Transfusion Independence

I am wondering if anyone has followed up on the theory of iron overload PREceding the thalassemia and its' contributing to the CAUSE of thalassemia as opposed to a SECONDARY result OF the thalassemia .. ?
As is evidenced in these two articles in which the lowering of the iron seems to lead to significant recovery in closely related disease states .. ?

"Complete recovery after iron chelation in aplastic anemia"

They treated this kid for five years .. aggressively .. and when and
ONLY when the kid was failing DUE TO their interventions / iron
buildup .. did they finally cure the kid / chelated the iron.

Removed the iron **totally** ..
IE: targeted the iron .. and the kid was cured.
---------

Complete hematopoietic recovery after continuous iron chelation
therapy in a patient with severe aplastic anemia with secondary
hemochromatosis.
Park SJ, Han CW
J Korean Med Sci 2008 Apr; 23(2):320-3.

A 16-yr-old male patient with hemochromatosis due to multiple packed
red blood cell transfusions was referred to our emergency center for
the treatment of severe aplastic anemia and dyspnea.
He was diagnosedwith aplastic anemia at 11-yr of age.
He had received continuous transfusions because an HLA-matched marrow
donor was unavailable.
Following a continuous, approximately 5-yr transfusion, he was noted
to develop hemochromatosis.
He had a dilated cardiomyopathy and required diuretics and digitalis,
multiple endocrine and liver dysfunction, generalized bleeding, and
skin pigmentation.
A total volume of red blood cell transfusion before deferoxamine
therapy was about 96,000 mL.
He received a regular iron chelation therapy (continuous intravenous
infusion of deferoxamine, 50 mg/kg/day for 5 days q 3-4 weeks) for
approximately seven years after the onset of multiple organ failures.
His cytopenia and organ dysfunctions began to be gradually recovered
since about 2002, following a 4-yr deferoxamine treatment.
He showed completely normal ranges of peripheral blood
cellcounts, heart size, and liver function two years ago.
He has notreceived any transfusions for the last four years.
This findingsuggests that a continuous deferoxamine infusion
may play a role inthe immune regulation in addition to iron
chelation effect.

Journal of Korean medical science
[J Korean Med Sci]

---------

"Iron restriction healed a leg ulcer."

Improvement of sickle cell anemia by iron-limited erythropoiesis.
Castro O, Poillon WN, Finke H, Massac E.
Center for Sickle Cell Disease, Howard University College of
Medicine,
Washington, D.C. 20059.
Am J Hematol. 1994 Oct;47(2):74-81. Links
Comment in:
Am J Hematol. 1995 Sep;50(1):68-9.

We report the hematologic and clinical features of four adult
patients
(Pts.) with sickle cell anemia and iron-limited erythropoiesis.
Two of the Pts. had spontaneous iron deficiency (chronic GI bleeding,
low-grade hemoglobinuria).
In the other two Pts. iron restriction was induced by periodic RBC
aphereses as part of a pilot protocol designed to decrease
intracellular HbS polymerization by MCHC reduction.
Iron-limited erythropoiesis was defined by reduction in red cell
indices (MCV range 60.4-67 fl) in the presence of low serum ferritin
(range < 10-20 ng/ml).
In these Pts. iron restriction did not cause clinically significant
worsening of the anemia (Hb 7.8-9.0 g/dl).
In two Pts. the anemia actually improved.
Other hematologic effects of iron restriction were: decreased MCHC,
reticulocyte count, RDW, and dense cells.
A reduced hemolytic rate was suggested by a lowering of serum
bilirubin and LDH.
In one of the Pts. the 51Cr RBC T1/2 survival increased from 12 to
16 days.
The intracellular HbS polymer fractions (fp) were determined at 25% O2
by Csat and with the use of the conservation of mass equation.
The baseline fp values ranged from 0.48-0.53.
After iron restriction they ranged from 0.33-0.48.
The fp decreased even though iron-limited erythropoiesis also lowered
the Hb F concentration in three of our Pts.
In one of the two Pts. with induced iron depletion, hospitalization
days for pain crises decreased from an average of 4.5 days/month (2
year baseline period) to an average of 0.5 days/month in the 3 year
follow-up after iron depletion.
The second patient with induced iron restriction experienced the rapid
healing of a leg ulcer.
Controlled iron restriction should be explored as a therapeutic
strategy in selected SS patients.

PMID: 7522396

They have some real results with the oral chelator .. hydroxyurea .. and sooo again gives evidence of the iron PREceding the anemia .. ?

Oral liquid hydroxyurea promising for long-term use in babies with
sickle cell anemia
17 Jun 2005

Treating babies who have sickle cell anemia (SCA) with oral liquid
hydroxyurea appears to prevent the onset of long-term complications
triggered by this disease, according to results of a preliminary study
by investigators at St. Jude Children's Research Hospital.


The study's findings are important because the onset of damage caused
by SCA complications can occur as early as three months after birth.
Starting treatment before those complications begin could dramatically
reduce the chance of organ damage and premature death. A report on the
study appears in the June 14 online edition of Blood.


In SCA, a genetic mutation causes oxygen-carrying protein hemoglobin
(Hb) to form rigid cords in red blood cells, causing the cells to take
on a bent, sickled shape. The sickled cells clog small blood vessels,
causing pain and serious damage to the brain, kidneys, spleen and other
organs; and the subsequent premature death of the abnormal red cells
causes anemia. In the United States, SCA is found mostly among African
Americans.


