Activated protein C, protein S, and tissue factor pathway inhibitor cooperate to inhibit thrombin activation

Xian Li, Xiaohong Song, Dlovan F.D. Mahmood, Martha M.S. Sim, Sara J. Bidarian, Jeremy P. Wood

Research output: Contribution to journalArticlepeer-review

3 Scopus citations

Abstract

Introduction: Thrombin, the enzyme which converts fibrinogen into a fibrin clot, is produced by the prothrombinase complex, composed of factor Xa (FXa) and factor Va (FVa). Down-regulation of this process is critical, as excess thrombin can lead to life-threatening thrombotic events. FXa and FVa are inhibited by the anticoagulants tissue factor pathway inhibitor alpha (TFPIα) and activated protein C (APC), respectively, and their common cofactor protein S (PS). However, prothrombinase is resistant to either of these inhibitory systems in isolation. Materials and methods: We hypothesized that these anticoagulants function best together, and tested this hypothesis using purified proteins and plasma-based systems. Results: In plasma, TFPIα had greater anticoagulant activity in the presence of APC and PS, maximum PS activity required both TFPIα and APC, and antibodies against TFPI and APC had an additive procoagulant effect, which was mimicked by an antibody against PS alone. In purified protein systems, TFPIα dose-dependently inhibited thrombin activation by prothrombinase, but only in the presence of APC, and this activity was enhanced by PS. Conversely, FXa protected FVa from cleavage by APC, even in the presence of PS, and TFPIα reversed this protection. However, prothrombinase assembled on platelets was still protected from inhibition, even in the presence of TFPIα, APC, and PS. Conclusions: We propose a model of prothrombinase inhibition through combined targeting of both FXa and FVa, and that this mechanism enables down-regulation of thrombin activation outside of a platelet clot. Platelets protect prothrombinase from inhibition, however, supporting a procoagulant environment within the clot.

Original languageEnglish
Pages (from-to)84-93
Number of pages10
JournalThrombosis Research
Volume230
DOIs
StatePublished - Oct 2023

Bibliographical note

Publisher Copyright:
© 2023 Elsevier Ltd

Keywords

  • Platelet
  • Protein C
  • Protein S
  • Prothrombinase
  • TFPI
  • Thrombin

ASJC Scopus subject areas

  • Hematology

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