The Hemoglobin E Thalassemias

Suthat Fucharoen1 and David J. Weatherall2

1
Thalassemia Research Centre, Institute of Science and Technology for Research and Development, Mahidol
University, Bangkok, Thailand
2
Weatherall Institute of Molecular Medicine, University of Oxford, John Radcliffe Hospital, Oxford OX3 9DS,
United Kingdom
Correspondence: [email protected]

Hemoglobin E (HbE) is an extremely common structural hemoglobin variant that occurs at

high frequencies throughout many Asian countries. It is a b-hemoglobin variant, which is
produced at a slightly reduced rate and hence has the phenotype of a mild form of b
thalassemia. Its interactions with different forms of a thalassemia result in a wide variety of
clinical disorders, whereas its coinheritance with b thalassemia, a condition called hemo-
globin E b thalassemia, is by far the most common severe form of b thalassemia in Asia and,
globally, comprises approximately 50% of the clinically severe b-thalassemia disorders.
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s discussed by Williams and Weatherall 1956 by Chernoff and colleagues (1956). Much
A (2012), HbE occurs at an extremely high
frequency in many countries in Asia. Because
later, groups in Thailand began a detailed analysis
of the interaction of the various forms of a thal-
there is also a high frequency of different b- assemiawithHbE,which result in acomplex series
thalassemia alleles in these populations, the co- of phenotypes, most of which are much milder
inheritance of HbE and b thalassemia, HbE b than HbE b thalassemia (Wasi et al. 1969).
thalassemia, occurs very frequently. Similarly,
because different forms of a thalassemia are
MOLECULAR PATHOLOGY AND
also very common in these countries, HbE also
PROPERTIES OF HEMOGLOBIN E
occurs together with them, producing a com-
plex series of phenotypes. At least in vitro, HbE appears to be mildly un-
The first description of HbE b thalassemia stable and shows increased sensitivity to oxi-
appeared in a paper by Minnich and her col- dants (Frischer and Bowman 1975). However,
leagues in 1954 under what, at the time, was the in vitro studies of hemoglobin synthesis do not
rather surprising title “Mediterranean Anaemia: show evidence of instability similar to that
A study of 32 cases in Thailand” (Minnich et al. found in other unstable hemoglobin variants,
1954). In the same year, the first electrophoretic although HbE is unstable at increased tempera-
identificationofHbEwasreportedindependently tures, similar to those that would occur in a wide
(Itano et al. 1954). The first detailed clinical de- range of infective diseases (Rees et al. 1998). The
scription of HbE b thalassemia was reported in whole-blood oxygen dissociation curves of

Editors: David Weatherall, Alan N. Schechter, and David G. Nathan

Additional Perspectives on Hemoglobin and Its Diseases available at www.perspectivesinmedicine.org
Copyright # 2012 Cold Spring Harbor Laboratory Press; all rights reserved; doi: 10.1101/cshperspect.a011734
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1
 S. Fucharoen and D.J. Weatherall

homozygotes for HbE appear to be normal or

very slightly right-shifted. HbE is synthesized at
a slightly reduced rate and homozygotes show
mild globin-chain imbalance, similar to that ob-
served in b-thalassemia heterozygotes. It is
caused by a base substitution at codon 26 of
the b-globin gene, GAG-AAG, which results in
the substitution of lysine for glutamic acid. This
mutation also activates a cryptic splice site that
causes abnormal messenger RNA processing
(Orkin et al. 1982). Because the normal donor
site has to compete with this new site, the level of
normally spliced bE messenger RNA is reduced Figure 2. The peripheral blood film in the homozy-
(Traeger et al. 1980), resulting in the clinical gous state for hemoglobin E showing large numbers
phenotype of a mild form of b thalassemia. of target cells.
The heterozygous state for HbE is character-
ized by minimal morphological abnormalities severity. The molecular basis for the different
of the red cells and normal red cell indices; forms of a and b thalassemia, which are coin-
HbE constitutes 25% – 30% of the hemoglobin herited with HbE, are described by Thein (2012)
(Fig. 1). Homozygotes for HbE have hypochro- and Higgs (2012).
mic microcytic red cells with significant mor- The various interactions of HbE and a thal-
phological abnormalities including increased assemia, which have been defined in the Thai
numbers of target cells (Fig. 2). They are mildly population, and occur elsewhere in SE Asia, are
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anemic and the overall hematological findings described by their particular hemoglobin con-
are very similar to those of heterozygous b thal- stitutions (Table 1). Heterozygotes for HbE,
assemia. which are also heterozygous for aþ thalassemia
(2a/aa), have similar levels of HbE to HbE
heterozygotes, whereas those that are heterozy-
THE INTERACTIONS OF HEMOGLOBIN E
gous for a0 thalassemia (2/aa) have mild thal-
WITH DIFFERENT FORMS OF THALASSEMIA
assemic red cell changes and the level of HbE
Although HbE alone does not cause any signifi- ranges between 19% and 21%. HbE heterozy-
cant clinical problems, its interactions with var- gotes who also inherit the genotype of HbH
ious forms of a and b thalassemia produce a disease (2/2a) have a marked decrease of
very wide range of clinical syndromes of varying HbE in the 13%– 15% range and a thalassemic
disorder of intermediate severity, which is called
HbAE Bart’s disease.
Hemoglobin E homozygotes who coinherit
the heterozygous state for aþ or a0 thalassemia
have a mild hypochromic microcytic anemiawith
slightly elevated levels of HbF. Those who coin-
herit the genotype of HbH disease have a thal-
assemic disorder of intermediate severity with
moderate anemia and elevated levels of HbF and
Bart’s, a condition called EF Bart’s disease.
The compound heterozygous state for HbE
and b thalassemia, HbE b thalassemia, is a re-
markably heterogenous disease with a pheno-
Figure 1. The peripheral blood film in hemoglobin E type ranging from mild anemia to the most se-
trait showing normal red cell morphology. vere forms of b-thalassemia major (Weatherall

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Table 1. Hematological data and clinical picture of subjects with HbE with different kinds of a-globin gene interactions
a-Globin
Hb E gene Hb (g/dl) MCV (fl) Hb typing Hb E (%) HbBart’s (%) Hb F (%) Clinical
Hb E heterozygote aa/aa 12.8 + 1.5 84 + 5 EA 29 + 2.3 - 0.9 + 0.7 Normal
2a/aa 13.1 + 1.4 88 + 4 EA 28 + 1.5 - 0.7 + 0.6 Normal
2/aa 12.5 + 1.4 77 + 5 EA 21 + 1.2 - 0.9 + 0.4 Normal
2/2a 9.1 + 1.1 60 + 3 EFA Bart’s 13 + 2.1 4.5 + 1.9 2.2 + 1.9 Thal intermedia (AEBart’s disease)
Hb E homozygote aa/aa 10.6 + 1.2 65 + 3 EF 88 + 2.6 - 3.6 + 1.6 Normal
2a/aa 11.0 + 1.6 65 + 4 EF 87 + 3.3 - 4.8 + 3.7 Normal
2/aa 10.5 + 2.4 64 + 7 EF 88 + 5.7 - 3.8 + 2.1 Normal
2/2a 7.5 + 0.8 60 + 2 EF Bart’s 81 + 1.5 4.2 + 1.1 6.4 + 1.2 Thal intermedia (EFBart’s disease)
Hb E b thalassemia aa/aa 7.1 + 1.4 59 + 3 EF 58 + 9.5 - 38 + 11.7 Mild to severe disease
2a/aa 8.5 + 1.1 55 + 3 EF 71 + 7.5 - 24 + 8.7 Mild disease
2/aa 9.3 + 0.5 52 + 1 EF 84 + 3.8 - 12 + 2.5 Mild disease
2/2a 7.6 + 1.2 61 + 2 EF Bart’s 82 + 2.5 1.5 + 0.3 5.5 + 0.7 Thal intermedia (EFBart’s disease)

