal Jaundice
Non-Erythroid Effect of Glucose-6-Phosphate Dehydrogenase Deficiency
Laboratory Manifestations
Diagnosis
Prognosis
Therapy
Future Directions
Pyruvate Kinase Deficiency
Introduction
Genetics
Epidemiology
Pathobiology
Tolerance of Anemia
Clinical and Laboratory Manifestations
Hemolysis and Anemia
Iron Overload
Diagnosis
Biochemical Testing
Genetic Testing
Therapy
Prognosis
Future Directions
Glucose Phosphate Isomerase Deficiency
Introduction
Pathobiology
Clinical and Laboratory Features
Therapy
Pyrimidine 5′ Nucleotidase-1 Deficiency
Introduction
Pathobiology
Clinical and Laboratory Features
Therapy
Other Enzymopathies of the Glutathione Pathway
γ-Glutamylcysteine Synthase Deficiency
Glutathione Synthetase Deficiency
Glutathione Reductase Deficiency
Glutathione Peroxidase Deficiency
Other Enzymopathies of the Glycolytic Pathway
Hexokinase Deficiency
Phosphofructokinase Deficiency
Aldolase Deficiency
Phosphoglycerokinase Deficiency
Triosephosphate Isomerase Deficiency
Other Enzymopathies
Transaldolase Deficiency
Adenosine Deaminase Hyperactivity
Enzymopathies Associated with Erythrocytosis
Bisphosphoglycerate Mutase Deficiency
Cytochrome b5 Reductase Deficiency
Prolyl Hydroxylase 2 Deficiency
Enzymopathies Associated with Methemoglobinemia
Introduction
Epidemiology
Pathobiology
Acute Methemoglobinemia
b5 Reductase Deficiency
Clinical Manifestations
Acute Methemoglobinemia
Chronic Methemoglobinemia
Laboratory Manifestations
Differential Diagnosis
Prognosis
Therapy
Suggested Readings
46
Red Blood Cell Membrane Disorders
Vertical and Horizontal Interactions of Membrane Proteins and Disorders of Red Blood Cell Shape
Acanthocytosis, Stomatocytosis, and the Bilayer Couple Hypothesis
Hereditary Spherocytosis
Introduction and Epidemiology
Pathobiology
Molecular Pathology
Isolated Spectrin Deficiency
Combined Deficiency of Spectrin and Ankyrin
Deficiency of Band 3 Protein
Deficiency of Protein 4.2
Molecular Basis of Surface Area Deficiency
Alterations in Cation Content and Permeability
Entrapment of Nondeformable Spherocytes in the Spleen
Splenic Conditioning and Destruction
Inheritance
Clinical Manifestations
Typical Forms
Mild Forms and Carrier State
Severe and Atypical Forms
Hereditary Spherocytosis and Nonerythroid Manifestations
Laboratory Manifestations
Blood Film
Osmotic Fragility and Eosin-5′-Maleimide Binding
Autohemolysis and Other Tests
Detection of the Underlying Molecular Defect
Complications
Gallstones
Crises
Other Complications
Differential Diagnosis
Therapy and Prognosis
Splenectomy
Indications for Splenectomy
Operative Considerations
Subtotal (Partial) Splenectomy
Postsplenectomy Failures
Genetic Counseling
Future Directions
Hereditary Elliptocytosis and Related Disorders
Introduction and Epidemiology
Pathobiology of Common Hereditary Elliptocytosis
Spectrin Mutations
Protein 4.1R Mutations
Glycophorin C Deficiency
Membrane Effects
Inheritance
Clinical Manifestations
Mild Hereditary Elliptocytosis and Asymptomatic Carrier State
Hereditary Elliptocytosis With Sporadic Hemolysis
Hereditary Elliptocytosis With Neonatal Poikilocytosis
Hereditary Elliptocytosis With Chronic Hemolysis
Homozygous and Compound Heterozygous Hereditary Elliptocytosis
Hereditary Pyropoikilocytosis
Molecular Determinants of Clinical Severity
Laboratory Manifestations
Blood Film and Laboratory Evidence of Hemolysis
Osmotic and Thermal Fragility
Electrophoretic Separation of Solubilized Membrane Proteins
Nondenaturing Gel Electrophoresis of Low-Ionic-Strength Spectrin Extract
Tryptic Peptide Mapping of Spectrin and the Detection of the Underlying DNA Defect
Differential Diagnosis
Therapy and Prognosis
Spherocytic Elliptocytosis
Southeast Asian Ovalocytosis
Laboratory Manifestations
Molecular Basis of Southeast Asian Ovalocytosis Membrane Rigidity and Malaria Resistance
Acanthocytosis and Related Disorders
Spur Cell Hemolytic Anemia of Severe Liver Disease
Pathobiology
Clinical Manifestations
Abetalipoproteinemia
Pathobiology
Clinical Manifestations
Neuroacanthocytosis Syndromes
McLeod Phenotype
Acanthocytosis in Other Conditions
Differentiation of Acanthocytes From Other Spiculated Red Blood Cells
Echinocytes (Burr Cells)
Keratocytes, Bizarre Poikilocytes, and Schistocytes
Red Blood Cell Membrane Disorders Manifested by Target Cell Formation
Liver Disease
Lecithin-Cholesterol Acyltransferase Deficiency
Stomatocytosis and Related Disorders
Hereditary Stomatocytosis-Hydrocytosis
Hereditary Xerocytosis and the Intermediate Syndromes
Rh Deficiency Syndrome
Familial Deficiency of High-Density Lipoproteins
Sitosterolemia
Acquired Stomatocytosis
Red Cell Membrane Variants and Infectious Disease
Malaria and the Erythrocyte Membrane
Erythrocyte Preference
Attachment and Invasion
Duffy Antigen
Glycophorins
Protein 4.1R and Spectrin
Band 3 and Southeast Asian Ovalocytosis
Knops Blood Group System
Suggested Readings
47
Autoimmune Hemolytic Anemia
History
Epidemiology
Pathobiology
Warm Antibody Hemolytic Anemia
Cold Antibody Hemolytic Anemia
Mixed Warm and Cold Autoimmune Hemolytic Anemia
Atypical Autoimmune Hemolytic Anemia
Etiology and Pathophysiology
Symptoms, Clinical Findings, and Risks
Laboratory Diagnosis of Autoimmune Hemolytic Anemia
Diagnostic Steps
Step 1: Hemolytic anemia?
Step 2: Autoimmune Hemolytic Anemia?
Falsely Negative and Positive Direct Antiglobulin Test Results Without Hemolysis or Anemia
Step 3: Warm or Cold Autoimmune Hemolytic Anemia?
Step 4: Primary or Secondary Autoimmune Hemolytic Anemia?
Immunologic Phenomena Associated with Autoimmune Hemolytic Anemia
Temporal Relationship of Secondary Autoimmune Hemolytic Anemia to the Underlying Condition
Serologic Type of Autoimmune Hemolytic Anemia in Secondary Autoimmune Hemolytic Anemia
Autoimmune Hemolytic Anemia in Immune Diseases
Autoimmune Hemolytic Anemia in Systemic Lupus Erythematosus and Primary Antiphospholipid Syndrome
Autoimmune Hemolytic Anemia in Inflammatory Bowel Disease
Autoimmune Hemolytic Anemia in Other Immune Diseases
Autoimmune Hemolytic Anemia in Transplanted Patients
Autoimmune Hemolytic Anemia in Pregnancy and After Blood Transfusion
Autoimmune Hemolytic Anemia in Malignancies
Autoimmune Hemolytic Anemia in Lymphoproliferative Disorders
Autoimmune Hemolytic Anemia as a Risk Factor for Lymphoproliferative Disorder
Autoimmune Hemolytic Anemia in Chronic Lymphocytic Leukemia
Autoimmune Hemolytic Anemia in Monoclonal Gammopathy With Unknown Significance and Lymphoplasmacytic Lymphoma
Autoimmune Hemolytic Anemia in Other Lymphoproliferative Diseases and Myeloma
Autoimmune Hemolytic Anemia in Myeloid Disorders
Autoimmune Hemolytic Anemia in Solid Tumors
Infection-Related Autoimmune Hemolytic Anemia
Drug-Induced Autoimmune Hemolytic Anemia
Autoimmune Hemolytic Anemia in Immune Deficiency States
Differential Diagnosis
Treatment
Goals of Treatment
Blood Transfusions
Treatment of Primary Warm Antibody Hemolytic Anemia
First-Line Treatment With Steroids
Second-Line Treatment
Rituximab
Third-Line Treatment
Azathioprine
Cyclosporine
Mycophenolate mofetil
Splenectomy
Treatment Options Beyond Third Line.
Novel agents in clinical studies.
Treatment of Secondary Warm Autoimmune Hemolytic Anemia
Warm Autoimmune Hemolytic Anemia Associated With Systemic Lupus Erythematosus
Warm Autoimmune Hemolytic Anemia Associated With Chronic Lymphocytic Leukemia
Warm Autoimmune Hemolytic Anemia in Other Non-Hodgkin Lymphomas
Drug-Related Warm Autoimmune Hemolytic Anemia
Treatment of Warm Autoimmune Hemolytic Anemia in Congenital and Acquired Immune Deficiency States and Special Serologic Typ ...
Treatment of Cold Autoimmune Hemolytic Anemia
Primary Chronic Cold Agglutinin Disease
First-Line Therapy
Second-Line Therapy
Emergency Situations and Further Treatment Lines
Secondary Cold Agglutinin Syndrome
Future Directions
Acknowledgments
Suggested Readings
References
48
Extrinsic Nonimmune Hemolytic Anemias
Fragmentation Hemolysis: Microangiopathy
Clinical Manifestations
Pathophysiology
Differential Diagnosis
Therapy
Other Forms of Mechanical Damage to Red Blood Cells
Heat Denaturation
Mechanical Trauma
Cardiopulmonary Bypass
Osmotic Attack
Hypersplenism
Infection
Parasite Infections
Alteration of the Red Blood Cell Surface by Bacterial Products
Bacterial Products Causing Hemolysis by Direct Damage to Red Blood Cells
Hemolysis Caused by Less Well Understood Infections
Hemolysis Associated With Liver Disease
Hemolysis in Renal Disease
Venoms, Bites, Stings, and Toxins
Insect, Spider, and Snake Bites
Drugs and Chemicals Exclusive of Those Producing Oxidative Hemolysis
Potassium Chlorate
Copper
Lead
Ribavirin
Drug-Induced Oxidative Hemolysis
General Concepts
Pathophysiology
Miscellaneous, Poorly Characterized Causes of Extrinsic Hemolytic Anemias
Interferon-α as a Cause of Hemolytic Anemia
Hemolysis With Intravenous Immunoglobulin G
ACKNOWLEDGMENT
References
PART VI NON-MALIGNANT LEUKOCYTES.pdf
49
Neutrophilic Leukocytosis, Neutropenia, Monocytosis, and Monocytopenia
Neutrophilic Leukocytosis (Neutrophilia)
Leukemoid Reaction Versus Chronic Leukemia
Infection
Inflammation and Stress
Hereditary and Congenital Neutrophilias
Smoking
Drugs
Malignancy
Asplenia
Obesity
Alcoholic Liver Disease
Neutropenia (and Agranulocytosis)
Severe Congenital Neutropenias
Warts, Hypogammaglobulinemia, Infections, and Myelokathexis Syndrome
Lower Neutrophil Count With Fy(a-b-) Status (Previously Known as Benign Ethnic Neutropenia)
Autoimmune Neutropenia (Primary and Secondary)
Large Granular Lymphocyte Leukemia
Neutropenia With Infectious Diseases
Hypersplenism
Chemotherapy-Induced Neutropenia
Drug-Induced Neutropenia
Monocytosis
Infectious Diseases
Connective Tissue Disorder
Hematopoietic Malignancies
Monocytopenia
Hairy Cell Leukemia
GATA2 Deficiency
References
50
Lymphocytosis, L­ym­ph­oc­yt­op­enia, H­yp­er­ga­mm­ag­lo­bu­linemia, and H­yp­ogammaglobulinemia
Quantitative Disorders of Lymphocytes
Lymphocytosis
Clonal Disorders
Infectious Causes
Physiologic Stress
Drug Reactions
Polyclonal B-Cell Lymphocytosis
Lymphocytopenia
Inherited Disorders
Infections
Collagen Vascular Disorders
Malignancies
Systemic Disorders
Drug Effects
Quantitative Disorders of Immunoglobulins
Hypogammaglobulinemia
Secondary Causes
Primary Immunodeficiencies
Hypergammaglobulinemia
Disorders Producing Polyclonal Gammopathy
Disorders Producing Monoclonal Gammopathy
References
51
Disorders of Phagocyte Function
Approach to Diagnosis of Phagocyte Function Disorders
Disorders of the Respiratory Burst Pathway
Chronic Granulomatous Disease
Molecular Genetics of Chronic Granulomatous Disease
Clinical Manifestations
Diagnosis
Prognosis and Treatment
Neutrophil Glucose-6-Phosphate Dehydrogenase Deficiency
Disorders of Glutathione Metabolism
Myeloperoxidase Deficiency
Disorders of Phagocyte Adhesion and Chemotaxis
Leukocyte Adhesion Deficiency Type I
Molecular Genetics of Leukocyte Adhesion Deficiency Type I
Clinical Features
Diagnosis
Prognosis and Treatment
Leukocyte Adhesion Deficiency Types II and III
Hyperimmunoglobulin E Syndrome
Clinical Manifestations
Diagnosis
Therapy
Miscellaneous Chemotactic Disorders
Defects in the Structure and Function of Lysosomal Granules
Chédiak-Higashi Syndrome
Molecular Genetics
Clinical Manifestations
Diagnosis
Therapy
Specific Granule Deficiency
Miscellaneous Inherited and Acquired Disorders of Phagocyte Function
References
52
Congenital Disorders of Lymphocyte Function
Defects of Thymus Organogenesis
DiGeorge Syndrome
FOXN1 Deficiency
CHARGE Syndrome
PAX1 Deficiency
Severe Combined Immune Deficiency Due To Early Defects In T-Lymphocyte Development
Pathobiology and Genetics
Cytokine Receptor Signaling Defects
Defects in Lymphocyte Survival
Defects of Expression and Signaling Through the Pre–T-Cell Receptor and the T-Cell Receptor
Clinical and Laboratory Manifestations
Diagnosis by Universal Newborn Screening
Prognosis, Therapy, and Future Directions
Supportive Management
General Principles of Stem Cell Transplantation for Severe Combined Immune Deficiency
Survival and Long-Term Outcomes After Stem Cell Transplantation for Severe Combined Immune Deficiency
Gene Therapy for Severe Combined Immune Deficiency
Other Combined Immunodeficiencies
Defects of T-Cell Receptor Signaling
Coronin-1A Deficiency
Human Leukocyte Antigen Class II Deficiency
Human Leukocyte Antigen Class I Deficiency
CD40 Ligand and CD40 Deficiencies
Defects of Nuclear Factor κB Signaling
FCHO1 Deficiency and Transferrin Receptor Deficiency
Moesin Deficiency
Dedicator of Cytokinesis 2 Deficiency
Dedicator of Cytokinesis 8 Deficiency
Activated RAC2 Defect
Wiskott-Aldrich Syndrome
Combined Immunodeficiencies With Osseous Dysplasia
Other Combined Immunodeficiencies
Disorders With T-Cell-Mediated Immune Dysregulation
Autoimmune Polyendocrinopathy Candidiasis Ectodermal Dystrophy Syndrome
Immune Dysregulation Polyendocrinopathy Enteropathy X-Linked Syndrome
CD25 and STAT5B Deficiencies
Cytotoxic T Lymphocyte Antigen 4 Deficiency
Lipopolysaccharide Responsive Beige-Like Anchor Protein Deficiency
DEF6 deficiency
Defects of Calcium Flux
Autoimmune Lymphoproliferative Syndrome
Other Conditions With Immune Dysregulation
Defects Of Cell-Mediated Cytotoxicity
Hemophagocytic Lymphohistiocytosis
Human Leukocyte Antigen Associated With Pigmentary Dilution Disorders
X-Linked Lymphoproliferative Disease
Defects Of B-Cell Development And Function
X-Linked Agammaglobulinemia
Autosomal Recessive Agammaglobulinemia
Common Variable Immunodeficiency
B-Cell–Intrinsic Defects Of Class-Switch Recombination
Other Immunoglobulin Defects
Suggested Readings
References
Chapter
53
Pediatric and Adult Histiocytic Disorders
Langerhans Cell Histiocytosis
Epidemiology
Pathophysiology
Clinical Presentations
Bony Involvement
Cutaneous Involvement
Involvement of Other Organ Systems
Other Clinical Features
Laboratory Manifestations
Differential Diagnosis
Prognosis
Therapy
Surgery and Radiotherapy
Chemotherapy
Long-Term Follow-Up
Future Directions
Juvenile Xanthogranulomatous Disease
Erdheim-Chester Disease
Rosai-Dorfman-Destombes Disease (or Sinus Histiocytosis with Massive Lymphadenopathy)
Hemophagocytic Lymphohistiocytosis
Epidemiology
Pathophysiology
Diagnosis
Clinical Manifestations
Prolonged Fever
Liver Disease and Coagulopathy
Bone Marrow Failure
Skin Manifestations
Pulmonary Dysfunction
Brain, Ophthalmic, and Neuromuscular Symptoms
Laboratory Manifestations
Differential Diagnosis of Hemophagocytic Lymphohistiocytosis
Therapy
Induction Therapy
Central Nervous System Disease
Supportive Care
Continuation Therapy
Salvage or Second-Line Therapy
Hematopoietic Cell Transplantation
Prognosis
Distinctive Clinical Contexts
Hemophagocytic Lymphohistiocytosis Associated with Malignancies
Diagnosis and Treatment
Hemophagocytic Lymphohistiocytosis in the Context of a Rheumatologic Disease (R-HLH)
Diagnosis and Treatment
Hemophagocytic Lymphohistiocytosis in the Context of Immune-Activating Therapies (Rx-HLH)
Diagnosis and Treatment
Hemophagocytic Lymphohistiocytosis in the Context of Immune Compromise (IC-HLH)
Diagnosis and Treatment
Future Directions
Suggested Readings
References
54
Lysosomal Storage Diseases, Focusing On Gaucher Disease: Perspectives And Principles
Lysosomal Storage Diseases
Lysosomal Protein Biosynthesis and Sorting
Genetics of Lysosomal Storage Diseases
Diagnosis of Lysosomal Storage Diseases
Screening Programs
Laboratory Diagnosis
Baseline and Sequential Assessment
Specific Treatment
General Principles
Cellular Therapy, Including Gene Therapy
Small Molecule Therapy
General Aspects of Treatment
Hematologic Aspects of Individual Lysosomal Storage Disorders
Splenomegaly
Excessive Bruising/Bleeding
Thrombosis
Abnormal Morphologic Appearances: Bone Marrow and Peripheral Blood
Gaucher Disease
Genetics and Biochemistry
Epidemiology
Clinical Manifestations
Type 1 (GD1)
Types 2 (GD2) and 3 (GD3)
GD2
GD3
Laboratory Findings
Imaging Findings
Differential Diagnosis
Symptomatic Therapy
Specific Treatments
Enzyme Replacement Therapy
Background
Results of Treatment
Substrate Reduction Therapy
Associated Diseases: Parkinson and Malignancies
Prognosis
New Therapeutic Modalities, Including Gene Therapy
Conclusions and Future Directions
References
55
Epstein-Barr Virus and Associated Lymphoproliferative Conditions
Biology of Epstein-Barr Virus
Primary Epstein-Barr Virus Infection
Latent Epstein-Barr Virus Infection
Immune Response to Epstein-Barr Virus
Humoral Immune Responses
Heterophile Antibodies
Epstein-Barr Virus–Specific Antibodies
Cellular Immune Responses
Epstein-Barr Virus Vaccine Development
Infectious Mononucleosis
Epidemiology
Clinical Manifestations
Complications of Infectious Mononucleosis
Hematologic Complications
Anemia
Neutropenia
Thrombocytopenia
Splenic Rupture
Neurologic Complications
Other Organ Involvement
Diagnosis
Differential Diagnosis
Treatment
Inherited Immunodeficiency Disorders and Predisposition to Epstein-Barr Virus–Associated Neoplasms
X-Linked Lymphoproliferative Diseases
X-Linked Lymphoproliferative Disease 1
X-Linked Lymphoproliferative Disease 2
Other Inherited Immunodeficiency Disorders Associated with Epstein-Barr Virus Disease
Epstein-Barr Virus–Associated Neoplasia
Lymphoproliferative Disorders and Lymphomas of B-Cell Origin
Immunodeficiency-Associated Lymphoproliferative Disorders
Burkitt Lymphoma
Hodgkin Lymphoma
Other B-Cell Neoplasms Associated With Epstein-Barr Virus
Lymphoproliferative Disorders and Lymphomas of T/Natural Killer–Cell Origin
Chronic Active Epstein-Barr Virus
Epstein-Barr Virus–Associated T/Natural Killer–Cell Lymphomas
Epstein-Barr Virus–Associated Hemophagocytic Lymphohistiocytosis
