The effect of triple-dose-intravenous tranexamic acid on blood loss in patients undergoing total hip arthroplasty without affecting blood coagulopathy: A prospective thromboelastographic analysis

Abstract

Objective:

This study aimed to assess the safety and efficacy of triple-dose intravenous tranexamic acid (TXA) in patients following total hip arthroplasty (THA) using thromboelastography (TEG).

Methods:

One hundred thirty patients undergoing THA were prospectively enrolled in the study. According to the intravenous infusion TXA dose, patients were divided into single-dose (n = 65; mean age = 60.8 ± 8.1 years) and triple-dose groups (n = 65; mean age = 61.8 ± 8.6 years). Complete blood count (CBC), conventional coagulation tests (CCT), and TEG were conducted 1 day before the operation, on postoperative day 1 (POD1), and postoperative day 7 (POD7). Color Doppler ultrasonography was performed 1 day before the operation and on POD7. Drainage blood loss, total blood loss (TBL), hidden blood loss (HBL), deep vein thrombosis (DVT) incidence, and blood transfusion rates were calculated and recorded. The CCT, CBC, and TEG parameters were compared between the 2 groups.

Results:

Single- and triple-dose groups had significantly different hematocrit on POD7 (P < .05). No significant differences were found in CCT and hemoglobin at any corresponding time point between the 2 groups (P > .05). Despite the reaction time (R) on POD1 (P < .05), there were no significant differences in other TEG parameters at any other time point between the 2 groups (P > 0.05). For drainage blood loss and TBL, the triple-dose group had lesser blood loss than the single-dose group (P < .05). However, no significant differences were found for blood transfusion rate, HBL, or incidence of DVT (P > .05).

Conclusion:

Compared with single-dose, triple-dose TXA can be more effective in decreasing blood loss without increasing DVT incidence in patients undergoing THA. Although there is a notable disparity in the R time on POD1, the administration of triple-dose TXA does not substantially impact the coagulation status as assessed by TEG and CCT.

Level of Evidence:

Level I, Therapeutic study.

Highlights

• Tranexamic acid (TXA) is frequently used in total hip arthroplasty to reduce blood loss and decrease transfusions. The best dosing and schedule regimen is yet to be determined. This study investigated the effects of a triple dose of TXA on reducing blood loss and DVT incidence in THA patients compared to those given a single dose.

• The results showed that compared with single-dose TXA, triple doses of TXA reduced blood loss more effectively and did not increase deep vein thrombosis (DVT) incidence. From a microscopic perspective (thromboelastography), 3 doses of TXA did not significantly affect a patient’s coagulation state.

• The results from this study indicate that triple doses of TXA may be more effective in reducing blood loss without causing an increase in DVT incidence.

Introduction

Currently, total hip arthroplasty (THA) is used for correcting hip deformities and improving hip function in patients with end-stage hip osteoarthritis (OA).¹ However, THA is associated with considerable blood loss. Allogeneic blood transfusions are often required with THA transfusion rate ranging from 7.1% to 18%.^2-4

Tranexamic acid (TXA) is a synthetic lysine derivative that competitively inhibits fibrinolysis by binding to kringle domains, reducing the proteolytic action on fibrinogen and fibrin monomers. This ultimately leads to clot stabilization. Tranexamic acid can also competitively inhibit tissue plasminogen activator by blocking the lysine-binding sites of plasminogen, inhibiting plasminogen activation, and fibrin binding to plasminogen, thereby disrupting the fibrinolytic process.^1,5 Tranexamic acid is frequently used in THA because it can significantly reduce blood loss and decrease transfusions.^6,7 There are different dosages and schedules of administration in the literature, with protocols ranging from preoperative single-dose, postoperative multiple-dose, and intra-articular administrations as well as final administration as late as 8 to 12 hours after the initial dose.^8-11 Although several studies have shown that TXA does not increase venous thromboembolism (VTE) incidence, theoretical risks exist because of its ability to disrupt fibrinolytic processes.¹² In elderly patients undergoing total knee arthroplasty, 3 doses of intravenous TXA decrease postoperative blood loss, inflammation, and fibrinolysis without increasing complications.¹³ However, multiple doses of TXA are associated with an aggravated hypercoagulable state compared with single-dose TXA.¹⁴

