Epidemiology and outcomes of pediatric transplant-associated thrombotic microangiopathy in Hong Kong
Corresponding Author
Wilson Yau Ki Chan
Paediatric Hematology, Oncology and Hematopoietic Stem Cell Transplantation Team, Department of Paediatrics and Adolescent Medicine, Hong Kong Children's Hospital, Hong Kong Special Administrative Region, China
Correspondence
Wilson Yau Ki Chan, Paediatric Hematology, Oncology and Hematopoietic Stem Cell Transplantation Team, Department of Paediatrics and Adolescent Medicine, Hong Kong Children's Hospital, Hong Kong Special Administrative Region, China.
Email: [email protected]
Search for more papers by this authorAlison Lap Tak Ma
Pediatric Nephrology team, Department of Paediatrics and Adolescent Medicine, Hong Kong Children's Hospital, Hong Kong Special Administrative Region, China
Search for more papers by this authorEugene Yu Hin Chan
Pediatric Nephrology team, Department of Paediatrics and Adolescent Medicine, Hong Kong Children's Hospital, Hong Kong Special Administrative Region, China
Search for more papers by this authorAmanda Nim Chi Kan
Department of Pathology, Hong Kong Children's Hospital, Hong Kong Special Administrative Region, China
Search for more papers by this authorWai Fu Ng
Department of Pathology, Hong Kong Children's Hospital, Hong Kong Special Administrative Region, China
Search for more papers by this authorPamela Pui Wah Lee
Paediatric Hematology, Oncology and Hematopoietic Stem Cell Transplantation Team, Department of Paediatrics and Adolescent Medicine, Hong Kong Children's Hospital, Hong Kong Special Administrative Region, China
Search for more papers by this authorDaniel Ka Leung Cheuk
Paediatric Hematology, Oncology and Hematopoietic Stem Cell Transplantation Team, Department of Paediatrics and Adolescent Medicine, Hong Kong Children's Hospital, Hong Kong Special Administrative Region, China
Search for more papers by this authorAlan Kwok Shing Chiang
Paediatric Hematology, Oncology and Hematopoietic Stem Cell Transplantation Team, Department of Paediatrics and Adolescent Medicine, Hong Kong Children's Hospital, Hong Kong Special Administrative Region, China
Search for more papers by this authorWing Leung
Paediatric Hematology, Oncology and Hematopoietic Stem Cell Transplantation Team, Department of Paediatrics and Adolescent Medicine, Hong Kong Children's Hospital, Hong Kong Special Administrative Region, China
Search for more papers by this authorGodfrey Chi Fung Chan
Paediatric Hematology, Oncology and Hematopoietic Stem Cell Transplantation Team, Department of Paediatrics and Adolescent Medicine, Hong Kong Children's Hospital, Hong Kong Special Administrative Region, China
Search for more papers by this authorCorresponding Author
Wilson Yau Ki Chan
Paediatric Hematology, Oncology and Hematopoietic Stem Cell Transplantation Team, Department of Paediatrics and Adolescent Medicine, Hong Kong Children's Hospital, Hong Kong Special Administrative Region, China
Correspondence
Wilson Yau Ki Chan, Paediatric Hematology, Oncology and Hematopoietic Stem Cell Transplantation Team, Department of Paediatrics and Adolescent Medicine, Hong Kong Children's Hospital, Hong Kong Special Administrative Region, China.
