Case Report: Superotemporal branch retinal vein occlusion following COVID-19 vaccination and SARS-CoV-2 infection while taking oral contraceptives

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Branch retinal vein occlusion (BRVO) generally develops mid-60s patients. Herein, we present a case of superotemporal BRVO caused by the above mentioned risk factors in a young woman. To the best of our knowledge, this is the first report about superotemporal BRVO associated with oral contraceptives, COVID-19 vaccination, and SARS-CoV-2. A 21-year-old woman presented with loss of visual acuity in her right eye for 10 days. She had been receiving oral contraceptives for 2 years for oligomenorrhea before noticing ophthalmological symptoms. Despite having received two doses of an mRNA COVID-19 vaccine, she contracted COVID-19 and developed fever, sore throat, cough, low back pain, and general malaise about 40 days before the initial visit. However, only cough persisted for more than a month. The right eye showed superotemporal BRVO with macular edema (ME). She did not smoke nor had diabetes or hypertension. Blood test results, including cardiolipin antibody IgG, were normal. She was treated with an intravitreal aflibercept injection. ME in the fundus showed rapid improvement and resolution. Although more than 20 months have passed since the first injection, there has been no relapse of ME. The combination of oral contraceptive use, COVID-19 vaccination, and subsequent SARS-CoV-2 infection could induce the development of venous thromboembolism, thereby leading to superotemporal BRVO. Given that cases of COVID-19 have increased globally, patients with retinal vein occlusion who use oral contraceptives are likely to be encountered more frequently." } { "@context": "http://schema.org", "@type": "BreadcrumbList", "itemListElement": [ { "@type": "ListItem", "position": "1", "item": { "@id": "https://f1000research.com/", "name": "Home" } }, { "@type": "ListItem", "position": "2", "item": { "@id": "https://f1000research.com/browse/articles", "name": "Browse" } }, { "@type": "ListItem", "position": "3", "item": { "@id": "https://f1000research.com/articles/13-460", "name": "Case Report: Superotemporal branch retinal vein occlusion following..." } } ] } Home Browse Case Report: Superotemporal branch retinal vein occlusion following... ALL Metrics - Views Downloads Get PDF Get XML Cite How to cite this article Muto T, Sakamoto M, Machida S et al. Case Report: Superotemporal branch retinal vein occlusion following COVID-19 vaccination and SARS-CoV-2 infection while taking oral contraceptives [version 2; peer review: 1 not approved] . F1000Research 2025, 13 :460 ( https://doi.org/10.12688/f1000research.148251.2 ) NOTE: If applicable, it is important to ensure the information in square brackets after the title is included in all citations of this article. Close Copy Citation Details Export Export Citation Sciwheel EndNote Ref. Manager Bibtex ProCite Sente EXPORT Select a format first Track Share ▬ ✚ Case Report Revised Case Report: Superotemporal branch retinal vein occlusion following COVID-19 vaccination and SARS-CoV-2 infection while taking oral contraceptives [version 2; peer review: 1 not approved] Tetsuya Muto https://orcid.org/0000-0003-1690-9254 1-3 , Masaaki Sakamoto 2 , Shigeki Machida 2 , Shinichiro Imaizumi 3 , Yoshinobu Hamada 4 , Koju Kamoi 5 Tetsuya Muto https://orcid.org/0000-0003-1690-9254 1-3 , Masaaki Sakamoto 2 , [...] Shigeki Machida 2 , Shinichiro Imaizumi 3 , Yoshinobu Hamada 4 , Koju Kamoi 5 PUBLISHED 17 Feb 2025 Author details Author details 1 Department of Ophthalmology, Fukushima Medical University, Fukushima, Fukushima, 960-1295, Japan 2 Department of Ophthalmology, Dokkyo Medical University Saitama Medical Center, Koshigaya, Saitama, 343-8555, Japan 3 Department of Ophthalmology, Imaizumi Eye Hospital, Koriyama, Fukushima, 963-8877, Japan 4 Department of Obstetrics and Gynecology, Dokkyo Medical University Saitama Medical Center, Koshigaya, Saitama, 343-8555, Japan 5 Department of Ophthalmology and Visual Science, Tokyo Medical and Dental University, Tokyo, Tokyo, 113-8519, Japan Tetsuya Muto Roles: Conceptualization, Writing – Original Draft Preparation Masaaki Sakamoto Roles: Resources Shigeki Machida Roles: Supervision Shinichiro Imaizumi Roles: Supervision Yoshinobu Hamada Roles: Supervision Koju Kamoi Roles: Supervision, Writing – Review & Editing OPEN PEER REVIEW DETAILS REVIEWER STATUS Abstract Oral contraceptive use, vaccination for Coronavirus disease 2019 (COVID-19), and severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection are risk factors for venous thromboembolism. Branch retinal vein occlusion (BRVO) generally develops mid-60s patients. Herein, we present a case of superotemporal BRVO caused by the above mentioned risk factors in a young woman. To the best of our knowledge, this is the first report about superotemporal BRVO associated with oral contraceptives, COVID-19 vaccination, and SARS-CoV-2. A 21-year-old woman presented with loss of visual acuity in her right eye for 10 days. She had been receiving oral contraceptives for 2 years for oligomenorrhea before noticing ophthalmological symptoms. Despite having received two doses of an mRNA COVID-19 vaccine, she contracted COVID-19 and developed fever, sore throat, cough, low back pain, and general malaise about 40 days before the initial visit. However, only cough persisted for more than a month. The right eye showed superotemporal BRVO with macular edema (ME). She did not smoke nor had diabetes or hypertension. Blood test results, including cardiolipin antibody IgG, were normal. She was treated with an intravitreal aflibercept injection. ME in the fundus showed rapid improvement and resolution. Although more than 20 months have passed since the first injection, there has been no relapse of ME. The combination of oral contraceptive use, COVID-19 vaccination, and subsequent SARS-CoV-2 infection could induce the development of venous thromboembolism, thereby leading to superotemporal BRVO. Given that cases of COVID-19 have increased globally, patients with retinal vein occlusion who use oral contraceptives are likely to be encountered more frequently. READ ALL READ LESS Keywords branch retinal vein occlusion, COVID-19, SARS-CoV-2 infection, macular edema, oral contraceptive Corresponding Author(s) Tetsuya Muto ( [email protected] ) Close Corresponding author: Tetsuya Muto Competing interests: No competing interests were disclosed. Grant information: The author(s) declared that no grants were involved in supporting this work. Copyright: © 2025 Muto T et al . This is an open access article distributed under the terms of the Creative Commons Attribution License , which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited. How to cite: Muto T, Sakamoto M, Machida S et al. Case Report: Superotemporal branch retinal vein occlusion following COVID-19 vaccination and SARS-CoV-2 infection while taking oral contraceptives [version 2; peer review: 1 not approved] . F1000Research 2025, 13 :460 ( https://doi.org/10.12688/f1000research.148251.2 ) First published: 08 May 2024, 13 :460 ( https://doi.org/10.12688/f1000research.148251.1 ) Latest published: 17 Feb 2025, 13 :460 ( https://doi.org/10.12688/f1000research.148251.2 ) Revised Amendments from Version 1 We revised the manuscript following the reviewer’s comment. We mentioned STBRVO and not just BRVO. The title was amended to “Superotemporal branch retinal vein occlusion following COVID-19 vaccination and SARS-CoV-2 infection while taking oral contraceptives: A case report” Furthermore, we changed part of the abstract. We mentioned routine blood investigations in Table 1 and 2. We added the sentence below in the discussion section. “To the best of our knowledge, this is the first reported case of superotemporal BRVO involving all three risk factors.” We stated what blood investigations favored a possible thrombotic cause in this case in the discussion section. We described STRVO in discussion and added references no. 13 and 14. We provided OCT photos 24 months since the first administration (figure 4). We added the sentence below in case report section. “No ME was noted after 24 months (Figure 4), and the decimal BCVA remained at 1.2.” We discussed the mechanism of thrombosis following COVID-19 infection in the discussion as below and we added reference no. 12. Coagulation disorder in COVID-19 is thought to occur through vascular damage caused by virus infection 12 . Various factors, including reduced antithrombogenicity of the vascular endothelium, release of von Willebrand factor and coagulation factor VIII, complement activation, increased fibrinogen, and cytokine storm, are intricately interwoven 12 . Thrombus can then form in any vessel, such as arteries, veins, and capillaries 12 . We revised the manuscript following the reviewer’s comment. We mentioned STBRVO and not just BRVO. The title was amended to “Superotemporal branch retinal vein occlusion following COVID-19 vaccination and SARS-CoV-2 infection while taking oral contraceptives: A case report” Furthermore, we changed part of the abstract. We mentioned