Conventional coagulation tests (CCT), including D-dimer (D-D), fibrin degradation products, prothrombin time (PT), and activated partial thromboplastin time (APTT), are commonly used to assess the coagulation status of patients undergoing THA. However, several studies have shown that D-D can only be considered as an exclusion criterion for deep vein thrombosis (DVT) because of its low specificity.^15,16 The APTT and PT have high specificity but lack sensitivity; they are plasma-based tests that cannot evaluate clot formation rate, extent of fibrinolysis, or clot lysis.¹⁷ A meta-analysis reported that the rate of missed diagnoses of lower-extremity DVT was at 50%, despite using ultrasound.¹⁸ Considering that patients may not have developed thrombosis after THA but their coagulation status had already changed, thromboelastography (TEG) parameters were used as the measures of main outcome. The TEG was more sensitive than CCT.¹⁹ Compared with CCT, TEG can analyze the kinetics of clot formation from the initial fibrin threads to fibrinolysis.^20,21 Unlike plasma-based tests, TEG can provide a comprehensive analysis of a patient’s coagulation status.^22,23 Additionally, the most important merits of TEG are its ability to perform coagulation analysis at the patient’s body temperature and measure the formation and dissolution of the overall clot in real time.^1,24

In this study, we hypothesized that (1) triple-dose TXA can effectively reduce blood loss in THA patients compared with the single-dose group, and (2) triple-dose TXA does not significantly affect the coagulation status and does not increase DVT incidence. The coagulation status was assessed using TEG. The CCTs, DVT incidence, and perioperative blood loss were also compared between the 2 groups in a series of patients.

Materials and methods

A prospective study was conducted in patients undergoing cementless unilateral primary THA after obtaining approval from the Ethics Committee of the Affiliated Hospital of Xuzhou Medical University (Approval No: XYFY2019-KL111-02). Written informed consent was obtained from all patients. All consecutive patients aged >50 years who were diagnosed with osteonecrosis of the femoral head or hip OA but in whom conservative treatment failed were included in this study. Patients were excluded if they had (1) coagulopathy; (2) received anticoagulant therapy within 1 month before THA; (3) preoperative hemoglobin (Hb) < 90 g/L; (4) lower extremity DVT that was confirmed by preoperative color Doppler ultrasonography; (5) a history of hip fracture; and (6) clinically significant impairment of renal function, severe liver disease, or any other disease that could influence coagulation. Finally, 130 patients who met the inclusion criteria between January 2019 and December 2021 were included. The patients were divided into either a single-dose group or a triple-dose group using a random number table.

Surgical approach and perioperative managements

All THAs were performed under general anesthesia using a posterolateral approach by the same senior surgeon. Rowe et al²⁵ reported that the maximum drainage volume was reached within 6 hours after THA, accounting for 75% of the total drainage; therefore, we added 2 more doses of TXA in the triple-dose group at that time. The TXA used in this study was TXA sodium chloride injection (batch number: 20020442, specification: 100 mL, TXA: 0.5 g; sodium chloride: 0.85 g, Changchun Tiancheng Pharmaceutical Co., Ltd., Changchun, China). Intravenous infusion was completed within 25-30 minutes at a dose of 15 mg/kg. Patients in the single-dose group received intravenous TXA infusion half an hour before incision (15 mg/kg). Patients in the triple-dose group received intravenous TXA infusion half an hour before incision (15 mg/kg), 3 hours later, and 6 hours later, along with 15 mg/kg of intravenous TXA infusion. Sodium nitroprusside was used as a hypotensive agent to maintain blood pressure between 100/60 mmHg and 110/70 mmHg.²⁶ Joint capsule, gluteus medius, piriformis, gluteus maximus, deep fascia, and skin were closed after prosthesis implantation. A drainage tube was applied and removed 48 hours after THA in both groups. All patients were instructed to perform venous foot pump exercises as mechanical prophylaxis after surgery, and we encouraged early ambulation and had professional rehabilitation physicians massage their lower limbs frequently and observe their status regularly. For VTE chemoprophylaxis, according to the National Institute for Health and Clinical Excellence (NICE) guidelines, rivaroxaban is recommended for preventing thrombosis after lower limb arthroplasty because its effectiveness is comparable to that of low-molecular-weight heparin (LMWH) in preventing VTE.²⁷ Compared with LMWH, rivaroxaban can significantly reduce DVT incidence while preventing VTE after total joint arthroplasty.²⁸ For chemoprophylaxis, 10 mg rivaroxaban was prescribed 6 hours after surgery, followed by 10 mg at 24-hour interval, and continued for 35 days if no bleeding events occurred. After removing the drainage tube, all patients were instructed to perform rehabilitation exercises to prevent lower limb thrombosis. The CCTs, complete blood count (CBC), and TEG were performed on pre-operative day 1 and postoperative day 1 (POD1). All patients were screened for DVT using color Doppler ultrasonography of both lower extremities 1 day pre-operatively. On postoperative day 7 (POD7), all patients were reviewed for CCT, CBC, TEG, and Doppler ultrasound to determine whether they had anemia, infection, hypercoagulability, or thrombosis. Patients with DVT were treated after consultation with the Department of Vascular Surgery.

