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Blood Protein Changes May Unravel Long COVID Mysteries

— Links between complement and coagulation systems could lead to long COVID therapies

MedpageToday
 A computer rendering of activated platelets and red blood cells.

Long COVID was identified in blood proteins, an analysis of longitudinal data suggested.

Blood samples from long COVID patients showed changes to blood serum proteins at 6 months that indicated activation of the immune system's complement cascade, altered coagulation, and tissue injury, reported Onur Boyman, MD, of the University of Zurich in Switzerland, and co-authors in .

"Our multicenter, longitudinal study provides evidence of an inflammatory signature restricted to patients with active long COVID, with diagnostic accuracy 6 months after symptom onset and independent of any information on COVID-19 history, thus facilitating clinical applicability," Boyman and colleagues wrote.

Factors underpinning long COVID are not well understood, the researchers observed. Current hypotheses include tissue damage, viral reservoirs, autoimmunity, or persistent inflammation.

"This study is very important in illustrating the role of the complement in the pathogenesis of long COVID," said Akiko Iwasaki, PhD, of Yale School of Medicine, who wasn't involved with the research.

"The complement system tags unwanted invaders for elimination and is an important immunological arsenal against infectious agents," Iwasaki told MedPage Today. "However, when complement is activated chronically, this can cause collateral damage to the blood vessels and tissues. This study suggests that inhibitors of the complement pathway may be useful in treating long COVID."

This evidence implicating complement activation and thromboinflammation ties in with other research that showed an increased propensity for clotting in people with long COVID, added Ziyad Al-Aly, MD, of the VA St. Louis Health Care System, who also wasn't part of the study.

"The findings from this paper could galvanize search for biomarkers, diagnostics, and ways to potentially treat long COVID," Al-Aly told MedPage Today. "I am very optimistic that the mechanisms of long COVID are being elucidated so rapidly. Our understanding of the biology and mechanisms of long COVID is improving by the day."

Boyman and colleagues followed 113 COVID-19 patients in Europe and the U.S. -- 40 of whom had long COVID symptoms at 6-month follow-up -- and compared data from these individuals with 39 healthy controls. Patients with severe or mild acute COVID-19 were analyzed during acute infection and 6 months later.

Long COVID was defined by as one or more persisting COVID-related symptoms that couldn't be explained by an alternative diagnosis. People reporting isolated changes in smell or taste were excluded from the long COVID group.

Clinical assessments were paired with blood draws and a total of 268 longitudinal blood samples were included in the analysis. Overall, the researchers assessed serum levels of 6,596 human proteins across study participants.

A comparison of the 40 long COVID patients, 73 recovered patients, and 39 healthy controls showed that most serum biomarkers that were elevated in long COVID at 6 months overlapped with those that were altered in the subgroup of the cohort with severe acute COVID-19.

Compared with others in the study, long COVID patients showed elevated tissue injury markers in blood and a thromboinflammatory signature characterized by markers of endothelial activation, like von Willebrand factor (vWF), and red blood cell lysis. At the cellular level, this signature was linked with increased monocyte-platelet aggregates.

During acute COVID-19, complement and coagulation systems can become activated and remain locally activated in various tissues in long COVID patients, observed Wolfram Ruf, MD, of the Johannes-Gutenberg University Medical Center in Mainz, Germany, and the Scripps Research Institute in La Jolla, California, in an .

"Although therapeutic interventions with coagulation and complement inhibitors in acute COVID-19 produced mixed results, the pathological features specific for long COVID suggest potential interventions for clinical testing," Ruf wrote.

"Microclots are also observed in ME-CFS [myalgic encephalomyelitis-chronic fatigue syndrome] patients, indicating crucial interactions between complement, vWF, and coagulation-mediated fibrin formation in postviral syndromes," Ruf pointed out.

"Target-specific coagulation inhibitors can reprogram innate immune phenotypes and interrupt the microangiopathic roles of vWF," he added. "Rebalancing complement activation can be achieved by blocking distinct amplification points with monoclonal antibodies that are clinically approved or in development."

  • Judy George covers neurology and neuroscience news for MedPage Today, writing about brain aging, Alzheimer’s, dementia, MS, rare diseases, epilepsy, autism, headache, stroke, Parkinson’s, ALS, concussion, CTE, sleep, pain, and more.

Disclosures

Researchers were supported by the Swiss National Science Foundation, Clinical Research Priority Program of University of Zurich, Pandemic Fund of University of Zurich, innovation grants of University Hospital Zurich, Digitalization Initiative of Zurich Higher Education Institutions, Swiss Academy of Medical Sciences, Young Talents in Clinical Research, Filling the Gap Program, Botnar Research Centre for Child Health Postdoctoral Excellence Programme, European Union's Horizon 2020 research program, Swiss Personalized Health Network, NOMIS Foundation, Schwyzer Winiker Stiftung and Baugarten Stiftung, and the Swiss canton of Grisons.

Boyman and several co-authors were listed as inventors on a patent application on long COVID biomarkers. Another co-author worked as an adviser for Eliptica.

Iwasaki reported relationships with Roche, Genentech, Xanadu Bio, Paratus Sciences, and InvisiShield Technologies.

Al-Aly reported uncompensated consulting for Pfizer.

Ruf received grant support from the Deutsche Forschungsgemeinschaft. He reported holding patents and consulting for ARCA Biopharma and Endpoint Health.

Primary Source

Science

Cervia-Hasler C, et al "Persistent complement dysregulation with signs of thromboinflammation in active long COVID" Science 2024; DOI: 10.1126/science.adg7942.

Secondary Source

Science

Ruf W "Immune damage in long COVID" Science 2024; DOI:10.1126/science.adn1077.