Intravenous administration of the glycoprotein IIb-IIIa receptor antagonist 7E3 induces reperfusion of an acute thrombotic occlusion of the canine coronary artery.
The ability of the F(ab')2 fragment of the murine monoclonal antibody 7E3 directed against the platelet glycoprotein IIb-IIIa receptor complex, to cause reperfusion of a totally occluding coronary artery thrombus was examined alone and in combination with aspirin and heparin in a canine model of coronary artery thrombosis. A localized thrombus was produced in the left circumflex coronary artery in open-chest dogs by electrolytic injury of the endothelium. Intravenous administration of a single injection of 5.0 mg/kg aspirin and heparin (80 U/kg bolus plus 30 U/kg/hr x 2 hr) maintained vessel patency for approximately 101 +/- 15 minutes. After vessels had been completely occluded for 5 minutes (in the presence of aspirin + heparin), a single intravenous injection of saline (10 ml) or 0.8 mg/kg 7E3 was administered. Reperfusion was observed in all dogs (6 of 6) receiving 7E3; 4 of 6 dogs maintained vessel patency throughout the course of the 2 hour observation period. Activated partial thromboplastin and thrombin times were elevated 1.4 and 9 fold, respectively, in groups that received heparin. Template bleeding times were significantly elevated in the groups receiving 7E3. In the control group, 2 of 5 dogs reperfused briefly, however neither were patent at the end of the observation period. A third group of 4 dogs which did not receive the aspirin + heparin regimen was allowed to occlude and 5 minutes later received a single intravenous injection of 0.8 mg/kg 7E3. None of the 4 dogs in this group reperfused at any time during the study. There were no significant differences between groups in regards to hematological or hemodynamic measurements during the experiment. We concluded from these findings that the monoclonal antibody, 7E3 can promote the dissolution of friable coronary artery thrombi that evolve during standard anticoagulant and antiplatelet therapy.
Shetler
T J
TJ
Cardiovascular Research Division, Lilly Research Laboratories, Eli Lilly and Company, Indianapolis, Indiana 46285-0524, USA.
Bailey
B D
BD
Jakubowski
J A
JA
Jackson
C V
CV
D000077284:Abciximab; D000208:Acute Disease; D000818:Animals; D000911:Antibodies, Monoclonal / Q000008:administration & dosage*; D000925:Anticoagulants / Q000008:administration & dosage; D001241:Aspirin / Q000008:administration & dosage; D001777:Blood Coagulation / Q000187:drug effects; D003131:Combined Modality Therapy; D003326:Coronary Circulation / Q000187:drug effects; D003328:Coronary Thrombosis / Q000188:drug therapy / Q000503:physiopathology / Q000628:therapy*; D004195:Disease Models, Animal; D004285:Dogs; D005260:Female; D006493:Heparin / Q000008:administration & dosage; D007140:Immunoglobulin Fab Fragments / Q000008:administration & dosage*; D007275:Injections, Intravenous; D008297:Male; D051379:Mice; D015425:Myocardial Reperfusion / Q000379:methods*; D010975:Platelet Aggregation Inhibitors / Q000008:administration & dosage; D019039:Platelet Glycoprotein GPIIb-IIIa Complex / Q000037:antagonists & inhibitors*
D000911:Antibodies, Monoclonal; D000925:Anticoagulants; D007140:Immunoglobulin Fab Fragments; D010975:Platelet Aggregation Inhibitors; D019039:Platelet Glycoprotein GPIIb-IIIa Complex; D006493:Heparin; D001241:Aspirin; D000077284:Abciximab