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 Table of Contents  
ORIGINAL ARTICLE
Year : 2012  |  Volume : 24  |  Issue : 3  |  Page : 83-92

Correlations of folic acid, vitamin B12, homocysteine, and thrombopoietin to platelet count in HCV infection


1 Department of Internal Medicine, Al Azhar Faculty of Medicine for Girls, Egypt
2 Department of Clinical Pathology, National Liver Institute, Menoufiya University, Sadat City, Egypt
3 Department of Tropical Medicine, Al Azhar Faculty of Medicine for Girls, Egypt
4 Department of Physiology, Al Azhar Faculty of Medicine for Girls, Egypt
5 Department of Public Health and Community Medicine, National Liver Institute, Menoufiya University, Sadat City, Egypt
6 Department of Medical Biochemistry, Al Azhar Faculty of Medicine for Girls, Egypt

Date of Submission21-Aug-2012
Date of Acceptance09-Sep-2012
Date of Web Publication16-Jul-2014

Correspondence Address:
Somayh S. Eissa
131 Saker Quriesh, New Maadi, 11435 Cairo
Egypt
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Source of Support: None, Conflict of Interest: None


DOI: 10.7123/01.EJIM.0000422603.17424.31

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  Abstract 

Introduction

The platelet count is known to decrease in proportion to the advancement of the stage of liver disease in chronic hepatitis C (CHC) viral infection. The platelet count is currently used as an index for fibrosis staging. The pathophysiology of thrombocytopenia (TCP) in patients with hepatitis C virus (HCV) infection is not completely understood.

Purpose

This work aimed to study the correlations of folic acid (FA), vitamin B12 (Vit B12), homocysteine (Hcy), and thrombopoietin to the platelet count in HCV infection.

Patients and methods

Sixty-seven patients (51 men and 16 women) with HCV infection were included in this study. All patients were sero-negative for hepatitis B viral markers. In addition, 20 healthy volunteers, matched for sex and age, were included as a control group. All patients and control individuals were subjected to the following: assessment of medical history, thorough clinical examination, and laboratory investigations including the following: complete blood cell counts, viral hepatitis markers, liver and renal function tests, HCV-RNA by quantitative PCR, serum folate, Vit B12, thrombopoietin, and plasma Hcy. Abdominal ultrasonography and ultrasound-guided liver biopsy for histopathologic examinations were carried out for the patients. Patients were divided into two groups of 36 patients with CHC and 31 patients with cirrhosis with HCV liver cirrhosis (LC).

Results

The results indicated a significant decrease in the platelet count in CHC and LC patients compared with the healthy control group. There was a highly significant decrease in the FA level in CHC and LC patients compared with the control group; also, a significant decrease in the platelet count was found in LC patients compared with CHC patients. Hcy was significantly increased in CHC and LC patients. There was a nonsignificant decrease in Vit B12 in CHC patients, whereas it was significantly increased in LC patients. There was a nonsignificant decrease in thrombopoietin in CHC patients compared with the control group, whereas in LC patients, there was a highly significant decrease. There was a highly significant positive correlation between the platelet count and FA, but an insignificant correlation between the platelet count and Hcy, Vit B12, thrombopoietin, and viral load.

Conclusion

This study concluded that TCP in HCV-related chronic liver diseases is multifactorial and decreased FA is involved in its pathogenesis as an independent risk factor. Increased Hcy may cause TCP through platelet activation and endothelial dysfunction.

Keywords: folic acid, homocysteine, thrombocytopenia and hepatitis C virus, thrombopoietin, vitamin B12


How to cite this article:
Eissa SS, Hendy OM, Younis F, Omar Samy AK, Abdallah AR, Ahmed LA. Correlations of folic acid, vitamin B12, homocysteine, and thrombopoietin to platelet count in HCV infection. Egypt J Intern Med 2012;24:83-92

How to cite this URL:
Eissa SS, Hendy OM, Younis F, Omar Samy AK, Abdallah AR, Ahmed LA. Correlations of folic acid, vitamin B12, homocysteine, and thrombopoietin to platelet count in HCV infection. Egypt J Intern Med [serial online] 2012 [cited 2019 Sep 19];24:83-92. Available from: http://www.esim.eg.net/text.asp?2012/24/3/83/136004


  Introduction Top


Hepatitis C virus (HCV) is a leading cause of chronic liver disease (CLD), namely, chronic hepatitis C (CHC), cirrhosis, and hepatocellular carcinoma, as well as the most common indication for liver transplantation in many countries 1.

