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Summary of the current concepts in ROP. At birth, premature infants are deficient in several maternally derived factors such as -3 PUFAs and IGF-1 that are essential for healthy blood vessel development . Moreover, when the premature are mechanically ventilated to overcome pulmonary insufficiencies, the excessive supplemental oxygen contributes to retinal vascular obliteration due to oxidant stress and suppression of oxygen-regulated proangiogenic factors such as VEGF and erythropoietin (Epo). Following the initial phase of vascular dropout, a second phase of compensatory and destructive neovascularization results and is driven by hypoxia-induced angiogenic factors, such as VEGF and metabolite factors (succinate). Vasorepulsive molecules (Sema3A) also operate, avoiding the revascularization to the avascular zones. Current therapeutic interventions rely on invasive procedures such as laser photocoagulation, whereby affected areas of the retina are cauterized. A number of future treatments, including anti-VEGF therapy and the use of antioxidants , are currently being evaluated.
Source publication
Retinopathy of prematurity (ROP), an ocular disease characterized by the onset of vascular abnormalities in the developing retina, is the major cause of visual impairment and blindness in premature neonates. ROP is a complex condition in which various factors participate at different stages of the disease leading to microvascular degeneration follo...
Contexts in source publication
Context 1
... therapies including cryotherapy and laser photocoagulation are the procedures most commonly used in the clinic for the treatment of ROP ( fig. 4 ). These treatments destroy tissue in the avascular retina includ- ing those that generate VEGF which promotes aberrant preretinal neovascularization. Despite this form of ther- apy, visual acuity remains largely unaffected and, as ex- pected, peripheral vision is inevitably lost [2] ...
Context 2
... promising strategy to counter ROP is the use of the anti-VEGF therapy ( fig. 4 ). Bevacizumab, a VEGF-specif- ic neutralizing antibody is currently used for treatment of several diseases including diabetic retinopathy and mac- ular degeneration. Until recently, bevacizumab was used for ROP in the absence of randomized trials [72] ; timing (stage/zone of ROP), dose (0.4-12.5 mg intravitreal) and frequency of ...
Context 3
... -3 fatty acids [70] , and (4) the potential administra- tion of cytoprotective growth factors such as erythropoi- etin and/or IGF-1 could be more desirable than treatment of an established disorder. However, although promising, other than limiting post-natal hemoglobin-oxygen satu- ration, the other modalities remain speculative at this point ( fig. 4 ). PUFAs and IGF-1 that are es- sential for healthy blood vessel develop- ment. Moreover, when the premature are mechanically ventilated to overcome pul- monary insufficiencies, the excessive sup- plemental oxygen contributes to retinal vascular obliteration due to oxidant stress and suppression of oxygen-regulated pro- angiogenic ...
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... By analyzing a publicly available scRNA-seq (Drop-seq) dataset (GSE150703) that compared OIR and normal conditions [56], we observed an increase in Adam17 substrates in rod photoreceptor cells in OIR mice (Fig. 4C). These substrates are involved in various aspects of pathophysiology of ROP including angiogenesis, inflammation, and cell adhesion as well as migration (Fig. 4C) [57,58]. In summary, our data suggest that the upregulation of c-Fos expression in rod photoreceptors leads to transcriptional regulation of Adam17. ...
Pathological retinal angiogenesis profoundly impacts visual function in vascular eye diseases, such as retinopathy of prematurity (ROP) in preterm infants and age-related macular degeneration in the elderly. While the involvement of photoreceptors in these diseases is recognized, the underlying mechanisms remain unclear. This study delved into the pivotal role of photoreceptors in regulating abnormal retinal blood vessel growth using an oxygen-induced retinopathy (OIR) mouse model through the c-Fos/A disintegrin and metalloprotease 17 (Adam17) axis. Our findings revealed a significant induction of c-Fos expression in rod photoreceptors, and c-Fos depletion in these cells inhibited pathological neovascularization and reduced blood vessel leakage in the OIR mouse model. Mechanistically, c-Fos directly regulated the transcription of Adam17 a shedding protease responsible for the production of bioactive molecules involved in inflammation, angiogenesis, and cell adhesion and migration. Furthermore, we demonstrated the therapeutic potential by using an adeno-associated virus carrying a rod photoreceptor-specific short hairpin RNA against c-fos which effectively mitigated abnormal retinal blood vessel overgrowth, restored retinal thickness, and improved electroretinographic (ERG) responses. In conclusion, this study highlights the significance of photoreceptor c-Fos in ROP pathology, offering a novel perspective for the treatment of this disease.
