Preserving the National Blood Supply
Gary M. Brittenham, Harvey G. Klein, James P. Kushner, and Richard S. Ajioka
This paper examines the current state of the blood
supply in the US and focuses on the potential for
augmenting blood availability by attention to the
iron status of donors. Increasing demands are
being made upon the national blood supply as
rates of blood donation are declining, in part
because of the loss of blood donors as a result of
enhanced screening and testing procedures. Iron-
related means of expanding the blood supply
include the use of blood from individuals undergo-
ing therapeutic phlebotomy for hereditary hemo-
chromatosis and enhancing the retention and
commitment of women of childbearing age as
donors by using iron supplementation to prevent
iron deficiency.
In Section I, Dr. Klein discuss the circum-
stances responsible for a decline in the population
of eligible donors, including public attitudes toward
donation, factors influencing the retention of
donors by blood centers, and the effects of in-
creased screening and testing to maintain the
safety of the blood supply.
I. THE SHRINKING POOL OF BLOOD DONORS
Harvey G. Klein, MD*
According to the 2000 Nationwide Blood Collection and
Utilization Survey conducted by the National Blood Data
Resource Center (NBDRC), the most recent national data
set available regarding blood collections,1 13,760,000
units of whole blood were collected in 1999. An addi-
tional 116,000 units of red blood cells were collected by
the process of apheresis including the newly licensed 2-
unit technique. Overall, red cell supply in 1999 was
13,876,000 units, a 10.1% increase over the collections
* NIH Clinical Center/DTM, 9000 Rockville Pike, Bethesda
MD 20892
Dr. Klein serves on the board of directors for Haemonetics
Corporation and is scientific advisor for Sangart, Viacell,
Zymequest, Vitex, Gambro-BCT, and Alliance.
422
In Section II, Drs. Kushner and Ajioka focus on
the consequences of the decision by the US Food
and Drug Administration (FDA) to develop recom-
mendations to permit blood centers to collect blood
from patients with hereditary hemochromatosis
and to distribute this blood obtained without
disease labeling if all other screening and testing
procedures are passed. After summarizing the
pathophysiology of hereditary hemochromatosis,
the use by blood centers of blood obtained from
heterozygotes and homozygotes for hereditary
hemochromatosis is considered.
In Section III, Dr. Brittenham reviews the use of
low dose, short-term carbonyl iron supplementa-
tion for women donors of childbearing age. Replac-
ing the iron lost at donation can help prevent iron
deficiency in women of childbearing age and, by
decreasing deferral, enhance the retention and
commitment of women who give blood regularly.
He emphasizes the use by blood centers of iron-
related means to enhance recruitment and reten-
tion of blood donors.
reported in 1997, the last previous year for which na-
tional data are available.2 In view of this information,
one could reasonably question whether there is a short-
age of blood in the US and whether there is a problem
regarding the size of the blood donor pool and the will-
ingness of volunteers to donate blood. Nonetheless, blood
usage has been rising more rapidly than has whole blood
collection, and additional testing and screening standards,
as well as a variety of social and demographic changes,
have progressively pared down the number of eligible
donors.
Protection of the Recipient
Blood donor deferrals are introduced for two purposes:
to protect the health of the transfusion recipient and to
protect the health of the donor. Although screening and
testing of blood donors long predated the human immu-
nodeficiency virus (HIV) epidemic, increasing concerns
regarding blood safety during this period resulted in new
emphasis on donor screening and testing. Measures in-
American Society of Hematology
troduced to increase blood safety have also had the un-
intended consequence of decreasing blood availability.
Results from demographic studies indicate that certain
donor groups or donor sites present an unacceptable risk
of disease transmission. For example, blood collectors
no longer schedule mobile drives at prisons or institu-
tions for the mentally retarded because of the recognized
high prevalence of transfusion-transmissible viruses.3,4
Few would argue with the risk-benefit ratio of these ex-
clusions. More questionable were the temporary exclu-
sions of soldiers exposed to multiple tick bites at Fort
Chaffee, Arkansas, and the half-million Desert Storm
veterans who were deferred for a year because of the
fear that they might harbor Leishmania donovani, an
agent not known to be associated with transfusion risk.
Donors who have received human growth hormone in-
jections have been indefinitely deferred because of the
possible risk of transmitting Creutzfeldt-Jakob disease.
The impact of this deferral on the blood supply has been
negligible. In contrast, the recent exclusion of donors
who resided in the United Kingdom for an total of six
months or longer between 1980 and 1996, designed to
reduce the theoretic risk of transmission of the human
variant of “mad cow disease,” has eliminated an esti-
mated 2.2% of US donors. The proposed expansion of
this geographic exclusion to the European continent is
estimated to eliminate another 2–8% of otherwise ac-
ceptable blood donors (Alan E. Williams, Ph.D., per-
sonal communication).