Acquired Immunodeficiency and Epstein-Barr Virus–Associated Neoplasms
Posttransplant Lymphoproliferative Disorders
Treatment of Posttransplant Lymphoproliferative Disorders
Epstein-Barr Virus–Associated Non-Hodgkin Lymphoma in Human Immunodeficiency Virus Patients
Immunotherapy for Epstein-Barr Virus–Associated Neoplasms
Monoclonal Antibody Therapy for Lymphoproliferative Disease
Epstein-Barr Virus–Directed T-Cell Therapies
Adoptive Immunotherapy for Epstein-Barr Virus+ Lymphomas in Immunocompetent Individuals
Immediately Available “Off-the-Shelf” Epstein-Barr Virus–Specific T-Cell Options
Other Epstein-Barr Virus–Associated Diseases
Nasopharyngeal Carcinoma
Multiple Sclerosis
Future Directions
Suggested Readings
References
PART VII HEMATOLOGIC MALIGNANCIES
56
Progress in the Classification of Hematopoietic and Lymphoid Neoplasms: Clinical Implications
Progress in the Diagnosis and Classification of Myeloid Neoplasms
Clinical Implications
The Myeloproliferative Neoplasms
Acute Myeloid Leukemia
The Myelodysplastic Syndromes
The Overlap Myelodysplastic/Myeloproliferative Neoplasms
Evolving Concepts in Classification of Lymphoid Neoplasms
Early Events in Lymphoid Neoplasms
Age as a Disease-Defining Feature
Aggressive B-Cell Lymphoma, Borderline Entities, and Site-Specific Categories
Follicular Lymphoma Grading
Mature T-Cell Neoplasms
Anaplastic Large Cell Lymphoma
T-Cell Lymphomas of T-Follicular Helper Cell Origin
Peripheral T-Cell Lymphoma, Not Otherwise Specified
Cutaneous T-Cell Lymphoma
T-Cell Lymphoma of the Gastrointestinal Tract
Epstein-Barr Virus−Associated Neoplasms of T and Natural Killer Cells
Precursor Lymphoid Neoplasms
Hodgkin Lymphoma
Dendritic Cell and Histiocytic Neoplasms
References
57
Conventional and Molecular Cytogenomic Basis of Hematologic Malignancies
Methods
Cytogenetic Analysis
Fluorescence In Situ Hybridization Methods
Comparative Genomic Hybridization and Next Generation Sequencing
Next-Generation Karyotyping
Clonal Origin of Leukemia
In Utero Mutations and Clonal Origin of Hematologic Malignancies
Clonal Hematopoiesis of Indeterminate Potential (CHIP) and Age-Related Clonal Hematopoiesis
Loss of Y chromosome
Loss of X chromosome
Chronic Myeloproliferative Neoplasms
Chronic Myeloid Leukemia (see Chapter 69)
Ph-Negative Chronic Myeloproliferative Neoplasm
Myelodysplastic Syndromes
Acute Myeloid Leukemia
Acute Myeloid Leukemia With a Normal Karyotype
Acute Myeloid Leukemia with an Abnormal Karyotype
Down Syndrome–Associated Acute Myeloid Leukemia
Monosomal Karyotype
Gain or Loss of Chromosomes in Acute Myeloid Leukemia
MYC Amplicon in Acute Myeloid Leukemia
Acute Myeloid Leukemia With Complex Karyotype
Acute Myeloid Leukemia in Children (Chapter 63)
Chromothripsis in Acute Myeloid Leukemia
Therapy-Related Acute Myeloid Leukemia and Therapy-Related Myelodysplastic Syndrome
The Pathway Forward
Acute Myeloid Leukemia in the Elderly
Acute Lymphoblastic Leukemia
“BCR-ABL1-like” Acute Lymphoblastic Leukemia
Complex and Monosomal Karyotype
Somatic Mutations
Prenatal Origin and Multistep Pathogenesis of Acute Lymphoblastic Leukemia
Chronic B-Cell Lymphocytic Leukemia (Chapter 76)
Gene Mutations as Diagnostic and Prognostic Biomarkers
Genome Complexity in Chronic Lymphocytic Leukemia
Richter Syndrome
Multiple Myeloma
Hyperdiploid Multiple Myeloma
Nonhyperdiploid Multiple Myeloma
Translocations in Multiple Myeloma
Lymphoma
Blastic Plasmacytoid Dendritic Cell Neoplasms (Chapter 64)
Hairy Cell Leukemia (Chapter 77)
T-Cell Lymphoproliferative Neoplasms (Chapter 89)
Allogeneic Hematopoietic Stem Cell Transplantation
Future Directions
References
58
Pharmacology and Molecular Mechanisms of Antineoplastic Agents for Hematologic Malignancies​
Tumor Cell Heterogeneity of Hematologic Malignancies
Development of Chemotherapeutic Agents
Screening for Antitumor Activity Among Chemotherapeutic Agents
Phase I Clinical Trial Design
Phase II Drug Development
Phase III Clinical Trials
Traditional Cytotoxic Antineoplastic Agents Targeting The Cell Cycle and DNA
Targeting Tumor Cell Growth Kinetics
Pharmacology of Traditional Chemotherapeutic Agents
Alkylating Agents
Mechanisms of Resistance
Nitrogen Mustard
Nitrosoureas
Methylating Agents
Bendamustine
Alkylating Agent–Induced Leukemias
Antimicrotubule Agents
Molecular Targets
Inhibitors of Nucleotide Synthesis
Hydroxyurea
Folic Acid Analogs (e.g., Methotrexate)
Nucleoside Analogs
Mechanisms of Resistance
Clinical Use
5-Azacytidine and Decitabine
Gemcitabine
Fludarabine
Clofarabine
Nelarabine
Inhibitors of DNA Topoisomerase I and II
DNA Topoisomerase I
DNA Topoisomerase II
DNA Topoisomerase I Inhibitors
DNA Topoisomerase II Inhibitors
Drug Resistance to Topoisomerase Inhibitors
Platinum Analogs
Mechanism of Action
Clinical Activity
Miscellaneous Agents
Pharmacology of Targeted Antineoplastic Agents
Signaling Inhibitors (Table 58.4​ and Fig. 58.6​)
Imatinib Mesylate and Other BCR-ABL Kinase Inhibitors
Imatinib Mesylate
Dasatinib
Nilotinib
Bosutinib
Ponatinib
Asciminib
Bruton Tyrosine Kinase Inhibitors
Efficacy of BTK inhibitors
PI3K/AKT/mTOR Inhibitors
PI3K Inhibitors
AKT Inhibitors
Inhibitors of the Mammalian Target of Rapamycin
Anaplastic Lymphoma Kinase Inhibitors
Inhibitors of the RAF1/MEK/ERK Pathway
Vemurafenib and Dabrafenib
Inhibitors of fms-like Tyrosine Kinase 3 (FLT3)
Sorafenib
Midostaurin
Gilteritinib
Quizartinib
Crenolanib
Janus Kinase 2 Inhibitors
Ruxolitinib
Fedratinib
Other JAK2 Inhibitors
Cyclin-Dependent Kinase Inhibitors
Flavopiridol
Targeting Apoptosis Signaling in Hematologic Malignancies
Proapoptotic Targets of Anticancer Agents
Death Receptor–Initiated Apoptotic Signaling
Mitochondria-Initiated Apoptotic Signaling
Selective Antiapoptotic Agents or Strategies
BCL2 Family of Proteins as Targets for Anticancer Drug Design
BH3 Peptide/Mimetics or Bcl-2/Bcl-XL Small-Molecule Antagonists
Agents Targeting Complex Multicomponent Cellular Processes
Proteasome Inhibitors
First-Generation Proteasome Inhibitors
Bortezomib.
Second-Generation Proteasome Inhibitors
Carfilzomib.
Ixazomib.
Toxicities of Proteasome Inhibitors
Peripheral Neuropathy.
Hematologic Toxicity.
Herpes Zoster Reactivation.
Other Toxicities.
Hypomethylating Agents
Histone Deacetylase Inhibitors
Classes of Histone Deacetylase Inhibitors
Vorinostat and Other Hydroxamic Acid Derivative Histone Deacetylase Inhibitors.
Short-Chain Fatty Acid Histone Deacetylase Inhibitors.
Synthetic Benzamide Derivative Histone Deacetylase Inhibitors.
Cyclic Tetrapeptide Histone Deacetylase Inhibitors.
Toxicity of Histone Deacetylase Inhibitors in Clinical Trials
Combinations of Histone Deacetylase Inhibitors With Other Agents
EZH2 Inhibitors
Protein Translation Inhibitors
Omacetaxine
Isocitrate Dehydrogenase Inhibitors
Hedgehog Pathway Inhibitors
Immunomodulatory Agents and Cereblon E3 Ligase Modulation Drugs
Lenalidomide
Pomalidomide
CELMoDs
Denileukin Diftitox
Drug Resistance to Chemotherapeutic Agents or Multidrug Resistance
Leukemia Stem Cells
Clonal Evolution
P-Glycoprotein (ABC-B1 Transporter)
Structure and Function
P-Glycoprotein Expression in Human Malignancies
Acute Myeloid Leukemia
Clinical Studies With Modulators of P-Glycoprotein
Multidrug Resistance-Associated Protein (ABC G2 Transporter)
Structure and Function
Multidrug-Resistance Protein Expression in Hematologic Malignancies
DNA Repair Pathway Mechanisms of Drug Resistance
O6-methylguanine-DNA methyltransferase
Mismatch Repair
Major Molecular Response Mutations and Methylating Agent Resistance
Base Excision Repair
Drug Resistance to Antimetabolites
Mechanisms of Resistance to Signal Transduction Inhibitors
Genetic Modifications Leading to Resistance to Signal Transduction Inhibitors
Ibrutinib Resistance
BCR-ABL Inhibitor Resistance
Venetoclax Resistance
Idelalisib Resistance
Lenalidomide Resistance
Bortezomib Resistance
Future Directions
SUGGESTED READINGS
Reference
59
Pathobiology of Acute Myeloid Leukemia
Phenotype of Acute Myeloid Leukemia
Etiology of Acute Myeloid Leukemia
Toxins and Exposures
Prior Hematologic Malignancy
Congenital Bone Marrow Failure Syndromes
Mendelian Acute Myeloid Leukemia Predisposition Syndromes
Clonal Hematopoiesis
Genetic and Epigenetic Alterations in Acute Myeloid Leukemia
Chromosomal Abnormalities
Retinoic Acid Receptor Rearrangements
Core Binding Factor Rearrangements
Mixed-Lineage Leukemia Gene Rearrangements
Rare Translocations
Amplifications and Deletions
Recurrently Mutated Genes
Cytokine Signaling
Transcription Factors
Tumor Suppressor Genes
Regulators of Deoxyribonucleic Acid Methylation
Polycomb-Associated Proteins
Spliceosome Complex
Cohesin Complex
Nucleophosmin
Epigenetic Alterations in Acute Myeloid Leukemia
Biology of Acute Myeloid Leukemia
The Leukemic Niche
Clonal Hierarchy of Acute Myeloid Leukemia
Leukemia Stem Cells
Extramedullary Acute Myeloid Leukemia
Biology of Relapsed/Refractory Acute Myeloid Leukemia
Future Directions
Suggested Readings
60
Clinical Manifestations and Treatment of Acute Myeloid Leukemia​
Epidemiology
Clinical and Laboratory Manifestations
Diagnosis and Classification
Prognosis
Therapeutic Considerations at Initial Presentation
Initial Therapy: Intensive Versus Less Intensive Treatment Algorithm
Intensive Therapy: Induction
Intensive Therapy: Post-Remission
Maintenance Therapy
Recent Advances in Intensive Therapy
Midostaurin for FLT3-mutated AML
CPX-351 for t-AML and AML-MRC
Addition of Gemtuzumab Ozogamicin to Intensive Therapy
Less Intensive Therapy
Salvage Therapy for Relapsed/Refractory Acute Myeloid Leukemia
Acute Promyelocytic Leukemia
Blastic Plasmacytoid Dendritic Cell Neoplasm (Chapter 64​)
Extramedullary Acute Myeloid Leukemia
Central Nervous System Disease
Pregnancy
Future Directions
Suggested Readings
61
Myelodysplastic Syndromes
History
Classification
Epidemiology
Pathobiology
Myelodysplastic Syndromes Cell of Origin
Genetic Alterations
Germline Predisposition
Somatic Mutations
Originating Mutations
TET2
DNMT3A
ASXL1
SF3B1
SRSF2
U2AF1
TP53
PPM1D
Intermediate Mutations
EZH2
RUNX1
BCOR
ETV6
Cohesin Complex Genes
Transforming Mutations
Karyotypic Abnormalities
Del(5q)
Chromosome 7 Abnormalities
Trisomy 8
Del(20q)
17p Deletions
Complex and Monosomal Karyotypes
Other Karyotypic Abnormalities
The Marrow Microenvironment in Myelodysplastic Syndromes
Immune Dysregulation
Abnormal Apoptosis
Transformation to Acute Leukemia
Clinical Manifestations
Signs and Symptoms
Dermatologic Manifestations
Autoimmune Manifestations
Laboratory Manifestations
Erythroid Lineage
Myeloid Lineage
Megakaryocytic Lineage
Lymphoid Lineage
Other Objective Findings
Specific Clinical Syndromes
The 5q− Syndrome
Hypocellular Myelodysplastic Syndromes
Myelodysplastic Syndromes/Myeloproliferative Neoplasm Overlap Syndromes and Myelodysplastic Syndromes With Fibrosis
Therapy-Related Myelodysplastic Syndromes
Differential Diagnosis
Prognosis
IPSS and IPSS-R
Other Risk Stratification Systems
Treatment of Patients with Myelodysplastic Syndromes
Lower-Risk Disease
Management of Anemia
Management of Neutropenia and Infections
Management of Thrombocytopenia and Bleeding
Management of Iron Overload (Transfusional Hemosiderosis)
Other Therapies for Lower-Risk Disease
Lenalidomide
Low-Dose Cytarabine and DNA Hypomethylating Agents
Anti-Tumor Necrosis Factor Therapy
Immunosuppressive Therapy
Manipulating the Microenvironment: Vascular Endothelial Growth Factor and Other Targets
Signal Transduction Inhibitors
Other Agents
Higher-Risk Disease
Hypomethylating Agents
Venetoclax
APR-246
“Histone” Deacetylase Inhibitors
Induction Chemotherapy
Allogeneic Hematopoietic Cell Transplantation
Other Therapies for Higher-Risk Disease
Other Drugs
Future Directions
Suggested Readings
References
62
Allogeneic Hematopoietic Stem Cell Transplantation for Acute Myeloid Leukemia and Myelodysplastic Syndrome in Adults
Hematopoietic Stem Cell Transplantation for Acute Myeloid Leukemia
Hematopoietic Stem Cell Transplantation for Acute Myeloid Leukemia in First Complete Remission
Prognostic Factors for Acute Myeloid Leukemia in First Complete Remission
Good-Risk Acute Myeloid Leukemia
Intermediate-Risk Acute Myeloid Leukemia
Poor-Risk Acute Myeloid Leukemia
Measurable Residual Disease Assessment in Acute Myeloid Leukemia
Transplantation Regimen Intensity in Acute Myeloid Leukemia
Alternative Donor Transplantation in Acute Myeloid Leukemia
Unrelated Adult Donors
Umbilical Cord Blood Donors
Haploidentical Donors
Hematopoietic Stem Cell Transplantation for Relapsed, Refractory, and Induction-Failure Acute Myeloid Leukemia
Hematopoietic Stem Cell Transplantation for Therapy-Related and Secondary Acute Myeloid Leukemia
Hematopoietic Stem Cell Transplantation for Acute Myeloid Leukemia in Older Adults
Acute Myeloid Leukemia Relapse After Transplantation
Transplantation for Myelodysplastic Syndrome
Transplantation Trials in Myelodysplastic Syndrome—Comparison With Non-Transplantation Therapies
Contemporary Results in Ablative and Reduced-Intensity Transplantation for Myelodysplastic Syndrome
Using Prognostic Models to Define the Timing of Transplantation
Molecular Prognostic Factors
The Role of Pretransplantation Therapy in Myelodysplastic Syndrome
Transplantation in Older Patients and in Patients With Comorbidity
Alternative Donor Transplantation in Myelodysplastic Syndrome
Treatment and Prevention of Relapse Following Transplantation
Future Directions
References
Suggested Readings
63
Acute Myeloid Leukemia in Children
Epidemiology
Pathobiology
Fusion Genes Resulting From Chromosomal Rearrangements
Chromosomal Rearrangements Affecting Core-Binding Factor
KMT2A Gene Rearrangements
RARA Gene Rearrangements
NUP98 Rearrangements
Chromosomal Rearrangements Involving E26 Transformation Specific Family Members
DEK/NUP214
KAT6A Fusions
RBM15/MRTFA
CBF2A3/GLIS2
Cytogenetically Normal Acute Myeloid Leukemia
Small Insertion and Deletions
CCAAT/Enhancer-Binding Protein Alpha (C/EBPα)
Wilms’ Tumor 1
Nucleophosmin 1
GATA1 Mutations
FMS-Like Tyrosine Kinase 3
RAS Mutations
Specific Acute Myeloid Leukemia Subtypes
Acute Promyelocytic Leukemia
Transient Myeloproliferative Disease and Myeloid Leukemia of Down Syndrome
Clinical and Laboratory Manifestations and Diagnosis of Acute Myeloid Leukemia in Children
Prognostic Factors
Risk-Group Stratification
Therapy
Supportive Care
Late Effects
Future Directions
Tyrosine Kinase Inhibitors
Antibody-Based Therapies
Epigenetic Agents
Chimeric Antigen Receptor-Modified T Cells
Regulatory Landscape and Initiatives
Conclusion
Suggested Reading
References
64
Blastic Plasmacytoid Dendritic Cell Neoplasm
Epidemiology
Pathobiology
Clinical Manifestations and Recommended Diagnostic Evaluation
Histopathology
Differential Diagnosis
Acute Myeloid Leukemia and Other CD56+ Neoplasms With Skin Involvement
Mature Plasmacytoid Dendritic Cell Proliferation
Prognosis
Therapy
Tagraxofusp
Tagraxofusp Side Effects and Management of Capillary Leak Syndrome
Chemotherapy
Disease Response Assessment in Blastic Plasmacytoid Dendritic Cell Neoplasm
Alternative Regimens for First-Line Therapy and Treatment of Relapsed/Refractory Disease
Hematopoietic Cell Transplantation
Treatment of Blastic Plasmacytoid Dendritic Cell Neoplasm in Children (<18 Years of Age)
Future Directions
Suggested Readings
References
65
Myelodysplastic Syndromes and Myeloproliferative Neoplasms in Children
Myelodysplastic Syndromes
Epidemiology
Pathobiology
Classification
Clinical Manifestations
Laboratory Manifestations
Differential Diagnosis
Therapy
Prognosis
Secondary Myelodysplastic Syndrome
Myeloproliferative Neoplasms
Juvenile Myelomonocytic Leukemia
Epidemiology
Pathogenesis
Model Systems
Clinical Manifestations
Laboratory Manifestations
Differential Diagnosis
Therapy
Down Syndrome–Associated Transient Abnormal Myelopoiesis
Epidemiology
Pathobiology
Clinical Manifestations
Laboratory Manifestations
Therapy and Prognosis
Chronic Myeloid Leukemia
Epidemiology
Pathogenesis
Clinical Manifestations
Laboratory Manifestations
Therapy
Prognosis
Other Myeloproliferative Neoplasms
Essential Thrombocythemia
Idiopathic Myelofibrosis
Polycythemia Vera
Future Directions
Suggested Readings
References
66
Pathobiology of Acute Lymphoblastic Leukemia
Introduction
Lineage-Specific Features of Leukemic Lymphoblasts
Mature B-Cell Acute Lymphoblastic Leukemia
B-Cell Acute Lymphoblastic Leukemia
T-Cell Acute Lymphoblastic Leukemia
Mixed-Phenotype Acute Leukemia
Genetic Basis of Acute Lymphoblastic Leukemia
Aberrant Activation of Oncogenic Transcriptional Programs
Activation of Structurally Intact Transcription Factors
MYC in Mature B-Cell Acute Lymphoblastic Leukemia
TAL1 and LMO Genes in T-Cell Acute Lymphoblastic Leukemia
Homeobox Genes
Chimeric Transcription Factor Oncogenes
ETV6-RUNX1 Fusions in B-Cell Acute Lymphoblastic Leukemia
TCF3-PBX1 Fusion Genes in B-Cell Acute Lymphoblastic Leukemia
TCF3–HLF Fusion Genes in B-Cell Acute Lymphoblastic Leukemia
MEF2D Gene Fusions in B-Cell Acute Lymphoblastic Leukemia
ZNF384 Gene Fusions in B-Cell Acute Lymphoblastic Leukemia
CALM–AF10 Fusion Gene in T-Cell Acute Lymphoblastic Leukemia
SPI1 Fusion Genes in T-Cell Acute Lymphoblastic Leukemia
Activating Point Mutations of Oncogenic Transcription Factors
NOTCH1 in T-Cell Acute Lymphoblastic Leukemia
MYC Mutations in Mature B-Cell Lymphoblastic Leukemia
Mutations of Histone-Modifying Enzymes
KMT2A Fusion Genes
PRC2 Mutations in T-Cell Acute Lymphoblastic Leukemia
Focal Activating Mutations of Noncoding Gene-Regulatory Elements
TAL1 Super-Enhancer Mutations in T-Cell Acute Lymphoblastic Leukemia
Duplications of the NOTCH-Driven Enhancer of MYC in T-Cell Acute Lymphoblastic Leukemia
