Haematology: Anaemia

• Anaemia: Approach to Anaemia | Iron Deficiency Anaemia | B12 and Folate Deficiency | Anaemia of Inflammation and CKD
• Haemolysis: Approach to Haemolysis | Inherited Haemolytic Anaemias | Autoimmune Haemolytic Anaemia | Microangiopathic Haemolysis | Paroxysmal Nocturnal Haemoglobinuria
• Marrow and blood counts: Aplastic Anaemia and Red Cell Aplasia | Approach to Pancytopenia | Abnormal White Cell Counts | Raised Haemoglobin | The Spleen and Hyposplenism
• Revision: Drug Reference Table | Spot the Diagnosis | Exam-style Scenarios | Key Points | Guidelines and Further Reading

🩸 Red cell disorders are among the commonest problems in medicine. Anaemia is a sign, not a diagnosis - the job is to find the cause. The full blood count, MCV, reticulocyte count and blood film usually point the way. Sickle cell disease, thalassaemia and transfusion have their own chapter.
Your four questions for every patient: Is the anaemia small-cell, normal-cell or large-cell? Is the marrow responding (reticulocytes), or is it failing? Is there blood loss, haemolysis or a deficiency? Are the other cell lines normal - or is this pancytopenia?

Approach to Anaemia

Definition: Haemoglobin below the normal range - roughly under 130 g/L in men and under 120 g/L in women (under 110 g/L in pregnancy). Ranges vary by laboratory.

Symptoms:

• Tiredness; breathlessness on exertion.
• Palpitations; headaches.
• Angina, worsening heart failure, or falls in older people.
• Slowly developing anaemia can be surprisingly well tolerated.

Use the MCV to narrow the causes:

Key tests:

• Reticulocyte count:
  • High - the marrow is working: bleeding or haemolysis.
  • Low - production problem: deficiency, marrow failure, CKD.
• Blood film - often the most useful single test.
• Ferritin (and transferrin saturation), B12, folate.
• U&E, LFTs, TFTs, CRP.
• Haemolysis screen if suspected.
• Serum protein electrophoresis (myeloma) in older people with unexplained normocytic anaemia.
• Bone marrow examination if the cause remains unclear, or other cell lines are abnormal.

💡 Clinical Pearl: A normal MCV can hide a mixed deficiency (e.g. iron plus folate deficiency in coeliac disease). A raised RDW (red cell distribution width) and the film help to spot it.

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Iron Deficiency Anaemia

The basics: The commonest anaemia worldwide.

• Ferritin under 30 µg/L confirms iron deficiency. Ferritin is raised by inflammation, so a "normal" ferritin doesn't rule out deficiency when CRP is high - use transferrin saturation (under 20%).
• The film shows small, pale cells (microcytic, hypochromic) and pencil cells.

Causes:

• Blood loss - heavy periods, GI bleeding (cancer, ulcers, angiodysplasia, NSAIDs), urinary tract, frequent blood donation.
• Poor absorption - coeliac disease, atrophic gastritis, H. pylori, gastric surgery, PPIs.
• Increased need - pregnancy, growth.
• Poor intake - diet (rarely the only cause in adults in the UK).

Investigation:

• Men and postmenopausal women - GI investigation for cancer (OGD and colonoscopy), coeliac serology and urinalysis (BSG 2021).
• Full details are in the GI Investigations and Nutrition chapter.

Treatment:

• Oral iron - e.g. ferrous sulfate 200 mg once daily or on alternate days. Alternate-day dosing is better absorbed and tolerated.
• Expect Hb to rise by about 20 g/L in 3–4 weeks. Continue for about 3 months after Hb normalises to refill stores.
• Side effects: Nausea, constipation, dark stools.
• IV iron (ferric carboxymaltose, ferric derisomaltose):
  • If oral iron fails, isn't tolerated, or absorption is poor (IBD, coeliac disease, after bariatric surgery).
  • CKD, heart failure (improves symptoms), late pregnancy, before surgery.
  • Watch for: Low phosphate (ferric carboxymaltose); rare hypersensitivity.
• Failure to respond - check adherence, ongoing blood loss, malabsorption, wrong diagnosis (thalassaemia), or a coexisting problem.