... Excess oxygen supplement leads to vasoconstriction and vasoconstriction to hypoxia followed by the release of various growth factors VGEF, IGF-1 stimulates neovascularization. Abnormal blood vessel growth leads to tractional RD [5]. Figure 2 shows the pathogenesis of ROP. ...
... The author self-created the figure using the information from [5]. ...
Retinopathy of prematurity (ROP) is a rare proliferative ocular condition that can happen in premature babies (born preterm <36 weeks) or who weigh <1.5 kg at birth (low birth weight babies). ROP is a major cause of childhood blindness. It is a premature disease since retina vascularization is completed only by 40 weeks of life. The survivability for preterm infants has increased owing to recent improvements in neonatal care during the past decade. As a result, the prevalence of ROP has risen concurrently. The abnormal development of blood vessels in the retina is the cause of this illness.
It occurs in two phases, phases 1 and 2. Most preterm infants weighing <1.5 kg need supplemental oxygen for respiratory support at birth. This leads to the initiation of phase 1 (vasoconstrictive phase). Phase 1 is characterized by loss of maternal-fetal connection and hyperoxia due to supplemental oxygen therapy. Oxygen's vasoconstrictive and obliterative action is primarily observed in developing retinal vessels. The inhibition of vascular endothelial growth factor follows from this. Phase 2 (vasoproliferative phase) shows the dilatation and tortuosity of the bigger existing vessels together with neovascularization and proliferation of new vessels into the vitreous when the baby is shifted from respiratory support to room air. Now, the retina gets hypoxic, where the retina becomes more metabolically active but is yet minimally vascularized, leading to VEGF-induced vasoproliferation, which might result in retinal detachment.
Patients with ROP face the danger of loss of vision. If correct and quick treatment is not provided, they might land into permanent blindness. Yet, ROP remains one of the most preventable causes of childhood blindness worldwide. Blindness caused by ROP can only be avoided if screening programs are readily available, pertinent, and appropriate. The initial stage in the therapy of ROP is the screening of premature neonates. Timely screening and management for ROP is important to avoid this irreversible loss of vision. The treatment is based on the severity of the disease. Management may include pharmacological interventions like intravitreal and anti-vascular endothelial growth factor and non-pharmacological interventions like laser surgery, vitrectomy, and scleral buckling.
We conducted a thorough literature search of studies on pathogenesis, risk factors, classification, and various treatment options for retinopathy of prematurity in infants, using a mixture of pertinent keywords. Only those studies published in peer-reviewed journals between 2010 and 2023 and written in English were included. Duplicate studies, unavailable in full-text for free, or studies unrelated to our subject matter were excluded. After thoroughly evaluating the selected studies, the results were synthesized and presented narratively. This article sheds light on the pathogenesis of ROP, particularly its relation to oxygen use, screening, and potential therapeutic management of ROP. Today advances in screening techniques have improved the outcomes for infants with ROP. Still, ongoing research is needed to optimize management strategies and reduce the burden of this condition.
... ROP is characterized by abnormal blood vessel development in the retina with excessive vascularization 6 that is strongly linked to intensive oxygen therapy. Other contributing factors have also been proposed as pathogenetic mechanisms 7 -e.g., reduced ghrelin, oxidative stress, and erythropoietin dysregulation-the roles remain fully clarified 8 . ...
