Surgical Treatment of Hemorrhagic Complications of Age- Related Macular Degeneration, Predictive Factors and Outcomes

Surgical Treatment of Hemorrhagic Complications of Age- Related Macular Degeneration, Predictive Factors and Outcomes | Research Square window.SnipcartSettings = { analytics: { enabled: false } }; (function() { var accessVector = localStorage.getItem('access_vector') || ''; window.dataLayer = window.dataLayer || []; if (accessVector) { window.dataLayer.push({ user: { profile: { profileInfo: { snid: accessVector } } } }); } })(); (function(w,d,s,l,i){w[l]=w[l]||[];w[l].push({'gtm.start':new Date().getTime(),event:'gtm.js'});var f=d.getElementsByTagName(s)[0],j=d.createElement(s),dl=l!='dataLayer'?'&l='+l:'';j.async=true;j.src='https://www.googletagmanager.com/gtm.js?id='+i+dl;f.parentNode.insertBefore(j,f);})(window,document,'script','dataLayer','GTM-K279D39R'); Browse Preprints In Review Journals COVID-19 Preprints AJE Video Bytes Research Tools Research Promotion AJE Professional Editing AJE Rubriq About Preprint Platform In Review Editorial Policies Our Team Advisory Board Help Center Sign In Submit a Preprint Cite Share Download PDF Research Article Surgical Treatment of Hemorrhagic Complications of Age- Related Macular Degeneration, Predictive Factors and Outcomes Jela Valaskova, Pavol Vesely, Vladimir Krasnik, Ivajlo Popov, and 3 more This is a preprint; it has not been peer reviewed by a journal. https://doi.org/ 10.21203/rs.3.rs-5442181/v1 This work is licensed under a CC BY 4.0 License Status: Under Review Version 1 posted 9 You are reading this latest preprint version Abstract Purpose: The objective of this study was to evaluate the functional and clinical outcome of submacular hemorrhage (SMH) in age related macular degeneration (ARMD) displacement using pneumatic displacement with intravitreal expansile gas by 23Gauge pars plana vitrectomy with subretinal injection of recombinant tissue plasminogen activator (rtPA). Patients and methods: Retrospective interventional case series of 58 pseudophakic patients, who underwent surgical treatment with inclusion criteria: subretinal, subretinal pigment epithelium (subRPE), or combined central hemorrhage associated with ARMD, 23 Gauge pars plana vitrectomy using rtPA sulfur hexafluoride (SF6). Patients were classified according to the clinical picture, the size of the hemorrhage, into group with small hemorrhage up to 2x2 papillary diameter (PD) 32 eyes, moderate hemorrhage (up to 4x4PD, to the arcades) 19 eyes and massive hemorrhage (from 5x5PD hemorrhage through the arcades to the periphery) 7 eyes. Medical records were reviewed for diagnosis, logMAR best corrected visual acuity (BCVA), preop and postop clinical findings, complications, and all medical history up to 6 months after surgery. Results: Improvement of average postoperative BCVA was the best in group with moderate extension of hemorrhage, 1.58 logMAR preoperative to 1.14 logMAR postoperative. Improvement of average postoperative BCVA was the best in group with shortest medical history of hemorrhage (up to 7 days). Age was not a crucial predictive factor. Regarding association between hemorrhage category and clinical outcome, there was a significant positive association between the hemorrhage size before the operation and the scored clinical outcome. In association between anticoagulant treatment (ACT) and clinical outcome there was negative, but not significant association between the treatment and the scored clinical outcome (P = 0.5197). Comorbidities, as diabetes mellitus or arterial hypertension after adjustment on the baseline and ACT were not significantly associated with worsened vision measured on the LogMAR scale. Conclusion: We consider surgical treatment of the hemorrhagic complication of ARMD to be beneficial, massive hemorrhages have a worse prognosis for improving BCVA than moderate and small hemorrhages. Anticoagulants are associated with massive hemorrhage and, at the same time, with the better postoperative BCVA than massive hemorrhage without total ACT. subretinal neovascularization hemorrhage anticoagulation treatment recombinant tissue plasminogen activator Figures Figure 1 Figure 2 Figure 3 Figure 4 Figure 5 Figure 6 Introduction Age-related macular degeneration (ARMD) is a chronic degenerative disease of the central part of the retina that occurs in older age (after 50 years of age). The wet form of ARMD can be treated or stabilized using intravitreal applications of anti-growth factors. One of the most severe ocular complications of the wet form of ARMD in treated or untreated patients is hemorrhage at the site of choroidal neovascularization (CNV) in the macula. The natural course of hemorrhage resorption, without any medical intervention, is associated with a poor visual prognosis, so today the aim is to surgically remove the hemorrhage in the macula as quickly as possible. In surgical treatment, we use recombinant tissue plasminogen activator (rtPA) in combination with expansion gas and continue to treat the underlying disease during the following follow-up. In recent years, there has been a growing number of records in the literature about an increased frequency of hemorrhagic eye complications with the simultaneous use of anticoagulants based on various general diseases. ACT has clear significant benefits, but it is also considered a risk factor increasing the complications of hemorrhage, specifically hemorrhage in the macula. Hemorrhage into the macula, the place of the sharpest vision, is an acute condition associated with a sudden deterioration of visual functions. The most common cause is CNV in patients with ARMD, less often myopia, trauma, uveitis, or even after laser therapy. Hemorrhage into the macula without the presence of CNV can be associated with retinal macroaneurysms, Valsava maneuver, choroidal rupture, Terson syndrome or even proliferative diabetic retinopathy. About 80% of information is perceived by sight, sight is the most important of all sensory organs. The sensory organ of vision is the eye. Our visual perception begins with the passage of a light beam through several structures of the eye and its absorption by photoreceptors, rods and cones, located in the outer nuclear layer of the retina. The human eye contains 100 million rods and 6 million cones. Photoreceptors are specialized sensory neurons that use proteins to convert light into a nerve signal that can be interpreted by the nervous system. Photoreceptors die when they are mechanically, for a variety of reasons, including hemorrhage, separated from the retinal pigment epithelium (RPE) and choroidal vessels that provide metabolic support to the outer layers of the retina. Photoreceptors do not have the ability to reproduce. The natural course of hemorrhage into the macula leads to a significant and permanent deterioration of best corrected visual acuity (BCVA). In animal models, irreversible changes occur after 24 hours and complete loss of photoreceptors after 7 days [ 6 ]. There are several reasons. Iron toxicity in the blood causes irreversible damage to retinal photoreceptors [ 6 , 13 ]. The mechanical barrier of the blood clot reduces the transfer of nutrients between the retina and the choroid. The fibrin membrane leads to traction damage to the RPE and photoreceptors. During hemorrhage, an induced inflammation occurs, which leads to the accumulation of macrophages [ 2 , 5 , 17 , 21 , 24 ]. All these mechanisms lead to the gradual destruction of photoreceptors. In an acute condition, hemorrhage into the macula, there is currently a definite preference for invasive treatment over conservative treatment. Rapid invasive surgical treatment can lead to improvement of central BCVA [ 1 ]. The goal of invasive treatment is to remove the blood clot and affect the underlying disease, CNV in ARMD. Invasive treatment can be carried out in two ways, by applying drugs and expansion gases by injection into the vitreous, the so-called intravitreal application, or in the form of 23/25/27 Gauge pars plana vitrectomy, with simultaneous removal of the vitreous, while the application of drugs in this case has multiple locations, the drug can be applied into the vitreous cavity or under the retina. Alteplase, a recombinant tissue plasminogen activator, has been used for almost two decades to dissolve a blood clot. It is a fibrinolytic, the body's own factor, produced by the endothelium, which promotes the conversion of plasminogen to plasmin. Plasmin is a protease that cleaves fibrin in a blood clot into fibrin degradation products. Resorbable expansion gases, SF6 and C3F8, are used to mechanically expel hemolyzed blood from the macula. In addition to dissolving the blood clot, ophthalmologists try to influence the underlying disease by intraoperative application of anti-vascular endothelial growth factor (anti-VEGF), the so-called anti-VEGF substances into the vitreous cavity. Today there are used several drugs, ranibizumab, aflibercept, brolucizumab, faricimab and off-label bevacizumab. Several results have been published, preferring different surgical procedures with the application of different drugs. There are several studies devoted to long-term post-intervention follow-up. In 2018, a new classification of hemorrhage in the macula was proposed by a group of German authors [ 7 ]. The so-called FLATCAPS classification (FLATCAPS from English F- foveal involvement, L- layer, A- age, T- thickness, C- cause/ pathogenesis, S- size, PD - papillary diameter). The purpose of the classification is to recommend the optimal surgical procedure based on several input factors, to determine the prognosis of BCVA after surgery and the possibility of comparing different factors. The aim of this work was to evaluate information about a set of patients with hemorrhagic complications in ARMD, treated surgically in our clinic from 2018 to 2021, we evaluate this type of treatment as well as the share and the joint effect of several predictors on the outcome including ACT. The aim of our study was to evaluate the surgical treatment of the entire group by way of 23G PPV using rtPA and SF6 on the basis of BCVA 2 months after operations and clinical picture, presence of hemorrhage, 2 months after operations, to determine the effect of size hemorrhage not the resulting BCVA. We wanted to find out the influence of local factors on hemorrhage like medical history, duration of hemorrhage, size of hemorrhage before surgery. We wanted to determine the share of overall factors on the result after treatment, such as anticoagulant treatment or patient’s age. Material and methods A retrospective interventional case series of 58 patients with pseudophakia, who underwent surgical treatment in period 2018–2023 with inclusion criteria: subretinal, subretinal pigment epithelium (subRPE), or combined central hemorrhage verified on optical coherence tomography - OCT (SD-OCT, Heidelberg Engineering, Heidelberg Germany) associated with ARMD, 23 Gauge (DORC) pars plana vitrectomy using rtPA (Actilyse®, Boehringer, Ingelheim, Germany), sulfur hexafluoride (SF6), rtPA was applied subretinally through a 41 Gauge subretinal cannula. Medical records were reviewed for diagnosis, logMAR BCVA, preop and postop clinical findings, complications, and all medical history up to 6 months after the surgery. Preoperatively, during hospitalization, blood samples, blood counts, biochemistry, hemocoagulation factors were taken from all patients, and a general internal preoperative examination with anesthesiology examination was performed. Patients were operated on within 24 hours of admission under local anesthesia, which is a combination of retrobulbar administered marcaine 0.5% and lidocaine 2% and intravenous support of myorelaxants, anxiolytics and painkillers. The surgical procedure via 23 Gauge (23G) pars plana vitrectomy (PPV) included subretinally applied recombinant tissue plasminogen activator at a concentration of 50 µg in 0.05 ml saline with tamponade of the vitreous cavity with SF6 expansion gas. After the operation, the patients were asked to position themselves face down for at least 24 hours after the operations. The aim of our study was to evaluate the surgical treatment of the entire group by way of 23G PPV using rtPA and SF6 on the basis of BCVA 2 months after operations and clinical picture, presence of hemorrhage, 2 months after operations, to determine the effect of size hemorrhage not the resulting BCVA. We wanted to find out the influence of local factors on hemorrhage like medical history, duration of