Journal of Gastroenterology

, Volume 45, Issue 8, pp 876–884 | Cite as

Thrombocytopenia is more severe in patients with advanced chronic hepatitis C than B with the same grade of liver stiffness and splenomegaly

  • Kazuaki Tejima
  • Ryota Masuzaki
  • Hitoshi Ikeda
  • Haruhiko Yoshida
  • Ryosuke Tateishi
  • Yosuke Sugioka
  • Yukio Kume
  • Tomoko Okano
  • Tomomi Iwai
  • Hiroaki Gotoh
  • Sachiko Katoh
  • Atsushi Suzuki
  • Yukako Koike
  • Yutaka Yatomi
  • Masao Omata
  • Kazuhiko Koike
Original Article—Liver, Pancreas, and Biliary Tract


Background and aim

The mechanism responsible for thrombocytopenia in chronic liver diseases (CLD) is not yet fully understood. The prevalence of thrombocytopenia has been reported to be higher in patients with hepatitis C virus-related hepatocellular carcinoma (CLD-C) than in those with hepatitis B virus-related hepatocellular carcinoma (CDC-B). We have examined the potential difference in thrombocytopenia between patients with CLD-B and those with CLD-C in terms of liver fibrosis adjustment and splenomegaly.


The study cohort consisted of 102 patients with CLD-B and 143 patients with CLD-C were enrolled. Liver stiffness, which is reported to be well correlated with the degree of liver fibrosis, was measured by transient elastography.


The analysis of covariance with liver stiffness as a covariate revealed that the platelet count was lower in CLD-C patients than in CLD-B patients. Following stratification for liver stiffness, thrombocytopenia was found to be more severe in CLD-C patients than CLD-B patients with advanced liver stiffness, whereas the degree of splenomegaly was not significantly different. The plasma thrombopoietin level was not different between CLD-B and CLD-C patients with advanced liver stiffness, and the immature platelet number was lower in CLD-C patients despite thrombocytopenia being more severe in these patients.


CLD-C patients with advanced liver stiffness presented with more severe levels of thrombocytopenia than CLD-B patients even with the same grade of splenomegaly. Impaired platelet production rather than enhanced platelet destruction may underlie the mechanism responsible for thrombocytopenia in patients with CLD.


Liver stiffness Splenomegaly Thrombocytopenia Thrombopoietin Transient elastography 



