Page
301
1 the body that
need it. These tissues pick up
2 the iron
through transferrin receptors that
3 are related on
their surface. The transferrin
4 binds and is
then internalized and released
5 within the
cell for use.
6 In essence
each cell looks after
7 its own iron
metabolism, its own iron program,
8 and picks up
just what it needs. It
9 determines
what it gets by how it expresses
10 these transferrin
receptors on the surface.
11 Most of the
transferrin receptors in the body
12 are really on the
erythroid cells because
13 those are the cells
that have the greatest
14 need for iron to
make new hemoglobin.
15 At the end of
their lifespan the
16 cells are taken up
by these macrophages here.
17 The red cells are
broken down. The iron is
18 released and then
exported again through
19 ferroportin back
out to transferrin to be
20 recycled.
21 Now, I have to
mention hepcidin.
22 Hepcidin was
discovered just a little over
Page 302
1 five years ago
-- was recognized just a little
2 over five
years ago. It's a very short 25
3 amino acid
peptide that is the master
4 regulator of
iron metabolism. It is
5 absolutely an
ingenious system.
6 The way it
works is that the cells
7 that can
donate iron either via the
8 enterocytes in
the GI tract from the GI tract,
9 or from the
iron that is recycled from
10 macrophages or the
iron that comes from
11 hepatocytes.
12 The hepcidin
simply binds to this
13 exit protein, the
ferroportin and immobilizes
14 it so that when the
body believes it has
15 enough iron it
increases the hepcidin, it gets
16 rid of all the ways
the iron can enter into
17 the system so the
iron drops. Conversely, if
18 there is not enough
iron available, the
19 hepcidin is
decreased. More iron exporters go
20 to the surface of
the cell and increase the
21 iron.
22 So just now I
think our frontier
Page 303
1 in
understanding iron metabolism is
2 understanding
exactly how the production of
3 hepcidin is
regulated within hepatocytes. It
4 is a
fascinating and complex system of
5 regulation so
that the body iron is precisely
6 calibrated to
the needs of all the cells.
7 Now, I show
this again to
8 recalibrate
you because now I would like to
9 define what we
mean when we talk about iron
10 depletion and iron
deficiency. In iron
11 depletion you see
what has happened is that
12 we've lost the
stores so this is meant to
13 refer to the time
when the iron that is kept
14 in reserve has been
exhausted.
15 The next red cell
that's made
16 won't have enough
iron and that is where we
17 really have iron
deficiency. Something we
18 know much less
about is what happens to all
19 the cells in the
rest of the body, how they
20 are affected by not
having enough iron for all
21 the
needs.
22 A key question is
what
Page 304
1 consequences
are there of having just iron
2 depletion.
This is the stage before there is
3 any anemia
that's present so what difference
4 does it
make?
5 The first is
that you no longer
6 have reserves.
The reserves are there to
7 provide a
rapid means of responding to blood
8 loss.
Otherwise, you are limited to absorbing
9 just one or
two or three milligrams of iron a
10 day from the
diet.
11 If you lost a unit
of blood, it's
12 going to take many,
many days before you can
13 absorb from the
diet that blood again. If you
14 have reserves, you
can build it back quite
15 rapidly. Similarly,
if there is a lack of
16 iron reserves, then
they won't be available
17 for pregnancy which
puts tremendous demands on
18 the need for
iron.
19 I think -- I'm
sure -- I'm almost
20 sure when Paul
McCurdy discussed this that
21 people might have
said then that maybe the
22 main consequence of
iron depletion was limited
Page 305
1 to this, but
there is more recent information
2 that suggested
perhaps that is not true.
3 There are
studies now that I have
4 shown and
referenced here that you can even at
5 this stage of
iron depletion have muscle
6 fatiguability,
impaired endurance, and that it
7 affects
cognitive function. If you look
8 carefully and
test specifically, you can show
9 that there are
cognitive defects that are
10 corrected with iron
repletion.
11 I have to say
about the muscle
12 fatiguability and
impaired endurance, these
13 are defects that
come out only with testing.
14 You might not be
aware of them in daily life
15 unless you are
trying to perform at peak
16 capacity.
17 Now, the next
phase if the iron
18 deficiency
progresses, if there is less and
19 less iron, then
that is when we see anemia
20 develop. We have to
follow up on a comment
21 that Dr. Holness
made. We use population
22 standards for
anemia but the way we set the
Page 306
1 population
standards are the level below which
2 only five
percent of the population would be
3 found. If you
are using that to define it, it
4 means that in
95 percent above by the time
5 they get below
they are much below what their
6 hemoglobin
was. Each of us has an optimal
7 hemoglobin and
for most of us, or 95 percent
8 of us, it's
above this minimum level that we
9 use to define
anemia in a population.
10 What are the
consequences of
11 having iron
deficiency anemia? There are
12 specific
manifestations that I'll illustrate
13 and I might mention
Restless Leg Syndrome.
14 This is a
relatively recently recognized -- a
15 recently
appreciated condition. It's been
16 recognized, I
think, for some time. It seems
17 to be greatly
increased in which the
18 proportion of
people with iron deficiency
19 seems to be greatly
increased. Especially
20 perhaps in the
summary from Dr. Allen he makes
21 a forceful case
that iron is -- that iron
22 greatly increases
the risk of all the
Page 307
1 populations
that are at risk for developing
2 this
problem.
3 There are
certain things that are
4 more or less
characteristic, not necessarily
5 simply
specific for iron deficiency. Angular
6 stomatitis is
one. These are mostly related
7 to the fact
that the cells that have the
8 greatest need
for iron are those that are
9 turning over
most rapidly so that includes not
10 only the blood
cells but all the epithelial
11 cells in the body
so the corners of the mouth,
12 the tongue. There
is a very curious one
13 called pagophagia
that is said to be almost
14 diagnostic of iron
deficiency where
15 individuals develop
a craving for ice perhaps
16 because the
epithelial surfaces are
17 uncomfortable and
it's an effort to try to
18 soothe those and
consume enormous amounts of
19 ice and crushed
ice. Sometimes there are
20 other foods that
are there as pica but this is
21 one that is thought
to be reasonably specific
22 for iron
deficiency.
Page 308
1 Koilonychia
we don't see as much.
2 It's a
consequence of a more severe iron
3 deficiency but
it's this sort of spoon shaped
4 deformity of
the nails. Then blue sclerae is
5 another one.
The epithelial covering of the
6 eye thins so
you can see the venous
7 circulation
beneath and giving this blue
8 tinge.
9 Then there
are the consequences
10 that are common to
all anemias, the pallor,
11 palpitations,
tinnitus, headache, being
12 irritable, dizzy,
all of these sorts of
13 nonspecific things.
The latter two, the
14 reduced exercise
capacity and the decreased
15 work productivity,
I think there is an
16 enormous body of
evidence that these are
17 consequences of
this.
18 Now, within the
field of iron
19 there is an
argument over how much of this is
20 due to iron itself
and how much of this is due
21 to anemia. I think
for our purposes today
22 that is of no
consequence because this is what
Page 309
1 we can
produce, I think, by the policies we
2 have in place
on iron deficiency anemia and it
3 doesn't
matter. These are definitely
4 liabilities
that arise from having iron
5 deficiency
anemia.
6 How
symptomatic people are often
7 depends just
on how rapidly it comes on. If
8 the anemia
developed suddenly, then it's much
9 more likely to
be symptomatic than if it's
10 something that
develops very, very slowly over
11 a long period of
time.
12 So now what I
would like to do is
13 turn to discuss and
focus on iron metabolism
14 and iron deficiency
in women of childbearing
15 age. This is a
slide from Jim Cook and one of
16 our committee
members today, Barry Skikne, who
17 examined using
serum ferritin and transferrin
18 receptor estimated
by the iron in men and
19 women over the
course of life.
20 You can see that
in males the body
21 iron is
substantially higher than it is in
22 females on the
average beginning at around the
Page 310
1 time of
puberty and then ending at the time --
2 and then they
tend to converge in post-
3 menopausal
women and are much more similar in
4 later life.
5 So when we
are making regulations
6 that have to
do with iron, we have to be
7 conscious of
this fundamental difference in
8 the iron
stores that are available to men and
9 to women. Once
again, this is just to
10 calibrate so you
can see these are the iron
11 stores in a normal
adult man. The blue
12 corresponds to what
would be equivalent to
13 about three units
of blood. The average
14 amount of excess
iron stores is some 750
15 milligrams. That
would be roughly what you
16 would find in three
units of blood.
17 By contrast, in a
woman of
18 childbearing age,
because of menstrual losses,
19 the reserve is
decreased so it is equivalent
20 to about one unit
of blood, a little over 220
21 milligrams of iron.
Women, thus, have a
22 reserve of only one
unit on average if that's
Page 311
1 available.
2 So what does
it mean when we take
3 a unit of
blood from a woman of childbearing
4 age? On
average then we will deplete her
5 stores at that
time. Now, the body responds
6 by increasing
absorption. The normal iron
7 requirement
for a woman is about a milligram
8 and a half a
day. For a man it's one. For a
9 woman it's one
and a half because of menstrual
10 losses.
11 There's some 13
and a half
12 milligrams of iron
again on average. So
13 already a woman
needs simply to maintain
14 herself 50 percent
more iron absorbed each day
15 from dietary
sources. Then the only way this
16 can be made back,
that this can be returned to
17 the system, is by
absorbing dietary iron this
18 way and increasing
the amounts there.
19 Perhaps this slide
is the most
20 pertinent for the
particular discussion. At
21 least the studies
we did, the iron lost at
22 donation is
something like 225 milligrams of
Page 312
1 iron. The
maximum amount of iron that can be
2 absorbed from
the diet is something like three
3 to four
milligrams a day so I have taken 3.5
4 milligrams as
an average estimate. A woman
5 has a basal
requirement of 1.5 just to stay
6 even. That
means she can only absorb to make
7 up for the
iron that has been lost at donation
8 from the usual
American diet 2 milligrams of
9 iron a day. So
over the 56-day donation
10 interval that means
only 112 milligrams of
11 iron can be
acquired. After 56 days when we
12 ask someone to
return, then it means there is
13 a deficit that is
there that corresponds to
14 roughly a half unit
of blood. What that means
15 is if a woman comes
and donates according to
16 regulation, then
after the first donation she
17 is down one half
unit of blood. After two
18 donations, after
the next 56 days, she's down
19 a unit of blood.
After the next donation if
20 she is allowed to
donate six times a year, you
21 can go through that
she can have quite a
22 deficit at the end
and winds up with frank
Page 313
1 iron
deficiency anemia. These are committed
2 women who are
trying to donate doing just what
3 the
regulations specify. Yet, what happens is
4 they will return at the end of the time as a
5 consequence of this having exhausted their
6 iron stores and be rejected as donors. Often
7 what this means is that we then lose them as
8 donors.
9 I would like
to end really by
10 going and talking
about a program of iron
11 replacement that we
tried to examine to see if
12 it were possible to
at the time of donation
13 return to women the
amount of iron that they
14 had given in the
donation itself.
