Effects of ibrutinib on in vitro platelet aggregation in blood samples from healthy donors and donors with platelet dysfunction

Hematology
Joi NinomotoMark Crowther

Abstract

Background: Ibrutinib, a first-in-class, once-daily inhibitor of Bruton's tyrosine kinase (BTK), is approved in the US and EU for the treatment of various B-cell malignancies. In clinical studies, BTK inhibitors have been associated with increased bleeding risk, which may result from BTK inhibition in platelets.Methods: To better understand the mechanism of ibrutinib in bleeding events, we isolated platelet-rich plasma from healthy donors (n = 8) and donors with conditions associated with impaired platelet function or with potentially increased bleeding risk (on hemodialysis, taking aspirin, or taking warfarin; n = 8 each cohort) and used light transmission aggregometry to assess platelet aggregation in vitro after exposure to escalating concentrations of ibrutinib, spanning and exceeding the pharmacologic range of clinical exposure.Results: Platelet aggregation was induced by agonists of 5 major platelet receptors: adenosine diphosphate (ADP), thrombin receptor-activating peptide 6 (TRAP6), ristocetin, collagen, or arachidonic acid (AA). Platelet aggregation induced by ADP, TRAP6, ristocetin, and AA was not meaningfully inhibited by the maximal concentrations of ibrutinib (10 µM). In contrast, collagen-induced platelet aggrega...Continue Reading

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Citations

Apr 4, 2021·Cancers·Philipp von Hundelshausen, Wolfgang Siess
Jun 16, 2021·Thrombosis and Haemostasis·Bibian M E TullemansMarijke J E Kuijpers
Oct 7, 2021·British Journal of Haematology·David J Kuter

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