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Full Terms & Conditions of access and use can be found at http://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 thalassemia and thalassemia intermedia: epidemiology, complications, and management Elliott Vichinsky MD To cite this article: Elliott Vichinsky MD (2015): Non-transfusion-dependent thalassemia and thalassemia intermedia: epidemiology, complications, and management, Current Medical Research 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: 19 Oct 2015. Submit your article to this journal Article views: 54 View related articles View Crossmark data

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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.

Submit your article to this journal

Article views: 54

View related articles

View Crossmark data

© 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

Just Accepted articles is subject to the express understanding that the papers have not yet gone through the full quality control process prior to publication.

Just Accepted by Current Medical Research & Opinion

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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Figure 1.

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Figure 2.

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Figure 3.

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Figure 4.

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Figure 5A.

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Figure 5B.

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