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Differences in hemostatic potency of natural, full length recombinant FVIII molecule and B-domain deleted recombinant FVIII

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Differences in hemostatic potency of natural, full-length recombinant FVIII molecule and B-domain deleted recombinant FVIII

Gerald Schrenk, Herbert Gritsch, Stefan Romeder-Finger, Sabine Knappe, Michael Dockal, Peter L. Turecek, Friedrich Scheiflinger

Baxter Innovations GmbH, Vienna, Austria

Introduction

Various recombinant FVIII (rFVIII) preparations that provide efficacious replacement therapy in hemophilia A patients are available. These preparations include full-length rFVIII, which is equivalent to the naturally occurring FVIII molecule, and genetically engineered B-domain deleted rFVIII (BDD-rFVIII), mainly developed to increase the manufacturing yield (Pipe SW, Haemophilia 2009, 15, 1187–1196). Determination of
an accurate FVIII activity is crucial for manufacturing and especially for product dosing in clinical settings and testing of patient plasma.

A number of studies have demonstrated that assessing reliable FVIII activity for BDD-rFVIII is a significant challenge due to the major discrepancy in results obtained with FVIII chromogenic and 1-stage clotting assay. Moreover, FVIII 1-stage clotting activity depends on the type of aPTT reagent used. Here, we compared two full-length rFVIII with two BDD-rFVIII products using both FVIII chromogenic and 1-stage clotting assay. We also determined FVIII 1-stage clotting activity using seven different aPTT reagents (three ellagic acid type and four silica type activators).

 

Summary & Conclusions

•FVIII potency as determined by 1-stage clotting assay depends on the aPTT reagent:
−BDD-rFVIII products showed higher variability
−Variability was less pronounced for FL-rFVIII
•Ratio FVIII clotting/chromogenic assay also showed a broader variance for BDD-rFVIII, independent of reference preparation type
•Ratio FVIII clotting/chromogenic assay was on average lower
for BDD-rFVIII and showed higher variation than for FL-rFVIII confirming the previously identified higher discrepancy between FVIII chromogenic and 1-stage clotting assay for BDD-rFVIII
•Determination of FVIII activity in clinical settings using 1-stage clotting assays might be more challenging for BDD-rFVIII