T hal as s e mi as

Alissa Martin, MD, Alexis A. Thompson, MD, MPH*

KEYWORDS
! Thalassemia ! Iron overload ! Hemoglobinopathies ! Anemia

KEY POINTS
! The thalassemia syndromes are a heterogeneous group of disorders characterized by
variable degrees of hemolysis, chronic anemia, and ineffective erythropoiesis.
! Because more patients are living longer, disease- and treatment-related complications
are becoming more common.
! Optimal and safe transfusion support, iron chelation, noninvasive iron assessments, and
stem cell therapies provide new tools for effective management of thalassemia.

INTRODUCTION/HISTORY

The thalassemia syndromes are a group of inherited hemoglobinopathies that result

from significantly reduced or absent synthesis of normal hemoglobin. The type of thal-
assemia is based on the defective globin gene involved; patients with affected
b-globin genes have b-thalassemia, and those with affected a-globin genes have
a-thalassemia. Patients with thalassemia have widely variable clinical presentations,
ranging from nearly asymptomatic to severe anemia requiring lifelong blood transfu-
sions with complications in multiple organ systems. The mainstay of therapy for thal-
assemia remains red blood cell transfusion, which then necessitates iron chelation.
This article focuses on the diagnosis and clinical manifestations of thalassemia.

EPIDEMIOLOGY

Although thalassemia is rare in the United States, an estimated 5% of the world’s pop-
ulations carry at least one variant globin allele.1 In general, these conditions are
inherited in an autosomal recessive pattern. Numerous studies have confirmed that
red blood cells in thalassemia carriers are less susceptible to invasion by Plasmodium
falciparum, thus conferring a survival advantage in malaria-endemic regions.2 The
prevalence of thalassemia is highest in geographic regions that historically were
most affected by malaria, including the Mediterranean, sub-Saharan Africa, the Middle

The authors have no relevant financial relationships to disclose.

Division of Hematology/Oncology, Ann and Robert H. Lurie Children’s Hospital of Chicago, 225
East Chicago Avenue, Box #30, Chicago, IL 60611, USA
* Corresponding author.
E-mail address: a-thompson@northwestern.edu

Pediatr Clin N Am 60 (2013) 1383–1391

http://dx.doi.org/10.1016/j.pcl.2013.08.008 pediatric.theclinics.com
0031-3955/13/$ – see front matter ! 2013 Elsevier Inc. All rights reserved.
1384 Martin & Thompson

East, the Asian-Indian subcontinent, and Southeast Asia. Resources available in many
regions have substantially improved patient survival over time.3 In 1973, fewer than
2% of patients with thalassemia were older than 25 years; today that cohort repre-
sents 36% of patients with thalassemia in the United States. Immigration has also
contributed to the ethnic diversity of the thalassemia population in the United States.4

a-THALASSEMIA

a-Thalassemia is caused by absent or decreased production of a-globin chains. The

a gene locus contains paired alleles (aa/aa) on chromosome 16. Clinical severity
varies based on the number of alleles affected and also on the type of genetic muta-
tion.5 Deletional defects involving the a-globin gene locus can be from nonhomolo-
gous recombination or other mechanisms that either completely or at least partially
delete both a-globin chains. Nondeletional mutations result in reduced production
of a-globin and, in some cases, varying amounts of structurally aberrant a-globins
that are associated with a more severe clinical phenotype.
Persons with one mutated allele are silent carriers (aa/a-). Patients with a-thalas-
semia trait have 2 deletions (aa/–) on the same chromosome (cis) or on opposite
(a-/a-) chromosomes (trans.). The arrangement of these anomalies have important
implications on reproduction. Inheritance of 2 mutant a alleles in cis from one parent,
combined with a single mutation from a parent who is a silent carrier, may result in a
clinically significant condition involving 3 of 4 genes in the offspring. a-Thalassemia
involving all 4 a genes typically has a severe clinical phenotype, often causing intra-
uterine anemia and hydrops fetalis.6
Hemoglobin H (HbH) disease is caused by mutations of 3 of the 4 alleles, with
compound heterozygosity for a1 and a0 mutations. In fetal development, the excess
g chains form homotetramers (g4), also called Hb Bart’s, which are detectable tran-
siently at birth. Later, excess b-globin chains form b4 homotetramers (HbH), which
are unstable and precipitate in developing red cells. The globin chain imbalance con-
tributes to ineffective erythropoiesis and local intracellular oxidative damage in circu-
lating red blood cells and shortened red cell life span. Most patients with HbH disease
are not transfusion-dependent but may require transfusion support for infections and
other oxidative stresses.7,8
The most common nondeletional form of HbH disease is HbH Constant Spring. The
Constant Spring a-globin mutation results in the elongation of 30 mRNA sequences,
abnormally elongated a-globin chains, and reduced globin production from the unaf-
fected allele.8 Intracellular precipitation of oxidized chains of hemoglobin Constant
Spring damages red cell membranes, which causes hemolysis and a more severe
anemia. Unlike most other forms of HbH disease, patients with HbH Constant Spring
are often transfusion-dependent.

