Von Willebrand factor-containing factor VIII concentrates and inhibitors in haemophilia A

Summary

The development of inhibitors that neutralise the function of factor VIII (FVIII) is currently not only the most challenging complication associated with the treatment of haemophilia A but it also increases the disease-related morbidity as bleeding episodes do not respond to standard therapy. The main short-term goal of the treatment of inhibitor patients is to control bleeding episodes while the long-term one is to permanently eradicate the inhibitor by immune tolerance induction, particularly in the case of high-titer antibodies. Due to some in vitro studies and clinical observations, some investigators have suggested that FVIII concentrates containing von Willebrand factor (VWF) may be less immunogenic than high-purity or recombinant FVIII products. It has also been suggested that success rates for immune tolerance induction are higher when plasma-derived FVIII products are used. The currently available data from laboratory and clinical studies on the role of VWF in inhibitor development and eradication in haemophilia A is critically analysed in this review. As a result, we have not found definitive evidence supporting a role for product type on inhibitor incidence and inhibitor eradication in haemophilia A patients.

Keywords

FVIII - inhibitors - haemophilia A - immune tolerance induction (ITI) - VWF

• References

• 1 Haya S, Moret A, Cid AR. et al. Inhibitors in haemophilia A: current management and open issues. Haemophilia 2007; 13 (Suppl. 05) 52-60.
• 2 Lusher JM, Arkin S, Abildgaard CF. et al. Recombinant factor VIII for the treatment of previously untreated patients with hemophilia A. Safety, efficacy, and development of inhibitors. Kogenate Previously Untreated Patient Study Group. N Engl J Med 1993; 328: 453-459.
• 3 Bray GL, Gomperts ED, Courter S. et al. A multicenter study of recombinant factor VIII (recombinate): safety, efficacy, and inhibitor risk in previously untreated patients with hemophilia A. The Recombinate Study Group. Blood 1994; 83: 2428-2435.
• 4 Wight J, Paisley S. The epidemiology of inhibitors in haemophilia A: a systematic review. Haemophilia 2003; 09: 418-435.
• 5 Addiego J, Kasper C, Abildgaard C. et al. Frequency of inhibitor development in haemophiliacs treated with low-purity factor VIII. Lancet 1993; 342: 462-464.
• 6 de Biasi R, Rocino A, Papa ML. et al. Incidence of factor VIII inhibitor development in hemophilia A patients treated with less pure plasma derived concentrates. Thromb Haemost 1994; 71: 544-547.
• 7 Lusher JM, Roth DA. The safety and efficacy of B-domain deleted recombinant factor VIII concentrates in patients with severe haemophilia A: an update. Haemophilia 2005; 11: 292-293.
• 8 Lee CA, Lillicrap D, Astermark J. Inhibitor development in hemophiliacs: the roles of genetic versus environmental factors. Semin Thromb Hemost 2006; 32 (Suppl. 02) 10-14.
• 9 Astermark J, Berntorp E, White GC. et al. The Malmo International Brother Study (MIBS): further support for genetic predisposition to inhibitor development in hemophilia patients. Haemophilia 2001; 07: 267-272.
• 10 Gill JC. The role of genetics in inhibitor formation. Thromb Haemost 1999; 82: 500-504.
• 11 Wang X, Lu Y, Ding Q. et al. Haemophilia A in two unrelated females due to F8 gene inversions combined with skewed inactivation of X chromosome. Thromb Haemost 2009; 101: 775-778.
• 12 Viel KR, Ameri A, Abshire TC. et al. Inhibitors of factor VIII in black patients with hemophilia. N Engl J Med 2009; 360: 1618-1627.
• 13 Oldenburg J, Picard JK, Schwaab R. et al. HLA genotype of patients with severe haemophilia A due to intron 22 inversion with and without inhibitors of factor VIII. Thromb Haemost 1997; 77: 238-242.
• 14 Hay CR, Ollier W, Pepper L. et al. HLA class II profile: a weak determinant of factor VIII inhibitor development in severe haemophilia A. UKHCDO Inhibitor Working Party. Thromb Haemost 1997; 77: 234-237.
