Platelets (Fourth Edition)

Platelets, Fourth Edition, integrates the entire field of platelet biology, pathophysiology, and clinical medicine with contributions from 142 world experts from 18 countries. This award-winning reference provides clear presentations by basic scientists on the cellular, molecular, and genetic mechanisms of platelets and the role of platelets in thrombosis, hemorrhage, inflammation, antimicrobial host defense, wound healing, angiogenesis and cancer. It also provides start-of-the-art presentations by hematologists, cardiologists, stroke physicians, blood bankers, pathologists and other clinicians on platelet function testing, disorders of platelet numbers and function, antiplatelet therapy and therapy to increase platelet numbers and/or function. Since the publication of the Third Edition of Platelets, there has been a rapid expansion of knowledge in both basic biology of platelets and the clinical approach to platelet-related diseases. This Fourth Edition of Platelets draws all this information into a single, comprehensive and authoritative resource. Comprehensive and definitive source of state-of-the-art knowledge about platelets Integrates the entire field of platelet biology, pathophysiology, and clinical medicine Written for clinicians, pathologists and scientists by 142 world-renowned experts from 18 countries Completely revised and updated, with 11 new chapters on topics such as platelet glycobiology, the platelet transcriptome, platelet inhibitory receptors, platelet function testing in clinical research trials, therapeutic platelet-rich plasma in wound healing, and new antiplatelet drugs Full color textbook with over 250 illustrations and 15,000 references Cover Platelets Copyright Contributors Preface Foreword: A Brief History of Ideas About Platelets in Health and Disease The Role of Platelets in Human Hemostasis, Platelet Transfusion, and Bleeding Time Immune Thrombocytopenia Alloantigens, Single Nucleotide Polymorphisms, and Alloimmune Thrombocytopenias Platelet Physiology, Assays of Platelet ``Adhesiveness, ́ ́ ADP, Platelet Aggregation, Myocardial Infarction, and P2Y12 Antag ... Aspirin, Arachidonic Acid, Prostaglandins, Eicosanoids, Nitric Oxide, Endothelial Ecto-ADPase (CD39), Angiogenesis, Micropa ... Clot Retraction, Glanzmann Thrombasthenia, GPIIb/IIIa Receptor, and αIIbβ3 (GPIIb/IIIa) Antagonists Bernard-Soulier Syndrome, the GPIb-IX-V Complex, von Willebrand Factor, Shear, ADAMTS-13, and Thrombotic Thrombocytopenic P ... Thrombin-Induced Platelet Activation Platelets, Metastases, Sialic Acid, Platelet Aging, Sepsis, and Platelet Survival Reflections on the Past and Thoughts About the Future References PART I: Platelet Biology 1 The Evolution of Mammalian Platelets Introduction Invertebrates Nonmammalian Vertebrates Comparative Hemostasis A Comparison of Human Platelets and Limulus Amebocytes The Evolution of Hemostasis and Blood Coagulation Megakaryocytes and Mammals Marine Mammals Order Monotremata Order Marsupialia Platelet Levels A Comparison of Nonplacental and Placental Mammals Conclusions References 2 Megakaryocyte Development and Platelet Formation Introduction Megakaryocyte Development The Hematopoietic Program Committed Megakaryocyte Progenitor Cells Immediate Megakaryocyte Precursors Endomitosis and Polyploid Formation Megakaryocyte Cytoplasmic Maturation Invaginated Membrane System Dense Tubular System Granules Platelet Formation Mechanisms of Platelet Production Budding From the Megakaryocyte Surface Cytoplasmic Fragmentation via the Invaginated Membrane System Proplatelet Formation The Proplatelet Theory Proplatelet Morphogenesis The Cytoskeletal Mechanics of Proplatelet Formation Microtubules Power Proplatelet Elongation Actin-Dependent Proplatelet Branching Organelle Transport in Proplatelets Spectrin-Based Membrane Skeleton in Platelet Production Release of Platelets The Sites of Platelet Formation In Vivo Platelet Formation in