CLINICAL SPECTRUM AND THERAPEUTIC ADVANCES IN PEDIATRIC PAROXYSMAL NOCTURNAL HEMOGLOBINURIA
Abstract
Background: Paroxysmal nocturnal hemoglobinuria (PNH) is a rare, acquired hematopoietic stem cell disorder driven by somatic PIGA mutations, leading to uncontrolled complement activation, intravascular hemolysis, and thrombotic risk. Pediatric PNH represents fewer than 10% of cases and demonstrates a distinct clinical phenotype that complicates diagnosis and management.
Methods: A comprehensive literature search of PubMed, Embase, Web of Science, and Scopus was conducted through July 2025 using predefined keywords related to PNH, pediatrics, bone marrow failure, and complement inhibitors. Eligible studies included clinical trials, registry data, systematic reviews, case series, and case reports. Relevant adult studies were also reviewed when mechanistic or therapeutic insights were applicable to pediatric disease. Data were synthesized narratively, focusing on pathophysiology, clinical spectrum, diagnostic approaches, and therapeutic advances.
Results: Pediatric PNH most often presents with bone marrow failure syndromes rather than classic hemolytic features. Hemoglobinuria is infrequent, while cytopenias predominate. Thrombosis, though less common than in adults, remains a serious complication. High-sensitivity flow cytometry enables early and accurate diagnosis, particularly for small clone sizes. Complement inhibitors—including eculizumab, ravulizumab, and crovalimab—have markedly improved survival and reduced morbidity, while emerging agents targeting proximal complement pathways (pegcetacoplan, iptacopan, danicopan) show promise. Hematopoietic cell transplantation remains the only curative option but is reserved for selected patients.
Conclusions: Pediatric PNH differs significantly from adult disease in presentation and management. Advances in complement inhibition have transformed prognosis, but further pediatric-specific research and inclusion in clinical trials are urgently needed to establish evidence-based guidelines and optimize long-term outcomes.
References
Ali, E. A., Al-Sadi, A., Ali, S., Rozi, W., Idriss, M., Jain, M., Mohamed, A., & Yassin, M. A. (2024, Dec). Direct Oral Anticoagulants and Paroxysmal Nocturnal Hemoglobinuria: A Systematic Review and Update on Evidence. Cureus, 16(12), e76702. https://doi.org/10.7759/cureus.76702
Andolina, J. R., Reinish, A. L., Akhtar, R., Noronha, S., Shand, J. C., Girvin, A., Korones, D. N., Bruckner, L. B., Mullen, C. A., Curran, K. J., & Boulad, F. (2018, Aug). Successful reduced-intensity conditioning hematopoietic stem cell transplantation for paroxysmal nocturnal hemoglobinuria with aplastic anemia in two children. Pediatric Blood & Cancer, 65(8), e27218. https://doi.org/10.1002/pbc.27218
Bektas, M., Copley-Merriman, C., Khan, S., Sarda, S. P., & Shammo, J. M. (2020, Dec). Paroxysmal nocturnal hemoglobinuria: role of the complement system, pathogenesis, and pathophysiology. J Manag Care Spec Pharm, 26(12-b Suppl), S3-s8. https://doi.org/10.18553/jmcp.2020.26.12-b.s3
