Extended Half-Life Factor VIII/Factor IX Products: Assay Discrepancies and Implications for Hemophilia Management

Abstract

Due to structural differences between extended half-life (EHL) factor VIII (FVIII) or FIX products and equivalent plasma wild-type molecules used for assay calibration, reagent-dependent discrepancies during monitoring of FVIII- and FIX-replacement therapies with EHL products have been described. To assess the performance of available one-stage clotting and chromogenic substrate assays on the Siemens Atellica COAG 360 analyzer, an in vitro study using spiked plasma samples was performed. The described results confirm previously described findings and allowed allocation of each EHL product to an appropriate assay. In addition, corresponding EHL product–specific analytes were defined within the order entry system of the University Hospital Bonn. The requirement of product-specific FVIII and FIX assays complicates patient monitoring and demonstrates the need for both continuous education and communication between treating physicians and the coagulation laboratory.

Zusammenfassung

Aufgrund struktureller Unterschiede zwischen FVIII- und FIX-Produkten mit verlängerter Halbwertszeit (EHL) und den zur Kalibration der Testsysteme verwendeten plasmatischen Faktoren kommt es zu reagenzabhängigen Diskrepanzen von im Rahmen der Therapie mit EHL-Konzentraten erhobenen Aktivitätswerten. Zur entsprechenden Überprüfung der uns auf dem Atellica Coag 360 Analysensystem zur Verfügung stehenden Einstufen- und chromogenen Testverfahren wurde eine in-vitro-Studie mit entsprechend präparierten Plasmaproben durchgeführt. Die gefundenen und hier beschriebenen Ergebnisse bestätigen zuvor publizierte Daten und erlaubten die Zuordnung der einzelnen EHL-Produkte zu einem jeweils geeigneten Testverfahren. Die produktspezifischen Testverfahren wurde durch die Anlage entsprechender Analyte im Order-Entry-System des Universitätsklinikums Bonn (UKB) hinterlegt. Die Notwendigkeit produktspezifischer FVIII- und FIX-Tests kompliziert das Patientenmonitoring und verdeutlicht die Notwendigkeit entsprechender Fortbildungen als auch einer guten Kommunikation zwischen behandelndem Arzt und Labor.

