Pediatric Hematology and Oncology

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Guidelines for Diagnosis and Management of Beta-

Thalassemia Intermedia

Mehran Karimi, Nader Cohan, Vincenzo De Sanctis, Naji S. Mallat & Ali Taher

To cite this article: Mehran Karimi, Nader Cohan, Vincenzo De Sanctis, Naji S. Mallat & Ali Taher
(2014) Guidelines for Diagnosis and Management of Beta-Thalassemia Intermedia, Pediatric
Hematology and Oncology, 31:7, 583-596, DOI: 10.3109/08880018.2014.937884

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Pediatric Hematology and Oncology, 31:583–596, 2014
Copyright C Informa Healthcare USA, Inc.
ISSN: 0888-0018 print / 1521-0669 online
DOI: 10.3109/08880018.2014.937884

REVIEW

Guidelines for Diagnosis and Management of

Beta-Thalassemia Intermedia

Mehran Karimi,1 Nader Cohan,1 Vincenzo De Sanctis,2 Naji S. Mallat,3

and Ali Taher3
1
Hematology Research Center, Shiraz University of Medical Sciences, Shiraz, Iran; 2 Private
Accredited Hospital Quisisana, Ferrara, Italy; 3 Department of Internal Medicine, American
University of Beirut Medical Center, Beirut, Lebanon

Beta-thalassemia intermedia (β-TI) is a genetic variant of beta-thalassemias with a clinical disorder

whose severity falls between thalassemia minor and thalassemia major. Different genetic defects
are involved in this disorder and, based on severity of disease, clinical complications like skeletal
deformities and growth retardation, splenomegaly, extramedullary hematopoiesis, heart failure,
and endocrine disorders may be present in untreated patients. Precise diagnosis and management
are essential in these patients for prevention of later clinical complications. Diagnosis of TI is based
on clinical and laboratory data. There are some treatment strategies like modulation of gamma-
globulin chain production with hydroxyurea or other drugs, transfusion, splenectomy, and stem
cell transplantation. Iron chelation therapy is also needed in many of these patients even if they are
not transfused. The aim of this manuscript is to review the clinical manifestations, complications,
genetic defects, and unmet treatments needs in TI.
Keywords beta-thalassemia intermedia, clinical complications, diagnosis, management

INTRODUCTION
Beta-thalassemia is one of the most common genetic disorders worldwide which
is caused by decreased synthesis of beta-globin chain subunits and subsequently
alpha/beta-globin chain imbalance. Accumulation and deposition of free excessive al-
pha globin chains and their degradation products on the red cells and their precursor’s
cell membrane caused generation of reactive oxygen species. It damages cellular lipids
and proteins (e.g., protein band 4.1) as well as IgG autoantibody and complement pro-
teins to neoantigents. The later process results from clustering of transmembrane pro-
tein band 3 in the red cells and their precursors, so that the destruction of these cells by
macrophages leads to ineffective erythropoiesis and hemolytic anemia [1, 2]. Ineffec-
tive erythropoiesis, chronic hemolytic anemia, and iron overload are the main patho-
physiologic complications in beta-thalassemia intermedia (β-TI). Beta-thalassemias
are diverse groups of disease based on a wide spectrum of clinical phenotypes. The
clinical phenotypes usually include asymptomatic forms of beta-thalassemia minor

Received 7 May 2014; accepted 19 June 2014.

We thank Prof. Alan Cohen for helpful comments and editing the manuscript.
Address correspondence to Mehran Karimi MD, Professor of Pediatric Hematology-Oncology,
Hematology Research Center, Shiraz University of Medical Science, Shiraz, Iran. E-mail:
Karimim@sums.ac.ir


 M. Karimi et al.

to severe transfusion dependent of beta-thalassemia major (β-TM). It results from

homozygous or compound heterozygous forms of beta-gene mutations, is a severe
hemolytic anemia that is usually presented in the first year of life and necessitates reg-
ular transfusions and careful medical attention for their survival. β-TI is a form of dis-
ease which lies between thalassemia minor and TM based on its clinical phenotypes.
It is usually clinically milder than TM and causes mild to severe hemolytic anemia. Al-
though TI is a nontransfusion-dependent thalassemia form, some patients occasion-
ally need blood transfusions. They also require careful medical attention like TM to
improve quality of life [3, 4].