Alanine aminotransferase


Analysis of covariance


Chronic liver disease


Hepatitis B envelope antigen


Hepatitis B surface antigen


Hepatitis B virus


Hepatitis C virus


Immature platelet fraction


Interquartile ranges


  1. 1.
    McHutchison JG, Dusheiko G, Shiffman ML, Rodriguez-Torres M, Sigal S, Bourliere M, et al. Eltrombopag for thrombocytopenia in patients with cirrhosis associated with hepatitis C. N Engl J Med. 2007;357:2227–36.CrossRefPubMedGoogle Scholar
  2. 2.
    National Institutes of Health. NIH Consensus Development Conference Statement: Management of hepatitis C. Hepatology. 2002;36:S3–20.Google Scholar
  3. 3.
    Poynard T, Yuen MF, Ratziu V, Lai CL. Viral hepatitis C. Lancet. 2003;362:2095–100.CrossRefPubMedGoogle Scholar
  4. 4.
    Liaw YF, Tai DI, Chu CM, Chen TJ. The development of cirrhosis in patients with chronic type B hepatitis: a prospective study. Hepatology. 1988;8:493–6.CrossRefPubMedGoogle Scholar
  5. 5.
    Fattovich G, Brollo L, Giustina G, Noventa F, Pontisso P, Alberti A, et al. Natural history and prognostic factors for chronic hepatitis type B. Gut. 1991;32:294–8.CrossRefPubMedGoogle Scholar
  6. 6.
    Aster RH. Pooling of platelets in the spleen: role in the pathogenesis of “hypersplenic” thrombocytopenia. J Clin Invest. 1966;45:645–57.CrossRefPubMedGoogle Scholar
  7. 7.
    Schmidt KG, Rasmussen JW, Bekker C, Madsen PE. Kinetics and in vivo distribution of 111-In-labelled autologous platelets in chronic hepatic disease: mechanisms of thrombocytopenia. Scand J Haematol. 1985;34:39–46.PubMedGoogle Scholar
  8. 8.
    Peck-Radosavljevic M. Hypersplenism. Eur J Gastroenterol Hepatol. 2001;13:317–23.CrossRefPubMedGoogle Scholar
  9. 9.
    Bolognesi M, Merkel C, Sacerdoti D, Nava V, Gatta A. Role of spleen enlargement in cirrhosis with portal hypertension. Dig Liver Dis. 2002;34:144–50.CrossRefPubMedGoogle Scholar
  10. 10.
    Adinolfi LE, Giordano MG, Andreana A, Tripodi MF, Utili R, Cesaro G, et al. Hepatic fibrosis plays a central role in the pathogenesis of thrombocytopenia in patients with chronic viral hepatitis. Br J Haematol. 2001;113:590–5.CrossRefPubMedGoogle Scholar
  11. 11.
    Karasu Z, Tekin F, Ersoz G, Gunsar F, Batur Y, Ilter T, et al. Liver fibrosis is associated with decreased peripheral platelet count in patients with chronic hepatitis B and C. Dig Dis Sci. 2007;52:1535–9.CrossRefPubMedGoogle Scholar
  12. 12.
    Lu SN, Wang JH, Liu SL, Hung CH, Chen CH, Tung HD, et al. Thrombocytopenia as a surrogate for cirrhosis and a marker for the identification of patients at high-risk for hepatocellular carcinoma. Cancer. 2006;107:2212–22.CrossRefPubMedGoogle Scholar
  13. 13.
    Imbert-Bismut F, Ratziu V, Pieroni L, Charlotte F, Benhamou Y, Poynard T. Biochemical markers of liver fibrosis in patients with hepatitis C virus infection: a prospective study. Lancet. 2001;357:1069–75.CrossRefPubMedGoogle Scholar
  14. 14.
    Myers R, Tainturier M, Ratziu V, Piton A, Thibault V, Imbert-Bismut F, et al. Prediction of liver histological lesions with biochemical markers in patients with chronic hepatitis B. J Hepatol. 2003;39:222–30.CrossRefPubMedGoogle Scholar
  15. 15.
    Yeh WC, Li PC, Jeng YM, Hsu HC, Kuo PL, Li ML, et al. Elastic modulus measurements of human liver and correlation with pathology. Ultrasound Med Biol. 2002;28:467–74.CrossRefPubMedGoogle Scholar
  16. 16.
    Saito H, Tada S, Nakamoto N, Kitamura K, Horikawa H, Kurita S, et al. Efficacy of non-invasive elastometry on staging of hepatic fibrosis. Hepatol Res. 2004;29:97–103.CrossRefPubMedGoogle Scholar
