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Circulation, Vol 79, 125-133, Copyright © 1989 by American Heart Association

ARTICLES

Time course of thrombolysis induced by intravenous bolus or infusion of tissue plasminogen activator in a rabbit jugular vein thrombosis model

JP Clozel, T Tschopp, E Luedin and P Holvoet
F. Hoffmann-La Roche & Co, Ltd, Pharmaceutical Research Department, Basel, Switzerland.

Tissue plasminogen activator is a thrombolytic agent that has been shown to be efficient in patients with myocardial infarction or pulmonary embolus. However, little is known about the time course and the dose dependency of its thrombolytic effect. The goal of our study was to investigate the time course of the thrombolysis induced by increasing doses of tissue plasminogen activator (t-PA) given either as a continuous infusion (0.0625-1 mg/kg) or as a bolus (0.05-0.4 mg/kg). For this purpose, we modified a previously described rabbit jugular vein thrombosis model by using an external gamma counter to follow continuously the thrombolysis. After administration of t-PA as either an infusion or a bolus, the rate and the extent of thrombolysis were dose dependent. The thrombus size decreased regularly following an exponential curve and reached a lower asymptote implicating an unlysable thrombus. As expected, after bolus injection, t-PA was rapidly inhibited resulting in a duration of action of approximately 15 minutes; this was independent of the dose. Surprisingly, during continuous infusion of t-PA for as long as 4 hours, the duration of action was limited to about 2 hours, although the plasma t-PA activity levels remained stable. Although the rate of inhibition was lower and thus the duration of action was longer during continuous infusion of t- PA than after a bolus injection, the extent of thrombolysis was similar when the same dose of t-PA was given as either a bolus or an infusion. These findings could be attributed to the higher initial rate of thrombolysis observed after a bolus injection.(ABSTRACT TRUNCATED AT 250 WORDS)