Retinopathy of prematurity (ROP) is a severe condition affecting premature infants, leading to abnormal retinal blood vessel growth, retinal detachment, and potential blindness. While semi-automated systems have been used in the past to diagnose ROP-related plus disease by quantifying retinal vessel features, traditional machine learning (ML) models face challenges like accuracy and overfitting. Recent advancements in deep learning (DL), especially convolutional neural networks (CNNs), have significantly improved ROP detection and classification. The i-ROP deep learning (i-ROP-DL) system also shows promise in detecting plus disease, offering reliable ROP diagnosis potential. This research comprehensively examines the contemporary progress and challenges associated with using retinal imaging and artificial intelligence (AI) to detect ROP, offering valuable insights that can guide further investigation in this domain. Based on 89 original studies in this field (out of 1487 studies that were comprehensively reviewed), we concluded that traditional methods for ROP diagnosis suffer from subjectivity and manual analysis, leading to inconsistent clinical decisions. AI holds great promise for improving ROP management. This review explores AI's potential in ROP detection, classification, diagnosis, and prognosis.
... rombocytes and megakaryocytes store both pro-and antiangiogenic mediators in α-granules. VEGF is one of the proangiogenic factors that contribute to vascular endothelial cell proliferation and has a critical role in the pathogenesis of ROP. e limitative effect of thrombocytes in pathological retinal neovascularization has been also reported [5][6][7]. While thrombocytopenia was found significantly associated with severe ROP in some studies [7][8][9][10], no significant difference was found in mean PLT counts in another study [11]. ...
Purpose:
To investigate the role of thrombocyte parameters in retinopathy of prematurity (ROP) development.
Materials and methods:
This retrospective study included 120 preterm infants in total. Group 1 was formed by infants who developed type-1 ROP and received treatment. Group 2 was formed by infants who developed ROP and were not treated for ROP. Infants who did not develop ROP and whose retinal vascularization was completed in their follow-up formed Group 3. Gestational age, birth weight, and genders of groups were recorded. Platelet (PLT) count, mean platelet volume (MPV), and platelet distribution width (PDW) values were obtained from complete blood count. Platelet mass index (PMI) was calculated by multiplying the PLT count by MPV value. Thrombocytopenia was defined as PLT count <150 × 1000/μL. All parameters were compared between the groups.
Results:
There were 40 preterm infants in each group. The mean PLT count was 272.43 ± 122.67 in Group 1, 333.32 ± 133.06 in Group 2, and 310.03 ± 119.41 in Group 3. The difference in PLT count between the groups was not significant (p=0.094). Thrombocytopenia was observed in 25% of Group 1, 10% of Group 2, and 10% of Group 3 (p=0.095). No statistically significant difference was found in terms of MPV, PDW, and PMI values between the groups (p=0.102, p=0.097, and p=0.298, respectively).
Conclusions:
Although PLT count was lower and thrombocytopenia rate was higher in the type-1 ROP group, the differences were not found to be significant. Further prospective studies are required to evaluate the role of thrombocytes in ROP pathogenesis.
... The relative hyperoxia leads to the initial vaso-obliteration phase of ROP, wherein normal retinal vascular development stops and the existing microvasculature of the retina regresses following EC death [15,17]. As the retina develops its metabolic demand increases leading to a higher requirement of blood supply than the depleted microvascular can provide [18]. The retina becomes hypoxic, triggering the release of VEGF and initiating the second vaso-proliferative phase of ROP. ...
... The retina becomes hypoxic, triggering the release of VEGF and initiating the second vaso-proliferative phase of ROP. The vaso-proliferative phase is characterized by hypoxiainduced compensatory pathological neovascularization with poorly patterned and abnormally leaky vessels, which can lead to the formation of fibrous scarring and in severe cases retinal detachment and blindness [17][18][19]. eNOS knockout mice appear to be protected from the initial oxygen-induced vaso-obliteration and display reduced pathological neovascularization after hyperoxia [20]. Conversely, transgenic overexpression of eNOS in mice increased vascular closure in the obliterative phase and exacerbated the formation of neovascular tufts [21]. ...
