Molecular biology and pathophysiology of APC resistance: Current insights and clinical implications

APC resistance is often associated with the occurrence of a single point mu tation in factor V (factor V-Leiden) at a predominant cleavage site for the natural anticoagulant, activated protein C (APC), In this article we will discuss the effects of this mutation (Arg(506)-->Gln) on the down-regulatio n of factor Va cofactor activity and on thrombin formation by APC in model systems and in plasma. Our studies on the effects of APC on thrombin format ion in plasma resulted in the development of a new method for the screening of APC resistance that is based on measurement of the effect of APC on the endogenous thrombin potential (the time integral of thrombin generated in clotting plasma). It appeared that sensitivities for APC determined via thi s method were considerably affected by the use of oral contraceptives (OC) and that women who use OC become acquired APC resistant. The fact that acqu ired APC resistance in women who use third-generation OC was more pronounce d than in users of second-generation OC may explain the further increased r isk for venous thrombosis associated with the use of third-generation OC.