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Abstract About 180 million people are having hepatitis C virus infection (HCV) worldwide. In addition to progression to cirrhosis and hepato-carcinoma, HCV patients may develop extrahepatic manifestations. HCV infection is considered as one of the most important health problems all over the world. Egypt is one of the countries with a high prevalence of HCV infection, with an estimated prevalence of 22 percent among the adult population. The prevalence of thrombocytopenia in HCV patients ranges from 0.16 percent to 45 percent, and more than half of the studies reported a prevalence of 24 percent or more. Anti-platelet glycoprotein antibodies are common with HCV infection, even without thrombocytopenia. Antiviral antibodies that are cross-reactive with GPIIIa, have been identified in many cases. Production of thrombopoietin may be decreased with advanced liver disease. Infection of the megakaryocytes by the virus may impair platelet production. There are many proposed theories and mechanisms that explain the pathophysiology of autoimmunity in HCV infection. HCV can facilitate lymphotropism causing clonal B-lymphocyte expansion which causes a widespread autoantibody production. The envelope protein E2 of the virus can bind to CD81 molecule which is expressed on the hepatocytes and the B-lymphocytes, leading to a cytokine dysregulation with enhanced T-helper 1 immune response. This may cause autoimmunity induced by the self-reactive lymphocytes in the chronic HCV patient. Cross-reactivity between cytochrome P2-E1 (CYP2E1) and specific sequences in the HCV-NS5b protein has been recently shown to be responsible for the production of numerous auto-antibodies that can target the self-proteins. Patients with fibrosis and thrombocytopenia have attained >90% sustained virologic response (SVR) with direct antiviral agents (DAAs), even if lower in respect to patients with a normal platelet count. Thus, direct antiviral agents can be continued in most patients without interruption, and thrombopoietin mimetics should be used only in cases with severe thrombocytopenia. For immune reconstitution after DAA therapy, it is likely that viral elimination will decrease the intrahepatic inflammation, and will reconstitute the innate immune mediators such as natural killer cells (NK), but there will be a minimal effect on Mucosal associated invariant T cells (MAIT), and there are very limited data suggesting reduced activation of the lymphocytes after DAA therapy. The effect on tumor- associated antigens specific T (TAA-T) cells is unknown, and preliminary studies suggest that T regulatory cells (Treg) do not normalize in the blood after DAA therapy. If DAA therapy does not significantly alter the localization and suppressive activity of Treg cells, this will create an immunosuppressive environment. The aim of this work was to evaluate the effect of DAA (sofosbuvir and daclatasvir) therapy on HCV associated thrombocytopenia, and tracking the platelet level changes during and after treatment of HCV infection. To our knowledge this is the first study on this issue in Egypt. This was a prospective study on 104 patients with HCV-associated thrombocytopenia receiving DAA (sofosbuvir and daclatasvir) in Menoufia University Hospitals and National Liver Institute. Patients with any of the following were excluded from this study: - concomitant HBV or HIV infection - History of IFN therapy. - Hepatocellular carcinoma (HCC). - Autoimmune and endocrinal diseases. - H. pylori infection. All patients were followed up every 4 weeks during anti-viral therapy (for 12 weeks), and at SVR24 (at 24 weeks), clinically by weekly symptoms checklist, and by CBC. PCR for HCV RNA was done at start of therapy, 12 & 24 weeks of therapy. Patients were divided into several groups according to presence or absence of splenomegaly, the child Pugh class (A, and B), and Firbroscan score (F1, F2, and F3), and comparison between similar groups regarding the baseline platelet count and serial platelet counts during and after the treatment was done. The present study revealed that: 1- HCV associated thrombocytopenia is more common in middle aged females. 2- The platelet count is expected to decrease initially on starting the DAA antiviral treatment, then increases gradually and steady during and after the treatment. 3- DAA therapy in patients with HCV-associated thrombocytopenia and compensated liver disease is safe with platelet count improvement in most cases. 4- Further large-scale studies, including studies of the immune system reconstitution behavior with DAA therapy are needed. 5- Further studies evaluating the effect of DAA therapy on other extrahepatic HCV immune mediated diseases are needed to understand the exact immune system reconstitution and behavior with HCV |