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New Insights into COVID-19’s Clotting Issues and Potential Treatments

A recent study has significantly altered the understanding of COVID-19 and its complicated symptoms, revealing that the blood coagulation protein fibrin is responsible for notable clotting and inflammation associated with the disease while hindering the body’s capability to eliminate the virus.

Moreover, the research team has identified a promising antibody therapy aimed at mitigating these harmful effects.

Published in Nature, the study conducted by the Gladstone Institutes in collaboration with other researchers challenges the existing belief that blood clotting is simply a byproduct of inflammation seen in COVID-19 patients. Through experimental work involving both laboratory settings and mice, the scientists demonstrate that blood clotting actually acts as a primary driver of issues such as toxic inflammation, difficulties in viral clearance, and neurological symptoms common among those affected by COVID-19 and long COVID.

The problematic factor is fibrin, which generally assists in healthy blood coagulation. However, this study emphasizes its harmful role in COVID-19, as it binds with both the virus and immune cells, forming abnormal clots that lead to inflammation, fibrosis, and neuronal damage.

“Recognizing that fibrin instigates inflammation and neurological complications allows us to pursue new treatment strategies targeting the root cause,” explains Katerina Akassoglou, PhD, a leading investigator at Gladstone and director of its Center for Neurovascular Brain Immunology in collaboration with UC San Francisco. “Our mouse model experiments suggest that neutralizing this blood toxicity using fibrin antibody therapy can safeguard both the brain and the body post-COVID infection.”

Since the onset of the pandemic, atypical blood clotting and stroke have manifested as puzzling consequences of COVID-19 even in asymptomatic patients. The rise of long COVID further heightened the urgency to understand the etiology behind these symptoms, including neurological issues. An estimated 400 million individuals globally have suffered from long COVID since the pandemic’s outset, resulting in a projected annual economic burden of approximately $1 trillion.

Rethinking Existing Theories

Initially, many researchers and medical authorities speculated that the immune response’s inflammatory reaction to the virus was the primary instigator of blood clotting and strokes. However, even in the early days of the pandemic, Akassoglou and her colleagues found this explanation unsatisfactory.

“Numerous viruses induce cytokine storms during infections but do not result in the extensive blood clotting observed with COVID-19,” remarked Warner Greene, MD, PhD, a senior investigator at Gladstone and co-leader of the study alongside Akassoglou.

“This prompted us to consider whether blood clots may play a central role in COVID-19 — that perhaps the virus adapted to exploit the clotting process for its advantage,” Akassoglou added.

Further experiments revealed that the spike protein of the virus directly interacts with fibrin, resulting in abnormally structured blood clots that exhibit heightened inflammatory responses. Utilizing genetic techniques, the researchers generated a specific mutation that blocked fibrin’s inflammatory characteristics without compromising its essential clotting functions.

When mice were genetically engineered to lack fibrin or were modified to express mutation, the team observed a significant reduction in inflammation, oxidative stress, fibrosis, and clotting in their lungs following COVID-19 infection.

Additionally, the research indicated that fibrin not only incites inflammation but also inhibits the function of the body’s natural killer (NK) cells, which typically help clear viruses. Remarkably, when fibrin levels were reduced in the test subjects, their NK cells were effective in removing the virus.

These results underscore that fibrin plays a crucial role in enabling the virus to inflict harm on the body.

Clarifying Vaccine-related Complications

The fibrin-related mechanisms discussed in this research are distinct from the exceedingly rare incidences of thrombotic complications tied to low platelet counts linked to adenoviral DNA COVID-19 vaccines, which are currently not in use within the U.S.

In contrast, an expansive study involving 99 million vaccinated individuals, spearheaded by The Global COVID Vaccine Safety Project, indicated that mRNA vaccines facilitating spike protein production demonstrated no significant association with troublesome clotting or blood disorders that would raise safety alarms. Instead, mRNA vaccines appeared to provide protection from clotting-related issues that could arise due to the virus.

