STATE OF THE ART
The challenges of managing donor haemoglobin
Dr Joanna Speedy, 301 Pirie St, Adelaide SA 5000, Australia
Haemoglobin screening has long provided blood services with a means to determine the eligibility of prospective donors. Screening aims to protect donors from donating whilst anaemic, minimise the risk of anaemia developing as a result of donation and ensure an adequate red cell component for the transfusion recipient.
Addressing the limitations, risks and benefits of haemoglobin screening to both donor and recipients requires continuous surveillance and an evidence-based response to evolving clinical research and technological innovations. Challenges include determination of appropriate thresholds in specific populations, management of donors with low haemoglobin, realising the limitations of haemoglobin as a predictor of iron status, and the assessment and selection of alternative screening devices.
Current haemoglobin thresholds are now in doubt, with recent large US population studies re-defining normal ranges for haemoglobin. A further confounding factor is local and international research highlighting the significant prevalence of iron deficiency in eligible donor populations. This reinforces the limitations of haemoglobin as a stand-alone point of care screening test.
Current practice at the Australian Red Cross Blood Service (Blood Service) to assess donor haemoglobin involves a pre-donation capillary finger prick sample analysed on the HemoCue® 201+. Minimum thresholds for whole blood donation are 120 and 130 g/l for females and males respectively. Donors with low haemoglobin are deferred, offered ferritin testing, and referred to their GP for management if subsequently identified as anaemic and/or iron deficient.
The management of low haemoglobin deferrals is currently under review. These account for 16% of all deferrals. Routine ferritin testing of low haemoglobin-related deferrals indicates 75% are associated with iron deficiency, with approximately 60% in females aged ≤50 years. Local research indicates a substantial loss of donations due to delayed or non-return following a low haemoglobin deferral. Additional local research suggests that screening with haemoglobin and iron indices enables prediction of donors at risk of subsequent anaemia and who would most benefit from prevention strategies.
Technological advances may allow additional means by which to improve donor experience and safety. These include the use of a more palatable non-invasive haemoglobin analyser, and point of care ferritin testing, both of which are to be assessed by the Blood Service for accuracy and feasibility of implementation.
The greatest challenge is to manage the balance of donor health and well-being with the potential supply loss from healthy donors. To optimise donor iron status and subsequently improve efficiency and supply through reduced deferrals and improved return rates, the Blood Service is considering a comprehensive targeted strategy. Options include improving informed decision-making for donors, education, ferritin screening, donation frequency modification and/or iron supplementation. Our recently completed randomised, double blind trial of carbonyl iron supplementation in premenopausal female blood donors will be a valuable resource in the development of this strategy. Initiatives need to be responsive to the needs and expectations of donors, community and health professionals, whilst considering the immediate and long-term impacts on inventory and logistics of implementation. The Blood Service has established a cross-functional Iron Taskforce to scope and develop such strategies.
The management of donor haemoglobin is a complex process with constantly evolving clinical and technological challenges. Although some issues are unique to individual institutions, many are universal, leading to research and debate at international forums. Challenges recognised by the Blood Service include determination of appropriate minimum and maximum haemoglobin thresholds for donation, selection of the most suitable screening devices, and management and referral of donors with low haemoglobin.
Low haemoglobin represents the single most common reason for deferral of donors. Of these, approximately 75% are associated with iron deficiency. In the absence of a point of care measure for iron status, otherwise eligible donors may proceed to donation with undetected iron deficiency. Additional challenges therefore include preventing donation from iron deficient individuals, mitigating donor iron deficiency, and establishing predictors of future deferral.
These challenges demand comprehensive strategies to optimise the health and well being of our donors, improve the donor experience and contribute to efficiency and long term inventory sufficiency. Towards these goals, the Blood Service is undertaking a comprehensive review of internal policy and practice based on a critical appraisal of clinical research and review of technological innovations. There is a particular focus on duty of care, risk management, supply and demand modelling, implementation practicalities and cost-benefit analyses.
The areas currently under evaluation by the Blood Service include measures to enable informed decision-making by donors, improved education of donors and health practitioners, new screening technologies, post-donation iron supplementation and the development of predictive models which will allow a targeted approach to reduce low haemoglobin deferrals.
The following discussion provides an overview of the Blood Service’s past and present challenges of managing haemoglobin in whole blood donors, and future strategic approach. The management of high haemoglobin is outside the scope of this paper.
