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. Key Features 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 Readership Hematologists, cardiologists, stroke physicians, blood bankers, pathologists, and researchers in thrombosis and hemostasis Cover......Page 1 Platelets ......Page 3 Copyright......Page 4 Contributors......Page 5 Preface......Page 11 The Role of Platelets in Human Hemostasis, Platelet Transfusion, and Bleeding Time......Page 12 Immune Thrombocytopenia......Page 16 Alloantigens, Single Nucleotide Polymorphisms, and Alloimmune Thrombocytopenias......Page 17 Platelet Physiology, Assays of Platelet ``Adhesiveness, ́ ́ ADP, Platelet Aggregation, Myocardial Infarction, and P2Y12 Antag .........Page 18 Aspirin, Arachidonic Acid, Prostaglandins, Eicosanoids, Nitric Oxide, Endothelial Ecto-ADPase (CD39), Angiogenesis, Micropa .........Page 19 Clot Retraction, Glanzmann Thrombasthenia, GPIIb/IIIa Receptor, and αIIbβ3 (GPIIb/IIIa) Antagonists......Page 20 Bernard-Soulier Syndrome, the GPIb-IX-V Complex, von Willebrand Factor, Shear, ADAMTS-13, and Thrombotic Thrombocytopenic P .........Page 21 Platelets, Metastases, Sialic Acid, Platelet Aging, Sepsis, and Platelet Survival......Page 22 Reflections on the Past and Thoughts About the Future......Page 23 References......Page 24 Invertebrates......Page 36 Nonmammalian Vertebrates......Page 38 A Comparison of Human Platelets and Limulus Amebocytes......Page 41 The Evolution of Hemostasis and Blood Coagulation......Page 46 Megakaryocytes and Mammals......Page 48 Order Monotremata......Page 50 Order Marsupialia......Page 51 Platelet Levels......Page 52 Conclusions......Page 53 References......Page 55 The Hematopoietic Program......Page 59 Committed Megakaryocyte Progenitor Cells......Page 60 Endomitosis and Polyploid Formation......Page 61 Dense Tubular System......Page 62 Budding From the Megakaryocyte Surface......Page 63 The Proplatelet Theory......Page 64 The Cytoskeletal Mechanics of Proplatelet Formation......Page 65 Microtubules Power Proplatelet Elongation......Page 66 Organelle Transport in Proplatelets......Page 69 The Sites of Platelet Formation In Vivo......Page 70 Platelet Formation in the Bloodstream......Page 71 Apoptosis and Platelet Production......Page 72 GATA-1......Page 73 Filamin A......Page 74 Rab Geranylgeranyl Transferase......Page 75 References......Page 76 The Glycocalyx......Page 81 The Plasma Membrane......Page 82 The Spectrin Membrane Skeleton in Resting Platelets......Page 84 The Microtubule Cytoskeleton in Resting Platelets......Page 87 The Actin Cytoskeleton in Resting Platelets......Page 90 General Overview......Page 91 Lysosomes......Page 92 Dense Tubular System......Page 93 Other Platelet Structural Components......Page 94 Actin-Binding Proteins Positively Regulated by PI(4,5)P2......Page 95 Actin-Binding Proteins Negatively Regulated by PI(4,5)P2......Page 96 Rho Family GTPases......Page 97 Changes in the Spectrin Membrane Skeleton......Page 98 Changes in the Microtubule Cytoskeleton......Page 99 Actin Monomer Sequestration......Page 100 De Novo Generation of Actin Filaments......Page 101 Actin Filament Turnover......Page 102 References......Page 104 N- and O-Linked Glycans......Page 112 ``Glycan-Capping ́ ́ Glyco-Transferases (Glyco-Ts)......Page 114 Platelet Production, Glycans, and GLYCO-TS......Page 115 The von Willebrand Factor Receptor Complex, GPIb-IX-V......Page 116 The Collagen Receptor GPVI......Page 117 The Thrombopoietin Receptor Mpl......Page 118 Platelet-mediated Extrinsic Glycan Remodeling......Page 119 Platelet Senescence and Sialic Acid......Page 120 Feedback Between Liver and Bone Marrow......Page 121 Platelet In Vitro Aging and Sialic Acid......Page 122 Immune Thrombocytopenia (ITP) and Sialic Acid......Page 123 Other Mechanisms of Platelet Lifespan Regulation......Page 124 References......Page 125 Introduction......Page 131 Platelet Function Measurements at Population Scales......Page 133 The GWAS Era and Common Variants......Page 134 