talassemia pediatrica

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Pediatric Thalassemia
Updated: Aug 19, 2022
Author: Hassan M Yaish, MD; Chief Editor: Vikramjit S Kanwar, MBBS, MBA, MRCP(UK) 
Overview
Practice Essentials
Of genetic disorders worldwide, thalassemia syndromes are among the most common. Normal adult hemoglobin produced
after birth (hemoglobin A [HbA]) consists of a heme molecule linked to two α-globin and two β-globin chains (α2β2), with α-
globin chain production dependent on four genes on chromosome 16, and β-globin chain production arising from two genes
on chromosome 11. Deletions or mutations of one or more of these genes so that the rate of production of α- or β-globin
chains is reduced results in alpha thalassemia or beta thalassemia, respectively. Thalassemia is usually asymptomatic in
carriers, or presents with anemia of varying degrees in patients in whom globin-chain production is more severely impaired.
[1]
Patients with alpha-thalassemia trait or beta-thalassemia trait are asymptomatic but have mild microcytic hypochromic
anemia, which often goes undiagnosed or is confused with iron deficiency anemia. Recognizing the possibility of
thalassemia trait by taking a complete family history and appropriate testing is important in making an accurate diagnosis.
Individuals with thalassemia trait may be at risk of having a severely affected child and should be referred for genetic
counseling when appropriate.[2] Similarly, the birth of a child with severe thalassemia is a trigger for genetic counseling and
future prenatal testing.
Patients with severe beta thalassemia are dependent on red cell transfusions either regularly (thalassemia major) or
intermittently (thalassemia intermedia). Regardless of their transfusion needs, such patients should be followed at a
thalassemia comprehensive care center under the care of a hematologist, so that they can be monitored for short- and long-
term complications of chronic transfusions, including iron overload with cardiac and liver damage, as well as for growth and
endocrine issues, bone pathology, and infertility. Curative therapy such as bone marrow transplantation may be an option for
some patients, and novel agents, as well as gene therapy, are in the pipeline.[3, 4, 5]
Patients with severe alpha thalassemia requiring red cell transfusion (HbH disease) should be monitored closely in a similar
fashion. Recognizing that nonimmune hydrops fetalis in mothers of Southeast Asian origin can be due to severe alpha
thalassemia is important for genetic counseling and future prenatal testing. Rarely, patients with Hb Bart hydrops fetalis
have been salvaged with intrauterine transfusions, but there is considerable morbidity, and this is not the standard of care.
[6]
Presentation in pediatric thalassemia
Severe forms of beta thalassemia are characterized by the following physical findings, particularly if the patient is
inadequately transfused:
Severe pallor, scleral icterus
Enlarged abdomen due to hepatosplenomegaly
Severe bony changes due to ineffective erythroid production (eg, frontal bossing, prominent facial bones, dental
malocclusion)
Neuropathy/paralysis due to extramedullary hematopiesis
Growth retardation and short stature
Patients with alpha thalassemia, even those with a severe form (having lost 3 out of 4 genes), will have findings of mild to
moderate hemolytic anemia, as follows: 
Pallor, scleral icterus
Splenomegaly (hepatomegaly is less common)
Absence of bony deformities
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Workup in pediatric thalassemia
Complete blood count (CBC) results and red cell indices, along with peripheral blood film examination outcomes, are usually
sufficient to suspect a diagnosis of thalassemia. Hb electrophoresis can usually confirm the diagnosis of beta thalassemia,
HbH disease, and HbE/β-thalassemia.
Globin chain synthesis, which was once used in postnatal diagnosis, has also been used on fetal cells obtained by
fetoscopy to screen the fetus for thalassemia.
Since polymerase chain reaction (PCR) assay techniques became available, several new methods have come into use to
identify affected babies or carrier individuals accurately and quickly. Moreover, the sensitivity of next-generation sequencing
(NGS) has allowed noninvasive screening to be done on fetal DNA obtained from maternal plasma.
Management
Splenectomy is the principal surgical procedure used for some patients with thalassemia. However, with reports made of
venous thromboembolic events (VTEs) after splenectomy, one should carefully consider the benefits and risks before
splenectomy is advocated.
Patients typically receive PRBC transfusions (up to 20 mL/kg) every 3-4 weeks, with clinicians aiming for a 9-10 g/dL
hemoglobin level prior to the next transfusion. In some patients, shorter intervals between transfusions may be beneficial.[7]
Routine administration of iron chelation is essential to avoid transfusion-related iron overload and multiorgan (especially
cardiac and liver) toxicity.
In 2019, the European Union conditionally approved the use of betibeglogene autotemcel (Zynteglo), the first gene therapy
for the treatment of transfusion-dependent beta thalassemia.[5, 8, 9] The FDA approved the betibeglogene autotemcel in
August 2022. 
Background
Beta thalassemia was the first described in 1925, by Thomas Cooley, a Detroit pediatrician, who reported on children of
Italian origin who presented with severe microcytic anemia and other red cell abnormalities (see image below), enlarged
liver and spleen, and skull and bony abnormalities. Because of the patients’ ethnic origin, “Cooley's anemia” was later
renamed thalassemia (thalassa in Greek means "great sea" or Mediterranean).[10] In 1959, Ingram and Stratton postulated
that decrease in β-globin or α-globin production led to a transfusion-dependent anemia, and in the latter case it resulted in
HbH (β4) disease, which we now recognize as severe alpha thalassemia.[11] Three years later, Lie-injo Luan Eng, an
Indonesian pathologist, described a stillbirth with Hb Bart hydrops fetalis, the most severe manifestation of alpha
thalassemia.[12] We now recognize a number of thalassemia syndromes and have a better understanding of the underlying
pathophysiology.
Peripheral blood film in Cooley anemia.
Pathophysiology
HbA, or α2β2, consists of heme combined with two α-globin and two β-globin chains. On chromosome 16, each DNA
strand has two α-globin genes, whereas chromosome 11 has a single pair of β-globin genes. Nevertheless, the globin-chain
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output of these genes is closely matched to effectively produce HbA. In the thalassemia syndromes, mutations affecting
either gene affect this balanced production of α-globin and β-globin chains, resulting in decreased hemoglobin and varying
degrees of anemia.[8]
Alpha chain genes in duplication on chromosome 16 pairing with non-alpha chains to produce various normal
hemoglobins.
During fetal development, globin-producing genes are switched on and off to produce different hemoglobins (see figure
above). The γ-globin gene is switched on for the majority of the time in utero, producing fetal hemoglobin (HbF), or α2γ2.
