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

Research output: Contribution to journalArticle

Authors

External organisations

  • University of Birmingham, Birmingham.
  • Birmingham Heartlands Hospital
  • University of Munster, Münster, Germany.
  • Queen Elizabeth Hospital Birmingham, Queen Elizabeth Medical Centre
  • Institute for Cardiovascular and Metabolic Research, Harborne Building, University of Reading, Reading
  • Institute of Cardiovascular and Metabolic Research, School of Biological Sciences, University of Reading

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.

Details

Original languageEnglish
Number of pages25
JournalHaematologica
Early online date16 Jan 2020
Publication statusE-pub ahead of print - 16 Jan 2020

Keywords

  • platelets, disorders of platelet function, venous thrombosis, molecular pharmacology