Anaemias & RBC Morphology
Pathology · Haematology · lean revision notes
Anaemias & RBC Morphology
Anaemia is one of the highest-yield, highest-frequency areas in NEET PG Medicine — and the questions are increasingly image-based, asking you to read a peripheral smear or interpret indices. This note builds the MCV-based framework, layers in smear morphology, reticulocyte logic, and named indices (Mentzer), and ends with rapid-fire one-liners for the night before.
Anaemia (WHO) is a reduction in haemoglobin (Hb) below the age- and sex-specific cut-off — <13 g/dL in adult men, <12 g/dL in non-pregnant women, <11 g/dL in pregnancy. It is a sign, not a diagnosis; the job is always to find the cause.
High-yield: WHO Hb cut-offs: Men <13, Women <12, Pregnancy <11, Children 6–59 months <11. These exact numbers are repeatedly tested.
Classification — the MCV approach (master this first)
The single most useful first step is the mean corpuscular volume (MCV), normal 80–100 fL. Every classic anaemia slots into microcytic (<80), normocytic (80–100), or macrocytic (>100).
| MCV category | MCV (fL) | Classic causes (mnemonic) |
|---|---|---|
| Microcytic | < 80 | TAILS — Thalassaemia, Anaemia of chronic disease (late), Iron deficiency, Lead poisoning/sideroblastic, Sideroblastic |
| Normocytic | 80–100 | Acute blood loss, haemolysis, aplastic anaemia, anaemia of chronic disease (early), CKD, mixed deficiency |
| Macrocytic | > 100 | Megaloblastic: B12 / folate deficiency. Non-megaloblastic: alcohol, liver disease, hypothyroidism, reticulocytosis, drugs (hydroxyurea, methotrexate, zidovudine), myelodysplasia |
High-yield: Iron deficiency anaemia (IDA) is the commonest anaemia worldwide and the commonest microcytic anaemia. In a microcytic picture, IDA vs thalassaemia trait is THE favourite discriminator.
A second axis adds MCH/MCHC (hypochromic vs normochromic) and the RDW (red cell distribution width, anisocytosis). RDW is the cheap tie-breaker:
High-yield: RDW is HIGH in iron deficiency (mixed cell sizes) but NORMAL in thalassaemia trait (uniformly small cells). This is a classic single-best-answer point.
Microcytic anaemias
Iron deficiency anaemia (IDA)
Pathophysiology: Negative iron balance → exhausted stores → reduced haem synthesis → hypochromic microcytic red cells. Causes: chronic blood loss (menorrhagia in women, GI loss/hookworm in men and post-menopausal women), poor intake, malabsorption (coeliac), increased demand (pregnancy, infancy).
Sequence of iron studies as deficiency progresses (flow): ↓ serum ferritin → ↓ serum iron → ↑ TIBC/transferrin → ↓ transferrin saturation → microcytosis on smear.
High-yield: Serum ferritin is the single best (most specific) test for iron deficiency and the earliest to fall. BUT ferritin is an acute-phase reactant — it rises with infection/inflammation/malignancy, so a "normal" ferritin does not exclude IDA in an inflamed patient. Soluble transferrin receptor (sTfR) helps here (raised in IDA, normal in ACD).
Smear: microcytic, hypochromic cells, pencil/cigar cells, target cells, increased central pallor, anisopoikilocytosis.
Treatment: Oral ferrous sulphate (elemental iron ~ 100–200 mg/day; each 325 mg ferrous sulphate tablet ≈ 65 mg elemental iron). Best absorbed on empty stomach with vitamin C; alternate-day dosing improves absorption (lower hepcidin). First haematological response = reticulocytosis at day 5–10; Hb rises ~2 g/dL in 3 weeks. Continue 3–6 months after Hb normalises to refill stores. IV iron (ferric carboxymaltose) for intolerance, malabsorption, CKD, or non-compliance.
