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 Table of Contents  
ORIGINAL ARTICLE
Year : 2014  |  Volume : 39  |  Issue : 3  |  Page : 114-121

Antiplatelet antibodies in chronic hepatitis C patients: correlation with platelet count and viral load


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

Date of Submission15-Jul-2014
Date of Acceptance04-Aug-2014
Date of Web Publication31-Dec-2014

Correspondence Address:
Abeer S Elhadidi
Department of Clinical Pathology, Faculty of Medicine, Alexandria University, PO Box 22758, Alexandria
Egypt
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Source of Support: None, Conflict of Interest: None


DOI: 10.4103/1110-1067.148232

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  Abstract 

Background HCV associated thrombocytopenia is one of the most frequent manifestations of hepatitis C virus (HCV) infection; which typically worsens with progression of the liver disease and can become a major clinical complication that prevents chronic HCV patients from receiving the standard peg-interferon/ribavirin therapy.
The aim of the present work was to study the role of anti-platelet antibodies in the pathogenesis of HCV-associated thrombocytopenia and to correlate it with the extent of thrombocytopenia, level of viremia, and ALT level in patients with chronic HCV infection.
Patients and Methods This study was conducted on 200 patients with chronic HCV, divided into 2 groups, group I included 100 patients with normal platelet count (platelet count ≥150 × 109 /L), whereas group II included 100 patients with thrombocytopenia (platelet count <150 × 109 /L). Direct and indirect anti-platelet antibodies were detected by flowcytometry and immunofluorescence respectively.
The results demonstrated statistically significant correlations between presence of anti-platelet antibodies and degree of thrombocytopenia, viral load, and the extent of the liver damage.

Keywords: antiplatelet antibodies, hepatitis C, platelet count, viral load


How to cite this article:
Omar AS, Elhadidi AS, Zaki NE, Tawfik RH. Antiplatelet antibodies in chronic hepatitis C patients: correlation with platelet count and viral load. Egypt J Haematol 2014;39:114-21

How to cite this URL:
Omar AS, Elhadidi AS, Zaki NE, Tawfik RH. Antiplatelet antibodies in chronic hepatitis C patients: correlation with platelet count and viral load. Egypt J Haematol [serial online] 2014 [cited 2019 Dec 14];39:114-21. Available from: http://www.ehj.eg.net/text.asp?2014/39/3/114/148232


  Introduction Top


Thrombocytopenia [platelet (PLT) count <150 × 10 9 /l] is one of the most common hematological abnormalities in patients with chronic liver disease. Its prevalence and severity increase with increasing hepatocellular damage. It occurs in 64-76% of patients with cirrhosis and/or fibrosis. Severe thrombocytopenia is associated with life-threatening complications that occur in end-stage liver disease. The pathophysiology of thrombocytopenia in patients with hepatitis C virus (HCV)-related chronic liver disease is complex and multifactorial [1],[2] .

Pathological mechanisms include hypersplenism, bone marrow suppression by the virus, immune dysfunction, decreased thrombopoietin (TPO) levels/activity, treatment-related factors (antiviral therapy), direct infection of PLTs, and megakaryocytes by HCV [3] .

In patients with HCV-related liver disease, autoantibodies directed against PLT surface antigens can promote PLT sequestration and destruction by cells of the reticuloendothelial system (fixed macrophages) in the spleen and liver [3] . PLT autoantibodies also bind to megakaryocytes and PLT production may be decreased due to interference with megakaryocyte proliferation and maturation [4] . The most likely target antigens for PLTs antibodies were glycoprotein (GP) IIb/IIIa (CD41a) (30%), followed by GP IIIa (20.5%), GP IIb (13.3%), GP Ib (CD42b) (13.3%), and then GP Ia (10%) [5] .

In patients with extensive liver cirrhosis and/or fibrosis and subsequent reduction in functioning hepatocytes, production of TPO, which is the primary cytokine governing megakaryocyte maturation and PLT formation, can be reduced [6],[7] .

