Skip to main content

Advertisement

SpringerLink
Log in

Anemia and thrombocytosis induced by ribavirin monotherapy in patients with chronic hepatitis C

  • Original Article—Liver, Pancreas, and Biliary Tract
  • Published:
Journal of Gastroenterology Aims and scope Submit manuscript

Abstract

Background

An inosine triphosphatase (ITPA) single-nucleotide polymorphism (SNP) is associated with anemia induced by pegylated interferon and ribavirin (RBV) combination therapy in patients with chronic hepatitis C (CHC). However, there are very few reports on the hematological effects of RBV monotherapy. Here, hematological changes were monitored in patients with CHC who received RBV monotherapy, and the mechanism of these changes was investigated.

Methods

Patients with CHC (n = 30) received RBV monotherapy for 4 weeks. The RBV dose was determined on the basis of body weight. Complete blood count, and serum erythropoietin (EPO) and thrombopoietin (TPO) levels were assessed. The associations between these parameters and the ITPA SNP (rs1127354) were analyzed.

Results

Over the 4 weeks, the median hemoglobin level of all patients decreased significantly, from 13.6 (10.5–16.6) to 11.7 (9.4–14.9) g/dl (P < 0.001), and the platelet counts increased, from 14.0 × 104 (8.9–37.4 × 104) to 15.8 × 104 (10.2–40.6 × 104) /mm3 (P = 0.003). At week 4, hemoglobin levels differed between patients with the ITPA CC genotype and those with the AA or AC genotypes [11.1 (9.4–13.5) vs. 12.9 (12.5–14.9) g/dl, P = 0.001]. The platelet change ratio (i.e., platelet count at week 4/platelet count at baseline) in the patients with developing anemia was correlated with the increase in the serum EPO level over 4 weeks (r = 0.88, P = 0.002), but not with the increase in the serum TPO level over 4 weeks.

Conclusions

RBV monotherapy induced anemia and affected thrombocytosis in patients with CHC. Elevated endogenous EPO may stimulate platelet production.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Log in via an institution

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Institutional subscriptions

Fig. 1
Fig. 2
Fig. 3
Fig. 4
Fig. 5
Fig. 6
Fig. 7

Similar content being viewed by others

Abbreviations

ITPA :

Inosine triphosphatase

SNP:

Single-nucleotide polymorphism

PEG-IFN:

Pegylated interferon

RBV:

Ribavirin

CHC:

Chronic hepatitis C

EPO:

Erythropoietin

TPO:

Thrombopoietin

HCV:

Hepatitis C virus

GWASs:

Genome-wide association studies

IL28B:

Interleukin 28B

DDRGK1 :

DDRGK domain-containing protein 1

References

  1. Lavanchy D. Evolving epidemiology of hepatitis C virus. Clin Microbiol Infect. 2011;17:107–15.

    Article  PubMed  CAS  Google Scholar 

  2. Thomas DL, Astemborski J, Rai RM, Anania FA, Schaeffer M, Galai N, et al. The natural history of hepatitis C virus infection: host, viral, and environmental factors. JAMA. 2000;284:450–6.

    Article  PubMed  CAS  Google Scholar 

  3. di Iulio J, Ciuffi A, Fitzmaurice K, Kelleher D, Rotger M, Fellay J, et al. Estimating the net contribution of interleukin-28B variation to spontaneous hepatitis C virus clearance. Hepatology. 2011;53:1446–54.

    Article  PubMed  Google Scholar 

  4. Fried MW, Shiffman ML, Reddy KR, Smith C, Marinos G, Goncales FL, et al. Peginterferon alfa-2a plus ribavirin for chronic hepatitis C virus infection. N Engl J Med. 2002;347:975–82.

    Article  PubMed  CAS  Google Scholar 

  5. Hadziyannis SJ, Sette H, Morgan TR, Balan V, Diago M, Marcellin P, et al. Peginterferon-alpha2a and ribavirin combination therapy in chronic hepatitis C: a randomized study of treatment duration and ribavirin dose. Ann Intern Med. 2004;140:346–55.

    PubMed  CAS  Google Scholar 

  6. Sidwell RW, Huffman JH, Khare GP, Allen LB, Witkowski JT, Robins RK. Broad-spectrum antiviral activity of Virazole: 1-beta-d-ribofuranosyl-1,2,4-triazole-3-carboxamide. Science. 1972;177:705–6.

