Platelets. Edition No. 4

Table of Contents

PART I: Platelet Biology 1. The Evolution of Mammalian Platelets 2. Megakaryocyte Development and Platelet Formation 3. The Structure of Resting and Activated Platelets 4. Platelet Glycobiology and the Control of Platelet Function and Lifespan 5. Platelet Genomics 6. Platelet MicroRNAs 7. The Platelet Transcriptome in Health and Disease 8. The Platelet Proteome 9. Platelet Receptors 10. The Glycoprotein Ib-IX-V Complex 11. GPVI and CLEC-2 12. Integrin aIIb�3 13. Protease-Activated Receptors 14. The Platelet P2 Receptors 15. Platelet Inhibitory Receptors 16. Interactions Between Platelets, Leukocytes, and the Endothelium 17. Inhibition of Platelet Function by the Endothelium 18. Platelet Signal Transduction 19. Platelet Secretion 20. Hemostatic Thrombus Formation in Flowing Blood 21. Interactions Between Platelets and the Coagulation System 22. Platelet-Derived Extracellular Vesicles 23. Regulation of Fibrinolysis by Platelets 24. The Role of Platelets in Angiogenesis 25. Platelet Function in the Newborn

PART II: The Role of Platelets in Disease 26. The Role of Platelets in Atherothrombosis 27. The Role of Platelets in Diabetes Mellitus 28. The Role of Platelets in Inflammation 29. The Role of Platelets in Antimicrobial Host Defense 30. The Role of Platelets in Tumor Growth, Metastasis, and Immune Evasion 31. The Role of Platelets in Sickle Cell Disease

PART III: Clinical Tests of Platelet Function 32. Platelet Counting 33. Clinical Tests of Platelet Function 34. Platelet Aggregation 35. Flow Cytometry 36. Laboratory Monitoring of Antiplatelet Therapy 37. Platelet Function Testing in Clinical Research Trials

PART IV: Disorders of Platelet Number and/or Function 38. The Clinical Approach to Disorders of Platelet Number and Function 39. Immune Thrombocytopenia (ITP) 40. Drug-Induced Thrombocytopenia 41. Heparin-Induced Thrombocytopenia 42. Thrombotic Thrombocytopenic Purpura and Hemolytic-Uremic Syndromes 43. Thrombocytopenia in Pregnancy 44. Thrombocytopenia in the Newborn 45. Alloimmune Thrombocytopenia 46. Inherited Thrombocytopenias 47. Thrombocytosis and Essential Thrombocythemia 48. Inherited Disorders of Platelet Function 49. Acquired Disorders of Platelet Function

PART V: Antiplatelet Therapy 50. Aspirin 51. P2Y12 Antagonists 52. aIIb�3 (GPIIb-IIIa) Antagonists 53. PAR-1 Antagonists 54. Phosphodiesterase Inhibitors 55. Novel Antiplatelet Therapies 56. Antiplatelet Drugs in the Management of Coronary Artery Disease 57. Antiplatelet Drugs in the Management of Cerebral Ischemia 58. Antiplatelet Drugs in the Management of Thrombotic/Ischemic Events in Peripheral Artery Disease 59. Antiplatelet Drugs in the Management of Venous Thromboembolism, Cardioembolism, Ventricular Assist Devices, and Pregnancy Complications 60. Antiplatelet Drugs in the Management of Thrombotic/Ischemic Events in Children

PART VI: Therapy to Increase Platelet Numbers and/or Function 61. Thrombopoietin Receptor Agonists 62. Desmopressin (DDAVP) 63. Factor VIIa 64. Platelet Transfusion Medicine 65. Therapeutic Platelet-Rich Plasma in Wound Healing 66. Stem Cell-Derived Platelets 67. Gene Therapy for Platelet Disorders