Additional donor exclusions appear to be on the
horizon. The geographic exclusion for visitors to regions
where malaria is endemic is longstanding, but the length
of exclusion and provisions of the exclusion (length of
stay, area of the country, possibility of mosquito expo-
sure) have been debated for years and frequently modi-
fied. Geographic exclusions to address the transmission
of Trypanosoma cruzi (the agent that causes Chagas’
disease), Babesia microti (the parasite associated with
babesiosis), and Borellia burgdorferi (the agent associ-
ated with Lyme disease) have all been discussed. Such
exclusions would likely have little impact on blood safety,
but each shrinks the potentially eligible volunteer donor
pool.
Donor medications constitute another significant
area of deferral losses. Certain medications, for example
etretinate (Tegison), isotretinoin (Accutane) and fina-
steride (Proscar), have been identified by the US Food
and Drug Administration (FDA) as posing a risk to trans-
fusion recipients because of their teratogenic potential
at low plasma concentrations. For other medications,
blood centers set their own policies. Most blood centers
defer donors on antibiotic therapy, although such defer-
rals are generally short. These deferrals usually reflect
the concern that antibiotics are being administered for
Hematology 2001
some bacterial infection that might taint the collected
unit. As rules and policies become more complicated,
and as increasing numbers of Americans take prescrip-
tion and non-prescription drugs, more and more donors
are lost.
More troublesome are donor deferrals resulting from
false-positive infectious disease screening tests. This
problem has been recognized since the introduction of
serologic tests for syphilis. However, over the past fif-
teen years the introduction of as many as seven new
screening tests and the immanent licensure of nucleic
acid testing (NAT) have resulted in numerous deferrals
for “questionable” test results and either complex reen-
try algorithms or no approved method to re-qualify such
donors. Each year an estimated 14,000 donors are de-
ferred from donating blood for an indefinite period be-
cause of repeatedly reactive EIA screening tests for HIV
and hepatitis C virus, and several hundred donors are
deferred for apparently false-positive NAT tests. (Louis
Katz M.D., personal communication). The American
Red Cross does not engage in donor re-entry, nor do
40% of non-Red Cross community blood centers.
Protection of the Donor
Donor screening criteria are designed to protect the do-
nor as well as the patient. In practice these criteria are
not currently decreasing the donor pool to any substan-
tial degree. The criteria are designed to identify indi-
viduals predisposed to postdonation reactions (e.g. small
donors), to restrict donors for whom a postdonation re-
action might have particularly severe consequences (e.g.
those with coronary artery disease), and to protect the
donor from iron deficiency as a result of frequent dona-
tion. In fact the most common cause of on-site donor
deferral is failure to meet the hemoglobin standard (12.5
g/dL). The Red Cross transition from earlobe sampling,
a practice that overestimated venous hematocrit, to
fingerstick sampling in August of 2000 resulted in an
immediate deferral of 6% of donors, primarily women.
How many of these donors will eventually qualify for
donation is uncertain. Whether the increasing use of
noninvasive methods to detect asymptomatic vascular
disease or the trend toward strict vegetarian diets lead-
ing to a reduction in iron stores will affect donor qualifi-
cation and donations adversely remains to be seen.
Social and Demographic Issues
Comprehensive studies of donor motivation, attitudes
toward blood donation, and decisions about participa-
tion and nonparticipation were carried out in the early
1980s.5 In a study using controlled populations in cities
representative of different kinds of blood supplies (New
York, Hartford, Houston) and interviewers skilled in
seven languages, Drake et al concluded that donation is
423
limited primarily by the actual need for blood. While
there may be more active donors in other countries, the
issue in the US is how to make collections efficient and
predictable, not how to significantly increase the donor
base. With an estimated 5% of the eligible population
donating annually and 25% having donated at some time,
there appeared to be no shortage in the potential donor
pool.
Unfortunately the US population has changed dra-
matically since 1982, and no comparably detailed analy-
sis of donors and donor motivation has been carried out.
The American population, like that of most of Western
Europe and Japan, is aging and the World War II gen-
eration of donors is disappearing. The country has be-
come culturally more diverse, which raises issues of both
recruitment strategies and deferral characteristics. No
data are available to indicate whether the current US
population is either as willing or as eligible to donate
blood as the previous generation of volunteers. Conven-
tional wisdom asserts that the current generation is less
altruistic and thus less likely to volunteer to donate blood.
I have seen no data to substantiate this opinion. It does
appear that, in the wake of the AIDS epidemic, the popu-
lar impression of blood transfusion has evolved from a
“gift of life” to a risk to be avoided, and, anecdotally,
the image of blood donation has suffered as a result.
During the height of the AIDS epidemic in the US, 25–
50% of surveyed adults believed that donating blood
could lead to their being infected with HIV.
The disappearances of large manufacturing plants,
sites of large mobile blood drives in the past, and the
reluctance of small employers to allow employees to
participate more than once or twice a year may make
recruitment more challenging but probably does not
greatly shrink the donor pool. On the other hand, labor
shortages have made employers less willing to
provide time to donate blood during work hours
(Ronald Gilcher, M.D., personal communica-
tion). The complicated and sometimes confron-
tational screening process, occasionally re-
ferred to as the “donor inquisition,” also may
have discouraged otherwise eligible volunteers.