• 15 Pavlova A, Delev D, Lacroix-Desmazes S. et al. Impact of polymorphisms of the major histocompatibility complex class II, interleukin-10, tumor necrosis factor-alpha and cytotoxic T-lymphocyte antigen-4 genes on inhibitor development in severe hemophilia A. J Thromb Haemost 2009; 07: 2006-2015.
• 16 Scharrer I, Bray GL, Neutzling O. Incidence of inhibitors in haemophilia A patients--a review of recent studies of recombinant and plasma-derived factor VIII concentrates. Haemophilia 1999; 05: 145-154.
• 17 Oldenburg J, Schroder J, Brackmann HH. et al. Environmental and genetic factors influencing inhibitor development. Semin Hematol 2004; 41 (01) (Suppl. 01) 82-88.
• 18 Santagostino E, Mancuso ME, Rocino A. et al. Environmental risk factors for inhibitor development in children with haemophilia A: a case-control study. Br J Haematol 2005; 130: 422-427.
• 19 Kurnik K, Bidlingmaier C, Engl W. et al. New early prophylaxis regimen that avoids immunological danger signals can reduce FVIII inhibitor development. Haemophilia 2010; 16: 256-262.
• 20 Key NS. Inhibitors in congenital coagulation disorders. Br J Haematol 2004; 127: 379-391.
• 21 Aledort LM. Is the incidence and prevalence of inhibitors greater with recombinant products? Yes. J Thromb Haemost 2004; 02: 861-862.
• 22 Goudemand J, Laurian Y, Calvez T. Risk of inhibitors in haemophilia and the type of factor replacement. Curr Opin Hematol 2006; 13: 316-322.
• 23 Meijer P, Verbruggen B. The between-laboratory variation of factor VIII inhibitor testing: the experience of the external quality assessment program of the ECAT foundation. Semin Thromb Hemost 2009; 35: 786-793.
• 24 Kitchen S, Jennings I, Preston FE. et al. Interlaboratory variation in factor VIII:C inhibitor assay results is sufficient to influence patient management: data from the UK national quality external assessment scheme for blood coagulation. Semin Thromb Hemost 2009; 35: 778-785.
• 25 Verbruggen B, van Heerde WL, Laros-van Gorkom BA. Improvements in factor VIII inhibitor detection: From Bethesda to Nijmegen. Semin Thromb Hemost 2009; 35: 752-759.
• 26 White GC, DiMichele D, Mertens K. et al. Utilization of previously treated patients (PTPs), noninfected patients (NIPs), and previously untreated patients (PUPs) in the evaluation of new factor VIII and factor IX concentrates. Recommendation of the Scientific Subcommittee on Factor VIII and Factor IX of the Scientific and Standardization Committee of the International Society on Thrombosis and Haemostasis. Thromb Haemost 1999; 81: 462.
• 27 DiMichele DM, Hoots WK, Pipe SW. et al. International workshop on immune tolerance induction: consensus recommendations. Haemophilia 2007; 13 (Suppl. 01) 1-22.
• 28 Oldenburg J, Schwaab R, Brackmann HH. Induction of immune tolerance in haemophilia A inhibitor patients by the ‘Bonn Protocol‘: predictive parameter for therapy duration and outcome. Vox Sang 1999; 77 (Suppl. 01) 49-54.
• 29 Rocino A, de Biasi R. Successful immune tolerance treatment with monoclonal or recombinant factor VIII concentrates in high responding inhibitor patients. Vox Sang 1999; 77 (Suppl. 01) 65-69.
• 30 DiMichele DM, Kroner BL. The North American Immune Tolerance Registry: practices, outcomes, outcome predictors. Thromb Haemost 2002; 87: 52-57.
• 31 Nilsson IM, Berntorp E, Zettervall O. Induction of immune tolerance in patients with hemophilia and antibodies to factor VIII by combined treatment with intravenous IgG, cyclophosphamide, and factor VIII. N Engl J Med 1988; 318: 947-950.
