Department of Paediatrics, University Hospital Carl Gustav Carus, Dresden, Germany.
Department of Dentistry, McGill University, Shriners Hospital for Children, Montreal, Canada.
Hamostaseologie. 2023 Jun;43(3):179-187. doi: 10.1055/a-1892-0074. Epub 2023 Jan 24.
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 ( = 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.
酪氨酸激酶抑制剂 (TKIs) 伊马替尼、达沙替尼、博舒替尼和尼洛替尼已被确立为慢性髓性白血病 (CML) 的一线治疗药物，但可能会引起出血和血栓并发症等副作用。我们通过 lumiaggregometry 和 PFA-100 测试研究了 TKI 在抗凝全血 (WB) 样本中对体外血小板功能的影响。将（每个 TKI 为 15 个样本）样品与治疗相关的最终浓度的 TKI 孵育 30 分钟。通过胶原 (1 µg/mL)、花生四烯酸 (0.5 mmol/L) 和凝血酶 (0.5 U/mL) 诱导聚集和 ATP 释放。与对照组相比，伊马替尼、博舒替尼和尼洛替尼显著增加了胶原诱导的聚集。此外，还检测到博舒替尼和尼洛替尼在诱导花生四烯酸后聚集的显著增加。这些三种 TKI 对 ATP 释放和 PFA-100 闭合时间没有显著影响。相比之下，达沙替尼表现出胶原诱导的聚集和 ATP 释放的浓度依赖性抑制作用，以及胶原/肾上腺素筒的 PFA-100 闭合时间的显著延长。其他激动剂的聚集和 ATP 释放以及胶原/ADP 筒的闭合时间没有显著影响。总之，我们清楚地显示达沙替尼在 WB 中浓度依赖性地抑制胶原诱导的血小板功能，证实了先前在富含血小板血浆中获得的结果。博舒替尼和尼洛替尼没有对血小板激活造成损害。相反，两种 TKI 都显示出血小板激活的迹象。当将我们的结果与现有数据进行比较时，治疗相关浓度的伊马替尼不会损害血小板功能。
