Risk Factors for Portal Vein System Thrombosis After Laparoscopic Splenectomy in Cirrhotic Patients with Hypersplenism

Abstract

Background:

Portal vein system thrombosis (PVST) is a frequent and potentially life-threatening complication after laparoscopic splenectomy (LS) in cirrhotic patients with hypersplenism. The mechanisms and risk factors of PVST are poorly understood. This study investigated risk factors for PVST following LS in cirrhotic patients with hypersplenism.

Materials and Methods:

A total of 56 consecutive cirrhotic patients with hypersplenism who underwent successful LS between 2013 and 2014 were included in this retrospective study. Based on the absence or presence of postoperative PVST on postoperative day (POD) 7, the patients were divided into non-PVST and PVST groups. Demographic and preoperative factors were analyzed.

Results:

PVST increased in size in 24 (42.9%) of 56 patients after LS on POD 7. Logistic multivariate regression showed that a portal vein diameter >13 mm (relative risk 35.796, 95% confidence interval 4.534–282.614, and P = .001) and age >50 years (relative risk 20.127, 95% confidence interval 3.598–112.578, and P = .001) were significant independent risk factors for PVST. The incidence of PVST after LS in the portal vein diameter >13 mm group was significantly higher than that in the portal vein diameter ≤13 mm group (P = .001). Similarly, the incidence of PVST after LS in the age >50 years group was significantly higher than that in the age ≤50 years group (P = .001).

Conclusion:

A portal vein diameter >13 mm and age >50 years are independent risk factors for PVST after LS in cirrhotic patients with hypersplenism due to portal hypertension.

Introduction

Portal vein system thrombosis (PVST) is a serious and potentially life-threatening complication, especially for advanced cirrhotic patients after splenectomy or splenectomy and azygoportal disconnection. The 10-year survival rate in adults with PVST is 38%–60%. The mortality rate from variceal bleeding in cirrhotic patients with PVST is 30%–70%, which is significantly higher than the 5% mortality rate from variceal bleeding in noncirrhotic patients with PVST.¹ PVST may aggravate liver function, increase the risk of variceal bleeding with portal hypertension, or lead to ischemic intestinal necrosis.^2–5 Furthermore, PVST can also increase the difficulty of future liver transplantation and is correlated with poor patient survival.^6,7

The incidence of postsplenectomy PVST in noncirrhotic patients is reported as 6%–11%.^8–12 According to previous studies, the incidence of PVST in cirrhotic patients with hypersplenism after open splenectomy (OS) is approximately 24.0%–29.0%,^13,14 and that after open splenectomy and azygoportal disconnection (OSD) ranges from 30.1% to 47.8%.^15–17 The reason why the incidence of PVST in cirrhotic patients is higher than that in noncirrhotic patients after OS or OSD may be due to the specific pathophysiological characteristics of cirrhotic portal hypertension and changes in postoperative hemodynamics.

With the recent major progress in laparoscopic techniques in almost all fields of conventional abdominal surgery, laparoscopic splenectomy (LS) has gradually become more accepted as a treatment for cirrhotic patients with secondary hypersplenism. LS is preferable to OS and technically feasible and safe with many advantages, including minimal surgical trauma, less pain, fewer complications, and more rapid recovery. However, notably, PVST is a more frequent complication of LS than of OS. Ikeda et al.¹⁸ reported that the incidence of PVST in the LS group was 55% (12/22), which was significantly higher than that of 19% (4/21) in the OS group. Similarly, more patients develop PVST after laparoscopic splenectomy and azygoportal disconnection (LSD) than after OSD.¹⁷ The mechanism by which LS contributes to a higher rate of PVST than OS is not yet clear. The different operative procedures in LS other than OS may be the potential causes of PVST.

PVST is a potentially fatal postoperative complication after OS or LS. The mechanisms and risk factors of PVST are poorly understood, especially in cirrhotic patients with portal hypertension. Therefore, this study aimed to clarify the incidence and characteristics of PVST and to investigate risk factors for PVST following LS in cirrhotic patients with hypersplenism.

Materials and Methods

Patients

From January 2013 to March 2014, 56 cirrhotic patients were diagnosed with secondary hypersplenism due to portal hypertension in our department and underwent successful LSD. The inclusion criteria were as follows: a clinical, radiological, or histological diagnosis of cirrhosis of any etiology; age 18–75 years; splenomegaly with secondary hypersplenism and severe thrombocytopenia and/or leucopenia (PLT <50 × 10⁹/L and WBC <3 × 10⁹/L); Child–Pugh liver function grade A or B; no evidence of PVST by ultrasound evaluation the day before operation; and successful LS without conversion to laparotomy.

