How Does COVID-19 Cause Blood Clots?

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How Does COVID-19 Cause Blood Clots?

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How Does COVID-19 Cause Blood Clots?

Scientists have uncovered that fibrinogen, a key blood clotting protein, plays a crucial role in the havoc caused by the COVID-19 virus, linking thrombotic inflammation and neurological changes to this protein.

At the onset of the COVID-19 pandemic, scientists were puzzled by one particular phenomenon: the irregular blood clotting and strokes observed among patients. This issue persisted in asymptomatic individuals and those suffering from long COVID.

This was perplexing.

Some researchers speculated that the immune system’s rapid response to the virus, accompanied by inflammation, led to blood clots and strokes. However, this hypothesis didn’t fully explain the severity of clotting caused by COVID-19, as many other viruses also trigger immune responses but do not result in such extensive blood clotting.

Katerina Akassoglou and Warner Greene from the University of California, San Francisco, proposed a bold hypothesis. They suggested that blood clots might not just be a byproduct of inflammation but a necessary tool for the virus, evolved to aid its survival and spread.

This theory was confirmed by a study published in Nature.

Researchers discovered that fibrinogen, the main component of blood clots, is a key target of the COVID-19 virus. The virus’s spike protein specifically binds to fibrinogen, triggering inflammation, oxidative stress, and promoting blood clot formation. Moreover, fibrinogen inhibits natural killer (NK) cells, weakening their ability to destroy the virus.

Building on previous findings, fibrinogen was shown to overstimulate microglial cells, leading to neuroinflammation and neuron loss. This process is independent of the virus’s infection of the brain or lung immunity, and researchers believe it is a major cause of neurological symptoms like brain fog in COVID-19 and long COVID patients.

This research challenges the previous understanding of blood clots in COVID-19, highlighting their role in inflammation, impaired viral clearance, and the common neurological symptoms associated with both COVID-19 and long COVID.

Blood clots are notably common in COVID-19 patients, including those with mild infections, breakthrough infections, long COVID, and even young individuals. These clots are also linked to neurological complications and are notoriously resistant to anticoagulant treatments.

The findings suggest that COVID-19-induced blood clots are unique.

Researchers speculate that the virus may directly interact with fibrinogen, not only promoting clot formation but also altering the structure and function of the clots.

Experimental results showed that fibrinogen, although with lower affinity than ACE2, can indeed bind to the spike protein. Structurally, the γC domain of fibrinogen binds to specific epitopes on the spike protein, activating the innate immune response.

Co-incubation of fibrinogen with the spike protein significantly delayed fibrinogen dissolution, consistent with previous studies on blood clots in COVID-19 patients. The spike protein significantly enhances reactive oxygen species (ROS) release by bone marrow-derived macrophages (BMDMs) induced by fibrinogen, meaning the virus amplifies fibrinogen-induced inflammation.

In mouse experiments, COVID-19 infection induced inflammation, oxidative stress, and fibrosis through fibrinogen signaling, mediated by CD11b-CD18. Knocking out fibrinogen or disrupting its CD11b-CD18 binding motif significantly reduced macrophage infiltration and collagen deposition in the lungs after infection.

Interestingly, when researchers analyzed the lung transcriptome of infected mice, they found significant changes in genes related to NK cell surface antigens, such as Klrb1a, in fibrinogen-deficient mice. This indicates that fibrinogen also plays a role in regulating NK cell function.

NK cells are critical for viral clearance, and weakened NK cell recruitment and activation are linked to poor outcomes in COVID-19.

RNA sequencing results showed that fibrinogen significantly inhibits the expression of various genes related to mitochondrial function, leukocyte migration, cytokine/chemokine production, inflammatory response, and proliferation. Fibrinogen downregulates multiple targets of the JAK-STAT pathway and p38 MAP kinase, weakening NK cell activation.

The role of fibrinogen does not depend on active COVID-19 infection. Researchers injected mice with a pseudovirus containing the spike protein, which still induced oxidative stress and lung fibrinogen deposition. In mice with fibrinogen-induced encephalomyelitis, injection of the spike protein also intensified microglial reactivity.

In other words, even without an active infection, the combination of fibrinogen and the spike protein can still trigger inflammation and oxidative stress, potentially explaining the persistence of long COVID symptoms.

Given these findings, fibrinogen has emerged as a potential therapeutic target for treating long COVID-related inflammation and protecting the nervous system.

Researchers tested a monoclonal antibody, 5B8, targeting the inflammatory domain of fibrinogen. In mice, preventive administration of 5B8 significantly reduced macrophage activation, oxidative stress, collagen accumulation, and fibrinogen deposition caused by COVID-19 infection, while enhancing lung NK cell responses. Administering 5B8 within 24 hours post-infection also significantly reduced macrophage activation and oxidative stress.

5B8 is already in Phase 1 clinical trials. Fibrinogen is also involved in the pathology of diseases like multiple sclerosis and Alzheimer’s disease (AD), so this drug may hold promise for related treatments. Previous experiments showed that eliminating the inflammatory domain of fibrinogen protected AD mice from synaptic loss and cognitive impairment.

While the COVID-19 pandemic has subsided, millions worldwide still suffer from long COVID. Hopefully, effective solutions will emerge soon.

How Does COVID-19 Cause Blood Clots?

References:

[1]https://www.nature.com/articles/s41586-024-07873-4

[2]https://www.sciencedaily.com/releases/2024/08/240828114448.htm

(source:internet, reference only)

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