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Semin Thromb Hemost 2009; 35(8): 735-751
DOI: 10.1055/s-0029-1245106
© Thieme Medical Publishers

Inhibitors in Hemophilia A: Advances in Elucidation of Inhibitory Mechanisms and in Inhibitor Management with Bypassing Agents

Natalya M. Ananyeva1 , Timothy K. Lee1 , Nisha Jain2 , Midori Shima3 , Evgueni L. Saenko4
  • 1Laboratory of Hemostasis, Division of Hematology, Office of Blood Research and Review, Center for Biologics Evaluation and Research (CBER), Food and Drug Administration (FDA), Rockville, Maryland
  • 2Clinical Review Branch, Division of Hematology, Office of Blood Research and Review, CBER, FDA, Rockville, Maryland
  • 3Department of Pediatrics, Nara Medical University, Nara, Japan
  • 4Center for Theoretical Problems of Physico-Chemical Pharmacology, Russian Academy of Sciences, Moscow, Russia
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Publication History

Publication Date:
18 February 2010 (online)

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ABSTRACT

Development of inhibitory antibodies (inhibitors) to factor VIII (FVIII) is the most serious adverse event in replacement therapy of hemophilia A patients. The etiology and management of this condition remain major challenges for both researchers and clinicians. In the present review, we discuss recent advances in understanding the molecular mechanisms by which inhibitors inactivate FVIII and experimental approaches used for the mapping of inhibitor epitopes. We also present a comparative analysis of treatment of hemophilia A patients with inhibitors with currently available bypassing agents—activated prothrombin complex concentrate (FEIBA VH; Baxter Healthcare Corp., Westlake Village, CA) and recombinant activated factor VII (NovoSeven; Novo Nordisk, Princeton, NJ)—and describe some ongoing research programs aimed at developing new treatment options for these patients. Availability of sensitive and standardized laboratory assays that would assist in monitoring the effectiveness of bypass therapies is essential for designing customized treatment regimens and improvement in the management of health conditions of hemophilia patients with inhibitors.

KEYWORDS

Factor VIII - hemophilia A - inhibitor - epitope - bypass therapy

REFERENCES

  • 1 Fay P J. Factor VIII structure and function.  Int J Hematol. 2006;  83(2) 103-108
    CrossrefPubMedGoogle Scholar
  • 2 Mannucci P M. Back to the future: a recent history of haemophilia treatment.  Haemophilia. 2008;  14(suppl 3) 10-18
    PubMedGoogle Scholar
  • 3 DiMichele D M. Inhibitors in hemophilia: a primer. In: Treatment of hemophilia. 4th ed. Montreal, Quebec, Canada; World Federation of Hemophilia 2008
    PubMedGoogle Scholar
  • 4 Oldenburg J, Pavlova A. Genetic risk factors for inhibitors to factors VIII and IX.  Haemophilia. 2006;  12(suppl 6) 15-22
    PubMedGoogle Scholar
  • 5 Astermark J, Berntorp E, White G C, Kroner B L. MIBS Study Group . The Malmö International Brother Study (MIBS): further support for genetic predisposition to inhibitor development in hemophilia patients.  Haemophilia. 2001;  7(3) 267-272
    CrossrefPubMedGoogle Scholar
  • 6 Scharrer I, Bray G L, Neutzling O. Incidence of inhibitors in haemophilia A patients—a review of recent studies of recombinant and plasma-derived factor VIII concentrates.  Haemophilia. 1999;  5(3) 145-154
    CrossrefPubMedGoogle Scholar
  • 7 Viel K R, Ameri A, Abshire T C et al.. Inhibitors of factor VIII in black patients with hemophilia.  N Engl J Med. 2009;  360(16) 1618-1627
    CrossrefPubMedGoogle Scholar
  • 8 Oldenburg J, Tuddenham E. Inhibitors to factor VIII—molecular basis. In: Lee CA, Berntorp EE, Hoots WK Textbook of hemophilia. New York, NY; Blackwell 2005: 59-63
