Portal vein thrombosis (PVT) is complete or partial blood flow obstruction in the main trunk and branches of the portal vein, which is common in patients with cirrhosis.
In patients with cirrhotic portal hypertension, those with PVT have a worse prognosis and a higher rebleeding rate after treatment [
In our previous study, the rebleeding rate is higher in the patients whose PVT developed during follow-up (47.6%) than those with perioperative PVT (9.8%) (
There are many factors related to PVT occurrence during short-term follow-up after splenectomy such as a wider portal vein, low preoperative white blood cell count, high postoperative platelet count, prolonged prothrombin time, pericardial devascularization, and a larger spleen size [
The risk factors for PVT were different in different studies, and it has been suggested that an increase in morbidity may result from surgical procedures rather than from splenectomy [
In this study, we retrospectively explored the risk factors for PVT in patients with liver cirrhosis after splenectomy and devascularization surgery.
This is a nested case-control study. The study retrospectively analyzed the medical record from cirrhosis patients 18 years or older who underwent devascularization to prevent esophageal variceal rebleeding in our hospital between January 1, 2008, and December 20, 2014. The exclusion criteria were as follows: (1)
Patients were enrolled based on the inclusion and exclusion criteria and medical history information that was collected retrospectively. The follow-up period ended October 16, 2015. Patients underwent an imaging examination of the portal system on day 7, 6 months after the surgery, and every 6 months thereafter. Medical history, physical examination results, imaging data, and laboratory examination results including preoperative, perioperative, and follow-up information were collected retrospectively using the hospital’s medical records, and attempts were made to complete missing or uncertain items by telephone follow-up.
Patients were divided into two groups based on the perioperative and postdischarge follow-up period. Patients without preoperative thrombosis were divided into case and control groups based on whether they had perioperative thrombosis, and risk factors for perioperative thrombosis were analyzed. Patients without perioperative thrombosis were divided into case and control groups based on whether they developed PVT during follow-up, and risk factors for follow-up PVT were analyzed.
The SPSS19.0 (SPSS Inc., Chicago, IL, USA) was used to analyze the study data. Univariate analysis was used first to identify possible risk factors. Continuous variables with normal distribution are expressed as the
All procedures performed in studies involving human participants were in accordance with the ethical standards of the institutional research committee (Ethics Committee of Zhongshan Hospital Fudan University + B2015-13R) and with the 1964 Helsinki Declaration and its later amendments or comparable ethical standards.
From January 1, 2008, to December 20, 2014, 289 patients were admitted to our department for general surgery because of portal hypertension. All these patients were taken to surgery because of severe hypersplenism or endoscopic treatment failure. Among these patients, 165 were excluded based on the exclusion criteria, and 124 patients (42.91%) were enrolled into the study. The enrollment process is shown in Figure
Research flowchart.
The average age was 49.83 years (range, 18–77 years), comprising 83 males (66.94%) and 41 females (33.06%). The patients underwent the following procedures after admission to the hospital: 98 (79.03%) underwent splenectomy combined with combined devascularization, and 26 (20.97%) underwent splenectomy combined with pericardial devascularization.
The average follow-up time was 42.73 months for all patients until October 16, 2015, with a median follow-up of 41.43 months (range, 5.47–95.30 months). A total of 22 (17.7%) patients had rebleeding and 10 (8.1%) patients died during follow-up (including four patients who developed rebleeding). A life table was used to obtain the nonbleeding and survival rates for all patients, and the 1-, 3-, and 5-year rebleeding-free rate was 92%, 83%, and 69%, respectively. The 1-, 3-, and 5-year survival rate was 96%, 92%, and 85%. A total of 25 patients received other special treatments during follow-up, including 23 patients who underwent endoscopic treatment, one of whom was treated using balloon-occluded retrograde transvenous obliteration (BRTO) and two who were treated using TIPS.
There were 61 (49.2%) patients who developed thrombosis during the perioperative period. Of the 63 patients who did not develop thrombosis during the perioperative period, 21 (16.94%) had thrombosis during the follow-up period and 42 (33.87%) had no thrombosis during follow-up.
