PLATELETS is the definitive current source of state-of-the-art knowledge about platelets and covers the entire field of platelet biology, pathophysiology, and clinical medicine. Recently there has been a rapid expansion of knowledge in both basic biology and the clinical approach to platelet-related diseases including thrombosis and hemorrhage. Novel platelet function tests, drugs, blood bank storage methods, and gene therapies have been incorporated into patient care or are in development. This book draws all this information into a single, comprehensive and authoritative resource.
Table of Contents:
Dedication
List of Contributors
Preface
Foreword: A Brief History of Ideas About Platelets in Health and Disease
I The Role of Platelets in Human Hemostasis, Platelet Transfusion, and the Bleeding Time
II Immune Thrombocytopenia
III Alloantigens, Single Nucleotide Polymorphisms, and Alloimmune Thrombocytopenias
IV Platelet Physiology, Assays of Platelet “Adhesiveness”, ADP, Platelet Aggregation, Myocardial Infarction, and P2Y12 Antagonists
V Aspirin, Arachidonic Acid, Prostaglandins, Gpiib-iiia, Nitric Oxide, Endothelial Gpiib-iiia, and Angiogenesis
VI Clot Retraction, Glanzmann Thrombasthenia, GPIIb-IIIa Receptor, and GPIIb-IIIa Antagonists
VII Bernard-Soulier Syndrome, the Gpib-IX-V Complex, von Willebrand Factor, Shear, ADAMTS-13, and Thrombotic Thrombocytopenic Purpura
VIII Thrombin-induced Platelet Activation
IX Platelets and Metastases
X Reflections on the Past and Thoughts About the Future
Part I: Platelet Biology
Chapter 1. The Evolution of Mammalian Platelets
I Introduction
II Invertebrates
III Nonmammalian Vertebrates
IV Comparative Hemostasis
V A Comparison of Human Platelets and Limulus Amebocytes
VI The Evolution of Hemostasis and Blood Coagulation
VII Megakaryocytes and Mammals
VIII Conclusions
Acknowledgments
References
Chapter 2. Megakaryocyte Development and Platelet Formation
I Introduction
II Megakaryocyte Development
III Platelet Formation
IV Regulation of Megakaryocyte Development and Platelet Formation
V Murine Model Systems and Human Diseases as Tools to Study Platelet Biogenesis
References
Chapter 3. The Regulation of Platelet Life Span
I Introduction
II History
III Methods for the Measurement of Platelet Life Span
IV An Introduction to Apoptosis
V An Apoptotic Pathway Regulates Platelet Survival and Life Span
VI Distinct Pathways Promote Platelet Procoagulant Function
VII Clearance Mechanisms of Platelets and Clearance Signals
VIII Future Questions
Acknowledgments
References
Chapter 4. Platelet Genomics
I Introduction
II Human Genomics
III Platelet Genomic Association Studies: Phenotype Issues
IV Genome-Wide Association Studies (GWAS)
V Cardiovascular Disease Genomic (DNA) Association Studies
VI Platelet Genomic Studies with Intermediate (Platelet QTL) Outcomes
VII Platelet-Megakaryocyte Transcriptome Association Studies
VIII Mechanistic Insights from Platelet Genomic Studies
IX Platelet Pharmacogenetics
X GWAS Perspectives
XI The Future
References
Chapter 5. Platelet microRNAs
I The microRNA Pathway of Human Cells
II Platelets
III The microRNA Pathway of Platelets
IV Use of Platelet microRNAs as Biomarkers
V Therapeutic Applications
VI Conclusion and Perspectives
Acknowledgments
References
Chapter 6. The Platelet Proteome
I Introduction
II The Platelet Proteome
III Factors that Influence the Make-Up of the Platelet Proteome
IV Evaluating the Platelet Proteome
V Summary and Future Directions
References
Chapter 7. Platelet Structure
I Introduction
II Peripheral Zone
III The Sol-Gel Zone
IV Organelle Zone
V Platelet Membrane Systems
References
Chapter 8. The Platelet Cytoskeleton
I Introduction
II The Structure of the Resting Platelet
III The Cytoskeleton of the Resting Platelet
IV The Structure of the Activated Platelet
V Signals Activating Actin Assembly
VI Membrane Dynamics and Actin Filament Turnover in Platelets
VII Platelet Contraction
VIII Diseases of the Platelet Cytoskeleton
References
Chapter 9. Platelet Receptors
I Introduction
II Integrins
III Leucine-Rich Repeat (LRR) Family
IV Seven-Transmembrane Receptors
V Immunoglobulin Superfamily
