Risk Factors For Inhibitor Development Research Articles

A Study of Clinical Profile and Treatment in Adult Hemophilia Patients with Special Reference to the Inhibitor Levels.

Introduction Hemophilia is an uncommon, X-linked recessive bleeding condition characterized by a lack of either factor VIII or factor IX. It is more prevalent in men. Due to the substantial impact inhibitor development has on patient prognosis, the primary treatment for hemophilia is the transfusion of recombinant factors. The aim of our study is to investigate 40 adult patients with hemophilia in terms of their clinical profile, clinically relevant risk factors for inhibitor development, therapy-related aspects such as treatment duration, factor requirements, transfusion frequency, presence of inhibitors, and complications. Methods Thiscross-sectional observational study involving 40patients ofhemophilia over 12 years of age was conducted at a tertiary care hospital in Gujarat. Data on sociodemographic characteristics, presenting complaints, bleeding episodes, hemophilia type, and medical history were gathered over a one-year span. Patients were stratified into mild, moderate, and severe groups based on their respective levels of factor activity. Various parameters, including the frequency of factor therapy, percentage of factor concentrate, inhibitor presence, and disease and therapy-related complications, were analyzed. The distribution of patients across these parameters was calculated and illustrated using pie charts. Results Nineteen out of 40 patients were from 20 to 40 years of age. The majority of cases (n=24), however, had been diagnosed before the patients reached the age of 10. All patients were male, and half of the patients (n=20) suffered from mild disease. The most common site of bleeding was the knee joint, and 33 cases had one to 10 bleeding episodes per year. Thirty-twoout of 40 patients needed less than 40 factor vial transfusions, whereaseight needed more than 40 factor vial transfusions. Two cases of severe disease were positive for inhibitors of factor VIII, whereas one patient was found to have a hepatitis B virus (HBV) infection. Conclusions Hemophilia, a rare bleeding disorder, has primarily been studied in pediatric populations. This study, however, shifts the focus toward adult individuals. Our cohort consisted exclusively of male patients, with the predominant group diagnosed with hemophilia A and falling within the age range of 20 to 40 years. Most patients had been diagnosed before 10 years of age. The primary complication observed was joint bleeding, with the knee joint being the most commonly affected site. Approximately two-thirds of cases had a history of minor trauma necessitating factor replacement, yet only 5% exhibited the presence of inhibitors.

Unearthing the genotype-inhibitor phenotype association in severe haemophilia A: A north Indian cohort study.

Various risk factors for inhibitor development in haemophilia A (HA) have been described but Indian data remains scanty. We aimed to evaluate the genetic changes in Indian HA-patients that are associated with the development of inhibitors. All HA-patients with inhibitors who availed coagulation-laboratory services from January-2015 till December-2021 and had their samples preserved for DNA extraction were included in this study. An equal number of severity-matched HA patients without inhibitors were also included as controls. Intron 22 and intron 1 inversions in Factor VIII gene were identified using inverse-shifting-PCR. Inversion-negative patients were further assessed by targeted NGS, MLPA. Thirty HA-patients with inhibitors were identified. All had severe-HA. Thirty severe-HA-patients without inhibitors were also included as controls. Intron 22 inversion (63.3%) and large deletions (15%) were the commonest variants identified. There was no difference in genetic variants in patients with low and high titre inhibitors. A3, A2 and C2 were the most common domains involved in inversion-negative patients with inhibitors. However, there was no significant difference in domain involvement among inversion-negative patients with and without inhibitors. Seven novel-variants were identified, including three large deletions, one large duplication and two nonsense variants in inhibitor-positive patients, and one frameshift variant in inhibitor-negative patient. After adjusting for clinical risk-factors, large deletions were independently associated with the presence of inhibitors [aOR:6.1 (1.41-56.3)]. Intron 22 inversions are the commonest variant in Indian patients with severe-HA. Large deletions predispose to inhibitor development independent of clinical risk factors.

