Comparison of TNK With Wild-Type Tissue Plasminogen Activator in a Rabbit Embolic Stroke Model

Abstract

Background and Purpose-Tissue plasminogen activator (tPA) is an effective treatment for stroke, but its utility is limited by fear of cerebral hemorrhage. Tenecteplase (TNK), a genetically modified form of wild-type tPA, exhibits a longer biological half-life and greater fibrin specificity, features that could lead to fewer cerebral hemorrhages than wild-type tPA in stroke patients. Methods-We injected radiolabeled blood clots into the cerebral circulation of New Zealand White rabbits. One hour later, we administered tPA (nϭ57), 0.6 mg/kg TNK (nϭ43), 1.5 mg/kg TNK (nϭ27), or vehicle control (nϭ37). A blinded observer examined the brains for macroscopic hemorrhage using a semiquantitative score. We estimated thrombolysis by assessing the amount of radiolabel remaining in the cerebral vessels postmortem. Results-Both wild-type tPA and TNK caused thrombolysis in most subjects. Hemorrhage was detected in 26% (6/23) of the control group, 66% (27/41) of the wild-type tPA group, 55% (16/29) in the 0.6-mg/kg TNK group, and 53% (9/17) in the 1.5-mg/kg TNK group (PϽ0.05, 2 test). The tPA group was statistically significantly different from the control group, but the TNK and tPA groups did not differ from each other. Neither TNK nor tPA affected the size of the hemorrhages. Conclusions-TNK shows comparable rates of recanalization compared with wild-type tPA in a model of embolic stroke.While tPA increases hemorrhage rate, the hemorrhage associated with TNK treatment is not statistically different compared with controls or the tPA group. These findings suggest that TNK shows promise as an alternative thrombolytic treatment for stroke, but we could not demonstrate improved safety compared with wild-type tPA.

Targeting of a Mutant Plasminogen Activator to Circulating Red Blood Cells for Prophylactic Fibrinolysis

“…Even newly designed mutant PAs with enhanced potency, including tPA variants with a mutated PAI-1 binding site and deleted accessory domains implicated in tPA clearance and adverse vascular signaling, i.e., Retavase and Tenekteplase (Chapman et al, 2001), are likely to show limited diffusion into occlusive clots. Furthermore, all existing PAs are short-lived (Ͻ30 min), which makes them fundamentally inadequate for prophylaxis, and small (proteins with molecular mass of 30 -60 kDa, Ͻ10 nm diameter), which permits diffusion into hemostatic clots, increasing the risk of bleeding and increasing the propensity for collateral tissue damage, especially in the CNS.…”

Effect of recombinant human prourokinase on thrombolysis in a rabbit model of thromboembolic stroke

“…Brains were removed subsequent to perfusion and coronally sliced into 5 mm sections. The hemorrhage was estimated used a semi-quantitative method by counting the number of sections where hemorrhage was present (13)(14)(15)(16). Each brain slice has two 'faces' and the score counting criteria were 1 for a hemorrhage on 1 'face'and 2 for a hemorrhage on 2 'faces', then the total bleeding score was calculated.…”

Intravenous Thrombolytics for Ischemic Stroke

“…Embolic stroke models using rabbits have explored a headto-head comparison between rt-PA and TNK [61]. Chapman et al [61] compared 4 groups of animals using radio-labeled injected blood clots: control (no lytic), rt-PA, low-dose TNK (0.6 mg/kg), and high-dose TNK (1.5 mg/kg).…”

“…Chapman et al [61] compared 4 groups of animals using radio-labeled injected blood clots: control (no lytic), rt-PA, low-dose TNK (0.6 mg/kg), and high-dose TNK (1.5 mg/kg). Both the rt-PA and the TNK animals verified thrombolysis resulting in the conclusion that both drugs lyse clots.…”