PB0775 - Evaluation of Hemorrhage and Edema Expansion, Including Effect on Neutrophil-Mediated Neuroinflammation in Intracerebral Hemorrhage, Using Ir-CPI, a Thromboinflammation Inhibitor

Background: Intracerebral hemorrhage (ICH) is a subtype of stroke with a high mortality and functional disability rate. The inflammation and coagulation responses after ICH would accelerate the formation of perihematomal edema (PHE), resulting in brain herniation-related death and neurological deficits. Patients with ICH also frequently present with thrombotic events, including secondary intracerebral ischemic lesions and in-hospital thromboembolic complications. However, medical treatments for inflammation and safe prevention of thrombosis are lacking during the hyperacute phase of ICH.
Ixodes ricinus-Contact Phase Inhibitor (Ir-CPI) is an inhibitor of both coagulation factors (Factors XIIa and XIa) and neutrophils, with proven antithrombotic effect in various animal models.

Aims: We evaluated the effects of Ir-CPI on PHE and hemorrhage volumes, on neutrophil infiltration and neuronal degeneration in mice using an ICH model.

Methods: ICH was induced by injecting collagenase into the right striatum. Mice were allocated to either PBS, Ir-CPI (30.7 mg/kg + 8.3 mg/kg/h) or enoxaparin (20 mg/kg) (n = [6-8]). Treatments were administered intravenously immediately after stroke induction as a bolus followed by a 3-day infusion. Dose of Ir-CPI used was previously proven to be antithrombotic in mice. P-values were calculated using a Kruskal-Wallis test with Dunn's multiple comparison test.

Results: Ir-CPI did not increase PHE and hemorrhage volumes measured by magnetic resonance imaging 1 and 3 days after ICH, as compared to PBS. Ir-CPI decreased neutrophil infiltration and significantly decreased the number of neutrophil-releasing NETs at collagenase injection site (p < 0.05). Ir-CPI also reduced the number of degenerating neurons in the hemorrhagic zone (p < 0.05 at the injection site). In contrast, enoxaparin increased PHE and hemorrhage volumes as compared to Ir-CPI (p < 0.05) and PBS and had no significant impact on neutrophil infiltration and degenerating neurons.

Conclusion(s): Ir-CPI administration after ICH induction is safe, reduces neutrophil infiltration including neutrophil-releasing NETs, and attenuates neuronal degeneration.