scholarly journals Anti-A2 and anti-A1 domain antibodies are potential predictors of immune tolerance induction outcome in children with hemophilia A

2015 ◽  
Vol 13 (4) ◽  
pp. 540-547 ◽  
Author(s):  
P. Lapalud ◽  
C. Rothschild ◽  
E. Mathieu-Dupas ◽  
J. Balicchi ◽  
Y. Gruel ◽  
...  
Keyword(s):  
Immune Tolerance ◽  
Hemophilia A ◽  
Tolerance Induction ◽  
Immune Tolerance Induction ◽  
A1 Domain

Benefits of prophylactic emicizumab in enhancing immune tolerance induction in a boy with hemophilia A and very high inhibitor titer

2021 ◽  
Author(s):  
Nongnuch Sirachainan ◽  
Ampaiwan Chuansumrit ◽  
Surapan Parapakpenjune ◽  
Pakawan Wongwerawattanakoon ◽  
Surapong Lertthammakiat ◽  
...  
Keyword(s):  
Immune Tolerance ◽  
Hemophilia A ◽  
Tolerance Induction ◽  
Immune Tolerance Induction ◽  
Inhibitor Titer ◽  
Very High

scholarly journals IgG subclasses of anti-FVIII antibodies during immune tolerance induction in patients with hemophilia A

2008 ◽  
Vol 142 (4) ◽  
pp. 644-652 ◽  
Author(s):  
Pauline M. W. van Helden ◽  
H. Marijke van den Berg ◽  
Samantha C. Gouw ◽  
Paul H. P. Kaijen ◽  
Marleen G. Zuurveld ◽  
...  
Keyword(s):  
Immune Tolerance ◽  
Hemophilia A ◽  
Tolerance Induction ◽  
Igg Subclasses ◽  
Immune Tolerance Induction

Successful Treatment of Inhibitor Formation in Adult Congenital Hemophilia A with Rituximab.

Blood ◽  
2006 ◽  
Vol 108 (11) ◽  
pp. 4074-4074 ◽  
Author(s):  
Chirag J. Amin ◽  
Alice D. Ma
Keyword(s):  
Factor Viii ◽  
Knee Replacement ◽  
Immune Tolerance ◽  
Bolus Dose ◽  
Hemophilia A ◽  
High Titer ◽  
Tolerance Induction ◽  
Recombinant Factor Viii ◽  
Promising Alternative ◽  
Immune Tolerance Induction

Abstract Inhibitor development in congenital hemophiliacs can be clinically catastrophic. Immune tolerance induction therapy has previously been the standard of care in eradicating inhibitors; however due to a multitude of factors, this may not be applicable in certain patients. The role of Rituximab is receiving more attention in this subset of patients. In this abstract, we report that treatment with Rituximab led to successful eradication of high-titer inhibitors in 3 patients with mild to moderate hemophilia A who developed inhibitors after receiving intensive treatment with recombinant Factor VIII (FVIII). Patient Characteristics: Three patients, aged 50–70, with baseline FVIII levels of 2–9%, developed inhibitors after recombinant Factor VIII infusion. Patient A was treated with continuous infusion FVIII for a post-surgical hemarthrosis for approximately 7 days. Patient B received bolus dose FVIII for a GI bleed for at least 10 days, and Patient C received bolus dose FVIII for knee replacement for 10 days. Factor VIII inhibitors were detected in these patients after one month. None of these patients had been treated with immune tolerance previously or had known inhibitors. Each patient received Rituximab 375mg/m2 every week for 4 weeks total. During and after treatment, FVIII levels and Bethesda inhibitor titers (BU) were monitored. Results: All three patients had eradication of their inhibitors (Figure 1) and return of their FVIII levels to baseline by six months post-treatment. Notably, patient C’s inhibitor peak was 117 BUs, 7 months prior to Rituximab treatment. Patient C’s initial response to Rituximab has been previously reported at ASH in abstract form. We now report that 4 years later, this patient has had a recurrence of his inhibitor after monoclonal FVIII for a contralateral knee replacement but with a peak titer of only 2 (Table 1). Inhibitor Trends after Rituximab Treatment Inhibitor Trends after Rituximab Treatment Bethesda Inhibitor Titer (BU) per Month (*) after Receiving Rituximab 0* 1 3 6 36 48 51 NA=Not applicable as data has not matured yet Patient A (BU) 5 0.7 0 0 NA NA NA Patient B (BU) 17 7 2 0 NA NA NA Patient C (BU) 40 4 0 0 0 2 0.5 Conclusion: Inhibitors in patients with mild-moderate hemophilia differ from those with severe FVIII deficiency, behaving more like the autoantibodies seen in patients with spontaneous FVIII inhibitors. In support of this idea, we successfully treated high titer inhibitors which developed in 3 patients with baseline FVIII levels of 2–9%. All three patients had prompt resolution of their inhibitor titers during the course of therapy, with return of their baseline FVIII levels. Historically, patients with mild-moderate hemophilia treated at the Harold R. Roberts Comprehensive Hemophilia Center at the University of North Carolina were treated either with immune tolerance induction or by bypass agents alone, with inhibitor eradication taking months to years (data not shown). While performance of larger prospective trials would be ideal, the small number of patients with this condition limits the ability to perform these trials. Our findings, in combination with other case series from other institutions, reveal a promising alternative for prompt and reliable treatment in mild-moderate hemophiliacs with inhibitors.