15 Here the primary
goal is to
16 replace -- the
primary goal is to prevent iron
17 deficiency. We're
not trying to treat it,
18 we're trying to
prevent it. By preventing
19 iron deficiency we
can decrease deferral from
20 donation because of
low hemoglobin. The
21 donors who are
trying to return can do so
22 successfully and
not suffer rejection. And
Page 314
1 iron
replacement can improve iron status even
2 as they -- sorry -- can improve iron status
3 even as they increase donations.
4 So, what are the risks of giving
5 iron to donors? The major ones from the
6 donors themselves are giving iron to
7 individuals with undiagnosed hereditary
8 hemochromatosis or masking pathological
9 conditions that are associated with blood
10 loss.
11 We tried to design
a program that
12 would avoid these
risks, that would seek to
13 minimize these
risks. We considered giving
14 iron then only to
women 18 to 40 years of age
15 who are
menustrating and committed to donating
16 more than two units
of blood per year.
17 If you are
donating less, then you
18 probably over the
course of time can get
19 enough back from
the diet. We asked for a
20 family or personal
history of these other
21 conditions to try
to minimize risk as I
22 mentioned. We
exclude men, post-menopausal
Page 315
1 women, and
women who are otherwise not
2 eligible for
donation.
3 Because this
program went beyond
4 the consent
that is provided when a blood
5 donor normally
signs on, we had an additional
6 consent and a
health questionnaire to try to
7 be sure that
we excluded these conditions that
8 would increase
risk.
9 For our iron
supplement we chose
10 carbonyl iron. I
want to emphasize there is
11 nothing special
about the carbonyl iron. We
12 chose it simply
because at the time it seemed
13 the safest kind of
iron to give. I would just
14 like to explain
that. I think the other major
15 risk of giving iron
to women of childbearing
16 age is poisoning
their children so you need to
17 take special care
to avoid that.
18 We thought the
carbonyl iron was a
19 good way to do
that. It's simply a small --
20 it's simply
metallic iron in a small highly
21 purified form. The
carbonyl describes how it
22 is produced, not
its chemical composition.
Page 316
1 It's simply
pure iron in very, very small
2 microscopic
spheres.
3 It's really
generally made for
4 special uses,
industrial uses. It's safe
5 really because
it has to first be solubilized
6 in gastric
acid before it can be absorbed. So
7 even if you
take a massive dose, you can't
8 absorb more
than your own gastric acid can
9 solubilize and
deliver. Paul Whitaker
10 actually, at the
FDA now, did a study, as
11 well, demonstrating
that it is extraordinarily
12 safe. The lethal
dose is something like 200
13 milligrams per
kilo.
14 Here is this --
I'm sorry. I'm
15 not very skilled at
operating my device. Here
16 was the whole
scheme. Potentially eligible
17 women would come
and then if they don't
18 succeed in
donating, then they don't get iron.
19 We didn't give
iron to women who
20 were not accepted
for donation. It's only
21 those who donate
that we give iron. We are
22 not treating iron
deficiency. We are trying
Page 317
1 to prevent it
by returning to the donors the
2 iron they have
given in the blood donation.
3 This is a
study that we did at the
4 Red Cross at
the time in Cleveland, Ohio.
5 This slide
shows that most of the donors took
6 their carbonyl
iron most of the time. We had
7 them bring
back bottles and counted how many
8 capsules were
left. At the time this was done
9 for what was
called a VIP group. It was a
10 group of donors
committed to giving more than
11 four times a year,
and they had scheduled
12 visits. For these
studies we had to have a
13 group to factor out
the effect of just
14 scheduling the
visit. We had the current
15 practice group,
which was the VIP group, ones
16 where we didn't
give iron but just scheduled
17 their visits, and
then the carbonyl iron group
18 where we did both.
19 In our study
anytime someone
20 dropped below a
hemoglobin of 11 we excluded
21 them from further
study. This just shows that
22 this happened much
less frequently in the
Page 318
1 group that got
iron than in the others.
2 If you look
at the number of
3 deferrals from
donations for low hemoglobin
4 concentration,
you can see that the carbonyl
5 iron program
didn't stop it but it cut the
6 rate by half.
This is a slide that shows the
7 time before
the first deferral for low
8 hemoglobin
concentration.
9 I think it's
interesting as much
10 for the ones who
didn't get carbonyl iron as
11 for those who did
because in this group you
12 see the ones
treated by current practice are
13 the ones with
scheduled donations. Half the
14 donors are deferred
in the course of a year.
15 We could
substantially defer that although
16 even with this
program not completely.
17 This was in spite
of the fact that
18 the donors who
received carbonyl iron actually
19 gave more blood
than others. The current
20 practice group we
take this as a hundred. The
21 total number of
donations from the donors
22 receiving carbonyl
iron were actually
Page 319
1 increased by
50 percent.
2 We thought
that this defined a
3 program that
was safe, that minimized the risk
4 of giving
iron, and that improved the status
5 of the most
committed donors. Let me end just
6 by saying that
with current FDA guidelines the
7 women of
childbearing age who are our safest
8 donors, our
most valuable donors, are at the
9 greatest risk
of developing iron deficiency.
10 Thank
you.
11 DR. SIEGAL: Thank
you very much,
12 Dr.
Brittenham.
13 Are there
questions for this
14 speaker?
15 DR. FLEMING: There
are a lot of
16 questions I would
have about the randomized
17 trial in terms of
whether it's an ITT
18 analysis, did you
include all randomized
19 people even when
they were randomized to the
20 arm of getting the
iron replacements if they
21 somehow declined or
did you keep them in that
22 group.
Page 320
1 But let me
get to the core issue.
2 Could you go
back to your slide that shows the
3 Kaplan-Meier
curves?
4 DR.
BRITTENHAM: Sure.
5 DR. FLEMING:
My understanding is
6 this is in
essence giving us an indication
7 that you're
doing something about avoiding low
8 hemoglobin
concentration. Is that possibly an
9 inadequate
answer as to whether you are truly
10 avoiding the
negative consequences in these
11 women of
childbearing age regarding what is
12 truly clinical
risk. Are you impacting their
13 iron stores, etc.,
etc.?
14 I think there has
been a lot that
15 you and others have
said that hemoglobin
16 concentration
doesn't tell the whole story
17 about the concerns
you would have with iron
18 deficiency and
might this just say, "Sure, if
19 you give this
intervention, you can do
20 something about
avoiding low hemoglobins," but
21 does it really mean
also that you have
22 addressed the more
fundamental issues of iron
Page 321
1 deficiency?
2 DR.
BRITTENHAM: Well, I certainly
3 would be the
last to advocate hemoglobin as
4 the way to
detect iron deficiency. Really in
5 this
presentation what I was trying to focus
6 on was the
consequences for deferral. In the
7 study people
were, in fact, randomized and
8 randomly
allocated to the treatments as much
9 as possible.
10 You have to
remember that all
11 these women were
VIP donors. Most of the
12 women when we began
the trial were already
13 iron deficient. We
are starting with a
14 population that has
a great deal of iron
15 deficiency already
introducing the program.
16 The ideal way to
do this would be
17 to prevent it from
the beginning in women who
18 are there. But, as
I say, my purpose in
19 describing this
isn't to advocate this is the
20 solution. It's just
to give you evidence of
21 how severe the
problem is. There are other
22 solutions that
could be used to detect iron
Page 322
1 deficiency.
2 Certainly
what we're doing now
3 doesn't. There
are certainly are measures
4 that can be
done with blood counters,
5 reticulocyte
hemoglobin content, for example,
6 can identify
donors who pass the hemoglobin
7 test but who
are still iron deficient. There
8 are many ways
to try to solve this.
9 This was just
one attempt, and I
10 thought I would
show it to give you a sense of
11 the magnitude of
the problem. I think you'll
12 hear this from many
of the other speakers
13 today.
14 DR. FLEMING: But
your conclusion
15 on the next slide
really reflected, or maybe
16 it was the one
after this conclusion, that
17 this
supplementation in essence was being put
18 forward as potential evidence that this could
19 be a good strategy.
20
If we go back one more time to
21 that Kaplan-Meier
curve, your very thoughtful
22 insights and
insights from what others have
Page 323
1 written and
the materials that have been
2 shared with us
at least indicated to me there
3 is a real
complexity here about iron
4 deficiency and
there are important clinical
5 consequences
that you and others have pointed
6 out, so the
goal, I would think, would be to
7 think of
strategies that maximize the
8 flexibility to
donate and minimize those true
9 clinical
consequences.
10 But what this is
looking at is if
11 you essentially say
we are going to allow more
12 frequent donations
to occur if you are able to
13 achieve a more
standardized hemoglobin, and
14 you, in fact, said
that happened in this case,
15 this could actually
be a bad thing because you
16 might be covering
up continued losses in your
17 iron
storage.
18 By giving a
supplementation like
19 this you are giving
the appearance that you
20 can now give more
often and those frequent
21 donors are now
going to be in even greater
22 jeopardy because
they are getting this
Page 324
1 supplementation that is camouflaging the real
2 negative clinical circumstance.
3 Ultimately, and I know it would be
4 a much more complicated trial, isn't the issue
5 let's look at supplementation yes versus no
6 over a long term to see whether or not it
7 impacts clinical consequences of iron
8 deficiency?
9 DR.
BRITTENHAM: That wasn't what
10 this trial was
designed to do. It is
11 certainly true that
there are women who are
12 taking the
supplement for whom it's
13 inadequate. I
didn't mean it as a perfect
14 solution to the
problem but rather to try to
15 show the magnitude
of the difficulty that's
16 there. I think you
will hear more.
17 DR. FLEMING: Maybe
just one brief
18 follow up. Did you
assess, for example, in
19 this trial a
relative comparison of measures
20 of iron storage,
etc., to see --
21 DR. BRITTENHAM:
Yes.
22 DR. FLEMING: And
you have that
Page 325
1 kind of --
that would be interesting maybe
2 offline or
something to see whether the
3 supplementation enhanced the stores in
4 addition to --
5 DR.
BRITTENHAM: Oh, there's no
6 question. Even
though the carbonyl iron
7 donors gave
more, their iron stores actually
8 improved over
time, so we do have that data.
9 DR. SIEGAL:
Dr. Bracey.
10 DR. BRACEY: Yes.
In some of the
11 reading it really
appeared as though iron
12 deficiency,
particularly in this population,
13 is viewed as a
public health problem.
14 With this
particular notion you
15 are focusing
primarily on preventing
16 additional iron
depletion related to blood
17 collection, but
what are your thoughts about
18 the role of -- you
know, we turn away donors
19 but we may not
fully understand why we turn
20 away donors that
have low iron levels. What
21 are your thoughts
about the role of addressing
22 women that are
turned away or may not donate
Page 326
1 more than
twice a year?
2 DR.
BRITTENHAM: Well, I think the
3 problem with
donors who are turned away is a
4 very difficult
one because one can never be
5 sure. We
could, for example, have a system
6 where we take
donors and we assess their
7 reticulocyte
hemoglobin content to identify
8 those who are
likely to be iron deficient. If
9 they are
deferred because there is evidence of
10 iron deficiency, we
could give them iron. The
11 difficulty that
that policy would seem to me
12 is that we can
never be sure that they are
13 iron deficient
because of the blood donation.