Hemoglobin E Thalassemias
3
 S. Fucharoen and D.J. Weatherall

and Clegg 2001). This condition may also be co- 10% of the hemoglobin; the remainder is Hb
inherited with a variety of different forms of a Bart’s. The presence of Hb Bart’s indicates that
thalassemia. The coinheritance of the heterozy- there are excess g-globin chains. However, no
gous states for aþ and a0 thalassemia have an inclusion bodies or HbH are present, probably
ameliorating effect on the disease, whereas those because the abnormal bE-globin chains do not
who also inherit the genotype of HbH disease form tetramers. Four genotypes of HbEF Bart’s
have a form of HbEF Bart’s disease, as described disease have been identified. They result from
above. interactions between the genotype for HbH dis-
These complex interactions, which are sum- ease, either a0 thalassemia/aþ thalassemia or
marized in Table 1, produce three significant a0 thalassemia/Hb Constant Spring, with ei-
clinical disorders; HbAE Bart’s disease, HbEF ther homozygous HbE or HbE b thalassemia.
Bart’s disease, and HbE b thalassemia. Hb Constant Spring and small amounts of HbA
may be observed in patients with the a0 thalas-
semia/Hb Constant Spring and HbE bþ thalas-
HbAE BART’S DISEASE semia genotype. To differentiate among these
This thalassemia syndrome is characterized by genotypes, family studies and further investiga-
the presence of HbA, HbE, and Hb Bart’s, and tion by DNA analysis are required.
results from the interaction of the genotype of Overall, the interactions of the different ge-
HbH disease (see Higgs 2012; Vichinsky 2012) notypes for HbH disease with the homozygous
with heterozygous HbE (Wasi et al. 1967; Thon- state for HbE produce relatively mild forms of
glairuam et al. 1989). Two common subtypes of thalassemia intermedia, not dissimilar to HbH
HbAE Bart’s disease have been observed: aþ disease (see Vichinsky 2012). Their interactions
thalassemia/a0 thalassemia—A/E and a0 thal- with HbE b thalassemia are more complex and
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assemia/Hb Constant Spring—A/E. Clinically, clinically variable, and are discussed in more
HbAE Bart’s disease is similar to HbH disease, detail in the next section.
and like the latter, the a0 thalassemia/Hb Con-
stant Spring interaction is more severe (see Vi- HEMOGLOBIN E b THALASSEMIA
chinsky 2012). However, in this syndrome there
In general, HbE b thalassemia is a thalassemia
are no hemolytic crises during stress similar to
syndrome of intermediate severity with a very het-
those seen in HbH disease. The amount of HbE
erogeneous clinical spectrum. Two types have
is decreased to 13%– 15%. This is because a-
been described, depending on the presence or ab-
globin chains have a lower affinity for bE than
sence of HbA. In HbE, b0 thalassemia, bA-globin
bA-globin chains. Small amounts of Hb Bart’s
chains are not synthesized and the condition is
are always present in this genotype and intra-
characterized by the production of HbE and
erythrocytic inclusion bodies (HbH inclusions)
HbF without detectable HbA; HbE constitutes
can be demonstrated in 5% of the erythro-
between 30% and 70% of the hemoglobin with
cytes, indicating the presence of small amounts
the remainder HbF. Variable amounts of HbA are
of HbH that is insufficient to be detected by
detected, in addition to HbE and HbF, in HbE bþ
electrophoresis.
thalassemia. Different bþ thalassemia mutations
The diagnosis of this disorder requires de-
result in variable severity of the disease, reflecting
tailed family studies together with DNA analysis
different levels of HbA.
to define the type of a thalassemia. Management
is similar to HbH disease (see Vichinsky 2012).
Pathophysiology
HbEF BART’S DISEASE
The pathophysiology of HbE b thalassemia re-
HbEF Bart’s disease is characterized by the pres- flects both the reduced output of HbE together
ence of HbE, HbF, and Hb Bart’s (Fucharoen with the added globin-chain imbalance conse-
et al. 1988b). HbE constitutes 80% and HbF quent on the coinheritance of b thalassemia.

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 Hemoglobin E Thalassemias

Although early studies suggested that HbE is 2007). This may be at least partly responsible for
slightly unstable and may precipitate under some of the remarkable phenotypic heterogene-
conditions of oxidative stress, later biosynthetic ity observed during the early years of develop-
analyses showed little evidence of its instability ment in babies with HbE b thalassemia.
in the red cells of patients with HbE b thalasse-
mia. The one exception was if the cells were ex-
Clinical Features
posed to increased temperatures at the level that
might be encountered in severe forms of infec- One of the most striking features of HbE b thal-
tion at which there was evidence of instability assemia is its remarkable clinical heterogeneity.
(Rees et al. 1998). However, the remarkable At one end of the spectrum, there are patients
ameliorating effect on the phenotype that re- whose clinical course is almost indistinguishable
sults from the coinheritance of a thalassemia from that of severe b-thalassemia major; where-
or other modifiers of the degree of globin chain as at the other end, there are patients who grow
imbalance (see later section) suggests that defec- and develop normally without the need for
tive b chain synthesis is the major factor in the blood transfusion, albeit often at a relatively
pathophysiology of this condition (reviewed by low hemoglobin level.
Weatherall and Clegg 2001). Like other forms of At birth, infants with severe HbE b thalas-
severe b thalassemia, there is marked expansion semia are asymptomatic because HbF levels are
of the erythroid bone marrow with ineffective high. As HbF production decreases and is re-
erythropoiesis. Interestingly, using a combina- placed by HbE at 6– 12 months of age, anemia
tion of electron-microscopic and immunocy- with splenomegaly develops. Signs of impaired
tochemical studies, Wickramasinghe and Lee growth appear during the first decade of life. The
(1997) demonstrated that the erythroblast in- initial complaints vary from patient to patient,
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clusions in the bone marrow of patients with and several symptoms usually appear simulta-
this condition consist entirely of precipitated a neously (Table 2). Most common are the de-
chains; there is no evidence of coprecipitation of velopment of a mass in the left upper quadrant
bE chains. Therefore the mechanisms of damage and pallor. With time and without transfusions,
to red cells and their precursors are similar to anemia, jaundice, hepatosplenomegaly, growth
those described in other forms of b thalassemia
(see Nienhuis and Nathan 2012).
Recent studies have suggested that there Table 2. Presenting symptoms in 378 HbE b-thalas-
are important differences in the compensatory semia patients in Thailand
mechanisms between HbE b thalassemia and Symptoms Number %
other forms of severe thalassemia intermedia. 1. Pallor 150 39.7
In particular, patients with HbE b thalassemia 2. Fever 72 19.1
appear to be able to compensate for anemia by a 3. Abdominal mass 36 9.5
right shift in their oxygen dissociation curves, 4. Abdominal pain 23 6.1
unlike those with many other forms of b-thal- 5. Combined: Abdominal mass 21 5.6
assemia intermedia (Allen et al. 2010). This and pain
probably reflects both the properties of HbE 6. Yellow eyes ( jaundice) 16 4.2
and the lower mean levels of HbF that occur 7. Edema 9 2.4
8. Pregnancy with anemia 3 0.8
in HbE b thalassemia compared with other
9. Bone pain 3 0.8
forms of b-thalassemia intermedia. Studies of 10. Paraplegia 2 0.5
the erythropoietin response to anemia in this 11. Headache and dizziness 2 0.5
condition have shown that hemoglobin level 12. Miscellaneousa 41 10.8
and age are independent variables with respect Total 378 100
to the erythropoietin level and that there is a a
Miscellaneous includes lymphadenopathy, skin rashes,
relative reduction in response to a particular chest pain, request for plastic surgery, joint pain, and cases
hemoglobin level with aging (O’Donnell et al. with multiple symptoms.

