The end game for the COVID-19 pandemic seems to be approaching, and attention is increasingly focusing on its aftermath. As many as 30% of the people who have had severe (or even asymptomatic) COVID-19 have debilitating symptoms weeks or months after the acute illness. Now, researchers have tried a treatment based on good clinical practice that combats the microclots that may block the lungs and inhibit oxygen transport to body tissues. The treatment appears to warrant controlled clinical trials.
Fatigue, shortness of breath, cognitive dysfunction, joint pain and insomnia are some of the most common late sequelae experienced months after becoming ill by 100 million people who have had COVID-19. Many have serious complications so long after the illness that they cannot cope on a daily basis. So even when the COVID-19 pandemic subsides one day, the world faces a huge health challenge for which there is no recognised treatment.
“The problem is the microclots and the hyperactivation of the platelets that occur during illness among most people with severe COVID-19. With a clinical colleague, we therefore treated a few with direct oral anticoagulants and dual antiplatelet therapy for 1 month,” explains a main author, Douglas Kell, Professor, Department of Biochemistry and Systems Biology, Institute of Systems, Molecular and Integrative Biology, University of Liverpool, United Kingdom and Associated Scientific Director, Novo Nordisk Foundation Center for Biosustainability, Technical University of Denmark, Kongens Lyngby.
"Most symptoms disappeared completely and the fatigue almost vanished, so we think that there is a basis for testing the strategy carefully, along with the necessary coagulability monitoring, in larger clinical trials," Douglas Kell continues.
An approach based on reducing blood microclots
The study is part of a longstanding collaboration with Resia Pretorius, Professor at the University of Stellenbosch in South Africa. The researchers’ interest in investigating late sequelae of COVID-19 was aroused in part because of the lack of known physiological mechanisms that could explain the many diverse symptoms reported. A large global study of 3,762 people who had had COVID-19 from 56 countries showed that almost half were still unable to work full time 6 months after developing COVID-19 because of fatigue, shortness of breath, insomnia, cognitive dysfunction and even anxiety or depression.
Douglas Kell’s research colleagues had previously discovered in many chronic diseases that fibrinogen can clot into an amyloid form that makes it resistant to being dissolved again in the body.
Amyloids arise when proteins change their shape slightly so that they become less soluble and begin to clump together, such as the proteins synuclein in Parkinson’s disease and amyloid-beta in Alzheimer’s disease.
“To advance our knowledge on what happens to these people, we examined 845 people with late sequelae, and most had hypertension and high cholesterol levels. We also examined blood samples more closely using a method that we established about 5 years ago and detected the presence of many fibrin amyloid microclots and signs of platelet hyperactivation in all of them,” says Douglas Kell.
The results were convincing
The researcher therefore looked at blood from patients that their clinical collaborator, Jaco Laubscher, treated after identifying the patients with long COVID.
"We investigated whether his best clinical practice treatment could dissolve these microclots and calm down the platelets. In addition, we investigated whether the symptoms would improve if we saw that the microclot and platelet pathology were reduced. We therefore looked at blood samples of 24 patients before and after they were on a treatment regimen of two antiplatelet drugs that prevent blood clots and an anticoagulant that reduces blood clotting. The patients were continually observed for bleeding and the coagulation status of their blood,” explains Douglas Kell.
After the regimen, each of the 24 patients reported that the most important late sequelae of COVID-19 symptoms were significantly reduced and that their fatigue symptoms improved. The researchers reanalysed the patients’ blood and found that both fibrin amyloid microclots had disappeared and the patients’ platelet activity was normalised.
“The results were so convincing that we believe that the strategy should undergo proper clinical trials as soon as possible, since we think that this indicates an important treatment option that appears to be extremely effective. In addition, however, it is important to monitor the whole-blood coagulability of the individuals throughout, since there is a danger of bleeding among those who may have a tendency in that direction in the first place,” says Douglas Kell.
A vicious circle
Douglas Kell also emphasises the need for new and better knowledge about and treatment of late sequelae. Current treatments are suboptimal at best.
“The symptoms of people with late COVID reveal several similarities with those of people with chronic diseases such as myalgic encephalomyelitis/chronic fatigue syndrome, and we know from these that exercise can be more harmful than beneficial for improving people’s health. Microclots seem to block the capillaries and inhibit the transport of oxygen to the tissues, so I worry when some doctors prescribe exercise as a cure for these late sequelae. This may turn out to do more harm than good,” explains Douglas Kell.
Douglas Kell also hopes that screening COVID-19 for the presence of the microclots will be a way to raise awareness of their existence and, in time, help to prevent them. They help to intensify a vicious circle of inflammation, which in turn amplifies the formation of blood clots. All of this creates difficulty in breathing for the people who are severely affected.
“This is the key feature of severe COVID-19. The virus induces endothelialitis: inflammation of the blood vessels that deactivates the normal coagulation of the blood and activates the platelets. Understanding the mechanism that starts this process will enable us to avoid these very serious sequelae more easily before they happen, and this applies to COVID-19 and many other virus-induced diseases,” concludes Douglas Kell.