the Bone Marrow Platelet Formation in the Bloodstream Platelet Formation in the Lung Apoptosis and Platelet Production Production of Platelets for Infusion Murine Model Systems and Human Diseases as Tools to Study Platelet Biogenesis Transcription Factors GATA-1 Nuclear Factor-Erythroid 2 Cytoskeletal Proteins β1-Tubulin Glycoprotein Ib-IX-V Complex Filamin A Nonmuscle Myosin Heavy Chain A ADF/Cofilin Profilin1A and WASP/WIP Arp2/3 CIP4/Pacsin2/Dynamin Rab Geranylgeranyl Transferase Concluding Remarks References 3 The Structure of Resting and Activated Platelets Introduction The Resting Platelet The Glycocalyx, Plasma Membrane, and Submembrane Regions The Glycocalyx The Plasma Membrane The Submembranous Region The Cytoskeleton of the Resting Platelet General Overview The Spectrin Membrane Skeleton in Resting Platelets The Microtubule Cytoskeleton in Resting Platelets The Actin Cytoskeleton in Resting Platelets Platelet Organelles and Internal Membranous Systems General Overview Alpha Granules (α-Granules) Dense Granules (δ-Granules) Lysosomes Surface Connected Open Canalicular System Dense Tubular System Mitochondria Other Platelet Structural Components Changes in Platelet Structure Following Activation The Mechanism of Shape Change General Overview Platelet Shape Change and Spreading Signals Controlling Cytoskeletal Assembly Phosphatidylinositides Actin-Binding Proteins Positively Regulated by PI(4,5)P2 Actin-Binding Proteins Negatively Regulated by PI(4,5)P2 Cytosolic-Free [Ca2+] Rho Family GTPases Changes in the Spectrin Membrane Skeleton Changes in the Microtubule Cytoskeleton Changes in the Actin Cytoskeleton Initial Shape Change Actin Monomer Sequestration Uncapping of Filament Barbed Ends De Novo Generation of Actin Filaments Actin Filament Turnover Platelet Thrombus Contraction References 4 Platelet Glycobiology and the Control of Platelet Function and Lifespan Introduction to Glycans N- and O-Linked Glycans ``Glycan-Capping ́ ́ Glyco-Transferases (Glyco-Ts) Platelet Production, Glycans, and GLYCO-TS Glycans in Platelet Function and Hemostasis Surface Sialic Acid and Platelet Activation, Inflammation, and Immune Responses Glycans and Platelet Receptors in Hemostasis Integrins and N-Glycans The von Willebrand Factor Receptor Complex, GPIb-IX-V The Collagen Receptor GPVI PECAM-1 G Protein-Coupled Receptors The Thrombopoietin Receptor Mpl Lectins (Glycan Binding Proteins, Receptors) P-Selectin Galectins CLEC-2 Platelet-mediated Extrinsic Glycan Remodeling Glycans and Platelet Lifespan Methods for the Measurement of Platelet Lifespan Sialic Acid and Platelet Lifespan Platelet Senescence and Sialic Acid Feedback Between Liver and Bone Marrow Alternative GPIb-IX Signaling and Glycan Platelet Clearance Platelet In Vitro Aging and Sialic Acid Genetic Ablation, Loss of Sialic Acid, and Lectin-Mediated Platelet Clearance Accelerated Platelet Clearance in Wiskott-Aldrich Syndrome Immune Thrombocytopenia (ITP) and Sialic Acid Sepsis, Bacteria, and Virus-Induced Loss of Sialic Acid Other Mechanisms of Platelet Lifespan Regulation References 5 Platelet Genomics Introduction Platelet Phenotypes Applied in Population Genetic Studies and Related Issues Platelet Count and Mean Platelet Volume Platelet Function Measurements at Population Scales Approaches to Functional and Molecular Studies of Genetic Findings Genomic Studies of Platelet CBC Indices Heritability of PLT and MPV The GWAS Era and Common Variants Ethnic Diversity and GWAS Whole Exome Sequencing Studies and Detection of Lower Frequency Coding Variants Exome-Based Genotyping Arrays Pleiotropy and Genetic Inter-Relationships Between Platelets and Other Phenotypes and Disorders Whole Genome Sequencing: Rare Noncoding Variants and Beyond Translating GWAS to Function Genomic Studies of Platelet Function Platelet Function Trait Heritability Candidate Gene Studies and Variants in the GWAS Era Novel Platelet Function Loci Primarily Originating From