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 S. Fucharoen and D.J. Weatherall

Table 3. Clinical signs in 378 adult HbE b-thalasse- b thalassemia in Sri Lanka, at least 20 cases
mia patients in Thailand changed from a mild to a more severe phenotype
Signa Number % during the first 15 years of life.
1. Splenomegaly 369 97.6
2. Jaundice 350 92.6 Laboratory Findings
3. Hepatomegaly 337 89.1
4. Thalassemic facies 313 82.8 The steady-state hemoglobin levels in HbE b
5. Growth retardation 284 75.1 thalassemia range widely between the different
6. Anemia 152 40.2 phenotypes, from 3 g/dl or less to as high as
7. Abnormal cardiovascular systemb 70 18.5 11 g/dl. The red-cell indices and morphological
8. Respiratory tract infection 44 11.6 changes are similar to those described in other
9. Arthritis and bone pain 40 10.6
forms of severe b thalassemia (Fig. 3). Hemo-
10. Abnormal neurological systemc 32 8.5
globin analysis reveals a preponderance of HbE
11. Chronic leg ulcer 31 8.2
12. Soft tissue infection 7 1.8 with low levels of HbA in those who have inher-
a
ited a bþ-thalassemia mutation. The mean level
Most patients have more than one clinical sign.
b
Abnormal cardiovascular manifestations are mainly
of HbF in 200 patients from Sri Lanka was ap-
related to congestive heart failure (50 cases), deep vein proximately 28%, ranging from less than 10% to
thrombosis (five cases), pericarditis (four cases), and others. 50%; even higher levels of HbF have been re-
c
Abnormal neurological features are mainly weakness of ported from Thailand. Family studies reveal
both hands (14 cases), headache (11 cases), and paraplegia the carrier state for HbE in one parent and for
(two cases).
b-thalassemia trait in the other. The laboratory
findings associated with different complications
are discussed in the following sections.
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retardation, and thalassemic facies evolve (Table

3). Absence of secondary sexual development is Complications
common and chronic leg ulcers are sometimes
observed. These manifestations, which are sec- Hypersplenism
ondary to decreased oxygen delivery to tissue, Splenomegaly, together with pooling of red cells
ineffective erythropoiesis, and iron overload, re- and their increased rate of destruction, is extreme-
semble those of b-thalassemia major. ly common. In the more severe phenotypes, it
Patients with the milder forms of HbE b often progresses rapidly from the first few years
thalassemia tend to grow and develop reason-
ably well during early childhood and are fully
active. There may be some delay in the pubertal
growth spurt and in the appearance of secondary
sexual characteristics but they usually attain a
reasonable height and sexual maturation. Fur-
ther work is required to determine whether they
develop the later complications that have been
described in older patients with other forms
of thalassemia intermedia, such as renal disease,
pulmonary hypertension, cerebral infarcts, and
others (see Musallam et al. 2012). Certainly
some of them accumulate iron through in-
creased absorption and may develop associated
endocrine complications including diabetes.
Furthermore, there is undoubtedly phenotypic Figure 3. The peripheral blood film in hemoglobin E
instability in the early years of life; in a series b thalassemia after splenectomy showing numerous
of children observed over 15 years with HbE nucleated red cells and a high platelet count.

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 Hemoglobin E Thalassemias

of life, whereas in the milder phenotypes, al- marked contrast to enormous iron deposition
though the spleen is palpable, it usually does in the liver and pancreas. Cardiomegaly is pro-
not attain a size greater than 5–6 cm below the portional to the severity of anemia and systolic
costal margin. Much less common, and usually in murmurs are frequently present (Jootar and Fu-
the milder phenotypes, splenomegaly may slowly charoen 1990). Chronic pericarditis following
increase over 10–20 years and only become a upper respiratory tract infection is frequently en-
problem later in life. As well as resulting in in- countered, more commonly in splenectomized
creasing anemia, progressive enlargement of the patients. A pericardial rub may be detected, often
spleen is quite often associated with pain and transiently. Intractable pericardial effusion may
discomfort in the left upper quadrant. follow, causing cardiac tamponade and failure,
and requires aspiration. In avery few cases, chron-
ic constrictive pericarditis develops, requiring
Infection
surgical intervention.
Patients with HbE b thalassemia are susceptible Heart rate variability (HRV) has been de-
toviral, bacterial, and fungal infection, which are veloped to determine cardiac autonomic func-
common causes of mortality (Aswapokee et al. tion and is applied to investigate patients with
1988a,b). In splenectomized patients, septi- thalassemia major (De Chiara et al. 2005). Stud-
cemia can be very acute and overwhelming, lead- ies of the HRV in HbE b thalassemia have ob-
ing to death in a short period. Gram-negative tained similar results to those in thalassemia
and gram-positive bacteria are frequent causes major (Rutjanaprom et al. 2009). The depressed
of septicemia. Fungal infectionwith Pythium can HRV compared to normal suggests that HRV
lead to arterial occlusion and gangrene of the legs may be a marker of cardiac sympatho-vagal im-
(Sathapatayavongs et al. 1989; Wanachiwanawin balance as well as an early indicator of cardiac
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et al. 1993). The mechanism that causes increased involvement in both thalassemia major and
susceptibility to infections is not known. Recent HbE b thalassemia.
studies have suggested that patients with HbE b Pulmonary hypertension and right heart
thalassemia may be more prone to infection by failure are discussed in the following sections.
both P. falciparum and P. vivax malaria, particu-
larly the latter, and that those who have under-
Hypoxemia
gone splenectomy may be even more susceptible
(O’Donnell et al. 2009). The majority of splenectomized HbE b-thalas-
semia patients in Thailand develop hypoxemia
with low arterial pO2 (Wasi et al. 1982). Platelet
Cardiac Disease
counts in these patients are double those of
Approximately half of the patients with HbE b nonsplenectomized patients; young and larger
thalassemia in Thailand die of heart failure. This platelets are also observed in the absence of
is associated with failure of other organs, delayed the spleen. Platelet microaggregates have been
growth and sexual maturation, hepatomegaly, detected in the circulation of these splenecto-
and endocrinopathies. Organ failure results mized patients. One hypothesis for the patho-
from iron deposition in the heart and other tis- genesis of hypoxemia in HbE b thalassemia is
sues (Vannasaeng et al. 1981; Sonakul et al. 1988; that platelets increase in number, are younger
Thakerngpol et al. 1988) resulting from increased and more active after splenectomy, and aggre-
absorption and blood transfusion. Myocardial gate in the circulation and in the pulmonary
iron deposition is usually limited, occurring pri- vasculature. Substances released during platelet
marily as small granules in perinuclear areas, with aggregation may cause constriction of the ter-
later accumulation throughout the muscle fibers, minal bronchioles leading to decreased oxygen-
predominantly subepicardial and occasionally ation and hypoxemia. Administration of aspirin
subendocardial (Sonakul et al. 1984). The small to inhibit platelet aggregation reduces the de-
amount of iron deposited in the heart is in gree of hypoxemia in the majority of cases

