Platelets

✍ Scribed by Alan D. Michelson, Andrew Frelinger, Marco Cattaneo, Peter Newman

Publisher: Academic Press, Elsevier Science
Year: 2019
Tongue: English
Leaves: 1228
Edition: 4th Edition
Category: Library

No coin nor oath required. For personal study only.

✦ Synopsis

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

✦ Table of Contents

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 toMind 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 Arteries......Page 1039
The Cerebral Microvasculature and Platelet Activation......Page 1040
Contributions of Microvessel Obstruction to Neurological Outcome......Page 1041
Hemorrhagic Transformation......Page 1042
Aspirin......Page 1043
Aspirin and Dipyridamole......Page 1044
Clopidogrel......Page 1046
Sulfinpyrazone......Page 1047
Ticlopidine and Clopidogrel......Page 1048
Other Interventions......Page 1049
Cardioembolic Stroke in Atrial Fibrillation......Page 1050
Prosthetic Mechanical Cardiac Valves......Page 1051
References......Page 1052
Antiplatelet Drugs in PAD......Page 1063
Aspirin......Page 1064
Nonaspirin Drugs Inhibiting the Platelet Arachidonic Acid Pathway......Page 1065
Drugs Inhibiting the Platelet P2Y12 Receptors for ADP......Page 1066
Comparison of Efficacy of Antiplatelet Treatments in PAD......Page 1067
References......Page 1068
Role of Platelets in the Pathogenesis of Arterial and Venous Thrombosis......Page 1071
Primary VTE Prevention in High-Risk Patients......Page 1072
Antiplatelet Therapy Versus Placebo......Page 1073
Prosthetic Heart Valves......Page 1074
Left Ventricular Assist Devices......Page 1075
Prevention of Preeclampsia and Its Complications......Page 1076
Conclusions and Future Directions......Page 1077
References......Page 1078
Randomized Controlled Trials of Antiplatelet Therapy in Children......Page 1082
Pediatric Guidelines for Antiplatelet Therapy......Page 1083
References......Page 1085
Introduction......Page 1087
The EPO-Like Domain of TPO......Page 1088
Importance of TPO Glycosylation......Page 1089
Cellular Effects of TPO......Page 1090
Effects of In Vivo Administration of TPO......Page 1091
Lessons Learned From TPO and TPO-R Knock-Out Mice......Page 1092
Mechanisms Regulating TPO Levels......Page 1093
Circulating TPO Levels in Hematological Disorders......Page 1094
TPO Receptor Agonists......Page 1095
Peptide TPO Receptor Agonists......Page 1096
Nonpeptide TPO Receptor Agonists......Page 1097
Ex Vivo Expansion of Bone Marrow Stem Cells......Page 1098
Chemotherapy for Solid Tumors......Page 1099
Immune Thrombocytopenia (ITP)......Page 1100
Hepatitis C-Associated Thrombocytopenia......Page 1101
Surgical Disorders With Thrombocytopenia......Page 1102
Increasing Platelet Apheresis Yields......Page 1103
Thrombocytosis and Thrombosis......Page 1104
Promoting Tumor Growth......Page 1105
References......Page 1106
Congenital Hemophilia A and von Willebrand Disease......Page 1113
Acquired Hemophilia and von Willebrand Syndrome......Page 1114
Acquired and Drug-induced Disorders of Hemostasis......Page 1115
Desmopressin as a Blood-Saving Agent in Major Surgery......Page 1116
Mechanisms of Desmopressin-Induced Increase in Plasma Factor VIII and VWF......Page 1117
Conclusions......Page 1118
References......Page 1119
Pharmacology......Page 1123
Negative Clinical Studies and Case Reports......Page 1125
Congenital Platelet Function Disorders......Page 1126
Thromboembolic Adverse Events in Other Approved Indications for rFVIIa Use......Page 1128
High-Dose FVIIa-mediated Thrombin Generation: TF-dependent and TF-independent Models, and Effects on Fibrin Clot Structure......Page 1129
Aggregation of Glanzmann Thrombasthenia Platelets Mediated by High-Dose FVIIa......Page 1130
FVIIa Analogs in Clinical Development......Page 1131
References......Page 1132
Platelet Concentrates Prepared From Whole Blood by Platelet-Rich Plasma and Buffy Coat Methods......Page 1138
Buffy Coat Method......Page 1139
Platelet Counting in Platelet Concentrates......Page 1140
Platelet Storage and Storage Injury......Page 1141
Anticoagulants......Page 1142
Platelet Activation During Storage......Page 1143
Leukocyte Reduction of Platelet Components......Page 1144
Pathogen Inactivation Technology......Page 1145
General Considerations in Platelet Transfusion Therapy......Page 1146
Prophylactic Platelet Transfusion......Page 1147
Platelet Dosing......Page 1148
Cardiac Surgery......Page 1149
Febrile Reactions to Platelet Transfusion......Page 1150
Bacterial Contamination of Platelet Concentrates......Page 1151
Hypotensive Reactions During Platelet Transfusions......Page 1152
References......Page 1153
PRP Definition......Page 1161
In Vitro Studies......Page 1163
Wound Healing......Page 1164
Tendon Injury......Page 1165
Standardization and Classification of PRP......Page 1166
References......Page 1167
Steady-State Platelet Generation......Page 1172
Acute Platelet Generation......Page 1173
Revision to the Classical Model......Page 1174
HSCs......Page 1175
ESCs......Page 1176
iPSCs and Cell Reprogramming......Page 1177
Stem Cells for In Vivo Platelet Generation......Page 1178
Small Chemicals......Page 1179
Bioreactors......Page 1180
Clinical Efforts......Page 1182
References......Page 1183
Introduction......Page 1189
Hematopoietic Stem Cells as Targets......Page 1190
Preparation of the Recipients Marrow......Page 1192
Vectors......Page 1193
Promoters and Locus Control Regions for Megakaryocyte-Specific Transgene Expression......Page 1194
State-of-the-Art Animal Models for Disorders Affecting Platelets......Page 1195
Gene Therapy for GPIIb-Deficient Dogs Affected With GT......Page 1196
Gene Therapy for FVIII-Deficient Mice Affected with Hemophilia A......Page 1197
Conclusions......Page 1198
References......Page 1199
Index......Page 1204
Back Cover......Page 1228

✦ Subjects

Hematology; Platelets; Biological Sciences; Haemostasis &Thrombosis

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