Hepatitis C in haemophiliacs

Massimo Franchini

doi:10.1160/TH04-08-0510

Thrombosis and Haemostasis, Table of Contents

Thromb Haemost 2004; 92(06): 1259-1268
DOI: 10.1160/TH04-08-0510

Review Article

Schattauer GmbH

Hepatitis C in haemophiliacs

Massimo Franchini

¹Servizio di Immunoematologia e Trasfusione – Centro Emofilia, Azienda Ospedaliera di Verona, Verona, Italy

› Author Affiliations

Abstract

Summary

Virtually all haemophiliacs who received non-virucidally treated, large-pool clotting factor concentrates before 1986 became infected with hepatitis C virus (HCV). Although approximately one-tenth of HCV-infected people have been shown to clear the infection naturally, in the remaining cases the infection slowly progresses. Unfortunately, a significant percentage of HCV-infected hemophilic patients were also co-infected with human immunodeficiency virus (HIV), which can accelerate the progression to cirrhosis and liver failure. As regards treatment, combination therapy with interferon (IFN) and ribavirin has improved the poor results obtained with IFN monotherapy and has become the standard treatment of chronic hepatitis C. Given the positive results obtained with pegylated interferon in non-haemophiliacs, ongoing trials are evaluating this promising therapy in HCV-chronically infected haemophilic patients. Finally, anti-HCV treatment should also be considered for those haemophiliacs co-infected with HIV in whom anti-retroviral treatment has stabilized the HIV infection.

