Age at first treatment and immune tolerance to factor VIII in severe hemophilia

2003 ◽  
Vol 89 (03) ◽  
pp. 475-479 ◽  
Author(s):  
Eveline Mauser-Bunschoten ◽  
Kathelijn Fischer ◽  
Marijke van den Berg ◽  
Johanna van der Bom
Keyword(s):  
Cohort Study ◽  
Factor Viii ◽  
Hemophilia A ◽  
Treatment Center ◽  
Clotting Factor ◽  
Confounding Factors ◽  
Severe Hemophilia ◽  
Inhibitory Antibodies

SummaryFindings from a recent study suggest that earlier start of treatment with factor VIII in patients with severe hemophilia is associated with a higher risk to develop inhibitors.We set out to assess the association between age of first administration of clotting factor VIII and the risk to develop inhibitors in infants with severe hemophilia A.This work was a cohort study, carried out in the national hemophilia treatment center. The study included eighty-one consecutive patients with severe hemophilia A who received their first dose of factor VIII between 1975 and 1998. Patients were followed until their last visit in 2001 or 2002.The average follow-up was 16 years (range 3-26). Persistent inhibitory antibodies developed in 12 of 81 patients (15%).Cumulative incidence at 100 exposure days was 34% (95% confidence interval 7-61%) in patients starting therapy before the age of 6 months, 20% (4-36%) in patients starting therapy between 6 months and 1 year, 13% (0-27%) in those starting therapy between 1 and 1.5 years, and 0% in those who started therapy beyond 1.5 years of age (p for trend 0.03).Our findings confirm that age of first factor VIII administration in children with severe hemophilia A is inversely associated with the risk to develop antibodies against factor VIII. The role of confounding factors such as the type of factor VIII mutation and environmental factors needs to be evaluated.

Factor VIII Half-Life and Clinical Characteristics of Severe Hemophilia A.

Blood ◽  
2004 ◽  
Vol 104 (11) ◽  
pp. 3091-3091
Author(s):  
Karin van Dijk ◽  
Johanna G. van der Bom ◽  
Eveline P. Mauser-Bunschoten ◽  
Goris Roosendaal ◽  
Peter J. Lenting ◽  
...  
Keyword(s):  
Factor Viii ◽  
Half Life ◽  
Clinical Characteristics ◽  
Hemophilia A ◽  
Linear Regression Analysis ◽  
Median Number ◽  
Clotting Factor ◽  
Severe Hemophilia ◽  
Single Centre

Abstract Introduction Patients with severe hemophilia A have considerably different factor VIII half-lives. Whether this is associated with clinical characteristics has not been reported. The aim of this study was to describe the effect of half-life on the clinical characteristics of patients with severe hemophilia. Patients and Methods Patients were selected from a single-centre cohort of 214 patients with severe hemophilia, born between 1944 and 1995. To improve efficiency we measured factor VIII half-life in the patients with the most severe and the mildest clinical phenotypes of severe hemophilia. Patients were selected according to age at first joint bleed, annual joint bleed frequency, clotting factor consumption and radiological Pettersson scores. A first blood sample was taken after a period of 72 hours in which the patient did not use factor VIII. After infusion with 50 IU factor VIII/kg, blood was collected at 15, 30 minutes and 1, 3, 5, 24, 30, 48 and 60 hours. From 1972 onwards, data on joint bleed frequency, clotting factor use and age at first joint bleed were collected from the patients’ files. Pettersson scores were performed at five-year intervals. For calculations of annual clotting factor use (IU/kg/yr) and number of joint bleeds per year, the last 5 years of follow-up were used. Linear regression analysis was used to assess the relation between clinical characteristics and factor VIII half-life. Results Factor VIII half-life was measured in 42 patients and ranged from 7.4–20.4 hours, with a median of 11.8 hours. One hour increase in factor VIII half life was associated with a decrease of 96 (SD 45) IU clotting factor use per kg per year (p<0.05). Joint bleed frequency was similar in patients with a shorter and a longer factor VIII half-life. Median number of joint bleeds was 2.9 per year (interquartile range (IQR) 1.1–4.4) in patients with a factor VIII half-life shorter than 12 hours and 2.6 per year (IQR 1.0–4.8) in patients with a factor VIII half-life longer than 12 hours (p=0.84). Patients with a factor VIII half-life shorter than 12 hours had a median Pettersson score of 52 points (IQR 12–61) and patients with a factor VIII half-life longer than 12 hours had a median Pettersson score of 29 points (IQR 16–52; p=0.90). Conclusion: Patients with a shorter factor VIII half-life need more clotting factor to prevent joint bleeds and subsequent arthropathy than patients with a longer factor VIII half-life.

Impact of Treatment Intensity and Factor VIII Products On the Development On High Titre Inhibitors in Children with Severe Hemophilia A: Results of a Non-Concurrent Cohort Study.

Blood ◽  
2009 ◽  
Vol 114 (22) ◽  
pp. 1303-1303 ◽  
Author(s):  
Karin Kurnik ◽  
Susan Halimeh ◽  
Daniela Manner ◽  
Susanne Holzhauer ◽  
Carmen Escuriola Ettingshausen ◽  
...  
Keyword(s):  
Cohort Study ◽  
Factor Viii ◽  
Hemophilia A ◽  
High Titre ◽  
Treatment Intensity ◽  
Severe Hemophilia ◽  
Free Survival ◽  
Inhibitor Development ◽  
Off Label

Abstract Abstract 1303 Poster Board I-325 Background A number of environmental and genetic factors have been identified to influence inhibitor development in children with severe hemophilia A (HA): among them, individual therapeutic regimens and the use of different factor VIII products have been controversially discussed. Methods In the present multicenter cohort study we evaluated the impact of i) treatment intensity [median individual dose administered during the first 6 to 8 weeks] and ii) type of factor VIII product [plasma-derived (pd); recombinant-derived (r)] on the risk of high-titre inhibitor development in 150 previously untreated patients with severe hemophilia A (HA) consecutively ascertained between 1982 and 2007 from five German catchment areas. Patients were followed over a period of 200 exposure days from HA onset. Study endpoint was inhibitor-free survival time related to treatment with adjustment for treatment period. Plasma levels of factor VIII were determined by one-stage clotting assays. Inhibitor testing was performed at least monthly to 3 monthly when on therapy using the Bethesda method or its modification [Nijmegen]: The lower detection limit was set at 0.6 Bethesda units [BU]. A peak inhibitor titer of > 5 BU was defined as high responder [HR]. A positive inhibitor testing was stated when an inhibitor was measured at least in two independent follow-up visits. The cumulative inhibitor-free survival was calculated using multivariate Cox regression [hazard ratio (HR) and 95% confidence intervals [CIs]]. Results During the follow-up period 30 of 150 children (20.0%) developed a high titre inhibitor. In univariate analysis the median dose increase per IU/kgbw significantly increased the hazard towards HR inhibitor development [HR/CI: 1.08/1.05-1.11]. In addition, 14 of 52 children treated with rFVIII concentrates (27%) versus 16 of 98 children (16.3%) treated with pdFVIII concentrates developed HR during the observation period [HR/CI: 1.9/0.9-3.9]. In multivariate analysis treatment intensity adjusted for FVIII products and treatment period were independently associated with the development of clinical meaningful inhibitors [HR/95%CI: 1.08/1.1-1.1]. Conclusion Data presented here support the hypothesis that clinical meaningful inhibitor development is of multifactorial origin and that treatment intensity plays a major role. Disclosures Off Label Use: Enoxaparin (LMWH) is used off-label in children to prevent symptomatic thromboembolism.

Increased Prevalence of Inhibitors in Mexican-Hispanic Patients with Severe Hemophilia A Enrolled in the Universal Data Collection Project.

