FVII, FVIIa, and downstream markers of extrinsic pathway activation differ by EPCR Ser219Gly variant in healthy men

Arterioscler Thromb Vasc Biol. 2009 Nov;29(11):1968-74. doi: 10.1161/ATVBAHA.109.191551. Epub 2009 Aug 20.

Abstract

Objective: The purpose of this study was to determine the effect of a variant in EPCR (Ser219Gly), previously shown to affect EPCR shedding, on plasma FVII, FVIIa, and downstream markers of activated coagulation.

Methods and results: Statistical analysis was undertaken in approximately 2000 healthy middle aged men (NPHSII). Higher soluble EPCR levels were confirmed for Gly allele carriers (P<0.0001). Significantly higher levels of FVII, FVIIa, and downstream markers of activated coagulation in the extrinsic pathway (FIX activation pep [FIXpep]; FX activation pep [FXpep]), and prothrombin F1+2 (F1+2) were identified in baseline samples, in Gly carriers compared to Ser/Ser (P<or=0.04 for trend). In repeat samples collected for up to 5 years, levels of FVII and F1+2 were higher in Gly allele carriers compared to Ser/Ser by (FVII: 6.9% CI 5.5 to 8.4 in Ser/Gly; and 23.4% CI 16.3 to 30.8 in Gly/Gly, P<0.0001), (F1+2: 8.1% CI 5.2 to 11.1 in Ser/Gly; 25.2% CI 11.8 to 40.3 in Gly/Gly, P<0.04), confirming reproducibility of findings at baseline. Molar ratios for FIXpep, FXpep, and F1+2 to FVIIa were constant in Ser/Ser and Ser/Gly but tended to be higher in Gly/Gly, reaching statistical significance for FIXpep:FVIIa (P=0.04).

Conclusions: These data suggest that higher levels of FVII and FVIIa circulate when EPCR shedding is greatest. Furthermore, these results suggest consequences for activation of extrinsic coagulation.

Publication types

  • Comparative Study
  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Antigens, CD / metabolism*
  • Blood Coagulation / genetics*
  • Blood Coagulation / physiology
  • Cohort Studies
  • Endothelial Protein C Receptor
  • Enzyme-Linked Immunosorbent Assay
  • Factor VII / metabolism*
  • Factor VIIa / metabolism*
  • Genetic Markers*
  • Genetic Predisposition to Disease
  • Genetic Variation*
  • Genotype
  • Heterozygote
  • Humans
  • Male
  • Men's Health*
  • Middle Aged
  • Prospective Studies
  • Receptors, Cell Surface / metabolism*
  • Reference Values

Substances

  • Antigens, CD
  • Endothelial Protein C Receptor
  • Genetic Markers
  • PROCR protein, human
  • Receptors, Cell Surface
  • Factor VII
  • Factor VIIa