A Case Report：Secondary macular hole after subretinal injection of t-PA for the treatment of subretinal hemorrhage

A Case Report：Secondary macular hole after subretinal injection of t-PA for the treatment of subretinal hemorrhage | 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 Case Report A Case Report：Secondary macular hole after subretinal injection of t-PA for the treatment of subretinal hemorrhage Xi Lv, Yanyan Liang, Kejun Li, Jialin Niu, Zhiyang Jia, Jianmin Wang This is a preprint; it has not been peer reviewed by a journal. https://doi.org/ 10.21203/rs.3.rs-6553877/v1 This work is licensed under a CC BY 4.0 License Status: Posted Version 1 posted You are reading this latest preprint version Abstract Background: The Secondary macular hole after subretinal injection of t-PA for the treatment of subretinal hemorrhage is rare. Case Presentation: In this case, we recorded a patient who underwent vitrectomy combined with subretinal injection of t-PA to treat subretinal hemorrhage and subsequently developed macular hole. The patient experienced extensive pre retinal and subretinal bleeding due to ruptured retinal artery aneurysm. After one week of treatment with t-PA injection, macular holes appeared .We successfully closed the macular hole by autologous blood filling and injection of silicone oil. Conclusions: subretinal injection of t-PA for the treatment of subretinal hemorrhage can lead to secondary macular holes. The injection of t-PA should be handled with caution. as the possibility of secondary macular hole closure is low,autologous blood filling can be chosen for the treatment of such macular holes. Subretinal injection of t-PA Retinal large artery aneurysm Subretinal hemorrhage Macular hole Autologous blood filling Figures Figure 1 Background Retinal hemorrhage caused by ruptured retinal aneurysms can occur in various locations, including subretinal, intraretinal, pre retinal, and vitreous cavities. In recent years, many scholars believe that vitrectomy combined with inert gas or air injection into the vitreous cavity and subretinal injection of t-PA is an effective way to treat subretinal hemorrhage. Although subretinal injection of t-PA can directly reach the lesion and have a more comprehensive effect, it may also cause complications such as macular holes. The appearance of macular holes can cause irreversible damage to visual function. Therefore, when treating subretinal hemorrhage with t-PA injection, the possibility of secondary macular holes should be fully considered, and caution should be exercised to avoid the formation of macular holes as much as possible. For this type of macular hole, the possibility of autism is low,using autologous blood to fill and injecting silicone oil can successfully close the macular hole. Case presentation The patient is a 70 year old male have unclear vision in his left eye for 2 days. systemic history of hypertension. Ophthalmic examination: BCVA: 0.8 in the right eye and 0.08 in the left eye, with intraocular pressure of 14mmHg in both eyes.Anterior segment examination of both eyes revealed lens cortex opacity, normal fundus in the right eye, and a large dark red bleeding lesion of about 17PD visible in the anterior and subretinal regions of the left eye, covering the macular area (Fig. 1A). Optical coherence tomography examination showed high elevation of retinal tissue in the macular area, low reflex signals in the anterior and subretinal regions, and a macular fovea thickness of 1258 µ m (Fig. 1B). The patient was diagnosed with pre retinal and subretinal hemorrhage in the left eye, and age-related cataracts in both eyes .we provide the patient with left eye cataract phacoemulsification, intraocular lens implantation, vitrectomy, subretinal injection of t-PA, removal of inner limiting membrane, and gas filling surgery .Intraoperative removal of pre retinal and subretinal hemorrhage revealed aneurysmal dilation of the retinal vascular arch near the macula. Supplementary diagnosis: retinal artery aneurysm in the right eye. During the operation, a 41G needle was used to inject 50ng (0.05ml) of tissue plasminogen activator (t-PA) into the retina near the lesion on the macular vascular arch. Postoperatively, patient requests to maintain supine position. After a follow-up examination one week later, it was found that about 1/2PD hole was visible in the macular area of the left eye. After observing for two weeks, there was no change in the macular hole (Fig. 1C-D). Subsequently, the patient was given autologous blood filling and silicone oil filling surgery for the macular hole of the left eye. The macular hole closed two days after surgery (Fig. 1E-F), and two months after surgery, left eye silicone oil extraction surgery was performed. The left eye BCVA increased to 0.15. Discussion and Conclusion Subretinal hemorrhage in the macular area can lead to irreversible decline in vision, which can be caused by various reasons. The most common ones include