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Review
. 2015 Jan;13(1):21-31.
doi: 10.2450/2014.0053-14. Epub 2014 Sep 12.

Classic and alternative red blood cell storage strategies: seven years of "-omics" investigations

Lello Zolla  1 , Angelo D'alessandro  2 , Sara Rinalducci  1 , Gian Maria D'amici  1 , Simonetta Pupella  3 , Stefania Vaglio  4 , Giuliano Grazzini  3
Affiliations
Review

Classic and alternative red blood cell storage strategies: seven years of "-omics" investigations

Lello Zolla et al. Blood Transfus. 2015 Jan.
No abstract available

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Figures

Figure 1
Figure 1
The figure can be read from the upper-left corner in an anti-clockwise direction. An overview of the main biochemical changes of red blood cells (RBC) ageing in vitro under blood bank conditions. Cation homeostasis (K+, Ca2+) is dysregulated by low temperatures and progressive depletion of high-energy phosphate reservoirs (adenosine triphosphate - ATP and 2,3-diphosphoglycerate - DPG). Glucose (additive solution) is internalised through GLUT transporters and consumed through the Emden-Meyerhof glycolytic pathway, in order to produce ATP, lactate (LAC) and promote pH lowering. Storage also results in a progressive decrease of S-nitrosothiol-haemoglobin (Hb). However, low temperatures and the progressive accumulation of oxidative stress (probably triggered by Hb-mediated Fenton reactions) promote a metabolic diversion towards the pentose phosphate pathway, in order to produce oxidized glutathione (GSSG)- reducing NADPH from glucose 6-phosphate (G6P). Pentose phosphate pathway intermediates can re-enter glycolysis or proceed towards the purine salvage pathway (also influenced by adenosine and inosine in the additive/rejuvenation solution). Alterations to calcium (Ca2+) homeostasis (and of other second messenger signalling molecules, such as cAMP and AMP) promote the activation of specific kinases (e.g. PKC, PKA, AMPK) or activate proteolytic enzymes (such as calpains) that start digesting structural and functional proteins in the cytosol and membrane, above all band 3 (AE1). Anion exchanger 1/band 3 (AE1) is responsible for the chloride shift, whereby bicarbonate (HCO3−) is exchanged for chloride (Cl−), thus modulating anion homeostasis, intracellular pH and, indirectly, Hb-oxygen affinity and thus gas exchange. Fragmentation of the cytosolic domain of AE1 (also mediated by reactive oxygen species, ROS) promotes displacement of glycolytic enzymes (thereby bound/inhibited) and structural proteins (ankyrin, ANK, band 4.2 and 4.1). Enhanced oxidation of cytosolic proteins is partly challenged by antioxidant defences (SOD1, PRDX2) and chaperone molecules (heat shock proteins, HSP), while they progressively result in the accumulation of redox modifications to proteins (carbonylation, glycation of haemoglobin [HbA1c], protein fragmentation) and lipids (lipid peroxidation, accumulation of prostaglandins in the supernatant). Alternative degradation strategies for proteins (proteasome, eventually extruded in the supernatant) and lipids (sphingomyelinase-dependent accumulation of ceramides) also play a role in this process. Progressive leaching of plasticizers (DEHP) from the plastic bag results in local accumulation in cell membranes. At the membrane level, AE1 clusters, exposure of phosphatidylserine (PS) in the outer leaflet, and lipid raft formation alter the pro-immunogenic potential of RBC. Taken together, these alterations affect membrane deformability, increase osmotic fragility and promote vesiculation, a process in which micro- and nanovesicles are shed in order to eliminate irreversibly altered proteins (including traces of glycolytic enzymes), enriched with haemoglobin and lipid raft proteins, membrane portions (also exposing common rheological antigens, such as CD47, Rh, RhAG, glycophorin A-GPA). Reprinted with permission from D’Alessandro and Zolla, Biochemistry of red cell aging in vivo and storage lesions. European Haematology Association - EHA 18 Educational Book; Haematologica 2013; 98 (Suppl 1): 389–96.
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