New study urges platelet testing to manage bleeding risk in EDS

The functioning of platelets, the tiny cell fragments that help blood clot, is impaired in people with Ehlers-Danlos syndrome (EDS), likely contributing to an increased risk of bruising and bleeding, a new study reveals.

Researchers found that altered receptor signaling in platelets appeared to drive these defects in both EDS patients and a mouse model.

“Collectively, our data indicate that platelet dysfunction in EDS is likely contributing to hemorrhagic [bleeding] complications” among some individuals with this group of connective tissue disorders, the researchers wrote.

As such, the team urged that platelet testing be considered for certain EDS patients — most particularly, those who may be having surgery or other invasive procedures.

“Our novel findings suggest a rationale for platelet function testing and platelet-directed therapies for people with EDS at high risk of hemorrhagic complications,” the researchers wrote.

Details of the discovery were described in “Platelet defects in patients and mice with Ehlers-Danlos syndrome,” a study published in the journal Blood.

EDS is a group of genetic disorders that affect connective tissues, which provide structure to skin, joints, blood vessels, and other tissues and organs. It’s mainly characterized by unusually mobile joints and soft, stretchy skin.

Those living with EDS have higher risk of bleeding

People with EDS also have a higher risk of bleeding, ranging from mild bruising to life-threatening hemorrhage, which has been attributed to fragile blood vessels due to weakened connective tissue.

However, studies have suggested that EDS patients also may have defects in platelet function. These small cell fragments in the bloodstream normally contribute to blood clot formation to stop bleeding after an injury.

Now, a team led by researchers from the University of Iowa sought to examine the extent of platelet dysfunction in people with different types of EDS and in an EDS mouse model.

“A definitive understanding of why platelets are less reactive in people with EDS could improve diagnostic approaches and guide therapeutic strategies for managing their bleeding risk,” the scientists wrote.

Platelets were isolated from blood samples collected from 44 individuals with any one of four EDS subtypes: hypermobile EDS, classical EDS, classical-like EDS, and vascular EDS. A group of healthy individuals, matched for age and sex to these patients, served as controls.

The results showed that platelets isolated from individuals with EDS were functionally impaired, as indicated by a reduced tendency to aggregate, or clump together to form a clot, in response to stimulation.

This was accompanied by a marked reduction in the activation of integrin alpha-2b-beta-3, a highly abundant protein receptor on platelet surfaces that drives aggregation. Further tests suggested that these defects were, in part, attributable to reduced production of two signaling receptors, GPVI and PAR1, implicated in platelet activation .

The scientists also detected defects in platelet spreading, in which platelets flatten and extend onto tissue surfaces to initiate and stabilize clot formation. In EDS samples, the percentage of fully spread platelets was lower, whereas the percentage of early-phase (nonspread) platelets was higher than in healthy controls.

Results of testing in mice mirror findings in humans

To further investigate platelet defects in EDS, the team examined mice harboring a Col5a1 mutation, an underlying cause of classical EDS (cEDS). Mimicking the bleeding tendency seen in people with EDS, both male and female cEDS mice had prolonged tail bleeding times compared with healthy animals.

Platelets from cEDS mice also exhibited features observed in EDS patient samples, including abnormalities related to platelet aggregation, integrin alpha-2b-beta-3 activation, GPVI/PAR1 signaling, and platelet spreading.

“Collectively, these findings in [cEDS] mice recapitulate the platelet functional abnormalities and signaling defects seen in people with EDS,” the team wrote.

This work suggests that platelet dysfunction is a driver of the bleeding [tendency] of EDS. … Platelet function testing could identify people with EDS who have a high risk of bleeding, for example, prior to invasive procedures or surgery, and might benefit from platelet-targeted therapy.

The researchers noted that, while controlled blood clotting helps to stop bleeding after an injury, abnormal clot formation can also cause health problems, such as arterial thrombosis. In this condition, a blood clot forms in an artery, blocking blood flow to organs, a process that also depends on platelets.

When examined, cEDS mice were less susceptible to induced arterial thrombosis than healthy mice. Less than half of the cEDS mice developed a complete blood vessel blockage after 40 minutes, whereas all healthy mice reached this threshold within 25 minutes.

These findings are consistent with studies suggesting that EDS is associated with reduced risk of complications caused by arterial thrombosis, including heart attack and stroke, according to the researchers.

“This work suggests that platelet dysfunction is a driver of the bleeding [tendency] of EDS,” the team wrote. “Platelet function testing could identify people with EDS who have a high risk of bleeding, for example, prior to invasive procedures or surgery, and might benefit from platelet-targeted therapy.”

The researchers say this work could lead to new treatment strategies for patients.

“These insights provide a new understanding of the complex nature of EDS and lay the groundwork for improved clinical risk prediction, laboratory testing, and therapeutic approaches for people with EDS,” the team wrote.