Trends in Pediatrics 2021;2(1):1-7 Trends in Pediatrics 2021;2(1):1-7

doi:10.5222/TP.2021.10820 Review

Thalassemia

Tekin Aksu , Şule Ünal

ID ID

Hacettepe University, Department of Pediatric Hematology, ABSTRACT

Ankara, Turkey
Defects in protein structure or synthesis of hemoglobin are called
hemoglobinopathies. Thalassemia is the most common
Cite as: Aksu T, Ünal Ş. Thalassemia. Trends in Pediatrics hemoglobinopathy, and it is estimated that 5% of the world
2021;2(1):1-7. population carries at least one variant allele of thalassemia. The
thalassemias can be classified as alpha or beta thalassemias. Beta
thalassemia may present as silent carriers with normal
Received: 08 November 2020 hematological parameters, while beta thalassemia carriers have
Accepted: 18 January 2021 hypochromic microcytic anemia, associated with a high HbA2.
Publication date: 30 March 2021
However, patients with beta thalassemia intermedia and beta
thalassemia major need transfusion intermittently or regularly
and they are called non-transfusion dependent thalassemias or
Keywords: Beta thalassemia, alpha thalassemia, pathophysiology,
transfusion-dependent thalassemias, respectively. This review
treatment
focuses on pathophysiology, clinical, laboratory features of
thalassemias along with their treatment and follow-up.
Şule Ünal
Hacettepe University, Department of Pediatric Hematology,
Ankara, Turkey
ORCID: 0000-0002-3842-8788
✉ suleunal@hacettepe.edu.tr

T. Aksu 0000-0003-4968-109X

INTRODUCTION Hb of adulthood, gradually prevails in comparison to

HbF. HbA2 (α2 δ2) is synthesized in scant amounts
Hemoglobin is a tetrameric protein that contains two after birth. The final Hb pattern is obtained at least
pairs of globin chains. The defects in protein structure six months after birth and consists of 95% HbA, 3.5%
or synthesis of hemoglobin are called HbA2, and <2.5% HbF.4
hemoglobinopathies. To date, more than 800
hemoglobin variants have been identified.1 Two The thalassemia comes from the Greek word
gene clusters are responsible for hemoglobin “thalassa” which means sea, and –emia originates
production; the alpha (α) gene cluster consists of from a Latin word that means blood. The disease
zeta (ζ), alpha 1 (α1), and alpha 2 (α2) genes located was first described in the Mediterranean population
on chromosome 16.2,3 The beta (β) gene cluster and was referred to as Mediterranean anemia.
consists of epsilon (ε), gamma 1 (γ1), gamma 2 (γ2), Thalassemia is the most common hemoglobinopathy,
delta (δ) and beta (β) genes located on chromosome and it is estimated that 5% of the world population
11.2,3 The embryonic hemoglobins Gower-1 (2 ε2), carries at least one variant allele of thalassemia.5
Gower-2 (α2 ε2) and Portland (ζ2 γ2) are formed Although thalassemias often show an autosomal
starting from the 8th week of fetal life. HbF (α2 γ2), recessive inheritance pattern, some types of
which is the main Hb of fetal life, is noticed from the thalassemias have rare dominant inheritance
9th week on, while HbA (α2 β2), which is the main pattern.5 The thalassemias can be classified as alpha

© Copyright Aydın Pediatric Society. This journal published by Logos Medical Publishing.
Licenced by Creative Commons Attribution 4.0 International (CC BY)

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T. Aksu and Ş. Ünal, Thalassemia Trends in Pediatrics 2021;2(1):1-7

