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Anemia and Rheumatoid Arthritis

In international webinars, social media posts, and team calls on their way to work, cardiologists treating COVID-19 patients are repeating the same two words: blood clots.

“Amongst the hot topics in COVID-19 land over the past weeks, I would say blood clotting is probably the top of the list,” says cardiologist Michelle Weisfelner Bloom, MD, an associate professor of medicine at Stony Brook University Medical Center in New York. “What we’re seeing particularly in hospitalized patients — and it’s likely also happening in outpatients [people not in the hospital] — is an extraordinary amount of abnormal clotting.”

Such complications are adding to the gathering realization that COVID-19 is much more than just a respiratory condition.

“What we first thought from physicians in China and Italy was that SARS-CoV-2 predominantly caused a bad form of acute lung injury,” says Sean Pinney, MD, director of heart failure and transplantation for the Mount Sinai Health System in New York City. “What has since emerged is that this is really a thrombotic [clotting] disorder. What determines severe illness — and often what determines whether patients live or die — is the degree of blood clotting and the consequent organ dysfunction and failure that results.”

These shared insights are also showing up in a growing list of medical literature.

“Recent observations suggest that respiratory failure in COVID-19 is not driven by the development of the acute respiratory distress syndrome (ARDS) alone, but that (microvascular) thrombotic processes may play a role as well,” according to a recent special report in the journal Radiology. “There is a strong association between D-dimer levels [which indicate clotting], disease progression, and chest CT features suggesting venous thrombosis.”

As the medical community has started zeroing in on blood clots in COVID-19 patients, anticoagulant medications have become a key part of doctors’ treatment arsenals for COVID-19.

But if you’re someone with an underlying condition who has already been taking anticoagulant therapy, what does all this mean for you?

The Nature of COVID-19 Blood Clots

Cardiologists are used to hospitalized patients developing blood clots, but the type of clotting that is occurring in COVID-19 cases is different.

“We’re seeing blood clots everywhere,” says Dr. Pinney. This degree of clotting with a viral infection is very unusual.

“The most prevalent clotting is in small arteries that carry blood into various tissues and organs, like the kidneys, lungs, or heart,” he says. “But we’re also seeing blood clots forming in the veins, such as in the legs, and if those get big enough, they can break apart and travel to the lungs.”

In addition, clots are forming at the ends of tiny vessels, like in the fingertips, where they’re causing frostbite-like blanching and tissue loss.

“In a normal situation if you have a trauma or infection, your body can form a clot to wall off that site, but when clotting happens all over the place, it becomes a very big problem,” says Amish Raval, MD, director of the level one heart attack program and director of clinical cardiovascular research at UW Health in Madison, Wisconsin.

The clotting is making certain procedures more challenging. “My colleagues and I have noticed that when we do procedures that are vitally necessary, such as advancing catheters or placing dialysis lines, COVID-19 patients tend to clot a lot more.”

In addition, the blood of COVID-19 patients is clotting in dialysis machines and test tubes after blood draws, says Satjit Bhusri, MD, associate director of cardiology at Lenox Hill Hospital in New York City and assistant professor of cardiology at Zucker School of Medicine at Hofstra/Northwell.

Who Is Getting Blood Clots from COVID-19

In terms of which patients are most likely to form clots, the coronavirus is frustrating doctors’ expectations.

“We’re seeing clots in patients you’d never expect: Healthy 35-year-olds with no risk factors are coming in COVID-positive, and they’re having these strange strokes in one of the large vessels in the brain,” says Dr. Bloom.

Clotting is also being seen in already at-risk groups. “Clots have always been a concern with critically ill patients in the ICU. But even among that typically high-risk population, we’re seeing even higher rates of pulmonary embolism and other types of clotting in the COVID-19 patients.”

Causes of COVID-19 Blood Clots

The race to understand blood clots in COVID-19 cases is the subject of national and global communications among doctors, as well as a growing number of reviews and clinical trials.

“It’s still so poorly understood what’s driving this illness, but there are a lot of circulating theories on the mechanisms behind the increased occurrence of blood clots,” says Dr. Bloom.

Cytokine Storm

One theory faults the system-wide inflammation that can develop in serious COVID-19 cases.

Often called a “cytokine storm” this severe immune response floods the entire body with cytokines (proteins involved in immunity), causing overwhelming inflammation that can lead to organ failure and death.

It is possible this widespread inflammation irritates the endothelium — the inner lining of the blood vessels — which contributes to blood clot formation. “The cytokine storm caused by coronavirus is a real danger, and the inflammation tends to lead to a propensity of clotting,” says Dr. Raval.

Endothelial Infection

Another theory says the coronavirus could have the ability to directly infect the endothelial cells, causing clots. “This could be the reason that a catheter rubbing against the endothelium could cause clots to form around it,” Dr. Raval adds.

The Role of Anticoagulant Therapy

Under ideal circumstances, cardiologists treat well-understood conditions using research-backed protocols developed by expert societies. But the coronavirus has opened up a grey area.

“There are no official, universal guidelines for blood clots in COVID-19. You have to try your best based on the experience you have,” says Dr. Bloom.

This is certainly true when it comes to the use of anticoagulant therapy. This is a category of medications that helps blood to flow through the body’s veins and arteries by preventing it from clumping into clots. This group includes a number of medications, such as apixaban (Eliquis), heparin (Fragmin, Innohep, and Lovenox), andwarfarin (Coumadin and Jantoven).

