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Full Terms & Conditions of access and use can be found athttp://www.tandfonline.com/action/journalInformation?journalCode=icmo20
Download by: [Chinese University of Hong Kong] Date: 19 November 2015, At: 20:38
Current Medical Research and Opinion
ISSN: 0300-7995 (Print) 1473-4877 (Online) Journal homepage: http://www.tandfonline.com/loi/icmo20
Non-transfusion-dependent thalassemiaand thalassemia intermedia: epidemiology,complications, and management
Elliott Vichinsky MD
To cite this article: Elliott Vichinsky MD (2015): Non-transfusion-dependent thalassemia andthalassemia intermedia: epidemiology, complications, and management, Current MedicalResearch and Opinion, DOI: 10.1185/03007995.2015.1110128
To link to this article: http://dx.doi.org/10.1185/03007995.2015.1110128
Accepted author version posted online: 19Oct 2015.
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© 2015 Taylor & Francis. This provisional PDF corresponds to the article as it appeared upon acceptance. Fully formatted PDF and full text (HTML) versions will be made available soon. DISCLAIMER: The ideas and opinions expressed in the journal’s Just Accepted articles do not necessarily reflect those of Taylor & Francis (the Publisher), the Editors or the journal. The Publisher does not assume any responsibility for any injury and/or damage to persons or property arising from or related to any use of the material contained in these articles. The reader is advised to check the appropriate medical literature and the product information currently provided by the manufacturer of each drug to be administered to verify the dosages, the method and duration of administration, and contraindications. It is the responsibility of the treating physician or other health care professional, relying on his or her independent experience and knowledge of the patient, to determine drug dosages and the best treatment for the patient. Just Accepted articles have undergone full scientific review but none of the additional editorial preparation, such as copyediting, typesetting, and proofreading, as have articles published in the traditional manner. There may, therefore, be errors in Just Accepted articles that will be corrected in the final print and final online version of the article. Any use of the
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REVIEW
Non-transfusion-dependent thalassemia and thalassemia intermedia: epidemiology, complications, and management
Elliott Vichinsky, MD
doi: 10.1185/03007995.2015.1110128
Abstract
Objective: The non-transfusion-dependent thalassemias (NTDT), including thalassemia intermedia (TI), hemoglobin E beta thalassemia, and hemoglobin H disease, have sometimes been regarded as less severe than their transfusion-dependent variants; however, these disorders carry a substantial disease burden (e.g., splenomegaly, iron overload, skeletal effects, and cardiopulmonary disease). The aim of this review is to increase clinician awareness of the growing global problem of NTDT and TI, and discuss the current management strategies for these conditions.
Methods: Recent peer-reviewed articles (publication years 2000 through 2015) addressing the epidemiology, complications, management, and monitoring of NTDT were identified in the PubMed database and reviewed.
Results: The changing epidemiology of thalassemia constitutes a growing health problem. Increased clinician awareness is necessary for the appropriate diagnosis and management of patients with NTDT.
Conclusions: Management of NTDT requires a comprehensive approach, beginning with screening and prenatal diagnosis, monitoring for iron overload and associated complications, and iron chelation therapy. Several novel strategies are in the early stages of investigation and may help increase treatment options in patients with NTDT. Importantly, ethnic or cultural barriers may exist within the affected populations and need to be considered in the management approach.
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REVIEW
Non-transfusion-dependent thalassemia and thalassemia intermedia: epidemiology,
complications, and management
Elliott Vichinsky, MD
UCSF Benioff Children’s Hospital, Oakland, University of California, San Francisco, CA,
USA
Address for correspondence: Elliott Vichinsky, MD, Medical Director, Hematology/Oncology
UCSF Benioff Children’s Hospital, 747 52nd Street, Oakland, CA 94609 USA. Tel: +1 510 428 3651;
Fax: +1 510 450 5647; [email protected]
Key words: iron chelation therapy, iron overload, non-transfusion-dependent thalassemia, thalassemia
intermedia
[Short title: Non-transfusion-dependent thalassemia/thalassemia intermedia]
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ABSTRACT
Objective: The non-transfusion-dependent thalassemias (NTDT), including thalassemia intermedia
(TI), hemoglobin E beta thalassemia, and hemoglobin H disease, have sometimes been regarded as
less severe than their transfusion-dependent variants; however, these disorders carry a substantial
disease burden (e.g., splenomegaly, iron overload, skeletal effects, and cardiopulmonary disease). The
aim of this review is to increase clinician awareness of the growing global problem of NTDT and TI,
and discuss the current management strategies for these conditions.
Methods: Recent peer-reviewed articles (publication years 2000 through 2015) addressing the
epidemiology, complications, management, and monitoring of NTDT were identified in the PubMed
database and reviewed.
Results: The changing epidemiology of thalassemia constitutes a growing health problem. Increased
clinician awareness is necessary for the appropriate diagnosis and management of patients with
NTDT.
Conclusions: Management of NTDT requires a comprehensive approach, beginning with screening
and prenatal diagnosis, monitoring for iron overload and associated complications, and iron chelation
therapy. Several novel strategies are in the early stages of investigation and may help increase
treatment options in patients with NTDT. Importantly, ethnic or cultural barriers may exist within the
affected populations and need to be considered in the management approach.
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INTRODUCTION
Hemoglobinopathies are a group of autosomal recessive disorders of hemoglobin (Hb), and mutations
that cause these conditions can be divided into two main groups: Qualitative Hb variants (Hb S, Hb C,
and Hb E), which change the amino acid structure of the globin, and quantitative mutations, which
result in defective synthesis of the alpha or beta globin chains of adult Hb A1,2
. The alpha and beta
thalassemias result from quantitative mutations, and are named after the affected globin chain.
Mutation of the alpha or beta chains can result in the complete absence of globin chain synthesis (α0
or β0) or reduced globin chain synthesis (α
+ or β
+)
2. Both types of disorders are inherited in a recessive
Mendelian manner1–3
.
