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Protein S as cofactor for TFPI

Tilman M Hackeng1, Jan Rosing

  • 1Department of Biochemistry, Cardiovascular Research Institute Maastricht, University Maastricht, Maastricht, The Netherlands.

Arteriosclerosis, Thrombosis, and Vascular Biology
|August 8, 2009
PubMed

Insights

Protein S exhibits anticoagulant activity independently of activated protein C (APC). It functions as a cofactor for tissue factor pathway inhibitor (TFPI), enhancing the inhibition of factor Xa, particularly under low procoagulant conditions.

Area of Science:

  • Biochemistry
  • Hematology
  • Molecular Biology

Background:

  • Protein S traditionally known as a cofactor for activated protein C (APC) in coagulation regulation.
  • Emerging evidence suggests APC-independent anticoagulant functions of protein S.
  • Distinguishing between APC-dependent and independent activities has been challenging due to complex mechanisms.

Purpose of the Study:

  • To elucidate the mechanisms behind protein S's APC-independent anticoagulant activity.
  • To differentiate between observed activities in model systems versus plasma.
  • To identify the specific molecular interactions mediating protein S's anticoagulant effects.

Main Methods:

  • Analysis of protein S activity in phospholipid-dependent model systems.
  • Investigation of protein S anticoagulant function in plasma.
  • Assays to determine the role of protein S in the tissue factor pathway inhibitor (TFPI) system.

Main Results:

  • APC-independent activity in model systems attributed to protein S multimers inhibiting phospholipid binding.
  • In plasma, protein S's anticoagulant activity is independent of phospholipid concentration but dependent on tissue factor (TF) levels.
  • Protein S identified as a cofactor for TFPI, enhancing the inhibition of factor Xa by approximately 10-fold.

Conclusions:

  • Protein S possesses a distinct APC-independent anticoagulant function mediated by its role as a TFPI cofactor.
  • This TFPI/protein S system is particularly effective in inhibiting the tissue factor pathway under conditions of low procoagulant stimuli.
  • Understanding this pathway offers new insights into hemostasis and potential therapeutic targets.

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