The Office of Blood Research and Review (OBRR), Center for Biologics Evaluation and Research (CBER), Food and Drug Administration (FDA) convened this workshop – co-sponsored by AABB, America's Blood Centers, Plasma Protein Therapeutic Association (PPTA), the National Heart, Lung and Blood Institute (NHLBI) and the Office of the Assistant Secretary for Health, U.S. Department of Health and Human Services (HHS) – on the National Institutes of Health (NIH) campus November 8-9, 2011. The goal of the workshop was to discuss blood donor safety and blood availability issues related to donor hemoglobin qualification standards in the United States and possible measures to decrease the incidence of iron deficiency in blood donors. Jay Epstein, MD, director, OBRR, and Richard Davey, MD, director, Division of Blood Application (DBA), OBRR, stated that the agency was also interested in a review of current scientific information and stakeholder input while seeking a path forward for better management of donors and the blood supply, recognizing that there is a balance between protecting donor health and the blood supply. Presenters and participants in panel discussions included experts knowledgeable in the field from academic institutions, government agencies and industry.
Orieji Illoh, MD, DBA, reviewed current standards in use for whole blood donors as well as some issues related to donor safety and blood supply. The threshold of 12.5g/dL (hemoglobin) and 38% (hematocrit) for males and females (21 CFR 640.3(b)(3)) was established in the regulations in 1958 and has not changed. The purpose for the standard, in regulations, is to ensure donor safety and to ensure collection of a potent product. Hemoglobin measurement is used as an indirect measurement of iron status, although studies show that hemoglobin is not a good indicator of iron stores. It was noted that some other countries use different criteria/algorithms. The current standard of 12.5 g/dL would appear to allow some male donors who are anemic and defer some females who are not, according to national studies of U.S. populations. In a November 2007 Proposed Rule, FDA proposed that changes be made to the then-current criteria and requested comments and data from interested parties. The Blood Products Advisory Committee (BPAC) – September 2008, July 2010 – and the Advisory Committee on Blood Safety and Availability (ACBSA) – December 2008 – made recommendations that included advice on iron supplementation; dietary recommendations; adoption of different, gender-appropriate acceptance values; an increase in the hemoglobin requirement for male donors/no decrease for female donors; and a caution to await final analysis of the REDS II (Retrovirus Epidemiology Donor Study-II) Iron Status Evaluation (RISE) study before considering any changes to the interdonation interval.
Bryan Spencer, MPH, American Red Cross (ARC), presented results of the REDS II project on hemoglobin distribution and deferral patterns in blood donors. The study was conducted from December 2007 to December 2009 and enrolled first-time and reactivated donors as well as frequent repeat donors of both genders. The analysis looked for hemoglobin distribution in first-time donors and predictors of hemoglobin deferral. Odds ratios were used to depict the relative risk of deferral, based on age, gender, race, weight, donation intensity, or donation interval. Additional factors such as hemoglobin recovery following phlebotomy, the impact of raising male donor hemoglobin requirements, and the value of hemoglobin as a surrogate for iron status were also included in the study. Spencer's summation noted:
- Hemoglobin is a poor surrogate for donor iron status.
- There is wide variability in donor hemoglobin recovery times following phlebotomy.
- There is considerable variability in fingerstick sampling and in hemoglobin measurements.
- Donor screening methods /qualification guidelines should target specific objectives.
- Caution should be applied when implementing any measures without
- ensuring the desired objective will be achieved.
- carefully balancing anticipated benefits of improvements to donor health with likely costs to blood availability.
Richard Forshee, PhD, Office of Biostatistics and Epidemiology (OBE), CBER, reviewed a regression model that was developed to study the impact of any changes in hemoglobin standards on blood availability. The outcome variable in this model has been the fingerstick hemoglobin. FDA worked with the REDS-RISE Analysis Group to develop this model that has benn used to predict the percentage of donors who would be deferred for low hemoglobin at alternative thresholds. The model is overestimating the percentage of females deferred at the current hemoglobin cutoff value, and the source of the overestimation is being explored. Regarding further applications of the model, FDA believes the approach could be used to model potential blood donation loss as a result of any increase in the minimum interdonation interval.
Richard Benjamin, MD, PhD, chief medical officer, ARC, provided an industry perspective on hemoglobin and hematocrit cutoff and donation intervals. He made a strong request that changes in policy be evidence-based: iron stores assessed by laboratory indices rather than a surrogate marker; observational studies of donor harm rather than anecdotal accounts — noting the lack of systematic data despite more than 50 years of experience; and prospective risk/benefit studies of any intervention to eliminate unintended consequences of an intervention. Benjamin also pointed out that replacement donors likely to be recruited for male donors who would be deferred as a result of an increase in the cutoff will be young, first-time donors who tend to be iron-poor and susceptible to donor injuries. His recommendations:
- Educate donors on iron replacement.