In patients without perioperative thrombosis, if the platelet count was
Four patients with perioperative thrombosis and one patient with follow-up PVT had taken anticoagulants during follow-up, and the remaining patients did not receive anticoagulant therapy.
Patients were divided into two groups based on whether thrombosis occurred during the perioperative period, and the indicators were analyzed by univariate analysis (Table
Univariate analysis of risk factors for perioperative thrombosis.
Factor | Without PVT | PVT | ||
---|---|---|---|---|
Age | ||||
Meld score | 0.723 | |||
The time from the first hemorrhage to surgery (years) | 0.4 (0.2-0.9) | 0.4 (0.2-1.15) | 0.633 | |
Spleen length (cm) | ||||
Spleen width (cm) | ||||
Spleen thickness (cm) | ||||
Red blood cells (×1012/L) | 0.7 | |||
Hemoglobin (g/L) | 0.251 | |||
White blood cells (×109/L) | ||||
Platelets (×109/L) | 57 (36-75) | 47 (35.5-71) | 0.312 | |
Total bilirubin ( | 0.476 | |||
Combined bilirubin ( | ||||
Albumin (g/L) | ||||
Alanine aminotransferase (U/L) | 25 (18-37) | 26 (19.5-36) | 0.982 | |
Aspartate aminotransferase (U/L) | 32 (25.72-43.5) | 31.0 (23.0-43.5) | 0.560 | |
Creatinine ( | 69 (59-80) | 72 (59-82) | 0.690 | |
Urea (mmol/L) | 4.7 (3.8-5.7) | 5 (4.15-5.95) | 0.656 | |
Uric acid ( | ||||
Activated partial thromboplastin time (s) | ||||
International normalization ratio | 0.427 | |||
Thrombin time (s) | 0.665 | |||
Prothrombin time (s) | 14.3 (13.6-15.6) | 14.5 (13.75-15.65) | 0.517 | |
Fibrinogen (mg/dL) | 0.485 | |||
Portal vein diameter (mm) | ||||
Portal vein blood flow velocity (m/s) | 0.535 | |||
Postoperative platelets (×109/L) | 0.321 | |||
Spleen volume (cm3) | ||||
Previous history of endoscopic therapy | No | 47 (74.6%) | 51 (83.6%) | 0.218 |
Yes | 16 (25.4%) | 10 (16.4%) | ||
Child-Pugh grade | A | |||
B+C | ||||
History of abdominal surgery | No | 57 (90.5%) | 58 (95.1%) | 0.492 |
Yes | 6 (9.5%) | 3 (4.9%) | ||
Combined devascularization | No | |||
Yes | ||||
Peripheral blood vessel dissection | No | |||
Yes | ||||
Hypertension | No | 56 (88.9%) | 58 (95.1%) | 0.324 |
Yes | 7 (11.1%) | 3 (4.9%) | ||
Diabetes | No | 54 (85.7%) | 55 (90.2%) | 0.447 |
Yes | 9 (14.3%) | 6 (9.8%) | ||
Smoking | No | |||
Yes | ||||
History of blood transfusion | No | 34 (54.0%) | 31 (50.8%) | 0.726 |
Yes | 29 (46.0%) | 30 (49.2%) | ||
Grade of splenomegaly | 0 | 21 (33.3%) | 9 (14.8%) | 0.440 |
I | 14 (22.2%) | 21 (34.4%) | (0.007) | |
II | 6 (9.5%) | 16 (26.2%) | ||
III | 22 (34.9%) | 15 (24.6%) | ||
Grade of esophageal varices | No | 1 (1.6%) | 0 (0%) | 0.593 |
Mild | 1 (1.6%) | 1 (1.6%) | (0.737) | |
Moderate | 9 (14.3%) | 7 (11.5%) | ||
Severe | 52 (82.5%) | 49 (80.3%) | ||
With gastric varices | No | |||
Yes | ||||
Ascites | No | 47 (74.6%) | 43 (70.5%) | 0.608 |
Yes | 16 (25.4%) | 18 (29.5%) | ||
Hepatic encephalopathy | No | 62 (98.4%) | 60 (98.4%) | 1.0 |
Yes | 1 (1.6%) | 1 (1.6%) | ||
Posthepatitic cirrhosis | No | 23 (36.5%) | 18 (29.5%) | 0.407 |
Yes | 40 (63.5%) | 43 (70.5%) |
Finally, the preoperative leukocyte count, postoperative portal vein diameter, and the presence of varicose veins were independent factors for perioperative thrombosis (
Multivariate analysis of risk factors for perioperative thrombosis (logistic regression: forward-LR).
