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Ticagrelor prevents infective endocarditis by mitigating Staphylococcus aureus virulence

N. Jacques1, S. Meyers2, K. Leeten1, M. Lox3, M. Debuisson1, P. Delvenne4, A. Nchimi1, M. Kuijpers5, T. Vanassche6, K. Martinod7, P. Verhamme3, P. Lancellotti8, C. Oury1

1Laboratory of Cardiology, GIGA Institute, University of Liège, Liège, Belgium, Liege, Liege, Belgium, 2Center for Molecular and Vascular Biology, KU Leuven, Leuven, Belgium, Leuven, Vlaams-Brabant, Belgium, 3Center for Molecular and Vascular Biology, Department of Cardiovascular Sciences, KU Leuven, Leuven, Belgium, Leuven, Vlaams-Brabant, Belgium, 4Department of Pathology, CHU of Liège, Liège, Belgium ; Laboratory of Experimental Pathology, GIGA Institute, University of Liège, Liège, Belgium, Liège, Liege, Belgium, 5Department of Biochemistry, Cardiovascular Research Institute Maastricht (CARIM), Maastricht University; Thrombosis Expertise Centre, Heart and Vascular Centre, Maastricht University Medical Centre, Maastricht, The Netherlands, Maastricht, Limburg, Netherlands, 6University Hospitals Leuven, KULeuven, Leuven, Belgium, Leuven, Vlaams-Brabant, Belgium, 7KU Leuven, Leuven, Vlaams-Brabant, Belgium, 8Laboratory of Cardiology, GIGA Institute, University of Liège, Liège, Belgium; Gruppo Villa Maria Care and Research, Maria Cecilia Hospital, Cotignola, and Anthea Hospital, Bari, Italy, Liege, Liege, Belgium

Abstract Number: PB0762

Meeting: ISTH 2022 Congress

Theme: Hemostatic Systems in Cancer, Inflammation and Immunity » Platelets and Infection

Background: Infective endocarditis (IE) is a deadly disease mainly caused by the gram-positive and highly virulent bacteria Staphylococcus aureus (SA). Due to lack of efficacy of current antibiotic therapy, there is an urgent need to discover new strategies that could prevent this disease.

Aims: To assess the ability of the antiplatelet drug ticagrelor, which also displays antibacterial activity against gram-positive bacteria, to prevent SAIE.

Methods: We used a mouse model of infective endocarditis induced by a SAIE clinical isolate. Ticagrelor was administered orally at a conventional dosage (3mg/kg, single dose) prior to infection and local histamine infusion on the aortic valve. Infected vegetation presence was determined by Gram staining on heart sections after three days. Antibacterial effect of ticagrelor at dosages equivalent to plasma levels achieved in patients (0.75-1.25mg/L) was assessed in vitro in human blood.

Results: Ticagrelor significantly prevented the formation of infected vegetation, with IE in only 14.3% of ticagrelor-treated mice (n=21) compared to 52.3% of vehicle-treated mice (n=37). Ex vivo ADP-induced platelet aggregation assays confirmed rapid reversibility of antiplatelet activity (4 hours), which made it unlikely that solely the antiplatelet effect would explain IE prevention by ticagrelor. Bacterial survival in blood was not diminished three days post-infection. We therefore assessed whether ticagrelor could affect bacterial virulence. We found that growing SA in the presence of 1.25mg/L ticagrelor inhibited alpha-toxin RNA expression and protein secretion, which was corroborated with drastically reduced hemolysis and platelet aggregation induced by bacterial supernatants. Ticagrelor-treated bacteria could no longer adhered to fibrinogen, and in whole blood perfusion experiments, flow-dependent bacterial adhesion on activated endothelial cells was severely impaired.

Conclusion(s): Our study demonstrates the unprecedented ability of ticagrelor to prevent IE by a novel mechanism of directly mitigating bacterial virulence. Hence, clinical trials using ticagrelor as adjunct therapy to antibiotics in patients at risk for IE are warranted.

To cite this abstract in AMA style:

Jacques N, Meyers S, Leeten K, Lox M, Debuisson M, Delvenne P, Nchimi A, Kuijpers M, Vanassche T, Martinod K, Verhamme P, Lancellotti P, Oury C. Ticagrelor prevents infective endocarditis by mitigating Staphylococcus aureus virulence [abstract]. https://abstracts.isth.org/abstract/ticagrelor-prevents-infective-endocarditis-by-mitigating-staphylococcus-aureus-virulence/. Accessed September 29, 2023.

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