Platelets

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