ifetroban and Carotid-Artery-Thrombosis

We determined the effects of aspirin and a novel thromboxane A2/prostaglandin endoperoxide (TP)-receptor antagonist, BMS-180291, on thrombosis and bleeding times in skin and mesenteric arteries. In anesthetized rats, occlusive thrombosis was induced in the carotid artery by topical application of ferrous chloride and in the vena cava by blood flow stasis combined with either infusion of thromboplastin or hypotonic saline. Aspirin (1, 10, and 50 mg/kg) did not reduce arterial or venous thrombus weight significantly. BMS 180,291 (150 micrograms/kg/min) decreased arterial thrombus weight and hypotonic saline-induced caval thrombus weight by 58 and 57%, respectively. BMS-180291 lacked antithrombotic activity at a lower dose (50 micrograms/kg/min) and failed to inhibit thromboplastin-induced caval thrombosis. BMS-180291 (150 micrograms/kg/min) significantly reduced arterial thrombus weight by 40% when plasma epinephrine concentration was increased to 5 ng/ml. BMS-180291 and aspirin produced increases of only < or = 30% in bleeding times. These results demonstrate that BMS-180291 has antithrombotic activity in experimental aspirin-resistant arterial and venous thrombosis. Both aspirin and BMS-180291 have only modest effects on small artery hemostasis in rats.

Topics: Animals; Aspirin; Bleeding Time; Bridged Bicyclo Compounds, Heterocyclic; Carotid Artery Thrombosis; Disease Models, Animal; Epinephrine; Male; Mesenteric Arteries; Oxazoles; Platelet Aggregation Inhibitors; Propionates; Rats; Rats, Sprague-Dawley; Receptors, Thromboxane; Thrombosis; Venae Cavae

These studies describe experimental conditions where aspirin is less effective than other antiplatelet and anticoagulant drugs in inhibiting acute arterial thrombosis. External electrolytic injury of the rat carotid artery was used to induce occlusive thrombi in 97% of vehicle-treated rats. Thrombi were revealed by light and electron microscopy to be comprised primarily of platelets enmeshed in a fibrin network. The thrombin inhibitor D-phenylalanyl-L-prolyl-L-arginyl chloromethylketone (PPACK; 6 mg/kg, i.v.) decreased thrombus weight by 90%. Aspirin alone (1, 10 and 30 mg/kg, i.v.), dipyridamole alone (5 mg/kg i.v.) and aspirin (1 and 10 mg/kg, i.v.) in combination with dipyridamole (5 mg/kg, i.v.) did not inhibit thrombosis. The platelet-activating factor (PAF) antagonist, WEB 2086, (1 mg/kg i.v.) was also ineffective. Other drugs had intermediate activity. Thrombi were decreased 56% by the thromboxane receptor antagonist, BMS 180,291, either alone (5.8 mg/kg i.v.) or in combination with aspirin (10 mg/kg, i.v.). Heparin (900 U/kg, i.v.), warfarin (0.25 mg/kg, p.o. once daily for 3 days) and ticlopidine (200 mg/kg, p.o. once daily for 3 days) reduced thrombus weight by 63, 73 and 43% respectively. Reductions in thrombus weight were always associated with improvements in either average blood flow or vessel patency.

Topics: Amino Acid Chloromethyl Ketones; Animals; Aspirin; Azepines; Bridged Bicyclo Compounds, Heterocyclic; Carotid Artery Thrombosis; Dipyridamole; Fibrinolytic Agents; Heparin; Male; Oxazoles; Propionates; Rats; Rats, Sprague-Dawley; Thrombolytic Therapy; Ticlopidine; Triazoles; Warfarin