Note: COVER -- TITLE -- COPYRIGHT -- CONTENTS -- CONTRIBUTORS -- PREFACE -- GLOSSARY -- CHAPTER 1 THE STRUCTURE AND PRODUCTION OF BLOOD PLATELETS -- INTRODUCTION -- 1. THE STRUCTURE OF THE RESTING PLATELET -- The intracellular components of the resting platelet -- Granules -- Organelles -- Membrane systems -- Open canalicular system -- Dense tubular system -- The cytoskeleton of the resting platelet -- The marginal band of microtubules -- The actin cytoskeleton -- The spectrin membrane skeleton -- MEGAKARYOCYTE DEVELOPMENT AND PLATELET FORMATION -- Commitment to the megakaryocyte lineage -- Endomitosis -- Cytoplasmic maturation -- Platelet formation -- The cytoskeletal machine of platelet production -- Platelet formation in vivo -- Regulation of megakaryocyte development and platelet formation -- Apoptosis and platelet biogenesis -- THE STRUCTURE OF THE ACTIVATED PLATELET -- The platelet shape change -- Granule secretion -- FUTURE AVENUES OF RESEARCH -- REFERENCES -- CHAPTER 2 PLATELET IMMUNOLOGY: STRUCTURE, FUNCTIONS, AND POLYMORPHISMS OF MEMBRANE GLYCOPROTEINS -- INTRODUCTION -- THE GP Ib/IX/V COMPLEX -- Structure of the GP Ib/IX/V complex -- Signaling and functions of GP Ib/IX/V complex -- Polymorphisms of the GP Ib/IX/V Complex -- THE…NTEGRIN (GP IIb/IIIaCOMPLEX, CD41/CD61) -- Structure of the αIIbβ3 integrin -- Affinity regulation of the αIIbβ3 integrin -- Location of the ligand-binding site -- Location of epitopes for conformation-dependent mAbs -- Polymorphisms of the αIIbβ3 complex -- GP IIIa (β3 integrin) -- GP IIb(αIIb integrin) -- Clinical relevance and future directions -- α2β1 INTEGRIN (GP Ia/IIa) -- Structure of α2β1 integrin -- Signaling of α2β1 integrin -- Polymorphisms of the α2β1 complex -- GP Ia(α2 integrin) -- CD36 (GP IV, GP IIIb) -- CD36 Polymorphisms -- GP VI -- GP VI Polymorphisms -- FUTURE AVENUES OF RESEARCH -- REFERENCES. , CHAPTER 3 MECHANISMS OF PLATELET ACTIVATION -- INTRODUCTION -- THREE STAGES OF PLATELET PLUG FORMATION -- Stage I: The initiation of platelet activation -- Stage II: Extension of the hemostatic plug through recruitment of additional platelets -- G Protein-mediated signaling in platelets -- Platelet activation in vivo -- Gq and the activation of phospholipase Cβ -- Gq, G13, and the actin cytoskeleton -- Signaling through Gi family members -- ADP: Two receptors with distinguishable functions -- Thrombin: two receptors with overlapping functions -- Epinephrine: potentiator of other agonists -- Thromboxane A2: twin receptor(s) coupled to Gq and G12/13 -- Stage III: Perpetuation (stabilization) of the platelet plug -- Integrins, adhesion, and outside-in signaling -- Other adhesion molecules -- Receptor: ligand interactions at the platelet:platelet interface -- PROTEOMICS AND PLATELETS -- FUTURE AVENUES OF RESEARCH -- REFERENCES -- CHAPTER 4 PLATELET PRIMING -- INTRODUCTION -- EFFECT OF PLATELET PRIMERS IN VITRO -- Proteins -- Gas6 -- Factor VIII -- Matrix metalloproteinases -- MMP-1 -- MMP-2 -- Soluble CD40 ligand (sCD40L) -- Low-density lipoproteins (LDLs) -- CYTOKINES -- Vascular endothelial growth factor (VEGF) -- Thrombopoietin (TPO) -- Chemokines -- Leptin -- Hormones -- Estrogens -- Epinephrine -- Histamine -- Prostaglandins -- Prostaglandin E2 -- Ions -- Zinc -- Others -- Lipopolysaccharides (LPS) -- Foreign substances -- Succinate -- EFFECT OF PLATELET PRIMERS IN VIVO: EVIDENCE FROM ANIMAL STUDIES -- Proteins -- Gas6 -- Matrix metalloproteinase 2 (MMP-2) -- CD40L -- Cytokines -- Thrombopoietin -- Leptin -- Hormones -- Epinephrine -- Prostaglandins -- Prostaglandin E2 -- Others -- Lipopolysaccharides (LPS) -- Exogenous Substances -- EFFECT OF PLATELET PRIMERS IN VIVO: STUDIES IN HUMANS -- Proteins -- Cytokines -- Hormones -- Prostaglandins. , CONCLUSION -- FUTURE AVENUES OF RESEARCH -- REFERENCES -- CHAPTER 5 PLATELETS AND COAGULATION -- INTRODUCTION -- EFFECTS OF PLATELETS AND THEIR PRODUCTS ON COAGULATION -- Platelet products that enhance TF synthesis -- Platelet products that increase TF production -- PLATELET PROCOAGULANT ACTIVITY -- Overview of coagulation -- Exposure of phosphatidylserine -- Platelet microvesicles -- Alpha-granule proteins -- Defects in platelet procoagulant activity -- Platelet heterogeneity and coated platelets -- Platelets and TF -- Effect of platelet antagonists on procoagulant activity -- FUTURE AVENUES OF RESEARCH -- REFERENCES -- CHAPTER 6 VESSEL WALL-DERIVED SUBSTANCES AFFECTING PLATELETS -- INTRODUCTION -- Vascular endothelium -- Normal endothelial function -- Endothelial dysfunction -- Platelets -- Platelet activation and adhesion -- Platelet-endothelium interaction -- Platelet-endothelium interactions in thrombosis and hemostasis -- Platelet-endothelium interactions in inflammation -- ENDOTHELIUM-DERIVED SUBSTANCES THAT AFFECT PLATELETS -- Nitric oxide -- NO synthesis -- Effect of NO on platelet function -- Prostaglandins (PGs) -- PG synthesis -- Effect of PG on platelet function -- Ecto-ATPDase -- SURFACE-BOUND ENDOTHELIAL ANTIPLATELET FACTORS -- Platelet-endothelial cell adhesion molecule-1 (PECAM-1) -- ENDOTHELIUM, PLATELETS, AND VASCULAR DISEASE -- Mechanisms underlying endothelial dysfunction in vascular disease -- Endothelium-derived vasodilators -- Reactive oxygen species (ROS) -- Vascular disease -- Cardiovascular disease -- Hypertension -- Hypercholesterolemia -- Diabetes mellitus -- FUTURE AVENUES OF RESEARCH -- REFERENCES -- CHAPTER 7 PLATELET-LEUKOCYTE-ENDOTHELIUM CROSS TALK -- INTRODUCTION -- PLATELET-DERIVED INFLAMMATORY MEDIATORS -- Platelet-derived chemokines -- Platelet-derived cytokines and cytokine-like factors. , Platelet-derived adhesion proteins -- Platelet-derived coagulation factors -- Platelet-derived growth factors -- Platelet-derived eicosanoids and lipid mediators -- Platelet-derived proteases -- PLATELET-ENDOTHELIAL CELL CROSS TALK -- Platelet-endothelial cell adhesion -- Platelet-endothelial signaling, thrombosis, and inflammation -- PLATELET-LEUKOCYTE CROSS TALK -- Platelet-leukocyte adhesion -- Platelet-leukocyte signaling, thrombosis, and inflammation -- ANTI-INFLAMMATORY EFFECTS OF PLATELET INHIBITION -- COX inhibition, aspirin, and selective COX-2 inhibitors -- ADP-receptor (P2Y12) antagonists -- GP IIb/IIIa receptor antagonists -- Phosphodiesterase inhibitors -- CONCLUSIONS AND CLINICAL IMPLICATIONS -- FUTURE AVENUES OF RESEARCH -- REFERENCES -- CHAPTER 8 LABORATORY INVESTIGATION OF PLATELETS -- INTRODUCTION -- BLOOD SAMPLING -- TESTS OF PLATELET MORPHOLOGY -- Platelet count -- Platelet size and appearance -- Exercise and MPV -- Vascular disease -- TESTS OF GLOBAL PLATELET FUNCTION -- Bleeding time -- Rapid platelet function assay -- PLATELET AGGREGATION TESTS -- Optical (turbidometric) platelet aggregometry -- Sample preparation -- Advantages/limitations -- Agonist-induced platelet aggregation -- ADP -- Epinephrine -- Collagen -- Ristocetin -- Other platelet-aggregating agents -- VerifyNow® -- Impedance (whole-blood) platelet aggregometry -- Advantages/limitations -- Platelet activation under controlled shear conditions: PFA-100® -- Variables that influence the PFA-100® -- The PFA-100® versus the bleeding time -- Clinical utility -- Platelet function under flow -- FLOW CYTOMETRIC ASSESSMENT OF PLATELET FUNCTION -- Monoclonal antibodies -- Methodologic aspects -- Advantages/limitations -- SOLUBLE PLATELET ACTIVATION MARKERS -- Platelet granular contents (β-thromboglobulin and platelet factor 4) -- Glycoprotein