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B12 and Folate Deficiency

Why they matter: Both cause megaloblastic anaemia (large red cells, hypersegmented neutrophils). B12 deficiency also damages the nervous system - sometimes without anaemia.

Causes of B12 deficiency:

• Autoimmune gastritis (pernicious anaemia) - no intrinsic factor (anti-intrinsic factor antibodies).
• Gastrectomy or bariatric surgery.
• Ileal disease or resection (Crohn's).
• Bacterial overgrowth; fish tapeworm.
• Drugs - metformin, long-term PPIs, nitrous oxide (inactivates B12).
• Diet - vegans.

Features of B12 deficiency:

• Anaemia; mild jaundice (ineffective red cell production).
• Glossitis.
• Neurological:
  • Peripheral neuropathy.
  • Subacute combined degeneration of the cord.
  • Cognitive impairment; mood change.
  • Optic neuropathy.

Causes of folate deficiency:

• Poor diet (older people, alcohol).
• Increased need - pregnancy, haemolysis, exfoliative skin disease.
• Malabsorption - coeliac disease.
• Drugs - methotrexate, trimethoprim, phenytoin.

Testing (NICE NG239, 2024):

• Serum B12 (or active B12).
• If the result is borderline - methylmalonic acid (raised in B12 deficiency) or homocysteine.
• Anti-intrinsic factor antibodies for autoimmune gastritis.
• Don't wait for test results if there are neurological symptoms - treat.

Treatment:

• B12 without neurological features: Hydroxocobalamin 1 mg IM three times a week for 2 weeks, then 1 mg every 2–3 months (lifelong if pernicious anaemia).
• With neurological features: 1 mg IM on alternate days until no further improvement, then every 2 months.
• Diet-related deficiency - oral cyanocobalamin may be enough.
• Folate: Folic acid 5 mg daily for about 4 months (longer if the cause persists).
• Always check and treat B12 before (or with) folate - folate alone can worsen B12 neurological damage.
• Watch potassium in severe anaemia when treatment starts (it can fall); transfusion is rarely needed.

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Anaemia of Inflammation and CKD

• Anaemia of inflammation (anaemia of chronic disease):
  • The second commonest anaemia - in infection, autoimmune disease, cancer, heart failure and CKD.
  • Inflammation raises hepcidin, which locks iron in stores so it can't be used.
  • Blood tests: Normocytic (sometimes microcytic); normal or high ferritin; low transferrin saturation; low TIBC.
  • Treatment: Treat the underlying disease; IV iron if there is also true iron deficiency.
• Anaemia of CKD:
  • Reduced erythropoietin, plus iron deficiency and inflammation.
  • Common once eGFR is under 30.
  • Management (NICE NG203):
    • Correct iron first - often IV iron.
    • Then erythropoiesis-stimulating agents (e.g. epoetin, darbepoetin) with a Hb target of about 100–120 g/L.
    • Higher targets increase stroke and VTE risk.
    • HIF prolyl hydroxylase inhibitors (roxadustat, daprodustat) are oral alternatives.
  • See the CKD chapter.
• Other normocytic causes: Hypothyroidism, liver disease, hypogonadism, marrow infiltration (cancer, myeloma, myelofibrosis), MDS.

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Approach to Haemolysis

What it is: Red cells are destroyed early.

• Extravascular - in the spleen and liver (most).
• Intravascular - in the blood vessels: haemoglobinuria (dark urine), very low haptoglobin.

Clues:

• Anaemia with jaundice (unconjugated bilirubin).
• Dark urine (intravascular).
• Splenomegaly.
• Gallstones (pigment).
• Family history.

Haemolysis screen:

• Raised reticulocytes.
• Raised unconjugated bilirubin and LDH.
• Low haptoglobin.
• Blood film:
  • Spherocytes - hereditary spherocytosis or warm AIHA.
  • Schistocytes (fragments) - MAHA.
  • Bite cells and Heinz bodies - G6PD deficiency.
  • Sickle cells.
  • Agglutination - cold AIHA.
• Direct antiglobulin test (DAT, Coombs) - positive in immune haemolysis.
• Urine for haemoglobin and haemosiderin.

