Retinal vascular occlusion (RVO), a major cause of vision loss, has been associated with thrombotic and vascular conditions. Recent reports suggest a potential link between COVID-19 vaccinations, especially mRNA-based vaccines like Moderna’s mRNA-1273, and retinal vascular events. This paper investigates whether the mRNA-1273 vaccine increases the risk of retinal vascular occlusion (RVO) and retinal artery occlusion (RAO). By analyzing data from a large cohort, this paper will discuss the mechanisms behind thrombotic events post-vaccination and explore possible causal relationships between mRNA-1273 and retinal vascular diseases.

Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) is responsible for the ongoing COVID-19 pandemic, prompting the rapid development of vaccines, including the Moderna mRNA-1273 vaccine. While vaccinations have proven instrumental in preventing severe illness and deaths, emerging data suggests possible adverse effects, including retinal vascular occlusion (RVO) and retinal artery occlusion (RAO), following mRNA vaccinations.

The ocular complications post-vaccination are concerning due to the delicate nature of the retinal vasculature. RVO and RAO are primarily caused by thromboembolism, vasospasm, or vascular degeneration, leading to vision impairment. Though rare, growing evidence points to an increased risk of retinal vascular complications following mRNA COVID-19 vaccinations, specifically Moderna’s mRNA-1273 vaccine.

Retinal Vascular Occlusion: A Clinical Overview

Retinal vascular occlusion (RVO) includes both retinal artery occlusion (RAO) and retinal vein occlusion (RVO). RVO is the second most common cause of retinal vascular disease after diabetic retinopathy and can be classified into branch retinal vein occlusion (BRVO) and central retinal vein occlusion (CRVO). RAO similarly is divided into central retinal artery occlusion (CRAO) and branch retinal artery occlusion (BRAO). Both conditions result from ischemic events related to impaired blood flow, often triggered by thrombotic or embolic blockages.

Mechanisms of RVO and RAO:

• RVO: Typically results from thromboembolic events or vessel degeneration leading to blood stagnation in the retinal veins. The underlying risk factors include systemic diseases such as diabetes, hypertension, and arteriosclerosis.
• RAO: RAO involves occlusion of the retinal arteries, often caused by emboli originating from systemic vasculature (e.g., the carotid artery). RAO’s etiology can be linked to thromboembolism, vasospasm, or inflammation of arterial walls.

Category	Subcategory	Description/Details
Retinal Vascular Occlusion (RVO)	General Overview	Retinal vascular occlusion (RVO) refers to the blockage of blood flow in the retinal arteries or veins, leading to ischemia and vision impairment.
Causes	Thrombotic Events	Thrombus formation in the retinal vasculature due to blood clotting factors, often associated with systemic conditions like hypertension, diabetes, and hyperlipidemia.
	Embolic Blockages	Emboli from carotid artery plaques or the heart lodge in retinal vessels, disrupting blood flow and leading to ischemia and tissue damage.
	Vasospasm or Inflammation	Vasospasm (narrowing of the vessel) or inflammation of the vessel walls may lead to reduced blood flow and occlusion, contributing to ischemic events in retinal arteries or veins.
Risk Factors	Systemic Diseases	Hypertension, diabetes, atherosclerosis, and hyperlipidemia increase the risk of RVO by contributing to vessel wall damage, thrombus formation, or emboli development.
	Age and Gender	Older age and male gender are associated with higher risks of retinal vascular occlusion.
	Other Factors	Smoking, obesity, and oral contraceptive use can increase the risk of blood clotting and occlusive events.

Types of Retinal Vascular Occlusion (RVO)	Description	Details
Retinal Artery Occlusion (RAO)	General Overview	Retinal artery occlusion (RAO) refers to the blockage of arterial blood flow, leading to ischemia and subsequent retinal tissue damage. This condition can cause sudden, painless vision loss.
	Pathophysiology	RAO results from embolic or thrombotic blockages in the retinal arteries, reducing oxygen and nutrient delivery to the retina and leading to retinal ischemia and infarction.
Central Retinal Artery Occlusion (CRAO)	Definition	CRAO occurs when the central retinal artery, the main vessel supplying the retina, is blocked, causing widespread retinal ischemia and profound vision loss.
	Pathophysiology	CRAO is typically caused by an embolus or thrombus from the carotid artery or heart, blocking the central retinal artery and cutting off the oxygen supply to the inner layers of the retina.
	Clinical Presentation	Sudden, painless vision loss in one eye, with a pale retina and a “cherry-red spot” at the macula seen on fundoscopic examination.
Branch Retinal Artery Occlusion (BRAO)	Definition	BRAO refers to the occlusion of a smaller branch of the retinal artery, leading to localized retinal ischemia and vision loss affecting a specific region of the visual field.
	Pathophysiology	BRAO results from the embolic blockage of a smaller branch of the retinal artery, leading to localized retinal tissue damage. It is less severe than CRAO, with partial vision loss.
	Clinical Presentation	Sudden loss of vision in a segment of the visual field corresponding to the area of the retina supplied by the occluded artery. The rest of the retina remains functional.

Retinal Vein Occlusion (RVO) and Its Subtypes

Category	Subcategory	Description
Retinal Vein Occlusion (RVO)	General Overview	Retinal vein occlusion (RVO) occurs when a vein in the retina becomes blocked, leading to a backup of blood and fluid leakage into the retina, causing swelling, hemorrhage, and vision impairment.
	Pathophysiology	The blockage in the retinal vein leads to increased venous pressure, which causes blood and fluid to leak into the retinal tissue. This can result in macular edema and neovascularization due to ischemia and hypoxia.
Central Retinal Vein Occlusion (CRVO)	Definition	CRVO occurs when the central retinal vein, which drains blood from the retina, becomes blocked, leading to widespread retinal hemorrhages, edema, and vision loss.
	Pathophysiology	CRVO is often associated with systemic conditions like hypertension and diabetes, which contribute to vessel wall damage and thrombus formation. The blocked vein causes blood to pool in the retina, leading to widespread damage.
	Clinical Presentation	Painless, sudden vision loss in one eye, with the appearance of retinal hemorrhages, cotton wool spots, and swelling (macular edema) on fundoscopic examination.
Branch Retinal Vein Occlusion (BRVO)	Definition	BRVO involves the blockage of one of the smaller branches of the retinal vein, leading to localized retinal swelling and hemorrhage, with partial vision loss.
	Pathophysiology	BRVO occurs when a small retinal vein branch becomes occluded, usually due to thrombus formation at a crossing point with an artery. This causes localized retinal hemorrhage and ischemia.
	Clinical Presentation	Vision loss is typically confined to a portion of the visual field, depending on which branch of the retinal vein is occluded. Retinal hemorrhages and edema are visible in the affected area.

Complications of Retinal Vein Occlusion

Complication	Description	Details
Macular Edema	Definition	Swelling of the macula (central part of the retina) caused by fluid leakage from blood vessels, a common complication of RVO.
	Pathophysiology	Increased pressure in retinal veins causes fluid to leak from damaged capillaries, leading to macular thickening and impaired central vision.
Neovascularization	Definition	Abnormal growth of new blood vessels in the retina in response to ischemia. These vessels are fragile and prone to bleeding, leading to further complications like vitreous hemorrhage.
	Pathophysiology	Chronic retinal ischemia from occlusion leads to the release of angiogenic factors like VEGF (vascular endothelial growth factor), stimulating new, abnormal vessel growth.

Diagnostic Approaches	Description	Details
Fundoscopy	Definition	Examination of the retina using an ophthalmoscope to assess the presence of retinal hemorrhages, cotton wool spots, macular edema, or pale retinal areas (signs of occlusion).
Fluorescein Angiography	Definition	Imaging technique where fluorescein dye is injected into the bloodstream, allowing visualization of blood flow through the retinal vessels, identifying areas of occlusion or leakage.
Optical Coherence Tomography (OCT)	Definition	Non-invasive imaging that provides cross-sectional images of the retina, useful for detecting macular edema and structural changes following RVO or RAO.

Treatment Options	Description	Details
Intravitreal Anti-VEGF Injections	Mechanism	Anti-VEGF injections, such as ranibizumab and bevacizumab, inhibit VEGF to reduce abnormal blood vessel growth and decrease macular edema.
Intravitreal Steroids	Mechanism	Steroid injections (e.g., dexamethasone) reduce inflammation and vascular leakage, improving macular edema.
Laser Photocoagulation	Mechanism	Laser treatment used to create controlled burns in areas of ischemia to prevent neovascularization and reduce the risk of vitreous hemorrhage.
Systemic Treatment	Description	Managing systemic conditions like hypertension, diabetes, and hyperlipidemia can reduce the risk of further occlusive events and improve overall prognosis.

mRNA-1273 and Vaccine-Induced Thrombotic Events:

Vaccination-induced adverse effects, particularly vascular and thrombotic complications, have been observed in rare cases post-COVID-19 vaccination. The mechanisms potentially linking mRNA vaccines like Moderna’s mRNA-1273 to thrombotic events such as RVO and RAO include:

• Hypercoagulability and Immune Response:
  COVID-19 vaccinations induce immune activation and inflammatory responses, which can lead to a transient hypercoagulable state. Pro-inflammatory cytokines, endothelial cell activation, and platelet aggregation are implicated in creating a pro-thrombotic environment.
• Vaccine-Induced Immune Thrombotic Thrombocytopenia (VITT):
  VITT, a rare but severe complication seen in adenoviral vector vaccines, may present similarly with mRNA vaccines. VITT involves the formation of platelet-activating antibodies against platelet factor 4 (PF4), causing abnormal clot formation, which can lead to venous and arterial thrombosis.
• Molecular Mimicry:
  It has been suggested that components of the mRNA vaccines, particularly the spike protein they encode, may share homology with certain human proteins, leading to molecular mimicry and autoimmune-like thrombotic responses. This mechanism may contribute to retinal vascular occlusion through endothelial damage and subsequent clot formation in retinal vessels.

