AUTHOR AND EDITOR INFORMATION

Section 1 of 10  

• Authors and Editors
• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Follow-up
• Miscellaneous
• Multimedia
• References

INTRODUCTION

Section 2 of 10  

• Authors and Editors
• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Follow-up
• Miscellaneous
• Multimedia
• References

Background

The oxygen carrying capability of the red blood cells (RBC) relies on hemoglobin, a tetramer protein consisting of 2 pairs of globin chains bound to the heme molecule. There are 4 major types of globins labeled as alpha (α), beta (β), gamma (γ), and delta (δ). The dominant hemoglobin in adults (hemoglobin A) is composed of 2 alpha and 2 beta chains. This is achieved by the very tightly controlled globin chain production maintaining the ratio of alpha to non-alpha chains 1.00 (± 0.05). Thalassemia refers to a spectrum of diseases characterized by reduced or absent production of one or more globin chains, thus disrupting this ratio.

Minor forms of hemoglobins constitute a small percentage of the normal blood and are referred to as hemoglobin F (fetal), composed of 2 alpha chains and 2 gamma chains, and hemoglobin A2, composed of 2 alpha chains and 2 delta chains.

Relative excess of beta chains due to impaired production of alpha globin results in less stable chains. This leads to the clinical disease known as alpha thalassemia. Similarly, impaired production of beta globin chains manifests with a more severe disease known as beta thalassemia.

Pathophysiology

The absence of normal production of a-chains results in a relative excess of γ-globin chains in the fetus and newborn, and β-globin chains in children and adults. Further, the β-globin chains are capable of forming soluble tetramers (beta-4, or HbH); yet this form of hemoglobin is unstable and tends to precipitate within the cell forming insoluble inclusions (Heinz bodies) that damage the red cell membrane. Furthermore, diminished hemoglobinization of individual red blood cells results in damage to erythrocyte precursors and ineffective erythropoiesis in the bone marrow, as well as hypochromia and microcytosis of circulating red blood cells.

Genes that regulate both synthesis and structure of different globins are organized into 2 separate clusters. The a-globin genes are encoded on chromosome 16 and the γ, δ, and β-globin genes are encoded on chromosome 11 (see Image 1). Each individual normally carries a linked pair of a-globin genes, 2 from the paternal chromosome, and 2 from the maternal chromosome. Alpha thalassemia results when there is disturbance in production of α-globin from any or all four of the α-globin genes.
 
Normal hemoglobin biosynthesis requires an intact gene, silencers, enhancers, promoters, and locus control region (LCR) sequences. Several hundred mutations causing thalassemia have been described. These may affect any step in globin gene expression, transcription, pre-mRNA splicing, mRNA translation and stability, and post-translational assembly and stability of globin polypeptides.

The most common mechanism of aberrant a-globin production is due to deletions of either portions of the a-globin genes themselves or the genetic regulatory elements that control their expression. Regulatory elements may be located on the same chromosome (cis acting elements) or on separate chromosomes (trans acting elements).

Production of functional hemoglobin is also impaired in alpha thalassemia when point mutations, frame shift mutations, nonsense mutations, and chain termination mutations occur within or around the coding sequences of the a-globin gene cluster. These gene level mutations may in turn affect RNA splicing, initiation of mRNA translation, or result in the generation of unstable a-chain variants.

Mutations affecting transcription, pre-mRNA splicing, or canonical splice signals are rare causes of alpha thalassemia. Other forms of alpha thalassemia are caused by either premature or failed translation termination. More rare mutations have been found to cause thalassemia by interfering with the normal folding of otherwise normal globin peptide.

From a genetic standpoint, alpha thalassemias are extremely heterogeneous; however, phenotypic expression of alpha thalassemias may be described in simplified clinical terms related to the number of alpha globin genes affected:

