Anemia – Part 4 – Thalassemia, Discussion and Work Up

Thalassemia
History of Thalassemia
- Thalassemia derives from the combination of the Greek word Thalassa means sea, Haima means blood.
- This was known as Mediterranean anemia because of the most common occurrence in the Mediterranean population.
- This is characterized by a decreased rate of production of globin chains. These are classified according to the globin which is involved.
- The consequence is defective globin chain production.
- To understand thalassemia, we need to discuss and understand the structure of the Hemoglobin:
- The normal globin, which is part of the hemoglobin, consists of 2 alpha chains and 2 beta chains.
- Genetic code is located on chromosomes 11, are γ, δ, ε, and β-chains.
- While on chromosome 16, there are α and ζ loci.
- Thalassemia syndrome may occur because of the abnormality of:
- Coding sequence.
- Transcription.
- Processing or defects in gene translation.
Various types of hemoglobin:
Type of hemoglobin Genotype of hemoglobin Functions of the hemoglobin Hb A α2β2 This is the main adult Hb Hb A2 α2/δ2 This is present in a small amount Hb F α2/γ2 Main fetal Hb in late stages Hb gower1 ζ2/ε2 This Hb is present in the early life of the fetus Hb gower2 α2/ε2 This Hb is present in a small amount in the early fetal life
Classification of the Thalassemia:
Alpha- thalassemia:
- α-thalassemia is usually manifested immediately after birth or even in utero because the α-gene is activated early in fetal life.
- α-thalassemia has a wide range of clinical presentations.
- Chromosome 16 carries 2 α genes, and the total will be 4 α-genes. This will vary the severity of the diseases, depending upon one: two, three, or four genes affected in one patient.
- Another feature of α-thalassemia is that decreased or absent α-gene production will result in more than γ-chain during fetal life and at birth and excess of β–chain later on. This will lead to stable tetramers, γ4 (Hb Bart’s) and β4 (Hb H). Hemoglobin Bart’s and H precipitate in the older RBCs. These may lead to hemolytic crises by infection. This abnormal hemoglobin can be detected by electrophoresis.
- α-thalassemia minor, there is decreased production of the α-chain (α+ -α / ββ).
- One α-globin gene is affected = -α/αα.
- These are the silent carrier, and there is no marked anemia.
- MCV will be normal to decrease slightly.
- Hb H (1% to 2%) is present at birth which disappears later on.
- α-thalassemia trait, 2 α-globin genes are affected = α-/α- or αα/–.
- RBCs show microcytosis and hypochromic anemia.
- MCV is <70fl.
- There is mild anemia.
- Serum electrophoresis showed 5% to 10% Hb H (4 β) at birth, which will disappear later on.
- α-thalassemia major is Hb H disease.
- Three α-globin genes are affected = α-/–.
- There is microcytic, hypochromic anemia.
- MCV is <70 fl.
- Serum electrophoresis showed predominantly Hb Bart’s, and this consists of 4 gamma chains at birth.
- There is a gradual shift to Hb H 5% to 30% over the first few months of life.
Alpha-thalassemia Characteristic features:
Clinical features | Genotype structure | Electrophoresis pattern | Peripheral blood smear |
Normal | αα/αα | Normal | Normal picture |
α-Thalassemia carrier | -α/αα | Normal | Normal picture, asymptomatic |
α-thalassemia trait | -α/-α or –/αα | Normal | Mild hypochromasia and microcytosis |
α-thalassemia major | –/-α | Shows Hb H (β4) | Severe hypochromasia and microcytosis |
Hydrops fetalis | –/– | Shows Hb Bart’s (γ4) | Severe hypochromasia and microcytosis |
- Clinical features of alpha-thalassemia:
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- In case of loss of all 4 α-genes, it is incompatible life and leads to the fetus’s death (hydrops fetalis).
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- Microcytic hypochromic anemia with splenomegaly. This is known as Hb H disease because of the presence of the Hb H (β4). This Hb can be found on electrophoresis.
- In fetal life, Hb Bart’s is seen.
