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Blood, 27 August 2009, Vol. 114, No. 9, pp. 1722-1723. This Article Abstract Full Text (PDF) Alert me when this article is cited Alert me if a correction is posted 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 CrossRef Google Scholar Articles by McKenzie, S. E. Articles by Reilly, M. P. PubMed PubMed Citation Articles by McKenzie, S. E. Articles by Reilly, M. P. Related Collections Related Article in Blood Online Social Bookmarking                   What's this?  Previous Article  |  Table of Contents  |  Next Article  PLATELETS & THROMBOPOIESIS Comment on Gratacap et al, page 1884 The clot thickens (or not) Steven E. McKenzie, and Michael P. Reilly THOMAS JEFFERSON UNIVERSITY Abstract In this issue of Blood, Gratacap and colleagues analyze the effects of the multikinase inhibitor dasatinib on platelets, helping to explain the occurrence of bleeding related to its use for CML patients resistant to or intolerant of imatinib.1 In addition, by virtue of careful experimentation using multiple functional platelet assays, these authors are paving the way for the development of kinase inhibitors as antithrombotic agents. Dasatinib is one of the second generation BCR-ABL inhibitors, along with bosutinib and nilotinib,2,3 used to treat chronic myeloid leukemia (CML) patients resistant to or intolerant of imatinib. These ATP-competitive inhibitors share potent inhibition of BCR-ABL, but differ significantly in their spectrum of multikinase inhibition (see table).4,5 The fact that imatinib also inhibits the kinases c-kit and PDGF-R has been appreciated for some time and taken advantage of clinically. Both dasatinib and nilotinib inhibit c-kit and PDGF-R, while bosutinib does not. However, both dasatinib and bosutinib also inhibit src-family kinases (SFK). Although bleeding during dasatinib use had been reported in association with thrombocytopenia, Quintas-Cardama, Cortes, and colleagues noted dose-related internal and mucosal bleeding in the absence of thrombocytopenia.2,6 The bleeding could not be explained by concomitant use of antiplatelet or anticoagulant medications. They went on to show defective platelet function in the PFA-100 assay to epinephrine/collagen, but not ADP/collagen, when dasatinib was present at a concentration of 400 nM. Aggregation of platelets from CML patients receiving dasatinib was abnormal in response to arachidonic acid and epinephrine, but normal with low- and high-dose ADP, ristocetin, and high-dose collagen. Of note, imatinib use resulted in decreased aggregation in response to arachidonic acid only, while neither nilotinib-treated nor bosutinib-treated patients showed abnormal aggregation to any agonist tested. View larger version (16K): [in this window] [in a new window]   Multikinase profile of the BCR-ABL inhibitors in CML treatment. – indicates no inhibition; +, moderate inhibition; ++, strong inhibition at clinically relevant concentrations; and nr, not reported.   It is in this context that the contribution by Gratacap, Payrastre, and colleagues can be examined further. These authors studied human platelet activation by thrombin, ADP, collagen (low- and intermediate-dose), and agonists of the FcRIIa receptor in the presence of dasatinib. The potency of dasatinib, active at concentrations of less than 20 nM in inhibiting platelet activation via both collagen receptor GPVI/FcR and FcRIIa, is striking. These receptors share the immunoreceptor tyrosine activation motif (ITAM) mode of activating platelets via SFKs and syk. Dasatinib affected thrombin-mediated activation only at low doses of thrombin, whereas imatinib did not affect any of the platelet functions tested. Indeed, thrombus volume was decreased by dasatinib but not imatinib in flow of either human or mouse blood over a collagen surface at arterial shear rates. Mice