Response by Petzold et al to Letter Regarding Article, "Rivaroxaban Reduces Arterial Thrombosis by Inhibition of Fxa-Driven Platelet Activation via Protease Activated Receptor-1"

HomeCirculation ResearchVol. 126, No. 10Response by Petzold et al to Letter Regarding Article, "Rivaroxaban Reduces Arterial Thrombosis by Inhibition of Fxa-Driven Platelet Activation via Protease Activated Receptor-1" Free AccessLetterPDF/EPUBAboutView PDFView EPUBSections ToolsAdd to favoritesDownload citationsTrack citationsPermissions ShareShare onFacebookTwitterLinked InMendeleyReddit Jump toFree AccessLetterPDF/EPUBResponse by Petzold et al to Letter Regarding Article, "Rivaroxaban Reduces Arterial Thrombosis by Inhibition of Fxa-Driven Platelet Activation via Protease Activated Receptor-1" Tobias Petzold, Lisa Dannenberg, Manuela Thienel, Samantha Ahlbrecht, Philipp Mourikis, Carolin Helten, René M’Pembele, Alina Achilles, Dorothee Zikeli, Zhe Zhang, Enzo Lüsebrink, Leo Nicolai, Inas Saleh, Christian Jung, Norbert Gerdes, Till Hoffmann, Bodo Levkau, Thomas Hohlfeld, Tobias Zeus, Christian Schulz, Malte Kelm and Amin Polzin Tobias PetzoldTobias Petzold From the Medizinische Klinik und Poliklinik I, Klinikum der Universität München, Ludwig-Maximilians University Munich (T.P., M.T., Z.Z., E.L., L.N., I.S., C.S.) DZHK (German Centre for Cardiovascular Research), partner site Munich Heart Alliance, Germany (T.P., M.T., E.L., L.N., C.S.) *T.P., L.D., and M.T. contributed equally to this article. Search for more papers by this author , Lisa DannenbergLisa Dannenberg Department of Cardiology, Pulmonology and Vascular Medicine, Cardiovascular Research Institute Düsseldorf (CARID) (L.D., S.A., P.M., C.H., R.M., A.A., D.Z., C.J., N.G., T.Z., M.K., A.P.), Medical Faculty of the Heinrich Heine University Düsseldorf, Germany *T.P., L.D., and M.T. contributed equally to this article. Search for more papers by this author , Manuela ThienelManuela Thienel From the Medizinische Klinik und Poliklinik I, Klinikum der Universität München, Ludwig-Maximilians University Munich (T.P., M.T., Z.Z., E.L., L.N., I.S., C.S.) DZHK (German Centre for Cardiovascular Research), partner site Munich Heart Alliance, Germany (T.P., M.T., E.L., L.N., C.S.) *T.P., L.D., and M.T. contributed equally to this article. Search for more papers by this author , Samantha AhlbrechtSamantha Ahlbrecht Department of Cardiology, Pulmonology and Vascular Medicine, Cardiovascular Research Institute Düsseldorf (CARID) (L.D., S.A., P.M., C.H., R.M., A.A., D.Z., C.J., N.G., T.Z., M.K., A.P.), Medical Faculty of the Heinrich Heine University Düsseldorf, Germany Search for more papers by this author , Philipp MourikisPhilipp Mourikis Department of Cardiology, Pulmonology and Vascular Medicine, Cardiovascular Research Institute Düsseldorf (CARID) (L.D., S.A., P.M., C.H., R.M., A.A., D.Z., C.J., N.G., T.Z., M.K., A.P.), Medical Faculty of the Heinrich Heine University Düsseldorf, Germany Search for more papers by this author , Carolin HeltenCarolin Helten Department of Cardiology, Pulmonology and Vascular Medicine, Cardiovascular Research Institute Düsseldorf (CARID) (L.D., S.A., P.M., C.H., R.M., A.A., D.Z., C.J., N.G., T.Z., M.K., A.P.), Medical Faculty of the Heinrich Heine University Düsseldorf, Germany Search for more papers by this author , René M’PembeleRené M’Pembele Department of Cardiology, Pulmonology and Vascular Medicine, Cardiovascular Research Institute Düsseldorf (CARID) (L.D., S.A., P.M., C.H., R.M., A.A., D.Z., C.J., N.G., T.Z., M.K., A.P.), Medical Faculty of the Heinrich Heine University Düsseldorf, Germany Search for more papers by this author , Alina AchillesAlina Achilles Department of Cardiology, Pulmonology and Vascular Medicine, Cardiovascular Research Institute Düsseldorf (CARID) (L.D., S.A., P.M., C.H., R.M., A.A., D.Z., C.J., N.G., T.Z., M.K., A.P.), Medical Faculty of the Heinrich Heine University Düsseldorf, Germany Search for more papers by this author , Dorothee ZikeliDorothee Zikeli Department of Cardiology, Pulmonology and Vascular Medicine, Cardiovascular Research Institute Düsseldorf (CARID) (L.D., S.A., P.M., C.H., R.M., A.A., D.Z., C.J., N.G., T.Z., M.K., A.P.), Medical Faculty of the Heinrich Heine University Düsseldorf, Germany Search for more papers by this author , Zhe ZhangZhe Zhang From the Medizinische Klinik und Poliklinik I, Klinikum der Universität München, Ludwig-Maximilians University Munich (T.P., M.T., Z.Z., E.L., L.N., I.S., C.S.) Search for more papers by this author , Enzo LüsebrinkEnzo Lüsebrink From the Medizinische Klinik und Poliklinik I, Klinikum der Universität München, Ludwig-Maximilians University Munich (T.P., M.T., Z.Z., E.L., L.N., I.S., C.S.) DZHK (German Centre for Cardiovascular Research), partner site Munich Heart Alliance, Germany (T.P., M.T., E.L., L.N., C.S.) Search for more papers by this author , Leo NicolaiLeo Nicolai From the Medizinische Klinik und Poliklinik I, Klinikum der Universität München, Ludwig-Maximilians University Munich (T.P., M.T., Z.Z., E.L., L.N., I.S., C.S.) DZHK (German Centre for Cardiovascular Research), partner site Munich Heart Alliance, Germany (T.P., M.T., E.L., L.N., C.S.) Search for more papers by this author , Inas SalehInas Saleh From the Medizinische Klinik und Poliklinik I, Klinikum der Universität München, Ludwig-Maximilians University Munich (T.P., M.T., Z.Z., E.L., L.N., I.S., C.S.) Search for more papers by this author , Christian JungChristian Jung Department of Cardiology, Pulmonology and Vascular Medicine, Cardiovascular Research Institute Düsseldorf (CARID) (L.D., S.A., P.M., C.H., R.M., A.A., D.Z., C.J., N.G., T.Z., M.K., A.P.), Medical Faculty of the Heinrich Heine University Düsseldorf, Germany Search for more papers by this author , Norbert GerdesNorbert Gerdes Department of Cardiology, Pulmonology and Vascular Medicine, Cardiovascular Research Institute Düsseldorf (CARID) (L.D., S.A., P.M., C.H., R.M., A.A., D.Z., C.J., N.G., T.Z., M.K., A.P.), Medical Faculty of the Heinrich Heine University Düsseldorf, Germany Search for more papers by this author , Till HoffmannTill Hoffmann Institute of Transplantation Diagnostics and Cell Therapeutics, Heinrich Heine University Medical Center Düsseldorf, Germany (T. Hoffmann) Search for more papers by this author , Bodo LevkauBodo Levkau Institute of Pathophysiology, West German Heart and Vascular Center, University Hospital Essen, University of Duisburg-Essen, Germany (B.L.). Search for more papers by this author , Thomas HohlfeldThomas Hohlfeld Institute of Pharmacology and Clinical Pharmacology (T. Hohlfeld), Medical Faculty of the Heinrich Heine University Düsseldorf, Germany Search for more papers by this author , Tobias ZeusTobias Zeus Department of Cardiology, Pulmonology and Vascular Medicine, Cardiovascular Research Institute Düsseldorf (CARID) (L.D., S.A., P.M., C.H., R.M., A.A., D.Z., C.J., N.G., T.Z., M.K., A.P.), Medical Faculty of the Heinrich Heine University Düsseldorf, Germany Search for more papers by this author , Christian SchulzChristian Schulz From the Medizinische Klinik und Poliklinik I, Klinikum der Universität München, Ludwig-Maximilians University Munich (T.P., M.T., Z.Z., E.L., L.N., I.S., C.S.) DZHK (German Centre for Cardiovascular Research), partner site Munich Heart Alliance, Germany (T.P., M.T., E.L., L.N., C.S.) Search for more papers by this author , Malte KelmMalte Kelm Department of Cardiology, Pulmonology and Vascular Medicine, Cardiovascular Research Institute Düsseldorf (CARID) (L.D., S.A., P.M., C.H., R.M., A.A., D.Z., C.J., N.G., T.Z., M.K., A.P.), Medical Faculty of the Heinrich Heine University Düsseldorf, Germany Search for more papers by this author and Amin PolzinAmin Polzin Department of Cardiology, Pulmonology and Vascular Medicine, Cardiovascular Research Institute Düsseldorf (CARID) (L.D., S.A., P.M., C.H., R.M., A.A., D.Z., C.J., N.G., T.Z., M.K., A.P.), Medical Faculty of the Heinrich Heine University Düsseldorf, Germany Search for more papers by this author Originally published7 May 2020https://doi.org/10.1161/CIRCRESAHA.120.316905Circulation Research. 