Differential effect of recombinant tissue plasminogen activator-induced thrombolysis in the central nervous system and systemic arteries

Abstract

Recombinant tissue plasminogen activator (rTPA) has been more effective in inducing thrombolysis in laboratory studies of intracranial thrombosis than clinical studies of systemic or coronary thrombosis would indicate. To evaluate this discrepancy, 21 rabbits were subjected to embolic occlusion of the right internal carotid artery (ICA) by retrograde injection of a tin-tagged, 2-hour-old autologous clot through the external carotid artery with angiographic monitoring in the same manner as in a previously reported model. The emboli lodged intracranially at the bifurcation of the ICA in 10 animals and in the cervical ICA in 11 animals. Digital subtraction angiography confirmed total occlusion of the ICA in all animals. Treatment started one-half hour after embolization and consisted of a bolus of 0.5 mg/kg of rTPA followed by an infusion of 1 mg/kg/h for 2 hours. All of the animals with intracranial emboli and 6 of the animals with cervical emboli were treated intravenously. The remaining 5 animals with cervical emboli were treated by intracarotid infusion of the same dose of rTPA. In the intravenously treated group, serial digital subtraction angiography documented thrombolysis in 9 of the 10 animals with intracranial emboli and only 1 of the 6 with cervical emboli. Thrombolysis occurred in 4 of the 5 rabbits with cervical emboli treated with intracarotid rTPA. Intravenous rTPA therapy produced a significantly (P less than 0.01) higher rate of thrombolysis in intracranial as compared to cervical thrombus.(ABSTRACT TRUNCATED AT 250 WORDS)

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

“…However, there is mounting evidence that the cerebral endothelial cells respond differently to the presence of TPA compared with their peripheral counterparts, de Bono et al 37 showed that TPA-induced cerebral bleeding as a result of injury was inhibited with tranexamic acid, whereas aprotinin was more potent in reducing peripheral bleeding times. Further evidence was presented by Chehrazi et al, 33 who showed TPA to be more potent at lysing equivalent clots in the central nervous system compared with clots in the peripheral vasculature. Thus, the reason for reduced cerebral hemorrhages may be more complicated than simply attenuating circulating plasmin levels.…”

The March of Thrombolytic Therapy for Acute Ischemic Stroke to Clinical Trials: Pre-clinical Thrombolysis and Adjuncts to Thrombolysis Research

“…Further, there is experimental data suggesting that rt-PA is more effective in inducing thrombolysis within precerebral vessels than systemic vessels [ 21 ]. At present, IV rt-PA at 0.9 mg/kg is licensed in many countries and appears to represent best practice and other drugs (see new thrombolytics below), doses or routes of administration should only be used in randomised controlled trials [ 22 ].…”