Use of Factor VIII/Von Willebrand Factor Complex for Inducing Immune Tolerance in Hemophilia a Patients Who Have Failed with Recombinant Fviii: Recent Canadian Experience

Blood ◽  
2008 ◽  
Vol 112 (11) ◽  
pp. 4520-4520
Author(s):  
Anne-Marie Vincent ◽  
Anthony Chan ◽  
Sara J. Israels ◽  
Man-Chiu Poon ◽  
John K. Wu ◽  
...  
Keyword(s):  
Factor Viii ◽  
Von Willebrand Factor ◽  
Immune Tolerance ◽  
Tolerance Induction ◽  
Anamnestic Response ◽  
Canadian Experience ◽  
Development Inhibitor ◽  
Recombinant Fviii ◽  
Von Willebrand ◽  
Willebrand Factor

Abstract Immune tolerance induction (ITI) is effective in approximately 63–83% of hemophilia patients with inhibitors. Poor prognostic factors are age > 18 years, ITI started > 4 years after inhibitor development, inhibitor peaks > 200 BU, inhibitor titre > 10 BU at ITI initiation, and previously failed ITI. It has been reported that patients who have failed ITI with a recombinant FVIII concentrate achieved and maintained immune tolerance when VWF/FVIII complex concentrates were used. We present our Canadian experience with a factor VIII/von Willebrand factor concentrate (Humate-P) for inducing immune tolerance in patients who have previously failed ITI. A questionnaire was sent to all Hemophilia Treatment Centers of Canada. Data collected included baseline FVIII level, mutation, date at initial diagnosis of inhibitor, peak titer, concentrate associated with development of inhibitor, inhibitor titer at initiation of first ITI, concentrate and regimen used, and concentrate, dosing and outcome of secondary ITI with Humate-P. All Hemophilia Centers agreed to participate. 5 Centers submitted data about 8 patients. One patient resistant to initial ITI with Kogenate FS achieved good partial response with Humate-P, with titers going down from 40 to values between 0,6 and 4 BU. One patient who responded to initial ITI with Kogenate FS with peaking of inhibitor to 380 BU was remaining above 100 BU and lowered to 28 BU on Humate-P. In three patients, Humate-P induced an anamnestic response. Two of those patients had a concomitant line infection at time of switching to Humate-P. The third of those three patients had a transient anamnestic response after introduction of Humate-P. One patient had successfull induction of immune tolerance using multiple therapies (cyclophosphamide, Immunate, IVIG, Rituximab) and maintained remission under Humate-P. One patient was on ITI for 27 months using Recombinate and switched to Humate-P when Recombinate was withdrawn from the market. After 12 months, the inhibitor had gone from 12 to 7.3 BU. One patient attained complete remission during primary ITI using recombinant FVIII concentrate (Advate) and maintained remission when switched to Humate-P. In subjects failing ITI with recombinant factor VIII concentrates, Humate-P may be considered as a second line for inducing immune tolerance.

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

2010 ◽  
Vol 104 (11) ◽  
pp. 931-940 ◽  
Author(s):  
Giuseppe Lippi ◽  
Massimo Franchini
Keyword(s):  
Factor Viii ◽  
Von Willebrand Factor ◽  
Immune Tolerance ◽  
High Titer ◽  
Tolerance Induction ◽  
Haemophilia A ◽  
Immune Tolerance Induction ◽  
Bleeding Episodes ◽  
Von Willebrand ◽  
Willebrand Factor

SummaryThe 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.

Factor VIII Inhibitor Antibodies with C2 Domain Specificity Are Less inhibitory to Factor VIII Complexed with von Willebrand Factor

1996 ◽  
Vol 76 (05) ◽  
pp. 749-754 ◽  
Author(s):  
Suzuki Suzuki ◽  
Morio Arai ◽  
Kagehiro Amano ◽  
Kazuhiko Kagawa ◽  
Katsuyuki Fukutake
Keyword(s):  
Complex Formation ◽  
Factor Viii ◽  
Von Willebrand Factor ◽  
Domain Specificity ◽  
Factor Viii Inhibitor ◽  
C2 Domain ◽  
Recombinant Fviii ◽  
Von Willebrand ◽  
A2 Domain ◽  
Willebrand Factor

