Paradigm shift for the treatment of hereditary haemophilia: Towards precision medicine

Abstract Patients with haemophilia A (HA) or B (HB) experience spontaneous limb- or life-threatening bleedings which are prevented by regular prophylactic intravenous infusions of the deficient coagulation factor (FVIII or FIX). Prophylaxis with subcutaneous long-acting non-factor products that improve in vivo thrombin generation is now under intensive investigation (concizumab, fitusiran) or successfully employed (emicizumab) in haemophilia patients. Both haemophilia patients with/without inhibitors take advantage of non-factor products employed alone. In those who also need bypassing agents (or FVIII concentrates) for breakthrough bleeds, thromboembolic events and/or thrombotic microangiopathy may occur. By enhancing thrombin generation, prothrombotic mutations co-segregating with FVIII/FIX gene mutations may trigger thrombotic episodes in HA patients carrying acquired thrombogenic factors (e.g. venous catheters). A thorough knowledge of individual needs increasingly contributed to improve comprehensive care and personalize treatments in haemophilia. Integrating genomics, lifestyle and environmental data is expected to be key to: 1) identify which haemophilia patients are less likely to benefit from a given intervention; 2) define optimal dosing and scheduling of bypassing agents (or FVIII) to employ in combination with non-factor products; 3) establish tests to monitor in vivo thrombin generation; 4) improve communication and deliver results to individuals. As individual outcomes will be improved and the risk of adverse events minimized, non-factor products will come into wider use within the haemophilia community, and patients will hopefully have no more risks of breakthrough bleeds. The risks of a normal life for a “former haemophilia patient” is likely to change the treatment landscape and the structure of haemophilia Centers.