RATIONALE AND AIM

Recombinant tissue plasminogen activator alteplase is the only FDA-approved thrombolytic agent for thrombolytic treatment of ischemic stroke. 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.[1]

Mutant pro-urokinase has been developed and evaluated pre-clinically by prof Victor Gurewich and his team.[2] 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.

References

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.