Fibrinolytic factors: friends or foes in the fate of COVID-19?
Dr. Adrianne Watson - 20 July 2026
Aleksandra Franczak
Summer is finally here, but before long, the arrival of fall will bring another season of viral infections. While vaccines and immunity from previous infections have reduced the threat of COVID-19 for many people, SARS-CoV-2, the virus that causes COVID-19, continues to cause thousands of hospitalizations and many deaths each year, especially among those with compromised health that are more prone to infection.
Although COVID-19 is often thought of as a respiratory illness, the virus can affect many organs throughout the body. One of its most serious complications is the formation of blood clots inside blood vessels, a process known as thrombosis. These clots can block blood flow and contribute to life-threatening conditions such as pulmonary embolism or stroke.
So, how does severe COVID-19 cause blood clots? It disrupts the body’s delicate balance between forming blood clots and breaking them down. One of the key proteins involved in the body’s clot-dissolving system, known as fibrinolysis, is plasminogen. When activated, plasminogen is converted into plasmin, which is an enzyme responsible for breaking down the protein mesh that holds blood clots together. Plasminogen is also a precursor of angiostatin, a protein best known for regulating the formation of new blood vessels.
During severe COVID-19, both the clotting and clot-dissolving systems become activated as the body attempts to maintain this delicate balance. Although the body increases the production of proteins involved in fibrinolysis, this response may not be sufficient to counteract the excessive clot formation caused by the infection.
In their previous study, Dr. Paul Jurasz and post-doctoral fellow Dr. Aleksandra Franczak (a PhD candidate at the time), together with the labs of Drs. Tyrrell, Hobman, and Barakat found that blood levels of plasminogen and angiostatin are higher in patients with COVID-19 than in healthy individuals. This suggests that both proteins may play important roles during COVID-19.
The researchers also discovered that angiostatin may act like a double-edged sword during COVID-19. On one hand it binds to the SARS-CoV-2 spike protein, the protein that the virus uses to enter human cells; and by doing so, angiostatin can reduce infection. On the other hand, under conditions often seen in severe COVID-19, such as low oxygen (hypoxia) and increased acidity (acidosis), high levels of angiostatin can promote cell death.
These discoveries raised an important question: could blood levels of plasminogen and angiostatin help predict which patients die from COVID-19 and which do not?
To answer this, Dr. Jurasz and Dr. Franczak measured plasminogen and angiostatin levels in blood samples from 120 patients hospitalized for COVID-19: 60 who survived and 60 who did not. Then in collaboration with Dr. Irina Dinu from the School of Public Health they examined if differences in these proteins were associated with survival after accounting for patients’ overall health.
As expected, patients who died from COVID-19 had a greater burden of underlying health conditions than those who survived. This was assessed using the Charlson Comorbidity Index, a scoring system that estimates a person’s risk of death based on the presence of chronic conditions such as cardiovascular disease, cancer, and liver disease.
Patients who died had also lower blood levels of both plasminogen and angiostatin. Lower plasminogen was associated with higher hazard of death, regardless of a patient’s Charlson Comorbidity Index, consistent with previous studies linking reduced plasminogen levels to poorer COVID-19 outcomes. Although plasminogen levels in patients who died remained higher than those seen in healthy individuals in the first study, they were lower than in survivors, suggesting that a weaker fibrinolytic response may contribute to the thrombotic complications and death in severe COVID-19.
Unlike plasminogen, angiostatin did not show a straightforward relationship with survival. Instead, in exploratory analysis its association depended on the patient’s burden of underlying diseases. In patients with few comorbidities, lower angiostatin levels were suggestive of poorer survival. In contrast, among patients with a high burden of chronic conditions, both low and high angiostatin levels were suggestive of worse outcome. One possible explanation comes from the team’s earlier work. Low angiostatin levels may reflect an inadequate protective response against the SARS-CoV-2 virus, while very high levels may indicate an exaggerated response, that under the stressful conditions of severe COVID-19 can damage the cells lining blood vessels, potentially leading to organ damage or even death. The results suggest that when it comes to angiostatin both too little and too much might be harmful. As with many processes in biology, the “sweet spot” may lie somewhere in between. In the future, identifying this “sweet spot” could help guide more personalized therapies. Patients with low angiostatin levels might benefit from therapies that restore its protective antiviral effect, while those with excessive angiostatin response might benefit from treatments that limit its harmful effects on blood vessel cells.
One promising approach comes from the team’s earlier work. They have developed peptides that block angiostatin’s cell damaging effect while preserving its ability to interfere with SARS-CoV-2 virus infection. In other words, rather than simply increasing or blocking angiostatin, these peptides might allow researchers to keep the good while eliminating the bad.
In summary, this study shows that plasminogen and angiostatin provide different insights into severe COVID-19. Lower plasminogen levels consistently identified patients at greater risk of dying, regardless of their underlying health conditions. Angiostatin, on the other hand, had a more complex pattern, suggesting that its role in COVID-19 depends on the patient’s overall health. This work also lays the foundation for future research. By identifying how angiostatin levels relate to patients’ outcomes and building on the team’s earlier discovery that angiostatin can be both protective and harmful, researchers can now test if peptides that preserve angiostatin’s antiviral activity while blocking its harmful effects can improve outcomes in preclinical models of severe COVID-19. If successful, this strategy could ultimately lead to treatments that use the body’s own protective responses while preventing them from becoming harmful.