Longitudinal Studies of Blood Availability
The balance between transfusion demand and
blood collection determines adequacy of the
blood supply. Demand drives the blood sys-
tem. More than 95% of the transfusion demand
originates in the approximately 4,500 hospi-
tals in the US, and changes in demand may
occur relatively abruptly. From 1987 to 1997 * autologous included
there was a pronounced decline in the number
of allogeneic transfusions followed by an even
Figure 1. Allogeneic whole blood and red cell collections and transfusions,
greater decline in allogeneic collections (Fig- 1987-1999.
424
ure 1). The margin of supply over demand, the “safety
margin” of inventory, fell to 5.4% in 1997, about half of
what it had been only two years earlier. Demand changed
again in the subsequent two years as allogeneic transfu-
sions increased more than 8%. Despite the increased col-
lections, the margin between supply and demand was
only 9.1%, a decline of 35.7% over that in the decade
1989-99. If demand for red blood cells continues to in-
crease at the same rate, an additional 1.1 million units of
blood will be required to meet demand in 2001 and to
avoid further reduction of this margin. Autologous col-
lections totaled an additional 651,000 units, an increase
of 1.2% over 1997. By contrast, autologous transfusions
declined 12.6% from 1997 and represented only 3% of
all units of red cells transfused. The number of units
discarded because of positive screening tests was
226,000.
The number of units collected per thousand US in-
habitants of usual donor age (18–65 years old) was 80.8
in 1999. While this compares favorably with the rate of
72.2 per thousand in 1997, it pales in comparison with
the 100 units per thousand population collected in Swit-
zerland. While it is treacherous to try to interpret these
numbers, they do suggest that US collecting facilities
are performing more efficiently. Data from the National
Red Cross indicate that the average volunteer donates
about 1.7 times a year (Jacqueline Frederick, American
National Red Cross, personal communication). Red cell
transfusion rate in 1999 was 45.5 units per thousand
population, an upward trend.1 Outdated red cells ac-
counted for 5.3% of the supply, but given the fact that
red cells can be transfused only to compatible recipients,
the number of usable units outdated appears to be extremely
small. More than 99% of group O units and 97% of group
A units were transfused.
American Society of Hematology
 An estimate of supply adequacy is difficult to ob-
tain. It is probably insufficient to record blood center
and hospital inventories or orders partially filled or un-
filled. In any case, such data are not available. Nonethe-
less, of the more than 2,500 hospitals surveyed, 6.6%
reported that elective surgeries were cancelled on one
or more days during the survey year because of blood
shortages and 16.2% of responding hospitals reported
at least one day in which non-surgical transfusion needs
could not be met.1
Augmentation of Supply
Several approaches are being undertaken to augment the
nation’s blood supply. The American Association of
Blood Banks has appealed to the US Department of
Health and Human Resources to support a national cam-
paign for increasing public awareness of the need for
blood. The American Red Cross has recently announced
a $5 million national campaign, the first in its history, to
recruit additional blood donors. New technology has
made it possible to collect double units of red cells from
selected donors and to freeze supplies more efficiently
for better inventory control. It has been estimated that
the use of hereditary hemochromatosis patients could
add between 202,500 and 3 million additional donors to
the pool.6 While the actual number of new donors and
the contribution of red cell units from patients with he-
reditary hemochromatosis continues to be debated, in a
small ongoing study at the NIH Clinical Center, some
4% of red cell transfusions currently come from donors
with hereditary hemochromatosis who are homozygous
for the C282Y mutation. Continuing to assemble infor-
mation from those with hereditary hemochromatosis re-
garding management and safety may help address some
of the concerns regarding the shrinking blood donor pool.
II. HEMOCHROMATOSIS AND THE BLOOD BANK
James P. Kushner, MD,* and Richard S. Ajioka, PhD
Hemochromatosis is the most common monoallelic in-
herited disease in people of European ancestry, occur-
ring with a frequency of approximately 5 per 1000.1 The
disorder is usually due to homozygosity for a mutation
in the HLA-linked hemochromatosis gene (HFE), caus-
ing a change from cysteine to tyrosine at position 282 in
the HFE protein (C282Y).2 Wild type HFE protein forms
a heterodimer with β2-microglobulin, and the hetero-
dimer is expressed on the surface of many cells as part
of a high-affinity complex with the transferrin recep-
tor.3,4 The C282Y mutation alters the configuration of
* University of Utah Medical Center, Dept. of Hematology/
Oncology, 50 North Medical Drive, Salt Lake City UT 84132
Hematology 2001
the HFE protein, impairing the assembly of the transferrin
receptor-HFE-β2-microglobulin complex in the endoplas-
mic reticulum.5 Formation of the complex reduces the affin-
ity of the transferrin receptor for diferric transferrin,
somehow resulting in down-regulation of cellular iron
uptake through the diferric transferrin-transferrin recep-
tor-mediated endocytic pathway.6-8 In the absence of HFE
protein, cellular iron uptake via this pathway is enhanced,
but the mechanism by which HFE regulates the transfer
of dietary iron across the absorptive enterocyte and into
plasma remains unresolved (Figure 2; color page 550).
