ArticleBlood advances2019
Ibrutinib, but not zanubrutinib, induces platelet receptor shedding of GPIb-IX-V complex and integrin αIIbβ3 in mice and humans.
Article in Blood advances, 2019. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 34 papers.
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Who cites it
34 citing papers in PubMed, 57 citations in OpenAlex.
- Zanubrutinib for the treatment of patients with Waldenström macroglobulinemia: 3 years of follow-up.Blood · 2020Trial
- Comparison of variably specific Bruton tyrosine kinase inhibitors on platelet aggregation mediated by Fcγ receptor (FcγR) IIa, glycoprotein VI, and platelet endothelial aggregation receptor (PEAR) 1: implications for Bruton tyrosine kinase inhibitors as antithrombotic therapy.Research and practice in thrombosis and haemostasis · 2026Article
- Cardiovascular Toxicity of BTKi in Chronic B-Cell Malignancies.Reviews in cardiovascular medicine · 2026Review
- BTK inhibitors potently impair platelet aggregation as a class effect independent of BTK specificity or dose in CLL and MCL.Journal of clinical and experimental hematopathology : JCEH · 2025Article
- Ibrutinib pharmacokinetics in B-lymphoproliferative disorders discloses exposure-related incidence of hypertension.Journal of hypertension · 2025Article
- Functional proteoform group deconvolution reveals a broader spectrum of ibrutinib off-targets.Nature communications · 2025Article
- New hopes and challenges in targeted therapy and immunotherapy for primary central nervous system lymphoma.Frontiers in immunology · 2025Review
- A pharmacovigilance study of Bruton's tyrosine kinase inhibitors: a multidimensional analysis based on FAERS and VigiBase.Frontiers in immunology · 2025Article
- Patients with Waldenström macroglobulinemia have impaired platelet and coagulation function.Blood advances · 2024Article
- Bruton Tyrosine Kinase Inhibition Decreases Inflammation and Differentially Impacts Phagocytosis and Cellular Metabolism in Mouse- and Human-derived Myeloid Cells.ImmunoHorizons · 2024Article
- Targeting Bruton's tyrosine kinase (BTK) as a signaling pathway in immune-mediated diseases: from molecular mechanisms to leading treatments.Advances in rheumatology (London, England) · 2024Review
- Underlying Mechanisms of Thrombosis Associated with Cancer and Anticancer Therapies.Current treatment options in oncology · 2024Review
- Adverse effects of tyrosine kinase inhibitors in cancer therapy: pathophysiology, mechanisms and clinical management.Signal transduction and targeted therapy · 2023Review
- Management of relapsed/refractory Chronic Lymphocytic Leukemia.American journal of hematology · 2022Review
- Bleeding Propensity in Waldenström Macroglobulinemia: Potential Causes and Evaluation.Thrombosis and haemostasis · 2022Review
- Platelets and tyrosine kinase inhibitors: clinical features, mechanisms of action, and effects on physiology.American journal of physiology. Cell physiology · 2022Review
- Ibrutinib Inhibits Angiogenesis and Tumorigenesis in a BTK-Independent Manner.Pharmaceutics · 2022Article
- Bruton's Kinase Inhibitors for the Treatment of Immunological Diseases: Current Status and Perspectives.Journal of clinical medicine · 2022Review
- Factors Associated with Platelet Activation-Recent Pharmaceutical Approaches.International journal of molecular sciences · 2022Review
- Comparison of inhibitory effects of irreversible and reversible Btk inhibitors on platelet function.EJHaem · 2021Article
Corrections and comments
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Authors and funding
10 authors at 2 institutions in 2 countries.
Funding
No grant is acknowledged in the PubMed record.
Abstract
The Bruton's tyrosine kinase (Btk) inhibitor ibrutinib has proven to be efficacious in the treatment of B-cell chronic lymphocytic leukemia (B-CLL) and related diseases. However, a major adverse side effect of ibrutinib is bleeding, including major hemorrhages. The bleeding associated with ibrutinib use is thought to be due to a combination of on-target irreversible Btk inhibition, as well as off-target inhibition of other kinases, including EGFR, ITK, JAK3, and Tec kinase. In this study, we investigated the effects of ibrutinib vs zanubrutinib (a more selective Btk inhibitor) on platelet activation, glycoprotein expression, and thrombus formation. Ibrutinib, but not zanubrutinib, induced a time- and dose-dependent shedding of GPIb-IX complex and integrin αIIbβ3, but not of GPVI and GPV, from the platelet surface. The shedding of GPIbα and GPIX was blocked by GM6001 and TAPI-2, an ADAM17 inhibitor but not ADAM10 inhibitor. Ibrutinib but not zanubrutinib treatment of human platelets increased ADAM17 activation. Pretreatment of C57BL/6 mice with ibrutinib (10 mg/kg), but not zanubrutinib (10 mg/kg), inhibited ex vivo and in vivo thrombus growth over time. Platelets from ibrutinib-treated patients with CLL showed reduced GPIb-IX complex and integrin αIIbβ3 surface expression and reduced ex vivo thrombus formation under arterial flow, which was not observed in zanubrutinib-treated patients. In mice, ibrutinib, but not zanubrutinib, led to increased soluble GPIbα and soluble αIIb levels in plasma. These data demonstrate that ibrutinib induces shedding of GPIbα and GPIX by an ADAM17-dependent mechanism and integrin αIIbβ3 by an unknown sheddase, and this process occurs in vivo to regulate thrombus formation.
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