RATIONALE AND AIM
Recombinant tissue plasminogen activator alteplase is the only FDA-approved thrombolytic agent for thrombolytic treatment of ischemic stroke in patients presenting within 4.5 hours after symptom onset. Its effectiveness is limited and the occurrence of intra- and extracerebral hemorrhage is a major limitation.
Preclinical and clinical studies have indicated that dual thrombolytic therapy, mimicking the physiological design of thrombolysis, with low dose alteplase pre-treatment followed by a mutant pro-urokinase has a significant potential to be safer and more efficacious than the FDA-approved regimen of standard dose alteplase alone (0.9 mg/kg). Mutant pro-urokinase is a mutation of pro-urokinase with less susceptibility to non-specific activation to urokinase. Moreover, m-pro-urokinase by itself does not lyse hemostatic fibrin, only degraded fibrin. When alteplase is cleared from the systemic circulation, mutant pro-urokinase will only induce intravascular clot lysis while sparing hemostatic fibrin. Therefore, this therapeutic regimen has the potential to be safer.
Mutant pro-urokinase has been developed and evaluated pre-clinically by prof Victor Gurewich and his team. In this video he explains the rationale and mechanism of action.
The aim of DUMAS is to test the safety and preliminary efficacy of a dual acute thrombolytic treatment consisting of a small intravenous (IV) bolus of alteplase followed by IV infusion of m-pro-urokinase against usual treatment with IV alteplase in patients presenting with ischemic stroke.
1. Gurewich V, Pannell R, Simmons-Byrd A, Sarmientos P, Liu JN, Badylak SF: Thrombolysis vs. bleeding from hemostatic sites by a prourokinase mutant compared with tissue plasminogen activator. J Thromb Haemost 2006, 4(7):1559-1565.
2. Pannell R, Li S, Gurewich V: Highly effective fibrinolysis by a sequential synergistic combination of mini-dose tPA plus low-dose mutant proUK. PLoS One 2015, 10(3):e0122018.