VI C-Type Lectin Receptor Family
VII Tetraspanins
VIII Glycosyl Phosphatidylinositol (GPI)-Anchored Proteins
IX Glycosaminoglycan-Carrying Receptors
X Tyrosine Kinase Receptors
XI Miscellaneous Platelet Membrane Glycoproteins
Acknowledgment
References
Chapter 10. The GPIb-IX-V Complex
I Introduction/Structure
II Function
III Signaling
IV Conclusions
References
Chapter 11. GPVI and CLEC-2
I Introduction to Platelet ITAM and HemITAM Receptors
II GPVI
III CLEC-2
IV Conclusions
References
Chapter 12. Integrin αIIbβ3
I Introduction
II αIIbβ3 as an Integrin and a Platelet Protein
III Structure of αIIbβ3
IV “Inside-Out” Signaling and αIIbβ3 Activation
V Conclusions
References
Chapter 13. Protease-Activated Receptors
I Introduction
II Structure and Mechanism of Activation of PARS
III A Dual Protease-Activated Receptor System for Human Platelet Activation
IV Pharmacology of PAR Ligands and Antagonists in Platelets
V PAR1 and PAR4 Signaling in Platelets
VI Role of Secreted ADP in Thrombin-Induced Platelet Aggregation
VII PAR-Activated Prothrombinase Activity and Thrombin Generation
References
Chapter 14. The Platelet P2 Receptors
I P2 Receptors
II Roles of Adenine Nucleotides in Platelet Function
III P2Y1
IV P2Y12
V P2X1
VI Interplay Between the Platelet P2 Receptors
VII Desensitization of the Platelet P2 Receptors
VIII Conclusions
References
Chapter 15. PECAM-1
I Introduction
II PECAM-1 Genomic Organization and Protein Domain Structure
III Expression and Adhesive Properties of the Extracellular Domain
IV Phosphorylation, Cytoskeletal Association, and Protein Interactions of the PECAM-1 Cytoplasmic Domain
V PECAM-1 as a Bidirectional Regulator of Platelet Reactivity and Thrombosis
VI Allelic and Soluble Isoforms of PECAM-1 and their Association with Cardiovascular Disease
VII Conclusions
References
Chapter 16. Interactions Between Platelets, Leukocytes and the Endothelium
I Mediators
II Functional Consequences
III Pathophysiologic Roles
IV Concluding Remarks
Acknowledgments
References
Chapter 17. Inhibition of Platelet Function by the Endothelium
I Introduction
II Nitric Oxide
III Prostacyclin
IV CD39 (NTPDase-1)
V Summary
Acknowledgements
References
Chapter 18. Platelet Secretion
I Introduction: Platelet Granules
II Formation of Platelet Granules
III Platelet Granule Content
IV Mechanisms of Platelet Granule Secretion
V Function of Platelet Granule Secretion
VI Platelet Granule Disorders
VII Conclusions
Acknowledgments
References
Chapter 19. Signal Transduction During Platelet Plug Formation
I Overview
II Early Events of Platelet Activation via G-Protein-Coupled Receptors
III An Agonist-Centric View of Platelet Activation
IV Contact-Dependent and Contact-Facilitated Events that Reinforce Platelet Activation
V Regulators of Platelet Activation: Obtaining an Optimal Response to Injury
VI Concluding Thoughts
References
Chapter 20. Platelet Thrombus Formation in Flowing Blood
I Introduction
II Initial Events in Thrombus Formation under Flow
III Thrombus Propagation under Flow
IV Conclusions
References
Chapter 21. Interactions Between Platelets and the Coagulation System
I Overview of the Role of Platelets in Hemostasis
II Enzyme Complex Formation Regulates the Coagulant Response
III Model Systems Defining the Role of Platelets in Tissue FACTOR-INITIATED Thrombin Generation
IV Intrinsic Platelet Molecules Involved in the Coagulant Response
V Coagulation Reactions Supported by the Activated Platelet Surface
VI Positive and Negative Effectors of Platelet Coagulant Activity
VII Summary
Acknowledgement
References
Chapter 22. Platelet-Derived Microparticles
I Introduction
II Microparticle Structure
III Detection of Microparticles
IV Formation and Clearance of Platelet Microparticles
V Microparticle Function
VI Clinical Disorders Associated with Microparticles
VII Future Developments
References
Chapter 23. The Role of Platelets in Fibrinolysis
I Introduction
II Key Mechanisms and Components of Fibrinolysis
III Inhibitors of Fibrinolysis
IV Platelet-Associated Fibrinolytic Activity
V Integrin αIIbβ3 Interactions
VI Platelet-Mediated Effects on Fibrin Structure
VII Plasmin-Mediated Platelet Activation
