Haguet Hélène, Douxfils Jonathan, Chatelain Christian, Graux Carlos, Mullier François, Dogné Jean-Michel
University of Namur, Namur Thrombosis and Hemostasis Center (NTHC), Namur Research Institute for Life Sciences (NARILIS), Department of Pharmacy, Namur, Belgium.
Université catholique de Louvain, CHU UCL Namur, Namur Thrombosis and Hemostasis Center, Hematology Laboratory, Yvoir, Belgium.
TH Open. 2018 Feb 14;2(1):e68-e88. doi: 10.1055/s-0038-1624566. eCollection 2018 Jan.
Imatinib, the first-in-class BCR-ABL tyrosine kinase inhibitor (TKI), had been a revolution for the treatment of chronic myeloid leukemia (CML) and had greatly enhanced patient survival. Second- (dasatinib, nilotinib, and bosutinib) and third-generation (ponatinib) TKIs have been developed to be effective against BCR-ABL mutations making imatinib less effective. However, these treatments have been associated with arterial occlusive events. This review gathers clinical data and experiments about the pathophysiology of these arterial occlusive events with BCR-ABL TKIs. Imatinib is associated with very low rates of thrombosis, suggesting a potentially protecting cardiovascular effect of this treatment in patients with BCR-ABL CML. This protective effect might be mediated by decreased platelet secretion and activation, decreased leukocyte recruitment, and anti-inflammatory or antifibrotic effects. Clinical data have guided mechanistic studies toward alteration of platelet functions and atherosclerosis development, which might be secondary to metabolism impairment. Dasatinib, nilotinib, and ponatinib affect endothelial cells and might induce atherogenesis through increased vascular permeability. Nilotinib also impairs platelet functions and induces hyperglycemia and dyslipidemia that might contribute to atherosclerosis development. Description of the pathophysiology of arterial thrombotic events is necessary to implement risk minimization strategies.
伊马替尼是首个获批的BCR-ABL酪氨酸激酶抑制剂（TKI），它为慢性髓性白血病（CML）的治疗带来了革命性变化，并显著提高了患者生存率。第二代TKI（达沙替尼、尼洛替尼和博舒替尼）以及第三代TKI（普纳替尼）已被研发出来，用于对抗使伊马替尼疗效降低的BCR-ABL突变。然而，这些治疗与动脉闭塞事件有关。本综述收集了有关这些BCR-ABL TKI所致动脉闭塞事件病理生理学的临床数据和实验。伊马替尼与极低的血栓形成率相关，提示该治疗对BCR-ABL阳性CML患者可能具有心血管保护作用。这种保护作用可能是通过减少血小板分泌和活化、减少白细胞募集以及抗炎或抗纤维化作用介导的。临床数据引导了针对血小板功能改变和动脉粥样硬化发展的机制研究，这可能继发于代谢损害。达沙替尼、尼洛替尼和普纳替尼会影响内皮细胞，并可能通过增加血管通透性诱导动脉粥样硬化形成。尼洛替尼还会损害血小板功能，并诱发高血糖和血脂异常，这可能促进动脉粥样硬化发展。描述动脉血栓形成事件的病理生理学对于实施风险最小化策略很有必要。
