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(Arteriosclerosis, Thrombosis, and Vascular Biology. 2009;29:1968.)
© 2009 American Heart Association, Inc.

Clinical and Population Studies

FVII, FVIIa, and Downstream Markers of Extrinsic Pathway Activation Differ by EPCR Ser219Gly 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

From the Division of Medicine (H.A.I., J.A.C., F.D., J.A., J.P.M., S.E.H.), University College London, UK; Beth Israel Deaconess Medical Center, Molecular Medicine Unit (K.A.B.), Boston, Mass; the College of Medicine (J.H.M.), University of Illinois at Urbana-Champaign; and the Nuffield Department of Clinical Laboratory Sciences (M.P.E.), John Radcliff Hospital, Oxford, UK.

Correspondence to Dr Helen Ireland, Centre for Cardiovascular Genetics, Division of Medicine, University College London, UK. E-mail h.ireland{at}ucl.ac.uk

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.

In 2000 healthy middle aged men (NPHSII), FVII, FVIIa, FIX activation peptide, FX activation peptide, and prothrombin F1+2 levels were significantly higher in those with the rare allele for a variant (EPCR Ser219Gly) previously shown to have functional consequences for EPCR shedding. These findings extend previous in vitro analysis for FVII and FVIIa binding to membrane associated EPCR.

Key Words: endothelial protein C receptor • FVIIa • extrinsic coagulation • FIX activation peptide • FX activation peptide • prothrombin F1+2

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