• Alpha (0) thalassemia – More than 20 different genetic mutations that result in the functional deletion of both pair of a-globin genes have been identified. Individuals with this disorder are not able to produce any functional a-globin and thus are unable to make any functional hemoglobin A, F, or A2. This leads to the development of hydrops fetalis, also known as hemoglobin Bart, a condition that is incompatible with extra uterine life.
• Alpha (+) thalassemia – There are more than 15 different genetic mutations that result in decreased production of a-globin usually due to the functional deletion of 1 of the 4 alpha globin genes. Based on the number of inherited alpha genes, alpha (+) thalassemia is subclassified into 3 general forms:
• • A- Thalassemia (-α/αα) is characterized by inheritance of 3 normal α-genes. These patients are referred to clinically as silent carrier of alpha thalassemia. Other names for this condition are alpha thalassemia minima, alpha thalassemia-2 trait, and heterozygosity for alpha (+) thalassemia minor. The affected individuals  exhibit no abnormality clinically and may be hematologically normal or have mild reductions in red cell mean corpuscular volume (MCV) and mean corpuscular hemoglobin (MCH).
  • B- Inheritance of 2 normal alpha genes due to either heterozygosity for alpha (0) thalassemia (αα/--) or homozygosity for alpha (+) thalassemia (-α/-α) results in the development of alpha thalassemia minor or alpha thalassemia-1 trait. The affected individuals are clinically normal but frequently have minimal anemia and reduced mean corpuscular volume (MCV) and mean corpuscular hemoglobin (MCH). The red blood cell count is usually increased to over 5.5 x 1012/L.
  • C- Inheritance of one normal alpha gene (-α/--) results in abundant formation of hemoglobin H composed of tetramers of excess beta chains. This condition is known as HbH disease. The affected individuals have moderate to severe lifelong hemolytic anemia, modest degrees of ineffective erythropoiesis, splenomegaly, and variable bony changes.

Frequency

United States

Recent reports suggest an increasing incidence of all subtypes of alpha thalassemia in the United States secondary to immigration of individuals from endemic areas. It is estimated that about 15% of American blacks are silent carriers for α-thalassemia. In addition, α-thalassemia trait (minor) occurs in 3% of American blacks and in 1-15% of persons of Mediterranean origin.

According to the National Institutes of Health sponsored North American Thalassemia Clinical Research Network (TCRN) study of the epidemiology of thalassemia in North America, 59% of patients with alpha thalassemia have the (-α/--) genotype, 8% have 4 alpha gene deletion (--/--), and 33% have gene deletions with structural mutations.

International

It is estimated that there are 270 million carriers of mutant globin genes that can potentially cause severe forms of thalassemia. In addition, 300,000-400,000 severely affected infants are born every year, more than 95% of which occur in Asia, India, and the Middle East.

Before the introduction of DNA analysis, population surveys for alpha thalassemia were based entirely on the measurement of hemoglobin Bart levels in cord blood. However, single gene deletion heterozygotes do not always have detectable hemoglobin Bart in the neonatal period. As a result, reliable data on population frequencies for various types of alpha thalassemia are not always available.

Alpha thalassemia is common throughout parts of the world where malaria is endemic. Multiple studies have suggested that the presence of both single and double a-globin gene deletions confer a protective effect from malaria. Listed below are the approximate percentages of various populations with some forms of alpha thalassemia:

• Europe – 4-12%
• Middle East and western Asia - 12-55%
• Southeast Asia –  6-75%
• Africa – 11-50%
• South America and the Caribbean - 7%

Mortality/Morbidity

The morbidity and mortality of alpha thalassemia are related to the degree of imbalanced globin production and, therefore, correlate well with the number of affected α-globin genes. Individuals with milder alpha thalassemia phenotypes, including those with single and double gene deletions (-α/αα, --/ αα, -α/-α) have mild anemia as the only major morbidity associated with their disease. Patients with hemoglobin H (HbH) disease may develop hypersplenism, gallstones, leg ulcers, frequent infections, and various forms of venous thrombosis. The most severe form of alpha thalassemia, hemoglobin Bart is characteristic of individuals with no functional α-globin genes (--/--). Following a gestation of about 33 weeks, these infants develop hydrops fetalis syndrome and usually die in utero, during delivery, or within an hour or two of birth.

Race

Abnormalities affecting the α-globin genes have been documented in almost all ethnic groups yet are much more common in people of Asian, African, and Mediterranean heritage. The North American Thalassemia Clinical Research Network (TCRN) study showed that 85% of patients with alpha thalassemia are Asian, 4% are white, and 11% are of other ethnicities, including African, black, mixed ethnicity, and unknown.

Sex

Abnormalities of α-globin genes are equally distributed between males and females. A notable exception is the unusual alpha thalassemia associated with mental retardation, known as alpha thalassemia mental retardation-X syndrome (ATR-X), which affects exclusively males.

Age

Alpha thalassemia is a genetic disorder, thus patients are born with the disorder, with the exception of patients with acquired alpha thalassemia myelodysplastic syndrome (ATMDS), in which case patients are usually elderly with a mean age at diagnosis of 68 years.

