A patient has an abnormal hemoglobin with markedly increased oxygen affinity (left-shifted ODC) and compensatory erythrocytosis. The most likely molecular basis is:

• A Substitution at the alpha1-beta2 interface stabilizing the R (oxy) state
• B A mutation preventing 2,3-BPG from entering the central cavity
• C Both A and B represent pathways to high-affinity hemoglobins ✓
• D Loss of the Bohr effect due to His HC3 mutation

Explanation

High-affinity hemoglobin variants arise through several mechanisms: (1) mutations at the alpha1-beta2 interface (e.g., HbCheapeake) stabilize the R conformation, preventing T-state formation; (2) mutations preventing 2,3-BPG binding reduce the allosteric stabilization of the T state (e.g., HbHiroshima, where 2,3-BPG binding site is disrupted); and (3) mutations in the C-terminal region of beta chains disrupting salt bridges (e.g., HbRanier). Both A and B are correct mechanisms. The compensatory erythrocytosis occurs because tissue hypoxia from impaired O2 release stimulates EPO production.

Reference: Harper's Illustrated Biochemistry, 32nd ed.

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Written and medically reviewed by the StethoPrep medical team.