What is the appropriate management for a patient with chronic thrombocytosis (elevated platelet count), mild hepatomegaly, and symptoms including migraines, peripheral neuropathy, and easy bruising?

Management of Chronic Thrombocytosis with Systemic Symptoms

This patient requires urgent evaluation for a myeloproliferative neoplasm (MPN), specifically essential thrombocythemia (ET), given the 7-year history of persistent thrombocytosis (447-589 × 10⁹/L), giant platelet forms, hepatomegaly, and constellation of microvascular symptoms (migraines, peripheral neuropathy, tinnitus, easy bruising). 1, 2

Immediate Diagnostic Workup Required

The presence of hepatomegaly definitively excludes primary immune thrombocytopenic purpura (ITP), as ITP should have a normal physical examination aside from bleeding manifestations. 3 Less than 3% of ITP patients have organomegaly, making this a critical red flag for alternative diagnoses. 3

Essential Laboratory and Molecular Testing

• Peripheral blood smear examination by a hematologist/pathologist to identify giant platelets, abnormal cells, and atypical morphology 3, 1
• JAK2V617F mutation testing (present in 64% of ET patients) 1, 2
• CALR mutation testing (present in 23% of ET patients) 1, 2
• MPL mutation testing (present in 4% of ET patients) 1, 2
• Bone marrow aspiration and biopsy with cytogenetics to confirm diagnosis and exclude prefibrotic myelofibrosis, which can present similarly 1, 2
• HIV and hepatitis C testing, as these infections can cause thrombocytopenia clinically indistinguishable from primary disorders 3, 4

Critical Exclusions

• Rule out reactive thrombocytosis from iron deficiency (though patient's history shows this resolved), inflammation (normal inflammatory markers noted), infection, or malignancy 1, 2
• Exclude polycythemia vera (check hemoglobin/hematocrit) 1, 2
• Exclude chronic myeloid leukemia (BCR-ABL1 testing) 1, 2

Risk Stratification for Essential Thrombocythemia

This patient appears to be intermediate-to-high risk based on age (26 years, but with significant symptoms), microvascular symptoms (migraines, peripheral neuropathy, tinnitus), and easy bruising suggesting acquired von Willebrand syndrome from extreme thrombocytosis. 1, 2

Risk Categories

• Very low risk: Age ≤60 years, no thrombosis history, JAK2 wild-type 2
• Low risk: Age ≤60 years, no thrombosis history, JAK2 mutation present 2
• Intermediate risk: Age >60 years with JAK2 mutation 2
• High risk: History of thrombosis OR age >60 years with JAK2 mutation 2

However, the presence of significant microvascular symptoms (headaches, peripheral neuropathy, acral paresthesias) elevates this patient's management needs regardless of traditional risk category. 2, 5

Treatment Recommendations

Aspirin Therapy

Start low-dose aspirin (81-100 mg) TWICE daily immediately for control of microvascular symptoms. 6, 2

• Plain aspirin should be preferred over enteric-coated formulations due to poor responsiveness ("resistance") to enteric-coated aspirin in some ET patients 6
• Twice-daily dosing is critical in ET because once-daily aspirin does not maintain adequate platelet thromboxane A2 inhibition for 24 hours in most patients due to high platelet production 6
• Exception: If platelet count exceeds 1,000 × 10⁹/L, check for acquired von Willebrand syndrome (ristocetin cofactor and multimer analysis) before starting aspirin, as aspirin may increase bleeding risk 4, 2

Cytoreductive Therapy Considerations

Given the symptomatic microvascular disturbances (migraines, peripheral neuropathy, tinnitus, easy bruising), cytoreductive therapy should be strongly considered even if traditional risk stratification suggests low risk. 2

First-Line Cytoreductive Options

Pegylated interferon-α is the preferred first-line agent for this young patient (26 years old) to avoid long-term mutagenic risks of alkylating agents. 2

• Starting dose: 45 mcg subcutaneously weekly 4
• Rationale: Preserves fertility, avoids leukemogenic risk of hydroxyurea in young patients 2
• Alternative: Hydroxyurea (starting 15-20 mg/kg/day) if interferon is not tolerated or contraindicated 2

Hydroxyurea is appropriate if rapid platelet reduction is needed or if cost/access to pegylated interferon is prohibitive. 1, 2 In a randomized trial of 114 high-risk patients, hydroxyurea significantly reduced thrombotic events compared to no cytoreduction (3.6% vs 24%; P < .01). 1

Specific Management of Symptoms

For migraines and vasomotor symptoms: Aspirin twice daily is first-line; if inadequate response after 2-4 weeks, add cytoreductive therapy 6, 2

For peripheral neuropathy: Ensure this is ET-related (not B12 deficiency or other causes); cytoreductive therapy to normalize platelet count typically improves symptoms 2, 5

For easy bruising: Check for acquired von Willebrand syndrome if platelet count >1,000 × 10⁹/L; if present, avoid aspirin until platelet count is reduced with cytoreduction 4, 2

Critical Pitfalls to Avoid

• Do not delay bone marrow examination in the presence of hepatomegaly and chronic thrombocytosis—this is mandatory to establish diagnosis and exclude prefibrotic myelofibrosis 3, 1
• Do not use once-daily aspirin in ET patients with high platelet counts, as inadequate 24-hour platelet inhibition occurs due to high platelet production 6
• Do not withhold cytoreductive therapy in symptomatic young patients based solely on age-based risk stratification; microvascular symptoms are an indication for treatment 2, 5
• Do not use hydroxyurea as first-line in young patients if pegylated interferon is available, due to potential long-term leukemogenic risk 2
• Do not start aspirin without checking for acquired von Willebrand syndrome if platelet count exceeds 1,000 × 10⁹/L 4, 2

Monitoring Strategy

• Platelet count every 2-4 weeks during initial treatment adjustment 2
• Complete blood count with differential monthly once stable 2
• Annual bone marrow examination is not routinely needed unless clinical deterioration or cytopenias develop 2
• Monitor for transformation: 10-year risk of myelofibrosis transformation is approximately 10%; acute leukemia risk is <1% at 10 years but higher with JAK2 mutation and extreme thrombocytosis 1, 2