title: Effect of factor X inhibition on coagulation activation and cytokine induction in human systemic inflammation.
abstract: Anticoagulants have gained increasing attention in the treatment of sepsis. This study used danaparoid to investigate the role of factor Xa in endotoxin-induced coagulation and inflammation and its effectiveness when coagulation activation has already occurred. Thirty healthy volunteers were enrolled in the randomized, placebo-controlled trial. Subjects received 2 ng/kg endotoxin and danaparoid 10 min or 3 h thereafter or placebo. Endotoxin increased prothrombin fragment 1+2 (F(1+2)) levels from 0.5 to 7.0 nmol/L at 5 h in the placebo group. Early danaparoid infusion inhibited endotoxin-induced thrombin formation: maximum F(1+2) levels reached only 1.8 nmol/L (P<.01, vs. baseline or placebo). Delayed danaparoid infusion effectively blocked further thrombin formation. However, danaparoid did not alter endotoxin-induced changes in the fibrinolytic system, cytokine levels, activation of leukocytes, or tissue factor expression on monocytes. Danaparoid therefore selectively attenuates endotoxin-induced coagulopathy, even with delayed administration when coagulation activation is well under way.
authors.affiliation: Department of Clinical Pharmacology, Division of Infectious Diseases, Hanusch Krankenhaus, University of Tromso, Tromso, Norway.
authors.forename: Ursula M
authors.initials: UM
authors.lastname: Hollenstein
authors.forename: Thomas
authors.initials: T
authors.lastname: Pernerstorfer
authors.forename: Monika
authors.initials: M
authors.lastname: Homoncik
authors.forename: John B
authors.initials: JB
authors.lastname: Hansen
authors.forename: Haike
authors.initials: H
authors.lastname: Finzen
authors.forename: Sylvia
authors.initials: S
authors.lastname: Handler
authors.forename: Bernd
authors.initials: B
authors.lastname: Jilma
mesh_terms: D000328:Adult; D000925:Anticoagulants / Q000494:pharmacology*; D001777:Blood Coagulation / Q000187:drug effects / Q000502:physiology*; D018932:Chemokine CCL2 / Q000097:blood; D002809:Chondroitin Sulfates / Q000494:pharmacology*; D016207:Cytokines / Q000235:genetics*; D003871:Dermatan Sulfate / Q000494:pharmacology*; D004338:Drug Combinations; D004731:Endotoxins / Q000276:immunology / Q000633:toxicity; D005170:Factor X / Q000037:antagonists & inhibitors*; D006497:Heparan Sulfate / Q000494:pharmacology*; D006801:Humans; D007249:Inflammation / Q000139:chemically induced / Q000276:immunology*; D015850:Interleukin-6 / Q000097:blood; D007700:Kinetics; D008070:Lipopolysaccharides / Q000633:toxicity*; D010865:Pilot Projects; D012016:Reference Values; D000979:alpha-2-Antiplasmin / Q000378:metabolism
chemical_list: D000925:Anticoagulants; D018932:Chemokine CCL2; D002809:Chondroitin Sulfates; D016207:Cytokines; D003871:Dermatan Sulfate; D004338:Drug Combinations; D004731:Endotoxins; D005170:Factor X; D006497:Heparan Sulfate; D015850:Interleukin-6; D008070:Lipopolysaccharides; D000979:alpha-2-Antiplasmin; C035838:danaparoid