Keywords

Hepatitis C virus infection - haemophilia - therapy

Full Text

References

References
1 Fried MW. Management of hepatitis C in the haemophilia patient. Am J Med 1999; 107: 85-9.
2 Lee CA. Hepatitis C infection and its management. Haemophilia 2000; 06: 133-7.
3 Makris M, Preston FE, Triger DR. et al. Hepatitis C antibody and chronic liver disease in haemophilia. Lancet 1990; 335: 1117-9.
4 Troisi CL, Hollinger FB, Hoots WK. et al. A multicenter study of viral hepatitis in a United States haemophilic population. Blood 1993; 81: 412-8.
5 Morfini M, Mannucci PM, Ciavarella N. et al. Prevalence of infection with the hepatitis C virus among Italian haemophiliacs before and after the introduction of virally inactivated clotting factor concentrates: a retrospective evaluation. Vox Sang 1994; 67: 178-82.
6 Sabin CA, Telfer P, Phillips AN. et al. The association between hepatitis C virus genotype and human immunodeficiency virus disease progression in a cohort of haemophilic men. J Infect Dis 1997; 175: 164-8.
7 Dieterich DT. Hepatitis C virus and human immunodeficiency virus: clinical issues in coinfection. Am J Med 1999; 107: 79S-84S.
8 Eyster ME, Diamondstone LS, Lien JM. et al. for the Multicenter Haemophilia Cohort Study. Natural history of hepatitis C virus infection (HCV) in multitransfused haemophiliacs: effect of coinfection with human immunodeficiency virus (HIV). J Acquir Immune Defic Syndr 1993; 06: 602-10.
9 Eyster ME, Fried MW, Di Bisceglie AM. et al for the Multicenter Haemophilia Cohort Study. Increasing hepatitis C virus RNA levels in haemophiliacs: relationship to human immunodeficiency virus infection and liver disease. Blood 1994; 84: 1020-3.
10 Makris M, Preston FE, Rosendaal FR. et al. The natural history of chronic hepatitis C in haemophiliacs. Br J Haematol 1996; 94: 746-52.
11 Telfer P, Sabin C, Devereux H. et al. The progression of HCV-associated liver disease in a cohort of haemophilic patients. Br J Haematol 1994; 87: 555-61.
12 Yee TT, Griffioen A, Sabin CA. et al. The natural history of HCV in a cohort of haemophilic patients infected between 1961 and 1985. Gut 2000; 47: 845-51.
13 Meijer K, Haagsma EB, Kok T. et al. Natural history of hepatitis C in HIV-negative patients with congenital coagulation disorders. J Hepatol 1999; 31: 400-6.
14 Franchini M, Rossetti G, Tagliaferri A. et al. The natural history of chronic hepatitis C in a cohort of HIV-negative Italian patients with hereditary bleeding disorders. Blood 2001; 98: 1836-41.
15 Brettler DB, Alter HJ, Dienstag JL. et al. Prevalence of hepatitis C virus antibody in a cohort of haemophilia patients. Blood 1990; 76: 254-6.
16 Mauser-Bunschoten EP, Bresters D, van Drimmelen AAJ. et al. Hepatitis C infection and viremia in Dutch haemophilia patients. J Med Virol 1995; 45: 241-5.
17 Franchini M, Capra F, Tagliaferri A. et al. Update on chronic hepatitis C in haemophiliacs. Haematologica 2002; 87: 542-9.
18 Lee C, Dusheiko G. The natural history and antiviral treatment of hepatitis C in haemophilia. Haemophilia 2002; 08: 322-9.
19 Jarvis LM, Ludlam CA, Simmonds P. Hepatitis C virus genotypes in multitransfused individuals. Haemophilia 1995; 01: 3-7.
20 Zoulim F. Hepatitis C virus infection in special groups. J Hepatol 1999; 31 (Suppl. 01) 130-5.
21 Trepo C, Pradat P. Hepatitis C virus infection in Western Europe. J Hepatol 1999; 31 (Suppl. 01) 80-3.
22 Roffi L, Ricci A, Ogliari C. et al. HCV genotypes in Northern Italy: a survey of 1368 histologically proven chronic hepatitis C patients. J Hepatol 1998; 29: 701-6.
23 Lau JYN, Davis GL, Prescott LE. et al. Distribution of hepatitis C virus genotypes determined by line probe assay in patients with chronic hepatitis C seen at tertiary referral centers in the United States. Ann Intern Med 1996; 124: 868-76.
24 Takayama S, Taki M, Meguro T. et al. Virological characteristics of HCV infection in Japanese haemophiliacs. Haemophilia 1997; 03: 131-6.
25 Eyster ME, Shermann KE, Goedert JJ. et al for the Multicenter Haemophilia Cohort Study. Prevalence and changes in hepatitis C virus genotypes among multitransfused persons with haemophilia. J Infect Dis 1999; 179: 1062-9.
