Seminar

Thalassaemia
Ali T Taher, David J Weatherall, Maria Domenica Cappellini

Inherited haemoglobin disorders, including thalassaemia and sickle-cell disease, are the most common monogenic Lancet 2018; 391: 155–67
diseases worldwide. Several clinical forms of α-thalassaemia and β-thalassaemia, including the co-inheritance of Published Online
β-thalassaemia with haemoglobin E resulting in haemoglobin E/β-thalassaemia, have been described. The disease July 31, 2017
http://dx.doi.org/10.1016/
hallmarks include imbalance in the α/β-globin chain ratio, ineffective erythropoiesis, chronic haemolytic anaemia, S0140-6736(17)31822-6
compensatory haemopoietic expansion, hypercoagulability, and increased intestinal iron absorption. The
Department of Internal
complications of iron overload, arising from transfusions that represent the basis of disease management in most Medicine, American University
patients with severe thalassaemia, might further complicate the clinical phenotype. These pathophysiological of Beirut Medical Centre,
mechanisms lead to an array of clinical manifestations involving numerous organ systems. Conventional Beirut, Lebanon
(Prof A T Taher MD); MRC
management primarily relies on transfusion and iron-chelation therapy, as well as splenectomy in specific cases.
Weatherall Institute of
An increased understanding of the molecular and pathogenic factors that govern the disease process have Molecular Medicine, University
suggested routes for the development of new therapeutic approaches that address the underlying chain imbalance, of Oxford, Oxford, UK
ineffective erythropoiesis, and iron dysregulation, with several agents being evaluated in preclinical models and (Sir D J Weatherall MD); and
Department of Clinical Sciences
clinical trials. and Community, University of
Milan, IRCCS Ca’Granda
Introduction sub-Saharan Africa, through the Mediterranean region and Foundation Maggiore
Since the first published description of severe thalass­ Middle East, to the Indian subcontinent and east and Policlinico Hospital, Milan, Italy
(Prof M D Cappellini MD)
aemia over 90 years ago by Cooley and Lee,1 several southeast Asia.8–14 Thus, over 90% of patients with these
Correspondence to:
accounts of the disease have been described and an disorders live in low-income and middle-income countries.
Prof Ali T Taher, Department of
extensive amount has been learnt.2–4 Although the cellular The number of patients with these diseases is expected to Internal Medicine, American
and molecular basis of this group of diseases was initially increase in the coming years as infant mortality from University of Beirut Medical
unknown, in the past 50 years a considerable amount has infectious and nutritional causes declines in many regions Center, PO Box 11–0236,
Beirut 11072020, Lebanon
been discovered to create a substantial body of work.5 of the world. As a result, when discussing management
ataher@aub.edu.lb
Using these resources we now have a refined under­ strategies, we will often focus on the current best practices,
standing of the pathophysiology of the thalassaemia but it is important for clinicians to be aware of the
syndromes. However, despite our understanding of the substantial limitations in implementing even these stan­
pathophysiology, management of these diseases has been dard therapies to many patients around the world. Therefore
complex and is progressing gradually.3,4 Additionally, the we will focus our discussion on the need for improved
available therapeutic routes for thalassaemias and the therapies, as well as on more standardised and easy-to-
complications that result from current treatments are few. implement strategies for use in resource-poor countries. It
Although a great deal of excitement has developed around should also be noted that because of continued migration,
newer therapeutic approaches and potential curative these diseases are now becoming increasingly common in
strategies,6 much remains to be understood about the large multiethnic cities in Europe and North America,
clinical variability of these disorders, the natural history of making it a global health concern.15–18
the thalassaemia syndromes, and the optimal use of the
currently available treatments. In this Seminar, we aim to Molecular and clinical forms
provide an overview of the thalass­aemia syndromes and At the molecular level, haemoglobin synthesis is controlled
comprehensively discuss our current approach to the by two multigene clusters on chromosome 16 (encoding
clinical management of these diseases. As will become
evident, this under­standing is crucial to ensuring that
new therapies can be effectively integrated into the Search strategy and selection criteria
repertoire of existing management strategies. We searched PubMed using the terms “thalassaemia OR
Thalassaemia, sickle-cell disease, and other inherited thalassemia” in combination with “molecular” or
haemoglobin disorders are the most pervasive mono­ ­ “epidemiology” or “diagnosis” or “pathophysiology” or
genic diseases worldwide. The high frequency of in­ “clinical complications” or “treatment OR management”.
herited haemoglobin variants in certain regions reflects We limited our search to publications in English. We mostly
their heterozygote resistance to Plasmodium falciparum selected publications from January, 2006, to May, 2017, but
malaria, and extensive studies7 have shown that this did not exclude frequently referenced and highly regarded
resis­tance is certainly the case for α-thalassaemia, older publications. We also searched the reference lists of
β-­thalassaemia, and haemoglobin E. An estimated 1–5% of articles identified by this search strategy and selected the
the global population are carriers for a genetic thalassaemia most relevant ones. Review articles and book chapters are
mutation.8–14 Although the epidemiology of the various cited to provide readers with more details and more
clinical forms remains poorly recognised, the disease is references than can be addressed in this Seminar.
known to be highly prevalent in the area extending from