Keywords

hemophilia A/B - factor concentrates - extended half-life products - prophylaxis

Schlüsselwörter

Hämophilie A/B - Faktorenkonzentrate - Verlängerte Halbwertszeit - Prophylaxe

Publication History

Received: 15 September 2020

Accepted: 05 October 2020

Article published online:
13 November 2020

• References

• 1 Bolton-Maggs PH, Pasi KJ. Haemophilias A and B. Lancet 2003; 361 (9371): 1801-1809
• 2 Franchini M, Mannucci PM. The history of hemophilia. Semin Thromb Hemost 2014; 40 (05) 571-576
• 3 Schramm W. The history of haemophilia - a short review. Thromb Res 2014; 134 (Suppl. 01) S4-S9
• 4 Adcock DM, Strandberg K, Shima M, Marlar RA. Advantages, disadvantages and optimization of one-stage and chromogenic factor activity assays in haemophilia A and B. Int J Lab Hematol 2018; 40 (06) 621-629
• 5 Oldenburg J, Pavlova A. Discrepancy between one-stage and chromogenic factor VIII activity assay results can lead to misdiagnosis of haemophilia A phenotype. Hamostaseologie 2010; 30 (04) 207-211
• 6 Pavlova A, Delev D, Pezeshkpoor B, Müller J, Oldenburg J. Haemophilia A mutations in patients with non-severe phenotype associated with a discrepancy between one-stage and chromogenic factor VIII activity assays. Thromb Haemost 2014; 111 (05) 851-861
• 7 Pezeshkpoor B, Gazorpak M, Berkemeier AC. et al. In silico and in vitro evaluation of the impact of mutations in non-severe haemophilia A patients on assay discrepancies. Ann Hematol 2019; 98 (08) 1855-1865
• 8 Mikaelsson M, Oswaldsson U, Sandberg H. Influence of phospholipids on the assessment of factor VIII activity. Haemophilia 1998; 4 (04) 646-650
• 9 Mikaelsson M, Oswaldsson U, Jankowski MA. Measurement of factor VIII activity of B-domain deleted recombinant factor VIII. Semin Hematol 2001; 38 (02) (Suppl. 04) 13-23
• 10 Wilmot HV, Hogwood J, Gray E. Recombinant factor IX: discrepancies between one-stage clotting and chromogenic assays. Haemophilia 2014; 20 (06) 891-897
• 11 Chowdary P. Extended half-life recombinant products in haemophilia clinical practice - expectations, opportunities and challenges. Thromb Res 2019; (epub ahead of print) DOI: 10.1016/j.thromres.2019.12.012.
• 12 Peyvandi F, Kenet G, Pekrul I, Pruthi RK, Ramge P, Spannagl M. Laboratory testing in hemophilia: impact of factor and non-factor replacement therapy on coagulation assays. J Thromb Haemost 2020; 18 (06) 1242-1255
• 13 Hörber S, Lehmann R, Peter A. Evaluation of the Atellica COAG 360 coagulation analyzer in a central laboratory of a maximum care hospital. Int J Lab Hematol 2020; 42 (01) 28-36
• 14 Frampton JE. Efmoroctocog alfa: a review in haemophilia A. Drugs 2016; 76 (13) 1281-1291
• 15 Paik J, Deeks ED. Damoctocog alfa pegol: a review in haemophilia A. Drugs 2019; 79 (10) 1147-1156
• 16 Al-Salama ZT, Scott LJ. Lonoctocog alfa: a review in haemophilia A. Drugs 2017; 77 (15) 1677-1686
• 17 Konkle BA, Stasyshyn O, Chowdary P. et al. Pegylated, full-length, recombinant factor VIII for prophylactic and on-demand treatment of severe hemophilia A. Blood 2015; 126 (09) 1078-1085
• 18 Ezban M, Hansen M, Kjalke M. An overview of turoctocog alfa pegol (N8-GP; ESPEROCT^® ) assay performance: Implications for postadministration monitoring. Haemophilia 2020; 26 (01) 156-163
• 19 Lyseng-Williamson KA. Coagulation factor IX (Recombinant), albumin fusion protein (albutrepenonacog alfa; Idelvion^®): a review of its use in haemophilia B. Drugs 2017; 77 (01) 97-106
• 20 Hoy SM. Eftrenonacog alfa: a review in haemophilia B. Drugs 2017; 77 (11) 1235-1246
• 21 Syed YY. Nonacog beta pegol: a review in haemophilia B. Drugs 2017; 77 (18) 2003-2012
• 22 Young GA, Perry DJ. International Prophylaxis Study Group (IPSG). Laboratory assay measurement of modified clotting factor concentrates: a review of the literature and recommendations for practice. J Thromb Haemost 2019; 17 (04) 567-573
• 23 Gray E, Kitchen S, Bowyer A. et al. Laboratory measurement of factor replacement therapies in the treatment of congenital haemophilia: a United Kingdom Haemophilia Centre Doctors' Organisation guideline. Haemophilia 2020; 26 (01) 6-16
• 24 Rosén P, Rosén S, Ezban M, Persson E. Overestimation of N-glycoPEGylated factor IX activity in a one-stage factor IX clotting assay owing to silica-mediated premature conversion to activated factor IX. J Thromb Haemost 2016; 14 (07) 1420-1427
• 25 St Ledger K, Feussner A, Kalina U. et al. International comparative field study evaluating the assay performance of AFSTYLA in plasma samples at clinical hemostasis laboratories. J Thromb Haemost 2018; 16 (03) 555-564
• 26 Dodt J, Hubbard AR, Wicks SJ. et al. Potency determination of factor VIII and factor IX for new product labelling and postinfusion testing: challenges for caregivers and regulators. Haemophilia 2015; 21 (04) 543-549
• 27 Sommer JM, Moore N, McGuffie-Valentine B. et al. Comparative field study evaluating the activity of recombinant factor VIII Fc fusion protein in plasma samples at clinical haemostasis laboratories. Haemophilia 2014; 20 (02) 294-300
• 28 Meijer P, Marlar RA, Teare JM, Adcock D. Inter-laboratory evaluation of the recovery of Bay 94-9027 [Jivi®] with one-stage clotting and chromogenic assays. Blood 2019; 134 (Suppl. 01) 1124
• 29 Hillarp A, Bowyer A, Ezban M, Persson P, Kitchen S. Measuring FVIII activity of glycopegylated recombinant factor VIII, N8-GP, with commercially available one-stage clotting and chromogenic assay kits: a two-centre study. Haemophilia 2017; 23 (03) 458-465
• 30 Turecek PL, Romeder-Finger S, Apostol C. et al. A world-wide survey and field study in clinical haemostasis laboratories to evaluate FVIII:C activity assay variability of ADYNOVATE and OBIZUR in comparison with ADVATE. Haemophilia 2016; 22 (06) 957-965
• 31 Bulla O, Poncet A, Alberio L. et al. Impact of a product-specific reference standard for the measurement of a PEGylated rFVIII activity: the Swiss Multicentre Field Study. Haemophilia 2017; 23 (04) e335-e339
• 32 Butenas S, Parhami-Seren B, Undas A, Fass DN, Mann KG. The “normal” factor VIII concentration in plasma. Thromb Res 2010; 126 (02) 119-123