A massive US-based study involving tens of thousands of military veterans has concluded there is a negligible risk of developing a blood clot as a result of a COVID-19 vaccine.

While the results might do little to convince many anti-vaccine advocates of the relative safety of vaccinations, it will hopefully reinforce confidence in communities that vaccines are far safer than the disease they're intended to prevent, which is known to elevate risks of developing a venous thromboembolism (VTE).

"This population-based study found only a trivial risk for VTE following COVID-19 vaccination," says Peter L. Elkin, MD, first author on the paper as well as professor and chair of the Department of Biomedical Informatics at the University of Buffalo.

"Given the large risk of VTE from COVID-19 infection, the risk-benefit ratio strongly favored vaccination," Elkin says.

That has been the general consensus among experts all along, and fortunately it has resonated in much of the world, with 9.23 billion doses of COVID-19 vaccines administered globally so far.

Negligible clearly doesn't mean the risk is zero. Yet any chance of getting blood clots is several orders of magnitude higher if you are unvaccinated and infected by SARS-CoV-2, an outcome that is incredibly likely in an unvaccinated population with minimal safety measures in place.

Vaccines are widely credited with helping blunt the ongoing COVID-19 pandemic, saving countless lives in the process, and there is abundant evidence of their safety and efficacy.

Yet they have drawn suspicion from anti-vaccine advocates, many of whom point to news that emerged in 2021 about a possible link between COVID-19 vaccines and blood clots.

That concern has lingered, despite scant evidence of a significant risk from vaccines, and its prevalence on social media and other public forums does suggest more clarity might help.

"There was concern by some that COVID-19 vaccination might cause undue harm and VTE was one of the mechanisms implicated by anti-vaxxers," Elkin says. "We wanted to know the truth."

To do that, Elkin and his colleagues studied data from 855,686 people, all US military veterans at least 45 years old who had received at least one dose of a SARS-CoV-2 vaccine at least 60 days earlier.

The control group included 321,676 people, also all US veterans in the same age range, but who were still unvaccinated.

The data came from the US Department of Veterans Affairs National Surveillance Tool, and covered a time period from January 1, 2020 – which was just before the first known US case of COVID-19 – to March 6, 2022.

The researchers accounted for a range of known VTE risk factors, including age, race, sex, and body mass index, to help focus on any effect from vaccines.

Vaccinated subjects had a VTE rate of 1.3755 per 1,000 people, the study found, which is 0.1 percent higher than the baseline VTE rate of 1.3741 per 1,000 among unvaccinated people.

"The excess risk was about 1.4 cases per million patients vaccinated," Elkin says. "Given the fact that the rate of VTE with COVID-19 is several orders of magnitude greater than the trivial risk from vaccination, our study reinforces the safety and importance of staying current with COVID-19 vaccinations."

The minimally higher risk might stem from vaccine-induced immune thrombotic thrombocytopenia (VITT), the researchers note, an immune response that alters the quantity and quality of platelets, potentially leading to VTE.

"VITT is now recognized as a rare complication of adenoviral vector-based SARS-CoV-2 vaccines," they write, referring to a category that includes the COVID-19 vaccines from Janssen (Johnson & Johnson) and AstraZeneca.

The study suggests this small risk increase applies both to adenoviral vector vaccines and mRNA vaccines, including those produced by Moderna and Pfizer. In either case, the researchers argue, the risk is "trivial."

The risk of VTE from an actual COVID-19 infection, on the other hand, is not.

VTE is a prominent consequence of COVID-19, the researchers note, occurring in about 8 percent of hospitalized patients and 23 percent of patients in the ICU.

Based on 28 days of data from 21 June 2021, these figures suggest at least 3,203 COVID-19-related excess VTE cases would have occurred out of the recorded 257,125 new COVID-19 cases during this time. But if all those people had been vaccinated, the expected number of excess VTE cases becomes less than one (0.36).

"This study shows the power of big data, where we can use electronic health record data in a rigorous way to answer questions that could never be properly answered with a randomized controlled trial, due to the small effect size and the need to recruit millions of patients to the trial," Elkin says.

"It's an example of how biomedical informatics is answering important clinical questions," he adds, "that can help people to recognize the benefit of COVID-19 vaccination and improve adherence to this approved clinical guideline."

The study was published in the Journal of Clinical and Translational Science.