Circulating activated protein C in subjects with heterozygous GIn506-factor V

Congenital resistance to activated protein C due to a point mutation in the factor V gene (Gln506-FV) is the most common genetic risk factor for famil ial venous thrombosis. Considering the central role of activated protein C as a physiological anticoagulant, the question of why the thrombotic risk a ssociated with Gln506-FV was not more pronounced was asked. We hypothesized that in Gln506-FV heterozygotes, enhanced thrombin formation might prefere ntially activate protein C and thereby constitute a compensatory antithromb otic effect. We compared the circulatory level of activated protein C in tw elve heterozygous carriers of Gln506-FV mutation with that in eighteen nonc arriers in same families, and used prothrombin fragment 1+2 as a measure of thrombin generation. The circulating level of activated protein C was high er but not significantly different in heterozygotes compared with normal re latives. Activated protein C levels correlated strongly and positively with protein C antigen levels in both carriers (Spearman R 0.684, p < 0.05) and controls (Spearman R 0.642, p < 0.01). Correlation between activated prote in C and prothrombin fragment 1+2 levels was of borderline significance (Sp earman R 0.354, p = 0.055). In the current study, thrombin formation assess ed by prothrombin fragment 1+2 levels was not significantly enhanced in sub jects with heterozygous Gln506-FV compared with family members without the mutation. In conclusion, enhanced thrombin formation is not present in all healthy Gln506-FV heterozygotes in basal conditions. It seems that enhanced protein C activation by thrombin does not constitute a compensatory antico agulant feedback loop in heterozygous carriers of Gln506-FV. However, the p ositive correlation between prothrombin fragment 1+2 and activated protein C suggests that, in healthy subjects and in basal conditions, thrombin upre gulates the anticoagulant protein C pathway. Thus, it is questionable wheth er prothrombin fragment 1+2 can directly be used as an indicator of a hyper coagulable state.