Thalassemia

• Thalassemia


  A generic name for a group of blood disorders
• Haemoglobin


  • Consists of two different protein chains: an alpha and a beta globin
• α-thalassemia


  A condition where the patient does not have enough alpha protein
• β-thalassemia


  A condition where there is a deficiency in the beta protein
• Types of β-thalassemia


  • Thalassemia minor
  • Thalassemia intermedia
  • Thalassemia Major (Cooley's Anaemia) - the most severe form
• Thalassemia major


  There is a complete lack of beta protein, arises from point mutations affecting m-RNA production or processing, patients develop life-threatening anaemia within a few months of birth
• Iron Overload


  Problem with regular blood transfusions - iron from the transfusion is not eliminated, ineffective erythropoiesis causes increased dietary iron absorption, iron may exceed storage capacity of ferritin resulting in free radicals that attack liver and cardiac cells

  
• Chelation Therapy


  Patients require life-long chelating agents to promote excretion of excess iron from regular blood transfusions

  
• Desferrioxamine (Desferal, DFO)


  Iron-chelating siderophore, hexadentate, forms 11 complex with iron, promotes urinary iron excretion, leads to negative iron balance but has disadvantages of high molecular weight, not orally active, requires infusion, poor patient compliance, expensive, can have detrimental effects on hearing and vision

  
• Deferiprone (Ferriprox)


  Orally active, bidentate ligand forming 13 complex, promotes urinary excretion of iron, more effective at mobilising intracellular iron than desferrioxamine but inferior iron mobilisation, less selective for iron, requires large dosage, side effects include joint pain, agranulocytosis, mild reduction in white blood cell count

  
• Deferasirox (Exjade, ICL670)


  Tridentate triazole derived from salicylic acid, forms 21 complex with iron, more effective at removing intracellular iron than desferrioxamine, long half-life allowing single daily dose, dose of 20 mg/kg/day similar reduction in serum ferritin to 40-60 mg/kg/day of desferrioxamine, side effects include GI disturbances, skin rash, kidney damage, effects on hearing and eyesight, can cause gastrointestinal bleeding

  
• Estimated Relative Costing


  • Desferrioxamine: £7,500-£22,000 p.a.
  • Deferiprone: £4,000 p.a.
  • Deferasirox: £18,000 p.a.

  
• Combined Therapies


  Desferrioxamine in combination with orally active deferiprone or deferasirox may provide effective synergistic therapies, with oral drugs promoting mobilisation of intracellular iron and desferrioxamine enhancing urinary and faecal excretion
• Desferrioxamine is not an ideal drug
• Deferiprone is an effective orally active iron chelator but long-term effectiveness and toxicity are in question

  
• Deferasirox seems to be a very effective orally-active alternative to Desferrioxamine offering new hope to β-thalassemia sufferers, but its long term effectiveness and toxicity is still in doubt, and cost will likely limit availability in the third world

  
• A bone-marrow transplant is currently the only prospect of a cure for thalassemia