Vol. 301, Issue 3, 1151-1156, June 2002

Intimatan Prevents Arterial and Venous Thrombosis in a Canine Model of Deep Vessel Wall Injury

James K. Hennan, Ting-Ting Hong, Ardamanpal K. Shergill, Edward M. Driscoll, Alan D. Cardin and Benedict R. Lucchesi

University of Michigan Medical School, Department of Pharmacology, Ann Arbor, Michigan (J.K.H., T.-T.H., A.K.S., E.M.D., B.R.L.); and Celsus Laboratories, Inc., Cincinnati, Ohio (A.D.C.)

Resistance of fibrin-bound thrombin to inactivation by the heparin/antithrombin III complex is considered a limitation in the use of heparin as an antithrombotic agent. Intimatan (dermatan 4,6-di-O-sulfate) is a heparin cofactor II agonist that inhibits both free and bound forms of thrombin. The present study examines the hypothesis that Intimatan prevents thrombotic occlusion in response to vascular wall injury in a canine model of carotid artery/jugular vein thrombosis. The left carotid artery and right jugular vein served as vehicle-treated control vessels, whereas the right carotid artery and left jugular vein were subjected to electrolytic injury after administration of Intimatan (9 mg/kg bolus + 300 µg/kg/min infusion, i.v.) or dalteparin (Fragmin) (400 IU/kg, s.c.). Intimatan significantly increased time to carotid artery (226.0 ± 14.0 min) and jugular vein (240.0 ± 0.0 min) thrombosis, compared with control vessels (carotid artery, 87.1 ± 7.9 min; jugular vein, 60.6 ± 7.4 min). Vessel patency was maintained in eight of eight jugular veins and seven of eight carotid arteries during treatment with Intimatan. Dalteparin significantly increased time to carotid artery thrombosis (122.1 ± 17.5 min) compared with control (64.3 ± 8.2 min), but did not change the time to thrombosis in the jugular vein. Only one carotid artery remained patent at the end of the dalteparin protocol. The two drugs produced minimal increases in bleeding times, and Intimatan increased the activated partial thromboplastin time above that observed with dalteparin. The results demonstrate that Intimatan is effective in preventing occlusive arterial and venous thrombosis in an experimental model of deep vascular wall injury.