Aberrant Growth Factor Signaling
BCR-ABL1 in Acute Lymphoblastic Leukemia
BCR-ABL1-Like Acute Lymphoblastic Leukemia
NUP214–ABL1 in T-Cell Acute Lymphoblastic Leukemia
B-Cell Receptor Signaling in Acute Lymphoblastic Leukemia
RAS Gene Mutations
PTEN–PI3K–AKT Mutations in T-Cell Acute Lymphoblastic Leukemia
FLT3 Mutations and Overexpression in Acute Lymphoblastic Leukemia
CRLF2 and JAK2 Mutations in B-Cell Acute Lymphoblastic Leukemia
Interleukin-7 Receptor Mutations in Acute Lymphoblastic Leukemia
Tumor Suppressor Gene Inactivation
p53 and CDKN2A Mutations
FBXW7 and Cyclin C in T-Cell Acute Lymphoblastic Leukemia
PAX5 and Other B-Cell Developmental Gene Alterations in B-Cell Acute Lymphoblastic Leukemia
IKZF1 Deletions in B-Cell Acute Lymphoblastic Leukemia
Inactivation of LEF1 in T-Cell Acute Lymphoblastic Leukemia
BCL11B Inactivation in T-Cell Acute Lymphoblastic Leukemia
PHF6 Mutations in T-Cell Acute Lymphoblastic Leukemia
Ribosomal Protein Gene Mutations in T-Cell Acute Lymphoblastic Leukemia
Hedgehog Pathway Activation in T-Cell Acute Lymphoblastic Leukemia
Fanconi-BRCA Mutations in T-Cell Acute Lymphoblastic Leukemia
Abnormalities of Leukemia Cell Ploidy
Hyperdiploidy
Hypodiploidy
Polysomy 21
Germline Predisposition in Acute Lymphoblastic Leukemia
Susceptibility Loci in Acute Lymphoblastic Leukemia
Rare Variation in Familial Acute Lymphoblastic Leukemia
Inherited ETV6 Loss of Function Mutations in B-Cell Acute Lymphoblastic Leukemia
Inherited PAX5 Mutations in B-Cell Acute Lymphoblastic Leukemia
Inherited Alterations of IKZF1 in B-Cell Acute Lymphoblastic Leukemia
Germline TP53 Mutations in Hypodiploid B-Cell Acute Lymphoblastic Leukemia
Chemotherapy Resistance Mechanisms and Novel Therapeutic Targets
Apoptosis Resistance and Mitochondrial Apoptosis
NT5C2 Nucleosidase Gene Mutations in Acute Lymphoblastic Leukemia
Pharmacologic PP2A Activation in T-Cell Acute Lymphoblastic Leukemia
Future Directions
Suggested Readings
67
Clinical Manifestations and Treatment of Childhood Acute Lymphoblastic Leukemia
Epidemiology
Pathobiology
Genomics of Acute Lymphoblastic Leukemia
B-Acute Lymphoblastic Leukemia Genomics
T-Acute Lymphoblastic Leukemia Genomics
Early T-Cell Precursor Acute Lymphoblastic Leukemia Genomics
Clinical Manifestations
Differential Diagnosis
Prognosis
Therapy, Including Stem Cell Transplantation
Dose Schedule
Therapeutic Innovations Being Incorporated Into Contemporary Personalized Acute Lymphoblastic Leukemia Therapy
Acute Lymphoblastic Leukemia Relapse
Immunotherapeutic Options for Acute Lymphoblastic Leukemia
Chimeric Antigen Receptor-Modified T Cells Targeting Acute Lymphoblastic Leukemia
Supportive Care
Drug Interactions
Late Effects of Treatment
Future Directions
References
68
Acute Lymphoblastic Leukemia in Adults​
Epidemiology
Etiology
Clinical Manifestations
Clinical and Laboratory Evaluation
Approach to Diagnosis
Morphology
Cytochemistry
Immunophenotype
Cytogenetics and Molecular Genetics
Differential Diagnosis
Prognosis
Minimal Residual Disease
Treatment of Acute Lymphoblastic Leukemia
Historical Perspective
Remission Induction
Postremission Therapy
Central Nervous System Disease: Prophylaxis and Treatment
Maintenance Therapy
Allogeneic Stem Cell Transplant In First Complete Remission
Stem Cell Sources and Preparative Regimens for Allogeneic Stem Cell Transplantation
Autologous Stem Cell Transplantation
Therapy for Specific Disease Subsets
Philadelphia Chromosome–Positive Acute Lymphoblastic Leukemia
Role of Transplantation for Philadelphia Chromosome–Positive ALL in the Era of Tyrosine Kinase Inhibitor–Based Therapy
Burkitt Lymphoma/Leukemia
Adolescents and Young Adults With Acute Lymphoblastic Leukemia: The Intersection Between Pediatric And Adult Care
Differences in Treatment for B- Versus T-Cell Acute Lymphoblastic Leukemia
Comparison of Pediatric-Inspired Regimens With Allogeneic Transplant for Adolescents and Young Adults
Older Adults With Acute Lymphoblastic Leukemia
Relapsed Acute Lymphoblastic Leukemia
Novel Therapies
Immunotherapy
Novel Chimeric Antigen Receptor T-Cell Therapies
Daratumumab
BH3 Mimetics
Kinase Inhibitors for ALL
Targeting Intracellular Signaling Pathways
Epigenetic Modulation
Survivorship
Future Directions
Suggested Readings
References
69
Chronic Myeloid Leukemia
Introduction and Historical Perspective
Epidemiology
Molecular Biology
BCR-ABL1 Translocation and Fusion Gene (Chapter 57)
BCR and ABL1 Proteins and Their Contribution to Cellular Transformation
Constitutive Kinase Activation in the BCR-ABL1 Fusion Protein
Aberrant Signaling in BCR-ABL1 Transformed Cells
Phosphatidylinositol-3 Kinase
RAS/Mitogen-Activated Protein Kinase Pathways
Janus Kinase (JAK)/Signal Transducer and Activator of Transcription (STAT) Pathway
Cytoskeletal Proteins
DNA Damage Surveillance and Repair Pathways
Cellular Biology
Cell of Origin
Chronic Myeloid Leukemia Hematopoiesis
Transformation To Accelerated And Blast Phase
Molecular Basis Of Tyrosine Kinase Inhibitor Resistance
BCR-ABL1–Dependent Tyrosine Kinase Inhibitor Resistance
BCR-ABL1–Independent Resistance
Diagnosis And Initial Workup
Clinical Evaluation
Signs and Symptoms
Laboratory Manifestations
Complete Blood Count (CBC)
Bone Marrow Aspirate and Biopsy
Bone Marrow Karyotyping
Fluorescence In Situ Hybridization
Reverse Transcription Polymerase Chain Reaction
Myeloid Mutation Screening
Imaging
Risk Stratification
Disease Phases
Risk Scores in Chronic Phase of Chronic Myeloid Leukemia
Differential Diagnosis
Monitoring Response To Therapy
Hematologic Response (CHR)
Cytogenetic Response
Molecular Response
BCR-ABL1 Mutation Testing
Therapy
Cytotoxic Agents
Interferon-α
Omacetaxine
Tyrosine Kinase Inhibitors
Imatinib
Dasatinib
Nilotinib
Bosutinib
Ponatinib
Drug Combinations
Allogeneic Stem Cell Transplantation
Approach To The Newly Diagnosed Chronic Phase Patient
Approach To The Patient With Tyrosine Kinase Inhibitor Resistance
Chronic Phase of Chronic Myeloid Leukemia
Accelerated Phase/Blast Phase Chronic Myeloid Leukemia
Treatment-Free Remission
Future Directions
Acknowledgments
Suggested Readings
References
70
The Polycythemias​
Erythropoiesis
Erythropoietin, Oxygen Sensing, and Hypoxia-Inducible Factor
The Erythropoietin Receptor
The Renin–Angiotensin System and Hematopoiesis
Definition and Classification of Polycythemia
Relative Polycythemia
Absolute Polycythemias
Primary Familial and Congenital Polycythemia
Secondary Polycythemias
Acquired Secondary Polycythemias
Polycythemias of Cyanotic Heart Disease and Pulmonary Disease
Obstructive Sleep Apnea–Induced Polycythemia
Pickwickian Syndrome and Polycythemia
Polycythemia Caused by High Altitude
Smokers’ Polycythemia or Carbon Monoxide-Induced Polycythemia
Postrenal Transplantation Erythrocytosis
Polycythemia Accompanying Kidney and Liver Diseases and Neoplastic Disorders
Polycythemia in Endocrine Disorders
Congenital Secondary Polycythemias
High-oxygen-affinity hemoglobins and bisphosphoglycerate deficiency.
Hypoxia-Inducible Factor Pathway Mutations Leading to Erythrocytosis
Neonatal Polycythemia
Drug-induced Erythrocytosis
Polycythemia Vera
Epidemiology
Pathobiology
Identification of JAK2V617F Mutation in Polycythemia Vera
Other JAK2 Mutations in Polycythemia Vera
JAK2V617F Is Likely Not the Only Event That Determines if Polycythemia Vera Develops
The JAK2V617F Mutation Is Present in Hematopoietic Stem Cells in Polycythemia Vera
Structural and Functional Aspects of JAK2V617F-Mediated Transformation
Additional Mutations Associated With Polycythemia Vera
The Hypercoagulable State That Characterizes Polycythemia Vera
Polycythemia Vera and the Risk of Hemorrhage
Post-Polycythemia Vera Myelofibrosis and MPN-BP
Clinical Manifestations
Laboratory Manifestations
Cytogenomic Abnormalities
Differential Diagnosis
Prognosis
Therapy
Future Directions
Suggested Readings
References
71
Essential Thrombocythemia​
Epidemiology
Pathobiology
Mutational Spectrum in Essential Thrombocythemia
Thrombosis and Hemorrhage in Essential Thrombocythemia
Clinical Manifestations
Laboratory Manifestations
Differential Diagnosis
Prognosis
Therapy
COVID-19 in Essential Thrombocythemia Patients
Future Directions
References
72
Primary Myelofibrosis and Chronic Neutrophilic Leukemia​
Phylogeny of the Nomenclature: Primary Myelofibrosis​
Epidemiology
Pathobiology of Primary Myelofibrosis
Driver mutations
The role of epigenetic mutations in the molecular landscape of primary myelofibrosis
Extramedullary hematopoiesis in primary myelofibrosis
Bone marrow fibrosis in primary myelofibrosis
Clonal Evolution of Primary Myelofibrosis
Clinical Manifestations
Laboratory Manifestations
Differential Diagnosis
Prognosis
Evolution of Prognostic Models in Primary Myelofibrosis
Management of PRIMARY MYELOFIBROSIS
Treatment of the anemic patient
Treatment of spleen-related and systemic symptoms
Allogeneic hematopoietic stem cell transplantation
Investigational therapeutic options
Future Directions
Chronic Neutrophilic Leukemia
Molecular pathogenesis of chronic neutrophilic leukemia
Clonal evolution
Clinical and laboratory features of chronic neutrophilic leukemia
Diagnosis
Differential diagnosis
Prognosis
Management of chronic neutrophilic leukemia
Future directions
References
73
Myelodysplastic Syndrome/Myeloproliferative Neoplasm Overlap Syndromes
Epidemiology
Diagnostic Evaluation and Criteria
Chronic Myelomonocytic Leukemia
Atypical Chronic Myeloid Leukemia
Myelodysplastic/Myeloproliferative Syndrome With Ring Sideroblasts and Thrombocytosis
Myelodysplastic/Myeloproliferative Syndrome, Unclassifiable
Juvenile Myelomonocytic Leukemia
Pathogenesis and Molecular Characterization
Shared Pathogenic Mechanisms
Epigenetic/Transcription Factor Mutations
Spliceosome Mutations
Cell Signaling Gene Mutations
Risk Stratification and Prognosis
Chronic Myelomonocytic Leukemia Risk Stratification
Chromosomal Abnormalities Associated With Myelodysplastic Syndrome/Myeloproliferative Neoplasm Overlap Syndromes
Atypical Chronic Myeloid Leukemia Prognosis
Myelodysplastic Syndrome/Myeloproliferative Neoplasm With Ring Sideroblasts and Thrombocytosis Prognosis
Myelodysplastic Syndrome/Myeloproliferative Neoplasm Unclassifiable
Juvenile Myelomonocytic Leukemia Prognosis
Treatment Approaches
General Treatment Considerations
Chronic Myelomonocytic Leukemia Management
Atypical Chronic Myeloid Leukemia Management
Myelodysplastic Syndrome/Myeloproliferative Neoplasm With Ring Sideroblasts and Thrombocytosis Management
Myelodysplastic Syndrome/Myeloproliferative Neoplasm Unclassifiable Management
Juvenile Myelomonocytic Leukemia Management
Future Directions
Conclusion
References
74
Eosinophilia, Eosinophilic Neoplasms, and the Hypereosinophilic Syndromes
Epidemiology
Morphology And Phenotype Of Eosinophils
Origin, Differentiation, Recruitment, And Activation Of Eosinophils
Eosinophilopoiesis
Mobilization and Migration of Eosinophils to Sites of Inflammation
Role of Mast Cells in Eosinophil Recruitment and Accumulation
Monitoring Of Eosinophil Numbers And Activity In Health And Disease
Etiology And Pathobiology Of Hypereosinophilia
Pathogenesis of Eosinophil-Associated End-Organ Damage in Patients With Hypereosinophilic Syndrome
Definition And Classification Of Hypereosinophilia And Hypereosinophilic Syndrome
Definition of Hypereosinophilia
Diagnostic Algorithm
Classification of Hypereosinophilia and Hypereosinophilic Syndrome
Clinical Manifestations Of Hypereosinophilic Syndrome In Various Organ Systems And Differential Diagnosis
Cardiac Manifestations in Patients With Hypereosinophilic Syndrome
Pulmonary Manifestations
Cutaneous Manifestations
Neurologic Manifestations
Gastrointestinal Manifestations
Hematologic Manifestations and Bone Marrow Involvement
Underlying Hematologic Disorders and Differential Diagnoses
Acute Eosinophilic Leukemia
Chronic Eosinophilic Leukemia
MPN-eo, MPN/MDS-eo, MDS-eo, and SM-eo
Lymphoid Neoplasms, Lymphomas
Reactive, Immunologic and Paraneoplastic Conditions Associated With Hypereosinophilia
Specific Syndromes and Conditions Associated With Hypereosinophilia
Organ-Restricted Hypereosinophilic Syndromes
Treatment Algorithm, Treatment Options, And Prognosis
Primary Management and Algorithm
Corticosteroids
Conventional Cytoreduction and Chemotherapy
Interferon-Alpha
Cyclosporin A
Targeted Treatment Approaches Using Tyrosine Kinase Inhibitors
Targeted Antibodies
Leukapheresis
Anticoagulation and Antiplatelet Agents
Splenectomy
Allogeneic Hematopoietic Stem Cell Transplantation
Cardiac Surgery
Summary And Future Perspectives
References
75
Mast Cells and Mastocytosis
Origin and Development of Mast Cells
KIT and Stem Cell Factor (KIT Ligand)
KIT
Stem Cell Factor
Mast Cell Activation and Function
Tools to Study Human Mast Cells
Mouse Models to Study Human Mastocytosis
FIP1L1::PDGFRA- and NPM::ALK-Based Murine Models
Germline Susceptibility to Mast Cell Disorders and Familial Mastocytosis
Epidemiology and Classification of Mastocytosis
Mast Cell Activation Syndromes
Diagnostic Evaluation of Mastocytosis
Serum Tryptase Level
Clinical Manifestations
Organomegaly
Nonhematologic Organ Damage
Hematologic Organ Involvement
Molecular Features of Systemic Mastocytosis
Additional Diagnostic Studies
Diagnostic Decision Making
Survival and Prognostic Factors
Cytogenetic/Molecular Determinants of Prognosis and the Evolution of Prognostic Scoring Systems
Treatment
Mast Cell Activation Symptoms/Anaphylaxis
Cytoreductive Agents
Interferon-α
Cladribine
Tyrosine Kinase Inhibitors
Dasatinib and Nilotinib
Imatinib
Masitinib
Midostaurin
Avapritinib
Other Agents
Allogeneic Hematopoietic Stem Cell Transplantation
Response Criteria for Advanced Systemic Mastocytosis
Future Directions
Suggested Readings
References
76
Chronic Lymphocytic Leukemia
Epidemiology
Familial Chronic Lymphocytic Leukemia
Pathobiology
B-Cell Receptor Pathway And Its Role In Pathogenesis
IGHV Mutational Status
Defective Apoptosis
Genetic Abnormalities
Recurring Mutations in Chronic Lymphocytic Leukemia
Immune and Micro-Environmental Features
Clinical Manifestations
Diagnosis And Laboratory Manifestations
Monoclonal B-Cell Lymphocytosis
Laboratory Manifestations
Prognosis
Thymidine Kinase Activity and β2-Microglobulin
IGHV Mutational Status and Surrogates
Other Prognostic Markers
Chromosomal Aberrations
Mutational Analysis
Treatment
Initiation of Treatment of Newly Diagnosed or Previously Untreated Patients
Targeted Therapy
Bruton Tyrosine Kinase Inhibitors
Ibrutinib in Untreated Chronic Lymphocytic Leukemia
Acalabrutinib in Untreated Chronic Lymphocytic Leukemia
Venetoclax in Untreated Chronic Lymphocytic Leukemia
Treatment Of Patients With Relapsed Chronic Lymphocytic Leukemia
Ibrutinib for Relapsed Disease
Acalabrutinib for Relapsed Disease
Venetoclax in Relapsed Chronic Lymphocytic Leukemia
PI3-Kinase Inhibitors
Role of Novel Agents in the Management of Patients With Del(17p13.1)
Sequencing of Therapy and Management of Patients Relapsing After Novel Therapies
Other Emerging Therapeutic Modalities for Chronic Lymphocytic Leukemia
Chimeric Antigen Receptor T-Cell Therapy
Hematopoietic Stem Cell Transplantation
Management of Chronic Lymphocytic Leukemia in Specialized Centers
Special Clinical Scenarios In Chronic Lymphocytic Leukemia
Young Patients (Younger Than 50 Years of Age) With Chronic Lymphocytic Leukemia
Richter Syndrome
Secondary Malignancies in Chronic Lymphocytic Leukemia
Hypersensitivity in Chronic Lymphocytic Leukemia to Mosquitoes and Insect Bites and Treatment
Infections In Patients With Chronic Lymphocytic Leukemia
Prophylactic Strategies for Infections
Autoimmune Complications Of Chronic Lymphocytic Leukemia
SARS-COV-2 And Chronic Lymphocytic Leukemia
Future Directions
Suggested Readings
77
Hairy Cell Leukemia
Epidemiology
Etiology and Cell of Origin
Clinical Presentation and Diagnosis
Differential Diagnosis
Treatment
Indications for Therapy
Historic Aspects of Therapy
Purine Nucleoside Analogs
Monoclonal Antibodies
Minimal Residual Disease and Its Significance
Treatment of Disease Relapse
Incidence of Second Malignancies
Future Directions
References
78
The Pathologic Basis for the Classification of Non-Hodgkin and Hodgkin Lymphomas
Introduction and Historical Background
Mature B-Cell Neoplasms
Chronic Lymphocytic Leukemia/Small Lymphocytic Lymphoma
Lymphoplasmacytic Lymphoma
Mantle Cell Lymphoma
Follicular Lymphoma
Extranodal Marginal-Zone Lymphoma of Mucosa-Associated Lymphoid Tissue Type
Nodal Marginal-Zone B-Cell Lymphoma
Splenic Marginal-Zone Lymphoma
Diffuse Large B-Cell Lymphoma, Not Otherwise Specified
Diffuse Large B-Cell Lymphomas, Other Variants, and Subtypes
Intravascular Large B-Cell Lymphoma
Primary Mediastinal (Thymic) Large B-Cell Lymphoma
B-Cell Lymphoma, Unclassifiable, With Features Intermediate Between Diffuse Large B-Cell Lymphoma and Classic Hodgkin Lymph ...
Burkitt Lymphoma
High-Grade B-Cell Lymphoma, with MYC and BCL2 and/or BCL6 Rearrangements
T-CELL and Natural Killer-Cell Lymphomas
Overview of the Classification of T-Cell Neoplasms
Angioimmunoblastic T-Cell Lymphoma
Adult T-Cell Leukemia/Lymphoma
Peripheral T-Cell Lymphomas, Not Otherwise Specified
Anaplastic Large Cell Lymphoma, Anaplastic Lymphoma Kinase-Positive
Anaplastic Large Cell Lymphoma, ALK-Negative
Primary Cutaneous Anaplastic Large Cell Lymphoma
Mycosis Fungoides/Sézary Syndrome
Subcutaneous Panniculitis-Like T-Cell Lymphoma
Primary Cutaneous Gamma-Delta T-Cell Lymphoma
Primary Cutaneous CD8+ Aggressive Epidermotropic Cytotoxic T-Cell Lymphoma and Primary Cutaneous CD4+ Small/Medium T-Cell L ...