VIII Platelet Disorders and Fibrinolysis
IX Net Effects
Acknowledgments
References
Chapter 24. The Role of Platelets in Angiogenesis
I The Role of Platelets in Angiogenesis
II Platelets and Angiogenesis in Tissue Regeneration and Wound Healing
III The Effects of Platelets on Tumor Dynamics
References
Chapter 25. Platelet Function in the Newborn
I Introduction
II Platelet Number and Size
III Platelet Production
IV Platelet Structure
V Measurements of Platelet Function
VI Platelet Activation During Delivery
VII Platelet Adhesion
VIII Platelet Signal Transduction
IX Platelet Secretion
X Platelet Procoagulant Activity
XI Effects of Drugs on Fetal and Neonatal Platelet Function
XII Effects of Maternal Disease on Fetal and Neonatal Platelet Function
XIII Conclusions
References
Part II: Tests of Platelet Function
Chapter 26. Clinical Tests of Platelet Function
I Introduction
II Early Tests of Platelet Number and Function
III Overview of Currently Available Platelet Function Tests
IV Use of Platelet Function Testing in the Clinical Setting
V Summary and the Future of Platelet Function Testing
References
Chapter 27. Platelet Counting
I Introduction
II Manual Platelet Counting
III Automated Platelet Counting
IV Reticulated Platelets/Immature Platelet Fraction
V Conclusions
References
Chapter 28. Platelet Aggregation
I Overview of Methods for the Evaluation of Platelet Aggregation
II Preparation of Samples for Platelet Aggregation Tests
III Analytical Considerations and Potential Interferences for Aggregation Tests
IV Quantitative Endpoints of Aggregation and Release Assays
V Aggregation Interpretation in the Assessment of Bleeding Disorders
VI Quality Evaluation of Platelet Aggregation Tests
References
Chapter 29. Flow Cytometry
I Introduction
II Measurement of Platelet Activation
III Diagnosis of Specific Disorders
IV Monitoring of Antiplatelet Agents
V Monitoring of Thrombopoiesis
VI Blood Bank Applications
VII Platelet-Associated IgG
VIII Platelet Count
IX Other Research Applications
References
Chapter 30. Monitoring of Antiplatelet Therapy
I Introduction
II Rationale for Monitoring Antiplatelet Therapy
III Aspirin
IV Clopidogrel
V Role of Platelet Function Measurement in Patients Undergoing Coronary Artery Bypass Surgery
VI Monitoring Antiplatelet Therapy During Combination Therapies
VII Monitoring of Antiplatelet Therapy in the Medically Managed Acute Coronary Syndrome Patient
VIII Monitoring Antiplatelet Therapy During Clopidogrel and Proton Pump Inhibitor Therapy
IX Monitoring Antiplatelet Therapy During GPIIb-IIIa Antagonist Therapy
X Guidelines
XI Future
References
Chapter 31. Real Time In Vivo Imaging of Platelets During Thrombus Formation
I Introduction
II Equipment and Methods
III Data Acquisition and Analysis
IV Study of Thrombus Formation
V Conclusions
References
Part III: The Role of Platelets in Disease
Chapter 32. Atherothrombosis and Coronary Artery Disease
I Platelets Initiate Atherosclerosis—A Model of Platelet-Induced Disease
II Platelet Adhesion Promotes Initiation of Atherosclerosis
III Platelet Secretion and Generation of Cytokines
IV Platelets and Dendritic Cells
V Impact of Platelets on Endothelial Regeneration
VI Platelets and Thrombosis in the Course of Atherosclerosis
VII Therapeutic Implications and Management of Coronary Artery Disease
VIII Conclusions
References
Chapter 33. Central Nervous System Ischemia
I Introduction
II Ischemic Cerebrovascular Disease
III Platelet Activation in the Development of Focal Cerebral Ischemia
IV Hemorrhagic Transformation
V Antiplatelet Interventions in Cerebral Ischemia
VI Carotid Artery Atherothrombotic Disease
VII Cerebral Embolism from a Cardiac Source
VIII Conclusions
References
Chapter 34. Peripheral Vascular Disease
I Overview of Peripheral Arterial Disease
II Platelet-Vessel Wall Interactions in PAD
III Characteristics of Platelet Function in PAD
IV Platelet-Focused Therapy in PAD
V Platelets in Venous Disease
VI Conclusions
References
Chapter 35. Diabetes Mellitus
I Accelerated Atherothrombosis: Epidemiological and Clinical Findings
II Are Platelets the Key Player in Diabetic Atherothrombosis?
