Covid, here's why it can cause thrombosis: the study

A particular enzyme would play a key role

COVID-19 and thrombosis: the key role of the Mpro enzyme in the onset of SARS-CoV-2 thrombotic diseases has been revealed. This is the finding of a study conducted by a team of researchers at the University of Padua, coordinated by Vincenzo De Filippis of the Department of Pharmaceutical Sciences. The work—published in Communications Biology—demonstrates that the virus, through the Mpro enzyme, can also directly activate the coagulation cascade and lead to the formation of pathological clots.

Thrombotic diseases, a statement from the University of Padua states, are the leading cause of death and hospitalization. They can arise as independent conditions or be associated with complications of other diseases (type 2 diabetes, cancer, inflammatory autoimmune diseases, and amyloidosis). Clinical evidence indicates that infectious diseases, caused by bacteria or viruses, are also significant risk factors. Coagulation itself is a physiological process aimed at preventing blood loss from the cardiovascular system. However, if abnormally activated, pathological clots (thrombi) form, causing the occlusion of blood vessels and the death of tissues located downstream of the occlusion. The COVID-19 pandemic has highlighted the association between severe viral infection and thrombotic complications and the strong correlation between the onset of thrombotic complications and mortality. In severe cases of COVID-19, there is a strong activation of the innate immune response and a massive release of pro-inflammatory proteins and peptides (cytokines and bradykinin), which, in turn, activate coagulation. SARS-CoV-2 infection would therefore indirectly increase the risk of thrombosis by inducing a severe inflammatory state.

The new study demonstrates that the virus can also activate the coagulation cascade directly. It does so through the main protease Mpro, an enzyme capable of severing chemical bonds in proteins. Specifically, Mpro produces the protein subunits that then form the protein shell essential for the virus's survival. As previously demonstrated, Mpro can be released by the virus into the extracellular space and circulate in the blood and other biological fluids, representing a useful molecular target for the development of new drugs capable of inhibiting the enzyme and blocking viral maturation.

But what does Mpro have to do with clot formation? The coagulation cascade, the statement continues, is characterized by the sequential "cutting" of enzymes that circulate inactively in the blood and become active only after this cut. To stop bleeding, the cascade culminates with the formation of thrombin, which generates the clot, made up of fibrin and aggregated platelets. "Under physiological conditions," says Vincenzo De Filippis, research coordinator, "coagulation is triggered by the exposure of proteins found in the inner lining of blood vessels, and coagulation factors VII and XII are activated. In our work, we have demonstrated that Mpro causes human plasma to coagulate."

"In particular," the scientist explains, "Mpro is capable of activating coagulation factors at precisely the same peptide bonds that are cleaved under physiological conditions and cause blood clotting. Furthermore, Mpro is produced by the SARS-CoV-2 virus, which belongs to the coronavirus family. Coronaviruses exhibit a high degree of genetic mutability and, for this reason, are prime candidates for new large-scale viral infections that may arise in the future."

"The study, which identifies a possible mechanism by which severe SARS-CoV-2 infections cause thrombosis," De Filippis concludes, "leads us to believe that the development of drugs capable of inhibiting Mpro would not only block the maturation and replication of the virus, but also prevent the thrombotic effects associated with coronavirus infection."