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 Seminar

the α-like globins) and on chromosome 11 (encoding the
β-like globins; figure 1).19,20 The genes in such clusters are
arranged along the chromosome in the order that they are
expressed during development to produce different
haemoglobin tetramers during embryonic, fetal, and adult
life. The high homology of the α-globin genes can result
in unequal-meiotic cross­over, which is the basis for the
deletions that cause the α-thalassaemias discussed later in
this section. Within the β-globin gene cluster, the ε-gene is
expressed only in early embryos, and downstream from
this gene are two γ-genes, the product of which is found in
fetal haemoglobin (Hb F, α2γ2)—the haemoglobin form
that predominates throughout most of gestation. The
δ-gene product forms a minor haemoglobin component,
Hb A2 (α2δ2), which is useful in the diagnosis of the
thalassaemias. The β-gene product combines with
A α-thalassaemias or β-thalassaemias. The type and severity
5’
IVS-I
ξ ψξ ψ α 1 α 2 α 1
5’
16
5’ ψβ 2 ε Gγ Αγ ψβ 1
α-globin to form Hb A (α2β2), the major haemoglobin
component of adult red blood cells. During the first
month of gestation, embryonic haemoglobins β2ε2, α2ε2,
and β2γ2 are formed in erythroid cells located primarily in
the yolk sac. During the remainder of fetal life, the sites of
erythropoiesis gradually shift from the liver and spleen to
the bone marrow, with red blood cells mainly containing
Hb F (α2γ2). A switch from γ-globin to β-globin expression
begins before birth and completes by the time the baby
reaches 6 months of age. After this time over 95% of the
haemoglobin in normal red blood cells is adult Hb A
(α2β2), with the remaining haemoglobin consisting of two
minor components, Hb A2 and Hb F.19,20 Hb F is usually
confined to a small number of red blood cells known as
F cells. Underlying molecular defects in the α-globin or
β-globin gene clusters form the basis of defective
haemoglobin synthesis and the various inherited forms of
3’ of these clinical forms can also rely on additional and
IVS-II independent intrinsic and extrinsic factors, which will be
explained in this section. The thalassaemias can also
manifest from co-inheritance of β-thalassaemia and
3’ structural haemoglobin variants like haemoglobin S, C,
and E.11,21 Several clinically recognisable forms of
5 kb
haemoglobin S/β-thalassaemia and haemoglobin
C/β-thalassaemia exist, each of which have unique
δ β 3’
character­istics and management peculiarities;20 however,
these will not be covered in this seminar.

11 β-Thalassaemia
5’ IVS-I IVS-II 3’
Patients with β-thalassaemia have been typically cate­
gorised as minor, major, or intermedia on the basis of
their α-globin or β-globin chain imbalance, severity of
B
50 anaemia, and clinical picture at presentation. Over
α 200 mutations in the β-globin gene that cause disease
γ β have been recognised, ranging from silent mutations
40
(silent β), to mild mutations that cause a relative reduction
Total globin synthesis (%)

in β-globin chain production (β+), to severe mutations that

30
result in complete absence of β-globin chain synthesis
(β0), with deletions of the gene being uncommon.22
20 ε
β-Thalassaemia minor (trait or carrier) represents the
heterozygous inheritance of a β-thalassaemia mutation,
10 ξ
β with patients often having clinically-asymptomatic-micro­
γ
cytic anaemia, although others can have no identified
6 12 18 24 30 36 1 6 12 18 24 30 36 42 48 haematological abnormalities—so-called silent carriers.
Patients with β-thalassaemia major usually present with
Postconceptual age (weeks) Birth Postnatal age (weeks)
severe anaemia in infancy and become transfusion
Yolk sac Site of erythropoiesis dependent for life, whereas patients with β-thalassaemia
intermedia can present later in life with mild-to-moderate
Liver Bone marrow anaemia and variable transfusion requirements.23–25 Both
β-thalassaemia major and intermedia can result from the
Spleen homozygous or compound-heterozygous inheritance of
mutations in the β-globin gene.
Figure 1: Globin synthesis at the molecular level Several modifications can result in patients having
(A) Organisation of the α-globin family on chromosome 16 and the β-globin family on chromosome 11.
(B) The sites of erythropoiesis and the pattern of globin synthesis during development. ψ designates
β-thalassaemia intermedia rather than major, including
non-expressing pseudogenes. The three exons of the globin genes are shown in pale blue. Reproduced from the extent of the α-globin to β-globin chain imbalance,
Bunn and colleagues19 with permission from McGraw-Hill Education. IVS=intervening segments (or introns). ineffectiveness of erythropoiesis, and the resulting

