BioMed Research International
Volume 2020 (2020), Article ID 8172673, 9 pages
https://doi.org/10.1155/2020/8172673

Research Article

No Association between Ischemic Stroke and Portal Vein Thrombosis in Liver Cirrhosis

Kexin Zheng,1,2 Xiaozhong Guo,¹ Fangfang Yi,1,3 Le Wang,1,3 Andrea Mancuso,⁴ and Xingshun Qi¹

¹Liver Cirrhosis Study Group, Department of Gastroenterology, General Hospital of Northern Theater Command (Formerly General Hospital of Shenyang Military Area), Shenyang, Liaoning Province, China
²Postgraduate College, Jinzhou Medical University, Jinzhou, Liaoning Province, China
³Postgraduate College, Dalian Medical University, Dalian, Liaoning Province, China
⁴Medicina Interna 1, Azienda di Rilievo Nazionale ad Alta Specializzazione Civico-Di Cristina-Benfratelli, Piazzale Leotta 4, 90100 Palermo, Italy

Correspondence should be addressed to Xiaozhong Guo; guo_xiao_zhong@126.com and Xingshun Qi; xingshunqi@126.com

Received 28 February 2020; Revised 17 May 2020; Accepted 11 June 2020; Published 2 July 2020

Academic Editor: Eberval G. Figueiredo

Copyright © 2020 Kexin Zheng et al. This is an open access article distributed under the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.

Abstract.

Background and Aims. There seems to be a higher risk of ischemic stroke and portal vein thrombosis in liver cirrhosis. Both of them may be associated with hypercoagulability. We aim to explore the association between ischemic stroke and portal vein thrombosis in liver cirrhosis. Study Design and Methods. We selected patients from our prospectively established database of liver cirrhosis from December 2014 to July 2019. The difference between patients with and without stroke was compared. A 1 : 1 propensity score matching (PSM) analysis was performed to adjust the effect of age, sex, Child-Pugh score, and MELD score on our statistical results. Results. There were 349 cirrhotic patients in the cross-sectional study. The prevalence of stroke, ischemic stroke, hemorrhagic stroke, and portal vein thrombosis was 8.88% (31/349), 8.31% (29/349), 1.15% (4/349), and 28.65% (100/349) in liver cirrhosis, respectively. Patients with ischemic stroke were significantly older and had significantly higher proportions of alcohol abuse, smoking, and arterial hypertension and higher levels of white blood cell and low-density lipoprotein. However, statistical analyses with and without PSM did not find any significant association between ischemic stroke and portal vein thrombosis in patients with liver cirrhosis. Conclusion. Ischemic stroke might not be associated with portal vein thrombosis in liver cirrhosis.

1. Introduction

Stroke, an acute cerebrovascular disease, is the leading cause of death and disability worldwide, especially in Asia [1]. It has been traditionally considered that stroke, especially atherosclerotic ischemic stroke, is closely associated with hypercoagulability, such as increased homocysteine and lipoprotein(a) and antiphospholipid antibodies [2]. Liver cirrhosis, which often has an increased level of factor VIII (FVIII) and decreased level of protein C (PC) and mean lifetime of platelet, has been also considered as a potential risk factor of stroke [3, 4]. Besides, it is associated with the development of venous thromboembolism, including portal vein thrombosis [5].