Blood ◽  
2009 ◽  
Vol 114 (22) ◽  
pp. 3488-3488 ◽  
Author(s):  
Shannon Carpenter ◽  
J. Michael Soucie ◽  
Sophia Sterner ◽  
Rodney J Presley
Keyword(s):  
African Americans ◽  
Data Collection ◽  
Factor Viii ◽  
Hemophilia A ◽  
Conflicts Of Interest ◽  
Treatment Center ◽  
Hispanic Population ◽  
Severe Hemophilia ◽  
Inhibitor Development ◽  
Insurance Type

Abstract Abstract 3488 Poster Board III-425 Neutralizing inhibitor formation occurs in up to 20-30% of patients with severe factor VIII deficiency, leading to significantly increased morbidity in affected individuals. It has been well-established that patients of African descent have a higher prevalence of inhibitor development. [Oldenburg, J et al. Semin Hematol, 2004] The Hispanic population also has been assumed to have an increase in inhibitor development when compared with Caucasians. The study presented here is the first to definitively demonstrate an increased prevalence of inhibitors in the Hispanic population. We compared inhibitor prevalence among various racial and ethnic groups in a cross-sectional analysis of 6198 males with severe hemophilia A that participated in the Universal Data Collection project sponsored by the Centers for Disease Control and Prevention. We used logistic regression analysis to control for potential confounding variables including age, insurance type (as a proxy for access to care and socio-economic status), age at first bleed, age at diagnosis and use of prophylaxis. The included table shows those variables that were determined to be independently predictive of inhibitors. We assigned Mexican derivation to participants who labeled themselves as Hispanic and who were born either in Mexico, in states bordering Mexico or in states with large Mexican populations as established by Census data. The prevalence of high titer inhibitors in the Mexican-Hispanic population was 26.3% compared to 16.4% for Caucasian patients [OR 1.5, 95% CI 1.1, 1.9], and 26.8% for African-Americans. The underlying cause of increased inhibitor prevalence in these populations is still unknown, though a recent study in African-Americans demonstrated wild-type factors unique from commercially available product. [Viel KR, et al. Inhibitor of Factor VIII in Black Patients with Hemophilia. N Engl J Med, 2009] Further investigation of this phenomenon in the Mexican-Hispanic population, as well as the potential impact of differing immune responses, is warranted. Multivariate analysis of ethnicity and other variables found to be independently predictive of a prevalent inhibitor Characteristic Odds Ratio 95% CI Race/Ethnicity African-American 1.5 1.2 - 1.9 Mexican Hispanic 1.5 1.1 - 1.9 Hispanic 1.2 0.9 - 1.7 Other 1.2 0.9 - 1.6 White Ref Age* (years) <2 4.2 3.0 - 5.9 2-5 6.4 5.1 - 8.0 6-10 2.8 2.2 - 3.5 11-18 1.7 1.4 – 2.1 >18 Ref Insurance type Medicare 1.8 1.4 - 2.3 Medicaid 1.3 1.1 - 1.5 State program 1.1 0.6 - 1.9 TRICARE 1.0 0.4 - 2.1 Other 0.8 0.6 - 1.2 Uninsured 1.6 1.0 - 2.4 Commercial Ref Prophylaxis Yes 0.6 0.5 - 0.7 No Ref * Age with inhibitor or last UDC visit if no inhibitor The authors wish to acknowledge the contributions of the Hemophilia Treatment Center Network Investigators in the completion of this study. Disclosures: No relevant conflicts of interest to declare.

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.

T-Cell Alterations in Hemophiliacs Treated with Commercial Clotting Factor Concentrates

1983 ◽  
Vol 50 (02) ◽  
pp. 552-556 ◽  
Author(s):  
K Lechner ◽  
H Niessner ◽  
P Bettelheim ◽  
E Deutsch ◽  
I Fasching ◽  
...  
Keyword(s):  
T Cell ◽  
Factor Viii ◽  
Hemophilia A ◽  
Indirect Evidence ◽  
Absolute Number ◽  
Hemophilia B ◽  
Clotting Factor ◽  
Severe Hemophilia ◽  
T Helper ◽  
Immunological Parameters

SummaryVarious immunological parameters were determined in 46 patients with severe hemophilia A and in 9 patients with severe hemophilia B. All patients were treated over many years with commercial factor VIII or IX concentrates. Patients with severe classic hemophilia had a significantly reduced relative and absolute number of T-helper cells and a significantly increased relative and absolute number of T-suppressor cells. About half of these patients had an inverse T-helper/suppressor cell ratio. Patients with moderate hemophilia A and severe hemophilia B did not show these abnormalities. Hemophiliacs with an inverse ratio had a significantly higher concentration of serum total protein, IgG and IgM. No relationship between the amount of factor VIII concentrate administered, the HLA-type of the patient, the presence or absence of CMV-antibodies, hepatitis markers, thrombocytopenia and abnormal liver function tests to the T-cell abnormalities could be established. Lymphadenopathy was frequently associated with an inverse ratio. Indirect evidence suggests that the alterations of the immune system began in 1979/80.

