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Transfusion Clinique et Biologique xxx (2017) xxx–xxx

State of art
Management of iron overload in hemoglobinopathies
Traitement de la surcharge en fer des hémoglobinopathies
a,b,d a,∗,b,d a,b,d a,b b,c
S. Allali , M. de Montalembert , V. Brousse , M. Chalumeau , Z. Karim
a
Department of General Pediatrics and Pediatric Infectious Diseases, Necker-Enfants malades hospital, AP–HP, Paris Descartes University,
149, rue de Sèvres, 75015 Paris, France
b
Laboratory of Excellence GR-ex, 75015 Paris, France
c
Inserm UMR 1149/ERL, CNRS 8252, Paris-Diderot University, Bichat site, Sorbonne- Paris city, 75018 Paris,
d
France Pediatric Reference Center for Sickle cell Disease, 75015 Paris, France

Abstract
Hemoglobinopathies, thalassemia and sickle cell disease are among the most frequent monogenic diseases in the world. Transfusion has
improved dramatically their prognosis, but provokes iron overload, which induces multiple organ damages. Iron overload is related to
accumulation of iron released from hemolysis and transfused red cell, but also, in thalassemic patients, secondary to ineffective erythropoiesis,
which increases intestinal iron absorption via decreased hepcidin production. Transfusion-related cardiac iron overload remains a main cause of
death in thalassemia in well-resourced countries, and is responsible for severe hepatic damages in sickle cell disease. Regular monitoring by
Magnetic Resonance Imaging (MRI) using myocardial T2* (ms) and Liver Iron Content (LIC) (mg of iron/g dry weight) are now standards of
care in chronically transfused patients. Serum ferritin level measurements and record of the total number of transfused erythrocyte concentrates
are also helpful tools. Three iron chelators are currently available, deferoxamine, which must be injected subcutaneously or intravenously, and
two oral chelators, deferiprone and deferasirox. We will review the main characteristics of these drugs and their indications. © 2017 Elsevier
Masson SAS. All rights reserved.

Keywords: Iron overload; Thalassemia; Sickle cell disease; Deferoxamine; Deferiprone; Deferasirox

Résumé
Les hémoglobinopathies, les syndromes thalassémiques et drépanocytaires, sont parmi les maladies monogéniques les plus fréquentes au
monde. Leur pronostic a été profondément amélioré par la transfusion sanguine, mais celle-ci entraîne une surcharge en fer responsable de
l’atteinte de différents organes. Le fer provient de l’hémolyse des globules rouges du patient et de ceux transfusés, et, chez les patients
thalassémiques, d’une hyperabsorption intestinale secondaire à l’érythropoïèse inefficace avec diminution de la production d’hepcidine. La
surcharge en fer cardiaque est aujourd’hui la principale cause de décès des patients thalassémiques vivant dans des pays développés ; les
patients drépanocytaires souffrent surtout des conséquences hépatiques de cette surcharge. Les techniques d’IRM de mesure du temps T2* au
niveau du coeur et de la concentration en fer au niveau du foie sont les outils diagnostiques de référence de la surcharge en fer. Les contrôles de
la ferritinémie sérique et le nombre de concentrés érythrocytaires transfusés peuvent aussi être utilisés. Trois chélateurs, la deferoxamine, qui
doit être injectée par voie sous-cutanée ou intraveineuse, et deux chélateurs oraux, la deferiprone et le deferasirox, sont disponibles aujourd’hui.
Nous présenterons leurs principales caractéristiques et indications.
© 2017 Elsevier Masson SAS. Tous droits reserv´es´.

Mots clés : Surcharge en fer ; Thalassémie ; Drépanocytose ; Deferoxamine ; Deferiprone ; Deferasirox

∗
Corresponding author.
E-mail address: Mariane.demontal@aphp.fr (M. de Montalembert).

http://dx.doi.org/10.1016/j.tracli.2017.06.008
1246-7820/© 2017 Elsevier Masson SAS. All rights reserved.

