A new study by researchers from the Gladstone Institutes and collaborators shows that the blood coagulation protein fibrin is the culprit that causes the unusual clotting and inflammation that are the primary symptoms of COVID-19. The discovery upends the prevailing view that blood clotting is a consequence of the inflammation from COVID-19 and instead shows it is the primary driver of the cascade of problems that are hallmarks of the infection including toxic inflammation, impaired viral clearance, and neurological symptoms.
Significantly, the findings, published in the journal Nature, identified a new antibody therapy to combat the range of symptoms associated with infection by the SARS-CoV-2 virus.
“Knowing that fibrin is the instigator of inflammation and neurological symptoms, we can build a new path forward for treating the disease at the root,” said Katerina Akassoglou, PhD, a senior investigator at Gladstone and the director of the Center for Neurovascular Brain Immunology at Gladstone and UC San Francisco. “In our experiments in mice, neutralizing blood toxicity with fibrin antibody therapy can protect the brain and body after COVID infection.”
It’s the fibrin, not cytokine storm
The Gladstone researchers had long been skeptical about the prevailing opinion of many scientists and clinicians who had hypothesized that it was the immune system’s rapid response—a cytokine storm—that led to blood clotting and stroke from COVID-19, even in patients that remained free of other symptoms.
“We know of many other viruses that unleash a similar cytokine storm in response to infection, but without causing blood clotting activity like we see with COVID,” said Warner Greene, MD, PhD, senior investigator and director emeritus at Gladstone, co-leader of the study with Akassoglou.
Instead, the Gladstone team surmised that perhaps it was the clotting itself that played a principal role, effectively using blood clotting for its own benefit, Akassoglou noted.
In multiple experiments with mice, the Gladstone team found that fibrin binds to the SARS-CoV-2 spike protein resulting in proinflammatory blood clots that drive systemic thromboinflammation and neuropathology. They also genetically engineered mice to have a specific mutation to block only the inflammatory properties of fibrin without interfering with its blood clotting properties.
Mice that were genetically altered, or those that had no fibrin in their bloodstream, either didn’t exhibit inflammation, oxidative stress, fibrosis, and clotting in the lungs, or showed symptoms that were significantly reduced.
While the discovery that fibrin is causative of inflammation was groundbreaking, another important finding of the study is that fibrin also suppresses the activity of natural killer (NK) cells whose function is to clear the virus from the body. When the team depleted fibrin in mice, the NK cells did their normal work and cleared the virus.
Effects on the brain
With fibrin positively identified as a driver of the body’s reaction to the SARS-CoV-2 virus, Akassoglou drew on her previous research by her lab into how fibrin that leaks into the brain can trigger neurological diseases like Alzheimer’s disease (AD) and multiple sclerosis (MS). Fibrin accomplishes this via its influence on the immune system to set off a series of harmful effects that are often irreversible.
Turning back to their lab mice, the team showed that fibrin was also responsible for the harmful activation of microglia, the brain’s immune cells that are involved in neurodegeneration. When they inhibited fibrin the toxic microglia in the brains of the mice was significantly lowered.
“Fibrin that leaks into the brain may be the culprit for COVID-19 and long COVID patients with neurologic symptoms, including brain fog and difficulty concentrating,” Akassoglou said. “Inhibiting fibrin protects neurons from harmful inflammation after COVID-19 infection.”
Monoclonal antibody treatment
Armed with the knowledge that fibrin both activates a form of chronic inflammation and suppresses NK cell response “we realized if we could neutralize both of these negative effects, we could potentially resolve the severe symptoms we’re seeing in patients with COVID-19 and possibly long COVID,” Greene noted.
In previous work, Akassoglou’s lab had developed monoclonal antibody that only affects fibrin’s inflammatory activity without adversely affecting its blood clotting properties. Earlier research had shown that this potential therapy protected mice from AD and MS.
Now, a humanized version of this monoclonal antibody is being tested in Phase I safety studies and if it clears that hurdle, will be moved into more advance clinical trials in people with COVID and long COVID.
