Laboratory Monitoring in Emicizumab-Treated Persons with Hemophilia A

Jens Müller; Isabell Pekrul; Bernd Pötzsch; Beate Berning; Johannes Oldenburg; Michael Spannagl

doi:10.1055/s-0039-1692427

Thrombosis and Haemostasis, Table of Contents

CC BY-NC-ND 4.0 · Thromb Haemost 2019; 119(09): 1384-1393
DOI: 10.1055/s-0039-1692427

Review Article

Georg Thieme Verlag KG Stuttgart · New York

Laboratory Monitoring in Emicizumab-Treated Persons with Hemophilia A

Jens Müller

¹Institute of Experimental Hematology and Transfusion Medicine, University of Bonn, Bonn, Germany

²Center for Rare Diseases Bonn (ZSEB), University Clinic Bonn, Bonn, Germany

,

Isabell Pekrul

³Department of Anaesthesiology, Ludwig Maximilian University (LMU) of Munich, Munich, Germany

⁴Department of Transfusion Medicine, Cell Therapeutics and Hemostaseology, Ludwig Maximilian University (LMU) of Munich, Munich, Germany

,

Bernd Pötzsch

¹Institute of Experimental Hematology and Transfusion Medicine, University of Bonn, Bonn, Germany

²Center for Rare Diseases Bonn (ZSEB), University Clinic Bonn, Bonn, Germany

,

Beate Berning

⁵Roche Pharma AG, Grenzach-Wyhlen, Germany

,

Johannes Oldenburg

¹Institute of Experimental Hematology and Transfusion Medicine, University of Bonn, Bonn, Germany

²Center for Rare Diseases Bonn (ZSEB), University Clinic Bonn, Bonn, Germany

,

Michael Spannagl

⁴Department of Transfusion Medicine, Cell Therapeutics and Hemostaseology, Ludwig Maximilian University (LMU) of Munich, Munich, Germany

› Author Affiliations

Abstract

Hemophilia A (HA) is an X-linked hereditary bleeding disorder caused by deficiency of coagulation factor (F) VIII activity. One of the greatest complications in the treatment of HA is the development of neutralizing alloantibodies, known as FVIII inhibitors. HA patients who develop FVIII inhibitors have limited treatment options available to them and experience greater disease- and treatment-related burdens than HA patients without FVIII inhibitors. Emicizumab, a recently approved bispecific monoclonal antibody, mimics the function of FVIIIa by bridging FIXa and FX to restore effective hemostasis. Although emicizumab and FVIII show some functional similarities, several key differences influence the results of standard laboratory assays when conducted in the presence of emicizumab, and can result in a misleading interpretation of coagulation assays in emicizumab-treated patients. Here, we discuss current laboratory monitoring methods, including activated partial thromboplastin time, FVIII one-stage clotting assays, FVIII chromogenic assays, and global coagulations assays; address why these conventional methods may be inappropriate for monitoring of HA patients receiving emicizumab; and suggest alternative methods applicable to monitoring HA treatment in an evolving treatment landscape.

