CHIMERIC 7E3 PREVENTS CAROTID-ARTERY THROMBOSIS IN CYNOMOLGUS MONKEYS

Background and Purpose We compared the current antithrombotic strategy of antiplatelet therapy with aspirin, and anticoagulant therapy with heparin, with a specific genetically engineered chimeric antibody (c7E 3 Fab) directed against the human glycoprotein IIb/IIIa receptor in an animal model of arterial thrombosis. Methods Anesthetized cynomolgus monkeys (Macaca fascicularis) were instrumented for monitoring of arte rial blood pressure, heart rate, and carotid artery flow velocity. Ani mals were treated with saline (n=6), aspirin (25 mg PO daily for 3 day s; n=6), heparin (100 U/kg IV plus infusion adjusted to maintain activ ated partial thromboplastin time at 2 to 3 times baseline; n=6), aspir in plus heparin (as administered separately, n=6), or c7E3 Fab (0.10 m g/kg IV, n=7; 0.15 mg/kg IV, n=6; 0.20 mg/kg IV, n=6; 0.25 mg/kg IV, n =6). Thrombus formation via anodal electrolytic stimulation (100 mu A) to the intimal surface of the right carotid artery was initiated 15 m inutes after drug administration and continued for 180 minutes. Electr olytic injury to the left carotid artery began 210 minutes after drug administration and continued for 180 minutes. Whole blood cell counts, glycoprotein IIb/lIIa receptor blockade, ex vivo platelet aggregation , template bleeding time, and activated partial thromboplastin time we re assessed at various time points throughout the experimental protoco l. Results Hemodynamic and hematologic parameters were comparable amon g groups at baseline. Treatment with c7E3 Fab inhibited ex vivo platel et aggregation, increased bleeding time, decreased thrombus weight, an d increased time to occlusion in a dose-dependent manner in both vesse ls. Treatment with aspirin, heparin, or the combination of aspirin plu s heparin was ineffective for the prevention of carotid artery thrombo sis in this model. Conclusions Inhibition of the platelet glycoprotein IIb/IIIa receptor with c7E3 Fab was found to be safe and effective fo r the prevention of primary thrombus formation, whereas treatment with either aspirin or heparin or the combination of the two agents failed to protect against occlusive thrombus formation in cynomolgus monkeys .