Hydroxyurea increases the production of fetal hemoglobin (HbF), the
main oxygen transport protein in fetal red blood cells. Because HbF
prevents red blood cells from "sickling," clinicians have used
hydroxyurea for about a decade to reactivate HbF production in adults
and older children with SCA. In addition, hydroxyurea reduces the
severity of symptoms suffered by adolescents and adults with SCA, such
as lung infections, organ damage, stunted growth, impaired brain
development and acute chest syndrome (ACS). ACS refers to an infection
in the lungs that causes difficulty breathing, pain and other symptoms
and can be fatal.


The current St. Jude study was an extension of a previous clinical
trial, Hydroxyurea Safety and Organ Toxicity (HUSOFT), which was the
first in which young babies were treated with hydroxyurea. The original
HUSOFT study, published in 2001, demonstrated that short-term oral
liquid hydroxyurea therapy can be safe and effective in babies with
SCA. In the extension study, these infants were followed for up to six
years of therapy.


"Our results are promising and justify a larger multicenter clinical
trial to confirm that treating babies with hydroxyurea is safe and
effective," said Jane S. Hankins, M.D., a physician at the St. Jude
Comprehensive Sickle Cell Center and the study's lead author. "If a
larger trial supports our observations in the HUSOFT Extension, the
treatment of sickle cell anemia will undergo a significant change."


"This study is particularly encouraging because it suggests that we
can treat babies with hydroxyurea for several years without side
effects serious enough to limit the use of this drug," said Winfred
Wang, M.D., St. Jude Comprehensive Sickle Cell Center director. "Our
aim is to make sickle cell anemia a survivable disease that doesn't
significantly reduce a person's quality of life." Wang is the senior
author of the paper in Blood.


A two-year pilot study of 21 babies with SCA, the original HUSOFT was
designed to examine the feasibility of treating infants with liquid
hydroxyurea; to determine the toxicity of this drug in babies; to
assess hydroxyurea's effects on fetal Hb levels; and to observe if this
treatment could preserve spleen function. Patients received 20
milligrams/kilgrams of body weight/day (mg/kg/day) of hydroxyurea. All
21 patients who completed the initial study were enrolled by their
parents into the HUSOFT Extension study. In that study, the dose of
hydroxyurea was elevated from 20 to 30 mg/kg/day for an average of 4.0
years (range 2.1 - 6.0 years).


The aim of the HUSOFT Extension was to determine if this higher dose,
given for an extended period of time, provided significant long-term
benefits without causing unacceptable side effects in children ranging
in age from 2.6 to 4.4 years (median age 3.4 years).


After four years of hydroxyurea therapy, the concentrations of Hb, HbF
and the volume of red blood cells were significantly increased in the
children receiving hydroxyurea. Moreover, the HbF level often exceeded
20 percent of the total amount of Hb, Hankins said. "In children who
weren't treated with hydroxyurea, the level of HbF declined
significantly," she added. "The fact that HbF levels rose in babies
treated with hydroxyurea suggests that the drug is effective in babies,
as well as in adolescents and adults."


Babies receiving hydroxyurea also weighed more and were taller than
those untreated children 2 to 5 years old who had been observed in a
previous, long-term national study called the Cooperative Study for
Sickle Cell Disease. The average weight gain for babies in the St. Jude
study was more than 4.5 pounds per year; and the gain in height was
more than 3 inches, the researchers report.


"Hydroxyurea could also prove to be an effective way to improve the
care of sickle cell anemia patients who live in underprivileged areas
of the world," said Russell E. Ware, M.D., Ph.D., director of the
Hematology division of the Department of Hematology-Oncology at St.
Jude. "Treatment with hydroxyurea requires periodic checkups, but the
medication is relatively inexpensive and should be adaptable to
countries with limited resources," he said. Ware is a co-author of
the paper.


Other authors of the article include Zora Rogers (University of Texas,
Dallas); Lynn W. Wynn, MSN, PNP, CCRP (St. Jude); Peter A. Lane (Emory
University, Atlanta, GA); and J. Paul Scott (Medical College of
Wisconsin, Milwaukee).


This work was supported in part by a General Clinical Research Center
grant and ALSAC.


St. Jude Children's Research Hospital


St. Jude Children's Research Hospital is internationally recognized for
its pioneering work in finding cures and saving children with cancer
and other catastrophic diseases. Founded by late entertainer Danny
Thomas and based in Memphis, Tenn., St. Jude freely shares its
discoveries with scientific and medical communities around the world.
No family ever pays for treatments not covered by insurance, and
families without insurance are never asked to pay. St. Jude is
financially supported by ALSAC, its fund-raising organization. For more
information, please visit http://www.stjude.org.


Contact: Carrie Strehlau
carrie.streh...@stjude.org
901-495-2295
Marc Kusinitz, Ph.D.
marc.kusin...@stjude.org
901-495-5020


St. Jude Children's Research Hospital
http://www.stjude.org


---------------------------------------------------------------------------­-----


Prevention of sickle cell crises with multiple phlebotomies.
Bouchair N, Manigne P, Kanfer A, Raphalen P, de Montalembert M, Hagege
I, Verschuur A, Maier-Redelsperger M, Girot R
Service de pediatrie, CHU,
Constantine, Algerie.


OBJECTIVES:
Sickle cell disease patients suffering from frequent painful crises
were submitted to phlebotomies in order to reduce hospitalization days
due to pain, through hemoglobin (Hb) level reduction and iron
deficiency in patients with an hemoglobin level equal to or above 9.5
g/dL.

PATIENTS:
Seven sickle cell disease patients (four SC, three SS), aged four to 24
years, were submitted to sequential phlebotomies during periods from 18
months to four years.

METHODS:
The number of hospitalization days for crises was considered.
The volumes and frequencies of phlebotomies were adjusted according to
the patients ages, the hemoglobin concentrations and the serum ferritin
levels.

