How do I determine risk in a patient with JAK2-positive myeloproliferative neoplasm, such as Polycythemia Vera (PV) or Essential Thrombocythemia (ET)?

Risk Determination in JAK2-Positive Myeloproliferative Neoplasms

Risk stratification in JAK2-positive PV and ET is based primarily on age and thrombosis history, with ET requiring additional consideration of JAK2 mutation status and cardiovascular risk factors using the IPSET-thrombosis scoring system. 1

Risk Stratification for Polycythemia Vera

For PV, use a two-tier risk classification system based on age and thrombosis history only. 1

High-Risk PV

• Age >60 years OR
• Prior history of thrombosis at any age 1

Low-Risk PV

• Age ≤60 years AND
• No prior history of thrombosis 1

Note that while leukocyte count is implicated in thrombogenesis, an intermediate-risk category incorporating leukocytosis or cardiovascular risk factors has not been formally validated in PV. 1 Therefore, do not use these factors to modify the two-tier risk classification, though they should still be managed aggressively. 1

Risk Stratification for Essential Thrombocythemia

For ET, use the revised IPSET-thrombosis scoring system, which stratifies patients into four risk categories based on age, thrombosis history, JAK2V617F mutation status, and cardiovascular risk factors. 1

Very Low Risk ET

• Age ≤60 years AND
• No prior thrombosis history AND
• JAK2V617F negative (wild-type) AND
• No cardiovascular risk factors 1

Low Risk ET

• Age ≤60 years AND
• No prior thrombosis history AND
• JAK2V617F positive (mutated) AND
• No cardiovascular risk factors 1

Intermediate Risk ET

• Age >60 years AND
• No prior thrombosis history AND
• JAK2V617F negative (wild-type) 1

High Risk ET

• Prior history of thrombosis at any age OR
• Age >60 years with JAK2V617F mutation present 1

Cardiovascular risk factors to assess include smoking habit, diabetes mellitus, arterial hypertension, and hypercholesterolemia. 1 These factors significantly impact thrombosis risk, with annual thrombosis rates ranging from 0.44% in very low-risk patients to 2.57% in those with both JAK2 mutation and cardiovascular risk factors. 1

Additional Risk Considerations

Bleeding Risk Assessment

• Extreme thrombocytosis (platelet count >1,000 × 10⁹/L or >1,500 × 10⁹/L) increases bleeding risk and may be associated with acquired von Willebrand syndrome. 1
• Screen for acquired von Willebrand syndrome with ristocetin cofactor and multimer analysis before administering aspirin in patients with extreme thrombocytosis. 1
• Extreme thrombocytosis is regarded as an indication for cytoreductive therapy. 1

Prognostic Factors for Survival

While not part of thrombosis risk stratification, certain factors predict shortened survival and disease progression: 2, 3, 4

• Advanced age
• Leukocytosis
• Abnormal karyotype (present in 15%-20% of PV patients) 4
• Adverse mutations including SRSF2, IDH2, RUNX1, U2AF1, and ASXL1 1, 4

However, these prognostic factors should not alter the thrombosis-based risk stratification used to guide cytoreductive therapy decisions. 1

Special Populations

In pregnancy, prior pregnancy loss is the most important predictor of subsequent fetal loss in ET patients. 1 Obtain a careful obstetric history identifying recurrent first trimester or late miscarriages, gestational complications, and prior MPN-related thrombotic events to guide risk-adapted therapeutic strategy. 1

Common Pitfalls to Avoid

• Do not create an intermediate-risk category in PV based on leukocytosis or cardiovascular risk factors, as this has not been validated. 1
• Do not use JAK2V617F allele burden quantification for risk stratification at diagnosis—mutation presence/absence is sufficient. 1
• Do not overlook cardiovascular risk factors in ET, as they are integral to the IPSET-thrombosis score. 1
• Do not assume all patients with extreme thrombocytosis require aspirin—first rule out acquired von Willebrand syndrome to avoid increasing bleeding risk. 1