blood clots
Can Autoimmune Antibodies Explain Blood Clots in COVID-19?
Posted on by Dr. Francis Collins
For people with severe COVID-19, one of the most troubling complications is abnormal blood clotting that puts them at risk of having a debilitating stroke or heart attack. A new study suggests that SARS-CoV-2, the coronavirus that causes COVID-19, doesn’t act alone in causing blood clots. The virus seems to unleash mysterious antibodies that mistakenly attack the body’s own cells to cause clots.
The NIH-supported study, published in Science Translational Medicine, uncovered at least one of these autoimmune antiphospholipid (aPL) antibodies in about half of blood samples taken from 172 patients hospitalized with COVID-19. Those with higher levels of the destructive autoantibodies also had other signs of trouble. They included greater numbers of sticky, clot-promoting platelets and NETs, webs of DNA and protein that immune cells called neutrophils spew to ensnare viruses during uncontrolled infections, but which can lead to inflammation and clotting. These observations, coupled with the results of lab and mouse studies, suggest that treatments to control those autoantibodies may hold promise for preventing the cascade of events that produce clots in people with COVID-19.
Our blood vessels normally strike a balance between producing clotting and anti-clotting factors. This balance keeps us ready to seal up vessels after injury, but otherwise to keep our blood flowing at just the right consistency so that neutrophils and platelets don’t stick and form clots at the wrong time. But previous studies have suggested that SARS-CoV-2 can tip the balance toward promoting clot formation, raising questions about which factors also get activated to further drive this dangerous imbalance.
To learn more, a team of physician-scientists, led by Yogendra Kanthi, a newly recruited Lasker Scholar at NIH’s National Heart, Lung, and Blood Institute and his University of Michigan colleague Jason S. Knight, looked to various types of aPL autoantibodies. These autoantibodies are a major focus in the Knight Lab’s studies of an acquired autoimmune clotting condition called antiphospholipid syndrome. In people with this syndrome, aPL autoantibodies attack phospholipids on the surface of cells including those that line blood vessels, leading to increased clotting. This syndrome is more common in people with other autoimmune or rheumatic conditions, such as lupus.
It’s also known that viral infections, including COVID-19, produce a transient increase in aPL antibodies. The researchers wondered whether those usually short-lived aPL antibodies in COVID-19 could trigger a condition similar to antiphospholipid syndrome.
The researchers showed that’s exactly the case. In lab studies, neutrophils from healthy people released twice as many NETs when cultured with autoantibodies from patients with COVID-19. That’s remarkably similar to what had been seen previously in such studies of the autoantibodies from patients with established antiphospholipid syndrome. Importantly, their studies in the lab further suggest that the drug dipyridamole, used for decades to prevent blood clots, may help to block that antibody-triggered release of NETs in COVID-19.
The researchers also used mouse models to confirm that autoantibodies from patients with COVID-19 actually led to blood clots. Again, those findings closely mirror what happens in mouse studies testing the effects of antibodies from patients with the most severe forms of antiphospholipid syndrome.
While more study is needed, the findings suggest that treatments directed at autoantibodies to limit the formation of NETs might improve outcomes for people severely ill with COVID-19. The researchers note that further study is needed to determine what triggers autoantibodies in the first place and how long they last in those who’ve recovered from COVID-19.
The researchers have already begun enrolling patients into a modest scale clinical trial to test the anti-clotting drug dipyridamole in patients who are hospitalized with COVID-19, to find out if it can protect against dangerous blood clots. These observations may also influence the design of the ACTIV-4 trial, which is testing various antithrombotic agents in outpatients, inpatients, and convalescent patients. Kanthi and Knight suggest it may also prove useful to test infected patients for aPL antibodies to help identify and improve treatment for those who may be at especially high risk for developing clots. The hope is this line of inquiry ultimately will lead to new approaches for avoiding this very troubling complication in patients with severe COVID-19.