Authors

Alan D. Michelson Professor of Pediatrics and Professor of Medicine, Harvard Medical School, Boston, MA, USA; Director, Center for Platelet Research Studies and Director, Thrombosis and Anticoagulation Program, Dana-Farber/Boston Children's Cancer and Blood Disorders Center, Boston, MA, USA. Dr. Michelson is Professor of Pediatrics and Professor of Medicine at Harvard Medical School in Boston, Massachusetts, U.S.A. He is also the Director of the Center for Platelet Research Studies (www.platelets.org) and the Director of the Thrombosis and Anticoagulation Program at Dana-Farber/Boston Children's Cancer and Blood Disorders Center. After receiving his medical degree with honors from the University of Adelaide, Australia, Dr. Michelson continued his medical and research training on a Fulbright Scholarship at Boston Children's Hospital, Brigham and Women's Hospital, and Harvard Medical School. In 2019 he received the International Society on Thrombosis and Haemostasis (ISTH) Esteemed Career Award. Dr. Michelson has been an invited participant in numerous National Institutes of Health working groups, international workshops and consensus conferences. He is the co-organizer and co-chair of the biennial International Platelets Symposium. Dr. Michelson is a past Chairman of the Platelet Physiology Scientific Subcommittee of the ISTH. He has published more than 450 original research articles, original research abstracts, and invited reviews - nearly all on the topic of platelets. Dr. Michelson has been the principal investigator on more than 100 research grants. He has been an invited speaker at over 200 major medical conferences worldwide. Dr. Michelson is an inventor on two awarded and three provisional U.S. patents. Marco Cattaneo Dipartimento di Scienze della Salute, Universit� degli Studi di Milano, Milan, Italy. Marco Cattaneo is Professor of Internal Medicine and Director of the Unit of Internal Medicine at Ospedale San Paolo, Universit� degli Studi di Milano, Italy. After gaining his MD at the Universit� degli Studi di Milano in 1975, he specialized in Clinical and Laboratory Haematology at the Universit� degli Studi di Pavia, followed by a Residency at the A. Bianchi Bonomi Haemophilia and Thrombosis Centre and Institute of Internal Medicine at the Ospedale Maggiore, Universit� degli Studi di Milano. He has been Post-Doctoral Fellow at McMaster University, Hamilton, Ontario and Guest or Visiting Scientist at McMaster University, Hamilton, Ontario, Temple University, Philadelphia and The Scripps Research Institute, La Jolla, California. In 2001 he was awarded the International Society on Thrombosis and Haemostasis (ISTH) 10th Biennial Award for Contributions to Haemostasis and Thrombosis. He has been Editor of Thrombosis Research and on the Editorial Board/Advisory Board for a number of other high-tier journals, including Jornal of Thrombosis and Haemostasis, Haematologica, Platelets, Thrombosis and Haemostasis and Arteriosclerosis, Thrombosis and Vascular Biology. He was Chair of the Working Party on Platelet Aggregation, and Chair of the Scientific Subcommittee on Platelet Physiology, Scientific and Standardization Committee, ISTH. He was a member of the Council of the ISTH from 2010 through 2016. He was President-Elect, President and Past-President of SISET, the Italian Society on thrombosis and hemostasis, in the years 2002-2008. His main research interests focus on pathophysiology of primary haemostasis, pharmacology of antiplatelet agents and the role of homocysteine in thrombotic disease. Andrew Frelinger Assistant Professor of Pediatrics, Harvard Medical School, Boston, MA, USA; Associate Director, Center for Platelet Research Studies and Staff Scientist, Dana-Farber/Boston Children's Cancer and Blood Disorders Center, Boston, MA, USA. Dr. Andrew L. "Larry� Frelinger is Assistant Professor of Pediatrics at Harvard Medical School and Associate Director of the Center for Platelet Research Studies (www.platelets.org) and Staff Scientist at Boston Children's Hospital in Boston, Massachusetts, U.S.A. He received his Ph.D. from Case Western Reserve University in 1986, and began his work on platelets at the Scripps Research Institute, La Jolla, California, in the laboratory of Dr. Mark Ginsberg. Between 1993 and 1998 Dr. Frelinger worked in positions of increasing responsibility in the biotechnology industry. He returned to academia in 1998 as Associate Director of the Center for Platelet Function Studies and Research Associate Professor of Pediatrics at the University of Massachusetts Medical School, Worcester, Massachusetts. In 2009 Dr. Frelinger moved to his current position at Boston Children's Hospital and Harvard Medical School. He is Co-Chair of the Platelet Physiology Scientific Subcommittee of the International Society on Thrombosis and Haemostasis and first author of the subcommittee's position statement on monitoring of P2Y12 inhibitors. Dr. Frelinger is Principal Editor for the journal Platelets, has published more than 100 peer-reviewed original research articles, and is an inventor on three awarded and three provisional U.S. patents. Peter Newman Vice President for Research, BloodCenter of Wisconsin, Jacquelyn Fredrick Endowed Chair for Foundational Research, Associate Director, Blood Research Institute,
Milwaukee, WI, USA. Peter Newman is the Vice President for Research and Associate Director of the BloodCenter's 125 person Blood Research Institute. Dr. Newman's major research accomplishments include elucidation of the molecular basis of the major human platelet alloantigen systems, including the PlA1/PlA2 polymorphism, the discovery of PECAM-1, and numerous contributions to the understanding of the role of activating and inhibitory receptors that control platelet activation. Dr. Newman has published more than 175 original research articles, book chapters and reviews on the subject of platelet and endothelial cell biology, cell adhesion, and signal transduction. Current research activities include the structural biology of PECAM-1, the role of PECAM-1 in endothelial cell junctional integrity, and novel applications of CRISPR/Cas9 gene editing technology to modify platelet- and megakaryocyte-specific alloantigens in induced pluripotent stem (iPS) cells.

Professionally, Dr. Newman served on the Executive Committee of the Arteriosclerosis, Thrombosis, and Vascular Biology (ATVB) Council of the American Heart Association (AHA) from 1999-2004, chaired its Annual Meeting in 2004 and served on its Council from 2010-2012. He chaired the Hemostasis Gordon Conference in 2008, served from 2006-2014 as a member of the American Society of Hematology (ASH) Government Affairs Committee that meets annually with members of Congress, and is a current member of the ASH Audit and Investment Committee. Dr. Newman has been on the editorial board of Blood, has reviewed dozens of grants for both the NIH and the AHA, and currently serves the AHA as Associate Editor of the platelet and thrombosis section of the journal ATVB. He was an Established Investigator of the AHA from 1992-1997, and received a Special Recognition Award from their ATVB Council in 2001. Dr. Newman received an Investigator Recognition Medal from the International Society of Thrombosis (ISTH) in 1997, the Emil von Behring Award from the German Society for Transfusion Medicine in 2007, the E.T.S. Walton Award from Science Foundation of Ireland for his studies on the Molecular Mechanisms of Platelet Activation and Adhesion in 2008, and a Distinguished Career Award from the ISTH in 2013. He recently received a seven-year Outstanding Investigator award from the National Heart Lung and Blood Institute of the National Institutes of Health that supports the majority of his current research program.