Pathogenesis of Vascular Retinal Manifestations in COVID-19 Patients: A Review.

Pandemic infection secondary to coronavirus disease 2019 (COVID-19) had an important impact on the general population affecting not only respiratory tract but also many other organs. Ocular manifestations are quite common at the level of the anterior segment (conjunctivitis, dry eye), while posterior segment and, in particular, retinal findings are less frequent. In the retina, COVID-19 is associated with vascular events. Since retinal arteries and veins represent an accessible window to the microvasculature of the rest of the body, a better understanding of the profile of retinal vascular occlusive events may help elucidate mechanisms of thrombo-occlusive complications in other organs in patients affected by COVID-19. In this review, we conducted a systematic literature search focused on retinal arterial and/or retinal venous manifestations. Twenty-one studies were included, describing a wide range of manifestations from mild signs like cotton wool spots, focal and flame-shaped hemorrhages, and vein dilation to more severe retinal artery and vein occlusions. Two principal pathogenetic mechanisms are considered responsible for these complications: a hypercoagulative state and a massive inflammatory response leading to a disseminated intravascular coagulation-like syndrome.

The Complex Relation between Atrial Cardiomyopathy and Thrombogenesis.

Heart disease, as well as systemic metabolic alterations, can leave a 'fingerprint' of structural and functional changes in the atrial myocardium, leading to the onset of atrial cardiomyopathy. As demonstrated in various animal models, some of these changes, such as fibrosis, cardiomyocyte hypertrophy and fatty infiltration, can increase vulnerability to atrial fibrillation (AF), the most relevant manifestation of atrial cardiomyopathy in clinical practice. Atrial cardiomyopathy accompanying AF is associated with thromboembolic events, such as stroke. The interaction between AF and stroke appears to be far more complicated than initially believed. AF and stroke share many risk factors whose underlying pathological processes can reinforce the development and progression of both cardiovascular conditions. In this review, we summarize the main mechanisms by which atrial cardiomyopathy, preceding AF, supports thrombogenic events within the atrial cavity and myocardial interstitial space. Moreover, we report the pleiotropic effects of activated coagulation factors on atrial remodeling, which may aggravate atrial cardiomyopathy. Finally, we address the complex association between AF and stroke, which can be explained by a multidirectional causal relation between atrial cardiomyopathy and hypercoagulability.

Thrombin generation by calibrated automated thrombography in goat plasma: Optimization of an assay.

The goat model of atrial fibrillation (AF) allows investigation of the effect of AF on coagulation. However, assays for goat plasma are not available from commercial sources. Calibrated automated thrombography (CAT) provides a global view of the coagulation profile by assessing in vitro thrombin generation (TG). We describe the customization of the CAT assay in goat platelet-poor plasma (PPP) and in factor Xa (FXa)-inhibitor-anticoagulated PPP. TG was initiated in the presence of phospholipids and either (a) PPP reagent, reagent low, or reagent high; (b) goat brain protein extraction (GBP); or (c) Russell's viper venom-factor X activator (RVV-X). Contact activation was assessed by adding corn trypsin inhibitor. Different concentrations of prothrombin complex concentrate (PCC) were used to determine the sensitivity of both the GBP and RVV-X method. To obtain FXa-inhibitor anticoagulated plasma, rivaroxaban was added to plasma. TG settings with human reagents were not suitable for goat plasma. TG triggered with GBP increased peak height and ETP values. Similarly, the RVV-X method produced comparable TG curves and was more sensitive to PCC titration. Finally, both methods were able to detect the decrease in clotting potential induced by FXa inhibition. This is the first study that reports the customization of the CAT assay for goats. The GBP and RVV-X methods were comparable in triggering TG in goat plasma. The RVV-X method seemed to better discriminate changes in TG curves due to increases in clotting potential as well as to FXa inhibition by rivaroxaban in goat plasma.

Coagulation Factor Xa Induces Proinflammatory Responses in Cardiac Fibroblasts via Activation of Protease-Activated Receptor-1.

