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.

  • Article
  • Published:

Incidence, risk factors, and outcomes of transplant-associated thrombotic microangiopathy in pediatric patients after allogeneic hematopoietic cell transplantation: a single-institution prospective study

Bone Marrow Transplantation volume 60, pages 447–457 (2025)Cite this article

Subjects

Abstract

Transplant-associated thrombotic microangiopathy (TA-TMA) is an increasingly recognized complication in hematopoietic cell transplantation (HCT). Given the rarity of prospective pediatric studies on TA-TMA, this study aimed to evaluate the incidence, survival outcomes, and risk factors for predicting early the development of TA-TMA in a pediatric population following allogeneic HCT. We conducted a prospective analysis of 173 pediatric patients to evaluate the incidence, survival outcome, and risk factors of TA-TMA. The cumulative incidence of TA-TMA at one-year post-HCT was 4.7% (95% CI, 2.2–8.6%). Patients with TA-TMA showed significantly poorer 1-year overall survival (OS) rate, 50.0% ± 17.7% compared to 85.4% ± 2.8% in those without TA-TMA (p = 0.008). Additionally, the non-relapse mortality (NRM) rate was higher in the TA-TMA group at 12.5% (95% CI, 3.7–55.8%) versus 7.0% (95% CI, 2.8–10.1%) (p = 0.598). A urine protein/creatinine ratio ≥ 1 mg/mg on day 30 post-HCT was significantly associated with TA-TMA occurrence (adjusted HR, 9.5; [95% CI], 1.28–70.39; p = 0.028). This study showed the significantly unfavorable clinical outcomes associated with TA-TMA in pediatric patients and emphasized the importance of early identification of patients at risk. Further research is needed to explore additional strategies for early detection and intervention to improve outcomes.

Access through your institution
Buy or subscribe

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

Access options

Access through your institution

Buy this article

  • Purchase on SpringerLink
  • Instant access to full article PDF
Buy now

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

Fig. 1
Fig. 2: One-year cumulative incidence of TA-TMA after allogeneic HCT 4.7% (95% CI, 2.2–8.6%).
Fig. 3: One-year overall survival and NRM by TMA of allogeneic HCT.
Fig. 4: The time course of laboratory markers from TA-TMA diagnosis. (a, b, c, d).

Similar content being viewed by others

Data availability

The datasets generated during and/or analyzed during the current study are available from the corresponding author on reasonable request.

References

  1. Li A, Bhatraju PK, Chen J, Chung DW, Hilton T, Houck K, et al. Prognostic biomarkers for thrombotic microangiopathy after acute graft-versus-host disease: a nested case-control study. Transpl Cell Ther. 2021;27:308.e301–e308. https://doi.org/10.1016/j.jtct.2020.12.010.

    Article  CAS  Google Scholar 

  2. 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. https://doi.org/10.1097/01.tp.0000230373.82376.46.

    Article  PubMed  Google Scholar 

  3. Jodele S, Fukuda T, Vinks A, Mizuno K, Laskin BL, Goebel J, et al. Eculizumab therapy in children with severe hematopoietic stem cell transplantation-associated thrombotic microangiopathy. Biol Blood Marrow Transplant. 2014;20:518–25. https://doi.org/10.1016/j.bbmt.2013.12.565.

    Article  CAS  PubMed  Google Scholar 

  4. 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;124:645–53. https://doi.org/10.1182/blood-2014-03-564997.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  5. Jodele S, Dandoy CE, Myers KC, El-Bietar J, Nelson A, Wallace G, et al. New approaches in the diagnosis, pathophysiology, and treatment of pediatric hematopoietic stem cell transplantation-associated thrombotic microangiopathy. Transfus Apher Sci. 2016;54:181–90. https://doi.org/10.1016/j.transci.2016.04.007.

    Article  PubMed  PubMed Central  Google Scholar 

  6. Jodele S, Sabulski A. Transplant-associated thrombotic microangiopathy: elucidating prevention strategies and identifying high-risk patients. Expert Rev Hematol. 2021;14:751–63. https://doi.org/10.1080/17474086.2021.1960816.

    Article  CAS  PubMed  Google Scholar 

  7. Jodele S, Laskin BL, 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. https://doi.org/10.1016/j.blre.2014.11.001.

