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

Abstract

Genetic polymorphisms in blood donors may contribute to donor-specific differences in the survival of red blood cells (RBCs) during cold storage and after transfusion. Genetic variability is anticipated to be high in donors with racial admixture from malaria endemic regions such as Africa and Asia. The purpose of this study was to test the hypothesis that donor genetic background, reflected by sex and self-reported ethnicity, significantly modulates RBC phenotypes in storage. High throughput hemolysis assays were developed and used to evaluate stored RBC samples from 11 115 African American, Asian, white, and Hispanic blood donors from 4 geographically diverse regions in the United States. Leukocyte-reduced RBC concentrate-derived samples were stored for 39 to 42 days (1-6°C) and then evaluated for storage, osmotic, and oxidative hemolysis. Male sex was strongly associated with increased susceptibility to all 3 hemolysis measures (P < .0001). African American background was associated with resistance to osmotic hemolysis compared with other racial groups (adjusted P < .0001). Donor race/ethnicity was also associated with extreme (>1%) levels of storage hemolysis exceeding US Food and Drug Administration regulations for transfusion (hemolysis >1% was observed in 3.51% of Asian and 2.47% of African American donors vs 1.67% of white donors). These findings highlight the impact of donor genetic traits on measures of RBC hemolysis during routine cold storage, and they support current plans for genome-wide association studies, which may help identify hereditable variants with substantive effects on RBC storage stability and possibly posttransfusion outcomes.

Graphical abstract

Figure 1.

Flowchart of the RBC-Omics study cohort and donor testing for hemolysis.

Figure 2.

Distribution of spontaneous storage or stress-induced hemolysis by donor age and sex. RBC concentrates from male or female donors age 18 to 90 years old were stored (1-6°C) for 39 to 42 days in transfer bags and tested for storage or stress-induced hemolysis as described in “Materials and methods.” (A) Percent spontaneous storage hemolysis. (B) Percent osmotic hemolysis (4-hour Pink test). (C) Percent AAPH-induced oxidative hemolysis (incubation conditions: 150 mmol/L, 1.5 hours, 37°C). The fitted line indicates the predicted mean hemolysis for corresponding age, and the shaded areas highlight the 95% confidence intervals for the standard error of the mean.

Figure 3.

Frequency distribution of spontaneous storage or stress-induced hemolysis by donor racial background. RBC concentrates from RBC-Omics donors were stored (1-6°C) for 39 to 42 days in transfer bags and tested for storage or stress-induced hemolysis as described in “Materials and methods.” The plots represent the frequency distribution of percentage of storage or stress-induced hemolysis in donors of different racial backgrounds including non-Hispanic white, Hispanic white, non-Hispanic African American, and non-Hispanic Asian. For simplification, hemolysis data from other donors were excluded from this figure and can be viewed in Table 3. (A) Percent osmotic hemolysis (4-hour Pink test). (B) Percent AAPH-induced oxidative hemolysis (incubation conditions: 150 mmol/L, 1.5 hours, 37°C). (C) Percent storage hemolysis at the range of 0% to 1% (acceptable for transfusion) and (D) above 1%.