BJH - volume 16, issue 3, may 2025
Q. Van Thillo MD, PhD
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)
Read moreBJH - volume 13, issue 8, december 2022
Q. Van Thillo MD, PhD
T-cell acute lymphoblastic leukaemia (T-ALL) is a devastating disease, which mainly occurs in childhood. Despite an improvement of the overall survival, the current treatments have many side effects, and patients with relapsed or refractory disease continue to have a very poor prognosis. T-ALL arises from T-cell progenitors that have acquired multiple genomic lesions, which co-operate to drive leukaemia development. For some genetic alterations, such as the TCF7::SPI1 fusion or ectopic expression of TLX3, their role in driving leukaemia remains largely unknown. Therefore, we first investigated the co-operation between TCF7::SPI1 and NRAS(G12D). Using a mouse model, we were able to show that β-catenin is a crucial coactivator for the oncogenic function of the TCF7::SPI1 fusion protein. In the second part, we demonstrated that TLX3 and FLT3-ITD co-operate in driving leukaemia by activating the SPI1/PU.1 transcriptional program in an ex vivo pro-T-cell model and mouse model. This oncogenic function of TLX3 was shown to be dependent on other cofactors. Together, these two models of oncogenic co-operation in T-ALL demonstrate that the interaction between oncogenic transcription factors and cofactors is paramount for their function. Thus, these data provide a rationale for developing treatments directed at these protein interactions in the future for leukaemia.
(BELG J HEMATOL 2022;13(8):325–7)
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