The laparoscopic procedures used for LSD were described in our previous study.¹⁹ During the preoperative discussion, all the patients were informed that LS is a minimally invasive procedure compared with the typical OS. The selection of procedure was based on the patient's decision. All the patients provided written informed consent. This study was approved by the Ethics Committee of the Clinical Medical College of Yangzhou University. All operations were performed by the same surgical team.

Clinical data

Retrospectively collected preoperative data of the patients included age, sex, etiology of cirrhosis, Child–Pugh classification, model for end-stage liver disease, platelet count, prothrombin time, international normalized ratio, D-dimer concentration, longitudinal diameter of the spleen, portal vein diameter, splenic vein diameter, and velocity of portal blood flow. Intraoperative data included operation time, estimated intraoperative blood loss, and volume of intraoperative blood transfused. Postoperative data included Doppler ultrasound screening for the occurrence of PVST on postoperative day (POD) 7.

The postoperative unified anticoagulation regimen was as follows. From POD 3, patients received 100 mg aspirin enteric-coated tablets (Bayer, Leverkusen, Germany) once daily for 1 year. They underwent subcutaneous injection of 4100 IU of low–molecular weight heparin (LMWH; CS Bio, Hebei, China) once daily for 5 days and administration of 25 mg oral dipyridamole (Henan Furen, Henan, China) thrice daily for 3 months.

Statistical analyses

Data are presented as mean (standard deviation), median (interquartile range), or percentage. Group means were compared using the Student's t-test or the Mann–Whitney U test, as appropriate. Percentages were compared using the chi-square test. Bivariate correlation was used to determine the significant level of the factors of patients' age and portal vein diameter. Multivariate regression analysis was performed with forward stepwise elimination of nonsignificant variables. A P value <.05 was considered statistically significant. All analyses were performed with SPSS 13.0 software (Chicago, IL).

Results

Of the 56 patients, 24 (42.9%) had PVST complication after LS. Main portal vein thrombosis occurred in 6 (10.7%) patients, main portal vein and intrahepatic portal branch thrombosis in 1 (1.8%), main portal vein and spleen vein thrombosis in 7 (12.5%), spleen vein thrombosis in 8 (14.3%), and intrahepatic portal branch thrombosis in 2 (3.6%).

Demographic and preoperative clinical characteristics in the non-PVST and PVST groups on POD 7 are shown in Table 1. Etiology of cirrhosis between the non-PVST and PVST groups on POD 7 is listed in Table 2. Significant variables between the two groups included age and portal vein diameter. Compared with the non-PVST group, the PVST group had older age (P = .020) and a wider portal vein diameter (P = .002).

Table 1.

Demographic and Preoperative Clinical Characteristics Between the Non-PVST and PVST Groups on POD 7

Variable	Non-PVST (n = 32)	PVST (n = 24)	P
Gender (female/male)	12/20	11/13	.530
Age (years)	49.9 ± 10.5	56.3 ± 9.0	.020
Child–Pugh classification (A/B)	9/23	8/16	.675
MELD	9.7 ± 1.9	10.0 ± 1.9	.599
PLT (×10⁹/L)	38.0 ± 9.2	36.1 ± 10.9	.480
PT (s)	16.30 ± 1.09	16.88 ± 1.40	.089
INR	1.34 ± 0.12	1.39 ± 0.15	.160
D-dimer (mg/L)	1.20 ± 1.16	0.91 ± 0.80	.290
Longitudinal diameter of spleen (mm)	179.3 ± 24.8	186.3 ± 24.4	.298
Portal vein diameter (mm)	13.4 ± 2.2	15.4 ± 2.3	.002
Splenic vein diameter (mm)	10.9 ± 2.3	11.7 ± 2.6	.265
Velocity of portal blood flow (cm/s)	14.0 (11.1–19.4)	13.15 (9.6–13.7)	.055
Duration of surgery (minutes)	102.8 ± 42.5	115.4 ± 43.2	.278
Intraoperative blood loss (mL)	131.9 ± 162.8	101.7 ± 147.4	0.478
Volume of intraoperative blood transfused	25.0 ± 101.6	16.7 ± 81.6	.743

Data are mean ± standard deviation, median (interquartile range) values, or number of patients, as indicated.

