Chronic red blood cell (RBC) transfusion sustains patients with diverse hematologic disorders, but repeated transfusion leads to iron overload and alloimmunization. Reducing transfusion burden requires identifying donor units that circulate more effectively after storage, yet determinants of this variability remain incompletely defined. Here, we integrate forward genetics in mice, multi-omics analyses of over 13,000 human donors, and studies of two families with hereditary ATP11c mutations to reveal a central role for this phospholipid flippase in transfusion efficacy. We show that common ATP11C variants, including the missense SNP V972M, and rare familial loss-of-function alleles impair RBC survival by disrupting membrane lipid remodeling and cytoskeletal stability—a mechanism distinct from oxidative damage pathways. Together, these findings establish ATP11c as a novel determinant of transfusion outcomes across species and genetic contexts, and highlight opportunities for donor stratification and improved storage technologies to advance precision transfusion medicine.

Abstract Introduction SARS-CoV-2-CoV-2 infection is known to induce autoantibodies across a wide range of targets, including immune modulatory proteins and pro-thrombotic factors. It is not known if vaccination with SARS-CoV-2 mRNA vaccines would induce a similar autoantibody profile, or whether prior vaccination would protect recipients from autoantibody production upon SARS-CoV-2 infection. Methods Our group followed a cohort of over 65,000 blood donors across repeat donations in the COVID-19 era. We identified SARS-CoV-2 naïve donors who were infected without prior vaccination (n = 150) or were vaccinated then became infected (n = 100). We tested samples from the naïve time point and 6-10 weeks after infection (2 paired samples) or naïve then vaccination then infection (three samples) using a T7 bacteriophage array displaying 731,724 peptides (49 amino acids each) spanning the human proteome. Data were partitioned into five random groups and peptide comparisons between groups were performed using ranksum, with 80% used for training and 20% used for testing iteratively. Results Autoantibodies targeting 15 peptides were induced with a z-score >2 after SARS-CoV-2 infection of unvaccinated naïve donors (p < 1x10-5). Of these infection-induced autoantibodies, 1 was induced after mRNA vaccination, as well as 2 distinct vaccine induced autoantibodies. In donors who were infected after prior vaccination, autoantibody responses were blunted, targeting 7 of 15 peptides. Conclusion In contrast to SARS-CoV-2 infection of immunologically naïve individuals, SARS-CoV-2 mRNA vaccination induces only a limited autoantibody repertoire. Furthermore, prior vaccination protects against development of approximately half the autoantibodies induced by SARS-CoV-2 infection in this study. These data confirm the induction of autoantibodies following infection and underline both the safety of mRNA vaccines in terms of autoantibody induction, as well as potential protective effects of vaccination from COVID-19 associated autoimmunity. Funding Source NIH Topic Categories Viral Immunology (VIR)

BACKGROUND AND OBJECTIVES:Best platelet transfusion practices are unclear across intracranial hemorrhage (ICH) types, given the mortality risk. Reasons for this risk are unknown, but ABO-incompatible platelet transfusions may confer risk in certain populations. We assessed contemporary ICH platelet transfusion practices and whether ABO-incompatible platelet transfusions increase ICH mortality risk. METHODS:Adult patients with spontaneous intracerebral hemorrhage (sICH), traumatic ICH, and aneurysmal subarachnoid hemorrhage hospitalizations between 2019 and 2024 were assessed from a multicenter transfusion network. Relationships of platelet transfusions with 30-day mortality were assessed using logistic regression models adjusting for demographics, ICH type/severity, comorbidities, and other hemorrhage control therapies/transfusions. Among those receiving platelet transfusions, relationships of major ABO-incompatible platelet units with mortality risk were investigated using Cox models adjusting for similar covariates. Analyses were performed across the cohort and stratified by ICH subtype. RESULTS:Among 13 068 patients with ICH, 60% were male individuals, mean age was 66 (±19) years, 23% were from sICH, 69% from traumatic ICH, and 8% from aneurysmal subarachnoid hemorrhage cohorts. Acute platelet transfusions were given to 12% of the patients. Thrombocytopenia (<100 000 platelets/μL) and neurosurgical procedures, seen in 6% and 18% of the patients, respectively, were largest factors for platelet transfusions. In regression analyses, platelet transfusions themselves did not associate with mortality (adjusted hazard ratio [HR]: 1.14 [0.96-1.35]). However, among patients with ICH receiving platelet transfusions, ABO-incompatible units were common (37%) and had dose-dependent relationships with mortality (adjusted HR ≥2 exposures: 1.78 [1.18-2.70]). Stratified analyses revealed that patients with sICH were particularly vulnerable to mortality from even single exposures of ABO-incompatible units (adjusted HR 1 exposure: 1.97 [1.13-3.45]; ≥2 exposures: 2.78 [0.98-7.87]) compared with other ICH subtypes. CONCLUSION:Acute platelet transfusion practice remains prevalent in ICH, and platelet transfusion-related 30-day mortality risk may be influenced by ABO-incompatible platelet units. Clinical trials are needed to assess whether transfusion practice changes in providing ABO-matched platelets can improve outcomes in certain patients with ICH.