Anaemia of chronic disease (ACD / anaemia of inflammation)
Driven by hepcidin (↑ in inflammation) which blocks ferroportin → iron trapped in macrophages → functional iron deficiency. Usually normocytic, can become microcytic.
| Feature | Iron deficiency | Anaemia of chronic disease | Thalassaemia trait |
|---|---|---|---|
| Serum iron | ↓ | ↓ | Normal |
| TIBC | ↑ | ↓ / normal | Normal |
| Ferritin | ↓ | ↑ / normal | Normal/↑ |
| Transferrin saturation | ↓ | ↓ / normal | Normal |
| RDW | ↑ | Normal/↑ | Normal |
| Marrow iron stores | Absent | Increased (but unavailable) | Present |
High-yield: TIBC is the cleanest IDA-vs-ACD discriminator: HIGH TIBC = iron deficiency; LOW/normal TIBC = ACD. Ferritin low only in IDA.
Thalassaemia trait & the Mentzer index
Beta-thalassaemia trait gives disproportionately low MCV for a near-normal Hb, with a high RBC count and normal RDW — the body makes many small cells.
High-yield — Mentzer Index = MCV ÷ RBC count.
- Mentzer < 13 → Thalassaemia trait (low MCV, high RBC count).
- Mentzer > 13 → Iron deficiency (low MCV, low RBC count). Diagnosis confirmed by HbA2 > 3.5% on haemoglobin electrophoresis/HPLC in beta-thalassaemia trait.
Smear in thalassaemia: microcytic hypochromic cells with target cells, basophilic stippling, and in major/intermedia, nucleated RBCs and marked anisopoikilocytosis.
Sideroblastic & lead
Defective haem synthesis → iron loads into mitochondria ringing the nucleus = ringed sideroblasts (Prussian-blue stain on marrow). Causes: hereditary (ALA-synthase defect), lead poisoning, alcohol, isoniazid (B6-responsive), myelodysplasia. Lead poisoning → basophilic stippling, ↑ serum iron and ferritin, microcytic; treat the cause and chelate.
Macrocytic / megaloblastic anaemias
Megaloblastic anaemia = impaired DNA synthesis (B12 or folate deficiency) → nuclear–cytoplasmic asynchrony → large cells. Pancytopenia can occur because all marrow lineages are affected.
Smear hallmarks: oval macrocytes (macro-ovalocytes) and hypersegmented neutrophils (≥5 lobes; or ≥1 cell with 6 lobes) — the earliest and most sensitive smear sign.
| Feature | Vitamin B12 deficiency | Folate deficiency |
|---|---|---|
| Onset | Slow (years; large stores) | Fast (months; small stores) |
| Neurological signs | Yes — SCDC, neuropathy, dementia | No (except in infants) |
| Serum level | Low B12 | Low folate / RBC folate |
| Methylmalonic acid (MMA) | ↑ | Normal |
| Homocysteine | ↑ | ↑ |
| Classic cause | Pernicious anaemia, ileal disease, vegan, metformin | Poor diet, alcohol, pregnancy, methotrexate, phenytoin |
High-yield: MMA is raised in B12 deficiency but NORMAL in folate deficiency — the key biochemical discriminator. Both raise homocysteine.
High-yield — NEVER give folate alone to a B12-deficient patient: it corrects the anaemia but the neurological disease (subacute combined degeneration of cord — dorsal columns + corticospinal tracts) progresses and may become irreversible. Always replace B12 first / together.
Pernicious anaemia: autoimmune atrophic gastritis, anti-intrinsic factor and anti-parietal cell antibodies, achlorhydria; associated with gastric carcinoma. The Schilling test is the classic (now historical) test. Treat with parenteral (IM) hydroxocobalamin.
Non-megaloblastic macrocytosis: alcohol (commonest cause of macrocytosis without anaemia), liver disease, hypothyroidism, reticulocytosis (young red cells are large), and drugs.
Normocytic anaemias & the reticulocyte logic
When MCV is normal, the reticulocyte count / index splits the differential into destruction/loss (high retics) vs underproduction (low retics).
Reticulocyte production index (RPI) flow: Corrected retic % = retic % × (patient Hct ÷ 45) → divide by maturation factor → RPI.
- RPI > 2–3 (high) → adequate marrow response → haemolysis or acute blood loss.
