Protein S deficiency and novel oral anticoagulants: an intriguing case.

Vitamin K dependent protein S (ProS) is a plasma glycoprotein with anticoagulant properties [1]. Its anticoagulant function is well established in the literature based on clinical data, its genetics and on laboratory assays. ProS is able to prolong the clotting time acting as a cofactor for activated protein C. Furthermore, since the 1980’ies it is known that hereditary ProS deficiency (PSD) increases the risk of venous thrombosis in families with hereditary thrombophilia [2], later found to be mostly caused by mutations in its coding gene, PROS1. Indeed, mutations in PROS1 have been shown to confer more than a 7-fold increased risk of thrombosis in selected families with PSD [3]. The recent establishment of mice strains with mutations in Pros1 has emphasized the importance of ProS as a pleiotropic anticoagulant in vivo [4,5]. Nevertheless, although the view of ProS as an essential natural anticoagulant is well-grounded, we could consider that ProS is one of the components of the coagulation cascade that has brought more surprising discoveries in recent years. The seminal work by Dahlbäck demonstrating that ProS interacted with high affinity with the complement regulator C4b-binding protein (C4BP) and that a highmolecular weight 1:1 ProS-C4BP complex was present in human plasma [6], was an early basis for the concept of hemostasis and inflammation as parts of a global response to damage, which has led to the present concept of thromboinflammation [7]. The C4BP-ProS complex has implications in PSD, which has been classified in three categories: type I corresponding to concentrations of total ProS antigen below the normal range (quantitative deficiency), type II being normal levels of a ProS with low activity (qualitative deficiency) and type III corresponding to a specific quantitative deficiency of free, uncomplexed ProS in plasma despite levels of total ProS antigen inside the normal range [1,8]. More recently, the discovery of ProS and GAS6 as ligands of receptor tyrosine kinases and the discovery of its growth-factor like properties have brought new functional horizons to ProS, including its important implication in apoptotic cell removal (efferocytosis) and “taming” of inflammatory reactions [4,8,9,10]. Its role as an anticoagulant has also been revised by the suggestion of newmechanisms, including the binding and effect of Zn ions [11] and the ProS-dependent inhibition of factor Xa by TFPI [12]. From these studies, an antithrombotic activity of ProS that is independent of the action on activated protein C has been proposed and corroborated by in vivo studies in mice [4] and primates [13]. The study of the molecular basis of PSD has also provided some surprises. Studies of thrombophilia in different geographical areas have found that the incidence and type of PSD is very heterogeneous among populations [14]. In families with hereditary PSD where the traditional sequence technology failed to find a causativemutation, the use of new genetic screening techniques have discovered a relatively high frequency of small and large deletions in or close to the PROS1 locus