Half of patients hospitalized with COVID-19 have autoantibodies to phospholipids and phospholipid-binding proteins (aPL), which could contribute to the feedback loop of inflammation and coagulation that occurs in severely ill patients, a new study shows. "We speculate that local immune stimulation due to viral infection (including potentially the infection of endothelial cells) could synergize with circulating aPL antibodies and thereby lead to a particularly severe thrombo-inflammatory insult to the lungs of COVID-19 patients," Dr. Yogendra Kanthi of the National Heart, Lung and Blood Institute in Bethesda, Maryland, and colleagues write in Science Translational Medicine. Before the COVID-19 pandemic, the authors had shown that persantine (dipyridamole) reduced the release of neutrophil extracellular traps (NETs), webs of genetic material that contribute to blood clotting, in mouse models of antiphospholipid syndrome. In April, they reported that release of NETS was strongly associated with worse oxygenation and respiratory failure in COVID patients. Based on these findings, they launched a phase-2 trial of persantine in hospitalized COVID-19 patients. In the current study, the authors looked at levels of eight aPL antibodies in serum samples from 172 patients hospitalized with COVID-19. Anti-phosphatidylserine/prothrombin (aPS/PT) IgG was found in 24%, anticardioliptin IgM in 23% and aPS/PT IgM in 18%. Overall, 52% of samples were positive for aPL based on the manufacturer's cutoff, or 30% based on a stricter threshold of at least 40 ELISA-specific units. Patients with higher levels of aPL antibodies had more neutrophil hyperactivity, including NETs release; higher platelet counts; worse respiratory disease and worse kidney function based on estimated glomerular filtration rate. IgG isolated from patients' serum triggered the release of NETs in neutrophils from healthy humans in the lab, while IgG injections increased venous thrombosis in two mouse models. Approved by the U.S. Food and Drug Administration more than 20 years ago, and available as a generic, persantine "has a very favorable safety profile," Dr. Kanthi noted. "We found that this drug is also really great at inducing a type-1 interferon response, which is an important physiological response to fight viruses." "We need to find out which autoantibodies are actually triggering thrombosis, and then we need to find out whether these antibodies go away with time," he added. "We expect that they will, but we need to understand that better." Another question, Dr. Kanthi said, is whether current treatments for COVID can prevent patients from developing autoantibodies. "I think we understand that there is no single treatment for COVID that's curative, but rather targeting different aspects of COVID will be important to finding better treatments. It may be that medications that reduce both inflammation and coagulation . . . will be important tools for doctors to use in managing their patients with COVID," he concluded. The study had no commercial funding. —Anne Harding Source
