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Semin Thromb Hemost 2018; 44(06): 544-550
DOI: 10.1055/s-0037-1612626
Review Article
Thieme Medical Publishers 333 Seventh Avenue, New York, NY 10001, USA.

Inhibitors in Hemophilia: Treatment Challenges and Novel Options

Assaf Arie Barg
1   The Israeli National Hemophilia Center and Thrombosis Unit, Sheba Medical Center, Tel Hashomer, Israel
2   Hematology Department, Sackler School of Medicine, Tel Aviv University, Tel Aviv, Israel
,
Tami Livnat
1   The Israeli National Hemophilia Center and Thrombosis Unit, Sheba Medical Center, Tel Hashomer, Israel
2   Hematology Department, Sackler School of Medicine, Tel Aviv University, Tel Aviv, Israel
,
Gili Kenet
1   The Israeli National Hemophilia Center and Thrombosis Unit, Sheba Medical Center, Tel Hashomer, Israel
2   Hematology Department, Sackler School of Medicine, Tel Aviv University, Tel Aviv, Israel
› Institutsangaben
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Publikationsverlauf

Publikationsdatum:
12. Dezember 2017 (online)

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Abstract

Hemophilia A (HA) and hemophilia B (HB) are rare congenital severe bleeding disorders, that may be controlled by proper administration of adequate prophylaxis with factor VIII (FVIII), and factor IX (FIX) concentrates, respectively, to prevent joint damage due to recurrent bleeding. However, approximately 30% of patients develop inhibitory antibodies that render factor replacement therapy ineffective. Due to the high variability of patients' bleeding tendency, there is a need to “individually tailor treatment” for this unique group of patients. While replacement therapy with FVIII or FIX can be used for treating HA or HB patients with low responding inhibitors, hemophilia patients with high-responding inhibitors are treated with bypassing agents. Unfortunately, the Bethesda assay applied for inhibitor measurement in most laboratories does not fully predict either bleeding tendency or therapy response. Immune tolerance induction (ITI) may eradicate most inhibitors, yet treatment is challenging during bleeding episodes. The role of bypassing agents and their various treatment strategies still deserves attention. Recently, new nonreplacement therapies have emerged for patients with hemophilia including patients with inhibitors. Adequate monitoring of bypassing therapy and of the new nonreplacement therapies in inhibitor patients is extremely challenging, thus global hemostatic assays are increasingly used to assess clot formation. This review aims to summarize the current treatment and monitoring challenges for inhibitor patients; in this perspective, we will discuss our institutional approach for optimal decision-making and individual therapy tailoring.

Keywords

hemophilia - inhibitors - bypassing agents - immune tolerance - nonreplacement therapy
 