- Facilitate iron replacement to replace losses.
- Research and quantitate the incidence and prevalence of iron-related adverse effects in donors.
- Pilot and study effects of 12.0 g/dL (female) and 13.0 g/dL (male) hemoglobin cutoffs.
- Make no immediate change to current criteria.
Toby L. Simon, MD, CSL Behring, spoke on behalf of PPTA about the impact of any changes in hemoglobin standards on source plasma donations. Historically, the hemoglobin /hematocrit standard has been the same for source plasma and whole blood donors. Data gathered by PPTA show that if the criteria for males is raised it will have a significant negative impact on source plasma donations. A change in acceptability levels that results in temporary deferrals is a significant event, since experience has shown that many donors who are deferred do not return. Simon concluded his presentation saying that PPTA is not aware of a known health impact to source plasma donors related to the current standard and that changes for source plasma donors are not warranted since there is no significant RBC loss associated with the plasmapheresis process.
Louis M. Katz, MD, medical director, Mississippi Valley Regional Blood Center, reviewed data on the potential impact of changes in hemoglobin thresholds on plateletpheresis at his facility. Currently, platelet donors must meet the same criteria as donors of red cell containing products. Katz studied the platelet donor population at this center and noted that the mean hemoglobin in platelet donations were lower than that of the red cell donations. After further evaluation he concluded:
- The impact of any changes to the hemoglobin standard on plateletpheresis collections would be substantial and similar to the impact on whole blood.
- The observation needs confirmation elsewhere.
- The lower hemoglobin that has been observed may be due to recruitment of plateletpheresis donors with high platelet counts attributable to iron depletion from prior whole blood donation, maintained continuing losses from apheresis.
- A study is in progress.
Mindy Goldman, MD, executive medical director, Canadian Blood Services, reviewed instrumentation and sampling methods for measurement of hemoglobin in blood donors. Important factors in hemoglobin measurement are: sensitivity (so that donors below the cutoff are deferred – particularly those likely to be anemic); specificity (so that eligible donors are not deferred, since they may never return); accurate results (which support donor counseling and rebooking strategies); and donor satisfaction (generally correlated with a speedy process, as little pain as possible and results that will be concordant with what the donor may receive from a physician's office). Operational logistics, such as general ease of use including mobile collection sites, simple algorithms and low cost are very important as well. Samples are currently sourced from venous phlebotomies, venous samples from donations kits and fingerstick capillary samples. Data on noninvasive measurements are available; however, no devices are approved for donor use in North America or Europe. Samples are collected immediately predonation, or in some instances donors are qualified based on previous results. Methods of measurement include color comparison, copper sulfate, microhematocrit, photometers and laboratory autoanalyzers.
Goldman noted that a comparison of methods was difficult to make, because the available studies are difficult to compare. Different donor populations, with differing percentages of female donors and eligibility criteria are used. The pretest probability of failure is different, affecting the sensitivity and specificity of the test. Any of the tests performs better in studies with predominately male donors and lower eligibility criteria. Microhematocrit and photometers are more sensitive and specific than copper sulfate, and in general photometers are more sensitive than the spun microhematocrit. Different photometers may vary. Capillary (fingerstick) sampling results in great variability in measurement due to the anatomic position and hydration of the donor, the ambient temperature and the operator's training and skill. Goldman concluded that small inaccuracies may have a large impact on deferral rates. Hemoglobin measurement is being used as a screening test in healthy individuals. Test accuracy of ± 0.3 g/dL would not influence treatment in a patient care setting; however, since the 12.5 g/dL cutoff is in the normal range for females, a shift in measurement of ± 0.3 g/dL could have a major impact on deferral rates.
Josephine Bautista, MS, MT(ASCP), Device Review Branch, DBA, provided some insight into the regulatory review process of hemoglobin devices cleared by CBER for use in screening blood donors. The 510(k) process is currently used, because the devices have been reviewed and determined to be substantially equivalent to a predicate device. Bautista did note that copper sulfate was grandfathered, as it was widely used before the current regulations went into effect.
Richard G. Cable, MD, scientific director, ARC, Northeast Division, compared fingerstick to venous samples and provided data from the REDS II RISE project. In all of the six centers participating in the study, fingerstick hemoglobin overestimated venous hemoglobin in the upper range and underestimated venous hemoglobin in the lower range. He noted that the point at which fingerstick values equaled venous varied by donor (influenced by gender and iron stores) but was also markedly different by center. In most iron-depleted females and in some iron-depleted males fingerstick samples overestimated when the venous hemoglobin was near the cutoff.
