Anaemia

Meet the patient

A 62-year-old man sees his GP for tiredness and breathlessness on the stairs. He has noticed his stools are darker but put it down to iron tablets he never actually took. Hb 78, MCV 68, ferritin 6.[2]

The easy (and wrong) move is to write a prescription for ferrous sulphate and book a follow-up in three months. The consultant's question is the one that finds the cancer: why is a 62-year-old man iron-deficient? Microcytic anaemia in a man or a post-menopausal woman is gastrointestinal blood loss until proven otherwise — the iron tablets can wait until the colonoscopy and oesophagogastroduodenoscopy are booked.[2]

Anaemia is a sign, not a diagnosis — two classifications, one patient

Anaemia is defined by the World Health Organization as a haemoglobin concentration below the lower limit of the normal range for age, sex and physiological state. The number tells you that something is wrong; the MCV, reticulocyte count and film tell you what. The single biggest cognitive error in anaemia is to chase the number with iron or transfusion before asking why.[1]

WHO haemoglobin thresholds (sea level)[1]

Why "anaemia" is a sign — the functional consequences

Haemoglobin is the oxygen carrier: a fall in Hb reduces arterial oxygen content, and oxygen delivery to an organ depends on blood flow, oxygen-carrying capacity and oxygen extraction. The body compensates non-haemodynamically — increased erythropoietin production stimulating erythropoiesis, and increased oxygen extraction via a rightward shift of the oxyhaemoglobin dissociation curve mediated by raised 2,3-diphosphoglycerate — and haemodynamically: increased cardiac output (lower afterload, increased preload, positive inotropic and chronotropic effects, tachycardia). When compensation fails — severe anaemia, or underlying heart disease — tissue hypoxia, angina and high-output failure appear.[16]

Classification — the MCV frame plus the reticulocyte split

There are two complementary classifications — every anaemic patient must be classified by both.[2]

Morphological classification (by MCV)

Kinetic classification (by mechanism)

1. Decreased production (reticulocytes inappropriately low) — substrate or hormone deficiency (iron, B12, folate, EPO), marrow failure (aplastic, infiltration, myelofibrosis), chronic disease (hepcidin block).
2. Increased destruction — haemolysis (reticulocytes high) — hereditary (membrane, enzyme, haemoglobinopathies) versus acquired (immune, microangiopathic, infections, drugs).
3. Blood loss (reticulocytes high once marrow responds, about 5 to 7 days after an acute bleed) — acute (trauma, GI, obstetric) or chronic (menorrhagia, GI, hookworm).[2]

The bedside three-step diagnostic algorithm

• Step 1 — Confirm anaemia (Hb below threshold); check MCV.
• Step 2 — Reticulocyte count (or reticulocyte production index, RPI): low = underproduction; high = haemolysis or bleeding.
• Step 3 — Targeted tests by MCV class (iron studies, haemolysis screen, B12 and folate, marrow).[2]

Epidemiology — the commonest haematological disorder on earth

Anaemia affects an estimated 1.6 to 1.9 billion people — about 25 to 30 percent of the global population — and iron deficiency is responsible for about half of all cases.[1]

Risk-factor profile: pre-school children (under 5) carry the highest prevalence (about 40 to 45 percent globally) from rapid growth, low dietary iron and recurrent infection; pregnant women (about 30 to 40 percent) from fetal demand and expanded maternal blood volume; women of reproductive age from menstruation and repeated pregnancies; older adults (over 65) where causes are multifactorial (chronic disease, GI blood loss from cancer or NSAIDs, B12 deficiency, CKD); chronic disease cohorts (CKD with low EPO, IBD, rheumatoid arthritis, heart failure, malignancy); diet and lifestyle (strict vegan or vegetarian, alcohol excess); geography and ethnicity (thalassaemia in Mediterranean, Middle Eastern, South Asian and South-East Asian populations; sickle cell in sub-Saharan Africa, India, Middle East; G6PD deficiency in malarial belts); drugs (NSAIDs, aspirin, anticoagulants, PPIs, metformin, methotrexate, trimethoprim, phenytoin, chemotherapy, sulfasalazine); and postsurgical (gastrectomy, ileal resection, bariatric surgery — B12 and iron malabsorption).[1]

Pathophysiology — iron, B12/folate and haemolysis

Erythropoiesis and red-cell lifespan

Erythroid precursors mature in the marrow over about 7 days under EPO drive, extruding the nucleus to become reticulocytes, then mature erythrocytes (lifespan about 120 days). A normal marrow replaces the 1 percent of red cells lost daily and can increase output 6 to 8 fold under sustained EPO stimulation. A reticulocyte count above about 2 percent (corrected for anaemia, RPI over 2) therefore indicates the marrow is responding — pointing to haemolysis or blood loss, not underproduction.[4]

