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CLINICAL OBSERVATIONS IN HEPATOLOGY |
Hepatology, VOL. 0, NO. 0, 2019
Regression of Idiopathic
Thrombocytopenic Purpura in a Patient
With Eradication of Hepatitis C Virus
by Direct-Acting Antivirals
Yusuke Johira,1* Haruna Hatooka,2* Nami Mori,1 Takayuki Fukuhara,1 Shintaro Takaki,1 Yumi Shimomura,2 Michio Imamura,2
C. Nelson Hayes,2 Keiji Tsuji,1 and Kazuaki Chayama2
I
diopathic thrombocytopenic purpura (ITP) is
an autoimmune disorder that is characterized
by antibody-mediated platelet destruction and
decreased platelet production. ITP is associated with
high morbidity in hepatitis C virus (HCV)–infected
patients,(1) but the relationship between these diseases
is unclear. Although interferon therapy was hampered
due to thrombocytopenia, recent direct-acting antiviral (DAA) therapies permit HCV eradication in
patients with chronic hepatitis complicated with ITP.
Here, we report a case of successful regression of ITP
following HCV eradication by DAA therapy.
A 42-year-old man visited our hospital with purpura in March 2014. Blood testing revealed a platelet
count of 2 × 103/μL and a serum alanine aminotransferase (ALT) level of 142 IU/mL. He was diagnosed
with ITP by bone marrow examination and chronic
genotype 2a HCV infection without any evidence of
cirrhosis assessed by computed tomography, blood
examination, and liver fibrosis marker (total bilirubin, 0.6 mg/dL; albumin, 4.7 g/dL; mac-2 binding
protein, 1.41 cutoff index). He received a platelet
transfusion and immunoglobulin and was treated
with prednisolone and eltrombopag, a thrombopoietin receptor agonist (Fig. 1). Although the platelet
count increased to 30 × 103/μL, eltrombopag was
switched to romiplostim because ALT levels elevated to approximately 700 IU/L. Subsequently,
the serum ALT level decreased, and the bleeding
symptoms disappeared with weekly administration
of romiplostim. Then from August 2015 he received
12 weeks of sofosbuvir plus ribavirin therapy for
HCV infection. Serum HCV RNA became negative during the therapy, and he achieved sustained
virological response (SVR) 12 and 24 (serum HCV
RNA-negative 12 and 24 weeks after treatment completion, respectively). Although 5 mg/day of prednisolone and 1,750 μg/month of romiplostim were
required to maintain a platelet count of >50 × 103/μL
at the start of anti-HCV therapy, these requirements
were gradually relaxed. Despite withdrawal of prednisolone and romiplostim 12 and 32 months after
achievement of SVR, respectively, his platelet counts
have been maintained at >100 × 103/μL for 1 year.
Abbreviations: ALT, alanine aminotransferase; HCV, hepatitis C virus; ITP, idiopathic thrombocytopenic purpura; NS, nonstructural (protein);
WES, capillary western immunoassay.
Received February 22, 2019; accepted July 25, 2019.
*These authors contributed equally to this work.
Supported by the Research Program on Hepatitis from the Japan Agency for Medical Research and Development (17fk0210104h0001).
Part of this work was carried out at the Analysis Center of Life Science, Natural Science Center for Basic Research and Development, Hiroshima
University. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.
© 2019 by the American Association for the Study of Liver Diseases.
View this article online at wileyonlinelibrary.com.
DOI 10.1002/hep.30900
Potential conflict of interest: Dr. Chayama has received honoraria from Bristol-Myers Squibb and MSD and research funding from Dainippon
Sumitomo Pharma and AbbVie. Dr. Imamura has received research funding from Bristol-Myers Squibb.
1
JOHIRA, HATOOKA, ET AL.
Hepatology, Month 2019
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FIG. 1. Clinical course of the patient treated for ITP and HCV infection. Dotted line indicates serum HCV RNA titers. Arrows
indicate the time points when pretreatment and posttreatment antibodies were tested by western blotting. Abbreviation: IVIg, intravenous
immunoglobulin.
