scholarly journals Failure of Combined Factor VIII and Cyclophosphamide to Suppress Antibody to Factor VIII in Hemophilia

Blood ◽  
1973 ◽  
Vol 42 (6) ◽  
pp. 919-923 ◽  
Author(s):  
Marilyn A. Hruby ◽  
Irving Schulman
Keyword(s):  
Antibody Response ◽  
Factor Viii ◽  
Hemophilia A ◽  
Response Factor ◽  
Intravenous Cyclophosphamide ◽  
Antibody Titers ◽  
Factor Viii Concentrates

Abstract Two patients with hemophilia A and antifactor VIII antibodies were treated with infusions of factor VIII concentrates and intravenous cyclophosphamide in an attempt to suppress the antibody response. Factor VIII levels of 23% and 95% were achieved immediately postinfusion, and prompt control of bleeding ensued. Sequential antibody titers demonstrated no change in antibody response in either patient when compared to previous studies following factor VIII infusion alone. These results are in contrast to the previously reported suppression of factor VIII antibody in a nonhemophilic patient using an identical regimen.

A Survey of the Effectiveness of Prothrombin Complex Concentrates in Controlling Hemorrhage in Patients with Hemophilia and Anti-Factor VIII Antibodies

1980 ◽  
Vol 44 (01) ◽  
pp. 039-042 ◽  
Author(s):  
Philip M Blatt ◽  
Doris Ménaché ◽  
Harold R Roberts
Keyword(s):  
Factor Viii ◽  
Ad Hoc ◽  
Hemophilia A ◽  
Working Party ◽  
International Committee ◽  
Factor Ix ◽  
Prothrombin Complex Concentrates ◽  
Factor Viii Concentrates

SummaryThe treatment of patients with hemophilia A and anti-Factor VIII antibodies is difficult. Between July 1977 and June 1978, a survey was carried out by an ad hoc working party of the subcommittee on Factor IX concentrates of the International Committee on Thrombosis and Hemostasis to assess the effectiveness of Prothrombin Complex Concentrates in controlling hemorrhage in these patients. The results are presented in this paper and, although subjective, support the view that these concentrates are not as effective in patients with inhibitors as Factor VIII concentrates are in patients without inhibitors.

Enhanced Half-Life Recombinant Factor VIII Concentrates for Hemophilia A: Final Results from Extension Studies

2021 ◽  
Author(s):  
Matteo Nicola Dario Di Minno ◽  
Alessandro Di Minno ◽  
Ilenia Calcaterra ◽  
Ernesto Cimino ◽  
Francesco Dell'Aquila ◽  
...  
Keyword(s):  
Factor Viii ◽  
Half Life ◽  
Hemophilia A ◽  
Recombinant Factor Viii ◽  
Factor Viii Concentrates

Replacement Therapy in Hemophilia Patients with Inhibitors

1979 ◽  
Author(s):  
S.S. Shapiro
Keyword(s):  
Factor Viii ◽  
Antibody Titer ◽  
Hemophilia A ◽  
Double Blind Study ◽  
Cooperative Study ◽  
Double Blind ◽  
Antibody Titers ◽  
High Degree ◽  
High Treatment ◽  
Dependent Factor

Approximately 15% of patients with hemophilia A develop inhibitors to Factor VIII. These inhibitors have a high degree of specificity for Factor VIII procoagulant activity. Inhibitor patients seem to fall into 2 groups: roughly 3/4 are “strong” responders, whose Factor VIII antibody titer rises substantially after exposure to Factor VIII, while the remainder are “weak” responders, whose antibody level remains below 3-5 Bethesda units/ml despite exposure to Factor VIII. The latter group can be treated successfully with Factor VIII, although the dose required may be greater than in non-inhibitor patients. The “strong” responders can be treated with Factor VIII if their antibody titer is very low, although anamnesis will ensue within 3-4 days, reaching a maximum in 10-20 days. When antibody titers are high, treatment can be extremely difficult. Use of Factor VIII may still be possible, when combined with massive plasmapheresis; otherwise treatment with vitamin K-dependent factor concentrates may be attempted. A variety of such concentrates is available, both “non-activated” and “activated”. The former type of product may have become less useful for the treatment of inhibitor patients in recent years. The NTH Cooperative Study of Factor VIII Inhibitors in Hemophilia A has recently conducted a double-blind study of Konyne and Proplex in the treatment of Inhibitor patients. These results will be presented.

