The Role of Thrombin in Proliferative Vitreoretinopathy

Bastiaans, Jeroen; Meurs, Jan C. van; Mulder, Verena C.; Nagtzaam, Nicole M. A.; Nijenhuis, Marja Smits-Te; Goorbergh, Diana C M Dufour-van den; Hagen, P. Martin van; Hooijkaas, Herbert; Dik, Willem A.

doi:10.1167/iovs.14-14818

Cited by 43 publications

(50 citation statements)

References 32 publications

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“…1, 2) [1]. In contrast to our previous experiment, which showed significantly higher thrombin activity in established PVR, we could not detect a difference in F1+2 and TAT values between patients with uncomplicated RRD and patients with established PVR.…”

Section: Discussioncontrasting

confidence: 99%

“…In the previous experiments, we used the small thrombin-specific chromogenic substrate Tos-Gly-Pro-Arg-pNA (MW 662.7 Da) for the measurements of intravitreal thrombin activity [1]. Although the substrate is very well split by thrombin, other serine proteases such as plasma kallikrein and plasmin are also known to act on the substrate due to its small MW.…”

Section: Discussionmentioning

confidence: 99%

“…Activation of the coagulation cascade has recently been identified as a potential factor in the development of proliferative vitreoretinopathy (PVR) [1]. We found significantly higher intravitreal thrombin concentrations in patients with established PVR and demonstrated that intravitreal thrombin stimulates retinal pigment epithelial cells to produce pro-inflammatory and pro-fibrotic mediators [1, 2].…”

Section: Introductionmentioning

confidence: 85%

“…We found significantly higher intravitreal thrombin concentrations in patients with established PVR and demonstrated that intravitreal thrombin stimulates retinal pigment epithelial cells to produce pro-inflammatory and pro-fibrotic mediators [1, 2]. …”

Section: Introductionmentioning

confidence: 99%

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Thrombin Generation in Vitreous and Subretinal Fluid of Patients with Retinal Detachment

et al. 2018

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Purpose: To measure prothrombin fragments (F1+2) and thrombin-antithrombin complex (TAT) in vitreous and subretinal fluid (SRF) of rhegmatogenous retinal detachment (RRD) patients and to validate and further specify our earlier finding of increased thrombin activity in patients with proliferative vitreoretinopathy (PVR). Methods: F1+2 and TAT were measured in 31 vitreous and 16 SRF samples using the Enzygnost® immunoassays. Results: We found significant levels of F1+2 and TAT in the vitreous of all patients with RRD compared to patients with macular hole or macular pucker. However, there was no significant difference between patients who would develop PVR in the future, had established PVR, and patients with uncomplicated RRD both in vitreous concentrations of F1+2 (Kruskal-Wallis p = 0.963) and TAT (p = 0.516). Conclusion: The analysis of F1+2 and TAT confirmed significant thrombin generation in both vitreous and SRF of patients with RRD. An imbalance between the thrombin regulation mechanisms TAT and α2-macroglobulin possibly explains the difference from our previous findings.

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Section: Discussioncontrasting

confidence: 99%

Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 85%

Section: Introductionmentioning

confidence: 99%

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Thrombin Generation in Vitreous and Subretinal Fluid of Patients with Retinal Detachment

et al. 2018

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“…Under these conditions, Müller glia and retinal astrocytes release factors such as vascular endothelial growth factor (VEGF) and cytokines that contribute to further disrupt the BRB 6 and to promote MC proliferation. 7 Recent studies have shown that thrombin activity is increased in the vitreous from proliferative vitreoretinopathy (PVR) patients, 8 suggesting thrombin involvement in the pathogenesis of PVR, characterized by the proliferation, dedifferentiation, and migration of MCs and transdifferentiation of RPE cells into the vitreous and the assembly of contractile cellular membranes on retinal surfaces, thus promoting retinal detachment. 9 It has been previously shown that thrombin stimulates glial cell proliferation in a dosedependent manner 10,11 and that it has an inhibitory effect on inwardly rectifying K þ current (IK(IR)).…”

Section: M¨umentioning

confidence: 99%

PKC-ζ Regulates Thrombin-Induced Proliferation of Human Müller Glial Cells

Lee-Rivera

López

Carranza-Pérez

et al. 2016

Invest. Ophthalmol. Vis. Sci.

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Citation: Lee-Rivera I, López E, Carranza-Pérez MG, López-Colomé AM. PKC-f regulates thrombin-induced proliferation of human Müller glial cells. Invest Ophthalmol Vis Sci. 2016;57:3769-3779. DOI:10.1167/ iovs.16-19574 PURPOSE. To investigate the effect of thrombin on the proliferation of human Müller glial cells (MCs) and define the possible signaling mechanisms involved in this process.METHODS. Protease-activated receptor (PARs 1-4) expression was analyzed using RT-PCR and Western blot in the MIO-M1 Müller cell line (MC). Müller cell proliferation was assessed by the MTS reduction method. Wound healing and immunoreactivity to Ki67 antigen were used to dissociate proliferation and migration. Cell migration was examined using transwell migration assays. The involvement of extracellular signal-regulated kinase (ERK1/2) phosphorylation/activation in thrombin-induced human MC proliferation was determined by Western blot. Intracellular pathways involved in ERK1/2 activation were analyzed by pharmacologic inhibition. RESULTS.We first demonstrated that human MCs express PARs 1 to 4. Our results show that thrombin dose-dependently stimulates MC proliferation by 44%, with a calculated Ec 50 of 0.86 nM. Müller cell maximal proliferation required sustained thrombin treatment for 72 hours, in contrast to our previous findings in RPE cells showing maximal thrombin-induced proliferation at 24-hour stimulation. We demonstrate that thrombin induces MC cell proliferation through the Ras-independent activation of the Raf/MEK/ERK cascade, under the control of protein kinase C (PKC)-f.CONCLUSIONS. The breakdown of blood-retina barrier (BRB) exposes MCs to thrombin contained in serum. Our findings further strengthen the critical involvement of thrombin in the development of proliferative retinopathies and may provide pharmacologic targets for the prevention or treatment of these diseases.

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RPE and the Vascular Endothelial Growth Factor

Klettner

2020

Retinal Pigment Epithelium in Health and Disease

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The Role of Thrombin in Proliferative Vitreoretinopathy

Abstract: Thrombin activity is increased in vitreous of patients with established PVR and is involved in the activation of proinflammatory and profibrotic pathways in RPE cells. Inhibition of thrombin activity may therefore represent a potential treatment option for proliferative vitreoretinopathy.

Cited by 43 publications

References 32 publications

Thrombin Generation in Vitreous and Subretinal Fluid of Patients with Retinal Detachment

Thrombin Generation in Vitreous and Subretinal Fluid of Patients with Retinal Detachment

PKC-ζ Regulates Thrombin-Induced Proliferation of Human Müller Glial Cells

RPE and the Vascular Endothelial Growth Factor

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