Bessler, M., Mason, P. J., Hillmen, P., Miyata, T., Yamada, N., Takeda, J., Luzzatto, L., & Kinoshita, T. (1994, Jan 1). Paroxysmal nocturnal haemoglobinuria (PNH) is caused by somatic mutations in the PIG-A gene. Embo j, 13(1), 110-117. https://doi.org/10.1002/j.1460-2075.1994.tb06240.x
Bharti, R., Dey, G., Lin, F., Lathia, J., & Reizes, O. (2022, Dec 28). CD55 in cancer: Complementing functions in a non-canonical manner. Cancer Lett, 551, 215935. https://doi.org/10.1016/j.canlet.2022.215935
Borowitz, M. J., Craig, F. E., Digiuseppe, J. A., Illingworth, A. J., Rosse, W., Sutherland, D. R., Wittwer, C. T., Richards, S. J., & Clinical Cytometry, S. (2010, Jul). Guidelines for the diagnosis and monitoring of paroxysmal nocturnal hemoglobinuria and related disorders by flow cytometry. Cytometry. Part B: Clinical Cytometry, 78(4), 211-230. https://doi.org/10.1002/cyto.b.20525
Brodsky, R. A. (2014, Oct 30). Paroxysmal nocturnal hemoglobinuria. Blood, 124(18), 2804-2811. https://doi.org/10.1182/blood-2014-02-522128
Brodsky, R. A., Young, N. S., Antonioli, E., Risitano, A. M., Schrezenmeier, H., Schubert, J., Gaya, A., Coyle, L., de Castro, C., Fu, C. L., Maciejewski, J. P., Bessler, M., Kroon, H. A., Rother, R. P., & Hillmen, P. (2008, Feb 15). Multicenter phase 3 study of the complement inhibitor eculizumab for the treatment of patients with paroxysmal nocturnal hemoglobinuria. Blood, 111(4), 1840-1847. https://doi.org/10.1182/blood-2007-06-094136
Chonat, S., Kulagin, A., Maschan, A., Bartels, M., Buechner, J., Punzalan, R., Richards, M., Ogawa, M., Hicks, E., Yu, J., Baruchel, A., & Kulasekararaj, A. G. (2024, Jun 11). Pharmacokinetics, pharmacodynamics, efficacy, and safety of ravulizumab in pediatric paroxysmal nocturnal hemoglobinuria. Blood Adv, 8(11), 2813-2824. https://doi.org/10.1182/bloodadvances.2023012267
Colden, M. A., Kumar, S., Munkhbileg, B., & Babushok, D. V. (2022, 2022-January-28). Insights Into the Emergence of Paroxysmal Nocturnal Hemoglobinuria [Review]. Frontiers in Immunology, Volume 12 - 2021. https://doi.org/10.3389/fimmu.2021.830172
Couves, E. C., Gardner, S., Voisin, T. B., Bickel, J. K., Stansfeld, P. J., Tate, E. W., & Bubeck, D. (2023, Feb 16). Structural basis for membrane attack complex inhibition by CD59. Nat Commun, 14(1), 890. https://doi.org/10.1038/s41467-023-36441-z
Curran, K. J., Kernan, N. A., Prockop, S. E., Scaradavou, A., Small, T. N., Castro-Malaspina, H., Araten, D., DiMichele, D., O'Reilly, R. J., & Boulad, F. (2010). Paroxysmal Nocturnal Hemoglobinuria (PNH) In Pediatric Patients: Review of a Single Center Series. Blood, 116(21), 2231-2231. https://doi.org/10.1182/blood.V116.21.2231.2231
Curran, K. J., Kernan, N. A., Prockop, S. E., Scaradavou, A., Small, T. N., Kobos, R., Castro-Malaspina, H., Araten, D., DiMichele, D., O'Reilly, R. J., & Boulad, F. (2012, Sep). Paroxysmal nocturnal hemoglobinuria in pediatric patients. Pediatric Blood & Cancer, 59(3), 525-529. https://doi.org/10.1002/pbc.23410
DeZern, A. E., & Brodsky, R. A. (2015, Jun). Paroxysmal nocturnal hemoglobinuria: a complement-mediated hemolytic anemia. Hematol Oncol Clin North Am, 29(3), 479-494. https://doi.org/10.1016/j.hoc.2015.01.005
Griesser, C., Myskiw, M., & Streif, W. (2020, Jan). Paroxysmal Nocturnal Hemoglobinuria: An Underestimated Cause of Pediatric Thromboembolism. TH Open, 4(1), e36-e39. https://doi.org/10.1055/s-0040-1702155
