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In Vitro
Journal Article
Research Support, Non-U.S. Gov't
Factor V and protein S as synergistic cofactors to activated protein C in degradation of factor VIIIa.
Journal of Biological Chemistry 1994 July 23
Inherited resistance to activated protein C (APC) is a recently identified major cause of thrombosis. It is associated with a mutation in the factor V gene affecting one of the cleavage sites for APC. APC resistance was recently found to be corrected by factor V, suggesting that factor V may have anticoagulant properties as a cofactor to APC. To elucidate this further, we have studied the effect of factor V and protein S, which is a known cofactor to APC, on APC-mediated degradation of factor VIIIa in a purified system. The APC-mediated degradation of factor VIIIa was monitored by a factor X activation reaction using purified factor IXa, phospholipid, and calcium. In the presence of both factor V and protein S, APC was found to inhibit factor VIIIa activity efficiently. APC alone or together with factor V was ineffective, whereas APC in combination with protein S was less efficient than when factor V was also included in the reaction. Two monoclonal antibodies, one against protein S and the other directed toward factor V, were found to inhibit the APC cofactor activity of the factor V-protein S mixture. Factor Va did not express APC cofactor activity, and addition of excess factor Va over factor V did not inhibit the APC cofactor function of a factor V-protein S mixture. In conclusion, the results suggest that factor V and protein S work in synergy as phospholipid-bound cofactors to APC.
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