14 There is always the
possibility that they have
15 an occult, other
cause of blood loss that then
16 we would cover up
by treating. This
17 particular strategy
we chose is that what we
18 were doing we are
not treating the donors long
19 term. We were just
treating them for 56 days
20 to try to replace
the iron that they had lost.
21 That was the very
limited goal.
22 DR. BRACEY: I
guess I was
Page 327
1 thinking not
so much about treatment but
2 rather
diagnosis and referral.
3 DR.
BRITTENHAM: It certainly
4 would be
possible to identify at least those
5 donors who are
deferred because of anemia and
6 iron
deficiency.
7 DR. DI
BISCEGLIE: I'm not sure
8 any of the
other speakers are going to address
9 this. In this
study did you make any attempt
10 to look for
hemochromatosis? It obviously
11 wouldn't be
manifest in women of childbearing
12 age, but you might
find some with raised
13 transferrin
saturations above 40 percent. I'm
14 not sure if this
was done in the era of HFE
15 screening and so
on.
16 DR. BRITTENHAM:
Once again, the
17 intent of this was
to try to do it in such a
18 way we were
replacing the iron that was given.
19 The additional
increment we can make in
20 somebody who had
hemochromatosis was minimal.
21 We are only giving
iron for 56 days. We are
22 not doing it a
continuous long term. We have
Page 328
1 done previous
studies to show that that would
2 on average
replace the iron lost at donation
3 in most
women.
4 DR. DI
BISCEGLIE: So this was
5 just one cycle
of 56 days --
6 DR.
BRITTENHAM: One cycle.
7 DR. DI
BISCEGLIE: -- but the
8 effect seemed
to carry out for up to 30
9 months.
10 DR. BRITTENHAM:
Yes. At each
11 donation then the
donor would be given iron
12 but only for this
eight-week period and then
13 stop. The risk of
worsening hereditary
14 hemochromatosis we
thought was quite minimal.
15 Similarly the risk
of covering up discovery of
16 an occult kind of
blood loss was minimal.
17 DR. FINNEGAN: How
did you counsel
18 the women about
discussing this with either
19 their OB or
PCP?
20 DR. BRITTENHAM:
I'm sorry?
21 DR. FINNEGAN: Did
you counsel the
22 women about
discussing this with either their
Page 329
1 OB or their
primary care doctor?
2 DR.
BRITTENHAM: Yes. They got
3 the standard
sort of counseling for women who
4 were deferred
so, yes.
5 DR. KULKARNI:
In the donation --
6 I mean, in the
blood collected was there an
7 increase in
reticulocytes and, therefore, the
8 lifespan of
the red cells?
9 DR.
BRITTENHAM: I'm not sure I
10 understand.
11 DR. KULKARNI: Once
these women
12 got iron, one would
assume that their
13 reticulocyte count
would increase. Correct?
14 DR. BRITTENHAM:
Yes.
15 DR. KULKARNI:
Would that then
16 cause an increase
-- I mean, we do that for
17 sickle cell, the
erythrocyte apheresis, so
18 that you kind of
give them reticulocytes so
19 that their lifespan
increases.
20 DR. BRITTENHAM: We
didn't really
21 -- in this specific
study we didn't follow
22 them after that. We
just see them at the time
Page 330
1 of donation.
They would be given the iron and
2 then when they
came back for the next
3 donation, so
we didn't do laboratory studies
4 or assess the
reticulocyte counts or other
5 things in the
interim.
6 DR. KULKARNI:
Or even in the bag
7 of blood
collected.
8 DR.
BRITTENHAM: Yes.
9 DR. RENTAS:
I'm just interested
10 on autologous
donors the FDA standards are
11 different. You can
go down to 11 percent
12 hemoglobin. Yet,
you may be donating two
13 units in one week.
Have you done any studies
14 on
that?
15 DR. BRITTENHAM:
No, we haven't
16 looked at double
donation, but I think what
17 has been done is
that in essence when you give
18 two units you are
deferred not for eight weeks
19 but for 16 weeks.
If you go back and look at
20 the math again, you
wind up in the same
21 position.
22 DR. RENTAS:
Actually, that's not
Page 331
1 quite what I
was asking. You are donating for
2 yourself. You
are having surgery in three
3 weeks. You may
be donating a unit now and
4 another unit
next week, yet your hemoglobin
5 may be around
11 or 11.2. You haven't done
6 any studies on
that?
7 DR.
BRITTENHAM: No. We didn't
8 examine
autologous donation. I think that is
9 quite a
different set of problems.
10 DR. SIEGAL: Okay.
Thank you very
11 much.
12 The next speaker
will be Sarah
13 Cusick, Ph.D., from
CDC discussing normal
14 values for
hemoglobin and iron stores. We
15 know Dr. Cusick is
going to have to leave
16 promptly after her
talk so we'll take
17 questions right
away.
18 DR. CUSICK: Good
afternoon. I am
19 Sarah Cusick, and
I'm a micronutrient
20 specialist with the
International
21 Micronutrient
Malnutrition Prevention and
22 Control Program, or
the IMMPaCt Program, at
Page 332
1 the U.S.
Centers for Disease Control and
2 Prevention in
Atlanta.
3 My main area
of research is iron
4 and iron
deficiency both in the United States
5 and around the
world. Today I'll be
6 presenting on
the epidemiology of iron
7 deficiency and
assessment of iron status in
8 U.S.
adults.
9 Although
typically considered to
10 be a developing
world problem, iron deficiency
11 remains a public
health concern among certain
12 populations, even
in the United States, and
13 particularly among
women of childbearing age.
14 Here I've presented
data from two different
15 national health and
nutrition examination
16 surveys, or NHANE
surveys.
17 The first was
conducted in 1988 to
18 '94 and the second
in '99 to 2002. As you can
19 see, among women 16
to 49 years the prevalence
20 of iron deficiency
is highest, 11.5 percent.
21 This prevalence
actually increased somewhat to
22 15.7 percent among
adolescent girls and 13.7
Page 333
1 percent among
women 20 to 49 years.
2 Among
post-menopausal women,
3 however, the
prevalence was approximately half
4 as great in
each survey. Among men 16 to 69
5 years the
prevalence was much lower, just over
6 1 percent in
each survey and increasing
7 somewhat among
men 70 years and older.
8 Among women
of childbearing age
9 iron
deficiency is really most prevalent among
10 minority women and also lower income women.
11 As you can see, among white women the
12 prevalence was 8.2 percent in the first and
13 11.4 in the second. It was nearly twice as
14 great among black women and even greater among
15 Mexican American women with more than one in
16 five black and Mexican-American women found to
17 be iron deficient in the latter survey.
18
Among women living in households
19 earning less than
130 percent of the poverty
20 threshold iron
deficiency was greatest, about
21 17 percent in both
surveys, and decreased
22 steadily with
increasing income in both
Page 334
1 surveys.
2 And in a
subsample of women with
3 information on
blood donation in NHANES 1988
4 to 1994 iron
deficiency was also associated
5 with recent
donation or blood donation in at
6 least once in
the preceding 12 months.
7 Among women
16 years and older
8 15.3 percent
of them who had reported giving
9 blood at least
once in the preceding 12 months
10 were iron deficient
compared to 8.8 percent
11 among non-donors
and this was statistically
12 significant.
13 However, when this
analysis was
14 stratified by age,
you can see that the
15 association really
existed among women 16 to
16 49 years, women of
childbearing age, with a
17 prevalence of 17.6
and 10.9 percent with a
18 prevalence of iron
deficiency much lower and
19 not statistically
different among women 50
20 years and
older.
21 Iron deficiency
anemia is the most
22 severe form of iron
deficiency and among women
Page 335
1 20 to 49 years
it's prevalence was about 50
2 percent in
both surveys and was least among
3 white women,
slightly less than 3 percent, and
4 greatest among
black women and slightly lower
5 than that
among Mexican American women.
6 In each of
these surveys iron
7 status was
determined using four different
8 indicators,
serum ferritin, transferrin
9 saturation,
erythrocyte protoporphyrin, and
10 hemoglobin. Each
indicator reflects a
11 different stage in
iron storage, transport,
12 and incorporation
to the red blood cell.
13 Serum ferritin is
a measure of
14 iron stores with
higher values reflecting
15 greater iron stores
although this can also be
16 confounded by
inflammation as serum ferritin
17 is also an acute
phase response protein.
18 Nevertheless,
values less than 12 are
19 considered to
reflect depleted iron stores.
20 Transferrin
saturation is a
21 measure of the
proportion of the iron
22 transport protein
transferrin which is bound
Page 336
1 to iron with
values less than 15 percent
2 reflecting
iron deficient erythropoiesis.
3 Erythrocyte
protoporphyrin is a
4 heme precursor
which increases in red blood
5 cells when
iron is not available for
6 incorporation
for hemoglobin synthesis with
7 values greater
than 70-80 micrograms per
8 deciliter also
reflecting iron deficient
9 erythropoiesis.
10 Finally,
hemoglobin reflects
11 anemia and CDC
cutoffs for anemia, as shown
12 here, for women 16
years and older, less than
13 12 grams per
deciliter, and for men 16 to 17
14 years less than
13.3 grams per deciliter, and
15 18-year and older
men less than 13.5 grams per
16 deciliter.
17 Iron deficiency in
these studies
18 was defined using a
multiple indicator model.
19 An individual was
designated as being iron
20 deficient if he or
she had an abnormal value
21 for two of the
three of the first three
22 indicators. Iron
deficiency anemia was
Page 337
1 diagnosed if
the individual had iron
2 deficiency and
low hemoglobin.
3 A multiple
indicator model is
4 necessary
because no single indicator can
5 really reflect
iron status, the entire range
6 of iron
deficiency. Rather, indicators
7 together
reflect the range of iron deficiency
8 ranging from
normal all the way to iron
9 deficiency
anemia.
10 In this very
simplistic drawing,
11 which is not to
scale, I simply have iron
12 stores on the left
axis ranging from present
13 to absent. Any red
above the black line
14 reflects iron in
storage and any red below the
15 line reflects
circulating iron which is why
16 it's not really to
scale so there is much more
17 circulating
iron.
18 In the far left
column you can see
19 the normal iron
status. Iron stores are
20 present and the
indicators are each within
21 normal range. Iron
depletion is the first
22 stage of iron
deficiency. As you can see,
Page 338
1 iron stores as
measured by serum ferritin have
2 dropped below
12 but all of the other
3 indicators
remain within normal range.
4 In iron
deficient erythropoiesis
5 iron
availability to marrow is restricted. In
6 addition to serum ferritin being below 12
7 other indicators of iron deficient
8 erythropoiesis including transferrin
9 saturation and protoporphyrin also reach
10 abnormal levels but hemoglobin production is
11 maintained above normal -- not above normal,
12 within normal ranges.
13 Finally, in iron
deficiency anemia
14 iron availability
to the marrow is so
15 restricted that
hemoglobin production is also
16 compromised and
abnormal values for each of
17 these indicators
are observed. You can see
18 that if you measure
simply hemoglobin that is
19 really only
capturing the most severe form of
20 iron
deficiency.
21 Now I present
distributions for
22 each of these
indicators as assessed by
Page 339
1 NHANES. This
is the distribution for serum
2 ferritin in
NHANES 2002 along with the 5th,
3 50th, and 95th
percentiles for females and
4 males.
