The blood film examination is the most important investigation in normocytic anaemia that GPs rarely request but haematologists rely on — the peripheral blood film provides information that the automated FBC cannot: the morphology of red cells (spherocytes in AIHA or hereditary spherocytosis; sickle cells; target cells in haemoglobin C disease; schistocytes/fragmented cells in TTP/HUS/MAHA — mechanical haemolysis); the white cell differential (blast cells in acute leukaemia, smear cells in CLL, atypical lymphocytes in viral infection); and platelet morphology (large platelets in ITP, platelet clumping). Any patient with unexplained normocytic anaemia — particularly with abnormal WBC or platelets — should have a blood film requested or the laboratory asked to perform a manual film review. This single investigation can identify TTP (schistocytes = haematological emergency), acute leukaemia (blasts), or CLL (smear cells) within minutes.

Anaemia of chronic disease (ACD) and iron deficiency anaemia (IDA) frequently coexist — particularly in patients with inflammatory bowel disease, rheumatoid arthritis, or malignancy. The challenge: ferritin (the standard iron stores marker) is an acute phase protein that rises with inflammation, meaning ferritin can be normal or elevated even when true iron stores are depleted in the context of inflammation. This leads to missed iron deficiency in inflammatory conditions. The most useful discriminating tests: soluble transferrin receptor (sTfR) — elevated in iron deficiency regardless of inflammatory state, not affected by inflammation (unlike ferritin); sTfR/log ferritin ratio (Thomas plot) — a ratio >2 suggests iron-deficient erythropoiesis superimposed on ACD; reticulocyte haemoglobin content (CHr or Ret-He) — the haemoglobin content of newly synthesised reticulocytes reflects real-time iron availability, a sensitive functional iron deficiency marker. GPs seeing anaemia in inflammatory conditions should request these additional markers before concluding that iron stores are adequate.

The reticulocyte count is the pivotal investigation that separates the two fundamental mechanisms of normocytic anaemia: reticulocytosis (elevated reticulocytes) indicates the bone marrow is responding appropriately to anaemia from haemolysis or blood loss — the marrow is working; reticulocytopenia (low or inappropriately normal reticulocytes) indicates impaired bone marrow production — hypoproliferative, aplastic, or infiltrative process. This single result directs the entire subsequent investigation pathway: elevated reticulocytes (>100 × 10⁹/L) → investigate for haemolysis (DAT, LDH, unconjugated bilirubin, haptoglobin, blood film for schistocytes/spherocytes) or acute haemorrhage; low or normal reticulocytes with anaemia → investigate for marrow failure, CKD, hypothyroid, ACD, or early iron/B12 deficiency. Requesting a reticulocyte count is a free addition to the FBC in most UK hospital laboratories and should be standard practice for any unexplained normocytic anaemia.

The TTP (thrombotic thrombocytopenic purpura) pentad must be in every GP's emergency diagnostic vocabulary because it is rapidly fatal without treatment — the classic pentad: thrombocytopenia, microangiopathic haemolytic anaemia (MAHA — schistocytes on blood film), fever, renal failure, and neurological symptoms (confusion, stroke-like). In practice, the majority of patients present with only thrombocytopenia + MAHA without all five features. The mechanism: deficiency of ADAMTS13 (a protease that cleaves von Willebrand factor multimers) allows ultra-large vWF multimers to accumulate, causing platelet adhesion and microthrombi throughout the microvasculature. Diagnosis: blood film showing schistocytes (fragmented red cells) + thrombocytopenia in an unwell patient = haematology emergency. Treatment: plasma exchange (large volume — replaces ADAMTS13) + corticosteroids + rituximab. Without treatment, mortality is approximately 90%; with treatment, survival is approximately 80-90%.

