Predictive Role of Gene Polymorphisms Affecting Thrombin-Generation Pathway in Variable Efficacy of Photodynamic Therapy for Neovascular Age-Related Macular Degeneration

Parmeggiani, Francesco; Gemmati, Donato; Costagliola, Ciro; Sebastiani, Adolfo; Incorvaia, Carlo

doi:10.2174/187221509788654151

Cited by 12 publications

(7 citation statements)

References 66 publications

(157 reference statements)

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“…They demonstrated that the FVL and FV HR2 variants are associated with APC resistance and, further, that the anticoagulant activity of FV plays a pivotal role in the regulation of thrombin formation. 12,46,47 Moreover, an alteration in the FV protein function leads to an increased thrombin generation, 48 and the chronic influence of higher levels of thrombin can cause the development and/or progression of atherosclerosis. 46,49,50 A recent meta-analysis of 191 studies, investigating 7 common hemostatic gene polymorphisms in cardiovascular disease, indicated that both 1691A variant of the FV gene and 20210A variant of the prothrombin gene, promoting thrombin generation in blood, might be associated with the risk of CAD.…”

Section: Discussionmentioning

confidence: 99%

Association of FV G1691A Polymorphism but not A4070G With Coronary Artery Disease

Amara

Mrad

Sayeh

et al. 2017

Clin Appl Thromb Hemost

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Coronary artery disease (CAD) is one of the chief causes of death in the world. Several hypotheses have been promoted as for the origin of the disease, among which are genetic predispositions and/or environmental factors. The aim of this study was to determine the effect of factor V (FV) gene polymorphisms (Leiden, G1691A [FVL] and HR2 A4070G) and to analyze their association with traditional risk factors in assessing the risk of CAD. Our study population included 200 Tunisian patients with symptomatic CAD and a control group of 300 participants matched for age and sex. All participants were genotyped for the FVL and HR2 polymorphisms. Multivariate logistic regression was applied to analyze independent factors associated with the risk of CAD. Our analysis showed that the FVL A allele frequency ( P < 10, odds ratio [OR] = 2.81, 95% confidence interval [CI] = 1.6-4.9) and GA genotype ( P < 10, OR = 4.03, 95% CI = 2.1-7.6) are significantly more prevalent among patients with CAD compared to those controls and may be predisposing to CAD. We further found that the FVL mutation is an independent risk factor whose effect is not modified by other factors (smoking, diabetes, hypertension, dyslipidemia, and a family history of CAD) in increasing the risk of the disease. However, analysis of FV HR2 variation does not show any statistically significant association with CAD. The FVL polymorphism may be an independent risk factor for CAD. However, further investigations on these polymorphisms and their possible synergisms with traditional risk factors for CAD could help to ascertain better predictability for CAD susceptibility.

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Section: Discussionmentioning

confidence: 99%

Association of FV G1691A Polymorphism but not A4070G With Coronary Artery Disease

Amara

Mrad

Sayeh

et al. 2017

Clin Appl Thromb Hemost

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“…clearly indicates the presence of a high level of plausibility concerning the role of coagulation-balance SNPs and individual variable efficacy of PDT-V [129][130][131][132]. The beneficial effect is obtained with a laser-light-induced thrombosis of CNV, selectively photosensitized by verteporfin preferentially bounded to the endothelium of the aberrant neovessels in comparison with that of the normal microvascular networks.…”

Section: Novel Pharmacogenetics Aspects Of Fxiiia Genementioning

confidence: 99%

Coagulation Factor XIIIA (F13A1): Novel Perspectives in Treatment and Pharmacogenetics