The Blood Service – donation and donor profile
Fully funded by Australian governments, the Blood Service works to ensure Australia has ‘an adequate, safe, secure and affordable supply of blood products, blood related products and blood related services’ . Australia has a population of 22 million and covers an area of 7·7 million km2. The Blood Service operates from more than 100 static and mobile sites around the country. More than 550 000 voluntary non-remunerated donors, who represent 3·3% of the eligible population, donate over one million whole blood, 330 000 plasma, and 40 000 platelet donations annually. Female donors contribute to 52%, 43% and 30% of the whole blood, plasma and platelet donation panel respectively. The average donation frequency for whole blood donors is 1·9 per annum.
History of haemoglobin thresholds
Haemoglobin screening has long provided blood services with a means to determine the eligibility of prospective donors. Screening aims to protect donors from donating whilst anaemic, minimise the risk of anaemia developing as a result of donation, and ensure an adequate red cell component for the transfusion recipient .
The Therapeutic Goods Administration (TGA), Australia’s regulatory authority for therapeutic goods, mandates the Council of Europe (CoE) 14th Edition ‘Guide to the preparation, use and quality assurance of blood components’  as a standard for the Blood Service, including minimum haemoglobin thresholds of 135 g/l for males and 125 g/l for females.
In 2002, the TGA mandated increases of 5 g/l to minimum haemoglobin limits for both males (from 125 to 130 g/l) and females (from 115 to 120 g/l) to move towards compliance with CoE guidelines. A phased increase commencing in 2004 was agreed to allow an opportunity to develop and implement strategies to offset the impact on supply and improve donor acceptability. To address the remaining compliance gap, the TGA commissioned a 2004 Blood Service study to determine the impact of a further 5 g/l increase on both supply and prevalence of donor iron deficiency. Data from this study [Doherty, K., unpublished] indicated that parity with CoE would not significantly reduce the prevalence of iron deficiency in the remaining eligible population, and would exclude large numbers of healthy donors. These findings, together with the Blood Service commitment to implement strategies to optimise donor care were pivotal in negotiating an ongoing exemption from compliance with CoE thresholds. Strategies included the introduction of ferritin testing of donors with low haemoglobin and a donor ‘haemoglobin and iron’ education campaign.
The current minimum haemoglobin thresholds for whole blood donation are 120 and 130 g/l for females and males respectively. The history of the Blood Service haemoglobin thresholds is presented in Table 1.
Table 1. History of the Australian Red Cross Blood Service minimum haemoglobin thresholds for whole blood donation
|Haemoglobin threshold prior to 1/1/2004||115||125|
|Haemoglobin threshold from 1/1/2004||118||128|
|Haemoglobin threshold from 1/1/2005 (current threshold)||120||130|
|Council of Europe threshold ||125||135|
Applying haemoglobin reference limits
The application of haemoglobin reference limits (reference ranges) to set donation thresholds has long been problematic, as highlighted by the ongoing US Food and Drug Administration (FDA) Blood Products Advisory Committee (BPAC) dialogue regarding haemoglobin and iron status in blood donors [4,5]. The FDA mandated haemoglobin donation threshold for both males and females is currently 125 g/l . Changes to the FDA thresholds have been under consideration, in part as a result of recent population studies challenging World Health Organisation (WHO) haemoglobin lower limits defining anaemia . Beutler and Waalen  reviewed data from the NHANES III (the Third US National Health and Nutrition Examination Survey) and the Scripps-Kaiser database. Excluding data from individuals with a transferrin saturation of <16% or serum ferritin <10 μg/l, they identified a minimum haemoglobin below which there was only a 5% chance of having a normal value, based on the population studied (Table 2). The level identified was 3 g/l lower than the current FDA haemoglobin threshold for female whole blood donors and at least 7 g/l higher than that for males. There has been no change to the FDA donation thresholds to date but it is anticipated that this topic will again be on the agenda for the FDA BPAC meeting in November 2011.
