Gregory M. Vercellotti, MD
Dr. Vercellotti indicated no relevant conflicts of interest.
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. Blood. 2010;115:4284-4292.
Red blood cell (RBC) transfusions are lifesaving procedures for severe blood loss, but needless transfusions performed on anemic euvolemic patients may be detrimental. Clinical trials restricting transfusions improved clinical outcomes in acutely ill individuals.1 Prolonged storage of RBCs (> 14-21 days before transfusion) increases mortality, infections, inflammation, and multi-organ failure.2,3 The proposed mechanisms linking RBC storage duration to adverse clinical consequences include impaired ability to deliver oxygen and stimulation of pro-inflammatory pathways.4 The former may be attributed to storage-mediated changes in RBC metabolites (such as 2,3-DPG), ATP depletion, or hemolysis, while the latter may be due to activation of cytokines, coagulation, or cells (including white blood cells [WBCs], platelets, and endothelial cells). Pathophysiologically, prolonged RBC storage may promote RBC microparticle formation, altered membrane phospholipids, impaired clearance, free hemoglobin release with subsequent scavenging of nitric oxide (NO), release of free iron, and oxidative stress. Hod et al. from Steven Spitalnik’s laboratory at Columbia College of Physicians and Surgeons in New York demonstrated that “tired” stored red cells are rapidly cleared by the monocyte/macrophage system and deliver an excess iron load that can activate cytokine production and enhance proliferation of certain bacterial pathogens.
In these experiments, murine leuko-reduced RBCs, fresh or stored for 14 days, were transfused into normal recipients. Sixteen percent of the stored RBCs were rapidly (< 2 hours) cleared by the spleen. The fate of hemoglobin iron was compared in mice infused with fresh RBCs, stored RBCs, washed stored RBCs, supernatants from stored RBCs, or RBC ghosts derived from stored RBCs. Only stored and washed stored RBCs increased plasma nontransferrin-bound iron (NTBI) two hours after infusion. Twenty-four hours later NTBI levels returned to baseline. Macrophages in the liver and spleen were responsible for clearing the stored RBCs. Only stored RBCs, but not ghosts or hemoglobin containing RBC lysates, induced elevated plasma cytokine levels. Transfusions using stored RBCs induced an acute-phase inflammatory response and exacerbated inflammation induced by endotoxin. Plasma from these animals promoted the growth of E.Coli in vitro. Remarkably, iron-chelators desferoxmine (DFO) or iron-laden feroxamine (FO) partially ameliorated the inflammatory response.
Obviously, the study invokes more questions than answers. It is fascinating that something essential in the stored RBCs caused enhanced clearance of these cells by monocyte/macrophages with rapid breakdown of heme iron with release into the plasma. What caused these cells to be so rapidly eliminated? Was there oxidative damage to the RBC membrane? Was deformability affected by DPG and ATP depletion? Did phospholipid vesiculation, excessive membrane phosphatidylserine expression, loss of complement/cytokine clearance, enhanced “senescence” antigen expression, Band-3 modifications, or altered interaction with microvascular endothelium play a role? Why was iron so rapidly released? Was heme oxygenase-1 not fully upregulated? Was apo-ferritin not available to store the iron? Were haptoglobin, hemopexin, and transferrin overwhelmed? If NO is pivotal in the adverse outcomes of stored blood, why didn’t hemoglobin lysate induce the cytokine response? Why did both DFO and FO modulate the cytokine response?
Blood is precious, and as hematologists we must not allow colleagues to inappropriately transfuse patients. But, how can we expand the blood supply by allowing safe prolonged storage? Would adding anti-oxidants or iron chelators help? Years ago an advertisement for an iron tonic promised to be an antidote for “tired blood.” Today, we need prospective human studies to further clarify whether stored “tired” RBCs could be rejuvenated and not deliver toxic iron.
- Koch CG, Li L, Sessler DI, et al. Duration of red-cell storage and complications after cardiac surgery. N Engl J Med. 2008;358:1229-1239.
- Gauvin F, Spinella PC, Lacroix J, et al. Association between length of storage of transfused red blood cells and multiple organ dysfunction syndrome in pediatric intensive care patients. Transfusion. 2010. [Epub ahead of print]
- Tinmouth A, Fergusson D, Yee IC, et al. Clinical consequences of red cell storage in the critically ill. Transfusion. 2006;46:2014-2027.
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