Unraveling the Mysteries of COVID-19

Severe blood clotting in patients has sent researchers in search of answers to optimize treatment and recovery  

As the virus that causes COVID-19 invades cells and replicates its code for infection, the body’s immune response fights back. However, for some people this can lead to extreme blood clotting – which can increase the risk for heart attack, stroke, or the need for lifesaving organ support. Part of helping people recover from these types of events includes looking beneath the surface. What causes severe blood clotting in some people with COVID-19? Can personalized treatments stop these mechanisms and speed up recovery? And how can vascular and blood researchers use what they’ve learned about COVID-19 to advance knowledge about other conditions?    

Yogen Kanthi, M.D., a cardiologist and Lasker Clinical Research Scholar, leads NHLBI’s vascular thrombosis and inflammation laboratory. Here, he shares his insights.      

Immune function   

Q: Can you describe what’s happening in the body when it has a severe immune response to COVID-19?      

A: The human body contains about five liters of blood, which helps sustain basic functions – from sleeping, breathing, walking, and talking to fighting off mild and severe immune threats. For example, when a person falls down and scrapes a knee, different types of blood and immune cells rush to the surface to repair broken blood vessels and reduce the risk for infection. These cells do a similar thing when potentially harmful bacteria and viruses, like the one that causes COVID-19, show up. Problems emerge when the body can’t switch off this immune response. In other words, the cells just keep fighting even after the initial response is sufficient. And that can result in the body harming itself and lead to severe outcomes.

Q. What do doctors do in these cases?  

A. When this happens in people with COVID-19, medical teams may provide anti-inflammatory medications, like steroids, to regulate immune and clotting responses. The goal is to keep blood flowing throughout the body and support its organs and systems, like the heart, circulatory system, and brain. In other cases, they may provide patients with temporary support, like breathing assistance, if the lungs are severely affected and can’t function on their own. Throughout the pandemic, researchers from multiple fields have discussed immune, blood, and blood vessel responses that they have found while studying COVID-19. By sharing and collaborating this way, researchers hope to help patients with severe COVID-19 infections recover faster and mitigate risks for further injury. 

Risks for blood clotting   

Q: Why are some people more likely to experience extreme blood clotting? What role do genes or other factors play in this kind of immune response?    

A: These are questions researchers are asking now.     

Research has shown that genes, blood cells, and other factors, like autoantibodies [antibodies that mistakenly target a person’s own tissues or organs], can be involved in processes that trigger these kinds of haywire immune responses and negatively affect blood fluidity, which can create an environment that leads to clotting.  

Some researchers are studying immune pathways, such as complement, that can activate and sustain inflammation. Others are looking at links to autoantibodies that may be preventing the body from using its natural defenses to not only trap viruses but clear them out.   

For example, a research team I was on, partially supported by NHLBI, studied 328 patients hospitalized for COVID-19. We found that patients with higher levels of autoantibodies that prevent that type of viral clearance had higher levels of inflammation and were more likely to need temporary breathing support. These types of signs help physicians predict which patients will be at risk for advanced illness.   

Other researchers have found connections between genes associated with severe blood clots in blood vessels surrounding the lungs and an increase in COVID-19 respiratory failure. Still others have found that COVID-19 can activate pathways and genes in platelets, which can cause severe inflammation and blood clotting. Studies like these are helping explain why some patients, including older adults or those with underlying health conditions, can develop more serious infection and take longer to recover from COVID-19.     

Q: Does a person’s blood type influence their likelihood of having a severe COVID-19 infection?  

A: We’re not sure about this association, even though blood types and COVID-19 severity is a topic that researchers have followed. Early in the pandemic, studies suggested people with ABO blood types had different degrees of COVID-19 infection. For example, people with blood type A looked like they were more susceptible to COVID-19, while people with blood type O had fewer infections. But a recent review of research, reported in JAMA Network Open, analyzed these studies and more recent ones. The researchers found that while previous studies suggested that people with blood types AB, A, and B were more likely to have severe COVID-19 outcomes compared to those with blood type O, those with blood type AB may have more protection against severe COVID-19. This is just one example of how research evolves.