  • References

  • 1 Pipe SW, Valentino LA. Optimizing outcomes for patients with severe haemophilia A. Haemophilia 2007; 13 (Suppl. 04) 1-16 , quiz 3, 16
    PubMedGoogle Scholar
  • 2 Hermans C, De Moerloose P, Fischer K. , et al; European Haemophilia Therapy Standardisation Board. Management of acute haemarthrosis in haemophilia A without inhibitors: literature review, European survey and recommendations. Haemophilia 2011; 17 (03) 383-392
    CrossrefPubMedGoogle Scholar
  • 3 Kempton CL, Meeks SL. Toward optimal therapy for inhibitors in hemophilia. Blood 2014; 124 (23) 3365-3372
    CrossrefPubMedGoogle Scholar
  • 4 Franchini M, Santoro C, Coppola A. Inhibitor incidence in previously untreated patients with severe haemophilia B: a systematic literature review. Thromb Haemost 2016; 116 (01) 201-203
    Artikel in Thieme ConnectPubMedGoogle Scholar
  • 5 Walsh CE, Jiménez-Yuste V, Auerswald G, Grancha S. The burden of inhibitors in haemophilia patients. Thromb Haemost 2016; 116 (Suppl. 01) S10-S17
    Artikel in Thieme ConnectPubMedGoogle Scholar
  • 6 Leissinger CA. Advances in the clinical management of inhibitors in hemophilia A and B. Semin Hematol 2016; 53 (01) 20-27
    CrossrefPubMedGoogle Scholar
  • 7 Peyvandi F, Ettingshausen CE, Goudemand J, Jiménez-Yuste V, Santagostino E, Makris M. New findings on inhibitor development: from registries to clinical studies. Haemophilia 2017; 23 (Suppl. 01) 4-13
    CrossrefPubMedGoogle Scholar
  • 8 Berntorp E, Collins P, D'Oiron R. , et al. Identifying non-responsive bleeding episodes in patients with haemophilia and inhibitors: a consensus definition. Haemophilia 2011; 17 (01) e202-e210
    CrossrefPubMedGoogle Scholar
  • 9 Shima M, Lillicrap D, Kruse-Jarres R. Alternative therapies for the management of inhibitors. Haemophilia 2016; 22 (Suppl. 05) 36-41
    CrossrefPubMedGoogle Scholar
  • 10 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
  • 11 Hoffman M, Dargaud Y. Mechanisms and monitoring of bypassing agent therapy. J Thromb Haemost 2012; 10 (08) 1478-1485
    CrossrefPubMedGoogle Scholar
  • 12 Tran HT, Sørensen B, Bjørnsen S, Pripp AH, Tjønnfjord GE, Andre Holme P. Monitoring bypassing agent therapy-a prospective crossover study comparing thromboelastometry and thrombin generation assay. Haemophilia 2015; 21 (02) 275-283
    CrossrefPubMedGoogle Scholar
  • 13 Eubanks J, Baldwin WH, Markovitz R. , et al. A subset of high-titer anti-factor VIII A2 domain antibodies is responsive to treatment with factor VIII. Blood 2016; 127 (16) 2028-2034
    CrossrefPubMedGoogle Scholar
  • 14 Livnat T, Dunn AL, Azar-Avivi S, Baldwin WH, Kenet G, Meeks SL. Epitope specific discrepancies between antibody mediated inhibition of RFVIII and plasma derived FVIII containing von Willebrand factor affecting all domains of FVIII. Blood 2013; 122 (21) 1089
    CrossrefPubMedGoogle Scholar
  • 15 Waters B, Lillicrap D. The molecular mechanisms of immunomodulation and tolerance induction to factor VIII. J Thromb Haemost 2009; 7 (09) 1446-1456
    CrossrefPubMedGoogle Scholar
  • 16 DiMichele DM, Hoots WK, Pipe SW, Rivard GE, Santagostino E. International workshop on immune tolerance induction: consensus recommendations. Haemophilia 2007; 13 (Suppl. 01) 1-22
    PubMedGoogle Scholar
  • 17 Hay CR, DiMichele DM. ; International Immune Tolerance Study. The principal results of the International Immune Tolerance Study: a randomized dose comparison. Blood 2012; 119 (06) 1335-1344
    CrossrefPubMedGoogle Scholar
  • 18 Batorova A, Morongova A, Tagariello G, Jankovicova D, Prigancova T, Horakova J. Challenges in the management of hemophilia B with inhibitor. Semin Thromb Hemost 2013; 39 (07) 767-771
    Artikel in Thieme ConnectPubMedGoogle Scholar
  • 19 Shibata M, Shima M, Misu H, Okimoto Y, Giddings JC, Yoshioka A. Management of haemophilia B inhibitor patients with anaphylactic reactions to FIX concentrates. Haemophilia 2003; 9 (03) 269-271
