Chapter 56: Sickle Cell Anemia

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 ...