Strain-specific red blood cell storage, metabolism, and eicosanoid generation in a mouse model

Authors

  • James C. Zimring,

    Corresponding author
    1. Puget Sound Blood Center Research Institute, Seattle, Washington
    2. Department of Pathology and Laboratory Medicine, Center for Transfusion and Cellular Therapies, Department of Pediatrics, Aflac Cancer and Blood Disorders Center, Emory University School of Medicine, Atlanta, Georgia
    3. Metabolon, Inc., Research Triangle Park, North Carolina
    4. Laboratory of Transfusion Biology, Department of Pathology and Cell Biology, Columbia University Medical Center–New York Presbyterian Hospital, New York, New York
    5. Department of Medicine, University of Washington, Seattle, Washington
    • Address reprint requests to: James C. Zimring, MD, PhD, Puget Sound Blood Center Research Institute, 1551 Eastlake Avenue East, Seattle, WA 98102; e-mail: jzimring@psbc.org.

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  • Nicole Smith,

    1. Puget Sound Blood Center Research Institute, Seattle, Washington
    2. Department of Pathology and Laboratory Medicine, Center for Transfusion and Cellular Therapies, Department of Pediatrics, Aflac Cancer and Blood Disorders Center, Emory University School of Medicine, Atlanta, Georgia
    3. Metabolon, Inc., Research Triangle Park, North Carolina
    4. Laboratory of Transfusion Biology, Department of Pathology and Cell Biology, Columbia University Medical Center–New York Presbyterian Hospital, New York, New York
    5. Department of Medicine, University of Washington, Seattle, Washington
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  • Sean R. Stowell,

    1. Puget Sound Blood Center Research Institute, Seattle, Washington
    2. Department of Pathology and Laboratory Medicine, Center for Transfusion and Cellular Therapies, Department of Pediatrics, Aflac Cancer and Blood Disorders Center, Emory University School of Medicine, Atlanta, Georgia
    3. Metabolon, Inc., Research Triangle Park, North Carolina
    4. Laboratory of Transfusion Biology, Department of Pathology and Cell Biology, Columbia University Medical Center–New York Presbyterian Hospital, New York, New York
    5. Department of Medicine, University of Washington, Seattle, Washington
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  • Jill M. Johnsen,

    1. Puget Sound Blood Center Research Institute, Seattle, Washington
    2. Department of Pathology and Laboratory Medicine, Center for Transfusion and Cellular Therapies, Department of Pediatrics, Aflac Cancer and Blood Disorders Center, Emory University School of Medicine, Atlanta, Georgia
    3. Metabolon, Inc., Research Triangle Park, North Carolina
    4. Laboratory of Transfusion Biology, Department of Pathology and Cell Biology, Columbia University Medical Center–New York Presbyterian Hospital, New York, New York
    5. Department of Medicine, University of Washington, Seattle, Washington
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  • Lauren N. Bell,

    1. Puget Sound Blood Center Research Institute, Seattle, Washington
    2. Department of Pathology and Laboratory Medicine, Center for Transfusion and Cellular Therapies, Department of Pediatrics, Aflac Cancer and Blood Disorders Center, Emory University School of Medicine, Atlanta, Georgia
    3. Metabolon, Inc., Research Triangle Park, North Carolina
    4. Laboratory of Transfusion Biology, Department of Pathology and Cell Biology, Columbia University Medical Center–New York Presbyterian Hospital, New York, New York
    5. Department of Medicine, University of Washington, Seattle, Washington
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  • Richard O. Francis,

    1. Puget Sound Blood Center Research Institute, Seattle, Washington
    2. Department of Pathology and Laboratory Medicine, Center for Transfusion and Cellular Therapies, Department of Pediatrics, Aflac Cancer and Blood Disorders Center, Emory University School of Medicine, Atlanta, Georgia
    3. Metabolon, Inc., Research Triangle Park, North Carolina
    4. Laboratory of Transfusion Biology, Department of Pathology and Cell Biology, Columbia University Medical Center–New York Presbyterian Hospital, New York, New York
    5. Department of Medicine, University of Washington, Seattle, Washington
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  • Eldad A. Hod,

