Abstract
Objective
This study aimed to investigate the relationship between plasma D‐dimer level, preoperative complications, and thrombosis in liver transplant recipients.
Methods
The clinical data of 525 liver transplant recipients with end‐stage liver disease (ESLD) in the First Affiliated Hospital of Zhejiang University from October 2012 to December 2015 were retrospectively analyzed. The patients were grouped based on thrombosis before and after surgery to determine the risk factors for postoperative thrombosis recurrence.
Results
Of the preoperative complications assessed, esophageal varices and thrombosis were significantly correlated (P = 0.000); ascites, spontaneous bacterial peritonitis, and hepatic encephalopathy were significantly correlated with preoperative D‐dimer level (P < 0.001, P < 0.001, and P = 0.002, respectively); during the first week after surgery, the D‐dimer level was significantly and consecutively higher than that before surgery and was significantly higher in the group with both preoperative and postoperative thrombosis than in the other groups on the first day after surgery (P < 0.001); the area under the curve (AUC) for diagnosis of postoperative thrombosis recurrence in the preoperative thrombosis group using plasma D‐dimer level on the first day after surgery was 0.698 (P = 0.001); Cox regression analysis showed that D‐dimer was an independent risk factor for postoperative thrombosis recurrence (HR = 3.062, P = 0.029).
Conclusion
D‐dimer level on the first day after liver transplant is related to thrombosis recurrence and is an independent risk factor for postoperative thrombosis recurrence.
Keywords: coagulation, complications, D‐dimer, liver transplant, thrombosis
1. INTRODUCTION
Patients undergoing liver transplant for end‐stage liver disease (ESLD) usually have either end‐stage liver cirrhosis, acute or subacute liver failure, or liver cancer, with systemic pathophysiological changes, including severe ascites, hepatic encephalopathy, esophageal varices bleeding, and coagulation disorders. In addition, thrombosis cannot be ignored. According to data from the Chinese liver transplant center from January 1993 to July 2013, the prevalence of portal vein thrombosis (PVT) was as high as 8.82%1 among patients who met the transplant criteria, while the incidence of PVT in patients with liver cirrhosis registered in the multidisciplinary liver transplant center of University of Michigan between January 1995 and May 2007 was 4.5%.2 After surgical resection or thrombectomy, the portal vein intimal wall in these PVT liver transplant recipients was no longer intact leading to thrombosis recurrence, and the recurrence rate fluctuated between 2% and 36%.3, 4, 5 In addition, portal vein reconstruction is another challenge in liver transplant recipients with concurrent PVT, which increases perioperative complications and mortality rate.6 Liver transplant is an effective method for the treatment of ESLD.7 Due to advances in immunosuppressants, the incidence of acute rejection has significantly reduced; however, thrombosis often occurs, and prevention has become a key issue.
Procoagulation factors II, V, VII, IX, and X and fibrinogen synthesis are decreased in patients with ESLD, resulting in an increased risk of bleeding. On the other hand, a deficiency of anticoagulation factor synthesis including antithrombin, protein C, protein S, and plasminogen and increased synthesis of factor VIII and von Willebrand factor can lead to a hypercoagulable state.8, 9 Some studies have proposed that the coagulation balance should be adjusted in the perioperative period of liver transplant by coagulation monitoring.10 However, some believe that the prothrombin time (PT) and international normalized ratio (INR) cannot be used as independent indicators for the prediction of bleeding risk.11 Increased activated partial thromboplastin time (APTT) or INR cannot predict spontaneous anticoagulation in patients,12 while elevated INR does not mean that thrombosis can be completely avoided.13 As there is no effective clinical treatment for thrombosis, prediction and prevention using reasonable indicators are particularly important. This study evaluated the risk of postoperative thrombosis in relation to preoperative complications and plasma D‐dimer level, with the aim of preventing and controlling thrombosis.
2. MATERIALS AND METHODS
2.1. Study subjects
This study retrospectively analyzed the clinical data of 525 ESLD patients with complete medical records and follow‐up results, who underwent liver transplant from October 2012 to December 2015 in the center for liver transplant of Zhejiang University, which included 521 cases of modified piggyback and 4 cases of classic orthotropic liver transplant. The study met all ethical standards and was approved by the hospital ethics committee.
