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 Table of Contents  
ORIGINAL ARTICLE
Year : 2016  |  Volume : 41  |  Issue : 1  |  Page : 15-22

Serum thrombopoietin and platelet antibodies in thrombocytopenic patients with chronic hepatitis C virus: clinical application of platelet indices


1 Department of Internal Medicine, Faculty of Medicine, Tanta University, Tanta, Egypt
2 Department of Clinical Pathology, Faculty of Medicine, Tanta University, Tanta, Egypt

Date of Submission05-Aug-2015
Date of Acceptance08-Aug-2015
Date of Web Publication10-Mar-2016

Correspondence Address:
Tamer A Elbedewy
Department of Internal Medicine, Faculty of Medicine, Tanta University, 51719 Tanta
Egypt
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Source of Support: None, Conflict of Interest: None


DOI: 10.4103/1110-1067.178473

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  Abstract 

Background Chronic hepatitis C virus (HCV) infection is prevalent in 160 million individuals worldwide. Egypt has the highest prevalence of HCV in the world. HCV is known to cause thrombocytopenia even in the absence of overt hepatic disease. The pathophysiology of thrombocytopenia with chronic HCV is complex.
Aims To evaluate serum thrombopoietin (TPO) and platelet antibodies in thrombocytopenic patients with chronic HCV and to assess the diagnostic utility of mean platelet volume (MPV) and platelet distribution width (PDW).
Patients and methods The present study included 70 patients with chronic HCV with thrombocytopenia divided into two groups; 20 age-matched and sex-matched HCV patients without thrombocytopenia were also included as controls. Serum TPO, platelet autoantibodies, MPV, and PDW were measured in all participants.
Results A significantly lower serum TPO level and platelet count were found with advancing degree of liver fibrosis and activity. Significantly higher MPV and PDW were found in patients with antiplatelet autoantibodies formation. The platelet count showed significant positive correlations with TPO level, MPV, and PDW, and inverse correlations with aspartate aminotransferase, alanine aminotransferase, and viral load.
Conclusion The dominant mechanism in mild thrombocytopenic HCV patients was the formation of antiplatelet autoantibodies, whereas in moderate to severe thrombocytopenic patients, the dominant mechanism was combined bone marrow affection and formation of antiplatelet autoantibodies. Serum TPO level was decreased in patients with HCV-induced thrombocytopenia. MPV and PDW may be used as indicators for the dominant mechanism. Egyptian J Haematol 41:-0 ͹ 2016 The Egyptian Society of Haematology.

Keywords: hepatitis C virus, platelet antibodies, platelet indices, thrombocytopenia, thrombopoietin


How to cite this article:
Elbedewy TA, Ghazy MA, Mabrouk MM. Serum thrombopoietin and platelet antibodies in thrombocytopenic patients with chronic hepatitis C virus: clinical application of platelet indices. Egypt J Haematol 2016;41:15-22

How to cite this URL:
Elbedewy TA, Ghazy MA, Mabrouk MM. Serum thrombopoietin and platelet antibodies in thrombocytopenic patients with chronic hepatitis C virus: clinical application of platelet indices. Egypt J Haematol [serial online] 2016 [cited 2019 Dec 15];41:15-22. Available from: http://www.ehj.eg.net/text.asp?2016/41/1/15/178473


  Introduction Top


Hepatitis C virus (HCV) is a Flaviviridae family member, genus Hepacivirus [1] . It is estimated that chronic HCV infection is prevalent in 160 million individuals worldwide, representing ~3% of the world's population. Egypt has the highest prevalence of HCV in the world [2] . The prevalence of HCV among the 15-59 years age group is 14.7% [3] . After acute infection, about 80% of these individuals develop chronic hepatitis; among these, in 10-20% of patients, progression to cirrhosis occurs with both hepatic and extrahepatic complications [4] . HCV infection is also associated with several immune-related extrahepatic disorders such as immune thrombocytopenic purpura [5] .

Thrombocytopenia was defined as a peripheral platelet count below 150 × 10 9 /l and occurs in 64-76% of patients with liver cirrhosis and/or fibrosis [6] . HCV infection is strongly associated with thrombocytopenia, which is correlated with hepatocellular damage and hepatic fibrosis [7] . HCV is known to cause thrombocytopenia even in the absence of overt hepatic disease and is considered a surrogate marker for the severity of liver disease [8],[9] . The pathophysiology of thrombocytopenia in patients with chronic liver disease resulting from HCV infection is complex and involves several complementary mechanisms that likely act in concert [10] .