Red blood cell (RBC) membrane lipid peroxidation during blood bank storage profoundly impacts transfusion efficacy; however, the genetic determinants underlying RBC resilience remain incompletely defined. Here, we identify a critical role for glutathione peroxidase 4 (GPX4) - a pivotal enzyme protecting against iron-dependent lipid peroxidation (ferroptosis) - in regulating RBC storage quality and post-transfusion survival. Conditional erythroid-specific deletion of Gpx4 in mice exacerbated lipid hydroperoxide accumulation, oxidation and ubiquitination of membrane proteins, and reduced RBC recovery after transfusion. Multi-omics analyses in 13,091 human blood donors from the REDS RBC Omics cohort identified regulatory intergenic (rs8178962), intronic and missense genetic variants in GPX4 (rs73507255, rs8178967), particularly prevalent among donors of African descent, that were linked to increased lipid peroxidation and compromised post-transfusion hemoglobin increments. Single protein- and metabolome-wide association studies (pQTL/mQTL) highlighted genetic variants associated with enhanced (rs8178962) or impaired GPX4 expression, disrupted glutathione homeostasis, lipid hydroperoxide accumulation, accelerated membrane damage, and activation of ferroptotic signatures during RBC storage. These effects were exacerbated by genetic traits impairing redox homeostasis, including glucose 6-phosphate dehydrogenase (G6PD) deficiency (African variant rs1050828 V68M/N126D). Storage of murine RBCs in presence of the ferroptosis inhibitor ferrostatin-1 prevented storage-induced lipid peroxidation and boosted post-transfusion recovery, a beneficial effect in part phenocopied by supplementation of lipophilic antioxidants vitamin E and Lands cycle fueling via L-carnitine, and in part ablated by GPX4 inhibition via the covalent inhibitor ML210. This study offers mechanistic insights into RBC ferroptosis and positions GPX4 genetic status as a promising biomarker for precision transfusion medicine.

BACKGROUND:Storage of packed red blood cells (RBCs) for transfusion leads to biochemical and morphological changes, increasing hemolysis risk. Urate levels in blood bags at donation contribute to the molecular heterogeneity and hemolytic propensity of stored RBCs. However, studies to date have been underpowered to investigate at scale the contribution of donor demographics and genetics to the heterogeneity in urate levels across donations. STUDY DESIGN AND METHODS:Urate levels were measured in 13,091 RBC units from the REDS study. Characteristics tested included hemolysis parameters (spontaneous, osmotic, oxidative) at storage end and post-transfusion hemoglobin (Hb) increments in recipients. Donor demographics, urate levels, and genetic variants were analyzed for associations with these outcomes. RESULTS:Elevated urate levels were linked to male sex, older age, high BMI, and Asian descent. Units with high urate levels exhibited increased spontaneous and osmotic hemolysis, while oxidative hemolysis was unaffected. Genetic variants in SLC2A9 (V282I) and ABCG2 (Q141K) were strongly associated with elevated urate, particularly in Asian donors. Post-transfusion analyses revealed that units from female donors carrying these variants were associated with reduced Hb increments, with up to a 31% reduction in efficacy. This effect was not observed in male donors. DISCUSSION:RBC urate levels and genetic traits significantly impact storage quality and transfusion outcomes. These findings highlight the importance of donor molecular characteristics for optimizing transfusion strategies. Moreover, genetic and metabolic insights may inform donor recruitment efforts, providing health feedback to volunteers while ensuring effective transfusion products.