Retinal Vascular Occlusion in Post-Vaccination Cohorts

Recent studies using large databases like TriNetX have shown an increased risk of RVO and RAO after mRNA vaccinations. A study of 95 million individuals indicated a higher incidence of retinal vascular occlusion in vaccinated individuals compared to unvaccinated individuals, particularly in the 12-week period following the first and second doses of the mRNA-1273 vaccine.

Findings from the Cohort Study:

• Increased Incidence:
  A 2.19-fold increased risk of retinal vascular occlusion was observed in vaccinated individuals two years after receiving the Moderna vaccine. Both branch and central forms of retinal artery and vein occlusions saw a significant increase, particularly in the first 12 weeks post-vaccination.
• Bi-weekly Risk Elevations:
  The study highlighted that the risk of retinal vascular events was highest within the first 2 weeks post-vaccination and persisted for up to 12 weeks, with varying peaks depending on the type of occlusion. For example, BRVO and BRAO presented the highest risk within days 3-6 after vaccination, while CRAO and CRVO peaked between 15-45 days post-vaccination.
• Moderna and BNT162b2 Comparisons:
  The study also compared mRNA-1273 with BNT162b2 (Pfizer-BioNTech) and found no significant difference between the two mRNA vaccines regarding retinal vascular risks, although both showed elevated risks compared to unvaccinated groups.

Pathophysiological Mechanisms of Retinal Occlusion Post-mRNA-1273 Vaccination:

Several hypotheses attempt to explain how the Moderna mRNA-1273 vaccine could contribute to retinal vascular occlusion:

• Endothelial Damage and Thromboinflammation:
  The spike protein expressed post-vaccination could cause local endothelial damage in the retinal vasculature, leading to platelet adhesion and clot formation.
• Systemic Inflammatory State:
  Vaccination activates the immune system, creating a systemic inflammatory response that could enhance thrombotic activity, increasing the risk of retinal vascular blockages.
• VITT-like Mechanisms:
  While VITT has primarily been observed with adenoviral vector vaccines, there is speculation that a similar immune-mediated response could occur with mRNA vaccines, contributing to clot formation in the retinal vessels.

Limitations of Current Evidence:

Although the data points to a correlation between the Moderna vaccine and retinal vascular occlusion, limitations exist in establishing a definitive causal link:

• Retrospective Study Design:
  The observational nature of the study, relying on medical records, limits the ability to control for all confounding variables.
• Underreporting:
  Mild cases of RVO or RAO may not have been reported, leading to possible underestimation of incidence rates.
• Thrombosis Risk Factors:
  The vaccinated cohort may have higher baseline risks for thrombosis due to comorbidities like diabetes, hypertension, and cardiovascular disease.

The analysis suggests a significant but rare association between Moderna mRNA-1273 vaccination and retinal vascular occlusion. While the precise mechanism remains unclear, immune activation, thromboinflammatory processes, and possibly VITT-like syndromes could contribute to the pathogenesis. However, the benefits of vaccination against COVID-19 far outweigh the risks of these rare adverse events. Further clinical research is required to understand the mechanisms fully and identify individuals at higher risk of such complications post-vaccination.

Detailed Pathophysiological Mechanisms Linking Moderna mRNA-1273 COVID-19 Vaccination to Retinal Vascular Occlusion

Category	Detail	Numeric/Incidence Data	Meaning/Explanation
Increased Risk of Retinal Vascular Occlusion (RVO)	Increased risk following COVID-19 vaccination	2.19-fold increase	Retinal vascular occlusion refers to blockage of the veins or arteries in the retina, causing vision issues. This category reflects the increased risk after receiving COVID-19 vaccines.
RVO Prevalence (Global)	RVO	0.77%	Prevalence of RVO globally in individuals aged 30–89 years.
RVO Prevalence (US)	RVO	0.7%–0.8%	Prevalence of retinal vascular occlusion in the United States.
BRVO Prevalence (Global)	BRVO	0.64%	Branch retinal vein occlusion (BRVO) is a specific type of RVO, where blockage occurs in the smaller branches of retinal veins. Prevalence data for this condition globally.
BRVO Prevalence (US)	BRVO	0.6%	Prevalence of BRVO in the United States.
CRVO Prevalence (Global)	CRVO	0.13%	Central retinal vein occlusion (CRVO) refers to the blockage in the central retinal vein, affecting the entire retina. This shows the global prevalence.
CRVO Prevalence (US)	CRVO	0.1%–0.2%	Prevalence of CRVO in the United States.
Vaccination Impact on COVID-19 Deaths	Estimated deaths prevented worldwide	14.4 million excess deaths prevented	The estimated number of COVID-19 deaths that were prevented due to vaccination between December 2020 and December 2021.
ChAdOx1 nCoV-19 Risk (VTE)	Risk increase 8–14 days post-vaccination	1.10-fold	Venous thromboembolism (VTE) risk increase following vaccination with ChAdOx1 nCoV-19, an adenovirus vector-based vaccine, within the first 8–14 days post-vaccination.
ChAdOx1 nCoV-19 Risk (ATE)	Risk increase	1.21-fold	Arterial thromboembolism (ATE) refers to blood clots in arteries. This shows the risk increase after ChAdOx1 nCoV-19 vaccination.
BNT162b2 Risk (ATE)	Risk increase	1.06-fold	Risk increase for arterial thromboembolism after receiving the BNT162b2 vaccine (Pfizer-BioNTech).
VITT Mortality Rate	VITT overall mortality rate	23%	Vaccine-induced immune thrombotic thrombocytopenia (VITT) is a rare but serious blood clotting condition following certain COVID-19 vaccines, with an overall 23% mortality rate.
VITT Incidence Rate	Following ChAdOx1-S vaccination	7.7 per million	Incidence rate of VITT following the ChAdOx1-S vaccine (AstraZeneca) per million doses.
VITT Incidence Rate (First Dose of ChAdOx1-S)	Incidence rate	13.4 per million	Incidence of VITT after the first dose of ChAdOx1-S per million doses.
VITT Incidence Rate (Second Dose of ChAdOx1-S)	Incidence rate	1.7 per million	Incidence of VITT after the second dose of ChAdOx1-S per million doses.
Retinal Vascular Occlusion Incidence	Ad26.COV2.S vaccine	5.7 per million	Incidence rate of retinal vascular occlusion following the Ad26.COV2.S (Johnson & Johnson) vaccine.
Retinal Vascular Occlusion Incidence	BNT162b2 vaccine	0.05 per million	Incidence rate of retinal vascular occlusion following the BNT162b2 (Pfizer-BioNTech) vaccine.
Retinal Vascular Occlusion Incidence	mRNA-1273 vaccine	0.2 per million	Incidence rate of retinal vascular occlusion following the mRNA-1273 (Moderna) vaccine.
VITT Negative Functional Assay	Median time for negative functional assay results	15.5 weeks (95% CI, 5–28 weeks)	The median time for functional assays (tests) to turn negative for VITT patients.
Highest Risk Period After Vaccination for RVO Subtypes	BRAO	6 days post-vaccination	Highest risk period for branch retinal artery occlusion (BRAO), a specific type of retinal vascular occlusion, after COVID-19 vaccination.
Highest Risk Period After Vaccination for RVO Subtypes	BRVO	3 days post-vaccination	Highest risk period for branch retinal vein occlusion (BRVO) after vaccination.
Highest Risk Period After Vaccination for RVO Subtypes	CRAO	15 days post-vaccination	Highest risk period for central retinal artery occlusion (CRAO) after vaccination.
Highest Risk Period After Vaccination for RVO Subtypes	CRVO	45 days post-vaccination	Highest risk period for central retinal vein occlusion (CRVO) after vaccination.
TTS/VITT Reports	Netherlands (Lareb)	3 reports (BNT162b2, mRNA-1273)	Thrombosis with thrombocytopenia syndrome (TTS) or VITT reports received in the Netherlands’ Lareb database.
Thrombocytopenia Risk	After a single dose of ChAdOx1-S vaccine	30% greater risk	Increased risk of low platelet count (thrombocytopenia) after a single dose of ChAdOx1-S vaccine.
ChAdOx1-S Risk of Venous TTS	Compared with BNT162b2	Trend toward increased risk	There is a trend showing an increased risk of venous TTS (blood clotting) with ChAdOx1-S compared to the Pfizer-BioNTech vaccine.
Number of Individuals Vaccinated in US (as of August 2, 2022)	Completed primary series	223.04 million people	The total number of people in the U.S. who had completed their primary COVID-19 vaccination series by August 2, 2022.

