Sickle Cell Trait Increases Red Blood Cell Storage Hemolysis and Post-Transfusion Clearance in Mice

Abstract

BackgroundTransfusion 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.MethodsWe 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).FindingsHuman 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.InterpretationThe common genetic variant HbAS enhances RBC storage dysfunction and raises provocative questions about the use of HbAS RBCs at the limits of approved storage.

Ethnicity, sex, and age are determinants of red blood cell storage and stress hemolysis: results of the REDS-III RBC-Omics study

“…30,31 A recent study that evaluated the impact of sickle cell trait on RBC storage stability and posttransfusion recovery demonstrated that sickle trait RBCs exhibited high resistance to osmotic hemolysis, with accelerated degradation during cold storage and reduced posttransfusion recovery in mice. 7 Because sickle cell trait affects 8% to 10% of African Americans, 32 given the magnitude of our observations, we hypothesize that other genetic factors may also modulate the osmotic hemolysis pattern of stored RBCs from African American donors. This finding also likely relates to the high prevalence of alpha-thalassemia variants in African Americans, 33 because they are associated with enhanced resistance to osmotic fragility.…”

“…In preclinical rodent studies of RBCs and transfusion, we found that alterations in osmotic and storage hemolysis do predict lower posttransfusion RBC recovery. 6,7 In patients with hereditary spherocytosis, enhanced susceptibility of hereditary spherocytosis RBCs to osmotic fragility was associated with poor RBC in vivo recovery after autologous transfusion of stored RBCs. 25 A few observational studies that examined the association between donor characteristics and patient outcomes suggested that female RBCs may increase the risk of posttransfusion mortality, 5,26 whereas comparable studies found no associations between donor sex or age and posttransfusion mortality.…”

“…1 A growing number of studies have discussed the potential impact of donor characteristics on RBC storage lesions 2 and posttransfusion outcomes, 3–7 which led to the scrutiny of genetic and biological factors in blood donors that may contribute to variations in the quality of RBC units. Although the clinical consequences of such differences have not been established in humans, studies in mice have demonstrated strain-specific susceptibility to RBC injury from cold storage that correlates with posttransfusion RBC recovery and function.…”

“…Current understanding of genetic and biological variables that may affect RBC storage quality is limited to known RBC disorders, in which genetic enrichment for mutations related to hemolytic diseases, such as sickle cell disease, 7 thalassemia, or glucose-6-phosphate dehydrogenase deficiency, may modulate RBC rheology or antioxidant capacity and may compromise RBC recovery during storage and after transfusion. 16,17 Functionally relevant RBC polymorphisms are anticipated to be high in donors with racial origin or admixture from malaria-endemic regions, such as equatorial Africa, Asia, and South and Central America.…”

“…For example, prolonged cold storage of blood from donors with sickle cell trait reduces cellular viability and posttransfusion recovery in murine models. 7 …”