BACKGROUND:Despite data supporting the safety of SARS-CoV-2 vaccination, concerns regarding the receipt of blood products from donors previously infected or vaccinated against SARS-CoV-2 persist. We assessed whether transfusions of plasma or platelet products from donors with prior SARS-CoV-2 infection or vaccination were associated with adverse outcomes in patients without COVID-19. METHODS:We linked donor SARS-CoV-2 spike and nucleocapsid antibody data and vaccination history to blood products transfused between June 1, 2020 and March 31, 2022. We used logistic regression, adjusting for demographics and comorbidities, to calculate odds ratios and 95% confidence intervals (CI) for posttransfusion thrombosis, increased respiratory requirement, and hospital mortality. Outcomes were assessed as per transfused unit from previously infected or vaccinated donors compared to units from uninfected or unvaccinated donors. RESULTS:Among 8715 hospitalizations of 7773 transfusion recipients linked to donor SARS-CoV-2 antibody data, there were 251 thromboses, 700 hospitalizations with increased respiratory requirements, and 1443 deaths. Among 15,167 transfused plasma units, 4993 and 1106 were from vaccinated donors and previously infected donors, respectively. Among 19,295 transfused platelet units, 8530 and 1368 were from vaccinated and previously infected donors, respectively. There were no associations between the transfusion of blood products from vaccinated or previously infected donors and thrombosis, increased respiratory requirements, or hospital mortality (all CI including 1). Nor were there associations between the receipt of blood products from recently infected or vaccinated donors or high SARS-CoV-2 antibody titers and adverse outcomes. DISCUSSION:Donor SARS-Cov-2 infection and vaccination were not associated with adverse patient outcomes and do not need to be considered in blood allocation.

Mitochondrial DNA (mtDNA) shares characteristics with bacterial DNA and activates immune cells via TLR9Extracellular vesicles (EVs) and mtDNA have been found in blood products and can activate immune cells; we sought to characterize their evolution in stored blood products. From a previous study of hemolysis in 13,403 blood donors, a second blood unit was drawn from 651 donors and sampled at days 10, 21, and 42. EV counts and RBC-EVs increased with storage time, and EV levels were higher in males and in RBC units processed in AS-1 compared with AS-3. mtDNA levels were higher in females and RBC units processed in AS-3. EV populations and mtDNA levels were highly correlated within donors for 98 donations obtained 2-12 months apart. Quantitative trait locus analysis revealed several genetic associations, most notably linking mtDNA levels with polymorphisms in ANKLE1, which encodes an erythroid-specific protein that preferentially cleaves mtDNA. These data suggest that donor-intrinsic factors may influence mtDNA and EV levels found in RBC units. This finding lends impetus to determining if genetic or environmental factors control levels of these immune mediators in blood donors.

Recent large-scale population studies in humans and in murine models of red blood cell (RBC) function identified associations between metabolic phenotypes, or genetic traits linked to them, and transfusion effectiveness. These metabolic phenotypes were identified in independent studies focusing on different mechanistic aspects of the storage lesion. The lack of an integrated analysis raised the question as to whether these signatures were redundant measures of the same underlying processes or could be evaluated together to inform a Precision Medicine approach to clinical transfusion practice. To bridge this gap, we performed an integrated analysis in 5,386 patients who received 6,220 single-unit RBC transfusions, evaluating donor metabolic and genetic results from several studies on hemoglobin increments following RBC transfusion. Our results indicate that previously reported metabolic and genetic predictors of hemoglobin increments remain significant, with an effect size between 0.05 and 0.15 g/dL, when evaluated concurrently. Our observational findings indicate that transfusing RBC units from donors with specific genetic traits, are not only negatively associated with immediate effectiveness but also increased downstream RBC transfusion events, further highlighting the need for refined donor screening practices. Altogether, this evidence supports adoption of a Precision Medicine approach to transfusion practice, where genetic screening of donors at first donation and longitudinal metabolic profiling could inform blood inventory management and allocation strategies, ensuring optimal outcomes for transfusion recipients.

