Antiviral therapy decreases GpIIb/IIIa activation of platelets in patients with chronic hepatitis C

Wolfgang Sieghart; Monika Homoncik; Bernd Jilma; Elisabeth Formann; Peter Ferenci; Alfred Gangl; Markus Peck-Radosavljevic

doi:10.1160/TH05-12-0781

Thrombosis and Haemostasis, Table of Contents

Thromb Haemost 2006; 95(02): 260-266
DOI: 10.1160/TH05-12-0781

Platelets and Blood Cells

Schattauer GmbH

Antiviral therapy decreases GpIIb/IIIa activation of platelets in patients with chronic hepatitis C

Wolfgang Sieghart

¹Department of Internal Medicine IV, Division of Gastroenterology and Hepatology, Vienna, Austria

²Department of Clinical Pharmacology, Medical University of Vienna, Vienna, Austria

,

Monika Homoncik

¹Department of Internal Medicine IV, Division of Gastroenterology and Hepatology, Vienna, Austria

,

Bernd Jilma

²Department of Clinical Pharmacology, Medical University of Vienna, Vienna, Austria

,

Elisabeth Formann

¹Department of Internal Medicine IV, Division of Gastroenterology and Hepatology, Vienna, Austria

,

Peter Ferenci

¹Department of Internal Medicine IV, Division of Gastroenterology and Hepatology, Vienna, Austria

,

Alfred Gangl

¹Department of Internal Medicine IV, Division of Gastroenterology and Hepatology, Vienna, Austria

,

Markus Peck-Radosavljevic

¹Department of Internal Medicine IV, Division of Gastroenterology and Hepatology, Vienna, Austria

› Author Affiliations

Abstract

Summary

Interferon alpha (IFN-α) is used to treat haematological and solid malignancies and is the gold standard therapy for chronic hepatitisC infection in combination with ribavirin. It has a well known platelet lowering effect and was recently shown to impair platelet aggregation in the presence of various agonists and has been accused to increase patients’ bleeding risk during IFN-α therapy. Thus, we hypothesised that antiviral treatment decreases GpIIb/IIIa activation and affects global platelet function. In a prospective clinical trial, we examined the effects of combination therapy with pegylated IFN-α 2a (PegIFN-α 2a) and ribavirin on platelet GpIIb/IIIa activation and platelet secretion in 20 patients with chronic hepatitis C at week 2, 4, 8 and 12 after the beginning of therapy. In addition, we determined global platelet function (CEPI-CT) with the PFA-100 and vWF-Ag levels. Antiviral therapy significantly decreased GpIIb/IIIa activation in a time dependent manner, whereas markers of platelet secretion (P-selectin, β-thromboglobulin) remained unchanged. Despite a marked elevation of vWF-Ag levels, CEPI-CT did not change compared to baseline levels. Antiviral therapy significantly decreases GpIIb/IIIa activation in patients with chronic hepatitis C, while vWG-Antigen levels are markedly increased and α-granule secretion is not affected. This does not result in an alteration of global platelet function as assessed by the PFA-100, because elevated vWF-Antigen levels might compensate for the acquired defect.

Keywords

Platelet activation markers - von Willebrand factor - clinical / epidemiological studies

