SIGNIFICANT NEW STUDY PUBLISHED TODAY IN NATURE!
Length: • 5 mins
Annotated by Nick
SIGNIFICANT NEW STUDY PUBLISHED TODAY IN NATURE!
Fibrin "binds to the SARS-CoV-2 spike protein," forming clots that "drive systemic thromboinflammation and neuropathology," and it happens "independently of active infection."
Simplified breakdown of the paper below!
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This paper has SEVERAL MAJOR FINDINGS, spanning multiple major aspects of COVID pathology!
IMO, this paper is a MAJOR BREAKTHROUGH, as the authors "establish fibrin as a key driver of inflammation and neuropathology in SARS-CoV-2 infection."
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Interestingly, the specific mechanism that is driving this doesn't seem to be one that's critical to normal blood clotting processes.
So, there's already a THERAPEUTIC IN PHASE 1 CLINICAL TRIALS (which tests the safety and tolerability of the treatment) based on this study!
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So what is fibrin? (This slide is from a thread about a preprint with extremely similar results )
The most important thing to know is that FIBRIN is a major component of blood clots, after being converted from FIBRINOGEN. (FIBRINogen generates FIBRIN).
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Some important background info:
FIBRINOGEN is a protein that just kinda hangs out in the blood, waiting.
FIBRIN is a fibrous protein that forms a mesh to hold platelets together to form a blood clot.
THROMBIN is the enzyme that converts FIBRINOGEN into FIBRIN.
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The central question being investigated here can be summed up simply: What the hell is up with the abnormal clotting that is associated with COVID-19?
These issues occur even in young people with mild infections, and they can persist as Long COVID.
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Of course, fibrin deposits have been associated with tissue damage—including blood–brain barrier (BBB) disruption—found in OTHER autoimmune, inflammatory, and neurodegenerative diseases.
BBB disruption is associated with LC, so it's a good place to start.
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So what did they find? Let's start with the easy one: both fibrin and fibrinogen (the protein that is converted into fibrin) bind to the SARS-CoV-2 spike protein.
After confirming the binding, they infected mice via intranasal spray, but they ALSO...
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...administered another set of mice an IV that contained only spike and fibrinogen proteins. In both sets of mice, the spikes and fibrinogens were found concentrated together in lung tissue, showing the interaction of these proteins.
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When they compared the structure of the spike protein with fibrinogen, they found that the spike protein actually binds to a (normally hidden) receptor on the fibrinogen that is part of the activation of the innate immune response!
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Next, they put some fibrinogen and thrombin (the conversion enzyme) in healthy donor blood plasma, and they found the dense clots found in COVID!
They also found a concentration-dependent effect, "suggesting that the SARS-CoV-2 virus enhances fibrin-induced inflammation."
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When fibrinogen becomes fibrin, its hidden binding site is exposed; it's already known that targeting this site can have significant effects in other autoimmune and inflammatory conditions!
So they tested some mice that lack fibrinogen (OR that lack only that binding site).
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Fibrinogen-deficient mice fared better in multiple ways!
This suggests "fibrin signalling through CD11b–CD18 [the hidden binding site that becomes exposed] induces inflammatory cell infiltration, oxidative stress and fibrosis in SARS-CoV-2 infection"
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Moreover, just a whole shitload of genes related to harmful responses to SARS-CoV-2 infection in the lungs were found to be expressed LESS in the fibrinogen-deficient mice—included an interferon-induced gene that is associated with SEVERE COVID (via cytokine storm)!
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Now here's where it starts getting interesting. In the fibrinogen-deficient mice, there was a much better natural killer (NK) cell response; this would impair viral clearance, and it suggests "a role for fibrin as a regulator of NK cells in infection."
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That also lines up with the known mechanism of a TOTALLY DIFFERENT pathology: Complement Receptor 3 on NK cells (which fibrinogen can interact with), has been found to down-regulate NK cell quantities when activated, negatively impacting tumor surveillance in cancers!
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NK cells are an important part of the immune response to viral infections.
"Fibrin markedly suppressed a network of pathways [related to NK cells], including mitochondrial function, leukocyte migration, [signal] production, inflammatory response, [and] proliferation"
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And in the fibrinogen-deficient mice, depleting their NK cells eliminated the protective effects of their fibrinogen-deficiency.
So all those different ways NK cells are getting fucked up? It's fibrinogen that seems to be doing it. Fibrinogen suppresses viral clearance!
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When they infected mice with a pseudovirus that ONLY had the spike protein, they again found a whole bunch of fibrin-related damage. This suggests a "fibrin-dependent mechanism that elicits inflammatory and oxidative stress responses in the presence" of the spike protein!
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It's important to note that this mechanism is UNRELATED to the rare clotting complications seen with the AstraZeneca and J&J vaccines; that was an adverse reaction to the VECTOR, rather than the spike protein! (And the mRNA spike has some tweaks: )
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What about the mRNA vaccines—they produce a spike protein, so can they also cause this problem? Nope!
The spike design used in the vaccines has a couple of tweaks to make it more stable, and those changes prevent it the vaccine-based spike protein from causing cell fusion!
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That brings us to TREATMENT! There's already a monoclonal antibody, 5B8, which targets the problem-causing binding site on fibrin. When mice were infected with SARS-CoV-2 and given 5B8 prophylactically, it worked astoundingly well.
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I've been highlighting the lung tissue results, but every single one of these findings was also paralleled in microglia—the immune cells of the central nervous system. Microglia activation correlates with fibrin deposits in the brain!
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This part is amazing: Mice with human ACE2 receptors were infected with a neuroinvasive strain of SARS-CoV-2. Normally, these mice are super dead at 6 days; almost a quarter of 5B8-treated mice were still alive at 9 days! They also had different gene expression in the brain!
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The takeaway? Abnormal clotting isn't just a byproduct of infection-related inflammation; these clots are the "driver of infection-induced thromboinflammation and neuropathology." It's driving the hyper-inflammation that causes neuropathology.
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They have shown that "fibrin has an immunomodulatory role promoting increased viral load and thromboinflammation in COVID-19."
NK cells, one of the most important aspects of the innate immune response to viral infections, are impaired by these fibrin clots.
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And these results MIGHT generalize to OTHER conditions! These findings are consistent with results which suggest "a role for fibrin in other diseases with vascular damage and impaired NK cell cytotoxicity, such as cancer and autoimmune diseases."
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Leaky BBB is already associated with COVID-19 neuropathology. And other work shows fibrin is involved in autoimmune and neurodegenerative conditions!
Thus, "high plasma fibrinogen levels in COVID-19 may contribute to BBB disruption and ensuing neuropathology"—and 5B8 helps!
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More research is needed to figure out the specifics, especially with regard to timing and dosing of 5B8, but these results are EXCITING! Unfortunately, they may not explain all aspects of COVID pathology.
Of course,...
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The best way to avoid this fibrin-spike complication is to avoid infection! Fortunately, filtering respirators are specifically designed to filter airborne particulate and can keep you safe! Mask up for YOUR health, please!
Article, open access: nature.com/articles/s4158...
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