Retinal vascular occlusion (RVO), encompassing both retinal artery occlusion (RAO) and retinal vein occlusion (RVO), is a significant cause of vision loss, primarily driven by thromboembolic or vascular events. Recent reports suggest a potential association between COVID-19 mRNA vaccines, particularly Moderna’s mRNA-1273, and retinal vascular complications. This paper aims to meticulously describe the sequence of molecular and immunological events that could lead to retinal vascular occlusion post-vaccination with the Moderna mRNA-1273 vaccine. A detailed examination of thrombotic pathways, endothelial cell activation, and immune responses is presented to elucidate how vaccination may contribute to retinal vascular events.

Since the introduction of mRNA-based COVID-19 vaccines, including Moderna’s mRNA-1273, millions have been vaccinated to combat SARS-CoV-2. While the vaccines have demonstrated remarkable efficacy in preventing severe COVID-19 illness, rare adverse events, including retinal vascular occlusion (RVO), have been reported. The retina is a highly vascularized tissue, and any impairment in its blood flow can lead to significant visual disturbances or blindness. This detailed analysis will explore how the Moderna mRNA-1273 vaccine may trigger retinal vascular occlusion, focusing on molecular, immune, and thrombotic pathways.

Step-by-Step Pathogenesis of Retinal Vascular Occlusion Post-mRNA-1273 Vaccination:

Introduction of the Moderna mRNA-1273 Vaccine:

Moderna’s mRNA-1273 vaccine contains a lipid nanoparticle-encapsulated mRNA that encodes the spike (S) protein of SARS-CoV-2. Upon administration, the mRNA enters host cells, particularly dendritic cells and macrophages, where it is translated into the spike protein. This initiates an immune response, including antibody production and T-cell activation, essential for viral neutralization.

Lipid Nanoparticle Interaction and Cellular Entry:

The lipid nanoparticles (LNPs) of the mRNA-1273 vaccine facilitate the mRNA’s entry into cells by fusing with cell membranes. These nanoparticles have a specific composition, which includes ionizable lipids that increase the uptake of the mRNA in cells. Once inside the cells:

• The mRNA is released into the cytoplasm.
• Host ribosomes translate the mRNA into the spike protein.

Key Detail: The spike protein mimics the surface protein of the virus, allowing the immune system to recognize it as a foreign antigen, thus triggering a robust immune response. However, the LNPs themselves can also cause transient inflammatory responses at the site of injection and systemically by activating innate immune pathways like Toll-like receptors (TLRs).

Spike Protein Expression and Immune Activation:

The spike protein produced by the cells is processed and presented on the cell surface via the major histocompatibility complex (MHC). This presentation triggers:

• Humoral Immunity: B-cells recognize the spike protein and produce neutralizing antibodies.
• Cellular Immunity: CD8+ cytotoxic T-cells recognize infected cells and initiate their destruction. CD4+ helper T-cells enhance the immune response by activating macrophages and supporting B-cell antibody production.

Systemic Inflammation and Vascular Implications:

• The immune response to the spike protein can lead to a systemic inflammatory response, which includes the release of cytokines like IL-6, TNF-α, and IFN-γ. These cytokines increase vascular permeability and induce the expression of adhesion molecules on endothelial cells.
• This creates a pro-inflammatory environment that predisposes the vasculature to dysfunction and thrombotic events.

Endothelial Activation and Damage:

Endothelial cells line the blood vessels, including those in the retina. They are critical in maintaining vascular homeostasis and preventing thrombosis. The activation of these cells, either by the spike protein or by the systemic inflammatory response, can disrupt this balance:

• Increased Expression of Adhesion Molecules: Endothelial cells upregulate molecules like ICAM-1 and VCAM-1, which attract immune cells, particularly monocytes and neutrophils. This leads to leukocyte adhesion and infiltration into the vessel walls.
• Endothelial Cell Injury: Prolonged immune activation can result in endothelial cell apoptosis or dysfunction, compromising the barrier integrity of the retinal vessels.
• Release of Von Willebrand Factor (vWF): Damaged endothelial cells release vWF, a glycoprotein essential for platelet adhesion. This release enhances the likelihood of thrombus formation in the retinal vasculature.

Key Detail: The systemic inflammation, coupled with endothelial cell activation, primes the retinal vasculature for thrombus formation, leading to occlusion.

Thromboinflammatory Pathways and Microvascular Thrombosis:

Thrombosis in the retinal vessels can result from a combination of:

• Platelet Activation: Activated endothelial cells release factors like vWF and tissue factor, which activate platelets. The spike protein or vaccine components may also contribute to platelet aggregation through unknown mechanisms.
• Coagulation Cascade Activation: The inflammation induced by the immune response triggers the coagulation cascade, especially through tissue factor pathway activation. Elevated levels of D-dimer and fibrinogen indicate an active thrombotic process, particularly in small, highly sensitive vessels like those in the retina.

Key Detail: This thromboinflammatory state can lead to the formation of microthrombi in the retinal veins or arteries, depending on where the endothelial damage is most pronounced.

Retinal Vascular Occlusion:

Retinal vascular occlusion occurs when a thrombus forms in the retinal vasculature, blocking blood flow. This can manifest as:

• Branch Retinal Vein Occlusion (BRVO): The obstruction of a branch of the retinal vein leads to localized ischemia, resulting in retinal swelling, hemorrhage, and vision loss.
• Central Retinal Vein Occlusion (CRVO): Occlusion of the central retinal vein results in more widespread retinal ischemia and more severe visual disturbances.
• Branch Retinal Artery Occlusion (BRAO): Thromboembolism in a branch of the retinal artery leads to localized ischemia and tissue death in a specific region of the retina.
• Central Retinal Artery Occlusion (CRAO): This is the most severe form, where the central retinal artery is blocked, leading to a more profound and potentially irreversible loss of vision.

Key Detail: The spike protein-induced endothelial dysfunction, combined with the hypercoagulable state induced by the immune response, creates the perfect environment for thrombus formation, leading to retinal vascular occlusion.

Vaccine-Induced Immune Thrombotic Thrombocytopenia (VITT)-like Mechanism:

While VITT has primarily been observed in adenoviral vector vaccines, some researchers hypothesize a similar, albeit less frequent, mechanism may occur with mRNA vaccines like mRNA-1273:

• Platelet Factor 4 (PF4) Antibodies: It has been observed that some vaccinated individuals develop antibodies against PF4, leading to abnormal platelet activation. This leads to thrombocytopenia and simultaneous thrombus formation.
• Thrombosis in Retinal Vasculature: In rare cases, this mechanism could cause thrombi to form in retinal vessels, particularly if the vaccine-induced immune response triggers an exaggerated activation of coagulation pathways.

Key Detail: Although rare, this mechanism could explain some of the cases of retinal vascular occlusion observed post-mRNA-1273 vaccination.

Time Course and Risk Factors:

The timeline of retinal vascular occlusion post-vaccination typically follows a pattern of heightened risk within the first 12 weeks post-vaccination. The risk peaks within the first 2 weeks and diminishes over time but remains elevated compared to the unvaccinated population.

• Peak Risk Periods for Retinal Occlusion:
  • BRAO and BRVO: Occur primarily within the first 6 days post-vaccination.
  • CRAO and CRVO: Show heightened risk around 15-45 days post-vaccination.
• Risk Modifiers: Pre-existing conditions such as diabetes, hypertension, and cardiovascular disease increase the likelihood of retinal vascular occlusion. These conditions exacerbate the prothrombotic environment and vascular fragility.

The pathophysiology linking Moderna’s mRNA-1273 vaccine to retinal vascular occlusion is multifactorial, involving immune activation, endothelial dysfunction, systemic inflammation, and thromboinflammatory processes. The spike protein plays a pivotal role in initiating this cascade, leading to a hypercoagulable state that affects sensitive microvasculature like the retina. Though the risk is low, individuals with pre-existing risk factors may be more susceptible to these rare complications. Further studies are needed to fully elucidate the mechanisms behind these events, but current evidence suggests that mRNA vaccines, including mRNA-1273, can induce retinal vascular occlusion through complex immunological and thrombotic pathways.

Inherited Blood Coagulation Disorders and the Challenges Presented by COVID-19 Vaccines

Inherited blood coagulation disorders are complex and diverse conditions that arise from congenital or acquired defects within the blood coagulation system. These disorders, which predispose individuals to either excessive bleeding or abnormal clotting, have become more critically examined in the context of the COVID-19 pandemic and the rollout of vaccines aimed at curbing its spread. As the intersection between these coagulopathies and the immune response to vaccination emerges, the medical community faces new challenges in ensuring safe and effective treatment for those affected.

