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The lipoprotein-associated coagulation inhibitor that inhibits the factor
VII-tissue factor complex also inhibits factor Xa: insight into its
possible mechanism of action
GJ Broze , LA Warren, WF Novotny, DA Higuchi, JJ Girard and JP Miletich
Division of Hematology/Oncology, Washington University School of Medicine,
Jewish Hospital, St Louis, MO 63110.
Blood coagulation is initiated when plasma factor VII(a) binds to its
essential cofactor tissue factor (TF) and proteolytically activates factors
X and IX. Progressive inhibition of TF activity occurs upon its addition to
plasma. This process is reversible and requires the presence of VII(a),
catalytically active Xa, Ca2+, and another component that appears to be
associated with the lipoproteins in plasma, a lipoprotein-associated
coagulation inhibitor (LACI). A protein, LACI(HG2), possessing the same
inhibitory properties as LACI, has recently been isolated from the
conditioned media of cultured human liver cells (HepG2). Rabbit antisera
raised against a synthetic peptide based on the N-terminal sequence of
LACI(HG2) and purified IgG from a rabbit immunized with intact LACI(HG2)
inhibit the LACI activity in human serum. In a reaction mixture containing
VIIa, Xa, Ca2+, and purified LACI(HG2), the apparent half-life (t1/2) for
TF activity was 20 seconds. The presence of heparin accelerated the initial
rate of inhibition threefold. Antithrombin III alpha alone had no effect,
but antithrombin III alpha with heparin abrogated the TF inhibition.
LACI(HG2) also inhibited Xa with an apparent t1/2 of 50 seconds. Heparin
enhanced the rate of Xa inhibition 2.5-fold, whereas phospholipids and Ca2+
slowed the reaction 2.5-fold. Xa inhibition was demonstrable with both
chromogenic substrate (S-2222) and bioassays, but no complex between Xa and
LACI(HG2) could be visualized by sodium dodecyl sulfate-polyacrylamide gel
electrophoresis (SDS-PAGE). Nondenaturing PAGE, however, showed that
LACI(HG2) bound to Xa but not to X or Xa inactivated by diisopropyl
fluorophosphate. Thus, LACI(HG2) appears to bind to Xa at or near its
active site. Bovine factor Xa lacking its gamma-carboxyglutamic
acid-containing domain, BXa(-GD), through treatment with
alpha-chymotrypsin, was used to further investigate the Xa requirement for
VIIa/TF inhibition by LACI(HG2). LACI(HG2) bound to BXa(-GD) and inhibited
its catalytic activity against a small molecular substrate (Spectrozyme
Xa), though at a rate approximately sevenfold slower than native BXa.
Preincubation of LACI(HG2) with saturating concentrations of BXa(-GD)
markedly retarded the subsequent inhibition of BXa. The VII(a)/TF complex
was not inhibited by LACI(HG2) in the presence of BXa(-GD), and further,
preincubation of LACI(HG2) with BXa(-GD) slowed the inhibition of VIIa/TF
after the addition of native Xa. The results are consistent with the
hypothesis that inhibition of VII(a)/TF involves the formation of a
VIIa-TF-XA-LACI complex that requires the GD of XA.(ABSTRACT TRUNCATED AT
400 WORDS)
Volume 71,
Issue 2,
pp. 335-343,
02/01/1988
Copyright © 1988 by The American Society of Hematology
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