Inhibition of thrombin generation by protein S at low procoagulant stimuli: implications for maintenance of the hemostatic balance

• Published in: Blood 2004-12, Vol.104 (12), p.3624-3630
• Main Authors: Seré, Kristin M., Rosing, Jan, Hackeng, Tilman M.
• Format: Article
• Language: English
• Subjects: Adult; Biological and medical sciences; Blood Coagulation - drug effects; Blood coagulation. Blood cells; Dose-Response Relationship, Drug; Female; Fundamental and applied biological sciences. Psychology; General aspects, investigation methods, hemostasis, fibrinolysis; Hemostasis - drug effects; Humans; Male; Middle Aged; Molecular and cellular biology; Phospholipids - pharmacology; Plasma; Protein C - pharmacology; Protein S - pharmacology; Thrombin - antagonists & inhibitors; Thrombin - biosynthesis; Thrombomodulin; Thromboplastin - pharmacology
• ISSN: 0006-4971; 1528-0020
• DOI: 10.1182/blood-2004-03-1146

The activated protein C (APC)–independent anticoagulant activity of protein S on tissue factor–induced thrombin generation was quantified in plasma. In absence of APC, protein S significantly decreased the endogenous thrombin potential (ETP) in a concentration-dependent manner. The APC-independent anticoagulant activity of protein S in plasma was not affected by phospholipid concentrations but strongly depended on tissue factor concentrations: protein S inhibited the ETP from 6% at 140 pM tissue factor to 74% at 1.4 pM tissue factor. Plasma with both 60% protein S and 140% prothrombin showed an ETP of 240% compared to normal plasma, suggesting an APC-independent protective role of protein S in the development of thrombosis as a result of protein S deficiency and the prothrombin-G20210A mutation. At high tissue-factor concentrations, protein S hardly expressed APC-independent anticoagulant activity but exerted potent APC-cofactor activity when thrombomodulin or APC were added to plasma. Neutralization of protein S under these conditions resulted in a 20-fold reduction of the anticoagulant activity of APC. The present study shows that protein S effectively regulates coagulation at 2 levels: at low procoagulant stimuli, protein S maintains the hemostatic balance by directly inhibiting thrombin formation, and at high procoagulant stimuli, protein S restores the hemostatic balance via its APC-cofactor activity.