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Prepublished online as a Blood First Edition Paper on May 15, 2003; DOI 10.1182/blood-2003-02-0416.
Submitted February 12, 2003
Accepted April 28, 2003
Recombinant human activated protein C (rhAPC, drotrecogin alfa activated) has minimal effect on markers of coagulation, fibrinolysis and inflammation in acute human endotoxemia
Ulla Derhaschnig, Rosemarie Reiter, Paul Knobl, Magdalena Baumgartner, Priska Keen, and Bernd Jilma*
Clinical Pharmacology, University of Vienna, Vienna, Austria; Emergency Medicine, University of Vienna, Vienna, Austria
Clinical Pharmacology, University of Vienna, Vienna, Austria
Haematology and Haemostaseology, University of Vienna, Vienna, Austria
Clinical Pharmacology, University of Vienna, Vienna, Austria; Pharmacology, University of Vienna, Vienna, Austria
* Corresponding author; email: bernd.jilma{at}univie.ac.at.
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. 24 volunteers were randomized to receive either 24µg/kg/h rhAPC or placebo iv. for 8h. LPS (2ng/kg) was administered 2h after starting the infusions.
rhAPC decreased basal tissue factor (TF)-mRNA-expression, 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 nor 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.
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