- α-Thalassemia trait is caused by the loss of one or two α-genes are not usually associated with anemia, but MCV and MCH are low.
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Beta-thalassemia:
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- Definition:
- There is decreased production of the β-chain (α2 / β0 β0). There is a globin gene mutation that causes partial β-gene or total β-gene chain loss.
- The number of genes affected, partial or complete, will determine the severity of the disease.
- There is an increase in the production of γ-chains and δ-chains, resulting in an increased level of Hb F and Hb A2.
- There is the replacement of the β chain by the 2-γ chain, which will form Hb F, and the other replaced by δ-chains will form Hb A2.
- β-thalassemia minor where single β-gene is affected (β0/β).
- There is mild anemia Hb 9 to 11 g/dL or no anemia.
- Normal to increased RBC count.
- RBCs are microcytes, MCV 60 to 70 fl.
- Electrophoresis shows a mild increase in the Hb F and Hb A2 (3% to 8%).
- β-thalassemia intermedia is most commonly caused by partial deletion of β0 of both beta genes.
- These are homozygous (β+β+) genes.
- It will give a wide spectrum of the disease with moderate to severe anemia, and Hb will be 6 to 10 g/dL.
- There are growth retardation and bony abnormalities.
- This usually occurs later than the thalassemia major type.
- Electrophoresis shows Hb F 20% to 40% and increased Hb A2, 3% to 8%.
- β-thalassemia major are usually homozygous (β0β0):
- β0β0-thalassemia is a more severe variant. No β-chains are synthesized.
- No Hb A found on electrophoresis.
- Only HbF (>90%) and HbA2 (3% to 8%) are found.
- This is also called Cooley anemia.
- There is marked microcytosis and hypochromasia.
- MCV is <70 fl and Hb is 2 to 3 g/dL.
- There is hepatosplenomegaly, bony deformities, and failure to thrive as an infant.
- These patients are dependent upon blood transfusion.
- Another classification:
- β0+ shows a complete absence of the production of the beta chains.
- This is found in the Mediterranean area, particularly in Northern Italy, Greece, Algeria, Suadi Arabia. and Southeast Asia.
- β+-thalassemia is less severe.
- There are three groups of this gene rearrangement.
- 1β+ thalassemia gene produces less amount of the beta-chain around 10% of normal production. This group is found throughout the Mediterranian region, middle east, Indian subcontinent, and Southeast Asia.
- 2β+ thalassemia gene produces more amount fo the beta-chain around 50% of the normal population. This is found in the blacks of North America and West Africa.
- 3β+thalassemia gene produces even more amount of beta chains and gives rise to milder disease. It is found particularly in Italy, Greece, and the Middle east.
- Severe thalassemia is called thalassemia major.
- Sever hypochromic, and microcytic anemia develops during the first year of life.
- Hemoglobin is <7 g/dL and consists mostly of HbF and HbA2.
- Homozygous type 2 and 3 beta+ causes a milder form of the thalassemia called thalassemia intermedia.
- The heterozygous beta-thalassemia gene causes a milder form of anemia.
- This also shows mild hypochromasia, and microcytosis called thalassemia minor.
- The heterozygous beta-thalassemia gene causes a milder form of anemia.
- The minor group may show delta-chain abnormality.
- Severe thalassemia is called thalassemia major.
- β0+ shows a complete absence of the production of the beta chains.
- Beta-delta thalassemia (δβ) is another occasional form of thalassemia characterized by the combined defect in δ and β chain synthesis.
- This group may have a normal level of Hb A2 and usually a high level of Hb F in the heterozygote, and absent Hb A and A2 in the homozygote.
- δβ-thalassemia can be divided into two groups according to Hb F found:
- If γ-gene is active, then that group is called GγAγδβ thalassemia.
- Another type that has inactive γ, δ, and β genes is called Gγδβ thalassemia.
Clinical features of beta-thalassemia:
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- In beta-thalassemia major, there is severe anemia, which appears at 3 to 6 months after birth.
- There is an enlargement of the liver and spleen due to increased destruction of the RBCs, intramedullary hemopoiesis, and later on by the iron overload.
