title: Tissue factor pathway inhibitor dose-dependently inhibits coagulation activation without influencing the fibrinolytic and cytokine response during human endotoxemia.
abstract: Inhibition of the tissue factor pathway has been shown to attenuate the activation of coagulation and to prevent death in a gram-negative bacteremia primate model of sepsis. It has been suggested that tissue factor influences inflammatory cascades other than the coagulation system. The authors sought to determine the effects of 2 different doses of recombinant tissue factor pathway inhibitor (TFPI) on endotoxin-induced coagulant, fibrinolytic, and cytokine responses in healthy humans. Two groups, each consisting of 8 healthy men, were studied in a double-blind, randomized, placebo-controlled crossover study. Subjects were studied on 2 different occasions. They received a bolus intravenous injection of 4 ng/kg endotoxin, which was followed by a 6-hour continuous infusion of TFPI or placebo. Eight subjects received 0.05 mg/kg per hour TFPI after a bolus of 0.0125 mg/kg (low-dose group), and 8 subjects received 0.2 mg/kg per hour after a bolus of 0.05 mg/kg (high-dose group). Endotoxin injection induced the activation of coagulation, the activation and subsequent inhibition of fibrinolysis, and the release of proinflammatory and antiinflammatory cytokines. TFPI infusion induced a dose-dependent attenuation of thrombin generation, as measured by plasma F1 + 2 and thrombin-antithrombin complexes, with a complete blockade of coagulation activation after high-dose TFPI. Endotoxin-induced changes in the fibrinolytic system and cytokine levels were not altered by either low-dose or high-dose TFPI. The authors concluded that TFPI effectively and dose-dependently attenuates the endotoxin-induced coagulation activation in humans without influencing the fibrinolytic and cytokine response. (Blood. 2000;95:1124-1129)
authors.affiliation: Department of Intensive Care, Laboratory of Experimental Internal Medicine, Academic Medical Center, University of Amsterdam, Central Laboratory of the Red Cross Blood Transfusion Service, Amsterdam, The Netherlands.
authors.forename: E
authors.initials: E
authors.lastname: de Jonge
authors.forename: P E
authors.initials: PE
authors.lastname: Dekkers
authors.forename: A A
authors.initials: AA
authors.lastname: Creasey
authors.forename: C E
authors.initials: CE
authors.lastname: Hack
authors.forename: S K
authors.initials: SK
authors.lastname: Paulson
authors.forename: A
authors.initials: A
authors.lastname: Karim
authors.forename: J
authors.initials: J
authors.lastname: Kesecioglu
authors.forename: M
authors.initials: M
authors.lastname: Levi
authors.forename: S J
authors.initials: SJ
authors.lastname: van Deventer
authors.forename: T
authors.initials: T
authors.lastname: van Der Poll
mesh_terms: D000328:Adult; D000925:Anticoagulants / Q000008:administration & dosage / Q000494:pharmacology*; D000990:Antithrombin III / Q000378:metabolism; D001777:Blood Coagulation / Q000187:drug effects*; D001794:Blood Pressure / Q000187:drug effects; D001831:Body Temperature / Q000187:drug effects; D018592:Cross-Over Studies; D016207:Cytokines / Q000097:blood*; D004311:Double-Blind Method; D004334:Drug Administration Schedule; D019446:Endotoxemia / Q000097:blood* / Q000188:drug therapy / Q000276:immunology; D004927:Escherichia coli Infections / Q000097:blood / Q000188:drug therapy / Q000276:immunology; D005342:Fibrinolysis / Q000187:drug effects; D006339:Heart Rate / Q000187:drug effects; D006801:Humans; D007262:Infusions, Intravenous; D007275:Injections, Intravenous; D008070:Lipopolysaccharides / Q000008:administration & dosage; D008074:Lipoproteins / Q000008:administration & dosage / Q000494:pharmacology*; D008297:Male; D010447:Peptide Hydrolases / Q000378:metabolism; D017395:Plasminogen Activator Inhibitor 1 / Q000097:blood
chemical_list: D000925:Anticoagulants; D016207:Cytokines; D008070:Lipopolysaccharides; D008074:Lipoproteins; D017395:Plasminogen Activator Inhibitor 1; C046193:antithrombin III-protease complex; C051928:lipoprotein-associated coagulation inhibitor; D000990:Antithrombin III; D010447:Peptide Hydrolases