To the Editor:—  We read with interest the study of Atzil et al.  1on the deleterious effect of storage of erythrocytes on cancer progression in two tumor rat models. Using different transfusion products, the impact of erythrocytes, leukocytes, and leukocyte-derived soluble factors on host ability to clear circulating cancer cells and host survival rates was assessed. Blood transfusion was found to be an independent risk factor for cancer progression. Surprisingly, aged erythrocytes (9 days and older), rather than leukocytes or soluble factors, mediated the effects. The authors hypothesized that aged erythrocytes may preoccupy host-innate immune effector cells, leaving tumor cells unattended.

Besides cancer progression, other adverse effects of blood transfusion may also be influenced by storage time of erythrocytes. Transfusion of nonleucoreduced aged erythrocytes was found to be associated with an increase in postoperative infectious complications.2,3To date, the mechanism of this phenomenon is not clear. A role for leukocytes and/or soluble factors in the stored blood products has been suggested. The results of the present study may suggest another mechanism of blood transfusion–related infections. It could be hypothesized that patients transfused with aged erythrocytes may develop a disturbed host immune defense, either via  suppression of the interaction of host immune cells with bacteria, or via  suppression of cytokine secretion, which may result in a vulnerability to develop pneumonia or other infections. If erythrocytes indeed play a role, this may explain why studies comparing leucoreduced with nonleucoreduced red blood cell transfusions showed no effect on the incidence of infectious complications.4 

Besides infectious complications, transfusion of outdated erythrocytes is associated with the onset of acute lung injury,2,5which may be mediated by biologically active lipids and/or cytokines that accumulate during storage of blood products.6,7In our laboratory, we performed preliminary experiments with transfusion of healthy rats with stored erythrocytes from the same animal species. Stored erythrocytes resulted in respiratory symptoms and worsening of the condition of the animals, suggestive of acute lung injury. Did the authors of the article under discussion notice any respiratory failure in the animals transfused with stored erythrocytes, as compared with controls transfused with fresh erythrocytes or saline, before the inoculation of the cancer cells?

In conclusion, the authors have pointed to aged erythrocytes as mediators of cancer progression, raising questions about potential other effects of storage of erythrocytes on host immune response. We would like to call for further experimental and clinical studies assessing the role of aged erythrocytes in transfusion-related infectious complications and on transfusion-related acute lung injury.

*Academic Medical Center, Amsterdam, The Netherlands.

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Koch CG, Li L, Sessler DI, Figueroa P, Hoeltge GA, Mihaljevic T, Blackstone EH: Duration of red-cell storage and complications after cardiac surgery. N Engl J Med 2008; 358:1229–39
Leal-Noval SR, Jara-Lopez I, Garcia-Garmendia JL, Marin-Niebla A, Herruzo-Aviles A, Camacho-Larana P, Loscertales J: Influence of erythrocyte concentrate storage time on postsurgical morbidity in cardiac surgery patients. Anesthesiology 2003; 98:815–22
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Gajic O, Rana R, Winters JL, Yilmaz M, Mendez JL, Rickman OB, O'Byrne MM, Evenson LK, Malinchoc M, DeGoey SR, Afessa B, Hubmayr RD, Moore SB: Transfusion-related acute lung injury in the critically ill: Prospective nested case-control study. Am J Respir Crit Care Med 2007; 176:886–91
Silliman CC, Clay KL, Thurman GW, Johnson CA, Ambruso DR: Partial characterization of lipids that develop during the routine storage of blood and prime the neutrophil NADPH oxidase. J Lab Clin Med 1994; 124:684–94
Silliman CC, Voelkel NF, Allard JD, Elzi DJ, Tuder RM, Johnson JL, Ambruso DR: Plasma and lipids from stored packed red blood cells cause acute lung injury in an animal model. J Clin Invest 1998; 101:1458–67