After birth, this changes in a few months to adult hemoglobin (HbA), or α2β2, with small amounts of HbA2, or α2δ2 (δ-globin
production being physiologically impaired). Not shown in the figure are genes active only in early embryonic life: ζ-globin,
which precedes α-globin, combines with γ-globin to produce Hb Portland (ζ2γ2), and ε-globin, which precedes γ-globin and
forms Hb Gower (ζ2ε2, α2ε2), a hemoglobin of no clinical significance. Upstream of these globin gene clustersrequirements in a
study of patients with β-thalassemia. Blood. 2019 Mar 21. 133 (12):1279-89. [QxMD MEDLINE Link]. [Full Text].
47. Koren A, Levin C, Dgany O, et al. Response to hydroxyurea therapy in beta-thalassemia. Am J Hematol. 2008 May. 83(5):366-
70. [QxMD MEDLINE Link].
48. Karimi M, Borzouee M, Mehrabani A, Cohan N. Echocardiographic finding in beta-thalassemia intermedia and major: absence of
pulmonary hypertension following hydroxyurea treatment in beta-thalassemia intermedia. Eur J Haematol. 2009 Mar. 82(3):213-
8. [QxMD MEDLINE Link].
49. Geffner ME, Karlsson H. Use of recombinant human growth hormone in children with thalassemia. Horm Res. 2009 Jan. 71
Suppl 1:46-50. [QxMD MEDLINE Link].are
regulatory elements that help to switch globin gene activity on and off.
Each globin gene consists of three coding exons and two noncoding introns, or intervening sequences (IVS) (see image
below). This knowledge is especially relevant for beta thalassemia, in which over 200 point mutations can impair β-globin
synthesis, and the location of these mutations is often described in terms of relationship to IVS-1 or IVS-2.
Alpha and beta globin genes (chromosomes 16 and 11, respectively).
The synthesis of globin proteins at a molecular level is well understood, but to summarize: when a globin gene is
transcribed, a messenger RNA (mRNA) precursor corresponding to one of the gene's DNA strands is synthesized. This
contains exons and introns, so the mRNA is then processed by eliminating the introns and splicing together the exons,
which requires recognition of specific GT/AG base pairs at the “splice sites.” The 5’ and 3’ ends of the mRNA are then
modified, and the processed mRNA moves from the nucleus to the cytoplasm. In conjunction with a ribosome, this mRNA
now acts as a template for a series of transfer RNA (tRNA) molecules, each bringing an amino acid based on codon-
anticodon base pairing. This translation process assembles a string of amino acids into a peptide, which continues until a
specific “stop” codon is reached. The completed globin chain then drops off the ribosome-mRNA complex and joins a heme
molecule and 3 other globin chains to form a hemoglobin molecule.
Beta thalassemia is usually caused by mutations affecting a single nucleotide substitution, which can impact each step of
this process (see figure below). Authors refer to severe mutations, with complete absence of β-globin production, as β0
mutations, and refer to less severe mutations as β+ mutations. It is important to keep in mind that the severity of the
mutation may not always correlate with the clinical picture.[13] Splice-site mutations, which are especially common, change
the critical GT/AG bases around the splice site (eg, IVS1-1 G>T), rendering the splice site unrecognizable by the normal
splicing process. In a “nonsense” mutation, a single base change in the exon generates a stop codon in the mRNA, resulting
in premature termination of the globin chain. In a “frameshift” mutation, one or more bases on the exon are lost or inserted,
resulting in a change in the reading frame of the genetic code or the production of a new stop codon. Mutations in exons
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may also activate a cryptic splice site, as in HbE, in which a mutation at codon 26 (G>A) results in alternate splicing,
reducing the amount of β-globin production (similar to β+ thalassemia).[14] Rarely, deletions, rather than point
mutations, have been described; in Hb Lepore, a deletion leads to a fused δ/β gene, under the control of the δ-globin gene
promoter, which is weak (so that mild beta-thalassemia–like behavior results).
Various mutations in the beta gene that result in beta thalassemia.
Alpha thalassemia results from the deletion of one or both of the α-globin genes on the same DNA strand, with more than 35
such deletions described. Severe α0-thalassemia carriers are represented as αα/- - to show the absence of both α-globin
genes on the same strand, which is due to large deletions such as --SEA, --MED, --FIL, --THAI, or --20.2. This is a common
finding in alpha-thalassemia carriers from Southeast Asia, southern China, or the Middle East, who are therefore at risk of
having a stillbirth with Hb Bart hydrops fetalis (- -/- -). In contrast, in α+-thalassemia, smaller deletions of 3.7 or 4.2 kb from
the α-globin gene (α-3.7 or α-4.2) remove only a single gene, so that alpha-thalassemia carriers from Africa (- α/- α) are not
at risk within their own community. If an α+-thalassemia carrier and an α0-thalassemia carrier have a child, there is a risk of
HbH disease (- -/- α). In addition, point mutations can occur so that in Hb Constant Spring (αCSα) or Hb Quong Sze the stop
codon for the α-globin gene is affected, generating a long, unstable globin chain. Such nondeletional alpha-thalassemia
mutations interfere with the remaining α-globin gene production on the same DNA strand, so that - -/ αCSα causes HbH
disease that is more severe than that resulting from gene deletion.[15]
Mortality/Morbidity
In patients with thalassemia, mortality and morbidity vary according to the severity of the disease and the quality of care
provided. Severe cases of beta-thalassemia major are transfusion-dependent, and chronic iron overload or undertransfusion
can lead to cardiac failure, liver disease, chronic or acute infection, and other complications. Even patients receiving well-
designed treatment regimens may be at risk for a variety of complications.[16]
Hb Bart hydrops fetalis is lethal, and fetuses are stillborn with severe anemia, which is traumatic to the mother and family.
Intrauterine blood transfusions have salvaged some patients in specialized centers, but there is considerable morbidity, and
this is not a standard of care or an option for the vast majority of patients affected worldwide.[15]
Patients with HbH disease usually have mild hemolytic anemia requiring only occasional blood transfusions, but some
patients who have co-inherited nondeletional mutations such as Hb Constant Spring or Hb Quong Sze have more severe,
transfusion-dependent anemia. These patients may require splenectomy, and morbidity is very similar to patients with beta-
thalassemia intermedia.[17]
Epidemiology
Thalassemias are encountered among all ethnic groups and in almost every country around the world, with 15 million
people worldwide having clinical thalassemic disorders. There is a wide variation in the prevalence rate for alpha and beta
thalassemia in different parts of the world. In areas endemic for beta thalassemia, such as the Mediterranean countries and
islands, the Middle East, and the Indian subcontinent, the carrier rate is 10-15%. The lack of systematic preventive
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measures in lower-income countries, means that in India alone, 10,000 new beta-thalassemia patients are added to the
population each year.[18] Regions impacted by severe alpha thalassemia are Southeast Asia, the Middle East, and southern
China, where the carrier rate exceeds 5%, with the rate approaching 5% in Thailand. In southern China, there are 2-3 times
more fetuses afflicted with the lethal Hb Bart hydrops fetalis than with severe beta thalassemia.[19, 15]
In the United States, a diverse immigrant population has meant that thalassemia can occur in any part of the country.