Coagulation factor (F) Xa induces proinflammatory responses through activation of protease-activated receptors (PARs). However, the effect of FXa on cardiac fibroblasts (CFs) and the contribution of PARs in FXa-induced cellular signalling in CF has not been fully characterised. To answer these questions, human and rat CFs were incubated with FXa (or TRAP-14, PAR-1 agonist). Gene expression of pro-fibrotic and proinflammatory markers was determined by qRT-PCR after 4 and 24 h. Gene silencing of F2R (PAR-1) and F2RL1 (PAR-2) was achieved using siRNA. MCP-1 protein levels were measured by ELISA of FXa-conditioned media at 24 h. Cell proliferation was assessed after 24 h of incubation with FXa ± SCH79797 (PAR-1 antagonist). In rat CFs, FXa induced upregulation of Ccl2 (MCP-1; >30-fold at 4 h in atrial and ventricular CF) and Il6 (IL-6; ±7-fold at 4 h in ventricular CF). Increased MCP-1 protein levels were detected in FXa-conditioned media at 24 h. In human CF, FXa upregulated the gene expression of CCL2 (>3-fold) and IL6 (>4-fold) at 4 h. Silencing of F2R (PAR-1 gene), but not F2RL1 (PAR-2 gene), downregulated this effect. Selective activation of PAR-1 by TRAP-14 increased CCL2 and IL6 gene expression; this was prevented by F2R (PAR-1 gene) knockdown. Moreover, SCH79797 decreased FXa-induced proliferation after 24 h. In conclusion, our study shows that FXa induces overexpression of proinflammatory genes in human CFs via PAR-1, which was found to be the most abundant PARs isoform in this cell type.

Burr-Assisted Peripheral Superficial Keratectomy for the Treatment of Persistent Symptomatic Peripheral Corneal Edema.

PURPOSE: To describe a simple technique of diamond burr-assisted superficial keratectomy for the treatment of peripheral corneal edema. CASES PRESENTATION: Two patients with persistent symptomatic peripheral corneal edema underwent superficial keratectomy with the use of a diamond ophthalmic burr. The efficacy of the treatment was evaluated clinically as well as with anterior segment optical coherence tomography. During the postoperative follow-up period, no adverse events were observed and corneal edema reduced significantly. The patients were asymptomatic, no epithelial cysts could be identified clinically, and visual acuity remained unchanged. CONCLUSION: Peripheral superficial keratectomy could be an effective alternative for the treatment of peripheral, symptomatic corneal edema.

Refractory neovascular age-related macular degeneration: time-dependent changes of central retinal thickness with anti-VEGF treatment.

PURPOSE: To assess the influence of time interval since last injection and time from baseline on central retinal thickness (CRT) in neovascular age-related macular degeneration (nAMD) with fluid refractory to monthly anti-VEGF treatment. METHODS: This retrospective study included nAMD eyes with incomplete response to anti-VEGF defined by the presence of intra- or subretinal fluid on optical coherence tomography despite maximal (monthly) anti-VEGF dosing. The outcome measure was CRT, and two time variables (time from last injection ant time from baseline) were the independent factors included in the individual correlation analyses. In addition, an association analysis was performed. RESULTS: Sixty eyes of 56 patients (67.9% females, mean age: 78.7 ± 6.8 years) were included with a mean included time period of 35.6 months. A significant positive correlation between CRT and the time from last injection occurred in 24 (40%) and 25 (42%) eyes by univariate and multivariate analysis, respectively. Time from baseline was significantly correlated with CRT in 29 (48.3%) and 30 (50%) eyes by univariate and multivariate analysis, respectively. This correlation was positive in 12 (20%) and negative in 18 eyes (30%). No association with such correlation was found. CONCLUSION: So-called refractory nAMD frequently shows a correlation of CRT with the interval in days from the preceding anti-VEGF injection, revealing that there is a subgroup of short-term responsiveness of the residual fluid. Moreover, slower CRT changes may occur over the years, either decrease or increase. In case of a slow CRT increase, this might require a diagnostic workup and therapeutic change.

Thrombo-Inflammation in Cardiovascular Disease: An Expert Consensus Document from the Third Maastricht Consensus Conference on Thrombosis.

Thrombo-inflammation describes the complex interplay between blood coagulation and inflammation that plays a critical role in cardiovascular diseases. The third Maastricht Consensus Conference on Thrombosis assembled basic, translational, and clinical scientists to discuss the origin and potential consequences of thrombo-inflammation in the etiology, diagnostics, and management of patients with cardiovascular disease, including myocardial infarction, stroke, and peripheral artery disease. This article presents a state-of-the-art reflection of expert opinions and consensus recommendations regarding the following topics: (1) challenges of the endothelial cell barrier; (2) circulating cells and thrombo-inflammation, focused on platelets, neutrophils, and neutrophil extracellular traps; (3) procoagulant mechanisms; (4) arterial vascular changes in atherogenesis; attenuating atherosclerosis and ischemia/reperfusion injury; (5) management of patients with arterial vascular disease; and (6) pathogenesis of venous thrombosis and late consequences of venous thromboembolism.

