Scientists have recently unraveled the mystery behind the peculiar blood clotting and inflammation observed in COVID-19 patients, leading to the identification of a potential treatment approach.
In a groundbreaking study that changes our understanding of COVID-19 and its perplexing symptoms, researchers found that the blood coagulation protein fibrin is responsible for the abnormal clotting and inflammation often seen in the disease, while also hindering the body’s ability to eliminate the virus.
Crucially, the research team has pinpointed a new antibody therapy that could counteract these harmful effects.
Published in Nature, the study conducted by Gladstone Institutes and its collaborators challenges the previous belief that blood clotting is simply a result of inflammation in COVID-19. Through laboratory tests and experiments on mice, the researchers demonstrated that blood clotting is actually an initial cause, leading to other complications such as damaging inflammation, reduced viral clearance, and neurological issues commonly seen in patients with COVID-19 and long COVID.
The instigator is fibrin, a protein that typically aids in healthy blood clotting, but is known to provoke toxic inflammatory responses. In their study, scientists discovered that in COVID-19 cases, fibrin becomes increasingly harmful as it attaches to both the virus and immune cells, forming abnormal clots that incite inflammation, fibrosis, and neuron loss.
“With the understanding that fibrin triggers inflammation and neurological symptoms, we can establish a new avenue for addressing the disease at its core,” says Katerina Akassoglou, PhD, a leading researcher at Gladstone and director of the Center for Neurovascular Brain Immunology at Gladstone and UC San Francisco. “In our mouse studies, using fibrin antibody therapy to neutralize blood toxicity proved effective in safeguarding the brain and body following COVID infection.”
From the onset of the pandemic, unusual instances of blood clotting and strokes emerged as puzzling consequences of COVID-19, even among individuals who showed no symptoms. As long COVID became a pressing public health concern, understanding the origins of its various symptoms—especially neurological effects—became even more critical. Over 400 million people globally have experienced long COVID since the pandemic began, with an estimated economic impact of $1 trillion annually.
Shifting the Narrative
Many experts believed that the inflammation triggered by the immune system’s rapid response to the COVID virus caused clotting and strokes. However, even in the early days of the pandemic in 2020, Akassoglou and her colleagues were skeptical of this explanation.
“Numerous other viruses cause a similar cytokine storm during infection but do not result in the blood clotting seen in COVID,” notes Warner Greene, MD, PhD, senior investigator and director emeritus at Gladstone, who co-led the study with Akassoglou.
“We started considering whether blood clots might play a central role in COVID — if this virus adapted to exploit clotting for its own advantage,” Akassoglou added.
Indeed, through a series of tests on mice, the researchers found that the virus’s spike protein interacts directly with fibrin, leading to abnormal blood clots with heightened inflammatory properties. The team utilized genetic tools to develop a specific mutation that inhibits only the inflammatory impacts of fibrin while preserving its essential blood-clotting function.
When they genetically modified mice to produce the mutant fibrin or to lack fibrin in their bloodstream, the researchers observed that inflammation, oxidative stress, fibrosis, and clotting in the lungs were either absent or significantly diminished following COVID-19 infection.
Additionally, the researchers found that fibrin also dampens the activity of the body’s “natural killer” (NK) cells, which normally help to rid the body of the virus. Remarkably, depletion of fibrin in the mice allowed these NK cells to effectively eliminate the virus.
These results suggest that fibrin plays a critical role in enabling the virus to inflict damage on the body.
Mechanism Unrelated to Vaccines
The fibrin mechanism discussed in the study does not relate to the extremely rare thrombotic side effects linked to adenoviral DNA COVID-19 vaccines, which are currently unavailable in the United States.
In contrast, a study involving 99 million individuals vaccinated against COVID, led by The Global COVID Vaccine Safety Project, revealed that mRNA-based vaccines do not cause excessive clotting or blood disorders that raise safety concerns. Instead, mRNA vaccines offer protection against clotting issues that arise from the infection.