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anaemia. The primary modifier is the severity of the
mutation or mutations in the β-globin gene. Secondary
modifiers include co-inheritance of α-thalas­saemia, and
increased synthesis of γ-chains and fetal haemoglobin
production after infancy.22–26 Some rare forms of
β-­thalassaemia intermedia result from deletions removing
the upstream-regulatory elements, but leaving the globin
genes intact. Other rare mutations linked on the same
chromosome have been important in developing our
understanding of how the switch from γ-globin to β-globin
gene expression is regulated. All these mutations result in
variable concentrations of increased γ-globin expression
and increased concentrations of fetal haemoglobin, leading
to what is known as hereditary persistence of fetal
haemoglobin. Other forms of hereditary persistence of
fetal haemoglobin result from deletions removing the
adult δ-globin and β-globin genes, but leaving at least
one γ-globin gene intact (δβ-thalassaemia).19,20 Tertiary
modifiers include genetic and environmental factors
that alter specific complication rates.23–25,27 β-Thalassaemia
intermedia might also result from the increased production
of α-globin chains by a triplicated or quadruplicated
α-genotype associated with β-heterozygosity, or when a
single β-globin locus is affected and the other is completely
normal (dominant inclusion body β-thalassaemia).23–25
When β-thalassaemia is co-inherited with the structural
variant haemoglobin E (haemoglobin E/β-thalassaemia),
which results in β-globin chain synthesis similar to a mild
β-gene mutation, the resulting clinical forms can also be of
varying severity depending on age and the degree of
anaemia at presentation. The clinical forms of haemoglobin
E/β-thalassaemia are commonly classified as mild,
moderate, and severe, with the severe form being similar
to β-thalassaemia major, and the mild and moderate forms
being similar to β-thalassaemia intermedia.28,29 The same
primary, secondary, and tertiary genetic and environmental
modifiers are also relevant in the case of haemoglobin
E/β-thalassaemia, and influence the clinical severity of
the disease.30,31
α-Thalassaemia
α-Thalassaemia has two main forms, α+-thalassaemia
and α⁰-thalassaemia, and their classifications depend
on whether one or both of the linked α-globin genes
are deleted or reduced in activity by mutation. The two
common forms of α+-thalassaemia are designated –α³·⁷
and –α⁴·² to describe the lengths of the underlying
deletions. α+-Thalassaemia has several forms that result
from point mutations, the most common being caused
by the chain-termination mutant haemoglobin Constant
Spring, designated αCSα. In their heterozygous state
these conditions are silent and in their homozygous state
they are characterised by mild-hypochromic anaemia.
α⁰-Thalassaemias are usually caused by the deletion of
both the linked α-globin genes and are designated by the
place of discovery of the first case (eg, –Med and –SEA,
reflecting the first cases to have been found in the
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Seminar
Mediterranean region and southeast Asia). The
compound heterozygous states for α+-thalassaemia and
α⁰-thalassaemia, –α/— or αCSα/—, result in a large excess
of β-chain production with the formation of β4 tetramers,
designated as haemoglobin H. These β4 tetramers are a
highly unstable variant of the β-chain and they precipitate
in red blood cells causing haemoglobin H disease,
which is characterised by variably severe haemolysis
and consequent anaemia. The homozygous state for
α⁰-thalassaemia, —/—, results in the production of
tetramers of γ-chains (γ4) known as haemoglobin Bart’s,
named after the hospital in London, UK, where it was
first discovered. This homozygous state of α⁰-thalassaemia
is associated with a condition called haemoglobin Bart’s
Hydrops fetalis, which is usually characterised by death
in utero or just after birth. Rarer causes of α-thalassaemias
include deletions or mutations of regulatory mutations
involving the α-globin gene cluster.4,17
There is another group of α-thalassaemias that, unlike
those described above, occur in no particular ethnic
groups. They are described under the general title of
α-thalassaemia and mental retardation. One thalassaemia
in this group is known as ATR-16 syndrome. This
syndrome involves the whole α-globin gene complex on
chromosome 16 and is associated with mild-to-moderate
mental retardation. Another member of this group is
known as α-thalassaemia X-linked intellectual disability
(ATRX) syndrome and results from mutations of the ATRX
gene leading to severe developmental abnormalities, facial
dysmorphism, and other disorders in addition to its
α-thalassaemia phenotype. Finally, there is another form of
mild hemoglobin H disease that occurs predominantly in
men and is associated with a form of myelodysplastic
syndrome and pre-leukaemia, which has also been found
to be associated with mutations involving ATRX.17
Screening and diagnosis
Screening and prevention programmes for thalassaemia
are now widespread, with their adoption being dependent
on regional distribution and cultural factors. Programmes
of nationwide screening, and premarital and neonatal
screenings have been implemented. Confirmation of a
thalassaemia diagnosis requires analysis of red blood
cells combined with haemoglobin electrophoresis, with
DNA analysis required to confirm the diagnosis of
α-thalassaemia and haemoglobin E. Specific guidance on
the pathway to establish a thalassaemia diagnosis has
been reviewed elsewhere and is available from recent
clinical management guidelines.23,32,33
Clinical classification
Over the past decade, a gradual transition in the labelling
of the thalassaemias has occurred, moving away from the
molecular forms to a more simplified categorisation
largely based on clinical-management criteria. Transfusion
therapy remains the basis of management for these
disorders, and the frequency and magnitude of transfusion
 Seminar
Iron overload
α/β-Chain imbalance Ineffective erythropoiesis
Anaemia
Figure 2: Pathophysiology of patients with thalassaemia syndromes
requirements indirectly reflects the underlying severity of
the disease. Moreover, transfusion therapy is not only able
to control most of the underlying pathophysiological
mechanisms but it also contributes a great deal to
secondary morbidity.23,33 Thus, patients today are com­
monly categorised as having transfusion-dependent
thalassaemia (TDT)—patients who are not capable of
producing sufficient haemoglobin to survive without
blood transfusions—or non-transfusion-dependent
thalassaemia (NTDT).23,33 However, several points of
caution should be highlighted when using such cate­
gorisations. For instance, patients with NTDT can still
require transfusion therapy sporadically, or even regularly,
but not for their entire lifetime. This treatment would be
for the prevention or management of certain disease
manifestations—and will be illustrated in subsequent
sections—whereas patients with TDT require lifelong
transfusion treatment for survival. Patients with
β-thalassaemia intermedia, haemoglobin H disease, and
mild-to-moderate forms of haemoglobin E/β-thalassaemia
often fall under the classification of NTDT; whereas
patients with β-thalassaemia major and severe forms of
haemoglobin E/β-thalassaemia are classified as having
TDT.23,24,33 Additionally, it should be noted that some
patients categorised as having TDT might have been
misclassified. For instance, if transfusions had been
started to treat low haemoglobin concentrations as a result
of an acute complication (eg, an infection) in childhood,
and the patient’s transfusion requirements had not been
revisited and the transfusions thus never halted.34 Also, it
should be highlighted that TDT and NTDT are fluid
categories based on clinical variables and a patient
might move from one group to another as a result of
variations and advances in clinical management, or
because of changes in other disease modifiers—thus
these designations should primarily represent a patient’s
current clinical status with the understanding that the
categories are interchangeable.23,24,33,34
Pathophysiology and associated morbidity
The underlying disease process in patients with thalass­
aemia remains similar for those patients categorised as
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Marrow expansion and bone disease
Extramedullary haemopoiesis and organomegaly
Organ damage
(heart, liver, endocrine)
Peripheral haemolysis and gall stones
Hypercoagulability and vascular disease
having NTDT or TDT, and the role of transfusion therapy
in ameliorating much of these pathogenic mechanisms
(while introducing other secondary complications) is best
illustrated in studies showing the different morbidity
profile between the two catagories.24,35 The hallmarks of
the disease—with or without treatment—are the α-globin
or β-globin chain imbalance leading to ineffective erythro­
poiesis, an array of subsequent pathophysiological mecha­
nisms, and a multimorbidity profile (figure 2).24,36 In
β-thalassaemia, accumulation of unstable α-globin chain
tetramers in erythroid cells leads to premature cell death
inside (ineffective erythropoiesis) and outside (peripheral
haemolysis) the bone marrow, facilitated by reactive-
oxygen-species formation and structural-membrane de­
formities leading to senescence-antigen exposure.37,38 The
immediate resulting manifestation is chronic-haemolytic
anaemia that can result in acute compli­cations such as
cholelithiasis and short-term and long-term detrimental
effects on growth, organ, and vascular function.39 In­
creased proliferation of erythroid precursors in the bone
marrow leads to medullary expansion and subsequent
bone deformities and low bone mass.37 Compensatory
haemo­poietic points out­side the bone marrow are also
activated, primarily in the spleen (splenomegaly) and liver
(hepatomegaly), but can also be activated in any body
tissues with haemopoietic potential, leading to the
formation of extramedullary pseudotumours in high-risk
anatomic locations such as the spinal canal.40 The ex­
posure of erythroid cells to senescence antigens, such
as phosphatidylserine, during ineffective erythro­poiesis
gives them prothrombotic potential. Alongside other
abnor­ malities in platelets and the coagulation system,
hyper­coagulability and associated vascular mani­festations
like venous thrombosis and pulmonary hypertension are
commonly seen in patients with thalassaemia, especially
in patients who have been splenectomised and in whom
such markers are further elevated.41 Finally, ineffective
erythropoiesis results in increased iron absorption and
primary iron overload mediated by the hepatic hormone
hepcidin. An erythroid factor has been postulated as
communicating to the liver the need of iron for the
incoming red blood cells. This factor would be produced