Reference:
[1] Prothrombotic autoantibodies in serum from patients hospitalized with COVID-19. Zuo Y, Estes SK, Ali RA, Gandhi AA, Yalavarthi S, Shi H, Sule G, Gockman K, Madison JA, Zuo M, Yadav V, Wang J, Woodard W, Lezak SP, Lugogo NL, Smith SA, Morrissey JH, Kanthi Y, Knight JS. Sci Transl Med. 2020 Nov 2:eabd3876.
Links:
Coronavirus (COVID-19) (NIH)
Antiphospholipid Antibody Syndrome (National Heart Lung and Blood Institute/NIH)
Kanthi Lab (National Heart, Lung, and Blood Institute, Bethesda, MD)
Knight Lab (University of Michigan)
ACTIV (NIH)
NIH Support: National Heart, Lung, and Blood Institute
Months After Recovery, COVID-19 Survivors Often Have Persistent Lung Trouble
Posted on by Dr. Francis Collins
The pandemic has already claimed far too many lives in the United States and around the world. Fortunately, as doctors have gained more experience in treating coronavirus disease 2019 (COVID-19), more people who’ve been hospitalized eventually will recover. This raises an important question: what does recovery look like for them?
Because COVID-19 is still a new condition, there aren’t a lot of data out there yet to answer that question. But a recent study of 55 people recovering from COVID-19 in China offers some early insight into the recovery of lung function [1]. The results make clear that—even in those with a mild-to-moderate infection—the effects of COVID-19 can persist in the lungs for months. In fact, three months after leaving the hospital about 70 percent of those in the study continued to have abnormal lung scans, an indication that the lungs are still damaged and trying to heal.
The findings in EClinicalMedicine come from a team in Henan Province, China, led by Aiguo Xu, The First Affiliated Hospital of Zhengzhou University; Yanfeng Gao, Zhengzhou University; and Hong Luo, Guangshan People’s Hospital. They’d heard about reports of lung abnormalities in patients discharged from the hospital. But it wasn’t clear how long those problems stuck around.
To find out, the researchers enrolled 55 men and women who’d been admitted to the hospital with COVID-19 three months earlier. Some of the participants, whose average age was 48, had other health conditions, such as diabetes or heart disease. But none had any pre-existing lung problems.
Most of the patients had mild or moderate respiratory illness while hospitalized. Only four of the 55 had been classified as severely ill. Fourteen patients required supplemental oxygen while in the hospital, but none needed mechanical ventilation.
Three months after discharge from the hospital, all of the patients were able to return to work. But they continued to have lingering symptoms of COVID-19, including shortness of breath, cough, gastrointestinal problems, headache, or fatigue.
Evidence of this continued trouble also showed up in their lungs. Thirty-nine of the study’s participants had an abnormal result in their computed tomography (CT) lung scan, which creates cross-sectional images of the lungs. Fourteen individuals (1 in 4) also showed reduced lung function in breathing tests.
Interestingly, the researchers found that those who went on to have more lasting lung problems also had elevated levels of D-dimer, a protein fragment that arises when a blood clot dissolves. They suggest that a D-dimer test might help to identify those with COVID-19 who would benefit from pulmonary rehabilitation to rebuild their lung function, even in the absence of severe respiratory symptoms.
This finding also points to the way in which the SARS-CoV-2 virus seems to enhance a tendency toward blood clotting—a problem addressed in our Accelerating COVID-19 Therapeutic Interventions and Vaccines (ACTIV) public-private partnership. The partnership recently initiated a trial of blood thinners. That trial will start out by focusing on newly diagnosed outpatients and hospitalized patients, but will go on to include a component related to convalescence.
Moving forward, it will be important to conduct larger and longer-term studies of COVID-19 recovery in people of diverse backgrounds to continue to learn more about what it means to survive COVID-19. The new findings certainly indicate that for many people who’ve been hospitalized with COVID-19, regaining normal lung function may take a while. As we learn even more about the underlying causes and long-term consequences of this new infectious disease, let’s hope it will soon lead to insights that will help many more COVID-19 long-haulers and their concerned loved ones breathe easier.
