Red Cell Membrane Disorders
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Direct answer
A biconcave disc that must survive 120 days of relentless shear needs its membrane skeleton intact: spectrin tetramers form a horizontal lattice, while vertical links — spectrin to ankyrin to band 3, and spectrin-actin to protein 4.2 — tether the skeleton to the lipid bilayer. Hereditary spherocytosis, mostly autosomal dominant and most often from ankyrin or spectrin deficiency, weakens the vertical links, so the spleen progressively snips off unsupported membrane; cells round up into spherocytes and are destroyed extravascularly — anaemia, jaundice, splenomegaly and pigment gallstones in every combination. The eosin-5-maleimide (EMA) binding test by flow cytometry screens sensitively, the osmotic fragility test confirms, and a negative direct Coombs test separates the condition from warm autoimmune haemolytic anaemia, its exact morphological twin. Hereditary elliptocytosis, a horizontal-lattice defect of spectrin self-association, gives elliptocytes with usually mild haemolysis.
What you must remember
- Protein-deficiency ladder for HS: ankyrin (the commonest in Western series), beta-spectrin and band 3 in dominant disease, alpha-spectrin in recessive (and most severe, because alpha-spectrin is made in three-fold excess) and protein 4.2; beta-spectrin dominant disease tends to be severe.
- The spleen's dual role: splenic conditioning — repeated passage through the cords of Billroth strips membrane without destroying the cell immediately; spherocytes, less deformable, are then trapped and eaten by cordal macrophages. The spleen is the executioner, not the cause.
- Diagnosis with numbers: EMA binding test — sensitive screen, reduced fluorescence; osmotic fragility — spherocytes lyse in higher (less hypotonic) saline concentrations; autohaemolysis test increased and corrected by added glucose.
- The Coombs rule: spherocytes plus a positive direct antiglobulin test means warm autoimmune haemolytic anaemia; spherocytes with a negative Coombs test in a positive family mean HS — the single most examinable distinction in haemolysis.
- Classical complications: pigment gallstones (ultrasound in every symptomatic patient), folate deficiency from chronic haemolysis, and aplastic crisis with parvovirus B19 — abrupt anaemia and reticulocytopenia in a previously compensated child.
- Splenectomy rules: indicated for transfusion dependence, severe anaemia or gallstone disease; defer beyond about six years of age where possible; vaccinate against pneumococcus, meningococcus and Haemophilus influenzae type b before surgery, and give lifelong penicillin prophylaxis — post-splenectomy sepsis is the feared late event, and Howell-Jolly bodies confirm the spleen is gone.
- Elliptocytosis family: hereditary elliptocytosis from defective spectrin self-association or protein 4.1 — mostly mild; hereditary pyropoikilocytosis, the homozygous or compound severe form, with bizarre poikilocytes and thermal instability of the red cell.
- Indian corner: South-East Asian ovalocytosis, a band 3 gene deletion producing rigid ovalocytes, is prevalent in parts of north-east India and South-East Asia and protects against cerebral malaria — haematology meeting evolutionary biology in one MCQ.
The child with anaemia, jaundice and a big spleen
An eight-year-old presents with tiredness, yellow sclerae and a palpable spleen; haemoglobin 8.2 g/dL, reticulocytes 9 per cent, unconjugated bilirubin raised. The smear shows dense, small, deeply stained cells without central pallor — spherocytes. The reasoning now runs itself: haemolysis is established (reticulocytosis, indirect hyperbilirubinaemia, high LDH); the question is immune or inherited. Direct Coombs test negative — with a father "who was jaundiced as a child" — points to hereditary spherocytosis; EMA binding is reduced and osmotic fragility increased, closing the case. Management layers: folic acid daily for the chronically haemolysing marrow, abdominal ultrasound for gallstones now and at intervals, and splenectomy deferred or scheduled depending on severity — with vaccines arranged before the date and the family counselled that fever after splenectomy is an emergency. One smear, two tests, one family history: the full logic of a membrane disorder in a single patient.
Where students slip
Assuming all spherocytes are HS loses the case: warm autoimmune haemolytic anaemia produces identical morphology, and only the direct Coombs test separates them — the examiner's opening move in nearly every haemolysis viva. Second error: splenectomy "cures" HS. It removes the destruction site; the spherocytes persist and osmotic fragility remains abnormal, which is worth stating precisely. Third, ABO haemolytic disease of the newborn shows spherocytes too — neonatal context changes the differential completely. And remember that a normal osmotic fragility on a fresh sample can occur in mild HS; the incubated test improves sensitivity.
Frequently asked questions
Which protein deficiency most often causes hereditary spherocytosis?
Ankyrin deficiency in most Western series, followed by beta-spectrin and band 3; alpha-spectrin loss is recessive and severe.
How does the EMA binding test work?
Eosin-5-maleimide binds band 3 and related membrane proteins; reduced fluorescence by flow cytometry indicates skeleton deficiency — a sensitive screening test.
What distinguishes HS from warm autoimmune haemolytic anaemia?
The direct antiglobulin (Coombs) test — positive in warm AIHA, negative in HS — since both produce spherocytes and extravascular haemolysis.
Why does parvovirus B19 cause aplastic crisis in HS?
It destroys erythroid precursors in the marrow, so a child whose survival depends on a high compensatory reticulocyte count abruptly decompensates.
What vaccinations precede splenectomy for HS?
Pneumococcal, meningococcal and Haemophilus influenzae type b vaccines, ideally at least two weeks before surgery, with lifelong awareness of post-splenectomy sepsis.