Quantitative determination of activated coagulation factor XI as an impurity in therapeutic immunoglobulins from Chinese blood fractionation companies

Abstract

ABSTRACT.Residual activated coagulation factor XI (FXIa) has been suggested to play an important role in thromboembolic events associated with the use of intravenous immunoglobulin (IVIG) lots. This study investigated the predominant plasma proteases in 42 IVIG lots from 4 Chinese manufacturers. In one-stage clotting assays, the procoagulant activities of factors II, VII, IX, X, XI, and XII were quantified. Non-activated partial thromboplastin time and a modified thrombin generation test served as global and FXIaspecific clotting assays, respectively. We found that coagulation factor clotting activities of the 42 IVIG lots were below the detection limit of the assays, except for the products of manufacturer B (lots of 2010), in which 0.030 to 0.032 IU/mL FXI:C were detected. The peak time of thrombin using a thrombin generation test was greater than 35 min, the relevant amount of FXIa was below 0.37 nM, and non-activated partial thromboplastin time was greater than 200 s. Consequently, the 42 IVIG lots showed non-significant ©FUNPEC-RP www.funpecrp.com.br Genetics and Molecular Research 12 (3): 2556-2561 (2013 Identification of FXIa in therapeutic immunoglobulins 2557 procoagulant potential. Further study is required to determine whether a program for FXIa determination in IVIG products should be launched in China.

Absence of in vitro Procoagulant Activity in Immunoglobulin Preparations due to Activated Coagulation Factors

“…The global test NAPTT was used to determine the presence of activated coagulation factors, allowing for detection of an important prolongation of the coagulation time in fraction II and the subsequent steps of the manufacturing process. These results were in accordance with the levels of FXIa since the NAPTT test is highly sensitive to this factor [15]. Indeed, a dramatic drop in the levels of FXIa below the detection limits of the assay was accompanied by an important prolongation of NAPTT.…”

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

“…In order to show the absence or removal of procoagulant factors such as FXIa, accurate assay methods must be available. Methods such as the non‐activated partial thromboplastin time, thrombin generation assays and non‐specific FXIa chromogenic assays have been used for investigating procoagulant activity in IG products or their manufacturing intermediates [ 9 , 16 , 17 , 18 , 19 ]. At the time, specific FXIa chromogenic assays were not available, but two FXIa chromogenic assays are now commercially available and have been used by manufacturers to demonstrate the reduction or removal of FXIa during their manufacturing process [ 20 , 21 , 22 ].…”