Prophylaxis in patients with haemophilia: introduction

Prophylaxis, i.e. regular preventive infusions of factor replacement therapy [Factor VIII (FVIII) or Factor IX (FIX)] [1,2], is widely accepted as the gold-standard treatment in children with severe haemophilia [3,4]. Long-term prophylaxis has proven effective in reducing bleeds and thus preventing haemophilic arthropathy [5–7]. Given the acceptance of prophylaxis as a mainstay of bleeding control and prevention in patients with haemophilia, it is surprising that unresolved differences remain concerning regimen implementation and dosing schedules. Treatment of patients who develop inhibitors (antibodies) to factor replacement may include prophylaxis with bypass agents, but few results are available in this field and evidence for efficacy are of the lowest level. ‘Prevention in patients with haemophilia’ was an international meeting held in Marseille, France, on 2 July 2009, that involved world-renowned experts based in Europe and North America who met to review country-specific variations in current prophylaxis practice, and discuss future directions in haemophilia management for patients with and without inhibitor. This supplement is a compilation of the presentations and discussions held at the meeting that highlight experience with haemophilia prophylaxis in a global context, while also reviewing current data and areas for ongoing research. Frequency of prophylaxis use in boys without inhibitor varies between countries, which may be a reflection of differences in timing of treatment initiation or intensity of treatment in the regimens used. In the first article of this supplement, Professors Rolf Ljung, Manuel Carcao and I discuss current prophylaxis treatment strategies employed in Swedish, Canadian and French centres. Using these examples, the authors outline areas of agreement (e.g. early prophylaxis) or debate (e.g. when to intensify treatment) that, with further refinement, could be used to optimize practice approach. Difficulties involved in implementing prophylaxis regimens, such as risk of complications arising from the use of central venous access devices (CVADs), high costs and the specific concern of intracranial haemorrhage and development of inhibitors, are also highlighted. The development of inhibitors to factor replacement therapy, currently the most serious iatrogenic complication that affects patients with haemophilia [8–10], has profound effects on strategies for continuing therapy. A better understanding of the causes and circumstances of inhibitor development might be useful to prevent their occurrence. Numerous risk factors for inhibitor development have been identified or hypothesized, with genetics and environmental considerations combining as crucial contributory components [11,12]. Identification of haemophilic patients with a higher risk of inhibitor formation may allow for individual tailoring of therapy, and thus ensure optimal benefit for patients. In a following article, I discuss the risk factors, with a particular focus on modifiable conditions such as age at exposure to factor replacement, type of replacement factor used or treatment intensity because their identification as risk factors might be taken into account to define preventive strategies for inhibitor formation. Addressing this issue, I introduce SIPPET, the Survey of Inhibitors in Plasma-Product Exposed Toddlers study, a prospective, randomized trial that aims to evaluate immunogenicity of plasma-derived or recombinant replacement factors while also defining environmental factors for increased risk of inhibitor development [13]. Such a study might provide complementary data to studies drawn from different ongoing cohorts of pups. In patients who have developed inhibitors, immune tolerance induction (ITI) with high doses of FVIII or FIX may allow reinstatement of conventional prophylaxis [14]. A substantial proportion of patients (approximately 20–40%) with clinically significant inhibitors do not benefit from ITI therapy [15], and bleeding is controlled with bypassing agents [16]. The article by Professor Manuel Carcao and Dr Thierry Lambert reviews and discusses international experience of using the bypassing agents NovoSeven® [recombinant factor VIIa (rFVIIa); Novo Nordisk, Bagsvaerd, Denmark] and the plasma-derived activated prothrombin complex concentrate (pd-aPCC) FEIBA® (FVIII inhibitor bypassing activity; Baxter AG, Vienna, Austria) as prophylaxis for patients with haemophilia and inhibitors. Retrospective studies and case reports showing a reduction in joint bleeds and prevention of joint damage with aPCC or rFVIIa prophylaxis are described, and upcoming studies investigating bypassing agents as prophylaxis are introduced. Studies have demonstrated the efficacy and safety of rFVIIa in prophylactic regimens and evidence suggests a prolonged biological effect of rFVIIa [17]; however, the perception remains that the short plasma half-life [18] and consequent need for repeated daily injections could potentially limit its use for long-term prophylaxis [19]. In the final article of this supplement, Drs Achim Obergfell and Mirella Ezban provide an overview of selected animal models examining efforts to bypass these potential limitations through gene technologies that promote continuous expression of FVIIa. Preliminary results from these animal models suggest development of gene transfer techniques, which represent a potentially attractive novel approach to haemostasis in patients with haemophilia and other platelet disorders. In this supplement, we discuss current prophylaxis treatment strategies for patients with haemophilia and highlight future directions for continued research. Through an improved understanding of prophylaxis in patients with haemophilia, including the potential use of bypassing agents as primary prophylaxis in those who have developed inhibitors, we aim to develop more optimal treatment strategies that further improve the quality of life of patients. The author states that he has no interests that might be perceived as posing a conflict or bias.

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