COVID-19-Associated Nonocclusive Fibrin Microthrombi in the Heart

Circulation. 2021 Jan 19;143(3):230-243. doi: 10.1161/CIRCULATIONAHA.120.050754. Epub 2020 Nov 16.

Abstract

Background: Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) and its resultant clinical presentation, coronavirus disease 2019 (COVID-19), is an emergent cause of mortality worldwide. Cardiac complications secondary to this infection are common; however, the underlying mechanisms of such remain unclear. A detailed cardiac evaluation of a series of individuals with COVID-19 undergoing postmortem evaluation is provided, with 4 aims: (1) describe the pathological spectrum of the myocardium; (2) compare with an alternate viral illness; (3) investigate angiotensin-converting enzyme 2 expression; and (4) provide the first description of the cardiac findings in patients with cleared infection.

Methods: Study cases were identified from institutional files and included COVID-19 (n=15: 12 active, 3 cleared), influenza A/B (n=6), and nonvirally mediated deaths (n=6). Salient information was abstracted from the medical record. Light microscopic findings were recorded. An angiotensin-converting enzyme 2 immunohistochemical H-score was compared across cases. Viral detection encompassed SARS-CoV-2 immunohistochemistry, ultrastructural examination, and droplet digital polymerase chain reaction.

Results: Male sex was more common in the COVID-19 group (P=0.05). Nonocclusive fibrin microthrombi (without ischemic injury) were identified in 16 cases (12 COVID-19, 2 influenza, and 2 controls) and were more common in the active COVID-19 cohort (P=0.006). Four active COVID-19 cases showed focal myocarditis, whereas 1 case of cleared COVID-19 showed extensive disease. Arteriolar angiotensin-converting enzyme 2 endothelial expression was lower in COVID-19 cases than in controls (P=0.004). Angiotensin-converting enzyme 2 myocardial expression did not differ by disease category, sex, age, or number of patient comorbidities (P=0.69, P=1.00, P=0.46, P=0.65, respectively). SARS-CoV-2 immunohistochemistry showed nonspecific staining, whereas ultrastructural examination and droplet digital polymerase chain reaction were negative for viral presence. Four patients (26.7%) with COVID-19 had underlying cardiac amyloidosis. Cases with cleared infection had variable presentations.

Conclusions: This detailed histopathologic, immunohistochemical, ultrastructural, and molecular cardiac series showed no definitive evidence of direct myocardial infection. COVID-19 cases frequently have cardiac fibrin microthrombi, without universal acute ischemic injury. Moreover, myocarditis is present in 33.3% of patients with active and cleared COVID-19 but is usually limited in extent. Histological features of resolved infection are variable. Cardiac amyloidosis may be an additional risk factor for severe disease.

Keywords: COVID-19; SARS-CoV-2; autopsy; heart; pathology.

Publication types

  • Comparative Study

MeSH terms

  • Adolescent
  • Adult
  • Aged
  • Aged, 80 and over
  • Angiotensin-Converting Enzyme 2 / biosynthesis
  • COVID-19* / metabolism
  • COVID-19* / mortality
  • COVID-19* / pathology
  • Child
  • Child, Preschool
  • Coronary Thrombosis* / metabolism
  • Coronary Thrombosis* / mortality
  • Coronary Thrombosis* / pathology
  • Female
  • Fibrin / metabolism*
  • Gene Expression Regulation, Enzymologic
  • Humans
  • Immunohistochemistry
  • Infant
  • Male
  • Middle Aged
  • Myocardium* / metabolism
  • Myocardium* / pathology
  • SARS-CoV-2 / metabolism*

Substances

  • Fibrin
  • ACE2 protein, human
  • Angiotensin-Converting Enzyme 2