FVII, FVIIa, and downstream markers of extrinsic pathway activation differ by EPCRser219Gly variant in healthy men

Helen A. Ireland, Jackie A. Cooper, Fotios Drenos, Jayshree Acharya, Jacqueline P. Mitchell, Ken A. Bauer, James H. Morrissey, M. Peter Esnouf, Stephen E. Humphries

Research output: Contribution to journalArticlepeer-review

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 ≈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<=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.

Original languageEnglish (US)
Pages (from-to)1968-1974
Number of pages7
JournalArteriosclerosis, Thrombosis, and Vascular Biology
Volume29
Issue number11
DOIs
StatePublished - Nov 2009

Keywords

  • Endothelial protein C receptor
  • Extrinsic coagulation
  • FIX activation peptide
  • FVIIa
  • FX activation peptide
  • Prothrombin F12

ASJC Scopus subject areas

  • Cardiology and Cardiovascular Medicine

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