Development of stroke and portal vein thrombosis in liver cirrhosis seems to share several common pathophysiological mechanisms or risk factors. First, both of them relate to the hypercoagulability of cirrhosis [3], which is characterized as reduced PC in combination with increased FVIII [6]. Second, both stroke and portal vein thrombosis relate to portal hypertension. Reduced portal vein flow velocity and portosystemic collateral shunt are common characteristics of portal hypertension, which aggravate the development of portal vein thrombosis [7]. Ascites and esophageal variceal bleeding are major clinical manifestations of portal hypertension, which result in the decrease of effective circulating blood volume and hypovolemia of organs, thereby leading to ischemic stroke [8]. Third, diabetic patients have approximately 2-4 times higher risk of ischemic stroke than those with normal glucose levels [9]. Meanwhile, diabetes is also an independent risk factor of portal vein thrombosis [10]. Fourth, antiphospholipid syndrome may increase the risk of ischemic stroke as well as portal vein thrombosis. Irregular thickening of the valve leaflets secondary to antiphospholipid syndrome and lupus anticoagulants are significant risk factor of stroke [11]. Meanwhile, anticardiolipin antibodies levels were higher in liver cirrhosis with portal vein thrombosis than that without portal vein thrombosis [12, 13]. Fifth, Helicobacter pylori not only acts as a promoter of antiphospholipid syndrome through chronic inflammation [14] but also stimulates the production of plasminogen activator inhibitor-2, which has an effect on increasing the risk of ischemic stroke and portal vein thrombosis [15]. Sixth, methylenetetrahydrofolate reductase (MTHFR) mutation is a common risk factor of stroke and portal vein thrombosis, which relates to endothelial damage [16]. MTHFR activity is reduced in the patients with MTHFR mutations, thereby leading to the deficiency of folate and hyperhomocysteinemia. MTHFR is responsible for catalyzing the reduction of 5,10-methylenetetrahydrofolate to 5-methyltetrahydrofolate in the folate cycle, which further produces the active form of folate for the remethylation of homocysteine to methionine [17]. There is a significant association between hyperhomocysteinemia and stroke [18]. An elevated homocysteine concentration significantly increases the risk of stroke [19]. Folic acid supplementation is effective in stroke prevention [20]. And MTHFR A1298C mutation is associated with increased risk of ischemic stroke [21]. On the other hand, MTHFR C677T mutation may increase the risk of portal vein thrombosis in cirrhotic patients [22]. The prevalence of hyperhomocysteinemia is significantly higher in cirrhotic patients with portal vein thrombosis than those without portal vein thrombosis [22]. Taken together, we hypothesized that cirrhotic patients with stroke might have an increased risk of portal vein thrombosis. Herein, this retrospective study was aimed at elucidating this issue.

2. Methods

2.1. Study Design

The study population was selected from our prospectively established database of cirrhotic patients without malignancy of the Department of Gastroenterology of our hospital from December 2014 to July 2019. All included patients must undergo abdominal enhanced computed tomography or magnetic resonance and endoscopy at their first enrollment. Age, sex, and the etiologies of liver cirrhosis were not limited. Repeated admissions of the same patients were excluded. Patients with abdominal surgery, including splenectomy, and splenic arterial embolization were excluded. Patients in whom a history of stroke cannot be accurately evaluated were excluded. Patients in whom the location of portal vein thrombosis cannot be evaluated due to missing images were also excluded. The study protocol was approved by the Medical Ethics Committee of our hospital. The ethical approval number was k(2019)39. The patient’s informed consent was not required in our retrospective study.

2.2. Medical Data

The data were collected as follows.

(1)Demographic information: age and sex(2)Systolic and diastolic blood pressure at admission(3)Etiologies of liver diseases: hepatitis B virus (HBV), hepatitis C virus (HCV), alcohol abuse, drug related liver diseases, Budd-Chiari syndrome, and autoimmune liver diseases, etc.(4)Clinical presentations at admission: hepatic encephalopathy, acute gastrointestinal bleeding, and ascites(5)Medical history: venous thrombus, hematological diseases, diabetes mellitus, arterial hypertension, smoking, and cardiac diseases(6)Laboratory tests: red blood cell, hemoglobin, white blood cell, platelet, total bilirubin, direct bilirubin, indirect bilirubin, albumin, alanine aminotransferase, aspartate aminotransferase, alkaline phosphatase, γ-glutamyl transpeptidase, blood urea nitrogen, serum, creatinine, potassium, sodium homocysteine, total cholesterol, triglyceride, high-density lipoprotein, low-density lipoprotein, lipoprotein α, prothrombin time, international normalized ratio (INR), activated partial thromboplastin time, D-dimer, antithrombin III, PC activity, and PS activity(7)Child-Pugh and model for the end-stage liver diseases (MELD) score

2.3. Definitions

Stroke was defined as previous history of stroke as well as a diagnosis of stroke at their enrollment. Type of stroke was divided into ischemic and hemorrhagic stroke according to previous medical history, clinical manifestations, and/or the results of brain imaging examination. Location of portal vein thrombosis was determined by our study group via the images of enhanced computed tomography or magnetic resonance. Portal system vessels include left portal vein (LPV), right portal vein (RPV), main portal vein (MPV), confluence of superior mesenteric vein (SMV) and splenic vein (SV), SMV, and SV.

2.4. Statistical Analyses

Continuous and categorical variables were expressed by median (range) and frequency (percentage), respectively. The difference between patients with and without stroke was compared using Mann-Whitney test and test, as appropriate. A 1 : 1 propensity score matching (PSM) analysis was performed to adjust the effect of age, sex, Child-Pugh score, and MELD score on our statistical results. If a value was less than 0.05, it would be considered statistically significant. SPSS statistical software, version 22.0 (IBM Corp, Armonk, NY, USA), was employed to perform statistical analyses.

