2024-01-28 02:40:00
Autopsies of nine people who died from severe COVID-19 revealed distinct patterns of changes in pulmonary vascular structure and blood clot formation. This article describes for the first time the subcellular aspects of endothelial damage and associated thrombotic phenomena caused by infection. The article points out that the impact of acute inflammation on pulmonary microvascular circulation is a key factor leading to severe COVID-19, which will help deepen the understanding of the pathophysiology of the disease and the development of novel treatment strategies.
“This study conclusively proves what we have pointed out from the beginning of the epidemic – severe COVID-19 is a thrombotic disease. The SARS-CoV-2 virus attaches to the endothelium, the cell layer of blood vessels. . When it invades endothelial cells, it will first affect microvascular circulation.” said Elnara Negri, first author of the article, professor and pulmonologist at the University of São Paulo School of Medicine (FM-USP): “The problem Clotting begins in the capillaries (tiny blood vessels that surround the alveoli) in the lungs and then in larger vessels that can reach any other organ.” She was the first in the world to conclude that severe COVID-19 is a thrombotic disease one of the researchers.
Researchers from the University of the South Pacific analyzed lung tissue from nine patients who died from COVID-19. Source: Elia Caldini
In the FAPESP-funded study, researchers used transmission and scanning electron microscopy to observe the effects of the virus on lung endothelial cells in severely ill COVID-19 patients who died at Clínicas Hospital, a general hospital run by FM-USP.
Nine samples obtained through minimally invasive autopsies all showed high rates of thrombotic microangiopathy — tiny blood clots in arterioles and capillaries that can cause organ damage and ischemic tissue damage. The samples were from patients hospitalized between March and May 2020 who required intubation and intensive care and died from refractory hypoxemia and acute respiratory failure.
Of note, none of the patients in this study received anticoagulants, as this was not part of the COVID-19 treatment regimen at the time. During this time, there are also no COVID-19 vaccines available.
endothelial glycocalyx shedding
Negri explained that the endothelium itself has a gel-like glycoprotein layer called the glycocalyx, which serves as a barrier that regulates the entry of large molecules and blood cells into the endothelial surface. This barrier prevents blood clotting by inhibiting the interaction of platelets with the endothelium.
Previous research conducted by Helena Nader of the Federal University of São Paulo showed that SARS-CoV-2 invades cells mainly by binding to the receptor ACE-2 (a protein on the surface of various cells such as respiratory epithelial cells and endothelial cells). But before doing so, it binds to heparin sulfate, a polysaccharide that is a major component of the glycocalyx of endothelial cells. “When it invades endothelial cells, it triggers shedding and destruction of the glycocalyx, leading to tissue exposure and intravascular coagulation. This process begins in the microcirculation,” explained Negri.
Because the virus initially acts on the microcirculation of the lungs, contrast tests conducted during the pandemic to investigate the presence of blood clots in large blood vessels in patients with severe COVID-19 failed to detect the problem at any early stage. However, endothelial dysfunction is a key phenomenon in COVID-19 as it is directly linked to the activation of the inflammatory response that is characteristic of the disease. “Large-scale viral invasion and disruption of the endothelium disrupts the endothelial barrier, impairs recruitment of circulating immune cells, and activates pathways associated with thrombosis and inflammation,” she said.
In their study, the researchers found that endothelial damage often precedes two processes common in cases of respiratory distress: alveolar-capillary membrane leakage and intra-alveolar fibrin accumulation (associated with blood coagulation and wound healing).
A study including transcriptomics (analysis of all RNA transcripts, both coding and non-coding) conducted by the same research group at FM-USP, led by Thais Mauad, showed that inflammation precedes the onset of inflammation in the lungs of patients with damaged alveoli. , some pathways related to coagulation and platelet activation have been activated.
The analysis also confirmed that coagulation is not a typical process triggered by activation of clotting factors. “In COVID-19, clotting is due to endothelial damage and is caused by NETosis,” Negri said.[一种通过形成中性粒细胞胞外捕获物或NET而导致程序性细胞死亡的免疫机制], red blood cell malformations, and platelet activation, all of which make the blood thicker and lead to many complications. “
She added that patients must stay hydrated when the blood is thick and thrombosis rates are high, whereas diffuse alveolar damage from other causes of acute respiratory distress syndrome requires less fluids. In addition, the timing and strict control of anticoagulation are also crucial.