Iron homeostasis and the hepcidin axis

The body controls iron balance at absorption and export: iron leaves duodenal enterocytes and macrophages through ferroportin into plasma, where it binds transferrin for delivery to the marrow; stores are held as ferritin and haemosiderin. Hepcidin, a liver peptide hormone secreted in response to iron loading and inflammation, binds ferroportin and induces its internalisation and degradation, blocking iron export: hepcidin overproduction leads to hypoferremia and the anaemia of inflammation, whereas decreased hepcidin leads to tissue iron overload.[11]

Haem synthesis and the megaloblastic mechanism

Red cells are produced by repeated DNA synthesis, which requires vitamin B12 (cobalamin) and folate as coenzymes for thymidylate and purine synthesis. Deficiency of either impairs DNA replication while RNA (and protein) synthesis continues — producing nuclear-cytoplasmic asynchrony (large immature nuclei, abundant cytoplasm). The marrow shows megaloblastic change (giant metamyelocytes, large erythroblasts) and the blood shows macro-ovalocytes and hypersegmented neutrophils (5 or more lobes, or at least 5 percent with 6 lobes). Ineffective erythropoiesis causes intramedullary destruction to raised LDH, raised indirect bilirubin, low haptoglobin and a pancytopenia.[5]

B12 versus folate — absorption and the neurological lesion

• Vitamin B12 (cobalamin) — in the stomach B12 is released from food proteins and binds haptocorrin (R-binder); pancreatic proteases degrade haptocorrin in the duodenum and B12 transfers to intrinsic factor; the B12-intrinsic-factor complex is absorbed through the cubilin-amnionless receptor in the terminal ileum, with transcobalamin delivering B12 to tissues.[17] Deficiency causes megaloblastic anaemia AND neurological impairment — treatment should not be delayed to avoid neurological impairment.[5]
• Folate — absorbed in the proximal small intestine without intrinsic factor; deficiency produces the same megaloblastic anaemia, and serum folate is the first-line test of folate status.[5]

Etymology for viva gold: megaloblastic — from Greek megalos (great) and blastos (bud or germ). The "great bud" is the giant erythroblast in the marrow, arrested mid-division because it cannot copy its DNA. The word survived because the marrow picture is unmistakable once seen.[5]

Haemolysis mechanism

Red-cell destruction occurs intravascularly (free haemoglobin released; depleted haptoglobin; haemoglobinuria, methaemalbumin) or extravascularly (macrophages of spleen and liver; raised unconjugated bilirubin and LDH; spherocytes if antibody-coated). The marrow responds with reticulocytosis within 5 to 7 days.[4]

Clinical presentation — when anaemia declares itself

Anaemia is often well tolerated until severe because non-haemodynamic and haemodynamic compensation maintain oxygen delivery; compensation is limited — in the absence of cardiovascular disorders, congestive heart failure develops only at severe anaemia (Hb below about 40 to 50 g per L), whereas coronary artery disease intensifies angina at much higher haemoglobins, and rapid-onset anaemia tolerates least.[16]

General symptoms (any cause): fatigue, weakness, lethargy, reduced exercise tolerance; dyspnoea on exertion (progressing to dyspnoea at rest when severe); palpitations, exertional chest pain, syncope or near-syncope; light-headedness, headache, tinnitus, difficulty concentrating; cold extremities (peripheral vasoconstriction).[1]

General signs: the compensatory high-output state — tachycardia, increased stroke volume, hyperdynamic circulation, wide pulse pressure — with flow murmurs; long-standing anaemia drives eccentric left ventricular hypertrophy (reversible if the anaemia is corrected before myocardial disease develops), and severe or uncorrected anaemia proceeds to congestive cardiac failure.[16]

Features pointing to a specific cause

• Iron deficiency — koilonychia, angular cheilitis or stomatitis, atrophic glossitis (smooth sore tongue), pica (craving for ice, earth or starch — pagophagia for ice is highly specific), Plummer-Vinson syndrome (dysphagia, oesophageal web, glossitis — risk of post-cricoid cancer), beeturia.
• B12 deficiency — glossitis (beefy red sore tongue), neurological: peripheral neuropathy (paraesthesia, numbness, loss of vibration and joint position sense in the lower limbs first), subacute combined degeneration (spastic paraparesis, extensor plantars, Romberg positive, sensory ataxia), optic atrophy, cognitive impairment or dementia, mood disturbance or psychosis ("megaloblastic madness"), autonomic and bladder or bowel dysfunction. Also mild jaundice (lemon-yellow) from ineffective erythropoiesis, and melanin pigmentation of knuckles.
• Folate deficiency — glossitis and megaloblastic anaemia as above, but no neurological signs; may cause infertility and is teratogenic (neural tube defects).
• Haemolysis — jaundice (lemon-yellow, pre-hepatic), dark urine (haemoglobinuria in intravascular), splenomegaly, gallstones (pigment), leg ulcers (sickle).
• Anaemia of chronic disease — signs of the underlying condition (RA, SLE, CKD, malignancy, chronic infection).
• Aplastic or marrow infiltration — features of pancytopenia: infection (low neutrophils), bleeding (low platelets), mucosal pallor; lymphadenopathy or hepatosplenomegaly suggest infiltration (leukaemia, lymphoma, myelofibrosis).[1]

