Retinal Vascular Occlusion Following COVID-19 Vaccination: A Comprehensive Review of Observational Study and Pathophysiological Mechanisms

Abstract

Background: Retinal vascular occlusion (RVO) and retinal artery occlusion (RAO) have been reported as rare adverse events following COVID-19 vaccination, raising concerns about vaccine safety. This review synthesizes cohort and case-control studies assessing the association between COVID-19 vaccines and RVO/RAO, while exploring potential pathophysiological mechanisms. Methods: We analyzed large-scale population-based studies from South Korea, Europe, and the TriNetX database, focusing on odds ratios (OR), hazard ratios (HR), and relative risks (RR) across mRNA and adenoviral vector vaccines. Pathological processes were hypothesized based on molecular and clinical evidence. Results: Studies investigating the association between COVID-19 vaccination and retinal vascular occlusion show conflicting results; some studies report no association (e.g., OR 0.93, 95% CI 0.60-1.45), others suggest reduced risk (e.g., OR 0.80, 95% CI 0.64-0.99), and one indicates increased risk over two years (HR 2.19, 95% CI 2.00-2.39). Adenoviral vector vaccines, particularly ChAdOx1, show higher RAO incidence in specific cohorts. Proposed mechanisms include vaccine-induced immune thrombotic thrombocytopenia (VITT) via anti-PF4 antibodies, spike protein-mediated endothelial dysfunction, and adjuvant-driven inflammation. Conclusions: While causality remains unproven, temporal heterogeneity and vaccine type-specific risks warrant further investigation. Longitudinal studies with robust controls are needed to clarify these associations in the post-pandemic context.

Keywords: COVID-19 vaccination; PF4 antibodies; adenoviral vector vaccines; mRNA vaccines; pathophysiological mechanisms; retinal artery occlusion (RAO); retinal vascular occlusion (RVO); spike protein; vaccine-induced immune thrombotic thrombocytopenia (VITT).

Figure 2

The schematic diagram illustrates currently proposed hypotheses of pathophysiological mechanisms associated with thromboembolic events or vasculopathic responses following administration of adenoviral vector-based and mRNA COVID-19 vaccines. This image was drawn using Figdraw.

Figure 3

This figure delineates the pathophysiological mechanisms underlying hemodynamic disturbances and neurovascular architecture deconstruction in the delicate retinal tissue, mediated by systemic vascular risk factors, culminating in vision loss. This image was drawn using Figdraw.

Figure 1

Arrows denote causal directions (exposure→mediator→outcome). Four confounder groups (demographics/pre-existing conditions, indicated by purple boxes) affect both vaccine exposure (indicated by blue boxes) and RVO risk. Unmeasured variables (dashed boxes) indicate residual confounding. Green boxes represent possible pathologicalmechanisms.Excluded factors were intentionally controlled in some of studies. DAG guides bias adjustment and mechanistic analysis.