However, the number of patients with severe alpha or beta thalassemia is limited, so finding more than 2-5 patients in any
pediatric hematology center is unusual (except in a few referral centers). Nonetheless, alpha thalassemia is increasingly
prevalent in the United States and accounts for more than 50% of non–transfusion-dependent thalassemia (unpublished
data, courtesy of Janet Kwiatkowski). The prevalence of alpha and beta thalassemia, as well as of HbE/β-thalassemia, is
increasing in California, due to a high prevalence of individuals of Asian origin, and the cord-blood screening program for
detection of hemoglobinopathy there annually detects 10-14 cases of beta-thalassemia major and HbE/β-thalassemia and
40 cases of HbH disease.[20]
Prognosis
Patients with alpha- or beta-thalassemia trait have a normal lifespan, while Hb Bart hydrops fetalis (homozygous α0
thalassemia) is lethal in utero. With regular transfusions of red cells and comprehensive care, including aggressive iron
chelation, life expectancy in birth cohorts with severe beta thalassemia has been found to extend into the fourth decade andbeyond. Patients with HbH disease or beta-thalassemia intermedia can be expected to survive at least as long, depending
on transfusion needs and availability of care.[7]
 
Presentation
History
Patient history in thalassemia varies widely, depending on the type of thalassemia and the severity of the underlying defect.
In most patients with thalassemia trait, no unusual signs or symptoms are encountered. The diagnosis is usually suspected
in children or adults with an unexplained mild microcytic hypochromic anemia, especially those who belong to one of the
ethnic groups at risk or are being treated for possible iron deficiency anemia with no response.[2]
Patients with beta-thalassemia major remain asymptomatic until 3-6 months of age or more, when HbF production falls and
adequate HbA cannot be produced. (In some patients with persistent HbF production or a β+ mutation, the diagnosis may
be delayed until after the first year of life, and patients may not need regular transfusions [thalassemia intermedia].) The
symptoms are a progressive, severe microcytic hypochromic anemia (see image below), with abdominal enlargement due to
hepatosplenomegaly and occasionally slight icterus. If left untreated, bony and facial changes may manifest, as well as
stunted growth. Patients with HbE/β-thalassemia behave similarly to severe beta thalassemia.[10]
Patients with severe alpha thalassemia (HbH disease) may be diagnosed only when they develop aplastic crisis with severe
pallor, or hyperhemolysis with jaundice, due to intercurrent infection. Patients with coinheritance of a nondeletional mutation
such as Hb Constant Spring (- -/ αCSα) or Hb Quong Sze (- -/ αQZα) have more severe hemolysis and are usually
diagnosed in the first year of life, whereas those with 3-gene deletions (- -/- α) have milder disease and may be diagnosed
later. The most severe form alpha thalassemia, with 4-gene deletion (- -/- -), presents as stillbirth with hydrops fetalis (Hb
Bart hydrops fetalis).[6] 
Peripheral blood film in Cooley anemia.
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Physical examination
Physical findings in thalassemia vary widely, depending on the type of thalassemia and the severity of the underlying
genetic abnormality. Patients with thalassemia trait will have no abnormal physical findings.
In severe forms of beta thalassemia, since the excess α-globin chains are insoluble, they precipitate in red blood cell (RBC)
precursors, destroying them and causing ineffective erythropoiesis. This leads to the following physical findings, usually if
the patient is inadequately transfused:
Severe pallor, scleral icterus
Enlarged abdomen due to hepatosplenomegaly
Severe bony changes due to ineffective erythroid production (eg, frontal bossing, prominent facial bones, dental
malocclusion)
Neuropathy/paralysis due to extramedullary hematopiesis
Growth retardation and short stature
A cross-sectional study by Jeelani et al indicated that in pediatric patients with beta thalassemia, dental malocclusion tends
to be more severe than that found in children without the disease. Investigating such dental malformation in transfusion-
dependent children with homozygous beta thalassemia, it was found that Angle class II malocclusion was the most
prevalent type in these patients (present in 59% of them), compared with a prevalence of class I in controls (67.5%).
Children with beta thalassemia had a significantly greater mean overjet and overbite, while the presence of severe tooth
displacement (rotation >45° or displacement >2 mm) was 3.5 times higher than that found in controls.[21]
In alpha thalassemia, the excess globin chains are γ-globin chains and, later, β-globin chains, which form soluble molecules
such as Hb Bart (γ4) and HbH (β4); thus, red cell production is not as badly affected. The anemia seen is often less severe
and not associated with ineffective erythropoiesis. Even patients with severe alpha thalassemia (having lost 3 out of 4
genes), with HbH disease, will have findings of mild to moderate hemolytic anemia, as follows: 
Pallor, scleral icterus
Splenomegaly (hepatomegaly is less common)
Absence of bony deformities
Loss of all four α-globin genes leads to hydrops fetalis and is incompatible with life, with the affected fetus being stillborn (Hb
Bart hydrops fetalis).
 
DDx
Diagnostic Considerations
The differential diagnoses will depend on the presentation, and patients fall into three clinical categories.
Asymptomatic patients in childhood or later, with mild microcytic
hypochromic anemia
Alpha- and beta-thalassemia trait need to be differentiated from iron-deficiency anemia, which is the most common cause of
microcytic hypochromic anemia in children. Assessment of the patient's nutritional and family history must be included in this
differentiation. A review of the complete blood count (CBC) can be diagnostic, owing to the fact that in thalassemia trait the
anemia is mild (usually Hb >9-10 g/dL), with the RBC count elevated and the mean corpuscular volume (MCV) significantly
decreased. This discordance is reflected in the Mentzer index, where MCV/RBC is less than 13 in patients with thalassemia
trait.
In iron-deficiency anemia, Hb electrophoresis results can be misleading, since the production of HbA2 is suppressed; if
there is a strong clinical suspicion, the test should be repeated after the iron-deficiency anemia has been treated.
Confirmation of alpha-thalassemia trait can be hard, since Hb electrophoresis is normal, but commercially available
polymerase chain reaction (PCR) screening for α-globin 3.7 kb and 4.2 kb deletions has made it easier to screen for
patients who are α+ thalassemia carriers, with these individuals commonly being of African or Middle Eastern origin.[2]
Patients with severe hemolytic anemia presenting a few months after birth,
or in early childhood.
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The concern in this category would be severe beta thalassemia (major or intermedia) or alpha thalassemia (HbH disease).
