TFPI inhibition: a new paradigm in the treatment of hemophilia A and B through rebalancing therapies

Abstract

The treatment of hemophilia A and B is undergoing a paradigm shift, evolving from traditional replacement therapy toward non-replacement strategies. Anti-TFPI (tissue factor pathway inhibitor) antibodies are a therapeutic alternative within these strategies. TFPI is the primary regulator of the initiation phase of coagulation; its inhibition allows for sustained thrombin generation independently of factors VIII or IX. This article provides an in-depth analysis of two anti-TFPI monoclonal antibodies: concizumab and marstacimab. Both therapies offer critical advantages: subcutaneous administration, stable pharmacokinetics without peaks and troughs, and universality for both HA and HB, with or without inhibitors. However, they present therapeutic challenges, including the intrinsic risk of thrombosis resulting from interactions with bypassing agents or underlying patient risk factors. Furthermore, their monitoring is complex, as their hemostatic effect is not reflected in routine coagulation assays. In conclusion, anti-TFPI agents represent a disruptive innovation aimed at normalizing hemostasis and improving quality of life, although they require close clinical surveillance and specialized management of intercurrent events.