Enteropathy-Associated T-Cell Lymphoma
Hepatosplenic T-Cell Lymphoma
Extranodal Natural Killer/T-Cell Lymphoma, Nasal Type
Hodgkin Lymphoma
Nodular Lymphocyte-Predominant Hodgkin Lymphoma
Classic Hodgkin Lymphoma, Nodular Sclerosis
Classic Hodgkin Lymphoma, Mixed Cellularity
Classic Hodgkin Lymphoma, Lymphocyte Depletion
Classic Hodgkin Lymphoma, Lymphocyte-Rich
Acknowledgment
Suggested Readings
References
79
Origin of Hodgkin Lymphoma and Therapeutic Targets
CHARACTERISTICS AND ORIGIN OF HODGKIN LYMPHOMA
Classification of Hodgkin Lymphoma
B-Cell Development and Differentiation
Cellular Origin of Lymphocyte Predominant Cells in Nodular Lymphocyte Predominant Hodgkin Lymphoma
Cellular Origin of Hodgkin and Reed-Sternberg Cells in Classic Hodgkin Lymphoma
T Cell–Derived Classic Hodgkin Lymphoma
Hodgkin Lymphoma Cell Lines
Relationship Between Hodgkin Cells and Reed-Sternberg Cells
Potential Hodgkin and Reed-Sternberg Precursor or Stem Cells
Lessons From Composite Lymphomas
The Role of Epstein-Barr Virus in Classic Hodgkin Lymphoma
Genetic Lesions in Hodgkin and Reed-Sternberg and Lymphocyte Predominant Cells
Therapeutic Targets
Conclusions and Future Directions
References
80
Hodgkin Lymphoma
Epidemiology And Etiology Incidence and Age of Onset
Etiology
Pathobiology of Hodgkin Lymphoma
Nodular Lymphocyte-Predominant Hodgkin Lymphoma
Classic Hodgkin Lymphoma
Diagnosis and Staging
Diagnosis
Staging
Clinical Features
Prognostic Factors, Risk Stratification, and Treatment Groups
Treatment According to Prognostic Group
Treatment of Early-Stage Hodgkin Lymphoma
Early-Stage Nodular Lymphocyte-Predominant Hodgkin Lymphoma
Early-Stage Classic Hodgkin Lymphoma
Radiation Therapy Planning and Treatment
Response-Adapted Treatment Approach
Treatment of Advanced-Stage Hodgkin Lymphoma
ABVD
BEACOPP
ABVD Versus Escalated BEACOPP
Relapsed and Refractory Hodgkin Lymphoma
Prognostic Factors in Relapsed or Refractory Hodgkin Lymphoma
Treatment of Relapsed or Refractory Hodgkin Lymphoma
Salvage Chemotherapy and Autologous Stem Cell Transplant
Treatment Post Autologous Stem Cell Transplant
Brentuximab Vedotin
Checkpoint Inhibitors
Special Considerations
Hodgkin Lymphoma in the Elderly
Hodgkin Lymphoma During Pregnancy
Long-Term Complications of Treatment in Hodgkin Lymphoma
Suggested Readings
References
Chapter
81
Origin of Non-Hodgkin Lymphoma and Therapeutic Targets
Overview of B-Cell Lymphomas
Diffuse Large B-Cell Lymphoma
Gene Expression Profiles Define Diffuse Large B-Cell Lymphoma Subtypes (Table 81.1)
Molecular Pathogenesis of Diffuse Large B-Cell Lymphoma
The Tumor Microenvironment and Diffuse Large B-Cell Lymphoma
Conclusions
Burkitt Lymphoma
Follicular Lymphoma
BCL2 Rearrangements and Other Genomic Alterations in Follicular Lymphoma
Tumor Microenvironment and Survival in Follicular Lymphoma
Mantle Cell Lymphoma
Cyclin D1 and Mantle Cell Lymphoma
Secondary Genomic Alterations in Mantle Cell Lymphoma
Molecular Pathways and Profiles in Mantle Cell Lymphoma
Other Non-Hodgkin Lymphomas
Future Directions
Suggested Readings
82
Clinical Manifestations, Staging, and Treatment of Follicular Lymphoma
Epidemiology
Pathogenesis
Clinical Presentation
Diagnosis of Follicular Lymphoma
Staging
Natural History
Treatment of Follicular Lymphoma
When to Institute Therapy
Stage I–II Disease
Bulky Stage II and Stage II/IV Disease
Treatment Approaches
Alkylating Agents
Purine Analogues
Bendamustine
Biologic Therapy
Monoclonal Antibody Therapy
Chemoimmunotherapy
Conjugated Radio-Labeled Monoclonal Antibody Therapy
High-Dose Therapy as Consolidation of First Remission
Treatment of Relapsed Follicular Lymphoma
Novel Agents
Therapies Targeting the Tumour Microenvironment
The Role of Transplant in Relapsed Indolent Lymphomas
Allogeneic Bone Marrow Transplant
CAR-T Cells
Suggested Readings
References
Chapter
83
Marginal Zone Lymphomas (Extranodal/Malt, Splenic, and Nodal)
Initial Evaluation of Marginal Zone Lymphoma
Staging of Marginal Zone Lymphoma
Extranodal Marginal Zone Lymphoma of Mucosa-Associated Lymphoid Tissue Type
Epidemiology and Manifestations
Pathobiology and Differential Diagnosis
Etiology
Histology
Immunophenotype
Genetics
Therapy for Early-Stage (I/II) Disease
Gastric Extranodal Marginal Zone Lymphoma
Ocular Extranodal Marginal Zone Lymphoma
Cutaneous Extranodal Marginal Zone Lymphoma
Immunoproliferative Small Intestinal Disease
Other Extranodal Marginal Zone Lymphoma
Therapy for Advanced-Stage (III/IV) Disease
Single Agent Rituximab
Alkylating Agents
Purine Analogues
Other Agents
Combination Chemotherapy
Radioimmunotherapy
Therapy for Relapsed Disease
Prognosis
Splenic Marginal Zone Lymphoma
Epidemiology and Manifestations
Pathobiology and Differential Diagnosis
Etiology
Histology
Immunophenotype
Genetics
Therapy
Anti-Hepatitis C Virus Therapy
Rituximab-Based Regimens
Splenectomy
Ibrutinib
Chemotherapy
Radiation Therapy
Prognosis
Nodal Marginal Zone Lymphoma
Epidemiology and Manifestations
Pathobiology and Differential Diagnosis
Etiology
Histology and Immunophenotype
Genetics
Therapy
Prognosis
Suggested Readings
References
84
Diffuse Large B-Cell Lymphoma of​ ​the Central Nervous System​
Epidemiology
Pathogenesis
Genomic Landscape and Aberrant Pathways
MicroRNA Expression
Adhesion and Chemokine Molecules
Immune Evasion and Its Implications
Cell of Origin and Its Implications
Epstein-Barr Virus–Associated (Tissue-Positive) Primary Central Nervous System Lymphoma and Its Implications
Clinical Presentation
Brain Parenchyma
Primary Vitreoretinal Lymphoma
Leptomeninges
Neuroimaging
Magnetic Resonance Imaging Brain With and Without Gadolinium
Magnetic Resonance Spectroscopy
Neuroimaging And Differential Diagnosis Prior To Biopsy
Stroke
Infection
Immune Mediated Diseases
Other Central Nervous System Cancers
Tissue Diagnosis
Brain Stereotactic Biopsy
Misinterpretation of Stereotactic Biopsy
Risks With Brain Biopsy
Cerebrospinal Fluid Assessment for Diagnosis
Cerebrospinal Fluid Testing in Human Immunodeficiency Virus–Infected Individuals
Ophthalmology Exam And Vitreoretinal Specimen Testing For Diagnosis
Histology Characterization
Biomarkers For Diagnosis
Serologic Biomarkers
Cerebrospinal Biomarkers
Vitreous Biomarker for Vitreoretinal Lymphoma
Staging
Frontline Therapy And Response Assessment
Immediate Conservative Management: Best Practices
Induction Therapy
Prevention and Management of High-Dose Methotrexate Renal Toxicity
Consolidation
Whole Brain Radiation Therapy Consolidation
Nonmyeloablative Therapy Consolidation-CALGB 50202 (Alliance 50202)
Myeloablative Chemotherapy Versus Whole-Brain Radiation Therapy as Consolidation Therapy
Authors’ Preference of Consolidation
Primary Central Nervous System Lymphoma in Older Adults
Induction In Older Adults—Should It Be REDUCED?
AUTOLOGOUS Hematopoietic Stem Cell Transplantation In Older Adults As Consolidation Therapy
Maintenance Therapy—Emerging Concept
Older Frail (or “Unfit”) Adults Who Are Not Candidates for Consolidation
Maintenance Therapy After Consolidation
Treatment Of Primary Vitreoretinal Lymphoma - A Subset Of Primary Central Nervous System Lymphoma
Intraocular Lymphoma Without Brain Parenchyma Involvement
Intraocular Lymphoma With Brain Parenchyma Involvement
Concerns and Adverse Events With Local Therapy for Primary Vitreoretinal Lymphoma
Real-World Treatment Patterns And Outcomes—Data From Population-Based Studies
United States
France
Netherlands
United Kingdom
Primary Central Nervous System Lymphoma In The Immunocompromised Host
Human Immunodeficiency Virus: An Acquired Immunodeficiency Syndrome–Defining Illness
Post-Transplant Lymphoproliferative Disease–Related Primary Central Nervous System Lymphoma
Autoimmune Disease–Related Primary Central Nervous System Lymphoma
Experimental Therapeutics In Primary Central Nervous System Lymphoma
Osmotic Blood-Brain Barrier Disruption With Cerebral Intra-Arterial Chemotherapy
NGR-Human Tumor Necrosis Factor With R-CHOP
Front-line Treatment Challenges and Controversies
Therapeutic Role of Surgical Resection Followed by Induction Therapy?
Definition of High-Dose Methotrexate, its Frequency, and Definition of Failure of High-Dose Methotrexate?
High-Dose Methotrexate-Based Monotherapy Versus Combination Therapy?
Induction Cycles, Response Assessment, and Timing of Consolidation?
Intravenous Rituximab?
Prophylactic Intrathecal Chemotherapy?
Therapeutic Intrathecal Chemotherapy in PCNSL?
High-Dose Methotrexate–Related Neurotoxicity
Whole-Brain Radiation Therapy–Related Neurotoxicity
Lower Dose of Whole-Brain Radiation Therapy?
Conditioning Regimen for Autologous Hematopoietic Stem Cell Transplantation?
Incorrect or Ambiguous Definition of the Term “Elderly”
Prognostic And Predictive Markers
International Extranodal Lymphoma Study Group Model281
Memorial Sloan-Kettering Cancer Center Model282
Differences Between the Two Models
Prognosis of Vitreoretinal Lymphoma With and Without Central Nervous System Parenchymal Disease
Additional Prognostic And Predictive Markers
BCL-6 Overexpression and Rearrangement
c-MYC and/or BCL2 Overexpression
O6-Methylguanine-DNA Methyltransferase (MGMT) Gene Promoter Methylation
PD-1 and PD-L1
MicroRNA Signature
Relapsed And Refractory Disease
Salvage Chemotherapy and Rituximab
Autologous Transplant
Non-Chemotherapeutic Targets And Agents
Bruton Tyrosine Kinase Inhibitors
Immunomodulatory Agents
mTOR Inhibitor
Intrathecal Rituximab as Monotherapy
Intrathecal Rituximab in Combination
Immunotherapy Agents
Adoptive Immunotherapy
Allogeneic Hematopoietic Stem Cell Transplantation
Salvage Radiation Therapy
Salvage Stereotactic Radiosurgery
Prevention Of Cns Relapse For Aggressive Systemic Lymphomas And Controversies
Central Nervous System International Prognostic Index
Controversies
Group With Highest Risk for CNS Disease and in Need of Prophylactic CNS-Directed Therapy
Preventive Interventions
Perspective And Future Directions
Acknowledgments
Suggested Readings
References
85
High-Grade B-Cell Lymphomas
Diffuse Large B-Cell Lymphoma
Epidemiology
Pathobiology
Clinical Features
Investigation
History and Physical Examination
Laboratory Investigations
Imaging and Staging
Prognosis
Treatment
Primary Central Nervous System Lymphoma
Burkitt Lymphoma
Epidemiology
Pathobiology
Clinical Features
Investigation
History and Physical Examination and Laboratory Investigations
Imaging and Staging
Prognosis
Treatment
Salvage Therapy
Late Complications of Treatment and Follow-Up
Future Directions
References
Chapter
86
Mantle Cell Lymphoma
Epidemiology
Pathobiology
Genetic Alteration of Proliferative Pathways
Antiapoptotic and Prosurvival Pathways
Clinical Manifestations
Laboratory Manifestations
Diagnosis
Differential Diagnosis
Staging
Therapy
Wait-and-Watch Strategy
Therapy Options: Non-Transplant Directed
Therapy Options: Upfront Intensified With or Without Consolidation Autologous Stem Cell Transplantation
Central Nervous System Prophylaxis
Relapsed or Refractory Mantle-Cell Lymphoma
Cellular Therapy in Relapsed/Refractory Mantle Cell Lymphoma
Prognosis
Future Directions
References
87
Virus-Associated Lymphoma
Epstein-Barr Virus
Viral Biology
Epidemiology of Viral Infection
Epstein-Barr Virus Detection in Clinical Specimens
Association with Particular Types of Lymphoma
Posttransplantation Lymphoproliferative Disorder
Hodgkin Lymphoma
Burkitt Lymphoma
Kaposi Sarcoma–Associated Herpesvirus
Virus and Tumor Epidemiology
Diagnostic and Therapeutic Considerations
Human T-Lymphotropic Virus-1
Viral Biology
Epidemiology of Viral Infection and Adult T-Cell Leukemia/Lymphoma
Adult T-Cell Leukemia/Lymphoma Diagnostic Considerations
Therapies Specific to Human T-Lymphotropic Virus-1 Adult T-Cell Leukemia
Human Immunodeficiency Virus-Associated Lymphomas
Viral Biology and Pathogenesis
Epidemiology
Diagnostic Considerations Specific to Lymphoma in Patients With Human Immunodeficiency Virus
Therapy
Antiretroviral Therapy
Supportive Care
Bone Marrow Transplant in Patients With Human Immunodeficiency Virus
Hepatitis C Virus
Viral Biology and B-Lymphocyte Proliferation
Epidemiology of Viral Infection and Associated Lymphoma
Diagnostic and Prognostic Considerations
Therapy
Future Directions
Suggested Readings
References
88
Malignant Lymphomas in Childhood
Non-Hodgkin Lymphoma
Epidemiology
Classification
Lymphoblastic Lymphoma
Introduction
Epidemiology
Pathobiology
Clinical Manifestations
Differential Diagnosis
Prognosis (Staging)
Therapy
Burkitt Lymphoma
Introduction
Epidemiology
Pathobiology
Clinical Manifestations
Differential Diagnosis
Prognosis (Staging)
Therapy
Diffuse Large B-Cell Lymphoma
Introduction
Epidemiology
Pathobiology
Clinical Manifestations
Differential Diagnosis.
Prognosis (Staging)
Therapy
Anaplastic Large Cell Lymphoma
Introduction and Epidemiology
Pathobiology
Clinical Manifestations
Diagnosis and Differential Diagnosis
Prognosis (Staging)
Therapy
Relapsed Non-Hodgkin Lymphoma-Management
Post-Transplant Lymphoproliferative Disorder
Hodgkin Lymphoma
Epidemiology
Pathobiology
Clinical Manifestations
Staging
Treatment
Management of Relapsed Hodgkin Lymphoma
Rare Subtypes of Lymphoma
Future Directions
Suggested Reading
References
89
T-Cell Lymphomas
Classification And Cell Of Origin
Chronic T-Cell Leukemias
T-Cell Prolymphocytic Leukemia
Morphology and Pathobiology
Clinical Manifestations
Diagnosis
Differential Diagnosis
Therapy
Prognosis
Peripheral T-Cell Lymphomas
Epidemiology of Peripheral T-Cell Lymphomas
Shared Pathogenetic Mechanisms
Diagnosis and Staging
Peripheral T-Cell Lymphoma, Not Otherwise Specified
Morphology and Pathobiology
Clinical Manifestations
Prognosis
Angioimmunoblastic T-Cell Lymphoma
Morphology and Pathobiology
Clinical Manifestations
Laboratory Manifestations
Prognosis
Anaplastic Large-Cell Lymphoma
Morphology and Pathobiology
Clinical Manifestations
Prognosis
Hepatosplenic T-Cell Lymphoma
Morphology and Pathobiology
Clinical Manifestations
Prognosis
Primary Intestinal T-Cell Lymphomas
Enteropathy-Associated T-cell lymphoma
Morphology and Pathobiology
Clinical Manifestations
Refractory Celiac Disease
Prognosis
Monomorphic Epitheliotropic Intestinal T-Cell Lymphoma
Morphology and Pathobiology
Clinical Manifestations
Extranodal NK/T-Cell Lymphomas
Morphology and Pathobiology
Clinical Manifestations
Prognosis
Subcutaneous Panniculitis-Like T-Cell Lymphoma
Morphology and Pathobiology
Clinical Manifestations
Prognosis
First-Line Therapy
Induction Regimens
Combination of New Drugs With Standard Chemotherapy
Frontline Autologous Stem Cell Transplantation
Treatment of Specific Disease Subtypes
Low-risk ALCL-ALK+ (IPI 0 to 1)
BIA-ALCL
EATL and MEITL
SPTCL
ENKL
Relapsed and Refractory Disease
Licensed Agents
Pralatrexate
Histone Deacetylase Inhibitors
Brentuximab Vedotin
Mogamulizumab
Off-Label Compounds
Lenalidomide
Bendamustine
Gemcitabine
New Drugs
Demethylating Agents
Ruxolitinib
Duvelisib
Immunotherapy
Allogeneic Hematopoietic Stem Cell Transplantation
Future Directions
Cutaneous T-Cell Lymphomas
Mycosis Fungoides and Sézary Syndrome
Morphology
Pathobiology
Clinical Manifestations
Diagnosis and Staging
Prognosis
Treatment of Limited-Stage MF
Topical Treatments
Phototherapy
Total Skin Electron Beam Irradiation
Treatment of Advanced-Stage MF and SS and Management of Relapsed Disease
Bexarotene
Histone Deacetylase Inhibitors
Brentuximab Vedotin
Mogamulizumab
Extracorporeal Photopheresis
Systemic Chemotherapy
Primary Cutaneous CD30+ T-Cell Lymphoproliferative Disorders
Primary Cutaneous Anaplastic Large-Cell Lymphoma
Morphology
Clinical Manifestations
Therapy
Prognosis
Lymphomatoid Papulosis
Morphology
Clinical Manifestations
Therapy
Prognosis
Future Directions
References
Suggested Readings
Chapter
90
Monoclonal Gammopathy of Undetermined Significance and Smoldering Multiple Myeloma
Monoclonal Gammopathy of Undetermined Significance
Epidemiology
****
Prevalence
Incidence
Other Risk Factors
Pathobiology
Clinical Manifestations
Association of Monoclonal Gammopathy of Undetermined Significance With Other Diseases
Monoclonal Gammopathy Associated Neuropathy
Monoclonal Gammopathy Associated Renal Disorders
Monoclonal Gammopathy Associated Dermatologic Diseases
Other Associations of Monoclonal Gammopathy of Undetermined Significance
Laboratory Manifestations
Differential Diagnosis
Prognosis
Size of M Protein
Type of M Protein
Abnormal Serum-Free Light Chain Ratio
Other Risk Factors
Risk Stratification
Life Expectancy
Therapy
MGUS Associated Disorders
Variants of Monoclonal Gammopathy of Undetermined Significance
Secondary Monoclonal Gammopathy of Undetermined Significance
Biclonal and Triclonal Gammopathy
Smoldering Multiple Myeloma
Introduction
Epidemiology
Pathobiology
Clinical Manifestations
Laboratory Manifestations
Differential Diagnosis
Prognosis
Size and Type of M Protein
Extent of Bone Marrow Involvement
Suppression of Uninvolved Immunoglobulins
Magnetic Resonance Imaging
Positron Emission Tomography-Computed Tomography
Serum Free Light Chain Assay
Multiparametric Flow Cytometry
Cytogenetic Abnormalities
Change in Monoclonal Protein Level
Risk Stratification
Therapy
Future Directions
References
91
Multiple Myeloma
Screening, Epidemiology, and Risk Factors
Pathogenesis
Genomic Landscape of Multiple Myeloma at Presentation
Primary Genomic Driver Events
Genomic Drivers of Progression From Precursor to Myeloma and Beyond
Clinical Implications of Clonal Heterogeneity and Evolution
Immune and Bone Marrow Microenvironment
Clinical Manifestations
Bone Disease
Hypercalcemia
Renal Failure
Anemia
Neurologic Symptoms
Hyperviscosity
Immune Deficiency
Coagulation Disorders
Amyloidosis
Laboratory and Radiologic Studies for the Diagnosis and Monitoring of Multiple Myeloma and Related Entities
Investigations to Detect Clonality
Protein Electrophoresis
Serum Free Light Chains
Bone Marrow Examination
Investigations to Detect End-Organ Damage
Radiographic Evaluation
Renal Function
Blood Counts and Serum Calcium
Ancillary Studies
Minimal Residual Disease
Staging, Prognosis, and Risk Stratification
Genomic Biomarkers
Differential Diagnosis
Indications for Treatment
Response Criteria
Solitary Plasmacytoma: Medullary and Extramedullary
Plasma Cell Leukemia
Overview of Therapy for Multiple Myeloma
Treatment of Newly Diagnosed Myeloma
Chemotherapy with Cytotoxic Agents
Combinations of Three, Four, or More Classes of Novel Agents
Selected Trials of Induction Therapy With Novel Agents
Practical Considerations of Induction Therapy
Skeletal Protection
High-Dose Melphalan Therapy and Consolidation
Specific Trials of High-Dose Melphalan With Autologous Stem Cell Transplant
Maintenance
Relapsed Disease
Managing Relapsed Multiple Myeloma
Disease-Related Factors
Patient-Related Factors
Treatment-Related Factors
Role of Salvage Autologous and Allogeneic Stem Cell Transplant
Practical Approach to the First Relapse
Approach to Second Relapse and Beyond
Investigational Therapies in Relapsed and/or Refractory Disease
Future Directions
Suggested Readings
References
92
Waldenström Macroglobulinemia/Lymphoplasmacytic Lymphoma
Epidemiology
Pathogenesis
Nature of the Waldenström Macroglobulinemia Clone
Mutation in MYD88
CXCR4 Whim Mutations
Other Somatic Events
Impact of WM Genomics on Clinical Presentation
Marrow Microenvironment
Clinical Features
Morbidity Mediated by the Effects of Immunoglobulin M
Hyperviscosity Syndrome
Cryoglobulinemia
Autoantibody Activity
Immunoglobulin M–Related Neuropathy
Cold Agglutinin Hemolytic Anemia
Immunoglobulin M Tissue Deposition
Manifestations Related to Tissue Infiltration by Neoplastic Cells
Lung
Gastrointestinal Tract
Renal System
Skin
Joints
Eye
Central Nervous System
Laboratory Findings
Blood Abnormalities
Marrow Findings
Immunologic Abnormalities
Serum Viscosity
Imaging
Lymph Node Biopsy
Treatment
Initiating Treatment
Initial Therapy
Oral Alkylating Agents
Nucleoside Analogue Therapy
CD20-Directed Antibody Therapy
Proteasome Inhibitors
Combination Therapies
Novel Therapeutics
Maintenance Therapy
High-Dose Therapy and Stem Cell Transplant
Treatment Recommendations During the COVID-19 Pandemic
Response Criteria in Waldenström Macroglobulinemia
Course and Prognosis
Future Directions
Suggested Readings
References
93
Immunoglobulin Light-Chain Amyloidosis (Primary Amyloidosis)
Epidemiology
Pathobiology of the Disease
Clinical Manifestations
Patient 1
Comment on Patient 1
Patient 2
Comment on Patient 2
Laboratory Manifestations
Differential Diagnosis
Excluding Localized Amyloidosis
