Which of the following is the PRIMARY mechanism of anemia in β-thalassemia major?

Explanation

## Pathophysiology of Anemia in β-Thalassemia Major **Key Point:** The anemia in β-thalassemia major results from **hemolysis due to precipitation of excess α-globin chains**, not simply from reduced hemoglobin synthesis. ### Mechanism of α-Globin Precipitation 1. **β-globin deficiency** → imbalance in globin chain synthesis 2. **Excess α-globin chains** accumulate (no β-chains to pair with) 3. **Unpaired α-globin chains precipitate** → form insoluble inclusions (Heinz bodies) 4. **RBC membrane damage** → hemolysis and ineffective erythropoiesis 5. **Severe hemolytic anemia** with reticulocytosis **High-Yield:** This is why β-thalassemia major is fundamentally a **hemolytic anemia**, not just a hypoproliferative anemia. The RBCs are destroyed in the bone marrow (ineffective erythropoiesis) and in the spleen (extravascular hemolysis). ### Ineffective Erythropoiesis vs. Hemolysis | Process | Contribution to Anemia | | --- | --- | | **Ineffective erythropoiesis** | 70–80% of RBC loss (destroyed in bone marrow) | | **Extravascular hemolysis** | 20–30% of RBC loss (destroyed in spleen) | **Clinical Pearl:** Patients with β-thalassemia major have: - **Marked reticulocytosis** (>10%) — bone marrow response - **Splenomegaly** — from extramedullary hematopoiesis and hemolysis - **Elevated indirect bilirubin** — from hemolysis - **Elevated LDH** — from hemolysis and ineffective erythropoiesis ### Why Simple Reduced Synthesis Is Insufficient If anemia were **only** from reduced β-globin synthesis, patients would have: - Mild-to-moderate anemia (like in iron deficiency) - Normal reticulocyte response - No hemolysis markers Instead, β-thalassemia major shows **severe hemolytic anemia** because of the **toxic effect of precipitated α-globin chains** on RBC membranes. **Mnemonic:** **ALPHA** — **A**lpha chains accumulate, **L**ead to precipitation, **P**recipitates damage membrane, **H**emolysis results, **A**nemia is severe. [cite:Robbins 10e Ch 12]