Please cite this article in press as: Allali S, et al. Management of iron overload in hemoglobinopathies. Transfusion Clinique et Biologique
(2017), http://dx.doi.org/10.1016/j.tracli.2017.06.008
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Hemoglobinopathies, thalassemia and Sickle Cell Disease
(SCD) are among the most frequent monogenic diseases in the
word [1]. Their prognosis depends not only on the causative
genetic mutation, which have highly variable clinical and
hema-tological expressions but also on the affordability of
medical care, and above all transfusion and iron chelation.
Here we will present keys issues in iron chelation in patients
with hemoglobinopathies living in France.
1. Epidemiological data
A register of thalassemia published in 2010 has identified
378 patients living in France [2].
There is no register of patients with SCD. The systematic
neonatal screening program, generalized in 2000 in France,
identifies a major sickle cell syndrome in around 400
newborns every year. The current estimation is that around
20,000 patients, children and adults, are living in France.
2. Transfusional needs
Thalassemia is caused by mutations affecting the pro-
duction of globin chains (a and b chains for a and b
thalassemia respectively). Severity of anemia depends of the
degree of imbalance between a and b chains produc-tion,
which is associated with accumulation of free globin chains,
generation of reactive oxygen species, membrane damages,
apoptosis, and ineffective erythropoiesis. Clinically, some
patients have a major thalassemic syndrome (their dis-ease is
called Transfusion-Dependent Thalassemia, previously called
Cooley’s anemia), and require monthly transfusions to
maintain permanently hemoglobin (Hb) level > 9–10 g/dL,
threshold demonstrated to allow normal growth and activ-ity.
Other patients have less severe anemia (their disease is called
thalassemia intermedia, or Non-Transfusion-Dependent
Thalassemia). Recent surveys have demonstrated that long-
term severe complications, such as pulmonary hypertension,
thromboembolic events, hematopoietic extramedullary tumors
have a high frequency in NTDT patients, and that regular
transfusions decrease their risk of occurrence. Recently, there-
fore, NTDT patients may be prescribed regular transfusion
programs [3].
Transfusion needs are very different in patients with SCD.
Polymerization of HbS induces occlusion in microcirculation
by sickled red cells, and chronic hemolytic anemia. Median
baseline Hb level is around 8 g/dL. Erythropoiesis is in most
cases very active in SCD patients, and increased reticulocyte
production alleviates anemia. Transfusions may be required in
emergency, to correct a sudden drop in Hb level (in case of
infection, pain, Parvovirus B19 infection, or splenic sequestra-
tion). Transfusion may also aim to bring new deformable red
cell, either in emergency (in case of stroke, acute chest
syndrome. . .) or in patients with cerebral vasculopathy to
prevent a first episode or a recurrence of stroke [4].
Please cite this article in press as: Allali S, et al. Management of iron overload in hemoglobinopathies. Transfusion Clinique et Biologique
(2017), http://dx.doi.org/10.1016/j.tracli.2017.06.008
3. Origins of iron overload in hemoglobinopathies
Iron accumulates from 3 different origins in patients with
hemoglobinopathies, with different rates according to the dis-
ease and the treatments:
1. hemolysis releases iron-bound Hb which is taken up by
macrophages. Iron necessary for Hb synthesis is normally
carried by transferrin to bone marrow to produce new red
cells. However, when hemolysis is very high, the
transferrin capacity to bind iron is also overwhelmed, and
Non Transfer-rin Bound Iron (NTBI) appears and
accumulates toxically in parenchyma particularly the heart
and endocrine tissue. It has been shown that NTBI form
enters the myocytes through the voltage-dependent L-type
calcium channels and the hepa-tocytes via soluble carrier
SLC39A14, also called ZIP14 [5];
2. in diseases characterized by inefficient erythropoiesis, whether
inherited such as thalassemia or acquired such as
myelodysplactic syndromes, iron is not well consumed
through erythropoiesis. In addition, hepcidin production is
suppressed and iron absorption is increased [6,7]. This mech-
anism explains why NTDT patients may have significant iron
overload while they have not been transfused;
3. one milliliter of packed red blood cells brings 1.08 mg of iron.
Iron derived from transfused red blood cells initially
accumulates in macrophages, but later accumulates in the
liver. One year of regular transfusion for a thalassemic patient
weighing 60 kg brings 9 g of iron. In SCD patients undergo-
ing chronic transfusion regimen, in whom transfusion does not
aim to increase Hb level but to decrease HbS percent-age,
exchange transfusion is preferable to simple transfusion,
because it decreases the global amount of iron [8]. To note,
automated procedure, i.e. erythrocytapheresis, needs higher
number of erythrocyte concentrates than manual exchange
transfusion to control HbS.
Cardiac iron overload is the leading cause of death in patients
with thalassemia who require chronic transfusion [9]. Main
targets for iron overload are also the liver, endocrine glands,
notably the pancreas with therefore risks of cirrhosis, diabetes,
hypothyroidism, hypoparathyroidism, and infertility [10]. The
relationship between excess iron and mortality in SCD is more
