What is the recommended evaluation and treatment approach for a patient with an elevated platelet count (thrombocytosis)?

Management of Elevated Platelet Count (Thrombocytosis)

The first critical step is distinguishing primary (clonal) thrombocytosis from secondary (reactive) thrombocytosis, as this fundamentally determines management—reactive thrombocytosis requires treatment of the underlying condition and does not require antiplatelet therapy or cytoreduction, while primary thrombocytosis demands risk-stratified treatment with aspirin and potentially cytoreductive agents. 1

Initial Diagnostic Approach

Distinguish Primary from Secondary Thrombocytosis

Order JAK2V617F mutation testing immediately when primary thrombocytosis is suspected, as a positive result (found in 50-60% of essential thrombocythemia cases) can obviate the need for immediate bone marrow biopsy in mutation-positive patients. 1, 2

• Reactive thrombocytosis accounts for the vast majority of cases in hospitalized patients (3-13% of hospitalized children, similar patterns in adults) and never causes thrombosis or bleeding, even at platelet counts >1,000 × 10⁹/L. 3, 4

• Common causes of reactive thrombocytosis include: infection, chronic inflammation, iron deficiency, tissue damage, malignancy, recent surgery, and functional/surgical splenectomy 5, 4

• If molecular markers (JAK2, CALR, MPL) are negative or additional cytopenias are present, perform bone marrow aspiration and biopsy to confirm essential thrombocythemia and exclude other myeloproliferative neoplasms (polycythemia vera, primary myelofibrosis) or myelodysplastic syndrome. 1

Key Diagnostic Red Flags

• The presence of hepatomegaly excludes primary immune thrombocytopenic purpura and mandates bone marrow examination to establish diagnosis and exclude prefibrotic myelofibrosis. 6

• Peripheral blood smear examination by a hematologist/pathologist is necessary to identify giant platelets, abnormal cells, and atypical morphology in suspected essential thrombocythemia. 6

• Exclude polycythemia vera by confirming hemoglobin <18.5 g/dL in men and <16.5 g/dL in women; in iron deficiency cases, trial iron replacement to exclude occult polycythemia vera. 1

• Exclude chronic myeloid leukemia by demonstrating absence of BCR-ABL fusion gene. 1

Risk Stratification for Primary Thrombocytosis

Once primary thrombocytosis (essential thrombocythemia) is confirmed, immediately stratify thrombotic risk using the following categories: 1, 2

Risk Categories

• 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: History of thrombosis OR (age >60 years with JAK2 mutation) 1

Additional Risk Modifiers

• JAK2V617F mutation increases thrombotic risk in essential thrombocythemia. 1

• MPL and CALR-1 mutations are associated with increased risk of myelofibrosis transformation; spliceosome mutations with inferior overall and myelofibrosis-free survival; TP53 with leukemic transformation. 2

Treatment Algorithm for Primary Thrombocytosis

All Risk Categories

Start low-dose aspirin (81-100 mg) once daily for all patients with essential thrombocythemia unless contraindicated. 1, 2

• For patients with microvascular symptoms (headaches, lightheadedness, acral paresthesias), use aspirin 81-100 mg twice daily, with plain aspirin preferred over enteric-coated formulations due to poor responsiveness in some essential thrombocythemia patients. 6, 2

• Critical contraindication: Do not start aspirin without checking for acquired von Willebrand syndrome if platelet count exceeds 1,000 × 10⁹/L, as this increases bleeding risk. 6, 2

• Screen for acquired von Willebrand syndrome with ristocetin cofactor activity and multimer analysis when platelet count exceeds 1,000/μL. 1

High-Risk Patients

Initiate cytoreductive therapy with hydroxyurea as first-line treatment for high-risk patients (age >60 years and/or history of thrombosis), targeting a platelet count <400,000/μL. 1

• Add low-dose aspirin (81-100 mg/day) unless contraindicated by acquired von Willebrand syndrome or active bleeding. 1

• Alternative first-line option: Pegylated interferon-α is preferred for young patients (to avoid long-term mutagenic risks of alkylating agents), with a starting dose of 45 mcg subcutaneously weekly, achieving 76% complete hematologic response and 18% complete molecular response at 42 months. 1, 6

• Second-line option: Busulfan for patients who fail or are intolerant of hydroxyurea or interferon. 2

Low-Risk and Intermediate-Risk Patients

For low-risk patients (age ≤60 years, no history of thrombosis) with JAK2 mutation, consider low-dose aspirin (81-100 mg/day). 1

• For JAK2-unmutated patients with low-risk primary thrombocytosis, observation alone is reasonable, and aspirin should be avoided in extreme thrombocytosis without ruling out acquired von Willebrand syndrome. 1

• Initiate cytoreductive therapy if symptomatic thrombocytosis, progressive leukocytosis, or disease-related symptoms develop in low-risk patients. 1

• Cytoreductive therapy should be strongly considered in symptomatic patients with microvascular disturbances, even if traditional risk stratification suggests low risk. 6

Management of Acute Thrombotic Complications

For patients with active thrombotic event and platelet count >50 × 10⁹/L, initiate full-dose therapeutic anticoagulation. 1

• Urgent cytoreduction is indicated alongside anticoagulation for patients with thrombocytosis and thrombosis. 1

• For platelet counts between 20 × 10⁹/L and 50 × 10⁹/L, give half the standard dose of low-molecular-weight heparin with close laboratory monitoring. 1

• When platelet counts are <20 × 10⁹/L, therapeutic anticoagulation should be withheld to minimize bleeding risk. 1

Special Clinical Scenarios

Perioperative Management

Ensure thrombosis and bleeding risk are well controlled prior to elective surgery, particularly orthopedic surgeries or procedures with prolonged immobilization, using appropriate anticoagulant prophylaxis and cytoreductive therapy. 1

• For high-risk venous thromboembolism procedures, consider extended prophylaxis with low-molecular-weight heparin. 1

Extreme Thrombocytosis (>1,000 × 10⁹/L)

Refer to hematology for platelet count >1,000/μL regardless of etiology. 1

• Assess for bleeding manifestations, including petechiae, purpura, or mucosal bleeding, as acquired von Willebrand syndrome may occur with extreme thrombocytosis. 1

Monitoring and Follow-Up

Regular monitoring of complete blood count is necessary to assess response to cytoreductive therapy, with a target platelet count <400,000/μL for patients on cytoreductive therapy. 1

• Monitor for side effects of cytoreductive agents, such as myelosuppression with hydroxyurea. 1

• Leukemic transformation rate at 10 years is <1% but may be higher in JAK2-mutated patients with extreme thrombocytosis and those with abnormal karyotype. 2

Management of Reactive Thrombocytosis

For reactive thrombocytosis, identify and treat the underlying condition—no antiplatelet therapy or cytoreduction is indicated. 3

• Reactive thrombocytosis, even at platelet counts >1,000 × 10⁹/L, has never been shown to cause thrombosis or bleeding. 3

• In the majority of reactive thrombocytosis cases, no treatment is necessary, and the patient should be closely monitored. 4