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Hemoglobin E Syndromes

Article  in  Hematology · February 2007

DOI: 10.1182/asheducation-2007.1.79 · Source: PubMed

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 Hemoglobin E Syndromes
Elliott Vichinsky
Children’s Hospital & Research Center at Oakland, Oakland, California
Hemoglobin (Hb) E is one of the world’s most common
and important mutations. It results in a heterogeneous
group of disorders whose phenotype range from
asymptomatic to severe. Hb E trait and Hb EE are mild
disorders. The combination of Hb E and Hb S (Hb SE)
results in a sickle cell disease syndrome similar to
sickle β+ thalassemia. It is important to distinguish Hb
E disorders diagnostically because of this marked
difference in clinical course among different geno-
types. Screening tests, including hemoglobin electro-
phoresis and high-pressure liquid chromatography
(HPLC), may suggest other mutations, unless one is
familiar with the findings. E β-thalassemia, the most
serious form of E syndromes, affects a million people
worldwide and is increasing in North America. Its
phenotype ranges from mild anemia to severe transfu-
sion-dependent thalassemia major. Several genetic
modifiers affect the phenotype, including the type of β-
thalassemia mutation, Hb F levels, and co-inheritance
of α-thalassemia. However, the cause of the pheno-
Introduction: Demography
Hemoglobin (Hb) E is one of the world’s most common and
important mutations.1-4 The resistance of Hb AE red cells to
invasion by Plasmodium falciparum is most likely the cause
for its high prevalence throughout the world.5 E β-thalas-
semia affects at least a million people worldwide. Since its
classic description by Chernoff et al,6 it has been noted to
be an important health problem in the Indian subcontinent
and Southeast Asia. It has replaced β-thalassemia as the
most common thalassemia disorder in many regions, in-
cluding coastal North America. The frequency of Hb E ap-
proaches 60% in many regions of Thailand, Laos and Cam-
bodia. The World Health Organization (WHO) estimates
that in Thailand at least 100,000 new cases of Hb E β-
thalassemia are expected in the next few decades.1,2,7 High
estimates are predicted for India, Sri Lanka, Malaysia, and
southern China. In the last two decades, most immigrants
in North America came from areas where Hb E mutations
were prevalent.8 These demographic changes have resulted
in E β-thalassemia becoming a health problem in North
America. The prevalence of Hb E in California parallels the
rise in Asian births. In California, 1 in 4 Cambodian births
and 1 in 9 Thai/Laotian births are Hb E carriers.9 The natu-
ral history of Hb E thalassemia is highly variable. The phe-
notype, for patients with similar mutations, can range from
asymptomatic to transfusion dependent.
Hematology 2007
typic variability is largely unknown. A prospective
natural history study of E β-thalassemia in Sri Lanka
suggests that environmental modifiers are
prognostically important. The clinical course of E β-
thalassemia is punctuated by acute and chronic
complications that may cause serious morbidity and
mortality. Recent studies indicate these patients are at
high risk for thromboembolism secondary to a
hypercoagulable state increased by splenectomy.
Morbidity from iron overload in nontransfused patients
secondary to increased gastrointestinal iron absorp-
tion is common. Cardiopulmonary disease, including
pulmonary hypertension, requires ongoing monitoring
and is secondary to iron overload, thromboembolism,
and hemolysis-induced nitric oxide deficiency. These
patients are excellent candidates for Hb F–modulating
agents because moderate changes in hemoglobin
may result in marked improvement in phenotype.
Recent studies with hydroxyurea indicate 40% of
patients will clinically improve with hydroxyurea.
Diagnosis
Hb E is caused by a substitution of glutamic acid by lysine
at codon 26 of the β-globin gene. This mutation also acti-
vates a cryptic mRNA splice site, which results in reduced
synthesis of the β-E chain and leads to a thalassemia phe-
notype. Hb E has a weakened α/β interface, leading to some
instability during conditions of increased oxidant stress.
Hb E trait has no clinical significance. Patients may have
mild microcytosis without anemia (see Table 1).10 The pic-
ture may be confused with iron deficiency unless labora-
tory studies are completed. The red cell morphology may
show targeting Hb EE individuals are asymptomatic with
very mild anemia and microcytosis.11 The red cell mor-
phology picture may be similar to other thalassemia traits
or mild thalassemia intermedia conditions. Targeted and
irregularly contracted cells are commonly seen. Occasion-
ally, patients have splenomegaly.
