Hemoglobinopathies

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    Thalassemia

    • Introduction:
      • Common in african americans and mediterraneans.
      • Defects in production of various hemoglobin molecules. 
      • Genes:
        • 4 α-globin --> 2 copies on chromosome 16 (x2 alleles) 
        • 2 β-globin --> 1 copy on chromosome 11 (x2 alleles)
        • 2 γ-globin --> 1 copy (x2 alleles)
        • 2 δ-globin --> 1 copy (x2 alleles)
      • Types of Hemoglobin in RBC's:
        • Fetal hemoglobin = HbF (2α, 2γ), switches to Adult at 3-6mo of life.
        • Adult hemoglobin = HbA (2α, 2β) and HbA2 (2α, 2δ)
          • Typically 97% is HbA, and ~3% is HbA2
    • HbA constitutes 97% of adult hemoglobin

    • HbA2 constitutes 3% of adult hemoglobin 

    • Thalassemia
      • Defect in one or more Hb genes.
      • Number of genes affected = severity of disease.
        • Ineffective erythropoeisis (production)
        • Intravascular hemolysis
    • Divited into:
      • alpha and beta thalassemia
    • Chromosome 16: two duplicated copies of alpha-chain.
    • Labs:
      • Microcytic, hypochromic erythrocytes + target cells (targets look like vases)
      • To distinguish from Iron Deficiency Anemia: Look at RDW:
        • RDW is high in Iron Deficiency Anemia (large variety of sizes/shapes of RBC)
        • RDW is normal in thalassemia.
        • Can actually measure Mentzer Index (1973)  MCV / Erythrocyte-count = ..
          • > 13 = Iron Deficiency
          • < 13 = Thalassemia (RBC count preserved, so lower ratio)
    • Treatment:
      • Can absorb iron well, can develop overload.

     

     

    Syndrome e Symptoms Treatment

    α-Thalassemia Silent

    (-α/αα)

    [1-gene deletion]

    Medeterranean

    +

    African &

       SE Asia

     

    (Also, Middle-

    Eastern)

    Asymptomatic, clinically silent. None

    α-Thalassemia Minor

    (-α/-α) or (--/αα)

    [2-gene deletion]

    (2-3% of all blacks)

    Asymptomatic, mild microcytic anemia, low MCV.

    Often mistaken for iron deficiency, but iron studies = normal.

    Electropheresis is normal! (no substitution happens)

    None

    Hemoglobin H Disease

    (--/-α)

    "β4 tetramers"

    [3-gene deletion]

    Mod-to-Severe Anemia, low MCV, splenomegaly

    Electropheresis: Detects HbH

    Intermittent transfusion

    Hemoglobin Barts (--/--)

    [4-gene deletion]

    Lethal in utero (Hydrops Fetalis)

    In utero transfusion?

    β-Thalassemia Minor

    (- β)

    [1-gene deletion]

    Medeterranean

    (also SE Asia,

    India, Pakistan)

    Asymptomatic, mild microcytic anemia (Hb=90-140 g/L)

    (Hypochromia, target cells)

    - Electropheresis helpful --> instead of β chains,

      make δ and γ as substitution.

       - Shows increased HbA2 (α2δ2) and HbF (α2γ2)

    None

    β-Thalassemia intermedia

    (mild form of β-Thal Maj)

    Moderate to severe anemia, iron overload

    - Severity depends on degree of β expression.

    Intermittent transfusion,

    iron chelation

    β-Thalassemia major

    (- -) or (β°)

    [2-gene deletion]

    Severe anemia, poor growth, skeletal abnormalities,

    iron overload.  Hemolysis, underproduction, increased HbF.

    Hb = 40-60 g/L

    - Lifelong Transfusions,

    - Iron chelation

    (deferoxamine),

    - Splenectomy to decr

    transfusion requirements

    - HSCT

     

    (Information to make this table came from MKSAP 16 from ACP).

     

    Beta Thalassemia

    • Types:
      • Minor - Asymptomatic
      • Intermedia - Mild anemia
      • Major - SEVERE (poor growth, skeletal abnormalities, iron overload)
    • Labs:
      • Hemoglobin electrophoresis
        • Hemoglobin A
        • Hemoglobin A2 (elevated, diagnostic)
        • Hemoglobin F (residual)
    • Low-level hemolysis typically occurs
    • Generally deficient in folate
    • (TODO: management)

    Other Hemoglobinopathies

    • Examples (there are hundreds!)
      • Hemoglobin E (from SE Asia)- Heterozygous:  Microcytosis.
      • Hemoglobin E and B-Thal -> Variable based on mutations
      • Hemoglobin C - Target cells, normal Hb.
        • If inherited with Hemoglobin S (SC)  - sickling occurs.
      • Hemoglobin D
        • HbDD or HbAD (homozygous or heterozygous) do not cause hemolysis
        • Co-inheritance with S = sickling syndrome. 
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