Approach

In any patient with thrombocytopenia, exclude pseudothrombocytopenia (a laboratory artifact attributable to the presence of EDTA-dependent antibody in the circulation) by one of the following:

  • Perform a fingerstick peripheral smear

  • Draw the blood into a heparin or citrated tube

  • Manually count on a sample diluted without anticoagulants.

Once true thrombocytopenia is confirmed, clinical history, examination, full blood count and peripheral blood smear will narrow down the differential diagnosis.

History

Key symptoms: it is important to identify the time in which symptoms began, to establish whether thrombocytopenia is acute or chronic.

  • Easy bruising

  • Petechiae

  • Epistaxis

  • Gum bleeding

  • Gastrointestinal or genitourinary bleeding.

Associated symptoms are often non-specific but may be indicative of:

Malignancy:

  • Bone pain

  • Night sweats

  • Nausea

  • Anorexia

  • Fatigue/malaise

  • Weakness

  • Shortness of breath

  • Left upper quadrant discomfort (splenomegaly)

  • Excessive thirst, urination, and constipation (myeloma).

Infection:

  • Fever

  • Cough

  • Shortness of breath

  • Altered sense of smell or taste

  • Haemoptysis (tuberculosis)

  • Night sweats

  • Chills

  • Rigors

  • Rash

  • Pharyngitis (infectious mononucleosis)

  • Diarrhoea, vomiting, and nausea.

Inflammatory or autoimmune disorders:

  • Joint discomfort

  • Arthralgias

  • Morning stiffness (rheumatoid arthritis)

  • Malar rash (systemic lupus erythematosus [SLE])

  • Fatigue

  • Weight loss

  • Cough

  • Dyspnoea

  • History of miscarriage (antiphospholipid syndrome)

  • Diarrhoeal illness in child (haemolytic uraemic syndrome [HUS])

  • Confusion, seizures and neurological changes (thrombotic thrombocytopenic purpura [TTP]).

Intravascular trauma:

  • Recent surgery or procedure

  • Confusion, dyspnoea, and cough (disseminated intravascular coagulation [DIC]).

Toxicity:

  • Excess alcohol.

Genetic disorders:

  • Atopy (Wiskott-Aldrich syndrome)

  • Hearing loss (May-Hegglin anomaly)

  • Familial thrombocytopenia and/or presence of myeloid neoplasms in an immediate family member.

Endocrine disorders:

  • Symptoms of hypothyroidism: for example, weight gain, constipation, fatigue.

Other:

  • Symptoms of anaemia: for example, fatigue, breathlessness, pallor

  • Abdominal distension (paroxysmal nocturnal haemoglobinuria), portal vein thrombosis/Budd-Chiari syndrome

  • Pruritus, early satiety, left upper quadrant pain, alcohol withdrawal (cirrhosis).

Additional history:

  • Old platelet counts to verify a history of low or normal levels

  • Infection with certain viruses, particularly HIV and severe acute respiratory syndrome coronavirus 2

  • History of rheumatologic conditions

  • History of malignancy

  • A recent history of surgery or transfusion is important

  • Family history of bleeding or low platelet counts

  • Dietary (e.g., folic acid), B12 low in pernicious anaemia (although anaemia may be more important presenting problem)

  • Travel to endemic area (malaria)

  • Recent illnesses

  • Recent injections such as vaccinations

  • Intensive care unit admission

  • Alcohol or illicit drug misuse (cirrhosis).

Female patients:

  • Pregnancy status is important as patients are at risk for TTP, gestational thrombocytopenia (in which secreted placental factors lead to a decrease in platelet count), and haemolysis, elevated liver enzymes, low platelets (HELLP) syndrome.

Medication history:

  • Recent ingestion of new medications

  • Quinine exposure (e.g., tonic water ingestion, non-prescription pills for leg cramps)

  • Sulfur-containing medicines and antiepileptic medicines

  • Chemotherapeutic drugs, which may be used for treatment of neoplastic disorders, vasculitis, inflammatory bowel disease, and other rheumatological disorders

  • Exposure to heparin.

Physical examination

Key clinical findings pertinent to thrombocytopenia:

  • Petechiae or ecchymoses

  • Retinal haemorrhage, a possible sign of intracranial haemorrhage

  • Bleeding occurring at the back of the buccal mucosa, advancing to the front, is often a worrisome finding for impending intracranial bleeding in an individual with an extremely low platelet count.