hemorrhage, size of hemorrhage before surgery. We wanted to determine the share of overall factors on the result after treatment, such as anticoagulant treatment or patient’s age. Patients were classified according to the clinical picture, the size of the hemorrhage, into groups: small-size hemorrhage (up to 2x2PD) 32 eyes, medium-size hemorrhage (up to 4x4PD, to the arcades) 19 eyes and massive hemorrhage (from 5x5PD hemorrhage through the arcades to the periphery) 7 eyes. As part of comorbidities, 48 patients were treated for arterial hypertension, 9 patients were treated for diabetes mellitus, and 35 patients (60.3%) were on anticoagulant treatment for various reasons. All patients were followed up for at least 6 months. Evaluation of the results of the whole group after 23G PPV with rtPA and SF6 based on pre- and postoperative BCVA (2 months after the operations) and clinical findings of the occurrence of hemorrhage in the macula (2 months after the operations). The clinical findings of residual hemorrhage after operation were classified into 4 categories, 1st category - no hemorrhage, 2nd category - residual hemorrhage, 3rd category - hemophthalmos, and 4th category - other complication. Statistical analysis The patients' demographics, clinical and laboratory characteristics were summarized and analyzed using descriptive and inferential statistics. Categorical variables are presented as counts and percentages in a contingency table. Fisher's exact test was used to determine if there was a nonrandom association between the two variables. The patients were tested for between-group and within-group differences in all relevant characteristics. Univariate analysis of continuous outcome (BCVA) in two or more groups was made using one-way or two-way analysis of variance (ANOVA). Where appropriate, matching across subjects was considered (e.g. for analysis of repeated examinations across time). Relationship between continuous outcome and one or more prognostic factors (e.g. baseline clinical picture or DM) and treatment effects (e.g. ACT) was analyzed using multiple regression. Univariate analysis of association between categorical outcome (hemorrhage severity after operation) and a categorical predictor grouped in two-way contingency tables was performed using Pearson's chi-square test for independence. Multivariable analysis was performed using multinomial logistic regression. Relationship between a continuous dependent variable and one or more predictor variables was modelled using simple and multiple linear regression. For the data processing and analysis, the software Microsoft Office Excel 2016 (Microsoft Corporation ), GraphPad Prism 9.0 (GraphPad Software Inc., San Diego, CA, US) and StatsDirect® 4.0.2 were used (StatsDirect Ltd., Cheshire, UK). All of the tests were two-tailed and conducted at a significance level α = 0.05. Results The group consisted of 58 patients, 21 male, 37 female, the difference in proportions was statistically significant (P = 0.0479). Average age 77.8 years, (male 77.2 and female 78.1 years, P = 0.713), the age distribution ranged from 53 to 93 years. The diagnosis of neovascular age-related macular degeneration (nAMD) was in 100% of cases. The left eye was operated more often, 32 times, the right eye 26 times. Hemorrhage history ranged from one day to three months. There were 28 patients with a patient’s record up to 7 days, 18 patients with a patient’s record up to one month, and 12 patients with a patient’s record longer than a month. Postoperative improvement in reduction of submacular hemorrhage was noticed in 93% cases, total postoperative hemorrhage absorption in 51.7% cases. Mean baseline BCVA (24 hours before operation) in the whole group was 1.467 on the logMAR scale, and two months postoperative BCVA was 1.145 logMAR (Fig. 1 and Table S1 ). This difference was statistically significant on both, the univariate analysis (P = 0.0009) and after adjustment to anticoagulation treatment by stratifying the whole sample according to ACT (P = 0.0008). In the subgroups by ACT, we did not find any statistical difference in the baseline BCVA values (P = 0.9987; Fig. 2 , left). After the operation, the mean BCVA values were lower in the subgroup of patients with ACT (P = 0.0923; Fig. 2 , right). Another important baseline predictor of the effect of surgery was preoperative clinical picture according to the categorized size of the hemorrhage. The largest group was that of small-size hemorrhages, 32 eyes (55% of the total). The group of medium-size hemorrhages consisted of 19 eyes (33%). Patients with massive hemorrhages formed the smallest group (7 eyes, 12%). The outcome evaluated by crude BCVA values two months after operation was significantly associated with the preoperative clinical picture (P = 0.0006). The lowest value of BCVA was found (as expected) in the group of small-size hemorrhages (BCVA = 0.991 from the preoperative value of 1.317 LogMAR) followed by the group of medium-size hemorrhages (BCVA = 1.145 LogMAR from 1.579 logMAR). For the group of massive hemorrhages zero improvement from the baseline value of 1.850 LogMAR was found). The best improvement in the mean postoperative BCVA relative to the preoperative BCVA was reached in group with medium-size hemorrhage (difference of – 0.434 LogMAR). Since our sample size was rather small, only limited number of variables for the prediction model could be considered. Therefore, we adjusted analysis for other predictors for preoperative (baseline) values of BCVA using the difference (BCVA 2 months after operation minus 24 hours before operation) as an alternative to the effect “clinical findings of residual hemorrhage after operation”. The association between the clinical outcome and the difference in BCVA after-before operation was proved to be statistically significant (P = 0.0440), with the most improved BCVA values in groups with no or residual hemorrhage (Fig. 3 ). This association was also confirmed by cross-tabulation analysis (P = 0.0156; Table 1 ), where clinical outcomes on the degree of postoperative hemorrhage depended on the baseline clinical picture categorized according to the size of the hemorrhage (Goodman-Kruskal gamma for ordinal association = 0.524 (P = 0.0032). Table 1 The relationship between ordered categories of baseline clinical picture and clinical outcome categorized by hemorrhage severity Characteristic Hemorrhage Clinical outcome category Baseline category no hemorrhage residual hemorrhage hemophthalmos Total small-size 19 (63.3%) 12 (50%) 0 (0%) 31 (54.4%) medium-size 11 (36.7%) 8 (33.3%) 0 (0%) 19 (33.3%) massive 0 (0%) 4 (16.7%) 3 (100%) 7 (12.3% Total 30 (100%) 24 (100%) 3 (100%) 57 (100%) Relative counts are expressed as % of column total. Approximate chi-square test of independence: P = 0.0156; Goodman-Kruskal gamma for ordinal association = 0.524 (P = 0.0032). The category “other complication” in the outcome consisted of one case and was omitted from the analysis. From the cross-tabulation analysis of clinical findings based on the presence of hemorrhage in the macula of the entire group before and after surgery we can conclude that the resorption of hemorrhage after operations was found in more than half of patients (51.72%; 30 out of 58 patients). In total, 54 patients, 93%, improved in terms of the clinical finding of hemorrhage resorption. Evaluation of other assumed predictors. Improvement of average postoperative BCVA was best in the subgroup with shortest medical history of hemorrhage (up to 7 days), from 1.461 logMAR preoperative to 1.021 logMAR postoperative. In the second subgroup where the duration was in weeks up to a month, the mean value of BCVA before operation was 1.483 logMAR and after operation 1.225 logMAR. In the third group with duration of more than a month the mean value of BCVA before operation was 1.461 logMAR and after operation 1.313 logMAR). Age was not a crucial predictive factor, neither for postoperative complications (P = 0.6571), nor for vision improvement (P = 0.6907). Evaluation of the effect of age at operation on the post-pre-operation differences in BCVA measurements showed no significant relationship (P = 0.6907) (Fig. 4 ). Further, improvement of vision was not dependent on the side of eye (P = 0.8309). As to the comorbidities, diabetes mellitus or arterial hypertension after adjustment on the baseline and ACT were not significantly associated with worsened vision measured on the LogMAR scale. The only relevant predictor was concurrent anticoagulant treatment. In the entire group of 58 patients, 35 patients, 60.3% of the total group, were on ACT. We have found that ACT did not worsen the outcomes in terms of BCVA. On the contrary, after operation the group with massive hemorrhage where were mostly patients with ACT (n = 5, 71.4%) had significantly better postoperative reduction in BCVA values relative to the baseline, as did the group with massive hemorrhage and without ACT treatment (-0.170 vs. +0.425, respectively). According to the amount of hemorrhage, there were 20 patients with ACT in the first group with no hemorrhage after operation, 13 patients with ACT in the second group of residual hemorrhage, and 2 patients in the third group with hemophthalmos. The overall association between ACT and clinical outcome categorized according to the severity of postoperative hemorrhage was also negative, even if not significant due to low numbers of cases in the categories (Goodman-Kruskal's gamma coefficient = -0.252; P = 0.2939). The mutual effect of ACT and time of examination on the BCVA measurements, as well as possible interaction between treatment and time was analyzed using two-way analysis of variance with data matched across time categories. Results are given in Fig. 5 . P-value for the main effect of factor Time equaled 0.0008, whereas the main effect of ACT was not significant (P = 0.4801). We did not observe a significant interaction between Time and Treatment with anticoagulants (P = 0.3050). The simple effect of time within each treatment condition in given in Fig. 6 left: P-value for ACT group was equal to 0.0006 and P-value for untreated patients amounted to 0.1120. On the other hand, simple effects for examinations performed within 24 hours before operation and those performed two months after operation were not significant (P = 0.9987 and P = 0.2439, respectively; Fig. 6 right). To summarize the obtained results, two months after the surgery the average BCVA of the entire group improved what is the reaction on partial or complete hemorrhage resorption we see in clinical findings. The best outcomes were in the group with the shortest patient’s record of the hemorrhage with the moderate size. Discussion Anticoagulants are associated with massive hemorrhage and, at the same time, better postoperative BCVA than massive hemorrhage without ACT, which implies the necessity of sufficient control of coagulation factors in correlation with local eye findings in treated wet forms of ARMD. A common retinal vascular disorder causing bleeding and visual deterioration in the age over 60 is retinal vein occlusion, where complications include macular ischemia, neovascularisations, but also vitreous hemorrhages. We can see central and branch retinal vein occlusions but also their ischemic and nonischemic subtypes. Branch occlusions and nonischemic conditions are associated with better visual acuity prognosis. Up today there have been various types of therapy with not relevant effect. Due to the lack of effective monotherapy, there is probably a need to combine the therapy approach [ 4 ]. The entry criteria in our retrospective study were hemorrhagic complication of wet form of ARMD, surgical treatment of 23G PPV using rtPA and SF6. We evaluated preoperative and postoperative BCVA in the entire group of patients. We found out that 2 months after the operations, the average BCVA of the entire group improved. When investigating the effect of ACT in more detail, we divided our group into two parts, with ACT, 35 patients’ treatment and without ACT, 23 patients and we found that there is a difference in the resulting BCVA of these two sets, this however, the difference is not statistically significant. Patients with ACT given were most represented in the group with massive hemorrhage, 71.4%. In a more detailed breakdown of the total group according to the present ACT and according to the size of the hemorrhage, we found that there is a statistically significant difference in the result of BCVA after surgery between the group with massive hemorrhage