CM-352 EFFICACY IN A MOUSE MODEL OF ANTICOAGULANT-ASSOCIATED INTRACRANIAL HAEMORRHAGE

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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.

Alternative title
CM-352 as a novel antihaemorrhagic strategy
Location
Deutsche Nationalbibliothek Frankfurt am Main
Extent
Online-Ressource
Language
Englisch

Bibliographic citation
CM-352 EFFICACY IN A MOUSE MODEL OF ANTICOAGULANT-ASSOCIATED INTRACRANIAL HAEMORRHAGE ; day:03 ; month:02 ; year:2022
Thrombosis and haemostasis ; (03.02.2022)

Contributor
Navarro-Oviedo, Manuel
Marta-Enguita, Juan
Roncal, Carmen
Rodriguez, Jose A.
Zandio, Beatriz
Lecumberri, Ramón
Hermida, Jose
Oyarzabal, Julen
Pineda-Lucena, Antonio
Paramo, Jose A.
Muñoz, Roberto
Orbe, Josune

DOI
10.1055/a-1759-9962
URN
urn:nbn:de:101:1-2022032412141814521166
Rights
Open Access; Der Zugriff auf das Objekt ist unbeschränkt möglich.
Last update
15.08.2025, 7:35 AM CEST

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Associated

  • Navarro-Oviedo, Manuel
  • Marta-Enguita, Juan
  • Roncal, Carmen
  • Rodriguez, Jose A.
  • Zandio, Beatriz
  • Lecumberri, Ramón
  • Hermida, Jose
  • Oyarzabal, Julen
  • Pineda-Lucena, Antonio
  • Paramo, Jose A.
  • Muñoz, Roberto
  • Orbe, Josune

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