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Protein S: a conduit between anticoagulation and inflammation
Alan C Rigby1, Marianne A Grant
1Center for Hemostasis, Thrombosis, and Vascular Biology, Beth Israel Deaconess Medical Center, and the Department of Medicine, Harvard Medical School, Boston, MA 02115, USA. arigby@bidmc.harvard.edu
Critical Care Medicine
|May 1, 2004
Summary
Protein S plays dual roles in anticoagulation and inflammation. Both free and C4b-binding protein-bound protein S are crucial, binding to phosphatidylserine-rich surfaces via its gamma-carboxyglutamic acid-rich domain.
Area of Science:
- Biochemistry
- Hematology
- Immunology
Background:
- Protein S is a key regulator of the protein C anticoagulant pathway, crucial for preventing excessive thrombin generation.
- Its anticoagulant activity is modulated by plasma concentration, with free protein S (approx. 40%) being active, while bound protein S (approx. 60%) to C4b-binding protein is inactive.
- Recent studies highlight novel functions of protein S independent of activated protein C, particularly when bound to C4b-binding protein.
Purpose of the Study:
- To review the diverse functions of anticoagulant protein S.
- To elucidate its roles in both anticoagulation and inflammation pathways.
- To understand the interplay between these pathological states.
Main Methods:
- Comprehensive literature review of original research and review articles.
- Articles sourced from PubMed, published in English within the last 30 years.
- Focus on studies investigating protein S, protein C pathway, and inflammation.
Main Results:
- Protein S exhibits anticoagulant activity, acting as a cofactor for activated protein C in factor Va and factor VIIIa inactivation.
- The binding of protein S to C4b-binding protein limits its anticoagulant function but is essential for other roles.
- Emerging evidence indicates activated protein C-independent functions for protein S, especially when complexed with C4b-binding protein.
Conclusions:
- Protein S is integral to both anticoagulation and inflammation processes.
- Both free and C4b-binding protein-bound forms of protein S are physiologically significant.
- The dichotomous functions of protein S mechanistically involve high-affinity membrane binding to phosphatidylserine-rich surfaces via its gamma-carboxyglutamic acid-rich domain.