Pathogenesis

The sickling disorders consist of: (1,2)

• 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.

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 anaemia 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

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

Reference

1. Bain BJ, Daniel Y, Henthorn J, et al. Significant haemoglobinopathies: a guideline for screening and diagnosis: a British Society for Haematology guideline. Br J Haematol. 2023 Jun;201(6):1047-65.
2. DeBaun MR, Jordan LC, King AA, et al. American Society of Hematology 2020 guidelines for sickle cell disease: prevention, diagnosis, and treatment of cerebrovascular disease in children and adults. Blood Adv. 2020 Apr 28;4(8):1554-88.