Activated protein C

Drotrecogin Alfa (activated) is the first therapeutic intervention shown to reduce all-cause mortality in severe sepsis. At 28 days 24-7% of Drotrecogin Alfa (activated) patients died versus 308% of patients treated with placebo. There was a 19 4% reduction in the relative risk of death

(numbers needed to treat =16). Significant decreases in levels of protein C have been well documented in severe sepsis. The benefit of giving activated protein C is explained by the fact that it inhibits the generation of thrombin via inactivation of factor Va and Villa. D-dimer levels are seen to decrease in the first week of infusion and rise when the infusion is stopped. Activated protein C (APC) also reduces inflammation -interleukin 6 levels are reduced in studies. it is postulated that APC inhibits neutrophil activation, cytokine release, and adhesion of cells to the vascular endothelium, and has antithrombotic activity. Reductions in risk of death were seen whether or not patients had baseline low levels of activated protein C. Bleeding was the most common adverse event -one serious bleed occurred for every 66 patients treated. This was more likely in patients with gastrointestinal ulceration, trauma to a blood vessel, injury of a vascular organ, or highly abnormal coagulation (low platelets, raised PT, and APTT), for example in liver disease.

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