or beta thalassemias since the primary globin type of erythrocyte G6PD enzyme deficiency, thalassemias
adults is HbA (α2 β2). are common in areas where malaria was once
endemic.8 Carriers of thalassemia are more resistant
PATHOPHYSIOLOGY to malaria than normal individuals, and malaria
infection has a milder clinical course in these carriers.
Thalassemias are a group of diseases in which the Approximately 150 million people who are carriers
the balance between alpha globin, and beta globin is of thallassemia live in the Mediterranean countries,
impaired. This imbalance is caused by a decrease in the Arabian peninsula, the Middle East countries,
the production of one or more globin genes. The the west of Africa, Iran, Pakistan, Afghanistan, India,
reduced globin chain causes unpairing of the and Southeast Asia. Today, due to global migration
remaining globins, which are precipitated in and ethnic interactions, β thalassemia can be
erythrocyte precursors (ineffective erythropoiesis) encountered in all parts of the world. The frequency
or destroyed in the circulation (hemolysis) ultimately.4 of β thalassemia carriers in Turkey is 2.1%, and this
As a result, patients have varying degrees of anemia rate rises to 13% in some of the provinces in the
and extramedullary hematopoiesis. While beta Mediterranean region.9,10
thalassemias often develop with point mutations,
alpha thalassemias mostly develop with deletional Beta thalassemia patients may present as silent
mutations.6,7 If the mutation is a “missense” mutation carriers with normal hematological parameters and
in beta thalassemias, this causes decreased beta normal Hb A2 levels with several mutations, such as
globin chain synthesis called β+. In “nonsense” -101 promoter mutation.9,10 These individuals can
mutations, β0 is a phenotype in which there is no not be distinguished by routine screening. Beta
beta globin synthesis. If one of the two beta globin thalassemia carriers have hypochromic microcytic
genes carries a mutation, these individuals are called anemia, associated commonly with a high HbA2
thalassemia carriers or thalassemia minors, who are (3.5-8%), HbA2 and HbF (5-20%) levels.4 An
usually clinically asymptomatic. Individuals with a erythrocytosis (RBC> 5x1012/L), microcytosis, normal
homozygous or compound heterozygote thalassemia RDW are common for beta thalassemia carriers, but
mutation in the beta globin gene may present with also iron deficiency anemia, alpha thalassemia trait,
either thalassemia major or thalassemia intermedia and chronic disease anemia should be considered for
phenotype. To distinguish between thalassemia differential diagnosis.
major and intermedia, several clinical and laboratory
findings should be considered (Table 1). In beta thalassemia intermedia (BTI) patients do not
need a regular transfusion regimen. They need less
BETA THALASSEMIAS than five transfusions within a year and are called
non-transfusion dependent thalassemias (NTDT).
Most commonly seen in the Mediterranean region, They show decreased hemoglobin, erythrocyte
they are also found in Asia and Africa regions close count, erythrocyte indices (MCV, MCH, MCHC), and
to the equator. As with sickle cell anemia and increased RDW. In peripheral smear, severe

Table 1. Clinical and laboratory differences between thalassemia major and thalassemia intermedia

β- thalassemia major β- thalassemia intermedia

Onset (year) <2 >2

Hemoglobin (gr/dL) <7 8-10
Hepatosplenomegaly Severe Mild to moderate
HbF (%) >50 10-50

HbF: Fetal hemoglobin

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T. Aksu and Ş. Ünal, Thalassemia Trends in Pediatrics 2021;2(1):1-7

hypochromia, microcytosis, anisocytosis, regular transfusions should be done every 3 to 4