    1. Puget Sound Blood Center Research Institute, Seattle, Washington
    2. Department of Pathology and Laboratory Medicine, Center for Transfusion and Cellular Therapies, Department of Pediatrics, Aflac Cancer and Blood Disorders Center, Emory University School of Medicine, Atlanta, Georgia
    3. Metabolon, Inc., Research Triangle Park, North Carolina
    4. Laboratory of Transfusion Biology, Department of Pathology and Cell Biology, Columbia University Medical Center–New York Presbyterian Hospital, New York, New York
    5. Department of Medicine, University of Washington, Seattle, Washington
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  • Jeanne E. Hendrickson,

    1. Puget Sound Blood Center Research Institute, Seattle, Washington
    2. Department of Pathology and Laboratory Medicine, Center for Transfusion and Cellular Therapies, Department of Pediatrics, Aflac Cancer and Blood Disorders Center, Emory University School of Medicine, Atlanta, Georgia
    3. Metabolon, Inc., Research Triangle Park, North Carolina
    4. Laboratory of Transfusion Biology, Department of Pathology and Cell Biology, Columbia University Medical Center–New York Presbyterian Hospital, New York, New York
    5. Department of Medicine, University of Washington, Seattle, Washington
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  • John D. Roback,

    1. Puget Sound Blood Center Research Institute, Seattle, Washington
    2. Department of Pathology and Laboratory Medicine, Center for Transfusion and Cellular Therapies, Department of Pediatrics, Aflac Cancer and Blood Disorders Center, Emory University School of Medicine, Atlanta, Georgia
    3. Metabolon, Inc., Research Triangle Park, North Carolina
    4. Laboratory of Transfusion Biology, Department of Pathology and Cell Biology, Columbia University Medical Center–New York Presbyterian Hospital, New York, New York
    5. Department of Medicine, University of Washington, Seattle, Washington
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  • Steven L. Spitalnik

    1. Puget Sound Blood Center Research Institute, Seattle, Washington
    2. Department of Pathology and Laboratory Medicine, Center for Transfusion and Cellular Therapies, Department of Pediatrics, Aflac Cancer and Blood Disorders Center, Emory University School of Medicine, Atlanta, Georgia
    3. Metabolon, Inc., Research Triangle Park, North Carolina
    4. Laboratory of Transfusion Biology, Department of Pathology and Cell Biology, Columbia University Medical Center–New York Presbyterian Hospital, New York, New York
    5. Department of Medicine, University of Washington, Seattle, Washington
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  • These studies were funded in part by NIH R01 HL092977.

Abstract

Background

Red blood cell (RBC) transfusion is a lifesaving therapy, the logistic implementation of which requires RBC storage. However, stored RBCs exhibit substantial donor variability in multiple characteristics, including hemolysis in vitro and RBC recovery in vivo. The basis of donor variability is poorly understood.

Study Design and Methods

We applied a murine model of RBC storage and transfusion to test the hypothesis that genetically distinct inbred strains of mice would demonstrate strain-specific differences in RBC storage. In vivo recoveries were determined by monitoring transfused RBCs over 24 hours. Timed aliquots of stored RBCs were subjected to tandem chromatography/mass spectrometry analysis to elucidate metabolic changes in the RBCs during storage.

Results

Using independent inbred mouse strains as donors, we found substantial strain-specific differences in posttransfusion RBC recovery in vivo after standardized refrigerated storage in vitro. Poor posttransfusion RBC recovery correlated with reproducible metabolic variations in the stored RBC units, including increased lipid peroxidation, decreased levels of multiple natural antioxidants, and accumulation of cytidine. Strain-dependent differences were also observed in eicosanoid generation (i.e., prostaglandins and leukotrienes).

Conclusion

These findings provide the first evidence of strain-specific metabolomic differences after refrigerated storage of murine RBCs. They also provide the first definitive biochemical evidence for strain-specific variation of eicosanoid generation during RBC storage. The molecules described that correlate with RBC storage quality, and their associated biochemical pathways, suggest multiple causal hypotheses that can be tested regarding predicting the quality of RBC units before transfusion and developing methods of improved RBC storage.

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