A 4-year-old girl of Mediterranean origin presents with severe anemia (Hb 4.5 g/dL), hepatosplenomegaly, and facial bone deformities. HPLC reveals HbF 95%, HbA2 3.5%, and HbA absent. Her parents have mild microcytic anemia. Which of the following best explains the pathophysiology of extramedullary hematopoiesis causing hepatosplenomegaly in this condition?

• A Excess iron from repeated transfusions deposits in hepatic Kupffer cells, causing reactive hepatomegaly via inflammatory cytokine release
• B Hemolysis of mature sickled cells in sinusoidal vessels causes direct hepatic congestion and passive splenomegaly
• C Beta-globin chain accumulation within hepatocytes directly triggers hepatocyte proliferation via HIF-1α activation
• D Ineffective erythropoiesis in the marrow leads to massive erythroid hyperplasia and EMH; elevated EPO from chronic hypoxia drives hematopoietic stem cells to liver, spleen, and other sites capable of supporting erythropoiesis ✓

Explanation

Beta-thalassemia major (HbA absent, HbF 95%) results from biallelic beta-globin gene mutations. Excess unpaired alpha-chains precipitate within erythroid precursors, causing massive intramedullary destruction (ineffective erythropoiesis — >90% of erythroid precursors die in the marrow). Severe anemia drives markedly elevated erythropoietin secretion from the kidneys, which recruits hematopoietic progenitor cells to fetal hematopoietic sites (liver and spleen), and even to extraosseous sites (paravertebral masses). This EMH, combined with RBC sequestration, accounts for hepatosplenomegaly. Facial deformities result from marrow expansion within craniofacial bones.

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

High-yield for: NEET PGINI-CETNExTFMGEUSMLEPLABMRCP

Written and medically reviewed by the StethoPrep medical team.