Yee, Thynn Thynn; (2003) Complications of haemophilia therapy. Doctoral thesis (M.D.), UCL (University College London).

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Abstract

The aim of this thesis is to evaluate and investigate the magnitude of the two major complications of haemophilia treatment: the development of inhibitory antibodies to exogenous clotting factor proteins and blood borne viral infections and their sequelae experienced in a large population of people with haemophilia. All retrospective and prospective studies presented in this thesis have been conducted on a population of 580 haemophilia patients registered through out the years from 1964 to the present time at the Katharine Dormandy Haemophilia Centre and Haemostasis Unit (KDHC and HU), and for whom a comprehensive database has been established. A 25 year follow-up study of 310 patients with inherited bleeding disorders infected with hepatitis C virus between 1961 and 1985 as a result of treatment with non-virally attenuated blood products has shown that 19% of HIV/HCV co-infected patients progressed to liver disease whilst only 3% of HCV mono-infected patients progressed to liver disease. In the era of highly active antiretroviral therapy (HAART) a reduction in the incidence of AIDS has been seen within this cohort, but the death rate has remained high as a consequence of the large number of deaths related to liver disease secondary to chronic hepatitis C infection. Patients with haemophilia who were infected with HIV between 1979-1985 are facing new challenges and complications in the era of HAART such as the unique side-effect of the increased bleeding tendency associated with the use of protease inhibitors. Parvovirus B19, a non-lipid enveloped virus still escapes the virological surveillance system and clinical problems related to this virus have been noted in patients who have contracted this virus through the use of virucidally treated plasma derived clotting factor concentrates. 431 haemophilia A patients of all severities have been followed-up for a total of 5,626 patient years and the frequency of inhibitors was found to be 10% in the severe haemophilia A patients and a third of the inhibitors occurred in children less than 10 years of age. An inhibitor study of 37 previously untreated children with severe haemophilia A who have had treatment with the first heat-treated factor VIII product produced in the United Kingdom showed absence of inhibitors. A series of patients with mild and moderate haemophilia A have developed inhibitors more recently in the KDHC and HU and a change in the practice of replacement therapy in haemophilia may well play a role in the development of these inhibitors. Therapy for haemophilia has progressed substantially not only in the replacement therapeutic materials but also in the treatment strategies and mode of delivery of these therapeutic products. Regular prophylaxis in children with severe haemophilia at our centre has required insertion of central venous catheters because of difficult venous access in some children. A catheter infection rate of 1.74 per 1000 catheter-days has been noted. Thus optimal comprehensive care for this group of patients requires the haemohilia physician to be aware of the complications of therapy: the sequelae of transfusion transmitted infections; the emerging challenges seen in those patients surviving with HIV in the era of HAART; and the development of inhibitory antibodies to replaced clotting factor proteins.

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