5 The first
thing you'll notice is
6 that values
are much higher among males than
7 they are for
females with the 5th percentage
8 among females
of every age, except for 60
9 years and
older, well below the 12 microgram
10 per liter
threshold.
11 In fact, among
women 20 to 39
12 years the 5th
percentile was actually below
13 the limit of
detection for the assay. So low
14 that the assay
couldn't even measure it.
15 Median serum
ferritin, or the 50th percentile,
16 increased somewhat
with age from about 26 to
17 86 micrograms per
liter.
18 Among males you
will first notice
19 that the values
among adolescent males are
20 lower. This is as
they are undergoing growth
21 spurts and peak
muscle mass is being obtained
22 and increasing
blood volume. Once this has
Page 340
1 been obtained,
you can see that median serum
2 ferritin
remains relatively in a narrow range
3 of 134 to
150.
4 These are the
distributions for
5 transferrin
saturation. You'll notice the
6 percentiles
are slightly different here. This
7 is the 10th,
50th, and 90th percentiles.
8 These were all
published in this national
9 report on
biochemical indicators.
10 At the time when
they published
11 this they only had
two years of data for some
12 of these indicators
so in order to get more
13 robust estimates
they narrowed in on the
14 distribution and
that is why this is slightly
15 different than the
ferritin one.
16 Nevertheless,
you'll see again
17 that female values
are much lower than male
18 values, and the
50th percentile for women
19 ranges from 19.8 to
22.3 increasing somewhat
20 with age. Among
males, again, it's higher
21 ranging from 25 to
27 and it's higher -- I
22 should say lower
among adolescent males than
Page 341
1 males 60 years
and older.
2 This is
protoporphyrin and, again,
3 values
increased with iron deficient
4 erythropoiesis
so values among women are much
5 greater than
those among men. You'll see,
6 again, the
90th percentile here is, for every
7 single age
group, is above the 70 to 80
8 microgram per
deciliter cutoff that is
9 adopted.
10 The median values
are a relatively
11 tight range from 49
to 52 increasing somewhat
12 with age again.
Among males, again, the
13 values are lower
and the median values range
14 from about 39 to
45. Again, you can see a
15 slightly higher
value among males 60 years and
16 older.
17 Then these are
hemoglobin. I did
18 these numbers, and
I'm using four years of
19 data so, again, we
have the 5th, 50th, and
20 95th percentile.
Among females hemoglobin is
21 much lower and the
5th percentile for
22 hemoglobin values
the range is really
Page 342
1 relatively
tight along the age group from 11.4
2 to 11.8. The
CDC cutoff for anemia which was
3 set at the 5th
percentile of a preceding NHANE
4 study is
12.
5 The 50th
percentile is about 13.5
6 to 13.8 grams
per deciliter. Among males the
7 distribution
is much greater and median values
8 range are
about 15 to 15.6 and, again,
9 slighter lower
values among adolescent males
10 and males 60 years
and older.
11 Then when this
analysis was
12 stratified by race,
you can see that the
13 values among women
are much lower among non-
14 Hispanic black
women, approximately 1 gram per
15 deciliter less than
white women and also lower
16 than Mexican
American women.
17 This is also the
case among men
18 with non-Hispanic
black men having lower
19 hemoglobin
distributions than either white or
20 Mexican American
men. The CDC does not
21 currently recommend
differing hemoglobin
22 cutoffs for anemia
because the reason for this
Page 343
1 difference is
not clear.
2 Each of these
indicators can be
3 measured by a
different laboratory method and
4 each method
does have some disadvantages which
5 is associated
with it. Ferritin can be
6 measured in
serum or plasma by immunoassay.
7 The main
disadvantage is that it is affected
8 by
inflammation which really necessitates the
9 concurrent measurement of an acute phrase
10 response protein such as CRP which increases
11 cost.
12 Transferrin
saturation is also
13 measured in serum
or plasma and is just the
14 ratio of serum iron
to total iron-binding
15 capacity. This
advantage is associated with
16 this indicator are
really the same as serum
17 iron which is added
diurnally and after meals.
18 It's easily
contaminated and it's suppressed
19 by chronic
disease.
20 Protoporphyrin is
measured in
21 whole blood by
fluorescence spectrophotometry
22 or by
hematofluorometer. It, too, is affected
Page 344
1 by
inflammation, though, and also by increases
2 during exposure to lead.
3 Hemoglobin measured in whole blood
4 using color imagery or also HemoCue. A
5 disadvantage of hemoglobin is that anemia also
6 occurs without iron deficiency. As you also
7 saw, hemoglobin only measures the most severe
8 form if iron deficiency as well.
9 In 1998 the CDC published
10 recommendations for
the prevention and control
11 of iron deficiency
in the United States. In
12 those
recommendations the CDC recommended that
13 there be no routine anemia screening for men
14 or post-menopausal women but primary
15 prevention of iron deficiency through diet for
16 adolescent girls and women of childbearing age
17 and secondary prevention through screening,
18 diagnosis and treatment of iron deficiency
19 anemia.
20 In terms of
screening, CDC
21 recommends that all
non-pregnant women be
22 screened for anemia
every five to 10 years.
Page 345
1 Women with
risk factors for iron deficiency
2 including
heavy menstrual blood loss, previous
3 diagnosis of
iron deficiency anemia or other
4 blood loss are
to be screened annually.
5 Once a
positive anemia screen is
6 obtained, this
test needs to be confirmed with
7 a repeat
hemoglobin test and then anemic
8 adolescent
girls or women should be treated
9 with a dose of
60 to 120 milligrams of iron
10 per day. Then the
screening should be repeated
11 in four
weeks.
12 A hemoglobin
increase of 1 gram
13 per deciliter or
more confirms a diagnosis of
14 iron deficiency
anemia and dietary counseling
15 and iron therapy
should continue with a
16 hemoglobin check
two to three months and then
17 again six months
later. If the hemoglobin
18 increase was less
than a gram per deciliter,
19 this would require
further evaluation of
20 anemia with
additional laboratory tests.
21 That's all I have.
Thank you very
22 much.
Page 346
1 DR. SIEGAL:
Thank you, Dr.
2 Cusick.
3 Are there any
questions for Dr.
4 Cusick?
5 DR. CRYER: So
what's the presumed
6 mechanism for
the racial distribution of
7 anemia? It
can't be diet in the United
8 States. Can
it?
9 DR. CUSICK:
You know, in studies
10 where they're
looked at it they controlled for
11 diet and the
difference was still there so
12 it's not diet. It's
really unclear. I've
13 done some reading
on it.
14 In one paper I
read it was that
15 there was really no
-- in NHANES, for
16 instance, it's
self-described race so we see
17 it -- I've labeled
it as white and non-
18 Hispanic black but
actually there could be --
19 you know, there are
more racial differences
20 than that and so
this difference might not
21 be --
22 It's more of a
range of hemoglobin
Page 347
1 than we are
really seeing which the paper I
2 was reading
was actually arguing against using
3 different
racial cutoffs but there are
4 certainly
those on the contrary. The
5 mechanism is
not known which is why we don't
6 say to lower
the hemoglobin value.
7 We just
recommend in the
8 recommendations that people interpreting these
9 be aware of the possibility of more false
10 positives among African-American patients
11 because you can get more positive screens for
12 anemia just based on the distribution and you
13 might want to follow up with a ferritin test.
14
DR. DI BISCEGLIE: It might be a
15 role for HFE, the
gene for hemochromatosis.
16 The gene frequency
for that is one in 15 among
17 caucasians and
virtually zero among African
18 Americans. As you
say, they are self-
19 described so that
is one possible explanation.
20 DR. CUSICK:
Okay.
21 DR. KULKARNI: Yes.
Coming from
22 the Division of
Blood Disorders, the CDC, I
Page 348
1 can tell you I
think one of the interests of
2 the division
is to look at women with
3 menorrhagia.
There was a recent study done by
4 the division
that showed that a number of
5 African-American women had platelet function
6 disorder as a cause for their blood loss
7 rather than Von Willebrand disease which is
8 usually seen in white females.
9 The other
reason why there might
10 be racial
differences and that's another thing
11 that we are looking
into is perhaps
12 hemoglobinopathies,
filtrates and things like
13 that which might
present with low hemoglobin.
14 DR. SIEGAL: All
right. If there
15 are no more
comments form the Committee, let's
16 proceed. Thank you
very much, Dr. Cusick.
17 Now we will hear
from Karin
18 Magnussen from
Copenhagen University Hospital
19 speaking on
European studies of iron
20 replacement for
blood donors.
21 DR. MAGNUSSEN: Hi.
Good
22 afternoon. I'm
honored to be here to talk to
Page 349
1 you on my
European studies on iron replacement
2 for blood
donors. The outline for the study
3 is European
legislation regard hemoglobin,
4 iron, and
donation intervals, donation
5 frequencies in
Europe, hemoglobin and ferritin
6 in Danish
blood donors including blood donors
7 donating more
than 100 times, the study on
8 iron
replacement in blood donors low in
9 hemoglobin,
and ending with conclusion and
10 recommendations.
11 As I'm sure it is
here the
12 legislation for
blood banks in Europe is
13 extensive but on
today's subject they only
14 mention the
hemoglobin concentration which
15 should be for men
more than 13.5 and for women
16 more than
12.5.
17 We have the
Council of Europe who
18 every here issues
guidelines for blood banks
19 which everybody
follows. They concur with the
20 hemoglobin and adds
that the donation interval
21 should be at least
two months with a maximum
22 donation for women
of four times a year.
Page 350
1 Also, we
should pay attention to
2 possible iron
deficiency. To answer your
3 question on
donation frequencies in Europe, e-
4 mails were
sent throughout Europe and 15
5 countries
replied.
6 There is
quite a difference in
7 donation
frequency ranging from Italy where
8 the men are
allowed to donate three times a
9 year and the
women two times a year, to
10 Germany and Austria
where men are allowed to
11 donate six times a
year and women four times
12 a year. Only four
countries measure ferritin,
13 Norway, Sweden,
France, and Denmark. In the
14 French speaking
part of Belgium they measure
15 MCV.
16 Now to hemoglobin
and ferritin
17 results from
studies done on Danish blood
18 donors, random
blood donors as opposed to low
19 hemoglobin donors.
In a study in 2005 in 118
20 men the geometric
mean of ferritin was 54
21 ranging from --
oops, sorry -- ranging from
22 five to
353.
Page 351
1 The men with
the high ferritin
2 level donated
between one and seven times.
3 Fifteen
percent had low iron stores, that is,
4 below 30. In
three percent the hemoglobin
5 concentration
was below 13.5. Their ferritin
6 was five, 22,
and 67. The two with the low
7 ferritin are
still actively donating. The one
8 with a
ferritin of 67 was deferred in 2006 due
9 to
medication.
10 In 108 women the
ferritin was 28
11 ranging from four
to 160. More than half had
12 low iron stores and
six percent had a
13 hemoglobin
concentration below 12.5. In six
14 the ferritin was
very low and in one it was
15 38. Six of the
women are still actively
16 donating and one
has been deferred due to
17 small
veins.
