Transfusion of red blood cells after prolonged storage produces harmful effects that are mediated by iron and inflammation
Open accessAbstract
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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The harmful effects of blood transfusion, called storage lesions, are thought to be caused by hemolysis.
“The harmful effects of blood transfusion, called storage lesions, are thought to be caused by hemolysis [25].”
From Free hemoglobin concentration in severe sepsis: methods of measurement and prediction of outcome (2012) · cites this paper as [25]
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Cites
Schreck, R., Albermann, K., & Baeuerle, P. A. (1992) · Free Radical Research Communications · doi:10.3109/10715769209079515 · Cited by 1,411 · see citing works
Duration of Red-Cell Storage and Complications after Cardiac Surgery
Koch, C. G., Li, L., Sessler, D. I., Figueroa, P., Hoeltge, G. A., Mihaljević, T., & Blackstone, E. H. (2008) · New England Journal of Medicine · doi:10.1056/nejmoa070403 · Cited by 1,362 · see citing works
Age of transfused blood is an independent risk factor for postinjury multiple organ failure
Zallen, G. S., Offner, P. J., Moore, E. E., Blackwell, J., Ciesla, D. J., Gabriel, J., Denny, C., & Silliman, C. C. (1999) · The American Journal of Surgery · doi:10.1016/s0002-9610(99)00239-1 · Cited by 515 · see citing works
Volume of blood required to detect common neonatal pathogens
Schelonka, R. L., Chai, M. K., Yoder, B. A., et al. (1996) · The Journal of Pediatrics · doi:10.1016/s0022-3476(96)70254-8 · Cited by 450 · see citing works
Association of mortality with age of blood transfused in septic ICU patients
Purdy, F. R., Tweeddale, M., & Merrick, P. M. (1997) · Canadian Journal of Anesthesia/Journal canadien d anesthésie · doi:10.1007/bf03012772 · Cited by 358 · see citing works
Transfusion of Blood Components and Postoperative Infection in Patients Undergoing Cardiac Surgery
Leal-Noval, S. R., Rincón-Ferrari, M. D., García-Curiel, A., Herruzo-Avilés, Á., Laraña, P. C., Garnacho‐Montero, J., & Amaya‐Villar, R. (2001) · CHEST Journal · doi:10.1378/chest.119.5.1461 · Cited by 348 · see citing works
Increased Rate of Infection Associated With Transfusion of Old Blood After Severe Injury
Offner, P. J. (2002) · Archives of Surgery · doi:10.1001/archsurg.137.6.711 · Cited by 334 · see citing works
The coordination of signaling during Fc receptor-mediated phagocytosis
Swanson, J. A., & Hoppe, A. D. (2004) · Journal of Leukocyte Biology · doi:10.1189/jlb.0804439 · Cited by 326 · see citing works
Iron and infection: the heart of the matter
Bullen, J. J., Rogers, H. J., Spalding, P. B., & Ward, C. G. (2005) · FEMS Immunology & Medical Microbiology · doi:10.1016/j.femsim.2004.11.010 · Cited by 273 · see citing works
Evaluation of proposed FDA criteria for the evaluation of radiolabeled red cell recovery trials
Dumont, L. J., AuBuchon, J. P., & Collaborative, B. E. F. S. T. (. (2008) · Transfusion · doi:10.1111/j.1537-2995.2008.01642.x · Cited by 260 · see citing works
Luten, M., Roerdinkholder‐Stoelwinder, B., Schaap, N. P., DeGrip, W. J., Bos, H. J., & Bosman, G. J. C. G. M. (2008) · Transfusion · doi:10.1111/j.1537-2995.2008.01734.x · Cited by 226 · see citing works
Blood transfusion increases radical promoting non-transferrin bound iron in preterm infants
Hirano, K., Morinobu, T., Kim, H., et al. (2001) · Archives of Disease in Childhood Fetal & Neonatal · doi:10.1136/fn.84.3.f188 · Cited by 181 · see citing works
Nature of non-transferrin-bound iron: studies on iron citrate complexes and thalassemic sera
Evans, R. W., Rafique, R., Zarea, A., Rapisarda, C., Cammack, R., Evans, P., Porter, J. B., & Hider, R. C. (2007) · JBIC Journal of Biological Inorganic Chemistry · doi:10.1007/s00775-007-0297-8 · Cited by 164 · see citing works
Wang, L., Johnson, E. E., Shi, H. N., Walker, W. A., Wessling-Resnick, M., & Cherayil, B. J. (2008) · The Journal of Immunology · doi:10.4049/jimmunol.181.4.2723 · Cited by 159 · see citing works
Debets, J. M. H., van der Linden, J., Dieteren, I. E. M., et al. (1988) · The Journal of Immunology · doi:10.4049/jimmunol.141.4.1197 · Cited by 159 · see citing works
Dissociation of phagocytosis from stimulation of the oxidative metabolic burst in macrophages.
