High Levels of Coagulation Factor XI as a Risk Factor for Venous Thrombosis

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Abstract
Factor XI, a component of the intrinsic pathway of coagulation, contributes to the generation of thrombin, which is involved in both the formation of fibrin and protection against fibrinolysis. A deficiency of factor XI is associated with bleeding, but a role of high factor XI levels in thrombosis has not been investigated. We determined factor XI antigen levels in the patients enrolled in the Leiden Thrombophilia Study, a large population-based, case–control study (with a total of 474 patients and 474 controls) designed to estimate the contributions of genetic and acquired factors to the risk of deep venous thrombosis. Odds ratios were calculated as a measure of relative risk. The age- and sex-adjusted odds ratio for deep venous thrombosis in subjects who had factor XI levels above the 90th percentile, as compared with those who had factor XI levels at or below that value, was 2.2 (95 percent confidence interval, 1.5 to 3.2). There was a dose–response relation between the factor XI level and the risk of venous thrombosis. Adjustment of the odds ratios for other risk factors such as oral-contraceptive use, homocysteine, fibrinogen, factor VIII, female sex, and older age did not alter the result. Also, when we excluded subjects who had known genetic risk factors for thrombosis (e.g., protein C or S deficiency, antithrombin deficiency, the factor V Leiden mutation, or the prothrombin G20210A mutation), the odds ratio remained the same, indicating that the risk of venous thrombosis associated with elevated levels of factor XI was not the result of one of the known risk factors for thrombosis. High levels of factor XI are a risk factor for deep venous thrombosis, with a doubling of the risk at levels that are present in 10 percent of the population.