It is important to distinguish Hb E disorders diagnosti-
cally because of this marked difference in clinical course.
DNA-based diagnosis of Hb E disorders is optimal and nec-
essary before genetic counseling is undertaken. Screening
tests may suggest other mutations, unless one is familiar
with the findings.12 In testing with alkaline Hb electrophore-
sis, Hb E migrates with C, O Arab, and A2. In acid pH elec-
trophoresis, it migrates with Hb A2. When used together,
the diagnosis can be clearly made. Hb E is better separated
on isoelectric focusing, but migrates close to Hb O Arab. In
high-pressure liquid chromatography (HPLC) screening
programs, Hb E similar retention times as Hb A2 and Hb
79
Table 1. Hematologic data in various hemoglobin E syndromes10 (modified).

Alkali
denaturation
Hb, MCV, MCH, MCHC, RDW, test
g/dL fL pg g/dL % (Hb F), % Hb typing
Normal M15.9 ± 0.9 87 ± 6 31 ± 1.1 33 ± 0.9 13.1 ± 0.8 0.5 ± 0.2 A2 (2.5 ± 0.2) + A
F12.5 ± 2.0
Hb E trait 12.8 ± 1.5 84 ± 5 30 ± 2.4 33 ± 1.8 14.1 ± 0.6 0.9 ± 0.7 E (29.4 ± 2.3%) + A
Hb E α-thalassemia 2 13.1 ± 1.4 88 ± 4 ND ND ND E (28.5 ± 1.5%) + A
Hb E α-thalassemia 1 12.5 ± 1.4 77 ± 5 23 ± 1.1 32 ± 1.6 ND 0.9 ± 0.4 E (20.7 ± 1.2%) + A
Homozygous HbE 11.4 ± 1.8 70 ± 4 22 ± 1.9 33 ± 1.7 15.6 1.8 ± 1.4 E (87.7 ± 5.9%)
Hb E/β0-thalassemia 7.8 ± 2.6 67 ± 6 19 ± 3.6 28 ± 4.8 26.5 ± 5.6 42 ± 1.5 E (58 ± 1.5%) + F
AE Bart’s disease E (13.0 ± 2.1%) + A
α-thalassemia 1/ 9.1 ± 1.1 60 ± 3 17 ± 2 31 ± 4 ND 2.0 ± 0.7 + Bart’s (2.2 ± 1.8%)
α-thalassemia 2-Hb E
α-thalassemia 1/ 8.0 ± 0.9 67 ± 4 19 ± 2 29 ± 2 ND 2.3 ± 1.4 CS (1.1 ± 0.4%) + E
Hb CS-Hb E (13.9 ± 1.8%) + A +
Bart’s (3.9 ± 1.5%)
Hb EE + Hb H 8.0 ± 1.3 63 ± 6 18 ± 2 29 ± 2 ND 5.8 ± 3.7 E (80%) + F + Bart’s
(5%) or CS (1.9 ± 0.9%)
+ E (86.4 ± 8%) + F
+ Bart’s (3.7 ± 1.9%)
Hb SE12 11.2 ± 1.8 75 ± 10 ND ND ND ND Hb S (62.8% ± 7.4%),
Hb E (33.3% ± 3.6%),
Hb F (range 1 – 5.2)

Abbreviations: CS, Hb Constant Spring; D, decreased; Hb, hemoglobin; MCH, mean corpuscular hemoglobin; MCHC, mean corpus-
cular hemoglobin concentration; MCV, mean corpuscular volume; N, normal; ND, not determined; RDW, red cell distribution width

Lepore. The percentage of Hb E in heterozygotes is ap-
proximately 30%. Diagnosis of concomitant α-thalassemia
requires DNA testing. The concomitant inheritance of α-
thalassemia often occurs and lowers the percentage of Hb
E.13,14 In Hb E trait in combination with Hb H, Hb E drops to
10%.13,15 Iron deficiency also lowers the Hb E percentage.