Email: [email protected]
Search for more papers by this authorAlison Lap Tak Ma
Pediatric Nephrology team, Department of Paediatrics and Adolescent Medicine, Hong Kong Children's Hospital, Hong Kong Special Administrative Region, China
Search for more papers by this authorEugene Yu Hin Chan
Pediatric Nephrology team, Department of Paediatrics and Adolescent Medicine, Hong Kong Children's Hospital, Hong Kong Special Administrative Region, China
Search for more papers by this authorAmanda Nim Chi Kan
Department of Pathology, Hong Kong Children's Hospital, Hong Kong Special Administrative Region, China
Search for more papers by this authorWai Fu Ng
Department of Pathology, Hong Kong Children's Hospital, Hong Kong Special Administrative Region, China
Search for more papers by this authorPamela Pui Wah Lee
Paediatric Hematology, Oncology and Hematopoietic Stem Cell Transplantation Team, Department of Paediatrics and Adolescent Medicine, Hong Kong Children's Hospital, Hong Kong Special Administrative Region, China
Search for more papers by this authorDaniel Ka Leung Cheuk
Paediatric Hematology, Oncology and Hematopoietic Stem Cell Transplantation Team, Department of Paediatrics and Adolescent Medicine, Hong Kong Children's Hospital, Hong Kong Special Administrative Region, China
Search for more papers by this authorAlan Kwok Shing Chiang
Paediatric Hematology, Oncology and Hematopoietic Stem Cell Transplantation Team, Department of Paediatrics and Adolescent Medicine, Hong Kong Children's Hospital, Hong Kong Special Administrative Region, China
Search for more papers by this authorWing Leung
Paediatric Hematology, Oncology and Hematopoietic Stem Cell Transplantation Team, Department of Paediatrics and Adolescent Medicine, Hong Kong Children's Hospital, Hong Kong Special Administrative Region, China
Search for more papers by this authorGodfrey Chi Fung Chan
Paediatric Hematology, Oncology and Hematopoietic Stem Cell Transplantation Team, Department of Paediatrics and Adolescent Medicine, Hong Kong Children's Hospital, Hong Kong Special Administrative Region, China
Search for more papers by this authorAbstract
Background
Transplant-associated thrombotic microangiopathy (TA-TMA) is an under-recognized yet potentially devastating complication of hematopoietic stem cell transplantation (HSCT) which had increased awareness in recent years. This report summarizes the demographics and outcomes of pediatric TA-TMA in Hong Kong.
Methods
All patients aged below 18 years who underwent HSCT in the Hong Kong Children's Hospital and were diagnosed to have TA-TMA during the 2-year period from April 1, 2019 to March 31, 2021 were included.
Results
A total of 73 transplants (51 allogeneic and 22 autologous) in 63 patients had been performed. Six patients (four males and two females) developed TA-TMA at a median duration of 2.5 months post-HSCT. The incidence rate was 9.52%. Of the six TA-TMA patients, five underwent allogenic one underwent autologous HSCT, respectively. Three of them were histologically proven. All four patients with cyclosporine had stopped the drug once TA-TMA was suspected. Median six doses of eculizumab were administered to five out of six patients. Three patients died (two due to fungal infection and one due to acute-on-chronic renal failure) within 3 months upon diagnosis of TA-TMA. Among three survivors, two stabilized with mild stage 2 chronic kidney disease (CKD) while the other suffered from stage 5 end-stage CKD requiring lifelong dialysis.
Conclusion
In conclusion, recognition and diagnosis of TA-TMA are challenging. Early recognition and prompt administration of complement blockage with eculizumab may be beneficial in selected cases. Further prospective research studies are recommended to improve the management and outcomes of TA-TMA.
CONFLICTS OF INTEREST
All authors have disclosed no conflicts of interest.
Open Research
DATA AVAILABILITY STATEMENT
The data that support the findings of this study are available from the corresponding author upon reasonable request.
REFERENCES
- 1Daly AS, Xenocostas A, Lipton JH. Transplantation-associated thrombotic microangiopathy: twenty-two years later. Bone Marrow Transplant. 2002; 30(11): 709-715.
- 2Dvorak 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; 9(7): 133.
- 3Jodele S, Dandoy CE, Myers KC, et al. New approaches in the diagnosis, pathophysiology, and treatment of pediatric hematopoietic stem cell transplantation-associated thrombotic microangiopathy. Transfus Apher Sci. 2016; 54(2): 181-190.
