Innowacyjna metoda prowadzenia ITI za pomocą preparatu czynnika VIII z frakcją Fc u pacjentów z hemofilią A z obecnością inhibitora czynnika VIII – przegląd literaturowy

2018 ◽  
Vol 22 (3) ◽  
Author(s):  
Maciej Trzaska ◽  
Marek Karwacki ◽  
Paweł Łaguna ◽  
Michał Matysiak
Keyword(s):  
Factor Viii ◽  
Tolerance Induction ◽  
Standard Of Care ◽  
Preliminary Evidence ◽  
Immunological Tolerance ◽  
Therapeutic Benefit ◽  
High Titre ◽  
Haemophilia A ◽  
Severe Haemophilia ◽  
First Time

Eradication of factor VIII inhibitors using Immune tolerance induction (ITI) treatment is the standard of care for severe haemophilia A patients presenting with factor VIII inhibitors, but is not always effective. A description of the potential immunological tolerance effect of the IgG Fc domain of recombinant factor VIII Fc fusion protein (rFVIIIFc), as well as published experience with rFVIIIFc for ITI in patients with severe haemophilia A and high-titre inhibitors. Review of published literature describing cases of ITI with rFVIIIFc in patients with severe haemophilia A and high-titre inhibitors between November 2015 and June 2018. Four publications has been found. Of 56 patients with haemophilia A who presented with FVIII inhibitors, 28 achieved a negative Bethesda titre (< 0.6) after ITI treatment using rFVIIIFc. Additional patients continued on rFVIIIFc ITI at the time of publication, while a few were reported to have switched to bypass therapy alone or other factors . For those still undergoing ITI, longer follow-up is needed to determine final outcomes. No adverse events were reported. Based on literature review, preliminary evidence of FVIIIFc use in high risk, first-time ITI suggests rapid time to tolerization. For rescue ITI, rFVIIIFc showed therapeutic benefit in some patients who previously failed ITI. These findings give hope but highlight the need for further evaluation in ongoing clinical trials.

scholarly journals A new era of treatment for patients with haemophilia A?

2017 ◽  
Vol 37 (03) ◽  
pp. 216-218 ◽  
Author(s):  
Robert Klamroth
Keyword(s):  
Factor Viii ◽  
Treatment Options ◽  
Clinical Signs ◽  
Tolerance Induction ◽  
Haemophilia A ◽  
Dependent Manner ◽  
Severe Haemophilia ◽  
Factor X ◽  
Igg Antibody ◽  
Ongoing Research

SummaryTreatment and prevention of bleeding episodes in patients with severe haemophilia A require frequent intravenous injection of factor VIII. Inhibitory antibodies against factor VIII occur in approximately 30 % of these patients during the first exposure days and immune tolerance induction to eradicate the inhibitor is challenging. Prevention of bleeds in patients with haemophilia A and inhibitors is less effective and there is ongoing research for alternative treatment options. A promising approach in 2016 is the development of emicizumab (ACE910), a bispecific IgG antibody to factor IXa and factor X, that mimics the cofactor function of factor VIII. Due to the different structure of this antibody it cannot be neutralized by factor VIII inhibitors and has the possibility to achieve haemostasis in patients with severe haemophilia A with and without inhibitors. First studies in healthy volunteers and in patients showed a shortened activated partial thromboplastin time and increased peak height of thrombin generation in a dose-dependent manner. The halflife of the drug was 4 to 5 weeks. There were no clinical signs of thrombosis and no laboratory abnormalities indicating hypercoagulability. In a first study with 18 patients with severe haemophilia A with and without inhibitors a remarkable reduction in the annualised bleeding rate occurred. Safety of the drug has to be proven in ongoing research. Mimicking the cofactor activity of factor VIII by a bispecific antibody for the treatment of severe haemophilia A is so far safe and seems to be effective and is one highlight in haemostasis 2016.

Successful liver transplantation in a patient with severe haemophilia A and a high-titre factor VIII inhibitor

Haemophilia ◽  
2004 ◽  
Vol 10 (6) ◽  
pp. 735-737 ◽  
Author(s):  
A. A. Ashrani ◽  
M. T. Reding ◽  
A. Shet ◽  
J. Osip ◽  
A. Humar ◽  
...  
Keyword(s):  
Liver Transplantation ◽  
Factor Viii ◽  
High Titre ◽  
Factor Viii Inhibitor ◽  
Haemophilia A ◽  
Severe Haemophilia ◽  
Viii Inhibitor

Risk Factors for the Progression from Low to High Titres in 260 Children with Severe Haemophilia A and Newly Developed Inhibitors

2017 ◽  
Vol 117 (12) ◽  
pp. 2274-2282 ◽  
Author(s):  
Maria Elisa Mancuso ◽  
Kathelijn Fischer ◽  
Elena Santagostino ◽  
Johannes Oldenburg ◽  
Helen Platokouki ◽  
...  
Keyword(s):  
Risk Factors ◽  
Immune Tolerance ◽  
Laboratory Data ◽  
Tolerance Induction ◽  
High Titre ◽  
High Dose ◽  
Haemophilia A ◽  
Severe Haemophilia ◽  
Immune Tolerance Induction ◽  
Potential Risk Factors

