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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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Submitted March 30, 2004
Accepted July 13, 2004
Inhibition of thrombin generation by protein S at low procoagulant stimuli: implications for maintenance of the haemostatic balance
Kristin M Sere, Jan Rosing, and Tilman M Hackeng*
Department of Biochemistry, Cardiovascular Research Institute Maastricht, University Maastricht, The Netherlands
* Corresponding author; email: t.hackeng{at}bioch.unimaas.nl.
The 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 two levels: at low procoagulant stimuli protein S maintains the haemostatic balance by directly inhibiting thrombin formation, and at high procoagulant stimuli protein S restores the haemostatic balance via its APC-cofactor activity.
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