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How to investigate and treat anaemia – for doctors, medical students and exams


Causes of anaemia

  • May be classified as inherited vs. acquired, or disorders of red cell production vs. excessive loss, although there is some overlap, e.g. chronic bleeding leads to iron deficiency and chronic haemolysis leads to folate deficiency.
  • Note in pregnancy plasma volume rises and therefore Hb concentration falls, but this is physiological and not a disease state.
Inherited causes due to defective production
  • Thalassaemia (inadequate production of alpha or beta chains of haemoglobin)
  • Other inherited anaemias (congenital dyserythropoietic anaemia, Diamond-Blackfan anaemia, Schwachman-Diamond syndrome, sideroblastic anaemia)
Inherited causes due to increased destruction (haemolysis)
  • Structural haemoglobin defects (sickle cell anaemia, HbC disease, HbE disease)
  • Red cell membrane defects (hereditary spherocytosis, elliptocytosis, and pyropoikilocytosis)
  • Red cell enzyme defects (G6PD deficiency, pyruvate kinase deficiency)
Acquired causes due to defective production
  • Deficiencies
    • Iron, vitamin B12 or folate deficiency
    • Low erythropoietin due to chronic kidney disease
  • Inflammation
    • ‘Anaemia of chronic disease’
    • HIV infection
  • Marrow issues
    • Bone marrow poisoning due to alcohol, cytotoxic drugs, antibiotics
    • Bone marrow infiltration (by haematological malignancy or solid organ malignancy)
    • Myelofibrosis
    • Myelodysplastic syndrome
    • Bone marrow aplasia due to viral infection (transient) or idiopathic aplastic anaemia (persistent)
  • Liver disease
Acquired causes due to excessive loss or destruction
  • Bleeding
  • Haemolysis, immune-mediated
    • Warm autoimmune haemolytic anaemia
    • Cold agglutinin disease
    • Paroxysmal cold haemoglobinuria
    • Drug-induced haemolytic anaemia
    • Haemolytic disease of the newborn
    • Post-transfusion haemolytic reactions
  • Haemolysis, non-immune mediated
    • Mechanical heart valves
    • Congenital heart defects
    • March haemoglobinuria
    • Spur cell anaemia
    • Paroxysmal nocturnal haemoglobinuria
    • Microangiopathic haemolytic anaemia (DIC, HUS, TTP)
    • Infection (malaria, C. perfringens)
    • Burns
    • Oxidant drugs (dapsone, primaquine, sulfonamides, sulfasalazine)
    • Hypersplenism
  • Note causes of haemolysis may also be categorised as intravascular or extravascular


Video on the basics of anaemia


History in anaemia

  • Presenting complaint
    • Shortness of breath
    • Fatigue
    • Dizzyness
    • Angina (where co-incident coronary artery disease)
    • Incidental finding (commonly)
  • History of presenting complaint
    • Duration and onset of symptoms
    • History of bleeding [menstrual most commonly, also traumatic, epistaxis, oral bleeding, melaena/PR bleeding, haematuria]
    • Recent infection [cold agglutinin following Mycoplasma infection, red cell aplasia following viral infections esp. Parvovirus B19]
    • Associated symptoms [renal failure and low platelets suggest HUS,
  • Past medical history
    • Chronic kidney disease or liver disease
    • Previous cancers and previous chemotherapy or radiotherapy
    • Lymphoproliferative disease (increased risk of autoimmune haemolytic anaemia)
    • Congenital, ischaemic or valvular heart disease
    • Gastrointestinal malabsorption [coeliac disease, inflammatory bowel disease] or malnutrition
    • Gallstones (increased bile pigments in chronic haemolysis)
    • Ischaemic or valvular heart disease (will exacerbate symptoms)
  • Medications
    • Marrow aplasia [trimethoprim, penicillamine, carbimazole, propylthiouracil, carbamazepine]
    • Drug-induced autoimmune haemolysis [beta lactam antibiotics, NSAIDs, co-trimoxazole]
    • Haemolysis via oxidative damage to erythrocytes [dapsone, ribavirin, rifampicin, primaquine, paraquat]
    • Proton pump-inhibitors and H2 antagonists impair iron absorption by increasing gastric pH.
  • Family history
    • There may be a family history in autosomal dominant inherited anaemias (hereditary spherocytosis) or common autosomal recessive anaemias (sickle cell and thalassaemias)
    • G6PD deficiency is X-linked recessive, so affected males may have an affected maternal grandfather.
  • Social history
    • Alcohol excess
    • Diet (vegetarian / vegan), tea (inhibits iron absorption)


