Recurrent venous thrombosis in myeloproliferative neoplasms: impact of cytoreductive control and antithrombotic strategy

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We assessed the incidence of recurrent VTE in the nationwide French cohort of patients with polycythemia vera or essential thrombocythemia who experienced a non-splanchnic VTE within 12 months prior to MPN diagnosis. Among 5,163 patients, 117 exhibited initial VTE of their MPN. With a median follow-up of 4.3 years (IQR 1.9–8.8), 13 recurrent VTE events occurred, yielding an incidence rate of 1.80 per 100 patient-years (95% CI 0.96–3.08). The 5-year cumulative incidence of recurrence was 6.36% (95% CI 0.73–11.66). Demographic characteristics, MPN subtype, and antithrombotic strategy were not significantly associated with recurrence. In contrast, achievement of an ELN-defined cytoreductive response was strongly associated with lower recurrence risk. The incidence rate was 0.25 per 100 patient-years in ELN responders versus 4.49 per 100 patient-years in non-responders (p < 0.001). All but one recurrent event occurred in patients who did not meet ELN criteria. Long-term anticoagulation was not associated with a statistically significant reduction in recurrence (2.24 vs 1.38 per 100 patient-years; p = 0.285). In conclusion, recurrent VTE after MPN-associated usual-site thrombosis was infrequent and predominantly observed in patients without effective cytoreductive control. Health sciences/Medical research/Epidemiology Health sciences/Diseases/Haematological diseases/Haematological cancer/Myeloproliferative disease Figures Figure 1 Figure 2 Figure 3 Introduction Myeloproliferative neoplasms (MPNs) are acquired clonal disorders of hematopoietic stem cells and are revealed by a thrombotic event in 20% of patients 1 . Although thrombosis in MPNs is more commonly arterial, venous thromboembolism (VTE) represents the presenting manifestation in a 6.2% of patients 1 . VTE include deep vein thrombosis (DVT) of the limbs, pulmonary embolism and thrombosis of the cerebral and splanchnic veins (hepatic, portal, mesenteric and splenic veins). Patients with MPN and previous thrombosis belong to the high-risk group which indicates cytoreduction in order to reduce thrombosis risk recurrence 2 . In addition to cytoreduction, patients with MPN and VTE receive anticoagulation for at least 3 months in case of distal VTE, at least 6 months for proximal DVT and pulmonary embolism, and usually lifelong for thrombosis of unusual sites (splanchnic vein thrombosis and cerebral vein thrombosis). But the optimal duration of anticoagulant therapy after a VTE that reveals an MPN is still unclear 3 . In the general population, the duration of anticoagulation following a first episode of VTE is determined by the presence and nature of provoking risk factors 4 . Anticoagulation is usually discontinued after 3 to 6 months in patients with VTE provoked by transient risk factors, whereas lifelong anticoagulation is recommended for unprovoked VTE or VTE associated with persistent risk factors, given the high risk of recurrence after treatment discontinuation. Active cancer is classically considered a persistent thrombotic risk factor warranting prolonged anticoagulation; however, thrombotic risk in cancer is highly heterogeneous and depends on tumor type, treatment, and associated factors 5 . Importantly, current clinical guidelines for cancer-associated VTE do not include MPNs among active malignancies, suggesting that thrombotic risk recurrence in MPNs should be assessed separately rather than extrapolated from solid tumors. The risk of recurrence of VTE at usual sites in patients with MPN was assessed in a large retrospective study 10 years ago. It was reported to be of 9.6 per 100 patients-years in patients who were treated with Vitamin K antagonists (VKA) and who discontinued. This risk was divided by 2.2 (4.2 per 100 patients-years) in patients on long-term VKA 6 . This constituted the rationale to propose long term VKA in MPN patients with VTE at usual sites and no other provoking factor 7 . Nevertheless, most recurrent events reported in this study occurred in patients who were either not receiving cytoreductive treatment or were not achieving effective cytoreduction 6 . It may thus be that the risk of VTE recurrence in MPN patients with proper control of their MPN would be lower. Altogether, while newly diagnosed MPNs represent a major risk factor for venous thrombosis, whether patients who are adequately controlled with cytoreductive therapy remain at high risk of VTE recurrence is unclear. This uncertainty currently precludes evidence-based recommendations regarding the duration of anticoagulation in this population and highlights the need for studies specifically designed to evaluate VTE recurrence in patients with MPNs, taking into account both cytoreductive efficacy and antithrombotic strategy. In this context, we aimed to assess, in a nationwide retrospective French cohort, the incidence of recurrent venous thrombotic events in patients with MPNs and a history of non-splanchnic deep vein thrombosis, according to cytoreductive control and antithrombotic strategy. Material and Methods Study patients The French Intergroup of Myeloproliferative neoplasms (FIM) clinical and biological database (FIMBANK) includes patients with a diagnosis of PV or ET from 2005 according to the World Health Organization (WHO) 2016 or 2022 classifications 8 , 9 . FIMBANK includes patient data at diagnosis and during follow-up of patients recruited in 33 French hospitals. For the present study, we included all patients from the BCB FIMBANK who had presented with an episode of VTE within the year preceding the diagnosis of MPN. VTE was defined as the occurrence of deep vein thrombosis at the following sites: lower limb, upper limb, pulmonary embolism or cerebral venous thrombosis. Patients who had experienced an episode of splanchnic vein thrombosis prior to the diagnosis of MPN were excluded. Methods The primary endpoint of the study was the occurrence of recurrent VTE during follow-up. The following recurrent VTE sites were recorded: deep vein thrombosis of the lower or upper limb, pulmonary embolism, cerebral venous thrombosis and splanchnic vein thrombosis. Patient data were extracted from the BCB FIMBANK database. The following baseline characteristics were collected: demographic data (patient age at diagnosis and sex); MPN characteristics (PV or ET, blood count, presence of JAK2V617F mutation and variant allele frequency); VTE date and location. Follow-up data regarding the occurrence of VTE (date and site), cytoreductive and antithrombotic treatments, and blood counts were collected annually or at the occurrence of a clinical event. For patients who did not experience VTE recurrence during follow-up, cytoreductive and antithrombotic treatments and blood counts recorded at the date of last follow-up were collected. For patients who experienced VTE recurrence, the cytoreductive and antithrombotic treatments collected were those recorded at the follow-up visit preceding the thrombotic event. The blood count with the sampling date closest to the thrombotic event was collected, provided that the interval did not exceed 180 days. The diagnoses of PV or ET were made according to the WHO 2016 or 2022 classifications, depending on the year of diagnosis 8 , 9 . Patients’ response to cytoreductive therapy was assessed according to the European Leukemia Net criteria (ELN/IWG-MRT) 10 . Statistical analyses and informed consent Categorical variables were analyzed as frequencies with percentages and were compared using a χ2 test or Fisher's exact test as appropriate. Continuous variables were expressed as median and interquartile range, and a Mann-Whitney U test was used for comparisons. The annual incidence of recurrent VTE was calculated by dividing the number of events by the total number of patient-years. For assessing recurrent VTE outcome, we estimated cumulative incidence of VTE using Kaplan-Meier analyses, with time defined as the interval between the diagnosis of MPN and the recurrent VTE or the last follow-up visit (censored observations). We performed log-rank tests to analyze the differences between groups. Statistical analysis was performed using Rstudio software (version 4.5.2; R foundation for Statistical Computing. Patients provided their informed consent to be included in the BCB FIMBANK and the present project has been registered by the French Data Protection Authority (PADS25-009; CSE25-74). Results Description of the patient cohort Between