A donor safety evidence literature review of the short- and long-term effects of plasmapheresis.

Many blood establishments are expanding plasmapheresis collection capacity to achieve increasing plasma for fractionation volume targets, driven by immunoglobulin product demand. Some adverse events occur in both apheresis and whole blood collection, such as venepuncture-related trauma and vasovagal reactions. Others are specifically related to the apheresis procedure, such as citrate reactions, haemolysis, infiltration and air embolism. Whilst plasmapheresis procedures are generally well tolerated, theoretical longer term donor health considerations, such as the effects on donor plasma protein levels, bone mineral density, iron deficiency and malignancy also require consideration. An evidence-based framework that supports a safe and sustainable increase in the collection of plasma is essential. Our review demonstrates a lack of high-quality evidence on risks and outcomes specifically in plasmapheresis. Whilst conservative procedural controls and donor harm minimization policies will mitigate risk, high-quality evidence is needed to facilitate practice change that is safe and sustainable and maximizes the potential of individual donor differences.

The value of genetic data from 665,460 individuals in managing iron deficiency anaemia and suitability to donate blood.

BACKGROUND AND OBJECTIVES: Although the genetic determinants of haemoglobin and ferritin have been widely studied, those of the clinically and globally relevant iron deficiency anaemia (IDA) and deferral due to hypohaemoglobinemia (Hb-deferral) are unclear. In this investigation, we aimed to quantify the value of genetic information in predicting IDA and Hb-deferral. MATERIALS AND METHODS: We analysed genetic data from up to 665,460 participants of the FinnGen, Blood Service Biobank and UK Biobank, and used INTERVAL (N = 39,979) for validation. We performed genome-wide association studies (GWASs) of IDA and Hb-deferral and utilized publicly available genetic associations to compute polygenic scores for IDA, ferritin and Hb. We fitted models to estimate the effect sizes of these polygenic risk scores (PRSs) on IDA and Hb-deferral risk while accounting for the individual's age, sex, weight, height, smoking status and blood donation history. RESULTS: Significant variants in GWASs of IDA and Hb-deferral appear to be a small subset of variants associated with ferritin and Hb. Effect sizes of genetic predictors of IDA and Hb-deferral are similar to those of age and weight which are typically used in blood donor management. A total genetic score for Hb-deferral was estimated for each individual. The odds ratio estimate between first decile against that at ninth decile of total genetic score distribution ranged from 1.4 to 2.2. CONCLUSION: The value of genetic data in predicting IDA or suitability to donate blood appears to be on a practically useful level.

Iron status in Dutch and Finnish blood donor and general populations: A cross-cohort comparison study.

BACKGROUND AND OBJECTIVES: Blood donors are at risk of developing iron deficiency (ID) (ferritin <15 µg/L, World Health Organization definition). Blood services implement different strategies to mitigate this risk. Although in Finland risk group-based iron supplementation is in place, no iron supplementation is provided in the Netherlands. We aim to describe differences in ferritin levels and ID prevalence in donor and general populations in these countries. MATERIALS AND METHODS: Six cohorts, stratified based on sex, and for women age, in the Netherlands and Finland were used to evaluate differences in ferritin levels and ID between donor populations (Donor InSight-III and FinDonor 10,000) and general populations (Prevention of Renal and Vascular End-Stage Disease [PREVEND], FinRisk 1997 and Health 2000) and newly registered Dutch donors. Multivariable logistic regression was used to quantify associations of various explanatory factors with ID. RESULTS: In total, 13,443 Dutch and 13,933 Finnish subjects were included. Donors, except for women aged ≤50 years old in Finland, had lower median ferritin levels compared with the general population and new donors. Dutch regular blood donors had higher or similar prevalence of ID as compared with the Dutch general population, including new donors. In contrast, Finnish donors showed similar prevalence of ID compared with the general population, except for a markedly lower prevalence in ≤50-year-old women who routinely receive iron supplements when donating. CONCLUSION: Iron status in blood donors differs from that in the general population. The Finnish blood service donor management policy, for example, iron supplementation for risk groups, seemingly protects young female blood donors from developing ID.

Menstrual blood loss is an independent determinant of hemoglobin and ferritin levels in premenopausal blood donors.

