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: