Anticoagulation Therapy with Warfarin Versus Low-Dose Aspirin Prevents Portal Vein Thrombosis After Laparoscopic Splenectomy and Azygoportal Disconnection

Abstract

Background:

Portal vein system thrombosis (PVST) is a frequent and potentially life-threatening complication after laparoscopic splenectomy and azygoportal disconnection (LSD) in patients with cirrhotic portal hypertension. The objective of this study was to investigate the safety and effectiveness of warfarin with a target international normalized ratio (INR) of 2.0–2.5 for the prevention of PVST after LSD. Hitherto, this is the first study to assess the use of warfarin in this field.

Materials and Methods:

We retrospectively analyzed a database of 73 consecutive patients who underwent LSD from January 2013 to September 2014. Patients were categorized into the warfarin group (34 patients) and the aspirin group (39 patients). The INR and incidence of PSVT were monitored for 90 days.

Results:

Compared with the aspirin group, the warfarin group had a lower incidence of PVST on postoperative day (POD) 30 [17/34 (50.0%) versus 29/39 (74.4%); P = .032] and POD 90 [8/34 (23.5%) versus 30/39 (76.9%); P < .0001] and main portal vein thrombosis (MPVT) on POD 90 [3 (8.8%) versus 13 (33.3%); P = .012]. From POD 30 to 90, the warfarin group achieved more complete recanalization of PVST [9/17 (52.9%) versus 3/29 (10.3%), P = .005] and MPVT [9/12 (75.0%) versus 3/12 (25.0%), P = .039]. Multiple logistic regression analysis revealed that warfarin was an independent protective factor for PVST at POD 90 (relative risk, 0.027; 95% confidence interval, 0.004–0.168; P < .001). No patients developed bleeding complications.

Conclusions:

Anticoagulation therapy with warfarin is safe and effective for the prevention of PVST in cirrhotic patients with portal hypertension after LSD.

Introduction

Portal vein system thrombosis (PVST) is an alarming and potentially life-threatening complication of open splenectomy (OS) or open splenectomy and azygoportal disconnection (OSD). PVST may lead to liver damage, variceal bleeding with portal hypertension, or ischemic intestinal necrosis.^1–4 Furthermore, PVST can contribute to more difficult future liver transplantation.^5,6 The 10-year survival rate among adults with PSVT is reportedly 38%–60%, and the mortality rate from variceal bleeding in patients with PSVT with cirrhosis is 30%–70%; this is significantly higher than the 5% mortality rate from variceal bleeding in patients with PSVT without cirrhosis.⁷

Because of the special pathophysiological characteristics of cirrhotic portal hypertension and changes in postoperative hemodynamics, the incidence of PSVT in cirrhotic patients should be higher compared with noncirrhotic patients after OS^8–14 or OSD.^15–17

Some previous studies have found a significantly higher incidence of PSVT in the laparoscopic splenectomy (LS) group than in the OS group.^18–19 Ikeda et al.¹⁸ reported that the incidence of PSVT in the LS group was 55% (12/22), which was significantly higher than the incidence of 19% (4/21) in the OS group.

Some studies have suggested that the prevalence rate of PVST should be higher after laparoscopic splenectomy and azygoportal disconnection (LSD) in patients with cirrhosis with portal hypertension.^17,20 Zhe et al.¹⁷ reported that the PVST morbidity rate was significantly higher in the LSD group (50.0%, 40/80) than in the OSD group (30.1%, 22/71).

In Asia, OSD has been widely used in the surgical treatment of patients with liver cirrhosis, portal hypertensive esophagogastric variceal bleeding (EGVB), and secondary hypersplenism. With the rapid development of laparoscopic techniques, LSD has been gradually accepted and applied for such patients. Recent studies have shown that LSD is preferable to OSD and is technically feasible and safe with many advantages, including minimal surgical trauma, less pain, fewer complications, lower inflammatory immune responses, and more rapid recovery. Notably, however, PSVT is a more frequent complication after LS than OS.¹⁸ Similarly, more patients develop PVST after LSD than after OSD.¹⁷

Considering the danger of PVST, certain effective therapeutic measures are necessary to prevent postoperative PVST and thus ensure better long-term clinical outcomes, especially for cirrhotic patients. How to decrease the incidence of postoperative PVST and hinder the progression of PVST remains unclear. Prophylactic anticoagulation therapy is a prime method with which to prevent PSVT. Routine use of aspirin and clopidogrel has not been shown to control the incidence of PVST.²¹

The present study was performed to evaluate the efficacy and safety of warfarin in this clinical setting. We retrospectively studied and compared the outcomes between the warfarin group and the aspirin group in terms of preventing postoperative PSVT in 73 cirrhotic patients who underwent LSD at our institution from January 2013 to September 2014.