• 32 Mauser-Bunschoten EP, Nieuwenhuis HK, Roosendaal G. et al. Low-dose immune tolerance induction in hemophilia A patients with inhibitors. Blood 1995; 86: 983-988.
• 33 Kreuz W, Becker S, Lenz E. et al. Factor VIII inhibitors in patients with hemophilia A: epidemiology of inhibitor development and induction of immune tolerance for factor VIII. Semin Thromb Hemost 1995; 21: 382-389.
• 34 Brackmann HH, Oldenburg J, Schwaab R. Immune tolerance for the treatment of factor VIII inhibitors--twenty years’ ‘bonn protocol‘. Vox Sang 1996; 70 (Suppl. 01) 30-35.
• 35 Lenk H. The German National Immune Tolerance Registry, 1997 update. Study Group of German Haemophilia Centres. Vox Sang 1999; 77 (Suppl. 01) 28-30.
• 36 Barnes C, Rivard GE, Poon MC. et al. Canadian multi-institutional survey of immune tolerance therapy (ITT) -- experience with the use of recombinant factor VIII for ITT. Haemophilia 2006; 12: 1-6.
• 37 Goudemand J. Inhibitor development in haemophilia A: the role of von Wille-brand factor/factor VIII concentrates. Haemophilia 2007; 13 (Suppl. 05) 47-51.
• 38 Ettingshausen CE, Kreuz W. Role of von Willebrand factor in immune tolerance induction. Blood Coagul Fibrinolysis 2005; 16 (Suppl. 01) S27-31.
• 39 Kreuz W. The role of VWF for the success of immune tolerance induction. Thromb Res 2008; 122 (Suppl. 02) S7-S12.
• 40 Kaveri S, Gringeri A, Heisel-Kurth M. et al. Inhibitors in haemophilia A: the role of VWF/FVIII concentrates--a meeting report. Haemophilia 2009; 15: 587-591.
• 41 Franchini M, Lippi G. The role of von Willebrand factor in hemorrhagic and thrombotic disorders. Crit Rev Clin Lab Sci 2007; 44: 115-149.
• 42 Vlot AJ, Koppelman SJ, Bouma BN. et al. Factor VIII and von Willebrand factor. Thromb Haemost 1998; 79: 456-465.
• 43 Scandella D. New characteristics of anti-factor VIII inhibitor antibody epitopes and unusual immune responses to Factor VIII. Semin Thromb Hemost 2002; 28: 291-296.
• 44 Gharagozlou S, Sharifian RA, Khoshnoodi J. et al. Epitope specificity of anti-factor VIII antibodies from inhibitor positive acquired and congenital haemophilia A patients using synthetic peptides spanning A and C domains. Thromb Haemost 2009; 101: 834-839.
• 45 Kallas A, Talpsep T. von Willebrand factor in factor VIII concentrates protects against neutralization by factor VIII antibodies of haemophilia A patients. Haemophilia 2001; 07: 375-380.
• 46 Gensana M, Altisent C, Aznar JA. et al. Influence of von Willebrand factor on the reactivity of human factor VIII inhibitors with factor VIII. Haemophilia 2001; 07: 369-374.
• 47 Suzuki T, Arai M, Amano K. et al. Factor VIII inhibitor antibodies with C2 domain specificity are less inhibitory to factor VIII complexed with von Willebrand factor. Thromb Haemost 1996; 76: 749-754.
• 48 Shima M, Nakai H, Scandella D. et al. Common inhibitory effects of human anti-C2 domain inhibitor alloantibodies on factor VIII binding to von Willebrand factor. Br J Haematol 1995; 91: 714-721.
• 49 Astermark J, Voorberg J, Lenk H. et al. Impact of inhibitor epitope profile on the neutralizing effect against plasma-derived and recombinant factor VIII concentrates in vitro. Haemophilia 2003; 09: 567-572.
• 50 Tagariello G, Zanotto D, Radossi P. et al. In vitro reactivity of factor VIII inhibitors with von Willebrand factor in different commercial factor VIII concentrates. Am J Hematol 2007; 82: 460-462.
• 51 Salvagno GL, Astermark J, Ekman M. et al. Impact of different inhibitor reactivities with commercial factor VIII concentrates on thrombin generation. Haemophilia 2007; 13: 51-56.
