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.

  • Correspondence
  • Published:

Use of defibrotide to treat adult patients with transplant-associated thrombotic microangiopathy

Bone Marrow Transplantation volume 54, pages 142–145 (2019)Cite this article

Subjects

Hematopoietic cell transplantation (HCT)-associated thrombotic microangiopathy (TA-TMA) is an early and potentially life-threatening complication of the procedure. Multiple factors such as conditioning regimen, unrelated donor-derived grafts, calcineurin inhibitors (CNI), infections or graft-versus-host disease (GVHD), in genetically predisposed recipients, may induce a generalized endothelial dysfunction [1]. Along with endothelial injury, complement system activation by the alternative pathway underlies the pathogenesis of TA-TMA, resembling that of an atypical hemolytic uremic syndrome [2,3,4]. This process leads to the formation of fibrin and platelet-rich thrombi within the microcirculation, precipitating hemolytic anemia, thrombocytopenia, and potentially causing end-organ damage, especially targeting kidneys, but also central nervous system, gut, liver, or lungs.

The diagnosis of TA-TMA is challenging and based on stringent clinical hallmarks with limited sensitivity and specificity [5, 6]. Cho et al. [7] introduced a broader clinical entity of “probable TA-TMA” allowing for an early identification of patients that present with all TA-TMA features, except for renal or neurological dysfunction. Such early identification may allow prompt intervention to improve the otherwise dismal prognosis of severe advanced forms of this transplant complication. Even with a timely diagnosis, beyond removal or treatment of precipitating factors, TA-TMA remains to date a therapeutic challenge. Potential treatments include plasma exchange, apparently less effective in this form of TMA and not devoid of complications, rituximab, and more recently, daclizumab and eculizumab [8,9,10]. The latter, a first-in-class complement inhibitor obtained Food and Drug Administration and European Medicines Agency approvals for the treatment of atypical hemolytic uremic syndrome in 2011. Additionally, defibrotide, with marked protective effects on the endothelium and the potential to restore thrombotic-fibrinolytic homeostasis in small vessels [11], may be considered a therapeutic option for this complication.

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

Relevant articles

Open Access articles citing this article.

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

References

  1. Uderzo C, Bonanomi S, Busca A, Renoldi M, Ferrari P, Iacobelli M, et al. Risk Factors and severe outcome in thrombotic microangiopathy after allogeneic hematopoietic stem cell transplantation. Transplantation. 2006;82:638–44.

    Article  Google Scholar 

  2. Jodele S, Davies SM, Lane A, Khoury J, Dandoy C, Goebel J, et al. Diagnostic and risk criteria for HSCT-associated thrombotic microangiopathy: A study in children and young adults. Blood. 2014;124:645–65.

    Article  CAS  Google Scholar 

  3. Jodele S, Laskin B, Dandoy CE, Myers KC, El-Bietar J, Davies SM, et al. A new paradigm: Diagnosis and management of HSCT-associated thrombotic microangiopathy as multi-system endothelial injury. Blood Rev. 2015;29:191–204.

    Article  Google Scholar 

  4. Obut F, Kasinath V, Abdi R. Post-bone marrow transplant thrombotic microangiopathy. Bone Marrow Transplant. 2016;51:891–7.

    Article  CAS  Google Scholar 

  5. Ho VT, Cutler C, Carter S, Martin P, Adams R, Horowitz M, et al. Blood and Marrow Transplant Clinical Trials Network Toxicity Committee consensus summary: Thrombotic microangiopathy after hematopoietic stem cell transplantation. Biol Blood Marrow Transplant. 2005;11:571–5.

    Article  Google Scholar 

  6. Ruutu T, Barosi G, Benjamin RJ, Clark RE, George JN, Gratwohl A, et al. Diagnostic criteria for hematopoietic stem cell transplant-associated microangiopathy: Results of a consensus process by an International Working Group. Haematologica. 2007;92:95–100.

    Article  Google Scholar 

  7. Cho B-S, Yahng S-A, Lee S-E, Eom K-S, Kim Y-J, Kim H-J, et al. Validation of Recently proposed consensus criteria for thrombotic microangiopathy after allogeneic hematopoietic stem-cell transplantation. Transplantation. 2010;90:918–26.

    Article  CAS  Google Scholar 

  8. Daly AS, Xenocostas A, Lipton JH. Transplantation-associated thrombotic microangiopathy: Twenty-two years later. Bone Marrow Transplant. 2002;30:709–15.

    Article  CAS  Google Scholar 

  9. Fernández C, Lario A, Forés R, Cabrera R. Eculizumab treatment in a patient with hematopoietic stem cell transplantation-associated thrombotic microangiopathy and steroid-refractory acute graft versus host disease. Hematol Rep. 2015;7:88–9.