INR, international normalized ratio; MELD, model for end-stage liver disease; PLT, platelets; POD, postoperative day; PT, prothrombin time; PVST, portal vein system thrombosis.

Table 2.

Etiology of Cirrhosis Between the Non-PVST and PVST Groups on POD 7

Etiology	Non-PVST (n = 32)	PVST (n = 24)	P
HBV cirrhosis	16	13	.757
HCV cirrhosis	3	4	.683
Schistosomiasis cirrhosis	2	1	1.000
Alcoholic cirrhosis	2	2	1.000
Autoimmunity cirrhosis	4	3	1.000
Idiopathic cirrhosis	5	1	.350

HBV, hepatitis B virus; HCV, hepatitis C virus; POD, postoperative day; PVST, portal vein system thrombosis.

Bivariate correlation analysis was performed for the relationship between these significant variables and occurrence of PVST on POD 7. Variables, including age and portal vein diameter, were divided into groups from low values to high values. According to the correlation coefficient, the most significant levels of portal vein diameter (Table 3) and age (Table 4) were for a portal vein diameter >13 mm and age >50 years.

Table 3.

Procedure of Statistically Significant Level of Patients' Portal Vein Diameter

Correlation factor	Correlation coefficient	P
Portal vein diameter (mm)
>10	0.240	.075
>11	0.354	.008
>12	0.404	.002
>13	0.442	.001
>14	0.167	.220

Table 4.

Procedure of Statistically Significant Level of Patients' Age

Correlation factor	Correlation coefficient	P
Age (years)
>40	0.300	.025
>45	0.333	.012
>50	0.433	.001
>55	0.108	.430

The most significant levels of significant variables were regarded as independent variables, and PVST on POD 7 was regarded as the dependent variable. Logistic multivariable regression showed that age >50 years and portal vein diameter >13 mm were significant independent risk factors for PVST (Table 5).

Table 5.

Outcome of Logistic Multivariate Regression

Independent variables	B	SE	Wald	df	Sig	Exp(B)	95% CI
Portal vein diameter >13 (mm)	3.578	1.054	11.518	1	0.001	35.796	4.534–282.614
Age >50 (years)	3.002	0.878	11.681	1	0.001	20.127	3.598–112.578

CI, confidence interval; SE, standard error.

The incidence of PVST after LS in the portal vein diameter >13 mm group was significantly higher than that in the portal vein diameter ≤13 mm group (22/38 [57.9%] versus 2/18 [11.1%]; P = .001). Similarly, the incidence of PVST after LS in the age >50 years group was significantly higher than that in the age ≤50 years group (18/28 [64.3%] versus 6/28 [21.4%]; P = .001).

Discussion

Some previous studies have evaluated the predictors for PVST after OSD^15,20 or OS²¹ for portal hypertension. However, few studies have assessed the predictors for PVST after LS. The present study aimed to clarify the incidence and risk factors for PVST after LS in cirrhotic patients with secondary hypersplenism due to portal hypertension.

Splenectomy is performed on patients with a normal-sized spleen who have hematological disorders or splenomegaly with hypersplenism mainly due to cirrhotic portal hypertension. PVST is a frequent event after splenectomy, especially after LS for hypersplenism due to cirrhotic portal hypertension. The mechanism of progress of PVST after OS and LS for different diseases is complex and still unclear. There are some causes that might lead to postoperative PVST. First, the velocity of portal vein blood flow is decreased because of splenectomy. Second, cirrhotic portal hypertension leads to a slower velocity of portal vein blood flow. Third, dilated portal vein and spleen vein due to portal hypertension cause damage of the venous intima. This leads to attachment by platelets (PLT), resulting in platelet agglutination. Finally, the different surgery procedures of LS other than OS may contribute to a higher rate of PVST than OS. The main differences during LS are as follows: (1) CO₂ in the pneumoperitoneum that has been reported to cause a hypercoagulable state during laparoscopic surgery,^22,23 (2) the technique used for splenic vessel ligation (stapled vascular transection en masse), and (3) use of the LigaSure vessel-sealing device (Covidien, Boulder, CO) or harmonic shears (Ethicon, Cincinnati, OH), which may contribute to venous intimal damage because of heat energy or oscillation. The OSD procedure involved splenic vessels and the surrounding ligaments of the spleen, mainly using a traditional clamp and a ligature or suture with silk.¹⁷

