Effect of Bruton's tyrosine kinase inhibitors on platelet aggregation in patients with acute myocardial infarction

Bhatti, Maria, Ayton, Sarah, Michail, Olga, Gollop, Nicholas D., Ryding, Alisdair, Rushworth, Stuart, Bowles, Kristian, Geisler, Tobias and Flather, Marcus (2019) Effect of Bruton's tyrosine kinase inhibitors on platelet aggregation in patients with acute myocardial infarction. Thrombosis Research, 179. pp. 64-68. ISSN 0049-3848

[img]
Preview
PDF (Accepted_Manuscript) - Submitted Version
Download (466kB) | Preview

Abstract

Aims: Despite widespread use of dual antiplatelet therapy in acute myocardial infarction, there remains a residual risk of morbidity and mortality. Bruton's Tyrosine Kinase inhibitors have been found to inhibit platelet aggregation through the Glycoprotein VI collagen-mediated pathway. The Bruton's Tyrosine Kinase inhibitor, Ibrutinib is used in the management of haematological malignancies and another Bruton's Tyrosine Kinase inhibitor, ONO-4059 (also known as tirabrutinib), is in clinical development. This is an observational study to evaluate the effects of Ibrutinib and ONO-4059 on platelet aggregation after acute myocardial infarction. Methods and results: Twenty patients with a confirmed diagnosis of acute myocardial infarction were enrolled and blood samples obtained within 48 h of hospital admission. All patients were on dual antiplatelet therapy; aspirin plus a P2Y12 inhibitor (clopidogrel or ticagrelor). Blood samples were treated ex vivo with increasing concentrations of Ibrutinib (0, 0.5, 1, 2 μM) and ONO-4059 (0, 0.2, 0.5, 1 μM). Platelet aggregation was measured in response to collagen using a Multiplate analyser to estimate the area under the curve, with lower values indicating lower platelet aggregation. The median age was 63 years and 80% were male. The median area under the curve values for Ibrutinib concentrations 0 (control), 0.5, 1 and 2 mmol/l were 18.5, 8 (P = 0.0004), 4.5 (P < 0.0001) and 2 (P < 0.0001) units and for ONO-4059 concentrations 0 (control), 0.2, 0.5 and1μM, median area under the curve values were 13, 12 (P = 0.7), 6.5 (P = 0.0001) and 5.5 (P = 0.0004 compared to control). Conclusion: The Bruton's Tyrosine Kinase inhibitors, Ibrutinib and ONO-4059, show further inhibition of platelet aggregation in blood samples from patients with acute myocardial infarction, receiving dual antiplatelet therapy in a dose dependent manner. These results provide a rationale for Bruton's Tyrosine Kinase inhibitors to be tested as a potential new antiplatelet strategy for acute myocardial infarction.

Item Type: Article
Faculty \ School: Faculty of Medicine and Health Sciences > Norwich Medical School
Depositing User: LivePure Connector
Date Deposited: 30 Apr 2019 14:30
Last Modified: 05 Jul 2020 23:51
URI: https://ueaeprints.uea.ac.uk/id/eprint/70758
DOI: 10.1016/j.thromres.2019.04.024

Actions (login required)

View Item View Item