Thrombocytopenia is sometimes the only manifestation of HCV [11] . The severity of thrombocytopenia is highly variable; it may range from mild to severe. Thrombocytopenia is a well-known relative contraindication for the initiation of antiviral therapy in HCV-infected patients. Thrombocytopenia may also result in the postponement of many invasive procedures that chronic liver disease patients may need such as paracentesis and radiofrequency ablation for hepatocellular carcinoma [9] . Platelet transfusions are generally effective for only a few hours; moreover, these may be associated with multiple potential complications [12] .

Therefore, the aim of this study was to evaluate serum thrombopoietin (TPO) and platelet antibodies in thrombocytopenic patients with chronic HCV and to assess the diagnostic utility of mean platelet volume and platelet distribution width.


  Patients and methods Top


Patients

This study was carried out at Tanta University Hospital, Internal Medicine department, between March 2014 and March 2015. A total of 70 patients with chronic HCV with thrombocytopenia were included, and were divided into two groups (group I and group II) according to the severity of thrombocytopenia; 20 age-matched and sex-matched chronic HCV patients without thrombocytopenia were also included in the study as a control group (group III). None of the patients were receiving any therapy. This study was carried out in accordance with the guidelines of the declaration of Helsinki 1975 and its subsequent amendments (1983). Participation in the study was voluntary after an informed written consent was obtained from the participants before the study after a full explanation of the benefits and risks of the study was provided.

Depending on the severity of platelet reduction, the patients were divided into two groups [13],[14] :

Group I: 40 chronic HCV patients with mild thrombocytopenia: from 75 × 10 9 /l to less than 150 × 10 9 /l.

Group II: 30 chronic HCV patients with moderate to severe thrombocytopenia: less than 75 × 10 9 /l.

Exclusion criteria

  1. Patients who had clinical and/or laboratory evidence of compensated or decompensated cirrhosis.
  2. Patients with portal hypertension and splenomegaly using established ultrasound criteria (splenomegaly was considered if the splenic length was >13 cm) [15] .
  3. Patients with a history of blood transfusion for bleeding secondary to thrombocytopenia before documentation of HCV infection.
  4. Hepatitis B virus-infected or HIV-infected patients.
  5. Patients with a history of alcohol intake, upper gastrointestinal bleeding, sclerotherapy, band ligation, those receiving prophylactic treatment for portal hypertension, diuretics, and interferon (current or preceding 6 months).
  6. Patients with portal vein thrombosis or hepatoma on abdominal ultrasound.



  Methods Top


  1. Full assessment of history including drugs.
  2. Clinical examination of the patients.


Laboratory and other assessment

  1. Complete blood count was performed including mean platelet volume (MPV) and platelet distribution width (PDW). An automatic Blood Cell Counter model PCE-210N (ERM A Inc., Yushima 2-31-6, Bunkyoku, Tokyo, Japan) was used.
  2. Liver function tests were performed [alanine aminotransferase (ALT), aspartate aminotransferase (AST), serum bilirubin, alkaline phosphatase, serum albumin, and prothrombin time].
  3. HCV-RNA by PCR assay was carried out by real-time PCR using the real-time PCR Step One instrument and software (Applied Biosystems, 850 Lincoln Centre Drive, Foster City, California 94404, USA) and the degree of viremia was assessed.
  4. Detection of platelet antibodies using flow cytometry: samples of 2-5 ml of peripheral blood were collected in EDTA. The platelet-rich plasma was prepared by centrifugation at 100g for 15 min. The isolated platelets were washed twice with PBS containing 10 mmol/l EDTA and 0.5% bovine albumin (PBS/EDTA). Fluorescein isothiocyanate (FITC)-conjugated F(ab) 2 fragments of rabbit anti-human IgG, IgA, and IgM (Dako, Glostrup, Denmark) were used to detect platelet antibodies; pycoerythrin (PE)-conjugated CD 41 monoclonal antibody (Becton-Dickinson, Franklin Lakes, New Jersey, USA) was used to identify the platelet population. Nonspecific fluorescence was established by the isotypic control of PE-conjugated or FITC-conjugated mouse monoclonal antibody. Platelets were dually stained with FITC-conjugated antibody and PE-conjugated CD 41 monoclonal antibody. Three tubes were prepared for 200 μl of platelet suspension mixed with 4 μl of each FITC-conjugated antibody and 4 μl of PE-conjugated CD 41 monoclonal antibody. The mixture was incubated at room temperature for 15 min. Flow cytometry was performed using a FACScan cytometer (Becton-Dickinson). The platelet population was gated with forward scatter light and right angle scatter light, and CD 41 -positive platelets were regated. Blood samples of patients with a normal platelet count range were used as a control and the cut-off line for positivity was positioned with less than 2% positivity in controls.
  5. Serum TPO levels were measured using a commercial quantitative sandwich enzyme immunoassay (Quantikine, Human TPO Immunoassay, Catalog Number DTP00B; R&D Systems, Inc., 614 McKinley Place NE, Minneapolis, MN 55413, USA).
  6. Abdominal ultrasonography.
  7. Percutaneous liver biopsy was performed in which the METAVIR score [16] was used for assessment of liver fibrosis and activity in patients with a platelet count higher than 75 × 10 9 /l (group I and III).
  8. Bone marrow aspiration was performed in groups I and II (thrombocytopenic groups). It was examined for megakaryocyte series (megakaryocytes hypoplasia), megakaryocyte function (thrombogenesis), and identification of any dysplastic changes. The presence of any of the above criteria indicated a central mechanism for thrombocytopenia.