by erythroid cells, especially under the condition of
ineffective erythro­poiesis, and acts to suppress hepcidin
synthesis in the liver, leading to increased intestinal iron
absorption and increased release of recycled iron from the
reticulo­endothelial system. Various erythroid factors have
been investigated, including growth differentiation factor
15 (GDF15), twisted-gastrulation 1 (TWSG1), and erythro­
ferrone (ERFE); although only ERFE was shown to be
increased in animals with β-thalassaemia compared with
those without β-thalassaemia.42,43 Such iron overload
concen­trations can reach clinically significant thresholds
and lead to morbidities in various organ systems,
especially the liver.44 Notably, both anaemia and iron
overload can also further worsen ineffective erythropoiesis
and complicate patho­ physiology.42,43 In patients with
α-thalassaemia, the concepts of α-chain to β-chain
imbalance and ineffective erythropoiesis is similar to
β-thalassaemia. β-Globin chains can form soluble
tetramers—β4, or haemoglobin H—that precipitate within
the cell forming insoluble inclusions (Heinz bodies) that
damage the red blood cell’s membrane. Although
downstream manifestations like primary iron overload
and hypercoagulability exist, they tend to be milder in
patients with α-thalassaemia than in patients with
β-thalassaemia, and the key pathological mechanism is
peripheral haemolysis and chronic anaemia, rather than
ineffective erythropoiesis, as is seen in patients with
β-thalassaemia.24,36
Since adequate and regular transfusion therapy can be
considered part of the disease profile of patients with
TDT, it is fair to say that the majority of these patho­­
genic mechanisms and associated morbidities are more
commonly encountered in patients with NTDT.24,35
Whereas adverse transfusion-related complications, in­
cluding secondary-iron overload and subsequent organ
dysfunction, have become hallmarks of clinical mor­
bidity in well transfused patients with TDT.45 Clinical
aspects of all such morbidities in patients with thalass­
aemia are further highlighted in the relevant manage­
ment sections below.
Conventional management
Without intervention, any form of thalassaemia (excluding
carrier status) is a progressive disease with increased
morbidity as the patient advances in age.46 Moreover, the
availability of effective therapeutic options and improved
patient survival could allow multiple morbidities to
manifest with age and the quality of life of the patient to
deteriorate.47,48 Adult and elderly patients (older than
40 years) with thalassaemia should also be considered at
risk of diseases that are common in non-thalassaemic
populations, such as cancer and cardiovascular disease.
Management guidelines for both patients with TDT and,
more recently, NTDT, are available as part of the global
efforts of the Thalassaemia International Federation
to improve the outcomes of patients affected by these
disorders.23,33
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Seminar
Transfusion
Transfusion therapy works by supplying normal
erythrocytes and suppressing ineffective erythropoiesis,
essentially controlling all downstream pathophysio­
logical mechanisms in thalassaemia.49–51 Advances in
transfusion and iron-chelation therapy were associated
with improvements in survival in long-term follow-up
studies evaluating different birth cohorts of patients with
β-thalassaemia major.52,53 Blood product screening,
preparation, and administration practices have largely
improved over the past 3 decades,53,54 and nowadays most
patients with TDT can successfully achieve target
haemoglobin concentrations of 90–105 g/L (110–120 g/L
in those with heart disease); although access to blood for
transfusion therapy remains a challenge in resource-
poor countries and poses a substantial public health
burden.33 In patients with NTDT, however, the indicators
for when blood transfusion is necessary are not as well
established, although increased morbidity has been
identified in patients with β-thalassaemia intermedia
who have haemoglobin concentrations of less than
100 g/L.39 Transfusions are sporadically given to patients
when under acute stress or experiencing a drop in
haemoglobin concentration, such as during infections,
pregnancy, or surgery. Some patients are maintained on
a regular transfusion programme following these
incidents—a practice that in many cases might not be
clinically indicated. Haemoglobin concentrations in
isolation should not be an indication for lifelong, regular
transfusions in patients with NTDT, especially given that
many patients can adapt to their chronic anaemia without
substantial bone marrow stress.55,56 Nonetheless, a role
for regular transfusion therapy for a period of months or
years has been established in patients with NTDT.
Although data have emerged from obser­vational studies
reporting improved growth variables in children, and a
lower proportion of morbidities in regularly transfused
adults than in those not regularly transfused, especially
in patients with β-thalassaemia intermedia patients,
including leg ulcers, throm­ botic events, pulmonary
hypertension, silent strokes, and extramedullary-­
haemopoietic pseudo­tumours.23,34,55–61 Collectively, these
data might explain the differential clinical picture and
increased proportion of such mor­bidities in patients with
NTDT than in those with TDT.24,25,35 Transfusion therapy,
however, does not come without its own side-effects.
Although the risks of alloimmunisation and blood-borne
infection remain a concern in transfused patients, the
greatest challenge with regular transfusion therapy is
secondary-iron overload.23,33
The human body has no means to excrete iron.
Transfused blood contains around 200–250 mg of iron
per unit. Patients receiving 2–4 units of blood per month
will have an annual accumulation of 5000–10 000 mg of
iron or 0·3–0·6 mg/kg per day.33,62 With continued
transfusions, the reticuloendothelial system—primarily
in the liver—can no longer retain all the extra iron.
 Seminar
Iron then enters the plasma in amounts that exceed
the transport capacity of circulating transferrin.