Thrombocytopenia (TCP) is known to occur in chronically infected HCV patients. The prevalence of TCP ranges from 0.16 to 45.4%, and may interfere with diagnostic procedures, such as liver biopsy, because of the risk of bleeding. It may also exclude patients from effective antiviral treatment. The most widely used definition of TCP is a platelet count of up to 150×109/l 2.

The pathophysiology of TCP in patients with an HCV infection is not completely understood, but is believed to be multifactorial 2. TCP appears to be related to the severity of the liver disease and is more common in patients with cirrhosis 3. Hypersplenism, formation of antiplatelet antibodies caused by aberration of the immune system (autoimmune TCP), and decreased thrombopoietin production are reported causes 2. The vascular endothelial dysfunction is also involved in TCP during a chronic HCV infection 4. In addition, patients with HCV who undergo antiviral treatment with interferon and ribavirin can typically experience TCP as a common side effect 5.

The liver stores large amounts of vitamins, including vitamin B12 (Vit B12), and lesser amounts of folate. Megaloblastic anemia is a cause of TCP 6. Halifeoglu et al. 7 have reported that plasma folate and Vit B12 were decreased in cirrhotic patients. Hyperhomocysteinemia has been reported in CHC and proved to promote steatosis and fibrosis 8. Folate circulates as 5-methyltetrahydrofolate and serves as a methyl donor to homocysteine (Hcy), which is converted into methionine, in a reaction catalyzed by methionine synthase, a Vit B12-dependent enzyme. Hcy is a sulfur-containing amino acid that is formed as an intermediatecompound in methionine metabolism. Folate deficiency disturbs hepatic methionine metabolism and causes impaired Hcy catabolism in the liver and other tissues inhibiting Hcy remethylation, which can lead to liver damage 9. Thrombopoietin is a glycoprotein hormone produced mainly by the liver and the kidney. It stimulates the production and differentiation of platelets by the bone marrow 10.

This work aimed to study serum folic acid (FA), Vit B12, thrombopoietin (TPO), and plasma Hcy levels and determine their correlations to the platelet count in patients with HCV-related CLDs.


  Patients and methods Top


Sixty-seven patients (51 men and 16 women) with HCV-related CLD were included in this study. They were selected from inpatient and outpatients clinics of the Hepatology Department, National Liver Institute (NLI), Menoufiya University, and internal medicine and tropical medicine departments of Al Zahra University Hospital. They had virologic, biochemical (HCV Ab and PCR for HCV RNA), and histological findings compatible with HCV-related CLD. All patients were sero-negative for hepatitis B viral markers (HBs Ag, HBe Ag, and HBc-Ab). They provided informed consent before participation in the study.

Exclusion criteria

Patients with CLDs other than HCV (alcoholic, nonalcoholic steatohepatitis, autoimmune hepatitis, biliary disorders, schistosomal patients), hepatocellular carcinoma, or other malignancies, congestive heart failure, diabetes mellitus, renal disease, and hypertension were excluded. None of the patients were receiving antiviral, antimalignancy, or antiplatelet therapy.

In addition, 20 healthy volunteers, matched for sex (15 men and five women) and age (33.75±5.75), were included as a control group. These control individuals had a normal complete blood count, normal liver and renal function tests, and were sero-negative for HCV antibodies and hepatitis B virus (HBV) markers.

The patients and control individuals were subjected to the following:

  1. Assessment of medical history and thorough clinical examination.
  2. Abdominal ultrasonography.
  3. Ultrasound-guided liver biopsy (when possible) was performed for patients using a true-cut needle or a liver biopsy gun for the patients for histopathologic examinations. The specimens were fixed in 10% saline-buffered formalin and processed for routine diagnostic histopathological examination. Assessment of the stage of liver fibrosis (0–6) was carried out using the Ishak scoring system 11: the stage 0=no fibrosis, stage 1–2=portal fibrosis (minimal fibrosis), stage 3–4=bridging fibrosis (moderate fibrosis), and stage 5–6=cirrhosis (advanced fibrosis).


