Inhibition of thrombin generation by protein S at low procoagulant stimuli: implications for maintenance of the hemostatic balance.
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.
Department of Biochemistry, Cardiovascular Research Institute Maastricht, University Maastricht, 6200 MD Maastricht, the Netherlands.
Kristin M
KM
Seré
Jan
J
Rosing
Tilman M
TM
Hackeng
D000328:Adult; D001777:Blood Coagulation / Q000187:drug effects; D004305:Dose-Response Relationship, Drug; D005260:Female; D006487:Hemostasis / Q000187:drug effects*; D006801:Humans; D008297:Male; D008875:Middle Aged; D010743:Phospholipids / Q000494:pharmacology; D010949:Plasma; D011486:Protein C / Q000494:pharmacology; D017293:Protein S / Q000494:pharmacology*; D013917:Thrombin / Q000037:antagonists & inhibitors* / Q000096:biosynthesis; D018180:Thrombomodulin; D013925:Thromboplastin / Q000494:pharmacology
D010743:Phospholipids; D011486:Protein C; D017293:Protein S; D018180:Thrombomodulin; D013925:Thromboplastin; D013917:Thrombin