AbstractIn children with severe haemophilia A, inhibitors to factor VIII (FVIII) usually develop during the first 50 treatment exposure days and are classified as low or high titre depending on the peak inhibitor titre being greater or less than 5 Bethesda units/mL (BU/mL). Classification of the inhibitor may change with time, as some low-titre inhibitors progress to high titre following re-exposure to FVIII concentrate. The aim of this study was to investigate potential risk factors for such a progression in children with severe haemophilia A and newly diagnosed inhibitors. This study was a follow-up study of the PedNet Registry and included 260 children with severe haemophilia A and inhibitors born between 1990 and 2009 and recruited consecutively from 31 haemophilia centres. Clinical and laboratory data were collected from the date of each child's first positive inhibitor test for at least 3 years. At the time of first positive inhibitor test, 49% (n = 127) had low-titre inhibitors, with 50% of them progressing to high titre and only 25% maintaining low titres. The FVIII gene (F8) mutation type was known in 247 patients (95%), and included 202 (82%) null mutations. The progression to high-titre inhibitors was associated with null F8 mutations (odds ratio [OR]: 2.6; 95% confidence interval [CI]: 1.0–6.5), family history of inhibitors (OR: 7.2; 95% CI: 1.8–28.4) and the use of high-dose immune tolerance induction, defined as ≥100 IU FVIII concentrate/kg/d (OR: 3.9; 95% CI: 1.5–10.0). These results suggest that high-dose immune tolerance induction should be avoided as the initial strategy in patients who develop low-titre FVIII inhibitors.

Inhibitors in nonsevere haemophilia A: outcome and eradication strategies

2015 ◽  
Vol 114 (07) ◽  
pp. 46-55 ◽  
Author(s):  
Alice S. van Velzen ◽  
Corien L. Eckhardt ◽  
Daniel P. Hart ◽  
Marjolein Peters ◽  
Savita Rangarajan ◽  
...  
Keyword(s):  
Factor Viii ◽  
Medical Center ◽  
Academic Medical Center ◽  
Treatment Strategies ◽  
Tolerance Induction ◽  
High Titre ◽  
Source Population ◽  
Haemophilia A ◽  
Anamnestic Response ◽  
Sustained Success

SummaryIn nonsevere haemophilia A (HA) patients the presence of an inhibitor may exacerbate the bleeding phenotype dramatically. There are very limited data on the optimal therapeutic approach to eradicate inhibitors in these patients. We aimed to describe inhibitor eradication treatment in a large cohort of unselected nonsevere HA patients with inhibitors. We included 101 inhibitor patients from a source population of 2,709 nonsevere HA patients (factor VIII 2–40 IU/dl), treated in Europe and Australia (median age 37 years, interquartile range (IQR) 15–60; median peak titre 7 BU/ml, IQR 2–30). In the majority of the patients (71 %; 72/101) the inhibitor disappeared; either spontaneously (70 %, 51/73) or after eradication treatment (75 %, 21/28). Eradication treatment strategies varied widely, including both immune tolerance induction and immunosuppression. Sustained success (no inhibitor after rechallenge with factor VIII concentrate after inhibitor disappearance) was achieved in 64 % (30/47) of those patients rechallenged with FVIII concentrate. In high-titre inhibitor patients sustained success was associated with eradication treatment (unadjusted relative risk 2.3, 95 % confidence interval 1.3–4.3), compared to no eradication treatment. In conclusion, in nonsevere HA patients most inhibitors disappear spontaneously. However, in 35 % (25/72) of these patients an anamnestic response still can occur when rechallenged, thus disappearance in these patients does not always equal sustained response. Treatment for those requiring eradication has to be decided case by case, as one single approach is unlikely to be appropriate for all.Study was carried out in: Emma Children’s Hospital, Academic Medical Center, Amsterdam, the Netherlands.

scholarly journals Immune Tolerance Therapy for Haemophilia A Patients with Acquired Factor VIII Alloantibodies: Comprehensive Analysis of Experience at a Single Institution

1999 ◽  
Vol 81 (01) ◽  
pp. 35-38 ◽  
Author(s):  
K. J. Spence ◽  
E. L. Waters ◽  
R. Beresford-Webb ◽  
M. J. Mitchell ◽  
J. Cuttler ◽  
...  
Keyword(s):  
Factor Viii ◽  
Dose Reduction ◽  
Immune Tolerance ◽  
Phase 1 ◽  
Tolerance Induction ◽  
Hla Class I ◽  
High Titre ◽  
Pharmacokinetic Analysis ◽  
Haemophilia A ◽  
Immune Tolerance Induction

SummaryEleven children with severe haemophilia A associated with the IVS 22 inversion and acquired high titre neutralising antibodies to factor VIII underwent immune tolerance induction. HLA class I and high resolution class II type is detailed for each patient. A three phase approach to immune tolerance induction was used. During phase 1, which lasted a median of six weeks, patients received factor VIII 100 IU/kg twice daily. Phase 2 comprised a factor VIII dose reduction to 100 IU/kg once daily, and continued for a median duration of 14 weeks. Subsequently 10 of the 11 patients satisfied the criteria of absent factor VIII neutralising activity by the Bethesda method, and a factor VIII elimination half life of greater than 5 h, allowing progression to phase 3, a further factor VIII dose reduction to 50 IU/kg three times weekly. A model for dose reduction as factor VIII tolerance evolves, based on pharmacokinetic analysis, is described.

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