3. Results

3.1. Patients’ Characteristics

Overall, 349 cirrhotic patients were included, of whom 31 (8.88%) had stroke and 318 did not have stroke. Among the 31 patients with stroke, 29 (8.31%), 4 (1.15%), and 2 (0.57%) patients had ischemic stroke, hemorrhagic stroke, and hemorrhagic combined with ischemic stroke, respectively. The prevalence of portal vein thrombosis was 28.65% (100/349). The prevalence of thrombosis within LPV, RPV, MPV, confluence of SMV and SV, SMV, and SV was 8.31% (29/349), 9.46% (33/349), 16.05% (56/349), 11.46% (40/349), 15.19% (53/349), and 3.72% (13/349), respectively.

3.2. Comparison between Liver Cirrhosis with and without Stroke

Compared with the patients without stroke, those with stroke were significantly older (60.21 versus 54.21 years, ) and had significantly higher proportions of alcohol abuse (64.5% versus 43.7%, ), smoking (67.7% versus 42.5%, ), and arterial hypertension (38.7% versus 12.9%, ) and higher levels of white blood cell (4.50 versus /L, ) and low-density lipoprotein (2.12 versus 1.65 mmol/L, ) (Table 1). There was no difference in the prevalence of portal vein thrombosis and location of portal vein thrombosis between patients with and without stroke.

Table 1: Comparison between patients with and without stroke.

Variables
Stroke
No stroke
value

No. pts
Median (range) or frequency (percentage)
No. pts
Median (range) or frequency (percentage)

Age (years)
31
60.21 (38.72-77.30)
318
54.21 (20.57-88.73)
0.003

Gender (male)
31
25 (80.6%)
318
230 (72.3%)
0.319

Systolic blood pressure (mmHg)
31
125.00 (90.00-173.00)
317
122.00 (83.00-193.00)
0.594

Diastolic blood pressure (mmHg)
31
75.00 (50.00-117.00)
317
75.00 (34.00-118.00)
0.844

Etiology of liver diseases

    Hepatitis B virus infection
31
10 (32.3%)
318
125 (39.3%)
0.442

    Hepatitis C virus infection
31
1 (3.2%)
318
20 (6.3%)
0.494

    Alcohol abuse
31
20 (64.5%)
318
139 (43.7%)
0.026

    Drug related
31
4 (12.9%)
318
21 (6.6%)
0.194

    Budd-Chiari syndrome
31
0 (0.0%)
318
1 (0.3%)
0.755

    Autoimmune liver diseases
31
0 (0.0%)
318
22 (6.9%)
0.130

Clinical presentations at admission

    Hepatic encephalopathy
31
1 (3.2%)
318
8 (2.5%)
0.812

    Acute gastrointestinal bleeding
31
9 (29.0%)
318
101 (31.8%)
0.755

    Ascites (no/mild/moderate-severe)
31
16 (51.6%)/8 (25.8%)/7 (22.6%)
318
127 (39.9%)/108 (34.0%)/83 (26.1%)
0.440

History

    History of venous thrombus
31
0 (0.0%)
318
7 (2.2%)
0.404

    History of hematological diseases
31
1 (3.2%)
318
5 (1.6%)
0.499

    History of diabetes mellitus
31
8 (25.8%)
318
51 (16.0%)
0.166

    History of arterial hypertension
31
12 (38.7%)
318
41 (12.9%)
<0.001

    History of smoking
31
21 (67.7%)
318
135 (42.5%)
0.007

    History of cardiac diseases
31
5 (16.1%)
318
23 (7.2%)
0.082

Laboratory tests

    Red blood cell (10¹²/L)
31
3.33 (1.15-5.20)
318
3.27 (1.45-5.46)
0.432

    Hemoglobin (g/L)
31
101.00 (37.00-174.00)
318
92.50 (28.00-156.00)
0.104

    White blood cell (10⁹/L)
31
4.50 (1.30-22.70)
318
3.40 (0.70-20.80)
0.001

    Platelet (10⁹/L)
31
86.00 (37.00-377.00)
318
73.00 (19.00-470.00)
0.169

    Total bilirubin (μmol/L)
31
21.10 (5.70-132.70)
318
22.00 (5.20-281.10)
0.775

    Direct bilirubin (μmol/L)
31
8.90 (2.00-78.20)
318
9.45 (2.00-210.40)
0.920

    Indirect bilirubin (μmol/L)
31
11.90 (3.60-76.00)
318
11.30 (3.20-93.80)
0.677

    Albumin (g/L)
31
32.50 (22.10-44.50)
316
32.35 (14.20-50.60)
0.482

    Alanine aminotransferase (U/L)
31
20.06 (7.74-176.68)
318
24.34 (4.23-613.24)
0.396

