Thursday, April 15, 2021

FIOCRUZ Researchers Making The Case That COVID-19 Should Be Considered A `Thrombotic Viral Fever'


Although originally billed as a primarily SARS-like viral pneumonia, COVID-19 has repeatedly shown that pneumonia is only part of its extensive repertoire (see Nature Med. Review: Extrapulmonary manifestations of COVID-19).  While ARDS and pneumonia are often associated with severe SARS-CoV-2 infection, other organs - including the brain, heart, and kidneys - are often involved as well.

Often, thrombotic events (blood clots, strokes, etc.) have been associated with COVID-19, including:

We've seen other evidence as well, including a huge increase in out-of-hospital cardiac arrests (see CIDRAP's  COVID-19 tied to spikes in out-of-hospital cardiac arrests), along with other reports, including:

EID Journal: Two Reports On Thrombotic Events In COVID-19 Patients

EID Journal: Pulmonary Embolism and Increased Levels of d-Dimer in COVID-19 Patients

New research highlights blood clot dangers of COVID-19

Ten researchers from Brazil's well-respected FIOCRUZ (Fundação Oswaldo Cruz) recently published a paper where they propose that COVID-19 should be classified as a `Viral Thrombotic Fever', as opposed to a SARS-like disease.

We have a (translated) article from the FIOCRUZ website summarizing their findings and defending their conclusions, followed by a link to the original study. 

Covid-19: article defends new classification for the disease


Maíra Menezes (IOC / Fiocruz) 

Several viruses, including those that cause dengue and yellow fever, can impair clotting, causing bleeding in the most severe cases. For this reason, these conditions are considered hemorrhagic viral fevers. In a recently published article in the scientific journal Memórias do Instituto Oswaldo Cruz , a group of ten researchers argues that the new coronavirus (Sars-CoV-2) is the first agent recognized for acting in the opposite direction: increasing the formation of clots (also called thrombi) that can obstruct circulation. Considering the evidence of hypercoagulation in the disease, the authors propose that Covid-19 is the first infection classified as thrombotic viral fever. Currently, the condition is classified as Severe Acute Respiratory Syndrome (SARS).

The study is signed by specialists in intensive care, cardiology, hematology, virology, pathology, immunology and molecular biology, who work in six health care and scientific research institutions in Brazil. They are: Hospital Pró-Cardíaco, Instituto Oswaldo Cruz (IOC / Fiocruz), Faculty of Medicine of Petrópolis (Unifase), National Cancer Institute (Inca), Carlos Chagas Institute (Fiocruz Paraná) and United Health Group. At the IOC / Fiocruz, the Comparative and Environmental Virology, AIDS and Molecular Immunology, Inflammation, Pathology and Immunopharmacology Laboratories participate.

Scientific evidence

Almost a year after the emergence of the new coronavirus in China, several studies show that, contrary to what was thought at the beginning of the pandemic, Covid-19 goes far beyond pulmonary conditions. In the Netherlands, a survey identified complications linked to excessive clot formation in 16% of patients in intensive care units, including cases of pulmonary embolism, stroke and venous thrombosis. In a French survey, the index went over 40%. In addition, in people who died from the infection, analyzes found significant damage to the endothelium, tissue that lines blood vessels. Research indicates that Sars-CoV-2 infects endothelial cells and inflammation of the tissue favors a state of hypercoagulation.

“In hospitalized patients, we see thrombotic manifestations in spite of the usual clinical practice of thromboprophylaxis [therapy to prevent the formation of clots]. There is also a description of thromboembolic events after hospital discharge, and excessive clot formation is observed in histopathological analyzes in cases of death by Covid-19 ”, says the ICU coordinator at Hospital Pró-Cardíaco and first author of the article, Rubens Costa Son.

For the authors of the study, the classification of thrombotic viral fever reflects the advance in knowledge about the disease and may contribute to the clinical management of cases and scientific research. "This definition highlights the need for measures to monitor and treat coagulation changes and points to issues that need to be clarified, such as the identification of biomarkers of severity, which can be used to guide therapeutic approaches", says the researcher at IOC Comparative and Environmental Virology Laboratory and senior author of the study, José Paulo Gagliardi Leite.

The researchers also explain that the change in classification would not impact the current monitoring systems that contribute so much to the definition of public health strategies. “SRAG is a nomenclature used to portray a nonspecific clinical involvement, since it can cover a series of manifestations. Thrombotic viral fever, on the other hand, would represent a specific syndrome. This definition is fundamental in the area of ​​Health ”, stresses Costa Filho.

Diagnosis and therapeutic target

In addition to gathering scientific evidence about hypercoagulation at Covid-19, the article discusses the advantages and limitations of the tests available to diagnose the problem and points out a promising target in the search for therapies. Among several tests, the researchers draw attention to the potential of an old and easily accessible methodology: rotational thromboelastometry. Applied since the 1940s, the test assesses the viscoelastic properties of blood, contemplating the interaction between platelets, blood cells and clotting factors. Recent studies demonstrate that the technique is capable of detecting hypercoagulation in patients infected with Sars-CoV-2.

