Strategies for Performing Factor Assays in the Presence of Emicizumab or Other Novel/Emerging Hemostatic Agents

Abstract

For several decades, therapeutic options for inherited deficiencies of factor VIII or IX (hemophilia A or B, respectively) have largely been the replacement of the missing clotting factor with plasma-derived or recombinant products. Hemostasis laboratories use standard activated partial thromboplastin time (aPTT)-based clotting or chromogenic assays to monitor plasma factor levels to guide therapy. The emergence in the past 10 years of extended half-life replacement products and other novel therapies for hemophilia has led to a reappraisal of assay suitability, with studies of product measurement showing some existing assay types or reagents to be unsuitable for some products. The hemostasis laboratory must adapt to the changing landscape by adding new assays or modifying existing assays to ensure accurate results for product measurement. These strategies include switching from a chromogenic assay to a clotting assay, or vice versa, changing an aPTT reagent brand, or introducing product specific calibrators. This article evaluates the effects of some of the newer treatment options on the laboratory testing of factor levels and related assays.

Keywords

emicizumab - Mim8 - rpFVIII - efanesoctocog alfa - FVIII

Publication History

Article published online:
12 June 2024

• References

• 1 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
• 2 Mannucci PM. Hemophilia treatment innovation: 50 years of progress and more to come. J Thromb Haemost 2023; 21 (03) 403-412
• 3 Abraham S, Duncan EM. A review of factor VIII and factor IX assay methods for monitoring extended half-life products in hemophilia A and B. In: Favaloro E, Gosselin R. eds. Hemostasis and Thrombosis Methods and Protocols. 2nd ed. 2023: 569-588
• 4 Kitchen S, Tiefenbacher S, Gosselin R. Factor activity assays for monitoring extended half-life FVIII and factor IX replacement therapies. Semin Thromb Hemost 2017; 43 (03) 331-337
• 5 Zanon E, Pasca S, Borchiellini A. et al. Susoctocog-alfa (Obizur^®) in the treatment of nine elderly patients with acquired haemophilia A: an Italian multicentre real world experience. Blood Transfus 2020; 18 (04) 312-321
• 6 Lauritzen B, Bjelke M, Björkdahl O. et al. A novel next-generation FVIIIa mimetic, Mim8, has a favorable safety profile and displays potent pharmacodynamic effects: Results from safety studies in cynomolgus monkeys. J Thromb Haemost 2022; 20 (06) 1312-1324
• 7 Kitazawa T, Esaki K, Tachibana T. et al. Factor VIIIa-mimetic cofactor activity of a bispecific antibody to factors IX/IXa and X/Xa, emicizumab, depends on its ability to bridge the antigens. Thromb Haemost 2017; 117 (07) 1348-1357
• 8 Muto A, Yoshihashi K, Takeda M. et al. Anti-factor IXa/X bispecific antibody ACE910 prevents joint bleeds in a long-term primate model of acquired hemophilia A. Blood 2014; 124 (20) 3165-3171
• 9 Muto A, Yoshihashi K, Takeda M. et al. Anti-factor IXa/X bispecific antibody (ACE910): hemostatic potency against ongoing bleeds in a hemophilia A model and the possibility of routine supplementation. J Thromb Haemost 2014; 12: 206-213
• 10 Mahlangu J, Oldenburg J, Paz-Priel I. et al. Emicizumab prophylaxis in patients who have hemophilia A without inhibitors. N Engl J Med 2018; 379 (09) 811-822
• 11 Oldenburg J, Mahlangu JN, Bujan W. et al. The effect of emicizumab prophylaxis on health-related outcomes in persons with haemophilia A with inhibitors: HAVEN 1 Study. Haemophilia 2019; 25 (01) 33-44
• 12 Oldenburg J, Mahlangu JN, Kim B. et al. Emicizumab prophylaxis in hemophilia A with inhibitors. N Engl J Med 2017; 377 (09) 809-818
• 13 Shima M, Hanabusa H, Taki M. et al. Factor VIII-mimetic function of humanized bispecific antibody in hemophilia A. N Engl J Med 2016; 374 (21) 2044-2053
• 14 Müller J, Pekrul I, Pötzsch B, Berning B, Oldenburg J, Spannagl M. Laboratory monitoring in emicizumab-treated persons with hemophilia A. Thromb Haemost 2019; 119 (09) 1384-1393
• 15 Bowyer A, Kitchen S, Maclean R. Effects of emicizumab on APTT, one-stage and chromogenic assays of factor VIII in artificially spiked plasma and in samples from haemophilia A patients with inhibitors. Haemophilia 2020; 26 (03) 536-542
