Recombinant human activated protein C (rhAPC; drotrecogin alfa [activated]) has minimal effect on markers of coagulation, fibrinolysis, and inflammation in acute human endotoxemia.
Inflammatory and procoagulant host responses are closely related in sepsis. The protein C pathway serves as a regulatory pathway with anti-inflammatory and anticoagulant properties. Recently, recombinant human activated protein C (rhAPC) was shown to reduce mortality in severe sepsis. Nevertheless, the effects of rhAPC in humans are still ill defined. The infusion of low endotoxin doses into humans provides a standardized model to study inflammatory and hemostatic mechanisms. Thus, we investigated whether rhAPC acts as an anticoagulant or anti-inflammatory drug in human endotoxemia. There were 24 volunteers randomized to receive either 24 microg/kg per hour rhAPC or placebo intravenously for 8 hours. Lipopolysaccharide (LPS, 2 ng/kg) was administered 2 hours after starting the infusions. rhAPC decreased basal tissue factor (TF)-mRNA expression, and thrombin formation and action. In contrast, rhAPC did not significantly blunt LPS-induced thrombin generation. Consistently, rhAPC did not reduce LPS-induced levels of TF-mRNA or D-dimer and had no effect on fibrinolytic activity or inflammation. Finally, endogenous APC formation was enhanced during endotoxemia and appeared to be associated with inflammation rather than thrombin formation. In conclusion, even low-grade endotoxemia induces significant protein C activation. Infusion of rhAPC decreases "spontaneous" activation of coagulation but does not blunt LPS-induced, TF-mediated coagulation in healthy volunteers, which is in contrast to a number of anticoagulants.
Department of Clinical Pharmacology, University of Vienna, Währinger Gürtel 18-20, A-1090 Vienna, Austria.
Ulla
U
Derhaschnig
Rosemarie
R
Reiter
Paul
P
Knöbl
Magdalena
M
Baumgartner
Priska
P
Keen
Bernd
B
Jilma
D000208:Acute Disease; D000293:Adolescent; D000328:Adult; D015415:Biomarkers; D001777:Blood Coagulation / Q000187:drug effects*; D001794:Blood Pressure / Q000187:drug effects; D004730:Endothelium, Vascular / Q000276:immunology / Q000378:metabolism; D019446:Endotoxemia / Q000139:chemically induced / Q000188:drug therapy* / Q000276:immunology; D005342:Fibrinolysis / Q000187:drug effects*; D005343:Fibrinolytic Agents / Q000008:administration & dosage* / Q000493:pharmacokinetics; D006339:Heart Rate / Q000187:drug effects; D006801:Humans; D008070:Lipopolysaccharides; D008297:Male; D010314:Partial Thromboplastin Time; D010973:Platelet Adhesiveness / Q000187:drug effects; D011486:Protein C / Q000008:administration & dosage* / Q000378:metabolism / Q000493:pharmacokinetics; D011994:Recombinant Proteins / Q000008:administration & dosage* / Q000493:pharmacokinetics
D015415:Biomarkers; D005343:Fibrinolytic Agents; D008070:Lipopolysaccharides; D011486:Protein C; D011994:Recombinant Proteins; C421124:drotrecogin alfa activated