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🩸 Thalassemia — Pathology (NEET PG 2026)

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Pathophysiology Diagram — Beta-Thalassemia

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Core Concept: Globin Chain Imbalance

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β-Thalassemia: Step-by-Step Pathology

Step 1 — Molecular Defect

• Mutations in β-globin gene → reduced (β⁺) or absent (β⁰) β-chain synthesis
• Result: Excess unpaired α-chains → cannot form stable tetramers → precipitate inside erythroblasts

Step 2 — Hemichrome Formation & ROS

• Precipitated α-chains → hemichromes → generate reactive oxygen species (ROS)
• ROS → membrane lipid peroxidation → erythroblast membrane damage

Step 3 — Ineffective Erythropoiesis ⭐ (Most Important Mechanism)

• Damaged erythroblasts are destroyed within the bone marrow before entering circulation
• This is called intramedullary hemolysis / ineffective erythropoiesis
• Predominant cause of anemia in β-thalassemia (Harrison's, p. 2927)
• GDF11/GDF15 signaling → ↑ p-SMAD2/3 → ↓ GATA1 → ↑ apoptosis of erythroid precursors

Step 4 — Peripheral Hemolysis (Minor Component)

• Cells that escape into circulation: ↓ deformability + phosphatidylserine exposure → extravascular + intravascular hemolysis

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Consequences of Ineffective Erythropoiesis

Severe Anemia
     ↓
Marrow Expansion (erythroid hyperplasia)
     ↓
┌──────────────────────────┬──────────────────────────┐
│ Skeletal Changes         │ Extramedullary            │
│ • "Hair on end"          │ Hematopoiesis             │
│   skull X-ray            │ • Hepatosplenomegaly       │
│ • Crew-cut appearance    │ • Paraspinal masses        │
│ • Frontal bossing        │                           │
│ • Rodent facies          │                           │
└──────────────────────────┴──────────────────────────┘
     ↓
Iron Overload (↑ GI absorption + transfusions)
     ↓
Hemosiderosis → Liver cirrhosis, Dilated CMP,
                Diabetes, Hypogonadism

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Iron Overload Mechanism (High-Yield)

NEET PG Key Point: Ineffective erythropoiesis → ↑ ERFE → ↓ Hepcidin → Iron overload. This is independent of transfusions.

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α-Thalassemia: Clinical Spectrum

HbH inclusions stain with brilliant cresyl blue — "golf ball" cells

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β-Thalassemia: Clinical Classification

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Hemoglobin Electrophoresis Findings

NEET PG Key: HbA2 >3.5% = hallmark of β-thalassemia trait. Used for carrier screening.

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Peripheral Blood Smear Findings

• Microcytic hypochromic RBCs
• Target cells (codocytes) ⭐
• Nucleated RBCs (nRBCs) — due to marrow stress
• Basophilic stippling
• Poikilocytosis (tear drop cells, elliptocytes)
• Elevated reticulocyte count (though paradoxically low given the degree of anemia)

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Complications Summary (Thalassemia Major)

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Treatment (NEET PG Essentials)

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High-Yield One-Liners for NEET PG 2026

1. Predominant mechanism of anemia in β-thalassemia = Ineffective erythropoiesis (not hemolysis)
2. α-thalassemia = gene deletions; β-thalassemia = gene point mutations
3. HbA2 >3.5% = β-thalassemia trait (carrier screening test)
4. Hb Barts (γ₄) = 4-gene deletion α-thal = hydrops fetalis
5. HbH (β₄) = 3-gene deletion = golf ball cells with BCB stain
6. Ferritin ↑↑ in thalassemia major despite iron deficiency picture on smear (due to overload)
7. Cardiac hemosiderosis = #1 cause of death in thalassemia major
8. Curative treatment = Allogeneic HSCT
9. Rodent facies + hair-on-end skull X-ray = thalassemia major (marrow expansion)
10. Target cells on smear + microcytic anemia with normal/high serum iron = think thalassemia (not IDA)

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