The rare coexistence of high titer inhibitor development and gastrointestinal stromal tumor in a patient with severe hemophilia: A case report

2018 ◽  
Vol 57 (3) ◽  
pp. 398-400
Author(s):  
Abdulkerim Yıldız ◽  
Osman Şahin ◽  
Okan Yayar ◽  
Çiğdem Pala Öztürk ◽  
Hacer Berna Afacan Öztürk ◽  
...  
Keyword(s):  
Case Report ◽  
Gastrointestinal Stromal Tumor ◽  
Hemophilia A ◽  
High Titer ◽  
Stromal Tumor ◽  
Severe Hemophilia ◽  
Inhibitor Development

scholarly journals F8 gene mutation type and inhibitor development in patients with severe hemophilia A: systematic review and meta-analysis

Blood ◽  
2012 ◽  
Vol 119 (12) ◽  
pp. 2922-2934 ◽  
Author(s):  
Samantha C. Gouw ◽  
H. Marijke van den Berg ◽  
Johannes Oldenburg ◽  
Jan Astermark ◽  
Philip G. de Groot ◽  
...  
Keyword(s):  
Systematic Review ◽  
Gene Mutation ◽  
Hemophilia A ◽  
High Titer ◽  
Meta Analysis ◽  
Gene Mutations ◽  
Secondary Outcome ◽  
Missense Mutations ◽  
Severe Hemophilia ◽  
Inhibitor Development

Abstract This systematic review was designed to provide more precise effect estimates of inhibitor development for the various types of F8 gene mutations in patients with severe hemophilia A. The primary outcome was inhibitor development and the secondary outcome was high-titer-inhibitor development. A systematic literature search was performed to include cohort studies published in peer-reviewed journals with data on inhibitor incidences in the various F8 gene mutation types and a mutation detection rate of at least 80%. Pooled odds ratios (ORs) of inhibitor development for different types of F8 gene mutations were calculated with intron 22 inversion as the reference. Data were included from 30 studies on 5383 patients, including 1029 inhibitor patients. The inhibitor risk in large deletions and nonsense mutations was higher than in intron 22 inversions (pooled OR = 3.6, 95% confidence interval [95% CI], 2.3-5.7 and OR = 1.4, 95% CI, 1.1-1.8, respectively), the risk in intron 1 inversions and splice-site mutations was equal (pooled OR = 0.9; 95% CI, 0.6-1.5 and OR = 1.0; 95% CI, 0.6-1.5), and the risk in small deletions/insertions and missense mutations was lower (pooled OR = 0.5; 95% CI, 0.4-0.6 and OR = 0.3; 95% CI, 0.2-0.4, respectively). The relative risks for developing high titer inhibitors were similar.

Recombinant versus plasma-derived factor VIII products and the development of inhibitors in previously untreated patients with severe hemophilia A: the CANAL cohort study

Blood ◽  
2007 ◽  
Vol 109 (11) ◽  
pp. 4693-4697 ◽  
Author(s):  
Samantha C. Gouw ◽  
Johanna G. van der Bom ◽  
Günter Auerswald ◽  
Carmen Escuriola Ettinghausen ◽  
Ulf Tedgård ◽  
...  
Keyword(s):  
Cohort Study ◽  
Factor Viii ◽  
Hemophilia A ◽  
High Titer ◽  
Recombinant Factor Viii ◽  
Severe Hemophilia ◽  
Inhibitor Development ◽  
Von Willebrand ◽  
Relationship Of ◽  
Viii Product

Abstract It has been suggested that plasma-derived factor VIII products induce fewer inhibitors than recombinant factor VIII products. We investigated the relationship of factor VIII product type and switching between factor VIII products with the risk to develop inhibitors. This multicenter retrospective cohort study included 316 patients with severe hemophilia A born between 1990 and 2000. The outcome was clinically relevant inhibitor development, defined as the occurrence of at least 2 positive inhibitor titers with decreased recovery. The risk of inhibitor development was not clearly lower in plasma-derived compared with recombinant factor VIII products (relative risk [RR], 0.8; 95% confidence interval [CI], 0.5-1.3). Among high-titer inhibitors, the possible reduction in risk was even less pronounced (RR, 0.9; CI, 0.5-1.5). Plasma-derived products with considerable quantities of von Willebrand factor (VWF) carried the same risk for inhibitor development as recombinant factor VIII products (RR, 1.0; CI, 0.6-1.6). Switching between factor VIII products did not increase the risk for inhibitors (RR, 1.1; CI, 0.6-1.8). In conclusion, our findings support neither the notion that plasma-derived factor VIII products with considerable concentrations of VWF confer a lower risk to develop inhibitory antibodies than recombinant factor VIII products, nor that switching between factor VIII product brands increases inhibitor risks in previously untreated patients with severe hemophilia A.

