We demonstrated a higher risk and incidence rate of retinal vascular occlusion following COVID-19 vaccination, after adjusting for potential confounding factors18. The risk of retinal vascular occlusion, except for CRAO, has been promptly observed in individuals receiving vaccines against SARS-CoV-2. The risk factors for retinal vascular occlusion include diabetes, hypertension, obesity, coronary artery disease, and stroke19,20,21. To ensure the reliability of the results, we appropriately balanced the baseline characteristics in both cohorts before analysis.
The widespread occurrence of microvascular thrombosis in COVID-19 patients have been demonstrated22. Vaccination with ChAdOx1 nCoV-19 can result in the rare development of immune thrombotic thrombocytopenia mediated by platelet-activating antibodies against platelet factor 4 (PF4), which clinically mimics autoimmune heparin-induced thrombocytopenia23. A large cohort study24 showed that the risk of VTE slightly increased 1.10-fold 8–14 days after ChAdOx1 nCoV-19 vaccination but found no difference for individuals who were administered BNT162b2 vaccination; the risk of ATE following ChAdOx1 nCoV-19 and BNT162b2 vaccination increased 1.21-fold and 1.06-fold, respectively.
Thrombosis that manifests before thrombocytopenia is referred to as vaccine-induced immune thrombotic thrombocytopenia (VITT). Two adenoviral vector-based immunizations, ChAdOx1 nCoV-19 and Ad26.COV2.S, have been associated with the development of VITT. VITT cerebral venous sinus thrombosis is predominantly from adenovirus viral vector vaccines. The pathological mechanism of thrombosis has been hypothesized to entail either an innate or adaptive response, involving the activation of B and T cells and CD4 T cells are essential for regulating the production of PF4/heparin-specific antibodies25.
VITT is a very rare, life-threatening adverse complication with a 23% overall mortality rate26. Certain inflammatory vaccine adjuvants and delivery techniques may induce immune cell recruitment during the VITT. Antibodies that detect platelet-bound PF4 are the cause of VITT. These antibodies are immunoglobulin G (IgG) molecules that activate platelets by binding to platelet FcγIIa with a modest affinity27. VITT typically appears as uncommon thromboses (cerebral venous sinus thrombosis and splanchnic vein thrombosis), although it can also manifest as typical thromboses (stroke, pulmonary embolism, and deep vein thrombosis) with severe thrombocytopenia.
Thrombosis with thrombocytopenia syndrome (TTS) is a more general descriptive name for the syndrome of thrombosis and thrombocytopenia of any cause following COVID-19 vaccination. Some individuals with TTS may not have been evaluated for anti-PF4 antibodies; or have causes of thrombosis and thrombocytopenia other than VITT, such as antiphospholipid syndrome, cancer-associated thrombosis and thrombocytopenia, thrombotic thrombocytopenic purpura, or disseminated intravascular coagulation.
A series of 65 individuals with serologically confirmed VITT who repeated functional assays over time found that the functional assays became negative in 74% of individuals, at a median of 15.5 weeks (95% Cl, 5–28 weeks)28. VITT plays a fundamental role in retinal vascular disease and may well explain the significantly increased risk of all forms of retinal vascular occlusion in 12 weeks observed in the subgroup analysis. In an examination of the temporal change of the risk of retinal vascular occlusion, which increased significantly shortly after vaccination, especially BRAO and BRVO. The highest hazards of subtypes of retinal vascular occlusion varied. The riskiest period after COVID vaccination for BRAO, BRVO, CRAO, and CRVO was 6, 3, 15, and 45 days, respectively. For BRAO and BRVO, direct embolism may be the preferred mechanism, whereas for CRAO and CRVO, VITT secondary to immunization may be the cause. VITT has a predilection for venous thrombosis in the CNS, splanchnic or adrenal veins, with patients presenting neurologic signs in addition to fever and mild bruising as early as 4–28 and up to 30 days post-COVID-19 vaccination. The relevant literatures on it are extremely limited29.