U.S. Cohort Study of Previously Untreated Patients with Congenital Hemophilia (ATHN 8: PUPs Study): Inhibitor Development and Treatment Characteristics

Background: Persons with hemophilia (PWH) are at risk of developing neutralizing inhibitors to factor product. While some risk factors for inhibitor development are known, mechanisms to delay or prevent this complication are less well understood. American Thrombosis and Hemostasis Network (ATHN) 8: U.S. Cohort Study of Previously Untreated Patients (PUPs) with Congenital Hemophilia (NCT03818529) is a longitudinal cohort study of PUPs with moderate or severe hemophilia A (HA) or B (HB) born between 1/2010 and 12/2021 and enrolled from participating ATHN-affiliated hemophilia treatment centers (HTCs). Through this study we sought to understand variables that contribute to inhibitor development. Methods: At each HTC, data were entered for participants until 50 clotting factor exposure days (EDs), development of a confirmed neutralizing inhibitor, or study closure. The primary outcome was inhibitor development defined as a Bethesda Unit (BU) titer of >0.6 for HA or >0.3 for HB and a change in treatment. Secondary outcomes included diagnosis and treatment characteristics. Summary statistics were performed. For participants who met study endpoints at the time of enrollment, logistic regression analysis was utilized to evaluate birth cohort, race, hemophilia severity, genetic variant (for F8 gene only, classified as large structural changes >50 bp, other, and not sequenced), prophylaxis, and 5 or more consecutive EDs as risk factors for inhibitor development. Results: The study enrolled 234 eligible male participants including 135 who had met study endpoints at the time of enrollment; 94 with 50 EDs and 41 with inhibitor. A total of 128 (128/234 = 55%) were White, non-Hispanic. Of 114 HA participants who met a study endpoint prior to enrollment, 38 (38/114 = 33%) developed an inhibitor (3 moderate, 35 severe). The median EDs prior to inhibitor development was 14 (min 1, max 75). Of 21 HB participants who met a study endpoint prior to enrollment, 3 (3/21 = 14%) developed an inhibitor, all with severe disease. The median EDs to inhibitor development was 9 (min 8, max 10). Of the 234 eligible participants, 135 (135/234 = 58%) were on prophylactic treatment at any point. Of these, 33 (33/135 = 24%) received extended half-life (EHL) factor products (HA 20/114 = 17.5%; HB 13/21= 62%), while 14 (14/114 = 12%) with HA were receiving emicizumab. Over the course of the study, the rate of usage of emicizumab rose from 2% to 12% in participants with HA. Seventeen (17/39 = 44%) with HA were on prophylaxis at the time of inhibitor development, including 11 (11/39 = 28%) on standard half-life clotting factor, 1 (3%) on EHL clotting factor, and 0 on emicizumab. One participant with HB was on prophylaxis at the time of inhibitor development: none on standard half-life clotting factor, 1 (1/3 = 33%) on EHL clotting factor. Those who were on prophylaxis had decreased risk of confirmed inhibitor compared to those who were not (Odds ratio 0.24; 95% CI 0.09, 0.67). 89 participants with HA had F8 genetic testing completed, including 10 (11%) with large structural deletions. Large structural deletions were associated with higher inhibitor risk compared to other mutations in PUPs with HA at the time of inhibitor development (Odds Ratio = 5.32 vs. those with other mutations, 95% CI 1.27, 22.25). Race, ethnicity, birth cohort, and 5 or more consecutive EDs were not associated with inhibitor development. Conclusion: In ATHN 8, inhibitor rates for PUPs with HA were consistent with published data and within the typical ED range. Prophylaxis appears to decrease the risk of inhibitor development. As expected, inhibitor development was associated with large structural deletions compared to other variant types in HA. Inhibitor occurrence was not associated with other traditional risk factors. For HB, the inhibitor rate was higher than most previous reports, which may be due to the small number of participants. For PUPs with HA, emicizumab prophylaxis increased over the course of the study period. These results support the use of prophylaxis as a prevention strategy for inhibitor development. Longitudinal follow-up is needed to determine if new treatment products (EHL clotting factor and emicizumab) are associated with changes in inhibitor rates or age at inhibitor development. Although ATHN 8 was closed to enrollment, PUPs will continue to be enrolled and followed in ATHN Transcends (NCT04398628), a natural history study including PUPs with hemophilia.

