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Hematology

Hemoglobinopathies

Overview of Hemoglobinopathies

  • Definition: A group of inherited (genetic) disorders characterized by abnormalities in the structure or synthesis of hemoglobin (HGB)
  • Genetic Basis: Caused by mutations in the genes encoding the globin chains (alpha, beta, gamma, delta) of the hemoglobin molecule
  • Classification:
    • Structural Hemoglobin Variants: Abnormal hemoglobin molecules due to amino acid substitutions or other structural changes in the globin chains (e.g., Hemoglobin S, Hemoglobin C)
    • Thalassemias: Reduced or absent synthesis of one or more globin chains (see separate study guide on Thalassemias)
  • Prevalence: Common worldwide, particularly in populations from Africa, the Mediterranean, the Middle East, and Asia
  • Clinical Significance: Can range from asymptomatic to severe, life-threatening conditions depending on the specific mutation and its effect on hemoglobin function and RBC survival

Normal Hemoglobin Structure and Types

  • Hemoglobin (Hb): A tetrameric protein found in red blood cells (RBCs) that is responsible for oxygen transport
  • Structure:
    • Composed of four globin chains (two alpha-like and two beta-like)
    • Each globin chain contains a heme molecule, which contains an iron (Fe2+) atom that binds to oxygen
  • Normal Hemoglobin Types:
    • Hemoglobin A (HbA): α2β2 (two alpha and two beta chains). Predominant hemoglobin in adults (95-98%)
    • Hemoglobin A2 (HbA2): α2δ2 (two alpha and two delta chains). Minor component in adults (2-3%)
    • Hemoglobin F (HbF): α2γ2 (two alpha and two gamma chains). Predominant hemoglobin in fetuses and newborns. Normally <1% in adults