For patients who are transfusion dependent, congenital dyserythropoietic anemia and Diamond-Blackfan anemia should be
in the differential. For patients who are not transfusion dependent, Gaucher disease and other storage disorders, as well
as malignant osteopetrosis, should be considered. In almost all cases, review of the red cell indices, peripheral blood smear,
and Hb electrophoresis, of the child and parents, is usually adequate to reveal the diagnosis. Rarely does any other testing
need to be done.
HbH disease can be diagnosed based on inclusions in the RBCs (Heinz bodies), provided a supravital stain is performed,
but on Hb electrophoresis, the HbH band tends to be unstable and can be missed. Patients with HbH disease have more
than 20% Hb Bart at birth, which allows diagnosis in a newborn screening program.[20]
Patients stillborn with hydrops fetalis
Homozygous α0 thalassemia is not compatible with life (unless intrauterine blood transfusion is administered, which is a rare
situation), and a stillbirth with Hb Bart hydrops fetalis usually occurs. Other causes of immune and nonimmune hydrops
fetalis should be differentiated from alpha-thalassemia major, a condition that is commonly encountered in Southeast Asia
and southern China but is rarely seen outside those regions.[15]
Differential Diagnoses
Acute Anemia
Chronic Anemia
Gaucher Disease
Hemolytic Anemia
Hydrops Fetalis Imaging
Iron Deficiency Anemia
Osteopetrosis
Thalassemia Intermedia
Workup
 
Workup
Imaging Studies
In patients with beta thalassemia major who are not regularly transfused, plain radiographs reveal classic changes in the
bones. The striking expansion of the erythroid marrow widens the marrow spaces, thinning the cortex and causing
osteoporosis. In addition to the classic "hair on end"appearance of the skull (shown below), which results from widening of
the diploic spaces and is observed on plain radiographs, the maxilla may overgrow, which results in maxillary overbite,
prominence of the upper incisors, and separation of the orbit. These changes contribute to the classic "chipmunk" facies
observed in patients with thalassemia major.[10] Other bony structures, such as the ribs, long bones, and flat bones, may
also be sites of major deformities. Plain radiographs of the long bones may reveal a lacy trabecular pattern with osteopenia
and osteoporosis. Changes in the pelvis, skull, and spine become more evident during the second decade of life, when
marrow activity shifts primarily to those bones, and compression fractures may be noted in the vertebrae.[22]
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The classic "hair on end" appearance on plain skull radiographs of a patient with Cooley anemia.
Laboratory Studies
CBC results and red cell indices, along with peripheral blood film examination outcomes, are usually sufficient to suspect a
diagnosis of thalassemia. Laboratory results are as follows:
In severe forms of thalassemia, the Hb level ranges from 2-8 g/dL
Mean corpuscular volume (MCV) and mean corpuscular Hb (MCH) are significantly low, but, unlike thalassemia trait,
thalassemia major is associated with a markedly elevated red cell distribution width (RDW), reflecting extreme
anisocytosis
The white blood cell (WBC) count is usually elevated in beta-thalassemia major; this is due, in part, to a miscount
of the many nucleated RBCs as leukocytes; leukocytosis is usually present, even after excluding the nucleated
RBCs, with a shift to the left
The platelet count is usually normal, unless the spleen is markedly enlarged, in which case it may be diminished
Peripheral blood film examination reveals marked hypochromasia and microcytosis, hypochromic macrocytes that
represent the polychromatophilic cells, nucleated RBCs, basophilic stippling, and occasional immature leukocytes, as
shown below
Peripheral blood film in Cooley anemia.
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Contrast this with the peripheral blood film shown below, which on supravital staining shows intracellular Heinz body
inclusions (β4) associated with HbH, a severe alpha thalassemia
Supra vital stain in hemoglobin H disease that reveals Heinz bodies (golf ball appearance).
Hb electrophoresis can usually confirm the diagnosis of beta thalassemia, HbH disease, and HbE/β-thalassemia.
The electrophoresis usually reveals an elevated HbF fraction, which is distributed heterogeneously in the RBCs of patients
with beta thalassemia. HbH is usually found in patients with HbH disease (but it is unstable), while Hb Bart is found in
newborns with alpha-thalassemia trait. In β0 thalassemia, no HbA is usually present; only HbA2 and HbF are found.
In cases that are less clear-cut, checking both biologic parents' CBC, reticulocyte count, and red cell indices and performing
Hb electrophoresis on the parents can be helpful in arriving at a diagnosis.
A complete RBC phenotype assessment, a hepatitis screen, folic acid level evaluation, and human leukocyte antigen (HLA)
typing are recommended before initiation of blood transfusion therapy.
Prenatal diagnosis
Globin chain synthesis, which was once used in postnatal diagnosis, has also been used on fetal cells obtained by
fetoscopy to screen the fetus. This test reveals imbalanced production of certain globin chains that are diagnostic of
thalassemia.
Since PCR assay techniques became available, several new methods have come into use to identify affected babies or
carrier individuals accurately and quickly. The DNA material is obtained by chorionic villus sampling (CVS), and mutations
that change restriction enzyme cutting sites can be identified.
Because many of the mutations that cause alpha and beta thalassemia have become known, identifying such mutations on
the amplified β-globin gene region is now possible with specific labeled oligonucleotide probes. Moreover, the sensitivity of
next-generation sequencing (NGS) has allowed noninvasive screening to be done on fetal DNA obtained from maternal
plasma. While highly promising, such techniques should be used with caution and need to be validated for each laboratory,
given the consequences of the results obtained.[23]
Other Tests
The following tests may be indicated:
HLA typing is performed in patients for whom bone marrow transplantation is being considered
Eye examinations, hearing tests, renal function tests, liver function tests, and frequent blood counts are required to
monitor the effects of chelating agents routinely used (see Treatment, Medication)
Procedures
Bone marrow aspiration is rarely needed but may be used in certain patients at the time of the initial diagnosis to exclude
other conditions that may manifest with signs and symptoms similar to those of thalassemia major.
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Staging
A classification system introduced by Lucarelli is used for patients with severe thalassemia who are candidates for
hematopoietic stem cell transplantation (HSCT). This predicts outcome based on:
Degree of hepatomegaly
Presence of portal fibrosis in liver biopsy sample
Effectiveness of chelation therapy prior to transplantation
Class 1 patients lack any of these risk factors, and their event-free survival (EFS) rate after allogeneic HSCT is 90%. In
contrast, those who have all 3 risk factors (class 3) have an EFS rate of only 56%. Class 2 patients have 1-2 risk factors,
and their outcome lies between those for class 1 and class 3.[4]
 
Treatment
Surgical Care
Splenectomy is the principal surgical procedure used for some patients with thalassemia. With reports made of venous
thromboembolic events (VTEs) after splenectomy, one should carefully consider the benefits and risks before splenectomy
is advocated. Splenectomy may be justified when the spleen becomes hyperactive, leading to excessive destruction of
RBCs and increasing the need for transfusion to over 200-250 mL/kg of packed RBCs (PRBCs) per year to maintain an Hb
concentration of more than 10 g/dL. It can also be helpful in patients with severe HbH disease, since most of the red cells
with inclusion bodies are being destroyed in the spleen.[15]
The risks associated with splenectomy are small but not trivial. The risk of postsplenectomy infections with encapsulated
organisms and malaria in endemic areas is always a concern. Although presplenectomy immunizations and
postsplenectomy prophylactic antibiotics have decreased that risk, the procedure is delayed whenever possible until the
child is aged 4-5 years or older. Given the risk of thrombosis, low-dose daily aspirin should be considered if the platelet
count is greater than 600,000/µL postsplenectomy.