Yamamoto, K., & Johnston, R. B. (1984) · The Journal of Experimental Medicine · doi:10.1084/jem.159.2.405 · Cited by 159 · see citing works
Iron overload following red blood cell transfusion and its impact on disease severity
Ozment, C. P., & Turi, J. L. (2008) · Biochimica et Biophysica Acta (BBA) - General Subjects · doi:10.1016/j.bbagen.2008.09.010 · Cited by 159 · see citing works
Transfusions in the Less Severely Injured: Does Age of Transfused Blood Affect Outcomes?
Weinberg, J. A., McGwin, G., Marques, M. B., Cherry, S. A., Reiff, D. A., Kerby, J. D., & Rue, L. W. (2008) · The Journal of Trauma: Injury, Infection, and Critical Care · doi:10.1097/ta.0b013e318184aa11 · Cited by 153 · see citing works
Regulation of cytokine gene expression by reactive oxygen and reactive nitrogen intermediates
Remick, D. G., & Villarete, L. H. (1996) · Journal of Leukocyte Biology · doi:10.1002/jlb.59.4.471 · Cited by 145 · see citing works
Nature of nontransferrin‐bound iron
Hider, R. C. (2002) · European Journal of Clinical Investigation · doi:10.1046/j.1365-2362.2002.0320s1050.x · Cited by 139 · see citing works
A novel mouse model of red blood cell storage and posttransfusion in vivo survival
Gilson, C. R., Kraus, T. S., Hod, E. A., Hendrickson, J. E., Spitalnik, S. L., Hillyer, C. D., Shaz, B. H., & Zimring, J. C. (2009) · Transfusion · doi:10.1111/j.1537-2995.2009.02173.x · Cited by 121 · see citing works
Self-citationIron primes hepatic macrophages for NF-κB activation in alcoholic liver injury
Tsukamoto, H., Lin, M., Ohata, M., Giulivi, C., French, S. W., & Brittenham, G. M. (1999) · American Journal of Physiology-Gastrointestinal and Liver Physiology · doi:10.1152/ajpgi.1999.277.6.g1240 · Cited by 121 · see citing works
Self-citationLoss of red cell chemokine scavenging promotes transfusion-related lung inflammation
Mangalmurti, N. S., Xiong, Z., Hulver, M., Ranganathan, M., Liu, X. H., Oriss, T. B., Fitzpatrick, M. E., Rubin, M. A., Triulzi, D. J., Choi, A. M. K., et al. (2008) · Blood · doi:10.1182/blood-2008-07-166264 · Cited by 110 · see citing works
FACTORS INFLUENCING HOST RESISTANCE TO SALMONELLA INFECTIONS
Kaye, D., Gill, F. A., & Hook, E. W. (1967) · The American Journal of the Medical Sciences · doi:10.1097/00000441-196708000-00011 · Cited by 100 · see citing works
Moore, G. L., Ledford, M. E., & Merydith, A. (1981) · Biochemical Medicine · doi:10.1016/0006-2944(81)90043-0 · Cited by 100 · see citing works
Zhang, N., Ahsan, M. H., Purchio, A. F., & West, D. B. (2005) · The Journal of Immunology · doi:10.4049/jimmunol.174.12.8125 · Cited by 96 · see citing works
Self-citationUniformity of liver density and nonheme (storage) iron distribution.
