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Autopsies on patients who died from COVID-19 are providing important clues on how to treat the disease. In an analysis of 40 hearts from COVID-19 patients who died early in the pandemic, myocyte necrosis was seen in 14 hearts, or 35%.
In the majority of these hearts, pathologists found both small areas of focal necrosis and cardiac thrombi, most of which were microthrombi in myocardial capillaries, arterioles, and small muscular cells.
In an interview, senior author Aloke V. Finn, MD, CVPath Institute, Gaithersburg, Maryland, stressed the importance of understanding what they saw, but also what they didn’t see.
“What we saw in the majority of patients with myocardial injury were these small areas of infarct and microthrombi in small vessels. What we didn’t see was any evidence of myocarditis and or huge infarcts in, like, the LAD artery,” he said.
“What we’re seeing here is not clinically detectable…. There is no test that will tell you there are microthrombi and no imaging tests that will show these focal areas of necrosis, but that doesn’t mean it’s not there,” he added.
The finding of myocyte necrosis in about one-third of samples is consistent with another study that showed that 30% to 40% of patients hospitalized with COVID-19 have elevated troponins, noted Finn. The investigators were unable to obtain troponin levels on their patients, which could limit the clinical translation of myocardial necrosis detected at autopsy.
Finn and colleagues, including first author Dario Pellegrini, MD, from Ospedale Papa Giovanni XXIII in Bergamo, Italy, published their findings online in Circulation on January 22.
The report is a follow-up to another just published by Finn’s group in the Journal of the American College of Cardiology, which showed that myocarditis is a very rare finding in COVID-19 autopsies.
Only three of 14 individuals (21.4%) with evidence of myocyte necrosis showed evidence of acute myocardial infarction, which Finn and colleagues define as an area of necrosis at least 1 cm2 in size. The remaining 11 (78.6%) had only discrete areas of myocyte necrosis (>20 necrotic myocytes with an area of ≥0.05 mm2, but <1 cm2).
“This makes sense when we saw what type of thrombus there was in these cases; it wasn’t thrombus in major epicardial vessels but microthombi in small vessels,” said Finn.
In those with necrosis, cardiac thrombi were present in 11 of 14 (78.6%) cases, with two of 14 (14.2%) having epicardial coronary artery thrombi and none of 14 (64.3%) having microthrombi in myocardial capillaries, arterioles, and small muscular arteries.
Further supporting the role of COVID-related hypercoagulability as the cause of myocardial injury in many patients, the investigators note that the incidence of severe coronary artery disease (defined as >75% cross sectional narrowing) did not differ significantly between those with and without necrosis.
COVID vs Non-COVID Thrombi
Going one step further, Finn’s team compared cardiac microthrombi from their COVID-19 positive autopsy cases with intramyocardial thromboemboli from COVID-19 cases. They also compared the samples with aspirated thrombi obtained during primary percutaneous coronary intervention from uninfected and COVID-19-infected patients presenting with ST-segment elevation myocardial infarction (STEMI).
The autopsy-obtained microthrombi had significantly more fibrin and terminal complement C5b-9 immunostaining than intramyocardial thromboemboli from COVID-19-negative subjects and than aspirated thrombi from either COVID-positive or COVID-negative STEMI patients.
“Basically, what we’re seeing in these thrombi is evidence of an immune-mediated reaction,” said Finn, explaining that complement C5b-9 is an innate immune system protein that circulates in the blood in response to any kind of activation of the immune system. “It is nonspecific but can also lead to coagulation problems,” he said.
Anticoagulation, Yes, but Dose Unclear
These findings clearly support the use of anticoagulation in hospitalized COVID patients, said Jeffrey Weitz, MD, director, Thrombosis & Atherosclerosis Research Institute, McMaster University, Hamilton, Ontario, Canada. But the details of how much anticoagulation, what kind, and for whom are still a moving target.
“I think what we can say at this point is that these autopsy findings fit with previous studies that have shown microthrombi in the lungs and thrombi in the legs and gut, and support the notion that these patients should receive prophylactic doses of anticoagulants if they’re sick enough to be hospitalized,” said Weitz.
“But it’s not as simple as to say that this study shows clots form in the heart of COVID patients and therefore more anticoagulation is going to be better than less anticoagulation,” he told theheart.org | Medscape Cardiology.
Recent top-line findings from three linked clinical trials — REMAP-CAP, ACTIV-4, and ATTACC — show that full-dose anticoagulation was beneficial in moderately ill patients hospitalized for COVID-19 and reduced the need for mechanical ventilation.
Moderately ill patients are those not in intensive care and who did not require organ support, such as mechanical ventilation, at the time of enrolment.
However, the same group reported findings in December that showed that routine use of full-dose anticoagulation when started in the ICU in critically ill patients was not beneficial and possibly harmful.
Weitz was only a little bit surprised by this finding of potential harm in the sickest patients. “I figured everybody should get prophylaxis but I wasn’t sure that everybody should get intensified anticoagulant. But my assumption was that if anybody is going to benefit from it, it would be the ICU patients.”
It was notable, said Weitz, that levels of D-dimer, a fibrin degradation product, were not associated with outcomes.
“So, it doesn’t seem to be that patients with evidence of more clotting are more likely to benefit, which might indicate that it’s not the anticoagulant effect of the heparin that’s helping, but maybe the anti-inflammatory effect. At this point, we just don’t know.”
All three studies have paused enrolment of the critically ill subgroup, but are continuing to enroll patients with moderate illness and expect to publish results in the coming months, according to previous theheart.org | Medscape Cardiology coverage.
The study was funded by CVPath, a nonprofit institute that receives funding from a number of different industry entities. Finn and Weitz report no relevant conflicts of interest.
Circulation. Published online January 22, 2021. Abstract