EFFICACY AND SELECTIVITY OF TISSUE-TYPE AND UROKINASE-TYPE PLASMINOGEN ACTIVATORS IN A HUMANIZED PULMONARY-EMBOLISM MODEL

The potency and selectivity of tissue-type (t-PA) and urokinase-type (u-PA) plasminogen activators have been compared in a guinea pig pulmonary embolism model. Radiolabelled human whole blood clots were embolised to the lungs and the animals supplemented with human plasminogen in order to mimic more closely the activity of thrombolytic enzymes in man. Addition of human plasminogen increased sensitivity of the model. Under these conditions of plasminogen supplementation, infused t-PA had a similar selectivity profile to that seen in the clinic; that is, at high doses, there was measurable fibrinogen depletion as determined by a clotting rate assay. By contrast, bolus doses of urokinase resulting in only modest thrombolysis produced completely unclottable plasmas. Whether given by bolus or infusion, t-PA showed similar potency at a 1 1 2 h end-point; u-PA was also equally potent when given by bolus or infusion, although whatever the method of administration it was less potent than t-PA on a molar basis. The results suggest that it is possible to simulate the clinical profile of the selectivity of t-PA and u-PA by using a 'humanised' model. © 1990.