b-THALASSEMIA

The b-globin locus on chromosome 11 includes genes that encode g-, d-, and b-glo-
bins, which pair with a-globin chains to create fetal hemoglobin (HbF), hemoglobin A2,
and normal adult hemoglobin (HbA), respectively. Hundreds of b-globin gene muta-
tions cause b-thalassemia, involving both coding and intervening (noncoding) DNA
sequences. The disease severity, or degree of transfusion dependence, correlates
with the degree of a-globin chain excess.9 Patients usually present with anemia as
early as the first 6 months of life when HbF production declines,10 or they can present
in early childhood with symptoms such as abdominal distention, hepatosplenomegaly
from extramedullary hematopoiesis, irritability, jaundice, and poor growth.
 Thalassemias 1385

Operationally, b-thalassemia can be described based on blood transfusion require-

ments. Thalassemia major describes patients who require regular blood transfusions,
usually more than 8 to 12 times per year. Thalassemia intermedia describes patients
who can, under normal circumstances, maintain an adequate hemoglobin concentra-
tion and require red cell transfusions fewer than 8 times per year, or only in times of
physiologic stress.
Hemoglobin E (HbE)/b-thalassemia is a b-thalassemia subtype that deserves spe-
cial mention. It has been estimated that half of all patients worldwide with clinically
severe thalassemia actually have the HbE/b-thalassemia genotype.11 It is also the
most common form of b-thalassemia now detected on newborn screening in some
parts of the United States. HbE is a structural b-globin variant that results in both
decreased b-globin chain synthesis and production of a structurally abnormal
bE-globin that has impaired interactions with a-globin. When coinherited with a b-thal-
assemia mutation, HbE/b-thalassemia results in a phenotype that is extremely vari-
able, ranging from full transfusion dependence to only requiring occasional
transfusions during times of physiologic stress, such as during acute febrile illnesses.

PATHOPHYSIOLOGY

Normally, a-globin production begins during fetal development and is constant

throughout later life. g-Globin is turned on during early embryonic development to
create HbF (a2g2), which typically declines in the first 6 months after birth. b-Globin
production begins in late gestation to create HbA (a2b2), which reaches adult levels
by 1 year of life.
The fundamental derangement that underpins thalassemia syndromes is globin
synthesis imbalance, and often it is the relative excess of a given chain that is most
destructive. In b-thalassemia, the reduced production of b-globin chains leads to
decreased amounts of HbA per cell, and interaction of the relative excess a-globin
chains with the red cell membrane causes hemolysis and premature intramedullary
cell death. This ineffective erythropoiesis is compounded by sequestration of defec-
tive red cells in the spleen. In the absence of transfusion therapy, severe anemia
over time contributes to growth retardation and high-output cardiac failure in thalas-
semia, and tissue hypoxia stimulates increased erythropoietin production and marrow
expansion that causes bony deformities and fractures. Increased intestinal iron
absorption and regular red cell transfusions contribute to parenchymal iron deposi-
tion. Excess tissue iron causes cirrhosis, cardiac dysfunction, and endocrinopathies.