Consequentially, non-transferrin-bound iron exists in
the plasma as a heterogeneous mixture of iron complexes
that appear to be the major mediators of hepatic and
extrahepatic tissue damage in transfusional iron
overload.63 Non-transferrin-bound iron enters specific
cells, particularly hepatocytes, cardio­myocytes, anterior
pituitary cells, and pancreatic β cells. In these cells iron
accumulation leads to the generation of reactive-oxygen
species, resulting in damage to lipids, proteins, DNA,
and subcellular organelles, including lysosomes and
mitochondria. This injury can result in cellular
dysfunction, apoptosis, and necrosis that translates into
target organ toxicity and dysfunction.63 The clinical
burden of iron overload and its management are further
illustrated in the following section.
Iron chelation
Whether iron overload develops from increased intestinal
absorption—such as in patients with NTDT—or is
secondary to regular transfusions, it can cause substantial
morbidity and mortality, and so warrants prompt diag­
nosis and effective management. In patients with TDT,
iron accumulation in organ tissues is evident in children
aged as young as 2–6 years,64–67 with cumulative iron
overload subsequently leading to organ toxic-effects and
dysfunction, for instance in the heart, liver, or endocrine
glands.33 Cardiomyopathy has been the leading cause of
death in patients with TDT,33,52 although more recently
large cohort studies68 have also highlighted the high
incidence of mortality from hepatic causes in patients
with TDT. Iron overload in patients with NTDT is a
cumulative process with advancing age, and concerns
over secondary morbidities start beyond the ages of
10–15 years.24,46,69,70 Although cardiac iron overload is
commonly absent in patients with NTDT,71–74 an association
between iron overload and hepatic fibrosis has been
observed in patients with β-thalassaemia intermedia,75
and the occurrence of hepatocellular carcinoma is
increasingly being reported.76 Cumulative iron overload in
patients with NTDT also increases their risk of developing
thrombosis, pulmonary hypertension, silent strokes,
hypo­­thyroidism, hypogonadism, osteo­porosis, and renal
disease, as is evident from studies in patients with
β-thalassaemia intermedia.61,69,77–81
Several methods are currently available for the diagnosis
and monitoring of iron overload in patients with TDT and
NTDT. Serum ferritin assessment is widely available and
might be the only assessment that is affordable in
resource-poor countries. The assessment of serial serum
ferritin concentrations can be a good indicator of iron
chelator effectiveness,33 and available guidelines recom­
mend measurement of serum ferritin concen­trations
every 3 months.23,33,82 Serum ferritin thresholds are
commonly used to indicate the need for initiation or
modification of iron-chelation therapy. In patients with
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TDT, maintaining concentrations lower than 1000 μg/L of
ferritin is associated with lower morbidity and mortality,
and this threshold is most commonly used to indicate the
need for initiation of iron-chelation therapy.33,52,83,84 Serum
ferritin concentrations consistently higher than 2500 μg/L
are associated with an increased risk of cardiac and
endocrine disease, and thus are commonly used to flag
the need for dose optimisation or a change in iron-
chelation therapy.33,83,84 However, although the association
of high serum ferritin concentrations with hepatic
siderosis is usually clear, a study85 using imaging tech­
niques to evaluate organ-specific iron overload failed to
establish an association between serum ferritin concen­
trations and cardiac siderosis. Moreover, single measure­
ments of serum ferritin concentration are prone to
mis­interpretation or not being representative of a patient’s
condition, considering their high variability when a patient
is experiencing inflammation, infection, vitamin C
deficiency, hepatic dysfunction, and severe iron overload
with values higher than 4000 μg/L.33,86 This high variability
suggests that, when available and affordable, the use of
imaging to evaluate organ-specific siderosis should be
recommended.33 Worth mentioning is that several case
reports on patients with NTDT have confirmed that serum
ferritin concentrations are commonly lower than in
patients with TDT with the same hepatic iron concen­
tration.87 In patients with NTDT (patients with
β-­thalassaemia intermedia), concentrations of greater
than 800 μg/L are associated with an increased risk of
morbidity, and concentrations of less than 300 μg/L are
associated with an absence of risk of morbidity. These
thresholds are thus used to indicate the need for iron
chelation initiation or interruption.23,69
Measurement of liver iron concentration has become
common practice since the early 2000s, considering the
strong correlation with total-body iron stores.88 Initial
reports relied primarily on the use of liver biopsy, although
the technique is now used less frequently and only
reserved for those situations when assessment of hepatic
histology is needed.89 The use of a Superconducting
Quantum Interference Device (SQUID) is also still
practised, but the technology is only available in few
centres worldwide.33,90 The introduction of MRI for the
non-invasive assessment of liver iron concentration, and
later myocardial iron concentration, is considered one of
the most important advances in thalassaemia care over
the past decade. The use of MRI in clinical practice can
allow better tailoring of iron-chelation therapy. For
measurement of liver iron concentration, both the R2 and
T2* techniques are used as they have been validated
against liver biopsy measurements of iron.91,92 They are
internationally reproducible and accurately measure liver
iron concentration throughout the clinically relevant
range with appropriate calibration and MRI acquisition
techniques, and give a measurement of liver iron
concentration in mg of iron per g of dry liver weight.93,94
They are also equally effective in evaluating chronic
 Seminar

