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Tissue factor pathway inhibitor: the carboxy-terminus is required for
optimal inhibition of factor Xa
R Wesselschmidt, K Likert, T Girard, TC Wun and GJ Broze
Division of Hematology/Oncology, Jewish Hospital, Washington University
Medical Center, St Louis, MO 63110.
Tissue factor pathway inhibitor (TFPI) is a multivalent Kunitz-type
protease inhibitor that binds to and inactivates factor Xa directly, and in
a factor Xa-dependent fashion inhibits the factor VIIa/tissue factor
catalytic complex. TFPI is a slow, tight-binding, competitive, and
reversible inhibitor of factor Xa, in which the formation of an initial
encounter complex between TFPI and factor Xa is followed by slow
isomerization to a final, tightened complex. Wild-type recombinant TFPI
(rTFPI), expressed in mouse C127 cells, separates into two forms on
heparin-agarose chromatography that elute at 0.3 mol/L and 0.6 mol/L NaCl.
Western blot analysis shows that both forms contain the N- terminus of
full-length TFPI, but only rTFPI(0.6) is recognized by an antibody directed
against the C-terminus. rTFPI(0.3) and rTFPI(0.6) inhibit factor Xa with
1:1 stoichiometry and inhibit factor VIIa/tissue factor equally in an
endpoint-type assay. However, rTFPI(0.6) is a more potent inhibitor than
rTFPI(0.3) of coagulation in normal plasma induced by either factor Xa or
tissue factor. The initial inhibition of factor Xa (less than 5 seconds)
produced by rTFPI(0.6) is several-fold greater than that produced by
rTFPI(0.3), presumably reflecting a lower Ki of the immediate encounter
complex between factor Xa and TFPI. The differential effect of these forms
of TFPI on tissue factor-induced coagulation in normal plasma appears to be
directly related to their ability to inhibit factor Xa. To confirm the role
of the C-terminal region of TFPI in optimal factor Xa inhibition, a
carboxy-terminal mutant of rTFPI, which is truncated after leucine 252 and
thus lacks the basic sequence K T K R K R K K Q R V K (residues 254-265),
was expressed in C127 cells. This form of rTFPI elutes from heparin-agarose
at 0.28 mol/L NaCl and inhibits factor Xa at a rate that is slower than
rTFPI(0.3). The Ki(final)s for factor Xa inhibition by rTFPI(0.6),
rTFPI(0.3), and rTFPI1-252 are 3.1 +/- 0.6, 19.6 +/- 0.8, and 19.6 +/- 3.0
pmol/L, respectively.
Volume 79,
Issue 8,
pp. 2004-2010,
04/15/1992
Copyright © 1992 by The American Society of Hematology
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