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

Abstract

As we enter year 3 of SARS-CoV-2 pandemic, long-term consequences of COVID-19 have become a major public health issue worldwide; however, the molecular and cellular underpinnings of 'long COVID' remain very poorly understood. A paradigm has recently emerged that thrombo-inflammatory consequences of SARS-CoV-2's impact on endothelial cells and platelets likely play a significant role in the development of chronic symptomatology associated with COVID-19. In this brief overview, we discuss the recent findings pertaining to the detection of SARS-CoV-2 virions in vascular cell subtypes, the contribution of the coagulation system to the development of 'long COVID', and the potential role of stem/progenitor cells in the viral and thrombotic dissemination in this disorder.

Keywords: endothelium; long COVID; platelets; thrombosis.

Figure 1

Pathophysiological hallmarks of acute SARS-CoV-2 infection and its chronic consequences (long COVID). 1. Infection by SARS-CoV-2 occurs via inhalation of virus-containing respiratory droplets. 2 and 3. SARS-CoV-2 infects alveolar cells. 4. In alveoli, ACE2-expressing alveolar type II cells comprise SARS-CoV-2’s target (ACE2 is depicted in the drawing with a viral particle bound to it: ). ACE2 facilitates viral entry into the cells; subsequently, viral replication leads to the development of alveolitis and necrotic inflammation accompanied by basal membrane disruption whereby viral particles come in contact with endothelial cells of alveolar capillaries. Endothelial cells are progressively damaged by inflammation and, at high viral titers, become infected even though the levels of ACE2 expressed on their surfaces are quite low. Viral replication does not seem to occur in endothelial cells; however, their damage leads to a pro-thrombotic phenotype, exemplified by the release of von Willebrand factor. The resultant pathological changes comprise thrombotic microvascultis of the lung, which is accompanied by a pro-thrombotic shift in the plasma proteome. 5. SARS-CoV-2 originating from lung microvascular endothelium enters the bloodstream, which comprises the onset of the septic phase during which – aside from the systemic viral dissemination and inflammation, vasculitis, and hyper-coagulation – infection of stem/progenitor cells in the bone marrow and other tissues is a significant pathological hallmark. 7. ACE2 is also expressed in several types of other progenitor cells, including hematopoietic and endothelial progenitors, which renders them vulnerable to SARS-CoV-2. 8 and 9. Megakaryocytes express their own alternative gateways for coronavirus entry, for example, BSG/CD147 (depicted in the drawing with a viral particle bound to it ). Viral replication does not seem to occur in megakaryocytes; however, aberrations of the transcriptome have been described in megakaryocytes as well as platelets produced by them, likely with pro-thrombotic consequences. 10. Damage to the lung endothelium caused by the infection of endothelial cells, hematogenous viral dissemination, infection of the cellular precursors of endothelial cells/platelets, and transcriptome-level thrombogenic aberrations caused by the virus in infected cells significantly contribute to a) the severity of early SARS-CoV-2 infection; b) the emergence of SARS-CoV-2 infection’s septic multi-organ and thrombo-vascular complications; c) the development of long COVID.