Antiplatelet monoclonal F(ab′) 2 antibody directed against the platelet [formula omitted] receptor complex prevents coronary artery thrombosis in the canine heart

Abstract

Interactions between platelets with injured vascular endothelium contribute to thrombotic occlusion. A murine monoclonal antibody [7E3 F(ab′) 2] to the platelet GPIIb IIIa receptor complex was used to inhibit platelet aggregation in an experimental model of coronary artery thrombosis. Prevention of thrombotic occlusion by 7E3 F(ab′) 2 (0.8 mg/kg bolus i.v.) was studied in dogs with direct current induced intimal injury (100 μA for 5 h) and critical stenosis of the left circumflex coronary artery (LCCA). Baseline LCCA blood flow (CBF) was similar in 7E3 F(ab′) 2 and control groups, but decreased in the controls [24 ± 2 ml/min to 0 ± 0 ml/min, n = 13 (mean ± s.e.m.)] due to thrombotic occlusion in each case (time to thrombosis 136 ± 15 min). In the group treated with 7E3 F(ab′) 2, CBF did not change significantly (27 ± 3 ml/min to 22 ± 3 ml/min, n = 6) and thrombotic occlusion did not occur during the 5-h observation period in which intimal injury was produced in the LCCA ( P < 0.001). Oscillations in CBF preceded thrombosis in the control group, but did not occur with 7E3 F(ab′) 2 treatment (2.2 ± 0.7 vs. 0 ± 0, P < 0.05). The thrombus mass recovered from the LCCA 30 min after occlusion was 8.8 ± 1.3 mg in the controls compared to 2.2 ± 1.2 mg determined 5 h after administration of 7E3 F(ab′) 2 ( P < 0.05). When studied ex vivo, before the administration of the test agents, platelets from both groups of dogs aggregated in response to ADP and arachidonic acid. However, after treatment, the ex vivo aggregation of platelets from 7E3 F(ab′) 2 animals was inhibited whereas platelets from the control animals continued to aggregate ex vivo throughout the period of the experimental protocol ( P < 0.05). The labeling of platelets with 111indium showed accumulation of radio-activity within the thrombus and upon the vascular endothelium which was less in 7E3 F(ab′) 2 treated dogs as compared to the control group ( P < 0.05). The murine monoclonal antibody 7E3 F(ab′) 2 did not affect hemodynamic values or the circulating platelet count during the experimental protocol. In conclusion, antibody to platelet GPIIb IIIa receptors: (1) prevented thrombotic LCCA occlusion, (2) inhibited ex vivo platelet aggregation, (3) minimized platelet deposition on injured vascular endothelium and within formed thrombi, and (4) stabilized CBF during 5 h of continuous direct currrent induced intimal injury of the LCCA.