Severe COVID-19 infections are marked by severe pneumonia, acute inflammation and blood clots. The inflammation and clots together cause organs to fail and ultimately death.
This ‘flow’ of processes is not entirely new. Any infection – viral, bacterial or fungal – causes the blood to coagulate. But sometimes, an overactive coagulative system could cause disseminated intravascular coagulation (DIC). This is a condition in which clots in the bloodstream are disseminated throughout the body.
Inflammation, another innate immune response, also triggers coagulation. More importantly, the interaction between coagulation and inflammation is bi-directional: one system activates and controls the other, by sending biochemical signals.
COVID-19 is typically marked by hyper-inflammation due to cytokineamia. Cytokinaemia is the process that activates cytokines, which are small proteins secreted by various immune cells in the body. Cytokines play an important role to inhibit the spread of pathogens through the body.
But some cytokines, called pro-inflammatory cytokines, trigger inflammation even as they cause the blood to clot. Some of them include interleukin-6 (IL-6), interleukin-1 (IL-1) and tumour necrosis factor-α (TNF-α).
Studies have already shown that the novel coronavirus evokes a polyphasic immune response. This means the body responds to it in multiple phases and with different magnitudes. First, a patient suffers from cytokinaemia, followed by an immunosuppressive stage in which the immune response gets suppressed. In people with severe COVID-19, a cytokine storm occurs, an uncontrollable secretion of pro-inflammatory cytokines in a short span of time that can cause death.
In this context, coagulation is not as bad as it seems. This physiological system prevents unnecessary blood loss and hampers the pathogen’s movement in the body.
Also read: Explained: What is a Cytokine Storm?
The human blood consists of blood cells and plasma, plus twelve blood clotting factors – the enzymes that facilitate clotting. The presence of each factor affects the others.
Coagulation begins with the prothrombin factor, which a compound called a prothrombinase complex transforms to thrombin. Thrombin converts another coagulation factor called fibrinogen to fibrin. Along with blood platelets, fibrin forms clots.
Once the blood has clotted, the part of the blood free of any fibrinogen is called the blood serum – a.k.a. the yellowish fluid that escapes from the wound once you stop bleeding.
Thrombin also controls several physiological responses, including augmenting an inflammation when a pathogen is attacking the body. The prime mediators of inflammation-induced activation of coagulation are the pro-inflammatory cytokines. Research has shown that IL-6 activates coagulation and thrombin generation, and IL-1 and TNF-α control the activity of anti-coagulants.
When too much thrombin is produced, the anti-coagulants receive a signal to prevent thrombin generation and inhibit unwanted clotting. However, this control mechanism could fail if there aren’t enough anti-coagulants during inflammation, which could lead to the formation of small blood clots in an event called microthrombosis.
Here, we return to COVID-19: The anti-coagulant called anti-thrombin prevents the coagulative activity of fibrin if too much fibrin is present. Researchers have found that patients who don’t survive COVID-19 have up to 7% lower concentration of anti-thrombin in the blood compared to those who do survive COVID-19.
The uncontrollable coagulation that happens in COVID-19 patients increases the risk of a thromboembolic complication: of blood clots forming in blood vessels and then breaking loose. The blood then carries them to different parts of the body, where they could get stuck to other blood vessels and block their passage.
Also read: Explained: What Is Convalescent Plasma?
In COVID-19 patients, these clots block vessels in the lungs, the brain, in the gastrointestinal tract, and in the liver and kidneys. This is one of the reasons people with severe COVID-19 undergo multi-organ failure and finally die. Over-clotting can also cause blood to leak through vessels in organs.
Clots in the blood vessels of the lungs is called a pulmonary embolism. It causes the respiratory system to rapidly deteriorate, causing breathing problems. Clots in the brain’s blood vessels could cause a cerebral stroke.
This isn’t idle speculation: postmortem studies conducted with the bodies of COVID-19 patients have found the presence of small blood clots in vessels of the lungs and other organs.
The concentration of D-dimers substantially increases during inflammation and coagulation; D-dimers are fibrin fragments that linger in the blood after a blood clot has has been degraded. They’re not normally present in the blood plasma of healthy humans, and show up only after coagulation has been activated. So tests that look for D-dimers in the blood are now routinely used with patients suspected to have clots in their veins. The more D-dimers there are, the likelier the vessels have coagulated.
In one study, researchers found that COVID-19 patients with a mean D-dimer concentration of 2.12 mg/l of blood didn’t survive.
As a result of these findings, anti-coagulants and anti-inflammatory agents have emerged as potentially useful ways to keep a COVID-19 infection from worsening. Now, we must wait for clinical trials to confirm (or invalidate) this hypothesis, as well as check if these agents are both safe and efficacious.
Madhurima Pattanayak is a freelancer science writer from Kolkata.