    CrossrefPubMedGoogle Scholar
  • 20 Bon A, Morfini M, Dini A. , et al. Desensitization and immune tolerance induction in children with severe factor IX deficiency; inhibitors and adverse reactions to replacement therapy: a case-report and literature review. Ital J Pediatr 2015; 41: 12
    CrossrefPubMedGoogle Scholar
  • 21 Collins PW, Chalmers E, Hart DP. , et al; UK Haemophilia Centre Doctors. Diagnosis and treatment of factor VIII and IX inhibitors in congenital haemophilia: (4th edition). Br J Haematol 2013; 160 (02) 153-170
    CrossrefPubMedGoogle Scholar
  • 22 Meeks SL, Chapman RL, Kempton C, Dunn AL. Late immune tolerance induction in haemophilia A patients. Haemophilia 2013; 19 (03) 445-448
    CrossrefPubMedGoogle Scholar
  • 23 Valentino LA, Kempton CL, Kruse-Jarres R, Mathew P, Meeks SL, Reiss UM. ; International Immune Tolerance Induction Study Investigators. US Guidelines for immune tolerance induction in patients with haemophilia a and inhibitors. Haemophilia 2015; 21 (05) 559-567
    CrossrefPubMedGoogle Scholar
  • 24 Kreuz W, Escuriola Ettingshausen C, Vdovin V. , et al; ObsITI study group; ObsITI committee. First prospective report on immune tolerance in poor risk haemophilia A inhibitor patients with a single factor VIII/von Willebrand factor concentrate in an observational immune tolerance induction study. Haemophilia 2016; 22 (01) 87-95
    CrossrefPubMedGoogle Scholar
  • 25 Oldenburg J, Jiménez-Yuste V, Peiró-Jordán R, Aledort LM, Santagostino E. Primary and rescue immune tolerance induction in children and adults: a multicentre international study with a VWF-containing plasma-derived FVIII concentrate. Haemophilia 2014; 20 (01) 83-91
    CrossrefPubMedGoogle Scholar
  • 26 van Velzen AS, Peters M, van der Bom JG, Fijnvandraat K. Effect of von Willebrand factor on inhibitor eradication in patients with severe haemophilia A: a systematic review. Br J Haematol 2014; 166 (04) 485-495
    CrossrefPubMedGoogle Scholar
  • 27 Rocino A, Cortesi PA, Scalone L, Mantovani LG, Crea R, Gringeri A. ; European Haemophilia Therapy Strategy Board (EHTSB); European Haemophilia Therapy Strategy Board EHTSB. Immune tolerance induction in patients with haemophilia a and inhibitors: effectiveness and cost analysis in an European Cohort (The ITER Study). Haemophilia 2016; 22 (01) 96-102
    CrossrefPubMedGoogle Scholar
  • 28 Janbain M, Pipe S. What is the role of an extended half-life product in immune tolerance induction in a patient with severe hemophilia A and high-titer inhibitors?. Hematology (Am Soc Hematol Educ Program) 2016; 2016 (01) 648-649
    CrossrefPubMedGoogle Scholar
  • 29 Ehrlich HJ, Henzl MJ, Gomperts ED. Safety of factor VIII inhibitor bypass activity (FEIBA): 10-year compilation of thrombotic adverse events. Haemophilia 2002; 8 (02) 83-90
    CrossrefPubMedGoogle Scholar
  • 30 Abshire T, Kenet G. Safety update on the use of recombinant factor VIIa and the treatment of congenital and acquired deficiency of factor VIII or IX with inhibitors. Haemophilia 2008; 14 (05) 898-902
    CrossrefPubMedGoogle Scholar
  • 31 Astermark J, Donfield SM, DiMichele DM. , et al; FENOC Study Group. A randomized comparison of bypassing agents in hemophilia complicated by an inhibitor: the FEIBA NovoSeven Comparative (FENOC) Study. Blood 2007; 109 (02) 546-551
    CrossrefPubMedGoogle Scholar
  • 32 Young G, Shafer FE, Rojas P, Seremetis S. Single 270 microg kg(-1)-dose rFVIIa vs. standard 90 microg kg(-1)-dose rFVIIa and APCC for home treatment of joint bleeds in haemophilia patients with inhibitors: a randomized comparison. Haemophilia 2008; 14 (02) 287-294
    CrossrefPubMedGoogle Scholar
  • 33 Leissinger C, Gringeri A, Antmen B. , et al. Anti-inhibitor coagulant complex prophylaxis in hemophilia with inhibitors. N Engl J Med 2011; 365 (18) 1684-1692
    CrossrefPubMedGoogle Scholar
