Induction of sustained patency after clot-selective coronary thrombolysis with hybrid-B, a genetically engineered plasminogen activator with a prolonged biological half-life

Background. Despite the utility of tissue-type plasminogen activator (t-PA) in eliciting coronary thrombolysis clinically, early reocclusion remains a problem, occurring despite anticoagulation in 5-30% of patients with initially successful recanalization. This study evaluated the utility of Hybrid-B, a molecular variant of t-PA with a prolonged half-life in the circulation, in eliciting coronary thrombolysis and maintaining patency in the presence of a continuing thrombogenic stimulus. Methods and Results. In intact, anesthetized dogs, either 18 mg Hybrid-B over 30 minutes (n=15) or 50 mg t-PA (Activase) over 60 minutes (n=8) was administered starting 60 minutes after left anterior descending coronary artery occlusion was induced with a thrombogenic copper coil. Time to lysis averaged 54±26 (means±SD) minutes and 64±34 minutes with Hybrid-B and t-PA, respectively (p=NS). When Hybrid-B was administered as a bolus (20 mg over 1 minute) to induce a high initial concentration in blood, time to lysis was shortened markedly and averaged 15±5 minutes. Dogs given Hybrid-B by either infusion or bolus exhibited prolonged time to reocclusion (337±192 minutes compared with 192±125 minutes in dogs given t-PA, p<0.03), reflecting maintenance of a subthrombolytic but persistently active concentration of activator in blood. Despite the persistence of Hybrid-B in blood, concentrations of fibrinogen and α₂-antiplasmin were not depleted markedly and remained at 77±25 and 56±24%, respectively, of control values. Conclusions. Thus, Hybrid-B, a novel variant of t-PA with unique pharmacokinetic properties, elicits prompt, sustained, and clot-selective coronary thrombolysis.