Rbc disorders-5

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Rbc disorders-5

  1. 1. Thalassemia Syndromes Dr.CSBR.Prasad, M.D.,
  2. 2. Thalassemias• They are QUANTITATIVE defects in globin chain synthesis• Heme synthesis is normal
  3. 3. Name some diseases involving heme synthesis? Porphyrias
  4. 4. Cooley’s anemia
  5. 5. Usual types of HGBs in adults• Different types of HGBs seen in adults – Hb A (α2 β2) (97%) – Hb A2 (α2 δ2) (1.5-3.5%) – Hb F (α2 γ2) (<1%)
  6. 6. Fetal hemoglobin - HbF• The main oxygen transport protein in the fetus during the last seven months of development in the uterus and• After birth HBF levels gradually fall reaching adult levels by the age of 6-9 months
  7. 7. Oxygen dissociation curve
  8. 8. Facial abnormalities
  9. 9. Organomegaly
  10. 10. Hemoglobin• HbA (α2β2)• FOUR α-globin genes on chr 16• TWO β-globin gene on chr 11
  11. 11. Globin genes
  12. 12. Thalassemia• Inherited genetic disorder of globin chain synthesis of HbA (α2β2)• AR• Decreased synthesis may involve α or β globin chain  α-Thalassemias [↓ α-chain]  β-Thalassemias [↓ β-chain]
  13. 13. Normal HGB• Hb A - α2β2• α : β = 1:1 (+/- 0.05)• Disproportionate synthesis is associated with relative excesses of the other
  14. 14. Figure 1. The two chromosomes #11 have one beta globin gene each (for a total of two genes). The two chromsomes #16 have twoalpha globin genes each (for a total of four genes). Hemoglobin protein has two alpha subunits and two beta subunits. Each alpha globingene produces only about half the quantity of protein of a single beta globin gene. This keeps the production of protein subunits equal. Thalassemia occurs when a globin gene fails, and the production of globin protein subunits is thrown out of balance.
  15. 15. Thalassemia• Low HGB levels• Relative excess of unimpaired chains form insoluble inclusions  Hemolysis
  16. 16. β-Thalassemia
  17. 17. β-Thalassemia• ↓ Synthesis of structurally normal β globin chain with unimpaired synthesis of α globin chain• β globin chain is coded by two globin genes located on Ch 11• α globin chain is coded by two pairs of globin genes located on Ch 16
  18. 18. β-Thalassemia• β0 Thalassemia – Total absence of β globin chain in homozygous state• β+ Thalassemia – reduced β globin chain synthesis in homozygous state
  19. 19. β-Thalassemia• More than 100 different causative MUTATIONS• Point mutations – most common• Promoter region mutations – Reduces transcription rate by 75-80% - Β+ Thalassemia• Chain terminator mutation – Premature chain termination - Β0Thalassemia• Splicing mutation – More common cause of Β+ Thalassemia
  20. 20. β-Thalassemia• Thalassemia major – Homozygous for β-Thalassemia genes – Genotype β0 / β0 or β+ / β+ – Severe tranfusion dependent anemia• Thalassemia minor – Heterozygous with one thalassemia gene and one normal gene β0 / β or β+ / β• Thalassemia intermedia – Genetically heterogenous group with milder variant of β0 / β0 or β+ / β+ and severe form of heterozygous thalassemia β0 / β or β+ / β
  21. 21. Thalassemia major• Mediterranean, Africa and south east Asia• Manifest 6-9 months after birth• Hb – 3-6 gm/dl• PBS – Anisocytosis - microcytes, – poikilocytosis, target cells, basophilic stippling, fragmented RBC, NRBCs – Reticulocytosis – ↑ ↑ Hb F – Hb A2 - N, ↑, ↓
  22. 22. Transfusion dependent anemia
  23. 23. Hereditary - AR
  24. 24. Microcytic hypochromic RBCs
  25. 25. Target cells
  26. 26. NRBs and Punctate basophilia
  27. 27. Thalassemia major• Morphology• Bone marrow hyperplasia – “CREW CUT” appearance on skull X ray• Splenomegaly – upto 1500 gms• Hemosiderosis and secondary hemochromatosis – due to repeated blood transfusion and ↑ absorption of dietary iron – affects heart, liver and pancreas• Early death in untreated cases
  28. 28. “CREW CUT” appearance on skull X ray
  29. 29. Thalassemia minor• More common• Heterogenous carrier of β0 or β+ gene• Asymptomatic / mild anemia• PBS – Microcytic hypochromic RBCs, basophilic stippling• ↑ Hb A2 ; 4-8% (N 2.5%)• DD – Iron deficiency anemia
  30. 30. α Thalassemia
