Trauma‐targeted delivery of tranexamic acid improves hemostasis and survival in rat liver hemorrhage model. (15th July 2019)

• Record Type: Journal Article
• Authors: Girish, Aditya; Hickman, DaShawn A.; Banerjee, Ankush; Luc, Norman; Ma, Yifeng; Miyazawa, Kenji; Sekhon, Ujjal D. S.; Sun, Michael; Huang, Stephanie; Sen Gupta, Anirban
• Is Part Of: Journal of thrombosis and haemostasis. Volume 17:Number 10(2019)
• Page Start: 1632
• Page End: 1644
• Publication Date: 2019-07-15
• Subjects: fibrinolysis -- hemorrhage -- rat model -- targeted delivery -- tranexamic acid -- trauma; Thrombosis -- Periodicals; Hemostasis -- Periodicals; Blood coagulation disorders -- Periodicals; 616.1
• DOI: 10.1111/jth.14552
• Languages: English
• ISSNs: 1538-7933

Abstract

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.