title: The effects of supra-normal protein C levels on markers of coagulation, fibrinolysis and inflammation in a human model of endotoxemia.
abstract: The protein C pathway serves as a modulating system with both anti-inflammatory and anticoagulant properties and is intimately involved in the pathophysiology of inflammation and sepsis. Treatment with recombinant human activated protein C (rhAPC) can reduce the mortality of severe sepsis. We investigated whether an elevation of plasma protein C levels to supra-normal levels by infusion of a protein C zymogen concentrate has an effect on coagulation, protein C activation or inflammation in a human endotoxemia model. Eleven healthy male volunteers were enrolled in a double-blind, placebo-controlled two-way cross-over trial. Ten minutes after infusion of 2ng/kg endotoxin each volunteer received either placebo or a plasma-derived protein C zymogen concentrate (Ceprotin, Baxter) (150 U/kg as a slow bolus infusion followed by 30 U/kg/h continuous infusion until 4 hours after LPS-infusion). Protein C antigen and activity increased 4- to 5-fold after infusion of the concentrate. APC was generated during endotoxin-induced inflammation in the placebo (1.6 fold increase) and the protein C period (4.0-fold increase). The increase of APC levels correlated with the TNF-alpha and IL-6 release in both periods (r = 0.65-0.68; p < 0.05) and paralleled the protein C antigen and activity levels in the period with supranormal protein C levels. Supra normal protein C levels resulted in slightly, although non-significant, lower tissue factor mRNA expression and thrombin generation (TAT, F1+2). Systemic inflammation (TNF-alpha, IL-6) was not influenced by protein C zymogen concentrate administration. Infusion of protein C zymogen was safe and no adverse effects occurred. The increase of protein C levels several fold above the normal range resulted in a proportional increase of the APC levels, but had no major anticoagulant, anti-inflammatory or profibrinolytic effects. Low grade endotoxemia itself induces significant protein C activation, which correlates with the TNF release.
authors.affiliation: Departments of Clinical Pharmacology, Medical University of Vienna, Vienna, Austria.
authors.forename: Alexander O
authors.initials: AO
authors.lastname: Spiel
authors.forename: Christa
authors.initials: C
authors.lastname: Firbas
authors.forename: Florian B
authors.initials: FB
authors.lastname: Mayr
authors.forename: Judith M
authors.initials: JM
authors.lastname: Leitner
authors.forename: Bily
authors.initials: B
authors.lastname: Schmidt
authors.forename: Paul
authors.initials: P
authors.lastname: Knöbl
authors.forename: Katalin
authors.initials: K
authors.lastname: Varadi
authors.forename: Bernd
authors.initials: B
authors.lastname: Jilma
mesh_terms: D000328:Adult; D001777:Blood Coagulation / Q000187:drug effects*; D018592:Cross-Over Studies; D004311:Double-Blind Method; D019446:Endotoxemia / Q000097:blood* / Q000139:chemically induced; D004731:Endotoxins / Q000008:administration & dosage; D005341:Fibrinolysin / Q000378:metabolism; D005342:Fibrinolysis / Q000187:drug effects*; D006801:Humans; D007249:Inflammation / Q000097:blood* / Q000139:chemically induced; D007262:Infusions, Intravenous; D015850:Interleukin-6 / Q000097:blood; D008297:Male; D009000:Monocytes / Q000187:drug effects / Q000378:metabolism; D015539:Platelet Activation / Q000187:drug effects; D011486:Protein C / Q000008:administration & dosage* / Q000493:pharmacokinetics; D012333:RNA, Messenger / Q000378:metabolism*; D013917:Thrombin / Q000378:metabolism; D013925:Thromboplastin / Q000235:genetics / Q000378:metabolism; D014409:Tumor Necrosis Factor-alpha / Q000378:metabolism
chemical_list: D004731:Endotoxins; D015850:Interleukin-6; D011486:Protein C; D012333:RNA, Messenger; D014409:Tumor Necrosis Factor-alpha; C044101:endotoxin, Escherichia coli; D013925:Thromboplastin; D013917:Thrombin; D005341:Fibrinolysin