title: Riboflavin and ultraviolet light treatment of platelets triggers p38MAPK signaling: inhibition significantly improves in vitro platelet quality after pathogen reduction treatment.
abstract: BACKGROUND
  Pathogen reduction technologies (PRTs) significantly reduce the risk of transmission of infectious agents in platelet (PLT) concentrates; however, in vitro studies reveal a negative impact on PLT quality after PRT treatment including effects on PLT aggregation, integrin αIIbβ3 conformation, and actin dynamics. Clinically, the interval between transfusions is shortened.
  
  
  METHODS
  Seeking to understand the biochemical mechanisms underlying these observed effects, we analyzed signal transduction in PLT concentrates after riboflavin and ultraviolet light (UV; Mirasol) treatment and subsequent storage focusing on the phosphorylation levels of selected protein kinases.
  
  
  RESULTS
  Among identified candidates, p38MAPK increased fourfold in phosphorylation after PRT. Incubation of PLT concentrates with a p38MAPK-specific inhibitor before PRT significantly improved numerous PLT quality measures. Phosphorylation levels of the p38MAPK substrates AKT, VASP, and HSP27 also decreased with inhibitor treatment. Phospho-HSP27 decrease in the presence of the inhibitor correlated with a reduction in PLT activation determined by surface expression of P-selectin.
  
  
  CONCLUSIONS
  These findings support a model of one dominant underlying molecular signaling mechanism that is impacted by the riboflavin and UV (Mirasol) PRT process resulting in alterations in PLT quality. The identification of such a target should assist in the development of strategies to ameliorate this negative aspect of an otherwise beneficial and important safety development for transfusion medicine.
authors.affiliation: Canadian Blood Services, Vancouver, BC, Canada; Centre for Blood Research, University of British Columbia, Vancouver, BC, Canada; Department of Pathology and Laboratory Medicine, University of British Columbia, Vancouver, BC, Canada; Terumo BCT Biotechnologies, Lakewood, Colorado.
authors.forename: Peter
authors.initials: P
authors.lastname: Schubert
authors.forename: Danielle
authors.initials: D
authors.lastname: Coupland
authors.forename: Brankica
authors.initials: B
authors.lastname: Culibrk
authors.forename: Raymond P
authors.initials: RP
authors.lastname: Goodrich
authors.forename: Dana V
authors.initials: DV
authors.lastname: Devine
mesh_terms: D001792:Blood Platelets / Q000187:drug effects* / Q000378:metabolism / Q000528:radiation effects*; D006801:Humans; D017713:Platelet Transfusion; D012256:Riboflavin / Q000494:pharmacology*; D015398:Signal Transduction / Q000187:drug effects; D014466:Ultraviolet Rays; D048051:p38 Mitogen-Activated Protein Kinases / Q000378:metabolism*
chemical_list: D048051:p38 Mitogen-Activated Protein Kinases; D012256:Riboflavin