- 4Moiseev IS, Tsvetkova T, Aljurf M, et al. Clinical and morphological practices in the diagnosis of transplant-associated microangiopathy: a study on behalf of Transplant Complications Working Party of the EBMT. Bone Marrow Transplant. 2019; 54(7): 1022-1028.
- 5Gavriilaki E, Sakellari I, Batsis I, et al. Transplant-associated thrombotic microangiopathy: incidence, prognostic factors, morbidity, and mortality in allogeneic hematopoietic cell transplantation. Clin Transplant. 2018; 32(9):e13371.
- 6Batts ED, Lazarus HM. Diagnosis and treatment of transplantation-associated thrombotic microangiopathy: real progress or are we still waiting? Bone Marrow Transplant. 2007; 40(8): 709-719.
- 7Ho VT, Cutler C, Carter S, 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(8): 571-575.
- 8Pettitt AR, Clark RE. Thrombotic microangiopathy following bone marrow transplantation. Bone Marrow Transplant. 1994; 14(4): 495-504.
- 9Fuge R, Bird JM, Fraser A, et al. The clinical features, risk factors and outcome of thrombotic thrombocytopenic purpura occurring after bone marrow transplantation. Br J Haematol. 2001; 113(1): 58-64.
- 10Jodele S, Laskin BL, Dandoy CE, et al. A new paradigm: diagnosis and management of HSCT-associated thrombotic microangiopathy as multi-system endothelial injury. Blood Rev. 2015; 29(3): 191-204.
- 11Laskin BL, Goebel J, Davies SM, Jodele S. Small vessels, big trouble in the kidneys and beyond: hematopoietic stem cell transplantation-associated thrombotic microangiopathy. Blood. 2011; 118(6): 1452-1462.
- 12Arai Y, Yamashita K, Mizugishi K, Watanabe T, Sakamoto S, Kitano T, Kondo T, Kawabata H, Kadowaki N, Takaori-Kondo A Serum neutrophil extracellular trap levels predict thrombotic microangiopathy after allogeneic stem cell transplantation. Biol Blood Marrow Transplant 2013; 19(12): 1683–9.
- 13Nakamae H, Yamane T, Hasegawa T, et al. Risk factor analysis for thrombotic microangiopathy after reduced-intensity or myeloablative allogeneic hematopoietic stem cell transplantation. Am J Hematol. 2006; 81(7): 525-531.
- 14Hale GA, Bowman LC, Rochester RJ, et al. Hemolytic uremic syndrome after bone marrow transplantation: clinical characteristics and outcome in children. Biol Blood Marrow Transplant. 2005; 11(11): 912-920.
- 15Worel N, Greinix HT, Leitner G, et al. ABO-incompatible allogeneic hematopoietic stem cell transplantation following reduced-intensity conditioning: close association with transplant-associated microangiopathy. Transfus Apher Sci. 2007; 36(3): 297-304.
- 16Willems E, Baron F, Seidel L, Frere P, Fillet G, Beguin Y. Comparison of thrombotic microangiopathy after allogeneic hematopoietic cell transplantation with high-dose or nonmyeloablative conditioning. Bone Marrow Transplant. 2010; 45(4): 689-693.
- 17Uderzo C, Bonanomi S, Busca A, et al. Risk factors and severe outcome in thrombotic microangiopathy after allogeneic hematopoietic stem cell transplantation. Transplantation. 2006; 82(5): 638-644.
- 18Shayani S, Palmer J, Stiller T, et al. Thrombotic microangiopathy associated with sirolimus level after allogeneic hematopoietic cell transplantation with tacrolimus/sirolimus-based graft-versus-host disease prophylaxis. Biol Blood Marrow Transplant. 2013; 19(2): 298-304.
