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

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.
Competing Interests: Declaration of competing interest All the Authors assisted with the writing of this manuscript. None of the Authors received remuneration for preparation of this manuscript and no sponsors were involved with writing of the manuscript. The views expressed in the manuscript are those of the authors alone. The authors stated that they had no interests which might be perceived as posing a conflict or bias. PC, protein C; APC, activated protein C; AT, antithrombin; TF, tissue factor; TFPI, tissue factor pathway inhibitor; EPCR, endothelial protein C receptor; PAR1, protease activated receptor 1. Abbreviations: APC = activated protein C; TFPI = tissue factor pathway inhibitor; TF = tissue factor; EPCR = Endothelial protein C receptor (key for active transport and storage of FVIIa in extravascular tissue and for PAR1 activity [barrier protection]). See text for details. Natural anticoagulant mechanisms are indicated (red lines) and points of interventions of current non-factor products are reported (purple boxes). (For interpretation of the references to colour in this figure legend, the reader is referred to the web version of this article.)
(Copyright © 2019. Published by Elsevier Ltd.)