TXA, among antifibrinolytic agents, has demonstrated efficacy in preventing bleeding complications across various hemostatic challenges while minimizing adverse effects (Hunt, 2015; Chornenki et al., 2019). The landmark WOMAN study illustrated the survival benefits of TXA in postpartum hemorrhage patients (WOMAN Trial Collaborators, 2017). Additionally, a systematic review revealed TXA’s ability to reduce blood loss in surgical patients by nearly one-third compared to placebo (Ker et al., 2013). The CRASH-2 trial further confirmed TXA’s effectiveness in acute traumatic hemorrhage, showing a one-third reduction in mortality when administered within 3 hours of the inciting event (Roberts et al., 2013).

In addition to these extensively researched indications, TXA has shown promising clinical benefits in various other areas. Some emerging fields currently under investigation include gastrointestinal bleeding, subdural and subarachnoid hemorrhage, spontaneous chronic urticaria, chemotherapy-induced thrombocytopenia, and ruptured abdominal aortic aneurysm (Cai et al., 2020). In clinical practice, TXA is widely applied across a spectrum of specialties, including obstetrics (WOMAN Trial Collaborators, 2017), acute trauma (Perel et al., 2013), orthopedic surgery (Elwatidy et al., 2008), cardiothoracic surgery (Myles et al., 2017), dental procedures (Myles et al., 2017), hemoptysis (Márquez-Martín et al., 2010), epistaxis (Zahed et al., 2018), as well as primary and secondary hemostatic disorders (Estcourt et al., 2016).

This study observed a significant increase in AERs related to TXA in recent years, with a notable surge in adverse reactions occurring in 2019. This trend aligns with the rising utilization rate and expanding indications of TXA during this period. Several studies suggest that 2019 may have been a period when the clinical application of TXA became more widely recognized (Ahmadzia et al., 2020; Sterling et al., 2023). TXA was more extensively used in 2019 to treat various types of bleeding symptoms, such as those resulting from surgeries, injuries, or postpartum haemorrhage (Bolliger and Tanaka, 2020; Bharath et al., 2019; CRASH-3 trial collaborators, 2019; Brenner et al., 2019). With the widening scope of medication usage, more patients received treatment, potentially accompanied by less cautious application by healthcare practitioners, thereby resulting in the notable increase in adverse reaction reports.

Additionally, AERs associated with TXA were more commonly reported among female patients compared to male patients. This could be attributed to females being more inclined to report AEs frequently or to the more prevalent use of TXA in treating conditions such as menorrhagia and postpartum hemorrhage among females. Regarding age, the distribution of reports across different age groups was relatively uniform, indicating no significant age bias in TXA adverse reactions. It is noteworthy that the majority of reports were submitted by healthcare professionals, ensuring the professionalism and authenticity of AERs. Since most reports originated from the United States, this may also reflect reporting trends specific to certain regions or cultures, necessitating further investigation to confirm potential regional or cultural biases. Finally, the majority of ADEs occurred within 7 days of medication use, with indications primarily associated with bleeding and menorrhagia, aligning with the pharmacological characteristics of TXA as an indirect fibrinolysis inhibitor and its primary indications.

AEs associated with TXA primarily involve Vascular disorders, Cardiac disorders, Nervous system disorders, Injury, poisoning, and procedural complications, as well as General disorders and administration site conditions. Of particular note, Nervous system disorders are specific to this medication and are not mentioned in the drug’s labeling, warranting further investigation and attention. At the PT level, higher rates of myoclonus, thrombosis, and epilepsy were observed. Additionally, this study identified AEs not documented in the drug’s labeling, such as ureter perforation, renal cortical necrosis, hepatic cyst rupture, and retinal artery occlusion. These AEs all exhibited high signals in quantitative signal detection, indicating a certain level of associated risk with the use of TXA.

TXA is available in both intravenous and oral formulations, acting as an antifibrinolytic agent by blocking lysine binding sites on plasminogen molecules. This action inhibits the interaction between plasminogen and formed plasmin and fibrin, thereby stabilizing the preformed fibrin meshwork generated during secondary hemostasis (McCormack, 2012; Stansfield et al., 2020; Wu et al., 2020). However, this mechanism also presents risks of thrombosis and subsequent vascular and cardiovascular complications, which may be inevitable. Nonetheless, studies suggest that early administration of TXA to trauma patients with significant bleeding or at risk of bleeding can reduce the risk of bleeding-related mortality without a notable increase in fatal or non-fatal thrombotic events. Additionally, tranexamic acid can significantly lower overall mortality (Shakur et al., 2010). Nevertheless, caution should be exercised when using TXA in patients with active intravascular coagulation, active thromboembolic disease, or an imbalance in the hemostatic system favoring thrombus formation, to prevent thrombus formation.

