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

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

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

scholarly journals Distribution of F8 Gene Mutations in 81 Inhibitor-Free, Severe Hemophilia a Patients with Full Exposure to FVIII

Blood ◽  
2014 ◽  
Vol 124 (21) ◽  
pp. 1527-1527
Author(s):  
Anna Pavlova ◽  
Irina Matytsina ◽  
Morio Arai ◽  
Johannes Oldenburg
Keyword(s):  
Hemophilia A ◽  
Gene Mutations ◽  
Missense Mutations ◽  
Severe Hemophilia ◽  
Nonsense Mutations ◽  
Inhibitor Development ◽  
Large Deletions ◽  
Previously Treated ◽  
Mutation Distribution ◽  
The Guardian

Abstract Introduction: Factor (F) VIII genotype has been shown to be a risk factor for inhibitor development, where different mutation types are associated with different degrees of risk (Oldenburg J, et al.Haemophilia 2006;12 Suppl 6:15–22). However, it is not clear why some patients with a specific mutation develop inhibitors while others with the same mutation do not, including those with high-risk defects such as null mutations. Patients with severe hemophilia A (HA) with low-risk mutations are thought to produce some functional or non-functional FVIII that is sufficient to induce immune tolerance (Oldenburg J, et al.Haemophilia 2002;8 Suppl 2:23–29). In the present study, the distribution of F8 gene mutations in 81 patients fully exposed to FVIII with severe HA and no inhibitors is compared to data on mutation distribution among severe HA patients with/without inhibitors. Materials & Methods: Turoctocog alfa (NovoEight®) is a new recombinant FVIII product with a truncated B-domain. Previously treated patients (PTPs) with severe HA participated in the pivotal trials guardian™1 (n=150; 12–65 yrs) or guardian™3 (n=63; <12 yrs), in which they received turoctocog alfa as prophylaxis and to treat bleeds. The majority continued in an ongoing extension trial, guardian™2. All patients ≥12 yrs had a history of ≥150 exposure days (EDs) to FVIII products and patients <12 yrs had ≥50 EDs. No patients had inhibitors prior to or after turoctocog alfa treatment. Distribution of mutation types has previously been reported in populations with HA that consisted of or included patients with inhibitors (Salviato R, et al. Haemophilia 2007;13:361–372; Gouw SC, et al.Blood 2012;119:2922–2934). Here we report mutation distribution in a sample of guardian™ patients with severe HA who had long been previously treated with FVIII protein and remained inhibitor free, and compared this distribution with that from 2 published studies (Oldenburg J, et al. 2006; Salviato R, et al. 2007). Results: Eighty-one patients enrolled in the guardian™ trials had F8 gene mutation analyzed. For 52 patients <12 yrs old, genotype was analyzed during guardian™3. For 29 patients ≥12 yrs old, genotype analysis was done prior to enrollment and obtained from medical records. In 77/81 patients, the F8 gene defect was identifiable. Distribution of gene mutations in guardian™, in a population with severe HA with inhibitors, and in a population with severe HA with/without inhibitors are compared in table 1. It is interesting that the overall distribution of mutations among the populations appears quite similar, pointing toward the multifactorial nature of inhibitor development. Null mutations (inversions, nonsense mutations, and large deletions) were present in 66% and 75% of patients with severe HA and severe HA with inhibitors, respectively (table 1). In guardian™, 57% (46/81) of patients had null mutations despite never having developed an inhibitor. The difference in distribution of null mutations in the 3 populations is mainly accounted for by large deletions and nonsense mutations, while distribution of inversions was similar. It should be noted that in guardian™, 10/11 patients with missense mutations had these located outside the C1/C2 domain, which reportedly has a lower frequency of inhibitors compared with missense mutations at the C1/C2 domain (Oldenburg J, et al. 2006). Conclusions: Eighty-one patients in the guardian™ trial with severe hemophilia A had their genotype analyzed and all of them were inhibitor-free over their lifetime. Interestingly, the prevalence of high-risk mutation types does not seem to differ markedly from previously published data in patients with inhibitors, probably indicating the relevance of other factors in inhibitor development. Table 1. Distribution of F8 gene mutation types guardian™ Additional studies guardian™ patients (N) Distribution (%) in guardian™ patients (severe HA without inhibitors) Distribution (%) in patients with severe HA and inhibitors (Salviato R, et al. 2007)* Distribution (%) in patients with severe HA with/without inhibitors (Oldenburg J, et al. 2006) Total, N 81 81 76 753 Intron 22 inversion 33 40.7 44.7 45.0 Intron 1 inversion 3 3.7 1.3 2.5 Nonsense 8 9.9 18.4 13.5 Large deletion 2 2.5 10.5 5.0 Missense 11 13.6 5.2 14.5 Small del/ins/dupl 16 19.8 10.5 16.0 Splice site 4 4.9 5.2 3.5 Unidentified/ not enough information 4 4.9 3.9 0.0 Total 81 100.0 100.0 100.0 *Only patients with severe HA included. Disclosures Matytsina: Novo Nordisk A/S: Employment. Arai:Novo Nordisk Pharma, Ltd: Employment. Oldenburg:Baxter, Bayer, Biogen Idec, Biotest, CSL-Behring, Grifols, Novo Nordisk, Octapharma, Swedish Orphan Biovitrum and Pfizer: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding.

