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New research finds elevated blood clot markers in people with long COVID who also have a reduced capacity to exercise. Roberto Moiola/Sysaworld/Getty Images
  • Researchers do not yet fully understand the mechanisms underlying the symptoms of long COVID.
  • A new study shows that 28% of individuals with long COVID show higher levels of markers associated with the formation of blood clots.
  • Abnormal levels of these markers were associated with impaired exercise capacity but not other long COVID symptoms.
  • These results could inform future research on treatments to reduce such abnormalities associated with blood clotting in people with long COVID.

All data and statistics are based on publicly available data at the time of publication. Some information may be out of date. Visit our coronavirus hub for the most recent information on the COVID-19 pandemic.

A recent study published in the journal Blood Advances found elevated levels of blood clotting markers in more than one in two (55%) people with long COVID who also had abnormal exercise testing results.

Individuals with elevated blood clotting marker levels were four times more likely to show persistent deficits in exercise capacity.

These results suggest that individuals with long COVID should be screened for impaired exercise capacity and markers associated with blood clotting. The study’s author, Dr. Nithya Prasannan, a researcher at the University College London Hospital, says:

“I hope that people will view this research as a step forward in understanding what causes long COVID, which will hopefully help us guide future treatment options.”

According to the World Health Organization, more than 500 million individuals across the globe have been diagnosed with COVID-19 so far. Although estimates vary widely, a recent meta-analysis suggests that nearly one-third of all individuals with COVID-19 may experience persistent symptoms 3 months after symptom onset.

These COVID-19 symptoms that linger for at least three months after a SARS-CoV-2 infection have been collectively described as ‘long COVID’ or ‘post-acute COVID-19 syndrome’. Some of the common symptoms of long COVID include impaired exercise capacity, fatigue, breathlessness, muscle pain, brain fog, and headaches.

Despite the growing number of individuals with long COVID, the mechanisms underlying these persistent symptoms of COVID-19 are not well-understood.

Recent studies have shown that individuals with long COVID are more likely to develop small clots in blood capillaries and show abnormalities in the levels of factors that promote blood clotting. Such micro clots can interfere with the supply of oxygen and nutrients to the body and potentially result in long COVID symptoms such as fatigue.

Acute COVID-19 is associated with an increased risk of blood clots. Consistently, individuals with acute COVID-19 are more likely to show elevated levels of proteins that promote blood clotting.

One such protein is the von Willebrand Factor (VWF), which helps to form a clot to seal off damaged blood vessels at the injury site. Subsequently, an enzyme called ADAMTS13 cleaves the VWF protein into smaller fragments to reduce its activity and prevent the formation of clots in blood vessels.

An elevated ratio of VWF to ADAMTS13 is associated with an increased risk of blood clots in acute COVID-19. Such a condition involving an increased risk of blood clots is referred to as a prothrombotic state.

In the present study, the authors investigated whether such a prothrombotic state was associated with the severity of long COVID symptoms, including exercise capacity.

The present study consisted of 330 individuals who had persistent symptoms 3 or more months after the SARS-CoV-2 infection and were visiting an outpatient long COVID clinic. The majority (83%) had never been in hospital.

At the time of the visit, the researchers administered two tests to assess the participants’ endurance and exercise capacity. These exercise tests involved walking at a normal pace for 6 minutes and repeatedly switching from a sitting to a standing position for a minute.

The researchers used an oxygen monitor to measure blood oxygen levels during the test. They also measured changes in the levels of blood lactate, which is produced by the body when there is an insufficient supply of oxygen to sustain the activity of muscles.

To assess the risk of blood clotting, the researchers used blood samples to categorize the participants into two groups based on whether their VWF/ADAMTS13 ratio was normal (less than 1.5) or abnormal (greater than or equal to 1.5).

The researchers found that around 28% of the study’s participants had abnormal VWF/ADAMTS13 levels. The VWF/ADAMTS13 ratio was not correlated with the severity of long COVID symptoms, including headaches, fatigue, and cognitive deficits.

However, abnormal VWF/ADAMTS13 levels were associated with impaired exercise capacity, as measured by blood oxygen and lactate levels. Nearly 20% of participants showed impaired exercise capacity, and 55% of individuals within this group had elevated VWF/ADAMTS13 levels.

Elevated VWF/ADAMTS13 levels were four times more likely in individuals with impaired exercise capacity than those with normal performance in the exercise tests. In addition, the levels of VWF and the blood-clotting protein Factor VIII were also higher in individuals with impaired exercise capacity.

Dr. Artur Fedorowski, a professor at Karolinska University Hospital, Stockholm, Sweden, spoke to MNT about the study. He w

“The higher VWF/ADAMTS13 ratio may suggest that some long COVID patients have a predisposition to microclot generation, potentially impairing the normal blood flow through various crucial areas such as lung or cerebral circulation. Thus, in normal condition, the patient may feel normal and compensated, whereas physical or mental effort may reveal a lack of compensatory reserve and produce characteristic symptoms.”

“This hypothesis is mechanistically very attractive, but we should keep in mind that the majority of long COVID patients had normal VWF/ADAMTS13 ratio. Either is the detected abnormality only one of many symptom-generating mechanisms of long COVID or there might be no causal association.”

“Instead, the real long COVID mechanism may cause symptoms and increased prothrombotic ratio in some susceptible patients,” added Dr. Fedorowski.

Addressing future research directions, Dr. Prasannan told MNT, “Assessing the VWF/ADAMTS13 ratio has become a part of the routine investigations performed in Long COVID patients.”

“As a part of current ongoing research in the Haemostasis Research Unit, a shear flow-based assay (a platform that mimics blood flow through blood vessels) is being used to assess for the formation of microclots in patients with long COVID.”