Skip to main content

Thank you for visiting nature.com. You are using a browser version with limited support for CSS. To obtain the best experience, we recommend you use a more up to date browser (or turn off compatibility mode in Internet Explorer). In the meantime, to ensure continued support, we are displaying the site without styles and JavaScript.

  • Original Article
  • Published:

Therapy

Ibrutinib inhibits collagen-mediated but not ADP-mediated platelet aggregation

Leukemia volume 29, pages 783–787 (2015)Cite this article

Subjects

Abstract

The BTK (Bruton’s tyrosine kinase) inhibitor ibrutinib is associated with an increased risk of bleeding. A previous study reported defects in collagen- and adenosine diphosphate (ADP)-dependent platelet responses when ibrutinib was added ex vivo to patient samples. Whereas the collagen defect is expected given the central role of BTK in glycoprotein VI signaling, the ADP defect lacks a mechanistic explanation. In order to determine the real-life consequences of BTK platelet blockade, we performed light transmission aggregometry in 23 patients receiving ibrutinib treatment. All patients had reductions in collagen-mediated platelet aggregation, with a significant association between the degree of inhibition and the occurrence of clinical bleeding or bruising (P=0.044). This collagen defect was reversible on drug cessation. In contrast to the previous ex vivo report, we found no in vivo ADP defects in subjects receiving standard doses of ibrutinib. These results establish platelet light transmission aggregometry as a method for gauging, at least qualitatively, the severity of platelet impairment in patients receiving ibrutinib treatment.

This is a preview of subscription content, access via your institution

Access options

Buy this article

  • Purchase on Springer Link
  • Instant access to full article PDF
Buy now

Prices may be subject to local taxes which are calculated during checkout

Figure 1
Figure 2

Similar content being viewed by others

References

  1. Byrd JC, Furman RR, Coutre SE, Flinn IW, Burger JA, Blum K et al. Targeting BTK with ibrutinib in relapsed chronic lymphocytic leukemia. N Engl J Med 2013; 369: 32–42.

    Article  CAS  Google Scholar 

  2. Byrd JC, Brown JR, O'Brien S, Barrientos JC, Kay NE, Reddy NM et al. Ibrutinib versus ofatumumab in previously treated chronic lymphoid leukemia. N Engl J Med 2014; 371: 213–223.

    Article  Google Scholar 

  3. Wang ML, Rule S, Martin P, Goy A, Auer R, Kahl BS et al. Targeting BTK with ibrutinib in relapsed or refractory mantle-cell lymphoma. N Engl J Med 2013; 369: 507–516.

    Article  CAS  Google Scholar 

  4. Advani RH, Buggy JJ, Sharman JP, Smith SM, Boyd TE, Grant B et al. Bruton tyrosine kinase inhibitor ibrutinib (PCI-32765) has significant activity in patients with relapsed/refractory B-cell malignancies. J Clin Oncol 2013; 31: 88–94.

    Article  CAS  Google Scholar 

  5. Quek LS, Bolen J, Watson SP . A role for Bruton's tyrosine kinase (Btk) in platelet activation by collagen. Curr Biol 1998; 8: 1137–1140.

    Article  CAS  Google Scholar 

  6. Atkinson BT, Ellmeier W, Watson SP . Tec regulates platelet activation by GPVI in the absence of Btk. Blood 2003; 102: 3592–3599.

    Article  CAS  Google Scholar 

  7. Honigberg LA, Smith AM, Sirisawad M, Verner E, Loury D, Chang B et al. The Bruton tyrosine kinase inhibitor PCI-32765 blocks B-cell activation and is efficacious in models of autoimmune disease and B-cell malignancy. Proc Natl Acad Sci USA 2010; 107: 13075–13080.

    Article  CAS  Google Scholar 

  8. Farooqui M, Lozier JN, Valdez J, Saba N, Wells A, Soto S et al. Ibrutinib (PCI 32765) rapidly improves platelet counts in chronic lymphocytic leukemia/small lymphocytic lymphoma (CLL/SLL) patients and has minimal effects on platelet aggregation. ASH Annual Meeting Abstracts 2012; 120: 1789.

    Google Scholar 

  9. Rushworth SA, MacEwan DJ, Bowles KM . Ibrutinib in relapsed chronic lymphocytic leukemia. N Engl J Med. 2013; 369: 1277–1278.

