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Thromb Haemost 2022; 122(01): 092-104
DOI: 10.1055/s-0041-1730312
Cellular Haemostasis and Platelets

Tyrosine Kinase Inhibitor Sunitinib Delays Platelet-Induced Coagulation: Additive Effects of Aspirin

Bibian M. E. Tullemans
1   Department of Biochemistry, Cardiovascular Research Institute Maastricht (CARIM), Maastricht University, The Netherlands
,
Delia I. Fernández‡   *
1   Department of Biochemistry, Cardiovascular Research Institute Maastricht (CARIM), Maastricht University, The Netherlands
2   Platelet Proteomics Group, Center for Research in Molecular Medicine and Chronic Diseases (CIMUS), Universidade Santiago de Compostela, Santiago de Compostela, Spain
,
Alicia Veninga‡   *
1   Department of Biochemistry, Cardiovascular Research Institute Maastricht (CARIM), Maastricht University, The Netherlands
,
Constance C. F. M. J. Baaten
1   Department of Biochemistry, Cardiovascular Research Institute Maastricht (CARIM), Maastricht University, The Netherlands
3   Institute for Molecular Cardiovascular Research (IMCAR), University Hospital Aachen, Aachen, Germany
4   Interdisciplinary Center for Clinical Research (IZKF), RWTH Aachen University, Aachen, Germany
,
Linsey J. F. Peters
3   Institute for Molecular Cardiovascular Research (IMCAR), University Hospital Aachen, Aachen, Germany
4   Interdisciplinary Center for Clinical Research (IZKF), RWTH Aachen University, Aachen, Germany
5   Department of Pathology, Maastricht University Medical Centre, Cardiovascular Research Institute Maastricht (CARIM), Maastricht, Netherlands
,
Maureen J. B. Aarts
6   Department of Medical Oncology, Maastricht University Medical Centre, Maastricht, The Netherlands
,
Johannes A. Eble
7   Institute of Physiological Chemistry and Pathobiochemistry, University of Münster, Münster, Germany
,
Elena Campello
8   Department of Medicine, University of Padua Medical School, Padova, Italy
,
Luca Spiezia
8   Department of Medicine, University of Padua Medical School, Padova, Italy
,
Paolo Simioni
8   Department of Medicine, University of Padua Medical School, Padova, Italy
,
Emiel P. C. van der Vorst
3   Institute for Molecular Cardiovascular Research (IMCAR), University Hospital Aachen, Aachen, Germany
4   Interdisciplinary Center for Clinical Research (IZKF), RWTH Aachen University, Aachen, Germany
5   Department of Pathology, Maastricht University Medical Centre, Cardiovascular Research Institute Maastricht (CARIM), Maastricht, Netherlands
9   Institute for Cardiovascular Prevention (IPEK), Ludwig-Maximilians-University Munich, Munich, Germany
,
Paola E. J. van der Meijden
1   Department of Biochemistry, Cardiovascular Research Institute Maastricht (CARIM), Maastricht University, The Netherlands
10   Thrombosis Expertise Center, Heart and Vascular Center, Maastricht University Medical Center, Maastricht, The Netherlands
,
Johan W. M. Heemskerk
1   Department of Biochemistry, Cardiovascular Research Institute Maastricht (CARIM), Maastricht University, The Netherlands
,
Marijke J. E. Kuijpers
1   Department of Biochemistry, Cardiovascular Research Institute Maastricht (CARIM), Maastricht University, The Netherlands
10   Thrombosis Expertise Center, Heart and Vascular Center, Maastricht University Medical Center, Maastricht, The Netherlands
› Author Affiliations Funding This study was supported by Pfizer as an Investigator-Initiated Research grant to M.J.E.K. (Tracking Number WI209458) and funds from the Department of Medicine, University of Padua Medical School (to P.S.). D.I.F. received funding from the European Union's Horizon 2020 research and innovation program under Marie Sklodowska-Curie grant agreement No. 766118 and is enrolled in a joint PhD program of the universities of Maastricht and Santiago de Compostela. C.C.F.M.J.B was funded by the Dutch Heart Foundation (2020T020) and the START-Program of the Faculty of Medicine at the RWTH Aachen University (105/20). J.A.E was funded by the Deutsche Forschungsgemeinschaft (DFG grant: SFP1009 project A09). E.P.C.v.d.V was funded by a grant from the Interdisciplinary Center for Clinical Research within the faculty of Medicine at the RWTH Aachen University and NWO-ZonMw Veni (91619053).
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Abstract

Background Sunitinib is a multitarget tyrosine kinase inhibitor (TKI) used for cancer treatment. In platelets, sunitinib affects collagen-induced activation under noncoagulating conditions. We investigated (1) the effects of sunitinib on thrombus formation induced by other TK-dependent receptors, and (2) the effects under coagulating conditions. Cardiovascular disease is a comorbidity in cancer patients, resulting in possible aspirin treatment. Sunitinib and aspirin are associated with increased bleeding risk, and therefore we also investigated (3) the synergistic effects of these compounds on thrombus and fibrin formation.

Methods Blood or isolated platelets from healthy volunteers or cancer patients were incubated with sunitinib and/or aspirin or vehicle. Platelet activation was determined by TK phosphorylation, flow cytometry, changes in [Ca2+]i, aggregometry, and whole blood perfusion over multiple surfaces, including collagen with(out) tissue factor (TF) was performed.

Results Sunitinib reduced thrombus formation and phosphatidylserine (PS) exposure under flow on collagen type I and III. Also, sunitinib inhibited glycoprotein VI-induced TK phosphorylation and Ca2+ elevation. Upon TF-triggered coagulation, sunitinib decreased PS exposure and fibrin formation. In blood from cancer patients more pronounced effects of sunitinib were observed in lung and pancreatic as compared to neuroglioblastoma and other cancer types. Compared to sunitinib alone, sunitinib plus aspirin further reduced platelet aggregation, thrombus formation, and PS exposure on collagen under flow with(out) coagulation.

Conclusion Sunitinib suppresses collagen-induced procoagulant activity and delays fibrin formation, which was aggravated by aspirin. Therefore, we urge for awareness of the combined antiplatelet effects of TKIs with aspirin, as this may result in increased risk of bleeding.

Keywords

platelets - thrombus - tyrosine kinase inhibitor - sunitinib - procoagulant activity - aspirin

* Authors contributed equally.


Supplementary Material



Publication History

Received: 21 December 2020

Accepted: 14 April 2021

Article published online:
15 June 2021

© 2021. Thieme. All rights reserved.

Georg Thieme Verlag KG
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