Thrombin in complex with dabigatran can still interact with PAR-1 via exosite-I and instigate loss of vascular integrity

S.C. Dolleman, S.M. Agten, H.M.H. Spronk, T.M. Hackeng, M.H.A. Bos, H.H. Versteeg, A.J. van Zonneveld, H.C. de Boer*

*Corresponding author for this work

Research output: Contribution to journalArticleAcademicpeer-review

Abstract

Background Atrial fibrillation (AF) can lead to the loss of microvascular integrity thereby enhancing AF progression. Mechanistically, the pro-coagulant state that drives the risk of stroke in patients with AF may also play a causal role in microvascular loss. Direct oral anticoagulants (DOACs), the preferred anticoagulants for AF, can target factors upstream (factor Xa [FXa]) or downstream (thrombin) in the coagulation cascade and mediate differential vascular effects through interaction with protease-activated receptors (PARs). Objective To investigate the potential effect of different DOACs on vascular integrity. Methods To model the impact of DOACs on vascular integrity, we utilized platelet-free plasma in thrombin generation assays and endothelial barrier assays under identical experimental conditions. These multifactorial systems provide all coagulation factors and their respective natural inhibitors in physiological ratios in combination with the pro-coagulant endothelial surface on which coagulation is initiated. Furthermore, the system provides pro- and anti-barrier factors and monitoring both assays simultaneously permits coupling of thrombin kinetics to endothelial barrier dynamics. Results We provide evidence that the anti-FXa DOAC rivaroxaban and the anti-thrombin DOAC dabigatran are efficient in blocking their target proteases. However, while rivaroxaban could preserve endothelial barrier function, dabigatran failed to protect endothelial integrity over time, which could be prevented in the presence of a custom-made peptide that blocks thrombin's exosite-I. Conclusions Proteolytically inactive thrombin in complex with dabigatran evokes loss of barrier function that can be prevented by a protease-activated receptor-1 mimicking peptide blocking thrombin's exosite-I.
Original languageEnglish
Pages (from-to)996-1007
Number of pages12
JournalJournal of Thrombosis and Haemostasis
Volume20
Issue number4
Early online date2 Feb 2022
DOIs
Publication statusPublished - Apr 2022

Keywords

  • anticoagulant drugs
  • atrial fibrillation
  • coagulation
  • direct thrombin inhibitors
  • endothelium
  • TISSUE FACTOR
  • ENDOTHELIAL-CELLS
  • RECEPTOR
  • PATHWAY
  • HYPERCOAGULABILITY
  • INFLAMMATION
  • ACTIVATION
  • EXPRESSION
  • RELEASE

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