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The effect of leukocyte elastase on tissue factor pathway inhibitor
DA Higuchi, TC Wun, KM Likert and GJ Broze
Department of Medicine, Jewish Hospital, Washington University Medical
Center, St Louis, MO 63110.
Tissue factor pathway inhibitor (TFPI) is a multivalent Kunitz-type
inhibitor that directly inhibits factor Xa and, in a factor Xa- dependent
fashion, also inhibits the factor VIIa/tissue factor (TF) catalytic
complex. The Kunitz-2 domain in TFPI is needed for the binding and
inhibition of factor Xa, while the Kunitz-1 domain appears to be
responsible for binding factor VIIa in a quaternary factor Xa- TFPI-factor
VIIa/TF inhibitory complex. Human leukocyte elastase (HLE) proteolytically
cleaves TFPI between threonine-87 and threonine-88 within the polypeptide
that links the Kunitz-1 and Kunitz-2 domains in the TFPI molecule. HLE
treatment not only affects the ability of TFPI to inhibit factor VIIa/TF,
but also dramatically reduces its inhibition of factor Xa. Both purified
HLE and stimulated neutrophils regenerate TF activity from a preformed
factor Xa-TFPI-factor VIIa/TF inhibitory complex. Kinetic analysis suggests
that HLE cleavage does not effect the affinity of the initial encounter
interaction between factor Xa and TFPI, whereas it markedly reduces the
affinity of the final factor Xa:TFPI complex with Ki (final) values for
untreated and HLE-treated TFPI of 58 pmol/L and 4.4 nmol/L, respectively.
Thus, an epitope in the amino-terminal region of TFPI or a conformation of
the TFPI molecule that requires the presence of this region is needed in
concert with the Kunitz-2 domain to produce optimal inhibition of factor Xa
by TFPI.
Volume 79,
Issue 7,
pp. 1712-1719,
04/01/1992
Copyright © 1992 by The American Society of Hematology
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