The roles of nitric oxide (NO) and endothelial NO synthase (eNOS) in the regulation of angiogenesis are well documented. However, the involvement of eNOS in the sprouting of endothelial tip-cells at the vascular front during sprouting angiogenesis remains poorly defined. In this study, we show that downregulation of eNOS markedly inhibits VEGF-stimulated migration of endothelial cells but increases their polarization, as evidenced by the reorientation of the Golgi in migrating monolayers and by the fewer filopodia on tip cells at ends of sprouts in endothelial cell spheroids. The effect of eNOS inhibition on EC polarization was prevented in Par3-depleted cells. Importantly, downregulation of eNOS increased the expression of polarity genes, such as PARD3B, PARD6A, PARD6B, PKCΖ, TJP3, and CRB1 in endothelial cells. In retinas of eNOS knockout mice, vascular development is retarded with decreased vessel density and vascular branching. Furthermore, tip cells at the extremities of the vascular front have a marked reduction in the number of filopodia per cell and are more oriented. In a model of oxygen-induced retinopathy (OIR), eNOS deficient mice are protected during the initial vaso-obliterative phase, have reduced pathological neovascularization, and retinal endothelial tip cells have fewer filopodia. Single-cell RNA sequencing of endothelial cells from OIR retinas revealed enrichment of genes related to cell polarity in the endothelial tip-cell subtype of eNOS deficient mice. These results indicate that inhibition of eNOS alters the polarity program of endothelial cells, which increases cell polarization, regulates sprouting angiogenesis and normalizes pathological neovascularization during retinopathy.
... Reductions happen in hemoglobin (Hb) levels and in the hematocrit (HCT) owing to many causes in newborns with ROP, and these reductions can further enhance VEGF secretion. Angiogenesis adjusted via local releasing of proangiotic or angiogenic factor is an additional critical stage in the progress of pathological ROP [6]. ...
... 6 The rapid fluctuations in oxygen cause a substantial stress to the retina tissue, which can activate apoptotic pathways that lead to retinal cell death. 7 In line with these findings, an expansion of studies suggests that autophagy is involved in retinal diseases and contributes to the progressive visual dysfunction. 8,9 Autophagy is an intracellular degradation system, essential to eliminate unnecessary cell components, including unfolded proteins and damaged organelles, through the intermediary formation of the autophagosome, a double membrane-bound vesicle that fuses with the lysosome to promote the degradation of its content by the cellular lysosomal system. ...
In retinopathy of prematurity (ROP), the abnormal retinal neovascularization is often accompanied by retinal neuronal dysfunction. Here, a rat model of oxygen‐induced retinopathy (OIR), which mimics the ROP disease, was used to investigate changes in the expression of key mediators of autophagy and markers of cell death in the rat retina. In addition, rats were treated from birth to postnatal day 14 and 18 with 3‐methyladenine (3‐MA), an inhibitor of autophagy. Immunoblot and immunofluorescence analysis demonstrated that autophagic mechanisms are dysregulated in the retina of OIR rats and indicated a possible correlation between autophagy and necroptosis, but not apoptosis. We found that 3‐MA acts predominantly by reducing autophagic and necroptotic markers in the OIR retinas, having no effects on apoptotic markers. However, 3‐MA does not ameliorate retinal function, which results compromised in this model. Taken together, these results revealed the crucial role of autophagy in retinal cells of OIR rats. Thus, inhibiting autophagy may be viewed as a putative strategy to counteract ROP.
... This association depended on the timing and duration of oxygen supplementation [22]. Hypoxemic events are one of the common problems in premature infants and they play a significant role in the pathogenesis of ROP [26]. Therefore, an explanation for our results could be the increased frequency of hypoxemic events when using noninvasive ventilation methods compared to invasive methods in the treatment of RDS [27]; however, due to the retrospective data analysis without recording of hypoxemic events, we were unable to confirm this as a possible cause of ROP. ...
