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Blood, Vol. 95 No. 4 (February 15), 2000:
pp. 1124-1129
Tissue factor pathway inhibitor dose-dependently inhibits
coagulation activation without influencing the fibrinolytic and
cytokine response during human endotoxemia
Evert de Jonge,
Pascale E. P. Dekkers,
Abla A. Creasey,
C. Erik Hack,
Susan K. Paulson,
Aziz Karim,
Jozef Kesecioglu,
Marcel Levi,
Sander J. H. van Deventer, and
Tom van der Poll
From the Department of Intensive Care, Laboratory of Experimental
Internal Medicine, and the Department of Vascular Medicine, Academic
Medical Center, University of Amsterdam, Central Laboratory of the Red
Cross Blood Transfusion Service, Amsterdam, The Netherlands; Searle
Research & Development, Skokie, IL; and Chiron Corporation, Emeryville,
CA.
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.
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