Anaemia: approach and common causes

At a glance

• Anaemia is a haemoglobin under 130 g/L in men and 120 g/L in non-pregnant women (WHO 2024). It is a sign, so the job is to find the cause.
• Two numbers frame the work-up: the MCV (small, normal or large cells) and the reticulocyte count (is the marrow responding?).
• Iron deficiency is the commonest cause. Its work-up, including endoscopy, is in Iron deficiency, pallor and fatigue.
• Look at the other counts. Anaemia with low white cells or platelets points to the marrow.
• Transfuse on symptoms and haemoglobin, one unit at a time.

Approach

Step	Question	Tests
1	Is it new, and how fast did it fall?	Old FBCs
2	Is the marrow responding?	Reticulocyte count
3	What size are the cells?	MCV, film
4	Are other lineages affected?	White cells, platelets, film
5	Is there haemolysis or bleeding?	LDH, bilirubin, haptoglobin, DAT; history and stool

• A high reticulocyte count (absolute over about 100 x 10^9/L) means loss or destruction: bleeding or haemolysis.
• A low or normal reticulocyte count in an anaemic patient means underproduction: deficiency, inflammation, CKD or marrow disease.

Causes

MCV	Common causes	Less common
Microcytic (under 80 fL)	Iron deficiency, thalassaemia trait, anaemia of inflammation (late)	Sideroblastic anaemia, lead poisoning
Normocytic (80 to 100 fL)	Anaemia of inflammation, CKD, acute bleeding, early iron deficiency, mixed deficiency, haemolysis	Marrow infiltration, aplastic anaemia, endocrine (hypothyroidism, hypopituitarism, Addison disease), pure red cell aplasia
Macrocytic, megaloblastic	B12 deficiency, folate deficiency	Drugs blocking DNA synthesis (methotrexate, hydroxyurea, azathioprine, zidovudine)
Macrocytic, not megaloblastic	Alcohol, liver disease, hypothyroidism, reticulocytosis	MDS, myeloma, pregnancy

• Pitfall: a normal MCV can hide two problems. Iron deficiency plus B12 deficiency (coeliac disease, after gastrectomy) gives a normal MCV with a high RDW and a dimorphic film.
• An MCV over about 115 fL is rarely alcohol alone. Think of B12 or folate deficiency, MDS or hydroxyurea.

Focused history

• Tempo and symptoms: breathlessness, angina, syncope, heart failure. A slow fall is tolerated far better than an acute one.
• Bleeding: melaena, rectal bleeding, menorrhagia, haematuria; antiplatelets, anticoagulants and NSAIDs.
• Diet and absorption: vegan diet, alcohol, coeliac symptoms, gastrectomy or bariatric surgery, terminal ileal Crohn's disease or resection.
• Drugs: metformin and PPIs (B12), methotrexate, trimethoprim, phenytoin (folate), hydroxyurea, azathioprine; recreational nitrous oxide.
• Haemolysis: dark urine, jaundice, gallstones; recent new drug (dapsone, primaquine in G6PD deficiency); prosthetic valve.
• Systemic disease: CKD, inflammatory disease, cancer symptoms, weight loss, night sweats.
• Ethnicity and family history: thalassaemia, sickle cell disease, G6PD deficiency, hereditary spherocytosis.
• Neurological symptoms: paraesthesia, unsteady gait, memory change (B12 deficiency).

Focused examination

• Haemodynamics; signs of heart failure.
• Pallor, jaundice (haemolysis, ineffective erythropoiesis), glossitis, angular cheilitis, koilonychia.
• Splenomegaly (haemolysis, thalassaemia, lymphoma, myelofibrosis), lymphadenopathy, signs of chronic liver disease.
• Rectal examination when GI bleeding is possible.
• Posterior column and pyramidal signs with peripheral neuropathy: subacute combined degeneration (absent ankle jerks with upgoing plantars).

Red flags

• Anaemia with chest pain, syncope or haemodynamic compromise: transfuse and look for bleeding.
• Pancytopenia or blasts on the film: urgent haematology review.
• Schistocytes with low platelets: thrombotic microangiopathy. See Thrombocytopenia.
• Neurological signs with suspected B12 deficiency: treat the same day.
• Iron deficiency in a man or postmenopausal woman: GI investigation.

Investigations

First line

• FBC, film and reticulocyte count.
• Iron studies with CRP, B12, folate, renal and liver function, TSH.
• The film often gives the answer: pencil cells (iron), target cells (thalassaemia, liver), hypersegmented neutrophils and oval macrocytes (megaloblastic), spherocytes, schistocytes, rouleaux (myeloma), teardrop cells and leucoerythroblastic change (marrow infiltration or fibrosis), dysplasia (MDS).

Haemolysis screen

Test	Haemolysis
Reticulocytes	High
LDH	High
Unconjugated bilirubin	High
Haptoglobin	Low (often undetectable)
Urine	Haemosiderin or haemoglobinuria in intravascular haemolysis

• Then the direct antiglobulin test (DAT). Positive with IgG points to warm autoimmune haemolysis (idiopathic, CLL, lymphoma, SLE, drugs). Positive with C3d alone suggests cold agglutinin disease (BSH 2017).
• DAT negative: look at the film for spherocytes, schistocytes or bite cells, and test G6PD (after the acute episode, since young cells have more enzyme) and haemoglobin variants.