and simultaneous use of anticoagulants and the group with massive hemorrhage without the simultaneous use of anticoagulants. We found that patients with massive hemorrhage with concomitant use of anticoagulants have significantly better postoperative BCVA. That means, that ACT seems to be a "good" predictive factor of better BCVA after operations for massive hemorrhage. Given that it is a hemorrhagic complication of a local disease, it also means that patients who receive ACT the hemorrhage is more massive as in patients without ACT. But after surgical removal of the hemorrhage, they have better BCVA than patients without ACT. This means that local retinal disease does not represent as much retinal destruction in patients with ACT as in patients without ACT, it is only potentiated by ACT. What does this mean for clinical practice? Patients with the exudative form of ARMD and concurrent ACT should be checked frequently enough in terms of hemocoagulation parameters adequate for ACT, among other things, also for possible hemorrhagic complications of local eye disease. In the case of an acute hemorrhagic complication of ARMD with concurrent ACT, such a patient has a higher chance of massive hemorrhage, but at the same time, after surgical treatment, of better postoperative BCVA than a patient without ACT. The possible question of a higher frequency of hemorrhagic complications in patients with concurrent ACT is provided by this file only in terms of its scope, out of 58 patients with a hemorrhagic complication, 35 patients, 60.3%, were on concurrent anticoagulant treatment. As part of the overall predictive factors, we found that despite the wide age range (from 53 to 93) and the higher average age (77.8) in this group, age was not a significant determinant of the postoperative outcome. Comparison with studies: In the study of 31 patients from 2021 [ 18 ] from Germany and Switzerland they compared the same surgical treatment with rtPA and SF6 with the same incisional criteria, with the conclusion confirming the effectiveness of surgical treatment, while when comparing the subsets with the additive application of bevacizumab, the results are comparable between the subsets. In the subset without bevacizumab application, 14 patients achieved an average BCVA of 1.48 ± 0.48 to 1.01 ± 0.38 logMAR, while the removal of hemorrhage reached 50% of patients. A cohort of 25 eyes from Italy [ 8 ] evaluated 23G PPV with subretinal rtPA and SF6 as a safe and effective technique, recommending treatment within 14 days of symptom onset. Average BCVA 12 months after surgery decreased from 1.81 ± 0.33 to 1.37 ± 0.52 LogMAR. There are several case reports and several files confirming the negative impact of anticoagulants and the wet form of ARMD [ 11 , 12 , 14 , 20 ], which leads to massive hemorrhages. These works did not evaluate the effect of surgical treatment on hemorrhage. Other studies compared three treatment modalities for AMD complicated by a submacular hemorrhage (SMH). They included an extended spectrum of hemorrhage sizes as well as a larger number of patients than previous studies. In one study they divided patients according to the SMH size and analyzed the treatment outcomes of three different modalities to identify their effects in each subgroup with homogeneity in terms of size. The overall mean BCVA improved significantly from the baseline during the 12 months follow-up period. However, different outcomes were observed according to the SMH size and treatment modalities. In the small-sized group, anti-VEGF monotherapy was performed on the majority of patients (51.1%) and it significantly improved the BCVA. The two other treatment modalities also increased the mean BCVA and the magnitude of improvement showed no difference among the treatment modalities [ 10 ]. In our study we did not compare anti-VEGF therapy and influence to BCVA. Study TIGER is a phase 3, pan-European, two-group, active-control, observer-masked, superiority, randomized controlled surgical trial. Eligible participants have large, fovea-involving SMH of no more than 15 days duration due to treatment-naïve or previously treated neovascular AMD, including idiopathic polypoidal choroidal vasculopathy and retinal angiomatous proliferation. A total of 210 participants are randomized in a 1:1 ratio to pars plana vitrectomy, off-label subretinal TPA up to 25 µg in 0.25 ml, intravitreal 20% sulfur hexafluoride gas and intravitreal aflibercept, or intravitreal aflibercept monotherapy. Aflibercept 2 mg is administered to both groups monthly for 3 doses, then 2-monthly to month 12 [ 9 ]. In the study of compared outcomes of subretinal versus intravitreal injection of recombinant r-tPA and gas in cases of SMH secondary to AMD the results of both treatment options proved equal efficacy in displacing SMH in AMD. A multicenter trial in the future may delineate a desirable algorithm of treatment [ 22 ]. In the review article the authors aimed to explore the current treatment strategies and supporting literature regarding both surgical and nonsurgical, of SRH in patients with AMD. The accented to highlight the distinct treatment modalities corresponding to different sizes of SRH [ 16 ]. Caporossi et al. in the study evaluated the different postoperative outcomes of patients affected by macular neovascularization (MNV) complicated by SMH that underwent subretinal implant of human amniotic membrane (hAM) or subretinal injection of tPA. In the retrospective but non-randomized interventional study of 44 eyes, where 22 eyes underwent PPV plus SMH and MNV removal, with a subretinal implant of hAM and silicone oil. The second half of the study group underwent PPV, subretinal injection of tPA, and 20% sulphur hexafluoride. Due to their results they found out that both techniques report similar BCVA improvements and postoperative complications, but transplantation of hAM seems to have a significant benefit in inhibiting MNV recurrence [ 3 ]. In the recent study of authors where the aim was to describe surgical results and fundus autofluorescence (FAF) patterns after PPV combined with tPA + anti-VEGF and intravitreal tPA + anti-VEGF + sulfur hexafluoride (SF6) tamponade and to compare them to intravitreal tPA + anti-VEGF + SF6. Due to their results FAF patterns did not depend on the treatment used, but only from the duration of SMH before therapy. They realized, that SMH if not treated prompt enough might cause long-standing photoreceptor cell and RPE defect, which is represented by hypo- and hyper-autofluorescence. Performing a subretinal injection of tPA and anti-VEGF does not cause any defects associated with the injection site. That might be associated with previous local internal limiting membrane peeling [ 15 ]. Due to recent study results not only prompt treatment of SMH but also further continuation of intravitreal anti-VEGF therapy is mandatory to maintain anatomical and but also functional results. One of the first studies to compare the surgical outcomes of pneumatic displacement versus subretinal application of tPA, anti-VEGF agent, and gas was published by Szeto et al. [ 19 ]. They demonstrated novel technique in cases with thick and extensive SMH or as a rescue secondary operation in selected cases and realized that subretinal application of cocktail injection has positive impact to small but also massive SMH. Their study provided new data and for the future it will have impact on the decision how to manage SMH. In their study subretinal cocktail injection achieved higher rate of successful displacement of SMH. Surgical displacement of SMH leads to clinically meaningful improvement in better function and better BCVA. PPV with subretinal cocktail injection is more effective than pneumatic displacement in displacing SMH with similar safety profile despite longer interval before operation [ 19 ]. In the recent meta-analysis of Veritti et al. in 257 initial reports where met inclusion criteria the authors realized the significant improvement in BCVA and successful SMH with combined tPA and anti-VEGF therapy, but no significant differences were found between subretinal and intravitreal tPA administration. Today in managing SMH in nAMD patient the combined tPA and anti-VEGF therapy is effective, significantly improving BCVA and SMH displacement, but the location of tPA and anti-VEGF delivery did not significantly impact clinical results [ 23 ]. Conclusion Based on these results, we consider surgical treatment of the hemorrhagic complication of ARMD to be beneficial, while its effect increases with a shorter history of the disease and a moderate extent of hemorrhage. Massive hemorrhages have a worse prognosis for improving BCVA than moderate and small hemorrhages. From the overall parameters, the age of the patient is not decisive for the effect of the treatment, while anticoagulant treatment is associated with a higher risk of massive hemorrhage, but at the same time, probably as a factor prevailing over the local finding, after surgical treatment with rtPA with SF6 with a better functional and anatomical result. The final result of surgical treatment for hemorrhagic complications of ARMD is primarily determined by the local state of the retina before hemorrhage, the type of treatment and the concomitant use of anticoagulants. Declarations Acknowledgments Disclosure The author(s) report no conflicts of interest in this work. Statement of Ethics This case report adhered to the tenets of the Declaration of Helsinki. Written informed consent was obtained from the patient for publication of the details of their medical case and any accompanying images. Ethical approval is from Institutional Ethics Committee of University Hospital in Bratislava, Slovakia (protocol code EK/ 060/ 2024 from June 17, 2024). Conflict of Interest Statement Authors have no financial or proprietary interest in any material or method mentioned. Data Availability Statement All data related to this case report are included in the article and supplemental material. Further inquiries must be directed to the corresponding author. Funding Statement The authors received no specific funding for this work. Data analysis was supported by the project APVV-22-0154. References Agostini HT, Bopp S, Feltgen N (2017) [Prognosis and treatment of macular bleeding in neovascular age-related macular degeneration]. Ophthalmologe 114:476–480. https://doi.org/10.1007/s00347-017-0487-x el Baba F, Jarrett WH, Harbin TS et al (1986) Massive hemorrhage complicating age-related macular degeneration. Clinicopathologic correlation and role of anticoagulants. Ophthalmology 93:1581–1592. https://doi.org/10.1016/s0161-6420(86)33540-1 Caporossi T, Bacherini D, Governatori L et al (2022) Management of submacular massive haemorrhage in age-related macular degeneration: comparison between subretinal transplant of human amniotic membrane and subretinal injection of tissue plasminogen activator. 