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