Treatment and Prevention of Bleeds in Haemophilia Patients with Inhibitors to Factor VIII/IX

Abstract

The development of alloantibodies neutralising therapeutically administered factor (F) VIII/IX (inhibitors) is currently the most severe complication of the treatment of haemophilia. When persistent and at a high titre, inhibitors preclude the standard replacement treatment with FVIII/FIX concentrates, making patients' management challenging. Indeed, the efficacy of bypassing agents, i.e., activated prothrombin complex concentrates (aPCC) and recombinant activated factor VII (rFVIIa), needed to overcome the haemostatic interference of the inhibitor, is not comparable to that of factor concentrates. In addition, the therapeutical response is unpredictable, with a relevant inter-individual and even intra-individual variability, and no laboratory assay is validated to monitor the efficacy and safety of the treatment. As a result, inhibitor patients have a worse joint status and quality of life compared to inhibitor-free subjects and the eradication of the inhibitor by immune tolerance induction is the preeminent therapeutic goal, particularly in children. However, over the last decades, treatment with bypassing agents has been optimised, allowing home treatment and the individualisation of regimens aimed at improving clinical outcomes. In this respect, a growing body of evidence supports the efficacy of prophylaxis with both bypassing agents in reducing bleeding rates and improving the quality of life, although the impact on long-term outcomes (in particular on preventing/reducing joint deterioration) is still unknown. This review offers an update on the current knowledge and practice of the use of bypassing agents in haemophiliacs with inhibitors, as well as on debated issues and unmet needs in this challenging setting.

Keywords: bleeding; bypassing therapy; haemophilia; inhibitors; prophylaxis.

Figure 1

The administration of FVIII concentrates on-demand or, in particular, on long-term prophylaxis is the effective and safe standard of care in patients with severe hemophilia A, enabling to preserve joint status and a satisfactory quality of life. These achievements are precluded in approximately 30% of previously untreated patients (PUPs) who develop neutralizing alloantibodies (inhibitors), associated with reduced efficacy of treatment and increased bleeding risk, resulting in higher morbidity, severe joint deterioration and, in turn, worse quality of life and marked increase of healthcare costs. Inhibitor eradication through immune tolerance induction (ITI), able to restore FVIII replacement, is the primary objective of management of patients with high-responding inhibitors and of those with low-responding inhibitors in whom FVIII treatment is unfeasible in spite of increased doses. While awaiting inhibitor eradication and in patients failing ITI, patients with HR inhibitors are managed with bypassing agents given on-demand or on prophylaxis.