Another surgical procedure in patients with severe thalassemia on transfusion therapy is the placement of a central line for
ease of venous access.
Bone marrow transplantation from a matched sibling donor is curative and can yield thalassemia-free survival rates of close
to 90%. However, this procedure carries potential morbidity and is not available to themajority of affected patients.[4]
Medical Care
Red cell transfusion administration
The Thalassemia Clinical Research Network (TCRN) developed a series of guidelines for ongoing thalassemia
management. These guidelines primarily refer to beta-thalassemia major but can be extrapolated to all patients with severe
thalassemias. They can also be modified for low-resource countries, where the bulk of severe thalassemia patients are
found.[7]
Patients typically receive PRBC transfusions (up to 20 mL/kg) every 3-4 weeks, with clinicians aiming for a 9-10 g/dL
hemoglobin level prior to the next transfusion. In some patients, shorter intervals between transfusions may be beneficial. A
record of the patient's transfusion history should be kept. Extended RBC antigen matching to include C, E, and Kell may
reduce alloantibodies, but the reported benefit varies. Premedication with acetaminophen and diphenhydramine is often
needed in patients with a history of febrile or urticarial reactions.[7]
Immune-mediated hemolytic transfusion reactions, which can be acute or may be delayed by as much as 14 days, have
been found in 16.6% of patients. Cross-matching can be complicated and the safe provision of blood delayed when anti-
RBC antibodies are present. The use of immunomodulation to treat allosensitization is not recommended, although some
studies have employed corticosteroids, intravenous immunoglobulin (IVIG), and rituximab against autoimmune hemolysis or
hemolytic transfusion reactions.[7]
Routine, age-appropriate immunizations, as well as annual surveillance serologic testing for hepatitis A, B, and C viruses
and human immunodeficiency virus (HIV), should be performed in transfused patients with thalassemia. Annual surveillance
strategies—for example, annual liver ultrasonographic evaluation and alpha-fetoprotein monitoring to assess for
hepatocellular carcinoma secondary to hepatitis B or C—should be carried out according to disease-specific guidelines in
patients who have seroconverted for any of these pathogens.[7]
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Iron chelators
Routine administration of iron chelation is essential to avoid transfusion-related iron overload and multiorgan (especially
cardiac and liver) toxicity.[7] These agents are discussed in more detail under Medication.
Gene therapy
Betibeglogene autotemcel 
β-globin gene insertion has been shown to be effective in pilot studies, and in 2019, the European Union conditionally
approved the use of betibeglogene autotemcel (Zynteglo), the first gene therapy for the treatment of transfusion-dependent
beta thalassemia. However, the expense of such therapy is likely to restrict its application.[5, 8, 9, 24] The US Food and
Drug Administration (FDA) approved betibeglogene autotemcel in August 2022.
The autologous, one-time IV infusion transduces autologous CD34+ cells via a lentiviral vector, thus providing a patient’s
hematopoietic stem cells (HSCs) with functional copies of a modified β-globin gene. Adding the functional gene addresses
the underlying genetic cause of beta thalassemia.[25, 26]
Consultations
The following consultations may be indicated:
Pediatric surgeon
Pediatric endocrinologist
Pediatric ophthalmologist
Pediatric otolaryngologist
Pediatric gastroenterologist
Pediatric HSCT specialist
Diet
A normal diet is recommended, with emphasis on the following supplements: folic acid, small doses of ascorbic acid (vitamin
C), and alpha tocopherol (vitamin E). Iron should not be given, and foods rich in iron should be avoided. Depletion of trace
elements is common in older patients, and supplements containing copper and zinc should be considered.[27]
 
Activity
Patients with well-controlled disease are usually fully active. Patients with anemia, heart failure, or massive
hepatosplenomegaly are restricted according to their tolerances.
Complications
Patients with severe thalassemia who are regularly transfused and undergo adequate chelation can live normal, healthy
lives. However, chronic blood transfusion carries a risk of specific complications, including iron overload. These
complications are discussed below.
Iron overload
Approximately 100 mg of elemental iron (Fe) is contained in 100 mL of PRBCs. Since the normal intake of iron into the body
is only 1-2 mg/day, this results in an iatrogenic iron overload after 10-20 transfusions. Iron overload is one of the major
causes of morbidity in all patients with severe thalassemia, regardless of whether they are regularly transfused. Increased
iron absorption is the cause in nontransfused patients, but the reason behind this phenomenon is not clear.[28]
Serum ferritin level is the most commonly used test for evaluation of body iron stores, but it is important to keep in mind the
following limitations of this test:
It reflects only 1% of the total iron storage pool
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At high levels, marginal changes have little meaning
Inflammatory conditions such as fever and infection may cause the serum ferritin level to rise
T2*-weighted magnetic resonance imaging (MRI) is a noninvasive technique to assess iron loading of the liver and heart, as
well as other organs, and has largely replaced liver biopsy and other invasive techniques.
Cardiac complications
Most deaths in patients with thalassemia are due to cardiac involvement secondary to iron overload. Complications range
from constrictive pericarditis to heart failure and arrhythmias. Cardiac hemosiderosis does not occur without significant
accumulation of iron in other tissues; aggressive chelation therapy may help reverse some of the changes.
Cardiac T2*-weighted MRI has been used to estimate iron deposition in the myocardium. A shortening of myocardial T2*-
weighted MRI to less than 20 ms is associated with a 10% likelihood of decreased left ventricular ejection fraction (LVEF),
and the risk increases to 70% when it falls to below 5 ms.[29]
The LVEF measured by echocardiography has been found to be insensitive for detecting high myocardial iron as a single
measurement, but serial echocardiography has proven to be accurate and reproducible. A reduction in the LVEF of 7% or
greater over time is a strong predictor for cardiac morbidity.[30]
The liver can be cleared of iron loading much earlier than the heart, so persistent abnormal results from cardiac T2*-
weighted MRI should not be ignored.[31]
Hepatic complications
Iron deposition in the liver can cause liver enlargement, but liver enzyme levels are not typically elevated. A report on
chelation use and iron burden in over 300 North American and British patients with thalassemia who were followed from
2002-2011 showed that advances in organ-specific imaging and the availability of oral deferasirox have improved clinical
care and outcome in this patient population.[16]
Liver biopsy has historically been used to assess liver iron concentration and is a sensitive method to assess total body iron
burden, but it is an invasive procedure and has been mostly replaced by T2* MRI of the liver. Normal iron values in liver
biopsy are up to 1.8 mg Fe/g dry weight, with levels of more than 15 mg/g/dry weight associated with progression to liver
fibrosis.[28]
Gallstones
Associated with chronic hemolysis, multiple pigment gallstones are seen in over half of patients with beta-thalassemia major
by age 15 years.