• 52 Verbruggen B, van Heerde W, Budde U. Methodological shortcomings in assessment of factor VIII concentrate inhibition. Haemophilia 2007; 13: 680-681.
• 53 Macfarlane RG, Biggs R. A thrombin generation test; the application in haemophilia and thrombocytopenia. J Clin Pathol 1953; 06: 3-8.
• 54 Verbruggen B, Giles A, Samis J. et al. The type of factor VIII deficient plasma used influences the performance of the Nijmegen modification of the Bethesda assay for factor VIII inhibitors. Thromb Haemost 2001; 86: 1435-1439.
• 55 Fijnvandraat K, Peters M, ten Cate JW. Inter-individual variation in half-life of infused recombinant factor VIII is related to pre-infusion von Willebrand factor antigen levels. Br J Haematol 1995; 91: 474-476.
• 56 Vlot AJ, Koppelman SJ, Meijers JC. et al. Kinetics of factor VIII-von Willebrand factor association. Blood 1996; 87: 1809-1816.
• 57 Moreau A, Lacroix-Desmazes S, Stieltjes N. et al. Antibodies to the FVIII light chain that neutralize FVIII procoagulant activity are present in plasma of nonresponder patients with severe hemophilia A and in normal polyclonal human IgG. Blood 2000; 95: 3435-3441.
• 58 Bjorkman S, Folkesson A, Jonsson S. Pharmacokinetics and dose requirements of factor VIII over the age range 3–74 years: a population analysis based on 50 patients with long-term prophylactic treatment for haemophilia A. Eur J Clin Pharmacol 2009; 65: 989-998.
• 59 Prescott R, Nakai H, Saenko EL. et al. The inhibitor antibody response is more complex in hemophilia A patients than in most nonhemophiliacs with factor VIII autoantibodies. Recombinate and Kogenate Study Groups. Blood 1997; 89: 3663-3671.
• 60 Lin Y, Yang X, Chevrier MC. et al. Relationships between factor VIII:Ag and factor VIII in recombinant and plasma-derived factor VIII concentrates. Haemophilia 2004; 10: 459-469.
• 61 Koedam JA, Meijers JC, Sixma JJ. et al. Inactivation of human factor VIII by activated protein C. Cofactor activity of protein S and protective effect of von Wille-brand factor. J Clin Invest 1988; 82: 1236-1243.
• 62 Dasgupta S, Repesse Y, Bayry J. et al. VWF protects FVIII from endocytosis by dendritic cells and subsequent presentation to immune effectors. Blood 2007; 109: 610-612.
• 63 Kaveri SV, Dasgupta S, Andre S. et al. Factor VIII inhibitors: role of von Wille-brand factor on the uptake of factor VIII by dendritic cells. Haemophilia 2007; 13 (Suppl. 05) 61-64.
• 64 Lenting PJ, CJ VANS, Denis CV. Clearance mechanisms of von Willebrand factor and factor VIII. J Thromb Haemost 2007; 05: 1353-1360.
• 65 Pfistershammer K, Stockl J, Siekmann J. et al. Recombinant factor VIII and factor VIII-von Willebrand factor complex do not present danger signals for human dendritic cells. Thromb Haemost 2006; 96: 309-316.
• 66 Matzinger P. Tolerance, danger, and the extended family. Annu Rev Immunol 1994; 12: 991-1045.
• 67 Ehrenforth S, Kreuz W, Scharrer I. et al. Incidence of development of factor VIII and factor IX inhibitors in haemophiliacs. Lancet 1992; 339: 594-598.
• 68 Yee TT, Williams MD, Hill FG. et al. Absence of inhibitors in previously untreated patients with severe haemophilia A after exposure to a single intermediate purity factor VIII product. Thromb Haemost 1997; 78: 1027-1029.
• 69 Kreuz W, Ettingshausen CE, Zyschka A. et al. Inhibitor development in previously untreated patients with hemophilia A: a prospective long-term follow-up comparing plasma-derived and recombinant products. Semin Thromb Hemost 2002; 28: 285-290.