ABSTRACT:Red blood cell (RBC) metabolism regulates hemolysis during aging in vivo and in the blood bank. However, the genetic underpinnings of RBC metabolic heterogeneity and extravascular hemolysis at population scale are incompletely understood. On the basis of the breeding of 8 founder strains with extreme genetic diversity, the Jackson Laboratory diversity outbred population can capture the impact of genetic heterogeneity in like manner to population-based studies. RBCs from 350 outbred mice, either fresh or stored for 7 days, were tested for posttransfusion recovery, as well as metabolomics and lipidomics analyses. Metabolite and lipid quantitative trait loci (QTL) mapped >400 gene-metabolite associations, which we collated into an online interactive portal. Relevant to RBC storage, we identified a QTL hotspot on chromosome 1, mapping on the region coding for the ferrireductase 6-transmembrane epithelial antigen of the prostate 3 (Steap3), a transcriptional target to p53. Steap3 regulated posttransfusion recovery, contributing to a ferroptosis-like process of lipid peroxidation, as validated via genetic manipulation in mice. Translational validation of murine findings in humans, STEAP3 polymorphisms were associated with RBC iron content, lipid peroxidation, and in vitro hemolysis in 13 091 blood donors from the Recipient Epidemiology and Donor Evaluation Study. QTL analyses in humans identified a network of gene products (fatty acid desaturases 1 and 2, epoxide hydrolase 2, lysophosphatidylcholine acetyl-transferase 3, solute carrier family 22 member 16, glucose 6-phosphate dehydrogenase, very long chain fatty acid elongase, and phospholipase A2 group VI) associated with altered levels of oxylipins. These polymorphisms were prevalent in donors of African descent and were linked to allele frequency of hemolysis-linked polymorphisms for Steap3 or p53. These genetic variants were also associated with lower hemoglobin increments in thousands of single-unit transfusion recipients from the vein-to-vein database.

Mature red blood cells (RBCs) lack mitochondria and thus exclusively rely on glycolysis to generate adenosine triphosphate (ATP) during aging in vivo or storage in blood banks. Here, we leveraged 13,029 volunteers from the Recipient Epidemiology and Donor Evaluation Study to identify associations between end-of-storage levels of glycolytic metabolites and donor age, sex, and ancestry-specific genetic polymorphisms in regions encoding phosphofructokinase 1, platelet (detected in mature RBCs); hexokinase 1 (HK1); and ADP-ribosyl cyclase 1 and 2 (CD38/BST1). Gene-metabolite associations were validated in fresh and stored RBCs from 525 Diversity Outbred mice and via multi-omics characterization of 1,929 samples from 643 human RBC units during storage. ATP and hypoxanthine (HYPX) levels-and the genetic traits linked to them-were associated with hemolysis in vitro and in vivo, both in healthy autologous transfusion recipients and in 5,816 critically ill patients receiving heterologous transfusions, suggesting their potential as markers to improve transfusion outcomes.

