Date of Award

2007

Degree Type

Dissertation

Department

Chemistry

First Advisor

Kalafatis, Michael

Subject Headings

Blood coagulation factors, Coagulants -- Physiology, Prothrombin, Factor V, Blood coagulation, Prothrombinase, APC, Thrombin, Factor V. Leiden, Electronic books. -- local

Abstract

The mainstay of the blood coagulation cascade is the formation of the fibrin clot, catalyzed by the serine protease, thrombin. The prothrombinase complex catalyzes the activation of prothrombin to thrombin and, is composed of the enzyme, factor Xa, and the protein cofactor, factor Va, in the presence of divalent metal ions associated on a membrane surface. The enzyme, factor Xa, alone can activate prothrombin by two sequential proteolytic cleavages at Arg271 and Arg320 resulting in the intermediates, Fragment 1.2 and Prethrombin 2. The overall rate of this reaction is not compatible with survival. On the other hand, the incorporation of an excess of the cofactor, factor Va, into prothrombinase reverses the order of the proteolytic cleavages and increases the catalytic activity of factor Xa by 5 orders of magnitude, making this reaction compatible with survival. The goal of this research is to identify the precise amino acids of the central portion of the factor Va heavy chain involved in its incorporation into the prothrombinase complex and the cofactor function it exerts on the catalytic efficiency of prothrombin activation

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