Topical tranexamic acid inhibits fibrinolysis more effectively when formulated with self‐propelling particles

Abstract

Background Endogenous fibrinolytic activation contributes to coagulopathy and mortality after trauma. Administering tranexamic acid (TXA), an antifibrinolytic agent, is one strategy to reduce bleeding; however, it must be given soon after injury to be effective and minimize adverse effects. Administering TXA topically to a wound site would decrease the time to treatment and could enable both local and systemic delivery if a suitable formulation existed to deliver the drug deep into wounds adequately. Objectives To determine whether self‐propelling particles could increase the efficacy of TXA. Methods Using previously developed self‐propelling particles, which consist of calcium carbonate and generate CO2 gas, TXA was formulated to disperse in blood and wounds. The antifibrinolytic properties were assessed in vitro and in a murine tail bleeding assay. Self‐propelled TXA was also tested in a swine model of junctional hemorrhage consisting of femoral arteriotomy without compression. Results Self‐propelled TXA was more effective than non‐propelled formulations in stabilizing clots from lysis in vitro and reducing blood loss in mice. It was well tolerated when administered subcutaneously in mice up to 300 to 1000 mg/kg. When it was incorporated in gauze, four of six pigs treated after a femoral arteriotomy and without compression survived, and systemic concentrations of TXA reached approximately 6 mg/L within the first hour. Conclusions A formulation of TXA that disperses the drug in blood and wounds was effective in several models. It may have several advantages, including supporting local clot stabilization, reducing blood loss from wounds, and providing systemic delivery of TXA. This approach could both improve and simplify prehospital trauma care for penetrating injury.

Percutaneous delivery of self-propelling thrombin-containing powder increases survival from noncompressible truncal hemorrhage in a swine model of coagulopathy and hypothermia

“…17 In addition, SPTP managed nasal bleeding in a sheep model without thrombosis or pulmonary embolism for up to 15 days postrecovery. 20 Self-propelling thrombin-containing powder appeared safe in this acute study and has been shown to be safe previously in multiple models, [17][18][19][20][21][22] but the long-term impact of SPTP on animals needs to be evaluated. This includes the breakdown of residual SPTP, which is expected to occur within several days, and evaluating its potential for forming adhesions.…”

Severe upper gastrointestinal bleeding is halted by endoscopically delivered self-propelling thrombin powder: A porcine pilot study

“…1). In previous studies, our group has shown that SPTP halted multiple lethal femoral artery and carotid hemorrhages in pigs and sheep, respectively [10][11][12][13].…”

Topical hemostatic materials for coagulopathy

“…The follow-up in vitro clot lysis assays verified that the self-propelling TXA particles alone could enhance clot retention in hyperfibrinolytic plasma deficient of α2-AP, an endogenous plasmin inhibitor, even without loading thrombin. 37 The particles may be useful in treating intraoperative internal bleeding, such as in the uterus, sinus, and gastrointestinal tract, where traditional topical agents cannot reachable. Moreover, given that CaCO 3 microparticles can absorb biomolecules nonspecifically, the self-propelled vehicle is ideal for drug delivery in complex vascular geometries with the assistance of intravascular catheters.…”