Inflammation: The protein C pathway

The protein C pathway serves as one of the most important negative regulatory mechanisms in coagulation. Unlike most pathways in coagulation, the protein C pathway can be downregulated by inflammatory mediators at the levels of protein C activation and function. Antiphospholipid antibodies can selectively block protein C function. In gram negative sepsis, protein C in humans and activated protein C (APC) in baboons and rodents have been shown to block the lethal response, at least in part by blocking the DIC response and probably by modulating the cytokine cascade. The mechanisms by which the pathway modulates inflammation remains unclear, but a novel endothelial cell specific receptor has recently been identified that binds APC and modulates enzyme specificity. Like thrombomodulin, the receptor is downregulated by the inflammatory cytokine, TNF. These observations provide a basis for a model in which the protein C pathway serves as a major regulatory mechanism in the control of coagulation and inflammation.