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 Table of Contents  
ORIGINAL ARTICLE
Year : 2021  |  Volume : 34  |  Issue : 3  |  Page : 813-818

Study the relation of protein S and portal vein thrombosis in patients with liver cirrhosis


1 Department of Internal Medicine, Faculty of Medicine, Menoufia University, Menoufia, Egypt
2 Department of Clinical Pathology, Faculty of Medicine, Menoufia University, Menoufia, Egypt
3 Department of Internal Medicine, Birket Elsaba General Hospital, Menoufia, Egypt

Date of Submission14-Jun-2020
Date of Decision16-Aug-2020
Date of Acceptance30-Aug-2020
Date of Web Publication18-Oct-2021

Correspondence Address:
Ahmed N Talkhan
Birket Elsaba, Menoufia
Egypt
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Source of Support: None, Conflict of Interest: None


DOI: 10.4103/mmj.mmj_186_20

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  Abstract 


Objective
The aim was to investigate serum protein S (PS) levels in cirrhotic patients with portal vein thrombosis (PVT).
Background
PS is an important guardian in controlling thrombin generation and fibrinolysis, although the contribution of these properties to the anticoagulant functions of PS is still unclear.
Patients and methods
The present study was conducted on 90 subjects who were classified as follows: 36 cirrhotic patients without PVT, 34 cirrhotic patients with PVT, and 20 healthy persons as a control. The study was conducted in the period between December 2010 and March 2012. Complete blood picture, liver function tests, and renal function test were done. PS was measured by enzyme-linked immunosorbent assay. Abdominal ultrasonography was done to confirm diagnosis of liver cirrhosis (LC) by giving idea about liver echogenicity, irregularity of liver outline, liver size, presence of liver nodules, and also portal vein diameter and presence of PVT.
Results
The mean PS level in the LC group was significantly lower than the mean level in the control group (P1 = 0.0123) and the mean PS level in LC with PVT group was highly significant lower than the control group (P2 < 0.0001). Moreover, the mean PS level in LC with PVT group was highly significant lower than in the LC group (P3 = 0.0001).
Conclusion
PS concentration is a potential biochemical marker in the diagnostic strategy of PVT in patients with cirrhosis. PS less than 3.15 is highly indicative of PVT in cirrhotic patients with high sensitivity but low specificity.

Keywords: liver cirrhosis, portal vein diameter, portal vein thrombosis, Protein S


How to cite this article:
Atty EA, Elkholy RM, Talkhan AN, Ezz EAA. Study the relation of protein S and portal vein thrombosis in patients with liver cirrhosis. Menoufia Med J 2021;34:813-8

How to cite this URL:
Atty EA, Elkholy RM, Talkhan AN, Ezz EAA. Study the relation of protein S and portal vein thrombosis in patients with liver cirrhosis. Menoufia Med J [serial online] 2021 [cited 2024 Mar 29];34:813-8. Available from: http://www.mmj.eg.net/text.asp?2021/34/3/813/328308




  Introduction Top


Liver cirrhosis (LC) has become one of the major causes of morbidity and mortality. The Global Burden of Disease reported that more than one million people died owing to cirrhosis in 2010 worldwide, compared with 676 000 deaths in 1980. As the survival rate of cirrhosis is relatively low, data on the incidence of geographical variations are essential to prevent its related disability and mortality [1]. LC is a worldwide health problem, which usually develops from chronic hepatitis and transitions into compensated cirrhosis, after which there is a progression into decompensated cirrhosis. Cirrhosis is associated with various complications and high mortality [2].

Portal vein thrombosis (PVT) represents a well-known complication during the natural course of LC, ranging from asymptomatic cases to life-threating conditions related to portal hypertension and hepatic decompensation. Portal flow stasis, complex acquired hypercoagulable disorders, and exogenous factors leading to endothelial dysfunction have emerged as key factors for PVT development. However, PVT occurrence remains unpredictable and many issues regarding its natural history, prognostic significance, and treatment are still elusive [3].

Thrombosis involves various genetic and environmental factors. Under normal physiological conditions, the mechanism of coagulation control works in a multilevel cascade to prevent clot formation in blood vessels, and coagulation reactions do not occur excessively even if the blood vessels are injured. It was reported that deficiency in the coagulation inhibition of protein S (PS), which is a regulator of physiological coagulation, poses a risk for thrombus formation [4].

