Circulating antiphospholipid autoantibodies may contribute to endothelial cell activation and dysfunction in severe COVID-19, researchers report.
In 2020, the same researchers reported results from a preclinical study demonstrating that autoantibodies from patients with active COVID-19 caused clotting in mice.
Dr. Eline T. Luning Prak
The new study, published in Arthritis and Rheumatology, found higher-than-expected levels of antiphospholipid autoantibodies in the blood samples of 244 patients hospitalized with COVID-19.
“While endothelial dysfunction has been implicated in the widespread thromboinflammatory complications of COVID-19, the upstream mediators of endotheliopathy remain for the most part cryptic,” write Hui Shi, MD, PhD, and coauthors from the University of Michigan, Ann Arbor, and the National Heart, Lung, and Blood Institute.
When asked for comment on the study, Eline T. Luning Prak, MD, PhD, professor of pathology and laboratory medicine at the Hospital of the University of Pennsylvania in Philadelphia, said, “The autopsy cases for COVID-19 strongly point to thromboembolic complications in many individuals who succumbed to sequelae of the infection.
“Importantly, however, many factors can contribute to this pathology, including the inflammatory milieu, monocyte activation, neutrophil extracellular traps, immune complexes, complement, as well as effects on endothelial cells,” explained Dr. Luning Prak, who was not involved in the study.
“The findings in this paper nicely complement another study by Schmaier et al. that came out recently in JCI Insight that also suggests that endothelial cells can be activated by antibodies, she said.
‘Even stronger connection between autoantibody formation and clotting in COVID-19’
Dr. Shi and her team cultured human endothelial cells in serum or plasma from 244 patients hospitalized with COVID-19 and plasma from 100 patients with non-COVID sepsis. Using in-cell enzyme-linked immunosorbent assay, they measured levels of key cell adhesion molecules.
After analysis, the researchers found that serum from COVID-19 patients activated cultured endothelial cells to express surface adhesion molecules essential to inflammation and thrombosis, particularly E-selectin, ICAM-1, and VCAM-1.
“The presence of circulating antiphospholipid antibodies was a strong marker of the ability of COVID-19 serum to activate endothelium,” they explain.
Further analyses revealed that, for a subset of serum samples from patients with severe infection, this activation could be mitigated by depleting total immunoglobulin G.
In addition, supplementation of control serum with patient IgG was adequate to trigger endothelial activation.
On the basis of these results, the researchers hypothesize that antiphospholipid autoantibodies may characterize antibody profiles in severe COVID-19 that activate the endothelium and transition the usually quiescent blood-vessel wall interface toward inflammation and coagulation.
“[These findings] provide an even stronger connection between autoantibody formation and clotting in COVID-19,” Dr. Shi said in an accompanying press release.
Clinical implications
From a clinical perspective, Dr. Shi and her team question whether patients with severe COVID-19 should be tested for antiphospholipid antibodies to assess their risk of thrombosis and progression to respiratory failure.
Moreover, they question whether patients with high antiphospholipid antibody titers might benefit from therapies used in conventional cases of severe antiphospholipid syndrome, such as plasmapheresis, anticoagulation therapy, and complement inhibition, Dr. Shi added.
The researchers hope to answer these and other remaining questions in future studies. “Eventually, we may be able to repurpose treatments used in traditional cases of antiphospholipid syndrome for COVID-19.
“As we await definitive solutions to the pandemic, these findings add important context to the complex interplay between SARS-CoV-2 infection, the human immune system, and vascular immunobiology,” she concluded.
The study was supported by grants from the Rheumatology Research Foundation, the Michigan Medicine Frankel Cardiovascular Center, and the A. Alfred Taubman Medical Research Institute. One author is an inventor on an unrelated pending patent to the University of Michigan. The other authors and Dr. Luning Prak have disclosed no relevant financial relationships.
A version of this article first appeared on Medscape.com.