Commentary on Brackmann and Gormsen (Lancet 1977; ii: 933): Massive factor‐VIII infusion in haemophiliac with factor‐VIII inhibitor, high responder

Abstract

This letter, describing a curative treatment for inhibitor development by induction of immune tolerance, was published one-third of a century ago. This became the basis for the ‘Bonn protocol’, a high-dose regimen designed to induce lifelong tolerance towards substituted factor VIII (FVIII) [1]. Brackmann himself has described the birth of the Bonn protocol [2]. A patient, aged 1.5 years, who had experienced severe bleeding episodes in the right shoulder, right upper arm and right chest and an inhibitor titre of >500 Bethseda units had presented to the Bonn centre. Brackmann knew of the report by Kurczinsky and Penner in 1974 which described the successful treatment of bleeding episodes in patients with an inhibitor using activated prothrombin complexes (APCCs) [3]. However, this product was not available on the German market at that time and therefore Brackmann used high dosages of FVIII with a regular prothrombin concentrate. The regimen was given twice daily to the patient and the bleeding was controlled. After 3 weeks, the patient recovered and the inhibitor titre reduced to 40 BU. The treatment was evaluated in further patients and although an initial booster of the inhibitor titre was observed in some patients, in all cases, the inhibitor titre decreased after some weeks. It was therefore decided not to stop but to continue the treatment. The success of the treatment was shown by the disappearance of the inhibitor and the normalization of the half-life of FVIII. The initial Bonn protocol had two treatment phases – the first used 100 IU FVIII kg−1 and 50 IU APCC given twice daily until the inhibitor titre was <1 BU and the 30-min recovery was measurable. In the second phase, treatment was continued with 150 IU FVIII kg−1 twice daily until the inhibitor disappeared and the half-life normalized. Later modification used 150 IU FVIII kg−1 twice daily. FEIBA was used to treat patients with increased bleeding [1, 4]. To a certain extent, the management of inhibitors was left in abeyance in the 1980s and 1990s because the overwhelming attention was to transfusion transmitted disease, particularly HIV and HCV, and the development of virally safe concentrates. The widespread availability of safe recombinant and plasma-derived concentrates has brought the problem of inhibitors to the forefront again and attention has been given to the assessment of eradication regimens. The international prospective randomized immune tolerance study was recently terminated [5]. This study, commenced in 1992, compared a high-dose regimen, 200 IU FVIII kg−1 daily and a low-dose regimen, 50 IU FVIII kg−1 three times weekly. Preliminary results show equal efficacy of the high-dose and low-dose regimens with 76% patients reaching tolerance at study endpoint. However, the study was terminated because there were significantly more bleeds in the low-dose arm. Thus in 2010, we may be reverting to the regimen pioneered by Brackmann in 1977. This early publication is a great tribute to the clinical observation together with the brave pioneering spirit of Hans Brackmann. C. A. Lee is a co-editor for Haemophilia.