Protein S levels and the risk of venous thrombosis: results from the MEGA case-control study

In thrombophilic families, protein S deficiency is clearly associated with venous thrombosis. We aimed to determine whether the same holds true in a population-based case-control study (n=5317). Subjects were regarded protein S deficient when protein S levels were <2.5th percentile of the controls. Free- and total protein S deficiency was not associated with venous thrombosis: free protein S <53 U/dL, odds ratio [OR] 0.82 (95%CI, 0.56-1.21) and total protein S <68 U/dL, OR 0.90 (95%CI, 0.62-1.31). When lower cut-off values were applied, it appeared that subjects at risk of venous thrombosis could be identified at levels <0.10th percentile of free protein S (<33 U/dL, OR 5.4; 95% CI, 0.61-48.8). In contrast, even extremely low total protein S levels were not associated with venous thrombosis. PROS1 was sequenced in 48 subjects with free protein S level <1st percentile (<46 U/dL), and copy number variations were investigated in 2718 subjects, including all subjects with protein S (free or total) <2.5th percentile. Mutations in PROS1 were detected in five patients and five controls reinforcing the observation that inherited protein S deficiency is rare in the general population. Protein S testing and PROS1 testing should not be considered in unselected patients with venous thrombosis.