Coagulopathic hemorrhagic diatheses, also known as coagulopathies, refer to conditions where an individual has an abnormal tendency to bleed, often because of a defect in the coagulation pathway. This bleeding tendency may be hereditary or acquired, and it can manifest in varying degrees of severity. Most inherited coagulation disorders are the result of qualitative or quantitative defects in a single coagulation factor, causing a range of bleeding complications, from spontaneous bleeding episodes to life-threatening hemorrhages.

A central concern in these patients revolves around how the COVID-19 infection and the subsequent vaccines affect their coagulation profiles, especially given the virus’s association with clotting abnormalities and thrombotic events. Understanding the underlying mechanisms of these inherited disorders and their interactions with COVID-19 vaccines is crucial for developing appropriate treatment and vaccination strategies for affected individuals.

Inherited Coagulation Disorders: An Overview

The most common inherited blood coagulation disorders fall into three major categories: defects in platelet adhesion, defects in platelet aggregation, and disorders of platelet release reactions. These disorders significantly increase the risk of abnormal bleeding, which can complicate both routine medical procedures and the management of more serious health conditions.

Among the sex-linked coagulation disorders, hemophilia A, hemophilia B, and von Willebrand’s disease are the most well-known and clinically significant. Hemophilia A, also known as classic hemophilia, is a deficiency in factor VIII, a protein essential for proper blood clotting. Hemophilia B, also known as Christmas disease, is caused by a deficiency in factor IX. Both conditions are inherited in an X-linked recessive pattern, meaning that the disease primarily manifests in males, while females typically carry the gene without developing symptoms.

Von Willebrand’s disease is another prevalent inherited coagulopathy that affects platelet aggregation due to a defect in von Willebrand factor (vWF), a protein critical for platelet adhesion. Unlike hemophilia, von Willebrand’s disease is inherited in an autosomal dominant manner, meaning that both males and females can be affected. Individuals with this disorder tend to experience spontaneous bleeding from mucous membranes, as well as excessive bleeding from minor wounds.

In these inherited disorders, bleeding episodes can range from mild to severe, depending on the specific defect and the level of functional clotting factor in the blood. For example, patients with hemophilia may experience intra-articular hemorrhages, leading to long-term joint damage and deformity. Even seemingly minor trauma, such as a dental procedure, can result in dangerous and prolonged bleeding in these individuals. In severe cases, bleeding into critical organs or tissues can become life-threatening without prompt medical intervention.

Hemophilia A and COVID-19: A Complex Interaction

COVID-19 presents a unique challenge for patients with inherited bleeding disorders, particularly those with hemophilia A. While COVID-19 has been widely associated with coagulation abnormalities and an increased risk of thrombotic events, it was unclear in the early stages of the pandemic how the infection might affect patients with underlying coagulation defects. One of the most significant studies addressing this issue was a retrospective analysis conducted by Mericliler and Narayan, which examined the outcomes of 1,758 adult male patients with hemophilia A who contracted COVID-19.

The study found that, while COVID-19 did not significantly increase the mortality rate among patients with hemophilia A, it did raise their risk of bleeding and hospitalization. This finding suggests that the virus may exacerbate the underlying bleeding tendency in these patients, even though it is more commonly associated with increased clotting in the general population. This heightened bleeding risk underscores the need for careful management of hemophilia A patients who contract COVID-19, including close monitoring of their clotting factor levels and prompt administration of replacement therapy when needed.

The Vaccine Challenge for Hemophilia Patients

With the introduction of COVID-19 vaccines, particularly those administered intramuscularly, new challenges arose for patients with inherited coagulation disorders. Vaccination in hemophilia patients presents a dilemma, as intramuscular injections carry a risk of causing bleeding at the injection site. This risk is particularly concerning for hemophilia patients, as they may require several days or even weeks of treatment with clotting factor concentrates to control post-vaccine bleeding.

The World Health Organization (WHO) and the World Federation of Hemophilia (WFH) issued guidelines recommending that hemophilia patients receive subcutaneous vaccines whenever possible to minimize the risk of bleeding. However, this precautionary measure proved problematic for COVID-19 vaccines, which are primarily administered via intramuscular injection. Despite the challenges, vaccination is critical for this patient population, as they remain vulnerable to the severe complications of COVID-19, including the potential for exacerbated bleeding due to the virus’s impact on coagulation.

Recent reports have also raised concerns about the possibility of developing acquired hemophilia A following COVID-19 vaccination. This rare condition, which involves the development of antibodies that neutralize factor VIII, has been linked to immune system activation following vaccination. In one case study described by Duminuco et al., a patient developed hemorrhagic complications after receiving the COVID-19 vaccine, likely due to the formation of factor VIII inhibitors. While such cases are exceedingly rare, they highlight the need for ongoing surveillance and research into the long-term effects of COVID-19 vaccines in patients with inherited and acquired coagulation disorders.

Von Willebrand’s Disease and COVID-19

Patients with von Willebrand’s disease have also faced unique challenges during the pandemic. As previously mentioned, this disease is characterized by impaired platelet aggregation due to a defect in von Willebrand factor, which plays a critical role in the formation of blood clots. While COVID-19 has been shown to increase von Willebrand factor levels and activity in severe cases, little data is available on the specific impact of the virus on patients with von Willebrand’s disease.

Given the limited information available, it is difficult to predict how COVID-19 might affect the bleeding risk in these patients. However, it is plausible that the virus’s pro-thrombotic effects could complicate the underlying coagulopathy, leading to an increased risk of both bleeding and clotting. Further research is needed to clarify the interaction between COVID-19 and von Willebrand’s disease and to develop appropriate management strategies for affected individuals.

Thrombophilia and COVID-19 Vaccines: A Balancing Act

While most inherited coagulation disorders predispose individuals to bleeding, thrombophilia represents the opposite end of the spectrum. Thrombophilia is a condition of increased blood clotting, and it can be caused by various inherited defects, such as the Factor V Leiden mutation, protein C and S deficiencies, and antithrombin III deficiency.

One of the most well-known inherited thrombophilias is the Factor V Leiden mutation, which increases the risk of venous thromboembolism (VTE) by enhancing the pro-thrombotic actions of activated factor Va. Protein C and S deficiencies similarly increase the risk of VTE by disrupting the normal regulation of thrombin production. Antithrombin III deficiency, meanwhile, carries the highest venous thromboembolism risk among all hereditary thrombophilias, as it impairs the body’s ability to inhibit circulating thrombin.

In the context of COVID-19, thrombophilia patients face an elevated risk of both thrombotic events and bleeding complications, especially when undergoing vaccination. A large observational study conducted at the Mayo Clinic found no statistically significant difference in the occurrence of venous thromboembolism between patients with thrombophilia who received the COVID-19 vaccine and those without thrombophilia. Nevertheless, the study did emphasize the importance of balancing the risk of thrombosis with the need for vaccination, particularly in high-risk patients.

Circulating Anticoagulants and Acquired Hemophilia

Circulating anticoagulants, often appearing as autoantibodies, target specific clotting factors and interfere with their normal function, leading to bleeding disorders. For example, autoantibodies against factor VIII or factor V can lead to the development of acquired hemophilia, a rare but serious condition. Similarly, antibodies may target phospholipid-bound proteins, as seen in lupus anticoagulant hypoprothrombinemia or antiphospholipid syndrome, causing abnormal bleeding or clotting tendencies depending on the context of the autoantibody’s action.

Lupus anticoagulant, often associated with autoimmune diseases, is of particular concern when considering thrombotic events. This autoantibody interacts with phospholipids in the coagulation pathway, leading to an increased risk of thrombosis. In contrast, some autoantibodies in antiphospholipid syndrome bind to prothrombin–phospholipid complexes, paradoxically resulting in bleeding. The appearance of such autoantibodies can be induced by medications or may follow infections or vaccinations. Indeed, there have been a few documented cases of acquired hemophilia emerging after COVID-19 vaccination, highlighting the need for careful patient monitoring in such scenarios.

Impaired Synthesis of Clotting Factors

Another mechanism leading to acquired coagulation disorders is the impaired synthesis of clotting factors. This may occur in the setting of severe liver disease, such as fulminant hepatitis, cirrhosis, or acute liver failure, which reduces the liver’s ability to produce clotting factors. Vitamin K deficiency, often arising from inadequate intake or conditions that impair fat absorption (e.g., celiac disease or cystic fibrosis), also disrupts the synthesis of critical clotting factors, including prothrombin, factor VII, factor IX, protein C, and protein S.

These deficiencies can lead to significant coagulopathies, and while liver disease and vitamin K deficiency have been implicated in various bleeding disorders, there have been no specific reports directly linking impaired synthesis of clotting factors to COVID-19 vaccination. Nonetheless, understanding the underlying pathophysiology of liver disease and vitamin K deficiency remains essential in managing patients who may be at risk of bleeding or thrombotic events, particularly in the context of the immune activation seen with vaccines.