poikilocytosis, target cells, polychromasia, basophilic weeks. A subgroup-appropriate, leucodepleted
stippling, and normoblasts are observed. A slight erythrocyte suspensions should be preferred.
increase in reticulocyte level (2-4%) can be observed. Alloimmunization, transfusion-related viral infections,
In hemoglobin electrophoresis, HbA decreases transfusion reactions, and annual transfusion rates
(10-20%), HbF (70-80%) and HbA2 increases.4 The should be monitored in these patients.
mother and father should also be screened for
thalassemia carrier state with complete blood count In transfusion-dependent thalassemias, iron overload
and hemoglobin electrophoresis, but in rare inevitably will develop due to iron gained from
instances, molecular diagnosis may be required. transfusions and increased gastrointestinal iron
absorption, which is responsible for morbidity and
The patients with beta thalassemia major (BTM) are mortality. Iron accumulates primarily in the liver,
transfusion-dependent. Laboratory features of BTM followed by endocrine organs and the heart.
are similar to BTI. However, since HbA synthesis is far Hypothyroidism, hypogonadotropic hypogonadism,
less compared to BTI, HbA is not seen in hemoglobin growth hormone deficiency, hypoparathyroidism,
electrophoresis, and HbF is more than 80% of total and diabetes mellitus may develop due to iron
hemoglobin. overload.11 Besides, iron overload in the heart,
causing arrhythmias and heart failure, can be fatal.
BETA THALASSEMIA MAJOR Chelation therapy is necessary to prevent these
complications, and iron overload should be regularly
Patients with homozygous β0-thalassemia often monitored for adequate chelation. Monitoring of
present with severe anemia due to inadequate HbA serum ferritin, measured at least 3- month intervals,
synthesis in the first 3 to 4th months of life. However, facilitates chelation management, but it does not
depending on the type of mutation and HbF reflect tissue iron status properly. Today, T2* and
production, the need for transfusion may be delayed R2* MR imaging has become the standard for
up to 2 years of age. In patients who do not receive indirect, quantitative measurement of iron
adequate transfusion therapy, growth retardation, accumulation in heart and liver.12 It is recommended
hepatosplenomegaly, hypersplenism, bone changes to start the follow-up with MRIs after the age of 8-10
due to bone marrow enlargement, thalassemic face and once a year henceforth.
(maxillary hyperplasia, frontal bossing, depressed
nasal bridge) develop.4 Transfusion therapy aims to Iron chelation should be initiated after 10 to 15
prevent these changes due to ineffective transfusions or when serum ferritin rises above
erythropoiesis. 1,000 ng/mL.13 However, iron chelators are not
approved for use under two years of age. Information
At the onset, to differentiate thalassemia major and on three different iron chelators is shown in Table
intermedia transfusion should be deferred until Hb 2. These drugs can be used alone or together with
level drops below 7 gr/dL. However, in patients with deferiprone to reduce cardiac iron load. Ideally,
growth retardation, thalassemic facial changes, and serum ferritin level is desired to be between 500-
progressive splenomegaly, transfusion therapy 1000 ng/mL. When the serum ferritin level
should be initiated earlier. It is necessary to evaluate decreases below 500 ng/mL in transfusion
Hb electrophoresis, Rh and Kell subgroups, viral dependent patients, it is recommended to suspend
serology (CMV, HIV, Hepatitis B, HCV) tests before chelator therapy.13-15
transfusion. Contemporary transfusion programs
recommend that a lower hemoglobin limit of 9-9.5 Splenectomy should be recommended in cases of
gr/dL should be set before transfusions.5. Since a Hb hypersplenism, with signs such as the mass effect of
decrease of 1 gr/dL per week is expected in patients, the spleen, also in cytopenias or increased annual

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T. Aksu and Ş. Ünal, Thalassemia Trends in Pediatrics 2021;2(1):1-7

Table 2. Iron chelators

Deferoxamine Deferiprone Deferasirox

Administration iv, sc, 8-12 h/day, 5-7 day/week Oral tablets, suspension Oral dispersible and film-coated tablet,
3 times daily Once daily

Dose 25-60 mg/kg/d 75-100 mg/kg/d 20-40 mg/kg/d (dispersible)

14-28 mg/kg/d (film-coated)

Excretion Urine, feces Urine Feces

Adverse reactions Local reactions, retinal toxicity, Agranulocytosis, arthralgia Gastrointestinal disturbances, increase
ototoxicity, bone toxicity in hepatic transaminase levels , rash,
mild creatinine increase, ophthalmologic
toxicity, ototoxicity

Monitoring Eye examination and hearing Complete blood count, ALT Serum creatinine, ALT, total and direct
parameters test once a year monitoring bilirubin once a month