PS is a vitamin K-dependent anticoagulant protein. Its major function is as a cofactor to facilitate the action of activated protein (APC) on its substrates, activated factor V (FVa), and activated factor VIII (FVIIIa). PS deficiencies are associated with thrombosis. PS possesses both APC-dependent and independent anticoagulant properties and thus is an important guardian in controlling thrombin generation and fibrinolysis, although the contribution of these properties to the anticoagulant functions of PS is still unclear. Furthermore, PS is thought to play a role in other systems [5]. Concentrations of PS decline with deteriorating liver function. It may also be involved in PVT formation in patients with cirrhosis. The aim of this study was to investigate serum PS levels in cirrhotic patients with PVT.


  Patients and methods Top


This study was carried out at the Internal Medicine Department and Clinical Pathology Department, Faculty of Medicine, Menoufia University, during December 2010 to December 2012. This study included 70 patients, including 36 cirrhotic patients without PVT and 34 cirrhotic patients with PVT, as well as 20 apparently healthy individuals as the control group. Patients on anticoagulant therapy, age less than 18 years, inflammatory or bleeding events in previous 2 months, history of personal (familial in first-degree relatives) unprovoked thromboembolism, diabetic mellitus, and hepatocellular carcinoma are excluded from the study.

Ethical consideration

All participants were volunteers. Before the study initiation, All of them signed a written informed consent after explaining the aim of the study. Approval of the study protocol was obtained by Ethical Scientific Committee of Menoufia University Hospital.

Inclusion criteria were adults age older than 18 years, both sexes, established diagnosis of hepatitis C virus (HCV) positive LC, and established diagnosis of HCV positive LC with PVT.

Exclusion criteria were anticoagulant therapy, age less than 18 years, inflammatory or bleeding events in previous 2 months, history of personal (or familial in first-degree relatives) unprovoked thromboembolism, diabetic mellitus, and hepatocellular carcinoma.

All participants in the study were subjected to the following: history taking and clinical examination such as age, sex, body mass index, symptoms and signs of chronic liver disease such as ascites, encephalopathy, and gastrointestinal bleeding; Child classification and etiology of LC; and investigation such as complete blood picture using Sysmex KX-21 automatized hematology analyzer (Sysmex Corporation, Tokyo, Japan), liver function tests such as serum bilirubin (BLB), albumin, and antiprothrombin time (PT) using a biochromatic (405–510 nm) rate technique, and kidney function tests such as serum urea and creatinine using the open system autoanalyzer Synchron CX5 (Beckman, New York, New York, USA), as well as serum level of protein S.

Abdominal ultrasonography was done by Siemens 2002 Model to confirm diagnosis of LC by giving idea about liver echogenicity, irregularity of liver outline, liver size, presence of liver nodules, and also portal vein diameter and presence of PVT.

The PS assay kit was supplied by Bio-Diagnostics (Giza, Egypt). The kit uses a double-antibody sandwich enzyme-linked immunosorbent assay to assay the level of human PS in samples. Serum was added to human PS monoclonal antibody, and then PS antibodies labeled with biotin were added and combined with streptavidin-horseradish peroxidase to form immune complex, and then chromogen solution was added, and the color of the liquid changed into yellow and was positively correlated.

Samples were collected by sterile venipuncture. Each sample was 5 ml and was divided into three parts: 1 ml for assay of complete blood picture, 3 ml for assay of kidney function test and liver function test, and 1 ml was left to clot in a plain vacutainer tube at room temperature, and sera was separated by centrifugation and stored at –20 to −80°C for estimation of serum PS.

Principle of the tests of protein S

The kit uses a double-antibody sandwich enzyme-linked immunosorbent assay to assay the level of human PS (PROS; LSBio Company, Seattle, Washington, USA) in samples. Protein S (PROS) was added to monoclonal antibody enzyme well, which is precoated with human protein S (PROS) monoclonal antibody, and incubated. Then, protein S (PROS) antibodies labeled with biotin was added and combined with streptavidin-horseradish peroxidase to form immune complex. Then, it was incubated and washed to remove the uncombined enzyme. Then chromogen solutions A and B were added, and the color of the liquid changed into the blue. With the effect of acid, the color finally became yellow. The chroma of color and the concentration of the human substance protein S (PROS) of sample were positively correlated.

Sample size

It was calculated using PASS 11.0 NCSS LLC company, 329 North 1000 East Kaysville, Utah 84037 USA based on the study by Chawla and Bodh [6] who reported the prevalence of PVT in patients with LC was 15% (5–26%). Assuming α = 0.05 (standard value of 1.96), we calculated that we would need 90 patients (36 cirrhotic patients without PVT and 34 cirrhotic patients with PVT, as well as 20 apparently healthy individuals) to achieve a power of 80% (0.8).

Statistical analysis

Data entry, coding, and analysis were conducted using Statistical Package for the Social Sciences, IBM Corp., Released 2017 (IBM SPSS Statistics for Windows, Version 25.0; IBM Corp., Armonk, New York, USA). Description of quantitative variables was in the form of mean and SD. Description of the qualitative variables was by frequency and percentage. χ2 test and t-test were used. P value less than or equal to 0.05 was set to be statistically significant.