routine blood investigations in Table 1 and 2. We added the sentence below in the discussion section. “To the best of our knowledge, this is the first reported case of superotemporal BRVO involving all three risk factors.” We stated what blood investigations favored a possible thrombotic cause in this case in the discussion section. We described STRVO in discussion and added references no. 13 and 14. We provided OCT photos 24 months since the first administration (figure 4). We added the sentence below in case report section. “No ME was noted after 24 months (Figure 4), and the decimal BCVA remained at 1.2.” We discussed the mechanism of thrombosis following COVID-19 infection in the discussion as below and we added reference no. 12. Coagulation disorder in COVID-19 is thought to occur through vascular damage caused by virus infection 12 . Various factors, including reduced antithrombogenicity of the vascular endothelium, release of von Willebrand factor and coagulation factor VIII, complement activation, increased fibrinogen, and cytokine storm, are intricately interwoven 12 . Thrombus can then form in any vessel, such as arteries, veins, and capillaries 12 . See the authors' detailed response to the review by Pradeep Kumar Panigrahi READ REVIEWER RESPONSES Introduction The Coronavirus disease 2019 (COVID-19), which is caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), is the latest pandemic and has lasted approximately 3 years in Japan. A special characteristic of COVID-19 is its propensity to cause venous thromboembolism (VTE), 1 which could result in fatal complications. In ophthalmology, COVID-19 reportedly causes retinal vein occlusion (RVO). 2 – 4 Branch RVO (BRVO) is a major retinal vascular disease that occurs following venous thrombosis at arteriovenous crossing points. Arteriosclerosis accompanied by hypertension is a risk factor for BRVO; therefore, it primarily affects older people. BRVO causes blood–retinal barrier dysfunction, resulting in macular edema (ME). Photoreceptor cell apoptosis caused by chronic ME is responsible for the reduced vision in patients with BRVO. Therefore, a missed treatment window may lead to irreversible loss of vision. 5 , 6 Anti-vascular endothelial growth factor agents are the first-line treatment for ME secondary to BRVO. 7 Over 100 million women worldwide practice contraception and use intrauterine devices, combined estrogen and progestin oral contraceptives, and progestin -only preparations (oral contraceptives, implants, or injections). 8 Oral contraceptives contain estrogen, which increase the risk of VTE due to activation the coagulation cascade. The incidence of VTE in women receiving oral contraceptives is approximately twice as high as that in the normal population. 9 Generally, the age group susceptible to RVO associated with oral contraceptive use is younger than that for typical RVO. Herein, we present a case of a 21-year-old woman using oral contraceptives who developed superotemporal BRVO with ME following COVID-19. To the best of our knowledge, this is the first report suggesting that oral contraceptive intake combined with COVID-19 may be a risk factor for the development of superotemporal BRVO. Case report A 21-year-old woman was diagnosed with polycystic ovary syndrome accompanied by oligomenorrhea at 19 years old. Consequently, she had been taking oral contraceptives (norethisterone and ethinylestradiol mix tablet) for the improvement of oligomenorrhea. She did not have diabetes or systemic hypertension, and she did not smoke. She had no family history of VTE. Her height, body weight, and body mass index were 1.62 m, 52 kg, and 19.8, respectively. Although she had received an mRNA COVID-19 vaccine twice approximately 5 months prior to presentation, she experienced fever, sore throat, cough, low back pain, and general malaise, prompting her to visit a clinic. Polymerase chain reaction of her saliva sample showed a positive reaction to SARS-CoV-2. Her cough persisted for a month, but other symptoms improved without post-COVID-19 sequelae. Approximately 40 days after being diagnosed with COVID-19, she presented with decreased vision in the right eye and was diagnosed with ME secondary to superotemporal BRVO. On her initial visit to our hospital, the decimal best-corrected visual acuity (BCVA) values were 0.4 in the right eye and 1.2 in the left eye. In both eyes, intraocular pressure was normal, and slit-lamp biomicroscopy did not detect inflammation. Fundus examination revealed retinal hemorrhage in the superior-temporal quadrant of the retina in the right eye ( Figure 1 ). Optical coherence tomography (RS-3000 Advance, Nidek Corporation, Japan) demonstrated cystoid ME and intraretinal fluid in the right eye ( Figure 2 ). Blood test results, including cardiolipin antibody IgG, were within normal limits ( Tables 1 and 2 ). Figure 1. Retinal haemorrhage in the right eye at the initial visit. Figure 2. Optical coherence tomography showing macular edema at the initial visit. Table 1. Blood test results at the initial visit 1. Factors Values GOT (U/L) 14 GPT (U/L) 8 γ-GTP (U/L) 12 total bilirubin (mg/dL) 0.49 direct bilirubin (mg/dL) 0.02 indirect bilirubin (mg/dL) 0.47 total protein 8g/dL) 7.3 albumin (g/dL) 4.44 Na (mmol/L) 141 K (mmol/L) 4.1 Cl (mmol/L) 105 Ca (mg/dL) 9.5 BUN (mg/dL) 11 Cre (mg/dL) 0.56 Uric acid (mg/dL) 4.1 BS (mg/dL) 89 total cholesterol (mg/dL) 192 triglyceride (mg/dL) 78 HDL cholesterol (mg/dL) 64 LDL cholesterol (mg/dL) 116 LDL/HDL 1.8 WBC (x10 9 /L) 5.4 RBC (x10 9 /L) 4.18 Hb (g/dL) 12.2 Ht (%) 37.5 MCV (fL) 89.7 MCH (pg) 29.2 MCHC (g/dL) 32.5 Table 2. Blood test results at the initial visit 2. Factors Values Platelet (x10 9 /L) 252 neutrophils (%) 50.4 ESR (mm/1h) 10 lymphocyte (%) 42.2 monocyte (%) 3.9 eosinophils (%) 2.8 basophil leukocyte (%) 0.7 PT (sec) 11.1 APTT (sec) 28.8 CRP (mg/dL) 0.11 IgG (mg/dL) 1138.6 IgA (mg/dL) 238.1 IgM (mg/dL) 118.1 C3 (mg/dL) 108.2 C4 (mg/dL) 24.8 cardiolipin antibody IgG (U/mL) < 4.0 ACE (U/L) 6.1 RA (IU/mL) < 5 The clinical diagnosis was ME secondary to superotemporal BRVO following COVID-19. We contacted her gynecologist about her eye condition, and oral contraceptives for oligomenorrhea were changed to a progestational hormone agent (dydrogesterone). Additionally, the patient was treated with intravitreal aflibercept (Eylea ® ; Regeneron, Tarrytown, NY, USA). ME resolved after 1 month ( Figure 3 ), and the decimal BCVA improved to 1.2 in the right eye. After more than 20 months since the first administration, no additional intravitreal aflibercept has been administered. No ME was noted after 24 months ( Figure 4 ), and the decimal BCVA remained at 1.2. Figure 3. Optical coherence tomography showing improvement in macular edema 1 month after intravitreal aflibercept injection. Figure 4. Optical coherence tomography showing improvement in macular edema was maintained for 24 months after intravitreal aflibercept injection. Discussion The estimated incidence of combined oral contraceptive-related ocular complications is 1 in 230,000 persons and includes dry eyes, corneal edema, lens opacities and retinal neuro–ophthalmologic, or vascular complications. 8 Sinawat et al. analyzed patients with RVO aged <50 years and reported that 3 of 70 patients with central RVO had taken oral contraceptives for 5–6 years and 1 of 30 patients with BRVO had taken oral contraceptives for 10 years. 10 As persons aged mid-60s are the most susceptible to RVO, our case is extremely rare. According to a 2013 survey regarding VTE, the risk of VTE in women receiving oral contraceptives is twice as high as that in women not receiving oral contraceptives. 9 Lidegaard et al. reported that the VTE risk related to oral contraceptive use is 1.0 for women aged 15–19 years, 1.32 for 20–24 years, 1.99 for 25–29 years, 2.91 for 30–34 years, 4.01 for 35–39 years, 5.29 for 40–44 years, and 6.58 for 45–49 years. 11 Therefore, the VTE risk increases with increasing age. 11 As our patient was 21 years old, the risk for RVO appeared to be low. Coagulation disorder in COVID-19 is thought to occur through vascular damage caused by virus infection. 12 Various factors, including reduced antithrombogenicity of the vascular endothelium, release of von Willebrand factor and coagulation factor VIII, complement activation, increased fibrinogen, and cytokine storm, are intricately interwoven. 12 Thrombus can then form in any vessel, such as arteries, veins, and capillaries. 12 Battaglia et al. reported that among 144 patients with BRVO, 128 (88.9%) had temporal BRVO, while 16 (11.1%) had nasal BRVO. 13 The two groups showed no differences in systemic hypertension, diabetes mellitus, glaucoma, or ischemic heart disease. 13 Nasal BRVO cases exhibited better visual acuity but higher levels of capillary non-perfusion, retinal neovascularization, and vitreous hemorrhage. 13 Kumral et al. found that among 64 BRVO patients, 38 had superotemporal BRVO, and 26 had inferior temporal BRVO. 14 Superotemporal BRVO required significantly more intravitreal ranibizumab injections. 14 In our case of superotemporal BRVO, ME resolved with a single intravitreal aflibercept injection. Several reports have described BRVO development following SARS-CoV-2 infection. 