Receptor Tyrosine Kinases in Human Platelets: A Review of Expression, Function and Inhibition in Relation to the Risk of Bleeding or Thrombocytopenia from Phase I through Phase III Trials

Sater, Houssein Abdul; G, Arpita Shah; hi,; Dainer, Paul; Pantin, Jeremy

doi:10.15406/jcpcr.2017.08.00298

Cited by 1 publication

(1 citation statement)

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“…As the ATP binding site is a hallmark of several kinases, TKIs show inhibitory offtarget effects on multiple other tyrosine kinases in vitro. 7,8 These off-target effects were verified in vivo in clinical trials 9 and characterize each TKI's target kinase profile, its safety, and efficacy. 10 Among the off-target effects described in vitro and in vivo are alterations of platelet function and vascular endothelium 11,12 ; thus, BCR-ABL1-TKIs are associated with both bleeding and thrombotic complications.…”

Section: Introductionmentioning

confidence: 88%

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

et al. 2023

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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.

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