26 Telfer PT, Devereux H, Savage K. et al. Chronic hepatitis C virus infection in haemophilic patients: clinical significance of viral genotype. Thromb Haemost 1995; 74: 1259-64.
27 Tagariello G, Pontisso P, Davoli PG. et al. Hepatitis C virus genotypes and severity of chronic liver disease in haemophiliacs. Br J Haematol 1995; 91: 708-13.
28 Preston FE, Jarvis LM, Makris M. et al. Heterogeneity of hepatitis C virus genotypes in haemophilia: relationship with chronic liver disease. Blood 1995; 85: 1259-62.
29 Santagostino E, Colombo M, Cultraro D. et al. High prevalence of serum cryoglobulins in multitransfused haemophilic patients with chronic hepatitis C. Blood 1998; 92: 516-9.
30 Alberti A, Chemello L, Benvegnu’ L. Natural history of hepatitis C. J Hepatol 1999; 31 (Suppl. 01) 17-24.
31 Seef LB. Why is there such difficulty in defining the natural history of hepatitis C?. Transfusion 2000; 40: 1161-4.
32 Alter HJ, Seef LB. Recovery, persistence, and sequelae in hepatitis C virus infection: a perspective on long-term outcome. Semin Liver Dis 2000; 20: 17-35.
33 Seef LB, Miller RN, Rabkin CS. et al. 45-year follow-up of hepatitis C virus infection in healthy young adults. Ann Intern Med 2000; 132: 105-11.
34 Liang TJ, Rehermann B, Seef LB. et al. Pathogenesis, natural history, treatment and prevention of hepatitis C. Ann Intern Med 2000; 132: 296-305.
35 Thomas DL, Astemborski J, Rai RM. et al. The natural history of hepatitis C virus infection. JAMA 2000; 284: 450-6.
36 Tong MJ, El-Farra NS, Reikes AR. et al. Clinical outcomes after transfusion-associated hepatitis C. N Engl J Med 1995; 332: 1463-6.
37 Seef LB. The natural history of hepatitis C. Am J Med 1999; 107: 10S-15S.
38 Koretz RL, Abbey H, Coleman E. et al. Non-A, non-B post-transfusion hepatitis: looking back in the second decade. Ann Intern Med 1993; 119: 110-5.
39 Yano M, Kumada H, Kage M. The long-term pathological evolution of chronic hepatitis C. Hepatology 1996; 23: 1334-40.
40 Wong VS, Egner W, Elsey T. et al. Incidence, character and clinical relevance of mixed cryoglobulinemia in patients with chronic hepatitis C virus infection. Clin Exp Immunol 1996; 104: 25-31.
41 Akriviadis EA, Xanthakis I, Navrozidou C. et al. Prevalence of cryoglobulinemia in chronic hepatitis C virus infection and response to treatment with interferon-alpha. J Clin Gastroenterol 1997; 25: 612-8.
42 Lunel F, Musset L. Cryoglobulinemia in chronic liver diseases: role of hepatitis C virus and liver damage. Gastroenterology 1994; 106: 1291-300.
43 Gandini G, Franchini M, Capra F. et al. Clinical relevance of serum cryoglobulins in haemophilic patients with hepatitis C virus infection. Ann Ital Med Int 1999; 14: 166-71.
44 Niederau C, Lange S, Heintges T. Prognosis of chronic hepatitis C: results of a large prospective cohort study. Hepatology 1998; 28: 1687-95.
45 Kernoff PBA, Lee CA, Karayiannis P. et al. High risk of non-A non-B hepatitis after a first exposure to volunteer or commercial clotting factor concentrates: effects of prophylactic immune serum globulin. Br J Haematol 1985; 60: 469-79.
46 Jarvis LM, Ludlam CA, Ellender JA. Investigation of the relative infectivity and pathogenicity of different hepatitis C virus genotypes in haemophiliacs. Blood 1996; 87: 3007-11.
47 Mondelli MU, Silini E. Clinical significance of hepatitis C virus genotypes. J Hepatol 1999; 31 (Suppl. 01) 65-70.
48 Colombo M, Mannucci PM, Brettler DB. et al. Hepatocellular carcinoma in haemophilia. Am J Hematol 1991; 37: 243-6.
49 Tradati F, Colombo M, Mannucci PM. et al. A prospective multicenter study of hepatocellular carcinoma in Italian haemophiliacs with chronic hepatitis C. Blood 1998; 91: 1173-7.
50 Darby SC, Ewart DW, Giangrande PL. et al. Mortality from liver cancer and liver disease in haemophilic men and boys in UK given blood products contaminated with hepatitis C. Lancet 1997; 350: 1425-31.
51 Lee CA. Investigation of chronic hepatitis C infection in individuals with haemophilia. Br J Haematol 1997; 96: 425-6.
52 Hanley JP, Jarvis LM, Andrews J. et al. Investigation of chronic hepatitis C infection in individuals with haemophilia: assessment of invasive and non-invasive methods. Br J Haematol 1996; 94: 159-65.
