Summary The aim of this study was to evaluate the thrombolytic activity of two hybrid plasminogen activators (HPAs) in a rabbit jugular vein thrombosis model. In the two HPAs the kringle-2 domain (K2tu-PA) or the finger and the kringle-2 domains (FK2tu-PA) of tissue-type plasminogen activator (t-PA) are linked to the catalytic protease domain of single chain urokinase type plasminogen activator (scu-PA). The two HPAs were compared with rt-PA and scu-PA on a weight/weight basis. K2tu-PA, FK2tu-PA, rt-PA and scu-PA were infused at doses of 0.4, 0.8 and 1.2 mg/kg over 3 h. Saline served as control. Saline produced 11 ± 2% thrombolysis. The three doses of K2tu-PA led to 38 ± 4%, 66 ± 5% and 89 ± 7% thrombolysis, respectively; the three doses of FK2tu-PA: 18 ± 3%, 29 ± 5% and 33 ± 6%, respectively; the three doses of rt-PA 32 ± 2%, 49 ± 3% and 68 ± 6%, respectively; the three doses of scu-PA 16 ± 2%, 24 ± 3% and 32 ± 4%, respectively. K2tu-PA and rt-PA showed a statistically significant higher thrombolytic activity than FK2tu-PA and scu-PA at the three tested doses (p <0.01). The thrombolytic activity of K2tu-PA was significantly higher than rt-PA at the two higher doses (p <0.01). Both K2tu-PA and rt-PA produced a statistically significant reduction of fibrinogen, α2-antiplasmin and plasminogen 3 h after the start of the infusions of the two higher doses. No statistically significant differences between K2tu-Pa and rt-PA were observed. Concomitant with the lower thrombolytic activity, the systemic proteolytic effects of FK2tu-PA and scu-PA were less pronounced. We conclude that the two HPAs we tested are effective thrombolytic agents. K2tu-PA deserves particular attention in future experiments.
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