Statistics

The collected data were tabulated and analyzed using SPSS, version 17 software (SPSS Inc., Chicago, Illinois, USA). Categorical data were presented as number and percentages, whereas quantitative data were expressed as mean and SD. Comparison of continuous data between two groups was made using an unpaired t-test for parametric data and the Mann-Whitney test for nonparametric data. Comparison of continuous data between more than two groups was made using one-way analysis of variance for parametric data and the Kruskal-Wallis test for nonparametric data. Fisher's exact and χ2 tests were used for comparison between categorical data. Spearman and Pearson tests were used to test for correlations between different parameters (nonparametric and parametric, respectively). The accepted level of significance in this work was established at 0.05 (P < 0.05 was considered significant).


  Results Top


This study included three groups (age and sex matched): group I included 40 chronic HCV patients (21 men and 19 women) with mild thrombocytopenia; their ages ranged from 23 to 49 years (mean 36.7 ± 8.197). Group II included 30 chronic HCV patients (16 men and 14 women) with moderate to severe thrombocytopenia; their ages ranged from 20 to 49 years (mean 36.57 ± 7.257). Group III included 20 chronic HCV patients (10 men and 10 women) without thrombocytopenia; their ages ranged from 19 to 49 years (mean 38.5 ± 8.975).

Comparisons between the three groups in terms of laboratory investigations are shown in [Table 1].
Table 1 Comparison between the studied groups as regards laboratory investigations


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Our study showed that the dominant mechanism of thrombocytopenia was antiplatelet autoantibodies formation in group I, whereas in group II, combined bone marrow affection and antiplatelet autoantibodies formation were the dominant mechanism ([Table 2]).
Table 2 Mechanisms of thrombocytopenia in thrombocytopenic patients (groups I and II)


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Our study showed that platelet autoantibodies were present in 28 patients (70%) in group I, 19 patients (63.33%) in group II, and three patients (15%) in group III.

Our results found a significantly lower serum TPO level in group II (mean 61.87 ± 10.61 pg/ml) compared with group I (mean 78.95 ± 14.72 pg/ml) (P < 0.0001) and group III (mean 120.5 ± 13.36 pg/ml) (P < 0.0001); also, a significantly lower serum TPO level was found in group I compared with group III (P < 0.0001) ([Table 1]). Serum TPO level and platelet count were significantly lower with advancing degree of liver fibrosis and activity ([Table 3]).
Table 3 Platelet count and serum thrombopoitein in different fibrosis stages and activity grades (groups I and III)


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A significantly lower platelet count was found in patients with combined bone marrow affection and antiplatelet autoantibodies formation (mean 52 ± 20.8 × 10 9 /l) compared with patients with bone marrow affection only (mean 79.13 ± 11.84 × 10 9 /l) (P < 0.0001) or patients with antiplatelet autoantibodies formation only (mean 113.7 ± 27.92 × 10 9 /l) (P < 0.0001) ([Table 4]).
Table 4 Comparison between different mechanisms of thrombocytopenia as regard platelet count, MPV, and PDW