Hill, A., Kelly, R. J., & Hillmen, P. (2013, Jun 20). Thrombosis in paroxysmal nocturnal hemoglobinuria. Blood, 121(25), 4985-4996; quiz 5105. https://doi.org/10.1182/blood-2012-09-311381
Hillmen, P., Hall, C., Marsh, J. C., Elebute, M., Bombara, M. P., Petro, B. E., Cullen, M. J., Richards, S. J., Rollins, S. A., Mojcik, C. F., & Rother, R. P. (2004, Feb 5). Effect of eculizumab on hemolysis and transfusion requirements in patients with paroxysmal nocturnal hemoglobinuria. New England Journal of Medicine, 350(6), 552-559. https://doi.org/10.1056/NEJMoa031688
Hillmen, P., Lewis, S. M., Bessler, M., Luzzatto, L., & Dacie, J. V. (1995, Nov 9). Natural history of paroxysmal nocturnal hemoglobinuria. N Engl J Med, 333(19), 1253-1258. https://doi.org/10.1056/nejm199511093331904
Hillmen, P., Szer, J., Weitz, I., Roth, A., Hochsmann, B., Panse, J., Usuki, K., Griffin, M., Kiladjian, J. J., de Castro, C., Nishimori, H., Tan, L., Hamdani, M., Deschatelets, P., Francois, C., Grossi, F., Ajayi, T., Risitano, A., & Peffault de Latour, R. (2021, Mar 18). Pegcetacoplan versus Eculizumab in Paroxysmal Nocturnal Hemoglobinuria. New England Journal of Medicine, 384(11), 1028-1037. https://doi.org/10.1056/NEJMoa2029073
Holt, M., Newton, D. J., Griffin, M., Schmidt, C. Q., & Kelly, R. J. (2024). A review of the pathophysiology of paroxysmal nocturnal hemoglobinuria. Annals of Blood, 9. https://aob.amegroups.org/article/view/10256
Johnston, J. J., Gropman, A. L., Sapp, J. C., Teer, J. K., Martin, J. M., Liu, C. F., Yuan, X., Ye, Z., Cheng, L., Brodsky, R. A., & Biesecker, L. G. (2012, Feb 10). The phenotype of a germline mutation in PIGA: the gene somatically mutated in paroxysmal nocturnal hemoglobinuria. Am J Hum Genet, 90(2), 295-300. https://doi.org/10.1016/j.ajhg.2011.11.031
Karwacki, M., Adamowicz-Salach, A., & Matysiak, M. (2019). Pb1864 More Than 2 Years Delay in Diagnosis of Pnh Due to Gastrointestinal Mask of Bone Marrow Insufficiency. HemaSphere, 3(S1). https://doi.org/10.1097/01.HS9.0000565960.75002.be
Karwacki, M. W., Adamowicz-Salach, A., Matysiak, M., & Pankiewicz, A. (2019). Nocna napadowa hemoglobinuria u dzieci jako przykład rzadkich schorzeń ukrywających się pod różnymi maskami rozpoznań klinicznych. Dylematy kliniczne, etyczne i społeczne rozpoznawania chorób ultrarzadkich na kanwie przypadku. Nowa Pediatria, 23(1). https://doi.org/10.25121/np.2019.23.1.51
Kokoris, S., Polyviou, A., Evangelidis, P., Grouzi, E., Valsami, S., Tragiannidis, K., Gialeraki, A., Tsakiris, D. A., & Gavriilaki, E. (2024, Nov 11). Thrombosis in Paroxysmal Nocturnal Hemoglobinuria (PNH): From Pathogenesis to Treatment. International Journal of Molecular Sciences, 25(22). https://doi.org/10.3390/ijms252212104
Krishnaprasadh, D., Kaminecki, I., Sechser Perl, A., & Teitelbaum, J. (2019). Paroxysmal Nocturnal Hemoglobinuria: Diagnostic Challenges in Pediatric Patient. Case Rep Pediatr, 2019, 4930494. https://doi.org/10.1155/2019/4930494
Kulasekararaj, A., Griffin, M., Piatek, C., Shammo, J., Nishimura, J. I., Patriquin, C., Schrezenmeier, H., Barcellini, W., Panse, J., Gaya, A., Patel, Y., Liu, P., Filippov, G., Sicre de Fontbrune, F., Risitano, A., & Lee, J. W. (2025, Feb 20). Long-term efficacy and safety of danicopan as add-on therapy to ravulizumab or eculizumab in PNH with significant EVH. Blood, 145(8), 811-822. https://doi.org/10.1182/blood.2024026299