In addition, multiple alleles of alpha and beta globin genes can be present in a given population. The
interactions between these alleles can result in a wide spectrum of disease severity — even within the
same class of disease. For example, Hb H alpha thalassemias that are caused by triple deletions in
alpha globin genes produce a mild phenotype. However, patients with certain non-deletional mutant
alpha globin alleles — such as Hb Constant Spring disease — can present with severe anemia4. The
interactions between alpha and beta globin genes also dictate disease severity. For patients with Hb E
beta alleles, coinheritance with alpha mutations tends to produce mild phenotypes while coinheritance
with mutant beta alleles has a wider range of disease phenotypes5. Finally, these different forms of
thalassemia may occur at varying frequencies within the same population1,6,7
.
The principle pathophysiology of thalassemia results from ineffective erythropoiesis and peripheral
hemolysis, which results in anemia2. Chronic anemia can induce compensatory changes in the
hematopoietic system and subsequently cause complications such as splenomegaly or osteoporosis. In
addition, transfusions that are used to treat patients with thalassemia can cause further complications
as a result of iron overload. Therefore, it is essential to accurately determine disease status and
phenotypic stability to ensure proper management.
Thalassemias are known to occur at higher frequencies in certain regions of the world, which may
result from selective advantages such as resistance to severe forms of malaria, longer lifespan, and
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greater number of offspring1,8
. In addition, the higher incidence of consanguineous marriages likely
contributes to the prevalence of inherited recessive diseases within these regions. Altogether, these
factors may lead to a patchy distribution of thalassemia genes due to selective pressures in certain
geographic areas8.
The problem of thalassemia is notably different today than it was in the past, and various ethnicities,
phenotypes, and treatments now characterize this heterogeneous group of blood disorders.
Additionally, because patients are surviving longer, there is a different pattern of complications than
previously observed in this population9,10
. Moreover, the natural history is varied and poorly studied,
with severity that can range from asymptomatic to transfusion dependency among patients with
similar mutations9. The non-transfusion-dependent thalassemias (NTDT) include beta thalassemia
intermedia (TI), Hb E beta thalassemia, and alpha TI (Hb H disease)1,2
. NTDTs have sometimes been
regarded as less severe than their transfusion-dependent variants, but these disorders still carry a
substantial burden of morbidity and mortality11,12
. Indeed, recent studies indicate that patients with
transfusion-independent thalassemia have much greater morbidity than previously thought, including
a high rate of complications such as thrombosis, pulmonary hypertension, nonfocal brain infarction,
iron overload, spinal cord compression, and decreasing quality of life with age11,13-23
. The current
article highlights the growing public health problem of NTDT, and discusses the importance of
appropriate monitoring and disease management.
Multiple searches were conducted in the PubMed database using various terms, including, but not
limited to, “non-transfusion dependent thalassemia,” “thalassemia intermedia,” “hemoglobin E
thalassemia,” “epidemiology,” “pathogenesis,” “iron overload,” “complications,” and “iron chelation
therapy.” Peer-reviewed publications were given first priority and articles were limited to publication
years 2000 through 2015; articles deemed not relevant to the current topic were not utilized.
Epidemiology of thalassemias: an increasing health problem
Inherited Hb disorders are observed in an estimated 300,000 births yearly and consist mostly of sickle
cell disease and thalassemias1,8
. However, the actual burden of diseases such as thalassemia is difficult
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to estimate for several reasons8. Most data were collected before 1980, and information on clinical
course, mortality, and complications are scarce in poorer, developing countries where thalassemias are
most common; data are also limited in wealthier countries. As such, it has been suggested that the
current situation regarding management and control of Hb disorders is unsatisfactory8. Most
epidemiologic data should be interpreted with caution as they are based on data from a limited
number of centers in each country. Moreover, micromapping studies, which take into account
multiple centers within the same country, indicate heterogeneity in the distribution of thalassemias,
even within the same region8. Therefore, additional micromapping studies are needed within countries
that have a high prevalence of thalassemias.
Approximately 80% of thalassemias are observed in the low- and middle-income countries of the
tropical belt, which extends from sub-Saharan Africa to the Mediterranean region, the Middle East,
and South and Southeast Asia1. Many regions of the world where thalassemias are common are
undergoing an epidemiologic transition, whereby improved health and nutrition are allowing for
greater survival of affected children1,8
. Growth of the thalassemia population must also be considered
in those regions with a high prevalence of thalassemia and rapid population increases, such as Africa
and Southeast Asia8. All of these factors will lead to an increasing incidence of Hb disorders
8. A study
of neonatal hemoglobinopathy screening programs in California, for example, reported the frequency
of alpha thalassemia as one in 9000 births and beta thalassemia as one in 55,000 births; screening
programs like these provide for the accurate diagnosis of hemoglobinopathies24
. Results of such
studies also demonstrate an increasing incidence of diverse mutations that will require new strategies
for screening, counseling, and management24
.
Thalassemias are a growing health problem worldwide, with increasing numbers of clinically
significant cases expected over the next 2 decades, and individuals with Hb E beta thalassemia
expected to account for much of this projected increase10
. The epidemiology of thalassemia is also
changing, due in part to changes in migration patterns to North America and improved treatments10,12
.
For example, the highly common Hb E variant affects approximately 1 million people around the
world and causes Hb E beta thalassemia, which has a variable phenotype ranging from asymptomatic
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to transfusion-dependent7. Changes in the prevalence of Hb E beta thalassemia may be due to the
migration to North America from regions with a high prevalence of Hb E mutations (e.g., Thailand,
Laos, and Cambodia)7,25
. A rise in immigration to North America from Southeast Asian countries over
several decades has been paralleled by an increase in some thalassemia mutations24,26
. For example,
the overall distribution of ethnicity in newborns in California with Hb H disease reveals a very high
prevalence among Southeast Asian immigrants, including those of Laotian/Thai (26%), Filipino
(15%), Vietnamese (9%), and Cambodian (5%) ethnicity (Figure 1)27
.
