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
ABSTRACT 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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- "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. "
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 · 4.96 Impact Factor
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- "Alternatively, the low circulation rate might be caused by injury to imERYPCs in vitro, which would then be removed from the body within 2 hr after transfusion (Hod et al., 2010). To test that possibility, human PB-RBCs (100% enucleated) and carboxyfluorescein succinimidyl ester (CSFE)-labeled imERYPCs (>99% nucleated) were simultaneously infused intraperitoneally to clodronate-pretreated NOG mice, after which the chimerism was examined (Figure S4B). "
ABSTRACT: The lack of knowledge about the mechanism of erythrocyte biogenesis through self-replication makes the in vitro generation of large quantities of cells difficult. We show that transduction of c-MYC and BCL-XL into multipotent hematopoietic progenitor cells derived from pluripotent stem cells and gene overexpression enable sustained exponential self-replication of glycophorin A(+) erythroblasts, which we term immortalized erythrocyte progenitor cells (imERYPCs). In an inducible expression system, turning off the overexpression of c-MYC and BCL-XL enabled imERYPCs to mature with chromatin condensation and reduced cell size, hemoglobin synthesis, downregulation of GCN5, upregulation of GATA1, and endogenous BCL-XL and RAF1, all of which appeared to recapitulate normal erythropoiesis. imERYPCs mostly displayed fetal-type hemoglobin and normal oxygen dissociation in vitro and circulation in immunodeficient mice following transfusion. Using critical factors to induce imERYPCs provides a model of erythrocyte biogenesis that could potentially contribute to a stable supply of erythrocytes for donor-independent transfusion.Stem Cell Reports 12/2013; 1(6):499-508. DOI:10.1016/j.stemcr.2013.10.010 · 5.64 Impact Factor
- " . , 2008 ) and endothelial cell malfunction in coronary artery disease ( Duffy SJ et al . , 2001 ) in human subjects . Recent studies have shown that NTBI increases acutely in sickle cell patients in crisis ( Gladwin MT et al . , 2004 ) , and following transfusion of red blood cells that have undergone prolonged storage ( Ozment and Turi , 2009 ; Hod et al . , 2010 ) . The supernatant of aged red blood cells has also been shown to cause lung inflammation ( Vlaar et al . 2010 ) . Previous work has revealed a role for chelatable iron in mediating oxidative ( Sanders SP et al . , 1993 ) and nitrosative ( Yee EL , et al . , 1996 ) stress in pulmonary endothelium and other cell types ( Kalyanaraman B ,"