Abstract Background Cerebral venous thrombosis is a rare form of stroke predominantly affecting young women and is associated with a 6–15% risk of death or long-term dependency. We investigated the impact of age, sex, and genetic risk factors on cerebral venous thrombosis onset, clinical severity, and long-term outcomes among individuals of European ancestry. Methods The BEAST (Biorepository to Establish the Aetiology of Sinovenous Thrombosis) study is an international, prospective, observational cohort that enrolled 1309 adult cerebral venous thrombosis patients from 11 countries (United Kingdom, United States of America, Mexico, and European nations). Genetic analyses assessed associations with factor VIII concentrations and cerebral venous thrombosis risk. Clinical predictors of coma and poor long-term outcomes were identified using logistic regression and non-parametric neural network models. Additionally, a meta-analysis of 25 studies comprising 2301 patients was conducted to compare the long-term (≥ 6 months) safety and efficacy of direct oral anticoagulants and warfarin in cerebral venous thrombosis management. Results Women developed cerebral venous thrombosis ~9 years earlier than men, whilst individuals with ≥2 identifiable risk factor experienced cerebral venous thrombosis onset ~12 years earlier than those without risk factors. Amongst patients aged 45 years or older, malignancy was associated with a 3.6-fold increased risk of cerebral venous thrombosis (OR 3.6; 95% CI: 1.4–9.0; P = 0.006). Genetic analyses identified five PROC (protein C) single nucleotide polymorphisms (rs1799810, rs41280570, rs1158867, rs2069919, rs5937) as novel genetic determinants, each conferring an approximately 1.3-fold increased risk of cerebral venous thrombosis in individuals of European ancestry. Strong linkage disequilibrium amongst these variants implicated rs1799810 in the 5’ UTR promoter region as a functional single nucleotide polymorphisms. Elevated factor VIII concentrations (≥150 IU/dL), an X-linked inherited trait, were associated with an approximately 8-fold increased risk of superior sagittal sinus thrombosis in men and a 2-fold increased risk in women. Although cerebral venous thrombosis was more prevalent in women, men exhibited a 2-fold higher risk of coma. The meta-analysis demonstrated comparable safety and efficacy between direct oral anticoagulants and warfarin, with similar rates of favourable clinical outcomes, intracranial haemorrhage, all-cause mortality, non-recanalisation, and recurrent venous thrombosis. Conclusions Protein C variants, particularly rs1799810, and elevated factor VIII concentrations are significant genetic determinants of cerebral venous thrombosis risk amongst Europeans, with distinct sex-specific effects. Whilst direct oral anticoagulants and warfarin demonstrate equivalent long-term efficacy and safety, direct oral anticoagulants offer practical advantages through simplified clinical management.
Ranjan et al. (2026) studied this question.