DIAGNOSIS OF THALASSEMIA

The complete blood cell (CBC) count, including hemoglobin and red cell indices, and
reticulocyte count are useful screening studies for thalassemia. Most patients with
thalassemia will have microcytosis and hypochromia. The red blood cell count may
be relatively elevated. The peripheral blood smear shows many bizarrely shaped, frag-
mented, microcytic red cells and may reveal red blood cell inclusion bodies (globin
chains) after supravital staining.
Hemoglobin electrophoresis or high-performance liquid chromatography (HPLC)
can be diagnostic for b-thalassemia, with predominant HbF, low or absent HbA,
and elevated HbA2. HbE may also be detected in patients with HbE/b-thalassemia.
For patients with HbH disease or other forms of a-thalassemia, HPLC can detect
elevated Hb Bart’s at birth, HbH later in life, and Hb Constant Spring variants. In gen-
eral, DNA-based testing is essential for a definitive diagnosis of a-thalassemia, and
should be used for confirmatory testing in patients with suspected b-thalassemia.
1386 Martin & Thompson

COMPLICATIONS OF THALASSEMIA
Growth Impairment
Children with thalassemia are at risk for growth failure from chronic anemia, and a
hypermetabolic state from high-volume ineffective erythropoiesis.12 Nutritional defi-
ciencies, chelation toxicity, and iron-induced endocrinopathies also contribute to sub-
optimal linear growth and weight gain. Pubertal development may also be delayed
because of iron loading and/or severe anemia.

Bone Abnormalities
Marked erythroid expansion can cause significant bony abnormalities in patients with
thalassemia, particularly those with b-thalassemia.12,13 Radiographic abnormalities in
untreated patients can become marked after the first year of age.14 Long bones show
cortical thinning with expansion of the medullary space, and become prone to patho-
logic fractures. Skull findings are classic, with marked widening of the diploic space
and a resultant “hair on end” appearance (Fig. 1). Other skeletal findings include failed
pneumatization of maxillary sinuses and maxillary overgrowth that contributes to the
classic thalassemic facies, widening of the ribs, and squared vertebral bodies.
Osteopenia, osteoporosis, and related complications are prevalent in patients with
b-thalassemia major and thalassemia intermedia.15 Low bone mass can begin in child-
hood with an imbalance between osteoblastic bone formation and osteoclastic bone
resorption. By adulthood, up to 50% of patients with b-thalassemia major have oste-
oporosis.14,16,17 Up to 40% of patients will have at least one pathologic bone fracture.
The cause of decreased bone mineral density in patients with thalassemia is multifac-
torial, including delayed sexual maturation, deficiencies of insulin-like growth factor
1 (IGF-1), and growth hormone, and direct toxic effects of iron on osteoblasts.

Endocrinopathies
Hypogonadotropic hypogonadism is common in adults with thalassemia, with re-
ported rates upward of 50%.3,12,18 Iron toxicity has been implicated as a major
contributor to hypogonadism and impaired fertility from pituitary, hypothalamic,
and, to a lesser degree, gonadal iron deposition.19 Hypothyroidism and diabetes
are also prevalent complications because of iron-induced tissue injury. Although

Fig. 1. Skull X-rays of a child with thalassemia, anterior-posterior (left) and lateral (right)
views. Note expansion of the medullary space which is most prominent in the frontal and
parietal regions with associated “hair on end” appearance.
 Thalassemias 1387

uncommon in thalassemia, hypoparathyroidism can be associated with impaired cal-

cium metabolism and suboptimal responses to vitamin D supplementation.
Prevention is the best treatment for bone disease and other endocrinopathies in
thalassemia. This entails adequate transfusion and chelation to prevent chronic ane-
mia and iron loading, and adequate vitamin D and calcium intake, particularly during
skeletal development. Hormone replacement therapy improves quality of life and alle-
viates manifestations of hypogonadism, and may improve bone mineral density in
patients with thalassemia. Insulin and thyroid hormone are often needed to manage
diabetes and hypothyroidism. Treatment of osteoporosis with bisphosphonates can
improve bone density.13

Splenomegaly and Hypersplenism

Splenic enlargement in thalassemia may be caused by extramedullary hematopoiesis
and sequestration of defective red blood cells. Splenomegaly is particularly problem-
atic in patients who are inadequately transfused, and may result in leukopenia, throm-
bocytopenia, and exacerbation of anemia from hypersplenism. Splenectomy alone
may be sufficient to control anemia and obviate transfusions in thalassemia interme-
dia, and may be indicated for patients with b-thalassemia major whose transfusion
requirements are higher than expected.20

