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

Louis M Aledort, Caroline Cromwell
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Published Online: Aug 20th 2011 US Hematology, 2007;1(1):14-6 DOI: https://dx.doi.org/10.17925/ohr.2007.01.01.14
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Article

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.

Non-genetic Risk Factors

There are conflicting data regarding early versus late therapeutic intervention leading to inhibitor formation. Intensive replacement therapy in patients with mild/moderate hemophilia,5 continuous infusion with replacement therapy during surgery,6,7 premature birth, lack of breast-feeding, FVIII treatment during infections, surgical procedures, use of prophylaxis prior to inhibitor development, and central nervous system bleeding have all been reported to be associated with inhibitor induction. In-depth, long-term studies are needed to determine definitive correlations between these potential risk factors and the development of inhibitors.

Immunogenicity of Product

The role of the type of product used for therapy—recombinant versus human-derived product (HDP)—in terms of relative immunogenicity has received much attention. Within the category of HDP, the presence of vWF may well reduce its immunogenicity. In vitro data from Berntorp demonstrated that vW-containing products had less affinity for hemophilia antibodies;8 others have corroborated these findings. The question of in vivo immunogenicity of HDP versus recombinant products has led to further laboratory and clinical studies. The work of Kaveri et al. in France has repeatedly demonstrated that recombinant products have a greater affinity with the antigen-presenting cell, known as the dendritic cell, compared with vWF.9,10 In addition, they demonstrated that antibody formation was more rigorous with recombinant products as measured by interleukin (IL)-10 formation than with vWF. These findings were extended to demonstrate that vWF itself could modify and reduce the immunogenicity of recombinant FVIII (rFVIII) by pre-incubating them together in the in vitro system. These observations were recently confirmed by a large clinical study by Goudemand et al. in France.11 Using prospective and retrospective data, they demonstrated that previously untreated patients (PUPs) had an adjusted relative risk (RR) for inhibitor development with human rFVIII versus plasma-derived FVIII (pd-VIII) of 2.4 for all inhibitors, and 2.6 for high-titered inhibitors.

Eradication of Inhibitors

The Bonn Regime, using a high dose of FVIII of 100IU/kg given twice daily,12 was the first report of tolerance of high-titered inhibitors in FVIII patients. However, the optimum dosing regimen for ITI has not yet been achieved. An international ITI study is ongoing to deal with one aspect of this matter: high- versus low-dose regimen. Large registries of ITI patients have identified several factors that affect treatment outcomes of patients with ITI.13 ITI has been shown to be more effective in patients with a titer of less than 10 Bethesda units (BU) at onset of treatment, as well as in those who have not had an FVIII peak >200BU—or a long interval between the initiation of ITI from the diagnosis of inhibitors—and a high FVIII regimen.

Choice of Factor Product

In 1996, Kreuz et al. were the first group to study the effectiveness of monoclonal FVIII/rFVIII concentrate versus pd-vWF/FVIII concentrate.14 In the study, four patients with hemophilia A experiencing no positive effect from ITI with recombinant/monoclonal therapy were switched to treatment with the vWF/FVIII concentrate, and all responded well. Following this result, high-dose vWF/FVIII concentrate was administered to 21 patients with hemophilia A from 1979 to 1993, with a 91% success rate and an average time to tolerance of four months.14 This compared with a 29% tolerance success rate for 14 hemophilia A patients treated with high-dose recombinant therapy between 1993 and 2001.15 Similarly, a success rate of 91% in 51 hemophilia A patients administered with high-dose vWF/FVIII concentrate was noted, in contrast to a success rate of 53% over an 11-year-period in 14 hemophilia A patients treated with the recombinant therapy.16 Furthermore, eight high-titer hemophilia A patients treated on a high-dose FVII/vWH regime achieved tolerance of 85% within eight to 12 months.17 Recent data from Italy and Spain also suggest that the FVIII/vWF concentrate is successful in patients with poor prognostic factors. Patients with one or more of the negative factors for treatment with ITI still had a positive outcome to FVIII/vWF concentrate treatment.18
These early studies, supported by in vitro data, have led to an explosion of interest in HDP-containing vWF in ITI. There has been concern over the safety of these products since the recognition of transfusion-transmitted viral diseases such as hepatitis A, B, and C, parvovirus, and HIV. With current donor-screening techniques and polymerase chain reaction (PCR) testing of virus, these products have a stellar record of safety, with no viral transmission since 1987. The literature is now replete with small anecdotes, as well as larger19 cohorts of patients, demonstrating that HDP-containing vWF may well be a rescue product for ITI failures; the Randomized Evaluation of Strategic Intervention in multi-drug resiStant patients with Tipranavira (RESIST) study will examine this topic prospectively. In addition, it will be able to evaluate this regimen as a primary therapeutic approach to ITI. Matters such as efficacy, time to achieve tolerance, and relative costs of this treatment versus recombinant products will be evaluated. Whether ITI is carried out in countries with total coverage or in those with pluralistic third-party payer programs such as the US, high- or low-dose ITI is costly, as it uses large quantities of FVIII over one to two years. Therefore, choosing the optimal patient, the ideal regimen, and the appropriate product is important. Currently, recombinant products are more costly than vWF-containing HDPs. As guidelines develop, these choices will make therapeutic choices simpler. However, if vWF-containing HDPs are as efficacious as recombinant products—or more so, which may contract the time to success—this costly endeavor may well become more affordable.

Future Considerations for Immune Tolerance Induction

The most important consideration for the use of FVIII/vWF concentrate in hemophilia A is whether the risk of inhibitor production is lower for one product versus another. Data have suggested that the risk of inhibitor development is lower using FVIII/vWF concentrate, although this has not been confirmed. Furthermore, long-term studies are needed to evaluate the risk between the pd products and recombinant therapy. Another research area that needs to be addressed is the presence of genetic or environmental risk factors that can determine the development of inhibitors. The confirmation of risk factors could identify groups of hemophilia A patients who could be treated with preventive treatment to inhibitor development, thereby reducing the need for ITI. The immune systems of patients with inhibitors need to be compared with those without inhibitors to identify any potential causes for antibody production.

Summary

Inhibitors remain the greatest therapeutic challenge to the patient and care-giver. The eradication of the inhibitors, currently using ITI as the most effective technique, has raised many concerns. The basic science data on reduced immunogenicity of vW-containing products and their success in achieving ITI have provided the opportunity to explore this less costly approach to both primary and secondary ITI so it can hold its place in the management of inhibitors to FVIII in hemophilia. â– 

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References

  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.
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