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)
Such good content and a relatable post, keep sharing. Thank you!
Does having Hemophilia help you from getting blood clots from covid19
Curious, since this was published June 11, has there been any further recommendations for a 30 year old, male, heterozygous for Factor V Leiden, who is not, yet, on an anticoagulant, to start taking one, before possibly contracting Covid-19?
I am curious if anyone is/has tried inhaled heparin to treat COVID-19 patients?
Therapeutic use of heparin and derivatives beyond anticoagulation in patients with bronchial asthma or COPD
https://pubmed.ncbi.nlm.nih.gov/29455115/?from_term=shute+jk&from_pos=1
Not a very nice idea for DIC, I think
Science for better health FOR ALL. A sincere thanks when threats come from many…
Are you looking into CMV and Factor 5 Leiden? With CMV – think Spanish Flu/ Philly Parade Celebration. I am sure that you must have gone down this route.
On another note, I want to mention other thoughts with you can share:
The symptoms of Covid (having all) are the same as vasculitis. Ask any of us (including me with MPA – focal Kidney), a rare autoimmune disease is not what is first thought of.
Also think what rare autoimmune diseases that focus on the lungs ? RA, or Vasculitis – Granulomatosis with Polyangittis. Churg-Strauss (chronic asthma). Perhaps testing for ANCA, PR3 or MPO for MPA? But stay in the Vasculitic Syndromes. One last thought – perhaps lung or kidney biopsies to confirm.
When you look at the children with Kawaski’s-Like disease, they were Covid asymptomatic and tests showed the antibodies. This makes me think that the virus will trigger syndromes that will not show its ugly head until later. With Vasculitis there is the trifecta: Stress/weaken immune, Birth/Genes/ and a Virus or bacterial infection.
Regarding senior in Nursing Homes – Hypertension/CHF, COPD and diabetes are the three conditions most prevalent. Average age 88. Hypertension and diabetes are narrowing the vessels. The question is: which are asymptomatic and which are symptomatic, and those that die from Covid? (side Note: Covid is spread asymptomatically by staff, and there are nursing home residents that are asymptomatic. No one would know unless all staff and all “residents/patients” in the nursing home are tested.
I seriously want to know the answer to your first question. I have Factor Five Leiden and very considered for my daughters who are only 6 and 3. I want to know if I should go the route of genetic testing to see if either of them have the same genome and with that information, how it might play out for school in the fall. I need answers!
I’m also interested in more about Factor V affects. Me and my daughter have this.
My daughter also has spherocytosis. Do you see any affects on how that might affect a patient who contacts COVID-19?
I am also interested in more about Factor V and covid. Several members of my family are affected, including myself, father, and son.
Also curious as my son and I carry the gene, and possibly my daughter too (not sure yet).
As a lay-person, I reached out to the CDC on this issue and it does not currently have guidelines pertaining to Factor V Leiden. Although, it was recommended to visit the Society of Hematology’s website, specifically guidelines within topic “NON-MALIGNANT TOPICS,” see COVID-19 and VTE/Anticoagulation (Version 3.0; last reviewed June 23, 2020).” I was told this section is closest related to Factor IV.
Is the presence of genetic coagulation disorders being studied in the population of people, particularly younger people, who develop clots? Is there a reason to think that people with these gene mutations could be at higher risk of developing clots should they contract COVID-19?
Hypoxemia leads to de-activated mitochondria and excess copper in the bloodstream = causal to uncontrolled clotting? Unreleased (low) zinc in the bloodstream (from the same above-mentioned source) = causal to skin and foot lesions?
Any infectious disease is bound to cause Multi organ involvement and failure too. Liver, you are bound to get disseminated intravascular coagulation (DIC)! Not a very difficult thing to understand. ICU protocols regarding the use of Heparin should be remembered always, treating Covid in ICU is also the same !!!!!!
I have heterozygous prothrombin gene mutation.
I’ve had 1 DVT and 3 superficial phlebitis.
Sister and Mother had numerous DVT’s and one PE.
Would this make me more likely to develop blood clots during COVID-19?
Might not recovery phase blood clots be prevented by using low oil, whole food, plant-based diets with lots of colorful, antioxidant foods, especially dark leafy greens? Such diets already have proven successful in preventing recurrent cardiovascular events by Caldwell Esselstyn, Jr. and others. Clinicians and researchers involved in The Plantrician Project could be asked to email former patients eating this way, for their experiences with Covid 19. They could be the experimental group to compare with matched controls to see if there are any clues regarding benefits. I suspect patients at home in recovery may eat highly inflammatory high animal protein diets in an effort to recover lost strength. Then again, if they’ve lost kidney function and are counseled to keep protein lower, maybe even plant-based, do they experience fewer clots? Teen boys who got the Kawasaki-like illness- What did they eat in recovery?
