Endothelial cell protein C receptor plays an important role in protein C activation in vivo

Endothelial cell protein C receptor (EPCR) augments protein C activation by the thrombin-thrombomodulin complex about 5-fold in vitro. Augmentation is EPCR concentration dependent even when the EPCR concentration is in excess of the thrombomodulin, EPCR is expressed preferentially on large blood ves sel endothelium, raising questions about the importance of protein C-EPCR i nteraction for augmenting systemic protein C activation. In these studies, this question was addressed directly by infusing thrombin into baboons in t he presence or absence of a monoclonal antibody to EPCR that blocks protein C binding. Activated protein C levels were then measured directly by captu ring the enzyme on a monoclonal antibody and assaying with chromogenic subs trate. Blocking protein C-EPCR interaction resulted in about an 88% decreas e in circulating activated protein C levels generated in response to thromb in infusion, Leukocyte changes, fibrinogen consumption, fibrin degradation products, and vital signs were similar between the animals infused with thr ombin alone and those infused with thrombin and the anti-EPCR antibody. The results indicate that EPCR plays a major role in protein C activation and suggest that defects in the EPCR gene might contribute to increased risk of thrombosis. (Blood, 2001;97:1685-1688) (C) 2001 by The American Society of Hematology.