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Transfusion Independence

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ironjustice:
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

ironjustice:
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


--

ironjustice:
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

ironjustice:
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
 

ironjustice:
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

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