Anticoagulant protein S—New insights on interactions and functions

Abstract

Protein S was first isolated and characterized in 1977 and since then it has been suggested to have important functions in a range of processes. 1 These include participation in regulation of coagulation; cell proliferation;, apoptosis; and regulation of inflammation, atherosclerosis, and vasculogenesis. 2,3 For many years, though, it was mainly considered important as a cofactor in the activated protein C (APC) pathway, where it enhances the ability of APC to inactivate coagulation factors (F) Va and VIIIa (Figure 1). 4,5 However, protein S was relatively soon discovered to also have important APCindependent anticoagulant functions through directly inhibiting the intrinsic tenase and prothrombinase complexes. 6-8 This was followed by the discovery of protein S functioning as a cofactor in the tissue factor pathway inhibitor (TFPI) pathway, in which it enhances both the inhibition of FXa generation by TF-FVIIa and the direct inhibition of FXa activity by TFPIα. 9,10 Both APC and TFPIα are highly dependent on protein S for efficient regulation of coagulation. The clinical importance of protein S is evident by the increased thrombotic risk associated with all types of its deficiency. 11 Homozygous mutations

Pleiotropic anticoagulant functions of protein S, consequences for the clinical laboratory. Communication from the SSC of the ISTH

“…The high affinity of PS toward negatively charged phospholipid membranes is essential for its APCcofactor function. 1 In fact, PS has been shown to enhance the binding of APC to phospholipids, an effect that is even more pronounced in the presence of FVa. 11…”

“…In turn, PS, by virtue of its high affinity for negatively charged phospholipid surfaces, may be instrumental in the complement system by localizing C4BP on the surface of apoptotic cells. 1 C4BP interacts with the SHBG-like region of PS 32 ( Figure 1C) and inhibits the TFPIα-cofactor activity of PS 14 as well as the cofactor activity of PS in the inactivation of FVa by APC. 33 Interestingly, C4BP inhibited the FV-dependent but not the FV-independent cofactor activity of PS in the APC-mediated inactivation of FVIIIa.…”

“…45 However, while many of the interaction sites involved in the two pathways are different, it is possible that some pleiotropic effects may still exist. For example, Gla-domain-mediated binding to phospholipids is involved in both APC-and TFPIα-dependent cofactor activities of protein S. 1,4 Thus, a qualitative PS defect may selectively decrease the APC-or the TFPIα-cofactor activity of PS, or pleiotropically affect both. In recognition of this, it seems adequate to propose an adjustment of the current classification (Table 1) Sweden (bjorn.dahlback@med.lu.se).…”

“…The most studied function of PS is its role as a cofactor of APC in the protein C pathway. APC regulates the activities of the prothrombinase complex (FXa and FVa assembled on negatively charged phospholipids) and tenase complex (activated factor IX [FIXa] and FVIIIa bound to negatively charged phospholipids) via proteolytic inactivation of their essential cofactors FVa and FVIIIa (reviewed in Gierula and Ahnström 1 ). PS contributes to this regulation by stimulating the inactivation of both cofactors.…”

“…Although the SHBG‐like region of PS is involved in its APC‐cofactor activity, 7 the direct interaction with APC most likely involves PS residues located in the TSR and EGF1 and EGF2 domains 8‐10 (Figure 1C). The high affinity of PS toward negatively charged phospholipid membranes is essential for its APC‐cofactor function 1 . In fact, PS has been shown to enhance the binding of APC to phospholipids, an effect that is even more pronounced in the presence of FVa 11 …”