Materials and Methods

Patients

From January 2013 to September 2014, 76 cirrhotic patients were diagnosed with having EGVB and secondary hypersplenism in our department and underwent successful LSD. The laparoscopic procedures used for LSD were described in our previous article.²¹

The inclusion criteria were as follows: clinical, radiological, or histological diagnosis of cirrhosis of any etiology; age of 18–75 years; splenomegaly with secondary hypersplenism; EGVB; Child–Pugh liver function grade of A or B; no evidence of PVST by ultrasound evaluation and computed tomography angiography; informed consent to participate in the study; and successful LSD without conversion to laparotomy.

The exclusion criteria were as follows: hepatocellular carcinoma or any other malignancy; a hypercoagulable state other than that related to liver disease; use of oral contraceptives, anticoagulation, or antiplatelet drugs; baseline international normalized ratio (INR) of >2.0; recent peptic ulcer disease; history of hemorrhagic stroke; pregnancy; uncontrolled hypertension; and human immunodeficiency virus infection.

The 76 patients were divided into warfarin and aspirin groups according to their anticoagulation regimen. The selection of anticoagulation therapeutic regimens was based on each patient's decision. The warfarin group comprised 35 patients, and the aspirin group comprised 41 patients. The treatments were as follows: from postoperative day (POD) 3, patients in the warfarin group received 2.5 mg of oral warfarin (Harvest, Shanghai, China) once daily with titration of the dose to maintain a target INR of 2.0–2.5 for 1 year; patients in the aspirin group received 100 mg aspirin enteric-coated tablets (Bayer, Leverkusen, Germany) once daily for 1 year; and both groups 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 of oral dipyridamole (Henan Furen, Henan, China) thrice daily for 3 months.

Retrospectively collected preoperative data included age, sex, etiology of cirrhosis, Child–Pugh classification, model for end-stage liver disease (MELD), platelet (PLT) count, prothrombin time (PT), INR, d-dimer concentration, longitudinal diameter of the spleen, thickness 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 PT, INR, and PLT count on PODs 1, 7, 30, and 90. Doppler ultrasound screening for the occurrence of PVST was performed on PODs 7, 30, and 90. Ultrasound measurement was described in the previous article.²²

A total of 34 patients in the warfarin group (one was lost during follow-up) and 39 patients in the aspirin group (two were lost during follow-up) were analyzed in the study. All operations were performed by the same surgical team. All patients provided written informed consent. This study was approved by the Ethics Committee of the Clinical Medical College of Yangzhou University.

Statistical analyses

Parametric data were expressed as mean (standard deviation), nonparametric data were expressed as median (interquartile range), and categorical data were presented as percentage. Parametric data were compared using Student's t test, nonparametric data were compared using the Mann–Whitney U test, and categorical data were compared using the chi-square test. Perioperative indices, including the PLT count and INR, were compared by two-way repeated-measures analysis to determine the dynamic changes in the two groups at different time points. Logistic multivariable regression was performed with stepwise elimination of nonsignificant variables. A P value of <.050 was considered statistically significant. All statistical analyses were performed using SPSS 13.0 software (SPSS, Inc., Chicago, IL).

Results

The baseline demographic and preoperative clinical characteristics of the warfarin and aspirin groups are shown in Table 1. There were no significant differences between the two groups, including sex, age, etiology of cirrhosis, Child–Pugh classification, MELD, PLT count, PT, INR, d-dimer concentration, longitudinal diameter of the spleen, thickness of the spleen, portal vein diameter, splenic vein diameter, velocity of portal blood flow, operation time, estimated intraoperative blood loss, and volume of intraoperative blood transfused (all P > .05).

