title: Protein S levels and the risk of venous thrombosis: results from the MEGA case-control study.
abstract: 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 (< 4 6 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.
authors.affiliation: Einthoven Laboratory for Experimental Vascular Medicine.
authors.forename: Maria Carolina
authors.initials: MC
authors.lastname: Pintao
authors.forename: Daniel D
authors.initials: DD
authors.lastname: Ribeiro
authors.forename: Irene D
authors.initials: ID
authors.lastname: Bezemer
authors.forename: Andrea A
authors.initials: AA
authors.lastname: Garcia
authors.forename: Marieke C H
authors.initials: MC
authors.lastname: de Visser
authors.forename: Carine J M
authors.initials: CJ
authors.lastname: Doggen
authors.forename: Willem M
authors.initials: WM
authors.lastname: Lijfering
authors.forename: Pieter H
authors.initials: PH
authors.lastname: Reitsma
authors.forename: Frits R
authors.initials: FR
authors.lastname: Rosendaal
mesh_terms: D000328:Adult; D000368:Aged; D016022:Case-Control Studies; D056915:DNA Copy Number Variations; D005260:Female; D006801:Humans; D008297:Male; D008875:Middle Aged; D009154:Mutation; D016017:Odds Ratio; D017293:Protein S / Q000235:genetics / Q000378:metabolism*; D018455:Protein S Deficiency / Q000097:blood / Q000235:genetics / Q000378:metabolism*; D018570:Risk Assessment; D012307:Risk Factors; D017422:Sequence Analysis, DNA; D020246:Venous Thrombosis / Q000097:blood / Q000378:metabolism*
chemical_list: D017293:Protein S