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.


METHODS
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.


METHODS
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.
Grinnell
B W
BW
Division of Research Technology, Lilly Corporate Center, Indianapolis, IN 46285, USA. grinnell@lilly.com
Joyce
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D000894:Anti-Inflammatory Agents, Non-Steroidal / Q000276:immunology / Q000494:pharmacology / Q000627:therapeutic use*; D017209:Apoptosis / Q000187:drug effects / Q000502:physiology; D004730:Endothelium, Vascular / Q000187:drug effects* / Q000502:physiology*; D005343:Fibrinolytic Agents / Q000276:immunology / Q000494:pharmacology / Q000627:therapeutic use*; D006487:Hemostasis / Q000187:drug effects / Q000502:physiology; D006801:Humans; D007249:Inflammation; D009102:Multiple Organ Failure / Q000382:microbiology; D011486:Protein C / Q000276:immunology / Q000494:pharmacology / Q000627:therapeutic use*; D011994:Recombinant Proteins / Q000276:immunology / Q000494:pharmacology / Q000627:therapeutic use*; D018805:Sepsis / Q000150:complications / Q000276:immunology / Q000503:physiopathology / Q000628:therapy*; D013927:Thrombosis / Q000382:microbiology; D016896:Treatment Outcome
D000894:Anti-Inflammatory Agents, Non-Steroidal; D005343:Fibrinolytic Agents; D011486:Protein C; D011994:Recombinant Proteins; C421124:drotrecogin alfa activated