EPCR knockout: inflaming the discussion.

In this issue of Blood, Magisetty et al provide some surprising results from their studies of the role of endothelial protein C receptor (EPCR) in hemophilic arthropathy. There is a rationale for studying EPCR in hemophilia. It is well recognized that EPCR promotes the activation of protein C (PC) to activated PC (aPC) on endothelial surfaces. The aPC has antithrombotic effects by inactivating factor Va (FVa) on nearby endothelial surfaces. Like aPC, activated coagulation FVIIa can also bind to EPCR. Pavani et al showed that binding to EPCR enhances the hemostatic effect of FVIIa in a mouse hemophilia model, when assayed as ferric chloride–induced thrombosis. The Rao group showed that hemostatic levels of FVIIa displace PC from EPCR, and blockade of EPCR reduces the level of FVIIa needed for hemostasis in a saphenous vein bleeding assay. However, they reported that EPCR blockade by itself did not reduce the severity of bleeding in hemophilic mice. They concluded that downregulation of aPC generation is the major mechanism by which FVIIa interaction with EPCR contributes to the hemostatic effect of FVIIa in hemophilia.