Gr. Thomas et al., A LONG-HALF-LIFE AND FIBRIN-SPECIFIC FORM OF TISSUE-PLASMINOGEN ACTIVATOR IN RABBIT MODELS OF EMBOLIC STROKE AND PERIPHERAL BLEEDING, Stroke, 25(10), 1994, pp. 2072-2078
Background and Purpose We compared the activity of a new long-half-lif
e, fibrin-specific tissue-type plasminogen activator (TPA) variant wit
h that of wild-type TPA in rabbit models of embolic stroke and periphe
ral bleeding. Methods In the embolic stroke model, TPA-induced clot ly
sis is followed by continuous monitoring of a radiolabeled clot lodged
in the middle cerebral artery. Twenty-four hours after embolization a
nd treatment with either thrombolytic agent or excipient, the brains a
re removed, fixed, and evaluated for cerebral hemorrhage. In a paralle
l template bleeding time experiment, the effects of equipotent doses o
f the two TPA molecules were measured. Results Infusion of wild-type T
PA or bolus administration of the TPA variant resulted in dose-depende
nt clot lysis. The TPA variant was found to be an order of magnitude m
ore potent than wild-type TPA on a milligram-per-kilogram basis. Unlik
e wild-type TPA, the variant caused less systemic activation of plasmi
nogen (P<.05) and fewer hemorrhagic transformations in this model (P<.
05). The TPA variant did not extend template bleeding times. Conclusio
ns These findings show that by combining increased fibrin specificity
with decreased plasma clearance, it is possible to produce a thromboly
tic agent that is more convenient and more potent than wild-type TPA.
At the same time the significant reduction in hemorrhagic conversions
may be attributable to the conservation of systemic plasminogen seen w
ith this molecule.