March 2005 and March 2025, 5,163 PV and ET patients were included in FIMBANK. Overall, 585 (13%) patients presented an inaugural thrombosis defined by an arterial and/or venous thrombosis within 12 months prior to the diagnosis of their MPN, and/or a history of splanchnic vein thrombosis regardless of the delay. Three hundred twenty-eight patients (6.4%) experienced a VTE. Among these 328 patients, 195 (59.4%) presented with splanchnic vein thrombosis and 16 (4.9%) with superficial vein thrombosis. These two groups were excluded from our study. For this present study, we thus selected 117 patients (35.7%) who had experienced an initial non splanchnic deep VTE ( Supplemental Fig. 1 ). Main clinical and biological characteristics of the patient cohort at the time of MPN diagnosis The clinical and laboratory features of the 117 patients are reported in Table 1 . PV and ET were diagnosed in respectively 76 patients (65.0%) and 41 (35%) of the patients. ET patients were younger than PV patients (median age: 51.0 vs 66.5 years; p = 0.002). The JAK2V617F mutation was present in all PV patients and in 92.7% of ET patients. The allele burden was higher in PV patients (39.0% vs 13.0%; p < 0.0001). At diagnosis, PV patients had higher hemoglobin and hematocrit levels than ET patients (17.0 vs 14.3 g/dL, p < 0.0001; and 53.0% vs 43.9%, p < 0.0001, respectively). Platelet counts were higher in ET patients (659.0 vs 430.0 G/L; p < 0.0001) and PV patients exhibited higher neutrophil counts (8.2 vs 6.5 G/L; p = 0.03). Most DVT occurred in usual sites with 45.3% in the lower limb, and 31.6% as pulmonary embolism with no significant difference between ET and PV patients. In 6 patients (5.1%), DVT occurred in the upper limb. Cerebral venous thrombosis occurred in 21 patients (17.9%), and more frequently in ET patients than in PV patients (31.7% vs 10.5%; p = 0.01). Incidence of VTE recurrence With a median follow-up of 4.3 years (IQR, 1.9–8.8), VTE recurrence occurred in 13 patients (11.1%) ( Table 2 ). The sites of recurrences are described in Table 2 . The 3 patients with initial cerebral venous thrombosis had recurrence in unusual sites, i.e. one recurrence of cerebral venous thrombosis and two splanchnic vein thrombosis. The overall observation time was 721 years and the incidence rate of recurrent VTE was 1.80 per 100 patient-years (95% CI: 0.96–3.08). Kaplan-Meyer curve is depicted in Fig. 1 . The cumulative incidence of VTE recurrence at 1 year, 3 years and 5 years was respectively 0%, 3.38% (95% CI: 0-7.08) and 6.36% (95% CI: 0.73–11.66). Comparison of patients with or without VTE recurrence We did not observe any difference at diagnosis in term of sex, age, MPN subtype, presence of the JAK2V617F mutation and its allele burden, between patients with or without VTE recurrence ( Table 3 ). We then investigated whether there were differences in term of cytoreductive and antithrombotic treatments at the time of recurrence for patients with recurrence or at the last update for patients without recurrence. The majority of patients received cytoreductive therapy (mostly hydroxyurea), with no difference between those with and without recurrence (84.6% vs 94.2%, respectively; p = 0.22). Similarly, more than 92% of patients were treated with antithrombotic therapy in both groups. The majority of patients were treated with anticoagulant, either alone or in combination with antiplatelet therapy, with no differences between patients with recurrence (61.6%) and patients without recurrence (57.3%; p = 0.50). Almost 31% of patients with recurrence were treated with antiplatelet agent alone at the time of recurrence, which was not significantly different from patients without recurrence (35%) ( Table 3 ). The main difference between patients with and without VTE recurrence was whether they had achieved effective cytoreduction according to ELN criteria. Indeed, only 1 of 12 patients with recurrent VTE (8.3%) met ELN response criteria, compared with 65 of 95 patients without recurrence (68.4%; p < 0.0001) ( Tables 2 and 3 ). Effect of anticoagulation or cytoreduction on VTE recurrence The total observation time of the patients who received anticoagulant therapy without discontinuation was 358 patient-years. For the patients who received anticoagulation after the index VTE case but for whom anticoagulation was discontinued, the total observation time was 362 patient-years. There was no difference in VTE recurrence incidence between patients who were still on anticoagulation and the ones who had discontinued (2.24 vs 1.38 per 100 patient-years, respectively; p = 0.285) ( Table 4 and Fig. 2 a). We then investigated the effect of adequate cytoreduction and compared patients achieving an ELN response with patients who did not, independently of the presence of long-term anticoagulation. The incidence of VTE recurrence was significantly lower in patients meeting ELN response criteria (0.25 per 100 pt-years), compared with patients who were not achieving effective cytoreduction (4.49 per 100 pt-years) (p < 0.001) ( Table 4 ). In patients meeting ELN response criteria, the cumulative incidence of VTE recurrence at 5 years was 0%. In patients who did not respond to cytoreductive therapy according to ELN response criteria, the cumulative incidence of VTE recurrence at 1 year, 3 years and 5 years was respectively 0%, 9.11% (95% CI: 0-18.43%) and 16.10% (95% CI: 2.03–28.15) (Fig. 2 b). Effect of the combination of long-term anticoagulation and adequate cytoreduction on VTE recurrence We then stratified patients into four groups according to maintenance of anticoagulant therapy and achievement of ELN criteria. A difference in cumulative incidence of VTE recurrence was observed across the four groups (log-rank p < 0.001) (Fig. 3 ). Patients who met ELN criteria (groups A and B, Fig. 3 ) did not experience VTE recurrence in the 5 years following their diagnosis, regardless of their anticoagulant therapy. No difference was observed between patients receiving anticoagulation (group B) and those who did not (group A) among ELN responders. In contrast, patients who did not meet ELN criteria and without anticoagulation (group C, Fig. 3 ) exhibited a cumulative incidence of VTE recurrence at 1 year, 3 years and 5 years at 0%, 10% (95% CI: 0-22.23) and 15.62% (95% CI:0-30.45) respectively. At last, patients who did not meet ELN criteria and with anticoagulation (group D, Fig. 3 ) exhibited a cumulative incidence of VTE recurrence at 1 year, 3 years and 5 years at 0%, 7.69% (95% CI: 0-21.10) and 16.92% (95% CI:0-35.91) respectively. Discussion In this nationwide cohort of patients with PV or ET who experienced a non-splanchnic VTE within the year preceding MPN diagnosis, ineffective cytoreduction according to ELN criteria emerged as the sole determinant of recurrent VTE. Neither age, sex, MPN subtype, JAK2V617F allele burden, nor antithrombotic strategy influenced recurrence risk. The overall annual incidence of recurrent VTE was low (1.8 per 100 patient-years), with a 5-year cumulative incidence of 6.4%. By restricting inclusion to patients whose VTE occurred within 12 months prior to MPN diagnosis, we deliberately focused on events most plausibly attributable to an underlying and persistent prothrombotic driver — the MPN itself. Exclusion of splanchnic vein thrombosis allowed analysis of a clinically homogeneous population with usual-site VTE, avoiding the specific pathophysiological and therapeutic challenges associated with splanchnic events 11 . Within this framework, the recurrence rate observed here is substantially lower than previously reported in retrospective series 6 , 7 , 12 , 13 . The most clinically relevant finding is the absence of a measurable protective effect of long-term anticoagulation once cytoreductive response is considered. Recurrence-free survival curves were virtually superimposable between anticoagulated and non-anticoagulated patients during the first five years of follow-up. In contrast, ELN-defined response was strongly associated with outcome. Patients achieving effective cytoreduction had an incidence rate of 0.25 per 100 patient-years and no recurrence within five years, whereas non-responders exhibited a markedly higher incidence (4.49 per 100 patient-years) and a 5-year cumulative incidence exceeding 16%. Notably, all but one recurrent event occurred in patients who did not meet ELN criteria. The single recurrence in an ELN responder occurred late (8.9 years after diagnosis) at age 70, raising the possibility of age-related or non–MPN-related contributors. These findings provide a potential