Genetic determinants of activated factor VII antithrombin complex plasma concentration include tissue factor, factor VII and endothelial protein C receptor gene variants

Background: Plasma concentration of activated factor VII (FVIIa)- antithrombin (AT) complex has been proposed to be a thrombophilic biomarker, potentially reflecting tissue factor (TF) exposure and TFFVIIa interaction. Endothelial protein C receptor (EPCR) has been shown to bind FVIIa, but the physiological significance of this interaction in hemostasis is unclear. Aims: To reveal determinants of the FVIIa-AT plasma concentration exploiting functional gene polymorphisms, known to modulate F7, TF and EPCR levels. Methods: We evaluated in 605 subjects (75.0% males, mean age 61.0 10.9 years, 80.0% with coronary artery disease) FVIIa-AT plasma levels (ELISA assay) and genotypes for TF (-603 A>G and +5466 A>G), F7 (-402 G>A, -323 A1/A2 and R353Q), and EPCR (S219G). Results: F7 -323A2 and 353Q allele carriers and TF -603GG-homozygotes had lower FVIIa-AT complex levels. Differently, EPCR 219G minor allele carriers had higher levels. Including the polymorphisms in a linear regression model, F7 -323A1/A2 (b = 0.226; P < 0.001), TF -603 A>G (b = 0.126; P = 0.001) and EPCR S219G (b = 0.080; P = 0.044) polymorphisms remained significant predictors of FVIIa- AT concentration. They explained an overall level variability (6.7%) similar to that (7.1%) of other major determinants, i.e. renal function (b = 0.194; P < 0.001) and plasma lipids (HDL-cholesterol: b = 0.195; P < 0.001; triglyceride: b = 0.117; P = 0.011). The genetic contribution was virtually unchanged after adjustment for sex, age, CAD diagnosis, as well as renal function and plasma lipids. Conclusion: Our results show the interplay of several genetic components as independent determinants of FVIIa-AT plasma concentration, and indicate for the first time the contribution of EPCR gene variants. Since the investigated polymorphisms modulate proteins directly involved in FVIIa-AT complex formation and potentially influence their interaction, our study may add novel elements to understand the regulation “in vivo” of the FVII-TF pathway