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

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.

Blood ◽  
2011 ◽  
Vol 118 (21) ◽  
pp. 25-25
Author(s):  
Maria Elisa Mancuso ◽  
Pier Mannuccio Mannucci ◽  
Angiola Rocino ◽  
Isabella Garagiola ◽  
Annarita Tagliaferri ◽  
...  

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.


Blood ◽  
2010 ◽  
Vol 116 (21) ◽  
pp. 1407-1407 ◽  
Author(s):  
Yohann Repesse ◽  
Philippe Gautier ◽  
Annie Borel-Derlon

Abstract Abstract 1407 The development of factor VIII (FVIII) inhibitors is usually considered uncommon among patients with mild and moderate hemophilia A (HA) and less frequent than in patients with severe HA. We report here the prevalence of FVIII inhibitors and their caracteristics in 167 patients with mild and moderate HA followed in Caen Hemophilia Treatment Centre (Table). FVIII molecular defects were identified by direct sequencing in 167 patients including 30 and 137 with mild and moderate HA, respectively. Following FVIII concentrates infusions, FVIII inhibitors occured in 7.8% of patients (13/167). Fifteen percent (2/13) were low-responding inhibitors. The risk of inhibitor development appeared to be associated with high-risk FVIII genotypes clustered in the A2 and C2 domains, especially p.Arg2150His (50%) and p.Arg593Cys mutations. Interestingly, we described inhibitor development associated with novel missense-mutations (p.Tyr1786Ser, p.Asp115Tyr and -219C>T substitutions in FVIII gene promoter). In addition, high regimen infusion of FVIII concentrates appeared as risk factor for FVIII inhibitors development. Indeed, 60% (8/13) developped FVIII inhibitors following massive infusion of FVIII concentrates associated with FVIII:C levels above 1.2 UI/dL. Inhibitors in mild HA usually cross-react with endogenous factor VIII reducing the circulating basal FVIII:C level and are associated with more bleeding events. Similarly, we observed the evolution of bleeding patterns in our cohort to severe phenotypes. Bleedings were treated with FVIII concentrates and bypassing therapies (activated FVII and activated-prothrombin complex). About 25% (3/13) of these inhibitors disappeared spontaneously. Induction of Immune Tolerance (ITI) protocoles with high doses of FVIII were initiated for 7 high-responding patients with a success rate of 85 % (6/7). However, inhibitors persisted long-term and remained troublesome in 1 of these patients despite of ITI protocole. For two patients, immunosuppressive treatment with corticosteroids was started. Inhibitors disappeared and the levels of FVIII:C became detectable within 6 months. Development of FVIII inhibitors, their disappearance and the efficacy of ITI regimen seem to be different from our experience between patients with mild or moderate HA and severe HA. Disclosures: No relevant conflicts of interest to declare.


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 ◽  
...  

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.


1998 ◽  
Vol 80 (11) ◽  
pp. 779-783 ◽  
Author(s):  
Y. Laurian ◽  
E. P. Satre ◽  
A. Borel Derlon ◽  
H. Chambost ◽  
P. Moreau ◽  
...  

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.


Blood ◽  
2007 ◽  
Vol 110 (11) ◽  
pp. 1163-1163 ◽  
Author(s):  
Rebecca Kruse-Jarres ◽  
Nick M. Pajewski ◽  
Cindy A. Leissinger

