Severe COVID-19 Infection Associated with Endothelial Dysfunction Induces Multiple Organ Dysfunction: A Review of Therapeutic Interventions

Abstract

Since December 2019, the SARS-CoV-2 (COVID-19) pandemic has transfixed the medical world. COVID-19 symptoms vary from mild to severe and underlying chronic conditions such as pulmonary/cardiovascular disease and diabetes induce excessive inflammatory responses to COVID-19 and these underlying chronic diseases are mediated by endothelial dysfunction. Acute respiratory distress syndrome (ARDS) is the most common cause of death in COVID-19 patients, but coagulation induced by excessive inflammation, thrombosis, and disseminated intravascular coagulation (DIC) also induce death by multiple-organ dysfunction syndrome. These associations imply that maintaining endothelial integrity is crucial for favorable prognoses with COVID-19 and therapeutic intervention to support this may be beneficial. Here, we summarize the extent of heart injuries, ischemic stroke and hemorrhage, acute kidney injury, and liver injury caused by immune-mediated endothelial dysfunction that result in the phenomenon of multi-organ dysfunction seen in COVID-19 patients. Moreover, the potential therapeutic effect of angiotensin receptor blockers and angiotensin-converting enzyme inhibitors that improve endothelial dysfunction as well as the bradykinin storm are discussed.

Persistent Endothelial Dysfunction in Post-Acute COVID-19 Syndrome: A Case-Control Study

“…The relationship between endothelial dysfunction and CV disease is well known [49]. Accordingly, mounting evidence suggests that a dysfunctional endothelium may be the main pathogenic mechanism of the prothrombotic state in COVID-19 [50][51][52]. Moreover, it has been hypothesized that a residual activation of the immune system following the acute phase of COVID-19 may be responsible for a persistent endothelial dysfunction during convalescence [18].…”

Clinical Assessment of Endothelial Function in Convalescent COVID-19 Patients Undergoing Multidisciplinary Pulmonary Rehabilitation

“…However, endothelial dysfunction is not only a consequence of direct virus infection with subsequent cellular death, potentially depending also on systemic inflammation [50]. Inflammatory cytokines from activated leukocytes, such as interleukin 1 (IL1) and tumor necrosis factor α (TNFα), bind specific receptors on ECs' surface, thus enhancing the expression of a number of mediators, including intercellular adhesion molecule-1 (ICAM-1), vascular cell adhesion molecule-1 (VCAM-1), E-selectin, P-selectin, fibrinogen and von Willebrand factor (vWF) [51,52]. This results in platelet activation as well as leukocyte adherence and extravasation [52][53][54].…”

“…Inflammatory cytokines from activated leukocytes, such as interleukin 1 (IL1) and tumor necrosis factor α (TNFα), bind specific receptors on ECs' surface, thus enhancing the expression of a number of mediators, including intercellular adhesion molecule-1 (ICAM-1), vascular cell adhesion molecule-1 (VCAM-1), E-selectin, P-selectin, fibrinogen and von Willebrand factor (vWF) [51,52]. This results in platelet activation as well as leukocyte adherence and extravasation [52][53][54]. A decline in nitric oxide (NO) bioavailability is another key aspect of a dysfunctional endothelium in COVID-19 [55], potentially depending on the high levels of circulating interleukin 6 (IL6) and other inflammatory markers [56].…”

Thromboembolic Complications in Covid-19: From Clinical Scenario to Laboratory Evidence

“…The culprit organs are those with elevated blood perfusion in which a high concentration of virus can pivot. Of note, coronary and cardiac districts, the cerebrovascular system, and kidneys are the sites in which the virus can cause clinical complication by direct toxicity or by endothelial dysfunction located in different sites leading to thrombotic events and multi-organ failure [ 19 , 20 ].…”

“…The two-way association between systemic inflammation and activation of coagulation is named immunothrombosis [ 28 , 29 ]. The main mediators of immunothrombosis in patients with SARS-CoV-2 include interleukin-6 (IL-6), interleukin-1β (IL-1β) and tissue factor (TF) [ 19 ]. IL-6 can induce TF expression in mononuclear cells and initiates coagulation activation and thrombin generation.…”