{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,6,5]],"date-time":"2026-06-05T02:57:22Z","timestamp":1780628242516,"version":"3.54.1"},"reference-count":27,"publisher":"MDPI AG","issue":"10","license":[{"start":{"date-parts":[[2025,5,15]],"date-time":"2025-05-15T00:00:00Z","timestamp":1747267200000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["JCM"],"abstract":"<jats:p>Purpose: Acute submacular hemorrhage (SMH) is a vision-threatening complication common in patients affected by age-related macular degeneration (AMD). This study evaluates safety, long-term clinical outcomes and associated treatment factors following intravitreal triple injection of recombinant tissue plasminogen activator (rtPA), SF6 gas, and Bevacizumab due to acute SMH secondary to AMD. Methods: A retrospective analysis on patients who received treatment between January 2014 and December 2020 (n = 37) was conducted. Visual acuity (VA), central retinal thickness (CRT), central retinal volume (CRV), and axial pigment epithelial detachment height were analyzed at baseline (B), 4 weeks after triple injection (FU1), after the following anti-VEGF injection series (FU2), after 1 year (FU3), after 2 years (FU4), and at the final follow-up examination after 4.4 \u00b1 1.6 years (FU5). Further, treatment courses and clinical outcomes were compared to a patient cohort treated for exudative AMD without prior SMH. Furthermore, an explorative data analysis on final VA was conducted, and adverse events following triple therapy were investigated. Results: Triple injection was performed on average 5.6 \u00b1 5.7 days after onset of symptoms. Patients received 16 \u00b1 3 additional intravitreal anti-VEGF injections due to persistent macular edema over the subsequent 2 years. Significant improvements were observed at FU1 in VA (p &lt; 0.001), CRT (p = 0.005), and CRV (p = 0.007), as well as at FU2 in axial PED height (p &lt; 0.001), with all improvements being stable until final follow-up examination. In the group comparison, patients with SMH demonstrated significantly worse functional and anatomical outcomes at 24 months except for the 24-month CRT, and patients on average received more intravitreal injections. Five of 37 patients (13.5%) experienced a retinal pigment epithelial tear following triple injection. Final VA correlated positively and significantly with FU1 VA, while no correlation was observed with baseline VA, the size or height of SMH, or the number of additional anti-VEGF injections. Conclusions: Triple injection constitutes a simple and effective therapy with long-term functional and anatomical improvements following treatment due to SMH, although patients have an increased risk for RPE tears. The 4-week postoperative VA following triple injection was predictive for long-term visual function.<\/jats:p>","DOI":"10.3390\/jcm14103449","type":"journal-article","created":{"date-parts":[[2025,5,15]],"date-time":"2025-05-15T04:39:16Z","timestamp":1747283956000},"page":"3449","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":4,"title":["Safety and Long-Term Efficacy of Intravitreal rtPA, Bevacizumab and SF6 Injection in Patients with Submacular Hemorrhage Secondary to Age-Related Macular Degeneration"],"prefix":"10.3390","volume":"14","author":[{"given":"Peter","family":"Wolfrum","sequence":"first","affiliation":[{"name":"Department of Ophthalmology, University Medical Center of the Johannes Gutenberg-University Mainz, Langenbeckstr. 1, 55131 Mainz, Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0009-0009-6273-3684","authenticated-orcid":false,"given":"Elsa Wilma","family":"B\u00f6hm","sequence":"additional","affiliation":[{"name":"Department of Ophthalmology, University Medical Center of the Johannes Gutenberg-University Mainz, Langenbeckstr. 1, 55131 Mainz, Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Simon","family":"K\u00f6nig","sequence":"additional","affiliation":[{"name":"Department of Ophthalmology, University Medical Center of the Johannes Gutenberg-University Mainz, Langenbeckstr. 1, 55131 Mainz, Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-1755-7396","authenticated-orcid":false,"given":"Katrin","family":"Lorenz","sequence":"additional","affiliation":[{"name":"Department of Ophthalmology, University Medical Center of the Johannes Gutenberg-University Mainz, Langenbeckstr. 1, 55131 Mainz, Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Bernhard","family":"Stoffelns","sequence":"additional","affiliation":[{"name":"Department of Ophthalmology, University Medical Center of the Johannes Gutenberg-University Mainz, Langenbeckstr. 1, 55131 Mainz, Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-7572-4749","authenticated-orcid":false,"given":"Christina A.","family":"Korb","sequence":"additional","affiliation":[{"name":"Department of Ophthalmology, University Medical Center of the Johannes Gutenberg-University Mainz, Langenbeckstr. 