Disseminated Intravascular Coagulation (DIC)

Perhaps one of the most dangerous acquired coagulation disorders is disseminated intravascular coagulation (DIC), a condition characterized by excessive thrombin and fibrin production in the blood. DIC is typically triggered by the exposure of tissue factor to the bloodstream, setting off the extrinsic coagulation pathway. Cytokine release and impaired microvascular flow play crucial roles in this process, leading to the release of tissue plasminogen activator (tPA) from endothelial cells. tPA and plasminogen bind to fibrin, and the resulting plasmin breaks down fibrin into D-dimers and other fibrin degradation products.

This uncontrolled clotting cascade can lead to widespread thrombosis, followed by excessive bleeding due to the consumption of platelets and clotting factors. DIC can progress rapidly, sometimes within hours or days, and is associated with high mortality if not properly managed. Several cases of DIC following adenovirus vector-based COVID-19 vaccines (such as ChAdOx1-nCoV-19 and Ad26.COV2.S) have been described in the literature, underscoring the need for vigilance in identifying and managing this condition in vaccinated individuals.

Thrombotic Disorders Related to COVID-19 Infection

The link between COVID-19 and thrombotic disorders has been a focus of extensive research, with the novel coronavirus demonstrating a unique ability to trigger a hypercoagulable state in infected patients. COVID-19 can present with a wide spectrum of clinical symptoms, ranging from asymptomatic cases to severe respiratory illness and multiorgan failure. Among the more severe cases, hypercoagulation, endothelial damage, and an increased risk of venous and arterial thrombotic complications have been noted.

Endothelial cells play a pivotal role in mediating the inflammatory and coagulation responses in COVID-19. SARS-CoV-2 binds to the angiotensin-converting enzyme 2 (ACE2) receptor on endothelial cells, initiating a cascade of inflammatory signals that disrupt endothelial function. This includes upregulation of vascular adhesion molecules, such as vascular cell adhesion molecule (VCAM)-1, as well as inflammatory cytokines like interleukin (IL)-8 and monocyte chemoattractant protein (MCP)-1. Simultaneously, COVID-19 has been associated with elevated levels of von Willebrand factor (vWF), a critical protein involved in platelet adhesion, while the enzyme responsible for breaking down vWF, ADAMTS-13, is downregulated. The resulting imbalance between vWF and ADAMTS-13 contributes to the development of thrombotic events in COVID-19 patients.

This endothelial dysfunction, combined with microvascular thrombosis, is particularly damaging to the lungs, which are often the first organs affected by COVID-19. The pulmonary vasculature becomes inflamed and thrombosed, contributing to acute respiratory distress syndrome (ARDS) and the high mortality seen in severe COVID-19 cases. Thrombotic events, such as venous thromboembolism, myocardial infarction, and stroke, have also been reported at higher rates in patients with severe COVID-19, particularly those with preexisting vascular conditions like hypertension, diabetes, and coronary artery disease.

Thrombotic Complications in Children and Adolescents

While thrombotic complications related to COVID-19 have been well-documented in adults, the situation in children and adolescents is less clear. Children generally experience milder forms of COVID-19, but some have developed a severe postinfectious complication known as multisystem inflammatory syndrome in children (MIS-C). This syndrome, which appears weeks after SARS-CoV-2 infection, is characterized by hyperinflammation, cardiovascular shock, and Kawasaki disease-like symptoms. Importantly, MIS-C has also been linked to coagulopathy, with evidence suggesting that the underlying pathology may involve vascular dysfunction.

Since the emergence of MIS-C in April 2020, previously healthy children have presented with fever, cardiovascular collapse, and multisystem involvement following SARS-CoV-2 infection. Many of these children tested negative for the virus at the time of presentation but had positive antibody titers, indicating a past infection. The CDC and WHO quickly recognized MIS-C as a serious post-COVID complication, and it has since been included in public health advisories. Given the connection between MIS-C and coagulopathy, understanding how COVID-19 triggers vascular dysfunction in children remains an important area of ongoing research.

Management of Coagulation and Thrombotic Disorders in COVID-19 Patients

Managing coagulation disorders in patients with COVID-19 requires a careful balance between preventing thrombosis and minimizing the risk of bleeding. Immobile patients with severe COVID-19 and those with pronounced inflammatory responses are at particularly high risk of venous thromboembolism (VTE), a leading cause of morbidity and mortality in hospitalized patients. Preventive measures, including both pharmaceutical and mechanical interventions, are essential for reducing the risk of thrombotic events.

Pharmaceutical thromboprophylaxis with low-molecular-weight heparin (LMWH) has been widely used in hospitalized COVID-19 patients. Early in the pandemic, there was significant debate over the appropriate dosing of anticoagulants, with some advocating for empirical therapeutic-dose anticoagulation or intermediate-dose anticoagulation in severe cases. However, recent evidence suggests that a more individualized approach is warranted, particularly given the risk of bleeding in patients with DIC or other coagulopathies.

Heparin, a cornerstone of thromboprophylaxis in COVID-19, may be administered in therapeutic doses to patients with confirmed thromboembolic events, while prophylactic doses are sufficient to prevent VTE in most patients. In patients with renal failure, unfractionated heparin infusion may be preferred, and monitoring anti-factor Xa levels can help guide dosing. Alternatives, such as fondaparinux, argatroban, or bivalirudin, may be considered in patients with heparin-induced thrombocytopenia.

The growing recognition of bleeding complications in COVID-19 patients has led to increased caution in the use of anticoagulants. Clinicians are now encouraged to carefully assess the risk-benefit ratio of anticoagulation therapy in each patient, with particular attention paid to those with DIC or other bleeding tendencies.

Thrombotic and Bleeding Events Following COVID-19 Vaccination: Hypotheses for Pathogenesis and Therapeutic Interventions

With the introduction and widespread administration of COVID-19 vaccines, a significant reduction in hospitalizations and severe disease outcomes has been achieved. However, with the advent of mass vaccination campaigns, several cases of vaccine-induced thrombotic complications have emerged, particularly following the use of adenoviral vector vaccines such as ChAdOx1 nCoV-19 (AstraZeneca) and Ad26.COV2.S (Johnson & Johnson/Janssen). These cases raised concerns about the potential for thrombotic and bleeding events following immunization, particularly given the rare but serious complications that occurred in some vaccine recipients.

Early reports of vaccine-induced thrombotic thrombocytopenia (VITT) or thrombosis with thrombocytopenia syndrome (TTS) described patients who developed a combination of thrombosis and thrombocytopenia within days or weeks of receiving their COVID-19 vaccine. These cases primarily involved unusual venous thrombotic events, such as cerebral venous sinus thrombosis (CVST) and splanchnic vein thrombosis, often accompanied by low platelet counts. VITT was later identified as an immune-mediated disorder in which platelet-activating antibodies, specifically those targeting platelet factor 4 (PF4), trigger widespread clotting in the veins, similar to autoimmune heparin-induced thrombocytopenia (HIT).

Pathogenesis of VITT: Platelet Factor 4 and Vaccine-Induced Immune Response

The underlying pathogenesis of VITT is thought to involve an immune response in which vaccine components, particularly in adenoviral vector vaccines, activate the immune system and lead to the production of antibodies against PF4. These PF4-antibody complexes then activate platelets, resulting in their aggregation and the formation of blood clots. The process bears significant similarities to HIT, where antibodies also target PF4-heparin complexes, leading to thrombosis.

Studies have confirmed that these vaccine-induced antibodies are predominantly of the IgG subtype and that they interact with Fcγ receptors on platelets, further propagating the thrombotic response. Interestingly, while both adenoviral vector and mRNA vaccines have been associated with thrombotic events, the incidence of VITT appears much higher following adenoviral vector vaccination. It has been suggested that the viral vector may play a direct role in stimulating the immune response against PF4, though this remains an area of ongoing investigation.

The timeline for the development of VITT is typically within 4 to 42 days following vaccination. Patients with suspected VITT often present with symptoms such as severe headache (indicating CVST), abdominal pain (suggesting splanchnic vein thrombosis), or shortness of breath. Thrombocytopenia is a hallmark feature, along with elevated D-dimer levels and low fibrinogen levels, further supporting a diagnosis of VITT. Prompt recognition of these signs is critical for initiating appropriate treatment and preventing severe complications or death.

Therapeutic Interventions for VITT

Managing VITT requires a delicate balance between addressing the thrombotic events and avoiding exacerbating the thrombocytopenia. The cornerstone of VITT treatment involves the use of non-heparin anticoagulants to prevent further clot formation, as heparin could theoretically worsen the condition by increasing the activation of platelets through PF4-heparin complexes. Alternatives such as direct thrombin inhibitors (e.g., argatroban) or factor Xa inhibitors (e.g., fondaparinux) are recommended in place of heparin.

In addition to anticoagulation, intravenous immunoglobulins (IVIG) have been used to block the Fcγ receptor-mediated activation of platelets by anti-PF4 antibodies. The administration of high-dose IVIG can effectively disrupt this pro-thrombotic mechanism and has been shown to improve platelet counts and reduce clot formation in VITT patients. Corticosteroids may also be considered to modulate the immune response, though their use should be tailored to the individual patient’s condition.

