Summary

The protein C pathway serves as a modulating system with bothanti-inflammatory and anticoagulant properties and is intimatelyinvolved in the pathophysiology of inflammation and sepsis.Treatment with recombinant human activated protein C(rhAPC) can reduce the mortality of severe sepsis.We investigatedwhether an elevation of plasma protein C levels to supranormallevels by infusion of a protein C zymogen concentratehas an effect on coagulation, protein C activation or inflammationin a human endotoxemia model. Eleven healthy malevolunteers were enrolled in a double-blind, placebo-controlledtwo-way cross-over trial. Ten minutes after infusion of 2ng/kgendotoxin each volunteer received either placebo or a plasmaderivedprotein C zymogen concentrate (Ceprotin® , Baxter)(150 U/kg as a slow bolus infusion followed by 30 U/kg/h continuousinfusion until 4 hours after LPS-infusion). Protein Cantigen and activity increased 4– to 5-fold after infusion of the concentrate. APC was generated during endotoxin-inducedinflammation in the placebo (1.6 fold increase) and the protein Cperiod (4.0-fold increase).The increase of APC levels correlatedwith the TNF- a and IL-6 release in both periods (r=0.65–0.68;p<0.05) and paralleled the protein C antigen and activity levels inthe period with supranormal protein C levels.Supra normal proteinC levels resulted in slightly, although non-significant, lowertissue factor mRNA expression and thrombin generation (TAT,F1+2). Systemic inflammation (TNF- a , IL-6) was not influencedby protein C zymogen concentrate administration. Infusion ofprotein C zymogen was safe and no adverse effects occurred.The increase of protein C levels several fold above the normalrange resulted in a proportional increase of the APC levels, buthad no major anticoagulant, anti-inflammatory or profibrinolyticeffects. Low grade endotoxemia itself induces significant proteinC activation, which correlates with the TNF release.