Retinopathy of prematurity (nROP) among extremely low gestational age newborns (ELGAN) in Slovenia has increased in recent years. At the same time mortality has further decreased and less invasive approaches for treatment of respiratory distress syndrome have been established. With the aim to study the possible association between the incidence of ROP and the duration of noninvasive ventilation, this retrospective study comprised ELGANs born during the first period (2010/2011), when invasive respiratory support was the prevalent method and in the second period (2015/2016), when noninvasive respiratory support was adopted. The results showed that the duration of noninvasive ventilation is a potential risk factor for ROP. Controlling for known risk factors for ROP and then adjusting for gestational age, number of transfusions and fraction of inspired oxygen (FiO2), the odds of ROP were 1.22 times greater (95% confidence interval, CI 1.01-1.48) with every additional week of noninvasive ventilation (p = 0.03).
... We also need to understand the role of platelets in neonatal angiogenesis [ 53 , 54 ]. Stimulation of α-granules in platelets and megakaryocytes can cause release of proangiogenic and antiangiogenic agents [55] which appear to be critical elements in the pathologic process of retinopathy of prematurity (ROP) which is a potentially devastating consequence of prematurity which can cause blindness [56][57][58] . Activated platelets may have a role in the pathogenesis of ROP [58] . ...
Preterm neonates with severe thrombocytopenia are frequently prescribed prophylactic platelet transfusions despite no evidence of benefit. Neonatal platelet transfusion practice varies, both nationally and internationally. Volumes and rates of transfusion in neonatology are based on historic precedent and lack an evidence base. The etiology of harm from platelet transfusions is poorly understood. Neonates are expected to be the longest surviving recipients of blood produce transfusions, and so avoiding transfusion associated harm is critical in this cohort. This article reviews the evidence for and against platelet transfusion in the neonate and identifies areas of future potential neonatal platelet transfusion research.
... The long-term visual outcome for children with ROP involves an increased risk for visual impairment. ROP develops in two consecutive phases: phase I, in which peripheral retinal vascular formation is halted due to hyperoxia, and phase II that is characterized by abnormal retinal neovascularization secondary to cytokines induced by the resulting hypoxia [1]. Predominant cytokines during these phases are different; therefore the variety of recruited inflammatory cells; and their behavior may differ. ...
PurposeTo evaluate the relationship of novel inflammatory markers neutrophil-to-lymphocyte ratio (NLR) and platelet-to-lymphocyte ratio (PLR) with retinopathy of prematurity (ROP) development and requirement for laser photocoagulation (LP) treatment.Methods
The charts of infants screened for ROP were reviewed retrospectively, and 120 newborns who had complete blood count (CBC) data in the first 24 hours after delivery (early period) and between 35 and 37th gestational weeks (late period) were included. Study population consisted of 34 infants who required LP for ROP treatment, 52 newborns with ROP that regressed without treatment, and 34 controls who did not developed any ROP stages. Demographics, etiological factors and CBC data including NLR and PLR values were noted. Risk factors for ROP development and treatment requirement were investigated using logistic regression analyses.ResultsSignificantly lower NLR was found in ROP cases compared to non-ROP group during late period (p = 0.003), while there was no difference in NLR during early period (p = 0.298). No significant difference was observed in PLR during both early and late periods (p = 0.230 and p = 0.349, respectively). Multivariate analysis revealed daily weight gain as major risk factor for ROP development (p = 0.001; OR: 0.870, 95% CI: 0.799–0.947), and hyperbilirubinemia as an independent risk factor for LP requirement (p = 0.045; OR: 0.204, 95% CI: 0.043–0.966).ConclusionNLR or PLR does not appear to be predictive risk factors for treatment requirement in cases with ROP. CBC values during first 24 h of life may be misleading; therefore, a late period CBC is recommended to evaluate prognostic factors for ROP development.
