In an adult with polycythemia, what is the role of low‑dose aspirin in preventing ischemic stroke and what is the underlying stroke pathophysiology?

Aspirin for Stroke Prevention in Polycythemia Vera

All adults with polycythemia vera should receive low-dose aspirin 100 mg once daily for stroke prevention unless contraindicated, as this regimen significantly reduces both arterial and venous thrombotic events including ischemic stroke without substantially increasing bleeding risk. 1

Stroke Pathophysiology in Polycythemia Vera

The thrombotic risk in polycythemia vera stems from multiple interconnected mechanisms:

• Hyperviscosity from elevated red cell mass increases blood viscosity and impairs cerebral blood flow, creating a prothrombotic milieu 1
• Quantitative and qualitative platelet abnormalities are central to stroke pathogenesis, with both elevated platelet counts and intrinsic platelet dysfunction promoting arterial thrombosis 2
• Increased thromboxane A2 production by abnormal platelets drives vasoconstriction and platelet aggregation, directly contributing to microvascular and macrovascular occlusion 3, 2
• Endothelial activation and inflammation in myeloproliferative neoplasms further amplify thrombotic risk beyond simple cell count elevation 1

The stroke risk in polycythemia vera is both arterial (ischemic stroke) and includes microcirculatory disturbances that manifest as transient neurological symptoms 1, 2.

Evidence-Based Aspirin Recommendations

Primary Prevention in Polycythemia Vera

The landmark ECLAP trial provides the strongest evidence for aspirin in polycythemia vera, demonstrating:

• Significant 60% reduction in the combined endpoint of nonfatal MI, nonfatal stroke, pulmonary embolism, major venous thrombosis, or cardiovascular death (RR 0.40; 95% CI 0.18-0.91; P=0.03) 1, 4
• Trend toward 59% reduction in cardiovascular death, nonfatal MI, and nonfatal stroke (RR 0.41; 95% CI 0.15-1.15; P=0.09) 1, 4
• No significant increase in major bleeding compared to placebo (RR 1.62; 95% CI 0.27-9.71) 4, 5

Optimal Dosing Strategy

100 mg once daily is the evidence-based dose for polycythemia vera, established by the ECLAP trial and endorsed by multiple guidelines 1, 6:

• This dose provides maximal platelet cyclooxygenase inhibition while minimizing bleeding risk 1, 6
• Lower doses (50-75 mg) are insufficient for polycythemia vera, though adequate for isolated stroke prevention 1, 6
• Higher doses (>100 mg) increase bleeding without additional antithrombotic benefit 6

Integration with Comprehensive Management

Aspirin is a cornerstone therapy but must be combined with other interventions 1:

• All patients require phlebotomy to maintain hematocrit <45% regardless of risk category 1
• High-risk patients (age >60 years or prior thrombosis) require cytoreductive therapy (hydroxyurea or interferon-alpha) in addition to aspirin and phlebotomy 1
• Cardiovascular risk factor modification is essential: aggressive management of hypertension, diabetes, hyperlipidemia, and smoking cessation 1

Critical Contraindications and Precautions

Absolute Contraindications

Withhold aspirin in the following scenarios 1, 7:

• Aspirin allergy or hypersensitivity (consider clopidogrel 75 mg daily as alternative) 1
• Active bleeding or high bleeding risk 1, 7
• Acquired von Willebrand syndrome, particularly with extreme thrombocytosis >1,500 × 10⁹/L 1

Common Pitfall: Extreme Thrombocytosis

Patients with platelet counts >1,000 × 10⁹/L are at paradoxically increased bleeding risk due to acquired von Willebrand syndrome, and aspirin may enhance hemorrhagic complications in this setting 2, 8. Cytoreduction to platelet count <400 × 10⁹/L should precede or accompany aspirin initiation 2.

Monitoring and Pharmacodynamic Considerations

Inadequate Response Recognition

One-third of polycythemia vera patients on standard once-daily aspirin display less-than-maximal platelet inhibition 3:

• These patients are characterized by significantly higher platelet counts and residual thromboxane B2 production 3
• Serum thromboxane B2 measurement can guide precision dosing when inadequate response is suspected 3
• Twice-daily aspirin (50 mg BID) achieves complete platelet inhibition in patients with inadequate response to once-daily dosing 3

Formulation Matters

Use regular (non-enteric-coated) aspirin for reliable platelet inhibition 1, 6:

• Regular aspirin achieves peak plasma levels at 30-40 minutes with platelet inhibition evident within 1 hour 1
• Enteric-coated formulations have lower bioavailability and may take 3-4 hours to reach peak levels, resulting in inadequate platelet inhibition 6, 7

Secondary Stroke Prevention

For polycythemia vera patients who suffer ischemic stroke despite aspirin, the 100 mg daily dose satisfies both the polycythemia vera indication and secondary stroke prevention requirements 1:

• This dose falls within the recommended 75-100 mg range for long-term secondary stroke prevention 1, 6
• Alternative antiplatelet agents (clopidogrel 75 mg daily or aspirin/extended-release dipyridamole 25/200 mg BID) may be considered for recurrent events 1
• Addition of warfarin to aspirin may be considered for recurrent cerebral ischemic events on aspirin alone, though bleeding risk increases substantially 9

Duration of Therapy

Aspirin should be continued indefinitely unless contraindications develop, as polycythemia vera is a chronic myeloproliferative neoplasm with persistent thrombotic risk 1.