Reference:
[1] Follow-up study of the pulmonary function and related physiological characteristics of COVID-19 survivors three months after recovery. Zhao YM, Shang YM, Song WB, Li QQ, Xie H, Xu QF, Jia JL, Li LM, Mao HL, Zhou XM, Luo H, Gao YF, Xu AG. EClinicalMedicine.2020 Aug 25:100463
Links:
Coronavirus (COVID-19) (NIH)
How the Lungs Work (National Heart, Lung, and Blood Institute/NIH)
Computed Tomography (CT) (National Institute of Biomedical Imaging and Bioengineering/NIH)
Zhengzhou University (Zhengzhou City, Henan Province, China)
Accelerating COVID-19 Therapeutic Interventions and Vaccines (ACTIV) (NIH)
Searching for Ways to Prevent Life-Threatening Blood Clots in COVID-19
Posted on by Dr. Francis Collins
Six months into the coronavirus disease 2019 (COVID-19) pandemic, researchers still have much to learn about the many ways in which COVID-19 can wreak devastation on the human body. Among the many mysteries is exactly how SARS-CoV-2, which is the novel coronavirus that causes COVID-19, triggers the formation of blood clots that can lead to strokes and other life-threatening complications, even in younger people.
Recently, I had a chance to talk with Dr. Gary Gibbons, Director of NIH’s Heart, Lung, and Blood Institute (NHLBI) about what research is being done to tackle this baffling complication of COVID-19. Our conversation took place via videoconference, with him connecting from his home in Washington, D.C., and me linking in from my home just up the road in Maryland. Here’s a condensed transcript of our chat:
Collins: I’m going to start by asking about the SARS-CoV-2-induced blood clotting not only in the lungs, but in other parts of the body. What do we know about the virus that would explain this?
Gibbons: It seems like every few weeks another page gets turned on COVID-19, and we learn even more about how this virus affects the body. Blood clots are one of the startling and, unfortunately, devastating complications that emerged as patients were cared for, particularly in New York City. It became apparent that certain individuals had difficulty getting enough oxygen into their system. The difficulty couldn’t be explained entirely by the extent of the pneumonia affecting the lungs’ ability to exchange oxygen.
It turned out that, in addition to the pneumonia, blood clots in the lungs were compromising oxygenation. But some patients also had clotting, or thrombotic, complications in their veins and arteries in other parts of the body. Quite puzzling. There were episodes of relatively young individuals in their 30s and 40s presenting with strokes related to blood clots affecting the arterial circulation to the brain.
We’re still trying to understand what promotes the clotting. One clue involves the endothelial cells that form the inner lining of our blood vessels. These cells have on their surface a protein called the angiotensin-converting enzyme 2 (ACE2) receptor, and this clue is important for two reasons. One, the virus attaches to the ACE2 receptor, using it as an entry point to infect cells. Two, endothelial-lined blood vessels extend to every organ in the body. Taken together, it seems that some COVID-19 complications relate to the virus attaching to endothelial cells, not only in the lungs, but in the heart and multiple organs.
Collins: So, starting in the respiratory tree, the virus somehow breaks through into a blood vessel and then gets spread around the body. There have been strange reports of people with COVID-19 who may not get really sick, but their toes look frostbitten. Is “COVID toes,” as some people call it, also part of this same syndrome?
Gibbons: We’re still in the early days of learning about this virus. But I think this offers a further clue that the virus not only affects large vessels but small vessels. In fact, clots have been reported at the capillary level, and that’s fairly unusual. It’s suggestive that an interaction is taking place between the platelets and the endothelial surface.
Normally, there’s a tightly regulated balance in the bloodstream between pro-coagulant and anticoagulant proteins to prevent clotting and keep the blood flowing. But when you cut your finger, for example, you get activation for blood clots in the form of a protein mesh. It looks like a fishing net that can help seal the injury. In addition, platelets in the blood stream help to plug the holes in that fishing net and create a real seal of a blood vessel.
Well, imagine it happening in those small vessels, which usually have a non-stick endothelial surface, almost like Teflon, that prevents clotting. Then the virus comes along and tips the balance toward promoting clot formation. This disturbs the Teflon-like property of the endothelial lining and makes it sticky. It’s incredible the tricks this virus has learned by binding onto one of these molecules in the endothelial lining.
