Mixed Intravascular and Extravascular Hemolysis Despite Eculizumab in Paroxysmal Nocturnal Hemoglobinuria: A Case of Switching to Pegcetacoplan

To the Editor, Paroxysmal nocturnal hemoglobinuria (PNH) leads to complement-mediated hemolysis, thrombosis, and variable marrow dysfunction [1].Although C5 inhibitors control intravascular hemolysis [2], surviving erythrocytes may undergo C3-mediated extravascular clearance [3].An 80-year-old woman diagnosed with classic PNH at age 70 in 2017 started eculizumab.Initial bone marrow biopsy showed hypercellularity, with PNH clones of 97.27%, 97.35%, and 3% in granulocytes, monocytes, and erythrocytes, respectively.Declining hemoglobin prompted shortening the dosing interval to 12 days in 2018 and increasing the dose to 1,200 mg every 12 days in 2020.Hemoglobin subsequently remained at 7-10 g/dL for a period.In 2023, her hemoglobin decreased to 6.6 g/dL, with LDH >1,800 U/L (135-214 U/L) and indirect bilirubin of 3.83 mg/dL.The direct antiglobulin test (DAT) was negative for IgG and positive for C3d (2+).Despite continued eculizumab at 1,200 mg every 12 days, she required 1-2 units of packed red blood cells per month.A one-month empirical trial of prednisolone (1 mg/kg/day) was initiated in an attempt to suppress extravascular hemolysis but produced no meaningful response and was discontinued well before pegcetacoplan was initiated.During eculizumab treatment between 2023 and 2025, LDH levels ranged from 300 to 900 U/L.Eculizumab and transfusion support continued until the switch to pegcetacoplan in 2025.Markedly elevated LDH and hemoglobinuria despite intensified eculizumab indicated intravascular hemolysis, while persistent anemia, transfusion dependence, indirect hyperbilirubinemia, and C3d positivity suggested concurrent extravascular hemolysis, supporting a mixed pattern.CH50 and free C5 levels were not measured; therefore, incomplete terminal complement blockade during eculizumab treatment cannot be excluded.Eculizumab was discontinued due to an inadequate response eight weeks before pegcetacoplan initiation; therefore, the recommended four-week overlap was not implemented.Other causes of anemia were excluded.In 2025, pegcetacoplan 1,080 mg subcutaneously twice weekly was initiated.The last red blood cell transfusion was given one month before pegcetacoplan initiation.Eculizumab was stopped eight weeks before pegcetacoplan initiation, without overlap.Meningococcal, pneumococcal, and Hib vaccinations had previously been completed and were up to date at the time of switching to pegcetacoplan: no booster or antibiotic prophylaxis was given.During eculizumab treatment, the white blood cell count was 3.85 × 10⁹/L, hemoglobin 8.4 g/dL, absolute reticulocyte count was 277.9 × 10⁹/L (10.18%), platelet count 80 × 10⁹/L, LDH >1,800 U/L, total bilirubin 2.08 mg/dL, and indirect bilirubin 1.88 mg/dL.Monospecific DAT for C3d was repeated immediately before pegcetacoplan initiation and remained positive.At month 1, fatigue and hemoglobinuria resolved; hemoglobin, WBC, and platelets increased to 13.8 g/dL, 4.27 × 10⁹/L, and 154 × 10⁹/L, respectively, while LDH and indirect bilirubin decreased to 183 U/L and 0.12 mg/dL.Hemoglobin/LDH were 14.9 g/dL/199 U/L at month 3 and 13.5 g/dL/175 U/L at month 9, when DAT for C3d became negative.At month 12, hemoglobin was 14.4 g/dL, LDH 274 U/L, indirect bilirubin 0.27 mg/dL, haptoglobin <0.1 g/L, and absolute reticulocytes 150.3 × 10⁹/L (3.63%); DAT for C3d remained negative (Figure 1).At month 12, persistently low u n c o r r e c t e d p r o o f haptoglobin and mild reticulocytosis suggested possible residual compensated hemolysis despite normalization of hemoglobin.No adverse events or red cell transfusions were reported during 12 months of pegcetacoplan treatment.The phase 3 PEGASUS trial demonstrated that pegcetacoplan was superior to eculizumab in patients with PNH who remained anemic despite C5 inhibition.At week 16, pegcetacoplan resulted in a 3.84 g/dL greater improvement in hemoglobin compared with eculizumab (P<0.001), while transfusion avoidance was achieved in 85% and 15% of patients, respectively [4].In a real-world cohort of 48 patients, mean hemoglobin increased from 9.1 to 11.6 g/dL after three months of pegcetacoplan [5].These findings support the benefit of proximal C3 inhibition in controlling both intravascular and extravascular hemolysis.Similarly, our patient achieved rapid hematologic improvement and transfusion independence after switching from long-term eculizumab to pegcetacoplan.In patients with persistent anemia and transfusion dependence despite C5 inhibition, the decision to switch to proximal complement inhibition should be based on the overall clinical and laboratory assessment, including hemoglobin, transfusion requirement, reticulocyte count, indirect bilirubin, and evaluation of other causes of anemia.C3d-positive DAT supports C3 opsonization but should not be used as an independent criterion for switching treatment.