Comparison of the effectiveness and safety of different regimens of tranexamic acid in complex tibial plateau fracture: a retrospective study


 Background Previous studies have demonstrated the effectiveness and safety of tranexamic acid (TXA) in orthopedics. However, no study has investigated TXA in complex tibial plate surgery. Therefore, the purpose of this study was to confirm the safety and effectiveness of IV (intravenous) TXA and topical TXA. Material and methods This was a retrospective analysis of prospectively collected data. The control group received an equal amount of placebo (physiological saline solution); the IV group received 1.0 g TXA by intravenous injection before the tourniquet was inflated and before the surgical incision was closed, and the topical group received 3.0 g TXA in 75 mL of physiological saline solution before 5 min prior to the final tourniquet release. Perioperative blood loss, vascular events, wound complications, and adverse reactions were compared for the three groups. Results Baseline data were comparable for all groups. The IV group showed the best results for total blood loss (TBL) and hidden blood loss (HBL) (424.5 ± 29.4 ml, 219.3 ± 33.4 ml, respectively, all p values < 0.001). The topical group performed excellently with regard to postoperative vascular events, wound complications, and adverse reactions, but there was no statistical significant in the incidence of these between the groups. Conclusion This study presents the first information to show that both IV TXA and topical TXA are safe and effective for complex tibial plateau fractures. The IV regimen effectively reduced blood loss during the perioperative period, whereas the topical regimen had a better safety profile.

fracture often result in excessive fibrinolysis and massive blood loss after surgery. Antifibrinolytic therapy, as an important part of blood management, has emerged as a particular focus of research.
Tranexamic acid (TXA) is a traditional antifibrinolytic drug that binds to lysine and forms a reversible complex with plasminogen and plasmin; it is an effective agent against plasmin, tissue plasminogen activators, and plasminogen 5 . Several studies reported that TXA could effectively reduce the perioperative RBC transfusion, blood loss, and blood drainage, and did not increase the risk of DVT formation; in addition, it has been shown to be cost-effective [6][7][8] .
The purpose of this study was to investigate the effectiveness and safety of different TXA regimen in the application of complex tibial plateau fracture.

Materials And Methods
The present study was a part of a RCT, which was registered in the Chinese Clinical Trial Registry (ChiCTR-TRC-1800017754), so this was a retrospective analysis of prospectively collected data.
Approval was obtained from the Clinical Trials and Biomedical Ethics Committee of Hong Hui Hospital (Approval Number: 2018002), and written informed consent was obtained from all participants. bone may have affected the results.

Intervention
Patients were divided into the control group, IV group, and topical group based on a computergenerated randomization schedule. The control group received an equal amount of placebo (physiological saline solution) IV or topical. The IV group received 1.0 g IV TXA before the tourniquet was inflated and before the surgical incision was closed. Five minutes prior to final tourniquet release, the topical group received 3.0 g TXA in 75 mL of physiological saline solution and the IV group received 75 mL of saline solution directly on the wound. The therapeutic doses of these regimens were determined from previous studies 9-12 .

Surgical Methods and Postoperative Management
All other drugs, except for TXA and physiological saline solution during general anesthesia, were same in all three groups. The pressure of the balloon-type tourniquet on the affected limb was set to 450 mmHg, and the mean arterial blood pressure (MAP) was maintained at 60-70 mmHg. This surgical technique has been described previously 13,14 . Briefly, a medial and lateral double incision approach, combined with double locking steel plates, was used to fix the fracture block. Primarily, a medial incision (posterior medial approach) was performed to expose the fractured end of the medial platform, Kirschner wire was used for temporary reduction, and this area was fixed with the anatomical locking plate of the proximal tibia. Then, the joint was opened through a lateral incision (anterolateral approach) to fully expose lateral condyle, the lateral dissection plate of the proximal tibia was used for fixation, and then use artificial bone grafts. Before the incision was closed, two drainage tubes were placed in patients in group, the incision was sutured layer by layer, and the tourniquet was loosened with compression with elastic bandage. Drainage pipes for each patient were temporary clamped for 4 h after the operation. Postoperatively, the leg was raised for 3 to 4 days, and the drainage tubes were removed within 48 h. Functional exercises related to the active and passive range of motion were started approximately 2 weeks after surgery. The RBC transfusion indications formulated by our institution were: 1) Hb < 70 g/L; 2) 70 g/L < Hb < 100 g/L, when the patient has symptoms of dizziness, palpitation, asthma, and lassitude.

