Soluble thrombomodulin, plasma-derived unactivated protein C, and recombinant human activated protein C in sepsis

Objective: To review the physiologic and biochemical mechanisms and the rationale for the use of soluble thrombomodulin, plasma-derived protein C, and recombinant human activated protein C in sepsis. Data Sources and Study Selection: Research and review articles related to the protein C pathway published in English from 1960 to present. Data Extraction and Synthesis: The protein C anticoagulant pathway plays a major role In controlling microvascular coagulation and inflammation. Protein C is the zymogen of the vitamin K-dependent serine protease activated protein C. Protein C is converted to activated protein C when thrombin complexes with thrombomodulin, an endothelial surface transmembrane glycoprotein. Activated protein C Inactivates factors Va and VIIIa and effectively limits further thrombin generation. This protein also enhances endogenous fibrinolytic activity and modulates the inflammatory response. A rapid depletion of protein C occurs in sepsis, which contributes to sepsis-induced coagulopathy and correlates with a poor prognosis. The decrease in tissue levels of thrombomodulin in patients with meningococcemia suggests that the ability to convert protein C to activated protein C may also be compromised. The ability of soluble thrombomodulin to block fibrinogen clotting and cell activation, to activate protein C, and to promote thrombin inhibition in different animal models suggests that soluble thrombomodulin could be a useful therapeutic agent in sepsis. However, soluble thrombomodulin Is less effective in blocking fibrinogen and platelet activation and In promoting thrombin inhibition than endothelial surface membrane-bound thrombomodulin. Only activated protein C, and not protein C, has clearly shown a reduction in mortality in experimental animal models of sepsis and in humans. Conclusions: The multipotent pharmacodynamic effects (anti-thrombotic, profibrinolytic, and anti-inflammatory) of activated protein C may explain why recombinantly derived human activated protein C is the first experimental agent to demonstrate a significant survival benefit in patients with severe sepsis.