title: Pathogen inactivation by riboflavin and ultraviolet light illumination accelerates the red blood cell storage lesion and promotes eryptosis.
abstract: Pathogen reduction treatment using riboflavin and ultraviolet light illumination (Mirasol) effectively reduces the risk of transfusion-transmitted infections. This treatment is currently licensed for only platelets and plasma products, while its application to whole blood (WB) to generate pathogen-inactivated red blood cells (RBCs) is under development. RBC storage lesion, constituting numerous morphologic and biochemical changes, influences RBC quality and limits shelf life. Stored RBCs further show enhanced susceptibility to RBC programmed cell death (eryptosis) characterized by increased cytosolic Ca2+-provoked membrane phosphatidylserine (PS) externalization.
  
  
  
  Using a "pool-and-split" approach, we examined multiple variables of RBC storage lesion and eryptosis in RBC units, derived from Mirasol-treated or untreated WB, after 4 to 42 days of storage, under blood bank conditions.
  
  
  
  In comparison to untreated RBC units, Mirasol treatment significantly altered membrane microvesiculation, supernatant hemoglobin, osmotic fragility, and intracellular adenosine triphosphate levels but did not influence membrane CD47 expression and 2,3-diphosphoglycerate levels. Mirasol-treated RBCs showed significantly higher PS exposure after 42, but not after not more than 21, days of storage, which was accompanied by enhanced cytosolic Ca2+activity, ceramide abundance, and oxidative stress, but not p38 kinase activation. Mirasol treatment significantly augmented PS exposure, Ca2+entry, and protein kinase C activation after energy depletion, a pathophysiologic cell stressor. Mirasol-treated RBCs were, however, more resistant to cell shrinkage.
  
  
  
  Prolonged storage of Mirasol-treated RBCs significantly increases the proportion of eryptotic RBCs, while even short-term storage enhances the susceptibility of RBCs to stress-induced eryptosis, which could reduce posttransfusion RBC recovery in patients.
authors.affiliation: Centre for Innovation, Canadian Blood Services, McMaster University, Hamilton, Ontario, Canada.|Department of Pathology and Molecular Medicine, McMaster University, Hamilton, Ontario, Canada.
authors.forename: Syed M
authors.initials: SM
authors.lastname: Qadri
authors.affiliation: Centre for Innovation, Canadian Blood Services, University of British Columbia, Vancouver, British Columbia, Canada.|Centre for Blood Research, University of British Columbia, Vancouver, British Columbia, Canada.|Department of Pathology and Laboratory Medicine, University of British Columbia, Vancouver, British Columbia, Canada.
authors.forename: Deborah
authors.initials: D
authors.lastname: Chen
authors.affiliation: Centre for Innovation, Canadian Blood Services, University of British Columbia, Vancouver, British Columbia, Canada.|Centre for Blood Research, University of British Columbia, Vancouver, British Columbia, Canada.|Department of Pathology and Laboratory Medicine, University of British Columbia, Vancouver, British Columbia, Canada.
authors.forename: Peter
authors.initials: P
authors.lastname: Schubert
authors.affiliation: Department of Pathology and Molecular Medicine, McMaster University, Hamilton, Ontario, Canada.
authors.forename: Darian L
authors.initials: DL
authors.lastname: Perruzza
authors.affiliation: Centre for Innovation, Canadian Blood Services, McMaster University, Hamilton, Ontario, Canada.
authors.forename: Varsha
authors.initials: V
authors.lastname: Bhakta
authors.affiliation: Centre for Innovation, Canadian Blood Services, University of British Columbia, Vancouver, British Columbia, Canada.|Centre for Blood Research, University of British Columbia, Vancouver, British Columbia, Canada.|Department of Pathology and Laboratory Medicine, University of British Columbia, Vancouver, British Columbia, Canada.
authors.forename: Dana V
authors.initials: DV
authors.lastname: Devine
authors.affiliation: Centre for Innovation, Canadian Blood Services, McMaster University, Hamilton, Ontario, Canada.|Department of Pathology and Molecular Medicine, McMaster University, Hamilton, Ontario, Canada.
authors.forename: William P
authors.initials: WP
authors.lastname: Sheffield
mesh_terms: D001793:Blood Preservation; D004203:Disinfection; D000072817:Eryptosis / Q000187:drug effects / Q000528:radiation effects; D004912:Erythrocytes / Q000378:metabolism* / Q000473:pathology; D005260:Female; D006801:Humans; D008297:Male; D012256:Riboflavin / Q000009:adverse effects / Q000494:pharmacology; D013997:Time Factors; D014466:Ultraviolet Rays / Q000009:adverse effects*
chemical_list: D012256:Riboflavin