1, 55131 Mainz, Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2025,5,15]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"195","DOI":"10.1016\/S0039-6257(97)00089-1","article-title":"Pathophysiology and management of subretinal hemorrhage","volume":"42","author":"Hochman","year":"1997","journal-title":"Surv. Ophthalmol."},{"key":"ref_2","doi-asserted-by":"crossref","first-page":"221","DOI":"10.1055\/s-0028-1109750","article-title":"Combination of Intravitreal rTPA, gas and ranibizumab for extensive subfoveal haemorrhages secondary to neovascular age-related macular degeneration","volume":"227","author":"Matt","year":"2010","journal-title":"Klin. Monbl. Augenheilkd."},{"key":"ref_3","doi-asserted-by":"crossref","first-page":"316","DOI":"10.1016\/j.ajo.2009.08.033","article-title":"Subretinal hemorrhages associated with age-related macular degeneration in patients receiving anticoagulation or antiplatelet therapy","volume":"149","author":"Fischer","year":"2010","journal-title":"Am. J. Ophthalmol."},{"key":"ref_4","doi-asserted-by":"crossref","unstructured":"Pierre, M., Mainguy, A., Chatziralli, I., Pakzad-Vaezi, K., Ruiz-Medrano, J., Bodaghi, B., Loewenstein, A., Ambati, J., de Smet, M.D., and Tadayoni, R. (2021). Macular Hemorrhage Due to Age-Related Macular Degeneration or Retinal Arterial Macroaneurysm: Predictive Factors of Surgical Outcome. J. Clin. Med., 10.","DOI":"10.3390\/jcm10245787"},{"key":"ref_5","doi-asserted-by":"crossref","first-page":"18","DOI":"10.1016\/j.survophthal.2015.04.004","article-title":"Submacular hemorrhage in neovascular age-related macular degeneration: A synthesis of the literature","volume":"61","author":"Balta","year":"2016","journal-title":"Surv. Ophthalmol."},{"key":"ref_6","doi-asserted-by":"crossref","first-page":"48","DOI":"10.1186\/s40942-019-0200-0","article-title":"Traumatic submacular hemorrhage: Available treatment options and synthesis of the literature","volume":"5","author":"Casini","year":"2019","journal-title":"Int. J. Retin. Vitr."},{"key":"ref_7","doi-asserted-by":"crossref","first-page":"97","DOI":"10.1159\/000027400","article-title":"Natural history of macular subretinal hemorrhage in age-related macular degeneration","volume":"213","author":"Scupola","year":"1999","journal-title":"Ophthalmologica"},{"key":"ref_8","doi-asserted-by":"crossref","first-page":"1240","DOI":"10.1161\/STROKEAHA.119.027921","article-title":"Trends of r-tPA (Recombinant Tissue-Type Plasminogen Activator) Treatment and Treatment-Influencing Factors in Acute Ischemic Stroke","volume":"51","author":"Marko","year":"2020","journal-title":"Stroke"},{"key":"ref_9","doi-asserted-by":"crossref","first-page":"1485","DOI":"10.1016\/S0161-6420(01)00648-0","article-title":"Intravitreous injection of tissue plasminogen activator and gas in the treatment of submacular hemorrhage under various conditions","volume":"108","author":"Hattenbach","year":"2001","journal-title":"Ophthalmology"},{"key":"ref_10","doi-asserted-by":"crossref","unstructured":"He, X., Cao, W., Wang, Z., Zhang, N., Xu, K., Yu, L., Xing, Y., and Yang, N. (2023). Efficacy Evaluation of Tissue Plasminogen Activator with Anti-Vascular Endothelial Growth Factor Drugs for Submacular Hemorrhage Treatment: A Meta-Analysis. J. Clin. Med., 12.","DOI":"10.3390\/jcm12031035"},{"key":"ref_11","doi-asserted-by":"crossref","first-page":"36","DOI":"10.1097\/IAE.0b013e3181e37884","article-title":"Intravitreous injection of bevacizumab, tissue plasminogen activator, and gas in the treatment of submacular hemorrhage in age-related macular degeneration","volume":"31","author":"Guthoff","year":"2011","journal-title":"Retina"},{"key":"ref_12","doi-asserted-by":"crossref","first-page":"487","DOI":"10.1055\/s-0042-121575","article-title":"Efficacy of Vitrectomy Combined with Subretinal rtPA Injection with Gas or Air Tamponade","volume":"234","author":"Waizel","year":"2017","journal-title":"Klin. Monbl. Augenheilkd."},{"key":"ref_13","first-page":"391","article-title":"Vitrectomy with subretinal tissue plasminogen activator (r-TPA) and intravitreal injection of anti-vascular endothelial growth factor (anti-VEGF) for submacular hemorrhages treatment: Retrospective analysis of 22 cases","volume":"97","author":"Pospoki","year":"2022","journal-title":"Arch. Soc. Esp. Oftalmol."},{"key":"ref_14","unstructured":"Berufsverband der Augen\u00e4rzte Deutschlands e.V. (2022). RG Stellungnahme der Deutschen Ophthalmologischen Gesellschaft, der Retinologischen Gesellschaft und des Berufsverbandes der Augen\u00e4rzte Deutschlands, Berufsverband der Augen\u00e4rzte Deutschlands e.V."