Differential diagnosis — the three MCV buckets

Microcytic anaemia (MCV under 80 fL)

Normocytic anaemia (MCV 80 to 100 fL)

Macrocytic anaemia (MCV over 100 fL) — megaloblastic versus non-megaloblastic

Clinical and bedside assessment

History structures the questioning around the cause: symptoms of anaemia (onset acute versus chronic, severity, progression); blood loss (overt — melaena, haematemesis, haematuria, menorrhagia; occult — NSAIDs, aspirin, anticoagulants); dietary (vegetarian or vegan, pica, alcohol); GI symptoms (dyspepsia, change in bowel habit, weight loss, dysphagia); gynaecological (menstrual loss, pregnancies); drugs and toxins (NSAIDs, PPIs, metformin, methotrexate, phenytoin, trimethoprim, sulfasalazine, chemotherapy, lead exposure); past history (gastrectomy or bariatric, IBD, CKD, autoimmune disease, malignancy, rheumatoid arthritis); family history (thalassaemia, sickle cell, hereditary spherocytosis, G6PD, pernicious anaemia); travel and exposure (malaria, hookworm, tuberculosis); neurological (paraesthesia, numbness, unsteadiness, visual or cognitive change — B12); and systemic features (fever, night sweats, weight loss — malignancy, infection; bone pain — myeloma, metastases).[1]

Examination looks for the bedside signs: pallor (conjunctiva with the patient looking up is the most reliable), jaundice (haemolysis or ineffective erythropoiesis), lymphadenopathy and hepatosplenomegaly (infiltration, haemolysis, infection), and stigmata of chronic disease (clubbing, koilonychia). Specific cause signs: iron deficiency (koilonychia, angular cheilitis, atrophic glossitis, Plummer-Vinson triad); B12 deficiency (glossitis, impaired vibration and joint position sense tested with a 128 Hz tuning fork at the medial malleolus, spastic paraparesis, extensor plantars, Romberg positive); haemolysis (splenomegaly, frontal bossing and maxillary hypertrophy in chronic congenital haemolysis, leg ulcers); pernicious anaemia or autoimmune (vitiligo, thyroid goitre or scar, signs of Addison — autoimmune polyglandular cluster); lead (gingival blue line, wrist drop, abdominal tenderness). Cardio-respiratory examination grades severity (tachycardia, ejection systolic flow murmur, venous hum, signs of high-output cardiac failure). A rectal examination may reveal melaena (upper GI bleed), fresh blood (lower GI bleed), or a mass.[1]

Investigations — first-line panel, then targeted by MCV

The first-line panel is the FBC, reticulocyte count and peripheral film, supplemented by iron studies in virtually every adult.[2]

Step 1 — confirm and characterise

• Full blood count — Hb, MCV, MCH, MCHC, RDW (red-cell distribution width — raised RDW suggests a mixed or dimorphic population, e.g. iron deficiency developing or recovering, or combined deficiency).
• Reticulocyte count — as percent and absolute count. Corrected reticulocyte count = retic percent times (patient Hct divided by normal Hct). Reticulocyte production index (RPI) = corrected retic divided by 2 (maturation correction). RPI over 2 = adequate marrow response, so haemolysis or blood loss. RPI under 2 = underproduction.
• Peripheral blood film — morphology dictates the next step (microcytic hypochromic, target cells, spherocytes, sickle cells, schistocytes, macro-ovalocytes, hypersegmented neutrophils, blasts, nucleated red cells).[2]

Step 2 — iron studies

Diagnostic ferritin thresholds (BSH and British Society of Gastroenterology): ferritin under 30 micrograms per L is diagnostic of iron deficiency (sensitivity and specificity over 90 percent) in primary care without inflammation. Ferritin under 70 in inflammatory states (CRP raised, infection, malignancy, CKD) — iron deficiency still likely; treat. Ferritin normal or high does NOT exclude iron deficiency in inflammation — measure soluble transferrin receptor (sTfR), sTfR to log ferritin ratio, or proceed to marrow iron stain (gold standard).[2]

Step 3 — by MCV class

If microcytic: ferritin, iron, TIBC, percent saturation (iron studies); Hb electrophoresis or HPLC for thalassaemia (raised HbA2 over 3.5 percent in beta-thalassaemia trait) — send if iron studies normal or after a trial of iron shows no response; blood lead if lead poisoning suspected (occupational, abdominal pain, basophilic stippling, encephalopathy in children); marrow with Prussian-blue stain if sideroblastic suspected (ring sideroblasts) or to confirm iron stores.[2]

If normocytic with high reticulocytes (haemolysis or loss): LDH (raised), haptoglobin (low — most sensitive for haemolysis), indirect (unconjugated) bilirubin (raised), AST (raised, from young red cells), urine haemosiderin or haemoglobin (intravascular haemolysis); direct antiglobulin test (DAT or direct Coombs) — distinguishes immune (positive) from non-immune (negative) haemolysis; osmotic fragility, G6PD assay (not during active haemolysis — reticulocytes have normal enzyme, giving a false-normal result; retest after recovery), flow cytometry for CD55 or CD59 (PNH).[2]

