Circulating activated protein C in subjects with heterozygous Gln506-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 familial venous thrombosis. Considering the central role of activated protein C as a physiological anticoagulant, the question of why the thrombotic risk associated with Gln506-FV was not more pronounced was asked. We hypothesized that in Gln506-FV heterozygotes, enhanced thrombin formation might preferentially activate protein C and thereby constitute a compensatory antithrombotic effect. We compared the circulatory level of activated protein C in twelve heterozygous carriers of Gln506-FV mutation with that in eighteen noncarriers in same families, and used prothrombin fragment 1+2 as a measure of thrombin generation. The circulating level of activated protein C was higher but not significantly different in heterozygotes compared with normal relatives. 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 protein C and prothrombin fragment 1+2 levels was of borderline significance (Spearman R 0.354, p = 0.055). In the current study, thrombin formation assessed by prothrombin fragment 1+2 levels was not significantly enhanced in subjects 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 anticoagulant feedback loop in heterozygous carriers of Gln506-FV. However, the positive correlation between prothrombin fragment 1+2 and activated protein C suggests that, in healthy subjects and in basal conditions, thrombin upregulates the anticoagulant protein C pathway. Thus, it is questionable whether prothrombin fragment 1+2 can directly be used as an indicator of a hypercoagulable state.
Petäjä
J
J
Department of Molecular and Experimental Medicine,The Scripps Research Institute, La Jolla, Calif., USA. jari.petaja@dlc.fi
Hakala
L
L
Rasi
V
V
Griffin
J H
JH
D000293:Adolescent; D000328:Adult; D000368:Aged; D004789:Enzyme Activation; D005165:Factor V / Q000235:genetics*; D005260:Female; D006580:Genetic Carrier Screening; D005973:Glutamine / Q000235:genetics*; D006801:Humans; D008297:Male; D008875:Middle Aged; D009154:Mutation; D011486:Protein C / Q000032:analysis*
D011486:Protein C; C095381:factor V Leiden; D005973:Glutamine; D005165:Factor V