B12 and folate

• Total serum B12 or active B12 (holotranscobalamin) first (NICE 2024):

Total B12	Active B12	Interpretation
Under 133 pmol/L (180 ng/L)	Under 25 pmol/L	Deficiency confirmed
133 to 258 pmol/L	25 to 70 pmol/L	Indeterminate: consider methylmalonic acid
Over 258 pmol/L (350 ng/L)	Over 70 pmol/L	Deficiency unlikely

• NICE allows labs to substitute validated local thresholds where assays vary.
• Nitrous oxide inactivates B12, so serum B12 can be normal. Use MMA or homocysteine first.
• Use active B12 in pregnancy, when total B12 normally falls.
• Cause: intrinsic factor antibody (specific, positive in about half of pernicious anaemia), coeliac serology, and a review of diet, surgery and drugs.
• Red cell folate is less affected by a recent meal than serum folate but is less available. A low serum folate in a sick inpatient often reflects recent intake.

Bone marrow

• For unexplained cytopenias, an abnormal film, suspected MDS, myeloma or infiltration, or anaemia that doesn't respond as expected.

Management

Iron deficiency

• Oral iron once daily or on alternate days; IV iron when oral fails, is not tolerated or is too slow. Investigate the source. Details in Iron deficiency, pallor and fatigue.

B12 deficiency

• Hydroxocobalamin 1,000 micrograms IM. BSH 2014: three times a week for 2 weeks, then every 3 months. With neurological involvement, alternate days until no further improvement, then every 2 months.
• Don't delay treatment for results when neurological symptoms or megaloblastic anaemia are present (NICE 2024). Take the blood first.
• Lifelong IM for autoimmune gastritis (pernicious anaemia), total gastrectomy or terminal ileal resection (NICE 2024). For other malabsorption (coeliac disease, partial gastrectomy, bariatric surgery) NICE suggests considering IM; if oral is used for any malabsorption, give at least 1 mg daily. Diet-related deficiency is treated orally unless there is anaemia, neurological disease, frailty, recent admission or doubt about adherence, when IM is preferred.
• Expect reticulocytes to peak at about day 7 and haemoglobin to normalise over about 8 weeks. Check potassium early in severe anaemia.
• Pernicious anaemia raises the risk of gastric neuroendocrine tumours and possibly adenocarcinoma. Endoscopy for upper GI symptoms.

Folate deficiency

• Folic acid 5 mg daily for about 4 months, after B12 deficiency is excluded or treated.
• Causes: poor diet, alcohol, coeliac disease, haemolysis and exfoliative skin disease (high turnover), methotrexate, trimethoprim, phenytoin, pregnancy.

Anaemia of inflammation

• Hepcidin rises with IL-6, locking iron in macrophages and blocking absorption. Ferritin is normal or high, transferrin saturation low.
• Treat the disease. IV iron if absolute iron deficiency coexists (ferritin under 100 µg/L or transferrin saturation under 20%, measured together: ASH 2026).

Anaemia of CKD

• Replete iron first (KHA 2024 targets ferritin over 100 µg/L and transferrin saturation over 20%; KDIGO 2026 thresholds are in Anaemia of chronic kidney disease), then consider an ESA if haemoglobin stays under about 100 g/L. Aim no higher than about 115 g/L: a target of 130 g/L (darbepoetin) roughly doubled stroke in TREAT. See Chronic kidney disease.

Haemolysis

• Warm autoimmune haemolysis: prednisolone 1 mg/kg, folic acid, VTE prophylaxis; rituximab second line or earlier in severe cases. Cold agglutinin disease: keep warm; steroids don't work. G6PD deficiency: stop the trigger.

Transfusion

• Restrictive thresholds: transfusion is likely appropriate below 70 g/L, may be appropriate at 70 to 100 g/L depending on symptoms and comorbidity, and is rarely needed above 100 g/L. These come from NBA PBM Module 3 (2012), archived by the NBA in July 2026 but still consensus practice. AABB 2023 also supports a 70 g/L threshold for most stable inpatients, with 75 g/L in cardiac surgery and 80 g/L in orthopaedic surgery or pre-existing cardiovascular disease. It makes no recommendation in acute MI, where MINT (2023) trended towards benefit from a liberal threshold; see Complications of blood transfusion.
• Give one unit, then reassess. See Complications of blood transfusion for TACO risk.
• Don't transfuse a stable patient with B12, folate or iron deficiency who can be treated with the haematinic.

Special populations

• Pregnancy: haemoglobin under 110 g/L (under 105 g/L in the second trimester, WHO 2024). Plasma volume expands more than red cell mass. Check ferritin early.
• Older people: anaemia is common but not normal. Look for GI loss, CKD and MDS, and recognise that up to a third have no cause found.
• Aboriginal and Torres Strait Islander people: iron deficiency is common in remote communities, as are CKD and chronic infection.
• Renal impairment: expect a normocytic, hypoproliferative anaemia from G3 onwards, but exclude iron deficiency before blaming the kidneys.

Pitfalls

• Giving folic acid alone in megaloblastic anaemia.
• Missing a B12 myelopathy in a nitrous oxide user because the serum B12 is normal.
• Calling a normocytic anaemia "chronic disease" without checking reticulocytes, iron studies and the film.
• Repeated transfusion of a stable patient with a haematinic deficiency.
• Overlooking a high RDW and normal MCV hiding combined iron and B12 deficiency.
• Testing G6PD during acute haemolysis and getting a falsely normal result.
• Stopping lifelong B12 injections in pernicious anaemia because the count has normalised.