In Hb EE, the electrophoresis generally indicates 90% or
more Hb E with a mild elevation in Hb F. Hb E β+-thalas-
semia may have an extremely variable laboratory picture.
They usually have a mild anemia of approximately 9.5 g/
dL. However, significant ranges of anemia has been ob-
served, with Hb as low as 5.7 g/dL. The mean corpuscular
volume (MCV) has been approximately 72 ± 6 fL and mean
corpuscular Hb concentration (MCHC) has been 29 ± 2
fL.11 The electropheresis demonstrates both Hb E and Hb
A, with a marked range for the amount of Hb A. The differ-
ential diagnosis includes Hb E β0-thalassemia. In this dis-
ease, Hb E ranges from 40% to 60%, with Hb F markedly
elevated. In neonates, DNA analysis is required to differen-
tiate these two syndromes in neonates and is increasingly
being used routinely for diagnosis of Hb E disorders.
There are several compound heterozygotes with Hb E
and an uncommon β-globin mutation. Hb E Lepore and Hb
E δβ-thalassemia are compound heterozygotes with mild
phenotypes. Hb SE is being more frequently diagnosed
due to changing population migration patterns and inter-
marriage of at-risk individuals. It is often initially misdiag-
nosed as HB SC because of the comigration of C and E
patterns on electrophoresis. Patients are mildly anemic with
microcytic red cells. The electropheretic pattern demon-
strates 60% S and 30% E. The clinical phenotype is similar
to sickle β+-thalassemia. Medical complications appear to
increase as patients get older. Painful episodes, acute chest
syndrome, splenic sequestration, and avascular necrosis of
hip have all been observed.16
Pathophysiology and Clinical Variability
The most serious Hb E syndrome is Hb E β0-thalassemia.
The compound heterozygote state of Hb E β-thalassemia
results in a variable phenotype ranging from a complete
lack of symptoms to transfusion dependency.1,10,17 In re-
view of 378 patients with Hb E-β0-thalassemia from Thai-
land, the hemoglobin concentrations ranged from 3 to 13
g/dL, with an average of 7.7 g/dL17 (Figure 1). Approxi-
mately one-half of the patients are phenotypically similar
to patients with thalassemia major who require regular trans-
fusion therapy, and the other half resembles thalassemia
intermedia.1,10,17
The pathophysiology of Hb E β-thalassemia is com-
plex. Ineffective erythropoiesis, apoptosis, and oxidative
damage are central components of the disease and its short-
ened red cell survival.1,18,19 The instability of Hb E is a
minor factor in its pathophysiology, but in febrile patients,
may account for accelerated hemolysis.20 The interaction

80 American Society of Hematology


β thalassemia patients
Figure 1. Hemoglobin levels in E/β
(Thailand)1 (modified).
between Hb E and β-thalassemia alleles is the main deter-
minant in the pathophysiology.1 The globin chain imbal-
ance that results from these mutations correlates with the
severity of the disease. However, the cause of the striking
variability in individuals with E β-thalassemia remains largely
unknown. Patients with the same mutations within a family
may show significant differences in clinical severity.
Hb F level is the strongest predictor of morbidity.21-25
However, the basis of increased Hb F is usually unknown.23,26
The inheritance of a β-thalassemia chromosome with the
Xmn I(+) polymorphism in the promoter region of the G γ-
globin gene may be responsible for increased Hb F and a
milder clinical course.1,17,22,23 However, the Xmn mutation
only explains a small percentage of patients with high Hb
F expression.1,10,17 The degree of severity is also affected by
the type of β-thalassemia mutation.27 β0-thalassemia muta-
tions generally result in a more severe phenotype than β+
thalassemia mutations. However, some β+ mutations pro-
duce minimal amounts of β-globin chains and are similar
to β0-thalassemia. The two common mutations, IVS1-5
(G→C) and IVS1-1 (G→A), are severe â +- and â 0-thalas-
semia mutations, and most others cases include â 0-thalas-
semia mutations.1,26 These primary mutations do not explain
the marked clinical diversity.1,27-29 Co-inheritance of α-thalas-
semia mutations decrease the globin chain imbalance and
improve the anemia. This occurs in fewer than 15% of pa-
tients. Triplicated or quadruplicated α-globin genes in-
crease the severity of E-thalassemia and occur in approxi-
mately 4% of the population. Other genetic factors most
likely play a major role in its clinical variability. However,
screening studies have not uncovered other significant pre-
dictors. Sripichai et al screened 1060 patients with Hb E â-
thalassemia with a candidate gene approach to uncover
secondary genetic modifiers.30,31 The study focused on single
nucleotide polymorphisms (SNPs) selected for genes en-
coding the transcription factors, β-protein 1, the α-hemo-
globin stabilizing protein, and genes involved in erythro-
poiesis. None were predictive of severity.