Structural Hemoglobin Variants

  • Hemoglobin S (HbS) - Sickle Cell Anemia
    • Genetic Defect:
      • A point mutation in the β-globin gene on chromosome 11
      • Substitution of valine for glutamic acid at the 6th position of the beta-globin chain (β6 Glu→Val)
    • Pathophysiology:
      • Under conditions of low oxygen tension, HbS molecules polymerize, forming long fibers that distort the RBC into a sickle shape
      • Sickled RBCs are rigid, less deformable, and prone to:
        • Vaso-occlusion: Blockage of small blood vessels, leading to tissue ischemia and pain
        • Hemolysis: Premature destruction of sickled RBCs in the spleen
    • Clinical Features:
      • Sickle Cell Trait (HbAS):
        • Heterozygous for HbS (one normal beta-globin gene and one HbS gene)
        • Usually asymptomatic
        • May experience hematuria or splenic infarction at high altitudes or during extreme exercise
      • Sickle Cell Anemia (HbSS):
        • Homozygous for HbS (two HbS genes)
        • Severe chronic hemolytic anemia
        • Vaso-occlusive crises: Painful episodes caused by blockage of blood vessels
        • Acute chest syndrome: Vaso-occlusion in the lungs, leading to chest pain, fever, and respiratory distress
        • Stroke: Vaso-occlusion in the brain
        • Splenic sequestration: Sudden pooling of blood in the spleen, leading to severe anemia and hypovolemic shock
        • Aplastic crisis: Temporary cessation of erythropoiesis due to parvovirus B19 infection
        • Chronic organ damage: Affects the lungs, kidneys, heart, and bones
    • Laboratory Findings:
      • CBC:
        • HGB: Decreased (6-8 g/dL in HbSS)
        • HCT: Decreased
        • MCV: Normal or slightly increased
        • MCH: Normal or decreased
        • MCHC: Increased (often > 36 g/dL)
        • WBC: Elevated (especially during crises)
        • Platelets: Elevated
      • Peripheral Blood Smear:
        • Sickle cells (drepanocytes)
        • Target cells
        • Howell-Jolly bodies
        • Polychromasia
        • Nucleated RBCs (after splenectomy or in severe anemia)
      • Reticulocyte Count: Elevated (often > 10%)
      • Hemoglobin Electrophoresis:
        • HbAS (Sickle Cell Trait): HbA (50-60%) and HbS (35-45%)
        • HbSS (Sickle Cell Anemia): Predominantly HbS (80-95%) and elevated HbF (5-15%); HbA is absent
      • Sickle Solubility Test:
        • Positive: Detects the presence of HbS (not specific for sickle cell anemia)
        • Used as a screening test
    • Diagnosis:
      • Based on clinical presentation, peripheral blood smear, hemoglobin electrophoresis, and genetic testing
    • Treatment:
      • Hydroxyurea: Increases HbF production, reducing sickling and vaso-occlusive crises
      • L-glutamine: Reduces oxidative stress
      • Crizanlizumab: Monoclonal antibody that prevents vaso-occlusion
      • Voxelotor: Binds to hemoglobin and increases its affinity for oxygen, reducing sickling
      • Pain Management: Analgesics for vaso-occlusive crises
      • Vaccinations: To prevent infections (especially encapsulated organisms)
      • Prophylactic Penicillin: In children to prevent pneumococcal infections
      • Blood Transfusions: For severe anemia, acute chest syndrome, stroke, or other complications
      • Hematopoietic Stem Cell Transplantation (HSCT): Potentially curative option
    • Gene Therapy: Emerging therapeutic approach
  • Hemoglobin C (HbC)
    • Genetic Defect:
      • A point mutation in the β-globin gene on chromosome 11
      • Substitution of lysine for glutamic acid at the 6th position of the beta-globin chain (β6 Glu→Lys)
    • Pathophysiology:
      • HbC molecules tend to crystallize within RBCs, leading to increased rigidity and premature destruction in the spleen
    • Clinical Features:
      • HbAC (Hemoglobin C Trait):
        • Heterozygous for HbC
        • Usually asymptomatic
      • HbCC (Hemoglobin C Disease):
        • Homozygous for HbC
        • Mild to moderate hemolytic anemia
        • Splenomegaly
    • Laboratory Findings:
      • CBC:
        • HGB: Decreased (10-12 g/dL in HbCC)
        • HCT: Decreased
        • MCV: Normal or slightly decreased
        • MCHC: Increased (often > 36 g/dL)
      • Peripheral Blood Smear:
        • Target cells (prominent)
        • HbC crystals (may be seen after splenectomy)
        • Microspherocytes
      • Reticulocyte Count: Slightly elevated
      • Hemoglobin Electrophoresis:
        • HbAC (Hemoglobin C Trait): HbA (60%) and HbC (40%)
        • HbCC (Hemoglobin C Disease): Predominantly HbC (90-95%); HbF may be slightly elevated
      • Diagnosis:
        • Based on peripheral blood smear and hemoglobin electrophoresis
    • Treatment:
      • Usually supportive
      • Folic acid supplementation
      • Splenectomy may be considered in severe cases
  • Hemoglobin E (HbE)
    • Genetic Defect:
      • A point mutation in the β-globin gene on chromosome 11
      • Substitution of lysine for glutamic acid at the 26th position of the beta-globin chain (β26 Glu→Lys)
    • Pathophysiology:
      • HbE is unstable and can lead to mild reduction in beta-globin chain synthesis
    • Clinical Features:
      • HbAE (Hemoglobin E Trait):
        • Heterozygous for HbE
        • Usually asymptomatic or mild microcytic anemia
      • HbEE (Hemoglobin E Disease):
        • Homozygous for HbE
        • Mild microcytic anemia
        • Splenomegaly may occur
      • HbE-Beta Thalassemia:
        • Inheritance of HbE gene and a beta-thalassemia gene
        • Severity varies depending on the specific beta-thalassemia mutation
        • Can range from mild anemia to severe thalassemia major
    • Laboratory Findings:
      • CBC:
        • HGB: Decreased (variable)
        • HCT: Decreased (variable)
        • MCV: Decreased (microcytic)
        • MCH: Decreased
      • Peripheral Blood Smear:
        • Target cells
        • Microcytes
      • Hemoglobin Electrophoresis:
        • HbAE (Hemoglobin E Trait): HbA and HbE
        • HbEE (Hemoglobin E Disease): Predominantly HbE
        • HbE-Beta Thalassemia: HbE and elevated HbF
      • Diagnosis:
        • Based on peripheral blood smear and hemoglobin electrophoresis
    • Treatment:
      • HbAE (Hemoglobin E Trait): No treatment is required
      • HbEE (Hemoglobin E Disease): Usually no treatment is required; folic acid supplementation may be beneficial
      • HbE-Beta Thalassemia: Treatment depends on the severity; may require blood transfusions and iron chelation

Diagnostic Approach to Hemoglobinopathies

  • Suspect Hemoglobinopathy:
    • Anemia with suggestive features (e.g., microcytosis, hemolysis)
    • Family history of hemoglobinopathy
    • Ethnic background
  • Complete Blood Count (CBC) and Peripheral Blood Smear:
    • Assess RBC morphology (e.g., sickle cells, target cells, spherocytes)
    • Determine MCV, MCH, and MCHC
  • Hemoglobin Electrophoresis:
    • Separates and quantifies different hemoglobin types (HbA, HbA2, HbF, HbS, HbC)
    • Essential for diagnosing structural hemoglobin variants and thalassemias
  • Sickle Solubility Test:
    • Positive in the presence of HbS
    • Used as a screening test for sickle cell disease
  • Specialized Tests (If Indicated):
    • Globin chain synthesis assays
    • DNA analysis for specific mutations

Key Terms

  • Hemoglobinopathy: A genetic disorder affecting the structure or synthesis of hemoglobin
  • Hemoglobin S (HbS): Abnormal hemoglobin that causes sickle cell anemia
  • Hemoglobin C (HbC): Abnormal hemoglobin that can cause mild hemolytic anemia
  • Hemoglobin E (HbE): Abnormal hemoglobin that can cause mild microcytic anemia
  • Sickle Cell Trait (HbAS): Heterozygous carrier of HbS; usually asymptomatic
  • Sickle Cell Anemia (HbSS): Homozygous for HbS; causes severe hemolytic anemia and vaso-occlusive crises
  • Hemoglobin Electrophoresis: Technique to separate and quantify hemoglobin types
  • Target Cells: Red blood cells with a bullseye appearance
  • Vaso-occlusion: Blockage of blood vessels by sickled RBCs