Protein S and Risk for Venous Thrombosis

Protein S circulates freely or binds to complement-binding protein; only the free form inhibits coagulation, functioning as the cofactor for both protein C and the tissue-factor pathway inhibitor. Traditionally, thrombophilia testing panels for patients with unprovoked venous thrombosis (VT) have included proteins S and C, factor V Leiden, prothrombin G20210A, and antithrombin.

To determine whether free protein S deficiency is a risk factor for thrombosis, investigators in the Netherlands measured free and bound protein S in more than 2300 patients 3 or more months after a first VT and in age and gender-matched controls. Patients were enrolled in the prior population-based, case-control MEGA study (JAMA 2005; 293:715).

Patients with levels of free protein S and total protein S that were less than levels in the 2.5th percentile of controls were not at increased risk for thrombosis: odds ratios, 0.82 (95% confidence interval, 0.56–1.21) and 0.92 (95% CI, 0.63–1.33), respectively. After excluding patients who were pregnant, postpartum, or estrogen users, the ORs were 1.51 (95% CI, 0.82–2.78) and 1.34 (95% CI, 0.74–2.44). If free protein S was <0.10th percentile, the OR was higher, but not significantly so (OR, 5.4; 95% CI, 0.61–48.8), and even very low levels of total protein S were not associated with VT. Furthermore, ORs were not significantly increased when the analysis was confined to patients with a family history of VT. Gene sequencing in the 48 participants with the lowest free protein S levels disclosed mutations in the protein S gene in five patients but also in five controls without VT, indicating that some mutations in this gene are incidental and not detrimental.