scholarly journals Factor VIII inhibitor development in Egyptian hemophilia patients: does intron 22 inversion mutation play a role?

2020 ◽  
Vol 46 (1) ◽  
Author(s):  
Laila M. Sherief ◽  
Osama A. Gaber ◽  
Hala Mosaad Youssef ◽  
Hanan S. Sherbiny ◽  
Wesam a Mokhtar ◽  
...  
Keyword(s):  
Factor Viii ◽  
Hemophilia A ◽  
Factor Viii Inhibitor ◽  
Inhibitor Development ◽  
Fviii Inhibitor ◽  
Intron 22 Inversion ◽  
Egyptian Patients ◽  
Factor Viii Concentrates ◽  
Viii Inhibitor ◽  
Almost All

Abstract Background Hemophilia A (HA) is an X-linked recessive bleeding disorder characterized by qualitative and quantitative deficiency of factor VIII (FVIII). The development of inhibitor antibodies against FVIII is the most challenging complication of treatment. Mutations in the FVIII gene is one of the genetic factors that leads to development of FVIII inhibitors especially intron 22 inversion (Inv22). Objectives This study was carried out to assess the frequency of Inv22 of FVIII gene in Egyptian patients with hemophilia A and its role as a risk factor for developing inhibitors. Patients and methods Seventy-two patients with severe HA and 48 patients with moderate HA were enrolled in the current study. All patients were treated on demand with either plasma-derived factor VIII or recombinant factor VIII concentrates. Genotyping of FVIII Inv22 was performed by LD-PCR while the presence and magnitude of inhibitor activity in blood was determined by the Bethesda assay. Results Around 23% of all hemophilia cases had positive Inv22. Intron 22 inversion mutation was detected in 6 and 33% of patients with moderate and severe HA respectively. Twenty-one cases (18%) of all hemophilic patients developed inhibitors. Thirty-7% of patients with Inv22 had inhibitor in their blood, almost all, but one, had severe HA. The risk of an inhibitor development during replacement therapy was four folds higher among Inv22 positive cases as compared with mutation negative peers (OR 4.3, 95% CI 1.6–11.9, P = 0.003). Conclusions The prevalence of Inv22 of F VIII in Egyptian hemophiliacs is nearly like that of other population. This mutation was more frequently detected among severe hemophilic patients as compared with moderately affected peers. The presence of Inv22 mutation significantly predispose to FVIII inhibitor development.

scholarly journals Marginal zone B cells are critical to factor VIII inhibitor formation in mice with hemophilia A

Blood ◽  
2017 ◽  
Vol 130 (23) ◽  
pp. 2559-2568 ◽  
Author(s):  
Patricia E. Zerra ◽  
Courtney Cox ◽  
W. Hunter Baldwin ◽  
Seema R. Patel ◽  
Connie M. Arthur ◽  
...  
Keyword(s):  
B Cells ◽  
Factor Viii ◽  
Marginal Zone ◽  
Hemophilia A ◽  
Factor Viii Inhibitor ◽  
Marginal Zone B Cells ◽  
Inhibitor Development ◽  
Fviii Inhibitor ◽  
Key Points ◽  
Viii Inhibitor

Key Points FVIII colocalizes with MZ B cells following infusion into hemophilia A mice. Depletion of MZ B cells prevents FVIII inhibitor development in hemophilia A mice.

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.

Non-Classical Anti-Factor VIII C2 Domain Inhibitors Are Present in the Plasmas of Most Factor VIII Inhibitor Patients.