    Article  Google Scholar 

  10. Squizzato A, Keller T, Romualdi E, Middeldorp S . Clopidogrel plus aspirin versus aspirin alone for preventing cardiovascular disease. Cochrane Database Syst Rev 2011; (1): CD005158.

  11. Lewis BB, Bates I . Dacie and Lewis Practical Haematology. 10th edn. Churchill Livingstone, Elsevier, 2006.

    Google Scholar 

  12. Gratacap MP, Martin V, Valera MC, Allart S, Garcia C, Sie P et al. The new tyrosine-kinase inhibitor and anticancer drug dasatinib reversibly affects platelet activation in vitro and in vivo. Blood 2009; 114: 1884–1892.

    Article  CAS  Google Scholar 

  13. Winkelstein JA, Marino MC, Lederman HM, Jones SM, Sullivan K, Burks AW et al. X-linked agammaglobulinemia: report on a United States registry of 201 patients. Medicine (Baltimore) 2006; 85: 193–202.

    Article  Google Scholar 

  14. Arthur JF, Dunkley S, Andrews RK . Platelet glycoprotein VI-related clinical defects. Br J Haematol 2007; 139: 363–372.

    Article  CAS  Google Scholar 

  15. Zahid M, Mangin P, Loyau S, Hechler B, Billiald P, Gachet C et al. The future of glycoprotein VI as an antithrombotic target. J Thromb Haemost 2012; 10: 2418–2427.

    Article  CAS  Google Scholar 

Download references

Acknowledgements

We thank Bernard Payrastre and Cedric Garcia (Inserm, U1048 and Université Toulouse 3) for assistance in platelet testing, and acknowledge the generosity of the subjects who participated in this study. This work was funded by the authors’ institutions.

Author information

Authors and Affiliations

  1. Department of Hematology, St Vincent’s Hospital, Melbourne, Victoria, Australia

    S Kamel, L Horton, S Tan, M Cole-Sinclair, R Filshie, S Schischka, H Nandurkar & C S Tam

  2. Département d'Hématologie, IUCT-Oncopole, Toulouse, France

    L Ysebaert

  3. Inserm, U1048 and Université Toulouse 3, Toulouse, France

    M Levade

  4. Laboratoire d’Hématologie CHU de Toulouse, Toulouse, France

    M Levade

  5. Department of Hematology, Peter MacCallum Cancer Centre, Melbourne, Victoria, Australia

    K Burbury, A Khot, S Sandhu & C S Tam

  6. Faculty of Health, Deakin University, Melbourne, Victoria, Australia

    J Reynolds

  7. Leukemia Department, University of Texas MD Anderson Cancer Center, Houston, TX, USA

    M J Keating

  8. University of Melbourne, Parkville, Victoria, Australia

    H Nandurkar & C S Tam

Authors
  1. S Kamel
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. L Horton
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. L Ysebaert
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. M Levade
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. K Burbury
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. S Tan
    View author publications

    You can also search for this author in PubMed Google Scholar

  7. M Cole-Sinclair
    View author publications

    You can also search for this author in PubMed Google Scholar

  8. J Reynolds
    View author publications

    You can also search for this author in PubMed Google Scholar

  9. R Filshie
    View author publications

    You can also search for this author in PubMed Google Scholar

  10. S Schischka
    View author publications

    You can also search for this author in PubMed Google Scholar

  11. A Khot
    View author publications

    You can also search for this author in PubMed Google Scholar

  12. S Sandhu
    View author publications

    You can also search for this author in PubMed Google Scholar

  13. M J Keating
    View author publications

    You can also search for this author in PubMed Google Scholar

  14. H Nandurkar
    View author publications

    You can also search for this author in PubMed Google Scholar

  15. C S Tam
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to C S Tam.

Ethics declarations

Competing interests

Dr Tam received honorarium from Janssen-Cilag and Pharmacyclics. The remaining authors declare no conflict of interest.

Additional information

Supplementary Information accompanies this paper on the Leukemia website

Supplementary information

Rights and permissions

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Kamel, S., Horton, L., Ysebaert, L. et al. Ibrutinib inhibits collagen-mediated but not ADP-mediated platelet aggregation. Leukemia 29, 783–787 (2015). https://doi.org/10.1038/leu.2014.247

Download citation

  • Received:

  • Revised:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1038/leu.2014.247

This article is cited by

Search

Advanced search

Quick links