Kulasekararaj, A. G., Hill, A., Rottinghaus, S. T., Langemeijer, S., Wells, R., Gonzalez-Fernandez, F. A., Gaya, A., Lee, J. W., Gutierrez, E. O., Piatek, C. I., Szer, J., Risitano, A., Nakao, S., Bachman, E., Shafner, L., Damokosh, A. I., Ortiz, S., Roth, A., & Peffault de Latour, R. (2019, Feb 7). Ravulizumab (ALXN1210) vs eculizumab in C5-inhibitor-experienced adult patients with PNH: the 302 study. Blood, 133(6), 540-549. https://doi.org/10.1182/blood-2018-09-876805
Kumar, S., & Babushok, D. V. (2021, Dec). Analysis of evolutionary conservation of GPI-anchored proteins between humans and mice. Blood Cells Mol Dis, 92, 102622. https://doi.org/10.1016/j.bcmd.2021.102622
Lee, J. W., Griffin, M., Kim, J. S., Lee Lee, L. W., Piatek, C., Nishimura, J. I., Carrillo Infante, C., Jain, D., Liu, P., Filippov, G., Sicre de Fontbrune, F., Risitano, A., Kulasekararaj, A. G., & Investigators, A.-P.-. (2023, Dec). Addition of danicopan to ravulizumab or eculizumab in patients with paroxysmal nocturnal haemoglobinuria and clinically significant extravascular haemolysis (ALPHA): a double-blind, randomised, phase 3 trial. Lancet Haematol, 10(12), e955-e965. https://doi.org/10.1016/S2352-3026(23)00315-0
Lee, J. W., & Kulasekararaj, A. G. (2020, Mar). Ravulizumab for the treatment of paroxysmal nocturnal hemoglobinuria. Expert Opinion on Biological Therapy, 20(3), 227-237. https://doi.org/10.1080/14712598.2020.1725468
Lee, J. W., Sicre de Fontbrune, F., Wong Lee Lee, L., Pessoa, V., Gualandro, S., Fureder, W., Ptushkin, V., Rottinghaus, S. T., Volles, L., Shafner, L., Aguzzi, R., Pradhan, R., Schrezenmeier, H., & Hill, A. (2019, Feb 7). Ravulizumab (ALXN1210) vs eculizumab in adult patients with PNH naive to complement inhibitors: the 301 study. Blood, 133(6), 530-539. https://doi.org/10.1182/blood-2018-09-876136
Medof, M. E., Gottlieb, A., Kinoshita, T., Hall, S., Silber, R., Nussenzweig, V., & Rosse, W. F. (1987, Jul). Relationship between decay accelerating factor deficiency, diminished acetylcholinesterase activity, and defective terminal complement pathway restriction in paroxysmal nocturnal hemoglobinuria erythrocytes. J Clin Invest, 80(1), 165-174. https://doi.org/10.1172/jci113043
Narita, A., Muramatsu, H., Okuno, Y., Sekiya, Y., Suzuki, K., Hamada, M., Kataoka, S., Ichikawa, D., Taniguchi, R., Murakami, N., Kojima, D., Nishikawa, E., Kawashima, N., Nishio, N., Hama, A., Takahashi, Y., & Kojima, S. (2017, Sep). Development of clinical paroxysmal nocturnal haemoglobinuria in children with aplastic anaemia. British Journal of Haematology, 178(6), 954-958. https://doi.org/10.1111/bjh.14790
Parker, C., Omine, M., Richards, S., Nishimura, J., Bessler, M., Ware, R., Hillmen, P., Luzzatto, L., Young, N., Kinoshita, T., Rosse, W., Socie, G., & International, P. N. H. I. G. (2005, Dec 1). Diagnosis and management of paroxysmal nocturnal hemoglobinuria. Blood, 106(12), 3699-3709. https://doi.org/10.1182/blood-2005-04-1717
