Scientific publications

CM-352 efficay in a mouse model of anticoagulant-associated intracranial haemorrhage

Aug 1, 2022 | Magazine: Thrombosis and Haemostasis

Manuel Navarro-Oviedo  1 , Juan Marta-Enguita  1   2 , Carmen Roncal  1   3 , Jose A Rodriguez  3   1 , Beatriz Zandio  2 , Ramón Lecumberri  3   4 , Jose Hermida  3   5 , Julen Oyarzabal  6 , Antonio Pineda-Lucena  6 , Jose A Paramo  3   1   4 , Roberto Muñoz  7   2 , Josune Orbe  3   1

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.

CITATION  Thromb Haemost. 2022 Aug;122(8):1314-1325.  doi: 10.1055/a-1759-9962.  Epub 2022 Feb 3