The Netherlands’ Lareb30 showed that the incidence rate of VITT and TTS in individuals receiving the ChAdOx1-S vaccine was 7.7 per million vaccinations. Among them, 13.4 per million people who received the first dose and 1.7 per million people who received the second dose. The reported rates of retinal vascular occlusion for Ad26.COV2.S, BNT162b2, and mRNA-1273 per million vaccines were 5.7, 0.05, and 0.2, respectively. The Netherlands Pharmacovigilance Centre Lareb has received three reports of VITT/TTS with BNT162b2 and mRNA-1273; however, the associations are not sufficiently strong. A large international network cohort study31 demonstrated a 30% greater risk of thrombocytopenia after a single dose of the ChAdOx1-S vaccine, as well as a trend toward an increased risk of venous TTS after vaccination of Ad26.COV2.S compared with BNT162b2. In this study, though higher risk of retinal vascular occlusion on Ad26.COV2.S recipients was observed in 2-year and 12-week periods, there is no significant increase. Intriguingly, a trend was noted that the risk is more pronounced following immunization with Ad26.COV2.S than BNT162b2 or mRNA-1273.
The SARS-CoV-2 genome encodes ten genes, two-thirds of which are nonstructural. The other one-third of the genome comprises four major structural genes, including spike, envelope, matrix, and nucleocapsid proteins, as well as five auxiliary proteins32. Messenger RNA vaccines contain fully functional mRNAs that can be directly translated into the S protein33,34. BNT162b2 and mRNA-1273, two mRNA vaccines currently in broad use, are technologically extremely similar. They comprise codon-optimized sequences for effective production of the whole S protein and utilize the actual signal sequence for its biosynthesis. Molecular mimicry of the S protein, which shares sequence homology with human proteins, may play a central role in retinal vascular occlusion35.
The global prevalence of RVO, BRVO, and CRVO in individuals aged 30–89 years was 0.77%, 0.64%, and 0.13%36. In the United States, the prevalence of RVO, BRVO, and CRVO is 0.7%–0.8%, 0.6%, and 0.1%–0.2%, respectively37,38. However, studies on the prevalence of RAO are limited. The current study revealed a strong correlation between vaccination with a mRNA vaccine and retinal vascular occlusion. However, we recommend that individuals without a history of severe allergic reaction to any component of the vaccine be vaccinated to protect against COVID-19, owing to the lack of definite causation between retinal vascular occlusion and vaccinations. Based on the official COVID-19 death reports, it is estimated that vaccinations have prevented 14.4 million excess COVID-19 deaths worldwide between December 2020 and December 202139. Thus, vaccination is the most effective method for preventing the spread of SARS-CoV-2.
The number of reported ophthalmic complications has remained low, and vaccine-related retinal vascular occlusion is very rare, although the number of COVID-19 vaccinations is enormous. As of August 2 2022, 223.04 million people had completed a primary series of COVID-19 vaccines in the US39. However, we still suggest that patients on medications that may alter blood osmolarity should be aware of this possibility of adverse effects. Additional research is required to draw a solid conclusion regarding the association between retinal vascular occlusion and COVID-19 vaccines.
Strengths and weakness
Emerging cases of retinal vascular occlusion in outpatient settings have prompted us to address this concern. However, since this is the first study on this topic, these discoveries may have a significant impact on public health. To ensure the validity of the analysis, we conducted a comprehensive evaluation of confounding factors. However, this study had several limitations. First, since the existence of retinal vascular occlusion was defined by diagnostic codes, the diagnostic accuracy cannot be further confirmed. Second, the HR can be calculated using the TriNetX database; however, the p-value is not provided. Third, despite the fact that multiple confounding variables were accounted for, residual confounding variables may still exist and bias the results. Additional clinical investigations are required to validate the efficacy of mRNA vaccination against retinal vascular occlusion. Fourth, underprivileged people are more difficult to seek medical help under COVID-19 pandemic thought they do not have to pay for COVID-19 vaccines. Moreover, retinal vascular occlusion with no or mild symptoms may not be noted. Thus, under-reporting of retinal vascular occlusion and vaccination may bias the study to some extent. Lastly, TriNetX collects patient information only when the patient receives care from one of the participating healthcare organizations. The inclusion of care obtained from other institutions was not possible in this analysis. Loss to follow-up has the potential to distort the distributions of covariates and occurrence of outcomes. In brief, the data should be evaluated critically and cautiously owing to the retrospective nature of this investigation.
This large-scale cohort spanning two years investigate the association between retinal vascular occlusion and COVID-19 vaccination. A 2.19-fold increased risk of retinal vascular occlusion after COVID-19 vaccination was observed. Limited evidence and low frequency of the disease has complicated the establishment of a definitive association between both. The current findings support the conclusions of this case series. This emphasizes the necessity for a thorough study and ophthalmologists to consider the likelihood of retinal vascular occlusion in vulnerable patients following the administration of COVID-19 vaccines. Vaccination is suggested to protect against COVID-19, since the incidence of retinal vascular occlusion remains extremely low.