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 S. Fucharoen and D.J. Weatherall

(Fucharoen et al. 1981), suggesting that aspirin Extramedullary Hemopoiesis

should be routinely given to splenectomized
Erythropoiesis is massively increased to 10–15
patients with HbE b thalassemia. Interestingly,
times normal because anemia stimulates ery-
this combination of pulmonary hypertension
thropoietin production. Extensive erythropoie-
and hypoxemia, together with right ventricular
sis can be found in the liver, spleen, bone mar-
failure, has not been observed so frequently in
row, and in extramedullary sites. Erythropoietic
other populations, suggesting that other factors
masses in the spinal canal can cause spinal cord
may be involved in the Thai population.
compression and paraplegia, and when they oc-
cur intracranially, convulsions may result (Issa-
Thromboembolism ragrisil et al. 1981). Massive erythropoiesis leads
to fragility and distortion of the bones and de-
Autopsy findings in a large number of Thai
creases bone density because of osteoporosis and
patients with HbE b thalassemia revealed strik-
osteomalacia, as observed in irregularly trans-
ing pulmonary artery occlusion (Fig. 4) (Sona-
fused patients (Pootrakul et al. 1980).
kul et al. 1980). Thromboembolism in HbE b
thalassemia seems to involve platelets, a reactive
thalassemic red cell surface, coagulation fac- Jaundice, Gallstones, and Cholecystitis
tors, and abnormal endothelium (Butthep et al. Some HbE b-thalassemia patients have severe
2002; Pattanapanyasat et al. 2004). and persistent jaundice in the absence of defin-
able liver disease. It turns out that this is a result
Hypertension, Convulsions, and of the homozygous inheritance of the TA(7) al-
Cerebral Hemorrhage lele of the promoter of the glucuronyltransferase
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1 gene, a polymorphism that is particularly com-

Some patients in Thailand develop hyperten- mon in Sri Lanka (Premawardhena et al. 2001).
sion, convulsions, and cerebral hemorrhage af- These patients have a highly significant increase
ter transfusion of 2 units or more of blood (Wasi in the incidence of gallstones. Homozygosity for
et al. 1978). This complication may develop as the TA(7) allele occurs in 10% – 25% of some
late as 2 weeks after multiple transfusions, sug- populations of Africa and the Indian subconti-
gesting that blood volume overload is not the nent but at a much lower frequency in Southeast
cause of hypertension. Monitoring blood pres- Asia (Premawardhena et al. 2003). Stones are
sure during and after blood transfusions with found in approximately 50% of HbE b-thalas-
prompt antihypertensive intervention has re- semia patients in Thailand (Chandcharoensin-
duced deaths from this complication. This syn- Wilde et al. 1988). For the detection of biliary
drome has not been reported in other popula- calculi, ultrasonography is more sensitive than
tions. oral cholecystography and plain abdominal
films. Cholecystitis and ascending cholangitis
may occur with abdominal pain, fever, and in-
creasing jaundice (Vathanopas et al. 1988).

Iron Overload
Iron overload occurs commonly (Pootrakul
et al. 1981). Excessive iron accumulates because
of blood transfusions and enhanced gastrointes-
tinal absorption. The skin is darkened and iron
deposition occurs in the bone marrow, liver,
spleen, heart, pancreas, and elsewhere (Sonakul
Figure 4. Pulmonary vascular occlusion in hemoglo- et al. 1988; Thakerngpol et al. 1988). The related
bin E b thalassemia after splenectomy. cardiac complications were discussed earlier.

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 Hemoglobin E Thalassemias

Although liver fibrosis from iron overload is transfusion requirements. A novel scoring sys-
common, ascites and other signs of cirrhosis tem based on six independent parameters—he-
are very rare. Diabetes mellitus, secondary to moglobin level, age at disease presentation, age
iron deposition in the pancreas, frequently devel- at receiving first blood transfusion, requirement
ops in untreated adult patients (Vannasaeng et al. for transfusion, spleen size, growth and develop-
1981). A terminal wasting stage occurs in some ment—was able to separate patients into three
patients who survive to their fourth and fifth distinctive severity categories: mild, moderate,
decades. They develop severe skin pigmentation, and severe. The scoring system consisting of
poor appetite, weight loss, and increasing ane- six clinical criteria scored as 0, 0.5, 1, or 2, ac-
mia, and eventually die. This is believed to result cording to clinical presentation. HbE b-thalas-
from organ failure caused by uncontrolled tissue semia patients with total scores ranging from 0
oxidation from chronic, severe iron overload. to 3.5, 4 to 7, and 7.5 to 10 are grouped as mild,
Recently, it has been possible to obtain more moderate, and severe cases, respectively. The se-
direct data about the liver iron concentration in vere patients are very anemic and are usually
HbE b thalassemia using spin density projec- transfusion dependent; some may have marked
tion assisted R2-MRI technology (Olivieri et al. growth retardation, whereas the mild cases have
2011). These studies showed a marked variation mild anemia and usually have normal growth
in hepatic iron levels even in patients who had and development (Sripichai et al. 2008).
received only minimal transfusion. They also As indicated by recent studies in Sri Lanka,
underlined the rather poor agreement between the application of a clearly defined scoring sys-
hepatic iron levels as measured in this way and tem for severity combined with a long period
serum ferritin values. Clearly, a great deal more of observation and genetic and environmental
work is required to try to determine the reasons analysis (Premawardhena et al. 2005; Olivieri
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for the variable rate of iron accumulation by et al. 2010) should help us to understand the
increased intestinal absorption and, in particu- factors that determine the broad range of se-
lar, whether this reflects polymorphisms in one verity of HbE b thalassemia.
or more of the genes that are involved in the
regulation of iron absorption.
b-Thalassemia Mutations
Other Endocrine Disorders Although b0 thalassemia is caused by many mu-
tations, all result in absence of b-globin chain
As well as diabetes there are other important
production by the abnormal gene. b0 thalas-
endocrine disorders that occur as a result of
semia is more severe than bþ thalassemia, in
iron loading. In particular hypothyroidism and
which a wide range of b-globin chain produc-
hypoparathyroidism are quite common and the
tion is observed. In most countries with a high
former is frequently associated with growth re-
frequency of HbE b thalassemia, the common
tardation. It is vital, therefore, to carry out reg-
b-thalassemia mutations are either b0 thalas-
ular assessments of thyroid and parathyroid
semia or bþ thalassemia associated with very
function in patients with HbE b thalassemia,
small amounts of b-globin chain synthesis.
regardless of the severity of their phenotype.
The fact that there is still considerable clinical
heterogeneity in these patients is clearly not a
Genotype– Phenotype Interaction result of variation in b-globin chain synthesis
directed by the chromosome containing the b-
Definition of Severity
thalassemia mutation. There are, however, cer-
Despite seemingly identical genotypes, com- tain milder forms of bþ thalassemia associated
pound heterozygotes for b thalassemia and with much higher levels of b-chain production
HbE have remarkably variable phenotypes. No- and, when inherited together with HbE, pro-
table are variations in the degree of anemia, duce a much milder form of HbE b thalassemia.
growth, development, hepatosplenomegaly, and The phenotypes and hemoglobin findings in