    Aspartate aminotransferase (U/L)
31
30.73 (9.74-143.00)
318
34.33 (9.63-761.63)
0.824

    Alkaline phosphatase (U/L)
31
88.23 (28.83-337.00)
318
94.40 (31.00-983.93)
0.641

    γ-Glutamyl transpeptidase (U/L)
31
70.00 (10.00-1779.18)
318
42.64 (7.54-1283.02)
0.121

    Blood urea nitrogen (mmol/L)
31
5.85 (3.52-47.25)
314
5.31 (0.64-24.80)
0.226

    Serum creatinine (μmol/L)
31
70.90 (42.82-267.63)
314
64.07 (23.83-178.55)
0.228

    Potassium (mmol/L)
31
4.01 (2.80-5.41)
317
3.86 (2.42-5.28)
0.066

    Sodium (mmol/L)
31
138.00 (134.10-145.50)
317
138.90 (118.00-152.90)
0.574

    Homocysteine (μmol/L)
16
10.49 (6.70-31.79)
170
9.16 (1.59-102.81)
0.145

    Total cholesterol (mmol/L)
20
3.68 (1.82-6.58)
208
3.11 (1.14-6.29)
0.148

    Triglyceride (mmol/L)
20
0.83 (0.41-6.22)
208
0.85 (0.35-4.81)
0.661

    High-density lipoprotein (mmol/L)
20
0.93 (0.47-1.39)
208
0.94 (0.24-2.29)
0.766

    Low-density lipoprotein (mmol/L)
20
2.12 (0.99-4.37)
208
1.65 (0.47-4.06)
0.013

    Lipoprotein α (mg/L)
20
88.70 (17.90-466.40)
208
63.20 (3.60-911.40)
0.108

    Prothrombin time (seconds)
31
15.30 (12.70-20.40)
314
15.70 (10.30-28.00)
0.188

    International normalized ratio
31
1.23 (0.99-1.75)
314
1.27 (0.89-2.77)
0.164

    Activated partial thromboplastin time (seconds)
31
40.20 (19.80-53.80)
314
39.90 (23.10-71.30)
0.808

    D-dimer (mg/L)
19
1.32 (0.16-10.56)
252
0.86 (0.10-46.17)
0.873

    Antithrombin III (%)
11
65.30 (40.00-84.00)
118
63.00 (21.00-123.00)
0.933

    Protein C activity (%)
6
57.30 (49.80-75.10)
54
59.65 (24.00-119.30)
0.721

    Protein S activity (%)
6
61.55 (55.60-73.30)
54
63.50 (20.70-123.60)
0.873

Child-Pugh score
31
7.00 (5.00-10.00)
313
7.00 (5.00-13.00)
0.837

MELD score
31
10.46 (7.23-18.00)
312
10.41 (6.43-30.03)
0.736

Portal vein thrombosis
31
8 (25.8%)
318
92 (28.9%)
0.713

    LPV

4 (12.9%)

25 (7.9%)
0.332

    RPV

2 (6.5%)

31 (9.7%)
0.549

    MPV

4 (12.9%)

52 (16.4%)
0.617

    Confluence of SMV and SV

5 (16.1%)

35 (11.0%)
0.393

    SMV

2 (6.5%)

51 (16.0%)
0.156

    SV

0 (0.0%)

13 (4.1%)
0.251

No. pts: number of patients; MELD: model for the end-stage liver diseases; LPV: left portal vein; RPV: right portal vein; MPV: main portal vein; SMV: superior mesenteric vein; SV: splenic vein.

3.3. Comparison between Cirrhotic Patients with Ischemic Stroke and Those without Stroke

Compared with the patients without stroke, those with ischemic stroke were significantly older (61.08 versus 54.21 years, ) and had significantly higher proportions of alcohol abuse (65.5% versus 43.7%, ), smoking (69.0% versus 42.5%, ), and arterial hypertension (37.9% versus 12.9%, ) and higher levels of white blood cell (4.90 versus /L, ), potassium (4.05 versus 3.86 mmol/L, ), and low-density lipoprotein (2.12 versus 1.65 mmol/L, ) (Table 2). There was no significant difference in the prevalence of portal vein thrombosis and location of portal vein thrombosis between patients with and without stroke.

