The thrombotic nature of cardiac injury in subjects dying of COVID-19 infection

Junior commentary:

Regardless of the worldwide diffusion of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) pandemic, still little is known concerning the pathophysiological mechanism leading to multiorgan damage in coronavirus disease 2019 (COVID-19). Already at the early stage of SARS-CoV-2 diffusion, several studies reported a hypercoagulable state as well as a high incidence of thrombotic and cardiovascular events in hospitalized COVID-19 patients^1–7. Meanwhile, the features of COVID-19 induced coagulopathy have been described as an immunothrombotic dysregulation, alterations of platelet transcriptome and proteome as well as increased platelet reactivity^8–11. However, the clinical relevance of COVID-19 induced coagulopathy still needs to be determined. Moreover, acute myocardial involvement is common in COVID-19^12–14. While the clinical presentation could be compatible with severe acute myocarditis, a pathological study anecdotally demonstrated low-grade myocardial inflammation with no virus localization into cardiac myocytes¹⁵. Up to now, pathological studies are lacking and the characterization of acute myocardial injury in COVID‐19 patients still needs to be further investigated.

Pellegrini and colleagues tried to address this issue. They present a systematic analysis of 40 hearts from hospitalized patients dying of COVID-19. One-third of them had pathological evidence of myocyte necrosis.  78% of them showed evidence of focal myocyte necrosis and 64% had microthrombi in myocardial capillaries, arterioles, and small muscular arteries.  Interestingly, microthrombi had significantly greater fibrin and terminal complement C5b-9 compared to intramyocardial thromboemboli from COVID-19 negative subjects. Thus, microthrombi was the most common cause of myocyte necrosis in COVID-19 patients and their composition was different compared to coronary thrombi from STEMI (regardless of if from COVID-19 patients or not). Of note, the presence of viral invasion in the heart did not correlate with the development of necrosis, suggesting that the direct viral action on the myocardium does not play a major role.

The main finding of this systematic analysis is the detection of microthrombi as the major cause of myocardial necrosis in COVID-19 disease. The pathophysiological mechanism leading to myocardial injury seems to be different from the typical endocardial vessel obstruction.

A clear limitation of this study consists of its autoptic nature: only patients dying due to COVID-19 have been included in this analysis. Thus, the incidence of microthrombi and necrosis severity in patients surviving SARS-CoV-2 could not be investigated and its clinical relevance requires further investigation.

This study provides further insights concerning COVID-19 coagulopathy. Together with recent findings on platelet biology and thromboimmune dysregulation^9,16 this study raises the question if an antithrombotic treatment in severe COVID-19 could provide clinical benefits. However, whether microthrombi and focal necrosis could be challenged with tailored anti-thrombotic therapy still need to be determined.

Senior commentary:

COVID‐19 pandemic is an ongoing global public health emergency, that as of March 5th 2021, has led to 116,291,845 confirmed cases and 2,583,173 deaths.¹⁷ Besides of the acute respiratory complications, COVID‐19 has shown to prominently affect the cardiovascular system.¹⁸ In fact, a close association exists between COVID-19 and the occurrence of cardiac arrhythmias, myocardial infarction, cardiomyopathy, shock, and cardiac arrest.¹⁹

In February 2021 the group by K. Hong has published the first meta-analysis exploring the prevalence and impact of cardiac injury on COVID-19.²⁰ For this purpose, a total of 21 studies including 7.076 COVID‐19 patients were selected and assessed. The authors evidenced that cardiac injury is common in hospitalized patients with advanced age (>60 years 2-fold higher vs those <60 years) and severe COVID-19 infection (seven-fold prevalence vs their non-severe counterparts). Furthermore, cardiac injury was associated with an increased risk of all-cause mortality in patients with COVID-19 (OR 10.11, 95% CI 4.49-22.77), an effect that was found to be even more notorious in severe COVID-19 patients (OR: 16.79, 95% CI: 5.52-51.02).²⁰

Several mechanisms have been proposed to induce myocardial injury including myocardial inflammation (due to direct viral infection or “cytokine storm”), endotheliitis, coronary vasculitis, myocarditis, plaque destabilization and right ventricular failure. ^21-24

In the following paper, Pellegrini and colleagues shed light on a new potential mechanism by which COVID-19 induces cardiac injury, the microthrombi.²⁵ The authors find, in a systematic pathology analysis of 40 hearts from patients who died from COVID-19 in Bergamo (Italy), that 35% of the patients had evidence of cardiac injury, as indicated by cardiomyocyte necrosis, mainly in the left ventricular inferior wall. Most importantly, microthrombi was found to be the most common cause of necrosis (64%). Further pathological studies revealed no differences in the inflammatory infiltrate between patients with and without cardiac infection and several molecular cardiac approaches and ultrastructural analysis showed no definitive evidence of direct myocardial infection as a major mechanism behind microthrombi formation. The authors further analyze thrombus constituents and report that COVID-19 microthrombi were characterized by higher levels of fibrin and terminal complement as compared to that of intramyocardial thrombi from patients without COVID-19 and thrombus aspirates retrieved from the culprit lesion of epicardial coronaries from STEMI patients with or without COVID-19.

In summary, multiple factors seem to contribute to cardiac injury in COVID-19 patients. Nicolai et al have evidenced the presence of inflammatory microvascular thrombi containing neutrophil extracellular traps associated with platelets and fibrin in the heart of severely affected COVID-19 patients.16 The findings of this paper provide new insights about the thrombotic nature of cardiac injury in subjects dying of COVID-19 infection and strengthen the contribution of fibrin in such deleterious effects likely supporting a potential protective role for anticoagulation in COVID-19 patients.²⁶