Risk factors | Regression coefficients | OR | 95% confidence interval for OR | |
---|---|---|---|---|
Preoperative white blood cells | -0.777 | 0.002 | 0.460 | 0.284-0.744 |
Diameter of portal vein trunk preoperatively | 0.330 | 0.005 | 1.391 | 1.102-1.757 |
With gastric varices | -1.335 | 0.003 | 0.263 | 0.108-0.638 |
Constant | -1.533 | 0.339 | 0.216 |
Of the 63 patients who did not develop thrombosis during the perioperative period, 21 had thrombosis during the follow-up procedure, and the median time to thrombosis was 24.3 months (range, 0.73–87.63 months). Forty-two patients had no thrombosis during the follow-up period.
Among patients who did not develop thrombosis during the perioperative period, those who developed cancer during follow-up were excluded. The remaining patients underwent a nested case-control study based on whether thrombosis occurred during follow-up to explore the risk factors associated with thrombosis, except for tumors. Univariate analysis was also used to the possible indicators (Table
Univariate analysis of risk factors for thrombosis during follow-up.
Factor | PVT ( | Without PVT ( | ||
---|---|---|---|---|
Age (years old) | 0.859 | |||
First bleeding time from surgery (years) | 0.4 (0.17~0.80) | 0.4 (0.20-1.00) | 0.649 | |
Meld score | ||||
Spleen length (cm) | ||||
Spleen width (cm) | 0.742 | |||
Spleen thickness (cm) | 6 (5~6.5) | 6 (5-6) | 0.802 | |
Red blood cell (×1012/L) | 0.987 | |||
Hemoglobin (g/L) | 0.903 | |||
White blood cell (×109/L) | 0.423 | |||
Platelet (×109/L) | 0.968 | |||
Total bilirubin ( | 0.779 | |||
Conjugated bilirubin ( | 6.7 (5.4~10.5) | 5.8 (4.7~7.8) | 0.394 | |
Albumin (g/L) | ||||
Alanine aminotransferase (U/L) | 0.684 | |||
Aspartate aminotransferase (U/L) | 0.881 | |||
Creatinine ( | ||||
Urea (mmol/L) | 5.2 (3.4~7.1) | 4.7 (3.8~5.3) | 0.650 | |
Uric acid ( | 0.361 | |||
Activated partial thromboplastin time (s) | 0.287 | |||
International normalization ratio | 0.395 | |||
Thrombin time (s) | 0.694 | |||
Prothrombin time (s) | ||||
Fibrinogen (mg/dL) | 0.625 | |||
Portal vein diameter (mm) | ||||
Portal vein flow rate (m/s) | 0.580 | |||
Postoperative platelets (×109/L) | 0.536 | |||
Platelet differences between preoperative and postoperative (×109/L) | 0.486 | |||
Postoperative portal vein trunk diameter (mm) | 11 (10~12) | 11 (10~12) | 0.367 | |
Postoperative portal vein trunk flow rate (m/s) | 0.545 | |||
Spleen volume (cm3) | 0.272 | |||
Previous history of endoscopic treatment | No | |||
Yes | ||||
Child-Pugh grade | A | 15 (78.9%) | 24 (68.6%) | 0.416 |
B | 4 (21.1%) | 11 (31.4%) | ||
Gender | Female | 8 (42.1%) | 12 (34.3%) | 0.520 |
Male | 11 (57.9%) | 23 (65.7%) | ||
Abdominal surgery history | No | 17 (89.5%) | 31 (88.6%) | 1.0 |
Yes | 2 (10.5%) | 4 (11.4%) | ||
Combined devascularization | No | 7 (36.8%) | 10 (25.7%) | 0.392 |
Yes | 12 (63.2%) | 26 (74.3%) | ||
Peripheral blood vessel dissection | No | 12 (70.9%) | 26 (74.3%) | 0.392 |
Yes | 7 (36.8%) | 10 (25.7%) | ||
Hypertension | No | |||
Yes | ||||
Diabetes | No | 14 (73.7%) | 31 (88.6%) | 0.251 |
Yes | 5 (26.3%) | 4 (11.4%) | ||