Blood transfusion protocol

A common restrictive transfusion protocol was established ascribing to the guidelines for perioperative transfusion provided by the Chinese Ministry of Health. Patients received red blood cell (RBC) transfusions if 1 of the following conditions were met: (1) patient Hb concentration was <70 g/L, independent of symptoms; (2) patient Hb levels ranged from 71 to 100 g/L, but they developed clinical symptoms associated with anemia or uncontrolled hypovolemia, such as hypotension, dizziness, and tachycardia (regardless of Hb concentration). Whether another transfusion was administered was determined based on the patient Hb levels and symptoms.

Outcome measures

The parameters of TEG included reaction time (R), α angle, clotting time (K), coagulation index (CI), maximal amplitude of the trace (MA), and lysis after 30 minutes (LY30). Reaction time represents the time required for coagulation to begin when the coagulation factor is lacking, and its value increases. Clotting time reflects thrombus formation speed. The α angle is affected primarily by the rate of thrombin generation, which is vital for the conversion of fibrinogen to fibrin. The greater the α angle, the faster the rate of clot formation via this interaction. Maximal amplitude of the trace indicates the greatest strength of the clot where fibrinolysis ensues. Lysis after 30 minutes represents the percentage reduction in the area under TEG tracking from MA to MA after 30 minutes, which indicates fibrinolysis.²⁹ According to previous research reports, we believe that the patient is in a hypercoagulable state when the TEG parameters have the following conditions: K < 2 minutes, R < 9 minutes, MA > 64 mm, or α angle > 58.³⁰ The CCTs and CBC were recorded as secondary outcomes. The volume of postoperative drainage, number of patients transfused, and volume of transfusions per patient were recorded. The total blood loss (TBL) and the hidden blood loss (HBL) were calculated. The DVT incidence was also compared between the 2 groups.

According to the Gross equation, TBL was calculated using hematocrit (HCT) reduction³¹:

Calculated TBL (mL) = BV (Hct_pre-op − Hct_post-op) ∕ Hct_ave

In the above equation, BV is the patient’s estimated total body blood volume, BV (L) = 0.3561 H³ + 0.03308 W + 0.1833 in female, BV (L) = 0.3669 H³ + 0.03219 W + 0.6041 in male, where H (m) represents the patient’s stature, W (kg) represents the patient’s weight, Hct_pre-op represents the preoperative Hct level, Hct_post-op is determined by the lower value of HCT on POD1 and POD7, and Hct_ave represents the average of Hct_pre-op and Hct_post-op. If a transfusion was performed, the calculated TBL equals the blood loss calculated from the gross equation plus the volume transfused. The HBL equals the calculated TBL minus the visible blood loss (VBL) plus the volume transfused.³² In our study, VBL was the sum of the postoperative drainage blood loss and intraoperative blood loss.

Statistical analysis

Statistical analyses were performed using Statistical Package for the Social Sciences Statistics software version 25.0 (IBM SPSS Corp.; Armonk, NY, USA). Continuous data were presented as mean ± SD. Categorical variables were described using counts and percentages. Continuous variables were compared between the 2 groups using an independent samples t-test. Pearson’s chi-square and Fisher’s exact tests were performed to analyze the proportion of categorical variables. Statistical significance was set at P < .05.

Results

Patients’ characteristics

There were no significant differences in the baseline characteristics of the 2 groups (Table 1).

Table 1.

