Risk of bleeding in 15,495 patients with myeloproliferative neoplasms by treatment type and thrombotic history

Abstract Patients with myeloproliferative neoplasms (MPNs) are inherently at increased risk of both thrombotic and bleeding events due to the nature of the condition. Disease management often includes anticoagulants, antiplatelet agents, and/or cytoreductive therapy to mitigate these risks. On the contrary, these therapies can also increase the risk of bleeding, presenting a clinical challenge in balancing the prevention of thrombosis with the management of bleeding complications. The relationship between treatment type, thrombotic events, and bleeding risk remains underexplored in large, real-world populations. This Swedish population-based study aimed to describe how the risk of bleeding in patients living with MPN differs by treatment strategy, and how timing of thrombotic events influences this risk. A total of 15,495 patients diagnosed with MPN between 2006 and 2021, aged 18–90, were identified through the Swedish Cancer Register and the Swedish Patient Register. Bleeding rates were estimated using Cox proportional hazards models with time-split survival data. Treatment categories were defined as follows: no therapy, anticoagulant monotherapy (e.g., warfarin, direct oral anticoagulants [DOACs]); antiplatelet monotherapy (e.g., aspirin, clopidogrel); cytoreductive monotherapy (e.g., hydroxyurea, interferon); and combination therapy, defined as any combination of at least two of the three aforementioned therapies. All treatment categories were compared to anticoagulant monotherapy. Both treatment exposure and thrombotic status were modelled as time-varying covariates, allowing individuals to contribute across multiple thrombosis and treatment combinations over time. Models were adjusted for age at diagnosis, sex, year of diagnosis, and MPN subtype. The cohort was 52% female, with a median age at diagnosis of 71 years (IQR 60–79). The most common MPN subtypes were polycythemia vera (39%) and essential thrombocythemia (38%), followed by MPN-unclassifiable (16%) and primary myelofibrosis (7%). A history of thrombosis at MPN diagnosis was present in 22% of patients, and 19% had a history of bleeding. Among the 10,487 patients receiving combination therapy, the majority included antiplatelet agents: 57% received antiplatelet + cytoreductive therapy, 12% received antiplatelet + anticoagulant therapy, and 22% received all three therapies. Only 8% received anticoagulant + cytoreductive therapy without antiplatelet agents. Patients receiving no therapy had the lowest bleeding rate overall (HR 0.63, 95% CI 0.53–0.75), likely reflecting individuals with less severe disease or contraindications to treatment. Among patients with no thrombotic event, those receiving antiplatelet monotherapy had a 35% lower rate of bleeding compared to those on anticoagulant monotherapy (HR 0.65, 95% CI 0.56–0.76). Combination therapy was associated with a reduced rate of similar magnitude (HR 0.68, 95% CI 0.59–0.78), while cytoreductive monotherapy showed no significant difference (HR 0.96, 95% CI 0.76–1.21). In patients with a prior thrombotic event, antiplatelet monotherapy remained protective (HR 0.59, 95% CI 0.43–0.79), and combination therapy was associated with a slightly lower bleeding rate compared to anticoagulant monotherapy (HR 0.78, 95% CI 0.61–0.99). The estimate for cytoreductive monotherapy in this group (HR 2.04, 95% CI 0.89–4.68) was based on a small number of patients and had wide confidence intervals, limiting interpretability. These findings suggest that bleeding risk in MPN patients is influenced by both treatment type and thrombotic history. Antiplatelet monotherapy and combination therapy were associated with lower bleeding rates than anticoagulant monotherapy, both in patients with and without prior thrombosis, though the effect was more pronounced in those without prior thrombosis. By accounting for the complete patient pathway and modelling treatment and thrombotic status as time-varying exposures, a more accurate representation of real-world treatment dynamics is presented here. Given that the majority of combination therapy regimens included antiplatelet agents, these results underscore the potential protective role of antiplatelet therapy in managing bleeding risk. These insights may support clinical decision-making, and guide personalized treatment strategies and risk assessment in patients diagnosed with MPN.