    Article  PubMed  CAS  Google Scholar 

  7. Reddy KR, Shiffman ML, Morgan TR, Zeuzem S, Hadziyannis S, Hamzeh FM, et al. Impact of ribavirin dose reductions in hepatitis C virus genotype 1 patients completing peginterferon alfa-2a/ribavirin treatment. Clin Gastroenterol Hepatol. 2007;5:124–9.

    Article  PubMed  CAS  Google Scholar 

  8. Sulkowski MS, Wasserman R, Brooks L, Ball L, Gish R. Changes in haemoglobin during interferon alpha-2b plus ribavirin combination therapy for chronic hepatitis C virus infection. J Viral Hepat. 2004;11:243–50.

    Article  PubMed  CAS  Google Scholar 

  9. Tanaka Y, Nishida N, Sugiyama M, Kurosaki M, Matsuura K, Sakamoto N, et al. Genome-wide association of IL28B with response to pegylated interferon-alpha and ribavirin therapy for chronic hepatitis C. Nat Genet. 2009;41:1105–9.

    Article  PubMed  CAS  Google Scholar 

  10. Fellay J, Thompson AJ, Ge D, Gumbs C, Urban TJ, Shianna K, et al. ITPA gene variants protect against anaemia in patients treated for chronic hepatitis C. Nature. 2010;464:405–8.

    Article  PubMed  CAS  Google Scholar 

  11. Ochi H, Maekawa T, Abe H, Hayashida Y, Nakano R, Kubo M, et al. ITPA polymorphism affects ribavirin-induced anemia and outcomes of therapy—a genome-wide study of Japanese HCV virus patients. Gastroenterology. 2010;139:1190–7.

    Article  PubMed  CAS  Google Scholar 

  12. Tanaka Y, Kurosaki M, Nishida N, Sugiyama M, Matsuura K, Sakamoto N, et al. Genome-wide association study identified ITPA/DDRGK1 variants reflecting thrombocytopenia in pegylated interferon and ribavirin therapy for chronic hepatitis C. Hum Mol Genet. 2011;20:3507–16.

    Article  PubMed  CAS  Google Scholar 

  13. Homma M, Jayewardene AL, Gambertoglio J, Aweeka F. High-performance liquid chromatographic determination of ribavirin in whole blood to assess disposition in erythrocytes. Antimicrob Agents Chemother. 1999;43:2716–9.

    PubMed  CAS  Google Scholar 

  14. Pawlotsky JM, Dahari H, Neumann AU, Hézode C, Germanidis G, Lonjon I, et al. Antiviral action of ribavirin in chronic hepatitis C. Gastroenterology. 2004;126:703–14.

    Article  PubMed  CAS  Google Scholar 

  15. Hézode C, Forestier N, Dusheiko G, Ferenci P, Pol S, Goeser T, et al. Telaprevir and peginterferon with or without ribavirin for chronic HCV infection. N Engl J Med. 2009;360:1839–50.

    Article  PubMed  Google Scholar 

  16. Canonico PG, Kastello MD, Cosgriff TM, Donovan JC, Ross PE, Spears CT, et al. Hematological and bone marrow effects of ribavirin in rhesus monkeys. Toxicol Appl Pharmacol. 1984;74:163–72.

    Article  PubMed  CAS  Google Scholar 

  17. Streja E, Kovesdy CP, Greenland S, Kopple JD, McAllister CJ, Nissenson AR, et al. Erythropoietin, iron depletion, and relative thrombocytosis: a possible explanation for hemoglobin-survival paradox in hemodialysis. Am J Kidney Dis. 2008;52:727–36.

    Article  PubMed  CAS  Google Scholar 

  18. Homoncik M, Jilma-Stohlawetz P, Schmid M, Ferlitsch A, Peck-Radosavljevic M. Erythropoietin increases platelet reactivity and platelet counts in patients with alcoholic liver cirrhosis: a randomized, double-blind, placebo-controlled study. Aliment Pharmacol Ther. 2004;20:437–43.

    Article  PubMed  CAS  Google Scholar 

  19. Dessypris EN, Gleaton JH, Armstrong OL. Effect of human recombinant erythropoietin on human marrow megakaryocyte colony formation in vitro. Br J Haematol. 1987;65:265–9.

