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 . 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.
 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.
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)
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Tags: Accelerating COVID-19 Therapeutic Interventions and Vaccines, ACE2, ACTIV, anticoagulants, arteries, biomarkers, blood, blood clots, blood thinner, brain, circulation, clinical trial, clotting, COVID toes, COVID-19, COVID-19 treatment, D-dimer, endothelial cells, health disparities, heart, lungs, novel coronavirus, pandemic, SARS-CoV-2, stroke, thrombo-prophylactic, toes, underserved communities, veins, younger people
Is it possible for those who are deemed asymptomatic to actually have sticky blood and for it not to have been picked up? I ask as my mother was asymptomatic, but then after the time period when she may have developed symptoms, she suddenly deteriorated and died within a few hours, as if she’d had a stroke or similar. Just wondered if asymptomatics could be carrying some hidden or less obvious symptoms.
Looks like there is a correlation with Metabolic Syndrome and acute glycemic state.
Is there any evidence of a correlation between anti phospholipid syndrome and COVID-19?
I have been diagnosed with Factor V of Leiden. What role will this condition have on catching the virus Covid 19.
I tested positive for covid and developed clots in my lungs. Currently being treated in the hospital. Just doing research and came across your article.
I have homozygous factor V leiden and take eliquis to prevent clotting. I was diagnosed 20 years ago in my Thirties, and used warfarin for 18 years before changing meds. Would there be any need for volunteers to obtain blood samples for study, and if so, how can I help?
My 38 year old son went to ER with severe pain in leg… they found 9 bloodclots in right leg and two in the left. They held him in the hospital and planned surgery in 3-4 days; they did a covid test and found he has covid-19! He doesn’t have symptoms. They are kicking him out of the hospital right now saying they won’t operate to remove the bloodclots until he no longer has covid-19. If covid worsens blood clotting, aren’t they sending him home to die?! To make matters worse, he will loose his health insurance at the end of this month. Is there anything he can do to receive treatments quickly?!
I’m not a doctor but I had a stroke and I am wondering if the stroke could have been brought on by covid and I didn’t know it and i was not checked for covid my blood BECAME so thick that they could not pull blood from my arm with a huge needle and I said oh my God get the doctor my blood is clotting up inside me I was hospitalized last year for approximately 3 months the doctor immediately put me on blood thinners I would suggest you get him to a doctor and have the doctor put him on blood thinner medication not a doctor but I have studied this ..and my children’s father just died last night from covid-19 I think if they would have given him a blood thinner when he went in maybe he would have been alive today he was alert he was a strong man and had never been hospitalized except when he had an accident when he was very young… I think this covid 19..has something to do with clotting the blood I sure hope a doctor OR SCIENTIST sees what I have written here as I have studied because I wanted to become a nurse and had a freak accident but I was only a CNA please contact a physician IMMEDIATELY! God bless you and God bless your husband 🙏🙏🙏
Should a person with factor V leiden that has had blood clots get a covid vaccination?
Hello Frank, I am wondering the same thing? I have had DVT in 2006 and I am still on warfarin… thanks for your comment… hopefully someone gets to answer these important questions/comments
Not a doctor but please ask YOUR Doctor to be safe.. I’m on blood thinner do to a stroke.. my doctor hasn’t suggested it..but ,I have other underlying health conditions … discuss with your doctor would be very important they are the specialist!
I am scheduled to get my first COVID-19 vaccination on Thursday. Should I be worried about my auto immune diseases – Hashimoto’s disease, Sjogren’s and a mild form of scleroderma? I am a 75-year-old female.
Are there any reports of blood clots after receiving the Pfizer or Moderna vaccine?
Any connection of blood clots between MTHFR and Covid vaccines? I have a history of DVT and pulmonary embolisms and am afraid to get vaccinated.
My 16 year old son never had COVID symptoms but it definitely went through our home. Not long after he started becoming so short of breath he had to stop all sports. He’s always been very athletic. His doctor found that his VEG-F was dangerously low and he is on Lumbrokinase currently but still unable to do any kind of aerobic exercise. Any other thoughts for how to cure this problem?