explanation for discrepancies with earlier reports. In the study by De Stefano et al., the incidence rate of recurrent VTE reached 5.2 per 100 patient-years, and prolonged vitamin K antagonist therapy appeared protective. However, inadequate hematologic control was documented in a substantial proportion of patients at recurrence. In that cohort, poor control of myeloproliferation was observed in 69% of recurrent cases during cytoreduction. In contrast, in our study, only one of thirteen recurrences occurred under ELN-defined response. The lower recurrence rate observed here likely reflects a higher proportion of patients achieving sustained hematologic control. Together, these data suggest that the biological activity of the MPN — rather than anticoagulation per se — is the principal driver of recurrent venous thrombosis. The clinical characteristics of our cohort are otherwise consistent with prior literature. The high prevalence of JAK2V617F mutation, including in ET patients, likely reflects thrombotic enrichment and is concordant with data identifying JAK2 mutation as a major venous thrombotic risk factor compared with CALR-mutated disease 14 , 15 , 16 . From a clinical standpoint, our results challenge the systematic extrapolation of cancer-associated thrombosis paradigms to MPN. Current guidelines do not uniformly categorize MPN as an “active cancer” requiring indefinite anticoagulation 17 , 18 . Our data support a risk-adapted approach: in patients achieving durable ELN-defined cytoreductive response, the MPN may no longer behave as a persistent high-risk condition for venous recurrence. Given that long-term anticoagulation carries a non-negligible hemorrhagic risk, the balance of benefit and harm may differ substantially according to cytoreductive control. Whether anticoagulation can be safely discontinued in ELN responders — potentially maintaining antiplatelet therapy in line with primary thrombosis prevention — warrants prospective evaluation. This study has several strengths. It is based on one of the largest contemporary multicenter cohorts addressing VTE recurrence in MPN, with nationwide recruitment, harmonized data collection, and substantial follow-up. However, limitations must be acknowledged. The partly retrospective design and absence of central adjudication of recurrent events may introduce classification bias. Despite the large source population, the absolute number of recurrences remains limited, precluding multivariable modeling and detailed analyses according to specific cytoreductive agents. Bleeding outcomes were not systematically collected and therefore net clinical benefit could not be assessed. Prospective validation of these findings would be highly desirable but may prove challenging given the relatively low recurrence rate observed. Future studies should also address splanchnic vein thrombosis separately, as ELN response criteria are not readily applicable in that context and recurrence risk remains high despite therapy. In conclusion, in patients with PV or ET presenting with usual-site VTE, achievement of ELN-defined cytoreductive response is strongly associated with a markedly reduced risk of recurrence, whereas long-term anticoagulation alone does not appear to confer additional protection. These data suggest that optimal hematologic control may represent the cornerstone of secondary venous thrombosis prevention in MPN and should be central in future risk-adapted therapeutic strategies. Abbreviations PV Polycythemia Vera ET Essential thrombocythemia VTE Venous Thromboembolism. IQR:interquartile range Declarations Acknowledgements The authors thank the French group of Myeloproliferative neoplasms ( France Intergroupe Syndrome Myéloproliferatifs, FIM) and the FIMBANK team for the support in the conception and elaboration of the study. Author contributions CJ, GV, PS designed the study; GV, HP, LB collected data; PS performed statistical analyses; JCI, LS, DLP, VU coordinated data management of the FIMBANK biobank; GV, PS and CJ wrote the manuscript; all authors provided data and approved the final manuscript. Competing interests The authors declare no competing financial interests related to this work. Data Availability For original data, please contact [email protected] Ethics approval statement Written consent was obtained from all study participants, and the study has obtained the authorization of the committee for the protection of individuals. Funding statement This work is a deliverable of the FIMBANK network, which was founded by the French ‘Institut National du Cancer’ (INCa BCB 2013 & 2022)” References Rungjirajittranon T, Owattanapanich W, Ungprasert P, Siritanaratkul N, Ruchutrakool T. 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Tables Tables 1 to 4 are available in the supplementary files section Additional Declarations There is NO conflict of interest to disclose. Supplementary Files Table1.xlsx.docx Table 1 Table2.xlsx.docx Table 2 Table3.xlsx.docx Table 3 Table4.xlsx.docx Table 4 SupplementaryFigure.pptx Supplemental figure 1. Detailed patients flowchart: * Patients with prior splanchnic thrombosis regardless the time between thrombosis and MPN diagnosis are included Cite Share Download PDF Status: Posted Version 1 posted You are reading this latest preprint version Research Square lets you share your work early, gain feedback from the community, and start making changes to your manuscript prior to peer review in a journal. As a division of Research Square Company, we’re committed to making research communication faster, fairer, and more useful. We do this by developing innovative software and high quality services for the global research community. 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Also discoverable on Platform About Our Team In Review Editorial Policies Advisory Board Help Center Resources Author Services Accessibility API Access RSS feed Manage Cookie Preferences © Research Square 2026 | ISSN 2693-5015 (online) Privacy Policy Terms of Service Do Not Sell My Personal Information {"props":{"pageProps":{"initialData":{"identity":"rs-9104169","acceptedTermsAndConditions":true,"allowDirectSubmit":true,"archivedVersions":[],"articleType":"Article","associatedPublications":[],"authors":[{"id":605655029,"identity":"e7a99fb7-d99c-452b-97ce-1ca6d85a5ab3","order_by":0,"name":"Chloe 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Conception","correspondingAuthor":false,"prefix":"","firstName":"Geoffroy","middleName":"","lastName":"Venton","suffix":""},{"id":605655031,"identity":"644cccf6-61b8-4a58-8692-6f1570980a0b","order_by":2,"name":"Pierre Suchon","email":"","orcid":"","institution":"Hôpital de la Timone, Marseille,","correspondingAuthor":false,"prefix":"","firstName":"Pierre","middleName":"","lastName":"Suchon","suffix":""},{"id":605655032,"identity":"e8aa582e-1050-4f23-b2f4-ab9c8f16142e","order_by":3,"name":"Jean-Christophe Ianotto","email":"","orcid":"https://orcid.org/0000-0001-9074-7287","institution":"CHRU de Brest","correspondingAuthor":false,"prefix":"","firstName":"Jean-Christophe","middleName":"","lastName":"Ianotto","suffix":""},{"id":605655033,"identity":"5b00ac7c-bea5-4df3-a2ff-2e9936fc7810","order_by":4,"name":"Hélène PASQUER","email":"","orcid":"","institution":"Université Paris Cité, APHP, Hôpital Saint-Louis","correspondingAuthor":false,"prefix":"","firstName":"Hélène","middleName":"","lastName":"PASQUER","suffix":""},{"id":605655034,"identity":"9418cd78-582b-4d7b-a857-cb076779b147","order_by":5,"name":"Lina Benajiba","email":"","orcid":"https://orcid.org/0000-0001-5440-1115","institution":"Université Paris Cité, Saint-Louis hospital, APHP","correspondingAuthor":false,"prefix":"","firstName":"Lina","middleName":"","lastName":"Benajiba","suffix":""},{"id":605655035,"identity":"82f82732-0a54-42f1-ac8b-4a93dfc93edd","order_by":6,"name":"Léa Sureau","email":"","orcid":"https://orcid.org/0000-0002-5451-3464","institution":"CHU Angers","correspondingAuthor":false,"prefix":"","firstName":"Léa","middleName":"","lastName":"Sureau","suffix":""},{"id":605655036,"identity":"0f616688-bdee-459e-aaa7-7512b6be63d4","order_by":7,"name":"Valérie Ugo","email":"","orcid":"https://orcid.org/0000-0002-4678-2138","institution":"CHU Angers","correspondingAuthor":false,"prefix":"","firstName":"Valérie","middleName":"","lastName":"Ugo","suffix":""},{"id":605655037,"identity":"a3affc31-a316-4022-9ae6-44124b9ebe81","order_by":8,"name":"Damien Luque-Paz","email":"","orcid":"","institution":"CHU Morvan","correspondingAuthor":false,"prefix":"","firstName":"Damien","middleName":"","lastName":"Luque-Paz","suffix":""}],"badges":[],"createdAt":"2026-03-12 11:26:31","currentVersionCode":1,"declarations":"","doi":"10.21203/rs.3.rs-9104169/v1","doiUrl":"https://doi.org/10.21203/rs.3.rs-9104169/v1","draftVersion":[],"editorialEvents":[],"editorialNote":"","failedWorkflow":false,"files":[{"id":104876500,"identity":"e5c1c00a-54df-4635-ab01-78e2b57907d5","added_by":"auto","created_at":"2026-03-18 08:42:40","extension":"png","order_by":1,"title":"Figure 1","display":"","copyAsset":false,"role":"figure","size":31206,"visible":true,"origin":"","legend":"\u003cp\u003eCumulative incidence of VTE recurrence irrespective of the achievement of effective cytoreduction and the long term antithrombotic treatment after the index VTE.