53 Aledort LM, Levine PH, Hilgartner M. et al. A study of liver biopsies and liver disease among haemophiliacs. Blood 1985; 66: 367-72.
54 Wong VS, Baglin T, Beacham E. et al. The role for liver biopsy in haemophiliacs infected with the hepatitis C virus. Br J Haematol 1997; 97: 343-7.
55 Telfer P. Liver biopsy for haemophilic patients with chronic HCV infection. Br J Haematol 1997; 99: 239-40.
56 Venkataramani A, Behling C, Rond R. et al. Liver biopsies in adult haemophiliacs with hepatitis C: a United States Center’s experience. Am J Gastroenterol 2000; 95: 2374-6.
57 Darby SC, Ewart DW, Giangrande PLF. et al. Mortality before and after HIV infection in the complete UK population of haemophiliacs. Nature 1995; 377: 79-82.
58 Ragni MV. Progression of HIV in haemophilia. Haemophilia 1998; 04: 601-9.
59 Lauer GM, Walker BD. Hepatitis C virus infection. N Engl J Med 2001; 345: 41-52.
60 Santagostino E, Colombo M, Rivi M. et al, for the Study Group of the Association of Italian Haemophilia Centers. A 6-month versus a 12-month surveillance for hepatocellular carcinoma in 559 haemophiliacs infected with the hepatitis C virus. Blood 2003; 102: 78-82.
61 Alter MJ. Transmission of hepatitis C virus – route, dose, and titer. N Engl J Med 1994; 330: 784-5.
62 Gordon SC, Eloway RS, Long JC. et al. The pathology of hepatitis C as a function of mode of transmission. Blood transfusion versus intravenous drug use. Hepatology 1993; 18: 1338-43.
63 Toyoda H, Fukuda Y, Koyama Y. et al. Nucleotide sequence diversity of hypervariable region 1 of hepatitis C virus in Japanese haemophiliacs with chronic hepatitis C and patients with chronic post-transfusion hepatitis. Blood 1996; 88: 1488-93.
64 Tagariello G, Gerotto M, Pontisso P. et al. Hepatitis C virus quasispecies in the natural course of HCV-related disease in patients with haemophilia. Haemophilia 2004; 10: 81-6.
65 Degos F. Hepatitis C and alcohol. J Hepatol 1999; 31 (Suppl. 01) 113-8.
66 Wilde JT. HIV and HCV co-infection in haemophilia. Haemophilia 2004; 10: 1-8.
67 Lesens O, Deschenes M, Steben M. et al. Hepatitis C virus is related to progressive liver disease in HIV-positive haemophiliacs and should be treated as an opportunistic infection. J Infect Dis 1999; 179: 1254-8.
68 Goedert JJ, Eyster ME, Lederman MM. et al. for the . End-stage liver disease in persons with haemophilia and transfusion-associated infections. Blood 2002; 100: 1584-9.
69 Rockstroh JK, Theisen A, Kaiser R. et al. Antiretroviral triple therapy decreases HIV viral load but does not alter hepatitis C virus (HCV) serum levels in HIV-HCV-co-infected haemophiliacs. AIDS 1998; 12: 829-30.
70 Ragni MV, Bontempo FA. Increase in hepatitis C virus load in haemophiliacs during treatment with highly active antiretroviral therapy. J Infect Dis 1999; 180: 2027-9.
71 Llibre JM, Garcia E, Aloy A. et al. Hepatitis C virus and progression of infection due to human immunodeficiency virus. Clin Infect Dis 1993; 16: 182.
72 Quan CM, Krajden M, Grigoriew GA. et al. Hepatitis C virus infection in patients infected with the human immunodeficiency virus. Clin Infect Dis 1993; 17: 117-9.
73 Wright TL, Hollander H, Pu X. et al. Hepatitis C in HIV infected patients with and without AIDS: prevalence and relationship to patient survival. Hepatol 1994; 20: 1152-5.
74 Dorrucci M, Pezzotti P, Phillips AN. et al. Coinfection of hepatitis C virus with immunodeficiency virus and progression to AIDS. J Infect Dis 1995; 172: 1254-8.
75 Macias J, Pineda JA, Leal M. et al. Influence of hepatitis C virus infection on the mortality of antiretroviral treated patients with HIV disease. Eur J Clin Microb Infect Dis 1998; 17: 167-70.
76 Haydon GH, Flegg PJ, Blair CS. et al. The impact of chronic hepatitis C virus infection on HIV disease and progression in intravenous drug users. Eur J Gastroenterol Hepatol 1998; 10: 485-9.
77 Staples Jr CT, Rimland D, Dudas D. Hepatitis C in the HIV Atlanta VA (Veterans Affairs Medical Center) Cohort Study (HAVACS): the effect of coinfection on survival. Clin Infect Dis 1999; 29: 150-4.
78 Piroth L, Duong M, Quantin C. et al. Does hepatitis C virus co-infection accelerate clinical and immunological evolution of HIVinfected patients?. AIDS 1998; 12: 381-8.
