Meeting, September 10-11, 2008
Iron Status in Blood Donors
Issue: FDA seeks
advice from the Committtee on the impact of blood donation on donor iron stores and donor health and, if
needed, on possible strategies to
mitigate iron depletion in the donor setting.
Iron is found in all cells and functions as
a major component of hemoglobin
About 70% of body iron is in the form of red
cell hemoglobin. Most of the remainder
is in a storage compartment, while smaller amounts are in myoglobin and still
smaller amounts in labile pools, intracellular respiratory enzymes, and
associated with transport glycoproteins.
Men generally have a total of ~3.8
g and women ~2.3 g of iron. The amount
of iron in the body is determined by intake through diet or iron
supplementation and losses from the gastrointestinal tract, menses, pregnancy,
breast feeding, and intravascular hemolysis.
The primary reasons for iron deficiency in healthy women of child
bearing age are menstruation, pregnancy, breast feeding and inadequate diet.
Deficiency of iron is one of the most common
nutritional deficiencies. Iron
deficiency ranges from iron depletion with limited or no physiological consequences
to iron deficiency anemia which can affect multiple organs. Iron is primarily used for erythropoiesis
with the vast majority of iron recovered from senescent erythrocytes (the iron
cycle). Transferrin transports iron to
the bone marrow for use in erythrocyte production. Iron is mainly stored in a water soluble form
as ferritin (9 mg/kg in men, 4mg/kg in women), but some is stored in a water
insoluble form as hemosiderin (4 mg/kg in men and 1 mg/kg in women). As iron stores become depleted, iron is
mobilized as measured by serum ferritin.
There may not be physiologic consequences of iron depletion in the early
stages. However, as iron depletion
progresses, storage iron is exhausted and transport iron is reduced as measured
by a diminished transferrin saturation. Iron-deficient erythropoiesis may result. In children, normal growth or development of
cognitive function may be impacted. With
the depletion of iron, production of red blood cells is impaired and free
erythrocyte protoporhyrin concentration increases. In iron deficiency anemia there is
underproduction of needed iron containing compounds including hemoglobin. Red blood cells (RBC) from these anemic
individuals are microcytic and hypochromic.
In infants and young children, iron deficiency
anemia can result in developmental delays, low birth weight, and
malnutrition. In adults, iron
deficiency anemia has been reported to impact work capacity in the developing
world. In pregnant women, iron deficiency
anemia during the first two trimesters is associated with an increased risk for
preterm delivery and a three-fold increase in low birthweight. Other symptoms that may be associated with
lower iron levels include fatigue, restless leg syndrome and pica. In contrast, a limited number of recent
studies have suggested a potential cardiac benefit with reduced iron
The NHANES (1999-2000) survey found that 12%
of women 16-49 years of age were iron deficient and about 3-4 % had iron
deficiency anemia. For women 50 years or
older about 9% were iron deficient and 3 % had iron defiency anemia. In contrast, for men 16-69 years old about 2%
were iron deficient and 1% had iron deficiency anemia. However, iron deficiency was greater in
certain racial or ethnic groups. CDC
defined iron deficiency as abnormal value for at least two of three indicators:
serum ferritin, transferrin saturation, and free erythrocyte
protoporhoryin. Individuals with iron deficiency
and low hemogoblin were considered to have iron deficiency anemia.
The NHANES III survey (1994-1998) found that
95% of men over 18 years had a hemoglobin concentration that was greater than
13.5g/dl or 39.9% hematocrit, while 95% of women greater than 18 years had
hemoglobin levels of 12.0g/dl or 35.7% hematocrit. These levels were established as the defining
levels for iron deficiency anemia and are consistent with other population
based studies. However, hemoglobin and
hematocrit levels can vary by race.
African-Americans have slightly lower hemoglobin or hematocrit levels
(about 0.8g/dl or 2% for adults) while some studies suggest even lower levels for
African-American females. Some of this
difference can be accounted for by the relatively high prevalence of alpha-thalassemia
in African-Americans. Other conditions
can also have an impact on hemoglobin or hematocrit levels include high
altitude residence, seasonal variation in temperature, and smoking.
In the blood bank setting, hemoglobin or
hematocrit measurements are used to determine donor eligibility. The FDA standard for the lower level for
hemoglobin is 12.5 g/dL or 38% hematocrit for both men and women. The standards for hemoglobin/hematocrit vary
and some countries have different standards for men and women. The FDA standard allows men who are below the
“normal level” for hemoglobin based on population levels to donate.
