The impact of PROS1 mutation position on thrombotic risk in protein S-deficient patients

Inherited protein S deficiency is a thrombophilic risk factor associated with venous thromboembolism. However, there is not much data on the impact of mutation position on thrombotic risk.

The aim of this study was to evaluate the risk of thrombosis due to mutations located in the sex hormone-binding globulin (SHBG)-like region as opposed to the rest of the protein.

Genetic analysis of PROS1 was performed in 76 patients with suspected inherited protein S deficiency, and the effect of missense mutations present in the SHBG region on thrombosis risk was analyzed by statistical methods.

We found 30 unique mutations (13 of them novel), of which 17 were missense mutations, in 70 patients. Patients with missense mutations were then divided into 2 groups: the "SHBG-region" mutation group (27 patients) and the "non-SHBG" group (24 patients). The multivariable binary logistic regression analysis showed that mutation position in the SHBG region of protein S is an independent risk factor for thrombosis in deficient patients (OR, 5.17; 95% CI, 1.29-20.65; P = .02). The patients with a mutation in the SHBG-like region also developed a thrombotic event at a younger age compared to the "non-SHBG" group in the Kaplan-Meier analysis (median thrombosis-free survival of 33 vs 47 years, respectively; P = .018).

Our findings show that a missense mutation located in the SHBG-like region may contribute to higher thrombotic risk rather than a missense mutation located elsewhere in the protein. However, as our cohort was relatively small, these findings should be taken with this limitation.