While the immune system is needed to fight Covid-19, severe disease progression shows characteristic “out-of-control” inflammation causing pneumonia and lung damage. This, so called acute respiratory distress syndrome (ARDS), causes shortness of breath and limited oxygen uptake leading – in the worst case- to multi organ failure and death.
Another common complication is thrombosis. Abnormal coagulation, in particular levels of d-dimers (a fibrin degradation produced when clots are dissolved) correlate with poor outcome and mortality of Covid-19 patients. A new study out of Michigan University now links this clinical feature of Covid-19 to the immune system. Again the immune system is the bad guy.
The scientists identified auto-immune antibodies in combination with neutrophil activation to be a cause of clots in Covid-19 patients.
Looking for autoantibodies targeting phospholipids and phospholipid-binding proteins (aPL antibodies), which have previously been described as source of life-threatening thrombophilia in Antiphospholipid Syndrome, they found these antibodies in 52% of the 172 hospitalised Covid-19 patients analysed. Levels of aPL antibodies correlated with a range of clinical parameters. Patients with high titers tended to show activation of neutrophils – a highly prevalent innate immune cell that is a front line responder during viral infections. Neutrophils can expel their DNA to form NETs, which catch pathogens and locally enrich anti-microbial and proinflammatory messenger molecules. The presence of these NETs also correlated with aPL antibody titers. Neutrophils and NETs have long been discussed to promote thrombosis in some settings.
The researchers went on to test the causality behind the correlation. To do so, neutrophils isolated from the blood of healthy volunteers were cultured with serum antibodies (IgG) isolated from Covid-19 patients in a dish. Neutrophils exposed to IgG from patients with high aPL levels showed significantly more NET formation (= Neutrophil activation) compared to neutrophils exposed to IgG from patients with low aPL levels. Using different mouse models of thrombosis showed that aPL antibodies can accelerate thrombosis. Injecting serum IgG from aPL antibody high Covid-19 patients increased thrombus size in two independent models of thrombosis (stenosis and electrolytic).
Formation of aPL antibodies and Antiphospholipid syndrome during infection is not uncommon. They are found in a wide range of infection from pneumonia and HIV to skin or urinary tract infections. However, most of the time their presence is transient and without dramatic effect on coagulation. Why these auto-immune antibodies form is still unclear. It is likely a combination of genes, previous antigen exposure and level of surrounding immune activation. The last factor, we know to be extremely high in the worst cases of Covid-19. A catastrophic spiral of innate immune activation and autoantibody formation may follow – causing tissue damage and thrombosis.
Targeting aPL antibodies in patients with particularly high titers may offer a clinical intervention. Indeed, dipyridamole – an FDA-approved antithrombotic medication- can stop aPL anti-medited NET release in vitro. A clinical trial testing the drug in Covid-19 patients is currently underway.
Picture credit: Blood clot. Credit: Anne Weston, Francis Crick Institute. Attribution-NonCommercial 4.0 International (CC BY-NC 4.0)