Blood ◽  
2007 ◽  
Vol 110 (11) ◽  
pp. 786-786
Author(s):  
Shannon L. Meeks ◽  
John F. Healey ◽  
Rachel T. Barrow ◽  
Ernest T. Parker ◽  
Pete Lollar
Keyword(s):  
Factor Viii ◽  
Hemophilia A ◽  
Factor Viii Inhibitor ◽  
C2 Domain ◽  
Proteolytic Activation ◽  
Autoimmune Antibodies ◽  
Fviii Inhibitor ◽  
Fviii Activity ◽  
Viii Inhibitor ◽  
Murine Mabs

Abstract Approximately 30% of patients with severe hemophilia A will develop inhibitory antibodies to factor VIII (fVIII inhibitors). The immune response to fVIII currently is the most significant complication in the management of patients with hemophilia A. In addition, autoimmune antibodies to fVIII can develop in non-hemophiliacs, producing acquired hemophilia A, which frequently produces life- or limb-threatening bleeding. These inhibitors primarily are directed against the A2 or C2 domains of fVIII. The human response to the C2 domain of fVIII classically has been thought to inhibit fVIII activity by blocking its binding to phospholipid. We recently characterized the antibody response to the C2 domain of human fVIII in a murine hemophilia model and described 5 structural groups of antibodies. Groups A, AB, and B are classical anti-C2 antibodies. Groups BC and C consist of non-classical anti-C2 antibodies that inhibit the proteolytic activation of fVIII but do not block the binding of fVIII to phospholipid. Most non-classical antibodies have inhibitor titers greater than 10,000 Bethesda units/mg IgG. To determine if non-classical antibodies are present in fVIII inhibitor patients, patient plasmas were tested in an ELISA for their ability to block the binding of representative antibodies from the different anti-human fVIII C2 antibody groups. Classical and non-classical monoclonal antibodies (MAbs) were biotinylated and serially diluted into either fVIII deficient plasma or patient inhibitor plasma and then added to microtiter wells coated with fVIII. The ability of patient plasma to block the binding of the murine MAbs to fVIII was determined. A total of 16 patient plasmas were assessed: 4 from patients with a C2 predominant response, 2 with a non-C2 predominant response, and 10 with unknown specificities. Three of the 4 patients with C2 predominant responses had non-classical anti-C2 antibodies, while the 2 with non-C2 predominant responses did not. In the unknown plasmas, 6 of 10 had evidence of non-classical antibodies. Figure 1 shows representative results of the effect of 3 patient plasmas on the binding of a biotinylated non-classical MAb to fVIII. Patient plasmas 1 and 2 blocked MAb binding while patient plasma 3 did not. This study indicates that the majority of patients with fVIII inhibitors have non-classical anti-C2 antibodies in their response to fVIII. Figure Figure

Anti-CD3 prevents factor VIII inhibitor development in hemophilia A mice by a regulatory CD4+CD25+-dependent mechanism and by shifting cytokine production to favor a Th1 response

Blood ◽  
2009 ◽  
Vol 113 (1) ◽  
pp. 193-203 ◽  
Author(s):  
Braden Waters ◽  
Mohammad Qadura ◽  
Erin Burnett ◽  
Rouzbeh Chegeni ◽  
Andrea Labelle ◽  
...  
Keyword(s):  
Factor Viii ◽  
Cytokine Production ◽  
Hemophilia A ◽  
Phenotypic Characterization ◽  
Factor Viii Inhibitor ◽  
Related Complication ◽  
Fviii Inhibitor ◽  
Short Course ◽  
Viii Inhibitor

Abstract Non–Fc-receptor binding anti-CD3 Ab therapy, in the setting of several different autoimmune disorders, can induce antigen-specific and long-lasting immunologic tolerance. Because factor VIII (FVIII) inhibitor formation is the most serious treatment-related complication for hemophilia A patients, we tested the efficacy of anti-CD3 to prevent FVIII inhibitor formation in hemophilia A BALB/c and C57BL/6 mice. A short course of low-dose anti-CD3 significantly increased expression of CD25 and the proportion of CD4+CD25+ regulatory T cells in the spleen and potently prevented the production of inhibitory and non-neutralizing anti-FVIII antibodies in both strains of mouse. Depleting the CD4+CD25+ cells during anti-CD3 therapy completely ablated tolerance to FVIII. Further phenotypic characterization of regulatory cells in tolerant mice showed a consistently higher number of CD4+GITR+ and CD4+FoxP3+ cells in both strains of mice. In addition, in tolerant C57BL/6 mice we observed an increase in CD4+CD25+CTLA-4+ and CD4+CD25+mTGF-β1+ cells. Finally, in vitro cytokine profiling demonstrated that splenocytes from tolerant BALB/c and C57BL/6 were polarized toward a Th1-immune response. Taken together, these findings indicate that anti-CD3 induces tolerance to FVIII and that the mechanism(s) regulating this response almost certainly occurs through the generation of several distinct regulatory T-cell lineages and by influencing cytokine production and profile.