Understanding the extreme clinical variability of E β-
thalassemia requires prospective, laboratory, and clinical
studies of the natural history of the disease. In 1997,
Weatherall and colleagues initiated a long-term Hb E β-
thalassemia study.19,21,24,28 As part of this study, transfusion
Hematology 2007
therapy was stopped in order to better define their baseline
clinical condition and laboratory data. Patients were clas-
sified into five categories ranging in severity. The mildest
group, group 1, never received transfusions, presented at
16 years of age and demonstrated normal growth and de-
velopment, fertility, with mild iron loading. In group 2 pa-
tients had received intermittent transfusions and presented
at the age of 10 years; these patients tolerated removal of
long-term transfusion therapy and continued to demon-
strate normal maturation. Groups 3 and 4 presented at 3.5
years of age, required splenectomy for hypersplenism, and
generally required transfusion therapy. Group 5 presented
at 1 year of age, were severely affected, and corresponded
to the severe β-thalassemia phenotype. The study uncov-
ered several important observations. The difference in the
steady-state hemoglobins between mild groups and severe
groups was small. Why a small change in hemoglobin has
such a profound effect is not fully explained.
Several important genetic and environmental predic-
tors of severity were noted in the Sri Lanka population
over time. Age of presentation, growth rate, splenomegaly,
and hemoglobin F levels were prognostic indicators of se-
verity. The time of onset of symptoms was useful in pre-
dicting the long-term clinical phenotype. Severe anemia
with symptoms that begin between 6 and 12 months indi-
cated a thalassemia-major phenotype. A stable clinical con-
dition at 5 years generally indicated a thalassemia inter-
media phenotype, at least through early adulthood. Marked
splenomegaly, even if responsive to splenectomy, suggested
a more severe clinical course. As patients aged, their eryth-
ropoietin levels fell and correlated with a decreased hemo-
globin level. This observation explains the increased re-
quirements for transfusions in older patients. The high fre-
quency of gallstones in this population was strongly asso-
ciated with 7/7 genotype of the UGTA1A promoter.32 The
study also found environmental factors remain an impor-
tant modifier of severity. Patients with a positive serology
for P falciparum and P vivax were more likely to be severe.
It is unclear whether this increased rate of malaria exposure
indicates severe patients are more prone to infection or the
infection itself changes the chronic phenotypic expression
of the disease.
Clinical Course and Treatment Strategies
The clinical course of E β-thalassemia is punctuated by
acute and chronic complications that may cause serious
morbidity and mortality. The marked expansion of eryth-
ropoiesis is responsible for much of the pathology of the
disease, including hepatosplenomegaly, extramedullary
hematopoietic masses, growth retardation, delayed sexual
maturation, and bone deformities.1,10,11,17,33
Splenomegaly often develops in severely affected pa-
tients. In the past, splenectomy was routinely performed in
an attempt to increase hemoglobin levels. Increasing evi-
dence of the risk of thromboembolism in patients has led to
reconsideration of the role of splenectomy.34-36 Splenec-
81
tomy results in thrombocytosis and an increased exposure
of red cell membrane phosphatidylserine.37 These changes
induce a hypercoagulable state with endothelial activa-
tion.34,38 Thrombi may occur in any organ, but the lung is
particularly vulnerable.35 Autopsy data in splenectomized
patients often show widespread pulmonary artery throm-
bosis that may be responsible for the chronic hypoxemia
often seen in these patients.1,10
Iron overload in nontransfused patients is common,
secondary to increased gastrointestinal absorption of iron.39
End organ failure secondary to iron overload may not be
suspected because the serum ferritin level is disproportion-
ately low.39 Hemosiderosis-induced cirrhosis has been ob-
served in nontransfused patients, particularly after sple-
nectomy. Quantitative liver iron measurements are neces-
sary to identify iron overload even in nontransfused pa-
tients with Hb E β0-thalassemia.