The role of infections in the pathogenesis of bleeding among patients with haemophilia-A: A primer for haemophilia caregivers in the tropics

Haemophiliacs are often transfusion-dependent, and are at risk of HIV and non-HIV immuno-suppression, making them vulnerable to transfusion-transmissible infections (TTIs) and non-TTIs, many of which can cause infection-associated bleeding (IAB) even in non-haemophilic individuals. Haemophiliacs are particularly susceptible to IAB due to vicious interaction between pre-existing ‘inherited’ FVIII deficiency and infection-induced ‘acquired’ pro-haemorrhagic abnormalities. IAB in haemophiliacs manifests as undue musculoskeletal and/or mucocutaneous haemorrhages. It is thus important for haemophilia caregivers in general (and in the tropics in particular) to have thorough understanding of IAB. Clinico-pathological perspectives of IAB in haemophilia are fragmented, and not comprehensively appraised in previous literature. This review presents updated, comprehensive but concise overview of pathogenesis, trigger mechanisms, clinical implications, therapy and prevention of IAB in haemophiliacs as accrued from literature.
 Methodology: Online databases such as PubMed, Medline, Google Scholar and others were interrogated using the search terms; ‘haemophilia-A’, ‘viral, bacterial and parasitic infections’, ‘bleeding’, ‘mucocutaneous’, ‘thrombocytopenia’, ‘ecchymosis’, ‘purpura’, ‘haematuria’, ‘melena’, ‘haematemesis’, and ‘haemoptysis’ in various combinations.
 Results: Pathogenesis of IAB in haemophilia include mucosal ulcerations, acquired coagulopathy, and/or portal hypertension. As long as the causative infections are untreated, IAB is often persistent or recurrent, predisposing patients to absenteeism from school/work, iron deficiency, excessive exposure to blood products, high risk of acquiring additional TTIs and increased risk of developing inhibitors to FVIII. Haemophilia caregivers should investigate stool, urine, sputum, blood and/or radiographs of all cases of persistent or recurrent bleeding, especially if bleeding is unabated by blood products transfusion alone, and more-so in patients presenting with constitutional and/or systemic indicators of infections such as pyrexia, asthenia, dysuria, cough, diarrhoea, jaundice, or history of passage of worms in the stool. Transfusion of blood products alone would not suffice for IAB, and transfusions of FVIII containing products without concurrent anti-infection chemotherapy may even promote the development of inhibitors since active infections and inflammations are important risk factors for inhibitor development in haemophiliacs.
 Conclusion: It is therapeutically essential to combine transfusion therapy with anti-infective chemotherapy in order to achieve prompt and sustained stoppage of IAB. Haemophilia caregivers should also counsel patients on hygiene, barrier protection against vectors, and vaccination protocols.

F8 gene mutation spectrum in severe hemophilia A with inhibitors: A large cohort data analysis from a single center in China

IntroductionType of F8 gene mutation is the most important risk factor for inhibitor development in people with severe hemophilia A. However, there are few large cohort studies on the F8 mutation spectrum of people with severe hemophilia A with inhibitors. ObjectiveThis was the first large cohort study in children with severe hemophilia A with inhibitors from China that aimed to analyze the association between F8 variant types and inhibitor status. MethodsThe single‐center retrospective cohort study was conducted on children with severe hemophilia A with inhibitors admitted from January 2015 to December 2021. The clinical data were collected, and F8 genetic tests were performed. ResultsAmong the 203 patients investigated, a mutation in F8 was identified in 196 cases. Most patients had deleterious mutations (153; 75.4%), including 82 cases of intron 22 inversions (40.4%); 40 cases of nonsense mutations (19.7%), with 15 cases in the light chain and 25 cases in the heavy chain; and 31 cases of large deletions or insertions (15.3%), with 29 cases involving more than one exon and 2 cases involving one exon. The large deletions or insertions encompassing multiple exons and nonsense mutations residing in the light chain were associated with not only the progression to a high‐titer inhibitor (P< .05) but also higher peak inhibitor titer (P< .05). ConclusionThe F8 gene deleterious mutations, including intron 22 inversions, nonsense mutations, and large deletions or insertions, constitute the main mutation types in people with severe hemophilia A with inhibitors in China, with the latter mutation types (large deletions or insertions in multiple exons, and nonsense mutations in the light chain) signifying for a higher peak titer of inhibitor.

