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A mysterious blood-clotting
complication is killing coronavirus patients
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"I have to remind American doctors: normal life is changing,"
"The virus can bind to the endothelial cells and may cause damage to the blood vessel especially the microcirculation of the small blood vessels," which leads to platelet aggregation, he said. "You can imagine that it is not a myocardial infection, it is not a stroke, it is the clots all over the body. So you can imagine why the high D-dimer. It is because of the wide spread of abnormal coagulation all over the body."
In 12-year follow-up of a cohort with another type of coronavirus, SARS, there were cardiovascular system abnormalities in 44% of the 25 patients, high lipids in 68%, and glucose metabolism problems in 60%.
Antiviral drugs used to treat COVID-19 may also interact with cardiovascular drugs -- for instance, liver injury and muscle enzyme elevations if lopinavir/ritonavir (Kaletra) is taken with certain statins, Chen said. Also, there is sudden cardiac death risk with chloroquine, and risk of bradycardia with lopinavir/ritonavir.
https://www.washingtonpost.com/health/2020/04/22/coronavirus-blood-clots/
Blood clots, in which the red liquid turns gel-like, appear to be the opposite of what occurs in Ebola, Dengue, Lassa and other hemorrhagic fevers that lead to uncontrolled bleeding. But they actually are part of the same phenomenon - and can have similarly devastating consequences.
Autopsies have shown some people's lungs fill with hundreds of microclots. Errant blood clots of a larger size can break off and travel to the brain or heart, causing a stroke or heart attack. On Saturday, Broadway actor Nick Cordero, 41, had his right leg amputated after being infected with the novel coronavirus and suffering from clots that blocked blood from getting to his toes.
"The problem we are having is that while we understand that there is a clot, we don't yet understand why there is a clot," Kaplan said. "We don't know. And therefore, we are scared."
Once thought a relatively straightforward respiratory virus, covid-19 is proving to be much more frightening
"We had the nurse at the bedside pushing heparin to keep the machine from clotting off. That's very rare," Hibbert said.
Hibbert said she awaits the day when a study will nail down how often Covid-19 patients are having clotting issues, and what to do about them.
"This is one of the many challenges in taking care of critically ill patients and trying to decide if what you're seeing at the bedside is rare and happening by chance, or if it's part of a larger pattern that could change your practice," she said.
An international consortium of experts from more than 30 hospitals gathered to consider the issue. Their conclusion: It's unclear exactly why, but coronavirus patients may be predisposed to having clots.
The Dutch study of 184 patients in the ICU with Covid-19-related pneumonia found that more than 20% were having clotting issues. A study of 81 similarly ill patients in Wuhan, China, found a 25% incidence of clots.
Bikdeli, a cardiovascular medicine fellow at Columbia University Irving Medical Center, said there are three major reasons why Covid-19 patients might have an especially high risk of clotting.
One is that vast majority of patients who become severely ill with coronavirus have underlying medical problems, such as diabetes, heart disease and high blood pressure. These patients -- whether they have coronavirus or not - have a higher tendency to clot than healthy patients.
Second, one way coronavirus can kill patients is through a "cytokine storm," where the body's own immune response turns on itself.
Patients experiencing that storm, because of coronavirus, influenza, or any other reason are at a higher risk for clotting.
The third reason is that there could be something about the novel coronavirus itself that's causing clots.
"The number of clotting problems I'm seeing in the ICU, all related to Covid-19, is unprecedented," Dr. Jeffrey Laurence, a hematologist at Weill Cornell Medicine in New York City, wrote in an email to CNN. "Blood clotting problems appear to be widespread in severe Covid."
Laurence and his colleagues looked at autopsies on two patients and found blood clots in the lungs and just beneath the surface of the skin, according to a study published last week. They also found blood clots beneath the skin's surface on three living patients.
In the Netherlands, a study found "remarkably high" rates of clotting among Covid patients in the ICU.