rupture of retinal aneurysms (RAM), age-related macular degeneration, polypoid choroidal vascular disease, etc [ 1 , 2 ] . RAM caused by pathological dilation of the retinal artery, and its exact pathogenesis is not yet clear. Most studies believe that it is closely related to systemic diseases such as hypertension, arteriosclerosis, and hyperlipidemia, and is more likely to occur on the temporal 1st to 3rd branches of the central retinal artery. Hypertension and arteriosclerosis can cause fibrous tissue proliferation in the vascular wall, leading to irregular thickening and decreased elasticity of the arterial wall. Persistent hypertension can cause the vascular wall to bulge and form large aneurysms, accompanied by retinal edema, exudation, and bleeding [ 3 ] .Subretinal hemorrhage can block signal transduction between retinal neuroepithelial layers, affecting the metabolism of substances between retinal pigment epithelium and neuroepithelium. In addition, red blood cell breakdown and hemoglobin degeneration can lead to the release of iron ions, which can cause irreversible damage to retinal photoreceptor cells by free radicals generated by iron ion mediated redox reactions [ 4 ] . Retinal hemorrhage caused by RAM rupture can occur in various locations, including subretinal, intraretinal, pre retinal, and vitreous cavities [ 5 ] . In recent years, many scholars have believed that vitrectomy combined with inert gas or air injection into the vitreous cavity and subretinal injection of t-PA is an effective way to treat subretinal hemorrhage [ 6 – 7 ] .Tissue plasminogen activator can obtain a serine protease by cloning and expressing the human t-PA gene, which can specifically activate plasminogen in thrombus to become plasmin, and plasmin dissolves fibrin to cause thrombolysis .The principle of subretinal injection of t-PA is to directly introduce the drug into the lesion site to dissolve the accumulated blood, while the gas acts as a mechanical top pressure to move the liquefied blood away from the macula [ 8 ] . Although subretinal injection of t-PA can directly reach the lesion and have a more comprehensive effect, it may also cause complications such as macular hole, retinal detachment, vitreous hemorrhage, and recurrent macular hemorrhage [ 9 ] . The cause of macular hole after subretinal injection of t-PA is unclear, and there may be multiple reasons Sagara et al.Retrospectively analyzed 56 patients with retinal aneurysms, of whom 7 eyes (12.5%) had macular holes, and all 7 patients had subretinal hemorrhage, indicating that subretinal hemorrhage may cause macular holes [ 10 ] .Scholars have reported that the overall condition of patients and underlying eye diseases may also affect the occurrence of macular hole after t-PA injection,for example, uncontrolled hypertension may increase the risk of macular hole [ 11 ] . It is mentioned in the literature that if the injection site of t-PA is close to the macular fovea or the injection speed is too fast, it may cause local tearing and form retinal holes [ 12 ] . In addition, t-PA promotes blood absorption by activating plasminogen to dissolve fibrin, while excessive fibrinolysis may weaken the structural support of retinal tissue and promote the formation of macular holes. The patient has been suffering from hypertension for many years, and with a large amount of blood accumulation in the macular area of the eye, with a bleeding range greater than 15 PD. The thickness of the macular fovea is greater than 1000 µ m. A large amount of blood accumulation under the macula or in front of the retina exerts a great pressure on the tissue of the macular fovea. In addition, injecting 0.05 ml of t-PA solution into the subretinal area near the macular fovea during surgery further increases the subretinal pressure. The mechanical pressure and fiber dissolution of t-PA may lead to the formation of macular holes. Uemoto and Mizuk [ 13 ] reported a case of an elderly woman who experienced spontaneous closure of a macular hole secondary to RAM bleeding without intervention for 2 weeks. During the subsequent 7-month follow-up, the hole gradually closed completely and restored good macular foveal morphology, but most macular holes still required vitrectomy for treatment,the success rate of macular hole surgery secondary to RAM is about 57.1–75%, which is lower than that of idiopathic macular hole [ 14 ] . The patient's macular hole was discovered one week after t-PA surgery, and the hole diameter was relatively large. After observing for two weeks, the subretinal blood accumulated and absorbed more than before, but there was no trend of spontaneous closure of the macular hole. Therefore, we chose to fill the macular hole with autologous blood and inject silicone oil.In this case, autologous blood is obtained from the patient's own venous vessels during the surgical process. Some scholars believe that various growth factors in autologous blood stimulate the migration and growth of