    PubMedGoogle Scholar
  • 9 Kempton C L, White II G C. How we treat a hemophilia A patient with a factor VIII inhibitor.  Blood. 2009;  113(1) 11-17
    CrossrefPubMedGoogle Scholar
  • 10 Goudemand J, Rothschild C, Demiguel V FVIII-LFB and Recombinant FVIII study groups et al. Influence of the type of factor VIII concentrate on the incidence of factor VIII inhibitors in previously untreated patients with severe hemophilia A.  Blood. 2006;  107(1) 46-51
    CrossrefPubMedGoogle Scholar
  • 11 Gouw S C, van den Berg H M, le Cessie S, van der Bom J G. Treatment characteristics and the risk of inhibitor development: a multicenter cohort study among previously untreated patients with severe hemophilia A.  J Thromb Haemost. 2007;  5(7) 1383-1390
    CrossrefPubMedGoogle Scholar
  • 12 Gouw S C, van der Bom J G, Auerswald G, Ettinghausen C E, Tedgård U, van den Berg H M. Recombinant versus plasma-derived factor VIII products and the development of inhibitors in previously untreated patients with severe hemophilia A: the CANAL cohort study.  Blood. 2007;  109(11) 4693-4697
    CrossrefPubMedGoogle Scholar
  • 13 Hoots W K, Lusher J. High-titer inhibitor development in hemophilia A: lack of product specificity.  J Thromb Haemost. 2004;  2(2) 358-359
    CrossrefPubMedGoogle Scholar
  • 14 Saenko E L, Ananyeva N M, Tuddenham E G, Kemball-Cook G. Factor VIII—novel insights into form and function.  Br J Haematol. 2002;  119(2) 323-331
    CrossrefPubMedGoogle Scholar
  • 15 Scandella D H, Nakai H, Felch M et al.. In hemophilia A and autoantibody inhibitor patients: the factor VIII A2 domain and light chain are most immunogenic.  Thromb Res. 2001;  101(5) 377-385
    CrossrefPubMedGoogle Scholar
  • 16 Healey J F, Lubin I M, Nakai H et al.. Residues 484-508 contain a major determinant of the inhibitory epitope in the A2 domain of human factor VIII.  J Biol Chem. 1995;  270(24) 14505-14509
    CrossrefPubMedGoogle Scholar
  • 17 Fay P J, Scandella D. Human inhibitor antibodies specific for the factor VIII A2 domain disrupt the interaction between the subunit and factor IXa.  J Biol Chem. 1999;  274(42) 29826-29830
    CrossrefPubMedGoogle Scholar
  • 18 Fay P J, Koshibu K. The A2 subunit of factor VIIIa modulates the active site of factor IXa.  J Biol Chem. 1998;  273(30) 19049-19054
    CrossrefPubMedGoogle Scholar
  • 19 Ansong C, Miles S M, Fay P J. Epitope mapping factor VIII A2 domain by affinity-directed mass spectrometry: residues 497-510 and 584-593 comprise a discontinuous epitope for the monoclonal antibody R8B12.  J Thromb Haemost. 2006;  4(4) 842-847
    CrossrefPubMedGoogle Scholar
  • 20 Healey J F, Parker E T, Barrow R T, Langley T J, Church W R, Lollar P. The humoral response to human factor VIII in hemophilia A mice.  J Thromb Haemost. 2007;  5(3) 512-519
    CrossrefPubMedGoogle Scholar
  • 21 Healey J F, Barrow R T, Tamim H M et al.. Residues Glu2181-Val2243 contain a major determinant of the inhibitory epitope in the C2 domain of human factor VIII.  Blood. 1998;  92(10) 3701-3709
    PubMedGoogle Scholar
  • 22 Scandella D, Gilbert G E, Shima M et al.. Some factor VIII inhibitor antibodies recognize a common epitope corresponding to C2 domain amino acids 2248 through 2312, which overlap a phospholipid-binding site.  Blood. 1995;  86(5) 1811-1819
    PubMedGoogle Scholar
  • 23 Pratt K P, Shen B W, Takeshima K, Davie E W, Fujikawa K, Stoddard B L. Structure of the C2 domain of human factor VIII at 1.5 A resolution.  Nature. 1999;  402(6760) 439-442
    CrossrefPubMedGoogle Scholar
  • 24 Stoilova-McPhie S, Villoutreix B O, Mertens K, Kemball-Cook G, Holzenburg A. 3-Dimensional structure of membrane-bound coagulation factor VIII: modeling of the factor VIII heterodimer within a 3-dimensional density map derived by electron crystallography.  Blood. 2002;  99(4) 1215-1223