INTRODUCTION: To prevent blood donors from developing iron deficiency (ferritin <15 µg/L) and subsequent anemia (hemoglobin <120 g/L), blood services rely on information about known risk factors, including the donor's sex and age. For example, while Finnish women are able to donate whole blood with a minimum donation interval of 91 days, women in the 18 to 25-year-old age group are recommended to donate no more than once per year. Menstrual blood loss is not accounted for in blood donation interval recommendations, despite being a known risk factor of iron deficiency. We aim to investigate to what extent menstrual bleeding is associated with ferritin and hemoglobin levels in female blood donors, and quantify the association of other menstruation-related variables not currently accounted for by blood services (i.e., use of hormonal contraception, heavy menstrual bleeding) with iron deficiency or anemia. MATERIAL AND METHODS: The study population consisted of 473 premenopausal and 491 postmenopausal Dutch whole blood donors. Exclusion criteria were current pregnancy, BMI ≥50, ferritin ≥200, pictorial blood assessment chart (PBAC) ≥400, and age <18 or ≥70 years. Menstrual blood loss was quantified using a PBAC, a semiquantitative method to evaluate the number of used menstrual products and the degree of staining. We identified predictors of log(ferritin)/hemoglobin and iron deficiency/anemia using Bayesian linear and logistic regression models and quantified the average percentage of variance in log(ferritin) and hemoglobin explained by the covariates. RESULTS: Menstrual blood loss accounted for most of the explained variance in hemoglobin (8%) and second only to the number of days since last donation for ferritin (8%). Heavy menstrual bleeding (PBAC ≥150, OR = 3.56 [1.45-8.85], prevalence 13%) was associated with anemia, and use of levonorgestrel-releasing intrauterine device was negatively associated with iron deficiency (OR = 0.06 [0.01-0.44]). After statistical control for menstrual blood loss, age was not associated with iron status. CONCLUSIONS: Menstrual blood loss and blood donation were the most important determinants of iron status in premenopausal women. Thus, results suggest that accounting for menstrual blood loss in donation interval guidelines may benefit blood donors.

Low ferritin levels appear to be associated with worsened health in male repeat blood donors.

BACKGROUND AND OBJECTIVES: Frequent blood donation depletes iron stores of blood donors. Iron depletion may lead to anaemia, but the health effects of iron depletion without anaemia in healthy blood donors are not well understood. We studied in the FinDonor cohort whether worsening of self-rated health of blood donors during the study period was associated with biomarkers for iron levels or other self-reported changes in lifestyle. MATERIALS AND METHODS: We included 1416 participants from the cohort who answered an 89-item questionnaire on their health and lifestyle during their enrolment visit and again at the end of the study. We performed multivariate logistic regression to test if blood donation-related factors affected the probability of reporting worsened health. To set these findings into a more holistic context of health, we subsequently analysed all other questionnaire items with a data-driven exploratory analysis. RESULTS: We found that donation frequency in men and post-menopausal women and ferritin level only in men was associated negatively with worsened health between questionnaires. In the exploratory analysis, stable physical condition was the only questionnaire item that was associated negatively with worsened health in both women and men. CONCLUSION: Our results suggest that low ferritin level is associated with worsened health even in non-anaemic repeat donors, although we find that when health is analysed more holistically, ferritin and other factors primarily related to blood donation lose their importance.

How donor selection criteria can be evaluated with limited scientific evidence: lessons learned from the TRANSPOSE project.

BACKGROUND AND OBJECTIVE: Donor selection criteria (DSC) are a vital link in the chain of supply of Substances of Human Origin (SoHO) but are also subject to controversy and differences of opinion. Traditionally, DSC have been based on application of the precautionary principle. MATERIALS AND METHODS: From 2017 to 2020, TRANSPOSE (TRANSfusion and transplantation PrOtection and SElection of donors), a European research project, aimed to identify discrepancies between current DSC by proposing a standardized risk assessment method for all SoHO (solid organs excluded) and all levels of evidence. RESULTS: The current DSC were assessed using a modified risk assessment method based on the Alliance of Blood Operators' Risk-based decision-making framework for blood safety. It was found that with limited or diverging scientific evidence, it was difficult to reach consensus and an international standardized method for decision-making was lacking. Furthermore, participants found it hard to disregard their local guidelines when providing expert opinion, which resulted in substantial influence on the consensus-based decision-making process. CONCLUSIONS: While the field of donation-safety research is expanding rapidly, there is an urgent need to formalize the decision-making process regarding DSC. This includes the need for standardized methods to increase transparency in the international decision-making process and to ensure that this is performed consistently. Our framework provides an easy-to-implement approach for standardizing risk assessments, especially in the context of limited scientific evidence.

