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MOLECULAR DESCRIPTION

NORMAL ADULT HEMOGLOBIN STRUCTURE

  • Hemoglobin A (Hb A): A protein tetramer composed of two α and two β chains. Each chain contains:

    • An iron-containing heme group = binds oxygen

      • Identical in each chain

    • A globin chain = amino acid sequence

      • Variable in each chain

SICKLE CELL HEMOGLOBIN STRUCTURE

  • Hemoglobin S (Hb S): Mutation in the adult β-globin chain allele, which replaces valine (hydrophobic) for glutamine/glutamic acid (hydrophilic) at the position of the sixth amino acid.

  • Sickle cell anemia (SCA): Patients possess two abnormal β-globin chain alleles (homozygous) of the hemoglobin molecule (Hb SS).

  • Sickle cell trait (SCT): Patients possess one normal and one abnormal β-globin chain allele (heterozygous) of the hemoglobin molecule (Hb AS).

INHERITANCE PATTERN

  • Autosomal recessive

SICKLE CELL DISEASE (SCD) PHENOTYPE

PRODUCTION OF SICKLED ERYTHROCYTES

  • Hemoglobin deoxygenation and polymerization:

    • Exposure to deoxyhemoglobin increases Hb S polymerization and causes it to take on the classic sickle shape.

    • Increased Hb S polymerization the longer the erythrocyte is exposed to a deoxygenated, cold, and acidic environment.

    • Irreversible polymerization leads to decreased erythrocyte flexibility.

EFFECTS OF SICKLED ERYTHROCYTES ON THE BODY

  • The increased Hb S polymerization and sickle cell formation leads to:

    • Chronic hemolysis

    • Recurrent vascular occlusions

    • Painful crises

    • Ischemic end-organ injury (chronic)

    • Acute life-threatening manifestations of the disease

    • Chronic organ dysfunction

PATHOPHYSIOLOGY OF SICKLE CELL COMPLICATIONS

INTERACTION BETWEEN ABNORMAL HEMOGLOBIN AND THE CIRCULATORY SYSTEM

  • Erythrocytes:

    • The abnormal β-globin allele causes:

      • Accelerated breakdown of oxygenated hemoglobin

      • Decreased solubility of deoxygenated hemoglobin

    • Accumulation of Hb S causes:

      • Polymerization of Hb S

      • Precipitation of deoxygenated Hb S

      • Formation of an erythrocyte-deforming gel

    • Erythrocyte cell membrane damage causes:

      • Loss of membrane flexibility

      • Inability of erythrocyte to traverse capillary beds

      • Ischemic injury

    • Depletion of erythrocyte glutathione can lead to:

      • Increase in erythrocyte hemolysis

      • Increased risk of developing pulmonary hypertension.

  • Hemoglobin:

    • Accelerated destruction of the globin chain causes:

      • Increased oxidation of iron to the ferric state

      • Increased generation of superoxide, hydrogen peroxide, and hydroxyl radical, increasing oxidative injury

      • Disruption of normal phospholipid membrane structure

      • Increased mean corpuscular hemoglobin concentration (MCHC)

  • Endothelium:

    • There is an amplified expression of cell surface adhesion molecules that increase vascular inflammation, including vascular cell adhesion molecule-1 (VCAM-1), intercellular adhesion molecule-1 (ICAM-1), E-selectin, and P-selectin

    • Activated endothelial cells promote thrombosis and vasculopathy via increased affinity for interactions with abnormal erythrocytes, activated leukocytes, hemostatic pathway, and activated platelets

  • Leukocytes:

    • Vascular injury in SCD due to leukocyte adhering to endothelial cells and causing release of destructive proteolytic enzymes

  • Platelets:

    • Platelet activation is prominent.

    • Platelets are in a chronic state of heightened activity.

    • Platelets have a shortened life span due to rapid destruction and increased turnover.

  • Coagulation cascade:

    • Increased risk of vascular thrombosis ...

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