Donor genetic and nongenetic factors affecting red blood cell transfusion effectiveness

Abstract

BACKGROUNDRBC transfusion effectiveness varies due to donor, component, and recipient factors. Prior studies identified characteristics associated with variation in hemoglobin increments following transfusion. We extended these observations, examining donor genetic and nongenetic factors affecting transfusion effectiveness.METHODSThis is a multicenter retrospective study of 46,705 patients and 102,043 evaluable RBC transfusions from 2013 to 2016 across 12 hospitals. Transfusion effectiveness was defined as hemoglobin, bilirubin, or creatinine increments following single RBC unit transfusion. Models incorporated a subset of donors with data on single nucleotide polymorphisms associated with osmotic and oxidative hemolysis in vitro. Mixed modeling accounting for repeated transfusion episodes identified predictors of transfusion effectiveness.RESULTSBlood donor (sex, Rh status, fingerstick hemoglobin, smoking), component (storage duration, γ irradiation, leukoreduction, apheresis collection, storage solution), and recipient (sex, BMI, race and ethnicity, age) characteristics were associated with hemoglobin and bilirubin, but not creatinine, increments following RBC transfusions. Increased storage duration was associated with increased bilirubin and decreased hemoglobin increments, suggestive of in vivo hemolysis following transfusion. Donor G6PD deficiency and polymorphisms in SEC14L4, HBA2, and MYO9B genes were associated with decreased hemoglobin increments. Donor G6PD deficiency and polymorphisms in SEC14L4 were associated with increased transfusion requirements in the subsequent 48 hours.CONCLUSIONDonor genetic and other factors, such as RBC storage duration, affect transfusion effectiveness as defined by decreased hemoglobin or increased bilirubin increments. Addressing these factors will provide a precision medicine approach to improve patient outcomes, particularly for chronically transfused RBC recipients, who would most benefit from more effective transfusion products.FUNDINGFunding was provided by HHSN 75N92019D00032, HHSN 75N92019D00034, 75N92019D00035, HHSN 75N92019D00036, and HHSN 75N92019D00037; R01HL126130; and the National Institute of Child Health and Human Development (NICHD).

Keywords: Clinical practice; Genetic variation; Hematology.

Figure 1. Study flow diagram.

Figure 2. Effect of storage age and irradiation on hemoglobin and bilirubin increments.

(A and B) The adjusted changes in total bilirubin (n = 19,205) and hemoglobin (n = 102,043) levels between pre- and posttransfusion laboratory measures are shown stratified by week of storage, as labeled. Hemoglobin and bilirubin increments were adjusted for concomitant donor, component, and recipient factors presented in Table 3 and plotted as derivatives of the regression equation. P < 0.0001 for linear association between storage duration and change in laboratory measure for both figure panels.

Figure 3. Adjusted hemoglobin increments stratified by sex and glucose-6-phosphate dehydrogenase (G6PD) deficiency.

Adjusted change in hemoglobin level between pre- and posttransfusion measures is shown stratified by male (n = 3458) and female (n = 2584) sex and G6PD genotype, as labeled. As G6PD is X-linked, males labeled (–) are G6PD deficient (n = 43) and females labeled (+/–) are heterozygous (n = 46). Hemoglobin is adjusted for concomitant donor, component, and recipient factors. ****P < 0.0001, *P < 0.05 for 1-way ANOVA comparison as indicated. Line represents median, boxes represent 25th to 75th percentile, and whiskers represent the 5th to 95th percentile.