SummaryIn order to clarify the potential role of von Willebrand factor (vWf) in attenuating the inactivation of factor VIII (fVIII) by those antibodies with C2 domain specificity, we investigated a panel of 14 human antibodies to fVIII. Immunoblotting analysis localized light chain (C2 domain) epitopes for four cases, heavy chain (A2 domain) epitopes in five cases, while the remaining five cases were both light and heavy chains. The inhibitor titer was considerably higher for Kogenate, a recombinant fVIII concentrate, than for Haemate P, a fVIII/vWf complex concentrate, in all inhibitor plasmas that had C2 domain specificity. In five inhibitor plasmas with A2 domain specificity and in five with both A2 and C2 domain specificities, Kogenate gave titers similar to or lower than those with Haemate P. The inhibitory effect of IgG of each inhibitor plasma was then compared with recombinant fVIII and its complex with vWf. When compared to the other 10 inhibitor IgGs, IgG concentration, which inhibited 50% of fVIII activity (IC50), was remarkably higher for the fVIII/vWf complex than for fVIII in all the inhibitor IgGs that had C2 domain reactivity. Competition of inhibitor IgG and vWf for fVIII binding was observed in an ELISA system. In 10 inhibitors that had C2 domain reactivity, the dose dependent inhibition of fVIII-vWf complex formation was observed, while, in the group of inhibitors with A2 domain specificity, there was no inhibition of the complex formation except one case. We conclude that a subset of fVIII inhibitors, those that bind to C2 domain determinants, are less inhibitory to fVIII when it is complexed with vWf that binds to overlapping region in the C2 domain.

A Case Series Evaluating the Use of a Von Willebrand Factor/Factor VIII Concentrate (Wilate®) for Immune Tolerance Induction (ITI) in Children with Severe Factor VIII Deficiency

Blood ◽  
2014 ◽  
Vol 124 (21) ◽  
pp. 5050-5050
Author(s):  
Mark J. Belletrutti ◽  
Roxanne Seiferman-Nelson ◽  
Bonny Granfield
Keyword(s):  
Prognostic Factors ◽  
High Risk ◽  
Factor Viii ◽  
Immune Tolerance ◽  
Hemophilia A ◽  
Tolerance Induction ◽  
Immune Tolerance Induction ◽  
Bleeding Episodes ◽  
Recombinant Fviii ◽  
Von Willebrand

Abstract Introduction: Development of circulating anti-factor VIII antibodies (inhbitors) is the most serious and challenging complication in the treatment of hemophilia A. Up to 38% of hemophilia patients develop inhibitors with recombinant FVIII (rFVIII) products (Gouw et al. N Engl J Med. 2013; 368:231-239). The presence of inhibitors leads to an increased risk of bleeding, poor physical functioning and quality of life (Benson et al., Eur. J. Haematol. 2012; 88:371-379). Immune tolerance induction (ITI) is the most common method for eliminating inhibitors, historically performed with high dose, and prolonged treatment with plasma-derived (pd), or recombinant FVIII (rFVIII) concentrates. Although ITI for the eradication of inhibitors has become standard of care for hemophilia patients the therapeutic superiority of a particular product type (rFVIII vs. pd-FVIII) has not yet been conclusively demonstrated. In accordance with its role in stabilizing FVIII, the presence of von Willebrand factor (VWF) in pd-FVIII concentrates has been shown to improve the outcome of ITI. Wilate® (Octapharma) is a high-purity human plasma derived complex containing two proteins (VWF and FVIII) in a 1:1 ratio. The aim of this study was to determine the effectiveness of Wilate for primary ITI therapy for six patients with severe hemophilia A. Patients and Methods: The case history for six pediatric hemophilia A patients prior to and during primary Wilate ITI was reviewed. For 5/6 patients, inhibitors developed during rFVIII factor replacement therapy. For the sixth patient, inhibitors were detected at the time of hemophilia diagnosis. ITI began once patients achieved an inhibitor titer of less than 10 BU/mL. The ITI dosing regimen ranged from 50-60 IU/Kg of Wilate three times per week to 200 IU/Kg once daily. Inhibitor titers were measured regularly, prior to and during ITI using the Nijmegen-Bethesda assay. The number of port-a-cath infections and bleeding episodes were also monitored. ITI success was defined as: an undetectable inhibitor level (<0.6 BU/mL), FVIII plasma recovery ≥ 66% of predicted, and FVIII half-life ≥6 hours. Results: Wilate ITI was well tolerated in all patients, with no product-related adverse events. All patients had a port-a-cath device inserted for Wilate injections. Two port-a-cath infections occurred during ITI. Five of six patients had poor prognostic factors for ITI outcome. These poor prognostic factors included a high-risk FVIII gene mutation, historical peak inhibitor titer greater than 50 BU/mL, age of ITI onset greater than 6 years, and ITI onset more than 12 months from inhibitor development. The frequency of these poor prognostic factors varied amongst the patients: 1 patient had 4, 1 patient had 2, and 3 patients presented with 1 poor prognostic factor. Despite the presence of these high-risk factors, Wilate was successful at reducing the inhibitor titers to undetectable levels in all patients. Furthermore, inhibitor titers have remained low or undetectable without significant spikes for the duration of treatment. Patient plasma recovery and FVIII half-life results have also indicated that patients are progressing towards successful ITI. Importantly, for 6/6 patients (including 3 patients who had previously been treated with Anti-Inhibitor Coagulant Complex (FEIBA) prophylaxis therapy) - Wilate therapy was successful at reducing the number of bleeding episodes allowing for the cessation of FEIBA prophylaxis. Since commencing Wilate ITI, 6/6 patients have not reported any major bleeding episodes. The improved clinical outcome was perceived by the patients as an improved well-being, and quality of life. Conclusion: Wilate ITI was found to be well tolerated, safe, and successful at reducing inhibitor levels to below the detectable range for six severe hemophilia A patients. Patients experienced no treatment related adverse events, had a low rate of port-a-cath infections, and did not present with any major bleeding episodes while on Wilate ITI. In light of the 3-5 fold increase in overall treatment costs of immune tolerance induction, careful consideration should be given to choice of product (rFVIII versus pd-FVIII) – especially for patients at high-risk of failure. (Dimichele et al. Haemophilia 2004: 10 Suppl 4;140-145). The present data suggest that Wilate, a pd-FVIII product, is effective in managing patients with inhibitors. Disclosures Belletrutti: Baxter Canada: Honoraria, Membership on an entity's Board of Directors or advisory committees; CSL Behring Canada: Honoraria.