Peffault de Latour, R., Roth, A., Kulasekararaj, A. G., Han, B., Scheinberg, P., Maciejewski, J. P., Ueda, Y., de Castro, C. M., Di Bona, E., Fu, R., Zhang, L., Griffin, M., Langemeijer, S. M. C., Panse, J., Schrezenmeier, H., Barcellini, W., Mauad, V. A. Q., Schafhausen, P., Tavitian, S., Beggiato, E., Chew, L. P., Gaya, A., Huang, W. H., Jang, J. H., Kitawaki, T., Kutlar, A., Notaro, R., Pullarkat, V., Schubert, J., Terriou, L., Uchiyama, M., Wong Lee Lee, L., Yap, E. S., Sicre de Fontbrune, F., Marano, L., Alashkar, F., Gandhi, S., Trikha, R., Yang, C., Liu, H., Kelly, R. J., Hochsmann, B., Kerloeguen, C., Banerjee, P., Levitch, R., Kumar, R., Wang, Z., Thorburn, C., Maitra, S., Li, S., Verles, A., Dahlke, M., & Risitano, A. M. (2024, Mar 14). Oral Iptacopan Monotherapy in Paroxysmal Nocturnal Hemoglobinuria. New England Journal of Medicine, 390(11), 994-1008. https://doi.org/10.1056/NEJMoa2308695
Perry, C., Von Buttlar, X., & Thota, S. (2025, May 22). The Advancing Landscape of Paroxysmal Nocturnal Hemoglobinuria Treatment. Turk J Haematol, 42(2), 74-81. https://doi.org/10.4274/tjh.galenos.2025.2025.0054
Pu, J. J., & Brodsky, R. A. (2011, Jun). Paroxysmal nocturnal hemoglobinuria from bench to bedside. Clinical and Translational Science, 4(3), 219-224. https://doi.org/10.1111/j.1752-8062.2011.00262.x
Reiss, U. M., Schwartz, J., Sakamoto, K. M., Puthenveetil, G., Ogawa, M., Bedrosian, C. L., & Ware, R. E. (2014, Sep). Efficacy and safety of eculizumab in children and adolescents with paroxysmal nocturnal hemoglobinuria. Pediatric Blood & Cancer, 61(9), 1544-1550. https://doi.org/10.1002/pbc.25068
Rittirsch, D., Flierl, M. A., & Ward, P. A. (2008, Oct). Harmful molecular mechanisms in sepsis. Nat Rev Immunol, 8(10), 776-787. https://doi.org/10.1038/nri2402
Roth, A., He, G., Tong, H., Lin, Z., Wang, X., Chai-Adisaksopha, C., Lee, J. H., Brodsky, A., Hantaweepant, C., Dumagay, T. E., Demichelis-Gomez, R., Rojnuckarin, P., Sun, J., Hoglund, M., Jang, J. H., Gaya, A., Silva, F., Obara, N., Kelly, R. J., Beveridge, L., Buatois, S., Chebon, S., Gentile, B., Lundberg, P., Sreckovic, S., Nishimura, J. I., Risitano, A., & Han, B. (2024, Sep). Phase 3 randomized COMMODORE 2 trial: Crovalimab versus eculizumab in patients with paroxysmal nocturnal hemoglobinuria naive to complement inhibition. American Journal of Hematology, 99(9), 1768-1777. https://doi.org/10.1002/ajh.27412
Rother, R. P., Bell, L., Hillmen, P., & Gladwin, M. T. (2005). The Clinical Sequelae of Intravascular Hemolysis and Extracellular Plasma HemoglobinA Novel Mechanism of Human Disease. JAMA, 293(13), 1653-1662. https://doi.org/10.1001/jama.293.13.1653
Schmidt, C. Q., Lambris, J. D., & Ricklin, D. (2016, Nov). Protection of host cells by complement regulators. Immunol Rev, 274(1), 152-171. https://doi.org/10.1111/imr.12475
Sutherland, D. R., Acton, E., Keeney, M., Davis, B. H., & Illingworth, A. (2014, Jan). Use of CD157 in FLAER-based assays for high-sensitivity PNH granulocyte and PNH monocyte detection. Cytometry. Part B: Clinical Cytometry, 86(1), 44-55. https://doi.org/10.1002/cyto.b.21111
Telen, M. J., & Green, A. M. (1989, Jul). The Inab phenotype: characterization of the membrane protein and complement regulatory defect. Blood, 74(1), 437-441.
