Despite considerable investigation the basic causes of this discrepancy remain unknown, although it is thought that the extensive processing applied to both plasma-derived and recombinant concentrates could lead to differences

in their rates of activation and inactivation in the two method types from the FVIII in normal plasma, and there is some evidence for this from recent studies [29]. A resolution of this problem is only possible when the exact causes of the discrepancy are discovered; it may then be possible to adjust one or both of the methods to give similar Rucaparib nmr values. In the meantime, a practical solution which has been discussed by the FVIII/FIX Subcommittee of ISTH/SSC is to regard the post infusion samples as concentrates, ‘diluted’ in a patient’s plasma, which is essentially what they are, learn more and use a concentrate standard, diluted in haemophilic plasma, instead of a plasma standard, to construct the standard curve.

However, the nature of the concentrate standard needs to be carefully considered; it should be as similar as possible to the injected product. This approach has been tested in a number of in vivo recovery studies, and the discrepancy between one-stage and chromogenic methods using the plasma standard was completely abolished with the appropriate concentrate MCE standard [30]. However, in one case

the use of a concentrate standard, in this case not the same as the product infused, made the situation worse. Therefore, the use of concentrate standards needs to be product specific, and should probably be restricted to recombinant and very high-purity plasma-derived products. Most recently, a number of modified FVIII and FIX concentrates have been developed with novel properties, introduced through structural or chemical modifications (e.g. truncation, pegylation, fusion) to improve manufacturing yield or to prolong plasma half-life. These will challenge the traditional approach to potency labelling relative to the WHO IS [31, 32]. Potency estimation of pegylated versions of both FVIII and FIX, by the one-stage clotting method, appears to be associated with particular issues relating to the direct interference of the polyethylene glycol with some APTT reagents [33], and it may be necessary in some cases to use product specific standards for monitoring. However, there are indications that most modified products are amenable to potency estimation using conventional methods. Nonetheless, decisions on the potency labelling should be guided by a thorough characterization, in vitro relative to the WHO IS, which should include the effect of different reagents (e.g.