2 , 4 SARS-CoV-2 infection is a high-risk factor of VTE. 1 Pur et al. reported a case of BRVO after mRNA COVID-19 vaccination. 15 They postulated that the vaccine evoked an immunological response that induced VTE in a healthy patient. 15 A thrombotic cause was unclear from the patient’s blood results. The literature shows that D-dimer is commonly elevated in patients with COVID-19 16 and oral contraceptive users. 17 However, no special blood factors have been reported linking RVO with oral contraceptive use, SARS-CoV-2 infection, and COVID-19 vaccination. Identifying the cause was challenging. Thus, the combination of oral contraceptive use, SARS-CoV-2 infection, and COVID-19 vaccination could be a risk factor for the development of RVO. To the best of our knowledge, this is the first reported case of superotemporal BRVO involving all three risk factors. Ethics and consent Written informed consent for publication of the clinical details and clinical images was obtained from the patient. Data availability No data are associated with this article. Acknowledgments We have uploaded our report to Research Square in the form of a preprint (DOI: https://doi.org/10.21203/rs.3.rs-2067517/v1 ). References 1. Demelo-Rodríguez P, Ordieres-Ortega L, Ji Z, et al. : Long-term follow-up of patients with venous thromboembolism and COVID-19: analysis of risk factors for death and major bleeding. Eur. J. Haematol. 2021; 106 (5): 716–723. PubMed Abstract | Publisher Full Text | Free Full Text 2. Duff SM, Wilde M, Khurshid G: Branch retinal vein occlusion in a COVID-19 positive patient. Cureus. 2021; 13 (2): e13586. PubMed Abstract | Publisher Full Text | Free Full Text 3. Finn AP, Khurana RN, Chang LK: Hemi-retinal vein occlusion in a young patient with COVID-19. Am. J. Ophthalmol. Case Rep. 2021; 22 : 101046. PubMed Abstract | Publisher Full Text | Free Full Text 4. Karasu B, Kesim E: Bilateral branch retinal vein occlusion following the diagnosis of mild coronavirus disease. Arq. Bras. Oftalmol. 2023; 86 (3): 274–276. PubMed Abstract | Publisher Full Text 5. Daruich A, Matet A, Moulin A, et al. : Mechanisms of macular edema: beyond the surface. Prog. Retin. Eye Res. 2018; 63 : 20–68. PubMed Abstract | Publisher Full Text 6. Iijima H: Mechanisms of vision loss in eyes with macular edema associated with retinal vein occlusion. Jpn. J. Ophthalmol. 2018; 62 (3): 265–273. PubMed Abstract | Publisher Full Text 7. Ogura Y, Kondo M, Kadonosono K, et al. : Current practice in the management of branch retinal vein occlusion in Japan: survey results of retina specialists in Japan. Jpn. J. Ophthalmol. 2019; 63 (5): 365–373. PubMed Abstract | Publisher Full Text 8. Moschos MM, Nitoda E: The impact of combined oral contraceptives on ocular tissues: a review of ocular effects. Int. J. Ophthalmol. 2017; 10 (10): 1604–1610. eCollection 2017. PubMed Abstract | Publisher Full Text | Free Full Text 9. ESHRE Capri Workshop Group: Venous thromboembolism in women: a specific reproductive health risk. Hum. Reprod. Update. 2013; 19 (5): 471–482. PubMed Abstract | Publisher Full Text 10. Sinawat S, Bunyavee C, Ratanapakorn T, et al. : Systemic abnormalities associated with retinal vein occlusion in young patients. Clin. Ophthalmol. 2017; 11 : 441–447. eCollection 2017. PubMed Abstract | Publisher Full Text | Free Full Text 11. Lidegaard Ø, Nielsen LH, Skovlund CW, et al. : Risk of venous thromboembolism from use of oral contraceptives containing different progestogens and oestrogen doses: Danish cohort study, 2001-9. BMJ. 2011; 343 : d6423. PubMed Abstract | Publisher Full Text | Free Full Text 12. Conway EM, Mackman N, Warren RQ, et al. : Understanding COVID-19-associated coagulopathy. Nat. Rev. Immunol. 2022; 22 (10): 639–649. PubMed Abstract | Publisher Full Text | Free Full Text 13. Battaglia Parodi M, Iacono P, Di Crecchio L, et al. : Clinical and angiographic features in nasal branch retinal vein occlusion. Ophthalmologica. 2004; 218 (3): 210–213. PubMed Abstract | Publisher Full Text 14. Kumral ET, Yenerel NM, Ercalik NY, et al. : Comparison of ranibizumab treatment response of superior and inferior temporal branch retinal vein occlusion: a year follow-up. Beyoglu Eye J. 2022; 7 (3): 207–212. eCollection 2022. PubMed Abstract | Publisher Full Text | Free Full Text 15. Pur DR, Catherine Danielle Bursztyn LL, Iordanous Y: Branch retinal vein occlusion in a healthy young man following mRNA COVID-19 vaccination. Am. J. Ophthalmol. Case Rep. 2022; 26 : 101445. PubMed Abstract | Publisher Full Text | Free Full Text 16. Iba T, Levy JH, Levi M, et al. : Coagulopathy in COVID-19. J. Thromb. Haemost. 2020; 18 (9): 2103–2109. PubMed Abstract | Publisher Full Text | Free Full Text 17. Westhoff CL, Eisenberger A, Tang R, et al. : Clotting factor changes during the first cycle of oral contraceptive use. Contraception. 2016; 93 (1): 70–76. PubMed Abstract | Publisher Full Text | Free Full Text Comments on this article Comments (0) Version 2 VERSION 2 PUBLISHED 08 May 2024 ADD YOUR COMMENT Comment Author details Author details 1 Department of Ophthalmology, Fukushima Medical University, Fukushima, Fukushima, 960-1295, Japan 2 Department of Ophthalmology, Dokkyo Medical University Saitama Medical Center, Koshigaya, Saitama, 343-8555, Japan 3 Department of Ophthalmology, Imaizumi Eye Hospital, Koriyama, Fukushima, 963-8877, Japan 4 Department of Obstetrics and Gynecology, Dokkyo Medical University Saitama Medical Center, Koshigaya, Saitama, 343-8555, Japan 5 Department of Ophthalmology and Visual Science, Tokyo Medical and Dental University, Tokyo, Tokyo, 113-8519, Japan Tetsuya Muto Roles: Conceptualization, Writing – Original Draft Preparation Masaaki Sakamoto Roles: Resources Shigeki Machida Roles: Supervision Shinichiro Imaizumi Roles: Supervision Yoshinobu Hamada Roles: Supervision Koju Kamoi Roles: Supervision, Writing – Review & Editing Competing interests No competing interests were disclosed. Grant information The author(s) declared that no grants were involved in supporting this work. Article Versions (2) version 2 Revised Published: 17 Feb 2025, 13:460 https://doi.org/10.12688/f1000research.148251.2 version 1 Published: 08 May 2024, 13:460 https://doi.org/10.12688/f1000research.148251.1 Copyright © 2025 Muto T et al . This is an open access article distributed under the terms of the Creative Commons Attribution License , which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited. Download Export To Sciwheel Bibtex EndNote ProCite Ref. Manager (RIS) Sente metrics Views Downloads F1000Research - - PubMed Central info_outline Data from PMC are received and updated monthly. - - Citations open_in_new 0 open_in_new 0 open_in_new SEE MORE DETAILS CITE how to cite this article Muto T, Sakamoto M, Machida S et al. Case Report: Superotemporal branch retinal vein occlusion following COVID-19 vaccination and SARS-CoV-2 infection while taking oral contraceptives [version 2; peer review: 1 not approved] . F1000Research 2025, 13 :460 ( https://doi.org/10.12688/f1000research.148251.2 ) NOTE: If applicable, it is important to ensure the information in square brackets after the title is included in all citations of this article. COPY CITATION DETAILS track receive updates on this article Track an article to receive email alerts on any updates to this article. TRACK THIS ARTICLE Share Open Peer Review Current Reviewer Status: ? Key to Reviewer Statuses VIEW HIDE Approved The paper is scientifically sound in its current form and only minor, if any, improvements are suggested Approved with reservations A number of small changes, sometimes more significant revisions are required to address specific details and improve the papers academic merit. Not approved Fundamental flaws in the paper seriously undermine the findings and conclusions Version 1 VERSION 1 PUBLISHED 08 May 2024 Views 0 Cite How to cite this report: Panigrahi PK. Reviewer Report For: Case Report: Superotemporal branch retinal vein occlusion following COVID-19 vaccination and SARS-CoV-2 infection while taking oral contraceptives [version 2; peer review: 1 not approved] . F1000Research 2025, 13 :460 ( https://doi.org/10.5256/f1000research.162540.r351857 ) The direct URL for this report is: https://f1000research.com/articles/13-460/v1#referee-response-351857 NOTE: it is important to ensure the information in square brackets after the title is included in this citation. Close Copy Citation Details Reviewer Report 26 Dec 2024 Pradeep Kumar Panigrahi , Institute of Medical Sciences & SUM Hospital, Siksha O Anusandhan (deemed to be University), Odisha, India Not Approved VIEWS 0 https://doi.org/10.5256/f1000research.162540.r351857 1. Oral contraceptives intake and COVID-19 infection/ vaccination are all known risk factors associated with RVO. The case report does not add much to what is already known. 2. Kindly provide the list of blood investigations performed along with ... Continue reading READ ALL 1. Oral contraceptives intake and COVID-19 infection/ vaccination are all known risk factors associated with RVO. The case report does not add much to what is already known. 