title: Identified metabolic signature for assessing red blood cell unit quality is associated with endothelial damage markers and clinical outcomes.
abstract: BACKGROUND
  There has been interest in determining whether older red blood cell (RBC) units have negative clinical effects. Numerous observational studies have shown that older RBC units are an independent factor for patient mortality. However, recently published randomized clinical trials have shown no difference of clinical outcome for patients receiving old or fresh RBCs. An overlooked but essential issue in assessing RBC unit quality and ultimately designing the necessary clinical trials is a metric for what constitutes an old or fresh RBC unit.
  
  
  METHODS
  Twenty RBC units were profiled using quantitative metabolomics over 42 days of storage in SAGM with 3- to 4-day time intervals. Metabolic pathway usage during storage was assessed using systems biology methods. The detected time intervals of the metabolic states were compared to clinical outcomes.
  
  
  RESULTS
  Using multivariate statistics, we identified a nonlinear decay process exhibiting three distinct metabolic states (Days 0-10, 10-17, and 17-42). Hematologic variables traditionally measured in the transfusion setting (e.g., pH, hemolysis, RBC indices) did not distinguish these three states. Systemic changes in pathway usage occurred between the three states, with key pathways changing in both magnitude and direction. Finally, an association was found between the time periods of the metabolic states with the clinical outcomes of more than 280,000 patients in the country of Denmark transfused over the past 15 years and endothelial damage markers in healthy volunteers undergoing autologous transfusions.
  
  
  CONCLUSIONS
  The state of RBC metabolism may be a better indicator of cellular quality than traditional hematologic variables.
authors.affiliation: Sinopia Biosciences, San Diego, California.
authors.forename: Aarash
authors.initials: A
authors.lastname: Bordbar
authors.affiliation: Section for Transfusion Medicine, Capital Region Blood Bank, Rigshopitalet, University of Copenhagen, Copenhagen, Denmark.
authors.forename: Pär I
authors.initials: PI
authors.lastname: Johansson
authors.affiliation: Center for Systems Biology, University of Iceland, Reykjavik, Iceland.
authors.forename: Giuseppe
authors.initials: G
authors.lastname: Paglia
authors.affiliation: Novo Nordisk Foundation Center for Biosustainability, Technical University of Denmark, Lyngby, Denmark.
authors.forename: Scott J
authors.initials: SJ
authors.lastname: Harrison
authors.affiliation: Center for Systems Biology, University of Iceland, Reykjavik, Iceland.
authors.forename: Kristine
authors.initials: K
authors.lastname: Wichuk
authors.affiliation: Center for Systems Biology, University of Iceland, Reykjavik, Iceland.
authors.forename: Manuela
authors.initials: M
authors.lastname: Magnusdottir
authors.affiliation: Center for Systems Biology, University of Iceland, Reykjavik, Iceland.
authors.forename: Sóley
authors.initials: S
authors.lastname: Valgeirsdottir
authors.affiliation: Section for Transfusion Medicine, Capital Region Blood Bank, Rigshopitalet, University of Copenhagen, Copenhagen, Denmark.
authors.forename: Mikkel
authors.initials: M
authors.lastname: Gybel-Brask
authors.affiliation: Section for Transfusion Medicine, Capital Region Blood Bank, Rigshopitalet, University of Copenhagen, Copenhagen, Denmark.
authors.forename: Sisse R
authors.initials: SR
authors.lastname: Ostrowski
authors.affiliation: Sinopia Biosciences, San Diego, California.|Center for Systems Biology, University of Iceland, Reykjavik, Iceland.
authors.forename: Sirus
authors.initials: S
authors.lastname: Palsson
authors.affiliation: Center for Systems Biology, University of Iceland, Reykjavik, Iceland.
authors.forename: Ottar
authors.initials: O
authors.lastname: Rolfsson
authors.affiliation: Blood Bank, Landspitali-University Hospital.|School of Science and Engineering, Reykjavik University, Reykjavik, Iceland.
authors.forename: Olafur E
authors.initials: OE
authors.lastname: Sigurjónsson
authors.affiliation: Section for Transfusion Medicine, Capital Region Blood Bank, Rigshopitalet, University of Copenhagen, Copenhagen, Denmark.
authors.forename: Morten B
authors.initials: MB
authors.lastname: Hansen
authors.affiliation: Blood Bank, Landspitali-University Hospital.
authors.forename: Sveinn
authors.initials: S
authors.lastname: Gudmundsson
authors.affiliation: Center for Systems Biology, University of Iceland, Reykjavik, Iceland.
authors.forename: Bernhard O
authors.initials: BO
authors.lastname: Palsson
mesh_terms: D015415:Biomarkers / Q000097:blood / Q000378:metabolism*; D001793:Blood Preservation / Q000379:methods / Q000592:standards; D003718:Denmark; D004730:Endothelium, Vascular / Q000378:metabolism / Q000473:pathology*; D017707:Erythrocyte Transfusion / Q000592:standards*; D004912:Erythrocytes / Q000166:cytology / Q000378:metabolism*; D064368:Healthy Volunteers; D006801:Humans; D007055:Iceland; D008297:Male; D055442:Metabolome; D055432:Metabolomics; D011786:Quality Control; D016896:Treatment Outcome
chemical_list: D015415:Biomarkers