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


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.
Ireland
Helen A
HA
Centre for Cardiovascular Genetics, Division of Medicine, University College London, UK. h.ireland@ucl.ac.uk
Cooper
Jackie A
JA
Drenos
Fotios
F
Acharya
Jayshree
J
Mitchell
Jacqueline P
JP
Bauer
Ken A
KA
Morrissey
James H
JH
Esnouf
M Peter
MP
Humphries
Stephen E
SE
D015703:Antigens, CD / Q000378:metabolism*; D001777:Blood Coagulation / Q000235:genetics* / Q000502:physiology; D015331:Cohort Studies; D000074283:Endothelial Protein C Receptor; D004797:Enzyme-Linked Immunosorbent Assay; D005167:Factor VII / Q000378:metabolism*; D015942:Factor VIIa / Q000378:metabolism*; D005819:Genetic Markers; D020022:Genetic Predisposition to Disease; D014644:Genetic Variation; D005838:Genotype; D006579:Heterozygote; D006801:Humans; D008297:Male; D054526:Men's Health; D008875:Middle Aged; D011446:Prospective Studies; D011956:Receptors, Cell Surface / Q000378:metabolism*; D012016:Reference Values
D015703:Antigens, CD; D000074283:Endothelial Protein C Receptor; D005819:Genetic Markers; C478370:PROCR protein, human; D011956:Receptors, Cell Surface; D005167:Factor VII; D015942:Factor VIIa
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