BACKGROUND: Complement activation may contribute to venous thromboembolism, including deep venous thrombosis and pulmonary embolism. We tested the hypothesis that high complement C3 concentrations are associated with high risk of venous thromboembolism in the general population.

METHODS: We included 80 517 individuals without venous thromboembolism from the Copenhagen General Population Study recruited in 2003-2012. Plasma complement C3 concentrations were measured at baseline, and venous thromboembolism (n = 1176) was ascertained through April 2013 in nationwide registries. No individuals were lost to follow-up.

RESULTS: Complement C3 concentrations were approximately normally distributed, with a mean value of 1.13 g/L (interquartile range 0.98-1.26; SD 0.21). The cumulative incidence of venous thromboembolism was higher with progressively higher tertiles of complement C3 (log-rank trend: P = 3 × 10(-8)): at age 80, 7%, 9%, and 11% of individuals in the first, second, and third tertiles, respectively, had developed venous thromboembolism. Multivariable-adjusted hazard ratios for venous thromboembolism compared with individuals in the first tertile were 1.36 (95% CI, 1.16-1.59) for those in the second tertile and 1.58 (1.33-1.88) for those in the third tertile. Corresponding values were 1.36 (1.16-1.60) and 1.57 (1.33-1.87) after additional adjustment for C-reactive protein and 1.27 (1.09-1.49) and 1.31(1.10-1.57) after additional adjustment for body mass index. These results were similar for deep venous thrombosis and pulmonary embolism separately. The multivariable-adjusted hazard ratio for venous thromboembolism for a 1-g/L increase in complement C3 was 2.43 (1.74-3.40).

CONCLUSIONS: High concentrations of complement C3 were associated with high risk of venous thromboembolism in the general population.