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—We tested the hypothesis that the in vivo antithrombotic efficacy of SM-20302, a GP IIb/IIIa receptor antagonist, correlates with the ex vivo platelet inhibition in heparinized platelet rich plasma (hPRP) but not in citrated PRP (cPRP). The studies were performed in a canine model of carotid artery thrombosis in which thrombus formation was induced by electrolytic injury. Thrombosis of the right carotid artery was induced immediately after the administration of saline (n=12). Thirty minutes after persistent occlusive thrombosis was obtained, the vessel segment was ligated, and the time to occlusion and thrombus weight were noted. Subsequently, thrombosis of the left carotid artery was initiated in the presence of SM-20302 (100, 300, 600, or 1000 μg/kg IV; n=4 to 6). All the doses of SM-20302 inhibited (by ≥90%) the ex vivo platelet aggregation induced by ADP and arachidonic acid (AA) in cPRP. In hPRP, a dose-dependent inhibition of ex vivo platelet aggregation was observed. The maximal inhibition produced by 100 to 1000 μg/kg SM-20302 ranged from 18% to 80% for ADP and 44% to 88% for AA. Maximal prolongation of the template bleeding time induced by the 100-, 300-, 600-, and 1000-μg/kg doses were 2.5-, 9.5-, 10-, and &gt;10-fold, respectively. All the injured carotid arteries (n=12) in the saline-treated group occluded. SM-20302 pretreatment produced a dose-dependent maintenance of the carotid artery patency, and the incidence of occlusion at 4 hours was 5/6, 3/6, 0/6, and 0/6 for the 100-, 300-, 600-, and 1000-μg/kg doses, respectively. The results indicate that SM-20302 prevents carotid artery thrombosis in response to electrolytic arterial wall injury and that its in vivo antithrombotic efficacy can be correlated accurately with the ex vivo platelet inhibition in PRP prepared from heparinized blood but not from citrated blood.

arteriosclerosis, thrombosis, and vascular biology

In Vivo Efficacy of SM-20302, a GP IIb/IIIa Receptor Antagonist, Correlates With Ex Vivo Platelet Inhibition in Heparinized Blood but Not in Citrated Blood