retinal pigment epithelium and Müller cells through autocrine and paracrine mechanisms .In addition, as an intraoperative aid, it can play a role in bonding and covering the hole, while the blood clot contracts, promoting the centripetal movement of the macular area retina[15]. The appearance of macular hole can cause irreversible damage to visual function, so when injecting t-PA under the retina to treat macular hemorrhage, the possibility of secondary macular hole should be fully considered. Preoperative instructions should be given, and careful operation should be carried out to avoid the formation of macular hole as much as possible .For this type of macular hole with low possibility of autism,in this situation, autologous blood filling and injection of silicone oil can successfully close the macular hole. However, more case reports and prospective studies are needed for the natural outcome and surgical outcomes of this type of macular hole. Declarations Acknowledgements We thank all the patients who participated in this study. Authors’contributions Xi Lv wrote the main manuscript text，Kejun Li revised the manuscript，Zhiyang Jia and Jianmin Wang participated in the diagnosis, treatment and review of the patient.All authors reviewed the manuscript. Funding None Availability of data and materials All the data were included in the manuscript. Ethics approval This study adhered to the tenets of the Declaration of Helsinki and approved by the Medical Ethics Committee of Hebei General Hospital. Consent for publication The patient provided written informed consent for the publication of this case. The consent form is available for review by the Editor of this journal. Competing interests The authors declare that they have no competing interests. References Stanescu-Segall D, Balta F, Jackson TL. Submacular hemorrhage in neovascular age-related macular degeneration: A synthesis of the literature. Surv Ophthalmol. 2016 Jan-Feb;61(1):18-32. doi: 10.1016/j.survophthal.2015.04.004. Epub 2015 Jul 23. PMID: 26212151. Quiroz-Mendoza JL, Valera-Cornejo DA, García-Roa M, Ramírez-Neria P, Villalpando-Gómez Y, Romero-Morales V, García-Franco R. Different approaches in the management of macular hemorrhage: Case reports and a literature review. Medwave. 2020 Mar 3;20(2):e7831. Spanish, English. doi: 10.5867/medwave.2020.02.7831. PMID: 32225130. Balas M, Mandell MA, Arjmand P. Juxtafoveal Retinal Arterial Macroaneurysm Diagnosed on Ancillary Imaging. J Vitreoretin Dis. 2024 Jul 24;8(5):609-613. doi: 10.1177/24741264241262102. PMID: 39318990; PMCID: PMC11418749. Chang YS, Kim JH, Kim JW, Kim CG, Lee DW. Development of Submacular Hemorrhage in Neovascular Age-related Macular Degeneration: Influence on Visual Prognosis in a Clinical Setting. Korean J Ophthalmol. 2018 Oct;32(5):361-368. doi: 10.3341/kjo.2017.0095. PMID: 30311458; PMCID: PMC6182213. Rajabian F , Arrigo A , Grazioli A ,et al.Retinal arterial macroaneurysm associated with macular pucker.[J].Eur J Ophthalmol, 2020(5).DOI:10.1177/1120672119891667. van Zeeburg, EJ, van Meurs, JC. Literature review of recombinant tissue plasminogen activator used for recent-onset submacular hemorrhage displacement in age-related macular degeneration. OPHTHALMOLOGICA. 2013; 229 (1): 1-14. doi: 10.1159/000343066 Waizel, M, Todorova, MG, Kazerounian, S, et al. Efficacy of Vitrectomy Combined with Subretinal Recombinant Tissue Plasminogen Activator for Subretinal versus Subpigment Epithelial versus Combined Hemorrhages. OPHTHALMOLOGICA. 2016; 236 (3): 123-132. doi: 10.1159/000449172 Hattenbach L O , Klais C , Koch F H J ,et al.Intravitreous injection of tissue plasminogen activator and gas in the treatment of submacular hemorrhage under various conditions[J].Ophthalmology, 2001, 108(8):1485-1492.DOI:10.1016/S0161-6420(01)00648-0. Hillenkamp, J, Surguch, V, Framme, C, et al. Management of submacular hemorrhage with intravitreal versus subretinal injection of recombinant tissue plasminogen activator. GRAEF ARCH CLIN EXP. 2010; 248 (1): 5-11. doi: 10.1007/s00417-009-1158-7 Sagara N , Kawaji T , Koshiyama Y ,et al.Macular hole formation after macular haemorrhage associated with rupture of retinal arterial macroaneurysm.[J].British Journal of Ophthalmology, 2009, 93(10):1337-40.DOI:10.1136/bjo.2008.149195. Tsuiki, E, Kusano, M, Kitaoka, T. Complication associated with intravitreal injection of tissue plasminogen activator for treatment of submacular hemorrhage due to rupture of retinal arterial macroaneurysm. Am J Ophthalmol Case Rep. 2019; 16 Am J Ophthalmol Case Rep. doi: 10.1016/j.ajoc.2019.100556 Tripepi, D, Jalil, A, Ally, N, et al. The Role of Subretinal Injection in Ophthalmic Surgery: Therapeutic Agent Delivery and Other Indications. Int J Mol Sci. 2023; 24 (13): doi: 10.3390/ijms241310535 Uemoto R , Mizuki N .Spontaneous closure of a macular hole caused by a ruptured retinal arterial macroaneurysm[J].European Journal of Ophthalmology, 2008, 18(3):462-465.DOI:10.1007/s10633-007-9092-7. Sagara N , Kawaji T , Koshiyama Y ,et al.Macular hole formation after macular haemorrhage associated with rupture of retinal arterial macroaneurysm.