Specifications Low adherence Effective in reducing High adherence

cardiac iron

iv: Intravenous, sc: Subcutaneous, ALT: Alanine aminotransferase

need for blood transfusion (> 200 mL/kg) in patients Gene therapy seems to be an alternative, curative
with thalassemia.5,16 Splenectomy is often not treatment option in patients with thalassemia major
recommended before the age of 5, as the risk of who do not have suitable HSCT donors. Autologous
sepsis is high. Apart from the risk of infection after HSCT is performed after correction of beta-globin
splenectomy, the risk of thrombosis and pulmonary mutation mediated by lentiviral vectors or gene
hypertension also increases.16 Because of the editing.19 In addition, activation of HbF synthesis by
possibility of pneumococcal sepsis, polyvalent these methods alleviates the clinical signs of beta
pneumococcal vaccine and then lifelong prophylactic thalassemia. Initial results are exciting, and
penicillin is recommended for at least 3-4 weeks permanent increase in Hb, decrease in the need for
before splenectomy. transfusion, and improvement in quality of life have
been reported.
It has been 30 years since the first hematopoietic
stem cell trasplantation (HSCT) performed for There is an increase in GDF11 production as a result
thalassemia major patients. Today, allogeneic of intramedullary apoptosis and ineffective
transplantation is a curative method and standard erythropoiesis. GDF11 is a “transforming growth
clinical practice in patients with thalassemia major. factor β ligand” and inhibits the differentiation of
Therefore, all patients with thalassemia major should erythroid precursors. More effective erythropoiesis
be screened for family donors, and HSCT should be can be achieved with new treatment strategies
recommended before organ damage due to based on the principle of binding to GDF11. For this
development of iron overload. In Turkey, a study purpose, there are two molecules developed as
conducted with 245 children with thalassemia major, luspatercept (ACE-536) and sotatercept (ACE-011).
disease-free survival was 68%, overall survival 85%, Luspatercept prevents GDF11 from binding to its
and transplant-related mortality 7.7%.17 According to receptor. Its subcutaneous administration every
Pesaro experience, hepatomegaly, portal fibrosis, three weeks has been recommended. According to
and insufficient iron chelation are independent the results of the Phase II study, in the thalassemia
adverse risk factors for transplantation.18 major group, a reduction of more than 33% in need

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T. Aksu and Ş. Ünal, Thalassemia Trends in Pediatrics 2021;2(1):1-7

for blood transfusion was observed in 83% of the first three months. Detection of these individuals
patients. On the other hand, in the non-transfusion outside the neonatal period is only possible by performing
dependent thalassemia group, Hb levels increased in vitro Hb chain synthesis or molecular tests.
by more than 1 gr/dL in 78% and 1.5 gr/dL in 56% of
the patients. The results are similar in the In severe alpha carrier state or alpha thalassemia-1,
Luspatercept Phase III study (BELIEVE study).20 hematological features are similar to beta thalassemia
carriers. MCV is low, and RBC is often high. However,
BETA THALASSEMIA INTERMEDIA HbA2 levels are normal or lower than normal. In
peripheral blood smear, erythrocytes have
Patients with BTI are not transfusion dependent; hypochromia, microcytosis, anisocytosis,
however, they may need a transfusion during poikilocytosis, polychromasia, and basophilic
infections, inflammation, and pregnancy due to stippling. Hb Barts is seen in 5 to 10% of newborns
increased hemolysis. Hypochromia and microcytic which disappears after six months of life. A definitive
anemia are present, and Hb levels are between 6-10 diagnosis is made by in vitro Hb chain synthesis and
gr/dL. Medullary expansion in bone marrow, DNA studies.22-24
hepatosplenomegaly, hypersplenism, extramedullary
hematopoiesis, pulmonary hypertension, leg ulcers, Patients with HbH disease may present with
thrombosis, and growth retardation can be seen in hemoglobin between 8-10 gr/dL and hypochromia,
patients with beta thalassemia intermedia.21 microcytosis, anisocytosis, poikilocytosis,
Hemosiderosis may develop due to increased polychromasia, and target cells in peripheral blood
gastrointestinal iron absorption, especially in the smears. Inclusion bodies are seen on the erythrocytes
liver. In these patients, it is more challenging to after incubation of erythrocytes with bright cresyl
monitor iron overload by serum ferritin since iron blue.25 In 20-40% newborns Hb Barts is detected in
accumulation is mainly in hepatocytes compared to Hb electrophoresis, replaced by HbH in 5-30% of the
macrophages. On the other hand, with or without cases in time. A definitive diagnosis should be made
hepatitis C infection, the risk of hepatocellular cancer based on a decrease in α chain synthesis and DNA
is higher in patients with beta thalassemia intermedia studies. Acquired HbH disease has also been reported
than patients with thalassemia major. Regular secondary to myeloproliferative and myelodysplastic
transfusion may also be required in patients with TI diseases.26
when growth retardation, exercise intolerance,
hypersplenism, bone changes, and extramedullary HbH disease presents with hypochromia and
hematopoiesis develop.21 microcytic moderate to severe anemia. Splenomegaly,
scleral icterus, and gallstones can be observed in
ALPHA (α) THALASSEMIAS patients. Since they do not show symptoms except
during infection, inflammation, or pregnancy, It may
Alpha thalassemias are more common, especially in not be diagnosed until the second decade. HbH
Southern China, Malaysia, and Thailand. The milder patients should be monitored for growth, osteopenia,
phenotypes are also found in people with African and iron accumulation. Also, folic acid supplementation
origin. The risk of hydrops fetalis is higher in Asians should be initiated.23,24
since alpha thalassemia-1 carriership (i.e., presence
of 2 alpha globin gene deletions in the αα/- in cis ERADICATION AND PRENATAL DIAGNOSIS
position) are more prevalent in Asians.
In Turkey, pre-marital screening has been carried out
In silent alpha carrier state (alpha thalassemia-2), Hb since the 2000s, and as of November 2018, pre-
Barts is detected at a rate of 2-5% in the cord blood marital screening was extended to all over the
in the neonatal period, which disappears after the country. Prenatal diagnosis was made for the first