Cite this article as Cold Spring Harb Perspect Med 2012;2:a011734 9

 S. Fucharoen and D.J. Weatherall

patients of this type are summarized by Weath- cance. The percentage of alternative spliced bE-
erall and Clegg (2001). globin mRNA was determined by the reverse
transcriptase polymerase chain reaction tech-
Coinheritance of a Thalassemia nique in 14 patients with the same thalassemia
mutation (Winichagoon et al. 1995). Prelimi-
The concomitant inheritance of a thalassemia nary results showed abnormally spliced bE-glo-
or Hb Constant Spring may be responsible for bin mRNA in patients with severe symptoms
less severe anemia and a milder phenotype in and low hemoglobin levels between 2.9% and
HbE b0 thalassemia (Winichagoon et al. 1985, 6.1%, whereas those with higher hemoglobin
1993). Coinheritance of a0 thalassemia with levels had values from 1.6% to 2.6%. The ma-
HbE b0 thalassemia may lead to so mild a con- jority of patients with the Xmnl-negative geno-
dition that the individuals do not have a clinical type had more severe anemia and a higher
abnormality that requires medical attention. percentage of abnormally spliced bE-globin
Similar findings have been observed in Sri Lan- mRNA. This indicated that the amount of alter-
kan populations, in which the coinheritance of natively spliced E-globin mRNAwas a more im-
the heterozygous state for aþ thalassemia has portant factor in determining severity of anemia
been found to result in a remarkable degree of than the pattern of Xmnl polymorphism or the
amelioration of the clinical severity of HbE b level of HbF. Recently, Tubsuwan et al. used the
thalassemia (Premawardhena et al. 2005). allele-specific RT-qPCR to study bE-globin gene
expression and found that the correctly to aber-
Association with Increased HbF rantly spliced bE-globin mRNA ratio in 30% of
Coinheritance of determinants that increase mild HbE b-thalassemia patients was higher
than that of the severe patients. It appears there-
www.perspectivesinmedicine.org

HbF expression can ameliorate the severity of

HbE b thalassemia. Inheritance of a chromo- fore that the splicing process of bE-globin pre-
some with the C ! T polymorphism that re- mRNA differs among HbE b-thalassemia pa-
sults in an Xmn-1 cleavage site at position 2158 tients and serves as one of the modifying factors
to the Gg-globin gene is associated with increased for disease severity (Tubsuwan et al. 2011). It
HbF and milder anemia (Winichagoon et al. will be important to determine whether this
1987). Two copies of this allele (Xmn-1 þ/þ) phenomenon occurs in other ethnic groups.
are necessary to produce a significant clinical ef-
fect. Increased expression of the Gg-globin gene Pyrimidine 50 Nucleotidase Deficiency
was also detected in the Xmn-1 þ/þ patients.
This increase of g-globin gene activity reduces In a Bangladeshi family, an individual homozy-
the overall globin chain imbalance and thus ame- gous for both HbE and pyrimidine 50 nucleo-
liorates the anemia. The association between the tidase deficiency was found. The patient had a
Xmn-1 þ/þ genotype and a highly significant severe hemolytic anemia in contrast to HbE ho-
increase in the absolute level of HbF and a milder mozygotes. Globin chain synthesis experiments
phenotype has also been observed in patients with showed that the mechanism underlying the in-
HbE b thalassemia in Sri Lanka (Premawardhena teraction between these two genotypes was a
et al. 2005). It is likely that several other polymor- marked decrease in the stability of HbE in py-
phisms will have this effect (see later section and rimidine 50 nucleotidase-deficient red blood
Sankaran and Orkin 2012). cells. In these cells, free a-globin chains but
not bE-globin chains accumulated on the mem-
brane. It was hypothesized that the marked in-
Amount of Alternatively Spliced
stability of HbE in the enzyme-deficient cells
bE-Globin mRNA
resulted from oxidant damage to mildly unsta-
An underproduction of b-globin chains from ble HbE (Rees et al. 1996). Clearly this interac-
the bE-globin gene strongly suggests that al- tion also has the potential to modify the phe-
ternative RNA splicing is of functional signifi- notype of HbE b thalassemia.

10 Cite this article as Cold Spring Harb Perspect Med 2012;2:a011734

 Hemoglobin E Thalassemias

Genome-Wide Association Study ther elucidate environmental factors that may

modify the phenotype.
Recently, a genome-wide association study
(GWAS) was performed in 618 Thai HbE b0-
thalassemia patients using the Illumina Human Conclusion
610-Quad BeadChips array (Nuinoon et al.
The genotypic factors that can be used to predict
2010). DNAs were extracted from 383 severe
a mild phenotype in HbE b thalassemia are mild
and 235 mild phenotypes, by a validated scoring
bþ-thalassemia mutations, the coinheritance of
system, after the exclusion of a thalassemia.
a thalassemia, the polymorphisms associated
Twenty-three single nucleotide polymorphisms
with HbF production such as homozygosity
(SNPs) in three independent genes/regions
for Xmn-l restriction site 50 to the Gg-globin
were identified as being significantly associated
gene and the BCL11A gene. Some complications
with the disease severity. The highest association
of the disease such as severe jaundice are also
was observed with SNPs in the b-globin gene
affected by genetic modifiers. And it is also clear
cluster (chr.11p15). The second was identified
that at least some factors that modify the re-
in the intergenic region between the HBS1L and
sponse to anemia or the environment of pa-
MYB genes (chr.6q23), and the third region was
tients with this disease are also responsible for
located in the BCL11A gene (chr.2p16.1). An
phenotypic diversity. But although progress has
association to HbF levels with SNPs in these
been made, it is still only possible to explain part
three regions was observed. This result suggests
of its wide phenotypic diversity.
that several genetic loci act in concert to influ-
ence HbF levels of HbE b0-thalassemia patients
(see Sankaran and Orkin 2012). Treatment
www.perspectivesinmedicine.org

Because HbE b thalassemia has such a variable

Variation in Adaptation to Anemia and
phenotype and patients with this disorder—
Environmental Factors
probably because they have relatively lower lev-
As already mentioned, there appears to be a els of HbF and reflecting the oxygen affinity of
reduction in erythropoietin production in rela- HbE—are able to adapt to anemia better than
tionship to a similar hemoglobin level with ag- patients with other forms of thalassemia inter-
ing, a finding which may explain some of the media, it is vital to observe babies and young
phenotypic instability during the early years of children with this condition after presentation
life. Whether there is a genetic component to for a reasonable period before deciding on the
the magnitude of erythropoietin response re- best approach to management. It is important
mains to be determined. Undoubtedly, patients to remember that they may present with a par-
with HbE b thalassemia adapt more readily ticularly low hemoglobin level consequent to a
to low hemoglobin levels than those with other recent infection, and it is particularly important
forms of b-thalassemia intermedia (Allen et al. therefore not to establish them on a regular
2010). Although as is the case for most inherited transfusion until their steady-state hemoglobin
hemoglobin disorders, the role of the environ- level and level of growth and degree of spleno-
ment in modifying the phenotype has been ne- megaly has been assessed. Particularly in areas
glected; recent studies suggest that patients where malaria is endemic it is also important to
with HbE b thalassemia are more susceptible exclude chronic P. vivax infection as a possible
to malaria infection, particularly that caused cause of rapidly progressive splenomegaly.
by P. vivax, than age-matched controls in the The hemoglobin level alone should not
population (O’Donnell et al. 2009). There is be the major factor in initiating transfusion.
also reasonable evidence that those who have Rather, the broader picture should be consid-
been exposed to malaria tend to have larger ered with particular attention to growth failure,
spleens and fall into the more severe phenotypic lack of activity, and the earlier appearance of
categories. Much more work is required to fur- skeletal change. If it is clear that the patient

