What is the diagnostic workup and treatment for thrombocytopenia (low platelet count) of unknown cause?

Diagnostic Workup for Thrombocytopenia of Unknown Cause

The diagnostic workup for thrombocytopenia of unknown cause should begin with a complete blood count, peripheral blood smear examination, and basic coagulation tests, followed by targeted second-line testing based on clinical presentation.

Initial Evaluation

First-Line Laboratory Testing

• Complete blood count (CBC) with platelet count confirmation 1, 2
• Peripheral blood smear examination by a qualified hematologist/pathologist 1, 2
• Coagulation studies:
  • Prothrombin time (PT)
  • Activated partial thromboplastin time (APTT)
  • Thrombin time 1
• Von Willebrand factor (VWF) screening tests:
  • VWF antigen
  • Ristocetin cofactor activity
  • Factor VIII coagulant activity 1
• HIV testing (all adult patients) 2
• Hepatitis C virus (HCV) testing (all adult patients) 2
• Blood group and Rh(D) typing (especially if anti-D immunoglobulin therapy is being considered) 2

Peripheral Blood Smear Findings in ITP

• Thrombocytopenia with normal-sized or slightly larger platelets
• Normal red blood cell morphology
• Normal white blood cell morphology
• Absence of schistocytes, blasts, or other abnormal cells 1, 2

Second-Line Testing

If first-line testing is normal or inconclusive, proceed with:

• Platelet function testing (light transmission aggregometry) 1
• Assessment of platelet granule release 1
• Flow cytometry for platelet surface glycoproteins 1
• Additional coagulation factor assays (FII, FV, FVII, FX, FXIII) 1
• Bone marrow examination in specific cases:
  • Patients older than 60 years
  • Patients with systemic symptoms or abnormal signs
  • Persistent thrombocytopenia (>6-12 months)
  • Patients unresponsive to initial therapy 2
• Helicobacter pylori testing in adults (urea breath test or stool antigen test preferred) 2
• Thyroid function tests 1
• Iron studies 1

Specialized Testing (When Indicated)

• Genetic/genomic testing when inherited thrombocytopenia is suspected 1
• Antinuclear antibody (ANA) testing when autoimmune disease is suspected 1
• Direct antiglobulin test (DAT) when immune-mediated hemolysis is suspected 1
• Antiphospholipid antibodies when thrombosis is present with thrombocytopenia 1

Diagnostic Algorithm

1. Rule out pseudothrombocytopenia:

   • Repeat platelet count using a tube containing sodium citrate or heparin 3

2. Determine if thrombocytopenia is acute or chronic:

   • Review previous platelet counts if available 3
   • Acute severe thrombocytopenia may require emergency hospitalization

3. Assess severity and bleeding risk:

   • Platelet count >50 × 10³/μL: Generally asymptomatic
   • Platelet count 20-50 × 10³/μL: May have mild skin manifestations
   • Platelet count <10 × 10³/μL: High risk of serious bleeding 3

4. Evaluate for emergency causes requiring immediate hospitalization:

   • Heparin-induced thrombocytopenia
   • Thrombotic microangiopathies
   • HELLP syndrome (in pregnant patients) 3

5. Investigate common non-emergency causes:

   • Immune thrombocytopenia (ITP)
   • Drug-induced thrombocytopenia
   • Hepatic disease 3, 4

Treatment Considerations

For severe thrombocytopenia with active bleeding or platelet counts <10 × 10³/μL:

• Platelet transfusions may be necessary 3
• For ITP, consider thrombopoietin receptor agonists like romiplostim for patients with insufficient response to corticosteroids, immunoglobulins, or splenectomy 5

Common Pitfalls to Avoid

• Overdiagnosis by performing unnecessary tests in patients with typical ITP presentation 2
• Missing secondary causes by failing to test for HIV or HCV in adults 2
• Overlooking pseudothrombocytopenia due to EDTA-dependent platelet agglutination 2
• Failing to recognize inherited thrombocytopenias by not carefully examining the peripheral smear 2
• Performing routine bone marrow examination in all patients regardless of clinical presentation 2
• Overlooking drug-induced thrombocytopenia (review all medications) 3
• Failing to recognize conditions where both bleeding and thrombosis can occur (antiphospholipid syndrome, heparin-induced thrombocytopenia, thrombotic microangiopathies) 3

By following this systematic approach, the cause of thrombocytopenia can be identified in most cases, allowing for appropriate treatment and management to reduce morbidity and mortality associated with bleeding complications.