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Hemoglobin E Syndromes
Hemoglobin E Syndromes
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Hemoglobin E Syndromes
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Elliott Vichinsky
UCSF Benioff Children’s Hospital Oakland
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Hemoglobin (Hb) E is one of the world’s most common typic variability is largely unknown. A prospective
and important mutations. It results in a heterogeneous natural history study of E β-thalassemia in Sri Lanka
group of disorders whose phenotype range from suggests that environmental modifiers are
asymptomatic to severe. Hb E trait and Hb EE are mild prognostically important. The clinical course of E β-
disorders. The combination of Hb E and Hb S (Hb SE) thalassemia is punctuated by acute and chronic
results in a sickle cell disease syndrome similar to complications that may cause serious morbidity and
sickle β+ thalassemia. It is important to distinguish Hb mortality. Recent studies indicate these patients are at
E disorders diagnostically because of this marked high risk for thromboembolism secondary to a
difference in clinical course among different geno- hypercoagulable state increased by splenectomy.
types. Screening tests, including hemoglobin electro- Morbidity from iron overload in nontransfused patients
phoresis and high-pressure liquid chromatography secondary to increased gastrointestinal iron absorp-
(HPLC), may suggest other mutations, unless one is tion is common. Cardiopulmonary disease, including
familiar with the findings. E β-thalassemia, the most pulmonary hypertension, requires ongoing monitoring
serious form of E syndromes, affects a million people and is secondary to iron overload, thromboembolism,
worldwide and is increasing in North America. Its and hemolysis-induced nitric oxide deficiency. These
phenotype ranges from mild anemia to severe transfu- patients are excellent candidates for Hb F–modulating
sion-dependent thalassemia major. Several genetic agents because moderate changes in hemoglobin
modifiers affect the phenotype, including the type of β- may result in marked improvement in phenotype.
thalassemia mutation, Hb F levels, and co-inheritance Recent studies with hydroxyurea indicate 40% of
of α-thalassemia. However, the cause of the pheno- patients will clinically improve with hydroxyurea.
Hematology 2007 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- nosed as HB SC because of the comigration of C and E
proximately 30%. Diagnosis of concomitant α-thalassemia patterns on electrophoresis. Patients are mildly anemic with
requires DNA testing. The concomitant inheritance of α- microcytic red cells. The electropheretic pattern demon-
thalassemia often occurs and lowers the percentage of Hb strates 60% S and 30% E. The clinical phenotype is similar
E.13,14 In Hb E trait in combination with Hb H, Hb E drops to to sickle β+-thalassemia. Medical complications appear to
10%.13,15 Iron deficiency also lowers the Hb E percentage. increase as patients get older. Painful episodes, acute chest
In Hb EE, the electrophoresis generally indicates 90% or syndrome, splenic sequestration, and avascular necrosis of
more Hb E with a mild elevation in Hb F. Hb E β+-thalas- hip have all been observed.16
semia may have an extremely variable laboratory picture.
They usually have a mild anemia of approximately 9.5 g/ Pathophysiology and Clinical Variability
dL. However, significant ranges of anemia has been ob- The most serious Hb E syndrome is Hb E β0-thalassemia.
