## Why ATP depletion in erythrocytes due to impaired terminal glycolytic flux is right Pyruvate kinase (**C**) catalyzes the final ATP-generating step of glycolysis: phosphoenolpyruvate → pyruvate + ATP. Deficiency of this enzyme directly impairs ATP production in erythrocytes, which lack mitochondria and depend entirely on glycolysis for energy. ATP depletion compromises Na⁺/K⁺-ATPase function, leading to loss of membrane ion homeostasis, cell dehydration, membrane rigidity, and chronic hemolysis. This is the pathophysiological hallmark of pyruvate kinase deficiency hereditary hemolytic anemia, the second most common enzymatic cause after G6PD deficiency (Harper 32e Ch 18; Robbins 10e Ch 14). The normal osmotic fragility and absence of spherocytes distinguish this from hereditary spherocytosis. ## Why each distractor is wrong - **Impaired glucose phosphorylation preventing entry of glucose into the glycolytic pathway**: This describes hexokinase/glucokinase (**A**) deficiency, not pyruvate kinase. Glucose entry is not the rate-limiting step in pyruvate kinase deficiency. - **Accumulation of 2,3-bisphosphoglycerate causing abnormal hemoglobin oxygen affinity**: While 2,3-BPG may accumulate proximal to the block, this is not the primary hemolytic mechanism. The critical problem is ATP depletion, not oxygen affinity shifts. - **Defective lactate production leading to systemic acidosis and secondary red cell lysis**: Lactate production is downstream of pyruvate kinase and is actually preserved (pyruvate is still formed and converted to lactate). Systemic acidosis is not the primary driver of hemolysis in this condition. **High-Yield:** Pyruvate kinase deficiency = ATP depletion → membrane pump failure → chronic non-spherocytic hemolytic anemia (second only to G6PD among enzyme defects). [cite: Harper 32e Ch 18; Robbins 10e Ch 14]
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