Cite this article as Cold Spring Harb Perspect Med 2012;2:a011734 11

 S. Fucharoen and D.J. Weatherall

requires regular transfusion the regimen to be in which carrier rates for different types of
followed, including chelation, is similar to that thalassemia are very high (see Brittenham and
for the management of thalassemia major (see Olivieri 2012). In Thailand, screening has
Brittenham and Olivieri 2012). Those who do improved by using an automatic high-perfor-
not require transfusion should be maintained mance liquid chromatography (HPLC) system
on folic acid supplements and advised about (Fucharoen et al. 1998). In recent years, a na-
the early treatment of infective episodes. Al- tionwide program in Thailand has been devel-
though some patients with increasing splen- oped to prevent homozygous b thalassemia,
omegaly and evidence of hypersplenism may HbE b thalassemia, and Hb Bart’s hydrops fe-
benefit from splenectomy, this should be avoid- talis, with encouraging results (Tongsong et al.
ed where possible because of the particularly 2000). The prospective screening consisted of
high risk of infection. osmotic fragility (OF) and HbE screening tests
Patients who do not require regular transfu- in pregnant women, followed by testing the
sion should have serum ferritin or hepatic MRI husbands of the women with a positive re-
estimations at least twice per year. Increased sult. Subsequently, the OF test was replaced by
iron levels should be controlled by intermittent mean corpuscular volume (MCV) when auto-
courses of chelating agents. mated cell counters became available nation-
Hydroxyurea therapy may increase HbF lev- wide. If both partners of the couple have a pos-
els (Fucharoen et al. 1996), although recent itive result, further diagnostic tests by HPLC
studies in other populations have shown that and genotyping of the carrier are carried out.
this effect is not great, even when combined A pregnancy in which both partners of the
with erythropoietin. For those who present ear- couple are carriers is considered as a couple at
ly with severe disease, bone marrow transplan- risk, and further detailed counseling and pre-
www.perspectivesinmedicine.org

tation remains an important option (Issaragrisil natal diagnosis is offered for the severe thalas-
1994; Leelahavarong et al. 2010). semia syndromes (Fucharoen and Winichagoon
Rapidly expanding extramedullary hemo- 2007).
poietic masses, particularly involving the brain Since the program began, the number of
or spinal cord, require urgent treatment by new cases of thalassemia in Thailand has grad-
blood transfusion, hydroxyurea, or possibly, ra- ually decreased. In the first few years of the
diotherapy. Limited experience in those with program, its cost-effectiveness was evaluated
profound jaundice as a result of genetic inability and it was found that among a total pregnant
to conjugate bilirubin suggest that, at least in population of 21,000 individuals that were
some cases, very low doses of phenobarbitone screened, 80 affected fetuses had been identi-
may be helpful. fied and the pregnancy terminated. The total
The first successful report of gene therapy cost of the prevention program was about U.S.
in thalassemia involved a patient with HbE $257,140, and the cost of management of these
b thalassemia (Cavazzana-Calvo et al. 2010). affected cases, if they had been born, would have
Although the patient showed clinical improve- been U.S. $7,200,000. The cost-benefit ratio
ment and did not need further blood transfu- was 1:28, which indicates a highly cost-effective
sion, it is not yet clear whether this is mainly project.
because of the action of the inserted “normal”
b-globin gene. The improvement also seems to
CONCLUSIONS
be at least partly a result of an increase in HbF
levels by an unknown mechanism. HbE b thalassemia is a major public health
problem in Southeast Asia and in other Asian
countries. Although some progress has been
Prevention of HbE b Thalassemia
made toward a better understanding of its path-
Effective prevention programs for thalassemia ophysiology and clinical management a great
have been demonstrated in many countries deal remains to be learned. Recent work has

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 Hemoglobin E Thalassemias

made it absolutely clear that there must be other REFERENCES

genetic modifiers to be discovered that are re-  Reference is also in this collection.
sponsible for the variable phenotype. A better
approach to predicting the phenotype is urgent- Allen A, Fisher C, Premawardena A, Peto T, Allen S, Ara-
mbepola K, Thayalsuthan V, Olivieri N, Weatherall D.
ly required, particularly if prenatal diagnosis is 2010. Adaptation to anemia in hemoglobin E-b thalas-
to be widely used for the control of this condi- semia. Blood 116: 5368– 5370.
tion and, even more so, if experimental forms of Aswapokee N, Aswapokee P, Fucharoen S, Wasi P. 1988a.
gene therapy become available in the future. A study of infective episodes in patients with b-thal-
assemia/Hb E disease in Thailand. Birth Defects 23:
Because it may be some time before there are 513 –520.
more definitive forms of treatment, it is impor- Aswapokee P, Aswapokee N, Fucharoen S, Sukroongreung S,
tant to utilize the information that we already Wasi P. 1988b. Severe infection in thalassemia: A prospec-
have more effectively. For example, in malarious tive study. Birth Defects 23: 521 –526.
areas it will be very important to conduct trials  Brittenham G, Olivieri N. 2012. Cold Spring Harb Perspect
Med (to be published).
of malaria prophylaxis. With particular respect Butthep P, Rummavas S, Wisedpanichkij R, Jindadamrong-
to the phenotype of patients with this condition wech S, Fucharoen S, Bunyaratvej A. 2002. Increased cir-
early in life, and because recent evidence sug- culating activated endothelial cells, vascular endothelial
gests that the erythropoietin response to anemia growth factor, and tumor necrosis factor in thalassemia.
Am J Hematol 70: 100 –106.
tends to decline with age, the possibility of tran- Cavazzana-Calvo M, Payen E, Negre O, Wang G, Hehir K,
sient periods of transfusion during maximum Fusil F, Down J, Denaro M, Brady T, Westerman K, et al.
erythroid expansion should be seriously consid- 2010. Transfusion independence and HMGA2 activation
after gene therapy of human b-thalassaemia. Nature 467:
ered. And because genetic evidence indicates 318 –322.
that the phenotype in this condition may be Chandcharoensin-Wilde C, Chairoongruang S, Jitnuson P,
improved quite dramatically with only a modest
www.perspectivesinmedicine.org