III Mechanisms Contributing to In Vivo Platelet Activation
IV Antiplatelet Therapy for the Primary and Secondary Prevention of Atherothrombotic Events
V Less-than-Expected Response to Aspirin
VI Possible Determinants of Hyporesponsiveness to Aspirin in Diabetes
VII Conclusions
Acknowledgments
References
Chapter 36. Inflammation
I Introduction
II Platelet Interactions with Endothelium and Leukocytes
III Platelet Signaling Receptors, Integrins, and Immunoreceptors
IV Platelet Toll-Like Receptors
V The Platelet Secretome and Other Modes of Intercellular Signaling in Inflammation and Immune Syndromes
VI The Platelet Transcriptome and New Mechanisms for Signal-Dependent Modification of the Platelet Proteome in Inflammation
VII Platelets in Innate and Adaptive Immune Responses
VIII Platelets in Inflammation: Animal Models of Disease
IX Platelets in Human Inflammatory Diseases and Syndromes
X Platelets: Protean Activities in Defense and Disease
Acknowledgments
References
Chapter 37. Antimicrobial Host Defense
I Introduction
II Mammalian Platelets are Multipurpose Host Defense Cells
III Early Studies were Interpreted to Suggest Platelets Promote Infection
IV Platelets Likely Play Multiple Roles in Antimicrobial Host Defense
V Platelets Contain Antimicrobial Effector Molecules that Contribute to Host Defense
VI Platelet Host Defense Polypeptides Likely Function via Multiple Mechanisms of Action
VII Platelet Host Defense Polypeptides Potentiate Conventional Antibiotics
VIII PMPs and Platelet Kinocidins Modulate Pathogen Interactions with Platelets and Endothelial Cells
IX Platelets Modulate Complement Activation
X Platelets Influence the Host Defense Roles of Lymphocytes
XI Platelets Potentiate the Antimicrobial Functions of Leukocytes
XII Platelets are Integral to Antimicrobial Host Defense In Vivo
XIII Certain Pathogens May Subvert Platelet Host Defenses
XIV Correlates of Platelet Quantity or Function and Risk of Infection
XV Future Studies
XVI Summary
Acknowledgment
References
Chapter 38. Tumor Growth and Metastasis
I Introduction
II The Platelet–Tumor Cell Axis
III Platelet–Tumor Cell Emboli and Ischemia
IV Platelets, Tumor Cells, and Innate Immunity
V Platelets and Angiogenesis
VI Platelet Activation and Metastasis
VII Platelet Therapies and Cancer
VIII Conclusion and Perspectives
References
Part IV: Disorders of Platelet Number and Function
Chapter 39. The Clinical Approach to Disorders of Platelet Number and Function
I Introduction
II Clinical History
III Physical Examination
IV Clinical Tests
V Differential Diagnosis
VI Specific Disorders
Reference
Chapter 40. Immune Thrombocytopenia (ITP)
I Introduction
II Incidence
III Etiology and Pathophysiology
IV Diagnosis and Clinical Assessment
V Management
VI Prognosis
VII Summary
Acknowledgments
References
Chapter 41. Drug-Induced Thrombocytopenia
I Introduction
II Drug-Induced Suppression of Platelet Production
III Drug-Induced Platelet Destruction by Nonimmune Mechanisms
IV Drug-Induced Platelet Destruction by Immune Mechanisms
References
Chapter 42. Heparin-Induced Thrombocytopenia
I Introduction
II Historical Aspects and Nomenclature
III Pathogenesis
IV Frequency
V Clinical Features
VI Diagnosis
VII Management
References
Chapter 43. Thrombotic Thrombocytopenic Purpura and the Hemolytic-Uremic Syndrome
I Introduction
II TTP