Cardiopulmonary disease is the most common cause
of death in Hb E β-thalassemia. Cardiomyopathy, second-
ary to hemosiderosis, often occurs in chronically transfused
patients. The nontransfused patient is at particular risk for
pulmonary hypertension and right-heart failure. However,
transfused patients have also developed this complication.10
Thromboembolism and hemolysis-induced nitric oxide
deficiency result in pulmonary vascular injury and subse-
quent cardiac disease.34,40 The dysregulated arginine me-
tabolism observed in patients with sickle cell with pulmo-
nary hypertension has also been seen in this population.41
Transfusion therapy and sildenafil may be beneficial.
Patients with Hb E β-thalassemia are excellent candi-
dates for agents directed at elevating Hb F production. A
small increase in the steady-state hemoglobin concentra-
tion might be of major clinical benefit. In a multicenter
trial of 42 patients with E β0-thalassemia treated with hy-
droxyurea (HU), almost half the patients demonstrated a
significant increase in steady-state hemoglobin level.25 HU
was started at 7 mg/kg/day and increased to a maximum
dose of 20 mg/kg/day without any significant toxicity.
Thirty-eight percent of patients maintained a mean hemo-
globin increase of almost 1.5 gm/dL for years. This increase
in hemoglobin corresponded to a rise in Hb F and a de-
crease in markers of erythropoietic stress. A high baseline
Hb F was the best predictor of response to HU. HU, in com-
bination with erythropoietin, was only beneficial in pa-
tients with low baseline erythropoietin levels. Thirteen of
27 patients who were regularly transfused have become
transfusion independent and demonstrated a marked de-
crease in their iron status. Some of these patients were
thalassemia intermedia phenotypes placed on chronic trans-
fusions for subjective reasons. While HU therapy may be
beneficial to these patients, responses are unpredictable.
Clinical trials with decitabine and short-chain fatty acid
compounds have recently been initiated and may result in
more consistent responses.42
In summary, Hb E disorders are a heterogeneous group
of diseases that are rapidly increasing worldwide. The eti-
82
ology for the marked variation in phenotype remains largely
unknown. Correct laboratory diagnosis is essential to sepa-
rate asymptomatic genotypes from severe mutations. Both
transfused and nontransfused patients with Hb E β0-thalas-
semia are at risk for life-threatening complications and
should be followed by a multidisciplinary team. Annual
monitoring for complications from anemia and/or iron over-
load is necessary. Cardiac, endocrine, pulmonary, hepato-
biliary, and skeletal systems may be affected. In addition to
falling Hb, close monitoring of organ function and quality
of life are necessary in order to determine the initiation of
chronic transfusion therapy. Chelation therapy may be nec-
essary in both the transfused and nontransfused patients.
Comprehensive care, including genetic counseling, psy-
chological support and access to new therapy, are impor-
tant for all patients with E β0-thalassemia.
Correspondence
Elliott Vichinsky, MD, Children’s Hospital and Research Center
Oakland, 747 52nd Street, Oakland, CA 94609; phone (510)
428-3651; fax (510) 450-5647; evichinsky@mail.cho.org
References
1. Gibbons R, Higgs DR, Olivieri NF, Wood WG. The β and δβ
thalassaemias in association with structural haemoglobin
variants. In: Weatherall DJ, Clegg JB, eds. The
Thalassaemia Syndromes (Fourth ed). Oxford, United
Kingdom: Blackwell Science; 2001:393-449.
2. Old JM, Olivieri NF, Thien SL. Avoidance and population
control. In: Weatherall DJ, Clegg JB, eds. The Thalassaemia
Sydromes. United Kingdom: Blackwell Science; 2001:597-629.
3. de Silva S, Fisher CA, Premawardhena A, et al.
Thalassaemia in Sri Lanka: implications for the future health
burden of Asian populations. Sri Lanka Thalassaemia Study
Group. Lancet. 2000;355:786-791.
4. Weatherall DJ. Introduction to the problem of hemoglobin E-
B thalassemia. J Pediatr Hematol Oncol. 2000;22:551.
