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.

Predicting haemoglobin deferral using machine learning models: Can we use the same prediction model across countries?

BACKGROUND AND OBJECTIVES: Personalized donation strategies based on haemoglobin (Hb) prediction models may reduce Hb deferrals and hence costs of donation, meanwhile improving commitment of donors. We previously found that prediction models perform better in validation data with a high Hb deferral rate. We therefore investigate how Hb deferral prediction models perform when exchanged with other blood establishments. MATERIALS AND METHODS: Donation data from the past 5 years from random samples of 10,000 donors from Australia, Belgium, Finland, the Netherlands and South Africa were used to fit random forest models for Hb deferral prediction. Trained models were exchanged between blood establishments. Model performance was evaluated using the area under the precision-recall curve (AUPR). Variable importance was assessed using SHapley Additive exPlanations (SHAP) values. RESULTS: Across the validation datasets and exchanged models, the AUPR ranged from 0.05 to 0.43. Exchanged models performed similarly within validation datasets, irrespective of the origin of the training data. Apart from subtle differences, the importance of most predictor variables was similar in all trained models. CONCLUSION: Our results suggest that Hb deferral prediction models trained in different blood establishments perform similarly within different validation datasets, regardless of the deferral rate of their training data. Models learn similar associations in different blood establishments.

Increasing the upper age limit for blood donation: Perspectives from older donors.

BACKGROUND AND OBJECTIVES: In the Netherlands, as of April 2018, the upper age limit for blood donation has been raised from 69 to 79 years, providing an opportunity to study older donors' perspectives regarding donating at older age. This study aims to explore whether older donors agree with the increase of the age limit, if they feel obliged to continue donating, to identify their motivators and barriers for donating blood and describe donation-related experiences and complications. MATERIALS AND METHODS: An online survey was distributed among Dutch blood donors aged 68-73 years. The survey contained questions regarding the increase of the upper age limit, motivations and barriers for donating, donation-related experiences and obligatory feelings to continue donating. RESULTS: Six hundred sixty donors (55%) were included in the analyses, including 38 stopped donors. Most donors (92%) agreed with the increase of the upper age limit. Approximately 63% of participating donors felt obliged to continue donating, especially women with high education. Donors indicated they felt healthy enough to keep donating (95%), and 72% thought it is good for their health to keep donating. Few donors reported that they found it hard to keep donating (5%) or indicated that they did not feel healthy enough to donate or thought it was not safe for them anymore (3.4%). CONCLUSION: Most of the older donors agree with the increase of the upper age limit for blood donation, report only few and minor donation-related experiences or complications and are highly motivated to continue their donor career at an older age.

Safety and protection of plasma donors: A scoping review and evidence gap map.

BACKGROUND AND OBJECTIVES: As part of a large-scale project to safely increase plasma collection in Europe, the current scoping review identifies the existing evidence (gaps) on adverse events (AEs) and other health effects in plasmapheresis donors, as well as factors that may be associated with such events/effects. MATERIALS AND METHODS: We searched six databases and three registries. Study characteristics (publication type, language, study design, population, outcomes, associated factors, time of assessment, duration of follow-up, number and frequency of donations, convalescent plasma [y/n], setting and location) were synthesized narratively and in an interactive evidence gap map (EGM). RESULTS: Ninety-four research articles and five registrations were identified. Around 90% were observational studies (57 controlled and 33 uncontrolled), and most of them were performed in Europe (55%) or the United States (20%). Factors studied in association with donor health included donor characteristics (e.g., sex, age) (n = 27), cumulative number of donations (n = 21), donation frequency (n = 11), plasma collection device or programme (n = 11), donor status (first time vs. repeat) (n = 10), donation volume per session (n = 8), time in donation programme (n = 3), preventive measures (n = 2) or other (n = 9). CONCLUSION: The current scoping review provides an accessible tool for researchers and policymakers to identify the available evidence (gaps) concerning plasmapheresis donation safety. Controlled prospective studies with long-term donor follow-up are scarce. Furthermore, additional experimental studies comparing the health effects of different donation frequencies are required to inform a safe upper limit for donation frequency.