    CrossrefPubMedGoogle Scholar
  • 25 Spiegel Jr P C, Jacquemin M, Saint-Remy J M, Stoddard B L, Pratt K P. Structure of a factor VIII C2 domain-immunoglobulin G4kappa Fab complex: identification of an inhibitory antibody epitope on the surface of factor VIII.  Blood. 2001;  98(1) 13-19
    CrossrefPubMedGoogle Scholar
  • 26 Nogami K, Shima M, Giddings J C, Takeyama M, Tanaka I, Yoshioka A. Relationship between the binding sites for von Willebrand factor, phospholipid, and human factor VIII C2 inhibitor alloantibodies within the factor VIII C2 domain.  Int J Hematol. 2007;  85(4) 317-322
    CrossrefPubMedGoogle Scholar
  • 27 Saenko E L, Scandella D. The acidic region of the factor VIII light chain and the C2 domain together form the high affinity binding site for von Willebrand factor.  J Biol Chem. 1997;  272(29) 18007-18014
    CrossrefPubMedGoogle Scholar
  • 28 Gilbert G E, Kaufman R J, Arena A A, Miao H, Pipe S W. Four hydrophobic amino acids of the factor VIII C2 domain are constituents of both the membrane-binding and von Willebrand factor-binding motifs.  J Biol Chem. 2002;  277(8) 6374-6381
    CrossrefPubMedGoogle Scholar
  • 29 Saenko E L, Shima M, Gilbert G E, Scandella D. Slowed release of thrombin-cleaved factor VIII from von Willebrand factor by a monoclonal and a human antibody is a novel mechanism for factor VIII inhibition.  J Biol Chem. 1996;  271(44) 27424-27431
    CrossrefPubMedGoogle Scholar
  • 30 Meeks S L, Healey J F, Parker E T, Barrow R T, Lollar P. Antihuman factor VIII C2 domain antibodies in hemophilia A mice recognize a functionally complex continuous spectrum of epitopes dominated by inhibitors of factor VIII activation.  Blood. 2007;  110(13) 4234-4242
    CrossrefPubMedGoogle Scholar
  • 31 Nogami K, Shima M, Hosokawa K et al.. Role of factor VIII C2 domain in factor VIII binding to factor Xa.  J Biol Chem. 1999;  274(43) 31000-31007
    CrossrefPubMedGoogle Scholar
  • 32 Nogami K, Shima M, Hosokawa K et al.. Factor VIII C2 domain contains the thrombin-binding site responsible for thrombin-catalyzed cleavage at Arg1689.  J Biol Chem. 2000;  275(33) 25774-25780
    CrossrefPubMedGoogle Scholar
  • 33 Meeks S L, Healey J F, Parker E T, Barrow R T, Lollar P. Nonclassical anti-C2 domain antibodies are present in patients with factor VIII inhibitors.  Blood. 2008;  112(4) 1151-1153
    CrossrefPubMedGoogle Scholar
  • 34 Lenting P J, van de Loo J W, Donath M J, van Mourik J A, Mertens K. The sequence Glu1811-Lys1818 of human blood coagulation factor VIII comprises a binding site for activated factor IX.  J Biol Chem. 1996;  271(4) 1935-1940
    CrossrefPubMedGoogle Scholar
  • 35 Fijnvandraat K, Celie P H, Turenhout E A et al.. A human alloantibody interferes with binding of factor IXa to the factor VIII light chain.  Blood. 1998;  91(7) 2347-2352
    PubMedGoogle Scholar
  • 36 Zhong D, Saenko E L, Shima M, Felch M, Scandella D. Some human inhibitor antibodies interfere with factor VIII binding to factor IX.  Blood. 1998;  92(1) 136-142
    PubMedGoogle Scholar
  • 37 Foster P A, Fulcher C A, Houghten R A, de Graaf Mahoney S, Zimmerman T S. Localization of the binding regions of a murine monoclonal anti-factor VIII antibody and a human anti-factor VIII alloantibody, both of which inhibit factor VIII procoagulant activity, to amino acid residues threonine351-serine365 of the factor VIII heavy chain.  J Clin Invest. 1988;  82(1) 123-128
    CrossrefPubMedGoogle Scholar
  • 38 Lapan K A, Fay P J. Localization of a factor X interactive site in the A1 subunit of factor VIIIa.  J Biol Chem. 1997;  272(4) 2082-2088