Clotting is immune failure. Bolster the immune system with healthy human adult male facial skin surface lipid p.o. just be sure to take off the aversive sentinel sub-pheromone volatiles first. That will stop the clotting and improve NK cell numbers, diminish leucopenia generally, and save lives…
My husband has blood clots in his legs, painful, feverish and some have moved. The Dr sent him for ultrasound and the results are : “not blood clots and unknown what it is”. What does a person do with that? No other tests have been ordered. I guess we just hope it resolves itself.
Check with a rheumatologist as it may be an autoimmune problem.
I don’t know, but since we’re looking at at an over 98% recovery rate, I think we’d best ignore the far greater danger of driving an automobile, shut down the entire world economy, ignore the far greater danger of driving an automobile, suicide (radically on the increase thanks to the scamdemic), seasonal flu, HIV… Instead we should ignore the success of Sweden, who left its people free and its economy functioning, and shut down the greatest economy on Earth! …
I feel for you man, and I’m sorry that it is so hard to trust science.The problem with writing off 2% of the population is, where do you draw the line? Is it OK to let 3% die? 5%? 50%? And who gets to decide what is in “acceptable“ rate of death? Talk to the people who have lost loved ones. We need more empathy.
In San Diego county, Hispanic patients have a larger number of deaths. Followed by Whites. Blacks are third. How is it that we have different numbers? Seems odd.
3 refs that may be relevant to the issue of treating CoVID patients early (mild/moderate breathing problems) with anticoagulants to bring down mortality rates.
1. Oudkerk M et.al. Diagnosis, Prevention, and Treatment of Thromboembolic Complications in COVID-19: Report of the National Institute for Public Health of the Netherlands. Radiology Published Online Apr 23 2020. https://doi.org/10.1148/radiol.2020201629
2. McGonagle D, O’Donnell JS, Sharif K, Emery P, Bridgewood C. Immune mechanisms of pulmonary intravascular coagulopathy in COVID-19 pneumonia. Lancet Rheumatology May 7 2020. https://doi.org/10.1016/S2665-9913(20)30121-1
3. Mortus JR, Manek SE, Brubaker LS, et al. Thromboelastographic Results and Hypercoagulability Syndrome in Patients With Coronavirus Disease 2019 Who Are Critically Ill. JAMA Netw Open. 2020;3(6):e2011192. doi:10.1001/jamanetworkopen.2020.11192
Observational science may be just as valid as placebo controlled trials in a pandemic!
I am extremely grateful to have Dr. Collins leading the NIH during these troubling times. Thank you from all of those who understand that it is at the intersection of science, public health and faith where we will find a way through these troubling times. We are all in this together and leaders like Dr. Collins and dedicated public servants from these three pillars of our society will help us every step of this challenging journey.
I guess the only way to prevent the spread of COVID and futher victims is still the old-fashioned isolation and containment. We gotta look after our own.
My nineteen year old son developed a DVT and PE after a case of presumed COVID in May. On the eleventh day of the virus, he began to limp and said he might have pulled a muscle in his thigh. The next morning he was admitted with a large blood clot from his pelvis to his knee.
My son’s oxygen levels dropped into the low 80s and the supplemental oxygen he was given did little to raise his levels. The ER had diagnosed pneumonia, but X-rays two days later showed it clearing away. Still, he struggled to get his oxygen levels up, and his heart rate was dangerously high.
My normally robust and extremely clean living son spent five days in the hospital before being released with blood thinners and several follow-up appointments with a hematologist. Thank God my son survived – all thanks to his talented team of quick thinking and determined doctors and compassionate nurses.
As a former journalist, I researched and found tons of cases referencing the blood clot – COVID connection in patients throughout Europe and China. This is one sneaky and unpredictable virus.
I am a 55 yr old woman with compromised immune system due to long term lyme disease. In mid August I had a high fever for two weeks, dr said it was viral. A few weeks later I suffered a stroke suddenly, caused by two blood clots in my head. Fortunately with therapy I recovered. With some issues I’m stuck with. I have not been tested for antibodies, should I ? I would cooperate in any form to find out
I must say I am astounded that with such emphasis on hypercoagulability that platelets do not enter the discussion. I wrote a manuscript but I will be brief here. Injury to a vessel where the Coronavirus has been implicated in endothelial dysfunction will stimulate platelet activation, increase Von Willebrand factor decrease ADAMTS13. Briefly then addition of aspirin to anticoagulation would be expected to improve outcome.
There is a correlation between type O blood, blot clots, and Covid 19. Patients with blood type O have been shown to have lower levels of von Willebrand factor, a blood clotting agent, than those with other blood types …