RESULTS:
One hundred and forty-four hospitalization days were recorded in the
seven patients in the year preceding the treatment.
During the study period, the annual numbers of hospitalization days
were respectively 20, five, six and one.
Mean hemoglobin concentration was 10.7 g/dL before phlebotomies and 8.8
to 9.2 g/dL during the four years of treatment.
Mean corpuscular volume, mean corpuscular hemoglobin concentration and
serum ferritin were also reduced.
The volume of phlebotomies was 116 to 39 mL/kg/year according to the
patients.
COMMENTS AND CONCLUSION:
The striking decrease of the number of hospitalization days for all the
patients suggests a closed relationship between therapy and clinical
improvement.
The mechanism of this effect is probably multifactorial:
a) the concentration of Hb level is known to influence the blood
viscosity and its decrease always improved rheology in sickle cell
disease patients;
b) the mean corpuscular hemoglobin concentration is a critical factor
concerning the HbS molecule polymerization in sickle cell disease, and
its slight reduction may have an important biological effect.
We observed these two biological modifications in our patients and
suggest that they mediate the clinical effects.
The iron deficiency induced by phlebotomies has no evident deleterious
consequence either on height and weight in the children or on
intellectual performance in any patients.


Publication Types: * Clinical trial
PMID: 10761600, UI: 20224666
--------

Promising New Class of Antibiotics Causes Bacteria
to Commit Suicide
By Stuart Fox
Posted 12.17.2009

As bacteria continue to grow more resistant to a wide
range of antibiotics, doctors are searching furiously
for better ways to kill infectious microbes.
Enter hydroxyurea.
Researchers at MIT and Boston University have discovered
that hydroxyurea, normally a drug prescribed for
sickle-cell anemia or psoriasis, also causes bacteria to
create their own poisons and kill themselves.


In all cases, hydroxyurea prevents DNA transcription.
When used to treat psoriasis or sickle-cell anemia,
hydroxyurea simply slows down the production of sick
cells.
But when used against a bacterium, the cessation of
DNA transcription begins a chain reaction that ends
with the bacterium producing hydroxyl free radicals.
Those free radical are like molecular buzz saws, and
they quickly chop the bacterium apart from the inside
out.
In fact, many antibiotics currently in use also kill
bacteria by inducing hydroxyl free radical production,
but hydroxyurea does so in a totally novel way.
Thus, no bacteria on Earth has evolved any resistance
to it.
That lack of resistances means hydroxyurea can serve
either as an antibiotic on its own, or as a helper to
other, more widely resisted, antibiotics.


And with multiple-drug-resistant bacteria becoming a
bigger and bigger problem, any help is welcome.


----------------------


Iron chelators hydroxyurea and bathophenanthroline
disulfonate inhibit DNA synthesis by different pathways.
Biochemistry and molecular biology international
1994;34(2):273-9.
1994: Alcaín F J; Löw H; Crane F L; Navas P
We previously showed that thrombin-stimulated DNA synthesis
in CCL 39 cells was inhibited by hydroxyurea (HU) and
bathophenanthroline disulfonate (BPS)
(Proc. Natl. Acad. Sci. USA, in press).
A clear difference exists between these two inhibitors.
Inhibition mediated by HU was immediate and must be present
in the culture medium.
BPS was equally effective when it was present in the medium
or after preincubation, but it required at least 12 h to
achieve maximal effect.
The permeable form 1,10 phenanthroline had the same inhibitory
effect in short-term incubations that BPS.
Moreover, 1,10 phenanthroline was cytotoxic in long-term
incubations indicating that the site of BPS inhibition was
outside the cell.
Further, long-term incubations with HU did not affect the
ability of the cell to reinitiate DNA synthesis after removal
of the chelator.

This article raises the possibility thalassemia IS related to hemochromatosis.
Iron overload BEFORE / during disease process.

Reish O, Shefer-Kaufmann N, Shimshoni DC, Renbaum P, Orr-Urtreger A, Steiner H, Rapoport M, Levy-Lahad E, Altarescu G
Frequencies of C282Y and H63D alleles in the HFE gene among various Jewish ethnic groups in Israel: a change of concept required. [JOURNAL ARTICLE]
Genet Med 2010 Jan 15.



PURPOSE:: Hereditary hemochromatosis has not been fully evaluated in the non-Ashkenazi population and is considered to be relatively rare. After ascertaining three unrelated hereditary hemochromatosis families of North African Jewish origin with the HFE C282Y/C282Y genotype, we evaluated the C282Y and H63D allele frequencies among the different Jewish ethnic groups in Israel, in particular North African Jews.
METHODS:: Data were collected from three Israeli Medical Centers. North African, Oriental, Yemenite, and Sephardic Jewish healthy individuals were assessed for the C282Y and H63D alleles.
RESULTS:: The C282Y allele frequency was 1.02% (6/586 chromosomes), and the H63D allele frequency was 13.82% (81/586 chromosomes) in the North African Jewish group. The C282Y allele was not detected in the other non-Ashkenazi groups. The H63D allele frequency was 12.5% (38/304 chromosomes) in Oriental Jews, 14.9% (14/94 chromosomes) in Yemenite Jews, and 9.3% (11/118 chromosomes) in Sephardic Jews.
DISCUSSION:: Hereditary hemochromatosis is underrecognized among North African Jews, who have carrier frequencies of 1/58 and 1/4 for C282Y and H63D, respectively. HFE-hereditary hemochromatosis is not rare among this population as currently thought and merits increased awareness to prevent endpoint disease. The frequent occurrence of beta-thalassemia trait and HFE-H63D in non-Ashkenazi Jews raises the possibility of genetic interactions contributing to iron overload when coinherited and requires further evaluation.



