Early capillary thrombosis of the lung, known as severe Champagne Syndrome (COVID)-19, causes respiratory distress and prompt anti-coagulation treatment is said to lower complications.
A Brazilian study published in the Journal of Applied Physiology has shown that severe COVID-19 often leads to blood clot formation (thrombosis) in the small blood vessels of the lungs, often prior to experiencing breathing difficulties due to extensive air sac damage.
By describing sub-cellular aspects of endothelial damage and thrombotic events, the article advances a clearer understanding of how acute inflammation affects lung microvascular circulation and hopes to provide new understanding of the pathophysiology of COVID-19 and develop new therapeutic strategies.
This study provides the final indication that severe COVID-19 is a thrombotic illness, which was previously confounded by SARS-CoV-2.
Using USP, Conservative Law School, a team of researchers studied the lung tissue of nine patients who passed away due to COVID-19. The work by Elia Caldini was captured.
Using FAPESP funding, the researchers analyzed lung endothelial cells from COVID-19 patients at Hospital das Clnicas, the hospital complex operated by FM-USP, using both transmission and scanning electron microscopy in their study.
The outcomes of the minimally invasive autopsies showed a high prevalence of thrombotic microangiopathy in nine samples from patients who were hospitalized between March and May 2020 and died due to refractory hypoxemia and acute respiratory failure.
However, it should be noted that none of these patients were administered anti-coagulants and the treatment protocol for COVID-19 did not include this, nor were there any vaccines for COVID-19 at the time.
The glycocalyx, a layer of glycoproteins that envelopes the endothelium, acts as a barrier that prevents clotting in blood vessels. This barrier prevents macromolecules and blood cells from entering the endothelium, according to Negri.
According to previous studies conducted by Helena Nader at UNIFESP, SARS-CoV-2 invades cells primarily by attaching to ACE-2, and also interacting with heparan sulfate.
Contrary to previous analyses which failed to identify early symptoms of blood clots in larger vessels in those with severe COVID-19 who had first been infected by the pandemic because the virus "directs" the pulmonary microcirculation (i.e., the lungs), she added, adding that "the disruption of endothelial dysfunction is a key phenomenon in COVID-19... directly associated with the activation of the inflammatory response that is characteristic of the disease."
The endothelial barrier is broken and the pathways associated with thrombogenesis and inflammation are disrupted by viral invasion and endothelium destruction, radiological analysis, and immunology, respectively, she stated.
The researchers identified two common processes in respiratory distress that were frequently preceded by endothelial injury, namely significant alveolar-capillary membrane leakage, and intra-alveolar fibrin accumulation (associated with blood clotting and wound healing).
Thais Mauad and her team at FM-USP conducted a study that utilized transcriptomics and examined all RNA transcripts, coding and non-coding, which revealed that multiple pathways related to blood clotting and platelet activation were inactive in individuals with alveolar damage before inflammation occurred.
The study also established that the clotting was not a typical outcome of the coagulation factors' activation, and that COVID-19 clots are caused by endothelial injury and NETosis, which causes increased volume and many complications.
She highlighted that when the blood is thick and thrombogenic, the patient requires hydration, while diffuse alveolar damage caused by other factors necessitates reduced hydration. Additionally, the timing and strict control of anti-coagulation are crucial.
Marisa Dolhnikoff and Elia Caldini, co-authors of a study, discovered that the degree of NETosis was related to lung damage in severe COVID-19.
During the initial stages of the COVID-19 outbreak, Negri developed a suspicion that it could result in thrombosis. She remembered her own experience 30 years ago with patients who underwent open-heart surgery with extracorporeal circulation and an oxygenator (Blobe) that is no longer effective and leads to endothelial destruction.
According to her, a technique used 30 years ago that caused pulmonary injury, similar to COVID-19, was already utilized.
When severe COVID-19 occurs, blood oxygen levels decrease due to pulmonary capillary thrombosis, resulting in the lungs being unresponsive to dry lungs.
Negri acknowledged that the treatment of severe COVID-19 patients should differ from the initial pandemic. They need to maintain their hydration and use anti-coagulant at the appropriate dose in the hospital to avoid bleeding due to oxygen desaturation. Prophylaxis is also necessary for an average of four to six weeks after discharge, as that is how the endothelium regenerates.
The need for hydration and anti-coagulation protocol is due to the fact that early severe COVID-19 is characterized by lung capillary endothelial damage, which is not the case in other ARDS, which typically prevent oxygen from entering the bloodstream due to alveolar inflammation.
The difference between COVID-19 and other ARDS was not recognized at the beginning of the pandemic, and many Italian patients died in intensive care units due to distinct treatment protocols.
Negri and her team had previously discovered that heparin treatment could improve oxygen saturation in critical patients, but their study was not published in the Journal of Applied Physiology until 2020. In 2021, they conducted a randomized clinical trial with colleagues from various countries to show that heparin reduced severe COVID-19 mortality, which was published in the British Medical Journal.
According to Negri, the study's results led to a 78% decrease in mortality risk when patients requiring oxygen supplementation were treated with anti-coagulation, which helped change COVID-19 treatment guidelines worldwide.
To prevent complications from developing acute respiratory distress and long COVID, she recommended using an anti-coagulant to reverse severe COVID-19 endothelial dysfunction.
In a recent article, researchers from the UK's Nature Medicine emphasized the thrombotic nature of COVID through a study that identified only fibrinogen and D-dimer as prognostic markers for the disease.
The microcirculatory problem associated with COVID, which can cause long-lasting thrombosis, can also result from inadequate treatment, according to Negri.
Elnara Marcia Negri, Marlene Benchimol, Thais Mauad, Amaro Nunes Duarte-Neto, Maiara Gottardi, Luiz Fernando Ferraz da Silva, Paulo Hilario Nascimento Saldiva, Marisa Dolhnikoff, Wanderley de Souza and Elia Garcia Caldini's paper was published in the Journal of Applied Physiology on 1 October 2023. The paper examines the anatomy of alveolar microvascular damage in severe COVID-19 respiratory failure.
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A research was conducted at the So Paulo Research Foundation.