Pharmacokinetic analysis identifies a factor VIII immunogenicity threshold after AAV gene therapy in hemophilia A mice

AbstractAdvances in the development of novel treatment options for hemophilia A are prevalent. However, the anti–factor VIII (FVIII) neutralizing antibody (inhibitor) response to existing FVIII products remains a major treatment challenge. Although some novel products are designed to function in the presence of inhibitors, they do not specific address the immunogenicity risk or mechanistic causes of inhibitor development, which remain unclear. Furthermore, most preclinical studies supporting clinical gene therapy programs have reported immunogenicity signals in animal models, especially at higher vector doses and sometimes using multiple vector designs. In these settings, immunogenicity risk factor determination, comparative immunogenicity of competing vector designs, and the potential for obtaining meaningful prognostic data remain relatively unexplored. Additionally, there remains the opportunity to investigate clinical gene therapy as an alternative to standard immune tolerance induction therapy. The current study was designed to address these issues through longitudinal dose-response evaluation of 4 adeno-associated viral (AAV) vector candidates encoding 2 different FVIII transgenes in a murine model of hemophilia A. Plasma FVIII activity and anti-FVIII antibody data were used to generate a pharmacokinetic model that (1) identifies initial AAV-FVIII product expression kinetics as the dominant risk factor for inhibitor development, (2) predicts a therapeutic window where immune tolerance is achieved, and (3) demonstrates evidence of gene therapy–based immune tolerance induction. Although there are known limitations to the predictive value of preclinical immunogenicity testing, these studies can uncover or support the development of design principles that can guide the development of safe and effective genetic medicines.

Hemophilia: The Past, the Present, and the Future.

Hemophilia: The Past, the Present, and the Future.

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

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.−308G > 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 −380G > 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 −380G > 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.

Treatment‐related risk factors for inhibitor development in non‐severe hemophilia A after 50 cumulative exposure days: A case‐control study

BackgroundNon‐severe hemophilia A patients have a life‐long inhibitor risk. Yet, no studies have analyzed risk factors for inhibitor development after 50 factor VIII (FVIII) exposure days (EDs). ObjectivesThis case‐control study investigated treatment‐related risk factors for inhibitor development in non‐severe hemophilia A and assessed whether these risk factors were different for early versus late inhibitor development. Patients/MethodsNon‐severe hemophilia A patients (FVIII:C 2%–40%) were selected from the INSIGHT study. Inhibitor‐positive patients were defined as early (<50 EDs) or late (>50EDs) cases and matched to 1–4 inhibitor‐negative controls by year of birth, cumulative number of EDs, and center/country. We investigated treatment intensity during the last 10 EDs prior to inhibitor development. Intensive treatment was defined as: surgery, peak treatment (10 consecutive EDs), and high mean FVIII dose (>45 IU/kg/ED). Odds ratios (OR) were calculated by logistic regression. ResultsOf 2709 patients, we analyzed 63 early and 26 late cases and 195 and 71 respectively matched controls. Peak treatment was associated with early and late inhibitor risk (crude OR 1.8, 95% confidence interval [CI] 1.0–3.4; 4.0, 95%CI 1.1–14.3). This association was slightly less pronounced after adjustment for mean FVIII dose. High mean FVIII dose was also associated with early and late inhibitor risk (crude OR 2.8, 95%CI 1.5–5.1; 4.5, 95%CI 1.2–16.6). Surgery increased inhibitor risk for early cases. This was less pronounced for late cases. ConclusionsOur findings suggest that intensive FVIII treatment remains a risk factor for inhibitor development in non‐severe hemophilia A after more than 50 EDs. Therefore, persistent caution is required throughout the life‐time treatment course.

Genetic Risk Factors for Inhibitor Development in Hemophilia A

Genetic Risk Factors for Inhibitor Development in Hemophilia A

Risk factors for antibody formation in children with hemophilia: methodological aspects and clinical characteristics of the HEMFIL cohort study.

