Alhawiti Naif, Burbury Kate L, Kwa Faith A, O'Malley Cindy J, Shuttleworth Peter, Alzard Mohamad, Hamadi Abdullah, Grigg Andrew P, Jackson Denise E
Thrombosis and Vascular Diseases Laboratory, School of Health and Biomedical Sciences, RMIT University, Bundoora, Victoria, Australia.
Haematology Department, Peter MacCallum Cancer Centre, East Melbourne, Australia.
Thromb Res. 2016 Sep;145:54-64. doi: 10.1016/j.thromres.2016.07.019. Epub 2016 Jul 30.
Tyrosine kinase inhibitors (TKI) such as imatinib, nilotinib and dasatinib are now established as highly effective frontline therapies for chronic myeloid leukaemia (CML). Disease control is achieved in the majority of patients and survival is excellent such that recent focus has been on toxicities of these agents. Cumulative data have reported an excess of serious vascular complications, including arterial thrombosis and peripheral arterial occlusive disease, in patients receiving nilotinib in comparison with other TKIs, with resultant interest in delineating the pathophysiology and implications for rationale cardiovascular risk modification. To address this issue, we studied the effects of imatinib, nilotinib and dasatinib on platelet function and thrombus formation in human and mouse models using in vitro, ex vivo and in vivo approaches. In vitro studies demonstrated that dasatinib and imatinib but not nilotinib inhibited ADP, CRP, and collagen-induced platelet aggregation and moreover, that nilotinib potentiated PAR-1-mediated alpha granule release. Pretreatment of wild-type C57BL/6 mice with nilotinib but not imatinib or dasatinib, significantly increased thrombus growth and stability, on type I collagen under ex vivo arterial flow conditions and increased thrombus growth and stability following FeCl3-induced vascular injury of mesenteric arterioles and carotid artery injury in vivo. Whole blood from nilotinib-treated CML patients, demonstrated increased platelet adhesion ex vivo under flow, increased plasma soluble P- and E-selectin, sICAM-1, sVCAM-1, TNF-alpha, IL-6 levels and endogenous thrombin potential (ETP) levels in vivo, despite being on daily low-dose aspirin. These results demonstrate that nilotinib can potentiate platelet and endothelial activation and platelet thrombus formation ex vivo and in vivo.
酪氨酸激酶抑制剂（TKI），如伊马替尼、尼洛替尼和达沙替尼，现已成为慢性髓性白血病（CML）的高效一线治疗药物。大多数患者实现了疾病控制，生存率极佳，因此近期关注点在于这些药物的毒性。累积数据显示，与其他TKI相比，接受尼洛替尼治疗的患者出现严重血管并发症的情况更多，包括动脉血栓形成和外周动脉闭塞性疾病，这引发了人们对阐明其病理生理学以及合理进行心血管风险修正的影响的兴趣。为解决这一问题，我们使用体外、离体和体内方法，研究了伊马替尼、尼洛替尼和达沙替尼对人和小鼠模型中血小板功能及血栓形成的影响。体外研究表明，达沙替尼和伊马替尼可抑制ADP、CRP和胶原诱导的血小板聚集，而尼洛替尼则不能，此外，尼洛替尼可增强PAR-1介导的α颗粒释放。用尼洛替尼而非伊马替尼或达沙替尼预处理野生型C57BL/6小鼠，在离体动脉血流条件下，可显著增加I型胶原上血栓的生长和稳定性，在体内，可增加FeCl3诱导的肠系膜小动脉血管损伤和颈动脉损伤后血栓的生长和稳定性。尽管接受每日低剂量阿司匹林治疗，但来自接受尼洛替尼治疗的CML患者的全血在体外流动条件下显示血小板黏附增加，在体内显示血浆可溶性P-选择素和E-选择素、sICAM-1、sVCAM-1、TNF-α、IL-6水平以及内源性凝血酶潜力（ETP）水平升高。这些结果表明，尼洛替尼可在体外和体内增强血小板和内皮细胞活化以及血小板血栓形成。