\u003c/p\u003e","description":"","filename":"Binder21.png","url":"https://assets-eu.researchsquare.com/files/rs-9104169/v1/0445260110e995c0ca035308.png"},{"id":104876343,"identity":"96c3d3f5-1d52-4b77-8410-3d02d0751f0e","added_by":"auto","created_at":"2026-03-18 08:42:16","extension":"png","order_by":2,"title":"Figure 2","display":"","copyAsset":false,"role":"figure","size":63964,"visible":true,"origin":"","legend":"\u003cp\u003eCumulative incidence of VTE recurrence according to anticoagulation at the time of recurrence (a) or achievement of an ELN response (b)\u003c/p\u003e","description":"","filename":"Binder22.png","url":"https://assets-eu.researchsquare.com/files/rs-9104169/v1/2bd3671a5869928fd7093916.png"},{"id":104876295,"identity":"552797fd-627c-4d04-81de-c582dab436ec","added_by":"auto","created_at":"2026-03-18 08:42:13","extension":"png","order_by":3,"title":"Figure 3","display":"","copyAsset":false,"role":"figure","size":131400,"visible":true,"origin":"","legend":"\u003cp\u003eCumulative incidence of VTE recurrence according to ELN response criteria and anticoagulation therapy. A: no anticoagulation and ELN response criteria met. B: anticoagulation and ELN response criteria met. C: anticoagulation and ELN response criteria unmet. D: anticoagulation and ELN response criteria unmet. * The difference between the groups A vs. C, A vs. D, B vs. C and B vs. D regarding recurrence free-survival are statistically significant (p\u0026lt;0.05)\u003c/p\u003e","description":"","filename":"Binder23.png","url":"https://assets-eu.researchsquare.com/files/rs-9104169/v1/46010009f4300b713c76c4e9.png"},{"id":106402010,"identity":"5f81d4b7-d22e-41af-8a05-7cb50eb04281","added_by":"auto","created_at":"2026-04-08 09:10:41","extension":"pdf","order_by":0,"title":"","display":"","copyAsset":false,"role":"manuscript-pdf","size":1020014,"visible":true,"origin":"","legend":"","description":"","filename":"manuscript.pdf","url":"https://assets-eu.researchsquare.com/files/rs-9104169/v1/764a1f7d-333a-451f-accf-480f5f7818e2.pdf"},{"id":104876629,"identity":"78e356d6-4638-4401-b82d-c9e39234a0bc","added_by":"auto","created_at":"2026-03-18 08:43:11","extension":"docx","order_by":1,"title":"","display":"","copyAsset":false,"role":"supplement","size":14923,"visible":true,"origin":"","legend":"Table 1","description":"","filename":"Table1.xlsx.docx","url":"https://assets-eu.researchsquare.com/files/rs-9104169/v1/66490b977c92fe83cf04ea61.docx"},{"id":104876310,"identity":"7608c1eb-d0d1-4e23-944f-db365e07fb8e","added_by":"auto","created_at":"2026-03-18 08:42:14","extension":"docx","order_by":2,"title":"","display":"","copyAsset":false,"role":"supplement","size":17083,"visible":true,"origin":"","legend":"Table 2","description":"","filename":"Table2.xlsx.docx","url":"https://assets-eu.researchsquare.com/files/rs-9104169/v1/c51f0680b9dc0961f860ea6a.docx"},{"id":104876659,"identity":"435a64d8-1da5-495e-a251-7e598bd042cb","added_by":"auto","created_at":"2026-03-18 08:43:17","extension":"docx","order_by":3,"title":"","display":"","copyAsset":false,"role":"supplement","size":14129,"visible":true,"origin":"","legend":"\u003cp\u003eTable 3\u003c/p\u003e","description":"","filename":"Table3.xlsx.docx","url":"https://assets-eu.researchsquare.com/files/rs-9104169/v1/6c8c81e96cbb09725daa3033.docx"},{"id":104876388,"identity":"e76caef5-84ce-4af8-ae89-06d93aa21db6","added_by":"auto","created_at":"2026-03-18 08:42:26","extension":"docx","order_by":4,"title":"","display":"","copyAsset":false,"role":"supplement","size":13163,"visible":true,"origin":"","legend":"\u003cp\u003eTable 4\u003c/p\u003e","description":"","filename":"Table4.xlsx.docx","url":"https://assets-eu.researchsquare.com/files/rs-9104169/v1/907fb93d748bc4e1af903032.docx"},{"id":104876298,"identity":"149996ca-6770-4e47-9b24-bbcc4d5f48b9","added_by":"auto","created_at":"2026-03-18 08:42:13","extension":"pptx","order_by":5,"title":"","display":"","copyAsset":false,"role":"supplement","size":35485,"visible":true,"origin":"","legend":"\u003cp\u003e\u003cu\u003e\u003cstrong\u003eSupplemental figure 1.\u003c/strong\u003e\u003c/u\u003e\u003cu\u003e \u003c/u\u003eDetailed patients flowchart: *\u003csup\u003e \u003c/sup\u003ePatients with prior splanchnic thrombosis regardless the time between thrombosis and MPN diagnosis are included\u003c/p\u003e\n\u003cp\u003e\u0026nbsp;\u003c/p\u003e","description":"","filename":"SupplementaryFigure.pptx","url":"https://assets-eu.researchsquare.com/files/rs-9104169/v1/48c620dfeb8857d571e81d85.pptx"}],"financialInterests":"There is \u003cb\u003eNO\u003c/b\u003e conflict of interest to disclose.","formattedTitle":"Recurrent venous thrombosis in myeloproliferative neoplasms: impact of cytoreductive control and antithrombotic strategy","fulltext":[{"header":"Introduction","content":"\u003cp\u003eMyeloproliferative neoplasms (MPNs) are acquired clonal disorders of hematopoietic stem cells and are revealed by a thrombotic event in 20% of patients \u003csup\u003e\u003cspan citationid=\"CR1\" class=\"CitationRef\"\u003e1\u003c/span\u003e\u003c/sup\u003e. Although thrombosis in MPNs is more commonly arterial, venous thromboembolism (VTE) represents the presenting manifestation in a 6.2% of patients \u003csup\u003e\u003cspan citationid=\"CR1\" class=\"CitationRef\"\u003e1\u003c/span\u003e\u003c/sup\u003e. VTE include deep vein thrombosis (DVT) of the limbs, pulmonary embolism and thrombosis of the cerebral and splanchnic veins (hepatic, portal, mesenteric and splenic veins).\u003c/p\u003e \u003cp\u003ePatients with MPN and previous thrombosis belong to the high-risk group which indicates cytoreduction in order to reduce thrombosis risk recurrence\u003csup\u003e\u003cspan citationid=\"CR2\" class=\"CitationRef\"\u003e2\u003c/span\u003e\u003c/sup\u003e. In addition to cytoreduction, patients with MPN and VTE receive anticoagulation for at least 3 months in case of distal VTE, at least 6 months for proximal DVT and pulmonary embolism, and usually lifelong for thrombosis of unusual sites (splanchnic vein thrombosis and cerebral vein thrombosis). But the optimal duration of anticoagulant therapy after a VTE that reveals an MPN is still unclear\u003csup\u003e\u003cspan citationid=\"CR3\" class=\"CitationRef\"\u003e3\u003c/span\u003e\u003c/sup\u003e.\u003c/p\u003e \u003cp\u003eIn the general population, the duration of anticoagulation following a first episode of VTE is determined by the presence and nature of provoking risk factors \u003csup\u003e\u003cspan citationid=\"CR4\" class=\"CitationRef\"\u003e4\u003c/span\u003e\u003c/sup\u003e. Anticoagulation is usually discontinued after 3 to 6 months in patients with VTE provoked by transient risk factors, whereas lifelong anticoagulation is recommended for unprovoked VTE or VTE associated with persistent risk factors, given the high risk of recurrence after treatment discontinuation. Active cancer is classically considered a persistent thrombotic risk factor warranting prolonged anticoagulation; however, thrombotic risk in cancer is highly heterogeneous and depends on tumor type, treatment, and associated factors \u003csup\u003e\u003cspan citationid=\"CR5\" class=\"CitationRef\"\u003e5\u003c/span\u003e\u003c/sup\u003e. Importantly, current clinical guidelines for cancer-associated VTE do not include MPNs among active malignancies, suggesting that thrombotic risk recurrence in MPNs should be assessed separately rather than extrapolated from solid tumors.