Intravenous Hemostat: Nanotechnology to Halt Bleeding

Synthetic platelets composed of functionalized nanoparticles halve bleeding time in a rat injury model and may prove useful in treating human trauma victims. Basic first aid teaches us to put immediate pressure on a bleeding wound to stop the blood flow and allow natural clotting to occur. But what about when the wound is inside the body or difficult to compress? By coating polymer particles with peptides that promote platelet aggregation, Bertram et al. have made a synthetic “platelet” that accelerates natural platelet clotting and can be administered directly into the blood system to get access to internal organs. These tiny spheres can markedly decrease bleeding time in a rodent model with a serious injury to the femoral artery. Because blood clotting is well understood, the authors knew to choose the peptide arginine-glycine-aspartic acid (RGD) to attach to ~600 ends of the polyethylene glycol arms that extended from their 170-nm polylysine spheres. RGD binds to receptors on the surface of activated platelets, so the particles with multiple RGDs specifically adhered to multiple platelets, facilitating their aggregation. The authors optimized other features of the nanoparticles to guarantee that they would be useful in the emergency room or on the battlefield. The materials used to make the particles have all been used in devices previously approved by the U.S. Food and Drug Administration. The small RGD peptide can be inexpensively synthesized, and its size makes it unlikely to cause immunological problems. When stored dry, the platelet-like nanoparticles are stable and remain effective for at least 2 weeks, far surpassing the 5- to 7-day shelf life of donated platelets. They are cleared from the system (in rats) within 24 hours. To test how well these particles augmented blood clotting, the authors injected them into rats with a wound in the femoral artery. Whether the particles were injected before or, more realistically, after the wound was created, they reduced the bleeding time by 25% to 50%. Even the current standard of care for traumatic uncontrolled bleeding, a recombinant version of the natural clotting molecular factor VIIa, was less effective than the nanoparticles. Scanning electron micrographs of the blood clots from these treated rats confirmed that they contained numerous RGD-coated nanoparticles, nestled among blood cells, and a fibrin network. These nanoparticles augment only one of the many functions of real platelets—injury-induced aggregation—but, in a traumatic situation, that could be the critical function that is needed. Blood loss is the major cause of death in both civilian and battlefield traumas. Methods to staunch bleeding include pressure dressings and absorbent materials. For example, QuikClot effectively halts bleeding by absorbing large quantities of fluid and concentrating platelets to augment clotting, but these treatments are limited to compressible and exposed wounds. An ideal treatment would halt bleeding only at the injury site, be stable at room temperature, be administered easily, and work effectively for internal injuries. We have developed synthetic platelets based on Arg-Gly-Asp functionalized nanoparticles, which halve bleeding time after intravenous administration in a rat model of major trauma. The effects of these synthetic platelets surpass other treatments, including recombinant factor VIIa, which is used clinically for uncontrolled bleeding. Synthetic platelets were cleared within 24 hours at a dose of 20 mg/ml, and no complications were seen out to 7 days after infusion, the longest time point studied. These synthetic platelets may be useful for early intervention in trauma and demonstrate the role that nanotechnology can have in addressing unmet medical needs.