Beta-Thalassemia Intermedia
I: Definition and Clinical Manifestations
The term TI is clinically descriptive of beta-thalassemic patients whose clinical man-
ifestations are not as mild as thalassemia minor or as severe as TM [5]. The first de-
scription of TI was made by Rietti Greppi Micheli in 1955. He described a thalassemic
patient with clinical phenotype between thalassemia minor and TM [6]. Genetic het-
erogeneity of TI is associated with wide clinical spectrum presentations from mild to
severe hemolytic anemia and can be divided into two subgroups: (1) Some patients
are mildly affected leading to mild clinical problems until adult life. These patients
maintain hemoglobin levels between 7 and 11 gr/dL and are usually transfusion in-
dependent or rarely require blood transfusions. (2) Patients with more severe anemia
who generally present at ages 2–6 years old. Although they may not require regular
transfusions like the first subgroup, without occasional transfusions and appropriate
management, they frequently develop clinical symptoms such as skeletal deformities
and growth retardation [6–9]. While TI and TM have some overlap in their clinical pre-
sentations, differentiation of the two disorders is essential for optimal management
and prevention of their later complications. TI can present with pallor, jaundice, ane-
mia, splenomegaly or skeletal deformities during childhood or later. Diagnosis of TI is
usually made after the age of 2 years with initial Hb levels of 7 gr/dL or more in patients
with beta-thalassemia who are free of infection and have adequate folic acid. One of
their parents is also atypical carrier of beta-thalassemia such as normal or borderline
HbA2 or isolated increased HbF (usually up to 10%) [6, 8, 10]. The patients are usu-
ally referred with microcytic-hypochromic anemia (low MCV and low MCH) and the
peripheral smear shows mild to severe microcytosis and hypochromia, anisopoikilo-
cytosis, polychromasia, target cell, basophilic stippling, and nucleated RBC (NRBC).
Hb electrophoresis includes: HbA: up to 80%; HbA2: normal or up to 7%HbF: > 10%.
Serum iron, serum ferritin and transferrin saturation may be increased. Diagnostic al-
gorithm of β-TI and its differential diagnosis is shown in Figure 1. Differential diagno-
sis between TI and TM is essential because the first step for management of patients
with TI is usually not transfusion; however, the first choice of TM management is blood
transfusion. Table 1 shows some differentiating parameters between TI and TM.

II: Mutation Analysis and Molecular Definition of TI

TI arises from gene mutations affecting beta-globin production. Most patients are ho-
mozygotes or compound heterozygotes for beta-thalassemia. Less commonly only
one beta-globin gene is affected [11, 12]. The different phenotypes of patients with
TI arise from different gene defects that cause a mild to severe alpha/beta-globin
chains imbalance. The molecular defects of TI can be divided in four major groups:
I: Beta-globin gene mutations that lead to slight reduction in this globin chain [7,
12–14]. II: Co-inheritance of alpha-thalassemia with beta-TM can ameliorate the clin-
ical course of beta-TM patients and cause a different spectrum disease by reduc-
ing alpha/beta-globin chain imbalance [7, 15]. III: Co-inheritance of gene defects

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 Thalassemia Intermedia 

FIGURE 1 Diagnostic algorithm of beta-thalassemia intermedia and its differential diagnosis.

that cause an increased production of gamma-globin chain can also ameliorate the
clinical course of beta-TM patients by increased production of HbF that leads to re-
duced alpha/beta-globin chain imbalance. Homozygous or compound heterozygous
of beta-thalassemia with heterocellular hereditary persistence of fetal hemoglobin,
some forms of delta/beta-thalassemia and Xmn-I polymorphism are related to higher
level of gamma-globin chain production and ameliorate the clinical course of beta-
thalassemia [5, 16]. IV: Heterozygosity for beta-thalassemia and triplicated or qua-
druplicated alpha-gene locus and compound heterozygosity for beta- or delta/beta-
thalassemia [5, 17].

III: Clinical Complications and Management in TI

Like TM, three main factors are responsible for the clinical manifestations in untreated
TI patients: ineffective erythropoiesis, chronic hemolytic anemia, and iron overload.
Ineffective erythropoiesis is responsible for erythroid marrow hyperplasia and skeletal
deformities, hemolytic anemia and extramedullary hematopoiesis (EMH). Hemolysis
is commonly associated with splenomegaly, hypercoagulable state, and pulmonary
hypertension (PHT).
EMH: Erythropoietic tissue masses occur as a compensatory mechanism to over-
come chronic hemolysis, EMH is most commonly found in the liver, spleen, and lymph
nodes. Paraspinal masses can cause cord compression and neurological damage (Fig-
ure 2). Paraspinal EMH mainly presents as pseudotumors, which may possibly cause a
variety of neurological symptoms due to spinal compression. Most of the cases remain
asymptomatic, but various neurological clinical presentations have been reported.

