The Impact of Factor VIII/von Willebrand Factor Products in Inhibitor Development and Management of Patients with Hemophilia A with Inhibitors

US Hematology, 2007;1(1):14-6 DOI:
Citation US Hematology, 2007;1(1):14-6 DOI:

Factor VIII (FVIII) and von Willebrand factor (vWF) are glycoproteins that circulate in plasma in a tightly bound complex. Structural defects or deficiencies in either glycoprotein are responsible for the development of the most common inherited bleeding disorders: hemophilia A and von Willebrand disease (vWD). These diseases manifest spontaneous bleeding in the severe form of the disease. Based on circulating levels of plasmatic and, in vWD, platelet levels, bleeding manifestations may occur only when challenged with trauma or surgery, and thus may go undetected. The immunogenicity of replacement products for both of these diseases can lead to antibody formation. In hemophilia, inhibitors can occur early—with mean exposure days as low as nine—and continue throughout life, and have been reported as high as 52%. Severity of disease, ethnicity, setting, and type of product are factors affecting outcome. Inhibitors following treatment of vWD are rare. The challenge of inhibitor induction in hemophilia is both the therapy for bleeding episodes and their eradication. Factor-bypassing products (FBPs) have been used to treat bleeding episodes in patients with inhibitors. However, these products are less effective than FVIII concentrates as hemostasis cannot be predicted, and they are also expensive. Patients treated on demand with FBPs also have a higher morbidity rate, with more likely chronic synovitis, and have an early onset of degenerative arthritis and long-term joint arthropathy, in addition to having bleeding episodes. Immune tolerance induction (ITI) therapy is an alternative approach that aims to create tolerance to inhibitors and return patients to their original state.
Risk Factors for Inhibitor Development
Genetic Risk Factors
The development of inhibitors in patients with hemophilia A has been noted in 48% of patients with a family history of inhibitors, in comparison with 15% of cases with no family history of inhibitors.1 In an analysis of 249 families with hemophilia A, a concordance of 78.3% was calculated between siblings for the presence of inhibitors.2 Inhibitor incidence in severe hemophilia A is twice that in African patients compared with Caucasian patients.3,4 These propensities are believed to be influenced by both the FVIII genotype and the genetic characteristics of the immune system.
  1. Astermark J, Berntorp E, White GC, et al., MIBS Study Group, The Malmo international brother study (MIBS): further support for genetic predisposition to inhibitor development in hemophilia patients, Haemophilia, 2001;7:267–72.
  2. Astermark J, Oldenburg J, Escobar M, et al., Malmo International Brother Study Group, The Malmo international brother study (MIBS), Genetic defects and inhibitor development in siblings with severe hemophilia A, Haematologica, 2005;90:924–31.
  3. Addiego JE, Kasper C, Abildgaard T, et al., Increased frequency of inhibitors in African American hemophilic patients, Blood, 1994;1: 293a.
  4. 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;5:145–54.
  5. Hay CR, Ludlam CA, Colvin BT, et al., Factor VIII inhibitors in mild and moderate-severity haemophilia A, UK Haemophilia Centre Directors Organisation, Thromb Haemost, 1998;79:762–6.
  6. Sharathkumar A, Lillicrap D, Blanchette VS, et al., Intensive exposure to factor VIII is a risk factor for inhibitor development in mild haemophilia A, J Thromb Haemost, 2003;1:1228–36.
  7. Von Auer C, Oldenburg J, Von Depka M, et al., Inhibitor development in patients with hemophilia A after continuous infusion of factor VIII concentrates, Ann NY Acad Sci, 2005;1051: 498–505.
  8. Berntorp E, Ekman M, Gunnarsson M, et al., Variation in factor VIII inhibitor reactivity with different commercial factor VIII preparations, Haemophilia, 1996;2:95–9.
  9. Kaveri SV, Dasgupta S, Andre S, et al., Factor VIII inhibitor: role of von Willebrand factor on the uptake of factor VIII by dendritic cells, Haemophilia, 2007;13(55):561–4.
  10. Dasgupta S, Repesse Y, Bayry J, et al., VWF protects F VIII ondocytosis by dendritic cells and subsequent presentation to immune effectors, Blood, 2007;109:610–12.
  11. 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.
  12. Brackmann HH, Oldenburg J, Schwaab R, Immune tolerance for the treatment of factor VIII inhibitors—twenty years of the Bonn Protocol, Vox Sang, 1996;70(Suppl. 1):30–35.
  13. Mariani G, Kroner B, Immune Tolerance Study Group (ITSG), Immune tolerance in hemophilia with factor VIII inhibitors: predictors of success, Throm Haemost, 2002;87:52–7.
  14. Kreuz W, Joseph-Steiner J, Mentzer D, Successful immune tolerance therapy of FVIII-inhibitors in children after changing from high to intermediate purity FVIII concentrate, Ann Hematol, 1996;72(Suppl. 1):339.
  15. Kreuz W, Ettingshausen CE, Auerswalf G, et al., Epidemiology of inhibitors and current treatment strategies, Haematologica, 2003; 88(Suppl. 9):17–20.
  16. Auserwald G, Spanger T, Brackmann H, The role of factor VIII/von Willebrand factor concentrates in the treatment of hemophilia A patients, Haematologica, 2003;88(Suppl. 9):21–5.
  17. 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;90:1288–90.
  18. Gringeri A, Musso R, Bernasconi S, et al., Immune tolerance induction (ITI) with a high-purity VWF concentrates in inhibitor patients with a high risk of a poor response to ITI: a prospective surveillance, J Thromb Haemost, 2005;3(Suppl. 1):A207.
  19. Kurth MAH, 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, NY Acad Sci, 2005;1051:498–505.