III Shiga Toxin-associated HUS
IV Atypical HUS
Acknowledgments
References
Chapter 44. Thrombocytopenia in Pregnancy
I Introduction
II Specific Causes of Pregnancy-Associated Thrombocytopenia
III Summary and Conclusions
References
Chapter 45. Thrombocytopenia in the Newborn
I Introduction
II Fetal Megakaryocytopoiesis and Platelet Production
III Incidence of Neonatal Thrombocytopenia
IV Natural History of Neonatal Thrombocytopenias
V Conditions Leading to Clinically Significant Neonatal Thrombocytopenia
VI Diagnosis of Neonatal Thrombocytopenia
VII Platelet Transfusion for Neonatal Thrombocytopenia
VIII Future Therapeutic Options for Neonatal Thrombocytopenia
IX Summary
References
Chapter 46. Alloimmune Thrombocytopenia
I Introduction
II Fetal and Neonatal Alloimmune Thrombocytopenia
III Post-Transfusion Purpura
IV Passive Alloimmune Thrombocytopenia
V Unresolved Questions and Future Directions
References
Chapter 47. Inherited Thrombocytopenias
I Introduction
II The Microthrombocytic Thrombocytopenias
III The Normothrombocytic Thrombocytopenias
IV The Macrothrombocytic Thrombocytopenias
V An Approach to Patients with Suspected Congenital Thrombocytopenia
References
Chapter 48. Pseudothrombocytopenia
I Introduction
II EDTA-Dependent Pseudothrombocytopenia
III Citrate-Dependent Pseudothrombocytopenia
IV Other Anticoagulants
V Clinical Aspects
VI Pseudothrombocytopenia Agglutinins as Natural Antibodies
VII Clinical Laboratory Procedures
VIII Pseudothrombocytopenia Due to Platelet Satellitism
IX Pseudothrombocytopenia Due to Therapeutic Monoclonal Antibodies
X Conclusions
References
Chapter 49. Thrombocytosis and Essential Thrombocythemia
I Introduction
II Congenital Thrombocytosis
III Reactive Thrombocytosis
IV Primary Thrombocytosis and the Myeloproliferative Neoplasms
V Distinguishing Reactive Thrombocytosis from Primary Thrombocytosis
VI Essential Thrombocythemia
VII Concluding Comments
References
Chapter 50. Congenital Disorders of Platelet Function
I Introduction
II Classification of Congenital Disorders of Platelet Function
III Abnormalities of the Platelet Receptors for Adhesive Proteins
IV Abnormalities of the Platelet Receptors for Soluble Agonists
V Defects of Platelet Granules
VI Defects of Signal Transduction
VII Abnormalities of Membrane Phospholipids
VIII Miscellaneous Disorders of Platelet Function
IX Hereditary Defects of Adhesive Proteins, Affecting Platelet Function
X Prevalence of and Diagnostic Evaluation of Congenital Disorders of Platelet Function
XI Treatment of Congenital Platelet Function Disorders
XII Future Avenues of Research
XIII Conclusions
References
Chapter 51. Acquired Disorders of Platelet Function
I Introduction
II Uremia
III Myeloproliferative Diseases
IV Acute Leukemias and Myelodysplastic Syndromes
V Dysproteinemias
VI Acquired von Willebrand Disease
VII Acquired Storage Pool Disease
VIII Antiplatelet Antibodies and Platelet Dysfunction
IX Liver Disease
X Miscellaneous Conditions with Impaired Platelet Function
XI Drugs That Inhibit Platelet Function
Acknowledgments
References
Chapter 52. Cardiopulmonary Bypass
I Introduction
II Clinical Aspects of CPB Relevant to Platelet Pathophysiology
III Inflammation and CPB
IV Clinical Hemostatic Alterations During and After CPB
V Quantitative Platelet Abnormalities During CPB
VI Qualitative Platelet Abnormalities During CPB