Iron supplementation: A qualitative study on the perception of blood donors, blood collection staff and donor physicians.

BACKGROUND AND OBJECTIVES: Iron supplementation is an effective strategy to mitigate donation-induced iron deficiency in blood donors. However, evidence on the perception of individuals involved in blood donation on iron supplementation as a blood service policy is lacking. This study aimed to evaluate the knowledge and perception of whole blood donors (donors), blood collection staff (collection staff) and donor physicians (physicians) regarding donation-induced iron loss and iron supplementation. MATERIALS AND METHODS: Online focus group discussions had four to six participants and followed a structured questioning approach. All participants had to be fluent in Dutch to participate, and donors had donated at least five times. Sixteen donors, eight collection staff members and four physicians participated in this study. Recordings were transcribed, coded and analysed using a grounded theory approach. RESULTS: Awareness of donation-induced iron loss was limited in donors. Donors and physicians were predominantly positive towards iron supplementation; the primary motivator for donors was to prevent deferral and reduce iron-deficiency-related symptoms. Improving donor health was the main argument for physicians to advocate iron supplementation. Staff had a critical view on iron supplementation as a policy, as they perceived it as unethical and possibly ineffective. A knowledge gap might underlie their concerns. CONCLUSION: Most individuals involved in blood donation are positive towards iron supplementation as a blood service policy. If implemented, guidance and monitoring is desired and adequate education of all stakeholders is required.

Individual and environmental determinants of serum ferritin levels: A structural equation model.

BACKGROUND AND OBJECTIVES: Serum ferritin levels are increasingly being used to assess iron stores. Considerable variation in ferritin levels within and between individuals has been observed, but our current understanding of factors that explain this variation is far from complete. We aim to combine multiple potential determinants in an integrative model, and investigate their relative importance and potential interactions. METHODS: We use ferritin measurements collected by Sanquin Blood Bank on both prospective (N = 59 596) and active blood donors (N = 78 318) to fit a structural equation model with three latent constructs (individual characteristics, donation history, and environmental factors). Parameters were estimated separately by sex and donor status. RESULTS: The model explained 25% of ferritin variance in prospective donors, and 40% in active donors. Individual characteristics and donation history were the most important determinants of ferritin levels in active donors. The association between environmental factors and ferritin was smaller but still substantial; higher exposure to air pollution was associated with higher ferritin levels, and this association was considerably stronger for active blood donors than for prospective donors. DISCUSSION: In active donors, individual characteristics explain 20% (17%) of ferritin variation, donation history explains 14% (25%) and environmental factors explain 5% (4%) for women (men). Our model presents known ferritin determinants in a broader perspective, allowing for comparison with other determinants as well as between new and active donors, or between men and women.

An international comparison of haemoglobin deferral prediction models for blood banking.

BACKGROUND AND OBJECTIVES: Blood banks use a haemoglobin (Hb) threshold before blood donation to minimize donors' risk of anaemia. Hb prediction models may guide decisions on which donors to invite, and should ideally also be generally applicable, thus in different countries and settings. In this paper, we compare the outcome of various prediction models in different settings and highlight differences and similarities. MATERIALS AND METHODS: Donation data of repeat donors from the past 5 years of Australia, Belgium, Finland, the Netherlands and South Africa were used to fit five identical prediction models: logistic regression, random forest, support vector machine, linear mixed model and dynamic linear mixed model. Only donors with five or more donation attempts were included to ensure having informative data from all donors. Analyses were performed for men and women separately and outcomes compared. RESULTS: Within countries and overall, different models perform similarly well. However, there are substantial differences in model performance between countries, and there is a positive association between the deferral rate in a country and the ability to predict donor deferral. Nonetheless, the importance of predictor variables across countries is similar and is highest for the previous Hb level. CONCLUSION: The limited impact of model architecture and country indicates that all models show similar relationships between the predictor variables and donor deferral. Donor deferral is found to be better predictable in countries with high deferral rates. Therefore, such countries may benefit more from deferral prediction models than those with low deferral rates.

