Download PDF
Semin Thromb Hemost 2023; 49(06): 651-660
DOI: 10.1055/s-0043-1768660
Review Article

The Use of Bypassing Treatment Strategies in Hemophilia and Their Effect on Laboratory Testing

Rajiv K. Pruthi
1   Division of Hematology, Department of Internal Medicine, Comprehensive Hemophilia Center, Rochester, Minnesota
2   Division of Hematopathology, Department of Laboratory Medicine and Pathology, Special Coagulation Laboratory, Mayo Clinic, Rochester, Minnesota
,
Dong Chen
2   Division of Hematopathology, Department of Laboratory Medicine and Pathology, Special Coagulation Laboratory, Mayo Clinic, Rochester, Minnesota
› Author Affiliations
› Further Information
    Permissions and Reprints

Abstract

Factor VIII and IX inhibitors in congenital hemophilia A and B, respectively, neutralize the infused coagulation factor concentrate rendering them ineffective. Bypassing agents (BPAs) that circumvent the block imposed by the inhibitors are used for the prevention and management of bleeding. Activated prothrombin complex concentrate was the original BPA, recombinant activated factor VII was then introduced, and more recently nonfactor agents that target the procoagulant and anticoagulant systems have been developed and are in clinical use (e.g., emicizumab, a bispecific antibody for hemophilia A). Other BPAs are in clinical trials (e.g., fitusiran targets antithrombin, concizumab and marstacimab target tissue factor pathway inhibitor, and SerpinPC targets activated protein C). The BPAs have a varied effect on coagulation assays, and as more patients are exposed to these agents, it is important to be aware of the effects. Herein, we present an overview of the effect of BPAs on routine and specialized coagulation assays including thrombin generation and viscoelastic assays.

Keywords

bypassing agent - bispecific antibody - coagulation assays - viscoelastic


Publication History

Article published online:
05 May 2023

© 2023. Thieme. All rights reserved.

Thieme Medical Publishers, Inc.
333 Seventh Avenue, 18th Floor, New York, NY 10001, USA

 

