Hibernating bears, paralyzed humans, and pigs kept in small enclosures all avoid developing dangerous blood clots—venous thromboembolisms (VTEs)—despite being immobile for what can be extremely long periods. The results of new studies involving brown bears, human spinal cord injury (SCI) patients, and healthy volunteer humans assigned to prolonged bed rest, have now shown how the reduction of a platelet heat shock protein, HSP47, prevents the formation of blood clots, potentially for months, or even years.

Research lead Jon Gibbins, PhD, at the University of Reading, explained: “It seems counterintuitive that people who have severe paralysis don’t appear to be at higher risk of blood clots. This tells us that something interesting is happening. And it turns out that reducing levels of HSP47 plays a key role in preventing clots, not just in humans, but in other mammals, including bears and pigs.” The team’s research findings, which were supported by studies in pigs and in mice, suggest that HSP47-associated thromboprotection is conserved across several mammalian species and could be used to develop new antithrombotic therapeutics. “When we see something like this in multiple species, that reinforces its importance. Having HSP47 must have been an evolutionary advantage,” Gibbins added.

Gibbins, together with University of Reading colleagues and partners in Denmark, Germany, Norway, and Sweden, reported their findings in Science, in paper titled, “Immobility-associated thromboprotection is conserved across mammalian species from bear to human,” in which they concluded, “This cross-species conserved platelet signature may give rise to antithrombotic therapeutics and prognostic markers beyond immobility-associated VTE.”

Researchers hike through snowy woodland with their equipment. [Copyright: Tobias Petzold, Ludwig-Maximilians University Munich]

VTE—a cardiovascular condition that occurs when a blood clot forms in a vein—can result in death or severe disability. Anyone who has taken a long-haul flight may have taken advice to help prevent the risk of forming a deep vein thrombosis in one or both legs, while sitting for multiple hours. This may involve getting up and walking around, or wearing compression socks to keep the blood from pooling in the legs. And while the majority of people won’t experience a clot if they take care on a flight, there is a serious risk for some people who are pre-disposed to blood clots, due to genetic factors.

Interestingly, while people who experience short-term immobility due to illness or injury are at increased risk of developing VTE, paradoxically, the authors noted, chronically paralyzed individuals with spinal cord injuries do not have increased VTE risk. So, while “short-term immobility-related conditions are a major risk factor for the development of VTE,” the authors wrote, “despite long-term immobilization, chronically paralyzed patients with spinal cord injuries exhibit a VTE risk similar to that of the general population.”

And looking beyond humans, hibernating brown bears (Ursus arctos)—which remain immobile for months at a time—also do not appear to be at an increased risk for immobility-associated thrombosis during winter hibernation episodes. These animals do possess a “thromboinflammatory machinery” that is similar to that in humans, and so they can develop VTE, but, the authors noted, “… they appear to be protected from immobility-associated VTE during hibernation.”  Such observations suggest an underlying molecular mechanism that protects against thromboinflammation during long periods of immobilization in both humans and brown bears.

To better understand this thromboprotection, Gibbins, together with first author Manuela Thienel, PhD, at University Hospital, LMU Munich, and colleagues analyzed blood from free-ranging brown bears in Sweden as well as from humans experiencing chronic immobilization. Their analyses included blood samples taken from hibernating bears in winter, as well as from active bears in the spring. They also compared blood samples from people who were immobilized with those who can move and walk. In addition, blood samples from pigs kept in small pens were compared with others that were free to move around in barns.

Researchers work with a hibernating brown bear. [Copyright: Tobias Petzold, Ludwig-Maximilians University Munich]

Using mass spectrometry-based proteomics, the team discovered that, compared with platelets from active brown bears, the platelets in hibernating bears exhibited an antithrombotic signature that was characterized by decreased expression of HSP47 and reduced biomarkers of thromboinflammation. “On average, HSP47 was 55-fold down-regulated in the platelets of hibernating bears,” the scientists noted. A similar pattern was observed in chronically immobilized humans, when compared to their active counterparts.

The findings were further backed up by data from pigs, and from additional data in mice. To study the effect of immobilization in a physiological setting, the authors also consigned a group of healthy human volunteers to bed rest immobilization and found that HSP47 became drastically reduced after 27 days.

HSP47 is released by platelets—the sticky blood cells that trigger blood clotting. Usually clotting is an important response to an injury, to prevent blood loss, and HSP47 is one of the components that enables platelets to do their job. Examining the role of HSP47 in clotting function, the team found that when released into the blood of bears, mice, and humans, the protein promoted conditions that may give rise to deep vein thrombosis.

Results from analyzing the blood from immobilized humans and hibernating bears indicated that the significant down-regulation of HSP47 due to chronic or long-term immobilization conveys protection from VTE by reversing the pro-thromboinflammatory state that normally follows immobilization. “Through HSP47 down-regulation, chronic immobilization conveys protection from VTE by reversing the pro-thromboinflammatory state that normally follows immobilization,” they stated. “Our findings provide mechanistic insight into the paradox that the VTE risk of long-term immobilized SCI patients resembles the risk of the general population.”

The team suggests the discovery that HSP47 is dramatically reduced when an individual is immobilized for a much longer period than a flight could lead to new medicines to help those who have inherited blood clotting disorders that put them at risk for pulmonary embolism, heart attack, and stroke. “… patients at risk of VTE beyond immobilization might benefit from treatments mimicking the here described thromboprotective mechanism,” they wrote. “Toward clinical application, our findings thus suggest a concept for treating thromboinflammatory cardiovascular diseases by making use of naturally occurring thromboprotective mechanisms … We, therefore, suggest that HSP47 is a promising target to prevent VTE in patients exposed to immobilization, that might be evolutionarily conserved across mammals.”

In a related perspective, Mirta Schattner, at the Instituto de Medicina Experimental (IMEX), CONICET–Academia Nacional de Medicina, wrote, “The study by Thienel et al. shows that looking at nature is a good way to learn about human biology … Identifying signaling pathways that down-regulate prothrombotic and/or up-regulate thromboprotective molecules will not only enable us to complement existing therapies for the prevention of DVT in the various thromboinflammatory diseases but also to select safer targets with less host im­pact.”

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