Newswise – When the body tries to fight off an infection, immune cells called neutrophils can produce toxic spider web-like protein networks to help contain the invaders. However, when not properly regulated, these web-shaped extracellular neutrophil traps, or NETs, play a role in the formation of blood clots and in the promotion of inflammation for several diseases, including COVID-19. .
Using the rare drug defibrotide, researchers were recently able to stop the formation and progression of harmful NETs. Defibrotide is a complex mixture of short DNA fragments purified from pig intestinal cells. It is currently used to treat blockages in the blood vessels in the liver after a stem cell transplant.
NETs are major contributors to blood clotting in patients with an autoimmune disease known as antiphospholipid syndrome, also commonly referred to as PSA. Defibrotide was first reported as a possible treatment for a potentially fatal form of APS about 20 years ago, but the mechanism was unknown.
Inspired by this observation, a team of rheumatologists from Michigan Medicine recently tested how defibrotide interacts with immune cells. They found that the treatment not only prevented neutrophils from releasing NETs, but also reduced downstream blood clotting in mice with PSA, according to results published in Arthritis and rheumatology.
The treatment was so effective in neutralizing NETs and thrombosis that it allowed mice with PSA to look and behave like perfectly healthy mice, said Jason Knight, MD, Ph.D., author. article principal and associate professor of rheumatology at Michigan Medicine.
“It could be important for the more severe forms of PSA, the cases that bring people to the hospital where they need emergency treatment,” Knight said. “Progress has been stalled on appropriate clinical trials given the poor understanding of the mechanisms by which defibrotide aided APS. We hope this work will help change that.
The first and only case of defibrotide and PSA was written 20 years ago by Doruk Erkan, MDMPH, article co-author and rheumatologist at the Hospital for Special Surgery in New York City.
“This study is historic,” Erkan said. “Two decades after the only report of the use of defibrotide in catastrophic APS, we now have scientific support on how it may interfere with thrombosis associated with APS. “
In a separate complementary study, published in JCI Overview, the Knight team found that beyond the release of NETs, defibrotide also effectively neutralized NETs once they had already formed. The team found that the biochemical properties of the defibrotide molecule make it ideal for binding histones, one of the most toxic types of proteins found in NETs. Histones are known to activate the walls of blood vessels and cause blood clots.
“Because the defibrotide molecule has a negative charge, it is really effective at suppressing histones, serving as a kind of sponge that absorbs this toxic part of NETs and thus prevents activation of blood vessel cells,” said Knight. “This property of defibrotide could have wide use for many diseases where NETs cause inflammation and coagulation.”
An example arose last year when researchers, including Knight’s group, found that the most severe COVID-19 patients had higher levels of NETs. The web-shaped traps also play a detrimental role in various other diseases ranging from autoimmune diseases to cancer.
“While more research needs to be done, the hope is that drugs like defibrotide can prevent inflammatory types of blood clotting, sometimes called immunothrombosis, in a way that will not increase the risk of bleeding,” said Knight. “It really is the holy grail, and we hope it will bring us a little closer.”
Disclosure: For both studies, Jazz Pharmaceuticals funded the preclinical experiments, but made no contributions regarding the experimental design or data analysis.
Cited Articles / DOI:
“Defibrotide inhibits NET formation mediated by antiphospholipid antibodies and venous thrombosis”, Arthritis and rheumatology. DOI: 10.1002 / art.42017
“Protective properties of the endothelium and neutralizing the histones of the polyanionic agent defibrotide”, JCI Overview. DOI: 10.1172 / jci.insight.149149