Laboratory investigations

Venous blood samples were withdrawn under aseptic conditions from all the patients and controls for routine evaluation. Serum was separated and blood samples were withdrawn in EDTA, centrifuged, and stored within 15 min from collection to prevent an in-vitro increase in Hcy, because of its release by red blood cells 12; both serum and plasma samples were stored at −80°C until used. The serum folate, serum Vit B12, and plasma Hcy levels were measured using a fluorescence polarization immunoassay (Axym analyser; Abbott Laboratories, Rungis, France). The normal reference ranges were as follows: FA 7.0–28.0 ng/ml; Vit B12 from 223 to 1132 pg/ml; and Hcy: 5–14 µmol/l. Serum TPO was measured using a commercially available ELISA kit (Quantikine human TPO immunoassay; R&D system Minneapolis, Minnesota, USA), reference value 0–228 pg/ml. Complete blood cell counts were measured using a Sysmix K-21 automatic cell counter (Japan). Liver function tests including alanine aminotransferase, aspartate aminotransferase, serum albumin, and total bilirubin were carried out on COBAS-Intergra 400 (Roche, Germany). Hepatitis markers (HBVs Ag, HBe Ag, anti-HBc-Ab, and HCV antibody) were assessed by enzyme immunoassay (COBAS-Amplicore; Roche). HCV-RNA by quantitative PCR HCV-RNA levels were analyzed by a reverse transcriptase PCR using a commercial kit (Roche Diagnostic, Branchburg, New Jersey, USA) according to the manufacturer’s instructions. Alpha fetoprotein was measured by automated chemiluminescence using ACS-180SE (Chiron Diagnostic, Germany).

According to the laboratory, radiological, and histological examinations, the patients were divided into two groups of 36 patients with chronic hepatitis C without cirrhosis (CHC), mean age±SD (38.39±6.83), and 31 patients with liver cirrhosis with HCV (LC), mean age±SD (48.52±5.603).

Statistical analysis

Data were collected and entered into the computer using the statistical package for social science program for statistical analysis (version 19; SPSS Inc., Chicago, Illinois, USA). Two types of statistics were determined: (a) Descriptive statistics, where qualitative data were expressed as frequency and percent, and quantitative data, shown as mean and SD, and (b) Analytical statistics, where the t-test was used for comparison of two groups with quantitative normally distributed data. The Mann–Whitney test was used when the data were not normally distributed. The one-way analysis of variance test was used for comparison between three or more groups with quantitative normally distributed data and the post-hoc test was carried out; Pearson’s correlation was used to study the correlation between two variables with normally distributed data. However, Spearman’s correlation was used when data were not normally distributed. A P-value was considered statistically significant when it was less than 0.05.


  Results Top


[Table 1] shows the descriptive data of the patients; we found that 16 (44.4%) of the CHC patients and seven (22.6%) of the cirrhotic patients had normal spleens.
Table 1: Descriptive data of the patient groups

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[Table 2] shows that there were significant differences between CHC and controls in all the parameters studied, except for age and alpha fetoprotein serum level.
Table 2: Comparison of CHC and control groups in terms of the studied parameters

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[Table 3] shows that there were significant differences between CHC and LC groups in all the parameters studied except for aspartate aminotransferase, alkaline phosphatase, gamma glutamic transeferase, total bilirubin, mean corpuscular volume (MCV), and mean corpuscular hemoglobin (MCH).
Table 3: Comparison of CHC and LC groups in the studied variables

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[Table 4] shows that there were significant differences between the three groups (LC, CHC, control) in all the variables studied (FA, TPO, Vit B12, Hcy); these differences were mainly because of significant differences between the three groups (LC, CHC, control) in FA, between LC and control LC and CHC in TPO, between LC and control, LC and CHC in Vit B12, and between CHC and control LC and control in Hcy.
Table 4: Comparison between the three groups in FA, Hcy, Vit B12, and TPO levels

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[Table 5] shows that there were significant positive correlations between FA and platelet count and Hb, and Vit B12 and serum albumin; however, significant negative correlations were found between FA and MCV [Figure 1] and Hcy and MCH in the CHC group. There were insignificant correlations between all of Hcy, Vit B12 and TPO, and platelet count.
Table 5: Correlation between the levels of FA, TPO, Hcy, Vit B12, and some parameters in the CHC group

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Figure 1: Correlation between FA and MCV levels in CHC and LC groups. Significant negative correlation between FA and MCV levels in both groups. CHC, chronic hepatitis C; FA, folic acid; MCV, mean corpuscular volume.