  • References

  • 1 Soucie JM, Evatt B, Jackson D. The Hemophilia Surveillance System Project Investigators. Occurrence of hemophilia in the United States. Am J Hematol 1998; 59 (04) 288-294
    CrossrefPubMedGoogle Scholar
  • 2 Franchini M, Mannucci PM. Hemophilia A in the third millennium. Blood Rev 2013; 27 (04) 179-184
    CrossrefPubMedGoogle Scholar
  • 3 Srivastava A, Brewer AK, Mauser-Bunschoten EP. et al; Treatment Guidelines Working Group on Behalf of The World Federation Of Hemophilia. Guidelines for the management of hemophilia. Haemophilia 2013; 19 (01) e1-e47
    CrossrefPubMedGoogle Scholar
  • 4 Kempton CL, Meeks SL. Toward optimal therapy for inhibitors in hemophilia. Hematology (Am Soc Hematol Educ Program) 2014; 2014 (01) 364-371
    CrossrefPubMedGoogle Scholar
  • 5 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
    CrossrefPubMedGoogle Scholar
  • 6 Mahlangu JN, Andreeva TA, Macfarlane DE, Walsh C, Key NS. Recombinant B-domain-deleted porcine sequence factor VIII (r-pFVIII) for the treatment of bleeding in patients with congenital haemophilia A and inhibitors. Haemophilia 2017; 23 (01) 33-41
    CrossrefPubMedGoogle Scholar
  • 7 Ruan GJ, Mao JJ, Sytsma TT. et al. Continuous infusion of recombinant porcine factor VIII for neurosurgical management of intracranial haemorrhage in a patient with severe haemophilia A with factor VIII inhibitor. Haemophilia 2020; 26 (03) e141-e144
    PubMedGoogle Scholar
  • 8 Pasi KJ, Rangarajan S, Georgiev P. et al. Targeting of antithrombin in hemophilia A or B with RNAi therapy. N Engl J Med 2017; 377 (09) 819-828
    CrossrefPubMedGoogle Scholar
  • 9 Shapiro AD, Angchaisuksiri P, Astermark J. et al. Subcutaneous concizumab prophylaxis in hemophilia A and hemophilia A/B with inhibitors: phase 2 trial results. Blood 2019; 134 (22) 1973-1982
    CrossrefPubMedGoogle Scholar
  • 10 Mahlangu J, Luis Lamas J, Cristobal Morales J. et al. Long-term safety and efficacy of the anti-tissue factor pathway inhibitor marstacimab in participants with severe haemophilia: Phase II study results. Br J Haematol 2023; 200 (02) 240-248
    CrossrefPubMedGoogle Scholar
  • 11 Aymonnier K, Kawecki C, Arocas V, Boulaftali Y, Bouton MC. Serpins, new therapeutic targets for hemophilia. Thromb Haemost 2021; 121 (03) 261-269
    Article in Thieme ConnectPubMedGoogle Scholar
  • 12 Ozelo MC, Yamaguti-Hayakawa GG. Impact of novel hemophilia therapies around the world. Res Pract Thromb Haemost 2022; 6 (03) e12695
    CrossrefPubMedGoogle Scholar
  • 13 Young G, Sørensen B, Dargaud Y, Negrier C, Brummel-Ziedins K, Key NS. Thrombin generation and whole blood viscoelastic assays in the management of hemophilia: current state of art and future perspectives. Blood 2013; 121 (11) 1944-1950
    CrossrefPubMedGoogle Scholar
  • 14 Lancé MD. A general review of major global coagulation assays: thrombelastography, thrombin generation test and clot waveform analysis. Thromb J 2015; 13: 1
    CrossrefPubMedGoogle Scholar
  • 15 Rodgers G, Lehman CM. Hemostasis screening assays. In: Bennett ST, Lehman CM, Rodgers GM. eds. Laboratory Hemostasis. Springer; 2007: 85-101
    Google Scholar
  • 16 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
    CrossrefPubMedGoogle Scholar
  • 17 Ninivaggi M, de Laat-Kremers R, Tripodi A. et al. Recommendations for the measurement of thrombin generation: communication from the ISTH SSC Subcommittee on Lupus Anticoagulant/Antiphospholipid Antibodies. J Thromb Haemost 2021; 19 (05) 1372-1378
    CrossrefPubMedGoogle Scholar
  • 18 Depasse F, Binder NB, Mueller J. et al. Thrombin generation assays are versatile tools in blood coagulation analysis: a review of technical features, and applications from research to laboratory routine. J Thromb Haemost 2021; 19 (12) 2907-2917
    CrossrefPubMedGoogle Scholar
  • 19 Kintigh J, Monagle P, Ignjatovic V. A review of commercially available thrombin generation assays. Res Pract Thromb Haemost 2017; 2 (01) 42-48
    CrossrefPubMedGoogle Scholar
  • 20 Wu G, Krebs CR, Lin FC, Wolberg AS, Oldenburg AL. High sensitivity micro-elastometry: applications in blood coagulopathy. Ann Biomed Eng 2013; 41 (10) 2120-2129
    CrossrefPubMedGoogle Scholar
  • 21 Faraoni D, DiNardo JA. Viscoelastic hemostatic assays: update on technology and clinical applications. Am J Hematol 2021; 96 (10) 1331-1337
    CrossrefPubMedGoogle Scholar
  • 22 Morimont L, Donis N, Bouvy C, Mullier F, Dogné JM, Douxfils J. Laboratory testing for the evaluation of phenotypic activated protein C resistance. Semin Thromb Hemost 2022; 48 (06) 680-689