Fucharoen S, Vathanopas V. 1988. Gallstones in thalasse-

increase in steady-state hemoglobin level, more mia. Birth Defects 23: 263–267.
efforts should be directed at trying to raise the Chernoff AI, Minnich V, Na-Nakorn S, Tuchinda S,
Kashamsant C, Chernoff RR. 1956. Studies on hemoglo-
HbF level in these patients. bin E: I. The clinical, hematologic, and genetic character-
istics of the hemoglobin E syndromes. J Lab Clin Med 47:
490 –498.
Other Interactions of HbE De Chiara B, Crivellaro W, Sara R, Ruffini L, Parolini M,
Fesslova V, Carnelli V, Fiorentini C, Parodi O. 2005. Early
This article has considered the most common detection of cardiac dysfunction in thalassemic patients
by radionuclide angiography and heart rate variability
and important clinical interactions of HbE. Be- analysis. Eur J Haematol 74: 517 –522.
cause it is so common it is not surprising that Frischer H, Bowman J. 1975. Hemoglobin E, an oxidatively
many rare interactions between this variant and unstable mutation. J Lab Clin Med 85: 531–539.
a wide variety of structural hemoglobin vari- Fucharoen S, Weatherall DJ. 2009. Hemoglobin E disorders.
ants and related conditions have been reported. In Disorders of hemoglobin (ed. Steinberg MH, Forget BG,
Higgs DR, Weatherall DJ), pp. 417–433. Cambridge Uni-
The resulting disorders are described briefly versity Press, Cambridge.
in a recent review (Fucharoen and Weather- Fucharoen S, Winichagoon P. 2007. Prevention and control
all 2009). of thalassemia in Asia. Asian Biomed 1: 1 –6.
Fucharoen S, Youngchaiyud P, Wasi P. 1981. Hypoxaemia
and the effect of aspirin in thalassaemia. Southeast Asian
J Trop Med Public Health 12: 90–93.
ACKNOWLEDGMENTS Fucharoen S, Winichagoon P, Thonglairuam V. 1988a. Beta-
thalassemia associated with a-thalassemia in Thailand.
This work is supported by the Office of the Hemoglobin 12: 581 –592.
Higher Education Commission and Mahidol Fucharoen S, Winichagoon P, Thonglairuam V, Wasi P.
University under the National Research Univer- 1988b. EF Bart’s disease: Interaction of the abnormal a-
sity Initiative and the National Center for Ge- and b-globin genes. Eur J Haematol 40: 75–78.
netic Engineering, Thailand and The Wellcome Fucharoen S, Siritanaratkul N, Winichagoon P, Chowtha-
worn J, Siriboon W, Muangsup W, Chaicharoen S,
Trust, UK. We thank Liz Rose for her help in Poolsup N, Chindavijak B, Pootrakul P, et al. 1996. Hy-
preparing this work. droxyurea increases hemoglobin F levels and improves

Cite this article as Cold Spring Harb Perspect Med 2012;2:a011734 13

 S. Fucharoen and D.J. Weatherall

the effectiveness of erythropoiesis in b-thalassemia/he- Congress of European Hematology Association, London,

moglobin E disease. Blood 87: 887– 892. June 9 –12.
Fucharoen S, Winichagoon P, Wisedpanichkij R, Sae-Ngow Orkin SH, Kazazian HH, Antonarakis SE, Ostrer H, Goff SC,
B, Sriphanich R, Oncoung W, Muangsapaya W, Chow- Sexton JP. 1982. Abnormal RNA processing due to
thaworn J, Kanokpongsakdi S, Bunyaratvej A, et al. 1998. the exon mutation of bE-globin gene. Nature 300: 768–
Prenatal and postnatal diagnoses of thalassemias and 769.
hemoglobinopathies by HPLC. Clin Chem 44: 740 –748. Pattanapanyasat K, Noulsri E, Fucharoen S, Lerdwana S,
 Higgs DR. 2012. The molecular basis of a thalassemia. Cold Lamchiagdhase P, Siritanaratkul N, Webster HK. 2004.
Spring Harb Perspect Med doi: 10.1101/cshperspect. Flow cytometric quantitation of red blood cell vesicles
a011718. in thalassemia. Cytometry B Clin Cytom 57: 23– 31.
Issaragrisil S. 1994. Bone marrow transplantation in Thai- Pootrakul P, Rugkiatsakul R, Wasi P. 1980. Increased trans-
land. Bone Marrow Transplant 13: 721–723. ferrin iron saturation in splenectomized thalassaemia pa-
Issaragrisil S, Piankigagum A, Wasi P. 1981. Spinal cord tients. Brit J Haematol 46: 143 –145.
compression in thalassemia. Report of 12 cases and rec- Pootrakul P, Vougsmasa V, Laongpanich P, Wasi P. 1981.
ommendations for treatment. Arch Intern Med 141: Serum ferritin levels in thalassemias and the effect of
1033– 1036. splenectomy. Acta Haematol 66: 244– 250.
Itano HA, Bergren WR, Sturgeon P. 1954. Identification of a Premawardhena A, Fisher CA, Fathiu F, de Silva S, Perera
fourth abnormal human hemoglobin. J Am Chem Soc 76: W, Peto TE, Olivieri NF, Weatherall DJ. 2001. Genetic
2278. determinants of jaundice and gallstones in haemoglobin
Jootar P, Fucharoen S. 1990. Cardiac involvement in b-thal- E b thalassaemia. Lancet 357: 1945–1946.
assemia/hemoglobin E disease: Clinical and hemody- Premawardhena A, Fisher CA, Liu YT, Verma IC, de Silva S,
namic findings. Southeast Asian J Trop Med Public Health Arambepola M, Clegg JB, Weatherall DJ. 2003. The global
21: 269 –273. distribution of length polymorphisms of the promoters
Leelahavarong P, Chaikledkaew U, Hongeng S, Kasemsup V, of the glucuronosyltransferase 1 gene (UGT1A1): Hema-
Lubell Y, Teerawattananon Y. 2010. A cost-utility and bud- tologic and evolutionary implications. Blood Cells Mol
get impact analysis of allogeneic hematopoietic stem cell Dis 31: 98–101.
transplantation for severe thalassemic patients in Thai-
Premawardhena A, Fisher CA, Olivieri NF, de Silva S, Aram-
land. BMC Health Serv Res 10: 209.
bepola M, Perera W, O’Donnell A, Peto TEA, Viprakasit
www.perspectivesinmedicine.org

Minnich V, Na-Nakorn S, Chongchareonsuk S, Kochaseni S. V, Merson L, et al. 2005. Haemoglobin E b thalassaemia

