Association of Agent Orange and myeloproliferative neoplasms, thrombosis, and bleeding among veterans.
Authors: Tiu Andrew Chua , McKinnell Zoe , Liu Shanshan , Diao Guoqing , Gill Puneet , Srinivasa Nandan , Shancer Zoe , Antonio Martha , Subrahmanyam Ramesh , Jain Maneesh Rajiv 
Published: June 2023

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Background: The Myeloproliferative Neoplasms (MPNs) which include Polycythemia Vera (PV), Essential Thrombocythemia (ET), and Primary Myelofibrosis (MF) are acquired stem cell disorders with constitutively activated pathways from shared mutations leading to thrombotic and bleeding complications. Agent Orange (AO) is a chemical herbicide that was utilized during the Vietnam War and was associated with sarcomas and B-cell lymphomas. There is inadequate evidence of the association between AO exposure and development of MPNs, increased risk of bleeding, arterial thrombosis (AT), and venous thrombosis (VT). Methods: Utilizing the Veterans Affairs Informatics and Computing Infrastructure (VINCI) database, we performed a case control study from January 1, 2006 - January 26, 2023. We utilized ICD-9 and 10 codes to identify MPN patients, any AT, VT, and bleeding events. Age-matched controls (1:1) were selected from VINCI database. Qualitative data was compared by chi-square test. Results: We included all 95,768 MPN patients (0.7% MPN crude prevalence rate), 43,263 ET, 48,854 PV, and 3,651 MF patients. Among all MPNs, 6.4% were female, 93.6% were male, 76% were White, 13.8% Black, 0.8% American Indian, 0.9% Pacific Islander, and 8.5% unknown race. 86.8% of patients with MPN were aged 60 years or older. When comparing MPNs vs. controls, there was increased AT (29.5% vs. 24.5%, p < 0.0001), VT (6.7% vs. 3.8%, p < 0.0001), and both AT & VT (8.1% vs. 4.2%, p < 0.0001). Among female MPN patients, there were 16.2% AT, 6.1% VT, 45.5% bleeding events vs. 30.4% AT, 6.7% VT, and 39% bleeding events among male MPN patients, respectively, p < 0.0001. Among MPN patients who are greater than 60 years old, 95.4% had AT, 88% had VT, 94.4% had both AT & VT, and 89.4% had bleeding events. Bleeding events were higher in ET (44%), PMF (41.5%), PV (35%) vs. the control group (24.6%), p < 0.0001, and gastrointestinal bleeding was the most common site for both controls and MPNs followed by genitourinary or pulmonary. Among the different races, there is higher AT (range 22.6-31.5%) compared to VT (range 5.3-7.8%). There is a significant association between AO exposure and development of MPNs (odds ratio 1.61, 95% CI 1.57 to 1.65, p < 0.0001). There is a higher AT (36%) among MPNs with AO exposure compared to 28.2% in MPNs without AO exposure, p < 0.0001. There is a higher AT (28.7%) among controls with AO exposure compared to 24% in controls without AO exposure, p < 0.0001. There was 41.2% bleeding event with MPN with AO exposure compared to 39% in MPN without AO exposure, p < 0.0001. Conclusions: This is the largest database evaluating MPNs, thrombosis, and bleeding in veterans exposed to AO. There is an association of increased risk of development of MPNs, increased AT, and increased bleeding with AO exposure. Further studies including JAK2 mutation, CHIPs, and cardiovascular risk factors will be needed to evaluate contribution to thrombosis and bleeding risk.