Blood donor exposome and impact of common drugs on red blood cell metabolism.

Computational models based on recent maps of the RBC proteome suggest that mature erythrocytes may harbor targets for common drugs. This prediction is relevant to RBC storage in the blood bank, in which the impact of small molecule drugs or other xenometabolites deriving from dietary, iatrogenic, or environmental exposures ("exposome") may alter erythrocyte energy and redox metabolism and, in so doing, affect red cell storage quality and posttransfusion efficacy. To test this prediction, here we provide a comprehensive characterization of the blood donor exposome, including the detection of common prescription and over-the-counter drugs in blood units donated by 250 healthy volunteers in the Recipient Epidemiology and Donor Evaluation Study III Red Blood Cell-Omics (REDS-III RBC-Omics) Study. Based on high-throughput drug screenings of 1366 FDA-approved drugs, we report that approximately 65% of the tested drugs had an impact on erythrocyte metabolism. Machine learning models built using metabolites as predictors were able to accurately predict drugs for several drug classes/targets (bisphosphonates, anticholinergics, calcium channel blockers, adrenergics, proton pump inhibitors, antimetabolites, selective serotonin reuptake inhibitors, and mTOR), suggesting that these drugs have a direct, conserved, and substantial impact on erythrocyte metabolism. As a proof of principle, here we show that the antacid ranitidine - though rarely detected in the blood donor population - has a strong effect on RBC markers of storage quality in vitro. We thus show that supplementation of blood units stored in bags with ranitidine could - through mechanisms involving sphingosine 1-phosphate-dependent modulation of erythrocyte glycolysis and/or direct binding to hemoglobin - improve erythrocyte metabolism and storage quality.

Retrospective cohort studies of repeat donors reveal donor-dependent variability in the recovery of transfused platelets.

BACKGROUND: The in vivo recovery of transfused platelets is variable and often unpredictable. Although many recipient-dependent factors are well described, donor-dependent variables remain poorly understood. STUDY DESIGN AND METHODS: To explore donor-dependent variables we conducted 2 retrospective studies of platelet transfusion outcomes in repeat donors. One study analyzed multiple autologous, radiolabeled platelet transfusions, and a second study analyzed multiple clinical platelet transfusions from a small cohort of repeat donors. RESULTS: In 36 subjects, multiple within-subject determinations of recovery and survival of radiolabeled autologous platelets revealed a relative consistency in platelet recoveries within donors compared to the range of recoveries among donors. Intraclass correlation coefficients for platelet recovery were 43% to 93%. In 524 ABO-compatible clinical platelet transfusions derived from seven donors, a linear mixed-effects model revealed significant donor-dependent differences in corrected count increments for units stored for 4 or 5 days. CONCLUSIONS: These two studies indicate reproducible donor-dependent differences in transfused platelet recovery, suggesting a possible heritable influence on the quality of transfused platelets.

Impact of taurine on red blood cell metabolism and implications for blood storage.

BACKGROUND: Taurine is an antioxidant that is abundant in some common energy drinks. Here we hypothesized that the antioxidant activity of taurine in red blood cells (RBCs) could be leveraged to counteract storage-induced oxidant stress. STUDY DESIGN AND METHODS: Metabolomics analyses were performed on plasma and RBCs from healthy volunteers (n = 4) at baseline and after consumption of a whole can of a common, taurine-rich (1000 mg/serving) energy drink. Reductionistic studies were also performed by incubating human RBCs with taurine ex vivo (unlabeled or 13 C15 N-labeled) at increasing doses (0, 100, 500, and 1000 µmol/L) at 37°C for up to 16 hours, with and without oxidant stress challenge with hydrogen peroxide (0.1% or 0.5%). Finally, we stored human and murine RBCs under blood bank conditions in additives supplemented with 500 µmol/L taurine, before metabolomics and posttransfusion recovery studies. RESULTS: Consumption of energy drinks increased plasma and RBC levels of taurine, which was paralleled by increases in glycolysis and glutathione (GSH) metabolism in the RBC. These observations were recapitulated ex vivo after incubation with taurine and hydrogen peroxide. Taurine levels in the RBCs from the REDS-III RBC-Omics donor biobank were directly proportional to the total levels of GSH and glutathionylated metabolites and inversely correlated to oxidative hemolysis measurements. Storage of human RBCs in the presence of taurine improved energy and redox markers of storage quality and increased posttransfusion recoveries in FVB mice. CONCLUSION: Taurine modulates RBC antioxidant metabolism in vivo and ex vivo, an observation of potential relevance to transfusion medicine.