Table 1.

Demographic and Perioperative Clinical Characteristics of the Warfarin and Aspirin Groups

Variable	Warfarin (n = 34)	Aspirin (n = 39)	P
Sex (male/female)	13/21	20/19	.264
Age, years	55.2 ± 10.3	51.9 ± 8.7	.138
Etiology (1/2/3/4/5/6^a)	17/3/1/1/6/6	24/5/2/1/4/3	.684
Child–Pugh classification (A/B)	27/7	27/12	.323
MELD	9.9 ± 1.7	10.1 ± 2.4	.580
PLT (×10⁹/L)	45.8 ± 15.2	42.5 ± 15.8	.374
PT, seconds	16.84 ± 1.31	16.59 ± 1.26	.401
INR	1.37 ± 0.14	1.36 ± 0.14	.686
d-dimer, mg/L	0.705 (0.40–1.12)	0.770 (0.56–1.76)	.155
Longitudinal diameter of spleen, mm	175.3 ± 28.3	182.9 ± 23.2	.211
Thickness of spleen, mm	57.9 ± 10.4	57.8 ± 8.6	.959
Portal vein diameter, mm	14.0 ± 2.6	14.8 ± 1.9	.113
Splenic vein diameter, mm	11.3 ± 2.5	11.4 ± 2.4	.928
Velocity of portal blood flow, cm/second	13.5 ± 3.7	14.1 ± 3.4	.521
Duration of surgery, minutes	172.4 ± 39.1	182.0 ± 38.9	.295
Intraoperative blood loss, mL	140.6 ± 158.1	120.3 ± 143.2	.566
Volume of intraoperative blood transfused	14.7 ± 85.7	23.1 ± 106.3	.715

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

Hepatitis B/hepatitis C/schistosomiasis/alcohol/autoimmunity/idiopathic cirrhosis.

INR, international normalized ratio; MELD, model for end-stage liver disease; PLT, platelet; PT, prothrombin time.

Incidence of PVST

Although there was no difference in the incidence of PVST between the warfarin and aspirin groups on POD 7, the incidences of PVST in the warfarin group on POD 30 and POD 90 were lower than those in the aspirin group (Table 2).

Table 2.

Incidence of PVST, MPVT, and SVT Between the Warfarin and Aspirin Groups

Variable	Warfarin (n = 34)	Aspirin (n = 39)	P
PVST day 0	0	0
PVST day 7	16/34 (47.1)	18/39 (46.2)	.938
PVST day 30	17/34 (50.0)	29/39 (74.4)	.032
PVST day 90	8/34 (23.5)	30/39 (76.9)	<.0001
MPVT day 0	0	0
MPVT day 7	9/34 (26.5)	7/39 (17.9)	.380
MPVT day 30	12/34 (35.3)	12/39 (30.8)	.681
MPVT day 90	3/34 (8.8)	13/39 (33.3)	.012
SVT day 0	0	0
SVT day 7	3/34 (8.8)	11/39 (28.2)	.036
SVT 30	4/34 (11.8)	15/39 (38.5)	.010
SVT 90	2/34 (5.9)	15/39 (38.5)	.001

Values in parentheses are percentages.

Day 0, day of admission; day 7, postoperative day 7; day 30, postoperative day 30; day 90, postoperative day 90; MPVT, main portal vein thrombosis; PVST, portal vein system thrombosis; SVT, splenic vein thrombosis.

Incidences of main portal vein thrombosis

The incidences of main portal vein thrombosis (MPVT) on POD 7 and POD 30 did not differ significantly between the warfarin and aspirin groups. However, the incidence of MPVT was significantly lower on POD 90 in the warfarin group than the aspirin group (Table 2).

Incidence of splenic vein thrombosis

Compared with the aspirin group, the warfarin group exhibited a lower incidence of splenic vein thrombosis (SVT) on POD 7, POD 30, and POD 90 (Table 2).

Incidence of bleeding complications

The incidence of postoperative recurrent EGVB was similar in the warfarin and aspirin groups [0 versus 2 (5.1%); P = .535]. No postoperative active abdominal bleeding occurred in either group.