As medical societies start forming preliminary recommendations regarding anticoagulant therapy, and medical centers and health systems develop their own protocols, some treatment practices have become common, while others are more varied.

“Most centers have adopted an approach of at least using prophylactic [preventive] anticoagulation in all hospitalized patients who are positive for COVID-19, unless there’s a reason they can’t, like having a major bleeding history,” says Dr. Bloom. “Where the discrepancies start is what to do above and beyond that initial prophylactic dose.”

To guide decisions about higher anticoagulant doses, many institutions are using a lab test that measures D-dimers, which are protein fragments released into the blood when clots are present.

“In our institution we’re using certain cut-offs in D-dimer levels to determine how aggressive to be about anticoagulation,” Dr. Bloom explains. “People who have a D-dimer above a certain level get a moderate dose, then people who have a D-dimer level above a higher cut-off generally get full-dose anticoagulation.”

What “full-dose anticoagulation” means in the context of treating hospitalized patients with COVID-19 could be slightly different from your previous full dose for a different condition, such as pulmonary embolism.

Dr. Raval agrees that these higher dose decisions can be tough to make.

“In normal situations before, if a patient had already developed a clot in the lungs or had a stroke or heart attack, everybody could agree it’s time for a higher dose,” he says. “What we don’t know now is, if we have a COVID-19 patient with elevated D-dimers, when do we pull the trigger and switch from a low intensity to high intensity prophylactic dose? It’s very hard to say.”

And what is the medication of choice?

“We prefer to use heparin, if possible,” says Dr. Pinney. “The reason is these medicines have specific anti-inflammatory properties, and they may also directly antagonize the virus.”

Unfractionated heparin, he adds, comes with the disadvantage of needing to be adjusted several times a day based on blood tests, and hospitals are trying to avoid unnecessarily exposing health care workers to patients with COVID-19. “Instead we prefer to use low molecular weight heparin, like Lovenox, which can be given either once or twice a day subcutaneously as an injection.”

With studies forthcoming, physicians say the use of anticoagulants for COVID-19 patients does seem to control the clotting to a degree, says Dr. Raval. “But whether or not they lead to a reduction in hospital stay or an improvement in survival we just don’t know yet.”

As for discharge instructions, some COVID-19 patients who recover and head home are being told to continue anticoagulation for a time because they might still be considered high risk for clotting, Dr. Bloom adds.

“We’re recognizing the risk of blood clotting extends even beyond the time that COVID-19 patients are in the hospital,” Dr. Pinney agrees. “At least in our health system we’re recommending you continue on some form of anticoagulant for two weeks after hospitalization.”

Are Patients Who Already Take Anticoagulants Protected from COVID-19 Clotting?

What does all of this mean for the many people already on anticoagulant therapy for a range of conditions, from heart attack and stroke to deep vein thrombosis and pulmonary embolism?

“The main question is this: If you’re already taking an anticoagulant and you become infected with COVID-19, does the fact that you were on an anticoagulant reduce your risk of blood clotting complications?” asks Dr. Pinney. “The answer is, we don’t know yet.”

“As our hospital system looks at the thousands of the COVID-19 cases that have come through — many of whom were already on anticoagulants — we’ll start to have data soon to answer that question,” he adds.

In the meantime, clinicians do know some things for sure.

 “If you’ve already been on anticoagulation drugs, you’re already at higher risk of developing COVID-19 related complications because of your underlying illness,” says Dr. Raval. “For example, if you’ve had a pulmonary embolism that has since resolved and you’re now maintaining on an anticoagulation drug, you’re still at higher risk for developing a pulmonary embolism if you were to develop COVID-19.”

And that higher risk is what makes it especially important for anyone with a chronic cardiovascular condition to observe social distancing precautions, such as staying home as much as possible, and wearing a mask plus maintaining at least six feet of distance from others if you have to go out.

The Most Important Point for Anyone Currently on Anticoagulants

With all of the unknowns surrounding COVID-19 and blood clots, cardiologists are definite on this point:

“The worst thing patients can do is change critical medicines like a blood thinner on their own,” says Dr. Bhusri. “Patients who have questions should call their doctor. If my own patients were concerned, I’d want them to call me so we can talk about it.”

Dr. Raval agrees. “People who are on oral anticoagulation for any reason need to keep taking their medication as prescribed,” he says.

But due to the increased importance of social distancing for high-risk groups, he adds a caveat that might be worth a discussion with your doctor.

“If you’re on warfarin, which requires you to leave your home [for monitoring], you’re risking more exposure to coronavirus. Your doctor may consider switching you to a direct oral anticoagulant that doesn’t require as much monitoring. But again, do not make any changes on your own.”

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Interview with Amish Raval, MD, director of the level one heart attack program and director of clinical cardiovascular research at UW Health in Madison, Wisconsin

Interview with Michelle Weisfelner Bloom, MD, cardiologist and associate professor of medicine at Stony Brook University Medical Center in New York

Interview with Satjit Bhusri, MD, associate director of cardiology at Lenox Hill Hospital in New York City and assistant professor of cardiology at Zucker School of Medicine at Hofstra/Northwell

Interview with Sean Pinney, MD, cardiologist and director of heart failure and transplantation for the Mount Sinai Health System in New York City

Magro C, et al. Complement associated microvascular injury and thrombosis in the pathogenesis of severe COVID-19 infection: A report of five cases. Translational Research. April 9, 2020. doi: https://doi.org/10.1016/j.trsl.2020.04.007.

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. April 23, 2020. doi: https://doi.org/10.1148/radiol.2020201629.

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