3) [31]. Although the PK parameters of FVIII:C are well characterised and widely investigated, this is not the case for FIX. The PKs of FIX are more complicated than those of FVIII, and also differ between plasma-derived and recombinant FIX CFCs resulting in variation between studies. The different properties of the factor concentrates and how they behave in factor assays may explain some differences and an important issue is that FIX has a longer half-life in the circulation than FVIII, and therefore requires longer sampling schedules for determination of PK properties [32].

The PKs of FIX therefore warrant RXDX-106 nmr further investigation, including comparative studies of prophylaxis with varying concentrates, before attempting clinical application in people with haemophilia B [8]. In addition, FIX:C levels are routinely determined by bioassays, and the conventional 1% target level lies close to the lower limit of the

assay, where the accuracy can be expected to be rather poor [23]. Furthermore, UK National External Quality Assessment Service data have shown discrepancies between measured factor levels in people with mild, moderate and severe haemophilia, highlighting the issues with assaying. There are interesting experimental data that add weight to the concept that measuring plasma FIX activity may not fully Stem Cells inhibitor reflect the haemostatic efficacy of infused FIX. These data demonstrate the potential availability of clinically significant extravascular stores of FIX, which are thought to act as a reservoir of FIX at a haemostatically functional location. It may therefore be proposed that a therapeutic focus limited to increasing the terminal plasma half-life of FIX alone, at the expense of its tissue distribution, may not be the optimal approach for the treatment of haemophilia B. Furthermore, there are experimental find more data demonstrating that FIX bound to collagen IV may be a source of haemostatically active FIX without it being measurable

by plasma assays [33, 34]. These data warrant further investigation. Since the current guideline recommendation for treatment of haemophilia B is to maintain a minimum plasma level of 1% of normal coagulation factor activity (FIX:C) [23], trough levels are often targeted as a key endpoint of therapy. However, due to inter-individual variations in PK parameters, targeting a particular trough level may not be appropriate for every individual [15]. Ahnström and colleagues found the overall relationship between factor concentrate levels and incidence of joint bleeding to be very weak, with no relationship between coagulation factor level and incidence of other bleeds [15]. In this cohort (n = 64; 51 haemophilia A, 13 haemophilia B), it was found that some patients did not bleed despite displaying a trough level of <1%, while conversely, others developed bleeds despite trough levels >3%.