The glycosylated multivalent three-domain Kunitz inhibitor
TFPI is a natural inhibitor of
tissue factor-FVIIa complex in the presence of FXa.
TFPI has an experimental antithrombotic capacity indistinguishable from
LMWH in a prophylactic dose, regardless of glycosylation and of the third domain. An inherited equilibrium between antithrombosis and haemorrhage exists. The aim of the study was to evaluate whether a two-domain non-glycosylated
TFPI (117QTFPI1-161) has a
bleeding potential in a rat gastric mucosa model. Groups; placebo,
LMWH (
tinzaparin) 60 and 250 anti-Xa IU/kg and 117 QTFPI1-161 1.0 and 10.0 mg/kg, given i.v. (bolus injection), randomised double dummy design. All actively treated groups significantly prolonged both the
bleeding volume (493-984 microliters) and the bleeding time (10-20 min) compared to placebo (41 microliters, 2 min). It was not possible to distinguish a difference between the lower dose of
LMWH and 117QTFPI1-161 in either parameter (p = 0.23-0.71). The two doses of 117QTFPI1-161 caused elevation of plasma-
TFPI, 18 and 150 times baseline value. Both
LMWH doses (0.6-3.2 anti-Xa IU/ml) and both 117QTFPI1-161 doses (0.2-2.7 anti-Xa IU/ml), caused significant effect in the anti-Xa assay, however 117QTFPI1-161 significantly less. Only the largest dose of 117QTFPI1-161 caused significant prolongation in the APTT assay (34 s). Both doses of
LMWH caused significant prolongation (60-300 s).
LMWH was the only substance to prolong the dilute-PT assay. Non-glycosylated two-domain 1.0 mg/kg
TFPI, yielding supraphysiological plasma concentration, has an experimental haemorrhagic potential indistinguishable from
LMWH in a prophylactic dose. The effect mediated by this type of
TFPI could primarily be due to an inhibition of FXa.