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 M. Karimi et al.

TABLE 1 Differentiation Between Thalassemia Intermedia and Thalassemia Major

Thalassemia intermedia Thalassemia major
Clinical manifestations
Age of presentation (years) >2 <2
Splenomegaly Moderate to severe Mild in case of optimal
management
Transfusion Nondependent or occasionally Dependent
Pallor, jaundice Usually yes No or mild if optimal
management
Skeletal deformities Usually yes No or mild if optimal
management
Hematologic data
Hb levels (g/dL) ≥6–7 <6–7
HbF (%) 10–50 (may be up to 100%) >50 (may be less than 50%)
HbA2 (%) ≥3.5 <3.5
Mean cell volume (MCV) Decrease Normal, if optimal
management
Nucleated red blood cells Increase Normal, if optimal
(NRBC) management
White blood cell (WBC) Increase Normal, if optimal
management
Complications
Thrombosis Common Less common
Pulmonary hypertension Common Rare
Right-sided heart failure Common Rare
Left-sided heart failure Rare Common
Leg ulcer Common Rare
Extramedullary Common Rare
hematopoiesis
Endocrine complications Uncommon Common
Viral hepatitis Rare Common
Genetic and molecular characteristics
Parents One or both are atypical Both are typical carriers of
carriers of beta-thalassemia beta-thalassemia minor
minor
Type of mutation Silent to mild Severe
Coinheritance of Yes No
alpha-thalassemia,
hereditary persistence of
fetal hemoglobin,
delta-thalassemia, XmnI
polymorphism

The size and location of lesions as well as the extent of spinal cord involvement de-
termine the severity, and multiplicity of signs and symptoms [18]. EMH has also been
reported in pleura, pericardium, chest (Figure 2), intracranial cavity, adrenal glands,
and some other organs [19]. Hydroxyurea (HU) therapy, blood transfusion, and ra-
diation therapy are therapeutic options for EMH in these patients. There are several
reports showing that HU can be effective and safe. The dosage of HU should be higher
(20–30 mg/kg/d) compared to the dosage that it is usually used for TI for enhancement
of gamma globin chain synthesis (8–15 mg/kg/d). There are four case reports (3 TI and
1 TM) that were successfully treated with HU alone [20]. The other treatment modali-
ties should be considered if the patient does not respond to HU therapy. Surgery is not
recommended as it has been related to bleeding in these patients.
Thrombosis: In a cohort study that was done on 8860 thalassemia patients (6670
TM and 2190 TI) it was demonstrated that thromboembolic event (TEE) occurred

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 Thalassemia Intermedia 

FIGURE 2 (1) Bilateral leg ulcers in TI, 1A. Before treatment 1B. After treatment 2. EMH in spinal
cord of a patient with TI cause to cord compression, 2A. Before treatment 2B. After treatment 3. Brain
MRI in a TI patient showing multifocal hyperintense lesions in the matter suggestive of ischemia,
3A. Axial T2-weighted 3B. FLAIR image 4. Rib expansion in TI.

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 M. Karimi et al.

