Study reveals the role of blood clotting in COVID-19

In a study that reshapes what we know about COVID-19 and its most baffling symptoms, scientists have discovered that the blood-clotting protein fibrin causes the unusual clotting and inflammation that have become hallmarks of the disease, while also inhibiting the ability of suppresses the body to clear the disease. virus.

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

Published in Nature, the research by Gladstone Institutes and collaborators debunks the prevailing theory that blood clotting is merely a consequence of inflammation in COVID-19. Through experiments in the laboratory and with mice, the researchers show that blood clotting is instead a primary effect that causes other problems; including toxic inflammation, reduced viral clearance and neurological symptoms common in people with COVID-19 and long COVID.

The trigger is fibrin, a protein in the blood that normally allows healthy blood clotting but has previously 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 unusual clots that lead to inflammation, fibrosis and loss of neurons.

Knowing that fibrin is the instigator of inflammation and neurological symptoms, we can take a new path to treating the disease at its root. In our experiments in mice, neutralizing blood toxicity with fibrin antibody therapy can protect the brain and body after COVID infection.”

Katerina Akassoglou, PhD, Senior Investigator and Director, Center for Neurovascular Brain Immunology, Gladstone Institutes

From the early months of the pandemic, irregular blood clotting and stroke emerged as puzzling consequences of COVID-19, even in otherwise asymptomatic patients. Later, as COVID became a major public health problem, the stakes became even higher to understand the cause of the other symptoms of this disease, including its neurological effects. More than 400 million people worldwide have had COVID since the pandemic began, with an estimated economic cost of about $1 trillion per year.

Turn the conversation around

Many scientists and medical professionals have hypothesized that inflammation resulting from the immune system’s rapid response to the COVID-causing virus leads to blood clotting and stroke. But even at the start of the pandemic in 2020, that explanation did not sound good to Akassoglou and her scientific collaborators.

“We know of many other viruses that unleash a similar cytokine storm in response to infection, but without causing blood clotting activity, as we see with COVID,” said Warner Greene, MD, PhD, senior investigator and director emeritus at Gladstone, who co-led the research with Akassoglou.

“We started to wonder if blood clots played a key role in COVID, if this virus evolved in such a way that it hijacked clotting for its own benefit,” Akassoglou added.

Through multiple experiments in mice, the researchers discovered that the virus spike protein binds directly to fibrin, causing structurally abnormal blood clots with increased inflammatory activity. The team used genetic tools to create a specific mutation that only blocks the inflammatory properties of fibrin without affecting the protein’s beneficial blood-clotting properties.

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

In addition to discovering that fibrin causes inflammation, the team made another important discovery: fibrin also suppresses the body’s ‘natural killer’ (NK cells), which normally work to clear the virus from the body. Remarkably, once the scientists depleted the fibrin in the mice, the NK cells were able to clear the virus.

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

Mechanism not activated by vaccines

The fibrin mechanism described in the article is not related to the extremely rare low platelet thrombotic complication that has been associated with 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 use mRNA technology to produce spike proteins in the body did not show excessive clotting or blood-based disorders that met the threshold for safety problems. . Instead, mRNA vaccines protect against clotting complications otherwise caused by infection.

Protecting the brain

Akassoglou’s lab has long studied how fibrin leaking into the brain causes neurological diseases such as Alzheimer’s disease and multiple sclerosis, mainly by hijacking the brain’s immune system and triggering a cascade of harmful, often irreversible effects.

The team now showed that in COVID-infected mice, fibrin is responsible for the damaging activation of microglia, the brain’s immune cells involved in neurodegeneration. After infection, the scientists found fibrin along with toxic microglia and when they inhibited fibrin, the activation of these toxic cells in the brains of mice was significantly reduced.

“Fibrin leaking into the brain may be the culprit for COVID-19 and long COVID patients with neurological symptoms, including brain fog and concentration problems,” says Akassoglou. “Inhibiting fibrin protects neurons from harmful inflammation after COVID-19 infection.”

The team tested its approach on different strains of the virus that causes COVID-19, including strains that can infect the brain and strains that do not. Neutralizing fibrin was beneficial in both types of infections, highlighting the harmful role of fibrin in the brain and body in COVID-19 and highlighting the broad implications of this study.

A new potential therapy

This study shows that fibrin is harmful in at least two ways: by activating a chronic form of inflammation and by suppressing a beneficial NK cell response that can clear virally infected cells.

“We realized that if we could neutralize both negative effects, we could potentially solve the severe symptoms we see in patients with COVID-19 and possibly long COVID,” Greene says.

Akassoglou’s lab previously developed a drug, a therapeutic monoclonal antibody, that acts only on the inflammatory properties of fibrin without adverse effects on blood clotting and protects mice against 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 administering 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 neuron survival in mice after infection.

A humanized version of Akassoglou’s first-in-class fibrin-targeted immunotherapy is already in Phase 1 clinical trials for safety and tolerability in healthy people by Therini Bio. The drug cannot be used in patients until this Phase 1 safety evaluation is completed, and should then be tested in more advanced trials of COVID-19 and long COVID-19.

Looking ahead to such studies, Akassoglou says patients could be selected based on the levels of fibrin products in their blood – a measure believed to be a predictive biomarker for cognitive impairment in long COVID.

“The fibrin immunotherapy could be tested as part of a multi-pronged approach, along with prevention and vaccination, to reduce the adverse health outcomes of long COVID,” Greene added.

The power of team science

The study’s findings intersect the scientific fields of immunology, hematology, virology, neuroscience and drug discovery – and required many labs at different institutions to work together to conduct experiments needed to solve the blood clotting mystery. Akassoglou founded the Center for Neurovascular Brain Immunology at Gladstone and UCSF in 2021, specifically for the purpose of conducting multidisciplinary, collaborative studies that address complex problems.

“I don’t think any single laboratory could have accomplished this on its own,” said Melanie Ott, MD, PhD, director of the Gladstone Institute of Virology and co-author of the study, citing key contributions from teams at Stanford, UC notes. San Francisco, UC San Diego and UCLA. “This tour-de-force study highlights the importance of collaboration in tackling these big questions.”

This study not only answers a big question, but also in a way that paves a clear clinical path for helping patients who have few options today, says Lennart Mucke, MD, director of the Gladstone Institute of Neurological Disease.

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