Ethnic Diversity and GWAS......Page 135 Exome-Based Genotyping Arrays......Page 136 Pleiotropy and Genetic Inter-Relationships Between Platelets and Other Phenotypes and Disorders......Page 137 Whole Genome Sequencing: Rare Noncoding Variants and Beyond......Page 138 Translating GWAS to Function......Page 139 Candidate Gene Studies and Variants in the GWAS Era......Page 140 Novel Platelet Function Loci Primarily Originating From GWAS Approaches......Page 141 GWAS of Platelet Function Following Antiplatelet Therapy......Page 142 PEAR1: An Example of Integrative Omics Discovery and Refinement in Platelet Biology......Page 143 Exome Studies of Platelet Function......Page 144 The Clinical Impacts of Genomic Studies of Platelet Biology......Page 147 Conclusions and Prospects for the Future of Platelet Genomics......Page 148 References......Page 149 The Repertoire of Human MicroRNAs......Page 159 Role of MicroRNAs......Page 160 MicroRNAs in Health and Disease......Page 161 The Platelet Transcriptome......Page 162 The Repertoire of Platelet MicroRNA Sequences......Page 163 A Role for MicroRNAs in Platelet Function?......Page 165 Platelet MicroRNAs and Cancer......Page 166 Therapeutic Applications......Page 167 References......Page 168 The Discovery of RNA and mRNA in Platelets......Page 171 Platelet RNA Content......Page 172 The Central Dogma: DNA-RNA-Protein Is Divided between Megakaryocytes and Platelets......Page 173 Overview of Transcriptional Regulation......Page 174 Platelet mRNA Processing......Page 175 Regulation of mRNA Stability in Platelets......Page 176 The Platelet RNA-Proteome Correlation......Page 177 The Mouse Platelet Transcriptome......Page 178 Platelet RNAs Associated With Hematologic Conditions......Page 179 Platelet Pharmaco-Transcriptomics......Page 180 References......Page 181 The Proteome Make-up of Platelets......Page 186 Protein Degradation Mechanism in Megakaryocytes and Platelets......Page 187 Gel-Free Proteomics......Page 188 Proteome of Resting Platelets......Page 190 Proteome of Platelet Membranes......Page 191 Proteome of Platelet Microparticles......Page 192 Phosphoproteome and Glycoproteome of Platelets......Page 193 Application of Proteomic Research in Disease......Page 194 References......Page 195 9 Platelet Receptors......Page 199 αnuβ3......Page 200 α2β1......Page 201 α6β1......Page 202 Toll-Like Receptors......Page 203 Thromboxane (TX) Receptors......Page 204 Chemokine Receptors......Page 205 GPVI......Page 206 Intercellular Adhesion Molecule 2 (ICAM-2)......Page 207 CD93 (C1q-Rp)......Page 208 Tetraspanins......Page 209 Thrombopoietin Receptor (c-mpl, CD110)......Page 210 Platelet-Endothelial Aggregation Receptor-1 (PEAR1)......Page 211 C3-Specific Binding Protein (Membrane Cofactor Protein, CD46)......Page 212 Tight Junction Receptors......Page 213 Glutamate Receptors......Page 214 References......Page 215 The Extracellular Domain of GPIbα......Page 223 Transmembrane (TM) Domains of GPIb-IX......Page 225 Molecular Pathogenesis of Bernard-Soulier Syndrome (BSS)......Page 226 VWF......Page 227 Kininogen, Factor XI, and Factor XII......Page 229 VWF: Type 2B VWD, PT VWD, Thrombotic Thrombocytopenia......Page 230 Anti-LBD Antibodies: Fc-Independent Immune Thrombocytopenia......Page 231 14-3-3zeta......Page 232 Apolipoprotein E Receptor 2 (ApoER2)......Page 233 Conclusions......Page 234 References......Page 235 GPVI Structure......Page 242 GPVI Ligands and Ligand Binding......Page 243 GPVI Distribution in the Cell Membrane......Page 244 Introduction to CLEC-2......Page 245 CLEC-2 Ligands and Ligand Binding......Page 246 The Function of GPVI in Hemostasis and Thrombosis......Page 247 The Function of CLEC-2 in Hemostasis and Thrombosis......Page 248 Conclusions......Page 250 References......Page 251 Structure of αIIbβ3......Page 256 The Extracellular Domain......Page 257 The Cytoplasmic Domain......Page 258 ``Inside-Out ́ ́ Signaling and αIIbβ3 Activation......Page 259 Pathways Leading to Integrin Activation......Page 260 Regulation