  Results Top


In this study, mean age was 56 ± 9.54 years in control, 64.72 ± 8.3 years in group of LC, and 55.97 ± 7.34 years in group of LC and PVT. So, there was a highly significant difference between the studied groups regarding age (P < 0.0001). There was no significant difference between the studied groups regarding sex (P = 0.4267) [Table 1].
Table 1: Statistical comparison between studied groups regarding age and sex

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In the present study, there was no significant difference between the studied groups regarding total leukocytic count and white blood cells (WBC) (P1 = 0.0904, P2 = 0.2290, and P3 = 0.8561). However, hemoglobin was significantly lower in LC and PVT group (9.83 ± 0.93 g/dl) and LC group (10.18 ± 0.86 g/dl) than the mean of the control group (13.605 ± 1.2 g/dl). Moreover, mean platelet count was significantly decreased in group of LC (95.22 ± 26.06 × 103/mm3) and in LC and PVT group (88.38 ± 30.23 × 103/mm3) than controls (252.05 ± 29 × 103/mm3). However, mean PT was significantly higher in group of LC (18.94 ± 1.76 s) and LC and PVT (19.79 ± 1.75 s) than controls (12.49 ± 0.41 s). In addition, the mean level of albumin was higher in controls (4.16 ± 0.31 g/dl) than in group of LC (2.56 ± 0.53 g/dl) and in group of LC and PVT (2.3 ± 0.53 g/dl). Additionally, aspartate transaminase (AST), alanine aminotransferase (ALT), BLB, creatinine, and urea levels were significantly increased among LC group and LC and PVT than controls. Mean PS was significantly lower in LC group (12.59 ± 12.96 IU/dl) and LC and PVT group (2.04 ± 1.85) IU/dl) than controls (20.82 ± 12.33 IU/dl) [Table 2]. In this study, regarding grade of PVT in group LC and PVT, there were 28 (82.4%) patients with grade I PVT and four (11.8%) patients with grade II PVT and two (5.9%) patients with grade III PVT [Table 3]. Our results showed that in LC group, there was a significant positive correlation between PS and serum urea, creatinine, and Fibrosis-4 (FIB-4). However, a negative but insignificant correlation was recorded between PS and total leukocytes count, hemoglobin (Hb), platelets (PLT), albumin, ALT, BLB, spleen size, and PV diameter. In LC-PVT group, there was a significant positive correlation between PS with PT (P = 0.0293), AST to platelet ratio index (P = 0.0281), and FIB-4 (P = 0.0463), whereas a significant negative correlation was obtained between protein C with PV diameter (P = 0.0223) [Table 4].
Table 2: Comparison between the studied groups regarding laboratory investigations

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Table 3: Grade PVT of group of liver cirrhosis with portal vein thrombosis by ultrasound

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Table 4: Correlation between protein S with different clinical, biochemical, and radiological parameters

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  Discussion Top


In this study, statistical analysis of the studied groups revealed no significant difference regarding age and sex distribution. This ensures that demographic data had no effect on the results of the study. This disagrees with Pradat et al. [7], who found that most HCV-infected patients, if untreated, are expected to develop cirrhosis at approximately 65 years of age, irrespective of the age at infection. Thus, age itself seems even more important than age at infection for predicting the occurrence of LC. A specific active monitoring and therapeutic approach should be adopted in older patients to prevent progression to cirrhosis and its complications. In this study, statistical analysis of the cirrhotic patients with PVT showed that most patients with PVT were grade I (82.4%), 11.8% of patients were grade II, and only 5.9% of patients with PVT were grade III. In the present study, there was no significant difference in total leukocytic count between the studied group. However, WBC was elevated in patients with LC and PVT than patients with LC, although this difference still was nonsignificant. It was found that WBC count was identified as a risk factor for PVT in cirrhotic patients, including the study by Kinjo et al. [8].

Hemoglobin was significantly lower in LC and PVT group (9.83 ± 0.93 g/dl) and LC group (10.18 ± 0.86 g/dl) than the mean of the control group (13.605 ± 1.2 g/dl). In accordance with our findings, Abdel-Razik et al. [9] found that hemoglobin was significantly decreased in patients with LC and PVT than LC patients [9]. Theoretically, HB levels are expected to be an independent risk factor for PVT in this study. In fact, because splenomegaly decreases the HB level and hypersplenism is more severe in patients with PVT, the lower HB level may be more appropriately attributed to splenomegaly. Thus, although HB was associated with PVT, it was not an independent risk factor of PVT [8]. Mean platelet count was significantly decreased in group of LC (95.22 ± 26.06 × 103/mm3) and in LC and PVT group (88.38 ± 30.23 × 103/mm3) than controls (252.05 ± 29 × 103/mm3). In accordance with our findings, Stine et al. [10] found that platelet count was significantly decreased in patients with LC and PVT than LC patients [10]. Mean PT was significantly higher in group of LC (18.94 ± 1.76 s) and LC and PVT (19.79 ± 1.75 s) than controls (12.49 ± 0.41 s). In a previous retrospective cohort study, Dabbagh et al. [11] demonstrated that a higher PT level did not translate into a decreased risk of thrombosis in cirrhosis patients [11].