Urbano-Ispizua, Á., Muus, P., Schrezenmeier, H., Almeida, A. M., Wilson, A., & Ware, R. E. (2017, Mar). Different clinical characteristics of paroxysmal nocturnal hemoglobinuria in pediatric and adult patients. Haematologica, 102(3), e76-e79. https://doi.org/10.3324/haematol.2016.151852
Ussowicz, M., Przystupski, D., Mensah-Glanowska, P., & Piekarska, A. (2024). Current status and perspectives of hematopoietic cell transplantation in patients with paroxysmal nocturnal hemoglobinuria. Frontiers in Immunology, 15, 1521484. https://doi.org/10.3389/fimmu.2024.1521484
van den Heuvel-Eibrink, M. M. (2007). Paroxysmal nocturnal hemoglobinuria in children. Paediatr Drugs, 9(1), 11-16. https://doi.org/10.2165/00148581-200709010-00002
Walport, M. J. (2001a, Apr 5). Complement. First of two parts. N Engl J Med, 344(14), 1058-1066. https://doi.org/10.1056/nejm200104053441406
Walport, M. J. (2001b, Apr 12). Complement. Second of two parts. N Engl J Med, 344(15), 1140-1144. https://doi.org/10.1056/nejm200104123441506
Ware, R. E., Hall, S. E., & Rosse, W. F. (1991, Oct 3). Paroxysmal nocturnal hemoglobinuria with onset in childhood and adolescence. N Engl J Med, 325(14), 991-996. https://doi.org/10.1056/nejm199110033251403
Wilcox, L. A., Ezzell, J. L., Bernshaw, N. J., & Parker, C. J. (1991, Aug 1). Molecular basis of the enhanced susceptibility of the erythrocytes of paroxysmal nocturnal hemoglobinuria to hemolysis in acidified serum. Blood, 78(3), 820-829.
Wong, R. S. M., Navarro-Cabrera, J. R., Comia, N. S., Goh, Y. T., Idrobo, H., Kongkabpan, D., Gomez-Almaguer, D., Al-Adhami, M., Ajayi, T., Alvarenga, P., Savage, J., Deschatelets, P., Francois, C., Grossi, F., & Dumagay, T. (2023, Jun 13). Pegcetacoplan controls hemolysis in complement inhibitor-naive patients with paroxysmal nocturnal hemoglobinuria. Blood Adv, 7(11), 2468-2478. https://doi.org/10.1182/bloodadvances.2022009129
Yen, T. A., Lu, M. Y., Kuo, M. F., Huang, C. C., Chen, J. S., & Yang, Y. L. (2012, Jul 15). Eculizumab treatment of paroxysmal nocturnal hemoglobinuria presenting as moyamoya syndrome in a 9-year-old male. Pediatric Blood & Cancer, 59(1), 203-204. https://doi.org/10.1002/pbc.24070
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