Study Objectives
The following demographic data were recorded for each patient: sex, age, body mass index, medical history, American Society of Anesthesiologists score 15 (ASA), fracture type, preoperative hemoglobin (Hb), preoperative hematocrit (Hct), preoperative D-dimer, and preoperative fibrinogen (FIB). The operation time and intraoperative blood loss were also included in the statistics. Furthermore, routine blood tests and coagulation tests (e.g., Hb, Hct, D-dimer, and FIB) were evaluated 24 h after surgery on and the third postoperative day (POD #3). To evaluate the safety of TXA in this study, the following parameters were evaluated: any vascular event that occurred within 12 weeks after surgery, including deep vein thrombosis of the lower extremity (DVT, confirmed by ultrasound), pulmonary embolism (PE, confirmed by pulmonary spiral CT), cerebrovascular accidents (confirmed by spiral CT or MRI), and gastrointestinal hemorrhage. In addition, we recorded the incidence of wound complications (e.g., dehiscence, hematoma, edge necrosis, and infection). Potential adverse side effects of TXA, including epilepsy, rash, headache, nausea, and vomiting, were also monitored 16,17 .

Calculation of perioperative blood loss
Perioperative total blood loss (TBL) and hidden blood loss (HBL) were the items that this research focuses on. The intraoperative blood loss (IBL) was estimated from the weight of the surgical sponges and the measurement of the volume of blood collected by the suction canisters; the weight of the irrigation fluids added to the surgical field and the sponge weight were then subtracted from this value 18 . The total postoperative drainage (TPD) was the weight of fluid in the drainage bag collected over 48 h.
Then, the total blood loss (TBL) was calculated according to the Gross Eq. 2 0 , TBL (ml) = PBV × (Hct 1 -Hct 2 ) Hb trans . Hct 1 is the first routine blood test after the patient was admitted to the hospital; Hct 2 is the lowest value obtained by routine blood tests after surgery; Hb trans is the weight of the transfused packed red blood cells (PRBCs), and two units of PRBCs can cause an increase of approximately 5.2 g/dL in Hb 21 . All transfused blood products were fresh and stored frozen.

Statistical Analysis
Statistical analyses were computed by using GraphPad Prism 8.0. Continuous variables were reported as the mean and standard deviation. One-way analysis of variance (ANOVA) was used to compare the differences among multiple groups. Student's t-test was utilized to compare the difference between two groups, and the Chi-square test was used for the analysis of categorical data. P-values of < 0.05 were considered to indicate a statistically significant difference.

Patient Demographics
All 90 patients included in the study were followed up for 12 weeks postoperatively; no patients were lost to follow-up. There was no significant difference in demographic data and preoperative blood test results between the three groups of patients (Table 1).  Abbreviations:POD#3, the third postoperative day. P 1 represents the p value obtained by comparison between control group and IV group; P 2 represents the p value obtained by comparison between control group and topical group; P 3 represents the p value obtained by comparison between IV group and topical group; Intergroup comparisons performed using AVONA or Chi-square test (aANOVA; bChi-square test).

Postoperative Blood Tests
The results of routine blood tests and blood coagulation tests in the three groups were summarized in Table 2. The mean value of post-operative Hb of 24 hours in control group, IV group and topical group were 11.7 ± 1.1, 12.2 ± 2.2, 11.9 ± 0.8 g/dL respectively, and no significant difference between groups (p = 0.430). The mean value of POD#3 Hb in control group, IV group, and topical group was 11.2 ± 2.4, 12.5 ± 3.4, and 11.6 ± 1.2 g/dL respectively; there was no significant difference between groups (p = 0.125). Similarly, there were no significant differences in mean Hct values for the above two time points between each groups. However, there was a statistically significant difference in the average real Hb reduction between the three groups (p < 0.001): the values were 1.8 ± 0.6 g/dL in the control group, 0.9 ± 0.3 g/dL in the IV group, and 1.3 ± 0.7 g/dL in the topical group. The best effect was observed for the IV group (p = 0.006 versus the topical group).
The mean value of post-operative D-dimer after 24 h in the control group, IV group and topical group was 9.6 ± 3.4, 8.1 ± 2.9, and 8.4 ± 3.3 mg/L, respectively, with no significant difference between groups (p = 0.165). The mean value of POD #3 D-dimer in the control group, IV group, and topical group was 11.2 ± 4.1, 9.8 ± 3.1, 10.3 ± 3.8 mg/L, respectively, with no significant difference between groups (p = 0.335). Similarly, there were no significant differences between three groups for mean FIB values at the above two time points.

Blood Loss and Transfusion
After careful calculation and verification, we found that there were significant differences in TBL between the three groups (p < 0.001). The pairwise comparisons and statistical analysis, namely, control group vs IV group, IV group vs topical group, and control group vs topical group, all showed statistically significant differences (Fig. 1). The same results were also found for HBL: HBL in control group, IV group and topical group was 341.1 ± 43.7, 219.3 ± 33.4, and 224.5 ± 33.6 mL, respectively (all intergroup p values < 0.001) (Fig. 2).
The final analysis revealed that two patients in the control group were transfused with 2 units of PRBCs owing to postoperative anemia symptoms, whereas no patients in the IV group and the topic group required blood transfusion treatment. No statistical differences were found in the transfusion rate between three groups (p = 0.129) ( Table 2).

Vascular Events, Wound Complications, and Adverse Reactions
In this study, the venous plexus of calf muscle was the most common site for DVT, followed by the popliteal vein. No severe complications, such as pulmonary embolism, myocardial infarction, or cerebral infarction, occurred in this study. There were no significant differences in wound complications and adverse reactions between three groups. The specific data are described in Table 3.