18 Recently we
measured ferritin and
19 hemoglobin on 58
men. The ferritin was 50
20 ranging from six to
345. These donors with a
21 high ferritin level
donated between zero and
22 two times.
Twenty-four percent had low iron
Page 352
1 stores and
none had a hemoglobin concentration
2 below
13.5.
3 In 51 women
the ferritin was 24
4 ranging from
four to 143. Again, more than
5 half had low
iron stores. Four percent had
6 hemoglobin
concentration below 12.5 and they
7 had very low
ferritin, four and nine
8 respectively.
9 Now to the
donors donating more
10 than 100 times over
a couple of weeks we found
11 26 and they donated
between 102 and 159 times.
12 Their geometric
mean ferritin was 43 ranging
13 from 14 to 158.
Thirty percent had low iron
14 stores and none had
a hemoglobin concentration
15 below 13.5. Three
of the donors were women.
16 Their ferritin was
6, 32, and 37 respectively
17 and they all had
hemoglobin concentration of
18 at least
12.5.
19 Now to the study
on low hemoglobin
20 donors and iron
replacement. It was a study
21 done in Copenhagen
from July 2005 to July 2006
22 and has been
published. The ferritin
Page 353
1 concentration
of 30 equals 215 milligrams of
2 iron which
approximately corresponds to one
3 donation.
Therefore, we believe that ferritin
4 concentration
for blood donors of 60 would be
5 desirable for
blood donors.
6 The iron
supplementation that we
7 can offer in
our blood banks is the Danish
8 product called
Iron C which is ferrihumorate
9 with vitamin C
that contains 100 milligrams of
10 elemental iron. In
case of abdominal
11 discomfort we can
offer ferritin which
12 contains less iron
but the absorption is
13 presumed to be
superior.
14 In agreement with
European
15 legislation a
health questionnaire is always
16 filled in and
reviewed before donation. The
17 hemoglobin from the
last donation was looked
18 at and if they are
okay a venous sample is
19 secured from a
pre-sample bag, a diversion
20 pouch actually, and
the hemoglobin is analyzed
21 after
donation.
22 If there is a
history of low
Page 354
1 hemoglobin the
hemoglobin is measured and a
2 venous sample
before donation. If there is
3 any suspicion
of disease, the donor is not
4 bled and if
the suspicion arises after
5 donation, the
unit is discarded.
6 Our aim was
to standardize and
7 optimize the
iron supplementation based on the
8 ferritin
level. We wanted the procedures to
9 be safe and
simple to follow for all blood
10 donors and all
staff at any blood bank or
11 collection site. We
also wanted the results
12 of the study to
reflect the everyday situation
13 in the blood
bank.
14 Inclusion criteria
were based on
15 the hemoglobin
concentration measured in the
16 blood bank where we
used the HemoCue. A
17 hemoglobin
concentration for the men of 13.5
18 or less and for the
women 12.5 or less they
19 would be included
in the study as would donors
20 who had a drop
since the last donation of more
21 than 2 grams per
deciliter. Also in the
22 study, as it
happens, a few donors with a
Page 355
1 history of low
hemoglobin concentration.
2 So the plan
was and what we did
3 was blood
donors low in hemoglobin would be
4 given 50 iron
tablets to be taken one daily.
5 They would
also receive simple oral and
6 written advice
and samples would be secured
7 also from a
diversion pouch for measuring of
8 ferritin
controlled hemoglobin and MCV.
9 It takes one
hour to analyze
10 ferritin but we
usually saw the results the
11 following day. For
the donors which were most
12 of the donors who
were below 60, I should also
13 say that the
ferritin results would be written
14 in the donor file.
Those with a ferritin
15 below 60 would
receive 20 tablets with all
16 future
donations.
17 The donors who had
a ferritin
18 concentration above
60 would receive further
19 investigation and
would be referred to the TP.
20 879 donors were
included, 80 percent were
21 women and 20
percent were men. The hemoglobin
22 concentration in
the men was 13.2 ranging from
Page 356
1 11.1 to 14.5
and the women 12.2 ranging from
2 9.2 to
13.9.
3 The MCV was
88 in the men ranging
4 from 72 to 104
and 87 in the women ranging
5 from 70 to
104. The ferritin concentration
6 was 29 in the
men ranging from three to 522.
7 The guy with
522 turned out to have cirrhosis
8 of the liver
so he, of course, was deferred.
9 The ferritin
for the women the geometric mean
10 was 14.2 ranging
from two to 187.
11 Regular blood are
faithful and
12 don't complain much
but most, if not all, were
13 frustrated with
their low hemoglobin. Many
14 when asked would
admit to fatigue but they
15 frequently
attributed it to workload or
16 personal problems.
A few had restless legs,
17 the symptoms of
which disappeared after iron
18 supplementation.
19 Many others have
found that their
20 ferritin is low in
donors donating more than
21 five to 10 times.
The same is true in these
22 donors low in
hemoglobin concentration. What
Page 357
1 is also seen
is that the higher the donation
2 frequency the
lower the ferritin. During a
3 study period
421 blood donors returned once
4 and they had
been given 50 iron tablets
5 together with
simple oral and written advice
6 on
iron.
7 Here is the
result on the
8 hemoglobin
concentration where 97 men
9 increased from
13.2 to 13.9. Most of the
10 donors were above
the limit of 13.5. In the
11 324 women they
increased from 12.2 to 13 and
12 the increase was
highly significant.
13 The increase in
ferritin is also
14 significant though
less impressive. The men
15 increased from 25
to 29 and the women from
16 13.4 to 20. This
leads me to believe that the
17 iron
supplementation was used for
18 erythropoiesis.
19 Fifty-five donors
returned to the
20 blood bank twice
during the study period and
21 the 19 men
increased from 13.3 to 14 where it
22 stayed. The 36
women increased from 12.2 to
Page 358
1 13.1 and here
it's 12.9.
2 There is no
different
3 statistically
between the two last donations
4 but I know
that some of these men had not
5 taken their
iron supplementation because that
6 is not what
men used to do at our blood bank
7 before. With
further counseling they took it.
8 For the women
they took the iron
9 supplementation when the hemoglobin was low
10 but now when the hemoglobin was normal they
11 thought it wouldn't be necessary and some of
12 the women are here.
13 The P values here
represents the
14 difference between
the first and the third
15 donation. There is
an increase but it is in
16 no way impressive
with the iron
17 supplementations
that we gave. The men ended
18 up with a ferritin
of 33 and the women only
19 20.
20 In the summer of
2007 we did a
21 follow-up on the
879 blood donors included in
22 the study. By then
704 of the donors were
Page 359
1 still active
as donors. That is, 85 percent
2 of the men and
79 percent of the women. 115
3 donors had not
reappeared in the blood bank
4 and 36 had
stopped due to low hemoglobin.
5 Fifteen had
been deferred
6 permanently
due to decease, four had canceled,
7 four had
cardiac disease, one suffered a
8 stroke. This
is the guy with cirrhosis of the
9 liver. One had
severe back problems and in
10 five cases we
didn't know the disease. Nine
11 donors were
deferred due to unrelated reasons,
12 for instance, age.
Our age limit is 65.
13 We tried to find
out what made the
14 115 no-shows stay
away from the blood bank.
15 The response rate
was 55 and the main reason
16 was the low
hemoglobin which was the reason
17 for 24 percent of
the blood donors. Actually,
18 21 percent of the
donors had moved.
19 Some of them now
donated at
20 different blood
banks. Eleven percent of the
21 donors had
miscellaneous diseases like thyroid
22 diseases. One had
whiplash, one had chronic
Page 360
1 abdominal
problems, all different kinds of
2 diseases.
Eleven percent could give no
3 reasons and
they actually booked an
4 appointment
with the blood bank when they
5 called
them.
6 Ten percent
were pregnant or had
7 been pregnant
recently. Eight percent were
8 busy. Six
percent had donated within the last
9 few weeks and
nine percent gave other
10 miscellaneous
reasons. One, for instance,
11 parking problems.
Of the 63 donors that we
12 reached 14 percent
donated again, 11 with no
13 reasons and some of
those that were busy or
14 pregnant.
15 Some conclusions
from the low
16 hemoglobin study.
Iron supplementation
17 according to our
protocol increases the
18 hemoglobin
concentration while the increase in
19 storage iron is
only modest. In our opinion
20 it is important
only to offer iron
21 supplementation on
the basis of known iron
22 status to avoid
giving iron to donors with
Page 361
1 unrecognized
hemochromatosis and to those
2 inherently low
in hemoglobin. Not least, to
3 delineate
donors in need for further clinical
4 examination.
5 What we
experienced is increased
6 satisfaction
among the donors and the staff
7 with this
protocol and we have retained most
8 of the donors.
Also, a unit of blood from an
9 iron replete
donor contains more hemoglobin.
10 What is also clear
is that to have adherence
11 to the protocol
regular vacation of the staff
12 is
necessary.
13 Our recommendation
based on the
14 study is to measure
ferritin in female first-
15 time blood donors,
in male donors after the
16 fifth donation, and
to all donors with low
17 hemoglobin
concentration.
18 The iron
supplementation we
19 suggest is 50 iron
tablets when the hemoglobin
20 is found to be low.
If the ferritin is below
21 20, at least 50
tablets with the next
22 donation. To donors
with a ferritin below 60
Page 362
1 they should
have something on the line of 20
2 tablets with
every donation.
3 Thank you for
your attention. For
4 those who
don't recognize it, Denmark and
5 Copenhagen is
here.
6 DR. SIEGAL:
Thank you, Dr.
7 Magnussen.
8 Are there
questions for this
9 speaker? All
right. Thank you. That was
10 very nice. We will
proceed.
11 The next speaker
will be Barbara
12 Bryant, M.D., from
the University of Texas,
13 Medical Branch in
Galveston which we hope is
14 still there.
Management of iron status in
15 blood
donors.
16 DR. BRYANT: Well,
thank you very
17 much. I'm Barbara
Bryant. I am from
18 Galveston, Texas
and last I heard we are in
19 the path of the
hurricane, or hopefully not.
20 Maybe it will
turn.
21 Thank you for
inviting me to talk
22 today on the
management of iron status in
Page 363
1 blood donors.
As we heard earlier today, we
2 all know that
iron deficiency in first time
3 and repeat
blood donors is a challenge in
4 transfusion
medicine. Iron is an essential
5 element lost
with each blood donation. Men
6 lose about 242
milligrams of iron and women
7 about 217 with
each whole blood donation.
8 The normal
iron stores in men is
9 1,000
milligrams and in women is about 350
10 milligrams. In
order for a donor to
11 compensate for the
iron lost during donating
12 blood, iron is
mobilized from the body's iron
13 stores and the
absorption is regulated in the
14 GI system. This
balance can be difficult to
15 maintain in
premenopausal females and regular
16 blood donors since
there is an ongoing blood
17 loss.
18 At the NIH we
wanted to take a
19 look at this and do
a study on the role of
20 oral iron
replacement and the routine
21 management of blood
donors. We knew at the
22 NIH eight to 12
percent of all whole blood
Page 364
1 donor visits
to the DTM ended in deferral for
2 low
fingerstick hemoglobin level. We
3 instituted a
three-year study at the NIH.
4 This is an
NHLBI IRB-approved procotol called
5 Iron
Replacement or Not, IRON.
