Global Comparative Antithrombin Field Study: Impact of Laboratory Assay Variability on the Assessment of Antithrombin Activity Measurement at Fitusiran Clinical Decision‐Making Points

Introduction Fitusiran is a subcutaneous, investigational small interfering RNA therapeutic that lowers antithrombin (AT) to increase thrombin generation and rebalance haemostasis in people with haemophilia A or B with or without inhibitors. Aim To evaluate and compare the performance of commercially available in vitro diagnostic (IVD) AT activity assays. Methods Field study sample kits with plasma AT activity levels (100, 36, 14 and 9 IU/dL or % of normal) were created and distributed to global haemostasis laboratories. Values were assigned based on Siemens INNOVANCE AT activity assay using BCS-XP analyser. Reliability (relative accuracy estimate), intra- and inter-laboratory variability of IVDs in measuring AT activity in plasma samples using various commercially available AT assays was assessed. Results At normal AT activity level (i.e., 100%), all AT assays reliably measured AT activity with acceptable recovery. Accurate results were observed for all samples across sites using Siemens INNOVANCE AT assay. Increased variability was observed for all other assays at low AT levels. Siemens Berichrom and Stago STA-Stachrom assays accurately measured 100% and 36% AT activity; however, lab-to-lab variability was observed for <= 15% AT activity (CV >20%). All laboratories for the Stago STA-Stachrom assay failed to measure 9% AT activity. The HemosIL assay significantly underestimated AT activity levels <= 36%. There were no reported values for the 14% and 9% AT samples. Conclusions Siemens INNOVANCE AT assay can reliably measure AT activity at clinical decision points of 15-35% of normal and is most suitable for clinical management of patients taking fitusiran.