Platelet Substitute Mitigates Coagulopathy and Improves Survival of Rats with Traumatic Brain Injury Induced by Laser-Induced Shockwave

Abstract

Traumatic brain injury (TBI) is frequently complicated by coagulopathy, characterized by a complex interaction between hypercoagulability and hyperfibrinolysis. TBI-induced coagulopathy is a critical factor in neurological deterioration, resulting in poor prognoses. Despite recent advances in the clinical management of TBI, few effective therapies are available for TBI-induced coagulopathy. Tranexamic acid (TXA) and various concentrates of coagulation factors are ineffective because these agents promote secondary rather than primary hemostasis. Currently, only platelet concentrates are involved in the formation of platelet clots for primary hemostasis. We aimed to develop H12-(adenosine 5′-diphosphate [ADP])-liposomes, a novel platelet substitute. This platelet-targeted hemostatic agent comprises liposomes with the H12 peptide, which selectively binds to activated platelets and encapsulates ADP to locally promote platelet activation and thrombus formation, subsequently halting bleeding. Similar to platelet concentrates, H12-(ADP)-liposomes can promote primary hemostasis. To elucidate the effects of H12-(ADP)-liposome treatment on TBI and TBI-induced coagulopathy, an appropriate animal model of TBI-induced coagulopathy is required. As only few reliable models are available, we established a novel rat model of TBI-induced coagulopathy induced by laser-induced shockwave (LISW) exposure. This model did not require surgical craniotomy and allowed us to focus on TBI-induced coagulopathy. In this model, expansion of the intracranial hematoma volume within 30 min of LISW exposure was the determining factor for mortality. The 24-h survival rate of LISW-exposed animals was 70.3% (26 of 37 rats). In this model, treatment with TXA showed a modest potential to rescue animals from TBI owing to its antifibrinolytic effects. However, TXA did not improve endothelial injury or prevent coagulopathy. In contrast, treatment with H12-(ADP)-liposomes after LISW exposure prevented endothelial injury and expansion of intracranial hematoma. H12-(ADP)-liposome treatment also prevented prolongation of the prothrombin time after 16 h of LISW exposure. Consequently, this treatment significantly improved the acute prognosis of LISW-exposed animals. These findings demonstrate that our LISW-based TBI model replicates the essential aspects of TBI-induced coagulopathy and that H12-(ADP)-liposomes have therapeutic potential for mitigating trauma-induced coagulopathy and improving TBI outcomes.