GWAS Approaches GWAS of Platelet Function Following Antiplatelet Therapy PEAR1: An Example of Integrative Omics Discovery and Refinement in Platelet Biology Exome Studies of Platelet Function The Clinical Impacts of Genomic Studies of Platelet Biology Conclusions and Prospects for the Future of Platelet Genomics References 6 Platelet MicroRNAs The MicroRNA Pathway of Human Cells Biogenesis and Function of MicroRNAs The Repertoire of Human MicroRNAs Role of MicroRNAs Identification of mRNAs Regulated by MicroRNAs MicroRNAs in Health and Disease Platelets The Platelet Proteome The Platelet Transcriptome Platelet mRNA 3UTRs The MicroRNA Pathway of Platelets Platelet MicroRNAs Detection of Platelet MicroRNAs Biogenesis of Platelet MicroRNAs The Repertoire of Platelet MicroRNA Sequences Function of MicroRNAs in Platelets MicroRNAs as Possible Regulators of mRNA Translation in Platelets A Role for MicroRNAs in Platelet Function? A Role for Platelet MicroRNAs in Other Cell Types Platelet MicroRNA Data: Between Mice and Men Use of Platelet MicroRNAs as Biomarkers Platelet MicroRNAs and Reactivity Platelet MicroRNAs and Cancer Platelet MicroRNAs and Diabetes Platelet MicroRNAs and Chronic Kidney Disease Clinical Monitoring of Platelet MicroRNAs Therapeutic Applications Conclusion and Perspectives References 7 The Platelet Transcriptome in Health and Disease Introduction The History of RNA-Based Studies That Have Contributed to Our Understanding of the Platelet Transcriptome The Discovery of RNA and mRNA in Platelets Early Studies Defining Individual mRNAs in Platelets Platelet RNA Content Platelet Isolation and Purity The Basics of Gene Expression That Underlie the Origins and Properties of Megakaryocyte and Platelet RNAs The Central Dogma: DNA-RNA-Protein Is Divided between Megakaryocytes and Platelets Overview of Transcriptional Regulation Transcription of Platelet RNA Platelet mRNA Processing mRNA Stability and Decay in Platelets Regulation of mRNA Stability in Platelets Protein Synthesis in Platelets Knowledge Gained by Defining the Platelet Transcriptome in Health and Disease The Platelet RNA-Proteome Correlation The Mouse Platelet Transcriptome Genetic Association Studies Platelet RNAs Associated With Platelet Physiology Platelet RNAs Associated With Hematologic Conditions Platelet RNAs Associated With Nonhematologic Disease Tumor-Educated Platelets Platelet Pharmaco-Transcriptomics Summary and Future Perspectives References 8 The Platelet Proteome Introduction to Platelet Proteomics The Proteome Make-up of Platelets Protein Synthesis and Uptake by Megakaryocytes Protein Synthesis and Uptake by Platelets Protein Posttranslational Modification in Megakaryocytes and Platelets Protein Degradation Mechanism in Megakaryocytes and Platelets Proteomic Approaches Used in Platelets Research Gel-Based Proteomics Gel-Free Proteomics Proteomic Strategies to Decipher Platelets, Subcellular Fractions, and Posttranslational Modifications General Considerations for Setting Up a Proteomic Experiment Proteome of Resting Platelets Proteome of Activated Platelets and the Secretome Proteome of Platelet Membranes Proteome of Platelet Granules Proteome of Platelet Microparticles Phosphoproteome and Glycoproteome of Platelets Proteomics for Other Posttranslational Modifications Application of Proteomic Research in Disease Conclusions and Future Directions References 9 Platelet Receptors Introduction Integrins β3 Family αIIbβ3 αnuβ3 β1 Family α2β1 α5β1 α6β1 β2 Family αLβ2 Leucine-Rich Repeat (LRR) Family GPIb-IX-V Complex Toll-Like Receptors Nucleotide-Binding Oligomerization Domain 2 (NOD2) Seven Transmembrane Receptors Thrombin Receptors ADP Receptors Prostaglandin Family Receptors Thromboxane (TX) Receptors PGI2 Receptor PGD2 Receptor PGE2 Receptor Lipid Receptors Platelet Activating Factor (PAF) Receptor Lysophosphatidic Acid Receptor Sphingosine-1-Phosphate Receptors Choline Transporters Chemokine Receptors Other