2.2. Methods
Patient data recorded included gender, age, height, weight, primary disease, preoperative complications, and thrombosis, as well as related coagulation and biochemical indicators, and follow‐up for possible postoperative thrombosis recurrence. Liver cirrhosis was diagnosed based on medical history, signs of hepatic decompensation, and histopathological and imaging examinations.14 Hepatocellular carcinoma was diagnosed based on histopathological examination, chronic liver disease history, imaging, and laboratory examination.15 According to the 2015 EASL clinical practice guidelines,16 the scope of thrombosis was evaluated using color Doppler ultrasound, computed tomography (CT), or magnetic resonance imaging (MRI).
Preoperative complications included ascites, hepatic encephalopathy, hepatorenal syndrome, esophageal varices, spontaneous bacterial peritonitis, hepatocellular carcinoma, and thrombosis. The degree of ascites was evaluated according to EASL cirrhosis guidelines version 201017: Class 1 ascites referred to a small amount of ascites only observed by ultrasonography; class 2 ascites referred to moderate ascites with symmetrical abdominal bulge; and class 3 ascites referred to patients with a large amount of abdominal fluid, accompanied by significant abdominal distension. The severity of hepatic encephalopathy was evaluated by medical history and physical signs18 as stage one prodromal, stage two precoma, stage three lethargy, and stage four coma. Patients were grouped according to the presence of thrombosis before and after surgery as follows: the nonthrombosis group, preoperative thrombosis only group, postoperative thrombosis only group, and the group with both preoperative and postoperative thrombosis. Exclusion criteria are as follows: history of long‐term use of contraceptives, anticoagulation, or antiplatelet drugs; concurrent systemic lupus erythematosus, Crohn's disease, ulcerative colitis, and other inflammatory diseases; concurrent cardiovascular system disease; hematological system disease; and secondary thrombosis after other surgical trauma and nonliver disease.
2.3. Laboratory examinations
The preoperative and postoperative (two consecutive weeks) levels of D‐dimer, PT, INR, total bilirubin (TB), and creatinine (Cr) level were recorded, and the model for end‐stage liver disease (MELD) score was determined. Plasma D‐dimer and PT: The first 5 mL sample of morning fasting venous blood was collected in a plastic tube containing sodium citrate, and plasma was obtained after 10 minutes centrifugation at 1500 g. Plasma D‐dimer and PT were then measured by turbidimetry using a Sysmex CS5‐100 automatic blood coagulation analyzer and related reagents. Serum TB and Cr: A 5 mL sample of morning fasting venous blood was collected in a separate tube, and serum was obtained after 10 minutes centrifugation at 1500 g. Serum TB and Cr were then measured by the diazotization method and enzyme colorimetric determination using a Hitachi 7600S automatic biochemical analyzer and related reagents, respectively. INR was determined using the following equation: INR = (patient PT/PT of normal control) ISI. The MELD score was obtained using the following formula: R = 3.8 × ln [TB (mg/dL)] + 11.2 × ln (INR) + 9.6 × ln [Cr (mg/dL)] + 6.4 × cause (cause: 0 for cholesteric cirrhosis and alcoholic cirrhosis, 1 for virus and other reasons).
2.4. Statistical analysis
SPSS, version 16.0 (SPSS Inc., Chicago, IL, USA), and GraphPad Prism 5 software were used for statistical analysis and graphics. The data were expressed as the mean and standard deviation for continuous variables and frequencies for categorical variables. The chi‐squared test or Fisher exact test was used to evaluate the relationship between thrombosis and preoperative complications and the impact of the presence of preoperative thrombosis on the incidence of postoperative thrombosis. The Mann‐Whitney U test or Kruskal‐Wallis test was used to compare the continuous variables of two or more independent groups. Spearman rank correlation was used to evaluate the relationship between the level of plasma D‐dimer and the MELD score. Postoperative D‐dimer levels in the different thrombosis groups were compared using two‐way ANOVA or the Mann‐Whitney U test. Univariate analysis of risk factors for predicting postoperative thrombosis recurrence was performed using Cox proportional hazard regression analysis, and backward stepwise multivariate analysis was conducted to evaluate the independent clinical parameters predicting postoperative thrombosis recurrence. A receiver operating characteristic (ROC) curve was drawn to evaluate the accuracy of using D‐dimer level on the first day after surgery to predict postoperative thrombosis recurrence. A value of P < 0.05 was considered statistically significant.
