What is the management of thrombocytosis?

Management of Thrombocytosis

Thrombocytosis management depends critically on distinguishing primary (myeloproliferative neoplasm-driven) from secondary (reactive) causes, with cytoreductive therapy reserved for high-risk primary thrombocytosis patients to prevent thrombotic complications. 1

Initial Diagnostic Approach

Determine if thrombocytosis is primary or secondary:

• Primary thrombocytosis accounts for 12.5% of cases and is associated with myeloproliferative neoplasms (MPNs), particularly essential thrombocythemia (ET). 2
• Approximately 80% of ET patients harbor driver mutations (JAK2, CALR, MPL) in a mutually exclusive pattern, with 86% having at least one molecular marker. 1, 2
• Secondary thrombocytosis represents 83.1% of cases, with major causes including tissue injury (32.2%), infection (17.1%), chronic inflammatory disorders (11.7%), and iron deficiency anemia (11.1%). 2

Key diagnostic workup for suspected primary thrombocytosis:

• Bone marrow examination showing increased mature-appearing megakaryocytes in loose clusters. 1
• Molecular testing for JAK2, CALR, and MPL mutations. 1
• Exclude other myeloid neoplasms including prefibrotic myelofibrosis, polycythemia vera, chronic myeloid leukemia, and myelodysplastic syndromes. 1
• Karyotype analysis (abnormal in <10% of cases, includes +9/20q-/13q-). 1

Risk Stratification for Primary Thrombocytosis (Essential Thrombocythemia)

Four-tier risk classification guides treatment decisions:

• Very low risk: Age ≤60 years, no thrombosis history, JAK2 wild-type. 1
• Low risk: Age ≤60 years, no thrombosis history, JAK2 mutation present. 1
• Intermediate risk: Age >60 years, no thrombosis history, JAK2 mutation present. 1
• High risk: Prior thrombosis history OR age >60 years with JAK2 mutation. 1

Additional prognostic factors:

• MPL and CALR-1 mutations increase risk of myelofibrosis transformation. 1
• JAK2V617F mutation associates with increased thrombosis risk. 1
• TP53 mutations predict leukemic transformation. 1
• Median platelet counts and thrombosis incidence are significantly higher in primary versus secondary thrombocytosis. 2

Treatment Algorithm for Primary Thrombocytosis

High-Risk Disease

Cytoreductive therapy is mandatory:

• First-line options: Hydroxyurea OR pegylated interferon-α. 1
• Second-line option: Busulfan if first-line agents cannot be tolerated. 1
• Anagrelide is FDA-approved to reduce elevated platelet counts and decrease thrombosis risk in patients with thrombocythemia secondary to myeloproliferative neoplasms. 3
• Add once-daily low-dose aspirin (40-325 mg) if platelet count <1,500×10⁹/L. 4

Avoid aspirin if platelet count ≥1,500×10⁹/L due to acquired von Willebrand syndrome and bleeding risk. 4

Intermediate-Risk Disease

Cytoreductive therapy is optional:

• Consider treatment if cardiovascular risk factors are present. 1
• Options include hydroxyurea, pegylated interferon-α, or anagrelide. 4
• Low-dose aspirin can be used if platelet count <1,500×10⁹/L. 4

Low-Risk and Very Low-Risk Disease

Conservative management:

• Low-risk (JAK2-mutated): Twice-daily low-dose aspirin. 1
• Very low-risk (JAK2 wild-type): Once-daily low-dose aspirin. 1
• Observation alone is acceptable for patients <60 years without thrombosis history, cardiovascular risk factors, and platelet counts <1,500×10⁹/L. 4

Special Clinical Scenarios

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

This threshold increases bleeding risk due to acquired von Willebrand syndrome:

• Withhold aspirin until platelet count is reduced below 1,500×10⁹/L. 4
• Initiate cytoreductive therapy regardless of other risk factors. 4
• JAK2-mutated patients with extreme thrombocytosis have higher leukemic transformation risk. 1

Pregnancy

Special considerations for pregnant patients:

• Pegylated interferon-α is the cytoreductive agent of choice for high-risk pregnant women requiring treatment. 4
• Low-risk pregnant patients can be managed with observation or low-dose aspirin if platelet count <1,500×10⁹/L. 4
• No specific treatment has been shown to affect pregnancy outcomes in the Mayo Clinic experience. 4

Perioperative Management

Platelet count targets for procedures:

• Minor procedures: Platelets ≥50,000/μL. 5
• Major surgery: Platelets ≥50,000-100,000/μL. 5
• Ensure adequate platelet control before any invasive procedure. 5

Management of Secondary Thrombocytosis

Treatment focuses on the underlying cause:

• Address tissue injury, infection, chronic inflammation, or iron deficiency. 2
• Cytoreductive therapy is NOT indicated for secondary thrombocytosis. 2
• Thrombosis risk is significantly lower than in primary thrombocytosis. 2
• Low-dose aspirin may be considered if cardiovascular risk factors are present, but is not routinely required. 4

Critical Pitfalls to Avoid

• Do not use platelet count alone to determine thrombosis risk—age, thrombosis history, and JAK2 mutation status are more important. 6, 1
• Do not give aspirin with platelet counts ≥1,500×10⁹/L due to bleeding risk from acquired von Willebrand syndrome. 4
• Do not use direct oral anticoagulants (DOACs) with platelets <50,000/μL due to lack of safety data and increased bleeding risk. 5
• Do not normalize platelet counts as a treatment goal—the aim is to reduce thrombotic risk, not achieve normal platelet levels. 1
• Do not overlook the long-term leukemogenic potential of hydroxyurea, though it remains disputed and the drug is still first-line for high-risk disease. 7

Monitoring Strategy

• High-risk patients on cytoreductive therapy: Monitor complete blood count weekly during dose adjustment, then monthly once stable. 8
• Low-risk patients on observation: Periodic monitoring based on clinical stability. 4
• All patients: Assess for thrombotic or hemorrhagic complications at each visit. 1