Absorption of Dietary Iron
The average daily Western diet contains 15–25 mg of
iron, but in iron-replete normal adults only about 1 mg
is actually absorbed. The amount absorbed matches the
amount lost each day within sloughed cells. There is no
iron excretory pathway (Figure 3; color page 550. The
absorptive behavior of the enterocyte is influenced by
both the magnitude of body iron stores and by the rate
of erythropoiesis.9,10 A “store regulator,” as yet un-
characterized, increases iron absorption when iron defi-
ciency is present and reduces absorption when iron stores
are increased. The amount of dietary iron that can be
absorbed when iron deficiency is present is limited by
the bioavailability of dietary iron. Iron absorption, in the
absence of iron supplementation, rises to 3–4 mg daily
when iron deficiency anemia is present. When iron over-
load is produced in genetically normal subjects, daily
iron absorption is reduced to less than 0.5 mg.
Erythropoiesis also affects iron absorption, and the
effects of the “erythroid regulator” seem more pro-
nounced than the store regulator.9 The erythroid regula-
tor appears to be related to erythron mass and not to
erythropoietin. This point is emphasized by the findings
in aplastic anemia, where erythropoietin levels are high,
erythropoiesis is absent and iron absorption is not in-
creased.11 The ability of the erythroid regulator to in-
crease intestinal iron absorption is particularly evident
when ineffective erythropoiesis is present (as occurs in
thalassemia).12
Plasma iron, all of which is bound to transferrin, is
derived from three cellular sources: the absorptive
enterocytes of the duodenum and proximal jejunum; the
macrophage; and parenchymal cells of the liver and other
organs. The macrophage is the major source of plasma
iron (Figure 4; color page 550). Studies utilizing radio-
labeled iron have demonstrated that patients with hemo-
chromatosis hyperabsorb iron from the gut, but the in-
crease above normal is small, absorption equaling 2 or 3
mg daily. As iron overload develops, iron absorption is
down-regulated to normal or nearly normal levels, but
in relation to the greatly increased iron stores, absorp-
tion is inappropriately high. 13 During phlebotomy
425
therapy, absorption rises to high levels, presumably in
response to increased erythropoiesis.14-16 Once iron stores
are depleted, absorption remains high. These data indi-
cate that patients with hemochromatosis respond to the
store regulator, but the down-regulation response is
blunted. Patients with hemochromatosis appear to up-
regulate iron absorption appropriately in response to iron
depletion and to the erythroid regulator.
Export of iron from the macrophage (iron derived
mainly from senescent red cells) is also accelerated in
patients with hemochromatosis and explains the elevated
transferrin saturation that serves as the most reliable
phenotypic marker for the homozygous hemochroma-
tosis genotype. The transferrin saturation is high before
organ iron overload occurs, and remains high even after
iron stores have been depleted by phlebotomy therapy.17
Phenotypic Expression and Screening
Phenotypic expression of the homozygous hemochro-
matosis genotype may vary from that of a fully penetrant
clinical syndrome (with skin pigmentation, cirrhosis,
cardiomyopathy, endocrinopathy, and arthritis) to a
simple laboratory abnormality, namely an elevated per-
cent saturation of transferrin. Numerous factors influ-
ence phenotypic expression, including age, sex, and
modifier loci.18 The proportion of homozygotes destined
to develop organ damage due to iron overload remains a
controversial issue, mainly because of ascertainment
biases in the reported series. All homozygotes identi-
fied because of clinical sequelae of iron overload have
disease-related morbidity, whereas screening of healthy
subjects generally uncovers few clinically affected ho-
mozygotes. An accurate estimate of the frequency of
disease-related morbidity could be determined by a large-
scale population-based screening project in which the
entire population is screened, regardless of health sta-
tus. Either a phenotypic screen (measuring the transfer-
rin saturation) or a genotypic screen (detection of ho-
mozygosity for the C282Y mutation) could be employed.
A multicenter, NIH-funded study evaluating both screen-
ing methods is now being carried out in the US.19 A popu-
lation-based screening study in which HFE genotyping
was used as the screening probe identified 16 C282Y
homozygotes in a population of 3011 of Northern Euro-
pean ancestry, ranging in age from 20 to 79 years, living
in a small city in southwestern Australia (5.3 per 1000).20
Half of the homozygotes detected had clinical features
of hemochromatosis, but one-quarter had no evidence
of iron overload.
An alternate approach to determining the frequency
of disease-related morbidity in hemochromatosis ho-
mozygotes has been taken by Bulaj et al.18 Two hun-
dred-fourteen homozygous relatives of persons with
426
hemochromatosis were identified in pedigree studies by
using HLA typing and HFE genotyping. These homozy-
gous relatives were considered to be clinically unselect-
ed, as they were ascertained without regard to health
status. Nearly all underwent liver biopsy. Hepatic fibro-
sis, cirrhosis, abnormal liver function tests, and arthr-
opathy served as objective indicators of disease-related
morbidity. Eighty-five percent of the men (mean age, 41
years) studied had iron overload, as did 68% of the
women (mean age, 44 years). In spite of the high inci-
dence of iron overload as measured by hepatic iron con-
tent, disease-related morbidity was documented in only
38% of homozygous men and 10% of homozygous
women. With increasing age, the frequency of disease-
related morbidity increased, particularly in homozygous
men over 40 years of age. These data indicate that if
hemochromatosis homozygotes are identified as young
adults, most have no health-related consequences and
would be ideal blood donors.
