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

• Published in: Blood Vol. 122; no. 18; pp. 3210 - 3219
• Main Authors: Pintao, Maria Carolina, Ribeiro, Daniel D., Bezemer, Irene D., Garcia, Andrea A., de Visser, Marieke C.H., Doggen, Carine J.M., Lijfering, Willem M., Reitsma, Pieter H., Rosendaal, Frits R.
• Format: Journal Article
• Language: English
• Published: United States Elsevier Inc 31.10.2013
• Subjects: Adult; Aged; Case-Control Studies; DNA Copy Number Variations; Female; Humans; Male; Middle Aged; Mutation; Odds Ratio; Protein S - genetics; Protein S - metabolism; Protein S Deficiency - blood; Protein S Deficiency - genetics; Protein S Deficiency - metabolism; Risk Assessment; Risk Factors; Sequence Analysis, DNA; Venous Thrombosis - blood; Venous Thrombosis - metabolism
• ISSN: 0006-4971; 1528-0020; 1528-0020
• DOI: 10.1182/blood-2013-04-499335

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% confidence interval [CI], 0.56-1.21) and total protein S < 68 U/dL, OR 0.90 (95% CI, 0.62-1.31). When lower cutoff 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 5 patients and 5 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. Key Points