Collins: Who are the COVID-19 patients most at risk for this clotting problem?
Gibbons: Unfortunately, it appears right now that older adults are among the most vulnerable. They have a lot of the risks for the formation of these blood clots. What’s notable is these thrombotic complications are also happening to relatively young adults or middle-aged individuals who don’t have a lot of other chronic conditions, or comorbidities, to put them at higher risk for severe disease. Again, it’s suggestive that this virus is doing something that is particular to the coagulation system.
Collins: We’d love to have a way of identifying in advance the people who are most likely to get into trouble with blood clotting. They might be the ones you’d want to start on an intervention, even before you have evidence that things are getting out of control. Do you have any kind of biomarker to tell you which patients might benefit from early intervention?
Gibbons: Biomarkers are being actively studied. What we do know from some earlier observations is that you can assess the balance of clotting and anticlotting factors in the blood by measuring a biomarker called D-dimer. It’s basically a protein fragment, a degradation product, from a prior clot. It tells you a bit about the system’s activity in forming and dissolving clots.
If there’s a lot of D-dimer activity, it suggests a coagulation cascade is jazzed up. In those patients, it’s probably a clue that this is a big trigger in terms of coagulation and thrombosis. So, D-dimer levels could maybe tell us which patients need really aggressive full anticoagulation.
Collins: Have people tried empirically using blood thinners for people who seem to be getting into trouble with this clotting problem?
Gibbons: There’s a paper out of the Mount Sinai in New York City that looked at thousands of patients being treated for COVID-19 [1]. Based on clinical practice and judgments, one of the striking findings is that those who were fully anticoagulated had better survival than those who were not. Now, this was not a randomized, controlled clinical trial, where some were given full anticoagulation and others were not. It was just an observational study that showed an association. But this study indicated indirectly that by giving the blood thinners, changing that thrombotic risk, maybe it’s possible to reduce morbidity and mortality. That’s why we need to do a randomized, controlled clinical trial to see if it can be used to reduce these case fatality rates.
Collins: You and your colleagues got together and came up with a design for such a clinical trial. Tell us about that.
Gibbons: My institute studies the heart, lung, and blood. The virus attacks all three. So, our community has a compelling need to lean in and study COVID-19. Recently, NIH helped to launch a public-private partnership called Accelerating COVID-19 Therapeutic Interventions and Vaccines (ACTIV). As the name spells out, this initiative provides is a clinical platform to generate life-saving treatments as we wait for the development of a vaccine.
Through ACTIV, a protocol is now in the final stages of review for a clinical trial that will involve a network of hospitals and explore the question: is it sufficient to try a low-dose thrombo-prophylactic, or clot preventative, approach versus full anticoagulation? Some think patients ought to have full anticoagulation, but that’s not without risk. So, we want to put that question to the test. As part of that, we’ll also learn more about biomarkers and what could be predictive of individuals getting the greatest benefit.
If we find that fully anticoagulating patients prevents clots, then that’s great. But it begs the question: what happens when patients go home? Is it sufficient to just turn off the drip and let them go their merry way? Should they have a low dose thrombo-prophylactic regimen for a period of time? If so, how long? Or should they be fully anticoagulated with oral anticoagulation for a certain period of time? All these and other questions still remain.
Collins: This can make a huge difference. If you’re admitted to the hospital with COVID-19, that means you’re pretty sick and, based on the numbers that I’ve seen, your chance of dying is about 12 percent if nothing else happens. If we can find something like an anticoagulant that would reduce that risk substantially, we can have a huge impact on reducing deaths from COVID-19. How soon can we get this trial going, Gary?
Gibbons: We have a sense of urgency that clearly this pandemic is taking too many lives and time is of the essence. So, we’ve indeed had a very streamlined process. We’re leveraging the fact that we have clinical trial networks, where regardless of what they were planning to do, it’s all hands on deck. As a result, we’re able to move faster to align with that sense of urgency. We hope that we can be off to a quick launch within the next two to three weeks with the anticoagulation trials.