Hemochromatosis Homozygotes as Blood Donors
Recruitment of hemochromatosis homozygotes to serve
as regular blood donors is dependent upon identifying
homozygotes as young adults, before an appreciable in-
cidence of iron-induced organ damage occurs. Thus,
recruitment of donors and the implementation of large-
scale screening programs are intimately connected is-
sues. Data from the year 2000 US Census indicate that
there are approximately 127,000,000 Americans of Eu-
ropean origin between the ages of 20 and 74 years. The
incidence of homozygosity for hemochromatosis in this
group may approach 5 per 1000, or approximately
635,000 individuals, half men and half women. Identi-
fying even a portion of these individuals would benefit
the nation’s blood supply, but concerns related to dis-
crimination from health and life insurers and the reluc-
tance of organizations that distribute blood and blood
components to utilize donors with hemochromatosis re-
quire resolution.
The FDA does not currently prohibit the use of blood
from individuals with hemochromatosis but requires that
blood obtained through therapeutic phlebotomy be la-
beled with the donor’s disease.21 Blood obtained from
individuals with hemochromatosis is infrequently dis-
tributed for transfusion, as consignees have been reluc-
tant to accept blood that is labeled with a disease. The
labeling requirement has served as a barrier to the use
of blood from donors with hemochromatosis even though
this blood is as safe as blood from any other donors.22
The major barrier to the use of donors with hemochro-
matosis is the concern about creating an incentive to
donate blood (free of charge) in contrast to paying for a
therapeutic phlebotomy. In one study it was estimated
American Society of Hematology
that the average charge for a therapeutic phlebotomy
done in the home is $48, $52 in a blood center, $69 in a
physician’s office and $90 in a hospital.23 A donor with
hemochromatosis might have an incentive to deny dis-
qualifying conditions in order to avoid the costs associ-
ated with therapeutic phlebotomy.24 A number of stud-
ies have shown higher rates of post-transfusion hepatitis
when individuals with an incentive to donate (paid do-
nors) rather than volunteer donors were utilized.25 These
data may relate to the “high-risk” status of the popula-
tions from which these paid donors were recruited. Paid
cytapheresis donors from a “low-risk” population were
found to exhibit no increase in transfusion-transmittable
viral infections compared to volunteer whole-blood do-
nors.26
In the spring of 1999, the Public Health Service
Advisory Committee on Blood Safety and Availability
recommended that the Department of Health and Hu-
man Services (DHHS) create new policies removing the
potential financial incentive for individuals with hemo-
chromatosis to donate blood instead of paying for thera-
peutic phlebotomies. It was also suggested that the la-
beling requirement be eliminated as a barrier to the use
of donors with hemochromatosis.27 In response, the FDA
has made a commitment to consider case-by-case ex-
emptions to existing blood labeling regulations provid-
ing that the blood center can verify that therapeutic phle-
botomy is provided free of charge even if the prospec-
tive donor with hemochromatosis does not meet alloge-
neic donor suitability requirements.28 In addition, the
FDA will also require that safety data be collected and
submitted so that comparisons can be made with data
gathered on the general donor pool. For the foreseeable
future, therefore, blood centers planning to utilize do-
nated hemochromatosis blood without labeling will have
the responsibility of removing financial incentives for
these donors and the administrative responsibility for
additional data collection and submission.
A guidance document outlining the FDA’s require-
ments for the variances required for blood centers wish-
ing to use donors with hemochromatosis without label-
ing the donated blood is available on the web at
www.fda.gov/cber/guidelines.htm. The key requirement
is that the blood center verify that there will be no charge
for phlebotomies performed on individuals with hemo-
chromatosis, including those who do not meet alloge-
neic donor suitability requirements. This requirement
would cast blood centers in the role of a provider of cost-
free medical care for a portion of the population with
hemochromatosis. It seems unlikely that many blood
centers would wish to assume this role.
Hematology 2001
The treatment of hemochromatosis when hepatic
iron overload is established involves an initial phase of
rapid-sequence phlebotomy designed to eliminate ex-
cessive iron stores and minimize organ injury. Individu-
als with marked iron loading usually tolerate the removal
of 500 mL of blood 4 to 5 times monthly until iron-lim-
ited erythropoiesis occurs.29 Less marked iron overload
can be safely depleted with two 500 mL phlebotomies
per month. There is no inherent reason to exclude blood
obtained during the initial phase of treatment from the
donor pool, but current guidelines limit the frequency of
collection of blood from a donor to once every 8 weeks.
A variance permitting blood centers to collect blood from
donors with hemochromatosis more frequently would
require either a physician’s prescription for iron deple-
tion through therapeutic phlebotomy or certification by
a blood bank physician that the donor is in good health
on the day of donation in accordance to the current regu-
latory code.30
The issue of utilizing donors with hemochromato-
sis more frequently than every 8 weeks should become
moot if screening programs become accepted practice.