\u003c/p\u003e \u003cp\u003eThe risk of recurrence of VTE at usual sites in patients with MPN was assessed in a large retrospective study 10 years ago. It was reported to be of 9.6 per 100 patients-years in patients who were treated with Vitamin K antagonists (VKA) and who discontinued. This risk was divided by 2.2 (4.2 per 100 patients-years) in patients on long-term VKA \u003csup\u003e\u003cspan citationid=\"CR6\" class=\"CitationRef\"\u003e6\u003c/span\u003e\u003c/sup\u003e. This constituted the rationale to propose long term VKA in MPN patients with VTE at usual sites and no other provoking factor \u003csup\u003e\u003cspan citationid=\"CR7\" class=\"CitationRef\"\u003e7\u003c/span\u003e\u003c/sup\u003e. Nevertheless, most recurrent events reported in this study occurred in patients who were either not receiving cytoreductive treatment or were not achieving effective cytoreduction \u003csup\u003e\u003cspan citationid=\"CR6\" class=\"CitationRef\"\u003e6\u003c/span\u003e\u003c/sup\u003e. It may thus be that the risk of VTE recurrence in MPN patients with proper control of their MPN would be lower.\u003c/p\u003e \u003cp\u003eAltogether, while newly diagnosed MPNs represent a major risk factor for venous thrombosis, whether patients who are adequately controlled with cytoreductive therapy remain at high risk of VTE recurrence is unclear. This uncertainty currently precludes evidence-based recommendations regarding the duration of anticoagulation in this population and highlights the need for studies specifically designed to evaluate VTE recurrence in patients with MPNs, taking into account both cytoreductive efficacy and antithrombotic strategy.\u003c/p\u003e \u003cp\u003e In this context, we aimed to assess, in a nationwide retrospective French cohort, the incidence of recurrent venous thrombotic events in patients with MPNs and a history of non-splanchnic deep vein thrombosis, according to cytoreductive control and antithrombotic strategy.\u003c/p\u003e"},{"header":"Material and Methods","content":"\u003cdiv id=\"Sec3\" class=\"Section2\"\u003e \u003ch2\u003eStudy patients\u003c/h2\u003e \u003cp\u003eThe French Intergroup of Myeloproliferative neoplasms (FIM) clinical and biological database (FIMBANK) includes patients with a diagnosis of PV or ET from 2005 according to the World Health Organization (WHO) 2016 or 2022 classifications \u003csup\u003e\u003cspan citationid=\"CR8\" class=\"CitationRef\"\u003e8\u003c/span\u003e, \u003cspan citationid=\"CR9\" class=\"CitationRef\"\u003e9\u003c/span\u003e\u003c/sup\u003e. FIMBANK includes patient data at diagnosis and during follow-up of patients recruited in 33 French hospitals. For the present study, we included all patients from the BCB FIMBANK who had presented with an episode of VTE within the year preceding the diagnosis of MPN. VTE was defined as the occurrence of deep vein thrombosis at the following sites: lower limb, upper limb, pulmonary embolism or cerebral venous thrombosis. Patients who had experienced an episode of splanchnic vein thrombosis prior to the diagnosis of MPN were excluded.\u003c/p\u003e \u003c/div\u003e\n\u003ch3\u003eMethods\u003c/h3\u003e\n\u003cp\u003eThe primary endpoint of the study was the occurrence of recurrent VTE during follow-up. The following recurrent VTE sites were recorded: deep vein thrombosis of the lower or upper limb, pulmonary embolism, cerebral venous thrombosis and splanchnic vein thrombosis. Patient data were extracted from the BCB FIMBANK database. The following baseline characteristics were collected: demographic data (patient age at diagnosis and sex); MPN characteristics (PV or ET, blood count, presence of JAK2V617F mutation and variant allele frequency); VTE date and location. Follow-up data regarding the occurrence of VTE (date and site), cytoreductive and antithrombotic treatments, and blood counts were collected annually or at the occurrence of a clinical event. For patients who did not experience VTE recurrence during follow-up, cytoreductive and antithrombotic treatments and blood counts recorded at the date of last follow-up were collected. For patients who experienced VTE recurrence, the cytoreductive and antithrombotic treatments collected were those recorded at the follow-up visit preceding the thrombotic event. The blood count with the sampling date closest to the thrombotic event was collected, provided that the interval did not exceed 180 days. The diagnoses of PV or ET were made according to the WHO 2016 or 2022 classifications, depending on the year of diagnosis \u003csup\u003e\u003cspan citationid=\"CR8\" class=\"CitationRef\"\u003e8\u003c/span\u003e, \u003cspan citationid=\"CR9\" class=\"CitationRef\"\u003e9\u003c/span\u003e\u003c/sup\u003e. Patients\u0026rsquo; response to cytoreductive therapy was assessed according to the European Leukemia Net criteria (ELN/IWG-MRT) \u003csup\u003e\u003cspan citationid=\"CR10\" class=\"CitationRef\"\u003e10\u003c/span\u003e\u003c/sup\u003e.\u003c/p\u003e\n\u003ch3\u003eStatistical analyses and informed consent\u003c/h3\u003e\n\u003cp\u003eCategorical variables were analyzed as frequencies with percentages and were compared using a χ2 test or Fisher's exact test as appropriate. Continuous variables were expressed as median and interquartile range, and a Mann-Whitney U test was used for comparisons. The annual incidence of recurrent VTE was calculated by dividing the number of events by the total number of patient-years. For assessing recurrent VTE outcome, we estimated cumulative incidence of VTE using Kaplan-Meier analyses, with time defined as the interval between the diagnosis of MPN and the recurrent VTE or the last follow-up visit (censored observations). We performed log-rank tests to analyze the differences between groups.\u003c/p\u003e \u003cp\u003eStatistical analysis was performed using Rstudio software (version 4.5.2; R foundation for Statistical Computing. Patients provided their informed consent to be included in the BCB FIMBANK and the present project has been registered by the French Data Protection Authority (PADS25-009; CSE25-74).\u003c/p\u003e"},{"header":"Results","content":"\u003cdiv id=\"Sec7\" class=\"Section2\"\u003e \u003ch2\u003eDescription of the patient cohort\u003c/h2\u003e \u003cp\u003eBetween March 2005 and March 2025, 5,163 PV and ET patients were included in FIMBANK. Overall, 585 (13%) patients presented an inaugural thrombosis defined by an arterial and/or venous thrombosis within 12 months prior to the diagnosis of their MPN, and/or a history of splanchnic vein thrombosis regardless of the delay. Three hundred twenty-eight patients (6.4%) experienced a VTE. Among these 328 patients, 195 (59.4%) presented with splanchnic vein thrombosis and 16 (4.9%) with superficial vein thrombosis. These two groups were excluded from our study. For this present study, we thus selected 117 patients (35.7%) who had experienced an initial non splanchnic deep VTE (\u003cb\u003eSupplemental Fig.\u0026nbsp;1\u003c/b\u003e).\u003c/p\u003e \u003c/div\u003e \u003cdiv id=\"Sec8\" class=\"Section2\"\u003e \u003ch2\u003eMain clinical and biological characteristics of the patient cohort at the time of MPN diagnosis\u003c/h2\u003e \u003cp\u003eThe clinical and laboratory features of the 117 patients are reported in \u003cb\u003eTable\u0026nbsp;1\u003c/b\u003e. PV and ET were diagnosed in respectively 76 patients (65.0%) and 41 (35%) of the patients. ET patients were younger than PV patients (median age: 51.0 vs 66.5 years; p\u0026thinsp;=\u0026thinsp;0.002). The JAK2V617F mutation was present in all PV patients and in 92.7% of ET patients. The allele burden was higher in PV patients (39.0% vs 13.0%; p\u0026thinsp;\u0026lt;\u0026thinsp;0.0001).\u003c/p\u003e \u003cp\u003eAt diagnosis, PV patients had higher hemoglobin and hematocrit levels than ET patients (17.0 vs 14.3 g/dL, p\u0026thinsp;\u0026lt;\u0026thinsp;0.0001; and 53.0% vs 43.9%, p\u0026thinsp;\u0026lt;\u0026thinsp;0.0001, respectively). Platelet counts were higher in ET patients (659.0 vs 430.0 G/L; p\u0026thinsp;\u0026lt;\u0026thinsp;0.0001) and PV patients exhibited higher neutrophil counts (8.2 vs 6.5 G/L; p\u0026thinsp;=\u0026thinsp;0.03).\u003c/p\u003e \u003cp\u003eMost DVT occurred in usual sites with 45.3% in the lower limb, and 31.6% as pulmonary embolism with no significant difference between ET and PV patients. In 6 patients (5.1%), DVT occurred in the upper limb. Cerebral venous thrombosis occurred in 21 patients (17.9%), and more frequently in ET patients than in PV patients (31.7% vs 10.5%; p\u0026thinsp;=\u0026thinsp;0.01).\u003c/p\u003e \u003c/div\u003e\n\u003ch3\u003eIncidence of VTE recurrence\u003c/h3\u003e\n\u003cp\u003eWith a median follow-up of 4.3 years (IQR, 1.9\u0026ndash;8.8), VTE recurrence occurred in 13 patients (11.1%) (\u003cb\u003eTable\u0026nbsp;2\u003c/b\u003e). The sites of recurrences are described in \u003cb\u003eTable\u0026nbsp;2\u003c/b\u003e. The 3 patients with initial cerebral venous thrombosis had recurrence in unusual sites, i.e. one recurrence of cerebral venous thrombosis and two splanchnic vein thrombosis.