10. In Sickle cell anemia the RBC are sickle shaped due to
    (1) Change in shape of hemoglobin in oxygen unbound form
    (2) Change in shape of hemoglobin in oxygen bound form
    (3) Loss of spectrin cytoskeleton protein
    (4) Due to loss of ATP synthesis

Introduction

Sickle cell anemia is a genetic blood disorder characterized by red blood cells (RBCs) that are abnormally shaped like crescents or sickles rather than their normal round, biconcave disc form. This dramatic shape change causes the cells to become rigid, fragile, and prone to blocking blood flow in small vessels, leading to pain, organ damage, and anemia. The fundamental cause of this sickling lies in the abnormal behavior of hemoglobin molecules inside the RBCs under low oxygen conditions. This article explains why RBCs become sickle shaped, focusing on the role of hemoglobin in the oxygen-unbound form, and clarifies why options like cytoskeleton protein loss or ATP deficiency do not cause sickling.

What Is Hemoglobin?

Hemoglobin is the oxygen-carrying protein inside red blood cells. It binds oxygen in the lungs and releases it to tissues throughout the body. Adult hemoglobin (HbA) is comprised of two alpha and two beta globin chains. In sickle cell anemia, a genetic mutation alters the beta-globin chain, creating sickle hemoglobin (HbS).

Genetic Mutation Causing Sickle Hemoglobin (HbS)

The mutation responsible for HbS substitutes the amino acid valine for glutamic acid at the sixth position of the beta-globin chain (E6V mutation). This single amino acid change reduces the solubility and alters the conformation of hemoglobin molecules when deoxygenated.

Mechanism of RBC Sickling

• Polymerization of Deoxygenated HbS:
  Under low oxygen conditions, HbS molecules undergo a conformational change, exposing hydrophobic patches that cause them to stick together and polymerize, forming long, rigid fibers inside RBCs.

• Deformity of RBC Shape:
  These polymers distort the flexible biconcave shape of normal RBCs into the characteristic crescent or sickle shape. This shape is less deformable, causing the cells to be fragile and prone to hemolysis, and leads to blockage of small blood vessels.

• The oxygenated form of HbS does not polymerize and thus does not cause sickling. Sickling events are reversible initially but can become permanent with recurrent cycles.

Why Other Factors Are Not Responsible

• Loss of Spectrin Cytoskeleton Protein (Option 3):
  While the RBC cytoskeleton contributes to cell shape and flexibility, sickling in sickle cell anemia stems primarily from hemoglobin polymer formation, not cytoskeletal defects.

• Loss of ATP Synthesis (Option 4):
  ATP depletion affects cell energy and membrane ion pumps but is not the direct cause of sickling. ATP deficiency can worsen symptoms but is a secondary effect.

Clinical Implications of Sickling

• Sickled RBCs have reduced lifespan, causing chronic anemia.

• They obstruct microvasculature, leading to painful vaso-occlusive crises and ischemic organ damage.

• Hemolysis releases free hemoglobin which scavenges nitric oxide, exacerbating vascular complications.

Correct answer: (1) Change in shape of hemoglobin in oxygen unbound form.