[Research begins to pick apart the mechanisms behind a deadly
COVID-19 complication] [[link removed]]

CORONAVIRUS BLOOD-CLOT MYSTERY INTENSIFIES  
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Cassandra Willyard
May 8, 2020
Nature [[link removed]]

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_ Research begins to pick apart the mechanisms behind a deadly
COVID-19 complication _

There are multiple reasons that blood clots could be forming in
people with COVID-19, Steve Gschmeissner/Science Photo Library

 

Purple rashes, swollen legs, clogged catheters and sudden death —
blood clots, large and small, are a frequent complication of COVID-19,
and researchers are just beginning to untangle why. For weeks, reports
have poured in of the disease’s effects throughout the body, many of
which are caused by clots. “This is like a storm of blood clots,”
says Behnood Bikdeli, a fourth-year cardiology fellow at Columbia
University in New York City. Anyone with a severe illness is at risk
of developing clots, but hospitalized patients with COVID-19 appear to
be more susceptible.

Studies from the Netherlands and France suggest that clots appear in
20% to 30% of critically ill COVID-19 patients1
[[link removed]],2
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Scientists have a few plausible hypotheses to explain the phenomenon,
and they are just beginning to launch studies aimed at gaining
mechanistic insights. But with the death toll rising, they are also
scrambling to test clot-curbing medications.

Double whammy

Blood clots, jelly-like clumps of cells and proteins, are the body’s
mechanism to stop bleeding. Some researchers view clotting as a key
feature of COVID-19. But it’s not just their presence that has
scientists puzzled: it’s how they show up. “There are so many
things about the presentations that are a little bit unusual,” says
James O’Donnell, director of the Irish Centre for Vascular Biology
at the Royal College of Surgeons in Dublin.

Blood thinners don’t reliably prevent clotting in people with
COVID-19, and young people are dying of strokes caused by the
blockages in the brain. And many people in hospital have drastically
elevated levels of a protein fragment called D-dimer, which is
generated when a clot dissolves. High levels of D-dimer appear to be a
powerful predictor of mortality in hospitalized patients infected with
coronavirus3
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Researchers have also observed miniature clots in the body’s
smallest vessels. Jeffrey Laurence, a haematologist at Weill Cornell
Medicine in New York City, and his colleagues examined lung and skin
samples from three people infected with COVID-19 and found that the
capillaries were clogged with clots4
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groups, including a team led by O’Donnell, have reported similar
findings5
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“This is not what you'd expect to see in someone who just has a
severe infection,” he says. “This is really very new.” This
might help to explain why some people have critically low blood-oxygen
readings, and why mechanical ventilation often doesn’t help. It’s
a “double hit”, says O’Donnell. Pneumonia clogs the tiny sacs in
the lungs with fluid or pus, and microclots restrict oxygenated blood
from moving through them.

Viral impacts

Why this clotting occurs is still a mystery. One possibility is that
SARS-CoV-2 is directly attacking the endothelial cells that line the
blood vessels. Endothelial cells harbour the same ACE2 receptor that
the virus uses to enter lung cells. And there is evidence that
endothelial cells can become infected: researchers from the University
Hospital Zurich in Germany and Brigham and Women’s Hospital in
Boston, Massachusetts, observed SARS-Cov-2 in endothelial cells inside
kidney tissue6
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healthy individuals, the blood vessel is “a very smoothly lined
pipe”, says Peter Liu, chief scientific officer at the University of
Ottawa Heart Institute. The lining actively stops clots from forming.
But viral infection can damage these cells, prompting them to churn
out proteins that trigger the process.

The virus’s effects on the immune system could also affect clotting.
In some people, COVID-19 prompts immune cells to release a torrent of
chemical signals that ramps up inflammation, which is linked to
coagulation and clotting through a variety of pathways. And the virus
appears to activate the complement system, a defence mechanism that
sparks clotting. Laurence’s group found that small, clogged vessels
in lung and skin tissue from people with COVID-19 were studded with
complement proteins. All these systems — complement, inflammation,
coagulation — are interrelated, says Agnes Lee, director of the
Hematology Research Program at the University of British Columbia in
Vancouver, Canada. “In some patients with COVID, all of those
systems are kind of in hyperdrive.”

But Lee adds that there could be other factors at play that aren't
specific to COVID-19. People with the disease who become hospitalized
typically have a number of risk factors for clotting. They might be
elderly or overweight, and could have high blood pressure or diabetes.
They show up with high fevers and, because they’re seriously ill,
have probably been immobilized. They might have a genetic
predisposition to clotting, or be taking medications that increase the
risk. “It's kind of like a perfect storm,” she says.

Race to new therapies

Even as researchers begin to unravel how clotting occurs in people
with COVID-19, they’re sprinting to test new therapies aimed at
preventing and busting clots. Blood-thinning medications are standard
of care for patients in the intensive-care unit, and those with
COVID-19 are no exception. But dosing is a matter of hot debate.
“The question is now, how aggressive should you be?” says Robert
Flaumenhaft, chief of the division of homeostasis and thrombosis at
Beth Israel Deaconess Medical Center in New York City. Researchers
from Mount Sinai School of Medicine, also in New York City, reported
that hospitalized patients with COVID-19 on mechanical ventilation who
received blood thinners had a lower mortality than those who weren’t
treated with them. But the team couldn’t rule out other explanations
for the observation, and high doses of these drugs carry risks7
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At Columbia University in New York City, researchers are launching a
clinical trial to compare the standard clot-preventing doses of blood
thinners with a higher dose in people who are critically ill with
COVID-19. Similar trials are planned for Canada and Switzerland. And
scientists at Beth Israel Deaconess Medical Center have begun
enrolment for a clinical trial to evaluate an even more powerful
clot-busting medication called tissue plasminogen activator, or tPA.
This drug is more potent, but carries higher risks of serious bleeding
than do blood thinners.

Scientists hope that these trials and others will provide the data
necessary to help physicians to make difficult treatment decisions.
Lee worries about the amount of ‘reactionary medicine’ happening.
“People are changing their therapeutic approach in reaction to their
local and personal experience,” she says. She understands the
impetus, “but we have to remember the main thing is first do no
harm”.

_Cassandra Willyard is a science writer based in Madison, Wisconsin._

doi: 10.1038/d41586-020-01403-8

References

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Klok, F. A. _et al._ _Thromb. Res_.
[link removed]
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*
Poissy, J. _et al._ Circulation
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[[link removed]] (2020).

* Zhang, L. _et al._ _J. Thromb.
Haemost._ [link removed]
[[link removed]] (2020).
* Magro, C. _et al._ _Transl.
Res._ [link removed]
[[link removed]] (2020).
* Fogarty, H. _et al._ _British Journal of Haematology_,
[link removed] [[link removed]]
(2020).
* Varga, Z. _et al._ _Lancet_ 395, 1417–1418 (2020).
* Paranjpe, I. _et al._ _J. Am. Coll. Cardiol_.
[link removed]
[[link removed]] (2020).

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