    Article  PubMed  CAS  Google Scholar 

  20. Vaziri ND. Thrombocytosis in EPO-treated dialysis patients may be mediated by EPO rather than iron deficiency. Am J Kidney Dis. 2009;53:733–6.

    Article  PubMed  Google Scholar 

  21. Bilic E. Amino acid sequence homology of thrombopoietin and erythropoietin may explain thrombocytosis in children with iron deficiency anemia. J Pediatr Hematol Oncol. 2003;25:675–6.

    Article  PubMed  Google Scholar 

  22. Tekin D, Yavuzer S, Tekin M, Akar N, Cin S. Possible effects of antioxidant status on increased platelet aggregation in childhood iron-deficiency anemia. Pediatr Int. 2001;43:74–7.

    Article  PubMed  CAS  Google Scholar 

  23. Youdim MB, Woods HF, Mitchell B, Grahame-Smith DG, Callender S. Human platelet monoamine oxidase activity in iron-deficiency anaemia. Clin Sci Mol Med. 1975;48:289–95.

    PubMed  CAS  Google Scholar 

  24. Schmid M, Kreil A, Jessner W, Homoncik M, Datz C, Gangl A, et al. Suppression of haematopoiesis during therapy of chronic hepatitis C with different interferon alpha mono and combination therapy regimens. Gut. 2005;54:1014–20.

    Article  PubMed  CAS  Google Scholar 

  25. De Franceschi L, Fattovich G, Turrini F, Ayi K, Brugnara C, Manzato F, et al. Hemolytic anemia induced by ribavirin therapy in patients with chronic hepatitis C virus infection: role of membrane oxidative damage. Hepatology. 2000;31:997–1004.

    Article  PubMed  Google Scholar 

  26. Vanderheiden BS. Genetic studies of human erythrocyte inosine triphosphatase. Biochem Genet. 1969;3:289–97.

    Article  CAS  Google Scholar 

Download references

Acknowledgments

We appreciate the technical advice given by ProfessorYasuhito Tanaka.

Conflict of interest

Shuhei Hige has received a research grant from MSD. The other authors have declared that no conflict of interest exists.

Author information

Authors and Affiliations

  1. Department of Gastroenterology, Hokkaido University Hospital, North 17 Jo, West 5 Cho-me, Kita-ku, Sapporo, 060-8638, Japan

    Tomoe Kobayashi, Shuhei Hige, Katsumi Terashita, Masato Nakai, Hiromasa Horimoto, Takuya Sho, Mitsuru Nakanishi & Makoto Chuma

  2. Department of Gastroenterology, Hakodate Municipal Hospital, 10-1 Minato-cho, Hakodate, 041-8680, Japan

    Koji Ogawa

  3. Department of Gastroenterology and Hepatology, Tokyo Medical and Dental University, 1-5-45 Yushima, Bunkyo-ku, Tokyo, 113-8519, Japan

    Naoya Sakamoto

  4. Department of Cancer Preventive Medicine, Hokkaido University Graduate School of Medicine, North 12 Jo, West 7 Cho-me, Kita-ku, Sapporo, 060-0812, Japan

    Masahiro Asaka

Authors
  1. Tomoe Kobayashi
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Shuhei Hige
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Katsumi Terashita
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Masato Nakai
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. Hiromasa Horimoto
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. Takuya Sho
    View author publications

    You can also search for this author in PubMed Google Scholar

  7. Mitsuru Nakanishi
    View author publications

    You can also search for this author in PubMed Google Scholar

  8. Koji Ogawa
    View author publications

    You can also search for this author in PubMed Google Scholar

  9. Makoto Chuma
    View author publications

    You can also search for this author in PubMed Google Scholar

  10. Naoya Sakamoto
    View author publications

    You can also search for this author in PubMed Google Scholar

  11. Masahiro Asaka
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Shuhei Hige.

Rights and permissions

Reprints and permissions

About this article

Cite this article

Kobayashi, T., Hige, S., Terashita, K. et al. Anemia and thrombocytosis induced by ribavirin monotherapy in patients with chronic hepatitis C. J Gastroenterol 47, 1228–1237 (2012). https://doi.org/10.1007/s00535-012-0579-y

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s00535-012-0579-y

Keywords

Search

Navigation