Comparative Investigations on Factor VIII Assays

1975 ◽  
Author(s):  
R. Pflugshaupt ◽  
S. Moser ◽  
K. Züger ◽  
R. Bütler
Keyword(s):  
Factor Viii ◽  
High Activity ◽  
Hemophilia A ◽  
Statistical Evaluation ◽  
Two Stage ◽  
One Stage ◽  
Normal Plasma ◽  
Calibration Curves ◽  
Factor Viii Concentrates

Six one stage methods and one two stage method were tested for precision and reproducibility. With each method twenty calibration curves of normal plasma and two lots of Factor VIII concentrates were established. Statistical evaluation revealed only minor differences. Neither one of the methods was optimal for both the physiological-pathological region and the region of high activity preparations.Three selected methods were tested in vivo for accuracy: nine patients with hemophilia A were treated with equal amounts of Factor VIII concentrates or kryoprecipitates respectively. The methods showed different activities for preparations as well as for patient’s plasma. The discrepancy between measured and expected recovery differed for each method.

scholarly journals Anti-factor VIII antibodies of hemophiliac patients are frequently directed towards nonfunctional determinants and do not exhibit isotypic restriction

Blood ◽  
1993 ◽  
Vol 82 (8) ◽  
pp. 2452-2461 ◽  
Author(s):  
JG Gilles ◽  
J Arnout ◽  
J Vermylen ◽  
JM Saint-Remy
Keyword(s):  
Antibody Response ◽  
Factor Viii ◽  
Specific Antibody ◽  
Hemophilia A ◽  
Significant Proportion ◽  
Functional Method ◽  
Specific Antibody Response ◽  
Functional Assays ◽  
Epitope Specificity ◽  
Chromogenic Assay

Abstract A significant proportion of hemophilia A patients receiving transfusions of factor VIII (FVIII) develop a specific antibody response towards FVIII. These antibodies are usually detected by assays in which they inhibit the function of the molecule, such as the Bethesda clotting test. We have prepared anti-FVIII antibodies by specific immunoadsorption from the plasma of four hemophiliacs with stable inhibitor levels. The isotypic distribution of such antibodies was determined and their capacity to bind to insolubilized FVIII was compared with their inhibitory activity in two functional assays, namely, the Bethesda assay and a chromogenic assay. In addition, the FVIII epitope specificity was determined by competition with monoclonal antibodies for the binding to insolubilized FVIII. We show here that (1) anti-FVIII antibodies are not isotypically restricted; thus, a significant proportion of specific IgG2 was found; (2) antibodies are frequently directed towards epitopes of FVIII that are not directly involved in the function of the molecule and therefore escape detection in the Bethesda method or chromogenic assay; and (3) each patient shows a unique pattern of FVIII epitope recognition. We conclude that evaluation of anti-FVIII antibodies by a functional method does not provide an accurate evaluation of the specific antibody response. These findings have important implications for the comparison of the immunogenicity of FVIII molecules produced by different technologies and for the development of methods to control anti-FVIII antibody production.

Reduction of the inhibitory antibody response to human factor VIII in hemophilia A mice by mutagenesis of the A2 domain B-cell epitope

Blood ◽  
2004 ◽  
Vol 104 (3) ◽  
pp. 704-710 ◽  
Author(s):  
Ernest T. Parker ◽  
John F. Healey ◽  
Rachel T. Barrow ◽  
Heather N. Craddock ◽  
Pete Lollar
Keyword(s):  
Antibody Response ◽  
Factor Viii ◽  
B Cell ◽  
Human Factor ◽  
Hemophilia A ◽  
Cell Epitope ◽  
Inhibitory Antibody ◽  
B Cell Epitope ◽  
Human Factor Viii ◽  
Inhibitory Antibodies

AbstractApproximately 25% of patients with hemophilia A develop inhibitory antibodies after treatment with factor VIII. Most of the inhibitory activity is directed against epitopes in the A2 and C2 domains. Anti-A2 inhibitory antibodies recognize a 25-residue segment bounded by R484-I508. Several antigenic residues in this segment have been identified, including R484, R489, and P492. The immunogenicity of purified recombinant B domain–deleted (BDD) human factor VIII molecules containing mutations at R484A/R489A or R484A/R489A/P492A was studied in hemophilia A mice. Inhibitory antibody titers in mice receiving the R484A/R489A/P492A mutant, but not the R484A/R489A mutant, were significantly lower than in mice receiving control human BDD factor VIII. The specific coagulant activity and the in vivo clearance and hemostatic efficacy in hemophilia A mice of the R484A/R489A/P492A mutant were indistinguishable from human BDD factor VIII. Thus, the inhibitory antibody response to human factor VIII can be reduced by mutagenesis of a B-cell epitope without apparent loss of function, suggesting that this approach may be useful for developing a safer form of factor VIII in patients with hemophilia A.

