Abstract
In severe SARS-CoV-2 infections, emerging data including recent histopathological studies have emphasized the crucial role of endothelial cells (ECs) in vascular dysfunction, immunothrombosis, and inflammation.Histopathological studies have evidenced direct viral infection of ECs, endotheliitis with diffuse endothelial inflammation, and micro- and macrovascular thrombosis both in the venous and arterial circulations. Venous thrombotic events, particularly pulmonary embolism, with elevated D-dimer and coagulation activation are highly prevalent in COVID-19 patients. The pro-inflammatory cytokine storm, with elevated levels of interleukin-6 (IL-6), IL-2 receptor, and tumor necrosis factor-α, could also participate in endothelial dysfunction and leukocyte recruitment in the microvasculature. COVID-19-induced endotheliitis may explain the systemic impaired microcirculatory function in different organs in COVID-19 patients. Ongoing trials directly and indirectly target COVID-19-related endothelial dysfunctions: i.e., a virus-cell entry using recombinant angiotensin-converting enzyme 2 (ACE2) and transmembrane protease serine 2 (TMPRSS-2) blockade, coagulation activation, and immunomodulatory therapies, such as anti-IL-6 strategies. Studies focusing on endothelial dysfunction in COVID-19 patients are warranted as to decipher their precise role in severe SARS-CoV-2 infection and organ dysfunction and to identify targets for further interventions.
Highlights
Since December 2019, a novel betacoronavirus named SARS-CoV-2 has caused a global outbreak of respiratory illness described as COVID-19
At early stages of the pandemic, little attention has been paid to endothelial dysfunction in severe SARS-CoV-2 infection
The association of the clinical phenotype of COVID-19 respiratory failure, the dysregulated coagulation system with a hypercoagulable state, and elevated endothelial surrogate markers suggests a crucial role played by endothelial damage and inflammation during severe SARS-CoV-2 infection [67]
Summary
Since December 2019, a novel betacoronavirus named SARS-CoV-2 (severe acute respiratory syndrome coronavirus-2) has caused a global outbreak of respiratory illness described as COVID-19. The association of the clinical phenotype of COVID-19 respiratory failure, the dysregulated coagulation system with a hypercoagulable state, and elevated endothelial surrogate markers suggests a crucial role played by endothelial damage and inflammation during severe SARS-CoV-2 infection [67]. Ongoing trials directly and indirectly target COVID-19-related endothelial dysfunctions: i.e., a virus-cell entry using recombinant ACE2 and TMPRSS-2 blockade, immunomodulatory therapies such as anti-IL-6 strategies, complement blockade, and coagulation activation (Fig. 1). Endothelial dysfunction induced by SARS-CoV-2 infection results in a prothrombotic state leading to occlusion and microthrombi formation in COVID-19 patients, encouraging the use of prophylactic or even therapeutic anti-coagulation therapies. Two French studies are testing eculizumab in SARS-CoV-2 infection, hypothesizing that complement activation may be a key player in COVID-19 infectionrelated EC dysfunction and multi-organ failure (Clinical Trials NCT04346797 and NCT04355494)
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