Dynamic Simulation and Metabolome Analysis of Long-Term Erythrocyte Storage in Adenine–Guanosine Solution

Abstract

Although intraerythrocytic ATP and 2,3-bisphophoglycerate (2,3-BPG) are known as direct indicators of the viability of preserved red blood cells and the efficiency of post-transfusion oxygen delivery, no current blood storage method in practical use has succeeded in maintaining both these metabolites at high levels for long periods. In this study, we constructed a mathematical kinetic model of comprehensive metabolism in red blood cells stored in a recently developed blood storage solution containing adenine and guanosine, which can maintain both ATP and 2,3-BPG. The predicted dynamics of metabolic intermediates in glycolysis, the pentose phosphate pathway, and purine salvage pathway were consistent with time-series metabolome data measured with capillary electrophoresis time-of-flight mass spectrometry over 5 weeks of storage. From the analysis of the simulation model, the metabolic roles and fates of the 2 major additives were illustrated: (1) adenine could enlarge the adenylate pool, which maintains constant ATP levels throughout the storage period and leads to production of metabolic waste, including hypoxanthine; (2) adenine also induces the consumption of ribose phosphates, which results in 2,3-BPG reduction, while (3) guanosine is converted to ribose phosphates, which can boost the activity of upper glycolysis and result in the efficient production of ATP and 2,3-BPG. This is the first attempt to clarify the underlying metabolic mechanism for maintaining levels of both ATP and 2,3-BPG in stored red blood cells with in silico analysis, as well as to analyze the trade-off and the interlock phenomena between the benefits and possible side effects of the storage-solution additives.

Routine storage of red blood cell (RBC) units in additive solution‐3: a comprehensive investigation of the RBC metabolome

“…Previous metabolomics studies have focused on the impact of metabolic lesions on RBC viability during storage in the presence of different ASs, including SAGM, MAP, PAGGGM, and AS‐5 . Accordingly, we focus here on RBC storage in AS‐3, an AS that is characterized by half the level of saline in comparison to SAGM, AS‐1, and AS‐5 (70 mmol/L vs. 150, 154, and 150 mmol/L, respectively), high phosphate loading (23 mmol/L NaH 2 PO 4 , absent in other ASs, and only 5 mmol/L in MAP), almost a double dose of adenine in comparison to SAGM (2 mmol/L vs. 1.2 mmol/L) and half the dose of dextrose in comparison to AS‐1 (55 mmol/L vs. 111 mmol/L) .…”

“…During storage, RBCs are characterized by the progressive accumulation of biochemical products commonly known as the “storage lesion.” The storage lesion results in the impairment of cation homeostasis, the accumulation of reactive oxygen species, the alteration of proteomic profiles, and the progressive vesiculation of membrane portions that accompanies the loss of the discocytic morphology in exchange for a spheroechinocytic RBC morphology . Metabolomics studies have been completed on RBC units stored in a number of additive solutions (ASs), including SAGM, AS‐1, MAP, PAGGGM, and AS‐5 . These studies paved the way for preliminary investigations aimed at determining the influence of alternative storage solutions (e.g., supplementation of antioxidants, vitamin C, N ‐acetylcysteine, or serotonin) or strategies (such as anaerobic storage) on stored RBC metabolic profiles.…”

Biomarkers defining the metabolic age of red blood cells during cold storage

“…[2][3][4][5] In recent years, the storage lesion has been extensively studied through integrated omics and systems biology approaches. 4,[6][7][8][9][10][11][12][13][14][15][16][17] We recently reported how metabolomics was able to reveal a clear metabolic signature descriptive of the RBC storage lesion. 10 Then, we demonstrated that RBCs stored in the blood bank do not simply undergo a monotonic decay, but experience a more complex change in metabolism that involves the development of 3 discrete metabolic phenotypes.…”

Red blood cell storage in additive solution‐7 preserves energy and redox metabolism: a metabolomics approach

“…Metabolomics investigation of RBC lesion during storage in the blood bank have recently highlighted common and unique patterns depending on the AS in which RBCs are stored, AS‐1, AS‐3, or AS5 in the United States or SAGM, MAP, and PAGGGM in Europe and other countries. In this respect, encouraging results have been observed when storing RBCs in presence of alkaline solutions such as AS‐7, previously known as EAS‐81 …”