Keywords

hemophilia A - laboratory monitoring - FVIII activity - coagulation

Full Text

References

References
1 Franchini M, Mannucci PM. Hemophilia A in the third millennium. Blood Rev 2013; 27 (04) 179-184
2 Lai JD, Lillicrap D. Factor VIII inhibitors: advances in basic and translational science. Int J Lab Hematol 2017; 39 (Suppl. 01) 6-13
3 Berntorp E. Differential response to bypassing agents complicates treatment in patients with haemophilia and inhibitors. Haemophilia 2009; 15 (01) 3-10
4 Walsh CE, Soucie JM, Miller CH. ; United States Hemophilia Treatment Center Network. Impact of inhibitors on hemophilia A mortality in the United States. Am J Hematol 2015; 90 (05) 400-405
5 Food and Drug Administration. HEMLIBRA® (emicizumab-kxwh) injection for subcutaneous use, prescribing information. Initial U.S. approval: 2017 . Available at: https://www.accessdata.fda.gov/drugsatfda_docs/label/2017/761083s000lbl.pdf . Accessed January 9, 2019
6 European Medicines Agency. HEMLIBRA® solution for injection: emicizumab piIEa. Initial EU approval: 2018 . Available at: https://www.ema.europa.eu/documents/product-information/hemlibra-epar-product-information_en.pdf . Accessed January 9, 2019
7 Kitazawa T, Igawa T, Sampei Z. , et al. A bispecific antibody to factors IXa and X restores factor VIII hemostatic activity in a hemophilia A model. Nat Med 2012; 18 (10) 1570-1574
8 Sampei Z, Igawa T, Soeda T. , et al. Identification and multidimensional optimization of an asymmetric bispecific IgG antibody mimicking the function of factor VIII cofactor activity. PLoS One 2013; 8 (02) e57479
9 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
10 Oldenburg J, Mahlangu JN, Kim B. , et al. Emicizumab prophylaxis in hemophilia A with inhibitors. N Engl J Med 2017; 377 (09) 809-818
11 Pipe S, Shima M, Lehle M. , et al. A multicentre, open-label, phase 3 study to evaluate the efficacy, safety, and pharmacokinetics of emicizumab prophylaxis administered every 4 weeks in persons with haemophilia A. Lancet Haematol 2019;
12 Young G, Sidonio RF, Liesner R. , et al. Emicizumab prophylaxis provides flexible and effective bleed control in children with hemophilia A with inhibitors: results from the HAVEN 2 Study. 60th Annual Meeting of the American Society of Hematology (ASH) December 1–4, 2018 ; San Diego, CA
13 Moser KA, Adcock Funk DM. Chromogenic factor VIII activity assay. Am J Hematol 2014; 89 (07) 781-784
14 Teichman J, Chaudhry HR, Sholzberg M. Novel assays in the coagulation laboratory: a clinical and laboratory perspective. Transfus Apheresis Sci 2018; 57 (04) 480-484
15 Kitchen S, Kershaw G, Tiefenbacher S. Recombinant to modified factor VIII and factor IX - chromogenic and one-stage assays issues. Haemophilia 2016; 22 (Suppl. 05) 72-77
16 Al-Samkari H, Croteau SE. Shifting landscape of hemophilia therapy: implications for current clinical laboratory coagulation assays. Am J Hematol 2018; 93: 1082-1090
17 Amiral J, Seghatchian J. Usefulness of chromogenic assays for potency assignment and recovery of plasma-derived FVIII and FIX concentrates or their recombinant long acting therapeutic equivalents with potential application in treated pediatric hemophiliac patients. Transfus Apheresis Sci 2018; 57 (03) 363-369
18 Kitchen S, Blakemore J, Friedman KD. , et al. A computer-based model to assess costs associated with the use of factor VIII and factor IX one-stage and chromogenic activity assays. J Thromb Haemost 2016; 14 (04) 757-764
19 Trossaërt M, Regnault V, Sigaud M, Boisseau P, Fressinaud E, Lecompte T. Mild hemophilia A with factor VIII assay discrepancy: using thrombin generation assay to assess the bleeding phenotype. J Thromb Haemost 2008; 6 (03) 486-493
20 Lyall H, Hill M, Westby J, Grimley C, Dolan G. Tyr346-->Cys mutation results in factor VIII:C assay discrepancy and a normal bleeding phenotype - is this mild haemophilia A?. Haemophilia 2008; 14 (01) 78-80
21 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
22 Peyvandi F, Oldenburg J, Friedman KD. A critical appraisal of one-stage and chromogenic assays of factor VIII activity. J Thromb Haemost 2016; 14 (02) 248-261
23 Bowyer A, Key N, Dalton D, Kitchen S, Makris M. The coagulation laboratory monitoring of Afstyla single-chain FVIII concentrate. Haemophilia 2017; 23 (05) e469-e470
24 Friedman KD, Powell JS, Bensen-Kennedy D. Response: the coagulation laboratory monitoring of AFSTYLA single-chain FVIII concentrate. Haemophilia 2018; 24 (03) e129-e131
