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Thrombin in complex with dabigatran can still interact with PAR-1 via exosite-I and instigate loss of vascular
Sophie C Dólleman1, Stijn M Agten2, Henri M H Spronk2
1Department of Internal Medicine (Nephrology), Einthoven Laboratory for Vascular and Regenerative Medicine, Leiden, the Netherlands.
Insights
Direct oral anticoagulants (DOACs) impact vascular integrity differently. While rivaroxaban preserves endothelial barriers, dabigatran does not, suggesting distinct mechanisms of action for anticoagulants in atrial fibrillation (AF).
Area of Science:
- Cardiovascular Science
- Hematology
- Pharmacology
Background:
- Atrial fibrillation (AF) is linked to microvascular integrity loss, potentially driven by the pro-coagulant state associated with stroke risk.
- Direct oral anticoagulants (DOACs) are preferred for AF treatment, targeting factor Xa (FXa) or thrombin, with potential differential vascular effects via protease-activated receptors (PARs).
Purpose of the Study:
- To investigate the differential effects of various DOACs on vascular integrity.
- To understand the mechanistic basis for these differential effects on endothelial barrier function.
Main Methods:
- Utilized platelet-free plasma in thrombin generation and endothelial barrier assays under physiological conditions.
- Simultaneously monitored thrombin kinetics and endothelial barrier dynamics to link coagulation to barrier function.
- Assessed the impact of anti-FXa (rivaroxaban) and anti-thrombin (dabigatran) DOACs.
Main Results:
- Both rivaroxaban and dabigatran effectively inhibited their respective targets (FXa and thrombin).
- Rivaroxaban preserved endothelial barrier function.
- Dabigatran failed to maintain endothelial integrity over time, a deficit preventable by blocking thrombin's exosite-I.
Conclusions:
- The interaction of dabigatran-bound thrombin with endothelial cells contributes to barrier dysfunction.
- Blocking thrombin's exosite-I with a specific peptide can prevent dabigatran-induced barrier loss.
- DOACs exhibit distinct effects on vascular integrity, with implications for AF management and stroke prevention.
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.
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