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T. Aksu and Ş. Ünal, Thalassemia Trends in Pediatrics 2021;2(1):1-7

time in 1975 by fetal blood sampling between 18-22 8. Kariuki SN, Williams TN. Human genetics and malaria
weeks of gestation by in vitro hemoglobin chain resistance. Hum Genet. 2020;139(6-7):801-11.
https://doi.org/10.1007/s00439-020-02142-6
synthesis and measurement of α/β globin ratio.
9. Başak AN. The molecular pathology of β-thalassemia
Today, thalassemia mutations are analyzed by
in Turkey: The Boğaziçi University Experience.
isolating DNA from fetal chorionic villus samples. Hemoglobin. 2007;31:2:233-41.
https://doi.org/10.1080/03630260701296735
Conflict of Interest: The authors declared no poten- 10. Guvenc B, Canataroglu A, Unsal C, et al. β-Thalassemia
tial conflicts of interest with respect to the research, mutations and hemoglobinopathies in Adana, Turkey:
results from a single center study. Arch Med Sci.
authorship, and/or publication of this article.
2012;8(3):411-4.
Funding: The authors received no financial support
https://doi.org/10.5114/aoms.2012.28811
for the research, authorship, and/or publication of 11. Bilgin BK, Yozgat AK, Isik P, et al. The effect of deferasirox
this article. on endocrine complications in children with Thalassemia.
Informed Consent: Medical students, nurse trainees, Pediatr Hematol Oncol. 2020;37(6):455-64.
and parents of the patients provided informed con- https://doi.org/10.1080/08880018.2020.1734124
12. Fernandes JL. MRI for iron overload in thalassemia.
sent to publish the report.
Hematol Oncol Clin North Am. 2018;32(2):277-95.
https://doi.org/10.1016/j.hoc.2017.11.012
REFERENCES 13. Aydinok Y. Iron chelation therapy as a modality of
management. Hematol Oncol Clin North Am.
1. Giardine B, Borg J, Viennas E, et al. Updates of the 2018;32(2):261-75.
HbVar database of human hemoglobin variants and https://doi.org/10.1016/j.hoc.2017.12.002
thalassemia mutations. Nucleic Acids Res. 14. Saliba AN, El Rassi F, Taher AT. Clinical monitoring and
2014;42(Database issue):D1063-9. management of complications related to chelation
https://doi.org/10.1093/nar/gkt911 therapy in patients with β-thalassemia. Expert Rev
2. Kwiatkowski JL. Hemoglobinopathies. In: Lanzkowsky Hematol. 2016;9(2):151-68.
P, Lipton MJ, Fish JD (eds) Lanzkowsky Manuel of https://doi.org/10.1586/17474086.2016.1126176
Pediatric Hematology and Oncology. 6th Edition. 15. Olivieri NF, Brittenham GM. Management of the
Elsevier. London, UK. 2016;166-196 thalassemias. Cold Spring Harb Perspect Med.
3. Whitley KS, Kwiatkowski JL. Hemoglobinopathies. In: 2013;3(6):a011767.
Kliegman R, Geme J (eds) Nelson Textbook of Pediatrics. https://doi.org/10.1101/cshperspect.a011767
21th Edition (e-book). Elsevier. Philadelphia, USA. 16. Iolascon A, Andolfo I, Barcellini W, et al. Working Study