- RPI < 2 (low) → marrow underproduction → aplastic anaemia, pure red cell aplasia, CKD (↓ erythropoietin), ACD, marrow infiltration, B12/folate.
High-yield: A high reticulocyte count points to haemolysis or recent bleeding; a low/inappropriately normal retic in an anaemic patient = marrow production problem.
Haemolytic anaemias — labs and the Coombs test
Lab signature of haemolysis: ↑ reticulocytes, ↑ unconjugated (indirect) bilirubin, ↑ LDH, ↓ haptoglobin, ± haemoglobinuria (intravascular).
High-yield: ↓ haptoglobin + ↑ LDH + ↑ indirect bilirubin + reticulocytosis = haemolysis. The Direct Coombs test (DAT) separates immune (DAT positive) from non-immune (DAT negative) haemolysis.
Classic smear clues in haemolysis:
- Spherocytes → hereditary spherocytosis (↑ MCHC, ↑ osmotic fragility, EMA-binding test) or autoimmune haemolytic anaemia.
- Schistocytes / fragmented helmet cells → microangiopathic haemolytic anaemia (TTP, HUS, DIC, mechanical valve). A must-recognise emergency smear.
- Bite cells & Heinz bodies → G6PD deficiency (oxidative stress; X-linked; triggered by fava beans, primaquine, sulfa, infection).
- Sickle cells & target cells → sickle cell anaemia (HbS; sickling on deoxygenation).
Aplastic anaemia
Pancytopenia with a hypocellular ("dry/fatty") marrow and no splenomegaly, low reticulocytes. Causes: idiopathic/autoimmune, drugs (chloramphenicol, carbamazepine), benzene, radiation, viral (parvovirus B19 → pure red cell aplasia, hepatitis), Fanconi anaemia. Treatment: allogeneic HSCT (young, matched donor) or immunosuppression (ATG + ciclosporin) + eltrombopag.
Peripheral smear — recognise the cell, name the disease
This is where image MCQs live. Commit this table to memory.
| Smear finding | Most-associated condition(s) |
|---|---|
| Target cells | Thalassaemia, liver disease, HbC, post-splenectomy, IDA |
| Pencil / cigar cells | Iron deficiency anaemia |
| Sickle cells | Sickle cell anaemia (HbS) |
| Spherocytes | Hereditary spherocytosis, autoimmune haemolysis |
| Schistocytes (fragments) | MAHA — TTP, HUS, DIC, mechanical valve |
| Bite cells / Heinz bodies | G6PD deficiency |
| Basophilic stippling | Lead poisoning, thalassaemia, sideroblastic |
| Howell–Jolly bodies | Hyposplenism / post-splenectomy (DNA remnants) |
| Tear-drop cells (dacrocytes) | Myelofibrosis, marrow infiltration |
| Rouleaux | Multiple myeloma, high ESR states |
| Macro-ovalocytes + hypersegmented neutrophils | Megaloblastic (B12/folate) anaemia |
| Acanthocytes (spur cells) | Liver disease, abetalipoproteinaemia |
| Echinocytes (burr cells) | Uraemia / CKD |
| Nucleated RBCs | Marked haemolysis, thalassaemia major, leukoerythroblastic marrow |
High-yield: Howell–Jolly bodies on a smear should make you think the spleen is not working (asplenia/hyposplenism) — a classic one-liner MCQ.
Diagnostic approach — the stepwise algorithm
- Confirm anaemia by WHO Hb cut-off and check it is true (not dilutional).
- Look at the MCV → microcytic / normocytic / macrocytic.
- Microcytic → order iron studies + Mentzer index; ferritin low = IDA; high RBC + Mentzer <13 = thal trait → confirm with HPLC/HbA2.
- Macrocytic → smear for hypersegmented neutrophils; B12, folate, MMA, homocysteine; treat B12 first.
- Normocytic → reticulocyte count. High → haemolysis (LDH, bilirubin, haptoglobin, DAT) or bleed; Low → marrow study (aplastic/infiltration), check renal function and TFTs.