Smoking | No | 17 (89.5%) | 31 (88.6%) | 1.0 |
Yes | 2 (10.5%) | 4 (11.4%) | ||
History of blood transfusion | No | 9 (47.4%) | 20 (57.1%) | 0.492 |
Yes | 10 (52.6%) | 15 (42.9%) | ||
Grade of splenomegaly | 0 | |||
I | ||||
II | ||||
III | ||||
Grade of esophageal varices | No | 1 (5.3%) | 0 (0%) | 0.229 |
Mild | 0 (0%) | 1 (2.9%) | ||
Moderate | 1 (5.3%) | 8 (22.9%) | ||
Severe | 17 (89.5%) | 26 (74.3%) | ||
With gastric varices | No | 7 (36.8%) | 13 (37.1%) | 0.983 |
Yes | 12 (63.2%) | 22 (62.9%) | ||
Ascites | No | 14 (73.7%) | 26 (74.3%) | 1 |
Yes | 5 (26.3%) | 9 (25.7%) | ||
Hepatic encephalopathy | No | 18 (94.7%) | 35 (100%) | 0.352 |
Yes | 1 (5.3%) | 0 | ||
Posthepatitic cirrhosis | No | 8 (42.1%) | 15 (42.9%) | 0.957 |
Yes | 11 (57.9%) | 20 (57.1%) |
Multivariate analysis of thrombosis-related risk factors during follow-up (logistic regression: forward-LR method).
Risk factors | Regression coefficients | OR | 95% confidence interval for OR | |
---|---|---|---|---|
With hypertension | 2.220 | 0.039 | 9.208 | 1.116~75.958 |
Grade of spleen enlargement | 0.665 | 0.019 | 1.945 | 1.115~3.394 |
Creatinine | 0.049 | 0.028 | 1.050 | 1.005~1.098 |
Constant | -5.483 | 0.004 | 0.004 |
Endoscopic treatment, surgery, and TIPS are all options for secondary prevention for rebleeding. Although with the development of endoscopy and interventional technology, more patients may choose endoscopic treatment or TIPS, devascularization is still being performed in many centers.
The rebleeding rate and mortality after devascularization in patients with liver cirrhosis varied in previous studies. The 3-year survival rate of patients who underwent traditional devascularization was 95.52% according to Yang et al. [
PVT is a common complication after devascularization and splenectomy. The incidence of PVT after surgery varies in current studies. The incidence of PVT in patients with cirrhosis during the natural course of the disease is about 10%–25% [
The higher incidence of PVT in splenectomy patients in the short term after surgery is also related to these three factors. Previous studies showed that the factors potentially related to PVT in the short term after splenectomy were the preoperative portal vein diameter, preoperative leukocyte count, postoperative increase in the platelet count, prothrombin time prolongation, surgical approach including pericardial devascularization, and spleen size [
Additionally, 33.33% (21/63) of the patients who did not develop thrombosis during the perioperative period were followed up, and 33.33% (21/63) of them developed PVT during the follow-up period. There have been few studies on the patients who did not develop thrombosis during the perioperative period, and we found that the risk factors for perioperative PVT and follow-up PVT were different. We suggest that thrombosis occurring during the follow-up period is less affected by the surgery and may more closely resemble the PVT that develops in the natural disease course of cirrhosis, which occurs as a result of an imbalance in the anticoagulation-coagulation system.
