Excessive blood clotting is a recognized feature of severe COVID-19. But a new study suggests that some hospitalized patients may also be vulnerable to bleeding, which is associated with an increased risk of death.
Normally, our blood maintains a delicate balance between its tendency to form clots and its tendency to break them down.
In particular, the body does this by continually adjusting the activity of a protein in the blood called plasminogen, which promotes the breakup of blood clots, or “thrombolysis.”
The body performs this balancing act by changing the levels of two other proteins circulating in the bloodstream, known as tissue plasminogen activator (TPA) and plasminogen activator inhibitor-1.
As their names suggest, the former activates plasminogen and therefore promotes thrombolysis, while the latter has the opposite effect.
Early in the pandemic, research began to show that the blood of critically ill patients with COVID-19 is unusually “sticky” or prone to clotting, with potentially fatal consequences including deep vein thrombosis, stroke, and heart attack.
These findings led to the practice of giving high doses of anticoagulant drugs — which work in various ways to prevent the development of blood clots — to patients hospitalized with COVID-19 throughout their treatment.
However, a new study by researchers at Michigan Medicine and the University of Michigan in Ann Arbor suggests this may not be the best approach for all patients.
They measured levels of TPA and plasminogen activator inhibitor-1 in the blood of 118 patients hospitalized with COVID-19 as well as 30 healthy controls.
They found very high levels of both proteins in the blood of these patients. These proteins were associated with respiratory difficulties, but high levels of TPA had stronger correlations with mortality.
In the lab, the researchers also tested the tendency of the blood samples to clot by adding an enzyme called thrombin that promotes clotting.
As expected, this revealed that very high levels of plasminogen activator significantly enhanced the tendency to break down blood clots.
The research appears in Scientific Reports.
“Pathological blood clotting in COVID-19 patients has been studied extensively, but recognizing and addressing the high bleeding risk in a subgroup of patients is equally important,” says first author Yu (Ray) Zuo, MD, MSCS, a rheumatologist at Michigan Medicine.
The authors note that one large, multicenter study reported an overall bleeding risk of 4.8% among hospitalized COVID-19 patients, which increased to 7.6% among critically ill patients.
“We found a subset of COVID-19 patients with extremely high levels of [TPA] in which [the breakdown of blood clots] seems to dominate. This may at least partially explain the enhanced bleeding risk observed in some groups of patients with COVID-19.”
They conclude that the administration of anticoagulant treatments should therefore be “selective and cautious” to minimize this bleeding risk.
In addition, they call for further studies to assess whether TPA levels might be a useful biomarker for identifying patients at high risk of bleeding.
Due to research restrictions during the pandemic, the authors report that their study used blood samples from healthy controls who they recruited before the COVID-19 health crisis.
This meant that the scientists could not match patients to controls of the same age and gender, which could potentially have biased their results.
They also note that another protein, known as urokinase, also activates plasminogen and could therefore also play a vital function in blood clotting in COVID-19.
The researchers did not measure this protein, and therefore they could not determine or differentiate its role from the function of TPA in COVID-19 patients with excess bleeding.
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