Thalassemias can be considered an “emerging minority disease” in North America, as most cases of
NTDT occur in immigrant populations from high-risk areas for NTDT. Recently, the Centers for
Disease Control and Prevention’s report on thalassemia noted that 27% of US patients with
thalassemia who are studied were born outside of the United States28,29
. Overall, 80% of individuals
with NTDT were members of minority populations, particularly those from Southeast Asia, India, and
the Middle East29
. These findings underscore the growing health problem of NTDT, and a shifting
disease prevalence from predominantly underdeveloped nations, to major healthcare systems,
including those of the United States and Europe30
. Thalassemias are common in coastal regions, and
understanding specific target populations is an important consideration. A lack of cultural knowledge,
interpretation services, or didactic methods of healthcare delivery may have adverse health
consequences25
. Southeast Asian communities, encompassing diverse populations and minorities, are
particularly hard hit, with a high incidence of Hb E and Hb E beta thalassemia demonstrated in this
population25
. Addressing this problem requires counseling strategies that consider both cultural and
psychological aspects of these diverse populations. Increased awareness of the challenges that may
occur during interactions between patients and providers can help improve outcomes25
.
Pathogenesis and natural history of NTDT
The principle pathophysiology of TI involves ineffective erythropoiesis and hemolysis, which leads to
the clinical signs and symptoms of anemia and eventual transfusion dependence (Figure 2)2,30,31
.
Compensatory homeostatic mechanisms to overcome chronic anemia in NTDT include increased
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production of erythropoietin, reduced hepcidin levels, bone marrow expansion, and increased
absorption of iron in the gut; these mechanisms result in clinical complications observed in patients
with NTDT (e.g., osteoporosis, progressive splenomegaly) and other complications resulting from
iron overload (e.g., endocrinopathies, liver disease)30
. Pathophysiology in NTDT may also result from
other molecular mechanisms, such as dysregulation of coagulation mechanisms, leading to a
hypercoagulable state30
.
The natural history of TI is variable, ranging from mild (e.g., anemia, jaundice) to severe (e.g., severe
anemia, iron overload, hypersplenism, bone abnormalities, leg ulcers) symptomatology and
complications6,10
. Severity of disease depends on the balance of the alpha and non-alpha chains, and is
also impacted by genetic and nongenetic determinants6. The variation in clinical severity of the NTDT
(Table 1) may complicate diagnosis and treatment; despite frequently presenting with anemia, patients
with NTDT are by definition not dependent on regular transfusion for survival, a characteristic that
distinguishes NTDT from conditions such as beta thalassemia major or transfusion-dependent
thalassemia (TDT)3,30
. Moreover, although the survival of patients with NTDT is not dependent on
regular transfusion, transfusion requirements may change over time, and transfusions may be
occasionally required due to events such as pregnancy, splenomegaly, or infections (see below)1,6,30
.
The spectrum of disease in thalassemia is outlined in Figure 3. Among the three clinically distinct
forms, the transfusion requirements in alpha and beta thalassemia major are greatest2.
Screening, diagnosis, and assessment
Genetic testing is an important component in the management of thalassemias to ensure correct
diagnosis and guide treatment strategies. Genotype analysis helps to define clinical severity and plan
the therapeutic clinical course for the patient. Since TI often involves an interaction of both alpha and
beta thalassemia mutations, adequate diagnosis requires evaluating both globin genes as well as
genetic polymorphisms that alter the severity of the disease. There are three categories of genetic
modifiers for thalassemia. The primary modifier is the specific mutation of the alpha or beta globin
gene. Secondary modifiers are polymorphisms or mutations that minimize the globin chain imbalance.
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For instance, coinheritance of alpha thalassemia decreases the severity of beta thalassemia. Tertiary
modifiers are polymorphisms that alter the susceptibility to complications such as the common
coinheritance of the UGT1A1 gene (Gilbert’s syndrome). In the United States, almost 20% of beta TI
cases were initially identified as a beta thalassemia heterozygote28
. Alpha genotyping demonstrated
that many of these cases coinherited alpha triplication. Genotyping illustrated that many of these
patients coinherited alpha triplication or a dominant, severe beta thalassemia allele28
. A longitudinal
analysis of children with Hb H Constant Spring disease demonstrated that they were highly
susceptible to severe anemia during infection, had growth delays, required intermittent transfusion,
and were subject to iron overload within their first decade of life17
. In comparison, children with
deletional Hb H disease have a more benign clinical course as they rarely develop severe anemia
during infection and generally do not require transfusion. Adequate diagnosis of Hb H Constant
Spring disease usually requires DNA testing since it is an unstable Hb that is often missed by other
methods such as routine electrophoresis. Early genetic testing in newborns is important to correctly
distinguish between these distinct disorders to determine the best treatment approach17
. Novel
diagnostic methods such as multiplex ligation-dependent probe amplification are now being used to
identify both previously identified and novel deletions within the beta globin gene cluster32
. These
simple and reliable methods may be useful to clarify the clinical relevance of these large deletions
within the beta globin gene in affected individuals and carriers32
. In light of the changing
epidemiology of Hb disorders, genetic screening is becoming increasingly important1,28
. Prenatal
screening allows parents to be duly informed of the likelihood of producing a seriously affected child,
and provides important information to regional government health agencies as well as world health
authorities to help accurately estimate disease burden and incidence1. It is also important that patients
with thalassemias are accurately diagnosed in order to prevent a lifetime of potentially unnecessary
transfusions1. Indeed, thalassemias may appear as severe anemias early in life; therefore, it is
important for these patients to be judiciously followed up in order to evaluate their steady-state Hb
level1. For certain NTDTs, the clinical characteristics can also change significantly during a child’s
development. In Hb E beta thalassemias, the phenotype may be unstable in patients under 15 years of
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age and, during this time, it is possible for the disease to progress from mild to severe5. Therefore,
frequent follow-ups are also necessary in certain patient groups who present with mild disease.
The clinical characteristics of patients with thalassemia can be used to distinguish patients with TDT
or thalassemia major from NTDT (Table 2). Once a diagnosis of NTDT is confirmed, the presence of
severe anemia alone is not necessarily an indication for transfusion therapy; indeed the patient may
have an infection or acute hemolytic syndrome that is exacerbating the anemia in the short term3.
