title: The tyrosine kinase inhibitor, nilotinib potentiates a prothrombotic state.
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.
authors: Thrombosis and Vascular Diseases Laboratory, School of Health and Biomedical Sciences, RMIT University, Bundoora, Victoria, Australia.
authors: Naif
authors: N
authors: Alhawiti
authors: Haematology Department, Peter MacCallum Cancer Centre, East Melbourne, Australia.
authors: Kate L
authors: KL
authors: Burbury
authors: Thrombosis and Vascular Diseases Laboratory, School of Health and Biomedical Sciences, RMIT University, Bundoora, Victoria, Australia.
authors: Faith A
authors: FA
authors: Kwa
authors: Thrombosis and Vascular Diseases Laboratory, School of Health and Biomedical Sciences, RMIT University, Bundoora, Victoria, Australia.
authors: Cindy J
authors: CJ
authors: O'Malley
authors: Department of Clinical Haematology, Austin Health, Heidelberg, Victoria, Australia.
authors: Peter
authors: P
authors: Shuttleworth
authors: Thrombosis and Vascular Diseases Laboratory, School of Health and Biomedical Sciences, RMIT University, Bundoora, Victoria, Australia.
authors: Mohamad
authors: M
authors: Alzard
authors: Thrombosis and Vascular Diseases Laboratory, School of Health and Biomedical Sciences, RMIT University, Bundoora, Victoria, Australia.
authors: Abdullah
authors: A
authors: Hamadi
authors: Department of Clinical Haematology, Austin Health, Heidelberg, Victoria, Australia.
authors: Andrew P
authors: AP
authors: Grigg
authors: Thrombosis and Vascular Diseases Laboratory, School of Health and Biomedical Sciences, RMIT University, Bundoora, Victoria, Australia. Electronic address: denise.jackson@rmit.edu.au.
authors: Denise E
authors: DE
authors: Jackson
mesh_terms: D000818:Animals; D000970:Antineoplastic Agents / Q000008:administration & dosage / Q000627:therapeutic use*; D004195:Disease Models, Animal; D006801:Humans; D051379:Mice; D008810:Mice, Inbred C57BL; D011743:Pyrimidines / Q000008:administration & dosage / Q000627:therapeutic use*; D012307:Risk Factors; D013927:Thrombosis
chemical_list: D000970:Antineoplastic Agents; D011743:Pyrimidines; C498826:nilotinib
keywords: Bcr-Abl tyrosine kinase; Endothelial activation; Nilotinib; P-selectin; Platelet activation; Thrombosis