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. In practice, interpret ferritin with CRP, transferrin saturation and the clinical context rather than any single threshold. Reticulocyte haemoglobin content (CHr or Ret-He) or % hypochromic red cells are recommended in CKD where available (NICE NG203); sTfR and the sTfR/log ferritin ratio have limited availability and variable assays and are not routinely needed in primary care. Seek specialist advice if iron status remains uncertain.

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 (above the laboratory reference range) → 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 — arrange immediate hospital assessment and do not wait for ADAMTS13 results. Treatment: plasma exchange (large volume — replaces ADAMTS13) + corticosteroids + rituximab. Untreated TTP is usually fatal; prompt specialist treatment makes survival likely.

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. A practical starting dose is one preparation providing approximately 50–100 mg elemental iron once daily. BSG 2021 advises one tablet once daily (e.g. ferrous sulphate 200 mg = 65 mg elemental iron), or on alternate days if not tolerated — hepcidin rises after each dose and blocks further absorption for about 24 hours, so more frequent dosing adds side effects more than benefit. Tolerability differs between individuals and preparations; avoid modified-release preparations. The local formulary lists ferrous fumarate 322/305 mg (≈100 mg elemental iron) as first choice and ferrous sulfate 200 mg (≈65 mg) as an alternative. 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 some reduction in absorption. IV iron is not a routine GP treatment: it is given through the local hospital/ambulatory pathway (resuscitation facilities, staff able to manage anaphylaxis, observation during and for at least 30 minutes after) when oral iron is not tolerated, not absorbed (e.g. coeliac, IBD), ineffective, or rapid correction is required (perioperative, late pregnancy under obstetric care). Ferric carboxymaltose carries a risk of hypophosphataemia (MHRA).

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, BABY HUG) showed fewer painful crises, acute chest syndrome episodes and transfusions. Hydroxycarbamide is initiated and titrated by haematology; under the local shared-care protocol the GP may continue prescribing with regular FBC, renal, liver and reticulocyte monitoring as specified. It is a preventive treatment, not acute crisis management.

The iron supplementation patient counselling conversation is one of the most practically important in primary care — non-adherence to iron supplements is common, 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 on an empty stomach if tolerated; (3) separate from tea, coffee and dairy where practical; (4) if GI effects are severe, take with food (absorption is reduced, but this is better than not taking it); (5) try alternate-day dosing or a different preparation if not tolerated; (6) the anaemia will start to improve in 2-3 weeks but treatment continues for 3 months after the Hb normalises to 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 — 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.