Up to 35% of patients with hemophilia A and 5% with hemophilia B develop neutralizing antibodies which can inhibit the therapeutic activity of factor replacement (inhibitors). Despite the clinical relevance of antifactor VIII and IX neutralizing antibodies, there is still a major gap on the knowledge of risk factors for their development. Furthermore, most of the studies on risk factors for inhibitor development come from Caucasian and Afro-American populations. The HEMFIL is a Brazilian prospective cohort study of previously untreated children with hemophilia, which primary aim is to identify new risk factors related to inhibitor development. This manuscript aims at describing the study design and its methodology. After the diagnosis, children are followed up to 75 exposure days or to inhibitor development. Standardized forms and blood samples are collected to describe clinical characteristics and to perform the measurement of immunological and genetic biomarkers at three time points; Inclusion time (T0), at inhibitor development or at 75 exposure days without inhibitors (T1) and after immune tolerance induction for patients in whom it is indicated and performed (T2). Currently, 120 children have been included, of whom, 95 have completed the follow-up. For severe/moderately severe hemophilia A, the cumulative incidence of inhibitors at 75 exposure days was 35% (95% confidence interval, 26-46%). The inclusion of additional patients and a longer follow-up will allow the analysis of risk factors for inhibitor development.

HLA Variants and Inhibitor Development in Hemophilia A: A Retrospective Case-Controlled Study Using the ATHNdataset.

In hemophilia A (HA) patients, F8 gene-defects as genetic risk-factors for developing inhibitors to Factor VIII have been extensively studied. Here we provide estimates of inhibitor-risk associated with the patient's Human Leukocyte Antigen (HLA). We used next generation sequencing for high-resolution HLA Class II typing of 997 HA patients. Using inhibitor prevalence reports from the My Life Our Future (MLOF) research repository, we calculated Odds Ratios (OR) for inhibitor development in a multivariate model considering HLA-DRB1/3/4/5, HLA-DPB1, HLA-DQB1, race, F8 pathogenic variant type, and age. Participants with 1 HLA variant (DPB1*02:02) had developed inhibitors at a higher rate while participants with 2 HLA variants (DRB1*04:07; DRB1*11:04) had developed inhibitors at a lower rate. Additionally, patients with missense variants had developed inhibitors at a lower rate and participants with large structural changes (>50 bp) had developed inhibitors at a higher rate (both compared to Intron 22 inversion). Using a cohort of participants with a distribution of HLA-DRB1 alleles comparable to that in the North American population we show that the HLA repertoire of a HA patient can be a risk-factor for inhibitor development.

Risk factors of inhibitor development among hemophilia patients revealed in a 10-year prospective cohort study in Japan, J-HIS2 (Japan Hemophilia Inhibitor Study 2)

The development of an inhibitor is a serious complication for patients with hemophilia (PwH). Previous international studies have reported some therapeutic and genetic factors associated with inhibitor development. However, actual situations, such as genetic-background, treatment, and inhibitor development, have remained unclear in PwH in Japan. The Japan Hemophilia Inhibitor Study 2 (J-HIS2) was organized in 2008 to establish a nation-wide registry system for PwH in Japan and prospectively investigate the risk factors for inhibitor development. Patients who were newly diagnosed after 2007 without inhibitor and whose treatment was traceable from 0 to 75 exposure days were enrolled in J-HIS2. Of the 386 patients (hemophilia A [HA]: 315, hemophilia B [HB]: 71) from 46 facilities, inhibitor development was observed in 77 (HA: 71, HB: 6) by November 2018. Inhibitor development was observed in 31.6% of patients with severe hemophilia A, 6.5% with moderate hemophilia A, and 1.8% with mild hemophilia A. However, it was observed in 15.4% of those with severe hemophilia B. The relative-risk of the F8 null genotype for inhibitor development was higher than that of the non-null one (p<0.01). In patients with severe hemophilia A with 25 exposure days of infusions or inhibitor development, prophylaxis was more protective for inhibitor development than non-prophylaxis (p<0.01). A simultaneous infusion of FVIII-concentrates and vaccination seemed to exert a limited effect on inhibitor development. History of intracranial hemorrhage appears to be associated with inhibitor development.

Spectrum of F8 Genotype and Genetic Impact on Inhibitor Development in Patients with Hemophilia A from Multicenter Cohort Studies (J-HIS) in Japan.

