Exploratory Untargeted Plasma Lipidomics Suggests Subtype-Associated Lipid Alterations in Hereditary Hemolytic Anemias

Background/Objectives: Hereditary hemolytic anemias (HHAs) are rare genetic disorders characterized by chronic hemolysis, systemic oxidative stress, and inflammation. Altered lipid homeostasis has previously been reported in HHAs; however, untargeted plasma lipidomic studies comparing HHA subtypes remain limited. This exploratory study aimed to characterize shared and subtype-specific plasma lipid alterations across five HHA subtypes. Methods: Forty-eight participants were enrolled, including 29 patients with HHA (6 with β-thalassemia, 5 with hereditary xerocytosis, 7 with hereditary spherocytosis, 5 with sickle cell disease, and 6 with congenital dyserythropoietic anemia) and 19 healthy controls. Plasma lipids were analyzed by untargeted liquid chromatography–quadrupole time-of-flight mass spectrometry, followed by multivariate, univariate, and lipid pathway analyses. Results: A total of 375 lipid species were putatively annotated, revealing both shared and putative subtype-specific lipid alterations across the five HHA subtypes. The putatively annotated species Cer 59:7;4O and PC 46:1 remained significantly altered after false discovery rate correction, whereas species such as PC 34:4 and Cer 42:3;2O showed only nominal subtype-specific differences. Mostly nominal alterations in individual ceramide, triglyceride, and phosphatidylcholine species were observed across most hemolytic groups relative to controls. Congenital dyserythropoietic anemia exhibited the fewest nominal differences from controls. Among the 25 species with nominal Kruskal–Wallis differences, SM 37:1;2O was the only lipid species that nominally differed from controls exclusively in this subtype. Conclusions: These exploratory, hypothesis-generating findings suggest that plasma lipidomics may help characterize lipid alterations accompanying chronic hemolysis. However, the candidate lipid species and predicted pathways require validation in larger, age-matched, independent cohorts.