Role of coagulation Factor VIII in Thrombosis in vivo

University Of Michigan At Ann Arbor, Ann Arbor MI

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Abstract

PROJECT 2: Role of Coagulation Factor VIII in Thrombosis In Vivo Factor VIII is the plasma protein deficient or functionally defective in hemophilia A, an X-chromosome linked bleeding disorder affecting 1/5,000 males. Affected patients experience significant morbidity and mortality related to repeated and/or life-threatening bleeding events. Elevated levels of factor VIII are also associated with increased risk for arterial and venous thromboembolism. Thus, factor VIII has a pivotal role in both hemostasis and thrombosis. Efficient secretion of factor VIII requires the presence of a mannose- binding lectin within the endoplasmic reticulum-Golgi intermediate compartment, ERGIC53. Null expression of ERGIC53 is one cause of combined deficiency of factors V and VIII, a rare autosomal-recessive bleeding disorder. A major goal of the proposed studies is to elucidate the role of factor VIII plasma level, activation and inactivation in thrombosis and hemostasis. Findings from the proposed experiments will have direct impact on therapeutic intervention for the treatment of bleeding diseases and for thrombophilia. The proposed research will provide new insight into the regulation of factor VIII secretion, providing essential information relevant to the efficiency, efficacy, and safety of gene therapeutic applications directed towards a cure for hemophilia A. The specific aims of this proposal are to test the following three hypotheses: Specific Aim 1 hypothesis: Increased circulating factor VIII contributes to thrombosis in vivo. la hypothesis: Over-expression of factor VIII leads to a prothrombotic state in vivo. * Thrombosis will be studied in transgenic mice that express factor VIII at elevated levels. l b hypothesis: Factor Villa instability regulates procoagulant activity in vivo. * Transgenic mice that express mutant factor VIII molecules that are constitutively activated or that are resistant to chain dissociation will be tested in murine models of thrombosis. Specific Aim 2 hypothesis: A defect in another gene(s) product acting in the same or parallel pathway as ERGIC53 results in combined deficiency of factors V and VIII. * The mechanism by which defects in additional genes that cause FV/FVIII deficiency will be elucidated. Specific Aim 3 hypothesis: ERGIC53 is an effective therapeutic target for thrombophiliao * Thrombosis will be studied in mice that have a defective ERGIC53 pathway.