Seven Transmembrane Receptors V1a Vasopressin Receptor A2a-Adenosine Receptor β2-Adrenergic Receptor Serotonin Receptor Dopamine Receptors α7-Nicotinic Acetylcholine Receptors Cannabinoid Receptors Immunoglobulin Superfamily GPVI FcγRIIa FcεRI Platelet and T-cell Antigen 1 (PTA-1 [TLiSA1, DNAM-1, CD226]) Junction Adhesion Molecules (JAMs) JAM-A (JAM-1, F11) JAM-C (JAM-3) Intercellular Adhesion Molecule 2 (ICAM-2) PECAM-1 G6B CD47 Endothelial Cell-Selective Adhesion Molecule (ESAM) TREM-Like Transcript 1 (TLT-1) CD148 C-Type Lectin Receptor Family P-Selectin (CD62P) CD72 CD93 (C1q-Rp) CLEC-2 Other C-Type Lectin Receptors Tetraspanins CD9 (Tspan29) CD63 (Tspan30) CD82 CD151 (Tspan24, Platelet and Endothelial Cell Tetraspan Antigen 3, PETA-3) Tspan9 (NET-5) Glycosyl Phosphatidylinositol (GPI)-Anchored Proteins Glycosaminoglycan-Carrying Receptors Tyrosine Kinase Receptors Thrombopoietin Receptor (c-mpl, CD110) Leptin Receptor Tie-1 (Tyrosine Kinase With Immunoglobulin and Epidermal Growth Factor Homology-1) Receptor Insulin Receptor Platelet-Derived Growth Factor (PDGF) Receptor Gas6 Receptors (Axl, Sky, and Mer) Platelet-Endothelial Aggregation Receptor-1 (PEAR1) Ephrins and Eph Kinases Serine/Threonine Kinase Receptors TGFβ Miscellaneous Platelet Membrane Glycoproteins CD36 (GPIV, GPIIIb) C1q Receptor C3-Specific Binding Protein (Membrane Cofactor Protein, CD46) Serotonin Reuptake Receptor Lysosomal-Associated Membrane Proteins 1 and 2 (LAMP-1, CD107a; LAMP-2, CD107b) CD40 Ligand (CD40L, CD154) P-Selectin Glycoprotein Ligand 1 (PSGL-1, CD162) P2X1 Tight Junction Receptors Tumor Necrosis Factor (TNF) Receptor Semaphorin 3A Receptors: Neuropilin 1/Plexin A CD100 (Sema4D) Peroxisome Proliferator-Activated Receptor γ (PPARγ): An Intracellular Receptor for Lysophosphatidic Acid EMMPRIN (CD147) Glutamate Receptors Liver X Receptors Galectin Receptors References 10 The Glycoprotein Ib-IX-V Complex Introduction Structure of GPIb-IX-V The Extracellular Domain of GPIbα Extracellular Domains of GPIbβ and GPIX Transmembrane (TM) Domains of GPIb-IX Cytoplasmic Domains of GPIb-IX Molecular Pathogenesis of Bernard-Soulier Syndrome (BSS) GPV Evolutionary Consideration, Species Variations Functions and Regulation of GPIb-IX-V Platelet Adhesion and Aggregation VWF Thrombin Integrin αMβ2 (Mac-1) Kininogen, Factor XI, and Factor XII β2-Glycoprotein I (β2GPI) Thrombospondin Collagen P-Selectin Platelet Clearance VWF: Type 2B VWD, PT VWD, Thrombotic Thrombocytopenia Anti-LBD Antibodies: Fc-Independent Immune Thrombocytopenia Ectodomain Shedding of GPIbα: Platelet Storage Lesion Thrombopoiesis Intracellular Signaling of GPIb-IX-V Interactions in the Membrane and in the Cytoplasm 14-3-3zeta Filamin A (FlnA) Phosphoinositide 3-Kinase (PI3K) GPVI-FcRγ Complex FcγRIIa Apolipoprotein E Receptor 2 (ApoER2) Calmodulin Tumor Necrosis Factor Receptor-Associated Factor 4 (TRAF4) PECAM-1 Lipid Rafts Downstream Signaling Pathways Conclusions References 11 GPVI and CLEC-2 Introduction to GPVI and CLEC-2 GPVI Introduction to GPVI GPVI Structure GPVI Ligands and Ligand Binding GPVI-Induced Signal Transduction Regulation of GPVI and ITAM Signal Transduction GPVI Dimerization and Clustering GPVI Distribution in the Cell Membrane GPVI Shedding CLEC-2 Introduction to CLEC-2 CLEC-2 Structure CLEC-2 Ligands and Ligand Binding CLEC-2-Induced Signal Transduction CLEC-2 Clustering The Function of GPVI in Health and Disease The Function of GPVI in Hemostasis and Thrombosis Targeting GPVI in Antithrombotic Therapy The Function of GPVI in Vascular Integrity During Inflammation The Function of GPVI in Thromboinflammation The Function of GPVI in Infection and Immunity The Function of CLEC-2 in Health and Disease The Function of CLEC-2 in Hemostasis and Thrombosis The Function of CLEC-2 in Vascular Integrity During Inflammation The Function of CLEC-2 in Thromboinflammation The Function of CLEC-2 in Blood and Lymphatic Vessel Development Conclusions