Abstract
BACKGROUND: The storage of red blood cells (RBCs) is essential for transfusion but leads to storage lesions that compromise RBC quality and increase the risk of transfusion-related adverse effects, including allergic transfusion reactions (ATRs). Understanding storage-induced metabolic change is crucial for enhancing transfusion safety. STUDY DESIGN AND METHODS: We conducted targeted metabolomic profiling of RBC supernatants stored in PAGGS-M over 42 days, collecting 161 weekly samples from 23 units. We analyzed 188 metabolites across six compound classes (hexoses, amino acids, biogenic amines, acylcarnitines, glycerophospholipids, and sphingolipids) along with 20 hematological parameters. Additionally, a mast cell degranulation assay evaluated the impact of these changes on ATR risk. RESULTS: Over 100 of the 188 metabolites changed significantly during storage, indicating diverse pathway alterations. Key findings include the accumulation of acylcarnitines and depletion of methionine, with mast cell degranulation significantly increased in supernatants from 42-day-old pRBCs versus fresh units. Notably, methionine depletion coincided with a critical transition phase in storage-associated metabolic aging. In addition, elevated levels of acylcarnitines correlated with increased markers of membrane damage, highlighting potential mechanisms underlying allergic transfusion reactions. DISCUSSION: This study highlights the impact of storage-induced metabolic changes in exacerbating transfusion-related complications. Therefore, optimization of additive solutions, such as stabilizing methionine levels during storage, may mitigate storage lesions and improve outcomes. Additionally, the storage-time-related increase in mast cell activation suggests a need for targeted interventions, particularly for patients vulnerable to ATRs.