“Assessing coagulation parameters is at least as important as assessing respiratory parameters in patients with Covid-19. Thromboelastometry is an old and neglected diagnostic method, which should be applied in these cases ”, says the head of the Pathology Laboratory at IOC and author of the article, Marcelo Pelajo Machado.

As a potential therapeutic target, the article highlights a viral enzyme called MPro. The starting point of the proposal is the high degree of similarity between the enzyme and molecules that activate blood clotting. The discovery was made in a study led by the researcher at the Structural and Computational Proteomics Laboratory at Fiocruz-Paraná, Tatiana Brasil de Souza.

“In the computational screening of drugs with therapeutic potential against Sars-CoV-2, we observed that the substances that had the best interactions with MPro were anticoagulants. This led us to research the structure of the enzyme and we found a conserved region with a lot of similarity with thrombin and the X factor, substances that activate clotting ”, reports the researcher, who published the results of the work in June in the journal Memórias do Instituto Oswaldo Cross .

Based on the finding, the researchers plan to carry out experiments to analyze whether MPro can contribute to hypercoagulation in patients with Covid-19. “It is possible that this protein acts as a springboard for thrombotic phenomena and we are going to investigate this hypothesis”, says Hugo Castro Faria Neto, researcher at the Immunopharmacology Laboratory at IOC.

In the biology of Sars-CoV-2, MPro has the function of cutting proteins and its performance is fundamental for the assembly of new viral particles. In the laboratory, studies have already shown that inhibiting the enzyme blocks the replication of the virus. “Covid-19 patients still suffer from a lack of specific treatments. A drug with action on MPro could act against infection and have a protective effect against thrombosis ”, adds Hugo.

Complex disease

The researchers point out that Covid-19 is a complex disease, with manifestations in several organs, from the brain to the gastrointestinal tract. The classification of thrombotic viral fever is based on the proven impact of infection on blood clotting, which carries a high risk of death. However, other components of the disease should not be overlooked.

“Pulmonary impairment is certainly very relevant at Covid-19. What the article highlights is that, in the most severe cases, difficult to treat, with great inflammatory exacerbation, there is coagulopathy ”, says the researcher at the IOC's Inflammation Laboratory, Marco Aurélio Martins. “We cannot put all the files on a single factor in this disease. But there is no doubt that thrombosis occurs and can kill. This is an unequivocal point, which needs to be observed ”, completes the researcher from the Clinical Immunology Laboratory at IOC and professor at the Petrópolis Medical School, José Mengel.

Considering the many aspects of the pathophysiology of the condition that are still unclear, the authors highlight the importance of uniting professionals working in the clinic and in basic research. “The initial response to Sars-CoV-2 was based mainly on what was known of other human coronaviruses, which cause respiratory diseases. But we can make a parallel with Zika, when a new virus from the same dengue family surprised everyone with microcephaly. This shows that we are never prepared for a new pathogen and scientific research is fundamental to face these problems ”, says Gonzalo Bello Bentancor, a researcher at the IOC's Laboratory of AIDS and Molecular Immunology.

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Should COVID-19 be branded to Viral Thrombotic Fever?

Costa-Filho, RC1, +; Castro-Faria-Neto, HC2; Mengel, J3; Pelajo-Machado, M4; Martins, MA5; Leite, ET6; Mendonça-Filho, HTF7; Brasil de Souza,TAC8; Bentacor, GB9 ;Leite Gagliardi, JP10

DOI: 10.1590/0074-02760200552


Coronaviruses can cause a diverse array of clinical manifestations, from fever with symptoms of the common cold to highly lethal Severe Acute Respiratory Syndrome (SARS) and Middle East Respiratory Syndrome (MERS). SARS-CoV-2, the coronavirus discovered in Hubei province, China, at the end of 2019, became known worldwide for causing COVID-19. Over one time-period, the scientific community has produced a large bulk of knowledge about this disease and countless reports about its immune-pathological aspects.
This knowledge, including data obtained in postmortem studies, points unequivocally to a hypercoagulability state. However, the name COVID-19 tells us very little about the true meaning of the disease. Our proposal is more comprehensive; it intends to frame COVID-19 in more clinical terminology, making an analogy to Viral Hemorrhagic Fever (VHF). Thus, we found irrefutable evidence in the current literature that COVID-19 is the first viral disease that can be branded as a Viral Thrombotic Fever.
This manuscript points out that SARSCoV-2 goes far beyond pneumonia or SARS. COVID-19 infections promote remarkable interactions among the endothelium, coagulation, and immune response, building up a background capable of promoting a “thrombotic storm,” much more than a “cytokine storm.” The importance of a viral protease called main protease (Mpro) is highlighted as a key component for SARS-CoV-2 replication in the host cell. A deeper analysis of this protease and its importance on the coagulation system is also discussed for the first time, mainly because of its similarity with the thrombin and factor Xa molecules, as recently pointed out by structural comparison of crystallographic structures.

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