Recombinant full-length tissue factor pathway inhibitor (TFPI) prevents thrombus formation and rethrombosis after lysis in a rabbit model of jugular vein thrombosis.
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 micrograms/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 micrograms/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 micrograms/kg i.v. bolus + 600 micrograms/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 micrograms/kg i.v.) injected at the end of rt-PA administration caused a dose-dependent inhibition of thrombotic reocclusion after lysis. At 40 micrograms/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.
Friedrich Schiller University Jena, Medical Faculty, Erfurt, Germany.
B
B
Kaiser
J
J
Fareed
D000818:Animals; D000925:Anticoagulants / Q000627:therapeutic use*; D004195:Disease Models, Animal; D005260:Female; D005343:Fibrinolytic Agents / Q000627:therapeutic use*; D007601:Jugular Veins / Q000187:drug effects; D008074:Lipoproteins / Q000627:therapeutic use*; D011817:Rabbits; D011994:Recombinant Proteins / Q000627:therapeutic use; D012008:Recurrence; D013924:Thrombophlebitis / Q000188:drug therapy / Q000517:prevention & control*
D000925:Anticoagulants; D005343:Fibrinolytic Agents; D008074:Lipoproteins; D011994:Recombinant Proteins; C051928:lipoprotein-associated coagulation inhibitor