V (GPV) -- sP-Selectin. , Platelet adhesion assay -- Miscellaneous -- URINARY MARKERS OF PLATELET FUNCTION -- Urinary TxA2 metabolites -- Urinary TxB2 -- IS THERE AN IDEAL WAY TO QUANTIFY PLATELET PATHOPHYSIOLOGY? -- NOVEL TECHNIQUES FOR THE STUDY OF PLATELETS/MKS -- FUTURE AVENUES OF RESEARCH -- REFERENCES -- CHAPTER 9 CLINICAL APPROACH TO THE BLEEDING PATIENT -- INTRODUCTION -- INITIAL URGENT MEASURES -- INSPECTION FOR SUBCUTANEOUS BLEEDING -- FOCUSED MEDICAL HISTORY AND GENERAL PHYSICAL EXAMINATION -- FURTHER DIFFERENTIAL DIAGNOSIS -- CONCLUSION -- FUTURE AVENUES OF RESEARCH -- REFERENCES -- CHAPTER 10 THROMBOCYTOPENIA -- INTRODUCTION -- IMMUNE THROMBOCYTOPENIC PURPURA -- Epidemiology and presentation -- Differential diagnosis -- Initial evaluation -- Pathogenesis and laboratory diagnosis -- Additional clinical features of ITP -- Clinical management -- Initial treatment -- Emergent treatment -- Management of first relapse: splenectomy and alternative medical treatments -- Chronic ITP: splenectomy failures -- Chronic, refractory ITP -- Immunosuppression -- Investigational approaches -- ITP IN CHILDHOOD -- Presentation -- Differential diagnosis -- Management at presentation -- Management of acute ITP after the first week -- Chronic ITP: management after 6 to 12 months -- INHERITED THROMBOCYTOPENIA -- Myelodysplasia (MDS) -- DRUG-INDUCED THROMBOCYTOPENIA -- NEONATAL THROMBOCYTOPENIAS -- FETAL AND NEONATAL ALLOIMMUNE THROMBOCTOPENIA -- Pathogenesis -- Clinical presentation -- Intracranial hemorrhage -- Predictors of disease -- Diagnosis -- SCREENING PROGRAMS -- Management -- Antenatal management -- Severity of disease -- Intracranial hemorrhage -- Therapeutic procedures -- Overall approach to therapy -- Specific management strategies -- Very high risk -- High risk -- Standard risk -- No well-defined risk -- Long-term effects of antenatal management on the treated fetus. , Treatment in the newborn.

Note: Intro -- Foreword -- Contents -- Contents for Volume 2 -- Part I: Physiology -- A Brief History of Blood Platelets: A Personal View -- Introduction -- The Discovery of Blood Platelets and Early Research -- The 1960s -- The 1970s -- The 1980s and 1990s -- References -- Phylogeny of Blood Platelets -- Introduction -- Phylogeny of Platelets -- Phylogeny of Platelet Molecules and Receptors -- References -- Platelet Morphology and Ultrastructure -- Overall Morphology and Function of Platelets -- Visualization of Platelets -- The Resting Platelet Ultrastructure -- The Open Canalicular System -- The Dense Tubular System -- Peroxisomes -- Mitochondria -- α-Granules -- Dense Granules -- Lysosomes -- Platelet Cytoskeleton -- Platelet Microparticles (PMPs) and Exosomes -- Future Perspectives -- References -- Megakaryocyte Development and Platelet Production -- Megakaryocyte Development -- Commitment to the Megakaryocyte Lineage -- Polyploidization -- Cytoplasmic Maturation -- Platelet Formation -- The Proplatelet Theory -- Morphogenesis of Proplatelets -- The Cytoskeleton Powers Platelet Production -- Release of Individual Platelets -- Regulation of Platelet Formation In Vivo -- Conclusion -- References -- Platelet Heterogeneity -- Platelet Size Heterogeneity -- Age- and Maturation-Related Platelet Heterogeneity -- Heterogeneity of Platelet Genetics -- Heterogeneity of Activated Platelets (Procoagulant Platelets) -- Platelet Heterogeneity Within the Hemostatic Plug and Thrombus -- References -- Regulation of Platelet Adhesion Receptors -- Introduction -- Regulation of Platelet Integrins -- Positive Regulators of Integrin Activation -- ``Classical´´ Fluid-Phase Excitatory Platelet Agonists -- ``Nonclassical´´ Excitatory Agonists -- Matrix-Associated Platelet Agonists