Abstract Number: PB0244
Meeting: ISTH 2020 Congress
Theme: Coagulation and Natural Anticoagulants » Contact Pathway
Background: In 2010, an intravenous immunoglobulin (IVIG) product was temporarily removed from the market due to an association with serious thromboembolic events. Investigations by manufacturers and regulators revealed that factor XIa (FXIa) was present as a process-related impurity. Subsequently, efforts have been made by manufacturers to reduce or remove procoagulant activity from these therapeutics.
Aims: This study investigates levels of FXIa present in current marketed immunoglobulin products.
Methods: Nine immunoglobulin products (comprising IVIG and subcutaneous immunoglobulins) from 5 manufacturers were tested for FXIa content using the Rossix chromogenic assay. For 3 products, 2 different lots were tested. Samples were spiked with 1 mIU/ml FXIa, or left unspiked, and subsequently tested in duplicate across a minimum of 3 dilutions. Assays (n≥2 for each product) used the 1st International Standard (IS) for FXIa (13/100, NIBSC) as the standard.
Results: Results were analysed by parallel line assay and are shown in Tables 1 (IVIG) and 2 (subcutaneous immunoglobulins). Six of the products tested unspiked showed FXIa levels below the limit of quantification (LOQ) of 0.03 mIU/ml, with the corresponding spiked samples showing near 100% recovery of FXIa. One product had detectable and quantifiable levels of FXIa without spiking. Two products, unspiked, showed a dose response that was not parallel. Here, results ranges are reported, representing the 95% confidence limits. These products showed a FXIa recovery above 1 mIU/ml when spiked, the difference reflecting the level measured in the unspiked sample.
Conclusions: This study shows that current, marketed, immunoglobulin products can contain detectable levels of FXIa. Where valid results cannot be obtained from unspiked samples, this study has shown that spiking with FXIa brings the levels into the quantifiable range of the assay. Accurate measurement is important to inform on “safe” levels of FXIa in these products and allow future safety guidelines to be set.
| FXIa level in mIU/ml (95% confidence limits) | |||
| Manufacturer | IVIG Product | Unspiked sample | Sample spiked with 1 mIU/ml FXIa |
| A | 1 | 1.06 (0.97-1.15) | |
| 2A | – (0.26-0.31) | 1.30 (1.29-1.31) | |
| 2B | – (0.16-0.52) | 1.26 (1.07-1.49) | |
| B | 1 | 0.95 (0.94-0.95) | |
| C | 1A | 1.00 (0.76-1.32) | |
| 1B | 0.98 (0.75-1.30) | ||
| 2 | 0.96 (0.79-1.17) | ||
| D | 1 | 0.97 (0.70-1.35) | |
[Table 1: FXIa in Intravenous Immunoglobulins]
| FXIa level in mIU/ml (95% confidence limits) | |||
| Manufacturer | Subcutaneous Immunoglobulin Product | Unspiked sample | Sample spiked with 1 mIU/ml FXIa |
| A | 3A | 4.39 (4.29-4.49) | Not required |
| 3B | 1.52 (1.41-1.64) | Not required | |
| B | 2 | 0.94 (0.84-1.06) | |
| E | 1 | – (0.06-0.28) | 1.11 (0.93-1.32) |
[Table 2: FXIa in Subcutaneous Immunoglobulins]
To cite this abstract in AMA style:
Wilmot H, Gray E. Are Therapeutic Immunoglobulins Free from Factor XIa? [abstract]. Res Pract Thromb Haemost. 2020; 4 (Suppl 1). https://abstracts.isth.org/abstract/are-therapeutic-immunoglobulins-free-from-factor-xia/. Accessed October 2, 2023.« Back to ISTH 2020 Congress
ISTH Congress Abstracts - https://abstracts.isth.org/abstract/are-therapeutic-immunoglobulins-free-from-factor-xia/