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Varying effects of tyrosine kinase inhibitors on platelet function-A need for individualized CML treatment to minimize the risk for hemostatic and thrombotic complications?
Maulana Abul Kazam Azad Univ Technol, India.
Linköping University, Department of Clinical and Experimental Medicine, Division of Clinical Chemistry. Linköping University, Faculty of Medicine and Health Sciences. Region Östergötland, Center for Surgery, Orthopaedics and Cancer Treatment, Department of Haematology.
Linköping University, Department of Clinical and Experimental Medicine. Linköping University, Faculty of Medicine and Health Sciences. Region Östergötland, Center for Diagnostics, Department of Clinical Chemistry.
Linköping University, Department of Clinical and Experimental Medicine. Linköping University, Faculty of Medicine and Health Sciences. Region Östergötland, Center for Diagnostics, Department of Clinical Chemistry.
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2019 (English)In: Cancer Medicine, ISSN 2045-7634, E-ISSN 2045-7634Article in journal (Refereed) Epub ahead of print
Abstract [en]

Since their introduction, tyrosine kinase inhibitors (TKIs, eg, imatinib, nilotinib, dasatinib, bosutinib, ponatinib) have revolutionized the treatment of chronic myeloid leukemia (CML). However, long-term treatment with TKIs is associated with serious adverse events including both bleeding and thromboembolism. Experimental studies have shown that TKIs can cause platelet dysfunction. Herein, we present the first side-by-side investigation comparing the effects of currently used TKIs on platelet function and thrombin generation when used in clinically relevant concentrations. A flow cytometry multiparameter protocol was used to study a range of significant platelet activation events (fibrinogen receptor activation, alpha granule, and lysosomal exocytosis, procoagulant membrane exposure, and mitochondrial permeability changes). In addition, thrombin generation was measured in the presence of TKIs to assess the effects on global hemostasis. Results show that dasatinib generally inhibited platelet function, while bosutinib, nilotinib, and ponatinib showed less consistent effects. In addition to these general trends for each TKI, we observed a large degree of interindividual variability in the effects of the different TKIs. Interindividual variation was also observed when blood from CML patients was studied ex vivo with whole blood platelet aggregometry, free oscillation rheometry (FOR), and flow cytometry. Based on the donor responses in the side-by-side TKI study, a TKI sensitivity map was developed. We propose that such a sensitivity map could potentially become a valuable tool to help in decision-making regarding the choice of suitable TKIs for a CML patient with a history of bleeding or atherothrombotic disease.

Place, publisher, year, edition, pages
WILEY , 2019.
Keywords [en]
chronic myeloid; myelogenous leukemia; coagulation; hemostasis; personalized medicine; platelets; tyrosine kinase inhibitors
National Category
Cell and Molecular Biology
Identifiers
URN: urn:nbn:se:liu:diva-162315DOI: 10.1002/cam4.2687ISI: 000495746200001PubMedID: 31714021OAI: oai:DiVA.org:liu-162315DiVA, id: diva2:1374059
Note

Funding Agencies|Lions Forskningsfond; ALF Grants, Region Ostergotland; Hjart-Lungfonden [20170318]; Science and Engineering Research Board

Available from: 2019-11-28 Created: 2019-11-28 Last updated: 2020-01-16

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Boknäs, NiklasSjöström, ClaraTharmakulanathan, AnjanaLotfi, KouroshRamström, Sofia
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