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.

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.

Intensity of factor VIII treatment and inhibitor development in children with severe hemophilia A: the RODIN study

Blood ◽  
2013 ◽  
Vol 121 (20) ◽  
pp. 4046-4055 ◽  
Author(s):  
Samantha C. Gouw ◽  
H. Marijke van den Berg ◽  
Kathelijn Fischer ◽  
Günter Auerswald ◽  
Manuel Carcao ◽  
...  
Keyword(s):  
Factor Viii ◽  
Hemophilia A ◽  
Low Risk ◽  
High Dose ◽  
Severe Hemophilia ◽  
Inhibitor Development ◽  
Key Points

Key Points High-dose intensive factor VIII treatment increases the risk for inhibitor development in patients with severe hemophilia A. In patients with severe hemophilia A, factor VIII prophylaxis decreases inhibitor risk, especially in patients with low-risk F8 mutations.

Influence of the type of factor VIII concentrate on the incidence of factor VIII inhibitors in previously untreated patients with severe hemophilia A

Blood ◽  
2006 ◽  
Vol 107 (1) ◽  
pp. 46-51 ◽  
Author(s):  
Jenny Goudemand ◽  
Chantal Rothschild ◽  
Virginie Demiguel ◽  
Christine Vinciguerrat ◽  
Thierry Lambert ◽  
...  
Keyword(s):  
Factor Viii ◽  
Immune Tolerance ◽  
Hemophilia A ◽  
Tolerance Induction ◽  
Adjusted Relative Risk ◽  
Severe Hemophilia ◽  
Immune Tolerance Induction ◽  
Inhibitor Development ◽  
End Point ◽  
History Of

Abstract Inhibitor development is the major treatment complication in children with severe hemophilia A. It is not clear whether the risk of inhibitors is higher with recombinant factor VIII or with plasma-derived factor VIII. We used multivariate analysis to compare 2 cohorts of previously untreated patients (PUPs) with severe hemophilia A: 62 patients treated with the same brand of high-purity plasma-derived FVIII (pFVIII) containing von Willebrand factor (VWF) and 86 patients treated with full-length recombinant FVIII (rFVIII). In addition to the usual end points (all inhibitors, high inhibitors), we also examined a third end point (high inhibitors and/or immune tolerance induction). The risk of inhibitor development was higher in patients treated with rFVIII than in patients treated with pFVIII, regardless of other risk factors (F8 genotype; nonwhite origin; history of inhibitors in patients with a family history of hemophilia; age at first FVIII infusion). The adjusted relative risk (RRa) for inhibitor development with rFVIII versus pFVIII was 2.4 (all inhibitors), 2.6 (high inhibitors), and 3.2 (high inhibitors and/or immune tolerance induction), respectively, depending on the end point (above). The pathophysiology of this large effect must be understood in order to improve the characteristics of recombinant products and to reduce the incidence of inhibitors to FVIII.

Risk of Bleeding and Inhibitor Development After Circumcision in Minimally Treated Severe Hemophilia A Patients: A One Year Prospective Study,

Blood ◽  
2011 ◽  
Vol 118 (21) ◽  
pp. 4653-4653
Author(s):  
Mohsen Saleh Elalfy ◽  
Nancy Samir Elbarbary ◽  
Mohamed Soliman Eldebeiky
Keyword(s):  
Single Dose ◽  
Factor Viii ◽  
Hemophilia A ◽  
Recombinant Factor Viia ◽  
Factor Viia ◽  
High Titer ◽  
Severe Hemophilia ◽  
Inhibitor Development ◽  
Factor Concentrate