  • 34 Konkle BA, Ebbesen LS, Erhardtsen E. , et al. Randomized, prospective clinical trial of recombinant factor VIIa for secondary prophylaxis in hemophilia patients with inhibitors. J Thromb Haemost 2007; 5 (09) 1904-1913
    CrossrefPubMedGoogle Scholar
  • 35 Gringeri A, Leissinger C, Cortesi PA. , et al. Health-related quality of life in patients with haemophilia and inhibitors on prophylaxis with anti-inhibitor complex concentrate: results from the Pro-FEIBA study. Haemophilia 2013; 19 (05) 736-743
    CrossrefPubMedGoogle Scholar
  • 36 Teitel J, Berntorp E, Collins P. , et al. A systematic approach to controlling problem bleeds in patients with severe congenital haemophilia A and high-titre inhibitors. Haemophilia 2007; 13 (03) 256-263
    CrossrefPubMedGoogle Scholar
  • 37 Berntorp E. Differential response to bypassing agents complicates treatment in patients with haemophilia and inhibitors. Haemophilia 2009; 15 (01) 3-10
    CrossrefPubMedGoogle Scholar
  • 38 Schneiderman J, Nugent DJ, Young G. Sequential therapy with activated prothrombin complex concentrate and recombinant factor VIIa in patients with severe haemophilia and inhibitors. Haemophilia 2004; 10 (04) 347-351
    CrossrefPubMedGoogle Scholar
  • 39 Martinowitz U, Livnat T, Zivelin A, Kenet G. Concomitant infusion of low doses of rFVIIa and FEIBA in haemophilia patients with inhibitors. Haemophilia 2009; 15 (04) 904-910
    CrossrefPubMedGoogle Scholar
  • 40 Gringeri A, Fischer K, Karafoulidou A, Klamroth R, López-Fernández MF, Mancuso E. ; European Haemophilia Treatment Standardisation Board (EHTSB). Sequential combined bypassing therapy is safe and effective in the treatment of unresponsive bleeding in adults and children with haemophilia and inhibitors. Haemophilia 2011; 17 (04) 630-635
    CrossrefPubMedGoogle Scholar
  • 41 Ingerslev J, Sørensen B. Parallel use of by-passing agents in haemophilia with inhibitors: a critical review. Br J Haematol 2011; 155 (02) 256-262
    CrossrefPubMedGoogle Scholar
  • 42 Livnat T, Martinowitz U, Azar-Avivi S. , et al. Combined administration of FVIII and rFVIIa improves haemostasis in haemophilia A patients with high-responding inhibitors–a thrombin generation-guided pilot study. Haemophilia 2013; 19 (05) 782-789
    CrossrefPubMedGoogle Scholar
  • 43 Livnat T, Budnik I, Levy-Mendelovich S. , et al. Combination of hemostatic therapies for treatment of patients with hemophilia A and inhibitors. Blood Cells Mol Dis 2017; 66: 1-5
    CrossrefPubMedGoogle Scholar
  • 44 Tran HT, Sørensen B, Rea CJ. , et al. Tranexamic acid as adjunct therapy to bypassing agents in haemophilia A patients with inhibitors. Haemophilia 2014; 20 (03) 369-375
    CrossrefPubMedGoogle Scholar
  • 45 Zollner S, Schuermann D, Raquet E. , et al. Pharmacological characteristics of a novel, recombinant fusion protein linking coagulation factor VIIa with albumin (rVIIa-FP). J Thromb Haemost 2014; 12 (02) 220-228
    CrossrefPubMedGoogle Scholar
  • 46 Ljung R, Karim FA, Saxena K. , et al; Pioneer™1 Investigators. 40K glycoPEGylated, recombinant FVIIa: 3-month, double-blind, randomized trial of safety, pharmacokinetics and preliminary efficacy in hemophilia patients with inhibitors. J Thromb Haemost 2013; 11 (07) 1260-1268
    CrossrefPubMedGoogle Scholar
  • 47 Koh PL, Ng HJ, Lissitchkov T, Hardtke M, Schroeder J. The TRUST trial: anti-drug antibody formation in a patient with hemophilia with inhibitors after receiving the activated factor VII product Bay 86–6150. Blood 2013; 122 (21) 573
    PubMedGoogle Scholar
  • 48 Kempton CL, Abshire TC, Deveras RA. , et al. Pharmacokinetics and safety of OBI-1, a recombinant B domain-deleted porcine factor VIII, in subjects with haemophilia A. Haemophilia 2012; 18 (05) 798-804
    CrossrefPubMedGoogle Scholar
  • 49 Mahlangu J, Andreeva TA, Macfarlane D. , et al. A phase II open-label study evaluating hemostatic activity, pharmacokinetics and safety of recombinant porcine factor VIII (OBI-1) in hemophilia A patients with alloantibody inhibitors directed against human FVIII. Blood 2007; 110 (11) 783