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.

Induction of Immune Tolerance in a 7-Year-Old Hemophiliac with an Anaphylactoid Inhibitor

1995 ◽  
Vol 74 (04) ◽  
pp. 1039-1041 ◽  
Author(s):  
James L Harper ◽  
Joan C Gill ◽  
Russell J Hopp ◽  
John Evans ◽  
William D Haire
Keyword(s):  
Antibody Titer ◽  
Immune Tolerance ◽  
High Purity ◽  
Hemophilia A ◽  
Rare Complication ◽  
Tolerance Induction ◽  
Skin Tests ◽  
Severe Hemophilia ◽  
Immune Tolerance Induction

Summary Background: Anaphylactic reactions were a rare complication of low purity VIII concentrates, hut not with high purity VIII concentrates Case: 7 y/o WM with severe hemophilia A, received only cryoprecipitate and monoclonally purified VIII concentrates; developed post-infusional urticaria. A 2-Bethesda-unit inhibitor was detected. Generalized urticaria and bronchospasm following factor developed as the titer increased. Skin tests demonstrated reactivity to plasma derived VIII, but not recombinant VIII (rhVIII). Attempts at desensitization using rhVIII failed. KLISA revealed an anti-VIIl IgB antibody. He was treated with a modified tolerance regimen using rhVIII starting at 500 U/day with aggressive premedication. The dosage increased by 200 U weekly as tolerated to a maximum of l00U/kg/d without symptoms. Results: His antibody titer decreased rapidly once he started l00U/kg/d. Six months later, the inhibitor was <1 Bethesda unit. Conclusion: Immune tolerance induction using a graduated dosage of rhVIII was successful.

Immune Tolerance Induction (ITI) in Hemophilia A and Inhibitors using VWF Containing Factor VIII Concentrates.

Blood ◽  
2004 ◽  
Vol 104 (11) ◽  
pp. 3092-3092
Author(s):  
Wolfhart Kreuz ◽  
Carmen Escuriola Ettingshausen ◽  
Guenter K.H. Auerswald ◽  
Hans Herrmann Brackmann ◽  
Thomas Klingebiel
Keyword(s):  
Success Rate ◽  
Immune Tolerance ◽  
Hemophilia A ◽  
Meta Analysis ◽  
Tolerance Induction ◽  
Concomitant Treatment ◽  
Bleeding Tendency ◽  
Immune Tolerance Induction ◽  
Von Willebrand ◽  
High Responders

Abstract Immune tolerance induction using the Bonn protocol (ITI) is the most successful approach to eliminate inhibitors in hemophilia A patients. The influence of the type of concentrate, particularly the content of von-Willebrand-Factor (VWF) used for ITI is under discussion and has never been investigated comparatively. A longitudinal study at the Frankfurt center on the influence of VWF on ITI using the Bonn protocol (low responder: 50–100 IU FVIII/kg bw daily or every other day; high responder: 100–150 IU FVIII/kg bw every 12 hours; according to the bleeding tendency concomitant treatment with FEIBA®/Baxter) showed a significantly decreased success rate since the introduction of high purity plasma derived (pd) and recombinant (rec) F VIII products (success rate with pd VWF-F VIII 91% vs ultrapure F VIII 29%). Similar observations have been reported by the Bonn and Bremen centers (success rate with pd VWF-F VIII 87% vs ultrapure F VIII 54%). A meta-analysis of different ITI studies revealed a higher success rate with the use of VWF-FVIII concentrates (88% using VWF-FVIII and 63% using rec and pd/monoclonal purified F VIII). The change to VWF-FVIII concentrates during ITI in inhibitor patients who showed an unsatisfactory treatment course with ultrapure F VIII concentrates (n=12 high responders) led to success in 10 out of 12 patients after a median treatment period of 17 months (5–36 months). Successful IT after changing to VWF-F VIII concentrates was evaluated by a questionnaire in another 10 high responders who had unsatisfactory treatment courses with ultrapure F VIII concentrates. These observations indicate that VWF has a major impact on the success of ITI.

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