The role of SERPIN citrullination in thrombosis

Ronak Tilvawala, Venkatesh V. Nemmara, Archie C. Reyes, Nicoletta Sorvillo, Ari J. Salinger, Deya Cherpokova, Saeko Fukui, Sarah Gutch, Denisa Wagner, Paul R. Thompson

Research output: Contribution to journalArticlepeer-review

10 Scopus citations


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.

Original languageEnglish (US)
Pages (from-to)1728-1739.e5
JournalCell Chemical Biology
Issue number12
StatePublished - Dec 16 2021

All Science Journal Classification (ASJC) codes

  • Biochemistry
  • Molecular Medicine
  • Molecular Biology
  • Pharmacology
  • Drug Discovery
  • Clinical Biochemistry


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