The objective of screening programs is to detect hemo-
chromatosis homozygotes before iron loading and or-
gan damage occurs. In iron-loaded homozygotes, once
iron depletion is accomplished by rapid-sequence phle-
botomy, iron balance can be maintained with two to six
500 ml phlebotomies annually.29,31 Healthy homozygotes
detected through screening programs would be unlikely
to require phlebotomy more frequently than every 8
weeks (approximately 6 times per year).
A 500 ml phlebotomy contains approximately 200
mg of iron. It follows that to maintain normal iron stores
while donating blood 6 times annually would require
the absorption of 1200 mg of dietary iron or an average
of 3.3 mg of iron daily. This figure approaches the amount
of bioavailable iron in the average Western diet. A male
with hemochromatosis can achieve this level of iron ab-
sorption, but both men and women who are genetically
normal and donate frequently are likely to become iron
depleted.32-34
The response by the FDA to the recommendations
of the Public Health Service Advisory Committee on
Blood Availability has provided a mechanism permit-
ting blood centers to accept donors with hemochroma-
tosis but the barriers to using this resource have not
been eliminated. These barriers are not based on bio-
logical considerations. Patient advisory groups, physi-
cians, blood centers and the FDA will have to work to-
gether to achieve a more workable arrangement for in-
corporating healthy individuals with hemochromatosis
into the blood donor pool.
427
 III. CARBONYL IRON SUPPLEMENTATION FOR
WOMEN WHO GIVE BLOOD
Gary M. Brittenham, MD*
The final section in this chapter will consider the use of
low dose, short-term carbonyl iron to replace the iron
lost at donation and to prevent iron deficiency in women
of childbearing age. Carbonyl iron has a bioavailability
similar to that of ferrous sulfate but is a safe, non-toxic
form of elemental iron that virtually eliminates the risk
of iron poisoning in children.1-3 After briefly reviewing
the available evidence with respect to the need for iron
replacement in women who are committed blood do-
nors, we will summarize a draft protocol for a program
of carbonyl iron replacement that was presented at the
National Heart, Lung and Blood Institute meeting “Work-
shop on Maintaining Iron Balance in Women Blood
Donors of Child-Bearing Age” (Bethesda, MD, June 8,
2001). The overall aim of the draft protocol is to pro-
vide recommendations for consideration by blood cen-
ters that wish to develop a program of carbonyl iron re-
placement for women of childbearing age.
Background
A safe and effective means of preventing iron deficiency
resulting from blood donation is needed for women who
give blood.4-6 Phlebotomy of a unit of blood produces a
loss of 200 to 250 mg of iron in hemoglobin. Because
the average amount of storage iron in a woman of child-
bearing age is only about 300 mg,6 donation of a unit of
blood requires the subsequent mobilization of much or
all of this reserve. Further donations of blood will pro-
duce iron deficiency and then anemia. Normally iron
balance is maintained by controlling gastrointestinal iron
absorption; iron stores and iron absorption are recipro-
cally related so that as stores decline absorption in-
creases. In women who donate blood repeatedly, iron
absorption from a usual diet cannot increase sufficiently
to replace iron losses from frequent phlebotomy. Because
of menstrual losses of iron, which average 13.5 mg per
month, menstruating woman have a higher estimated
daily iron requirement than men (1.5 vs. 1.0 mg).4 A
minimum acceptable interval between donations of 56
days is recognized by the FDA and national blood col-
lection services. For menstruating women who donate
at this interval, an iron loss of 200 mg at donation in-
creases their estimated daily iron requirement to 5.1 mg
per day. Because the maximum iron absorption from a
usual Western diet is at most 3-4 mg per day,6 a net defi-
* Columbia University, College of Physicians and Surgeons,
Harkness Pavilion, Room HP 550, 180 Fort Washington, New
York NY 10032
428
cit of 62-118 mg of iron would be expected in the 56-
day interval. Repeated donations on this schedule make
iron deficiency and then anemia inevitable.
The national blood supply is provided by the volun-
tary donations of a small minority of the population;
overall about 45% of these dedicated donors are women,
most of childbearing age.6,21 Because the major factor
limiting the frequency of repeated blood donations is
iron depletion, the limited iron stores of donors is one of
the main determinants of blood availability. Virtually
every investigation of the iron status of women who give
blood has confirmed that iron deficiency is a common
problem and the major factor limiting the frequency of
repeated donation.6,16,17,19-21 Lack of iron is also the most
important medical reason for deferral from repeat dona-
tion. In donors deferred because of a low hemoglobin
concentration, evidence of iron deficiency was found in
more than 70%4.