Increasing global life expectancy motivates investigations of molecular mechanisms of aging and age-related diseases. This study examines age-associated changes in red blood cells (RBCs), the most numerous host cell in humans. Four cohorts, including healthy individuals and patients with sickle cell disease, were analyzed to define age-dependent changes in RBC metabolism. Over 15,700 specimens from 13,757 humans were examined, a major expansion over previous studies of RBCs in aging. Multi-omics approaches identified chronological age-related alterations in the arginine pathway with increased arginine utilization in RBCs from older individuals. These changes were consistent across healthy and sickle cell disease cohorts and were influenced by genetic variation, sex, and body mass index. Integrating multi-omics data and metabolite quantitative trait loci (mQTL) in humans and 525 diversity outbred mice functionally linked metabolism of arginine during RBC storage to increased vesiculation-a hallmark of RBC aging-and lower post-transfusion hemoglobin increments. Thus, arginine metabolism is a biomarker of RBC and organismal aging, suggesting potential new targets for addressing sequelae of aging.

Recent large-scale multi-omics studies suggest that genetic factors influence the chemical individuality of donated blood. To examine this concept, we performed metabolomics analyses of 643 blood units from volunteers who donated units of packed red blood cells (RBCs) on two separate occasions. These analyses identified carnitine metabolism as the most reproducible pathway across multiple donations from the same donor. We also measured L-carnitine and acyl-carnitines in 13,091 packed RBC units from donors in the Recipient Epidemiology and Donor Evaluation (REDS) study. Genome wide association studies against 879,000 polymorphisms identified critical genetic factors contributing to inter-donor heterogeneity in end-of-storage carnitine levels, including common non-synonymous polymorphisms in genes encoding carnitine transporters (SLC22A16, SLC22A5, SLC16A9); carnitine synthesis (FLVCR1, MTDH) and metabolism (CPT1A, CPT2, CRAT, ACSS2), and carnitine-dependent repair of lipids oxidized by ALOX5. Significant associations between genetic polymorphisms on SLC22 transporters and carnitine pools in stored RBCs were validated in 525 Diversity Outbred mice. Donors carrying two alleles of the rs12210538 SLC22A16 Single Nucleotide Polymorphism exhibited the lowest L-carnitine levels, significant elevations of in vitro hemolysis, and the highest degree of vesiculation, accompanied by increases in lipid peroxidation markers. Separation of RBCs by age, via in vivo biotinylation in mice and Percoll density gradients of human RBCs, showed age-dependent depletions of L-carnitine and acyl-carnitine pools, accompanied by progressive failure of the reacylation process following chemically induced membrane lipid damage. Supplementation of stored murine RBCs with L-carnitine boosted post-transfusion recovery, suggesting this could represent a viable strategy to improve RBC storage quality.

In the field of transfusion medicine, the clinical relevance of the metabolic markers of the red blood cell (RBC) storage lesion is incompletely understood. Here, we performed metabolomics of RBC units from 643 donors enrolled in the Recipient Epidemiology and Donor Evaluation Study, REDS RBC Omics. These units were tested on storage days 10, 23, and 42 for a total of 1929 samples and also characterized for end-of-storage hemolytic propensity after oxidative and osmotic insults. Our results indicate that the metabolic markers of the storage lesion poorly correlated with hemolytic propensity. In contrast, kynurenine was not affected by storage duration and was identified as the top predictor of osmotic fragility. RBC kynurenine levels were affected by donor age and body mass index and were reproducible within the same donor across multiple donations from 2 to 12 months apart. To delve into the genetic underpinnings of kynurenine levels in stored RBCs, we thus tested kynurenine levels in stored RBCs on day 42 from 13 091 donors from the REDS RBC Omics study, a population that was also genotyped for 879 000 single nucleotide polymorphisms. Through a metabolite quantitative trait loci analysis, we identified polymorphisms in SLC7A5, ATXN2, and a series of rate-limiting enzymes (eg, kynurenine monooxygenase, indoleamine 2,3-dioxygenase, and tryptophan dioxygenase) in the kynurenine pathway as critical factors affecting RBC kynurenine levels. By interrogating a donor-recipient linkage vein-to-vein database, we then report that SLC7A5 polymorphisms are also associated with changes in hemoglobin and bilirubin levels, suggestive of in vivo hemolysis in 4470 individuals who were critically ill and receiving single-unit transfusions.