Epidemiology of VITT and Thrombotic Events

Although VITT is a serious complication, it remains extremely rare. By September 2021, over 400 cases had been reported in the UK, with most occurring after the first dose of the AstraZeneca vaccine. The overall mortality rate was reported to be around 35.9%, with higher rates observed in patients who developed intracerebral hemorrhage (ICH) or cerebral venous sinus thrombosis (CVST). Younger individuals, particularly women under the age of 60, appear to be at greater risk of developing VITT, though cases have been observed across a wide demographic spectrum.

The risk of VITT after adenoviral vector vaccination has prompted changes in vaccine recommendations in several countries. In some regions, adenoviral vector vaccines are now recommended primarily for older populations, who appear to be at lower risk for VITT, while mRNA vaccines are recommended for younger individuals. Nevertheless, the overall benefit-risk profile of COVID-19 vaccines remains overwhelmingly positive, with the risk of severe complications from COVID-19 infection far outweighing the risk of vaccine-induced thrombosis.

While VITT has been most commonly associated with adenoviral vector vaccines, cases of thrombosis have also been reported following mRNA vaccination. These cases, however, tend to occur without the accompanying thrombocytopenia that defines VITT. For example, cerebral thrombosis has been reported following both Pfizer-BioNTech and Moderna vaccines, though the incidence is much lower than that seen with adenoviral vector vaccines. In these cases, the thrombotic events are thought to arise from a more generalized hypercoagulable state induced by the immune response to the vaccine, rather than a specific immune reaction targeting platelets.

Cerebral Venous Sinus Thrombosis (CVST) and Other Thrombotic Complications

Cerebral venous sinus thrombosis (CVST) is one of the most severe thrombotic complications reported following COVID-19 vaccination, particularly in the context of VITT. CVST occurs when a clot forms in the venous sinuses of the brain, leading to increased intracranial pressure and, in severe cases, hemorrhage. The incidence of CVST in the general population is estimated at around 2 cases per 100,000 people per year, but this rate increases significantly in the context of VITT, particularly among younger women.

The European Medicines Agency (EMA) has reported that nearly 88% of CVST cases following vaccination occurred after receiving the AstraZeneca vaccine, with the remainder occurring after mRNA vaccines such as Pfizer-BioNTech and Moderna. The temporary suspension of the Johnson & Johnson vaccine in the United States in April 2021 was also related to concerns about CVST, following the identification of several cases in vaccinated individuals.

Thrombocytopenia and Vaccine-Related Thrombotic Events

In addition to thrombotic complications, thrombocytopenia (low platelet count) has been reported in vaccine recipients. While the exact mechanism behind vaccine-induced thrombocytopenia is still under investigation, it is thought to result from an immune-mediated process in which the vaccine triggers the production of antibodies that attack platelets or interfere with their production.

In the UK, 60 cases of thrombocytopenia were reported following the AstraZeneca vaccine, and 34 cases were reported following the Pfizer-BioNTech vaccine. In the United States, the Vaccine Adverse Event Reporting System (VAERS) documented nearly 200 cases of thrombocytopenia following the administration of both mRNA and adenoviral vector vaccines. It is important to note that most cases of vaccine-induced thrombocytopenia are mild and resolve without serious complications.

Arterial Thrombotic Events Post-Vaccination

While much of the focus on post-vaccination thrombotic events has been on venous thromboses, there have also been reports of arterial thrombotic events following COVID-19 vaccination. Strokes, myocardial infarctions, and retinal artery occlusions have been observed in some vaccine recipients. One case report described a young, healthy patient who experienced a stroke after receiving the AstraZeneca vaccine, with laboratory findings showing the presence of anti-PF4 antibodies, suggesting a mechanism similar to VITT. Another case involved a patient with retinal artery occlusion following mRNA vaccination, further highlighting the potential for hypercoagulability as a contributing factor to arterial thrombosis.

Managing Thrombotic Risks and Optimizing Vaccine Safety

The identification of these thrombotic and bleeding events following COVID-19 vaccination has led to increased scrutiny of the underlying mechanisms and the development of strategies to mitigate the risks. For individuals at higher risk of thrombosis, such as those with a history of clotting disorders, healthcare providers may recommend delaying vaccination until the underlying condition is well-controlled or opting for an alternative vaccine platform.

Ultimately, while these adverse events are rare, they underscore the importance of careful monitoring and long-term surveillance in vaccine recipients. Continued research into the pathogenesis of VITT and other thrombotic events will be essential for improving vaccine safety and ensuring that future vaccines are developed with a focus on minimizing these rare but serious complications.

Diagnostics of Coagulopathies Following COVID-19 Vaccination through Imaging

Radiology has emerged as an essential tool in diagnosing vascular complications, including those associated with coagulopathies following COVID-19 vaccination. Imaging techniques are classified into two primary categories: those that use ionizing radiation, such as computed tomography (CT), and those that do not, such as ultrasound and magnetic resonance imaging (MRI) [162].

Ultrasound technology has seen significant advancements in recent years and has become a frontline method for diagnosing vascular diseases due to its safety, accessibility, and affordability. Ultrasound provides excellent imaging for diagnosing conditions affecting large blood vessels, peripheral vessels, and even vessels in the brain. Furthermore, advancements like Fused Ultrasound, which combines real-time ultrasound imaging with data from previously conducted CT or MRI scans, have expanded its diagnostic capabilities for conditions such as prostate, liver, and breast diseases, as well as various neurological conditions [163].

CT imaging, particularly CT angiography (CTA) and CT venography (CTV), has become the gold standard for diagnosing many vascular conditions, including stenoses, thrombosis, aneurysms, and dissections. The introduction of multidetector computed tomography and dual-energy CT (DECT) has revolutionized the field, offering non-invasive, accurate, and quick diagnostics, especially in emergency situations. For example, CT coronary angiography has increasingly replaced classical coronary angiography as a non-invasive diagnostic tool for coronary vessel diseases [164]. Importantly, CT has proven invaluable in detecting early complications in anticoagulated COVID-19 patients, such as retroperitoneal and abdominal bleeding, which emphasizes its critical role in managing such cases [166].

MRI, another non-invasive imaging tool, is particularly useful for diagnosing blood vessel abnormalities without the need for contrast agents, making it a preferable choice for patients with renal impairments. MRI can also be enhanced with magnetic resonance angiography (MRA) and magnetic resonance venography (MRV) using contrast agents that are safer for patients with moderate kidney dysfunction. However, MRI’s limitations include its high cost, longer examination times, and incompatibility with certain metal implants and pacemakers. Additionally, MRI is not typically used in emergency settings due to these limitations [167].

The importance of imaging in diagnosing rare coagulopathies, especially in the context of COVID-19 vaccination, cannot be overstated. Imaging plays a crucial role in identifying multiorgan complications and contributes significantly to early detection and appropriate treatment, even in rare post-vaccination complications [168,169].

Global Benefit/Risk Ratio of the Various Vaccination Types for Bleeding or Thrombotic Complications

Despite documented cases of bleeding or thrombotic complications following COVID-19 vaccination, the overall benefit/risk ratio remains heavily in favor of vaccination, as confirmed by the European Medicines Agency (EMA). The safety of vaccines has been consistently supported by data showing that while rare complications like menstrual irregularities, including heavy bleeding, have been observed, these cases were mostly non-serious and transient [170,171].

Nevertheless, there remain limitations in the current literature. For instance, while this review covers hereditary and acquired coagulation disorders, not all disorders were analyzed in detail due to limited data linking rare blood conditions to COVID-19 or its vaccines. Moreover, the current data on booster doses and their impact on coagulation-related adverse events are still scarce, leaving questions about the long-term risk profile of repeated vaccinations [172].

Despite these limitations, the review has offered a comprehensive look at both hereditary and acquired coagulation disorders in the context of COVID-19 vaccination. A key takeaway is that no definitive causal link has been established between vaccines and these adverse effects, despite hypotheses about immunological mechanisms, such as the production of autoantibodies following vaccination. If such a mechanism exists, one would expect subsequent doses to trigger immediate adverse reactions in patients with a previously activated abnormal immune response. However, clinical evidence has not supported this hypothesis, and real-world data indicate that the vast majority of patients tolerate subsequent vaccine doses without issue [85].

The evidence continues to show that the efficacy of COVID-19 vaccines in preventing morbidity, complications, and mortality far outweighs the risks associated with rare coagulation disorders. The pharmacovigilance data suggest a statistical correlation rather than a direct causal link between vaccination and these adverse events [173,174,175]. Additionally, the risk of thrombotic events is extraordinarily low, ranging from 1 in 100,000 to 1 in 1,000,000 vaccinated individuals [107,146,181,182].

Acquired hemophilia, another rare but serious condition, also does not appear to be significantly more prevalent in post-vaccination cases compared to its baseline occurrence of 1.5 per million people, making it difficult to assess the precise risk associated with vaccination [185,186].

Leading experts recommend against unnecessary preemptive measures like low molecular weight heparin, direct oral anticoagulants, or aspirin in the absence of clear clinical indicators of thrombophilia. Additionally, routine monitoring for D-dimer changes or venous echo-Doppler examinations post-vaccination is not recommended unless specific risk factors are identified [187].