Susan Leitman, MD, Department of Transfusion Medicine (DTM), NIH, reviewed an evaluation of low red blood cell mean corpuscular volume (MCV) in an apheresis donor population. Platelet (and leukapheresis) donors at the DTM Clinical Center are routinely evaluated with a CBC before each donation. Recurrent low red cell MCV in the presence of acceptable hemoglobin could be due to iron deficiency or a hemoglobinopathy. Study conclusions:
- Of apheresis donors with low MCV, 64 percent had iron deficiency and 51 percent had hemoglobin variants.
- Iron deficiency and hemoglobinopathy may coexist; hemoglobin, MCV and RDW (red blood cell distribution width) are often helpful distinguishing factors.
- Low MCV values may be treated empirically with oral iron in the donor setting.
Orieji Illoh, MD, DBA, opened the second day of the workshop with a review of FDA's concerns about iron loss following frequent blood donation and the impact that any changes to the interdonation interval might have on the blood supply. 21 CFR 640.3(b) requires that a person not serve as a source of whole blood more than once every eight weeks. Guidance documents issued with recommendations for double red cell collections list a 16-week deferral. An increase in the interdonation interval may 1) decrease the risk of iron deficiency, 2) allow more time for iron recovery and 3) decrease future donor deferral for low hemoglobin. An increase will adversely affect the blood supply. Particular negative effects mentioned include: 1) red blood cells, especially O negative RBCs and other rare phenotypes, 2) collections obtained by apheresis and 3) availability of donors for reagent manufacturers. Previous agency activity on the subject includes a public workshop in June 2001, a request from FDA via the November 2007 Proposed Rule for comments and supporting data on increasing the interdonation interval, BPAC (2008 and 2010) and ACBSA (2008). The ACBSA recommended that consent forms include information about the effects of repeat donation on the donor population with particular reference to gender-specific effects. Current workshop objectives for the subject were to discuss recent studies of iron status in blood donors and strategies to maintain iron balance in blood donors (testing methods available for iron stores, studies on iron supplementation and effects on blood availability).
Joseph E. Kiss, MD, medical director, Hemapheresis and Central Blood Bank, The Institute for Transfusion Medicine (ITxM), reviewed methods available for measurement of iron stores in blood donors. Ferritin was used to measure donor iron in the REDS II RISE study as it reflects body iron stores – loss of iron leads to a decrease in ferritin. Decreased hemoglobin level is a late consequence of iron depletion and does not accurately reflect body iron status. RBC indices do not appear to be as useful as ferritin to assess iron status. In the RISE study a ferritin level of approximately 26 ug/L is optimal as a measure of iron-deficient erythropoiesis.
Alan Mast, MD, PhD, Blood Research Institute, BloodCenter of Wisconsin (BCW), began his review of iron stores and iron deficiency in blood donors (REDS II RISE) by noting that males store on average 1 gram of iron, females store on average 270 mg and iron lost in one donation is approximately 250 mg. Conclusions of the review:
- Blood donation causes iron deficiency.
- Programs to assess iron status and prevent/treat any deficiency in blood donors are needed, with ferritin testing for frequent donors.
- Donors are at different risks for hemoglobin deferral.
- Women cannot donate as frequently as men (one to two times per year unless taking iron).
- Older men cannot donate as frequently as younger men (over 65 years only one to two times per year; no double RBCs).
- Lots of people donate blood and all are screened for anemia.
- Blood donors are a rich source for study of anemia and genetics of iron metabolism.
Mast was particularly concerned about the recruiting of young donors. He noted that many teenagers have poor nutrition and are still undergoing cognitive development. Iron deficiency induced by blood donation in these young donors should be a major concern of blood collection facilities. A teenager who begins to donate at age 16 can potentially provide four to six donations at high-school blood drives before graduating.
He went on to describe STRIDE (Strategies To Reduce Iron Deficiency), a multicenter study, funded by NHLBI, to develop and test methods for replacing iron lost during blood donation that can be readily implemented in community blood centers. BCW, ITxM and the New England Red Cross are the participating centers. Study Group 1 will receive letters that may discuss issues relevant to iron; Study Group 2 will receive iron tablets or placebos.
Barbara J. Bryant, MD, DTM, NIH, University of Texas Medical Branch, reviewed the I.R.O.N. Protocol (Iron Replacement or Not) that ran for 39 months at NIH. Goals of the study:
- Analyze the cause of low fingerstick hemoglobin.
- Quantitate the prevalence of iron deficiency.
- Study the long-term effects of blood donation on donors' hemoglobin levels and iron stores.
- Evaluate the safety, practicality and efficacy of distributing oral replacement iron to blood donors.
- Determine the effect of iron replacement therapy on the donor pool.
