Elevated levels of factor VIII and subsequent risk of all‐cause mortality: results from the MEGA follow‐up study

Background Factor VIII (FVIII) levels are increased in individuals with a non‐O blood group and play a role in the etiology of thrombosis. High FVIII levels have also been associated with increased all‐cause mortality. Objective We explored whether elevated FVIII levels are associated with an increased risk of death in patients who had venous thrombosis and in individuals from the general population, and to what extent this association is causal. Methods We followed 2178 patients with previous venous thrombosis and 2827 age and sex‐matched community controls for on average 5.5 years and measured their FVIII levels and ABO blood group. Results All‐cause mortality increased in a dose‐response fashion with increasing percentiles of FVIII levels. In the thrombosis patients the risk was highest above the 97.5th percentile (FVIII > 199 IU dL−1) with an adjusted hazard ratio (HR) of 3.1 (95% confidence interval [CI], 0.9–10.8) as compared with patients in the 25th percentile category (FVIII ≤ 85 IU dL−1). The adjusted HR was 4.5 (95% CI, 1.4–14.3) in controls. Using non‐O blood group as a measure of genetically elevated FVIII levels to determine a causal relationship between FVIII and death showed observed HRs of 0.99 (95% CI, 0.72–1.36) in patients and 1.25 (95% CI, 0.82–1.90) in controls. Conclusions We showed a dose‐response relationship between high FVIII levels and risk of death in venous thrombosis patients and in individuals from the general population. However, environmental factors, such as chronic comorbidities and chronic inflammation, are at least in part responsible for the association between factor VIII and mortality.