Systemic Forms of Amyloidosis Unrelated to Immunoglobulin Light Chain
Prognosis
Response Assessments and Importance of Supportive Care in Amyloid Light-Chain Amyloidosis
Treatment for Light-Chain Amyloidosis
Bortezomib
Daratumumab
Autologous Hematopoietic Stem Cell Transplantation
Mayo Clinic Treatment Approach in Newly Diagnosed Amyloid Light-Chain Amyloidosis
Organ Transplantation
Conclusions
Future Directions
References
Suggested Readings
PART VIII COMPREHENSIVE CARE OF PATIENTS WITH HEMATOLOGICMALIGNANCIES
94
Key Considerations for Managing Infections in the Compromised Host
Hematologic Conditions Predisposing To Infection
Malignant Hematologic Disorders
Antineoplastic Therapy
Acute Leukemias
Chronic Leukemias
Lymphomas
Myelodysplastic Syndrome
Multiple Myeloma
Uncommon Malignancies
Nonmalignant Hematologic Disorders
Aplastic Anemia
Paroxysmal Nocturnal Hemoglobinuria
Granulocytic Phagocyte Disorders
Erythrocyte Disorders
Hemoglobin Gene Variants
Coagulation Disorders
Blood Groups
Host Defense Impairment and Associated Infection Issues
Neutropenia
Defects in Cell-Mediated Immunity
Defects in the Humoral Immune System
Abnormalities in Splenic Function
Infections Associated With Immunotherapy
Anatomic Alterations in Host Defense
Infection in Patients With Acute Neutropenia or Lymphopenia Following Chemotherapy or Transplantation
Fever
Pulmonary Infiltrates
Bacteria
Viruses
Fungi
Malignancy-Associated Fever and Drug Fever
Infection Management In The Hematopoietic Stem Cell Transplant Recipient: A Model Of Severe Immune Deficiency
Pretransplantation Prophylactic Techniques in Hematopoietic Stem Cell Transplant Recipients
Assessment of Pretransplantation Serostatus
Herpes Simplex Virus
Cytomegalovirus
Varicella, Human Herpes Virus Type 6, and Epstein-Barr Virus
Hepatitis B and C
Human Immunodeficiency Virus
Syphilis
Toxoplasma
Review of Commonsense Measures to Prevent Infection
Environmental Measures to Prevent Infection
Infection in the Hematopoietic Stem Cell Transplant Recipient Preengraftment
Infection in the Hematopoietic Stem Cell Transplant Recipient After Engraftment
Cytomegalovirus
Varicella-Zoster Virus
Epstein-Barr Virus
Invasive Mold Infections
Pneumocystis
Parasitic Infections
Infection Issues in the Late Posttransplantation Period
Encapsulated Organism Prophylaxis
Vaccination
Suggested Readings
References
95
Principles of Radiation Therapy for Hematologic Disease
History and Background
Hodgkin Lymphoma and the Changing Landscape
Modern Radiation Planning and Treatment Techniques
Optimal Use of Imaging
Radiation Therapy by Diagnosis
Hodgkin Lymphoma
Nodular Lymphocyte Predominant Hodgkin Lymphoma
Relapsed/Refractory Hodgkin Lymphoma
Non-Hodgkin Lymphoma
Diffuse Large B Cell Lymphoma
Indolent Lymphoma
Relapsed/Refractory Diffuse Large B-Cell Lymphoma
Multiple Myeloma and Plasmacytoma
Leukemia
Skin Lymphoma
Rare/Miscellaneous and Special Situations
Dose Constraints and Tolerances
Summary of Guidelines
Future Directions
Suggested Readings
References
Chapter
96
Grading and Toxicity Management after Immune Effector Therapy
Cytokine Release Syndrome
Grading of Cytokine Release Syndrome
Management of Cytokine Release Syndrome
Immune Effector Cell–Associated Neurotoxicity Syndrome
Grading of Immune Effector Cell–Associated Neurotoxicity Syndrome
Management of Immune Effector Cell–Associated Neurotoxicity Syndrome
Other Toxicities From Immune Effector Therapy
Conclusions
References
97
Identification and Management of Checkpoint Inhibition Toxicity
Immunotherapy-Related Fatigue and Systemic Toxicities
Dermatologic/Mucosal Toxicity
Diarrhea/Colitis
Hepatitis
Pneumonitis
Endocrinopathies
Type 1 Diabetes Mellitus
Rare Immune-Related Toxicities
Neurological Adverse Events
Cardiac Toxicity
Rheumatologic Toxicity
Renal Toxicity
Hematologic Toxicities
Summary of Toxicity Management
Peritransplant Period, Impact on Graft-Versus-Host Disease
Patients with Autoimmune Disease
Conclusions
References
98
Psychosocial Aspects Of Hematologic Disorders
Clinical Course of Hematologic Malignancies
Time of Diagnosis
Treatment
Hematopoietic Stem Cell Transplantation
Psychological Considerations in Hematopoietic Stem Cell Transplantation
Immediate Period Following Diagnosis and Treatment
Time of Relapse
Survivorship
Terminal Stage and End-of-Life Care
Factors that Influence Psychosocial Adjustment
Patient Factors
Environmental Factors
Disease-Related Factors
Differentiating Psychiatric Complications from Expected Psychologic Response
Screening for Psychologic Distress
Screening for Positive Psychological Wellbeing
Management of Psychosocial Problems
Pharmacologic Interventions
Psychotherapeutic Interventions
Future Directions
Suggested Readings
References
99
Pain Management and Antiemetic Therapy in Hematologic Disorders
Taxonomy of Pain
Evaluation of the Pain Complaint
Initial Evaluation
Continued Assessment
Therapy Directed at the Underlying Etiology
Nonpharmacologic Methods of Pain Management
Cognitive-Behavioral Interventions
Education and Reassurance
Hypnosis
Meditation
Cognitive-Behavioral Techniques and Counseling
Cutaneous Techniques
Neuromodulation
Radiation Therapy
Vertebroplasty and Kyphoplasty
Anesthetic Techniques
Pharmacotherapy
Management of Mild-to-Moderate Pain
Management of Moderate-to-Severe Pain
Opioid Analgesics
Patient Education and Risk Assessment
Choice of Medication
Practical Considerations When Using Opioids
Routes of Delivery
Oral Route
Rectal Route
Transdermal Route
Transmucosal Route
Subcutaneous and Intravenous Routes
Spinal Route
Management of Opioid-Related Side Effects
Sedation
Constipation
Nausea
Respiratory Depression
Adjuvant Analgesics
Neuropathic Pain
Bone Pain
Cannabinoids
Specific Clinical Problems
Oral Complications
Postherpetic Neuralgia
Sickle Cell Anemia
Patients With Opioid Addiction
Hematopoietic Stem Cell Transplantation
Graft-Versus-Host Disease
Peripheral Neuropathy Caused by Chemotherapy Agents
Problems in Older Patients
Pathophysiology of Nausea and Vomiting
Patient Assessment
Anticipatory Nausea and Vomiting
Acute and Delayed Chemotherapy-Induced Nausea and Vomiting
Therapy
Antiemetic
Combination Antiemetic
Serotonin Receptor Antagonists: Ondansetron, Granisetron, and Palonosetron
Corticosteroids
Metoclopramide
Neurokinin-1 Inhibitors
Olanzapine
Anticipatory Nausea and Vomiting
Benzodiazepines
Cannabinoids
Other Drugs
Conclusion
Acknowledgments
Suggested Readings
References
100
Palliative Care
Communication
Prognosis and Decision Making
Pediatric Population
Adult Population
Communication in Serious Illness: Strategies
Cultivating Prognostic Awareness
Breaking Bad News
REMAP: A Framework to Facilitate Effective Late Goals of Care Conversations
Caregiver Distress
Relief of Suffering
Management of Physical Distress in Children
Management of Physical Distress in Adults
Social Concerns
Spiritual Concerns
Psychological Concerns
Anxiety and Depression
Delirium
Management Concerns During the Last Days of Life
Children
Adults
Hospice Programs
Bereavement
Conclusion and Future Directions
Palliative Care Integration with Hematologic Malignancy Care
References
101
Therapy-Related Late Effects of Hematologic Malignancies
Cardiovascular Disease
Cardiac Disease
Arterial Disease
Prevention of Cardiotoxicity
Pulmonary Effects
Endocrinologic Effects
Thyroid
Obesity
Gonadal Dysfunction
Musculoskeletal Effects
Cognitive Impairment
Psychosocial Effects
Other Toxicities
Ocular Effects
Audiologic Effects
Second and Subsequent Neoplasms
Subsequent Malignancies Among Survivors of Acute Lymphoblastic Leukemia
Subsequent Malignancies in Hodgkin Lymphoma Survivors
Subsequent Malignancies in Multiple Myeloma Survivors
Subsequent Malignancies in Non-Hodgkin Lymphoma Survivors
Subsequent Breast Cancer
Subsequent Thyroid Cancer
Therapy-Related Myelodysplasia/Acute Myeloid Leukemia
Molecular Basis for Subsequent Neoplasms
Late Mortality
Potential Late Effects By Diagnosis
Acute Lymphoblastic Leukemia
Acute Myeloid Leukemia
Hodgkin Lymphoma
Non-Hodgkin Lymphoma
Chronic Myeloid Leukemia
Providing Clinical Care to Survivors
Future Directions
Suggested Readings
References
PART IX TRANSPLANTATION AND OTHER CELL-BASED THERAPIES
102
Practical Aspects of Hematopoietic Stem Cell Harvesting and Mobilization
Stem Cell Donor
Selection of Autologous Donor
Selection Allogeneic Donor
Evaluation of Hematopoietic Stem Cell Donor Suitability and Eligibility
Determination of Suitability for Peripheral Blood Stem Cell Donation
Determination of Suitability for Bone Marrow Donation
Suitability and Eligibility for Umbilical Cord Blood Donation
Stem Cell Collection
Bone Marrow Collection Techniques
Complications of Bone Marrow Collection
Collection of Umbilical Cord Blood Stem Cells
CB Collection Techniques
Collection Peripheral Blood Stem Cells
Mobilization
Cytokine Mobilization
Granulocyte Colony-Stimulating Factors Including Biosimilars
Mobilization of Hematopoietic Stem Cells Using Granulocyte Colony-Stimulating Factor
Toxicity and Complications of Granulocyte Colony-Stimulating Factor
Plerixafor
Combination Regimen
Plerixafor Plus Granulocyte Colony-Stimulating Factor
Chemotherapy Plus Cytokine Mobilization
Granulocyte-Macrophage Colony-Stimulating Factor Plus Granulocyte Colony-Stimulating Factor
Other Hematopoietic Cytokines
Strategies for the Patient Who Is Difficult to Mobilize
Collection of Peripheral Blood Stem Cells by Apheresis
Apheresis Technology
Timing of Apheresis Using Granulocyte Colony-Stimulating Factor and Chemotherapy
Timing of Apheresis Using Granulocyte Colony-Stimulating Factor and Plerixafor
Large-Volume Leukapheresis
Anticoagulation During Apheresis
Venous Access
Pediatric Donors and Patients
Complications of Apheresis Collection
Hematopoietic Stem Cell Product Quality
Hematopoietic Stem Cell Product Composition
CD34+ Cell Enumeration and Dose
Bone Marrow
Peripheral Blood Stem Cells
Cord Blood
Tumor Contamination
Microbial Contamination
References
103
Graft Engineering and Cell Processing
Regulatory Issues With Cell Processing
Professional Standards
Manipulation Of Hematopoietic Stem Cell Transplantation Products
Routine Minimal Manipulation for Volume Reduction or ABO Incompatibility
Purging of Autologous Grafts
T-Cell Depletion of Allogeneic Products
Regulatory T Cells
Positive Selection of Progenitor Cells
Evaluation of Manipulated Allogeneic Grafts
Flow Cytometry
Functional Assays
Release of Manipulated Grafts for Clinical Administration
Cellular Therapy Products
Donor Leukocyte Infusions
Allodepleted Cells
Tumor-Infiltrating Lymphocytes
Suicide Gene-Transduced Lymphocytes
Antigen-Specific Cytotoxic T Lymphocytes
Chimeric Antigen Receptor T Cells
Analysis of Antigen-Specific T cells
Enzyme-Linked Immunosorbent Spot
Natural Killer Cells
Natural Killer T Cells
Dendritic Cells
Mesenchymal Stromal Cells
Cancer Vaccines
Future Directions
References
104
Principles of Cell-Based Genetic Therapies
Hematologic Diseases, Cellular Targets, and the Basis for Genetic Therapies
Vector Systems
Retrovirus Vectors
Lentivirus Vectors
Experience in Hematologic Clinical Trials to Date
X-Linked Severe Combined Immunodeficiency
Adenosine Deaminase Deficiency
Chronic Granulomatous Disease
Wiskott-Aldrich Syndrome
Childhood Cerebral X-Linked Adrenoleukodystrophy
β-Thalassemia
Sickle Cell Disease
Insertional Mutagenesis
Recent Modifications of Vector Systems Based on Clinical Experience
New Cell Targets in Genetic Engineering
Site-Directed Homologous Recombination to Correct Gene Mutations
Future Directions
Acknowledgments
Suggested Readings
References
105
Indications, Outcomes, and Donor Selection for Allogeneic Hematopoietic Cell Transplantation for Hematologic Malignanc ...
Background
Patient Population
Conditioning Regimens
Donor Factors
Graft Sources
Donor Selection
Graft-Versus-Host Disease Prophylaxis
Impact of Measurable Residual Disease
Prevention of Relapse after Allogeneic Transplantation
Timing of Transplantation
Patient- and Disease-Related Factors
Long-Term Survival after Allogeneic Transplantation
Disease-Specific Indications for Allogeneic Transplantation
Acute Myeloid Leukemia
Acute Lymphoblastic Leukemia
Chronic Myelogenous Leukemia
Chronic Lymphocytic Leukemia
Diffuse Large B-Cell Lymphoma
Follicular Lymphoma
Mantle Cell Lymphoma
T-Cell Lymphoma
Hodgkin Lymphoma
Multiple Myeloma
Suggested Readings
References
106
Unrelated Donor Hematopoietic Cell Transplantation
The Human Leukocyte Antigen and Killer-Cell Immunoglobulin-LIKE Receptor Genetic Systems
Genetics of the Human Leukocyte Antigen Complex
Human Leukocyte Antigen Typing Methods
Genetics of the Killer-CellImmunoglobulin-Like Receptors System
Killer-Cell Immunoglobulin-Like Receptors Typing Methods
Donor Identification and Likelihood of Transplantation
Human Leukocyte Antigen Criteria
Human Leukocyte Antigen Vector of Mismatching
Human Leukocyte Antigen Haplotypes
Donor Killer-Cell Immunoglobulin-LIKE Receptor Criteria
Clinical Significance of Human Leukocyte Antigen and Killer-Cell Immunoglobulin-LIKE Receptor in Transplantation
Human Leukocyte Antigen Matched Transplantation
Single-Locus Mismatched Transplantation
Importance of Killer-Cell Immunoglobulin-Like Receptor in Relapse After Transplantation
Summary
Beyond Classical Human Leukocyte Antigen
The Major Histocompatibility Complex in the Next-Generation Sequencing Era
Suggested Readings
References
107
Haploidentical Hematopoietic Stem Cell Transplantation​
Introduction
Historical Perspective
Immunological Considerations Of Major Human Leukocyte Antigen Mismatched Grafts
Natural Killer Cell Alloreactivity After Allogeneic Transplantation
Models of Natural Killer Cell Alloreactivity After Transplant
Modern approaches to haploidentical transplantation (Fig. 107.3​)
Refinements to the T-Cell Depletion Platform to Improve Immune Reconstitution
Alpha/Beta T-Cell Depleted Haploidentical Transplantation
G-CSF Stimulation of the Donor, Intensified Immunosuppression (CsA, MMF, and MTX), Anti-Thymocyte Globulin and Combination ...
Haploidentical Transplantation With Post-Transplant Cyclophosphamide
Clinical Studies Using Post-Transplant Cyclophosphamide-Based Graft-Versus-Host Disease Prophylaxis
Post-Transplant Cyclophosphamide in Combined Solid Organ—Hematopoietic Stem Cell Transplantation
Comparative Outcomes Between Haploidentical And Other Donor Grafts
Haploidentical Versus Cord Blood Transplants
Haploidentical Versus Human Leukocyte Antigen Matched and Mismatched Unrelated Donor Transplants
GIAC Protocol
α/β T-Cell Depleted Haploidentical Transplantation
Post-Transplant Cyclophosphamide
Haploidentical Versus Human Leukocyte Antigen-Matched Sibling Donor Transplants
GIAC Protocol
Post-transplant Cyclophosphamide
Potential Complications After Haploidentical Transplantation
Graft Failure
Treatment of Patients With Graft Failure After Transplantation
Toxicity From Chemotherapy
Complications Related to High-Dose Post-Transplant Cyclophosphamide
Cytokine Release Syndrome
Delayed Immunologic Reconstitution and Infectious Complications
Infectious Complications After Haploidentical Stem Cell Transplantation
Relapse Post-Transplant
Mechanisms of Disease Relapse Post Haplo-Transplant
Treatment of Relapsed Hematologic Malignancy After Human Leukocyte Antigen-Haploidentical Stem Cell Transplants
Prevention of Relapse After Haploidentical Stem Cell Transplantation
Unmodified Donor Lymphocyte Infusion
Modified Donor Lymphocyte Infusion With a Safety Switch
Chimeric Antigen Receptor Modified T Cells
Infusion of Ex Vivo Expanded Natural Killer Cells
Donor Selection For Haploidentical Transplantation (Table 107.4​)
Conclusions And Future Directions
References
Suggested Readings
108
Cord Blood Transplantation
Cord Blood As A Stem Cell Source
Cord Blood Unit Selection
Cell Dose
HLA-Matching
Cord Blood Bank
Donor-Specific Antibodies
Conditioning Regimens In CORD BLOOD Transplantation
Myeloablative Conditioning
Reduced-Intensity and Non-Myeloablative Conditioning
Conditioning Regimens for Non-Malignant Disease in Children
Graft-Versus-Host Disease In Cord Blood Transplantation
Graft-Versus-Host Disease Prophylaxis in Cord Blood Transplantation
Graft-Versus-Host Disease Outcomes in Cord Blood Transplantation
Outcomes Of Cord Blood Transplantation
Acute Leukemia and Myelodysplastic Syndrome
Mature Lymphoid Malignancies
Non-Malignant Diseases in Pediatrics
Other Diseases
Outcomes Of Cord Blood Relative To Other Donor Types
Strategies To Improve Cord Blood Transplantation Outcomes
Ex Vivo Cord Blood Expansion
Improving Homing of Cord Blood
Combination of Cord Blood and Haploidentical Donor
Supportive Care In Cord Blood Transplantation
Infection Prophylaxis
Growth Factor Support
Summary
Suggested Readings
References
109
Graft-Versus-Host Disease and Graft-Versus-Leukemia Responses​
Graft-Versus-Host Disease: Clinical And Pathologic Aspects
Acute Graft-Versus-Host Disease
Clinical Features of Acute Graft-Versus-Host Disease
Other Organs
Differential Diagnosis
Genetic Basis of Graft-Versus-Host Disease
Human Leukocyte Antigen Matching
Minor Histocompatibility Antigens
Other Non-HLA Genes
Pathophysiology Of Acute Graft-Versus-Host Disease
Phase 1: Host Tissue Injury and Activation of Antigen-Presenting Cells
Host Tissue Injury and the Microbiome
Microbial Changes in Acute Graft-Versus-Host Disease
Use of Antibiotics
Microbial Metabolites in Acute Graft-Versus-Host Disease
Short-Chain Fatty Acids
Dietary Resistant Starch and Short-Chain Fatty Acids
Short-Chain Fatty Acids and Acute Graft-Versus-Host Disease
Dietary Manipulation of the Microbiome-Metabolome Axis and Acute Graft-Versus-Host Disease
Phase 2: Donor T-Cell Activation, Differentiation, and Migration
Costimulation
T-Cell Subsets
CD4+ and CD8+ Cells
Naïve and Memory Subsets
Regulatory T Cells
T-Cell Apoptosis
Cytokines and T-Cell Differentiation
CD4+ and CD8+ T Cells
Naïve and Memory T Cells
Leukocyte Migration
Phase 3: Effector Phase
Cellular Effectors
Inflammatory Effectors
Biomarkers Of Graft-Versus-Host Disease
Prevention of Acute Graft-Versus-Host Disease
Evolution of Modern Clinical Graft-Versus-Host Disease Prevention Strategies
Therapy for Acute Graft-Versus-Host Disease
Chronic Graft-Versus-Host Disease
Clinical Manifestations of Chronic Graft-Versus-Host Disease
Dermatologic
Ocular
Oral
Gastrointestinal
Hepatic
Pulmonary
Hematopoietic
Immunologic
Musculoskeletal
Differential Diagnosis
Chronic Graft-Versus-Host Disease: Pathophysiology
Therapy For Chronic Graft-Versus-Host Disease
Syngeneic Graft-Versus-Host Disease
Transfusion-Associated Graft-Versus-Host Disease
Graft-Versus-Leukemia Responses
Clinical Features
Genetic Basis
KIR Polymorphisms
Immunobiology of Graft-Versus-Leukemia Responses
Phase 1: Activation of Antigen-Presenting Cells
Phase 2: Donor T Cell Activation
T-Cell Subsets
T-Cell Migration
Phase 3: Effector Phase of Graft-Versus-Leukemia
Donor Leukocyte Infusions
Complications of Donor Leukocyte Infusions
Future Directions
References
110
Supportive Care for the Transplant Patient​
Infections
Febrile Neutropenia
Cytomegalovirus Infection
Epidemiology and Risk Factors
Clinical Presentation and Diagnosis
Prevention and Treatment
Other Latent Viral Infections
Acquired Viral Infections
Fungal Infections
Candida infections
Aspergillus Infections
Pneumocystis jirovecii Pneumonia
Early Non-Infectious Complications
Graft Failure
Veno-occlusive Disease
Interstitial Pneumonitis
Infectious Causes of Interstitial Pneumonitis
Non-infectious Causes of Interstitial Pneumonitis
Idiopathic Pulmonary Syndrome
Diffuse Alveolar Hemorrhage
Other Complications
Late Non-Infectious Complications
Organ-Specific Late Effects
Second Cancers
Quality of Life After Transplantation
Graft-Versus-Host Disease
Acute Graft-Versus-Host Disease
Risk Factors and Clinical Features
Prophylaxis of Graft-Versus-Host Disease
Treatment of Acute Graft-Versus-Host Disease
Chronic Graft-Versus-Host Disease
Risk Factors and Clinical Features
Treatment of Chronic Graft-Versus-Host Disease
Future Directions
References
Suggested Readings
PART X TRANSFUSION MEDICINE
111
Human Blood Group Antigens and Antibodies
Erythrocyte Blood Group Antigens
Terminology
DNA-Based Typing for Blood Group Antigens
Blood Group Antibodies
Compatibility Procedures and Location of Antigen-Negative Blood
ABO
Rhesus
Antibody Screening
Compatibility Testing
Prevention of Alloimmunization
Blood Group Disease Association
Blood Group Systems
Carbohydrate Blood Groups
ABO and H
Antigens and Their Synthesis
Inherited and Acquired ABH Variation.