Causes:

• Inherited:
  • Membrane - hereditary spherocytosis.
  • Enzyme - G6PD and pyruvate kinase deficiency.
  • Haemoglobin - sickle cell disease, thalassaemia.
• Acquired:
  • Immune - AIHA, transfusion reactions, haemolytic disease of the newborn.
  • Mechanical - MAHA, prosthetic heart valves.
  • Infection - malaria, clostridial sepsis.
  • PNH.
  • Drugs and toxins - dapsone, ribavirin, snake venom.
  • Burns.

Everyone with chronic haemolysis: Folic acid (increased demand). Beware parvovirus B19, which stops red cell production and causes a sudden aplastic crisis.

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Inherited Haemolytic Anaemias

• Hereditary spherocytosis:
  • The commonest inherited haemolytic anaemia in Northern Europeans (usually autosomal dominant).
  • Faulty red cell membrane proteins make cells round (spherocytes); they are destroyed in the spleen.
  • Features:
    • Jaundice (including neonatal).
    • Anaemia; splenomegaly.
    • Gallstones at a young age.
    • Aplastic crises with parvovirus.
  • Tests: Spherocytes on film, DAT negative, EMA binding test.
  • Treatment:
    • Folic acid.
    • Splenectomy (partial or total) for severe disease - with vaccinations (see the Spleen section).
    • Cholecystectomy if gallstones cause symptoms.
• G6PD deficiency:
  • X-linked - mostly men of African, Mediterranean, Middle Eastern and Asian origin.
  • Red cells can't cope with oxidative stress, so attacks of acute intravascular haemolysis are triggered by:
    • Infection (the commonest).
    • Fava beans.
    • Drugs - primaquine and tafenoquine, dapsone, nitrofurantoin, quinolones, sulfonamides, rasburicase, methylene blue, high-dose aspirin.
  • Features: Sudden anaemia, jaundice and dark urine 1–3 days after the trigger. Neonatal jaundice.
  • Film: Bite cells, blister cells, Heinz bodies.
  • Diagnosis: G6PD assay - levels can be falsely normal during an attack (young cells have more enzyme); repeat after 2–3 months.
  • Treatment: Stop the trigger; transfuse if severe. Check G6PD before giving primaquine, dapsone or rasburicase.
• Pyruvate kinase deficiency: Autosomal recessive chronic haemolysis; mitapivat is a newer treatment.
• Hereditary elliptocytosis - usually mild.

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Autoimmune Haemolytic Anaemia

What it is: Antibodies against the patient's own red cells. The DAT is positive.

General points:

• Folic acid.
• VTE prophylaxis - haemolysis raises clotting risk.
• Transfusion can be difficult (antibodies make cross-matching hard) - but don't withhold blood in life-threatening anaemia; discuss with the blood bank.
• Look for an underlying cause (CT for lymphoma, autoantibodies).
• Evans syndrome - AIHA plus ITP.

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Microangiopathic Haemolysis

What it is: Red cells are sheared by damaged small vessels or abnormal surfaces, producing schistocytes (fragmented cells), usually with low platelets.

• Causes:
  • TTP (thrombotic thrombocytopenic purpura) - a medical emergency.
  • HUS - after E. coli O157 (children), or atypical (complement).
  • DIC.
  • Malignant hypertension.
  • Pre-eclampsia and HELLP.
  • Disseminated cancer.
  • Scleroderma renal crisis.
  • Drugs - calcineurin inhibitors, gemcitabine, quinine.
• Non-microangiopathic mechanical haemolysis: Leaking prosthetic heart valves; march haemoglobinuria (long-distance running).
• Key action: Schistocytes with low platelets needs urgent same-day haematology discussion - TTP must be excluded (ADAMTS13 activity), because untreated TTP is often fatal.
• See the Haematological Emergencies chapter for TTP, HUS and DIC.

