What is the initial workup and management for a patient presenting with thrombocytosis?

Diagnostic Approach to Thrombocytosis

The initial workup for thrombocytosis (platelet count >450×10⁹/L) should include a complete blood count with peripheral blood smear review, basic metabolic panel, inflammatory markers, iron studies, and molecular testing for JAK2, CALR, and MPL mutations to differentiate between primary and secondary causes.

Initial Assessment and Classification

Step 1: History and Laboratory Evaluation

• Complete blood count with differential and peripheral blood smear
• Comprehensive metabolic panel including liver and renal function
• Inflammatory markers (ESR, CRP)
• Iron studies (ferritin, transferrin saturation)
• Coagulation profile (PT, PTT, fibrinogen)

Step 2: Identify Secondary Causes

Secondary thrombocytosis (83% of cases) is commonly caused by 1:

• Tissue injury (32.2%)
• Infection (17.1%)
• Chronic inflammatory disorders (11.7%)
• Iron deficiency anemia (11.1%)
• Recent surgery
• Malignancy
• Splenectomy
• Post-vaccination (including COVID-19 vaccine)

Step 3: Evaluate for Primary Thrombocytosis

If secondary causes are excluded or clinical suspicion remains high:

• Molecular testing for driver mutations:
  • JAK2V617F (most common)
  • CALR mutations
  • MPL mutations
• Bone marrow examination with cytogenetics

Differentiating Primary vs Secondary Thrombocytosis

Clinical Features Suggestive of Primary Thrombocytosis

• History of arterial thrombosis 2
• Higher mean platelet volume (MPV)
• Higher hemoglobin and MCV
• Elevated RDW
• Presence of microcirculatory symptoms (headaches, lightheadedness, acral paresthesias)

Clinical Features Suggestive of Secondary Thrombocytosis

• Active malignancy
• Chronic inflammatory disease
• Recent splenectomy
• Iron deficiency anemia
• Higher neutrophil count
• Higher BMI 2

Management Based on Etiology

Primary Thrombocytosis (Essential Thrombocythemia)

1. Risk Stratification 3:

   • Very low risk: Age ≤60 years, no thrombosis history, JAK2 wild-type
   • Low risk: Age ≤60 years, no thrombosis history, JAK2 mutation present
   • Intermediate risk: Age >60 years, no thrombosis history, JAK2 mutation present
   • High risk: Thrombosis history or age >60 years with JAK2 mutation

2. Treatment Approach:

   • All patients: Low-dose aspirin once daily (twice daily for low-risk disease)
   • High-risk patients: Cytoreductive therapy (hydroxyurea or pegylated interferon-α)
   • Intermediate-risk patients: Consider cytoreductive therapy
   • Very low/low-risk patients: Observation and aspirin

Secondary Thrombocytosis

• Treat the underlying cause:
  • Antibiotics for infection
  • Iron supplementation for iron deficiency
  • Anti-inflammatory treatment for chronic inflammation
  • Supportive care post-surgery

Special Considerations

Extreme Thrombocytosis (>1,000×10⁹/L)

• Higher risk of both thrombotic and hemorrhagic complications
• Consider urgent cytoreduction in primary thrombocytosis
• Evaluate for acquired von Willebrand syndrome

Post-COVID-19 Vaccination Thrombocytosis

If thrombocytosis occurs 5-30 days post-vaccination with thrombosis:

• Check D-dimer levels
• If D-dimer >4000 μg/mL, consider VITT (vaccine-induced immune thrombocytopenia and thrombosis)
• Treat with IVIG 1g/kg immediately 4

Pregnancy-Associated Thrombocytosis

• Continue low-dose aspirin (unless bleeding)
• Consider interferon-α if platelet count ≥1,500×10⁹/L 4

Monitoring and Follow-up

• Primary thrombocytosis: Regular CBC monitoring (monthly after stable dose)
• Secondary thrombocytosis: Monitor until resolution of underlying cause
• Evaluate for transformation to myelofibrosis or acute leukemia in primary cases

Pitfalls to Avoid

1. Failing to distinguish between primary and secondary thrombocytosis
2. Missing masked myeloproliferative disorders in patients with splanchnic vein thrombosis
3. Overlooking iron deficiency as a cause of thrombocytosis
4. Not testing for JAK2V617F mutation in patients with unexplained thrombosis
5. Assuming normal platelet counts rule out myeloproliferative disorders (5% of patients with VITT have normal platelet counts initially) 4

By following this systematic approach, clinicians can effectively differentiate between primary and secondary thrombocytosis and implement appropriate management strategies to prevent complications.