served, with Hb as low as 5.7 g/dL. The mean corpuscular The compound heterozygote state of Hb E β-thalassemia
volume (MCV) has been approximately 72 ± 6 fL and mean results in a variable phenotype ranging from a complete
corpuscular Hb concentration (MCHC) has been 29 ± 2 lack of symptoms to transfusion dependency.1,10,17 In re-
fL.11 The electropheresis demonstrates both Hb E and Hb view of 378 patients with Hb E-β0-thalassemia from Thai-
A, with a marked range for the amount of Hb A. The differ- land, the hemoglobin concentrations ranged from 3 to 13
ential diagnosis includes Hb E β0-thalassemia. In this dis- g/dL, with an average of 7.7 g/dL17 (Figure 1). Approxi-
ease, Hb E ranges from 40% to 60%, with Hb F markedly mately one-half of the patients are phenotypically similar
elevated. In neonates, DNA analysis is required to differen- to patients with thalassemia major who require regular trans-
tiate these two syndromes in neonates and is increasingly fusion therapy, and the other half resembles thalassemia
being used routinely for diagnosis of Hb E disorders. intermedia.1,10,17
There are several compound heterozygotes with Hb E The pathophysiology of Hb E β-thalassemia is com-
and an uncommon β-globin mutation. Hb E Lepore and Hb plex. Ineffective erythropoiesis, apoptosis, and oxidative
E δβ-thalassemia are compound heterozygotes with mild damage are central components of the disease and its short-
phenotypes. Hb SE is being more frequently diagnosed ened red cell survival.1,18,19 The instability of Hb E is a
due to changing population migration patterns and inter- minor factor in its pathophysiology, but in febrile patients,
marriage of at-risk individuals. It is often initially misdiag- may account for accelerated hemolysis.20 The interaction
Hematology 2007 81
tomy results in thrombocytosis and an increased exposure ology for the marked variation in phenotype remains largely
of red cell membrane phosphatidylserine.37 These changes unknown. Correct laboratory diagnosis is essential to sepa-
induce a hypercoagulable state with endothelial activa- rate asymptomatic genotypes from severe mutations. Both
tion.34,38 Thrombi may occur in any organ, but the lung is transfused and nontransfused patients with Hb E β0-thalas-
particularly vulnerable.35 Autopsy data in splenectomized semia are at risk for life-threatening complications and
patients often show widespread pulmonary artery throm- should be followed by a multidisciplinary team. Annual
bosis that may be responsible for the chronic hypoxemia monitoring for complications from anemia and/or iron over-
often seen in these patients.1,10 load is necessary. Cardiac, endocrine, pulmonary, hepato-
Iron overload in nontransfused patients is common, biliary, and skeletal systems may be affected. In addition to
secondary to increased gastrointestinal absorption of iron.39 falling Hb, close monitoring of organ function and quality
End organ failure secondary to iron overload may not be of life are necessary in order to determine the initiation of
suspected because the serum ferritin level is disproportion- chronic transfusion therapy. Chelation therapy may be nec-
ately low.39 Hemosiderosis-induced cirrhosis has been ob- essary in both the transfused and nontransfused patients.
served in nontransfused patients, particularly after sple- Comprehensive care, including genetic counseling, psy-
nectomy. Quantitative liver iron measurements are neces- chological support and access to new therapy, are impor-
sary to identify iron overload even in nontransfused pa- tant for all patients with E β0-thalassemia.
tients with Hb E β0-thalassemia.
Cardiopulmonary disease is the most common cause Correspondence
of death in Hb E β-thalassemia. Cardiomyopathy, second- Elliott Vichinsky, MD, Children’s Hospital and Research Center
ary to hemosiderosis, often occurs in chronically transfused Oakland, 747 52nd Street, Oakland, CA 94609; phone (510)
patients. The nontransfused patient is at particular risk for 428-3651; fax (510) 450-5647; evichinsky@mail.cho.org
pulmonary hypertension and right-heart failure. However,
transfused patients have also developed this complication.10 References
1. Gibbons R, Higgs DR, Olivieri NF, Wood WG. The β and δβ
Thromboembolism and hemolysis-induced nitric oxide thalassaemias in association with structural haemoglobin
deficiency result in pulmonary vascular injury and subse- variants. In: Weatherall DJ, Clegg JB, eds. The
quent cardiac disease.34,40 The dysregulated arginine me- Thalassaemia Syndromes (Fourth ed). Oxford, United
tabolism observed in patients with sickle cell with pulmo- Kingdom: Blackwell Science; 2001:393-449.
2. Old JM, Olivieri NF, Thien SL. Avoidance and population
nary hypertension has also been seen in this population.41 control. In: Weatherall DJ, Clegg JB, eds. The Thalassaemia
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Patients with Hb E β-thalassemia are excellent candi- 3. de Silva S, Fisher CA, Premawardhena A, et al.
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trial of 42 patients with E β0-thalassemia treated with hy- B thalassemia. J Pediatr Hematol Oncol. 2000;22:551.
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Hematology 2007 83