  17. 17.
    Dienstag J. The role of liver biopsy in chronic hepatitis C. Hepatology. 2002;36:S152–60.CrossRefPubMedGoogle Scholar
  18. 18.
    Lok A, McMahon B. Chronic hepatitis B. Hepatology. 2001;34:1225–41.CrossRefPubMedGoogle Scholar
  19. 19.
    Maharaj B, Maharaj R, Leary W, Cooppan R, Naran A, Pirie D, et al. Sampling variability and its influence on the diagnostic yield of percutaneous needle biopsy of the liver. Lancet. 1986;1:523–5.CrossRefPubMedGoogle Scholar
  20. 20.
    McGill D, Rakela J, Zinsmeister A, Ott B. A 21-year experience with major hemorrhage after percutaneous liver biopsy. Gastroenterology. 1990;99:1396–400.PubMedGoogle Scholar
  21. 21.
    Sandrin L, Fourquet B, Hasquenoph JM, Yon S, Fournier C, Mal F, et al. Transient elastography: a new noninvasive method for assessment of hepatic fibrosis. Ultrasound Med Biol. 2003;29:1705–13.CrossRefPubMedGoogle Scholar
  22. 22.
    Castera L, Vergniol J, Foucher J, Le Bail B, Chanteloup E, Haaser M, et al. Prospective comparison of transient elastography, Fibrotest, APRI, and liver biopsy for the assessment of fibrosis in chronic hepatitis C. Gastroenterology. 2005;128:343–50.CrossRefPubMedGoogle Scholar
  23. 23.
    Ziol M, Handra-Luca A, Kettaneh A, Christidis C, Mal F, Kazemi F, et al. Noninvasive assessment of liver fibrosis by measurement of stiffness in patients with chronic hepatitis C. Hepatology. 2005;41:48–54.CrossRefPubMedGoogle Scholar
  24. 24.
    Verveer C, de Knegt RJ. Non-invasive measurement of liver fibrosis: application of the FibroScan in hepatology. Scand J Gastroenterol. 2006;41[Suppl 243]:85–8.CrossRefGoogle Scholar
  25. 25.
    Ganne-Carrie N, Ziol M, de Ledinghen V, Douvin C, Marcellin P, Castera L, et al. Accuracy of liver stiffness measurement for the diagnosis of cirrhosis in patients with chronic liver diseases. Hepatology. 2006;44:1511–7.CrossRefPubMedGoogle Scholar
  26. 26.
    Fraquelli M, Rigamonti C. Diagnosis of cirrhosis by transient elastography: what is hidden behind misleading results. Hepatology 2007;46:282 (author reply, p. 283).Google Scholar
  27. 27.
    Masuzaki R, Tateishi R, Yoshida H, Yoshida H, Sato S, Kato N, et al. Risk assessment of hepatocellular carcinoma in chronic hepatitis C patients by transient elastography. J Clin Gastroenterol. 2008;42:839–43.CrossRefPubMedGoogle Scholar
  28. 28.
    Lamb PM, Lund A, Kanagasabay RR, Martin A, Webb JA, Reznek RH. Spleen size: how well do linear ultrasound measurements correlate with three-dimensional CT volume assessments? Br J Radiol. 2002;75:573–7.PubMedGoogle Scholar
  29. 29.
    Kurata Y, Hayashi S, Kiyoi T, Kosugi S, Kashiwagi H, Honda S, et al. Diagnostic value of tests for reticulated platelets, plasma glycocalicin, and thrombopoietin levels for discriminating between hyperdestructive and hypoplastic thrombocytopenia. Am J Clin Pathol. 2001;115:656–64.CrossRefPubMedGoogle Scholar
  30. 30.
    Briggs C, Kunka S, Hart D, Oguni S, Machin SJ. Assessment of an immature platelet fraction (IPF) in peripheral thrombocytopenia. Br J Haematol. 2004;126:93–9.CrossRefPubMedGoogle Scholar
  31. 31.
    Cobbold JF, Morin S, Taylor-Robinson SD. Transient elastography for the assessment of chronic liver disease: Ready for the clinic? World J Gastroenterol. 2007;13:4791–7.PubMedGoogle Scholar
  32. 32.
    Bartley TD, Bogenberger J, Hunt P, Li YS, Lu HS, Martin F, et al. Identification and cloning of a megakaryocyte growth and development factor that is a ligand for the cytokine receptor Mpl. Cell. 1994;77:1117–24.CrossRefPubMedGoogle Scholar
