Establishment of the World Health Organization 2nd International Standard for Factor XI, Plasma, Human.

Helen Wilmot,Peter Rigsby,Jason Hockley,Elaine Gray

doi:10.3389/fmed.2017.00028

Helen Wilmot, Peter Rigsby + Show 2 more

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https://doi.org/10.3389/fmed.2017.00028

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Abstract

The 1st International Standard (IS) for blood coagulation factor XI (FXI), plasma, has been successfully used for potency labeling of FXI therapeutics and for diagnosis of FXI deficiency in patients. With stocks of the 1st IS near depletion, a replacement is required. In addition to the functional activity value, assignment of an antigen value to the 2nd IS would allow harmonization of antigen assay methods and differentiation of patients who have low functional activity but normal antigen FXI levels from patients who have both low functional and antigen FXI levels. The aims of this study were, therefore, to assign FXI functional activity to the 2nd IS for FXI, plasma, and to additionally assign a new analyte, FXI antigen, to the same International Standard. The candidate material was prepared from double-spun, virology negative, normal plasma, which was pooled and filled into siliconized glass ampoules and subsequently freeze-dried. Assignment of the functional activity (FXI:C) value in International Units (IUs) was performed by one-stage clotting assay by 29 laboratories, relative to the 1st IS. The overall geometric mean (GM) was 0.71 IU/amp with extremely low inter-laboratory variability (expressed as geometric coefficient of variation) of 1.8%. The antigen value assignment was performed by 11 laboratories and was calculated relative to normal plasma pools, as is customary with new coagulation factor analytes. The amount of antigen present in 1 ml of normal plasma was taken to be 1 U. The overall GM for the antigen assays was 0.78 IU/amp with an inter-laboratory variation of 10%. The candidate (National Institute for Biological Standards and Control code, 15/180) was established by the World Health Organization (WHO) Expert Committee on Biological Standardization in 2016 as the WHO 2nd IS for blood coagulation FXI, plasma, with a functional activity value (FXI:C) of 0.71 IU/amp and an antigen value (FXI:Ag) of 0.78 IU/amp.

Highlights

Bleeding disorders associated with factor XI (FXI) deficiency are generally mild and bleeding is most often associated with surgery or trauma, though bleeding phenotype can vary and is not always correlated to FXI coagulant activity
The activation status of this preparation was investigated by the non-activated partial thromboplastin time, which is known to be sensitive to activated coagulation factors such as FXIa
For FXI:C, participants were asked to assay coded duplicates A and B against sample S, the 1st International Standard (IS) for FXI Plasma

Summary

Introduction

Bleeding disorders associated with factor XI (FXI) deficiency are generally mild and bleeding is most often associated with surgery or trauma, though bleeding phenotype can vary and is not always correlated to FXI coagulant activity. Deficiency is most common in Ashkenazi Jews (around 1 in 190 are homozygous for mutation in the F11 gene and around 1 in 8 are heterozygous) but has. 2nd International Standard for FXI been identified in a wide variety of populations. There are a number of inherited mutations that cause FXI deficiency, most of which lead to a decrease in antigen and functional activity, though some patients (around 4%) experience a decrease in functional activity only [1]. The 1st International Standard (IS) for blood coagulation FXI, plasma (04/102), was established by the Expert Committee APTT reagent. Number of laboratories Actin FS Actin FSL APTT-SP Cephascreen Cephen CK Prest

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