Urokinase redux: route, compartment, access, and pharmacological evolution from native urokinase to recombinant prourokinase

Urokinase is often regarded as an older thrombolytic displaced by fibrin-selective agents in reperfusion medicine. Yet its decline has been uneven. This mini-review reframes its contemporary role through three determinants: route, compartment, and access. The systemic role of native urokinase has receded, particularly in stroke. Adjunctive thrombolysis after endovascular reperfusion remains unsettled: POST-UK and POST-TNK were neutral, whereas PEARL and ANGEL-TNK reported higher 90-day excellent-outcome rates. Trial differences preclude a uniform conclusion or generalization to primary intra-arterial thrombolysis and local fibrinolysis. Native urokinase retains a niche when delivered directly into clot-containing compartments or established catheters, including intracranial blood collections, chronic subdural hematoma, selected venous thromboembolism, loculated pleural disease, and catheter-related thrombotic dysfunction. In these settings, it functions as a low-cost, familiar, locally delivered fibrinolytic that facilitates clot clearance or drainage. Supporting evidence remains heterogeneous and often derives from retrospective cohorts, small studies, and variable protocols. Recombinant human prourokinase should be distinguished pharmacologically and clinically from native urokinase. As a zymogen precursor preferentially activated at the fibrin-rich thrombus surface, it represents a renewed systemic reperfusion pathway. Following the historical proof of concept provided by PROACT II, PROST and PROST-2 showed intravenous recombinant human prourokinase to be non-inferior to alteplase for excellent 90-day functional outcomes; PROST-2 additionally reported lower rates of symptomatic intracranial hemorrhage and major bleeding. External generalizability and direct comparison with tenecteplase remain unresolved. The contemporary urokinase pathway therefore reflects a dual evolution: native urokinase retains focused local and access-driven roles, whereas recombinant prourokinase has re-entered systemic reperfusion therapy.