Tissue factor pathway inhibitor dose-dependently inhibits coagulation activation without influencing the fibrinolytic and cytokine response during human endotoxemia.
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)
de Jonge
E
E
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.
Dekkers
P E
PE
Creasey
A A
AA
Hack
C E
CE
Paulson
S K
SK
Karim
A
A
Kesecioglu
J
J
Levi
M
M
van Deventer
S J
SJ
van Der Poll
T
T
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
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