Abstract Background: Repeatedly, it has been observed that inhibitors to factor VIII are more frequent in African American (AA) and Hispanic (H) patients with severe congenital hemophilia A than in Caucasian (C) patients. Large retrospective reviews have shown that the mortality rates between African American and Caucasian patients with hemophilia have been similar, although non-whites had significantly more bleeding complications, need for hospitalizations and joint limitations. One possible explanation suggested that whites were more likely to receive aggressive treatment strategies such as home infusion. In none of the above reviews were patients stratified by inhibitor status. Few non-white patients have been included in large studies of inhibitor development and natural history. The purpose of this study was to evaluate the impact of race and ethnicity on the clinical characteristics and outcomes of inhibitors in patients with severe hemophilia A. Methods: This is a retrospective review of the repository database of the Hemophilia and Thrombosis Research Society (HTRS). Due to skewed distributions, non-parametric Kruskal-Wallis tests were used to test for racial differences. Results: The HTRS database captured data from 658 hemophilia patients since January 2000. Within the HTRS registry, there were 562 patients with severe hemophilia A: 68.1% (n=383) Caucasian, 21.0% (n=118) African American, and 10.9% (n=61) Hispanic. In comparison to Caucasians, Hispanics had a higher age at hemophilia diagnosis (p-value <0.01), while there was not a significant difference with African-Americans (p-value =0.53). Amongst those subjects with a prior history of inhibitors, African-Americans and Hispanics had a higher family history of inhibitor development: 13.7% of C, 26.3% of AA (pwhite = 0.02), and 41.2% of H (pwhite = <0.01). In patients with a history of inhibitors, Caucasians reported the lowest prevalence of a history of Intracranial Hemorrhage (ICH): 15.8% of C, 29.8% of AA (pwhite = 0.03), and 20.6% of H (pwhite = 0.52). African-Americans reported the lowest rate of receiving ITT (64.9%), followed 76.5% in Hispanics and 84.9% in Caucasians. African-Americans also had the lowest success rate of ITT, 30.4% as compared to 35.3% in Hispanics and 60.3% in Caucasians. In comparison to African-Americans, Caucasians did not have a significantly higher rate of unrestricted function (p=0.13), while the rate was significantly higher in Hispanics (p=0.02). Conclusion: While the HTRS database did not assess overall bleeding complications, it did show a significantly higher incidence of ICH in African-Americans versus Caucasian inhibitor patients, which could not be confirmed in non-inhibitor patients. It also appears, that fewer African-Americans and Hispanics are receiving immune tolerance therapy and that they have a lower success rate than Caucasians. However, there were insufficient patients studied to reach statistically significant conclusions. Hispanics did report significantly higher level of function. However, the HTRS survey does not use a very intricate, detailed tool to assess function. The above data proposes further investigation of bleeding risk across race/ethnicity in inhibitor vs. non-inhibitor populations. It also prompts us to look at larger databases to assess use and outcome of immune tolerance across races. Thirdly, it poses the question, whether there is a racial/ethnic difference in functional status and whether there could be variation in severity and outcome of bleeds.


Blood ◽  
2009 ◽  
Vol 114 (22) ◽  
pp. 1308-1308
Author(s):  
Anne-Marie Vincent ◽  
David Lillicrap ◽  
Angie Tuttle ◽  
Laurence Dedeken ◽  
Christine Demers ◽  
...  

Abstract Abstract 1308 Poster Board I-330 Introduction The development of anti-Factor VIII antibodies (FVIII Abs) is the most serious complication of the treatment of hemophilia A. The prevalence and incidence of FVIII Abs is usually assessed by the functional Bethesda/Nijmegen assay. We hypothesized that some FVIII Abs might not be detected by the Bethesda/Nijmegen assay but would be apparent in an ELISA assay. The FVIII Ab ELISA may be more sensitive or it may be detecting Abs against both functional and non-functional epitopes of FVIII. Subjects and Methods In the Province of Quebec (population 7.8 × 106), all subjects with hemophilia must be registered with one of the four designated hemophilia centers to be allowed to be treated with FVIII concentrates. Over the last year, blood specimens were obtained from all registered severe hemophilia A subjects to be tested for FVIII Abs. Citrated plasma specimens obtained more than 48 hours after the last FVIII treatment were tested with the Bethesda/Nijmegen assay and three described ELISAs (Haemophilia 2009;15:374-6) using as the coating antigen two different full-length recombinant FVIII (FLRFVIII) concentrates, Helixate® FS and Advate® respectively, and a B domain-deleted recombinant FVIII (BDDRFVIII) concentrate, Xyntha®. Six normal plasmas were used as negative controls on each ELISA plate. Mean and standard deviation (SD) of absorbance were calculated for the total of all the plates used for each of the three coating antigens. Results were considered positive with Bethesda unit (BU) ≥ 0.4 /mL and ELISA absorbance ≥ 3 standard deviations (SD) of the mean of the normal plasmas. Results At time of writing this abstract ≥ 80% of the target subjects have been tested and the remaining are being tested. Twelve out of 114 (10.5 %) are positive with the Bethesda/Nijmegen assay. Eleven out of these 12 are ELISA positive. Ten out of the 102 Bethesda negative subjects (9.8 %) are positive for the FLRFVIII ELISAs, all of them being negative for the BDDRFVIII ELISA. The titre of FVIII Abs measured by the Bethesda assay was highly correlated (R=0.93) with the titre measured with the three ELISAs. Conclusion Our observed prevalence (10.5%) of Bethesda positive subjects is comparable with values reported in similar unselected severe hemophilia A populations. There is no published literature with which to compare our observed prevalence of 9.8% of ELISA positive amongst Bethesda negative subjects. Bethesda negative plasmas that are positive for the FLRFVIII ELISAs and negative for the BDDRFVIII ELISA are presumed to have FVIII Abs directed against the B domain of the FLRFVIII concentrates. The clinical significance of this observation is presently unknown but is being investigated with pharmacokinetic studies. Disclosures No relevant conflicts of interest to declare.


