DNMT3A and TET2 Mutations are Associated With Both Venous Thrombosis and Major Bleeding in Patients With Polycythemia Vera and Essential Thrombocythemia.
Key claim: DNMT3A and TET2 mutations are significantly associated with venous thrombosis and major bleeding in polycythemia vera and essential thrombocythemia, but not in myelofibrosis.
Abstract
INTRODUCTION: Thrombosis and bleeding events are major causes of morbidity and mortality in patients with myeloproliferative neoplasms (MPN). The contribution of non-driver mutations, in particular mutations in DNMT3A, TET2, and ASXL1 (collectively DTA) to thrombo-hemorrhagic risk remains unclear. METHODS: We conducted a retrospective analysis of 180 patients with MPN undergoing next generation sequencing to evaluate the association between DTA mutations and major bleeding and thrombotic events occurring from 3 years prior to diagnosis through follow-up. Patients were stratified by disease subtype, and Cox proportional hazards models were used for univariate and multivariate analyses. RESULTS: DTA mutations were present in 40% of the patients. 52 (29%) patients suffered from arterial or venous thrombotic events either following diagnosis or as early as 3 years prior to diagnosis, and 20 (11%) experienced major bleeding events during the same period. In patients with PV and ET, DNMT3A and TET2 (DT) mutations were significantly associated with venous thrombosis (HR 5.6, 95% CI 1.6-19.1) and were also associated with major bleeding in univariate analyses (HR 6.7, 95% CI 1.7-26.9). The association with venous thrombosis remained significant after multivariable adjustment, whereas the association with major bleeding was attenuated after adjustment for age and smoking status (HR 4.1, 95% CI 0.9-19.2). No such associations were observed in patients with myelofibrosis. CONCLUSION: Our findings highlight an association between DT mutations and thrombotic and bleeding complications in patients with PV and ET and support further evaluation of molecular markers as contributors to thrombo-hemorrhagic risk in MPN.
Why this matters
Thrombosis and bleeding are the dominant morbidities of chronic-phase MPNs, and risk stratification has historically been anchored on age, prior events, and JAK2/CALR/MPL driver status. Extending both thrombotic and hemorrhagic risk to non-driver DNMT3A/TET2 mutations — while explicitly showing this signal does not carry over to PMF — refines subtype-specific vascular-risk biology and supports genotype-aware secondary-prevention strategies in PV and ET.