Protein S: A conduit between anticoagulation and inflammation

OBJECTIVE:To review the multifaceted roles of the anticoagulant protein S, facilitating a better comprehension of this protein’s role in anticoagulation and inflammation pathways and the crosstalk between these pathologic states. DATA SOURCES AND STUDY SELECTION:Original research and review articles published in English pertaining to protein S, sourced from PubMed, during the last 30 yrs. DATA EXTRACTION AND SYNTHESIS:The protein C anticoagulant pathway is an essential mechanism for attenuating thrombin generation by the membrane-bound procoagulant complexes, tenase and prothrombinase. Protein S is a nonenzymatic protein. In the absence of activated protein C, it demonstrates anticoagulant activity; in the presence of activated protein C, it functions as a cofactor for activated protein C– dependent proteolytic inactivation of the coagulation cofactors factor Va and factor VIIIa. However, in plasma, these anticoagulant activities are limited by the concentration of free protein S (~40% of the total protein S plasma concentration). The remaining protein S (~60%) is found in a high-affinity, calcium-stabilized complex with C4b-binding protein, which renders this fraction devoid of anticoagulant function. Several recent investigations have attributed novel activated protein C–independent functions of protein S to the association of protein S with C4b-binding protein, thus establishing the importance of this fraction of plasma protein S. CONCLUSIONS:Together, these data support a role for protein S in both anticoagulation and inflammation, facilitating a better understanding of the need for both free and C4b-binding protein–bound protein S. Although these physiologic roles are truly dichotomous in terms of functional end point, mechanistically, both involve high-affinity membrane binding to phosphatidylserine-bearing surfaces. This binding is mediated by the n-terminal γ-carboxyglutamic acid-rich domain of this protein.