Photometric Assay of Factor VIIIC With a Chromogenic Substrate

1979 ◽  
Author(s):  
H. Vinazzer
Keyword(s):  
Factor Viii ◽  
Serine Proteases ◽  
Hemophilia A ◽  
Factor Xa ◽  
Factor Viii Inhibitor ◽  
Chromogenic Substrate ◽  
Normal Individuals ◽  
Factor Viii Concentrates ◽  
Viii Inhibitor ◽  
The Difference

By the aid of chromogenic substrates, highly specific assays of some serine proteases can be carried out. The substrate used for factor VIIIC-assays was Bz-Ile-Glu-Gly-Arg-pNA [S-2222 KABI) which measures factor Xa. When all components necessary for factor Xa activation except factor VIIIC are kept at constant levels, the resulting Xa-activity is in direct relation to the concentration of factor VIIIC. The substrate plasma was a mixture of hemophilia A plasma with factor VIII inhibitor plasma with a remaining inhibitor activity of between 0.1 and 0.5 units per ml. This substrate was defibrinated by ancrod. For assays of factor VIIIC, this plasma was mixed with the diluted test plasma, cepheloplastin, and calcium chloride at 37°C After a constant activation time, the chromogenic substrate was added and the difference in OD/min was measured at 405 nm. The calibration curve was linear between 1% and over 200% factor VIIIC activity, and the average CV was 7.9%. This method was compared to a standard one-stage method for factor VIIIC. Identical results were obtained in plasma samples of normal individuals, in samples of high factor VIIIC, activity, in plasma from hemophilia A patients, and in factor VIII concentrates. The advantages of this method over the clotting method are: independence of the results from variations of factors V,II, and I in the reaction mixture, stability of the reagents, a better discrimination of factor VIIIC levels in the range between 30% and over 100%, and the possibility of automatization of the method.

scholarly journals Risk stratification integrating genetic data for factor VIII inhibitor development in patients with severe hemophilia A

PLoS ONE ◽  
2019 ◽  
Vol 14 (6) ◽  
pp. e0218258
Author(s):  
Delphine Bachelet ◽  
Thilo Albert ◽  
Cyprien Mbogning ◽  
Signe Hässler ◽  
Yuan Zhang ◽  
...  
Keyword(s):  
Risk Stratification ◽  
Factor Viii ◽  
Hemophilia A ◽  
Genetic Data ◽  
Factor Viii Inhibitor ◽  
Severe Hemophilia ◽  
Inhibitor Development ◽  
Viii Inhibitor

Incidence of Factor VIII Inhibitor Development in Severe Hemophilia A Patients Treated only with One Brand of Highly Purified Plasma-Derived Concentrate

1995 ◽  
Vol 73 (02) ◽  
pp. 215-218 ◽  
Author(s):  
Claude Guérois ◽  
Yves Laurian ◽  
Chantal Rothschild ◽  
Armelle Parquet-Gernez ◽  
Anne-Marie Duclos ◽  
...  
Keyword(s):  
Factor Viii ◽  
High Purity ◽  
Hemophilia A ◽  
Cumulative Exposure ◽  
Factor Viii Inhibitor ◽  
Severe Hemophilia ◽  
Viral Inactivation ◽  
Inhibitor Development ◽  
Viii Inhibitor ◽  
Low Incidence

