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COVID-19: Abnormal Clotting Common in More Severe Disease

— Chinese clinicians on the early front lines argue for anticoagulation

MedpageToday
A computer rendering of a thrombosis traveling through an artery

This story was originally published on March 24, 2020. As part of 鶹ý's review of the past year's top stories, we are republishing it along with an update on antithrombotic prophylaxis in COVID-19 reviewing subsequent developments in 2020.

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 .

"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 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 in New Haven, Connecticut, 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 3 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

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 vessels 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 widespread 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 , 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 the cardiovascular system, and attention should be given to cardiovascular protection during treatment for COVID-19," Zheng said.