What is the recommended management for a patient with hypermobile Ehlers-Danlos syndrome (hEDS) and essential thrombocythemia (ET) with thrombocytosis (platelet count between 447 and 589) and possible microvascular symptoms?

Management of Suspected Essential Thrombocythemia in hEDS Patient with Chronic Thrombocytosis and Possible Microvascular Symptoms

This patient requires formal diagnostic workup for essential thrombocythemia including JAK2/CALR/MPL mutation testing and bone marrow biopsy, followed by risk stratification using the revised IPSET-Thrombosis score to determine if cytoreductive therapy is warranted. 1, 2

Diagnostic Confirmation Required

The 7-year history of persistent thrombocytosis (447-589 × 10⁹/L) with giant platelet forms and possible microvascular symptoms raises strong suspicion for ET, but formal diagnosis must be established before initiating treatment. 3, 4

• Bone marrow biopsy remains the cornerstone of diagnosis and is essential to confirm ET and exclude prefibrotic myelofibrosis, which has different prognosis and management. 3, 4
• Driver mutation testing (JAK2 V617F, CALR, MPL) should be performed, as approximately 90% of ET patients harbor one of these mutations. 3, 4
• The presence of JAK2 V617F mutation increases thrombotic risk and influences risk stratification. 2, 3

Risk Stratification Using IPSET-Thrombosis

The NCCN guidelines recommend using the revised IPSET-Thrombosis score to classify ET patients into risk categories. 1

Risk categories are defined as: 3, 4

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

Management Based on Risk Category and Microvascular Symptoms

If Microvascular Symptoms Are Confirmed

Low-dose aspirin (81-100 mg daily) is the treatment of choice for microvascular occlusive symptoms such as erythromelalgia, transient neurological symptoms, or digital ischemia, regardless of platelet count in this range. 1, 5, 3

• Aspirin has proven efficacy in reversing microvascular symptoms in ET patients. 6, 5
• The platelet count of 447-589 × 10⁹/L is well above the threshold where aspirin-related bleeding becomes a concern (which occurs primarily with extreme thrombocytosis >1500 × 10⁹/L). 7, 8

Cytoreductive Therapy Indications

Cytoreductive therapy is indicated for high-risk patients (prior thrombosis or age >60 with JAK2 mutation) to reduce thrombotic complications. 1, 2

• Hydroxyurea is the first-line cytoreductive agent with proven efficacy in preventing thrombotic complications in randomized trials. 1, 2, 3
• Target platelet count should be <400 × 10⁹/L while monitoring for cytopenias. 2
• Starting dose is typically 0.5-2.0 mg every 6 hours, with maximum daily dose of 12 mg. 9

For very low-risk or low-risk patients without thrombosis history and age ≤60 years, cytoreductive therapy may not be required even with persistent thrombocytosis in this range. 1, 3, 4

• The relationship between moderate thrombocytosis (400-600 × 10⁹/L) and thrombotic risk is controversial, and solid evidence supporting cytoreductive therapy based solely on platelet count in this range is lacking. 8
• Cytoreduction is generally reserved for platelet counts >1500 × 10⁹/L to prevent bleeding, or for high-risk patients to prevent thrombosis. 6, 5

Special Consideration: hEDS and Vascular Complications

The presence of hEDS adds complexity due to underlying connective tissue abnormalities that may predispose to vascular complications independent of ET. Close monitoring for both thrombotic and bleeding manifestations is warranted, as hEDS patients may have altered vascular integrity.

Monitoring Strategy

Regular complete blood count monitoring is essential to track platelet trends and assess response to any initiated therapy. 2

• Watch specifically for signs of thrombosis (arterial or venous events) and bleeding complications. 1
• Monitor for progression of microvascular symptoms including digital ischemia, visual disturbances, or neurological symptoms. 5
• Assess for signs of hydroxyurea intolerance if cytoreductive therapy is initiated (leg ulcers, mucocutaneous manifestations, cytopenias). 1

Common Pitfalls to Avoid

• Do not initiate cytoreductive therapy based solely on platelet count in the 400-600 × 10⁹/L range without proper risk stratification. 8, 3
• Do not withhold aspirin due to thrombocytosis in this range if microvascular symptoms are present—the bleeding risk is minimal and the benefit for symptom control is established. 7, 5
• Do not confuse ET with reactive thrombocytosis—the 7-year chronicity and giant forms support clonal disease, but bone marrow biopsy confirmation is mandatory. 3
• Do not fail to exclude prefibrotic myelofibrosis, which requires different management despite similar platelet counts. 3, 4