Atypical HUS with thrombomodulin mutation – clinical course and response to complement inhibition

Czech version

Authors: Ludmila Podracká ^1,2; Darina Buzašiová ²; Štefan Pavlík ³; Kamila Karľová ¹
Authors‘ workplace: Detská klinika, Lekárska fakulta Univerzity Komenského, Národný ústav detských chorôb, Bratislava ¹; Detská klinika intenzívnej medicíny a anesteziológie, Lekárska fakulta Univerzity Komenského, Národný ústav detských chorôb, Bratislava ²; Rádiologické oddelenie, Národný ústav detských chorôb, Bratislava ³
Published in: Čes-slov Pediat 2025; 80 (5): 239-243.
Category: Case Report
doi: https://doi.org/10.55095/cspediatrie2025/038

Overview

PodrackáĽ, Buzašiová D, Pavlík Š, Karľová K.

Atypical hemolytic uremic syndrome (aHUS) is a rare disease classified among thrombotic microangiopathies. It is characterized by hemolytic anemia, thrombocytopenia, and acute kidney injury, with dysregulation of the alternative complement pathway being the key pathogenic mechanism. We present the case of a 13-month-old child diagnosed with aHUS, in whom a rare mutation in the thrombomodulin gene (THBD, variant P501L) was identified. This mutation impairs the regulation of complement activation, thereby contributing to disease development. The clinical course was complicated by severe extra-renal manifestations, including neurological and pulmonary symptoms, which were unresponsive to plasma therapy. Initiation of targeted therapy with eculizumab, later switched to ravulizumab, led to rapid clinical stabilization and sustained remission without relapse of thrombotic microangiopathy. This case highlights the importance of genetic testing and a personalized therapeutic approach in children with aHUS, especially in the presence of rare genetic variants such as THBD mutations. The authors also address the issue of optimal duration of complement inhibition and the long-term prognosis in this specific patient subgroup.

Keywords:

atypical hemolytic uremic syndrome – eculizumab – Complement – thrombomodulin

Sources

1. Noris M, Remuzzi G. Atypical hemolytic-uremic syndrome. N Engl J Med 2020; 361(17): 1676–1687.

2. Legendre CM, Licht C, Loirat C, et al. Terminal complement inhibitor eculizumab in atypical hemolytic-uremic syndrome. N Engl J Med 2018; 368(23): 2169–2181.

3. Frémeaux-Bacchi V, Fakhouri F, Garnier A, et al. Genetics and outcome of atypical hemolytic uremic syndrome: a nationwide French series comparing children and adults. Clin J Am Soc Nephrol 2013; 8(4): 554–562.

4. Schaefer F, Ardissino G, Ariceta G, et al. Long-term outcomes of eculizumab in atypical hemolytic uremic syndrome: a registry-based study. Kidney Int 2024; 106(3): 678–689.

5. Sangeetha K, Devarajan P. The global incidence and impact of hemolytic uremic syndrome. Pediatr Nephrol 2021; 36(6): 1193–1201.

6. Fakhouri F, Zuber J, Frémeaux-Bacchi V, Loirat C. Haemolytic uraemic syndrome. Lancet 2022; 390(10095): 681–696.

7. Delvaeye M, Noris M, De Vriese A, et al. Thrombomodulin mutations in atypical hemolytic-uremic syndrome: a possible role in endothelial dysfunction. Blood 2009; 114(2): 283–290.

8. Frémeaux-Bacchi V, Dragon-Durey MA, Blouin J, et al. Complement factor I: a susceptibility gene for atypical haemolytic uraemic syndrome. J Med Genet 2023; 60(3): 206–212.

9. Noris M, Caprioli J, Bresin E, et al. Relative role of genetic complement abnormalities in sporadic and familial aHUS and their impact on clinical phenotype. Clin J Am Soc Nephrol 2010; 5(10): 1844–1859.

10. Huerta A, Rodríguez de Córdoba S, Goicoechea de Jorge E, et al. Genetic and acquired factors predisposing to atypical hemolytic uremic syndrome: a comprehensive analysis of a nationwide cohort. Kidney Int 2023; 104(5): 1023–1035.

11. Licht C, Greenbaum LA, Muus P, et al. Eculizumab in pediatric patients with atypical hemolytic uremic syndrome: interim results of a Phase II trial. Blood 2021; 125(3): 365–372.

12. Singhal D, Le Quintrec M, Oygar DD, et al. Complement inhibition for atypical hemolytic uremic syndrome: updated evidence from clinical trials. Am J Kidney Dis 2023; 82(2): 219–231.

13. Ultomiris HCP Prescribing Information. Alexion Pharmaceuticals, Inc. 2022.

14. Wong EK, Kavanagh D. Atypical hemolytic uremic syndrome and the role of complement. Clin Exp Immunol 2021; 197(2): 145–159.