pathogenesis

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The sickling disorders consist of:

  • heterozygous state or the sickle cell trait (AS),
  • homozygous state or sickle cell disease (SS)
  • compound heterozygous state for haemoglobin S with other structural haemoglobin variants or thalassaemias

Polymerised HbS forms rod-like structures with a diameter of about 11.6 nm.

  • it aligns with other polymerised HbS to form a bundle which results in distortion of the red cell to form the characteristic sickled appearance.
  • polymerisation is dependent on various factors like intra-erythrocytic HbS concentration, the degree of haemoglobin deoxygenation, pH and the intracellular concentration of HbF (1).

It is thought that there is a tendency for normal haemoglobin molecules to form similar arrays and that the beta 6 valine substitution stabilises these molecular stacks.

These deformed sickled red cells results in two essential pathological processes:

  • haemolysis -
    • results in anemia due to reduced mean life of a red cell and a functional deficiency of nitric oxide which causes  vascular endothelial damage
  • vaso-occlusion
    • due to adhesion of HbS containing cells and white cells to the endothelium of the microvascular circulation
    • results in acute and chronic ischaemia, acute pain and organ damage (2)

When HbS accounts for less than 40%, sickling only occurs under conditions of severe hypoxia.

Reference:

Last reviewed 01/2018

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