    CrossrefPubMedGoogle Scholar
  • 39 Raut S, Villard S, Grailly S et al.. Anti-heavy-chain monoclonal antibodies directed to the acidic regions of the factor VIII molecule inhibit the binding of factor VIII to phospholipids and von Willebrand factor.  Thromb Haemost. 2003;  90(3) 385-397
    PubMedGoogle Scholar
  • 40 Barrow R T, Healey J F, Gailani D, Scandella D, Lollar P. Reduction of the antigenicity of factor VIII toward complex inhibitory antibody plasmas using multiply-substituted hybrid human/porcine factor VIII molecules.  Blood. 2000;  95(2) 564-568
    PubMedGoogle Scholar
  • 41 Jacquemin M, Benhida A, Peerlinck K et al.. A human antibody directed to the factor VIII C1 domain inhibits factor VIII cofactor activity and binding to von Willebrand factor.  Blood. 2000;  95(1) 156-163
    PubMedGoogle Scholar
  • 42 Takeshima K, Smith C, Tait J, Fujikawa K. The preparation and phospholipid binding property of the C2 domain of human factor VIII.  Thromb Haemost. 2003;  89(5) 788-794
    PubMedGoogle Scholar
  • 43 Hsu T C, Pratt K P, Thompson A R. The factor VIII C1 domain contributes to platelet binding.  Blood. 2008;  111(1) 200-208
    CrossrefPubMedGoogle Scholar
  • 44 Lacroix-Desmazes S, Bayry J, Misra N et al.. The prevalence of proteolytic antibodies against factor VIII in hemophilia A.  N Engl J Med. 2002;  346(9) 662-667
    CrossrefPubMedGoogle Scholar
  • 45 Lacroix-Desmazes S, Wootla B, Dasgupta S et al.. Catalytic IgG from patients with hemophilia A inactivate therapeutic factor VIII.  J Immunol. 2006;  177(2) 1355-1363
    PubMedGoogle Scholar
  • 46 Wootla B, Mahendra A, Dimitrov J D et al.. Factor VIII-hydrolyzing IgG in acquired and congenital hemophilia.  FEBS Lett. 2009;  583(15) 2565-2572
    CrossrefPubMedGoogle Scholar
  • 47 Gilles J G, Jacquemin M G, Saint-Remy J M. Factor VIII inhibitors.  Thromb Haemost. 1997;  78(1) 641-646
    PubMedGoogle Scholar
  • 48 Lavigne-Lissalde G, Lacroix-Desmazes S, Wootla B et al.. Molecular characterization of human B domain-specific anti-factor VIII monoclonal antibodies generated in transgenic mice.  Thromb Haemost. 2007;  98(1) 138-147
    PubMedGoogle Scholar
  • 49 Fulcher C A, de Graaf Mahoney S, Roberts J R, Kasper C K, Zimmerman T S. Localization of human factor FVIII inhibitor epitopes to two polypeptide fragments.  Proc Natl Acad Sci U S A. 1985;  82(22) 7728-7732
    CrossrefPubMedGoogle Scholar
  • 50 Scandella D, De Graaf Mahoney S, Mattingly M, Roeder D, Timmons L, Fulcher C A. Epitope mapping of human factor VIII inhibitor antibodies by deletion analysis of factor VIII fragments expressed in Escherichia coli. .  Proc Natl Acad Sci U S A. 1988;  85(16) 6152-6156
    CrossrefPubMedGoogle Scholar
  • 51 Scandella D, Mattingly M, de Graaf S, Fulcher C A. Localization of epitopes for human factor VIII inhibitor antibodies by immunoblotting and antibody neutralization.  Blood. 1989;  74(5) 1618-1626
    PubMedGoogle Scholar
  • 52 Koshihara K, Qian J, Lollar P, Hoyer L W. Immunoblot cross-reactivity of factor VIII inhibitors with porcine factor VIII.  Blood. 1995;  86(6) 2183-2190
    PubMedGoogle Scholar
  • 53 Healey J F, Parker E T, Barrow R T, Langley T J, Church W R, Lollar P. The comparative immunogenicity of human and porcine factor VIII in haemophilia A mice.  Thromb Haemost. 2009;  102(1) 35-41
    PubMedGoogle Scholar
  • 54 Frank R. The SPOT-synthesis technique. Synthetic peptide arrays on membrane supports—principles and applications.  J Immunol Methods. 2002;  267(1) 13-26
    CrossrefPubMedGoogle Scholar
  • 55 Albert T, Lange S, Oldenburg J et al.. Characterization of factor VIII antibody epitopes from haemophilia A patients using cellulose bound FVIII peptide libraries [in German].  Hamostaseologie. 2003;  23(1) 13-17