  31. 31. Demographics: Thalassemia• Found most frequently in the Mediterranean, Africa, Western and Southeast Asia, India and Burma• Distribution parallels that of Plasmodium falciparum
  32. 32. Classification & Terminology Alpha Thalassemia• Terminology • Silent carrier • Minima • Minor • Intermedia • Major
  33. 33. Symbolism Alpha Thalassemia• Greek letter used to designate globin chain: 
  34. 34. Symbolism Alpha Thalassemia/ : Indicates division between genes inherited from both parents: /• Each chromosome 16 carries 2 genes. Therefore the total complement of  genes in an individual is 4
  35. 35. Symbolism Alpha Thalassemia- : Indicates a gene deletion: -/
  36. 36. Classification & Terminology Alpha Thalassemia• Normal /• Silent carrier - /• Minor -/- --/• Hb H disease --/-• Barts hydrops fetalis --/--
  37. 37. Symbolism Other Thalassemia• Greek letter used to designate globin chain: 
  38. 38. Symbolism Other Thalassemia+:Indicates diminished, but some production of globin chain by gene: +
  39. 39. Symbolism Other Thalassemia0 :Indicates no production of globin chain by gene: 0
  40. 40. Symbolism Other ThalassemiaSuperscript T denotes nonfunctioning gene: T
  41. 41. Classification & Terminology Beta Thalassemia• Normal /• Minor /0 /+• Intermedia 0/+• Major 0/0 +/+
  42. 42. Special Cases Thalassemia• Hb Lepore:  fusion seen in some types of  thalassemia• Hb Constant Spring •  chain with 31 additional amino acids • --/cs• Hereditary persistence of fetal hemoglobin (HPFH)
  43. 43. Special Cases: Thalassemia• Hb H • 4 tetramer • Associated with --/- thalassemia
  44. 44. Special Cases: Thalassemia• Hb Barts & hydrops fetalis • Barts is a 4 tetramer • Associated with --/-- • Lethal • High concentrations are capable of sickling
  45. 45. Different types of HGBs seen in adults• Hb A (α2 β2) 97%• Hb A2 (α2 δ2) (1.5-3.5%)• Hb F (α2 γ2) <1%• Adult HbH (β4)• Neonate Barts (γ4)
  46. 46. α Thalassemia• Reduced or absent synthesis of α globin chains• Excess of non α chain –ß, γ, δ – Hb A (α2 β2) – Hb A2 (α2 δ2) – Hb F (α2 γ2)
  47. 47. α Thalassemia• New born – formation of γ4 tetramer – Hb Barts• Adults – ß4 tetramer – HbH• Free ß, & γ chains are more soluble than α chains – hemolysis is less severe
  48. 48. α Thalassemia• Sevearity varies depending on number of α globin genes affected• DELETION of α- globin genes are more common• Hydrops fetalis -/- -/-• HbH disease -/- -/ α• α Thalassemia trait -/- α/ α (asian) -/ α -/ α ( black african)• Silent carrier -/ α α/ α
  49. 49. Figure 3. People of Asian ancestry oftenhave two alpha globin genes deleted on the same chromosome #16. The parents eachhave the mild thalassemia that results with two functioning alpha globin genes. The offspring that inherits the double deletion from one parent and the single from the other will have Hemoglobin H disease(Scenario 1). The offspring who inherits no alpha genes from the parents dies in utero (Scenario 2; hydrops fetalis).
  50. 50. Figure 4. People ofAfrican ancestry usually have only one alphaglobin gene deleted per chromosome. The parents each have the mild thalassemia that results with two functioning alpha globin genes. The offspring can, at most, inherit the relatively mild condition of the parents.
  51. 51. Hb H disease• Tetramer of β globin chain• High affinity for oxygen• Unstable HbH form precipitates• Resemble β-Thalassemia intermedia
  52. 52. HBH inclusions
  53. 53. HPLC pattern of a patient with HbH disease. The peaks of the different hemoglobins are indicated
  54. 54. Hydrops fetalis• Hb barts – tetramer of γ globin chains• ζ2 γ2 -Severe tissue anoxia• Pallor, generalised edema, massive hepatosplenomegaly• High mortality
  55. 55. Hydrops fetalis
  56. 56. Other causes for Hydrops fetalis• Rh incompatibility• Hypoplastic left heart syndrome
  57. 57. Common mechanism• Alfa thal- Deletion• Beta thal – Mutation
  58. 58. Gamma gene can be induced to function by some drugs• What is the clinical implication of this finding?
  59. 59. END
  60. 60. Dr.CSBR.Prasad, M.D.,Associate Professor of Pathology,Sri Devaraj Urs Medical College, Kolar-563101, Karnataka, INDIA. csbrprasad@reiffmail.com

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