Protein C anticoagulant pathway and its role in controlling microvascular thrombosis and inflammation

Objective: To review the physiologic and biochemical mechanisms that sugges t that protein C and activated protein C (APC) have unique properties that make them good candidates for the treatment of microvascular thrombosis, di sseminated intravascular coagulation, and sepsis, Data Sources:A summary of published medical literature from MEDLINE search files and published reviews on protein C physiology, biochemical properties , and activity in experimental and human sepsis, Data Summary:Protein C is critical to the regulation of microvascular coagu lation, as seen most clearly in humans born with congenital deficiency of p rotein C, who develop neonatal purpura fulminans, Protein C supplementation reverses the lesion formation. In primate models of sepsis, APC blocks dis seminated intravascular coagulation initiated by Escherichia coli infusion, and inhibition of APC function exacerbates both the coagulant and inflamma tory responses of the animals to sublethal levels of E, coil In vitro exper iments have shown that APC can inhibit neutrophil binding to selectins: End othelial cell protein C receptor, a protein C/APC binding receptor, can bin d to proteinase 3 bound to Mac-1 on leukocytes, potentially blocking tight leukocyte adhesion; and APC can inhibit tumor necrosis factor-alpha secreti on by monocytes and other cell lines by interfering with nuclear factor-kap paB nuclear translocation. By blocking nuclear factor-kappaB nuclear transl ocation, cytokine- and endotoxin-mediated adhesion molecule up-regulation i s decreased. These properties of APC are consistent with a large number of animal studies demonstrating that APC can diminish complications of crush i njury and leukocyte damage to lung and other tissues in response to sepsis and decrease the inflammatory response. The animal studies are consistent w ith the phase 2 studies reported on APC use in the treatment of human sepsi s, Conclusions:The protein C pathway is uniquely poised to interfere with the microvascular coagulation and inflammation that follows challenge with endo toxin, By limiting leukocyte activation, cytokine elaboration, and microvas cular coagulation, APC has been shown to prevent organ damage in experiment al models of sepsis, These results are consistent with the initial phase 2 reports of APC therapy in human sepsis suggesting a clinical benefit and de monstrating anti-inflammatory activity with several reports of apparent pro tein C effectiveness in severe sepsis, especially meningococcemia.