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[Table 6] shows that there were highly significant positive correlations between FA and all of Hb, MCH, and platelet count; however, the correlation was significantly negative between FA and MCV. Significant positive correlations were found between TPO and serum albumin and Hcy and Vit B12, whereas significant negative correlations were found between Hcy and both TPO and serum albumin in the LC group.
Table 6: Correlation between the levels of FA, TPO, Hcy, Vit B12, and some parameters in the LC group

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Our results indicated a significant decrease in the platelet count in CHC [Table 2] and LC [Table 3] patients compared with the healthy controls. There was a highly significant decrease in the FA level in CHC and LC patients [Figure 2] compared with the control group; also, a significant decrease was found in LC patients compared with CHC patients [Table 4]. Hcy was significantly increased in CHC and LC patients [Figure 3]. There was a nonsignificant decrease in Vit B12 in CHC patients, whereas it was significantly increased in LC patients [Figure 4]. There was a nonsignificant decrease in TPO in CHC patients compared with the controls, whereas in LC patients, there was a highly significant decrease [Figure 5]. There was a highly significant positive correlation between the platelet count and FA, but an insignificant correlation between the platelet count and all of Hcy, Vit B12, and TPO [Table 5] and [Table 6].
Figure 2: Levels of folic acid in the studied groups.

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Figure 3: Levels of homocysteine in the studied groups.

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Figure 4: Levels of vitamin B12 in the studied groups.

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Figure 5: Levels of TPO in the studied groups.

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In CHC patients, there was a significant positive correlation between the platelet count and FA, but an insignificant correlation between the platelet count and all of Hcy, Vit B12, TPO, and viral load. In LC patients, there was a significant correlation between the platelet count and FA, whereas no significant correlations were found between the platelet count and all of Hcy, Vit B12, TPO, and viral load [Table 7] and [Figure 6].
Table 7: Correlation between the levels of the platelet count and each of FA, TPO, Hcy, Vit B12, and viral load in CHC and LC groups

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Figure 6: Correlation between the platelet count and FA level in CHC and LC groups. Significant positive correlation between the platelet count and FA level in both groups. CHC, chronic hepatitis C; FA, folic acid.

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  Discussion Top


Egypt has one of the highest prevalence rates of HCV infection in the world 13. A strong correlation between liver fibrosis and TCP has been found, and the platelet count is currently used as an index for fibrosis staging 14. The prevalence of TCP within the HCV-infected population is also likely to increase 15.

The pathophysiology of TCP in patients with HCV infection is not completely understood, but is believed to be multifactorial 2. TCP appears to be related to the severity of the liver disease and is more common in patients with cirrhosis 3. Splenomegaly appears to be the factor most likely to be responsible for this, although there are several thrombocytopenic cases without splenomegaly, suggesting that other factors may also be responsible. The concept of hypersplenism was never proven without doubt, but was widely accepted because of the lack of an alternative explanation 16. The formation of antiplatelet antibodies is caused by an aberration of the immune system (autoimmune TCP) 2.

Fusegawa et al. 17 reported that patients with CHC have increased platelet activation and have a higher percentage of platelet microparticles, a marker of platelet activation, which may contribute toward the occurrence of TCP in CHC. However, they did not provide an explanation for the mechanism of platelet activation. The cause of TCP has not been clearly elucidated as yet.

Vascular endothelial dysfunction has also been suggested in TCP during chronic HCV infection by Makoto et al. 4, who observed a negative correlation between the platelet count and the vWF antigen value and a negative correlation between the platelet count and thrombomodulin (a marker of endothelial cell damage). Decreased thrombopoietin production is a reported cause 18.

To date, the mechanism of TCP in HCV infection is a matter of debate; thus, this work was designed to study serum FA, Vit B12, TPO, and plasma Hcy levels and their correlations to the platelet count in patients with HCV-related CLDs.

The results of this work indicated a highly significant decrease in the platelet count and serum FA level in CHC and LC patients compared with the control group, and also a significant decrease in LC patients compared with CHC patients. These findings are in agreement with those of Halifeoglu et al. 7, who observed decreased plasma folate in cirrhotic patients compared with the controls. Also, Sandra Hirsch et al. 9 found that serum folate was lower in patients with severe nonalcoholic fatty liver disease than those with minimal damage or without liver damage. Our results showed a highly significant positive correlation between FA and the platelet count, but a significant negative correlation between FA and MCV. There was no significant correlation between FA and both of Hcy and Vit B12. This finding is in agreement with that of Gracía-Tevijano et al. 19 and Halifeoglu et al. 7, and may indicate that decreased FA level is an independent risk factor for TCP in CLDs, especially that related to HCV infection.