[J].British Journal of Ophthalmology, 2009, 93(10):1337-40.DOI:10.1136/bjo.2008.149195. Bringmann, A, Jochmann, C, Unterlauft, JD, et al. Different modes of foveal regeneration after closure of full-thickness macular holes by (re)vitrectomy and autologous platelet concentrate. INT J OPHTHALMOL-CHI. 2020; 13 INT J OPHTHALMOL-CHI. doi: 10.18240/ijo.2020.01.06 Additional Declarations No competing interests reported. Supplementary Files CAREChecklist.docx Cite Share Download PDF Status: Posted Version 1 posted 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. Our growing team is made up of researchers and industry professionals working together to solve the most critical problems facing scientific publishing. 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-6553877","acceptedTermsAndConditions":true,"allowDirectSubmit":true,"archivedVersions":[],"articleType":"Case Report","associatedPublications":[],"authors":[{"id":462899804,"identity":"0f86d45d-c66b-4922-8667-8eff975bd3d6","order_by":0,"name":"Xi Lv","email":"","orcid":"","institution":"Hebei General Hospital","correspondingAuthor":false,"prefix":"","firstName":"Xi","middleName":"","lastName":"Lv","suffix":""},{"id":462899805,"identity":"9d57ce0e-b992-4806-a188-d099b8192332","order_by":1,"name":"Yanyan Liang","email":"","orcid":"","institution":"The First Hospital of Hebei Medical 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07:53:21","currentVersionCode":1,"declarations":"","doi":"10.21203/rs.3.rs-6553877/v1","doiUrl":"https://doi.org/10.21203/rs.3.rs-6553877/v1","draftVersion":[],"editorialEvents":[],"editorialNote":"","failedWorkflow":false,"files":[{"id":83767450,"identity":"97935570-00ca-4ee7-bdc0-9de6f65c317d","added_by":"auto","created_at":"2025-06-02 11:28:35","extension":"png","order_by":1,"title":"Figure 1","display":"","copyAsset":false,"role":"figure","size":601195,"visible":true,"origin":"","legend":"\u003cp\u003eA: Upon admission, fundus photography revealed a large dark red hemorrhagic lesion of approximately 17PD in the anterior and subretinal regions of the posterior pole of the left eye, covering the macular area\u003c/p\u003e\n\u003cp\u003eB: The OCT image upon admission showed a high elevation of retinal tissue in the macular area, with low pre retinal and subretinal reflex signals, and a macular fovea thickness of 1258 μ m\u003c/p\u003e\n\u003cp\u003eC: One week after t-PA surgery, fundus photography showed blood accumulation and absorption compared to before, with visible macular holes\u003c/p\u003e\n\u003cp\u003eD: One week after t-PA surgery, OCT images showed a macular hole size of approximately 690 μ m\u003c/p\u003e\n\u003cp\u003eE: Two days after autologous blood filling surgery, fundus photography revealed opacity in the refractive interstitium\u003c/p\u003e\n\u003cp\u003eF: OCT images taken 2 days after autologous blood filling surgery show that the macular hole has closed\u003c/p\u003e","description":"","filename":"1.png","url":"https://assets-eu.researchsquare.com/files/rs-6553877/v1/7aaa481ba5d97ba3a3aec0d4.png"},{"id":85909847,"identity":"92b8d80f-596c-44a6-9402-5bf15402daae","added_by":"auto","created_at":"2025-07-03 05:08:35","extension":"pdf","order_by":0,"title":"","display":"","copyAsset":false,"role":"manuscript-pdf","size":934386,"visible":true,"origin":"","legend":"","description":"","filename":"manuscript.pdf","url":"https://assets-eu.researchsquare.com/files/rs-6553877/v1/460e98b2-05ab-4fbf-adbb-7c381301441d.pdf"},{"id":83767451,"identity":"c94fb108-2595-40f1-bf86-2718a7630dbe","added_by":"auto","created_at":"2025-06-02 11:28:35","extension":"docx","order_by":0,"title":"","display":"","copyAsset":false,"role":"supplement","size":23578,"visible":true,"origin":"","legend":"","description":"","filename":"CAREChecklist.docx","url":"https://assets-eu.researchsquare.com/files/rs-6553877/v1/47a9261af853f0270e8d6cb3.docx"}],"financialInterests":"No competing interests reported.","formattedTitle":"A Case Report：Secondary macular hole after subretinal injection of t-PA for the treatment of subretinal hemorrhage","fulltext":[{"header":"Background","content":"\u003cp\u003eRetinal hemorrhage caused by ruptured retinal aneurysms can occur in various locations, including subretinal, intraretinal, pre retinal, and vitreous cavities. In recent years, many scholars believe that vitrectomy combined with inert gas or air injection into the vitreous cavity and subretinal injection of t-PA is an effective way to treat subretinal hemorrhage. Although subretinal injection of t-PA can directly reach the lesion and have a more comprehensive effect, it may also cause complications such as macular holes. The appearance of macular holes can cause irreversible damage to visual function. Therefore, when treating subretinal hemorrhage with t-PA injection, the possibility of secondary macular holes should be fully considered, and caution should be exercised to avoid the formation of macular holes as much as possible. For this type of macular hole, the possibility of autism is low,using autologous blood to fill and injecting silicone oil can successfully close the macular hole.