PF-05230907

Thromboembolic diseases are one of the leading causes of morbidity and mortality worldwide. For a long time, heparin and Vitamin K antagonist (VKA) drugs were used for treatment and prophylaxis of the thromboembolic diseases. The development of newer direct and novel oral anticoagulant medications (DOACs/NOACs) has changed clinical practice significantly. Lesser monitoring, ease with dosing, less drug interactions have made these drugs useful to the providers and the patients. But these drugs have bleeding as a side effect. There is ongoing research on the specific antidotes of these anticoagulants in case of life-threatening bleeding. Though the use of the DOACs and NOACs have increased, there is still not enough clinical evidence about the specific antidotes of these medications. Unlike heparin or VKA, reversal of life-threatening bleeding in the setting of DOAC use is still a clinical challenge. We need more data on the dose, pharmacokinetics, and clinical efficacy of those antidotes. Authors have reviewed articles on DOACs and their antidotes in Pubmed and also in the clinical trial website. Specific antidotes including Idarucizumab for Dabigatran, Andexanet alfa for factor Xa inhibitors are being used to reverse the actions of the anticoagulants. Ciraparantag is a universal antidote for the DOACs, which is still under investigation. FXaI16L is currently being investigated as a potential universal antidote for multiple anticoagulants, including dabigatran and rivaroxaban. Though mostly safe, the use of DOACs can still carry a risk of severe bleeding in patients. More data on the use of the antidotes is required to reverse the side effect of DOACs if clinically indicated.

Uncontrolled coagulation reactions contribute to pathological fibroproliferation in several organs, and yet their role in proliferative vitreoretinopathy (PVR) remains to be elucidated. In this study, we evaluated the profibrotic effects of FXa in RPE cells and in a mouse model of PVR.

FXa levels in the eyes of traumatic PVR patients and rabbit models of mechanical ocular trauma was measured by ELISA and immunohistochemistry. FXa-induced RPE EMT was assessed by examining cell proliferation, migration, tight junction changes, and expression of fibrotic markers. For in vivo study, FXa was injected into dispase-injured eyes, then intraocular fibrosis was evaluated by histological analysis and Western blotting. The therapeutic effect of FXa inhibitor was also examined in PVR mouse models.

Vitreous FXa were higher in patients with traumatic PVR compared to patients with macular hole. Moreover, expressions of FXa and PAR1 were found in the epiretinal membranes from traumatic PVR patients. Vitreous FXa were markedly increased after mechanical ocular trauma in rabbits. In vitro, FXa stimulated RPE EMT characterized as ZO-1 disruption, compromised cell polarity, and increased fibronectin expressions. Co-injection of FXa and dispase in mice induced more severely damaged retinal structures, and increased α-SMA expressions than FXa or dispase treatment alone. Oral FXa or thrombin inhibitors significantly blocked intraocular fibrosis in PVR mouse models. FXa promoted phospho-activation of p38 in ARPE19 cells, which was dependent on PAR1. Moreover, TGF-βR inhibitor also significantly alleviated FXa-induced intraocular fibrosis in mice.

FXa promotes intraocular fibrosis in mice via mechanisms involving RPE activation.