Hydrops fetalis in alpha-thalassemia results from hemoglobin Bart's (γ4 tetramers). What is the molecular consequence of having all four alpha-globin genes deleted, and why does hemoglobin Bart's cause tissue hypoxia despite apparently 'carrying' oxygen?
- A Hemoglobin Bart's has an extremely high oxygen affinity (left-shifted ODC), failing to release O2 at tissue pO2 levels ✓
- B Hemoglobin Bart's is unstable and rapidly precipitates intracellularly as Heinz bodies, causing hemolysis
- C Hemoglobin Bart's cannot bind 2,3-DPG, resulting in a right-shifted O2-dissociation curve with impaired loading
- D Hemoglobin Bart's lacks beta chains, making it incapable of cooperativity and dependent on dissolved plasma oxygen
Correct answer: A. Hemoglobin Bart's has an extremely high oxygen affinity (left-shifted ODC), failing to release O2 at tissue pO2 levels
Explanation
Hemoglobin Bart's (γ4 tetramers) has an oxygen dissociation curve (ODC) that is severely left-shifted with a P50 of approximately 1 mmHg (normal ~27 mmHg), because gamma-globin tetramers lack the allosteric DPG-binding pocket and have extremely high intrinsic O2 affinity. Although Hb Bart's can bind O2 in the lungs, it fails to offload O2 at tissue oxygen tensions, producing functional anemia — tissue hypoxia despite near-full hemoglobin O2 saturation. This drives fetal hydrops through high-output cardiac failure and severe anemia.
Reference: Robbins & Cotran Pathologic Basis of Disease, 10th ed.
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