Date of Award

2008

Degree Type

Dissertation

Department

Chemistry

First Advisor

Kalafatis, Michael

Subject Headings

Prothrombin, Hemostasis, Blood coagulation factors, fVa, fXa, Prothrombin, Prothrombinase, Electronic books. local

Abstract

Hemostasis occurs through the controlled activation and inactivation of clotting factors resulting in the arrest of bleeding without blockage to the vasculature, while thrombosis is the undesired formation of vascular blood clots, which adversely affects millions of people annually. Clotting factors circulate in blood as inactive zymogens, which are proteolytically activated in response to vascular injury, assembled into enzymatic complexes and in turn activate additional coagulation factors culminating in the production of thrombin from the enzymatic complex prothrombinase. The prothrombinase complex is composed of the activated enzymatic component factor Xa (fXa) complexed to the activated cofactor portion factor Va (fVa) assembled on a membrane surface in the presence of calcium. Prothrombinase enzymatic activity results in the conversion of prothrombin, the inactive precursor, to thrombin, the active enzyme following two sequential proteolytic cleavages. Thrombin in turn converts fibrinogen, a soluble precursor, to fibrin, the insoluble product which composes the meshwork of a fibrin clot. Therefore, the regulation of prothrombinase will result in the inhibition of clot formation. Incorporation of fVa into the prothrombinase complex increases the catalytic rate of fXa by five orders of magnitude and increasing kinetic studies have suggested that prothrombinase has two equilibrating forms which function in conjunction in the production of thrombin. The prothrombinase complex is unique in its function of activating thrombin making it the ideal enzyme to target for regulating thrombin production, however the molecular events governing prothrombinase assembly and function are not well understood, and a better understanding of these events will provide novel targets for therapeutic compounds capable of regulating thrombin production. The long-term goal of this study is to determine the molecular interactions governing prothrombinase assembly/function, because the specific inhibition of thrombin formation will be

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