Putting the spotlight on donation-related risks and donor safety - are we succeeding in protecting donors?

BACKGROUND AND OBJECTIVE: The European consortium project TRANSPOSE (TRANSfusion and transplantation: PrOtection and SElection of donors) aimed to assess and evaluate the risks to donors of Substances of Human Origin (SoHO), and to identify gaps between current donor vigilance systems and perceived risks. MATERIALS AND METHODS: National and local data from participating organizations on serious and non-serious adverse reactions in donors were collected from 2014 to 2017. Following this, a survey was performed among participants to identify risks not included in the data sets. Finally, participants rated the risks according to severity, level of evidence and prevalence. RESULTS: Significant discrepancies between anticipated donor risks and the collected data were found. Furthermore, many participants reported that national data on adverse reactions in donors of stem cells, gametes, embryos and tissues were not routinely collected and/or available. CONCLUSIONS: These findings indicate that there is a need to further develop and standardize donor vigilance in Europe and to include long-term risks to donors, which are currently underreported, ensuring donor health and securing the future supply of SoHO.

Variations in hemoglobin measurement and eligibility criteria across blood donation services are associated with differing low-hemoglobin deferral rates: a BEST Collaborative study.

BACKGROUND: Determination of blood donor hemoglobin (Hb) levels is a pre-requisite to ensure donor safety and blood product quality. We aimed to identify Hb measurement practices across blood donation services and to what extent differences associate with low-Hb deferral rates. METHODS: An online survey was performed among Biomedical Excellence for Safer Transfusion (BEST) Collaborative members, extended with published data. Multivariable negative-binomial regression models were built to estimate adjusted associations of minimum donation intervals, Hb cut-offs (high, ≥13.5 g/dL in men or ≥ 12.5 g/dL in women, vs. lower values), iron monitoring (yes/no), providing or prescribing iron supplementation (yes/no), post-versus pre-donation Hb measurement and geographical location (Asian vs. rest), with low-Hb deferral rates. RESULTS: Data were included from 38 blood services. Low-Hb deferral rates varied from 0.11% to 8.81% among men and 0.84% to 31.85% among women. Services with longer minimum donation intervals had significantly lower deferral rates among both women (rate ratio, RR 0.53, 95%CI 0.33-0.84) and men (RR 0.53, 95%CI 0.31-0.90). In women, iron supplementation was associated with lower Hb deferral rates (RR 0.47, 95%CI 0.23-0.94). Finally, being located in Asia was associated with higher low-Hb deferral rates; RR 9.10 (95%CI 3.89-21.27) for women and 6.76 (95%CI 2.45-18.68) for men. CONCLUSION: Differences in Hb measurement and eligibility criteria, particularly longer donation intervals and iron supplementation in women, are associated with variations in low-Hb deferral rates. These insights could help improve both blood donation service efficiency and donor care.

Venous sample is superior to repeated skin-prick testing in blood donor haemoglobin second-line screening.