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Clin Ophthalmol 15:3649–3659. https://doi.org/10.2147/OPTH.S324091 Jackson TL, Bunce C, Desai R et al (2022) Vitrectomy, subretinal Tissue plasminogen activator and Intravitreal Gas for submacular haemorrhage secondary to Exudative Age-Related macular degeneration (TIGER): study protocol for a phase 3, pan-European, two-group, non-commercial, active-control, observer-masked, superiority, randomised controlled surgical trial. Trials 23:99. https://doi.org/10.1186/s13063-021-05966-3 Jeong S, Park D-G, Sagong M (2020) Management of a Submacular Hemorrhage Secondary to Age-Related Macular Degeneration: A Comparison of Three Treatment Modalities. J Clin Med 9:3088. https://doi.org/10.3390/jcm9103088 Kiernan DF, Hariprasad SM, Rusu IM et al (2010) Epidemiology of the association between anticoagulants and intraocular hemorrhage in patients with neovascular age-related macular degeneration. Retina 30:1573–1578. https://doi.org/10.1097/IAE.0b013e3181e2266d Kingham JD, Chen MC, Levy MH (1988) Macular hemorrhage in the aging eye: the effects of anticoagulants. N Engl J Med 318:1126–1127. https://doi.org/10.1056/NEJM198804283181710 Koshibu A (1979) [Ultrastructural studies on absorption of an experimentally produced subretinal hemorrhage. III. Absorption of erythrocyte break down products and retinal hemosiderosis at the late stage (author’s transl)]. Nippon Ganka Gakkai Zasshi 83:386–400 Kuhli-Hattenbach C, Fischer IB, Schalnus R, Hattenbach L-O (2010) Subretinal hemorrhages associated with age-related macular degeneration in patients receiving anticoagulation or antiplatelet therapy. Am J Ophthalmol 149:316–321.e1. https://doi.org/10.1016/j.ajo.2009.08.033 Nawrocka ZA, Nawrocki J (2024) Fundus Autofluorescence Patterns in Subretinal Hemorrhages Associated with Neovascular Age-Related Macular Degeneration. Ophthalmologica 247:58–64. https://doi.org/10.1159/000535865 Oncel D, Oncel D, Mishra K et al (2023) Current Management of Subretinal Hemorrhage in Neovascular Age-Related Macular Degeneration. Ophthalmologica 246:295–305. https://doi.org/10.1159/000534440 Reynders S, Lafaut BA, Aisenbrey S et al (2002) Clinicopathologic correlation in hemorrhagic age-related macular degeneration. Graefes Arch Clin Exp Ophthalmol 240:279–285. https://doi.org/10.1007/s00417-002-0448-0 Rickmann A, Paez LR, Della Volpe Waizel M et al (2021) Functional and structural outcome after vitrectomy combined with subretinal rtPA Injection with or without additional intravitreal Bevacizumab injection for submacular hemorrhages. PLoS One 16:e0250587. https://doi.org/10.1371/journal.pone.0250587 Szeto SKH, Tsang CW, Mohamed S et al (2024) Displacement of Submacular Hemorrhage Using Subretinal Cocktail Injection versus Pneumatic Displacement: A Real-World Comparative Study. Ophthalmologica 247:118–132. https://doi.org/10.1159/000537953 Tilanus MA, Vaandrager W, Cuypers MH et al (2000) Relationship between anticoagulant medication and massive intraocular hemorrhage in age-related macular degeneration. Graefes Arch Clin Exp Ophthalmol 238:482–485. https://doi.org/10.1007/pl00007887 Toth CA, Morse LS, Hjelmeland LM, Landers MB (1991) Fibrin directs early retinal damage after experimental subretinal hemorrhage. Arch Ophthalmol 109:723–729. https://doi.org/10.1001/archopht.1991.01080050139046 Tranos P, Tsiropoulos GN, Koronis S et al (2021) Comparison of subretinal versus intravitreal injection of recombinant tissue plasminogen activator with gas for submacular hemorrhage secondary to wet age-related macular degeneration: treatment outcomes and brief literature review. Int Ophthalmol 41:4037–4046. https://doi.org/10.1007/s10792-021-01976-x Veritti D, Sarao V, Martinuzzi D et al (2024) Submacular hemorrhage during neovascular age-related macular degeneration: a meta-analysis and meta-regression on the use of tPA and anti-VEGFs. Ophthalmologica. https://doi.org/10.1159/000537939 Wolter JR, Till GO (1989) Multinucleated giant cells on Bruch’s membrane late in recurrent retinal and subretinal hemorrhaging. Ophthalmologica 199:53–59. https://doi.org/10.1159/000310017 Additional Declarations No competing interests reported. Supplementary Files Supplementarymaterial.pdf Cite Share Download PDF Status: Under Review Version 1 posted Editorial decision: Revision requested 20 Dec, 2024 Reviews received at journal 19 Dec, 2024 Reviewers agreed at journal 19 Dec, 2024 Reviews received at journal 19 Dec, 2024 Reviewers agreed at journal 19 Dec, 2024 Reviewers invited by journal 23 Nov, 2024 Editor assigned by journal 13 Nov, 2024 Submission checks completed at journal 13 Nov, 2024 First submitted to journal 12 Nov, 2024 You are reading this latest preprint version Research Square lets you share your work early, gain feedback from the community, and start making changes to your manuscript prior to peer review in a journal. As a division of Research Square Company, we’re committed to making research communication faster, fairer, and more useful. We do this by developing innovative software and high quality services for the global research community. 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Also discoverable on Platform About Our Team In Review Editorial Policies Advisory Board Help Center Resources Author Services Accessibility API Access RSS feed Manage Cookie Preferences © Research Square 2026 | ISSN 2693-5015 (online) Privacy Policy Terms of Service Do Not Sell My Personal Information {"props":{"pageProps":{"initialData":{"identity":"rs-5442181","acceptedTermsAndConditions":true,"allowDirectSubmit":false,"archivedVersions":[],"articleType":"Research Article","associatedPublications":[],"authors":[{"id":382511975,"identity":"8adb4961-3f99-4726-97e6-e7cda79859a6","order_by":0,"name":"Jela Valaskova","email":"","orcid":"","institution":"Comenius University Bratislava","correspondingAuthor":false,"prefix":"","firstName":"Jela","middleName":"","lastName":"Valaskova","suffix":""},{"id":382511977,"identity":"a7ccd3fc-f237-4cb2-99a1-514b47a8d7cb","order_by":1,"name":"Pavol Vesely","email":"","orcid":"","institution":"Comenius University Bratislava","correspondingAuthor":false,"prefix":"","firstName":"Pavol","middleName":"","lastName":"Vesely","suffix":""},{"id":382511978,"identity":"350d4882-6771-4d77-8467-ed7a8b2fb37e","order_by":2,"name":"Vladimir Krasnik","email":"","orcid":"","institution":"Comenius University Bratislava","correspondingAuthor":false,"prefix":"","firstName":"Vladimir","middleName":"","lastName":"Krasnik","suffix":""},{"id":382511979,"identity":"66f37280-e9f8-46f5-8810-d5feceb78635","order_by":3,"name":"Ivajlo Popov","email":"","orcid":"","institution":"Comenius University Bratislava","correspondingAuthor":false,"prefix":"","firstName":"Ivajlo","middleName":"","lastName":"Popov","suffix":""},{"id":382511980,"identity":"3dd6f93e-550e-496a-8dfa-015416c2afe6","order_by":4,"name":"Jan Juhas","email":"","orcid":"","institution":"Comenius University Bratislava","correspondingAuthor":false,"prefix":"","firstName":"Jan","middleName":"","lastName":"Juhas","suffix":""},{"id":382511981,"identity":"8d0c3b80-5945-4566-ae90-996e5aa144bc","order_by":5,"name":"Iveta Waczulikova","email":"","orcid":"","institution":"Comenius University Bratislava","correspondingAuthor":false,"prefix":"","firstName":"Iveta","middleName":"","lastName":"Waczulikova","suffix":""},{"id":382511982,"identity":"67644f4d-1899-4ad1-99e5-c3c7f3eab890","order_by":6,"name":"Alena Furdova","email":"data:image/png;base64,iVBORw0KGgoAAAANSUhEUgAAAZAAAAAyAQMAAABI0h/eAAAABlBMVEX///8AAABVwtN+AAAACXBIWXMAAA7EAAAOxAGVKw4bAAAA8klEQVRIiWNgGAWjYDACdsZmBgYbIOMAEH8AYjZ2QlqYQVrSIFoYZ4C0MBPUAoQwLcw8EBH8gL+ZudngR8LhfL7jPYafbX5tk+djZmD88DEHtxaJw4zNiT0Jhy1nnjljLJ3bd9uwDWiv5MxteKwBajnA++OwgcGNtATp3J7bjEAtbMy8eLTIA7Uc/JMA1pL827Lntj1BLQZALck8YC3Jx6QZftxOJKjFEKjFWCYh3UDyzOFjlr0Nt5PbgMGO1y9yx9sfS75JsDbgO97YfOPHn9u289ubD374iM/7KICxDUw2EKseBP6QongUjIJRMApGCgAApNdSkSEqewQAAAAASUVORK5CYII=","orcid":"","institution":"Comenius University Bratislava","correspondingAuthor":true,"prefix":"","firstName":"Alena","middleName":"","lastName":"Furdova","suffix":""}],"badges":[],"createdAt":"2024-11-12 21:08:07","currentVersionCode":1,"declarations":"","doi":"10.21203/rs.3.rs-5442181/v1","doiUrl":"https://doi.org/10.21203/rs.3.rs-5442181/v1","draftVersion":[],"editorialEvents":[],"editorialNote":"","failedWorkflow":false,"files":[{"id":71632674,"identity":"45ac0615-8378-47ba-86d0-185cca341248","added_by":"auto","created_at":"2024-12-17 09:46:36","extension":"jpg","order_by":1,"title":"Figure 1","display":"","copyAsset":false,"role":"figure","size":454407,"visible":true,"origin":"","legend":"\u003cp\u003eViolin plots showing data density of the best corrected visual acuity (BCVA), expressed as the decadic logarithm of the minimum angle of resolution (MAR), and grouped by time of examination. The frequency distribution curves are created using a kernel density estimate of the underlying empirical distribution. Group medians are depicted as blue lines; the difference between data distributions was statistically significant (P = 0.0063).\u003c/p\u003e","description":"","filename":"f1.jpg","url":"https://assets-eu.researchsquare.com/files/rs-5442181/v1/2d29058657ecfafc8f1ea2e5.jpg"},{"id":71632683,"identity":"bb1d1a67-50bf-419b-87e8-c8a79cb7ab84","added_by":"auto","created_at":"2024-12-17 09:46:36","extension":"jpg","order_by":2,"title":"Figure 2","display":"","copyAsset":false,"role":"figure","size":95515,"visible":true,"origin":"","legend":"\u003cp\u003eThe best corrected visual acuity (BCVA) 24 hours before operation (left) and 2 months after operation (right) in the subgroups of patients by anticoagulation treatment (ACT). In the box plots, the boundary of the box closest to zero indicates the 25th percentile, cross and diamond symbols present inside the box represent the mean and median of the data, and the boundary of the box farthest from zero indicates the 75th percentile. The largest and smallest observed values that are not outliers are shown as lines (whiskers) that are drawn from the ends of the box to those values. We did not observe any statistical difference in BCVA values determined 24 hours before operation in the subgroups of patients with and without anticoagulation treatment (P = 0.9987). Mean BCVA values determined 2 months after operation were lower in the subgroups of patients with anticoagulation treatment (P = 0.0923).\u003c/p\u003e","description":"","filename":"f2.jpg","url":"https://assets-eu.researchsquare.com/files/rs-5442181/v1/82bd65d952439d3c1bb39b02.jpg"},{"id":71632691,"identity":"1f617e38-76b5-40a3-bf7f-b47aa8be28a9","added_by":"auto","created_at":"2024-12-17 09:46:36","extension":"jpg","order_by":3,"title":"Figure 3","display":"","copyAsset":false,"role":"figure","size":109917,"visible":true,"origin":"","legend":"\u003cp\u003eDifference in the best corrected visual acuity (BCVA) 2 months after operation minus 24 hours before operation in the subgroups of patients by clinical outcome. BCVA is expressed in LogMAR scale (cf. Figure 1). In the box plots, the boundary of the box closest to zero indicates the 25th percentile, cross and diamond symbols present inside the box represent the mean and median of the data, and the boundary of the box farthest from zero indicates the 75th percentile. The largest and smallest observed values are shown as lines (whiskers) that are drawn from the ends of the box to those values. There was a significant association between clinical outcome and the effect of operation evaluated as the difference in BCVA after-before operation (P = 0.0440) with significantly improved BCVA values in groups with no or residual hemorrhage.\u003c/p\u003e","description":"","filename":"f3.jpg","url":"https://assets-eu.researchsquare.com/files/rs-5442181/v1/c17328bd77f2a387faf565bc.jpg"},{"id":71634221,"identity":"f6bb102a-2fe5-4789-bf8c-25a4766f693b","added_by":"auto","created_at":"2024-12-17 09:54:36","extension":"jpg","order_by":4,"title":"Figure 4","display":"","copyAsset":false,"role":"figure","size":135107,"visible":true,"origin":"","legend":"\u003cp\u003eRelationship between the effect of operation evaluated as the difference in BCVA after-before operation and age at operation. No significant association was observed, as the correlation coefficient (r = 0.0534) was not significantly different from zero (P = 0.6907).\u003c/p\u003e","description":"","filename":"f4.jpg","url":"https://assets-eu.researchsquare.com/files/rs-5442181/v1/06ac4346eb24863729c34bf6.jpg"},{"id":71634220,"identity":"32873e31-7bf5-4b23-a101-edd62298c9ff","added_by":"auto","created_at":"2024-12-17 09:54:36","extension":"jpg","order_by":5,"title":"Figure 5","display":"","copyAsset":false,"role":"figure","size":96999,"visible":true,"origin":"","legend":"\u003cp\u003eSeparated bar graph for the mean best corrected visual acuity (BCVA) grouped by time of examination. Analyzed using two-way analysis of variance with data matched across time categories. P-value for the main effect of factor Time equaled 0.0008, the main effect of ACT was not significant (P = 0.4801). We did not observe a significant interaction between Time and Treatment with anticoagulants (P = 0.3050).\u003c/p\u003e","description":"","filename":"f5.jpg","url":"https://assets-eu.researchsquare.com/files/rs-5442181/v1/c74ea3e46993cae8c4545737.jpg"},{"id":71632676,"identity":"ffe42e44-b06c-4871-b347-b8672671c375","added_by":"auto","created_at":"2024-12-17 09:46:36","extension":"jpg","order_by":6,"title":"Figure 6","display":"","copyAsset":false,"role":"figure","size":108261,"visible":true,"origin":"","legend":"\u003cp\u003eMultiple comparisons plot of the simple main effects on BCVA together with 95% confidence intervals. Analyzed using two-way analysis of variance with data matched across time categories. Left: the simple effect of time within each treatment condition: P-value for ACT group was equal to 0.0006, P-value for untreated patients amounted to 0.1120. Right: the simple effect of treatment within each time category: P-values for examinations performed within 24 hours before operation and those performed two months after operation were non-significant (P = 0.9987 and P = 0.2439, respectively).