of Integrin αIIbβ3 Activation by Cytoplasmic Tail Binding Partners......Page 261 References......Page 263 Protease-Activated Receptor-1 (PAR1)......Page 271 Thrombin Recognition of PAR1......Page 272 Thrombin Recognition of PAR4......Page 274 Physical Interactions Between PARs......Page 275 PAR1- and PAR4-Specific Signaling......Page 276 Protease-Activated Receptor 1 Antagonists......Page 278 Protease-Activated Receptor 4 Antagonists......Page 279 Polymorphisms and Sequence Variants......Page 280 References......Page 281 P2 Receptors......Page 286 Roles of Adenine Nucleotides in Platelet Function......Page 287 Role of P2Y1 in ADP-Induced Platelet Activation......Page 289 Other Functions of the Platelet P2Y1 Receptor......Page 290 Role of P2Y12 in ADP-Induced Platelet Activation......Page 291 Role of P2Y12 in Thrombin Generation......Page 292 Congenital Abnormalities of the P2Y12 Receptor......Page 293 Role of P2X1 in Platelet Activation and Thrombus Formation In Vitro and In Vivo......Page 294 Interplay Between the Platelet P2 Receptors......Page 295 Conclusions......Page 296 References......Page 297 Background......Page 305 Prostacyclin Receptor: Broad-Spectrum Inhibitor of Platelet Activation......Page 306 Soluble Guanylate Cyclase: Broad-Spectrum Inhibitor of Platelet Activation......Page 307 PECAM-1: Selective Inhibitor of Platelet Activation......Page 308 PECAM-1 Signaling......Page 310 G6b-B Function......Page 311 G6b-B Signaling......Page 312 Other Platelet ITIM-Containing Receptors......Page 313 PIR-B......Page 314 References......Page 315 Adhesive Receptors......Page 320 Soluble Mediators......Page 322 Functional Consequences......Page 324 Transcellular Biosynthesis of Eicosanoids......Page 325 Platelets and Neutrophil Extracellular Traps (NET)......Page 326 Vessel Passivation......Page 327 Platelets and the Vascular Endothelium, Development, and Vascular Integrity......Page 328 Vascular Integrity......Page 329 References......Page 330 Biosynthesis of NO and Characteristics of Endothelial NO Synthase......Page 336 The Effect of Endothelial and Platelet NO on Platelet Reactivity......Page 337 NO-Mediated Endothelial-Platelet Interactions and Thrombotic Disease......Page 338 Prostacyclin Biosynthesis and Characteristics of Endothelial Prostacyclin Synthase......Page 339 Prostacyclin-Signaling Mechanisms and Platelet Inhibition......Page 340 The Relevance of Prostacyclin In Vivo......Page 341 Endothelial CD39-Biochemistry, Structure and Function......Page 342 CD39-In Vivo Studies......Page 343 Emerging Concepts: Regulation of Platelet Function According to Platelet Size......Page 344 References......Page 345 Major Stimulatory and Inhibitory Receptors Expressed on the Platelet Surface......Page 353 G Protein-Coupled Receptors (GPCRs)......Page 354 (hem)ITAM and ITIM Receptors......Page 355 Phospholipase C......Page 356 Calcium Signaling......Page 357 PI3K and 3-Phosphorylated Phosphoinositide Signaling......Page 358 Cyclic Nucleotide Signaling......Page 360 Protein Kinase C (PKC)......Page 361 Protein Kinase A/Protein Kinase G (PKA/G)......Page 362 RAP1 Regulators......Page 363 Summary......Page 365 References......Page 366 Introduction: Platelet Granules......Page 373 Protein Sorting......Page 374 Endocytosis......Page 375 -Granule Heterogeneity......Page 376 Formation of Dense Granules......Page 377 α-Granule Content......Page 378 Lipid Composition......Page 379 SNAREs......Page 380 SNARE Regulators......Page 381 α-Granule Function in Hemostasis and Thrombosis......Page 382 α-Granules in Atherosclerosis......Page 383 Platelet Granule Disorders......Page 384 Dense Granule Deficiencies......Page 385 References......Page 386 Introduction......Page 395 What Does a Hemostatic Plug Actually Look Like and How Does It End Up Looking Like That?......Page 397 Reasons to ``Mind the Gaps ́ ́ Between Platelets......Page 401 Scaling Up Events in the Microcirculation to Larger Vessels......Page 402 Hemostatic Versus Pathologic Thrombi......Page 404 Using