| Clotting disorders in Covid patients were spotted by researchers in China in early 2020, but the true extent of the risk only became clear when even patients with mild respiratory symptoms began experiencing strokes. At first, doctors suspected these clots might result from a "cytokine storm" — an intense immune response releasing a surge of inflammation-signaling proteins. Others noted that the virus could directly damage blood vessel linings. But Katerina Akassoglou, a neurovascular brain immunologist at the Gladstone Institutes and UC San Francisco, wasn't convinced that the virus itself wasn't a cause. Navigating social distancing requirements that complicated lab work, Akassoglou and her collaborators conducted a series of experiments in mice to explore the pernicious role of the coronavirus's spike protein. They discovered that beyond serving as the virus's "key" to enter cells, spike binds with a blood clotting factor called fibrinogen, creating structurally abnormal, inflammation-promoting clumps of fibrin — the insoluble material that forms the mesh-like structures essential for wound healing. High levels of these abnormal clots not only push the body's clotting system into overdrive, increasing clot formation and inflammation, but also suppress natural killer cells — the immune system's virus-clearing soldiers. When this damaging cycle occurs alongside a breakdown in the protective layer of cells around the brain's blood vessels, toxins and bloodborne proteins, including fibrin, can seep into the body's most vital organ. Once there, these substances activate microglia — the brain's immune cells —which begin attacking healthy brain cells, contributing to the neurological symptoms of long Covid. Akassoglou had been studying this damaging cascade for decades in patients with Alzheimer's disease and multiple sclerosis. Still, until SARS-CoV-2 came along, she had no idea it could be triggered by a viral infection. "For some reason, this virus has evolved to interfere with the coagulation system in a way that other viruses do not," she told me. Fibrin's role in driving toxic inflammation is common in many diseases, but "in the presence of spike, it gets a lot worse." In experiments with mice lacking fibrinogen, Covid leads to much less inflammation, and the infection clears faster. "Studies suggest that if you deplete fibrin, inflammation improves, no matter what initially triggers it." Although Akassoglou's focus has been on the brain, she's hopeful this research will be expanded to understand the effects on the heart, liver, kidneys, and gastrointestinal tract. In the meantime, she's developing a way to halt this damaging reaction. A first-in-class antibody treatment designed to specifically block fibrin's toxic effects entered early-stage patient studies in May, with no reported safety concerns so far. Results are expected next year and could lead to more advanced clinical trials to test the immunotherapy's potential to treat not only long Covid but also other serious diseases like multiple sclerosis and Alzheimer's. —Jason Gale | 
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