Hypercoagulability
Several factors lead to an overall hypercoagulable state in patients with thalassemia.
The altered physiology of the red cell membrane makes the cells more rigid and more
likely to aggregate. Splenectomy may increase the susceptibility to thrombosis in
chronic hemolytic anemias (not just thalassemia). In patients who have undergone
splenectomy, thrombin generation is increased and protein C and S are decreased,
further contributing to the prothrombotic state. Chronic activation of platelets and
altered vascular endothelial physiology occur in thalassemia major after splenectomy,
and in patients with thalassemia intermedia regardless of history of splenectomy.21

Pulmonary Hypertension
Increased pulmonary arterial pressure has been increasingly described as a cause of
morbidity and mortality in thalassemia.22 Contributing factors may include activation
of the coagulation system, platelets, and endothelial cells, and inflammation. Risk
seems to be higher with increasing age and in patients who have undergone splenec-
tomy, particularly those with thalassemia intermedia. Echocardiography is the most
commonly used test to detect elevated regurgitant tricuspid jet velocity as a marker
for increased pulmonary artery pressure. Antiplatelet agents (aspirin and dipyridamole);
pulmonary vasodilators, such as prostaglandins and endothelin receptor antagonists;
and phosphodiesterase type 5 inhibitors have been used with varying success to
manage pulmonary hypertension in thalassemia and related conditions.

TREATMENT FOR THALASSEMIA

The only curative treatment for thalassemia is stem cell transplantation. The mainstay
of long-term management is red cell transfusion, but the resultant iron overload
causes severe complications.

Transfusion Therapy
The primary treatment for severe thalassemia remains red blood cell transfusion. The
decision to begin a transfusion regimen is based largely on clinical assessment and
1388 Martin & Thompson

the impact of chronic anemia on a patient’s life, including factors such as impaired
growth, bony deformities, and fatigue. In most patients with b-thalassemia major,
transfusions are initiated before 1 year of age. Specific transfusion goals may differ
among treatment centers, but in general, transfusion regimens should target a pre-
transfusion hemoglobin of 9 to 10 g/dL. Maintaining this hemoglobin level suppresses
endogenous erythropoietin levels and reduces marrow expansion and extramedullary
hematopoiesis. Measuring linear growth and weight gain are important in determining
if the transfusion regimen is adequate. Most patients will require 10 to 20 mL/kg of
packed red blood cells every 2 to 4 weeks, for a total of approximately 200 mL/kg/y.

HbF Induction
HbF may be important in ameliorating symptoms of b-thalassemia intermedia,
because increased g-globin production decreases the relative excess of a chains
and increases total hemoglobin levels.23 Three main classes of medications have
been investigated for efficacy in increasing HbF, although clinical experience in thal-
assemia still lags behind that in sickle cell disease.

Hydroxyurea
Despite success in treating sickle cell disease, hydroxyurea has not been extensively
studied in thalassemia and results have not been as consistent. Hydroxyurea does not
seem to have the same positive effects on red cell morphology and deformability in
thalassemia. However, some evidence suggests that hydroxyurea may diminish phos-
phatidylserine expression on red cell membranes in some patients with thalassemia,
which can prolong erythrocyte survival and decrease hypercoagulability.23 Hydroxy-
urea may rarely decrease transfusion requirements in patients with thalassemia major.
Combinations of hydroxyurea with other agents, such as recombinant erythropoietin,
improve total hemoglobin levels in some patients with non–transfusion-dependent
thalassemia.24

DNA methylation inhibitors

Repression of g-globin genes in adult red blood cells involves DNA methylation and
other epigenetic changes. Demethylating agents, such as 5-azacytidine, resulted in
a rapid increase in g-globin synthesis with increased total hemoglobin levels in single
patients and small case series; however, concerns over potential mutagenicity and
cytotoxicity limited its use clinically.23,24 Decitabine (5-aza-20 -deoxycytadine) has a
more favorable safety profile and resulted in increased total hemoglobin and absolute
HbF levels in a small pilot study of patients with b-thalassemia intermedia.23,25
Short-chain fatty acids
Short-chain fatty acids can ameliorate anemia in non–transfusion-dependent thalas-
semia through inducing HbF production.24 Sodium phenylbutyrate can result in
increased levels of total hemoglobin and improved markers of ineffective erythropoi-
esis in patients with b-thalassemia. Isobutyramide has had variable effect on HbF
levels but no change in markers of ineffective erythropoiesis. Clinical trials with other
short-chain fatty acids are either underway or currently being planned for both thalas-
semia and other hemoglobinopathies.

