Self-propelled particles loaded with tranexamic acid stop bleeding following trauma

Baylis, James R (University of British Columbia)
Lee, Michael M (University of British Columbia)
St. John, Alexander E (University of Washington)
Wang, Xu (University of Washington)
Simonson, Eric (University of Washington)
Cau, Massimo (University of British Columbia)
Kazerooni, Amir (University of British Columbia)
Gusti, Viona (Centre for Drug Research and Development)
Yoon, Jeff S J (University of British Columbia)
Liggins, Richard T (Centre for Drug Research and Development)
White, Nathan J (University of Washington)
Kastrup, Christian J (University of British Columbia)

Introduction

Bleeding is the leading cause of preventable death following trauma in both civilian and combat situations.1–4 If bleeding is not stopped rapidly, patients frequently develop hyperfibrinolysis and trauma-induced coagulopathy (TIC), which complicate efforts to manage bleeding and can drastically increase mortality.5 Tranexamic acid (TXA) is a potent inhibitor of fibrinolysis which is used clinically to improve hemostasis, but it is typically given intravenously following trauma and therefore cannot be administered immediately following injury and in early phases of care, such as in rural areas or on the battlefield. Recently, large multicenter clinical trials have shown that administering TXA immediately following injury maximizes its lifesaving effects, and these benefits drastically decrease within the first hours.1,3 The effectiveness of topical application of hemostatic agents, including TXA, is severely limited by their inabilities to penetrate blood flow and prevent flushing from the wound site.6,7  A material which could deliver tranexamic acid at the point of injury, while overcoming these transport limitations to simultaneously achieving primary hemostasis, would an invaluable for reducing mortality due to bleeding. Here we show that by formulating TXA with previously developed self-propelling particles (SPP-TXA), it can be delivered locally to the wound site, stop bleeding, and achieve therapeutic plasma concentrations within minutes of administration (Figure 1).

Materials and Methods

To measure SPP-TXA’s ability to inhibit fibrinolysis in vitro, a model of clot lysis was used which incorporated flowing and hyperfibrinolytic human plasma. To test if SPP-TXA could reduce bleeding in vivo, tails of mice were amputated, SPP-TXA was applied, and blood loss was measured. To measure the biocompatibility and pharmacokinetics of SPP-TXA, it was administered subcutaneously in mice and plasma concentrations of TXA were measured up to four days. To test if SPP-TXA could improve survival following massive non-compressible junctional hemorrhage, a swine femoral artery model of junctional hemorrhage was used. Animals received 5 mm femoral arteriotomies followed by wound packing using cotton gauze loaded with SPP-TXA with no subsequent compression. Over three hours post-injury, plasma concentrations of TXA were measured, and survival and was measured and compared to previously published data using the same model.

Results

In our in vitro model of clot lysis, SPP-TXA significantly increased clot retention compared to non-propelling formulations, in stagnant, flowing, and hyperfibrinolytic conditions. In a mouse tail amputation model of traumatic hemorrhage, mice receiving SPP-TXA had lost significantly less blood compared to mice who received a similar dose of TXA intravenously, as a topically applied solution, or as a topically applied non-propelling powder. Subcutaneously administered SPP-TXA was well tolerated by mice and TXA was cleared with a half-life of approximately 8 hr. Sixty seven percent of pigs who received gauze loaded with SPP-TXA survived to three hours, which appeared higher than pigs receiving Combat Gauze in a previous published study, but the difference was not significant. Pigs receiving SPP-TXA gauze had plasma concentrations which reached therapeutic levels by one hour post injury.

Discussion and Conclusion

Tranexamic acid formulated with self-propelling particles was effective at inhibiting fibrinolysis and reducing bleeding in several models. Gauze loaded with SPP-TXA was similar in its effectiveness to current clinical standards in its ability to achieve primary hemostasis, while simultaneously delivering a therapeutic dose of TXA. This suggests SPP-TXA could be very useful for achieving reliable hemostasis which is resistant to fibrinolysis in situations of prolonged field care, or in low-resource settings where access to care may be delayed. Additional studies are required to test SPP-TXA’s safety and efficacy at treating bleeding over longer periods of time.


Figure 1. Schematic showing dispersion of self-propelling particle formulated TXA (SPP-TXA) into bleeding wounds to form a clot which is resistant to fibrinolysis. Other topically applied agents (bottom) are typically washed out by blood flow, resulting in clots which are susceptible to lysis and su

References

1.        Gayet-Ageron, A. et al. The Lancet (2017).

2.        Pannell, D. et al. J. Trauma 71, S401-7 (2011).

3.        CRASH-2 trial collaborators et al. Lancet 376, 23–32 (2010).

4.        Eastridge, B. J. et al. J. Trauma Acute Care Surg. 73, S431–S437 (2012).

5.        Gonzalez, E. et al. Scand. J. Surg. 103, 89–103 (2014).

6.        Behrens, A. M., Sikorski, M. J. & Kofinas, P. J. Biomed. Mater. Res. - Part A 102, 4182–4194 (2014).

7.        Baylis, J. R. et al. Sci. Adv. 1, e1500379–e1500379 (2015).

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