- Always review the peripheral smear — it often gives the answer outright.
Investigation of choice highlights:
- IDA: serum ferritin (most specific screening test).
- Thalassaemia: HPLC / Hb electrophoresis (HbA2).
- B12 vs folate: methylmalonic acid.
- Haemolysis immune vs non-immune: Direct Coombs test.
- Aplastic anaemia: bone marrow biopsy (hypocellular).
- Hereditary spherocytosis: EMA-binding flow cytometry / osmotic fragility.
Key differentials & traps
- Low MCV with high-normal Hb and high RBC count → think thalassaemia trait, not IDA.
- Macrocytosis without anaemia in an adult → alcohol/liver disease until proven otherwise.
- Pancytopenia: distinguish megaloblastic (hypercellular marrow), aplastic (hypocellular), and infiltration/MDS (dysplastic).
- Normal/raised ferritin does not exclude IDA if inflammation present — use sTfR or marrow iron.
- Schistocytes + thrombocytopenia + fever/renal/neuro signs → think TTP–HUS (a haematological emergency) — do not transfuse platelets in TTP.
Complications
- Severe IDA: high-output cardiac failure, koilonychia, angular stomatitis, glossitis, Plummer–Vinson syndrome (dysphagia + oesophageal web + IDA, pre-malignant).
- B12 deficiency: subacute combined degeneration, peripheral neuropathy, dementia, glossitis (Hunter's), infertility; irreversible neuro damage if untreated.
- Thalassaemia major: transfusion-dependent iron overload (cardiac, hepatic, endocrine), extramedullary haematopoiesis, "hair-on-end" skull, chipmunk facies; needs chelation (deferasirox/deferoxamine).
- Haemolysis: pigment gallstones, aplastic crisis (parvovirus B19), folate depletion.
Recently asked / exam angle
- Image-based smear identification is now extremely common: pencil cells (IDA), schistocytes (MAHA), bite cells (G6PD), Howell–Jolly bodies (asplenia), hypersegmented neutrophils (megaloblastic).
- Mentzer index < 13 → thalassaemia trait has appeared verbatim.
- Best/earliest test for iron deficiency = serum ferritin; earliest lab response to oral iron = reticulocytosis (day 5–10).
- MMA raised only in B12 (not folate) deficiency; never folate alone in B12 deficiency.
- TIBC high in IDA, low in ACD; ferritin is an acute-phase reactant.
- Low haptoglobin = intravascular haemolysis marker; DAT separates immune vs non-immune.
- RDW high in IDA, normal in thalassaemia trait — a recurring single-line discriminator.
- Drug associations: chloramphenicol → aplastic anaemia; hydroxyurea/methotrexate/zidovudine → macrocytosis; isoniazid → sideroblastic (B6-responsive).
Rapid revision
- MCV is the first branch: <80 micro, 80–100 normo, >100 macro. Microcytic mnemonic = TAILS.
- IDA is commonest anaemia globally; smear shows pencil cells; ferritin is the most specific test and falls first.
- TIBC high = IDA, low = ACD; ferritin low only in IDA; ferritin is an acute-phase reactant.
- Mentzer index = MCV/RBC; <13 thalassaemia trait, >13 IDA; confirm thal with HbA2 >3.5%.
- RDW high in IDA, normal in thalassaemia trait.
- Hypersegmented neutrophils + macro-ovalocytes = megaloblastic anaemia (B12/folate).
- MMA raised in B12 deficiency, normal in folate; both raise homocysteine.
- Never give folate alone in B12 deficiency — risk of subacute combined degeneration.
- Haemolysis = ↑LDH, ↑indirect bilirubin, ↓haptoglobin, ↑retics; DAT = immune vs non-immune.
- Howell–Jolly bodies = hyposplenism; schistocytes = MAHA (TTP/HUS/DIC); bite cells = G6PD.
- High reticulocytes = haemolysis/blood loss; low reticulocytes = marrow failure (aplastic, CKD, infiltration).
- Aplastic anaemia = pancytopenia + hypocellular marrow, no splenomegaly; chloramphenicol is a classic cause.