title: Hemoglobin-driven pathophysiology is an in vivo consequence of the red blood cell storage lesion that can be attenuated in guinea pigs by haptoglobin therapy.
abstract: Massive transfusion of blood can lead to clinical complications, including multiorgan dysfunction and even death. Such severe clinical outcomes have been associated with longer red blood cell (rbc) storage times. Collectively referred to as the rbc storage lesion, rbc storage results in multiple biochemical changes that impact intracellular processes as well as membrane and cytoskeletal properties, resulting in cellular injury in vitro. However, how the rbc storage lesion triggers pathophysiology in vivo remains poorly defined. In this study, we developed a guinea pig transfusion model with blood stored under standard blood banking conditions for 2 (new), 21 (intermediate), or 28 days (old blood). Transfusion with old but not new blood led to intravascular hemolysis, acute hypertension, vascular injury, and kidney dysfunction associated with pathophysiology driven by hemoglobin (Hb). These adverse effects were dramatically attenuated when the high-affinity Hb scavenger haptoglobin (Hp) was administered at the time of transfusion with old blood. Pathologies observed after transfusion with old blood, together with the favorable response to Hp supplementation, allowed us to define the in vivo consequences of the rbc storage lesion as storage-related posttransfusion hemolysis producing Hb-driven pathophysiology. Hb sequestration by Hp might therefore be a therapeutic modality for enhancing transfusion safety in severely ill or massively transfused patients.
authors.affiliation: Laboratory of Biochemistry and Vascular Biology, Division of Hematology, Center for Biologics Evaluation and Research, FDA, Bethesda, Maryland 20892, USA.
authors.forename: Jin Hyen
authors.initials: JH
authors.lastname: Baek
authors.forename: Felice
authors.initials: F
authors.lastname: D'Agnillo
authors.forename: Florence
authors.initials: F
authors.lastname: Vallelian
authors.forename: Claudia P
authors.initials: CP
authors.lastname: Pereira
authors.forename: Matthew C
authors.initials: MC
authors.lastname: Williams
authors.forename: Yiping
authors.initials: Y
authors.lastname: Jia
authors.forename: Dominik J
authors.initials: DJ
authors.lastname: Schaer
authors.forename: Paul W
authors.initials: PW
authors.lastname: Buehler
mesh_terms: D058186:Acute Kidney Injury / Q000188:drug therapy / Q000209:etiology / Q000473:pathology / Q000503:physiopathology; D000818:Animals; D001011:Aorta / Q000473:pathology; D001793:Blood Preservation; D059347:Cardio-Renal Syndrome / Q000188:drug therapy / Q000209:etiology / Q000473:pathology / Q000503:physiopathology; D004907:Erythrocyte Deformability; D006168:Guinea Pigs; D006242:Haptoglobins / Q000378:metabolism / Q000627:therapeutic use*; D051547:Heme Oxygenase-1 / Q000032:analysis; D006454:Hemoglobins / Q000009:adverse effects* / Q000378:metabolism; D006461:Hemolysis; D006801:Humans; D007668:Kidney / Q000378:metabolism / Q000473:pathology*; D008099:Liver / Q000201:enzymology; D008297:Male; D009569:Nitric Oxide / Q000378:metabolism; D009996:Osmotic Fragility; D040901:Proteomics; D013154:Spleen / Q000201:enzymology; D013997:Time Factors; D065227:Transfusion Reaction
chemical_list: D006242:Haptoglobins; D006454:Hemoglobins; D009569:Nitric Oxide; C496541:HMOX1 protein, human; D051547:Heme Oxygenase-1