2020;126:e116–e117In Response:In the letter to the editor regarding our manuscript “Rivaroxaban reduces arterial thrombosis by inhibition of FXa driven platelet activation via protease activated receptor-1”, Violi et al discussed if the reduction of platelet aggregation and thrombus formation by rivaroxaban might be only by inhibition of Fxa (factor Xa)-driven PAR (protease-activated receptor)-1-mediated platelet activation or additionally due to interference of rivaroxaban with platelet receptors. This question is highly relevant, as, for example, eg,platelet reactivity is enhanced in dabigatran-treated patients due to interaction of dabigatran with glycoprotein (GP)Ibα and upregulation of platelet PAR-1 and -4.1,2 It was shown before that GPVI (glycoprotein VI) shedding by FXa3 was attenuated by rivaroxaban.4,5 Consequently, this should rather augment GPVI signaling. On the other hand, convulxin-induced platelet aggregation was found to be attenuated by rivaroxaban.5 In the present study, rivaroxaban did not affect GPVI-induced calcium signaling in washed platelets. Furthermore, we observed a reduction of collagen-induced thrombus formation and platelet aggregation, both in the presence of plasma. We demonstrated that platelet aggregation induced by collagen led to formation of catalytically active FXa in platelet-rich plasma. This leads to auto- and paracrine platelet activation via PAR that can be inhibited by rivaroxaban.6 Whether GPVI shedding is attenuated under this condition needs to be addressed in future studies. Hence, we agree with Violi et al that this warrants further investigations to understand the functional- and clinical-significance of platelet GPVI shedding in the presence of FXa inhibitors. However. such studies require a careful distinction between data generated in plasma-free conditions versus experiments performed in platelet-rich plasma, permissive for FXa generation and inhibition by rivaroxaban.Of note, we did not find any alteration of platelet receptor expression (GPVI, P2Y12, P2Y1, PAR1, and PAR4) under rivaroxaban under chronic conditions in samples generated from whole blood. Besides that, Violi et al discussed that rivaroxaban was shown to reduce urinary thromboxane B2 formation.4 On the contrary, Murphy et al7 found enhanced plasma levels of thromboxane A2 in rivaroxaban-treated patients. Indeed, this is very interesting, especially as a combination of aspirin with vascular dose rivaroxaban was shown to be superior to aspirin alone in the COMPASS trial.8 To address this question, we conducted arachidonic acid induced light-transmission aggregometry in 12 patients before and after intake of rivaroxaban. We found that single-dose rivaroxaban (20 mg) did not affect arachidonic acid–induced platelet aggregation (before: 34.13±32.81% versus after: 25.1±29.5%; P=0.27, n=12, paired t-test, Shapiro-Wilk test showed normal distribution). These experiments would support the hypothesis of Murphy et al that dual pathway inhibition with aspirin to block cyclooxygenase-induced platelet activation and rivaroxaban used in the COMPASS regime is favorable. However, we completely agree with Violi et al that this hypothesis needs to be tested in further analyses.In summary, our