These authors contributed equally to this work.
Binding of factor VIIa to the endothelial cell protein C receptor reduces its coagulant activity
Article first published online: 4 JUN 2007
© 2007 International Society on Thrombosis and Haemostasis
Journal of Thrombosis and Haemostasis
Volume 5, Issue 9, pages 1817–1824, September 2007
How to Cite
LÓPEZ-SAGASETA, J., MONTES, R., PUY, C., DÍEZ, N., FUKUDOME, K. and HERMIDA, J. (2007), Binding of factor VIIa to the endothelial cell protein C receptor reduces its coagulant activity. Journal of Thrombosis and Haemostasis, 5: 1817–1824. doi: 10.1111/j.1538-7836.2007.02648.x
- Issue published online: 4 JUN 2007
- Article first published online: 4 JUN 2007
- Received 15 May 2007, accepted 18 May 2007
- endothelial protein C receptor;
- factor VII;
- tissue factor
Summary. Background: Endothelial cell protein C receptor (EPCR) binds protein C through its γ-carboxyglutamic acid (Gla) domain and enhances its thrombin–thrombomodulin complex-dependent activation. So far, only protein C/activated protein C has been shown to interact with EPCR. Factor VII (FVII), the coagulation trigger upon tissue factor (TF) interaction, is a serine protease whose Gla domain is highly homologous to the Gla domain of protein C. Objectives: To characterize the binding of FVII/FVIIa to EPCR and its functional consequences. Methods and results: We demonstrated by surface plasmon resonance (SPR) that FVII/FVIIa binds to EPCR through its Gla domain. At therapeutic concentrations, FVIIa reduced the activation of protein C by 40%. Soluble EPCR (sEPCR) was also able to prolong dose-dependently the clotting time induced by the FVIIa–TF complex. SPR and amidolytic experiments showed that FVIIa is able to interact simultaneously with TF and EPCR, thus ruling out the possibility that the effect of EPCR on clotting time was due to the inhibition of the binding between FVIIa and TF. sEPCR inhibited dose-dependently the activation of FX by the FVIIa–TF complex. Notably, blocking the binding site of EPCR on the endothelial surface increased the generation of FXa 2-fold. Conclusions: EPCR binds to FVII/FVIIa and inhibits the procoagulant activity of the FVIIa–TF complex.