Assessment of anaemia

history of trauma (including gunshot wounds, major fractures, crush injuries); history of prior bleeding episodes; or use of anticoagulants or non-steroidal anti-inflammatory drugs (NSAID)

evidence of injury (wounds, bruises, deformities), hypotension, pallor, tachycardia, thready pulse, dyspnoea/air hunger, altered mental status or confusion; flat neck veins when supine indicate at least 30% to 40% total body volume loss

• FBC:

  normal or decreased haematocrit; decreased haemoglobin; reactive leukocytosis and thrombocytosis due to a stress response, thrombocytopenia from dilutional effect of multiple transfusions

• prothrombin time/activated partial thromboplastin time:

  usually normal; prolonged with anticoagulants, underlying defects in haemostasis, or consumptive coagulopathy

  More prothrombin time/activated partial thromboplastin time

  Consumptive coagulopathy may be due to repeated blood transfusions or to disseminated intravascular coagulation.

• joint or spine x-rays:

  identification of fractures

• diagnostic laparotomy:

  identification of bleeding source

• CT scan of affected body region:

  identification of internal injuries

history of prior episodes of gastrointestinal bleeding, gastritis, peptic ulcer disease, hiatal hernia, neoplastic disease, non-steroidal anti-inflammatory drug (NSAID) or corticosteroid use, alcohol use, cirrhosis, anticoagulants, ulcerative colitis, diverticular disease; symptoms of rectal bleeding, melaena, haematemesis, abdominal pain

hypotension, pallor, tachycardia, thready pulse, dyspnoea/air hunger, altered mental status or confusion; flat neck veins when supine indicate at least 30% to 40% total blood volume loss; ascites, hepatomegaly/splenomegaly, cirrhotic hard liver, caput medusae, gynaecomastia, melaena, or bright red blood on rectal examination

• FBC:

  normal or decreased haematocrit; decreased haemoglobin; reactive leukocytosis and thrombocytosis due to a stress response

• reticulocyte count:

  >2%

  More reticulocyte count

  average delay of 3-4 days before reticulocyte response, after acute blood loss.

• prothrombin time/activated PTT:

  usually normal; prolonged in cirrhosis, anticoagulant therapy, or underlying defects in haemostasis; elevated urea may be seen

• upper gastrointestinal endoscopy:

  bleeding varices or ulcers if source is from upper gastrointestinal tract

• colonoscopy:

  visualisation of bleeding lesion or mass

sudden tearing pain, affecting the back, abdomen or chest depending on aneurysm location, may be accompanied by loss of consciousness if major vessel involved; history of hypertension, collagen disorders, trauma, cocaine or amphetamine use

hypotension, pallor, tachycardia, dyspnoea/air hunger, altered mental status or confusion; flat neck veins when supine indicate at least 30% to 40% total blood volume loss; wide pulse pressure or absent distal pulses; thready pulse, may rapidly progress to circulatory collapse and death

• FBC:

  normal or decreased haematocrit; decreased haemoglobin; reactive leukocytosis and thrombocytosis due to a stress response

• reticulocyte count:

  >2%

  More reticulocyte count

  average delay of 3-4 days before reticulocyte response, after acute blood loss.

• ultrasonography of affected region:

  shows extent and nature of aneurysm

  More ultrasonography of affected region

  Intravascular ultrasound is more accurate if patient is stable.

• CT scan of affected region:

  shows extent and nature of aneurysm

  More CT scan of affected region

  Spiral CT or MRI are better if patient is stable.[Figure caption and citation for the preceding image starts]: CT scan of a ruptured abdominal aortic aneurysmUniversity of Michigan, specifically the cases of Dr Gilbert R. Upchurch reflecting the Departments of Vascular Surgery and Radiology [Citation ends].

• chest x-ray:

  may show widened mediastinum in thoracic aortic aneurysm

  More chest x-ray

  [Figure caption and citation for the preceding image starts]: Chest x-ray showing a widened mediastinumFrom the collection of Professor James Brown; used with permission [Citation ends].

Abdominal aortic aneurysm

recent surgery with at least moderate blood loss; history of bleeding disorders or excessive bruising; use of antibiotics

hypotension, pallor, tachycardia, thready pulse, continuous bleeding from surgical wound, petechiae, purpura; severe bleeding produces dyspnoea/air hunger, altered mental status or confusion; flat neck veins when supine indicate at least 30% to 40% total blood volume loss

• FBC:

  normal or decreased haematocrit; decreased haemoglobin; reactive leukocytosis and thrombocytosis due to a stress response

• reticulocyte count:

  >2%

• ultrasound of affected region:

  shows source and extent of bleeding

• CT scan of affected region:

  shows source and extent of bleeding

• diagnostic laparotomy:

  shows source and extent of bleeding

excessive menstrual bleeding; fatigue, dyspnoea on exertion, pica; history of fibroids

pallor, adnexal masses or fibroids

• FBC:

  chronic microcytic anaemia with normal WBC; reactive thrombocytosis if iron deficient

• serum ferritin:

  <33 picomol/L (<15 micrograms/L) if iron deficient

• pregnancy test:

  negative

• prothrombin time/activated partial thromboplastin time:

  usually normal; prolonged with anticoagulants, underlying defects in haemostasis, or consumptive coagulopathy

• thyroid-stimulating hormone (TSH)/free thyroxine (T4):

  elevated TSH with low free T4 in hypothyroidism

• transvaginal ultrasound:

  may see hyperplasia, dysplasia, fibroids, or polyps

  More transvaginal ultrasound

  Endometrial carcinoma should be excluded in patients >40 years.