Three potential means of preventing iron deficiency
in women who are committed blood donors of child-
bearing age are available: (i) further limitation of the
frequency of blood donation, (ii) improved methods for
detection and deferral of iron deficient donors, and (iii)
iron supplementation. Limiting donations by women of
childbearing age to 4 per year in the absence of iron
supplementation has been proposed but is unlikely to be
adequate because even among women who donate only
once per year, the prevalence of iron deficiency is as
much as 24%, as judged by a serum ferritin concentra-
tion < 12 µg/L.16 Attempting to exclude iron deficient
donors by increasing the hemoglobin concentration re-
quired for acceptability for donation would not be ef-
fective. Only standards for hemoglobin concentration
that would exclude most donors would protect against
iron depletion.5 Improved screening methods for donors
have been difficult to devise. Iron supplementation pro-
vides a potential means of preventing iron deficiency,
but blood collection services have been reluctant to sup-
ply routine iron supplementation after blood donation
because of the risk of accidental iron poisoning in the
small children of donors that is associated with the prepa-
rations of ferrous sulfate and other iron salts now avail-
able. Although unit packaging of potent iron supplements
is expected to decrease the risk, iron salts remain the
leading cause of death from accidental poisoning in chil-
dren in the US.18 Other possible disadvantages of supple-
mentation programs include limited compliance due to
side effects of ferrous salts, the possibility of masking
underlying pathological conditions associated with blood
loss and the risk of giving iron to individuals with undi-
agnosed hereditary hemochromatosis.
American Society of Hematology
Carbonyl Iron Supplementation
Low dose, short-term carbonyl iron after blood dona-
tion provides a potential method for iron replacement
that avoids many of the risks and disadvantages associ-
ated with other iron supplementation programs. Carbo-
nyl iron is a small particle preparation of highly purified
metallic iron. “Carbonyl” describes the process of manu-
facture of the iron particles, not their composition. Heat-
ing gaseous iron pentacarbonyl (Fe[CO]5) deposits me-
tallic iron as submicroscopic crystals that form micro-
scopic spheres of < 5 µm in diameter.3 The preparation
is more than 98% pure. Carbonyl iron is inert and inca-
pable of reacting with strong chelators of iron such as
transferrin and deferoxamine. When given orally, car-
bonyl iron is much less toxic than ionized forms of iron
such as ferrous sulfate. In humans, as in rats, the esti-
mated lethal dose of oral ferrous sulfate is about 200 mg
Fe/kg body weight.13,14,18 Adult human volunteers have
taken oral doses of 10,000 mg carbonyl iron (about 140
mg Fe/kg or 70% of the lethal dose of iron as ferrous
sulfate) “without deleterious effect.”4 Ethical consider-
ations preclude direct studies of the toxicity of carbonyl
iron in human infants and children. Formal toxicity stud-
ies of carbonyl iron in rats and guinea pigs found that
the LD0 (the dose that all animals survive) was 10,000-
15,000 mg Fe/kg and the lethal dose (LD100) was 50,000-
60,000 mg Fe/kg.1
Studies in animals have been carried out to deter-
mine the mechanism by which carbonyl iron is absorbed
and the reason for its low toxicity.8 Within the stomach,
iron is oxidized to the ferrous form by the reaction Fe0 +
2H+Cl- → Fe2+Cl2 + H2, in which the hydrogen ion is
derived from hydrochloric acid. In brief, the low toxic-
ity of carbonyl iron could be related to its pattern of ab-
sorption. Fatal amounts of iron may be absorbed through
an anatomically intact intestinal mucosa. With ferrous
iron, all the iron is in a soluble ionized form that is po-
tentially available for absorption. By contrast, with car-
bonyl iron only that fraction solubilized by gastric acid
is available for absorption; in addition, the rate of solu-
bilization is restricted by the rate of gastric acid produc-
tion. Iron toxicity, the result of the deleterious effects of
high concentrations of ionized iron, is minimized both
by the rate of gastric acid production and the equilib-
rium between production of ferrous iron by solubiliza-
tion by gastric acid and its discharge from the stomach
to the intestine. Thus solubilization of carbonyl iron by
gastric acid is a prerequisite for subsequent absorption.
The slow rate of solubilization results in a more pro-
longed absorption, which is responsible for the low tox-
icity of carbonyl iron. After oral administration of equiva-
lent amounts of carbonyl and ferrous iron, the amount
of iron absorbed and the internal distribution of the ab-
sorbed iron are all similar. These results indicate that,
Hematology 2001
after solubilization, the fate of iron given in the carbo-
nyl form is indistinguishable from that given in the fer-
rous state.8 Thus carbonyl iron is an inexpensive form of
iron with a safety margin 250 to 300 times greater than
that of ferrous sulfate and other iron salts.