Gemmati

Vigliano²,

Burini³

et al. 2016

CPD

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Factor XIII (FXIII) is a key molecule in the field of blood coagulation and in the last decades it has weakened attention within the field of angiogenesis and tissue repair. FXIII positively influences wound healing in several tissues by exerting multiple plasma and cellular functions. In the field of haemostasis, FXIII cross-links the neo formed fibrin fibers and supports platelet adhesion to the damaged sub-endothelium warranting a solid architecture. In addition, the pro-angiogenic functions of FXIII are directed by the interaction of vascular endothelial growth factor receptor 2 (VEGFR2) and the integrin αVβ3, on the cell membrane, favouring an important step in the formation of granulation tissue at the wound site for optimal tissue healing. Conversely, the same mechanisms could lead to undesired increased neovascularisation, for example in inflammatory bowel disease or in the retinal degenerative pathologies. The classical symptoms of FXIII deficiency span from intracranial haemorrhage to delay bleeding or the staying of chronic wounds in the skin including impaired mucosal healing. In this view, FXIII bridges primary haemostasis, coagulation and definite tissue healing. Another important recently discovered function ascribed to FXIII is its ability to limit bacterial spreading from the lesion by incorporating specific macromolecules addressed to cellular infiltration, favouring in turn cell migration and survival, as observed also in fibrin-heart cultures for stem cell recruitment. In the field of the novel prognostic biomarkers, the monitoring of the residual circulating FXIII level during acute myocardial infarction has been considered predictive of the post-myocardial infarction healing. Accordingly, adequate FXIII levels can drive and predict the prognosis of complex diseases and the outcome of the associated therapies or interventions. In addition, peculiar pharmacogenetics aspects of the FXIII gene are of extraordinary interest. The present review accounts for the recognized role of FXIII in the healing process and gives some examples on how to use it as prognostic biological/ molecular marker or as potential tailored therapeutic molecule in complex diseases.

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“…Proteomics analysis by LC-MS/MS showed that vitreous fluid obtained from AMD patients contains higher amounts of prothrombin compared with healthy controls (19). While no mutation has yet been reported as a risk factor for AMD, two single nucleotide polymorphisms (SNPs), the A-allele of factor V Leiden 1691 or the prothrombin 20210 gene have been found to expose the wet AMD carriers to a higher risk of failing therapeutic effectiveness of the photodynamic therapy with verteporfin (20).…”

Section: Introductionmentioning

confidence: 99%

Dabigatran and Wet AMD, Results From Retinal Pigment Epithelial Cell Monolayers, the Mouse Model of Choroidal Neovascularization, and Patients From the Medicare Data Base

et al. 2022

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BackgroundAge-related macular degeneration (AMD), the leading cause of irreversible blindness in elderly Caucasian populations, includes destruction of the blood-retina barrier (BRB) generated by the retinal pigment epithelium-Bruch’s membrane complex (RPE/BrM), and complement activation. Thrombin is likely to get access to those structures upon BRB integrity loss. Here we investigate the potential role of thrombin in AMD by analyzing effects of the thrombin inhibitor dabigatran.Material and MethodsMarketScan data for patients aged ≥65 years on Medicare was used to identify association between AMD and dabigatran use. ARPE-19 cells grown as mature monolayers were analyzed for thrombin effects on barrier function (transepithelial resistance; TER) and downstream signaling (complement activation, expression of connective tissue growth factor (CTGF), and secretion of vascular endothelial growth factor (VEGF)). Laser-induced choroidal neovascularization (CNV) in mouse is used to test the identified downstream signaling.ResultsRisk of new wet AMD diagnosis was reduced in dabigatran users. In RPE monolayers, thrombin reduced TER, generated unique complement C3 and C5 cleavage products, led to C3d/MAC deposition on cell surfaces, and increased CTGF expression via PAR1-receptor activation and VEGF secretion. CNV lesion repair was accelerated by dabigatran, and molecular readouts suggest that downstream effects of thrombin include CTGF and VEGF, but not the complement system.ConclusionsThis study provides evidence of association between dabigatran use and reduced exudative AMD diagnosis. Based on the cell- and animal-based studies, we suggest that thrombin modulates wound healing and CTGF and VEGF expression, making dabigatran a potential novel treatment option in AMD.

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Predictive Role of Gene Polymorphisms Affecting Thrombin-Generation Pathway in Variable Efficacy of Photodynamic Therapy for Neovascular Age-Related Macular Degeneration

Cited by 12 publications

References 66 publications

Association of FV G1691A Polymorphism but not A4070G With Coronary Artery Disease

Association of FV G1691A Polymorphism but not A4070G With Coronary Artery Disease

Coagulation Factor XIIIA (F13A1): Novel Perspectives in Treatment and Pharmacogenetics

Dabigatran and Wet AMD, Results From Retinal Pigment Epithelial Cell Monolayers, the Mouse Model of Choroidal Neovascularization, and Patients From the Medicare Data Base

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