**4. Discussion**

TXA is currently a commonly used perioperative antifibrinolytic agent. The antifibrinolytic is used in surgery but also in various other bleeding manifestations in congenital coagulopathies, such as fibrinogen deficiency [25]. With the increase in the number of TSAs performed, and the constant expansion of the indications qualifying for the procedure, there is a need to reduce postoperative complications and improve the procedure's results.

In this study, we evaluate results from three retrospective studies [10,16,22] and seven RCTs that compared outcomes in the TXA group and non-TXA group [17–21,23,24]. The main findings of this meta-analysis relate to nine factors, which we have sorted out for clarity: blood volume loss, hematocrit change, length of hospitalization, operation time, hematoma, drain output, need for revision and thromboembolic complications. In a retrospective study including an analysis of 155 complications after TSA, Anthony et al. highlights that the most common complication is bleeding-requiring transfusion [26].

Our study identified a notably increased blood volume loss in the non-TXA group of 0.834 ± 0.592 L compared to 0.66 ± 0.52 L in the TXA group, which is also reflected in the change in hematocrit values, whose change for the described groups was 7.9 ± 3.1% for the non-TXA group compared to TXA group 6.1 ± 2.7%, respectively. TXA successfully prevents perioperative blood loss. This decreases postoperative pain and reduces complications, postoperative mortality, and the length of hospitalization. At the same time, TXA has side effects limited to nausea and diarrhoea, making it a well-tolerated drug [27]. These benefits also carry a reduction in costs associated with postoperative care. As reported by Kandil et al. in 2016, the hospitalization time for patients after TSA who required a blood transfusion is 1.8 days longer which is \$11,794 more, compared to patients who did not receive a transfusion [28]. In our meta-analysis results, the hospitalization time of patients in the TXA group is 2.1 ± 1.7 vs. 2.2 ± 1.6 in the non-TXA group. This emphasizes the need for further in-depth analyses of the available studies due to the discrepancy with the reports mentioned above of Kandil et al., especially considering the difference we also showed in the duration of the operation itself. These times differed slightly (TXA 89.5 ± 33.0 min vs non-TXA 89.1 ± 32.2 min) but in the study by Friedman et al. performed on a group of 194 patients, the time in the recovery room in the TXA group was shorter on average by as much as 24 min [10].

Wang et al. in a 2021 study showed that patients with moderate to severe preoperative anemia were at increased risk of cardiac and pulmonary complications, postoperative blood transfusion, prolonged length of stay, reoperation, and death [29]. In our assessment, these results are transferable to the postoperative situation because it has been proven that TSA without antifibrinolytics is associated with high blood loss. According to studies, the volume of blood lost in the first postoperative day ranges from 159 to 1473 mL [10,16–21,23,24].

The reduction in postoperative pain is also associated with a significant difference in the incidence of postoperative hematoma. In our meta-analysis, the occurrence rate in the TXA group was 20.4%, while hematoma formation in non-TXA patients occurred 53.8%. Hematomas which result from continuous blood loss cause painful swelling, which contributes to the use of opioid medications and may even result in the need for surgical drainage, which directly delays hospital discharge time [17,21]. Moreover, persistent postoperative drainage may increase the risk of tissue contamination and deep infection, which prolongs the time and cumulates the costs of treatment [30,31].

Among the studies we analyzed that used drain output, only Cvetanovich et al. reported no statistically significant difference in drainage volume [18]. The other studies show a reduced volume in the TXA group (109.9 ± 104.3 mL) versus the non-TXA group (254.4 ± 200.5 mL). This difference shows the need for additional large randomized controlled trials. Additionally, in the two studies we analyzed, the TSA requiring revision surgery percentage was 0.9% in the non-TXA group, whereas patients after TXA application did not require revision. This may be related to the reported lower complications resulting from less blood loss in patients who received an antifibrinolytic agent.

Our meta-analysis also highlighted the finding of Cvetanovich et al. [18]. As indicated in the study, thromboembolic complications were not noted in any of the groups. This aspect is particularly relevant given that deep vein thrombosis and pulmonary embolism are considered the leading complications of orthopedic surgery [31,32]. This is consistent with other meta-analyses and RCTs that evaluated the safety of TXA in total joint arthroplasty. No increase in the risk of thromboembolic complications was demonstrated.

It is worth pointing out that in five analyzed studies, TXA was administered intravenously, only Gillespie et al. used in the treatment group 100 mL of normal saline infused with 2 g of TXA poured into the surgical wound and left in place for 5 min. To the best of our knowledge, there have not been many studies comparing these two methods of TXA application. Budge et al. in 2019 conducted a retrospective review on a group of only three patients comparing whether Intravenous and topical TXA are equivalent in improving postoperative hemoglobin in TSA [33]. However, Li et al., in a meta-analysis, evaluated the

efficiency and safety of combined use of intravenous and topical versus single intravenous TXA [34]. The meta-analysis concerns total primary knee and hip arthroplasty. The study team shows a statistically significant reduction in total blood loss with the combined application with no increase in the risk of thromboembolic complications [35]. The findings from our statistics and the described studies demonstrate the need to compare TXA application methods further.

In performed statistical analysis, we reported significant benefits for TXA in all described aspects. However, significant heterogeneity between the compared studies was demonstrated in terms of total blood loss or drain output. This phenomenon cannot be sufficiently explained by possible differences in the anaesthetic protocol used, the thromboembolic prophylaxis plan or the way TXA was applied. In the opinion of our research team, these differences may be due to individual variability of patients, inclusion or exclusion criteria, differences in surgical protocols and different methods of measuring outcomes.

This study has limitations related to the relatively small number of studies included and to its retrospective nature. However, the data collected indicate statistically and clinically significant findings regarding the manner and safety of TXA application. Because of the limited high-quality evidence currently available, there is a need for further in-depth analysis of the available studies in terms of the most beneficial way of TXA application.
