Predictive role of laboratory assessments and interval radiological imaging in adverse thrombohemorrhagic outcomes in living donor liver transplantation
Introduction
Coagulopathic alterations and thrombotic events represent critical hemostatic complications during the perioperative period of liver transplantation (LT), contributing substantially to postoperative morbidity and mortality. Literature reports indicate that these complications can account for mortality rates as high as 30% in transplant recipients (1-5). The incidence of perioperative bleeding varies significantly, ranging from 0% to 10%, influenced by factors such as surgical complexity, pre-existing coagulopathy, and intraoperative transfusion practices. Notably, pediatric patients exhibit a 2- to 3-fold higher risk of bleeding compared to adults, likely due to developmental differences in coagulation profiles, smaller vascular structures, and greater technical challenges during surgery (6,7).
According to the literature, portal vein thrombosis (PVT) occurs in 1–10% of cases, with an average of 4–6%, while venous thrombosis can occur in up to 4% of cases (8-10). Predicting the development of thrombosis and bleeding is challenging and heavily relies on the delicate balance of the hemostatic system at any given moment. The Cochrane database reports the lack of reliable predictors for thrombosis in solid organ transplantation, and routine coagulation tests are not sufficient for assessing and predicting coagulation-related bleeding (11). Dunn et al. (2022) identified only three significant factors out of 35 studied regarding reoperation frequency due to bleeding during LT, highlighting the difficulty of preoperatively predicting bleeding risk based on laboratory tests. Statistically significant differences between patient groups were observed only for leukocytes, platelets, and alanine aminotransferase (ALT) preoperatively, while postoperatively, significant differences also included hemoglobin levels, albumin, activated partial thromboplastin time (APTT), ionized calcium, and pH. However, multivariate analysis did not establish their prognostic significance, with hypoalbuminemia and the need for cryoprecipitate and erythrocyte transfusions indicating massive intraoperative blood loss (7). An et al. (2022) reported that massive intraoperative blood loss and transfusion of more than 7 units of washed red blood cells, along with cryoprecipitate transfusion, are significant risk factors for PVT. They developed a thrombosis prediction nomogram based on parameters such as blood loss (more than 31 mL/kg), hemoglobin, and hematocrit (3). Literature on the prognostic value of APTT, prothrombin complex, and other screening tests presents conflicting results (2-9). Consequently, identifying critical imbalances in the hemostatic system during the initiation of the thrombus formation cascade or hyperfibrinolysis remains challenging. Given the inverse correlation between survival after LT and the occurrence of thrombotic and hemorrhagic complications and the lack of a unified approach to their prevention and treatment, our study aims to investigate hemostatic system characteristics in recipients of both pre- and post-LT.
The aim of the study is to identify the diagnostic significance of laboratory tests in predicting adverse outcomes from thrombohemorrhagic complications in living-related LT. We present this article in accordance with the STROBE reporting checklist (available at https://qims.amegroups.com/article/view/10.21037/qims-24-2230/rc).
Methods
This study was conducted in accordance with the Declaration of Helsinki and its subsequent amendments. This study was conducted in accordance with ethical principles and approved by the Expert Council of the Republican Specialized Scientific and Practical Medical Center for Surgery named after V. Vakhidov Ethics Committee (Conclusion No. 178 RUzb, October 22, 2021). Informed consent was obtained from all participants prior to their inclusion in the study. Trial Registration: Clinical Trials.gov (ID: NCT06169592; Protocol ID: 05122023).
Among patients in the baseline status, the predominant etiologies of liver cirrhosis were viral hepatitis B and D, along with hepatitis C. Occasional cases also included cryptogenic and autoimmune hepatitis (Figure 1).
Study design and participants
This prospective, observational, analytical case-control study was conducted at the Hepatobiliary Surgery and Liver Transplantation Department No. 2 of the Republican Specialized Scientific and Practical Medical Center for Surgery named after V. Vakhidov, from October 2022 to October 2023. The study cohort comprised 30 adult patients who underwent orthotopic LT using grafts from living-related donors. Inclusion criteria encompassed individuals with end-stage liver disease or variceal bleeding necessitating transplantation, irrespective of Model for End-Stage Liver Disease (MELD) score. Notably, 90% of recipients presented with a MELD score >15, while the remaining 10% were urgently transplanted due to recurrent variceal hemorrhage despite lower MELD scores.
