Activated protein C versus protein C in severe sepsis

Objective: To delineate critical differences between activated protein C (A PC) and its precursor, protein C, with regard to plasma levels in health an d in severe sepsis, acid to discuss the implications of these differences a s they relate to treatment strategies in patients with severe sepsis. Data Source/Study Selection: Published literature including abstracts, manu scripts, and review articles reporting studies in both experimental animal models and humans that provide an understanding of the relationship and the critical differences between circulating levels of APC and protein C, Data Extraction and Synthesis: The protein C pathway represents one of the major regulatory systems of hemostasis, exhibiting antithrombotic, profibri nolytic and anti-inflammatory properties. This pathway also plays a critica l role in the pathophysiology of severe sepsis, Central to this pathway is the vitamin K-dependent serine protease, APC, and its precursor, protein C, The conversion of protein C to APC is dependent on the complex of thrombin and thrombomodulin, an integral endothelial surface receptor. The conversi on of protein C to APC is further augmented by another endothelial surface protein, the endothelial protein C receptor. Them are limited published dat a on APC levels in health and disease, probably due to the complexity of th e assay methodology for measuring APC and the absence of commercially avail able diagnostic kits. In animals and humans with normal functioning endothe lium, circulating levels of APC (1-3 ng/mL) are positively correlated with protein C (4000-5000 ng/ml) concentration and the amount of thrombin genera ted. In patients with severe sepsis, there is a generalized endothelial dys function, contributing to multiple organ failure with increased morbidity a nd mortality. Persistently low protein C levels are related to poor prognos is, Key to understanding the treatment strategy with APC or protein C is kn owledge of the functional status of the endothelium and, specifically, whet her the microvasculature in patients with severe sepsis can support the con version of protein C to APC, To date, only APC (drotrecogin alfa [activated ]) has been shown to reduce mortality in severe sepsis in a large, phase 3, placebo-controlled, double-blind international trial. In contrast, no data , other than open-label case studies, are available for evaluation of the e ffects of protein C in the treatment of severe sepsis, Conclusion: The limited data available indicate that lower levels of protei n C in sepsis occur in the absence of appreciable conversion to APC, These observations indicate that treatment with APC may be more efficacious than protein C in severe sepsis, where generalized endothelial dysfunction may i mpair conversion of protein C to APC, Additional research is required to co nfirm these observations.