ABOLITION OF IN VIVO PLATELET THROMBUS FORMATION WITH MONOCLONAL ANTIBODIES TO THE PLATELET GPIIb/IIla RECEPTOR: CORRELATION WITH PLATELET AGGREGATION AND BLEEDING TIME

We previously reported that 0.8 mg/kgof the F(ab’)₂ fragment of antibody 7E3, directed at theplatelet GPIIb/IIIa receptor, can abolish periodic platelet thrombus formation on partially stenosed carotid arteries in monkeys (Mnks). The present study was designed to: 1) test another antibody to GPIIb/IIIa (10E5), 2)find the minimum effective dose, and 3) correlate this effect with changesin the template bleeding time (BT) and platelet aggregation (PA). Periodicplatelet thrombi were established in the carotid arteries of 7 anesthetized Mnks after mechanical stenosis (∽70%) and intimal damage. 4 Mnks were treated with 7E3. Mnks 1 and 2 were given 0.2 mg/kg, and this dose: abolished thrombus formation and prevented its return in response to epinephrine infusion and increased intimal damage; abolished PA in response to ADP (10 μM); and increased the BT from 8.5 to 16 min and from 5 to 11 min. Mnk 3 was given 0.1 mg/kg, and this dose abolished the thrombi, inhibited PA by ∽41% and increased the BT only to 10 minfrom 8 min. Mnk 4 was givenincremental doses of 7E3. After 0.1 mg/kg, thrombi were reduced but not abolished, PA was minimally inhibited and the BTwas unchanged (7.5 vs 8 min pre). Afteranother 0.1 mg/kg, thrombi were abolished but could be partially restoredwith extreme provocation, PA was abolished and BT remained 7.5min. Afteranother 0.2 mg/kg, thrombicould not berestored, PA was abolished and the BTincreased to 21 min. After a final0.2mg/kg, the BT increased to 33 min. 3 Mnks were treated with 10E5. Mnk1received 0.4 mg/kg: thrombi and PA werebothabolished, and the BT increased from 5.5 to 14.5 min.Mnk 2 received 0.2mg/kg: thrombi and PA were again abolished while the BT increased to8.5from4.5 min. Mnk 3 received 0.1 mg/kg, and this abolished thrombus formation,butinhibitedPA by only ∽50%and increasedthe BT minimally (7.5 to 8.5 min). Increasedoozing from the neckwounds wasonly observed in animals with significant BT prolongations.We conclude that ∽0.1-0.2 mg/kg of eitherantibody can abolish in vivo thrombusformation, and that it is not necessary to abolish PA or cause marked prolongation ofthe BT in order toabolishthrombus formation in this model.