Principal Investigator: Susan M. Shea, PhD; Co-PI Matthew D. Neal, MD
Organization: University of Pittsburgh
Combat-associated traumatic hemorrhage is implicated in approximately 90% of preventable deaths in the prehospital phase of resuscitation in the military, and traumatic brain injury (TBI) is a leading cause of death and coagulopathy. Promptly restoring hemostasis via correction of trauma-induced coagulopathy (TIC) in patients with TBI is a critical aspect of resuscitation. In a far-forward setting, there are limited options to reduce ongoing hemorrhage in the brain, and TBI remains a leading cause of death in the warfighter. To improve outcomes, TBI-associated TIC (TBI-TIC) needs to be treated rapidly at point-of-injury and en route by transfusion of blood products that include platelets. Cold platelet usage has far-forward challenges due to cold chain requirements, limited availability, portability, and shelf-life. To address this need, a synthetic platelet surrogate (SynthoPlate, “SP”) was developed. SP is a platelet-mimetic nanoparticle construct that is surface-decorated with a combination of peptides to enhance hemostatic function of endogenous platelets. Lyophilization of SP (to yield “Lyo-SP”) will enable increased shelf stability and enhance feasibility of delivering SP during hemostatic resuscitation in far-forward and/or austere environments. Here we have designed a study to test Lyo-SP in ex vivo transfusion models in samples from TBI and polytrauma patients with and without tranexamic acid (TXA) to both shed light on the pathophysiology of TBI-TIC as well as support further development of Lyo-SP as a far-forward hemostatic adjunct.
SP has been well established both in vitro and in vivo as an efficacious platelet function amplifier (PMIDs: 27925685, 29449604, 35080915). Preliminary in vitro testing has been completed to support that Lyo-SP is an acceptable lyophilized product. Lyo-SP remains stable for at least 12 months at 4°C and room temperature, and at least 3 months at -20°C and 50°C. Lyo-SP is easily reconstituted with sterile water in under a minute with minimal agitation. SP maintains its physicochemical properties when lyophilized, such as composition, particle size, surface charge, and morphology. Preliminary testing has demonstrated that biological activity is also maintained, including binding to collagen, VWF, and active platelets after lyophilization and reconstitution, as demonstrated by flow cytometry, viscoelastic testing, and adhesion to collagen under flow. The potential concomitant effects of Lyo-SP and TXA are unknown, and given the importance of TXA in early treatment of traumatic hemorrhage, co-administration could further enhance hemostatic resuscitation.
We hypothesize that Lyo-SP will improve the ex vivo hemostatic function of patients with TBI-TIC and act synergistically with TXA. We will test Lyo-SP in a battery of hemostatic assays in simulated transfusion mixing models with TBI (N=100) and polytrauma (N=100) patient blood samples to characterize the pro-hemostatic effects of Lyo-SP (+/- TXA) in TBI-TIC.
The overall significance of this project is twofold. First, this study will provide critical data to the field regarding TBI-specific coagulopathy. Second, the data generated are anticipated to support potential efficacy of Lyo-SP in TBI-associated coagulopathy. This is a patient population with a major unmet need, and it is currently unclear what the optimal therapeutic approach is for these patients. This project may provide insights that could ultimately translate into improved hemostatic resuscitation for both civilians and warfighters.