Background: Alpha thalassemia,
the most prevalent of all thalassemias, is the deficient or absent production of
alpha-globin synthesis. Normally, alpha-globin chains bind with beta-globin
chains to form the tetramer aa/bb
in hemoglobin A. The imbalance of alpha- and beta-globin chains creates the
pathology in thalassemia. The alpha thalassemic genetic abnormality primarily
affects Southeast Asian and Mediterranean populations. However, the genetic
trait is found in 30% of asymptomatic African Americans. The condition results
in a variety of clinical syndromes depending on the degree of alpha chain
Pathophysiology: Normal adult hemoglobin contains a tetramer
of globin chains a2/b2.
Two conditions exist in the red blood cell when the alpha-globin synthesis
decreases or is absent altogether. Intracellular precipitation of unmatched beta
chains form inclusion bodies, causing damage to red blood cell precursors in the
marrow and ineffective erythropoiesis.
Diminished hemoglobinization of individual red cells results in hypochromia and
The alpha-globin genes are duplicated on the short arm of chromosome 16. Each
individual carries 4 separate loci, 2 from the paternal chromosome and 2 from
the maternal chromosome. This results in 4 possible genotypes, each resulting in
a different clinical syndrome.
Table 1. Alpha-Globin Genotypes and Clinical Syndromes
||Silent carrier or mild alpha thalassemia minor; alpha+ thalassemia trait
||Homozygous alpha+ thalassemia or --/aa alpha0
||Hemoglobin H disease
||Hydrops fetalis or homozygous alpha thalassemia; Barts hemoglobin
- In the US: The most common genotype in American blacks is
-a/aa, with a prevalence
of 30%. Hydrops fetalis and hemoglobin H are rare in blacks due to the low
incidence of --/aa; the homozygous alpha+
thalassemia, a-/a-, is
found in approximately 2-3%.
- Internationally: The highest frequency occurs in
Southeast Asia and Africa, where as many as 30% of the general population have
the condition. Other areas of increased incidence include Italy, the Middle
East, Greece, North Africa, and the Mediterranean.
Mortality/Morbidity: Each of the 4 genotypes has an
individual clinical course. The most severe alpha thalassemia genotype, --/--
(or hydrops fetalis), is not compatible with life and results in premature,
pale, bloated infants that usually are stillborn or in severe respiratory and
cardiogenic distress. Death usually occurs within hours after birth. Other
morbidities are discussed in
Race: The alpha thalassemic genetic abnormalities are common
in people of Asian, African, and Mediterranean heritage.
History: Clinical courses and
physical findings are different for each of the 4 genotypes. Concomitant beta
chain hemoglobinopathies and beta thalassemia alter the clinical course.
- Silent carrier: Clinical symptoms and physical findings are not present.
- Homozygous alpha+ thalassemia (a-/a-)
or heterozygous alpha0 thalassemia (--/aa):
Clinical symptoms do not exist. This is diagnosed by incidental laboratory
abnormalities (microcytosis) and family studies to characterize a relative.
- Hemoglobin H disease (--/a-)
- Splenomegaly occurs by age 1 year, with progression to jaundice and
- Skeletal changes due to expanded erythropoiesis in the marrow affect one
third of patients.
- Transfusions are not necessary unless concomitant illness exists.
- Acquired, not inherited, cases are observed in myeloproliferative
diseases (eg, acute myelogenous leukemia, erythroleukemia, refractory
sideroblastic anemia, acute lymphocytic leukemia).
- Hemoglobin Barts or hydrops fetalis (--/--)
- Premature infant or death in utero
- Edematous friable placenta
- Massive hepatomegaly secondary to extramedullary hematopoiesis
Hemoglobin C Disease
Iron Deficiency Anemia
Other Problems to be Considered:
Beta thalassemia major
Hemoglobin E thalassemia
Hemoglobin S thalassemia syndrome
Hereditary persistence of fetal hemoglobin
High hemoglobin F syndromes
- Hemoglobin is within the reference range.
- Reticulocyte count is within the reference range.
- Mean corpuscular volume (MCV) is 75-85 fL.
- Mean corpuscular hemoglobin (MCH) is 26 pg.
- Hemoglobin is within the reference range.
- Reticulocyte count is within the reference range.
- Reticulocyte count is 5-10%.
- The peripheral blood smear shows small misshapen red cells, hypochromia,
microcytosis, and targeting.
- Brilliant cresyl blue stain demonstrates hemoglobin H inclusion bodies.