\u003c/p\u003e"},{"header":"Case presentation","content":"\u003cp\u003eThe patient is a 70 year old male have unclear vision in his left eye for 2 days. systemic history of hypertension. Ophthalmic examination: BCVA: 0.8 in the right eye and 0.08 in the left eye, with intraocular pressure of 14mmHg in both eyes.Anterior segment examination of both eyes revealed lens cortex opacity, normal fundus in the right eye, and a large dark red bleeding lesion of about 17PD visible in the anterior and subretinal regions of the left eye, covering the macular area (Fig.\u0026nbsp;1A). Optical coherence tomography examination showed high elevation of retinal tissue in the macular area, low reflex signals in the anterior and subretinal regions, and a macular fovea thickness of 1258 µ m (Fig.\u0026nbsp;1B). The patient was diagnosed with pre retinal and subretinal hemorrhage in the left eye, and age-related cataracts in both eyes .we provide the patient with left eye cataract phacoemulsification, intraocular lens implantation, vitrectomy, subretinal injection of t-PA, removal of inner limiting membrane, and gas filling surgery .Intraoperative removal of pre retinal and subretinal hemorrhage revealed aneurysmal dilation of the retinal vascular arch near the macula. Supplementary diagnosis: retinal artery aneurysm in the right eye. During the operation, a 41G needle was used to inject 50ng (0.05ml) of tissue plasminogen activator (t-PA) into the retina near the lesion on the macular vascular arch. Postoperatively, patient requests to maintain supine position. After a follow-up examination one week later, it was found that about 1/2PD hole was visible in the macular area of the left eye. After observing for two weeks, there was no change in the macular hole (Fig.\u0026nbsp;1C-D). Subsequently, the patient was given autologous blood filling and silicone oil filling surgery for the macular hole of the left eye. The macular hole closed two days after surgery (Fig.\u0026nbsp;1E-F), and two months after surgery, left eye silicone oil extraction surgery was performed. The left eye BCVA increased to 0.15.\u003c/p\u003e "},{"header":"Discussion and Conclusion","content":"\u003cp\u003eSubretinal hemorrhage in the macular area can lead to irreversible decline in vision, which can be caused by various reasons. The most common ones include rupture of retinal aneurysms (RAM), age-related macular degeneration, polypoid choroidal vascular disease, etc\u003csup\u003e[\u003cspan citationid=\"CR1\" class=\"CitationRef\"\u003e1\u003c/span\u003e, \u003cspan citationid=\"CR2\" class=\"CitationRef\"\u003e2\u003c/span\u003e]\u003c/sup\u003e. RAM caused by pathological dilation of the retinal artery, and its exact pathogenesis is not yet clear. Most studies believe that it is closely related to systemic diseases such as hypertension, arteriosclerosis, and hyperlipidemia, and is more likely to occur on the temporal 1st to 3rd branches of the central retinal artery. Hypertension and arteriosclerosis can cause fibrous tissue proliferation in the vascular wall, leading to irregular thickening and decreased elasticity of the arterial wall. Persistent hypertension can cause the vascular wall to bulge and form large aneurysms, accompanied by retinal edema, exudation, and bleeding \u003csup\u003e[\u003cspan citationid=\"CR3\" class=\"CitationRef\"\u003e3\u003c/span\u003e]\u003c/sup\u003e .Subretinal hemorrhage can block signal transduction between retinal neuroepithelial layers, affecting the metabolism of substances between retinal pigment epithelium and neuroepithelium. In addition, red blood cell breakdown and hemoglobin degeneration can lead to the release of iron ions, which can cause irreversible damage to retinal photoreceptor cells by free radicals generated by iron ion mediated redox reactions\u003csup\u003e[\u003cspan citationid=\"CR4\" class=\"CitationRef\"\u003e4\u003c/span\u003e]\u003c/sup\u003e. Retinal hemorrhage caused by RAM rupture can occur in various locations, including subretinal, intraretinal, pre retinal, and vitreous cavities\u003csup\u003e[\u003cspan citationid=\"CR5\" class=\"CitationRef\"\u003e5\u003c/span\u003e]\u003c/sup\u003e.\u003c/p\u003e\u003cp\u003eIn recent years, many scholars have believed that vitrectomy combined with inert gas or air injection into the vitreous cavity and subretinal injection of t-PA is an effective way to treat subretinal hemorrhage \u003csup\u003e[\u003cspan citationid=\"CR6\" class=\"CitationRef\"\u003e6\u003c/span\u003e–\u003cspan citationid=\"CR7\" class=\"CitationRef\"\u003e7\u003c/span\u003e]\u003c/sup\u003e .Tissue plasminogen activator can obtain a serine protease by cloning and expressing the human t-PA gene, which can specifically activate plasminogen in thrombus to become plasmin, and plasmin dissolves fibrin to cause thrombolysis .The principle of subretinal injection of t-PA is to directly introduce the drug into the lesion site to dissolve the accumulated blood, while the gas acts as a mechanical top pressure to move the liquefied blood away from the macula \u003csup\u003e[\u003cspan citationid=\"CR8\" class=\"CitationRef\"\u003e8\u003c/span\u003e]\u003c/sup\u003e.