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Ponatinib Tyrosine Kinase Inhibitor Induces a Thromboinflammatory Response.

Authors
  • Hamadi, Abdullah1
  • Grigg, Andrew P2
  • Dobie, Gasim1
  • Burbury, Kate L3
  • Schwarer, Anthony P4
  • Kwa, Faith A1
  • Jackson, Denise E1
  • 1 Thrombosis and Vascular Diseases Laboratory, School of Health and Biomedical Sciences, RMIT University, Bundoora, Victoria, Australia. , (Australia)
  • 2 Department of Clinical Haematology, Austin Hospital, Heidelberg, Victoria, Australia. , (Australia)
  • 3 Department of Haematology, Peter MacCallum Cancer Centre, Parkville, Victoria, Australia. , (Australia)
  • 4 Department of Haematology, Eastern Health, Box Hill, Victoria, Australia. , (Australia)
Type
Published Article
Journal
Thrombosis and Haemostasis
Publisher
Georg Thieme Verlag KG
Publication Date
Jul 01, 2019
Volume
119
Issue
7
Pages
1112–1123
Identifiers
DOI: 10.1055/s-0039-1688787
PMID: 31079415
Source
Medline
Language
English
License
Unknown

Abstract

Both nilotinib, a second-generation tyrosine kinase inhibitor (TKI) used in the treatment of chronic myeloid leukaemia (CML), and ponatinib, a third-generation TKI used in CML and Philadelphia positive acute lymphocytic leukaemia, have been associated with an increase in arterial occlusive events, in contrast to other TKIs such as imatinib and dasatinib. We have previously demonstrated evidence of a pro-thrombotic state associated with nilotinib, using microvascular and arterial thrombosis C57BL/6 mouse models. In this study, we examined ponatinib and determined if a calcium channel blocker could ameliorate the pro-thrombotic and pro-inflammatory phenotypes. In vitro treatment of whole human or murine blood with ponatinib and nilotinib increased platelet activation, adhesion and three-dimensional thrombi over time compared with vehicle control or other TKIs. Treatment of wild-type C57BL/6 mice with ponatinib and nilotinib but not imatinib, dasatinib or vehicle control for 4 hours significantly increased thrombus growth following ex vivo perfusion on collagen and FeCl3-induced vascular injury of mesenteric arterioles and carotid artery in vivo and increased plasma levels of soluble P-selectin, tumour necrosis factor-α, interleukin-6, interferon-γ and thromboxane B2 (TxB2). Ponatinib-treated CML patients had increased ex vivo thrombus formation and a pro-inflammatory phenotype compared with healthy controls. Pre-treatment of mice with the calcium channel antagonist, diltiazem, prior to ponatinib or nilotinib reversed the pro-thrombotic phenotype and the increase in cytokine levels. These observations suggest that the pro-thrombotic effect of nilotinib and ponatinib is partially related to calcium channel activation and TxA2 generation and this should be explored clinically as a mechanism to prevent vascular events. Georg Thieme Verlag KG Stuttgart · New York.

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