Table 2: Comparison between patients with ischemic stroke and those without stroke.

Variables
Ischemic stroke
No stroke
value

No. pts
Median (range) or frequency (percentage)
No. pts
Median (range) or frequency (percentage)

Age (years)
29
61.08 (38.72-77.30)
318
54.21 (20.57-88.73)
0.002

Gender (male)
29
23 (79.3%)
318
230 (72.3%)
0.418

Systolic blood pressure (mmHg)
29
124.00 (90.00-173.00)
317
122.00 (83.00-193.00)
0.975

Diastolic blood pressure (mmHg)
29
73.00 (50.00-108.00)
317
75.00 (34.00-118.00)
0.700

Etiology of liver diseases

    Hepatitis B virus infection
29
10 (34.5%)
318
125 (39.3%)
0.610

    Hepatitis C virus infection
29
1 (3.4%)
318
20 (6.3%)
0.539

    Alcohol abuse
29
19 (65.5%)
318
139 (43.7%)
0.024

    Drug related
29
4 (13.8%)
318
21 (6.6%)
0.152

    Budd-Chiari syndrome
29
0 (0.0%)
318
1 (0.3%)
0.762

    Autoimmune liver diseases
29
0 (0.0%)
318
22 (6.9%)
0.143

Clinical presentations at admission

    Hepatic encephalopathy
29
1 (3.4%)
318
8 (2.5%)
0.762

    Acute gastrointestinal bleeding
29
8 (27.6%)
318
101 (31.8%)
0.643

    Ascites (no/mild/moderate-severe)
29
15 (51.7%)/7 (24.1%)/7 (24.1%)
318
127 (39.9%)/108 (34.0%)/83 (26.1%)
0.424

History

    History of venous thrombus
29
0 (0.0%)
318
7 (2.2%)
0.420

    History of hematological diseases
29
1 (3.4%)
318
5 (1.6%)
0.458

    History of diabetes mellitus
29
8 (27.6%)
318
51 (16.0%)
0.113

    History of arterial hypertension
29
11 (37.9%)
318
41 (12.9%)
<0.001

    History of smoking
29
20 (69.0%)
318
135 (42.5%)
0.006

    History of cardiac diseases
29
5 (17.2%)
318
23 (7.2%)
0.058

Laboratory tests

    Red blood cell (10¹²/L)
29
3.33 (1.15-5.20)
318
3.27 (1.45-5.46)
0.471

    Hemoglobin (g/L)
29
101.00 (37.00-174.00)
318
92.50 (28.00-156.00)
0.126

    White blood cell (10⁹/L)
29
4.90 (1.30-22.70)
318
3.40 (0.70-20.80)
<0.001

    Platelet (10⁹/L)
29
90.00 (37.00-377.00)
318
73.00 (19.00-470.00)
0.068

    Total bilirubin (μmol/L)
29
25.10 (5.70-132.70)
318
22.00 (5.20-281.10)
0.606

    Direct bilirubin (μmol/L)
29
9.00 (2.00-78.20)
318
9.45 (2.00-210.40)
0.892

    Indirect bilirubin (μmol/L)
29
12.40 (3.60-76.00)
318
11.30 (3.20-93.80)
0.576

    Albumin (g/L)
29
31.10 (22.10-44.50)
316
32.35 (14.20-50.60)
0.401

    Alanine aminotransferase (U/L)
29
21.33 (7.74-176.68)
318
24.34 (4.23-613.24)
0.643

    Aspartate aminotransferase (U/L)
29
31.44 (9.74-143.00)
318
34.33 (9.63-761.63)
0.902

    Alkaline phosphatase (U/L)
29
92.49 (28.83-337.00)
318
94.40 (31.00-983.93)
0.921

    γ-Glutamyl transpeptidase (U/L)
29
70.00 (10.00-1779.18)
318
42.64 (7.54-1283.02)
0.073

