Treatments for severe sepsis involving protein C/activated protein C pathway

Objective To review the results of treatments for severe sepsis involving the protein C/activated protein C pathway. Data Source Published research and review articles (PubMed, from 1985 to 2003) relating to compounds involving the protein C pathway. Results Protein C is converted to activated protein C when thrombin complexes with thrombomodulin. Sepsis is associated with rapid depletion of protein C and blunted endogenous protein C activation. A phase III trial of recombinant human activated protein C (drotrecogin alfa [activated]) in severe sepsis demonstrated a 6.1% absolute reduction in 28-day mortality compared with placebo. The short- and long-term survival rates associated with drotrecogin alfa (activated) were better in patients at high risk of death associated with a better cost/effectiveness ratio. Treatment with drotrecogin alfa (activated) was associated with an increased risk of serious bleeding compared with placebo during the 28-day study period (3.5% vs. 2.0%). Conclusions Treatment with drotrecogin alfa (activated) leads to substantial reduction in mortality and has an acceptable risk/benefit ratio in septic patients at high risk of death. however, a large trial involving a high dose is required to determine its effect on mortality and morbidity.