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Prophylaxis with recombinant factor VIIa for the management of bleeding episodes during immune tolerance treatment in a boy with severe haemophilia A and high‐response inhibitors

Dear Editor, The most severe complication of modern haemophilia treatment is the development of inhibitors to clotting factors. The incidence of inhibitor development in haemophilia A patients following exposure to clotting factor concentrate factor VIII (FVIII), is between 21% and 33% [1]. Long-term inhibitor development is associated with poor joint outcome and significantly reduced mobility and quality of life. The treatment of choice for children who develop inhibitors is eradication using immune tolerance therapy (ITT). Bypassing agents such as recombinant-activated factor VII (rFVIIa) and activated prothrombin complex concentrate (aPCC) are used for the prophylactic treatment of acute, joint-related, mild-to-moderate bleeding episodes [2]. It has been shown that eradicating inhibitors during childhood is associated with a higher success rate than eradication later in life, with the long-term incidence of haemophilic arthropathy being reduced and quality of life improved by early therapy. It has been suggested that the development of inhibitors is associated with the age at which first treatment is started and the intensity of that initial treatment. In addition, early, regular prophylaxis may protect patients with haemophilia against the development of inhibitors [3].There are essentially three different types of ITT: high-dose FVIII with concomitant use of bypassing agents (Bonn protocol); extracorporeal immunoadsorption of inhibitor antibodies, high-dose FVIII and immune suppression (Malmö protocol); and low-dose FVIII treatment schedules. All of these treatment regimens have been used with varying amounts of success; however, it has been suggested that regimens similar to the Bonn protocol are more effective than Malmö or low-dose protocols [4]. In general, it has been noted that ITT is more successful in young patients with a short interval between inhibitor development and ITT treatment, and lower maximum pretreatment inhibitor titres [4]. During ITT, breakthrough bleeding episodes are treated on-demand with bypassing agents; however, in some patients, on-demand therapy does not provide sufficient haemostatic control. This report details the case of a boy who was placed on an rFVIIa prophylactic treatment regimen on account of increased bleeding during ITT. Recombinantactivated FVII was chosen as clinical trials have demonstrated it to be a well-tolerated and effective therapy for the on-demand treatment of acute bleeding episodes [2], and furthermore, as a recombinant product, it is not associated with any known risk of transmission of blood-borne infections. Use of rFVIIa is also recommended prior to ITT in order to avoid an anamnestic response [1]. A boy with prenatally diagnosed severe FVIII deficiency, and with a family history of haemophilia and inhibitor formation, developed high-responding inhibitors to FVIII (iFVIII) (166.4 Bethesda units [BU] mL at inhibitor development [11 July 2002]) following four exposures to plasma-derived FVIII (pdFVIII) during the first year of life. Two doses of pdFVIII were administered to treat the bleeding after detaching the rest of his umbilical cord, and a further two doses of pdFVIII were given to treat the bleeding after intramuscular injection of his vaccines. Other than these two occasions, he did not experience any further bleeding during his first year of life. Correspondence: Jan Blatny, Consultant Haematologist, Children s University Hospital, Temple Street, Dublin 1, Ireland. Tel.: +353 1878 4692; fax: +353 8766 78640; e-mail: jan.blatny@cuh.ie