2. Kindly provide the list of blood investigations performed along with their values in a tabular form. Just mentioning routine blood investigations is incomplete. 3. What blood investigations favoured a possible thrombotic cause in this case? 4. Kindly be specific with the diagnosis. This is a case of STBRVO to be specific...so in diagnosis it should be mentioned STBRVO and not just BRVO. 5. Kindly provide a fundus photo or OCT of the recent most visit of the patient. 6. The mechanism of thrombosis following COVID-19 infection has not been discussed in the discussion. Is the background of the case’s history and progression described in sufficient detail? Partly Are enough details provided of any physical examination and diagnostic tests, treatment given and outcomes? No Is sufficient discussion included of the importance of the findings and their relevance to future understanding of disease processes, diagnosis or treatment? Partly Is the case presented with sufficient detail to be useful for other practitioners? Partly Competing Interests: No competing interests were disclosed. Reviewer Expertise: Vitreo-retina, medical retina, surgical retina I confirm that I have read this submission and believe that I have an appropriate level of expertise to state that I do not consider it to be of an acceptable scientific standard, for reasons outlined above. Close READ LESS CITE CITE HOW TO CITE THIS REPORT Panigrahi PK. Reviewer Report For: Case Report: Superotemporal branch retinal vein occlusion following COVID-19 vaccination and SARS-CoV-2 infection while taking oral contraceptives [version 2; peer review: 1 not approved] . F1000Research 2025, 13 :460 ( https://doi.org/10.5256/f1000research.162540.r351857 ) The direct URL for this report is: https://f1000research.com/articles/13-460/v1#referee-response-351857 NOTE: it is important to ensure the information in square brackets after the title is included in all citations of this article. COPY CITATION DETAILS Report a concern Author Response 02 Jan 2025 Tetsuya Muto , Department of Ophthalmology, Imaizumi Eye Hospital, Koriyama, 963-8877, Japan 02 Jan 2025 Author Response Dear reviewer, We have a question about the reviewer 's comment. What is STBRVO? Would you tell us ? 4. Kindly be specific with the diagnosis. This is ... Continue reading Dear reviewer, We have a question about the reviewer 's comment. What is STBRVO? Would you tell us ? 4. Kindly be specific with the diagnosis. This is a case of STBRVO to be specific...so in diagnosis it should be mentioned STBRVO and not just BRVO. Sincerely, Tetsuya Muto Dear reviewer, We have a question about the reviewer 's comment. What is STBRVO? Would you tell us ? 4. Kindly be specific with the diagnosis. This is a case of STBRVO to be specific...so in diagnosis it should be mentioned STBRVO and not just BRVO. Sincerely, Tetsuya Muto Competing Interests: No competing interests were disclosed. Close Report a concern Reviewer Response 11 Jan 2025 PRADEEP KUMAR PANIGRAHI , Institute of Medical Sciences & SUM Hospital, Siksha O Anusandhan (deemed to be University), Odisha, India 11 Jan 2025 Reviewer Response Superotemporal BRVO Competing Interests: No competing interests were disclosed. Superotemporal BRVO Superotemporal BRVO Competing Interests: No competing interests were disclosed. Close Report a concern Author Response 29 Jan 2025 Tetsuya Muto , Department of Ophthalmology, Imaizumi Eye Hospital, Koriyama, 963-8877, Japan 29 Jan 2025 Author Response Response to Reviewer Oral contraceptives intake and COVID-19 infection/ vaccination are all known risk factors associated with RVO. The case report does not add much to what is ... Continue reading Response to Reviewer Oral contraceptives intake and COVID-19 infection/ vaccination are all known risk factors associated with RVO. The case report does not add much to what is already known. Yes, we added below sentence in discussion section. To the best of our knowledge, this is the first reported case of superotemporal BRVO involving all three risk factors. 2. Kindly provide the list of blood investigations performed along with their values in a tabular form. Just mentioning routine blood investigations is incomplete. Yes, we added Table 1 and 2 as below. Table 1 Blood test results at the initial visit 1 factors values GOT(U/L) 14 GPT(U/L) 8 γ-GTP(U/L) 12 total bilirubin (mg/dL) 0.49 direct bilirubin (mg/dL) 0.02 indirect bilirubin (mg/dL) 0.47 total protein 8g/dL) 7.3 albumin (g/dL) 4.44 Na (mmol/L) 141 K (mmol/L) 4.1 Cl (mmol/L) 105 Ca (mg/dL) 9.5 BUN (mg/dL) 11 Cre (mg/dL) 0.56 Uric acid (mg/dL) 4.1 BS (mg/dL) 89 total cholesterol (mg/dL) 192 triglyceride (mg/dL) 78 HDL cholesterol (mg/dL) 64 LDL cholesterol (mg/dL) 116 LDL/HDL 1.8 WBC (x10 9 /L) 5.4 RBC (x10 9 /L) 4.18 Hb (g/dL) 12.2 Ht (%) 37.5 MCV (fL) 89.7 MCH (pg) 29.2 MCHC (g/dL) 32.5 Table 2 Blood test results at the initial visit 2 factors values Platelet (x10 9 /L) 252 neutrophils (%) 50.4 ESR (mm/1h) 10 lymphocyte (%) 42.2 monocyte (%) 3.9 eosinophils (%) 2.8 basophil leukocyte (%) 0.7 PT (sec) 11.1 APTT (sec) 28.8 CRP (mg/dL) 0.11 IgG (mg/dL) 1138.6 IgA (mg/dL) 238.1 IgM (mg/dL) 118.1 C3 (mg/dL) 108.2 C4 (mg/dL) 24.8 cardiolipin antibody IgG (U/mL) < 4.0 ACE (U/L) 6.1 RA (IU/mL) < 5 3. What blood investigations favoured a possible thrombotic cause in this case? Yes, we added below sentence in discussion section and we added references no. 14 and 15. A thrombotic cause was unclear from the patient’s blood results. The literature shows that D-dimer is commonly elevated in patients with COVID-19 16 and oral contraceptive users 17 . However, no special blood factors have been reported linking RVO with oral contraceptive use, SARS-CoV-2 infection, and COVID-19 vaccination. Identifying the cause was challenging. 16. Iba T, Levy JH, Levi M, Thachil J. Coagulopathy in COVID-19. J Thromb Haemost 2020; 18(9):2103–2109. doi: 10.1111/jth.14975. 17. Westhoff CL, Eisenberger A, Tang R, Cremers S, Grossman LV, Pike MC. Clotting factor changes during the first cycle of oral contraceptive use. Contraception 2016; 93(1):70-76. doi: 10.1016/j.contraception.2015.09.015. 4. Kindly be specific with the diagnosis. This is a case of STBRVO to be specific...so in diagnosis it should be mentioned STBRVO and not just BRVO. Yes, we changed the title as below. Superotemporal branch retinal vein occlusion following COVID-19 vaccination and SARS-CoV-2 infection while taking oral contraceptives: A case report Yes, we changed the abstract as below. Abstract Oral contraceptive use, vaccination for Coronavirus disease 2019 (COVID-19), and severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection are risk factors for venous thromboembolism. Branch retinal vein occlusion (BRVO) generally develops mid-60s patients. Herein, we present a case of superotemporal BRVO caused by the above mentioned risk factors in a young woman. To the best of our knowledge, this is the first report about superotemporal BRVO associated with oral contraceptives, COVID-19 vaccination, and SARS-CoV-2. A 21-year-old woman presented with loss of visual acuity in her right eye for 10 days. She had been receiving oral contraceptives for 2 years for oligomenorrhea before noticing ophthalmological symptoms. Despite having received two doses of an mRNA COVID-19 vaccine, she contracted COVID-19 and developed fever, sore throat, cough, low back pain, and general malaise about 40 days before the initial visit. However, only cough persisted for more than a month. The right eye showed superotemporal BRVO with macular edema (ME). She did not smoke nor had diabetes or hypertension. Blood test results, including cardiolipin antibody IgG, were normal. She was treated with an intravitreal aflibercept injection. ME in the fundus showed rapid improvement and resolution. Although more than 18 months have passed since the first injection, there has been no relapse of ME. The combination of oral contraceptive use, COVID-19 vaccination, and subsequent SARS-CoV-2 infection could induce the development of venous thromboembolism, thereby leading to superotemporal BRVO. Given that cases of COVID-19 have increased globally, patients with retinal vein occlusion who use oral contraceptives are likely to be encountered more frequently. Yes, we added a paragraph as below in discussion and added references no. 13 and 14. Battaglia et al. reported that among 144 patients with BRVO, 128 (88.9%) had temporal BRVO, while 16 (11.1%) had nasal BRVO 13 . The two groups showed no differences in systemic hypertension, diabetes mellitus, glaucoma, or ischemic heart disease 13 . Nasal BRVO cases exhibited better visual acuity but higher levels of capillary non-perfusion, retinal neovascularization, and vitreous hemorrhage 13 . Kumral et al. found that among 64 BRVO patients, 38 had superotemporal BRVO, and 26 had inferior temporal BRVO 14 . Superotemporal BRVO required significantly more intravitreal ranibizumab injections 14 . In our case of superotemporal BRVO, ME resolved with a single intravitreal aflibercept injection. 13. Battaglia Parodi M, Iacono P, Di Crecchio L, Sanguinetti G, Ravalico G. Clinical and angiographic features in nasal branch retinal vein occlusion. Ophthalmologica. 