1954. Mediterranean anemia: A study of 32 cases in Thai- in Sri Lanka. Lancet 366: 1467–1470.
land. Blood 9: 1 –23.
Rees DC, Duley J, Simmonds HA, Wonke B, Thein SL, Clegg
 Musallam KM, Taher AT, Rachmilewitz EA. 2012. b-Thal- JB, Weatherall DJ. 1996. Interaction of hemoglobin E
assemia intermedia: A clinical perspective. Cold Spring and pyrimidine 50 nucleotidase deficiency. Blood 88:
Harb Perspect Med doi: 10.1101/cshperspect.a013482. 2761–2767.
 Nienhuis AW, Nathan DG. 2012. Pathophysiology and clin- Rees DC, Clegg JB, Weatherall DJ. 1998. Is hemoglobin in-
ical manifestations of the b thalassemias. Cold Spring stability important in the interaction between hemoglo-
Harb Perspect Med doi: 10.1101/cshperspect.a011726. bin E and b thalassemia? Blood 92: 2141–2146.
Nuinoon M, Makarasara W, Mushiroda T, Setianingsih I, Rutjanaprom W, Kanlop N, Charoenkwan P, Sittiwangkul R,
Wahidiyat PA, Sripichai O, Kumasaka N, Takahashi A, Srichairatanakool S, Tantiworawit A, Phrommintikul
Svasti S, Munkongdee T, et al. 2010. A genome-wide as-
A, Chattipakorn S, Fucharoen S, Chattipakorn N. 2009.
sociation identified the common genetic variants influ-
Heart rate variability in b-thalassemia patients. Eur J
ence disease severity in b0-thalassemia/hemoglobin E.
Haematol 83: 483– 489.
Hum Genet 127: 303–314.
 Sankaran VG, Orkin SH. 2012. The switch from fetal to
O’Donnell A, Premawardhena A, Arambepola M, Allen SJ,
adult hemoglobin. Cold Spring Harb Perspect Med doi:
Peto TE, Fisher CA, Rees DC, Olivieri NF, Weatherall DJ.
10.1101/cshperspect.a011643.
2007. Age-related changes in adaptation to severe anemia
in childhood in developing countries. Proc Natl Acad Sci Sathapatayavongs B, Leelachaikul P, Prachaktam R, Atichar-
104: 9440–9444. takarn V, Sriphojanart S, Trairatvorakul P, Jirasiritham S,
O’Donnell A, Premawardhena A, Arambepola M, Samara- Nontasut S, Eurvilaichit C, Flegel T. 1989. Human py-
nayake R, Allen SJ, Peto TE, Fisher CA, Cook J, Corran thiosis associated with thalassemia hemoglobinopathy
PH, Olivieri NF, et al. 2009. Interaction of malaria with a syndrome. J Infect Dis 159: 274– 280.
common form of severe thalassemia in an Asian popula- Sonakul D, Pacharee P, Laohapand T, Fucharoen S, Wasi P.
tion. Proc Natl Acad Sci 106: 18716– 18721. 1980. Pulmonary artery obstruction in thalassaemia.
Olivieri NF, Thayalsuthan V, O’Donnell A, Premawardena Southeast Asian J Trop Med Public Health 11: 516–523.
A, Rigobon C, Muraca G, Fisher C, Weatherall DJ. 2010. Sonakul D, Pacharee P, Wasi P, Fucharoen S. 1984. Cardiac
Emerging insights in the management of hemoglobin E b pathology in 47 patients with b thalassaemia/haemo-
thalassemia. Ann NY Acad Sci 1202: 155– 157. globin E. Southeast Asian J Trop Med Public Health 15:
Olivieri NF, Thayalasuthan V, Muraca G, Weatherall D, Kim 554 –563.
C, Premawardhena A, Perera A, O’Donnell A, St Pierre Sonakul D, Pacharee P, Thakerngpol K. 1988. Pathologic
T. 2011. Relationship between serum ferritin and liver findings in 76 autopsy cases of thalassemia. Birth Defects
iron concentration in hemoglobin E thalassemia. 16th 23: 157– 176.

14 Cite this article as Cold Spring Harb Perspect Med 2012;2:a011734

 Hemoglobin E Thalassemias

Sripichai O, Makarasara W, Munkongdee T, Kumkhaek C, Wasi P, Sookanek M, Pootrakul S, Na-Nakorn S, Suingdum-

Nuchprayoon I, Chuansumrit A, Chuncharunee S, rong A. 1967. Haemoglobin E and a-thalassaemia. Br
Chantrakoon N, Boonmongkol P, Winichagoon P, et al. Med J 4: 29–32.
2008. A scoring system for the classification of b- Wasi P, Na-Nakorn S, Pootrakul S, Sookanek M, Distha-
thalassemia/Hb E disease severity. Am J Hematol 83: songcham P, Pornpatkul M, Manich V. 1969. Alpha-
482–484. and b-thalassemia in Thailand. Ann NY Acad Sci 165:
Thakerngpol K, Sonakul D, Fucharoen S, Vathanopas V, Stit- 60– 82.
nimankarn T. 1988. Histochemical study of liver tissue Wasi P, Na-Nakorn S, Pootrakul P, Sonakul D, Piankijagum
from thalassemic patients. Birth Defects 23: 193 –198. A, Pacharee P. 1978. A syndrome of hypertension,
 Thein SL. 2012. Molecular basis of b thalassemia. Cold convulsions, and cerebral haemorrhage in thalassaemic
Spring Harb Perspect Med doi: 10.1101/cshperspect. patients after multiple blood transfusions. Lancet ii:
a011700. 602 –604.
Thonglairuam V, Winichagoon P, Fucharoen S, Wasi P. 1989. Wasi P, Fucharoen S, Younghchaiyud P, Sonakul D. 1982.
The molecular basis of AE-Bart’s disease. Hemoglobin 13: Hypoxemia in thalassemia. Birth Defects 18: 213– 217.
117–124.
Weatherall DJ, Clegg JB. 2001. The thalassaemia syndromes.
Tongsong T, Wanapirak C, Sirivatanapa P, Sanguansermsri Blackwell Science, Oxford.
T, Sirichotiyakul S, Piyamongkol W, Chanprapaph P.
2000. Prenatal control of severe thalassaemia: Chiang Wickramasinghe SN, Lee MJ. 1997. Observations on
Mai strategy. Prenat Diag 20: 229–234. the relationship between g-globin chain content and
globin chain precipitation in thalassaemic erythro-
Traeger J, Wood WG, Clegg JB, Weatherall DJ, Wasi P. 1980.
blasts and on the composition of erythroblastic inclu-
Defective synthesis of Hb E is due to reduced levels of bE
sions in Hb E/b-thalassaemia. Eur J Haematol 59:
mRNA. Nature 288: 497– 499.
305 –309.
Tubsuwan A, Munkongdee T, Jearawiriyapaisarn N, Boon-
 Williams TN, Weatherall DJ. 2012. World distribution, pop-
choy C, Winichagoon P, Fucharoen S, Svasti S. 2011.
Molecular analysis of globin gene expression in different ulation genetics, and health burden of the hemoglobin-
thalassaemia disorders: Individual variation of b(E) pre- opathies. Cold Spring Harb Perspect Med doi: 10.1101/
mRNA splicing determine disease severity. Brit J Haema- cshperspect.a011692.
tol 154: 635 –643. Winichagoon P, Fucharoen S, Weatherall DJ, Wasi P. 1985.
Concomitant inheritance of a-thalassemia in b0-thalas-
www.perspectivesinmedicine.org

Vannasaeng S, Ploybutr S, Visutkul P, Tandhanand S, Suwa-

nik R, Wasi P. 1981. Endocrine function in thalassaemia. semia/Hb E disease. Am J Hematol 20: 217 –222.
Clin Endocrinol (Oxf ) 14: 165–173. Winichagoon P, Fucharoen S, Thonglairoam V, Wasi P. 1987.
Vathanopas V, Fucharoen S, Chandrcharoensin-Wilde C, Different severity of homozygous b-thalassemia among
Sukroongreung S, Nilakul C. 1988. Cholecystectomy in siblings. Hum Genet 76: 296 –297.
thalassemia. Birth Defects 23: 269 –273. Winichagoon P, Thonglairoam V, Fucharoen S, Wilairat P,
 Vichinsky E. 2012. Natural history and clinical manifesta- Fukimaki Y, Wasi P. 1993. Severity differences in b-thal-
tions of the a thalassemias. Cold Spring Harb Perspect assaemia haemoglobin E syndromes: Implication of ge-
Med doi: 10.1101/cshperspect.a011742. netic factors. Brit J Haematol 83: 633–639.
Wanachiwanawin W, Thianprasit M, Fucharoen S, Chaipra- Winichagoon P, Fucharown S, Wilairat P, Chihara K, Fuku-
sert A, Sudasna N, Ayudhya N, Sirithanaratkul N, Pian- maki Y. 1995. The role of alternatively spliced bE-globin
kijagum A. 1993. Fatal arteritis due to Pythium insidio- mRNA on clinical severity of b-thalassemia/hemoglobin
sum infection in patients with thalassaemia. Trans R Soc E disease. Southeast Asian J Trop Med Public Health 26:
Trop Med Hyg 87: 296– 298. 241 –245.

Cite this article as Cold Spring Harb Perspect Med 2012;2:a011734 15