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/

We tested the hypothesis that the in vivo antithrombotic efficacy of S M-20302, a GP IIb/IIIa receptor antagonist, correlates with the ex viv o platelet inhibition in heparinized platelet rich plasma (hPRP) but n ot in citrated PRP (cPRP). The studies were performed in a canine mode l of carotid artery thrombosis in which thrombus formation was induced by electrolytic injury. Thrombosis of the right carotid artery was in duced immediately after the administration of saline (n=12). Thirty mi nutes after persistent occlusive thrombosis was obtained, the vessel s egment was ligated, and the time to occlusion and thrombus weight were noted. Subsequently, thrombosis of the left carotid artery was initia ted in the presence of SM-20302 (100, 300, 600, or 1000 mu g/kg IV; n= 4 to 6). All the doses of SM-20302 inhibited (by greater than or equal to 90%) the ex vivo platelet aggregation induced by ADP and arachidon ic 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 mu g/kg SM-20302 ranged from 18% to 80% for ADP and 44% to 88% for AA. Maximal prolongation of the template bleeding time induce d by the 100-, 300-, 600-, and 1000-mu g/kg doses were 2.5-, 9.5-, 10- , and >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 inc idence of occlusion at 4 hours was 5/6, 3/6, 0/6, and 0/6 for the 100- , 300-, 600-, and 1000-mu g/kg doses, respectively. The results indica te that SM-20302 prevents carotid artery thrombosis in response to ele ctrolytic arterial wall injury and that its in vivo antithrombotic eff icacy can be correlated accurately with the ex vivo platelet inhibitio n in PRP prepared from heparinized blood but not from citrated blood.