Thalassemia Anemia

Snapshot

•  A 22-year-old Vietnamese woman presents for a routine gyn exam. Her menstrual cycle is normal, and there is no evidence of other bleeding. Guaiac is negative. Her hemoglobin is at 11 (12-16), RBC is 5.8 (3.5-5.5), and an MCV of 70 (80-100) with a normal RDW of 10. WBC and platelets are normal. Hemoglobin electrophoresis shows an increase in the amount of Hgb A2, and Hgb F.

Introduction

• Autosomal recessive disease caused by decreased production of hemoglobin
  • may involve mutations in α (α-thalassemia) or β (β-thalassemia) globin gene
• There are 4 α genes (2 on each chromosome) and 2 β genes that make up three forms of Hgb
  • Hgb A
    • subunits: α,α,β,β
    • 96-98% of adult hemoglobin
  • Hgb A2
    • subunits: α,α,δ,δ
    • present in trace amounts in adults.
  • Hgb F
    • subunits: α,α,γ,γ
    • declines in the first year of life
    • cannot bind 2,3 DPG so has a left-shifted curve
• α-thalassemia types
  • 1 gene deletion is asymptomatic
  • 2 gene deletion is associated with a mild anemia with RBC hyperplasia
    • called α-thalassemia trait
    • seen in Asians and Africans
      • Asians more commonly have a deletion of two α genes on 1 chromosome (cis deletion)
      • Africans more commonly have a deletion of 1 α gene from each chromosome (trans deletion)
  • 3 gene deletion is associated with severe anemia
  • 4 gene deletion is not compatible with life
    • will cause hydrops fetalis
• β-thalassemia types
  • 1 gene involvement
    • called β-thalassemia minor 
    • chain may be truncated (β⁺) or deleted (β⁰)
    • β/β⁺ is the most benign form
    • may be caused by mutation in Kozak consensus sequence
  • 2 gene involvement
    • called β-thalassemia major 
    • β⁰/β⁰ is the most severe form
• α,α,α,α hemoglobin present

Presentation

• Symptoms
  • α-thalassemia
    • mild anemia in 2 gene deletion
    • severe anemia in 3 gene deletion
      • symptoms being at birth
  • β-thalassemia 
    • minor form
      • largely asymptomatic 
    • intermedia form
      • hypochromic, microcytic anemia 
    • major form
      • severe anemia
      • symptoms begin after several months of life due to initial presence of HbF
      • chipmunk facies
        • secondary to extramedullary hematopoiesis in the skull
• Physical exam
  • β-thalassemia
    • major form
• hepatosplenomegaly due to chronic hemolysis, additionally exacerbated by extramedullary hematopoiesis in these organs

Evaluation

• Peripheral smear
  • 3 gene deletion α-thalassemia
    • target, hypochromic, microcytic cells, with Heinz bodies from HbH
  • β-thalassemia minor
    • target, hypochromic, microcytic cells
  • β-thalassemia major
    • nucleated RBCs
    • target, hypochromic, microcytic cells
• Hemoglobin gel-electrophoresis
  • α-thalassemia trait
    • normal
  • 3 gene deletion α-thalassemia
    • HbH (β,β,β,β)
  • 4 gene deletion α-thalassemia
    • Hb Barts (γ,γ,γ,γ)
  • β-thalassemia minor 
    • ↑ HbA₂, HbF
    • ↓ HbA
  • β-thalassemia major
    • ↑ HbA₂, HbF
    • no HbA
• Imaging 
  • β-thalassemia major
    • hair-on-end/crew cut appearance of the skull
• secondary to extramedullary hematopoiesis in the skull

Treatment

• β-thalassemia major 
  • frequent transfusions required
• can cause iron overload and hemochromatosis

Prognosis, Prevention, and Complications

• β-thalassemia major
  • ↑ risk of B19-mediated aplastic crises
• Thalassemia trait 
• protects against malaria