Genes and Enzymes.
ABO and Transplantation.
Antibodies.
Other Carbohydrate Blood Group Systems
Protein Blood Groups
Rhe, Rhe-associated Glycoprotein, and LW Blood Group Systems
Genes, Proteins, Antigens, and Phenotypes.
Antibodies.
RHAG Blood Group System
Lansteiner-Wiener Blood Group System
Kell and Kx Systems
McLeod Syndrome.
Duffy Blood Group System
Antigens.
Antibodies.
Kidd Blood Group System
Antigens.
Antibodies.
MNS System
Antibodies.
Other Protein Antigens
Lutheran System
Antibodies.
Diego System
Antibodies.
Yt Blood Group System
Antibodies.
Scianna Blood Group System
Antibodies.
Dombrock Blood Group System
Antibodies.
Colton Blood Group System
Antibodies.
Gerbich Blood Group System
Antibodies.
Cromer Blood Group System
Antibodies.
Knops Blood Group System
Antibodies.
Indian Blood Group System
Antibodies.
Chido/Rodgers Blood Group System
Antibodies.
Jr Blood Group System
Antibodies.
Lan Blood Group System
Antibodies.
Vel Blood Group System
Antibodies.
CD59 Blood Group System
Antibodies.
Augustine Blood Group System
Antibodies.
KANNO Blood Group System
Antibodies.
References
Chapter
112
Principles of Red Blood Cell Transfusion
Red Blood Cell Components
Whole Blood
Red Blood Cells
Leukocyte-Reduced Red Blood Cells
Washed Red Blood Cells
Irradiated Red Blood Cells
Frozen Red Blood Cells
Appropriate Transfusion Practice in Various Clinical Settings
Chronic Anemia
Perioperative Period
Red Blood Cell Transfusion in Neonates
Red Blood Cell Transfusion in the Allogeneic Hematopoietic Stem Cell Transplantation Recipient
Red Blood Cell Preservation and Storage
Biochemical Changes Associated with Red Blood Cell Storage
Adenosine Triphosphate Levels
2,3-Diphosphoglycerate Levels
Citrate
Potassium
Di(2-ethylhexyl)phthalate
Storage Length of Red Blood Cells
Current Status
Red Blood Cell Storage Lesion
Clinical Relevance of the Red Cell Storage Lesion
Red Cell Alloimmunization
Overview
Individuals at Risk
Molecular Pathophysiology
Red Blood Cell Alloimmunization Mitigation Strategies
Alternatives to Allogeneic Red Cell Transfusions
Autologous Blood Transfusion
Advantages of Autologous Blood Transfusion
Preoperative Autologous Blood Collection
Intraoperative Blood Salvage
Hemodilution
Blood Substitutes
Red Blood Cell Substitutes
Hemoglobin-Based Oxygen Carriers
Potential Clinical Applications
Red Blood Cells Derived From Stem Cells
Suggested Reading
113
Clinical Considerations in Platelet Transfusion Therapy
Platelet Collection and Manufacturing
Prophylactic Platelet Transfusion
Prophylactic Platelet Dosing
Prophylactic Platelets for Invasive Bedside Procedures
Prophylactic Platelets for Major Surgical Procedures
Platelets to Treat Bleeding
Adverse Effects of Platelet Transfusion
Infectious Risks
Allergic and Febrile Nonhemolytic Transfusion Reactions
ABO and Hemolytic Reactions to Platelets
Transfusion-Related Acute Lung Injury
D Sensitization
Platelet Refractoriness
Causes of Refractoriness to Platelet Transfusion
Diagnosis of Platelet Refractoriness
Detection of Anti-Human Leukocyte Antigen Antibodies
Detection of Antiplatelet Antibodies
Prevention of Alloimmunization
Management of Platelet-Refractory Patients
References
114
Human Leukocyte Antigen and Human Neutrophil Antigen Systems
The Genetics, Structure, and Function of Human Leukocyte Antigen Molecules
Organization of the Human Leukocyte Antigen Genes
Inheritance and Linkage Disequilibrium
Structure of the Human Leukocyte Antigen Class I and II
Expression of Human Leukocyte Antigen Molecules
Human Leukocyte Antigen Polymorphism and Its Clinical Significance
Nonclassic Major Histocompatibility Complex and Major Histocompatibility Complex Class I Chain-Related Molecules
Non-Human Leukocyte Antigen Polymorphism and Its Clinical Significance
Human Leukocyte Antigen Nomenclature
Immunologically Defined Human Leukocyte Antigen Nomenclature
Sequence-Defined Allelic Nomenclature
Human Leukocyte Antigen Typing in Clinical Hematology and Determination of Compatibility Human Leukocyte Antigen Typing
Testing for Allosensitization and Determination of Compatible Donor-RECIPIENT Pairs
The Human Leukocyte Antigen Molecules as Antigens and Human Leukocyte Antigen Alloimmunization
Human Leukocyte Antigen as a Functional Mediator of Graft-Versus-Host Disease and/or Graft-Versus-Neoplasia Effect
Graft-Versus-Host Disease
Graft-Versus-Neoplasia Effect
Human Leukocyte Antigen and T-Cell-Directed Immunization
Monitoring Immune Responses With Tetrameric Human Leukocyte Antigen-Peptide Complexes
Human Leukocyte Antigen Summary
Human Neutrophil Antigens and Their Clinical Significance
The HNA-1 Antigen System
Expression of HNA-1 Antigens
Biochemistry
Molecular Biology
HNA-1a, -1b, -1c and -1d Polymorphisms
FC γ RIIIB Deficiency
Function of HNA-1 Antigens
The Clinical Relevance of FC γ RIIIB Deficiency
The HNA-2 Antigen System
Expression of HNA-2
CD177 Glycoprotein Biochemistry
Molecular Biology
Polymorphisms
Clinical Relevance of HNA-2 Antigens
The HNA-3 Antigen System
HNA-4 and HNA-5 Antigen Systems
Clinical Significance of Antibodies to Neutrophil Antigens
Alloimmune Neonatal Neutropenia
Autoimmune Neutropenia of Childhood
Transfusion Reactions
Neutrophil Antigens Summary
References
Suggested Readings
115
Principles Of Plasma And Plasma Derivatives
Plasma
Products
FFP and FP24
Thawed Plasma
Cryoprecipitate-Reduced Plasma
Liquid Plasma
Lyophilized Plasma Also Known as Freeze-Dried Plasma
Solvent-Detergent Plasma
Pathogen-Reduced Plasma
Recovered and Source Plasma (Plasma for Manufacturing)
Convalescent Plasma
Indications
Liver Failure
Massive Transfusion
Disseminated Intravascular Coagulation
Rapid Reversal of Warfarin Effect
Thrombotic Thrombocytopenic Purpura and Other Thrombotic Microangiopathies
Prophylactic Use
Dosage
Compatibility
Adverse Events
Cryoprecipitate
Indications
Fibrinogen Deficiency
Fibrin Glue/Sealant
Massive Transfusion
Uremic Bleeding
Dosage
Compatibility
Adverse Events
Plasma Derivatives
Albumin
Indications
Intravascular Volume Expansion
Hypoalbuminemia
Cirrhosis
Nephrotic Syndrome
Ovarian Hyperstimulation Syndrome
Therapeutic Apheresis
Fluid Resuscitation in Sepsis/Burns
Dose
Adverse Effects
Human Immunoglobulin
Indications
Primary or Secondary Immune Deficiencies
B-Cell Chronic Lymphocytic Leukemia With Infection
Chronic Inflammatory Demyelinating Polyradiculoneuropathy
Immune Thrombocytopenia
Kawasaki Disease
Multifocal Motor Neuropathy
Hematopoietic Stem Cell Transplantation
Solid Organ Transplantation
Aplastic Anemia Secondary to Parvovirus
Dermatomyositis
Guillain-Barré Syndrome (Acute Inflammatory Demyelinating Polyneuropathy)
Hypogammaglobulinemia Associated With Multiple Myeloma
Lambert-Eaton Myasthenic Syndrome
Multiple Sclerosis
Myasthenia Gravis
Neonatal Alloimmune Thrombocytopenia
Hemolytic Disease of the Fetus and Newborn
Posttransfusion Purpura
Sepsis and Septic Shock in Adults
Stiff-Person Syndrome
Dosage
Adverse Effects
Hyperimmune Immunoglobulin Products
Antithymocyte Globulin
Dosage
Rh Immunoglobulin
Dosage
Adverse Effects
Coagulation Factor Concentrates
Recombinant Factor Concentrates
Dosage
References
Suggested Readings
116
Hemapheresis
Principles Of Apheresis
Technology And Techniques
Clinical Consultation With the Apheresis Service
Therapeutic Plasma Exchange (Plasmapheresis)
Replacement Fluids For Plasma Exchange
Hematologic Indications for Plasma Exchange
Neurological Disease Indications
Renal Disease Indications for Therapeutic Plasma Exchange
Immunoadsorption and Low-Density Lipoprotein Apheresis
Therapeutic Cytapheresis
Erythrocytapheresis
Leukapheresis
Extracorporeal Photopheresis
Thrombocytapheresis
Peripheral Blood Hematopoietic Stem and Progenitor Cell Collection
Mononuclear Cell Collection For Cellular Immunotherapies
Pediatric Hemapheresis
Technical Aspects
Complications Of Therapeutic Apheresis
Conclusions And Future Directions
References
117
Transfusion Reactions to Blood and Hematopoietic Stem Cell Therapy Products
Hemolytic Transfusion Reactions
Acute Intravascular Hemolytic Transfusion Reactions
Pathophysiology
Clinical Manifestations and Laboratory Testing
Acute Extravascular Hemolytic Transfusion Reactions
Hyperhemolysis
Delayed Hemolytic Reactions
Febrile Nonhemolytic Transfusion Reactions
Allergic Transfusion Reactions
Transfusion-Related Acute Lung Injury
Transfusion-Associated Circulatory Overload
TACO Risk Factors and TACO Prevention
Posttransfusion Infections and Bacterial Contamination
Posttransfusion Bacteremia/Sepsis
Hypotensive Transfusion Reaction
Posttransfusion Purpura
Transfusion-Associated Graft-Versus-Host Disease
Iron Overload—Hemosiderosis
Hemovigilance
Complications Associated With Hematopoietic Stem Cell Infusion
Dimethyl Sulfoxide Toxicity
Red Blood Cell Hemolysis
References
118
Transfusion-Transmitted Diseases
Hepatitis Viruses
Parenterally-Transmitted Hepatitides
Hepatitis B
Hepatitis D
Hepatitis C
Enterically Transmitted Hepatitides
Hepatitis A
Hepatitis E
Non–A-E Hepatitis
Retroviral Infections
Human Immunodeficiency Virus
Human T-Lymphotropic Virus-1 and Virus-2
Human Herpesvirus Infections
Cytomegalovirus
Epstein-Barr Virus (HHV-4)
Human Herpesvirus-8
Other Herpesviruses (Herpes Simplex, Varicella-Zoster Virus, Human Herpesviruses 6 and 7)
Parvovirus
West Nile Virus
Dengue Viruses
Chikungunya Virus
Zika Virus
SARS-CoV-2 (COVID-19)
Pandemic Influenza A
Bacterial Infections
Cellular Product Contamination
Spirochete Infections
Syphilis
Lyme Disease
Other Tick-Borne Bacteria
Parasitic Infections
Malaria
Babesiosis
Leishmaniasis
Toxoplasmosis
Chagas Disease
Transmissible Spongiform Encephalopathies
Future Directions
Suggested Readings
References
119
Pediatric Transfusion Medicine
Pediatric Blood Banking
Blood and Blood Components
Directed Donations
Technical Considerations/Mechanical Devices
Transfusion Medicine: General Indications And Dosing
Indications for Red Blood Cells Transfusion in Neonates, Children, and Adolescents
Neonates Less Than 4 Months Old
Older Infants, Children, and Adolescents
Platelets
Frozen Plasma and Cryoprecipitate
Granulocytes
Transfusion Medicine: Indications In Unique Pediatric Populations
Hemolytic Disease of the Fetus and Newborn
Neonatal Alloimmune Thrombocytopenia
Extracorporeal Membrane Oxygenation
Trauma
Hemoglobinopathies
Thalassemia
Autoimmune Hemolytic Anemia
Hematopoietic Cellular Transplant Patients
Apheresis
Special Processing and Prevention of Adverse Events in Pediatric Patients
Leukocyte-Reduced Blood Components
Cytomegalovirus-Seronegative Blood Components
Irradiation
Washing
Volume Reduction
Reconstitution of RBCs for Neonatal Exchange Transfusion
References
120
Transfusion and Apheresis Support for Sickle Cell Disease Patients
Hemodynamic Considerations
Clinical Considerations for Transfusion
Acute Anemia
Transfusion for Complications of Sickle Cell Disease
Apheresis Supported Red Cell Exchange
PREPARATIVE TRANSFUSION for Stem Cell Transplantation
Selection of Red Cell Components for Transfusion
Red Cell Antigen Matching
Complications of Transfusion Therapy
Iron Overload
References
PART XI HEMOSTASIS AND THROMBOSIS
121
Overview of Hemostasis and Thrombosis
Introduction
Hemostatic System
Vascular Endothelium
Platelet Inhibition
Anticoagulant Activity
Fibrinolytic Activity
Vascular Tone and Permeability
Platelets
Adhesion
Activation and Secretion
Aggregation
Coagulation
Extrinsic Tenase
Intrinsic Tenase
Contact Pathway
Prothrombinase
Termination
Fibrin Formation
Fibrinolytic System
Mechanism of Action of Tissue-Type Plasminogen Activator
Mechanism of Action of Urokinase-Type Plasminogen Activator
Mechanism of Action of Thrombin-Activatable Fibrinolysis Inhibitor
Disorders Of Hemostasis Or Thrombosis
Hemostatic Disorders
Disorders of Primary Hemostasis
Disorders of Secondary Hemostasis
Disorders of Tertiary Hemostasis
Thrombotic Disorders
Arterial Thrombosis
Intracardiac Thrombosis
Venous Thrombosis
Treatment Of Disorders Of Hemostasis And Thrombosis
References
122
Blood Vessels
Hemostatic, Hematopoietic, And Vascular Systems As A Functional Continuum
Structure And Function Of The Vessel Wall
Macrovasculature
Microvasculature
Endothelial Structure, Function, And Heterogeneity
High Endothelial Venules
Endothelium of Bone Marrow Sinuses
Physiologic Functions Of The Endothelium
Endothelium as a Barrier
Endothelium as a Non-Thrombogenic Surface
Endothelial Control of Vascular Tone
Interaction Of Blood Cells With The Vessel Wall
Leukocytes
Platelets
Red Blood Cells
Endothelial Cell Activation and Dysfunction
Molecular Regulators Of Vascular Growth Responses
Vascular Endothelial Growth Factors
Platelet-Derived Growth Factors
Prokineticins
Angiopoietins and TIE Receptors
Notch Pathway
Ephrins and Eph Receptors
WNT and Guidance Factors
Transforming Growth Factor β
Extracellular Matrix, Vascular Integrins, Cadherins, Cell Adhesion Molecules
Structural and Functional Roles of the ECM During Vascular Growth Processes
Adhesion Molecules Involved in Vascular Growth
Proteases
Pleiotropic Regulators Of Vascular Growth
Fibroblast Growth Factors
Inflammatory Mediators
Coagulation Factors
Extracellular Vesicles
Endogenous Inhibitors Of Vascular Growth
Cellular And Molecular Programs Involved In Blood Vessel Growth And Homeostasis
Prenatal Formation of the Vascular System
Postnatal Regulation of Vascular Growth
Vasculogenesis
Angiogenesis
Molecular Interplay Involved in Sprouting Angiogenesis
Vascular Maturation
Capillarization
Lymphangiogenesis
Vasculogenic Mimicry
Vascular Cooption
Vascular Remodeling, Regression, and Endothelial Apoptosis in the Course of Vascular Growth
Arteriogenesis
Mechanisms Triggering Blood Vessel Growth
Therapeutic Implications Of Endothelial And Angiogenic Responses To Disease
Revascularization Therapy
Antiangiogenic Therapy
Tumor Angiogenesis And Antiangiogenesis
Angiogenesis And Antiangiogenesis In Hematopoietic Malignancies
Hematologic Complications Associated With Blood Vessel-Directed Agents
Relationship Between The Vasculature And Hematopoiesis
Summary
Suggested Readings
References
123
Megakaryocyte And Platelet Structure
Megakaryocyte Development
Endomitosis
Cytoplasmic Maturation
Regulation Of Megakaryocyte Development
Platelet Formation
Proplatelets and the Cytoskeletal Mechanics of Platelet Formation
Platelet Maturation at the Proplatelet Tip
Release of Mature Platelets
Location of Platelet Release
Transcriptional Regulation of Platelet Formation
Platelets
Structure of the Resting Platelet
Cytoskeleton of the Resting Platelet
References
124
Molecular Basis of Platelet Function​
Molecular Basis of Platelet Adhesion
Substrates for Platelet Attachment and Spreading
Platelet Adhesion Receptors
Nomenclature
The Integrin Family of Adhesion Receptors
Role of GPIb–IX–V in Platelet Adhesion
Collagen Receptors
CLEC-2
Molecular Basis of Platelet Activation
Soluble Agonist Receptors
Thrombin Receptors
ADP and ATP Receptors28
Thromboxane A2 Receptor
Epinephrine Receptor
Activation Pathways
Heterotrimeric G Proteins Are Early Response Elements for Most Soluble Platelet Agonists36
Protein Tyrosine Kinases Activated by ITAM-linked Receptors Modulate Enzyme Activity and Allow for the Formation of Signali ...
Phospholipase C Is Responsible for the Hydrolysis of Membrane PI-4,5P236
Phosphatidylinositol 3-Kinase Forms 3-Phosphorylated Phosphoinositides36,37
Serine/Threonine Kinases Regulate the Activity of Other Proteins Involved in Platelet Activation33,36,44
Cytosolic Ca2+35,36,39
Phospholipase A2 Is Responsible for the Synthesis of TxA231
Small GTPases40–42
Cyclic Nucleotides Are Inhibitory36
Reorganization of the Actin Cytoskeleton
The Resting Platelet Cytoskeleton
Cytoskeletal Reorganization During Platelet Activation
Secretion of Granules
Dense Granules
α-Granules
Lysosomal Granules
Mechanism of Granule Secretion
Procoagulant Surface Exposure
Platelet-Derived Extracellular Vesicles
Molecular Basis of Platelet Aggregation
αIIbβ3 and Molecular Mechanisms of Aggregation
Laboratory Evaluation of Aggregation
Molecular Basis of Inherited Platelet Disorders
Inherited Platelet Function Disorders
Abnormalities of Platelet Adhesion
GPIb–IX–V15
Collagen Receptors103
Abnormalities of Platelet Activation
Soluble Agonist Receptors
Cytoskeletal Defects
Secretion Defects
Dense Granules105
α-Granules
Signaling Pathways
PS Exposure
Abnormalities of Platelet Aggregation
αIIbβ3115,116
Inherited Thrombocytopenias
Abnormalities of Megakaryocyte Differentiation
Congenital Amegakaryocytic Thrombocyto­penia
Thrombocytopenia With Absent Radii
Amegakaryocytic Thrombocytopenia With Radio-Ulnar Synostosis
Abnormalities of Megakaryocyte Maturation
Familial Platelet Disorder With Predisposition to Myeloid Malignancy
Paris-Trousseau Thrombocytopenia and Jacobsen Syndrome
ANKRD26-Related Thrombocytopenia
ETV6-Related Thrombocytopenia
GATA-1-Related Thrombocytopenias
Gray Platelet Syndrome
Abnormalities of Proplatelet Formation and Platelet Release
MYH9-Related Disease135
ACTN1- and FLNA-Related Thrombocytopenias
Bernard-Soulier Syndrome
ITGA2B/ITGB3-Related Thrombocytopenias
TUBB1-Related Thrombocytopenia
PRKACG-Related Macrothrombocytopenia
Wiskott-Aldrich Syndrome and Other Micro­thrombocytopenias
Platelets Beyond Hemostasis
Suggested Readings
References
125
Molecular Basis of Blood Coagulation​
Inventory: Procoagulant, Anticoagulant, and Fibrinolytic Proteins, Inhibitors and Receptors
The Vitamin K–Dependent Protein Family
Cofactor Proteins
Cell-Bound Cofactors
Tissue Factor
Thrombomodulin
Soluble Plasma Procofactors
Factor V
Factor VIII
von Willebrand Factor
The Intrinsic Accessory Pathway Proteins
Proteinase Inhibitors
Antithrombin
Tissue Factor Pathway Inhibitor
Heparin Cofactor II
Protein C Inhibitor
α2-Macroglobulin
Endothelium
Platelets
Clot Proteins
Fibrinolysis Proteins
Inhibitors of the Fibrinolytic System
Connectivity and Dynamics in Hemostasis
Initiation
Propagation
Termination
Elimination and Fibrinolysis
SUMMARY
Acknowledgments
Suggested Readings
References
126
Evaluation of the Patient With Suspected Bleeding Disorders
BLEEDING HISTORY EVALUATION
Bleeding Score
The Physical Examination
Epidemiology And Genetics
Laboratory Manifestations
Prognosis
Therapy
Summary
Suggested Readings
References
127
Laboratory Evaluation of Hemostatic and Thrombotic Disorders
Laboratory Evaluation Of Coagulation Proteins
The Physiology Underlying Laboratory Evaluation of Coagulation Proteins
Chromogenic Factor Assays
Screening for Coagulation Protein Defects: Activated Partial Thromboplastin Time, Prothrombin Time, and Thrombin Clotting T ...