If normocytic with low reticulocytes (underproduction): U&E, eGFR (CKD — low EPO), LFTs, TSH, CRP or ESR (chronic disease), HIV, viral hepatitis, parvovirus B19 IgM or PCR; bone marrow aspirate and trephine biopsy if pancytopenia, blasts, organomegaly or unexplained anaemia — diagnosing aplastic, leukaemia, myelodysplasia, myelofibrosis, infiltration.[2]

If macrocytic: serum B12 and serum and red-cell folate; if B12 borderline or normal but suspicion high — homocysteine (raised in both B12 and folate deficiency) and methylmalonic acid (MMA) (raised in B12 deficiency only) — the most sensitive markers of functional deficiency; intrinsic factor antibodies (highly specific for pernicious anaemia — but sensitivity only 50 percent), anti-parietal cell antibodies (sensitive but less specific), gastrin (high in pernicious anaemia due to achlorhydria); marrow if macrocytosis with pancytopenia and normal B12 or folate (MDS, aplastic).[2]

Step 4 — find the cause of iron deficiency (mandatory in adults)

Iron deficiency in an adult man or post-menopausal woman is GI blood loss until proven otherwise.[2]

• Coeliac serology (anti-tissue transglutaminase IgA plus total IgA) in all patients, especially the young.
• Faecal immunochemical test (FIT) or faecal occult blood.
• Upper GI endoscopy (OGD) — oesophagitis, peptic ulcer, gastric or oesophageal cancer, duodenal biopsy for coeliac.
• Colonoscopy — colorectal cancer, polyps, IBD, angiodysplasia.
• Capsule endoscopy if OGD and colonoscopy negative — small-bowel causes (Crohn, tumours, angiodysplasia).
• In premenopausal women with menorrhagia and otherwise well — gynaecological evaluation; endoscopic work-up reserved for symptoms or non-response to iron.
• Stool microscopy for hookworm in endemic areas; urinalysis (haematuria — schistosomiasis, GU cancer).[2]

Named scores reproduced verbatim

Mentzer index (MCV in fL divided by RBC count in millions per microL): over 13 = iron deficiency anaemia; under 13 = thalassaemia trait.[2]

Corrected reticulocyte count = reticulocyte percent times (patient Hct divided by 45).[2]

Reticulocyte production index (RPI) = corrected reticulocyte count divided by maturation factor (maturation factor = 1.0 at Hct 45 percent, 1.5 at 35 percent, 2.0 at 25 percent). RPI over 2 = adequate marrow response (haemolysis or bleeding); under 2 = underproduction.[2]

Management — resuscitation

The resuscitation priority is tissue oxygenation, not a number: a restrictive strategy of red-cell transfusion is at least as effective as, and possibly superior to, a liberal strategy in critically ill patients, with the possible exception of acute myocardial infarction and unstable angina.[3]

1. Assess ABC; oxygen by mask if hypoxic or shocked; two large-bore cannulae.
2. Identify and control bleeding (trauma, GI — endoscopic or surgical; obstetric).
3. Intravenous access and crystalloid (0.9 percent sodium chloride or balanced crystalloid) for volume if shocked.
4. Group and save or crossmatch; transfuse if:
   • Hb under 70 g per L (7 g per dL) in a stable critically ill adult — the restrictive TRICC trigger (transfuse below 7.0, maintain 7.0 to 9.0 g per dL), at least as effective as, and possibly superior to, a liberal strategy.[3]
   • Symptoms, or Hb under 80 g per L (8 g per dL), in older postoperative patients with cardiovascular risk factors — the FOCUS restrictive arm was non-inferior to a liberal 10 g per dL threshold.[8]
   • Acute upper GI bleeding — transfuse below 7 g per dL rather than 9 (restrictive improved survival and reduced rebleeding).[9]
   • With the possible exception of acute myocardial infarction and unstable angina, where the TRICC authors counselled caution.[3]
5. Transfuse slowly with monitoring — every unit carries risk; restrictive thresholds and transfusion avoidance are the guiding principles.[3]
6. Avoid transfusing to treat chronic iron-deficiency — reserve transfusion for patients with, or at risk of, cardiovascular instability due to the degree of their anaemia; treat the deficiency with iron.[7]

Specific resuscitation scenarios: acute upper GI bleed — a restrictive strategy (transfuse when Hb falls below 7 g per dL) improved 6-week survival versus a liberal 9 g per dL strategy (95 vs 91 percent), with less further bleeding (10 vs 16 percent) and fewer adverse events (40 vs 48 percent); the portal-pressure gradient rose only in the liberal group — over-transfusion worsens portal haemodynamics.[9] Megaloblastic crisis or severe B12 deficiency with neurological signs — treat without delay to avoid neurological impairment; parenteral therapy is standard and RCT evidence shows haematological and neurological responses with both oral and IM regimens.[5][13] Severe haemolysis — transfuse if life-threatening; resuscitate from vital signs and treat the cause.[7]

