Microclots explain why 1 in 10 people continue having long COVID symptoms

Disease and treatment 22. may 2022 3 min Professor and Associated Scientific Director Douglas Kell Written by Morten Busch

According to a researcher, the ripples from the COVID-19 pandemic have scarcely subsided before a larger and potentially more serious COVID-19 wave washes around the world. One in 10 people who have had COVID-19 experience breathlessness, fatigue, brain fog, tissue damage and serious comorbidities – both those who became very sick and those who had no symptoms. New research shows that microclots caused by COVID-19 block the supply of oxygen to various tissues and that anticoagulant drugs may be a possible treatment.

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Decision-makers, healthcare institutions and the general public would probably prefer to put the COVID-19 pandemic behind them as soon as possible. However, in addition to potential new waves of infection, there is a serious aftermath in the form of long COVID. It appears to affect up to 10% of those who have had COVID-19 and has resulted in millions of people worldwide on long-term sick leave. Although little research on the aftereffects of COVID-19 has been done, scientists are on the trail of both causes and possible treatment.

“Working with professor Resia Pretorius from Stellenbosch University, our studies of plasma from people with long COVID show extensive presence of persistent amyloid fibrin microclots that capture other proteins and are a major player in Long COVID. These microclots may block capillaries, limiting the passage of red blood cells and hence oxygen exchange. This explains the symptoms we see and why they do not go away on their own. These people should contact their physicians to discuss early treatment with drugs that can inhibit these microclots,” explains co-author Douglas Kell, Professor and Research Chair in Systems Biology, Department of Biochemistry and Systems Biology, University of Liverpool, United Kingdom and Associated Scientific Director, Novo Nordisk Foundation Center for Biosustainability, Technical University of Denmark, Kongens Lyngby.

Distinguishing between acute and long COVID

A few years ago, researchers discovered that fibrinogen, which when blood clots usually accumulate in large polymer networks called fibrin, can occasionally clot into an anomalous amyloid form of fibrin, somewhat in the same way as amyloids do in Parkinson’s disease. This amyloid form of fibrin creates these microclots, which are somewhat resistant to the normal means of proteolytic removal and may lead the immune system to mistakenly produce autoantibodies – in a process that leads to inflammation. This vicious circle bears similarities to post-viral syndromes and to myalgic encephalomyelitis/chronic fatigue syndrome.

“These microclots are more or less easily detected in blood plasma using the thioflavin T stain and a simple fluorescence microscope and are clearly present in up to 30% of the people who have been affected by COVID-19. Although the symptoms of long Covid are multifarious, we believe that these amyloid fibrin microclots can explain symptoms such as breathlessness, fatigue, brain fog, tissue damage, inflammation and coagulopathies,” says Douglas Kell.

The growing microclots can inhibit the transport of red blood cells to the capillaries and thus oxygen exchange to the lungs and brain. Examination of blood plasma samples from people in South Africa who had had COVID-19 showed the presence of many microclots among both people who had been seriously ill and people who had had no symptoms. Douglas Kell therefore advocates distinguishing between severe acute COVID-19 (in which the most severely affected people tend to be older men) and long COVID (which especially affects premenopausal women). His work has shown that formation of the aberrant amyloid fibrin microclots may be triggered by the SARS-CoV-2 spike protein itself, even when added in recombinant form (in vitro) to normal plasma.

“These microclots may also create novel antigens that trigger the immune response to produce autoantibodies, which can exacerbate symptoms further. We think understanding the role of these microclots may enable us to develop an effective strategy for treating long COVID and probably also other related conditions such as myalgic encephalomyelitis/chronic fatigue syndrome,” explains Douglas Kell.

Anticoagulant therapy on the way

According to Douglas Kell, a major problem is that many regulatory health bodies around the world still do not recognise long COVID as a separate disease but simply refer to it under the broad term of COVID-19.

“The demographics of long COVID are quite different from those of acute COVID-19 since some people who never had acute COVID-19 symptoms nevertheless develop long COVID symptoms months later. The people who have these symptoms are often advised that they need to engage in physical activity to get their system going. This is actually the worst possible advice, since it can aggravate long COVID further,” says Douglas Kell.

Douglas Kell says that long COVID is similar to other post-viral syndromes, including myalgic encephalomyelitis/chronic fatigue syndrome. Although these disorders have been known for years, it is only now – following a pandemic – and the growing problems caused by long COVID that research is intensifying to discover both the causes and how to treat these microclots. However, there is still a long way to go.

“Right now we are demonstrating that this phenomenon is not unique to South Africa, since we have found the same amyloid fibrin microclots among patients in the United Kingdom. In fact, we are already testing an anticoagulant therapy that removes the microclots and also eliminates the other symptoms. In addition, it is extremely important that general practitioners be equipped with the right diagnostic tools to enable them to determine whether patients have these microclots and whether they should be treated,” concludes Douglas Kell.

A central role for amyloid fibrin microclots in long COVID/PASC: origins and therapeutic implications” has been published in Biochemical Journal. Douglas Kell is Associated Scientific Director at the Novo Nordisk Foundation Center for Biosustainability, Technical University of Denmark, Kongens Lyngby.

I studied Biochemistry at Oxford University (including a Distinction in Chemical Pharmacology) followed by a D Phil at the same Institution. I spent m...

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