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PA16.1-3 | Sickle Cell Disease & Thalassaemia — Hereditary Haemolytic Anaemias — Part 4

The electrophoresis strip is your diagnostic key. Memorise the following:

Condition	HbA	HbS	HbF	HbA2
Normal adult	>95%	0	<1%	2–3.5%
HbSS (SCD)	0	>80%	↑ (compensatory)	Normal
HbAS (trait)	~60%	~40%	Normal	Normal
β-thal major (β0/β0)	0	0	>90%	↑
β-thal minor	Majority	0	Slightly ↑	>3.5% (key!)
β-thal major (β+)	Trace	0	↑	↑

HPLC is now the preferred method in most Indian labs — it provides quantitative data and simultaneously detects multiple Hb variants.

Hemoglobin electrophoresis pattern diagram showing characteristic band migration patterns for normal adult, sickle cell disease, sickle cell trait, and beta-thalassemia conditions. — **Panel A:** Five electrophoresis lanes showing Normal Adult (HbA >95%, HbA2 2-3.5%, HbF <1%), HbSS (HbS majority, elevated HbF, no HbA), HbAS (both HbA and HbS present), Beta-thalassemia Major (no HbA, elevated HbF and HbA2), and Beta-thalassemia Minor (HbA majority, HbA2 >3.5%) with cathode-to-anode migration direction.

Other Hereditary Haemolytic Anaemias: Membrane and Enzyme Defects

A four-panel educational diagram classifies hereditary haemolytic anaemias and compares membrane defects, G6PD deficiency, and pyruvate kinase deficiency with their smear findings and mechanisms. — **Panel A:** Classification branches for haemoglobinopathies, RBC membrane defects, and RBC enzyme defects; SCD, thalassaemia, hereditary spherocytosis, hereditary elliptocytosis, G6PD deficiency, and pyruvate kinase deficiency.. **Panel B:** Normal RBC membrane-cytoskeleton linkage with spectrin, ankyrin, and band 3; spherocyte with no central pallor; microspherocytes; elliptocytes; spleen-mediated extravascular haemolysis; Coombs test negative.. **Panel C:** Pentose phosphate pathway, G6PD, NADPH, reduced glutathione, oxidative stress, Heinz bodies, bite cells, blister cells, polychromasia, oxidant drugs, infections, and fava beans.. **Panel D:** Glycolysis, pyruvate kinase, ATP depletion, rigid RBCs, splenic trapping, extravascular haemolysis, autosomal recessive inheritance, and G6PD smear normal outside crisis..

Hereditary haemolytic anaemias span three mechanistic categories:

1. Haemoglobinopathies (abnormal Hb structure/quantity) — SCD, thalassaemia (covered above)

2. RBC membrane defects
- Hereditary spherocytosis (HS): Most common hereditary haemolytic anaemia in Northern Europeans. Mutations in spectrin, ankyrin, or band 3 destabilise the membrane–cytoskeleton linkage. RBCs lose membrane fragments → spherocytes (no central pallor, ↑ MCHC, ↑ osmotic fragility). Extravascular haemolysis (spleen). Smear: microspherocytes, polychromasia. Coombs test negative (distinguishes from autoimmune haemolysis).
- Hereditary elliptocytosis: Spectrin dimer self-association defects; milder clinical course; smear shows >25% elliptocytes.

3. RBC enzyme defects
- G6PD deficiency: X-linked; commonest enzyme deficiency in the world. G6PD protects RBCs from oxidative stress via the pentose phosphate pathway. Deficiency → oxidative damage → Heinz bodies (denatured Hb precipitates, seen with supravital stain) → haemolysis. Triggered by: oxidant drugs (primaquine, dapsone, nitrofurantoin), infections, fava beans. Smear during crisis: bite cells (splenic removal of Heinz body), blister cells, polychromasia. Outside a crisis the smear may be normal.
- Pyruvate kinase (PK) deficiency: Autosomal recessive; most common glycolytic enzyme defect; ATP depletion → rigid RBCs → extravascular haemolysis.

CLINICAL PEARL

The G6PD Coombs trap: A patient with G6PD deficiency presenting with acute haemolysis after a drug exposure can mimic autoimmune haemolytic anaemia (AIHA) clinically. The distinguishing test is the direct Coombs (direct antiglobulin) test — positive in AIHA, negative in G6PD deficiency. Always run a Coombs before attributing unexplained haemolysis to a non-immune cause.

SELF-CHECK

A 6-year-old child from Odisha, known case of beta-thalassaemia trait, has Hb 10.5 g/dL, MCV 62 fL, serum ferritin 45 ng/mL. Her mother insists she needs iron tablets. The correct response is:

A. Prescribe iron — ferritin is marginally low

B. Iron is NOT indicated; haemoglobin electrophoresis showing elevated HbA2 confirms thalassaemia trait, not iron deficiency

C. Order bone marrow biopsy to exclude combined deficiency

D. Start iron and folate supplementation empirically

Reveal Answer

Answer: B. Iron is NOT indicated; haemoglobin electrophoresis showing elevated HbA2 confirms thalassaemia trait, not iron deficiency

Beta-thalassaemia trait causes microcytic hypochromic anaemia with a NORMAL or elevated ferritin — iron stores are intact. HbA2 >3.5 % on electrophoresis confirms the diagnosis. Iron supplementation in thalassaemia trait risks iron loading without benefit and may mask the diagnosis. This is the classic 'do not treat thal trait with iron' teaching point. Combined IDA + thal trait is possible but requires both low ferritin AND electrophoresis confirmation before giving iron.