French Previously Untreated Patients with Severe Hemophilia A after Exposure to Recombinant Factor VIII : Incidence of Inhibitor and Evaluation of Immune Tolerance

1998 ◽  
Vol 80 (11) ◽  
pp. 779-783 ◽  
Author(s):  
Y. Laurian ◽  
E. P. Satre ◽  
A. Borel Derlon ◽  
H. Chambost ◽  
P. Moreau ◽  
...  
Keyword(s):  
Factor Viii ◽  
Immune Tolerance ◽  
Hemophilia A ◽  
High Titer ◽  
Recombinant Factor Viii ◽  
High Dose ◽  
Severe Hemophilia ◽  
Inhibitor Development ◽  
Intron 22 Inversion ◽  
Median Period

SummaryFifty French previously untreated patients with severe hemophilia A (factor VIII <1%), treated with only one brand of recombinant factor VIII (rFVIII), were evaluated for inhibitor development, assessment of risk factors and outcome of immune tolerance regimen. The median period on study was 32 months (range 9-74) since the first injection of rFVIII. Fourteen patients (28%) developed an inhibitor, four of whom (8%) with a high titer (≥10 BU). All inhibitor patients but one continued to receive rFVIII either for on-demand treatment or for immune tolerance regimen (ITR). Among these patients, inhibitor was transient in 2 (4%), became undetectable in 6 and was still present in 6. The prevalence of inhibitor was 12%. Presence of intron 22 inversion was found to be a risk factor for inhibitor development. Immune tolerance was difficult to achieve in our series despite a follow-up period of 16 to 30 months: immune tolerance was complete in only one out of the 3 patients undergoing low dose ITR and in one out of the 5 patients with high dose ITR.

scholarly journals Serum TNF-α Level as a Possible Predictor of Inhibitor Levels in Severe Hemophilia A

2021 ◽  
Vol 2021 ◽  
pp. 1-10
Author(s):  
Susi Susanah ◽  
Harry Raspati ◽  
Nur Melani Sari ◽  
Lulu Eva Rakhmilla ◽  
Yunia Sribudiani ◽  
...  
Keyword(s):  
Replacement Therapy ◽  
Hemophilia A ◽  
High Titer ◽  
Severe Hemophilia ◽  
West Java ◽  
Cross Sectional ◽  
Inhibitor Development ◽  
Fviii Inhibitor ◽  
Tnf Α ◽  
Α Level

Background. The development of factor VIII (FVIII) inhibitor in patients with hemophilia A (PWHA) is a great challenge for hemophilia care. Both genetic and environmental factors led to complications in PWHA. The development of inhibitory antibodies is usually induced by the immune response. Tumor necrosis factor α (TNF-α), one of the cytokines, might contribute to its polymorphism. In this study, we investigated the clinical factors, level of serum TNF-α, and polymorphism of c . − 308 G > A   TNF − α gene in inhibitor development in severe PWHA. Methods. A cross-sectional study was conducted among all PWHA in West Java province. The clinical parameters, FVIII, FVIII inhibitor, and serum TNF-α level were assessed. The genotyping of − 380 G > A TNF-α gene polymorphism was performed using polymerase chain reaction and Sanger sequencing. Results. Among the 258 PWHA, 216 (83.7%) were identified as severe PWHA. The FVIII inhibitor was identified in 90/216 (41.6%) of severe PWHA, consisting of 45 high-titer inhibitors (HTI) and 45 low-titer inhibitors (LTI). There was a significant correlation between serum TNF-α level and the development of HTI ( p = 0.043 ). The cutoff point of serum TNF-α level, which can be used to differentiate between HTI and LTI, was 11.45 pg/mL. The frequency of FVIII replacement therapy was significant only in HTI of severe PWHA regarding serum TNF-α level ( p = 0.028 ). There is no correlation between polymorphisms of − 380 G > A TNF-α gene and inhibitor development ( p = 0.645 ). Conclusions. The prevalence of FVIII inhibitor in severe PWHA in West Java, Indonesia, was 41.6%. The frequency of replacement therapy is a risk factor for inhibitor development. Serum TNF-α level might be used to differentiate between high and low inhibitor levels in severe hemophilia A, and this might support decision making regarding treatment options for inhibitor in severe hemophilia A.

scholarly journals Incidence of Inhibitors in a Previously Untreated Patients with Severe Hemophilia Α Cohort Treated with a Single Third-Generation Recombinant Factor VIII Concentrate