    Blood urea nitrogen (mmol/L)
29
5.82 (3.52-47.25)
314
5.31 (0.64-24.80)
0.271

    Serum creatinine (μmol/L)
29
70.90 (42.82-267.63)
314
64.07 (23.83-178.55)
0.253

    Potassium (mmol/L)
29
4.05 (2.80-5.41)
317
3.86 (2.42-5.28)
0.047

    Sodium (mmol/L)
29
137.90 (134.10-145.50)
317
138.90 (118.00-152.90)
0.430

    Homocysteine (μmol/L)
15
10.47 (6.70-31.79)
170
9.16 (1.59-102.81)
0.179

    Total cholesterol (mmol/L)
19
3.77 (1.82-6.58)
208
3.11 (1.14-6.29)
0.104

    Triglyceride (mmol/L)
19
0.86 (0.47-6.22)
208
0.85 (0.35-4.81)
0.414

    High-density lipoprotein (mmol/L)
19
0.92 (0.47-1.39)
208
0.94 (0.24-2.29)
0.762

    Low-density lipoprotein (mmol/L)
19
2.12 (0.99-4.37)
208
1.65 (0.47-4.06)
0.008

    Lipoprotein α (mg/L)
19
91.70 (17.90-466.40)
208
63.20 (3.60-911.40)
0.114

    Prothrombin time (seconds)
29
15.30 (12.70-20.40)
314
15.70 (10.30-28.00)
0.198

    International normalized ratio
29
1.23 (0.99-1.75)
314
1.27 (0.89-2.77)
0.170

    Activated partial thromboplastin time (seconds)
29
40.00 (19.80-53.80)
314
39.90 (23.10-71.30)
0.952

    D-dimer (mg/L)
19
1.32 (0.16-10.56)
252
0.86 (0.10-46.17)
0.873

    Antithrombin III (%)
11
65.30 (40.00-84.00)
118
63.00 (21.00-123.00)
0.933

    Protein C activity (%)
6
57.30 (49.80-75.10)
54
59.65 (24.00-119.30)
0.721

    Protein S activity (%)
6
61.55 (55.60-73.30)
54
63.50 (20.70-123.60)
0.873

Child-Pugh score
29
7.00 (5.00-10.00)
313
7.00 (5.00-13.00)
0.749

MELD score
29
10.46 (7.23-18.00)
312
10.41 (6.43-30.03)
0.892

Portal vein thrombosis
29
7 (24.1%)
318
92 (28.9%)
0.584

    LPV

3 (10.3%)

25 (7.9%)
0.638

    RPV

2 (6.9%)

31 (9.7%)
0.616

    MPV

4 (13.8%)

52 (16.4%)
0.720

    Confluence of SMV and SV

5 (17.2%)

35 (11.0%)
0.314

    SMV

2 (6.9%)

51 (16.0%)
0.190

    SV

0 (0.0%)

13 (4.1%)
0.267

No. pts: number of patients; MELD: model for the end-stage liver diseases; LPV: left portal vein; RPV: right portal vein; MPV: main portal vein; SMV: superior mesenteric vein; SV: splenic vein.

3.4. PSM Analysis between Cirrhotic Patients with Ischemic Stroke and Those without Stroke

Twenty-eight patients were matched in each group after a 1 : 1 PSM analysis (Table 3). There was no significant difference in demographics, etiology of liver disease, laboratory tests, clinical presentations, Child-Pugh score, and MELD score between the two groups. Notably, we still did not find any significant association between ischemic stroke and portal vein thrombosis.

Table 3: Characteristics of cirrhotic patients with ischemic stroke and those without stroke after propensity score matching.

Variables
Overall ()
Ischemic stroke ()
No stroke ()
value

Age (years)
59.68 (35.18-77.30)
60.65 (38.72-77.30)
58.44 (35.18-75.72)
0.258

Gender (male)
47 (83.9%)
22 (78.6%)
25 (89.3%)
0.275

Systolic blood pressure (mmHg)
125.00 (83.00-173.00)
124.50 (90.00-173.00)
126.50 (83.00-158.00)
0.491

Diastolic blood pressure (mmHg)
75.50 (44.00-108.00)
72.00 (50.00-108.00)
81.00 (44.00-107.00)
0.161

Etiology of liver diseases

    Hepatitis B virus infection
23 (41.1%)
10 (35.7%)
13 (46.4%)
0.415

    Hepatitis C virus infection
1 (1.8%)
1 (3.6%)
0 (0.0%)
0.313

    Alcohol abuse
35 (62.5%)
18 (64.3%)
17 (60.7%)
0.783

    Drug related
6 (10.7%)
4 (14.3%)
2 (7.1%)
0.388

    Budd-Chiari syndrome
0 (0.0%)
0 (0.0%)
0 (0.0%)
NA

    Autoimmune liver diseases
1 (1.8%)
0 (0.0%)
1 (3.6%)
0.313

Clinical presentations at admission

    Hepatic encephalopathy
2 (3.6%)
1 (3.6%)
1 (3.6%)
1.000

    Acute gastrointestinal bleeding
13 (23.2%)
7 (25.0%)
6 (21.4%)
0.752

    Ascites (no/mild/moderate-severe)
27 (48.2%)/14 (25.0%)/15 (26.8%)
15 (53.6%)/6 (21.4%)/7 (25.0%)
12 (42.9%)/8 (28.6%)/8 (28.6%)
0.710

