Dimorphisms in the membrane-spanning domain of EPCR impact systemic coagulation.

The role of vascular coagulation receptors, particularly modest changes in the levels of these proteins in terms of controlling downstream coagulation factor activation, remains largely unknown. The study reported by Ireland and colleagues in this issue of Arteriosclerosis, Thrombosis, and Vascular Biology1 demonstrates that a moderately common dimorphism in the endothelial cell protein C receptor (EPCR) influences the levels of markers of ongoing coagulation (Figure). Several of the key components, thrombomodulin and the EPCR, are subject to downregulation by inflammatory mediators that could play a role potentially in local thrombotic events. EPCR is an important regulatory factor in that it binds protein C and activated protein C,2 augments protein C activation by the thrombin-thrombomodulin complex,3 facilitates activated protein C cytoprotective activity,4 binds factor VII and VIIa,5–6 and leads to the internalization and degradation of both factor VII and protein C.7 In addition, the EPCR gene has a relatively common dimorphism in which there is a Ser to Gly substitution in the membrane spanning domain. This substitution leads to increased shedding, probably catalyzed by TACE (tumor necrosis factor converting enzyme),8 of EPCR as a soluble form from the endothelial cell surface.9 Shedding increases the levels of circulating EPCR at the expense of membrane-bound EPCR and hence should impact EPCR function. Indeed the 3 genotypes Ser-Ser, Ser-Gly, and Gly-Gly were identified in the human population and studied in the analysis by Ireland et al1 for alterations in a variety of markers of ongoing coagulation, particularly factor VII and VIIa levels, prothrombin fragment 1 to 2, and factor IX activation peptide. The fundamental observations of interest are that in individuals with the Gly variants, the levels of factors VII and VIIa were elevated. These studies are the first human studies to indicate in vivo that EPCR apparently serves as a significant reservoir for factor VII. These results are consistent with mouse studies7 in which the role of EPCR in controlling factor VII levels could be evaluated more directly than in the human studies. Also of interest is the finding that the people with the EPCR Gly variants had elevated levels of markers of coagulation factor activation. See accompanying article on page 1968