    PubMedGoogle Scholar
  • 56 Albert T, Egler C, Jakuschev S et al.. The B-cell epitope of the monoclonal anti-factor VIII antibody ESH8 characterized by peptide array analysis.  Thromb Haemost. 2008;  99(3) 634-637
    PubMedGoogle Scholar
  • 57 Kopecky E M, Greinstetter S, Pabinger I, Buchacher A, Römisch J, Jungbauer A. Mapping of FVIII inhibitor epitopes using cellulose-bound synthetic peptide arrays.  J Immunol Methods. 2006;  308(1–2) 90-100
    CrossrefPubMedGoogle Scholar
  • 58 Smith G P, Petrenko V A. Phage display.  Chem Rev. 1997;  97(2) 391-410
    CrossrefPubMedGoogle Scholar
  • 59 Villard S, Piquer D, Raut S, Léonetti J P, Saint-Remy J M, Granier C. Low molecular weight peptides restore the procoagulant activity of factor VIII in the presence of the potent inhibitor antibody ESH8.  J Biol Chem. 2002;  277(30) 27232-27239
    CrossrefPubMedGoogle Scholar
  • 60 Villard S, Lacroix-Desmazes S, Kieber-Emmons T et al.. Peptide decoys selected by phage display block in vitro and in vivo activity of a human anti-FVIII inhibitor.  Blood. 2003;  102(3) 949-952
    CrossrefPubMedGoogle Scholar
  • 61 Kessel C, Königs C, Linde R et al.. Humoral immune responsiveness to a defined epitope on factor VIII before and after B cell ablation with rituximab.  Mol Immunol. 2008;  46(1) 8-15
    CrossrefPubMedGoogle Scholar
  • 62 Kessel C, Kreuz W, Klich K et al.. Multimerization of peptide mimotopes for blocking of factor VIII neutralizing antibodies.  ChemMedChem. 2009;  4(8) 1364-1370
    CrossrefPubMedGoogle Scholar
  • 63 Martin P G, Sukhu K, Chambers E, Giangrande P L. Evaluation of a novel ELISA screening test for detection of factor VIII inhibitory antibodies in haemophiliacs.  Clin Lab Haematol. 1999;  21(2) 125-128
    CrossrefPubMedGoogle Scholar
  • 64 Shetty S, Ghosh K, Mohanty D. An ELISA assay for the detection of factor VIII antibodies—comparison with the conventional Bethesda assay in a large cohort of haemophilia samples.  Acta Haematol. 2003;  109(1) 18-22
    CrossrefPubMedGoogle Scholar
  • 65 Fulton R J, McDade R L, Smith P L, Kienker L J, Kettman Jr J R. Advanced multiplexed analysis with the FlowMetrix system.  Clin Chem. 1997;  43(9) 1749-1756
    PubMedGoogle Scholar
  • 66 Lavigne-Lissalde G, Tarrade C, Lapalud P et al.. Simultaneous detection and epitope mapping of anti-factor VIII antibodies.  Thromb Haemost. 2008;  99(6) 1090-1096
    PubMedGoogle Scholar
  • 67 FEIBA VH .Anti-inhibitor coagulant complex [package insert]. Westlake Village, CA; Baxter Healthcare Corp 2005
    PubMedGoogle Scholar
  • 68 Turecek P L, Váradi K, Gritsch H, Schwarz H P. FEIBA: mode of action.  Haemophilia. 2004;  10(Suppl 2) 3-9
    CrossrefPubMedGoogle Scholar
  • 69 Negrier C, Dargaud Y, Bordet J C. Basic aspects of bypassing agents.  Haemophilia. 2006;  12(suppl 6) 48-52 discussion 52-53
    CrossrefPubMedGoogle Scholar
  • 70 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
  • 71 Hoffman M, Monroe III D M. The action of high-dose factor VIIa (FVIIa) in a cell-based model of hemostasis.  Semin Hematol. 2001;  38(4, Suppl 12) 6-9
    PubMedGoogle Scholar
  • 72 Hedner U. Mechanism of action of recombinant activated factor VII: an update.  Semin Hematol. 2006;  43(Suppl 1) S105-S107
    CrossrefPubMedGoogle Scholar
  • 73 Roberts H R, Monroe D M, White G C. The use of recombinant factor VIIa in the treatment of bleeding disorders.  Blood. 2004;  104(13) 3858-3864
    CrossrefPubMedGoogle Scholar
  • 74 Lindley C M, Sawyer W T, Macik B G et al.. Pharmacokinetics and pharmacodynamics of recombinant factor VIIa.  Clin Pharmacol Ther. 1994;  55(6) 638-648
    CrossrefPubMedGoogle Scholar