Baseline characteristics of patients

	Single-dose group	Triple-dose group	P
n	65	65
Age (years)	60.8 ± 8.1	61.8 ± 8.6	.517
Body mass index (kg/m²)	24.0 ± 4.1	25.1 ± 3.2	.086
Operation time (minutes)	94.9 ± 33.6	90.4 ± 23.2	.377
Sex			.154
Male	34	42
Female	31	23
Preoperative HCT (%)	40.3 ± 4.6	40.8 ± 3.4	.490
Preoperative Hb (g/L)	133.0 ± 15.3	134.9 ± 12.2	.422

HCT, Hematocrit; Hb, Hemoglobin.

Conventional laboratory values

The CCTs and CBC of the 2 groups are shown in Table 2. Aside from HCT on POD7 (P < .05), there were no significant differences in CCTs, Hb levels, or other parameters between the 2 groups on POD1 or POD7 (P > .05) (Table 2).

Table 2.

Conventional coagulation tests and complete blood count at different time points

	Time points	Single-dose group	Triple-dose group	P
D-dimer (ng/mL)	Pre-op	0.8 ± 0.7	0.8 ± 0.8	.800
	POD1	4.6 ± 3.1	3.8 ± 2.8	.132
	POD7	3.7 ± 1.4	3.3 ± 1.6	.121
FDP (mg/L)	Pre-op	2.9 ± 2.1	3.2 ± 2.5	.503
	POD1	16.8 ± 17.7	12.9 ± 11.1	.135
	POD7	11.8 ± 4.1	10.7 ± 3.5	.096
PT (s)	Pre-op	11.0 ± 1.1	11.1 ± 3.9	.905
	POD1	12.1 ± 1.4	12.1 ± 1.1	.918
	POD7	11.9 ± 1.0	11.8 ± 0.6	.471
APTT (s)	Pre-op	27.6 ± 2.5	26.5 ± 5.4	.132
	POD1	30.3 ± 6.1	29.0 ± 3.4	.129
	POD7	27.8 ± 3.0	27.8 ± 2.7	.951
Hb (g/L)	Pre-op	133.0 ± 15.3	134.9 ± 12.2	.422
	POD1	108.0 ± 14.7	110.6 ± 14.2	.313
	POD7	97.9 ± 13.9	100.6 ± 13.4	.262
HCT (%)	Pre-op	40.3 ± 4.6	40.8 ± 3.4	.490
	POD1	32.9 ± 4.3	33.5 ± 3.9	.389
	POD7	28.4 ± 4.5	30.4 ± 4.0	.012*

APTT, activated partial thromboplastin time; FDP, fibrin degradation products; HCT, hematocrit; Hb, hemoglobin; POD1, postoperative day 1; POD7, postoperative day 7; Pre-op, preoperation; PT, prothrombin time.

^* P < .05

Perioperative blood loss outcomes

Drainage blood loss and TBL between the 2 groups were significantly different (P < .05). However, no significant differences were found between the 2 groups regarding the hidden blood loss, transfusion rate, or volume of blood transfused (P > .05) (Table 3). Ten of 65 patients (15.4%) in the single-dose group and 7 of 65 patients (10.8%) in the triple-dose group received a transfusion. In the single-dose group, 3 patients received a 400 mL RBC suspension and 7 patients received an 800 mL RBC suspension. In the triple-dose group, 7 patients received a 400 mL RBC suspension.

Table 3.

Perioperative blood loss outcomes

	Single-dose group	Triple-dose group	P
Drainage blood loss (mL) Hidden blood loss (mL)	269.3 ± 152.2 1136.9 ± 584.7	154.3 ± 84.6 1054.0 ± 531.3	.001* .399
Total blood loss (mL)	1594.7 ± 684.6	1372.8 ± 555.4	.044*
Transfusion rate (%)	15.4% (10/65)	10.8% (7/65)	.435
Volume of blood transfused (mL)	104.6 ± 257.7	43.1 ± 125.0	.086

^* P < .05

Thromboelastography assessment

There were no significant differences in any of the preoperative parameters between the 2 groups (P > .05). The R on POD1 in the triple-dose group was significantly lower than that in the single-dose group (P < .05). This indicates a higher state of blood hypercoagulability on POD1 in the triple-dose group than in the single-dose group. However, there were no significant differences in other parameters between the 2 groups on either POD1 or POD7 (P > .05) (Table 4).

Table 4.