Assessment of menorrhagia

history of poor dietary iron intake, coeliac disease, Crohn's disease, ulcerative colitis, small bowel resection, peptic ulcer disease, regular running, chronic blood loss (melaena, haematuria, menorrhagia, haemoptysis, frequent blood donation, self-harm), pica, salicylate ingestion, gastric bypass, hookworm infestation, pregnancy, or menorrhagia

pallor, dyspnoea, poor exercise tolerance, koilonychia, angular cheilosis, glossitis, thinning hair, systolic flow murmur; haemorrhoids, fresh blood or melaena on rectal examination; evidence of pregnancy; adnexal masses or fibroids

• FBC with peripheral smear:

  microcytic anaemia with thrombocytosis

• serum iron studies:

  low serum iron, elevated total iron-binding capacity, low ferritin, elevated soluble transferrin receptor

• immunoglobulin A-tissue transglutaminase (IgA-tTG) test:

  positive in coeliac disease

  More immunoglobulin A-tissue transglutaminase (IgA-tTG) test

  Guaiac can react with food or medicine leading to a false-positive result, but quantitative faecal immunochemical tests (FITs) use antibodies specific to the globin part of human haemoglobin to detect small amounts of blood. As globin degrades while traversing the gastrointestinal tract, theoretically these tests are less likely to detect globin from upper gastrointestinal bleeding.[65]National Institute for Health and Care Excellence. Quantitative faecal immunochemical tests to guide referral for colorectal cancer in primary care. 26 July 2017 [internet publication]. https://www.nice.org.uk/guidance/dg30 UK and US guidelines report risk thresholds for testing among low- to average-risk symptomatic populations.[51]National Institute for Health and Care Excellence. Suspected cancer: recognition and referral. 29 January 2021 [internet publication]. https://www.nice.org.uk/guidance/ng12 [52]Rex DK, Boland CR, Dominitz JA, et al. Colorectal cancer screening: recommendations for physicians and patients from the US Multi-Society Task Force on Colorectal Cancer. Am J Gastroenterol. 2017 Jul;112(7):1016-30. https://journals.lww.com/ajg/Fulltext/2017/07000/Colorectal_Cancer_Screening__Recommendations_for.13.aspx http://www.ncbi.nlm.nih.gov/pubmed/28555630?tool=bestpractice.com [53]National Comprehensive Cancer Network. Colorectal cancer screening. Jun 2020 [internet publication]. In 2021, the UK's National Institute for Health and Care Excellence added certain quantitative FITs to its guidance on recognition and referral for patients at low risk of colorectal cancer without rectal bleeding.[51]National Institute for Health and Care Excellence. Suspected cancer: recognition and referral. 29 January 2021 [internet publication]. https://www.nice.org.uk/guidance/ng12

• upper gastrointestinal endoscopy:

  identification of source of upper gastrointestinal bleeding; elevated gastric pH in achlorhydria

• colonoscopy:

  identification of source of lower gastrointestinal bleeding or chronic inflammation

• CT colonography:

  identification of source of lower gastrointestinal bleeding

  More CT colonography

  Useful alternative for patients who cannot tolerate colonoscopy.

• flow cytometry:

  identification of paroxysmal nocturnal haemoglobinuria

• transvaginal ultrasound:

  may see hyperplasia, dysplasia, fibroids, or polyps

  More transvaginal ultrasound

  Endometrial carcinoma should be excluded in patients aged >40 years.

• stool microscopy:

  visualisation of hookworm, whipworm, or Schistosoma eggs

• Helicobacter pylori test:

  positive result if H pylori present

  More Helicobacter pylori test

  Following negative endoscopy in the setting of persistent iron deficiency anaemia, H pylori testing may be considered when malignancies, B12 deficiency, and idiopathic thrombocytopenic purpura have been excluded.[50]Public Health England. Helicobacter pylori in dyspepsia: test and treat. 5 September 2019 [internet publication]. https://www.gov.uk/government/publications/helicobacter-pylori-diagnosis-and-treatment

Iron deficiency anaemia

history of coeliac or Crohn's disease, autoimmune thyroid disease, gastric bypass, chronic antibiotic use (intestinal bacterial overgrowth syndrome), vegan diet or alcohol abuse; fatigue, palpitations, distal paraesthesias, depression, confusion, tinnitus, dementia

impaired vibration sense and extremity numbness, vitiligo, glossitis, poor balance or co-ordination, tachycardia, pallor, hepatosplenomegaly

• FBC with peripheral smear:

  megaloblastic macrocytic anaemia; basophilic stippling may be seen

• serum vitamin B12 levels:

  low

• serum methylmalonic acid levels:

  elevated

  More serum methylmalonic acid levels

  Confirms deficiency if B12 levels are borderline.

• anti-intrinsic factor antibodies:

  positive in pernicious anaemia

• antiparietal cell antibodies:

  positive in pernicious anaemia

Vitamin B12 deficiency

history of coeliac or Crohn's disease, gastric bypass, haemodialysis, pregnancy, alcohol abuse, or use of anti-seizure medications; fatigue, palpitations, headaches

mild persistent pyrexia, tachycardia, pallor, hepatosplenomegaly, glossitis, angular stomatitis, patchy hyperpigmentation of skin and mucous membranes

• FBC with peripheral smear:

  megaloblastic macrocytic anaemia; basophilic stippling may be seen

• serum folate:

  low

• serum vitamin B12 levels:

  normal; low in combined vitamin B12 and folate deficiency

  More serum vitamin B12 levels

  Neurological symptoms will worsen if folate is corrected in the presence of low vitamin B12.

