The role of SERPIN citrullination in thrombosis

Cell Chem Biol. 2021 Dec 16;28(12):1728-1739.e5. doi: 10.1016/j.chembiol.2021.07.009. Epub 2021 Aug 4.


Aberrant protein citrullination is associated with many pathologies; however, the specific effects of this modification remain unknown. We have previously demonstrated that serine protease inhibitors (SERPINs) are highly citrullinated in rheumatoid arthritis (RA) patients. These citrullinated SERPINs include antithrombin, antiplasmin, and t-PAI, which regulate the coagulation and fibrinolysis cascades. Notably, citrullination eliminates their inhibitory activity. Here, we demonstrate that citrullination of antithrombin and t-PAI impairs their binding to their cognate proteases. By contrast, citrullination converts antiplasmin into a substrate. We recapitulate the effects of SERPIN citrullination using in vitro plasma clotting and fibrinolysis assays. Moreover, we show that citrullinated antithrombin and antiplasmin are increased and decreased in a deep vein thrombosis (DVT) model, accounting for how SERPIN citrullination shifts the equilibrium toward thrombus formation. These data provide a direct link between increased citrullination and the risk of thrombosis in autoimmunity and indicate that aberrant SERPIN citrullination promotes pathological thrombus formation.

Keywords: citrullination; deep vein thrombosis; rheumatoid arthritis; serine protease inhibitors.

Publication types

  • Research Support, N.I.H., Extramural

MeSH terms

  • Animals
  • Antifibrinolytic Agents / chemistry
  • Antifibrinolytic Agents / pharmacology*
  • Antithrombins / chemistry
  • Antithrombins / pharmacology*
  • Disease Models, Animal
  • Female
  • Male
  • Mice
  • Mice, Inbred C57BL
  • Peptide Hydrolases / metabolism
  • Plasminogen Inactivators / chemistry
  • Plasminogen Inactivators / pharmacology*
  • Serine Proteinase Inhibitors / chemistry
  • Serine Proteinase Inhibitors / pharmacology*
  • Venous Thrombosis / drug therapy*
  • Venous Thrombosis / metabolism


  • Antifibrinolytic Agents
  • Antithrombins
  • Plasminogen Inactivators
  • Serine Proteinase Inhibitors
  • Peptide Hydrolases