Microthrombi as a Major Cause of Cardiac Injury in COVID-19

Abstract

Background: Cardiac injury is common in hospitalized patients with COVID-19 and portends poorer prognosis. However, the mechanism and the type of myocardial damage associated with SARS-CoV-2 remain uncertain. Methods: We conducted a systematic pathologic analysis of 40 hearts from hospitalized patients dying of Coronavirus Disease 2019 (COVID-19) in Bergamo, Italy to determine the pathologic mechanisms of cardiac injury. We divided the hearts according to presence or absence of acute myocyte necrosis and then determined the underlying mechanisms of cardiac injury. Results: Of the 40 hearts examined, 14 (35%) had evidence of myocyte necrosis, predominantly of the left ventricle. As compared to subjects without necrosis, subjects with necrosis tended to be female, have chronic kidney disease, and shorter symptom onset to admission. The incidence of severe coronary artery disease (i.e., >75% cross sectional narrowing) was not significantly different between those with and without necrosis. 3/14 (21 .4%) subjects with myocyte necrosis showed evidence of acute myocardial infarction defined as ≥1 cm 2 area of necrosis while 11/14 (78.6%) showed evidence of focal (> 20 necrotic myocytes with an area of ≥ 0.05 mm 2 but <1 cm 2 ) myocyte necrosis. Cardiac thrombi were present in 11/14 (78.6%) cases with necrosis, with 2/14 (14.2%) having epicardial coronary artery thrombi while 9/14 (64.3%) had microthrombi in myocardial capillaries, arterioles, and small muscular arteries. We compared cardiac microthrombi from COVID-19 positive autopsy cases to intramyocardial thromboemboli from COVID-19 cases as well as to aspirated thrombi obtained during primary percutaneous coronary intervention from uninfected and COVID-19 infected patients presenting with ST-segment elevation myocardial infarction (STEMI). Microthrombi had significantly greater fibrin and terminal complement C5b-9 immunostaining as compared to intramyocardial thromboemboli from COVID-19 negative subjects and to aspirated thrombi. There were no significant differences between the constituents of thrombi aspirated from COVID-19 positive and negative STEMI patients. Conclusions: The most common pathologic cause of myocyte necrosis was microthrombi. Microthrombi were different in composition as compared to intramyocardial thromboemboli from COVID-19 negative subjects and to coronary thrombi retrieved from COVID-19 positive and negative STEMI patients. Tailored anti-thrombotic strategies may be useful to counteract the cardiac effects of COVID-19 infection.

The Right Ventricle in COVID-19

“…While coronary plaque rupture leading to ST-segment elevation myocardial infarction has been occasionally reported in COVID-19 [130], emerging evidence indicates that microcirculatory derangements may represent a more frequent mechanism of myocardial ischemia. This has been well documented in several histopathological studies demonstrating a high prevalence of microvascular thrombosis, associated with focal areas of necrosis [131,132]. The mechanisms responsible for these alterations are presumably similar to those previously discussed, including coagulopathy, endotheliopathy, and platelet and complement activation [122].…”

“…The mechanisms responsible for these alterations are presumably similar to those previously discussed, including coagulopathy, endotheliopathy, and platelet and complement activation [122]. Indeed, a recent study identified a unique composition of COVID-19 associated coronary microthrombi that were significantly enriched in fibrin and terminal complement [131]. These findings provide a pathological basis for the reported occurrence of myocardial infarction with non-obstructive coronary arteries (MINOCA) in COVID-19 patients [130,133].…”

Recovery of a critically ill patient with COVID-19 myocarditis

“…An additional mechanism of cardiac injury has been described by Pellegrini et al, from the Italian autopsy series. Cardiac myocyte necrosis from microthrombi was different in composition from thrombi from catheter aspirates from patients with acute coronary syndrome [ 9 ].…”

Demographic, multi-morbidity and genetic impact on myocardial involvement and its recovery from COVID-19: protocol design of COVID-HEART—a UK, multicentre, observational study

“…Troponin T release is commonly seen in critically ill patients because of oxygen supply–demand mismatch and cytokine release, acute heart failure, RV strain (secondary to pneumonia, hypoxia and increased pulmonary artery pressure) and acute arrhythmia [ 10 – 12 ]. Furthermore, the acute-phase response to severe coronavirus infection can lead to coagulopathy and microvascular thrombosis, for example in the pulmonary and coronary circulations [ 13 , 14 ]. Pre-existing coronary risk factors, such as hypertension and diabetes also predispose patients with COVID-19 to myocardial infarction in the acute setting, possibly implicating it as another potential disease mechanism [ 15 ].…”