Some genetic and treatment-related factors are risk factors for inhibitor development in patients with hemophilia A (PwHA). However, the genotype distribution of the factor VIII gene (F8) and genetic impact on inhibitor development in Japanese PwHA remain unknown. In 2007, the Japan Hemophilia Inhibitor Study 2 (J-HIS2) was organized to establish a nationwide registry system for hemophiliacs and to elucidate risk factors for inhibitor development, designed for prospective investigation following a retrospective study (J-HIS1) which had already finished. Patients, newly diagnosed after January 2007, were enrolled in J-HIS2 and followed up for inhibitor development and clinical environments since 2008 onward. In the present study, F8 genotypes of PwHA were investigated in the patients recruited from the J-HIS2 cohort as well as those with inhibitor from the J-HIS1 cohort. F8 variants identified in 59 PwHA with inhibitor in J-HIS1 were: 20 intron-22 inversions, 5 intron-1 inversions, 9 large deletions, 4 nonsense, 8 missense, 11 small in/del, and 2 splice-site variants. F8 variants identified in 267 (67 with inhibitor) PwHA in J-HIS2 were: 76(28) intron-22 inversions, 3(2) intron-1 inversion, 1(0) duplication, 8(5) large deletions, 21(7) nonsense, 109(7) missense, 40(11) small in/del, and 9(7) splice-site variants. Forty variants were novel. The cumulative inhibitor incidence rate in the severe group with null changes was 42.4% (95% confidence interval [CI]: 33.7-50.8), higher than that with nonnull changes (15.6% [95%CI: 6.8-27.8]), in J-HIS2. Relative risk for inhibitor development of null changes was 2.89. The spectrum of F8 genotype and genetic impact on inhibitor development in Japanese PwHA were consistent with the previous reports.

Gut dysbiosis modulates the immune response to factor VIII in murine hemophilia A

AbstractThe development of neutralizing FVIII antibodies is the most serious complication of hemophilia A treatment. The currently known patient- and treatment-related risk factors for inhibitor development do not accurately predict this adverse event in all patients. The composition of the gut microbiota has been shown to influence immune-mediated diseases at distant anatomical sites (eg, lungs, brain, and joints). We demonstrate that a disrupted gut microbiota can be created in a mouse model of hemophilia A using a broad-spectrum antibiotic. Under controlled conditions, this sustained dysbiosis was associated with an increase in splenic B cells and the development of higher titer, FVIII-specific immunoglobulin G antibodies after FVIII challenge. Splenic and mesenteric lymph node cytokines, T cells, and dendritic cells were unaffected before administration of FVIII. However, the immune transcriptome of both aforementioned secondary lymphoid organs was significantly modified. Short-chain fatty acids (SCFAs), which are immunomodulatory microbial metabolites, were depleted in cecal contents of the dysbiotic mice. Furthermore, supplementation of the drinking water with butyrate, the most immunologically active SCFA, successfully achieved attenuation of the FVIII immune response. Collectively, data from this exploratory study suggest that the composition of the gut microbiota alters the FVIII immune response via the action of specific microbial metabolites on the immune cell transcriptome and that oral supplementation with butyrate effectively reduces the FVIII immune response.

Product type and the risk of inhibitor development in nonsevere haemophilia A patients: a case-control study.

SummaryInhibitor development is a major complication of treatment with factor VIII concentrates in nonsevere haemophilia A. It has been suggested that plasma‐derived factor VIII (FVIII) concentrates elicit fewer inhibitors than recombinant FVIII concentrates, but studies in severe haemophilia A patients have shown conflicting results. We designed a case‒control study to investigate the clinical and genetic risk factors for inhibitor development in nonsevere haemophilia A patients. We investigated whether the type of FVIII concentrate was associated with inhibitor development in nonsevere haemophilia A patients. This nested case‒control study includes 75 inhibitor patients and 223 controls, from a source population of the INSIGHT study, including all nonsevere haemophilia A patients (FVIII:C 2–40%) that were treated with FVIII concentrates in 33 European and one Australian centre. Cases and controls were matched for date of birth and cumulative number of exposure days (CED) to FVIII concentrate. A conditional logistic regression model was used to calculate unadjusted and adjusted odds ratios. No increased risk for inhibitor development was found for any type of FVIII concentrate; either when comparing recombinant FVIII concentrates to plasma‐derived FVIII concentrates (adjusted odds ratio 0·96, 95% confidence interval (CI) 0·36–2·52) or for specific types of FVIII concentrates.

Inhibitor epidemiology and genetic-related risk factors in people with haemophilia from Côte d'Ivoire.