3. RESULTS
3.1. Basic clinical characteristics
A total of 525 patients were enrolled, including 447 males and 78 females, with an average age of 48.1 ± 11.4 years. Patient characteristics are shown in Table 1. The primary causes of ESLD were mainly different types of decompensated cirrhosis, including viral, alcoholic, and biliary cirrhosis, accounting for 97.8%, in addition to congenital biliary atresia, Wilson's disease, hepatocellular carcinoma, and liver failure. The main preoperative complications were ascites, hepatic encephalopathy, and esophageal varices. Preoperative thrombosis was observed in 85 patients, including PVT in 72 cases (13.7%), and other types of thrombosis in 13 cases (2.5%).
Table 1.
Demographic and clinical characteristics of the participants
| Variables | Liver transplant recipients (n = 525) |
|---|---|
| Sex (female/male) | 78/447 |
| Age (y) | 48.1 ± 11.4 |
| BMI (kg/m2) | 22.0 ± 3.5 |
| D‐dimer (mg/L FEU) | 7.2 ± 11.0 |
| Creatinine (μmol/L) | 82.0 ± 64.2 |
| Total bilirubin (μmol/L) | 186.8 ± 204.6 |
| INR | 1.7 ± 0.8 |
| MELD score | 15.0 ± 9.6 |
| Primary disease | |
| Viral cirrhosis [n (%)] | 427 (81.3) |
| Alcoholic cirrhosis [n (%)] | 20 (3.8) |
| Virus mixed alcoholic cirrhosis [n (%)] | 10 (1.9) |
| Congenital biliary atresia [n (%)] | 6 (1.1) |
| Autoimmune cirrhosis [n (%)] | 7 (1.3) |
| Wilson's disease [n (%)] | 6 (1.1) |
| Primary biliary cirrhosis [n (%)] | 20 (3.8) |
| Idiopathic portal hypertensive cirrhosis [n (%)] | 6 (1.1) |
| Others [n (%)] | 23 (4.4) |
| Complications | |
| Ascites [n (%)] | 410 (78.1) |
| HCC [n (%)] | 218 (41.5) |
| HE [n (%)] | 204 (38.9) |
| EV [n (%)] | 136 (25.9) |
| SBP [n (%)] | 66 (12.6) |
| HRS [n (%)] | 59 (11.2) |
| PVT [n (%)] | 72 (13.7) |
| OT [n (%)] | 13 (2.5) |
Data are expressed as mean ± SD or the number of patients (%).
BMI, body mass index; EV, esophageal varices; HCC, hepatocellular carcinoma; HE, hepatic encephalopathy; HRS, hepatorenal syndrome; INR, international normalized ratio; MELD, model for end‐stage liver disease; OT, other thrombosis; PVT, portal vein thrombosis; SBP, spontaneous bacterial peritonitis.
3.2. The relationship between preoperative complications and primary disease with thrombosis
By analyzing the relationship between preoperative complications and preoperative or postoperative thrombosis, it was found that only esophageal varices were significantly associated with thrombosis (P = 0.000). Using the post hoc test, the P‐values of the group with both preoperative and postoperative thrombosis compared with the nonthrombosis group, preoperative thrombosis only group, and postoperative thrombosis only group were then calculated as 0.000, 0.001, and 0.000, respectively, while other complications showed no statistically significant correlation with thrombosis (Table 2).
Table 2.
