A Large Deletion due to a New Mutation (Intron 13/Exon 23) in a Sporadic Case of Severe Hemophilia A

Abstract Background : Octanate is a highly purified, double virus inactivated, human plasma-derived factor VIII (FVIII) concentrate with all coagulation FVIII bound to its natural stabilizer VWF in a VWF:RCo/FVIII:C ratio of approximately 0.4. A prospective clinical trial has been initiated in 2000 in order to assess the immunogenicity, efficacy and tolerability of Octanate in previously untreated patients (PUPs). Materials and Methods: Patients with severe hemophilia A without previous exposure to FVIII or FVIII-containing products were enrolled. Inhibitor screening, using the modified Bethesda method, was performed prior to treatment, starting every 3-4 EDs (ED 1-20), and afterwards every 10 EDs (ED 21-100), but at least every three months. Efficacy and tolerability were assessed by a 4-point verbal rating scale. Results: The study is clinically completed, after fifty-one subjects with severe haemophilia A, at screening 0,01-5,61 years old (median 0,65 years; median 0,99 years at treatment start) have been enrolled. Three of them developed clinically relevant high titer inhibitors over the course of the study. Another two displayed transient inhibitors that disappeared spontaneously without changing the dose or dosing interval. All inhibitors developed under on-demand treatment and before ED 50. For 4 inhibitor patients an intron 22 inversion, for 1 inhibitor patient a large deletion of exons 7 – 12 was found. From 51 subjects, 45 exceeded 50 EDs. Octanate was well-tolerated and the adverse event profile was consistent with the population studied. The haemostatic efficacy in prophylaxis and treatment of bleeding episodes was generally rated as “excellent” and no complication was reported for any surgical treatment. Conclusion: Despite frequent inhibitor testing and predominant on-demand treatment, the data indicate a low overall inhibitor rate for Octanate in patients who exceeded 50 EDs (5/45) of which only 3 (6.7%) were clinically relevant. Disclosures Knaub: Octapharma AG: Employment. Klukowska:Octapharma AG: Investigator Other. Komrska:Octapharma AG: Investigator Other. Laguna:Octapharma AG: Investigator Other. Vladimir:Octapharma AG: Investigator Other. Jansen:Octapharma AG: Employment.

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A large deletion, spanning exons 1 to 25 of F8 gene, and a high‐titer factor VIII inhibitor, in severe hemophilia A

International Journal of Laboratory Hematology ◽

10.1111/ijlh.13174 ◽

2020 ◽

Vol 42 (3) ◽

Author(s):

Sayed Hamid Mousavi ◽

Seyed Alireza Mesbah‐Namin ◽

Sirous Zeinali ◽

Mohammad Jazebi ◽

Ali Dabbagh ◽

...

Keyword(s):

Factor Viii ◽

Hemophilia A ◽

High Titer ◽

Large Deletion ◽

Factor Viii Inhibitor ◽

Severe Hemophilia ◽

Viii Inhibitor

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New mutation in TSC1-gene in a sporadic case with initially mild phenotype

Neuropediatrics ◽

10.1055/s-0032-1307090 ◽

2012 ◽

Vol 43 (02) ◽

Author(s):

C Thiels ◽

C Köhler ◽

K Weigt-Usinger ◽

C Sutter ◽

T Lücke

Keyword(s):

Sporadic Case ◽

New Mutation ◽

Mild Phenotype ◽

Tsc1 Gene

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T Lymphocyte Proliferative Responses Induced by Recombinant Factor VIII in Hemophilia A Patients with Inhibitors

Thrombosis and Haemostasis ◽

10.1055/s-0038-1650515 ◽

1996 ◽

Vol 76 (01) ◽

pp. 017-022 ◽

Cited By ~ 27

Author(s):

Sylvia T Singer ◽

Joseph E Addiego ◽

Donald C Reason ◽

Alexander H Lucas

Keyword(s):

T Lymphocytes ◽

Factor Viii ◽

Cellular Proliferation ◽

Mononuclear Cells ◽

Hemophilia A ◽

Normal Subjects ◽

Normal Male ◽

Cell Fractionation ◽

Severe Hemophilia ◽

Human Factor Viii

SummaryIn this study we sought to determine whether factor VUI-reactive T lymphocytes were present in hemophilia A patients with inhibitor antibodies. Peripheral blood mononuclear cells (MNC) were obtained from 12 severe hemophilia A patients having high titer inhibitors, 4 severe hemophilia A patients without inhibitors and 5 normal male subjects. B cell-depleted MNC were cultured in serum-free medium in the absence or presence of 2 µg of recombinant human factor VIII (rFVIII) per ml, and cellular proliferation was assessed after 5 days of culture by measuring 3H-thymidine incorporation. rFVIII induced marked cellular proliferation in cultures of 4 of 12 inhibitor-positive hemophilia patients: fold increase over background (stimulation index, SI) of 7.8 to 23.3. The remaining 8 inhibitor-positive patients, the 4 hemophilia patients without inhibitors and the 5 normal subjects, all had lower proliferative responses to rFVIII, SI range = 1.6 to 6.0. As a group, the inhibitor-positive subjects had significantly higher proliferative responses to rFVIII than did the inhibitor-negative and normal subjects (p < 0.05 by t-test). Cell fractionation experiments showed that T lymphocytes were the rFVIII-responsive cell type, and that monocytes were required for T cell proliferation. Thus, rFVIII-reactive T lymphocytes are present in the peripheral circulation of some inhibitor-positive hemophilia A patients. These T cells may recognize FVIII in an antigen-specific manner and play a central role in the regulation of inhibitor antibody production