treated with dasatinib doses resulting in 100 to 150 nM plasma concentration of dasatinib, equivalent to human levels achieved with standard dosing, experienced significantly increased tail bleeding times. Finally, sera from patients with heparin-induced thrombocytopenia, which activates platelets in the presence of heparin via FcRIIa, were unable to activate platelets pretreated with dasatinib. Gratacap et al attribute the effects of dasatinib to its inhibition of SFKs, critical nonreceptor kinases directly involved in GPVI/FcR, and FcRIIa activation signals, as well as in IIb/β3 outside-in signaling. It will be interesting in future studies to compare bosutinib, which also inhibits SFKs but likely not platelet BTK or Eph kinases, with dasatinib to see how much of the platelet inhibition is specifically related to SFK inhibition. Their observations provide further proof of concept that platelet nonreceptor protein tyrosine kinases, such as the SFKs or syk7,8 may be excellent targets for therapy of atherothrombosis or heparin-induced thrombocytopenia and thrombosis. Footnotes Conflict-of-interest disclosure: S.E.M. and M.P.R. report receiving research support from Portola Pharmaceuticals. S.E.M. also reports receiving research support from NovoNordisk. REFERENCES Gratacap M-P, Martin V, Valéra M-C, et al. The new tyrosine-kinase inhibitor and anticancer drug dasatinib reversibly affects platelet activation in vitro and in vivo. Blood. 2009;114(9):1884–1892.[Abstract/Free Full Text] Quintas-Cardama A, Han X, Kantarjian H, Cortes J. Tyrosine kinase inhibitor-induced platelet dysfunction in patients with chronic myeloid leukemia. Blood. 2009;114(2):261–263.[Abstract/Free Full Text] Redaelli S, Piazza R, Rostagno R, et al. Activity of bosutinib, dasatinib, and nilotinib against 18 imatinib-resistant BCR/ABL mutants. J Clin Oncol. 2009;27(3):469–471.[Free Full Text] Rix U, Hantschel O, Durnberger G, et al. Chemical proteomic profiles of the BCR-ABL inhibitors imatinib, nilotinib, and dasatinib reveal novel kinase and nonkinase targets. Blood. 2007;110(12):4055–4063.[Abstract/Free Full Text] Bantscheff M, Eberhard D, Abraham Y, et al. Quantitative chemical proteomics reveals mechanisms of action of clinical ABL kinase inhibitors. Nat Biotechnol. 2007;25(9):1035–1044.[CrossRef][Medline] [Order article via Infotrieve] Khoury HJ, Guilhot F, Hughes TP, Kim DW, Cortes JE. Dasatinib treatment for Philadelphia chromosome-positive leukemias: practical considerations. Cancer. 2009;115(7):1381–1394.[CrossRef][Medline] [Order article via Infotrieve] Delaney S, Sinha U, Nanda N, et al. Specific pharmacological targeting of the Syk kinase activity in platelets: a novel, safe antithrombotic strategy [abstract]. Blood. 2008;112(suppl):157 Abstract 409. Reilly MP, Sinha U, Andre P, et al. PRT060318, a novel syk inhibitor, prevents heparin-induced thrombocytopenia in a transgenic mouse model [abstract]. Blood. 2008;112(suppl):106 Abstract 269. CiteULike    Connotea    Del.icio.us    Digg    Reddit    Technorati    What's this? Related Article in Blood Online: The new tyrosine-kinase inhibitor and anticancer drug dasatinib reversibly affects platelet activation in vitro and in vivo Marie-Pierre Gratacap, Valérie Martin, Marie-Cécile Valéra, Sophie Allart, Cédric Garcia, Pierre Sié, Christian Recher, and Bernard Payrastre Blood 2009 114: 1884-1892. [Abstract] [Full Text] [PDF] This Article Abstract Full Text (PDF) Alert me when this article is cited Alert me if a correction is posted 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 CrossRef Google Scholar Articles by McKenzie, S. E. Articles by Reilly, M. P. PubMed PubMed Citation Articles by McKenzie, S. E. Articles by Reilly, M. P. Related Collections Related Article in Blood Online Social Bookmarking                   What's this?

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