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PA16.1-3 | Sickle Cell Disease & Thalassaemia — Hereditary Haemolytic Anaemias — Part 3

β-Thalassaemia Major: Pathogenesis and Clinical Features

Infographic showing how reduced beta-globin chains in beta-thalassaemia major cause alpha-chain precipitation, ineffective erythropoiesis, peripheral haemolysis, marrow expansion, organ enlargement, transfusion dependence, and iron overload. — **Panel A:** Reduced beta-globin chains, excess unpaired alpha-chains, alpha-chain inclusion bodies, damaged erythroblast, bone marrow, ineffective erythropoiesis, intramedullary haemolysis. **Panel B:** Abnormal microcytic RBCs, spleen, splenic macrophage, extravascular haemolysis, peripheral haemolysis. **Panel C:** Expanded marrow spaces, erythroid hyperplasia, thinning cortical bone, frontal bossing, prominent malar eminences, hair-on-end skull X-ray, chipmunk facies. **Panel D:** HbF to HbA switch at 6-24 months, severe anaemia Hb less than 7 g/dL, massive hepatosplenomegaly, extramedullary haematopoiesis, growth retardation, lifelong transfusion dependence, secondary haemosiderosis, cardiac iron deposition, cardiomyopathy, arrhythmias, liver cirrhosis, diabetes mellitus, hypogonadism, hypothyroidism.

In β-thalassaemia major, absent or markedly reduced β-chains leave excess unpaired α-chains. These are unstable, precipitate inside erythroblasts as inclusion bodies, and cause:
1. Ineffective erythropoiesis — massive destruction of erythroblasts within the bone marrow before they are even released (intramedullary haemolysis); this is the dominant mechanism, unlike SCD where haemolysis is peripheral.
2. Peripheral haemolysis — abnormal RBCs that do escape are destroyed rapidly in the spleen (extravascular).

Compensatory responses and their sequelae:
- Bone marrow expansion → erythroid hyperplasia → thinning of cortical bone → frontal bossing, prominent malar eminences, 'hair-on-end' pattern on skull X-ray (chipmunk facies / rodent facies)
- Extramedullary haematopoiesis → hepatosplenomegaly (massive); paravertebral masses of haematopoietic tissue visible on imaging
- Repeat transfusions → secondary haemosiderosis → iron deposition in heart (cardiomyopathy, arrhythmias — #1 cause of death), liver (cirrhosis), endocrine glands (diabetes mellitus, hypogonadism, hypothyroidism)

Clinical timeline:
- Presents at 6–24 months (when HbF switches to HbA)
- Severe anaemia (Hb < 7 g/dL), massive hepatosplenomegaly, growth retardation
- Transfusion-dependent for life without bone marrow transplantation

Blood Film and Diagnosis in Thalassaemia

Medical infographic showing blood film features, diagnostic blood indices, and haemoglobin electrophoresis findings in beta-thalassaemia major. — **Panel A:** Peripheral blood film showing severe microcytosis, hypochromia, target cells, basophilic stippling, nucleated RBCs, tear-drop cells, elliptocytes, poikilocytosis, and polychromasia.. **Panel B:** Haematologic indices in thalassaemia major: Hb 3-7 g/dL, MCV 50-65 fL, low MCH, RBC count preserved or high, contrasted with iron deficiency anaemia where RBC count falls.. **Panel C:** Haemoglobin electrophoresis pattern showing absent HbA in beta-thalassaemia major, very high HbF, variable or increased HbA2, and electrophoresis marked as the definitive test..

Peripheral blood picture (β-thalassaemia major):

Morphology	Significance
Severe microcytic, hypochromic anaemia	↓ Hb per cell (less β-chain)
Target cells	Excess membrane relative to Hb content
Basophilic stippling	Precipitated ribosomal RNA aggregates in RBCs; very prominent
Nucleated RBCs	Massive erythroid drive
Poikilocytosis (tear-drop cells, elliptocytes)	Abnormal erythropoiesis
Polychromasia	Reticulocytosis (though suppressed relative to severity due to ineffective erythropoiesis)

Haematologic indices (thalassaemia major):
- Hb: 3–7 g/dL
- MCV: markedly low (50–65 fL) — microcytic
- MCH: low
- RBC count: often disproportionately preserved or high (unlike IDA where both fall)

Haemoglobin electrophoresis (the definitive test):
- β-thalassaemia major (β0/β0): No HbA, ↑↑ HbF (>90 %), ↑ HbA2
- β-thalassaemia major (β+): Trace HbA, ↑ HbF, ↑ HbA2
- β-thalassaemia minor: ↑ HbA2 (>3.5 %) is the HALLMARK — this is the single most reliable discriminator from IDA (where HbA2 is normal)
- α-Thalassaemia trait: HbA2 may be normal; diagnosis requires molecular studies

Cross-reference (Cluster H3): β-thalassaemia trait is the most important differential diagnosis of IDA on RBC indices alone (both microcytic, hypochromic). The discriminating tests: ferritin (low in IDA, normal in thal trait), HbA2 (↑ in thal trait, normal in IDA). Never treat thal trait with iron.

Compare this smear with the SCD smear seen earlier. Key differences:
- Size: thalassaemia cells are clearly small (microcytic); SCD cells are normal-sized
- Colour: thalassaemia cells have a large pale central area (hypochromic); SCD cells are normochromic
- Stippling: basophilic stippling (ribosomal RNA aggregates) is prominent in thalassaemia, absent in uncomplicated SCD
- Shapes: while both have target cells, sickle forms are seen only in SCD

Medical illustration showing peripheral blood smear of beta-thalassaemia major with labeled abnormal red blood cell morphologies including target cells, nucleated RBCs, and basophilic stippling. — **Panel A:** Complete blood smear field showing microcytic hypochromic RBCs, target cells, tear-drop cells, nucleated RBCs, and prominent poikilocytosis. **Panel B:** Detailed view of target cells (codocytes) with characteristic central hemoglobin concentration and hypochromic red blood cells. **Panel C:** Nucleated red blood cells (normoblasts) with prominent basophilic stippling visible as dark blue-purple granules within the cytoplasm.