Management — definitive and stepwise

Treat the cause, not the number. After resuscitation, definitive therapy is cause-specific. The four common examinable treatments are iron, vitamin B12, folate and erythropoiesis-stimulating agents.[2]

1. Iron deficiency anaemia

Principle — replace stores (not just correct Hb), and find and treat the cause.[2]

Oral iron — first line:[2]

• Oral iron is first-line — supplementation is given both to correct the anaemia and to replenish body stores.[7]
• Dose and schedule: classic regimens divide the daily dose (study regimens use 60 to 120 mg iron), but alternate-day dosing produces higher fractional absorption than consecutive-day dosing, and once-daily beats twice-daily split dosing — consecutive and split doses raise serum hepcidin and blunt absorption of subsequent doses.[10]
• Take on an empty stomach where tolerated, and separate administration from agents that reduce absorption.
• Expected response: follow the reticulocyte indices and haemoglobin trajectory, and continue until both anaemia and stores are restored.[7]
• Adverse effects: intolerance is the main problem — reducing to once-daily or alternate-day dosing improves both tolerability and fractional absorption.[10]
• If oral iron is not tolerated, parenteral iron is the recognised alternative.[7]
• Special oral: liquid ferrous fumarate or ferric ammonium citrate for children and those unable to swallow tablets.

Intravenous iron — second line:[2]

• Indications: intolerance of oral iron is the guideline-recognised indication for parenteral iron; ongoing losses and malabsorption are practical extensions.[7]
• Agents: ferric carboxymaltose (FCM) and ferric derisomaltose (iron isomaltoside, IIM) permit high-dose replacement; head-to-head safety data centre on their effects on phosphate (below).[15]
• Cautions: hypophosphataemia — FCM induced hypophosphataemia in 47 percent of patients across 42 trials versus 4 percent with IIM, persisting (up to 3 months) in up to 45 percent of FCM-treated patients — monitor phosphate after high-dose replacement, particularly when baseline ferritin is low.[15]

Find and treat the cause — GI workup mandatory in adults.[2]

Erythropoiesis-stimulating agents (ESAs) — indicated for the anaemia of chronic kidney disease, where epoetin alfa corrects erythropoietin-deficient anaemia — but target modestly, not normalisation: a target of 13.5 g per dL versus 11.3 g per dL (CHOIR) increased the composite of death, myocardial infarction, stroke and hospitalisation for heart failure (hazard ratio 1.34) with no incremental quality-of-life improvement and more serious adverse events at the higher target.[12]

2. Vitamin B12 deficiency

IM hydroxocobalamin is standard UK primary-care practice for B12 deficiency — most people are treated with intramuscular vitamin B12.[13]

UK BSH guidance (British Society of Haematology):[5]

• Treat without delay when the clinical picture strongly suggests deficiency, to avoid neurological impairment; treat per British National Formulary regimens.[5]
• Oral therapy may be suitable and acceptable provided appropriate doses are taken and compliance is not an issue.[5]
• RCT evidence on regimens: oral 2000 micrograms daily was at least as effective as IM 1000 micrograms initially daily, thereafter weekly and then monthly, for short-term haematological and neurological responses.[13]

Response and monitoring: hypokalaemia must be detected and treated during treatment of megaloblastic anaemia, and patients should be reassessed after treatment; concurrent infection should also be sought.[22]

3. Folate deficiency

• Folate deficiency — serum folate is the first-line test of folate status (equivalent to red-cell folate) and oral folic acid is the treatment.[5]
• CRITICAL: always exclude or treat coexisting B12 deficiency — when clinical features of cobalamin deficiency are strong, treatment should not be delayed to avoid neurological impairment; if both deficiencies are possible, treat both together.[5]
• Prophylaxis: folic acid supplementation starting before conception prevents neural tube defects — a 72 percent reduction in recurrence among high-risk women (MRC Vitamin Study).[14]

4. Other cause-specific treatments

• Anaemia of chronic disease (anaemia of inflammation) — hepcidin-mediated iron trapping; treat the underlying inflammatory disease.[11]
• Aplastic anaemia — frontline immunosuppressive therapy is horse antithymocyte globulin plus cyclosporine A; bone marrow transplant is pursued in younger patients with a matched sibling donor.[18]
• Anaemia of CKD — ESAs correct erythropoietin-deficient anaemia; use restrained Hb targets.[12]