The results of the present study showed that plasma Hcy was significantly increased in CHC and LC patients, but there was no significant correlation between Hcy and both FA and Vit B12, which is in agreement with the result of Adinolfi et al. 8, who found that plasma Hcy was significantly higher in patients with grade 3–4 of steatosis than that observed in patients with grade 1–2 steatosis and those without steatosis. Serum levels of both folate and Vit B12 did not correlate with plasma levels of Hcy or grade of steatosis. Also, Bosy-Westphal et al. 20 observed hyperhomocysteinemia in patients with cirrhosis, and a significant negative association between plasma Hcy and both FA and B12 was observed in healthy controls. However, in cirrhosis, only a weak correlation was found between Hcy and FA, which disappeared at advanced stages of liver diseases. They attributed hyperhomocysteinemia in cirrhotic patients to impaired liver function, which leads to impaired transsulfuration and remethylation. Gracía-Tevijano et al. 19 observed reduced expression of Hcy-metabolizing genes in both alcoholic and HCV cirrhosis, resulting in hyperhomocysteinemia that was not related to altered plasma levels of FA or Vit B12, and indicated that increased Hcy plays a role in vascular and liver damage in cirrhotic patients. Hcy-induced cell toxicity may explain platelet activation and endothelial vascular dysfunction observed by Fusegawa et al. 17 and Makoto et al. 4, respectively, in the cirrhotic patients, resulting in TCP. This finding may explain how some cirrhotic patients suffer from coronary or cerebrovascular thrombosis while have TCP and coagulopathy.

Our results showed a nonsignificant decrease in Vit B12 in CHC patients whereas, surprisingly, it was significantly increased in cirrhotic patients.

The results of the present work showed a nonsignificant decrease in TPO in CHC patients, which is not in agreement with the result of Ezzat et al. 18, who observed an increased TPO level in CHC patients and suggested that this increased TPO may be a compensatory response to a reduced platelet count by the still-functioning liver. Our showed a highly significant decrease in TPO in cirrhotic patients, but this decrease in TPO was not correlated with the platelet count and significantly positively correlated to serum albumin (synthetic function of the liver). Furthermore, Sanjo et al. 21 reported that no differences in serum TPO levels were observed in the cirrhosis and the control group.


  Conclusion Top


TCP in HCV-related CLDs is multifactorial, and decreased FA is involved in its pathogenesis as an independent risk factor. Increased Hcy may cause TCP through platelet activation and endothelial dysfunction. We can recommend the use of FA to treat TCP in HCV-related CLDs, and advice the patients to include plenty of fresh fruits and vegetables in their diet; further research work should be carried out to study TCP in HCV infection.[21]

 
  References Top

1.Chen SL, Morgan TR. The natural history of hepatitis C virus (HCV) infection. Int J Med Sci. 2006;3:47–48  Back to cited text no. 1
    
2.Louie KS, Micallef JM, Pimenta JM, Forssen UM, et al. Prevalence of thrombocytopenia among patients with chronic hepatitis C: a systematic review. J Viral Hepat. 2011;18:1–7  Back to cited text no. 2
    
3.Giannini EG. Thrombocytopenia in chronic liver disease and pharmacologic treatment options. Aliment Pharmacol Ther. 2006;23:1055–1065  Back to cited text no. 3
    
4.Makoto O, Makoto K, Minoru S, Masumi E, Koichi T, Katsue S, et al. Causes of thrombocytopenia in chronic hepatitis C viral infection. Clin Appl Thromb Hemost. 2012;18:272–280  Back to cited text no. 4
    
5.Weksler BB. Review article: the pathophysiology of thrombocytopenia in hepatitis C virus infection and chronic liver disease. Aliment Pharmacol Ther. 2007;26(Suppl 1):13–19  Back to cited text no. 5
    
6.Kumar P, Clark M Liver, biliary tract and pancreatic disease; Kumar and Clark's Clinical Medicine. 2011;7:321–322  Back to cited text no. 6
    