The ferrous sulphate prescribing convention for iron deficiency anaemia — 200 mg tablet contains 65 mg elemental iron — is a source of confusion because oral iron preparations are labelled in total salt weight not elemental iron content. The therapeutic elemental iron dose is 100-200 mg per day. Ferrous sulphate 200 mg BD (twice daily) = 130 mg elemental iron per day — adequate and widely recommended as first-line. Ferrous gluconate 300 mg BD (35 mg elemental iron per tablet) is better tolerated GI-wise but provides less elemental iron per dose. The most common reason for treatment failure with oral iron is GI side effects (nausea, constipation, abdominal cramps) leading to non-adherence — taking iron with food reduces side effects at the cost of approximately 40% reduction in absorption. IV ferric carboxymaltose (Ferinject — 500-1000 mg single infusion): used when oral iron is not tolerated, malabsorption is present (coeliac, IBD), or when rapid iron repletion is needed (perioperative, severe anaemia in late pregnancy).

The subacute combined degeneration of the spinal cord (SACD) from B12 deficiency is a preventable neurological catastrophe — the posterior and lateral columns of the spinal cord are demyelinated by B12 deficiency, causing a progressive syndrome: posterior column signs (loss of vibration sense, proprioception → sensory ataxia — Romberg positive), lateral column signs (upper motor neurone — pyramidal weakness, spasticity, hyperreflexia), and sometimes dementia or optic neuropathy. The critical principle: NEVER give folic acid alone to a patient with macrocytic anaemia without first confirming that B12 is normal — folate supplementation in B12-deficient patients can partially correct the haematological abnormalities (MCV, anaemia) while the neurological B12 deficiency continues to progress unchecked, potentially irreversibly. The rule: always check B12 before treating folate deficiency, or treat both simultaneously if B12 status is uncertain.

The hydroxycarbamide (hydroxyurea) dose titration protocol for sickle cell disease is an underutilised treatment in primary care that dramatically reduces vaso-occlusive crises — the mechanism: hydroxycarbamide increases foetal haemoglobin (HbF) production by stimulating γ-globin gene expression, and HbF does not polymerise with HbS, thereby reducing sickling. Clinical trials (MSH trial, BABY HUG trial) show hydroxycarbamide reduces painful crises by approximately 44%, acute chest syndrome by approximately 50%, transfusions by approximately 48%, and mortality by approximately 40%. Starting dose: 15 mg/kg/day (oral, once daily). Titrate to maximum tolerated dose (ideally 25-30 mg/kg/day) based on Hb and blood count response. Monitoring: FBC every 2-4 weeks during titration (dose-limiting toxicity is myelosuppression — hold if ANC <2.0 × 10⁹/L or platelets <80 × 10⁹/L). GPs in shared care with haematology for sickle cell patients should ensure hydroxycarbamide is prescribed and monitored appropriately.

The iron supplementation patient counselling conversation is one of the most practically important in primary care — the rate of iron supplementation non-adherence exceeds 50% in most studies, primarily due to GI side effects (constipation, nausea, dark stools, cramping) that patients interpret as adverse reactions requiring stopping. The key counselling points: (1) dark/black stools are expected and normal — it is the iron; (2) take with vitamin C (orange juice) to enhance absorption; (3) separate from tea, coffee, and dairy by at least 2 hours; (4) if GI effects are severe, take with food (absorption reduced by approximately 40% but better than not taking it); (5) switch to ferrous gluconate (lower elemental iron per tablet, usually better tolerated) or alternative if ferrous sulphate intolerable; (6) the anaemia will start to improve in 2-3 weeks but it takes 3-6 months to fully replete stores — do not stop when you feel better.

The non-response to oral iron at 4 weeks in a patient with confirmed iron deficiency anaemia is a clinical prompt requiring systematic reassessment before escalating to IV iron — the causes of oral iron non-response: (1) non-compliance (most common — ask explicitly, check dispensing records); (2) ongoing blood loss exceeding replacement (unidentified GI bleeding, menorrhagia); (3) malabsorption (coeliac disease — anti-tTG IgA should be checked in all patients with iron deficiency before diagnosing the cause as dietary); (4) incorrect diagnosis (ACD misidentified as iron deficiency, B12 masquerading as normocytic anaemia); (5) drug interaction (proton pump inhibitors reduce iron absorption by approximately 50% — take iron 2 hours before PPI). A full reassessment protocol at 4 weeks of non-response before proceeding to IV iron prevents unnecessary infusions and identifies serious underlying pathology.