    Article  PubMed  Google Scholar 

  8. Dvorak CC, Higham C, Shimano KA. Transplant-associated thrombotic microangiopathy in pediatric hematopoietic cell transplant recipients: a practical approach to diagnosis and management. Front Pediatr. 2019;7:133. https://doi.org/10.3389/fped.2019.00133.

    Article  PubMed  PubMed Central  Google Scholar 

  9. Schoettler ML, Carreras E, Cho B, Dandoy CE, Ho VT, Jodele S, et al. Harmonizing definitions for diagnostic criteria and prognostic assessment of transplantation-associated thrombotic microangiopathy: a report on behalf of the european society for blood and marrow transplantation, american society for transplantation and cellular therapy, Asia-Pacific blood and marrow transplantation group, and center for international blood and marrow transplant research. Transpl Cell Ther. 2023;29:151–63. https://doi.org/10.1016/j.jtct.2022.11.015.

    Article  CAS  Google Scholar 

  10. Young JA, Pallas CR, Knovich MA. Transplant-associated thrombotic microangiopathy: theoretical considerations and a practical approach to an unrefined diagnosis. Bone Marrow Transplant. 2021;56:1805–17. https://doi.org/10.1038/s41409-021-01283-0.

    Article  PubMed  PubMed Central  Google Scholar 

  11. Ramgopal A, Sridar S, Dalal J, Kalpatthi R. Thrombotic microangiopathy: multi-institutional review of pediatric patients who underwent HSCT. J Pers Med. 2021;11:467. https://doi.org/10.3390/jpm11060467.

    Article  PubMed  PubMed Central  Google Scholar 

  12. Mehta RL, Kellum JA, Shah SV, Molitoris BA, Ronco C, Warnock DG, et al. Acute Kidney Injury Network: report of an initiative to improve outcomes in acute kidney injury. Crit Care. 2007;11:R31. https://doi.org/10.1186/cc5713.

    Article  PubMed  PubMed Central  Google Scholar 

  13. Khwaja A. KDIGO clinical practice guidelines for acute kidney injury. Nephron Clin Pract. 2012;120:c179–84. https://doi.org/10.1159/000339789.

    Article  PubMed  Google Scholar 

  14. Koh KN, Sunkara A, Kang G, Sooter A, Mulrooney DA, Triplett B, et al. Acute kidney injury in pediatric patients receiving allogeneic hematopoietic cell transplantation: incidence, risk factors, and outcomes. Biol Blood Marrow Transplant. 2018;24:758–64. https://doi.org/10.1016/j.bbmt.2017.11.021.

    Article  PubMed  Google Scholar 

  15. Stevens PE, Levin A.Kidney Disease: Improving Global Outcomes Chronic Kidney Disease Guideline Development Work Group Members. Evaluation and management of chronic kidney disease: synopsis of the kidney disease: improving global outcomes 2012 clinical practice guideline. Ann Intern Med. 2013;158:825–30. https://doi.org/10.7326/0003-4819-158-11-201306040-00007.

    Article  PubMed  Google Scholar 

  16. Lameire NH, Levin A, Kellum JA, Cheung M, Jadoul M, Winkelmayer WC, et al. Harmonizing acute and chronic kidney disease definition and classification: report of a kidney disease: improving global outcomes (KDIGO) consensus conference. Kidney Int. 2021;100:516–26. https://doi.org/10.1016/j.kint.2021.06.028.

    Article  PubMed  Google Scholar 

  17. Przepiorka D, Weisdorf D, Martin P, Klingemann HG, Beatty P, Hows J, et al. 1994 Consensus conference on acute GVHD grading. Bone Marrow Transplant 1995;15:825–8.

    CAS  PubMed  Google Scholar 

  18. Lee SJ, Vogelsang G, Flowers ME. Chronic graft-versus-host disease. Biol Blood Marrow Transplant 2003;9:215–33. https://doi.org/10.1053/bbmt.2003.50026.

    Article  CAS  PubMed  Google Scholar 

  19. Akil A, Zhang Q, Mumaw CL, Raiker N, Yu J, de Mendizabal NV, et al. Biomarkers for diagnosis and prognosis of sinusoidal obstruction syndrome after hematopoietic cell transplantation. Biol Blood Marrow Transplant 2015;21:1739–45. https://doi.org/10.1016/j.bbmt.2015.07.004.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  20. Bajwa RPS, Mahadeo KM, Taragin BH, Dvorak CC, McArthur J, Jeyapalan A, et al. Consensus report by pediatric acute lung injury and sepsis investigators and pediatric blood and marrow transplantation consortium joint working committees: supportive care guidelines for management of veno-occlusive disease in children and adolescents, Part 1: focus on investigations, prophylaxis, and specific treatment. Biol Blood Marrow Transplant 2017;23:1817–25. https://doi.org/10.1016/j.bbmt.2017.07.021.