2004; 218(3):210-213. doi: 10.1159/000076847 14. Kumral ET, Yenerel NM, Ercalik NY, Karabas L. Comparison of ranibizumab treatment response of superior and inferior temporal branch retinal vein occlusion: a year follow-up. Beyoglu Eye J. 2022; 7(3):207-212. doi: 10.14744/bej.2022.46794. eCollection 2022. 5. Kindly provide a fundus photo or OCT of the recent most visit of the patient. Yes, we provided OCT photos 24 months since the first administration (figure 4). We added below sentence in case report section. No ME was noted after 24 months (Figure 4), and the decimal BCVA remained at 1.2. 6. The mechanism of thrombosis following COVID-19 infection has not been discussed in the discussion. Yes, we discussed it in the discussion as below and we added reference no. 12. Coagulation disorder in COVID-19 is thought to occur through vascular damage caused by virus infection 12 . Various factors, including reduced antithrombogenicity of the vascular endothelium, release of von Willebrand factor and coagulation factor VIII, complement activation, increased fibrinogen, and cytokine storm, are intricately interwoven 12 . Thrombus can then form in any vessel, such as arteries, veins, and capillaries 12 . 12. Conway EM, Mackman N, Warren RQ, et al . Understanding COVID-19-associated coagulopathy. Nat Rev Immunol 2022; 22(10): 639-649. doi: 10.1038/s41577-022-00762-9. Response to Reviewer Oral contraceptives intake and COVID-19 infection/ vaccination are all known risk factors associated with RVO. The case report does not add much to what is already known. Yes, we added below sentence in discussion section. To the best of our knowledge, this is the first reported case of superotemporal BRVO involving all three risk factors. 2. Kindly provide the list of blood investigations performed along with their values in a tabular form. Just mentioning routine blood investigations is incomplete. Yes, we added Table 1 and 2 as below. Table 1 Blood test results at the initial visit 1 factors values GOT(U/L) 14 GPT(U/L) 8 γ-GTP(U/L) 12 total bilirubin (mg/dL) 0.49 direct bilirubin (mg/dL) 0.02 indirect bilirubin (mg/dL) 0.47 total protein 8g/dL) 7.3 albumin (g/dL) 4.44 Na (mmol/L) 141 K (mmol/L) 4.1 Cl (mmol/L) 105 Ca (mg/dL) 9.5 BUN (mg/dL) 11 Cre (mg/dL) 0.56 Uric acid (mg/dL) 4.1 BS (mg/dL) 89 total cholesterol (mg/dL) 192 triglyceride (mg/dL) 78 HDL cholesterol (mg/dL) 64 LDL cholesterol (mg/dL) 116 LDL/HDL 1.8 WBC (x10 9 /L) 5.4 RBC (x10 9 /L) 4.18 Hb (g/dL) 12.2 Ht (%) 37.5 MCV (fL) 89.7 MCH (pg) 29.2 MCHC (g/dL) 32.5 Table 2 Blood test results at the initial visit 2 factors values Platelet (x10 9 /L) 252 neutrophils (%) 50.4 ESR (mm/1h) 10 lymphocyte (%) 42.2 monocyte (%) 3.9 eosinophils (%) 2.8 basophil leukocyte (%) 0.7 PT (sec) 11.1 APTT (sec) 28.8 CRP (mg/dL) 0.11 IgG (mg/dL) 1138.6 IgA (mg/dL) 238.1 IgM (mg/dL) 118.1 C3 (mg/dL) 108.2 C4 (mg/dL) 24.8 cardiolipin antibody IgG (U/mL) < 4.0 ACE (U/L) 6.1 RA (IU/mL) < 5 3. What blood investigations favoured a possible thrombotic cause in this case? Yes, we added below sentence in discussion section and we added references no. 14 and 15. A thrombotic cause was unclear from the patient’s blood results. The literature shows that D-dimer is commonly elevated in patients with COVID-19 16 and oral contraceptive users 17 . However, no special blood factors have been reported linking RVO with oral contraceptive use, SARS-CoV-2 infection, and COVID-19 vaccination. Identifying the cause was challenging. 16. Iba T, Levy JH, Levi M, Thachil J. Coagulopathy in COVID-19. J Thromb Haemost 2020; 18(9):2103–2109. doi: 10.1111/jth.14975. 17. Westhoff CL, Eisenberger A, Tang R, Cremers S, Grossman LV, Pike MC. Clotting factor changes during the first cycle of oral contraceptive use. Contraception 2016; 93(1):70-76. doi: 10.1016/j.contraception.2015.09.015. 4. Kindly be specific with the diagnosis. This is a case of STBRVO to be specific...so in diagnosis it should be mentioned STBRVO and not just BRVO. Yes, we changed the title as below. Superotemporal branch retinal vein occlusion following COVID-19 vaccination and SARS-CoV-2 infection while taking oral contraceptives: A case report Yes, we changed the abstract as below. Abstract Oral contraceptive use, vaccination for Coronavirus disease 2019 (COVID-19), and severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection are risk factors for venous thromboembolism. Branch retinal vein occlusion (BRVO) generally develops mid-60s patients. Herein, we present a case of superotemporal BRVO caused by the above mentioned risk factors in a young woman. To the best of our knowledge, this is the first report about superotemporal BRVO associated with oral contraceptives, COVID-19 vaccination, and SARS-CoV-2. A 21-year-old woman presented with loss of visual acuity in her right eye for 10 days. She had been receiving oral contraceptives for 2 years for oligomenorrhea before noticing ophthalmological symptoms. Despite having received two doses of an mRNA COVID-19 vaccine, she contracted COVID-19 and developed fever, sore throat, cough, low back pain, and general malaise about 40 days before the initial visit. However, only cough persisted for more than a month. The right eye showed superotemporal BRVO with macular edema (ME). She did not smoke nor had diabetes or hypertension. Blood test results, including cardiolipin antibody IgG, were normal. She was treated with an intravitreal aflibercept injection. ME in the fundus showed rapid improvement and resolution. Although more than 18 months have passed since the first injection, there has been no relapse of ME. The combination of oral contraceptive use, COVID-19 vaccination, and subsequent SARS-CoV-2 infection could induce the development of venous thromboembolism, thereby leading to superotemporal BRVO. Given that cases of COVID-19 have increased globally, patients with retinal vein occlusion who use oral contraceptives are likely to be encountered more frequently. Yes, we added a paragraph as below in discussion and added references no. 13 and 14. Battaglia et al. reported that among 144 patients with BRVO, 128 (88.9%) had temporal BRVO, while 16 (11.1%) had nasal BRVO 13 . The two groups showed no differences in systemic hypertension, diabetes mellitus, glaucoma, or ischemic heart disease 13 . Nasal BRVO cases exhibited better visual acuity but higher levels of capillary non-perfusion, retinal neovascularization, and vitreous hemorrhage 13 . Kumral et al. found that among 64 BRVO patients, 38 had superotemporal BRVO, and 26 had inferior temporal BRVO 14 . Superotemporal BRVO required significantly more intravitreal ranibizumab injections 14 . In our case of superotemporal BRVO, ME resolved with a single intravitreal aflibercept injection. 13. Battaglia Parodi M, Iacono P, Di Crecchio L, Sanguinetti G, Ravalico G. Clinical and angiographic features in nasal branch retinal vein occlusion. Ophthalmologica. 2004; 218(3):210-213. doi: 10.1159/000076847 14. Kumral ET, Yenerel NM, Ercalik NY, Karabas L. Comparison of ranibizumab treatment response of superior and inferior temporal branch retinal vein occlusion: a year follow-up. Beyoglu Eye J. 2022; 7(3):207-212. doi: 10.14744/bej.2022.46794. eCollection 2022. 5. Kindly provide a fundus photo or OCT of the recent most visit of the patient. Yes, we provided OCT photos 24 months since the first administration (figure 4). We added below sentence in case report section. No ME was noted after 24 months (Figure 4), and the decimal BCVA remained at 1.2. 6. The mechanism of thrombosis following COVID-19 infection has not been discussed in the discussion. Yes, we discussed it in the discussion as below and we added reference no. 12. Coagulation disorder in COVID-19 is thought to occur through vascular damage caused by virus infection 12 . Various factors, including reduced antithrombogenicity of the vascular endothelium, release of von Willebrand factor and coagulation factor VIII, complement activation, increased fibrinogen, and cytokine storm, are intricately interwoven 12 . Thrombus can then form in any vessel, such as arteries, veins, and capillaries 12 . 12. Conway EM, Mackman N, Warren RQ, et al . Understanding COVID-19-associated coagulopathy. Nat Rev Immunol 2022; 22(10): 639-649. doi: 10.1038/s41577-022-00762-9. Competing Interests: No competing interests were disclosed. Close Report a concern Respond or Comment COMMENTS ON THIS REPORT Author Response 02 Jan 2025 Tetsuya Muto , Department of Ophthalmology, Imaizumi Eye Hospital, Koriyama, 963-8877, Japan 02 Jan 2025 Author Response Dear reviewer, We have a question about the reviewer 's comment. What is STBRVO? Would you tell us ? 4. Kindly be specific with the diagnosis. This is ... Continue reading Dear reviewer, We have a question about the reviewer 's comment. What is STBRVO? Would you tell us ? 4. Kindly be specific with the diagnosis. This is a case of STBRVO to be specific...so in diagnosis it should be mentioned STBRVO and not just BRVO. Sincerely, Tetsuya Muto Dear reviewer, We have a question about the reviewer 's comment. What is STBRVO? Would you tell us ? 