Deferoxamine Deferiprone Deferasirox

Administration33
Method Subcutaneous or intravenous Oral Oral
Frequency 8–12 h, 5–7 days per week 3 times daily Once daily
Half-life of iron-free drug33 20–30 min 3–4 h 12–16 h
Lipid solubility33 Low Intermediate High
Route of iron excretion33 Urinary and faecal Urinary Faecal
Recommended dose23,33 30–60 mg/kg per day 75–100 mg/kg per day TDT: 20–40 mg/kg per day; NTDT: 5–20 mg/kg per day
TIF guidelines indication
TDT33 >2 years: first-line 2–6 years: no sufficient data; >6 years: second-line† 2–6 years: first-line (USA), second-line (EU); >6 years: first-line
NTDT23 No sufficient data No sufficient data >10 years: first-line
Most relevant clinical data
TDT33 Reduction in serum ferritin and liver Improvement of cardiac T2* in monotherapy or in Reduction in serum ferritin and liver iron concentration after
iron concentration;108 improvement combination with deferoxamine (higher doses than up to 5 years, and cardiac T2* after up to 3 years of therapy,
in cardiac T2*;108 improvement in commonly used in clinical practice)‡;110,111 improvement in even in patients with severe iron overload;115–118 not inferior to
cardiac dysfunction with continuous cardiac dysfunction in combination with deferoxamine†‡;112 deferoxamine for improving cardiac T2*;108 improvements in
infusion109 improvement in endocrine dysfunction in combination hepatic fibrosis and inflammation;119 stabilisation of heart
with deferoxamine or deferasirox113,114 function;108,115 stabilisation of endocrine function120
NTDT23 Data restricted to case series and Data restricted to case series and small studies Significant reduction in serum ferritin and liver iron
small studies concentration after up to 2 years of therapy121
Main adverse events33 Ocular and auditory symptoms, Gastrointestinal symptoms, arthralgia, agranulocytosis or Gastrointestinal symptoms, increased creatinine, increased
bone-growth retardation, local neutropenia hepatic enzymes
reactions, allergy
Pregnancy33 Contraindicated (but has been used Contraindicated Contraindicated
in third trimester)

TDT=transfusion-dependent thalassaemia. NTDT=non-transfusion-dependent thalassaemia. TIF=Thalassaemia International Federation. †In a recent Cochrane review122 it was concluded that in the absence of data
from randomised controlled trials, there is no evidence to suggest the need for a change in the current treatment recommendations. Specifically, deferiprone is indicated for treating iron overload in patients with
thalassaemia major when deferoxamine is contraindicated or inadequate. Intensified deferoxamine treatment, use of other oral iron chelators, or both, remains the established treatment to reverse cardiac
dysfunction due to iron overload. ‡Despite results of some trials110,111 indicating the superiority of deferiprone, or its combination with deferoxamine, compared with deferoxamine monotherapy in improving cardiac
T2*, a meta-analysis123 concluded that deferoxamine and deferiprone monotherapy appeared to reduce myocardial iron by similar amounts. Moreover, the addition of deferiprone to deferoxamine in a recent study124
did not enhance its ability to improve cardiac dysfunction compared to monotherapy. There is an urgent need for high-quality trials to compare the overall clinical efficacy and long-term outcome of treatment with
deferiprone combined with deferoxamine.122

Table 1: Characteristics and evidence on iron chelators for the management of iron overload in thalassaemia

response to iron chelation.95,96 R2 MRI has also been
validated in patients at different stages of liver fibrosis
and grades of liver inflammation and the technique
(FerriScan®, Resonance Health, Burswood, WA,
Australia) is approved by the US Food and Drug
Administration.94 Cardiac T2* MRI is used for the
assessment of cardiac iron (values in ms), with recent
validation against myocardial iron concentration in mg of
iron per g of dry heart weight from post-mortem cardiac
biopsies.97 The use of both techniques to evaluate iron
content in other organs—such as the endocrine gland—
has also been investigated, although they are less
commonly used in routine practice.98–100 Certain liver iron
concentrations and cardiac T2* thresholds have been
linked to morbidity in patients with thalassaemia. In
patients with TDT, liver iron concentrations greater than
7 mg/g are usually used to indicate increased risks of
complication, and lower target concentrations are used to
prevent iron-related complications, although this evidence
has mainly been extrapolated from patients with here­
ditary haemochromatosis.101–103 Concentrations greater
than 15 mg/g are associated with progressive liver fibrosis
and cardiac mortality. Cardiac T2* values of less than
20 ms are indicative of a declining left ventricular ejection
fraction and associated with arrhythmias, whereas values
of less than 10 ms are associated with clinical heart failure
and mortality.104–106 Thus, these thresholds are commonly
used to determine a patient’s iron-overload profile, to
evaluate their response to iron-chelation therapy in clinical
trials, and to tailor their chelator type and dose in routine
practice.33,107 In patients with NTDT (β-thalassaemia inter­
media), liver iron concentration values higher than 5 mg/g
are associated with increased morbidity,78 supporting the
recommendation of iron-chelation initiation in patients
showing liver iron concentrations greater than 5 mg/g.23 It
should be noted that patients with α-thalassaemia do tend
to show slower rates of iron overload than patients with
other NTDT forms, and lower-intensity iron chelation
standards are usually considered. Most available guide­
lines recommend assessment every 6, 12, or 24 months
depending on iron-overload severity and iron-chelation
adjustment needs.23,33,82
Three iron chelators are currently available for the
treatment of iron overload in patients with thalassaemia:
deferoxamine in subcutaneous or intravenous injection,
oral deferiprone in tablet or solution form, and oral
deferasirox in dispersible tablet and, more recently, film-
coated tablet forms (table 1), and guidelines for their use