Overmoyer, B. A., McLaren, C. E., & Brittenham, G. (1987) · PubMed · Cited by 82 · see citing works
Self-citationGordeuk, V., Ballou, S. P., Lozanski, G., & Brittenham, G. (1992) · Blood · doi:10.1182/blood.v79.7.1855.1855 · Cited by 74 · see citing works
Self-citationThe Influence of Hemolysis or Blood Loss on Susceptibility to Infection
Kaye, D., & Hook, E. W. (1963) · The Journal of Immunology · doi:10.4049/jimmunol.91.1.65 · Cited by 68 · see citing works
von Bonsdorff, L., Sahlstedt, L., Ebeling, F. T., Ruutu, T., & Parkkinen, J. (2003) · FEMS Immunology & Medical Microbiology · doi:10.1016/s0928-8244(03)00109-3 · Cited by 57 · see citing works
Cytokine storm in a mouse model of IgG-mediated hemolytic transfusion reactions
Hod, E. A., Cadwell, C. M., Liepkalns, J. S., Zimring, J. C., Sokol, S. A., Schirmer, D. A., Jhang, J. S., & Spitalnik, S. L. (2008) · Blood · doi:10.1182/blood-2008-01-132092 · Cited by 55 · see citing works
Self-citationVandromme, M. J., McGwin, G., Marques, M. B., Kerby, J. D., Rue, L. W., & Weinberg, J. A. (2009) · The Journal of Trauma: Injury, Infection, and Critical Care · doi:10.1097/ta.0b013e3181a5a8f9 · Cited by 54 · see citing works
Hershko, C. (2007) · Food and Nutrition Bulletin · doi:10.1177/15648265070284s403 · Cited by 54 · see citing works
Deferoxamine reduces tissue injury and lethality in LPS-treated mice
Vulcano, M., Meiss, R. P., & Isturiz, M. A. (2000) · International Journal of Immunopharmacology · doi:10.1016/s0192-0561(00)00026-6 · Cited by 48 · see citing works
An improved simple colorimetric method for quantitation of non-transferrin-bound iron in serum.
Zhang, D., Okada, S., Kawabata, T., & Yasuda, T. (1995) · PubMed · Cited by 47 · see citing works
Neupane, G. P., & Kim, D. (2009) · Transfusion · doi:10.1111/j.1537-2995.2009.02186.x · Cited by 42 · see citing works
Pai, A. B., Pai, M. P., Depczynski, J., McQuade, C. R., & Mercier, R.-C. (2006) · American Journal of Nephrology · doi:10.1159/000094343 · Cited by 39 · see citing works
Rao, G. H. R., Cox, A. C., Gerrard, J. M., & White, J. G. (1980) · Biochimica et Biophysica Acta (BBA) - General Subjects · doi:10.1016/0304-4165(80)90395-5 · Cited by 31 · see citing works
An Improved Simple Colorimetric Method for Quantitation of Non-Transferrin-Bound Iron in Serum
張, 大. (1995) · Institutional Repositories DataBase (IRDB) · doi:10.11501/3106550 · Cited by 29 · see citing works
Flow-Cytometric Determination of Survival Time and 24-Hour Recovery of Transfused Red Blood Cells
Zeiler, T. A., Müller, J. T., & Kretschmer, V. (2003) · Transfusion Medicine and Hemotherapy · doi:10.1159/000069340 · Cited by 19 · see citing works
Non‐Transferrin‐Bound Iron during Blood Transfusion Cycles in β‐Thalassemia Major
Grosse, R., Lund, U., Caruso, V., et al. (2005) · Annals of the New York Academy of Sciences · doi:10.1196/annals.1345.074 · Cited by 8 · see citing works
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On-demand erythrocyte disposal and iron recycling requires transient macrophages in the liver
Theurl, I., Hilgendorf, I., Nairz, M., Tymoszuk, P., Haschka, D., Asshoff, M., He, S., Gerhardt, L. M. S., Holderried, T. A. W., Seifert, M., et al. (2016) · Nature Medicine · doi:10.1038/nm.4146 · Cited by 412 · see citing works
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Hayden, S. J., Albert, T. J., Watkins, T. R., & Swenson, E. R. (2012) · American Journal of Respiratory and Critical Care Medicine · doi:10.1164/rccm.201110-1915ci · Cited by 271 · see citing works
Baek, J. H., D’Agnillo, F., Vallelian, F., Pereira, C. P., Williams, M. C., Jia, Y., Schaer, D. J., & Buehler, P. W. (2012) · Journal of Clinical Investigation · doi:10.1172/jci59770 · Cited by 280 · see citing works
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Gladwin, M. T., Kanias, T., & Kim-Shapiro, D. B. (2012) · Journal of Clinical Investigation · doi:10.1172/jci62972 · Cited by 196 · see citing works
Youssef, L. A., Rebbaa, A., Pampou, S., Weisberg, S. P., Stockwell, B. R., Hod, E. A., & Spitalnik, S. L. (2018) · Blood · doi:10.1182/blood-2017-12-822619 · Cited by 186 · see citing works
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Adamzik, M., Hamburger, T., Petrat, F., Peters, J., de Groot, H., & Hartmann, M. (2012) · Critical Care · doi:10.1186/cc11425 · Cited by 137 · see citing works
“The harmful effects of blood transfusion, called storage lesions, are thought to be caused by hemolysis [25].”