Abstract Abstract 4653 Background Circumcision is a cultural practice for males in the Middle-East during first weeks of life. All parents of hemophilics are eager to do circumcision to their sibs, however, it may carry a risk for development of factor VIII inhibitors as well as risk of excessive bleeding. Objective To evaluate post-circumcision bleeding and assess incidence and time of inhibitor development over 12 months follow-up period of minimally treated severe hemophilia A patients. Patients and methods This prospective analysis has been conducted on eighteen minimally treated patients with severe hemophilia A (age range 8–36 months) with a median age of 18 months, who underwent circumcision during 2009 and twenty four age matched non circumcised patients minimally treated severe hemophilia A. Both groups were followed up for12 months from study entry and all were treated on demand therapy with a single plasma-derived factor VIII product. Hemophilic patients who underwent circumcision were inhibitor negative except two with low- titer inhibitor(3.3 and 4.4 BU/ml) respectively. One hour before the operation, intravenous tranexamic acid (25 mg/ kg) and first dose of factor concentrate (25 unit / Kg) were given to the patients. After reaching a trough plasma factor level more than 90%, patients underwent circumcision using general anesthesia and same surgical technique for all. Bolus injections of factor VIII concentrate were repeated in a dose of (25 units / Kg ) twenty four hours after operation. However, the two patients with inhibitors were given factor VIII concentrate in a dose of (50 units /Kg) with an extra dose at forty-eight hours. Another dose of factor concentrate (25 units/ Kg) was given just before removal of gauze dressing at 5th −7th day post operative. Follow up for inhibitor development was assessed every 8 exposure days (EDs) for 12 months or 100 EDs whichever comes first. Results: Of the eighteen patients enrolled, only one of the 2 patients with low- titer inhibitor had postoperative bleeding at day 5 and 7 respectively. First attack responded to a single dose of factor administration (50 units/Kg), whereas haemostasis was achieved in the second episode after a single dose of Recombinant Factor VIIa (90 microgram/kg) and applying absorbable haemostatic agent (gelatin sponge) and binding. None of the other patients had any bleeding or infection at site of surgery. High -titer inhibitors developed in three patients (16.6 % ) during the follow-up; after 8, 16 and 40 EDs respectively in contrast to four patients (16.6 %) developed high titer inhibitor in the non circumcised group; after a median of 16 exposure days (range 8– 60 EDs). Conclusion: Our study has shown that bleeding following circumcision was absent except in low- titer inhibitor patient necessitating administration of Recombinant Factor VIIa. Moreover, circumcision was not a risk for development of inhibitor where the incidence of high- titer inhibitors during12 months follow up was low in this cohort of minimally treated patients and comparable to non circumcised group. Disclosures: No relevant conflicts of interest to declare.

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.

ITI Treatment is not First-Choice Treatment in Children with Hemophilia A and Low-Responding Inhibitors: Evidence from a PedNet Study

2020 ◽  
Vol 120 (08) ◽  
pp. 1166-1172
Author(s):  
H. Marijke van den Berg ◽  
Maria Elisa Mancuso ◽  
Christoph Königs ◽  
Roseline D'Oiron ◽  
Helen Platokouki ◽  
...  
Keyword(s):  
Hemophilia A ◽  
Real Life ◽  
Tolerance Induction ◽  
High Dose ◽  
Severe Hemophilia ◽  
Limited Data ◽  
Treatment Regimens ◽  
First Choice ◽  
Lost To Follow Up

Abstract Background Limited data exist on the clinical impact of low-responding inhibitors and the requirement for immune tolerance induction (ITI) treatment to establish tolerance, reduce bleeding, and improve outcome. The aim of this article is to describe the therapeutic management of children with severe hemophilia A and low-responding inhibitors and its effect on bleeding phenotype. Methods The REMAIN (Real-life Management of Inhibitors) study is a satellite study of the PedNet registry. It included unselected children with severe hemophilia A (factor VIII [FVIII] < 0.01 IU/mL) born between January 1, 1990 and December 31, 2009 who developed clinically relevant inhibitors and were followed-up for at least 3 years after the first positive inhibitor test. Results A total of 260 patients with inhibitors were identified and 68 of them (26%) had low-responding inhibitors (peak < 5 BU/mL). Five patients were lost to follow-up and 63 were included in this study. The median follow-up was 3.7 years (interquartile range: 3.0–7.5). ITI was started in 51/63 (81%) patients. The median time from ITI start to first negative inhibitor titer was similar with low-dose and high-dose ITI regimens (2.5 and 3.1 months, respectively). Ten of the 12 patients who did not receive ITI were treated with regular prophylaxis and reached a negative titer after a median of 6.5 months. Bleeding rate was low in all patients with no difference between treatment regimens. Conclusion In children with low-responding inhibitors negative titers were reached with regular FVIII treatment irrespective of the regimen (i.e., prophylaxis or ITI).

