Question

Briefly explain the process of sickling of Red Blood Cells (RBCs) during sickle cell anaemia. Why does sickle celled RBCs lead to anaemic conditions in patients?

Hint:

The sickle cell allele persists at high frequencies in malaria-endemic regions (like parts of Africa and India) because heterozygotes ($HbA/HbS$) have a survival advantage against malaria (Plasmodium falciparum), a phenomenon known as heterozygote advantage.

Answer 1

Step 1: Genetic Cause of Sickling
Sickle cell anemia is an autosomal recessive genetic disorder caused by a single point mutation (substitution) in the gene encoding the $\beta$-globin chain of hemoglobin:
$$\text{Codon } \text{GAG} \rightarrow \text{GUG} \quad \text{yielding: } \text{Glutamic acid} \rightarrow \text{Valine (at 6th position)}$$ This substitution replaces a polar, hydrophilic amino acid (glutamic acid) with a non-polar, hydrophobic amino acid (valine) on the surface of the protein.

Step 2: The Sickling Process
- In deoxygenated states (such as after tissue oxygen delivery), the mutant hydrophobic valine residues on adjacent hemoglobin molecules ($HbS$) associate with each other.
- This causes the $HbS$ tetramers to polymerize into long, rigid, insoluble fibrous rods inside the erythrocyte.
- These fibers distort the cell membrane, transforming the normally flexible, biconcave disc-shaped RBCs into rigid, crescent or sickle shapes.


Step 3: Why it Leads to Anemia
Sickle-shaped RBCs cause severe anemia through two main processes:
1. Accelerated Hemolysis (Short Lifespan): Normal red blood cells survive for about 120 days. In contrast, rigid sickle cells are fragile and break down easily, with a lifespan of only 10 to 20 days. The body cannot replace them quickly enough, causing chronic hemolytic anemia.
2. Vaso-occlusion and Spleen Sequestration: Sickle cells are rigid and sticky. They cannot deform to pass through capillaries, easily clogging microvessels (vaso-occlusion). This traps RBCs in tissues and the spleen (splenic sequestration), leading to rapid cell destruction.
Final Answer: Under low oxygen conditions, mutant $HbS$ polymerizes into rigid fibers due to a surface valine substitution, deforming RBCs into rigid sickle shapes. This causes anemia because these fragile cells are destroyed prematurely (surviving only 10-20 days) and clog capillaries, leading to rapid cell loss.