Participants were categorized into two comparative groups based on postoperative outcomes: a favorable outcome group and an unfavorable outcome group. Unfavorable outcomes included early postoperative complications such as PVT, hepatic venous outflow obstruction, intra-abdominal hemorrhage, or hemorrhagic stroke resulting in early postoperative mortality. All patients underwent comprehensive preoperative clinical, laboratory, radiological (ultrasound, contrast-enhanced MRI, CT angiography), and immunogenetic evaluations (human leukocyte antigen typing and crossmatch testing).
Surgical technique and hemostasis protocol
LT procedures were performed in dual operating theatres, facilitating simultaneous donor hepatectomy and recipient preparation. Following graft retrieval, in situ perfusion with cold preservation solutions was conducted, and bench preparation ensued. Venous drainage augmentation was achieved by reconstructing sizable (>4–5 mm) accessory hepatic veins using synthetic vascular prostheses (diameter 6–8 mm). Final hemostasis was accomplished using a multi-step protocol:
- Application of HEMOBEN® powdered hemostatic agent (10 mg/cm2) to the resected graft surface, excluding vascular and biliary hilum.
- Placement of oxidized regenerated cellulose sponge (e.g., SURGICEL®) over the graft surface and anastomotic lines.
- Topical administration of donor-derived fresh frozen plasma (20–30 mL) to saturate the sponge, followed by firm compression with sterile gauze.
- After polymerization (2–3 min), a second application of HEMOBEN® (10 mg/cm2) was performed, reinforced with an additional 10–15 mL of plasma.
- Following graft implantation, meticulous inspection for active bleeding was conducted. In cases of doubtful hemostasis in non-critical areas, additional bipolar coagulation and local application of HEMOBEN® were employed.
- Standard vascular (hepatic-caval and portal) and biliary anastomoses were constructed sequentially, followed by abdominal drainage placement and surgical wound closure.
Postoperative monitoring and immunosuppression
Postoperative surveillance included Doppler ultrasonography of vascular anastomoses and abdominal ultrasonography every 6 hours for the first 72 hours. Daily biochemical monitoring of liver and renal function was performed. Tacrolimus-based immunosuppressive therapy was initiated on postoperative day 2, and trough blood levels were measured on day 3 to guide dosing adjustments.
Laboratory investigations
Hematological parameters, including hemoglobin (Hb), hematocrit (Ht), total leukocyte count (WBC), and platelet count (Plt), were quantified using the DxH 500 hematology analyzer (Beckman Coulter, USA).
Biochemical assays, including albumin (Alb), total and direct bilirubin (TBil, DBil), aspartate aminotransferase (AST), ALT, gamma-glutamyl transferase (GGT), and alkaline phosphatase (ALP), were measured using the Vitros 5600 integrated system (Ortho Clinical Diagnostics, USA).
Coagulation studies were conducted using the ACL TOP 350 automated coagulometer (Instrumentation Laboratory, Werfen, USA). The screening panel included activated partial thromboplastin time (APTT), prothrombin time (PT), international normalized ratio (INR), thrombin time (TT), fibrinogen levels, and platelet counts. The confirmatory panel comprised antithrombin III (AT-III), protein C, protein S, plasminogen, and D-dimer levels. Blood samples were collected at baseline (preoperative), then at 12-hour intervals on postoperative day 1, and subsequently at 24, 48, and 72 hours, as well as on days 5 and 10 post-transplantation.
Statistical analysis
Data were analyzed using MedCalc software (MedCalc Software Ltd., Ostend, Belgium). Continuous variables were assessed for normality using skewness and kurtosis coefficients. Normally distributed data were expressed as mean ± standard deviation (SD) and 95% confidence intervals (CIs), whereas non-normally distributed data were presented as median and interquartile range (IQR, 5th–95th percentile). Categorical data were analyzed using Pearson’s Chi-square (χ2) test. Yates’ continuity correction was applied when expected frequencies were <10, and Fisher’s exact test was employed for contingency cells with counts <5. Correlations between continuous variables were evaluated using Pearson’s correlation coefficient (r). Diagnostic accuracy of individual biomarkers and predictive models was assessed by constructing receiver operating characteristic (ROC) curves. The area under the ROC curve (AUC), along with its standard error and 95% CI, was calculated to quantify the model’s discriminative ability. The optimal cutoff value for each predictor was determined by maximizing the Youden index (sensitivity + specificity − 1). A two-tailed P value <0.05 was considered statistically significant across all analyses.