Immune Tolerance with a High Purity Plasma Derived Factor VIII Containing Von Willebrand Factor in Haemophilia A Patients with High Responding Inhibitors.

Blood ◽  
2004 ◽  
Vol 104 (11) ◽  
pp. 3096-3096
Author(s):  
Benoit Polack ◽  
Philippe Beurrier ◽  
Chantal Rothschild ◽  
Frédérique Orsini ◽  
Albert Faradji ◽  
...  
Keyword(s):  
Factor Viii ◽  
Von Willebrand Factor ◽  
Immune Tolerance ◽  
High Purity ◽  
Cumulative Exposure ◽  
Treatment Schedule ◽  
Haemophilia A ◽  
Von Willebrand ◽  
Willebrand Factor ◽  
Partial Success

Abstract We report on 8 patients with severe haemophilia A and high responding anti-factor VIII (FVIII) inhibiting antibody in whom immune tolerance (IIT) was induced with a high purity plasma derived FVIII containing 14 to 20 IU/ml of von Willebrand factor (VWF) as a stabiliser. Their median ages at the diagnosis of the inhibitor was 10.6 months and ranged from 5 months to 9 years. At the onset of IIT, the median age was 1 year and 9 months and ranged from 9 months to 24.5 years. The median cumulative exposure days (CED) was 18.5 days and varied from 8 to 81 days when inhibitor was detected. The maximum level of inhibitor reached from 10 to 500 Bethesda Units (BU) with a median of 22.5 BU. Before inhibitor diagnosis 6 patients had received plasma derived high purity FVIII and 2 had received recombinant FVIII. The treatment schedule started with 50 IU/kg to 200 IU/kg FVIII every day. The time to reach an inhibitor level <1 BU was available for 5 patients; its median was 142 days and varied from 75 to 216 days. The treatment was considered successful when either the recovery or the half life of FVIII was normalized. The outcome was successful in 7 out of the 8 patients (87.5 %) who are now receiving FVIII concentrates either on demand or prophylactically. The last patient was considered as a partial success since the titre of his inhibitor was 0.8 BU and he could be treated by FVIII concentrates when needed. No definite IIT failure was observed in this cohort of patients. Since all the patients are by now back to FVIII treatment we can consider having a 100% success in IIT in this small cohort of patients. Therefore, despite the size of our cohort of patients, our study shows that high purity FVIII stabilized by VWF is an effective drug for the eradication of anti-FVIII inhibitors through induction of immune tolerance. Patients data Patient Age at FVIII 1st infussion Age at inhibitor diagnosis CED at inhibitor diagnosis Age at IIT Inhibitor max.titre (BU) Time (d) <1 BU IIT results N.A.; not available 1 9m 1y 9 1y 3m 52 93 Success 2 2d 4y 3m 81 4y 3m 21 N.A. Success 3 8y 10m 9y 33 24y 6m 30 N.A. Success 4 8m 10m 28 1y 8m 24 75 Success 5 8m 8.5m 8 9m 14.5 - Partial success 6 1y 1m 1y 10m 21 3y 1m 10 142 Success 7 6m 9m 10 11m 20 216 Success 8 4m 5m 16 1y 9m 500 176 Success

Immune Tolerance Resulting in a Dramatic Clinical Improvement in a High-Responding Inhibitor Hemophilia A Patient Using Immunosuppression with Mycofenolate Mofetil and a Factor VIII Concentrate Containing Von Willebrand Factor.