4.38 times more frequently in TI than TM patients [21]. The most important factor in-
volved in hypercoagulability is exposure of negatively charged phospholipids on the
RBCs membrane remnants as a result of oxidative stress and subsequent activation
of the prothrombinase complex and enhanced thrombin generation. However, some
other factors like decreased levels of the antithrombotic proteins C and S, endothelial
exposure to inflammation, and oxidative effects of hemolysis and increased number
of activated platelets in splenectomized patients are also involved in TEEs in these pa-
tients. Splenectomized TI patients have a higher incidence of TEE compared to non
splenectomized TI patients [4]. These patients who develop TEE are characterized by
high NRBC and platelet counts, and are more likely to have evidence of PHT and be
transfusion naive. Furthermore, high NRBC and platelet counts as well as transfusion
naivety are associated with earlier development of TEE after splenectomy [22].
Deep and portal vein thrombosis, pulmonary embolism, and brain ischemia and
infarction (Figure 2) resulting in stroke are the main thromboembolic complications
in TI patients [23, 24]. Overt stroke is much more common in TM than TI due to higher
stroke related risk factors such as diabetic mellitus, heart failure and arrhythmia in
these patients but silent ischemic brain lesions are more common in TI. The initial
study of neurologic disease in TI from 1999 assessed brain MRI in 16 patients and
showed silent ischemic brain lesion in 37.5% of patients [25]. Similar studies in Iran
and Lebanon also showed the frequency of silent ischemic brain lesions in 26% and
60% of these patients, respectively [23, 26].
Cerebrovascular accidents (CVA) and silent ischemic lesions are reported espe-
cially frequently in TI patients in the subgroup of patients who are adults, transfusion-
independent, splenectomized, and have a platelet count >500 ×10 9/L. It is highly rec-
ommended that patients with silent infarcts be treated with antiplatelet drugs. Blood
transfusion on a regular basis should be strongly considered in such patients and def-
initely initiated for patients with symptomatic CNS disease [23, 27]. There is also a
large study in Iran of 95 TI patients that showed the protective effect of HU therapy
in the prevention of silent ischemic brain lesions [28]. Thrombocytosis is a risk factor
for thrombotic events, especially in splenectomized patients. Antiplatelet drugs like
aspirin are indicated in this situation. Prophylactic anticoagulation therapy is also rec-
ommended in TI patients who are undergoing some types of surgery as well as those
who have a previous history of deep vein thrombosis, pulmonary embolism or stroke.
Low molecular weight heparin can be used for a period of 7–14 days postoperatively
to prevent postsurgery thrombosis. However, in patients with TEE life-long anticoag-
ulation seems to be rational and effective in prevention of recurrent TEE.
PHT: PHT, defined as systolic pulmonary artery pressure >35 mmHg, may be a
common complication in TI patients with a frequency that has been reported to be
as high as 60%. However, other studies found a frequency of 10–12% [29–31]. PHT is
the primary cause of right sided congestive heart failure in these patients, in contrast
to TM patients in whom left-sided ventricular failure is more common. Hemolysis has
a key role in the development of PH in TI patients. It was shown that chronic hemolysis
leads to nitric oxide depletion due to nitric oxide scavenging, arginine catabolism, and
endogenous nitric oxide synthesis inhibition. It also contributes to enhanced platelet
activation and increased endothelin-1 release [32,33], and thus, endothelial dysfunc-
tion, increased vascular tone, inflammation, hypercoagulability, vascular remodel-
ing, and destruction of pulmonary vasculature, which ultimately results in hemolytic
anemia–associated PH [32, 34].
Blood transfusion and sildenafil (in some cases) are recommended as an optimal
therapy in β-TI patients with PAH. Some studies have shown that HU therapy alone or
in combination with l-carnitine or magnesium can be effective in improving hemato-
logic parameters and cardiac status in patients with TI [29–31].

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 Thalassemia Intermedia 

Iron overload and Endocrine complications: increased iron absorption due to

chronic hemolytic anemia can cause iron overload and serious iron-related organ
complications like cardiac dysfunction and endocrine dysfunction including diabetic
mellitus, hypogonadism, infertility, and hypoparathyroidism [35]. Endocrine compli-
cations are less common in TI patients in comparison with TM patients because of
fewer blood transfusions and therefore less severe overload.
Viral infection commonly due to blood borne viruses such as hepatitis C is a signif-
icant cause of liver disease in TI.
Treatment of hepatitis C with α-interferon and ribavirin in these patients is asso-
ciated with difficulty due to hemolysis from treatment which has exacerbated anemia
and blood transfusion may be needed [36].
Involvement of liver by iron overload or hepatitis or both can lead to cirrhosis and
hepatocellular carcinoma in older patients [37, 38].
Leg ulcer: Leg ulcer is a serious complication in TI patients occurring in almost one
third of patients with poorly controlled disease (Figure 2). They usually appear in the
second decade of life and are generally located on the medial or lateral malleoli. The
ulcers can develop after minor trauma and tend to expand rapidly. Chronic anemia, re-
duced oxygen delivery to the distal regions and venous stasis in TI patients may cause
leg ulcers in older patients. Also, increased rigidity of erythrocytes cellular membrane,
local edema due to venous stasis, right sided heart failure, repetitive local trauma, skin
infections, hypercoagulablility, and prothrombotic tendency are other contributing
factors to ulcer formation. Blood transfusion (in some cases), local wound care, and
HU therapy are the major strategies in these cases. Although HU therapy specifically
seems to help in TI, it does not help in leg ulcers in sickle cell disease; however, it is
associated with ulcer development in other conditions [39, 40].
Other complications: Cachexia and hyperuricemia due to the hypercatabolism
of erythroid hyperplastic tissue (more prevalent in TI in comparison to TM) and
cholelithiasis induced by hyperbillirubinemia are some other metabolic complica-
tions in TI [16, 41]. Alloporinol therapy is recommended in cases with hyperuricemia.
The diagnosis and management of some clinical complications in TI are summa-
rized in Table 2. Management of TI
Treatment of TI is essential for prevention of clinical complications. The limited
options available for management of TI include transfusion therapy, iron chelation,
splenectomy, modulation of gamma-globulin chain production, and stem cell trans-
plantation. The OPTIMAL CARE study, performed to evaluate the rate of complica-
tions in relation to currently practiced treatment options [4] showed that the highest
rates of complications were seen in patients who did not receive any treatment (Table
3). This study showed the incidence of complications was lower among patients who
received HU therapy, transfusion and iron chelation therapy compared to those who
did not.

