What is the recommended management for a patient with comorbid hypermobile Ehlers-Danlos Syndrome (hEDS) and essential thrombocythemia (ET)?

Management of Comorbid Hypermobile EDS and Essential Thrombocythemia

For patients with both hypermobile Ehlers-Danlos syndrome (hEDS) and essential thrombocythemia (ET), cytoreductive therapy with hydroxyurea is strongly recommended to reduce thrombotic risk, while aspirin use requires extreme caution due to the compounded bleeding risk from both conditions. 1

Risk Stratification for Essential Thrombocythemia

The ET component must be classified according to thrombotic risk to guide treatment intensity:

• High-risk ET (age >60 years or prior thrombosis) mandates cytoreductive therapy with hydroxyurea plus low-dose aspirin (81-100 mg daily) 1
• Intermediate or low-risk ET may be managed with observation alone or aspirin monotherapy, though this requires careful reconsideration in the context of hEDS 1
• JAK2 V617F mutation status and cardiovascular risk factors further stratify thrombotic risk 1

The Critical Bleeding Risk Consideration in hEDS

The presence of hEDS fundamentally alters the risk-benefit calculation for aspirin therapy. Patients with hEDS have inherent vascular fragility, tissue fragility, and propensity for easy bruising and bleeding complications 2. When combined with ET—which itself carries bleeding risk, particularly with acquired von Willebrand disease at high platelet counts—the cumulative bleeding risk becomes substantial 1.

Specific Bleeding Risk Assessment Required:

• Screen for acquired von Willebrand disease through coagulation testing, especially if platelet count is elevated or patient has unexplained bleeding history 1
• Document baseline bleeding manifestations from hEDS (easy bruising, mucosal bleeding, prolonged bleeding from minor trauma) 2
• Assess for gastrointestinal manifestations of hEDS that could increase GI bleeding risk with aspirin 2

Cytoreductive Therapy as Primary Strategy

Hydroxyurea should be the cornerstone of management for high-risk ET in this population, as it addresses thrombotic risk while potentially reducing the need for aspirin. 1

Treatment Protocol:

• Target platelet count <400 × 10⁹/L to reduce both thrombotic and bleeding risk 3
• Hydroxyurea is preferred over anagrelide, as anagrelide was associated with higher rates of arterial thrombosis, serious hemorrhage, and transformation to myelofibrosis in randomized trials 1
• For younger patients or those with concerns about hydroxyurea, peginterferon alfa-2a or alfa-2b are alternatives that have shown efficacy in ET 1
• Monitor for hydroxyurea resistance or intolerance using established criteria 1

Modified Aspirin Strategy in hEDS-ET Patients

If aspirin is deemed necessary despite hEDS, use the lowest effective dose (81 mg daily) and consider withholding it entirely if bleeding manifestations are prominent. 1, 4

Aspirin Decision Algorithm:

1. Contraindications to aspirin in this population:

   • Active bleeding or significant bleeding history from hEDS 4
   • Acquired von Willebrand disease (test if platelet count >1000 × 10⁹/L) 1
   • Severe thrombocytopenia if it develops during treatment 5, 4

2. If aspirin is used:

   • Standard once-daily dosing (81-100 mg) is recommended initially 1
   • Twice-daily aspirin (100 mg every 12 hours) may be superior for platelet inhibition in ET due to accelerated platelet turnover, but this increases bleeding risk and should be reserved for carefully selected patients with inadequate response to once-daily dosing 1, 6, 7
   • Discontinue aspirin one week prior to any surgical procedure and restart 24 hours post-operatively only when bleeding risk is acceptable 1

3. Monitor closely for:

   • New or worsening bleeding manifestations (petechiae, ecchymosis, epistaxis, GI bleeding) 4
   • Vasomotor symptoms (erythromelalgia, digital ischemia) that might indicate need for aspirin despite bleeding risk 1

Surgical and Procedural Considerations

Patients with hEDS-ET face compounded surgical risks from both conditions and require meticulous perioperative planning. 1

• Multidisciplinary coordination between hematology, surgery, and specialists familiar with hEDS complications is mandatory 1
• Thrombosis and bleeding risk must be optimized (near-normalization of CBC) for at least 3 months before elective surgery 1
• Extended prophylaxis with low-molecular-weight heparin should be considered for high-risk procedures (orthopedic, cardiovascular, cancer surgery) 1
• Cytoreductive therapy can generally be continued perioperatively unless specific contraindications exist 1
• hEDS patients may have tissue fragility affecting wound healing and increased risk of surgical complications 2

Monitoring and Multidisciplinary Management

Regular surveillance is essential given the complexity of managing both conditions:

• Every 3-6 months: Complete blood count, symptom assessment using MPN-SAF TSS, evaluation for disease progression 1
• As indicated: Bone marrow biopsy if signs of progression, coagulation studies if bleeding concerns 1
• Ongoing: Cardiovascular risk factor management, as these patients are at very high cardiovascular risk 1
• Coordinate care between hematology and specialists managing hEDS manifestations (physical therapy, pain management, cardiology for orthostatic intolerance, gastroenterology) 2

Common Pitfalls to Avoid

• Do not reflexively prescribe aspirin to all ET patients without considering the hEDS bleeding risk—cytoreductive therapy alone may be sufficient 1, 4
• Do not use higher aspirin doses (>100 mg daily) as this increases bleeding risk without additional antithrombotic benefit in this population 4
• Do not overlook acquired von Willebrand disease in patients with very high platelet counts, as aspirin is contraindicated in this setting 1
• Do not confuse ET management with immune thrombocytopenia—these are distinct conditions with opposite platelet count abnormalities 5
• Do not underestimate the cumulative bleeding risk from the combination of hEDS vascular fragility and antiplatelet therapy 2