Development of thrombocytopenia is a well-known side effect of pegylated interferon (PEG-IFN), which together with ribavirin is the current treatment of choice for hepatitis C. During treatment with IFN-α2b, bone marrow suppression, including inhibition of megakaryocytopoiesis, is considered the major mechanism for IFN-induced thrombocytopenia in this setting. IFN-a treatment may also suppress the production or secretion of TPO. In contrast, IFN can induce the production of autoantibody against thrombocytes that can lead to immune-mediated thrombocytopenia [8] .

Interaction of PLTs with HCV is presumed to be one of the pathogenic mechanisms implicated in HCV-associated thrombocytopenia. Nevertheless, analysis of factors influencing the detection of HCV in PLTs is not well understood [9] .

PLT-associated GP-specific antibodies can be detected directly by flow cytometry [10] and indirectly by immunofluorescence test [11] .


  Aim Top


The aim of this work was to study the presence of anti-PLT antibodies (direct and indirect) in patients with HCV-associated thrombocytopenia and to correlate this with the degree of thrombocytopenia, the level of viremia, and alanine aminotransferase (ALT) level in these patients.


  Patients and methods Top


The study was conducted on 200 patients with chronic HCV who presented to the Hepatology and/or Hematology Clinics at Alexandria Main University Hospital. They were divided into two groups according to their PLT counts: group I, included 100 nonthrombocytopenic individuals (i.e. PLT count ≥150 × 10 9 /l) as the control group, and group II, included 100 thrombocytopenic patients (i.e. PLT count <150 × 10 9 /l).

All patients were subjected to detailed history taking and thorough clinical examination. Laboratory investigations included complete blood count (CBC), complete liver function tests, and renal function tests. Upper abdominal ultrasonography was performed to all patients. HCV-RNA was quantified by real-time PCR. Immunological profile was performed including antiphospholipid antibodies [immunoglobulin M (IgM) and immunoglobulin G (IgG)], antinuclear antibodies (ANA) [4] , anti-double-stranded DNA, and cryoglobulins. Anti-PLT antibodies were detected in EDTA blood by flow cytometry (for direct antibodies) using Becton Dickinson (USA) flow cytometer (Cell Quest Software; Becton Dickinson) [10] and by indirect immunofluorescence test (for indirect antibodies) [11] .


  Results Top


Two hundred Egyptian patients with chronic HCV were enrolled in this study. According to their PLT count, the patients were classified into two groups:

  1. Group I, included 100 patients with normal PLT count (i.e. ≥150 × 10 9 /l).
  2. Group II, included 100 patients with PLT count less than 150 × 10 9 /l.


There was no statistically significant difference between the two groups regarding age and sex. With respect to the CBC parameters, no statistically significant difference was detected between the two groups regarding hemoglobin (Hb) concentration (P = 0.158). In the meantime, the total leukocytic count (TLC) was significantly lower in group II compared with group I (P = 0.001). In addition, PLT count was significantly lower in group II compared with group I (P < 0.001) ([Table 1]).
Table 1 Comparison between the two studied groups according to different studied parameters

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With respect to liver enzymes, both ALT and aspartate aminotransferase (AST) were significantly higher in group II compared with group I (P < 0.001) ([Table 1]).

ALT/PLT ratio, AST/ALT ratio, and AST/PLT index ratio

A statistically significant difference was found between the two groups regarding ALT/PLT ratio (P < 0.001), being higher in group II compared with group I, and AST/PLT index ratio (P < 0.001), being higher in group II compared with group I; however, no difference was found between the two groups with respect to AST/ALT ratio (P = 0.883) ([Table 1]).

Ultrasonographic findings and viral load

On comparing group I and group II, there was statistically significant difference between the two groups regarding splenomegaly (P < 0.001), cirrhosis (P < 0.001), and viral load (P = 0.001). Group II patients were more likely to have splenomegaly and cirrhosis and higher viral load compared with group I ([Table 1]).

Immunological profile

On comparing group I and II, there was statistically significant difference between the two groups with respect to ANA (P < 0.001), anticardiolipin IgM and IgG (P = 0.003, 0.009), direct anti-PLT antibodies (P < 0.001), and indirect anti-PLT antibodies (P < 0.001). Group II patients were more likely to have positive ANA, anticardiolipin IgM and IgG, direct and indirect anti-PLT antibodies compared with group I. However, no significant difference was found between the two groups regarding anti-ds-DNA and serum cryoglobulins ([Table 1]).

