Key issues in inhibitor management in patients with haemophilia.

Abstract

Significant advances in the management of haemophilia have been achieved in the past several decades. These include the development of safe and efficacious plasma-derived and recombinant clotting factor products, use of prophylaxis as standard of care in bleeding prevention and appropriate surgical management of haemophilic arthropathy. Despite these advances, the development of high-titre anti-factor antibodies (inhibitors) remains an unresolved challenge in the management of people with haemophilia. Inhibitors develop in 25–30% of patients with severe haemophilia A and in 1–5% of those with severe haemophilia B1–3. They were first described by Lawrence and Johnson in 19414, and in the seven decades that followed our knowledge of their pathophysiology and risk factors remains incomplete and continues to evolve. This is partly a result of the small inhibitor population with significant intra- and inter-individual variability making the conduct of studies and interpretation of results difficult. The main reason for our incomplete knowledge in this area is that inhibitor development is a multi-factorial event resulting from the variable interplay between several genetic (non-modifiable) and non-genetic (modifiable to some extent) risk factors. Despite these limitations, a number of clinical evaluations analysing treatment of inhibitor patients have been performed including randomised controlled prospective studies5,6. These studies provide, in part, the evidence basis for our current inhibitor management principles and practice. Inhibitors remain a popular subject of haemostasis scientific meetings and many issues related to their pathophysiology and management are discussed and debated in the published literature. The main issues include: (i) the identification of clinically relevant risk factors for inhibitor development, (ii) the definition of the bleeding phenotype and clinical management of these patients, (iii) the usefulness and feasibility of prophylaxis with bypassing agents in the treatment of patients with inhibitors, (iv) the identification of predictive factors for inhibitor eradication, and (v) novel therapeutic approaches and molecules for the treatment and/or eradication of inhibitors. The aim of this review is to give an update on each of these issues with a focus on the current state-of-the-art knowledge and practice from the authors’ personal perspective. This review focuses mainly on factor VIII inhibitors as these occur much more frequently in clinical practice.