Does polycythemia increase the risk of thrombosis (blood clots)?

Does Polycythemia Cause Blood Clots?

Yes, polycythemia significantly increases the risk of thrombosis through multiple mechanisms, with elevated hematocrit being the primary driver of both arterial and venous blood clots. 1, 2

Primary Thrombotic Mechanism: Hyperviscosity

The elevated hematocrit in polycythemia vera creates a hyperviscosity state that directly increases thrombotic risk through impaired blood flow and altered cellular interactions. 1, 3 This is not merely theoretical—maintaining hematocrit strictly below 45% significantly reduces thrombotic events, as demonstrated by the landmark CYTO-PV trial. 1

• High hematocrit is the only consistently identified predictive factor for thrombosis in polycythemia vera. 4
• The mechanism involves decreased cerebral blood flow from alterations in arterial oxygen content, not just viscosity changes alone. 1
• Aggressive phlebotomy to control hematocrit has improved median survival from less than 2 years to over 10 years. 1

Clinical Thrombotic Burden

The thrombotic risk in polycythemia vera is substantial and affects both arterial and venous systems:

• At or before diagnosis, 16% of patients have already experienced arterial thrombosis and 7% have had venous thrombotic events. 2
• Thrombotic complications manifest as stroke, myocardial infarction, deep vein thrombosis, or pulmonary embolism. 3
• Venous thrombosis can occur in unusual sites, particularly splanchnic veins. 2
• Major symptoms relate to arterial hypertension and arterial/venous thrombosis, with strokes potentially being the first manifestation. 1

Flow-Dependent Thrombogenic Mechanisms

Beyond simple viscosity, polycythemia creates distinct thrombotic mechanisms depending on vessel type:

In large veins (low shear rate conditions):

• Axial migration of red blood cells displaces platelets, leukocytes, and proteins toward the endothelium, enhancing thrombogenic interactions. 1
• This explains the pattern of venous thrombosis in polycythemia vera patients. 1

In arterioles and small vessels (high shear rate conditions):

• Platelet-leukocyte-red blood cell interactions generate platelet aggregates through ADP release. 1
• Combined with decreased flow rates from high hematocrit, this creates conditions for arterial thrombosis. 1

Additional Prothrombotic Factors

Phlebotomy substantially reduces but does not abolish thrombosis risk, indicating that factors beyond hematocrit contribute significantly. 1 These include:

Qualitative Platelet Abnormalities:

• Diminished response of platelet adenylate cyclase to prostaglandin D2 (a physiological platelet aggregation inhibitor). 1
• Increased baseline production of thromboxane A2, a potent platelet aggregator. 1
• Abnormal in vivo activation of platelets, leukocytes, and endothelial cells. 1
• The PIA2 allele of platelet glycoprotein IIIa is associated with increased arterial thrombosis risk. 1

Systemic Prothrombotic State:

• Widespread activation of coagulation proteins. 1
• Reduced levels of physiologic anticoagulants, including antithrombin III, proteins C and S. 1
• Decreased fibrinolytic activity, partly due to increased plasminogen activator inhibitor levels. 1
• These abnormalities persist even with hematocrit control, explaining residual stroke risk. 1

Risk Stratification for Thrombosis

Current risk stratification identifies high-risk patients as:

• Age >60 years OR history of prior thrombosis. 5
• JAK2V617F mutation and cardiovascular risk factors are additional risk factors. 5
• Patients requiring 3 or more phlebotomies per year while on hydroxyurea have a significantly higher thrombosis rate (20.5% vs. 5.3% at 3 years). 6

Critical Caveat: Bleeding Risk

Extreme thrombocytosis (platelet count ≥1000 × 10⁹/L) can paradoxically cause bleeding through acquired von Willebrand disease. 2, 5

• Screening for acquired von Willebrand syndrome is recommended before administering aspirin in the presence of extreme thrombocytosis. 5
• This represents a critical pitfall where the prothrombotic state coexists with bleeding risk. 2

Management Implications

All patients with polycythemia vera should receive therapeutic phlebotomy (goal hematocrit <45%) and low-dose aspirin (if no contraindications) to decrease thrombosis risk. 2

• High-risk patients (age ≥60 years or prior thrombosis) benefit from cytoreductive therapy with hydroxyurea or interferon. 2
• Phlebotomy dependency under hydroxyurea therapy (≥3 phlebotomies per year) identifies patients with increased proliferation and higher thrombosis risk who may require treatment escalation. 6