• serum homocysteine levels:

  elevated

Folate deficiency

history of prior exposure to petroleum distillates (especially benzene), chemotherapy, or radiotherapy; fever, chills, fatigue, weakness, recurrent infection, anorexia, night sweats, shortness of breath, easy bruising

pallor, petechiae, purpura

• FBC:

  macrocytic anaemia with leukopenia, macro-ovalocytes; associated cytopenias include neutropenia and thrombocytopenia

• reticulocyte count:

  <2%

• bone marrow aspiration and biopsy:

  myeloblasts with immature precursors

  More bone marrow aspiration and biopsy

  Prussian blue iron staining of bone marrow aspirate can show ringed sideroblasts - abnormal erythroid precursor cells which have granules around the nucleus.

• cytogenetics of bone marrow biopsy:

  multiple chromosomal translocations possible, especially 5q-, 7q-, or trisomy 8 (+8)

• serum vitamin B12:

  normal

• folate:

  normal

Myelodysplastic syndrome

malaise, fatigue, easy bruising or bleeding, recurrent infections, fever, arthralgias, infection, anorexia, night sweats, shortness of breath, bony tenderness, epistaxis, bleeding gums, gingival hyperplasia

pallor, petechiae, purpura, tachycardia, hepatosplenomegaly, lymphadenopathy, painless scrotal enlargement, bleeding gums

• FBC with peripheral smear:

  pancytopenia, with ≥20% blasts; normocytic anaemia; may see hypereosinophilia

  More FBC with peripheral smear

  Up to 10% of patients do not have peripherally circulating blasts.

• reticulocyte count:

  <2%

• bone marrow aspirate and biopsy:

  ≥20% blasts

  More bone marrow aspirate and biopsy

  Immunohistochemistry, cytochemistry, and cytogenetics help to further classify disease.

Acute lymphocytic leukaemia

history of prior chemotherapy or radiotherapy; malaise, night sweats, fatigue, easy bruising or bleeding, recurrent infections, fever, bony tenderness, epistaxis, bleeding gums, gingival hyperplasia

pallor, petechia, purpura, dyspnoea, tachycardia

• FBC with peripheral smear:

  pancytopenia, with ≥20% blasts; normocytic anaemia; may see hypereosinophilia

  More FBC with peripheral smear

  Cytoplasmic granules indicate myeloid lineage of blasts. May also see Auer's rods.[Figure caption and citation for the preceding image starts]: Peripheral blood film of a patient with acute myelogenous leukaemia showing myeloid blasts with an Auer rodFrom the collection of Dr Kavita Raj and Dr Priyanka Mehta; used with patient consent [Citation ends].

• reticulocyte count:

  <2%

• bone marrow aspirate and biopsy:

  ≥20% blasts

  More bone marrow aspirate and biopsy

  Immunohistochemistry, cytochemistry, and cytogenetics help to further classify disease.

Acute myelogenous leukaemia

usually in middle-aged patients; fatigue, weight loss, night sweats, early satiety, petechiae, purpura, recurrent fevers, bone pain, gouty arthritis

tender splenomegaly, painful sternum, lymphadenopathy, splenomegaly

• FBC with peripheral smear:

  normocytic anaemia; myeloid maturing cells, elevated basophils, and eosinophils

• reticulocyte count:

  <2%

• bone marrow aspirate and biopsy:

  hypercellular with granulocytic hyperplasia

• cytogenetics:

  t(19;22) Philadelphia chromosome - bcr-abl translocation

• serum uric acid:

  elevated

  More serum uric acid

  Due to elevated leukocyte count and turnover.

Chronic myelogenous leukaemia

weakness, fatigue, weight loss, night sweats, early satiety, petechiae, purpura, recurrent fevers, abdominal discomfort or fullness due to large spleen

massive splenomegaly

• FBC with peripheral smear:

  pancytopenia with normocytic anaemia

  More FBC with peripheral smear

  Characteristic mononuclear 'hairy' cells, which stain positive for tartrate-resistant acid phosphatase

• reticulocyte count:

  <2%

• bone marrow aspirate and biopsy:

  core biopsy shows hairy cells

  More bone marrow aspirate and biopsy

  [Figure caption and citation for the preceding image starts]: Cytospin prepared from bone marrow aspirate illustrates the typical cell cytology, with oval- to bean-shaped nuclei and moderate amounts of cytoplasm with irregular cytoplasmic borders (Wright Giemsa 100x oil)From the collection of Lynn Moscinski, MD; used with permission [Citation ends].

Hairy cell leukaemia

history of hepatitis, HIV, benzene exposure, use of known causative medications, radiation exposure, paroxysmal nocturnal haemoglobinuria; malaise, fatigue, easy bruising or bleeding, recurrent infections, fever

pallor, petechiae, purpura, dyspnoea, tachycardia

• FBC with peripheral smear:

  pancytopenia with mild macrocytosis; normocytic anaemia

• reticulocyte count:

  <2%

• bone marrow aspirate and biopsy:

  hypocellular with decrease in all elements, replaced mostly by fat cells; no infiltration by fibrosis or malignant cells

  More bone marrow aspirate and biopsy

  Residual hematopoietic cells are morphologically normal

• serum vitamin B12:

  normal

• folate:

  normal

Aplastic anaemia

weight loss, malaise, fevers, fatigue, dyspnoea, easy bleeding or bruising; history of solid organ malignancy (particularly breast, prostate, lung, neuroblastoma)

pallor, petechiae, purpura, tachycardia, abnormal exam or presence of mass (if solid organ malignancy), bruising, cachexia

• FBC with peripheral smear:

  pancytopenia, teardrop cells, poikilocytes; normocytic anaemia

• reticulocyte count:

  <2%

• bone marrow aspirate and biopsy:

  infiltration of marrow space by malignant cells

  More bone marrow aspirate and biopsy

  Provide history to pathologist so appropriate stains can be ordered if metastatic malignancy is suspected.