    Article in Thieme ConnectPubMedGoogle Scholar
  • 23 Marlar RA, Gausman JN. Laboratory testing issues for protein C, protein S, and antithrombin. Int J Lab Hematol 2014; 36 (03) 289-295
    CrossrefPubMedGoogle Scholar
  • 24 Devreese KMJ, Ortel TL, Pengo V, de Laat B. Subcommittee on Lupus Anticoagulant/Antiphospholipid Antibodies. Laboratory criteria for antiphospholipid syndrome: communication from the SSC of the ISTH. J Thromb Haemost 2018; 16 (04) 809-813
    CrossrefPubMedGoogle Scholar
  • 25 FEIBA (Anti-Inhibitor Coagulant Complex): . Highlights of Prescribing Information. Lexington, MA: Takeda; 2020
    Google Scholar
  • 26 Novo Seven RT (Coagulation factor VIIa [Recombinant]): Highlights of prescribing information, Bagsvaerd, Denmark: Novo Nordisk. 2014
  • 27 Turecek PL, Váradi K, Gritsch H, Schwarz HP. FEIBA: mode of action. Haemophilia 2004; 10 (Suppl. 02) 3-9
    CrossrefPubMedGoogle Scholar
  • 28 Varadi K, Tangada S, Loeschberger M. et al. Pro- and anticoagulant factors facilitate thrombin generation and balance the haemostatic response to FEIBA(®) in prophylactic therapy. Haemophilia 2016; 22 (04) 615-624
    CrossrefPubMedGoogle Scholar
  • 29 Livnat T, Zivelin A, Martinowitz U, Salomon O, Seligsohn U. Prerequisites for recombinant factor VIIa-induced thrombin generation in plasmas deficient in factors VIII, IX or XI. J Thromb Haemost 2006; 4 (01) 192-200
    CrossrefPubMedGoogle Scholar
  • 30 Váradi K, Negrier C, Berntorp E. et al. Monitoring the bioavailability of FEIBA with a thrombin generation assay. J Thromb Haemost 2003; 1 (11) 2374-2380
    CrossrefPubMedGoogle Scholar
  • 31 Turecek PL, Váradi K, Keil B. et al. Factor VIII inhibitor-bypassing agents act by inducing thrombin generation and can be monitored by a thrombin generation assay. Pathophysiol Haemost Thromb 2003; 33 (01) 16-22
    CrossrefPubMedGoogle Scholar
  • 32 Sørensen B, Spahn DR, Innerhofer P, Spannagl M, Rossaint R. Clinical review: prothrombin complex concentrates – evaluation of safety and thrombogenicity. Crit Care 2011; 15 (01) 201
    CrossrefPubMedGoogle Scholar
  • 33 Hoffman M, Dargaud Y. Mechanisms and monitoring of bypassing agent therapy. J Thromb Haemost 2012; 10 (08) 1478-1485
    CrossrefPubMedGoogle Scholar
  • 34 Keeney M, Allan DS, Lohmann RC, Yee IH. Effect of activated recombinant human factor 7 (Niastase) on laboratory testing of inhibitors of factors VIII and IX. Lab Hematol 2005; 11 (02) 118-123
    CrossrefPubMedGoogle Scholar
  • 35 Telgt DS, Macik BG, McCord DM, Monroe DM, Roberts HR. Mechanism by which recombinant factor VIIa shortens the aPTT: activation of factor X in the absence of tissue factor. Thromb Res 1989; 56 (05) 603-609
    CrossrefPubMedGoogle Scholar
  • 36 Ejlersen E, Melsen T, Ingerslev J, Andreasen RB, Vilstrup H. Recombinant activated factor VII (rFVIIa) acutely normalizes prothrombin time in patients with cirrhosis during bleeding from oesophageal varices. Scand J Gastroenterol 2001; 36 (10) 1081-1085
    CrossrefPubMedGoogle Scholar
  • 37 Qi X, Zhao Y, Li K, Fan L, Hua B. Evaluating and monitoring the efficacy of recombinant activated factor VIIa in patients with haemophilia and inhibitors. Blood Coagul Fibrinolysis 2014; 25 (07) 754-760
    CrossrefPubMedGoogle Scholar
  • 38 Shima M. Understanding the hemostatic effects of recombinant factor VIIa by clot wave form analysis. Semin Hematol 2004; 41 (1, Suppl 1): 125-131
    CrossrefPubMedGoogle Scholar
  • 39 Hendriks HG, Meijer K, de Wolf JT. et al. Effects of recombinant activated factor VII on coagulation measured by thromboelastography in liver transplantation. Blood Coagul Fibrinolysis 2002; 13 (04) 309-313
    CrossrefPubMedGoogle Scholar
  • 40 Furukawa S, Nogami K, Ogiwara K, Yada K, Minami H, Shima M. Systematic monitoring of hemostatic management in hemophilia A patients with inhibitor in the perioperative period using rotational thromboelastometry. J Thromb Haemost 2015; 13 (07) 1279-1284
    CrossrefPubMedGoogle Scholar
  • 41 Blair HA. Emicizumab: a review in haemophilia A. Drugs 2019; 79 (15) 1697-1707
    CrossrefPubMedGoogle Scholar
  • 42 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
    CrossrefPubMedGoogle Scholar
  • 43 Schultz NH, Glosli H, Bjørnsen S, Holme PA. The effect of emicizumab and bypassing agents in patients with hemophilia - an in vitro study. Res Pract Thromb Haemost 2021; 5 (05) e12561
    CrossrefPubMedGoogle Scholar
