Biochemistry of Platelet Function
Dr. Silveira received his Ph.D. in 2001 from the Department of Biochemistry at the University of Vermont. His graduate work with Dr. Paula Tracy involved assessing the effects of post-translational modifications on the function of factor V, a critical component of the coagulation cascade. After completing his graduate work, Dr. Silveira obtained a postdoctoral fellowship and worked with Dr. Byron Caughey’s prion research group at the National Institutes of Health’s Rocky Mountain Laboratory facility in Hamilton, Montana. Dr. Silveira’s research on prions established a relationship between prion infectivity and the size of prion protein aggregates, revealing that smaller aggregates are inherently more infectious than larger ones. In 2006, Dr. Silveira returned to Vermont and joined the faculty of the Biochemistry department as a lecturer and a member of Dr. Paula Tracy’s research group. In 2011 he was promoted to Assistant Professor.
The prothrombinase complex, a membrane-bound, Ca2+-dependent complex comprised of the serine protease factor Xa and its essential cofactor factor Va, catalyzes the generation of thrombin and serves a critical role in hemostasis. While approximately 80% of the procofactor, factor V, is found in plasma, it is the remaining 20% found in the α-granules of platelets that constitutes the physiologically-relevant source of the molecule. The activation of platelets at sites of vascular injury results in release of the α-granule’s contents, providing a highly-concentrated bolus of the platelet-derived cofactor at a membrane surface where it can immediately support clot formation. As a member of Dr. Paula Tracy’s research group, I am interested in the role that platelets play in hemostasis, with a focus on understanding how the unique structural properties of platelet-derived factor Va make it such a robust cofactor for platelet-bound prothrombinase. To this end, a variety of physical and biochemical techniques are being used to characterize the unique post-translational modifications found on platelet-derived factor Va, so that these structural attributes of the cofactor may ultimately be related to the cofactor’s unique functional properties. Of similar interest are the origins of these unique modifications. Platelet-derived factor Va is formed within megakaryocytes, the progenitor cells of platelets, subsequent to the endocytosis of factor V from plasma. Such alteration and repackaging of an endocytosed molecule in preparation for subsequent use represents a novel paradigm in cellular trafficking, and identifying the locations and mechanisms involved in this process will provide new insights into the biological processes of cells. Ultimately, our detailed understanding of platelet-bound prothrombinase will enable increasingly well informed decisions to be made in the context of clinical interventions aimed at maintaining hemostasis and ameliorating its pathological extension, thrombosis.
Wood, J., Silveira, J., Maille, N., Haynes, L., and Tracy, P. Prothrombin activation on the activated platelet surface optimizes expression of procoagulant activity. Blood. 2011 Feb 3;117(5):1710-8.
DeMarco, M., Silveira, J., Caughey, B., and Daggett, V. Structural properties of prion protein protofibrils and fibrils: An experimental assessment of atomic models. Biochemistry 45:15573-15582, 2006.
Gould, W., Simioni, P., Silveira, J., Tormene, D., Kalafatis, M., and Tracy, P. Megakaryocytes endocytose and subsequently modify human factor V in vivo to form the entire pool of a unique platelet-derived cofactor. Journal of Thrombosis and Haemostasis 3(3):450-456, 2005.
Silveira J., Raymond G., Hughson A., Race R., Sim V., Hayes S., and Caughey B. The most infectious prion protein particles. Nature 437:257-261, 2005.
* indicates equal contribution
Wood JP, Silveira JR, Maille NM, Haynes LM, Tracy PB (2011) Prothrombin activation on the activated platelet surface optimizes expression of procoagulant activity. Blood 117(5): 1710-8.
Regis L, Souza WV, Furtado AF, Fonseca CD, Silveira Jr JC, Ribeiro Jr PJ, Melo-Santos MA, Carvalho MS, Monteiro AM (2009) An entomological surveillance system based on open spatial information for participative dengue control. An Acad Bras Cienc 81(4): 655-62.
Silveira JR, Hughson AG, Caughey B (2006) Fractionation of prion protein aggregates by asymmetrical flow field-flow fractionation. Methods Enzymol 412: 21-33.
Caughey B, Caughey WS, Kocisko DA, Lee KS, Silveira JR, Morrey JD (2006) Prions and transmissible spongiform encephalopathy (TSE) chemotherapeutics: A common mechanism for anti-TSE compounds? Acc Chem Res 39(9): 646-53.
Silveira JR, Raymond GJ, Hughson AG, Race RE, Sim VL, Hayes SF, Caughey B (2005) The most infectious prion protein particles. Nature 437(7056): 257-61.
Sánchez RM, Sierra AP, Obregón Fuentes AM, González IR, Gil AB, Suárez MB, Silveira JR, Gastón BD (2002) [Reactogenecity and immunogenecity of Cuban trivalent inactivated vaccine against human leptospirosis in different vaccination schedules]. Rev Cubana Med Trop 54(1): 37-43.
Gould WR, Simioni P, Silveira JR, Tormene D, Kalafatis M, Tracy PB (2005) Megakaryocytes endocytose and subsequently modify human factor V in vivo to form the entire pool of a unique platelet-derived cofactor. J Thromb Haemost 3(3): 450-6.
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