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

• Published in: Stroke (1970) Vol. 32; no. 3; pp. 748 - 752
• Main Authors: Chapman, Deborah F., Lyden, Patrick, Lapchak, Paul A., Nunez, Sonia, Thibodeaux, Harold, Zivin, Justin
• Format: Journal Article
• Language: English
• Published: Hagerstown, MD Lippincott Williams & Wilkins 01.03.2001
• Subjects: Animals; Biological and medical sciences; Blood. Blood coagulation. Reticuloendothelial system; Cerebral Hemorrhage - etiology; Cerebral Hemorrhage - pathology; Cerebral Hemorrhage - prevention & control; Disease Models, Animal; Intracranial Embolism - complications; Intracranial Embolism - drug therapy; Intracranial Embolism - pathology; Medical sciences; Neurology; Pharmacology. Drug treatments; Rabbits; Stroke - complications; Stroke - drug therapy; Stroke - pathology; Thrombolytic Therapy - adverse effects; Tissue Plasminogen Activator - adverse effects; Tissue Plasminogen Activator - therapeutic use; Treatment Outcome; Vascular diseases and vascular malformations of the nervous system; Animal model; Nervous system diseases; Stroke; Cerebral embolism; Rabbit; Cardiovascular disease; Lagomorpha; Cerebral disorder; Vascular disease; Vertebrata; Chemotherapy; Mammalia; Alteplase; Treatment; Animal; Central nervous system disease; Tenecteplase; Cerebrovascular disease; Comparative study; Fibrinolytic
• ISSN: 0039-2499; 1524-4628; 1524-4628
• DOI: 10.1161/01.STR.32.3.748

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 (n=57), 0.6 mg/kg TNK (n=43), 1.5 mg/kg TNK (n=27), or vehicle control (n=37). 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 ( P <0.05, χ 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.