According to a Brazilian study, blood clotting (thrombosis) in the capillaries of the lungs is one of the first consequences of a severe form of COVID-19, even before respiratory distress caused by diffuse alveolar damage. Autopsies of nine patients who died after developing severe disease showed a clearly characterized condition involving changes in the pulmonary vasculature and thrombosis.
The results of research were published in the Journal of Applied Physiology.
Covid19: here is an important update
For the first time, the subcellular aspects of endothelial damage and associated thrombotic phenomena caused by infection are described. It detects the impact of acute inflammation on pulmonary microvascular circulation as a key factor in severe COVID19, contributing to a deeper understanding of the pathophysiology of the disease and the development of new therapeutic strategies.
“This study has provided the final proof of what we have been emphasizing since the beginning of the pandemic: that severe COVID19 is a thrombotic disease. The SARS-CoV-2 virus has tropism for [è attratto] from the endothelium, the layer of cells that lines the blood vessels.
When it invades endothelial cells, it first affects the microvascular circulation. The problem begins in the capillaries of the lungs [i minuscoli vasi sanguigni che circondano gli alveoli]followed by coagulation in the largest vessels that can reach any other organ,” said pulmonologist Elnara Negri, first author of the article and professor at the Faculty of Medicine of the University of São Paulo (FM-USP).
She was one of the first researchers in the world to conclude that severe COVID19 is a thrombotic disease.
In the study, researchers used transmission and scanning electron microscopy to observe the effects of the virus on lung endothelial cells of severe COVID19 patients who died at Hospital das Clínicas, the hospital complex operated by FM-USP.
All nine samples obtained through minimally invasive autopsies showed a high prevalence of thrombotic microangiopathy, which are microscopic blood clots in small arteries and capillaries that can lead to organ damage and ischemic tissue injury.
The samples were from patients admitted to hospital between March and May 2020, who required intubation and intensive care and died due to refractory hypoxemia and acute respiratory failure.
It is worth noting that none of the patients included in the study were treated with anticoagulants, as these were not part of the COVI19 treatment protocol at the time. Nor were vaccines available for the pandemic infection in the period.
Negri explained that the endothelium is itself lined with a gelatinous layer of glycoproteins called the glycocalyx, which acts as a barrier to regulate the access of macromolecules and blood cells to the endothelial surface. This barrier prevents blood vessel clotting by inhibiting the interaction of platelets with the endothelium.
“Previous studies conducted by Helena Nader at UNIFESP [l’Università Federale di San Paolo] have shown that SARS-CoV-2 invades cells mainly by binding to the ACE-2 receptor [una proteina sulla superficie di vari tipi di cellule, comprese quelle epiteliali ed endoteliali cellule dell’apparato respiratorio] but first it binds to heparan sulfate [un polisaccaride]an important component of the glycocalyx of endothelial cells,” explained Negri.
“When it invades the endothelium, it triggers the loss and destruction of the glycocalyx, resulting in tissue exposure and intravascular coagulation. The process begins in the microcirculation.”
Because the virus initially affects the pulmonary microcirculation, contrast tests performed during the pandemic to investigate the presence of blood clots in larger vessels in severe Covid-19 patients failed to detect the problem at any early stage, he added. However, endothelial dysfunction is a key phenomenon in COVID19 as it is directly associated with the activation of the inflammatory response characteristic of the disease.
“Massive viral invasion and destruction of the endothelium breaks down the endothelial barrier and impairs the recruitment of circulating immune cells, activating pathways associated with thrombogenesis and inflammation,” he said.
In the study, the researchers found that endothelial injury tended to precede two processes common in respiratory distress: significant loss of the alveolar capillary membrane and intra-alveolar accumulation of fibrin (associated with blood clotting and wound healing).
A study by the same group at FM-USP, led by Thais Mauad and including transcriptomics (analysis of all RNA transcripts, coding and non-coding), demonstrated that several pathways associated with blood clotting and platelet activation had been activated before inflammation in the lungs of patients with alveolar damage.
The analysis also confirmed that the clotting was not typical of the normal process triggered by the activation of clotting factors. “In COVID19, clotting is due to endothelial injury and is exacerbated by NETosis [un meccanismo immunitario che coinvolge la morte cellulare programmata attraverso la formazione di trappole extracellulari di neutrofili o NET]dysmorphic red blood cells and platelet activation, which makes the blood thicker and causes many complications,” Negri said.
