Anticoagulant Function of Arterial Endothelial Cells

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Plasma protein C is an indispensable regulator of blood coagulation. Deficiencies in this molecule are associated with thrombotic disease, and knockout mice lacking protein C suffered lethal thromboses within 24 hours after birth. Protein C is a serine protease that circulates as a zymogen form, and functions only when converted into the active protease form. Protein C activation is promoted by thrombin on the endothelial cell surface. Two associate endothelial cell surface molecules have been identified. One is thrombomodulin (TM), which is capable of high-affinity specific binding of thrombin. We identified another endothelial cell surface molecule involved in the activation mechanism of protein C.The endothelial cell protein C receptor (EPCR) specifically binds protein C, and enables effective protein C activation mediated by the thrombin/TM complex. Knockout of the gene for EPCR or TM caused embryonic lethality, and did not allow in vivo analysis of the anticoagulant activities of these molecules. Here, we generated function blocking monoclonal antibodies (mAbs) against all these key murine factors. Anti-protein C mAbs, which specifically prevent the binding to EPCR, caused lethal thrombosis in injected mice. An anti-EPCR mAb induced severe thrombosis. We also generated function-blocking mAb against murine TM.This antibody again caused lethal thrombosis. These mAbs will be powerful tools for analyzing in vivo protein C pathway function.