25 Badle S, Barrie A, Spires J. , et al. Use of rotational thromboelastometry to monitor boys with severe haemophlia A and inhibitors on treatment with emicizumab. World Congress of the World Federation of Haemophilia (WFH) May 20–24, 2018 ; Glasgow, Scotland
26 Theusinger OM, Nürnberg J, Asmis LM, Seifert B, Spahn DR. Rotation thromboelastometry (ROTEM) stability and reproducibility over time. Eur J Cardiothorac Surg 2010; 37 (03) 677-683
27 Spiezia L, Bertini D, Boldrin M. , et al. Reference values for thromboelastometry (ROTEM®) in cynomolgus monkeys (Macaca fascicularis). Thromb Res 2010; 126 (04) e294-e297
28 Durila M. Nonactivated thromboelastometry able to detect fibrinolysis in contrast to activated methods (EXTEM, INTEM) in a bleeding patient. Blood Coagul Fibrinolysis 2016; 27 (07) 828-830
29 Mancuso ME, Fasulo MR. Thrombin generation assay as a laboratory monitoring tool during bypassing therapy in patients with hemophilia and inhibitors. Semin Thromb Hemost 2016; 42 (01) 30-35
30 Dargaud Y, Luddington R, Gray E. , et al. Standardisation of thrombin generation test--which reference plasma for TGT? An international multicentre study. Thromb Res 2010; 125 (04) 353-356
31 Miller CH. Laboratory testing for factor VIII and IX inhibitors in haemophilia: a review. Haemophilia 2018; 24 (02) 186-197
32 Allain JP, Frommel D. Antibodies to factor VIII. I. Variations in stability of antigen-antibody complexes in hemophilia A. Blood 1973; 42 (03) 437-444
33 Regnault V, Stoltz JF. Quantitation of factor VIII antibodies by an enzyme-linked immunoassay method. Blood 1994; 83 (04) 1155-1156
34 Sahud MA, Pratt KP, Zhukov O, Qu K, Thompson AR. ELISA system for detection of immune responses to FVIII: a study of 246 samples and correlation with the Bethesda assay. Haemophilia 2007; 13 (03) 317-322
35 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
36 Uchida N, Sambe T, Yoneyama K. , et al. A first-in-human phase 1 study of ACE910, a novel factor VIII-mimetic bispecific antibody, in healthy subjects. Blood 2016; 127 (13) 1633-1641
37 van Dijk K, van der Bom JG, Lenting PJ. , et al. Factor VIII half-life and clinical phenotype of severe hemophilia A. Haematologica 2005; 90 (04) 494-498
38 Knight T, Callaghan MU. The role of emicizumab, a bispecific factor IXa- and factor X-directed antibody, for the prevention of bleeding episodes in patients with hemophilia A. Ther Adv Hematol 2018; 9 (10) 319-334
39 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
40 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
41 Calatzis A, Chen DC, Paz-Priel I. , et al. Effects and interferences of emicizumab – a humanised bispecific antibody mimicking activated factor VIII cofactor function – on coagulation assays. 62nd Annual Meeting of the Gesellschaft für Thrombose- und Hämostaseforschung (GTH) February 20–23, 2018 ; Vienna, Austria
42 Adamkewicz JI, Soeda T, Kotani N. , et al. Effect of emicizumab (ACE910) – a humanized bispecific antibody mimicking FVIIIa cofactor function – on coagulation assays commonly in use for monitoring of hemophilia A patients. Scientific Symposium of the Hemostasis and Thrombosis Research Society (HTRS) April 6–8, 2017 ; Scottsdale, AZ
43 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
44 Lenting PJ, Denis CV, Christophe OD. Emicizumab, a bispecific antibody recognizing coagulation factors IX and X: how does it actually compare to factor VIII?. Blood 2017; 130 (23) 2463-2468
45 Ferrière S, Lenting PJ. Antibodies in the treatment of haemophilia A-a biochemical perspective. Hamostaseologie 2019; 39 (01) 36-41
46 Calhoon W, McInerney M, Calatzis A. , et al. Evaluation of a dedicated calibrator and controls for emicizumab quantification. 4th Scientific Meeting of the Thrombosis and Hemostasis Societies of North America (THSNA) April 22–25, 2018 ; Chicago, IL
47 Jonsson F, Mercier F, Prins NH. , et al. Exposure-response modeling of emicizumab for the prophylaxis of bleed counts in hemophilia A patients. 27th Meeting of the Population Approach Group in Europe (PAGE) May 29–June 1, 2018 ; Montreux, Switzerland
48 Schmitt C, Adamkewicz JI, Xu J. , et al. Pharmacokinetics (PK), pharmacodynamics (PD), and PK/PD relationships of emicizumab in persons with hemophilia A (PwHA) with inhibitors from adolescent/adult (HAVEN 1) and paediatric (HAVEN 2) phase 3 studies. 11th Annual Congress of the European Association for Haemophilia and Allied Disorders (EAHAD) February 7–9, 2018 ; Madrid, Spain
49 Yoneyama K, Schmitt C, Kotani N. , et al. A pharmacometric approach to substitute for a conventional dose-finding study in rare diseases: example of phase III dose selection for emicizumab in hemophilia A. Clin Pharmacokinet 2018; 57 (09) 1123-1134