Results
Out of 30 patients with a favorable outcome without complications, 17 (56.7%) were observed, while 13 (43.3%) experienced complications in the early postoperative period. Among them, fatal outcomes occurred in 5 (16.7%) patients, while complications were successfully managed in 8 patients. The most frequent complications observed were hepatic artery thrombosis (HAT) (7, 23.3%), PVT (1, 7.6%), intra-abdominal bleeding (5, 38.5%), and hemorrhagic stroke (2, 15.4%). Among the seven patients with HAT, one died; among the five patients with bleeding, one died; all cases of hemorrhagic stroke and PVT resulted in mortality. Causes of adverse outcomes leading to hospital mortality included thromboses (2, 40%), with one patient experiencing hepatic artery thrombosis and another experiencing PVT. One patient died from intra-abdominal bleeding that developed on the 17th day after hepatic artery thrombosis. Two (40%) patients died from hemorrhagic stroke: one on the 23rd day and the other on the first day after undergoing two complications—hepatic artery thrombosis and hemorrhagic stroke (Figure 2).
Representative imaging data are shown in the Picture Archiving and Communication System (PACS). Figure 3 illustrates an unfavorable case, including echinococcal cyst, pre- and postoperative multislice computed tomography (MSCT) imaging, specimen findings, and interventional therapy outcomes. Figure 4 demonstrates a favorable outcome, including “back table” preparation, use of Hemoben and Surgicel for hemostasis, and final graft status.
Hepatic artery thrombosis and subsequent complications are depicted in Figure 5. Recanalization by transluminal angioplasty was not possible; however, collateralized arteries maintained graft survival, though a liver abscess developed two months later. In contrast, favorable postoperative PACS findings are shown in Figure 6.
Before and after LT, the dynamics of laboratory parameters were evaluated over a 10-day observation period. The comparison group comprised patients with an uncomplicated postoperative course, as well as those in whom thrombohemorrhagic complications (TPA) were successfully resolved without fatal outcomes. Analysis of patients by gender and age in the compared groups revealed no statistically significant difference in average age, and the severity of the condition assessed by MELD and Child-Pugh scores was similar in both groups (P>0.05). Results from liver elastography were also comparable between groups. Notably, individuals with unfavorable outcomes exhibited a statistically significant reduction in baseline platelet count before surgery (P<0.05). At the same time, all biochemical parameters of the liver panel did not differ significantly between the groups (P>0.05). Among the screening tests of the coagulogram, activated partial thromboplastin time (APTT), prothrombin time (PT), and INR showed no statistically significant differences between groups, nor did fibrinogen levels before surgery. Regarding confirmatory tests, protein C, protein S, D-dimer, and plasminogen levels did not significantly differ between groups among patients with unfavorable outcomes (Table 1).
Table 1
| Parameter | Unfavorable outcome (n=5) | Favorable outcome (n=25) | P value |
|---|---|---|---|
| Age, years | 45.1 (38.9–52.8) | 41.1 (38.2–44.1) | 0.321 |
| Gender (male/female), N (%) | 2 (40.0)/3 (60.0) | 14 (56.0)/11 (44.0) | 0.763 |
| MELD score, points | 15.4 (14.1–16.7) | 17.4 (15.6–19.1) | 0.196 |
| Child-Pugh score, points | 10.3 (8.7–11.9) | 10.3 (9.6–11.05) | 0.997 |
| Transient elastography (FibroScan), kPa | 38.8 (33.8–43.9) | 32.7 (29.0–36.5) | 0.134 |
| Hemoglobin, g/L | 115.0 (107.5–122.5) | 105.6 (84.3–124.8) | 0.412 |
| Hematocrit, % | 33.1 (29.2–36.9) | 32.7 (30.0–35.4) | 0.851 |
| White blood cell count, 109/L | 4.02 (2.01–6.02) | 3.1 (2.04–4.21) | 0.233 |
| Platelet count, 109/L | 52.2 (42.1–60.7) | 79.6 (55.9–103.7) | 0.047* |
| Serum albumin, g/L | 26.0 (23.1–31.4) | 31.8 (25.9–37.6) | 0.079 |
| Total bilirubin, µmol/L | 48.7 (38.1–77.7) | 48.0 (36.5–73.9) | 0.943 |
| Direct bilirubin, µmol/L | 7.6 (2.9–15.9) | 8.7 (3.43–16.0) | 0.771 |
| Alanine aminotransferase, U/L | 64.4 (43.4–84.5) | 54.0 (38.8–70.7) | 0.397 |
| Aspartate aminotransferase, U/L | 76.0 (43.1–108.9) | 60.2 (48.6–71.7) | 0.272 |
| Alkaline phosphatase, U/L | 149.3 (94.0–179.5) | 155.3 (87.1–185.5) | 0.862 |
| Gamma‑glutamyl transferase, U/L | 88.2 (65.6–99.1) | 89.2 (68.1–94.3) | 0.933 |