4. Kindly be specific with the diagnosis. This is a case of STBRVO to be specific...so in diagnosis it should be mentioned STBRVO and not just BRVO. Sincerely, Tetsuya Muto Competing Interests: No competing interests were disclosed. Close Report a concern Reviewer Response 11 Jan 2025 PRADEEP KUMAR PANIGRAHI , Institute of Medical Sciences & SUM Hospital, Siksha O Anusandhan (deemed to be University), Odisha, India 11 Jan 2025 Reviewer Response Superotemporal BRVO Competing Interests: No competing interests were disclosed. Superotemporal BRVO Superotemporal BRVO Competing Interests: No competing interests were disclosed. Close Report a concern Author Response 29 Jan 2025 Tetsuya Muto , Department of Ophthalmology, Imaizumi Eye Hospital, Koriyama, 963-8877, Japan 29 Jan 2025 Author Response Response to Reviewer Oral contraceptives intake and COVID-19 infection/ vaccination are all known risk factors associated with RVO. The case report does not add much to what is ... Continue reading Response to Reviewer Oral contraceptives intake and COVID-19 infection/ vaccination are all known risk factors associated with RVO. The case report does not add much to what is already known. Yes, we added below sentence in discussion section. To the best of our knowledge, this is the first reported case of superotemporal BRVO involving all three risk factors. 2. Kindly provide the list of blood investigations performed along with their values in a tabular form. Just mentioning routine blood investigations is incomplete. Yes, we added Table 1 and 2 as below. Table 1 Blood test results at the initial visit 1 factors values GOT(U/L) 14 GPT(U/L) 8 γ-GTP(U/L) 12 total bilirubin (mg/dL) 0.49 direct bilirubin (mg/dL) 0.02 indirect bilirubin (mg/dL) 0.47 total protein 8g/dL) 7.3 albumin (g/dL) 4.44 Na (mmol/L) 141 K (mmol/L) 4.1 Cl (mmol/L) 105 Ca (mg/dL) 9.5 BUN (mg/dL) 11 Cre (mg/dL) 0.56 Uric acid (mg/dL) 4.1 BS (mg/dL) 89 total cholesterol (mg/dL) 192 triglyceride (mg/dL) 78 HDL cholesterol (mg/dL) 64 LDL cholesterol (mg/dL) 116 LDL/HDL 1.8 WBC (x10 9 /L) 5.4 RBC (x10 9 /L) 4.18 Hb (g/dL) 12.2 Ht (%) 37.5 MCV (fL) 89.7 MCH (pg) 29.2 MCHC (g/dL) 32.5 Table 2 Blood test results at the initial visit 2 factors values Platelet (x10 9 /L) 252 neutrophils (%) 50.4 ESR (mm/1h) 10 lymphocyte (%) 42.2 monocyte (%) 3.9 eosinophils (%) 2.8 basophil leukocyte (%) 0.7 PT (sec) 11.1 APTT (sec) 28.8 CRP (mg/dL) 0.11 IgG (mg/dL) 1138.6 IgA (mg/dL) 238.1 IgM (mg/dL) 118.1 C3 (mg/dL) 108.2 C4 (mg/dL) 24.8 cardiolipin antibody IgG (U/mL) < 4.0 ACE (U/L) 6.1 RA (IU/mL) < 5 3. What blood investigations favoured a possible thrombotic cause in this case? Yes, we added below sentence in discussion section and we added references no. 14 and 15. A thrombotic cause was unclear from the patient’s blood results. The literature shows that D-dimer is commonly elevated in patients with COVID-19 16 and oral contraceptive users 17 . However, no special blood factors have been reported linking RVO with oral contraceptive use, SARS-CoV-2 infection, and COVID-19 vaccination. Identifying the cause was challenging. 16. Iba T, Levy JH, Levi M, Thachil J. Coagulopathy in COVID-19. J Thromb Haemost 2020; 18(9):2103–2109. doi: 10.1111/jth.14975. 17. Westhoff CL, Eisenberger A, Tang R, Cremers S, Grossman LV, Pike MC. Clotting factor changes during the first cycle of oral contraceptive use. Contraception 2016; 93(1):70-76. doi: 10.1016/j.contraception.2015.09.015. 4. Kindly be specific with the diagnosis. This is a case of STBRVO to be specific...so in diagnosis it should be mentioned STBRVO and not just BRVO. Yes, we changed the title as below. Superotemporal branch retinal vein occlusion following COVID-19 vaccination and SARS-CoV-2 infection while taking oral contraceptives: A case report Yes, we changed the abstract as below. Abstract Oral contraceptive use, vaccination for Coronavirus disease 2019 (COVID-19), and severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection are risk factors for venous thromboembolism. Branch retinal vein occlusion (BRVO) generally develops mid-60s patients. Herein, we present a case of superotemporal BRVO caused by the above mentioned risk factors in a young woman. To the best of our knowledge, this is the first report about superotemporal BRVO associated with oral contraceptives, COVID-19 vaccination, and SARS-CoV-2. A 21-year-old woman presented with loss of visual acuity in her right eye for 10 days. She had been receiving oral contraceptives for 2 years for oligomenorrhea before noticing ophthalmological symptoms. Despite having received two doses of an mRNA COVID-19 vaccine, she contracted COVID-19 and developed fever, sore throat, cough, low back pain, and general malaise about 40 days before the initial visit. However, only cough persisted for more than a month. The right eye showed superotemporal BRVO with macular edema (ME). She did not smoke nor had diabetes or hypertension. Blood test results, including cardiolipin antibody IgG, were normal. She was treated with an intravitreal aflibercept injection. ME in the fundus showed rapid improvement and resolution. Although more than 18 months have passed since the first injection, there has been no relapse of ME. The combination of oral contraceptive use, COVID-19 vaccination, and subsequent SARS-CoV-2 infection could induce the development of venous thromboembolism, thereby leading to superotemporal BRVO. Given that cases of COVID-19 have increased globally, patients with retinal vein occlusion who use oral contraceptives are likely to be encountered more frequently. Yes, we added a paragraph as below in discussion and added references no. 13 and 14. Battaglia et al. reported that among 144 patients with BRVO, 128 (88.9%) had temporal BRVO, while 16 (11.1%) had nasal BRVO 13 . The two groups showed no differences in systemic hypertension, diabetes mellitus, glaucoma, or ischemic heart disease 13 . Nasal BRVO cases exhibited better visual acuity but higher levels of capillary non-perfusion, retinal neovascularization, and vitreous hemorrhage 13 . Kumral et al. found that among 64 BRVO patients, 38 had superotemporal BRVO, and 26 had inferior temporal BRVO 14 . Superotemporal BRVO required significantly more intravitreal ranibizumab injections 14 . In our case of superotemporal BRVO, ME resolved with a single intravitreal aflibercept injection. 13. Battaglia Parodi M, Iacono P, Di Crecchio L, Sanguinetti G, Ravalico G. Clinical and angiographic features in nasal branch retinal vein occlusion. Ophthalmologica. 2004; 218(3):210-213. doi: 10.1159/000076847 14. Kumral ET, Yenerel NM, Ercalik NY, Karabas L. Comparison of ranibizumab treatment response of superior and inferior temporal branch retinal vein occlusion: a year follow-up. Beyoglu Eye J. 2022; 7(3):207-212. doi: 10.14744/bej.2022.46794. eCollection 2022. 5. Kindly provide a fundus photo or OCT of the recent most visit of the patient. Yes, we provided OCT photos 24 months since the first administration (figure 4). We added below sentence in case report section. No ME was noted after 24 months (Figure 4), and the decimal BCVA remained at 1.2. 6. The mechanism of thrombosis following COVID-19 infection has not been discussed in the discussion. Yes, we discussed it in the discussion as below and we added reference no. 12. Coagulation disorder in COVID-19 is thought to occur through vascular damage caused by virus infection 12 . Various factors, including reduced antithrombogenicity of the vascular endothelium, release of von Willebrand factor and coagulation factor VIII, complement activation, increased fibrinogen, and cytokine storm, are intricately interwoven 12 . Thrombus can then form in any vessel, such as arteries, veins, and capillaries 12 . 12. Conway EM, Mackman N, Warren RQ, et al . Understanding COVID-19-associated coagulopathy. Nat Rev Immunol 2022; 22(10): 639-649. doi: 10.1038/s41577-022-00762-9. Response to Reviewer Oral contraceptives intake and COVID-19 infection/ vaccination are all known risk factors associated with RVO. The case report does not add much to what is already known. Yes, we added below sentence in discussion section. To the best of our knowledge, this is the first reported case of superotemporal BRVO involving all three risk factors. 2. Kindly provide the list of blood investigations performed along with their values in a tabular form. Just mentioning routine blood investigations is incomplete. Yes, we added Table 1 and 2 as below. Table 1 Blood test results at the initial visit 1 factors values GOT(U/L) 14 GPT(U/L) 8 γ-GTP(U/L) 12 total bilirubin (mg/dL) 0.49 direct bilirubin (mg/dL) 0.02 indirect bilirubin (mg/dL) 0.47 total protein 8g/dL) 7.3 albumin (g/dL) 4.44 Na (mmol/L) 141 K (mmol/L) 4.1 Cl (mmol/L) 105 Ca (mg/dL) 9.5 BUN (mg/dL) 11 Cre (mg/dL) 0.56 Uric acid (mg/dL) 4.1 BS (mg/dL) 89 total cholesterol (mg/dL) 192 triglyceride (mg/dL) 78 HDL cholesterol (mg/dL) 64 LDL cholesterol (mg/dL) 116 LDL/HDL 1.8 WBC (x10 9 /L) 5.4 RBC (x10 9 /L) 4.18 Hb (g/dL) 12.2 Ht (%) 37.5 MCV (fL) 89.7 MCH (pg) 29.2 MCHC (g/dL) 32.5 Table 2 Blood test results at the initial visit 2 factors values Platelet (x10 9 /L) 252 neutrophils (%) 50.4 ESR (mm/1h) 10 lymphocyte (%) 42.2 monocyte (%) 3.9 eosinophils (%) 2.8 basophil leukocyte (%) 0.7 PT (sec) 11.1 APTT (sec) 28.8 CRP (mg/dL) 0.11 IgG (mg/dL) 1138.6 IgA (mg/dL) 238.1 IgM (mg/dL) 118.1 C3 (mg/dL) 108.2 C4 (mg/dL) 24.8 cardiolipin antibody IgG (U/mL) < 4.0 ACE (U/L) 6.1 RA (IU/mL) < 5 3. What blood investigations favoured a possible thrombotic cause in this case? Yes, we added below sentence in discussion section and we added references no. 14 and 15. A thrombotic cause was unclear from the patient’s blood results. The literature shows that D-dimer is commonly elevated in patients with COVID-19 16 and oral contraceptive users 17 . However, no special blood factors have been reported linking RVO with oral contraceptive use, SARS-CoV-2 infection, and COVID-19 vaccination. Identifying the cause was challenging. 