  33. 33.
    Kaushansky K, Lok S, Holly RD, Broudy VC, Lin N, Bailey MC, et al. Promotion of megakaryocyte progenitor expansion and differentiation by the c-Mpl ligand thrombopoietin. Nature. 1994;369:568–71.CrossRefPubMedGoogle Scholar
  34. 34.
    Fielder PJ, Gurney AL, Stefanich E, Marian M, Moore MW, Carver-Moore K, et al. Regulation of thrombopoietin levels by c-mpl-mediated binding to platelets. Blood. 1996;87:2154–61.PubMedGoogle Scholar
  35. 35.
    Emmons RV, Reid DM, Cohen RL, Meng G, Young NS, Dunbar CE, et al. Human thrombopoietin levels are high when thrombocytopenia is due to megakaryocyte deficiency and low when due to increased platelet destruction. Blood. 1996;87:4068–71.PubMedGoogle Scholar
  36. 36.
    Li J, Xia Y, Kuter DJ. Interaction of thrombopoietin with the platelet c-mpl receptor in plasma: binding, internalization, stability and pharmacokinetics. Br J Haematol. 1999;106:345–56.CrossRefPubMedGoogle Scholar
  37. 37.
    Koike Y, Miyazaki K, Higashihara M, Kimura E, Jona M, Uchihashi K, et al. Clinical significance of detection of immature platelets: comparison between percentage of reticulated platelets as detected by flow cytometry and immature platelet fraction as detected by automated measurement. Eur J Haematol. 2010;84:183–4.CrossRefPubMedGoogle Scholar
  38. 38.
    Kajihara M, Okazaki Y, Kato S, Ishii H, Kawakami Y, Ikeda Y, et al. Evaluation of platelet kinetics in patients with liver cirrhosis: similarity to idiopathic thrombocytopenic purpura. J Gastroenterol Hepatol. 2007;22:112–8.CrossRefPubMedGoogle Scholar
  39. 39.
    Kaushansky K. Thrombopoietin: basic biology, clinical promise. Int J Hematol. 1995;62:7–15.CrossRefPubMedGoogle Scholar
  40. 40.
    Kaushansky K. Thrombopoietin: the primary regulator of megakaryocyte and platelet production. Thromb Haemost. 1995;74:521–5.PubMedGoogle Scholar
  41. 41.
    Eaton DL, de Sauvage FJ. Thrombopoietin: the primary regulator of megakaryocytopoiesis and thrombopoiesis. Exp Hematol. 1997;25:1–7.PubMedGoogle Scholar
  42. 42.
    Jelkmann W. The role of the liver in the production of thrombopoietin compared with erythropoietin. Eur J Gastroenterol Hepatol. 2001;13:791–801.CrossRefPubMedGoogle Scholar
  43. 43.
    Koike Y, Yoneyama A, Shirai J, Ishida T, Shoda E, Miyazaki K, et al. Evaluation of thrombopoiesis in thrombocytopenic disorders by simultaneous measurement of reticulated platelets of whole blood and serum thrombopoietin concentrations. Thromb Haemost. 1998;79:1106–10.PubMedGoogle Scholar
  44. 44.
    Peck-Radosavljevic M, Wichlas M, Zacherl J, Stiegler G, Stohlawetz P, Fuchsjager M, et al. Thrombopoietin induces rapid resolution of thrombocytopenia after orthotopic liver transplantation through increased platelet production. Blood. 2000;95:795–801.PubMedGoogle Scholar
  45. 45.
    Peck-Radosavljevic M. Thrombocytopenia in liver disease. Can J Gastroenterol. 2000;14[Suppl D]:60D–6D.PubMedGoogle Scholar
  46. 46.
    Wolber EM, Ganschow R, Burdelski M, Jelkmann W. Hepatic thrombopoietin mRNA levels in acute and chronic liver failure of childhood. Hepatology. 1999;29:1739–42.CrossRefPubMedGoogle Scholar
  47. 47.
    Kawasaki T, Takeshita A, Souda K, Kobayashi Y, Kikuyama M, Suzuki F, et al. Serum thrombopoietin levels in patients with chronic hepatitis and liver cirrhosis. Am J Gastroenterol. 1999;94:1918–22.CrossRefPubMedGoogle Scholar
  48. 48.
    Espanol I, Gallego A, Enriquez J, Rabella N, Lerma E, Hernandez A, et al. Thrombocytopenia associated with liver cirrhosis and hepatitis C viral infection: role of thrombopoietin. Hepatogastroenterology. 2000;47:1404–6.PubMedGoogle Scholar
