COVID-19 Latest: University Of Michigan And NIH Study Identifies Autoimmune Antibodies As New Cause Of COVID-19 Blood Clots
: A new study by researchers from University of Michigan, U.S. NIH-Bethesda and Shanghai Jiao Tong University School of Medicine-China have surprisingly discovered that the culprit that is causing blood clots in most severe COVID-19 infections is an autoimmune antibody that's circulating in the blood, attacking the cells and triggering clots in arteries, veins, and microscopic vessels. Blood clots can cause life-threatening events like strokes and in COVID-19, these microscopic clots may restrict blood flow in the lungs, impairing oxygen exchange.
Besides COVID-19 disease, these clot-causing antibodies are typically seen in patients who have the autoimmune disease called antiphospholipid syndrome.
Antiphospholipid syndrome is an acquired and potentially life-threatening thrombophilia in which patients develop pathogenic autoantibodies targeting phospholipids and phospholipid-binding proteins (aPL antibodies).
These aPL antibodies were recently detected in patients with COVID-19. In this study, the researchers measured eight types of aPL antibodies in serum samples from 172 patients hospitalized with COVID-19. These aPL antibodies included anticardiolipin IgG, IgM and IgA; anti-β2 glycoprotein I IgG, IgM, and IgA; and anti-phosphatidylserine/ prothrombin (aPS/PT) IgG and IgM. The study team detected aPS/PT IgG in 24% of serum samples, anticardiolipin IgM in 23% of samples, and aPS/PT IgM in 18% of samples. Antiphospholipid autoantibodies were present in 52% of serum samples using the manufacturer’s threshold and in 30% using a more stringent cutoff (≥40 ELISA-specific units). Higher titers of aPL antibodies were associated with neutrophil hyperactivity including the release of neutrophil extracellular traps (NETs), higher platelet counts, more severe respiratory disease, and lower clinical estimated glomerular filtration rate.
Similar to IgG from patients with antiphospholipid syndrome, IgG fractions isolated from COVID-19 patients promoted NET release from neutrophils isolated from healthy individuals. Furthermore, injection of IgG purified from COVID-19 patient serum into mice accelerated venous thrombosis in two mouse models.
These study findings suggest that half of patients hospitalized with COVID-19 become at least transiently positive for aPL antibodies and that these autoantibodies are potentially pathogenic.
The study findings were published in the peer reviewed journal: Science Translational Medicine https://stm.sciencemag.org/content/early/2020/11/02/scitranslmed.abd3876
The connection between autoantibodies and COVID-19 was unexpected, says co-corresponding author Dr Yogen Kanthi, M.D., an assistant professor at the University of Michigan Medicine Frankel Cardiovascular Center and a Lasker Investigator at the National Institutes of Health's National Heart, Lung, and Blood Institute.
Dr Kanthi told Thailand Medical News, "In patients with COVID-19, we continue to see a relentless, self-amplifying cycle of inflammation and clotting in the body. Now we are learning that autoantibodies could be a culprit in this loop of clotting and inflammation that makes
people who were already struggling even sicker."
The study team says that studies of COVID-19 have shown some of the worst clotting ever seen.
Dr Jason Knight, M.D., Ph.D., a rheumatologist at Michigan Medicine who has been studying antiphospholipid syndrome antibodies in the general population for years and is the co-corresponding author of the study commented, "Half of the patients hospitalized with COVID-19 were positive for at least one of the autoantibodies, which was quite a surprise.”
Dr Knight, also an associate professor of internal medicine and a leading expert on diseases caused by autoantibodies.
The study team found about half of the patients who were very sick with COVID-19 were exhibiting a combination of high levels of both the dangerous antibodies and super-activated neutrophils, which are destructive, exploding white blood cells. In April, the team was the first to report that patients hospitalized for severe COVID-19 had higher levels of neutrophil extracellular traps in their blood.
In order to learn more, they studied the explosive neutrophils and the COVID-19 antibodies together in mouse models to see if this could be the dangerous combination behind the clots.
Dr Kanthi added, "Antibodies from patients with active COVID-19 infection created a striking amount of clotting in animals some of the worst clotting we've ever seen. We have discovered a new mechanism by which patients with COVID-19 may develop blood clots."
The study team says these findings aren't yet ready for clinical practice, but they add a new perspective to the robust thrombosis and inflammation research in patients with COVID-19.
Dr Kanthi, Dr Knight, first author Dr Yu (Ray) Zuo, M.D., and colleagues now want to know whether severely ill patients with high levels of these antibodies would have better outcomes if the antibodies are blocked or removed.
Dr Zuo said if so, that might warrant an aggressive treatment like plasmapheresis, which is commonly used in severe autoimmune diseases,
Plasmapheresis involves draining blood through an IV, filtering it and replacing it with fresh plasma that doesn't contain those antibodies associated with blood clots.
Dr Zuo, an assistant professor of internal medicine and a rheumatologist at Michigan Medicine said, "We know people with the highest levels of autoantibodies did worse in terms of respiratory function, and the antibodies caused inflammation even in healthy cells. We don't yet know what is triggering the body to produce these antibodies, so the next step would be additional research to identify the triggers and the targets of the antibodies."
Furthermore, these findings bring up new questions surrounding the use of convalescent plasma as a possible COVID-19 treatment, but the team says more research is needed to examine this concern
Dr Knight said, "We're now investigating how long these antibodies remain in circulation after recovery from the novel coronavirus.”
The study team is also currently running a randomized clinical trial called DICER, which is testing a well-known anti-clotting agent, dipyridamole, in patients with COVID-19 to determine whether it's more effective than a placebo in reducing excessive blood clots.
Dr Kanthi said, "Dipyridamole is an old drug that is safe, inexpensive, and scalable. The U.S. FDA approved it 20 years ago to prevent clotting, but we only recently discovered its potential to block this specific type of inflammation that occurs in COVID."
The team concluded, “As we await definitive antiviral and immunological solutions to the current COVID-19 pandemic, we posit that testing for aPL antibodies, including aPS/PT antibodies, may lead to improved risk stratification and personalization of treatment for patients with COVID-19. We also suggest further investigation of aPL antibodies as a contributor to the complex thrombo-inflammatory milieu of COVID-19.”
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