--------------------------------------------------------------------------------
More from this journal
Genetics in medicine : official journal of the American College of Medical Genetics [Genet Med]

Dear Ironjustice,

Thank you for this article.  It would be great if "triggering" or "activating" the bone marrow could cure thalassemia.  In aplastic anemia, or perhaps in certain types of sickle cell anemia I can see how this can be helpful. 

In thalassemia major, and especially in beta zero patients this is next to impossible because these patients completely lack the genetic information to make red blood cells.  It is our genes that determine every function in our body.  Genes translate to the alignment of amino acids to make proteins which then make every cell in our body.  If the gene is missing there is no way on earth that our body can make the proteins that comprise red blood cells. 

In aplastic anemia the bone marrow is suppressed.  In thalassemia the bone marrow is not suppressed - and it will grow in order to expand its surface area in attempts to make more blood (which is what causes bone deformities and enlarged spleens in thalassemia).   

If we were dealing with a condition in which the bone marrow was suppressed then activating the bone marrow would be a goal.  That is not the problem in thalassemia so this research does not apply to thalassemia major. 

Some possiblities I have considered are adding spleen transplant or grafting donor tissue to an existing spleen to introduce the gene into a thalassemia major patient's body.  For one, this reduces rejection because once the spleen accepts the tissue the entire body is likely to.  Secondly, tissue from the spleen often finds its way into the bone marrow and begins to function.  As the spleen is capable of extra medullary hemopoesis - this may be a curative approach to thalassemia. 

Keep reasearching - you never know what you will find and what you may come up with,

Sharmin

There may be more to it than what is imagined or proven ..

-----------

New Method Fixes Broken Proteins to Treat Genetic Diseases
ScienceDaily (Jan. 16, 2010) —
Researchers at Fox Chase Cancer Center have demonstrated how it could
be possible to treat genetic diseases by enhancing the natural ability
of cells to restore their own mutant proteins. In particular, they
found that drugs called proteosome inhibitors could provide one way of
manipulating cells into producing more of a so-called chaperone
protein, named Hsp70, which helps amino acid chains fold into their
proper protein form.


Their latest findings, presented in the journal PLoS Genetics, expand
their previous research from yeast models of disease to human cell
cultures and animal models. According to the researchers, if this
approach works in humans, it could be a way to turn certain
debilitating -- or even fatal -- genetic diseases into more treatable,
chronic conditions.


"Hsp70 pulls misfolded mutant proteins apart like a twisted rubber
bands and allows them to snap back into place, eventually a
significant percentage of these proteins will snap back into something
approaching a functional shape," says the study's leader, Warren
Kruger, Ph.D., professor in Fox Chase's Cancer Biology program. "If
this can be done in humans, it could represent a way of reducing the
severity -- or perhaps correcting -- certain hereditary diseases, even
some familial cancers."


Genetic diseases are often caused by a specific type of genetic
alteration called a missense mutation that makes cells add an
incorrect amino acid into the protein chain. Since the shape of a
protein depends on the specific arrangement of amino acids, even a
single error amid a gene's very long stretch of DNA can cause the
gene's protein product to become misshapen. Kruger and his colleagues
studied ways to reverse the functional effects of missense
mutationsfor three genetic diseases: two severe inherited metabolic
disorders (CBS deficiency and MTHFR deficiency) and one inherited
cancer syndrome (Li-Fraumeini).


In each case, the Fox Chase researchers found that it was possible to
restore the function of the mutant proteins by tricking the cell into
increasing levels of Hsp70. "We have shown that the more opportunities
we give Hsp70 proteins to try to 'fix' mutants, the more likely it is
that they will succeed," Kruger says.


While this approach has yet to be applied to clinical medicine, there
are several drugs that are known to induce Hsp70 in humans. Kruger
found that treating yeast and mammalian cells with a drug called
bortezomib elevated the amount of available Hsp70 and rescued mutant
proteins. Bortezomib is a member of a class of drugs called proteasome
inhibitors, which decreases the effectiveness of enzymes that cells
use to dispose of non-functioning proteins. Bortezemib (known under
the brand name Velcade) is currently used to treat patients with
multiple myeloma.


"We found that bortezomib can stabilize and restore mutants by
tripling the amount of available Hsp70," Kruger says. "While we do not
yet know the entiremechanism, we do know that bortezomib doesn't
rescue mutants in cells that lack the gene for Hsp70."


Kruger and his colleagues are currently studying how to best adapt
these findings to human disease.


"Of course, the big question we need to answer is one of safety --
what are the long term effects of sustained Hsp70 elevation?" Kruger
says. "The answer may be very disease-specific, one of how many mutant
proteins must be restored to reduce the severity of a given genetic
disease."


Funding for this research comes from grants from the National
Institutes of Health and the Commonwealth of Pennsylvania.


-----------


Blueberry supplemented diet reverses age-related decline in
hippocampal
HSP70 neuroprotection.
Neurobiol Aging. 2005 Apr 30;
Galli RL, Bielinski DF, Szprengiel A, Shukitt-Hale B, Joseph JA.
Neuroscience Laboratory, USDA-ARS Human Nutrition Research Center on
Aging at Tufts University, 711 Washington St., Boston, MA 02111, USA;
Department of Psychology, Simmons College, 300 The Fenway, Boston, MA
02115-5898, USA.