    Article  PubMed  Google Scholar 

  21. Jones RJ, Lee KS, Beschorner WE, Vogel VG, Grochow LB, Braine HG, et al. Venoocclusive disease of the liver following bone marrow transplantation. Transplantation. 1987;44:778–83. https://doi.org/10.1097/00007890-198712000-00011.

    Article  CAS  PubMed  Google Scholar 

  22. McDonald GB, Sharma P, Matthews DE, Shulman HM, Thomas ED. Venocclusive disease of the liver after bone marrow transplantation: diagnosis, incidence, and predisposing factors. Hepatology. 1984;4:116–22. https://doi.org/10.1002/hep.1840040121.

    Article  CAS  PubMed  Google Scholar 

  23. Chemaly RF, Chou S, Einsele H, Griffiths P, Avery R, Razonable RR, et al. Definitions of resistant and refractory cytomegalovirus infection and disease in transplant recipients for use in clinical trials. Clin Infect Dis. 2019;68:1420–6. https://doi.org/10.1093/cid/ciy696.

    Article  CAS  PubMed  Google Scholar 

  24. Ljungman P, Boeckh M, Hirsch HH, Josephson F, Lundgren J, Nichols G, et al. Definitions of cytomegalovirus infection and disease in transplant patients for use in clinical trials. Clin Infect Dis. 2017;64:87–91. https://doi.org/10.1093/cid/ciw668.

    Article  PubMed  Google Scholar 

  25. Li SS, Zhang N, Jia M, Su M. Association between cytomegalovirus and epstein-barr virus co-reactivation and hematopoietic stem cell transplantation. Front Cell Infect Microbiol. 2022;12:818167. https://doi.org/10.3389/fcimb.2022.818167.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  26. Donnelly JP, Chen SC, Kauffman CA, Steinbach WJ, Baddley JW, Verweij PE, et al. Revision and update of the consensus definitions of invasive fungal disease from the European organization for research and treatment of cancer and the mycoses study group education and research consortium. Clin Infect Dis. 2020;71:1367–76. https://doi.org/10.1093/cid/ciz1008.

    Article  PubMed  Google Scholar 

  27. Kousha M, Tadi R, Soubani AO. Pulmonary aspergillosis: a clinical review. Eur Respir Rev. 2011;20:156–74. https://doi.org/10.1183/09059180.00001011.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  28. Kanj A, Abdallah N, Soubani AO. The spectrum of pulmonary aspergillosis. Respir Med. 2018;141:121–31. https://doi.org/10.1016/j.rmed.2018.06.029.

    Article  PubMed  Google Scholar 

  29. Law YM, Hoyer AW, Reller MD, Silberbach M. Accuracy of plasma B-type natriuretic peptide to diagnose significant cardiovascular disease in children: the Better Not Pout Children! Study. J Am Coll Cardiol. 2009;54:1467–75. https://doi.org/10.1016/j.jacc.2009.06.020.

    Article  CAS  PubMed  Google Scholar 

  30. Snowden JA, Hill GR, Hunt P, Carnoutsos S, Spearing RL, Espiner E, et al. Assessment of cardiotoxicity during haemopoietic stem cell transplantation with plasma brain natriuretic peptide. Bone Marrow Transplant. 2000;26:309–13. https://doi.org/10.1038/sj.bmt.1702507.

    Article  CAS  PubMed  Google Scholar 

  31. Rifai N Tietz textbook of clinical chemistry and molecular diagnostics, 6th edn Saunders: St. Louis, 2017.

  32. Schoettler M, Lehmann LE, Margossian S, Lee M, Kean LS, Kao PC, et al. Risk factors for transplant-associated thrombotic microangiopathy and mortality in a pediatric cohort. Blood Adv. 2020;4:2536–47. https://doi.org/10.1182/bloodadvances.2019001242.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  33. Cho BS, Yahng SA, Lee SE, Eom KS, Kim YJ, Kim HJ, et al. Validation of recently proposed consensus criteria for thrombotic microangiopathy after allogeneic hematopoietic stem-cell transplantation. Transplantation. 2010;90:918–26. https://doi.org/10.1097/TP.0b013e3181f24e8d.

