Epidemiological studies show that the transfusion of older stored blood is associated with increases in mortality, serious infections, multi-organ failure, and hospital length of stay. Our research is based on the overarching hypothesis that the adverse effects of the transfusion of stored blood result from the acute delivery of hemoglobin iron to the monocyte-macrophage system. By current FDA standards, a unit of stored red blood cells (RBC) is clinically acceptable for transfusion if as much as 25% of the RBC is cleared within 24 hours, thereby delivering a substantial dose of iron to the monocyte-macrophage system. We hypothesize that the pro-oxidant effects exerted by acute exposure to these massive amounts of hemoglobin iron induce a pro- inflammatory cytokine response that may lead to the serious consequences seen in human studies. Our pre- clinical studies using a well-characterized mouse model demonstrate that the transfusion of older stored RBC acutely delivers hemoglobin iron to the spleen, kidney, and liver, induces an intense pro-inflammatory cytokine response, and synergizes with the effects of endotoxin (a standard sepsis model) to enhance and prolong cytokine storm. Therefore, the main goal of the current proposal is to establish the relevance of these novel pre-clinical observations in humans. To this end, we propose carefully-controlled, prospective studies of healthy volunteers and patients with hemoglobinopathies. We will first study healthy individuals to avoid the confounding factors present in prior studies of critically-ill or surgical patients that examined whether transfusions of older stored RBC produce adverse effects. We will then extend these findings to two relevant human disease settings, by studying stable patients with either sickle cell disease or beta-thalassemia who regularly receive simple transfusions. Because these patients are treated with chronic iron-chelating therapy, which can be safely discontinued for short periods of time, this will allow us to evaluate our novel hypothesis implicating the role of acute iron delivery.
Aim #1 will test the hypothesis that transfusion of older stored RBC into healthy human volunteers induces an acute pro-inflammatory cytokine response.
Aim #2 will test the hypothesis that transfusion of older stored RBC induces an acute pro-inflammatory response in chronically transfused patients with either sickle cell disease or 2-thalassemia. In addition, we will determine whether other standard RBC products often used in this setting (i.e. washed RBC and cryopreserved RBC) induce similar effects. Finally, Aim #3 will test the hypothesis that treating sickle cell disease and 2-thalassemia patients with iron chelators will prevent the acute pro- inflammatory response induced by transfusing older stored RBC. The insights gained from completing this proposal will have an immediate impact on the current practice of transfusion medicine and will provide the foundation for developing rationally-designed approaches to improve the quality of human donor RBC and of human transfusion therapy.

Public Health Relevance

The ultimate goal of this project is to determine whether transfusions of standard, FDA-approved, units of older stored blood induce an acute inflammatory state in healthy human volunteers and in patients with either of two important and common hematological disorders: sickle cell disease and beta-thalassemia. The insights gained from completing this proposal will have an immediate impact on the current practice of blood transfusion and will provide the foundation for developing rationally-designed approaches to improve the quality of human donor blood and of human transfusion therapy.

Agency
National Institute of Health (NIH)
Institute
National Heart, Lung, and Blood Institute (NHLBI)
Type
Research Project (R01)
Project #
5R01HL098014-04
Application #
8298229
Study Section
Special Emphasis Panel (ZHL1-CSR-S (S1))
Program Officer
Welniak, Lisbeth A
Project Start
2009-09-17
Project End
2014-07-31
Budget Start
2012-08-01
Budget End
2014-07-31
Support Year
4
Fiscal Year
2012
Total Cost
$487,733
Indirect Cost
$184,793
Name
Columbia University (N.Y.)
Department
Pathology
Type
Schools of Medicine
DUNS #
621889815
City
New York
State
NY
Country
United States
Zip Code
10032
Wojczyk, Boguslaw S; Kim, Nina; Bandyopadhyay, Sheila et al. (2014) Macrophages clear refrigerator storage-damaged red blood cells and subsequently secrete cytokines in vivo, but not in vitro, in a murine model. Transfusion 54:3186-97
Spitalnik, Steven L (2014) Stored red blood cell transfusions: iron, inflammation, immunity, and infection. Transfusion 54:2365-71
Wagner, Stephen J; Glynn, Simone A; Welniak, Lisbeth A et al. (2014) Research opportunities in optimizing storage of red blood cell products. Transfusion 54:483-94
Francis, Richard O; Jhang, Jeffrey; Hendrickson, Jeanne E et al. (2013) Frequency of glucose-6-phosphate dehydrogenase-deficient red blood cell units in a metropolitan transfusion service. Transfusion 53:606-11
Francis, R O; Jhang, J S; Pham, H P et al. (2013) Glucose-6-phosphate dehydrogenase deficiency in transfusion medicine: the unknown risks. Vox Sang 105:271-82
Jang, Jung-Eun; Hod, Eldad A; Spitalnik, Steven L et al. (2011) CXCL1 and its receptor, CXCR2, mediate murine sickle cell vaso-occlusion during hemolytic transfusion reactions. J Clin Invest 121:1397-401
Brittenham, Gary M (2011) Iron deficiency in whole blood donors. Transfusion 51:458-61
Hod, Eldad A; Spitalnik, Steven L (2011) Harmful effects of transfusion of older stored red blood cells: iron and inflammation. Transfusion 51:881-5