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Cited by 116COVID-19 Clinical Research StudiesBlood properties and coagulationLong-Term Effects of COVID-19

Fibrin drives thromboinflammation and neuropathology in COVID-19

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Ryu, Jae Kyu, Yan, Zhaoqi, Montano, Mauricio, Sozmen, Elif G., Dixit, Karuna, Suryawanshi, Rahul K., Matsui, Yusuke, Helmy, Ekram +36 more·2024·Nature
DOI 10.1038/s41586-024-07873-4PMC PMC11424477
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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 infection 1–4. Despite the clinical evidence 1,5–7, 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 deficits 1,5,8–10. 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.

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  • A fibrin-targeting antibody that selectively inhibits microglia activation without adverse anticoagulant effects protects from neurodegeneration and suppresses AD-related gene networks in 5xFAD mice.

    “Accordingly, a fibrin-targeting antibody that selectively inhibits microglia activation without adverse anticoagulant effects protects from neurodegeneration and suppresses AD-related gene networks in 5xFAD mice.28,34”

    From Machine learning reveals prominent spontaneous behavioral changes and treatment efficacy in humanized and transgenic Alzheimer's disease models (2024) · cites this paper as [28]

    The ‘Fibrin-targeting antibody in SARS-CoV-2’ section says 5B8 protects against amyloid-driven neurodegeneration without adverse effects on haemostasis; the Discussion also says it does not affect normal clotting time. This paper reports reduced microglial reactivity and altered gene expression in SARS-CoV-2-infected mice, but does not establish that the antibody suppresses AD-related gene networks in 5xFAD mice. (LLM, conf=0.86)

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Authors
Ryu, J. K., Yan, Z., Montano, M., Sozmen, E. G., Dixit, K., Suryawanshi, R. K., Matsui, Y., Helmy, E., Kaushal, P., Makanani, S. K., Deerinck, T. J., Meyer-Franke, A., Rios Coronado, P. E., Trevino, T. N., Shin, M.-G., Tognatta, R., Liu, Y., Schuck, R., Le, L., Miyajima, H., Mendiola, A. S., Arun, N., Guo, B., Taha, T. Y., Agrawal, A., MacDonald, E., Aries, O., Yan, A., Weaver, O., Petersen, M. A., Meza Acevedo, R., Alzamora, M. D. P. S., Thomas, R., Traglia, M., Kouznetsova, V. L., Tsigelny, I. F., Pico, A. R., Red-Horse, K., Ellisman, M. H., Krogan, N. J., Bouhaddou, M., Ott, M., Greene, W. C., & Akassoglou, K.
Affiliations
  • Gladstone Institutes (US)
  • University of California, Los Angeles (US)
  • University of California San Diego (US)
  • San Diego Supercomputer Center (US)
  • University of California, San Francisco (US)
Corresponding author
  • Greene, Warner C.
  • Akassoglou, Katerina
ORCID
Venue
Nature
Publisher
Springer Science and Business Media LLC
Published
2024-08-28
Volume
633
Issue
8031
Pages
905-913
ISSN
  • 0028-0836 (ISSN-L)
  • 1476-4687
DOI
10.1038/s41586-024-07873-4
PMC
PMC11424477
OpenAlex
W4401947087
Cited by
116
References
9
Citations by year
2026: 48 · 2025: 52 · 2024: 16
FWCI
40.47
Type
journal article
Language
en
Open access
Licence
Locations
  • Nature (publishedVersion, cc-by)
  • PubMed Central (publishedVersion, cc-by)
  • PubMed (publishedVersion)
  • RePEc: Research Papers in Economics (submittedVersion)
  • eScholarship (California Digital Library) (submittedVersion, cc-by)
Funders
  • National Institutes of Health (1k99ai163868-01a1, 1s10rr028962-01, 1rf1ag064926-01, 1s10od021784-01a1)
  • National Institute on Aging (RF1 (AG064926))
  • National Heart, Lung, and Blood Institute (R01HL128503, T32HL094274)
  • National Institute of General Medical Sciences (R01GM138780, R24GM137200)
  • National Institute of Allergy and Infectious Diseases (T32AI007334, K99 AI163868, U19AI135990)
  • National Institute of Neurological Disorders and Stroke (R35NS097976, K99NS126707, R00NS126707, U24NS120055)
  • National Center for Research Resources (S10 RR028962)
Topics
  • Health Sciences › Medicine › Infectious Diseases › COVID-19 Clinical Research Studies
  • Health Sciences › Medicine › Pulmonary and Respiratory Medicine › Blood properties and coagulation
  • Health Sciences › Medicine › Neurology › Long-Term Effects of COVID-19
Keywords
fibrin, COVID-19 pandemic, SARS-CoV-2, thromboinflammation, coagulopathy, long COVID, fibrinogen, SARS-CoV-2 spike protein, oxidative stress, macrophage activation, natural killer cells, neuroinflammation, neuronal loss, microglial activation, innate immune activation, monoclonal antibodies
MeSH terms
COVID-19, SARS-CoV-2, Neuroinflammatory Diseases, Post-Acute COVID-19 Syndrome, Animals, Antibodies, Monoclonal, Brain, Mental Fatigue, Female, Fibrin, Fibrinogen, Humans, Immunity, Innate, Inflammation, Killer Cells, Natural, Lung, Macrophage Activation, Male, Neurons, Thrombosis, Microglia, Oxidative Stress, Mice, Spike Glycoprotein, Coronavirus

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