Table 2. Comparison of lower haemoglobin limits to define anaemia and minimum haemoglobin thresholds for donation
|Lower haemoglobin limits to define anaemia (g/l)|
|Beutler and Waalen (USA) ||122||122||137||132|
|World Health Organisation ||120||130|
|Australian Red Cross Blood Service||115||125|
|Lower haemoglobin thresholds for donation (g/l)|
|Australian Red Cross Blood Service – whole blood||120||130|
|Australian Red Cross Blood Service – apheresis||115||125|
|Food and Drug Adminisitration – whole blood ||125||125|
In Australia, there is considerable national variation in haemoglobin values that are reported as being in the normal range. The lower haemoglobin limits to define anaemia reported by Australian pathology providers, varies between 115–119 g/l for females and 125–135 g/l for males. The first Australian biomedical survey to be conducted on a national scale is currently underway . It remains to be seen how this data will impact on national reference ranges and how the Blood Service will apply the findings to the donor setting. Consideration will need to be given to the potential impact of threshold changes on donor risk, donor acceptance and supply.
Developing and benchmarking haemoglobin thresholds for donation is a complex process requiring consideration of specific population characteristics and haemoglobin reference ranges, minimum donation intervals, number of permitted donations per annum, maximum collection volumes and complementary strategies in use to measure and manage donor iron status. Consequently, there is unlikely to be an acceptable universal minimum threshold for donation. This is demonstrated by Karp and colleagues  who, in reviewing international practice, identified a 10 g/l variation in the minimum haemoglobin thresholds for both females (115–125 g/l) and males (125–135 g/l).
The Blood Service has a strong and ongoing commitment to maintaining donor health and safety, continuing to monitor and appraise local and international research regarding lower haemoglobin limits to define anaemia and minimum haemoglobin thresholds for donation.
Limitations of current screening technology
The Blood Service introduced haemoglobin screening in the 1970’s using the copper sulphate method. Donor haemoglobin is currently measured using a capillary fingerprick sample, analysed by photometry on the HemoCue® 201+. This method, whilst widely used, is uncomfortable for donors and risks blood exposure for interview staff. The cuvettes containing the working reagent have a limited temperature range for storage, necessitating processes for material management, which can be problematic, particularly on mobile collection sites. Operator variability, sample site, seasonal and postural factors [11–13] have all been demonstrated to influence results. Additionally, a substantial percentage of capillary haemoglobin values have been shown to be lower than those obtained from venous blood [11,14], which may result in unnecessary deferral of blood donors. These caveats emphasise the importance of validation, quality control and training.
Donor iron status
Blood donation is an independent risk factor for iron deficiency. Iron deficiency is associated with adverse outcomes including fatigue, pica, restless leg syndrome, negative impacts on physical performance and cognitive function, and progression to iron deficiency anaemia [15–23].
Body iron stores have been calculated to average approximately 300 mg in females 18–44 years, 600 mg in females 45–64 years and 780 mg in males 18–64 years . Approximately 213–236 mg of iron is lost with a whole blood donation of 470 ml . The Blood Service minimum whole blood donation interval is 12 weeks. To replace the iron loss within this time requires the absorption of twice the average daily requirement, which for susceptible individuals, may cause or exacerbate a state of iron deficiency.
Iron deficiency in the eligible population
A 2004 study of over 3000 Australian blood donors identified that 6·2% of eligible male and 21·9% of eligible female donors were iron deficient (ferritin <12 μg/l) [Doherty K., unpublished]. The prevalence of iron deficiency was higher in youth donors aged <25 years and female donors aged <50 years. An increasing prevalence of iron deficiency was found to be associated with higher donation frequencies in the preceding 12 months for both males and females. These findings, supported by international research [26–29], demonstrate the negative impact of donation on iron status and the limitations of haemoglobin as a stand alone screening test [30–32].
Consideration of alternative diagnostic markers and technologies are required to prevent donation in iron deficient donors. The challenge before us is to identify and operationalise cost-effective, validated, point of care analysers for the detection of iron deficiency. An alternative or complementary strategy would be the development and validation of predictive models for subsequent deferral.
Frequency and management of low haemoglobin deferrals
Low haemoglobin accounts for approximately 16% of all deferrals at the Blood Service. This is the single most common cause for deferral. Female donors account for 83% of these, of which 78% are aged ≤50 years. Routine ferritin testing of donors deferred with low haemoglobin indicates that approximately 75% are associated with iron deficiency. Of those iron deficient, approximately 60% are females aged ≤50 years.
