SEMINARS IN THROMBOSIS AND HEMOSTASIS-VOL. 24. NO. 4.1998 Molecular Biology and Pathophysiology of APC Resistance: Current Insights and Clinical lmplications

ABSTRACT APC resistance is often associated with the occurrence of a single point mutation in factor V (factor V".,u",) at a predominant cleavage site for the natural anticoagulant, activated protein C (APC). In this article we will discuss the effects of this mutation (Argso0-6rn) on the down-regulation 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 formation in plasma re-sulted in the development of a new method for the screening of APC resistance that is based on mea-surement of the effect of APC on the endogenous thrombin potential (the time integral of thrombin generated in clotting plasma). It appeared that sensi-tivities for APC determined via this method were considerably affected by the use of oral contracep-tives (OC) and that women who use OC become ac-quired APC resistant. The fact that acquired APC re-sistance in women who use third-generation OC was more pronounced than in users of second-generation OC may explain the further increased risk for yenous thrombosis associated with the use of third-genera-tion OC