| International normalized ratio | 1.44 (1.2–2.2) | 1.54 (1.3–2.4) | 0.616 |
| Activated partial thromboplastin time, s | 36.2 (29.4–42.9) | 34.8 (30.2–39.4) | 0.743 |
| Fibrinogen, mg/dL | 222.7 (136.9–308.6) | 270.6 (175.1–310.1) | 0.337 |
| Antithrombin III, % | 30.5 (13.7–39.7) | 39.5 (31.3–42.0) | 0.158 |
| Protein C activity, % | 31.5 (17.8–40.6)* | 32.6 (21.9–42.1) | 0.752 |
| Protein S activity, % | 88.4 (35.9–169) | 94.1 (35.9–156) | 0.809 |
| Plasminogen activity, % | 52.1 (20.2–80.2) | 56.4 (19.4–87.3) | 0.811 |
| D‑dimer, ng/mL | 2,221.2 (860.5–3,581.8) | 3,245.8 (879.7–4,130.0) | 0.503 |
Unfavorable outcome: thrombosis/bleeding leading to fatal outcomes in the early postoperative period. Favorable outcome: includes patients with successfully managed complications (n=8) and patients without complications (n=17). Data are presented as mean (95% CI), unless otherwise indicated. *, P<0.05. CI, confidence interval; MELD, Model for End-Stage Liver Disease.
The dynamics of platelet count in the context of fatal thrombohemorrhagic complications revealed a decrease within the first 2 days after LT. Conversely, patients without fatal outcomes showed no significant change in Plt levels during the initial 3 days post-surgery, with an increase to (147.9±34.6)×109/L by day 10. In contrast, individuals experiencing fatal thrombohemorrhagic complications exhibited a decrease in platelet count to (33.9±12.5)×109/L (Figure 7A). The dynamics of INR and APTT during the perioperative period did not correlate with outcomes, except for prolongation of APTT observed 12 hours after surgery in individuals with unfavorable outcomes (Figure 7B,7C). In favorable outcomes, AT-III levels increased over time. Conversely, patients with fatal outcomes exhibited significantly lower AT-III levels throughout the observation period, with a more notable decrease at 12 hours (24.6%±2.2% vs. 32.6%±1.4%; P<0.05), suggesting impaired liver synthetic function and hemostasis imbalance (Figure 7D). A low AT-III level may reduce the efficacy of heparin therapy post-LT, as AT-III, a cofactor of heparin, is essential for inactivating coagulation factors IX, X, and II. In the absence of AT-III, both high- and low-molecular-weight heparins may be ineffective. Protein C, together with its cofactor protein S, inactivates coagulation factors V and VIII, highlighting its prognostic role.
Deficiencies in protein C and plasminogen within the first 24 hours after surgery proved informative in predicting unfavorable outcomes. A protein C level below 17% demonstrated sensitivity of 75% and specificity of 100%, while a plasminogen level below 21% showed sensitivity of 66.7% and specificity of 87.5%. ROC analysis confirmed good predictive value with an AUC of 0.833 (P<0.05) for protein C and 0.813 (P<0.05) for plasminogen (Figure 8). Dynamics of protein C, plasminogen, and D-dimer in favorable and unfavorable outcomes are shown in Figure 9. In cases with unfavorable outcomes, reduced synthesis of plasminogen and protein C indicated slower recovery of liver synthetic function, correlating with clinical prognosis. Furthermore, fibrinogen levels below 160.1 mg/dL on postoperative day 1 demonstrated sensitivity of 89% and specificity of 96%, with an AUC of 0.896 (P<0.05), accurately predicting all unfavorable outcomes (Table 2). Among contributing factors, intraoperative blood loss exceeding 1,200 mL was significantly associated with bleeding and fatal complications during the early postoperative period (Figure 10). Deficiencies in protein C and plasminogen within the first 24 hours after surgery have proven to be informative in predicting unfavorable outcomes due to both thrombotic and hemorrhagic complications. For instance, a protein C level below 17% demonstrated a sensitivity of 75% and specificity of 100%, while a plasminogen level below 21% showed a sensitivity of 66.7% and specificity of 87.5%. These tests exhibit good prognostic value, with an AUC of 0.833 (P<0.05) for protein C and 0.813 (P<0.05) for plasminogen. It is notable that in cases with unfavorable outcomes, there was a decrease in plasminogen and protein C synthesis, indicating a slower recovery of liver synthetic functions, which correlates with the outcomes of LT. We posit that this decline in synthetic function within the first 3 days post-LT may stem from liver ischemia, underscoring the importance of perioperative measures to prevent it.