Vital signs

  • Fever may indicate infection, leukaemia, lymphoma, DIC, TTP, SLE, sarcoidosis or aplastic anaemia.

  • Hypotension and tachycardia can occur in DIC and sepsis.

  • Hypertension is a feature of HELLP syndrome.

Other physical findings should be identified to narrow the diagnosis:

General examination

  • Lymphadenopathy

  • Pallor

  • Bleeding at sites of intravascular lines, dialysis catheters, extracorporeal oxygenation devices, chest tubes, mediastinal or pericardial tubes

  • White spots on tongue (oropharyngeal candidiasis may be seen in HIV/AIDS)

  • Retinal changes (cytomegalovirus infection)com.bmj.content.model.assessment.Caption@34d14205[Figure caption and citation for the preceding image starts]: Fundoscopy (left eye) showing area of CMV retinitis inferonasally involving the vascular arcades and the optic disc, associated with vasculitis, and flame haemorrhagesAdapted from BMJ Case Reports 2009 (10.1136/bcr.02.2009.1576) [Citation ends].

  • Jaundice (may occur in malaria, TTP, HELLP syndrome and cirrhosis)

  • Signs of hypothyroidism: peripheral oedema, hair loss, bradycardia, hypothyroid facies, enlarged thyroid gland

  • Signs of chronic liver disease (spider telangiectasias on the chest, palmar erythema, pedal oedema)

Abdominal examination

  • Hepatosplenomegaly (may occur in leukaemia, lymphoma, bone marrow fibrosis, post-transfusion thrombocytopenia, malaria, Wiskott-Alrich syndrome, Gaucher disease)

  • Ascites (cirrhosis)

Cardiovascular examination

  • Irregular pulse may occur in TTP

Musculoskeletal examination

  • Joint deformity or swelling (SLE, rheumatoid arthritis)

  • Digital ischaemia and/or swollen extremities (antiphospholipid syndrome)

  • Bone pain (multiple myeloma)

  • Bone fractures (multiple myeloma)

Neurologic examination

  • Weakness or leg numbness (multiple myeloma)

  • Confusion may occur in DIC and TTP

  • Seizures and, focal neurologic symptoms may also occur in TTP

  • Decreased vibratory sensation and dementia may indicate vitamin B12 deficiency

Initial tests

The peripheral blood smear is an important next step in identifying the cause of thrombocytopenia.

  • Immune thrombocytopenia (ITP) is a diagnosis of exclusion, and the peripheral smear will show solely a low platelet count. The red cells should appear normal.[1]

  • Schistocytes and nucleated red blood cells along with thrombocytopenia on the smear indicate either TTP, HUS or DIC. Schistocytes are also seen in sepsis.

  • Blasts on the peripheral smear raise the possibility of acute leukaemia. If the peripheral blood smear shows blasts, the patient must be promptly referred to a haematologist/oncologist or other appropriate specialist.

  • Rouleaux formation indicates multiple myeloma.

  • Leukoerythroblastic changes may be seen in metastatic malignancy and bone marrow fibrosis.

  • Atypical lymphocytes may be seen in mononucleosis.

  • Macrocytosis can indicate alcohol misuse, B12 deficiency or folate deficiency.

  • Hypersegmented polymorphonuclear cells are a feature of B12 or folate deficiency.

  • Small platelets occur in Wiskott-Aldrich syndrome.

  • Large platelets occur in MYH9-related disorders, including May-Hegglin anomaly, and Bernard-Soulier syndrome. Döhle bodies in polymorphonuclear cells are also seen in MYH9-related disorders.

  • Platelet clumping will be visible in cases of pseudothrombocytopenia.

FBC with differential:

  • Identifies the extent of thrombocytopaenia

  • Identifies concomitant anaemia, leukocytopenia or leukocytosis.

  • It is important to review any previous FBC results for history of low platelet count.

  • Pseudothrombocytopenia shows low counts with an EDTA tube. However, platelet count is normal using a citrate- or heparin-coated tube.

Targeted tests

The results of the peripheral smear together with the clinical findings should narrow down the differential diagnosis and guide further investigation.

Laboratory investigations

  • Serum creatinine may be elevated in TTP, HUS, SLE, sepsis and multiple myeloma. BUN may be elevated and serum electrolytes deranged in sepsis.