  • 75 Fridberg M J, Hedner U, Roberts H R, Erhardtsen E. A study of the pharmacokinetics and safety of recombinant activated factor VII in healthy Caucasian and Japanese subjects.  Blood Coagul Fibrinolysis. 2005;  16(4) 259-266
    CrossrefPubMedGoogle Scholar
  • 76 Villar A, Aronis S, Morfini M et al.. Pharmacokinetics of activated recombinant coagulation factor VII (NovoSeven) in children vs. adults with haemophilia A.  Haemophilia. 2004;  10(4) 352-359
    CrossrefPubMedGoogle Scholar
  • 77 Shapiro A D, Gilchrist G S, Hoots W K, Cooper H A, Gastineau D A. Prospective, randomised trial of two doses of rFVIIa (NovoSeven) in haemophilia patients with inhibitors undergoing surgery.  Thromb Haemost. 1998;  80(5) 773-778
    PubMedGoogle Scholar
  • 78 Key N S, Aledort L M, Beardsley D et al.. Home treatment of mild to moderate bleeding episodes using recombinant factor VIIa (NovoSeven) in haemophiliacs with inhibitors.  Thromb Haemost. 1998;  80(6) 912-918
    PubMedGoogle Scholar
  • 79 Lloyd Jones M, Wight J, Paisley S, Knight C. Control of bleeding in patients with haemophilia A with inhibitors: a systematic review.  Haemophilia. 2003;  9(4) 464-520
    CrossrefPubMedGoogle Scholar
  • 80 Santagostino E, Mancuso M E, Rocino A, Mancuso G, Scaraggi F, Mannucci P M. A prospective randomized trial of high and standard dosages of recombinant factor VIIa for treatment of hemarthroses in hemophiliacs with inhibitors.  J Thromb Haemost. 2006;  4(2) 367-371
    CrossrefPubMedGoogle Scholar
  • 81 Dimichele D, Négrier C. A retrospective postlicensure survey of FEIBA efficacy and safety.  Haemophilia. 2006;  12(4) 352-362
    CrossrefPubMedGoogle Scholar
  • 82 Astermark J, Donfield S M, DiMichele D M FENOC Study Group et al. A randomized comparison of bypassing agents in hemophilia complicated by an inhibitor: the FEIBA NovoSeven Comparative (FENOC) Study.  Blood. 2007;  109(2) 546-551
    CrossrefPubMedGoogle Scholar
  • 83 Knight C, Danø A M, Kennedy-Martin T. Systematic review of efficacy of rFVIIa and aPCC treatment for hemophilia patients with inhibitors.  Adv Ther. 2009;  26(1) 68-88
    CrossrefPubMedGoogle Scholar
  • 84 Donfield S M, Astermark J, Lail A E, Gilbert S A, Berntorp E. Fenoc Study Group . Value added: increasing the power to assess treatment outcome in joint haemorrhages.  Haemophilia. 2008;  14(2) 276-280
    CrossrefPubMedGoogle Scholar
  • 85 Berntorp E. Differential response to bypassing agents complicates treatment in patients with haemophilia and inhibitors.  Haemophilia. 2009;  15(1) 3-10
    CrossrefPubMedGoogle Scholar
  • 86 Monroe D M, Hoffman M, Roberts H R. Platelets and thrombin generation.  Arterioscler Thromb Vasc Biol. 2002;  22(9) 1381-1389
    CrossrefPubMedGoogle Scholar
  • 87 Sørensen B, Ingerslev J. Whole blood clot formation phenotypes in hemophilia A and rare coagulation disorders. Patterns of response to recombinant factor VIIa.  J Thromb Haemost. 2004;  2(1) 102-110
    CrossrefPubMedGoogle Scholar
  • 88 Shetty S, Vora S, Kulkarni B et al.. Contribution of natural anticoagulant and fibrinolytic factors in modulating the clinical severity of haemophilia patients.  Br J Haematol. 2007;  138(4) 541-544
    CrossrefPubMedGoogle Scholar
  • 89 Allen G A, Hoffman M, Roberts H R, Monroe D M. Manipulation of prothrombin concentration improves response to high-dose factor VIIa in a cell-based model of haemophilia.  Br J Haematol. 2006;  134(3) 314-319
    CrossrefPubMedGoogle Scholar
  • 90 NovoSeven Coagulation Factor VIIa .(recombinant) [package insert]. Princeton, NJ; Novo Nordisk A/S 2006
    PubMedGoogle Scholar
  • 91 Hedner U. Recombinant factor VIIa (NovoSeven) as a hemostatic agent.  Dis Mon. 2003;  49(1) 39-48
    PubMedGoogle Scholar
