What investigations should be sent for a patient presenting with fever and thrombocytopenia (low platelet count)?

Fever with Thrombocytopenia: Essential Investigations

For any patient presenting with fever and thrombocytopenia, immediately send a complete blood count with differential, peripheral blood smear, malaria testing (thick/thin films and rapid diagnostic test), blood cultures, and basic metabolic panel including liver function tests. 1, 2, 3

Immediate First-Line Investigations (Send These Now)

Essential Core Tests

• Complete blood count with differential to identify isolated thrombocytopenia versus pancytopenia, assess severity, and detect anemia or leukopenia 1, 2
• Peripheral blood smear examination by a qualified hematologist or pathologist to exclude pseudothrombocytopenia (EDTA-dependent platelet clumping), identify schistocytes (suggesting TTP/HUS), detect malaria parasites, and assess platelet size/morphology 1, 2, 3
• Malaria testing (three thick films/rapid diagnostic tests over 72 hours if initial negative) in ALL patients who visited tropical countries within 1 year, as malaria is life-threatening and treatable 1
• Blood cultures (two sets before antibiotics) with sensitivity up to 80% for typhoid and other bacterial causes 1, 4
• Liver function tests and renal function to assess for hepatic involvement (dengue, leptospirosis, viral hepatitis) and renal complications 1, 3

Critical Coagulation Studies

• PT, aPTT, fibrinogen, and D-dimer to evaluate for disseminated intravascular coagulation (DIC), which can coexist with severe thrombocytopenia and carries high mortality 2, 3

Geographic and Exposure-Based Testing

Travel to Endemic Areas

• Dengue IgM ELISA if travel to dengue-endemic regions (most common cause of fever with thrombocytopenia in returning travelers) 5, 4
• Leptospirosis IgM ELISA if exposure to contaminated water or animal urine 1, 4
• Scrub typhus serology if travel to Asia-Pacific regions with rural/outdoor exposure 1, 5
• Rickettsial disease testing if tick exposure or compatible clinical syndrome 1

Mandatory Infectious Disease Screening

• HIV testing in ALL adults with fever and thrombocytopenia, as HIV-associated thrombocytopenia can occur years before other symptoms and is clinically indistinguishable from primary immune thrombocytopenia 1, 2
• Hepatitis C virus testing in ALL adults, as HCV-associated thrombocytopenia may precede other symptoms by years 1, 2

Second-Tier Investigations (Based on Clinical Context)

If Systemic Symptoms Present

• Bone marrow aspiration and biopsy with flow cytometry and cytogenetics if age >60 years, constitutional symptoms (weight loss, night sweats), hepatosplenomegaly, lymphadenopathy, or abnormal blood counts beyond isolated thrombocytopenia 1, 2, 3
• Autoimmune workup including ANA, anti-dsDNA if clinical features suggest systemic lupus erythematosus 1

If Drug Exposure or Recent Hospitalization

• Anti-PF4 antibodies (ELISA) if heparin exposure within past 3 months, as heparin-induced thrombocytopenia presents 5-10 days post-exposure with moderate thrombocytopenia and paradoxical thrombosis risk 1, 2
• Drug-dependent platelet antibody testing if temporal relationship between medication and thrombocytopenia, though samples must be collected during acute episode or within 3 weeks 2

If Recent Vaccination

• Anti-PF4 antibodies and D-dimer if symptoms began 5-30 days post COVID-19 vaccination to evaluate for vaccine-induced immune thrombocytopenia and thrombosis (VITT), which requires immediate treatment with IVIG and non-heparin anticoagulation 1

Critical Red Flags Requiring Urgent Additional Testing

Neurological Symptoms or Altered Mental Status

• Head CT venogram or MRI to exclude cerebral venous sinus thrombosis, especially if recent vaccination or heparin exposure 1
• Lumbar puncture if meningitis/encephalitis suspected (after imaging excludes mass effect) 1

Evidence of Microangiopathic Hemolysis

• ADAMTS13 activity and inhibitor if schistocytes present on smear, as thrombotic thrombocytopenic purpura requires immediate plasma exchange to prevent mortality 2, 6
• Direct antiglobulin test (Coombs) to confirm hemolysis 2

Abdominal Pain or Hepatosplenomegaly

• Abdominal ultrasound or CT venogram to identify portal/splanchnic vein thrombosis, which can occur with VITT or other prothrombotic conditions 1

Common Diagnostic Pitfalls to Avoid

• Never assume thrombocytopenia is real without peripheral smear confirmation, as pseudothrombocytopenia from EDTA-dependent platelet clumping is common and leads to unnecessary workup 1, 2
• Never skip malaria testing in febrile patients from endemic areas, as delayed diagnosis causes preventable deaths and malaria had the highest mortality rate in febrile thrombocytopenia studies 1, 5
• Never overlook HIV/HCV testing regardless of perceived risk factors, as these infections are clinically indistinguishable from primary immune thrombocytopenia and alter management 1, 2
• Never delay bone marrow examination in patients >60 years with unexplained cytopenias, as this age group requires exclusion of myelodysplastic syndromes and leukemias 1, 3
• Never forget to calculate the 4T score if any heparin exposure occurred, as heparin-induced thrombocytopenia causes thrombosis, not bleeding, and requires immediate heparin cessation 2

Algorithmic Approach Based on Platelet Count Severity

Platelet Count <10,000/µL (Hematologic Emergency)

• Immediate hospitalization, all core investigations stat, consider empiric treatment for life-threatening causes (malaria, sepsis, TTP) while awaiting results 1, 6

Platelet Count 10,000-50,000/µL

• Urgent evaluation within 24 hours, all core investigations, assess bleeding risk and need for platelet transfusion 1, 6

Platelet Count 50,000-150,000/µL

• Outpatient evaluation acceptable if no bleeding, complete core investigations, serial monitoring every 2-3 days until diagnosis established 1, 6