Maíra Menezes (IOC/Fiocruz)
Many viruses can hamper coagulation, including those that cause dengue fever and yellow fever. In more severe cases, they may lead to bleeding. This is why these diseases are considered hemorrhagic viral fevers. In a paper recently published in the science magazine “Memórias do Instituto Oswaldo Cruz”, a group of ten researchers argues that the new coronavirus (SARS-CoV-2) should be the first agent recognized as acting in the opposite fashion, by increasing the formation of blood clots (also called thrombi) that can obstruct blood flow. Taking into account available evidence of hypercoagulation in the disease, the authors propose that COVID-19 is the first infection classified as thrombotic viral fever. The disease is currently classified as a severe acute respiratory syndrome.
The paper is signed by specialists in intensive care, cardiology, hematology, virology, pathology, immunology, and molecular biology who work in six medical service and scientific research institutions in Brazil. Namely: Hospital Pró-Cardíaco, Oswaldo Cruz Institute (IOC/Fiocruz), Medical School of Petrópolis (Unifase), Brazilian National Cancer Institute (Inca), Carlos Chagas Institute (Fiocruz-Paraná) and United Health Group. The laboratories of the IOC that participated in the paper are the Compared and Environmental Virology, the AIDS and Molecular Immunology, the Inflammation Laboratory, and the Pathology and Immunopharmacology Lab.
Almost a year after the appearance of the new coronavirus in China, several studies have demonstrated that, unlike what was initially thought, COVID-19 goes way beyond pulmonary issues. In the Netherlands, a survey identified complications related to the excessive formation of blood clots in 16% of patients in intensive care units, including cases of pulmonary embolism, stroke, and venous thrombosis. In a French survey this rate exceeded 40%. In addition, tests made on people who died of the infection showed significant damage to the epithelium, the tissue that lines the inside of blood vessels. Surveys show that the SARS-CoV-2 infects endothelial cells, and tissue inflammation promotes hypercoagulation.
“In hospitalized patients we observe thrombotic manifestations in spite of the usual clinical practice of thromboprophylaxis [clot-preventing therapy]. There are also descriptions of thromboembolic events after hospital leave, and an excessive formation of blood clots is observed in histopathological tests carried out on cases of death by Covid-19”, states Rubens Costa Filho, coordinator of the ICU of Hospital Pró-Cardíaco and lead author of the paper.
For the authors of the paper, the classification as thrombotic viral fever reflects the advancement in the knowledge available on the disease, and can help with the clinical management of the cases and with scientific research. “This definition shines a light on the need for measures to monitor and treat coagulation alterations, and points to issues that still need to be clarified, such as the identification of severety biomarkers that can be used to guide therapeutic approaches”, says José Paulo Gagliardi Leite, researcher of the Compared and Environmental Virology Laboratory of the IOC and senior author of the article. The researchers also explain that a change in classification would not impact the current monitoring systems that help define public health strategies. “SARS is a term used to describe a non-specific clinical issue, as it can include a series of different manifestations. A thrombotic viral fever, on the other hand, would represent a specific syndrome. This definition is crucial in the field of health”, Costa Filho emphasizes.
Diagnosis and therapeutic target
In addition to collecting scientific evidence on hypercoagulation in Covid-19, the paper discusses the advantages and limitations of the tests available to diagnose the problem, and points to a promising goal in the search for treatments. From among different tests, the researchers draw attention to the potential of an old and easily available methodology: rotational thromboelastometry. In use since the 1940’s, the test assesses the viscoelastic properties of the blood, analyzing the interaction between platelets, blood cells, and coagulation factors. Recent studies show that the technique can detect hypercoagulation in patients infected by SARS-CoV-2.
“Assessing coagulation parameters is at least as important as evaluating respiratory parameters in Covid-19 patients. Thromboelastometry is an old and neglected diagnostic method that should be used in these cases”, states Marcelo Pelajo Machado, head of the IOC’s Pathology Laboratory and author of the paper.
As potential therapeutic target, the paper mentions a viral enzyme called Mpro. The starting point of the proposal is the high level of similarity between the enzyme and molecules that activate blood coagulation. This was discovered in a study led by Tatiana Brasil de Souza, researcher of the Structural and Computational Proteomics Laboratory of Fiocruz-Paraná.
“In the computational triage of drugs with therapeutic potential against the SARS-CoV-2, we observed that the substances with best interactions with Mpro were anticoagulants. This led us to research the structure of the enzyme, and we then found a preserved region that is very similar to thrombin and factor X, substances that activate blood clotting”, says the researcher, who published the results of the work last June, in “Memórias do Instituto Oswaldo Cruz”.
Based on this finding, the researchers are now planning to carry out experiments to assess whether MPro can contribute with the hypercoagulation condition in Covid-19 patients. “It is possible that this protein works as a propulsion drive for thrombotic phenomena and this is the hypothesis we will be investigating”, says Hugo Castro Faria Neto, researcher at the IOC’s Immunopharmacology Laboratory.
In the biology of the SARS-CoV-2, MPro is in charge of snipping proteins, and its action is crucial to assemble new viral particles. In laboratory settings, studies have already shown that inhibiting the enzyme prevents the virus from replicating. “Covid-19 patients still suffer with a lack of specific treatments. A drug that acts on MPro might work against the infection and have a protective effect against thrombosis”, adds Hugo.
A complex disease
The researchers emphasize that COVID-19 is a complex disease, with manifestations in several organs, from the brain to the gastrointestinal tract. The classification as thrombotic viral fever is based on the proven impact of the infection on blood coagulation, leading to a high risk of death. However, other components of the disease must not be forgotten.
“Pulmonary issues are certainly very relevant in COVID-19. What the paper emphasizes is that in the most severe cases, the ones that are hard to treat, with great inflammatory exacerbation, coagulopathy is present”, says Marco Aurélio Martins, researcher of the IOC’s Inflammation Laboratory. “We cannot put all our eggs in one basket when it comes to this disease. But there is no doubt that thrombosis does occur, and it can kill. This is an unequivocal point that must be observed”, adds José Mengel, researcher of the IOC’s Clinical Immunology Laboratory and professor at the Medical School of Petrópolis.
Considering the many aspects of the physiopathology of the disease that have not been clarified yet, the authors highlight the importance of the joining of forces by professionals who work in the clinical field and in basic research. “The initial response to the SARS-CoV-2 was based mainly on what we knew about other human coronaviruses, which cause respiratory diseases. But we can also use the Zika virus as an analogy: this new virus, of the same family of the dengue virus, surprised everyone when cases of microcephaly began to pop up. This shows we are never ready for a new pathogen and scientific investigation is crucial to fight these diseases”, declares Gonzalo Bello Bentancor, researcher of the IOC’s AIDS and Molecular Immunology Laboratory.