History

    History of venous thrombus
0 (0.0%)
0 (0.0%)
0 (0.0%)
NA

    History of hematological diseases
1 (1.8%)
1 (3.6%)
0 (0.0%)
0.313

    History of diabetes mellitus
12 (21.4%)
8 (28.6%)
4 (14.3%)
0.193

    History of arterial hypertension
13 (23.2%)
10 (35.7%)
3 (10.7%)
0.027

    History of smoking
39 (69.6%)
20 (71.4%)
19 (67.9%)
0.771

    History of cardiac diseases
8 (14.3%)
5 (17.9%)
3 (10.7%)
0.445

Laboratory tests

    Red blood cell (10¹²/L)
3.52 (1.15-5.20)
3.34 (1.15-5.20)
3.69 (1.74-5.08)
0.456

    Hemoglobin (g/L)
109.00 (37.00-174.00)
102.00 (37.00-174.00)
110.50 (58.00-156.00)
0.812

    White blood cell (10⁹/L)
4.25 (1.30-22.70)
4.70 (1.30-22.70)
4.05 (1.30-20.80)
0.063

    Platelet (10⁹/L)
84.50 (37.00-423.00)
88.00 (37.00-377.00)
75.00 (37.00-423.00)
0.961

    Total bilirubin (μmol/L)
24.25 (5.70-132.70)
25.30 (5.70-132.70)
24.15 (6.60-47.00)
0.718

    Direct bilirubin (μmol/L)
9.55 (2.00-78.20)
9.30 (2.00-78.20)
9.60 (2.50-27.00)
0.961

    Indirect bilirubin (μmol/L)
12.45 (3.60-76.00)
12.60 (3.60-76.00)
12.35 (4.10-27.70)
0.967

    Albumin (g/L)
32.55 (22.10-46.20)
30.75 (22.10-44.50)
33.95 (24.50-46.20)
0.201

    Alanine aminotransferase (U/L)
24.79 (7.53-176.68)
21.66 (7.74-176.68)
25.59 (7.53-140.00)
0.793

    Aspartate aminotransferase (U/L)
33.94 (9.74-166.49)
34.22 (9.74-143.00)
33.94 (13.94-166.49)
0.857

    Alkaline phosphatase (U/L)
98.86 (28.83-337.00)
93.60 (28.83-337.00)
102.83 (52.28-337.00)
0.481

    γ-Glutamyl transpeptidase (U/L)
60.87 (10.00-1779.18)
69.50 (10.00-1779.18)
56.00 (10.93-552.26)
0.611

    Blood urea nitrogen (mmol/L)
5.62 (2.96-47.25)
5.81 (3.52-47.25)
5.38 (2.96-20.15)
0.502

    Serum creatinine (μmol/L)
66.64 (42.82-267.63)
68.96 (42.82-267.63)
64.19 (44.50-117.53)
0.870

    Potassium (mmol/L)
3.99 (2.74-5.41)
4.03 (2.80-5.41)
3.89 (2.74-4.75)
0.517

    Sodium (mmol/L)
138.50 (133.50-145.50)
137.95 (134.10-145.50)
139.65 (133.50-145.20)
0.210

    Prothrombin time (seconds)
15.30 (12.70-20.40)
15.30 (12.70-20.40)
15.25 (12.00-18.90)
0.774

    International normalized ratio
1.24 (0.93-1.75)
1.24 (0.99-1.75)
1.24 (0.93-1.64)
0.883

    Activated partial thromboplastin time (seconds)
40.10 (19.80-53.80)
40.10 (19.80-53.80)
40.30 (27.50-50.80)
0.961

Child-Pugh score
7.00 (5.00-10.00)
7.00 (5.00-10.00)
7.00 (5.00-13.00)
0.259

MELD score
10.43 (6.43-18.00)
10.52 (7.23-18.00)
10.32 (6.43-15.58)
0.676

Portal vein thrombosis
14 (25.0%)
7 (25.0%)
7 (25.0%)
1.000

MELD: model for the end-stage liver diseases.