Discussion
Schatzker type Ⅴ and Ⅵ tibial plateau fractures are usually caused by severe crushing and collapse of the medial and lateral condyles owing to high-energy trauma; however, the internal and external double incision approach, combined with bone grafting and double steel plate fixation, can achieve ideal results 14 . As there are an abundance of blood vessels around the knee joint, an increase in the incision exposure range and the use of tourniquets can lead to a large amount of blood loss and fibrinolytic response during the perioperative period 22 . The safety and effectiveness of TXA has been proven in general surgery, joint surgery, and spine surgery. Currently, TXA is administered as intravenous, intramuscular, topical, and oral regimens. As the safety of intramuscular and oral regimens has not been supported by a large number of clinical trials, these methods were excluded from this study. Some scholars have suggested that when TXA is used topically in the joint cavity, joint cavity drainage must not be placed after surgery, to avoid loss of drug efficacy 23,24 . Therefore, to reduce the bias in the test results, a temporary clamping scheme for the drainage tube for 4 h after operation was used in this study 11,25 . Given the encouraging results for TXA, the purpose of this study was to confirm which approach was more effective and safe in complex tibial plateau fracture.
In this study, the use of TXA reduced IBL and TPD. Compared with the topical regimen, the IV regimen effectively reduced blood loss by approximately 28 mL (p < 0.001). The topical regimen can effectively reduce TPD by approximately 12 mL, but there was no significant difference to intravenous application; this conclusion was also reached by Artit et al. 26  to 1473 mL, which was approximately 2 to 3 times greater than the visible blood loss. Therefore, to reduce the blood loss in orthopedic surgery, reduction of the HBL should be the first priority. The main finding of our study was that both intravenous and topical use TXA can effectively reduce TBL during the perioperative period, and that the IV regimen had the strongest effect (approximately 50 mL compared with the topical group, p < 0.001). Similarly, the perioperative HBL was also reduced, but there was no significant difference between the IV regimen and topical regimen.
It has been proposed that the use of tourniquets will lead to excessive fibrinolysis and blood loss within the first 6 h of surgery 31 . In the current study, the second TXA application in the IV group was before the tourniquet was released and its effect may have be weakened as the fibrinolytic response was already in progress. The topical application of TXA allows it to rapidly reach the active bleeding point and directly interact with the wound, inhibit the fibrinolytic reaction in the blood, promote the formation of fibrin and maintain a stable clot, reduce the leakage of blood to the surface of the damaged tissue, and exert hemostatic effects 32 . Thus, this explains why there were no great differences between the IV group and topical groups in TBL and HBL.
Thus far, most orthopedic clinical trials have been designed to test the hemostatic effect of TXA instead of safety. For rare complications, such as pulmonary embolism, the current clinical trial sample size cannot reach a definitive conclusion. The results of this study show that patients were safe whether they received IV or topical treatment. The IV regimen appeared to increase the incidence of vascular events and adverse reactions, but with fewer wound complications compared with the topical group; however, the difference was not significant. Some studies have confirmed that plasmin not only promotes the activation of monocytes, platelets, and endothelial cells, but also plays an important role in stimulation of the release of inflammatory mediators and the induction of related proinflammatory gene expression. TXA is an inhibitor of plasmin, so ammonia TXA also has potential anti-inflammatory effects 33,34 . In addition, reducing the perioperative blood transfusion rate may reduce the incidence of wound complications 35 . We have reduced blood loss by the application of TXA and therefore may also reduce the incidence of wound complications. Hence, we believe that the application of TXA in this study has been shown to be safe.
There are some limitations to our study. First, the sample size of this study was small and the results are from a single center. A large-scale prospective, randomized case-control study is needed to confirm these results. Second, according to the perioperative rehabilitation guidelines for major orthopedic surgery designated by our institution, all patients received preventive anticoagulation after admission, which may have affected blood loss. Third, blood loss in postoperative wound dressings was not measured.

Conclusion
In summary, for complex tibial plateau fractures of Schatzker type Ⅴ and Ⅵ, the use of TXA is reasonable, safe, and effective. The IV regimen offers the advantage of lower perioperative blood loss, whereas the local regimen can reduce the incidence of vascular events, wound complications, and adverse reactions.

Consent for publication
Not applicable.

Availability of data and material
All data generated or analyzed during this study are included in this published article.

Declaration of conflict of interest
The authors declare no conflict of interest.  Abbreviations:POD#3, the third postoperative day. P 1 represents the p value obtained by comparison between control group and IV group; P 2 represents the p value obtained by comparison between control group and topical group; P 3 represents the p value obtained by comparison between IV group and topical group;

Funding
Intergroup comparisons performed using AVONA or Chi-square test ( a ANOVA; b Chi-square test). Chi-square test for intra-group comparison. Figure 1 Comparison of TBL in the three groups.

Figure 2
Comparison of HBL in the three groups.