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DOI: 10.1055/a-1759-9962
CM-352 Efficacy in a Mouse Model of Anticoagulant-Associated Intracranial Hemorrhage
Funding This work was supported by ISCIII (PI15/01807 and PI19/00065”), co-funded by ERDF, “A way to make Europe”, the Spanish Society of Thrombosis and Haemostasis (SETH), the Navarra Government (02/2015), and the Virto Group (Navarra, Spain).
Abstract
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.
Keywords
anticoagulants - fibrinolysis - hemorrhagic - stroke - matrix metalloproteinases - thrombosisAuthor Contributions
M.N.O. participated in the design of the project, experimental work, statistical analysis, and wrote, reviewed, and edited the manuscript; J.M.E. participated in the analysis of data, and edited and reviewed the manuscript; C.R. participated in experimental work, data analysis, and reviewed the manuscript; J.A.R., B.Z., J.H., J.O., J.A.P., and R.M. participated in the design of the project and reviewed the manuscript; A.P.L., and R.L. have provided intellectual content and reviewed the manuscript; and J.O. was in charge of project design, supervised the work and wrote, edited, and reviewed the manuscript.
Publication History
Received: 29 July 2021
Accepted: 05 January 2022
Accepted Manuscript online:
03 February 2022
Article published online:
05 May 2022
© 2022. The Author(s). This is an open access article published by Thieme under the terms of the Creative Commons Attribution-NonDerivative-NonCommercial License, permitting copying and reproduction so long as the original work is given appropriate credit. Contents may not be used for commercial purposes, or adapted, remixed, transformed or built upon. (https://creativecommons.org/licenses/by-nc-nd/4.0/)
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