For the past two years, one of Covid-19’s most enduring mysteries has been why some people end up with what’s come to be known as long Covid even though many of them only ever experienced mild symptoms during the active phase of the disease.

There are a number of reasons why the issue has been so hard to untangle. First and foremost, it’s still not clear how many people have had, or have, long Covid, nor for how long.  

Diagnosis is difficult because of the sheer number of side effects identified. The list tops 200 and many reported symptoms, such as fatigue and brain fog, can easily be attributed to other causes. 

Last November, researchers from the University of Michigan decided to hazard a guess. They settled on 100 million cases worldwide based on a meta-analysis of 40 global studies.

This data showed that 43% of people who contract Covid-19 will still be suffering the after-effects more than a month after diagnosis or recovery, with a skew towards women and a higher proportion in Asia (44%) compared to the US (30%).

However, getting a diagnosis may now prove much easier in the near future thanks to the identification of a potential biomarker. This should not only pave the way for the development of a clinical diagnostics tool, but also effective treatments.

Last summer, researchers at South Africa’s Stellenbosch University uncovered the first evidence that Covid-19 causes micro clots, which trap inflammatory molecules inside them. The list of molecules includes: the main clotting protein, fibrogen, plus von Willebrand factor (VWF), which plays a major role in blood coagulation and alpha2-antiplasmin, which prevents clots from breaking down.

When lead researcher, Professor Resia Pretorius, spun patients’ blood plasma, she also noted high levels of platelet activation. The platelets (cells that help blood to clot) were so fragile that hyper-activation was triggered even when they were simply placed on a slide for analysis.

It took a fluorescent microscope to spot the inflammatory markers hidden inside the clots. Routine blood tests cannot pick them up: hence why long Covid sufferers often leave their doctor’s surgery none the wiser about why they still feel so ill.

Pretorius and her team concluded that cellular hypoxia is the common denominator for long Covid symptoms. The micro clots partially block blood vessels, preventing red blood cells from carrying enough oxygen to different organs around the body, whether it’s the brain, lungs or heart.

When the body is functioning normally, there’s an ongoing balance between clotting and anti-clotting processes.

When a blood cell wall is injured, for example, platelets are activated to prevent bleeding. They change shape and, with the aid of VWF, thicken and stick to one another to plug the wound. Fibrin proteins mesh them together.

A second process called fibrinolysis subsequently breaks down the fibrin in the coagulated blood to prevent the formation of blood vessel-blocking clots.

However, viruses are known to disrupt this balance. When we’re infected with the Covid-19 virus, the spike protein enters our cells through their ACE2 receptors, much like a key being inserted into a lock.

When it does so, it activates platelets, which play a key role in infection detection and inflammation signalling. Clotting proteins are released, potentially triggering a domino effect.

Talking to Dr Amy Proal for the PolyBio Research Foundation podcast, Professor Pretorius said that, “the extent to which the spike protein does this is just mindboggling. I’ve never seen the size of clots and the amount of clots in acute and in long Covid.”

Her research underlines just how far our understanding of Covid-19 has evolved over the past two years. For we no longer think of it as a solely lung disease. It’s a vascular (blood flow) one too.

Autopsies routinely reveal widespread clotting, while hospitalised Covid patients frequently suffer from symptomatic venous thromboembolism (a form of deep vein thrombosis and pulmonary embolism), even after they’ve been administered anti-clotting drugs.

It is one of the reasons why people with chronic illnesses and autoimmune conditions such as type 2 diabetes, hypertension and rheumatoid arthritis have poorer outcomes from the virus. Prior to infection, they’re already suffering from higher levels of inflammation, which is damaging their blood vessels and provoking platelet activation.

It also means that some people dying from strokes and heart disease, not long after a Covid-19 infection, will be unreported victims of long Covid too. The reason why more don’t succumb is because the clots are tiny and in most cases, the clotting function returns to normal once the immune system clears the infection.

So how will this all get treated? Clinicians are already adopting a multipronged approach to long Covid.

The same is likely to apply to micro clots too: clear the existing ones from the body, while curtailing the circular process to prevent new ones from forming, thereby allowing blood vessel walls to heal and inflammatory markers to die down.

One suggested solution for the clearance procedure is a machine that cleanses patients’ blood, much as kidney dialysis machines rid it of waste products when kidneys stop functioning.

In Mülheim, Germany, Dr Beate Jaeger has been trialling a H.E.L.P apheresis machine on long Covid patients. For the past four decades, the machine has been filtering out excess cholesterol in patients with heart disease using heparin-induced extracorporeal LDL precipitation (HELP).

One of her patients is Dr Asad Khan, a British respiratory physician who caught Covid-19 in November 2020. Nearly one year later, long Covid had left him bed-bound, intolerant of light and sound.

He had so little energy that he fainted on arrival to Dr Beate’s clinic in a wheelchair.

Dr Khan later told the BBC how was blood taken out of one arm, cleaned of clots and then returned through the other arm. He had so many clots to start with that he broke the machine four times.

When his blood came out it was also black and full of fibrin. His venous oxygen saturation level (oxygen in the blood) was 32% compared to 65% to 80% for a normal adult.

However, by his seventh treatment, Dr Khan was well enough to start reading scientific papers again. By his twelfth, he’d also been prescribed three anticoagulants – aspirin, clopidogrel and a direct oral anticoagulant.

In recent interviews, he’s said that he’s feeling much better. Blood tests reveal little evidence of clotting, or platelet activation.

In South Africa, 24 long Covid patients, taking part in one experimental study, also responded well to a dual anti-platelet activation therapy. However, researchers flag the need for caution since anticoagulants can kill patients prone to bleeding unless they’re under clinical supervision.

Full clinical trials are still awaited, as is a simple diagnostic test to detect the inflammatory blood markers in the first place. Stellenbosch University hopes that it’s new start-up, BioCODE, will be the one to create it. 

Given the large numbers of people with suspected long Covid, policy makers have become increasingly concerned about the potential long-term costs to national health services. As such, any potential breakthroughs attract considerable attention.

And when it comes to recent ones regarding micro clots, the beneficiaries may extend well beyond long Covid too. There are many people suffering chronic fatigue syndrome and ME who’ve spent years trying to unpick why they don’t get better after falling ill with a virus. Research into long  Covid may help them to finally get the answers they have been waiting for.