• CT imaging:

  identification of site of primary malignancy

self-limiting disease: history of use of known causative medications, clinical features of causative infections (parvovirus B19, infectious mononucleosis, viral hepatitis, malaria, respiratory infections, gastroenteritis, primary atypical pneumonia, mumps); chronic disease: history of autoimmune disease (systemic lupus erythematosus [SLE], rheumatoid arthritis, dermatomyositis, scleroderma, polyarteritis nodosa), persistent infection, or thymoma

clinical signs of underlying infection or autoimmune disease

• FBC:

  normocytic anaemia

• reticulocyte count:

  <2%

• trial of discontinuation of causative medication:

  anaemia resolves

• antiparvovirus B19 antibodies:

  positive in parvovirus infection

  More antiparvovirus B19 antibodies

  The most common infectious cause.

• thick and thin peripheral smear:

  intracellular parasites seen with Wright's or Giemsa staining in malaria infection

• serum IgM + IgG anti-HAV:

  positive in hepatitis A infection

• serum IgM + IgG HBcAb:

  positive in hepatitis B infection

• serum HBsAg:

  positive in hepatitis B infection

• serum IgM + IgG anti-HCV:

  positive in hepatitis C infection

• antinuclear antibodies:

  positive in SLE or scleroderma

• ds-DNA, Smith's antigen:

  positive in SLE

• rheumatoid factor:

  positive in rheumatoid arthritis

• serum creatine kinase:

  elevated in dermatomyositis

• chest x-ray:

  infiltrates in atypical pneumonia; smooth mass in thymoma, typically projecting into one of the hemi-thoraces and obscuring the aortic arch, or silhouette sign

known or suspected ingestion of causative drug prior to onset of anaemia, poor exercise tolerance

pallor, jaundice (with haemolytic anaemia only), dyspnoea

• FBC with peripheral smear:

  typically normocytic anaemia; inhibitors of DNA synthesis, folate, or vitamin B12 produce megaloblastic macrocytic anaemia

• reticulocyte count:

  <2% if drugs suppress bone marrow; >2% if drugs produce haemolysis

• trial of discontinuation of causative medication:

  anaemia resolves

• serum bilirubin:

  elevated in haemolytic anaemia

history of known chronic inflammatory, autoimmune, or infectious states; sustained physiological stress, renal failure, heart failure, vasculitis or collagen vascular diseases, poor exercise tolerance; anaemia correlates with severity of inflammatory process

pallor, fatigue, dyspnoea; specific signs of underlying disease

• FBC:

  normocytic anaemia

  More FBC

  May be microcytic if anaemia of chronic disease is co-existent with iron deficiency anaemia.

• serum iron studies:

  low/normal serum iron, low total iron-binding capacity and normal/elevated ferritin; ferritin normal or elevated in acute-phase reaction

  More serum iron studies

  When anaemia of chronic disease is co-existent with iron deficiency anaemia, these parameters may be different.

• serum erythropoietin level:

  normal or elevated; often decreased in chronic kidney disease

  More serum erythropoietin level

  Elevation, if present, is usually inadequate to compensate for the degree of anaemia.

Anaemia of chronic disease

chronic kidney disease, poor exercise tolerance; features of secondary hypoparathyroidism: muscle cramps, bone pain

pallor, fatigue, dyspnoea; signs of renal failure: jaundice, skin bruising, lung rales, pericardial rub, oedema, poor concentration or memory, myoclonus; positive Chvostek's sign or Trousseau's sign in associated hyperparathyroidism

• FBC:

  normocytic or microcytic anaemia with thrombocytosis

• reticulocyte count:

  <2%

• serum creatinine:

  elevated

• urinalysis:

  haematuria and/or proteinuria

• serum iron studies:

  low serum iron and normal/elevated ferritin, high total iron-binding capacity in iron deficiency

• serum erythropoietin level:

  normal or decreased

• serum calcium level:

  decreased in associated secondary hyperparathyroidism

• serum intact parathyroid hormone level:

  increased in associated secondary hyperparathyroidism

• renal ultrasound:

  small kidney size; presence of obstruction or hydronephrosis; kidney stones

• kidney biopsy:

  identification of underlying kidney pathology

Chronic kidney disease

history of chronic liver disease, poor exercise tolerance; may be asymptomatic or with fatigue, weakness, weight loss, recurrent infections, decreased libido; altered mental status in hepatic encephalopathy

pallor, fatigue, dyspnoea, jaundice, lower-extremity swelling; hand and nail features: leukonychia, palmar erythema, finger clubbing, spider angiomata; facial features: telangiectasia, bruising, rhinophyma, parotid gland swelling, paper-dollar appearance of skin, seborrhoeic dermatitis, xanthelasma; abdominal features: caput medusae, bruising, hepatomegaly, splenomegaly, abdominal distension; in males, loss of secondary sexual hair and testicular atrophy, gynaecomastia

• FBC:

  non-megaloblastic macrocytic anaemia; thrombocytopenia may be present

• prothrombin time:

  decreased in hepatic synthetic dysfunction

• LFTs:

  abnormal; pattern depends on underlying cause

• abdominal ultrasound, CT, or MRI scanning:

  liver surface nodularity, small liver, possible hypertrophy of left/caudate lobe, evidence of ascites or collateral circulation