Comparison of coagulation function

Warfarin group versus aspirin group

Dynamic changes in perioperative coagulation function indicators on the day of admission and PODs 7, 30, and 90 were compared between the warfarin and aspirin groups by two-way repeated-measures analysis. There were no significant between-group differences in the PLT count (P = .154); however, the warfarin group had a significantly higher INR (P = .000). Compared with the aspirin group, the INR of the warfarin group was also significantly higher on POD 7 (2.10 ± 0.83 versus 1.29 ± 0.16; P < .0001), POD 30 (1.96 ± 0.91 versus 1.20 ± 0.12; P < .0001), and POD 90 (1.59 ± 0.34 versus 1.16 ± 0.11; P < .0001).

Non-PVST group versus PVST group on POD 90

Dynamic changes in perioperative coagulation function indicators on the day of admission and PODs 7, 30, and 90 were compared between the non-PVST and PVST groups on POD 90. There were no significant between-group differences in the PLT count (P = .329); however, the non-PVST group on POD 90 had a significantly higher INR (P = .000). Compared with the PVST group, the INR of the non-PVST group was also significantly higher on the day of admission (1.40 ± 0.15 versus 1.33 ± 0.12; P = .028), POD 7 (1.95 ± 0.86 versus 1.41 ± 0.37; P = .001), POD 30 (1.77 ± 0.93 versus 1.36 ± 0.38; P = .021), and POD 90 (1.44 ± 0.32 versus 1.28 ± 0.31; P = .034).

Non-MPVT group versus MPVT group on POD 90

Dynamic changes in perioperative coagulation function indicators on the day of admission and PODs 7, 30, and 90 were compared between the non-MPVT and MPVT groups on POD 90. There were no significant between-group differences in the PLT count (P = .425); however, the MPVT group had a higher INR on POD 90 (P = .021). Compared with the MPVT group, the INR of the non-MPVT group was significantly higher on POD 7 (1.78 ± 0.77 versus 1.35 ± 0.19; P < .001), POD 30 (1.62 ± 0.80 versus 1.31 ± 0.22; P = .012), and POD 90 (1.40 ± 0.35 versus 1.22 ± 0.18; P = .006).

Protective or risk factors for PVST on POD 90

Monofactorial analysis of 17 variables was made between the non-PVST and PVST groups on POD 90 (Table 3). Significant variables between the two groups included PT, INR, thickness of the spleen, portal vein diameter, and warfarin. The statistically significant variables were regarded as independent variables, and PVST on POD 90 was regarded as the dependent variable. Logistic multivariable regression was performed, and the statistically significant variables included preoperative thickness of the spleen, portal vein diameter, PT, and warfarin (Table 4).

Table 3.

Comparison of 17 Variables Between the Non-PVST and PVST Groups on Postoperative Day 90

Variable	non-PVST (n = 35)	PVST (n = 38)	P
Sex (male/female)	17/18	16/22	.579
Age, years	54.0 ± 9.4	52.9 ± 9.8	.642
Etiology (1/2/3/4/5/6^a)	19/3/1/1/6/5	22/5/2/1/4/4	.920
Child–Pugh classification (A/B)	24/11	30/8	.313
PLT (×10⁹/L)	45.9 ± 16.6	42.3 ± 14.4	.329
PT, seconds	17.08 ± 1.40	16.37 ± 1.07	.017
INR	1.40 ± 0.15	1.33 ± 0.12	.028
d-dimer, mg/L	0.69 (0.40–1.08)	0.77 (0.605–2.06)	.060
Longitudinal diameter of spleen, mm	175.3 ± 26.8	183.1 ± 24.6	.195
Thickness of spleen, mm	55.6 ± 10.2	59.9 ± 8.1	.049
Portal vein diameter, mm	13.4 ± 2.2	15.3 ± 1.9	<.001
Splenic vein diameter, mm	11.1 ± 2.2	11.6 ± 2.6	.323
Velocity of portal blood flow, cm/second	13.3 ± 3.7	14.3 ± 3.4	.216
Duration of surgery, minutes	172.0 ± 40.9	182.6 ± 37.0	.250
Intraoperative blood loss, mm	135.7 ± 150.8	124.2 ± 150.3	.745
Volume of intraoperative blood transfused, mL	8.6 ± 50.7	28.9 ± 125.0	.372
Warfarin	26 (74.3)	8 (21.1)	<.0001

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

Hepatitis B/hepatitis C/schistosomiasis/alcohol/autoimmunity/idiopathic cirrhosis.

