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Storage Lesion

Progressive RBC Damage During Storage

The storage lesion refers to the collection of changes that occur to red blood cells (RBCs) during storage. RBCs experience progressive damage during storage that may affect their viability, impact the ability of the vessels to facilitate blood flow, decrease the RBCs ability to deliver oxygen, and increase the generation of potentially harmful waste particles. The existence of the storage lesion process has been well established, and recent scientific work has increased the precision and depth. 7,8,10

Consequences of RBC Storage Lesion12

Depletion of ATP (1,2)

ATP Maintenance is Key for RBC Functionality

ATP is the source of energy within all living cells. It is produced within a cell by converting fuel molecules, then expended at other locations within the same cell for maintaining its vital functions. When ATP is lost, the red cell loses ability to maintain its characteristic shape as well as sustain its vital functions, resulting in removal from circulation. In RBC, ATP is produced by glycolysis, the breakdown of glucose. ATP in RBC also serves as a signaling molecule for regional vasodilation (widening of blood vessels) under oxygen-deprived conditions in tissue.2

Depletion of 2,3-DPG (2,3)

2,3-DPG Maintenance is Key for Oxygen Delivery

One of the most notable changes during RBC storage is the rapid fall of 2,3-DPG.2 This molecule influences hemoglobin (the oxygen carrier and main constituents of RBC giving its color) so that it releases oxygen to the tissues more easily. Without 2,3-DPG, oxygen would be more tightly bound to hemoglobin and thus less easily off-loaded to body tissues. Levels of 2,3-DPG have been shown to fall quickly during current methods of storage of RBC, becoming nearly undetectable within one to two weeks.2

Decreased RBC deformability (3)

Deformability is Key for Physiological Blood Flow

The physical shape of RBCs also goes through a progressive change during storage, affected by the oxidative damage to their membranes as well as the changes brought on by the depletion of ATP. These effects cause RBC to shed damaged membrane during storage thereby transforming RBC from a pliable biconcave disc that has the capacity to fold and deform into narrow capillaries, into a spherical shape that cannot deform because, unlike a balloon, the RBC membrane is not stretchable. In addition, the membrane is more adhesive to the endothelium. Alterations in the deformability and the adhesiveness12 of an RBC has substantial impact on its ability to traverse the microcirculation where capillary vessels may be as small as 3 to 8-µM in diameter, smaller than RBC’s 8.5µm diameter of the biconcave disc.2,3

Hemolysis (RBC destruction) (8)

RBC integrity is Key for Survival of Transfused RBCs in Circulation

Loss of red cell integrity during storage results in hemolysis (destruction of red cells) during storage and after transfusion. The transfusion of a large volume of damaged non-viable cells results in the release of hemoglobin and iron contained within hemoglobin as the body attempts to clear the waste from its system. These byproducts of oxidative stress can have an inflammatory effect on recipients, as well as increase the risk of bacterial infection.10,11,12

Accumulation of inflammatory and immunomodulatory byproducts resulting from oxidative damage (7,9)

Reduction In Oxidative Stress is Key for Reducing Proinflammatory Molecules

The accumulation of several bioactive substances, involving cytokines and proinflammatory lipids, also occur.12,16 Some of these modifications may be reversible whereas others are irreversible. They can lead to the rapid clearance of the RBCs from the recipient’s bloodstream or other physiological consequences, thus decreasing the beneficial impact of the transfusion and possibly being associated with deleterious side effects, including the activation of inflammatory genes in circulating leukocytes or iron overload in the recipient.12,15,16

Reduced oxygen unloading (13,14)

Oxygen Unloading is Key for the Circulatory System

The function of the cardiovascular or circulatory system is designed to ensure the survival of all cells of the body. The red blood cells within the circulatory system transport oxygen from the lungs to the tissues providing all cells with the required oxygen.14 Stored RBCs incur biochemical and morphological changes. Functionally, these storage lesions manifest as slower oxygen unloading from RBCs which may compromise the efficacy of transfusions where the clinical imperative is to rapidly boost oxygen delivery to tissues.14

Degradation of conventional RBCs over the storage period17


1. Almizraq R, Tchir JD, Holovati JL, Acker JP. Storage of red blood cells affects membrane composition, microvesiculation, and in vitro quality. Transfusion. 2013 Oct;53(10):2258-67. doi: 10.1111/trf.12080. 2. Kor DJ et al. Red Blood Cell Sorage Lesion. Bosnian Journal of Basic Medical Sciences 2009;9 (Supplement):S21-S27.  3. Cluitmans JC, Hardeman MR, Dinkla S, Brock R, Bosman GJ. Red blood cell deformability during storage: towards functional proteomics and metabolomics in the Blood Bank. Blood Transfus. 2012 May; 10(Suppl 2): s12–s18. doi: 10.2450/2012.004S. 4. Silliman CC, Moore EE, Kelher MR, Khan SY, Gellar L, Elzi DJ. Identification of lipids that accumulate during the routine storage of prestorage leukoreduced red blood cells and cause acute lung injury. Transfusion. 2011 Dec;51(12):2549-54. doi: 10.1111/j.1537-2995.2011.03186.x. 5. Roback JD, Neuman RB, Quyyumi A, Sutliff R. Insufficient nitric oxide bioavailability: a hypothesis to explain adverse effects of red blood cell transfusion. Transfusion 2011;51:859-66. 6.Alexander JT, El-Ali AM, Newman JL, et al. Red blood cells stored for increasing periods produce progressive impairments in nitric oxide-mediated vasodilation. Transfusion 2013. 7. D’alessandro A, Yoshida T, et al. Hypoxic storage of red blood cells improves metabolism and post-transfusion recovery. Transfusion. 2020;9999;1–13. 8.Kim-Shapiro D, Lee J, Gladwin M. Storage Lesion. Role of Red Cell Breakdown. 9.Torrance HD, Vivian ME, Brohi K, et al. Changes in gene expression following trauma are related to the age of transfused packed red blood cells. J Trauma Acute Care Surg. 2015;78:535–42. 10. Yoshida T, Shevkoplayas S. Anaerobic storage of red blood cells. Blood Transfus 2010; 8: 220-36. 11. Yoshida T, Blair A, D’Alessandro A, et al. Enhancing uniformity and overall quality of red cell concentrate with anaerobic storage. Blood Transfus 2017; 15 (2): 172-181. 12.Yoshida T, Prudent M, D’alessandro A. Red blood cell storage lesion: causes and potential clinical consequences. Blood Transfus 2019; 17 (1): 27-52.  13. Mohanty J, Nagababu E, and Rifkind J. Red blood cell oxidative stress impairs oxygen delivery and induces red blood cell aging. Front Physiol. 2014;5(84). Doi: Rabcuka J, Blonski S, Meli A, et al. Metabolic reprogramming under hypoxic storage preserves faster oxygen unloading from stored red blood cells. Blood Advance. 2022;6(18):5415-5428. 15.Bardyn M, Tissot JD and Prudent M. Oxidative stress and antioxidant defenses during blood processing and storage of erythrocyte concentrates. Transfusion Clinique et Biologique. 2018;25:96-100. 16. Escobar G, Cheng A, Moore E, et al. Stored packed red blood cell transfusion up-regulates inflammatory gene expression in circulating leukocytes. Ann Surg. 2007;246:129-134. 17. Mustafa et al. Time dependent assessment of morphological changes: leukodepleted packed red blood cells stored in SAGM. BioMed Research Intl. Vol 2016.

See a depiction of the RBC degradation process that occurs during blood storage and how it impacts two of the major functions of RBCs in a 3D animation.