LAUSR

The one‐stage factor VIII (FVIII) clotting assay measures the extent by which a plasma sample corrects the coagulation time of FVIII‐ deficient plasma in an activated partial thromboplastin time (aPTT)‐ based assay.1 The availability of this “surrogate” measure of FVIII activity has been the foundation of clinical diagnostics for hemo‐ philia as it can be used to establish a diagnosis of FVIII deficiency, assign severity, and identify the presence of neutralizing inhibitors.2 Approximately three‐quarters of all clinical laboratories globally rely on the one‐stage aPTT‐based clotting assay to measure FVIII.3 Other FVIII assays may be required for full diagnostic precision, such as chromogenic FVIII activity assays to accurately phenotype pa‐ tients with nonsevere hemophilia A.2 FVIII activity assays have also become a cornerstone for the management of hemophilia A, allowing for dose adjustment of FVIII replacement, monitoring of FVIII levels during treatment and pro‐ phylaxis, and optimization of FVIII dosing for pharmacokinetic (PK)‐ guided prophylaxis.4 In recent years, the recombinant platform has allowed for the bioengineering of FVIII with improved properties such as extended half‐life, reduced immunogenicity, and enhanced affinity for von Willebrand factor.5 The bioengineered FVIII mole‐ cules have posed some challenges because discrepancies have been observed between the one‐stage and the chromogenic assays, but these may be overcome with product‐specific standards.6,7 Where there may still be challenges in the interpretation of one‐stage and chromogenic FVIII assays, thrombin generation assays have also been used for monitoring FVIII replacement.8 However, the recent intro‐ duction of a novel therapeutic is changing the paradigm of reliance on these surrogate FVIII assays for the management of hemophilia. Emicizumab‐kxwh (Hemlibra, F. Hoffmann–La Roche, Basel, Switzerland) is a humanized bispecific monoclonal antibody that substitutes for missing FVIIIa by bridging FIXa and FX to promote effective hemostasis in persons with hemophilia A.9 It has no sequence homology to FVIII and therefore does not induce FVIII inhibitors and its function is not impaired in the presence of FVIII in‐ hibitors. Emicizumab has a high bioavailability, allowing for subcuta‐ neous administration, and has a half‐life of approximately 30 days.10 PK profiles demonstrate that, at steady‐state, trough levels can be maintained sufficient to provide effective bleed control with weekly, 2‐weekly and 4‐weekly maintenance dosing regimens.11 As such, dosing regimens can be chosen based on patient and/or physician preference and pharmacokinetic monitoring is not required. Does this new treatment paradigm mean that laboratory assays are no longer necessary when patients are on emicizumab prophy‐ laxis? Several management issues remain that could be addressed with another “surrogate” assay such as the one‐stage FVIII assay has served. There is evidence for interpatient variability of the peak and trough levels at steady state, although the clinical trials have not identified any significant correlation with clinical outcome mea‐ sures.10,12 However, a Japanese study in hemophilia with inhibitors showed a clinical improvement in four subjects with dose up‐titra‐ tion.13 Clinicians have 50 years of experience in the correlation of bleed control with FVIII levels in most every imaginable clinical sce‐ nario (e.g., minor and major surgery, trauma, central nervous sys‐ tem bleeding, use of concomitant anticoagulants). There may yet be some value in a similar correlation of bleeding control in such sce‐ narios with emicizumab prophylaxis within the range of inter‐ and intrapatient variability of their levels. More important, we do not have sufficient data on the PK profiles of the youngest infants and how that changes over time. This is an age group that represents a significant treatment gap because they are typically not placed on prophylaxis with FVIII replacement due to the challenges of intrave‐ nous infusions, and consequently may be one of the most significant beneficiaries of this therapy. In addition, antidrug antibodies, al‐ though they seem to occur infrequently with the use of emicizumab, can affect the clearance of the drug, or neutralize its function, either of which could impact bleed control.14 Given the vast clinical experi‐ ence with FVIII assays to date, it's not surprising that clinicians would Manuscript handled by: Flora Peyvandi