Fibrin drives thromboinflammation and neuropathology in COVID-19, 2024, Jae Kyu Ryu et al

Abstract
Life-threatening thrombotic events and neurological symptoms are prevalent in COVID-19 and are persistent in patients with long COVID experiencing post-acute sequelae of SARS-CoV-2 infection1,2,3,4. Despite the clinical evidence1,5,6,7, the underlying mechanisms of coagulopathy in COVID-19 and its consequences in inflammation and neuropathology remain poorly understood and treatment options are insufficient. Fibrinogen, the central structural component of blood clots, is abundantly deposited in the lungs and brains of patients with COVID-19, correlates with disease severity and is a predictive biomarker for post-COVID-19 cognitive deficits1,5,8,9,10.

Here we show that fibrin binds to the SARS-CoV-2 spike protein, forming proinflammatory blood clots that drive systemic thromboinflammation and neuropathology in COVID-19. Fibrin, acting through its inflammatory domain, is required for oxidative stress and macrophage activation in the lungs, whereas it suppresses natural killer cells, after SARS-CoV-2 infection.

Fibrin promotes neuroinflammation and neuronal loss after infection, as well as innate immune activation in the brain and lungs independently of active infection. A monoclonal antibody targeting the inflammatory fibrin domain provides protection from microglial activation and neuronal injury, as well as from thromboinflammation in the lung after infection. Thus, fibrin drives inflammation and neuropathology in SARS-CoV-2 infection, and fibrin-targeting immunotherapy may represent a therapeutic intervention for patients with acute COVID-19 and long COVID.

LINK

 

“The fibrin immunotherapy can be tested as part of a multipronged approach, along with prevention and vaccination, to reduce adverse health outcomes from long COVID.”

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

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

LINK

 

Gladstone Institutes (San Francisco): "Discovery of How Blood Clots Harm Brain and Body in COVID-19 Points to New Therapy”

Excerpts:

'In a study that reshapes what we know about COVID-19 and its most perplexing symptoms, scientists have discovered that the blood coagulation protein fibrin causes the unusual clotting and inflammation that have become hallmarks of the disease, while also suppressing the body’s ability to clear the virus. Importantly, the team also identified a new antibody therapy to combat all of these deleterious effects.’

'“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,” says 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.”

"Later, as long COVID became a major public health issue, the stakes grew even higher to understand the cause of this disease’s other symptoms, including its neurological effects."

"In addition to discovering that fibrin sets off inflammation, the team made another important discovery: fibrin also suppresses the body’s “natural killer,” or NK, cells, which normally work to clear the virus from the body. Remarkably, when the scientists depleted fibrin in the mice, NK cells were able to clear the virus.”

"Akassoglou’s lab has long investigated how fibrin that leaks into the brain triggers neurologic diseases, such as Alzheimer’s disease and multiple sclerosis, essentially by hijacking the brain’s immune system and setting off a cascade of harmful, often irreversible, effects."

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

"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 says. “Inhibiting fibrin protects neurons from harmful inflammation after COVID-19 infection.”

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

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

"Not only did this study address a big question, but it did so 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 touch every part of a person’s life, affecting cognitive function, memory, and even emotional health,” Mucke says. “This study presents a novel strategy for treating these devastating effects and addressing the long-term disease burden of the SARS-CoV-2 virus.”

 

I think this came out the same day as the blood biomarkers study, so it didnt get much attention. I'm curious as to what our resident scientists make of this?

Its being touted as a Big Deal in other corners of the internet.

 

It looks like ill-informed hype to me.
Tagging an antibody to fibrinogen would just leave you bleeding. Tagging it to fibrin would likely make the inflammation worse.
No serious scientist is going to come out with the sort of scattershot statements seen here.

 

the mice were infected and measured a handful of days later, unsure as to the relevance for LC

 

Not just nasal infection with virus.

They also looked at spike effects on healthy human plasma.

 

I find it hard to link these experiments to any significant understanding of human clinical problems. Injecting fibrinogen into brain is bound to activate microglia and has no relevance to either acute neurological events in humans or LC as far as I can see. It may be interesting that fibrinogen interacts with spike protein but all proteins bind with some sort of affinity to all others pretty much. My understanding is that you don't generally get neurological lesions in acute Covid unless you are seriously hypoxic from lung damage or have some form of intravascular coagulation. I don't see what injecting fibrinogen in brain tells us in relation to that.

 

Here's how the team introduced it —

That last sentence has one lung and two brain references. Post-mortem so you would think severe disease, hypoxic lung damage etc. But.

[8] Microvascular Injury in the Brains of Patients with Covid-19 (2020, New England Journal of Medicine)

[9] Neurovascular injury with complement activation and inflammation in COVID-19 (2022, Brain)

In our thread for [9] we noted Nath's comments during an NIH call —

I wonder whether this relates to his thoughts that LC is much more severe than ME/CFS. (It also seems to contradict the idea of no neuroinflammation).