Table 2
| Observation period | Unfavorable outcome (n=5) | Favorable outcome (n=25) | P |
|---|---|---|---|
| Before | 222.7 (136.9–308.6) | 270.6 (175.1–310.1) | 0.5518 |
| 12 hours | 145 (88.0–199.7) | 198.6 (165.4–231.9) | 0.0640 |
| 1 day | 114 (80.6–156.0) | 271.7 (235.4–308.1) | 0.0001 |
| 2 days | 153 (18.6–320.0) | 358 (249–467) | 0.0178 |
| 3 days | 277 (163–391) | 323 (210–420.4) | 0.4909 |
| 5 days | 212.3 (20.5–560.0) | 325.7 (213.9–437.6) | 0.2752 |
| 10 days | 325 (223–435) | 387.2 (215.5–558) | 0.2752 |
Unfavorable outcome: thrombosis/bleeding leading to fatal outcomes in the early postoperative period. Favorable outcome: includes patients with successfully managed complications (n=8) and patients without complications (n=17). Data are expressed as mean (95% confidence interval). LT, liver transplantation.
Our findings indicated that patients experiencing unfavorable outcomes due to thrombohemorrhagic complications not only exhibited plasminogen deficiency but also showed decreased fibrinogen levels during the postoperative period. Specifically, a fibrinogen level below 160.1 mg/dL on the first day after surgery demonstrated a sensitivity of 89% and specificity of 96%, with an AUC of 0.896 (P<0.05), accurately predicting all unfavorable outcomes (Table 2).
Among the reasons for decreased fibrinogen levels observed in liver transplant recipients with unfavorable outcomes in the postoperative period, we hypothesize reduced synthesis in the liver, as well as factors such as blood loss and hemodilution. Our investigation into the relationship between intraoperative blood loss and the onset of fatal complications confirmed these associations. We determined that intraoperative blood loss exceeding 1,200 mL was significantly linked to bleeding and unfavorable outcomes during the early postoperative period.
The pathogenesis underlying these complications lies in trauma-induced coagulopathy. Patients who maintained regulation of the hemostasis system and preserved liver synthetic function in terms of producing plasma hemostasis factors effectively managed hepatic artery thrombosis and bleeding postoperatively, resolving complications in 6 out of 7 cases (85.7%) with PVT and 4 out of 5 cases (80%) with bleeding. In contrast, patients with deficiencies in AT-III, protein C, and plasminogen experienced fatal thrombohemorrhagic complications in 5 out of 13 cases (38.5%).
Discussion
Liver resection, including right and left lobectomy, is a cornerstone in the management of hepatic malignancies, parasitic cysts, metabolic liver disorders, and in donor hepatectomy during LT (12). In LT, pathological fibrinolytic phenotypes occur in up to 80% of cases, with hyperfibrinolysis increasing mortality 11-fold and fibrinolysis inhibition sevenfold, the former causing hemorrhagic and the latter thrombotic complications (2,13,14). Fibrinogen, the most abundant coagulation factor, declines early during hemodilution, blood loss, hypothermia, or acidosis, and hypofibrinogenemia—often when hemoglobin <80 g/L—is linked to impaired hemostasis (2,3,15). Severe intraoperative blood loss may trigger disseminated intravascular coagulation (DIC), contributing to both thrombotic and hemorrhagic events (3,15,16). Effective patient blood management, including correction of anemia and thrombocytopenia, minimization of surgical blood loss, and treatment of coagulopathy, improves outcomes, whereas excessive transfusion worsens morbidity, mortality, and graft survival (16). Antifibrinolytic agents such as tranexamic acid significantly reduce intraoperative bleeding and transfusion needs in LT (6).