Dietary supplementation with antioxidant rich foods can decrease the
level of oxidative stress in brain regions and can ameliorate
age-related deficits in neuronal and behavioral functions. We examined
whether short-term supplementation with blueberries might enhance the
brain's ability to generate a heat shock protein 70 (HSP70) mediated
neuroprotective response to stress. Hippocampal (HC) regions from
young
and old rats fed either a control or a supplemented diet for 10 weeks
were subjected to an in vitro inflammatory challenge (LPS) and then
examined for levels of HSP70 at various times post LPS (30, 90 and
240min). While baseline levels of HSP70 did not differ among the
various groups compared to young control diet rats, increases in HSP70
protein levels in response to an in vitro LPS challenge were
significantly less in old as compared to young control diet rats at
the
30, 90 and 240min time points. However, it appeared that the blueberry
diet completely restored the HSP70 response to LPS in the old rats at
the 90 and 240min times. This suggests that a short-term blueberry
(BB)
intervention may result in improved HSP70-mediated protection against
a
number of neurodegenerative processes in the brain. Results are
discussed in terms of the multiplicity of the effects of the BB
supplementation which appear to range from
antioxidant/anti-inflammatory activity to signaling.


PMID: 15869824

Does this somewhat explain the link?
Iron chelation?

Autophagy of HSP70 and chelation of lysosomal iron in a non-redox-active form.
Kurz T, Brunk UT.
Autophagy. 2009 Jan 1;5(1):93-5.
Division of Pharmacology, Faculty of Health Sciences, Linköping University, Linköping, Sweden.

Lysosomes contain most of the cell's supply of labile iron, which makes them sensitive to oxidative stress.
To keep lysosomal labile iron at a minimum, a cellular strategy might be to autophagocytose iron binding proteins that temporarily would chelate iron in a non-redox-active form.
Previously we have shown that autophagy of metallothioneins, as well as of non-Fe-saturated ferritin, meets this goal.
Here we add another stress-regulated protein to the list, namely HSP70.

PMID: 18989099

This is another article which seems to point to a possible PREdisease iron loading and the lower iron level .. coincidentally .. leading to DEcreased disease ..
The iron overload CAUSES the hemolysis and by keeping the iron LOW the disease does not MANIFEST.
Therefore giving evidence to iron load BEfore the sickle disease.
The same 'could' be happening in thalassemia .. too ..
EXCEPT in thalassemia the iron loading manifests itself .. differently .. again evidenced by the associaton found between thalassemia and hemochromatosis .. genetically .. ?

Lower Ferritin Concentrations Are Associated with Decreased Hemolysis
in Sickle Cell Disease Children without Iron Overload.
Blood (ASH Annual Meeting Abstracts) 2009 114: Abstract 2571
Oswaldo L Castro, MD1, Mehdi Nouraie, M.D., Ph.D.*,1, Lori Luchtman-
Jones, MD2, Xiaomei Niu, M.D.*,1, Caterina Minniti, M.D.*,3, Andrew D.
Campbell, MD4, Sohail R Rana, MD*,5, Gregory J. Kato, MD6, Mark
Gladwin, MD7 and Victor R. Gordeuk, MD1
1 Center for Sickle cell Disease, Howard University, Washington, DC,
USA,
2 Children's National Medical Center, Washington, DC, USA,
3 Vascular Medicine Branch, NHLBI, Bethesda, MD, USA,
4 Pediatric Hematology/Oncology, Univ. of Michigan Med. Ctr., Ann
Arbor, MI, USA,
5 Department of Pediatric and Child Health, Howard University
Hospital, Washington, DC,
6 Pulmonary and Vascular Medicine Branch, National Heart, Lung, and
Blood Institute, National Institutes of Health, Bethesda, MD, USA,
7 Division of Pulmonary, Allergy and Critical Care Medicine,
University of Pittsburgh Medical Center, Pittsburgh, PA, USA

Abstract 2571


Poster Board II-548


The role of iron in the pathophysiology of sickle cell disease
(SCD) is complex and not fully understood.
Iron overload is associated with disease severity primarily
because multiple transfusions are linked to a severe SCD
clinical course.
Additionally, hemolysis, also associated with disease severity,
increases iron absorption.
Iron deficiency decreases red cell MCHC, which lowers Hb S
polymerization and thus may improve the clinical manifestations
of SCD.
Such a hypothesis is supported by our recent observation of a
homozygous SCD adult with iron deficiency anemia and a very low
hemolytic rate that increased dramatically with iron
supplementation.
This experience and similar case reports from the literature led
us to examine the relationship of ferritin levels with hemolysis
and other laboratory and clinical parameters in a group of non-iron
overloaded children with sickle cell disease.
All subjects in this analysis were enrolled in a prospective study
of the prevalence and significance of pulmonary hypertension in
children with SCD (PUSH).
Because of the known association of high serum ferritin with
multiple transfusions and with a severe clinical course in this
and other SCD populations, we excluded children who had ferritin
concentrations of 242 ng/ml or higher.
This cut-off value is 3 SDs above the geometric mean of the
ferritin concentrations in a group of 42 age, sex, and ethnicity
matched control children without SCD.
Hence the group of sickle cell children with ferritin levels of
< 242 ng/ml should include only those with iron deficiency or
with normal iron stores.