\u003c/p\u003e","description":"","filename":"f6.jpg","url":"https://assets-eu.researchsquare.com/files/rs-5442181/v1/03af4716ec663b58a2ea420d.jpg"},{"id":71632671,"identity":"03ea49f8-0138-4b3a-b7c8-d2c1eb229642","added_by":"auto","created_at":"2024-12-17 09:46:35","extension":"pdf","order_by":0,"title":"","display":"","copyAsset":false,"role":"manuscript-pdf","size":359098,"visible":true,"origin":"","legend":"","description":"","filename":"manuscript.pdf","url":"https://assets-eu.researchsquare.com/files/rs-5442181/v1/5ce15aff-2b44-4cbf-8044-23c2808fb42e.pdf"},{"id":71634219,"identity":"1f239f6b-fd2d-493e-b184-ffae77e4594f","added_by":"auto","created_at":"2024-12-17 09:54:36","extension":"pdf","order_by":1,"title":"","display":"","copyAsset":false,"role":"supplement","size":157040,"visible":true,"origin":"","legend":"","description":"","filename":"Supplementarymaterial.pdf","url":"https://assets-eu.researchsquare.com/files/rs-5442181/v1/7af0407bb16e2076301646e9.pdf"}],"financialInterests":"No competing interests reported.","formattedTitle":"\u003cp\u003eSurgical Treatment of Hemorrhagic Complications of Age- Related Macular Degeneration, Predictive Factors and Outcomes\u003c/p\u003e","fulltext":[{"header":"Introduction","content":"\u003cp\u003eAge-related macular degeneration (ARMD) is a chronic degenerative disease of the central part of the retina that occurs in older age (after 50 years of age). The wet form of ARMD can be treated or stabilized using intravitreal applications of anti-growth factors. One of the most severe ocular complications of the wet form of ARMD in treated or untreated patients is hemorrhage at the site of choroidal neovascularization (CNV) in the macula. The natural course of hemorrhage resorption, without any medical intervention, is associated with a poor visual prognosis, so today the aim is to surgically remove the hemorrhage in the macula as quickly as possible. In surgical treatment, we use recombinant tissue plasminogen activator (rtPA) in combination with expansion gas and continue to treat the underlying disease during the following follow-up. In recent years, there has been a growing number of records in the literature about an increased frequency of hemorrhagic eye complications with the simultaneous use of anticoagulants based on various general diseases. ACT has clear significant benefits, but it is also considered a risk factor increasing the complications of hemorrhage, specifically hemorrhage in the macula.\u003c/p\u003e \u003cp\u003eHemorrhage into the macula, the place of the sharpest vision, is an acute condition associated with a sudden deterioration of visual functions. The most common cause is CNV in patients with ARMD, less often myopia, trauma, uveitis, or even after laser therapy. Hemorrhage into the macula without the presence of CNV can be associated with retinal macroaneurysms, Valsava maneuver, choroidal rupture, Terson syndrome or even proliferative diabetic retinopathy.\u003c/p\u003e \u003cp\u003eAbout 80% of information is perceived by sight, sight is the most important of all sensory organs. The sensory organ of vision is the eye. Our visual perception begins with the passage of a light beam through several structures of the eye and its absorption by photoreceptors, rods and cones, located in the outer nuclear layer of the retina. The human eye contains 100\u0026nbsp;million rods and 6\u0026nbsp;million cones. Photoreceptors are specialized sensory neurons that use proteins to convert light into a nerve signal that can be interpreted by the nervous system. Photoreceptors die when they are mechanically, for a variety of reasons, including hemorrhage, separated from the retinal pigment epithelium (RPE) and choroidal vessels that provide metabolic support to the outer layers of the retina. Photoreceptors do not have the ability to reproduce.\u003c/p\u003e \u003cp\u003eThe natural course of hemorrhage into the macula leads to a significant and permanent deterioration of best corrected visual acuity (BCVA). In animal models, irreversible changes occur after 24 hours and complete loss of photoreceptors after 7 days [\u003cspan citationid=\"CR6\" class=\"CitationRef\"\u003e6\u003c/span\u003e]. There are several reasons. Iron toxicity in the blood causes irreversible damage to retinal photoreceptors [\u003cspan citationid=\"CR6\" class=\"CitationRef\"\u003e6\u003c/span\u003e, \u003cspan citationid=\"CR13\" class=\"CitationRef\"\u003e13\u003c/span\u003e]. The mechanical barrier of the blood clot reduces the transfer of nutrients between the retina and the choroid. The fibrin membrane leads to traction damage to the RPE and photoreceptors. During hemorrhage, an induced inflammation occurs, which leads to the accumulation of macrophages [\u003cspan citationid=\"CR2\" class=\"CitationRef\"\u003e2\u003c/span\u003e, \u003cspan citationid=\"CR5\" class=\"CitationRef\"\u003e5\u003c/span\u003e, \u003cspan citationid=\"CR17\" class=\"CitationRef\"\u003e17\u003c/span\u003e, \u003cspan citationid=\"CR21\" class=\"CitationRef\"\u003e21\u003c/span\u003e, \u003cspan citationid=\"CR24\" class=\"CitationRef\"\u003e24\u003c/span\u003e]. All these mechanisms lead to the gradual destruction of photoreceptors.\u003c/p\u003e \u003cp\u003eIn an acute condition, hemorrhage into the macula, there is currently a definite preference for invasive treatment over conservative treatment. Rapid invasive surgical treatment can lead to improvement of central BCVA [\u003cspan citationid=\"CR1\" class=\"CitationRef\"\u003e1\u003c/span\u003e]. The goal of invasive treatment is to remove the blood clot and affect the underlying disease, CNV in ARMD. Invasive treatment can be carried out in two ways, by applying drugs and expansion gases by injection into the vitreous, the so-called intravitreal application, or in the form of 23/25/27 Gauge pars plana vitrectomy, with simultaneous removal of the vitreous, while the application of drugs in this case has multiple locations, the drug can be applied into the vitreous cavity or under the retina. Alteplase, a recombinant tissue plasminogen activator, has been used for almost two decades to dissolve a blood clot. It is a fibrinolytic, the body's own factor, produced by the endothelium, which promotes the conversion of plasminogen to plasmin. Plasmin is a protease that cleaves fibrin in a blood clot into fibrin degradation products. Resorbable expansion gases, SF6 and C3F8, are used to mechanically expel hemolyzed blood from the macula. In addition to dissolving the blood clot, ophthalmologists try to influence the underlying disease by intraoperative application of anti-vascular endothelial growth factor (anti-VEGF), the so-called anti-VEGF substances into the vitreous cavity. Today there are used several drugs, ranibizumab, aflibercept, brolucizumab, faricimab and off-label bevacizumab.\u003c/p\u003e \u003cp\u003eSeveral results have been published, preferring different surgical procedures with the application of different drugs. There are several studies devoted to long-term post-intervention follow-up. In 2018, a new classification of hemorrhage in the macula was proposed by a group of German authors [\u003cspan citationid=\"CR7\" class=\"CitationRef\"\u003e7\u003c/span\u003e]. The so-called FLATCAPS classification (FLATCAPS from English F- foveal involvement, L- layer, A- age, T- thickness, C- cause/ pathogenesis, S- size, PD - papillary diameter). The purpose of the classification is to recommend the optimal surgical procedure based on several input factors, to determine the prognosis of BCVA after surgery and the possibility of comparing different factors.\u003c/p\u003e \u003cp\u003eThe aim of this work was to evaluate information about a set of patients with hemorrhagic complications in ARMD, treated surgically in our clinic from 2018 to 2021, we evaluate this type of treatment as well as the share and the joint effect of several predictors on the outcome including ACT. The aim of our study was to evaluate the surgical treatment of the entire group by way of 23G PPV using rtPA and SF6 on the basis of BCVA 2 months after operations and clinical picture, presence of hemorrhage, 2 months after operations, to determine the effect of size hemorrhage not the resulting BCVA. We wanted to find out the influence of local factors on hemorrhage like medical history, duration of hemorrhage, size of hemorrhage before surgery. We wanted to determine the share of overall factors on the result after treatment, such as anticoagulant treatment or patient\u0026rsquo;s age.\u003c/p\u003e"},{"header":"Material and methods","content":"\u003cp\u003eA retrospective interventional case series of 58 patients with pseudophakia, who underwent surgical treatment in period 2018\u0026ndash;2023 with inclusion criteria: subretinal, subretinal pigment epithelium (subRPE), or combined central hemorrhage verified on optical coherence tomography - OCT (SD-OCT, Heidelberg Engineering, Heidelberg Germany) associated with ARMD, 23 Gauge (DORC) pars plana vitrectomy using rtPA (Actilyse\u0026reg;, Boehringer, Ingelheim, Germany), sulfur hexafluoride (SF6), rtPA was applied subretinally through a 41 Gauge subretinal cannula. Medical records were reviewed for diagnosis, logMAR BCVA, preop and postop clinical findings, complications, and all medical history up to 6 months after the surgery.\u003c/p\u003e \u003cp\u003ePreoperatively, during hospitalization, blood samples, blood counts, biochemistry, hemocoagulation factors were taken from all patients, and a general internal preoperative examination with anesthesiology examination was performed. Patients were operated on within 24 hours of admission under local anesthesia, which is a combination of retrobulbar administered marcaine 0.5% and lidocaine 2% and intravenous support of myorelaxants, anxiolytics and painkillers. The surgical procedure via 23 Gauge (23G) pars plana vitrectomy (PPV) included subretinally applied recombinant tissue plasminogen activator at a concentration of 50 \u0026micro;g in 0.05 ml saline with tamponade of the vitreous cavity with SF6 expansion gas. After the operation, the patients were asked to position themselves face down for at least 24 hours after the operations.\u003c/p\u003e \u003cp\u003eThe aim of our study was to evaluate the surgical treatment of the entire group by way of 23G PPV using rtPA and SF6 on the basis of BCVA 2 months after operations and clinical picture, presence of hemorrhage, 2 months after operations, to determine the effect of size hemorrhage not the resulting BCVA. We wanted to find out the influence of local factors on hemorrhage like medical history, duration of hemorrhage, size of hemorrhage before surgery. We wanted to determine the share of overall factors on the result after treatment, such as anticoagulant treatment or patient\u0026rsquo;s age.\u003c/p\u003e \u003cp\u003ePatients were classified according to the clinical picture, the size of the hemorrhage, into groups: small-size hemorrhage (up to 2x2PD) 32 eyes, medium-size hemorrhage (up to 4x4PD, to the arcades) 19 eyes and massive hemorrhage (from 5x5PD hemorrhage through the arcades to the periphery) 7 eyes. As part of comorbidities, 48 patients were treated for arterial hypertension, 9 patients were treated for diabetes mellitus, and 35 patients (60.3%) were on anticoagulant treatment for various reasons. All patients were followed up for at least 6 months.\u003c/p\u003e \u003cp\u003eEvaluation of the results of the whole group after 23G PPV with rtPA and SF6 based on pre- and postoperative BCVA (2 months after the operations) and clinical findings of the occurrence of hemorrhage in the macula (2 months after the operations).\u003c/p\u003e \u003cp\u003eThe clinical findings of residual hemorrhage after operation were classified into 4 categories, 1st category - no hemorrhage, 2nd category - residual hemorrhage, 3rd category - hemophthalmos, and 4th category - other complication.\u003c/p\u003e \u003cdiv id=\"Sec3\" class=\"Section2\"\u003e \u003ch2\u003eStatistical analysis\u003c/h2\u003e \u003cp\u003eThe patients' demographics, clinical and laboratory characteristics were summarized and analyzed using descriptive and inferential statistics. Categorical variables are presented as counts and percentages in a contingency table. Fisher's exact test was used to determine if there was a nonrandom association between the two variables. The patients were tested for between-group and within-group differences in all relevant characteristics.