CLINICAL

Section 3 of 10  

• Authors and Editors
• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Follow-up
• Miscellaneous
• Multimedia
• References

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/alpha thalassemia-2 trait: Patients are essentially asymptomatic and the CBC, hemoglobin electrophoresis, and peripheral smear are usually normal. Slight hypochromia and microcytosis may be evident by microscopic evaluation. The silent carrier state becomes apparent in families when related carriers of this allele mate and have children with HbH disease.
• Homozygous alpha (+) thalassemia: The peripheral blood smear typically shows hypochromia, microcytosis, and target cells. The MCV is frequently less than 80 fL, and the MCH is always below 27 pg. RBC counts are usually higher than normal. Hemoglobin electrophoresis is normal. Although elevation of hemoglobin A2 does not occur, elevations of hemoglobin F have been reported. Individuals of African origin usually carry a homozygous state of the alpha-2 allele, and deletion usually involves the less active of 2 normal alleles. Alpha thalassemia-2 and alpha thalassemia-1 tend to be milder in this population.

In Asia, the cis deletion is common, and subpopulations exhibit more dramatic features of thalassemia trait. If patients have the hemoglobin CS mutation, a slowly migrating abnormal hemoglobin band is present on hemoglobin electrophoresis. Clinical symptoms do not exist. The condition is diagnosed as a result of incidental laboratory abnormalities and family studies to characterize a relative.

• Hemoglobin H disease: Marked impairment of α-globin production results in accumulation of excess beta globin chains that are soluble enough to form the homotetrameric HbH. This form of hemoglobin has a dramatically left-shifted oxygen dissociation curve that renders it of no value in oxygen transportation. In addition, it is structurally unstable during the later stages of erythropoiesis and during the circulating lifespan of the red blood cell. As HbH precipitates, it forms inclusion bodies within the red blood cell, thereby causing chronic hemolytic anemia.
• • Patients are often symptomatic at birth; many others present with neonatal jaundice or anemia, and some others have hydrops fetalis. Indirect hyperbilirubinemia, elevated lactate dehydrogenase levels, and reduced haptoglobin are all consistently seen with hemolytic anemia. Exacerbations of hemolysis may occur when patients are exposed to oxidant stressors such as infections or oxidizing drugs.
  • Other complications occur in varying degrees and include the following:
  • • Hepatosplenomegaly
    • Leg ulcers 
    • Gallstones 
    • Aplastic or hypoplastic crises 
    • Skeletal, developmental, and metabolic changes due to ineffective erythropoiesis (These resemble beta thalassemia intermedia or beta thalassemia major.) 
    • Prominent frontal bossing (due to bone marrow expansion) 
    • Delayed pneumatization of sinuses 
    • Marked overgrowth of the maxillae 
    • Ribs and long bones become box-like and convex 
    • Premature closure of epiphyses resulting in shortened limbs 
    • Compression fracture of the spine (which may result in cord compression or other neurological deficits) 
    • Osteopenia and fractures
  • Splenectomy or transfusional support is often necessary in the second or third decade of life. Iron overload may also occur due to increased iron absorption and frequent transfusions. 
  • Acquired cases are observed in myeloproliferative diseases (eg, acute myelogenous leukemia, erythroleukemia, refractory sideroblastic anemia, acute lymphocytic leukemia).
• Hemoglobin Bart or hydrops fetalis (--/--): This disease affects individuals with no functional α-globin genes (--/--). Infants with hemoglobin Bart/hydrops fetalis syndrome usually die in utero.
• • They have massive total body edema due to high output heart failure, pallor, massive hepatomegaly secondary to extramedullary hematopoiesis, and edematous friable placenta. 
• • There have now been several case reports of individuals with Hb Bart's that have survived for variable amounts of time, but many have developmental abnormalities, and all have required regular blood transfusion and chelation therapy.
• Alpha thalassemia with mental retardation syndromes: There are 2 clinical entities described in which patients are noted to have both mild forms of alpha thalassemia and mental retardation. ATR-16 is characterized by large chromosomal rearrangements that cause deletions of many genes from the short arm of chromosome 16. The second form, ATR-X, results from mutations in an X-chromosome encoded gene that acts (in trans) as a regulator of expression of the α-globin genes. Thus these patients have normal α-globin genes; however, expression of α-globin proteins is down-regulated. 
• Alpha thalassemia myelodysplastic syndrome: This disease is characterized by marked hypochromic microcytic anemia and presence of HbH demonstrated by hemoglobin electrophoresis and supravital staining. These patients are also found to have a very low α/β globin chain ratio (often <0.2). This is less than expected for patients with a single functioning α-globin gene (--/-α), which suggests down-regulation of all four α-globin genes by a trans acting mutation. Analysis of archival blood and bone marrow from the ATMDS registry has revealed acquired ATR-X mutations in the majority of these patients. 