Transfusion Therapy
Administration of regular blood transfusions is not a routine treatment strategy in all
TI patients but it is an essential treatment option in some situations (Table 4). Re-
cently published international guidelines for transfusion therapy are numerous. Oc-
casional transfusion should be done in pregnancy, surgery, and infections. More fre-
quent transfusions should be considered in patients with a declining hemoglobin level
in parallel with profound enlargement of the spleen, patients with growth failure, poor
performance at school, diminished exercise tolerance, and failure of secondary sex-
ual development in correlation with bone age. Furthermore, signs of bone changes,
and poor quality of life should prompt initiation of blood transfusion therapy. Trans-
fusion may also be considered for the primary prevention, management or secondary

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 M. Karimi et al.

TABLE 2 Definition and Management of Some Clinical Complications in Thalassemia Intermedia

Clinical complication
Extramedullary
hematopoiesis
Pulmonary hypertension
Endocrine dysfunction
Leg ulcer
Thrombotic events
Diagnosis Treatment
MRI, CT scan, X-ray Hydroxyurea therapy,
transfusion, radiotherapy
Echocardiography Regular transfusion, iron
chelation therapy, sildenafil
can be used in some cases
Diabetic mellitus Management consists of:
Fasting blood glucose, oral hormone-replacement
glucose tolerance test, therapies, vitamin D,
blood glucose 2 hours after bisphosphonates, and calcium
meal supplementation with
Hypothyroidism follow-up bone densitometry
TSH, FT4, bone age (X-ray
of wrist and hand)
Calcium metabolism and
Osteopenia/Osteoporosis
Calcium, phosphorus,
alkaline phosphatase,
25-hydroxy vitamin D,
parathyroid hormone
osteocalcin, C-terminal
telopeptide, bone
densitometry
Hypogonadism
Tanner staging, LH, FSH,
and sex steroids (estradiol
in females and testosterone
in males), bone age (X-ray
of wrist and hand), pelvic
ultrasound
Physical exam by visual Hydroxyurea with erythropoietin
inspection or platelet derived growth
factor, hygiene, transfusion in
some cases
Compression Anticoagulation: (1) As
ultrasonography or prophylaxis: in surgery. (2) As
Doppler sonography, treatment: in deep vein
contrast venography or thrombosis, pulmonary
angiography, CT scan, MRI embolism and stroke: it is
of brain recommended long-life.

prevention of patients having thrombotic or cerebrovascular disease, patients with

PHT with or without secondary heart failure, EMH, and leg ulcers. Alloimmunization
to red cell antigens in TI patients is more common than in TM and may be related to
the later age at which transfusions are begun. Alloimmunization is also more common
in splenectomized patients [5, 6, 42, 43]. Pretransfusion red cell antigen matching, par-
ticularly for the Rh and Kell systems, is recommended.

