Sickle cell trait (HbAS) confers partial protection against severe falciparum malaria because sickling occurs in parasitised cells. Which haemoglobin switch accounts for the observation that sickle cell disease (HbSS) does not manifest clinically at birth but becomes apparent at 4–6 months of age?

• A Foetal haemoglobin (HbF, α2γ2) replaces embryonic haemoglobin at birth and is progressively replaced by HbS after 6 months ✓
• B Maternal HbA transferred via placenta protects for the first 6 months of life
• C Neonates have higher 2,3-BPG levels that inhibit sickling during early infancy
• D Foetal erythrocytes have a shorter lifespan and carry predominantly HbF, delaying HbS accumulation

Explanation

Foetal haemoglobin (HbF, α2γ2) is the predominant haemoglobin in newborns and does not sickle because gamma chains lack the valine substitution at position 6. As developmental γ→β globin switching occurs over the first 6 months of life, HbF is progressively replaced by HbS in HbSS infants. Once HbF levels fall below ~20–25%, clinical manifestations (dactylitis, splenic sequestration) begin to emerge. This is why universal newborn screening is performed and HbF induction with hydroxyurea is therapeutically beneficial.

Reference: Robbins & Cotran Pathologic Basis of Disease, 10th ed.

High-yield for: NEET PGINI-CETNExTFMGEUSMLEPLABMRCP

Written and medically reviewed by the StethoPrep medical team.