• 70 White 2nd GC, Courter S, Bray GL. et al. A multicenter study of recombinant factor VIII (Recombinate) in previously treated patients with hemophilia A. The Recombinate Previously Treated Patient Study Group. Thromb Haemost 1997; 77: 660-667.
• 71 Lusher JM, Lee CA, Kessler CM. et al. The safety and efficacy of B-domain deleted recombinant factor VIII concentrate in patients with severe haemophilia A. Haemophilia 2003; 09: 38-49.
• 72 Seremetis S, Lusher JM, Abildgaard CF. et al. Human recombinant DNA-derived antihaemophilic factor (factor VIII) in the treatment of haemophilia A: conclusions of a 5-year study of home therapy. The KOGENATE Study Group. Haemophilia 1999; 05: 9-16.
• 73 Abshire TC, Brackmann HH, Scharrer I. et al. Sucrose formulated recombinant human antihemophilic factor VIII is safe and efficacious for treatment of hemophilia A in home therapy--International Kogenate-FS Study Group. Thromb Haemost 2000; 83: 811-816.
• 74 Yoshioka A, Shima M, Fukutake K. et al. Safety and efficacy of a new recombinant FVIII formulated with sucrose (rFVIII-FS) in patients with haemophilia A: a long-term, multicentre clinical study in Japan. Haemophilia 2001; 07: 242-249.
• 75 Tarantino MD, Collins PW, Hay CR. et al. Clinical evaluation of an advanced category antihaemophilic factor prepared using a plasma/albumin-free method: pharmacokinetics, efficacy, and safety in previously treated patients with haemophilia A. Haemophilia 2004; 10: 428-437.
• 76 Nemes L, Lissitchkov T, Klukowska A. et al. Evaluation of pharmacokinetics, efficacy and safety of Immunate solvent detergent in previously treated patients with severe haemophilia A. Haemophilia 2007; 13: 9-11.
• 77 Mauser-Bunschoten EP, Posthouwer D, Fischer K. et al. Safety and efficacy of a plasma-derived monoclonal purified factor VIII concentrate during 10 years of follow-up. Haemophilia 2007; 13: 697-700.
• 78 Delumeau JC, Ikegawa C, Yokoyama C. et al. An observational study of sucrose-formulated recombinant factor VIII for Japanese patients with haemophilia A. Thromb Haemost 2008; 100: 32-37.
• 79 Scharrer I, Ehrlich HJ. Reported inhibitor incidence in FVIII PUP studies: comparing apples with oranges?. Haemophilia 2004; 10: 197-198.
• 80 Iorio A, Halimeh S, Holzhauer S. et al. Rate of inhibitor development in previously-untreated hemophilia a patients treated with plasma-derived or recombinant factor VIII concentrates. A systematic review. J Thromb Haemost 2010; 08: 1256-1265.
• 81 Halimeh SBC, Escuriola C. Evidence for increased inhibitor incidence in children with severe hemophilia a treated with recombinant factor VIII products: a systematic review & meta-analysis. J Thromb Haemost 2009; 07: 247.
• 82 Goudemand J, Rothschild C, Demiguel V. 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: 46-51.
• 83 Chalmers EA, Brown SA, Keeling D. et al. Early factor VIII exposure and subsequent inhibitor development in children with severe haemophilia A. Haemophilia 2007; 13: 149-155.
• 84 Gouw SC, van der Bom JG, Auerswald G. et al. 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: 4693-4697.
• 85 Kreuz W, Ettingshausen CE, Auerswald G. et al. Epidemiology of inhibitors and current treatment strategies. Haematologica 2003; 88: EREP04.
• 86 Mannucci PM, Gringeri A, Peyvandi F. et al. Factor VIII products and inhibitor development: the SIPPET study (survey of inhibitors in plasma-product exposed toddlers). Haemophilia 2007; 13 (Suppl. 05) 65-68.
• 87 DiMichele DM. Immune tolerance: critical issues of factor dose, purity and treatment complications. Haemophilia 2006; 12 (Suppl. 06) 81-86.
