Discovery of how blood clots damage brain and body in COVID-19 points to new therapies

In a study that advances our understanding of COVID-19 and its most complex symptoms, scientists have found that the blood clotting protein fibrin causes the abnormal clots and inflammation that have become hallmarks of the disease, while also suppressing the body's ability to clear the virus.

Importantly, the team has also identified a new antibody therapy to combat all these harmful effects.

published in Nature, The study by the Gladstone Institute and collaborators overturns the prevailing theory that blood clotting is solely a result of inflammation in COVID-19.

Through experiments in the lab and on mice, researchers have shown that blood clotting is a primary effect that leads to other problems — including toxic inflammation, impaired viral clearance and neurological symptoms that are common in people with Covid-19 and long Covid.

The trigger is fibrin, a protein in the blood that normally enables healthy blood coagulation, but has already been shown to have toxic inflammatory effects. In the new study, scientists found that fibrin becomes even more toxic in COVID-19 because it binds to both the virus and immune cells, forming abnormal clots that lead to inflammation, fibrosis and loss of neurons.

“Knowing that fibrin is the catalyst for inflammation and neurological symptoms, we may be able to create a new route to treating the root cause of the disease,” says Katerina Akassoglou, Ph.D., senior investigator at Gladstone and director of the Center for Neurovascular Brain Immunology at Gladstone and UC San Francisco.

“In our experiments on mice, neutralizing blood toxicity with fibrin antibody therapy can protect the brain and body after COVID infection.”

From the early months of the pandemic, irregular blood clotting and strokes emerged as surprising effects of COVID-19, even in patients who were otherwise asymptomatic.

Later, when long Covid became a major public health issue, it became even more difficult to understand the cause of the disease's other symptoms, including its neurological effects. Since the start of the pandemic, more than 400 million people worldwide have suffered from long Covid, with an estimated economic cost of about $1 trillion each year.

Changing the direction of the conversation

Many scientists and medical professionals have speculated that inflammation caused by the immune system's rapid response to the COVID-causing virus causes blood clots and strokes. But even at the start of the pandemic in 2020, this explanation didn't seem right to Akassoglu and his scientific colleagues.

“We know of several other viruses that unleash a similar cytokine storm in response to infection, but do not produce the blood-clotting activity that we see with COVID,” says Gladstone senior investigator and director emeritus Warner Greene, M.D., Ph.D., who co-led the study with Akassoglou.

“We began to wonder whether blood clots play a major role in COVID — whether this virus has evolved in a way to control clot formation to its own advantage,” Akassoglu says.

Indeed, through a series of experiments on mice, the researchers found that the virus spike protein binds directly to fibrin, leading to structurally abnormal blood clots and increased inflammatory activity. The team leveraged genetic tools to create a specific mutation that inhibits only the inflammatory properties of fibrin without affecting the protein's beneficial blood-clotting abilities.

When mice were genetically altered to carry mutant fibrin or have no fibrin in their bloodstream, scientists found that inflammation, oxidative stress, fibrosis, and clotting in the lungs did not occur or were greatly reduced after COVID-19 infection.

In addition to finding that fibrin increases inflammation, the team made another important discovery: Fibrin also suppresses the body's “natural killer” or NK cells, which normally work to clear viruses from the body. Remarkably, when the scientists eliminated fibrin in the mice, the NK cells were able to clear the virus.

These findings support the view that fibrin is necessary for the virus to cause damage to the body.

Vaccines do not trigger mechanism

The fibrin mechanism described in the paper is not related to the extremely rare thrombotic complication involving low platelets that has been linked to adenoviral DNA COVID-19 vaccines, which are no longer available in the US.

In contrast, in a study of 99 million COVID-vaccinated individuals led by the Global COVID Vaccine Safety Project, vaccines that leverage mRNA technology to produce the spike protein in the body did not show excessive clotting or blood-based disorders that would meet the threshold for safety concerns. Instead, mRNA vaccines appear to protect against infection-induced clotting complications.

