title: Protein C/activated protein C pathway: overview of clinical trial results in severe sepsis.
abstract: OBJECTIVE
  To review the results from clinical trials of treatments for severe sepsis involving the protein C/activated protein C pathway.
  
  
  METHODS
  Published research and review articles (PubMed, from 1985 to 2003) relating to clinical trials of compounds involving the protein C pathway.
  
  
  METHODS
  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. Treatment with protein C concentrate is followed by increased activated protein C plasma levels and a dose-dependent decrease in d-dimer levels in children with purpura fulminans. This supplementation is safe. 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 protein C concentrate is followed by an improvement of the coagulopathy and is safe in children with purpura fulminans; however, a large trial involving a high dose is required to determine its effect on mortality and morbidity. 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.
authors.affiliation: Intensive Care and Emergency Department, Cochin University-Hospital, AP-HP, University of Paris 5, Paris, France.
authors.forename: Jean-François
authors.initials: JF
authors.lastname: Dhainaut
authors.forename: S Betty
authors.initials: SB
authors.lastname: Yan
authors.forename: Yann-Erick
authors.initials: YE
authors.lastname: Claessens
mesh_terms: D002986:Clinical Trials as Topic; D006801:Humans; D011486:Protein C / Q000502:physiology / Q000627:therapeutic use*; D011994:Recombinant Proteins / Q000627:therapeutic use; D018805:Sepsis / Q000188:drug therapy* / Q000276:immunology; D012720:Severity of Illness Index
chemical_list: D011486:Protein C; D011994:Recombinant Proteins