Trauma‐targeted delivery of tranexamic acid improves hemostasis and survival in rat liver hemorrhage model

Abstract

Background Trauma‐associated hemorrhage and coagulopathy remain leading causes of mortality. Such coagulopathy often leads to a hyperfibrinolytic phenotype where hemostatic clots become unstable because of upregulated tissue plasminogen activator (tPA) activity. Tranexamic acid (TXA), a synthetic inhibitor of tPA, has emerged as a promising drug to mitigate fibrinolysis. TXA is US Food and Drug Administration‐approved for treating heavy menstrual and postpartum bleeding, and has shown promise in trauma treatment. However, emerging reports also implicate TXA for off‐target systemic coagulopathy, thromboembolic complications, and neuropathy. Objective We hypothesized that targeted delivery of TXA to traumatic injury site can enable its clot‐stabilizing action site‐selectively, to improve hemostasis and survival while avoiding off‐target effects. To test this, we used liposomes as a model delivery vehicle, decorated their surface with a fibrinogen‐mimetic peptide for anchorage to active platelets within trauma‐associated clots, and encapsulated TXA within them. Methods The TXA‐loaded trauma‐targeted nanovesicles (T‐tNVs) were evaluated in vitro in rat blood, and then in vivo in a liver trauma model in rats. TXA‐loaded control (untargeted) nanovesicles (TNVs), free TXA, or saline were studied as comparison groups. Results Our studies show that in vitro, the T‐tNVs could resist lysis in tPA‐spiked rat blood. In vivo, T‐tNVs maintained systemic safety, significantly reduced blood loss and improved survival in the rat liver hemorrhage model. Postmortem evaluation of excised tissue from euthanized rats confirmed systemic safety and trauma‐targeted activity of the T‐tNVs. Conclusion Overall, the studies establish the potential of targeted TXA delivery for safe injury site‐selective enhancement and stabilization of hemostatic clots to improve survival in trauma.

Platelets and Fibrinogen: Emerging Complexity in Trauma-Induced Coagulopathy

“…SynthoPlates are liposomes decorated with ligands that bind VWF, collagen, and fibrin, which allow them to recapitulate the binding properties of activated platelets. [68][69][70] This platform has decreased hemorrhage and improved survival in preclinical bleeding trauma models, [71][72][73] and has also shown the ability to deliver hemostatic drugs to bleeding sites. 72 Synthetic platelets require further preclinical testing and validation but will likely soon be ready for human testing.…”

Hemostatic agents for prehospital hemorrhage control: a narrative review

“…For example, nano-and micromaterials have been developed for the treatment of internal bleeding and uncontrolled hemorrhage [223]; however, these novel hemostatic agents again may prove to be efficacious (or not) with further studies. There are also new delivery systems (e.g., self-driven and trauma-targeted delivery) that would make current hemostatic agents more effective [224,225].…”

Nanomedicines for hemorrhage control

“…Lipid‐based nanoparticles are commonly used in drug delivery and in many approved drugs. Liposomes loaded with tranexamic acid and targeted to sites of bleeding significantly reduced blood loss and improved survival after rat liver hemorrhage 29 . Particles composed of proteins are being developed, such as Synthocytes, which are albumin microparticles coated with fibrinogen 30 .…”