Rather, patients with NTDT should be monitored for several months following the initial diagnosis to
assess the need for transfusion or other therapy based on factors such as disease activity, growth and
development, and the presence of complications; clinicians should also be cognizant of conditions
such as growth spurt or pregnancy, which could further decompensate a low Hb level3. While there
are existing guidelines for the diagnosis and management of NTDT, these considerations also must be
factored in30,31
.
Complications associated with NTDT
Complications of NTDT include skeletal deformities, pregnancy complications, extramedullary
hematopoiesis (pseudotumors), silent brain infarctions, pulmonary hypertension, leg ulcers, endocrine
disorders (including growth failure), thromboembolic events, and iron overload (Figure 2)3,6,33
.
Whereas some complications are common to both TDT and NTDT (e.g., extramedullary
hematopoiesis, splenomegaly), others such as pulmonary hypertension and thrombosis are more
commonly observed in NTDT3. Transfusion may prevent many complications associated with NTDT
such as splenomegaly, growth retardation, skeletal abnormalities, and pulmonary hypertension3.
Skeletal-related complications
One study conducted across a large cohort of patients found a high prevalence of low bone mineral
density, fractures, and bone pain in patients with alpha and beta thalassemias34
. Patients with beta TI
commonly develop osteoporosis, which increases with age and is associated with pain, skeletal
deformities, and fractures. Osteoporosis and its consequences in patients with NTDT have not been
well-studied, but these patients may experience bone pain, fractures, and skeletal and spinal
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deformities; data on the benefit of preventive therapy such as bisphosphonates is limited in patients
with NTDT31,34
. Recommendations for the prevention of osteoporosis in patients with NTDT include
annual bone mineral density assessment, and imaging studies for events such as back pain; hormonal
and nutritional deficiencies contributing to osteoporosis should be corrected where possible, in
accordance with recommendations for transfusion-dependent patients with beta thalassemia major31
.
In the OPTIMAL CARE study, a benefit of iron chelation and hydroxyurea therapy was noted in
patients with TI who had lower rates of osteoporosis compared with those who were not treated31,35
.
Overall, lower rates of osteoporosis have been noted in patients with beta TI receiving iron
chelation36-39
.
Pregnancy complications
Because patients are surviving longer with TI, pregnancy is becoming an increasingly important issue,
and there is little information on the outcome of these patients16,40
. In general, fertility is preserved in
most patients with TI, but these pregnancies should be considered high-risk and followed by
multidisciplinary team care31
. Pregnancy is complicated by worsening maternal anemia, increased
pulmonary hypertension, cardiac decompensation, and thromboembolism; prematurity and
intrauterine growth retardation are relatively common. At the onset, discontinuation of iron chelators
and hydroxyurea should be discussed; transfusion therapy is often used during pregnancy to improve
fetal outcome and decrease maternal complications. Alloimmunization (from transfusion) is a
particular risk in patients who initiate transfusions later in life; these patients would benefit from the
use of extended red cell phenotypically-crossmatched units29,41
. In a recent study examining outcomes
of 60 pregnancies in 34 women with TI over a 20-year period, full-term pregnancies were reported in
49 patients. Although some complications did occur, the study suggests that successful deliveries can
be achieved with careful and frequent monitoring by a hematologist and obstetrician16
. General
recommendations for patients with NTDT who become pregnant include a need for comprehensive
counseling on the risk of having an affected child, and the introduction of blood transfusions
according to factors such as Hb level, cardiac and overall status of the mother, and the status of fetal
growth31
. Splenectomy, either prior to conception or postpartum, may be considered for pregnant
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patients with NTDT with hypersplenism or splenomegaly31
. Fully phenotype-matched blood should
be used for never- or minimally-transfused pregnant women with NTDT requiring transfusion, as they
can be considered at high risk for alloimmunization31
. In order to decrease the high rate of thrombotic
events, routine use of low molecular weight heparin in the peripartum period is recommended.
Extramedullary hematopoiesis
Ineffective erythropoiesis in TI can also drive extramedullary hematopoiesis in all body sites. One of
the most serious and common areas is the paraspinal space, which can result in sudden spinal cord
compression and paraplegia40
. On routine screening, asymptomatic paraspinal masses are noted in
approximately 15% of patients with TI who are imaged. As these patients age, they develop more
severe symptoms, including back pain, paresthesias, abnormal reflexes, and urinary and/or bowel
incontinence42,43
. Magnetic resonance imaging (MRI) is the diagnostic procedure of choice; in most
cases, acute transfusion or hydroxyurea treatment is therapeutic20
. In selected cases, low-dose
radiotherapy and/or surgical decompression may be necessary42,43
.
Neurological complications
The presence of asymptomatic white matter lesions detectable by MRI appears to be a common
finding in adult patients with TI who have been treated with splenectomy; white matter lesions may
be even more pronounced in patients of increasing age and those who are transfusion-naïve14
. In a
cross-sectional brain MRI study of 30 splenectomized adults with TI without neurologic dysfunction,
18 (60%) patients had ≥1 subcortical white matter infarction14
. Other studies have documented this
finding and have also noted associated mild cerebral atrophy and possible cognitive dysfunction14,15,44
.
Risk factors for central nervous system injury include low Hb levels, hypercoagulability,
thrombocytosis, iron overload, and older age15
. Optimal chelation therapy, aspirin prophylaxis, and
avoidance of splenectomy may be protective. All patients who present with nonfocal neurologic
symptoms require neuroimaging, but the optimal therapy for patients with lesions is unclear15
. Based
on data from patients with sickle cell disease, transfusion therapy is beneficial in both the primary and
secondary prevention of central nervous system lesions and should be studied in TI14,45,46
.