Table 4.

Outcome of Logistic Multivariate Regression

Independent variables	B	SE	Wald	df	Sig	Exp(B)	95% CI
Thickness of spleen, mm	0.113	0.046	6.157	1	0.013	1.120	1.024–1.225
Portal vein diameter, mm	0.755	0.271	7.762	1	0.005	2.127	1.251–3.617
PT, seconds	−1.005	0.337	8.878	1	0.003	0.366	0.189–0.709
Warfarin	−3.624	0.939	14.889	1	0.000	0.027	0.004–0.168

CI, confidence interval.

Discussion

LSD is less invasive than OSD and is being accepted as a feasible, effective, and safe surgical procedure for patients with concurrent liver cirrhosis, portal hypertensive bleeding, and hypersplenism.^17,23 However, the incidence of PVST is higher following LSD than OSD.¹⁷ As a potentially fatal complication, PVST can aggravate liver damage and increase the risk of gastrointestinal bleeding and intestinal necrosis.²⁴

PVST is a frequent event in patients with advanced cirrhosis because of changes in the portal vein blood flow dynamics, included decreased portal vein velocity, and increased portal vein diameter.^25,26 The high incidence of PVST after OSD is mainly due to the following two possible reasons: splenectomy causes slower portal vein velocity and the rapid increase in the PLT count promotes thrombus formation. The mechanism by which LSD contributes to a higher rate of PVST than OSD is not yet clear. Some factors that may contribute to the formation of PVST include CO₂ pneumoperitoneum, the technique used for splenic vessel ligation (stapled vascular transection en masse), and use of the LigaSure vessel-sealing device (Covidien, Boulder, CO) or harmonic shears (Ethicon, Cincinnati, OH), both of which may lead to venous intimal damage by heat energy or oscillation. The effects on the vessels and tissues by these processes may be potential factors that contribute to PVST.

Preoperative predictors of postoperative PVST have been investigated in some studies. Kinjo et al.¹³ reported that an increased spleen vein diameter and low white cell count were significant independent risk factors for PVST after OS in patients with cirrhosis and portal hypertension. Zhang et al.¹⁵ found that the blood velocity and portal vein diameter were the most accurate predictors of PVST after OSD in patients with hepatitis B cirrhosis-related portal hypertension.

Most of the above-mentioned factors leading to PVST are intrinsic or cannot be prevented. An effective treatment strategy is needed to prevent postoperative PVST in patients with cirrhotic portal hypertension.

If PVST cannot be prevented in a timely manner, it can progress to fibrosis, making drug-induced thrombolysis difficult. Furthermore, severe SVT may progress to portal vein thrombosis²⁷ or even disastrous superior mesenteric vein thrombosis.²⁸ Interventional and surgical methods to treat refractory PVST are complex and associated with relatively high risks. Anticoagulation and antiplatelet agglutination agents should be administered as early as possible to prevent PVST. However, the drug type, dosage, and timing have not been standardized. The most commonly used anticoagulation and antiplatelet agglutination agents include oral aspirin, clopidogrel bisulfate, and dipyridamole. Aspirin and clopidogrel bisulfate, however, are reportedly ineffective for prophylaxis of postoperative PVST.²¹

Various protocols to prevent PVST have been proposed, but the most effective protocols varied because the duration and doses of these drugs varied.^29,30 Therefore, no generally acceptable PSVT prophylactic regimen has been established for all patients.^30,31

Theoretically, because of the presence of intrinsic coagulation disorders and the high risk of postoperative bleeding in the operative area, preventive use of anticoagulants against PSVT in patients with cirrhotic portal hypertension early after surgery would counter the dilemma of bleeding. However, previous studies have demonstrated that early anticoagulant treatment in these patients is a safe and effective protocol with which to prevent PSVT.^21,32,33

Two previous studies found that LMWH is an effective and safe agent with which to reduce the incidence of PSVT in patients who undergo splenectomy with gastroesophageal devascularization.^32,33 The limitation of these two studies is that the duration of the prophylactic anticoagulation regimen and monitoring of PVST did not extend beyond 1 month, which may be too short.