BACKGROUND: Blood donor haemoglobin concentration (Hb) is commonly measured from a skin-prick sample. However, the skin-prick sample is prone to preanalytical error and variation, which may lead to false deferrals due to low Hb. STUDY DESIGN AND METHODS: We assessed the efficacy of two second-line screening models for the evaluation of blood donors failing the initial skin-prick test. In the venous model (n = 305), Hb was measured from a venous sample at the donation site. In the skin-prick model (n = 331), two additional skin-prick samples were measured. All on-site Hb measurements were performed with HemoCue Hb201+ (HemoCue AB) point-of-care (POC) device. Hb in the venous samples was later also determined with a hematology analyzer (Sysmex XN, Sysmex Co.) to obtain the donor's correct Hb. A questionnaire evaluated Blood Service nurses' preferences regarding Hb assessment. RESULTS: Significantly less donors were deferred from donation with venous model (40%) than with skin-prick model (51%; chi-square test P = 0·004). Only two donors (0·7%) were incorrectly accepted in the venous model. Further, Blood Service nurses preferred venous model over skin-prick model. After the study, the venous model was implemented nationwide, and in the first two months after implementation, the deferral rate due to low Hb decreased from 2·7% to 1·9%. CONCLUSION: A venous sample for blood donor Hb second-line screening significantly decreased low Hb deferrals compared to repeated skin-prick testing without compromising donor safety. Valuable donations can be recovered by implementing a practical second-line screening model based on venous sampling.

FinDonor 10 000 study: a cohort to identify iron depletion and factors affecting it in Finnish blood donors.

BACKGROUND AND OBJECTIVES: There is increasing evidence that frequent blood donation depletes the iron stores of some blood donors. The FinDonor 10 000 study was set up to study iron status and factors affecting iron stores in Finnish blood donors. In Finland, iron supplementation for at-risk groups has been in place since the 1980s. MATERIAL AND METHODS: A total of 2584 blood donors (N = 8003 samples) were recruited into the study alongside standard donation at three donation sites in the capital region of Finland between 5/2015 and 12/2017. All participants were asked to fill out a questionnaire about their health and lifestyle. Blood samples were collected from the sample pouch of whole blood collection set, kept in cool temperature and processed centrally. Whole blood count, CRP, ferritin and sTFR were measured from the samples, and DNA was isolated for GWAS studies. RESULTS: Participant demographics, albeit in general similar to the general blood donor population in Finland, indicated some bias towards older and more frequent donors. Participation in the study increased median donation frequency of the donors. Analysis of the effect of time lag from the sampling to the analysis and the time of day when sample was drawn revealed small but significant time-dependent changes. CONCLUSION: The FinDonor cohort now provides us with tools to identify potential donor groups at increased risk of iron deficiency and factors explaining this risk. The increase in donation frequency during the study suggests that scientific projects can be used to increase the commitment of blood donors.

The impact of analytical variation of hemoglobin measurement on blood donors' hemoglobin and deferral rates.

BACKGROUND: Donors' hemoglobin (Hb) level must be tested before blood donation. Low Hb is the leading reason for donor deferral. Many donor-related and external factors associated with low Hb are known, but no studies have been conducted concerning the effects of analytical variation on donor Hb measurements and deferrals. STUDY DESIGN AND METHODS: The effects of donors' age, the seasonal and daily distribution of donations, and batch-to-batch variation in HemoCue Hb 201+ cuvettes on donors' capillary Hb (cHb) measurements and deferrals were analyzed for more than 1.7 million donor visits in 2010 to 2016 at a national blood establishment. Furthermore, approximately 3.1 million cHb measurements from the years 2000 to 2009 were included in analyses to correlate measured cHb value and Hb deferral rate. RESULTS: A significant correlation between the mean annual cHb and Hb deferral rate was observed in both women and men. The season of the donation was the strongest explanatory factor for the monthly variation of predonation cHb (explaining 25 and 31% of the variation in women and men, respectively). Batch-to-batch variation in HemoCue cuvettes explained 6.8% of monthly variation in women and 7.4% in men. Monthly changes in donors' age distribution explained 2.5% of monthly variation in women and 2.4% in men. CONCLUSION: Small and, in most clinical settings, negligible analytical variation in Hb measurement methods can have significant consequences when used for Hb screening of blood donors. This should be minimized by using methods in which analytical variation is under control and kept as low as possible.

Season and time of day affect capillary blood hemoglobin level and low hemoglobin deferral in blood donors: analysis in a national blood bank.

