Inhibition of Btk by Btk-specific concentrations of ibrutinib and acalabrutinib delays but does not block platelet aggregation mediated by glycoprotein VI.

Nicolson, Phillip L R, Hughes, Craig E, Watson, Stephanie, Nock, Sophie H, Hardy, Alexander T, Watson, Callum N, Montague, Samantha J, Clifford, Hayley, Huissoon, Aarnoud P, Malcor, Jean-Daniel, Thomas, Mark R, Pollitt, Alice Y, Tomlinson, Michael G, Pratt, Guy and Watson, Steve P (2018) Inhibition of Btk by Btk-specific concentrations of ibrutinib and acalabrutinib delays but does not block platelet aggregation mediated by glycoprotein VI. Haematologica, 103 (12). pp. 2097-2108. ISSN 1592-8721. This article is available to all UHB staff and students via ASK Discovery tool http://tinyurl.com/z795c8c by using their UHB Athens login IDs

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Official URL: http://www.haematologica.org/content/103/12/2097

Abstract

Ibrutinib and acalabrutinib are irreversible inhibitors of Bruton tyrosine kinase used in the treatment of B-cell malignancies. They bind irreversibly to cysteine 481 of Bruton tyrosine kinase, blocking autophosphorylation on tyrosine 223 and phosphorylation of downstream substrates including phospholipase C-γ2. In the present study, we demonstrate that concentrations of ibrutinib and acalabrutinib that block Bruton tyrosine kinase activity, as shown by loss of phosphorylation at tyrosine 223 and phospholipase C-γ2, delay but do not block aggregation in response to a maximally-effective concentration of collagen-related peptide or collagen. In contrast, 10- to 20-fold higher concentrations of ibrutinib or acalabrutinib block platelet aggregation in response to glycoprotein VI agonists. studies on patients treated with ibrutinib, but not acalabrutinib, showed a reduction of platelet aggregation in response to collagen-related peptide indicating that the clinical dose of ibrutinib but not acalabrutinib is supramaximal for Bruton tyrosine kinase blockade. Unexpectedly, low concentrations of ibrutinib inhibited aggregation in response to collagen-related peptide in patients deficient in Bruton tyrosine kinase. The increased bleeding seen with ibrutinib over acalabrutinib is due to off-target actions of ibrutinib that occur because of unfavorable pharmacodynamics.

Item Type: Article
Additional Information: This article is available to all UHB staff and students via ASK Discovery tool http://tinyurl.com/z795c8c by using their UHB Athens login IDs
Subjects: QW Microbiology. Immunology
WH Haemic and lymphatic systems. Haematology
Divisions: Clinical Support > Pathology
Planned IP Care > Oncology and Clinical Haematology
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Depositing User: Beth Connors
Date Deposited: 28 Oct 2019 16:28
Last Modified: 28 Oct 2019 16:28
URI: http://www.repository.uhblibrary.co.uk/id/eprint/2533

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