\u003c/p\u003e\u003cp\u003eAlthough subretinal injection of t-PA can directly reach the lesion and have a more comprehensive effect, it may also cause complications such as macular hole, retinal detachment, vitreous hemorrhage, and recurrent macular hemorrhage \u003csup\u003e[\u003cspan citationid=\"CR9\" class=\"CitationRef\"\u003e9\u003c/span\u003e]\u003c/sup\u003e. The cause of macular hole after subretinal injection of t-PA is unclear, and there may be multiple reasons Sagara et al.Retrospectively analyzed 56 patients with retinal aneurysms, of whom 7 eyes (12.5%) had macular holes, and all 7 patients had subretinal hemorrhage, indicating that subretinal hemorrhage may cause macular holes \u003csup\u003e[\u003cspan citationid=\"CR10\" class=\"CitationRef\"\u003e10\u003c/span\u003e]\u003c/sup\u003e .Scholars have reported that the overall condition of patients and underlying eye diseases may also affect the occurrence of macular hole after t-PA injection,for example, uncontrolled hypertension may increase the risk of macular hole\u003csup\u003e[\u003cspan citationid=\"CR11\" class=\"CitationRef\"\u003e11\u003c/span\u003e]\u003c/sup\u003e. It is mentioned in the literature that if the injection site of t-PA is close to the macular fovea or the injection speed is too fast, it may cause local tearing and form retinal holes \u003csup\u003e[\u003cspan citationid=\"CR12\" class=\"CitationRef\"\u003e12\u003c/span\u003e]\u003c/sup\u003e. In addition, t-PA promotes blood absorption by activating plasminogen to dissolve fibrin, while excessive fibrinolysis may weaken the structural support of retinal tissue and promote the formation of macular holes.\u003c/p\u003e\u003cp\u003eThe patient has been suffering from hypertension for many years, and with a large amount of blood accumulation in the macular area of the eye, with a bleeding range greater than 15 PD. The thickness of the macular fovea is greater than 1000 µ m. A large amount of blood accumulation under the macula or in front of the retina exerts a great pressure on the tissue of the macular fovea. In addition, injecting 0.05 ml of t-PA solution into the subretinal area near the macular fovea during surgery further increases the subretinal pressure. The mechanical pressure and fiber dissolution of t-PA may lead to the formation of macular holes.\u003c/p\u003e\u003cp\u003eUemoto and Mizuk \u003csup\u003e[\u003cspan citationid=\"CR13\" class=\"CitationRef\"\u003e13\u003c/span\u003e]\u003c/sup\u003e reported a case of an elderly woman who experienced spontaneous closure of a macular hole secondary to RAM bleeding without intervention for 2 weeks. During the subsequent 7-month follow-up, the hole gradually closed completely and restored good macular foveal morphology, but most macular holes still required vitrectomy for treatment,the success rate of macular hole surgery secondary to RAM is about 57.1–75%, which is lower than that of idiopathic macular hole \u003csup\u003e[\u003cspan citationid=\"CR14\" class=\"CitationRef\"\u003e14\u003c/span\u003e]\u003c/sup\u003e.\u003c/p\u003e\u003cp\u003eThe patient's macular hole was discovered one week after t-PA surgery, and the hole diameter was relatively large. After observing for two weeks, the subretinal blood accumulated and absorbed more than before, but there was no trend of spontaneous closure of the macular hole. Therefore, we chose to fill the macular hole with autologous blood and inject silicone oil.In this case, autologous blood is obtained from the patient's own venous vessels during the surgical process. Some scholars believe that various growth factors in autologous blood stimulate the migration and growth of retinal pigment epithelium and Müller cells through autocrine and paracrine mechanisms .In addition, as an intraoperative aid, it can play a role in bonding and covering the hole, while the blood clot contracts, promoting the centripetal movement of the macular area retina[15].\u003c/p\u003e\u003cp\u003eThe appearance of macular hole can cause irreversible damage to visual function, so when injecting t-PA under the retina to treat macular hemorrhage, the possibility of secondary macular hole should be fully considered. Preoperative instructions should be given, and careful operation should be carried out to avoid the formation of macular hole as much as possible .For this type of macular hole with low possibility of autism,in this situation, autologous blood filling and injection of silicone oil can successfully close the macular hole. However, more case reports and prospective studies are needed for the natural outcome and surgical outcomes of this type of macular hole.