To the best of our knowledge, this is the first study to investigate oral warfarin for the prevention of PVST after LSD for cirrhotic patients with portal hypertension. Very few studies of PSVT have involved a prophylactic anticoagulation regimen that extends beyond 7 days, which makes our 3-month study unique.

Warfarin is an anticoagulant that suppresses the synthesis of the specific vitamin K-dependent coagulation factors, II, VII, IX, and X, as well as the two vitamin K-dependent plasma proteins, C and S. The advantages of warfarin are its low cost and high patient compliance.

Warfarin is the predominant oral anticoagulant used for the prevention of recurrent venous thrombus embolism.³⁴ It is recommended that warfarin treatment for venous thrombus embolism be continued for a minimum of 3 months.³⁵

How long should oral warfarin therapy be maintained to prevent PVST after LSD for cirrhotic patients with portal hypertension?

In the aspirin group of the present study, the incidence of postoperative PVST increased from POD 7 (46.2%) to POD 30 (74.4%) and POD 90 (76.9%). Furthermore, the differences between PODs 7 and 30 (P = .011) and between PODs 30 and 90 (P = .005) were statistically significant. Likewise, in the aspirin group, the incidence of postoperative MPVT increased from POD 7 (17.9%) to POD 30 (30.8%) and POD 90 (33.3%). Postoperative coagulation function (INR) also gradually and markedly improved, suggesting that the liver function benefits from the operation. Splenectomy is a proven method with which to improve coagulation function.^35,36 In the aspirin group, significant differences were noted in all comparisons of the perioperative INR between PODs 0 and 7 (1.36 ± 0.14 versus 1.29 ± 0.16; P < .0001), between PODs 7 and 30 (1.29 ± 0.16 versus 1.20 ± 0.12; P < 0.0001), and between PODs 30 and 90 (1.20 ± 0.12 versus 1.16 ± 0.11; P < .0001). The above-mentioned changes may illustrate that the ongoing increase in the incidences of postoperative PVST and MPVT during the first 3 months postoperatively accompanies continuous improvement in the INR. The improved INR may contribute to the progression of thrombosis and should be regulated by anticoagulation therapy.

Throughout the 3-month follow-up, the fastigium of PVST in the aspirin group appeared on POD 90 (Table 2), and the incidence of PVST on POD 90 only slightly exceeded that on POD 30. It was similar to the incidence of MPVT in the aspirin group (Table 2). Thus, we suggest a 3-month minimum warfarin treatment duration to upregulate the INR. Possibly, due to the effects of warfarin treatment, the fastigium of PVST and MPVT in the warfarin group appeared on POD 30, not POD 90 (Table 2).

Is it safe to maintain the target INR at 2.0–2.5 for postoperative patients with cirrhotic portal hypertension?

According to past clinical experience, this criterion is only fit for noncirrhotic patients. In this study, oral warfarin with a target INR of 2.0–2.5 was safe. It was difficult to maintain an INR always ranging from 2.0 to 2.5 because of the improved coagulation function after splenectomy.^36,37 No patients in the warfarin group developed bleeding complications during the 3-month follow-up.

The highest INR in the warfarin group on POD 7 was 2.10 ± 0.83 (∼2.0). In the warfarin group, the interquartile range of the INR on PODs 7, 30, and 90 was 1.50–2.34, 1.49–2.07, and 1.38–1.75. The entire range of the INR on PODs 7, 30, and 90 was 1.17–4.72, 1.07–4.65, and 1.05–2.31, respectively.

An adequately high INR may effectively prevent thrombosis. In the present study, both between the PVST and non-PVST groups on POD 90 and between the MPVT and non-MPVT groups on POD 90, the non-PVST group and non-MPVT group had a higher PT-INR level than their respective opposite groups on PODs 7, 30, and 90.

If the INR exceeded 3.0, vitamin K1 was administered and the warfarin dose was decreased. The PT-INR was then monitored daily until the INR returned to 2.0–2.5.

