Thrombosis in Low‐Risk Polycythemia Vera: Insights From a Large Real‐World Cohort

ABSTRACT Polycythemia vera (PV) is a myeloproliferative neoplasm driven by JAK2 mutations and associated with thrombotic complications. Current risk stratification classifies younger patients without prior thrombosis as low‐risk (LR), yet long‐term outcomes in this group remain poorly defined. In this retrospective cohort study, we used the Clalit Health Services database to identify patients aged 18–60 years with JAK2‐positive PV diagnosed between 2005 and 2022. Patients without prior or concurrent thrombosis were classified as LR. Clinical characteristics, treatments, and outcomes were analyzed. Logistic regression analysis was used to identify predictors of thrombosis. Among 505 patients, 437 (86.5%) were classified as LR. Median age was 51 years and 58.6% were male. Cytoreductive therapy was used in 61% of LR patients. Over a median follow‐up of 8.6 years, thrombosis occurred in 17.4% of LR patients (11.7% arterial, 5.7% venous). Cardiovascular risk factors (CV‐RFs) were strongly associated with thrombosis (≥ 2 CV‐RFs, OR = 3.10, 95% CI 1.25–7.72; p = 0.015), while hematologic parameters were not. Cytoreductive therapy was independently associated with a reduced risk of thrombosis. Secondary malignancies were diagnosed in 16.2%, mainly non‐melanoma skin cancer in 11.7%. Prior Hydroxyurea (HU) use was independently associated with secondary malignancy (OR = 2.73; 95% CI 1.33–5.61; p = 0.006), alongside age and leukocytosis. Disease progression to myelofibrosis, myelodysplastic syndrome, or acute myeloid leukemia occurred in 3.4%, 5.7%, and 1.6% of LR patients, respectively. HU use was associated with disease progression (OR = 2.9; 95% CI 1.33–6.42; p = 0.008). We concluded that despite being classified as low‐risk, younger patients with PV experience a substantial thrombotic burden, driven primarily by CV‐RFs. Cytoreductive therapy was associated with reduced thrombotic risk, while HU exposure was linked to secondary malignancies and disease progression, probably reflecting a high disease burden in the latter. This underscores the need for refined risk stratification and long‐term surveillance in LR‐PV.