THE EFFECT OF DEFIBROTIDE ON THROMBOEMBOLISM IN THE PULMONARY VASCULATURE OF MICE AND RABBITS AND IN THE CEREBRAL VASCULATURE OF RABBITS

1 Administration of bovine thrombin (100 u kg-1) into the carotid arte ry of rabbits induces a sustained accumulation of Indium-111-labelled platelets within the cranial vasculature over the subsequent 3 h. 2 In tracarotid (i.c.) administration of defibrotide (64 mg kg-1 bolus plus 64 mg kg- 1 h-1 for 1 h) prior to i.c. thrombin (100 u kg-1) signific antly reduces the ability of thrombin to induce cranial thromboembolis m in rabbits. 3 Intravenous (i.v.) administration of thrombin (20 u kg -1) in rabbits induces a reversible accumulation of radiolabelled plat elets into the thoracic circulation which is significantly reduced by i.v. administration of defibrotide (64 mg kg-1 bolus plus 64 mg kg-1 h -1 for 1 b) prior to i.v. thrombin. In contrast, platelet accumulation in response to adenosine diphosphate (ADP; 20 mug kg-1, i.v.) or plat elet activating factor (PAF; 50 ng kg-1, i.v.) is not significantly af fected by this treatment. 4 Intravenous administration of the nitric o xide (NO)-synthase inhibitor N(G)-nitro-L-arginine methyl ester (L-NAM E; 10 mg kg-1) potentiates platelet accumulation induced by low dose t hrombin (10 u kg-1, i.v.) within the pulmonary vasculature of rabbits. The potentiated response is significantly abrogated following pretrea tment with defibrotide (64 mg kg-1 bolus plus 64 mg kg-1 h-1 for 1 h, i.v.). 5 Intravenous injection of human thrombin (1250 u kg-1) to mice induces death within the majority of animals which is significantly r educed by pretreatment with defibrotide (150-175 mg kg-1, i.v.). In co ntrast, death induced by i.v. collagen (1.25 mg kg-1) plus adrenaline (75 mug kg-1) is not significantly affected by defibrotide pretreatmen t. 6 The inhibitory effect of defibrotide in mice is abolished followi ng concomitant treatment with the inhibitor of fribrinolysis, tranexam ic acid (100 mg kg-1, i.v.), but is unaffected following treatment wit h the cyclo-oxygenase inhibitor, aspirin (300 mg kg-1, i.p.). 7 The pr otective effect of defibrotide against thrombin-induced thromboembolis m in the mouse is potentiated by recombinant tissue-plasminogen activa tor (rt-PA; 1 mg kg-1, i.v.) or unfractionated heparin (10 u kg-1, i.v .) administration. 8 The results suggest that defibrotide may possess antithrombotic activity on thrombin-induced thromboembolism which, at least in the mouse, may be partially mediated via induction of the fib rinolytic pathway.