Dr Martin Juneau, M.D., FRCP
Cardiologue et Directeur de la prévention, Institut de Cardiologie de Montréal. Professeur titulaire de clinique, Faculté de médecine de l'Université de Montréal. / Cardiologist and Director of Prevention, Montreal Heart Institute. Clinical Professor, Faculty of Medicine, University of Montreal.See all articles
- A high proportion of patients with COVID-19 have clotting disorders that clinically manifest as venous thrombosis and pulmonary embolisms.
- These disorders are believed to be caused, at least in part, by a direct attack of the coronavirus on the endothelial cells that line the inside of blood vessels, causing abnormal formation of blood clots.
- The presence of these clots is particularly important in patients who develop severe complications from COVID-19 and contributes to the increased risk of mortality observed in this population.
As the COVID-19 pandemic progresses, it is becoming increasingly clear that the coronavirus responsible for this disease is a respiratory virus like no other. The lungs are, of course, the main organs affected by this virus, and most patients who develop severe complications or die from COVID-19 have serious lung damage. However, a large number of studies have reported several very specific clinical cases, which had so far never (or very rarely) been described for this type of viral infection, in particular severe damage to the heart, digestive system, kidneys, and brain.
Data collected so far indicates that abnormal blood clot formation (thrombosis) is another unusual manifestation of COVID-19 that may play a very important role in the severity of the disease. Since the beginning of the pandemic, several physicians have reported an abnormally high incidence of phenomena linked to a decrease in blood circulation, such as a bluish tint to the lower limbs (e.g. toes) as well as deep vein thrombosis (phlebitis). The presence of these blood clots in the veins is extremely dangerous, as they can migrate into the bloodstream, reach the right ventricle of the heart, and subsequently block the pulmonary arteries to cause embolisms. In this sense, it should be noted that studies carried out in the Netherlands and France indicate that approximately 20–30% of patients with severe forms of COVID-19 are affected by these venous thrombosis and that pulmonary embolisms represent the most common complication of these coagulation disorders. This was confirmed by an autopsy study of 12 patients who died from COVID-19: of these patients, 7 presented with deep thrombosis, and 4 of them died of pulmonary embolism.
These pulmonary embolisms really seem to represent a “signature” of the coronavirus responsible for COVID-19. For example, a study reported the presence of pulmonary embolisms in 17% of patients with severe respiratory syndrome caused by COVID-19, while these embolisms are present in only 2% of patients also suffering from a severe respiratory syndrome, but not related to COVID-19. The contribution of these clots to the severity of COVID-19 is well illustrated by studies showing that high blood levels of d-dimers, a marker of thrombosis, were associated with a very large increase (18 times) in the risk of mortality from COVID-19. In addition, 71% of patients who died from this disease were reported to have multiple blood clots scattered throughout their blood vessel network (disseminated intravascular coagulation), a phenomenon observed in only 0.6% of patients who survived the disease.
The coagulation disorders caused by the coronavirus are not limited to the veins, but also seem to affect the arteries. For example, one of the most surprising complications of COVID-19 is the observation of large-vessel strokes in young adults (under 50) living in New York. Studies in China have also documented the presence of these strokes in about 5% of patients; however, they were older than those affecting young New Yorkers. Taken together, these observations clearly show that bleeding disorders are a common consequence of infection with the SARS-CoV-2 coronavirus and contribute greatly to the development of serious complications of the disease.
Endothelial cells are targeted
One of the factors involved in this disruption of the normal coagulation process appears to be the direct action of the virus on the cells that line the blood vessels, called the endothelium. Under normal conditions, one of the main functions of this endothelium is to ensure good blood circulation, in particular by preventing the formation of blood clots. On the other hand, when these endothelial cells are damaged by physical (cut, wound) or biochemical (inflammation, pathogenic agents) aggressors, the rupture of the endothelial barrier allows the factors involved in coagulation to come into contact with the blood and form fibrin clots to restore the integrity of the endothelium.
In patients who develop severe forms of COVID-19, an exaggerated inflammatory response, often referred to as a “cytokine storm” (hypercytokinemia), is frequently observed. This high intensity inflammation makes the blood vessels very permeable and is therefore perceived by the body as an injury, which causes the activation of coagulation and the formation of clots. This process may be amplified by the presence of antiphospholipid antibodies, an autoimmune disorder also associated with an increased risk of thrombosis. It is also now known that the receptor that allows the entry of the coronavirus SARS-CoV-2 into cells is present in significant quantities on the surface of endothelial cells, so that the virus can directly attack the endothelium and cause damage that will trigger the activation of coagulation. This phenomenon was observed during an autopsy study recently published in the New England Journal of Medicine: by examining lung samples from patients who died of COVID-19, the researchers noted the presence of multiple viral particles in the blood vessels, as well as heavy damage to the structure of endothelial cells. This endothelial damage was accompanied by the presence of a large number of small clots obstructing blood flow in the pulmonary blood microvessels. These phenomena seem specific to COVID-19, because the parallel examination of the lungs of patients who died of influenza (H1N1) did not reveal any infection of the endothelial cells by the virus and showed a much lower incidence (9 times) of blood clots in the pulmonary vessels. This could explain why the mechanical ventilation of patients with severe forms of COVID-19 is often powerless to increase blood oxygen levels: not only is breathing compromised by the presence of fluid or pus in the pulmonary alveoli, but in addition, the damage inflicted on the endothelial cells and the presence of multiple clots obstructing the vessels prevent the blood from circulating and being oxygenated.
The impacts of these phenomena are obviously not exclusive to the lungs: every organ in the body is supplied with blood vessels, so that infection of the endothelium by the virus, combined with an increased formation of blood clots, can greatly contribute to the devastating effects of the virus on the functioning of several organs.