Differentials

Common

Trauma

History

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)

Exam

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 volume loss

1st investigation
  • FBC:

    normal or decreased haematocrit; decreased haemoglobin; hyperproliferative; 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
  • joint or spine x-rays:

    identification of fractures

Other investigations
  • diagnostic laparotomy:

    identification of bleeding source

  • CT scan of affected body region:

    identification of internal injuries

Acute gastrointestinal bleeding

History

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

Exam

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

1st investigation
  • FBC:

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

  • reticulocyte count:

    >2%

    More
  • 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

Other investigations

    Rupture of a vascular aneurysm

    History

    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

    Exam

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

    1st investigation
    • FBC:

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

    • reticulocyte count:

      >2%

      More
    • ultrasonography of affected region:

      shows extent and nature of aneurysm

      More
    • CT scan of affected region:

      shows extent and nature of aneurysm

      More
    Other investigations
    • chest x-ray:

      may show widened mediastinum in thoracic aortic aneurysm

      More

    Surgery

    History

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

    Exam

    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 volume loss

    1st investigation
    • FBC:

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

    Other investigations
    • 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

    Menorrhagia

    History

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

    Exam

    pallor, adnexal masses or fibroids

    1st investigation
    • FBC:

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

    • serum ferritin:

      <100 picomol/L (<45 micrograms/L) is suggestive of iron deficiency anaemia

      More
    Other investigations
    • pregnancy test:

      negative

    • prothrombin time/activated partial thromboplastin time:

      usually normal; prolonged with anticoagulants, underlying defects in haemostasis

    • 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

    Iron deficiency

    History

    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

    Exam

    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

    1st investigation
    • 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

    • tissue transglutaminase (tTG) IgA test and total IgA test (on gluten containing diet):

      tTG IgA level elevated in the presence of normal IgA indicates celiac disease

    • faecal occult blood (FOBT):

      positive if gastrointestinal bleeding is present

    • faecal immunochemical test (FIT):

      positive quantitative FIT suggests bleeding from lower gastrointestinal tract

      More
    Other investigations
    • 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
    • flow cytometry:

      identification of paroxysmal nocturnal haemoglobinuria

    • transvaginal ultrasound:

      may see hyperplasia, dysplasia, fibroids, or polyps

      More
    • stool microscopy:

      visualisation of hookworm, whipworm, or Schistosoma eggs

    • Helicobacter pylori test:

      positive result if H pylori present

      More

    Vitamin B12 deficiency

    History

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

    Exam

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

    1st investigation
    • FBC with peripheral smear:

      megaloblastic macrocytic anaemia; basophilic stippling may be seen

      More
    • serum vitamin B12 levels:

      low

      More
    • serum methylmalonic acid levels:

      elevated

      More
    • anti-intrinsic factor antibodies:

      positive in pernicious anaemia

    • antiparietal cell antibodies:

      positive in pernicious anaemia

    • tissue transglutaminase (tTG) IgA test and total IgA test (on gluten containing diet):

      tTG IgA level elevated in the presence of normal IgA indicates coeliac disease

    Other investigations
    • homocysteine levels:

      elevated

      More

    Folate deficiency

    History

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

    Exam

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

    1st investigation
    • FBC with peripheral smear:

      megaloblastic macrocytic anaemia; basophilic stippling may be seen

    • serum vitamin B12 levels:

      normal; low in combined vitamin B12 and folate deficiency

      More
    • serum folate:

      low

      More
    Other investigations
    • serum homocysteine levels:

      elevated

    Myelodysplastic syndrome

    History

    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

    Exam

    pallor, petechiae, purpura

    1st investigation
    • FBC:

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

    • reticulocyte count:

      <2%

    Other investigations
    • bone marrow aspiration and biopsy:

      myeloblasts with immature precursors

      More
    • cytogenetics of bone marrow biopsy:

      multiple chromosomal translocations possible, especially del(5q), -7/del(7q), trisomy 8 (+8), del(20q) and complex karyotype

    • serum vitamin B12:

      normal

      More
    • folate:

      normal

      More

    Acute lymphoblastic leukaemia

    History

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

    Exam

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

    1st investigation
    • FBC with peripheral smear:

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

      More
    • reticulocyte count:

      <2%

    Other investigations
    • bone marrow aspirate and biopsy:

      ≥20% blasts

      More

    Acute myeloid leukaemia

    History

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

    Exam

    pallor, petechiae, purpura, dyspnoea, tachycardia

    1st investigation
    • FBC with peripheral smear:

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

      More
    • reticulocyte count:

      <2%

    Other investigations
    • bone marrow aspirate and biopsy:

      ≥20% blasts

      More

    Chronic myeloid leukaemia

    History

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

    Exam

    tender splenomegaly, painful sternum, lymphadenopathy

    1st investigation
    • FBC with peripheral smear:

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

    • reticulocyte count:

      <2%

    • bone marrow aspirate and biopsy:

      hypercellular with granulocytic hyperplasia

    Other investigations
    • cytogenetics:

      t(19;22) Philadelphia chromosome - BCR::ABL1 translocation

    • serum uric acid:

      elevated

      More

    Hairy cell leukaemia

    History

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

    Exam

    massive splenomegaly

    1st investigation
    • FBC with peripheral smear:

      pancytopenia with normocytic anaemia

      More
    • reticulocyte count:

      <2%

    Other investigations
    • bone marrow aspirate and biopsy:

      core biopsy shows hairy cells

      More

    Acquired aplastic anaemia

    History

    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

    Exam

    pallor, petechiae, purpura, dyspnoea, tachycardia

    1st investigation
    • FBC with peripheral smear:

      hypoproliferative; pancytopenia with mild macrocytosis; normocytic anaemia

    • reticulocyte count:

      <2%

    Other investigations
    • bone marrow aspirate and biopsy:

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

      More
    • serum vitamin B12:

      normal

      More
    • folate:

      normal

      More

    Infiltration by secondary malignancy

    History

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

    Exam

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

    1st investigation
    • FBC with peripheral smear:

      hypoproliferative; pancytopenia, teardrop cells, poikilocytes; normocytic anaemia

    • reticulocyte count:

      <2%

    • bone marrow aspirate and biopsy:

      infiltration of marrow space by malignant cells

      More
    Other investigations
    • CT imaging:

      identification of site of primary malignancy

    Pure red cell aplasia

    History

    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

    Exam

    clinical signs of underlying infection or autoimmune disease

    1st investigation
    • FBC:

      hypoproliferative; normocytic anaemia

    • reticulocyte count:

      <2%

    • trial of discontinuation of causative medication:

      anaemia resolves

    • antiparvovirus B19 antibodies:

      positive in parvovirus infection

      More
    Other investigations
    • 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

    Drug toxicity

    History

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

    Exam

    pallor, jaundice (with haemolytic anaemia only), dyspnoea

    1st investigation
    • FBC with peripheral smear:

      hypoproliferative or hyperproliferative; 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

    Other investigations
    • serum bilirubin:

      elevated in haemolytic anaemia

    Anaemia of chronic disease

    History

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

    Exam

    pallor, fatigue, dyspnoea; specific signs of underlying disease

    1st investigation
    • FBC:

      normocytic anaemia

      More
    • 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
    Other investigations
    • serum erythropoietin level:

      normal or elevated; often decreased in chronic kidney disease

      More

    Chronic kidney disease

    History

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

    Exam

    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

    1st investigation
    • FBC:

      hypoproliferative; 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

    Other investigations
    • 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 liver disease

    History

    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

    Exam

    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

    1st investigation
    • FBC:

      non-megaloblastic macrocytic anaemia; thrombocytopenia may be present

    • prothrombin time:

      decreased in hepatic synthetic dysfunction

    • LFTs:

      abnormal; pattern depends on underlying cause

    Other investigations
    • 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

    Pregnancy

    History

    pregnancy, especially in third trimester

    Exam

    abdominal distension consistent with pregnancy, pallor

    1st investigation
    • FBC:

      microcytic anaemia with thrombocytosis in iron deficiency; megaloblastic macrocytic anaemia in folate deficiency; microangiopathic haemolytic anaemia with RBC fragmentation is a finding in HELLP (haemolysis, elevated liver enzyme levels, and thrombocytopaenia) syndrome

    Other investigations
    • 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

      More

    Uncommon

    Generalised malnutrition

    History

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

    Exam

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

    1st investigation
    • 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

    Other investigations
    • serum vitamin B12:

      low

    • serum folate:

      low

      More
    • serum copper level:

      low

      More

    Cytotoxic chemotherapy

    History

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

    Exam

    pallor, lethargy, dyspnoea

    1st investigation
    • FBC:

      hypoproliferative; pancytopenia with a normocytic anaemia

      More
    • reticulocyte count:

      <2%

      More
    Other investigations

      Radiotherapy

      History

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

      Exam

      pallor, lethargy, dyspnoea, skin erythema on radiation sites

      1st investigation
      • FBC:

        anaemia (pancytopenia)

      • reticulocyte count:

