Inhibition of activated protein C anticoagulant activity by prothrombin

In this study, we test the hypothesis that prothrombin levels may modulate activated protein C (APC) anticoagulant activity. Prothrombin in purified s ystems or plasma dramatically inhibited the ability of APC to inactivate fa ctor Va and to anticoagulate plasma. This was not due solely to competition for binding to the membrane surface, as prothrombin also inhibited factor Va inactivation by APC in the absence of a membrane surface. Compared with normal factor Va inactivation of factor Va Leiden by APC was much less sens itive to prothrombin inhibition. This may account for the observation that the Leiden mutation has less of an effect on plasma-based clotting assays t han would be predicted from the purified system. Reduction of protein C lev els to 20% of normal constitutes a significant risk of thrombosis, yet thes e levels are observed in neonates and patients on oral anticoagulant therap y. In both situations, the correspondingly low prothrombin levels would res ult in an increased effectiveness of the remaining functional APC of approx imate to 5-fold. Thus, while the protein C activation system is impaired by the reduction in protein C levels, the APC that is formed is a more effect ive anticoagulant, allowing protein C levels to be reduced without signific ant thrombotic risk. In situations where prothrombin is high and protein C levels are low, as in early stages of oral anticoagulant therapy, the reduc tion in protein C would result only in impaired function of the anticoagula nt system, possibly explaining the tendency for warfarin-induced skin necro sis. (C) 1999 by The American Society of Hematology.