79 Greub G, Ledergerber B, Battegay M. et al, for the Swiss HIV Cohort Study. Clinical progression, survival, and immune recovery during antiretroviral therapy in patients with HIV-1 and hepatitis C virus coinfection: the Swiss HIV cohort study. Lancet 2000; 356: 1800-5.
80 Daar ES, Lynn H, Donfield S. et al. Hepatitis C virus load is associated with human immunodeficiency virus type 1 disease progression in haemophiliacs. J Infect Dis 2001; 183: 589-95.
81 Wilde JT, Collins P, Sabin C. et al. Relationship between hepatitis C viraemia and CD4 cell count recovery in HIV positive haemophilia patients on highly active antiretroviral therapy. Haemophilia 2002; 08: 534.
82 Sulkowski MS, Moore RD, Mehta HS. et al. Hepatitis C and progression to HIV disease. JAMA 2002; 288: 199-206.
83 Poynard T, Marcellin P, Lee SS. et al. Randomised trial of interferon alpha2b plus ribavirin for 48 weeks or for 24 weeks versus interferon alpha2b plus placebo for 48 weeks for treatment of chronic infection with hepatitis C virus. Lancet 1998; 352: 1426-32.
84 Davis GL, Esteban-Mur R, Rustgi V. et al. Interferon alfa-2b alone or in combination with ribavirin for the treatment of relapse of chronic hepatitis C. N Engl J Med 1998; 339: 1493-9.
85 McHutchison JG, Gordon SC, Schiff ER. et al. Interferon alfa-2b alone or in combination with ribavirin as initial treatment for chronic hepatitis C. N Engl Med 1998; 339: 1485-92.
86 Reichard O, Norkrans G, Frydén A. et al. Randomised, double-blind, placebo-controlled trial of interferon α-2b with and without ribavirin for chronic hepatitis C. Lancet 1998; 351: 83-7.
87 Makris M, Preston FE, Triger DR. et al. A randomized controlled trial of recombinant interferon-α in chronic hepatitis C in haemophiliacs. Blood 1991; 78: 1672-7.
88 Meijer K, Smid WM, van der Meer J. Treatment of chronic hepatitis C in haemophilia patients. Haemophilia 2000; 06: 605-13.
89 Mauser-Bunschoten EP, Bresters D, Reesink HW. et al. Effect and side-effect of alpha interferon treatment in haemophilia patients with chronic hepatitis C. Haemophilia 1995; 01: 45-53.
90 Telfer P, Devereux H, Colvin B. et al. Alpha interferon for hepatitis C virus infection in haemophilic patients. Haemophilia 1995; 01: 54-8.
91 Makris M, Baglin G, Dusheiko G. et al. Guidelines on the diagnosis, management and prevention of hepatitis in haemophilia. Haemophilia 2001; 07: 339-45.
92 Ahmed MM, Mutimer DJ, Martin B. et al. Hepatitis C viral load, genotype and histological severity in patients with bleeding disorders. Haemophilia 1999; 05: 49-55.
93 Ahmed MM, Mutimer DJ, Elias E. et al. A combined management protocol for patients with coagulation disorders infected with hepatitis C virus. Br J Haematol 1996; 95: 383-8.
94 Aguilar C, Lucia JF, Simon MA. An emerging role for interferon in haemophiliacs with chronic hepatitis C?. Haemophilia 2001; 07: 6-8.
95 Peerlink K, Wilems M, Sheng L. et al. Rapid clearance of hepatitis C virus RNA in peripheral blood mononuclear cells of patients with clotting disorders and chronic hepatitis C treated with alpha-2b interferon is not a predictor for sustained response to treatment. Br J Haematol 1994; 86: 816-9.
96 Yoshikawa M, Fukui H, Kojima H. et al. Interferon treatment of chronic hepatitis C in patients with haemophilia or von Willebrand’s disease in Japan. J Gastroenterol 1995; 30: 367-71.
97 Yamada M, Fukuda Y, Koyama Y. et al. A long-term follow up study of interferon treatment for chronic hepatitis C in Japanese patients with congenital bleeding disorders. Eur J Haematol 1996; 57: 165-70.
98 Hanley JP, Jarvis LM, Andrews J. et al. Interferon treatment for chronic hepatitis C infection in haemophiliacs – influence of virus load, genotype and liver pathology on response. Blood 1996; 87: 1704-9.
99 Rumi MG, Santagostino E, Morfini M. et al. A multicenter controlled, randomized, open trial of interferon α2b treatment of antihuman immunodeficiency virus-negative haemophilic patients with chronic hepatitis C. Blood 1997; 89: 3529-33.
100 Pinilla J, Quintana M, Magallon M. Highdose and long-term therapy of α-interferon in haemophilic patients with chronic C virus hepatitis. Blood 1998; 91: 727-8.
