Researchers on Long COVID: the global health concern calls for a paradigm shift

Therapy Breakthroughs 15. aug 2023 7 min Professor and Associated Scientific Director Douglas Kell, Head of Department and Research Professor Resia Pretorius Written by Morten Busch

Long COVID, the prolonged and debilitating symptoms experienced by individuals after exposure to SARS-CoV-2, has emerged as a critical global health concern. However, its cause, diagnosis and treatment remain elusive and controversial. Researchers now shed light on the scientific community’s divided perspective on Long COVID and discuss groundbreaking research on the role of microclotting in the development and persistence of the condition. The biochemical underpinnings of Long COVID challenge prevailing psychological explanations and call for a paradigm shift to recognise it as a physiological disease.

As the world battled the enduring grip of the COVID-19 pandemic, a perplexing phenomenon emerged – Long COVID. This condition, characterised by persistent symptoms among individuals who have recovered from the acute phase of the virus (and may even have been asymptomatic), has generated substantial debate and controversy. The multifaceted nature of Long COVID, its various manifestations and treatment challenges have triggered an ongoing scientific quest for answers. Now, some key researchers in the quest to understand Long COVID are taking stock of current knowledge.

“Long COVID is a global phenomenon affecting individuals worldwide. It is a biochemical and physiological disease involving microclotting, platelet hyperactivation, endothelial damage and the persistence of viral proteins, particularly the spike protein. People with Long COVID often face a double burden: their symptoms are not acknowledged, and if they are, they are often dismissed as psychological. The absence of widely accepted diagnostic tools exacerbates this predicament, leaving clinicians and researchers in a dilemma,” explains Resia Pretorius, Head of Department and Research Professor in the Department of Physiological Sciences, Faculty of Science, Stellenbosch University, South Africa.

Symptoms simply never go away

Symptoms can last for up to 3 years (the period since the emergence of COVID-19) and may even extend beyond that. The SARS-CoV-2 virus has caused millions of deaths globally, making the COVID-19 pandemic the worst global health crisis since the influenza pandemic of 1918. Although most infected individuals experienced mild to moderate illness and recovered without specialised treatment, there are common symptoms associated with acute COVID-19.

“These include fatigue, breathlessness, cough, chest pain, headache, joint pain, weakness and loss of taste and smell. However, some individuals experienced severe complications, such as coagulopathy, thromboembolism, multiorgan failure, septic shock and death. And a significant percentage continue to experience symptoms beyond the acute phase. Long COVID can manifest as either the persistence of acute COVID symptoms or the emergence of new symptoms unrelated to the initial illness,” says Resia Pretorius.

Long COVID, also known as post-acute sequelae of COVID-19, is a condition that can be divided into two stages: post-acute COVID, which extends beyond 3 weeks up to 12 weeks, and chronic COVID, which persists beyond 12 weeks.

“We now know that between 10% and 30% of people with acute COVID will have some sort of Long COVID symptoms. These symptoms simply never go away. Remarkably, symptoms have lasted for up to 3 years in some cases. Understanding the pathophysiological factors contributing to Long COVID is crucial, particularly regarding the associated blood abnormalities,” explains Resia Pretorius.

The mechanisms of Long COVID

Resia Pretorius and her team have made groundbreaking discoveries regarding the mechanisms behind Long COVID. Their research focuses on microclotting as a central phenomenon in developing the condition.

“Already during the first wave in 2020, my clinical collaborator, Jaco Laubscher, a doctor specialising in internal medicine in Stellenbosch, South Africa, said that Long COVID is a thrombotic condition. It is not only a viral pneumonia, as everyone believed. Thus, Long COVID is a thrombotic illness driven by inflammatory molecules, particularly the spike protein. These molecules cause hyperactivation of platelets, leading to the formation of microclots that trap inflammatory molecules and disrupt various physiological processes,” says Resia Pretorius.

An international collaboration with co-author Douglas Kell, Professor and Research Chair in Systems Biology at the Department of Biochemistry, Cell & Systems Biology, University of Liverpool, United Kingdom and Associated Scientific Director at the Novo Nordisk Foundation Center for Biosustainability, Technical University of Denmark, Kongens Lyngby, has taken the theories about Long COVID even further.

