Activated protein C in sepsis: the promise of nonanticoagulant activated protein C

Purpose of review To discuss the potential use of recombinant activated protein C (aPC) variants with altered bioactivity in sepsis therapy. Recent findings Since the initial Protein C Worldwide Evaluation in Severe Sepsis trial demonstrating efficacy of aPC therapy to reduce mortality of severe sepsis, follow-up studies have failed to resolve concerns about the low overall risk-to-benefit ratio of this therapy and suggest that it might only be effective in severely ill patients with the most aggravated forms of coagulopathy. New studies begin to shed light on the potential mechanisms of how aPC therapy may alter sepsis outcome, and how recombinant aPC variants with altered bioactivities may improve the efficacy and safety of this therapy. Summary aPC variants with selectively diminished antithrombotic activity, but normal cytoprotective potential, may allow more efficient dosing without increasing adverse bleeding effects and therefore provide a safer and possibly more efficient alternative to normal aPC. Critical questions about the precise mechanisms by which aPC therapy reduces mortality remain to be resolved in order to identify patients most likely to benefit from it and to reevaluate potential efficacy of aPC therapy in children and patients with less than severe sepsis.