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Our results found significantly higher MPV in group I (mean 11.6 ± 3.03 fl) compared with group II (mean 8.63 ± 2.83 fl) (P < 0.0001); also, a significantly higher MPV was found in group III (mean 10.88 ± 1.54 fl) compared with group II (P < 0.0001) ([Table 1]). MPV was significantly higher in patients with antiplatelet autoantibodies formation only (mean 13.95 ± 0.67 fl) compared with patients with bone marrow affection only (mean 7.52 ± 0.58 fl) (P < 0.0001) or patients with combined bone marrow affection and antiplatelet autoantibodies formation (mean 7.74 ± 0.67 fl) (P < 0.0001) ([Table 4] and [Figure 1]).
Figure 1 MPV and PDW in different mechanisms of HCV thrombocytopenia. BM, bone marrow; HCV, hepatitis C virus; MPV, mean platelet volume; PDW, platelet distribution width.


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Our results found significantly higher PDW in group I (mean 15.04 ± 3.28%) compared with group II (mean 11.79 ± 2.42%) (P = 0.0001); also, a significantly higher PDW was found in group III (mean 13.41 ± 2.07%) compared with group II (P = 0.0003) ([Table 1]). PDW was significantly higher in patients with antiplatelet autoantibodies formation only (mean 17.42 ± 0.58%) compared with patients with bone marrow affection only (mean 10.91 ± 0.58%) (P<0.0001) or patients with combined bone marrow affection and antiplatelet autoantibodies formation (mean 10.69 ± 0.58%) (P < 0.0001) ([Table 4] and [Figure 1]).

In thrombocytopenic patients (groups I and II), the platelet count showed significant positive correlations with TPO level (P < 0.0001) ([Figure 2]), MPV (P < 0.0001) ([Figure 3]) and PDW (P < 0.0001) ([Figure 3]), whereas the platelet count showed significant inverse correlations with AST (P = 0.004), ALT (P<0.0001), and viral load (P < 0.0001) ([Table 5]).
Table 5 Correlation between platelet count and different variables among thrombocytopenic patients (groups I and II)


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Figure 2 Correlation between the platelet count and serum thrombopoietin level. TPO, thrombopoietin.



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Figure 3 Correlation between the platelet count and MPV and PDW. MPV, mean platelet volume; PDW, platelet distribution width.



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  Discussion Top


Various studies have shown that there is a specific tropism of HCV for many extrahepatic cell types, particularly for circulating blood cells [17] . Thrombocytopenia is frequently observed in chronic HCV as an isolated symptom or may coexist with other extrahepatic manifestations [18] . Different pathogenic mechanisms have been suggested to play a role in thrombocytopenia related to chronic HCV infection [19] . HCV-associated thrombocytopenia may be considered complex and multifactorial in origin as different mechanisms have been implicated in its pathophysiology [20] .

Our study showed that the dominant mechanism of thrombocytopenia was antiplatelet autoantibodies formation in mild thrombocytopenic patients, whereas in moderate to severe thrombocytopenic patients, combined bone marrow affection and antiplatelet autoantibodies formation was the dominant mechanism.

This was in agreement with Olariu et al. [21] , who found that in almost all patients (93.34%) presenting with severe thrombocytopenia, the peripheral and central mechanism coexisted. For patients with moderate thrombocytopenia, 26.93% had only bone marrow inhibition, 11.53% had autoimmune destruction, whereas the majority (61.54%) showed the presence of combined mechanisms. In the mild thrombocytopenia group, the dominant mechanism was peripheral.

TPO has long been considered to play a role in the progression of thrombocytopenia in patients with HCV [10] , but its exact role has not yet been clarified. Approximately 50% of TPO production occurs outside the liver as bone marrow stromal cells. The TPO level is regulated by uptake of the hormone by TPO receptors on platelets and megakaryocytes. TPO synthesis in the liver is also stimulated by inflammatory mediators. In view of these complex interactions between TPO synthesis and degradation, serum TPO levels in patients with chronic liver disease do not necessarily reflect the rate of TPO production and the usual inverse relationship between the platelet count and TPO level is frequently lost [22] . Under normal conditions, if the platelet production decreases, less TPO is bound to platelets, and subsequently, the plasma TPO concentration increases [23] . However, in patients with extensive liver fibrosis and/or cirrhosis with subsequent reduction in functioning hepatocytes, the production of TPO can be reduced [24] and can also be affected by liver functional impairment in patients with chronic HCV [25] , but conflicting findings have also been reported [26],[27],[28],[29] .