Previous studies have found that about 40-75%
of all deferrals are due to low hemoglobin value and 95% of these deferrals
occur in women. These deferrals also
discourage female donors from subsequent donations and result in a long term
loss of donors. The use of iron
supplements to increase the number of younger female donors who would meet
hemoglobin/hematocrit standards was discussed at an NIH workshop in 2001, however,
few blood establishments and transfusion services have piloted studies on the
use of iron supplements in blood donors.
Although measuring hemoglobin levels by a gravimetric test
using copper sulfate is a relatively easy and widely used method for determining
donor eligibility in the blood bank setting, there are other methods that
provide a more precise measure of iron status.
These methods include Mean Corpuscular Volume (MCV - the average volume
of red blood cells); Red Blood Cell Distribution Width (RDW); Erythrocyte
Protoporhyrin Concentration; Serum Ferritin Concentration; and Transferrin
saturation. However, measurements of
iron status such as serum ferritin and transferrin saturation, are not
routinely used in this country for donors and may not be practical for blood
bank screening .
A number of studies have shown that iron stores may be
depleted in donors with normal hemoglobin values. A healthy male blood donor loses about
200-250 mg of iron per donation. The loss is made up by mobilizing iron stores
in the form of ferritin. By contrast, a double RBC donation, permitted every 16
weeks, results in the loss of 500 mg of iron per donation. However, there are few reports documenting
adverse events due to the loss of iron in blood donors. The reported adverse effects include fatigue,
restless leg syndrome (RLS), and pica.
Screening techniques can detect iron depletion in blood
Mean ferritin levels are significantly lower in blood donors
than in non donors. Men usually have the
most dramatic drop in ferritin levels because of higher iron stores before
donation. Studies have shown that iron
stores decline with repeated blood donation.
After 6-8 phlebotomies the ferritin level is about 40 % lower than at
baseline. The proportion of male donors
with decreased iron stores went from 8 to 19 % with an increase from 5 to 6
donations per year.
In one study in Australia, it was found that about
19% of female blood donors were iron deficient at a hemoglobin level of 12.5
g/dL, while about 5% of male donors were iron deficient at a level of 13.5 g/dL
. Other countries have different
standards for hemoglobin levels and a longer interval between donations
presumably to reduce the risk of iron depletion in blood donors
The NHLBI REDS-II Donor Iron Status Evaluation Study aims to
evaluate the effects of blood donation intensity on iron and hemoglobin status
in first time and frequent blood donors and determine changes using baseline measures
as well as demographic, reproductive, and behavioral factors. The study will also identify optimal
laboratory procedures that predict the development of iron depletion and
hemoglobin deferral in blood donors.
Additionally, the study will help formulate optimal blood donation
guidelines by establishing a model that predicts the development of iron
depletion and hemoglobin deferral in individual blood donors.
The committee will hear presentations on (1)
population based studies on normal levels of hemoglobin; (2) the impact of
blood donation on blood donor iron stores; (3) studies that are in progress on
the iron status of blood donors; (4) potentially harmful or beneficial effects
of blood donation related to iron depletion; (5) experience of U.S. programs
that provide iron replacement to donors; and (6) the European experience and
perspective on iron management in donors.
Questions to the Committee:
Is iron depletion in blood donors a concern?
If so, are there tests for iron status that
would be practical and appropriate in the donor setting?
discuss the risks and benefits of alternative strategies to mitigate iron
depletion in donors including:
b) dietary recommendations;
modification of the inter-donation interval;
d) changing the acceptance standard
for donor hemoglobin/hematocrit.
Centers for Disease Control and Prevention.
Recommendations to prevent and control iron deficiency in the United States.
Morb Mortal Wkly Rep. 1998;47(RR-3):1-36.
Looker AC, Cogswell ME, Gunter EW. Iron
deficiency, United States, 1999–2000. Morb Mortal Wkly Rep. 2002;51:897-9.
Iron-Status Indicators in National Report on
Biochemical Indicators of Diet and Nutrition in the U.S. Population 1999-2002
Beutler E. and Wallen, J. The definition of
aneria: What is the lower limit of normal of the blood hemoglobin concentration
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Bianco C. et.al. Maintaining iron balance in
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Farrugia A, Iron and Blood Donation-An UnderRecognized
Safety Issue. Advances in Transfusion
Safety-(IV) Dev. Biol., Basel,
Karger, 2007, 127; 137-146.
Newman, B. Iron depletion by whole-blood
donation harms menstruating females: The current whole-blood-collcttion
paradigm needs to be changed.. Transfusion 2006;46: 1667-1681
Brittenham, GM. Iron balance in the red blood
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Magnussen K, Bork N, Asmussen L. The effect of a
standardized protocol for iron supplementation to blood donors low in hemoglobin
concentration Transfusion 2008;48:749-754