I.R.O.N did not achieve a sustained reduction in donor deferrals; however, average productive donor visits per donor per year were higher in the study population than in the entire donor population. Tangible costs per visit were approximately $12.00 ($10.00 for the labs and $1.40 for the iron tablets). Bryant noted that blood centers are confronted with the on-going challenges of iron deficiency in blood donors whether it is pre-existing or resultant. Iron replacement therapy is a cheap, safe and effective method of preventing iron deficiency in donors. The study-based recommendation is to administer a two-month supply of oral iron tablets to all donors with hemoglobin < 12.5 g/dL. Repeat male donors who do not respond within 60 days and first-time male donors should be referred to their primary care provider. Males with hemoglobin < 12 g/dL and females with hemoglobin < 10 g/dL should be referred to their primary care provider. A slightly different evidence-based recommendation would be routine administration of a two-month supply of oral iron tablets, sufficient to replace iron lost in one unit of whole blood, to all whole blood donors. Verification of non-hereditary hemochromatosis status would be achieved by a single ferritin level.
Anthony Keller, MD, Australian Red Cross Blood Service, provided an overview of a carbonyl iron trial – a prospective randomized double-blind placebo-controlled trial assessing the efficacy and safety of a post-donation course of 45 mg elemental iron daily for eight weeks in ameliorating the iron loss from whole blood donation in female donors aged 18-45 years. The Australian Red Cross minimum donation interval for whole blood donation for both male and female donors is 12 weeks. The results demonstrated effectiveness in ameliorating iron loss associated with whole blood donation and in reducing the proportion of iron-deficient donors. The iron was well tolerated and donors approved of the protocol. Keller noted that this was a short study that offers limited information on the potential benefits and issues of long-term post-donation iron replacement.
Richard Forshee, OBE, explained a compartment modeling approach the agency will use for exploring blood donation loss if there are changes in the minimum time interval between donations and minimum hemoglobin fingerstick test result requirements. Future work by OBE will include stratification by blood type and race/ethnicity to explore the impact on subpopulations of blood donors that are of particular concern.
Merlyn Sayers, MB, BCh, PhD, Carter BloodCare, reviewed the process his facility used to predict the effect that lengthening the red blood cell interdonation interval would have on inventory management. He concluded that:
- Changing use patterns at hospitals have important consequences for recruitment strategies at blood programs.
- Lengthening the interdonation interval will significantly compromise the availability of red blood cells, especially group O and Rh negative units.
Jed B. Gorlin, MD, MBA, medical director, Memorial Blood Centers, presented a progress report of the work of the AABB Interorganizational Task Force on Donor Hemoglobin. The task force has a mandate to evaluate:
- Existing data on the appropriate hemoglobin/hematocrit level for whole blood donors.
- Existing data on the appropriate interdonation interval for whole blood donors.
- The impact of any change to the hemoglobin/hematocrit level for whole blood donors on the collection of double red cells and apheresis platelets.
- The impact of any changes to the interdonation intervals on the availability of blood products.
- The potential to use measurements of serum iron as well as surrogate measures to qualify donors for subsequent donations.
- Iron supplementation for donors.
Preliminary observations of the task force include:
- International standards.
- U.S. and Canada are unique in not having gender-specific standards.
- Many other countries use 12.0g/dL for female donors and 13.0g/dL for male donors.
- Brazil has a longer interdonation interval for females.
- Current criteria result in over-deferral of female donors and allow anemic males to donate.
- Present cutoff of 12.5g/dL results in a high rate of deferral for women, many of whom are not iron deficient.
- Donation-related iron depletion.>
- Magnitude is documented by recent REDS II RISE study.
- Benefit is not supported by existing literature.
- Adverse effects may especially affect young donors.
- Iron replacement.
- NIH and Indiana Blood Centers programs reviewed.
- Selective standards.
- Various factors reviewed (i.e., age, environment, genetic, ethnic).
- The highest frequency of blood donor iron depletion is in premenopausal women.
- Iron replacement should be considered for these donors.
- The role of a longer donation interval for females, especially premenopausal women, was discussed without consensus.
- Donors deferred for low hemoglobin/hematocrit receive highly varied information on the medical significance of their deferral, when they should seek additional medical care and what they should do to decrease the likelihood of deferral.
- The role of ferritin testing and which donors to test (all, frequent or only those deferred) have not been fully explored by the task force.
Gorlin noted that the task force drafted a preliminary background report with plans to incorporate new data shared at the FDA workshop. Going forward, any changes to donor eligibility or donation interval criteria will need to be reconciled with requirements of the FDA and the AABB Standards for Blood Banks and Transfusion Services.
Jay Epstein, MD, director, OBRR, summarized the meeting. In his opinion three themes emerged from the discussions:
- Improve donor consent to completely communicate the disturbance in iron balance.
- Hemoglobin is not a reliable measurement of iron status and iron status should be looked at. Frequent source plasma donors may be important to evaluate.
- Blood centers reported a positive experience with iron replacement protocols and the focus should now be on feasibility and operational issues with implementation.
The goals of the workshop were accomplished and the broader challenge is how to proceed with next steps. FDA will work with centers who want to look at innovative programs.