50 Nogami K, Matsumoto T, Tabuchi Y. , et al. Modified clot waveform analysis to measure plasma coagulation potential in the presence of the anti-factor IXa/factor X bispecific antibody emicizumab. J Thromb Haemost 2018; 16 (06) 1078-1088
51 Yada K, Nogami K, Kasai R. , et al. Enhanced Global Hemostatic Potentials with a Bispecific Antibody to Factors IXa and X (ACE910) in Whole Blood By Rotation Thromboelastometry(ROTEM®). 57th Annual Meeting of the American Society of Hematology (ASH) December 5–8, 2015 ; Orlando, FL
52 Yada K, Nogami K, Kasai R. , et al. A novel hemostatic monitoring system convertible to FVIII activity based on non-activated ROTEM (NATEM) for hemophilia A patients during emicizumab prophylaxis. 60th Annual Meeting of the American Society of Hematology (ASH) December 1–4, 2018 ; San Diego, CA
53 Yada K, Nogami K, Kitazawa T. , et al. Mode of enhancement in the global hemostatic potentials with concomitant use of bypassing agents and emicizumab in hemophilia A patients with inhibitor evaluated by ROTEM. 26th Congress of the International Society on Thrombosis and Haemostasis (ISTH) July 11, 2017 ; Berlin, Germany
54 Soeda T, Kitazawa T, Muto A. , et al. In vitro characterization of ACE910, a humanized bispecific antibody to factors IXa and X. World Congress of the World Federation of Haemophilia (WFH) May 11–15, 2014 ; Melbourne, Australia
55 Adamkewicz JI, Muto A, Soeda T. , et al. In vitro thrombin generation testing and in vivo venous stasis model for assessing the pro-coagulant effects of FVIII, emicizumab, rFVIIa, and aPCC. 10th Annual Congress of the European Association for Haemophilia and Allied Disorders (EAHAD) February 1–3, 2017 ; Paris, France
56 Dargaud Y, Lienhart A, Janbain M, Le Quellec S, Enjolras N, Negrier C. Use of thrombin generation assay to personalize treatment of breakthrough bleeds in a patient with hemophilia and inhibitors receiving prophylaxis with emicizumab. Haematologica 2018; 103 (04) e181-e183
57 Calatzis A, Kotani N, Levy GG. , et al. Effect of emicizumab (ACE910) – a humanized bispecific antibody mimicking FVIII cofactor function – on a variety of assay systems. 1st European Congress on Thrombosis and Haemostasis (ECTH) September 28–30, 2016 ; The Hague, The Netherlands
58 Nogami K, Soeda T, Matsumoto T, Kawabe Y, Kitazawa T, Shima M. Routine measurements of factor VIII activity and inhibitor titer in the presence of emicizumab utilizing anti-idiotype monoclonal antibodies. J Thromb Haemost 2018; 16 (07) 1383-1390
59 Adamkewicz JI, Kim B, Steinbuesch D. , et al. Measurement of FVIII Inhibitor Titer Using a Chromogenic Bethesda Assay (CBA) in the Presence of Emicizumab (ACE910), a Humanized Bispecific Antibody Mimicking FVIIIa Cofactor Function. Scientific Symposium of the Hemostasis and Thrombosis Research Society (HTRS) April 6–8, 2017 ; Scottsdale, AZ
60 Adamkewicz JI, Schmitt C, Asikanius E. , et al. Pharmacodynamic data and coagulation biomarkers in person with hemophilia A with inhibitors: results from the HAVEN 1 emicizumab phase 3 study. 26th Congress of the International Society on Thrombosis and Haemostasis (ISTH) July 8–13, 2017 ; Berlin, Germany
61 Sadeghi-Kohmami A, Boylan M, Chen DC. , et al. Agreement between a chromogenic modified Nijmegen-Bethesda assay and a qualitative ELISA test in detection of factor VIII inhibitors in plasma from persons with hemophilia A (PwHA). World Congress of the World Federation of Hemophilia (WFH) May 20–24, 2018 ; Glasgow, Scotland
62 (CHMP) CfMPfHU. Guideline on Immunogenicity Assessment of Therapeutic Proteins. Amsterdam, the Netherlands: European Medicines Agency; 2017
63 Paz-Priel I, Chang T, Asikanius E. , et al. Immunogenicity of emicizumab in people with hemophilia A (PwHA): results from the HAVEN 1–4 studies. 60th Annual Meeting of the American Society of Hematology (ASH) December 1–4, 2018 ; San Diego, CA
64 Ahmad SS, London FS, Walsh PN. Binding studies of the enzyme (factor IXa) with the cofactor (factor VIIIa) in the assembly of factor-X activating complex on the activated platelet surface. J Thromb Haemost 2003; 1 (11) 2348-2355
65 Lapan KA, Fay PJ. Localization of a factor X interactive site in the A1 subunit of factor VIIIa. J Biol Chem 1997; 272 (04) 2082-2088
66 Lenting PJ, Donath MJ, van Mourik JA, Mertens K. Identification of a binding site for blood coagulation factor IXa on the light chain of human factor VIII. J Biol Chem 1994; 269 (10) 7150-7155