• liver biopsy:

  diagnosis of underlying cause or subsequent cirrhosis

Cirrhosis

pregnancy, especially in third trimester

abdominal distension consistent with pregnancy, pallor

• FBC:

  microcytic anaemia with thrombocytosis in iron deficiency; megaloblastic macrocytic anaemia in folate deficiency

• serum iron studies:

  low serum iron, elevated total iron-binding capacity, low ferritin, elevated soluble transferrin receptor in iron deficiency

• serum folate:

  low in folate deficiency

Overview of pregnancy complications

protein calorie deprivation; malabsorption syndrome; neglect; history of an eating disorder

loss of subcutaneous fat, apathy and lethargy, depigmentation, enlarged abdomen, winged scapula, flaky skin, bipedal oedema

• FBC with peripheral smear:

  microcytic anaemia in iron deficiency; megaloblastic macrocytic anaemia in vitamin B12 and folate deficiency; normocytic anaemia with combined vitamin and mineral deficiencies

• serum iron studies:

  low serum iron, elevated total iron-binding capacity, and low ferritin in iron deficiency

• serum vitamin B12:

  low

• serum folate:

  low

• serum copper level:

  low

  More serum copper level

  Copper deficiency needs to be considered in patients on prolonged total parenteral nutrition.

history of myelosuppressive chemotherapy; fatigue; headaches; poor exercise tolerance

pallor, lethargy, dyspnoea

• FBC:

  pancytopenia with a normocytic anaemia

  More FBC

  Counts usually reach nadir 7 to 10 days after administration of chemotherapy.

• reticulocyte count:

  <2%

history of recent radiation exposure, especially to pelvic or sternal areas; fatigue, headaches, poor exercise tolerance

pallor, lethargy, dyspnoea, skin erythema on radiation sites

• FBC:

  anaemia (pancytopenia)

• reticulocyte count:

  <2%

• bone marrow aspirate and biopsy:

  marrow fibrosis or malignant infiltration

history of chronic high alcohol intake

overweight status, increased prominence of superficial cutaneous vasculature, peripheral neuropathy, alterations in normal dentition and halitosis, possible signs of liver disease: hepatomegaly or small liver, jaundice, ascites

• FBC:

  macrocytic anaemia

• diagnostic interview:

  diagnosis of alcohol dependence

• alcohol level (breath and blood):

  elevated

Alcohol-use disorder

history of occupational or recreational exposure to lead products or old paint; neuropsychiatric disturbance, insomnia, abdominal pain, poor appetite, pica

blue gingival line (Burton's line), hypertension, gout (saturnine gout); wrist or foot drop

• FBC with peripheral smear:

  normocytic anaemia with basophilic stippling; microcytic anaemia if associated iron deficiency is present

• reticulocyte count:

  >2%

• whole blood lead level:

  elevated

Lead toxicity

weakness, lethargy, slow speech, feeling cold, forgetfulness, constipation, weight gain, poor exercise tolerance

pallor; dyspnoea; coarse, dry skin; eyelid oedema; thick tongue; facial oedema; bradycardia

• FBC:

  non-megaloblastic macrocytic anaemia

• serum thyroid-stimulating hormone:

  elevated

• serum thyroxine:

  reduced

• reticulocyte count:

  <2%

Primary hypothyroidism

history of autoimmune diseases (systemic lupus erythematosus [SLE], rheumatoid arthritis, or scleroderma), lymphoproliferative disorders (non-Hodgkin's lymphoma or chronic lymphocytic leukaemia), recent viral illness, or mononucleosis; may be asymptomatic; symptoms include weakness, fatigue, headaches, poor exercise tolerance, prior gallstones, dark urine, clay-coloured stools

pallor, lethargy, dyspnoea, tachycardia, jaundice, splenomegaly (especially if extravascular haemolysis)

• FBC with peripheral smear:

  normocytic anaemia, with spherocytes

• reticulocyte count:

  >2%; usually 4%

  More reticulocyte count

  The elevated reticulocyte count may incorrectly increase MCV on automated counters.[Figure caption and citation for the preceding image starts]: Peripheral blood smear with spherocytes, reticulocytes, and a nucleated red blood cell (RBC)From the collection of John Densmore, Department of Medicine, University of Virginia; used with permission [Citation ends].

• LDH:

  elevated

• haptoglobin:

  low

• direct antiglobulin (Coombs') test:

  usually positive; negative in 5% to 10% of cases

• serum bilirubin:

  elevated

• antinuclear antibodies:

  positivein SLE or scleroderma

• ds-DNA, Smith antigen:

  positive in SLE

• rheumatoid factor:

  positive in rheumatoid arthritis

Haemolytic anaemia

multiple prior transfusions; fever, back pain, and dyspnoea, usually within 6 hours of transfusion

pallor, lethargy, dyspnoea, dark urine, jaundice

• ABO typing:

  discrepancy to blood used for transfusion

  More ABO typing

  Most commonly a clerical error. Stop transfusion immediately and stabilise patient.