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Doctors try to untangle why they're seeing 'unprecedented' blood clotting among Covid-19 patients
By Elizabeth Cohen, CNN
Updated 12:50 AM ET, Wed April 22, 2020
https://www.cnn.com/2020/04/21/health/blood-clots-coronavirus/index.html
(CNN)Dr. Kathryn Hibbert's Covid-19 patient in the intensive care unit was not doing well. As his blood pressure plummeted, she tried to insert an intravenous line into an artery in his wrist.
A blood clot clogged the tubing.
Frustrated, Hibbert tried again with a new needle. A blood clot clogged up that line as well.
It took three tries to insert the IV.
"You just watch it clot right in front of you," said Hibbert, director of the medical intensive care unit at Massachusetts General Hospital. "It's rare to have that happen once, and extremely rare to have that happen twice."
Hibbert and other doctors are finding that some patients infected with the novel coronavirus have a propensity towards developing blood clots, which can be life threatening if the clot travels to the heart or lungs.
"The number of clotting problems I'm seeing in the ICU, all related to Covid-19, is unprecedented," Dr. Jeffrey Laurence, a hematologist at Weill Cornell Medicine in New York City, wrote in an email to CNN. "Blood clotting problems appear to be widespread in severe Covid."
Laurence and his colleagues looked at autopsies on two patients and found blood clots in the lungs and just beneath the surface of the skin, according to a study published last week. They also found blood clots beneath the skin's surface on three living patients.
In the Netherlands, a study found "remarkably high" rates of clotting among Covid patients in the ICU.
An international consortium of experts from more than 30 hospitals gathered to consider the issue. Their conclusion: It's unclear exactly why, but coronavirus patients may be predisposed to having clots.
"This is one of the most talked about questions in Covid right now," said Dr. Michelle Gong, chief of the division of critical care medicine at Montefiore Medical Center in New York City.
At Montefiore, they've started to put all Covid-19 patients on low doses of blood thinners to prevent clots, Gong said.
Not all hospitals have taken that step -- but they're still concerned.
"It's out of the norm, and we're wondering, are blot clots one of the reasons why these patients are dying," said Dr. Todd Rice, an associate professor of medicine at Vanderbilt University Medical Center in Nashville.
'Alarming' rates of blood clots
Being in the intensive care unit, sick and lying still, can be a perfect storm for blood clots for any patient.
"Even before Covid, we're on high alert for suspicion of clots in the ICU because they're at high risk," Gong said.
Even so, doctors have a hunch that Covid patients might be clotting even more than other ICU patients.
The Dutch study of 184 patients in the ICU with Covid-19-related pneumonia found that more than 20% were having clotting issues. A study of 81 similarly ill patients in Wuhan, China, found a 25% incidence of clots.
Dr. Behnood Bikdeli, who helped coordinate the international coalition of physicians looking into the clotting issue, called those numbers "alarming."
Bikdeli, a cardiovascular medicine fellow at Columbia University Irving Medical Center, said there are three major reasons why Covid-19 patients might have an especially high risk of clotting.
One is that vast majority of patients who become severely ill with coronavirus have underlying medical problems, such as diabetes, heart disease and high blood pressure. These patients -- whether they have coronavirus or not - have a higher tendency to clot than healthy patients.
Second, one way coronavirus can kill patients is through a "cytokine storm," where the body's own immune response turns on itself. Patients experiencing that storm, because of coronavirus, influenza, or any other reason are at a higher risk for clotting.
The third reason is that there could be something about the novel coronavirus itself that's causing clots.
Doctors say it's hard to know exactly what's behind what they're seeing with Covid-19 patients in the ICU.
"My gut tells me there are probably a subset of Covid patients who have really abnormal clotting behavior, that this is happening more frequently than we would expect it to," said Hibbert, an instructor at Harvard Medical School.
She quickly added, though, that doctors' gut feelings are "notoriously misleading" and that studies need to be done to get to the bottom of exactly how common clotting is among coronavirus patients.
A tricky fix
Fixing these clotting issues can be tricky.
While a low dose of blood thinners to prevent clots is generally considered low risk, that might not be enough to prevent clots in some patients. Giving larger doses, however, could make a patient bleed excessively, which can be deadly.