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Examination in anaemia

  • Signs of anaemia
    • Pallor, particularly conjunctival
    • Hyperdynamic circulation [bounding pulse, flow murmur]
  • Signs of iron, vitamin B12 and folate deficiency
    • Kolionychia (iron deficiency only)
    • Atrophic glossitis
    • Angular chelitis
  • Signs of haemolysis
    • Jaundice & scleral icterus
    • Dark urine
  • Signs of bleeding
    • Excessive bruising
    • Petechiae
    • Telangiectasiae or larger vascular malformations
  • Signs of malignancy
    • Muscle wasting
    • Oedema
    • Organomegaly
    • Lymphadenopathy
    • Palpable soft tissue masses


Investigation of anaemia

  • FBC
    • MCV (low in iron deficiency/thalassaemia/sickle cell, raised in B12 or folate deficiency, myelodysplasia, liver disease and brisk bleeding or haemolysis)
    • MCH (low in iron deficiency and thalassaemia, usually falls earlier than MCV)
    • Platelets (raised in iron deficiency, low in bone marrow failure)
    • White cell count (raised in inflammatory states, low in bone marrow failure)
  • Reticulocyte count (raised in bleeding/haemolysis, low in bone marrow failure or haematinic deficiencies)
  • Blood film
    • Pencil cells in iron deficiency
    • Oval macrocytes and polylobated neutrophils in B12/folate deficiency
    • Spherocytes and polychromasia in extravascular haemolysis
    • Schistocytes in intravascular haemolysis
    • Target cells and acanthocytes in liver disease
    • Stomatocytes in alcohol toxicity
    • Target cells, Howell-Jolly bodies in hyposplenism
    • Bite cells (oxidative stress such as G6PD deficiency)
    • Basophilic stippling in thalassaemia, alcohol toxicity and lead poisoning
    • Tear drop cells and nucleated red cells in myelofibrosis
    • Sickle cells
    • Burr cells/echinocytes in renal failure
    • Rouleux in myeloma
  • U&E, LFT, B12, folate, ferritin
  • If haemolysis is suspected: LDH, unconjugated bilirubin, haptoglobin (falls in intravascular haemolysis)
  • If haemolysis is proven: direct antiglobulin test (DAT; Coombs test)
  • If myeloma is suspected: serum electrophoresis and urinary free light chains (Bence-Jones protein) or serum free light chains
  • If an inherited haemoglobinopathy is suspected: haemoglobin electrophoresis
  • If a primary bone marrow pathology is suspected, bone marrow aspirate and trephine


Further investigation of iron deficiency anaemia

  • The gold standard test for iron deficiency is a bone marrow aspirate but this is rarely practical.
  • In otherwise well patients, serum ferritin closely corresponds to iron stores and so is  useful test for iron deficiency.
  • In the setting of acute inflammation, serum ferritin rises so it loses its utility as a test.
  • Serum iron concentration fluctuates with diurnal rhythm and falls in inflammation, so it and transferrin saturation are also rarely helpful. Soluble transferrin receptor levels are less influenced by inflammation but not widely available.
  • Acquired hypochromia, and to a lesser extent microcytosis, is almost always due to iron deficiency.
  • In the absence of menorrhagia, proven iron-deficiency anaemia should be investigated with upper and lower GI endoscopies.


Management of anaemia

  • Find and treat cause if possible. Specific management includes:
  • Emergencies
  • Deficiencies
    • Replace haematinics
    • e.g. folic acid 5mg PO once daily, hydroxocobalamin 1mg IM three times a week for two weeks, or ferrous fumarate 210mg twice daily with orange juice.
  • Warm autoimmune haemolytic anaemia
    • Steroid e.g. prednisolone 1mg/kg PO once daily and then wean slowly.
  • Cold haemolytic anaemias
    • Often be managed by avoiding cold exposure.
  • Anaemia in renal failure
    • Treated with iron supplementation if reticulocyte Hb <29pg, and erythropoietin if necessary, to maintain Hb between 100-120g/L.
  • Myelodysplasia
    • In myelodysplasia with isolated anaemia, erythropoietin therapy may avoid transfusion-dependence.
  • Irreversible bone marrow failure
    • Should be treated with transfusion aimed at minimising symptoms of anaemia.


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