Hod EA, Zhang N, Sokol SA, et al. Transfusion of red blood cells after prolonged storage produces harmful effects that are mediated by iron and inflammation

Department of Pathology and Cell Biology, Columbia University College of Physicians and Surgeons, New York, NY 10032, USA.
Blood (Impact Factor: 10.45). 03/2010; 115(21):4284-92. DOI: 10.1182/blood-2009-10-245001
Source: PubMed


Although red blood cell (RBC) transfusions can be lifesaving, they are not without risk. In critically ill patients, RBC transfusions are associated with increased morbidity and mortality, which may increase with prolonged RBC storage before transfusion. The mechanisms responsible remain unknown. We hypothesized that acute clearance of a subset of damaged, stored RBCs delivers large amounts of iron to the monocyte/macrophage system, inducing inflammation. To test this in a well-controlled setting, we used a murine RBC storage and transfusion model to show that the transfusion of stored RBCs, or washed stored RBCs, increases plasma nontransferrin bound iron (NTBI), produces acute tissue iron deposition, and initiates inflammation. In contrast, the transfusion of fresh RBCs, or the infusion of stored RBC-derived supernatant, ghosts, or stroma-free lysate, does not produce these effects. Furthermore, the insult induced by transfusion of stored RBC synergizes with subclinical endotoxinemia producing clinically overt signs and symptoms. The increased plasma NTBI also enhances bacterial growth in vitro. Taken together, these results suggest that, in a mouse model, the cellular component of leukoreduced, stored RBC units contributes to the harmful effects of RBC transfusion that occur after prolonged storage. Nonetheless, these findings must be confirmed by prospective human studies.

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Available from: Steven L Spitalnik, Nov 18, 2015
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    • "Plasma NTBI may be present when transferrin saturation exceeds about 60–70% and has been implicated in determining tissue iron distribution. Although plasma NTBI levels correlate loosely with markers of iron overload, additional factors, such as ineffective erythropoiesis (Wickramasinghe et al, 1999), suspension of erythropoiesis (Bradley et al, 1997) or recent blood transfusion (Hod et al, 2010) are also implicated with NTBI levels. High levels of ineffective erythropoiesis (IE), such as in TM, suppress hepcidin levels (Origa et al, 2007) through bone marrow-derived factors (Kautz et al, 2014), thereby potentially increasing transferrin saturation and NTBI generation. "
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    ABSTRACT: In transfusional iron overload, extra-hepatic iron distribution differs, depending on the underlying condition. Relative mechanisms of plasma non-transferrin bound iron (NTBI) generation may account for these differences. Markers of iron metabolism (plasma NTBI, labile iron, hepcidin, transferrin, monocyte SLC40A1 [ferroportin]), erythropoiesis (growth differentiation factor 15, soluble transferrin receptor) and tissue hypoxia (erythropoietin) were compared in patients with Thalassaemia Major (TM), Sickle Cell Disease and Diamond-Blackfan Anaemia (DBA), with matched transfusion histories. The most striking differences between these conditions were relationships of NTBI to erythropoietic markers, leading us to propose three mechanisms of NTBI generation: iron overload (all), ineffective erythropoiesis (predominantly TM) and low transferrin-iron utilization (DBA).
    British Journal of Haematology 09/2014; 167(5). DOI:10.1111/bjh.13081 · 4.71 Impact Factor
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    • "Several major projects are ongoing [8], [9], and clinical trials and laboratory studies have already shown that long-stored red blood cells have harmful effects [4], [9]–[19]. The structural and biochemical changes that RBCs go through during storage are likely to contribute to adverse transfusion effects [3], [11], [19]–[25]. A definitive determination of the potential risks associated with transfusion of RBCs stored for longer periods of time, however, is still elusive not only because the responsible mechanisms have not yet been identified, but also because some facts are not clear. "
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    ABSTRACT: Aims Numerous studies have suggested that transfusion of red blood cells (RBCs) stored over a long period of time may induce harmful effects due to storage-induced lesions. However, the underlying mechanisms responsible for this damage have not been identified. Furthermore, it is unclear why and how up to 30% of long-stored RBCs disappear from the circulation within 24 hours after transfusion. The aim of this study was to determine how the cell number of RBCs of different ages changes during storage and how these cells undergo cumulative structural and functional changes with storage time. Methods and Results We used Percoll centrifugation to fractionate the RBCs in blood bank stored RBC units into different aged sub-populations and then measured the number of intact cells in each sub-population as well the cells’ biomechanical and biochemical parameters as functions of the storage period. We found that the RBC units stored for ≤ 14 days could be separated into four fractions: the top or young cell fraction, two middle fractions, and the lower or old fraction. However, after 14 days of storage, the cell number and cellular properties declined rapidly whereby the units stored for 21 days only exhibited the three lower fractions and not the young fraction. The cell number within a unit stored for 21 days decreased by 23% compared to a fresh unit and the cells that were lost had hemolyzed into harmful membrane fragments, microparticles, and free hemoglobin. All remaining cells exhibited cellular properties similar to those of senescent cells. Conclusion In RBC units stored for greater than 14 days, there were fewer intact cells with no healthy cells present, as well as harmful membrane fragments, microparticles, and free hemoglobin. Therefore, transfusion of these stored units would not likely help patients and may induce a series of clinical problems.
    PLoS ONE 08/2014; 9(8):e105692. DOI:10.1371/journal.pone.0105692 · 3.23 Impact Factor
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    • "One important criterion used by the Regulatory Agencies before approval of a RBC storage system, is a measure of post-transfusion survival that is a measure of in vivo viability, which reflects the quality of stored RBC [25]. Recently, inventive efforts to study the post-transfusion survival of RBC in model animal systems have revealed important information related to the storage lesion and transfusion-related reactions [26]–[28]. Using such an established mouse model of blood banking [27], [28] we evaluated the impact of 5-HT supplementation on the 24h post-transfusion survival of stored RBC. In order to closely mimic the aging process undergone by human RBC during hypothermic storage, mouse RBC were collected in the conventional human storage solution CPDA-1, stored at 4°C after removal of the leukocytes by filtration, stained with CFDA-SE and transfused to a recipient to follow their post-transfusion survival. "
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    ABSTRACT: Serotonin (5-HT) is a monoamine originally purified from blood as a vasoactive agent. In nonneuronal tissues, its presence is linked with the expression of tryptophan hydroxylase 1 (TPH1) that catalyzes the rate-limiting step of its synthesis. Targeted disruption in mice of the TPH1 gene results in very low levels of circulating 5-HT. Previous analysis of the TPH1 knockout (TPH1(-/-)) mouse revealed that they develop a phenotype of macrocytic anemia with a reduced half-life of their circulating red blood cells (RBC). In this study, to establish whether the observed reduced half-life of TPH1(-/-) RBC is an intrinsic or an extrinsic characteristic, we compared their survival to RBC isolated from wild-type mice. Both in vivo and in vitro data converge to demonstrate an extrinsic protective effect of 5-HT since presence of 5-HT in the RBC environment protects RBC from senescence. The protective effect played by 5-HT is not mediated through activation of a classical pharmacological pathway as no 5-HT receptors were detected on isolated RBC. Rather, 5-HT acts as an effective antioxidant since reduction of 5-HT circulating levels are associated with a decrease in the plasma antioxidant capacity. We further demonstrate a link between oxidation and the removal of damaged RBC following transfusion, as supplementation with 5-HT improves RBC post-transfusion survival in a mouse model of blood banking.
    PLoS ONE 12/2013; 8(12):e83010. DOI:10.1371/journal.pone.0083010 · 3.23 Impact Factor
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