Mass spectrometry-based analysis on the impact of whole blood donation on the global plasma proteome.

BACKGROUND: Biomonitoring may provide important insights into the impact of a whole blood donation for individual blood donors. STUDY DESIGN AND METHODS: Here, we used unbiased mass spectrometry (MS)-based proteomics to assess longitudinal changes in the global plasma proteome, after a single blood donation for new and regular donors. Subsequently, we compared plasma proteomes of 76 male and female whole blood donors, that were grouped based on their ferritin and hemoglobin (Hb) levels. RESULTS: The longitudinal analysis showed limited changes in the plasma proteomes of new and regular donors after a whole blood donation during a 180-day follow-up period, apart from a significant short-term decrease in fibronectin. No differences were observed in the plasma proteomes of donors with high versus low Hb and/or ferritin levels. Plasma proteins with the highest variation between and within donors included pregnancy zone protein, which was associated with sex, Alfa 1-antitrypsin which was associated with the allelic variation, and Immunoglobulin D. Coexpression analysis revealed clustering of proteins that are associated with platelet, red cell, and neutrophil signatures as well as with the complement system and immune responses, including a prominent correlating cluster of immunoglobulin M (IgM), immunoglobulin J chain (JCHAIN), and CD5 antigen-like (CD5L). DISCUSSION: Overall, our proteomic approach shows that whole blood donation has a limited impact on the plasma proteins measured. Our findings suggest that plasma profiling can be successfully employed to consistently detect proteins and protein complexes that reflect the functionality and integrity of platelets, red blood cells, and immune cells in blood donors and thus highlights its potential use for donor health monitoring.

Ferritin Trajectories over Repeated Whole Blood Donations: Results from the FIND+ Study.

BACKGROUND: Depending on post-donation erythropoiesis, available iron stores, and iron absorption rates, optimal donation intervals may differ between donors. This project aims to define subpopulations of donors with different ferritin trajectories over repeated donations. METHODS: Ferritin levels of 300 new whole blood donors were measured from stored (lookback) samples from each donation over two years in an observational cohort study. Latent classes of ferritin level trajectories were investigated separately using growth mixture models for male and female donors. General linear mixed models assessed associations of ferritin levels with subsequent iron deficiency and/or low hemoglobin. RESULTS: Two groups of donors were identified using group-based trajectory modeling in both genders. Ferritin levels showed rather linear reductions among 42.9% of male donors and 87.7% of female donors. For the remaining groups of donors, steeper declines in ferritin levels were observed. Ferritin levels at baseline and the end of follow-up varied greatly between groups. CONCLUSIONS: Repeated ferritin measurements show depleting iron stores in all-new whole blood donors, the level at which mainly depends on baseline ferritin levels. Tailored, less intensive donation strategies might help to prevent low iron in donors, and could be supported with ferritin monitoring and/or iron supplementation.

A computational model for prediction of ferritin and haemoglobin levels in blood donors.

Blood donors are at risk of iron deficiency anaemia. While this risk is decreased through ferritin-based deferral, ideally ferritin monitoring should also aid in optimising donation frequencies. We extended an existing model of haemoglobin (Hb) synthesis with iron homeostasis and validated the model on a cohort of 300 new donors whose ferritin levels were measured from stored blood samples collected over a 2-year period. We then used the donor's gender, body weight, height, and baseline Hb and ferritin levels to predict subsequent Hb and ferritin levels. The prediction error was within measurement variability in 88% of Hb level predictions and 64% of ferritin level predictions. A sensitivity analysis of the model revealed that baseline ferritin level was the most important in predicting future ferritin levels. Finally, we used the model to calculate the annual donation frequency at which donors would keep their ferritin level >15 ng/ml when measured after donating for 2 years. The mean annual donation frequency would then be 1.9 for women and 4.1 for men. The computational model, requiring baseline values only, can predict future Hb and ferritin levels remarkably well. This enables determination of optimal donation frequencies for individual donors at the start of their donation career.

Whole blood donor return rates after deferral for tattooing or body piercing-Survey across blood donation services: The BEST collaborative study.