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Pulmonary hypertension
Pulmonary hypertension, particularly in splenectomized patients, occurs in approximately 30% of
patients with NTDT31
. Hemolysis, nitric oxide and arginine deficiency, and hypercoagulability are
factors that may contribute to vasculopathy and development of microthrombi2,47
. Diagnosis is
generally established by echocardiogram, which most likely overestimates prevalence2. Therefore,
right heart catheterization is indicated in patients with significant echocardiographic evidence of
likely pulmonary hypertension (tricuspid regurgitant velocity >3.2 m/sec)31
. Prospective therapeutic
trials are lacking; however, transfusion therapy appears to be beneficial31
. Practical management of
pulmonary hypertension in patients with NTDT includes annual echocardiographic assessment,
particularly for selected subgroups such as patients with beta TI and Hb E beta thalassemia,
splenectomized patients, and those with elevated platelet counts31
. Blood transfusion, hydroxyurea,
control of iron overload, and anticoagulant therapy may be beneficial for patients with possible,
likely, or confirmed pulmonary hypertension31
. In addition, although larger trials are needed, the
results of small-scale studies of sildenafil citrate have been encouraging, with good tolerability and
benefits observed in hemodynamic and functional status48,49
.
Leg ulcers
Leg ulcers are common in NTDT and occur in as many as one-third of patients, particularly in later
adulthood2,33
. They tend to recur and cause increasing morbidity. The etiology is multifactorial,
including local trauma, anemia, and hypercoagulability. Notably, a higher rate of leg ulcers has been
found to occur in patients with iron overload13,50
. Presently, there is insufficient evidence to
recommend treatments such as blood transfusion, iron chelation, or hydroxyurea therapy, although
some benefit of these treatments has been observed, and blood transfusion could be considered as a
primary treatment option; some simple lifestyle interventions (e.g., raising the feet 1–2 hours per day
above the heart) may also be beneficial31
. Other general recommendations for leg ulcer management
include regular skin examination of patients with NTDT on physical exam, and use of topical
antibiotics and dressings as needed; topical sodium nitrite may also be considered31
. Platelet-derived
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wound healing factors, anticoagulation therapy, vasodilators such as dilazep, skin grafting, and
oxygen chamber may be useful for controlling leg ulcers, but insufficient evidence exists from clinical
trials to recommend these therapies in patients with NTDT31
.
Iron overload
Hemosiderosis and induced organ dysfunction are major issues in NTDT. Even moderate
hemosiderosis in TI is a strong predictor of mortality and morbidity. For every 1-mg increase in liver
iron per gram of dry weight, there is a significant increased risk of pulmonary hypertension,
endocrinopathies, thrombosis, bone disease, and other target organ injuries33,50
. While cardiac iron
accumulation does occur, it is significantly slower than in thalassemia major. Patients with NTDT are
at particular risk for hepatic fibrosis and liver failure, which have recently been associated with
hepatocellular carcinoma. Elevated liver iron significantly increases morbidity of all NTDT
phenotypes regardless of severity, which is amplified as these patients age. The lack of early diagnosis
and treatment of hemosiderosis in NTDT is common. Many patients are not monitored, despite
recommendations that chelation be initiated at a significantly lower ferritin level than in transfusion-
dependent patients. Ferritin best correlates with reticular endothelial liver iron and underestimates iron
deposition in hepatocytes. In nontransfused patients, there is relatively more hepatocytic iron
deposition than in thalassemia major, resulting in high total body iron with lower than expected serum
ferritin levels.
Hypercoagulable state in NTDT
Patients with NTDT have laboratory evidence of increased risk of thrombosis, and with increasing
survival in patients with thalassemia, thrombotic complications are becoming an increasing concern,
particularly for patients with TI18,51,52
. The risk varies among subtypes and clinical characteristics. In
one study, a higher prevalence of thrombotic complications was observed among patients with TI
compared with transfused patients with thalassemia major (29% vs 2%), and the risk was greatest in
splenectomized patients18
. Consistent with these findings, plasma levels of markers of thrombin
activity were higher in splenectomized patients with TI compared with nonsplenectomized patients
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and those with thalassemia major18
. Similar findings were observed in a larger study, which showed a
significantly greater risk of thrombotic events in patients with TI compared with thalassemia major
(p<0.001), and risk was again greater in patients who had undergone splenectomy52
. Patients with
NTDT commonly have thrombocytosis and evidence of endothelial injury and dysfunction, and iron
overload may further exacerbate this risk2. Understanding of the morbidity of this hypercoagulable
state is increasing and suggests that the high rate of subclinical and overt strokes is in part due to this
thrombophilia18,52
. Although the role of interventions such as blood transfusion has not been evaluated
in sufficient trials, one of the general recommendations for addressing the hypercoagulable state in
patients with NTDT is to consider them at higher risk for thrombotic complications; splenectomized
patients with NTDT with elevated platelet counts should consider anticoagulant therapies such as
aspirin31
. Although a beneficial impact of iron chelation or hydroxyurea therapy may be observed
with different indications, neither intervention is currently recommended as primary or secondary
intervention31
.
Quality of life
The impact of these potential complications on patients living with these disorders is important to
consider. In a study comparing the impact of thalassemia on quality of life in patients with
transfusion-dependent (n=29) or transfusion-independent (n=19) disease, patients were asked to rate
various dimensions of health status11
. Results of the study showed that anxiety, depression, concern
about overall health, and recent deterioration in health status were the most commonly impacted
domains. Importantly, overall health was rated worse in non-transfusion-dependent patients. The
results demonstrate that NTDT has a significant impact on quality of life in affected patients11
. The
frequent assessment of health-related quality of life and mental health status, preferably with the use
of standardized instruments, is now recommended for patients with NTDT31
.
Disease management and monitoring in NTDT and TI
NTDT requires a multidisciplinary approach that focuses on each patient’s clinical course. Prevention
and early detection of complications previously discussed are necessary to prevent morbidity and poor
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quality of life. Principle management strategies for NTDT include four therapeutic options:
Splenectomy, transfusion therapy, iron chelation therapy, and fetal Hb induction2. Increased
understanding of the risks and benefits of these interventions over the last decade has dramatically
changed the approach to TI.
Splenectomy
Increase in splenic volume is common in patients with NTDT regardless of transfusional
requirements30
. Splenectomy may become necessary for patients with NTDT due to complications
such as recurrent infection and/or bleeding (resulting from chronic leukopenia and/or
thrombocytopenia), or complications associated with splenomegaly such as upper quadrant pain, early
satiety, and to reduce the risk of splenic rupture30
. Nevertheless, the risk for complications with
splenectomy, including thrombosis and infection, should be carefully considered for patients with
NTDT31
. Recent data indicate that splenectomy in thalassemia may markedly increase the morbidity
of babesiosis and malaria29
. In the OPTIMAL CARE study, splenectomized patients were found to
have higher rates for nearly all complications than were nonsplenectomized patients, whereas the
procedure was only protective for extramedullary hematopoiesis35
.