BACKGROUND: Low hemoglobin (Hb) is the most common reason for temporary blood donor deferral. However, factors that affect Hb measurement may not portray donor health but reflect external circumstances. STUDY DESIGN AND METHODS: The effects of season, time of day, donor age, ABO, and D on capillary blood Hb level (cHb) and low Hb deferral were analyzed in 1,396,645 donor registrations from the years 2010 to 2014 in a national blood bank. RESULTS: cHb was lower in the summer (July mean 154.1 g/L in men, 139.6 g/L in women) and in the evening (7 pm mean 153.8 g/L in men, 138.9 g/L in women) than in the winter (January mean 156.9 g/L in men, 141.8 g/L in women) and in the morning (11 am mean 157.2 g/L in men, 142.8 g/L in women; all p < 0.0001). This affected donor deferral due to low Hb, with 7.8% donors deferred in July at 7 pm and 1.6% deferred in January at 11 am (p < 0.0001). With age, cHb increased in women and decreased in men. The lowest cHb was observed in blood group A (mean 154.9 g/L in men, 140.3 g/L in women) and the highest in blood group B (mean 156.6 g/L in men, 141.5 g/L in women). D had no practically significant effect on cHb. CONCLUSION: External factors, which do not reflect donor health, affect cHb and donor deferral due to low Hb. These factors should be considered when donor eligibility guidelines and procedures are developed.

The effect of donation activity dwarfs the effect of lifestyle, diet and targeted iron supplementation on blood donor iron stores.

The iron status of blood donors is a subject of concern for blood establishments. The Finnish Red Cross Blood Service addresses iron loss in blood donors by proposing systematic iron supplementation for demographic at-risk donor groups. We measured blood count, ferritin and soluble transferrin receptor (sTfR) and acquired lifestyle and health information from 2200 blood donors of the FinDonor 10000 cohort. We used modern data analysis methods to estimate iron status and factors affecting it with a special focus on the effects of the blood service's iron supplementation policy. Low ferritin (< 15 µg/L), an indicator of low iron stores, was present in 20.6% of pre-menopausal women, 10.6% of post-menopausal women and 6% of men. Anemia co-occurred with iron deficiency more frequently in pre-menopausal women (21 out of 25 cases) than in men (3/6) or post-menopausal women (1/2). In multivariable regression analyses, lifestyle, dietary, and blood donation factors explained up to 38% of the variance in ferritin levels but only ~10% of the variance in sTfR levels. Days since previous donation were positively associated with ferritin levels in all groups while the number of donations during the past 2 years was negatively associated with ferritin levels in pre-menopausal women and men. FRCBS-provided iron supplementation was negatively associated with ferritin levels in men only. Relative importance analyses showed that donation activity accounted for most of the explained variance in ferritin levels while iron supplementation explained less than 1%. Variation in ferritin levels was not significantly associated with variation in self-reported health. Donation activity was the most important factor affecting blood donor iron levels, far ahead of e.g. red-meat consumption or iron supplementation. Importantly, self-reported health of donors with lower iron stores was not lower than self-reported health of donors with higher iron stores.

Users and non-users of web-based health advice service among Finnish university students - chronic conditions and self-reported health status (a cross-sectional study).

BACKGROUND: The Internet is increasingly used by citizens as source of health information. Young, highly educated adults use the Internet frequently to search for health-related information. Our study explores whether reported chronic conditions or self-reported health status differed among Finnish university students using the Finnish Student Health Services web-based health advice service compared with those not using the service. METHODS: Cross-sectional study performed by a national postal survey in 2004. MATERIAL: A random sample (n = 5 030) of a population of 101 805 undergraduate Finnish university students aged 19-35. The response rate: 63% (n = 3 153). MAIN OUTCOME MEASURES: Proportion of university students reporting use a of web-based health advice service, diagnosed chronic conditions, and self-reported health status of users and non-users of a web-based health advice service. STATISTICAL METHODS: Data were presented with frequency distributions and cross-tabulations and the chi2 test was used. RESULTS: 12% (n = 370) of Finnish undergraduate students had used the web-based health advice service and were identified as 'users'. The proportion of male students reporting allergic rhinitis or conjunctivitis was greater among users than non-users (24%, n = 22 vs. 15%, n = 154, chi2, P = .03). The proportion of female students reporting chronic mental health problems was greater among users than non-users (12%, n = 34 vs. 8%, n = 140, chi2, P = .03). There was no statistical significance between the group differences of male or female users and non-users in self-reported health status (good or fairly good, average, rather poor or poor). CONCLUSION: Among young, highly educated adults the use of a web-based health advice service is not associated with self-reported health status. However, a web-based health advice service could offer support for managing several specific chronic conditions. More research data is needed to evaluate the role of web-based health advice services that supplement traditional forms of health services.