  • 92 Allen G A, Persson E, Campbell R A, Ezban M, Hedner U, Wolberg A S. A variant of recombinant factor VIIa with enhanced procoagulant and antifibrinolytic activities in an in vitro model of hemophilia.  Arterioscler Thromb Vasc Biol. 2007;  27(3) 683-689
    CrossrefPubMedGoogle Scholar
  • 93 Sørensen B, Persson E, Ingerslev J. Factor VIIa analogue (V158D/E296V/M298Q-FVIIa) normalises clot formation in whole blood from patients with severe haemophilia A.  Br J Haematol. 2007;  137(2) 158-165
    CrossrefPubMedGoogle Scholar
  • 94 Holmberg H L, Lauritzen B, Tranholm M, Ezban M. Faster onset of effect and greater efficacy of NN1731 compared with rFVIIa, aPCC and FVIII in tail bleeding in hemophilic mice.  J Thromb Haemost. 2009;  7(9) 1517-1522
    CrossrefPubMedGoogle Scholar
  • 95 Møss J, Scharling B, Ezban M, Møller Sørensen T. Evaluation of the safety and pharmacokinetics of a fast-acting recombinant FVIIa analogue, NN1731, in healthy male subjects.  J Thromb Haemost. 2009;  7(2) 299-305
    CrossrefPubMedGoogle Scholar
  • 96 Stennicke H R, Ostergaard H, Bayer R J et al.. Generation and biochemical characterization of glycoPEGylated factor VIIa derivatives.  Thromb Haemost. 2008;  100(5) 920-928
    PubMedGoogle Scholar
  • 97 Palm L, Jepsen T, Garmer S F et al.. Analysis and characterization of glycopegylated recombinant human FVIIA.  J Thromb Haemost. 2009;  7(suppl 2) , Abstract PP-WE-585
    PubMedGoogle Scholar
  • 98 Sorensen B, Karpf D, Groth A V et al.. Effect of glycopegylation on the pharmacokinetic properties of FVIIa.  J Thromb Haemost. 2007;  5 (suppl 2) P-T-012
    PubMedGoogle Scholar
  • 99 Yatuv R, Dayan I, Carmel-Goren L et al.. Enhancement of factor VIIa haemostatic efficacy by formulation with PEGylated liposomes.  Haemophilia. 2008;  14(3) 476-483
    CrossrefPubMedGoogle Scholar
  • 100 Weimer T, Wormsbächer W, Kronthaler U, Lang W, Liebing U, Schulte S. Prolonged in-vivo half-life of factor VIIa by fusion to albumin.  Thromb Haemost. 2008;  99(4) 659-667
    PubMedGoogle Scholar
  • 101 Kronthaler U, Schmidbauer S, Liebing U et al.. Prolonged half-life of recombinant factor VIIA fusion protein—single dose study in rabbits.  J Thromb Haemost. 2009;  7(Suppl 2) , Abstract PP-TH-561
    PubMedGoogle Scholar
  • 102 Pan J, Kim J, Zhu D et al.. Binding to activated platelets and enhanced clotting properties of the recombinant FVIIa analogue Bay7.  J Thromb Haemost. 2009;  7(suppl 2) , Abstract OC-WE-059
    PubMedGoogle Scholar
  • 103 Liu T, Zhang X, Pan J et al.. Enhanced and prolonged efficacy of a novel recombinant FVIIa variant (BAY86–6150) for acute and prophylactic treatments in hemophilia A (HemA) mice.  J Thromb Haemost. 2009;  7(Suppl 2) , Abstract OC-WE-057
    PubMedGoogle Scholar
  • 104 Doering C B, Healey J F, Parker E T, Barrow R T, Lollar P. High level expression of recombinant porcine coagulation factor VIII.  J Biol Chem. 2002;  277(41) 38345-38349
    CrossrefPubMedGoogle Scholar
  • 105 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(3) 256-263
    CrossrefPubMedGoogle Scholar
  • 106 Kenet G, Lubetsky A, Luboshitz J, Martinowitz U. A new approach to treatment of bleeding episodes in young hemophilia patients: a single bolus megadose of recombinant activated factor VII (NovoSeven).  J Thromb Haemost. 2003;  1(3) 450-455
    CrossrefPubMedGoogle Scholar
  • 107 Parameswaran R, Shapiro A D, Gill J C, Kessler C M. HTRS Registry Investigators . Dose effect and efficacy of rFVIIa in the treatment of haemophilia patients with inhibitors: analysis from the Hemophilia and Thrombosis Research Society Registry.  Haemophilia. 2005;  11(2) 100-106
    CrossrefPubMedGoogle Scholar
