What is the initial approach to managing a patient with thrombocytosis?

Initial Management of Thrombocytosis

The first step in managing thrombocytosis is to test for JAK2V617F mutation to distinguish primary myeloproliferative neoplasms from reactive causes, as this single test determines whether the patient needs hematology referral and cytoreductive therapy versus treatment of an underlying condition. 1

Diagnostic Algorithm

Step 1: Confirm True Thrombocytosis and Obtain Mutation Testing

• Verify platelet count ≥450 × 10⁹/L on repeat testing to confirm persistent thrombocytosis 1, 2
• Order JAK2V617F mutation testing immediately as 86% of primary thrombocytosis cases harbor this or other myeloproliferative neoplasm (MPN) markers 2, 3
• Check complete blood count with differential, focusing on hemoglobin, MCV, RDW, MPV, white blood cell count, and neutrophil count 3
• Measure ferritin to identify iron deficiency, a common cause of secondary thrombocytosis 1, 3

Step 2: Assess for Secondary Causes

Secondary thrombocytosis accounts for 83% of cases and requires identification of the underlying trigger 2:

• Tissue injury (32% of secondary cases): recent surgery, trauma, burns 2
• Active infection (17%): bacterial, viral, or fungal infections 2
• Chronic inflammatory disorders (12%): rheumatoid arthritis, inflammatory bowel disease, vasculitis 2, 3
• Iron deficiency anemia (11%): check ferritin and treat with iron replacement 1, 2, 3
• Active malignancy: solid tumors or hematologic malignancies 3
• Post-splenectomy state: functional or surgical asplenia 3

Step 3: Clinical Risk Stratification

If JAK2V617F (or CALR/MPL) mutation is positive, proceed with MPN-specific risk stratification 1, 4:

High-Risk Essential Thrombocythemia

• Age >60 years with JAK2 mutation OR history of thrombosis at any age 5, 4
• Treatment: Hydroxyurea as first-line cytoreductive therapy PLUS low-dose aspirin (81 mg daily) 1, 5, 4
• Alternative cytoreductive agents if hydroxyurea not tolerated: pegylated interferon-α or anagrelide 5, 4

Intermediate-Risk Essential Thrombocythemia

• Age >60 years without JAK2 mutation and no thrombosis history 4
• Treatment: Consider cytoreductive therapy with hydroxyurea or observation with aspirin 1, 4

Low-Risk Essential Thrombocythemia

• Age ≤60 years, no thrombosis history, JAK2 mutation present 4
• Treatment: Low-dose aspirin 81 mg once daily 1, 4

Very Low-Risk Essential Thrombocythemia

• Age ≤60 years, no thrombosis history, JAK2 wild-type 4
• Treatment: Low-dose aspirin 81 mg once daily OR observation 1, 4

If JAK2V617F is negative and no secondary cause identified, order expanded mutation panel testing for CALR and MPL mutations, as these account for the remaining MPN cases 1, 4

Step 4: Management of Confirmed Reactive Thrombocytosis

For reactive thrombocytosis, treat the underlying cause—no antiplatelet or cytoreductive therapy is indicated 1:

• Iron deficiency: Iron replacement until hemoglobin normalizes 1
• Infection/inflammation: Treat underlying condition with appropriate antimicrobials or anti-inflammatory therapy 1
• Malignancy: Address cancer-specific treatment; consider antithrombotic prophylaxis based on validated risk scores 1

Step 5: Monitoring Strategy

For reactive thrombocytosis 1:

• Recheck platelet count in 2-4 weeks after initiating treatment for underlying cause
• If thrombocytosis persists or worsens, repeat JAK2V617F testing and refer to hematology for bone marrow evaluation
• If platelet count normalizes, no further hematologic workup needed

For confirmed MPN 4:

• Monitor complete blood count every 3-6 months in stable patients
• Assess for thrombotic or hemorrhagic complications at each visit
• Screen for disease transformation with annual bone marrow evaluation if clinically indicated

Critical Pitfalls to Avoid

• Do not start cytoreductive therapy without confirming primary thrombocytosis through mutation testing, as 83% of thrombocytosis is reactive and resolves with treatment of underlying cause 2
• Do not use low-dose aspirin in children with CML-related thrombocytosis due to risk of Reye syndrome and platelet dysfunction 6
• Do not assume thrombosis risk is proportional to platelet count in reactive thrombocytosis—no thrombotic events occurred in 51% of pediatric CML patients with thrombocytosis 6
• Do not order bone marrow biopsy initially unless clonal disorder cannot be excluded by clinical assessment and mutation testing 1
• Do not overlook acquired von Willebrand syndrome in patients with extreme thrombocytosis who present with bleeding despite elevated platelet counts 6

Special Considerations

Extreme Thrombocytosis (Platelets >1,500 × 10⁹/L)

• Increased risk of acquired von Willebrand syndrome causing paradoxical bleeding 6, 5
• Avoid aspirin until platelet count reduced below 1,500 × 10⁹/L due to hemorrhagic risk 5
• Consider more aggressive cytoreduction in symptomatic patients 4

Pregnancy

• Pegylated interferon-α is the only safe cytoreductive agent in pregnant women requiring treatment 5, 4
• Hydroxyurea and anagrelide are contraindicated in pregnancy 5

Thrombotic Complications

• History of arterial thrombosis strongly predicts primary thrombocytosis (essential thrombocythemia) over reactive causes 3
• Splanchnic vein thrombosis requires specific management strategies with anticoagulation and cytoreduction 4