    Article  CAS  PubMed  Google Scholar 

  34. Labrador J, Lopez-Corral L, Lopez-Godino O, Vazquez L, Cabrero-Calvo M, Perez-Lopez R, et al. Risk factors for thrombotic microangiopathy in allogeneic hematopoietic stem cell recipients receiving GVHD prophylaxis with tacrolimus plus MTX or sirolimus. Bone Marrow Transplant. 2014;49:684–90. https://doi.org/10.1038/bmt.2014.17.

    Article  CAS  PubMed  Google Scholar 

  35. Choi CM, Schmaier AH, Snell MR, Lazarus HM. Thrombotic microangiopathy in haematopoietic stem cell transplantation: diagnosis and treatment. Drugs. 2009;69:183–98. https://doi.org/10.2165/00003495-200969020-00004.

    Article  CAS  PubMed  Google Scholar 

  36. Bethge WA, Eyrich M, Mielke S, Meisel R, Niederwieser D, Schlegel PG, et al. Results of a multicenter phase I/II trial of TCRalphabeta and CD19-depleted haploidentical hematopoietic stem cell transplantation for adult and pediatric patients. Bone Marrow Transplant. 2022;57:423–30. https://doi.org/10.1038/s41409-021-01551-z.

    Article  CAS  PubMed  Google Scholar 

  37. Bertaina A, Zecca M, Buldini B, Sacchi N, Algeri M, Saglio F, et al. Unrelated donor vs HLA-haploidentical alpha/beta T-cell- and B-cell-depleted HSCT in children with acute leukemia. Blood. 2018;132:2594–607. https://doi.org/10.1182/blood-2018-07-861575.

    Article  CAS  PubMed  Google Scholar 

  38. Pagliuca S, Michonneau D, Sicre de Fontbrune F, Sutra del Galy A, Xhaard A, Robin M, et al. Allogeneic reactivity–mediated endothelial cell complications after HSCT: a plea for consensual definitions. Blood Adv. 2019;3:2424–35.

    Article  PubMed  PubMed Central  Google Scholar 

  39. Gavriilaki E, Sakellari I, Anagnostopoulos A, Brodsky RA. Transplant-associated thrombotic microangiopathy: opening Pandora’s box. Bone Marrow Transplant. 2017;52:1355–60. https://doi.org/10.1038/bmt.2017.39.

    Article  CAS  PubMed  Google Scholar 

  40. Arai Y, Yamashita K, Mizugishi K, Watanabe T, Sakamoto S, Kitano T, et al. Serum neutrophil extracellular trap levels predict thrombotic microangiopathy after allogeneic stem cell transplantation. Biol Blood Marrow Transplant. 2013;19:1683–9. https://doi.org/10.1016/j.bbmt.2013.09.005.

    Article  CAS  PubMed  Google Scholar 

  41. Oran B, Donato M, Aleman A, Hosing C, Korbling M, Detry MA, et al. Transplant-associated microangiopathy in patients receiving tacrolimus following allogeneic stem cell transplantation: risk factors and response to treatment. Biol Blood Marrow Transplant. 2007;13:469–77. https://doi.org/10.1016/j.bbmt.2006.11.020.

    Article  CAS  PubMed  Google Scholar 

  42. Daly AS, Hasegawa WS, Lipton JH, Messner HA, Kiss TL. Transplantation-associated thrombotic microangiopathy is associated with transplantation from unrelated donors, acute graft-versus-host disease and venoocclusive disease of the liver. Transfus Apher Sci. 2002;27:3–12. https://doi.org/10.1016/S1473-0502(02)00020-4.

    Article  PubMed  Google Scholar 

  43. Dandoy CE, Davies SM, Hirsch R, Chima RS, Paff Z, Cash M, et al. Abnormal echocardiography 7 days after stem cell transplantation may be an early indicator of thrombotic microangiopathy. Biol Blood Marrow Transplant. 2015;21:113–8. https://doi.org/10.1016/j.bbmt.2014.09.028.

    Article  PubMed  Google Scholar 

  44. Liem DA, Cadeiras M, Setty SP. Insights and perspectives into clinical biomarker discovery in pediatric heart failure and congenital heart disease—a narrative review. Cardiovasc Diagn Ther. 2023;13:83–99. https://doi.org/10.21037/cdt-22-386.

