Recombinant human activated protein C: a system modulator of vascular function for treatment of severe sepsis.

OBJECTIVE: To review the mechanisms of action and rationale for the use of recombinant human activated protein C in the treatment of severe sepsis. Specifically, we focus on the mechanisms of action in the protein C pathway that converge to modulate the pathophysiology of severe inflammatory disease and sepsis. This analysis includes a discussion of the role of activated protein C in directly modulating cell system biology, independent of antithrombotic activity.

DATA SOURCES/STUDY SELECTION: Published research and review articles relating to the protein C pathway, recombinant human protein C, and the role of protein C in sepsis. Data were also derived from broad gene profiling in model systems of endothelial dysfunction.

DATA EXTRACTION AND SYNTHESIS: Relevant studies were included to support discussion of the unique mechanistic aspect of protein C and its role in the pathogenesis of severe sepsis. We discuss the potential of activated protein C as a unique system modulator for the treatment of severe sepsis and other systemic inflammatory responses that result in microvascular coagulopathy, endothelial dysfunction, and vascular bed failure.

CONCLUSIONS: The protein C pathway plays a unique role in modulating vascular function. As an antithrombotic/profibrinolytic agent, it plays a clear role in maintaining vascular patency. Moreover, it has anti-inflammatory properties and appears to play a unique role as an antiapoptotic and endothelial cell survival factor. In states of systemic inflammatory activation, loss of protein C due to consumptive processes results in a compromised ability to modulate coagulation as well as inflammatory and cell survival functions. This compromise leads to vascular dysfunction, end-organ failure, and death. Replacement with recombinant human activated protein C offers a system-modulating approach to improved outcome.