The principal potential advantage of carbonyl iron
is its low toxicity. Studies in human volunteers have sug-
gested that the overall bioavailability of carbonyl iron is
high, about 70% that of ferrous sulfate, when expressed
in terms of elemental iron.12 Other studies with healthy,
nonanemic volunteers, with patients with iron deficiency
anemia7,10 and with women who were blood donors9
showed that carbonyl iron treatment could correct iron
deficiency anemia and replace iron stores. Because of
these results, a regimen for carbonyl iron supplementa-
tion in women of childbearing age who were committed
blood donors was devised that would replace iron losses
from donation in all, or nearly all, donors with minimal
or absent side effects. Carbonyl iron, 100 mg given once
daily at bedtime, was chosen as the treatment regimen
to be compared with placebo therapy. Administration at
bedtime was chosen to allow the carbonyl iron to re-
main in the gastrointestinal tract for as long as possible
without food buffering the stomach acid required for
solubilization of the elemental iron. In a trial of carbo-
nyl iron supplementation for blood donors11 with a ran-
domized, double-blind design, women 18-40 years of
age were given placebo or low-dose carbonyl iron, 100
mg po qhs, for 56 days after blood donation. Side ef-
fects with placebo and carbonyl iron were almost indis-
tinguishable; capsule counts indicated that compliance
with both regimens was similar. On the average, more
iron was absorbed by donors who initially had no iron
reserves (serum ferritin < 12 µg/L) than by those with
some stores. Overall, enough iron was absorbed to re-
place that lost at donation in 85% of the carbonyl iron
group but in only 29% of the placebo group (p < 0.001).11
This experience with single courses of supplementation
provided the basis for subsequent extended trials of car-
bonyl iron supplementation in committed women donors
of childbearing age.15
Draft protocol for carbonyl iron replacement for
women of childbearing age who are committed
blood donors
Participation in this program of iron replacement is re-
stricted to women, 18 to 40 years of age, who are men-
struating and meet other inclusion criteria (see below).
After each successful donation, eligible women are of-
fered a child-resistant bottle with 56 capsules, each con-
taining 100 mg of iron as carbonyl iron, and instructions
to take one capsule at bedtime until all capsules are gone.
After completing the 56-day course of iron supplemen-
tation, each donor is again eligible to donate and, after
429
each successful donation, receive another course of car-
bonyl iron replacement. The major features of the draft
iron replacement protocol are shown diagrammatically
in Figure 5.
Population eligible for participation in project;
inclusion and exclusion criteria
Eligible women must also meet the following inclusion
criteria: (i) They must intend to donate at least two units
of blood in the coming year; (ii) they must wish to re-
ceive the iron supplement; (iii) they must satisfy all other
blood center requirements for donation and (iv) success-
fully donate a unit of blood; and (v) they must be free of
any family or personal history of hereditary hemochro-
matosis, intestinal polyps, colon cancer, chronic gas-
trointestinal or other chronic medical problems. Donors
not meeting the above criteria will be excluded.
Consent process and documentation
Eligible women will generally first learn about the iron
supplementation program in a mailing from the Blood
Center, which contains a brochure describing the pro-
gram. Subsequently, after each successful donation, an
iron supplement will be offered to each eligible woman.
To receive the offered iron supplement, donors will be
required at the time of each donation to read and review
Figure 5. Draft protocol for carbonyl iron replacement.
430
the Program Brochure and sign an Iron Supplement Form
that includes a brief health questionnaire and the ele-
ments required for Informed Consent. Together the Pro-
gram Brochure and Iron Supplement Form are designed
to provide the information required for a standard In-
formed Consent Form but in a format consistent with
that used by blood centers to obtain consent for blood
donation.
Program procedures
All eligible donors who meet the program criteria will
be offered participation in the program through a mail-
ing from the Blood Center. Some Centers may wish to
offer each eligible woman a special donor card identify-
ing her as a participant. In the program, an iron supple-
ment will be offered after each donation to each partici-
pant. Fifty-six iron capsules will be contained in a child-
resistant bottle with instructions that a capsule should
be taken once daily at bedtime for 2 months after blood
donation until all have been taken. To receive the iron
supplement, donors will be required at the time of each
donation to read the Program Brochure and sign the Iron
Supplement Form, which includes a brief health question-
naire and the elements required for Informed Consent.
Risks and discomforts
The known risks of the program are (i) the risk of giving
iron to individuals with undiagnosed hereditary hemo-
chromatosis and (ii) the risk of masking underlying
pathological conditions associated with blood loss. The
inclusion and exclusion criteria, the use of low dose,
short-term iron supplementation, and the restriction of
provision of iron supplementation to only those women
who successfully donate a unit of blood are all intended
to minimize these risks. There may be other risks of par-
ticipation as yet unknown.
Other features of the draft protocol
This program requires no additional testing of donors.
The only additional expenses for the blood center are
those associated with the provision of the carbonyl iron
supplement (estimated cost about $1-$2/bottle). Women
participating in the program may also self-supplement
themselves with iron or other nutritional supplements
without restriction by the program. Men, post-meno-
pausal women and women who are not eligible for do-
nation for any reason are excluded from this program.
Conclusion
This draft protocol is presented to provide concrete rec-
ommendations for consideration by blood centers that
wish to develop a program of carbonyl iron replacement
for women of childbearing age. The primary goal of iron
replacement in these women donors is to prevent iron
American Society of Hematology
deficiency, their most common medical cause of defer-
ral from donation. By preventing iron deficiency and
consequent deferral from donation, iron replacement
enhances the retention and commitment of these dedi-
cated women donors and improves their iron status even
as they increase their blood donations. The adoption of
low dose, short-term carbonyl iron supplementation for
women of childbearing age who are committed blood
donors as a standard procedure for blood centers could
improve the iron status of these donors while increasing
the national blood supply.
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