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Synthetics Stop the Bleeding

Nanoparticles cut the bleeding time in half for rodents.
December 18, 2009

Nanoparticles designed to mimic the clotting capability of blood platelets have been shown to quickly reduce bleeding in rodents with severed arteries. The synthetic particles, which stick to the body’s own platelets, stanch bleeding more effectively than a clotting drug currently used to stem uncontrolled blood loss. “We’re helping to form the clot,” says Erin Lavik, a bioengineer at Case Western University in Cleveland, who led the research.

Coaxing clots: A cross section of clot is seen here after an injury to the femoral artery. Muscle cells are shown in blue; nanoparticles that are designed to bind to platelets to enhance blood clotting are shown in green.

If successful in further tests, researchers hope the nanoparticles could one day be injected soon after a traumatic injury by paramedics, or in the battlefield. Early safety tests are promising, but developing safe blood-clotting treatments has been a challenge. “There’s a balance between the two edges of the sword–bleeding too much and clotting too much,” says Mortimer Poncz, a physician at the University of Pennsylvania Medical School, in Philadelphia, who was not involved in the research. “You don’t want to stop bleeding in the leg but die of a heart attack or have a stroke.”

Uncontrolled bleeding is a major cause of trauma-related death. Existing methods of stemming blood loss are largely limited to treating open wounds or for use in the operating room. None have proven effective in stanching internal bleeding prior to arrival in a hospital.

After a traumatic injury, the body launches its own clotting cascade by activating platelets. These disc-shaped blood cells transform into spiky, sticky cells that adhere to each other and to molecules at the injury site, forming a blood clot. Physicians can already enhance the clotting process with drugs or materials that incorporate molecules in the clotting cascade. One such drug is NovoSeven, a synthetic protein derived from a human gene. But this drug is enormously expensive, costing $10,000 to $30,000, and some trauma surgeons question its effectiveness.

Attempts to mimic platelets themselves have so far been unsuccessful. Scientists have engineered red blood cells and blood-specific proteins to bind to platelets, “but those particles can build up in capillary beds, increasing the potential for [dangerous blood clots],” says Lavik.

Lavik and collaborator James Bertram, a graduate student at Yale, have now developed a nanoparticle small enough to flow through capillaries unfettered. It also has a platelet’s specific stickiness. The particle is about a third of the size of a normal platelet.

Each particle has a polymer core that’s coated with polyethylene glycol (PEG)–a water-soluble molecule that keeps them from sticking to each other or to the blood vessels. The PEG molecules are also topped with a peptide sequence that binds to activated platelets. “People had previously shown that activated platelets bind to [this sequence], so we optimized the chemistry to expose the molecule, presenting them to activated platelets,” says Lavik, who was recognized by Technology Review as a TR35 Young Innovator in 2003.

When injected into the bloodstream of rats with a nick in the femoral artery–the large artery in the thigh muscles–the nanoparticles bound activated platelets at the injury site. The treatment halved bleeding time in the rats from about four minutes to two, proving more effective than NovoSeven. The research was published this week in the journal Science Translational Medicine.

Lavik says the two treatments might prove to be complementary. NovoSeven, she says, “works to help build the fibrin mesh network that’s critical in building clot. Perhaps the synthetic platelets could help start building the clot and the drug might help stabilize it.”

“It sounds like it has the potential to be useful for controlling bleeding on the battlefield,” says John Weisel, a biologist at Penn Medical School, who was not involved in the research.

Early studies suggest the nanoparticles are safe, a major issue for treatments that enhance blood clotting. By studying fluorescently labeled versions of the nanoparticles, researchers found that the particles are easily cleared from the body. And the particles do not accumulate in noninjured tissue, such as the lungs or kidneys, to form dangerous clots. At very high doses–a concentration almost too thick to move through the syringe, says Lavik–the particles did trigger breathing issues in some animals. But such a high dose isn’t necessary to generate blood-clotting benefits, she says.

Nevertheless, extensive testing is needed before the particles can be used in humans. “The early research looks very promising, but the human system is different than a rat’s,” says Rutledge Ellis-Behnke, a researcher at MIT. “Care has to be taken that these do not coat the inside of the lungs and reduce the amount of oxygen transfer into red blood cells.”

Researchers plan to test the particles in larger animals, which more closely approximate the human circulatory system, as well as in different types of injuries, such as those that mimic the blast injuries that are particularly common among troops in Iraq and Afghanistan.

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