Blood ◽  
2017 ◽  
Vol 129 (10) ◽  
pp. 1245-1250 ◽  
Author(s):  
Antonino Cannavò ◽  
Carla Valsecchi ◽  
Isabella Garagiola ◽  
Roberta Palla ◽  
Pier Mannuccio Mannucci ◽  
...  

Key Points Nonneutralizing antibodies against FVIII are detected in untreated or minimally treated patients with hemophilia A. The presence of nonneutralizing antibodies is associated with a substantially increased risk of inhibitor development.


Blood ◽  
2019 ◽  
Vol 134 (Supplement_1) ◽  
pp. 1127-1127
Author(s):  
Risa Matsumura ◽  
Keita Tomioka ◽  
Shiho Nishimura ◽  
Yoko Mizoguchi ◽  
Hiroshi Kawaguchi ◽  
...  

Prophylactic administration of factor VIII products is necessary to prevent bleeding and preserve normal musculoskeletal function in children with severe hemophilia A (HA). Recently, extended half-life recombinant factor VIII (EHL-rFVIII) products have been utilized in HA patients. Therefore, the pharmacokinetics (PK) of EHL-rFVIII in individuals is needed to determine the appropriate administration for personalized prophylaxis according to the age, bleeding phenotype, the presence of arthropathy, and physical activity. The myPKFiTR ver 3.0 has been developed as the device to estimate the personalized dosing with a 2 sample PK based on the population PK (Bayesian) tool. In this study we report our single-center experience to study PK profiles and to individualize dose and dosing interval based on myPKFiTR. Eight patients with severe HA aged from 10 to 20 years were enrolled in this study for personalized prophylaxis. The half-life of EHL-rFVIII was approximately 15 to 18 hours in all patients studied. The clearance of FVIII was inversely correlated with the half-life of EHL-rFVIII. The EHL-rFVIII products have been basically administered twice a week. The trough levels of FVIII were more than 3% in all patients. The prophylactic regimen in adolescents was individually determined according to the personal simulation of PK study and to patients' life style and physical activities. Adolescent patients actively participated in sports, such as track and field, basketball, and football after school. The FVIII level after school was easily estimated by the use of myPKFiTR according to the dose and duration of replacement. The doses of EHL-rFVIII products were individually determined to have more than 10 to 30% of FVIII level at the time of sports activity. During personalized prophylaxis (6 to 18 months), all of patients studied have been no bleeds during sports as well as no spontaneous bleeds. Additionally, myPKFiTR has the capability of presenting the real-time FVIII level on the screen of smartphone after the replacement of EHL-rFVIII based on the individual PK. Some patients have referred their own FVIII level before the beginning of sports through their smartphone and then have decided the necessity of the replacement. These experiences suggest the enhancement of treatment concordance in the supportive relationship between patients and medical staff. Thus, the use of myPKFiTR may be essential for the optimization of prophylactic administration of EHL-rFVIII and for the medical adherence and concordance in each individual. Disclosures No relevant conflicts of interest to declare.


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