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

Superotemporal BRVO

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.

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.