“Our research on plasma from individuals experiencing Long COVID reveals a significant prevalence of enduring amyloid fibrin microclots, which efficiently trap other proteins and emerge as a central factor in the persistence of Long COVID symptoms. These microclots have the potential to obstruct capillaries, impeding the smooth flow of red blood cells and, consequently, restricting the exchange of oxygen. This underlying mechanism sheds light on the persistent symptoms observed and the frequent absence of spontaneous resolution,” explains Douglas Kell.

Microclots in every individual with Long COVID

A few years back, these researchers made an intriguing discovery about fibrinogen, the protein involved in forming blood clots. Fibrinogen typically forms large polymer networks known as fibrin during blood clotting. However, the researchers found that, in some instances, fibrinogen can clot into an abnormal amyloid form, similar to how amyloids behave in Parkinson’s disease.

“This unusual amyloid form of fibrin gives rise to microclots that possess a level of resistance to the usual process of proteolytic removal. Consequently, this may cause the immune system to generate autoantibodies mistakenly, leading to a cascade of inflammation. This process forms a vicious circle resembling post-viral syndromes and myalgic encephalomyelitis/chronic fatigue syndrome,” says Douglas Kell.

Detecting these microclots in blood plasma is fairly straightforward by using the thioflavin T stain and a basic fluorescence microscope. Astonishingly, these microclots are in every single individual with Long COVID.

“Amidst the varied array of Long Covid symptoms, we hypothesise that these amyloid fibrin microclots might elucidate breathlessness, fatigue, brain fog, tissue damage, inflammation and coagulopathies,” adds Douglas Kell.

The increasing formation of microclots can hinder the transport of red blood cells to the capillaries, leading to impaired oxygen exchange in both the lungs and the brain. Examination of blood plasma samples of individuals in South Africa who previously had COVID-19 showed that numerous microclots were present among those who had experienced severe illness and those who remained asymptomatic.

“As a result of these findings, we propose distinguishing between two COVID-19 conditions: severe acute COVID-19, which primarily affects older men, and Long COVID, which predominantly impacts premenopausal women,” says Douglas Kell.

A continuing cycle of inflammation and clotting

In an international collaboration – together with Resia Pretorius – Douglas Kell has demonstrated that the formation of abnormal amyloid fibrin microclots could be triggered by the SARS-CoV-2 spike protein itself, even when introduced in recombinant form (in vitro) to normal plasma.

“These microclots might give rise to new antigens, prompting the immune system to generate autoantibodies, potentially worsening the symptoms. By comprehending the significance of these microclots, we may pave the way for devising an efficacious approach to address Long COVID and related conditions such as myalgic encephalomyelitis/chronic fatigue syndrome,” explains Resia Pretorius.

Further, the microclots contain molecules that obstruct proper clot breakdown, worsening the damage to the endothelial cells and continuing the cycle of inflammation and clotting.

“Microclots play a crucial role in Long COVID. These microclots entrap inflammatory molecules, disrupt normal physiological functions and contribute to widespread endothelial damage. Addressing microclots and platelet hyperactivation is vital for the recovery of people with Long COVID,” underlines Douglas Kell.

A lack of acceptance and understanding of Long COVID

Resia Pretorius emphasises the importance and great benefit of early intervention and treatment, especially during the acute phase of COVID-19. By identifying clotting abnormalities and endothelial damage in the acute phase, clinicians can initiate appropriate treatment, potentially preventing the development of Long COVID. Anticoagulant therapy has shown promising results in preventing microclot formation and reducing platelet hyperactivation.

“If we prevent microclot formation and platelet hyperactivation, we give the body a chance to recover and mitigate the damage to the endothelial layers. Early intervention and anticoagulant therapy could be crucial in preventing Long COVID. However, widespread adoption of these treatment strategies and clinical trials are essential to establish their efficacy,” says Douglas Kell.

During the first pandemic wave in 2020, researchers in South Africa tried to give people with acute COVID-19 a combination of various anticoagulants, and they never developed Long COVID.

