Thalassemias

Overview of Thalassemias

Definition: A group of inherited (genetic) blood disorders characterized by decreased or absent synthesis of one or more of the globin chains (alpha or beta) that make up hemoglobin
Pathophysiology:
- Reduced globin chain synthesis leads to:
  - Decreased hemoglobin production, resulting in microcytic, hypochromic anemia
  - Imbalance in globin chain ratios, leading to precipitation of excess globin chains within red blood cell precursors, causing cellular damage and premature destruction (ineffective erythropoiesis)
Classification: Based on the affected globin chain:
- Alpha (α) Thalassemia: Decreased or absent synthesis of alpha-globin chains
- Beta (β) Thalassemia: Decreased or absent synthesis of beta-globin chains
Severity: Varies widely depending on the specific genetic defect and the number of affected genes

Genetics and Molecular Basis

Globin Genes:
- Alpha-globin genes: Located on chromosome 16 (two α-globin genes: αα/αα)
- Beta-globin gene: Located on chromosome 11 (one β-globin gene: β/β)
Inheritance:
- Autosomal recessive: Both parents must carry the affected gene for the child to inherit the disease
- Carriers: Individuals with one affected gene are usually asymptomatic (thalassemia trait or minor)
Mutations:
- Alpha-thalassemia: Usually caused by gene deletions
- Beta-thalassemia: Usually caused by point mutations or small insertions/deletions
Nomenclature:
- Normal: αα/αα (alpha), β/β (beta)
- Trait/Minor: α-/αα or - -/αα (alpha), β/βo or β/β+ (beta)
- Major/Disease: α-/–, –/– (alpha), βo/βo, β+/βo, β+/β+ (beta)
- Hemoglobin H disease: –/αα (alpha). Excess beta chains form HbH tetramers
- Hydrops fetalis: –/– (alpha). No alpha chains are produced, incompatible with life
- βo: No beta-globin chain production
- β+: Reduced beta-globin chain production

Alpha (α) Thalassemia

Genetic Basis: Decreased or absent synthesis of alpha-globin chains
Severity: Depends on the number of affected alpha-globin genes
Clinical Syndromes:
- Silent Carrier (αα/α-):
  - One alpha-globin gene is deleted or mutated
  - Usually asymptomatic
  - Can be diagnosed by genetic testing
- Alpha-Thalassemia Trait (α- /α- or αα/–):
  - Two alpha-globin genes are deleted or mutated
  - Mild microcytic, hypochromic anemia
  - May have slightly decreased MCV and MCH
  - Diagnosis is often made by exclusion of other causes of microcytic anemia
- Hemoglobin H Disease (–/αα):
  - Three alpha-globin genes are deleted or mutated
  - Moderate to severe microcytic, hypochromic anemia
  - Peripheral blood smear: Microcytes, hypochromia, target cells, and HbH inclusions (use brilliant cresyl blue stain)
  - HbH inclusions: Precipitated excess beta-globin chains
- Hydrops Fetalis (–/–):
  - All four alpha-globin genes are deleted or mutated
  - No alpha-globin chain production
  - Incompatible with life
  - Results in severe anemia, edema, and heart failure in the fetus
Laboratory Findings:
- CBC: Decreased HGB, HCT, and MCV
- Peripheral Blood Smear: Microcytes, hypochromia, target cells, and poikilocytosis
- Hemoglobin Electrophoresis:
  - Silent carrier: Usually normal
  - Alpha-thalassemia trait: Usually normal
  - HbH disease: Presence of HbH (fast-migrating band)
  - Hydrops fetalis: Predominantly Hb Bart’s (gamma tetramers) in fetal blood
- Iron Studies: Normal or elevated (not iron deficient)
- Genetic Testing: Confirms the diagnosis by detecting alpha-globin gene deletions or mutations

