CORONARY THROMBOSIS THROMBOLYSIS IN PIGS - EFFECTS OF HEPARIN, ASA, AND THE THROMBIN INHIBITOR INOGATRAN/

The aim of the present study was to develop a coronary thrombolysis mo del using the copper coil technique in closed-chest pigs. The first go al (protocol I) was to obtain a reproducible size of myocardial infarc tion by controlling the coronary occlusion period, a prerequisite for evaluation of myocardioprotective interventions. The second goal (prot ocol II) was to study if thrombin and platelet aggregation inhibitors influence the rate of thrombolysis, the degree of reocclusion, and the time of coronary patency when added to a thrombolytic regimen (recomb inant tissue-type plasminogen activator, rt-PA). Coronary thrombosis w as produced by insertion of a thrombogenic copper coil into the LAD of 40 anesthetized pigs. The animals were divided into six groups as fol lows: Protocol I, group 1: Open-chest, lysis initiated with intracoron ary rt-PA (50 mg) concomitant with intravenous heparin and acetylsalic ylic acid (ASA) (n = 6). Group 2: Closed-chest, lysis initiated with i ntracoronary rt-PA concomitant with intravenous heparin and ASA (n = 1 0). Protocol II, group 3: Closed-chest, lysis initiated with intraveno us rt-PA (n = 6). Group 4: Closed-chest, lysis initiated with intraven ous rt-PA concomitant with heparin tit = 6). Group 5: Closed-chest, ly sis initiated with intravenous rt-PA concomitant with inogatran, a low molecular weight thrombin inhibitor (n = 6). Group 6: Closed-chest, l ysis initiated with intravenous rt-PA immediately after intravenous ad ministration of ASA (n = 6). Protocol 1; Reperfusion was achieved in a ll closed- and open-chest pigs. The time to thrombolysis was 5 +/- 1.6 and 6 +/- 3.0 min (mean +/- SD) for closed- and open-chest pigs, resp ectively. Reocclusions were rare tone in group 1). The size of the isc hemic myocardial area was 21 +/- 11% of the left ventricular area in g roup 1 and 22 +/- 6% in group 2. The corresponding values for infarct size as a proportion of the ischemic area were 58 +/- 10% and 68 +/- 1 4%, respectively. The closed-chest model was subsequently used to stud y the effect of the thrombin and platelet aggregation inhibitors (inog atran, heparin, and ASA) as conjunctive agents to rt-PA-induced thromb olysis (groups 3-6). To mimic its clinical use, rt-PA was administered intravenously. Time to lysis after rt-PA only (group 3) was 33 +/- 24 min. Concomitant treatment with heparin (group 4), inogatran (group 5 ), and ASA (group 6) did not significantly influence time to lysis. Al l adjunctive compounds did, however, prolong the time to reocclusion, which occurred in 100%, 75%, 67%, and 20% of the animals in groups 3, 4, 5, and 6. Thus, concomitant treatment with heparin and inogatran di d not shorten time to lysis or reduce the reocclusion rate, and ASA tu rned out to be the only effective adjunct to rt-PA, significantly redu cing both time to and frequency of reocclusion (p < 0.05). Conclusion: The described closed-chest pig model was feasible as regards the indu ction and lysis of a thrombus in the left coronary artery, giving repr oducible areas of myocardial ischemia and infarction. This model was u seful for the evaluation of pharmacological interventions in the throm bolysis process. (C) 1998 Elsevier Science Inc.