        <2%

      Other investigations
      • bone marrow aspirate and biopsy:

        marrow fibrosis or malignant infiltration

      Alcohol misuse

      History

      history of chronic high alcohol intake

      Exam

      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

      1st investigation
      • FBC:

        macrocytic anaemia; megaloblastic or nonmegalobastic

      Other investigations
      • diagnostic interview:

        diagnosis of alcohol dependence

      • alcohol level (breath and blood):

        elevated

      Lead toxicity

      History

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

      Exam

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

      1st investigation
      • 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

      Other investigations

        Hypothyroidism

        History

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

        Exam

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

        1st investigation
        • FBC:

          hypoproliferative; normocytic anaemia; macrocytic, megaloblastic if hypothyroidism is associated with autoimmune disease

        • serum thyroid-stimulating hormone:

          elevated

        • serum thyroxine:

          reduced

        • reticulocyte count:

          <2%

        Other investigations

          Autoimmune haemolytic anaemia

          History

          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

          Exam

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

          1st investigation
          • FBC with peripheral smear:

            hyperproliferative; normocytic anaemia, with spherocytes

          • reticulocyte count:

            >2%; usually 4%

            More
          • LDH:

            elevated

          • haptoglobin:

            low

          • direct antiglobulin (Coombs') test:

            usually positive

            More
          • serum bilirubin:

            elevated

          Other investigations
          • antinuclear antibodies:

            positivein SLE or scleroderma

          • ds-DNA, Smith antigen:

            positive in SLE

          • rheumatoid factor:

            positive in rheumatoid arthritis

          Transfusion reaction

          History

          multiple prior transfusions; fever, back pain, and dyspnoea, usually within 6 hours of transfusion; recent blood transfusion may be associated with normocytic anaemia, haemolysis and hyperproliferation of reticulocytes due to a transfusion reaction

          Exam

          pallor, lethargy, dyspnoea, dark urine, jaundice

          1st investigation
          • ABO typing:

            discrepancy to blood used for transfusion

            More
          • 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

          Other investigations
          • direct antiglobulin (Coombs') test:

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

          • serum bilirubin:

            elevated

          Malaria

          History

          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

          Exam

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

          1st investigation
          • FBC:

            hypoproliferative; normocytic anaemia ± thrombocytopenia and leukopenia

          • reticulocyte count:

            >2%; usually 4%

            More
          • thick and thin peripheral smear:

            intracellular parasites seen with Wright's or Giemsa staining

            More
          Other investigations
          • serum bilirubin:

            elevated

          • rapid diagnostic tests (RDTs):

            detection of parasite antigen or enzymes

            More

          Viral hepatitis

          History

          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

          Exam

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

          1st investigation
          • FBC:

            hypoprolifeartive; 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

          Other investigations

            Toxoplasmosis

            History

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

            Exam

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

            1st investigation
            • FBC:

              hypoproliferative; 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
            • Sabin-Feldman dye test:

              IgG antibodies positive

            Other investigations
            • polymerase chain reaction for Toxoplasma gondii:

              positive

            Leishmaniasis

            History

            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

            Exam

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

            1st investigation
            • FBC:

              hypoproliferative; normocytic anaemia, thrombocytopenia, leukopenia, erythroblastosis

            • Leishmania serology:

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

              More
            Other investigations
            • reticulocyte count:

              >2%

            • DNA-based assays:

              Leishmania DNA

              More
            • splenic or bone marrow aspirate:

              presence of amastigotes of the parasite

              More
            • direct antiglobulin (Coombs') test:

              positive

            Parvovirus B19 infection

            History

            acute infection: characteristic skin rash with or without arthralgia

            Exam

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

            1st investigation
            • FBC:

              hypoproliferative; normocytic anaemia

            • reticulocyte count:

              <2%

            Other investigations
            • antiparvovirus B19 antibodies:

              positive

              More

            Infectious mononucleosis

            History

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

            Exam

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

            1st investigation
            • FBC with peripheral smear:

              hypoproliferative or hyperproliferative; normocytic anaemia, with spherocytes and atypical lymphocytes

            • reticulocyte count:

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

            Other investigations
            • LDH:

              elevated

            • haptoglobin:

              low

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

              positive

            Cytomegalovirus (CMV)

            History

            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

            Exam

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

            1st investigation
            • FBC:

              hyperproliferative; normocytic anaemia

            • reticulocyte count:

              >2%; usually 4%

            Other investigations
            • LDH:

              elevated

            • haptoglobin:

              low

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

              negative

              More
            • CMV IgM:

              positive

            Sickle cell anaemia

            History

            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

            Exam

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

            1st investigation
            • FBC with peripheral smear:

              hyperproliferative; normocytic anaemia with sickle cells

              More
            • reticulocyte count:

              >2%

            • haemoglobin (Hb) isoelectric focusing:

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

            • LDH:

              elevated

            • serum bilirubin:

              elevated

            Other investigations

              Thalassaemias

              History

              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

              Exam

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

              1st investigation
              • FBC with peripheral smear:

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

              • reticulocyte count:

                usually <2%, which differentiates impaired erythrocytosis from increased consumption of erythrocytes (which would result in a reticulocyte count of >2%)

                More
              • Hb analysis:

                elevated HbF; other Hb patterns consistent with respective thalassaemias

              Other investigations
              • serum ferritin:

                elevated in iron overload

              Hereditary spherocytosis

              History

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

              Exam

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

              1st investigation
              • FBC with peripheral smear:

                hyperproliferative; normocytic anaemia, with increased mean corpuscular haemoglobin and spherocytes

              • reticulocyte count:

                >2%

              • osmotic fragility test:

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

              Other investigations
              • direct antiglobulin (Coombs') test:

                negative

                More

              Glucose-6-phosphate dehydrogenase deficiency (G6PD)

              History

              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

              Exam

              pallor, jaundice, mild dyspnoea

              1st investigation
              • FBC with peripheral smear:

                hyperproliferative; normocytic anaemia with Heinz bodies, eccentrocytes, or bite cells

                More
              • reticulocyte count:

                >2%

              • serum haptoglobin:

                decreased

              • LDH:

                elevated

              Other investigations
              • G6PD enzyme assays:

                quantitative or qualitative abnormalities

                More
              • serum bilirubin:

                elevated indirect bilirubin

              • direct antiglobulin (Coombs') test:

                negative

                More

              Bone marrow failure syndromes

              History

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

              Exam

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

              1st investigation
              • FBC with peripheral smear:

                pancytopenia with normocytic or macrocytic nonmegaloblastic anaemia

                More
              • reticulocyte count:

                <2%

              Other investigations
              • 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

              Haemolytic uraemic syndrome

              History

              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

              Exam

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

              1st investigation
              • FBC with peripheral smear:

                hyperproliferative; normocytic anaemia, thrombocytopenia, schistocytes

              • erythrocyte count:

                >2%

              Other investigations
              • prothrombin time/activated PTT:

                normal

                More
              • serum haptoglobin:

                decreased

              • LDH:

                elevated

              • serum creatinine:

                may be elevated

              • serum bilirubin:

                elevated

              • direct antiglobulin (Coombs') test:

                negative

                More
              • 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

              Disseminated intravascular coagulation (DIC)

              History

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

              Exam

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

              1st investigation
              • FBC with peripheral smear:

                hyperproliferative; normocytic anaemia, thrombocytopenia, schistocytes

              • reticulocyte count:

                >3% assuming there is adequate marrow function

              • 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
              Other investigations

                Thrombotic thrombocytopenic purpura

                History

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

                Exam

                pallor, lethargy, dyspnoea, purpura, ecchymoses

                1st investigation
                • FBC with peripheral smear:

                  hyperproliferative; normocytic anaemia with schistocytes

                • reticulocyte count:

                  >2%

                • direct antiglobulin (Coombs') test:

                  negative

                  More
                Other investigations

                  Haemangioma

                  History

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

                  Exam

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

                  1st investigation
                  • FBC with peripheral smear:

                    hyperproliferative; normocytic anaemia, thrombocytopenia

                    More
                  • reticulocyte count:

                    >2%

                  Other investigations
                  • 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

                  Malignant hypertension

                  History

                  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

                  Exam

                  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

                  1st investigation
                  • FBC with peripheral smear:

                    hyperproliferative; 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

                  Other investigations
                  • chest x-ray:

                    evidence of pulmonary oedema indicating left ventricular failure

                  • head CT or MRI:

                    evidence of infarct or haemorrhage

                  Prosthetic valves and surfaces

                  History

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

                  Exam

                  pallor, lethargy, dyspnoea, petechiae, purpura, jaundice

                  1st investigation
                  • FBC with peripheral smear:

                    hyperproliferative; normocytic anaemia with schistocytes

                  • reticulocyte count:

                    >2%

                  • direct antiglobulin (Coombs') test:

                    negative

                    More
                  Other investigations

                    Cutaneous burns

                    History

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

                    Exam

                    epidermal or dermal loss consistent with burn injury

                    1st investigation
                    • FBC with peripheral smear:

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

                    Other investigations
                    • reticulocyte count:

                      >2%

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