\u003c/p\u003e \u003cp\u003eUnivariate analysis of continuous outcome (BCVA) in two or more groups was made using one-way or two-way analysis of variance (ANOVA). Where appropriate, matching across subjects was considered (e.g. for analysis of repeated examinations across time). Relationship between continuous outcome and one or more prognostic factors (e.g. baseline clinical picture or DM) and treatment effects (e.g. ACT) was analyzed using multiple regression.\u003c/p\u003e \u003cp\u003eUnivariate analysis of association between categorical outcome (hemorrhage severity after operation) and a categorical predictor grouped in two-way contingency tables was performed using Pearson's chi-square test for independence. Multivariable analysis was performed using multinomial logistic regression.\u003c/p\u003e \u003cp\u003eRelationship between a continuous dependent variable and one or more predictor variables was modelled using simple and multiple linear regression.\u003c/p\u003e \u003cp\u003eFor the data processing and analysis, the software Microsoft Office Excel 2016 (Microsoft Corporation ), GraphPad Prism 9.0 (GraphPad Software Inc., San Diego, CA, US) and StatsDirect\u0026reg; 4.0.2 were used (StatsDirect Ltd., Cheshire, UK). All of the tests were two-tailed and conducted at a significance level α\u0026thinsp;=\u0026thinsp;0.05.\u003c/p\u003e \u003c/div\u003e"},{"header":"Results","content":"\u003cp\u003eThe group consisted of 58 patients, 21 male, 37 female, the difference in proportions was statistically significant (P\u0026thinsp;=\u0026thinsp;0.0479). Average age 77.8 years, (male 77.2 and female 78.1 years, P\u0026thinsp;=\u0026thinsp;0.713), the age distribution ranged from 53 to 93 years. The diagnosis of neovascular age-related macular degeneration (nAMD) was in 100% of cases. The left eye was operated more often, 32 times, the right eye 26 times. Hemorrhage history ranged from one day to three months. There were 28 patients with a patient\u0026rsquo;s record up to 7 days, 18 patients with a patient\u0026rsquo;s record up to one month, and 12 patients with a patient\u0026rsquo;s record longer than a month.\u003c/p\u003e \u003cp\u003ePostoperative improvement in reduction of submacular hemorrhage was noticed in 93% cases, total postoperative hemorrhage absorption in 51.7% cases. Mean baseline BCVA (24 hours before operation) in the whole group was 1.467 on the logMAR scale, and two months postoperative BCVA was 1.145 logMAR (Fig.\u0026nbsp;\u003cspan refid=\"Fig1\" class=\"InternalRef\"\u003e1\u003c/span\u003e and Table \u003cspan refid=\"MOESM1\" class=\"InternalRef\"\u003eS1\u003c/span\u003e). This difference was statistically significant on both, the univariate analysis (P\u0026thinsp;=\u0026thinsp;0.0009) and after adjustment to anticoagulation treatment by stratifying the whole sample according to ACT (P\u0026thinsp;=\u0026thinsp;0.0008). In the subgroups by ACT, we did not find any statistical difference in the baseline BCVA values (P\u0026thinsp;=\u0026thinsp;0.9987; Fig.\u0026nbsp;\u003cspan refid=\"Fig2\" class=\"InternalRef\"\u003e2\u003c/span\u003e, left). After the operation, the mean BCVA values were lower in the subgroup of patients with ACT (P\u0026thinsp;=\u0026thinsp;0.0923; Fig.\u0026nbsp;\u003cspan refid=\"Fig2\" class=\"InternalRef\"\u003e2\u003c/span\u003e, right). Another important baseline predictor of the effect of surgery was preoperative clinical picture according to the categorized size of the hemorrhage. The largest group was that of small-size hemorrhages, 32 eyes (55% of the total). The group of medium-size hemorrhages consisted of 19 eyes (33%). Patients with massive hemorrhages formed the smallest group (7 eyes, 12%). The outcome evaluated by crude BCVA values two months after operation was significantly associated with the preoperative clinical picture (P\u0026thinsp;=\u0026thinsp;0.0006). The lowest value of BCVA was found (as expected) in the group of small-size hemorrhages (BCVA\u0026thinsp;=\u0026thinsp;0.991 from the preoperative value of 1.317 LogMAR) followed by the group of medium-size hemorrhages (BCVA\u0026thinsp;=\u0026thinsp;1.145 LogMAR from 1.579 logMAR). For the group of massive hemorrhages zero improvement from the baseline value of 1.850 LogMAR was found). The best improvement in the mean postoperative BCVA relative to the preoperative BCVA was reached in group with medium-size hemorrhage (difference of \u0026ndash; 0.434 LogMAR). Since our sample size was rather small, only limited number of variables for the prediction model could be considered. Therefore, we adjusted analysis for other predictors for preoperative (baseline) values of BCVA using the difference (BCVA 2 months after operation minus 24 hours before operation) as an alternative to the effect \u0026ldquo;clinical findings of residual hemorrhage after operation\u0026rdquo;. The association between the clinical outcome and the difference in BCVA after-before operation was proved to be statistically significant (P\u0026thinsp;=\u0026thinsp;0.0440), with the most improved BCVA values in groups with no or residual hemorrhage (Fig.\u0026nbsp;\u003cspan refid=\"Fig3\" class=\"InternalRef\"\u003e3\u003c/span\u003e). This association was also confirmed by cross-tabulation analysis (P\u0026thinsp;=\u0026thinsp;0.0156; Table\u0026nbsp;\u003cspan refid=\"Tab1\" class=\"InternalRef\"\u003e1\u003c/span\u003e), where clinical outcomes on the degree of postoperative hemorrhage depended on the baseline clinical picture categorized according to the size of the hemorrhage (Goodman-Kruskal gamma for ordinal association\u0026thinsp;=\u0026thinsp;0.524 (P\u0026thinsp;=\u0026thinsp;0.0032).\u003c/p\u003e \u003cp\u003e \u003c/p\u003e \u003cp\u003e \u003c/p\u003e \u003cp\u003e \u003c/p\u003e \u003cp\u003e \u003cdiv class=\"gridtable\"\u003e\u003ctable float=\"Yes\" id=\"Tab1\" border=\"1\"\u003e \u003ccaption language=\"En\"\u003e \u003cdiv class=\"CaptionNumber\"\u003eTable 1\u003c/div\u003e \u003cdiv class=\"CaptionContent\"\u003e \u003cp\u003eThe relationship between ordered categories of baseline clinical picture and clinical outcome categorized by hemorrhage severity\u003c/p\u003e \u003c/div\u003e \u003c/caption\u003e \u003ccolgroup cols=\"5\"\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c1\" colnum=\"1\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c2\" colnum=\"2\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c3\" colnum=\"3\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c4\" colnum=\"4\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c5\" colnum=\"5\"\u003e\u003c/div\u003e \u003cthead\u003e \u003ctr\u003e \u003cth align=\"left\" colname=\"c1\"\u003e \u003cp\u003eCharacteristic \u003cem\u003eHemorrhage\u003c/em\u003e\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colspan=\"3\" nameend=\"c4\" namest=\"c2\"\u003e \u003cp\u003eClinical outcome category\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c5\"\u003e\u0026nbsp;\u003c/th\u003e \u003c/tr\u003e \u003c/thead\u003e \u003ctbody\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eBaseline category\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003eno hemorrhage\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003eresidual hemorrhage\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003ehemophthalmos\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003eTotal\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003esmall-size\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e19 (63.3%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e12 (50%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e0 (0%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e31 (54.4%)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003emedium-size\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e11 (36.7%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e8 (33.3%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e0 (0%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e19 (33.3%)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003emassive\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e0 (0%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e4 (16.7%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e3 (100%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e7 (12.3%\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eTotal\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e30 (100%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e24 (100%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e3 (100%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e57 (100%)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003c/tbody\u003e \u003c/colgroup\u003e \u003ctfoot\u003e \u003ctr\u003e\u003ctd colspan=\"5\"\u003eRelative counts are expressed as % of column total.\u003c/td\u003e\u003c/tr\u003e \u003ctr\u003e\u003ctd colspan=\"5\"\u003eApproximate chi-square test of independence: P\u0026thinsp;=\u0026thinsp;0.0156; Goodman-Kruskal gamma for ordinal association\u0026thinsp;=\u0026thinsp;0.524 (P\u0026thinsp;=\u0026thinsp;0.0032).\u003c/td\u003e\u003c/tr\u003e \u003ctr\u003e\u003ctd colspan=\"5\"\u003eThe category \u0026ldquo;other complication\u0026rdquo; in the outcome consisted of one case and was omitted from the analysis.\u003c/td\u003e\u003c/tr\u003e \u003c/tfoot\u003e \u003c/table\u003e\u003c/div\u003e \u003c/p\u003e \u003cp\u003eFrom the cross-tabulation analysis of clinical findings based on the presence of hemorrhage in the macula of the entire group before and after surgery we can conclude that the resorption of hemorrhage after operations was found in more than half of patients (51.72%; 30 out of 58 patients). In total, 54 patients, 93%, improved in terms of the clinical finding of hemorrhage resorption.\u003c/p\u003e \u003cp\u003eEvaluation of other assumed predictors. Improvement of average postoperative BCVA was best in the subgroup with shortest medical history of hemorrhage (up to 7 days), from 1.461 logMAR preoperative to 1.021 logMAR postoperative. In the second subgroup where the duration was in weeks up to a month, the mean value of BCVA before operation was 1.483 logMAR and after operation 1.225 logMAR. In the third group with duration of more than a month the mean value of BCVA before operation was 1.461 logMAR and after operation 1.313 logMAR).\u003c/p\u003e \u003cp\u003eAge was not a crucial predictive factor, neither for postoperative complications (P\u0026thinsp;=\u0026thinsp;0.6571), nor for vision improvement (P\u0026thinsp;=\u0026thinsp;0.6907). Evaluation of the effect of age at operation on the post-pre-operation differences in BCVA measurements showed no significant relationship (P\u0026thinsp;=\u0026thinsp;0.6907) (Fig.\u0026nbsp;\u003cspan refid=\"Fig4\" class=\"InternalRef\"\u003e4\u003c/span\u003e).\u003c/p\u003e \u003cp\u003e \u003c/p\u003e \u003cp\u003eFurther, improvement of vision was not dependent on the side of eye (P\u0026thinsp;=\u0026thinsp;0.8309). As to the comorbidities, diabetes mellitus or arterial hypertension after adjustment on the baseline and ACT were not significantly associated with worsened vision measured on the LogMAR scale.\u003c/p\u003e \u003cp\u003eThe only relevant predictor was concurrent anticoagulant treatment. In the entire group of 58 patients, 35 patients, 60.3% of the total group, were on ACT.\u003c/p\u003e \u003cp\u003eWe have found that ACT did not worsen the outcomes in terms of BCVA. On the contrary, after operation the group with massive hemorrhage where were mostly patients with ACT (n\u0026thinsp;=\u0026thinsp;5, 71.4%) had significantly better postoperative reduction in BCVA values relative to the baseline, as did the group with massive hemorrhage and without ACT treatment (-0.170 vs. +0.425, respectively). According to the amount of hemorrhage, there were 20 patients with ACT in the first group with no hemorrhage after operation, 13 patients with ACT in the second group of residual hemorrhage, and 2 patients in the third group with hemophthalmos.\u003c/p\u003e \u003cp\u003eThe overall association between ACT and clinical outcome categorized according to the severity of postoperative hemorrhage was also negative, even if not significant due to low numbers of cases in the categories (Goodman-Kruskal's gamma coefficient = -0.252; P\u0026thinsp;=\u0026thinsp;0.2939).\u003c/p\u003e \u003cp\u003eThe mutual effect of ACT and time of examination on the BCVA measurements, as well as possible interaction between treatment and time was analyzed using two-way analysis of variance with data matched across time categories. Results are given in Fig.