That leaves doctors in a conundrum. Some patients might benefit from larger doses of blood thinners because they're very sick with Covid-19, and their blood tests show they have elevated levels of D-dimer, a substance that indicates they might have clotting issues.
Doctors at Harvard have proposed doing a large study on blood thinners for these patients, Hibbert said.
"There's a crying need for these kinds of rapid trials," Gong said.
Laurence, the hematologist at Weill Cornell, said since treating clotting can be so tricky, he wants to figure out what's causing the clotting in the first place.
"We're trying to shut off what's causing it," he said. "There's overexuberant clotting going on with Covid patients, and we're trying to keep ahead of it."
While studies sort this out, doctors are being extra vigilant with their Covid-19 patients.
Hibbert described how a nurse recently had to constantly administer a blood thinner called heparin to a Covid-19 patient while the patient was undergoing kidney dialysis, because clots kept clogging up the tubing in the machine.
"We had the nurse at the bedside pushing heparin to keep the machine from clotting off. That's very rare," Hibbert said.
Hibbert said she awaits the day when a study will nail down how often Covid-19 patients are having clotting issues, and what to do about them.
"This is one of the many challenges in taking care of critically ill patients and trying to decide if what you're seeing at the bedside is rare and happening by chance, or if it's part of a larger pattern that could change your practice," she said.
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"I have to remind American doctors: normal life is changing,"
COVID-19: Abnormal Clotting Common in More Severe Disease
- Chinese clinicians on the early front lines argue for anticoagulation
by Crystal Phend, Senior Editor, MedPage Today March 24, 2020
https://www.medpagetoday.com/infectiousdisease/covid19/85577
Endothelial damage and subsequent clotting is common in severe and critical COVID-19 coronavirus, which may have implications for treatment, Chinese clinicians said at a webinar co-sponsored by the Chinese Cardiovascular Association and American College of Cardiology.
"Clots in the small vessels of all organs, not only the lungs but also including the heart, the liver, and the kidney," were described by Bin Cao, MD, of the National Clinical Research Center for Respiratory Diseases in Beijing, who helped develop treatment strategies there from the beginning of the epidemic.
His group had reported March 11 in The Lancet that D-dimer levels over 1 μg/L at admission predicted an 18-fold increase in odds of dying before discharge among 191 COVID-19 patients seen at two hospitals in Wuhan, China.
D-dimer, a fibrin degradation product indicating thrombosis, can exceed 70 or 80 μg/L, he said
"Anticoagulation therapy should be initiated for severe COVID-19 patients [unless] otherwise contraindicated," said Cao, who is also president-elect of the Chinese Society of Respiratory Medicine.
"If you see a high D-dimer like that, you have to give anticoagulation, regardless of the underlying mechanism," agreed webinar moderator Junbo Ge, MD, president of the Chinese Cardiovascular Association and ACC China chapter governor.
However, Harlan Krumholz, MD, of Yale University, called for first testing whether anticoagulation helps.
"What's most important for us is to develop the means to study what works," he said on the webinar. "There will be many plausible approaches to the care of these patients."
"Our Chinese colleagues are reporting to us a very high rate of cardiac involvement," he continued. "I think most cardiologists in the U.S. are still thinking this is not a cardiac disease, this is something else. ... But saying to our colleagues that this does involve the heart is one of the central messages we're hearing."
Another was that physicians in the U.S. should expect the unexpected from COVID-19.
In China, "we had a very hard time, especially in the early period," said Ge. "Today we try to share our experience in the last three months. We try to help our colleagues ... to shorten the mistakes that we had in China and especially for the patients with multi-organ damage."
"I have to remind American doctors: normal life is changing," said Cao. "If you think you should live your normal life, it's not true. Normal life is changing, not only in China but in America and other countries. ... It's a pandemic life now."
The Mechanism of Cardiac Injury
Acute cardiac injury was reported in 12% of COVID-19 cases in a small case series in The Lancet cited by Cao. Another study suggested a rate of 7.2% among 138 patients from another hospital in Wuhan, noted Yundai Chen, MD, of the Chinese PLA General Hospital in Beijing, during the webinar.
