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PA16.2 | Sickle Cell Disease & Thalassaemia — Hereditary Haemolytic Anaemias — SDL Guide (Part 2)

Study the smear above carefully. Note that sickle cells (drepanocytes) are elongated with tapered pointed ends — not simply 'curved'. Target cells have a central dense spot, pale ring, and peripheral dense rim. Howell-Jolly bodies are small, singular, deeply stained inclusions within RBCs; their presence on a film is virtually diagnostic of a functionally or surgically asplenic patient.

Distinguishing feature on smear review: In SCD, both ISCs (permanently sickled) and reversibly sickled forms may be present. The ISC count correlates with disease severity — more ISCs = more chronic endothelial damage.

Medical diagram showing sickle cell disease blood smear with annotated abnormal cells alongside molecular mechanism of hemoglobin S polymerization. — **Panel A:** Sickle cells (drepanocytes), target cells (codocytes), nucleated RBC, Howell-Jolly body, normal RBCs for comparison. **Panel B:** Deoxygenated HbS molecules, β6 Val interactions, fiber nucleation, membrane distortion, reversible vs irreversible stages.

The diagram above captures the molecular cascade. Key teaching points:
1. The trigger is deoxygenation — clinical situations that promote crises (cold, infection, dehydration, high altitude) work by promoting deoxygenation or increasing MCHC.
2. Hydroxyurea increases HbF synthesis, diluting the HbS pool and reducing polymerisation — this is the molecular basis of the most effective medical therapy in SCD.
3. Each sickling–unsickling cycle progressively oxidises and cross-links the membrane skeleton, culminating in the irreversibly sickled cell even when oxygenated.

Four-panel sequence showing progression from normal oxygenated RBC to irreversibly sickled cell through HbS polymerization stages. — **Panel A:** Normal RBC with dispersed HbS molecules in oxygenated state. **Panel B:** Deoxygenated HbS molecules showing β6 Val hydrophobic interactions. **Panel C:** Early sickling with fiber nucleation and reversible membrane distortion. **Panel D:** Late irreversible sickling with rigid HbS fiber bundles and crescent-shaped RBC.

Thalassaemia: Pathogenesis and Classification

⚑ AI image — pending faculty review (auto-QA score 6/10; best of 3 attempts)

Infographic showing thalassaemia as reduced alpha or beta globin synthesis causing chain imbalance, ineffective erythropoiesis, hemolysis, and classification by affected chain and severity. — **Panel A:** Normal HbA formation, alpha-globin chains, beta-globin chains, reduced or absent globin synthesis, alpha:beta chain imbalance, excess unpaired chains, ineffective erythropoiesis, hemolysis, microcytic hypochromic RBCs, anemia. **Panel B:** Alpha-thalassaemia, reduced or absent alpha-globin, chromosome 16, four alpha-gene alleles, gene deletions, beta-thalassaemia, reduced or absent beta-globin, chromosome 11, two beta-gene alleles, point mutations. **Panel C:** 1 alpha allele deleted silent carrier, 2 alpha alleles deleted alpha-thalassaemia trait, 3 alpha alleles deleted HbH disease, 4 alpha alleles deleted Hb Bart's hydrops fetalis, progressive microcytosis and hypochromia. **Panel D:** Beta-plus thalassaemia with reduced beta-globin synthesis, beta-zero thalassaemia with absent beta-globin synthesis, beta-thalassaemia minor, beta-thalassaemia intermedia, beta-thalassaemia major, decreased HbA, increased HbF, increased HbA2.

Thalassaemias are a heterogeneous group of disorders caused by quantitative reduction or absence of structurally normal globin chain synthesis. The result is a stoichiometric imbalance between α and β chains.

Classification by affected chain:

Type	Defect	Chromosome	Genetics
α-Thalassaemia	↓/absent α-globin	16	Gene deletions (4 α-gene alleles)
β-Thalassaemia	↓/absent β-globin	11	Point mutations (2 β-gene alleles)

α-Thalassaemia severity by allele deletion:
- 1 allele deleted (α-/αα): Silent carrier — normal indices
- 2 alleles deleted (α-/α- or --/αα): α-Thalassaemia trait — mild microcytic, hypochromic anaemia
- 3 alleles deleted (--/α-): HbH disease — HbH (β4 tetramers) form, moderately severe haemolytic anaemia
- 4 alleles deleted (--/--): Hb Bart's hydrops fetalis — incompatible with postnatal life; γ4 tetramers (Hb Bart's) have extremely high O2 affinity

β-Thalassaemia classification:
- β0: Complete absence of β-chain synthesis (most severe mutations)
- β+: Reduced (partial) β-chain synthesis
- Thalassaemia minor (β-thal trait, heterozygous β0 or β+): Mild anaemia, microcytosis — clinically resembles IDA but ferritin is normal
- Thalassaemia intermedia: Moderately severe, not transfusion-dependent at baseline
- Thalassaemia major (Cooley's anaemia, homozygous β0/β0 or β0/β+): Severe, transfusion-dependent from first year of life