- Splenomegaly needs more blood and increases RBC destruction and pooling.
- Bone marrow hyperplasia in thalassemia leads to thalassemic face. There is thinning of the cortex, which may lead to bone fractures.
- X-rays may show the bossing of the skull and typically a hair-on-end appearance.
Lab findings of beta-thalassemia:
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- Low Hemoglobin.
- The peripheral blood smear shows Hypochromic and microcytic anemia.
- Hb electrophoresis confirms the diagnosis by the near absence of the decreased level of Hb A.
Hemoglobin on electrophoresis is different in different types of thalassemia.
Patient | % of the type of Hemoglobin |
Normal newborn |
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Infant 6 months of age |
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Normal adult |
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Alpha thalassemia |
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Beta thalassemia |
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Thalassemia types:
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- α-Thalassemia trait is due to double gene deletion.
- There are microcytes and hypochromasia.
- α-Thalassemia disease is due to three gene deletion.
- There are target cells, ovalocytes, microcytes, and Hb H inclusion in the RBCs.
- β-Thalassemia in heterozygotes and there is β gene deletion alone or combined with the δ gene.
- There are microcytes, target cells, elliptocytes, and basophilic stippling.
- β-Thalassemia in homozygotes and there is β gene deletion either alone or in combination with the δ gene.
- It is marked hypochromasia with polychromatic rims. There are target cells, ovalocytes, basophilic stippling, and HbH crystals.
- α-Thalassemia trait is due to double gene deletion.

Beta-Thalassemia smear
Beta-thalassemia differential diagnosis:
Characteristics | Homozygous | Heterozygous |
Hemoglobin | 2 to 5 g/dL | 9 to 11 g/dL |
RBC morphology |
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Reticulocytes count | ≥15% | It is mildly elevated. |
Platelets |
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WBC count |
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Bone marrow |
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Hb A2 | Variable | 3.5 to 7% |
Hb F | 10 to 90% |
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Storage iron |
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Treatment of thalassemia major:
- These patients survive by the blood transfusion. It is tried to maintain the hemoglobin levels over 10 g/dL.
- It usually requires 2 to 3 units every 4 to 6 weeks.
- Fresh blood, filtered to remove white blood cells, gives the best RBCs survival and fewer reactions.
- 500 mL of blood contains 250mg of iron.
- Regularly give the folic acid 5 mg/day.
- There is a complication of the iron overload, which needs chelating therapy to control the iron overload.
- Deferoxamine is the most common drug used for the chelation of iron.
- This can be given 1 to 2 mg with each unit of the blood.
- Give subcutaneously 40 mg/kg over 8 to 12 hours, 5 to 7 days weekly.
- This should be started in infants after the 10- to 15 units of the blood transfusion.
- Excess iron causes skin pigmentation and damages the heart.
- Assessment of the iron status, advises:
- Serum ferritin.
- Serum iron.
- % saturation of transferrin.
- Serum non-transferrin bound iron.
- Bone marrow biopsy for reticuloendothelial stores by Perl’s stain.
- Liver biopsy for parenchymal and reticuloendothelial stores.
- Assessment of the tissue damage caused by the iron overload:
- For heart damage by iron advice:
- X-ray chest.
- ECG, 24 hours monitoring.
- Echocardiography.
- Radionuclide scan to check left ventricular ejection.
- For liver damage by the iron advice:
- LFT.
- Liver biopsy.
- CT scan or MRI.
- For endocrine glands damage caused by iron, advice:
- Glucose tolerance test.
- Pituitary gonadotropin release test.
- Growth hormone assay.
- Radiology of the bones.
- Isotope bone density study.
- Functional tests of the thyroid, parathyroid, adrenal, and gonadal glands.
- For heart damage by iron advice:
- Vitamin C 200 mg/day. This will help in the excretion of iron produced by deferoxamine.
- Immunization against the Hepatitis B virus.
- Allogenic bone marrow transplantation will give a permanent cure.
- Infections are quite common in these patients and need treatment by antibiotics.