Another study by a team of researchers including Marisa Dolhnikoff and Elia Caldini showed that lung damage in severe COVID-19 patients is related to the degree of NETosis : The higher the level of NETs in lung tissue obtained at autopsy, the more severe the lung injury.
Negri said she began to suspect a link between COVID-19 and blood clots early in the pandemic, when she noticed a phenomenon that recalled some 30 years ago when she was using extracorporeal circulation and a bubble oxygenator. (No longer used due to endothelial damage) After thoracotomy, the patient experienced microvascular coagulation.
“This is a technique that was widely used 30 years ago, but the lung damage it causes is very similar to what’s seen in COVID-19. So I’ve seen that before. Besides the lung damage, another similarity is the appearance of peripheral Thrombosis, such as red toes,” she said.
When severe COVID-19 develops, a drop in blood oxygen levels occurs secondary to capillary thrombosis in the lungs. Initially, the lungs do not accumulate fluid, are not ‘saturated’, and have not lost compliance or elasticity.This means the lungs of early severe COVID-19 patients don’t behave like acute respiratory distress syndrome [ARDS] The patient is like a sponge filled with fluid. In contrast, respiratory failure associated with severe COVID-19 involves dehydration of the lungs. The alveoli are filled with air, but oxygen cannot enter the blood due to capillary clotting. This results in what we call ‘happy hypoxia’, where patients don’t feel short of breath or realize their oxygen saturation is dangerously low.
While observing the intubation process of a severely ill COVID-19 patient, Negri realized that such cases should be treated completely differently than they were at the beginning of the pandemic. “The secret to treating patients with severe COVID-19 is to keep the patient well hydrated and to use anticoagulants at the correct dosage, which is needed when oxygen saturation begins to desaturate (i.e., the amount of oxygen in the blood is low) in a hospital setting,” she said. dose. Thereafter, the therapeutic dose of anticoagulant must be calculated daily based on blood test results and must always be performed in a hospital setting to avoid any risk of bleeding. Prophylaxis is required for an average of four to six weeks after discharge due to endothelial regeneration It takes so long”.
She explained that this hydration and anticoagulation regimen is needed because unlike other types of ARDS, in which lung oxygen is prevented from entering the bloodstream primarily due to alveolar inflammation, pulmonary capillary endothelial damage is a major risk factor in early severe COVID-19. obstacle.
“At the beginning of the pandemic, no one knew this difference between COVID-19 and other types of ARDS. In fact, this was the reason why many Italian patients died in intensive care units,” she recalled. “The treatments used at the time The plan is different.”
In 2020, before the study was published in the Journal of Applied Physiology, Negri and her research team had observed that using the anticoagulant heparin improved blood oxygen saturation in critically ill patients. In 2021, they collaborated with colleagues in multiple countries to conduct a randomized clinical trial that successfully demonstrated that heparin treatment can reduce mortality in severe COVID-19 patients. The findings were published in the British Medical Journal.
“This study helped change COVID-19 treatment guidelines globally by showing that the risk of death from COVID-19 was reduced by 78% when patients who required supplemental oxygen but were not already in intensive care were started on anticoagulation,” Negri said.
She explained that in severe COVID-19, endothelial dysfunction should be reversed immediately with anticoagulants. “Blood clotting must be stopped as quickly as possible to avoid acute respiratory distress and other consequences of the disease, such as what is now known as Long-COVID,” she said.
Researchers at the UK Institute recently published an article in the journal Nature Medicine reporting on a study in which the only Long-COVID prognostic markers found were fibrinogen and D-dimer , which are both proteins involved in blood clotting, further confirming the thrombotic nature of the disease.
“This study shows that Long-COVID is the result of improperly treated blood clots. Microcirculatory problems can persist in multiple organs, including the brain, heart and muscles, just as if the patient had a minor heart attack,” Negri said.
Compiled source: ScitechDaily
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