Functioning Through Hemostatic Pathways. , Platelet Agonists Functioning Through Non-hemostatic Pathways -- Principal Signaling Pathways Downstream of Agonist Receptors Involved in Activation of αIIbbeta3 -- Integrin-Proximal Regulatory Events -- Negative Regulators of Integrin Activation -- Proteins that Prevent Basal Activation of Integrins -- Proteins that Promote Integrin Deactivation by Their Presence -- Regulation of Non-integrin Platelet Adhesion Receptors -- Perspective -- References -- The Platelet Glycoprotein Ib-IX-V Complex -- Introduction -- GPIb-IX-V Complex Structure and Biosynthesis -- Polypeptide Structures -- Functions of the Complex -- GPIb-IX-V Complex Signaling -- Summary -- References -- αIIbbeta3 (GPIIb/IIIa) Structure and Function -- Introduction -- αIIbbeta3 Biosynthesis -- Structure of the αIIbbeta3 Extracellular Domains -- αIIbbeta3 Activation -- Intramolecular Interactions Involving the αIIb and beta3 Cytoplasmic Domains -- Heteromeric Interaction of the αIIb and beta3 TM Domains -- Protein Binding to the beta3 Cytoplasmic Domain Causes αIIbbeta3 Activation -- αIIbbeta3-Mediated Outside-In Signaling in Platelets -- Ligand Binding to αIIbbeta3 -- References -- GPVI -- Key Discoveries -- GPVI Structure -- The GPVI Receptor-Signalling Pathway -- GPVI Ligands -- GPVI in Platelet Physiology -- The Role of GPVI in Thrombus Formation and Stability -- GPVI in Haemostasis -- GPVI in Inflammation -- Avenues for Future -- References -- The Role of CLEC-2 in and Beyond the Vasculature -- Introduction -- CLEC-2 Signalling -- (Hem)ITAM Receptors in Platelets -- (Hem)ITAM Signalling -- Functional Roles of CLEC-2 Signalling -- CLEC-2 in Development -- Blood-Lymphatic Vascular Separation Defect in CLEC-2-Deficient Mice -- Identifying the Causative CLEC-2-Expressing Cell That Underlies the Defects in Lymphatic Development. , Unravelling the Molecular Mechanism of the Impairment in Lymphatic Development -- Other Developmental Functions of CLEC-2 -- CLEC-2 Beyond Haemostasis: The Beneficial and Detrimental Role of the Interaction of CLEC-2 and Podoplanin -- The Role of CLEC-2-Podoplanin in Inflammatory Diseases -- The Role of CLEC-2 and Podoplanin in Infection -- The Role of CLEC-2 and Podoplanin in Cancer -- Conclusion -- References -- Anatomy of the Platelet Cytoskeleton -- Introduction -- The Cytoskeleton of the Resting Platelet -- Actin -- The Membrane Cytoskeleton -- Cross-Linking and Bundling Proteins -- Focal Adhesion and Membrane-Associated Proteins -- Contractile Proteins -- The Marginal Band -- The Cytoskeleton of the Activated Platelet -- Actin Filament Assembly -- Actin Monomer-Sequestering Proteins and Actin Filament Capping Proteins -- The Gelsolin Family -- The ADF/Cofilin Family -- Actin Nucleation by the Arp2/3 Complex -- WASp Family and Actin Nucleation-Promoting Factors -- Actin Nucleation by Formins -- Conclusion -- References -- Platelet Proteomics and its Applications to Study Platelet-Related Disorders -- Introduction to Platelet Proteomics -- Proteomic Methods Used for Platelet Research -- Gel-Based Proteomics -- Gel-Free Proteomics -- Proteomic Strategies to Decipher Platelet Biology -- General Considerations for Experimental Design of Platelet Proteomic Studies -- Proteomics of Resting Platelets -- Proteomics of Activated Platelets -- Analysis of Platelet Subproteomes -- Platelet Granules -- Platelet Microparticles -- Platelet Plasma Membrane -- Proteomics to Analyze Platelet Posttranslational Modifications -- Platelet Phosphoproteome -- Platelet Glycoproteome -- Platelet Palmitoylome -- Platelet Proteomics to Gain Insights in Human Diseases -- Platelet Proteomics to Study Platelet-Related Bleeding Disorders. , Platelet Proteomics