Platelets, June 2008; 19(4): 239–251 REVIEW Platelets: Developmental biology, physiology, and translatable platforms for preclinical investigation and drug development* NEAL S. KLEIMAN 1 , JANE E. FREEDMAN 2 , PAULA B. TRACY 3 , BARBARA C. FURIE 4 , PAUL F. BRAY 5 , SUNIL V. RAO 6 , DAVID R. PHILLIPS 7 , ROBERT F. STOREY 8 , CHRISTOPHER P. RUSCONI 9 , PATRICIA A. FRENCH 10 , STEVEN R. STEINHUBL 11 ,& RICHARD C. BECKER 12 1 Methodist DeBakey Heart Center, Houston, Texas, USA, 2 Boston University School of Medicine, Boston, MA, USA, 3 Department of Biochemistry, University of Vermont, Burlington, USA, 4 Division of Hemostasis and Thrombosis, Beth Israel Deaconess Medical Center, Boston, MA, USA, 5 Division of Hematology, Jefferson Medical College, Philadelphia, PA, USA, 6 Department of Medicine, Duke University Medical Center, Durham, NC, USA, 7 Portola Pharmaceuticals, Inc., South San Francisco, CA, USA, 8 Cardiovascular Research Unit, University of Sheffield, Sheffield, UK, 9 Regado Biosciences, Inc., Durham, NC, USA, 10 Left Lane Communications, Chapel Hill, NC, USA, 11 Division of Cardiology, University of Kentucky, Lexington, USA, and 12 Cardiovascular Thrombosis Center, Duke Clinical Research Institute, Durham, NC, USA (Received 17 December 2007; revised 23 January 2008; accepted 25 January 2008) Abstract This paper, developed from the proceedings of the 2007 Platelet Colloquium, considers emerging constructs in platelet biology, preclinical models of thrombosis, and their potential application to the development of platelet-directed pharmacotherapies. Discussed first is the developmental biology of platelets, including megakaryocyte maturation, and the role of apoptotic and growth factors and other proteins in thrombopoiesis. A brief overview of current methods and observations from platelet proteomic analyses is also presented, illustrating the complex interplay of genes, gene expression, protein expression, and protein modification in various atherothrombotic phenotypes. The factor Xa-platelet interface is used as a working model for discussion of anticoagulants as platelet antagonists, highlighting the importance of receptor expression, substrate binding kinetics, platelet subpopulations, and cofactors in thrombosis. Finally, we discuss the use of emerging technologies—such as intravital microscopy and ex vivo perfusion chambers—as translatable platforms for investigating the role of platelets and their pharmacologic inhibition in human health and disease. Keywords: Platelet, proteomics, glycoprotein, thrombin, factor Xa, microscopy Introduction Knowledge about the structure, biology, and function of platelets has evolved considerably since 1881, when Giulio Bizzozero linked newly identified, discrete particles in the blood, distinct from red and white blood cells, with the coagulation process [1]. The initial Platelet Colloquium [2–4], held in 2006, discussed the biology of platelet activation, current methods of measuring platelet performance, and how clinical investigations, drug-development programs, and clinical practice are hampered by a recognized disconnect between in vitro measures of platelet performance and clinical outcomes. This paper, developed from the proceedings of the 2007 Platelet Colloquium, examines the fundamental biology of platelets and provides a state-of-the-art summary of emerging constructs for scientific investigation and their translation to the development of platelet-directed pharmacotherapies in human atherothrombotic disorders. These include an overview of megakaryocyte maturation, thrombo- poiesis, platelet proteomics, the employment of the factor Xa-platelet interface as a working model for Correspondence: Richard C. Becker, MD, Duke Clinical Research Institute, 2400 Pratt Street, Terrace Level, Room 0311, Durham, NC 27705. Tel: 919-668-8179. Fax: 919-668-7056. E-mail: richard.becker@duke.edu *This manuscript reflects presentations given at the 2007 Platelet Colloquium, January 18–20, 2007, Amelia Island, Florida, USA (see Acknowledgments for sponsorship). ISSN 0953–7104 print/ISSN 1369–1635 online ß 2008 Informa UK Ltd. DOI: 10.1080/09537100801947442 Downloaded At: 13:58 24 March 2009