difficult to analyze, because patients with transfusion-related iron
overload are also those who have greater disease severity
requiring chronic transfusion [11]. The heart is relatively spared
and iron deposits mostly in the liver [12,13]. In a study of 141
patients with SCD who died in adulthood, at a mean age of 36 ±
11 years, Darbari et al. found that 16 (11.4%) had cirrhosis and
10 (7.1%) iron overload; seven of 16 (43.8%) patients with
cirrhosis had iron overload compared with 3 of the 125 without
cirrhosis (2.4%) (P < 0.001) [14].
4. Monitoring iron overload
Serum ferritin measurement is the most used tool worldwide
to assess the importance of iron burden, but it is not specific, as
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Table 1
Main proprieties of the three available iron chelators.
Deferoxamine
Molecular weight (Da) 657
Chelating properties Hexadentate
Recommended dose 30–60 mg/kg/d
Delivery Sub-cutaneous or intravenous,
8–12 hr,
5–7 d/wk
Half-life 8–10 min
Excretion 40%–60% fecal
Action on cardiac iron + +++
Action on liver iron +++
Toxicity Ocular, auditory toxicity, growth
retardation, local reactions at
injection site, allergy
ferritin level is increased in case of concomitant inflammation.
Besides, serum ferritin level has been reported to underscore
iron stores in patients with NTDT [3].
Magnetic Resonance Imaging (MRI), using myocardial T2*
(ms) and Liver Iron Content (LIC) (mg of iron/g dry weight) are
now standards of care in chronically transfused patients. A severe
myocardial iron overload is diagnosed when T2* is <10 ms, a
moderate one when T2* is between 10 and 20 ms, and no cardiac
iron loading when T2* is > 20 ms. A study performed in 109
thalassemic patients showed that all patients with left cardiac
dysfunction had T2* < 20 ms [15]. In the UK, routine MRI T2*
monitoring and improved iron chelation have been associated
with a 71% decrease in deaths due to thalassemia [16]. For liver,
thresholds of moderate and severe overload are 7 and 15 mg Fe/g
dry weight, respectively. A LIC > 16 mg Fe/g dry weight is
associated with a risk of hepatic fibrosis.
5. Indications for iron chelation
French recommendations for initiating iron chelation in
patients with thalassemia are (1) more than 20 transfusions, or
(2) serum ferritin level > 1000 mg/L. Chelation aims to keep
ferritin level ≤ 1000 mg/L [17]. In patients with SCD, recom-
mended thresholds to start chelation are (1) LIC > 7 mg
Fe/dry weight, or (2) transfusional rate > 100 mL/kg, or
several ferritin levels > 1000 mg/L [18].
6. Iron chelators
Three chelators are currently available, deferoxam-ine
(Desféral® ), deferiprone (Ferriprox® ), and deferasirox (Exjade®
). Their main characteristics are indicated on Table 1.
Deferoxamine (DFO) was the first available iron chelator.
DFO is licensed both in thalassemia and in SCD.
Dose must be half the one indicated in Table 1 when the drug
is given in young children, because of concerns on growth.
Neurotoxicity (hearing, vision) must be checked yearly, espe-
cially when DFO is prescribed in patients with low iron overload.
The need to give the drug intravenously or subcutaneously over
Please cite this article in press as: Allali S, et al. Management of iron overload in hemoglobinopathies. Transfusion Clinique et Biologique
(2017), http://dx.doi.org/10.1016/j.tracli.2017.06.008
3
Deferiprone Deferasirox
139 373
Bidentate Tridentate
75–100 mg/kg/d 20–40 mg/kg/d
Oral Oral once daily
3 times daily
1.5–4 h 12–18 h
90% urinary 90% fecal
++
+ +++
Gastrointestinal upset, Gastrointestinal upset, rash, ocular,
arthralgia, neutropenia, auditory toxicity, reversible increases
agranulocytosis in creatinine, hepatitis
8–12 hours, 5 d/week makes chelation extremely burdensome
for patients, and explains the low adhesion to DFO treatment.
Deferiprone was the first available oral chelator. It is
indicated in France in patients with thalassemia when “the
current chela-tion is contra-indicated or not adapted”. It is
highly active on cardiac iron overload, the more when it is
combined with DFO. Deferiprone can induce neutropenia,
which requires a weekly checking of the neutrophil count. It is
not licensed for patients with SCD.
Deferasirox is indicated in thalassemic patients aged 6 years
and older and older than 2 years of age with post transfusional
iron overload when deferoxamine is “contra-indicated or not
adapted”, and then, it is licensed in SCD. Main side effects are
rash, gastrointestinal troubles, and a non-progressive increase in
serum creatinine levels in approximately 30% patients. Globally,
safety is good, as well in thalassemia than in SCD [19]. As taste
was poor the company has very recently proposed a new
formulation, which should be available soon in France.
Whatever the drug, compliance to daily chelation is limited
and benefits from therapeutic education programs and, most
likely, newly created serious games.
In conclusion, chelation is absolutely needed in chronic trans-
fusion program to prevent morbi-mortality, need which was well
known in thalassemia, and more recently evidenced in SCD.
Drugs are effective and relatively well tolerated, but this daily
treatment is fastidious and requires therapeutic education and,
often, psychological support to increase patients’ adhesion.
Disclosure of interest
M. de Montalembert and V. Brousse: have received grants
from Novartis and Addmedica.S. Allali, M. Chalumeau, Z.
Karim declare that they have no competing interest.
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