Incidence of Factor VIII Inhibitor Development in Hemophilia A Patients Treated with Less Pure Plasma Derived Concentrates

1994 ◽  
Vol 71 (05) ◽  
pp. 544-547 ◽  
Author(s):  
R de Biasi ◽  
A Rocino ◽  
M L Papa ◽  
E Salerno ◽  
L Mastrullo ◽  
...  
Keyword(s):  
Factor Viii ◽  
High Purity ◽  
Hemophilia A ◽  
Cumulative Risk ◽  
Factor Viii Inhibitor ◽  
Anamnestic Response ◽  
Inhibitor Development ◽  
Increased Risk ◽  
Factor Viii Concentrates ◽  
Very High

SummaryVery-high-purity Factor VIII concentrates produced by monoclonal or recombinant technology have been postulated to be more antigenic resulting in an increased risk of inhibitor development in hemophilia A patients. However, previous reports, mainly based on prevalence figures, may have understimated the “true” risk of this complication in patients treated with less pure Factor VIII concentrates. The present study, started in 1975, has been designed to calculate the risk of inhibitor development in patients with severe or moderate hemophilia A, followed since their first exposure to intermediate or high-purity Factor VIII concentrates, produced by conventional technologies. Sixty-four hemophiliacs fulfilled the enrollment criteria. Inhibitors developed in 20.3% (13/64) of all patients and in 23% (11/48) of those with severe Factor VIII deficiency. Eleven patients manifested a strong anamnestic response after exposure to Factor VIII (high responders) and 2 had low inhibitor concenlialions despite repeated Factor Vlll infusions (low responders). The incidence of inhibitor development was 24.6 per 1000 patient yeuis of observalion. The, cumulative! risk of inhibitor formation was 19,9% at age of 6 years, and 20.3% at 5 years after the first exposure. The risk was 19.3% at 70 days of exposure to Factor VIII concentrates, and 17.2% after a total of 50,000 units of Factor VIII given.Further stuides are needed to confirm the above risk of acquiring an inhibitor, which indicates and under-estimations by previous studies. In addition, more data is needed to demonstrate whether very high purity Factor VIII concentrates may be more antigenie than conventional preparations.

scholarly journals The Inhibitor Antibody Response Is More Complex in Hemophilia A Patients Than in Most Nonhemophiliacs With Factor VIII Autoantibodies

Blood ◽  
1997 ◽  
Vol 89 (10) ◽  
pp. 3663-3671 ◽  
Author(s):  
Richard Prescott ◽  
Hiroaki Nakai ◽  
Evgueni L. Saenko ◽  
Inge Scharrer ◽  
Inga Marie Nilsson ◽  
...  
Keyword(s):  
Immune Response ◽  
Antibody Response ◽  
Factor Viii ◽  
Light Chain ◽  
Hemophilia A ◽  
Epitope Specificity ◽  
Extensive Analysis ◽  
Number Of Patients ◽  
Recombinant Fviii ◽  
Inhibitor Titer

Abstract Approximately 25% of hemophilia A patients infused with factor VIII (fVIII) mount an immune response, which leads to its inactivation. Anti-fVIII autoantibodies are also seen rarely in individuals with normal fVIII. We have previously demonstrated that some anti-A2 and anti-C2 domain antibodies are fVIII inhibitors and that many patients have additional inhibitors with a fVIII light chain (LCh) epitope outside C2. Because the contribution of the different antibodies to the plasma inhibitor titer had been examined in a limited number of patients (14), we report in this study a more extensive analysis of 55 plasmas. The dominant inhibitors in 62% (13 of 21) of autoantibody plasmas were directed only against C2 or A2, but not both, whereas this pattern was found in only 15% (5 of 34) of hemophilic plasmas. In addition, anti-A2 inhibitors were present in 71% (24 of 34) of hemophilic plasmas, but only 33% (7 of 21) of autoantibody plasmas. These results demonstrated that the inhibitor response in hemophiliacs was more complex and the epitope specificity was somewhat different. A comparison of hemophiliacs treated only with plasma fVIII or recombinant fVIII showed no significant differences in the complexity of the inhibitor response, as ≥ 2 different inhibitor antibodies were present in 78% (18 of 23) of the former and 82% (9 of 11) of the latter. In contrast, the major inhibitors in 35% (8 of 23) of hemophiliacs treated with plasma fVIII were directed against C2 and another LCh epitope within residues 1649-2137, but not A2, while none (0 of 11) treated with recombinant fVIII had this pattern.

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