References 12 Integrin αIIbβ3 Introduction αIIbβ3 as an Integrin and a Platelet Protein Structure of αIIbβ3 The Extracellular Domain The Transmembrane Domain The Cytoplasmic Domain Ligand Binding ``Inside-Out ́ ́ Signaling and αIIbβ3 Activation Pathways Leading to Integrin Activation Unclasping of the Cytoplasmic Tail Triggers αIIbβ3 Activation Regulation of Integrin αIIbβ3 Activation by Cytoplasmic Tail Binding Partners Involvement of αIIbβ3 in Infection Conclusion References 13 Protease-Activated Receptors Discovery of Protease-Activated Receptors (PARs) General Facts About PARs Genomic Organization and Evolution of PARs Protease-Activated Receptor-1 (PAR1) Protease-Activated Receptor-3 (PAR3) Protease-Activated Receptor-4 (PAR4) Expression of PARs Across Species Activation of PARs by Thrombin Thrombin Recognition of PAR1 Thrombin Recognition of PAR4 Physical Interactions Between PARs Thrombin Signaling in Human Platelets PAR1- and PAR4-Specific Signaling Termination of PAR Signaling Activation of PARs by Proteases Other Than Thrombin Pharmacologically Blocking PAR Signaling Protease-Activated Receptor 1 Antagonists Protease-Activated Receptor 4 Antagonists Structural Studies on PARs Polymorphisms and Sequence Variants Future Directions References 14 The Platelet P2 Receptors P2 Receptors Roles of Adenine Nucleotides in Platelet Function P2Y1 P2Y1 is Expressed on Platelets Role of P2Y1 in ADP-Induced Platelet Activation Role of P2Y1 in Platelet Responses to Agonists Other Than ADP Role of P2Y1 in Thrombin Generation Role of P2Y1 in Platelet Thrombus Formation In Vitro and In Vivo Other Functions of the Platelet P2Y1 Receptor Congenital Abnormalities of the P2Y1 Receptor P2Y12 P2Y12 is Expressed on Platelets Role of P2Y12 in ADP-Induced Platelet Activation Role of P2Y12 in Platelet Responses to Agonists Other Than ADP Role of P2Y12 in Thrombin Generation Role of P2Y12 in Inhibition of Adenylyl Cyclase Role of P2Y12 in Platelet Thrombus Formation In Vitro and In Vivo Other Functions of the Platelet P2Y12 Receptor Congenital Abnormalities of the P2Y12 Receptor Polymorphisms of the P2Y12 Gene P2X1 P2X1 is Expressed on Platelets Role of P2X1 in Platelet Activation and Thrombus Formation In Vitro and In Vivo Other Functions of the Platelet P2X1 Receptor Congenital Abnormalities of the P2X1 Receptor Interplay Between the Platelet P2 Receptors Desensitization of the Platelet P2 Receptors Conclusions References 15 Platelet Inhibitory Receptors Introduction Background Prostacyclin Receptor: Broad-Spectrum Inhibitor of Platelet Activation Soluble Guanylate Cyclase: Broad-Spectrum Inhibitor of Platelet Activation ITIM-Containing Receptors PECAM-1: Selective Inhibitor of Platelet Activation PECAM-1 Function PECAM-1 Signaling G6b-B: Critical Regulator of Platelet Homeostasis G6b-B Function G6b-B Signaling Other Platelet ITIM-Containing Receptors LAIR-1 TLT-1 CEACAM1 and CEACAM2 PIR-B Conclusion References 16 Interactions Between Platelets, Leukocytes, and the Endothelium Introduction Platelet-Leukocyte Interactions Adhesive Receptors Soluble Mediators Functional Consequences Induction of Inflammatory Gene Expression Transcellular Biosynthesis of Eicosanoids Induction of ROS and Granule Secretion (in PMN) Fibrin Formation and MP Formation Platelets and Neutrophil Extracellular Traps (NET) Induction of Ig Switch and Adaptive Immune Responses Vascular Remodeling Responses Vessel Passivation Platelet-Leukocyte Interactions in Atherothrombosis Platelets and the Vascular Endothelium, Development, and Vascular Integrity Vascular Development Vascular Integrity Concluding Remarks References 17 Inhibition of Platelet Function by the Endothelium Introduction Nitric Oxide Biosynthesis of NO and Characteristics of Endothelial NO Synthase The Effect of Endothelial and Platelet NO on Platelet Reactivity NO-Mediated Endothelial-Platelet Interactions and Thrombotic Disease Prostacyclin Prostacyclin Biosynthesis and