Beta (β) Thalassemia

Genetic Basis: Decreased or absent synthesis of beta-globin chains
Severity: Depends on the type of beta-globin gene mutation
Clinical Syndromes:
- Beta-Thalassemia Minor (β/βo or β/β+):
  - Heterozygous for a beta-globin gene mutation
  - Mild microcytic, hypochromic anemia
  - Often asymptomatic or mildly symptomatic
  - Peripheral blood smear: Microcytes, hypochromia, and target cells
  - Hemoglobin electrophoresis: Elevated HbA2 (3.5-7%) and slightly elevated HbF
- Beta-Thalassemia Intermedia:
  - Variable severity depending on the specific mutations
  - Moderate microcytic, hypochromic anemia
  - May require occasional blood transfusions
  - Peripheral blood smear: Microcytes, hypochromia, target cells, and nucleated RBCs
  - Hemoglobin electrophoresis: Variable increase in HbF and HbA2
- Beta-Thalassemia Major (Cooley’s Anemia) (βo/βo, β+/βo, β+/β+):
  - Homozygous or compound heterozygous for severe beta-globin gene mutations
  - Severe microcytic, hypochromic anemia
  - Requires regular blood transfusions to survive
  - Ineffective erythropoiesis leads to bone marrow expansion, skeletal deformities, hepatosplenomegaly, and iron overload
  - Peripheral blood smear: Severe microcytes, hypochromia, target cells, nucleated RBCs, and poikilocytosis
  - Hemoglobin electrophoresis: Little or no HbA, marked increase in HbF, and elevated HbA2
Laboratory Findings:
- CBC: Decreased HGB, HCT, and MCV
- Peripheral Blood Smear: Microcytes, hypochromia, target cells, basophilic stippling, and nucleated RBCs (especially in thalassemia major)
- Reticulocyte Count: Elevated (due to increased erythropoiesis)
- Iron Studies: Normal or elevated (not iron deficient)
- Hemoglobin Electrophoresis:
  - Beta-thalassemia minor: Elevated HbA2 (3.5-7%) and slightly elevated HbF
  - Beta-thalassemia intermedia: Variable increase in HbF and HbA2
  - Beta-thalassemia major: Little or no HbA, marked increase in HbF, and elevated HbA2
- Genetic Testing: Confirms the diagnosis by detecting beta-globin gene mutations

Clinical Management of Thalassemia

Beta-Thalassemia Minor:
- Usually requires no specific treatment
- Genetic counseling for family planning
- Avoid unnecessary iron supplementation
Beta-Thalassemia Intermedia:
- May require occasional blood transfusions to manage anemia
- Folic acid supplementation
- Monitoring for complications such as iron overload and splenomegaly
Beta-Thalassemia Major:
- Regular Blood Transfusions:
  - Maintain hemoglobin levels above 9-10 g/dL
- Iron Chelation Therapy:
  - To prevent iron overload from chronic transfusions
  - Deferoxamine (intravenous or subcutaneous)
  - Deferasirox or Deferiprone (oral)
- Folic Acid Supplementation
- Splenectomy:
  - May be considered to reduce transfusion requirements
  - Increases risk of infection with encapsulated organisms (e.g., Streptococcus pneumoniae, Haemophilus influenzae, Neisseria meningitidis)
  - Patients require vaccination against these organisms
- Hematopoietic Stem Cell Transplantation (HSCT):
  - Potentially curative option, especially in children
  - Requires a matched donor
General Management:
- Genetic Counseling:
  - For affected individuals and their families
  - Prenatal diagnosis and carrier screening
- Monitoring for Complications:
  - Iron overload (liver, heart, endocrine organs)
  - Infections
  - Thrombosis
  - Pulmonary hypertension
  - Endocrine dysfunction (e.g., diabetes, hypothyroidism)
New Therapies
- Gene Therapy

Key Laboratory Tests for Thalassemia

Complete Blood Count (CBC):
- HGB and HCT: Decreased
- MCV: Decreased (microcytic)
- MCH: Decreased (hypochromic)
- RBC count: May be normal or elevated relative to the degree of anemia
Peripheral Blood Smear:
- Microcytes
- Hypochromia
- Target cells
- Basophilic stippling
- Nucleated RBCs (in severe cases)
- HbH inclusions (in alpha-thalassemia)
Reticulocyte Count:
- Usually elevated (due to increased erythropoiesis)
Iron Studies:
- Normal or elevated (to rule out iron deficiency)
Hemoglobin Electrophoresis:
- Quantifies the percentages of different hemoglobin types (HbA, HbA2, HbF, HbS, HbC)
- Key for diagnosing and classifying thalassemia
Genetic Testing:
- Confirms the diagnosis and identifies specific gene mutations or deletions
Prenatal Testing:
- Chorionic villus sampling (CVS) or amniocentesis

Key Terms

Thalassemia: Inherited blood disorder with decreased globin chain synthesis
Alpha-Thalassemia: Decreased alpha-globin chain synthesis
Beta-Thalassemia: Decreased beta-globin chain synthesis
Microcytic: Small red blood cells (MCV < 80 fL)
Hypochromic: Decreased hemoglobin content (pale color)
Target Cells: Red blood cells with a bullseye appearance
Hemoglobin Electrophoresis: Technique to separate and quantify hemoglobin types
Iron Chelation Therapy: Treatment to remove excess iron
Hydrops Fetalis: Severe fetal condition with fluid accumulation
Ineffective Erythropoiesis: Premature destruction of red blood cell precursors in the bone marrow

Chronic Disease

Sideroblastic