SUMMARY
Thrombophilia is very prevalent in the general population. In patients with haemophilia, it leads to an attenuation of their bleeding phenotype. Rebalancing agents work in similar fashion by targeting the natural anticoagulants, which enhances thrombin generation, and restores the balance of coagulation. The most important targets are antithrombin, tissue factor pathway inhibitor (TFPI) and activated protein C with its cofactor protein S. Antithrombin levels can be lowered by the short interfering RNA fitusiran via subcutaneous injection, which results in more thrombin generation and clot formation. Its efficacy was demonstrated in patients with haemophilia A and B, with and without inhibitors. The other clinically advanced drugs are concizumab and marstacimab, which both inhibit TFPI, thereby relieving the suppression of the extrinsic pathway, and reducing the bleeding rate in patients with haemophilia. Initially, several thrombotic events were observed in patients using fitusiran and concizumab, but these could be managed by using an adapted dosing strategy. Finally, several compounds target either activated protein C or protein S. The development of SerpinPC, inhibiting protein C, was recently halted, but other drugs continue to be under clinical development and show promising results. In short, rebalancing agents are effective in selected patients with haemophilia, and they could potentially even open new possibilities to treat many hitherto neglected rare bleeding disorders.
(BELG J HEMATOL 2025;16(3):111–7)