Impact on Neurological Health

Akassoglou’s inquiry into fibrin’s role in the brain has previously revealed its involvement in neurological diseases such as Alzheimer’s and multiple sclerosis by manipulating brain immunity and initiating a cascade of detrimental effects. The latest research demonstrates that in models infected with COVID-19, fibrin is responsible for the harmful activation of microglia, the brain’s immune cells that are crucial for neurodegeneration.

After infection, the study identified a correlation between fibrin and the activation of toxic microglia; inhibiting fibrin substantially lessened this activation.

“Fibrin leaking into the brain seems to be a major contributor to neurological symptoms in COVID-19 and long COVID sufferers, including brain fog and challenges with concentration,” Akassoglou states. “Targeting fibrin appears to mitigate neuronal damage caused by harmful inflammation after a COVID-19 infection.”

The research also examined different strains of the COVID-19 virus, including some that penetrate the brain and others that do not, with the conclusion that neutralizing fibrin yielded benefits across various types of infections. This highlights fibrin’s damaging influence in both the brain and body within the context of COVID-19 and has wide-reaching implications.

A Promising New Therapy

The findings from this investigation reveal that fibrin is detrimental in at least two significant aspects: instigating a chronic inflammatory state and simultaneously suppressing a beneficial NK cell response that is essential for clearing infected cells.

“Recognizing the possibility of diminishing both of these adverse effects opens up avenues for alleviating the severe symptoms observed in COVID-19 and potentially long COVID patients,” Greene comments.

Akassoglou’s research team previously developed a therapeutic monoclonal antibody that exclusively targets the inflammatory properties of fibrin. This treatment has shown protective effects against both multiple sclerosis and Alzheimer’s disease in mice.

In the current study, they demonstrated that this antibody could block interactions between fibrin, immune cells, and the virus. Administering the immunotherapy to infected mice successfully prevented severe inflammation, reduced fibrosis, mitigated viral proteins in the lungs, and improved survival outcomes. In terms of neurological implications, this antibody treatment decreased harmful inflammation and preserved neuronal survival post-infection.

A humanized variant of this pioneering fibrin-targeting immunotherapy is currently undergoing Phase 1 safety and tolerability clinical trials by Therini Bio with healthy volunteers. This therapy will not be made available for patient use until the completion of this critical phase, followed by further trials specific to COVID-19 and long COVID.

Looking forward, Akassoglou suggests patient selection for upcoming trials based on the levels of fibrin products found in their blood, which are considered potential biomarkers for cognitive impairment associated with long COVID.

“This fibrin immunotherapy could be integrated into a comprehensive strategy alongside prevention methods and vaccinations to mitigate adverse health effects stemming from long COVID,” Greene suggests.

The Value of Collaborative Science

The implications of this study traverse multiple disciplines, including immunology, hematology, virology, neuroscience, and drug discovery, underscoring the necessity for collaborative efforts across institutions to unravel the complexities of blood clotting related to COVID-19. Akassoglou established the Center for Neurovascular Brain Immunology at Gladstone and UCSF precisely to foster multidisciplinary collaboration targeting intricate health issues.

“No single laboratory could have tackled this on their own,” asserts Melanie Ott, MD, PhD, director of the Gladstone Institute of Virology and a co-author of the study. She acknowledges the vital contributions from teams at Stanford, UC San Francisco, UC San Diego, and UCLA. “This remarkable study exemplifies the critical role of collaboration in addressing significant scientific inquiries.”

The research not only sought answers to critical questions surrounding COVID-19 but also charted a promising clinical pathway for aiding those with limited treatment options. Lennart Mucke, MD, director of the Gladstone Institute of Neurological Disease, emphasizes the broader implications of the findings.

“Neurological manifestations of COVID-19 and long COVID can deeply affect various facets of an individual’s life, including cognitive abilities, memory, and emotional well-being,” explains Mucke. “This investigation offers a novel strategy for addressing these debilitating effects and contributing to strategies for alleviating the long-term health consequences associated with the SARS-CoV-2 virus.”

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