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Patients with paroxysmal nocturnal hemoglobinuria (PNH) are susceptible to complement-mediated intravascular hemolysis and thrombosis. Factor H (FH) is the main regulator of the complement alternative pathway, which protects cells from unwanted complement-mediated damage. Although FH is not a glycosylphosphatidylinositol-linked molecule, it may play a role in PNH. We sought to determine if rare germline variants in complement factor H (CFH) affect the PNH course, screening 84 patients with PNH treated with eculizumab for rare variants in CFH, CFI, and C3 genes. We compared the allelic frequencies with populational data and a geographically-matched control group, looking for an association between presence of the variants and treatment response (transfusion independence by 6 months). Sixteen patients presented rare variants, 9 in CFH (10.7%). Germline CFH variants were more frequent among patients with PNH than among controls (P = .02) or public data (P < .001) and were more likely to be transfusion-dependent at 6 months after eculizumab initiation (P = .015). With a median follow-up of 5.8 years, 8 of 9 patients with the CFH variant received transfusions, and 2 developed thromboses. None of the patients with the CFH variant had severe aplastic anemia from eculizumab initiation until 6 months. We demonstrated for the first time that rare CFH variants are over-represented among patients with PNH and that germline genetic background may affect the response to eculizumab. © 2023 by The American Society of Hematology.


Pedro Henrique Prata, Jacques-Emmanuel Galimard, Flore Sicre de Fontbrune, Anna Duval, Paula Vieira Martins, Stephane Roncelin, Pierre-Édouard Debureaux, Anne-Claire Lepretre, Lise Larcher, Rudy Birsen, Ygal Benhamou, Jean Soulier, Gérard Socié, Véronique Fremeaux-Bacchi, Régis Peffault de Latour. Rare germline complement factor H variants in patients with paroxysmal nocturnal hemoglobinuria. Blood. 2023 Apr 13;141(15):1812-1816

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PMID: 36626252

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