18 June 2020

‘Molecular scissors', or heparinases, also play a role in the leakage of fluid from the blood vessels to lungs and kidneys in COVID-19 patients. The scissors cut the protective sugar layer (glycocalyx) in the blood vessels, making leakage easier. The more serious the disease, the more active the scissors, wrote Radboud university medical center researchers in an article in MedRxiv.
Severe forms of COVID-19 are associated with serious respiratory problems (ARDS; acute respiratory disease syndrome) and increased protein loss in urine (proteinuria). Leaking blood vessels play an important role in this, both in the lungs and kidneys. 

Sugar structures

The ‘lining’ of the blood vessels consists of endothelial cells. These well-connected cells form a protective inner layer that prevents leakage. They are helped enormously by irregularly shaped sugar structures that grow on those endothelial cells like a thick thicket. The structures stand with their feet in the endothelial cells and bend with their crests to the rhythm of the passing blood flow. The sugar structures on the endothelial cells mainly consist of heparan sulphate. The sugar structures as a whole are called glycocalyx. 

Molecular scissors

Vascular leakage occurs when that glycocalyx is damaged. It is known that the protein heparanase is a frequent cause of such damage. Like molecular scissors, heparanase cuts the glycocalyx short and small, which also stimulates all kinds of inflammatory processes. The only known, and already clinically applied, means of inhibiting this degradation is low molecular weight heparins (LMWH). 

Pruning the glycocalyx

Johan van der Vlag, theme Renal disorders, “We wondered if this heparanase might also play a role in the disease process of COVID-19. More specifically, does it contribute to leakage in lungs and kidneys by pruning the glycocalyx in the blood vessels? To answer that question, we investigated the heparanase activity in the blood plasma of COVID patients. Blood plasma is the liquid part of the blood without the blood cells and platelets. In that blood plasma, we can determine the amount of heparanase and cut off pieces of heparan sulphate.” 

Scissors and cut pieces

Researchers examined the plasma of 48 COVID-19 patients (34 in the clinical wards, 14 in the ICU) and 10 healthy controls without COVID-19. Van der Vlag: “We did indeed find that heparanase activity increased with the severity of the disease. This connection was confirmed by the fact that we also found an increasing number of heparan sulphate fragments in the plasma. The more active the scissors, the more cut pieces we found. And the greater the damage to the glycocalyx, the greater the chance of vascular leakage. This may partly explain the fluid accumulation in the alveoli and protein loss in urine in admitted COVID-19 patients.” 

Heparin does more?

COVID-19 patients also have an increased risk of blood clots, so some of them are given heparin as a preventive anticoagulant. These are the same LMWH that act as an inhibitor of heparanase. Van der Vlag: “We have been able to see what it does to this heparanase in a small number of COVID-19 patients. And indeed, it does mitigate the activity of the glycocalyx cutter. Some studies have also been published showing that heparin treatment of COVID-19 patients reduces the risk of death.”

Explaining the beneficial effects

These are interesting results, and Van der Vlag’s research group has also written a mini-review on the molecular mechanisms that can explain the beneficial effects. The review has been submitted for publication and will be published soon. At the same time, he remains cautious. “First ­– as is customary in medical science ­­– we need to show in larger, well-designed studies that in addition to its anticoagulation function, heparin does indeed have the beneficial effects we expect from it.”

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