HCV and other infections
Hepatitis C virus (HCV) infection is the paramount risk in patients who have been receiving blood transfusions all of their
lives. However, a 2004 report using the TCRN registry indicated that after 1990, when HCV screening of the US blood
supply was initiated, the incidence of infected thalassemia patients dropped from 70% to 5%.[32] Unfortunately, a high
incidence of HCV continues to occur in developing countries, where securing adequatelyscreened blood is a challenge.
Venous and arterial thrombosis
Venous thrombosis embolism (VTE) was encountered in significant numbers of patients with thalassemia intermedia and
may manifest with pulmonary hypertension. Patients with thalassemia are mildly hypercoagulable due to endothelial
dysfunction and increased platelet reactivity. Treatment with hydroxyurea may ameliorate this problem. In contrast,
splenectomy worsens coagulability, and low-dose aspirin is recommended for patients who have been splenectomized.[33,
34]
HbE/β-thalassemia has been associated with silent cerebral infarction, with research indicating the prevalence to be 24%. In
addition, the vascular disorder moyamoya syndrome has been reported in a patient with this form of thalassemia.[35, 36]
Endocrine complications
People with thalassemia major frequently exhibit features of diabetes mellitus; 50% or more exhibit clinical or subclinical
diabetes. This is usually associated with some degree of iron overload. Other endocrine issues are not
uncommon. Osteoporosis is a severe complication of thalassemia and may be related to a Wnt-signaling inhibitor termed
sclerostin, which inhibits osteoblast function.[37]
Growth retardation
Growth retardation is frequently severe in patients with thalassemia, occurring in about 30% of individuals with beta-
thalassemia major, and is exacerbated by hypoxia associated with chronic anemia. As a result, children with non–
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transfusion-dependent thalassemia may need to be temporarily put on regular PRBC transfusions to restore and/or allow
normal growth. Growth hormone (GH) deficiency has been postulated, and some recommend testing, but GH therapy
remains controversial; it has been shown by some to be ineffective and by others to be effective.[38]
Bony complications
Osteoporosis and osteopenia may occur even in patients who are well transfused and may result in pathologic fractures.
Compression fractures and paravertebral expansion of extramedullary masses, which can behave clinically like tumors,
more frequently occur during the second decade of life, when red cell production is confined to the central skeleton. These
changes usually disappear when marrow activity is halted by regular transfusions. In a series of adolescents and young
adults from Thailand with thalassemia syndrome, 13% were found to have fractures, and 30% of this group had multiple
vertebral fractures.[22]
Fertility and pregnancy complications
Adult patients with beta-thalassemia major have low fertility, which is thought to be related to endocrine toxicity as a
consequence of iron overload. One study reported that in 12 males with thalassemia major with a mean age of 24.8 years
and a long history of transfusion and chelation, 50% had low sperm count.[39]
Females with thalassemia major are frequently oligomenorrheic or amenorrheic, and gonadal dysfunction that results in
arrested or delayed puberty has been reported. Nevertheless, successful pregnancy and delivery of healthy babies is
possible, and in-vitro fertilization has shown that the quality of the oocytes is not compromised.[40, 41, 42]
Renal complications
In a retrospective study in which the charts and imaging studies of 89 patients with beta-thalassemia intermedia were
reviewed, renal stones were identified in 11 patients (12%), and 22 patients (25%) were on treatment for hyperuricemia.[43]
Prevention
If both parents have β-thalassemia trait, a detailed discussion with the couple should include all possible outcomes,
including the 1 in 4 chance of having a severely affected child with beta-thalassemia major. For α0 thalassemia carriers, who
are usually of Mediterranean or Southeast Asian origin, the large α-globin gene deletion removes both genes on the same
DNA strand, and genetic counseling for the couple is mandatory given the 1 in 4 risk of having a child with lethal hydrops
fetalis. In contrast, α+ thalassemia carriers (of African origin) have a single α-globin gene deletion and are not at risk for
having a newborn with severe alpha thalassemia. [15]
The decision to perform prenatal DNA testing when parents are known to be at risk for having a child with thalassemia is
complex and is influenced by several factors, such as religion, culture, education, and the number of children in the family.
Prenatal counseling can help the parents make an informed decision concerning such evaluation.[2]
New methods for neonatal screening have evolved to replace the complex techniques of DNA sequencing, restriction
enzyme PCR (RE-PCR) assay, and amplification refractory mutation system (ARMS) analysis. Such methods include
noninvasive NGS of fetal DNA obtained from maternal blood.[23]
Successful prevention programs in different parts of the world have resulted in a decline in the number of patients with
severe forms of beta thalassemia. Ferrara, Italy; Cyprus; Sardinia; Greece; and the United Kingdom were among the first to
report a significant decline in the birthrate of children with thalassemia major. Other regions with more limited resources are
struggling to recreate this achievement. Premarital screening programs, genetic counseling, and public education
campaigns are all part of the effort. [19, 18]
Long-Term Monitoring
Pain assessment, to screen for back pain, and other bony pain should be performed at each clinic visit. 
Psychosocial review to screen for anxiety and depression and decreased quality of life should be performed more frequently
in teenagers and adults.
