OC 76.4 - CM-352 reduces rivaroxaban-associated ICH by mechanisms dependent on MMP-10 and fibrinolysis inhibition

Wednesday, July 13, 2022

11:00 AM – 11:15 AM

Location: ExCel Center, ICC Capital Suite Room 2-4

Presentation Format: In-Person

Co-Author(s)

MN

Manuel Navarro-Oviedo

PhD
Cima-Universidad de Navarra
Pamplona, Navarra, Spain
JM

Juan Marta-Enguita

Neurologist
Cima-Universidad de Navarra
Pamplona, Navarra, Spain
Carmen Roncal, PhD

Researcher
Cima Universidad de Navarra
Pamplona, Navarra, Spain
JR

Jose A. Rodriguez

PhD
Cima Universidad de Navarra
Pamplona, Navarra, Spain
BZ

Beatriz Zandio

Neurologist
Complejo Hospital de Navarra
Pamplona, Navarra, Spain
RL

Ramón Lecumberri

Hematology Service
Clínica Universidad de Navarra
Pamplona, Navarra, Spain
FM

Florencio JDM Machado

MD
Cima-Universidad de Navarra
Pamplona, Navarra, Spain
JO

Julen Oyarzabal

PhD
Cima-Universidad de Navarra
Pamplona, Navarra, Spain
AP

Antonio Pineda-Lucena

PhD
Cima-Universidad de Navarra
Pamplona, Navarra, Spain
JP

Jose Antonio Páramo

Hematology Service
Clínica Universidad de Navarra
Pamplona, Navarra, Spain
RM

Roberto Muñoz

Neurologist
Complejo Hospital de Navarra
Pamplona, Navarra, Spain

Presenting Author(s)

Josune Orbe, PhD

Researcher
Centro de Investigación Médica Aplicada (CIMA), Universidad de Navarra
Pamplona, Navarra, Spain

Background: Intracranial haemorrhage (ICH) is one of the major devastating complications of anticoagulation. DOACs antiXa, aside from their anticoagulant effects, enhance fibrinolysis, thus patients treated with FXa inhibitors experiencing bleeding might benefit from antifibrinolytic compounds. Matrix metalloproteinases (MMPs) inhibition has been proposed as a novel pharmacological approach for ICH treatment.

Aims: We evaluated the effects of CM-352 (MMPs-fibrinolysis inhibitor) in an experimental ICH model associated with rivaroxaban as compared with clinically used prothrombin complex concentrate (PCC).

Methods: ICH was induced by collagenase injection into the striatum of WT (C57BL/6J) anticoagulated mice (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: 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. Interestingly, only CM-352 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, IL-6 levels and neutrophil infiltration, as well as better neurological score 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(s): CM-352 treatment, by diminishing fibrinolysis related to MMPs and rivaroxaban-, might be a novel antihaemorrhagic strategy for rivaroxaban-associated ICH.

Funding: ISCIII (PI15/01807 and PI19/00065"), co-funded by ERDF, "A way to make Europe", grants from the Spanish Society of Thrombosis and Haemostasis (SETH), Navarra Government (02/2015), and Virto Group (Navarra, Spain).
Patent family (EP 12382285) was licensed to Hemostatics Pharmaceuticals S.L.