Evaluation of Specific Coagulation Protein Defects
Evaluation of Specific Inhibitors of Coagulation Proteins
Evaluation of Acquired Inhibitors of Coagulation Proteins
Practical Approach To Laboratory Testing Of Coagulation Proteins
Laboratory Evaluation Of Platelets And Von Willebrand Factor
Screening for Disorders of Primary Hemostasis
Evaluation of Platelets
Evaluation of von Willebrand Factor
Laboratory Evaluation Of Fibrinolysis
Other Activities For Hemostasis Laboratories
Global Hemostasis Assays
Evaluation of Prothrombotic States
Monitoring Anticoagulant Therapy
Evaluating Activated Coagulation States
References
128
Acquired Disorders of Platelet Function
Drugs, Foods, and Additives that Affect Platelet Function
Antiplatelet Drugs
Activation Receptor Antagonists
Adenosine Diphosphate (ADP) Receptor Antagonists
Thrombin Receptor Antagonists
Direct-Acting Agents
Indirect Agents
Experimental Agents
Thromboxane Receptor Antagonists
GPVI Antagonists
GP I/IX/V Antagonists
Activation Receptor Agonists
Adenyl Cyclase Stimulators or Prostacyclin Analogues
Aggregation Inhibitors
Parenteral αIIbβ3 (GPIIb/IIIa) Inhibitors
Abciximab
Eptifibatide
Tirofiban
Oral αIIbβ3 Inhibitors
Signaling Molecule Inhibitors
Acetyl Salicylic Acid (ASA, Brand Names Including Aspirin)
ASA Resistance
Phosphodiesterase Inhibitors
Nonselective Phosphodiesterase Inhibitors
PDE5 Inhibitors
SYK Inhibitors
12-Lipoxygenase Inhibitors
Other Drugs that Adversely Affect Platelet Function
Nonsteroidal Antiinflammatory Drugs
Cardiovascular Drugs
Antibiotics
Antifungal Drugs
Psychiatric Drugs
Oncologic Drugs
Anesthetics
Plasma Expanders
Heparins and Thrombolytic Agents
Miscellaneous Drugs
Foods and Food Additives
Scurvy
Clonal Disorders
Hematological Clonal Disorders
Myeloproliferative Neoplasms
Paroxysmal Nocturnal Hemoglobinuria
Paraproteinemias
Leukemias and Myelodysplastic Syndromes
Solid Tumors
Systemic Metabolic Disorders
End-Stage Renal Disease
Liver Disease
Hypothermia
Trauma
Platelet Dysfunction Related with Extracorporeal Circuits
Infectious Diseases
SARS-CoV-2
Tropical Diseases
Antiplatelet Antibodies
Acquired Platelet Dysfunction With Eosinophilia
Suggested Readings
References
129
Diseases of Platelet Number: Immune Thrombocytopenia, Neonatal Alloimmune Thrombocytopenia, and Posttransfusion Purpur ...
Immune Thrombocytopenia
Epidemiology
Incidence and Prevalence of Immune Thrombocytopenia
Pathophysiology
Primary and Secondary Immune Thrombocytopenia
Clinical and Laboratory Features of Immune Thrombocytopenia
Thrombocytopenia
Clinical Features
Investigations of Patients With Suspected Immune Thrombocytopenia
Prognosis
Clinical Outcomes: Mortality, Bleeding, and Quality of Life
Treatment
Treatment Options
Corticosteroids
Intravenous Immunoglobulin and Rh-Immune Globulin (Anti-D)
Second-Line Therapy
Splenectomy
Rituximab
Thrombopoietin Receptor Agonists
Fostamatinib
Immune Suppressant Medications
Treatment of Refractory Immune Thrombocytopenia
COVID-19 and ITP
Neonatal Alloimmune Thrombocytopenia
Clinical Presentation
Pathophysiology
Laboratory Investigation of Suspected Neonatal Alloimmune Thrombocytopenia
Management
Postnatal Management of Infants After Delivery
Antenatal Management of Mothers in Subsequent Pregnancies
Antenatal Fetal Monitoring of At-Risk Fetuses
Mode of Delivery
Population Screening for Neonatal Alloimmune Thrombocytopenia
Posttransfusion Purpura
Epidemiology
Clinical Presentation
Diagnosis
Pathophysiology
Management
References
Suggested Readings
130
Thrombocytopenia Caused by Hypersplenism, Platelet Destruction, or Surgery/Hemodilution
Approach To Patients With Thrombocytopenia
History and Physical Examination
Timing of Onset and Severity of Thrombocytopenia
Laboratory Evaluation
Therapy
Anatomy And Physiology
The Spleen: Anatomy and Function
Physiologic Platelet Sequestration
Pathologic Platelet Sequestration: Hypersplenism
Definition
Pathogenesis
Diagnosis
Therapy
Drug-Induced Thrombocytopenic Syndromes
Drug-Induced Immune Thrombocytopenia
Pathogenesis
Clinical Features
Diagnosis
Management
Drug-Induced Immune Thrombocytopenia Of Rapid Onset
Thrombocytopenia Caused By Glycoprotein Iib/Iiia Receptor Antagonists
Malignancy
Hemodilution And Platelet Consumption After Surgery
Suggested Readings
References
131
Heparin-Induced Thrombocytopenia
Epidemiology
Pathobiology
Clinical And Laboratory Manifestations
Autoimmune Hit
Differential Diagnosis
Clinical Scoring Systems
Laboratory Diagnosis
Prognosis
Therapy
Indirect Factor Xa Inhibitors: Danaparoid and Fondaparinux
Indirect Factor Xa Inhibitors: Rivaroxaban, Apixaban, Edoxaban
Direct Thrombin Inhibitors: Bivalirudin, Argatroban
High-Dose Intravenous Immunoglobulin
Caveats in Treatment of Heparin-Induced Thrombocytopenia
Platelet Count Monitoring For Heparin-Induced Thrombocytopenia
Anticoagulation And Previous Heparin-Induced Thrombocytopenia
Suggested Readings
References
132
Thrombotic Thrombocytopenic Purpura and the Hemolytic Uremic Syndromes
Differential Diagnosis
THROMBOTIC THROMBOCYTOPENIC PURPURA
Epidemiology
Pathobiology
Clinical Manifestations
Laboratory Manifestations
Inherited ADAMTS13 Deficiency (cTTP)
Treatment of Thrombotic Thrombocytopenic Purpura
Initial Treatment
Plasma Exchange in Thrombotic Thrombocytopenic Purpura
Immunosuppression
Anti–von Willebrand Factor Therapy (Caplacizumab)
Other Modalities
Subsequent Therapy and Monitoring Response
Special Scenarios
Infection-Associated Hemolytic Uremic Syndrome
Clinical Manifestations
Epidemiology
Pathobiology
Laboratory Manifestations
Prognosis
Therapy
Atypical Hemolytic Uremic Syndrome
Epidemiology
Pathophysiology
Genetics
Clinical Manifestations
Laboratory Testing
Prognosis
Therapy
Other Thrombotic Microangiopathic Disorders
Post-Transplantation Thrombotic Microangiopathy
Recurrent Disease and “De-Novo Thrombotic Microangiopathies” After Renal Transplantation
Immunosuppressive Medications
Hematopoietic Stem Cell Transplantation
Cancer and Chemotherapy-Associated Thrombotic Microangiopathy
Streptococcus Pneumonia
Disordered Cobalamin Metabolism
Miscellaneous Drug-Associated Thrombotic Microangiopathy
HIV-Associated Thrombotic Microangiopathy
Pregnancy-Associated Thrombotic Microangiopathy
Suggested Readings
References
133
Structure, Biology, and Genetics of von Willebrand Factor
Functions of Von Willebrand Factor
Platelet Adhesion
Factor VIII Stabilization
Basal Von Willebrand Factor Levels
Von Willebrand Factor Gene
Domain Structure
Biosynthesis
Storage and Secretion
ADAMTS13
Clearance
ABO Blood Groups
Areas of Ongoing Investigation
Von Willebrand Disease
Epidemiology
Classification and Pathophysiology
Von Willebrand Disease Type 1
Von Willebrand Disease Type 2
Type 2A
Type 2B
Type 2M
Type 2N
Von Willebrand Disease Type 3
Low von Willebrand Factor
Clinical Manifestations
Penetrance
Laboratory Investigations
Screening Tests
Confirming a Diagnosis of von Willebrand Disease
Von Willebrand Factor: Antigen
Von Willebrand Factor Activity
Factor VIII: C Level
Discriminating Tests to Identify von Willebrand Disease Subtype
Von Willebrand Factor Multimer Analysis
Low-Dose Ristocetin-Induced Platelet Aggregation
Binding of Factor VIII by von Willebrand Factor
Collagen Binding Assay
Von Willebrand Factor Propeptide/Antigen Ratio
Desmopressin Responsiveness
Genotyping
Differential Diagnosis
Hemophilia A
Platelet-Type von Willebrand Disease
Acquired von Willebrand Syndrome
Management of von Willebrand Disease
Evaluations Following Initial Diagnosis
Treatment of von Willebrand Disease
Localized Measures
Indirect Therapies
Desmopressin
Von Willebrand Factor/Factor VIII Concentrates
Prophylaxis
Pediatric Issues
References
Suggested Readings
134
Hemophilia A and B
Epidemiology
Factor VIII Biology: Genetics, Structure, Function, And Pathophysiology
Factor VIII Gene and FVIII Expression
Factor VIII Expression
Biosynthesis of Factor VIII
Factor VIII Protein Structure
Storage, Secretion, Circulation, and Clearance of Factor VIII
Activation and Coagulant Function of FVIII
Pathophysiology Of Hemophilia A
Factor Ix Biology: Genetics, Structure, Function, And Pathophysiology
FIX Gene and FIX Expression
FIX Protein
Pathophysiology of Hemophilia B
Hemophilia Diagnosis
Phenotypic Diagnosis of Hemophilia
Genetic Diagnosis of Hemophilia
Differential Diagnosis of Hemophilia
Clinical Features Of Hemophilia
Hemophilia in Newborns
Intracranial Hemorrhage in Newborns
Circumcision in Newborns
Bleeding Manifestations With Hemophilia
Hemarthrosis
Soft Tissue Hemorrhages and Muscle Bleeds
Mucous Membrane Bleeding
Hematuria
Gastrointestinal Bleeding
Neurologic Bleeding
Surgery and Bleeding
Clinical Management Of Hemophilia
Preventive Therapy
Preventing Trauma and Promoting Activity
Vaccinations
Avoidance of Aspirin and Other Medications That Increase Risk of Bleeding
Haemostatic Replacement Therapy
Standard Half-Life Clotting Factor Concentrates
Extended Half-Life FVIII and FIX Concentrates (Table 134.6)
Prophylaxis
Individualization of Prophylaxis
When to Start Prophylaxis? Primary, Secondary, or Tertiary Prophylaxis
Emicizumab
Rebalancing Therapies (Fig. 134.11)
Anti-Tissue Factor Pathway Inhibitor
Fitusiran (Sanofi)
Other Rebalancing Agents
Treatment of Bleeds
Treatment of Bleeds With Factor Concentrates
Treatment of Bleeds With Desmopressin
Antifibrinolytic Agents
Fibrin Sealants
Adjunctive Management Strategies for Joint Bleeds
Surgery in Hemophilia
Complications of Treatment
Other Comorbidities in Patients With Hemophilia
Limitations to Treatment for Hemophilia
Inhibitors in Hemophilia
Epidemiology and Clinical Manifestations of Inhibitors
Diagnosis of Inhibitors
Clinical
Laboratory
Inhibitors in Hemophilia A
Pathophysiology of Inhibitor Development in Hemophilia A
Other Immune Responses to FVIII
Anaphylactic Reactions
Non-neutralizing Antibodies
Epidemiology
Genetic (Non-Modifiable) Risk Factors for Inhibitor Development in Hemophilia A (Fig. 134.14)
Treatment-Related and Modifiable Risk Factors
MANAGEMENT OF INHIBITORS IN HEMOPHILIA A
Treatment of Bleeds
Prophylaxis in Patients With Inhibitors to FVIII
Eradication of Inhibitors in Hemophilia A (ITI)
Prophylaxis of Patients During Immune Tolerance Induction
Inhibitors In Hemophilia B
Pathophysiology
Epidemiology and Risk Factors for Inhibitor Development in Hemophilia B
Clinical Manifestations
MANAGEMENT OF INHIBITORS IN HEMOPHILIA B
Eradication of Inhibitors in Hemophilia B
Gene Therapy For Hemophilia
Modes of Transgene Delivery
Clinical Trials of Hemophilia Gene Therapy
Hemophilia In The World—Economic Considerations
Acknowledgment
References
Suggested Readings
135
Rare Coagulation Factor Deficiencies​
Inherited Fibrinogen Deficiency (OMIM 202400)
Inherited Dysfibrinogenemia (Omim 134820 Aa Chain, 134830 Bb Chain, 134850 g Chain)
Acquired Disorders of Fibrinogen
Inherited Prothrombin Deficiency (Omim 176930)
Acquired Prothrombin Deficiency
Inherited Factor V Deficiency (Omim 227400)
Acquired Factor V Deficiency
Inherited Factor Vii Deficiency (Omim 227500)
Acquired Factor VII Deficiency
Inherited Factor X Deficiency (OMIM 227600)
Acquired Factor X Deficiency
Inherited Factor Xi Deficiency (Omim 264900)
Acquired Factor XI Deficiency
Deficiencies Of Factor Xii, Prekallikrein Or High Molecular Weight Kininogen
Factor XII Deficiency (OMIM 234000)
Prekallikrein Deficiency (OMIM 229000)
High Molecular Weight Kininogen Deficiency (OMIM 228960)
Inherited Factor Xiii Deficiency (Omim 134570 [A Subunit] And 134580 [B Subunit]
Acquired Factor XIII Deficiency
Inherited Deficiencies Involving Multiple Coagulation Factors
Combined Factor V and Factor VIII Deficiency (OMIM 227300)
Combined Deficiency of Vitamin K-Dependent Proteins (OMIM 277450 and 607473)
References
136
Transfusion Therapy for Coagulation Factor Deficiencies
Hemophilia A and B
Transfusion Therapy for Hemophilia A and B
History of Transfusion for Hemophilia
Infusion Regimens and Dosing for Hemophilia
Treatment of Hemophilia
Products Available for Treatment of Factor VIII Deficiency
Factor VIII Concentrates
Recombinant Factor VIII Products
Intermediate- and High-Purity Plasma-Derived Concentrates
Emicizumab-kxwh (Hemlibra, Genentech)
Novel Direction for Factor VIII Deficiency
Gene Therapy for Factor IX Deficiency
Gene Therapy for Factor VIII Deficiency
1-Deamino 8-d Arginine Vasopressin
Plasma/Cryoprecipitate
Products Available for Treatment of Factor IX Deficiency
Factor IX Concentrates
Other Useful Adjuncts for Treatment of Bleeding in Hemophilia A and B
Inhibitors of Factor VIII and Factor IX
Von Willebrand Disease
Transfusion Therapy for von Willebrand Disease
Nonprotein-Based Treatment
Plasma Protein–Based Therapy
Factor VIII Concentrates
von Willebrand Factor Concentrates (Plasma-Derived and Recombinant)
Cryoprecipitate
Acquired Factor VIII and Von Willebrand Factor Deficiency
Treatment
Other Coagulation Protein Deficiencies
Fibrinogen Deficiency
Prothrombin Deficiency
Factor V Deficiency
Factor VII Deficiency
Factor X Deficiency
Factor XI Deficiency
Factor XIII Deficiency
Other Plasma-Derived Protein Concentrates
Anticoagulant Proteins (Protein C and Antithrombin)
Immunoglobulins
α1-Protease Inhibitor (Antitrypsin)
Future Directions
Suggested Readings
References
137
Disseminated Intravascular Coagulation
Epidemiology
Pathobiology
Tissue Factor-Factor VII(a) Pathway
The Intrinsic Pathway
Cytokines and Other Amplification Pathways
Coagulation Protease Crosstalk Promotes Inflammation
Endogenous Anticoagulant Pathways in Disseminated Intravascular Coagulation
Fibrinolysis
Clinical Manifestations
Disseminated Intravascular Coagulation in Infectious Disease
Disseminated Intravascular Coagulation With Trauma, Brain Injury, Burns, and Heatstroke
Disseminated Intravascular Coagulation With Obstetric Complications
Disseminated Intravascular Coagulation With Malignancy
Disseminated Intravascular Coagulation With Vascular Disorders
Disseminated Intravascular Coagulation With Liver Disease
Disseminated Intravascular Coagulation With Toxic Reactions or Snake Bites
Laboratory Manifestations
Markers of Fibrin Generation and Degradation
Endogenous Coagulation Inhibitors
Fibrinolytic Markers
Point of Care Tests
Diagnostic Algorithm for Disseminated Intravascular Coagulation
Differential Diagnosis
Therapy
Platelet and Plasma Transfusion
Anticoagulant Treatment
Physiological Anticoagulant Factor Concentrates
Fibrinolytic Inhibitors
References
138
Hypercoagulable States
Inherited Hypercoagulable States
Loss of Function of Endogenous Anticoagulants
Antithrombin Deficiency
Protein C Deficiency
Protein S Deficiency
Gain of Function Mutations
Factor V Leiden
FII G20210A Mutation
Elevated Levels of Procoagulant Proteins
Other Hereditary Disorders
Acquired Hypercoagulable States
Lupus Anticoagulants and the Antiphospholipid Syndrome
Heparin-Induced Thrombocytopenia
Cancer and Its Treatment
Myeloproliferative Disorders
Paroxysmal Nocturnal Hemoglobinuria
Pregnancy
Assisted Conception and Ovarian Hyperstimulation Syndrome
Hormonal Therapy
Prior History of Venous Thromboembolism
Combined Inherited and Acquired Hypercoagulable States
Clinical Evaluation of Patients with Hypercoagulable States
Thrombophilia Screening
Laboratory Evaluation of Thrombophilia
Management of Thrombosis in Patients with Hypercoagulable States
Initial Treatment
Extended Therapy
Duration of Treatment
Treatment and Prevention of Thrombosis During Pregnancy
Thrombophilia and Fetal Loss
Conclusions and Future Directions
References
139
Antiphospholipid Syndrome
Definition of Antiphospholipid Syndrome
Antigenic Specificities of Antiphospholipid Antibodies
Pathogenic Effects of Antiphospholipid Antibodies
Activation of Complement
Inhibition of Anticoagulant and Fibrinolytic Mechanisms
Activation of Platelets, Monocytes, and Neutrophils
Effects on Vascular Endothelium
Effects on Trophoblasts and Endometrial Cells
Genetic and Proteomic Studies in Antiphospholipid Syndrome
Antiphospholipid Assays
Paths to Development
“Criteria” Antiphospholipid Syndrome Assays
Lupus Anticoagulant Tests
Patient Selection for Lupus Anticoagulant Testing
Anticardiolipin IgG and IgM Antibody Assays
Anti-β2-Glycoprotein I IgG and IgM Antibody Assays
Considerations and Limitations of Laboratory Immunoassays
Multipositivity for Antiphospholipid Tests and Other Scoring Systems for Clinical Risk
“Non-Critera” Antiphospholipid Syndrome Assays
IgA Antibodies Against Cardiolipin and β2-Glycoprotein I
Antiphosphatidylserine/Prothrombin Assays
Annexin A5 Resistance Assay and Anti-Annexin Assays
Anti-Domain I of β2-Glycoprotein I Assay
Complement Testing
Genomic and Biomarker Testing in Antiphospholipid Syndrome
Clinical Manifestations of the Antiphospholipid Syndrome
Criteria Manifestations of Antiphospholipid Syndrome
Systemic Vascular Thrombosis
Stroke and Transient Ischemic Attack
Reproductive Manifestations
Non-Criteria Manifestations of Antiphospholipid Syndrome
Cardiovascular Manifestations
Neurologic Manifestations
Cutaneous Manifestations
Pulmonary Manifestations
Hepatic and Gastrointestinal Manifestations
Renal and Adrenal Abnormalities
Retinal Abnormalities
Hematological Abnormalities
Catastrophic Antiphospholipid Syndrome
Coronavirus Disease–Associated Antiphospholipid Syndrome
Pediatric Antiphospholipid Syndrome
Treatment of Antiphospholipid Syndrome
Thrombosis
Stroke
Pregnancy Complications
Anticoagulant Monitoring Considerations
Catastrophic Antiphospholipid Syndrome
Asymptomatic Antiphospholipid Antibody-Positive Patients
Other Treatments for Antiphospholipid Syndrome
Hydroxychloroquine
Rituximab
Eculizumab
Suggested Readings
140
Venous Thromboembolism
Epidemiology
Pathogenesis Of Venous Thromboembolism
Hypercoagulability
Stasis, Hypoxia, and Endothelial Dysfunction
Initiators of Coagulation in Venous Thromboembolism
Stabilization, Embolization, and Resolution of Venous Thrombi
