Protein S inherited qualitative deficiency: novel mutations and phenotypic influence

Summary.  Background:  Only a few mutations associated with qualitative protein S deficiency have already been described. Sensitivity and specificity for type II PROS1 mutations of commercially available reagents for measuring Protein S (PS) activity are not well established. Whether these mutations are significant risk factors for thrombosis remains an unresolved question. Methods:  In order to address the first point, we present and discuss the results of PROS1 analysis performed in the 30 probands with type II PS‐inherited deficiency suspicion and 35 relatives, studied in our laboratory between 2000 and 2008. In order to investigate the influence of type II mutations on the coagulability level, thrombin generation tests were performed on plasma from 102 PROS1 type II, type I/III or PS Herleen mutation heterozygous carriers and controls. Results:  Mutations (12 novel, six already described) which probably explain the qualitative phenotype, were found in 27 (90%) out of the 30 probands studied. In relatives, 78% of heterozygotes presented with a type II phenotype. An APC resistance phenotype was documented in type II and type I/III defects heterozygous carriers; however, the effect of type II was milder than the effect of type I/III PS mutations. Conclusions: A PS functional assay (Staclot PS, Stago) was efficient in screening for PROS1 type II defects, particularly in probands. A significant positive influence of type II mutations on ex vivo thrombin generation was demonstrated. However, whether these mutations increase the risk of venous thromboembolism requires further investigation.