5. Chotivanich K, Udomsangpetch R, Pattanapanyasat K, et al.
Hemoglobin E: a balanced polymorphism protective against
high parasitemias and thus severe P falciparum malaria.
Blood. 2002;100:1172-1176.
6. Chernoff AI, Minnich V, Nanakorn S, et al. Studies on
hemoglobin E. I. The clinical, hematologic, and genetic
characteristics of the hemoglobin E syndromes. J Lab Clin
Med. 1956;47:455-489.
7. Weatherall DJ, Clegg JB. Inherited haemoglobin disorders:
an increasing global health problem. Bull World Health
Organ. 2001;79:704-712.
8. Vichinsky EP, MacKlin EA, Waye JS, Lorey F, Olivieri NF.
Changes in the epidemiology of thalassemia in North
America: a new minority disease. Pediatrics. 2005;116:e818-
e825.
9. Lorey F. Asian immigration and public health in California:
thalassemia in newborns in California. J Pediatr Hematol
Oncol. 2000;22:564-566.
10. Fucharoen S, Winichagoon P. Clinical and hematologic
aspects of hemoglobin E beta-thalassemia. Curr Opin
Hematol. 2000;7:106-112.
11. Lachant NA. Hemoglobin E: an emerging hemoglobinopathy
in the United States. Am J Hematol. 1987;25:449-462.
12. Bain BJ. Other significant haemoglobinopathies. In:
Haemoglobinopathy Diagnosis (2nd ed). Malden, MA:
Blackwell Publishing; 2006:201-211.
13. Charoenkwan P, Wanapirak C, Thanarattanakorn P, et al.
American Society of Hematology
 Hemoglobin E levels in double heterozygotes of hemoglobin
E and SEA-type alpha-thalassemia. Southeast Asian J Trop
Med Public Health. 2005;36:467-470.
14. Sanchaisuriya K, Fucharoen G, Sae-ung N, Jetsrisuparb A,
Fucharoen S. Molecular and hematologic features of
hemoglobin E heterozygotes with different forms of alpha-
thalassemia in Thailand. Ann Hematol. 2003;82:612-616.
15. Jindadamrongwech S, Wisedpanichkij R, Bunyaratvej A,
Hathirat P. Red cell parameters in alpha-thalassemia with
and without beta-thalassemia trait or hemoglobin E trait.
Southeast Asian J Trop Med Public Health. 1997;28:97-99.
16. Masiello D, Heeney MM, Adewoye AH, et al. Hemoglobin SE
disease-a concise review. Am J Hematol. 2007;B2:643-649.
17. Fucharoen S, Ketvichit P, Pootrakul P, Siritanaratkul N,
Piankijagum A, Wasi P. Clinical manifestation of beta-
thalassemia/hemoglobin E disease. J Pediatr Hematol Oncol.
2000;22:552-557.
18. Datta P, Basu S, Chakravarty SB, et al. Enhanced oxidative
cross-linking of hemoglobin E with spectrin and loss of
erythrocyte membrane asymmetry in hemoglobin E/beta-
thalassemia. Blood Cells Mol Dis. 2006;37:77-81.
19. Pootrakul P, Sirankapracha P, Hemsorach S, et al. A
correlation of erythrokinetics, ineffective erythropoiesis, and
erythroid precursor apoptosis in thai patients with thalas-
semia. Blood. 2000;96:2606-2612.
20. Jetsrisuparb A, Sanchaisuriya K, Fucharoen G, et al.
Development of severe anemia during fever episodes in
patients with hemoglobin E trait and hemoglobin H disease
combinations. J Pediatr Hematol Oncol. 2006;28:249-253.
21. Premawardhena A, Fisher CA, Olivieri NF, et al. Haemoglo-
bin E beta thalassaemia in Sri Lanka. Lancet.
2005;366:1467-1470.
22. Rees DC. Hemoglobin F and hemoglobin E/beta-thalas-
semia. J Pediatr Hematol Oncol. 2000;22:567-572.
23. Rees DC, Porter JB, Clegg JB, Weatherall DJ. Why are
hemoglobin F levels increased in HbE/beta thalassemia?
Blood. 1999;94:3199-3204.