Immunomonitoring of MSC-Treated GvHD Patients Reveals Only Moderate Potential for Response Prediction but Indicates Treatment Safety.

Mesenchymal stromal cells (MSCs) are used as salvage therapy to treat steroid-refractory acute graft-versus-host disease (aGvHD). We studied the immunological response to MSC treatment in 16 aGvHD patients by assessing lymphocyte profiles and three proposed aGvHD serum markers during the MSC treatment. Surprisingly, there were no obvious differences in the lymphocyte profiles between the responders and non-responders. The numbers of T, B, and NK cells were below the normal reference interval in all patients. CD4+ T helper (Th) cell levels remained particularly low throughout the follow-up period. The relative proportion of Th1 cells decreased, while regulatory T cells remained unaltered, and only very few Th2 and Th17 cells could be detected. Serum concentrations of regenerating islet-derived protein 3-alpha, cytokeratin-18 fragments (CK18F), and elafin were significantly elevated in patient samples compared with healthy controls, but only CK18F showed any potential in the prediction of patients' response to MSCs. No obvious markers for MSC therapy response were revealed in this study, but the results suggest that allogeneic MSCs do not provoke overt T cell-mediated immune responses at least in immunosuppressed aGvHD patients. The results advocate for the safety of MSC therapy and bring new insights in MSC immunomodulation mechanisms.

Retrospective analysis of capillary hemoglobin recovery in nearly 1 200 000 blood donor returns.

Measuring the concentration of capillary hemoglobin (cHb) is a standard procedure before blood donation. To further assess the time period needed for cHb recovery after blood donation and to have a more in-depth understanding of features of recovery, we used data-mining tools in a large, retrospective data pool containing all 1 163 524 donor returns that took place in Finland in 2010 to 2015. The results show that the average recovery times for cHb to return back to the level preceding donation were substantially longer, over 200 days in all age groups, than were the minimum allowed donation intervals. cHb recovery was especially poor in women under the age of 30 who returned to donate soon after the minimum allowed donation interval. It was of interest that frequent donors recovered substantially faster, with the average recovery times of ∼100 days in men and ∼200 days in women, than did infrequent donors, suggesting that there is a subpopulation of donors who can donate frequently without fear of iron deficiency. Return interval in fact explained only 1% of the variation in cHb recovery, which points to unknown, individual features, such as genetic or lifestyle factors, warranting further studies and suggesting that simply extending the allowed donation intervals may not suffice to improve cHb recovery. The study demonstrates that data mining of blood bank records is a powerful tool for depicting features of blood donor population.

Use of email for patient communication in student health care: a cross-sectional study.

BACKGROUND: Citizens increasingly use email in personal communication. It is not however clear to what extent physicians utilize it for patient communication. Our study was designed to examine physicians' activity in using email and to estimate the proportion of email messages missing from documentation in electronic patient records (EPR). METHODS: All physicians (n = 76; 48 general practitioners and 28 specialists) at the Finnish Student Health Service received a questionnaire by email, and were asked to print it and keep a daily tally of visits, phone calls and email messages over the study period of one working week (5.5.-9.5.2003). The response rate was 70%. The data originating from the questionnaire were compared with statistical data from the EPR during the study period. RESULTS: The majority (79%, 41/52) of doctors reported using email with patients, averaging 8.6 (range: 0-96) email contacts and a percentage rate of "email / visit" 20% (range: 0-185%) in one working week. Doctors in the capital city region and those doctors who had a positive attitude toward email for patient communication were most active in email use. Up to 73% of email contacts were not documented in the EPR. CONCLUSION: The activity in using email with patients verified among Finnish physicians is compatible with recent study results elsewhere. The notable proportion of un-recorded email messages establishes the need for an electric communication system built into the EPR to improve the quality of patient care and to limit medico-legal risks.