Thalassemia: Types, Causes, and Genetics

Thalassemias

• These are inherited disorders caused by mutations in globin genes
• The mutations lead to decreased synthesis of α- or β-globin
• Classified as α- or β-thalassemias based on whether the genetic defect or deletion affects α- or β-globin chain genes

α-Thalassemia

• α chains are encoded by two α-globin genes on chromosome 16
• Caused by defective synthesis of α-globin chains, resulting in impaired production of α-chain-containing hemoglobins (HbA, HbA2, HbF)
• Typically caused by deletions involving one or more α-globin genes

α-Thalassemia Types

• Hydrops fetalis: Hb Barts (g₄) is 100%, deletion of four α-genes, and is fatal in utero or in early infancy
• Hb-H disease: HbF is 10%, HbH is 2-4%, deletion of three α-genes, and results in haemolytic anaemia
• α-Thalassaemia trait: Almost normal, deletion of two α-genes, results in Microcytic/hypochromic blood and no anaemia

β-Thalassemia

• β chains are encoded by a single β-globin gene on chromosome 11
• Mutations disrupt β-globin synthesis in various ways
• Defective β-globin synthesis contributes to anemia through inadequate HbA formation and accumulation of unpaired α-globin chains that form toxic precipitates
• These precipitates damage red cell membranes and erythroid precursors

β-Thalassemia Types

• Homozygous form (β-Thalassaemia major): The most severe form of congenital hemolytic anemia, characterized by complete absence or incomplete suppression of β-chain synthesis
• β-Thalassaemia intermedia: Intermediate severity, regular blood transfusions not required
• Heterozygous form (β-thalassaemia minor) (trait): Mild, usually asymptomatic, with moderate suppression of β-chain synthesis

β-Thalassaemia Major

• Also known as Mediterranean or Cooley’s anaemia
• The most common form of congenital haemolytic anaemia
• Characterized by excessive formation of alternate hemoglobins, HbF and HbA2

β-Thalassaemia Major Lab Findings

• Severe anaemia
• Blood film shows marked microcytosis, hypochromia, poikilocytosis, anisocytosis, and nucleated red cells
• Serum bilirubin (unconjugated) is generally raised
• Reticulocytosis present
• MCV, MCH, and MCHC are significantly reduced
• Normal platelet count
• Haemoglobin electrophoresis shows increased HbF and HbA2, with almost complete absence/variable amounts of HbA
• Bone marrow aspirate examination shows normoblastic erythroid hyperplasia

β-Thalassemia Minor

• Characterized by moderate reduction in β-chain synthesis

β-Thalassemia Minor Lab findings

• Mild anaemia; MCV, MCH, and MCHC may be slightly reduced
• Blood film shows small (microcytic) and pale (hypochromic) red cells, target cells, and mild anisopoikilocytosis
• Serum bilirubin may be normal or slightly raised
• Mild reticulocytosis may be present
• Haemoglobin electrophoresis shows increased HbA2 and a slight elevation in HbF

Paroxysmal Nocturnal Haemoglobinuria (PNH)

• A hemolytic anemia from acquired mutations in PIGA, a gene for phosphatidylinositol glycan (PIG) synthesis
• PIG serves as a membrane anchor for many proteins
• The PIGA gene is X-linked
• Pathogenic mutations occur in an early hematopoietic progenitor
• This capable of giving rise to red cells, leukocytes, and platelets
• PIGA-deficient red cells are sensitive to lysis by the complement C5b-C9 membrane attack complex

Myelophthisic Anemia

• Marrow failure where space-occupying lesions replace normal marrow elements
• Causes include haematologic malignancies (leukemia, lymphoma, myeloma) and metastatic deposits from non-haematologic malignancies (breast, stomach, prostate, lung, thyroid cancer)
• Result from advanced tuberculosis

Aplastic Anaemia

• Defined as pancytopenia (anaemia, leucopenia, and thrombocytopenia) resulting from aplasia of the bone marrow
• More than half of cases are idiopathic
• Cases with known cause are classified into primary and secondary types

Primary Aplastic Anaemia

• Includes Fanconi’s anaemia and immunologically-mediated acquired form

Secondary Aplastic Anaemia

• More common than primary
• Causes include drugs (antimetabolites like methotrexate, alkylating agents like busulfan), toxic chemicals (benzene derivatives, insecticides), and infections (viral hepatitis, AIDS)

Aplastic Anaemia Lab Findings

• Haemoglobin levels are moderately reduced, resulting in anaemia
• Reduced or zero reticulocyte count
• Leucopenia present
• Thrombocytopenia always present, lowers platelet count
• Bone marrow aspirate may yield a 'dry tap'

Polycythemia

• Characterized by an abnormally high number of circulating red cells, usually with a corresponding increase in hemoglobin level

Classifications of Polycythemia

• Relative: Reduced plasma volume (hemoconcentration)
• Absolute Includes primary and secondary: Includes
  • Primary: caused by polycythemia vera and inherited erythropoietin receptor mutations
  • Secondary: Compensatory such as in lung disease , high altitude living and cyanotic heart disease; also paraneoplastic, such as from erythropoietin-secreting tumors