scholarly journals Clinical and ultrasound joint outcomes in severe hemophilia A children receiving episodic treatment in Indonesian National Hemophilia Treatment Center

2017 ◽  
Vol 26 (1) ◽  
pp. 47-53
Author(s):  
Teny T. Sari ◽  
Novie A. Chozie ◽  
Djajadiman Gatot ◽  
Angela B.M. Tulaar ◽  
Rahayuningsih Dharma ◽  
...  
Keyword(s):  
Factor Viii ◽  
Hemophilia A ◽  
Joint Destruction ◽  
Joint Damage ◽  
Cross Sectional Study ◽  
Treatment Center ◽  
Severe Hemophilia ◽  
Older Children ◽  
Cross Sectional ◽  
Episodic Treatment

Background: Recurrent joint bleeds leading to arthropathy is the main problem in severe hemophilia children. This study aimed to investigate joint status in severe hemophilia A children receiving episodic treatment in Cipto Mangunkusumo Hospital, Jakarta.Methods: A cross-sectional study was conducted in Cipto Mangunkusumo Hospital as Indonesian National Hemophilia Treatment Center on children (4–18 years) with severe hemophilia A, who previously received episodic treatment, with no history of inhibitor factor VIII. Hemophilia Joint Health Score was evaluated according to HJHS version 2.1 2011. Joint ultrasonography was done for six index joints (bilateral elbows, knees and ankles) using Haemophilia Early Arthropathy Detection with Ultrasound (HEAD-US) methods. Data of age of first joint bleed, number of target joints and inhibitor factor VIII were obtained from the Pediatric Hemophilia Registry and medical records.Results: There were 59 subjects aged 4 to 18 years. Twenty-nine out of 59 (49.2%) subjects experienced first joint bleed before of 2 years of age. The most common of joint bleeds was a right ankle. Mean total HJHS was 8.71±8.73. Subjects aged 4–10 years showed lower HJHS (4.6±3.7) as compared to subjects aged >10–18 years (12.3±10.3), p<0.001; 95% CI=4.9–13. Mean HEAD-US scores in subjects aged 4–10 years (18.7±5.6) was lower than in subjects aged >10–18 years (28±7.9), p<0.001, 95% CI= -12.9–-5.6.Conclusion: HJHS and HEAD-US scores of severe hemophilia A children receiving episodic treatment aged 4–10 years are lower compared to subjects aged >10–18 years, indicating more severe joint destruction in older children and progressivity of joint damage over time. It is important to start prophylactic treatment to prevent progressivity of joint damage.

scholarly journals Long-Term AAV-Mediated Factor VIII Expression in Nine Hemophilia A Dogs: A 10 Year Follow-up Analysis on Durability, Safety and Vector Integration

Blood ◽  
2019 ◽  
Vol 134 (Supplement_1) ◽  
pp. 611-611 ◽  
Author(s):  
Giang N. Nguyen ◽  
John K. Everett ◽  
Hayley Raymond ◽  
Samita Kafle ◽  
Elizabeth P. Merricks ◽  
...  
Keyword(s):  
Gene Therapy ◽  
Liver Function ◽  
Factor Viii ◽  
Copy Number ◽  
Hemophilia A ◽  
Clonal Expansion ◽  
Clotting Factor ◽  
Single Chain

