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. 2025 Aug 11.
doi: 10.1002/ajh.70032. Online ahead of print.

Characterization of Breakthrough Hemolysis in Patients With Paroxysmal Nocturnal Hemoglobinuria: An International Multicenter Experience

Bruno Fattizzo  1   2 , Giacinto Luca Pedone  1 , Elisabetta Metafuni  3 , Eloise Beggiato  4 , Valentina Giai  5 , Esther Natalie Oliva  6 , Antony Ricchiuti  1 , Marta Bortolotti  1 , Simona Raso  7 , Daniela Carlino  8 , Mara Memoli  9 , Sofia Vecchi  1 , Jennifer Vidler  10 , Sukanya Gogoi  10 , Shreya Goel  10 , Anna Corby  10 , Roochi Trikha  10 , Sneha Balakrishnan  10 , Francesco Passamonti  1 , Anna Paola Iori  11 , Simona Sica  3 , Shreyans Gandhi  10 , Wilma Barcellini  1 , Austin Kulasekararaj  10
Affiliations

Characterization of Breakthrough Hemolysis in Patients With Paroxysmal Nocturnal Hemoglobinuria: An International Multicenter Experience

Bruno Fattizzo et al. Am J Hematol. .

Abstract

Breakthrough hemolysis (BTH) is defined as a hemolytic exacerbation in a patient with paroxysmal nocturnal hemoglobinuria (PNH) treated with complement inhibitors (CIs). In the current era of several terminal and proximal inhibitors, there are no guidelines for defining BTH and its severity, and clinical management is not standardized. This retrospective, observational, and multicentric study evaluated BTH frequency and severity in PNH patients treated with complement inhibitors from 2007 until February 2025 at 10 centers across Italy (9 centers) and the United Kingdom (1 center). A total of 271 BTH events occurred in 102 out of 198 patients (51%), with 36/198 (18%) patients experiencing 3 or more BTH episodes over the 18-year follow-up. Most events (55%) were prompted by infections, and 24 (10%) were linked to poor compliance with oral alternative pathway inhibitors. BTH was clinically severe in about half of patients, requiring transfusion in 46%, CI dosing adjustment in 17%, and anticoagulant prophylaxis in 16%. Overall, 5 (2%) breakthrough thrombotic events occurred in patients not on prophylaxis, all during an infection. BTH incidence was 0.19 events per patient-year, maximal with proximal inhibitors (0.4 events per patient-year), and lower for anti-C5 (0.18 per patient-year). By logistic regression analysis, the main predictors of BTH were more severe disease at diagnosis (increased LDH and a shorter time to first complement inhibitor), treatment with proximal inhibitors, and poorer EBMT response category.

Keywords: breakthrough hemolysis; danicopan; eculizumab; iptacopan; paroxysmal nocturnal hemoglobinuria; pegcetacoplan; ravulizumab; thrombosis.

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