CM-352 Efficacy in a mouse model of anticoagulant-associated intracranial hemorrhage

Background: Intracranial hemorrhage (ICH) is one of the major devastating complications of anticoagulation. Matrix metalloproteinase (MMP) inhibition has been proposed as a novel pharmacological approach for ICH treatment. Objectives: We evaluated the effects of CM-352 (MMP-fibrinolysis inhibitor) i...

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Autores: Navarro-Oviedo, M. (Manuel)|||/items/a31a22a2-5c3f-4e19-9484-37ed161a46f9, Marta-Enguita, J. (Juan)|||/items/f3d5c8ce-b5d6-4e47-b7fb-87dc013e7f62, Roncal-Mancho, C. (Carmen)|||/items/6c0dc409-f0aa-412b-9d75-436ba8a0a4ff, Rodriguez, J.A. (José Antonio)|||/items/dfeeb791-bd5d-4472-bce8-b7f54cdf8f31, Zandio, B. (Beatriz)|||/items/70227b87-2ead-4a39-ae53-d7dc11bffc5d, Lecumberri-Villamediana, R. (Ramón)|||/items/d804c113-76a8-47fb-85ad-0f01acbe605a, Hermida-Santos, J. (José)|||/items/9e67bdb3-d55d-4819-847e-9b44cc487fdb, Oyarzabal, J. (Julen)|||/items/5fe770fd-2181-41c9-a467-28cc89a40250, Pineda-Lucena, A. (Antonio)|||/items/aabeed59-b8b3-4787-a803-a5fc7136ef9f, Páramo-Fernández, J.A. (José Antonio)|||/items/8c56baa6-2a43-4836-b91b-4eed15be3c96, Muñoz, R. (Roberto)|||/items/f9917ae1-528d-4043-be53-e8774ed26f8e, Orbe-Lopategui, J. (Josune)|||/items/033ea7ef-1eff-418a-9fc4-1e2d3498d726
Tipo de recurso: artículo
Fecha de publicación:2022
País:España
Institución:Universidad de Navarra
Repositorio:Dadun. Depósito Académico Digital de la Universidad de Navarra
Idioma:inglés
OAI Identifier:oai:dadun.unav.edu:10171/68826
Acceso en línea:https://hdl.handle.net/10171/68826
Access Level:acceso abierto
Palabra clave:Anticoagulants
Fibrinolysis
Hemorrhagic
Stroke
Matrix metalloproteinases
Thrombosis
Descripción
Sumario:Background: Intracranial hemorrhage (ICH) is one of the major devastating complications of anticoagulation. Matrix metalloproteinase (MMP) inhibition has been proposed as a novel pharmacological approach for ICH treatment. Objectives: We evaluated the effects of CM-352 (MMP-fibrinolysis inhibitor) in an experimental ICH model associated with oral anticoagulants as compared with clinically used prothrombin complex concentrate (PCC). Methods: ICH was induced by collagenase injection into the striatum of wild type (C57BL/6J) anticoagulated mice (warfarin or rivaroxaban) and Mmp10 -/- mice. Hematoma volume and neurological deficits were measured 24 hours later by diaminobenzidine staining and different behavioral tests. 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 hemorrhage volume and improved functional outcome in warfarin-ICH, but both PCC and CM-352 treatments diminished hemorrhage 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 hemorrhage area at 24 hours. The effect of CM-352 could be related to MMP-10 inhibition since Mmp10 -/- mice showed lower hemorrhage 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. Conclusion: CM-352 treatment, by diminishing MMPs and rivaroxaban-associated fibrinolytic effects, might be a novel antihemorrhagic strategy for rivaroxaban-associated ICH.

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