 
Guidelines
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Guidelines Summary
TCRN guidelines
The Thalassemia Clinical Research Network (TCRN) generated guidelines for monitoring patients with beta-thalassemia
major, but these can be extrapolated to all individuals with severe thalassemia and also modified for low resource countries,
where the bulk of severe thalassemia patients are found.[7]
Iron overload should be addressed as follows[7] :
Serum ferritin should be measured at least every 3 months, and levels >2000 ng/ml are historically associated with
increased risk of complications; although this measurement has several limitations, changes over time can reflect the
efficacy of chelation
Carry out liver function tests at least every 6 months, and more frequently in patients taking deferasirox
Liver biopsy should be initiated by age 5 years and rechecked every 1-2 years, with liver iron concentration (LIC) >15
mg/g dry weight reflecting significant iron overload; T2*-based MRI has proved to be an accurate noninvasive
substitute, and where available this has replaced liver biopsy
Echocardiography and cardiac T2*-weighted MRI should be initiated by age 10 years and continued annually;
cardiac risk as measured using T2*-weighted MRI is as follows: >20 ms, normal; 10-20 ms, moderate or at-risk;calcium should be monitored, and parathyroid hormone (PTH) and vitamin D should be evaluated
annually, to screen for deficiency (a source of bone pathology)
Assessment of linear growth and weight should be performed at least quarterly in children and adolescents with
thalassemia who are undergoing chronic transfusion therapy, and annual calculation of growth velocity should be
conducted annually from birth until adulthood, to screen for growth problems; GH testing can be considered only
after consulting an endocrinologist
Patients should be screened every 6 months, via measurement of sitting height, for chelator toxicity–associated
truncal shortening
Measurement of head circumference should be conducted every 6 months to screen for skull changes that anemia
and ineffective erythropoiesis can induce
Starting at age 10 years, the patient should be evaluated annually for low bone mass via dual-energy radiographic
absorptiometry (DRA)
 
Medication
Medication Summary
Medications for the treatment of beta thalassemia are primarily intended to minimize the complications associated with
chronic transfusions and the disease process. Chelation therapy is essential to mitigate the toxic effects of transfusional iron
overload, and monitoring includes assessment of iron burden, as well as any side effects from treatment.[28, 16, 7]
Deferoxamine, deferasirox, and deferiprone are the three chelators licensed for US use.[7] Adherence to chelation therapy
is key to successful long-term outcomes. Complications of chelator use include the following:
Deferoxamine, which is administered as a continuous subcutaneous infusion, commonly produces local reactions,
including erythema and induration [7]
Deferasirox is prone to causing gastrointestinal (GI) upset, which worsens adherence; there have been reports of
renal and hepatic dysfunction and cytopenias, so a CBC, a creatinine assessment, a urinalysis, and liver function
tests should be conducted monthly
Deferiprone is associated with reversible neutropenia occurring at a rate of 0.2/100 patient years, and regular blood
counts are advised; liver inflammation sometimes occurs, and serum alanine aminotransferase (ALT) should be
monitored at least every 3 months
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All three chelators may lead to zinc deficiency and skeletal changes, including rickets-like lesions; moreover, annual
ophthalmologic and audiologic evaluations are recommended for patients on any of these agents [44, 45]
Some medications, such as hydroxyurea and thalidomide, have the potential to increase the Hb level in a subset of patients.
In 2019, the novel agent luspatercept-aamt, which minimizes red cell destruction by decreasing α-globin production, was
approved by the FDA for the treatment of beta thalassemia.[46] 
The one-time gene therapy betibeglogene autotemcel has been approved in Europe and the United States. 
Antipyretics, analgesics
Class Summary
Administration before blood transfusion prevents or decreases febrile reactions.
Acetaminophen (Tylenol, Tempra, Panadol)
Antipyretic effect through action on hypothalamic heat-regulating center. Action equal to that of aspirin but preferred
because does not have adverse effects of aspirin.
Antihistamines
Class Summary
Administration prior to blood transfusion may decrease or prevent allergic reactions.
Diphenhydramine hydrochloride (Benadryl)
Antihistamine with anticholinergic and sedative effects.
Chelating agents
Class Summary
These agents are used to chelate excessive iron from the body in patients with iron overload.
Deferoxamine mesylate (Desferal)
Chelates iron from ferritin or hemosiderin but not from transferrin, cytochrome, or Hb.
Deferasirox (Exjade)
Deferasirox comes in tablet form for oral suspension. It is an oral iron chelation agent that reduces liver iron concentration
and serum ferritin levels. Deferasirox binds to iron with a high affinity, in a 2:1 ratio. It is approved to treat chronic iron
overload due to multiple blood transfusions and nontransfusion-dependent thalassemia.
Deferiprone (Ferriprox)
Deferiprone is an iron chelator indicated for adults and children aged 3 years or older, in whom transfusional iron overload
has resulted from a thalassemia syndrome or from sickle cell disease or other anemia. It is available in tablet form or as an
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oral solution.
Corticosteroids
Class Summary
Some patients may develop local reaction at the site of DFO injection. Hydrocortisone in the DFO solution may help to
reduce the reaction.
Hydrocortisone (Solu-Cortef, Cortef, Hydrocortone)
Anti-inflammatory action. Both Na succinate (Solu-Cortef) and Na phosphate (Cortef) forms used for IV infusion, but not Na
acetate form (Hydrocortone).
Antibacterial combinations
Class Summary
Yersinia enterocolitica infections are more common in iron-overloaded patients with transfusion-dependent thalassemia.
Appropriate therapy is a combination of trimethoprim-sulfamethoxazole and gentamicin. Patients who require splenectomy
need to receive prophylactic penicillin to reduce the risk of fulminant sepsis.
Trimethoprim-sulfamethoxazole (TMP/SMX, Bactrim, Septra)
In combination with gentamicin, DOC for infections by Y enterocolitica.
Gentamicin (Garamycin)
Aminoglycoside known to be effective against gram-negative microorganisms. Dosing regimens are numerous; adjust dose
based on CrCl and changes in volume of distribution.
Penicillin V (Pen-Vee, Veetids, V-Cillin K)
DOC for postsplenectomy prophylaxis; erythromycin used in patients allergic to penicillin. Active against most
microorganisms considered to be major offenders in splenectomized patients, namely, streptococcal, pneumococcal, and
some staphylococcal microorganisms, but not penicillinase-producing species.
Vitamins
Class Summary
Several vitamins are required, as either supplements or enhancers of the chelating agent.
Serum level of vitamin C is low in patients with thalassemia major, likely due to increased consumption in the face of iron
overload.
Ascorbic acid (Vitamin C, Cebid, Vita-C, Ce-Vi-Sol, Cecon, Dull-C)
Delays conversion of transferrin to hemosiderin, thus making iron more accessible to chelation.
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Alpha-tocopherol (Vitamin E, Aquasol E, Vita-Plus E Softgels, Vitec, E-
Vitamin)
An antioxidant. Prevents iron-mediated toxicity caused by peroxidation of cell membrane lipids, reducing extent of
accompanying hemolysis. Protects polyunsaturated fatty acids in membranes from attack by free radicals and protects
RBCs against hemolysis. Demonstrated to be deficient in patients with iron overload receiving chelation therapy.
Folic acid (Folvite)
Required for DNA synthesis; therefore in great demand in these patients because of increased cellular turnover. Deficient in
most patients with chronic hemolysis.
Vaccines
Class Summary
Splenectomized patients are usually prone to developing infections with the encapsulated organisms such as pneumococci,
Haemophilus influenzae, and meningococcal organisms. For this reason, such patients now are immunized against these
organisms 1-2 wk prior to the procedure to prevent infections.