Computational Approaches to Study Hemostasis......Page 405 Modeling Mass Transport......Page 406 Modeling Platelet Accumulation Under Flow......Page 408 The Hemodynamics of Hemostasis......Page 409 Factoring in a Pressure Drop......Page 410 Microfluidics in the Clinical Setting......Page 411 References......Page 412 Further Reading......Page 415 Overview of Coagulation......Page 416 Activation of FX or FIX by TF-FVIIa......Page 417 Activation of Prothrombin by Prothrombinase (FXa-FVa)......Page 418 FV......Page 419 Polyphosphate (polyP)......Page 420 References......Page 421 Improved Isolation and Detection......Page 424 Potential Types of Platelet EVs in Blood......Page 425 Isolation and Detection of Platelet EVs......Page 426 Detection......Page 428 Origin of Platelet EVs in Blood......Page 429 Proteins......Page 430 Coagulation......Page 431 Angiogenesis and Wound Healing......Page 432 Role in Health and Disease......Page 433 References......Page 434 Plasmin(ogen)......Page 440 Tissue-Type Plasminogen Activator......Page 441 Inhibitors of Fibrinolysis......Page 442 Protease Nexin-1......Page 443 Platelet-Associated Fibrinolytic Activity......Page 444 Platelet-Mediated Effects on Fibrin Structure......Page 446 Acquired Platelet Deficiencies......Page 447 References......Page 448 Platelets Contain an Abundance of Angiogenic Factors......Page 455 Proangiogenic Factors......Page 456 Lymphangiogenesis......Page 458 Platelets, Angiogenesis, and Promotion of Tumor Growth......Page 459 References......Page 460 Platelet Production......Page 464 Platelet Structure......Page 466 Platelet Activation and Signal Transduction......Page 467 Platelet Adhesion and Aggregation......Page 469 Platelet Procoagulant Activity......Page 470 Bleeding Time......Page 471 Platelet Aggregation......Page 472 Effects of Maternal and Neonatal Illness and Therapies on Neonatal Platelet Function......Page 473 Conclusions and Future Directions......Page 474 References......Page 475 Platelets and Vascular Inflammation......Page 479 Platelet-Derived Cytokines......Page 480 CXCL12......Page 481 Thromboinflammation......Page 482 Platelet/Lipid Interactions......Page 483 References......Page 485 The ``Diabetic Platelet ́ ́......Page 488 Metabolic Changes......Page 491 HMGB1......Page 493 CD40L......Page 494 CD36......Page 495 RAGE......Page 496 Oxidative Stress......Page 497 Endothelial Dysfunction......Page 498 Obesity......Page 499 MicroRNA......Page 500 Platelet Microparticles......Page 501 Reduction by Antidiabetic Drugs of Factors Contributing to Platelet Activation/Hyperreactivity and Cardiovascular Outcomes......Page 502 Secondary Prevention......Page 503 Primary Prevention......Page 504 Less-Than-Expected Response to Aspirin......Page 505 Oxidative Stress......Page 506 Peroxynitrite......Page 507 Increased Platelet Turnover......Page 508 Conclusions......Page 510 References......Page 512 Platelets in Clinical and Experimental Inflammatory Diseases and Syndromes......Page 523 The Lungs: Platelets and Megakaryocytes in Pulmonary Biology and Inflammatory Lung Diseases......Page 524 Malaria......Page 527 Sepsis......Page 529 Dengue......Page 531 Rheumatoid Arthritis......Page 532 Systemic Lupus Erythematosus......Page 534 References......Page 535 Platelets Have Structures of Immune Cells......Page 541 Platelets Have Functions of Immune Cells......Page 542 Pattern Recognition Receptors......Page 543 Platelets Interact With Viruses......Page 544 Platelets Interact With Bacteria......Page 545 Platelets Interact With Fungi......Page 546 Kinocidins Deploy in Context of Infection......Page 547 Platelets Execute Exocrine Subroutines in Response to Infection......Page 548 Kinocidins Potentiate Conventional Antibiotics......Page 549 Platelets Modulate Complement Activation......Page 550 Platelets Potentiate the Antimicrobial Functions of Leukocytes......Page 551 Platelets are Integral to Antimicrobial Host Defense In Vivo......Page 552 Certain Pathogens May Subvert Platelet Host Defenses......Page 