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Dose Requirement for Replacement Therapy in Hemophilia A

Thrombosis and Haemostasis ◽

10.1055/s-0038-1666930 ◽

1979 ◽

Vol 42 (03) ◽

pp. 825-831 ◽

Cited By ~ 34

Author(s):

Jean-Pierre Allain

Keyword(s):

Clinical Effect ◽

Hemophilia A ◽

Clinical Results ◽

Severe Hemophilia ◽

Dose Requirement ◽

Viii Level ◽

The Relationship ◽

In Vivo Recovery ◽

Different Doses

SummaryIn order to determine the correlation between different doses of F. VIII and their clinical effect,. 70 children with severe hemophilia A were studied after treatment with single doses of cryoprecipitate. The relationship between plasma F. VIII levels or doses calculated in u/ kg of body weight and clinical results followed an exponential curve. Plasma F. VIII levels of 0.35 and 0.53 u/ml corresponded to 95 and 99% satisfactory treatment, respectively. Similar clinical results were obtained with 20 and 31 u/kg. When the in vivo recovery of F. VIII after lyophilized cryoprecipitate was 0.015 u/ml for each u/kg injected, plasma F. VIII levels of 0.30 and 0.47 u/ml respectively were achieved. Since home treatment is largely based on single infusions of F. VIII, it is suggested that moderate and severe hemorrhages be treated with a dose which will provide a plasma F. VIII level of 0.5 u/ml.

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Long-term Efficacy and Safety of rVIII-SingleChain in Patients with Severe Hemophilia A: Interim Results of an Extension Study

10.1055/s-0039-1680221 ◽

2019 ◽

Author(s):

J. Mahlangu ◽

F. Abdul ◽

O. Stasyshyn ◽

B. Korczowski ◽

A. Brainsky ◽

...

Keyword(s):

Hemophilia A ◽

Extension Study ◽

Severe Hemophilia ◽

Efficacy And Safety ◽

Term Efficacy

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Faculty Opinions recommendation of AAV5-Factor VIII Gene Transfer in Severe Hemophilia A.

Faculty Opinions – Post-Publication Peer Review of the Biomedical Literature ◽

10.3410/f.732279394.793544825 ◽

2018 ◽

Author(s):

Valder Arruda ◽

Ben Samelson-Jones

Keyword(s):

Gene Transfer ◽

Factor Viii ◽

Hemophilia A ◽

Severe Hemophilia ◽

Factor Viii Gene

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Common Genetic Variants in ABO and CLEC4M Modulate the Pharmacokinetics of Recombinant FVIII in Severe Hemophilia A Patients

Thrombosis and Haemostasis ◽

10.1055/s-0040-1714214 ◽

2020 ◽

Vol 120 (10) ◽

pp. 1395-1406 ◽

Cited By ~ 1

Author(s):

Iris Garcia-Martínez ◽

Nina Borràs ◽

Marta Martorell ◽

Rafael Parra ◽

Carme Altisent ◽

...

Keyword(s):

Blood Group ◽

Half Life ◽

Robust Regression ◽

Hemophilia A ◽

Illumina Miseq ◽

Activity Levels ◽

Severe Hemophilia ◽

Single Nucleotide Variants ◽

Common Genetic Variants ◽

Recombinant Fviii

AbstractThe pharmacokinetic (PK) response of severe hemophilia A (HA) patients to infused factor VIII (FVIII) shows substantial variability. Several environmental and genetic factors are associated with changes in FVIII plasma levels and infused FVIII PK. Based on the hypothesis that factors influencing endogenous FVIII can affect FVIII PK, the contribution of single-nucleotide variants (SNVs) in candidate genes was investigated in 51 severe HA patients. The effects of blood group, F8 variant type, von Willebrand factor antigen and activity levels, age, and weight were also explored. The myPKFiT device was used to estimate individual PK parameters, and SNVs and clinically reportable F8 variants were simultaneously analyzed in an Illumina MiSeq instrument, using the microfluidics-based Fluidigm Access Array system. The contribution of SNVs to FVIII half-life and clearance was addressed by robust regression modeling, taking into account other modulators. In line with previous studies, we provide robust evidence that age, body weight, and blood group, as well as SNVs in ABO and CLEC4M, participate in the variability of FVIII PK in HA patients. Main results: each copy of the rs7853989 (ABO) allele increases FVIII half-life by 1.4 hours (p = 0.0131) and decreases clearance by 0.5 mL/h/kg (p = 5.57E-03), whereas each additional rs868875 (CLEC4M) allele reduces FVIII half-life by 1.1 hours (p = 2.90E-05) and increases clearance by 0.3 mL/h/kg (p = 1.01E-03). These results contribute to advancing efforts to improve FVIII replacement therapies by adjusting to each patient's PK profile based on pharmacogenomic data. This personalized medicine will decrease the burden of treatment and maximize the benefits obtained.

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