In our series, patients with poor outcomes exhibited significant elevations in D-dimer levels from 12 hours post-LT, peaking within 2–3 days, reflecting hyperthrombinemia and active thrombosis. In contrast, favorable outcomes correlated with postoperative declines in D-dimer, supporting its role as a prognostic biomarker. Additionally, early thrombocytopenia and deficiencies in AT-III, protein C, and plasminogen were associated with fatal thrombohemorrhagic events. Preservation of anticoagulant factor synthesis was linked to successful resolution of hepatic artery thrombosis (HAT) and bleeding in 85.7% and 80% of cases, respectively. Intraoperative blood loss exceeding 1,200 mL was a significant predictor of early hemorrhagic complications, consistent with prior studies highlighting the interplay of trauma-induced coagulopathy and impaired hepatic synthesis in LT (2,3,7,13,17).
Vascular complications remain a major cause of early graft loss. Early HAT, reported in 2.5–8% of cases, has been associated with pre-transplant hepatectomy, female donor status, low graft-to-recipient weight ratio, and extra-anatomic reconstructions (11). Technical precision in arterial anastomosis and use of microsurgical techniques are crucial to reducing risk (4,10). Comparative analyses have shown that arterial conduit interposition offers lower re-thrombosis rates than simple anastomotic revision for early HAT (18). In pediatric LT, thrombotic and hemorrhagic events, though less frequent, are linked to variant vascular anatomy, reduced allografts, high intraoperative blood loss, and prolonged prothrombin time (19,20). Blood loss ≥31.25 mL/kg has been identified as an independent predictor of post-transplant thrombosis (21). Biliary complications, such as bilomas, observed in our cohort, were associated with delayed peribiliary arteriole thrombosis, leading to ischemia and cholangiocyte necrosis (14). The hepatic arterial buffer response (HABR) may also play a role in graft dysfunction in living donor LT, potentially contributing to arterial or venous thrombosis in certain hemodynamic scenarios (22).
Limitations of this study include a small sample size (n=30), short follow-up (10 days), and the absence of comparative analysis with established prognostic models such as MELD. Future directions include multicenter validation, extended follow-up to assess late-onset complications, and mechanistic studies to clarify the biological pathways linking perioperative biomarker alterations to clinical outcomes.
Conclusions
This study highlights the coagulation-related biomarkers’ early postoperative predictive value in liver transplant recipients. ROC analysis revealed that decreased levels of AT-III (<15%), protein C (<17%), and plasminogen (<21%) on the first postoperative day were significantly associated with fatal thrombohemorrhagic complications. A fibrinogen level <160.1 mg/dL also demonstrated excellent prognostic accuracy (AUC =0.896, sensitivity =89%, specificity =96%, P<0.05). Patients with preserved anticoagulant function demonstrated higher rates of successful resolution of hepatic artery thrombosis and postoperative bleeding. Intraoperative blood loss exceeding 1,200 mL emerged as a significant risk factor for adverse outcomes. These findings emphasize the importance of integrating laboratory risk indicators with clinical decision-making and support the development of personalized perioperative management protocols in LT.
Acknowledgments
None.
Footnote
Reporting Checklist: The authors have completed the STROBE reporting checklist. Available at https://qims.amegroups.com/article/view/10.21037/qims-24-2230/rc
Data Sharing Statement: Available at https://qims.amegroups.com/article/view/10.21037/qims-24-2230/dss
Funding: None.
Conflicts of Interest: All authors have completed the ICMJE uniform disclosure form (available at https://qims.amegroups.com/article/view/10.21037/qims-24-2230/coif). The authors have no conflicts of interest to declare.
Ethical Statement: The authors are accountable for all aspects of the work in ensuring that questions related to the accuracy or integrity of any part of the work are appropriately investigated and resolved. This study was conducted in accordance with the Declaration of Helsinki and its subsequent amendments. This study was conducted by ethical principles and approved by the Expert Council of the Republican Specialized Scientific and Practical Medical Center for Surgery named after V. Vakhidov Ethics Committee (Conclusion No. 178 RUzb, October 22, 2021). Informed consent was obtained from all participants prior to their inclusion in the study.
Open Access Statement: This is an Open Access article distributed in accordance with the Creative Commons Attribution-NonCommercial-NoDerivs 4.0 International License (CC BY-NC-ND 4.0), which permits the non-commercial replication and distribution of the article with the strict proviso that no changes or edits are made and the original work is properly cited (including links to both the formal publication through the relevant DOI and the license). See: https://creativecommons.org/licenses/by-nc-nd/4.0/.
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