Full Text

References

References
1 Fried MW. Side effects of therapy of hepatitis C and their management. Hepatology 2002; 36 (05) (Suppl. 01) S237-S244.
2 Shrestha R, McKinley C, Bilir BM. et al. Possible idiopathic thrombocytopenic purpura associated with natural alpha interferon therapy for chronic hepatitis C infection. Am J Gastroenterol 1995; 90: 1146-7.
3 Pockros PJ, Duchini A, McMillan R. et al. Immune thrombocytopenic purpura in patients with chronic hepatitis C virus infection. Am J Gastroenterol 2002; 97: 2040-5.
4 Peck-Radosavljevic M, Wichlas M, Pidlich J. et al. Blunted thrombopoietin response to interferon α-induced thrombocytopenia during treatment for hepatitis C. Hepatology 1998; 28: 1424-9.
5 Panzer S, Seel E. Is there an increased frequency of autoimmune thrombocytopenia in hepatitis C infection? A review. Wien Med Wochenschr 2003; 153: 417-20.
6 Verfaillie CM, Bhatia R, Browne P. et al. Interferon-α restores β1-integrin-dependent, collagen-mediated platelet aggregation in a patient with chronic myelogenous leukemia. J Lab Clin Med 1998; 131: 163-9.
7 Catani L, Gugliotta L, Cascione ML. et al. Platelet function and interferon α-2a treatment in essential thrombocythaemia. Eur J Haematol 1991; 46: 158-62.
8 Gutman H, Schachter J, Stopel E. et al. Impaired platelet aggregation in melanoma patients treated with interferon-α-2b adjuvant therapy. Cancer 2002; 94: 780-5.
9 Ishak K, Baptista A, Bianchi L. et al. Histological grading and staging of chronic hepatitis. J Hepatol 1995; 22: 696-9.
10 Seymour RA, Williams FM, Oxley A. et al. A comparative study of the effects of aspirin and paracetamol (acetaminophen) on platelet aggregation and bleeding time. Eur J Clin Pharmacol 1984; 26: 567-71.
11 Stohlawetz PJ, Dzirlo L, Hergovich N. et al. Effects of erythropoietin on platelet reactivity and thrombopoiesis in humans. Blood 2000; 95: 2983-9.
12 Shattil SJ, Hoxie JA, Cunningham M. et al. Changes in the platelet membrane glycoprotein IIb. IIIa complex during platelet activation. J Biol Chem 1985; 260: 11107-14.
13 Homoncik M, Jilma B, Donham DC. et al. Activation of calcium-dependent calmodulin by calcium(II)3(3,5-diisopropylsalicylate)6(H2O)6 decreases thrombin receptor activating peptide-induced P-selectin expression. Blood Coagul Fibrinolysis 2003; 14: 131-8.
14 Pineda AA, Zylstra VW, Clare DE. et al. Viability and functional integrity of washed platelets. Transfusion 1989; 29: 524-7.
15 Perry CM, Jarvis B. Peginterferon-α-2a (40 kD): a review of its use in the management of chronic hepatitis C. Drugs 2001; 61: 2263-88.
16 Jilma B. Platelet function analyzer (PFA-100): a tool to quantify congenital or acquired platelet dysfunction. J Lab Clin Med 2001; 138: 152-63.
17 Harrison P. Progress in the assessment of platelet function. BrJ Haematol 2000; 111: 733-44.
18 Homoncik M, Blann AD, Hollenstein U. et al. Systemic inflammation increases shear stress-induced platelet plug formation measured by the PFA-100 Br J Haematol. 2000; 111: 1250-2.
19 Reiter RA, Mayr F, Blazicek H. et al. Desmopressin antagonizes the in vitro platelet dysfunction induced by GPIIb/IIIa inhibitors and aspirin. Blood 2003; 102: 4594-9.
20 Nusinow SR, Federici AB, Zimmerman TS. et al. Increased von Willebrand factor antigen in the plasma of patients with vasculitis. Arthritis Rheum 1984; 27: 1405-10.
21 Stevens TR, James JP, Simmonds NJ. et al. Circulating von Willebrand factor in inflammatory bowel disease. Gut 1992; 33: 502-6.
22 Michelson AD, Ellis PA, Barnard MR. et al. Downregulation of the platelet surface glycoprotein Ib-IX complex in whole blood stimulated by thrombin, adenosine diphosphate, or an in vivo wound. Blood 1991; 77: 770-9.
23 Shattil SJ. Signaling through platelet integrin αIIbβ3: inside-out, outside-in, and sideways. Thromb Haemost 1999; 82: 318-25.
24 Michelson AD, Furman MI. Laboratory markers of platelet activation and their clinical significance. Curr Opin Hematol 1999; 06: 342-8.
25 Heyns AD, Lotter MG, Badenhorst PN. et al. Kinetics, distribution and sites of destruction of 111indium-labelled human platelets. Br J Haematol 1980; 44: 269-80.
26 Stohlawetz P, Horvath M, Pernerstorfer T. et al. Effects of nitric oxide on platelet activation during plateletpheresis and in vivo tracking of biotinylated platelets in humans. Transfusion 1999; 39: 506-14.
27 Poujol C, Nurden A, Paponneau A. et al. Ultra structural analysis of the distribution of von Willebrand factor and fibrinogen in platelet aggregates formed in the PFA-100. Platelets 1998; 09: 381-9.
28 Moeller A, Weippert-Kretschmer M, Prinz H. et al. Influence of ABO blood groups on primary hemostasis. Transfusion 2001; 41: 56-60.
29 Chakroun T, Gerotziafas G, Robert F. et al. In vitro aspirin resistance detected by PFA-100 closure time: pivotal role of plasma von Willebrand factor. BrJ Haematol 2004; 124: 80-5.
30 Tomokiyo K, Kamikubo Y, Hanada T. et al. Von Willebrand factor accelerates platelet adhesion and thrombus formation on a collagen surface in plateletreduced blood under flow conditions. Blood 2005; 105: 1078-84.
31 Roche. Investigator’s brochure for PegInterferon alpha 2a. 2003
32 Manns MP, McHutchison JG, Gordon SC. et al. Peginterferon α-2b plus ribavirin compared with interferon α-2b plus ribavirin for initial treatment of chronic hepatitis C: a randomised trial. Lancet 2001; 358: 958-65.