Most of these factors involved in PVST are intrinsic or irresistible. The most commonly used anticoagulation and antiplatelet agglutination agents, including oral aspirin, dipyridamole, and clopidogrel bisulfate, are generally ineffective in prevention of postoperative PVST. Recently, LMWH has been reported as an effective and safe protocol to reduce the incidence of PVST in patients who undergo OS or LS with gastroesophageal devascularization.^24,25 A small, randomized, controlled trial showed that a 12-month course of LMWH 4000 IU/day was safe and effective in preventing PVST in patients with advanced cirrhosis.²⁶ Additionally, this treatment appeared to delay the occurrence of hepatic decompensation and improve survival.²⁶

The present study aimed to determine the most important risk factors for operative PVST. Patients with the most risk factors should have more attention paid to them and be managed with an effective anticoagulation regimen to prevent PVST in advance.

This study showed that a portal vein diameter >13 mm was an independent risk factor for PVST after LS in cirrhotic patients with secondary hypersplenism due to portal hypertension. Patients with a portal vein diameter >13 mm were more than 35 times as likely to have PVST after LS as those with a portal vein diameter ≤13 mm (relative risk 35.796 and 95% confidence interval 4.534–282.614). The findings in the present study are consistent with those of some previous studies.^15,20,21 Li et al.²¹ demonstrated that portal vein diameter >13 mm was an independent risk factor of PVST after OS in cirrhotic patients with hypersplenism. Two other studies, respectively, reported that portal vein diameters >13.5 and >13.15 mm were risk factors for PVST occurrence after OSD.^15,20

Kinjo et al.¹³ reported that an increased spleen vein diameter was a significant independent risk factor for PVST after OS in patients with cirrhosis and portal hypertension. Unfortunately, the portal vein diameter was not investigated as a variable in their study. The normal diameter of the portal vein ranges from 6 to 10 mm. To some extent, an enlarged portal vein diameter reflects the degree of portal hypertension. The wider the portal vein diameter, the more severe the portal hypertension is. A portal vein diameter of 13 mm may be a threshold value to be relevant to the progress of PVST after LS for cirrhotic patients with secondary hypersplenism due to portal hypertension.

This study showed that age >50 years was an independent risk factor for PVST after LS in cirrhotic patients with secondary hypersplenism due to portal hypertension. With old age, the risk suffered from deep vein thrombosis is increased. Possible reasons related to the specific pathophysiological characteristics of older people include reduced blood flow, damage of the vascular endothelium, and a hypercoagulable state. Together with the particular pathophysiological characteristics of cirrhotic portal hypertension and the effect of LS, the risk of obtaining PVST increases with age. Patients who were aged >50 years were more than 20 times as likely to have PVST after LS as those who were aged ≤50 years (relative risk 20.127 and 95% confidence interval 3.598–112.578).

Therefore, more attention should be paid to high-risk patients aged older than 50 years or those with a portal vein diameter >13 mm. To prevent PVST after LS in high-risk patients, effective anticoagulation management should be performed in a timely manner after LS, such as the use of LMWH.^24,25 Additionally, periodical and timely monitoring for the occurrence of PVST by Doppler ultrasound or computed tomographic angiography should be performed. If PVST has occurred and cannot be eliminated by the above-mentioned effective anticoagulation management, a thrombolytic therapy plan, even including interventional therapy, should be carried out.

Splenectomy improves not only leucopenia, thrombocytopenia, and anemia due to hypersplenism in patients with cirrhosis²⁷ but also liver function, coagulation function, and hepatic fibrosis.^28–29 Furthermore, with splenectomy, portal vein pressure is reduced, which alleviates esophagogastric varices and prevents esophagogastric variceal bleeding.³¹ Some studies have demonstrated that synchronous OS and hepatectomy improve disease-free survival rates and resolve hypersplenism without an increased surgical risk for cirrhotic patients with hepatocellular carcinoma and hypersplenism.^32,33 LS has become widely accepted as the approach of choice for the surgical treatment of hypersplenism due to cirrhotic portal hypertension. LS has advantages of lower bleeding, shorter hospital stay, and minor liver function impairment compared with OS.³⁴ However, postoperative PVST in cirrhotic patients with hypersplenism can reduce the benefits of splenectomy, especially LS with a higher incidence of PVST. Identification of risk factors for postoperative PVST, such as a portal vein diameter >13 mm and age >50 years found in this study, will help determine whether prophylactic treatment and periodical and timely monitoring of PVST are required after LS. This could make LS a more feasible option in patients with cirrhosis.

Footnotes

Disclosure Statement

No competing financial interests exist.

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