},{"key":"ref_15","doi-asserted-by":"crossref","first-page":"194","DOI":"10.1016\/S0002-9394(02)01825-1","article-title":"A computerized method of visual acuity testing: Adaptation of the early treatment of diabetic retinopathy study testing protocol","volume":"135","author":"Beck","year":"2003","journal-title":"Am. J. Ophthalmol."},{"key":"ref_16","first-page":"2699","article-title":"FARETINA-DME-Early Treatment Patterns and Outcomes in Patients with Diabetic Macular Edema Treated with Faricimab: An IRIS RegistryTM Analysis","volume":"64","author":"Tabano","year":"2023","journal-title":"Investig. Ophthalmol. Vis. Sci."},{"key":"ref_17","doi-asserted-by":"crossref","unstructured":"Inoue, N., Kato, A., Araki, T., Kimura, T., Kinoshita, T., Okamoto, F., Murakami, T., Mitamura, Y., Sakamoto, T., and Miki, A. (2022). Visual prognosis of submacular hemorrhage secondary to age-related macular degeneration: A retrospective multicenter survey. PLoS ONE, 17.","DOI":"10.1371\/journal.pone.0271447"},{"key":"ref_18","doi-asserted-by":"crossref","first-page":"952","DOI":"10.1038\/eye.2016.67","article-title":"Early treatment of acute submacular haemorrhage secondary to wet AMD using intravitreal tissue plasminogen activator, C3F8, and an anti-VEGF agent","volume":"30","author":"Bindra","year":"2016","journal-title":"Eye"},{"key":"ref_19","doi-asserted-by":"crossref","first-page":"27","DOI":"10.1186\/s40942-020-00228-x","article-title":"Surgical management of submacular hemorrhage due to n-AMD: A comparison of three surgical methods","volume":"6","author":"Grohmann","year":"2020","journal-title":"Int. J. Retin. Vitr."},{"key":"ref_20","doi-asserted-by":"crossref","first-page":"191","DOI":"10.1159\/000537939","article-title":"Submacular hemorrhage during neovascular age-related macular degeneration: A meta-analysis and meta-regression on the use of tPA and anti-VEGFs","volume":"247","author":"Veritti","year":"2024","journal-title":"Ophthalmologica"},{"key":"ref_21","doi-asserted-by":"crossref","first-page":"567","DOI":"10.1089\/jop.2013.0135","article-title":"Long-term visual outcome and its predictive factors following treatment of acute submacular hemorrhage with intravitreous injection of tissue plasminogen factor and gas","volume":"30","author":"Sobolewska","year":"2014","journal-title":"J. Ocul. Pharmacol. Ther."},{"key":"ref_22","doi-asserted-by":"crossref","first-page":"203","DOI":"10.1097\/IAE.0b013e3181babda5","article-title":"Optical coherence tomography-measured pigment epithelial detachment height as a predictor for retinal pigment epithelial tears associated with intravitreal bevacizumab injections","volume":"30","author":"Chan","year":"2010","journal-title":"Retina"},{"key":"ref_23","doi-asserted-by":"crossref","first-page":"1156","DOI":"10.1097\/IAE.0000000000000056","article-title":"Pigment epithelial tears associated with anti-VEGF therapy: Incidence, long-term visual outcome, and relationship with pigment epithelial detachment in age-related macular degeneration","volume":"34","author":"Doguizi","year":"2014","journal-title":"Retina"},{"key":"ref_24","doi-asserted-by":"crossref","first-page":"63","DOI":"10.1016\/j.jfo.2018.04.017","article-title":"Retinal pigment epithelial tears","volume":"42","author":"Wu","year":"2019","journal-title":"J. Fr. Ophtalmol."},{"key":"ref_25","first-page":"179","article-title":"Association between retinal pigment epithelium tear and anti-vascular endothelial growth factor therapy: A Systematic Review and Meta-Analysis","volume":"44","author":"Shi","year":"2024","journal-title":"Retina"},{"key":"ref_26","doi-asserted-by":"crossref","first-page":"512","DOI":"10.1055\/s-2002-33584","article-title":"Intravitreal injection of rt-PA and gas in the management of minor submacular haemorrhages secondary to age-related macular degeneration","volume":"219","author":"Hattenbach","year":"2002","journal-title":"Klin. Monbl. Augenheilkd."},{"key":"ref_27","first-page":"1800","article-title":"Predictive Factors for Visual Outcome after Submacular Hemorrhage\u2014A comparative Treatment Study","volume":"61","author":"Schwartz","year":"2020","journal-title":"Investig. Ophthalmol. Vis. Sci."}],"container-title":["Journal of Clinical Medicine"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.mdpi.com\/2077-0383\/14\/10\/3449\/pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,10,9]],"date-time":"2025-10-09T17:32:57Z","timestamp":1760031177000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.mdpi.com\/2077-0383\/14\/10\/3449"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2025,5,15]]},"references-count":27,"journal-issue":{"issue":"10","published-online":{"date-parts":[[2025,5]]}},"alternative-id":["jcm14103449"],"URL":"https:\/\/doi.org\/10.3390\/jcm14103449","relation":{},"ISSN":["2077-0383"],"issn-type":[{"value":"2077-0383","type":"electronic"}],"subject":[],"published":{"date-parts":[[2025,5,15]]}}}