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 Seminar

Splenectomy
Assessment considerations (indication) Management considerations
Splenectomies have traditionally been performed as an
Cardiac dysfunction Echocardiography (routine), As per standard care alternate or adjunct to transfusion therapy. Although
and arrhythmia electrocardiogram (routine)
some studies have found that splenectomies have
Pulmonary Tricuspid regurgitant jet velocity (routine), As per standard care, sildenafil citrate,
hypertension right-heart catheterisation (high risk) bosentan resulted in improvements in growth, quality of life, and
Cerebrovascular MRI and MRA (high risk) As per standard care, antiplatelet
haemoglobin concentration for some patients with
events prophylaxis haemoglobin E/β-thalassaemia.127 The procedure has
Venous thrombosis Standard imaging (suggestive of signs and Anticoagulant therapy, medical and now become almost obsolete in patients with TDT,
symptoms) surgical prophylaxis especially in the context of improved access to and safety
Leg ulcers Physical examination (routine) Topical measures, pentoxifylline, of blood transfusions with regards to blood-borne
hydroxycarbamide, hyperoxygenation infections. The procedure is still more commonly used
Viral hepatitis Viral serology (routine in transfused Hepatitis B vaccination, antiviral in patients with NTDT, because it might be enough to
patients), viral RNA-PCR (if positive serology) therapy
improve mild-to-moderate anaemia and avoid the need
Hepatic fibrosis, Live function tests (routine), ultrasound (high As per standard care
cirrhosis, and risk), α-fetoprotein (high risk), transient for transfusions.25,31,34,57,58 However, data for serious
cancer elastography (investigational) adverse events caused by splenectomies continue to
Endocrine disease Growth retardation (routine), sexual As per standard care accumulate in the thalassaemia patient population,
development (routine), endocrine-function alongside the known risk of infection and sepsis.
tests (routine), bone-mineral density (routine)
Removal of the spleen promotes a hypercoagulable state
Bone disease Bone-mineral density (routine) As per standard care, bisphosphonates
in thalassaemia because of the decreased ability to
Pregnancy As per high-risk pregnancy Revisit iron chelation, anticoagulation scavenge procoagulant red blood cells and activated
prophylaxis, maintenance of
haemoglobin concentration and platelets. Observational studies have further established
heart function that splenectomised NTDT patients are at a 4–5 fold
Extramedullary Physical exam and imaging to rule out Hypertransfusion, radiation, surgery increased risk of overt venous thrombosis and other
haematopoietic compression (suggestive signs and symptoms) vascular manifestations like pulmonary hypertension,
pseudotumours
leg ulcers, and silent strokes than non-splenectomised
Haemolytic crisis Infection screening, electrolytes Adequate hydration, correction of
(haemoglobin H blood electrolytes, control body
patients.60,61 In patients with β-thalassaemia intermedia,
disease) temperature, antibiotics or antivirals the long-term risk of thrombosis is further increased in
those with concomitant high counts of nucleated red
The frequency and age at the start of assessment should rely on the underlying diagnosis and individual patient’s
blood cells (≥300 × 10⁶ cells per L) and platelets (≥500 × 10⁹
needs. Further management details are available in the respective Thalassaemia International Federation guidelines.23,33
MRA=magnetic resonance angiography. platelets per L), and those patients who never received
any transfusions.128 The spleen also usually acts as a
Table 2: Management considerations for specific morbidities in thalassaemia patients beyond
reservoir for scavengers of toxic iron in the body, and so
transfusion and iron chelation
removal of the spleen could also decrease the ability of
these scavengers, thus putting patients at increased risk
are now widely available.23,33,82 Data from several large, of end-organ damage.60 The current recommendations
randomised trials since the development of MRI for splenectomy are restricted to those patients with an
technology showed the efficacy and safety of oral-iron- inability to receive transfusion and iron-chelation therapy,
chelation therapy in removing iron from the liver and as well as those with clinically symptomatic spleno­
heart, which represents a considerable advance in patient megaly or hyper­splenism.23,33 When indicated, appro­
management owing to the greater convenience compared priate treatment with vaccination and antibiotics is
to parenteral deferoxamine. However, parenteral deferox­ recommended, and prophylaxis with aspirin or low-
amine remains the treatment of choice in patients with molecular weight heparins for high-risk patients.23,33
decompensated heart disease, and might be the only
affordable option in resource-poor countries.33 None­ Management of specific morbidities
theless, the search for other novel iron chelators that can Prevention of morbidity in patients with thalassaemia
address the specific efficacy or safety shortcomings of starts with appropriate and adequate application of
these chelators continues.33 Moreover, successful conventional therapies including transfusion or iron
manage­ment of iron overload extends beyond chelator chelation, or both.23,33 Special clinical considerations and
efficacy and safety. Ensuring adherence to treatment is management options beyond conventional therapy are
essential, and applicable to most chelators irrespective of summarised in table 2 for key clinical complications.
their administrative form. Adherence to iron-chelation
therapy correlates with both effective management and Haemopoietic stem-cell transplantation
patient survival, as is evident from several studies.125,126 Replacement of mutant haemopoietic cells using
Moreover, appropriate dose determination and adjust­ haemopoietic stem-cell transplantation is the only
ment of the iron chelator according to baseline and existing curative therapy for thalassaemia and is now an
ongoing iron intake is essential to ensure adequate established approach to correct defective erythropoiesis,
response and avoid overchelation.33 particularly when matched sibling donors are available.

