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 Blood, 1 December 2004, Vol. 104, No. 12, pp. 3624-3630.
Prepublished online as a Blood First Edition Paper on August 3, 2004; DOI 10.1182/blood-2004-03-1146.

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HEMOSTASIS, THROMBOSIS, AND VASCULAR BIOLOGY

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

Kristin M. Seré, Jan Rosing, and Tilman M. Hackeng

From the Department of Biochemistry, Cardiovascular Research Institute Maastricht, University Maastricht, the Netherlands.

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.


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