Comparison of Thrombin Generation Assay (TGA) and Non-Activated Partial Thromboplastin Time (NAPTT) for the Assessment of Enhanced Procoagulant Activity in Immunoglobulin Solutions

The recent revision of the European Pharmacopoeia stipulates that all intravenous immunoglobulin solutions must be investigated with respect to procoagulant activity. Accordingly, the manufacturing processes must be validated regarding the removal of such compounds, to ensure a minimized thromboembolic risk for patients. Furthermore, based on recent studies, which identified the presence of occasionally elevated concentrations of activated factor XI (FXIa) in an immunoglobulin solution as root cause for thromboembolic events in patients, a thrombin generation assay (TGA) was validated and is routinely performed for Octagam® batch release. Non-activated partial thromboplastin time (NAPTT) is discussed as an alternative to TGA, because it is a suitable and wide-spread method to assess an enhanced procoagulant potential of coagulation factor concentrates. However, in order to meet the sensitivity provided by the validated TGA and its defined cut-off limits for Octagam® batch release, the corresponding limits of NAPTT would require a new definition to ensure a comparable safety margin. This means that under the usually performed NAPTT conditions several of those batches with a moderately increased procoagulant activity would be missed, which however would be identified by the implemented TGA criteria. Consequently, NAPTT might become an alternative only, if validated against TGA and its defined sensitive cut-off limits. This would include revision of generally communicated NAPTT assay protocols. As reported for TGA, factor XI deficient plasma (FXI-DP) revealed improved NAPTT performance when compared to fresh-frozen plasma or pooled normal plasma. This report also demonstrates that traces of other activated factors (FIXa and FXa) were detected in FXI-DP with high sensitivity. In conclusion, TGA with FXI-DP is the preferred assay for the exclusion of immunoglobulin solution batches with increased procoagulant potential. TGA is superior to established NAPTT performance.