Characteristics of Endothelial Prostacyclin Synthase The Platelet Prostacyclin Receptor-Biochemistry, Structure, and Function Prostacyclin-Signaling Mechanisms and Platelet Inhibition The Relevance of Prostacyclin In Vivo CD39 (NTPDase-1) Endothelial CD39-Biochemistry, Structure and Function The Effect of Endothelial CD39 on Platelet Reactivity CD39-In Vivo Studies Emerging Concepts: Regulation of Platelet Function According to Platelet Size Summary References 18 Platelet Signal Transduction Introduction Major Stimulatory and Inhibitory Receptors Expressed on the Platelet Surface G Protein-Coupled Receptors (GPCRs) (hem)ITAM and ITIM Receptors Second Messengers Phospholipase C Calcium Signaling Diacylglycerol Signaling PI3K and 3-Phosphorylated Phosphoinositide Signaling Cyclic Nucleotide Signaling Signal Integrators Kinases Protein Kinase C (PKC) Protein Kinase A/Protein Kinase G (PKA/G) Mitogen-Activated Protein Kinases (MAPKs) RAP GTPase Signaling and Platelet Integrin Activation RAP GTPases RAP1 Regulators Summary References 19 Platelet Secretion Introduction: Platelet Granules Formation of Platelet Granules Formation of α-Granules Synthetic Pathway Protein Sorting Endocytosis -Granule Heterogeneity Formation of Dense Granules Platelet Granule Content α-Granule Content Dense Granule Content Lysosome Content Mechanisms of Platelet Granule Secretion The Platelet Release Reaction Fusion of Platelet Granule Membranes Lipid Composition SNAREs SNARE Regulators Calcium Flux and Protein Phosphorylation in Granule Secretion Ca2+ Binding Proteins The Cytoskeleton and Granule Secretion Function of Platelet Granule Secretion Hemostasis and Thrombosis α-Granule Function in Hemostasis and Thrombosis Dense Granule Function in Hemostasis and Thrombosis The Secretory Machinery in Hemostasis and Thrombosis Inflammation α-Granules in Inflammation Dense Granules in Inflammation Atherosclerosis α-Granules in Atherosclerosis Dense Granules in Atherosclerosis Antimicrobial Host Defense Mitogenesis Angiogenesis Malignancy Wound Healing Platelet Granule Disorders α-Granule Deficiencies Dense Granule Deficiencies Defects in Granule Release Conclusion References 20 Hemostatic Thrombus Formation in Flowing Blood Introduction What Does a Hemostatic Plug Actually Look Like and How Does It End Up Looking Like That? Reasons to ``Mind the Gaps ́ ́ Between Platelets The Contribution of Platelet Procoagulant Activity to Hemostasis Scaling Up Events in the Microcirculation to Larger Vessels Hemostatic Versus Pathologic Thrombi How the Signaling Network Inside Individual Platelets Produces the Hemostatic Plug Structure Using Computational Approaches to Study Hemostasis Modeling Coagulation Modeling Mass Transport Modeling Platelet Accumulation Under Flow Using Microfluidic Devices to Study Hemostasis The Hemodynamics of Hemostasis Factoring in a Pressure Drop Other Examples Adding Endothelial Cells Microfluidics in the Clinical Setting References Further Reading 21 Interactions Between Platelets and the Coagulation System Overview of Coagulation Regulation of Coagulation by the Platelet Membrane Surface Coagulation Reactions That Take Place on the Platelet Surface Activation of FX or FIX by TF-FVIIa Activation of FXI Activation of FIX by FXIa Activation of FX by Intrinsic Tenase (FIXa-FVIIIa) Activation of Prothrombin by Prothrombinase (FXa-FVa) Platelet Products that Contribute to Coagulation Zinc Fibrinogen FXIII FV FXI Tissue Factor Pathway Inhibitor (TFPI) Protein S Protease nexin-2 (PN2) Calcium Pyrophosphate Polyphosphate (polyP) References 22 Platelet-Derived Extracellular Vesicles Introduction Nomenclature Improved Isolation and Detection New Protocols for Blood Collection and Handling to Analyze EVs Potential Types of Platelet EVs in Blood Isolation and Detection of Platelet EVs Isolation Detection Origin of Platelet EVs in Blood Biochemical Composition Proteins Lipids and Metabolites Nucleic Acids Formation and Clearance