data suggest that inhibition of FXa by rivaroxaban leads to reduced platelet activation and thrombus formation. The concept of dual pathway inhibition needs to be investigated in detail in future studies and trials.Sources of FundingThis work was supported by the Forschungskommission of the Medical Faculty of the Heinrich Heine University (No. 16-2014 to A. Polzin; No. 46-2016, and 2019-29 to L. Dannenberg) and by the German Research Foundation (LE 940/7-1 to B. Levkau and PO 2247/2-1 to A. Polzin, SFB1116 to A. Polzin and B. Levkau, and PE2704/2-1 to T. Petzold), by LMU Munich’s Institutional Strategy LMU excellent within the framework of the German Excellence Initiative (No. 806 32 006 LMU Excellent to T. Petzold) by the DZHK (German Center for Cardiovascular Research) to T. Petzold (Postdoc Start-up grant No. 100378833).DisclosuresNone.Footnotes*T.P., L.D., and M.T. contributed equally to this article.References1. Petzold T, Thienel M, Konrad I, Schubert I, Regenauer R, Hoppe B, Lorenz M, Eckart A, Chandraratne S, Lennerz C, et al. Oral thrombin inhibitor aggravates platelet adhesion and aggregation during arterial thrombosis.Sci Transl Med. 2016; 8:367ra168. doi: 10.1126/scitranslmed.aad6712CrossrefMedlineGoogle Scholar2. Achilles A, Mohring A, Dannenberg L, Grandoch M, Hohlfeld T, Fischer JW, Levkau B, Kelm M, Zeus T, Polzin A. Dabigatran enhances platelet reactivity and platelet thrombin receptor expression in patients with atrial fibrillation.J Thromb Haemost. 2017; 15:473–476. doi: 10.1111/jth.13595CrossrefMedlineGoogle Scholar3. Al-Tamimi M, Grigoriadis G, Tran H, Paul E, Servadei P, Berndt MC, Gardiner EE, Andrews RK. Coagulation-induced shedding of platelet glycoprotein VI mediated by factor Xa.Blood. 2011; 117:3912–3920. doi: 10.1182/blood-2010-08-301523CrossrefMedlineGoogle Scholar4. Pignatelli P, Pastori D, Bartimoccia S, Menichelli D, Vicario T, Nocella C, Carnevale R, Violi F. Anti Xa oral anticoagulants inhibit in vivo platelet activation by modulating glycoprotein VI shedding.Pharmacol Res. 2016; 113:484–489. doi: 10.1016/j.phrs.2016.09.035CrossrefMedlineGoogle Scholar5. Cammisotto V, Carnevale R, Nocella C, Stefanini L, Bartimoccia S, Coluccia A, Silvestri R, Pignatelli P, Pastori D, Violi F. Nox2-mediated platelet activation by glycoprotein (GP) VI: Effect of rivaroxaban alone and in combination with aspirin.Biochem Pharmacol. 2019; 163:111–118. doi: 10.1016/j.bcp.2019.02.016CrossrefMedlineGoogle Scholar6. Petzold T, Thienel M, Dannenberg L, Mourikis P, Helten C, Ayhan A, M’Pembele R, Achilles A, Trojovky K, Konsek D, et al. Rivaroxaban reduces arterial thrombosis by inhibition of FXa-driven platelet activation via protease activated receptor-1.Circ Res. 2020; 126:486–500. doi: 10.1161/CIRCRESAHA.119.315099LinkGoogle Scholar7. Murphy PT, Grace S, Glavey S, Quinn J. Rivaroxaban may increase platelet activation in vivo via thromboxane A2.Circ Res. 2019; 125:e9. doi: 10.1161/CIRCRESAHA.119.315453LinkGoogle Scholar8. Eikelboom JW, Connolly SJ, Bosch J, Dagenais GR, Hart RG, Shestakovska O, Diaz R, Alings M, Lonn EM, Anand SS, et al; COMPASS Investigators. Rivaroxaban with or without aspirin in stable cardiovascular disease.N Engl J Med. 2017; 377:1319–1330. doi: 10.1056/NEJMoa1709118CrossrefMedlineGoogle Scholar Previous Back to top Next FiguresReferencesRelatedDetailsCited By Хрыщанович В (2021) Dual Pathway of Inhibition and Vascular Protection in Patients with Atherosclerotic Disease, Кардиология в Беларуси, 10.34883/PI.2021.13.2.012:2, (280-300), Online publication date: 17-May-2021. May 8, 2020Vol 126, Issue 10 Advertisement Article InformationMetrics © 2020 American Heart Association, Inc.https://doi.org/10.1161/CIRCRESAHA.120.316905PMID: 32379578 Originally publishedMay 7, 2020 PDF download Advertisement