The tyrosine kinase inhibitor, nilotinib potentiates a prothrombotic state. Issue 145 (September 2016)

• Record Type: Journal Article
• Authors: Alhawiti, Naif; Burbury, Kate L.; Kwa, Faith A.; O'Malley, Cindy J.; Shuttleworth, Peter; Alzard, Mohamad; Hamadi, Abdullah; Grigg, Andrew P.; Jackson, Denise E.
• Is Part Of: Thrombosis research. Issue 145(2016)
• Page Start: 54
• Page End: 64
• Publication Date: 2016-09
• Subjects: Endothelial activation -- Nilotinib -- Platelet activation -- Bcr-Abl tyrosine kinase -- Thrombosis -- P-selectin; Thrombosis -- Periodicals; 616.135
• DOI: 10.1016/j.thromres.2016.07.019
• Languages: English
• ISSNs: 0049-3848

Abstract

Abstract: 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. Highlights: In this study we show that nilotinib, tyrosine kinase inhibitor producing a prothrombotic state in both microvascular and arteriolar thrombosis in a C57B6 mouse model. We show that nilotinib-treated chronic phase CML patients in complete haematological remission have platelet activation, endothelial dysfunction and inflammation shown by biomarker studies. Nilotinib-treated mice or humans resulted in increased ex vivo and in vivo thrombus formation on type I collagen under arterial flow conditions.