Relationship between direct and indirect anti-PLT antibodies and different studied parameters

There was statistically significant relationship between negative direct anti-PLT antibodies and sex of studied patients (P1 = 0.001) and between direct anti-PLT antibodies and age of studied patients (P1 = 0.048, P2 = 0.027). In addition, there was statistically significant relationship between negative indirect anti-PLT antibodies and sex of studied patients (P1 = 0.012). However, there was no statistically significant relationship between indirect anti-PLT antibodies and age of studied patients ([Table 2] and [Table 3]).
Table 2 Relationship between direct anti-PLT antibodies and different studied parameters

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Table 3 Relationship between indirect anti-PLT antibodies and different studied parameters

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With respect to the clinical data, a statistically significant relationship was found between each of splenomegaly, cirrhosis, and viral load in patients with HCV with negative direct anti-PLT antibodies (P1 < 0.001, P1 < 0.001, and P1 = 0.001, respectively), and there was significant relationship between cirrhosis in patients with HCV with positive direct anti-PLT antibodies (P2 = 0.039). The same relationships with respect to splenomegaly, cirrhosis, and viral load were found in patients with negative indirect anti-PLT antibodies (P1 < 0.001, P1 < 0.001, and P1 = 0.006, respectively) and in those with positive indirect anti-PLT antibodies (P2 = 0.010, 0.004, and 0.009, respectively) ([Table 2] and [Table 3]).

With respect to the CBC parameters, a statistically significant relationship was noted between the presence of direct and indirect anti-PLT antibodies and Hb concentration in group II (P = 0.004 and 0.033, respectively). A statistically significant difference between Hb in group I and group II was found in patients with negative direct and indirect anti-PLT antibodies (P1 = 0.012 and 0.037, respectively). A statistically significant difference between TLC in group I and group II was found in patients with negative direct and indirect anti-PLT antibodies (P1 = 0.012 and 0.004, respectively). With respect to PLT count, a significant relationship was found between the presence of direct anti-PLT antibodies and the presence of thrombocytopenia in group II (P = 0.009) ([Table 2] and [Table 3]).

With respect to liver functions, group I (control) individuals with negative direct and indirect anti-PLT antibodies had significantly lower ALT and AST values when compared with group II (thrombocytopenic) patients with negative direct and indirect anti-PLT antibodies (P1 < 0.001 and <0.001, respectively). However, there was no statistically significant relationship between positive direct and indirect anti-PLT antibodies and ALT and AST values of studied patients ([Table 2] and [Table 3]).

Relationship between direct, indirect anti-PLT antibodies, and immunological profile

Group I (control) individuals with negative direct anti-PLT antibodies were more likely to have negative ANA and negative anticardiolipin IgM and IgG when compared with group II (thrombocytopenic) patients (P1 < 0.001, P1 = 0.001, and P1 = 0.013, respectively). In addition, group I individuals with negative indirect anti-PLT antibodies were more likely to have negative ANA and negative anticardiolipin IgM when compared with group II patients (P1 < 0.001, P1 = 0.002, respectively) ([Table 2] and [Table 3]).

ALT/PLT ratio, AST/ALT ratio, and AST/PLT index ratio

No statistically significant relationship was noted between the presence of direct and indirect anti-PLT antibodies and each of ALT/PLT ratio, AST/ALT ratio, and AST/PLT index ratio ([Table 4]).
Table 4 Relationship between direct, indirect anti-PLT antibodies and ALT/PLT ratio, AST/ALT ratio, and AST/PLT index ratio

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Relationship between direct and indirect anti-PLT antibodies and the degree of thrombocytopenia

With respect to the degree of thrombocytopenia, statistically significant relationship was noted between each of mild and severe thrombocytopenia and the presence of direct anti-PLT antibodies (P = 0.004 and 0.004) and between mild thrombocytopenia and indirect anti-PLT antibodies (P = 0.018) ([Table 5]).
Table 5 Relationship between direct and indirect anti-PLT antibodies and the degree of thrombocytopenia