553 Prospectus......Page 554 References......Page 556 Thrombocytosis and Poor Cancer Outcome......Page 565 Paraneoplastic Thrombocytosis......Page 566 Tumor Cell-Induced Platelet Aggregation......Page 567 Platelet Activity on Tumor Growth......Page 568 Platelet-Induced EMT......Page 569 Platelets in Cancer Immune Tolerance......Page 571 Innate Immune Response to Cancer......Page 572 Adaptive Immune System......Page 573 Combination of Antiplatelet Therapy With Current Anticancer Treatments......Page 574 References......Page 575 Platelet-Dependent Pathophysiology in SCD......Page 580 Nitric Oxide Depletion......Page 581 Platelet TLR4 Activation......Page 582 Platelet Purinergic Receptor Activation......Page 583 VWF-Dependent Platelet Activation in SCD......Page 584 Intravascular Platelet Sequestration......Page 585 Platelet-Dependent Heterocellular Aggregation......Page 586 Increasing NO Bioavailability......Page 587 Anticoagulation......Page 588 References......Page 589 Introduction......Page 598 Automated Platelet Counting......Page 599 Impedance Platelet Counting......Page 600 Optical Platelet Counting......Page 601 Optical Fluorescence Platelet Counting......Page 602 Immunological Platelet Counting......Page 603 Image-Based Platelet Counting......Page 604 Reticulated Platelets/Immature Platelet Fraction......Page 606 References......Page 607 Preanalytical Precautions for Platelet Function Testing......Page 609 Advantages and Limitations of the Assay......Page 612 Clinical Applications......Page 613 VerifyNow......Page 614 Clinical Applications......Page 615 Advantages and Limitations of the Assay......Page 616 Viscoelastic Tests......Page 617 Summary and the Future of Platelet Function Testing......Page 619 References......Page 620 Proteins That Influence Turbidometric Aggregometry Findings......Page 625 Turbidometric Aggregation Findings With Different Agonists......Page 626 Mechanisms of Turbidometric Aggregation Responses to Different Agonists......Page 627 Whole Blood Aggregometry......Page 629 Measurement of Dense Granule Release With Aggregometry......Page 631 Preparation of Samples for Platelet Aggregation Tests......Page 632 Analytical Considerations and Potential Interferences for Aggregation Tests......Page 634 Quantitative Endpoints of Aggregation and Release Assays......Page 635 Aggregation Interpretation in the Assessment of Bleeding Disorders......Page 636 References......Page 639 Introduction......Page 643 Activation-dependent Monoclonal Antibodies......Page 644 Procoagulant Platelets and Platelet-Derived Extracellular Vesicles......Page 646 Phosphorylation of Intracellular Proteins......Page 648 Acute Coronary Syndromes......Page 649 Very Low Birth Weight Preterm Neonates......Page 650 Hematologic Malignancies......Page 651 Monitoring of Antiplatelet Agents......Page 652 Monitoring of Thrombopoiesis......Page 653 Platelet Survival, Tracking, and Function In Vivo......Page 654 Calcium Flux......Page 655 Platelet Recruitment to Growing Thrombi......Page 656 Mass Cytometry......Page 657 Imaging Flow Cytometry......Page 658 References......Page 659 Introduction......Page 668 Measurement of Thromboxane B2 (TXB2)......Page 670 Light Transmission Aggregometry (LTA)......Page 671 Vasodilator-Stimulated Phosphoprotein (VASP) Phosphorylation assay......Page 672 Aspirin......Page 673 Aspirin......Page 674 Clopidogrel......Page 676 Cangrelor......Page 677 Clopidogrel......Page 678 Vorapaxar......Page 679 Dyslipidemia......Page 680 Proton Pump Inhibitors (PPIs)......Page 681 Gain-of-Function Polymorphisms......Page 682 Clopidogrel......Page 683 Type of Antiplatelet Agent......Page 684 Dose and Type of Antiplatelet Agent......Page 685 References......Page 686 Introduction......Page 698 Rationale for Evaluation of Platelet Function......Page 699 Which Test or Tests?......Page 700 Timing of Testing......Page 702 On-Site Testing Versus Off-Site Core Laboratory Testing......Page 703 Light Transmission Aggregometry......Page 704 VerifyNow Assay......Page 