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Circulation, Vol 84, 244-253, Copyright © 1991 by American Heart Association

ARTICLES

Effective thrombolysis without marked plasminemia after bolus intravenous administration of vampire bat salivary plasminogen activator in rabbits

SJ Gardell, DR Ramjit, II Stabilito, T Fujita, JJ Lynch, GC Cuca, D Jain, SP Wang, JS Tung and GE Mark
Department of Biological Chemistry, Merck Research Laboratories, West Point, Pa, Sharp & Dohme 19486.

BACKGROUND. The use of recombinant tissue-type plasminogen activator (t- PA) in thrombolytic therapy is frequently associated with significant fibrinogenolysis. In contrast, recombinant vampire bat salivary plasminogen activator (Bat-PA) displays strict fibrin specificity, an attribute that could be desirable in a fibrinolytic agent. METHODS AND RESULTS. The efficacy and fibrin selectivity of Bat-PA was evaluated and compared with that of t-PA using a rabbit model of femoral arterial thrombosis. Administration of 8.1, 14, and 42 nmol Bat-PA/kg by bolus intravenous injection restored flow in 50%, 75%, and 80% of the rabbits, respectively. The incidence of reperfusion after bolus intravenous injection of 14 and 42 nmol t-PA/kg was 15% and 78%, respectively. The maximal femoral artery reperfusion flows were equivalent after treatment with 42 nmol Bat-PA/kg or 42 nmol t-PA/kg, but the time to reach maximal flow for Bat-PA was approximately one half that of t-PA. Furthermore, the rapid restoration of flow by 42 nmol Bat-PA/kg, in contrast to equimolar t-PA, was accomplished without fibrinogenolysis and with only small decreases in the plasminogen and alpha 2-antiplasmin levels. Equipotent doses of Bat-PA and t-PA both resulted in approximate 2.5-fold increases in the template bleeding times of aspirin-pretreated rabbits. The clearance of Bat-PA from rabbits exhibited biexponential elimination kinetics; approximately 80% was cleared by the relatively slow beta phase (half-life of 17.1 minutes). Overall, Bat-PA was cleared approximately fourfold slower than t-PA. CONCLUSIONS. Bolus intravenous administration of Bat-PA would facilitate prompt initiation of thrombolytic therapy, and the avoidance of plasminemia could result in fewer and less severe bleeding complications.

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