Thrombin inhibitors and anti-coagulants on thrombin-induced embolisation in rabbit cranial vasculature

111Indium-labelled platelets were continuously monitored in the cranial vasculature of anaesthetised rabbits and thrombin inhibitors and anti-coagulants were tested on the sustained platelet accumulation induced by intracarotid injection of thrombin (90 U/kg). Pretreatment, commencing 30 min prior to thrombin, with a 1-h intracarotid infusion of D-phenylalanyl-L-prolyl-L-arginine chloromethyl ketone (PPACK; 0.25-1.0 μg/kg per min), unfractionated heparin (Multiparin; 5-20 U/kg bolus + 0.75-3.0 U/kg per min infusion) or low molecular weight heparin (Fragmin; 2.4-9.6 U/kg per min) produced dose-related reductions in platelet accumulation. Continuous infusion of acetyl-(D)-phenylalanyl-prolyl-boroarginine (DuP-714 ester; 30 μg/kg per min) for 30 min induced marked accumulation of platelets in the pulmonary circulation in the absence of thrombin. Bolus intracarotid injection, 1 min before thrombin, of Hirulog (0.05-0.2 mg/kg), PPACK (10-30 μg/kg), Multiparin (25-100 U/kg), Fragmin (150 U/kg) or DuP-714 ester (15-30 μg/kg) caused significant reductions in platelet accumulation. When injected 1 min after thrombin, Hirulog (1 mg/kg), PPACK (100 μg/kg), Fragmin (150 U/kg) and DuP-714 ester (30 μg/kg) had no significant effect and Multiparin (100 U/kg) increased platelet accumulation. The results demonstrate that pretreatment with a range of thrombin inactivators, acting via different mechanisms, can inhibit thrombin-induced cerebral thromboembolism in the rabbit.