Endogenous protein C activation in patients with severe sepsis

OBJECTIVE: To review how endogenous protein C activation might change in disease states and to discuss the implications of these findings in the context of severe sepsis. DATA SOURCE: A review of the published literature in PubMed together with data from abstracts from 2001 to present. DATA EXTRACTION AND SYNTHESIS: Activated protein C (APC) supplementation has been shown to significantly reduce mortality in patients with severe sepsis, presumably by virtue of its ability to down-regulate coagulation, inflammation, and apoptosis. In vivo, endogenous APC is generated in the circulation when protein C is activated by the thrombin-thrombomodulin complex. Protein C activation is augmented by the endothelial cell protein C receptor. Thus, thrombomodulin and the endothelial cell protein C receptor are components of the endothelium-based "machinery" required for efficient activation of protein C. In healthy individuals, the amount of APC formed is proportional to thrombin levels. In vitro studies have shown that thrombomodulin and the endothelial cell protein C receptor are down-regulated by inflammatory cytokines, and the levels of these receptors are reduced in the endothelium of skin-biopsy specimens in children with severe meningococcal sepsis. However, endothelial studies of excised blood vessels provide only a partial picture of the APC pathway in vivo. Knowledge of endogenous plasma levels of protein C, thrombin, and APC may be helpful in assessing the functional status of the protein C pathway in the systemic circulation. To date, there are few reports available on endogenous APC levels in patients with severe sepsis, perhaps due to the lack of available assays that permit both rapid and accurate measurements. A unique feature of our study is that we have developed an APC assay that, for the first time, permits rapid and accurate measurements of plasma APC levels. Preliminary studies using this assay suggest that adult patients with severe sepsis vary markedly in their ability to generate APC endogenously. These results are intriguing because they suggest that, depending on individual defects in the protein C pathway, some patients have impaired protein C activation and might require APC therapy, whereas others may benefit from administration of protein C. Although the clinical efficacy of recombinant human APC (drotrecogin alfa [activated]) in severe sepsis has been reported in a phase III clinical trial, the efficacy of protein C in severe sepsis remains to be determined. CONCLUSIONS: Preliminary results suggest that adult patients with severe sepsis vary markedly in their ability to convert endogenous protein C to APC. Additional research is required to establish whether endogenous APC activation profiles are useful in the clinical management of patients with severe sepsis.