Interventions such as partial splenectomy and/or splenic embolization aim to maintain the benefit of
splenectomy without the potential pathologic consequences, but their long-term efficacy and toxicity
are poorly studied40
. The use of appropriate preventive measures such as antibiotic prophylaxis and
immunization is recommended for patients with NTDT post-splenectomy30,31
. Additionally, many
programs have initiated prophylactic aspirin or anticoagulant therapy before thrombotic events occur.
General indications for splenectomy in NTDT include progressive anemia resulting in growth
retardation, hypersplenism resulting in recurrent infection or bleeding, severe splenomegaly with
clinical symptoms or risk of splenic rupture, and in cases where interventions such as blood
transfusion or iron chelation therapy may be unavailable; splenectomy should generally be avoided in
patients less than 5 years of age31
.
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Transfusion therapy
The use of blood transfusion and iron chelation therapy have improved the prognosis of patients with
thalassemias over the last 3 decades9,40
. However, the decision to transfuse a patient with any
thalassemia should be based not only on Hb level but other individual factors such as activity level,
feeding, growth, and development1,40
. In addition, the need for transfusion must also be balanced with
the risks of transfusion-associated infection, hemosiderosis, and alloimmunization29,40
. In patients who
initiated transfusions later in life, alloimmunization rates are higher than in those transfused early in
life6,33
. Use of extended red cell phenotyping is beneficial in decreasing this risk29,40
.
Chronic transfusion therapy is increasingly being considered in patients with moderately severe
NTDT. Transfusions decrease erythroid activity and the side effects of ineffective erythropoiesis and
hemolysis40
. Transfusion therapy in thalassemia major is likely responsible for the low rate of
thrombosis, pulmonary hypertension, extramedullary pseudotumors, brain infarctions, skin ulcers, and
growth failure compared with NTDT. Temporary transfusion programs are being used in patients with
NTDT in order to prevent and treat specific complications40
.
Assessing iron overload
Patients with NTDT develop clinically significant iron overload irrespective of their transfusion
exposure. Ineffective erythropoiesis leads to low hepcidin levels and marked increase in intestinal iron
absorption. Iron overload is a major cause of morbidity for patients with NTDT and TI40
. Indeed, a
rise in liver iron in NTDT has been proportionally associated with an increased risk of multiple
complications, including thrombosis, cardiopulmonary disease, endocrinopathies, and osteoporosis50
.
Figure 4 shows liver iron concentrations (LICs) in patients with and without beta TI–associated
comorbidities; notably, LIC is significantly increased in patients with NTDT complications such as
leg ulcers (p=0.027), thrombosis (p=0.002), pulmonary hypertension (p<0.001), and osteoporosis
(p<0.001)50
. The dynamic state of ongoing, ineffective erythropoiesis with increased iron absorption
leads to preferential loading of hepatocyte iron compared with reticuloendothelial iron. Measuring
serum ferritin levels is an easy and inexpensive assessment method, but underestimates the severity of
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iron overload in NTDT. Serum ferritin primarily reflects reticuloendothelial iron and is lower in
patients with NTDT compared with patients with thalassemia major with the same total body iron
burden. In order to adequately use serum ferritin as an indicator of iron levels, it should be
periodically correlated with LIC2,21
.
Serum ferritin level guidelines for initiating chelation therapy in NTDT are lower than for transfusion-
dependent patients. Following thalassemia major guidelines will delay initiation and appropriate dose
of iron chelation therapy in NTDT21
. Chelation therapy should be considered for all iron-overloaded
patients with NTDT >10 years of age. Chelation is initiated when LIC reaches 5 mg Fe/g dry weight
and interrupted when the level drops to 3 mg Fe/g dry weight. If quantitative liver iron assessments
are unavailable, initiating iron chelation at >800 ng/mL and interrupting therapy at <300 ng/mL is
recommended. A decision on when to use iron chelation therapy may also be guided by use of a
decisional treatment algorithm. In an exploratory study, it has been proposed to initiate iron chelation
therapy in patients who have been transfused with >1000 g of red blood cells or when transferrin
saturation is >90% in patients with <1000 g transfused53
. This method will need to be validated in a
larger prospective study based on repeated transferrin saturation assessments.
Recently, the use of MRI for the direct assessment of LIC has become the new standard of care for
patients with NTDT when readily available, and assessment of LIC every 1 to 2 years has been
recommended; the extent of iron overload and the rate of iron accumulation as assessed by this
method is used to evaluate the need for iron chelation therapy3,30
. In the event that both MRI-assessed
LIC and serum ferritin levels are available, LIC should be the measurement of choice to guide
treatment decisions31
.
Management strategies: old and new
Managing iron overload
Several new therapeutic approaches to treat iron overload in TI, including new iron chelators and
drugs that decrease gastrointestinal iron absorption, are in preclinical and early trials54–60
. Presently,
there are three iron chelators—deferoxamine, deferiprone, and deferasirox—that are available and
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have been studied in NTDT; each has specific benefits and limitations. Deferoxamine has been
available for use in iron chelation therapy for more than 40 years, but has been associated with poor
adherence due to the requirement of parenteral infusion for at least 8 hours daily61,62
. Studies in NTDT
are limited but indicate improved iron balance. Deferiprone was the first available oral iron chelator
and has been extensively used in transfusion-dependent patients with thalassemia major; it was
recently approved in the United States for the treatment of iron overload in patients with TDT63
.