  49. 49.
    Giannini E, Borro P, Botta F, Fumagalli A, Malfatti F, Podesta E, et al. Serum thrombopoietin levels are linked to liver function in untreated patients with hepatitis C virus-related chronic hepatitis. J Hepatol. 2002;37:572–7.CrossRefPubMedGoogle Scholar
  50. 50.
    Giannini E, Botta F, Borro P, Malfatti F, Fumagalli A, Testa E, et al. Relationship between thrombopoietin serum levels and liver function in patients with chronic liver disease related to hepatitis C virus infection. Am J Gastroenterol. 2003;98:2516–20.CrossRefPubMedGoogle Scholar
  51. 51.
    Stockelberg D, Andersson P, Bjornsson E, Bjork S, Wadenvik H. Plasma thrombopoietin levels in liver cirrhosis and kidney failure. J Intern Med. 1999;246:471–5.CrossRefPubMedGoogle Scholar
  52. 52.
    Schoffski P, Tacke F, Trautwein C, Martin MU, Caselitz M, Hecker H, et al. Thrombopoietin serum levels are elevated in patients with hepatitis B/C infection compared to other causes of chronic liver disease. Liver. 2002;22:114–20.CrossRefPubMedGoogle Scholar
  53. 53.
    Aref S, Mabed M, Selim T, Goda T, Khafagy N. Thrombopoietin (TPO) levels in hepatic patients with thrombocytopenia. Hematology. 2004;9:351–6.CrossRefPubMedGoogle Scholar
  54. 54.
    Ozer B, Serin E, Sezgin N, Cosar A, Guclu M, Gur G, et al. Thrombopoietin or interleukin-6 has no effect on thrombocytopenia of cirrhosis. Hepatogastroenterology. 2007;54:1187–91.PubMedGoogle Scholar
  55. 55.
    Sagir A, Erhardt A, Schmitt M, Haussinger D. Transient elastography is unreliable for detection of cirrhosis in patients with acute liver damage. Hepatology. 2008;47:592–5.CrossRefPubMedGoogle Scholar
  56. 56.
    Arena U, Vizzutti F, Corti G, Ambu S, Stasi C, Bresci S, et al. Acute viral hepatitis increases liver stiffness values measured by transient elastography. Hepatology. 2008;47:380–4.CrossRefPubMedGoogle Scholar
  57. 57.
    Marcellin P, Ziol M, Bedossa P, Douvin C, Poupon R, de Ledinghen V, et al. Non-invasive assessment of liver fibrosis by stiffness measurement in patients with chronic hepatitis B. Liver Int. 2009;29:242–7.CrossRefPubMedGoogle Scholar
  58. 58.
    Ogawa E, Furusyo N, Toyoda K, Takeoka H, Otaguro S, Hamada M, et al. Transient elastography for patients with chronic hepatitis B and C virus infection: non-invasive, quantitative assessment of liver fibrosis. Hepatol Res. 2007;37:1002–10.CrossRefPubMedGoogle Scholar
  59. 59.
    Hui CK, Leung N, Shek TW, Yao H, Lee WK, Lai JY, et al. Sustained disease remission after spontaneous HBeAg seroconversion is associated with reduction in fibrosis progression in chronic hepatitis B Chinese patients. Hepatology. 2007;46:690–8.CrossRefPubMedGoogle Scholar

Copyright information

© Springer 2010

Authors and Affiliations

  • Kazuaki Tejima
    • 1
    • 2
  • Ryota Masuzaki
    • 3
  • Hitoshi Ikeda
    • 1
  • Haruhiko Yoshida
    • 3
  • Ryosuke Tateishi
    • 3
  • Yosuke Sugioka
    • 1
  • Yukio Kume
    • 1
  • Tomoko Okano
    • 1
  • Tomomi Iwai
    • 1
  • Hiroaki Gotoh
    • 1
  • Sachiko Katoh
    • 1
  • Atsushi Suzuki
    • 1
  • Yukako Koike
    • 1
  • Yutaka Yatomi
    • 1
  • Masao Omata
    • 3
  • Kazuhiko Koike
    • 3
  1. 1.Department of Clinical Laboratory MedicineThe University of TokyoBunkyo-kuJapan
  2. 2.Department of GastroenterologyToshiba General HospitalShinagawa-kuJapan
  3. 3.Department of GastroenterologyThe University of TokyoBunkyo-kuJapan

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