Detecting factor XIa in immune globulin products: Commutability of international reference materials for traditional and global hemostasis assays

BACKGROUND: Activated coagulation factor XIa (FXIa) is an impurity and primary source of procoagulant activity in thrombosis‐implicated immune globulin (IG) products. Several assays, of varying quality and precision are used to assess FXIa‐like procoagulant activity in units relevant to their respective principles. OBJECTIVES: To advance unified reporting, we sought to employ the World Health Organization reference reagents (RRs) to present the results of differing methodologies in units of FXIa activity and rank the sensitivity and robustness of these methodologies. METHODS: RR 11/236 served as a calibrator in several FXIa‐sensitive blood coagulation tests: two commercial chromogenic FXIa assays (CAs); a nonactivated partial thromboplastin time (NaPTT); an in‐house fibrin generation (FG) assay; an in‐house thrombin generation (TG) assay; and an assay for FXIa‐ and kallikrein‐like proteolytic activities based on cleavage of substrate SN13a. Some assays were tested in either normal or FXI‐deficient plasma. RESULTS: Each method demonstrated a sigmoidal dose‐response to RRs. NaPTT was the least sensitive to FXIa and the least precise; our in‐house TG was the most sensitive; and the two CAs were the most precise. All methods, except for SN13a, which is less specific for thrombotic impurities, gave comparable (within 20% difference) FXIa activity assignments for IG lots. CONCLUSIONS: Purified FXIa reference standards support quantitation of FXIa levels in IG products in all tested assay methodologies. This should help to standardize the measurement of thrombotic potentials in IG products and prevent products exhibiting high procoagulant activity from distribution for patient use. Further research is needed to address the effect of IG product‐specific matrixes on assay performance.