Safeguarding the Brain
Akassoglou’s lab has been investigating how fibrin leakage into the brain may trigger neurological diseases, such as Alzheimer’s and multiple sclerosis, by disrupting the brain’s immune defense system and initializing a series of damaging, often permanent, consequences.
In their latest research, the team discovered that in mice infected with COVID, fibrin is responsible for activating harmful brain immune cells called microglia, which are involved in neurodegeneration. After infection, the scientists observed fibrin alongside toxic microglia; however, when fibrin was inhibited, the activation of these harmful cells in the mice’s brains was substantially diminished.
“Fibrin leakage into the brain could be a key factor for COVID-19 and long COVID patients experiencing neurological symptoms, such as brain fog and concentration difficulties,” says Akassoglou. “Inhibiting fibrin can help protect neurons from damaging inflammation following a COVID-19 infection.”
The team evaluated their method against various strains of the COVID virus, including those that invade the brain as well as those that do not. Neutralizing fibrin proved beneficial regardless of the type of infection, highlighting fibrin’s detrimental role in both the brain and body during COVID-19 and underscoring the research’s broader implications.
A New Treatment Possibility
This research reveals that fibrin is harmful in two main ways: by inciting chronic inflammation and by inhibiting NK cell responses that typically help eliminate virus-infected cells.
“We realized that if we could neutralize both of these adverse effects, we could potentially alleviate the severe symptoms observed in COVID-19 patients and those suffering from long COVID,” Greene comments.
Akassoglou’s lab has developed a therapeutic monoclonal antibody designed to target only the inflammatory properties of fibrin, without impacting its positive blood-clotting functions, thereby protecting mice from multiple sclerosis and Alzheimer’s.
In this new study, the team demonstrated that the antibody effectively blocked fibrin’s interaction with immune cells and the virus. When they administered the immunotherapy to infected mice, it helped prevent severe inflammation, reduced fibrosis and viral proteins in the lungs, and improved survival rates. In the brain, the fibrin antibody therapy minimized damaging inflammation and enhanced neuronal survival in mice post-infection.
A human-friendly version of Akassoglou’s innovative fibrin-targeting immunotherapy is currently undergoing Phase 1 safety trials in healthy volunteers through Therini Bio. The drug cannot be given to patients until this initial safety assessment is complete, followed by more advanced testing for COVID-19 and long COVID.
Looking ahead, Akassoglou suggests patients could be chosen for trials based on fibrin product levels in their blood—considered a predictive biomarker for cognitive issues linked to long COVID.
“The fibrin immunotherapy could be tested alongside other prevention strategies and vaccinations to mitigate negative health impacts from long COVID,” Greene adds.
The Importance of Collaborative Science
The findings from this study connect various scientific fields including immunology, hematology, virology, neuroscience, and drug discovery, requiring teamwork from multiple laboratories across different institutions to tackle the complex experiments needed to resolve the blood-clotting puzzle. Akassoglou established the Center for Neurovascular Brain Immunology at Gladstone and UCSF in 2021 specifically to facilitate interdisciplinary collaboration aimed at addressing intricate issues.
“It’s unlikely any single lab could have achieved this on their own,” states Melanie Ott, MD, PhD, director of the Gladstone Institute of Virology and co-author of the study, recognizing significant contributions from teams at Stanford, UC San Francisco, UC San Diego, and UCLA. “This impressive study emphasizes the necessity of collaboration in addressing major scientific inquiries.”
This research not only addresses a significant question but also provides a clear clinical path forward for helping patients who currently have limited treatment options, according to Lennart Mucke, MD, director of the Gladstone Institute of Neurological Disease.
“Neurological symptoms resulting from COVID-19 and long COVID can profoundly impact various aspects of an individual’s life, affecting cognitive function, memory, and even emotional well-being,” Mucke remarks. “This study introduces a novel strategy for treating these serious effects and mitigating the long-lasting impact of the SARS-CoV-2 virus.”