705 Total Thrombus-Formation Analysis System (T-TAS)......Page 706 Platelet Surface Activated GPIIb-IIIa, P-Selectin, Ligand-Induced Binding Sites, Monocyte-Platelet and Neutrophil-Platelet .........Page 707 Serum and Plasma Markers......Page 708 References......Page 709 Medications......Page 716 Platelet Count......Page 717 Thrombocytopenia......Page 719 References......Page 720 Etiology and Pathophysiology......Page 721 Factors Involving T-Cells......Page 723 Infection......Page 724 Diagnosis and Clinical Assessment......Page 725 Management......Page 726 When to Initiate Treatment......Page 727 Treatment Considerations for Children......Page 728 First-Line Treatments Aiming to Increase Platelet Counts Rapidly......Page 729 Rituximab......Page 731 Multiagent Treatments for Acute and Maintenance Therapy......Page 732 References......Page 733 Idiosyncratic Drug-Induced Marrow Aplasia......Page 739 Tumor Necrosis Factor α/Interferon γ......Page 740 Induction of Hapten-Dependent Antibodies......Page 741 ``Quinine-Type, ́ ́ Drug-Induced Immune Thrombocytopenia (DITP)......Page 742 Thrombocytopenia Induced by Ligand-Mimetic Fibrinogen Receptor Antagonists (FRA)......Page 743 Amiodarone-Associated Thrombocytopenia......Page 744 Drug-Induced Platelet Destruction Involving Immune Complexes......Page 745 Sensitivity to Drug Metabolites as a Cause of Immune Thrombocytopenia......Page 746 Clinical Presentation......Page 747 Prognosis and Treatment......Page 748 References......Page 749 Historical Aspects and Nomenclature......Page 754 Immune HIT (Type II HIT)......Page 755 Immune Response......Page 757 Animal Models......Page 758 Heparin Flushes and Heparin-Coated Devices......Page 759 Nonimmune Heparin-Associated Thrombocytopenia (Type I HIT)......Page 760 Venous Thrombosis......Page 761 Laboratory Diagnosis......Page 762 14C-Serotonin Release Assay (SRA)......Page 763 ATP Release Test......Page 764 Sensitivity and Specificity......Page 765 Instrumentation-Based Assays......Page 766 Immune HIT (Type II HIT)......Page 767 Danaparoid (Orgaran)......Page 769 Dosing and Monitoring......Page 770 Danaparoid or Fondaparinux Versus DTI Therapy (Argatroban, or Bivalirudin)......Page 771 References......Page 772 Introduction......Page 781 ADAMTS13 and the Regulation of VWF-Platelet Interaction......Page 782 Changes of VWF Multimers in TTP......Page 785 Other Proposed Pathogenesis of TTP......Page 786 Causes of ADAMTS13 Deficiency......Page 787 Genetic Mutations of ADAMTS13......Page 788 Typical Presentation......Page 789 Diagnosis of TTP......Page 790 Plasma Therapy......Page 792 Other Treatment Options......Page 793 Pathophysiology......Page 794 Atypical Hemolytic-Uremic Syndrome (AHUS)......Page 795 Pathogenesis......Page 796 Pathophysiology......Page 797 Diagnosis of AHUS......Page 798 Organ Transplantation......Page 800 References......Page 801 Management......Page 807 Management of the Pregnant Patient With ITP......Page 808 Preeclampsia: Clinical Risk Factors......Page 810 Preeclampsia: Pathogenesis......Page 811 Preeclampsia: Thrombocytopenia and Microangiopathic Hemolytic Anemia......Page 812 HELLP: Thrombocytopenia......Page 813 Recurrent HELLP in Subsequent Pregnancies: Incidence and Prevention......Page 814 Atypical HUS: Clinical Manifestations and Comparison With TTP......Page 815 Management of TTP and HUS......Page 816 Type IIB von Willebrand Disease......Page 817 Summary and Conclusions......Page 818 References......Page 819 Fetal Megakaryocytopoiesis and Platelet Production......Page 825 Thrombocytopenia in NICU Patients......Page 826 Late-Onset Neonatal Thrombocytopenia (>72 Hours of Age)......Page 827 Management......Page 828 Perinatal Asphyxia (Hypoxic Ischemic Encephalopathy)......Page 829 Congenital/Inherited Thrombocytopenia (See Also Chapters 46 and 484648)......Page 830 TAR Syndrome......Page 832 Congenital Amegakaryocytic Thrombocytopenia (CAMT)......Page 833 DIAPH1-Related Thrombocytopenia......Page 834 Practical Diagnostic Approach to Thrombocytopenia