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Is severe COVID-19 a microvascular disease?

M3 India Newsdesk Sep 28, 2020

While a range of symptoms have made it difficult to appropriately categorise COVID-19, a recent report suggests that severe COVID-19 is most likely a microvascular disease.


For our comprehensive coverage and latest updates on COVID-19 click here.


The report was put together by authors Charles J. Lowenstein, MD, of Johns Hopkins University School of Medicine in Baltimore, and Scott D. Solomon, MD, of Brigham and Women’s Hospital in Boston. The study was partially funded by the National Institutes of Health National Heart Lung and Blood Institute.

Authors Lowenstein and Solomon have pointed out the possibility that severe COVID-19 is a microvascular disease in which the novel coronavirus, SARS-CoV-2, infection results in the activation of endothelial cells present in blood vessels. This in turn produces an exaggerated vascular response which manifests as inflammation of the vessels and thrombosis.

In a report that was published by the American Heart Association, the researchers have noted that arterial and venous thrombosis has been found in patients with severe COVID-19. Up to 70 percent of individuals who had died following severe COVID-19 were found to have had deep vein thrombosis as per the report. Many patients with severe COVID-19 also had lab findings that showed that there was widespread thrombosis and symptoms of hyperinflammation (cytokine storm). There was also an increase in the levels of markers of inflammation such as interleukin-6 (IL6) and C-reactive protein (CRP), which have been known to be related to severe pneumonia in sick patients. Many individuals’ blood reports also showed high levels of D-dimer, VWF, and Factor VIII.


The researchers studied a number of patients admitted to hospitals with severe COVID-19, in intensive care and otherwise. They also looked at the autopsy findings of individuals who had died due to COVID-19. All of which seemed to support the theory that severe COVID-19 is in fact a microvascular disease.

The authors wrote,

“We propose that the coronavirus SARS-CoV-2 triggers a unique endothelial response, endothelial exocytosis, which simultaneously activates two parallel pathways, microvascular inflammation and microvascular thrombosis, ultimately leading to hyperinflammation and diffuse thrombosis characteristic of severe COVID-19."

They have also explained that exocytosis is a normal response to injury, in this case specifically to the injury of endothelium, causing various agonists to bind to receptors on the surface of endothelial cells. This in turn causes a reaction of events which release granules from the endothelium into the bloodstream.


How is SARS-CoV-2 thought to activate endothelial exocytosis?

The authors have noted that there are a few different possibilities.

  1. In the first theory, it is thought that the virus directly prompts exocytosis by binding to a surface receptor on endothelial cells.
  2. Another possibility is that the virus indirectly is involved in bringing about exocytosis by activating the host’s (in this case the sick individual) immune responses which in turn triggers cytokines that then result in exocytosis.
  3. A third theory is that SARS-CoV-2 infects the endothelial cells which activate viral particles which then cause exocytosis as a response.

Injured endothelial cells could also play a key role in the reason behind the cytokine storm that is present in many patients who have contracted SARS-CoV-2 and have developed severe COVID-19 as a result. Excessive vascular inflammation can result in tissue injury which releases a number of cytokines (such as TNF-α, or IL6), which in turn can result in a prolonged hyperinflammatory state, as seen in many patients with severe COVID-19.

“In summary, accumulating clinical, laboratory, and autopsy evidence suggests that endothelial exocytosis plays a central role in the pathogenesis of severe COVID-19,” write Lowenstein and Solomon.

The authors of the study have also noted that better understanding the underlying pathological mechanisms will allow for targeted treatment and therapies to be carried out. In particular, factors that inhibit endothelial exocytosis could significantly reduce the hyperinflammatory state, and aid in controlling symptoms. For example, inhibiting P-Selectin, a protein present on the surface of endothelial cells, would help reduce certain responses which come about as a result of injury of the cell. This would then reduce certain features of exocytosis such as platelet adhesion to the lining of endothelium.

While other treatments have also been theorised, they have also acknowledged that appropriate and adequate studying would need to be done before anything was put into clinical practice.

 

Disclaimer- The views and opinions expressed in this article are those of the author's and do not necessarily reflect the official policy or position of M3 India.

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