Prevention of rethrombosis after coronary thrombolysis in a chronic canine model. II. Adjunctive therapy with r-hirudin.
We examined the effectiveness of the direct-acting thrombin inhibitor, recombinant hirudin (r-hirudin), for prevention of coronary rethrombosis after thrombolysis with recombinant tissue plasminogen activator (rt-PA) in a canine model of coronary artery thrombosis. The reocclusion rate of 15-30% associated with thrombolytic therapy emphasizes the need for adjunctive therapy to prevent rethrombosis. We studied r-hirudin for its potential to prevent reocclusion in a model of coronary artery thrombosis/thrombolysis. The circumflex coronary arteries of anesthetized dogs were instrumented with a flow probe, an intraluminal electrode, and a ligature stenosis. The dogs were reanesthetized on the ninth postoperative day, and intimal injury was induced with an anodal current. After occlusive thrombus formation, tissue plasminogen activator (rt-PA) was administered. The animals were allocated to receive either placebo, r-hirudin [5 mg/kg intravenously (i.v.) bolus, 2 mg/kg/h i.v., for 3.5 h] or r-hirudin (5 mg/kg i.v., bolus, 1 mg/kg/h i.v., for 12 h). Neither aspirin nor heparin was used. Ex vivo platelet function and coronary artery blood flow velocity were recorded on each of 5 consecutive days. Infarct size and residual thrombus weight were determined at the end of the protocol. r-Hirudin infusion (3.5 and 12 h) provided little benefit over rt-PA alone. Ex vivo platelet aggregation was not affected by r-hirudin. Little improvement in the incidence of reocclusion and mortality in a model of coronary artery thrombosis/thrombolysis resulted from adjunctive treatment with r-hirudin.
Rote
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Department of Pharmacology, University of Michigan Medical School, Ann Arbor 48108-0626.
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Bates
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Nedelman
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Lucchesi
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BR
D000818:Animals; D001777:Blood Coagulation / Q000187:drug effects; D002908:Chronic Disease; D003328:Coronary Thrombosis / Q000473:pathology / Q000503:physiopathology / Q000517:prevention & control*; D003331:Coronary Vessels / Q000473:pathology / Q000503:physiopathology; D004285:Dogs; D005343:Fibrinolytic Agents / Q000627:therapeutic use*; D024764:Hirudin Therapy; D008297:Male; D009203:Myocardial Infarction / Q000473:pathology / Q000503:physiopathology; D010974:Platelet Aggregation / Q000187:drug effects; D011994:Recombinant Proteins / Q000627:therapeutic use; D012008:Recurrence; D013997:Time Factors; D010959:Tissue Plasminogen Activator / Q000627:therapeutic use
D005343:Fibrinolytic Agents; D011994:Recombinant Proteins; D010959:Tissue Plasminogen Activator