Hypertension is a risk factor for deep vein thrombosis. In cirrhosis patients, endothelin (ET) and nitric oxide (NO) levels in peripheral blood or intrahepatic circulation were different from those in patients without cirrhosis. Hypertensive people have an increased peripheral blood ET level and a decreased NO level compared with those without hypertension, which is also an unbalanced state [
The incidence of PVT was associated with spleen size in previous studies, but the risk factors remained controversial. Spleen volume was a risk factor for PVT (
Hepatorenal syndrome is a possible complication in patients with decompensated cirrhosis. Additionally, thrombopoietin is mainly produced in the kidney, so changes in renal function may affect platelet number and function, while many scholars believe that thrombosis in patients after splenectomy is a result of changes in platelet function [
Because damage was greatly reduced, platelet levels in patients with splenectomy were significantly increased after surgery. The role of platelets in the development of PVT in cirrhosis patients is controversial. S. He and F. He found that platelet volume and average platelet volume were good predictors of thrombosis after splenectomy [
This study has some limitations. First, this study is a retrospective study. Information about treatment, development of thrombosis and rebleeding, and death were obtained via follow-up by phone, so there may be a memory bias, and there are some deficiencies in the data integrity. For example, in patients with hypertension, the details about taking antihypertensive drugs, the duration of hypertension, and blood pressure control were not obtained, which may have affected the results. Second, 15.67% of the patients were lost to follow-up during the follow-up period in this study, which is a high loss rate. Some patients were excluded because of a lack of data, which may lead to choice bias. Third, the study sample size is small and it is a single-center study. However, surgical and perioperative management both have an effect on the patient’s prognosis and PVT development. Additionally, the study included patients with a variety of liver cirrhosis causes, but all these patients underwent prophylactic surgery for hemorrhage and patients with hepatocellular carcinoma were excluded. Therefore, the conclusions may not be generalizable to the general public. Fourth, patients diagnosed with thrombosis underwent surgery using ultrasound, CTA, or magnetic resonance during follow-up. There was no comparison between each of these methods. However, different methods may have different diagnostic sensitivities, which may produce some diagnostic bias. Additionally, some patients had an earlier or irregular follow-up because of bleeding and other events that may affect the timing of thrombosis. Fifth, in exploring the risk factors for thrombosis during follow-up, tumors were considered to be a risk factor for deep venous thrombosis because of the hypercoagulable state caused by the tumor; because this is different from the risk factors for thrombosis in nontumor patients, patients who developed a tumor during the follow-up period were excluded. This may also affect the generalizability of the results.
A combination of different risk factors may lead to the development of the PVT after devascularization in cirrhosis patients. Patients who developed thrombosis during follow-up had different risk factors compared with those whose PVT occurred perioperatively and those without thrombosis. Therefore, patients without thrombosis perioperatively should be followed up for thrombosis, and thus, thrombosis may be actively prevented in patients with risk factors. However, additional large-scale prospective studies are needed to verify these conclusions.
Risk factors for perioperative PVT and PVT that occurs in the natural history of cirrhotic patients after surgery are different. Patients with a lower preoperative white blood cell count, a larger portal vein trunk diameter, and no gastric varices are more likely to have perioperative thrombosis. A history of hypertension, a larger spleen, and a higher creatinine level preoperatively are independent predictors for the occurrence of PVT during the follow-up period after surgery in patients without perioperative PVT.
The raw data used to support the findings of this study are restricted by the institution in order to protect patient privacy. If necessary, contact the corresponding author.
The authors declare that they have no conflict of interest.
Chen Shiyao and Wang Jian contributed equally to the work and share the corresponding authorship.
This study was supported by the Innovation Fund of Shanghai Scientific Committee (No. 15411950507). We thank Jodi Smith, PhD, from Edanz Group (