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.

Waterpipe Smoking Is Associated with Changes in Fibrinogen, FVII, and FVIII Levels

“…FVII is an enzyme that belongs to the serine protease class [28, 35], whereas FVIII is a protein that is required for the activation of other coagulation factors [36, 37]. The results of the current study showed significant increases in the levels of FVII and FVIII associated with waterpipe and cigarette tobacco smoking.…”

Expression and assembly of largest foreign protein in chloroplasts: oral delivery of human FVIII made in lettuce chloroplasts robustly suppresses inhibitor formation in haemophilia A mice

“…ITI utilizes daily high‐dose intravenous FVIII infusions and can take months or even years to complete, often posing costs of >$1 000 000. During that time, bypass agents can restore haemostasis, but require careful dosing to prevent thrombosis, and increased potential for morbidity and mortality remain during that time (Rocino et al ., ). Progress has been made in defining the risk factors for inhibitor formation.…”

Rendering factor Xa zymogen-like as a therapeutic strategy to treat bleeding

“…Over the past two to three decades, largely as a result of work aimed at preventing or stopping hemophilia-associated bleeding, several prohemostatic agents have been developed. Examples include prothrombin complex concentrates (PCCs or activated PCCs) and recombinant factor VIIa (rFVIIa), which are used to varying degrees to improve hemostasis and control bleeding [7–9]. …”