Premium
Dabigatran inhibits intravitreal thrombin activity
Author(s) -
Bastiaans Jeroen,
Mulder Verena C.,
Meurs Jan C.,
Smits te Nijenhuis Marja,
Holten Neelen Conny,
Hagen P. Martin,
Dik Willem A.
Publication year - 2018
Publication title -
acta ophthalmologica
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.534
H-Index - 87
eISSN - 1755-3768
pISSN - 1755-375X
DOI - 10.1111/aos.13630
Subject(s) - dabigatran , thrombin , antithrombins , pharmacology , medicine , chemistry , ophthalmology , warfarin , atrial fibrillation , platelet
Purpose Proliferative vitreoretinopathy ( PVR ) is a vitreoretinal disorder in which retinal pigment epithelial ( RPE ) cell activation contributes to both formation of fibrotic retinal membranes and inflammation. Vitreous of patients with PVR contains increased thrombin activity which induces profibrotic and proinflammatory programs in RPE cells. Inhibition of intravitreal thrombin activity may thus represent a therapeutic option for PVR . In this study, we examined the capacity of the clinically available direct thrombin inhibitor dabigatran to inhibit thrombin activity in vitreous fluids. Methods ARPE ‐19 cells were cultured with the following: (i) thrombin, (ii) vitreous without thrombin activity and (iii) vitreous with elevated thrombin activity ( PVR samples and thrombin spiked vitreous) either in the presence or absence of dabigatran (range: 10 −5 to 10 −7 M). Subsequently, CCL 2, CXCL 8, GMCSF , IL 6 and PDGFB mRNA expression levels were determined by RQ ‐ PCR and protein levels of 27 cytokines, chemokines and growth factors were detected in culture supernatants using a multiplex approach. In addition, the capacity of vitreous fluids obtained from patients after oral dabigatran intake was tested in an in vitro thrombin activity assay. Results Thrombin and vitreous fluids containing thrombin activity induced CCL 2, CXCL 8, GM ‐ CSF , IL ‐6 and PDGF ‐ BB expression by ARPE ‐19 cells, which was inhibited by dabigatran. In addition, dabigatran that reached the vitreous after repeated oral intake did inhibit thrombin activity in the in vitro activity assay. Conclusion Proliferative vitreoretinopathy ( PVR ) is associated with increased intravitreal thrombin activity that activates profibrotic and proinflammatory pathways in RPE cells. Our findings provide evidence that this activation pathway can potentially be inhibited by dabigatran.