There’s a reason long airplane flights increase your risk of blood clotting conditions such as deep vein thrombosis: immobility causes veins to kink, allowing blood to pool and potentially clot. But hibernating animals, like bears and ground squirrels, don’t have this problem.
Now, a study published in Science on April 13 helps explain why hibernating bears rarely get blood clots, despite moving their hulking bodies very little during the winter months. In it, researchers found that when bears enter their sleepy winter state, they tamp down on the production of heat-shock protein 47 (HSP47), which typically sits on the surface of platelets and helps them bind to collagen. This phenomenon isn’t unique to bears—humans and pigs also temper HSP47 production in times of immobility, the team discovered. The findings could help scientists detect who is at risk for deep vein thrombosis and pulmonary embolism, collectively known as venous thromboembolism, and pave the way for future treatments.
Blood clots are one the leading causes of death globally. “The clinical problem is well-known [and] of major clinical importance . . . [and yet] has puzzled investigators for a long while,” says Thomas Renné, a chemist at the University Medical Center Hamburg-Eppendorf who was not involved in the study but has collaborated with some of the authors previously.
So, for the study, the team used an unusual model species, hibernating Swedish brown bears (Ursus arctos), to figure out why the bears rarely ever get blood clots when they hibernate (although autopsies show they do sometimes die from blood clots in the summer months). The study was conducted in collaboration with the Scandinavian brown bear research project, which, for the past 30 years, has conducted ecological research on brown bears in Sweden and Norway.
During February and March 2019 and 2022, the researchers trekked through the snow-blanketed mountains and forests of Northern Sweden, tracking hibernating bears. Once the researchers located the GPS-tagged bears, they anesthetized the giants and collected blood samples. The following June, using a helicopter, they tracked down the now much rowdier bears, repeating the procedure. In sum, they collected blood from 13 bears on both occasions.
“I think the cool part of this paper is this unique approach,” Renné says.“It’s ultra-original.”
Study coauthor Tobias Petzold, an immunologist at Ludwig-Maximilians-University of Munich, recalls that since the samples needed to be analyzed immediately, the researchers set up a makeshift laboratory near the field site. Along with their scientific equipment, “we brought the blood to this romantic, red-painted wooden house,” he says. The researchers used the battery of in vitro platelet physiology assays to identify how hibernating brown bears might be protected from clot formation.
Various biological factors play a role in clot formation, including platelets, immune cells, and collagen. But an essential step is the activation of platelets by collagen: Platelets bind to collagen on the blood vessel wall and begin to clump up. However, platelets from hibernating bears failed to aggregate in collagen’s presence. In addition, a mass spectrometry analysis revealed that in hibernating bears, platelets produced about 55-fold less HSP47 than their peppier summer counterparts. On platelets, this protein is involved in collagen signaling alongside other collagen receptors involved in thrombosis. “The protein is highly conserved across the animal kingdom,” Petzold says. The researchers also found evidence of thromboinflammation.
So to test whether the protein indeed served an anti-clotting function in other species, the researchers created knockout mice without HSP47, finding that the mice formed smaller clots when their blood flow was restricted. Nursing pigs, which are also immobile for 21 to 28 days at a time, also had lower levels of platelet HSP47 than pigs that weren’t nursing. And, lo and behold, the researchers found similar signatures in human patients with spinal cord injuries, as the patients had lower HSP47 levels on their platelets than healthy age-matched controls. “This was really surprising for us,” says Petzold, “that it’s such a conserved mechanism.”
“It’s interesting that they were able to replicate it in multiple species,” says Scott Cooper, a biologist at the University of Wisconsin, La Crosse who was not involved in the study but calls the work “very thorough.”
“It makes sense from an evolutionarily perspective,” he adds.
The findings have clear clinical implications, says Renné. “We do a lot of testing for patients with high risk of venous and arterial thrombosis. There are a lot of factors known” to cause thrombosis, he says. Following up on this study’s findings, “you could easily make an assay to measure the levels of this heat shock protein” and determine whether it is a risk factor. The protein could also be a potential therapeutic target for venous thromboembolism, he adds.