The relationship between preoperative complications and Primary disease with thrombosis in liver transplant recipients
| Complications and primary disease | Group 1 (n = 391) | Group 2 (n = 61) | Group 3 (n = 49) | Group 4 (n = 24) | P |
|---|---|---|---|---|---|
| Ascites [n (%)] | |||||
| No | 78 (19.9) | 12 (19.7) | 13 (26.5) | 3 (12.5) | 0.943 |
| Stage 1 | 158 (40.4) | 25 (41.0) | 18 (36.7) | 10 (41.7) | |
| Stage 2 | 80 (20.5) | 12 (19.7) | 10 (20.4) | 4 (16.7) | |
| Stage 3 | 75 (19.2) | 12 (19.7) | 8 (16.3) | 7 (29.2) | |
| HE [n (%)] | |||||
| No | 239 (61.1) | 39 (63.9) | 28 (57.1) | 15 (62.5) | 0.891 |
| Stage 1‐2 | 123 (31.5) | 19 (31.1) | 19 (38.8) | 8 (33.3) | |
| Stage 3‐4 | 29 (7.4) | 3 (4.9) | 2 (4.1) | 1 (4.2) | |
| SBP [n (%)] | |||||
| No | 345 (88.2) | 51 (83.6) | 41 (83.7) | 22 (91.7) | 0.559 |
| Yes | 46 (11.8) | 10 (16.4) | 8 (16.3) | 2 (8.3) | |
| HRS [n (%)] | |||||
| No | 347 (88.7) | 51 (83.6) | 45 (91.8) | 23 (95.8) | 0.349 |
| Yes | 44 (11.3) | 10 (16.4) | 4 (8.2) | 1 (4.2) | |
| EV [n (%)] | |||||
| No | 306 (78.3) | 39 (63.9) | 37 (75.5) | 7 (29.2) | 0.000 |
| Yes | 85 (21.7) | 22 (36.1) | 12 (24.5) | 17 (70.8) | |
| HCC [n (%)] | |||||
| No | 229 (58.6) | 40 (65.6) | 29 (59.2) | 9 (37.5) | 0.131 |
| Yes | 162 (41.4) | 21 (34.4) | 20 (40.8) | 15 (62.5) | |
| Cirrhosis [n (%)] | |||||
| No | 25 (6.4) | 6 (9.8) | 3 (6.1) | 1 (4.2) | 0.436 |
| Yes | 366 (93.6) | 55 (90.2) | 46 (93.9) | 23 (95.8) | |
Data are expressed as the number of patients (%). Group 1: nonthrombosis; group 2: preoperative thrombosis only; group 3: postoperative thrombosis only; group 4: preoperative and postoperative thrombosis. The bold values represent that the results are statistically significant.
EV, esophageal varices; HCC, hepatocellular carcinoma; HE, hepatic encephalopathy; HRS, hepatorenal syndrome; SBP, spontaneous bacterial peritonitis.
3.3. The relationship between preoperative complications and primary disease with D‐dimer level
The relationship between preoperative complications and D‐dimer level was analyzed using a classification based on the severity of preoperative complications. The results showed that ascites, spontaneous bacterial peritonitis, and hepatic encephalopathy were significantly correlated with D‐dimer level (the P‐values were as follows: P < 0.001, P < 0.001, and P = 0.002, respectively), while other complications and D‐dimer level were not statistically correlated (Figure 1).
Figure 1.
The relationship between preoperative complications and primary disease with D‐dimer level. The relationship between hepatocellular carcinoma and D‐dimer level (A), esophageal varices and D‐dimer level (B), hepatorenal syndrome and D‐dimer level (C), ascites and D‐dimer level (D), spontaneous bacterial peritonitis and D‐dimer level (E), hepatic encephalopathy and D‐dimer level (F), portal vein thrombosis and D‐dimer level (G), other thrombosis and D‐dimer level (H), and cirrhosis and D‐dimer level (I). Data are expressed as box plots, in which the horizontal lines illustrate the 25th, 50th, and 75th percentiles of the D‐dimer levels. The vertical lines represent the 2.5th and 97.5th percentiles
3.4. Correlation analysis between D‐dimer level and MELD score
According to Spearman rank correlation analysis, D‐dimer level was positively correlated with MELD score (r = 0.247, P = 0.000, Figure 2).
Figure 2.