Pneumococcal vaccine polyvalent (Pneumovax)
Polyvalent polysaccharide vaccine (PS23) contains 23 serotypes that cause 70% of invasive infections. This vaccine should
not be given to childrencaused by H influenzae type b. Decreases
nasopharyngeal colonization. The CDC's Advisory Committee on Immunization Practices (ACIP) recommends that all
children receive one of the conjugate vaccines licensed for infant use beginning routinely at age 2 mo.
Conjugate form usually given in series of 3 doses at ages 2, 4, and 6 mo. Patients who have already received primary
vaccine and booster dose at age 12 mo or older are usually protected and do not require further vaccination prior to
splenectomy.
Meningococcal A C Y and W-135 polysaccharide vaccine combined
(Menomune A/C/Y/W-135)
Used only in children >2 y. Serogroup specific against groups A, C, Y, and W-135 Neisseria meningitidis.
Pneumococcal vaccine 13-valent (Prevnar 13)
Sterile solution of saccharides of capsular antigens of S pneumoniae serotypes 1, 3, 4, 5, 6A, 6B, 7F, 9V, 14, 18C, 19A, 19F,
and 23F individually conjugated to diphtheria CRM197 protein. Primary series consists of 4 doses at ages 2, 4, 6, and 12-15
months. Additionally, supplemental dose indicated for individuals at high risk. 
Antineoplastic agent
Class Summary
Some patients may respond to hydroxyurea and subsequently decrease or eliminate transfusion requirements. Patients with
homozygous or heterozygous XmnI polymorphism were found to respond favorably in one study.[47] Improvement of
pulmonary hypertension following hydroxyurea has also been observed.[48]
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Hydroxyurea (Droxia, Hydrea)
Inhibitor of deoxynucleotide synthesis.
Growth Hormone
Class Summary
Excessive chelation with deferoxamine may cause growth retardation. Growth hormone may be effective in increasing
growth rate in all thalassemic patient particularly the ones with growth hormone deficiency.[49]
Somatropin (Saizen, Genotropin, Humatrope, Norditropin, Tev-Tropin)
Human growth hormone produced by recombinant DNA technology (mouse C127 cell line). Elicits anabolic and anticatabolic
influence on various cells including: myocytes, hepatocytes, adipocytes, lymphocytes, and hematopoietic cells. Exerts
activity on specific cell receptors including insulinlike growth factor-1 (IGF-1).
Antiplatelet Agents, Hematologic
Class Summary
Antiplatelet agents are used for reduction of platelet adhesiveness in thrombotic disease and as anti-inflammatory agents for
immune-mediated or noninfectious inflammatory conditions.
Aspirin (Acetylsalicylic acid, ASA, Bayer Advanced Aspirin)
Aspirin inhibits prostaglandin synthesis, preventing the formation of platelet-aggregating thromboxane A2. It may be used in
a low dose to inhibit platelet aggregation and improve complications of venous stases and thrombosis.
Erythroid Maturation Agents
Class Summary
In November 2019, the first erythroid maturation agent was approved for anemia in adults with beta thalassemia who require
regular red blood cell (RBC) transfusions.
Luspatercept (Luspatercept-aamt, Reblozyl)
Suppresses growth differentiation factor 11 (GDF11), an activin receptor IIA (ActRIIA) ligand that is increased in
erythroblasts in beta thalassemia. Oxidative stress is consequently reduced, as is the amount of α-globin membrane
precipitate, thus increasing terminal erythroid differentiation and decreasing ineffective erythropoiesis.
Gene Therapy, Hematologics
Class Summary
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One-time IV infusion that transduces autologous CD34+ cells via a lentiviral vector, thus providing a patient’s hematopoietic
stem cells (HSCs) with functional copies of a modified β-globin gene. Adding the functional gene addresses the underlying
genetic cause of beta thalassemia.
Betibeglogene autotemcel (Zynteglo)
Indicated for beta thalassemia in patients in whom regular red blood cell transfusions have been required. After IV infusion,
engraftment of transduced CD34+ HSCs in bone marrow occurs, with these HSCs differentiating to produce RBCs carrying
biologically active betaA-T87Q-globin (a modified β-globin protein). When this protein combines with α-globin, functional
hemoglobin containing betaA-T87Q-globin (HbA-T87Q) is produced.
 
References
Contributor Information and Disclosures
Author
Hassan M Yaish, MD Medical Director, Intermountain Hemophilia and Thrombophilia Treatment Center; Professor of
Pediatrics, University of Utah School of Medicine; Director of Hematology, Pediatric Hematologist/Oncologist, Department of
Pediatrics, Primary Children's Medical Center
Hassan M Yaish, MD is a member of the following medical societies: American Academy of Pediatrics, American Medical
Association, American Society of Hematology, American Society of Pediatric Hematology/Oncology, Michigan State Medical
Society, New York Academy of Sciences
Disclosure: Nothing to disclose.
Specialty Editor Board
Mary L Windle, PharmD Adjunct Associate Professor, University of Nebraska Medical Center College of Pharmacy; Editor-
in-Chief, Medscape Drug Reference
Disclosure: Nothing to disclose.
James L Harper, MD Associate Professor, Department of Pediatrics, Division of Hematology/Oncology and Bone Marrow
Transplantation, Associate Chairman for Education, Department of Pediatrics, University of Nebraska Medical Center;
Associate Clinical Professor, Department of Pediatrics, Creighton University School of Medicine; Director, Continuing
Medical Education, Children's Memorial Hospital; Pediatric Director, Nebraska Regional Hemophilia Treatment Center
James L Harper, MD is a member of the following medical societies: American Society of Pediatric Hematology/Oncology,
American Federation for Clinical Research, Council on Medical Student Education in Pediatrics, Hemophilia and
Thrombosis Research Society, American Academy of Pediatrics, American Association for Cancer Research, American
Society of Hematology
Disclosure: Nothing to disclose.
Chief Editor
Vikramjit S Kanwar, MBBS, MBA, MRCP(UK) Professor Emeritus of Pediatrics, Albany Medical College; Chief of Pediatric
Oncology, Homi Bhabha Cancer Hospital, Varanasi, India
Vikramjit S Kanwar, MBBS, MBA, MRCP(UK) is a member of the following medical societies: Children's Oncology Group,
Indian Academy of Pediatrics, International Society of Pediatric Oncology
Disclosure: Nothing to disclose.
Additional Contributors
J Martin Johnston, MD Associate Professor of Pediatrics, Mercer University School of Medicine; Director of
Hematology/Oncology, The Children's Hospital at Memorial University Medical Center; Consulting Oncologist/Hematologist,
St Damien's Pediatric Hospital
J Martin Johnston, MD is a member of the following medical societies: American Academy of Pediatrics, American Society of
Pediatric Hematology/Oncology, International Society of Paediatric Oncology
Disclosure: Nothing to disclose.
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https://emedicine.medscape.com/article/958850-print 20/21
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