VII Diagnostic and Therapeutic Issues in CPB Hemostasis
References
Part V: Antiplatelet Therapy
Chapter 53. Aspirin
I Historical Background
II Mechanism of Action
III Pharmacokinetics and Pharmacodynamics
IV Drug Interactions
V Inter-Individual Variability in Drug Response
VI Clinical Readouts of Platelet COX-1 Inactivation
VII Balance of Benefits and Risks
VIII Conclusions
Acknowledgments
References
Chapter 54. ADP Receptor Antagonists
I Introduction
II Thienopyridines
III Direct P2Y12 Antagonists
IV Conclusions
References
Chapter 55. αIIbβ3 (GPIIb-IIIa) Antagonists
I Introduction
II General Information and Mechanism of Action
III Landmark Clinical Trials: Percutaneous Coronary Intervention
IV Landmark Clinical Trials: Non-ST-Elevation Acute Coronary Syndromes
V Landmark Clinical Trials: ST-Elevation Myocardial Infarction
VI Relative Efficacy of GPIIb-IIIa Antagonists
VII Special Circumstances and Alternative Strategies to GPIIb-IIIa Antagonists
VIII Side Effects
IX Conclusions
References
Chapter 56. Dipyridamole
I Introduction
II Absorption and Metabolism
III Mechanisms of Action
IV Side Effects
V Conclusions
References
Chapter 57. Cilostazol
I Introduction
II Mechanism of Action
III Antiplatelet Effects
IV Antithrombotic Effects
V Other Effects
VI Clinical Results
References
Chapter 58. Novel Antiplatelet Therapies
I Introduction
II Platelet Biology
III Current Antiplatelet Therapies
IV Novel Antiplatelet Therapies
V Conclusions
References
Part VI: Therapy to Increase Platelet Numbers and/or Function
Chapter 59. Thrombopoietin Mimetics
I Introduction
II TPO Structure
III The TPO Gene and Its Regulation
IV Functions of TPO
V Physiology of TPO
VI Pathophysiology of TPO
VII Therapeutic Thrombopoietins
VIII Clinical Effects of Therapeutic Thrombopoietins: Animal Studies
IX Clinical Effects of Therapeutic Thrombopoietins: Human Studies
X Adverse Effects of Therapeutic Thrombopoietins in Humans
XI Interleukin-11 (A Non-TPO Thrombopoietic Growth Factor)
References
Chapter 60. Desmopressin (DDAVP)
I Introduction
II Management with Desmopressin of Mild Hemophilia A and von Willebrand Disease
III Desmopressin as a General Hemostatic Agent
IV Side Effects
V Mechanisms of Action of Desmopressin
VI Conclusions
References
Chapter 61. Factor VIIa
I Introduction
II Pharmacology
III rFVIIa in the Treatment of Thrombocytopenia
IV rFVIIa in the Treatment of Platelet Function Disorders
V Adverse Events
VI Mechanisms of Action
VII FVIIa Analogs in Clinical Development
VIII Conclusions
Acknowledgements
References
Chapter 62. Platelet Transfusion Medicine
I Introduction
II Platelet Preparation
III Platelet Storage and Storage Injury
IV Postcollection Processing
V Platelet Transfusion Therapy
VI Adverse Reactions to Platelet Transfusion
VII Thrombopoietic Growth Factors in Platelet Transfusion Therapy
VIII Conclusions
References
Chapter 63. Making Platelets Ex Vivo
I Introduction
II Generating Human Megakaryocytes and Platelets Ex Vivo
III Targeted Therapy via Platelets
IV Conclusions
References
Chapter 64. Gene Therapy for Platelet Disorders
I Introduction
II Approach to Gene Transfer for Platelet Disorders
III Advances in Retrovirus-Mediated Transduction for Platelets
IV State-of-the-Art Animal Models for Disorders Affecting Platelets
V Conclusions
Acknowledgments
References
Index