6 We planned to
enroll a thousand
7 low hemoglobin
donors and up to 500 control
8 donors so
there were two arms in the study.
9 To be enrolled
as a low hemoglobin donor you
10 would have to
present on the day of donation
11 with a hemoglobin
less than 12.5 and be
12 deferred for
donation.
13 The control donors
had hemoglobins
14 greater than 12.5
and were not taking oral
15 iron at that time.
The hemoglobin
16 concentration was
determined by fingerstick
17 HemoCue device.
Now, these donors when they
18 were enrolled in
the protocol signed informed
19 consent.
20 They also had
laboratory testing
21 done. Before we did
any of that there was an
22 additional health
screening questionnaire. We
Page 365
1 wanted to
assess if there was a risk of an
2 underlying
process in which iron deficiency or
3 anemia would
be a hallmark.
4 We also asked
a lot of questions
5 about their
diet, family history of anemia.
6 personal
history of anemia, previously had
7 they been put
on iron, family history of GI
8 cancers in
particular. We were trying to see
9 if there was
something that could possibly be
10 underlying.
11 The laboratory
tests that were run
12 were CBC and iron
studies of ferritin, percent
13 transparent
saturation, serum iron and
14 transferrin. In
some situations depending on
15 the type of history
we were able to ascertain,
16 we may have done a
hemoglobin electrophoresis.
17 I need to note that
to participate in the
18 study they had to
be 18 years of age or older.
19 The goals of our
study were to
20 analyze the cause
of low finger-stick
21 hemoglobin in blood
donors, quanitate the
22 prevalence of iron
deficiency, study the long-
Page 366
1 term effect of
blood donation on the donor's
2 hemoglobin
level and iron stores, evaluate the
3 safety,
practicality, and efficacy of
4 distributing
oral iron replacement to blood
5 donors and
determine the effect of the iron
6 replacement
therapy on the donor pool.
7 Let me first
start by saying we
8 chose ferritin
as the determinant for iron
9 stores. There
are a lot of different tests
10 you can use but
ferritin is easy, it's cheap,
11 and I can get my
results back in 24 hours. We
12 defined iron
deficiency, iron depleted, and
13 iron replete for
both men and women.
14 The normal range
at the NIH for
15 ferritin in a woman
is nine to 120 micrograms
16 per liter. If a
woman had a ferritin level
17 less than nine, she
was iron deficient. If
18 her ferritin level
was between nine and 19, we
19 called her iron
depleted.
20 This was an
arbitrary number that
21 we picked. We read
the literature. Some
22 people said less
than 20 iron deplete and some
Page 367
1 said less than
30. We decided to go with the
2 less than 30.
We considered a woman iron
3 replete if her
ferritin level was 20 or
4 higher.
5 For men the
normal range for
6 ferritin is 18
to 370 so if the ferritin is
7 less than 18
they were iron deficient,
8 depleted if it
was between 18 and 29, and we
9 considered
them replete if it was greater than
10 30 -- 30 or
greater.
11 In a 30-month
period from January
12 2006 to July 2008
we enrolled 891 low
13 fingerstick
hemoglobin donors and 406 control
14 donors. The low
fingerstick hemoglobin donors
15 presented with low
hemoglobin that day of
16 donation by
fingerstick HemoCue. 86 percent
17 were females and
they had a mean finger stick
18 hemoglobin of 11.8.
Fourteen percent were
19 male with a
hemoglobin level of 11.9.
20 The control donors
36 percent were
21 female. These
donors, remember, have
22 hemoglobins greater
than or equal to 12.5 the
Page 368
1 day of
donation and they are not taking iron.
2 36 percent
females, 13.7 was the average
3 hemoglobin. In
males 64 percent with an
4 average
hemoglobin of 14.9.
5 Here are
donor demographics. This
6 is the low
hemoglobin arm and here is our
7 control arm.
As you can see, the low
8 hemoglobin arm
has more women, as we just
9 mentioned.
10 Also, the age
range for the women
11 in the low
hemoglobin group is about 40. The
12 control group was
46, a little bit older. The
13 men age 53 was the
average age in the low
14 hemoglobin group
and 49 in the control group.
15 There were more
caucasians in the control
16 group than in the
low hemoglobin group.
17 Nineteen percent
of the African-
18 Americans were in
the low hemoglobin group.
19 First-time donors
we had 31 percent first-time
20 donors in the low
hemoglobin group and only 12
21 percent of the
control group. I have to note
22 here these are
first-time donors to the NIH
Page 369
1 blood
center.
2 Now, the
number of prior whole
3 blood
donations in females was almost 11. It
4 ranged from
one to 95 in the low hemoglobin
5 group but it
was 30 in the men. It ranged
6 from one to
172 donations. The control group
7 was about 16
for women and about 26 for men.
8 What we did
was we took a look at
9 the
association of fingerstick hemoglobin
10 levels with the
iron status and the venous
11 hemoglobin. This is
in women. There were 912
12 women. This group
right here, greater than or
13 equal to 12.5, is
the control arm. We looked
14 at their iron
status, iron deficient,
15 depleted, or
replete. As you can see, even in
16 the normal
hemoglobin range 10 percent of the
17 women were iron
deficient. Another 30 percent
18 were iron depleted.
In the hemoglobin range
19 of 12 to 12.4 14
percent were iron deficient,
20 35 percent iron
depleted. In the 11.5 to 11.9
21 range of hemoglobin
23 percent were iron
22 deficient, 29
percent iron depleted. In the
Page 370
1 less than 11.5
40 percent iron deficient, 27
2 percent iron
depleted. Of interest if you
3 follow this
along you go 10 percent, 14 and
4 then you make
a jump to 23. If you were
5 looking at
where would be a nice cutoff to
6 base your
acceptable hemoglobin level for a
7 woman just
based on iron deficiency. Really
8 12.0 would be
a very nice spot right here
9 because you
jump from 14 percent iron
10 deficient to 23
percent.
11 Also, if you'll
note, even in the
12 category with less
than 11.5 grams of
13 hemoglobin 33
percent of these donors were
14 iron replete. They
are just set lower on the
15 hemoglobin
scale.
16 We compared this
fingerstick
17 hemoglobin to what
we really saw with the CBC
18 hemoglobin. There
are inherent problems with
19 fingerstick
hemoglobin screening and there is
20 also a positional
effect that takes place
21 since the donor
sits in the donor booth versus
22 gets up and moves
to a donor chair for us to
Page 371
1 draw the
CBC.
2 In the donors
that had hemoglobin
3 levels greater
than or equal to 12.5 by
4 fingerstick,
81 percent of those did have a
5 venous
hemoglobin that was greater than or
6 equal to
12.5.
7 Interestingly
in this range of 12
8 to 12.4 over
half of the donors had a CBC
9 hemoglobin
that was greater than or equal to
10 12.5. Then even in
the lower range it was 37
11 percent and 17
percent.
12 Now, for the men
there were 385
13 men in the study.
This group here, these last
14 three columns, are
my control donors but we
15 broke this out a
little bit more to get better
16 delineation. For
males with hemoglobin
17 greater than or
equal to 13.5 19 percent were
18 iron deficient,
outright iron deficient. The
19 13 to 13.4, 25
percent. This is the lower n.
20 This is an n of
20.
21 Here between 12.5
and 12.9 56
22 percent were iron
deficient but there were
Page 372
1 only nine in
this category. A hemoglobin of
2 12 to 12.4,
again 46 percent were iron
3 deficient and
then as you got lower less than
4 12.0 63
percent were iron deficient.
5 Overall in
the control arm of the
6 study 40
percent of the men and 41 percent of
7 the women had
either iron depletion or iron
8 deficiency but
normal hemoglobin to be able to
9 donate. Again,
with the venous hemoglobin it
10 matched up very
nicely in the higher ranges.
11 As you got lower
you still had in the range of
12 12 to 12.4 by
fingerstick. Sixty-eight
13 percent of these
donors really had venous
14 hemoglobin of 12.5
or better.
15 I put this slide
in here to talk a
16 little bit about
pica. We did screen our
17 donors for pica. As
mentioned earlier,
18 pagophagia is the
most common pica seen in
19 people who are iron
deficient.
20 They tell
elaborate stories about
21 bringing -- I mean,
they will come to the
22 donor booth holding
a big cup of ice and they
Page 373
1 talk about
going to bed with ice and eating
2 tons of ice
during the day. They could
3 identify the
best ice machine at the NIH. The
4 interesting
thing was several of them told me
5 the same
machine. This was very common.
6 We had donors that reported eating
7 frozen lettuce. This is cold. A donor is
8 eating Argo starch. We had a few donors that
9 ate dirt, raw pasta. We had a school teacher
10 who actually consumed large amounts of chalk.
11
It was interesting when we put
12 these donors on
iron replacement the pica
13 resolved very
quickly. Within five to eight
14 days they had a
decreased interest in what it
15 was they were
craving. This was completely
16 gone in 10 to 14
days.
17 Now, Restless Leg
Syndrome was
18 something else that
we also screened for.
19 This is called
secondary Restless Leg
20 Syndrome. It is
well recognized and actually
21 neurologists ask
questions about blood
22 donation to a lot
of their patients presenting
Page 374
1 with Restless
Leg Syndrome.
2 A neurologist
views a patient as
3 iron depleted
if their ferritin is less than
4 50. The
thought is that iron deficiency and
5 depletion can
cause or exacerbate symptoms of
6 Restless Leg
Syndrome. There have been some
7 studies that
indicate decreased CNS iron,
8 especially the
substantia nigra may be
9 responsible.
10 There were some
post-mortem exams
11 done and they were
compared to controls.
12 There were
documented changes at the cellular
13 level that you
would expect to see for iron
14 deficiency except
the transferrin receptor was
15 not increased. It
was decreased.
16 The low peripheral
iron stores may
17 interact with
compromised brain iron
18 management to
produce or exacerbate the
19 observed reduced
brain iron in Restless Leg
20 Syndrome.
21 Putting a donor
with Restless Leg
22 Syndrome on iron
replacement we saw
Page 375
1 improvement in
most of the donors within four
2 to six weeks.
It didn't always go away. In
3 some donors it
did but we at least saw an
4 improvement.
5 Now, here are
the studies
6 comparing the
fingerstick hemoglobin levels
7 with pica and
Restless Leg Syndrome in women.
8 Again, I have
broken it down by hemoglobin
9 levels. In the
lower category with the
10 hemoglobin less
than 11.5 in women, it's
11 statistically
significant.
12 Fourteen percent
presented with
13 pica and 16 percent
presented with Restless
14 Leg Syndrome.
Overall with the hemoglobin
15 less than 12.5 for
pica it approached
16 statistical
significance.
17 Now, for men in
the iron -- I'm
18 sorry, still women.
In the iron deficient
19 category versus
iron depleted it was
20 significant for
pica and for Restless Leg
21 Syndrome in the
iron deficient category.
22 For men it was only
significant when the
Page 376
1 hemoglobin was
less than 12.0 for pica and we
2 did not see
any significance with Restless Leg
3 Syndrome.
4 Then overall
with men breaking it
5 down by
category, iron deficient, iron
6 depleted, and
iron replete we just had
7 statistical
significance here because we had
8 zero reported
for the iron depleted category.