A scatter diagram of the correlation between D‐dimer level and MELD score. Coefficients (r) and P‐values were calculated by Spearman rank correlation analysis
3.5. Continuous monitoring of plasma D‐dimer level after liver transplant
Plasma D‐dimer level was significantly and consecutively higher during the first week after surgery than during the preoperative week and mostly recovered 2 weeks after surgery. Plasma D‐dimer level on the first day after surgery was significantly different in the nonthrombosis group, preoperative thrombosis only group, postoperative thrombosis only group, and the group with both preoperative and postoperative thrombosis (P < 0.001). Plasma D‐dimer level in the group with both preoperative and postoperative thrombosis on the first day after surgery was significantly higher than that in the other groups (compared with the nonthrombosis group, preoperative thrombosis only group, and postoperative thrombosis only group, the P‐values were 0.001, 0.005, and 0.002, respectively, Figure 3).
Figure 3.
The trend in D‐dimer level after liver transplant. The mean and SD of D‐dimer levels in the nonthrombosis group, preoperative thrombosis only group, postoperative thrombosis only group, and the group with both preoperative and postoperative thrombosis on the first day after liver transplant were 13.35 ± 17.09, 12.73 ± 14.52, 13.95 ± 23.57, and 18.07 ± 11.65 mg/L FEU, respectively. P‐values were calculated by two‐way ANOVA
3.6. Impact of the presence of preoperative thrombosis on the incidence of postoperative thrombosis
Eleven percent of patients without preoperative thrombosis developed postoperative thrombosis (49/440). However, the incidence of postoperative thrombosis recurrence in patients with preoperative thrombosis was as high as 28% (24/85). The chi‐squared test results suggested that the presence of preoperative thrombosis or not directly affected the incidence of postoperative thrombosis (P = 0.000), and thrombosis mainly occurred more than 48 hour postoperatively (Figure 4).
Figure 4.
A comparison of postoperative thrombosis rates. Thrombosis occurred in 11% (49/440) of patients without preoperative thrombosis, whereas thrombosis recurred in 28% (24/85) of patients with preoperative thrombosis
3.7. ROC curve analysis of D‐dimer level on the first day after surgery for predicting postoperative thrombosis recurrence
Receiver operating characteristic curve analysis results suggested that plasma D‐dimer level on the first day after surgery in patients with preoperative thrombosis was closely associated with the incidence of postoperative thrombosis recurrence. The AUC for predicting postoperative recurrence using plasma D‐dimer level on the first day after surgery in patients with preoperative thrombosis was 0.698, with a cutoff value of 8.82 mg/L FEU (Table 3).
Table 3.
Diagnostic efficacy of D‐dimer level for postoperative thrombosis recurrence on the first day after surgery
| Variables | Cutoff value (mg/L FEU) | AUC (95% CI) | P | SE | PPV (%) | NPV (%) |
|---|---|---|---|---|---|---|
| D‐dimer | 8.82 | 0.698 (0.598‐0.793) | 0.001 | 0.057 | 43.1 | 87.8 |
Cutoff value was calculated from ROC analysis.
AUC, area under the curve; NPV, negative predictive value; PPV, positive predictive value; SE, standard error.
3.8. Cox regression analysis of postoperative thrombosis recurrence
Following ROC curve analysis, it was calculated that the cutoff values for age, BMI, MELD score, PT, and INR were 52, 20.28, 16.1, 14.5, and 1.57, respectively. Cox univariate regression analysis suggested that D‐dimer level and esophageal varices were significantly correlated with postoperative thrombosis recurrence (P < 0.05), and relevant parameters such as preoperative PT and INT were not correlated with postoperative thrombosis recurrence. However, backward stepwise multivariate regression analysis found that only the regression analysis result for D‐dimer level was statistically significant (HR = 3.062, P = 0.029), indicating that D‐dimer is an independent risk factor for postoperative thrombosis recurrence (Table 4).
Table 4.
