Varying effects of tyrosine kinase inhibitors on platelet function—A need for individualized CML treatment to minimize the risk for hemostatic and thrombotic complications?

Abstract

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.

Thrombocytopathies: Not Just Aggregation Defects—The Clinical Relevance of Procoagulant Platelets

“…Inhibition of the procoagulant response of platelets was also observed with tyrosine kinase inhibitors used in oncology [ 207 , 208 , 209 , 210 ]. These pharmaceuticals reduce formation of procoagulant platelets by inhibiting tyrosine signalling downstream of GPVI activation.…”

Ex vivo platelet morphology assessment of chronic myeloid leukemia patients before and after Imatinib treatment

“…The study of CML pathogenesis has primarily focused on leukocyte populations and limited literature are available of the impact of CML on patients' platelets and further impact as a result of TKI treatment. One study reported on the effects of in vitro and ex vivo TKI exposure in CML patient's platelet function, it was found that TKI treatment resulted in inhibition of platelet function and stimulated pro-coagulant platelet formation, which elucidates the occurrence of bleeding and cardiovascular events due to thrombosis in TKI treated CML patients (Deb et al, 2020). It was concluded that there was marked inter-individual differences in response to TKI exposure (Deb et al, 2020).…”

“…One study reported on the effects of in vitro and ex vivo TKI exposure in CML patient's platelet function, it was found that TKI treatment resulted in inhibition of platelet function and stimulated pro‐coagulant platelet formation, which elucidates the occurrence of bleeding and cardiovascular events due to thrombosis in TKI treated CML patients (Deb et al, 2020). It was concluded that there was marked inter‐individual differences in response to TKI exposure (Deb et al, 2020). The incidence of TKI treatment resulting in impaired platelet function was reported by Ozgur Yurttas and Eskazan to be observed in 29.8% of a population cohort (Ozgur Yurttas & Eskazan, 2019).…”

Tyrosine Kinase Inhibitors and Vascular Adverse Events in Patients with Chronic Myeloid Leukemia: A Population-Based, Propensity Score-Matched Cohort Study

“…Additionally, nilotinib and ponatinib have been observed to impair endothelial cell and platelet function, which can increase platelet adhesion and activation [36,[43][44][45]. Dasatinib may damage platelet function and induce a bleeding tendency [36,46,47], and it may also induce dyslipidemia and potentiate the occurrence of VAEs [36,41,42]. This phenomenon may partly explain the inconsistent results in different studies.…”