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 act ivation of coagulation and to prevent death In a gram-negative bacteremia p rimate model of sepsis, It has been suggested that tissue factor influences inflammatory cascades other than the coagulation system. The authors sough t to determine the effects of 2 different doses of recombinant tissue facto r pathway inhibitor (TFPI) on endotoxin-induced coagulant, fibrinolytic, an d cytokine responses in healthy humans. Two groups, each consisting of 8 he althy men, were studied in a double-blind, randomized, placebo-controlled c rossover study. Subjects were studied on 2 different occasions. They receiv ed a bolus intravenous injection of 4 ng/kg endotoxin, which was followed b y 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 (tow-dose group), an d 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 p roinflammatory 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 coagulati on activation after high-dose TFPI. Endotoxin-induced changes in the fibrin olytic system and cytokine levels were not altered by either low-dose or hi gh-dose TFPI, The authors concluded that TFPI effectively and dose-dependen tly attenuates the endotoxin-induced coagulation activation in humans witho ut influencing the fibrinolytic and cytokine response.