A 72-year-old woman is found to have Hb 7.8 g/dL, MCV 110 fL, WBC 3,200/µL, and platelets 98,000/µL. The peripheral smear shows macro-ovalocytes and hypersegmented neutrophils (>5% with ≥5 lobes). Serum vitamin B12 is 85 pg/mL (normal >200). Which of the following is the PRIMARY pathophysiological mechanism of her anemia?
- A Impaired mitochondrial oxidative phosphorylation in erythroblasts
- B Reduced erythropoietin production from renal tubular atrophy
- C Defective DNA synthesis due to impaired thymidylate synthesis ✓
- D Increased RBC destruction by activated complement
Explanation
Vitamin B12 is required to convert methylmalonyl-CoA to succinyl-CoA and, critically for hematopoiesis, to regenerate tetrahydrofolate from methyltetrahydrofolate via methionine synthase. Without adequate THF, thymidylate synthesis is impaired, resulting in defective DNA replication in rapidly dividing cells (erythroblasts, myeloid precursors, GI epithelium). The consequent nuclear-cytoplasmic asynchrony produces megaloblastic changes, macro-ovalocytes, and hypersegmented neutrophils. Erythropoietin deficiency causes normocytic anemia; complement-mediated destruction is the mechanism in PNH.
Reference: Robbins & Cotran Pathologic Basis of Disease, 10th ed.
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