Red blood cells (RBCs) are essential for multicellular life, delivering oxygen to tissues that cannot obtain it directly from the air. To achieve this, RBCs are specialized with high concentrations of hemoglobin, lack nuclei and organelles, and have a limited lifespan of approximately 120 days in humans. During their circulation, RBCs are adept at carrying oxygen and sustaining metabolism, but they are eventually cleared by the reticuloendothelial system due to accumulated damage. However, when RBCs are stored outside the body, particularly in blood banks, they undergo storage-induced damage, termed “storage lesions,” which significantly affect their function.
Causes of RBC Storage Lesions
The development of storage lesions in RBCs during their storage in blood banks is driven by two primary factors: metabolic impairments and oxidative damage.
- Metabolic Impairment: When RBCs are removed from the donor’s circulation and stored in a hypothermic environment with limited solution volume, several metabolic changes occur. Glucose and essential substrates become depleted, and metabolic waste products such as lactic acid accumulate. This disruption of metabolic homeostasis results in a reduced pH, which impairs key enzymes involved in energy production and antioxidant defense. Additionally, storage leads to a reduction in ATP and 2,3-diphosphoglycerate (2,3-DPG), which are critical for RBC function, particularly for oxygen delivery. The breakdown of 2,3-DPG reduces hemoglobin’s ability to release oxygen to tissues.
- Oxidative Damage: RBCs are susceptible to oxidative stress, particularly under storage conditions. The accumulation of reactive oxygen species (ROS) causes damage to cellular components, including membrane proteins and hemoglobin. Over time, this oxidative stress exacerbates the functional decline of stored RBCs, further contributing to storage lesions. Recent advances in “omics” technologies have shed light on metabolic and redox pathways involved in RBC storage, revealing more complex biochemical changes than previously understood.
Storage Lesions and Their Effects on RBCs
Storage lesions encompass a range of cellular and biochemical alterations in RBCs during storage. These include depletion of energy reserves (ATP, 2,3-DPG), and the accumulation of metabolic byproducts. These changes negatively affect the RBC membrane, hemoglobin structure, and overall function, reducing the ability of stored RBCs to transport oxygen efficiently. Additionally, RBCs experience ion dysregulation, especially with respect to calcium, which further disrupts metabolic signaling and enzyme activity. The structural damage can also lead to the removal of RBCs by the reticuloendothelial system upon transfusion, contributing to poor post-transfusion recovery.
One key metabolic marker associated with the aging of stored RBCs is 5-oxoproline, which accumulates during storage and serves as an indicator of metabolic age. Additionally, the breakdown of ATP and the reduction of glutathione pools make RBCs increasingly vulnerable to oxidative damage. Despite the critical role of ATP in maintaining RBC function, replenishing ATP or glutathione in stored RBCs has proven ineffective.
Physiological Consequences and Clinical Impact
The physiological consequences of storage lesions are multifaceted. In vitro and animal studies have shown that the metabolic and structural damage to RBCs during storage negatively impacts their ability to deliver oxygen efficiently. Moreover, when stored RBCs are transfused into patients, their impaired function may lead to suboptimal oxygen delivery and contribute to various clinical issues, especially in critically ill or chronically transfused patients. However, the link between storage lesions and clinical outcomes remains complex, as multiple factors—such as pre-existing conditions and genetic variability—can influence patient responses.
Efforts to mitigate the development of storage lesions have focused on improving storage solutions and techniques. Additive solutions designed to preserve RBC metabolism, prevent oxidative damage, and maintain ATP and 2,3-DPG levels are central to these efforts. For example, solutions with higher glucose concentrations have been used to prevent glucose depletion and support metabolic activity during storage. Additionally, understanding the metabolic pathways involved in RBC aging has opened new avenues for targeted interventions, although no solution has yet been able to fully address the storage lesion problem.
Conclusions
RBCs undergo significant metabolic and oxidative stress during storage, leading to storage lesions that impair their function. While these changes are well-documented, their precise clinical consequences remain complex and difficult to predict. Current evidence suggests that transfusing the freshest available blood may have an impact on certain patient populations. Given the large number of patients who receive stored RBCs annually, it is crucial to continue improving storage techniques and to better understand the clinical implications of storage lesions. The future of RBC storage will likely involve more personalized approaches, considering the unique needs of different patient groups, donor variability, and technological advancements.
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