Donors deferred for low haemoglobin are offered venous HemoCue® testing. Those with venous haemoglobin below the minimum threshold are offered ferritin testing. Donors with haemoglobin and ferritin levels within the normal range, but not sufficient for whole blood donation, are encouraged to consider apheresis. Donors who have anaemia with normal ferritin levels are deferred indefinitely pending investigation, management and clearance by their general practitioner. Donors with ferritin levels below the Blood Service reference range (<15 μg/l for females and <30 μg/l for males) are deferred for 6 months and provided with a referral to their general practitioner. Ferritin testing may also be performed at the discretion of a medical officer if a >20 g/l drop in haemoglobin is demonstrated between successive donations.
The Blood Service does not routinely screen otherwise eligible donors for iron deficiency. The lower acceptable limits for ferritin of 15 μg/l for females and 30 μg/l for males, are somewhat conservative in comparison to other national limits, potentially impacting on interpretation and management. The supply impact of ferritin screening, if implemented, would need to be offset by strategies to mitigate iron deficiency and permit a return to regular donation.
Low haemoglobin deferrals produce additional workflow and clinical challenges to interview and collection staff. These include confirmatory venous testing, explanation of the deferral process, recruitment to apheresis where appropriate, reassurance regarding potential health implications, and liaison with internal medical staff. The implementation of strategies to improve donor management may introduce additional complexities, and transition into ‘business as usual’ processes should aim to minimise further disruptions to workflow and donor inconvenience.
The impact of temporary deferral due to low haemoglobin
A 3 year retrospective cohort study of almost 70 000 Australian whole blood donors demonstrated that deferral for low haemoglobin has a strong negative impact on donation patterns . In particular, deferred donors were far less likely to return than non-deferred donors (58·5% vs. 87·4%, P < 0·001), with a more marked effect in first-time donors. Those who did return were slower to return, with a median time to first return of 13·2 and 2·7 weeks, for the deferred and comparison group respectively. Deferred donors also contribute substantially fewer donations upon return (Table 3). High frequency of attendance before deferral was the strongest predictor of time to return and future donation frequency.
Table 3. The impact of a 6-month deferral due to low haemoglobin on the subsequent donation patterns of Australian blood donors 
|Total low haemoglobin deferred donors||591||58.5||420||41.5|
|Total non-deferred donors||60 027||87.4||8 648||12.6|
|Low haemoglobin deferred first time donors||27||20.9||102||79.1|
|Non-deferred first time donors||8 166||69.9||3 509||30.1|
|Low haemoglobin deferred repeat donors||564||64.0||318||36.1|
|Non-deferred repeat donors||51 861||91.0||5 139||9.0|
Predictors for future low haemoglobin deferral
Recent Blood Service research conducted in 261 eligible premenopausal female donors demonstrated that combined screening with haemoglobin and ferritin has the potential to predict the risk of subsequent low haemoglobin deferral . Other researchers have attempted to develop predictive or risk stratification models. Baart et al.  proposed a model to predict low haemoglobin using previous haemoglobin level, difference in haemoglobin levels between the previous two visits, gender, seasonality, time since previous visit, previous deferral and the total number of whole blood donations in the past 2 years. Badami and Taylor  proposed that stratified risk profiling could be used to individualise donation protocols using donor gender, age and donation history.
The challenge remains to determine the most effective means by which the substantial number of low haemoglobin related deferrals could be reduced. Iron deficiency mitigation strategies and predictive models to target cohorts for preventative strategies are both fundamental to this process. Reducing the negative impact of deferral on future donation patterns requires effective marketing and retention strategies to encourage regular donation as well as improved management of the deferral process to enhance donor experience and perception.
With these challenges before us, the Blood Service has acknowledged that a comprehensive strategy is required to address the issues identified above.
Future Blood Service strategic directions
The Blood Service has identified the management of donor haemoglobin and iron deficiency as a strategic initiative. The Iron Taskforce, a national, cross-functional, multidisciplinary team, has been established to co-ordinate the development of a comprehensive strategy and improve internal visibility of these issues. Key areas for development include education, strategies to mitigate iron deficiency and reduce low haemoglobin deferrals, improved management of those who are deferred, and identification of technologies to optimise donor care.
