Summary
In the jugular vein of rabbits thrombus formation was induced by vessel wall damage
using a balloon catheter and following reduction of blood flow by 80-90% for 60 min
(partial stasis). The blood flow in the vein was measured continuously and the incidence
of primary thrombus formation, the time until lysis with recombinant tissue-type plasminogen
activator (rt-PA) as well as the incidence of rethrombosis after lysis were determined.
At the end of the experiment the wet weight of the thrombus formed inside the vessel
was measured. For the determination of haemostaseological parameters blood was drawn
from the cannulated femoral artery.
Recombinant full-length tissue factor pathway inhibitor (TFPI) was studied with regard
to its effect both on primary thrombus formation and on rethrombosis after lysis.
In control animals damage of the vessel wall combined with partial stasis led to the
formation of occlusive venous thrombi. In vitro bolus injection of TFPI (5,10,20 Μg/kg)
at the time of thrombus induction prevented the formation of venous thrombi during
the 1 h period of partial stasis. In the subsequent observation period a dose-dependent
inhibition of later occurring partial or complete thrombotic occlusion was found.
At the dose of 20 Μg/kg i.v. in all animals TFPI prevented a complete thrombotic occlusion
of the vein up to 3 h after stasis. To study the effectiveness of TFPI on rethrombosis
after lysis TFPI was injected i.v. after lysis of the thrombus with rt-PA (600 Μg/kg
i.v. bolus + 600 Μg/kg i.v. infusion over 60 min). In saline treated control rabbits
a reocclusion of the vessel was seen in 8 of 10 animals. TFPI (10, 20, 40 Μg/kg i.v.)
injected at the end of rt-PA administration caused a dose-dependent inhibition of
thrombotic reocclusion after lysis. At 40 Μg/kg i.v. the formation of occlusive thrombi
was prevented up to 3 h after lysis. TFPI at the doses used caused modest anticoagulant
effects in global clotting assays; activated partial thromboplastin time (APTT), prothrombin
time (PT) and thrombin time (TT) were only slightly prolonged. A clear and dose-dependent
prolongation of clotting times was only seen in the Heptest® assay.
The results show that the physiologic coagulation inhibitor TFPI acts as a strong
antithrombotic agent in an experimental model of venous thrombus formation and thrombotic
reocclusion after lysis in rabbits.