2020; Chapter 489. Group on Red Cells and Iron of the EHA. Recommendations
4. Sankaran VG, Nathan DG, Orkin SH. Thalassemias. In: regarding splenectomy in hereditary hemolytic anemias.
Orkin SH, Nathan DG, Ginsburg D, Look AT, Fisher DE, Haematologica. 2017;102(8):1304-13.
Lux S (eds) Nathan and Oski’s Hematology and https://doi.org/10.3324/haematol.2016.161166
Oncology of Infancy and Childhood. Eight Edition. 17. Yesilipek MA, Ertem M, Cetin M, et al. HLA-matched
Elsevier. PA, USA. 2015;715-769. family hematopoetic stem cell transplantation in
5. Guidelines for the Management of Transfusion children with beta thalassemia major: the experience
Dependent Thalassaemia (TDT). Cappellini MD, Cohen of the Turkish Pediatric Bone Marrow Transplantation
A, Porter J, Taher A, Viprakasit V. 3rd ed. Thalassaemia Group. Pediatr Transplant. 2012;16(8):846-51.
International Federation TIF Publication No. 20. https://doi.org/10.1111/j.1399-3046.2012.01778.x
6. Ünal Ş, Gümrük F. The Hematological and molecular 18. Lucarelli G, Andreani M, Angelucci E. The cure of
spectrum of α-thalassemias in Turkey: The Hacettepe Thalassemia by bone marrow transplantation. Blood
Experience. Turk J Haematol. 2015;32(2):136-43. Rev. 2002;16(2):81-5.
https://doi.org/10.4274/tjh.2014.0200 https://doi.org/10.1054/blre.2002.0192
7. Aydınok Y, Oymak Y, Atabay B, et al. A national registry 19. Kunz JB, Kulozik AE. Gene Therapy of the
of thalassemia in Turkey: Demographic and disease Hemoglobinopathies. Hemasphere. 2020;4(5):e479.
characteristics of patients, achievements, and https://doi.org/10.1097/HS9.0000000000000479
challenges in prevention. Turk J Haematol. 20. Cappellini MD, Viprakasit V, Taher AT, et al. A phase 3 trial
2018;35(1):12-8. of luspatercept in patients with transfusion-dependent
https://doi.org/10.4274/tjh.2017.0039 β-thalassemia. N Engl J Med. 2020;382: 1219-31.

6
T. Aksu and Ş. Ünal, Thalassemia Trends in Pediatrics 2021;2(1):1-7

https://doi.org/10.1056/NEJMoa1910182 https://doi.org/10.1016/j.bcmd.2015.08.003
21. Karimi M, Cohan N, De Sanctis V, et al. Guidelines for 24. Harteveld CL, Higgs DR. Alpha-thalassaemia. Orphanet
diagnosis and management of beta-thalassemia J Rare Dis. 2010;5:13.
intermedia. Pediatr Hematol Oncol. 2014;31(7):583-96. https://doi.org/10.1186/1750-1172-5-13
https://doi.org/10.3109/08880018.2014.937884 25. Kulaç İ, Ünal Ş, Gümrük F. Brilliant cresyl blue staining
22. Galanello R, Cao A. Gene test review. Alpha-thalassemia. for screening hemoglobin H disease: Reticulocyte
Genet Med. 2011;13(2):83-8. smear. Turk J Haematol. 2009;26(1):45.
https://doi.org/10.1097/GIM.0b013e3181fcb468 26. Alli NA. Acquired haemoglobin H disease. Hematology.
23. Farashi S, Najmabadi H. Diagnostic pitfalls of less well 2005;10(5):413-8.
recognized HbH disease. Blood Cells Mol Dis. https://doi.org/10.1080/10245330500141689
2015;55(4):387-95.