Snake Venom-based Gel May Rapidly Reduce Bleeding

Marta Figueiredo, PhD avatar

by Marta Figueiredo, PhD |

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An innovative gel containing two snake venom proteins known to help blood clotting, rapidly and effectively forms stable clots and reduces bleeding even in the presence of a blood-clotting disorder, as is the case in hemophilia, a preclinical study shows.

The gel, which transitions to a liquid form below 22 degrees Celsius (about 71.6 degrees Fahrenheit), also was  shown not to induce immune reactions against it.

“When a traumatic injury occurs, the complexity of the healing process overloads the body’s capacity to control the bleeding,” Amanda Kijas, PhD, the study’s co-senior author, said in a press release.

Kijas is a postdoctoral research fellow in Alan Rowan’s group at the University of Queensland (UQ)’s Australian Institute for Bioengineering and Nanotechnology (AIBN). Rowan, PhD, is director of AIBN and the other co-senior author of the study.

“Nature has created the most elegant and sophisticated mechanisms, and we can repurpose them to save people from dying due to uncontrolled bleeding,” and “this even includes people with hemophilia and those using blood thinners,” Kijas added.

Results showed “there is five times less blood loss, and clots form three times more quickly when the venom gel is applied, compared to the body’s natural process,” Kijas said.

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These findings support the gel’s high potential to stop uncontrolled bleeds in both civilian and military settings, and also in people with impaired blood clotting due to either circumstantial conditions or genetic causes.

The team is currently confirming the gel’s safety and efficacy in larger animal models before it can be tested in people.

The study, “Snake Venom Hydrogels as a Rapid Hemostatic Agent for Uncontrolled Bleeding,” was published in the journal Advanced Healthcare Materials.

“As many as 40 percent of trauma-related deaths are the result of uncontrolled bleeding, and this figure is much higher when it comes to military personnel with serious bleeding in a combat zone,” Kijas said.

“A major limitation of existing hemostatic [bleed-controlling] agents is that they require a functioning clotting system to control the bleeding and are largely based on gauze delivery scaffolds,” the researchers wrote.

Bleeding control depends on a fine-tuned balance between blood clotting (coagulation) and blood clot breakdown (fibrinolysis). This balance is lost in trauma-induced bleeding, as well as in situations where the person is showing an abnormally low body temperature or a higher-than-normal acidity in the blood.

In addition, a person’s blood clotting system may be impaired, as in people with hemophilia, or suppressed by blood-thinning medications in people more prone to form blood clots and experience cardiovascular events.

Now, researchers at Rowan’s lab, along with a colleague at UQ, developed an innovative, thermoresponsive hydrogel that may overcome these limitations.

Hydrogels are natural or lab-made materials that can soak up large amounts of liquid without losing their three-dimensional structure. The gel’s thermoresponsive nature means that below 22 C it is in a liquid form, and that it transitions to a firm gel that helps seal wounds as it warms above 22 C.

The gel is composed of lab-made ecarin and textilinin, two proteins found in the venom of Australia’s eastern brown and scaled viper.

Ecarin is an enzyme that promotes the conversion of prothrombin into thrombin, one of the final steps in the blood-clotting cascade. As such, this enzyme “directly and rapidly activates the final stage of the coagulation pathway, rather than requiring the natural cascade of activation processes,” the researchers wrote. In turn, textilinin works by blocking the activity of plasmin, the enzyme responsible for breaking down blood clots.

Combined, the snake venom proteins are expected to not only promote the rapid formation of blood clots, but also prevent their destruction, ultimately accelerating blood clotting and bleeding control.

Using human blood with normal or low numbers of platelets — the tiny blood cell fragments responsible for blood clotting — researchers found that ecarin, on its own, rapidly promoted blood clot formation in normal physiological conditions, as well as in colder temperatures and high blood acidity.

Notably, in the presence of ecarin, stable clots were formed within 60 seconds, a pronounced improvement relative to the 8 minutes observed with normal clot formation. In addition, blood clot breakdown was effectively suppressed by textilinin.

The team next tested the hydrogel in a mouse bleeding model that was pre-treated with warfarin, an anti-coagulant (blood thinner), to mimic impaired blood clotting. They found that the gel rapidly controlled bleeding, lowering blood loss volume from 48% to 12%.

The hydrogel also was shown to promote only a slight increase in the levels of inflammation-related molecules, which was comparable to that observed with tranexamic acid, “which is an existing clinically employed antifibrinolytic,” the researchers wrote.

These findings support the discovery of a “new class of hemostatic agents that achieve formation of rapid and stable blood clots even in the presence of blood thinners,” the team wrote.

“This approach can now be adapted for the development of alternate delivery scaffolds to meet both clinical need and environment, where long term storage requirements of a hydrogel, may not be suitable for certain low-resource or extreme environments,” the researchers wrote.

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The venom-based gel is now being tested in larger animal models and scaled-up toward commercial application in collaboration with Mark Midwinter, MD, from UQ’s School of Biomedical Sciences.

“We hope this gel will accelerate the wound-healing processes needed for clotting and reducing blood flow, ultimately boosting the body’s capacity to heal large wounds,” Kijas said.

In the future, the gel could be sold in pharmacies, added to first-aid kits, and used by paramedics or military personnel in combat zones, to stop bleeding while a patient is taken to hospital.

The study was supported by funding from the U.S. Department of Defense and an Australian Research Council Laureate Fellowship. The blood was donated by the Australian Red Cross Lifeblood.

The team, in collaboration with the Metro North Health, at the Royal Brisbane and Women’s Hospital and Herston Biofabrication Institute in Australia, is exploring whether the new gel also could help treat burns and trauma injuries.