How red blood cell quality is starting to carry its weight

See article on page 435–448, in this issue 449–463, Red blood cell (RBC) transfusions can be a life-saving intervention for anemic or bleeding patients. However, carry both attributable and non-attributable risks, the latter exemplified by studies showing restrictive transfusion strategies lead to similar (or better) outcomes compared liberal strategies.1 Although RBCs other components are treated as standardized multiple regulatory bodies, there is increasing evidence that donor characteristics processing parameters may cause variability these complex biologic products.2, 3 This has led renewed interest studying “what's bag” better understand which factors could potentially harm As an example, storage time often been studied possible factor affecting RBC quality, but date no randomized controlled trials have demonstrated differences with standard age vs older RBCs.4 It only considering of stored studies, variables might affect quality related were not taken into account. Several groups recently begun investigating impact such sex, age, ethnicity, diet quality.3, 5-8 Elevated body mass index (BMI), associated numerous metabolic changes chronic medical conditions, also proposed alter biology relevant characteristic. Here, we discuss two reported TRANSFUSION BMI donated RBCs: one using data from Australian Cross Blood Service9 U.S. group donors Vitalant/the REDS-III RBC-Omics project.10 In pilot study, Sparrow et al9 assessed association between hemolysis linear logistic regression models corrected product/processing factors. The analysis was stratified sex (male subjects = 912; female 822). Increasing products male donors, greatest effect size seen highest quartile (BMI 30.3-51.4). trend toward increased only. Overall, 2.9% samples analyzed exceeded more conservative Council Europe limit 0.8%, higher proportion exceeding threshold (4.1%) those (1.7%). Hazegh al10 linkage BMI, hemolysis, metabolomics analyzing different populations (Vitalant NHLBI data) performing complementary experiments murine model. Throughout study they distinguish three distinct types vitro measured: storage, oxidative, osmotic. evaluating Vitalant (n 18), investigators found significant at later unit points osmotic oxidative hemolysis. set transfused immunocompromised mice, where obese significantly smaller increment earliest point (t 10 minutes), points. With cohort 13 317), after adjusting confounders. Different patient including race/ethnicity, number donations, sex; some BMI. An subset 30) extremes susceptibilities fatty acid amino composition/levels when comparing lowest BMIs. high BMIs had dysregulated antioxidant pathways levels oxidized lipids biomarkers, well nitric oxide metabolism. These shed new light RBCs, reporting consistent signals measures across international jurisdictions, methods, confounders, use metabolomics/animal model data. Both important hypothesis generation bring “bench bedside,” future directions include: (a) broader assessment panel markers, (b) gathering further details health status (including conditions syndrome) and/or confounding, (c) expanding sample sizes analyses (such al al). differed how defined statistical methods used control thus reached discrepant conclusions within their studies. suggests plausible mechanisms link obesity damage, even among profiles varied. If proven represent clinically meaningful risk hemolysis/decreased bank systems would need consider operationalize information center determining cut-offs-while potential nuances like variable thresholds based interacting Donor centers excluding currently eligible especially since younger prevalence being overweight/obese.11 While low vasovagal reactions,12 likely needed determine if adverse donation outcomes, observed stem donations.13 decisions considered care, originally thought harmful vindicated sophisticated account confounders-as longer time.4 all created equal. affected interactions factors, solutions. particular, comorbidities, therapies, inherited traits play role. All investigated, surrogates underlying damage. Hemolysis most commonly marker, while easy measure, its clinical relevance unclear. Modern easily meet historic limits, present few established thresholds. Other traditional markers include vivo recovery, ATP concentration, 2,3-DPG pH, morphology, Novel emerging free DNA (cfDNA), damage-associated molecular patterns (DAMPs), extracellular vesicles (EVs), cytokines, analyses: provide closer links inflammatory mediation. Heterogeneity individual confound donor/production/storage assessing population (see Mykhailova Transfusion 2020;60:2633-2646; accompanying editorial 2020; 60:2464-2465).14 Most importantly, highlight large-scale databases interrogated explore associations product quality. Examples exist worldwide, aforementioned SCANDAT databases15-which broadly linked registry so hypotheses generated. recipient arguably key piece fact clinicians aware believe “an RBC,” allows occur minimal selection biases For Chasse carried out large mortality recipients receiving RBCs.16 Similarly, Heddle mortality, finding fresh (≤7 days old) whole filtered (WBF) in-hospital mid-aged (8-35 red (RCF) reference group.17 Generally, produced RCF reduced lower residual leukocyte counts, less EVs, cfDNA, DAMPs WBF processed units.3 A recent units IL-8 production, mediated fewer platelet EVs downregulate inflammation.18 Ultimately, larger scale hard (mortality, hospitalization, etc.) will help assess whether statistically translate outcomes. role medicine specialty ensure continuum vein-to-vein safety concept part (Figure 1): appears great variation remains unclear requires study. Discussion stakeholders clinicians, hospital services, centers, regulators, patients, strike balance pragmatism precautionary principle. We propose next steps address challenges: manuscripts should criteria/characteristics, processing, production supplementary allow comparison generalizability robust updated database regarding effects program, jurisdictions registries incorporating lab system processes generation. remain many unknowns centuries practice, rich history collaboration necessary bio-therapeutic agent, it affects what ultimately ideal “standard” unit. thank Dr. Jason Acker providing his feedback expertise editorial. AWS consultant Octapharma Canada, participated advisory board CSL Behring, received unrestricted educational grant Hemerus Medical, LLC.