Deferiprone has a relatively short half-life and requires three times a day oral dosing63
. Due to the rare
risk of agranulocytosis-associated fatal bacteremia, weekly monitoring of white blood cell count is
required63
. Limited observations are available for deferiprone in NTDT, but suggest a reduction in
iron stores. In a study that included seven patients with beta TI or Hb E beta thalassemia not requiring
transfusions, treatment with deferiprone was associated with significant decreases in serum ferritin
(p=0.0005), hepatic iron (p<0.02), red cell membrane iron (p<0.0005), and serum non-transferrin-
bound iron (p<0.0005), and serum erythropoietin increased (p=0.034); adverse events were mainly
gastrointestinal events and arthralgia64
. In a study of 17 Chinese patients with non-transfusion-
dependent Hb H disease and serum ferritin over 900 μg/L, treatment with deferiprone was associated
with a significant reduction in serum ferritin at 6 (p=0.0498) and 18 months (p=0.0008), and levels
remained decreased at 24 months (6 months after stopping treatment). No agranulocytosis or severe
neutropenia was observed and the drug was well-tolerated by all but one patient65
.
Deferasirox has been extensively studied in hemosiderosis across multiple conditions, including
thalassemia major62
, sickle cell disease66
, and myelodysplastic syndromes61
, and these studies have
demonstrated stabilization and decrease in total body iron. Presently, deferasirox is the most well-
studied iron chelator in NTDT, having undergone prospective randomized clinical trials2,67
. It is the
only oral iron chelator that is approved by the US Food and Drug Administration for NTDT68
.
Deferasirox has a long half-life, allowing for once-daily dosing, which most likely improves patient
satisfaction68–70
. The most common adverse events are gastrointestinal disturbances and a
nonprogressive increase in serum creatinine61,62
. Due to the rare risk of severe renal toxicity, monthly
monitoring of renal function is required68
. The THALASSA study was the first large, randomized,
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placebo-controlled trial of iron chelation therapy in NTDT. A significant reduction in LIC was
observed in the 166 patients with NTDT treated with deferasirox, while an increase in iron levels was
seen in the control group67,68
. Over the 2-year extension study, a progressive reduction in iron
overload was observed in patients with NTDT treated with deferasirox (Figure 5). Nausea, rash, and
diarrhea were the most common drug-related adverse events67,68
.
Hydroxyurea and fetal Hb therapy
Drug therapy that increases production of the fetal beta globin like molecule (gamma globin) may
help to improve the alpha/beta globin chain imbalance in NTDT by binding the excess alpha chains,
increasing fetal Hb levels, and improving erythropoiesis2,31,71
. Several small and nonrandomized
clinical trials with fetal Hb–modulating drugs have been performed in patients with thalassemia, and
studied agents that affect different pathways in fetal Hb regulation. These drugs include hydroxyurea
(a ribonucleotide reductase inhibitor), sodium phenylbutyrate, arginine butyrate (histone deacetylase
inhibitors), decitabine and azacytidine (demethylating agents), and erythropoietin and darbepoetin
(erythropoiesis stimulating agents)71
. The best-studied agent for inducing fetal Hb production in
patients with NTDT is hydroxyurea, a cytotoxic, antimetabolic, antineoplastic agent, which has been
used extensively in treating sickle cell disease31,71
. Only hydroxyurea has sufficient long-term safety
data in thalassemia to be considered clinically indicated.
The overall response rate to hydroxyurea is quite variable, and studies are often not comparable.
However, approximately 40% of patients with NTDT will experience a 1-g/dL rise in Hb with
hydroxyurea treatment31,71
. In addition, there are reports from the OPTIMAL CARE study suggesting
that hydroxyurea treatment improves complications such as extramedullary hematopoietic tumors, leg
ulcers, and quality of life35
. Although the use of hydroxyurea cannot be recommended in an evidence-
based manner based on controlled clinical trials in patients with NTDT, its use can be considered for
those patients with selected comorbid conditions, including pulmonary hypertension, extramedullary
hematopoiesis, and pseudotumors, and in patients with leg ulcers, based on results of observational
cohort studies and small clinical trials31
. The efficacy of hydroxyurea is influenced by the primary
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mutation and associated polymorphisms in genes that regulate fetal Hb; patients with thalassemia are
more sensitive to hydroxyurea than patients with sickle cell disease, and starting and maximum doses
are lower2. Most investigators initiate therapy with 10 mg/kg/day, gradually increasing to a maximum
of 20 mg/kg/day, with concomitant folic acid supplementation recommended31,71
.
Several novel management strategies for stimulating erythropoiesis and modulating iron levels are
currently in the early stages of investigation; these therapies may have value as short- or long-term
management strategies for improving clinical symptoms in NTDT2. A fusion protein comprised of
modified activin receptor type IIB (ActRIIB; a member of the transforming growth factor beta [TGF-
β] superfamily) and human IgG1 Fc acts as a ligand trap for TGF-β superfamily ligands (e.g., activins
and/or growth and differentiation factors) and inhibits Smad2/3 signaling. This innovative therapy
promotes late-stage red blood cell precursor cell differentiation via a mechanism distinct from that of
erythropoietin56
. Additionally, clinical trials of a recombinant fusion protein containing ActRIIB and
IgG1 Fc have been developed for the treatment of anemias due to ineffective erythropoiesis. Results
of pilot studies in TI have been very encouraging. In healthy volunteers, the drug was well-tolerated
and increased Hb levels72
. In phase 2, open-label studies in TI, patients demonstrated increased Hb
and reduced erythropoiesis without adverse side effects73
. Results of dose-escalation trials and long-
term efficacy studies are ongoing.
The Janus kinase 2 (JAK2) pathway is essential for signaling by erythropoietin and its receptor and
plays an essential role in modulating erythrocyte proliferation, differentiation, and survival. In beta
thalassemias, overactivation of JAK2 leads to increased erythrocyte proliferation and reduced
differentiation, resulting in ineffective erythropoiesis56
. Inhibitors of the JAK2 pathway are therefore
being investigated for their potential to reduce symptoms, such as splenomegaly, resulting from
ineffective erythropoiesis in NTDT and TI56,74
. Also under investigation are modulators of the
hepcidin pathway, which serves to regulate iron homeostasis57,58
. Increased hepcidin production limits
intestinal absorption of iron and increases the sequestration of iron by macrophages, which are
involved in recycling iron from senescent erythrocytes; there is also evidence that erythropoiesis
serves to regulate hepcidin expression57
. Agonists of hepcidin (i.e., hepcidin mimetics) may therefore
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have clinical utility in conditions such as beta TI. However, these agents have only been investigated
in mouse models58
. Finally, the use of apotransferrin therapy is also under investigation as a possible
means of managing iron overload and improving anemia as the transferrin pathway serves to transport
iron between the major sites of uptake, storage, and utilization2.