Although previous infections with SARS-CoV-2 or other viruses may influence the risk of thrombotic events after vaccination, continuous surveillance and further research are needed to fully understand these interactions. This is particularly important for immunocompromised patients or those with preexisting conditions, who may require tailored vaccination strategies [188].

Medical Concept	Simplified Explanation	Details/Examples
Coagulopathy	A condition where the blood does not clot properly, leading to excessive bleeding or clotting.	Coagulopathies can be inherited (present from birth) or acquired (developed later due to other factors like disease).
Hemophilia A and B	Genetic disorders where the blood lacks essential clotting factors, causing easy bleeding.	Hemophilia A is caused by low levels of factor VIII, while Hemophilia B (Christmas disease) is caused by low levels of factor IX. Both conditions primarily affect men.
Von Willebrand’s Disease	A genetic disorder causing problems with blood clotting due to a deficiency of a specific protein.	Patients may experience spontaneous bleeding from mucous membranes, excessive bleeding after injuries, and increased risk during surgery or dental work.
Thrombophilia	A condition where the blood has an increased tendency to form clots.	It can be caused by genetic factors like the Factor V Leiden mutation or conditions like Protein C and S deficiency.
COVID-19 and Blood Clots	COVID-19 can cause blood to clot abnormally, leading to serious complications.	In severe COVID-19 cases, patients can experience increased clotting (thrombosis), which can lead to strokes, heart attacks, or deep vein thrombosis (DVT).
Vaccine-Induced Thrombotic Thrombocytopenia (VITT)	A rare but serious condition where blood clots form after receiving certain COVID-19 vaccines.	VITT typically involves low platelet counts and blood clots in unusual places like the brain (cerebral venous sinus thrombosis) or abdomen.
Platelet Factor 4 (PF4)	A protein involved in blood clotting. In some rare cases, vaccines can cause the immune system to attack PF4, leading to blood clots.	PF4 antibodies are responsible for triggering conditions like VITT and HIT (heparin-induced thrombocytopenia), where clots form due to immune system reactions.
Heparin-Induced Thrombocytopenia (HIT)	A condition where the body reacts abnormally to the blood thinner heparin, causing clots.	Similar to VITT, but triggered by heparin, a common blood thinner used in hospitals. It can lead to serious clotting problems.
Disseminated Intravascular Coagulation (DIC)	A serious condition where blood clots form throughout the body, using up all the clotting factors and causing severe bleeding.	DIC can occur in severe infections, trauma, or certain cancers and can result in both excessive clotting and dangerous bleeding.
Thrombocytopenia	A condition where there are fewer platelets in the blood than normal, leading to bleeding issues.	Platelets help with clotting. If there aren’t enough, a person can bruise easily, experience prolonged bleeding, or have blood clot complications, as seen in VITT.
Computed Tomography (CT) Angiography (CTA)	A non-invasive imaging test that helps visualize blood vessels using X-rays and a special dye.	CTA is used to diagnose conditions like blood vessel blockages, aneurysms, and blood clots. It is commonly used in emergencies for fast diagnosis.
Magnetic Resonance Imaging (MRI)	A non-invasive imaging method that uses magnetic fields to produce detailed images of the body.	MRI is especially useful in cases where contrast dye (used in CT scans) cannot be given due to kidney issues. It is used to examine soft tissues, including blood vessels.
Ultrasound Imaging	A non-invasive test that uses sound waves to produce images of internal organs and blood vessels.	Commonly used to detect issues with blood flow, blockages, or clots, especially in large vessels like the carotid artery or in pregnancy-related complications.
Global Benefit/Risk Ratio of Vaccines	A measure comparing the benefits of vaccines (like preventing COVID-19) to the risks of rare side effects (like clotting).	Even though rare side effects like VITT exist, the benefits of vaccination in preventing severe COVID-19 far outweigh the risks, which occur in extremely low numbers.
Menstrual Bleeding and Vaccines	Some women reported heavier menstrual bleeding after getting vaccinated for COVID-19.	These cases are generally temporary and not serious, with no long-term health risks identified.
Intravenous Immunoglobulin (IVIG) Therapy	A treatment used to manage conditions where the immune system attacks the body, such as VITT.	IVIG helps to stop the immune system from attacking platelets and causing dangerous blood clots. It’s also used in other immune-related conditions.

This table provides a simplified and comprehensive overview of key medical concepts related to coagulopathies, COVID-19, and the diagnostic methods used to detect these conditions.

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APPENDIX – 1 : The Vaccine Adverse Event Reporting System (VAERS), managed by the Centers for Disease Control and Prevention (CDC) and the Food and Drug Administration (FDA), is a national early warning system that monitors adverse effects following vaccination. In recent years, there have been increasing reports of retinal vascular occlusions potentially associated with the administration of COVID-19 vaccines, particularly those using mRNA technology, such as the Moderna (mRNA-1273) and Pfizer-BioNTech vaccines.

This research explores the occurrence of retinal vascular occlusions reported in the VAERS database. The example of a 45-year-old male patient who developed simultaneous CRVO, incomplete CRAO, and papillitis after receiving the Spikevax (Moderna) vaccine is a notable case that highlights the importance of investigating these potential vaccine-related adverse events. This research uses data extracted from VAERS through CDC WONDER to analyze trends in retinal vascular occlusions reported in relation to COVID-19 vaccinations.

Research on Retinal Vascular Occlusions in VAERS

The Vaccine Adverse Event Reporting System (VAERS) is a critical tool for monitoring the safety of vaccines in the United States. Data in VAERS, available through the CDC’s Wide-ranging Online Data for Epidemiologic Research (WONDER) system, are updated monthly, meaning results for the same query may change as new reports are added. For this study, the VAERS database was queried to identify reports of retinal vascular occlusions, including CRVO and CRAO, following COVID-19 vaccination.

According to the most recent query results, there were 326 total events related to retinal vascular occlusions reported in VAERS following the administration of various COVID-19 vaccines. The breakdown of these events is crucial for understanding the potential risks and for identifying trends or patterns that may be associated with specific vaccine types or patient demographics.