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Correlation and relationship between PLT count and different parameters

It was noted that the PLT count correlated positively with TLC and International Normalization Ratio (INR) and negatively correlated with age, Hb, ALT, AST, and viral load. However, statistically significant positive correlation was noted only with TLC (P < 0.001), and significant negative correlation was found between PLT count and ALT (P < 0.001) and AST (P < 0.001). In addition, significant negative correlation was found between PLT count and Hb concentration (P = 0.045) and viral load (P = 0.026) ([Table 6]).
Table 6 Correlation between PLT count and different parameters in total sample

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On considering the total cases (in the two groups) there was statistically significant relationship between PLT count and each of sex (P = 0.002), splenomegaly (P < 0.001), cirrhosis (P < 0.001), ANA (P < 0.001), anticardiolipin IgM (P = 0.004), anticardiolipin IgG (P = 0.002), and direct and indirect anti-PLT antibodies (P < 0.001), as shown in [Table 7]. However, no statistically significant relationship was noted between the PLT count and each of anti-ds-DNA and cryoglobulins ([Table 7]).
Table 7 Relationship between PLT count and different parameters in total sample

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Relationship between direct and indirect anti-PLT antibodies in each group

There was strong statistically significant association between direct and indirect anti-PLT antibodies in group II (P < 0.001), whereas no statistically significant association was noted between direct and indirect anti-PLT antibodies in group I ([Table 8]).
Table 8 Relationship between direct and indirect anti-PLT antibodies in the two studied groups

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  Discussion Top


In the current study, a significant splenomegaly and liver cirrhosis were observed in thrombocytopenic HCV-positive patients as compared with those with normal PLT count. This is in agreement with the studies by Aref et al. [5] and Abdallah et al. [12] .

In all 200 studied HCV-positive patients, the mean PLT count in patients with cirrhosis and splenomegaly was significantly lower than in those without cirrhosis and splenomegaly. The same relationship was found by Adinolfi et al. [13] , Wang et al. [14] , and Lai et al. [15] .

In the present study, it was noted that there was statistically significant relationship between each of splenomegaly, cirrhosis, and thrombocytopenia in HCV-positive patients with negative anti-PLT antibodies. This is in contrast to the studies by Aref et al. [5] and Sanjo et al. [16] who reported that the degree of platelet associated immunoglobulin (PAIg) elevation in the thrombocytopenic group is correlated with the spleen span. In addition, we found a statistically significant relationship between cirrhosis and positive direct anti-PLT antibodies. This is in agreement with the study by Christodoulou et al. [17] who found that cirrhotic patients irrespective of etiology of cirrhosis had a higher frequency of anti-PLT antibodies than noncirrhotic patients. The spleen is the key organ in the pathophysiology of immune thrombocytopenia, not only because PLT autoantibodies are formed in the white pulp, but also because mononuclear macrophages in the red pulp destroy Ig-coated PLTs [18] .

With respect to the viral load, it was noticed in the current study that the viral load was significantly higher in the thrombocytopenic group compared with the group with normal PLT count. In addition, a statistically significant relationship was noted between viral load and thrombocytopenia in HCV-positive patients with negative direct and indirect anti-PLT antibodies. Hassnin et al. [19] reported the same result. HCV-RNA can be abundant in PLTs and megakaryocytes of thrombocytopenic patients. Direct cytopathic involvement of HCV can be hypothesized [20] .

Regarding the liver function tests, our data showed that ALT and AST were significantly higher in thrombocytopenic HCV-positive patients compared with the nonthrombocytopenic group. In the meantime, the nonthrombocytopenic group with negative anti-PLT antibodies had significantly lower ALT and AST values when compared with the thrombocytopenic group. In addition, statistically significant negative correlation was noted between each of ALT, AST, and PLT counts in all the studied patients. Our results were in accordance with the results of Aref et al. [5] and Hassnin et al. [19] .

Serum ALT level is a well-known indicator of hepatocellular damage [8] . In the current study, an elevated serum ALT level was strongly associated with thrombocytopenia. Interestingly, Wang et al. [14] stated that an elevated serum ALT level was strongly associated with thrombocytopenia, even after adjusting anti-HCV positivity and other risk factors. This indicates that thrombocytopenia might be highly correlated with hepatocellular damage.