Physical

See History.

Causes

See Pathophysiology.

DIFFERENTIALS

Section 4 of 10  

• Authors and Editors
• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Follow-up
• Miscellaneous
• Multimedia
• References

Other Problems to be Considered

Beta thalassemia major
Hemoglobin E thalassemia
Hemoglobin S thalassemia syndrome
Hemoglobinopathies
Hereditary persistence of fetal hemoglobin
High hemoglobin F syndromes
Sideroblastic anemia
Thalassemia intermedia
Thalassemia minima
Thalassemia minor

WORKUP

Section 5 of 10  

• Authors and Editors
• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Follow-up
• Miscellaneous
• Multimedia
• References

Lab Studies

• Trait -a/aa
• • Hemoglobin level is within the reference range.
  • Reticulocyte count is normal. 
  • Mean corpuscular volume (MCV) ranges between 75 and 85 fL. 
  • Mean corpuscular hemoglobin (MCH) is around 26 pg.
• Alpha1 thalassemia minor
• • Hemoglobin level is within the reference range. 
  • Reticulocyte count is normal. 
  • MCV is 65-75 fL. 
  • MCH is around 22 pg.
• Hemoglobin H disease
• • Hemoglobin level is 7-10 g/dL. 
  • Reticulocyte count is 5-10%. 
  • MCV is 55-65 fL. 
  • MCH is 20 pg. 
  • 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 vasoocclusive crises. Interestingly, however, the incidence of stroke is lower than that in sickle cell disease alone.

Imaging Studies

• Imaging studies are not useful in these disorders.

Other Tests

• Hemoglobin electrophoresis separates hemoglobin into different types. Hemoglobin Bart is elevated at birth in patients with alpha thalassemia. In hemoglobin H disease, 20-40% of total hemoglobin is of hemoglobin Bart; however, in the silent carrier alpha thalassemia condition, the percentage is only 1-2% with low or normal amounts of hemoglobin A₂. Hemoglobin electrophoresis is generally not sufficiently sensitive to diagnose silent carrier alpha thalassemia.
• The imbalance between the quantities of α- and β-globin chains initially was used to define the thalassemias. β to α synthetic ratios are altered in both alpha and beta thalassemias. Increasing ratios of β- to α-globin chains are observed in alpha-2 thalassemia, alpha-1 thalassemia, and hemoglobin H disease, respectively. Tests are performed by incubation of red blood cells with radiolabeled amino acid and subsequently separating α- and β-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 alpha thalassemia.
• • Recombinant DNA technology can be diagnostic but is still a research tool.
  • Gene mapping
  • Polymerase chain reaction (PCR)
  • Restriction endonucleases
  • Anti-L globin monoclonal antibodies

Procedures

• Bone marrow aspiration and biopsy are not helpful in establishing the precise diagnosis and are not indicated unless other confounding problems exist.

Histologic Findings

Peripheral blood smear may reveal target cells, microcytosis, hypochromia, and anisopoikilocytosis. Most individuals with alpha2 thalassemia (trait) have only mild microcytosis, which can be differentiated from other common causes of microcytosis based on serum iron and ferritin concentrations within the reference range.

TREATMENT

Section 6 of 10  

• Authors and Editors
• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Follow-up
• Miscellaneous
• Multimedia
• References

Medical Care

• Avoid iron supplementation as 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 splenectomy, and administer appropriate vaccines to these individuals.
• Administer blood transfusions only if necessary.
• If chronic transfusion is needed (hemoglobin H disease), iron chelation therapy should be considered to avoid iron overloading.

Surgical Care

• Hemoglobin H disease
• • Perform splenectomy if transfusion requirements are increasing.
  • Surgical or orthodontic correction may be necessary to correct skeletal deformities of the skull and maxilla caused by erythroid hyperplasia.

FOLLOW-UP

Section 7 of 10  

• Authors and Editors
• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Follow-up
• Miscellaneous
• Multimedia
• References

Prognosis

• The prognosis is excellent for silent carriers.
• Because hydrops fetalis is incompatible with life, hemoglobin H (--/--) is the most serious syndrome.
• The overall survival for hemoglobin H disease is variable; however, it is generally good. Many patients survive into adulthood. However, some patients have a more complicated course and may not do as well.

