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Hamostaseologie 2023; 43(03): 179-187
DOI: 10.1055/a-1892-0074
Original Article

Impact of Tyrosine Kinase Inhibitors Applied for First-Line Chronic Myeloid Leukemia Treatment on Platelet Function in Whole Blood of Healthy Volunteers In Vitro

Falk Eckart
1   Department of Paediatrics, University Hospital Carl Gustav Carus, Dresden, Germany
,
Josephine T. Tauer
2   Department of Dentistry, McGill University, Shriners Hospital for Children, Montreal, Canada
,
Meinolf Suttorp
3   Paediatric Haematology and Oncology, Medical Faculty, TU Dresden, Germany
,
Ralf Knöfler
1   Department of Paediatrics, University Hospital Carl Gustav Carus, Dresden, Germany
3   Paediatric Haematology and Oncology, Medical Faculty, TU Dresden, Germany
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Abstract

The tyrosine kinase inhibitors (TKIs) imatinib, dasatinib, bosutinib, and nilotinib are established for first-line treatment of chronic myeloid leukemia (CML) but may cause side effects such as bleeding and thrombotic complications. We investigated the impact of TKIs on platelet function ex vivo in anticoagulated whole blood (WB) samples from healthy adults by lumiaggregometry and PFA-100 test. Samples (n = 15 per TKI) were incubated for 30 minutes with TKI at therapeutically relevant final concentrations. Aggregation and ATP release were induced by collagen (1 µg/mL), arachidonic acid (0.5 mmol/L), and thrombin (0.5 U/mL). Imatinib, bosutinib, and nilotinib significantly increased collagen-induced aggregation compared with controls. In addition, for bosutinib and nilotinib, a significant increase in aggregation after induction with arachidonic acid was detected. ATP-release and PFA-100 closure times were not influenced significantly by these three TKI. In contrast, dasatinib demonstrated a concentration-dependent inhibition of collagen-induced aggregation and ATP release and a significant prolongation of the PFA-100 closure time with the collagen/epinephrine cartridge. Aggregation and ATP release by other agonists as well as closure time with the collagen/ADP cartridge were not influenced significantly. In conclusion, we clearly show a concentration-dependent inhibition of collagen-induced platelet function in WB by dasatinib confirming prior results obtained in platelet-rich plasma. Bosutinib and nilotinib exerted no impairment of platelet activation. On the contrary, both TKI showed signs of platelet activation. When comparing our results with existing data, imatinib in therapeutic relevant concentrations does not impair platelet function.

Zusammenfassung

Die Tyrosinkinaseinhibitoren (TKI) Imatinib, Dasatinib, Bosutinib und Nilotinib sind als Erstlinientherapie der chronischen myeloischen Leukämie etabliert, können aber Nebenwirkungen wie Blutungen und thrombotische Komplikationen verursachen. Wir untersuchten den Einfluss dieser TKI auf die Thrombozytenfunktion ex vivo in antikoagulierten Vollblutproben gesunder Erwachsener mittels Lumiaggregometrie und dem PFA-100®-Test. Die Proben (n = 15 pro TKI) wurden für 30 Minuten mit TKI in therapeutisch relevanten Endkonzentrationen inkubiert. Aggregation und ATP-Freisetzung wurden durch Kollagen (1 µg/ml), Arachidonsäure (0,5 mmol/l) und Thrombin (0,5 U/ml) induziert. Für Imatinib, Bosutinib und Nilotinib konnte eine signifikante Steigerung der kollageninduzierten Aggregation im Vergleich zur Kontrolle gezeigt werden. Zusätzlich wurde für Bosutinib und Nilotinib eine signifikante Steigerung der Aggregation nach Arachidonsäure-Induktion gemessen. Die ATP-Freisetzung und die PFA-100®-Verschlusszeiten wurden durch diese drei TKI nicht signifikant beeinflusst. Im Gegensatz dazu zeigte Dasatinib eine konzentrationsabhängige Hemmung von kollageninduzierter Aggregation und ATP-Freisetzung sowie eine signifikante Verlängerung der PFA-100®-Verschlusszeiten mit der Kollagen/Epinephrin-Messzelle. Sowohl die Aggregation und ATP-Freisetzung durch andere Agonisten als auch die Verschlusszeiten der Kollagen/ADP-Messzelle wurden nicht signifikant beeinflusst. Zusammenfassend konnten wir eindeutig eine konzentrationsabhängige Hemmung der kollageninduzierten Thrombozytenfunktion im Vollblut durch Dasatinib zeigen und damit frühere Ergebnisse aus plättchenreichem Plasma bestätigen. Bosutinib und Nilotinib bewirkten keine Einschränkung der Thrombozytenaktivierung. Beide TKI führten im Gegenteil zu einer Thrombozytenaktivierung. Imatinib beeinträchtigt in Zusammenschau mit der verfügbaren Literatur in therapeutisch relevanten Konzentrationen die Plättchenfunktion nicht.

Keywords

tyrosine kinase inhibitors - platelet pathology inherited/acquired - chronic myeloid leukemia - BCR-ABL1 - primary hemostasis

Schlüsselwörter

Tyrosinkinaseinhibitoren - Pathologie der Blutplättchen vererbt/erworben - chronische myeloische Leukämie - BCR-ABL1 - primäre Hämostase

Ethical Vote

Institutional Ethical Board Committee, permit number EK 23012015 (date: April 28, 2015).


Author Contributions

The concept of this investigation was developed by all authors. F.E. performed all laboratory work as part of his medical doctoral thesis, sought informed consent, and collected blood from the voluntary donors. J.T.T. supervised the laboratory work and assisted with data interpretation. F.E. and R.K. collected and managed all data. R.K. and M.S. supervised all approaches, assisted F.E. with writing the first draft of the manuscript, and critically revised all comments. All authors revised the text and approved the final version of the manuscript.


Supplementary Material



Publication History

Received: 22 December 2021

Accepted: 05 July 2022

Article published online:
24 January 2023

© 2023. Thieme. All rights reserved.

Georg Thieme Verlag KG
Rüdigerstraße 14, 70469 Stuttgart, Germany

 

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