The protein C pathway performs a critical anticoagulant function by subverting the procoagulant effects of thrombin, and a paper by Taylor and colleagues (page 1685) suggests that an endothelial membrane cofactor besides thrombomodulin modulates this function in vivo. The protein C pathway begins with the binding of thrombin to thrombomodulin on endothelial cells, and the thrombin-thrombomodulin complex then activates protein C, a serine protease zymogen. In a reaction that is facilitated by plasma protein S, activated protein C (APC) degrades clotting factors Va and VIIIa, shutting down blood clotting. Defects in the protein C pathway are common causes of thrombosis, underlining the importance of this regulatory mechanism. Even a modest acquired or inherited decrease in the level of protein C or protein S confers a substantially increased risk of venous thrombosis, and total deficiency of protein C causes purpura fulminans, a neonatal thrombohemorrhagic disorder that is fatal if untreated.
The endothelial protein C receptor (EPCR) is a plasma membrane protein that binds protein C and accelerates its activation by thrombin-thrombomodulin at least 5-fold in vitro. Changes of this magnitude could have large effects on hemostatic balance. But the concentration of EPCR in vivo is highest in large vessels, whereas protein C activation by thrombin-thrombomodulin occurs mainly in the microcirculation. The apparent discrepancy between the localization of EPCR and protein C activation has raised questions about the biological relevance of EPCR to the protein C anticoagulant pathway function, although the immunohistochemical detection of EPCR in the microcirculation may not be sufficiently sensitive or quantitative to support conclusions about function.
Taylor and colleagues now have shown that EPCR plays a substantial role in protein C activation. Administration of low doses of thrombin to baboons causes a large increase (more than 200-fold) in circulating APC levels, and coadministration of a blocking antibody to EPCR inhibited this response by almost 90%. Thus the relatively low levels of EPCR in microvessels appear sufficient to strongly stimulate the protein C pathway in vivo. These data suggest that inherited or acquired variations in EPCR activity in specific vascular beds could determine the probability of thrombosis and, possibly, its location.
