What is the diagnosis, differential diagnosis, evaluation, and management of a patient with thrombocytosis (elevated platelet count)?

Elevated Platelet Count: Diagnosis, Differential, Evaluation and Management

The first step when encountering thrombocytosis (platelet count ≥450 × 10⁹/L) is to distinguish between primary (clonal myeloproliferative neoplasm) and secondary (reactive) causes, as this fundamentally determines management—secondary thrombocytosis requires treatment of the underlying condition without cytoreductive therapy, while primary thrombocytosis necessitates risk stratification and potential cytoreductive treatment with hydroxyurea or pegylated interferon-α. 1, 2

Diagnostic Approach

Initial Laboratory Evaluation

• Obtain a complete blood count with peripheral blood smear to exclude pseudothrombocytosis, identify other cell line abnormalities (suggesting myeloproliferative neoplasm), and assess platelet morphology 1, 3

• Review for other cytopenias or cytoses that would suggest a primary myeloproliferative disorder rather than reactive thrombocytosis 3

Distinguishing Primary from Secondary Thrombocytosis

Secondary thrombocytosis accounts for 83% of cases and is the most common etiology, particularly in younger patients. 4 The major causes include:

• Tissue injury/trauma (32% of cases): surgery, burns, fractures 2, 4
• Infection (17% of cases): acute bacterial or viral infections 2, 4
• Chronic inflammatory disorders (12% of cases): inflammatory bowel disease, rheumatoid arthritis 2, 4
• Iron deficiency anemia (11% of cases): must be excluded by trial of iron replacement before diagnosing essential thrombocythemia, as occult polycythemia vera may be masked 2, 4
• Post-splenectomy or hyposplenism 2
• Malignancy: solid tumors, lymphoproliferative disorders producing inflammatory cytokines 2
• Drug-induced: corticosteroids, epinephrine, erythropoiesis-stimulating agents 2

Primary thrombocytosis represents 12.5% of cases and includes myeloproliferative neoplasms: 4

• Essential thrombocythemia (ET): most common primary cause, characterized by sustained platelet count ≥450 × 10⁹/L with bone marrow showing proliferation of enlarged, mature megakaryocytes 2, 5
• Polycythemia vera (PV) 1, 2
• Primary myelofibrosis 2
• Chronic myeloid leukemia 2

Molecular Testing for Primary Thrombocytosis

If primary thrombocytosis is suspected, test for myeloproliferative neoplasm driver mutations: 1, 5

• JAK2V617F mutation: present in approximately 60% of essential thrombocythemia cases; increases thrombotic risk 1, 5
• CALR mutations: present in approximately 20-25% of cases; CALR-1 associated with increased myelofibrosis transformation risk 5
• MPL mutations (MPLW515L/K): present in approximately 3-5% of cases; associated with increased myelofibrosis transformation 1, 5

Among patients with primary thrombocytosis, 86% harbor at least one molecular marker indicative of myeloproliferative neoplasm. 4

When to Perform Bone Marrow Biopsy

Bone marrow aspiration and biopsy are required when molecular markers are negative but clinical features suggest myeloproliferative neoplasm, or when diagnosis remains unclear despite molecular testing. 3 This is essential to:

• Exclude prefibrotic myelofibrosis (which can present with thrombocytosis but has different prognosis) 5
• Exclude myelodysplastic syndromes with ring sideroblasts and thrombocytosis 5
• Confirm characteristic megakaryocyte proliferation pattern 5

Critical Diagnostic Pitfall

Before attributing thrombocytosis to primary or secondary causes, exclude heparin-induced thrombocytopenia, disseminated intravascular coagulation, and drug reactions. 2 In malignancy-related DIC, a decreasing platelet trend from an initially elevated level may be the only sign, even if the absolute count remains in the normal range. 2

Risk Stratification for Primary Thrombocytosis

Once primary thrombocytosis is confirmed, immediate stratification of thrombotic risk is necessary, as this determines treatment intensity. 1 The National Comprehensive Cancer Network recommends four risk categories: 1

Risk Categories

1. Very low risk: Age ≤60 years, no thrombosis history, JAK2 wild-type 1, 5

2. Low risk: Age ≤60 years, no thrombosis history, JAK2 mutation present 1, 5

3. Intermediate risk: Age >60 years, no thrombosis history, JAK2 wild-type 1, 5

4. High risk: History of prior thrombosis OR age >60 years with JAK2 mutation 1, 5

The median platelet count and incidence of thrombosis are significantly higher in primary versus secondary thrombocytosis. 4

Management

Management of Secondary Thrombocytosis

For secondary thrombocytosis, treatment of the underlying condition is the primary approach, and platelet-lowering therapy is generally not required. 2

• Antiplatelet therapy is not necessary unless other cardiovascular indications exist 2
• Monitor platelet count to confirm resolution with treatment of underlying cause 2
• Secondary thrombocytosis is generally benign and self-limited when the underlying cause resolves; venous thrombosis only occurs when additional risk factors are present 2

Management of Primary Thrombocytosis

Very Low and Low Risk Patients

For very low-risk patients (age ≤60 years, no thrombosis history, JAK2 wild-type), observation with close monitoring is appropriate. 3

For low-risk patients with JAK2 mutation, add low-dose aspirin 81-100 mg daily unless contraindicated or platelet count exceeds 1,500 × 10⁹/L (due to acquired von Willebrand syndrome risk). 1, 5

Intermediate Risk Patients

For intermediate-risk patients, treatment options include observation with close monitoring, low-dose aspirin if platelet count <1,500 × 10⁹/L, or cytoreductive therapy based on individual thrombotic risk assessment. 3

Initiate cytoreductive therapy if symptomatic thrombocytosis, progressive leukocytosis, or disease-related symptoms develop. 1

High Risk Patients

For high-risk patients (age >60 years and/or history of thrombosis), cytoreductive therapy is mandatory, targeting a platelet count <400,000/μL. 1

First-line cytoreductive therapy options: 1, 5

• Hydroxyurea: first-line agent, starting dose typically 15-20 mg/kg/day, adjusted to maintain platelet count <400,000/μL 1
• Pegylated interferon-α: alternative first-line agent, particularly in younger patients or pregnancy 5

Add low-dose aspirin 81-100 mg daily unless contraindicated. 1

Second-line cytoreductive therapy: 5

• Busulfan: reserved for patients intolerant or resistant to hydroxyurea and interferon 5
• Anagrelide: can be used but is not preferred first-line; starting dose 0.5 mg twice daily, titrated to maximum 12 mg/day 6

Special Clinical Scenarios

Extreme Thrombocytosis (Platelet Count >1,000/μL)

Referral to hematology is indicated for platelet count >1,000/μL regardless of etiology. 1

Screen for acquired von Willebrand syndrome with ristocetin cofactor activity and multimer analysis, as this affects bleeding risk and aspirin use. 1 If present, avoid aspirin until platelet count is reduced. 5

Thrombosis in Setting of Thrombocytosis

Initiate full therapeutic anticoagulation for platelet counts >50 × 10⁹/L. 1

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

Active Bleeding with Thrombocytosis

Platelet transfusion is not indicated for thrombocytosis, even with active bleeding. 1 The elevated platelet count in primary thrombocytosis is associated with qualitative platelet dysfunction, and transfusion does not improve hemostasis. 7, 8

Monitoring

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

Monitor for side effects of cytoreductive agents, particularly myelosuppression with hydroxyurea. 1

Monitor for disease transformation: leukemic transformation rate at 10 years is <1% but may be higher in JAK2-mutated patients with extreme thrombocytosis and those with abnormal karyotype. 5