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.

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.

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 Incidence of inhibitor development in a group of young hemophilia A patients treated exclusively with lyophilized cryoprecipitate

Blood ◽  
1993 ◽  
Vol 81 (12) ◽  
pp. 3332-3335 ◽  
Author(s):  
K Peerlinck ◽  
FR Rosendaal ◽  
J Vermylen
Keyword(s):  
Factor Viii ◽  
Patient Group ◽  
Hemophilia A ◽  
Cumulative Risk ◽  
Reference Population ◽  
Single Factor ◽  
Inhibitor Development ◽  
Age Dependent ◽  
The One ◽  
Suitable Reference

Abstract The incidence of neutralizing isoantibody formation to infused factor VIII in a cohort of 67 hemophilia A patients, born between January 1, 1971 and April 30, 1990, who had been treated exclusively with lyophilized cryoprecipitate, was 6% (5.3 per 1,000 patient years of observation). The age-dependent cumulative risk was 4.6% at 4 years of age and 6.7% at 8 years of age. Recent reports in patients treated with a variety of more pure concentrates show a much higher incidence of inhibitor formation and tend to be used as a reference when new concentrates are introduced. We believe that a patient group, such as the one studied here, is a more suitable reference population because these patients have been exclusively treated with a single factor VIII preparation.

Source and Purity of Factor VIII Products As Risk Factors for Inhibitor Development In Previously Untreated Patients with Severe Hemophilia A

Blood ◽  
2011 ◽  
Vol 118 (21) ◽  
pp. 25-25
Author(s):  
Maria Elisa Mancuso ◽  
Pier Mannuccio Mannucci ◽  
Angiola Rocino ◽  
Isabella Garagiola ◽  
Annarita Tagliaferri ◽  
...  
Keyword(s):  
Risk Factors ◽  
Factor Viii ◽  
High Purity ◽  
Hemophilia A ◽  
Conflicts Of Interest ◽  
Specific Activity ◽  
Sensitivity Analyses ◽  
Severe Hemophilia ◽  
Inhibitor Development ◽  
Treatment Data

Abstract Abstract 25 Background: Inhibitor development is influenced by several genetic and environmental factors and the type of factor VIII (FVIII) products may play a role. Methods: We designed a cohort study whose novelty resides in the classification of products not only according to the plasmatic (pdFVIII) or recombinant (rFVIII) source of FVIII but also to the degree of purity expressed as FVIII specific activity per mg of protein. The role of FVIII product as risk factor for inhibitor development was evaluated in a multivariate model adjusting for potential confounders (i.e. age at first FVIII exposure, intensive treatment and prophylaxis). Cumulative incidences of all and high-responding inhibitors were calculated for the whole cohort of 721 patients with severe and moderate hemophilia A followed-up in 3 Italian Hemophilia Centers. Detailed treatment data from the first FVIII infusion up to inhibitor development or 150 exposure days were available for 377 patients and in this group of patients risk factors for inhibitor development including the type of FVIII product and its degree of purity (i.e. low/intermediate-, high-purity pdFVIII and rFVIII) were analysed. Results: The overall cumulative incidence of inhibitors was 22% (n=160; 130 high-responders, 18%) and it was lower in patients first treated with pdFVIII (107/586, 18%) than in those treated with rFVIII (53/135, 39%). Similar results were obtained by evaluating only high-responding inhibitors and patients with severe hemophilia. The adjusted hazard ratio of inhibitor development was 4.9 with rFVIII and 2.0 with high-purity pdFVIII (95%CI: 2.9–8.3 and 1.1–4.0), taking as reference low/intermediate-purity pdFVIII. There was no difference in the frequency of inhibitor testing between treatment groups. Sensitivity analyses - in patients who never switched product type, previously untreated patients, those treated on-demand and those with high-risk F8 mutations - confirmed an increased inhibitor risk in patients first treated with rFVIII or high-purity pdFVIII than in those treated with low/intermediate-purity pdFVIII. In fact, in all the aforementioned subgroups by multivariate analysis the risk of inhibitor development was invariably 3- to 6-fold higher in patients first treated with rFVIII than in those first treated with pdFVIII, and similar results were obtained for both all inhibitors and high-responding inhibitors. Conclusions: This study shows that the degree of purity of FVIII products influences inhibitor development independently from other risk factors, and emphasizes that differences exist also within pdFVIII products. Disclosures: No relevant conflicts of interest to declare.