• inspection of plasma in centrifuged, anticoagulated venous blood sample:

  clear or pink-red within first few hours of haemoglobinaemia

• inspection of centrifuged urine:

  clear red in haemoglobinaemia

• direct antiglobulin (Coombs') test:

  IgG anti-A, anti-B, or anti-AB detected on circulating red cells

• serum bilirubin:

  elevated

Transfusion reaction

history of mosquito bite or habitation in malaria-prone region; fatigue, dyspnoea, fevers and prostration, decreased exercise tolerance, headaches, malaise; symptoms usually cycle every 48 to 72 hours, coinciding with red blood cell (RBC) destruction

jaundice or pallor, splenomegaly, dyspnoea, high flow cardiac murmur, pulmonary oedema, dark urine, fevers

• FBC:

  normocytic anaemia ± thrombocytopenia and leukopenia

• reticulocyte count:

  >2%; usually 4%

• thick and thin peripheral smear:

  intracellular parasites seen with Wright's or Giemsa staining

  More thick and thin peripheral smear

  Banana-shaped gametocytes or multiple signet-ring forms in RBCs are typical for Plasmodium falciparum, which requires hospital admission.

• serum bilirubin:

  elevated

Malaria infection

perinatal exposure, direct body fluid transmission, exposure to foodborne outbreak (in hepatitis A); nausea, vomiting, abdominal pain, fever, malaise, fatigue and headache, dark urine, acholic (clay-coloured) stools, jaundice, pruritus (in hepatitis B); hepatitis C is usually asymptomatic

jaundice, hepatomegaly, right upper quadrant pain, acholic stools, maculopapular or urticarial skin rash (in hepatitis B); usually normal in hepatitis C

• FBC:

  normocytic anaemia

• reticulocyte count:

  <2%

• serum aminotransferases:

  elevated

• serum IgM + IgG anti-HAV:

  positive in hepatitis A infection

• serum IgM + IgG HBcAb:

  positive in hepatitis B infection

• serum HBsAg:

  positive in hepatitis B infection

• serum IgM + IgG anti-hepatitis C virus:

  positive in hepatitis C infection

Assessment of liver dysfunction

usually seen in pregnant or immunosuppressed patients and newborns; history of exposure to domestic cats, sheep, or cattle, or to raw meat

jaundice, fever, fatigue, lethargy, rash, hepatosplenomegaly; newborns infected in utero may have chorioretinitis, microcephaly, seizures, mental retardation

• FBC:

  normocytic anaemia and thrombocytopenia; may see leukocytosis and eosinophilia

• reticulocyte count:

  >2%; usually 4%

• IgM enzyme-linked immunosorbent assay (ELISA) or IgG avidity test:

  IgM detected in acute infection; IgG detected in chronic or previous exposure

  More IgM enzyme-linked immunosorbent assay (ELISA) or IgG avidity test

  IgM may persist long after infection; its absence excludes infection.

• Sabin-Feldman dye test:

  IgG antibodies positive

• polymerase chain reaction for Toxoplasma gondii:

  positive

Toxoplasmosis

history of exposure to sandfly bite, especially in tropical or subtropical zones; AIDS, immunosuppression, or malnutrition; fatigue and anorexia; prolonged, persistent, low-grade intermittent fevers; failure to thrive, distended abdomen

pallor, jaundice, hepatosplenomegaly, lymphadenopathy, diarrhoea, skin ulcerations, nasopharyngeal ulcerations

• FBC:

  normocytic anaemia, thrombocytopenia, leukopenia, erythroblastosis

• Leishmania serology:

  positive for Leishmania antibodies, or antibody titre above locally validated threshold

  More Leishmania serology

  Recommended to confirm diagnosis of suspected visceral leishmaniasis.[66]Aronson N, Herwaldt BL, Libman M, et al. Diagnosis and treatment of leishmaniasis: clinical practice guidelines by the Infectious Diseases Society of America (IDSA) and the American Society of Tropical Medicine and Hygiene (ASTMH). Clin Infect Dis. 2016 Dec 15;63(12):1539-57. https://academic.oup.com/cid/article/63/12/1539/2645617 http://www.ncbi.nlm.nih.gov/pubmed/27941143?tool=bestpractice.com

  Considered the test of choice in immunocompetent patients with suspected visceral leishmaniasis, but it is less sensitive in immunosuppressed patients.

• reticulocyte count:

  >2%

• polymerase chain reaction:

  Leishmania DNA

  More polymerase chain reaction

  Recommended to confirm diagnosis of suspected cutaneous or visceral leishmaniasis, if available. More sensitive than microscopic examination or parasite culture for the diagnosis of suspected cutaneous and visceral leishmaniasis cases.[67]Aronson N, Herwaldt BL, Libman M, et al. Diagnosis and treatment of leishmaniasis: clinical practice guidelines by the Infectious Diseases Society of America (IDSA) and the American Society of Tropical Medicine and Hygiene (ASTMH). Clin Infect Dis. 2016 Dec 15;63(12):1539-57. https://academic.oup.com/cid/article/63/12/1539/2645617 http://www.ncbi.nlm.nih.gov/pubmed/27941143?tool=bestpractice.com

  Sensitivity estimates range from 70% to 100% when using tissue biopsies for cutaneous leishmaniasis diagnosis and when using peripheral blood for visceral leishmaniasis diagnosis.[68]Reithinger R, Dujardin JC. Molecular diagnosis of leishmaniasis: current status and future applications. J Clin Microbiol. 2007 Jan;45(1):21-5. https://www.doi.org/10.1128/JCM.02029-06 http://www.ncbi.nlm.nih.gov/pubmed/17093038?tool=bestpractice.com

• splenic or bone marrow aspirate:

  presence of amastigotes of the parasite

  More splenic or bone marrow aspirate

  Splenic aspirate is most sensitive technique (>95%), but carries a 1:1000 risk of major bleeding; considerable technical expertise is required.[69]Kager PA, Rees PH. Splenic aspiration. Review of the literature. Trop Geogr Med. 1983 Jun;35(2):111-24. http://www.ncbi.nlm.nih.gov/pubmed/6351381?tool=bestpractice.com

  Examination of bone marrow aspirate or lymph node fluid is safer, but is of lower sensitivity (70% to 90% and 58%, respectively).