Specific subtypes and scenarios

• Iron deficiency anaemia in depth — the commonest cause; in adult men and post-menopausal women, GI blood loss from colonic or gastric cancer and malabsorption in coeliac disease are the most important causes to seek.[7]
• Anaemia of chronic disease (anaemia of inflammation) — hepcidin overproduction causes hypoferremia by trapping iron in macrophages and enterocytes: low serum iron despite adequate stores.[11]
• Megaloblastic anaemia — B12 deficiency in depth. B12 deficiency arises from inadequate dietary intake (vegans) or malabsorption from digestive disease — loss of intrinsic factor (pernicious anaemia), gastrectomy, pancreatic insufficiency and terminal-ileum disease or resection.[17] Treatment should not be delayed to avoid neurological impairment.[5]
• Folate deficiency in depth — periconceptional folic acid supplementation prevents neural tube defects.[14]
• Acute blood loss — resuscitate from vital signs; reserve transfusion for patients with, or at risk of, cardiovascular instability due to the degree of anaemia, and replace iron stores afterwards.[7]
• Pregnancy-associated anaemia — 38 percent of pregnant women globally were anaemic in 2011; daily iron-folic acid supplementation in Indian pregnancy (per Anaemia Mukt Bharat guidelines) raised mean Hb from about 9.4 to 12.0 g per dL with high adherence.[6][25]
• Anaemia of prematurity — iron deficiency in infancy has long-lasting detrimental neurodevelopmental effects — prevent and treat early.[21]
• Anaemia in CKD — erythropoietin deficiency; ESA therapy with restrained Hb targets.[12]
• Anaemia in the elderly — multifactorial; restrictive transfusion thresholds are safe even with cardiovascular risk factors.[8]
• Anaemia in malignancy — treat the underlying disease; high Hb targets with ESA therapy increase cardiovascular risk.[12]

Complications and pitfalls

Complications of untreated anaemia: high-output cardiac failure (tachycardia, cardiomegaly, pulmonary oedema, peripheral oedema) in chronic severe anaemia; angina and myocardial infarction in those with coronary disease; cognitive impairment (especially iron deficiency in children — developmental delay, may be irreversible); impaired immunity; in pregnancy — preterm delivery, low birth weight, pre-eclampsia, postpartum haemorrhage, perinatal mortality; B12 deficiency neurological damage — permanent if untreated; tissue hypoxia — syncope, falls in the elderly.[1]

Complications of transfusion: transfusion is not risk-free — the reason trials support restrictive thresholds: TRICC found restrictive transfusion at least as effective as, and possibly superior to, liberal transfusion in critically ill patients (possible exception: acute MI and unstable angina),[3] FOCUS found no benefit of a liberal threshold in elderly patients with cardiovascular risk factors,[8] and in acute upper GI bleeding the restrictive strategy reduced adverse events (40 vs 48 percent).[9]

The classic pitfalls: treating the number, not the cause (e.g. transfusing chronic iron deficiency, missing a colon cancer); assuming iron deficiency without a GI work-up in men or post-menopausal women — always investigate; giving folate alone in B12 deficiency — precipitates or worsens subacute combined degeneration; misreading ferritin as normal in inflammation — measure CRP, sTfR, or marrow iron; missing a mixed deficiency (iron plus B12) — MCV may be normal, check both; over-transfusing the elderly or those with heart failure — risk TACO, single-unit prescribing; diagnosing G6PD deficiency during active haemolysis — false normal (young reticulocytes), retest after recovery; treating beta-thalassaemia trait with iron — ineffective and causes overload; confusing cold-agglutinin artefact with true macrocytosis — MCHC raised, MCV spuriously high; failure to detect ongoing blood loss during iron therapy — Hb fails to rise, reassess for occult bleeding.[1]

Prognosis and disposition

• Nutritional deficiency (iron, B12, folate) — good with treatment; treat cobalamin deficiency without delay to avoid neurological impairment.[5]
• Iron deficiency in early childhood — can have long-lasting detrimental neurodevelopmental effects — prevention matters.[21]
• Anaemia with heart disease — anaemia intensifies angina in coronary disease; the eccentric LV hypertrophy of chronic anaemia is reversible if corrected before decompensation; congestive heart failure supervenes only in the most severe chronic anaemia.[16]
• Severe untreated anaemia — urgent cause-directed therapy; restrictive transfusion strategies minimise exposure and risk.[3]

Disposition: outpatient — most chronic stable anaemia (oral iron, B12, folate, follow-up). Inpatient (ward) — symptomatic anaemia needing transfusion, severe B12 with neurology, haemolysis requiring therapy, diagnostic uncertainty with pancytopenia. ICU — massive haemorrhage, severe symptomatic anaemia with cardiac failure, transfusion reaction. Specialist referral — haematology (marrow disease, transfusion dependence, haemolysis), gastroenterology (iron-deficiency work-up), nephrology (CKD, ESA), gynaecology (menorrhagia), obstetrics (pregnancy).[1]

Special populations

Pregnancy

• Anaemia in pregnancy affects 38 percent of pregnant women globally — south Asia carries the heaviest burden.[6]
• Routine iron and folic acid supplementation in pregnancy — daily IFA per Indian (Anaemia Mukt Bharat) guidelines raises Hb substantially.[25]
• Oral iron first-line; parenteral iron when oral preparations are not tolerated.[7]
• Avoid transfusion for iron deficiency — reserve transfusion for cardiovascular instability.[7]
• Folic acid from before conception prevents neural tube defects.[14]