\u003c/p\u003e"},{"header":"Declarations","content":"\u003cp\u003e\u003cstrong\u003eAcknowledgements\u003c/strong\u003e\u003cstrong\u003e\u0026nbsp;\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eWe thank all the patients who participated in this study.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eAuthors\u0026rsquo;contributions\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eXi Lv wrote the main manuscript text，Kejun Li revised the manuscript，Zhiyang Jia and Jianmin Wang participated in the diagnosis, treatment and review of the patient.All authors reviewed the manuscript.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eFunding\u0026nbsp;\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eNone\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eAvailability of data and materials\u0026nbsp;\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eAll the data were included in the manuscript.\u0026nbsp;\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eEthics approval\u0026nbsp;\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eThis study adhered to the tenets of the Declaration of Helsinki and approved by the Medical Ethics Committee of Hebei General Hospital.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eConsent for publication\u0026nbsp;\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eThe patient provided written informed consent for the publication of this case. The consent form is available for review by the Editor of this journal.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eCompeting interests\u0026nbsp;\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eThe authors declare that they have no competing interests.\u003c/p\u003e"},{"header":"References","content":"\u003col\u003e\n\u003cli\u003eStanescu-Segall D, Balta F, Jackson TL. Submacular hemorrhage in neovascular age-related macular degeneration: A synthesis of the literature. Surv Ophthalmol. 2016 Jan-Feb;61(1):18-32. doi: 10.1016/j.survophthal.2015.04.004. Epub 2015 Jul 23. PMID: 26212151.\u003c/li\u003e\n\u003cli\u003eQuiroz-Mendoza JL, Valera-Cornejo DA, Garc\u0026iacute;a-Roa M, Ram\u0026iacute;rez-Neria P, Villalpando-G\u0026oacute;mez Y, Romero-Morales V, Garc\u0026iacute;a-Franco R. Different approaches in the management of macular hemorrhage: Case reports and a literature review. Medwave. 2020 Mar 3;20(2):e7831. Spanish, English. doi: 10.5867/medwave.2020.02.7831. PMID: 32225130.\u003c/li\u003e\n\u003cli\u003eBalas M, Mandell MA, Arjmand P. Juxtafoveal Retinal Arterial Macroaneurysm Diagnosed on Ancillary Imaging. J Vitreoretin Dis. 2024 Jul 24;8(5):609-613. doi: 10.1177/24741264241262102. PMID: 39318990; PMCID: PMC11418749.\u003c/li\u003e\n\u003cli\u003eChang YS, Kim JH, Kim JW, Kim CG, Lee DW. Development of Submacular Hemorrhage in Neovascular Age-related Macular Degeneration: Influence on Visual Prognosis in a Clinical Setting. Korean J Ophthalmol. 2018 Oct;32(5):361-368. doi: 10.3341/kjo.2017.0095. PMID: 30311458; PMCID: PMC6182213.\u003c/li\u003e\n\u003cli\u003eRajabian F , Arrigo A , Grazioli A ,et al.Retinal arterial macroaneurysm associated with macular pucker.[J].Eur J Ophthalmol, 2020(5).DOI:10.1177/1120672119891667.\u003c/li\u003e\n\u003cli\u003evan Zeeburg, EJ, van Meurs, JC. Literature review of recombinant tissue plasminogen activator used for recent-onset submacular hemorrhage displacement in age-related macular degeneration. OPHTHALMOLOGICA. 2013; 229 (1): 1-14. doi: 10.1159/000343066\u003c/li\u003e\n\u003cli\u003eWaizel, M, Todorova, MG, Kazerounian, S, et al. Efficacy of Vitrectomy Combined with Subretinal Recombinant Tissue Plasminogen Activator for Subretinal versus Subpigment Epithelial versus Combined Hemorrhages. OPHTHALMOLOGICA. 2016; 236 (3): 123-132. doi: 10.1159/000449172\u003c/li\u003e\n\u003cli\u003eHattenbach L O , Klais C , Koch F H J ,et al.Intravitreous injection of tissue plasminogen activator and gas in the treatment of submacular hemorrhage under various conditions[J].Ophthalmology, 2001, 108(8):1485-1492.DOI:10.1016/S0161-6420(01)00648-0.\u003c/li\u003e\n\u003cli\u003eHillenkamp, J, Surguch, V, Framme, C, et al. Management of submacular hemorrhage with intravitreal versus subretinal injection of recombinant tissue plasminogen activator. GRAEF ARCH CLIN EXP. 2010; 248 (1): 5-11. doi: 10.1007/s00417-009-1158-7\u003c/li\u003e\n\u003cli\u003eSagara N , Kawaji T , Koshiyama Y ,et al.Macular hole formation after macular haemorrhage associated with rupture of retinal arterial macroaneurysm.[J].British Journal of Ophthalmology, 2009, 93(10):1337-40.DOI:10.1136/bjo.2008.149195.