Emerging Role of Platelet-Endothelium Interactions in the Pathogenesis of Severe SARS-CoV-2 Infection-Associated Myocardial Injury

Abstract

Cardiovascular dysfunction and disease are common and frequently fatal complications of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection. Indeed, from early on during the SARS-CoV-2 virus pandemic it was recognized that cardiac complications may occur, even in patients with no underlying cardiac disorders, as part of the acute infection, and that these were associated with more severe disease and increased morbidity and mortality. The most common cardiac complication is acute cardiac injury, defined by significant elevation of cardiac troponins. The potential mechanisms of cardiovascular complications include direct viral myocardial injury, systemic inflammation induced by the virus, sepsis, arrhythmia, myocardial oxygen supply-demand mismatch, electrolyte abnormalities, and hypercoagulability. This review is focused on the prevalence, risk factors and clinical course of COVID-19-related myocardial injury, as well as on current data with regard to disease pathogenesis, specifically the interaction of platelets with the vascular endothelium. The latter section includes consideration of the role of SARS-CoV-2 proteins in triggering development of a generalized endotheliitis that, in turn, drives intense activation of platelets. Most prominently, SARS-CoV-2–induced endotheliitis involves interaction of the viral spike protein with endothelial angiotensin-converting enzyme 2 (ACE2) together with alternative mechanisms that involve the nucleocapsid and viroporin. In addition, the mechanisms by which activated platelets intensify endothelial activation and dysfunction, seemingly driven by release of the platelet-derived calcium-binding proteins, SA100A8 and SA100A9, are described. These events create a SARS-CoV-2–driven cycle of intravascular inflammation and coagulation, which contributes significantly to a poor clinical outcome in patients with severe disease.

COVID-19 and Parkinsonism: A Critical Appraisal

“…These findings can explain the coexistence of vascular and infectious/inflammatory signs in the reported neuroimaging studies of the patients. The pathological documentation of intramural inflammation in the small vessels of the brain is strictly related to the elevated levels of the SARS-CoV-2 receptor ACE2 in the brain vasculature, and it is associated with sign of severe infection and systemic thrombotic and inflammatory involvement [ 36 , 37 , 38 ]. In another autoptic series of ten patients [ 39 ], all brains had neutrophilic microvascular endothelitis, suggesting that vasculitis with autoimmune features occurred in all patients.…”

Long-term effect of SARS-CoV-2 infection on cardiovascular outcomes and all-cause mortality

“…Although severe inflammation is one of the known mechanisms of endothelial activation [35] , Johnson et al have recently found no evidence of cytokine-mediated activation, nor the expression of adhesion proteins such as intercellular adhesion molecule-1 (ICAM-1) and vascular adhesion molecule-1 (VCAM-1) in heart tissue [38] . Furthermore, in an in vitro study, exposure of ECs culture from the coronary artery to the viral nucleocapsid protein stimulates the expression of ICAM-1 and VCAM-1 [39] . Therefore, further investigation is required to clarify this aspect.…”

SARS-CoV-2, platelets, and endothelium: coexistence in space and time, or a pernicious ménage à trois?

“…NP of SARS-CoV-2 -but not that of other coronaviruses, that is, SARS-CoV, MERS-CoV, HUB1-CoV, and/or H1N1 -can strongly activate human endothelial cells via the engagement of TLR2/NFKB and MAPK signaling pathways. SARS-CoV-2 NP potentiates the expression of ICAM1 and VCAM1, thus promoting monocyte adhesion to endothelial surfaces, as well as such proinflammatory cytokines as SELE, MCP-1/CCL2, IL1B (mRNA), and TNF -a potent inducer of endothelial activation; it is notable that the nature and the magnitude of SARS-CoV-2 NP's effects on the endothelium are comparable to those of TNF (25,26). TNF and various selectins (of endothelial as well as platelet origin) are known to be potent stimulators of von Willebrand factor (vWF) and coagulation factor F8/(F)VIII secretion from the endothelium; in COVID-19, a strong elevation of vWF and F8 secretion from the endothelium has been reported (26,27).…”