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.

scholarly journals Incidence of inhibitor development in a group of young hemophilia A patients treated exclusively with lyophilized cryoprecipitate

Blood ◽  
1993 ◽  
Vol 81 (12) ◽  
pp. 3332-3335
Author(s):  
K Peerlinck ◽  
FR Rosendaal ◽  
J Vermylen
Keyword(s):  
Factor Viii ◽  
Patient Group ◽  
Hemophilia A ◽  
Cumulative Risk ◽  
Reference Population ◽  
Single Factor ◽  
Inhibitor Development ◽  
Age Dependent ◽  
The One ◽  
Suitable Reference

The incidence of neutralizing isoantibody formation to infused factor VIII in a cohort of 67 hemophilia A patients, born between January 1, 1971 and April 30, 1990, who had been treated exclusively with lyophilized cryoprecipitate, was 6% (5.3 per 1,000 patient years of observation). The age-dependent cumulative risk was 4.6% at 4 years of age and 6.7% at 8 years of age. Recent reports in patients treated with a variety of more pure concentrates show a much higher incidence of inhibitor formation and tend to be used as a reference when new concentrates are introduced. We believe that a patient group, such as the one studied here, is a more suitable reference population because these patients have been exclusively treated with a single factor VIII preparation.

Inhibitors in mild/moderate haemophilia A: An update

2006 ◽  
Vol 96 (08) ◽  
pp. 113-118 ◽  
Author(s):  
Gian Salvagno ◽  
Giuseppe Lippi ◽  
Massimo Franchini
Keyword(s):  
Factor Viii ◽  
Hemophilia A ◽  
Tolerance Induction ◽  
Factor Vii ◽  
Factor Viii Inhibitor ◽  
Increased Risk ◽  
Bypassing Agents ◽  
The Many ◽  
Activated Prothrombin Complex Concentrates ◽  
Optimal Approach

SummaryThe development of inhibitors in patients with mild/moderate hemophilia A is an increasingly recognized occurrence and is manifested by the patients’ bleeding pattern becoming more severe. Inherited (hemophilia genetic mutations) and acquired (type and delivery of factor VIII replacement therapy) factors have been associated with an increased likelihood of developing factor VIII inhibitors. Although the use of bypassing agents (i.e. activated prothrombin complex concentrates and recombinant factor VII activated) has been demonstrated to be effective in controlling bleeding episodes in patients who develop factor VIII inhibitors, the limited data available in the literature are insufficient to determine the optimal approach to the eradication of inhibitors (i.e. immune tolerance induction, immunosuppression or both) for this group. Particular attention should be directed to the prevention of this complication in those patients with mild/moderate hemophilia recognized to be at increased risk of developing a factor VIII inhibitor. In conclusion, large prospective trials are warranted in order to elucidate the many still unclear pathogenic and therapeutic aspects of the development of inhibitors in patients with mild/moderate hemophilia A.

Mild / Moderate Hemophilia A with Factor VIII Inhibitors (MHAI): Results of a French and Belgian Survey.

Blood ◽  
2004 ◽  
Vol 104 (11) ◽  
pp. 3088-3088
Author(s):  
Roseline d’Oiron ◽  
Jean Maurice Lavergne ◽  
Jenny Goudemand ◽  
Annie Borel-Derlon ◽  
Claude Guerois ◽  
...  
Keyword(s):  
Factor Viii ◽  
Immune Tolerance ◽  
Baseline Level ◽  
Hemophilia A ◽  
Immunosuppressive Agents ◽  
Specific Treatment ◽  
Cumulative Exposure ◽  
Anamnestic Response ◽  
Inhibitor Development ◽  
History Of