 

Here's some of the team's earlier papers —

Fibrinogen-induced perivascular microglial clustering is required for the development of axonal damage in neuroinflammation (2012, Nature Communications)

Fibrin-targeting immunotherapy protects against neuroinflammation and neurodegeneration (2018, Nature Immunology)

Fibrinogen in neurological diseases: mechanisms, imaging and therapeutics (2018, Nature Reviews Neuroscience)

Fibrin promotes oxidative stress and neuronal loss in traumatic brain injury via innate immune activation (2024, Journal of Neuroinflammation)

From another team —

Fibrin-targeting molecular MRI in inflammatory CNS disorders (2022)

Spoiler: Full abstract and links

Lohmeier, Johannes; Silva, Rafaela V.; Tietze, Anna; Taupitz, Matthias; Kaneko, Takaaki; Prüss, Harald; Paul, Friedemann; Infante-Duarte, Carmen; Hamm, Bernd; Caravan, Peter; Makowski, Marcus R.

BACKGROUND
Fibrin deposition is a fundamental pathophysiological event in the inflammatory component of various CNS disorders, such as multiple sclerosis (MS) and Alzheimer’s disease. Beyond its traditional role in coagulation, fibrin elicits immunoinflammatory changes with oxidative stress response and activation of CNS-resident/peripheral immune cells contributing to CNS injury.

PURPOSE
To investigate if CNS fibrin deposition can be determined using molecular MRI, and to assess its capacity as a non-invasive imaging biomarker that corresponds to inflammatory response and barrier impairment.

MATERIALS AND METHODS
Specificity and efficacy of a peptide-conjugated Gd-based molecular MRI probe (EP2104-R) to visualise and quantify CNS fibrin deposition were evaluated. Probe efficacy to specifically target CNS fibrin deposition in murine adoptive-transfer experimental autoimmune encephalomyelitis (EAE), a pre-clinical model for MS (n = 12), was assessed. Findings were validated using immunohistochemistry and laser ablation inductively coupled plasma mass spectrometry. Deposition of fibrin in neuroinflammatory conditions was investigated and its diagnostic capacity for disease staging and monitoring as well as quantification of immunoinflammatory response was determined. Results were compared using t-tests (two groups) or one-way ANOVA with multiple comparisons test. Linear regression was used to model the relationship between variables.

RESULTS
For the first time (to our knowledge), CNS fibrin deposition was visualised and quantified in vivo using molecular imaging. Signal enhancement was apparent in EAE lesions even 12-h after administration of EP2104-R due to targeted binding (M ± SD, 1.07 ± 0.10 (baseline) vs. 0.73 ± 0.09 (EP2104-R), p = .008), which could be inhibited with an MRI-silent analogue (M ± SD, 0.60 ± 0.14 (EP2104-R) vs. 0.96 ± 0.13 (EP2104-La), p = .006). CNS fibrin deposition corresponded to immunoinflammatory activity (R 2 = 0.85, p < .001) and disability (R 2 = 0.81, p < .001) in a model for MS, which suggests a clinical role for staging and monitoring. Additionally, EP2104-R showed substantially higher SNR (M ± SD, 6.6 ± 1 (EP2104R) vs. 2.7 ± 0.4 (gadobutrol), p = .004) than clinically used contrast media, which increases sensitivity for lesion detection.

CONCLUSIONS
Molecular imaging of CNS fibrin deposition provides an imaging biomarker for inflammatory CNS pathology, which corresponds to pathophysiological ECM remodelling and disease activity, and yields high signal-to-noise ratio, which can improve diagnostic neuroimaging across several neurological diseases with variable degrees of barrier impairment.

Link | PDF (European Journal of Nuclear Medicine and Molecular Imaging)

Related —

Neuroinflammation in post-acute sequelae of COVID-19 PASC as assessed by 11CPBR28 PET correlates with vascular disease measures (2024, Brain, Behavior, and Immunity)

Dysregulation of complement and coagulation pathways: emerging mechanisms in the development of psychosis (2021, Nature Molecular Psychiatry)

 

Some of them had died in bed, or in a subway, and so they did not have much respiratory symptoms.

If that is the level of argument I am not impressed, especially as one of the key features of Covid was severe hypoxia without much respiratory symptoms.

The stuff from the a paper all seems very muddled. People do not take into account the different ways things happen in different compartments with the same protein substrates. Fibrin is a classic example, as is complement.

I see so much guff about these things I continue to be very sceptical when papers claim to have nailed some key process with a disjointed series of only partly relevant mouse experiments.

 

Eric Topol interviews the senior author: Katerina Akassoglou: Blood Clots, Brain Inflammation, and Covid