Quantitative Proteomic Analysis of Circulating Extracellular Vesicles from VTE Patients Reveals the Anti-inflammatory Potential of Rivaroxaban

L. Weiss^1,2,3, J. Keaney⁴, P. Szklanna^1,2,3, T. Prendiville⁵, K. Egan^1,6, S. Kelliher⁵, Á. Lennon⁵, A. Blanco⁷, B. Kevane^1,3,5,6, S. Murphy^6,8,9, F. Ní Áinle^1,3,5,9,10, P. Maguire^1,2,3,11

¹UCD Conway SPHERE Research Group, Conway Institute, University College Dublin, Dublin, Ireland, ²School of Biomolecular and Biomedical Science, University College Dublin, Dublin, Ireland, ³Irish Centre for Vascular Biology, Royal College of Surgeons in Ireland, Dublin, Ireland, ⁴Department for Cardiology, Mater Misericordiae University Hospital, Dublin, Ireland, ⁵Department for Haematology, Mater Misericordiae University Hospital, Dublin, Ireland, ⁶School of Medicine, University College Dublin, Dublin, Ireland, ⁷Flow Cytometry Core, Conway Institute, University College Dublin, Dublin, Ireland, ⁸Department for Stroke Medicine, Mater Misericordiae University Hospital, Dublin, Ireland, ⁹School of Medicine, Royal College of Surgeons in Ireland, Dublin, Ireland, ¹⁰Department of Haematology, Rotunda Hospital, Dublin, Ireland, ¹¹Institute for Discovery, O'Brien Centre for Science, University College Dublin, Dublin, Ireland

Abstract Number: OC 39.1

Meeting: ISTH 2021 Congress

Theme: Diagnostics and OMICs » Epigenetics, OMICs and Bioinformatics

Background: Venous Thromboembolism (VTE) remains a significant cause of morbidity and mortality worldwide. Rivaroxaban, a direct oral factor Xa inhibitor, mediates anti-inflammatory and cardiovascular-protective effects besides its well-established anticoagulant properties, however, these remain poorly characterized. Extracellular vesicles (EVs) are important circulating messengers regulating a myriad of biological and pathological processes and may be highly relevant to the pathophysiology of VTE as they reflect alterations in platelet and endothelial biology. However, the effects of rivaroxaban on circulating pro-inflammatory EVs remain unknown. We hypothesized that rivaroxaban’s anti-inflammatory properties are reflected upon differential molecular profiles of circulating EVs.

Aims:

Assess differences in circulating EV levels
Perform comparative proteomic characterisation of patients with venous thromboembolism (VTE) anticoagulated with Rivaroxaban vs warfarin

Methods: Single-episode VTE patients anticoagulated with Rivaroxaban or warfarin, respectively, were recruited following informed consent. Differences in circulating EV size and concentration were assessed by nanoparticle tracking analysis and flow cytometry. Circulating EVs were enriched by ultracentrifugation and the presence of vesicular makers was confirmed by immunoblotting. High-throughput quantitative mass spectrometry (MS) was performed to detect differences in proteomic signatures.

Results: We found that circulating levels of small and large EVs did not differ between drug treatments. Following enrichment, confirmed using western blotting, EVs were subjected to tandem mass spectrometry analysis using a state-of-the-art timsTOF approach, combined with MaxQuant data analysis. 300 proteins were robustly quantified, the majority of which were previously attributed to EVs. Several proteins involved in the inflammatory response were found to be differentially expressed.

Conclusions: EV proteomic signatures were found to mirror Rivaroxaban’s anti-inflammatory potential. Our findings are of translational relevance towards characterizing the anti-inflammatory and cardiovascular-protective mechanisms associated with rivaroxaban therapy.

To cite this abstract in AMA style:

Weiss L, Keaney J, Szklanna P, Prendiville T, Egan K, Kelliher S, Lennon Á, Blanco A, Kevane B, Murphy S, Ní Áinle F, Maguire P. Quantitative Proteomic Analysis of Circulating Extracellular Vesicles from VTE Patients Reveals the Anti-inflammatory Potential of Rivaroxaban [abstract]. Res Pract Thromb Haemost. 2021; 5 (Suppl 2). https://abstracts.isth.org/abstract/quantitative-proteomic-analysis-of-circulating-extracellular-vesicles-from-vte-patients-reveals-the-anti-inflammatory-potential-of-rivaroxaban/. Accessed October 1, 2023.

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