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 microg/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.