to Study Cardiovascular Disease -- Platelet Proteomics to Study Other Disorders -- Conclusion -- References -- The Platelet PARs -- Introduction -- Historical Perspective -- Protease-Activated Receptor 1 (PAR1) -- Protease-Activated Receptor 3 (PAR3) -- Protease-Activated Receptor 4 (PAR4) -- Activation of PARs by Thrombin -- Thrombin Signaling in Human Platelets -- Overlapping Signaling Between PAR1 and PAR4 -- Calcium Mobilization -- Cooperation Between Thrombin and ADP Signaling -- Membrane Lipids and PAR1-PAR4 Downstream Signaling -- Granule Secretion and PAR1-PAR4 Downstream Signaling -- Biased Signaling of PARs -- Biased Signaling from PARs in Platelets -- Activation PARs by Proteases Other Than Thrombin -- Physical Interactions Between PARs -- Polymorphisms and Sequence Variants -- Structural Studies on PARs -- Species Differences in PARs Expression in Platelets -- References -- The P2 Receptors -- Introduction -- Biology of the Platelet P2 Receptors -- The P2Y1 Receptor -- The P2Y12 Receptor -- The P2Y14 Receptor -- The Platelet P2X1 Receptor -- Genetic Polymorphisms of the P2Y1 and P2Y12 Receptors -- Congenital Defects of the Platelet P2 Receptors -- Platelet P2 Receptors as Targets for Antithrombotic Drugs -- The P2Y12 Receptor -- The P2Y1 Receptor -- The P2X1 Receptor -- P2 Receptors in Inflammation -- The P2Y12 Receptor in Inflammation -- The P2Y1 Receptor in Inflammation -- The P2X1 Receptor in Inflammation -- Conclusion -- References -- Platelet Prostanoids and their receptors -- Prostanoid Biosynthesis -- Prostanoid Biology -- References -- Platelet Genomics -- Inherited Genetic Disorders Associated with Platelet Functional Variation -- Cytoskeleton Genetic Disorders -- Transcription Genetic Disorders -- Granule Biogenesis Genetic Disorder -- Cell Signaling Genetic Disorders. , Platelet Receptor Genetic Polymorphism Affecting Functional Responses -- ADP Receptors -- Collagen Receptors -- Fibrinogen Receptor -- Platelet Genome-Wide Association Studies (GWAS) -- GWAS: Platelet Counts and Volume -- GWAS: Antiplatelet Drug Response -- Aspirin -- Clopidogrel -- Prasugrel -- Ticagrelor -- Thrombin Receptor (PAR1) Antagonists -- GWAS: Platelet-Associated Diseases -- Myocardial Infarction -- Stroke -- Major Depressive Disorder -- Conclusion and Future Directions -- References -- The Platelet Transcriptome: Coding RNAs -- General Overview of the Platelet mRNA World -- The Inheritance of Platelet mRNAs -- NGS Overview -- Platelet Transcripts as Indicators of Altered Platelet Function -- Coding mRNA and Genetic Differences in Platelet Function -- Platelet Transcripts to Monitor Response to Therapy -- Platelet Transcripts as Diagnostic Biomarkers of Disease -- mRNA Profiles in Mouse Platelets -- Summary -- References -- Noncoding RNAs in Platelet Biology -- Introduction -- miRNAs -- miRNAs and Megakaryopoiesis -- miRNAs Positively Regulating Megakaryopoiesis -- miRNA Negatively Regulating Megakaryopoiesis -- miRNAs with Complex Effects on Megakaryopoiesis -- ThePlatelet miRNA Repertoire -- miRNAs in Platelet Physiology and Gene Expression -- Platelet miRNAs in Disease -- Platelet miR-223 in Disease -- miRNAs in Stored Platelets -- miRNA Transfer by Platelet Microparticles -- Circulating miRNAs -- lncRNAs -- Other Platelet ncRNAs -- miRNAs as Therapeutics or as Therapeutic Targets -- Summary and Future Directions -- References -- Implications of Platelet RNA to Vascular Health and Disease -- Introduction -- Historical Role of Platelets in Hemostasis -- Alternative Platelet Functions Throughout the Circulation -- Platelet Content -- Initial Platelet Content Analyses -- Platelet RNA Content -- Platelet RNA Content and Disease Associations. , Roles for Platelet RNA.