1 Administration of bovine thrombin (100ukg-1) into the carotid artery of rabbits induces a sustained accumulation of Indium-labelled platelets within the cranial vasculature over the subsequent 3h. 2 Intracarotid (i.c.) administration of defibrotide (64mg kg-1 bolus plus 64mg kg-1h-1 for 1h) prior to i.c. thrombin (100ukg-1) significantly reduces the ability of thrombin to induce cranial thromboembolism in rabbits. 3 Intravenous (i.v.) administration of thrombin (20ukg-1) in rabbits induces a reversible accumulation of radiolabelled platelets into the thoracic circulation which is significantly reduced by i.v. administration of defibrotide (64mg kg-1 bolus plus 64mg kg-1h-1 for 1h) prior to i.v. thrombin. In contrast, platelet accumulation in response to adenosine diphosphate (ADP; 20pg kg-1, i.v.) or platelet activating factor (PAF; 50ng kg1, i.v.) is not significantly affected by this treatment. 4 Intravenous administration of the nitric oxide (NO)-synthase inhibitor NG-nitro-L-arginine methyl ester (L-NAME; 10mgkg-1) potentiates platelet accumulation induced by low dose thrombin (10ukg-1, i.v.) within the pulmonary vasculature of rabbits. The potentiated response is significantly abrogated following pretreatment with defibrotide (64mg kg-1 bolus plus 64 mg kg-1 h-for 1h, i.v.). 5 Intravenous injection of human thrombin (1250u kg-1) to mice induces death within the majority of animals which is significantly reduced by pretreatment with defibrotide (150-175mg kg1, i.v.). In contrast, death induced by i.v. collagen (1.25mg kg-1) plus adrenaline (75gg kg-1) is not significantly affected by defibrotide pretreatment. 6 The inhibitory effect of defibrotide in mice is abolished following concomitant treatment with the inhibitor of fribrinolysis, tranexamic acid (100mg kg-1, i.v.), but is unaffected following treatment with the cyclo-oxygenase inhibitor, aspirin (300mg kg-1, i.p.). 7 The protective effect of defibrotide against thrombin-induced thromboembolism in the mouse is potentiated by recombinant tissue-plasminogen activator (rt-PA; 1 mg kg-1, i.v.) or unfractionated heparin (10ukg-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 fibrinolytic pathway.