Education for donors, staff and health care professionals has been identified as a priority. Donor education will support informed donor decision making and contribute to workflow efficiency and improved donor perception in the event of future deferral. The provision of appropriate learning and development opportunities for staff, in conjunction with a service excellence training program, should improve the donor experience and the delivery of accurate and consistent information. Providing health care professionals with access to management guidelines for iron deficiency and anaemia may increase awareness of the impact of donation on iron stores and prevent over or under-investigation of referred donors. The Blood Service is currently identifying gaps in knowledge and working towards the development of internet-based educational material for all audiences.
The Blood Service is currently evaluating the implications of a recently completed trial of post-donation iron replacement. The Carbonyl Iron Trial, a randomised, double-blind, placebo-controlled trial, investigated the safety and efficacy of post-donation iron replacement in women aged 18–45 years, with an 8 week daily course of 45 mg carbonyl iron. The primary endpoints compared total body iron (TBI) and prevalence of iron deficiency (ferritin <15 μg/l) at week 12 post-donation. Secondary endpoints were eligibility to donate at week 12 and incidence of gastrointestinal complaints. Carbonyl iron was effective and well tolerated. At week 12, donors receiving carbonyl iron had higher TBI, lower prevalence of iron deficiency, higher serum ferritin and higher capillary haemoglobin. Of those receiving carbonyl iron, 51·4% experienced at least one gastrointestinal side-effect, of which 77% were mild (Table 4). Importantly, 86·7% of donors who received carbonyl iron indicated they were prepared to take the supplement on an ongoing basis [Marks DC, Speedy J, Robinson KL, et al., unpublished].
Table 4. Carbonyl Iron Trial results. The Carbonyl Iron Trial, a randomised, double-blind, placebo-controlled trial, investigated the safety and efficacy of post-donation iron replacement in women aged 18–45 years, with an 8 week daily course of 45 mg carbonyl iron. Safety and efficacy evaluations were conducted at week 12
|Median TBI (mg/kg)a||5.39||7.88||<0.001|
|Iron deficiency (%)b||80.5||51.9||<0.001|
|Median ferritin at baseline (μg/l)||14.27||13.83||–|
|Median ferritin at week 12 (μg/l)||8.34||14.86||<0.001|
|Capillary haemoglobin (g/l)c||130.1 ± 10.0||134.7 ± 8.7||<0.001|
|At least one Gld side effect (%)||27.9||51.4||<0.001|
Progressing from a clinical trial to implementation will not be without difficulty. Implementation will need to consider availability and choice of iron preparation, cost-benefit, donor uptake and compliance, as well as integration with tailored donation frequencies and regular ferritin screening.
Low haemoglobin deferral study
The Blood Service is currently designing a prospective observational study to help us understand donor health-seeking behaviour, general practitioner management and clinical outcomes associated with low haemoglobin deferral.
Non-invasive haemoglobin screening
A non-invasive method of haemoglobin measurement could potentially streamline the screening process, improving donor experience, staff safety and workflow efficiency. There are several analysers which detect and measure haemoglobin using various mechanisms, including white light spectroscopy, occlusion spectroscopy or near infra-red, through a finger cuff [38,39]. The Blood Service is preparing to conduct a study comparing some of these systems with traditional capillary blood sampling platforms.
Point of care ferritin testing
Point of care ferritin testing provides an opportunity to enhance donor safety. Pre-donation ferritin testing can provide a baseline from which to determine eligibility for donation, iron replacement and/or tailored donation frequency. The Blood Service will be evaluating the accuracy and feasibility of point of care ferritin testing with the eventual goal of minimising collections from iron deficient donors. We anticipate the results of both the non-invasive haemoglobin screening and point of care ferritin studies will be available in 2012.
There are ample opportunities to optimise the management of donor haemoglobin and improve outcomes for donor health and well-being. Identifying strategies to detect and reduce the prevalence of iron deficiency are fundamental to the broader approach. There are many obstacles to address prior to implementation of these strategies, including competing funding priorities, risk management, supply consequences, donor acceptance and the logistical implications associated with both fixed and mobile sites located over such a vast geographical area. A multidisciplinary collaborative oversight with a strong research focus will support an evidence-based strategic approach designed to maximise donor care, prevent donation related adverse effects and meet the expectations of all key stakeholders.
We would like to acknowledge Australian governments that fully fund the Australian Red Cross Blood Service for the provision of blood products and services to the Australian community. We also thank and acknowledge Dr Lacey Johnson, Kate Barrows, and Dr Phil Mondy for their assistance in proof reading and editing this paper.
No conflicts of interest to disclose.