The EPIC Study: A Clinical Trial To Assess Whether Early Low Dose Prophylaxis In The Absence Of Immunological Danger Signals Reduces Inhibitor Incidence In Previously Untreated Patients (PUPs) With Hemophilia A

Blood ◽  
2013 ◽  
Vol 122 (21) ◽  
pp. 576-576 ◽  
Author(s):  
Guenter Auerswald ◽  
Karin Kurnik ◽  
Jan Blatny ◽  
Armin J Reininger
Keyword(s):  
Research Funding ◽  
Low Dose ◽  
Hemophilia A ◽  
Venous Access ◽  
Patient Specific ◽  
Missense Mutations ◽  
Severe Hemophilia ◽  
Prophylactic Regimen ◽  
Inhibitor Development ◽  
Danger Signals

Abstract Background Inhibitor development is a complex, multifactorial immune response involving both patient-specific and treatment-related factors. Of the known risk factors, intensive treatment at an early age has been shown to be significant, and clinical observations have suggested that early prophylaxis (i.e. first exposure to FVIII in the absence of a bleed in the first year of age) may protect patients from inhibitor development by inducing FVIII tolerance. Aim This study aimed to assess prospectively if a once-weekly, low-dose prophylactic regimen started before 1 year of age and before the onset of a severe bleeding phenotype (i.e. joint bleed), together with the minimization of immunological danger signals, could reduce the incidence of inhibitor formation in PUPs with severe and moderately severe hemophilia A to 15% or less. Methods The EPIC study was a Phase 3b, prospective, single arm, historically-controlled, international multicenter study to assess the incidence rate of inhibitor formation in PUPs with severe and moderately severe hemophilia A during the first 50 exposure days (EDs) of treatment with ADVATE starting with a once-weekly, low-dose (ADVATE 25 IU/kg once weekly), prophylactic regimen. If clinically indicated, it was permissible to increase the frequency of dosing to 2 or 3 times per week. In addition, infusions during the first 20 EDs had to be given 3 to 4 days before or after any vaccinations, which had to be given subcutaneously, not intramuscularly; infusions had to be avoided if the subject had high fever (above 38°C [100°F]). Main enrolment criteria were: severe and moderately severe hemophilia A (FVIII ≤2%), age <1 year, ≤3 EDs to any FVIII-containing product used for treatment of minor bleeds or for precautionary infusions following injury, adequate venous access (without need for central venous access device), no life-threatening conditions (intracranial hemorrhage, severe trauma) or requirement for surgery at the time of enrollment, no evidence of inhibitor ≥0.6 BU in Nijmegen-modified Bethesda assay at study start, no hemostatic defect other than hemophilia A, no clinically significant chronic disease other than hemophilia A,. Information about type of FVIII gene defect was obtained in 17 subjects. FVIII inhibitor tests were performed at screening, at study infusion #3, 6, 10, 15, 20, 30, 40, and 50, and at any other time point if an inhibitor was suspected. Positive inhibitor testing had to be confirmed by 2 positive inhibitor tests on samples drawn at least 1 week apart. Results A total of 22 subjects were enrolled in the study. Of 20 subjects who met all entry criteria, 19 received treatment; of these, all had severe hemophilia A (FVIII<1%). At study entry 11 of these 19 patients were never exposed to FVIII before (PUPs), while the remaining 8 patients had been treated with FVIII concentrates before. FVIII gene mutation analysis revealed intron 22 inversions in 8 out of 17 subjects, hemizygous missense mutations resulting in a stop-codon in 2 subjects, frame-shift mutations in 2 subjects, and hemizygous missense mutations in 5 subjects. A total of 8 subjects developed a confirmed inhibitor: 2 of these 8 subjects had only borderline positivity at inhibitor testing (never above 0.6 BU) with absence of any anti-FVIII antibodies (IgG, IgA, IgM and IgG subclasses) as tested by ELISA. Thus incidence of inhibitors >0.6 BU in PUPs were 27%. A total of 67 major protocol deviations (PD) were reported in 15 patients: 44 PDs of these were reported in 10 subjects and were related to the treatment regimen and therefore have contrasted with the protocol intention, which was to minimize immunological danger signals and low dose prophylactic regimen. As a result of the observed inhibitor incidence the study was terminated based on futility analysis, i.e. the probability to achieve the primary end-point of inhibitor rate reduction to ≤15%. Details on inhibitor patients will be presented. Discussion The EPIC study showed no safety issue as confirmed by the Data Safety Monitoring Board. To align treatment decisions in the presence of danger signals (which are not completely avoidable in children around 1 year of age) with a demanding study protocol was found to be challenging. Thus the hypothesis that an early low dose prophylaxis in the absence of immunological danger signals might reduce inhibitor incidence in PUPs with hemophilia A could neither be verified nor disproved within this study. Disclosures: Auerswald: Novo Nordisk: Consultancy, Research Funding; Biotest: Consultancy, Research Funding; CSL-Behring: Consultancy, Research Funding; Bayer: Consultancy, Research Funding; Baxter: Consultancy, Research Funding; Pfizer: Consultancy, Research Funding. Kurnik:Baxter: Consultancy, Research Funding; Bayer: Consultancy, Research Funding; Biotest: Consultancy, Research Funding; CSL-Behring: Consultancy, Research Funding; Novo Nordisk: Consultancy, Research Funding; Pfizer: Consultancy, Research Funding. Blatny:Baxter: speaker fee Other. Reininger:Baxter Innovations GmbH: Employment.

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

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

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

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

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

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

scholarly journals Inhibitor development in previously treated hemophilia A patients: a systematic review, meta-analysis, and meta-regression

2013 ◽  
Vol 11 (9) ◽  
pp. 1655-1662 ◽  
Author(s):  
M. Xi ◽  
M. Makris ◽  
M. Marcucci ◽  
E. Santagostino ◽  
P. M. Mannucci ◽  
...  
Keyword(s):  
Systematic Review ◽  
Hemophilia A ◽  
Meta Analysis ◽  
Inhibitor Development ◽  
Previously Treated ◽  
Meta Regression

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

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

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

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

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

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

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

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

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

Sign in / Sign up

Export Citation Format

Share Document