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Pediatric Hematology and Oncology
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
REVIEW
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 precursors
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 (-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
M. Karimi et al.
Beta-Thalassemia Intermedia
I: Denition 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 26 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 [69]. 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 -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.
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].
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M. Karimi et al.
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
(2030 mg/kg/d) compared to the dosage that it is usually used for TI for enhancement
of gamma globin chain synthesis (815 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
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 714 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 1012% [2931]. 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
anemiaassociated PH [32, 34].
Blood transfusion and sildenafil (in some cases) are recommended as an optimal
therapy in -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 [2931].
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.
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 12 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].
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M. Karimi et al.
Splenectomy
Removal of the spleen may be a useful treatment strategy in severe forms of TI increas-
ing the Hb levels by 12 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, [5962] 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,
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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