\u0026nbsp;\u003cspan refid=\"Fig5\" class=\"InternalRef\"\u003e5\u003c/span\u003e. P-value for the main effect of factor Time equaled 0.0008, whereas the main effect of ACT was not significant (P\u0026thinsp;=\u0026thinsp;0.4801). We did not observe a significant interaction between Time and Treatment with anticoagulants (P\u0026thinsp;=\u0026thinsp;0.3050). The simple effect of time within each treatment condition in given in Fig.\u0026nbsp;\u003cspan refid=\"Fig6\" class=\"InternalRef\"\u003e6\u003c/span\u003e left: P-value for ACT group was equal to 0.0006 and P-value for untreated patients amounted to 0.1120. On the other hand, simple effects for examinations performed within 24 hours before operation and those performed two months after operation were not significant (P\u0026thinsp;=\u0026thinsp;0.9987 and P\u0026thinsp;=\u0026thinsp;0.2439, respectively; Fig.\u0026nbsp;\u003cspan refid=\"Fig6\" class=\"InternalRef\"\u003e6\u003c/span\u003e right).\u003c/p\u003e \u003cp\u003e \u003c/p\u003e \u003cp\u003e \u003c/p\u003e \u003cp\u003eTo summarize the obtained results, two months after the surgery the average BCVA of the entire group improved what is the reaction on partial or complete hemorrhage resorption we see in clinical findings. The best outcomes were in the group with the shortest patient\u0026rsquo;s record of the hemorrhage with the moderate size.\u003c/p\u003e"},{"header":"Discussion","content":"\u003cp\u003eAnticoagulants are associated with massive hemorrhage and, at the same time, better postoperative BCVA than massive hemorrhage without ACT, which implies the necessity of sufficient control of coagulation factors in correlation with local eye findings in treated wet forms of ARMD.\u003c/p\u003e \u003cp\u003eA common retinal vascular disorder causing bleeding and visual deterioration in the age over 60 is retinal vein occlusion, where complications include macular ischemia, neovascularisations, but also vitreous hemorrhages. We can see central and branch retinal vein occlusions but also their ischemic and nonischemic subtypes. Branch occlusions and nonischemic conditions are associated with better visual acuity prognosis. Up today there have been various types of therapy with not relevant effect. Due to the lack of effective monotherapy, there is probably a need to combine the therapy approach [\u003cspan citationid=\"CR4\" class=\"CitationRef\"\u003e4\u003c/span\u003e].\u003c/p\u003e \u003cp\u003eThe entry criteria in our retrospective study were hemorrhagic complication of wet form of ARMD, surgical treatment of 23G PPV using rtPA and SF6. We evaluated preoperative and postoperative BCVA in the entire group of patients. We found out that 2 months after the operations, the average BCVA of the entire group improved.\u003c/p\u003e \u003cp\u003eWhen investigating the effect of ACT in more detail, we divided our group into two parts, with ACT, 35 patients\u0026rsquo; treatment and without ACT, 23 patients and we found that there is a difference in the resulting BCVA of these two sets, this however, the difference is not statistically significant. Patients with ACT given were most represented in the group with massive hemorrhage, 71.4%. In a more detailed breakdown of the total group according to the present ACT and according to the size of the hemorrhage, we found that there is a statistically significant difference in the result of BCVA after surgery between the group with massive hemorrhage and simultaneous use of anticoagulants and the group with massive hemorrhage without the simultaneous use of anticoagulants. We found that patients with massive hemorrhage with concomitant use of anticoagulants have significantly better postoperative BCVA. That means, that ACT seems to be a \"good\" predictive factor of better BCVA after operations for massive hemorrhage. Given that it is a hemorrhagic complication of a local disease, it also means that patients who receive ACT the hemorrhage is more massive as in patients without ACT. But after surgical removal of the hemorrhage, they have better BCVA than patients without ACT. This means that local retinal disease does not represent as much retinal destruction in patients with ACT as in patients without ACT, it is only potentiated by ACT. What does this mean for clinical practice? Patients with the exudative form of ARMD and concurrent ACT should be checked frequently enough in terms of hemocoagulation parameters adequate for ACT, among other things, also for possible hemorrhagic complications of local eye disease. In the case of an acute hemorrhagic complication of ARMD with concurrent ACT, such a patient has a higher chance of massive hemorrhage, but at the same time, after surgical treatment, of better postoperative BCVA than a patient without ACT. The possible question of a higher frequency of hemorrhagic complications in patients with concurrent ACT is provided by this file only in terms of its scope, out of 58 patients with a hemorrhagic complication, 35 patients, 60.3%, were on concurrent anticoagulant treatment. As part of the overall predictive factors, we found that despite the wide age range (from 53 to 93) and the higher average age (77.8) in this group, age was not a significant determinant of the postoperative outcome.\u003c/p\u003e \u003cp\u003eComparison with studies:\u003c/p\u003e \u003cp\u003eIn the study of 31 patients from 2021 [\u003cspan citationid=\"CR18\" class=\"CitationRef\"\u003e18\u003c/span\u003e] from Germany and Switzerland they compared the same surgical treatment with rtPA and SF6 with the same incisional criteria, with the conclusion confirming the effectiveness of surgical treatment, while when comparing the subsets with the additive application of bevacizumab, the results are comparable between the subsets. In the subset without bevacizumab application, 14 patients achieved an average BCVA of 1.48\u0026thinsp;\u0026plusmn;\u0026thinsp;0.48 to 1.01\u0026thinsp;\u0026plusmn;\u0026thinsp;0.38 logMAR, while the removal of hemorrhage reached 50% of patients.\u003c/p\u003e \u003cp\u003eA cohort of 25 eyes from Italy [\u003cspan citationid=\"CR8\" class=\"CitationRef\"\u003e8\u003c/span\u003e] evaluated 23G PPV with subretinal rtPA and SF6 as a safe and effective technique, recommending treatment within 14 days of symptom onset. Average BCVA 12 months after surgery decreased from 1.81\u0026thinsp;\u0026plusmn;\u0026thinsp;0.33 to 1.37\u0026thinsp;\u0026plusmn;\u0026thinsp;0.52 LogMAR.\u003c/p\u003e \u003cp\u003eThere are several case reports and several files confirming the negative impact of anticoagulants and the wet form of ARMD [\u003cspan citationid=\"CR11\" class=\"CitationRef\"\u003e11\u003c/span\u003e, \u003cspan citationid=\"CR12\" class=\"CitationRef\"\u003e12\u003c/span\u003e, \u003cspan citationid=\"CR14\" class=\"CitationRef\"\u003e14\u003c/span\u003e, \u003cspan citationid=\"CR20\" class=\"CitationRef\"\u003e20\u003c/span\u003e], which leads to massive hemorrhages. These works did not evaluate the effect of surgical treatment on hemorrhage.\u003c/p\u003e \u003cp\u003eOther studies compared three treatment modalities for AMD complicated by a submacular hemorrhage (SMH). They included an extended spectrum of hemorrhage sizes as well as a larger number of patients than previous studies. In one study they divided patients according to the SMH size and analyzed the treatment outcomes of three different modalities to identify their effects in each subgroup with homogeneity in terms of size. The overall mean BCVA improved significantly from the baseline during the 12 months follow-up period. However, different outcomes were observed according to the SMH size and treatment modalities. In the small-sized group, anti-VEGF monotherapy was performed on the majority of patients (51.1%) and it significantly improved the BCVA. The two other treatment modalities also increased the mean BCVA and the magnitude of improvement showed no difference among the treatment modalities [\u003cspan citationid=\"CR10\" class=\"CitationRef\"\u003e10\u003c/span\u003e]. In our study we did not compare anti-VEGF therapy and influence to BCVA.\u003c/p\u003e \u003cp\u003eStudy TIGER is a phase 3, pan-European, two-group, active-control, observer-masked, superiority, randomized controlled surgical trial. Eligible participants have large, fovea-involving SMH of no more than 15 days duration due to treatment-na\u0026iuml;ve or previously treated neovascular AMD, including idiopathic polypoidal choroidal vasculopathy and retinal angiomatous proliferation. A total of 210 participants are randomized in a 1:1 ratio to pars plana vitrectomy, off-label subretinal TPA up to 25 \u0026micro;g in 0.25 ml, intravitreal 20% sulfur hexafluoride gas and intravitreal aflibercept, or intravitreal aflibercept monotherapy. Aflibercept 2 mg is administered to both groups monthly for 3 doses, then 2-monthly to month 12 [\u003cspan citationid=\"CR9\" class=\"CitationRef\"\u003e9\u003c/span\u003e].\u003c/p\u003e \u003cp\u003eIn the study of compared outcomes of subretinal versus intravitreal injection of recombinant r-tPA and gas in cases of SMH secondary to AMD the results of both treatment options proved equal efficacy in displacing SMH in AMD. A multicenter trial in the future may delineate a desirable algorithm of treatment [\u003cspan citationid=\"CR22\" class=\"CitationRef\"\u003e22\u003c/span\u003e].\u003c/p\u003e \u003cp\u003e In the review article the authors aimed to explore the current treatment strategies and supporting literature regarding both surgical and nonsurgical, of SRH in patients with AMD. The accented to highlight the distinct treatment modalities corresponding to different sizes of SRH [\u003cspan citationid=\"CR16\" class=\"CitationRef\"\u003e16\u003c/span\u003e].\u003c/p\u003e \u003cp\u003eCaporossi et al. in the study evaluated the different postoperative outcomes of patients affected by macular neovascularization (MNV) complicated by SMH that underwent subretinal implant of human amniotic membrane (hAM) or subretinal injection of tPA. In the retrospective but non-randomized interventional study of 44 eyes, where 22 eyes underwent PPV plus SMH and MNV removal, with a subretinal implant of hAM and silicone oil. The second half of the study group underwent PPV, subretinal injection of tPA, and 20% sulphur hexafluoride. Due to their results they found out that both techniques report similar BCVA improvements and postoperative complications, but transplantation of hAM seems to have a significant benefit in inhibiting MNV recurrence [\u003cspan citationid=\"CR3\" class=\"CitationRef\"\u003e3\u003c/span\u003e].\u003c/p\u003e \u003cp\u003eIn the recent study of authors where the aim was to describe surgical results and fundus autofluorescence (FAF) patterns after PPV combined with tPA\u0026thinsp;+\u0026thinsp;anti-VEGF and intravitreal tPA\u0026thinsp;+\u0026thinsp;anti-VEGF\u0026thinsp;+\u0026thinsp;sulfur hexafluoride (SF6) tamponade and to compare them to intravitreal tPA\u0026thinsp;+\u0026thinsp;anti-VEGF\u0026thinsp;+\u0026thinsp;SF6. Due to their results FAF patterns did not depend on the treatment used, but only from the duration of SMH before therapy. They realized, that SMH if not treated prompt enough might cause long-standing photoreceptor cell and RPE defect, which is represented by hypo- and hyper-autofluorescence. Performing a subretinal injection of tPA and anti-VEGF does not cause any defects associated with the injection site. That might be associated with previous local internal limiting membrane peeling [\u003cspan citationid=\"CR15\" class=\"CitationRef\"\u003e15\u003c/span\u003e].\u003c/p\u003e \u003cp\u003eDue to recent study results not only prompt treatment of SMH but also further continuation of intravitreal anti-VEGF therapy is mandatory to maintain anatomical and but also functional results.\u003c/p\u003e \u003cp\u003eOne of the first studies to compare the surgical outcomes of pneumatic displacement versus subretinal application of tPA, anti-VEGF agent, and gas was published by Szeto et al. [\u003cspan citationid=\"CR19\" class=\"CitationRef\"\u003e19\u003c/span\u003e].\u003c/p\u003e \u003cp\u003eThey demonstrated novel technique in cases with thick and extensive SMH or as a rescue secondary operation in selected cases and realized that subretinal application of cocktail injection has positive impact to small but also massive SMH. Their study provided new data and for the future it will have impact on the decision how to manage SMH. In their study subretinal cocktail injection achieved higher rate of successful displacement of SMH. Surgical displacement of SMH leads to clinically meaningful improvement in better function and better BCVA. PPV with subretinal cocktail injection is more effective than pneumatic displacement in displacing SMH with similar safety profile despite longer interval before operation [\u003cspan citationid=\"CR19\" class=\"CitationRef\"\u003e19\u003c/span\u003e].