VAERS ID Code	Adverse
0913010-1	No prior vaccinations for this event.
0944507-1	No prior vaccinations for this event.
0963061-1	No prior vaccinations for this event.
0968972-1	No prior vaccinations for this event.
0990361-1	No prior vaccinations for this event.
1034014-1	No prior vaccinations for this event.
1036362-1	No prior vaccinations for this event.
1051980-1	No prior vaccinations for this event.
1086875-1	No prior vaccinations for this event.
1148707-1	No prior vaccinations for this event.
1148710-1	No prior vaccinations for this event.
1148729-1	No prior vaccinations for this event.
1153608-1	No prior vaccinations for this event.
1175398-1	No prior vaccinations for this event.
1189618-1	No prior vaccinations for this event.
1207947-1	No prior vaccinations for this event.
1209054-1	No prior vaccinations for this event.
1210443-1	No prior vaccinations for this event.
1214350-1	No prior vaccinations for this event.
1214909-1	No prior vaccinations for this event.
1214912-1	No prior vaccinations for this event.
1219785-1	No prior vaccinations for this event.
1221387-1	No prior vaccinations for this event.
1223204-1	A rash on the left arm one week after first dose of the COVID19 Moderna Vaccine
1231047-1	No prior vaccinations for this event.
1237051-1	No prior vaccinations for this event.
1245402-1	No prior vaccinations for this event.
1259187-1	No prior vaccinations for this event.
1271478-1	No prior vaccinations for this event.
1276711-1	No prior vaccinations for this event.
1280764-1	Pneumacocis
1281524-1	No prior vaccinations for this event.
1282292-1	No prior vaccinations for this event.
1290769-1	No prior vaccinations for this event.
1292743-1	No prior vaccinations for this event.
1293260-1	No prior vaccinations for this event.
1311279-1	No prior vaccinations for this event.
1312890-1	No prior vaccinations for this event.
1323370-1	No prior vaccinations for this event.
1327975-1	No prior vaccinations for this event.
1329167-1	No prior vaccinations for this event.
1329756-1	No prior vaccinations for this event.
1330938-1	No prior vaccinations for this event.
1334854-1	No prior vaccinations for this event.
1342243-1	No prior vaccinations for this event.
1345804-1	No prior vaccinations for this event.
1347222-1	No prior vaccinations for this event.
1353794-1	No prior vaccinations for this event.
1354016-1	No prior vaccinations for this event.
1357817-1	Moderna; pt reported having shingles after 1st Moderna dose; unable to corroborate details.
1359309-1	No prior vaccinations for this event.
1359893-1	No prior vaccinations for this event.
1364014-1	No prior vaccinations for this event.
1366884-1	No prior vaccinations for this event.
1373296-1	No prior vaccinations for this event.
1386314-1	No prior vaccinations for this event.
1391399-1	No prior vaccinations for this event.
1399328-1	No prior vaccinations for this event.
1410919-1	No prior vaccinations for this event.
1417144-1	No prior vaccinations for this event.
1427821-1	No prior vaccinations for this event.
1430197-1	No prior vaccinations for this event.
1445755-1	No prior vaccinations for this event.
1449719-1	No prior vaccinations for this event.
1449908-1	No prior vaccinations for this event.
1450170-1	No prior vaccinations for this event.
1461999-1	No prior vaccinations for this event.
1464066-1	No prior vaccinations for this event.
1465386-1	No prior vaccinations for this event.
1474281-1	No prior vaccinations for this event.
1492889-1	No prior vaccinations for this event.
1493676-1	No prior vaccinations for this event.
1498379-1	No prior vaccinations for this event.
1498869-1	No prior vaccinations for this event.
1500846-1	No prior vaccinations for this event.
1509187-1	No prior vaccinations for this event.
1510022-1	No prior vaccinations for this event.
1511597-1	No prior vaccinations for this event.
1512841-1	No prior vaccinations for this event.
1519734-1	No prior vaccinations for this event.
1522614-1	No prior vaccinations for this event.
1523677-1	No prior vaccinations for this event.
1542549-1	No prior vaccinations for this event.
1548596-1	No prior vaccinations for this event.
1549396-1	No prior vaccinations for this event.
1550475-1	No prior vaccinations for this event.
1551447-1	No prior vaccinations for this event.
1552411-1	No prior vaccinations for this event.
1555369-1	No prior vaccinations for this event.
1569046-1	No prior vaccinations for this event.
1569565-1	No prior vaccinations for this event.
1573777-1	No prior vaccinations for this event.
1587485-1	No prior vaccinations for this event.
1599389-1	No prior vaccinations for this event.
1605490-1	No prior vaccinations for this event.
1613228-1	No prior vaccinations for this event.
1622026-1	No prior vaccinations for this event.
1623220-1	No prior vaccinations for this event.
1628407-1	No prior vaccinations for this event.
1628571-1	No prior vaccinations for this event.
1633975-1	No prior vaccinations for this event.
1635265-1	No prior vaccinations for this event.
1640558-1	No prior vaccinations for this event.
1644754-1	No prior vaccinations for this event.
1644971-1	No prior vaccinations for this event.
1645028-1	No prior vaccinations for this event.
1665146-1	No prior vaccinations for this event.
1665182-1	No prior vaccinations for this event.
1666172-1	No prior vaccinations for this event.
1666343-1	No prior vaccinations for this event.
1672278-1	No prior vaccinations for this event.
1673080-1	No prior vaccinations for this event.
1673101-1	No prior vaccinations for this event.
1675664-1	No prior vaccinations for this event.
1681292-1	No prior vaccinations for this event.
1685469-1	No prior vaccinations for this event.
1685670-1	No prior vaccinations for this event.
1688742-1	No prior vaccinations for this event.
1691457-1	No prior vaccinations for this event.
1691908-1	No prior vaccinations for this event.
1695853-1	No prior vaccinations for this event.
1697217-1	No prior vaccinations for this event.
1702233-1	No prior vaccinations for this event.
1702260-1	No prior vaccinations for this event.
1730956-1	No prior vaccinations for this event.
1731090-1	No prior vaccinations for this event.
1731113-1	No prior vaccinations for this event.
1733305-1	No prior vaccinations for this event.
1747209-1	No prior vaccinations for this event.
1751816-1	No prior vaccinations for this event.
1756560-1	No prior vaccinations for this event.
1762220-1	No prior vaccinations for this event.
1766951-1	No prior vaccinations for this event.
1767687-1	No prior vaccinations for this event.
1771668-1	No prior vaccinations for this event.
1782707-1	No prior vaccinations for this event.
1839550-1	No prior vaccinations for this event.
1842563-1	No prior vaccinations for this event.
1845563-1	No prior vaccinations for this event.
1845725-1	No prior vaccinations for this event.
1850532-1	No prior vaccinations for this event.
1853082-1	No prior vaccinations for this event.
1853161-1	No prior vaccinations for this event.
1854662-1	No prior vaccinations for this event.
1856638-1	No prior vaccinations for this event.
1856660-1	No prior vaccinations for this event.
1858388-1	COVID-19 (2nd dose)- aches and chills (2/4/2021)
1879856-1	No prior vaccinations for this event.
1889078-1	No prior vaccinations for this event.
1891057-1	No prior vaccinations for this event.
1893865-1	No prior vaccinations for this event.
1897498-1	No prior vaccinations for this event.
1912889-1	No prior vaccinations for this event.
1917636-1	No prior vaccinations for this event.
1919149-1	No prior vaccinations for this event.
1920629-1	No prior vaccinations for this event.
1929074-1	redness, itching, swelling
1936046-1	No prior vaccinations for this event.
1939815-1	No prior vaccinations for this event.
1943163-1	No prior vaccinations for this event.
1944068-1	Adverse reaction to Moderna Injection shot 1. 12.31.2020, age 53, Moderna, Injected Left Arm.    Swelling, fever, chills, muscle
1947269-1	No prior vaccinations for this event.
1950369-1	No prior vaccinations for this event.
1955176-1	No prior vaccinations for this event.
1958228-1	No prior vaccinations for this event.
1964055-1	No prior vaccinations for this event.
1967450-1	No prior vaccinations for this event.
1974029-1	No prior vaccinations for this event.
1978634-1	No prior vaccinations for this event.
1991870-1	No prior vaccinations for this event.
1993228-1	No prior vaccinations for this event.
2002404-1	No prior vaccinations for this event.
2013793-1	No prior vaccinations for this event.
2020373-1	No prior vaccinations for this event.
2022073-1	No prior vaccinations for this event.
2034801-1	No prior vaccinations for this event.
2038297-1	No prior vaccinations for this event.
2043253-1	Negative reaction to shingles vaccine, Shingrix. Swollen lymph nodes for a week. Tired, low-grade fever and no appetite the firs
2050554-1	No prior vaccinations for this event.
2076031-1	No prior vaccinations for this event.
2091790-1	No prior vaccinations for this event.
2091919-1	No prior vaccinations for this event.
2104385-1	No prior vaccinations for this event.
2112411-1	No prior vaccinations for this event.
2112522-1	No prior vaccinations for this event.
2112534-1	No prior vaccinations for this event.
2116350-1	No prior vaccinations for this event.
2132265-1	No prior vaccinations for this event.
2139518-1	No prior vaccinations for this event.
2168679-1	No prior vaccinations for this event.
2188866-1	No prior vaccinations for this event.
2191206-1	No prior vaccinations for this event.
2201232-1	No prior vaccinations for this event.
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2227028-1	No prior vaccinations for this event.
2232762-1	No prior vaccinations for this event.
2248358-1	No prior vaccinations for this event.
2251393-1	No prior vaccinations for this event.
2252253-1	No prior vaccinations for this event.
2259027-1	No prior vaccinations for this event.
2259644-1	No prior vaccinations for this event.
2259645-1	No prior vaccinations for this event.
2261963-1	No prior vaccinations for this event.
2263101-1	No prior vaccinations for this event.
2263216-1	No prior vaccinations for this event.
2263769-1	No prior vaccinations for this event.
2265659-1	No prior vaccinations for this event.
2265822-1	No prior vaccinations for this event.
2271329-1	Flu Vaccine 2010
2276813-1	No prior vaccinations for this event.
2279537-1	No prior vaccinations for this event.
2283434-1	No prior vaccinations for this event.
2286849-1	No prior vaccinations for this event.
2293662-1	No prior vaccinations for this event.
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2304289-1	No prior vaccinations for this event.
2315904-1	No prior vaccinations for this event.
2318156-1	No prior vaccinations for this event.
2353248-1	No prior vaccinations for this event.
2362836-1	No prior vaccinations for this event.
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2366566-1	No prior vaccinations for this event.
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2453216-1	No prior vaccinations for this event.
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2461888-1	No prior vaccinations for this event.
2464576-1	No prior vaccinations for this event.
2470816-1	Vision problems in left eye: Sudden onset of eye floaters and flashing light on 11/15/2021 after receiving Moderna dose #3 on 11
2480573-1	The first COVID vaccine her arm killed her for about a week which she felt was normal.  The 2nd Moderna vaccine she was in bed f
2480734-1	No prior vaccinations for this event.
2481539-1	No prior vaccinations for this event.
2481743-1	38 years old
2489413-1	No prior vaccinations for this event.
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2666906-1	No prior vaccinations for this event.
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2683452-1	No prior vaccinations for this event.
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2698144-1	No prior vaccinations for this event.
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2743640-1	No prior vaccinations for this event.
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2753929-1	No prior vaccinations for this event.
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2774989-1	No prior vaccinations for this event.
2778988-1	No prior vaccinations for this event.
2781192-1	No prior vaccinations for this event.

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References:

1. Wong TY, et al. Retinal vein occlusion: epidemiology, pathogenesis, and management. JAMA Ophthalmology.
2. Naranjo MJ, et al. COVID-19 and vascular complications: a review.
3. American Academy of Ophthalmology, Retinal Vascular Occlusions in COVID-19 Patients.
4. https://www.nature.com/articles/s41541-023-00661-7
5. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10604891/

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