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Paroxysmal Nocturnal Haemoglobinuria

• What it is: A rare acquired stem cell disorder. Red cells lack protective proteins (CD55 and CD59), so complement destroys them.
• Features:
  • Intravascular haemolysis - dark urine, often in the morning.
  • Fatigue, abdominal pain, difficulty swallowing, erectile dysfunction.
  • Thrombosis in unusual sites - hepatic veins (Budd–Chiari), cerebral veins, mesenteric veins. The commonest cause of death.
  • Marrow failure - linked to aplastic anaemia.
  • Kidney injury.
• Diagnosis: Flow cytometry of blood (loss of CD55, CD59, FLAER). DAT negative; high LDH.
• Treatment:
  • Complement inhibitors - eculizumab, ravulizumab (C5), and newer agents (iptacopan, pegcetacoplan).
  • Meningococcal vaccination (and often antibiotic prophylaxis) is essential - complement blockers greatly raise the risk of meningococcal infection.
  • Anticoagulation for thrombosis.
  • Stem cell transplant for marrow failure.
  • Managed by the national PNH service.

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Aplastic Anaemia and Red Cell Aplasia

• Aplastic anaemia: Pancytopenia with an empty (hypocellular) bone marrow, without abnormal cells.
• Causes:
  • Idiopathic (immune-mediated - most).
  • Drugs - chloramphenicol, carbamazepine, sulfonamides, gold, NSAIDs, antithyroid drugs.
  • Viruses - seronegative hepatitis, EBV, HIV.
  • PNH.
  • Radiation; chemotherapy; benzene.
  • Pregnancy.
  • Inherited - Fanconi anaemia (short stature, thumb abnormalities, cancer risk), telomere disorders (dyskeratosis congenita).
• Features:
  • Anaemia.
  • Infections (neutropenia).
  • Bruising and bleeding (thrombocytopenia).
  • No splenomegaly or lymph nodes - these suggest another cause.
• Treatment (specialist):
  • Supportive - transfusions (irradiated products in transplant candidates), antibiotics, antifungals.
  • Immunosuppression - antithymocyte globulin (ATG) with ciclosporin, plus eltrombopag.
  • Stem cell transplant - first line in young patients with a matched sibling donor.
• Pure red cell aplasia (only red cells affected, very low reticulocytes):
  • Parvovirus B19 (in people with haemolysis, or chronic in the immunosuppressed - IVIg).
  • Thymoma.
  • Large granular lymphocyte leukaemia.
  • Drugs; anti-EPO antibodies.
  • Diamond–Blackfan anaemia (children).

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Approach to Pancytopenia

What it is: Low haemoglobin, white cells and platelets together.

• Reduced production (marrow problem):
  • Marrow failure - aplastic anaemia, MDS.
  • Marrow infiltration - leukaemia, lymphoma, myeloma, metastatic cancer, myelofibrosis, TB.
  • B12 and folate deficiency.
  • Drugs - methotrexate (especially with trimethoprim or in renal failure), azathioprine (TPMT deficiency), chemotherapy, clozapine and carbimazole (agranulocytosis), linezolid.
  • Alcohol.
  • Infections - HIV, viral hepatitis, overwhelming sepsis, TB, leishmaniasis.
• Increased destruction or pooling:
  • Hypersplenism (portal hypertension, splenomegaly).
  • SLE.
  • Haemophagocytic lymphohistiocytosis (HLH) - fever, very high ferritin, splenomegaly, cytopenias, high triglycerides; triggered by infection (EBV), lymphoma or autoimmune disease. Life-threatening.
• Investigation:
  • Urgent blood film - blasts (acute leukaemia), leukoerythroblastic picture (infiltration), hypersegmented neutrophils (B12).
  • B12, folate, LFTs, HIV, autoantibodies.
  • Bone marrow aspirate and trephine.
• Same-day haematology advice if blasts are present, the patient is unwell, the neutrophil count is under 0.5 × 10⁹/L, or platelets are under 20 × 10⁹/L.