Cox regression analysis of thrombosis recurrence after liver transplantation
| Univariate analysis | Multivariate analysis | |||
|---|---|---|---|---|
| Variables | Hazard ratio (95% CI) | P | Hazard ratio (95% CI) | P |
| Sex (Male vs Female) | 3.492 (0.470‐25.963) | 0.222 | 3.021 (0.394‐23.165) | 0.288 |
| Age (> 52 vs ≤ 52) | 0.734 (0.278‐1.876) | 0.518 | 0.557 (0.211‐1.471) | 0.237 |
| BMI (> 20.28 vs ≤ 20.28) | 0.647 (0.277‐1.514) | 0.316 | 0.749 (0.276‐2.036) | 0.571 |
| MELD score (> 16.1 vs ≤ 16.1) | 0.408 (0.138‐1.201) | 0.104 | 0.458 (0.154‐1.363) | 0.161 |
| PT (> 14.5 vs ≤ 14.5) | 1.508 (0.510‐4.458) | 0.457 | 2.157 (0.719‐6.473) | 0.170 |
| INR (> 1.57 vs ≤ 1.57) | 1.372 (0.600‐3.134) | 0.453 | 1.692 (0.532‐5.386) | 0.373 |
| D‐dimer (> 8.82 vs ≤ 8.82 mg/L FEU) | 3.404 (1.255‐9.231) | 0.016 | 3.062 (1.123‐8.349) | 0.029 |
| HCC (Y vs N) | 2.285 (0.975‐5.357) | 0.057 | 1.665 (0.674‐4.116) | 0.269 |
| EV (Y vs N) | 2.672 (1.089‐6.557) | 0.032 | 2.351 (0.953‐5.798) | 0.063 |
| SBP (Y vs N) | 0.442 (0.102‐1.927) | 0.277 | 0.453 (0.097‐2.106) | 0.312 |
| HRS (Y vs N) | 0.277 (0.037‐2.060) | 0.210 | 1.144 (0.120‐10.867) | 0.907 |
| HE (Stage 3‐4 vs Stage 0‐2) | 1.038 (0.139‐7.723) | 0.971 | 2.699 (0.260‐28.001) | 0.406 |
| Ascites (Stage 2‐3 vs Stage 0‐1) | 1.045 (0.447‐2.446) | 0.919 | 1.048 (0.401‐2.738) | 0.924 |
| Cirrhosis (Y vs N) | 1.372 (0.600‐3.134) | 0.453 | 1.074 (0.115‐10.043) | 0.950 |
The bold values represent that the results are statistically significant. BMI, body mass index; EV, esophageal varices; HCC, hepatocellular carcinoma; HE, hepatic encephalopathy; HRS, hepatorenal syndrome; INR, international normalized ratio; MELD, model for end‐stage liver disease; N, no; PT, prothrombin time; SBP, spontaneous bacterial peritonitis; Y, yes.
4. DISCUSSION
Portal vein thrombosis is a common complication of decompensated cirrhosis,19, 20 which can occur in the portal vein trunk, and may also extend to the mesenteric and splenic vein.21 The incidence of PVT is between 2% and 26% in patients with liver transplant,3, 4, 5, 22, 23 which may be related to its atypical clinical manifestations.24 These patients frequently suffer postoperative thrombosis recurrence, with a recurrence rate of approximately 2%‐36%.3, 4, 5 In the current study, the incidence of PVT in patients with liver transplant was 13.7%, and a postoperative thrombosis recurrence rate of 28% in those with preoperative thrombosis was observed, which was high and deserves extra attention.
Previous studies have shown that a hypercoagulable state is the main cause of PVT formation,25 and antithrombin III, protein C, and protein S deficiency may be risk factors for the occurrence of PVT.26 Therefore, when the liver is damaged, although the synthesis of related coagulation factors is reduced, the level of relative anticoagulant protein is also decreased, which may still lead to a hypercoagulable state and the promotion of thrombosis.27 Liver transplant recipients are prone to thrombosis due to two main factors: First, liver structure changes caused by cirrhosis increase flow resistance in the liver, decreasing portal venous velocity, resulting in increased portal venous pressure, and blood reflux obstruction, which are the basis of PVT formation.28 Second, due to the large amount of coagulation, anticoagulant factors and fibrinolytic factors produced in the liver, and when it is damaged, blood coagulation and anticoagulation have a new dynamic balance at a low level, which is relatively unstable and prone to bleeding or thrombosis,6, 20 and the formation of a hypercoagulable state under certain stress conditions.29 During liver transplant, damage to the coagulation system and homeostasis disorder may be more serious and can lead to postoperative thrombosis recurrence. Therefore, this study aimed to analyze the risk factors for postoperative thrombosis recurrence, which would be helpful for early clinical intervention.