Children

• Iron deficiency is the commonest childhood cause — iron-deficiency anaemia and iron deficiency without anaemia during infancy can have long-lasting detrimental effects on neurodevelopment; appropriate iron intakes for infants and toddlers and screening strategies are set out in the AAP clinical report.[21]
• Risk groups: preterm and low-birth-weight infants and unbalanced diets — prevention is the goal.[21]
• Anaemia affected 43 percent of children aged 6 to 59 months globally in 2011 — the highest-prevalence group.[6]
• Transfusion in children — restrictive thresholds are standard: in stable critically ill children, transfusing at Hb under 7 g per dL (versus 9) prevented one transfusion for every two children treated without increasing organ dysfunction.[19]

Elderly

• Restrictive thresholds are safe in the elderly — in patients aged 50 or over with cardiovascular disease or risk factors after hip-fracture surgery, a symptoms-guided strategy (transfuse for symptoms or Hb under 8 g per dL) matched a liberal 10 g per dL threshold for death and independent walking.[8]
• Atypical presentations — heart failure, angina, falls, confusion; anaemia intensifies angina and contributes to heart failure when coronary disease coexists.[16]
• Multifactorial causes are common — investigate rather than attribute to ageing: iron deficiency in older adults demands GI evaluation for cancer and coeliac disease.[7]

Immunocompromised, transplant or HIV

• Anaemia of chronic disease, drug marrow toxicity (zidovudine, ganciclovir, chemotherapy), parvovirus B19 pure red-cell aplasia (treat with IV immunoglobulin), opportunistic infection, malignancy.
• Irradiate cellular blood products to prevent transfusion-associated GVHD; CMV-negative products if CMV-seronegative transplant candidate.
• Leucodeplete all products.[1]

Anticoagulated or antiplatelet patients

• Increased GI bleeding risk (warfarin, DOACs, aspirin, clopidogrel) — check INR, drug levels; reverse per protocol if life-threatening bleed; balance bleeding versus thrombotic risk during transfusion or investigation.[1]

Evidence, guidelines and regional differences

Landmark evidence

• TRICC (Hébert 1999, NEJM) — restrictive strategy (transfuse when Hb under 7 g per dL, maintain 7.0 to 9.0) was at least as effective as, and possibly superior to, a liberal strategy in critically ill adults (30-day mortality 18.7 vs 23.3 percent), with the possible exception of acute MI and unstable angina.[3]
• TRIPICU (Lacroix 2007, NEJM) — in stable critically ill children, a transfusion threshold of 7 g per dL versus 9 g per dL avoided transfusion (NNT 2) without increasing new or progressive multiple-organ dysfunction.[19]
• FOCUS (Carson 2011, NEJM) — in elderly hip-fracture patients with cardiovascular risk factors, a liberal 10 g per dL threshold did not improve death or independent walking versus restrictive care.[8]
• Villanueva 2013 (NEJM) — in acute upper GI bleeding, restrictive (7 g per dL) beat liberal (9 g per dL): better survival, less rebleeding, fewer adverse events.[9]
• PREVENTT (2020, Lancet) — preoperative IV iron for anaemia before major open abdominal surgery did not reduce transfusion or death at 30 days.[20]

Regional differences

Controversies

• Oral versus IV iron first — oral remains first-line; IV iron first is increasingly advocated in IBD, heart failure, late pregnancy, dialysis and when rapid correction is needed.
• Oral iron schedule — alternate-day dosing produces higher fractional absorption than consecutive-day or split dosing, because repeated doses raise serum hepcidin and blunt absorption.[10]
• Hypophosphataemia after ferric carboxymaltose — 47 percent incidence across 42 trials versus 4 percent with iron isomaltoside; monitor phosphate, especially with low baseline ferritin.[15]
• Preoperative IV iron — PREVENTT found no reduction in transfusion or 30-day death with preoperative IV iron before major open abdominal surgery.[20]
• ESA targets — a higher Hb target (13.5 vs 11.3 g per dL) increased the composite of death, MI, stroke and heart-failure hospitalisation without quality-of-life gain.[12]
• Transfusion in upper GI bleed — restrictive (7 g per dL) improves survival; liberal transfusion raised the portal-pressure gradient.[9]
• B12 oral versus IM — oral 2000 micrograms daily matched IM regimens for short-term haematological and neurological response.[13]