In Sub-Saharan Africa, inhibitor prevalence data in people with haemophilia (PWH) are scarce, as are data on genetic or treatment-related risk factors. We performed a prospective study on PWH from Côte d'Ivoire to collect data into inhibitor prevalence, create a database of haemophilia genotypes, establish correlations between inhibitor presence and genetic variants identified amongst Ivoirian PWHs and evaluate exposure to CFCs. The study included 54 unrelated participants (43 severe, four moderate, two mild haemophilia A and five severe haemophilia B). PWH were treated on-demand with various product types for short periods, non-intensively, and using low-dose regimens. We reported similar distributions of intron 22 inversions (39.5%), point pathogenic variants (32.6%) and rearrangements in Ivoirian severe haemophilia A patients versus non-African ethnic groups. The haplotypes H1 (29.6%), H2 (36.3%) and H3 (34.1%) frequencies in haemophilia A were consistent with results published on African populations. We identified eight new causal variants. An inhibitor was found in 12% of haemophilia A patients previously exposed to replacement therapies. Among PWH with inhibitors, 66.7% had a positive intron 22 inversion and 50% the H1 haplotype. This study provides original data on molecular diagnosis of haemophilia, inhibitor prevalence and risk factors for inhibitor development previously associated with inhibitors in Côte d'Ivoire. The low inhibitor prevalence likely reflects the limited exposure to replacement therapy in Côte d'Ivoire. Further larger, multicentric and international studies are needed to gain more insight on inhibitor incidence and risk factors in African PWH.

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

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

The prevalence and risk factors of inhibitor development of FVIII in previously treated patients with hemophilia A.

BackgroundRisk factors for the development of inhibitors in previously untreated patients (PUPs) have been reported; this is not the case in previously treated patients (PTPs) owing to fewer studies. Risk factors may differ for the development of PTP versus PUP inhibitors. We aimed to identify risk factors for PTP inhibitor development.MethodsParticipants were patients at a hemophilia treatment center in Korea with current or past history of factor VIII or factor IX alloantibodies. Observed inhibitors were classified as PUP or PTP inhibitors based on the cumulative number of exposure days. We compared the type and severity of hemophilia, mutation type, and family history of inhibitor between PUPs and PTPs. Events within 3 months before the first inhibitor detection, such as change of the factor concentrate used, short-term high exposure or continuous infusion of factor concentrate, history of surgery, infection, diagnosis of cancer, use of immunosuppressive or immunomodulator agents, and vaccination were compared between PUPs and PTPs.ResultsWe observed 5 PUP inhibitors and 5 PTP inhibitors in 115 patients with hemophilia A. Events that might be related to the development of inhibitors within 3 months prior to the first inhibitor detection were observed in all 5 PTPs. On the contrary, no such events were observed in any PUPs. The observed events included a change in the factor concentrate used, subsequent chemotherapy, and short-term high exposure to factor concentrates for controlling hemorrhage and surgeries.ConclusionOur results suggest a greater role of nongenetic factors in PTP inhibitor development.

Inhibitors among patients with hemophilia in Basra, Iraq - A single center experience.

Inhibitor formation is a major complication of hemophilia treatment because it interferes with the clinical response to factor replacement and causes significant morbidity. This cross-sectional study was conducted to assess the presence and frequency of inhibitors among registered person with hemophilia and to identify risk factors associated with inhibitor development. A total of 143 hemophilics, 118 with hemophilia A (HA) and 25 with hemophilia B (HB), were enrolled for the study. Participant's clinical data were obtained through patient's medical records. Factor VIII and IX levels and the presence of inhibitors were assessed using a fully automated coagulometer. From the results of a Bethesda assay, patients were divided into those with high titers (≥5 BU) and those with low titers (<5 BU). The patient's age ranged from 1 to 67 years with median of 13.8 years. Inhibitors were detected in 18.6% and none of HA and HB patients, respectively. Of the 22 patients with HA and inhibitors, 18 (82%) had high titer inhibitors. The frequency of inhibitors was significantly higher among patients with severe hemophilia, a history of early exposure (≤3 months) to factor VIII concentrate, and family histories of autoimmune disease and immune system challenges (P < 0.05). The independent risk factors associated with inhibitor development were severe hemophilia (95% CIs = 1.02-55.6, OR = 7.5) and immune system challenges (95% CIs = 1.14-5.99, OR = 2.6). Inhibitors were common among HA patients, and both severe HA and immune system challenges (surgery and trauma) are independent risk factors for inhibitor development.