Curative effect of oral warfarin

Compared with the aspirin group, the warfarin group exhibited a lower incidence of PVST on PODs 30 and 90 (Table 2), MPVT on POD 90 (Table 2), and SVT on PODs 7, 30, and 90 (Table 2). These data suggest that thrombosis can be managed, but that certain duration is needed to resolve thrombosis by oral warfarin. A greater curative effect of warfarin was found on POD 90. The incidence of both PVST (23.5% versus 50.0%; P = .024) (Table 2) and MPVT (8.8% versus 35.3%; P = .008) (Table 2) on POD 90 was lower than that on POD 30 in the warfarin group. In the non-PVST group on POD 90, 26/35 (74.3%) received oral warfarin, while 8/38 (21.1%) received oral warfarin in the PVST group on POD 90.

Compared with the aspirin group, the warfarin group achieved more complete recanalization of PVST [9/17 (52.9%) versus 3/29 (10.3%); P = .005] and more complete recanalization of MPVT [9/12 (75.0%) versus 3/12 (25.0%); P = .039] from POD 30 to 90.

Based on the above-mentioned data, we can conclude that the warfarin group attained a better curative effect for prevention of thrombosis than did the aspirin group.

A previous study²¹ reported that early anticoagulation with LMWH is safe and effective in patients who undergo LSD for cirrhosis with portal hypertension. In that study, color Doppler ultrasound examination to detect thrombosis was only performed on PODs 3 and 7. The conventional anticoagulation group received 500 mL of intravenous low-molecular-weight dextran once daily for the first 7 days after surgery, followed by 100 mg of once-daily oral aspirin or 75 mg of clopidogrel bisulfate (Techno) for 30 days. The incidence of PVST and MPVT was 50.0% (40/80) and 15.0% (12/80), respectively, similar to the present results in the aspirin group on POD 7 [18/39 (46.2%) and 7/39 (17.9%), respectively]. The incidence of PVST in the warfarin group on POD 90 in the present study [8/34 (23.5%)] was superior to that in the LMWH group [42/139 (30.2%)] in the above-mentioned previous study.²¹ The difference between groups was not statistically significant, probably because of the small sample size. In fact, the INR in the warfarin group on POD 30 (1.96 ± 0.91), especially on POD 90 (1.59 ± 0.34), deviated from the target level of 2.0–2.5. If a better INR had been attained by managing the dose of oral warfarin, a lower incidence of PVST may have been achieved.

Multiple logistic regression analysis was performed to identify the most important factors for predicting PSVT on POD 90 (Table 4). The preoperative thickness of the spleen and the portal vein diameter were significant risk factors for PVST on POD 90, while the preoperative PT and warfarin were two independent protective factors for PVST on POD 90. There is positive correlation between the thickness and the splenic weight. Splenic weight was reported as a predictor of PVST after LS.³⁸ Li et al.³⁹ reported that prolonged PT was an independent risk factor of PVST after LS in patients with liver cirrhosis. Cirrhotic patients with prolonged preoperative PT also had prolonged postoperative PT, which may contribute to the lower incidence of PVST. One previous study also reported that enlarged portal vein diameter was an independent risk factor for PVST occurrence after OSD.⁴⁰ To some degree, an enlarged portal vein diameter reflects the degree of portal hypertension. The wider the portal vein diameter, the more severe portal hypertension is. The most important of the four factors was oral warfarin. The risk of PVST on POD 90 in a patient taking oral aspirin was 37 (1/0.027) times higher compared with a patient taking oral warfarin.

In conclusion, early anticoagulant therapy using warfarin accompanied by LMWH and dipyridamole is safe and effective for early prevention of PVST in patients with cirrhosis and portal hypertension after LSD. The warfarin group showed a significantly lower incidence of PVST (especially MPVT) than did the aspirin group without increasing the risk of bleeding complications. Randomized prospective trials with a longer follow-up period are required to confirm these findings.

Footnotes

Acknowledgments

This work was supported by the scientific research subject of Jiangsu Province Health Department (No. H201452) and six kinds of talents of Jiangsu Province (No. WSW-087).

Disclosure Statement

No competing financial interests exist.

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