9 The donors
when they were enrolled
10 in our protocol and
they had their lab work
11 done, I actually
called every donor with their
12 lab results and I
was able to talk to them
13 about the iron they
were given. These donors
14 were given iron at
the time they came in. I
15 was able to follow
up and ask how it was going
16 taking the
iron.
17 I was able to
encourage
18 compliance. The
iron that the donors were
19 given were either
ferrous sulfate or ferrous
20 gluconate, 325
milligrams. They were
21 instructed to take
the tablets, one tablet
22 half an hour before
bedtime with a half a
Page 377
1 glass of
water. The donors were given the
2 iron in child
resistant blister packs.
3 Most of the
donors indicated they
4 were adult
resistant. They had a hard time
5 getting into
them. This way we felt this was
6 safe issuing
the iron to them and they all
7 were told to
keep it out of the reach of
8 children.
9 The
compliance rate was 71
10 percent. Initially
82 percent of the donors
11 were given ferrous
sulfate. The other 18
12 percent reported
intolerance to ferrous
13 sulfate. These were
mostly women who had been
14 given iron during
pregnancy and they were put
15 on ferrous
gluconate to start with.
16 Of the 82 percent
that were given
17 ferrous sulfate 18
developed intolerance and
18 were switched to
ferrous gluconate. Now,
19 ferrous sulfate 325
milligrams has 65
20 milligrams of
elemental iron, whereas ferrous
21 gluconate has 38
milligrams of elemental iron
22 so you are dealing
with a little bit
Page 378
1 difference in
dosage and, of course, it's
2 digested
differently.
3 When I
switched them to ferrous
4 gluconate I
only had a 2.8 percent intolerance
5 rate to
ferrous gluconate. Now, within the
6 study since I
had the lab results I was able
7 to look and
see if someone had a ferritin
8 level or
transparent saturation suggestive of
9 hemochromatosis and we found no one.
10
There were no malignancies
11 reported or
detected during the study.
12 However, because we
were closely monitoring
13 these lab results
and asking these additional
14 questions on the
questionnaire, we were
15 actually able to
pick up situations that
16 warranted a donor
being referred to a
17 physician
immediately.
18 We picked up three
cases of GI
19 bleeding generally
in answer to the question,
20 "Have you ever had
blood in your stool or
21 black tarry
stools." Donors would say yes,
22 but they had not
told their primary care
Page 379
1 physician. We
also were able to see a donor's
2 response to
oral iron.
3 If they
didn't respond when they
4 came back 60
days later, we then were able to
5 refer them to
a physician to look for
6 something else
that could possibly be going
7 on. No
malignancies were reported or detected
8 and all donors
who had iron deficiency anemia
9 were given a
letter and a copy of their lab
10 results to take to
their primary care
11 physician.
12 Here are the
studies. This shows
13 the effect of oral
iron therapy in the low
14 fingerstick
hemoglobin donors. Here we are.
15 These are the
visits to the donor center and
16 these visits were
approximately three months
17 and a week apart.
These are the donors coming
18 in to donate each
time.
19 On the initial
visit, as you can
20 see, we have
fingerstick hemoglobin is the
21 pink line, venous
hemoglobin blue, RDW orange,
22 and MCV and the
ferritin is gold. Let's
Page 380
1 follow the
fingerstick hemoglobin. 11.8, 11.9
2 was what we
saw. We put the donors on iron
3 and on their
next visit they had gone up more
4 than a
gram.
5 They
continued to get iron with
6 each blood
donation and they continued to
7 donate blood
but their hemoglobin remained
8 steady. The
venous hemoglobin followed along
9 the same line.
The RDW, interestingly enough,
10 first bumps up as
you would expect when you
11 put someone on
iron, and then it comes back
12 down and
normalizes.
13 The MCV in these
donors, although
14 they weren't always
particularly low, they
15 were usually in the
mid to low '80s, went up
16 and then went more
into the normal range. The
17 ferritin level,
which started out low,
18 continued to
increase despite blood donation
19 and then tended to
level out.
20 Now, built into
this study just by
21 design was what I
call the safety arm of the
22 study. Since we
were giving iron replacement
Page 381
1 therapy to
these donors based on a fingerstick
2 value, we knew
that we would have some donors
3 that were not
iron deficient or iron depleted
4 that we had
just given iron to.
5 We wanted to
see what would happen
6 with these
donors so this is the effect of
7 iron therapy
in the low fingerstick hemoglobin
8 donors that
did not have iron depletion or
9 deficiency.
Here we are and I have this
10 broken out by
apheresis male, apheresis
11 female, whole blood
male, and whole blood
12 female. As you can
see, they all started
13 about in the same
area around 12.
14 We put them on
iron and even
15 though they were
not depleted or deficient
16 their hemoglobin
went up at least a gram and
17 then stabilized on
out. Their ferritin level.
18 I was concerned
that if they didn't need iron
19 and I gave them
iron, what would I do to their
20 ferritin
level.
21 Here we are the
same group of
22 donors starting at
various levels of ferritin.
Page 382
1 You might see
a little bit of a jump up but
2 then it pretty
much stabilized out and
3 remained the
same. In no particular donor did
4 we give iron
and the ferritin continued to go
5 up.
6 Now, the
control group in itself
7 is very
interesting. Remember these are
8 donors that
have never been deferred for low
9 hemoglobins.
They have a 12.5 or greater
10 hemoglobin. They
are not taking iron so what
11 happens to this
group of donors as you follow
12 them?
13 Well, here is what
happens. When
14 they come in here
is their ferritin level,
15 close to 60. With
each donation it keeps
16 dropping and
dropping and dropping and
17 dropping. Graph B
shows what happens when the
18 donors were started
on iron after their first
19 visit. In other
words, they came in the first
20 time.
21 I saw them as a
control donor, got
22 the labs, and then
had to make that phone call
Page 383
1 where I call
and tell them, "You have a normal
2 hemoglobin but
you are iron deficient," so we
3 sent them out
iron. Sure enough their
4 ferritin level
goes up and then kind of
5 stabilizes.
6 This is the
group that were okay
7 after the
first donation but we got them on
8 the second
donation. They were iron deficient
9 and we put
them on iron. We see the type of
10 graph. This is on
the third donation and then
11 on the fourth
donation. This shows that
12 control donors if
not given iron but they
13 continue to donate
will have a decrease in
14 ferritin level that
just goes straight down.
15 So the
considerations for the FDA
16 and BPAC today, for
female donors to possibly
17 consider lowering
the fingerstick hemoglobin
18 threshold to 12
grams per deciliter. For male
19 donors increasing
the threshold to 13 grams
20 per deciliter. This
is based on the fact that
21 the normal
hemoglobin range for men at our
22 institution has
been 12.7.
Page 384
1 That is low
range so a 12.5 is
2 actually below
the cutoff for a normal
3 hemoglobin. By
the time they are below 12.5
4 they are
actually anemic so to raise that a
5 little bit.
Our iron data shows although our
6 end was small
that there is a jump after 13 in
7 the amount of
iron deficiency.
8 For
conservative recommendation on
9 all donors
that we should administer a two-
10 month supply of
oral iron tablets to all
11 donors with a
fingerstick hemoglobin less than
12 threshold. Then
from an evidence-based
13 standpoint to
routinely administer a two-month
14 supply of oral iron
tablets sufficient to
15 replace the iron
lost in a unit of whole blood
16 to all whole blood
donors.
17 We found that this
actually works
18 for a donor. They
were more satisfied over
19 this. They liked to
come in and they liked to
20 follow their lab
results. They liked to get
21 their iron. They
feel better on the iron. We
22 actually see them
coming in more frequently.
Page 385
1 We tell them
they give us iron and we give
2 them iron back
so that's how that works.
3 I would like
to acknowledge Susan
4 Leitman, my
associate, and the rest of my
5 colleagues on
the Iron Protocol. Yu Ying Yau
6 is a database
coordinator, and then my two
7 nurses. Then,
of course, Dr. Klein and all of
8 our NIH blood
donors. Thank you.
9 DR. SIEGAL:
Okay. Thank you very
10 much. Will there be
questions for Dr. Bryant?
11 DR. FINNEGAN: Just
one question.
12 What was the
interval between your donations?
13 DR. BRYANT: On
average it was
14 three months and
one week.
15 DR. SIEGAL:
Anybody else? Ross.
16 DR. KUEHNERT: I
just had a
17 question about your
definition of iron
18 deficiency using
ferritin. Maybe I missed
19 this but I think
you said something about
20 having a variety of
iron measurements.
21 You showed them
how they changed
22 on iron but I
wondered at baseline whether you
Page 386
1 showed or
whether there's previous work to
2 show that just
measuring ferritin alone is
3 adequate for
diagnosing iron deficiency versus
4 the three
measurements that have been
5 discussed
earlier.
6 DR. BRYANT:
Sure. There's all
7 kinds of
debate how you define iron
8 deficiency.
Ferritin is very easy, simple
9 cheat. But the
problem with ferritin, as was
10 mentioned earlier,
it's an acute phase
11 reactant so it's
possible to get a high
12 ferritin on
somebody but they are still iron
13 deficient.
14 Because we did the
percent
15 saturation we were
able to see that. Just
16 look at the big
picture. If someone has a
17 ferritin of 150 but
they have a percent
18 saturation of 10,
normal range of percent sat.
19 is 15 to 62. Then
you realize that something
20 else was probably
going on.
21 I always talk to
these donors and
22 ask them, "Do you
have arthritis? Are you
Page 387
1 taking
anti-inflammatories? Do you have
2 something
going on?" That's true, but we also
3 look at the
MCV. I looked at blood smears.
4 DR. KUEHNERT:
So you're saying
5 you took more
into consideration than just
6 screening with
ferritin.
7 DR. BRYANT:
Right.
8 DR. KUEHNERT:
We interviewed
9 donors and
they are supposed to be healthy so
10 my question is how
many donors did you find
11 where you thought
their ferritin was an acute
12 phase reactant out
of this crowd?
13 DR. BRYANT: I
don't have the
14 exact numbers.
There was a good handful. A
15 lot of the baby
boomers, especially during
16 basketball season.
I did have some of the
17 older group that
had arthritis and that were
18 on medication for
arthritis but it wasn't a
19 huge
amount.
20 You know, with the
range being
21 nine to 120 for
women and 18 to 370 for men,
22 I started
questioning people when they were in
Page 388
1 the '80s what
was going on because that is a
2 little bit
high for ferritin. As you noticed,
3 even when I
put them on iron, keeping them at
4 50 was a
challenge even on iron constantly
5 with blood
donation so it did come up.
6 DR. SIEGAL:
Ms. Baker.
7 MS. BAKER:
Yes. Did you find any
8 differences in
the response to the iron
9 supplementation by race?
10 DR. BRYANT: I did
not find it by
11 race. I did have a
few donors that did not
12 respond to iron had
we had hoped. One in
13 particular
continued to have a small drop in
14 hemoglobin. He was
still in the normal
15 hemoglobin range.
He was one of my control
16 donors.