- Hydrops fetalis
- Hemoglobin is 4-10 g/dL.
- MCV is 110-120 fL.
- The peripheral blood smear shows severe anisopoikilocytosis, severe
hypochromia, and nucleated red blood cells.
- Alpha thalassemia combined with sickle cell anemia causes a higher
hemoglobin concentration and improved red blood cell survival. The alpha gene
deletion is associated with improved red cell deformability, but the improved
rheologic benefits often are overcome by the greater viscosity of a higher
hematocrit. Clinically, this is observed as a greater number of painful vaso-occlusive
pain crises with the combination of alpha thalassemia and sickle cell disease.
Interestingly, however, the incidence of stroke is lower than compared to
sickle cell disease alone.
- Imaging studies are not useful in these disorders.
- Hemoglobin electrophoresis will separate hemoglobin into different types.
Hemoglobin Barts is elevated at birth in patients with alpha thalassemia. For
example, in hemoglobin H disease, 20-40% hemoglobin Barts is present; however,
in the silent carrier alpha thalassemia condition, only 1-2% hemoglobin Barts
with low and normal-to-decreased amounts of hemoglobin A2 are
present. Hemoglobin electrophoresis generally is not sufficiently sensitive to
diagnose silent carrier alpha thalassemia.
- The imbalance between the quantity of alpha and beta chains initially was
used to define the thalassemias. Beta-to-alpha synthetic ratios are altered in
both alpha and beta chain thalassemias. Increasing ratios are observed in
alpha2 thalassemia, alpha1 thalassemia, and hemoglobin H disease,
respectively. Tests are performed by incubation of cells with radiolabeled
amino acid and subsequently separating alpha- and beta-globin chains using
urea carboxymethyl cellulose (CMC) chromatography.
- Currently, genetic testing is used to establish the diagnosis in patients
with a suggestive family history and/or hematologic findings suggestive of
- Recombinant DNA technology can be diagnostic, but it generally is a
- Polymerase chain reaction (PCR)
- Restriction endonucleases
- Anti-L globin monoclonal antibodies
- Bone marrow aspiration and biopsy are not helpful in establishing the
precise diagnosis and are not indicated unless other confounding problems
Histologic Findings: Review of the peripheral blood smear
may reveal target cells, microcytosis, hypochromia, and anisopoikilocytosis as a
clue to the presence of a thalassemic syndrome. Most individuals with alpha2
thalassemia (trait) have only mild microcytosis, which can be differentiated
from other common causes of microcytosis because these people have a serum iron
and ferritin concentration within the reference range.
- Avoid iron supplementation. It contributes to iron overload and does not
affect hematologic values or cell morphology.
- Administer folate supplementation to provide adequate amounts of the
vitamin for increased utilization resulting from the hemolytic process and
high bone marrow turnover rate.
- Provide prompt attention to infection, especially in children who have had
- Administer blood transfusions only if necessary.
- If chronic transfusion is needed (hemoglobin H disease), iron chelation
therapy should be considered to avoid iron overloading.
- Perform a splenectomy if transfusion requirements are increasing.
- Surgical or orthodontic correction may be necessary to correct skeletal
deformities of the skull and maxilla due to erythroid hyperplasia.
- The prognosis is excellent for silent carriers.
- Because hydrops fetalis is incompatible with life, hemoglobin H (a-/--)
is the most serious syndrome. The overall survival for hemoglobin H disease is
variable; however, it generally is very good. Many patients survive into
adulthood. However, some patients have a more complicated course and may not
do as well.
- Patients with a family history or known carrier state for alpha
thalassemia gene mutations should obtain genetic counseling to determine
genotype and risk to offspring. This especially is true in cases of suspected
- Alpha thalassemia frequently is mistaken for iron deficiency anemia
because both disorders have microcytic red blood cells. Iron therapy is not
required, and prolonged therapy may produce untoward effects from iron
overload. Similarly, the procedures used to find a source of bleeding in
patients with iron deficiency anemia have no value in patients with
thalassemia. Measurements of serum iron and ferritin can provide laboratory
evidence to exclude iron deficiency as the etiology for microcytosis
|Caption: Picture 1. Peripheral smear
from a patient with hemoglobin H disease showing target cells, microcytosis,
hypochromia, and anisopoikilocytosis. Morphological abnormalities are
similar to those observed in beta thalassemia. In alpha2 thalassemia (silent
trait) only mild microcytosis is observed.
|Picture Type: Photo
Section 10 of 10
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