In our study, we found a significantly lower serum TPO level in moderate to severe thrombocytopenic patients compared with mild thrombocytopenic patients and nonthrombocytopenic patients; also, a significantly lower serum TPO level was found in mild thrombocytopenic patients compared with nonthrombocytopenic patients. In terms of fibrosis and activity grades in the thrombocytopenic group, there was a significant decrease in serum TPO with advancing liver fibrosis or activity.

Our results are in agreement with those of Eissa et al. [30] and Omran et al. [31] , who found that the TPO level was significantly lower in the thrombocytopenic groups compared with the control group. In contrast to our findings, El Barbary et al. [32] , Zucker et al. [33] , found that there was no difference in the TPO levels between thrombocytopenic and nonthrombocytopenic patients.

Our study found significantly decreasing platelet count with advancing liver fibrosis or activity. A significantly lower platelet count was found in patients with combined bone marrow affection and antiplatelet autoantibodies formation compared with patients with bone marrow affection only or patients with antiplatelet autoantibodies formation only.

Our results were in agreement with those of Panzer et al. [34] , who found that platelet counts were significantly higher in patients with fibrosis stages 1-3 than stage 4. Also, Olariu et al. [21] , found a significant inverse correlation between the platelet count and the stage of liver fibrosis. Osada et al. [35] , found that the platelet count decreased with the progression of fibrosis staging and significant differences in the platelet count were observed between the stages.

MPV and PDW are markers of the platelet activation. Platelet size is related to the function and activation of platelet [36] . MPV distinguishes the excess of destruction or lack of production diseases [37] . Immune thrombocytopenic purpura causing increased platelet destruction should be considered in patients with thrombocytopenia with high MPV levels. However, low MPV levels may be present in hypoplasic platelet production [38] .

Our results found significantly higher MPV and PDW in group I compared with group II, and also a significantly higher MPV and PDW in group III compared with group II. MPV and PDW were significantly higher in patients with antiplatelet autoantibodies formation only compared with patients with bone marrow affection only or patients with combined bone marrow affection and antiplatelet autoantibodies formation.

Omran et al. [31] , found a significant reduction in MPV in HCV thrombocytopenia groups compared with the control group, whereas PDW were not significantly affected. Hussein et al. [39] , found a significant reduction in MPV in HCV thrombocytopenia groups compared with the control group and a significant increase in PDW in patients with chronic liver disease.

Our results in thrombocytopenic patients indicated that the platelet count had significant positive correlations with TPO, MPV, and PDW and inverse correlations with AST, ALT, and viral load.

Our results are in agreement with those of Aydogan et al. [40] , who found positive correlations between MPV and PDW and the number of platelets. Abou El Azm et al. [41] and Zucker et al. [33] , found a significant negative correlation between HCV-RNA viral load and platelet count. Olariu et al. [21] , found a statistically significantly negative correlation between the platelet counts and ALT level.

In contrast to our results, El Barbary et al. [32] , found a negative correlation between serum TPO level and the platelet count. Zucker et al. [33] , found no statistically significant correlation between TPO levels and platelet count in thrombocytopenic patients.


  Conclusion Top


The dominant mechanism in mild thrombocytopenic HCV patients was antiplatelet autoantibodies formation, whereas in moderate to severe thrombocytopenic patients, the dominant mechanism was combined bone marrow affection and antiplatelet autoantibodies formation. Serum TPO level was decreased in patients with HCV-induced thrombocytopenia. MPV and PDW may be used as indicators for the dominant mechanism.

Acknowledgements

Authors' contributions: Concept, design, definition of intellectual content, data acquisition, data analysis, statistical analysis, and clinical studies: Tamer A. Elbedewy, Medhat A. Ghazy; literature search, manuscript preparation, manuscript review, and manuscript editing: Tamer A. Elbedewy, Medhat A. Ghazy, Maaly M. Mabrouk; experimental studies: Maaly M. Mabrouk. All authors have read and approved the final version of the manuscript.

Financial support and sponsorship

Nil.

Conflicts of interest

There are no conflicts of interest.

 
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    Figures

  [Figure 1], [Figure 2], [Figure 3]
 
 
    Tables

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



 

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