In this group of non-iron overloaded SCD children and
adolescents (median age 12 y, range 3–20 y), lower
serum ferritin was related to higher serum transferrin
and to lower serum iron and MCV, documenting that serum
ferritin was reflective of iron status.
Hemolytic parameters such as reticulocyte count and the
hemolytic component were significantly lower with lower
ferritin levels.
In multivariable analysis these relationships remained
statistically significant (P for MCV and ferritin: 0.003,
P for hemolytic component and ferritin: 0.044) even after
correcting for alpha-thalassemia, which is known to also
lower MCV and hemolysis, and for markers of inflammation
(WBC) and liver disease (ALT), which could increase the
ferritin level regardless of iron stores.
Ferritin was significantly lower in older subjects, probably
as a result of growth-related red cell mass expansion in the
presence of marginal iron stores.
Our results thus suggest that low iron stores are independently
associated with decreased hemolysis.
Low hemolysis is likely to be beneficial in SCD by reducing
hemolysis-related vasculopathy, which in adult SCD patients
predicts an increased risk of pulmonary hypertension, leg
ulcers, priapism, and death.
Whether iron status per se plays a role in the pathogenesis
of SCD vasculopathy is not known.
In non-SCD adults, decreasing iron stores by frequent blood
donation has beneficial effects on endothelial function and
cardiovascular disease even within the normal range for iron
stores.
Hence, lowering iron stores could benefit SCD subjects by
an additional, hemolysis-independent mechanism.
Therapeutic iron depletion is not an option for children
because of their need for adequate iron stores for optimal
physical and neuro-psychological development.
However, carefully controlled studies should be considered to
reduce iron stores and so decrease the hemolytic rate in
adults with SCD.
It may be possible to achieve levels of iron reduction that
lower hemolysis but do not worsen the anemia: in our study
subjects, low iron stores were not associated with increased
anemia and the red cell counts were actually higher with
lower ferritin levels.


Disclosures: Gordeuk: TRF Pharma: Research Funding; Merck:
Research Funding; Biomarin pharmaceutical company:
Research Funding; Novartis: Speakers Bureau.


© 2009 American Society of Hematology


--

This article speaks to the finding of increased iron in thalassemia.
------
Non-haem iron-mediated oxidative stress in haemoglobin
E beta-thalassaemia.
Ann Acad Med Singapore. 2010 Jan;39(1):13-6.
Chakraborty I, Mitra S, Gachhui R, Kar M.
Department of Bio chemistry,
NRS Medical College & Hospital,
Kolkata, India.

INTRODUCTION:
Haemoglobin (Hb) E beta-thalassaemia is a common thalassaemic
disorder in Southeast Asia and is very common in the eastern and
north-eastern parts of India.
The disease cause rapid erythrocyte destruction due to the free
radical mediated injury but factors for the oxidative injury are not
clearly known.
We investigated the free reactive iron (non-haem) mediated insult
in Hb E beta-thalassaemia.
MATERIALS AND METHODS:
Thirty Hb E beta-thalassaemic patients (age range, 3 to 15 years)
who had undergone blood transfusion at least 1 month prior to
sampling and 32 normal healthy individuals (age range, 18 to 30
years) were included in this study.
We estimated the ferrozine detected intracellular erythrocytic free
reactive iron (nonhaem iron), reduced glutathione (GSH), glutathione
reductase activity, cellular damage marker serum thiobarbituric
acid reacting substances (TBARS) and also serum ferritin using
standard methods.
RESULTS:
We found that the erythrocytic free reactive iron was significantly
higher (P <0.001) in Hb E beta patients and was about 30% more
than in controls.
The elevated level of erythrocytic non-haem iron was associated with
a high level of serum TBARS which was about 86% higher in patients
than in controls.
The serum ferritin level was also significantly higher (P <0.001)
compared to controls.
The erythrocytic reduced glutathione level was significantly lower
(P <0.001) at about 65% less in the patients' group and the
erythrocytic glutathione reductase enzyme was also found to be
significantly lower (P <0.001) in Hb E beta-thalassaemia.
CONCLUSIONS:
We concluded that a significantly elevated level of erythrocytic
free reactive iron and lipid peroxidation end product was associated
with low erythrocytic GSH level.
This reflects non-haem iron mediated cellular damage in Hb E
beta-thalassaemia.

PMID: 20126808

This seems to say there is an "unrecognized" iron load in some with thalassemia.
Again pointing to a possibility of iron PREdisease as evidenced by the use of an iron chelating substance Hp70 to "reverse genetic disease" .. "In particular, they
found that drugs called proteosome inhibitors could provide one way of
manipulating cells into producing more of a so-called chaperone
protein, named Hsp70, which helps amino acid chains fold into their
proper protein form." ..?

Iron overload in thalassaemia intermedia: reassessment of iron chelation strategies
Authors: Taher, Ali1; Hershko, Chaim2; Cappellini, Maria Domenica3
Source: British Journal of Haematology, Volume 147, Number 5,
December 2009 , pp. 634-640(7)
Publisher: Blackwell Publishing

Abstract:

Summary

Thalassaemia intermedia (TI) is a syndrome marked by its diverse
underlying genetic basis although its pathophysiology remains
unclear, particularly regarding the nature of iron loading and toxicity.
It is, however, evident that there are key differences from the
extensively studied thalassaemia major (TM) population and
caution is required when assessing iron load based on serum
ferritin values, as this approach is known to underestimate the true
extent of iron loading in patients with TI.
Although effective iron chelation therapy has been available for
many years, studies in TI-specific populations are rare and evidence
suggests that management of iron levels may be less rigorous than
in patients with TM and other chronic anaemias.
Better understanding of the need to assess and treat iron overload
in both transfused and non-transfused TI patients is clearly required.
Keywords: thalassaemia intermedia; iron overload; iron chelation

Document Type: Research article

DOI: 10.1111/j.1365-2141.2009.07848.x

Affiliations: 1: American University of Beirut, Beirut, Lebanon 2:
Hebrew University of Jerusalem, Jerusalem, Israel 3:
Università di Milano, Policlinico Foundation IRCCS,
Milan, Italy
 

This seems to be another article about transfusion requirement going DOWN by chelation of iron.