Comorbid cardiovascular disease is a distinct risk factor for COVID-19, associated with a mortality rate of up to 10.5% among more than 70,000 patients in one study, she pointed out.
The SARS-CoV-2 virus that causes COVID-19 disease enters cells via the angiotensin converting enzyme 2 (ACE2) receptors, which is most commonly found in the alveolar epithelial cells, followed by endothelial cells, Cao noted.
"The virus can bind to the endothelial cells and may cause damage to the blood vessel especially the microcirculation of the small blood vessels," which leads to platelet aggregation, he said. "You can imagine that it is not a myocardial infection, it is not a stroke, it is the clots all over the body. So you can imagine why the high D-dimer. It is because of the wide spread of abnormal coagulation all over the body."
Along with endothelial shedding and thrombosis in vessels, autopsies showed inflammatory changes in the heart with fine interstitial mononuclear inflammatory infiltrates, but no viral inclusions in the heart, Chen added. Other potential mechanisms for the cardiac damage are hypoxia-induced myocardial injury, cardiac microvascular damage, and systemic inflammatory response syndrome.
However, in the majority of mild and moderate cases, the only cardiac impact was some tachycardia and little higher troponin, Chen noted. "Maybe preventing the transition to severe cases is crucial."
For severe COVID-19 patients with heart dysfunction, the strategy is to treat the symptoms, prevent complications, treat the pre-existing disease, and provide functional support in time, Chen said. Key points she highlighted were:
• Respiratory support with extracorporeal membrane oxygenation provided in time for ICU patients with acute heart failure
• Circulation support with sufficient fluid resuscitation, paying attention to fluid balance
• Continuous renal replacement therapy to protect the kidneys provided as early as possible
For severe or critical cases, monitoring ECG may turn up tachycardia, generally with a heart rate of 100 or 120 bpm, Chen noted. "It is quite dangerous for initiating acute coronary syndrome or acute myocardial infarction, so we need to also pay attention to this."
Notably, fulminant myocarditis from the disease can mimic ST-segment elevation myocardial infarction (STEMI).
Chen pointed to the case of a COVID-19-infected man with apparent STEMI by ECG, troponin T over 10,000 ng/L, and CK-MB of 113 ng/L, but for whom coronary angiography showed no stenosis. After treatment with steroids, immunoglobulin, norepinephrine, diuretic, a vasodilator, and antibiotics, the man's ejection fraction recovered from 27% to 66% and his enlarged heart normalized.
Fulminant myocarditis is rare, though, Ge noted. "The main issue is hypoxia," he said, because it makes myocardial ischemia more severe.
As far as treatment of pre-existing cardiovascular disease, management is not special, Chen said. ACE inhibitor and angiotensin receptor blocker (ARB) medication use "remains controversial," but those on antiplatelet drugs should stay on them while checking closely for bleeding; liver function should be monitored closely for those on statins, and selective beta-blockers are recommended if there is no hypoxia or airway spasms, she added.
Antiviral drugs used to treat COVID-19 may also interact with cardiovascular drugs -- for instance, liver injury and muscle enzyme elevations if lopinavir/ritonavir (Kaletra) is taken with certain statins, Chen said. Also, there is sudden cardiac death risk with chloroquine, and risk of bradycardia with lopinavir/ritonavir.
Future Implications
The long-term implications of COVID-19 cardiac injury aren't clear, said Ying-Ying Zheng, PhD, presenting in English on behalf of Yi-Tong Ma, MD, PhD, both of the First Affiliated Hospital of Xinjiang Medical University in China, in the webinar.
In 12-year follow-up of a cohort with another type of coronavirus, SARS, there were cardiovascular system abnormalities in 44% of the 25 patients, high lipids in 68%, and glucose metabolism problems in 60%.
"Given that SARS-CoV-2 has a similar structure to SARS-CoV, this novel virus may cause chronic damage to cardiovascular system, and attention should be given to cardiovascular protection during treatment for COVID-19," Zheng said.
Last Updated March 24, 2020
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