Because regression of ITP was achieved by
HCV eradication, we hypothesized that HCV antibody caused platelet destruction. HCV RNA was
extracted from patient serum and complementary
DNA (cDNA) of HCV core; nonstructural protein
3 (NS3), NS4, NS5A, and NS5B were amplified by
PCR (Fig. 2A); then HCV proteins were synthesized using an in vitro protein synthesis kit. Capillary
western immunoassay (WES) analysis was performed
on a WES system (004-600; ProteinSimple, San
Jose, CA) to clarify the relationship between HCV
antibodies and ITP. When synthesized HCV proteins were incubated with patient serum, anticore,
anti-NS3, anti-NS4, anti-NS5A, and anti-NS5B
antibodies were detected before anti-HCV therapy
(Fig. 2B). These antibodies had been reduced, and
ARTICLE INFORMATION:
From the 1 Department of Gastroenterology, Hiroshima Red Cross Hospital and Atomic-Bomb Survivors Hospital, Naka-ku,
Hiroshima, Japan; 2 Department of Gastroenterology and Metabolism, Graduate School of Biomedical and Health Sciences, Hiroshima
University, Minami-ku, Hiroshima, Japan.
ADDRESS CORRESPONDENCE AND REPRINT REQUESTS TO:
Nami Mori, M.D., Ph.D.
Department of Gastroenterology
Hiroshima Red Cross Hospital and Atomic-Bomb
Survivors Hospital
2
1-9-6 Sendamachi, Naka-ku
Hiroshima 734-8619, Japan
E-mail: [email protected]
Tel.: +81-82-241-3111
Hepatology, Vol. 0, No. 0, 2019
A
JOHIRA, HATOOKA, ET AL.
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FIG. 2. Relationship between HCV antibodies and platelet proteins. (A) The cDNA of HCV core, NS3, NS4, NS5A, and NS5B was
amplified by PCR. In vitro transcription and translation were performed using the TNT T7 Coupled Wheat Germ Extract System
(Promega, WI). Synthesized HCV proteins, core (19 kDa), NS3 (67 kDa), NS4 (27 kDa), NS5A (50 kDa), and NS5B (65 kDa) (B) or
extracted platelet proteins (57 kDa) (C) were reacted with patient serum obtained before and 24 weeks after antiviral therapy and analyzed
by WES. Arrow indicates HCV and platelet proteins. Molecular markers are in kilodaltons.
anti-NS3 antibody disappeared 24 weeks after antiviral therapy. Next, platelet proteins were extracted and
reacted with the serum. WES analysis showed the
presence of a 57-kDa band before treatment and disappearance 24 weeks after antiviral therapy (Fig. 2C).
These results suggest that anti-NS3 antibody might
cross-react as an antiplatelet antibody to platelet protein and, therefore, that regression of ITP might be
achieved by disappearance of anti-NS3 antibody by
HCV eradication.
Chronic HCV infection is associated with the
development of several extrahepatic alterations,
including thrombocytopenia. Pathogenesis of ITP is
gradually being elucidated, and autoantibodies to glycoprotein IIb/IIIa on the platelet surface have been
found to be associated with platelet destruction.(2)
HCV infection may lead to development of secondary
ITP by several mechanisms, such as cross-reaction of
antibody against HCV with platelet protein, infection
to platelet and megakaryocyte, low serum thrombopoietin level, or autoantibody to the thrombopoietin
receptor.(3-5) Our results indicate a possible mechanism in which anti-NS3 was related to ITP, and
regression of ITP was achieved by loss of anti-NS3
antibody following HCV eradication.
Acknowledgment: We thank Mitsuhiro Itagaki, Shinya
Katsutani, and Hideki Asaoku from the Department
of Hematology of Hiroshima Red Cross Hospital and
Atomic-Bomb Survivors Hospital for their special
treatment for ITP of the patient.
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TP, et al. Risk of immune thrombocytopenic purpura and autoimmune hemolytic anemia among 120908 US veterans with hepatitis
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3) Wei Z, Michael AN, William B, Zongdong L, Simon K. Role of
molecular mimicry of hepatitis C virus protein with platelet GPIIIa
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4) de Almeida AJ, Campos-de-Magalhães M, de Melo Marçal OP,
Brandão-Mello CE, Okawa MY, de Oliveira RV, et al. Hepatitis C
virus–associated thrombocytopenia: a controlled prospective, virological study. Ann Hematol 2004;83:434-440.
5) Ichimata S, Kobayashi M, Honda K, Shibata S, Matsumoto A,
Kanno H. Acquired amegakaryocytic thrombocytopenia previously diagnosed as idiopathic thrombocytopenic purpura in a
patient with hepatitis C virus infection. World J Gastroenterol
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Author names in bold designate shared co-first authorship.
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