101 Hayashi K, Fukuda Y, Nakano I. Poor response to interferon treatment for chronic hepatitis C in human immunodeficiency virus-infected haemophiliacs. Haemophilia 2000; 06: 677-81.
102 Shields PL, Mutimer DJ, Muir D. et al. Combined alpha interferon and ribavirin for the treatment of hepatitis C in patients with hereditary bleeding disorders. Br J Haematol 2000; 108: 254-8.
103 Sauleda S, Esteban JI, Altisen C. et al. Treatment with interferon plus ribavirin in anti-HIV negative patients with congenital coagulation disorders and chronic hepatitis C. Thromb Haemost 2000; 83: 807-10.
104 Lethagen S, Widell A, Berntorp E. et al. Clinical spectrum of hepatitis C-related liver disease and response to treatment with interferon and ribavirin in haemophilia or von Willebrand disease. Br J Haematol 2001; 113: 87-93.
105 Schulman S, Kinnmann N, Lindmarker P. et al. A randomized study of alpha-interferon plus ribavirin for 6 months or 12 months for the treatment of chronic hepatitis C in patients with bleeding disorders. Haemophilia 2002; 08: 129-35.
106 Fried MW, Peter J, Hoots K. et al. Hepatitis C in adults and adolescents with haemophilia: a randomized, controlled trial of interferon alfa-2b and ribavirin. Hepatology 2002; 36: 967-72.
107 Santagostino E, Rumi MG, Rivi M. et al. for the Hepatitis Study Group of the Association of Italian Haemophilia Centers. Sustained suppression of hepatitis C virus by interferon and ribavirin in haemophilic patients not responding to interferon monotherapy. Blood 2002; 99: 1089-91.
108 Franchini M, Tagliaferri A, Rossetti G. et al. Interferon and ribavirin in HIV-negative haemophiliacs with chronic hepatitis C who were nonresponders to a previous interferon treatment. Haemophilia 2002; 08: 794-7.
109 Santagostino E, De Filippi F, Rumi MG. et al. for the Hepatitis Study Group of the Association of Italian Haemophilia Centers. Sustained suppression of hepatitis C virus by high doses of interferon and ribavirin in adult haemophilic patients. Transfusion 2004; 44: 790-4.
110 Heathcote EJ, Shiffman ML, Cooksley WG. et al. Peginterferon α-2a in patients with chronic hepatitis C and cirrhosis. N Engl J Med 2000; 343: 1673-80.
111 Zeuzem S, Feinman SV, Rasenack J. et al. Peginterferon α-2a in patients with chronic hepatitis C. N Engl J Med 2000; 343: 1666-72.
112 Manns MP, McHutchison JG, Gordon SC. et al. Peginterferon alfa-2b plus ribavirin compared with interferon alfa-2b plus ribavirin for initial treatment of chronic hepatitis C: a randomised trial. Lancet 2001; 358: 958-65.
113 Soriano V, Rodríguez-Rosado R, García-Samaniego J. Management of chronic hepatitis C in HIV-infected patients. AIDS 1999; 13: 539-46.
114 Soriano V, Miró JM, García-Samaniego J. et al. Consensus conference on chronic viral hepatitis and HIV infection: updated Spanish recommendations. J Viral Hep 2004; 11: 2-17.
115 Soriano V, Puoti M, Sulkowski M. et al. Care of patients with hepatitis C and HIV co-infection. AIDS 2004; 18: 1-12.
116 Gane EJ, Portmann BC, Naoumov NV. et al. Long-term outcome of hepatitis C infection after liver transplantation. N Engl Med 1996; 334: 815-20.
117 Feray C, Caccamo L, Alexander GJ. et al. European collaborative study on factors influencing outcome after liver transplantation for hepatitis C. European Concerted Action on Viral Hepatitis (EUROHEP) Group. Gastroenterology 1999; 117: 619-25.
118 Lewis JH, Bontempo FA, Spero JA. et al. Liver transplantation in a haemophiliac. N Engl J Med 1985; 312: 1189-90.
119 Bontempo FA, Lewis JH, Gorenc TJ. et al. Liver transplantation in haemophilia A. Blood 1987; 69: 1721-4.
120 Ragni MV, Dodson SF, Hunt SC. et al. Liver transplantation in a haemophilia patient with acquired immunodeficiency syndrome. Blood 1999; 93: 1113-4.
121 Baudo F, Caimi TM, Redaelli R. et al. Orthotopic liver transplantation in a patient with severe haemophilia A and with advanced liver cirrhosis. Haemophilia 1999; 05: 276-7.
122 Gordon FH, Mistry PK, Sabin CA. et al. Outcome of orthotopic liver transplantation in patients with haemophilia. Gut 1998; 42: 744-9.
123 Mannucci PM, Tuddenham EGD. The haemophilias – From royal genes to gene therapy. N Engl J Med 2001; 344: 1773-9.