\u003c/p\u003e \u003cp\u003eThe overall observation time was 721 years and the incidence rate of recurrent VTE was 1.80 per 100 patient-years (95% CI: 0.96\u0026ndash;3.08). Kaplan-Meyer curve is depicted in Fig.\u0026nbsp;\u003cspan refid=\"Fig1\" class=\"InternalRef\"\u003e1\u003c/span\u003e. The cumulative incidence of VTE recurrence at 1 year, 3 years and 5 years was respectively 0%, 3.38% (95% CI: 0-7.08) and 6.36% (95% CI: 0.73\u0026ndash;11.66).\u003c/p\u003e \u003cp\u003e \u003c/p\u003e\n\u003ch3\u003eComparison of patients with or without VTE recurrence\u003c/h3\u003e\n\u003cp\u003eWe did not observe any difference at diagnosis in term of sex, age, MPN subtype, presence of the JAK2V617F mutation and its allele burden, between patients with or without VTE recurrence (\u003cb\u003eTable\u0026nbsp;3\u003c/b\u003e). We then investigated whether there were differences in term of cytoreductive and antithrombotic treatments at the time of recurrence for patients with recurrence or at the last update for patients without recurrence. The majority of patients received cytoreductive therapy (mostly hydroxyurea), with no difference between those with and without recurrence (84.6% vs 94.2%, respectively; p\u0026thinsp;=\u0026thinsp;0.22). Similarly, more than 92% of patients were treated with antithrombotic therapy in both groups. The majority of patients were treated with anticoagulant, either alone or in combination with antiplatelet therapy, with no differences between patients with recurrence (61.6%) and patients without recurrence (57.3%; p\u0026thinsp;=\u0026thinsp;0.50). Almost 31% of patients with recurrence were treated with antiplatelet agent alone at the time of recurrence, which was not significantly different from patients without recurrence (35%) (\u003cb\u003eTable\u0026nbsp;3\u003c/b\u003e).\u003c/p\u003e \u003cp\u003eThe main difference between patients with and without VTE recurrence was whether they had achieved effective cytoreduction according to ELN criteria. Indeed, only 1 of 12 patients with recurrent VTE (8.3%) met ELN response criteria, compared with 65 of 95 patients without recurrence (68.4%; p\u0026thinsp;\u0026lt;\u0026thinsp;0.0001) (\u003cb\u003eTables\u0026nbsp;2 and 3\u003c/b\u003e).\u003c/p\u003e \u003cdiv id=\"Sec11\" class=\"Section2\"\u003e \u003ch2\u003eEffect of anticoagulation or cytoreduction on VTE recurrence\u003c/h2\u003e \u003cp\u003eThe total observation time of the patients who received anticoagulant therapy without discontinuation was 358 patient-years. For the patients who received anticoagulation after the index VTE case but for whom anticoagulation was discontinued, the total observation time was 362 patient-years. There was no difference in VTE recurrence incidence between patients who were still on anticoagulation and the ones who had discontinued (2.24 vs 1.38 per 100 patient-years, respectively; p\u0026thinsp;=\u0026thinsp;0.285) (\u003cb\u003eTable\u0026nbsp;4 and\u003c/b\u003e Fig.\u0026nbsp;\u003cspan refid=\"Fig2\" class=\"InternalRef\"\u003e2\u003c/span\u003ea).\u003c/p\u003e \u003cp\u003e \u003c/p\u003e \u003cp\u003eWe then investigated the effect of adequate cytoreduction and compared patients achieving an ELN response with patients who did not, independently of the presence of long-term anticoagulation. The incidence of VTE recurrence was significantly lower in patients meeting ELN response criteria (0.25 per 100 pt-years), compared with patients who were not achieving effective cytoreduction (4.49 per 100 pt-years) (p\u0026thinsp;\u0026lt;\u0026thinsp;0.001) (\u003cb\u003eTable\u0026nbsp;4\u003c/b\u003e). In patients meeting ELN response criteria, the cumulative incidence of VTE recurrence at 5 years was 0%. In patients who did not respond to cytoreductive therapy according to ELN response criteria, the cumulative incidence of VTE recurrence at 1 year, 3 years and 5 years was respectively 0%, 9.11% (95% CI: 0-18.43%) and 16.10% (95% CI: 2.03\u0026ndash;28.15) (Fig.\u0026nbsp;\u003cspan refid=\"Fig2\" class=\"InternalRef\"\u003e2\u003c/span\u003eb).\u003c/p\u003e \u003c/div\u003e \u003cdiv id=\"Sec12\" class=\"Section2\"\u003e \u003ch2\u003eEffect of the combination of long-term anticoagulation and adequate cytoreduction on VTE recurrence\u003c/h2\u003e \u003cp\u003eWe then stratified patients into four groups according to maintenance of anticoagulant therapy and achievement of ELN criteria. A difference in cumulative incidence of VTE recurrence was observed across the four groups (log-rank p\u0026thinsp;\u0026lt;\u0026thinsp;0.001) (Fig.\u0026nbsp;\u003cspan refid=\"Fig3\" class=\"InternalRef\"\u003e3\u003c/span\u003e). Patients who met ELN criteria (groups A and B, Fig.\u0026nbsp;\u003cspan refid=\"Fig3\" class=\"InternalRef\"\u003e3\u003c/span\u003e\u003cb\u003e)\u003c/b\u003e did not experience VTE recurrence in the 5 years following their diagnosis, regardless of their anticoagulant therapy. No difference was observed between patients receiving anticoagulation (group B) and those who did not (group A) among ELN responders. In contrast, patients who did not meet ELN criteria and without anticoagulation (group C, Fig.\u0026nbsp;\u003cspan refid=\"Fig3\" class=\"InternalRef\"\u003e3\u003c/span\u003e) exhibited a cumulative incidence of VTE recurrence at 1 year, 3 years and 5 years at 0%, 10% (95% CI: 0-22.23) and 15.62% (95% CI:0-30.45) respectively. At last, patients who did not meet ELN criteria and with anticoagulation (group D, Fig.\u0026nbsp;\u003cspan refid=\"Fig3\" class=\"InternalRef\"\u003e3\u003c/span\u003e\u003cb\u003e)\u003c/b\u003e exhibited a cumulative incidence of VTE recurrence at 1 year, 3 years and 5 years at 0%, 7.69% (95% CI: 0-21.10) and 16.92% (95% CI:0-35.91) respectively.\u003c/p\u003e \u003cp\u003e \u003c/p\u003e \u003c/div\u003e"},{"header":"Discussion","content":"\u003cp\u003eIn this nationwide cohort of patients with PV or ET who experienced a non-splanchnic VTE within the year preceding MPN diagnosis, ineffective cytoreduction according to ELN criteria emerged as the sole determinant of recurrent VTE. Neither age, sex, MPN subtype, JAK2V617F allele burden, nor antithrombotic strategy influenced recurrence risk. The overall annual incidence of recurrent VTE was low (1.8 per 100 patient-years), with a 5-year cumulative incidence of 6.4%.\u003c/p\u003e \u003cp\u003eBy restricting inclusion to patients whose VTE occurred within 12 months prior to MPN diagnosis, we deliberately focused on events most plausibly attributable to an underlying and persistent prothrombotic driver \u0026mdash; the MPN itself. Exclusion of splanchnic vein thrombosis allowed analysis of a clinically homogeneous population with usual-site VTE, avoiding the specific pathophysiological and therapeutic challenges associated with splanchnic events \u003csup\u003e\u003cspan citationid=\"CR11\" class=\"CitationRef\"\u003e11\u003c/span\u003e\u003c/sup\u003e. Within this framework, the recurrence rate observed here is substantially lower than previously reported in retrospective series \u003csup\u003e\u003cspan citationid=\"CR6\" class=\"CitationRef\"\u003e6\u003c/span\u003e, \u003cspan citationid=\"CR7\" class=\"CitationRef\"\u003e7\u003c/span\u003e, \u003cspan citationid=\"CR12\" class=\"CitationRef\"\u003e12\u003c/span\u003e, \u003cspan citationid=\"CR13\" class=\"CitationRef\"\u003e13\u003c/span\u003e\u003c/sup\u003e.\u003c/p\u003e \u003cp\u003eThe most clinically relevant finding is the absence of a measurable protective effect of long-term anticoagulation once cytoreductive response is considered. Recurrence-free survival curves were virtually superimposable between anticoagulated and non-anticoagulated patients during the first five years of follow-up. In contrast, ELN-defined response was strongly associated with outcome. Patients achieving effective cytoreduction had an incidence rate of 0.25 per 100 patient-years and no recurrence within five years, whereas non-responders exhibited a markedly higher incidence (4.49 per 100 patient-years) and a 5-year cumulative incidence exceeding 16%. Notably, all but one recurrent event occurred in patients who did not meet ELN criteria. The single recurrence in an ELN responder occurred late (8.9 years after diagnosis) at age 70, raising the possibility of age-related or non\u0026ndash;MPN-related contributors.