Assessment of thromboelastography at different time points

	Time points	Single-dose group	Triple-dose group	P
R (minutes)	Pre-op	5.1 ± 1.7	4.8 ± 1.5	.197
	POD1	5.1 ± 1.6	4.4 ± 1.2	.015*
	POD7	5.1 ± 1.0	4.9 ± 1.0	.153
K (minutes)	Pre-op	2.3 ± 1.2	2.6 ± 1.6	.185
	POD1	2.3 ± 1.3	2.4 ± 0.9	.511
	POD7	2.0 ± 0.9	2.0 ± 2.0	.841
α angle (°)	Pre-op	60.5 ± 11.0	58.3 ± 12.9	.306
	POD1	61.0 ± 11.6	62.3 ± 9.0	.498
	POD7	65.5 ± 8.8	62.4 ± 11.5	.094
MA (mm)	Pre-op	55.9 ± 7.5	53.2 ± 9.2	.061
	POD1	56.4 ± 7.7	55.4 ± 8.3	.513
	POD7	58.9 ± 9.7	61.3 ± 9.9	.160
LY30 (%)	Pre-op	0.1 ± 0.2	0.1 ± 0.2	.933
	POD1	0.2 ± 0.8	0.3 ± 1.0	.645
	POD7	0.1 ± 0.3	0.0 ± 0.1	.409
CI	Pre-op	−0.5 ± 2.6	−0.9 ± 2.9	.404
	POD1	−0.3 ± 2.5	−0.4 ± 2.3	.899
	POD7	1.3 ± 1.8	0.7 ± 3.4	.183

CI, coagulation index; K, clotting time; LY30, lysis after 30 minutes; MA, maximum amplitude; POD1, postoperative day 1; POD7, postoperative day 7; Pre-op, preoperation; R, reaction time.

^* P < .05

Deep vein thrombosis incidence

In the single-dose group, 5 patients (7.7%) developed plexus venous leg muscle thrombosis. In the triple-dose group, 4 patients (6.2%) developed plexus venous leg muscle thrombosis. No significant differences were found between the 2 groups regarding DVT incidence (P > .05).

Discussion

In our study, there were significant differences in HCT on POD7, and R on POD1 between the 2 groups (P < .05). Compared with single-dose TXA, triple-dose TXA reduced drainage blood loss and TBL without increasing DVT incidence or influencing overall blood coagulopathy.

Total hip arthroplasty results in significant blood loss. As an antifibrinolytic hemostatic drug, TXA has been used in THA for over 20 years to reduce blood loss and transfusion rates. Wind et al³³ reported that in patients undergoing THA, the transfusion rates were 4.39% (21/478) and 19.86% (208/1047) in those with TXA compared with those without TXA, respectively. A double-blind, randomized controlled trial included 139 patients undergoing THA who were randomized to receive 2 g topical or IV TXA. The results showed that the transfusion rate for the topical TXA group was 18%, whereas that for the IV TXA group was 11%. Both groups showed significantly reduced transfusion rates.³⁴ In our study, 10 patients (15.4%) in the single-dose group received transfusion, including 3 patients who received a 400 mL transfusion and 7 patients (10.8%) who received an 800 mL transfusion. Meanwhile, 7 patients in the triple-dose group received a 400 mL transfusion. There were no significant differences in the transfusion rate and volume between the 2 groups. However, transfusion volume and rate in the triple-dose group were lower than those in the single-dose group with a trend toward significance in transfusion reduction.

Deep vein thrombosis is a common complication of orthopedic surgery, especially arthroplasty. Deep vein thrombosis incidence can be as high as 40% in the absence of an effective anticoagulation treatment.³⁵ However, several studies have reported that despite routine anticoagulation in patients undergoing THA, DVT incidence ranges from 1.8% to 19.8%.^36-38 Tranexamic acid can effectively reduce blood loss; however, considering its pharmacological properties, it may also affect a patient's coagulation status. Porter et al³⁹ reported that in high-risk patients undergoing surgical repair for intertrochanteric fracture, TXA administration was not associated with an increased risk of mortality, DVT, PE, myocardial infarction, or stroke within 90 days of surgery. However, TXA was associated with more than threefold increase in the odds of VTE with TXA being an independent risk factor for VTE.⁴⁰ In our study, DVT incidence in the 2 groups was 7.7% and 6.2%, respectively, which is within the normal range of DVT rates after THA in previous studies. Based on our results, we believe that triple-dose TXA does not increase DVT incidence in patients with THA compared with single-dose TXA.