  • Liver function tests (LFTs) (including bilirubin, alanine aminotransferase [ALT], aspartate aminotransferase [AST] and albumin) can distinguish between HELLP and gestational thrombocytopenia. Characteristic changes in cirrhosis include low serum albumin and elevated bilirubin. Malaria, dengue fever and Epstein-Barr virus infection can cause elevated transaminases. LFTs may be deranged in sepsis. Indirect bilirubin is elevated if there is hemolysis.

  • Serum calcium: may be elevated in multiple myeloma and sarcoidosis

  • Prothrombin time (PT), activated partial thromboplastin time (PTT) and fibrinogen can help to distinguish between DIC, post-transfusion thrombocytopenia, ITP and TTP. PT and activated PTT are prolonged in cirrhosis. Coagulation studies may be abnormal in sepsis.

  • D-dimer is elevated in DIC and normal in TTP.

  • Serum reticulocyte count and lactate dehydrogenase (LDH) are elevated in hemolysis.

  • Uric acid is elevated in acute myelogenous leukaemia.

  • If multiple myeloma is suspected, serum and urine protein electrophoresis, serum calcium, serum free light chains and serum beta-2-microglobulin should be measured.

  • If autoimmune or inflammatory conditions such as SLE, rheumatoid arthritis, antiphospholipid syndrome, and sarcoidosis are suspected, erythrocyte sedimentation rate, antinuclear antibodies, anti-double-stranded DNA antibodies, anti-Smith antibodies, rheumatoid factor, anti-cyclic citrullinated peptide antibodies, anticardiolipin antibodies, anti-beta2-glycoprotein I antibody and lupus coagulant may help to differentiate the diagnosis.

  • Hashimoto's thyroiditis is confirmed with anti-microsomal antibodies. Thyroid function tests show elevated thyroid stimulating hormone and low T4.

  • If B12 or folate deficiency is suspected, low levels will confirm diagnosis.

  • If an infective process is suspected, then the following tests should be ordered:

    • Sepsis: blood cultures, arterial blood gas, serum lactate, C-reactive protein, cultures from the suspected site of infection

    • COVID-19: real-time reverse transcriptase polymerase chain reaction to severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2)

    • Mononucleosis: heterophile antibody agglutination test, Epstein-Barr virus-specific antibodies

    • HIV: HIV antibody test plus CD4 count identifies the presence and progression of the HIV virus

    • Cytomegalovirus: serology

    • Malaria: peripheral thick smear

    • Sputum stain for acid-fast bacilli if there is suspicion of tuberculosis

  • Urinalysis: indicated in cases of suspected malaria, SLE, gestational thrombocytopenia and paroxysmal nocturnal haemoglobinuria.

Imaging tests

  • Computed tomography (CT) head is essential if there is suspicion for intracranial haemorrhage.

  • Skeletal survey, including x rays of the long bones, skull and spine, is performed in all patients with suspected multiple myeloma. Whole-body low-dose CT may also be used for this purpose.[30]

  • A CT of the abdomen helps identify pathology such as cirrhosis, splenomegaly, metastases, or lymphoma.

  • Chest x ray may show signs of miliary tuberculosis, lung cancer or sarcoidosis.com.bmj.content.model.assessment.Caption@77d93e32[Figure caption and citation for the preceding image starts]: Bilateral hilar adenopathy, associated with sarcoidosisFrom the collection of Muthiah P. Muthiah, MD, FCCP [Citation ends].

Specialised tests

Bone marrow aspiration and/or biopsy is performed if other studies are inconclusive. Bone marrow aspiration and/or biopsy may be used in the diagnosis of leukaemia, multiple myeloma, bone marrow fibrosis, ITP, TTP, HIV and aplastic anaemia. Bone marrow biopsy is usually only performed for suspected ITP if the clinical presentation is atypical or the patient does not respond to ITP therapy.

Cytogenetic analysis of bone marrow yields prognostic information in leukaemia and multiple myeloma.

Lymph node biopsy is indicated for suspected lymphoma.

Antigen assays for heparin-induced thrombocytopenia (HIT) antibodies are used to diagnose HIT.

If a genetic disorder is suspected, specific tests including single gene sequencing, next generation sequencing, skin fibroblast culture and platelet flow cytometry may be required.[31]

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