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Essentials    Nonacog beta pegol (N9‐GP) activity can be underestimated in clot method using diverse reagents.  Mimicking clotting phase with representative reagents reveals impaired FIX and N9‐GP activation.  Polyethylene glycol conjugation amplifies contact activator‐induced decrease in FIX activation.  The reagent is a pivotal factor for accurate measurement of N9‐GP activity in clinical samples.Background  In clinical practice, factor  IX  ( FIX ) activity is routinely quantified by measurement of the activated partial thromboplastin time ( APTT ) in a one‐stage ( OS )  FIX  clotting assay.  APTT  reagents provide a contact activator and phospholipid surfaces required for triggering and sustaining the plasma clotting process. The large diversity in reagent components is reflected in the variable recovery of nonacog beta pegol (N9‐ GP ; N‐glyco PEG ylated recombinant  FIX ) activity when assayed against a  FIX  standard. This variation warrants mechanistic studies and is plausibly attributable to the nature and amount of contact activator.    Objective  To identify the cause of the N9‐ GP  activity underestimation observed with a heterogeneous group of  APTT  reagents.    Methods  Experiments mimicking the clotting phase (omitting the contact activation phase) of the  OS  assay, complemented by measurements of activated factor  XI  ( FXI a) activity, were performed to characterize and explain the influence of  APTT  reagents/contact activators on the conversion of N9‐ GP  and regular  FIX  (N9) to activated  FIX  ( FIX a).    Results  In the presence of an intact underestimating  APTT  reagent or the isolated contact activator, clotting phase activation of N9‐ GP  proceeded at a reduced rate compared with that of N9.  APTT  reagent and contact activator negatively affected the activity of  FXI a, conceivably as a consequence of  FXI a adsorption. Thus, activation of  FIX  apparently poses a greater steric challenge after polyethylene glycol ( PEG ) conjugation.    Conclusions  Some  OS  clotting assay contact activators reduce  FXI a‐mediated activation of N9‐ GP  to a larger degree than that of N9, causing underestimation of N9‐ GP  activity of potential clinical significance.

Underestimation of N‐glyco PEG ylated factor IX one‐stage clotting activity owing to contact activator‐impaired activation