Abstract The development of anti-factor VIII inhibitors in mild/moderate hemophilia A (MHA) patients was described as an uncommon event. The largest cohort reported so far included 26 MHAI patients (Hay et al, 1998) and with other anecdotic reports underlined a special pattern of the bleeding reminiscent of acquired hemophilia, a generally poor response to immune tolerance protocol compared to severe patients, and potential factors contributing to a high-risk of inhibitor development such as the FVIII genotype, family related factors and intense substitutive therapy. The optimal therapeutic strategy in MAHI remains unknown. A retrospective data collection was therefore conducted. To date 45 MHAI patients from 29 french and belgian centers were included, with a median FVIII:C baseline level of 0.08 IU/ml (1–28). More than a half of the cases were detected within the last 4 years (y) for a total study period of 20 y. The median age for MHA diagnosis, first FVIII treatment and inhibitor disclosure was respectively 5-y (0 to 73-y),10.5-y (0 to 73-y) and 22.5-y (1 month to 81-y). One splice and 22 different missense mutations were identified for 34 patients (8 already described including 5 with inhibitor, and 15 new). Before the inhibitor appearance, patients received plasma derived (13) or recombinant (12) products only, or both (20). The median number of cumulative exposure days before inhibitor diagnosis was 29 (3–150). History of intense substitutive therapy (≥4 consecutive days or prophylactic treatment every other day for ≥8 days) was observed in 35 (77%) patients, and history of intracranial bleeding in 6/45 (13%). The median maximum historical titer was 6.6 UB (0.5 – 288). In 19 out of 45 (42%) patients FVIII:C baseline level was less than 0.01 IU/ml, while decreased but still detectable (0.01 IU/ml or higher) in 16 (35%), stable in 4 (9%), and unknown in the 6 others. No specific treatment to eradicate the inhibitor was used in 24 patients, while 19 received either an immune tolerance protocol (14 patients, including 6 with combined immunosuppressive drugs), either immunosuppressive agents alone (5 patients); specific treatment was unknown in 2. Apart 2 deaths unrelated to MHA and 3 unknown outcomes, the inhibitor disappeared for 30 patients with a median of 8 months, persisted as a plateau in 2, and was still decreasing in 7 after a median follow-up of 5 months. Anamnestic response defined as an increase of at least 30 % of the inhibitor titer after FVIII or aPCC concentrates was observed in 17 out of the 29 (65%) patients that were rechallenged, but none after recombinant factor VIIa (Novoseven®) or DDAVP. When an anamnestic response occured the median delay for inhibitor eradication increased from 3 to 11 months. This survey underlines: i) that MAHI is not rare, but likely better recognized nowadays, ii) the need for systematic inhibitor assessment after substitutive therapy in MHA, iii) the role of FVIII genotype, intense treatment and possibly inracranial bleeds as contributing factors for inhibitor development, iv) how treatment of bleeds in MHA have to be carefully discussed to limit the risk of respectively appearance or anamnestic response in patients without or with inhibitors.

scholarly journals Clinicopathological parameters influencing inhibitor development in patients with hemophilia A receiving on-demand therapy

2018 ◽  
Vol 9 (8) ◽  
pp. 213-226 ◽  
Author(s):  
Sanya Arshad ◽  
Anshima Singh ◽  
Namrata Punit Awasthi ◽  
Swati Kumari ◽  
Nuzhat Husain
Keyword(s):  
Factor Viii ◽  
Hemophilia A ◽  
Age At Onset ◽  
North India ◽  
Clinicopathological Parameters ◽  
Factor Viii Inhibitor ◽  
Inhibitor Development ◽  
On Demand ◽  
Group B ◽  
Subtype A

Background: Development of inhibitors to transfused factor VIII in patients with hemophilia A continues to be a challenge for professionals involved in hemophilia care. The majority of patients in India receive ‘on-demand’ rather than prophylactic therapy. The present study was done to assess the prevalence of factor VIII inhibitors in patients with hemophilia A (PWHA) receiving ‘on-demand’ therapy in a North Indian population and to study the clinicopathological parameters influencing the development of inhibitors. Methods: The study group comprised of 300 PWHA. Detailed clinical parameters, treatment history, bleeding profile including family history were recorded. Diagnosis of hemophilia A was confirmed by relevant coagulation tests. Inhibitors were screened using mixing based studies followed by quantification by Bethesda assay and Nijmegen modified Bethesda assay. Samples were collected from five cities in North India where a free supply of factor VIII was available and effectively used in three of these cities. Results: In the 300 PWHA, disease phenotype was severe in 219 (73%), moderate in 62 (20.67%) and mild in 19 (6.34%), based on the factor VIII bioassay. Inhibitor prevalence was 9.6% ( n = 29) and seen only in the severe phenotype. Inhibitor titers ranged from 0.8 to 108.8 BU/ml. A total of 12 PWHA had low and 17 had high titers. Correlation of various clinicopathological parameters in inhibitor-positive versus negative PWHA showed significant correlation with age at onset of disease, severity of disease, age at first exposure to treatment, annual factor intake (IU/kg/year), intense treatment episodes and bleeding manifestations like central nervous system bleed and hematuria. The total study sample had blood group B in 33.34% PWHA, followed by O (27.34%), A (24.34%) and AB (15%), however, in inhibitor-positive samples, significant inhibitor formation was associated with the ABO subtype A (19/29, 65.51%). Conclusions: Factor VIII inhibitor prevalence in PWHA receiving ‘on-demand’ therapy was 9.6%. Clinicopathological correlates of inhibitor development in such PWHA have been analyzed in this novel study.

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