Blood ◽  
2018 ◽  
Vol 132 (Supplement 1) ◽  
pp. 1211-1211
Author(s):  
Alessandra N L Prezotti ◽  
Monica H Cerqueira ◽  
Marilia Renni ◽  
Clarissa Ferreira ◽  
Ieda S. Pinto ◽  
...  
Keyword(s):  
Board Of Directors ◽  
Research Funding ◽  
Hemophilia A ◽  
High Titer ◽  
Severe Bleeding ◽  
Third Generation ◽  
Severe Hemophilia ◽  
Advisory Committees ◽  
Inhibitor Development ◽  
African Descendants

Abstract Introduction: One of the most important complications in the treatment of patients with hemophilia A is the formation of neutralizing antibodies (inhibitors) interfering in the coagulant activity of factor VIII (FVIII). The presence of inhibitor causes a direct impact on mortality and morbidity in these patients and considerably increases the cost of treatment. Among the non-genetic risk factors for inhibitor development, the influence of the type of factor concentrate used in replacement therapy (recombinant or plasma-derived) remains controversial. Thus, the evaluation of an additional population in the real world setting may contribute to elucidate this problem. Since August 2013, almost all previously untreated patients (PUPs) with hemophilia A in Brazil have been receiving exclusively the same third-generation recombinant FVIII (rFVIII) (Advate®, Shire). Objective: The aim of this study is to evaluate the immunogenicity of rFVIII (Advate®). In this context, we analyzed the occurrence of inhibitor among severe and moderately severe hemophilia A PUPs during the first 50 exposure days (EDs) to Advate®. Methods: This is an open-label, multicenter, prospective/retrospective, uncontrolled, observational study conducted in eight reference hemophilia treatment centers from distinct geographic areas in Brazil. The inclusion criteria were (a) diagnosis of severe or moderately severe hemophilia A (FVIII:C <2 IU/dL), (b) absence of previous exposure to other FVIII concentrates, except a maximum of 5 previous exposures to any blood components (whole blood, fresh-frozen plasma, packed red cells, platelets, or cryoprecipitate), and (c) exclusive treatment with Advate® until the 50th ED or until inhibitor development (primary endpoint). Positive inhibitor was defined as at least two consecutive plasma samples with Bethesda-Nijmegen assay results ≥0.60 BU/mL. Patients were considered as having low-titer inhibitors when peak titers were <5 BU/mL, and high-titer inhibitors if inhibitor titer was ≥5 BU/mL on at least one occasion. Any clinical information considered relevant for the risk of inhibitor development was analyzed when available, and included family history of inhibitor, F8 genotype, ethnicity (defined according physical traits and ancestry ethnic background in the last three generations), age at first rFVIII exposure, treatment regimens (prophylaxis or episodic), doses, occurrence of a severe bleeding episode, surgery, and use of FVIII concentrate simultaneously to infection or vaccination. Results: So far, 122 patients were enrolled, and 100 patients reached the 50th ED to rFVIII or developed inhibitor. Twenty-two are still on Advate® and have not achieved 50EDs (7 patients: 20 to 50EDs; 15 patients: <20ED). Overall, the median age at first exposure to Advate® was 11.9 months (interquartile range (IQR): 7.5-16.7), and most patients were African-descendants (48%), followed by Caucasians (45%). Positive inhibitor was detected in 35 of the 100 patients (35%), and 71% occurred during the first 20EDs. Most inhibitors were detected during prophylactic treatment (29 of 35; 82.9%). Twenty-five (25%) patients had high-titer inhibitor. Although not statistically significant, 19/48 (39.6%) of the African-descendants patients developed inhibitor, in contrast to 15/45 (33%) of the Caucasians. Interestingly, inhibitor was detected in only 1/7 (14.6%) of the patients with the indigenous background (native population). The influence of other risk factors, as severe bleeding episodes, presence of infection, surgery and history of blood transfusion, were not statistically significant. Conclusions: Overall inhibitor development in this cohort is consistent with results reported in other PUP studies with recombinant products. The majority of inhibitors developed during the first 20EDs. However, no other risk factor as intensive treatment was statistically significant, due to the small number of events observed. Although observational studies have limitations to assess the immunogenicity of FVIII products, our study contributes to this knowledge, since it evaluates a single third-generation rFVIII in a distinct population, with similar access to factor concentrate and same treatment regimen. Disclosures Prezotti: Shire: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Pfizer: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Bioverative: Membership on an entity's Board of Directors or advisory committees; Novo Nordisk: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Bayer: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Roche: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau. Medina:Shire: Speakers Bureau. Ozelo:Novo Nordisk: Honoraria, Research Funding, Speakers Bureau; BioMarin: Honoraria, Speakers Bureau; Shire: Honoraria, Research Funding, Speakers Bureau; Pfizer: Honoraria, Research Funding, Speakers Bureau; Bioverativ: Honoraria, Research Funding; Grifols: Honoraria.