When the blood is thick and highly thrombogenic, he added, the patient must be kept hydrated, while diffuse alveolar damage in acute respiratory distress syndromes due to other causes requires reduced hydration. “The timing and rigorous control of anticoagulation are also essential,” she underlined.
Another study by the same group of researchers, including Marisa Dolhnikoff and Elia Caldini, showed that lung damage in severe COVID19 is associated with the degree of NETosis: the higher the level of NET in lung tissue obtained by autopsy, the more the lungs are were damaged.
Negri said he began to suspect there was a link between COVID19 and thrombosis early in the pandemic when he noticed a phenomenon that was reminiscent of his experience about 30 years ago with patients who had microvascular clotting after heart surgery open with extracorporeal circulation and a bubble oxygenator. , no longer used because it causes endothelial damage.
“It was a technique widely used 30 years ago, but it causes lung damage very similar to that seen in Covid19. So I had seen it before. In addition to lung damage, another similarity is the occurrence of peripheral thrombotic phenomena, such as red fingers, for example,” he said.
“When severe COVID19 occurs, the drop in blood oxygen levels is secondary to pulmonary capillary thrombosis. Initially, there is no accumulation of fluid in the lungs, which are not “saturated” and do not lose their compliance or elasticity. This means that the lungs of COVID19 patients in early and severe stages do not feel like sponges filled with fluid, as in patients with acute respiratory distress syndrome [ARDS].”
“In contrast, respiratory failure associated with severe COVID19 results in dehydration of the lungs. The alveoli fill with air but oxygen cannot enter the bloodstream due to clotting of the capillaries. This leads to what we call ‘happy hypoxia’. where patients experience no shortness of breath and are unaware that their oxygen saturation is dangerously low.”
Observing the intubation of a patient suffering from severe COVID19, Negri realized that the treatment of such cases would have to be completely different from that used at the beginning of the pandemic.
“The secret to treating serious patients with Covid19 is to keep them hydrated and use anticoagulants at the right dose, i.e. the dose required in a hospital environment at the onset of oxygen desaturation, i.e. low levels of oxygen in the blood,” he explained. she said.
«After that, the therapeutic dose of the anticoagulant must be calculated daily on the basis of blood tests, always in a hospital environment to avoid any risk of bleeding. Prophylaxis is necessary on average for four to six weeks after discharge because this is how long it takes the endothelium to regenerate.”
This hydration and anticoagulation protocol is necessary because, unlike other types of ARDS where oxygen in the lungs is prevented from entering the bloodstream primarily due to alveolar inflammation, pulmonary capillary endothelial damage is the primary obstacle in severe initial phase of COVID19. she explained.
“No one knew about this difference between COVID19 and other types of ARDS at the beginning of the pandemic. Indeed, this is why so many Italian patients have died in intensive care, for example. The treatment protocol used then was different,” she recalled.
In 2020, before the study reported in the Journal of Applied Physiology, Negri and his team had already observed that the use of the anticoagulant heparin improved oxygen saturation in critically ill patients. In 2021, in collaboration with colleagues from several countries, they conducted a randomized clinical trial in which they managed to demonstrate that heparin treatment reduced severe mortality from COVID19. The findings were published in the British Medical Journal.
“This study helped bring about a global change in Covid19 treatment guidelines, demonstrating that the risk of Covid19 mortality decreased by 78% when anticoagulant therapy was started in patients who required oxygen supplementation but were not still in intensive care,” Negri said.
Endothelial dysfunction should be reversed without delay in severe COVID19, using anticoagulants, he explained. “Blood clotting must be stopped as soon as possible to avoid the development of acute breathing difficulties and other consequences of the disease, such as the problems now known as long COVID,” she said.
An article recently published in Nature Medicine by researchers affiliated with UK institutions reinforces the thrombotic nature of the disease, reporting a study in which the only long COVID prognostic markers identified were fibrinogen and D-dimer, proteins associated with coagulation.
“The study shows that long COVID is the result of inadequately treated thrombosis. The microcirculatory problem can persist in several organs, including the brain, heart and muscles, as if the patient were having small heart attacks,” said Negri.
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