\u003c/p\u003e \u003cp\u003eIn the recent meta-analysis of Veritti et al. in 257 initial reports where met inclusion criteria the authors realized the significant improvement in BCVA and successful SMH with combined tPA and anti-VEGF therapy, but no significant differences were found between subretinal and intravitreal tPA administration. Today in managing SMH in nAMD patient the combined tPA and anti-VEGF therapy is effective, significantly improving BCVA and SMH displacement, but the location of tPA and anti-VEGF delivery did not significantly impact clinical results [\u003cspan citationid=\"CR23\" class=\"CitationRef\"\u003e23\u003c/span\u003e].\u003c/p\u003e"},{"header":"Conclusion","content":"\u003cp\u003eBased on these results, we consider surgical treatment of the hemorrhagic complication of ARMD to be beneficial, while its effect increases with a shorter history of the disease and a moderate extent of hemorrhage. Massive hemorrhages have a worse prognosis for improving BCVA than moderate and small hemorrhages.\u003c/p\u003e \u003cp\u003eFrom the overall parameters, the age of the patient is not decisive for the effect of the treatment, while anticoagulant treatment is associated with a higher risk of massive hemorrhage, but at the same time, probably as a factor prevailing over the local finding, after surgical treatment with rtPA with SF6 with a better functional and anatomical result. The final result of surgical treatment for hemorrhagic complications of ARMD is primarily determined by the local state of the retina before hemorrhage, the type of treatment and the concomitant use of anticoagulants.\u003c/p\u003e"},{"header":"Declarations","content":"\u003ch3\u003eAcknowledgments\u0026nbsp;\u003c/h3\u003e\n\u003ch3\u003eDisclosure\u003c/h3\u003e\n\u003cp\u003eThe author(s) report no conflicts of interest in this work.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eStatement of Ethics\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eThis case report adhered to the tenets of the Declaration of Helsinki. Written informed consent was obtained from the patient for publication of the details of their medical case and any accompanying images. Ethical approval is from Institutional Ethics Committee of University Hospital in Bratislava, Slovakia (protocol code EK/ 060/ 2024 from June 17, 2024).\u0026nbsp;\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eConflict of Interest Statement\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eAuthors have no financial or proprietary interest in any material or method mentioned.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eData Availability Statement\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eAll data related to this case report are included in the article and supplemental material. Further inquiries must be directed to the corresponding author.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eFunding Statement\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eThe authors received no specific funding for this work. Data analysis was supported by the project APVV-22-0154.\u003c/p\u003e"},{"header":"References","content":"\u003col\u003e\u003cli\u003e\u003cspan\u003eAgostini HT, Bopp S, Feltgen N (2017) [Prognosis and treatment of macular bleeding in neovascular age-related macular degeneration]. Ophthalmologe 114:476\u0026ndash;480. \u003cspan class=\"ExternalRef\"\u003e\u003cspan class=\"RefSource\"\u003ehttps://doi.org/10.1007/s00347-017-0487-x\u003c/span\u003e\u003cspan address=\"10.1007/s00347-017-0487-x\" targettype=\"DOI\" class=\"RefTarget\"\u003e\u003c/span\u003e\u003c/span\u003e\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eel Baba F, Jarrett WH, Harbin TS et al (1986) Massive hemorrhage complicating age-related macular degeneration. Clinicopathologic correlation and role of anticoagulants. 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Int Ophthalmol 41:4037\u0026ndash;4046. \u003cspan class=\"ExternalRef\"\u003e\u003cspan class=\"RefSource\"\u003ehttps://doi.org/10.1007/s10792-021-01976-x\u003c/span\u003e\u003cspan address=\"10.1007/s10792-021-01976-x\" targettype=\"DOI\" class=\"RefTarget\"\u003e\u003c/span\u003e\u003c/span\u003e\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eVeritti D, Sarao V, Martinuzzi D et al (2024) Submacular hemorrhage during neovascular age-related macular degeneration: a meta-analysis and meta-regression on the use of tPA and anti-VEGFs. Ophthalmologica. \u003cspan class=\"ExternalRef\"\u003e\u003cspan class=\"RefSource\"\u003ehttps://doi.org/10.1159/000537939\u003c/span\u003e\u003cspan address=\"10.1159/000537939\" targettype=\"DOI\" class=\"RefTarget\"\u003e\u003c/span\u003e\u003c/span\u003e\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eWolter JR, Till GO (1989) Multinucleated giant cells on Bruch\u0026rsquo;s membrane late in recurrent retinal and subretinal hemorrhaging. Ophthalmologica 199:53\u0026ndash;59. \u003cspan class=\"ExternalRef\"\u003e\u003cspan class=\"RefSource\"\u003ehttps://doi.org/10.1159/000310017\u003c/span\u003e\u003cspan address=\"10.1159/000310017\" targettype=\"DOI\" class=\"RefTarget\"\u003e\u003c/span\u003e\u003c/span\u003e\u003c/span\u003e\u003c/li\u003e\u003c/ol\u003e"}],"fulltextSource":"","fullText":"","funders":[],"hasAdminPriorityOnWorkflow":false,"hasManuscriptDocX":true,"hasOptedInToPreprint":true,"hasPassedJournalQc":"","hasAnyPriority":false,"hideJournal":false,"highlight":"","institution":"","isAcceptedByJournal":true,"isAuthorSuppliedPdf":false,"isDeskRejected":"","isHiddenFromSearch":false,"isInQc":false,"isInWorkflow":false,"isPdf":false,"isPdfUpToDate":true,"isWithdrawnOrRetracted":false,"journal":{"display":true,"email":"[email protected]","identity":"bratislava-medical-journal","isNatureJournal":false,"hasQc":true,"allowDirectSubmit":false,"externalIdentity":"","sideBox":"Learn more about [Bratislava Medical Journal](https://link.springer.com/journal/44411)","snPcode":"44411","submissionUrl":"https://submission.springernature.com/new-submission/44411/3","title":"Bratislava Medical Journal","twitterHandle":"","acdcEnabled":true,"dfaEnabled":true,"editorialSystem":"stoa","reportingPortfolio":"Springer Hybrid","inReviewEnabled":true,"inReviewRevisionsEnabled":false},"keywords":"subretinal neovascularization, hemorrhage, anticoagulation treatment, recombinant tissue plasminogen activator","lastPublishedDoi":"10.21203/rs.3.rs-5442181/v1","lastPublishedDoiUrl":"https://doi.org/10.21203/rs.3.rs-5442181/v1","license":{"name":"CC BY 4.0","url":"https://creativecommons.org/licenses/by/4.0/"},"manuscriptAbstract":"\u003cp\u003e\u003cstrong\u003ePurpose:\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eThe objective of this study was to evaluate the functional and clinical outcome of submacular hemorrhage (SMH) in age related macular degeneration (ARMD) displacement using pneumatic displacement with intravitreal expansile gas by 23Gauge pars plana vitrectomy with subretinal injection of recombinant tissue plasminogen activator (rtPA).\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003ePatients and methods:\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eRetrospective interventional case series of 58 pseudophakic patients, who underwent surgical treatment with inclusion criteria: subretinal, subretinal pigment epithelium (subRPE), or combined central hemorrhage associated with ARMD, 23 Gauge pars plana vitrectomy using rtPA sulfur hexafluoride (SF6). Patients were classified according to the clinical picture, the size of the hemorrhage, into group with small hemorrhage up to 2x2 papillary diameter (PD) 32 eyes, moderate hemorrhage (up to 4x4PD, to the arcades) 19 eyes and massive hemorrhage (from 5x5PD hemorrhage through the arcades to the periphery) 7 eyes. Medical records were reviewed for diagnosis, logMAR best corrected visual acuity (BCVA), preop and postop clinical findings, complications, and all medical history up to 6 months after surgery.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eResults:\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eImprovement of average postoperative BCVA was the best in group with moderate extension of hemorrhage, 1.58 logMAR preoperative to 1.14 logMAR postoperative. Improvement of average postoperative BCVA was the best in group with shortest medical history of hemorrhage (up to 7 days). \u0026nbsp;Age was not a crucial predictive factor. Regarding association between hemorrhage category and clinical outcome, there was a significant positive association between the hemorrhage size before the operation and the scored clinical outcome. In association between anticoagulant treatment (ACT) \u0026nbsp;and clinical outcome there was negative, but not significant association between the treatment and the scored clinical outcome (P = 0.5197).\u003c/p\u003e\n\u003cp\u003eComorbidities, as diabetes mellitus or arterial hypertension after adjustment on the baseline and ACT were not significantly associated with worsened vision measured on the LogMAR scale.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eConclusion:\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eWe consider surgical treatment of the hemorrhagic complication of ARMD to be beneficial, massive hemorrhages have a worse prognosis for improving BCVA than moderate and small hemorrhages. Anticoagulants are associated with massive hemorrhage and, at the same time, with the better postoperative BCVA than massive hemorrhage without total ACT.\u003c/p\u003e","manuscriptTitle":"Surgical Treatment of Hemorrhagic Complications of Age- Related Macular Degeneration, Predictive Factors and Outcomes","msid":"","msnumber":"","nonDraftVersions":[{"code":1,"date":"2024-12-17 09:46:31","doi":"10.21203/rs.3.rs-5442181/v1","editorialEvents":[{"type":"communityComments","content":0},{"type":"decision","content":"Revision requested","date":"2024-12-20T06:08:03+00:00","index":"","fulltext":""},{"type":"editorInvitedReview","content":"","date":"2024-12-20T01:42:32+00:00","index":"hide","fulltext":""},{"type":"reviewerAgreed","content":"106561516292186177302087384417726280624","date":"2024-12-19T22:00:15+00:00","index":"hide","fulltext":""},{"type":"editorInvitedReview","content":"","date":"2024-12-19T16:46:25+00:00","index":"hide","fulltext":""},{"type":"reviewerAgreed","content":"215930573459940299593796040786855758925","date":"2024-12-19T16:21:29+00:00","index":"hide","fulltext":""},{"type":"reviewersInvited","content":"","date":"2024-11-23T18:42:57+00:00","index":"","fulltext":""},{"type":"editorAssigned","content":"","date":"2024-11-13T05:31:56+00:00","index":"","fulltext":""},{"type":"checksComplete","content":"","date":"2024-11-13T05:31:24+00:00","index":"","fulltext":""},{"type":"submitted","content":"Bratislava Medical Journal","date":"2024-11-12T20:53:45+00:00","index":"","fulltext":""}],"status":"published","journal":{"display":true,"email":"[email protected]","identity":"bratislava-medical-journal","isNatureJournal":false,"hasQc":true,"allowDirectSubmit":false,"externalIdentity":"","sideBox":"Learn more about [Bratislava Medical Journal](https://link.springer.com/journal/44411)","snPcode":"44411","submissionUrl":"https://submission.springernature.com/new-submission/44411/3","title":"Bratislava Medical Journal","twitterHandle":"","acdcEnabled":true,"dfaEnabled":true,"editorialSystem":"stoa","reportingPortfolio":"Springer Hybrid","inReviewEnabled":true,"inReviewRevisionsEnabled":false}}],"origin":"","ownerIdentity":"18df8a27-5f44-4da7-a622-01c19158155e","owner":[],"postedDate":"December 17th, 2024","published":true,"recentEditorialEvents":[],"rejectedJournal":[],"revision":"","amendment":"","status":"under-review","subjectAreas":[],"tags":[],"updatedAt":"2024-12-28T08:23:15+00:00","versionOfRecord":[],"versionCreatedAt":"2024-12-17 09:46:31","video":"","vorDoi":"","vorDoiUrl":"","workflowStages":[]},"version":"v1","identity":"rs-5442181","journalConfig":"researchsquare"},"__N_SSP":true},"page":"/article/[identity]/[[...version]]","query":{"redirect":"/article/rs-5442181","identity":"rs-5442181","version":["v1"]},"buildId":"qtupq5eGEP_6zYnWcrvyt","isFallback":false,"isExperimentalCompile":false,"dynamicIds":[84888],"gssp":true,"scriptLoader":[]}