7.Halifeoglu I, Gur B, Aydin S, Ozturk A. Plasma trace elements, vitamin B12, folate, and homocysteine levels in cirrhotic patients compared to healthy controls. Biochemistry (Mosc). 2004;69(693–696):14–15  Back to cited text no. 7
    
8.Adinolfi LE, Ingrosso D, Cesaro G, Cimmino A, D’Antò M, Capasso R, et al. Hyperhomocysteinemia and the MTHFR C677T polymorphism promote teatosis and fibrosis in chronic hepatitis C. Hepatology. 2005;41:995–1003  Back to cited text no. 8
    
9.Hirsch S, Poniachick J, Avendaño M, Csendes A, Burdiles P, Smok G, et al. Serum folate and homocysteine levels in obese females with non-alcoholic fatty liver. Nutrition. 2005;21:137–141  Back to cited text no. 9
    
10.Kaushansky K. Lineage-specific hematopoietic growth factors. N Engl J Med. 2006;354:2034–2045  Back to cited text no. 10
    
11.Ishak K, Baptista A, Bianchi L, Callea F, De Groote J, Gudat F, et al. Histological grading and staging of chronic hepatitis. J Hepatol. 1995;22:696–699  Back to cited text no. 11
    
12.Moller J, Ahola L, Abrahamsson L. Evaluation of DPC Immulite 2000 assay for total homocysteine in plasma. Scan J Clin Lab Invest. 2002;62:396–373  Back to cited text no. 12
    
13.Anwar WA, Khaled HM, Amra HA, El-Nezami H, Loffredo CA. Changing pattern of hepatocellular carcinoma (HCC) and its risk factors in Egypt: possibilities for prevention. Mutat Res. 2008;659:176–184 http://www.ncbi.nlm.nih.gov/pubmed/18346933  Back to cited text no. 13
    
14.Testa R, Testa E, Giannini E, Borro P, Milazzo S, Isola L, et al. Noninvasive ratio indexes to evaluate fibrosis staging in chronic hepatitis C: role of platelet count/spleen diameter ratio index. J Intern Med. 2006;260:142–150  Back to cited text no. 14
    
15.Kauf TL, Nelson DR, Schelfhout J, Delaney JA, Wang PF. Trends in the prevalence of thrombocytopenia among individuals infected with hepatitis C virus in the United States, 1999-2008. BMC Research Notes. 2012;5:142  Back to cited text no. 15
    
16.Peck-Radosavljevic M. Thrombocytopenia in liver disease. Can J Gastroenterol. 2000;14(Suppl D):60–66  Back to cited text no. 16
    
17.Fusegawa H, Shiraishi K, Ogasawara F, Shimizu M, Haruki Y, Miyachi H, et al. Platelet activation in patients with chronic hepatitis C. Tokai J Exp Clin Med. 2002;27:101–106  Back to cited text no. 17
    
18.Ezzat EO, Suliman SE, El-Yazeed SA, Ahmad FM, Said SK. Study of thrombopoietin level in egyptian patients with chronic liver diseases secondary to hepatitis C virus. Egypt J Int Med. 2012;24:5–11  Back to cited text no. 18
    
19.García-Tevijano ER, Berasain C, Rodríguez JA, Corrales FJ, Arias R, Martín-Duce A, et al. Hyperhomocysteinemia in liver cirrhosis, mechanisms and role in vascular and hepatic fibrosis. Hypertension. 2001;38:1217–1221  Back to cited text no. 19
    
20.Bosy-Westphal A, Ruschmeyer M, Czech N, Oehler G, Hinrichsen H, Plauth M, et al. Determinants of hyperhomocysteinemia in patients with chronic liver disease and after orthotopic liver transplantation. Am J Clin Nutr. 2003;77:1269–1277  Back to cited text no. 20
    
21.Sanjo A, Satoi J, Ohnishi A, Maruno J, Fukata M, Suzuki N. Role of elevated platelet-associated immunoglobulin G and hypersplenism in thrombocytopenia of chronic liver diseases. J Gastroenterol Hepatol. 2003;18:638–644  Back to cited text no. 21
    


    Figures

  [Figure 1], [Figure 2], [Figure 3], [Figure 4], [Figure 5], [Figure 6]
 
 
    Tables

  [Table 1], [Table 2], [Table 3], [Table 4], [Table 5], [Table 6], [Table 7]



 

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