A randomized trial of blood donor iron repletion on red cell quality for transfusion and donor cognition and well-being

Abstract

Although altruistic regular blood donors are vital for the blood supply, many become iron deficient from donation-induced iron loss. The effects of blood donation-induced iron deficiency on red cell transfusion quality or donor cognition are unknown. In this double-blind, randomized trial, adult iron-deficient blood donors (n = 79; ferritin < 15 μg/L and zinc protoporphyrin >60 μMol/mol heme) who met donation qualifications were enrolled. A first standard blood donation was followed by the gold-standard measure for red cell storage quality: a 51-chromium posttransfusion red cell recovery study. Donors were then randomized to intravenous iron repletion (1 g low-molecular-weight iron dextran) or placebo. A second donation ∼5 months later was followed by another recovery study. Primary outcome was the within-subject change in posttransfusion recovery. The primary outcome measure of an ancillary study reported here was the National Institutes of Health Toolbox-derived uncorrected standard Cognition Fluid Composite Score. Overall, 983 donors were screened; 110 were iron-deficient, and of these, 39 were randomized to iron repletion and 40 to placebo. Red cell storage quality was unchanged by iron repletion: mean change in posttransfusion recovery was 1.6% (95% confidence interval -0.5 to 3.8) and -0.4% (-2.0 to 1.2) with and without iron, respectively. Iron repletion did not affect any cognition or well-being measures. These data provide evidence that current criteria for blood donation preserve red cell transfusion quality for the recipient and protect adult donors from measurable effects of blood donation-induced iron deficiency on cognition. This trial was registered at www.clinicaltrials.gov as NCT02889133 and NCT02990559.

Graphical abstract

Figure 1.

Consort diagram for participant flow by treatment arm. ∗Due to pandemic-related restrictions for human subject research these participants were withdrawn. ^†Participants who completed at least 1 cognitive performance evaluation after randomization. ^‡Manufacturing errors included collection in storage solutions other than Additive Solution Formula 3, overfilled units, and otherwise compromised units. CRP, C-reactive protein; IV, intravenous.

Figure 2.

Laboratory measurements during the trial. The data points represent the estimated means based on a mixed-model repeated-measures analysis after adjustment for the baseline value. The vertical bars denote 95% CIs. The dependent variable was the laboratory value at each predetermined time point. Fixed effects included the interaction between treatment and time. Time was treated as a categorical variable. The subject was included in the model as a random effect. A first-order autoregressive covariance matrix was used to model the within-patient variance-covariance errors. Prespecified secondary outcomes were laboratory measures of (A) hemoglobin, (B) hematocrit, (C) zinc protoporphyrin, (D) reticulocyte hemoglobin, (E) ferritin, (F) soluble transferrin receptor, (G) transferrin saturation, and (H) hepcidin. PTR, posttransfusion recovery.

Figure 3.

Change in red blood cell posttransfusion recovery between randomization arms and by prespecified subgroups. Bars represent mean change in red blood cell posttransfusion recovery between the second measure performed after randomization and the first measure before randomization to placebo (open blue circles) or iron repletion (open red triangles). (A) Overall change in posttransfusion recovery among all randomized participants completing the primary outcome measure and by (B) sex, (C) age, and (D) race. Error bars represent SD. ∗P < .05 by unpaired t test. ns, not significant.

Figure 4.

Cognitive performance measurements during the trial. The data points represent the estimated means based on a mixed-model repeated-measures analysis after adjustment for the baseline value. The vertical bars denote 95% CIs. The dependent variable was the cognitive test score at each predetermined time point. Fixed effects included the interaction between treatment and time. Time was treated as a categorical variable. The subject was included in the model as a random effect. A first-order autoregressive covariance matrix was used to model the within-patient variance-covariance errors. The primary outcome was the (A) Cognition Fluid Composite Score. Prespecified secondary outcomes were the (B) raw score on the Auditory Verbal Learning Test (Rey), (C) Dimensional Change Card Sort Test, (D) Flanker Inhibitory Control and Attention Test, (E) List Sorting Working Memory Test, (F) Pattern Comparison Processing Speed Test, and (G) Picture Sequence Memory Test. Standard scores have a mean of 100 and SD of 15, with higher scores representing better cognitive performance. PTR, posttransfusion recovery.