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Physiological concentrations of tissue factor pathway inhibitor do not
inhibit prothrombinase
AE Mast and GJ Broze
Division of Laboratory Medicine, Washingon University School of Medicine,
St Louis, MO, USA.
Tissue factor pathway inhibitor (TFPI) is a Kunitz-type serine proteinase
inhibitor that directly inhibits factor Xa and, in a factor Xa dependent
manner, inhibits the factor VIIa/tissue factor catalytic complex. The
inhibitory effect of TFPI in prothrombin activation assays using purified
components of the prothrombinase complex was examined. When factor Xa is
added to mixtures containing TFPI, prothrombin, calcium ions, and
nonactivated platelets or factor V and phospholipids, TFPI significantly
reduces subsequent thrombin generation, and the inhibitory effect is
enhanced by heparin. If factor Xa is preincubated with calcium ions and
thrombin-activated platelets or factor Va and phospholipids to permit
formation of prothrombinase before the addition of prothrombin and
physiologic concentrations of TFPI (< 8 nmol/L), minimal inhibition of
thrombin generation occurs, even in the presence of heparin. Thus, contrary
to results in amidolytic assays with chromogenic substrates, prothrombinase
is resistant to inhibition by TFPI in the presence of its physiological
substrate, prothrombin. Higher concentrations of TFPI (approximately 100
nmol/L), similar to those used in animal studies testing for therapeutic
actions of TFPI, do effectively block prothrombinase activity.
Volume 87,
Issue 5,
pp. 1845-1850,
03/01/1996
Copyright © 1996 by The American Society of Hematology
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