    Article  PubMed  PubMed Central  Google Scholar 

  45. Teixeira J, Guillaume M, Nellessen E, Chapelle JP. BNP and NT-proBNP: reference values and cutoff limits [In French]. Rev Med Liege. 2012;67:38–43.

    CAS  PubMed  Google Scholar 

  46. Auerbach SR, Richmond ME, Lamour JM, Blume ED, Addonizio LJ, Shaddy RE, et al. BNP levels predict outcome in pediatric heart failure patients: post hoc analysis of the pediatric carvedilol trial. Circ Heart Fail. 2010;3:606–11. https://doi.org/10.1161/CIRCHEARTFAILURE.109.906875.

    Article  CAS  PubMed  Google Scholar 

  47. Mueller C, McDonald K, de Boer RA, Maisel A, Cleland JGF, Kozhuharov N, et al. Heart Failure Association of the European Society of Cardiology practical guidance on the use of natriuretic peptide concentrations. Eur J Heart Fail. 2019;21:715–31. https://doi.org/10.1002/ejhf.1494.

    Article  CAS  PubMed  Google Scholar 

  48. Schoettler M, Carreras E, Cho B, Dandoy C, Ho V, Jodele S, et al. Harmonizing definitions for diagnostic criteria and prognostic assessment of transplantation-associated thrombotic microangiopathy: a report on behalf of the European Society for Blood and Marrow Transplantation, American Society for Transplantation and Cellular Therapy, Asia-Pacific Blood and Marrow Transplantation Group, and Center for International Blood and Marrow Transplant Research. Transplant Cell Ther. 2023;29:151–63.

    Article  CAS  PubMed  Google Scholar 

Download references

Acknowledgements

This study was supported by a grant 2022IF0007 from the Asan Institute for Life Sciences, and donated funds of Asan Medical Center, Seoul, Korea. The statistical analyses conducted in this study were advised by the Department of Medical Statistics at Asan Medical Center.

Author information

Authors and Affiliations

  1. Division of Pediatric Hematology/Oncology, Department of Pediatrics, Asan Medical Center Children’s Hospital, University of Ulsan College of Medicine, Seoul, Republic of Korea

    Su Hyun Yoon, Sung Han Kang, Hyery Kim, Eun Seok Choi, Ho Joon Im & Kyung-Nam Koh

Authors
  1. Su Hyun Yoon
    View author publications

    Search author on:PubMed Google Scholar

  2. Sung Han Kang
    View author publications

    Search author on:PubMed Google Scholar

  3. Hyery Kim
    View author publications

    Search author on:PubMed Google Scholar

  4. Eun Seok Choi
    View author publications

    Search author on:PubMed Google Scholar

  5. Ho Joon Im
    View author publications

    Search author on:PubMed Google Scholar

  6. Kyung-Nam Koh
    View author publications

    Search author on:PubMed Google Scholar

Contributions

KN Koh conceptualized, designed and supervised this study. SH Yoon analyzed and interpreted the patient data. SH Yoon prepared figures, performed statistical analysis, and wrote the manuscript. All authors read and approved the final manuscript; and SH Kang, Hyery Kim, ES Choi, HJ Im provided vital conceptual insights for study design, assisted with study subject accrual and data collection, and edited the manuscript. All authors reviewed the manuscript.

Corresponding author

Correspondence to Kyung-Nam Koh.

Ethics declarations

Competing interests

The authors declare no competing interests.

Ethics approval and consent to participate

All methods were performed in accordance with the ethical standards of the Helsinki Declaration and were approved by the Asan Medical Center’s institutional review board (IRB No. 2018-0560). Written informed consent was obtained from all children and patients legal guardians prior to recruitment in the study.

Additional information

Publisher’s note Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.

Rights and permissions

Springer Nature or its licensor (e.g. a society or other partner) holds exclusive rights to this article under a publishing agreement with the author(s) or other rightsholder(s); author self-archiving of the accepted manuscript version of this article is solely governed by the terms of such publishing agreement and applicable law.

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Yoon, S.H., Kang, S.H., Kim, H. et al. Incidence, risk factors, and outcomes of transplant-associated thrombotic microangiopathy in pediatric patients after allogeneic hematopoietic cell transplantation: a single-institution prospective study. Bone Marrow Transplant 60, 447–457 (2025). https://doi.org/10.1038/s41409-024-02506-w

Download citation

  • Received:

  • Revised:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1038/s41409-024-02506-w

Search

Advanced search

Quick links