A long-half-life and fibrin-specific form of tissue plasminogen activator in rabbit models of embolic stroke and peripheral bleeding.

Publisher Website
Google Scholar
Abstract
We compared the activity of a new long-half-life, fibrin-specific tissue-type plasminogen activator (TPA) variant with that of wild-type TPA in rabbit models of embolic stroke and peripheral bleeding. In the embolic stroke model. TPA-induced clot lysis is followed by continuous monitoring of a radiolabeled clot lodged in the middle cerebral artery. Twenty-four hours after embolization and treatment with either thrombolytic agent or excipient, the brains are removed, fixed, and evaluated for cerebral hemorrhage. In a parallel template bleeding time experiment, the effects of equipotent doses of the two TPA molecules were measured. Infusion of wild-type TPA or bolus administration of the TPA variant resulted in dose-dependent clot lysis. The TPA variant was found to be an order of magnitude more potent than wild-type TPA on a milligram-per-kilogram basis. Unlike wild-type TPA, the variant caused less systemic activation of plasminogen (P < .05) and fewer hemorrhagic transformations in this model (P < .05). The TPA variant did not extend template bleeding times. These findings show that by combining increased fibrin specificity with decreased plasma clearance, it is possible to produce a thrombolytic agent that is more convenient and more potent than wild-tpe TPA. At the same time the significant reduction in hemorrhagic conversions may be attributable to the conservation of systemic plasminogen seen with this molecule.

This publication has 26 references indexed in Scilit: