INFLUENCE OF HEPARIN AND SYSTEMIC LYSIS ON CORONARY BLOOD-FLOW AFTER REPERFUSION-INDUCED BY THE NOVEL RECOMBINANT PLASMINOGEN-ACTIVATOR BM-06.022 IN A CANINE MODEL OF CORONARY-THROMBOSIS

Objectives. We sought to evaluate whether anticoagulation by an intrav enous heparin infusion prevents deterioration of coronary blood flow r estored by the novel recombinant plasminogen activator BM 06.022, and to compare the effects of profound fibrinogenolysis with those of an i ntravenous bolus injection of heparin. Background. Recent clinical stu dies indicate that heparin appears to be effective in reducing reocclu sion when combined with recombinant tissue-type plasminogen activator (rt-PA), but that heparin is associated with an increased bleeding inc idence. Therefore, the need for heparin has to be critically evaluated in the development of BM 06.022. Methods. BM 06.022 is an unglycosyla ted variant of human tissue-type plasminogen activator. Thrombus forma tion in anesthetized open chest dogs was induced by electrical injury. Left circumflex coronary artery blood flow was monitored for 4 h usin g an electromagnetic flow probe. Twenty dogs were randomized to receiv e intravenous heparin (100 IU/kg bolus plus 100 IU/kg per h) in group B or saline solution in group A before an intravenous bolus injection of 200 kU/kg (=0.34 mg/kg) BM 06.022 1 h after thrombus formation. Ano ther 14 dogs were randomized to receive a single intravenous bolus inj ection of 200 IU/kg heparin plus 200 kU/kg BM 06.022 in group D or sal ine solution plus 1,000 kU/kg BM 06.022 in group C. Results. In the ab sence of a systemic lytic state, heparin infusion prolonged (p < 0.05) the cumulative patency time (sum of time intervals during which the c oronary artery was patent) to 204.3 +/- 7.4 min (group B) compared wit h 34.6 +/- 10.8 min with saline solution (group A), and increased (p < 0.05) the area under the curve for coronary blood flow versus time (A UC(Flow)) to 34.0 +/- 3.4 ml.h.min-1 compared with 7.7 +/- 4.6 ml-h.mi n-1. Profound fibrinogenolysis after administration of 1,000 kU/kg BM 06.022 (group C) and a single intravenous heparin injection (group D) did not differ in their effects on the cumulative patency time (182 +/ - 30.3 vs. 177.5 +/- 25.4 min) and AUC(Flow) (36.0 +/- 10.3 vs. 30.5 /- 4.8 ml.b.min-1), but these values were improved (p < 0.05) compared with those obtained after administration of saline solution plus 200 kU/kg BM 06.022 (group A). Conclusions. In the absence of a systemic l ytic state, intravenous heparin is required as an adjunct to BM 06.022 to maintain coronary blood flow in dogs.