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Am J Physiol Cell Physiol. 2016 Mar 1;310(5):C373-80. doi: 10.1152/ajpcell.00325.2015. Epub 2015 Dec 9.

Oral administration of Bruton's tyrosine kinase inhibitors impairs GPVI-mediated platelet function.

Author information

1
Department of Biomedical Engineering, School of Medicine, Oregon Health & Science University, Portland, Oregon; rigg@ohsu.edu.
2
Department of Biomedical Engineering, School of Medicine, Oregon Health & Science University, Portland, Oregon; Department of Cell, Developmental & Cancer Biology, School of Medicine, Oregon Health & Science University, Portland, Oregon; and.
3
Department of Cell, Developmental & Cancer Biology, School of Medicine, Oregon Health & Science University, Portland, Oregon; and.
4
Department of Biomedical Engineering, School of Medicine, Oregon Health & Science University, Portland, Oregon;
5
Department of Biomedical Engineering, School of Medicine, Oregon Health & Science University, Portland, Oregon; Division of Hematology and Medical Oncology, School of Medicine, Oregon Health & Science University, Portland, Oregon.
6
Department of Biomedical Engineering, School of Medicine, Oregon Health & Science University, Portland, Oregon; Department of Cell, Developmental & Cancer Biology, School of Medicine, Oregon Health & Science University, Portland, Oregon; and Division of Hematology and Medical Oncology, School of Medicine, Oregon Health & Science University, Portland, Oregon.

Abstract

The Tec family kinase Bruton's tyrosine kinase (Btk) plays an important signaling role downstream of immunoreceptor tyrosine-based activation motifs in hematopoietic cells. Mutations in Btk are involved in impaired B-cell maturation in X-linked agammaglobulinemia, and Btk has been investigated for its role in platelet activation via activation of the effector protein phospholipase Cγ2 downstream of the platelet membrane glycoprotein VI (GPVI). Because of its role in hematopoietic cell signaling, Btk has become a target in the treatment of chronic lymphocytic leukemia and mantle cell lymphoma; the covalent Btk inhibitor ibrutinib was recently approved by the US Food and Drug Administration for treatment of these conditions. Antihemostatic events have been reported in some patients taking ibrutinib, although the mechanism of these events remains unknown. We sought to determine the effects of Btk inhibition on platelet function in a series of in vitro studies of platelet activation, spreading, and aggregation. Our results show that irreversible inhibition of Btk with two ibrutinib analogs in vitro decreased human platelet activation, phosphorylation of Btk, P-selectin exposure, spreading on fibrinogen, and aggregation under shear flow conditions. Short-term studies of ibrutinib analogs administered in vivo also showed abrogation of platelet aggregation in vitro, but without measurable effects on plasma clotting times or on bleeding in vivo. Taken together, our results suggest that inhibition of Btk significantly decreased GPVI-mediated platelet activation, spreading, and aggregation in vitro; however, prolonged bleeding was not observed in a model of bleeding.

KEYWORDS:

Bruton's tyrosine kinase; glycoprotein VI; ibrutinib; platelets

PMID:
26659727
PMCID:
PMC4971826
[Available on 2017-03-01]
DOI:
10.1152/ajpcell.00325.2015
[Indexed for MEDLINE]
Free PMC Article

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