Regarding the pathophysiology of sickle cell disease, all of the following statements are correct EXCEPT:

Question

Accepted Answer

D. Hemoglobin S has lower oxygen affinity than hemoglobin A, making it more prone to polymerization. ## Pathophysiology of Sickle Cell Disease

### Hemoglobin S Structure and Function

**Key Point:** HbS differs from HbA by a single nucleotide substitution (GAG → GTG) at codon 6 of the β-globin gene, resulting in glutamic acid being replaced by valine. This hydrophobic substitution is the fundamental molecular defect.

**High-Yield:** The polymerization of deoxygenated HbS occurs because valine (hydrophobic) at position 6 creates a sticky patch that polymerizes with the hydrophobic pocket of adjacent HbS molecules. This does NOT occur with HbA because glutamic acid (hydrophilic) does not interact with the hydrophobic pocket.

### Reversibility of Sickling

**Clinical Pearl:** Early sickling is reversible — when deoxygenated RBCs are re-oxygenated (e.g., in the lungs), HbS reverts to soluble form and fibers dissolve. However, repeated sickling-unsickling cycles cause membrane damage, leading to irreversible sickling and hemolysis.

### Oxygen Affinity Misconception

**Warning:** HbS has **HIGHER** (not lower) oxygen affinity than HbA due to the structural change. However, this does NOT explain polymerization. Polymerization occurs because of the hydrophobic interaction between deoxygenated HbS molecules, NOT because of altered oxygen affinity. The question tests this common misconception.

| Feature | HbA | HbS |
| --- | --- | --- |
| Codon 6 amino acid | Glutamic acid (hydrophilic) | Valine (hydrophobic) |
| Polymerization | Does not occur | Occurs when deoxygenated |
| Oxygen affinity | Standard | Slightly higher |
| P50 | ~26.6 mmHg | ~30 mmHg (right-shifted) |

**High-Yield:** The right-shifted oxygen-hemoglobin dissociation curve of HbS (higher P50) means it releases oxygen MORE readily to tissues, not that it has lower affinity. This is actually beneficial in some contexts but contributes to tissue hypoxia and sickling crises.

Answer

A. Point mutation at codon 6 of the β-globin gene results in substitution of glutamic acid with valine

Answer

B. The sickling process is reversible when hemoglobin is re-oxygenated in the lungs

Answer

C. Polymerization of deoxygenated HbS leads to formation of rigid fibers within red blood cells

Regarding the pathophysiology of sickle cell disease, all of the following statements are correct EXCEPT:

Explanation

Pathophysiology of Sickle Cell Disease

Hemoglobin S Structure and Function

Reversibility of Sickling

Oxygen Affinity Misconception

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Feature	HbA	HbS
Codon 6 amino acid	Glutamic acid (hydrophilic)	Valine (hydrophobic)
Polymerization	Does not occur	Occurs when deoxygenated
Oxygen affinity	Standard	Slightly higher
P50	~26.6 mmHg	~30 mmHg (right-shifted)