Serum creatinine and urea levels were significantly increased among LC group and LC and PVT than controls. This agrees with Serra et al. [12], who found that serum creatinine concentration is a parameter that should be included in the prognostic assessment of patients with decompensated cirrhosis [12]. Mean level of albumin was higher in controls (4.16 ± 0.31 g/dl) than in group of LC (2.56 ± 0.53 g/dl) and in group of LC and PVT (2.3 ± 0.53 g/dl). Meanwhile, our results agree with Nagao and Sata [13], who found that low serum albumin concentration indicates poor liver function [13]. AST, ALT, BLB, creatinine, and urea levels were significantly increased among LC group and LC and PVT than controls. These results agree with Sheha et al. [14], who stated that AST/ALT ratio predicts cirrhosis in patients with chronic hepatitis C virus infection [14] and also found that an AST/ALT ratio of 1 or more has been reported to have 100% specificity and 53% sensitivity in detecting cirrhosis. BLB level was significantly increased among LC group and LC and PVT than controls. In a previous study, patients with chronic liver disease with thrombosis had increased BLB levels compared with controls [15].

Regarding total PS level in blood, the mean of PS in the LC group was significantly lower than the mean of the control group, and the mean of PS in the LC with PVT group was significantly lower than the mean of control group. However, the mean of PS in the LC with PVT group was significantly lower than the mean of LC group. Previously, Zhou et al. [16] reported that PS deficiency can manifest as recurrent esophagogastric variceal bleeding secondary to PVT. In addition, PVT was reported to be provoked by S protein deficiency [17]. However, Bagheri et al. [18] found that PS in the cirrhotic patients was not associated with development of PVT.

In the present study, in LC group, there was a significant positive correlation between PS and serum urea, creatinine, and fibrosis (FIB-4). However, a negative but insignificant correlation was recorded between PS and total leukocytes count, HB, PLT, albumin, ALT, BLB, spleen size, and PV diameter. In LC-PVT group, there was a significant positive correlation between PS and PT, AST to platelet ratio index, and FIB-4. However, a significant negative correlation was obtained between protein C and PV diameter. The results of the present study are similar to those of previously published studies of patients with cirrhosis by Qi et al. [19]. A study by Geleto et al. [20] showed that portal vein diameter is increased in relation to PS in PVT [20].

Moreover, when comparing PVT and non-PVT cirrhotic patients in terms of PLT, PT, HB, FIB-4, PS, PC, D-dimer, plasminogen activator (t-PA), and plasminogen activator inhibitor-1 (PAI-1), PVT appeared to be independent of the progression of liver dysfunction, as it was not correlated with PLT, PT, HB, or FIB. In parallel, no correlation was found between PVT and the levels of t-PA and PAI-1. El-Nemr et al. [21] demonstrated that cirrhotic patients displayed dysfunctions in the coagulation, anticoagulation, and fibrolytic systems. The development of PVT in these patients may be independently associated with the decrease of PS. Furthermore, decreasing PS may be a risk factor inducing PVT in cirrhotic patients. This result agrees with Zhang et al. [22], who showed that plasma D-dimer and PS concentrations are potential biochemical markers in the diagnostic strategy of PVT in patients with cirrhosis. This agrees with Fisher et al. [23] who mentioned that protein C, PS, and antithrombin (AT) serum levels are decreased in patients with liver disease. This agrees with Gursoy et al. [24], who showed that elevated plasma values of PS are frequently found in patients with LC, with higher incidence in decompensated disease [24].


  Conclusion Top


PS concentration is a potential biochemical marker in the diagnostic strategy of PVT in patients with cirrhosis. PS less than 3.15 is highly indicator of PVT in cirrhotic patients with high sensitivity but low specificity. In the case of low PS concentrations, presence of PVT is suspected, and specific imaging techniques should be performed to confirm the diagnosis and initiate early treatment.

Financial support and sponsorship

Nil.

Conflicts of interest

There are no conflicts of interest.



 
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    Tables

  [Table 1], [Table 2], [Table 3], [Table 4]



 

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