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Blood, Vol. 94 No. 11 (December 1), 1999:
pp. 3839-3846
Inhibition of Activated Protein C Anticoagulant Activity by Prothrombin
Mikhail D. Smirnov,
Omid Safa,
Naomi L. Esmon, and
Charles T. Esmon
From the Cardiovascular Biology Research Program, Oklahoma Medical
Research Foundation, Oklahoma City; the Departments of Pathology and
Biochemistry and Molecular Biology, University of Oklahoma Health
Sciences Center, Oklahoma City; and the Howard Hughes Medical
Institute, Oklahoma City, OK.
In this study, we test the hypothesis that prothrombin levels may
modulate activated protein C (APC) anticoagulant activity. Prothrombin
in purified systems or plasma dramatically inhibited the ability of APC
to inactivate factor 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 sensitive to prothrombin
inhibition. This may account for the observation that the Leiden
mutation has less of an effect on plasma-based clotting assays than
would be predicted from the purified system. Reduction of protein C
levels to 20% of normal constitutes a significant risk of thrombosis,
yet these levels are observed in neonates and patients on oral
anticoagulant therapy. In both situations, the correspondingly low
prothrombin levels would result in an increased effectiveness of the
remaining functional APC of  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 effective anticoagulant, allowing protein
C levels to be reduced without significant thrombotic risk. In
situations where prothrombin is high and protein C levels are low, as
in early stages of oral anticoagulant therapy, the reduction in protein C would result only in impaired function of the anticoagulant system,
possibly explaining the tendency for warfarin-induced skin necrosis.
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