Anaemia Classification and Approach — WHO Cut-offs, Reticulocytes, MCV, Iron Studies and Haemolysis

Anaemia means a haemoglobin concentration too low for the person's age, sex and pregnancy status. In 2024 the WHO updated its haemoglobin cut-offs, which are now based on the 5th percentile of healthy populations. The adult values most often asked are < 13 g/dL in men and < 12 g/dL in non-pregnant women.

The WHO kept its older method for grading severity (mild, moderate, severe as roughly above 80%, 60–80% and below 60% of the cut-off) but applied it to the new cut-offs. For most adults and older children the bands are below.

Start with a complete blood count (Hb, haematocrit, RBC count, MCV, MCH, MCHC, RDW, white cells and platelets), a reticulocyte count and a peripheral smear. The question to answer first is not 'what size are the cells?' but 'is the marrow responding?'

1. Confirm anaemia against the WHO cut-off and check whether other cell lines are low too (a fall in two of three lines suggests a marrow problem such as myelodysplasia).
2. Reticulocyte count / reticulocyte production index (RPI). A normal reticulocyte count is about 0.5–2.5%. The RPI corrects this for the degree of anaemia.
3. RPI ≥ 2 = the marrow is responding → think haemolysis or acute blood loss. Confirm haemolysis with LDH, bilirubin and haptoglobin.
4. RPI < 2 = hypoproliferative anaemia → classify by MCV into microcytic, normocytic and macrocytic.
5. Order targeted tests: iron studies for microcytosis, B12/folate for macrocytosis, renal function, thyroid tests, haemoglobin electrophoresis, Coombs test or marrow examination as the pattern suggests.

Microcytic hypochromic anaemia reflects reduced haemoglobin synthesis — not enough iron, not enough globin, or a block in haem synthesis. The four classic causes are iron deficiency, thalassaemia, anaemia of chronic disease (inflammation) and sideroblastic anaemia (including lead poisoning).

Iron deficiency is the commonest cause of anaemia worldwide. Stores are used up first, so ferritin falls first, then serum iron and transferrin saturation fall while TIBC rises as a compensatory response. Soluble transferrin receptor is raised in true (absolute) iron deficiency and normal in functional deficiency. Examination may show koilonychia (spoon nails), atrophic glossitis, cheilosis, brittle nails and hair loss.

Anaemia of chronic disease is driven by IL-6 → hepcidin. Hepcidin binds the iron exporter ferroportin in macrophages, hepatocytes and enterocytes, so iron is trapped in stores: ferritin is high but iron cannot reach the marrow. In inflammation a ferritin below 100 ng/mL with transferrin saturation below 20% suggests coexisting true iron deficiency.

Both give a low MCV, and this is the single most-asked comparison. In thalassaemia the microcytosis is uniform (often a normal RDW), target cells are numerous, basophilic stippling may be seen, and the RBC count is normal or high for the degree of anaemia. Iron studies are normal, and β-thalassaemia trait shows HbA2 above 3.5%, sometimes with a raised HbF.

Sideroblastic anaemia is a failure to use iron inside the erythroblast. Iron piles up in the mitochondria, which sit around the nucleus, forming ring sideroblasts in the marrow. On Perls Prussian blue stain a ring sideroblast needs at least 5 granules covering at least one-third of the nuclear circumference. The blood may show a dimorphic (micro plus macro) population.

• Hereditary: commonest is X-linked, from mutation of ALAS2 (δ-aminolevulinate synthase 2), the first enzyme of haem synthesis. Pyridoxine (B6) 50–100 mg/day partly or fully corrects many cases, because B6 is the ALAS cofactor.
• Acquired: myelodysplastic neoplasm with ring sideroblasts, alcohol, copper deficiency (or zinc toxicity) and drugs — isoniazid (reversible with high-dose pyridoxine), chloramphenicol and linezolid.
• Lead poisoning inhibits δ-ALA dehydratase and ferrochelatase, giving a microcytic anaemia with coarse basophilic stippling (a classic but insensitive sign). Check blood lead when exposure is suspected.

Macrocytic anaemia is split into megaloblastic (impaired DNA synthesis, covered in detail on the megaloblastic anaemia page) and non-megaloblastic causes. In chronic kidney disease, raising Hb with ESAs to above 13 g/dL increased stroke, heart failure and death in the CHOIR, CREATE and TREAT trials, so targets are kept lower.

When the RPI is high and there is no bleeding, confirm haemolysis with the haemolysis panel: raised LDH, raised indirect (unconjugated) bilirubin, low or absent haptoglobin and raised reticulocytes. Haptoglobin is the most sensitive marker, because it is used up binding free haemoglobin.

Immune haemolysis: warm AIHA is the commonest, IgG-mediated and mainly extravascular in the spleen. Cold agglutinin disease is IgM reacting in the cold. Paroxysmal cold haemoglobinuria is an IgG autoantibody that fixes complement in the cold and lyses cells intravascularly on rewarming, with haemoglobinuria. The direct antiglobulin (Coombs) test is essential whenever spherocytes are seen. See also hypersensitivity reactions for type II immune injury.

Treat the cause — iron for iron deficiency, B12 or folate for megaloblastic anaemia, pyridoxine for responsive sideroblastic anaemia. Transfusion is guided by symptoms and haemoglobin. In the TRICC trial (838 ICU patients), a restrictive trigger of Hb ≤ 7 g/dL was non-inferior to a liberal trigger of ≤ 10 g/dL, and later trials supported restrictive strategies in most settings.

For related physiology, revise the oxygen–haemoglobin dissociation curve, and for hookworm as a cause of iron-deficiency anaemia see hookworm. Past questions are in the NEET PG Medicine PYQs.