• 16 Adamkewicz JI, Chen DC, Paz-Priel I. Effects and interferences of emicizumab, a humanised bispecific antibody mimicking activated factor VIII cofactor function, on coagulation assays. Thromb Haemost 2019; 119 (07) 1084-1093
• 17 Jenkins PV, Bowyer A, Burgess C. et al. Laboratory coagulation tests and emicizumab treatment A United Kingdom Haemophilia Centre Doctors' organisation guideline. Haemophilia 2020; 26 (01) 151-155
• 18 Schmitt C, Emrich T, Chebon S. et al. Low immunogenicity of emicizumab in persons with haemophilia A. Haemophilia 2021; 27 (06) 984-992
• 19 Kershaw G, Dix C. Measuring emicizumab levels in the hemostasis laboratory. In Favaloro E, Lippi G. eds. Hemostasis and Thrombosis Methods and Protocols. 2nd ed. New York:: Springer Science.; 2023. 2663. 589-595
• 20 Kershaw G, Dix C, Chen VM, Cai N, Khoo TL. Emicizumab assay evaluations and results from an Australian field study of emicizumab measurement. Pathology 2022; 54 (06) 755-762
• 21 Bowyer AE, Maclean RM, Kitchen S. The combination of emicizumab and recombinant factor VIII in plasma: which assays can we use for accurate measurement?. Int J Lab Hematol 2023; 45 (03) 368-376
• 22 Shima M, Amano K, Ogawa Y. et al. A prospective, multicenter, open-label phase III study of emicizumab prophylaxis in patients with acquired hemophilia A. J Thromb Haemost 2023; 21 (03) 534-545
• 23 Hamedani NS, Donners AAMT, van Luin M. et al. Functional determination of emicizumab in presence of factor VIII activity. J Thromb Haemost 2023; 21 (12) 3490-3500
• 24 Persson P, Amstrup AB, Coester HV, Matytsina I, Bas S. Mim8, a novel factor VIIIa mimetic bispecific antibody, shows favorable safety and pharmacokinetics in healthy adults. Res Pract Thromb Haemost 2023; 7 (06) 102181
• 25 Seremetis SV, Clausen WHO, Matytsina I, Nissen SM, Wåhlander K. Mim8 clinical development program: an overview of the frontier studies. Blood 2022; 140 (Suppl. 01) 5630-5631
• 26 Lentz SR, Chowdary P, Gil L. et al. FRONTIER1: a partially randomized phase 2 study assessing the safety, PK, and PD of Mim8, a factor VIIIa mimetic. J Thromb Haemost 2024; 22 (04) 990-1000
• 27 Bowyer AE, Kitchen S, Ezban M. The effect of a next generation factor VIII mimetic bispecific antibody (Mim8) on assays of factor VIII activity and thrombin generation. J Thromb Haemost 2023; 21 (03) 480-487
• 28 Bowyer AE, Hickey K, Kitchen S, Ezban M. A next generation FVIII mimetic bispecific antibody, Mim8, the impact on non-factor VIII related haemostasis assays. Haemophilia 2023; 29 (06) 1633-1637
• 29 Lillicrap D, Schiviz A, Apostol C. et al. Porcine recombinant factor VIII (Obizur; OBI-1; BAX801): product characteristics and preclinical profile. Haemophilia 2016; 22 (02) 308-317
• 30 Kruse-Jarres R, Kempton CL, Baudo F. et al. Acquired hemophilia A: updated review of evidence and treatment guidance. Am J Hematol 2017; 92 (07) 695-705
• 31 Kruse-Jarres R, St-Louis J, Greist A. et al. Efficacy and safety of OBI-1, an antihaemophilic factor VIII (recombinant), porcine sequence, in subjects with acquired haemophilia A. Haemophilia 2015; 21 (02) 162-170
• 32 Fosbury E, Drebes A, Riddell A, Chowdary P. Review of recombinant anti-haemophilic porcine sequence factor VIII in adults with acquired haemophilia A. Ther Adv Hematol 2017; 8 (09) 263-272
• 33 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
• 34 Vanguru VR, Kershaw G, Konda M, Chen VM. Laboratory monitoring issues in recombinant porcine FVIII replacement in acquired haemophilia A. Haemophilia 2018; 24 (02) e70-e74
• 35 Pipe S, Sadeghi-Khomami A, Konkle BA. et al. A global comparative field study to evaluate the factor VIII activity of efanesoctocog alfa by one-stage clotting and chromogenic substrate assays at clinical haemostasis laboratories. Haemophilia 2024; 30 (01) 1-10
• 36 Konkle BA, Shapiro AD, Quon DV. et al. BIVV001 fusion protein as factor VIII replacement therapy for hemophilia A. N Engl J Med 2020; 383 (11) 1018-1027
• 37 Seth Chhabra E, Liu T, Kulman J. et al. BIVV001, a new class of factor VIII replacement for hemophilia A that is independent of von Willebrand factor in primates and mice. Blood 2020; 135 (17) 1484-1496
• 38 von Drygalski A, Chowdary P, Kulkarni R. et al; XTEND-1 Trial Group. Efanesoctocog alfa prophylaxis for patients with severe hemophilia A. N Engl J Med 2023; 388 (04) 310-318