in the Newborn......Page 835 Indications for Platelet Transfusion......Page 836 References......Page 837 Pathophysiology......Page 844 Laboratory Diagnosis......Page 848 Rationale for the Use of IVIG......Page 850 Future Developments in Antenatal Management......Page 851 Laboratory Diagnosis......Page 852 References......Page 853 Wiskott-Aldrich syndrome (WAS) and X-Linked Thrombocytopenia (XLT)......Page 860 Congenital Amegakaryocytic Thrombocytopenia (CAMT)......Page 861 Thrombocytopenia With Absent Radii (TAR)......Page 862 Familial Platelet Disorder With Predisposition to Acute Myelogenous Leukemia (FPD/AML)......Page 863 Bernard-Soulier Syndrome (BSS)......Page 864 MYH9-related Diseases (May-Hegglin Anomaly, Sebastian Syndrome, Fechtner Syndrome, and Epstein Syndrome)......Page 865 Jacobsen Syndrome/Paris-Trousseau Thrombocytopenia......Page 866 Stormorken Syndrome and York Platelet Syndrome......Page 867 References......Page 868 Pathogenesis......Page 873 Distinguishing Reactive Thrombocytosis From Primary Thrombocytosis......Page 874 Molecular Pathogenesis......Page 875 Myeloid Colony Growth and Cytokine Response......Page 876 Clinical Features......Page 877 Prognosis......Page 878 Risk-Adapted Therapy: ``Low-Risk ́ ́ Disease......Page 879 Risk-Adapted Therapy: ``High-Risk ́ ́ Disease......Page 880 References......Page 881 Bernard-Soulier Syndrome......Page 887 Molecular Defects......Page 888 Platelet-Type von Willebrand Disease......Page 889 Molecular Defects......Page 892 Defects of the Platelet ADP Receptor P2Y12......Page 893 Defects of the Platelet Thromboxane A2 Receptor (TP)......Page 894 [Nonsyndromic] δ-Storage Pool Deficiency......Page 895 Familial Platelet Disorder With Predisposition to AML (FPD/AML)......Page 896 Gray Platelet Syndrome......Page 897 SRC-Related Disease......Page 898 Defects of the α- and δ-Granules......Page 899 Defects of Thromboxane Synthetase......Page 900 Leukocyte Adhesion Deficiency-III (LAD-III)......Page 901 Primary Secretion Defects......Page 902 Diagnosis......Page 903 Treatment of Inherited Platelet Function Disorders......Page 904 References......Page 905 Platelet Hyperreactivity and Prothrombotic State(s)......Page 915 Frequency of Acquired Platelet Disorders and Screening for Defects in Primary Hemostasis......Page 916 Drugs that Inhibit or Impair Platelet Function......Page 917 End-Stage Renal Disease......Page 918 Disseminated Intravascular Coagulation (DIC)......Page 919 Antiplatelet Antibodies......Page 920 Myeloproliferative Neoplasms (MPN)......Page 921 Relevant Disease-Specific Somatic Mutations......Page 922 Antiplatelet Therapy in MPN......Page 923 Aspirin Resistance in Essential Thrombocythemia......Page 924 Conclusions and Future Directions......Page 925 References......Page 926 Mechanism of Action......Page 931 Pharmacokinetics and Pharmacodynamics......Page 932 Drug-Drug Interactions......Page 933 Interindividual Variability in the Antiplatelet Response to Aspirin......Page 934 Reduced Risk of Atherothrombotic Complications......Page 935 Increased Risk of Bleeding Complications......Page 938 Reduced Risk of Colorectal Cancer......Page 940 Balance of Benefits and Risks......Page 941 Conclusions......Page 942 References......Page 943 Pharmacology......Page 947 Primary and Secondary Prevention of Vascular Events......Page 949 Coronary Revascularization......Page 950 Response Variability to Clopidogrel (See Also Chapter 36)......Page 951 Pharmacology......Page 953 Acute Coronary Syndromes......Page 954 Pharmacology......Page 955 Acute Coronary Syndromes......Page 956 Pharmacology......Page 957 Bridge Therapy in Patients Undergoing Surgery......Page 958 References......Page 959 Abciximab......Page 967 Eptifibatide......Page 968 Adjunct to Percutaneous Coronary Intervention With Stents......Page 969 Initial Medical Management During Non-ST-Segment Elevation Acute Coronary Syndrome......Page 971 Primary Percutaneous Coronary Intervention: Plain Old Balloon Angioplasty......Page 972 Facilitated