D‐dimer is formed by the specific degradation of cross‐linked fibrin, and increased D‐dimer level can reflect secondary fibrinolysis hyperthyroidism and fibrin thrombosis, which is mainly used for the exclusive diagnosis of diffuse intravascular coagulation, deep venous thrombosis, and pulmonary embolism.30 Due to hyperemia, edema, and necrosis of hepatocytes in patients with ESLD, the scavenging ability of activated fibrinolytic factor is reduced, resulting in the degradation of a large amount of fibrin and an increase in D‐dimer level. In recent years, studies have shown that plasma D‐dimer level in patients with PVT was significantly increased, which was an independent risk factor for PVT.31, 32 The meta‐analysis by DAI also suggested that D‐dimer may serve as a diagnostic marker for PVT formation in patients with cirrhosis.30 We found that plasma D‐dimer level increased significantly on the first day after liver transplant, which may be caused by the release of more plasminogen activator from hepatic sinusoidal endothelial cells in the transplanted liver, resulting in a cascade of fibrinolytic reactions, which in turn led to an increase in fibrin (original) degradation products and D‐dimer level. On the first day after surgery, the plasma D‐dimer level was significantly different in all the thrombosis groups, but was particularly high in the group with both preoperative and postoperative thrombosis. The multivariate Cox regression analysis showed that D‐dimer on the first day after surgery was an independent risk factor for postoperative thrombosis recurrence (HR = 3.062,P = 0.029), further confirming the predictive effect of high D‐dimer level on the first day after surgery on the formation of PVT, and suggesting that plasma D‐dimer level is closely related to postoperative thrombosis recurrence. In view of this, we believe that the first day after surgery is the best time to predict thrombosis recurrence. At the same time, the AUC was calculated to be 0.698 using ROC analysis, with a cutoff value of 8.82 mg/L FEU, which demonstrated diagnostic value. Thrombosis observed in this study mostly occurred more than 48 hour after surgery. It is possible that after 24‐48 hour of reperfusion, coagulation function was corrected step by step, while the recovery of antithrombin III, protein C, and protein S was relatively slow, in which case the coagulation and fibrinolytic system were not balanced, leading to thrombosis.33
In addition, the MELD score is currently widely used to predict the prognosis of patients with ESLD.34, 35 Patients with a higher MELD score have more complicated pathophysiological changes that may affect morbidity and late mortality after liver transplant.36 In this study, the MELD score and D‐dimer level were positively correlated; therefore, it is recommended that in the assessment of the risk of thrombosis, both the MELD score and D‐dimer level should be taken into consideration.
This study also showed that esophageal varices were significantly correlated with thrombosis, and ascites, spontaneous bacterial peritonitis, and hepatic encephalopathy were significantly correlated with D‐dimer level. It is possible that PVT formation in turn can aggravate portal hypertension, thereby exacerbating esophageal varices and ascites, leading to an increased incidence of relevant complications.20, 37
The traditional concept is that, due to coagulation dysfunction, patients with ESLD often have a tendency to bleed, making PVT treatment more difficult. New research suggests that portal hypertension is the leading cause of bleeding, instead of anticoagulant therapy.38 Additional studies19, 39, 40 have shown that after rational anticoagulation therapy, the incidence of complications can be reduced in patients with concurrent PVT without increasing the risk of bleeding. Rational anticoagulant therapy is effective and safe, with low molecular weight heparin anticoagulation recommended.39
In summary, plasma D‐dimer level on the first day after liver transplant is correlated with postoperative thrombosis recurrence, and D‐dimer is an independent risk factor for postoperative thrombosis recurrence. It is recommended that close attention is paid to plasma D‐dimer level and related complications in clinical practice, which allows preintervention for prevention and control.
ACKNOWLEDGMENTS
The assistance of Professor Chen and the Key Laboratory of Clinical in vitro Diagnostic Techniques of Zhejiang Province are acknowledged.
Zhang Q, Guo R, Chen Y. D‐dimer level in liver transplant recipients on the first day after surgery is correlated with postoperative thrombosis recurrence. J Clin Lab Anal. 2019;33:e22646 10.1002/jcla.22646
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