24. Rees DC, Styles L, Vichinsky EP, Clegg JB, Weatherall DJ.
The hemoglobin E syndromes. Ann N Y Acad Sci.
1998;850:334-343.
25. Singer ST, Kuypers FA, Olivieri NF, et al. Fetal haemoglobin
augmentation in E/beta(0) thalassaemia: clinical and
haematological outcome. Br J Haematol. 2005;131:378-388.
26. Fisher CA, Premawardhena A, de Silva S, et al. The
molecular basis for the thalassaemias in Sri Lanka. Br J
Haematol. 2003;121:662-671.
27. Winichagoon P, Fucharoen S, Chen P, Wasi P. Genetic
factors affecting clinical severity in beta-thalassemia
syndromes. J Pediatr Hematol Oncol. 2000;22:573-580.
28. Premawardhena A, De Silver S, Arambepola M, et al.
Hemoglobin E-beta-thalassemia: progress report from the
International Study Group. Ann N Y Acad Sci. 2005;1054:33-
39.
Hematology 2007
View publication stats
29. Winichagoon P, Thonglairoam V, Fucharoen S, Wilairat P,
Fukumaki Y, Wasi P. Severity differences in beta-
thalassaemia/haemoglobin E syndromes: implication of
genetic factors. Br J Haematol. 1993;83:633-639.
30. Sripichai O, Fucharoen S. Genetic polymorphisms and
implications for human diseases. J Med Assoc Thai.
2007;90:394-398.
31. Sripichai O, Whitacre J, Munkongdee T, et al. Genetic
analysis of candidate modifier polymorphisms in Hb E-beta
0-thalassemia patients. Ann N Y Acad Sci. 2005;1054:433-
438.
32. Premawardhena A, Fisher CA, Fathiu F, et al. Genetic
determinants of jaundice and gallstones in haemoglobin E
beta thalassaemia. Lancet. 2001;357:1945-1946.
33. Hough RE, Kelly R, Nakielny R, Winfield DA. Extramedullary
haemopoiesis in haemoglobin E/beta-thalassaemia. Br J
Haematol. 2003;120:918.
34. Eldor A, Rachmilewitz EA. The hypercoagulable state in
thalassemia. Blood. 2002;99:36-43.
35. Phrommintikul A, Sukonthasarn A, Kanjanavanit R,
Nawarawong W. Splenectomy: a strong risk factor for
pulmonary hypertension in patients with thalassaemia. Heart.
2006;92:1467-1472.
36. Singer ST, Kuypers FA, Styles L, Vichinsky EP, Foote D,
Rosenfeld H. Pulmonary hypertension in thalassemia:
association with platelet activation and hypercoagulable
state. Am J Hematol. 2006;81:670-675.
37. Atichartakarn V, Angchaisuksiri P, Aryurachai K, et al.
Relationship between hypercoagulable state and erythro-
cyte phosphatidylserine exposure in splenectomized
haemoglobin E/beta-thalassaemic patients. Br J Haematol.
2002;118:893-898.
38. Pattanapanyasat K, Gonwong S, Chaichompoo P, et al.
Activated platelet-derived microparticles in thalassaemia. Br
J Haematol. 2007;136:462-471.
39. Pakbaz Z, Fischer R, Fung E, Nielsen P, Harmatz P,
Vichinsky E. Serum ferritin underestimates liver iron
concentration in transfusion independent thalassemia
patients as compared to regularly transfused thalassemia
and sickle cell patients. Pediatr Blood Cancer. 2007;49:329-
332.
40. Atichartakarn V, Chuncharunee S, Chandanamattha P,
Likittanasombat K, Aryurachai K. Correction of hypercoagu-
lability and amelioration of pulmonary arterial hypertension
by chronic blood transfusion in an asplenic hemoglobin E/
beta-thalassemia patient. Blood. 2004;103:2844-2846.
41. Morris CR, Kuypers FA, Kato GJ, et al. Hemolysis-
associated pulmonary hypertension in thalassemia. Ann N Y
Acad Sci. 2005;1054:481-485.
42. Perrine SP, Castaneda SA, Boosalis MS, White GL, Jones
BM, Bohacek R. Induction of fetal globin in beta-thalassemia:
cellular obstacles and molecular progress. Ann N Y Acad
Sci. 2005;1054:257-265.
83