Andexanet alfa Reduces Hematoma Expansion Following Controlled Cortical Impact in Mice Pretreated with Rivaroxaban

OBJECTIVE: With the introduction of andexanet alfa, a specific antidote is now available to address life-threatening bleeding associated with factor Xa inhibitors. In this study, we explore its use in an experimental model of traumatic brain injury (TBI), mimicking a closed head trauma under rivaroxaban-induced anticoagulation. METHODS: Male C57BL6 mice were fed with rivaroxaban (10 mg/kg body weight). Subsequently, TBI was induced by controlled cortical impact (CCI) and andexanet alfa or placebo were administered as intravenous bolus injections. Edema and hemorrhage volume was quantified by magnetic resonance imaging (MRI) 24 h and 7 days after CCI. Functional outcome was assessed at day 1, 3, and 7 thereafter. RESULTS: Andexanet alfa led to reduced hemorrhage volume 24 h and 7 days after CCI as compared with control group without reversal of anticoagulation (2.9 ± 1.4 µl vs. 5.2 ± 3.3 µl, p = 0.02; 3.4 µl ± 1.5 µl vs. 5.5 µl ± 2.4 µl, p = 0.04). Along with the smaller hematoma sizes in the MRI, edema volume was significantly lower in mice treated with andexanet alfa 24 h and 7 days after CCI (-6.3% of contralateral hemisphere, p = 0.0002; and -7.1% of contralateral hemisphere, p = 0.006). While functional outcomes did not differ at 24 h following TBI, andexanet alfa improved neurological deficits after 7 days. CONCLUSIONS: Our experimental data suggests that the use of andexanet alfa improves functional outcomes by reduction of factor Xa inhibitor-associated hematoma expansion in the subacute phase following TBI.