What is the appropriate workup and treatment for a patient presenting with thrombocytosis (elevated platelet count)?

Thrombocytosis Workup

For a patient presenting with thrombocytosis (elevated platelet count), the primary goal is to distinguish reactive/secondary thrombocytosis from primary myeloproliferative neoplasms, as this distinction fundamentally determines management and prognosis.

Initial Diagnostic Approach

Confirm True Thrombocytosis and Assess Severity

• Verify the platelet count with repeat complete blood count (CBC) and peripheral blood smear examination to exclude pseudothrombocytosis and evaluate other cell lines 1, 2
• Thrombocytosis is defined as platelet count >450,000/μL, with severity classified as: mild (500,000-700,000/μL), moderate (700,000-900,000/μL), severe (>900,000/μL), and extreme (>1,000/μL) 3
• Examine the peripheral smear for morphologic abnormalities including abnormal platelet size, immature myeloid cells, or dysplastic features that suggest primary myeloproliferative disease 1, 2

Distinguish Secondary from Primary Thrombocytosis

Secondary (reactive) thrombocytosis accounts for the vast majority of cases and requires identification of the underlying cause 1, 2:

• Infection/inflammation: Most common cause; obtain inflammatory markers (CRP, ESR) and evaluate for acute or chronic infectious/inflammatory conditions 1, 3
• Iron deficiency: Check serum ferritin, iron studies; iron deficiency is a frequent cause even without anemia 1, 2
• Malignancy: Consider solid tumors (lung, GI, ovarian) or hematologic malignancies; thrombocytosis may be the presenting sign 1
• Tissue damage/surgery: Recent trauma, surgery, or tissue necrosis can cause reactive thrombocytosis 1, 3
• Hyposplenism/asplenia: Assess for functional or surgical splenectomy; examine smear for Howell-Jolly bodies 1
• Medications: Review for drugs that can elevate platelets (all-trans retinoic acid, epinephrine, growth factors) 1

Primary thrombocytosis (essential thrombocythemia and other myeloproliferative neoplasms) should be suspected when 1, 2, 4:

• Platelet count persistently >450,000/μL without identifiable secondary cause
• Platelet count >1,000/μL (more suggestive of primary disease)
• Associated symptoms: microcirculatory disturbances (headaches, lightheadedness, acral paresthesias), thrombotic events, or paradoxical bleeding 2, 4
• Splenomegaly on physical examination 1, 2

Workup for Suspected Primary Thrombocytosis

Molecular Testing (Essential First Step)

Order myeloproliferative neoplasm (MPN) driver mutation testing 1, 5, 2, 4:

• JAK2V617F mutation: Present in ~60% of essential thrombocythemia (ET) patients; associated with increased thrombotic risk 5, 2, 4
• CALR mutations: Present in ~25% of ET patients; CALR-1 associated with increased myelofibrosis transformation risk 5, 4
• MPL mutations (MPLW515L/K): Present in ~3-5% of ET patients; associated with increased myelofibrosis transformation 5, 2, 4
• Approximately 10-15% of ET patients are "triple-negative" (no JAK2/CALR/MPL mutations) 5, 4

Note: These mutations are not disease-specific and can be found in other MPNs (polycythemia vera, primary myelofibrosis), so positive results do not definitively establish ET diagnosis 2

Bone Marrow Evaluation

Bone marrow aspiration and biopsy with histologic examination is essential for definitive diagnosis 1, 5, 2:

• Perform bone marrow biopsy when: MPN driver mutation is positive, thrombocytosis persists without clear secondary cause, or clinical suspicion for primary disease is high 1, 5
• ET bone marrow findings: Increased number of mature-appearing megakaryocytes distributed in loose clusters, without significant granulocytic or erythroid proliferation 4
• Critical distinction: Must exclude prefibrotic primary myelofibrosis, which has different prognosis and management but can present with thrombocytosis; prefibrotic myelofibrosis shows increased reticulin fibrosis and atypical megakaryocyte clustering 5, 4

Additional Diagnostic Testing

• Karyotype analysis: Abnormal karyotype seen in <10% of ET cases; includes +9, 20q-, 13q-; TP53 mutations and abnormal karyotype associated with leukemic transformation 4
• Comprehensive mutation panel: Consider testing for TET2 (9-11%), ASXL1 (7-20%), DNMT3A (7%), SF3B1 (5%); spliceosome mutations associated with inferior survival and increased myelofibrosis transformation 5, 4
• Exclude other MPNs: Check hemoglobin/hematocrit to rule out polycythemia vera; BCR-ABL testing to exclude chronic myeloid leukemia 1, 4

Risk Stratification for Essential Thrombocythemia

Once ET is diagnosed, stratify thrombotic risk to guide treatment decisions 4:

Thrombotic Risk Categories

• Very low risk: Age ≤60 years, no thrombosis history, JAK2 wild-type 4
• Low risk: Age ≤60 years, no thrombosis history, JAK2 mutation present 4
• Intermediate risk: Age >60 years, no thrombosis history, JAK2 wild-type 4
• High risk: History of thrombosis OR age >60 years with JAK2 mutation 4

Prognostic Assessment

Apply the triple A survival risk model (Age, Absolute neutrophil count, Absolute lymphocyte count) to estimate long-term prognosis: high-risk (8 years median survival), intermediate-1 (14 years), intermediate-2 (21 years), and low-risk (47 years) 4

Management Principles

Secondary Thrombocytosis

Treat the underlying cause; platelet count typically normalizes with resolution of the precipitating condition 1, 3:

• No specific antiplatelet or cytoreductive therapy required for reactive thrombocytosis alone
• Monitor platelet count to confirm resolution after treating underlying condition
• Thrombotic complications are rare in secondary thrombocytosis even with extreme elevations 1, 3

Essential Thrombocythemia Treatment

All patients require cardiovascular risk factor modification and consideration of antiplatelet therapy 4:

• Low-dose aspirin (once daily): Recommended for all ET patients without contraindications to prevent thrombosis 4
• Twice-daily aspirin: Consider for very low-risk disease 4

Cytoreductive therapy indications 4:

• High-risk patients: Require cytoreductive therapy (age >60 with JAK2 mutation OR history of thrombosis) 4
• Intermediate-risk patients: Cytoreductive therapy is optional; consider based on additional risk factors 4
• Low/very low-risk patients: Aspirin alone is sufficient; cytoreductive therapy not indicated 4

First-line cytoreductive agents 6, 4:

• Hydroxyurea: First-line option for most patients 4
• Pegylated interferon-α: First-line option, particularly for younger patients and those planning pregnancy 4
• Anagrelide: FDA-approved to reduce elevated platelet count and risk of thrombosis in thrombocythemia secondary to myeloproliferative neoplasms 6

Second-line therapy: Busulfan for patients intolerant or refractory to first-line agents 4

Critical Pitfalls to Avoid

• Do not assume primary thrombocytosis without excluding secondary causes: Iron deficiency, infection, and malignancy are far more common than ET 1, 2
• Do not rely solely on molecular testing: JAK2/CALR/MPL mutations are not disease-specific; bone marrow histology is essential to distinguish ET from other MPNs, particularly prefibrotic myelofibrosis 5, 2, 4
• Do not treat based on platelet count alone: Treatment decisions in ET are based on thrombotic risk stratification, not platelet number; extreme thrombocytosis (>1,000/μL) does not automatically require cytoreduction in low-risk patients 4
• Do not overlook prefibrotic myelofibrosis: This entity has worse prognosis than ET but can present with thrombocytosis; careful bone marrow evaluation is mandatory 5, 4