Clinical Manifestations Of Venous Thromboembolism
Deep Vein Thrombosis
Pulmonary Embolism
Diagnosis Of Venous Thromboembolism
Diagnostic Tests
D-Dimer
Compression Ultrasonography
Venography
Computed Tomography Pulmonary Angiography
Ventilation/Perfusion Lung Scan
Pulmonary Angiography
Diagnostic Strategies for Suspected Deep Venous Thrombosis
Diagnostic Strategy for Suspected Pulmonary Embolism
Evaluation For Underlying Malignancy
Treatment Of Venous Thromboembolism
Severe Pulmonary Embolism
Extensive Iliofemoral Deep Vein Thrombosis
Anticoagulant Therapy for Acute Venous Thromboembolism
Long-Term Anticoagulant Therapy
Side Effects of Anticoagulant Therapy
VENOUS THROMBOEMBOLISM MANAGEMENT IN SPECIFIC POPULATIONS
Cancer-Associated Venous Thromboembolism
Venous Thromboembolism in Pregnancy
Antiphospholipid Syndrome
Diagnosis and Treatment of Recurrent Venous Thromboembolism
Vena Cava Filters
Long-Term Complications
Post-Thrombotic Syndrome
Chronic Thromboembolic Pulmonary Hypertension
Psychosocial Considerations
Prevention Of Venous Thromboembolism
Attributions
Suggested Readings
References
141
Prevention and Treatment of Venous Thromboembolism in Pregnancy
Epidemiology
Risk Factors
Pathophysiology
Clinical Manifestations
Differential Diagnosis
Laboratory Manifestations
Diagnosing Suspected Deep Vein Thrombosis in Pregnancy
Diagnosing Suspected Pulmonary Embolism in Pregnancy
Prognosis
Therapy
Anticoagulant Use During Pregnancy
Anticoagulant Therapy
Interventional Management of Venous Thromboembolism in Pregnancy
Prevention of Venous Thromboembolism
Management of Anticoagulant Therapy at Delivery and Postpartum
Anticoagulants and Breastfeeding
Covid-19 and Pregnancy
Venous Thromboembolism Risk in Pregnant Persons With COVID-19
Prevention of Venous Thromboembolism in Pregnant Individuals With COVID-19
Future Directions
References
142
Atherothrombosis​
Pathobiology
Central Role of Lipoproteins in Atherogenesis
Foam Cell Formation and the Fatty Streak
Lesion Evolution: Remodeling and the Vulnerable Plaque
Plaque Rupture and Acute Arterial Thrombosis
Hyperlipidemia, Atherosclerosis, and a Systemic Prothrombotic State
Cross Talk Between Coagulation and Inflammation Systems Impact Atherogenesis
Gut Microbiome and Atherothrombosis
Hematopoiesis and Atherothrombosis
Plaque Regression
Additional Future Directions
References
143
Antithrombotic Drugs​
Antiplatelet Drugs
Role of Platelets in Arterial Thrombosis
Aspirin
Mechanism of Action
Indications
Dosages
Side Effects
Aspirin Resistance
ADP Receptor Antagonists
Thienopyridines
Mechanism of Action
Indications
Dosing
Side Effects
Clopidogrel Resistance
Ticagrelor
Mechanism of Action
Indications
Dosing
Side Effects
Cangrelor
Mechanism of Action
Indications
Dosing
Side Effects
Dipyridamole
Mechanism of Action
Indications
Dosing
Side Effects
GPIIb/IIIa Receptor Antagonists
Mechanism of Action
Indications
Dosing
Side Effects
Vorapaxar
Mechanism of Action
Indications
Dosing
Side Effects
Anticoagulants
Parenteral Anticoagulants
Heparin
Mechanism of Action
Pharmacology
Monitoring
Dosing
Limitations
Side Effects
Bleeding
Thrombocytopenia
Osteoporosis
Elevated Levels of Transaminases
Low-Molecular-Weight Heparin
Mechanism of Action
Pharmacology
Monitoring
Dosing
Side Effects
Bleeding
Thrombocytopenia
Osteoporosis
Fondaparinux
Mechanism of Action
Pharmacology
Side Effects
Parenteral Direct Thrombin Inhibitors
Argatroban
Bivalirudin
Oral Anticoagulants
Warfarin
Mechanism of Action
Pharmacology
Monitoring
Dosing
Side Effects
Bleeding
Skin Necrosis
Pregnancy
Special Problems
Direct Oral Anticoagulants
Mechanism of Action
Dosages
Monitoring
Side Effects
Periprocedural Management
Management of Bleeding
Pregnancy
Novel Anticoagulants in Development
Fibrinolytic Drugs
Role of Fibrinolytic Therapy
Mechanism of Action
Streptokinase
Alteplase (Activase)
Tenecteplase
Reteplase
Desmoteplase
Conclusions and Future Directions
References
144
Stroke
Definition
Epidemiology
Frequency
Traditional Risk Factors for Stroke
Pathobiology
Etiological Classification of Ischemic Stroke
Large Artery Stroke
Cardioembolism
Precardiac
Intracardiac
Postcardiac
Small Vessel Disease
Ischemic Stroke of Other Determined Etiology
Cerebral Venous Sinus Thrombosis
Intracerebral Hemorrhage
Subarachnoid Hemorrhage
Covert Stroke
Hematological Disorders and Ischemic Stroke
Inherited Thrombophilia
Antiphospholipid Syndrome
Sickle Cell Disease
Myeloproliferative Disorders
Thrombotic Thrombocytopenic Purpura
Paraproteinemia
Genetic Risk Factors
Clinical Manifestations
Clinical Presentation
Ischemic Stroke Versus Intracerebral Hemorrhage
Measuring Stroke Severity
Risk of Stroke After Transient Ischemic Attack
Investigations
Computed Tomography of the Brain
Magnetic Resonance Imaging
Neurovascular Imaging
Cardiac Work-Up
Therapy
Reperfusion Therapy for Acute Ischemic Stroke
Thrombolysis for Acute Ischemic Stroke
Mechanical Thrombectomy
Intra-Arterial Fibrinolysis
Acute Stroke Unit
Blood Pressure in Acute Stroke
Antithrombotic Therapy in Acute Ischemic Stroke
Carotid Endarterectomy and Stenting
Intracranial Stenting
Prevention of Venous Thromboembolism
Acute Management of Intracerebral Hemorrhage
Stroke Rehabilitation
Secondary Prevention of Ischemic Stroke
Case Study
Antithrombotic Therapy
Lipid Modification
Blood Pressure
Patent Foramen Ovale Closure
Lifestyle Modification
Prognosis
Future Directions
LIST OF TRIAL ACRONYMS
Suggested Readings
145
Acute Coronary Syndromes
Classification
Pathophysiology
Antithrombotic Management
Reperfusion Therapy For St-Segment Elevation Myocardial Infarction
Primary Percutaneous Coronary Intervention
Fibrinolytic Therapy
Streptokinase
Alteplase
Reteplase
Tenecteplase
Adjunctive Antithrombotic Therapy in Patients Receiving Fibrinolytic Drugs
Intracranial Bleeding
Antiplatelet Therapy
Oral Antiplatelet Drugs
Aspirin
Clopidogrel
Prasugrel
Ticagrelor
Duration of Dual Antiplatelet Therapy
Intravenous Antiplatelet Drugs
Glycoprotein IIb/IIIa Inhibitors
Cangrelor
Anticoagulant Therapy
Heparin
Low-Molecular-Weight Heparin
Fondaparinux
Bivalirudin
Oral Anticoagulation
Conclusions and Future Directions
Suggested Readings
References
Chapter
146
Peripheral Artery​ Disease​
Epidemiology
Prevalence and Incidence
Risk Factors
Pathobiology
Clinical Manifestations
Diagnosis
Ankle–Brachial Index
Noninvasive Testing and Imaging for Diagnosis of Peripheral Artery Disease
Prognosis
Therapy
Dyslipidemia
Hypertension
Diabetes
Antiplatelet Therapy
Anticoagulant Therapy
Treatment of Lower Extremity Symptoms
Exercise Therapy
Pharmacologic Therapies
Revascularization
Future Directions
Suggested Readings
References
147
Atrial Fibrillation​
Epidemiology
Pathobiology and Classification of Atrial Fibrillation
Clinical Manifestations
Symptoms
Stroke and Thromboembolism
Heart Failure, Other Consequences and Death
Diagnosis
Key Investigations
Differential Diagnoses
An Integrated Approach to Atrial Fibrillation Management
“A” Avoid Stroke/Anticoagulation
“B” Better Symptom Control
“C” Cardiovascular Risk Factor and Comorbidity Management
Rate Control
Rhythm Control
Prevention of Stroke and Thromboembolism
Oral Anticoagulation
Secondary Stroke Prevention
Nonpharmacologic Strategies for Stroke Prevention
Periprocedural Anticoagulation
Anticoagulant-Related Bleeding
Reversal of Anticoagulation
Future Directions
References
148
Bleeding And Clotting Disorders In Pediatrics​
Developmental Hemostasis
Laboratory Evaluation
Blood Coagulation Proteins
Regulation of Thrombin
The Fibrinolytic System
Platelets
The Vessel Wall
Bleeding Disorders In Pediatrics
Evaluation of the Bleeding Child
Thrombocytopenia
Neonatal Thrombocytopenia
Neonatal Alloimmune Thrombocytopenia
Immune Thrombocytopenia
Platelet Function Disorders
Inherited Coagulation Disorders
Isolated Prolonged Prothrombin Time/INR
Isolated Prolonged Activated Partial Thromboplastin Time
Prolonged Prothrombin Time/INR and Activated Partial Thromboplastin Time
Hemophilia
von Willebrand Disease
FXIII Deficiency
Other Rare Inherited Factor Deficiencies
Liver Disease
Vitamin K Deficiency and Bleeding in Neonates and Infants
Intraventricular Hemorrhage in Neonates
Clotting Disorders In Pediatrics
Risk Factors for Pediatric Thrombosis
Indwelling Catheters
Hereditary Thrombophilia
Diagnosis
Specific Neonatal Thrombotic Syndromes
Renal Vein Thrombosis
Portal Vein Thrombosis
Cerebral Sinovenous Thrombosis
Purpura Fulminans
Ischemic Stroke
Specific Pediatric Thrombotic Syndromes
Pulmonary Embolism
Anatomic Abnormality–Associated Thrombotic Syndromes
May–Thurner Syndrome
Thoracic Outlet Syndrome
Principles of Therapy
Vitamin K Antagonist Therapy
Heparin (Unfractionated Heparin or Low-Molecular-Weight Heparin)
Direct Oral Anticoagulants
Thrombolytic Therapy
Post-Thrombotic Syndrome
COVID-19 and Thrombosis in Children
Suggested Readings
References
PART XII CONSULTATIVE HEMATOLOGY
149
Hematologic Changes in Pregnancy​
Anemia in Pregnancy
Physiologic Anemia of Pregnancy
Iron Deficiency Anemia
Folate and Vitamin B12 Deficiencies
Hemoglobinopathies and Pregnancy
Sickle Cell Disease
Thalassemia
Other Hemolytic Anemias
Hereditary Spherocytosis
Glucose 6-Phosphate Dehydrogenase Deficiency
Paroxysmal Nocturnal Hemoglobinuria
Autoimmune Hemolytic Anemia
Thrombocytopenia
Gestational Thrombocytopenia
Immune Thrombocytopenia
Pre-eclampsia With Severe Features and HELLP Syndrome
Thrombotic Thrombocytopenic Purpura and Complement-Mediated Hemolytic Uremic Syndrome
Leukemia and Lymphoma
Hodgkin Lymphoma
Non-Hodgkin Lymphoma
Acute Leukemias
Chronic Myeloid Leukemia
Myeloproliferative Neoplasms: Essential Thrombocythemia, Polycythemia Vera, and Primary Myelofibrosis
Bleeding Disorders
Disseminated Intravascular Coagulation
von Willebrand Disease
Hemophilia A AND B
Acquired Hemophilia A
Factor XI Deficiency
Other Platelet Function Disorders
Venous Thromboembolism
Prophylactic Anticoagulation During Pregnancy
Thrombophilias and Pregnancy
Antiphospholipid Antibody Syndrome
Mechanical Heart Valves
Future Directions
References
150
Hematologic Manifestations of End-Organ Failure​
Hematologic Manifestations of Liver Disease
Red Blood Cell Abnormalities
Morphologic Abnormalities
Anemia
White Blood Cell Abnormalities
Leukopenia
Platelet Abnormalities
Thrombocytopenia
Platelet Dysfunction
Coagulation and Liver Disease
Treatment of Liver Disease–Related Bleeding
Hypercoagulability and Thrombosis in Patients with Liver Disease
Hematologic Manifestations of Renal Disease
Anemia
Relative Erythropoietin Deficiency
True Iron Deficiency
Disordered Iron Homeostasis
Bleeding Risk
Thrombosis
Thrombotic Microangiopathies
Hematologic Manifestations of Other End-Organ Diseases
Functional and Anatomic Asplenia
Red Blood Cell Abnormalities
Immunological Consequences
Thrombosis Risk in Patients With Splenic Dysfunction
Respiratory Disease
Red Blood Cell Abnormalities
Heart Failure
Red Blood Cell Abnormalities
Thrombosis Risk in Patients With Heart Failure
Endocrinopathies
References
Suggested Readings
151
Hematologic Manifestations of Solid Tumors​
Erythrocytes
Anemia
Erythrocytosis
Platelets
Thrombocytopenia
Thrombocytosis
Platelet Dysfunction Secondary to Malignancy
Leukocytes
Neutropenia
Bone Marrow Metastases
Thrombosis and Cancer
Biologic Mechanisms Underlying Thrombosis in Cancer
Coagulation and Tumor Progression
Diagnosis of Coagulopathies in Cancer Patients
Intravenous Catheter Thrombosis in Malignancy
Future Directions
References
Suggested Readings
152
Hematologic Manifestations of HIV/AIDS
Introduction to Human Immunodeficiency Virus
Human Immunodeficiency Virus and Cytopenias
Human Immunodeficiency Virus and Lymphomas
Diffuse Large B-Cell Lymphoma
Burkitt Lymphoma
Primary Effusion Lymphoma
Hodgkin Lymphoma
T-Cell Lymphoma
Case Illustration
Initial Labs
Further Diagnostic Laboratory Studies
Management
Systematic Approach to Lymphadenopathy
Human Immunodeficiency Virus and Thrombosis
Summary
References
Suggested Readings
153
Hematologic Findings And Consequences Of Novel Coronavirus (SARS-COV-2) Infection
Thrombosis In Covid-19
Evidence for Thromboembolic Disease as a Pathophysiologic Factor in COVID-19
Limitations to Current Evidence Regarding Thromboembolic Disease in COVID-19
The Role of Anticoagulation in COVID-19
Covid-19 Associated Coagulopathy
Inflammatory Markers And Cytokine Storm
Characteristics Of The COMPLETE BLOOD COUNT and WHITE BLOOD CELL Differential In Covid-19
Lymphopenia
Thrombocytopenia
Other Complete Blood Count Abnormalities
Vaccination
Monoclonal Antibodies
References
154
Hematologic Aspects of Parasitic Diseases​
Malaria
Features of Malarial Anemia
Spectrum of Disease Caused by Malarial Infection
Clinical Features of Malarial Anemia
Hemolytic Syndromes, Including Blackwater Fever
Hematologic Features of Malarial Infection
Malarial Anemia in Pregnancy
Hyperreactive Malarial Splenomegaly
Anemia and P. vivax, P. ovale, and P. malariae Infection
Malaria Diagnosis
Management of Malaria
Malaria as a Transfusion-Transmitted Infection
Epidemiology
Parasitology
Pathology
Features of Visceral Leishmaniasis
Clinical Features
Immunocompromised Hosts
Hematologic Features
Laboratory Features
Morphology
Splenic Aspiration
Culture
Molecular Methods
Serologic Tests
Management
Leishmaniasis as a Transfusion-Transmitted Infection
Epidemiology
Parasitology
Pathology
Visceral Leishmaniasis
African Trypanosomiasis
Features of African Trypanosomiasis
Clinical Features
Trypanosoma brucei gambiense
Trypanosoma brucei rhodesiense
Children
HIV Infection and Other Immunosuppressed Patients
Hematologic and Laboratory Features
Parasitologic Assays
Cerebrospinal Fluid
Serology
Management
African Trypanosomiasis as a Transfusion-Transmitted Infection
Epidemiology
Parasitology
Trypanosoma rangeli Infections
Pathology
Features of American Trypanosomiasis
Clinical Features
Chronic Disease
Pregnancy and Congenital Infection
Immunocompromised Patients and Organ Transplantation
Human Immunodeficiency Virus
Hematologic and Laboratory Features
American Trypanosomiasis
Diagnosis
Microscopy
Xenodiagnosis
In Vitro Culture
Serology
Molecular Diagnosis
Treatment
American Trypanosomiasis as a Transfusion-Transmitted Infection
Parasitology
Clinical Features
Hematologic and Laboratory Features
Diagnosis
Treatment
Babesiosis as a Transfusion-Transmitted Infection
Eosinophilia in Travelers
Filariasis
Toxoplasmosis
Amebiasis
Giardiasis
Hookworm Infection
Tapeworm Infection
Schistosomiasis
Babesiosis
Eosinophilia
Other Parasitic Diseases
Future Directions
REFERENCES
Suggested Readings
Chapter
155
Hematologic Problems in the Surgical Patient: Bleeding and Thrombosis
preoperative evaluation of hemostatic risk
History
Coagulation Testing
Hemostatic Agents
Desmopressin
Topical Hemostatic Agents
Physical Agents
Absorbable Agents
Biologic Agents
Synthetic Agents
Hemostatic Dressings
Antifibrinolytics
Aminocaproic Acid and Tranexamic Acid
Recombinant Factor VIIa
Management of Patients With Hemostatic Abnormalities
Thrombocytopenia
Platelet Dysfunction
Kidney Disease
Liver Disease
Intraoperative and Postoperative Bleeding
Coagulopathy Associated With Massive Blood Loss/Transfusion
Cardiopulmonary Bypass
Orthotopic Liver Transplantation
Perioperative Anticoagulation Management
Perioperative Thromboprophylaxis
Non-orthopedic Surgery
Orthopedic Surgery
Summary
Suggested Readings
References
156
The Spleen and Its Disorders​
Normal Splenic Anatomy And Function
Embryology
Anatomy
Functions
The Red Pulp
Removal of Damaged and Aged Formed Elements
Recycling of Iron
Antibody Production
The White Pulp
Marginal Zone
Innate Immunity
Adaptive Immunity
Hematopoiesis
Stem Cells
Storage of Cells
Examination Of The Spleen
Imaging Of The Spleen
Tests Of Splenic Function
Asplenia And Hyposplenia
Splenic Infarction
Acquired Hyposplenism
Infarction in Sickle Cell Disease
Immunologic and Autoimmune Diseases
Therapy-Induced Splenic Hypofunction
Splenomegaly And Hypersplenism
Splenic Irradiation
Indications
Complications
Splenectomy
Indications and Timing
Surgical Options
Complications After Splenectomy
Prevention of Complications
Post-splenectomy Septicemia
Atherosclerosis
Conclusions And Future Directions
References
157
Aging and Hematologic Disorders
Anemia
General Principles in Older Adults with Hematologic Malignancies
Lymphoma in Older Adults
Myelodysplastic Syndromes
Acute Myeloid Leukemia
Multiple Myeloma in Older Adults
Hematopoietic Stem Cell Transplantation and Cellular Therapy in Older Adults
Conclusion
Acknowledgments
Suggested Readings
References
158
Onco-Cardiology: Focus on Cardiac Complications of Hematologic Treatments​
Cardiotoxicity From Chemotherapy Used In Hematological Malignancies (Table 158.1​)
Anthracyclines
Oncological Indication
Cardiotoxicity
Mechanism of Cardiotoxicity
Prevention and Treatment
Tyrosine Kinase Inhibitors
Imatinib
Dasatinib
Nilotinib
Ponatinib
Ibrutinib
Arsenic Trioxide
Oncological Indication
Cardiotoxicity
Mechanism of Cardiotoxicity
Prevention and Treatment
Cardiotoxicity From Immunotherapy Used In Hematological Malignancies
Immune Checkpoint Inhibitors
Oncological Indication
Cardiac Toxicity
Mechanism of Cardiotoxicity
Prevention and Treatment
CAR-T Therapy
Oncological Indication
Cardiac Toxicity
Mechanism of Cardiac Toxicity
Prevention and Treatment
Cardiotoxicity of Radiation Treatment
Cardiac Considerations During Hematopoietic Stem Cell Transplantation
Acute Cardiac Complications
Long-Term Cardiac Complications
Conclusion
References
Suggested Readings
159
Resources for the Hematologist: Interpretive Comments and Selected Reference Values for Neonatal, Pediatric, and Adult ...
Appendix Contents
RED BLOOD CELL TESTING
Estimated Blood Volumes (Includes Plasma Volume, Red Blood Cell Mass)
WHITE BLOOD CELL AND IMMUNOLOGIC TESTING
PLATELET AND COAGULATION TESTING
Coagulation Screening Tests