\u003c/p\u003e \u003cp\u003eThese findings provide a potential explanation for discrepancies with earlier reports. In the study by De Stefano et al., the incidence rate of recurrent VTE reached 5.2 per 100 patient-years, and prolonged vitamin K antagonist therapy appeared protective. However, inadequate hematologic control was documented in a substantial proportion of patients at recurrence. In that cohort, poor control of myeloproliferation was observed in 69% of recurrent cases during cytoreduction. In contrast, in our study, only one of thirteen recurrences occurred under ELN-defined response. The lower recurrence rate observed here likely reflects a higher proportion of patients achieving sustained hematologic control. Together, these data suggest that the biological activity of the MPN \u0026mdash; rather than anticoagulation per se \u0026mdash; is the principal driver of recurrent venous thrombosis.\u003c/p\u003e \u003cp\u003eThe clinical characteristics of our cohort are otherwise consistent with prior literature. The high prevalence of JAK2V617F mutation, including in ET patients, likely reflects thrombotic enrichment and is concordant with data identifying JAK2 mutation as a major venous thrombotic risk factor compared with CALR-mutated disease \u003csup\u003e\u003cspan citationid=\"CR14\" class=\"CitationRef\"\u003e14\u003c/span\u003e, \u003cspan citationid=\"CR15\" class=\"CitationRef\"\u003e15\u003c/span\u003e, \u003cspan citationid=\"CR16\" class=\"CitationRef\"\u003e16\u003c/span\u003e\u003c/sup\u003e.\u003c/p\u003e \u003cp\u003eFrom a clinical standpoint, our results challenge the systematic extrapolation of cancer-associated thrombosis paradigms to MPN. Current guidelines do not uniformly categorize MPN as an \u0026ldquo;active cancer\u0026rdquo; requiring indefinite anticoagulation \u003csup\u003e\u003cspan citationid=\"CR17\" class=\"CitationRef\"\u003e17\u003c/span\u003e, \u003cspan citationid=\"CR18\" class=\"CitationRef\"\u003e18\u003c/span\u003e\u003c/sup\u003e. Our data support a risk-adapted approach: in patients achieving durable ELN-defined cytoreductive response, the MPN may no longer behave as a persistent high-risk condition for venous recurrence. Given that long-term anticoagulation carries a non-negligible hemorrhagic risk, the balance of benefit and harm may differ substantially according to cytoreductive control. Whether anticoagulation can be safely discontinued in ELN responders \u0026mdash; potentially maintaining antiplatelet therapy in line with primary thrombosis prevention \u0026mdash; warrants prospective evaluation.\u003c/p\u003e \u003cp\u003eThis study has several strengths. It is based on one of the largest contemporary multicenter cohorts addressing VTE recurrence in MPN, with nationwide recruitment, harmonized data collection, and substantial follow-up. However, limitations must be acknowledged. The partly retrospective design and absence of central adjudication of recurrent events may introduce classification bias. Despite the large source population, the absolute number of recurrences remains limited, precluding multivariable modeling and detailed analyses according to specific cytoreductive agents. Bleeding outcomes were not systematically collected and therefore net clinical benefit could not be assessed.\u003c/p\u003e \u003cp\u003eProspective validation of these findings would be highly desirable but may prove challenging given the relatively low recurrence rate observed. Future studies should also address splanchnic vein thrombosis separately, as ELN response criteria are not readily applicable in that context and recurrence risk remains high despite therapy.\u003c/p\u003e \u003cp\u003eIn conclusion, in patients with PV or ET presenting with usual-site VTE, achievement of ELN-defined cytoreductive response is strongly associated with a markedly reduced risk of recurrence, whereas long-term anticoagulation alone does not appear to confer additional protection. These data suggest that optimal hematologic control may represent the cornerstone of secondary venous thrombosis prevention in MPN and should be central in future risk-adapted therapeutic strategies.\u003c/p\u003e"},{"header":"Abbreviations","content":"\u003cdiv class=\"DefinitionList\"\u003e \u003cdiv class=\"DefinitionListEntry\"\u003e \u003cdiv class=\"Term\"\u003ePV\u003c/div\u003e \u003cdiv class=\"Description\"\u003e \u003cp\u003ePolycythemia Vera\u003c/p\u003e \u003c/div\u003e \u003c/div\u003e \u003cdiv class=\"DefinitionListEntry\"\u003e \u003cdiv class=\"Term\"\u003eET\u003c/div\u003e \u003cdiv class=\"Description\"\u003e \u003cp\u003eEssential thrombocythemia\u003c/p\u003e \u003c/div\u003e \u003c/div\u003e \u003cdiv class=\"DefinitionListEntry\"\u003e \u003cdiv class=\"Term\"\u003eVTE\u003c/div\u003e \u003cdiv class=\"Description\"\u003e \u003cp\u003eVenous Thromboembolism. IQR:interquartile range\u003c/p\u003e \u003c/div\u003e \u003c/div\u003e \u003c/div\u003e"},{"header":"Declarations","content":"\u003cp\u003e\u003cstrong\u003eAcknowledgements\u0026nbsp;\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eThe authors thank the French group of Myeloproliferative neoplasms (\u003cem\u003eFrance Intergroupe Syndrome Myéloproliferatifs,\u0026nbsp;\u003c/em\u003eFIM) and the FIMBANK team for the support in the conception and elaboration of the study. \u0026nbsp;\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eAuthor contributions\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eCJ, GV, PS designed the study; GV, HP, LB collected data; PS performed statistical analyses; JCI, LS, DLP, VU coordinated data management of the FIMBANK biobank; GV, PS and CJ wrote the manuscript; all authors provided data and approved the final manuscript.\u0026nbsp;\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eCompeting interests\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eThe authors declare no competing financial interests related to this work.\u0026nbsp;\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eData Availability\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eFor original data, please contact [email protected]\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eEthics approval statement\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eWritten consent was obtained from all study participants, and the study has obtained the authorization of the committee for the protection of individuals.\u0026nbsp;\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eFunding statement\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eThis work is a deliverable of the FIMBANK network, which was founded by the French ‘Institut National du Cancer’ (INCa BCB 2013 \u0026amp; 2022)”\u003c/p\u003e"},{"header":"References","content":"\u003col\u003e\n \u003cli\u003eRungjirajittranon T, Owattanapanich W, Ungprasert P, Siritanaratkul N, Ruchutrakool T. A systematic review and meta-analysis of the prevalence of thrombosis and bleeding at diagnosis of Philadelphia-negative myeloproliferative neoplasms. \u003cem\u003eBMC Cancer\u003c/em\u003e 2019; \u003cstrong\u003e19\u003c/strong\u003e: 184.\u003c/li\u003e\n \u003cli\u003eDe Stefano V, Rossi E, Carobbio A, Ghirardi A, Betti S, Finazzi G \u003cem\u003eet al.\u003c/em\u003e Hydroxyurea prevents arterial and late venous thrombotic recurrences in patients with myeloproliferative neoplasms but fails in the splanchnic venous district. Pooled analysis of 1500 cases. \u003cem\u003eBlood Cancer Journal\u003c/em\u003e 2018; \u003cstrong\u003e8\u003c/strong\u003e: 112.\u003c/li\u003e\n \u003cli\u003eGuy A, Morange P-E, James C. How I approach the treatment of thrombotic complications in patients with myeloproliferative neoplasms. \u003cem\u003eBlood\u003c/em\u003e 2025; \u003cstrong\u003e145\u003c/strong\u003e: 1769\u0026ndash;1779.\u003c/li\u003e\n \u003cli\u003eOrtel TL, Neumann I, Ageno W, Beyth R, Clark NP, Cuker A \u003cem\u003eet al.\u003c/em\u003e American Society of Hematology 2020 guidelines for management of venous thromboembolism: treatment of deep vein thrombosis and pulmonary embolism. \u003cem\u003eBlood Adv\u003c/em\u003e 2020; \u003cstrong\u003e4\u003c/strong\u003e: 4693\u0026ndash;4738.\u003c/li\u003e\n \u003cli\u003eGirardi L, Wang T-F, Ageno W, Carrier M. Updates in the Incidence, Pathogenesis, and Management of Cancer and Venous Thromboembolism. \u003cem\u003eArterioscler Thromb Vasc Biol\u003c/em\u003e 2023; \u003cstrong\u003e43\u003c/strong\u003e: 824\u0026ndash;831.\u003c/li\u003e\n \u003cli\u003eDe Stefano V, Ruggeri M, Cervantes F, Alvarez-Larr\u0026aacute;n A, Iurlo A, Randi ML \u003cem\u003eet al.\u003c/em\u003e High rate of recurrent venous thromboembolism in patients with myeloproliferative neoplasms and effect of prophylaxis with vitamin K antagonists. \u003cem\u003eLeukemia\u003c/em\u003e 2016; \u003cstrong\u003e30\u003c/strong\u003e: 2032\u0026ndash;2038.