16. Iba T, Levy JH, Levi M, Thachil J. Coagulopathy in COVID-19. J Thromb Haemost 2020; 18(9):2103–2109. doi: 10.1111/jth.14975. 17. Westhoff CL, Eisenberger A, Tang R, Cremers S, Grossman LV, Pike MC. Clotting factor changes during the first cycle of oral contraceptive use. Contraception 2016; 93(1):70-76. doi: 10.1016/j.contraception.2015.09.015. 4. Kindly be specific with the diagnosis. This is a case of STBRVO to be specific...so in diagnosis it should be mentioned STBRVO and not just BRVO. Yes, we changed the title as below. Superotemporal branch retinal vein occlusion following COVID-19 vaccination and SARS-CoV-2 infection while taking oral contraceptives: A case report Yes, we changed the abstract as below. Abstract Oral contraceptive use, vaccination for Coronavirus disease 2019 (COVID-19), and severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection are risk factors for venous thromboembolism. Branch retinal vein occlusion (BRVO) generally develops mid-60s patients. Herein, we present a case of superotemporal BRVO caused by the above mentioned risk factors in a young woman. To the best of our knowledge, this is the first report about superotemporal BRVO associated with oral contraceptives, COVID-19 vaccination, and SARS-CoV-2. A 21-year-old woman presented with loss of visual acuity in her right eye for 10 days. She had been receiving oral contraceptives for 2 years for oligomenorrhea before noticing ophthalmological symptoms. Despite having received two doses of an mRNA COVID-19 vaccine, she contracted COVID-19 and developed fever, sore throat, cough, low back pain, and general malaise about 40 days before the initial visit. However, only cough persisted for more than a month. The right eye showed superotemporal BRVO with macular edema (ME). She did not smoke nor had diabetes or hypertension. Blood test results, including cardiolipin antibody IgG, were normal. She was treated with an intravitreal aflibercept injection. ME in the fundus showed rapid improvement and resolution. Although more than 18 months have passed since the first injection, there has been no relapse of ME. The combination of oral contraceptive use, COVID-19 vaccination, and subsequent SARS-CoV-2 infection could induce the development of venous thromboembolism, thereby leading to superotemporal BRVO. Given that cases of COVID-19 have increased globally, patients with retinal vein occlusion who use oral contraceptives are likely to be encountered more frequently. Yes, we added a paragraph as below in discussion and added references no. 13 and 14. Battaglia et al. reported that among 144 patients with BRVO, 128 (88.9%) had temporal BRVO, while 16 (11.1%) had nasal BRVO 13 . The two groups showed no differences in systemic hypertension, diabetes mellitus, glaucoma, or ischemic heart disease 13 . Nasal BRVO cases exhibited better visual acuity but higher levels of capillary non-perfusion, retinal neovascularization, and vitreous hemorrhage 13 . Kumral et al. found that among 64 BRVO patients, 38 had superotemporal BRVO, and 26 had inferior temporal BRVO 14 . Superotemporal BRVO required significantly more intravitreal ranibizumab injections 14 . In our case of superotemporal BRVO, ME resolved with a single intravitreal aflibercept injection. 13. Battaglia Parodi M, Iacono P, Di Crecchio L, Sanguinetti G, Ravalico G. Clinical and angiographic features in nasal branch retinal vein occlusion. Ophthalmologica. 2004; 218(3):210-213. doi: 10.1159/000076847 14. Kumral ET, Yenerel NM, Ercalik NY, Karabas L. Comparison of ranibizumab treatment response of superior and inferior temporal branch retinal vein occlusion: a year follow-up. Beyoglu Eye J. 2022; 7(3):207-212. doi: 10.14744/bej.2022.46794. eCollection 2022. 5. Kindly provide a fundus photo or OCT of the recent most visit of the patient. Yes, we provided OCT photos 24 months since the first administration (figure 4). We added below sentence in case report section. No ME was noted after 24 months (Figure 4), and the decimal BCVA remained at 1.2. 6. The mechanism of thrombosis following COVID-19 infection has not been discussed in the discussion. Yes, we discussed it in the discussion as below and we added reference no. 12. Coagulation disorder in COVID-19 is thought to occur through vascular damage caused by virus infection 12 . Various factors, including reduced antithrombogenicity of the vascular endothelium, release of von Willebrand factor and coagulation factor VIII, complement activation, increased fibrinogen, and cytokine storm, are intricately interwoven 12 . Thrombus can then form in any vessel, such as arteries, veins, and capillaries 12 . 12. Conway EM, Mackman N, Warren RQ, et al . Understanding COVID-19-associated coagulopathy. Nat Rev Immunol 2022; 22(10): 639-649. doi: 10.1038/s41577-022-00762-9. Competing Interests: No competing interests were disclosed. Close Report a concern COMMENT ON THIS REPORT Comments on this article Comments (0) Version 2 VERSION 2 PUBLISHED 08 May 2024 ADD YOUR COMMENT Comment keyboard_arrow_left keyboard_arrow_right Open Peer Review Reviewer Status info_outline Alongside their report, reviewers assign a status to the article: Approved The paper is scientifically sound in its current form and only minor, if any, improvements are suggested Approved with reservations A number of small changes, sometimes more significant revisions are required to address specific details and improve the papers academic merit. Not approved Fundamental flaws in the paper seriously undermine the findings and conclusions Reviewer Reports Invited Reviewers 1 Version 2 (revision) 17 Feb 25 Version 1 08 May 24 read Pradeep Kumar Panigrahi , Institute of Medical Sciences & SUM Hospital, Siksha O Anusandhan (deemed to be University), Odisha, India Comments on this article All Comments (0) Add a comment Sign up for content alerts Sign Up You are now signed up to receive this alert Browse by related subjects keyboard_arrow_left Back to all reports Reviewer Report 0 Views copyright © 2024 Panigrahi P. This is an open access peer review report distributed under the terms of the Creative Commons Attribution License , which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited. 26 Dec 2024 | for Version 1 Pradeep Kumar Panigrahi , Institute of Medical Sciences & SUM Hospital, Siksha O Anusandhan (deemed to be University), Odisha, India 0 Views copyright © 2024 Panigrahi P. This is an open access peer review report distributed under the terms of the Creative Commons Attribution License , which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited. format_quote Cite this report speaker_notes Responses (3) Not Approved info_outline Alongside their report, reviewers assign a status to the article: Approved The paper is scientifically sound in its current form and only minor, if any, improvements are suggested Approved with reservations A number of small changes, sometimes more significant revisions are required to address specific details and improve the papers academic merit. Not approved Fundamental flaws in the paper seriously undermine the findings and conclusions 1. Oral contraceptives intake and COVID-19 infection/ vaccination are all known risk factors associated with RVO. The case report does not add much to what is already known. 2. Kindly provide the list of blood investigations performed along with their values in a tabular form. Just mentioning routine blood investigations is incomplete. 3. What blood investigations favoured a possible thrombotic cause in this case? 4. Kindly be specific with the diagnosis. This is a case of STBRVO to be specific...so in diagnosis it should be mentioned STBRVO and not just BRVO. 5. Kindly provide a fundus photo or OCT of the recent most visit of the patient. 6. The mechanism of thrombosis following COVID-19 infection has not been discussed in the discussion. Is the background of the case’s history and progression described in sufficient detail? Partly Are enough details provided of any physical examination and diagnostic tests, treatment given and outcomes? No Is sufficient discussion included of the importance of the findings and their relevance to future understanding of disease processes, diagnosis or treatment? Partly Is the case presented with sufficient detail to be useful for other practitioners? Partly Competing Interests No competing interests were disclosed. Reviewer Expertise Vitreo-retina, medical retina, surgical retina I confirm that I have read this submission and believe that I have an appropriate level of expertise to state that I do not consider it to be of an acceptable scientific standard, for reasons outlined above. reply Respond to this report Responses (3) Author Response 02 Jan 2025 Tetsuya Muto, Department of Ophthalmology, Imaizumi Eye Hospital, Koriyama, 963-8877, Japan Dear reviewer, We have a question about the reviewer 's comment. What is STBRVO? Would you tell us ? 