Iron chelation therapy associated with improvement of hematopoiesis in transfusion-dependent patients
Transfusion
Early View (Articles online in advance of print)
Published Online: 5 Mar 2010
Esther Natalie Oliva, Francesca Ronco, Antonio Marino, Caterina Alati, Giulia Praticò, and Francesco Nobile
From the Hematology Division, Azienda Ospedaliera "Bianchi-Melacrino-Morelli," Reggio Calabria, Italy.
Correspondence to  Esther Natalie Oliva, Hematology Division, Azienda Osepdaliera "Bianchi-Melacrino-Morelli," Via Melacrino, 89100 Reggio Calabria, Italy; e-mail: estheroliva@hotmail.com.
Copyright © 2010 AABB
ABSTRACT
BACKGROUND: It is well known that iron overload may cause multiple organ failure. In chronically transfused patients, optimal iron chelation therapy is associated with reduced morbidity and mortality. Furthermore, chelation therapy has been associated with erythroid responses.

STUDY DESIGN AND METHODS: Among chronically transfused adults affected by myeloproliferative neoplasms and treated with iron chelators, two case reports are described.

CASE REPORT: A male adult patient with myelodysplastic syndrome (MDS) and a female adult with aplastic anemia (AA), both transfusion-dependent, were treated with deferasirox, an oral iron chelator.

RESULTS: A significant reduction in transfusion requirement was observed and was dependent on chelation therapy. The patient affected by AA also experienced a significant increase in hemoglobin levels. Minimal doses of deferasirox maintained the erythroid responses. Many mechanisms of action of the drug on erythropoiesis have been postulated. The early erythroid response seems to be independent of the removal of iron from deposits, per se, since the reduction of ferritin levels (a surrogate marker of iron deposits) below threshold levels occurs as a later event.

CONCLUSION: Although there are few reports on erythroid responses in patients undergoing iron chelation therapy, they may give new insights in the pathogenesis of MDS and other myeloproliferative neoplasms. AA may benefit in terms of erythroid response. The findings in these cases underline the clinical importance of treating patients with iron overload. A survival benefit of chelation in patients with myeloproliferative neoplasms is still to be confirmed.

Received for publication November 11, 2009; revision received January 4, 2010, and accepted January 7, 2010.

DIGITAL OBJECT IDENTIFIER (DOI)
10.1111/j.1537-2995.2010.02617.x About DOI

© 2010 AABB

I would like to hear from patients on this subject. For those who have gone from a high iron load to a low iron load that is under control through chelation, has there been any changes in your Hb levels or transfusion frequencies?

No, none whatsoever!
In fact it is the opposite that happens: the fewer the transfusions, the lower the body iron - provided you fully comply. Anyway, my ferritin has been maintained in a low level for years now but I have not noticed any difference in B/T I receive. I have not noticed that in my thal friends either. No, I think there is no connection between them two. Don't you think that if there was a connection, doctors would use it to urge patients to chelate?

Lena

This seems to be another article about transfusion requirement going DOWN by chelation of iron.

Iron chelation therapy associated with improvement of hematopoiesis in transfusion-dependent patients
Transfusion

This would be another 'human model' of becoming transfusion independent.

Red Blood Cell Transfusion Independence Following the Initiation of
Iron Chelation Therapy in Myelodysplastic Syndrome.
Blood (ASH Annual Meeting Abstracts) 2009 114: Abstract 4844
Maha A Badawi, MD*,1, Linda M Vickars, MD2, Jocelyn M Chase, MD*,1 and
Heather A Leitch, MD, PhD2
1 Medicine, University of British Columbia, Vancouver, BC, Canada,
2 Hematology, St. Paul's Hospital, University of British Columbia,
Vancouver, BC, Canada

Abstract 4844


Background: Iron chelation therapy (ICT) is often used to treat iron
overload (IOL) in patients (pts) requiring transfusion of red blood
cells (RBC) for chronic anemia. In myelodysplastic syndrome (MDS),
guidelines recommend consideration of ICT in pts with lower risk
International Prognostic Scoring System (IPSS) and IOL as defined by a
ferritin level >1000 ug/l; IOL related organ dysfunction; or receipt
of 20 RBC units. During treatment of a pt with MDS and IOL with ICT,
RBC transfusion requirement (TR) ceased. Here we report his course and
review reported cases of RBC transfusion independence (TI) or
decreased RBC TR in MDS pts receiving ICT.


Methods: The pt chart was reviewed and reported cases identified by
PubMed search using the terms ‘MDS’ and ‘iron chelation’. The clinical
characteristics and course of published cases were summarized.


Case: A 76 year (y) old man was referred in May 2004 for management of
MDS diagnosed in 1997, when the white blood cell (WBC) count was 2.4
x109/l; neutrophils, 0.7 x109/l; hemoglobin (Hb), 133 g/l; platelets,
108 x109/l. Bone marrow aspiration and biopsy showed refractory anemia
(RA), karyotype analysis 46,X,-Y,+8, and the IPSS score was
intermediate-1. The erythropoitin (epo) level was 148.3 mIU/ml and the
stem cell assay showed no epo-independent colony growth. In 2004 the
Hb dropped to 60 g/l prompting the initiation of RBC transfusion
support. He required 3 RBC units every 4 weeks to maintain a Hb >90 g/
l and complained of fatigue and functional limitation. Creatinine,
bilirubin, TSH, reticulocyte count, B12 and folate levels were all
normal. The ferritin level in 2004 was 1293 ug/l and 2197 ug/l in
2006. He declined ICT with deferoxamine (DFO) but in 2006 accepted
deferasirox (DFX). He required several dose interruptions and
adjustments for renal insufficiency; the current dose is 5mg/kg/d with
a normal creatinine. Two months (mo) after starting ICT, the Hb
increased spontaneously to 109 g/l and he has not required RBC
transfusion since. The mean Hb since starting ICT was 122 g/l and the
ferritin decreased to 1082 ug/l in 2009. The most recent neutrophil
count was 3.5 x109/l, platelets consistently clump and the MCV is
unchanged at 120 fl. He reports excellent energy and an improved
quality of life, and has remained clinically well and RBC transfusion
independent to the present, 36 mo from the initiation of ICT.