Previous reports on the dosage and timing of TXA in patients have varied. Wilde et al⁴¹ reported no significant differences in blood loss, transfusion rates, or complications between single-dose (1 g intravenous TXA just prior to incision) and double-dose groups (1 g intravenous TXA just prior to incision and 1 g intravenous TXA 6 hours after the initial dose) in patients with THA. Huang et al⁴² reported that all patients undergoing THA in the TXA group received intravenous TXA 5-10 minutes before skin incision (20 mg/kg) and 3, 6, 12, and 24 hours later (10 mg/kg) along with 1 g of topical TXA in 50 mL normal saline solution. Intraoperative blood loss, TBL, drainage volume, transfusion volume, and transfusion rate were lower in the TXA group than in the non-TXA group. However, our results supported that blood loss in the multiple-dose group were significantly lower than that in the single-dose group. We attribute the difference between our report and those of other studies on the hemostatic effects of different doses of TXA to our more frequent use of TXA at higher doses.

Owing to the sensitivity of TEG, it was used as the main indicator to monitor the coagulation and fibrinolytic status of patients and analyze the influence of different doses of TXA on DVT incidence and perioperative blood loss in patients after THA. Despite having no significant difference in DVT incidence between the 2 groups, coagulation status may be different; however, there were no significant differences in the CCTs and Hb on POD1 or POD7 between the single-dose and triple-dose TXA groups. In terms of TEG index, R on POD1 was significantly different between the 2 groups, but there was no significant difference in other indices. Therefore, compared with single-dose TXA, triple-dose TXA does not significantly influence the coagulation state of THA patients.

In this study, TEG was used to analyze the coagulation status of patients after THA and calculate perioperative blood loss. Triple-dose TXA effectively reduced blood loss without increasing DVT incidence. This is one of the few studies using TEG to evaluate the effects of different TXA doses on the coagulation state of patients undergoing THA. We determined the drug dose based on the patient's weight (15 mg/kg) and added 2 more doses of TXA within 6 hours after THA as compared to previous similar studies that only administered TXA at a fixed dose and repeatedly administered TXA¹⁴ without considering that the maximum drainage volume was reached within 6 hours after THA.²⁵ Therefore, we believe that our study is rigorous. However, this study has several limitations. First, owing to the wide application of TXA in the clinic,^43-44 we did not include a non-TXA group. Although there was no significant difference between the single-dose and triple-dose groups, blood coagulopathy in the triple-dose group may be different from that in the non-TXA group. Second, because there were no oral TXA tablets in our hospital, we only administered 3 doses of intravenous TXA and not the popular combination of oral and intravenous administration of TXA.⁴⁵ Third, the study population was relatively small; thus, the possibility of a type II error increased. According to the power analysis, the probability of a type II error was 19.24%, and the power of the sample size was 80.76%. Fourth, color Doppler ultrasonography was performed preoperatively and on POD7, and subsequent DVT may be ignored. However, the median time to DVT diagnosis was 7 days after THA.⁴⁶ Therefore, it may be reasonable to use this follow-up interval to collect DVT data. Fifth, according to an international consensus meeting⁴⁷ held in March 2022, delegates recommended the use of low-dose acetylsalicylic acid (ASA) as the main method for preventing VTE among all patients undergoing total joint arthroplasty, including medium- to high-risk patients. However, all patients in this study were included before 2022 (from January 2019 to December 2021). At that time, we used rivaroxaban instead of ASA as chemoprophylaxis for patients after surgery according to NICE guidelines. This may have affected the results. Finally, the half-life of intravenous TXA is approximately 3 hours. The ideal time point for obtaining TEG data was within this timeframe and before administrating thromboprophylaxis. However, frequent blood draws may cause additional harm to the patients. The CCTs, CBC, and TEG were performed on the morning of the first day after surgery and were not considered primary variables more than 10 hours after the end of the operation.

Compared with single-dose TXA, triple-dose TXA was more effective in decreasing blood loss without increasing the incidence of DVT in patients undergoing THA. Despite the significant difference in R time on POD1, it did not significantly affect the coagulation status based on TEG or CCTs.

Funding Statement

This work has received the financial support from the National Natural ­Science Foundation of China (82272523, 81902244), Natural Science Foundation of Jiangsu Province (BK20201154), Jiangsu Provincial Medical Youth Talent (QNRC2016801), Xuzhou Science and Technology Innovation Project (KC19063), and Changzhou Sci&Tech Program (CJ20220003).