• direct antiglobulin (Coombs') test:

  positive

Leishmaniasis

acute infection: characteristic skin rash with or without arthralgia

acute infection: 'slapped cheek' appearance followed by a reticular erythematous eruption on extremities, and arthritis of hands, wrists, knees, or ankles

• FBC:

  normocytic anaemia

• reticulocyte count:

  <2%

• antiparvovirus B19 antibodies:

  positive

  More antiparvovirus B19 antibodies

  Used to exclude parvovirus when typical clinical features are absent.

Erythema infectiosum

fatigue, malaise, sore throat, nausea, ocular pain, photophobia

fever, lymphadenopathy, pharyngitis, rash, tender splenomegaly, palatal petechiae, periorbital oedema, jaundice

• FBC with peripheral smear:

  normocytic anaemia, with spherocytes and atypical lymphocytes

• reticulocyte count:

  >2% and usually 4% in haemolytic anaemia, <2% in pure red cell aplasia

• LDH:

  elevated

• haptoglobin:

  low

• monospot test or viral capsid antigen (VCA) IgM:

  positive

Infectious mononucleosis

infection is usually asymptomatic; a maculopapular rash following administration of antibiotics may occur; fatigue occurs due to anaemia; symptomatic infection is a sign of underlying immunosuppression

usually normal; jaundice occurs due to haemolytic anaemia; symptomatic infection produces fever, lymphadenopathy, pharyngitis, rash, tender splenomegaly, palatal petechiae, periorbital oedema

• FBC:

  normocytic anaemia

• reticulocyte count:

  >2%; usually 4%

• LDH:

  elevated

• haptoglobin:

  low

• monospot test or viral capsid antigen (VCA) IgM:

  negative

  More monospot test or viral capsid antigen (VCA) IgM

  Rules out Epstein-Barr virus, which is clinically indistinguishable from CMV.

• CMV IgM:

  positive

Cytomegalovirus infection

known diagnosis of sickle cell disease in patient and/or parents; prior painful vaso-occlusive crises; fatigue, poor exercise tolerance, persistent pain in skeleton, chest, or abdomen, priapism, gallstones, stroke, lower-extremity skin ulcers, pneumonia-like syndrome

high fever, pallor, lethargy, dyspnoea, jaundice during acute crisis

• FBC with peripheral smear:

  normocytic anaemia with sickle cells

  More FBC with peripheral smear

  Pancytopenia occurs in aplastic crisis (usually self-limiting).[Figure caption and citation for the preceding image starts]: Red cells in sickle cell diseaseFrom the personal collection of Sophie Lanzkron, MD; used with permission [Citation ends].

• reticulocyte count:

  >2%

• haemoglobin (Hb) isoelectric focusing:

  elevated HbS/A ratio (close to 100/0)

• LDH:

  elevated

• serum bilirubin:

  elevated

Sickle cell anaemia

family history of blood disorders, especially requiring repeated transfusions; Mediterranean, Middle Eastern, or Southeast Asian descent; variable severity ranging from asymptomatic to severe transfusion-dependent symptoms

splenomegaly, jaundice, abdominal distension, icterus; skeletal abnormalities, large head, chipmunk facies, and misaligned teeth seen in beta-thalassaemia intermedia and major

• FBC with peripheral smear:

  microcytic anaemia with MCV typically closer to 70 fL, low mean corpuscular haemoglobin (Hb); target cells seen

• Hb electrophoresis:

  elevated HbF; other Hb patterns consistent with respective thalassaemias

• serum ferritin:

  elevated in iron overload

Beta-thalassaemia

family history of blood disorder, splenectomy, or pigmented gallstones; may be asymptomatic if extramedullary haematopoiesis compensates

may be normal or show pallor, jaundice, lower leg skin ulcers, splenomegaly

• FBC with peripheral smear:

  normocytic anaemia, with increased mean corpuscular haemoglobin and spherocytes

• reticulocyte count:

  >2%

• osmotic fragility test:

  positive (cells lyse on exposure to hypo-osmotic solution)

• direct antiglobulin (Coombs') test:

  negative

  More direct antiglobulin (Coombs') test

  Excludes immune-mediated haemolytic anaemias.

Hereditary spherocytosis

usually in males of African, Mediterranean, Sardinian, or Sephardic Jewish descent; self-limiting episodes of acute haemolysis when exposed to oxidant stress; life-threatening symptoms more common with the Mediterranean variant

pallor, jaundice, mild dyspnoea

• FBC with peripheral smear:

  normocytic anaemia with Heinz bodies, eccentrocytes, or bite cells

  More FBC with peripheral smear

  Heinz bodies are rapidly cleared by the spleen within 24 hours, resulting in 'bite cells'.

• reticulocyte count:

  >2%

• serum haptoglobin:

  decreased

• LDH:

  elevated

• G6PD enzyme assays:

  quantitative or qualitative abnormalities

  More G6PD enzyme assays

  May be falsely negative during the acute haemolytic event, owing to the destruction of affected cells.

• serum bilirubin:

  elevated indirect bilirubin

• direct antiglobulin (Coombs') test:

  negative

  More direct antiglobulin (Coombs') test

  Distinguishes glucose-6-phosphate dehydrogenase deficiency from immune haemolytic anaemias.