Iron Chelation Therapy

Removal of excessive iron is essential in TI patients with iron overload. Iron overload in
TI is frequently derived from transfusion therapy. In addition, chronic hemolysis, in-
effective erythropoiesis, and hypoxia may lead to increased intestinal iron absorption
through suppression of the regulatory protein hepcidin [44]. Until recently, the cut-
off for starting chelation was an LIC of 7 and above. A recent study, however, showed
that complications were more likely to occur at an LIC of 7 Fe/g dry weight and above,

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 Thalassemia Intermedia 

TABLE 3 The Mean Number of Complications for Different β-Thalassemia-Management

Scenarios in 584 Patients with TI
Mean number of
Hydroxyurea Transfusion Iron chelation complications
+ + + 0.83
+ + − 1.31
+ − + 1.30
− + − 2.02
− − − 2.43
+: Management protocol was done. −: Management protocol was not done.

thus the need to start chelating patients earlier [45]. Data from the first and largest
randomized clinical trial of the iron chelator deferasirox in 166 patients (THALASSA)
[44] showed that deferasirox therapy causes a significant reduction in liver iron con-
centration (LIC) compared to patients on placebo, following 1 year therapy in patients
above the age of 10 and with a baseline iron concentration of more than 5 mg Fe/g dry
weight. The Thalassemia International Federation (TIF) recommends to initiate iron
chelation therapy corresponding to a ferritin level of above 800 ng/mL and an LIC of
5 mg Fe/g dry weight or above. Suspension of therapy should be initiated when serum
ferritin level is 300ng/ml corresponding to an LIC level of 3 mg Fe/g dry weight or less.
The TIF also recommends that all patients above the age of 10 be frequently evaluated
for iron overload by LIC at 1–2 year intervals along with serial measurements of serum
ferritin every 3 months.
It can be said that serum ferritin alone is not a reliable measure of iron overload
in these patients because it underestimates the iron load, and annual assessment of
LIC by biopsy or preferably by noninvasive imaging methods like R2 and T2∗ MRI se-
quences have more reliable and reproducible results [44, 46, 47]. There are few clinical
studies of chelation therapy in TI patients, but all three licensed chelators including
deferoxamine (Desferal), deferiprone (Ferriprox), and deferasirox (Exjade) achieve a
good response [48, 49]. Compliance may be better with deferasirox than with defer-
oxamine or deferiprone [50] because it requires only one oral dose daily. Neverthe-
less, renal function should be closely evaluated due to more hyperuricemia and hyper-
catabulism in these patients compared to TM patients. In one study, hyperurecemia
and microscopic hematuria were found to be more common in TI than TM [41].

Modulation of Gamma-Globin Chain Production

Enhanced gamma-globin chain production might address some of the major clin-
ical manifestations in TI patients by increasing the production of HbF and reduc-
ing the alpha/beta-globin chain imbalance. One of the best known drugs to enhance

TABLE 4 Indications of Blood Transfusion in Thalassemia Intermedia

Regular transfusion Occasional transfusion
Pulmonary hypertension (PHT) Decrease exercise tolerance
Congestive heart failure (CHF) Cord compression
Persistent symptomatic severe anemia (Hb < Thrombosis
6–7 gr/dL) leading to persistent growth retardation Pregnancy
Progressive skeletal deformities Growth failure
Progressive pathologic fracture Leg ulcer
Priapism
Severe anemia (Hb < 6–7 gr/dL)

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 M. Karimi et al.

gamma-globin chain production is HU. The clinical impact of HU in treating TI has