In support of this explanation, we found a statistically significant difference between the two groups regarding ALT/PLT ratio and AST/PLT index ratio being higher in group II compared with group I; however, no difference was found between the two groups with respect to AST/ALT ratio.

Regarding the PLT counts and anti-PLT antibodies, we noted that group II has statistically significant lower PLT counts and more positive anti-PLT antibodies than group I. In addition, statistically significant relationship was found between the positivity of direct and indirect anti-PLT antibodies and the occurrence of thrombocytopenia in HCV patients. In the meantime, the anti-PLT antibodies (direct and indirect) were significantly related to the degree of thrombocytopenia. The presence of anti-PLT antibodies can produce mild, moderate, or severe thrombocytopenia.

Sanjo et al. [16] evaluated the role of elevated PAIgG in thrombocytopenia of chronic liver diseases. They found significant negative correlation between PLT counts and PAIgG. They stated that immune-mediated processes are one of thrombocytopenic mechanisms.

Our findings suggest an immune-based mechanism of thrombocytopenia in chronic HCV. This is in agreement with the study by Zucker et al. [21] who suggested that aberrations of the immune system result in formation of anti-PLT antibodies and/or immune complexes that bind to PLTs and facilitate their premature clearance. Moreover, Pockros et al. [22] reported that infection with HCV is known to cause profound changes in the host immune response, including the development of autoimmunity. These autoimmune mechanisms may play a role in pathogenesis of thrombocytopenia associated with HCV infection [5] .

Increased peripheral PLT destruction caused by immune or nonimmune mechanisms commonly leads to thrombocytopenia. Autoimmune thrombocytopenia may present as primary immune disorder directed only at PLTs or as a secondary complication of another autoimmune disease [23] .

There was statistically significant difference between the two studied groups (thrombocytopenic and nonthrombocytopenic) regarding ANA, anticardiolipin (ACL) IgM, ACL IgG, and anti-PLT antibodies, whereas no statistically significant difference was found between the two groups regarding anti-ds-DNA and cryoglobulins. The PLT counts were statistically significantly related to these antibodies and also to anti-PLT antibodies.

HCV is associated with different autoimmune manifestations. On the basis of different studies, 40-74% of HCV-infected patients may experience other complications during the course of the disease that are principally immunological. The prevalence of HCV infection is much higher among some of these conditions and suggests a pathogenetic role of the virus. HCV is a trigger for the autoimmune reactions resulting in production of autoantibodies [24] .

Some reports agree that non-organ-specific autoantibodies positivity does not influence either clinical or biochemical profile of chronic hepatitis C [25] . However, other studies demonstrated positive correlation between the presence of non-organ-specific autoantibodies and the biochemical and histological activity of the underlying liver disease [26] .

Our data showed that there was strong statistically significant association between detection of direct anti-PLT antibodies by flow cytometry and detection of indirect anti-PLT antibodies in the serum of patients by immunofluorescence in the thrombocytopenic group clarifying the significant role of the anti-PLT antibodies in pathogenesis of thrombocytopenia in Egyptian patients with HCV infection.

In conclusion, the mechanism involved in the pathogenesis of thrombocytopenia in HCV-positive patients appears to be complex and multifactorial. In our study, splenomegaly and cirrhosis represent two important causes in the pathogenesis of thrombocytopenia in hepatitis C patients. HCV infection plays an important immunological role in the development of thrombocytopenia through development of anti-PLT antibodies leading to immunological destruction of the PLTs in the reticuloendothelial system, but this is integrated with the other mechanisms. The degree of thrombocytopenia was significantly associated with the presence of direct and indirect anti-PLT antibodies. The PLT antibodies were significantly correlated to PLT counts, viral load, and ALT level.


  Acknowledgements Top


Conflicts of interest

There are no conflicts of interest.

 
  References Top

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  [Table 1], [Table 2], [Table 3], [Table 4], [Table 5], [Table 6], [Table 7], [Table 8]



 

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