Low dose Btk inhibitors selectively block platelet activation by CLEC-2.

Nicolson, Phillip L R, Nock, Sophie H, Hinds, Joshua, Garcia-Quintanilla, Lourdes, Smith, Christopher W, Campos, Joana, Brill, Alexander, Pike, Jeremy A, Khan, Abdullah O, Poulter, Natalie S, Kavanagh, Diedre M, Watson, Stephanie, Watson, Callum N, Clifford, Hayley, Huissoon, Aarnoud P, Pollitt, Alice Y, Eble, Johannes A, Pratt, Guy, Watson, Steve P and Hughes, Craig E (2020) Low dose Btk inhibitors selectively block platelet activation by CLEC-2. Haematologica. 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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Abstract

Inhibitors of the tyrosine kinase Btk have been proposed as novel antiplatelet agents. In this study we show that low concentrations of the Btk inhibitor ibrutinib block CLEC-2-mediated activation and tyrosine phosphorylation including Syk and PLCγ2 in human platelets. Activation is also blocked in patients with X-linked agammaglobulinaemia (XLA) caused by a deficiency or absence of Btk. In contrast, the response to GPVI is delayed in the presence of low concentrations of ibrutinib or in patients with XLA, and tyrosine phosphorylation of Syk is preserved. A similar set of results is seen with the second-generation inhibitor, acalabrutinib. The differential effect of Btk inhibition in CLEC-2 relative to GPVI signalling is explained by the positive feedback role involving Btk itself, as well as ADP and thromboxane A2 mediated activation of P2Y12 and TP receptors, respectively. This feedback role is not seen in mouse platelets and, consistent with this, CLEC-2-mediated activation is blocked by high but not by low concentrations of ibrutinib. Nevertheless, thrombosis was absent in 8 out of 13 mice treated with ibrutinib. These results show that Btk inhibitors selectively block activation of human platelets by CLEC-2 relative to GPVI suggesting that they can be used at 'low dose' in patients to target CLEC-2 in thrombo-inflammatory disease.

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
WG Cardiovascular system. Cardiology
WH Haemic and lymphatic systems. Haematology
Divisions: Planned IP Care > Oncology and Clinical Haematology
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Depositing User: Jamie Edgar
Date Deposited: 24 Jan 2020 15:30
Last Modified: 24 Jan 2020 15:30
URI: http://www.repository.uhblibrary.co.uk/id/eprint/2796

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