BACKGROUND AND OBJECTIVES: To protect transfusion recipients from transfusion-transmissible infections, blood donors are deferred from donating after recent tattooing or piercing. To explore to what extent and how this deferral impacts donor availability, we performed an international study to investigate how many donors were deferred for a recent tattoo or piercing and how many of these donors returned to donate. MATERIALS AND METHODS: We surveyed blood centre members of the Biomedical Excellence for Safer Transfusion (BEST) Collaborative and the European Blood Alliance Donor Studies Working Group on their numbers of donations, tattoo and piercing deferrals, and return rates in the year 2017. RESULTS: Eight blood centres participated. Overall, deferral rates were lower for repeat donors compared to new donors. Repeat donors were more likely to return than new donors. Women and young donors were more often deferred than male and older donors. Men were more demotivated by tattoo or piercing deferral, resulting in lower return rates compared to women. Return rates differed greatly between blood centres. CONCLUSION: Tattoo and piercing deferrals lead to missed donations and result in lower return rates. However, the numbers vary largely internationally, probably due to cultural and policy differences. Shortening deferral periods after tattooing or piercing may reduce the impact on donor availability, which should be investigated in single-centre studies.

Balancing non-discriminatory donor selection and blood safety in the Netherlands: Evaluation of an individual risk assessment of sexual behavior.

BACKGROUND: To better balance the safety of the blood supply and the inclusion of men who have sex with men (MSM), further improvements are needed to the risk management strategy employed in the Netherlands to reduce transfusion-transmissible infections (TTIs). A gender-neutral individual risk assessment could provide a solution by determining donor eligibility based on sexual behaviors known to increase the risk of TTIs. Our objective is to estimate the proportion of blood donors that would be deferred by such an assessment, as well as their discomfort answering such questions. STUDY DESIGN AND METHODS: Two surveys were distributed in May 2020 to assess sexual behavior in blood donors in the last 4, 6, and 12 months, as well as their discomfort reporting such information. A combination of both surveys measured the extent to which discomfort was associated with reporting sexual behavior. A high-risk sexual behavior pattern was defined as having had multiple sexual partners and having engaged in anal sex, without consistent condom use. RESULTS: Of all 2177 participating whole blood donors, 0.8% report engaging in high-risk sexual behaviors over the last 4 months and would therefore be ineligible to donate. When accounting for the additional proportion of donors that reported such questions would stop them from donating, 2.0% and 3.2% of female and male donors, respectively, would be lost. DISCUSSION: Gender-neutral eligibility criteria based on high-risk sexual behaviors may reduce the overall number of eligible donors in the Netherlands, but could make blood donation more accessible to a broader group of donors.

Cardiovascular Benefits for Blood Donors? A Systematic Review.

It has been proposed that blood donation could be protective against cardiovascular disease. The aim of this study is to systematically summarize and evaluate existing observational and experimental studies on effects of blood donation on cardiovascular risk and disease in donor and general populations. The electronic databases PubMed and EMBASE were searched until March 2019 for experimental and observational studies on blood donation and cardiovascular risk or disease. Excluded were studies performed in patient populations or with controls compared to a patient population, and studies performed in individuals aged <18 or >70. All identified studies were independently screened for eligibility and quality using validated scoring systems by 2 reviewers. A total of 44 studies met all criteria. We included 41 observational studies and 3 experimental studies. 14 studies had a quality assessment score of 7 or higher. Of those, a majority of 9 studies reported a protective effect of blood donation, while 5 studies found no effects on cardiovascular risk factors. Results on other various outcomes were inconsistent and study quality was generally poor. Whether or not blood donation protects against cardiovascular disease remains unclear. Studies showing beneficial effects may have inadequately dealt with the healthy donor effect. High quality studies are lacking and therefore definite conclusions cannot be drawn. Large RCTs or cohort studies of high quality with sufficient follow-up should be conducted to provide evidence on the possible association between blood donation and cardiovascular disease.

Blood donor eligibility criteria for medical conditions: A BEST collaborative study.