\u003c/li\u003e\n \u003cli\u003eDe Stefano V, Finazzi G, Barbui T. Antithrombotic therapy for venous thromboembolism in myeloproliferative neoplasms. \u003cem\u003eBlood Cancer Journal\u003c/em\u003e 2018; \u003cstrong\u003e8\u003c/strong\u003e: 65.\u003c/li\u003e\n \u003cli\u003eArber DA, Orazi A, Hasserjian R, Thiele J, Borowitz MJ, Le Beau MM \u003cem\u003eet al.\u003c/em\u003e The 2016 revision to the World Health Organization classification of myeloid neoplasms and acute leukemia. \u003cem\u003eBlood\u003c/em\u003e 2016; \u003cstrong\u003e127\u003c/strong\u003e: 2391\u0026ndash;2405.\u003c/li\u003e\n \u003cli\u003eArber DA, Orazi A, Hasserjian RP, Borowitz MJ, Calvo KR, Kvasnicka H-M \u003cem\u003eet al.\u003c/em\u003e International Consensus Classification of Myeloid Neoplasms and Acute Leukemias: integrating morphologic, clinical, and genomic data. \u003cem\u003eBlood\u003c/em\u003e 2022; \u003cstrong\u003e140\u003c/strong\u003e: 1200\u0026ndash;1228.\u003c/li\u003e\n \u003cli\u003eBarosi G, Mesa R, Finazzi G, Harrison C, Kiladjian J-J, Lengfelder E \u003cem\u003eet al.\u003c/em\u003e Revised response criteria for polycythemia vera and essential thrombocythemia: an ELN and IWG-MRT consensus project. \u003cem\u003eBlood\u003c/em\u003e 2013; \u003cstrong\u003e121\u003c/strong\u003e: 4778\u0026ndash;4781.\u003c/li\u003e\n \u003cli\u003eFinazzi G, De Stefano V, Barbui T. Splanchnic vein thrombosis in myeloproliferative neoplasms: treatment algorithm 2018. \u003cem\u003eBlood Cancer J\u003c/em\u003e 2018; \u003cstrong\u003e8\u003c/strong\u003e: 64.\u003c/li\u003e\n \u003cli\u003eBarbui T, Carobbio A, De Stefano V. Thrombosis in myeloproliferative neoplasms during cytoreductive and antithrombotic drug treatment. \u003cem\u003eRes Pract Thromb Haemost\u003c/em\u003e 2022; \u003cstrong\u003e6\u003c/strong\u003e: e12657.\u003c/li\u003e\n \u003cli\u003eGutwein O, Lavi N, Barzilai M, Shacham-Abulafia A, Leader A, Chubar E \u003cem\u003eet al.\u003c/em\u003e Management and Outcome of Venous Thrombosis in Patients with Myeloproliferative Neoplasms: Data from the Israeli MPN Working Group. \u003cem\u003eActa Haematol\u003c/em\u003e 2021; \u003cstrong\u003e144\u003c/strong\u003e: 438\u0026ndash;445.\u003c/li\u003e\n \u003cli\u003eTevet M, Ionescu R, Dragan C, Lupu AR. Influence of the JAK2 V617F Mutation and Inherited Thrombophilia on the Thrombotic Risk among Patients with Myeloproliferative Disorders. \u003cem\u003eMaedica (Bucur)\u003c/em\u003e 2015; \u003cstrong\u003e10\u003c/strong\u003e: 27\u0026ndash;32.\u003c/li\u003e\n \u003cli\u003eHaider M, Gangat N, Lasho T, Abou Hussein AK, Elala YC, Hanson C \u003cem\u003eet al.\u003c/em\u003e Validation of the revised International Prognostic Score of Thrombosis for Essential Thrombocythemia (IPSET-thrombosis) in 585 Mayo Clinic patients. \u003cem\u003eAm J Hematol\u003c/em\u003e 2016; \u003cstrong\u003e91\u003c/strong\u003e: 390\u0026ndash;394.\u003c/li\u003e\n \u003cli\u003eAndrikovics H, Krahling T, Balassa K, Halm G, Bors A, Koszarska M \u003cem\u003eet al.\u003c/em\u003e Distinct clinical characteristics of myeloproliferative neoplasms with calreticulin mutations. \u003cem\u003eHaematologica\u003c/em\u003e 2014; \u003cstrong\u003e99\u003c/strong\u003e: 1184\u0026ndash;1190.\u003c/li\u003e\n \u003cli\u003eStevens SM, Woller SC, Baumann Kreuziger L, Bounameaux H, Doerschug K, Geersing G-J \u003cem\u003eet al.\u003c/em\u003e Executive Summary: Antithrombotic Therapy for VTE Disease: Second Update of the CHEST Guideline and Expert Panel Report. \u003cem\u003eChest\u003c/em\u003e 2021; \u003cstrong\u003e160\u003c/strong\u003e: 2247\u0026ndash;2259.\u003c/li\u003e\n \u003cli\u003eKearon C, Ageno W, Cannegieter SC, Cosmi B, Geersing G-J, Kyrle PA \u003cem\u003eet al.\u003c/em\u003e Categorization of patients as having provoked or unprovoked venous thromboembolism: guidance from the SSC of ISTH. \u003cem\u003eJ Thromb Haemost\u003c/em\u003e 2016; \u003cstrong\u003e14\u003c/strong\u003e: 1480\u0026ndash;1483.\u003c/li\u003e\n\u003c/ol\u003e"},{"header":"Tables","content":"\u003cp\u003eTables 1 to 4 are available in the supplementary files section\u003c/p\u003e"}],"fulltextSource":"","fullText":"","funders":[],"hasAdminPriorityOnWorkflow":false,"hasManuscriptDocX":true,"hasOptedInToPreprint":true,"hasPassedJournalQc":"","hasAnyPriority":false,"hideJournal":true,"highlight":"","institution":"","isAcceptedByJournal":false,"isAuthorSuppliedPdf":false,"isDeskRejected":"","isHiddenFromSearch":false,"isInQc":false,"isInWorkflow":false,"isPdf":false,"isPdfUpToDate":true,"isWithdrawnOrRetracted":false,"journal":{"display":true,"email":"[email protected]","identity":"researchsquare","isNatureJournal":false,"hasQc":true,"allowDirectSubmit":true,"externalIdentity":"","sideBox":"","snPcode":"","submissionUrl":"/submission","title":"Research Square","twitterHandle":"researchsquare","acdcEnabled":true,"dfaEnabled":false,"editorialSystem":"","reportingPortfolio":"","inReviewEnabled":false,"inReviewRevisionsEnabled":true},"keywords":"","lastPublishedDoi":"10.21203/rs.3.rs-9104169/v1","lastPublishedDoiUrl":"https://doi.org/10.21203/rs.3.rs-9104169/v1","license":{"name":"CC BY 4.0","url":"https://creativecommons.org/licenses/by/4.0/"},"manuscriptAbstract":"\u003cp\u003eVenous thromboembolism (VTE) may reveal myeloproliferative neoplasms (MPNs), yet the risk of recurrence under contemporary cytoreductive management remains uncertain. We assessed the incidence of recurrent VTE in the nationwide French cohort of patients with polycythemia vera or essential thrombocythemia who experienced a non-splanchnic VTE within 12 months prior to MPN diagnosis. Among 5,163 patients, 117 exhibited initial VTE of their MPN. With a median follow-up of 4.3 years (IQR 1.9\u0026ndash;8.8), 13 recurrent VTE events occurred, yielding an incidence rate of 1.80 per 100 patient-years (95% CI 0.96\u0026ndash;3.08). The 5-year cumulative incidence of recurrence was 6.36% (95% CI 0.73\u0026ndash;11.66). Demographic characteristics, MPN subtype, and antithrombotic strategy were not significantly associated with recurrence. In contrast, achievement of an ELN-defined cytoreductive response was strongly associated with lower recurrence risk. The incidence rate was 0.25 per 100 patient-years in ELN responders versus 4.49 per 100 patient-years in non-responders (p\u0026thinsp;\u0026lt;\u0026thinsp;0.001). All but one recurrent event occurred in patients who did not meet ELN criteria. Long-term anticoagulation was not associated with a statistically significant reduction in recurrence (2.24 vs 1.38 per 100 patient-years; p\u0026thinsp;=\u0026thinsp;0.285). In conclusion, recurrent VTE after MPN-associated usual-site thrombosis was infrequent and predominantly observed in patients without effective cytoreductive control.\u003c/p\u003e","manuscriptTitle":"Recurrent venous thrombosis in myeloproliferative neoplasms: impact of cytoreductive control and antithrombotic strategy","msid":"","msnumber":"","nonDraftVersions":[{"code":1,"date":"2026-03-18 08:39:20","doi":"10.21203/rs.3.rs-9104169/v1","editorialEvents":[{"type":"communityComments","content":0}],"status":"published","journal":{"display":true,"email":"[email protected]","identity":"researchsquare","isNatureJournal":false,"hasQc":true,"allowDirectSubmit":true,"externalIdentity":"","sideBox":"","snPcode":"","submissionUrl":"/submission","title":"Research Square","twitterHandle":"researchsquare","acdcEnabled":true,"dfaEnabled":false,"editorialSystem":"","reportingPortfolio":"","inReviewEnabled":false,"inReviewRevisionsEnabled":true}}],"origin":"","ownerIdentity":"ca4bcbd0-655d-404c-85ea-d678fb7c6da7","owner":[],"postedDate":"March 18th, 2026","published":true,"recentEditorialEvents":[],"rejectedJournal":[],"revision":"","amendment":"","status":"posted","subjectAreas":[{"id":64458495,"name":"Health sciences/Medical research/Epidemiology"},{"id":64458496,"name":"Health sciences/Diseases/Haematological diseases/Haematological cancer/Myeloproliferative disease"}],"tags":[],"updatedAt":"2026-04-01T15:25:45+00:00","versionOfRecord":[],"versionCreatedAt":"2026-03-18 08:39:20","video":"","vorDoi":"","vorDoiUrl":"","workflowStages":[]},"version":"v1","identity":"rs-9104169","journalConfig":"researchsquare"},"__N_SSP":true},"page":"/article/[identity]/[[...version]]","query":{"redirect":"/article/rs-9104169","identity":"rs-9104169","version":["v1"]},"buildId":"XKTyCvWXoU3ODBz1xrDgd","isFallback":false,"isExperimentalCompile":false,"dynamicIds":[84888],"gssp":true,"scriptLoader":[]}