title: Potential contribution of mitochondrial DNA damage associated molecular patterns in transfusion products to the development of acute respiratory distress syndrome after multiple transfusions.
abstract: Massive transfusions are accompanied by an increased incidence of a particularly aggressive and lethal form of acute lung injury (delayed transfusion-related acute lung injury) which occurs longer than 24 hours after transfusions. In light of recent reports showing that mitochondrial (mt)DNA damage-associated molecular patterns (DAMPs) are potent proinflammatory mediators, and that their abundance in the sera of severely injured or septic patients is predictive of clinical outcomes, we explored the idea that mtDNA DAMPs are present in transfusion products and are associated with the occurrence of delayed transfusion-related acute lung injury.
  
  
  
  We prospectively enrolled fourteen consecutive severely injured patients that received greater than three units of blood transfusion products and determined if the total amount of mtDNA DAMPs delivered during transfusion correlated with serum mtDNA DAMPs measured after the last transfusion, and whether the quantity of mtDNA DAMPs in the serum-predicted development of acute respiratory distress syndrome (ARDS).
  
  
  
  We found detectable levels of mtDNA DAMPs in packed red blood cells (3 ± 0.4 ng/mL), fresh frozen plasma (213.7 ± 65 ng/mL), and platelets (94.8 ± 69.2), with the latter two transfusion products containing significant amounts of mtDNA fragments. There was a linear relationship between the mtDNA DAMPs given during transfusion and the serum concentration of mtDNA fragments (R = 0.0.74, p < 0.01). The quantity of mtDNA DAMPs in serum measured at 24 hours after transfusion predicted the occurrence of ARDS (9.9 ± 1.4 vs. 3.3 ± 0.9, p < 0.01).
  
  
  
  These data show that fresh frozen plasma and platelets contain large amounts of extracellular mtDNA, that the amount of mtDNA DAMPs administered during transfusion may be a determinant of serum mtDNA DAMP levels, and that serum levels of mtDNA DAMPs after multiple transfusions may predict the development of ARDS. Collectively, these findings support the idea that mtDNA DAMPs in transfusion products significantly contribute to the incidence of ARDS after massive transfusions.
  
  
  
  Prognostic study, level II; therapeutic study, level II.
authors.affiliation: From the Departments of Surgery (J.D.S., Y-L.L.L., M.L.M., S.B.B.) and Pharmacology (J.D.S., V.M.P., G.C., M.N.G.), Center for Lung Biology (J.D.S., V.M.P., G.C., C.A.M., D.C.M., M.N.G.), School of Medicine, University of South Alabama, Mobile, Alabama.
authors.forename: Jon D
authors.initials: JD
authors.lastname: Simmons
authors.forename: Yann-Leei L
authors.initials: YL
authors.lastname: Lee
authors.forename: Viktor M
authors.initials: VM
authors.lastname: Pastukh
authors.forename: Gina
authors.initials: G
authors.lastname: Capley
authors.forename: Cherry A
authors.initials: CA
authors.lastname: Muscat
authors.forename: David C
authors.initials: DC
authors.lastname: Muscat
authors.forename: Michael L
authors.initials: ML
authors.lastname: Marshall
authors.forename: Sidney B
authors.initials: SB
authors.lastname: Brevard
authors.forename: Mark N
authors.initials: MN
authors.lastname: Gillespie
mesh_terms: D000328:Adult; D000067531:Alarmins / Q000009:adverse effects* / Q000097:blood; D001792:Blood Platelets / Q000737:chemistry; D004249:DNA Damage; D004272:DNA, Mitochondrial / Q000097:blood / Q000378:metabolism*; D005260:Female; D006801:Humans; D008297:Male; D010949:Plasma / Q000737:chemistry; D011446:Prospective Studies; D012128:Respiratory Distress Syndrome / Q000209:etiology*; D065227:Transfusion Reaction; D014947:Wounds and Injuries / Q000628:therapy
chemical_list: D000067531:Alarmins; D004272:DNA, Mitochondrial