BackgroundSchaer, D. J., & Buehler, P. W. (2013) · Cold Spring Harbor Perspectives in Medicine · doi:10.1101/cshperspect.a013433 · Cited by 96 · see citing works
A Perspective on the Role of Extracellular Hemoglobin on the Innate Immune System
Lee, S. K., & Ding, J. L. (2013) · DNA and Cell Biology · doi:10.1089/dna.2012.1897 · Cited by 52 · see citing works
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Remy, K. E., Cortés-Puch, I., Solomon, S. B., Sun, J., Pockros, B. M., Feng, J., Lertora, J. J., Hantgan, R. R., Liu, X., Perlegas, A., et al. (2018) · JCI Insight · doi:10.1172/jci.insight.123013 · Cited by 49 · see citing works
Labile plasma iron levels predict survival in patients with lower-risk myelodysplastic syndromes
de Swart, L., Reiniers, C., Bagguley, T., van Marrewijk, C., Bowen, D., Hellström-Lindberg, E., Tatic, A., Symeonidis, A., Huls, G., Cermak, J., et al. (2018) · Haematologica · doi:10.3324/haematol.2017.171884 · Cited by 48 · see citing works
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- Authors
- Hod, E. A., Zhang, N., Sokol, S. A., Wojczyk, B. S., Francis, R. O., Ansaldi, D., Francis, K. P., Della-Latta, P., Whittier, S., Sheth, S., Hendrickson, J. E., Zimring, J. C., Brittenham, G. M., & Spitalnik, S. L.
- Affiliations
- New York Blood Center (US)
- Caliper Life Sciences, Alameda, CA;
- Columbia University (US)
- Department of Pathology and Cell Biology, Columbia University College of Physicians and Surgeons, New York, NY;
- Columbia University Irving Medical Center (US)
- Emory University (US)
- ORCID
- Venue
- Blood
- Publisher
- American Society of Hematology
- Published
- 2010-05-27
- Volume
- 115
- Issue
- 21
- Pages
- 4284-4292
- ISSN
- 0006-4971 (ISSN-L)
- 1528-0020
- PMC
- PMC2879099
- OpenAlex
- W1967872106
- Cited by
- 485
- References
- 41
- Citations by year
- 2026: 11 · 2025: 19 · 2024: 16 · 2023: 14 · 2022: 29 · 2021: 28 · 2020: 22 · 2019: 44 · 2018: 31 · 2017: 48 · 2016: 47 · 2015: 37 · 2014: 45 · 2013: 32 · 2012: 36
- FWCI
- 19.02
- Type
- journal article
- Language
- en
- Open access
- bronze
- doi.org
- Locations
- Blood (publishedVersion)
- PubMed Central (publishedVersion)
- PubMed (publishedVersion)
- Funders
- National Institutes of Health
- National Heart, Lung, and Blood Institute (R21HL089164, R21HL087906, K08HL092959)
- National Institute of Diabetes and Digestive and Kidney Diseases (DK069373, R01DK066251, R37DK049108, R01DK069373)
- Topics
- Health Sciences › Medicine › Biochemistry › Blood transfusion and management
- Health Sciences › Medicine › Critical Care and Intensive Care Medicine › Trauma, Hemostasis, Coagulopathy, Resuscitation
- Health Sciences › Medicine › Hematology › Iron Metabolism and Disorders
- Keywords
- red blood cell transfusion, stored red blood cells, transfusion-related acute lung injury, non-transferrin-bound iron, inflammation, monocyte-macrophage system, endotoxemia, bacterial growth, leukoreduced red blood cells, erythrocyte ghosts, transfusion reactions
- MeSH terms
- Acute-Phase Reaction, Animals, Blood Preservation, Deferoxamine, Disease Models, Animal, Endotoxins, Erythrocyte Aging, Escherichia coli Infections, Hemoglobins, Humans, Inflammation, Iron, Iron Chelating Agents, Kidney, Liver, Male, Mice, Inbred C57BL, Mice, Transgenic, Models, Biological, Spleen, Time Factors, Erythrocyte Transfusion, Inflammation Mediators, Endotoxemia, Mice
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