Treatment-related risk factors of inhibitor development in previously untreated patients with hemophilia A: the CANAL cohort study

Blood ◽  
2007 ◽  
Vol 109 (11) ◽  
pp. 4648-4654 ◽  
Author(s):  
Samantha C. Gouw ◽  
Johanna G. van der Bom ◽  
H. Marijke van den Berg
Keyword(s):  
Cohort Study ◽  
Neutralizing Antibodies ◽  
Hemophilia A ◽  
High Titer ◽  
Early Age ◽  
Severe Hemophilia ◽  
Concerted Action ◽  
Inhibitor Development ◽  
Related Risk ◽  
The Relationship

Abstract The CANAL Study (Concerted Action on Neutralizing Antibodies in severe hemophilia A) was designed to describe the relationship between treatment characteristics and inhibitor development in previously untreated patients with severe hemophilia A. This multicenter retrospective cohort study investigated 366 consecutive patients born between 1990 and 2000. The outcome was clinically relevant inhibitor development, defined as the occurrence of at least 2 positive inhibitor titers combined with a decreased recovery. Eighty-seven (24%) patients developed inhibitors (69 high titer [19%]). The incidence of inhibitors appeared to be associated with age at first treatment, decreasing from 41% for those treated within the first month of age to 18% in those treated after 18 months; after adjustment for treatment intensity, this association largely disappeared. Surgical procedures and peak treatment moments at start of treatment increased inhibitor risk (relative risk [RR], 3.7; 95% confidence interval [CI], 2.0-7.1; and RR, 3.3; CI, 2.1-5.3, respectively). Regular prophylaxis was associated with a 60% lower risk than on-demand treatment (RR, 0.4; CI, 0.2-0.8). Our findings suggest that the previously reported associated between an early age at first exposure and the risk of inhibitor development is largely explained by early, intensive treatment. The latter appears to be an independent risk factor for inhibitor development. In addition, early, regular prophylaxis may protect patients with hemophilia against the development of inhibitors.

scholarly journals Interim Analysis of the Extension Study with rVIII-SingleChain in Previously Untreated Patients (PUPs) with Severe Hemophilia A (CSL627-3001)

Blood ◽  
2019 ◽  
Vol 134 (Supplement_1) ◽  
pp. 162-162
Author(s):  
Elena Santagostino ◽  
Kathelijn Fischer ◽  
Christoph Koenigs ◽  
Claudia Djambas Khayat ◽  
Samantha Lucas ◽  
...  
Keyword(s):  
Research Funding ◽  
Low Dose ◽  
Hemophilia A ◽  
High Titer ◽  
Severe Hemophilia ◽  
Bleeding Events ◽  
Safety And Efficacy ◽  
Inhibitor Development ◽  
On Demand ◽  
Peak Titer