BACKGROUND:COVID-19 convalescent plasma (CCP) remains a treatment option for immunocompromised patients; however, the current FDA qualification threshold of ≥200 BAU/mL of spike antibody appears to be relatively low. We evaluated the levels of binding (bAb) and neutralizing antibodies (nAb) on serial samples from repeat blood donors who were vaccinated and/or infected to inform criteria for qualifying CCP from routinely collected plasma components. METHODS:Donors were categorized into four groups: (1) infected, then vaccinated, (2) vaccinated then infected during the delta, or (3) omicron waves, (4) vaccinated without infection. IgG Spike and total Nuclecapsid bAb were measured, along with S variants and nAb titers using reporter viral particle neutralization. RESULTS:Mean S IgG bAb peaks after infection alone were lower than after primary and booster vaccinations, and higher after delta and omicron infection in previously vaccinated donors. Half-lives for S IgG ranged from 34 to 66 days after first infection/vaccination events and up to 108 days after second events. The levels of S IgG bAb and nAb were similar across different variants, except for omicron, which were lower. Better correlations of nAb with bAb were observed at higher levels (hybrid immunity) than at the current FDA CCP qualifying threshold. DISCUSSION:Routine plasma donations from donors with hybrid immunity had high S bAb and potent neutralizing activity for 3-6 months after infection. In donations with high (>4000 BAU/mL) S IgG, >95% had high nAb titers (>500) against ancestral and variant S, regardless of COVID-19 symptoms. These findings provide the basis for test-based criteria for qualifying CCP from routine blood donations.

Background Exposure to antiretrovirals at or early after HIV acquisition can suppress viral replication and blunt antibody (Ab) responses; a reduced HIV detectability could impact diagnosis and blood donation screening. Methods We used three antigen (Ag)/Ab assays and one nucleic acid test (NAT) to analyze samples collected in pre-exposure prophylaxis (PrEP) trials (iPrEx; Partners PrEP) before infection detection by Ab-only rapid diagnostic tests (RDTs), and in early antiretroviral treatment (ART) initiation studies (RV254; SIPP). Results Reactivity using NAT and Ag/Ab assays in samples collected up to 8 weeks prior to the first reactive RDT from 251 PrEP trials participants varied between 49-61% for active PrEP users and between 27-37% for placebo users. Among RV254 participants, reactivity in Ag/Ab assays was <100% at all timepoints, and lower among those initiating ART earlier. Seroreversions occurred for 29% (16/55), and blood donation screening with NAT and Ag/Ab assays could have missed up to 36% (20/55) of RV254 participants. For SIPP participants, who started ART at later timepoints, Ag/Ab assays identified infections with no evidence of reactivity waning. Conclusion PrEP and early ART initiation can delay or reduce HIV detectability. Considerations for the implementation of NAT and Ag/Ab tests in PrEP/PEP programs relying on Ab-only RDTs should be balanced according to feasibility and public health impact. While blood transfusion services using Ab-only RDTs for HIV screening should adopt higher sensitivity tests, surveillance and further research are needed to determine the need for novel HIV testing algorithms for those already using NAT and Ag/Ab screening assays.

Nucleocapsid antibody assays can be used to estimate SARS-CoV-2 infection prevalence in regions implementing spike-based COVID-19 vaccines. However, poor sensitivity of nucleocapsid antibody assays in detecting infection after vaccination has been reported. We derived a lower cutoff for identifying previous infections in a large blood donor cohort (N = 142,599) by using the Ortho VITROS Anti-SARS-CoV-2 Total-N Antibody assay, improving sensitivity while maintaining specificity >98%. We validated sensitivity in samples donated after self-reported swab-confirmed infections diagnoses. Sensitivity for first infections in unvaccinated donors was 98.1% (95% CI 98.0-98.2) and for infection after vaccination was 95.6% (95% CI 95.6-95.7) based on the standard cutoff. Regression analysis showed sensitivity was reduced in the Delta compared with Omicron period, in older donors, in asymptomatic infections, <30 days after infection, and for infection after vaccination. The standard Ortho N antibody threshold demonstrated good sensitivity, which was modestly improved with the revised cutoff.

