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

Abstract

Objective: To review the physiologic and biochemical mechanisms that suggest that protein C and activated protein C (APC) have unique properties that make them good candidates for the treatment of microvascular thrombosis, disseminated 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 coagulation, as seen most clearly in humans born with congenital deficiency of protein C, who develop neonatal purpura fulminans. Protein C supplementation reverses the lesion formation. In primate models of sepsis, APC blocks disseminated intravascular coagulation initiated by Escherichia coli infusion, and inhibition of APC function exacerbates both the coagulant and inflammatory responses of the animals to sublethal levels of E. coli. In vitro experiments have shown that APC can inhibit neutrophil binding to selectins: Endothelial cell protein C receptor, a protein C/APC binding receptor, can bind to proteinase 3 bound to Mac-1 on leukocytes, potentially blocking tight leukocyte adhesion; and APC can inhibit tumor necrosis factor-alpha secretion by monocytes and other cell lines by interfering with nuclear factor-kappaB nuclear translocation. By blocking nuclear factor-kappaB nuclear translocation, cytokine- and endotoxin-mediated adhesion molecule up-regulation is decreased. These properties of APC are consistent with a large number of animal studies demonstrating that APC can diminish complications of crush injury and leukocyte damage to lung and other tissues in response to sepsis and decrease the inflammatory response. The animal studies are consistent with the phase 2 studies reported on APC use in the treatment of human sepsis.

Conclusions: The protein C pathway is uniquely poised to interfere with the microvascular coagulation and inflammation that follows challenge with endotoxin. By limiting leukocyte activation, cytokine elaboration, and microvascular coagulation, APC has been shown to prevent organ damage in experimental models of sepsis. These results are consistent with the initial phase 2 reports of APC therapy in human sepsis suggesting a clinical benefit and demonstrating anti-inflammatory activity with several reports of apparent protein C effectiveness in severe sepsis, especially meningococcemia.