Blood ◽  
2005 ◽  
Vol 106 (11) ◽  
pp. 3220-3220
Author(s):  
Thierry Lambert ◽  
Cécile Goujard ◽  
Anne Rafowicz ◽  
Benoît Guillet ◽  
Yacine Taoufik ◽  
...  
Keyword(s):  
Quality Of Life ◽  
Factor Viii ◽  
Clinical Improvement ◽  
Von Willebrand Factor ◽  
Immune Tolerance ◽  
Hemophilia A ◽  
Inhibitor Level ◽  
Von Willebrand ◽  
Willebrand Factor

Abstract A 40 year-old Caucasian patient with severe familial hemophilia A (FVIII <1%) related to an intron 22 inversion developed at the age of 2 a high-responding inhibitor. His elder brother also suffers from hemophilia A with high-responding inhibitor. Until 2000, the patient had been treated either using activated prothrombin complex concentrates (Autoplex® and Feiba®) or factor VIII (FVIII) concentrates of human (1983) and porcine origin (1992), resulting respectively in an inhibitor level rise at 360 Bethesda Units (BU) and 1800 BU. Between 2000 and 2003, the patient received exclusively recombinant activated Factor VII (NovoSeven®), and his inhibitor levels stabilized at a plateau of 15–20 BU. Between 2000 and 2003, several life or function threatening bleeding episodes occurred, such as hematomas of the iliopsoas muscles, spinal cord hematoma with transient paraplegia. Furthermore, due to hemarthroses the patient was confined to a wheelchair. Given the major impact of the inhibitor on the patient’s functional prognosis, life expectancy and quality of life, immune tolerance (IT) treatment was initiated, despite the high risk of failure (initiation 36 years after inhibitor onset, historical peak titer at 1800 BU, persistence of a plateau of 15–20 BU despite the absence of any stimulation with FVIII within the 3 last years). It started with an immunosuppressive drug, mycofenolate mofetil (Cellcept®) first given in may 2003 (no effect alone on inhibitor titer) and then in November 2003, infusions of a FVIII concentrate rich in von Willebrand factor, Factane® (LFB, Les Ulis, France) using 12,000 IU/day (150 IU/kg) of FVIII. The inhibitor peaked at 520 BU on D19 and was 0.5 BU by May 2004. Thus, the FVIII dosage was progressively reduced to 7000 IU/day. In July 2005, 24 hours after a 7000 IU FVIII infusion, inhibitor level was 0.7 BU, the residual FVIII level was 0.04IU/ml with a recovery of FVIIIc of 1.37%/IU/kg infused and a half-life of 4.9 hours. No significant change in the immunophenotype of peripheral blood lymphocytes was observed during this course. The patient’s quality of life was dramatically improved, with no hospitalization required and no bleeding episode observed within the 16 last months. The patient can now stand and has returned to his previous social activities. These preliminary results show that this IT treatment, performed despite a high theoretical risk of failure, resulted in this patient in a dramatic clinical improvement, even though biological criteria of success have not yet been achieved. The respective roles of the type of FVIII concentrate, and of immunosuppression remain to be assessed, as well as the cost/benefit analysis on a longer follow-up period.

Von Willebrand Factor Modulates Factor VIII Immunogenicity: Comparative Study of Different Factor VIII Concentrates in a Haemophilia A Mouse Model

2002 ◽  
Vol 88 (08) ◽  
pp. 221-229 ◽  
Author(s):  
Mathias Behrmann ◽  
John Pasi ◽  
Jean-Marie Saint-Remy ◽  
Ronald Kotitschke ◽  
Michael Kloft
Keyword(s):  
Immune Response ◽  
Factor Viii ◽  
Von Willebrand Factor ◽  
Major Complication ◽  
Epidemiological Studies ◽  
Haemophilia A ◽  
Epitope Specificity ◽  
Recombinant Fviii ◽  
Von Willebrand ◽  
Willebrand Factor

SummaryThe development of an immune response towards factor VIII (FVIII) remains the major complication of haemophilia A replacement therapy. Product-related risk factors have recently been identified on the basis of epidemiological studies, but the mechanism is not understood. To this end, various commercially available FVIII concentrates were administered by the IV route to FVIII-knockout mice and the resulting immune response was characterised. Significantly higher inhibitor titres (Bethesda assay) were observed for one recombinant FVIII and one plasma-derived FVIII product depleted in von Willebrand factor (VWF). Inhibitor titres were reduced upon pre-incubation of FVIII with purified VWF. Epitope specificity of anti-FVIII IgG was characterised using FVIII-fragments produced in E. coli. Concentrates with no or reduced VWF-level elicited antibodies recognising predominantly the acidic a1 and a3 regions. Addition of VWF prior to injection also modified the epitope specificity. FVIII concentrates, therefore, show qualitative and quantitative variations in immunogenicity, which are at least partly modulated by VWF.

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