Serial blood and mucosal samples were characterized for 102 participants enrolled a median of 7.0 days after coronavirus disease 2019 diagnosis. Mucosal RNA was detectable for a median of 31.5 (95% confidence interval [CI], 20.5-63.5) days, with persistence >= 1 month associated with obesity (body mass index [BMI] >= 30 kg/m2; odds ratio [OR], 3.9 [95% CI, 1.2-13.8]) but not age, sex, or chronic conditions. Fifteen participants had likely reinfection; lower serum anti-spike IgG levels were associated with reinfection risk. Nearly half of participants (47%) reported symptoms lasting >= 2-3 months; persistence >= 3 months was associated with BMI >= 30 kg/m2 (OR, 4.2 [95% CI, 1.1-12.8]) and peak anti-spike and anti-nucleocapsid antibody levels. Elevated body mass index is associated with mucosal viral persistence and prolonged symptoms after SARS-CoV-2 infection. Low serum anti-S IgG levels were associated with reinfection risk, and higher peak anti-S and anti-NC antibody levels were associated with persistent symptoms.

Cerebral amyloid angiopathy (CAA) is a progressive cerebrovascular and neurodegenerative disorder that is caused by the aberrant accumulation of soluble beta-amyloid isoforms in the small vessel walls of the cerebral and cerebellar cortices and the leptomeninges. Vascular beta-amyloid deposition increases vulnerability to intracerebral hemorrhage (ICH). Clinically, CAA can be the underlying cause of up to half of spontaneous lobar ICHs and can also present with convexity subarachnoid hemorrhage, transient focal neurologic episodes and progressive cognitive decline leading to dementia. The majority of CAA is sporadic, with increasing prevalence with age and often coexists with Alzheimer's Disease (AD). Genetic and iatrogenic etiologies are rare. Cases of CAA and AD have been linked to the use of cadaveric pituitary hormone and later life iatrogenic CAA has also been described following early-life neurosurgical procedures with cadaveric dura grafts. Together these data suggest a capacity of beta-amyloid transmissibility. A recent study found that in over 1 million transfusion recipients from donors who later developed (i) >1 ICH or (ii) one ICH event and dementia, had an elevated risk of developing future ICH. Considering prior reports of transfusion associated variant-Creutzfeldt Jakob Disease in humans and in vivo evidence in sheep, coupled with emerging data supporting beta-amyloid's prion-like properties, raises the question of whether CAA could be transmissible by blood transfusion. This would also have implications for screening, especially in an era of emerging plasma biomarkers of cerebral amyloidosis. At this juncture, though, the evidence is insufficient. However, given the public health concerns raised by this biologically plausible question, there is a need for future studies with well-characterized definitions – and temporal ascertainment – of CAA exposure and outcomes to examine whether CAA is transfusion-transmissible, and, if so, with what frequency and timing of onset.

Red blood cell (RBC) metabolic reprogramming upon exposure to high altitude contributes to physiological human adaptations to hypoxia, a multifaceted process critical to health and disease. To delve into the molecular underpinnings of this phenomenon, first, we performed a multi-omics analysis of RBCs from six lowlanders after exposure to high-altitude hypoxia, with longitudinal sampling at baseline, upon ascent to 5,100 m and descent to sea level. Results highlighted an association between erythrocyte levels of 2,3-bisphosphoglycerate (BPG), an allosteric regulator of hemoglobin that favors oxygen off-loading in the face of hypoxia, and expression levels of the Rhesus blood group RHCE protein. We then expanded on these findings by measuring BPG in RBCs from 13,091 blood donors from the Recipient Epidemiology and Donor Evaluation Study. These data informed a genome-wide association study using BPG levels as a quantitative trait, which identified genetic polymorphisms in the region coding for the Rhesus blood group RHCE as critical determinants of BPG levels in erythrocytes from healthy human volunteers. Mechanistically, we suggest that the Rh group complex, which participates in the exchange of ammonium with the extracellular compartment, may contribute to intracellular alkalinization, thus favoring BPG mutase activity.