Introduction：Paroxysmal nocturnal hemoglobinuria (PNH) is an extremely rare acquired clonal disorder of hematopoietic stem cells. It is characterized by complement-mediated intravascular hemolysis, bone marrow failure, and a high risk of thrombosis. With the advent of complement inhibitor therapy, the treatment of PNH has entered a new era. Following treatment with complement inhibitors, lactate dehydrogenase (LDH) levels in most patients rapidly decline and stabilize at relatively low levels. However, due to the presence of secondary extravascular hemolysis, LDH alone is no longer sufficient to accurately reflect the overall hemolytic burden in patients. The lifespan of red blood cells (RBC lifespan), defined as the duration red blood cells remain in circulation, is considered the “gold standard” for evaluating hemolysis. In this study, we employed a non-invasive method based on the measurement of endogenous carbon monoxide (CO) in exhaled breath to determine RBC lifespan. This approach was used to assess the degree of hemolysis improvement in PNH patients undergoing complement inhibitor therapy, thereby enabling a more accurate evaluation of the efficacy of different complement inhibitors.

Methods: A prospective, single-center cohort study was conducted.

Results: From June 2021 to January 2024, 22 patients diagnosed with PNH and treated with complement inhibitors were enrolled. The median age was 37 years (range: 15–67). Baseline characteristics included: hemoglobin (Hb) 74 g/L (48–120), reticulocyte (Ret) count 0.226 × 10¹²/L (0.097–0.4394), LDH 1916.9 U/L (1054–3366.3), granulocyte PNH clone 95.85% (33.21–99.9), and RBC lifespan 19 days (12–48). Among the patients, 4 were treated with Crovalimab: after 24 weeks, 2 achieved good partial response (GPR) and 2 achieved partial response (PR). Five patients received Iptacopan: 2 achieved complete remission (CR), 1 achieved marked partial remission (MAPR), 1 achieved GPR, and 1 achieved PR. One patient experienced breakthrough hemolysis after 20 weeks of treatment. Of the 6 patients in KP104 cohort 1, 2 achieved CR and 4 achieved GPR. One patient had breakthrough hemolysis at 12 and 24 weeks of treatment. All 3 patients in KP104 cohort 2 achieved CR. Four patients were treated with Eculizumab: 1 achieved CR, 2 achieved PR, and 1 achieved minimal partial remission (MIPR).

Following treatment, the median LDH level decreased by 1689 U/L (820–3114.6), and all patients had LDH levels below twice the upper limit of normal (ULN) within three weeks, with 20 maintaining this level. Median RBC lifespan increased by 30.5 days (-16–71), with the following changes by treatment group: Crovalimab: -3.5 days (-16–3); Iptacopan: +61 days (24–71); KP104 cohort 1: +37 days (26–62); KP104 cohort 2: +53 days (31–60); Eculizumab: -2 days (-7–12). Median reticulocyte count decreased by 0.0508 × 10¹²/L (-0.355–0.1816), although increases were observed in 4 Crovalimab-treated patients, 1 Iptacopan-treated patient, and 1 Eculizumab-treated patient. Coombs tests were positive in 3 patients treated with Crovalimab and all patients treated with Eculizumab.

Univariate analysis revealed a statistically significant difference in efficacy between the Crovalimab group and KP104 cohort 2 group (P = 0.025). Multivariate analysis identified hemoglobin levels during treatment as an independent predictor of treatment efficacy (P = 0.000; OR = 1.302; 95% CI: 1.215–1.397).Multiple regression analysis demonstrated that changes in reticulocyte count (δRET) and RBC lifespan (δRBC lifespan) were significantly correlated with changes in hemoglobin levels (δHb) (P = 0.035 and 0.003, respectively), with the following regression equation:

δHb = 22.032 – 86.308 × δRET + 0.575 × δRBC lifespan

(The absolute standardized coefficient for δRET was 0.367, and for δRBC lifespan was 0.547).

Conclusion: Different complement inhibitors, whether targeting upstream or downstream components of the complement system, demonstrate varying effects on PNH disease control. Hemoglobin levels during treatment are an independent factor influencing therapeutic outcomes, and RBC lifespan is closely associated with hemoglobin dynamics. RBC lifespan provides a quantitative measure of extravascular hemolysis and serves as a scientifically robust indicator for evaluating PNH disease activity and treatment response.

Keywords: Paroxysmal Nocturnal Hemoglobinuria, Complement Inhibitor Therapy, Red Blood Cell Lifespan

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2025
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