  • 108 Kavakli K, Makris M, Zulfikar B, Erhardtsen E, Abrams Z S, Kenet G. NovoSeven trial (F7HAEM-1510) investigators . Home treatment of haemarthroses using a single dose regimen of recombinant activated factor VII in patients with haemophilia and inhibitors. A multi-centre, randomised, double-blind, cross-over trial.  Thromb Haemost. 2006;  95(4) 600-605
    PubMedGoogle Scholar
  • 109 Lee D, Yoon B S, Spotts G, Ewenstein B M. Assessment of thrombotic adverse events (TAES) with activated prothrombin complex concentrates (APCCS): 17 year experience.  J Thromb Haemost. 2007;  5(Suppl 2) P-T-157
    PubMedGoogle Scholar
  • 110 Allen G A, Hoffman M, Roberts H R, Monroe D M. Manipulation of prothrombin concentration improves response to high-dose factor VIIa in a cell-based model of haemophilia.  Br J Haematol. 2006;  134(3) 314-319
    CrossrefPubMedGoogle Scholar
  • 111 Schneiderman J, Rubin E, Nugent D J, Young G. Sequential therapy with activated prothrombin complex concentrates and recombinant FVIIa in patients with severe haemophilia and inhibitors: update of our previous experience.  Haemophilia. 2007;  13(3) 244-248
    CrossrefPubMedGoogle Scholar
  • 112 Ng H J, Loh S M, Tan D C, Lee L H. Thrombosis associated with the use of recombinant activated factor VII: profiling two events.  Thromb Haemost. 2004;  92(6) 1448-1449
    PubMedGoogle Scholar
  • 113 Sørensen B, Johansen P, Christiansen K, Woelke M, Ingerslev J. Whole blood coagulation thrombelastographic profiles employing minimal tissue factor activation.  J Thromb Haemost. 2003;  1(3) 551-558
    CrossrefPubMedGoogle Scholar
  • 114 Sørensen B, Ingerslev J. Tailoring haemostatic treatment to patient requirements—an update on monitoring haemostatic response using thrombelastography.  Haemophilia. 2005;  11(Suppl 1) 1-6
    PubMedGoogle Scholar
  • 115 Ingerslev J, Poulsen L H, Sørensen B. Potential role of the dynamic properties of whole blood coagulation in assessment of dosage requirements in haemophilia.  Haemophilia. 2003;  9(4) 348-352
    CrossrefPubMedGoogle Scholar
  • 116 Hayashi T, Tanaka I, Shima M et al.. Unresponsiveness to factor VIII inhibitor bypassing agents during haemostatic treatment for life-threatening massive bleeding in a patient with haemophilia A and a high responding inhibitor.  Haemophilia. 2004;  10(4) 397-400
    CrossrefPubMedGoogle Scholar
  • 117 Young G, Blain R, Nakagawa P, Nugent D J. Individualization of bypassing agent treatment for haemophilic patients with inhibitors utilizing thromboelastography.  Haemophilia. 2006;  12(6) 598-604
    CrossrefPubMedGoogle Scholar
  • 118 Hemker H C, Giesen P, Al Dieri R et al.. Calibrated automated thrombin generation measurement in clotting plasma.  Pathophysiol Haemost Thromb. 2003;  33(1) 4-15
    CrossrefPubMedGoogle Scholar
  • 119 Dargaud Y, Béguin S, Lienhart A et al.. Evaluation of thrombin generating capacity in plasma from patients with haemophilia A and B.  Thromb Haemost. 2005;  93(3) 475-480
    PubMedGoogle Scholar
  • 120 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
  • 121 Dargaud Y, Lienhart A, Negrier C. Monitoring of recombinant FVIIa by thrombin generation test.  J Thromb Haemost. 2007;  5(Suppl 2) P-M-176
    PubMedGoogle Scholar
  • 122 Dargaud Y, Lienhart A, Meunier S et al.. Major surgery in a severe haemophilia A patient with high titre inhibitor: use of the thrombin generation test in the therapeutic decision.  Haemophilia. 2005;  11(5) 552-558
    CrossrefPubMedGoogle Scholar

Natalya M AnanyevaPh.D. 

Laboratory of Hemostasis, Division of Hematology, Office of Blood Research and Review, Center for Biologics Evaluation and Research

Food and Drug Administration, 1401 Rockville Pike, Rockville, MD 20852

Email: Natalya.Ananyeva@fda.hhs.gov

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