Glucose-6-phosphate dehydrogenase deficiency

recurrent infection shortly after birth, fever, easy bleeding or bruising, organ abnormalities, short stature

ill-appearing, with weight loss, pallor, lethargy, dyspnoea, petechiae, purpura, and/or thrush

• FBC with peripheral smear:

  pancytopenia with normocytic or macrocytic anaemia

  More FBC with peripheral smear

  Causes include Fanconi anaemia, dyskeratosis congenita, and Shwachman-Diamond syndrome.

• reticulocyte count:

  <2%

• bone marrow aspiration and biopsy:

  varies depending on underlying cause

• diepoxybutane or mitomycin-c fragility test:

  positive in Fanconi anaemia

• genetic testing:

  characteristic genetic mutations detected

acute renal failure usually following an enteric bacterial infection (Escherichia coli 0157:H7) with bloody diarrhoea, or Streptococcus pneumoniae; ciclosporin, tacrolimus, clopidogrel, oral contraceptive pills, and some chemotherapy drugs may cause haemolytic uraemic syndrome

pallor, lethargy, dyspnoea, petechiae, purpura, bloody diarrhoea; usually self-limiting in children

• FBC with peripheral smear:

  normocytic anaemia, thrombocytopenia, schistocytes

• erythrocyte count:

  >2%

• prothrombin time/activated PTT:

  normal

  More prothrombin time/activated PTT

  Excludes disseminated intravascular coagulation.

• serum haptoglobin:

  decreased

• LDH:

  elevated

• serum creatinine:

  may be elevated

• serum bilirubin:

  elevated

• direct antiglobulin (Coombs') test:

  negative

  More direct antiglobulin (Coombs') test

  Excludes immune-mediated haemolytic anaemias.

• stool culture and polymerase chain reaction tests:

  postive for enterohaemorrhagic E. coli genes

• enzyme-linked immunosorbent assay:

  positive for Shiga toxin

• urinalysis:

  may show haematuria and/or proteinuria

Haemolytic uraemic syndrome

ongoing severe infection, sepsis (typically gram-negative), malignancy, obstetric emergency, trauma, burns, envenomations, drug overdose, any cause of endothelial damage

diffuse bleeding, especially from puncture sites or minor trauma; unprovoked clots; clinical signs of underlying cause

• FBC with peripheral smear:

  normocytic anaemia, thrombocytopenia, schistocytes

• prothrombin time:

  prolonged

• activated partial thromboplastin time:

  varies depending on factor VII levels

• DIC panel:

  elevated D-dimer and fibrin degradation products with low fibrinogen

  More DIC panel

  Fibrinogen may be normal or elevated as an acute-phase reactant.

Disseminated intravascular coagulation

non-specific prodrome followed by headache, confusion, focal weakness, seizures, coma; menorrhagia may be seen due to bleeding

pallor, lethargy, dyspnoea, purpura, ecchymoses

• FBC with peripheral smear:

  normocytic anaemia with schistocytes

• reticulocyte count:

  >2%

• direct antiglobulin (Coombs') test:

  negative

  More direct antiglobulin (Coombs') test

  Excludes immune-mediated haemolytic anaemias.

Thrombotic thrombocytopenic purpura

typically young child or infant with expanding vascular skin lesion; may also be hepatic or in other visceral site

depends on location of lesion(s), which are typically reddish-brown or violaceous; other symptoms consistent with anaemia

• FBC with peripheral smear:

  normocytic anaemia, thrombocytopenia

  More FBC with peripheral smear

  Platelet sequestration in enlarging haemangiomas (Kasabach-Merritt syndrome) can cause life-threatening bleeding.

• reticulocyte count:

  >2%

• x-ray of suspected region:

  soft-tissue shadows, phleboliths

• MRI of suspected region:

  increased signal on both T1- and T2-weighted images with areas of signal void

Haemangioma

history of essential hypertension, renal disease, or eclampsia; older age, male gender, black ethnicity; dizziness, headache, mental status changes, loss of sensation or motor strength, chest pain or pressure, dyspnoea, oedema

systolic BP >210 mmHg and diastolic BP >130 mmHg, lethargy, new murmurs, third heart sound on auscultation of heart, jugular venous distension, rales or lower-extremity oedema, oliguria or polyuria, focal neurological signs, hypertensive retinopathy

• FBC with peripheral smear:

  normocytic anaemia with schistocytes

• reticulocyte count:

  >2%

• ECG:

  evidence of ischaemia or infarct such as ST- or T-wave changes

• serum creatinine:

  elevated with renal failure

• chest x-ray:

  evidence of pulmonary oedema indicating left ventricular failure

• head CT or MRI:

  evidence of infarct or haemorrhage

Hypertensive emergencies

history of aortic or mitral metallic valve replacement, with anticoagulation; weakness, fatigue, headaches; poor exercise tolerance, prior gallstones, dark urine

pallor, lethargy, dyspnoea, petechiae, purpura, jaundice

• FBC with peripheral smear:

  normocytic anaemia with schistocytes

• reticulocyte count:

  >2%

• direct antiglobulin (Coombs') test:

  negative

  More direct antiglobulin (Coombs') test

  Excludes immune-mediated haemolytic anaemias.

burn injury to at least 10% of total body surface area; multiple surgical procedures

epidermal or dermal loss consistent with burn injury

• FBC with peripheral smear:

  normocytic anaemia with thrombocytopenia; schistocytes from peripheral destruction seen on blood smear

• reticulocyte count:

  >2%

Cutaneous burns