There may be a link between blood types and how antibodies form and respond to the coronavirus. There may be connections between blood types and genes that activate and sustain inflammation. A larger body of evidence is necessary to confirm any potential connections between blood types and COVID-19. Right now, we’re not sure. As researchers, our job is to continue to evaluate data and understand factors that contribute to disease versus being loosely associated with it.  

Parallels to sepsis     

Q: Why is it important to understand similarities between COVID-19 and other conditions, such as sepsis – which is also a severe immune response to infection.  

A: Sepsis affects 1.7 million Americans each year and, like COVID-19, can impact multiple organs and have a lingering impact. Since blood clotting and elevated immune markers have appeared similar in both conditions, researchers are studying these similarities and differences – and this could inform future treatment strategies and clinical protocols. 

For example, one protein, plasminogen activator inhibitor 1 (PAI-1), which helps blood platelets form and supports blood clotting, appears higher in COVID-19 than in sepsis. Researchers are now studying how inhibiting PAI-1 may help patients with severe COVID-19 cases. They expect to know more about the effectiveness and safety of this approach next year.   

Treatment 

Q: What are some of the broader approaches to treating severe COVID-19?    

A: Several NIH-supported trials are taking place in the U.S. and throughout the world to see how patients respond to COVID-19 at different disease states and with different treatments. Other countries and regions have adopted similar models.   

For example, NIH-supported studies found that blood thinners helped patients receiving hospital care for moderate COVID-19 illness, but didn’t help patients with severe disease. This treatment strategy also didn’t help patients who did not need hospital care and had milder forms of COVID-19. Conversely, the United Kingdom’s Randomized Evaluation of Covid-19 Therapy (RECOVERY) trial, which was conducted through the National Health System, found that the anti-inflammatory steroid dexamethasone helped patients with severe COVID-19 illness but didn’t help and could even harm patients with moderate COVID-19 cases. These are just two examples of broad treatment findings that came from research conducted within multiple health systems and centers. They also reveal the complexity of finding treatments since efficacy can vary by timing and severity of illness.     

Q: What about more targeted approaches?  

Researchers are also looking for ways to personalize COVID-19 treatment. For example, what if instead of taking a broad approach to tamping inflammation in severe COVID-19 cases, you could inhibit an immune pathway with a molecule and create a balanced immune response? A small study, which was supported by the NIH Clinical Center, did just that. The study’s goal was to assess the safety profile of fostamatinib, an oral pill used to treat chronic immune thrombocytopenia (ITP), a rare bleeding disorder. And they wanted to see how it may impact patients with COVID-19 who were hospitalized and required breathing support.   

The trial included 59 patients and found that no additional adverse events occurred among those who received fostamatinib in addition to the best standard of care. That included the antiviral remdesivir and the anti-inflammatory steroid dexamethasone. The study, which was double-blinded, randomized and controlled, also hinted at early signs of efficacy. For example, patients with severe illness spent less time using supplemental oxygen or experiencing extreme blood clotting. These outcomes will be studied in future studies with hundreds of patients to determine if this treatment approach accelerates recovery. Patients who received the added treatment in this study also showed reductions in several biological markers of inflammation, including c-reactive protein, ferritin, d-dimer, and fibrinogen.      

Many other clinical trials are evaluating how targeting specific immune pathways, like adenosine and P2Y12, molecules tied to blood clotting, may impact patients with severe COVID-19 cases.

Q: What might all this mean for the long-term health of patients with COVID-19?    

A:  These are questions researchers continue to explore. Will patients recover faster? Will a tailored treatment approach reduce the number of patients who need lifesaving organ support? And could altering one or more immune pathways earlier in severe COVID-19 cases spell good news for a patient’s immediate and long-term health outcomes? We’re all working hard and fast to find out.    

To learn about the latest NHLBI-supported COVID-19 research, visit https://www.nhlbi.nih.gov/coronavirus.