• 88 Berntorp E. Immune tolerance induction: recombinant vs. human-derived product. Haemophilia 2001; 07: 109-113.
• 89 Auerswald G, Spranger T, Brackmann HH. The role of plasma-derived factor VIII/von Willebrand factor concentrates in the treatment of hemophilia A patients. Haematologica 2003; 88: EREP05.
• 90 Berntorp E, Nilsson IM. Immune tolerance and the immune modulation protocol. Vox Sang 1996; 70 (Suppl. 01) 36-41.
• 91 Sukhu K, Keeling DM, Giangrande PL. Variation in inhibitor reactivity in acquired haemophilia A with different concentrates. Clin Lab Haematol 2000; 22: 287-290.
• 92 Orsini F, Rotschild C, Beurrier P. et al. Immune tolerance induction with highly purified plasma-derived factor VIII containing von Willebrand factor in hemophilia A patients with high-responding inhibitors. Haematologica 2005; 90: 1288-1290.
• 93 Greninger DA, Saint-Remy JM, Jacquemin M. et al. The use of factor VIII/von Willebrand factor concentrate for immune tolerance induction in haemophilia A patients with high-titre inhibitors: association of clinical outcome with inhibitor epitope profile. Haemophilia 2008; 14: 295-302.
• 94 Kurth MA, Dimichele D, Sexauer C. et al. Immune tolerance therapy utilizing factor VIII/von Willebrand factor concentrate in haemophilia A patients with high titre factor VIII inhibitors. Haemophilia 2008; 14: 50-55.
• 95 Gringeri A, Musso R, Mazzucconi MG. et al. Immune tolerance induction with a high purity von Willebrand factor/VIII complex concentrate in haemophilia A patients with inhibitors at high risk of a poor response. Haemophilia 2007; 13: 373-379.
• 96 Rocino A, Santagostino E, Mancuso ME. et al. Immune tolerance induction with recombinant factor VIII in hemophilia A patients with high responding inhibitors. Haematologica 2006; 91: 558-561.
• 97 Unuvar A, Warrier I, Lusher JM. Immune tolerance induction in the treatment of paediatric haemophilia A patients with factor VIII inhibitors. Haemophilia 2000; 06: 150-157.
• 98 Barnes C, Lillicrap D, Pazmino-Canizares J. et al. Pharmacokinetics of recombinant factor VIII (Kogenate-FS) in children and causes of inter-patient pharmacokinetic variability. Haemophilia 2006; 12 (Suppl. 04) 40-49.
• 99 Batlle J, Lopez MF, Brackmann HH. et al. Induction of immune tolerance with recombinant factor VIII in haemophilia A patients with inhibitors. Haemophilia 1999; 05: 431-435.
• 100 Valentino LA, Recht M, Dipaola J. et al. Experience with a third generation recombinant factor VIII concentrate (Advate) for immune tolerance induction in patients with haemophilia A. Haemophilia 2009; 15: 718-726.
• 101 Kroner BL. Comparison of the international immune tolerance registry and the North American immune tolerance registry. Vox Sang 1999; 77 (Suppl. 01) 33-37.
• 102 Santagostino E, Mannucci PM, Bianchi Bonomi A. Guidelines on replacement therapy for haemophilia and inherited coagulation disorders in Italy. Haemophilia 2000; 06: 1-10.
• 103 Guidelines on the selection and use of therapeutic products to treat haemophilia and other hereditary bleeding disorders. Haemophilia 2003; 09: 1-23.
• 104 Hay CR, Baglin TP, Collins PW. et al. The diagnosis and management of factor VIII and IX inhibitors: a guideline from the UK Haemophilia Centre Doctors’ Organization (UKHCDO). Br J Haematol 2000; 111: 78-90.
• 105 Gringeri A, Mannucci PM. Italian guidelines for the diagnosis and treatment of patients with haemophilia and inhibitors. Haemophilia 2005; 11: 611-619.
• 106 Batlle J, Villar A, Liras A. et al. Consensus opinion for the selection and use of therapeutic products for the treatment of haemophilia in Spain. Blood Coagul Fibrinolysis 2008; 19: 333-340.