SummaryThe incidence of factor VIII inhibitor was studied in a cohort of 56 previously untreated patients with severe hemophilia A (factor VIII below 1 U/dl). They received only one brand of highly purified factor VIII concentrate (HPSD-VIII) prepared by conventional chromatography with a solvent-detergent step for viral inactivation. Followup since the first infusion of HPSD-VIII was from 1 to 76 months (mean = 29) and cumulative exposure days (CED) from 1 to over 100 (median = 26). Five patients (9%) developed an inhibitor after 6 to 19 CED, only one being a high responder (2%), showing a low incidence of inhibitor compared with previous studies using high purity plasma- derived or recombinant products.

A Higher than Expected Incidence of Factor VIII Inhibitors in Multitransfused Haemophilia A Patients Treated with an Intermediate Purity Pasteurized Factor VIII Concentrate

1993 ◽  
Vol 69 (02) ◽  
pp. 115-118 ◽  
Author(s):  
Kathelijne Peerlinck ◽  
Jef Arnout ◽  
Jean Guy Gilles ◽  
Jean-Marie Saint-Remy ◽  
Jos Vermylen
Keyword(s):  
Factor Viii ◽  
Randomized Trials ◽  
Specific Factor ◽  
Factor Viii Inhibitor ◽  
Haemophilia A ◽  
Viral Inactivation ◽  
Gradual Decline ◽  
Inhibitor Level ◽  
Factor Viii Concentrates ◽  
Viii Inhibitor

SummaryIn May 1990, 218 patients with haemophilia A regularly attending the Leuven Haemophilia Center were randomly assigned to a group receiving either of two newly introduced factor VIII concentrates: factor VIII-P, an intermediate purity pasteurized concentrate, or factor VIII-SD, a high purity concentrate treated with solvent-detergent for viral inactivation.Patients were followed from May 1990 until October 1991. Between August 1991 and October 1991 a clinically important factor VIII inhibitor was detected in five out of the 109 patients receiving factor VIII-P while none of the 109 patients receiving factor VIII-SD developed such antibodies. All patients acquiring an inhibitor had previously been clinically tolerant to transfused factor VIII with 200 to more than 1,000 days of exposure to factor VIII prior to May 1990. Patients with inhibitors were transfused daily with 30 U factor VIII-SD per kg body weight, which was associated with a gradual decline of the inhibitor level. In all patients the antibodies were relatively slow-acting and predominantly directed towards the light chain of factor VIII.This study demonstrates a higher than expected incidence of factor VIII inhibitors associated with the use of a specific factor VIII concentrate in multitransfused haemophilia A patients. It indicates the usefulness of evaluating newly introduced concentrates in prospective, randomized trials.

scholarly journals A Clinical and Experimental Study of Acquired Inhibitors to Factor VIII

Blood ◽  
1965 ◽  
Vol 26 (6) ◽  
pp. 805-818 ◽  
Author(s):  
HAROLD R. ROBERTS ◽  
MARGARET B. SCALES ◽  
JOHN T. MADISON ◽  
WILLIAM P. WEBSTER ◽  
GEORGE D. PENICK
Keyword(s):  
Experimental Study ◽  
Factor Viii ◽  
Mode Of Action ◽  
Exchange Transfusion ◽  
Hemophilia A ◽  
Retroperitoneal Hematoma ◽  
Factor Viii Inhibitor ◽  
Viii Inhibitor ◽  
Potent Factor

Abstract Factor VIII inhibitors which developed in four patients with hemophilia A are described. These inhibitors are apparently specific for Factor VIII and are capable of inducing a transient hemophilic state when injected into dogs. The genesis, properties, and mode of action of these inhibitors can be explained on an immunologic basis and it seems most likely that they represent an antibody to Factor VIII. One hemophilia A patient, with retroperitoneal hematoma and a potent Factor VIII inhibitor, was successfully treated by an exchange transfusion followed by administration of purified porcine Factor VIII.

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