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 (similar to40% 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 proteinbound protein S. Although these physiologic roles are truly dichotomous in terms of functional end point, mechanistically, both involve high-affinity membrane binding to phosphatidylserinebearing surfaces. This binding is mediated by the N-terminal,gamma-carboxyglutamic acid-rich domain of this protein.