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Abnormal White Cell Counts

• Neutrophilia:
  • Bacterial infection; inflammation.
  • Steroids; smoking.
  • Tissue damage (MI, burns).
  • Cancer.
  • CML and other MPNs (with basophils and immature cells).
  • Pregnancy.
• Neutropenia:
  • Drugs - chemotherapy, carbimazole, clozapine, sulfasalazine, co-trimoxazole.
  • Viral infection.
  • B12 or folate deficiency.
  • Autoimmune (SLE, Felty's syndrome - rheumatoid arthritis with splenomegaly).
  • Marrow disease.
  • Duffy-null-associated neutrophil count (benign ethnic neutropenia) - common and harmless in people of African and Middle Eastern descent; mild (1.0–1.5 × 10⁹/L) without infections.
  • Under 0.5 × 10⁹/L carries a high infection risk - neutropenic sepsis is an emergency (see the Oncological Emergencies chapter).
• Lymphocytosis:
  • Viral infections (EBV - atypical lymphocytes), pertussis.
  • CLL (smear cells).
  • Lymphoma.
  • Smoking; after splenectomy.
• Lymphopenia: HIV, steroids, chemotherapy, viral infections, alcohol, SLE, sarcoidosis.
• Eosinophilia:
  • Allergy (asthma, eczema).
  • Parasites (travel - strongyloides, schistosomiasis).
  • Drugs (including DRESS - rash, fever, organ injury).
  • EGPA.
  • Hodgkin lymphoma.
  • Addison's disease.
  • Hypereosinophilic syndrome - organ damage (heart).
• Monocytosis: Chronic infection (TB), recovery from neutropenia, CMML.
• Leukoerythroblastic film (immature white and red cells, teardrop cells): Marrow infiltration - cancer, myelofibrosis, TB, severe sepsis.

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Raised Haemoglobin

What it is: Persistently raised Hb or haematocrit (e.g. haematocrit over 0.52 in men or 0.48 in women).

• Relative (apparent) - normal red cell mass with low plasma volume: dehydration, diuretics, alcohol, obesity, smoking.
• Secondary - raised erythropoietin:
  • Hypoxia - COPD, obstructive sleep apnoea, smoking (carbon monoxide), high altitude, cyanotic heart disease, obesity hypoventilation.
  • EPO-secreting tumours - renal cell carcinoma, HCC, cerebellar haemangioblastoma, uterine fibroids, phaeochromocytoma.
  • Kidney cysts; after kidney transplant.
  • Drugs - testosterone, anabolic steroids, EPO misuse, SGLT2 inhibitors (mild rise).
• Primary - polycythaemia vera (JAK2 mutation in over 95%), often with raised platelets and white cells, splenomegaly, itch after bathing - see the Leukaemia, MPN and MDS chapter.
• Investigation:
  • Repeat FBC.
  • JAK2 mutation test.
  • Serum EPO (low in PV; normal or high in secondary).
  • Oxygen saturations; sleep study.
  • Kidney and liver imaging.
  • Drug history (testosterone).
• Treatment:
  • Treat the cause (stop smoking, CPAP, review testosterone).
  • PV - venesection to keep haematocrit under 0.45, plus aspirin.

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The Spleen and Hyposplenism

Causes of splenomegaly:

• Massive (into the right iliac fossa):
  • CML.
  • Myelofibrosis.
  • Malaria (chronic).
  • Visceral leishmaniasis.
  • Gaucher disease.
• Moderate:
  • Lymphoma; CLL; other MPNs.
  • Portal hypertension.
  • Haemolytic anaemias; thalassaemia.
  • Infections - EBV, endocarditis, TB, brucellosis.
  • Sarcoidosis; amyloidosis.
• Hypersplenism - a large spleen pools and destroys blood cells, causing cytopenias.

Hyposplenism and asplenia - high risk of overwhelming post-splenectomy infection (pneumococcus, meningococcus, Haemophilus influenzae), which can kill within hours.