Role of Phosphatidylserine in Formation and Clearance Functions of Platelet EVs Coagulation Immune Response and Inflammation Angiogenesis and Wound Healing Carcinogenesis Waste Management Role in Health and Disease Future Developments References 23 Regulation of Fibrinolysis by Platelets Introduction Key Players in Fibrinolysis and Their Function Plasmin(ogen) Plasminogen Activators Tissue-Type Plasminogen Activator Urinary-Type Plasminogen Activator Contact Activation of Fibrinolysis Inhibitors of Fibrinolysis α2 Antiplasmin Plasminogen Activator Inhibitor 1 Thrombin Activatable Fibrinolysis Inhibitor Additional Modulators Protease Nexin-1 Histidine-Rich Glycoprotein C1 Inhibitor Factor XIII Polyphosphate Platelet-Associated Fibrinolytic Activity Platelet αIIbβ3 Interactions Platelet-Mediated Effects on Fibrin Structure Plasmin-Mediated Platelet Activation Platelet Disorders and Fibrinolysis Quebec Platelet Disorder Gray Platelet Syndrome Acquired Platelet Deficiencies Net Effects References 24 The Role of Platelets in Angiogenesis Angiogenesis Platelets Contain an Abundance of Angiogenic Factors Platelets and Angiogenesis Angiogenic Mediators Present in Platelets Proangiogenic Factors Antiangiogenic Factors Platelet-Derived Microparticles and Angiogenesis Physiological Angiogenesis: Support From Platelets Platelets and Wound Healing Lymphangiogenesis Pathological Angiogenesis: Support From Platelets Platelets, Angiogenesis, and Promotion of Tumor Growth Conclusions References 25 Platelet Function in the Newborn Introduction Platelet Number and Size Platelet Production Platelet Structure Platelet Activation and Signal Transduction Platelet Adhesion and Aggregation Platelet Secretion Platelet Procoagulant Activity Platelet Transcriptome Differences Between Human and Murine Neonatal Platelets Measurements of Platelet Function Bleeding Time Platelet Function Analyzer-100 Cone and Plate(let) Analyzer Platelet Aggregation Flow Cytometry Thromboelastography Effects of Maternal and Neonatal Illness and Therapies on Neonatal Platelet Function Conclusions and Future Directions References PART II: The Role of Platelets in Disease 26 The Role of Platelets in Atherothrombosis Platelets and Vascular Inflammation Platelet-Derived Inflammatory Mediators Platelet-Derived Cytokines Platelet-Derived Chemokines CCL-5 CXCL4 CX3CL1 CXCL12 CXCL16 MIF DAMPs Thromboinflammation Platelet/Lipid Interactions Conclusions References 27 The Role of Platelets in Diabetes Mellitus Accelerated Atherothrombosis: Epidemiological and Clinical Findings The ``Diabetic Platelet ́ ́ Mechanisms Contributing to in vivo Platelet Activation Metabolic Changes Low-Grade Inflammation HMGB1 CD40L LIGHT CD36 DKK-1 RAGE Oxidative Stress Endothelial Dysfunction Obesity Novel Biomarkers of Platelet Activation in DM MicroRNA Platelet Microparticles Reduction by Antidiabetic Drugs of Factors Contributing to Platelet Activation/Hyperreactivity and Cardiovascular Outcomes Antiplatelet Therapy for the Primary and Secondary Prevention of Atherothrombotic Events in Diabetes Secondary Prevention Primary Prevention Less-Than-Expected Response to Aspirin Possible Determinants of Suboptimal Response to Aspirin in Diabetes Oxidative Stress Impaired COX-1 Inhibition Protein Glycation Hydroperoxides Peroxynitrite Extraplatelet Sources of Thromboxane Generation Driven by Low-Grade Inflammation Increased Platelet Turnover Conclusions References 28 The Role of Platelets in Inflammation Introduction Platelets in Clinical and Experimental Inflammatory Diseases and Syndromes The Lungs: Platelets and Megakaryocytes in Pulmonary Biology and Inflammatory Lung Diseases Malaria Sepsis Dengue Rheumatic Diseases Rheumatoid Arthritis Granulomatosis With Polyangiitis Systemic Lupus Erythematosus References 29 The Role of Platelets in Antimicrobial Host Defense Introduction Platelets are Archetypal Antimicrobial Host Defense Cells Platelets Have Structures of Immune