    Article  Google Scholar 

  10. Gavriilaki E, Sakellari I, Anagnostopoulos A, Brodsky RA. Transplant-associated thrombotic microangiopathy: Opening Pandora’s box. Bone Marrow Transplant. 2017;52:1355–60.

    Article  CAS  Google Scholar 

  11. Kornblum N, Ayyanar K, Benimetskaya L, Richardson P, Iacobelli M, Stein CA, et al. Defibtrotide, a polydisperse mixture of single-stranded phosphodiester oligonucleotides with lifesaving activity in severe hepatic veno-occlusive disease: clinical outcomes and potential mechanisms of action. Oligonucleotides. 2006;16:105–14.

    Article  CAS  Google Scholar 

  12. Bautista G, Cabrera JR, Regidor C, Forés R, García-Marco JA, Ojeda E. Cord blood transplants supported by co-infusion of mobilized hematopoietic stem cells from a third-party donor. Bone Marrow Transplant. 2009;43:365–73.

    Article  CAS  Google Scholar 

  13. Uderzo C, Fumagalli M, De Lorenzo P, Busca A, Vassallo E, Bonanomi S, et al. Impact of thrombotic thrombocytopenic purpura on leukemic children undergoing bone marrow transplantation. Bone Marrow Transplant. 2000;26:1005–9.

    Article  CAS  Google Scholar 

  14. Corti P, Uderzo C, Tagliabue A, Della Volpe A, Annaloro C, Tagliaferri E, et al. Defibrotide as a promising treatment for thrombotic thrombocytopenic purpura in patients undergoing bone marrow transplantation. Bone Marrow Transplant. 2002;29:542–3.

    Article  CAS  Google Scholar 

  15. Yeates L, Slatter M, Bonanomi S, Lim F, Ong S, Dalissier A, et al. Use of defibrotide to treat transplant-associated thrombotic microangiopathy: A retrospective study of the Paediatric Diseases and Inborn Errors Working Parties of the European Society of Blood and Marrow Transplantation. Bone Marrow Transplant. 2017;52:762–4.

    Article  CAS  Google Scholar 

  16. Picod A, Bonnin A, Battipaglia G, Giannotti F, Ruggeri A, Brissot E et al. Defibrotide for sinusoidal obstruction syndrome/veno-occlusive disease prophylaxis in high-risk adult patients: A single-center experience study. Biol Blood Marrow Transplant. 2018 https://doi.org/10.1016/j.bbmt.2018.02.015 [epub ahead of print].

Download references

Acknowledgements

MEM-M is supported by Fundación Española de Hematología y Hemoterapia (FEHH).

Author information

Authors and Affiliations

  1. Department of Hematology, Hospital Universitario Puerta de Hierro Majadahonda, Madrid, Spain

    M. E. Martínez-Muñoz, R. Forés, A. Lario, G. Bautista, J. L. Bueno, C. de Miguel, B. Navarro, A. De Laiglesia, J. R. Cabrera & R. F. Duarte

  2. Biomedical Research Institute Puerta de Hierro Segovia de Arana, Hospital Universitario Puerta de Hierro Majadahonda, Madrid, Spain

    M. E. Martínez-Muñoz, R. Forés, G. Bautista, J. L. Bueno, C. de Miguel, B. Navarro, A. De Laiglesia, A. Sánchez-Guerrero, J. R. Cabrera & R. F. Duarte

  3. Hospital Pharmacy, Hospital Universitario Puerta de Hierro Majadahonda, Madrid, Spain

    A. Sánchez-Guerrero

Authors
  1. M. E. Martínez-Muñoz
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. R. Forés
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. A. Lario
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. G. Bautista
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. J. L. Bueno
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. C. de Miguel
    View author publications

    You can also search for this author in PubMed Google Scholar

  7. B. Navarro
    View author publications

    You can also search for this author in PubMed Google Scholar

  8. A. De Laiglesia
    View author publications

    You can also search for this author in PubMed Google Scholar

  9. A. Sánchez-Guerrero
    View author publications

    You can also search for this author in PubMed Google Scholar

  10. J. R. Cabrera
    View author publications

    You can also search for this author in PubMed Google Scholar

  11. R. F. Duarte
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to R. F. Duarte.

Ethics declarations

Conflict of interest

R.F.D. reports receiving fees for serving as a speaker and on advisory boards for Jazz Pharmaceuticals and Omeros Pharmaceuticals. J.R.C. reports receiving research funds from Jazz Pharmaceuticals. The other authors declare that they have no conflict of interest.

Rights and permissions

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Martínez-Muñoz, M.E., Forés, R., Lario, A. et al. Use of defibrotide to treat adult patients with transplant-associated thrombotic microangiopathy. Bone Marrow Transplant 54, 142–145 (2019). https://doi.org/10.1038/s41409-018-0256-8

Download citation

  • Received:

  • Revised:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1038/s41409-018-0256-8

This article is cited by

Search

Advanced search

Quick links