Percutaneous Coronary Intervention......Page 973 Intracoronary Versus Intravenous Use of GPIIb-IIIa Antagonists......Page 974 Comparison With the Direct Thrombin Inhibitor Bivalirudin......Page 975 Tirofiban Versus Abciximab......Page 976 Utility of GPIIb-IIIa Antagonists in the Modern Era......Page 977 References......Page 978 Phase II Trials......Page 982 The TRACER Trial......Page 983 Secondary Analyses of TRACER and TRA 2P-TIMI 50......Page 984 References......Page 985 Introduction......Page 987 Cilostazol......Page 988 Effect of Cilostazol on Other Cells......Page 989 Clinical Studies......Page 990 Mechanism of Action......Page 992 Secondary Prevention of Myocardial Infarction......Page 993 References......Page 994 Evolving Selective Pressures and Unmet Needs......Page 998 New Approaches in Systems Biology and Drug Discovery......Page 1002 Synergistic Inhibition of Redundant Platelet Activation Pathways......Page 1003 Next-Gen Paradigms: From Inhibition to Modulation......Page 1005 Cangrelor......Page 1006 Focusing Antiplatelet Effects to Local Paracrine Signals......Page 1007 PAR Modulators......Page 1008 GPVI Antagonism......Page 1010 Intracellular Inhibitors of GPIIb-IIIA Signaling......Page 1011 Synergistic Antithrombotic/Fibrinolytic Conjugates......Page 1012 Platelet/Leukocyte Interaction Inhibitors......Page 1013 Conclusions......Page 1014 References......Page 1015 Historical Background of Antiplatelet Therapy for SCAD Patients With PCI......Page 1023 Current Practice Recommendation of DAPT in SCAD Patients With PCI......Page 1024 History of Antiplatelet Therapy in ACS Patients......Page 1026 Timing of P2Y12 Receptor Inhibitor......Page 1027 P2Y12 Receptor Inhibitor Selection in ACS......Page 1028 DAPT Duration in ACS Patients......Page 1029 A Paradigm Shift: Dropping Aspirin......Page 1030 Patients Undergoing CABG......Page 1031 References......Page 1032 Ischemic Cerebrovascular Disease......Page 1036 Systemic Evidence of Platelet Activation......Page 1037 Platelet Activation Associated With Brain-Supplying Arter Experts From All Areas Of Academic And Medical Research In Hematology, Oncology, Cardiology, And Pathology, Take Readers From The Bench Research Through The Role Of Platelets In Disease, To New Therapeutic Approaches. Platelets, Fourth Edition, Integrates The Entire Field Of Platelet Biology, Pathophysiology, And Clinical Medicine With Contributions From 125 World Experts From 14 Countries. This Award-winning Reference Provides Clear Presentations By Basic Scientists Of The Cellular, Molecular, And Genetic Mechanisms Of Platelets And The Subsequent Pathophysiological Processes Such As Thrombosis, Hemorrhage, Inflammation, And Cancer. It Also Provides Clear Presentations By Hematologists, Oncologists, Cardiologists, Pathologists, And Other Clinicians On How Antiplatelet Therapy, Gene Therapy, And Platelet Transfusion Can Lead To New Therapeutic Approaches To Diagnose And Treat Thrombosis And Other Cardiovascular Diseases. Since The Publication Of The Third Edition, There Continues To Be A Rapid Expansion Of Knowledge In Both Basic Biology And The Clinical Approach To Platelet-related Diseases Including Thrombosis And Hemorrhage. This Fourth Edition Of Platelets Will Continue To Draw All This Information Into A Single, Comprehensive And Authoritative Resource. Presents A Comprehensive, Translational Source For All Aspects Of Platelet Biology, Pathophysiology, And Clinical Manifestations In One Reference Work Contains New Chapters On Topics Such As The Regulators Of Gpvi Signaling, In Vivo Thrombosis Evaluations, Pharmaco Genomics Of Platelets, Interplay Between Anti-platelets And Anti-coagulants In Clinical Practice, And Redox Regulation Of Platelet Function Saves Researchers And Clinicians Time In Quickly Accessing The Very Latest Details On The Diverse Scientific And Clinical Aspects Of Platelets Provides A Full Color Reference With 250 Illustrations And Over 12,000 References

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