    CrossrefPubMedGoogle Scholar
  • 50 Mannucci PM, Franchini M. Porcine recombinant factor VIII: an additional weapon to handle anti-factor VIII antibodies. Blood Transfus 2017; 15 (04) 365-368
    PubMedGoogle Scholar
  • 51 Hartmann J, Croteau SE. 2017 Clinical trials update: Innovations in hemophilia therapy. Am J Hematol 2016; 91 (12) 1252-1260
    CrossrefPubMedGoogle Scholar
  • 52 Mannucci PM, Mancuso ME, Santagostino E, Franchini M. Innovative pharmacological therapies for the hemophilias not based on deficient factor replacement. Semin Thromb Hemost 2016; 42 (05) 526-532
    Artikel in Thieme ConnectPubMedGoogle Scholar
  • 53 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
    CrossrefPubMedGoogle Scholar
  • 54 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
    CrossrefPubMedGoogle Scholar
  • 55 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
    CrossrefPubMedGoogle Scholar
  • 56 Oldenburg J, Mahlangu JN, Kim B. , et al. Emicizumab prophylaxis in hemophilia A with inhibitors. N Engl J Med 2017; 377 (09) 809-818
    CrossrefPubMedGoogle Scholar
  • 57 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
  • 58 Sehgal A, Barros S, Ivanciu L. , et al. An RNAi therapeutic targeting antithrombin to rebalance the coagulation system and promote hemostasis in hemophilia. Nat Med 2015; 21 (05) 492-497
    CrossrefPubMedGoogle Scholar
  • 59 Pasi KJ, Georgiev P, Mant T. , et al. A subcutaneously administered investigational RNAi therapeutic, fitusiran (ALN-AT3), targeting antithrombin for treatment of hemophilia: interim results in patients with hemophilia A or B. Haemophilia 2016; 22 (Suppl. 04) 3-138
    PubMedGoogle Scholar
  • 60 Kenet G, Livnat T, Fosbury E. , et al. Antithrombin reduction corrected thrombin generation in samples from hemophilia A and B patients with inhibitors. Blood 2015; 126 (23) 552
    PubMedGoogle 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
  • 62 Chowdary P, Lethagen S, Friedrich U. , et al. Safety and pharmacokinetics of anti-TFPI antibody (concizumab) in healthy volunteers and patients with hemophilia: a randomized first human dose trial. J Thromb Haemost 2015; 13 (05) 743-754
    CrossrefPubMedGoogle Scholar
  • 63 Dargaud Y, Lienhart A, Negrier C. Prospective assessment of thrombin generation test for dose monitoring of bypassing therapy in hemophilia patients with inhibitors undergoing elective surgery. Blood 2010; 116 (25) 5734-5737
    CrossrefPubMedGoogle Scholar
  • 64 Livnat T, Martinowitz U, Zivelin A, Rima D, Kenet G. A highly sensitive thrombin generation assay for assessment of recombinant activated factor VII therapy in haemophilia patients with an inhibitor. Thromb Haemost 2011; 105 (04) 688-695
    Artikel in Thieme ConnectPubMedGoogle Scholar
  • 65 Dargaud Y, Bordet JC, Lienhart A, Negrier C. Use of the thrombin generation test to evaluate response to treatment with recombinant activated factor VII. Semin Hematol 2008; 45 (02) (Suppl. 01) S72-S73
    CrossrefPubMedGoogle Scholar
  • 66 Eichinger S, Lubsczyk B, Kollars M. , et al. Thrombin generation in haemophilia A patients with factor VIII inhibitors after infusion of recombinant factor VIIa. Eur J Clin Invest 2009; 39 (08) 707-713
    CrossrefPubMedGoogle Scholar
  • 67 Ay Y, Balkan C, Karapinar DY, Akin M, Bilenoğlu B, Kavakli K. Feasibility of using thrombin generation assay (TGA) for monitoring bypassing agent therapy in patients with hemophilia having inhibitors. Clin Appl Thromb Hemost 2013; 19 (04) 389-394
    CrossrefPubMedGoogle Scholar
  • 68 Mancuso ME, Chantarangkul V, Clerici M. , et al. Low thrombin generation during major orthopaedic surgery fails to predict the bleeding risk in inhibitor patients treated with bypassing agents. Haemophilia 2016; 22 (04) e292-e300
    CrossrefPubMedGoogle Scholar