Efficacy of rt-PA versus Urokinase in early time windows for minimally invasive intracerebral hemorrhage evacuation and exploratory TAFI pharmacogenomics

Background Minimally invasive hematoma evacuation with local thrombolysis is increasingly used for spontaneous intracerebral hemorrhage (ICH), yet comparative data on thrombolytic agents across early time windows remain limited. Whether the thrombin-activatable fibrinolysis inhibitor (TAFI) Thr325Ile polymorphism modulates thrombolytic efficacy in this setting is unknown. Methods We conducted a retrospective comparative cohort study involving 120 patients with supratentorial ICH. Following minimally invasive hematoma aspiration, patients were treated with either rt-PA ( n = 60) or urokinase ( n = 60). Each group was stratified by onset-to-surgery time into ultra-acute (3 to 6 h), acute (6 to 24 h), and subacute (24 to 72 h) subgroups. Neurological and functional outcomes, hematoma clearance, perihematomal edema, and TAFI genotypes were analyzed. Pre-specified exploratory subgroup analyses by dominant hemisphere and by hematoma volume stratum (30–50 mL vs. 51–80 mL) were also performed. Effect sizes with 95% confidence intervals (CIs) are reported alongside p- values, and the Bonferroni method was applied to control the family-wise error rate for primary between-group comparisons. Results rt-PA was associated with better neurological and functional outcomes than urokinase from discharge onward across all three time windows (all Bonferroni-adjusted p < 0.017), with higher hematoma clearance and lower perihematomal edema. The difference in 3-month NIHSS score within the ultra-acute subgroup was 5.24 points (95% CI: 4.30–6.18; Cohen’s d = 4.06). Ultra-acute treatment produced the most favorable outcomes regardless of agent. The TAFI Ile325 (TT) genotype was enriched in the ultra-acute rt-PA subgroup (80.00% vs. 22.22% acute and 29.63% subacute; p = 0.009; odds ratio for TT carriage vs. urokinase in the ultra-acute subgroup = 10.00 [95% CI: 1.80–55.71]) and positively correlated with hematoma clearance in that window ( r = 0.670, p = 0.006). No genotype–outcome association was observed with urokinase. Conclusion rt-PA was associated with more favorable outcomes than urokinase for minimally invasive ICH evacuation in this retrospective cohort, with the ultra-acute window conferring the greatest benefit. The TAFI Ile325 genotype may represent a candidate pharmacogenomic marker for enhanced rt-PA response during this early period. These hypothesis-generating findings require validation in prospective, multicenter studies.