Evaluation of Recombinant Tissue Plasminogen Activator in Embolic Stroke

Abstract

In an effort to determine the value of tissue-type plasminogen activator (TPA) in the treatment of embolic stroke, 17 rabbits were subjected to a model of embolic stroke in which 2-hour-old, tin-impregnated, autologous clots were embolized to the bifurcation of the internal carotid artery at the circle of Willis via retrograde injection into the cannulated external carotid artery. High-resolution digital subtraction radiography was used to localize clots intracranially at the carotid bifurcation. Circulation through the internal carotid artery and intracranial vessels was monitored with serial digital subtraction angiography before and after embolization and during treatment. Disappearance of the tin marker on the digital subtraction radiograph indicated dissolution of clot and was associated with reestablishment of circulation on the digital subtraction angiogram. Experimental animals were treated with human-specific recombinant TPA 30 minutes, 2 hours, or 4 hours after clot embolization. TPA was administered as an intravenous bolus of 0.5 mg/kg followed by an infusion of 1 mg/kg/h for 2 hours. Digital subtraction angiograms were performed every 30 minutes. All clots dissolved, and cerebral circulation was reestablished within 120 minutes of treatment. In control animals treated with saline, embolized clots were stable, and the internal carotid artery remained occluded. At the completion of each study, the animal was perfused with freshly prepared, buffered 2,3,5-triphenyltetrazolium chloride (TTC) for demarcation of cerebral infarction. Control animals demonstrated infarction of 50 +/- 3.6% of the ipsilateral cerebral hemisphere, with an infarct weight of 2.1 +/- 0.2 g.(ABSTRACT TRUNCATED AT 250 WORDS)

Influence of tissue plasminogen activator and heparin on cerebral ischemia in a rabbit model.

“…The absence of hemorrhagic change in the ischemic areas of the brains of our rabbits accords with the findings of Benes et al 6 (using rabbits treated with a 1 mg t-PA bolus 30 minutes after embolization, then 1 mg/kg/hr infusion for 2 hours and killed 6 hours later) and of Chehrazi et al 22 (dosage as above and killed immediately after completion of treatment), as well of Slivka and Pulsinelli 29 (whose animals survived 30 hours after receiving a single bolus of streptokinase 1 hour postembolization). These latter authors also found that hemorrhagic transformation of the stroke was common when treatment was delayed for 24 hours with 7-9 hours' subsequent survival.…”

“…Chehrazi et al 22 found that the radiographic image of a tin-tagged embolus disappeared and the volume of ischemic brain was significantly reduced when their animals received a 0.5 mg bolus of t-PA followed by a 1 mg/kg/hr infusion over 2 hours, treatment commencing 30 minutes, 2 hours, or 4 hours after embolization, but there is a trend in their data that suggests that the earlier the t-PA administration was commenced, the smaller the resulting infarct. With higher doses of t-PA (3 mg or 5 mg/kg), thrombolysis occurred when t-PA was administered 8 or even 24 hours after embolization, but neurological damage was not prevented.…”

“…Other investigators have since employed either a rabbit or a rat model, administering t-PA or an analogue at varying intervals after embolization of the MCA with either single or multiple thrombi of various sizes. 7101415 - 22 It appears that thrombolysis can be achieved in rabbits when 3 hours 14 or even longer 8^22 elapses from embolization to the administration of t-PA. However, the thrombi used in these studies were in most instances <24 hours old and all were "red" thrombi prepared by preclotting autologous or heterologous venous blood.…”

Reduction of infarct volume and mortality by thrombolysis in a rat embolic stroke model.

“…In animal models, neuropathologic microscopic examination of brain cells and tissue with volumetric measurement of infarct sizes, which may be considered one of the most reliable parameters, was done by Zivin et al 26 - 27 and Phillips et al, 15 who found no difference in infarct volume between thrombolytic-treated and control animals. In the studies of Benes et al, 20 Chehrazi et al, 13 In the animals treated with rt-PA, apart from slight oozing of blood during and shortly after operation, we observed no hemorrhagic complications. Because this phenomenon was rare in thrombolytic-treated as well as in controls, this model is probably not sensitive to hemorrhagic transformation of infarction.…”

Effect of intra-arterial tissue plasminogen activator and urokinase on autologous arterial emboli in the cerebral circulation of rabbits [corrected].

“…Numerous investigators have demonstrated the effectiveness of fibrinolytic therapy in clearing clotted blood from the cerebral arterial system in laboratory models of embolic stroke. 8 - 13 However, the arterial thrombus and thrombotic emboli responsible for clinical stroke differ markedly from the simple blood clots used in these experimental models. 1415 Unlike simple "red" clot, thrombus formed in the arterial system ("white" clot) is composed largely of platelets and fibrin.…”