- 19George JN, Li X, McMinn JR, Terrell DR, Vesely SK, Selby GB. Thrombotic thrombocytopenic purpura-hemolytic uremic syndrome following allogeneic HPC transplantation: a diagnostic dilemma. Transfusion. 2004; 44(2): 294-304.
- 20Schoettler M, Lehmann LE, Margossian S, et al. Risk factors for transplant-associated thrombotic microangiopathy and mortality in a pediatric cohort. Blood Adv. 2020; 4(11): 2536-2547.
- 21Choi CM, Schmaier AH, Snell MR, Lazarus HM. Thrombotic microangiopathy in haematopoietic stem cell transplantation: diagnosis and treatment. Drugs. 2009; 69(2): 183-198.
- 22Elfeky R, Lucchini G, Lum SH, et al. New insights into risk factors for transplant-associated thrombotic microangiopathy in pediatric HSCT. Blood Adv. 2020; 4(11): 2418-2429.
- 23Laskin BL, Nehus E, Goebel J, Furth S, Davies SM, Sonata J, et al. Estimated versus measured glomerular filtration rate in children before hematopoietic cell transplantation. Biol Blood Marrow Transplant 2014; 20(12): 2056–61.
- 24Laszik ZG, Kambham N, Silva FG. Thrombotic microangiopathies. In: JC Jennette, JL Olson, FG Silva, VD D'Agati, eds. Heptinstall's Pathology of the Kidney. 7th ed. Wolters Kluwer Health; 2014: 739-814.
- 25Cho BS, Yahng SA, Lee SE, et al. Validation of recently proposed consensus criteria for thrombotic microangiopathy after allogeneic hematopoietic stem-cell transplantation. Transplantation. 2010; 90(8): 918-926.
- 26Jodele S, Davies SM, Lane A, et al. Diagnostic and risk criteria for HSCT-associated thrombotic microangiopathy: a study in children and young adults. Blood. 2014; 124(4): 645-653.
- 27Corbacioglu S, Carreras E, Ansari M, et al. Diagnosis and severity criteria for sinusoidal obstruction syndrome/veno-occlusive disease in pediatric patients: a new classification from the European society for blood and marrow transplantation. Bone Marrow Transplant. 2018; 53(2): 138-145.
- 28Bonifazi F, Sica S, Angeletti A, et al. Veno-occlusive disease in HSCT patients: consensus-based recommendations for risk assessment, diagnosis, and management by the GITMO group. Transplantation. 2021; 105(4): 686-694.
- 29Harris A, Young R, Devine S, et al. International, multi-center standardization of acute graft-versus-host disease clinical data collection: a report from the MAGIC consortium. Biol Blood Marrow Transplant. 2016; 22(1): 4-10.
- 30Flynn JT, Kaelber DC, Baker-Smith CM, et al. Clinical practice guideline for screening and management of high blood pressure in children and adolescents. Pediatrics. 2017; 140(3):e20171904.
- 31Warren M, Jodele S, Dandoy C, et al. A complete histologic approach to gastrointestinal biopsy from hematopoietic stem cell transplant patients with evidence of transplant-associated gastrointestinal thrombotic microangiopathy. Arch Pathol Lab Med. 2017; 141(11): 1558-1566.
- 32El-Bietar J, Warren M, Dandoy C, et al. Histologic features of intestinal thrombotic microangiopathy in pediatric and young adult patients after hematopoietic stem cell transplantation. Biol Blood Marrow Transplant. 2015; 21(11): 1994-2001.
- 33Rossoff JE, Schneiderman J, Chaudhury S, Arva NC, et al. Diagnostic utility of complement immunohistochemical studies in post-stem cell transplant intestinal thrombotic microangiopathy: case report. J Pediatr Hematol Oncol. 2017; 39(4): 282-286.
- 34Dandoy CE, Davies SM, Hirsch R, et al. Abnormal echocardiography 7 days after stem cell transplantation may be an early indicator of thrombotic microangiopathy. Biol Blood Marrow Transplant. 2015; 21(1): 113-118.