Autologous transfusion recovery of WBC-reduced high-concentration platelet concentrates.

BACKGROUND: This study evaluates the recovery and survival of high-concentration platelets (HCPs) compared to standard apheresis platelets (APCs) in a double-label autologous human system. METHODS: Nine HCP units paired with APC units were stored, labeled with either 51Cr and 111In, and returned, and recovery and survival were determined. Standard in vitro platelet biochemical and functional parameters were monitored over the storage period and evaluated in a secondary analysis. RESULTS: Three each HCP units containing more than 2.2 x 10(11), 1.5 x 10(11) to 2.1 x 10(11), and 0.8 x 10(11) to 1.1 x 10(11) platelets in 59.4 +/- 2.5 mL were stored for 1, 2, or 5 days, respectively, and simultaneously with matched APC units (3.8 x 10(11) platelets, 282 mL). Recoveries were 72.3 +/- 8.6, 60.8 +/- 14.6, and 52.5 +/- 6.7 percent for HCPs, respectively; and 59.4 +/- 6.4 percent for APCs (p=0.37). HCP survivals were 202.0 +/- 14.9, 204.9 +/- 10.2, and 162.6 +/- 17.0 hours; APC survivals were 155.4 +/- 20.3 hours (p=0.001). Secondary analysis with P-selectin added as a predictor in the model resulted in significant difference in recoveries for Day 1 HCPs versus Day 5 APCs (p=0.024) with no difference shown for HCPs on Days 2 or 5 versus APCs. No significant difference was found in survival (p=0.16). CONCLUSION: HCPs may be stored 24 hours for high yield, 48 hours for intermediate yield, and up to 5 days for yields less than 1.6 x 10(11) platelets per bag with equivalent to superior recovery and survival of platelets in the autologous transfusion model compared to APCs.

Seven-day storage of single-donor platelets: recovery and survival in an autologous transfusion study.

BACKGROUND: Bacterial screening may effectively reduce the morbidity and mortality risk associated with extended storage of platelets. Platelet viability then becomes the primary determinant of acceptable storage time. This study evaluates the effectiveness of platelets stored in plasma for 7 days. STUDY DESIGN AND METHODS: WBC-reduced, single-donor platelets (n = 24) were collected and stored by standard methods at two sites. Standard in vitro platelet biochemical and functional parameters were monitored over the storage period. On Days 5 and 7 of storage, platelets were alternately labeled with 51Cr and (111)In and returned to the subject, and recovery and survival were determined. RESULTS: Component pH(22 degrees C) was maintained in the range 6.2 to 7.61 through 7 days and did not detrimentally affect either in vitro or in vivo outcomes. In vitro platelet characteristics were adequately maintained over 7 days. Day 5 platelets had better recovery (63.0 +/- 4.36 vs. 53.9 +/- 4.36%, p < 0.0001) and survival (161 +/- 8.1 vs. 133 +/- 8.1 hr, p = 0.006) than Day 7 platelets adjusting for radioisotope, center, and donor effects. CONCLUSION: Although declines in recovery and survival were noted, these are less than used previously to gain licensure of 7-day storage and are unlikely to be clinically significant. Extension of storage to 7 days could be implemented with bacterial screening methods to select out contaminated components without a significant effect on the platelet efficacy compared to 5-day components.