Compared to common AEs within the cardiovascular system, the strong association between TXA and AEs in the nervous system, particularly seizures, is unexpected and has not received widespread attention in drug labeling. There have been reports linking TXA to adverse neurological reactions, primarily occurring in the early postoperative period following cardiac surgery (de Leede-van der Maarl et al., 1999; Keyl et al., 2011; Koster et al., 2013). Several animal studies suggest that TXA’s proconvulsant properties may stem from its direct impact on the central nervous system. Administration of TXA to the cortex or injection into the brain ventricles of experimental animals can induce generalized seizures (Yamaura et al., 1980; Pellegrini et al., 1982; Schlag et al., 2002). Clinical research also supports this notion, indicating that TXA acts as a competitive antagonist of the receptors for glycine and gamma-aminobutyric acid (Furtmüller et al., 2002). Consequently, higher concentrations of TXA in the brain may heighten the risk of seizures. Studies further suggest that isoflurane or propofol could potentially prevent or treat early postoperative TXA-induced seizures (Mohseni et al., 2009; Kaabachi et al., 2011; Lecker et al., 2012), although additional research is warranted to mitigate the occurrence of severe neurological side effects.

Hemorrhagic rupture is a rare but life-threatening complication of simple hepatic cysts, often presenting with acute abdominal pain (Marion et al., 2013; Simon et al., 2015). Reports suggest that the acute administration of antithrombotic drugs in patients with hepatic cysts can exacerbate intraperitoneal hemorrhage and lead to hemodynamic instability (Tong et al., 2019). However, there are currently no other reported studies investigating the use of antifibrinolytic agents such as TXA in causing hepatic cyst rupture. For patients suspected of having hepatic cysts, abnormalities in liver function may accelerate intravascular coagulation and fibrinolysis (O'Leary et al., 2019). Therefore, during episodes of acute bleeding, extra caution should be exercised, with careful consideration given to the risk of hemorrhagic rupture.

TXA has been linked to ureter perforation and renal cortical necrosis, in line with relevant reports (Lee et al., 2022; Maresca et al., 2022). TXA treatment may induce the formation of urinary clots in hematuria patients, leading to secondary ureter perforation and other related adverse reactions, potentially culminating in renal failure (Lee et al., 2022). However, existing evidence has not conclusively demonstrated an increased risk of renal function failure in hematuria patients exposed to TXA. Further research is needed to explore this relationship.

Retinal artery occlusion is also a secondary adverse reaction caused by TXA-induced thrombosis, with limited relevant reports and the underlying mechanism remaining unclear (Parsons et al., 1988; Roumeliotis et al., 2020; Kiser et al., 2021). Healthcare professionals, both medical and non-medical, should be aware of this rare but potential AEs.

Finally, it’s important to note that many AEs result from errors in product administration, confusion in product appearance, and unclear product packaging. Therefore, there should be strengthened pharmaceutical regulation of TXA to prevent adverse reactions from occurring.

While this study offers robust scientific evidence for assessing the safety of TXA from various angles, it does have certain limitations. Primarily, the reliance on spontaneous reporting for data collection introduces potential biases and incomplete information. Consumer-reported data, for example, may not be as reliable or thorough as that provided by medical professionals. Moreover, there could be sampling biases in regions or countries with higher report numbers. Additionally, the data did not account for comorbidities associated with reported events, which could potentially confound any inference of causality between TXA and adverse events. Therefore, despite observing signals, establishing a causal relationship with TXA may prove challenging. Furthermore, limitations of the database, the retrospective nature of the study, and possible reporting biases could impact these findings. To achieve a more comprehensive and precise assessment, future research endeavors could explore employing stricter prospective methodologies, integrating clinical trials with epidemiological studies, thereby enhancing the accuracy of safety risk evaluations associated with TXA.

TXA stands as a cornerstone therapeutic agent in the management of hemorrhage across diverse medical specialties. While its efficacy in mitigating bleeding complications is well-established, comprehensive pharmacovigilance is imperative to discern and address potential adverse reactions associated with its administration. This study found that, apart from common adverse reactions, particular attention should be paid to adverse neurological effects, especially seizures. Additionally, caution is advised when administering TXA to patients with impaired liver or kidney function. Healthcare practitioners should be aware of the potential occurrence of rare thrombotic secondary adverse reactions. Lastly, there should be strengthened pharmaceutical regulation of TXA to prevent AEs.