Classification and Statistical Trend Analysis in Detecting Glaucomatous Visual Field Progression.

AIM: To evaluate the agreement between different methods in detection of glaucomatous visual field progression using two classification-based methods and four statistical approaches based on trend analysis. METHODS: This is a retrospective and longitudinal study. Twenty Caucasian patients (mean age 73.8 ± 13.43 years) with open-angle glaucoma were recruited in the study. Each visual field was assessed by Humphrey Field Analyzer, program SITA standard 30-2 or 24-2 (Carl Zeiss Meditec, Inc., Dublin, CA). Full threshold strategy was also accepted for baseline tests. Progression was analyzed by using Hodapp-Parrish-Anderson classification and the Advanced Glaucoma Intervention Study visual field defect score. For the statistical analysis, linear regression (r 2) was calculated for mean deviation (MD), pattern standard deviation (PSD), and visual field index (VFI), and when it was significant, each series of visual field was considered progressive. We also used Progressor to look for a significant progression of each visual field series. The agreement between methods, based on statistical analysis and classification, was evaluated using a weighted kappa statistic. RESULTS: Thirty-eight visual field series were analyzed. The mean follow-up time was 6.2 ± 1.53 years (mean ± standard deviation). At baseline, the mean MD was -7.34 ± 7.18 dB; at the end of the follow-up, the mean MD was -9.25 ± 8.65 dB; this difference was statistically significant (p < 0.001). The agreement to detect progression was fair between all methods based on statistical analysis and classification except for PSD r 2. A substantial agreement (κ = 0.698 ± 0.126) was found between MD r 2 and VFI r 2. With the use of all the statistical analysis, there was a better time-saving. CONCLUSIONS: The best agreement to detect progression was found between MD r 2 and VFI r 2. VFI r 2 showed the best agreement with all the other methods. GPA2 can help ophthalmologists to detect glaucoma progression and to help in treatment decisions. PSD r 2 was the worse method to detect progression.

Supraciliary versus intrascleral implantation with hema implant (Esnoper V-2000) in deep sclerectomy: a multicenter randomized controlled trial.

PURPOSE: To compare the supraciliary versus intrascleral implantation of the hema implant (Esnoper V-2000) in terms of the efficacy and safety in nonpenetrating deep sclerectomy (NPDS). PATIENTS AND METHODS: Prospective, randomized, unmasked, competitive and multicenter clinical trial. Eighty-three eyes from 83 patients suffering from open-angle glaucoma (40 males, 43 females) were enrolled and followed up for 12 months. Main outcome measures were best-corrected visual acuity (BCVA), intraocular pressure (IOP), perimetry (mean defect, MD and Visual Field Index, VFI), pachymetry, number of antiglaucoma medications and analysis of blebs according Moorfields Bleb Grading. RESULTS: The IOP was significantly reduced in both groups from 23.74 ± 6.9 mmHg (implant sutured to the sclera, group 1) and 23.46 ± 6.47 mmHg (implant placed in the suprachoroidal space, group 2) to 15.43 ± 4.27 mmHg (p < 0.001) and 14.62 ± 3.64 mmHg (p < 0.001), respectively. There were no statistically significant differences in mean IOP values between the groups a year after the surgery (p = 0.581). BCVA did not show statistical differences in comparison with baseline (p = 0.09, group 1; p = 0.42, group 2). The mean number of antiglaucoma medications was reduced in both groups from 2.58 ± 0.04 and 2.68 ± 0.02 before the surgery to 0.32 ± 0.76 and 0.24 ± 0.66 after surgery. CONCLUSION: Nonpenetrating deep sclerectomy using hema implant (Esnoper V-2000) is safe and effective regardless of the positioning of the implant. We achieved IOP decrease and reduction in antiglaucoma medications during the first year after surgery without significant differences between both techniques.

Diurnal Variations of Peripapillary and Macular Vessel Density in Glaucomatous Eyes Using Optical Coherence Tomography Angiography.