CONCLUSIONS
Although patients with NTDT in the past have been regarded to have less severe disease, it is now
known that these patients have a substantial disease burden that negatively impacts quality of
life11,40,75
. Indeed, over time, patients with NTDT and TI can accumulate similar levels of iron in the
liver as patients with TDT75
. The increasing incidence of these disorders in developed healthcare
systems such as those in North America and Europe calls for new strategies to increase access to
appropriate treatment24
. While there has been more prenatal diagnosis and neonatal screening to
confront this growing problem, a comprehensive approach is needed to further optimize care, with an
emphasis on increased understanding of the at-risk populations. Care of affected patients may be
improved by increasing physician awareness and addressing cultural and economic barriers to
therapy9,25
. Frequent screening of patients with thalassemia using relatively simple assessments such
as complete blood count and serum ferritin can also contribute toward identifying the functional
impairments that have the greatest impact on quality of life9. Management strategies such as iron
chelation therapy can reduce iron burden and have been well tolerated in patients with NTDT67,69,76
. A
number of other novel management strategies, such as JAK2 inhibitors and hepcidin mimetics, are
currently under investigation for these disorders2,33
. Management of NTDT should entail
comprehensive education and patient management strategies24,28
. It will also be important to continue
to develop screening, counseling, and prenatal diagnosis programs in the most affected developing
countries around the globe6.
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TRANSPARENCY
Declaration of funding:
Editorial assistance for this review was funded by Novartis Pharmaceuticals Corporation.
Declaration of financial/other relationships:
Dr. Vichinsky received no funding related to the development of this manuscript. He has disclosed
that he has received grants from the Centers for Disease Control and Prevention and the National
Heart, Lung, and Blood Institute; and grants and personal fees from Novartis Pharmaceuticals
Corporation for other work. He has also been a speaker for both Novartis Pharmaceuticals
Corporation and ApoPharma.
Acknowledgments:
We thank Jennifer Lee, PhD, of Phase Five Communications for medical editorial assistance with this
manuscript. Financial support for medical editorial assistance was provided by Novartis
Pharmaceuticals Corporation. Dr. Vichinsky was responsible for all content and editorial decisions of
the manuscript and received no honoraria related to its development.
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FIGURE LEGENDS
Figure 1. Ethnicity of hemoglobin H disease in California27
Figure 2. Pathophysiology of NTDT2,30
. GI, gastrointestinal; NTDT, non-transfusion-dependent
thalassemia; RBC, red blood cell.
Figure 3. Spectrum of transfusion requirements in thalassemias2. Hb, hemoglobin.
Figure 4. LICs in patients with beta thalassemia intermedia–associated morbidities50
. Squares
represent means and whiskers represent standard deviations, except for heart failure and diabetes
mellitus, for which corresponding markers represent medians and 25th and 75th percentiles,
respectively. p-values were calculated using independent samples t-test, except for heart failure and
diabetes mellitus, for which Mann-Whitney U test was used. ALF, abnormal liver function; dw, dry
weight; EMH, extramedullary hematopoiesis; LIC, liver iron concentration; PHT, pulmonary
hypertension. Reprinted from Musallam KM et al. Elevated liver iron concentration is a marker of
increased morbidity in patients with β thalassemia intermedia. Haematologica. 2011;96(11):1605-
1612. Obtained from the Haematologica Journal website http://www.haematologica.org.
Figure 5. THALASSA: Absolute change in (A) LIC and (B) serum ferritin35
. ap-value adjusted with
the Dunnett method. dw, dry weight; LIC, liver iron concentration; LSM, least squares mean; SEM,
standard error of the mean.
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Table 1. Overview of NTDT3,30
Thalassemia Subtype
and Etiology Disease Characteristics
Primary Geographic
Regions Common Complications
Alpha thalassemia (Hb H
disease)
Caused by
inactivation of
three alpha
globin genes
Most cases characterized
by mild to moderate
anemia, marked
microcytosis, and
hypochromia; phenotype
is rarely similar to alpha
thalassemia major
Prevalent in Southeast
Asia and Africa
Bone/skeletal
abnormalities, acute
hemolytic episodes,
cholelithiasis,
splenomegaly
Beta thalassemia
intermedia
Results from
inheritance of a
milder beta
thalassemia
phenotype
Clinical severity is
variable, ranging from
mild to moderate NTDT
Worldwide prevalence,
but most common in
Southeast Asia and the
Eastern Mediterranean
region
Splenomegaly,
pulmonary hypertension,
cholelithiasis,
leg ulcers, extramedullary
hematopoiesis,
thrombotic events
Hb E beta thalassemia
Caused by
coinheritance of
Hb E structural
Hb variant and
other beta
thalassemia
alleles
Clinical severity is
variable, ranges from
non-transfusion-
dependent to transfusion-
dependent
Prevalent in Southeast
Asia, Indian
subcontinent, and south
mainland China
Splenomegaly,
bone/skeletal
abnormalities, growth
retardation, acute
hemolytic episodes
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Hb, hemoglobin; NTDT, non-transfusion-dependent thalassemia.
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Table 2. Differentiating transfusion-dependent or major thalassemia and non-transfusion-dependent
or intermediate thalassemia3. Clinical characteristics based on data from Cappellini MD et al.
Guidelines for the Clinical Management of Thalassaemia [Internet]. 2nd Revised edition. Nicosia
(CY): Thalassaemia International Federation; 2008.
TDT/TM NTDT/TI
Age of clinical presentation 0–2 years 2–6 years
Hb concentration 6–7 g/dL 8–10 g/dL
HbA2 composition <4% >4%
Anemia severity Severe Moderate
Spleen and liver enlargement Severe Moderate
NTDT, non-transfusion-dependent thalassemia; TDT, transfusion-dependent thalassemia; TI,
thalassemia intermedia; TM, thalassemia major.
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