La unión del factor vii al epcr inhibe la vía extrínseca de la coagulaciónun nuevo mecanismo anticoagulante de la célula endotelial

Laburpena

Endothelial cell protein C receptor (EPCR) binds protein C through its gamma-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. We demonstrated by surface plasmon resonance (SPR) that FVII/FVIIa binds to EPCR through its Gla domain in a Ca2+ and Mg2+ dependent manner. The interaction follows a two-state conformational change kinetic, thus suggesting that factor VIIa is structurally rearranged upon complex formation. The alanine scanning mutagenesis of sEPCR residues known to participate in protein C/APC binding showed that factor VIIa and protein C/APC share their EPCR binding site. Soluble EPCR (sEPCR) was able to prolong dose dependently the clotting time induced by the FVIIa¿TF complex. Additionally, sinthetic peptides of the EPCR regions responsible for protein C binding showed potential to increase this clotting time. 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. Factor VIIa had no effect on the survival rate in a murine model of sepsis induced by lipopolysaccharide. EPCR binds to FVII/ FVIIa and inhibits the procoagulant activity of the FVIIa¿TF complex.