Literature review: There are 18 published cases of MDS showing
improvement in Hb with ICT; 9 became RBC transfusion independent.
Characteristics of the 10 TI pts were: median age at MDS diagnosis 58
(range 18-74) y; male, n=5. MDS subtype: RA, n=5; RARS, n=2, RCMD,
n=1; RAEB, n=2. IPSS (reported in 8): low, n=1; int-1, n=5; int-1 or
2, n=1; high, n=1. ICT was: DFO, n=7; DFX, n=3. Median time to RBC TI
was 17.5 (1-24) mo and TI duration 13 (3-28) mo to date. Of pts who
had decreased RBC transfusion requirements with ICT but did not
achieve transfusion independence: median age (reported in 3) was 67
(45-78) y; gender (reported in 3) female, n=3; MDS subtype: RA, n=8;
RAEB-t, n=1; IPSS: int-1, n=3; ICT: DFO, n=8; DFX, n=1. Median time to
decreased TR was 14.4 (3-24) mo; median duration of decreased TR
(reported in 3) 9 (6-32) mo; initial TR 50.9 (19.7-447) g Hb/mo;
median decrease in TR 12.7 (0.1-88) g Hb/mo. In one report of 6 pts, 2
with pancytopenia showed improvement with ICT in WBC from 1.4 to 1.9
x109/l (p<0.0001) and neutrophils from 0.51 to 0.94 x109/l (p<0.001).
The platelet count increased from 16.6 to 22.5 x109/l (p<0.001) and
14.6 to 29.6 x109/l (p<0.00001) within 3 mo and the MCV decreased
significantly in 5 by a mean of 5.1 (2.1-11.7) fl, normalizing in 2.
In a second report, neutrophils increased in 8 of 9 pts; in 4 the
initial neutrophil count was <1 x109/l, and platelet counts increased
in 7 of 11 pts, in 4 the initial platelet count was <20 x109/l.


Conclusions: In summary, our pt is the 19th patient with MDS reported
to date in whom improved Hb followed the initiation of ICT; 9 had a
decrease in RBC transfusion requirements, and RBC transfusion
independence occurred in 10. The remarkable course of these pts adds
to evidence that ICT may be of clinical benefit for selected patients
with MDS and IOL. Although the improvement in WBC and platelet counts
with ICT in some pts implies a suppressive effect of IOL on
hematopoiesis that may be abrogated by ICT, the mechanism by which the
effects of ICT on transfusion requirements occur, and the frequency
with which they occur, remains an area for future investigation.


Disclosures: Off Label Use: This presentation discusses the use of
iron chelation therapy deferoxamine and deferasirox in patients with
myelodysplastic syndrome.. Vickars: Novartis Canada: Honoraria,
Research Funding. Leitch: Novartis Canada: Honoraria, Research
Funding, Speakers Bureau.


© 2009 American Society of Hematology

For those who have gone from a high iron load to a low iron load that is under control through chelation, has there been any changes in your Hb levels or transfusion frequencies?

yes , there's a big change in everything related to me and my health after getting Fe within the safe range. ....  ii never seen my pre-tx Hb around 11 in my whole life but xperienceed that twice in last 2 months .... i dont know ther reason and the reality of it ... but i think Vhelation and managin  Fe within a safe range shows positive effects on ur health in many ways ....

Umair

This seems to say there is an "unrecognized" iron load in some with thalassemia.
Again pointing to a possibility of iron PREdisease as evidenced by the use of an iron chelating substance Hp70 to "reverse genetic disease" .. "In particular, they
found that drugs called proteosome inhibitors could provide one way of
manipulating cells into producing more of a so-called chaperone
protein, named Hsp70, which helps amino acid chains fold into their
proper protein form." ..?

Iron overload in thalassaemia intermedia: reassessment of iron chelation strategies
Authors: Taher, Ali1; Hershko, Chaim2; Cappellini, Maria Domenica3
Source: British Journal of Haematology, Volume 147, Number 5,
December 2009 , pp. 634-640(7)
Publisher: Blackwell Publishing

Abstract:

Summary

Thalassaemia intermedia (TI) is a syndrome marked by its diverse
underlying genetic basis although its pathophysiology remains
unclear, particularly regarding the nature of iron loading and toxicity.
It is, however, evident that there are key differences from the
extensively studied thalassaemia major (TM) population and
caution is required when assessing iron load based on serum
ferritin values, as this approach is known to underestimate the true
extent of iron loading in patients with TI.
Although effective iron chelation therapy has been available for
many years, studies in TI-specific populations are rare and evidence
suggests that management of iron levels may be less rigorous than
in patients with TM and other chronic anaemias.
Better understanding of the need to assess and treat iron overload
in both transfused and non-transfused TI patients is clearly required.
Keywords: thalassaemia intermedia; iron overload; iron chelation

Document Type: Research article

DOI: 10.1111/j.1365-2141.2009.07848.x

Affiliations: 1: American University of Beirut, Beirut, Lebanon 2:
Hebrew University of Jerusalem, Jerusalem, Israel 3:
Università di Milano, Policlinico Foundation IRCCS,
Milan, Italy
 

Ali Taher is a famous doctor in the Thal world. I've met him in Berlin but I'd no chance to ask him my questions.
I haven't read your article yet. In which databank do you look??