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Sotatercept
Luspatercept
↑ ROS
↑ GDF11
↓ Differentiation
α/β-Chain imbalance
↑ Proliferation
Gene therapy JAK2 inhibitors ↑ EPO
Gene editing
Figure 3: Novel targets and therapies for patients with β-thalassaemia
EPO=erythropoietin. ROS=reactive-oxygen species.
Haemopoietic stem-cell transplantation is now widely
applied with a disease-free survival exceeding 80%
with transplants from HLA-matched-sibling donors.129
Moreover, improvements in the management of graft-
versus-host disease and inducing graft tolerance have
encouraged the use of unrelated donors and umbilical-
cord blood as the haemopoietic stem-cell source for
patients who do not have a matched-sibling donor.
Nevertheless, matched-unrelated transplants for high-
risk patients with thalassaemia have an overall survival
of 65%. However, a 5–10% mortality from transplant
conditioning, graft-versus-host disease, and graft failure
continues to limit the acceptability of this treatment
method. The need for complete myeloablation, which
can result in infertility and other toxic-effects, is also a
concern, although improved approaches with reduced-
intensity conditioning are being developed.130 Clinical
guidelines specific to patients with thalassaemia are now
available.129
Future outlook
In the past decade several promising targets and
associated therapeutic options have emerged for patients
with thalassaemia, though primarily for those with
β-thalassaemia, which is reasonable considering the
patient’s more complex and advanced management
needs (figure 3).6,42,43 These therapeutic options can be
classified into three major categories on the basis of their
attempts to address different aspects of the underlying
pathophysiology of thalassaemia: correction of globin-
chain imbalance, addressing ineffective erythro­poiesis,
and improving how the body handles iron. In this section,
we will shortly discuss some of the emerging approaches
in each of these areas.
Gene therapy is based on the idea that if there is a defect
in the production of β-globin in β-thalassaemia, exo­
genous production of β-like globins could correct the
disorder. The haemopoietic system is convenient for such
approaches, since haemopoietic stem cells from an
individual with β-thalassaemia can be isolated and trans­
duced with viruses to introduce exogenous genetic
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Seminar
TMPRSS inhibitors
Iron overload
Minihepcidins ↓ Hepcidin TMPRSS6
Ineffective erythropoiesis Erythroferrone
Anaemia
material, such as β-like globin transgenes that can allow
for such exogenous gene expression. Following successful
application in a few patients with thalassaemia,131 clinical
trials have been initiated.
Several approaches are also being developed to address
the α-globin or β-globin chain imbalance in patients with
thalassaemia by stimulation of γ-globin production.26
Although many small trials have examined the use of
currently available cytotoxic agents, such as hydroxy­
carbamide, there is a scarcity of published results and
studies.132 The limitations of the currently available
approaches to address the α-globin or β-globin chain
imbalance have motivated a considerable amount of
research into better understanding the molecular
regulation of γ-globin. In recent years, human-genetic
studies have provided important insights into this area
and have suggested several promising molecular targets,
such as BCL11A, which is a transcription factor capable
of silencing the γ-globin genes specifically without
affecting production of red blood cells.26 Instead of gene
therapy, recent approaches have been developed to
directly correct genetic mutations in the endogenous
DNA of the cell or to disrupt specific DNA sequences in
the genome. This approach is known as genome editing
and has been facilitated through the identification of
several enzymes, including CRISPR/Cas9, that can intro­
duce DNA breaks in specific regions of the genome.
Although it is challenging to envision correcting every
one of the hundreds–thousands of mutations that cause
β-thalassaemia, disruption of factors that silence the
γ-globin genes, such as BCL11A, might allow more
immediate treatment of β-thalassaemia with current
genome editing approaches.6
Ineffective erythropoiesis is the major contributor to the
anaemia observed in patients with β-thalassaemia. In the
past few years, a group of ligand traps (which include
sotatercept and luspatercept) have been developed that
have shown potent stimulation of late-stage erythropoiesis
and improved ineffective erythropoiesis in patients with
β-thalassaemia.6,133,134 Ongoing clinical studies of these
drugs are evaluating their role in reducing transfusion
 Seminar
requirements and raising haemoglobin concentrations in
patients with TDT and NTDT, respectively. JAK2 inhibition,
an established therapy in patients with myeloproliferative
disorders, can also ameliorate ineffective erythropoiesis
and decrease spleen size in mice with thalassaemia, which
has motivated ongoing clinical trials in this area to evaluate
the role of JAK2 in patients with TDT.43
In NTDT mouse models, moderate transgenic hepcidin
expression decreased iron loading in the liver, and
resulted in an extended red blood cell lifespan, increased
haemoglobin concentrations and amelioration of
splenomegaly.43,135 Recent preclinical studies43,136 have
suggested that long-acting hepcidin analogues (mini­
hepcidins) could be beneficial to restrict iron absorption
and use in the setting of iron overload, with beneficial
effects on ineffective erythropoiesis. If such molecules
are developed for clinical use, these could help to further
restrict iron overload either alone or in combination with
currently available iron chelators. An alternative approach
is to stimulate endogenous hepcidin prod­uction through
the downregulation of a metallo­protease, TMPRSS6, that
plays a key role in hepcidin expression.137 Antisense
oligonucleotides and siRNAs targeting TMPRSS6 have
been effectively used to stimulate hepcidin, reduce the
iron burden, and improve in­effective erythropoiesis and
red blood cell survival in preclinical iron-overload
models138,139—clinical trials are expected soon.
Concluding remarks
Our improved understanding of the pathophysiology
and disease burden in patients with thalassaemia has
helped optimise disease management and construct a plan
for the development of novel therapeutics. With several
treatment options available, the need for comparative and
combinative clinical trials is essential to design the best
management approach. Nonetheless, the complexity of
thalassaemia as a disease might always imply the need for
individualised therapy, and offering the right treatment
approach to the right patient. The equal prioritisation of
efforts to promote the prevention of thalassaemia births
through nationwide screening programmes and pre­
marital policy adaptations should also be addressed.
Successful examples of a remarkable decline in disease
incidence from the Mediterranean should aim to be
reproduced in resource-poor countries where the disease
continues to pose public health concerns. This effort,
however, will require challenges attributed to economic,
cultural, and religious differences to be addressed with
innovative approaches to premarital and prenatal coun­
selling. Expanded-education pro­grammes and health-care-
system awareness are also needed nowadays in
high-income communities where thalassaemias were,
until recently, not commonly present. Lastly, collaborations
and partnerships between centres for the exchange of
expertise and resources could help improve the diagnosis
and management of the thalassaemias, especially in low-
income countries where they are most common.
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Contributors
ATT, DJW, and MDC participated in the literature search, manuscript
drafting, and review. All authors approved the final manuscript before
submission.
Declaration of interests
ATT and MDC report grants and personal fees from Novartis and Celgene,
outside the submitted work. DJW declares no competing interests.
Acknowledgments
We thank Khaled Musallam and Vijay Sankaran for their constructive
review of this manuscript. We apologise to those authors whose work
could not be cited in this review because of space limitations.
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