4. Kindly be specific with the diagnosis. This is a case of STBRVO to be specific...so in diagnosis it should be mentioned STBRVO and not just BRVO. Sincerely, Tetsuya Muto View more View less Competing Interests No competing interests were disclosed. reply Respond Report a concern Reviewer Response 11 Jan 2025 PRADEEP KUMAR PANIGRAHI, Institute of Medical Sciences & SUM Hospital, Siksha O Anusandhan (deemed to be University), Odisha, India Superotemporal BRVO View more View less Competing Interests No competing interests were disclosed. reply Respond Report a concern Author Response 29 Jan 2025 Tetsuya Muto, Department of Ophthalmology, Imaizumi Eye Hospital, Koriyama, 963-8877, Japan Response to Reviewer Oral contraceptives intake and COVID-19 infection/ vaccination are all known risk factors associated with RVO. The case report does not add much to what is already known. Yes, we added below sentence in discussion section. To the best of our knowledge, this is the first reported case of superotemporal BRVO involving all three risk factors. 2. Kindly provide the list of blood investigations performed along with their values in a tabular form. Just mentioning routine blood investigations is incomplete. Yes, we added Table 1 and 2 as below. Table 1 Blood test results at the initial visit 1 factors values GOT(U/L) 14 GPT(U/L) 8 γ-GTP(U/L) 12 total bilirubin (mg/dL) 0.49 direct bilirubin (mg/dL) 0.02 indirect bilirubin (mg/dL) 0.47 total protein 8g/dL) 7.3 albumin (g/dL) 4.44 Na (mmol/L) 141 K (mmol/L) 4.1 Cl (mmol/L) 105 Ca (mg/dL) 9.5 BUN (mg/dL) 11 Cre (mg/dL) 0.56 Uric acid (mg/dL) 4.1 BS (mg/dL) 89 total cholesterol (mg/dL) 192 triglyceride (mg/dL) 78 HDL cholesterol (mg/dL) 64 LDL cholesterol (mg/dL) 116 LDL/HDL 1.8 WBC (x10 9 /L) 5.4 RBC (x10 9 /L) 4.18 Hb (g/dL) 12.2 Ht (%) 37.5 MCV (fL) 89.7 MCH (pg) 29.2 MCHC (g/dL) 32.5 Table 2 Blood test results at the initial visit 2 factors values Platelet (x10 9 /L) 252 neutrophils (%) 50.4 ESR (mm/1h) 10 lymphocyte (%) 42.2 monocyte (%) 3.9 eosinophils (%) 2.8 basophil leukocyte (%) 0.7 PT (sec) 11.1 APTT (sec) 28.8 CRP (mg/dL) 0.11 IgG (mg/dL) 1138.6 IgA (mg/dL) 238.1 IgM (mg/dL) 118.1 C3 (mg/dL) 108.2 C4 (mg/dL) 24.8 cardiolipin antibody IgG (U/mL) < 4.0 ACE (U/L) 6.1 RA (IU/mL) < 5 3. What blood investigations favoured a possible thrombotic cause in this case? Yes, we added below sentence in discussion section and we added references no. 14 and 15. A thrombotic cause was unclear from the patient’s blood results. The literature shows that D-dimer is commonly elevated in patients with COVID-19 16 and oral contraceptive users 17 . However, no special blood factors have been reported linking RVO with oral contraceptive use, SARS-CoV-2 infection, and COVID-19 vaccination. Identifying the cause was challenging. 16. Iba T, Levy JH, Levi M, Thachil J. Coagulopathy in COVID-19. J Thromb Haemost 2020; 18(9):2103–2109. doi: 10.1111/jth.14975. 17. Westhoff CL, Eisenberger A, Tang R, Cremers S, Grossman LV, Pike MC. Clotting factor changes during the first cycle of oral contraceptive use. Contraception 2016; 93(1):70-76. doi: 10.1016/j.contraception.2015.09.015. 4. Kindly be specific with the diagnosis. This is a case of STBRVO to be specific...so in diagnosis it should be mentioned STBRVO and not just BRVO. Yes, we changed the title as below. Superotemporal branch retinal vein occlusion following COVID-19 vaccination and SARS-CoV-2 infection while taking oral contraceptives: A case report Yes, we changed the abstract as below. Abstract Oral contraceptive use, vaccination for Coronavirus disease 2019 (COVID-19), and severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection are risk factors for venous thromboembolism. Branch retinal vein occlusion (BRVO) generally develops mid-60s patients. Herein, we present a case of superotemporal BRVO caused by the above mentioned risk factors in a young woman. To the best of our knowledge, this is the first report about superotemporal BRVO associated with oral contraceptives, COVID-19 vaccination, and SARS-CoV-2. A 21-year-old woman presented with loss of visual acuity in her right eye for 10 days. She had been receiving oral contraceptives for 2 years for oligomenorrhea before noticing ophthalmological symptoms. Despite having received two doses of an mRNA COVID-19 vaccine, she contracted COVID-19 and developed fever, sore throat, cough, low back pain, and general malaise about 40 days before the initial visit. However, only cough persisted for more than a month. The right eye showed superotemporal BRVO with macular edema (ME). She did not smoke nor had diabetes or hypertension. Blood test results, including cardiolipin antibody IgG, were normal. She was treated with an intravitreal aflibercept injection. ME in the fundus showed rapid improvement and resolution. Although more than 18 months have passed since the first injection, there has been no relapse of ME. The combination of oral contraceptive use, COVID-19 vaccination, and subsequent SARS-CoV-2 infection could induce the development of venous thromboembolism, thereby leading to superotemporal BRVO. Given that cases of COVID-19 have increased globally, patients with retinal vein occlusion who use oral contraceptives are likely to be encountered more frequently. Yes, we added a paragraph as below in discussion and added references no. 13 and 14. Battaglia et al. reported that among 144 patients with BRVO, 128 (88.9%) had temporal BRVO, while 16 (11.1%) had nasal BRVO 13 . The two groups showed no differences in systemic hypertension, diabetes mellitus, glaucoma, or ischemic heart disease 13 . Nasal BRVO cases exhibited better visual acuity but higher levels of capillary non-perfusion, retinal neovascularization, and vitreous hemorrhage 13 . Kumral et al. found that among 64 BRVO patients, 38 had superotemporal BRVO, and 26 had inferior temporal BRVO 14 . Superotemporal BRVO required significantly more intravitreal ranibizumab injections 14 . In our case of superotemporal BRVO, ME resolved with a single intravitreal aflibercept injection. 13. Battaglia Parodi M, Iacono P, Di Crecchio L, Sanguinetti G, Ravalico G. Clinical and angiographic features in nasal branch retinal vein occlusion. Ophthalmologica. 2004; 218(3):210-213. doi: 10.1159/000076847 14. Kumral ET, Yenerel NM, Ercalik NY, Karabas L. Comparison of ranibizumab treatment response of superior and inferior temporal branch retinal vein occlusion: a year follow-up. Beyoglu Eye J. 2022; 7(3):207-212. doi: 10.14744/bej.2022.46794. eCollection 2022. 5. Kindly provide a fundus photo or OCT of the recent most visit of the patient. Yes, we provided OCT photos 24 months since the first administration (figure 4). We added below sentence in case report section. No ME was noted after 24 months (Figure 4), and the decimal BCVA remained at 1.2. 6. The mechanism of thrombosis following COVID-19 infection has not been discussed in the discussion. Yes, we discussed it in the discussion as below and we added reference no. 12. Coagulation disorder in COVID-19 is thought to occur through vascular damage caused by virus infection 12 . Various factors, including reduced antithrombogenicity of the vascular endothelium, release of von Willebrand factor and coagulation factor VIII, complement activation, increased fibrinogen, and cytokine storm, are intricately interwoven 12 . Thrombus can then form in any vessel, such as arteries, veins, and capillaries 12 . 12. Conway EM, Mackman N, Warren RQ, et al . Understanding COVID-19-associated coagulopathy. Nat Rev Immunol 2022; 22(10): 639-649. doi: 10.1038/s41577-022-00762-9. View more View less Competing Interests No competing interests were disclosed. reply Respond Report a concern Panigrahi PK. Peer Review Report For: Case Report: Superotemporal branch retinal vein occlusion following COVID-19 vaccination and SARS-CoV-2 infection while taking oral contraceptives [version 2; peer review: 1 not approved] . F1000Research 2025, 13 :460 ( https://doi.org/10.5256/f1000research.162540.r351857) NOTE: it is important to ensure the information in square brackets after the title is included in this citation. The direct URL for this report is: https://f1000research.com/articles/13-460/v1#referee-response-351857 Alongside their report, reviewers assign a status to the article: Approved - the paper is scientifically sound in its current form and only minor, if any, improvements are suggested Approved with reservations - A number of small changes, sometimes more significant revisions are required to address specific details and improve the papers academic merit. 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