Hemophilia is an X-linked bleeding disorder caused by a deficiency in clotting factor VIII (FVIII)(hemophilia A, HA) or factor IX (FIX)(hemophilia B, HB). While early clinical trials of AAV delivery of FIX for HB have demonstrated stable FIX expression for &gt;8 years, an ongoing clinical trial of AAV-FVIII delivery for HA achieved high levels of transgene expression that unexpectedly declined after 1 year. Here we describe preclinical studies of AAV-canine FVIII (cFVIII) delivery in nine HA dogs with sustained FVIII expression for the duration of the study, as long as 10 years. FVIII was delivered using two delivery approaches: (1) co-administration of two AAV vectors encoding separate cFVIII heavy and light chains driven by the thyroxine binding globulin (TBG) promoter (Two chain approach)(TC) (n=5) at two AAV doses (2.5 x 1013vg/kg; F24, Woodstock, J60) and (1.2 x 1013vg/kg; Linus, H19) or (2) delivery of cFVIII as a single chain driven by the human alpha-1 anti-trypsin (hAAT) promoter (Single chain approach)(SC)(n=4) at two AAV doses (4 x 1013 vg/kg; M50, M06) and (2 x 1013vg/kg; M66, L51) (Sabatino 2011). We demonstrated that both strategies were efficacious; preventing &gt;95% of spontaneous bleeding episodes without toxicity. We now report the long-term follow-up of between 2.2 and 10.1 years for these treated dogs. Dose-dependent cFVIII:C (Coatest SP4 FVIII) was observed. At the final time point, the cFVIII:C was 2.7% (F24), 7.1% (Woodstock), 4.5% (J60), 11.3% (Linus) and 2.5% (H19) for TC dogs. For the SC dogs, the cFVIII:C was 9.4% (M06), 10.3% (M50), 1.9% (L51) and 3.7% (M66). Stable FVIII expression was maintained for seven of the dogs over the course of the study. Two dogs (Linus, M50) had a gradual increase in FVIII:C that began about three years after vector administration and continued for an additional seven years (Linus) and four years (M50), until the termination of the study. Liver function tests, serum alpha-fetoprotein concentrations, fibrinogen levels as well as liver pathology did not suggest altered liver function or tumor development in Linus and M50 compared to the other dogs. Clinically, there was no evidence of malignancy and no tumors were detected at the time of necropsy in any dog. One of the safety concerns for AAV-mediated gene therapy approaches is the potential for AAV integration events to be genotoxic and lead to tumorigenesis. While recombinant AAV primarily remains as an episome, integration events have been observed in mouse models and hepatocellular carcinoma has been observed after neonatal delivery of AAV vectors. In addition, the increase in FVIII expression in Linus and M50 prompted us to investigate integration and clonal expansion as a potential mechanism for these observations. Vector copy number (VCN) analysis was performed on liver samples (5-29 per dog, n=8 dogs) by Q-PCR and detected DNA copy numbers between 0.0 and 7.8 per diploid genome (Fig 1A). We performed integration target site analysis on liver samples (n=3/dog) from six of the AAV-treated HA dogs and naïve HA dogs (n=2) by ligation-mediated PCR, Ilumina paired-end sequencing and analysis using the custom software pipeline, AAVenger. Analysis of the 20 samples identified &gt;2,000 unique AAV integration events (IE). There was a correlation between the DNA copy number and the number of integration events detected. Clonal abundances were estimated by counting the unique genome breaks associated with integration positions, which showed that the maximum clonal abundance ranged from 1 to 138. The integration events were distributed across the canine genome. Clonal expansions were observed with integration near genes previously associated with growth control and transformation in humans (Fig 1B) with the most abundant clones located in DLEU2L (Linus), PEBP4 (J60) and EGR3 (M50). Integration events in EGR3, EGR2, CCND1, LTO1 and ZNF365 were detected in multiple dogs. Validation of integration sites in the most abundant clones was performed using targeted PCR to isolate junction fragments followed by Sanger sequencing. While AAV integration and clonal expansion was observed, the dogs had no evidence for tumorigenesis and it is not clear if the increase in FVIII expression is associated with the clonal expansions detected. Overall, these studies demonstrate long-term sustained FVIII expression for up to 10 years with clonal expansion, but without clinical adverse events after AAV-mediated gene therapy for hemophilia. Disclosures Sabatino: Spark Therapeutics: Patents & Royalties.

Detection of Inhibitor Development in Hemophilia A Patients From the Time of First Exposure to Factor VIII: Performance of An ELISA-Based Factor VIII Antibody Screening Assay.