Patient Education

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 is especially true in cases of suspected concomitant hemoglobinopathy.

MISCELLANEOUS

Section 8 of 10  

• Authors and Editors
• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Follow-up
• Miscellaneous
• Multimedia
• References

Medical/Legal Pitfalls

Alpha thalassemia is frequently 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.

MULTIMEDIA

Section 9 of 10  

• Authors and Editors
• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Follow-up
• Miscellaneous
• Multimedia
• References

Media file 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.
	View Full Size Image
Media type:  Photo

REFERENCES

Section 10 of 10

• Authors and Editors
• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Follow-up
• Miscellaneous
• Multimedia
• References

• Arcasoy MO, Gallagher PG. Hematologic disorders and nonimmune hydrops fetalis. Semin Perinatol. Dec 1995;19(6):502-15. [Medline].
• Benz EJ. Clinical Manifestations of the thalassemias. UpToDate. 2006.
• Bernini LF, Harteveld CL. Alpha-thalassaemia. Baillieres Clin Haematol. Mar 1998;11(1):53-90. [Medline].
• Bunn HF, Forget BG. Hemoglobin. In: Molecular, Genetic and Clinical Aspects. Philadelphia, Pa: WB Saunders; 1986.
• Chui DH, Waye JS. Hydrops fetalis caused by alpha-thalassemia: an emerging health care problem. Blood. Apr 1 1998;91(7):2213-22. [Medline].
• Higgs DR. Hamm-Wasserman LectureGene Regulation in Hematopoiesis: New Lessons from Thalassemia. Hematology. 2004.
• Lee R, Foerster J, Lukens J. The thalassemias and related disorders:. In: quantitative disorders of hemoglobin synthesis. In: Wintrobe's Clinical Hematology. Philadelphia, Pa: Lippincott, Williams, and Wilkins; 1999:1405-1448.
• Schrier SL. Thalassemia: pathophysiology of red cell changes. Annu Rev Med. 1994;45:211-8. [Medline].
• Schrier SL. Pathophysiology of alpha thalassemia. UpToDate. 2006.
• Steensma DP, Gibbons RJ, Higgs DR. Acquired alpha-thalassemia in association with myelodysplastic syndrome and other hematologic malignancies. Blood. Jan 15 2005;105(2):443-52. [Medline].
• Vichinsky EP, MacKlin EA, Waye JS, Lorey F, Olivieri NF. Changes in the epidemiology of thalassemia in North America: a new minority disease. Pediatrics. Dec 2005;116(6):e818-25. [Medline].
• Weatherall DJ, Clegg JB. The Thalassaemia Syndromes Fourth Edition. 2004.
• Weatherall, DJ, Clegg, JB, Higgs, DR, et al. The hemoglobinopathies. In:. In: Scriver, CR, Beaudet, AL, Sly, WS, Valle, D (Eds). The Metabolic and Molecular Bases of Inherited Disease. 7^th edition. New York: McGraw-Hill; 1995:p.3417.
• Sgourou A, Routledge S, Antoniou M, Papachatzopoulou A, Psiouri L, Athanassiadou A. Thalassaemia mutations within the 5'UTR of the human beta-globin gene disrupt transcription. Br J Haematol. Mar 2004;124(6):828-35. [Medline].
• Schell T, Kulozik AE, Hentze MW. Integration of splicing, transport and translation to achieve mRNA quality control by the nonsense-mediated decay pathway. Genome Biol. 2002;3(3):REVIEWS1006. [Medline].
• Kazazian HH Jr, Dowling CE, Hurwitz RL, Coleman M, Stopeck A, Adams JG 3rd. Dominant thalassemia-like phenotypes associated with mutations in exon 3 of the beta-globin gene. Blood. Jun 1 1992;79(11):3014-8. [Medline].
• Chui DH, Fucharoen S, Chan V. Hemoglobin H disease: not necessarily a benign disorder. Blood. Feb 1 2003;101(3):791-800. [Medline].
• Weatherall D. The molecular basis for phenotypic variability of the common thalassaemias. Mol Med Today. Apr 1995;1(1):15-20. [Medline].
• Clegg JB, Weatherall DJ. Thalassemia and malaria: new insights into an old problem. Proc Assoc Am Physicians. Jul-Aug 1999;111(4):278-82. [Medline].

Article Last Updated: Sep 17, 2007