PURPOSE: The purpose of this study was to investigate the diurnal variation in peripapillary and macular vessel density (VD) measurements using optical coherence tomographic angiography (OCT-A) and its correlation to intraocular pressure (IOP) changes in glaucoma patients. METHODS: Prospective, observational cross-sectional study including 37 patients (74 eyes; age, 63.8±12.9 y) with open-angle glaucoma. OCT-A imaging and IOP measurements were performed at 08:00, 11:00, 14:00, and 16:00 timepoints on a single day. At each timepoint, 2 scan protocols were used to generate 3-dimensional en face OCT angiograms: 4.5×4.5-mm scan centered on the optic nerve head and 6×6-mm scan centered on the fovea. For each scan mode, the "radial peripapillary capillary" segment, composed of the vasculature of the retinal nerve fiber layer and ganglion cell layer, was calculated. Two trained readers reviewed OCT-A image quality. Only scans with signal strength intensity (SSI) higher than 46 and without image artifacts interfering with measurements were included. Variation in VD measurements assessed using analysis of variance (ANOVA) and the association between VD and IOP changes assessed using linear mixed modeling methods. RESULTS: The optic nerve head and peripapillary VD measurements at 14:00 and 16:00 timepoints were greater than the measurements at 08:00 and 11:00 timepoints. The 14:00 and 16:00 VD measurements were statistically significantly greater (P<0.05) than the 08:00 measurements for the whole en face (50.1% and 50.1% vs. 49.4%), inside disc (50.6% and 50.5% vs. 49.6%), and average peripapillary (58.2% and 58.5% vs. 57.5%) VDs. The macular VD measurements at the 14:00 timepoint were greater than the measurements at 08:00 and 11:00 timepoints. Changes in VD were significantly associated with changes in SSI but not IOP. CONCLUSIONS: Diurnal changes in OCT-A-measured VD in glaucoma patients were small and clinically insignificant. These changes were not associated with IOP changes.

Prospective Evaluation of Standalone XEN Gel Implant and Combined Phacoemulsification-XEN Gel Implant Surgery: 1-Year Results.

PURPOSE: To evaluate the safety and efficacy of XEN gel implant (Allergan Inc., Irvine) as a standalone versus combined XEN-Phacoemulsification surgery (XEN+cataract) in glaucoma patients. METHODS: Prospective, interventional study. One-hundred forty-nine eyes (113 patients) with open-angle glaucoma and uncontrolled intraocular pressure (IOP) despite medical treatment were enrolled at a tertiary glaucoma center and followed up for a minimum of 1 year. Approximately two-thirds of patients underwent combined XEN+cataract surgery, while the remainder had XEN alone surgery. Primary outcome was a 20% or more decrease in IOP from medicated baseline at 1 year. Mean IOP, mean number of medications at last follow-up, and incidence of adverse effects were analyzed. RESULTS: Of 149 enrolled eyes, data of 87 (58%) were available at 1 year. A total of 109 (73.2%) eyes underwent XEN+cataract surgery and 40 (26.8%) XEN alone surgery. Mean medicated IOP was 20.0±7.1 at baseline and 13.9±4.3 mm Hg at 1 year (P<0.01), a 31% IOP reduction. Mean medications dropped from 1.9±1.3 preoperatively to 0.5±0.8 at 1 year (P<0.001). In total, 62.1% of patients achieved a ≥20% IOP reduction; this proportion was higher in the XEN alone group. 57.7% of eyes achieved complete success (without any antiglaucoma medications) and 71.1% qualified success (with or without medications) when IOP<16 mm Hg was considered as the definition of success. In all, 37% of patients required needling intervention. Adverse effects included bleb revision in 5 eyes, choroidal detachment in 2 eyes, and second glaucoma surgery in 9 eyes. CONCLUSIONS: The XEN gel implant as a standalone procedure or combined with cataract surgery demonstrated safe and sustained IOP reduction after 1 year.

XEN-augmented Baerveldt: A New Surgical Technique for Refractory Glaucoma.

BACKGROUND: Glaucoma drainage devices have traditionally been reserved for patients with refractory glaucoma. However, these devices are prone to various sight-threatening complications. To prevent hypotony after placement of the Baerveldt tube, surgeons traditionally tie the tube with an absorbable suture until encapsulation occurs around the plate. We hypothesized that combining the XEN tube, placing it in the anterior chamber and connecting it to the Baerveldt tube posteriorly, outside the anterior chamber, would minimize 2 main potentially blinding complications: hypotony and corneal disease. PURPOSE: To describe a new surgical technique for refractory glaucoma, combining both the Baerveldt and the XEN tubes in the same surgery. SURGICAL TECHNIQUE: The Baerveldt implant was positioned in the superotemporal quadrant and sutured to the sclera. A scleral flap was executed extending from the anterior margin of the plate for the entire length of the tube to the limbus. The Baerveldt tube was correctly positioned by removing a deeper scleral flap. The XEN tube was then inserted ab externo and inserted into the Baerveldt tube's lumen. The newly formed double tube was then sutured and covered by the first scleral flap and usual suturing of the conjunctiva was performed. CONCLUSIONS: This technique is simple and potentially increases the safety of refractory glaucoma surgeries.