17 When he started he
had a
18 hemoglobin of 16
and I had to call and tell
19 him, "You're iron
deficient." I put on iron
20 but then he kept
doing one down and he didn't
21 respond. His
ferritin didn't come up. We
22 sent him to the
doctor and he gastritis so we
Page 389
1 watched that.
We didn't see anything by race.
2 I did notice,
however, as was
3 reported, that
the hemoglobin level in
4 African-Americans does run about .8 to 1 gram
5 lower. I did look for hemoglobinopathy
6 because I just love red cells. We talked to
7 a lot of donors about the fact, especially if
8 they had a family history if nobody in the
9 family can donate. I've tried all my life.
10
We ran a hemoglobin
11 electrophoresis
because we know in some
12 hemoglobinopathies
you have a shift in the
13 normal range,
hemoglobin C to some extent.
14 All the afathals.
We were able to pick up
15 several of those. I
picked up a hemoglobin G
16 filly. I have a
lapor Boston. I have five
17 beta filtrates that
actually donate blood and
18 do it quite
successfully because a beta
19 filtrate can have a
hemoglobin between 9.8 up
20 to 12.5 so I get
them every once in a while.
21 They come in and
they are 12.5, 12.6 and they
22 do donate. They are
great because they are
Page 390
1 special donors
because of their red cell
2 phenotypes. We
were able to identify and
3 provide
counseling in those situations.
4 DR. BRACEY:
Much has been made of
5 the RDW in
iron deficiencies and you had it
6 analyzed. Do
you think you can incorporate it
7 into your
diagnostic differential?
8 DR. BRYANT: I
looked at the whole
9 thing. I
looked at MCVs and RDWs. That was
10 part of it as well
in determining iron
11 deficiency. If
there was ever a question,
12 that was looked
at.
13 I got full CDCs on
everybody and
14 the RDW was
interesting to follow to see how
15 people responded.
Normally the RDW would be
16 in the 16 to 18
range. When I put them on
17 iron it would pop
up into the 20s and then it
18 would settle back
down over the next few
19 months back into
the normal range.
20 DR. SIEGAL:
Louis.
21 DR. KATZ: Why
didn't you use
22 carbonyl
iron?
Page 391
1 DR. BRYANT:
Well, I worked at the
2 NIH and we had
-- iron is very cheap, very,
3 very, very
cheap, and we felt that from the
4 safety
standpoint carbonyl iron does have all
5 the safety
profile that you look for but being
6 in these
blister-proof packages we felt this
7 was safe.
Donors were also given in writing
8 the warning.
We talked to them, "Don't give
9 this to your
children or animals." We stuck
10 with that for that
reason.
11 I want to make a
comment about
12 MCV. It was
interesting watching the MCVs
13 rise once I treated
them with iron. We picked
14 up four cases of
vitamin B-12 deficiency that
15 was covered up by
the iron deficiency. Once
16 we got the MCVs
fixed -- I mean, once we got
17 the iron deficiency
fixed the MCVs went up to
18 104 and I picked up
vitamin B-12 deficiency in
19 four of our donors
and sent them to their
20 physicians.
21 DR. SIEGAL:
Adrian.
22 DR. DI BISCEGLIE:
A question
Page 392
1 about the
correlation between venous
2 hemoglobin and
fingerstick hemoglobin. It
3 looked to me
from the data you showed that the
4 finger stick
underestimates venous hemoglobin
5 by about a
half a gram or so.
6 You ended
with a recommendation of
7 setting the
fingerstick hemoglobin higher for
8 men because
the normal range is 13 but that's
9 venous
hemoglobin. That didn't quite make
10 sense to
me.
11 DR. BRYANT: Right.
That is a
12 soft
recommendation. It's true that the
13 HemoCue system says
that you can be within .3
14 of what the venous
is. We actually did a
15 study where we
looked at doing venous HemoCue
16 and we did see
about that difference. It
17 wasn't significant
in whether we were
18 deferring or not
deferring donors.
19 When you look at
the CVC there was
20 a difference. What
we're nothing is that this
21 is related to
positional effect more than
22 anything. The
longer a donor sits in a donor
Page 393
1 booth, the
lower their hemoglobin goes to a
2 point.
3 What we are
doing is we are
4 actually doing
a study on the positional
5 affects of
fingerstick hemoglobins and CVCs.
6 The
recommendation of the 13 for men was based
7 on the iron deficiency graph, a table in which
8 we showed that the iron deficiency jumped up
9 as you got below 13.
10 DR. ZIMRIN: I'm
concerned about
11 the men with iron
deficiency anemia. How good
12 do you think a
questionnaire or an interview
13 is at ruling out an
occult GI malignancy?
14 DR. BRYANT: We
were real nervous
15 about that and
those were things that we spent
16 a long time
debating back and forth. We did
17 the best we could.
We were not doing occult
18 bloods from donors,
although I was asked to on
19 a couple of
occasions send them home with
20 cards by their
primary care physicians. The
21 incidence in this
population if iron
22 deficiency is
pretty low. We would have had
Page 394
1 to have over
150 donors based on the data for
2 us to pick up
a case but we were always
3 looking for
that case, somebody who just
4 didn't respond
to iron or it was just
5 suspicious or
reported some kind of GI
6 disturbance or
a problem with the GI system or
7 family
history. We referred a lot of people
8 to their
physicians because they were 50 years
9 old and it was
time to have a colonoscopy
10 anyway. These were
just some things that we
11 were very much
aware of.
12 DR. KULKARNI: Did
you pick up any
13 cases of
myelodysplastic syndrome?
14 DR. BRYANT: I did.
I'm glad you
15 asked. I picked up
some interesting things
16 along the way. I
did have one donor who had
17 a 9.8 gram
hemoglobin. She had been a regular
18 donor for many
years and all of a sudden her
19 hemoglobin started
dropping. She is one of
20 the donors I did
run a retic on and she was
21 not reticing. I
sent her to her physician and
22 he called and said,
"This may be -- there were
Page 395
1 teardrops on
the blood smear. I went and
2 looked at that
and I called her doctor. She
3 gave me
permission. I called and talked to
4 him. I sent
her over and he called me back
5 and said,
"This may be the earliest case of
6 myelodysplastic syndrome I have ever seen.
7 It's got to start somewhere so we are watching
8 her very carefully." Other interesting things
9 we picked up. We picked up a donor, a whole
10 blood donor, who had essential
11 thrombocytopenia.
He had a 1.3 million
12 platelet count and
didn't even know it so we
13 were able to refer
him for treatment.
14 DR. KULKARNI: How
about
15 menorrhagia in some
of these women as a risk
16 factor?
17 DR. BRYANT: That
was very
18 interesting. As you
know, in practicing
19 medicine and asking
about menstrual periods,
20 we did do menstrual
history on all women.
21 Even if they had
gone into menopause how long
22 ago was it or if
they had surgical menopause
Page 396
1 why was
it.
2 Some of the
histories you get are
3 just what you
get out in the iron clinics
4 where people
tell you these histories of
5 menorrhagia
and you are just like, "That is
6 not normal.
You need to go see your doctor."
7 We are always
aware that sooner or later we
8 should run
across a case of Von Willebrand
9 disease.
10 I haven't found
that one yet but
11 I'm still looking.
Yes, a lot of women were
12 sent to their
ObGyn. I became extremely
13 popular with this
study because people quit
14 chewing ice. I got
thank you notes from their
15 spouses. Restless
Leg Syndrome started going
16 away and in a lot
of women this issue of
17 menorrhagia was
taking care.
18 DR. FLEMING: One
question. It's
19 perplexing to refer
to the control group as
20 you do as a control
group. Those are what I
21 might call the
normals as opposed to those
22 with iron
deficiency. I'm not sure what we
Page 397
1 learned by
comparing to those. We also have
2 the potential
for rushing the mean bias based
3 on how they
are defined at baseline. I would
4 think even if
you leave them alone you might
5 see some drop
in the controls and some
6 increase in
the intervention and you do. I
7 have no idea
how much is regression of the
8 mean bias,
what is true treatment affect.
9 Since you had
about 1,000 participants why not
10 randomize them and
form a true control group.
11 If you really
wanted to understand what was
12 the influence of
the supplementation, why not
13 randomize the
deficient cohort of 1,000 to
14 receiving the
regiment against control.
15 Second question,
why not look
16 beyond the
laboratory measures that you looked
17 at that show some
interesting patterns, but
18 you are referring
here to some anecdotal
19 observations about
Restless Leg Syndrome and
20 fatigue and pica
being affected, but you
21 really need a
randomized blinded control trial
22 to assess that. Why
didn't you do that?
Page 398
1 DR. BRYANT:
That's a very good
2 question. When
we initially set the study up
3 it was just to
answer the questions we had up
4 front, how
would giving iron to donors affect
5 the
fingerstick hemoglobin and the iron
6 stores.
7 As we got
into this we thought,
8 "Oh, wouldn't
this have been nice to have an
9 arm that
received a placebo." That would have
10 been very nice but
that was just not how the
11 study was set up to
begin with but that would
12 be a very excellent
study.
13 DR. DI BISCEGLIE:
One more
14 disease if I may.
Celiac disease is the
15 disease of the day.
It's quite frequent by
16 some estimates. Was
that an issue in your low
17 hemoglobin?
18 DR. BRYANT: Yes.
Actually, it
19 is. Celiac disease,
inflammatory bowel
20 disease, some
ulcerive colitis came up.
21 Actually I was on
the phone two days ago with
22 a donor who when
asked the question reported
Page 399
1 to me on the
phone that she had indeed been GI
2 bleeding for
almost eight months now and she
3 had not told
her physician. Yes, we do see
4 that and we
are able to refer donors. Donors
5 are pretty
quick to tell you that they don't
6 want to take
anything that is going to upset
7 their stomach
because they have a GI problem.
8 Most of the
intolerance to ferrous sulfate or
9 ferrous
gluconate was GI symptoms so donors
10 were very quick to
talk to you about their GI
11 problem.
12 DR. SKIKNE: I have
a question
13 about patients
taking antiacids, H2 blockers,
14 PPIs. Did you look
at that or did you note a
15 problem with
response in any of those?
16 DR. BRYANT: Good
question. That
17 did come up a
couple of times. Most of the
18 donors were taking
their H2 blockers in the
19 morning and I had
them take the iron at night
20 so it wasn't a
problem but we knew that
21 possibly could
be.
22 Also what we noted
some of our
Page 400
1 donors who
didn't respond as well as I thought
2 they should
when I got to talking to them they
3 were taking
calcium at night at the same time
4 they were
taking their iron so we asked them
5 to move the
calcium to the morning and
6 immediately
saw better lab response to the
7 iron. Yes,
those can interfere. We always
8 made sure of
they took thyroid medicine or if
9 they were on
antibiotics they allowed at least
10 four hours between
the medication.
11 DR. SIEGAL: Okay.
If there are
12 no more questions,
thank you very much for a
13 very nice
discussion.
14 Next we are going
to hear from Dr.
15 Daniel Waxman at
the Indiana Blood Center on
16 a U.S. blood center
experience with iron
17 replacement.
18 Dr.
Waxman.
19 DR. WAXMAN: Thank
you very much.
20 Appreciate the
opportunity to be here. When
21 Dr. Holness called
me and said the FDA was
22 interested in this
topic, I gave him my
++