Long-Term Venous Access Catheters and Infections in Patients with Severe Hemophilia.

Blood ◽  
2004 ◽  
Vol 104 (11) ◽  
pp. 4117-4117
Author(s):  
Janet A. Harrison ◽  
Jerry S. Powell
Keyword(s):  
Immune Tolerance ◽  
Hemophilia A ◽  
Significant Risk ◽  
Clinical Decision ◽  
Primary Prophylaxis ◽  
Venous Access ◽  
Secondary Prophylaxis ◽  
Catheter Placement ◽  
Severe Hemophilia

Abstract Treatment of hemophilia A or B with factor concentrates requires uncomplicated venous access, and frequently this access uses venous access catheters, which have been associated with increased frequency of thrombophlebitis and catheter related infections. Reports have estimated the incidence of infection as 8.3% to 55%. A prospective multi-center study was undertaken to determine the rates of these complications associated with venous access catheters in patients with severe hemophilia. Inclusion criteria were: severe hemophilia, age 6 months to 70 years, and non-emergent need for a long-term venous access catheter. Excluded were catheters inserted for less than 28 days or in a femoral site, and other medical conditions compromising expected survival. 53 subjects (48 hemophilia A, 5 hemophilia B) were enrolled by nine hemophilia treatment centers, with 3 subjects receiving repeat catheter insertions, for a total of 56 catheter experiences. Factor replacement was given to all subjects during catheter placement. Families were trained in catheter use according to individual center practices, and each subject was followed at least monthly in the clinic or by telephone. 54 catheters were placed by a physician in an operating room under sterile conditions; antibiotics were used for catheter placement for 18 subjects. The ages at placement ranged from 10 months to 59 years (mean 8.9 years). Most of the Catheter types were Port-a-Cath (n = 43), 6 Broviac, 4 Hickman, and 3 PICC. The reasons for the catheters varied: primary prophylaxis, 10, secondary prophylaxis, 23, immune tolerance, 17, and for treatment after surgery or trauma, 6. Five subjects were positive for hepatitis C, 2 subjects for hepatitis B, and one for HIV. Of the 53 subjects, 10 have had catheter related infections. The infections were detected 19 to 762 days after catheter insertion (mean 272.7 days). Two subjects had recurrent infections, 4 and 3 respectively. The ages of the subjects at the time of infection ranged from 1.8 to 13.9 years old (mean = 5 years). The peripheral blood cultures and the catheter tip (if removed) cultures revealed a variety of different bacteria and one fungus (candida albicans). Perhaps surprisingly, staphylococcus epidermidis was found in only 2 subjects, and no case of s. aureus was detected. Klebsiella was cultured from 3 subjects who experienced infections. No subjects died during the study. Eight catheters were removed for reasons determined by the responsible clinician: 6 for infection, 1 by accident, 1 was no longer needed. Nine of the 10 subjects with infections received antibiotics. Of the 6 Broviacs, 2 subjects experienced infections (33%). Of the 43 Port-a-Caths, 8 subjects experienced infections (18.6%). The 2 subjects with repeated infections both had Port-a-Caths, and the first infections occurred at 354 and 120 days, respectively. Of the 17 subjects on immune tolerance, 2 subjects experienced infections (not significantly different from the larger cohort). No subjects experienced thrombophlebitis or other catheter failure. In summary, the results of this study demonstrate that long-term venous access catheter use in patients with severe hemophilia: 1) is associated with significant risk of catheter related infections, particularly in children, 2) that these infections can be managed clinically in most cases, with appropriate clinical monitoring, and, 3) the risk of thrombophlebitis is quite low. These data should assist to evaluate the risks and benefits of the clinical decision to use venous access catheters in patients with severe hemophilia.