been well documented in a few recent studies. The results show that a significant
number of transfusion-dependent TI patients became transfusion free or needed only
occasional transfusions. Significant increases of Hb levels in not transfused patients
were also reported [51, 52]. A recent study showed that combination therapy of HU
(8–15 mg/kg/d) with L-carnitine or magnesium chloride could be more effective in im-
proving hematologic parameters and cardiac status in patients with TI than HU alone
[53]. Also, it has been reported that HU therapy may be associated with decreased risk
of stroke [28].
HU may lower the risk of thrombotic events by reducing phospholipid expression
on the surface of erythrocytes and platelets and thereby reduce thrombin generation
[5]. Moreover, the OPTIMAL care study (the largest overview on the current status of
TI patients in 6 comprehensive care centers) demonstrated that HU can be protec-
tive against osteoporosis, PHT, EMH, and thrombosis [4]. Co-inheritance of alpha-
thalassemia, Hb E/β thalassemia, homozygosity for certain β-globin mutations [IVS
II-I (G>A) or IVS I-V (G>C)], younger age, higher Hb levels, higher age at the first trans-
fusion before HU therapy and history of splenectomy are predictors of a good response
to HU [5, 54]. In a large study on 232 β-TI patients in Iran a clinical and para clinical re-
sponse to HU was evaluated. Through this study optimal dose of HU (8–15 mg/kg/d)
was identified as well as the types of patients who would be most responsive to this
treatment. It was proved that response to the drug was not determined solely by beta
gene mutation, as previously believed, but that other clinical factors and genetic back-
grounds other than the beta gene locus seem to be responsible for susceptibility to HU
response [55].
During 10 years of observation, HU had no significant adverse effects in these pa-
tients such as malignancy, infertility, or bone marrow suppression when used at a dose
of 8–15 mg/kg/d [54, 56]. However, further studies regarding possible long-term ad-
verse effects of HU are needed. Nevertheless, based on data from a large observational
studies and small clinical trials, HU can be considered in certain groups of patients.
According to the Thalassemia International Federation, patients with TI homozygous
for the Xmnl polymorphism, patients with Lepore or δB-thalassemia, and patients for
which a transfusion course is required but are alloimmunized could be considered for
HU therapy. Furthermore, patients with PHT, EMH and leg ulcers are also considered
for HU therapy.
Recombinant human erythropoietin (rHuEPO) is another erythropoiesis and HbF
inducer that was shown to ameliorate the thalassemia clinical symptoms by increas-
ing HbF cells and HbF induction. A dose related increase in erythropoiesis was seen
in TI patients by a dose of 500–1000 IU/kg × 3/week in several studies [57]. A recent
study also showed that rHuEPO combined with HU has a superior therapeutic effect
in the clinical and hematological responses and improved quality of life in TI patients
in comparison with HU therapy alone [58].

Splenectomy
Removal of the spleen may be a useful treatment strategy in severe forms of TI increas-
ing the Hb levels by 1–2 g/dL and improving growth and development. Indications
for splenectomy in TI are numerous, however, splenectomized patients are at greater
risk of thrombosis, infection, and PHT, [59–62] therefore, the decision to remove the
spleen should be made with considerable caution. TIF guidelines on splenectomy in-
dicate that splenectomy should be avoided in nontransfusion dependent thalassemia
patients younger than 5 years of age. Furthermore, patients should undergo splenec-
tomy in case of worsening anemia leading to poor growth and development, in cases of
hypersplenism leading to worsening anemia, leucopenia, or thrombocytopenia. Also,

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 Thalassemia Intermedia 

splenomegaly accompanied by symptoms and massive splenomegaly with concern

of splenic rupture should motivate physicians for the splenectomy procedure. More-
over, it is very important to keep in mind that abdominal sonography is mandatory be-
fore surgery because the gallbladder and accessory spleen should be inspected during
splenectomy and removed in case of cholethiasis or accessory spleen.
Stem cell transplantation: It is not usually recommended in not transfused or irregu-
larly transfused patients with TI, although if these patients are transfusion dependent,
it may be considered.
Other treatment considerations: These include daily folic acid supplementation, an-
tioxidant, anticaogulation in the perioperative period, and adequate dietary or supple-
mental vitamin D and calcium for prevention of osteoporosis [5].

Survival and Health-Related Quality of Life in TI

Patients with thalassemias including TI have some mental and physical complications
that influence their health-related quality of life (HRQoL). These complications in-
clude the difficulties of living with a chronic disease, frequent physician and hospi-
tal visits, transfusion, chelation therapy, and family and social problems that are more
prominent in developing countries. Because TI is less severe than TM, some believe
that HRQoL must be better. However, two studies of HRQoL in children and adults with
TI showed that transfusion-independent TI patients actually have impaired HRQoL
compared with TM patients of similar age and sex who receive regular transfusions [63,
64]. These studies illustrate the importance of early diagnosis and appropriate man-
agement therapy of TI, especially with regard to prompt recognition of the need for
timely introduction of regular transfusions or chelation therapy and the provision of
psychological support of patients and their families struggling with chronic disease.
In conclusion, although the clinical manifestations of TI are usually milder that TM,
the prognosis and the rate of complications are often worse. Right-sided heart failure
due to long-standing PHT, thrombosis and brain ischemia, EMH in some vital regions
like spinal cord, and iron overload are major and life-threatening complications of TI.
Close follow-up and monitoring of these patients for prevention of such complications
and improved HRQoL are recommended.

Competing interests
The authors declare that they have no competing interests.

Declaration of Interest
The authors report no conflicts of interest. The authors alone are responsible for the
content and writing of the paper.
This study was supported by Shiraz University of Medical Sciences.

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