title: Sickle Cell Trait Increases Red Blood Cell Storage Hemolysis and Post-Transfusion Clearance in Mice.
abstract: BACKGROUND
  Transfusion of blood at the limits of approved storage time is associated with lower red blood cell (RBC) post-transfusion recovery and hemolysis, which increases plasma cell-free hemoglobin and iron, proposed to induce endothelial dysfunction and impair host defense. There is noted variability among donors in the intrinsic rate of storage changes and RBC post-transfusion recovery, yet genetic determinants that modulate this process are unclear.
  
  
  METHODS
  We explore RBC storage stability and post-transfusion recovery in murine models of allogeneic and xenogeneic transfusion using blood from humanized transgenic sickle cell hemizygous mice (Hbatm1PazHbbtm1TowTg(HBA-HBBs)41Paz/J) and human donors with a common genetic mutation sickle cell trait (HbAS).
  
  
  RESULTS
  Human and transgenic HbAS RBCs demonstrate accelerated storage time-dependent hemolysis and reduced post-transfusion recovery in mice. The rapid post-transfusion clearance of stored HbAS RBC is unrelated to macrophage-mediated uptake or intravascular hemolysis, but by enhanced sequestration in the spleen, kidney and liver. HbAS RBCs are intrinsically different from HbAA RBCs, with reduced membrane deformability as cells age in cold storage, leading to accelerated clearance of transfused HbAS RBCs by entrapment in organ microcirculation.
  
  
  CONCLUSIONS
  The common genetic variant HbAS enhances RBC storage dysfunction and raises provocative questions about the use of HbAS RBCs at the limits of approved storage.
authors: Pittsburgh Heart, Lung, Blood and Vascular Medicine Institute, University of Pittsburgh, Pittsburgh, PA, United States; Department of Molecular Pharmacology and Chemical Biology, University of Pittsburgh, Pittsburgh, PA, United States.
authors: David O
authors: DO
authors: Osei-Hwedieh
authors: Pittsburgh Heart, Lung, Blood and Vascular Medicine Institute, University of Pittsburgh, Pittsburgh, PA, United States.
authors: Tamir
authors: T
authors: Kanias
authors: Center for Biologic Imaging, University of Pittsburgh, Pittsburgh, PA, United States.
authors: Claudette St
authors: CS
authors: Croix
authors: Center for Biologic Imaging, University of Pittsburgh, Pittsburgh, PA, United States.
authors: Morgan
authors: M
authors: Jessup
authors: Division of Pulmonary, Allergy and Critical Care Medicine, University of Pittsburgh, Pittsburgh, PA, United States.
authors: Zeyu
authors: Z
authors: Xiong
authors: Pittsburgh Heart, Lung, Blood and Vascular Medicine Institute, University of Pittsburgh, Pittsburgh, PA, United States.
authors: Derek
authors: D
authors: Sinchar
authors: Center for Biologic Imaging, University of Pittsburgh, Pittsburgh, PA, United States.
authors: Jonathan
authors: J
authors: Franks
authors: Pittsburgh Heart, Lung, Blood and Vascular Medicine Institute, University of Pittsburgh, Pittsburgh, PA, United States.
authors: Qinzi
authors: Q
authors: Xu
authors: Pittsburgh Heart, Lung, Blood and Vascular Medicine Institute, University of Pittsburgh, Pittsburgh, PA, United States.
authors: Enrico
authors: E
authors: M Novelli
authors: Pittsburgh Heart, Lung, Blood and Vascular Medicine Institute, University of Pittsburgh, Pittsburgh, PA, United States.
authors: Jonas T
authors: JT
authors: Sertorio
authors: Pittsburgh Heart, Lung, Blood and Vascular Medicine Institute, University of Pittsburgh, Pittsburgh, PA, United States.
authors: Karin
authors: K
authors: Potoka
authors: Department of Immunology, University of Pittsburgh, Pittsburgh, PA, United States.
authors: Robert J
authors: RJ
authors: Binder
authors: Department of Physics, Wake Forest University, Winston-Salem, NC, United States.
authors: Swati
authors: S
authors: Basu
authors: Department of Physics, Wake Forest University, Winston-Salem, NC, United States.
authors: Andrea M
authors: AM
authors: Belanger
authors: Department of Physics, Wake Forest University, Winston-Salem, NC, United States.
authors: Daniel B
authors: DB
authors: Kim-Shapiro
authors: Institute for Transfusion Medicine, ITxM, Pittsburgh, PA, United States.
authors: Darrell
authors: D
authors: Triulzi
authors: Pittsburgh Heart, Lung, Blood and Vascular Medicine Institute, University of Pittsburgh, Pittsburgh, PA, United States; Division of Pulmonary, Allergy and Critical Care Medicine, University of Pittsburgh, Pittsburgh, PA, United States. Electronic address: jsl26@pitt.edu.
authors: Janet S
authors: JS
authors: Lee
authors: Pittsburgh Heart, Lung, Blood and Vascular Medicine Institute, University of Pittsburgh, Pittsburgh, PA, United States; Division of Pulmonary, Allergy and Critical Care Medicine, University of Pittsburgh, Pittsburgh, PA, United States; Department of Molecular Pharmacology and Chemical Biology, University of Pittsburgh, Pittsburgh, PA, United States. Electronic address: gladwinmt@upmc.edu.
authors: Mark T
authors: MT
authors: Gladwin
mesh_terms: D000818:Animals; D001793:Blood Preservation / Q000009:adverse effects; D004002:Clodronic Acid / Q000494:pharmacology / Q000627:therapeutic use; D004195:Disease Models, Animal; D017707:Erythrocyte Transfusion; D004912:Erythrocytes / Q000378:metabolism* / Q000473:pathology / Q000648:ultrastructure; D004913:Erythrocytes, Abnormal / Q000648:ultrastructure; D005260:Female; D006441:Hemoglobin A / Q000235:genetics / Q000378:metabolism; D006461:Hemolysis; D006801:Humans; D008297:Male; D051379:Mice; D008822:Mice, Transgenic; D009996:Osmotic Fragility / Q000235:genetics; D012805:Sickle Cell Trait / Q000097:blood* / Q000401:mortality / Q000628:therapy; D013156:Splenectomy
chemical_list: D004002:Clodronic Acid; C028672:hemoglobin AA; D006441:Hemoglobin A
keywords: Blood; Post-transfusion survival; RBC hemolysis; Red cell storage; Sickle cell trait; Transfusion practice