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.
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.
Authors: J A Cooper; G J Miller; K A Bauer; J H Morrissey; T W Meade; D J Howarth; S Barzegar; J P Mitchell; R D Rosenberg Journal: Circulation Date: 2000-12-05 Impact factor: 29.690
Authors: Xunzhen Zheng; Weihong Li; Jian-Ming Gu; Dongfeng Qu; Gary L Ferrell; Naomi L Esmon; Charles T Esmon Journal: Blood Date: 2006-10-05 Impact factor: 22.113
Authors: Roger J S Preston; Eva Ajzner; Cristina Razzari; Stalo Karageorgi; Sonia Dua; Björn Dahlbäck; David A Lane Journal: J Biol Chem Date: 2006-07-25 Impact factor: 5.157
Authors: G J Miller; H A Ireland; J A Cooper; K A Bauer; J H Morrissey; S E Humphries; M P Esnouf Journal: J Thromb Haemost Date: 2007-10-29 Impact factor: 5.824
Authors: Weihong Tang; Christine Schwienbacher; Lorna M Lopez; Yoav Ben-Shlomo; Tiphaine Oudot-Mellakh; Andrew D Johnson; Nilesh J Samani; Saonli Basu; Martin Gögele; Gail Davies; Gordon D O Lowe; David-Alexandre Tregouet; Adrian Tan; James S Pankow; Albert Tenesa; Daniel Levy; Claudia B Volpato; Ann Rumley; Alan J Gow; Cosetta Minelli; John W G Yarnell; David J Porteous; John M Starr; John Gallacher; Eric Boerwinkle; Peter M Visscher; Peter P Pramstaller; Mary Cushman; Valur Emilsson; Andrew S Plump; Nena Matijevic; Pierre-Emmanuel Morange; Ian J Deary; Andrew A Hicks; Aaron R Folsom Journal: Am J Hum Genet Date: 2012-06-14 Impact factor: 11.025
Authors: Weihong Tang; Saonli Basu; Xiaoxiao Kong; James S Pankow; Nena Aleksic; Adrian Tan; Mary Cushman; Eric Boerwinkle; Aaron R Folsom Journal: Blood Date: 2010-08-27 Impact factor: 22.113
Authors: Kira C Taylor; Leslie A Lange; Delilah Zabaneh; Ethan Lange; Brendan J Keating; Weihong Tang; Nicholas L Smith; Joseph A Delaney; Meena Kumari; Aroon Hingorani; Kari E North; Mika Kivimaki; Russell P Tracy; Christopher J O'Donnell; Aaron R Folsom; David Green; Steve E Humphries; Alexander P Reiner Journal: Hum Mol Genet Date: 2011-06-15 Impact factor: 6.150
Authors: Prosenjit Sen; Ramakrishnan Gopalakrishnan; Hema Kothari; Shiva Keshava; Curtis A Clark; Charles T Esmon; Usha R Pendurthi; L Vijaya Mohan Rao Journal: Blood Date: 2011-01-20 Impact factor: 22.113
Authors: Jessica Dennis; Candice Y Johnson; Adeniyi Samuel Adediran; Mariza de Andrade; John A Heit; Pierre-Emmanuel Morange; David-Alexandre Trégouët; France Gagnon Journal: Blood Date: 2012-01-17 Impact factor: 22.113
Authors: N C Olson; L M Raffield; L A Lange; E M Lange; W T Longstreth; G Chauhan; S Debette; S Seshadri; A P Reiner; R P Tracy Journal: J Thromb Haemost Date: 2017-12-08 Impact factor: 5.824