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Blood, 27 August 2009, Vol. 114, No. 9, pp. 1884-1892. Prepublished online as a Blood First Edition Paper on June 3, 2009; DOI 10.1182/blood-2009-02-205328. This Article Full Text Full Text (PDF) Supplemental Figures All Versions of this Article: blood-2009-02-205328v1 114/9/1884    most recent Alert me when this article is cited Alert me if a correction is posted Citation Map Services Email this article to a friend Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Rights and Permissions Citing Articles Citing Articles via HighWire Citing Articles via CrossRef Google Scholar Articles by Gratacap, M.-P. Articles by Payrastre, B. PubMed PubMed Citation Articles by Gratacap, M.-P. Articles by Payrastre, B. Related Collections Free Research Articles Myeloid Neoplasia Platelets and Thrombopoiesis Related Article in Blood Online Social Bookmarking                   What's this?  Previous Article  |  Table of Contents  |  Next Article  PLATELETS AND THROMBOPOIESIS The new tyrosine-kinase inhibitor and anticancer drug dasatinib reversibly affects platelet activation in vitro and in vivo Marie-Pierre Gratacap1,*, Valérie Martin1,*, Marie-Cécile Valéra1, Sophie Allart2, Cédric Garcia3, Pierre Sié3, Christian Recher1,4, and Bernard Payrastre1,3 1 Inserm U563, Centre de Physiopathologie de Toulouse Purpan, Département d'Oncogenèse, Signalisation et Innovation thérapeutique and Université Toulouse III Paul Sabatier, Toulouse; 2 Plateforme d'imagerie de l'IFR 30, Toulouse; and 3 Laboratoire d'Hématologie and 4 Service d'hématologie, Centre Hospitalier Universitaire de Toulouse, Toulouse, France Dasatinib is an oral potent adenosine triphosphate (ATP)–competitive inhibitor of BCR-ABL, cKIT, platelet-derived growth factor receptor, and SRC family kinases (SFKs), which has demonstrated high efficiency in patients with imatinib-resistant chronic myelogenous leukemia. Here, we show that dasatinib weakly affects platelet activation by thrombin or adenosine diphosphate but is a potent inhibitor of platelet signaling and functions initiated by collagen or FcRIIA cross-linking, which require immunoreceptor tyrosine-based activation motif phosphorylation by SFKs. Accordingly, dasatinib treatment rapidly decreases the volume of thrombi formed under arterial flow conditions in whole blood from patients or mice perfused over a matrix of collagen. Moreover, treatment of mice with dasatinib increases the tail bleeding time in a dose-dependent manner. Interestingly, these effects are rapidly reversible after interruption of the treatment. Our data clearly demonstrate that, in contrast to imatinib, dasatinib affects platelet functions in vitro and in vivo, which has important implications in clinic and could explain increased risks of bleeding observed in patients. Moreover, dasatinib efficiently prevents platelet activation mediated by FcRIIA cross-linking and by sera from patients with heparin-induced thrombocytopenia, suggesting that reversible antiplatelet agents acting as ATP-competitive inhibitors of SFKs may be of therapeutic interest in the treatment of this pathology. CiteULike    Connotea    Del.icio.us    Digg    Reddit    Technorati    What's this? Related Article in Blood Online: The clot thickens (or not) Steven E. McKenzie and Michael P. Reilly Blood 2009 114: 1722-1723. [Abstract] [Full Text] [PDF] This article has been cited by other articles: S. E. McKenzie and M. P. Reilly The clot thickens (or not) Blood, August 27, 2009; 114(9): 1722 - 1723. [Abstract] [Full Text] [PDF]

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