New Early Prophylaxis Regimen That Avoids Immunological Danger Signals Can Reduce Factor Eight (FVIII) Inhibitor Development Independent From Product Type Used.

Blood ◽  
2009 ◽  
Vol 114 (22) ◽  
pp. 221-221
Author(s):  
Guenter K.H. Auerswald ◽  
Christoph Bidlingmaier ◽  
Werner Engl ◽  
Heidi Chehadeh ◽  
Birgit M Reipert ◽  
...  
Keyword(s):  
High Risk ◽  
Odds Ratio ◽  
Low Dose ◽  
Hemophilia A ◽  
Venous Access ◽  
Historical Control ◽  
Control Group ◽  
Severe Hemophilia ◽  
Inhibitor Development ◽  
Danger Signals

Abstract Abstract 221 Introduction: Today, the most problematic and costly complication of the treatment of hemophilia A that remains to be overcome is the development of inhibitory antibodies (FVIII inhibitors) to FVIII replacement therapy, particularly in previously untreated patients (PUPs). Aim of the study: The highest risk of developing inhibitors to FVIII is during the first 20 exposure days (EDs). If the patient can be brought through this high risk period without inhibitor development, the subsequent risk is low. We therefore, as a pilot project, developed a prophylaxis regimen for the first 20–50 EDs specifically designed to induce tolerance to the administered FVIII and to minimize inhibitor development. Patients and Methods: Twenty-six consecutive PUPs with severe hemophilia A (<1% FVIII) as they appeared in the centers were treated with a once weekly low dose (250 Units) prophylaxis regimen started as soon as venous access allows without a Port-A-Cath. Thereby immunological danger signals were minimized by avoiding giving first FVIII into a bleed or during an infection, and avoiding surgery during the first 20 EDs. The incidence of inhibitor development in the study group was compared with that in a historical control group of 30 consecutive PUPs with severe hemophilia A treated with a standard joint protection prophylaxis regimen of 40–50 IU/kg FVIII three times a week, starting at or after the first joint or other severe bleed. The new prophylaxis regimen was started after a median of 1 FVIII EDs at a median age of 10.7 months compared to the historical control group were high dose prophylaxis was started later after a median of 30 FVIII on demand EDs at a median age of 19 months (p<0.006). Both plasma-derived and recombinant FVIII concentrates were used in 47% and 53% of the patients respectively. Results: There were no significant differences between the study and control groups in patient related inhibitor risk factors such as ethnicity (all Caucasian), severity of hemophilia (all <1% FVIII), severity of FVIII gene mutation (p<0.0006) and some treatment related factors such as the type of product, age at first exposure, vaccination regimen, need for surgery. However, 14 of 30 subjects (47%) given standard prophylaxis but only 1 of the 26 subjects (3.8%) given the new regimen developed an inhibitor (p=0.0003, odds ratio 0.048, 95% CI: 0.001 to 0.372). Eight subjects given standard prophylaxis but none of those given the new regimen were high responders (p=0.005, odds ratio for high response 0.00, 95% CI: 0.00 to 0.57). Conclusion: Our results indicate that early start of prophylaxis associated with minimizing immunological danger signals during the first 20 exposure days with FVIII may reduce the risk of inhibitor formation even in PUPs with a high risk genetic background independent from the FVIII product type used. Once the patients have developed tolerance to FVIII, usually after about 20 to 50 EDs on the low dose regimen, and venous access permitted, prophylaxis might be changed to the normal three times weekly regimen for optimal protection from joint bleedings. These results need to be confirmed in a larger prospective clinical study. Disclosures: Auerswald: Baxter, CSL-Behring and NovoNordisk.: Consultancy, Honoraria, Research Funding. Bidlingmaier:CSL Behring and Bayer : Honoraria. Engl:baxter: Employment. Chehadeh:baxter: Employment. Reipert:baxter: Employment.

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.

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.

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