LAUSR

BACKGROUND Intracranial haemorrhage (ICH) is one of the major devastating complications of anticoagulation. Matrix metalloproteinases (MMPs) inhibition has been proposed as a novel pharmacological approach for ICH treatment. OBJECTIVES We evaluated the effects of CM-352 (MMPs-fibrinolysis inhibitor) in an experimental ICH model associated with oral anticoagulants as compared with clinically used prothrombin concentrate complex (PCC). METHODS ICH was induced by collagenase injection into the striatum of WT (C57BL/6J) anticoagulated mice (warfarin or rivaroxaban) and Mmp10 -/- mice. Hematoma volume and neurological deficits were measured 24h later by diaminobenzidine staining and different behavioural test. Circulating plasminogen activator inhibitor-1 (PAI-1) activity and interleukin-6 (IL-6) were measured in plasma samples and local inflammation was assessed by neutrophil infiltration. Finally, fibrinolytic effects of MMP-10 and rivaroxaban were evaluated by thromboelastometry and thrombin-activatable fibrinolysis inhibitor (TAFI) activation assays. RESULTS Only PCC reduced haemorrhage volume and improved functional outcome in warfarin-ICH, but both, PCC and CM-352 treatments, diminished haemorrhage volume (46%, p<0.01 and 64%, p<0.001, respectively) and ameliorated functional outcome in rivaroxaban-ICH. We further demonstrated that CM-352, but not PCC decreased neutrophil infiltration in the haemorrhage area at 24h. The effect of CM-352 could be related to MMP-10 inhibition since Mmp10-/- mice showed lower haemorrhage volume, better neurological score, reduced IL-6 levels and neutrophil infiltration, and increased PAI-1 after experimental ICH. Finally, we found that CM-352 reduced MMP-10 and rivaroxaban-related fibrinolytic effects in thromboelastometry and TAFI activation. CONCLUSIONS CM-352 treatment, by diminishing MMPs and rivaroxaban-associated fibrinolytic effects, might be a novel antihaemorrhagic strategy for rivaroxaban-associated ICH.