Blood ◽  
2009 ◽  
Vol 114 (22) ◽  
pp. 3482-3482
Author(s):  
Joan Cox Gill ◽  
Michelle A Stapleton ◽  
Nancy Kern ◽  
Karen Stephany ◽  
Megan Gavin
Keyword(s):  
Factor Viii ◽  
Immune Tolerance ◽  
Neutralizing Antibodies ◽  
Hemophilia A ◽  
Venous Access ◽  
High Dose ◽  
Severe Hemophilia ◽  
Inhibitor Development ◽  
Antibody Screen

Abstract Abstract 3482 Poster Board III-419 About 25% of patients with severe hemophilia A develop neutralizing antibodies to factor VIII (FVIII), termed inhibitors, within a median of eleven exposure days to factor VIII containing therapeutic replacement products. Effective monitoring of inhibitor development in young hemophilic children is hampered by their frequently difficult venous access and their limitations on blood sample size, often making it a challenge to obtain samples suitable to carry out standard PTT based Bethesda assays. We evaluated the performance of the Factor VIII Antibody Screen (GTI Diagnostics, Waukesha, WI), an ELISA-based assay to detect FVIII antibodies in a cohort of hemophilia A patients as they were first exposed to FVIII replacement therapy for treatment of hemorrhages. FVIII antibodies were detected in the assay by incubation of duplicate patient samples and controls in microtiter wells coated with recombinant FVIII. After washing, bound FVIII antibody was detected with alkaline phosphatase conjugated goat anti-human IgG, and a colorimetric endpoint (optical density [OD] read at 405or 410 nm by spectrophotometry) determined in an ELISA plate-reader after incubation with p-nitrophenyl phosphate. Samples were considered positive if the average of the sample ODs was higher than the positive controls or negative if the average of the sample ODs was lower than the negative controls. Thirty consecutively identified patients with severe hemophilia A, who were enrolled in a longitudinal inhibitor study, and had samples of serum or plasma banked from the time of their first exposures to FVIII-containing therapeutic products were included. Patients were followed a median of 15.5 years (range 2 – 23 years). Nineteen (63%) of the patients never developed clinical or laboratory evidence of inhibitor development during follow-up. Eleven of the thirty (37%) developed an inhibitor during follow-up; one of these occurred in a 5 year-old after more than 650 exposure days to factor VIII concentrate. There were no differences in the time-to-first-exposure or pattern of hemorrhages in the two groups with the exception that all post-circumcision hemorrhages (N=6) occurred in the non-inhibitor group. In the non-inhibitor group, banked samples were selected corresponding to 0, 5, 10 and >50 factor VIII exposure-days; none of these samples had a positive result in the FVIII antibody screen ELISA. In the 11 inhibitor patients, banked samples were selected that corresponded with the earliest available sample, a sample obtained prior to the first positive Bethesda assay, the first Bethesda positive sample, a sample obtained at the initiation of immune tolerance induction (ITI), the peak Bethesda titer sample, the first negative Bethesda titer sample during ITI, and the most recent sample. All eleven of those who developed an inhibitor underwent successful immune-tolerance therapy with high dose (100 units/kg/day) factor VIII infusions. All Bethesda positive samples were positive by the FVIII antibody screen ELISA with one exception, a sample from one of the inhibitor patients just prior to development of a recurrent inhibitor. There were 5 Bethesda assay negative/FVIII antibody screen ELISA positive samples in the inhibitor patients; each of these samples had been obtained during ITI at 24-48 hours post factor VIII concentrate infusions, and were concordant with lower than expected factor VIII recoveries. We conclude that the ELISA-based FVIII antibody screen is sensitive and specific for the detection of factor VIII antibodies in patients with hemophilia A who develop inhibitors. Because it can be carried out with small serum as well as plasma samples, it provides a convenient method to obtain results in small patients with poor venous access, although quantification of the antibody titer in positive samples would require additional sample to carry out a PTT-based Bethesda assay. Unlike the Bethesda assay, this ELISA-based assay was able to detect antibodies in transfused patients undergoing ITI without the need for a prolonged washout period. Prospective studies to determine the utility and cost-effectiveness of this method are warranted. Disclosures: Gill: GTI Diagnositcs: Consultancy. Stapleton:GTI Diagnostics: Employment. Kern:GTI Diagnostics: Employment.

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