Stem Cell Transplantation

Hematopoietic stem cell transplantation (HSCT) using HLA-matched related donor
stem cells has become part of conventional treatment for thalassemia.26 Early studies
of HSCT in thalassemia identified hepatomegaly, portal fibrosis, and poor chelation his-
tory as patient characteristics that, when incorporated into the Pesaro classification,
 Thalassemias 1389

predict overall survival, thalassemia-free survival, and graft rejection.27 Patients with no
adverse features (class 1) had a probability of thalassemia-free survival of 87%. Class
2 patients with at least 1 adverse feature had an 85% thalassemia-free survival and
class 3 patients with 2 or more adverse features had a 53% thalassemia-free survival.
With modifications in the conditioning regimen used, the probability of thalassemia-free
survival in class 3 patients has improved.28 Additional risk factors that favor superior
HSCT outcomes using multivariate analysis include young age (<7 years), limited iron
burden, and minimal comorbidities, such as hepatic dysfunction.29 Results of HSCT
using alternative donors and reduced intensity or nonmyeloablative conditioning may
expand the availability of this treatment option while preserving fertility.30

Splenectomy
Although removal of the spleen can alleviate anemia in non–transfusion-dependent
thalassemia, splenectomy is now used less frequently in both thalassemia intermedia
and major.31 In addition to the potential infectious complications, increasing evidence
supports that patients who undergo splenectomy are at increased risk for thrombotic
events. Thrombin generation is increased and protein C and S are decreased in these
patients, further contributing to this prothrombotic state. Platelet counts are also

Box 1
Recommended thalassemia comprehensive care assessments

Monthly assessments
! CBC count
! Serum ferritin
! Comprehensive metabolic panel
! Urinalysis
Annual assessments
! Cardiac T2-star (T2*) magnetic resonance imaging (MRI) (>age 10 years)
! Liver iron measurement (R2* MRI or FerriScan)
! Bone mineral density
! Hearing
! Vision
Annual laboratory screening
! Fasting serum glucose
! Free T4, thyroid-stimulating hormone
! Parathyroid hormone
! Luteinizing hormone, follicle-stimulating hormone, estradiol/testosterone
! Ionized calcium
! Vitamin D
! IGF-1, IGF binding protein-3
! Vitamin C
! Trace elements: zinc, copper, selenium
! Viral studies (human immunodeficiency virus, hepatitis A, B, C)
1390 Martin & Thompson

higher in patients after splenectomy, but this is not necessarily associated with
increased clotting tendency.21 Patients should receive pneumococcal, meningo-
coccal, and Haemophilus influenzae vaccines before splenectomy and should take
lifelong penicillin for prophylaxis.

MANAGEMENT/OBSERVATION OF PATIENTS WITH THALASSEMIA

Patients should have regular comprehensive visits to evaluate the most common and
important complications of disease. In addition to CBC and reticulocyte counts, age-
appropriate laboratory studies should be performed to evaluate endocrine function
and nutritional deficiencies, and to screen for chelation-related toxicities. Bone density
measurements and noninvasive imaging for tissue iron burden provide important infor-
mation and opportunities for intervention. Recommended assessments are summa-
rized in Box 1.

SUMMARY

The thalassemia syndromes are a heterogeneous group of disorders characterized by

a variable degree of hemolysis, chronic anemia, and ineffective erythropoiesis.
Because more patients are living longer, disease- and treatment-related complica-
tions are becoming more common. Optimal and safe transfusion support, iron chela-
tion, noninvasive iron assessments, and stem cell therapies provide new tools for
effective management of thalassemia.

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