Laboratory Challenges in the Era of Novel Haemophilia Therapies

Recent advances in haemophilia A and B treatment, including extended half-life (EHL) factor concentrates, factor VIII (FVIII)-mimetic antibodies, gene therapies, and rebalancing agents, have substantially improved prophylaxis and bleed prevention. However, these therapeutic innovations have also introduced significant analytical challenges for laboratory monitoring. Conventional coagulation assays, particularly one-stage clotting assays and chromogenic substrate assays, frequently show assay-dependent discrepancies when applied to modified factor molecules, transgene-derived coagulation factors, or nonfactor therapies. In addition, antidrug antibodies (ADAs) against replacement products and novel biologics require adapted diagnostic strategies.

This review discusses current laboratory challenges associated with modern haemophilia therapies. The effects of EHL factor concentrates on FVIII/FIX activity measurements, assay discrepancies in gene therapy, and assay interferences caused by FVIII-mimetic antibodies are summarized. Furthermore, analytical considerations for rebalancing therapies targeting antithrombin or tissue factor pathway inhibitor are addressed. The review also outlines current approaches for inhibitor and ADA testing in the setting of modified factor products and nonfactor therapies. In addition, the role of global haemostatic assays, particularly thrombin generation assays (TGAs), as emerging tools for integrative assessment of coagulation potential is discussed.

Modern haemophilia therapies substantially affect the performance and interpretation of conventional coagulation assays and require therapy-specific analytical strategies. Reliable laboratory monitoring depends on detailed knowledge of assay characteristics, therapy-associated interferences, and appropriate methodological adaptations. Although global assays such as TGAs are increasingly investigated as integrative monitoring tools, further harmonization and clinical validation are required before widespread routine implementation.