• Causes:
  • Splenectomy.
  • Sickle cell disease (the spleen infarcts in childhood).
  • Coeliac disease.
  • Severe IBD; alcoholic liver disease.
  • Splenic irradiation.
• Film: Howell–Jolly bodies, target cells.
• Prevention (UK Green Book and BSH):
  • Vaccines - pneumococcal, MenACWY and MenB, Hib (if not immunised), and yearly influenza. Give at least 2 weeks before planned splenectomy, or 2 weeks after emergency splenectomy.
  • Antibiotic prophylaxis - phenoxymethylpenicillin (or erythromycin if allergic), lifelong for those at highest risk, or at least 2 years after splenectomy.
  • A supply of "standby" antibiotics (e.g. amoxicillin) to start at the first sign of fever.
  • Alert card; travel advice - malaria is more severe; avoid animal and tick bites.

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Drug Reference Table

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Spot the Diagnosis

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Exam-style Scenarios

1. A 74-year-old man has Hb 96 g/L, MCV 71 fL and ferritin 9 µg/L. He has no GI symptoms.
Answer: Iron deficiency anaemia - GI cancer must be excluded.

• Coeliac serology and urinalysis; urgent OGD and colonoscopy.
• Oral iron (ferrous sulfate 200 mg daily or alternate days); recheck Hb in 3–4 weeks.

2. A 58-year-old woman on metformin has tingling feet and MCV 108 fL. B12 is low.
Answer: B12 deficiency with neuropathy (metformin or pernicious anaemia).

• Test anti-intrinsic factor antibodies.
• Hydroxocobalamin 1 mg IM on alternate days until no further improvement, then every 2 months.
• Check folate; don't give folate alone.

3. A 30-year-old man of Mediterranean origin has jaundice and dark urine after a chest infection. Hb has fallen to 80 g/L.
Answer: Acute haemolysis - likely G6PD deficiency.

• Blood film (bite cells, Heinz bodies); haemolysis screen; DAT negative.
• Stop oxidant drugs; support; transfuse if needed.
• G6PD assay after recovery; give a list of drugs to avoid.

4. A 65-year-old with CLL has Hb 75 g/L, spherocytes and a positive DAT (IgG).
Answer: Warm AIHA secondary to CLL.

• Prednisolone 1 mg/kg; folic acid; VTE prophylaxis.
• Rituximab if refractory, or treat the CLL.
• Transfuse if life-threatening, with blood bank advice.

5. A 45-year-old is having a planned splenectomy for ITP.
Answer: Protect against overwhelming infection.

• Pneumococcal, MenACWY, MenB, Hib and influenza vaccines at least 2 weeks before surgery.
• Lifelong or long-term penicillin prophylaxis; standby antibiotics; alert card; travel and malaria advice.

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Key Points

• Classify anaemia by MCV, then check reticulocytes and the blood film.
• Ferritin under 30 µg/L confirms iron deficiency; inflammation raises ferritin - use transferrin saturation.
• Iron deficiency in men and postmenopausal women needs GI investigation.
• Oral iron once daily or on alternate days; IV iron for malabsorption, CKD, heart failure or oral failure.
• B12 deficiency can cause neurological damage without anaemia. Treat B12 before folate.
• Hydroxocobalamin 1 mg IM three times a week for 2 weeks (alternate days if neurological), then maintenance.
• Haemolysis: high reticulocytes, unconjugated bilirubin and LDH, low haptoglobin. The DAT separates immune from non-immune.
• Spherocytes: hereditary spherocytosis (DAT negative) or warm AIHA (DAT positive).
• G6PD deficiency: oxidant drugs, infection, fava beans; bite cells; test when recovered.
• Schistocytes with low platelets - exclude TTP urgently.
• PNH: haemolysis, unusual-site thrombosis, marrow failure - complement inhibitors plus meningococcal vaccination.
• Pancytopenia needs an urgent film and often a bone marrow.
• Raised Hb: look for secondary causes (smoking, OSA, testosterone, renal tumours) and test JAK2.
• Hyposplenism: vaccines, penicillin prophylaxis, standby antibiotics, alert card.

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