Collins: This is good because people are waiting on the vaccines, but realistically we won’t know whether the vaccines are working for several more months, and having them available for lots of people will be at the very end of this year or early 2021 at best. Meanwhile, people still are going to be getting sick with COVID-19. We want to be able to have as many therapeutic options as possible to offer to them. And this seems like a pretty exciting one to try and move forward as quickly as possible. You and your colleagues deserve a lot of credit for bringing this to everybody’s attention.
But before we sign off, I have to raise another issue of deep significance. Gary, I think both of us are struggling not only with the impact of COVID-19 on the world, but the profound sorrow, grief, frustration, and anger that surrounds the death of George Floyd. This brings into acute focus the far too numerous other circumstances where African Americans have been mistreated and subjected to tragic outcomes.
This troubling time also shines a light on the health disparities that affect our nation in so many ways. We can see what COVID-19 has done to certain underrepresented groups who have borne an undue share of the burden, and have suffered injustices at the hands of society. It’s been tough for many of us to admit that our country is far from treating everyone equally, but it’s a learning opportunity and a call to redouble our efforts to find solutions.
Gary, you’ve been a wonderful leader in that conversation for a long time. I want to thank you both for what you’re doing scientifically and for your willingness to speak the truth and stand up for what’s right and fair. It’s been great talking to you about all these issues.
Gibbons: Thank you. We appreciate this opportunity to fulfill NIH’s mission of turning scientific discovery into better health for all. If there’s any moment that our nation needs us, this is it.
Reference:
[1] Association of Treatment Dose Anticoagulation With In-Hospital Survival Among Hospitalized Patients With COVID-19. Paranjpe I, Fuster V, Lala A, Russak A, Glicksberg BS, Levin MA, Charney AW, Narula J, Fayad ZA, Bagiella E, Zhao S, Nadkarni GN. J Am Coll Cardiol. 2020 May 5;S0735-1097(20)35218-9.
Links:
Coronavirus (COVID-19) (NIH)
“Rising to the Challenge of COVID-19: The NHLBI Community Response,” Director’s Messages, National Heart, Lung, and Blood Institute/NIH, April 29, 2020.
Accelerating COVID-19 Therapeutic Interventions and Vaccines (ACTIV) (NIH)
Cool Videos: Heart Attack
Posted on by Dr. Francis Collins
Up next in our scientific film fest is an original music video, straight from the Big Apple. Created by researchers at The Rockefeller University, this song-and-dance routine provides an entertaining—and informative—look at how blood clots form, their role in causing heart attacks, and what approaches are being tried to break up these clots.
Before (or after!) you hit “play,” it might help to take a few moments to review the scientists’ description of their efforts: the key to saving the lives of heart attack victims lies in the molecules that control how blood vessels become clogged. This molecular biomedicine music video explains how ischemic injury can be prevented shortly after heart attack symptoms begin: clot blocking. The science is the collaborative work of Dr. Barry Coller of Rockefeller, Dr. Craig Thomas and his colleagues at the National Center for Advancing Translational Sciences (NCATS), and Dr. Marta Filizola and her Mount Sinai colleagues.
Links:
Laboratory of Blood and Vascular Biology, The Rockefeller University
Filizola Laboratory, Icahn School of Medicine at Mount Sinai
Center for Clinical and Translational Science, The Rockefeller University
Clinical and Translational Science Awards (NCATS/NIH)
NIH Common Fund Video Competition
NIH support: Common Fund; National Center for Advancing Translational Sciences
Cellular Shape-Shifters to the Rescue
Posted on by Dr. Francis Collins
Caption: Angular red blood cells, called polyhedrocytes, held together by platelets (blue) and fibrin protein (yellow).
Credit: John Weisel, University of Pennsylvania, Philadelphia
Just as superheroes often change their forms to save the day, so it seems do red blood cells as they mobilize to heal a wound. Red blood cells usually look like oval, bi-concave discs, but NIH-funded researchers recently discovered that they are actually talented shape-shifters.
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