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Tissue factor pathway inhibitor blocks cellular effects of endotoxin by
binding to endotoxin and interfering with transfer to CD14
CT Park, AA Creasey and SD Wright
Laboratory of Cellular Physiology and Immunology, The Rockefeller
University, New York, NY 10021, USA.
Tissue factor pathway inhibitor (TFPI) is a Kunitz-type plasma protease
inhibitor that inhibits factor Xa and the factor VIIa/tissue factor
catalytic complex. It plays an important role in feedback inhibition of the
coagulation cascade (Broze, Annu Rev Med 46:103, 1995). TFPI has also been
used successfully to prevent lethality and attenuate coagulopathic
responses in a baboon model of septic shock (Creasey et al, J Clin Invest
91:2850, 1993; and Carr et al, Circ Shock 44:126, 1995). However, the
mechanism of reduced mortality in these animals could not be explained
merely by the anticoagulant effect of TFPI, because TFPI-treated animals
also had a significantly depressed interleukin-6 response. Moreover,
inhibition of coagulopathic responses by other anticoagulants has failed to
block the organ damage or lethal effect of endotoxic shock (Coalson et al,
Circ Shock 5:423, 1978; Warr et al, Blood 75:1481, 1990; and Taylor et al,
Blood 78:364, 1991). We show here that recombinant TFPI can bind to
endotoxin in vitro. This binding prevents interaction of endotoxin with
both lipopolysaccharide binding protein and CD14, thereby blocking cellular
responses.
Volume 89,
Issue 12,
pp. 4268-4274,
06/15/1997
Copyright © 1997 by The American Society of Hematology
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