December 10, 2021

Therapeutic Immunoglobulins – Rox Factor XIa evaluated by NIBSC for detection of low levels of FXIa

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Enabling accurate measurement of activated factor XI (FXIa)
in therapeutic immunoglobulin products

Helen V. Wilmot & Elaine Gray
Haemostasis Section, Biotherapeutics, National Institute for Biological Standards and Control (NIBSC), South Mimms, Hertfordshire, UK
The International Journal of Transfusion Medicine, Volume 166 Issue 6, July 2021, Pages 656-664,

The publication is available online and in print



Background and objectives

In 2010, an intravenous immunoglobulin (IVIG) product was removed from the market due to an association with serious thromboembolic events. Investigations revealed that factor XIa (FXIa) was present as a process-related impurity. This study investigated the ability of two commercial FXIa assays to measure FXIa in immunoglobulin preparations and conducted a survey of FXIa activity in marketed immunoglobulin products.

Materials and methods

Factor XIa assays were modified to include spiking of samples with FXIa before testing. An immunoglobulin product and its excipient were used to assess the ability of the assays to recover the spiked FXIa levels.


The Biophen FXIa assay required a high pre-dilution of the sample to obtain statistically valid results and complete FXIa recovery. The ROX FXIa assay was more sensitive, giving statistically valid results at a lower sample pre-dilution and FXIa spike level. This modified ROX FXIa assay was used to assay 17 lots of immunoglobulin products for FXIa. Two product lots had measurable FXIa levels without the need for spiking. A further 3 lots produced detectable but not statistically valid FXIa results when left unspiked. Spiking produced statistically valid assays and recoveries above 100%, demonstrating inherent FXIa.


This study shows marketed immunoglobulin products can contain detectable levels of FXIa. Spiking brings the FXIa levels into the quantifiable range of the assay, allowing measurement of inherent FXIa. Accurate measurement is important to inform on ‘safe’ levels of FXIa in these products and allow future safety guidelines to be set.