BACKGROUND AND OBJECTIVES: Donor eligibility questions and criteria for medical conditions vary between blood centres, suggesting that they are based more on local regulations or experience, rather than on published data, which are limited. As the donor population ages, medical conditions become more common. We assessed donor health assessment criteria at blood centre members of the Biomedical Excellence for Safer Transfusion (BEST) Collaborative. Our aim was to compare eligibility criteria and determine their underlying basis. MATERIALS AND METHODS: A REDCap survey was sent to blood centre participants, based on medical conditions of greatest interest suggested by the Donor Studies Team of the BEST Collaborative. Participants were asked about current donor health assessment questions, deferral criteria and the basis for their deferral policy (donor risk, recipient risk or both) for 20 medical conditions. RESULTS: Complete responses were received from 26 blood donor centres (24 separate responses) representing a combination of hospital-based centres, large regional centres and community/national blood centres in 14 different countries. Most centres specifically ask about heart and lung conditions, whereas fewer than half inquire about kidney, gastrointestinal or neurological conditions. North American blood centres tended to be less restrictive, while regulatory restrictions are more prevalent in Europe. Most participants felt that the criteria were based on regulatory requirements or experience, rather than on published data. CONCLUSION: There is considerable variability in criteria by region. Ideally, criteria would be more evidence-based rather than based on regulatory requirements or experience. Deferral criteria must balance donor and recipient safety and maintain an adequate blood supply.

Associations Between Symptoms, Donor Characteristics and IgG Antibody Response in 2082 COVID-19 Convalescent Plasma Donors.

Many studies already reported on the association between patient characteristics on the severity of COVID-19 disease outcome, but the relation with SARS-CoV-2 antibody levels is less clear. To investigate this in more detail, we performed a retrospective observational study in which we used the IgG antibody response from 11,118 longitudinal antibody measurements of 2,082 unique COVID convalescent plasma donors. COVID-19 symptoms and donor characteristics were obtained by a questionnaire. Antibody responses were modelled using a linear mixed-effects model. Our study confirms that the SARS-CoV-2 antibody response is associated with patient characteristics like body mass index and age. Antibody decay was faster in male than in female donors (average half-life of 62 versus 72 days). Most interestingly, we also found that three symptoms (headache, anosmia, nasal cold) were associated with lower peak IgG, while six other symptoms (dry cough, fatigue, diarrhoea, fever, dyspnoea, muscle weakness) were associated with higher IgG concentrations.

Ferritin-guided iron supplementation in whole blood donors: optimal dosage, donor response, return and efficacy (FORTE)-a randomised controlled trial protocol.

BACKGROUND: Frequent whole blood donors have an increased risk of developing iron deficiency. Iron deficiency can have detrimental health effects when left untreated. Donation intervals are commonly too short to replenish iron stores and extending these reduces donor availability. Oral iron supplementation is known to shorten iron store recovery time but may also induce gastrointestinal complaints. We aim to optimise the effectiveness of iron supplements while minimising the risks of side effects. Therefore, we will evaluate the impact of different iron supplementation protocols in terms of dosage and frequency on ferritin and haemoglobin levels, gastrointestinal side effects, iron deficiency-related symptoms and donor return compared with placebo supplementation. METHODS: Twelve hundred whole blood donors with ferritin levels ≤30 µg/L are included into a double-blind, randomised controlled trial. Participants are randomly allocated to one of six arms, administering capsules containing 0 mg, 30 mg or 60 mg of iron, either on alternate days or daily for 56 days. At baseline and 56, 122 and 182 days of follow-up, ferritin and haemoglobin levels are measured, and compliance, donor return, dietary iron intake, gastrointestinal, iron deficiency-related symptoms and general health are assessed by questionnaire. ETHICS AND DISSEMINATION: This study will provide a comprehensive overview of the effects of different frequencies and dosages of administration of iron supplements on iron status and health effects, thereby considering individual differences in treatment adherence and lifestyle. The outcome will provide scientific evidence to guide the debate if and how oral iron supplements may support the recovery of whole blood donors with low ferritin levels. TRIAL REGISTRATION NUMBER: NL8590; The Dutch trial registry.