4. Discussion

Recently, a large population-based cohort study using Danish National Patient Registry demonstrated that splanchnic vein thrombosis significantly increased the risk of bleeding and arterial cardiovascular events as compared to patients with venous thromboembolism and general population [23]. In this study, splanchnic vein thrombosis referred to venous thrombosis within the portal, hepatic, mesenteric, and splenic veins; and arterial cardiovascular events included unstable angina pectoris, acute myocardial infarction, and ischemic stroke. They included 1,915 patients with splanchnic vein thrombosis, of whom 1,711 patients had portal vein thrombosis. They found that patients with splanchnic vein thrombosis had higher risk of bleeding and arterial cardiovascular events up to 1 year after diagnosis. In contrast to these findings, we did not find any significant association between stroke and portal vein thrombosis in liver cirrhosis, even in the PSM analysis. There were several potential reasons for this unexpected phenomenon. First, HCV infection, which should be regarded as a possible causative factor in the antiphospholipid syndrome with an increased prevalence of anticardiolipin antibodies [24] and an aggravated risk of hypercoagulability, is more prevalent in Western countries; by comparison, in our Chinese patients, HBV infection is the major etiology of liver cirrhosis, and the prevalence of HCV infection was only 6.02% (21/349) in our patients, which might lead to a low probability of antiphospholipid syndrome. Second, because Helicobacter pylori is an indirect risk factor of hypercoagulation and is not routinely detected in liver cirrhosis, our study did not have such data and could not compare the difference in the prevalence of Helicobacter pylori infection between patients with and without stroke. Third, our study demonstrated that the level of homocysteine was higher in patients with stroke or ischemic stroke than in patients without stroke, but the difference was not significant. This finding should be validated by expanding the number of patients who underwent laboratory tests of homocysteine levels.

Our study had several limitations. First, the number of our study population, especially patients with ischemic stroke, might not be adequate. Among the patients admitted to our Department of Gastroenterology, most of stroke events are usually asymptomatic. Therefore, in our retrospective observational study, the imaging examination of the brain has not been performed in every cirrhotic patient to evaluate the risk of asymptomatic stroke. Indeed, the imaging examination of the brain in every cirrhotic patient might not be approved by any ethical committee. Herein, the history of asymptomatic stroke, such as lacunar infarction, might be missed. Second, in the present study, we selected study population from a prospectively established database, in which only the patients undergoing enhanced computed tomography or magnetic resonance are included. Although enhanced computed tomography or magnetic resonance can evaluate more precisely the existence, extent, and degree of portal vein thrombosis, there was a potential bias in patient selection in this setting. Third, hypercoagulability is not evaluated in all patients. Fourth, Helicobacter pylori infection, which may be associated with both portal vein thrombosis and stroke, has not been studied in our study.

In conclusion, our study could not establish any association between stroke and portal vein thrombosis in liver cirrhosis. Certainly, well-designed large-scale prospective cohort studies will be necessary to confirm this finding.

Abbreviations

FVIII: | Factor VIII
PC: | Protein C
MTHFR: | Methylenetetrahydrofolate reductase
HBV: | Hepatitis B virus
HCV: | Hepatitis C virus
INR: | International normalized ratio
MELD: | Model for the end-stage liver diseases
LPV: | Left portal vein
RPV: | Right portal vein
MPV: | Main portal vein
SMV: | Superior mesenteric vein
SV: | Splenic vein
PSM: | Propensity score matching.

Data Availability

The datasets generated during and/or analyzed during the current study are available from the corresponding author on reasonable request.

Disclosure

The abstract was published in Asian-Pacific Association for the Study of the Liver (APASL) 2020 Conference. Please see the following link: https://link.springer.com/content/pdf/10.1007/s12072-020-10030-4.pdf.

Conflicts of Interest

The authors declare that they have no conflict of interest.

Authors’ Contributions

Kexin Zheng, Xiaozhong Guo, and Xingshun Qi were responsible for conceptualization. Kexin Zheng, Fangfang Yi, Le Wang, and Xingshun Qi were responsible for data curation. Kexin Zheng and Xingshun Qi were responsible for the formal analysis, investigation, methodology, software, and writing of the original draft. Xiaozhong Guo and Xingshun Qi were responsible for the funding acquisition, project administration, and supervision. Xingshun Qi provided resources and was responsible for the validation and visualization. Kexin Zheng, Xiaozhong Guo, Fangfang Yi, Le Wang, Andrea Mancuso, and Xingshun Qi were responsible for the writing, reviewing and editing.

Acknowledgments

We are indebted to our study team for establishing and updating our prospective database, including Han Deng, Ran Wang, Qianqian Li, Xiangbo Xu, Zhaohui Bai, Yanyan Wu, Li Luo, Shixue Xu, Yanglan He, and Yingying Li, of whom all had worked for our study group.

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