\u003c/li\u003e\n\u003cli\u003eTsuiki, E, Kusano, M, Kitaoka, T. Complication associated with intravitreal injection of tissue plasminogen activator for treatment of submacular hemorrhage due to rupture of retinal arterial macroaneurysm. Am J Ophthalmol Case Rep. 2019; 16 Am J Ophthalmol Case Rep. doi: 10.1016/j.ajoc.2019.100556\u003c/li\u003e\n\u003cli\u003eTripepi, D, Jalil, A, Ally, N, et al. The Role of Subretinal Injection in Ophthalmic Surgery: Therapeutic Agent Delivery and Other Indications. Int J Mol Sci. 2023; 24 (13): doi: 10.3390/ijms241310535\u003c/li\u003e\n\u003cli\u003eUemoto R , Mizuki N .Spontaneous closure of a macular hole caused by a ruptured retinal arterial macroaneurysm[J].European Journal of Ophthalmology, 2008, 18(3):462-465.DOI:10.1007/s10633-007-9092-7.\u003c/li\u003e\n\u003cli\u003eSagara N , Kawaji T , Koshiyama Y ,et al.Macular hole formation after macular haemorrhage associated with rupture of retinal arterial macroaneurysm.[J].British Journal of Ophthalmology, 2009, 93(10):1337-40.DOI:10.1136/bjo.2008.149195.\u003c/li\u003e\n\u003cli\u003eBringmann, A, Jochmann, C, Unterlauft, JD, et al. Different modes of foveal regeneration after closure of full-thickness macular holes by (re)vitrectomy and autologous platelet concentrate. INT J OPHTHALMOL-CHI. 2020; 13 INT J OPHTHALMOL-CHI. doi: 10.18240/ijo.2020.01.06\u003c/li\u003e\n\u003c/ol\u003e"}],"fulltextSource":"","fullText":"","funders":[],"hasAdminPriorityOnWorkflow":false,"hasManuscriptDocX":true,"hasOptedInToPreprint":true,"hasPassedJournalQc":"","hasAnyPriority":false,"hideJournal":true,"highlight":"","institution":"","isAcceptedByJournal":false,"isAuthorSuppliedPdf":false,"isDeskRejected":"","isHiddenFromSearch":false,"isInQc":false,"isInWorkflow":false,"isPdf":false,"isPdfUpToDate":true,"isWithdrawnOrRetracted":false,"journal":{"display":true,"email":"[email protected]","identity":"researchsquare","isNatureJournal":false,"hasQc":true,"allowDirectSubmit":true,"externalIdentity":"","sideBox":"","snPcode":"","submissionUrl":"/submission","title":"Research Square","twitterHandle":"researchsquare","acdcEnabled":true,"dfaEnabled":false,"editorialSystem":"","reportingPortfolio":"","inReviewEnabled":false,"inReviewRevisionsEnabled":true},"keywords":"Subretinal injection of t-PA, Retinal large artery aneurysm, Subretinal hemorrhage, Macular hole, Autologous blood filling","lastPublishedDoi":"10.21203/rs.3.rs-6553877/v1","lastPublishedDoiUrl":"https://doi.org/10.21203/rs.3.rs-6553877/v1","license":{"name":"CC BY 4.0","url":"https://creativecommons.org/licenses/by/4.0/"},"manuscriptAbstract":"\u003cp\u003e\u003cstrong\u003eBackground:\u003c/strong\u003eThe Secondary macular hole after subretinal injection of t-PA for the treatment of subretinal hemorrhage is rare.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eCase Presentation:\u003c/strong\u003eIn this case, we recorded a patient who underwent vitrectomy combined with subretinal injection of t-PA to treat subretinal hemorrhage and subsequently developed macular hole. The patient experienced extensive pre retinal and subretinal bleeding due to ruptured retinal artery aneurysm. After one week of treatment with t-PA injection, macular holes appeared .We successfully closed the macular hole by autologous blood filling and injection of silicone oil.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eConclusions: \u003c/strong\u003esubretinal injection of t-PA for the treatment of subretinal hemorrhage can lead to secondary macular holes. The injection of t-PA should be handled with caution. as the possibility of secondary macular hole closure is low,autologous blood filling can be chosen for the treatment of such macular holes.\u003c/p\u003e","manuscriptTitle":"A Case Report：Secondary macular hole after subretinal injection of t-PA for the treatment of subretinal hemorrhage","msid":"","msnumber":"","nonDraftVersions":[{"code":1,"date":"2025-06-02 11:28:30","doi":"10.21203/rs.3.rs-6553877/v1","editorialEvents":[{"type":"communityComments","content":0}],"status":"published","journal":{"display":true,"email":"[email protected]","identity":"researchsquare","isNatureJournal":false,"hasQc":true,"allowDirectSubmit":true,"externalIdentity":"","sideBox":"","snPcode":"","submissionUrl":"/submission","title":"Research Square","twitterHandle":"researchsquare","acdcEnabled":true,"dfaEnabled":false,"editorialSystem":"","reportingPortfolio":"","inReviewEnabled":false,"inReviewRevisionsEnabled":true}}],"origin":"","ownerIdentity":"cdb18b23-a5c2-43b5-b11d-e9f37735f3c3","owner":[],"postedDate":"June 2nd, 2025","published":true,"recentEditorialEvents":[],"rejectedJournal":[],"revision":"","amendment":"","status":"posted","subjectAreas":[],"tags":[],"updatedAt":"2025-07-03T05:08:09+00:00","versionOfRecord":[],"versionCreatedAt":"2025-06-02 11:28:30","video":"","vorDoi":"","vorDoiUrl":"","workflowStages":[]},"version":"v1","identity":"rs-6553877","journalConfig":"researchsquare"},"__N_SSP":true},"page":"/article/[identity]/[[...version]]","query":{"redirect":"/article/rs-6553877","identity":"rs-6553877","version":["v1"]},"buildId":"8U1c8b4HqxoKbykW_rLl7","isFallback":false,"isExperimentalCompile":false,"dynamicIds":[84888],"gssp":true,"scriptLoader":[]}