Protection of the brain

Akassoglu's lab has long investigated how fibrin that leaks into the brain leads to neurological diseases such as Alzheimer's disease and multiple sclerosis, primarily by having the brain's immune system take over, leading to a series of harmful, often irreversible, effects.

The team has now shown that in COVID-infected mice, fibrin is responsible for the harmful activation of microglia, which are immune cells in the brain involved in neurodegeneration. After infection, the scientists found fibrin associated with toxic microglia and when they blocked fibrin, the activation of these toxic cells in the brains of the mice was significantly reduced.

“Fibrin leaking into the brain may be responsible for neurological symptoms seen in patients with COVID-19 and long COVID, such as brain fog and difficulty concentrating,” says Akassoglu. “Preventing fibrin may protect neurons from harmful inflammation following a COVID-19 infection.”

The team tested their approach on different strains of the virus that causes COVID-19, including those that can infect the brain and those that cannot. Neutralizing fibrin was beneficial in both types of infections, pointing to a detrimental role for fibrin in the brain and body in COVID-19 and highlighting the broader implications of this study.

A new potential therapy

This study demonstrates that fibrin causes harm in at least two ways: by activating a chronic form of inflammation and by suppressing the beneficial NK cell response capable of clearing virus-infected cells.

“We felt that if we could neutralize both of these negative effects, we could potentially resolve the severe symptoms seen in patients with COVID-19 and possibly even long-haul COVID,” Green says.

Akassoglu's lab previously developed a drug, a therapeutic monoclonal antibody, that acts only on the inflammatory properties of fibrin without adversely affecting blood clotting and protected mice from multiple sclerosis and Alzheimer's disease.

In the new study, the team showed that the antibody blocked the interaction of fibrin with immune cells and the virus. By giving the immunotherapy to infected mice, the team was able to prevent and treat severe inflammation, reduce fibrosis and viral proteins in the lungs, and improve survival rates.

In the brain, fibrin antibody therapy reduced harmful inflammation and increased the survival of neurons in mice after infection.

The humanized version of Akassoglu's first-in-class fibrin-targeting immunotherapy is already in Phase I safety and tolerability clinical trials in healthy people by Therini Bio. The drug cannot be used on patients until it completes Phase I safety assessment, and will then need to be tested in more advanced trials for COVID-19 and Long COVID.

Given such tests, Akassoglu says patients could be selected based on the levels of fibrin products in their blood — a measure that is considered a biomarker predictive of cognitive impairment in long-haul Covid.

“Fibrin immunotherapy could be tested as part of a multipronged approach, alongside prevention and vaccination, to reduce adverse health outcomes from long-term COVID,” Green said.

The power of team science

The study’s findings bridge the scientific fields of immunology, hematology, virology, neuroscience and drug discovery — and required multiple laboratories across institutions to work together to perform the experiments needed to solve the blood clotting mystery.

Akassoglu founded the Neurovascular Brain Immunology Center at Gladstone and UCSF in 2021 specifically for the purpose of conducting multidisciplinary, collaborative studies addressing complex problems.

“I don’t think any one lab could have done this on its own,” says Melanie Ott, M.D., Ph.D., director of the Gladstone Institute of Virology and a co-author of the study. She noted the important contributions of teams at Stanford, UC San Francisco, UC San Diego, and UCLA. “This groundbreaking study highlights the importance of collaboration in tackling these big questions.”

Lennart Mucke, M.D., director of the Gladstone Institute of Neurological Diseases, says this study not only addressed a big question, but it did so in a way that paves a clear clinical path to help patients who have very few options today.

“The neurological symptoms of COVID-19 and Long COVID can affect every part of a person’s life, impairing cognitive function, memory, and even emotional health,” says Mucke. “This study presents a new strategy for treating these devastating effects and addressing the long-term disease burden of the SARS-CoV-2 virus.”