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Binding of factor VIIa to tissue factor permits rapid antithrombin
III/heparin inhibition of factor VIIa
LV Rao, SI Rapaport and AD Hoang
Department of Medicine, University of California, San Diego, La Jolla.
Because free factor VIIa is inactivated only very slowly by a plasma
concentration of antithrombin III (AT III) even in the presence of heparin,
it has been assumed that AT III plays no significant role in regulating the
initiation of tissue factor-dependent blood coagulation. However, in the
present study, we present evidence that factor VIIa bound to tissue factor,
unlike free factor VIIa, is readily inactivated by AT III in the presence
of heparin. In a reaction mixture containing calcium ions and approximately
equimolar concentrations of relipidated tissue factor (8.9 nmol/L) and
factor VIIa (10 nmol/L), AT III (100 micrograms/mL) plus heparin (1 U/mL)
inhibited 50% of the factor VIIa coagulant activity of the reaction mixture
within 5 minutes. AT III/heparin was also shown to inhibit the catalytic
activity towards factor X of factor VIIa/tissue factor complexes formed on
monolayers of an ovarian carcinoma cell line (OC-2008) that constitutively
expresses surface membrane tissue factor. AT III, even in the absence of
exogenously added heparin, substantially inhibited the functional activity
of factor VIIa/cell surface tissue factor complexes on intact monolayers.
AT III alone and AT III/heparin, to a greater extent, also inhibited factor
VIIa on "nonfunctional" factor VIIa/tissue factor complexes on intact
monolayers, with resultant inhibition of their expression of factor
VIIa/tissue factor catalytic activity toward factor X after cell lysis. The
potential physiologic significance of these findings is discussed.
Volume 81,
Issue 10,
pp. 2600-2607,
05/15/1993
Copyright © 1993 by The American Society of Hematology
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