“They survived much better than the untreated population with the same regimen. So, I think we must look at clotting instead of psychology from the acute phase throughout. Using various methods to determine whether there is clotting pathology in the acute phase is currently crucial for treatment,” elucidates Resia Pretorius.

We have to acknowledge that this is in the past

Unfortunately, the scientific and medical community is divided in understanding Long COVID. In their new review, the researchers identify two groups: those who approach it from a physiological and biochemical standpoint and those who perceive it primarily as a psychological condition, similar to what has equally erroneously been claimed for myalgic encephalomyelitis/chronic fatigue syndrome.

“The latter group tends to blame the patient, attributing the disease to psychological factors rather than recognising its biochemical and physiological basis, which I believe it possesses. This lack of acceptance and understanding of Long COVID has significant consequences for the people affected. They often struggle to receive optimal treatment because of the absence of consensus and effective therapies,” explains Douglas Kell.

According to Resia Pretorius, acute COVID should have been treated as a thrombotic condition from the beginning, so that people did not develop persistent clotting pathology. However, we have to acknowledge that this is in the past.

“But a percentage of people with Omicron will still get Long COVID if we do not treat them. So there is still a chance to treat the acute phase with anticoagulants. But we are still not doing it. We are still just telling people to go home, rest in bed, take lots of fluids and take vitamin C. And we hope that they will recover,” adds Resia Pretorius.

No longer a lone voice

Misdiagnosis and applying inappropriate treatments further compound the issue. Resia Pretorius argues that accurate diagnosis is crucial along with implementing proper treatment options that can improve people’s conditions. She highlights the urgent need for clinical trials to validate these treatment approaches.

“We do have proper diagnostic methods and treatment options that work and seem to be helping people get better. So, we need widespread implementation of diagnostics and clinical trials to validate these approaches,” emphasises Resia Pretorius.

The resistance to accepting Long COVID as a physiological disease stems from entrenched beliefs and the lack of comprehensive diagnostic tools. Resia Pretorius acknowledges the uphill battle in changing perspectives but remains optimistic. She emphasises the importance of awareness campaigns, scientific conferences and open dialogue among healthcare professionals.

“Challenging conventional thinking and adopting innovative approaches provides hope for more unified understanding and better treatment outcomes for Long COVID. We are making progress, and we are no longer alone in this fight. Awareness campaigns, conferences and scientific publications play a vital role in changing perspectives and ensuring that Long COVID is recognised and treated as a physiological disease,” explains Douglas Kell.

Doctors need to pay attention

Long COVID continues to pose significant challenges to individuals, healthcare systems and the scientific community. Resia Pretorius’ research offers valuable insights into the biochemical mechanisms underlying Long COVID, highlighting the importance of recognising microclotting and platelet hyperactivation as central factors.

“This is a global problem, and the tendency to not speak out or dismiss people’s experiences as psychological gaslights them. They feel silenced, and clinicians hesitate to address this because diagnostic tools are lacking. I have never seen this dilemma before in the scientific and medical community,” says Resia Pretorius.

According to Resia Pretorius, raising widespread awareness is now crucial so that all doctors become aware of and accept the phenomenon of Long COVID by shifting the narrative from psychological to physiological, raising awareness and advocating for early intervention and appropriate treatment:

“Doctors need to pay attention to what we have been saying. This is not something mystical or unexplained. Everything is right in front of you. Just observe them, assess clotting and conduct relevant tests. Clinically evaluate and you will see that they are prone to blood clotting. It is not something magical. Listen to what they are complaining about and treat them accordingly. Then there is hope for improved outcomes and a better quality of life for people with Long COVID,” concludes Resia Pretorius.

Long COVID: pathophysiological factors and abnormalities of coagulation“ has been published in Trends in Endocrinology & Metabolism. Co-author Douglas Kell is an Associated Scientific Director at the Novo Nordisk Foundation Center for Biosustainability, Technical University of Denmark, Kongens Lyngby.

My overarching research theme is: Blood coagulation, circulating inflammatory markers ​and how these play a role in inflammatory conditions like Type...

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