  • 44 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
    Article in Thieme ConnectPubMedGoogle Scholar
  • 45 Adamkewicz JI, Kiialainen A, Paz-Priel I. Effects and interferences of emicizumab, a humanized bispecific antibody mimicking activated factor VIII cofactor function, on lupus anticoagulant assays. Int J Lab Hematol 2020; 42 (02) e71-e75
    CrossrefPubMedGoogle Scholar
  • 46 Ogiwara K, Nogami K, Matsumoto N. et al. A modified thrombin generation assay to evaluate the plasma coagulation potential in the presence of emicizumab, the bispecific antibody to factors IXa/X. Int J Hematol 2020; 112 (05) 621-630
    CrossrefPubMedGoogle Scholar
  • 47 Kizilocak H, Marquez-Casas E, Phei Wee C, Malvar J, Carmona R, Young G. Comparison of bypassing agents in patients on emicizumab using global hemostasis assays. Haemophilia 2021; 27 (01) 164-172
    CrossrefPubMedGoogle Scholar
  • 48 Yada K, Nogami K, Ogiwara K. et al. Global coagulation function assessed by rotational thromboelastometry predicts coagulation-steady state in individual hemophilia A patients receiving emicizumab prophylaxis. Int J Hematol 2019; 110 (04) 419-430
    CrossrefPubMedGoogle Scholar
  • 49 Tiscia GLCF, De Laurenzo A, Colaizzo D. et al. Use of thromboelastography to monitor emicizumab in a patient with severe haemophilia A without inhibitor. Res Pract Thromb Haemost 2020; 4 (S01): 154
    PubMedGoogle Scholar
  • 50 Szanto T, Vaide I, Jouppila A, Lemponen M, Lassila R. Thromboelastometry detects enhancement of coagulation in blood by emicizumab via intrinsic pathway. Haemophilia 2021; 27 (04) e571-e574
    CrossrefPubMedGoogle Scholar
  • 51 Pasi KJ, Lissitchkov T, Mamonov V. et al. Targeting of antithrombin in hemophilia A or B with investigational siRNA therapeutic fitusiran - results of the phase 1 inhibitor cohort. J Thromb Haemost 2021; 19 (06) 1436-1446
    CrossrefPubMedGoogle Scholar
  • 52 Wang S, Kattula S, Ismail A, Leksa N, van Der Flier A, Salas J. Reducing antithrombin in plasma to levels observed in fitusiran-treated patients does not interfere with coagulation assays. In American Society of Hematology Annual Meeting (Virtual) 2020: 10
    PubMedGoogle Scholar
  • 53 Broze Jr GJ. Tissue factor pathway inhibitor and the current concept of blood coagulation. Blood Coagul Fibrinolysis 1995; 6 (Suppl. 01) S7-S13
    PubMedGoogle Scholar
  • 54 Kjalke M, Petersen HH, Hilden I. In Vitro Effect of Concizumab on Protein C Activation and Antithrombin Activity [abstract]. International Society on Thrombosis and Hemostasis; 2020
    Google Scholar
  • 55 Kjalke M, Kjelgaard-Hansen M, Hilden I. Concizumab Does Not Affect Activated Partial Thromboplastin Time, Prothrombin Time or Factor VIII/IX Activity Measured Using One-Stage Clotting or Chromogenic Substrate Assays [abstract]. International Society on Thrombosis and Haemostasis; 2020
    Google Scholar
  • 56 Kjalke M, Kjelgaard-Hansen M, Andersen S, Hilden I. Thrombin Generation Assay in Plasma from Hemophilia a Patients with or without Inhibitors on Concizumab Prophylaxis: Spiking with rFVIIa or aPCC. The American Society of Hematology Annual Meeting; 2019: 3639
    PubMedGoogle Scholar
  • 57 Eichler H, Angchaisuksiri P, Kavakli K. et al. Concizumab restores thrombin generation potential in patients with haemophilia: Pharmacokinetic/pharmacodynamic modelling results of concizumab phase 1/1b data. Haemophilia 2019; 25 (01) 60-66
    CrossrefPubMedGoogle Scholar
  • 58 Waters EK, Sigh J, Friedrich U, Hilden I, Sørensen BB. Concizumab, an anti-tissue factor pathway inhibitor antibody, induces increased thrombin generation in plasma from haemophilia patients and healthy subjects measured by the thrombin generation assay. Haemophilia 2017; 23 (05) 769-776
    CrossrefPubMedGoogle Scholar
  • 59 Kjalke M, Kjelgaard-Hansen M, Andersen S, Hilden I. Thrombin generation potential in the presence of concizumab and rFVIIa, APCC, rFVIII, or rFIX: in vitro and ex vivo analyses. J Thromb Haemost 2021; 19 (07) 1687-1696
    CrossrefPubMedGoogle Scholar
  • 60 Patel-Hett S, Martin EJ, Mohammed BM. et al. Marstacimab, a tissue factor pathway inhibitor neutralizing antibody, improves coagulation parameters of ex vivo dosed haemophilic blood and plasmas. Haemophilia 2019; 25 (05) 797-806
    CrossrefPubMedGoogle Scholar
  • 61 Polderdijk SG, Adams TE, Ivanciu L, Camire RM, Baglin TP, Huntington JA. Design and characterization of an APC-specific serpin for the treatment of hemophilia. Blood 2017; 129 (01) 105-113
    CrossrefPubMedGoogle Scholar