Cells Platelets Have Functions of Immune Cells Teleological Basis of Platelets in Host Defense Platelets Target and Intensify at Sites of Infection Platelets Sense Infected Endothelium Platelets Perform Key Roles in Antimicrobial Host Defense Platelets Recognize Signals of Infection Pattern Recognition Receptors Platelets Interact With Microbial Pathogens Platelets Interact With Viruses Platelets Interact With Bacteria Platelets Interact With Fungi Platelets Interact With Protozoa Platelets Contain Antimicrobial Effector Molecules Platelet Microbicidal Proteins and Kinocidins Kinocidins are Modular Host Defense Proteins Kinocidins Deploy in Context of Infection Kinocidins and the AEGIS Model of Host Defense Kinocidins Functions Promote Immune Syntax Platelets Execute Exocrine Subroutines in Response to Infection Kinocidins Exert Complex Mechanisms of Action Kinocidins Potentiate Conventional Antibiotics Platelets Modulate Pathogen Interactions With Host Tissues Platelets Modulate Complement Activation Platelets Influence the Host Defense Roles of Lymphocytes Platelets Potentiate the Antimicrobial Functions of Leukocytes In Vitro Correlates of Platelet Host Defense Roles Platelets are Integral to Antimicrobial Host Defense In Vivo Certain Pathogens May Subvert Platelet Host Defenses Correlates of Platelet Quantity or Function and Risk of Infection Prospectus Summary References 30 The Role of Platelets in Tumor Growth, Metastasis, and Immune Evasion Introduction Thrombocytosis and Cancer Thrombocytosis and Poor Cancer Outcome Paraneoplastic Thrombocytosis Platelets in Oncogenesis Platelet-Cancer Loop Tumor Cell-Induced Platelet Aggregation Platelet Activity on Tumor Growth Platelet-Derived Microparticles Platelets in Cancer Metastasis Platelet-Induced EMT Platelet-Induced Intravasation of Tumor Cell Platelets Promote Survival of Circulating Tumor Cells Platelet-Induced Extravasation of Circulating Tumor Cells Platelets Promote Distant Premetastatic Niche Platelets in Cancer Immune Tolerance Innate Immune Response to Cancer Adaptive Immune System Platelets, Cancer Diagnosis, and Therapy Platelets as Biomarkers for Cancer Diagnosis Platelets as a Means for Drug Delivery Combination of Antiplatelet Therapy With Current Anticancer Treatments Conclusions References 31 The Role of Platelets in Sickle Cell Disease Introduction Platelet-Dependent Pathophysiology in SCD Mechanisms of Platelet Activation in SCD Nitric Oxide Depletion Platelet TLR4 Activation Platelet Purinergic Receptor Activation Oxidative Stress in SCD NET-Dependent Platelet Activation in SCD VWF-Dependent Platelet Activation in SCD Coagulation-Dependent Platelet Activation in SCD Inflammasomes and Platelets Platelet Activation-Dependent Vascular Pathophysiology of SCD Intravascular Platelet Sequestration Platelet Adhesion to Endothelium Platelet-Dependent Heterocellular Aggregation Thrombosis Targeting Platelet Pathobiology as a Therapy in SCD Increasing NO Bioavailability Antiadhesion and Antiinflammatory Therapy Anticoagulation Antiplatelet Therapy Conclusions and Future Directions Acknowledgments References PART III: Clinical Tests of Platelet Function 32 Platelet Counting Introduction Manual Platelet Counting Automated Platelet Counting Impedance Platelet Counting Optical Platelet Counting Optical Fluorescence Platelet Counting Quality Control for Automated Hematology Analyzers Immunological Platelet Counting Automated Immunological Counting Image-Based Platelet Counting POC Platelet Counting Reticulated Platelets/Immature Platelet Fraction Conclusions References 33 Clinical Tests of Platelet Function Introduction Early Tests of Platelet Function Preanalytical Precautions for Platelet Function Testing Overview of Currently Available Platelet Function Tests Light Transmission Aggregometry Advantages and Limitations of the Assay Clinical Applications Modified 96-Well Plate Assay for Platelet Aggregation Advantages and Limitations of