- 35Jodele S, Dandoy CE, Lane A, et al. Complement blockade for TA-TMA: lessons learned from a large pediatric cohort treated with eculizumab. Blood. 2020; 135(13): 1049-1057.
- 36Cohn AC, MacNeil JR, Clark TA, et al. Prevention and control of meningococcal disease: recommendations of the Advisory Committee on Immunization Practices (ACIP). MMWR Recomm Rep. 2013; 62(RR-2): 1-28.
- 37Jodele S, Dandoy CE, Danziger-Isakov L, et al. Terminal complement blockade after hematopoietic stem cell transplantation is safe without meningococcal vaccination. Biol Blood Marrow Transplant. 2016; 22(7): 1337-1340.
- 38Tsoni SV, Kerrigan AM, Marakalala MJ, et al. Complement C3 plays an essential role in the control of opportunistic fungal infections. Infect Immun. 2009; 77(9): 3679-3685.
- 39Khosla J, Yeh A, Spitzer T, Dey BR. Hematopoietic stem cell transplant-associated thrombotic microangiopathy: current paradigm and novel therapies. Bone Marrow Transplant. 2018; 53(2): 129-137.
- 40Delvaeye M, Noris M, De Vriese A, et al. Thrombomodulin mutations in atypical hemolytic–uremic syndrome. N Engl J Med. 2009; 361(4): 345-357.
- 41Maga TK, Nishimura CJ, Weaver AE, Frees KL, Smith RJH. Mutations in alternative pathway complement proteins in American patients with atypical hemolytic uremic syndrome. Hum Mutat. 2010; 31(6): E1445-E1460.
- 42Martinez MT, Bucher C, Stussi G, et al. Transplant-associated microangiopathy (TAM) in recipients of allogeneic hematopoietic stem cell transplants. Bone Marrow Transplant. 2005; 36(11): 993-1000.
- 43Changsirikulchai S, Myerson D, Guthrie KA, McDonald GB, Alpers CE, Hingorani SR. Renal thrombotic microangiopathy after hematopoietic cell transplant: role of GVHD in pathogenesis. Clin J Am Soc Nephrol. 2009; 4(2): 345-353.
- 44Jodele S, Zhang K, Zou F, et al. The genetic fingerprint of susceptibility for transplant-associated thrombotic microangiopathy. Blood. 2016; 127(8): 989-996.
- 45Labrador J, Lopez-Corral L, Lopez-Godino O, 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(5): 684-690.
- 46Nomura E, Finn LS, Bauer A, et al. Pathology findings in pediatric patients with COVID-19 and kidney dysfunction. Pediatr Nephrol. 2022; 15: 1-7.
- 47El Sissy C, Saldman A, Zanetta G, et al. COVID-19 as a potential trigger of complement-mediated atypical HUS. Blood. 2021; 138(18): 1777-1782.
- 48Fattizzo B, Pasquale R, Bellani V, Barcellini W, Kulasekararaj AG. Complement mediated hemolytic anemias in the COVID-19 era: case series and review of the literature. Front Immunol. 2021; 25(12):791429.
- 49Gill J, Hebert CA, Colbert GB. COVID-19-associated atypical hemolytic uremic syndrome and use of Eculizumab therapy. J Nephrol. 2022; 35(1): 317-321.
- 50Alizadeh F, O'Halloran A, Alghamdi A, et al. Toddler with new onset diabetes and atypical hemolytic-uremic syndrome in the setting of COVID-19. Pediatrics. 2021; 147(2):e2020016774.
- 51Jodele S, Hirsch R, Laskin B, Davies S, Witte D, Chima R. Pulmonary arterial hypertension in pediatric patients with hematopoietic stem cell transplant-associated thrombotic microangiopathy. Biol Blood Marrow Transplant. 2013; 19(2): 202-207.
Citing Literature