Background: rVIII-SingleChain is a novel B-domain truncated recombinant Factor VIII comprised of covalently bonded FVIII heavy and light chains designed to have a high binding affinity to von Willebrand factor. Aims: This multicenter, open-label, phase III extension study investigates the safety and efficacy of rVIII-SingleChain for prophylaxis and on-demand treatment of bleeding episodes in 50 previously untreated patients (PUPs) for at least 50 Exposure Days (EDs). An ITI substudy was implemented to allow the use of rVIII-SingleChain to attempt inhibitor eradication for PUPs who develop an inhibitor to FVIII. Method: PUPs with severe hemophilia A (no prior exposure to any FVIII product, and endogenous Factor VIII &lt;1%) were assigned by the investigator to a prophylaxis or on-demand treatment regimen. Inhibitors were assessed monthly. Patients diagnosed with an inhibitor to FVIII (two consecutive central laboratory [CL] results of ≥0.6 BU/mL) could be enrolled into the ITI substudy or remain in the main study. The ITI substudy regimens are: 50 IU/kg 3x/week (low), 100 IU/kg daily (medium), or 200 IU/kg daily (high). Inhibitor eradication was defined as two consecutive CL results of &lt;0.6 BU/mL. One subject was withdrawn per protocol due to high titer inhibitor diagnosis prior to ITI substudy implementation. Results: As of March 28, 2019, 23 PUPs were treated with rVIII-SingleChain. Median age: 1 y (range 0-5). Mean (SD) time on study: 21.6 (12.6) months. Race distribution; Asian 2, Black 7, White 14. There have been 147 bleeding events treated with rVIII-SingleChain rated for hemostatic efficacy by the investigator. While patients were inhibitor negative, the overall treatment success (rating of excellent/good) was 93%, and the annualized spontaneous bleeding rate (AsBR) was 0.58. The adverse event profile was as expected, as the most frequently occurring adverse events were upper respiratory tract infections and inhibitors. Twelve subjects (52%) [95% CI 31%, 73%] were diagnosed with an inhibitor to FVIII; 6 (26%) high titer (peak titer ≥5 BU/mL), and 6 (26%) low titer (peak titer &lt;5 BU/mL). Seven of 11 inhibitor negative subjects achieved &gt;50 EDs, 1 achieved 47 EDs, and 3 achieved &lt;20 EDs. The median ED for inhibitor development (initial result) was 10, range 4-23. All PUPs enrolled had ≥1 risk factor for inhibitor development (Table 1) including genetic mutation, age of first exposure, initial treatment reason and assigned regimen, as well as bleeding events and infections; inhibitor positive and negative subjects were comparable. Of the 12 inhibitor positive subjects, 11 continued treatment with rVIII-SingleChain, 7 were treated with approximately 50 IU/kg 3x/week (low dose ITI), 3 with an increased prophylaxis regimen, 1 with no change in regimen, and 0 with high or medium dose ITI regimen (Table 2). Eight of 11 (73%) inhibitor positive subjects (2 high titer, 6 low titer) achieved eradication; 5 low titer subjects were eradicated within 6 months. The clinically relevant inhibitor subjects (2 high titer, and 1 persistent low titer) achieved eradication in a median of 15.7 months, 2 using low dose ITI, and 1 using increased prophylaxis. Eradicated patients were negative for a median of 13.6 months, and no inhibitor relapse was observed. Three remaining inhibitor positive patients are early in their rVIII-SingleChain inhibitor treatment (2.1, 3.5, and 5.4 months). Detailed analysis of the antibody signature was performed, and revealed epitope isotypes and subclass distribution comparable to other FVIII molecules. Conclusion: Overall, rVIII-SingleChain demonstrates a positive benefit:risk profile for safety and efficacy in PUPs. The crude high titer inhibitor rate is 26% which is consistent with other rFVIII products, whereas the crude low titer inhibitor rate is currently 26% which is on the higher end in comparison to other rFVIII products. Immunological analyses suggest a low affinity antibody population in subjects with low titer inhibitors. The majority of subjects (73%) who continued treatment with rVIII-SingleChain achieved eradication on a low dose ITI or prophylaxis regimen of approximately 50 IU/kg 3x/week or less. Additional time on study for the currently enrolled subjects is required to determine the final inhibitor and eradication rates in PUPs treated with rVIII-SingleChain. Disclosures Santagostino: Pfizer: Consultancy, Speakers Bureau; Bayer: Consultancy, Speakers Bureau; Shire / Takeda: Consultancy, Speakers Bureau. Koenigs:Roche: Consultancy; CSL Behring: Research Funding, Speakers Bureau; Bayer Vital GmbH: Research Funding, Speakers Bureau; Biotest AG: Research Funding, Speakers Bureau; Intersero: Research Funding; Grifols: Speakers Bureau; Pfizer: Research Funding, Speakers Bureau; Shire: Research Funding, Speakers Bureau; Sobi: Research Funding, Speakers Bureau. Djambas Khayat:Novo Nordisk: Consultancy, Speakers Bureau; Pfizer: Speakers Bureau. Lucas:CSL Behring: Employment. Salazar:CSL Behring: Employment. Brainsky:CSL Behring: Employment. Chung:CSL Behring: Employment. Goldstein:CSL Behring: Employment. Mahlangu:Roche: Consultancy, Honoraria, Research Funding, Speakers Bureau; Spark: Consultancy, Honoraria, Research Funding, Speakers Bureau; Biomarin: Research Funding; Novartis: Research Funding; Pfizer: Research Funding; Sanofi: Research Funding; Unique: Research Funding; Catalyst Biosciences: Consultancy, Honoraria, Research Funding, Speakers Bureau; Novo Nordisk: Consultancy, Honoraria, Research Funding, Speakers Bureau; Baxalta: Consultancy, Honoraria, Research Funding, Speakers Bureau; CSL Behring: Consultancy, Honoraria, Research Funding, Speakers Bureau.

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