Blood Donor Demographics and Transfusion Recipient Survival—No Country for Old Men?

Blood for transfusion is a drugor,more specifically, a biological medicine.1 The US Food and Drug Administration regulatesbloodforpurity,potency,andsafetyunder theFood,Drug, and Cosmetic Act of 1938. Regulatory authorities in most developed countries prescribe blood collection, storage, testing, labeling, and intended use. Facilities for blood component “manufacture” are licensed and inspected for compliance with current good manufacturing practices. Where blood differs from small-molecule pharmaceuticals and recombinant biologics is in its unit-to-unit heterogeneity (batch variability). Although blood donors are qualified as suppliers of “raw material” by rigorous selection and testing standards, each donor is biologically distinct. Therefore, every unit of blood is considered its own batch. Despite the acknowledged batch variability, unit-to-unit differences are not expected to be so significant as to affect transfusion outcomes. However, the association of donor characteristics with transfusion outcomes has not been carefully investigated. In this issue of JAMA Internal Medicine, Chasse and colleagues2 report the association of blood donor age and sex with recipient survival after red blood cell (RBC) transfusion. Their longitudinal cohort study links blood donor data routinely collectedby theCanadianBloodServices toRBC recipient clinical information gathered from databases containing the short-term and long-term patient outcomes from 4 academichospitals.The investigatorspredeterminedprimaryand secondary exposures (donor age and donor sex) and the primaryoutcome (recipient survival). The studyperiod spanned 7years and included80755blooddonors, 30503patients, and 187 960 RBC units. The investigators constructed a robust model supported by generally accepted statistical principles. Yet, evenwith rigorous analyses and sensitivity testing, their study remainsobservational andsubject to the risksofbiasand confounding. The findings should be consideredhypotheses, not evidence of causality. Theobservation that donordemographic factorsmight be associatedwith transfusionoutcome isnotnew.More than50 yearsago, the riskof transfusion-transmittedhepatitiswascorrelated with donor sex, age, socioeconomic status, and ethnicity.3 All of these associations were eventually found to be related to the donor’s risk of infectionwith hepatitis B or C viruses.However, the findingsbyChasse andcolleagues,2 particularly the primary exposure that transfused RBCs from youngerdonors areassociatedwithan increasedmortality risk of6%to8%,with thegreatest risk inmale recipients, arehardly expectedor intuitive.Whyshouldoldmenbe safer donors but more vulnerable recipients? The only other published study4 ofRBCdonor age and recipientmortality, a large,matched cohort investigation from the Danish and Swedish ScandinavianDonationsandTransfusions (SCANDAT)2database, found noassociationbetweendonor ageandpatient 30-dayor 1-year mortality afterRBCorplasma transfusion. The studies arenot precisely comparable. Patients in the SCANDAT2analysis had a lower RBC exposure. Similarly, in a single-center US study,5 noassociationwas foundbetweendonorageandrecipientoutcomeafterplasma transfusion ina largedatabase-linkedstudy of coronary artery bypass surgery.However, the absenceof an obvious mechanism or of confirmatory studies does not refute the findings byChasse and colleagues2 but indicates that verification is necessary before such findings canbe actedon. With the secondary exposure, Chasse and colleagues2 founda strongassociationbetween femaleRBCdonors and recipientmortality. The transfusionof each additional RBCunit from a female donor compared with a male donor was associated with an increased risk of death of 8%. Numerous biological differencesdistinguishblood fromfemaleandmaledonors, from lower hemoglobin levels and different protein concentrations to the frequency of HLA, platelet, and granulocyte alloantibodies. None of these factors are used in routine blood donor screening to determine the safety of RBC transfusion. However, plasma from female donors is routinely avoided, as are single-donor platelet concentrates from multiparous women who have not been screened for HLA alloantibodies, because of their association with transfusionrelated acute lung injury (TRALI). Still, the risk of TRALI, especially from blood components that contain minimal amounts of plasma, cannot explain an 8% mortality difference. Other genetic factors appear to be involved in the documented differences in donor RBC in vivo survival and ex vivo storage, although neither of these examples of batch variability has been associated with donor sex,6,7 nor have such differences been shown to affect survival of blood component recipients. Several featuresof the studybyChasseandcolleagues2deserve emphasis. Of course, the specific conclusions are tantalizingandclearlymerit furtherexploration.Moregenerally, this study highlights the need to further investigatewhich demographic and genetic donor factors aside from blood groups might influence the safety and efficacy of the different blood components. Such researchhasbeenovershadowedby theunderstandable focus on pathogen transmission. Perhaps the most significant message may be recognition, as the authors point out, that to perform such studies one has to be able to track blood from “vein to vein.” Themost efficient way to do thisona large scale is byexploitingexistingdatabases, thebest example of which is the previously cited SCANDAT database, a collaboration between Sweden and Denmark.4 Related article page 1307 Association of Blood Donor Age and SexWith Recipient Survival Original Investigation Research