Exam pearls

High-yield one-liners

• Most common cause of anaemia worldwide = iron deficiency.
• Iron deficiency in an adult man or post-menopausal woman = GI blood loss until proven otherwise.[2]
• Ferritin is an acute-phase reactant — false normal or high in inflammation; use sTfR or marrow.
• TIBC rises in iron deficiency, falls in ACD — the single best discriminator.
• Macro-ovalocytes plus hypersegmented neutrophils = megaloblastic anaemia (B12 or folate).
• NEVER delay B12 treatment when deficiency is clinically likely — treatment should not be delayed to avoid neurological impairment; treat cobalamin alongside folate.[5]
• Subacute combined degeneration = B12 deficiency (dorsal plus lateral columns; loss of vibration or proprioception, spastic paraparesis, extensor plantars).
• Methylmalonic acid raised in B12 but NOT folate deficiency — best discriminator.
• Reticulocyte count is the single most useful test to split anaemia into underproduction versus destruction or loss.
• RPI over 2 = haemolysis or blood loss; under 2 = underproduction.
• Pernicious anaemia = anti-intrinsic-factor antibodies; achlorhydria; increased gastric cancer risk.
• Restrictive transfusion (transfuse when Hb under 7 g per dL) is at least as effective as, possibly superior to, liberal in critical illness; a symptoms-guided threshold (under 8 g per dL) was safe in elderly cardiovascular-risk patients.[3][8]
• TRICC trial — restrictive (under 70) transfusion is non-inferior to liberal.
• Hypokalaemia can complicate B12 or folate treatment (vigorous erythropoiesis).
• Oral iron until anaemia AND stores are restored; alternate-day dosing improves fractional absorption.[7][10]
• B12 deficiency: parenteral therapy is standard; oral 2000 micrograms daily is effective — treat without delay if neurological features.[13]
• Pagophagia (ice pica) is highly specific for iron deficiency.
• Plummer-Vinson syndrome = iron deficiency plus dysphagia plus oesophageal web plus glossitis; risk of post-cricoid carcinoma.
• MDS is the commonest cause of sideroblastic anaemia in older adults.
• Lead poisoning inhibits ferrochelatase and ALA dehydratase; basophilic stippling, abdominal pain, neuropathy, encephalopathy in children.
• Nitrous oxide inactivates methionine synthase — can cause rapid B12 deficiency in recreational users.
• Metformin causes B12 deficiency — check in long-term diabetics.
• Cold agglutinins spuriously raise MCV (and MCHC) — artefact.
• G6PD assay is unreliable during active haemolysis — retest after recovery.
• Ferric carboxymaltose causes hypophosphataemia far more often than derisomaltose — monitor phosphate after high-dose replacement.[15]
• Anaemia Mukt Bharat — India's national anaemia-reduction programme; NFHS-5 found anaemia in 57 percent of women aged 15 to 49.[23]

The mantra

MCV first, retics second; iron deficiency in a man is cancer until scoped; never folate alone if B12 is possible; transfuse the patient, not the number.[1]

Ward-round test

Stem 1 — the man with the dark stools

A 62-year-old man, Hb 78, MCV 68, ferritin 6. The registrar prescribes ferrous sulphate. What must happen first?[2]

Answer

Find the cause — GI blood loss until proven otherwise. Book coeliac serology, an OGD and a colonoscopy before (or alongside) iron, because microcytic anaemia in a man or post-menopausal woman assumes colorectal cancer until excluded. Iron can be started, but the GI work-up is mandatory and not deferred to a 3-month follow-up.[2]

Stem 2 — the tingling and the macrocytes

A 70-year-old vegan, Hb 72, MCV 112, film shows hypersegmented neutrophils and macro-ovalocytes, paraesthesia and loss of vibration sense in the feet. What is the diagnosis, the first drug, and what must you NOT do?[5]

Answer

B12 deficiency with subacute combined degeneration. Treat without delay to avoid neurological impairment — parenteral therapy is standard UK practice, and RCT evidence shows IM 1000 micrograms initially daily, then weekly, then monthly and oral 2000 micrograms daily are both effective for short-term haematological and neurological response.[13] Do NOT give folate alone — treat the cobalamin deficiency concurrently.[5] Watch for and treat hypokalaemia during treatment.[22]

Stem 3 — the bleeding patient and the number

A 28-year-old with a massive GI bleed has Hb 65 and is tachycardic and postural. What transfusion target applies, and why not aim higher?[3]

Answer

In acute upper GI bleed, use a restrictive transfusion strategy: transfuse when Hb falls below 7 g per dL rather than 9 g per dL — 6-week survival was better (95 vs 91 percent), further bleeding less frequent (10 vs 16 percent), adverse events fewer, and the portal-pressure gradient rose only in the liberal group.[9] Resuscitate from vital signs, not the haemoglobin, and secure urgent endoscopy.

Stem 4 — the microcytic film and the index

A 25-year-old woman from a thalassaemia-endemic region has Hb 105, MCV 70, RBC count 6.2 million per microL. What index splits iron deficiency from thalassaemia trait?[2]

Answer

The Mentzer index = MCV divided by RBC count. Here 70 divided by 6.2 = 11.3, under 13 — thalassaemia trait (iron deficiency is over 13). Confirm with Hb electrophoresis (raised HbA2 over 3.5 percent in beta-thalassaemia trait). Iron therapy is ineffective and harmful — do not treat trait with iron.[2]

References

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2. [2]Fletcher A, Forbes A, Svenson N, et al. Guideline for the laboratory diagnosis of iron deficiency in adults (excluding pregnancy) and children. Br J Haematol, 2022.PMID 34693519
3. [3]Hébert PC, Wells G, Blajchman MA, et al. A multicenter, randomized, controlled clinical trial of transfusion requirements in critical care. Transfusion Requirements in Critical Care Investigators, Canadian Critical Care Trials Group. N Engl J Med, 1999.PMID 9971864
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