Ixodes ricinus ‐Contact Phase Inhibitor Promotes Functional Recovery and Attenuates Neutrophil Associated Neuroinflammation After Experimental Intracerebral Hemorrhage

AIMS: Neutrophil-associated inflammation contributes to secondary brain injury after intracerebral hemorrhage (ICH). We evaluated whether Ixodes ricinus-Contact Phase Inhibitor (Ir-CPI), a selective factor XIa/XIIa inhibitor with reported thromboinflammatory modulatory properties, improves outcome after experimental ICH without worsening bleeding. METHODS: In a collagenase-induced mouse ICH model, Ir-CPI was administered as an intravenous bolus followed by a 3-day infusion. Vehicle animals served as controls and enoxaparin as an anticoagulant comparator. Cohorts evaluated hemorrhage and lesion volumes, endothelial activation, neutrophil-associated inflammation, and longitudinal functional recovery. Ir-CPI association with human neutrophils was evaluated in vitro. RESULTS: Ir-CPI did not increase hemorrhage or lesion volumes versus PBS through Day 14, whereas enoxaparin showed a higher Day 1 hemorrhage volume than Ir-CPI. Flow cytometry showed Ir-CPI association with human neutrophils. In the mouse model, Ir-CPI produced region-specific reductions in neutrophil infiltration and NET formation and reduced neuronal degeneration at the injection site and caudal level, without affecting VCAM-1-associated endothelial activation. Ir-CPI accelerated functional recovery, improving neurological scores and sensorimotor asymmetry by Day 5, with restoration of baseline corner test performance by Day 14. CONCLUSION: Ir-CPI improves recovery after experimental ICH without exacerbating bleeding and is associated with reduced neutrophil-associated secondary brain injury. These findings support its translational potential as a therapeutic strategy for ICH.