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Inhibitor Formation (inhibitor + formation)
Selected AbstractsRisk factors for inhibitor formation in haemophilia: a prevalent case,control studyHAEMOPHILIA, Issue 5 2009M. V. RAGNI Summary., Inhibitor formation is a major complication of haemophilia treatment. In a prevalent case,control study, we evaluated blood product exposure, genotype and HLA type on haemophilia A inhibitor formation. Product exposure was extracted from medical records. Genotype was determined on stored DNA samples by detection of virtually all mutations-SSCP (DOVAM-S) and subcycling PCR. HLA typing was performed by PCR amplification and exonuclease-released fluorescence. Cases experienced higher intensity factor, 455 vs. 200 U per exposure, P < 0.005, more frequent central nervous system (CNS) bleeding, seven of 20 (35.0%) vs. one of 57 (1.7%), P = 0.001 and more commonly from inhibitor families, seven of 20 (35.0%) vs. zero of 57 (0%), P < 0.001, and African-American, 12 of 63 (19.0%) vs. six of 117 (5.1%), P = 0.015. Among the latter, CNS bleeding was more commonly the initial bleed, 60% vs. 0%, P < 0.001, and survival was shorter, 14 vs. 38 yr, P = 0.025. Inhibitor formation was uncommon in those with missense mutations, two of 65 (3.1%) vs. 31 of 119 (26.0%), P = 0.008, and unrelated to factor VIII immunogenic epitope, P = 0.388, or HLA type, P > 0.100. Genotype was not associated with race. Time to immune tolerance was shorter for titres <120 vs. ,120 BU/mL, six vs. 16 months, P < 0.01, but unaffected by tolerizing dose regimen, P > 0.50. Inhibitor formation is associated with high intensity product exposure, CNS bleeding, African-American race and low frequency of missense mutations. The ideal time to initiate prophylaxis to reduce CNS bleeding and inhibitor formation will require prospective studies. [source] Gene therapy for haemophilia,yes, but,with non-viral vectors?HAEMOPHILIA, Issue 3 2009A. LIRAS Summary., High-purity plasma-derived and recombinant factors are currently safe and efficient treatment for haemophilia. The mid-term future of haemophilia treatment will involve the use of modified recombinant factors to achieve advantages such as decreased immunogenicity in inhibitor formation and enhanced efficacy as a result of their longer half-life. In the long-term, gene therapy and cell therapy strategies will have to be considered. Achievements in cell therapy to date have been using embryonic stem cells and hepatic sinusoidal endothelial cells. Current gene therapy strategies for haemophilia are based on gene transfer using adeno-associated viruses and non-viral vectors. Gene therapy for haemophilia is justified because it is a chronic disease and because a very regular factor infusion is required that may involve fatal risks and because it is very expensive. Haemophilia is a very good candidate for use of gene therapy protocols because it is a monogenic disease, and even low expression is able to achieve reversion from a severe to a moderate phenotype. The current trends in haemophilia using adeno-associated viral vectors are safe but also involve immunogenicity problems. The other alternatives are non-viral vectors. There have been in recent years relevant advances in non-viral transfection that raise hope for considering this possibility. Several research groups are opting for this experimental alternative. An expression over 5%, representing a moderate phenotype, for a few months with a high safety, regarding vector, transfected cells, and implantation procedure, would already be a great success. This may represent an intermediate protocol in which the expression levels and times obtained are lower and shorter respectively as compared to viral vectors, but which provide a potential greater patient safety. This may more readily win acceptance among both patients and haematologists because fatal events in the past due to HIV/HCV infection may constrain the implementation of viruses as vectors. [source] Successful use of recombinant factor VIIa in a patient with inhibitor secondary to severe factor XI deficiencyHAEMOPHILIA, Issue 2 2002P. LAWLER Factor XI (FXI) inhibitors are a rare complication of inherited FXI deficiency. We report the successful use of recombinant factor VIIa (FVIIa) in a patient with a high-responding inhibitor undergoing cataract extraction. At the time of surgery there were limited available data on the optimal management of patients with FXI deficiency. A 62-year-old Ashkenazi Jewish woman had a lifelong history of excessive bleeding secondary to severe FXI deficiency (2 U dL,1), and received FXI concentrate (FXI:C) when she underwent a colposuspension procedure. She was subsequently diagnosed with a FXI inhibitor of 16 Bethesda units (BU) when she developed a poor response to FXI:C at the time of total hip replacement. Two months later she was admitted for cataract extraction. The FXI level was < 1 U dL,1 with an inhibitor titre of 48 BU. She received 90 ,g kg,1 of FVIIa immediately preoperatively followed by continuous infusion at a rate of 20 ,g kg,1 h,1 for 24 h. The cataract extraction was successful and there was no excess bleeding during surgery or in the postoperative period. Mutation analysis of the FXI gene showed that the patient was homozygous for the type II genotype [exon 5, Glu117,Ter]. The reason for the low prevalence of inhibitor formation in patients with FXI deficiency is unclear but may reflect a number of factors including reporting bias, the rarity of absent circulating FXI:C activity, and the infrequent use of FXI replacement therapy. [source] European data of a clinical trial with a sucrose formulated recombinant factor VIII in previously treated haemophilia A patientsHAEMOPHILIA, Issue 2002C. Rothschild Summary., To increase the safety of antihaemophilic treatment, the production process of full-length recombinant factor VIII (FVIII) KOGENATE® Bayer (Kogenate®FS)has been modified. Human albumin is no longer added as stabilizer during purification and in final formulation. Instead, the new KOGENATE® Bayer production process uses sucrose as a stabilizer in the formulation and adds solvent/detergent virus inactivation step. An European clinical trial was carried out in Germany and France in previously treated patients with severe haemophilia A who had more than 100 exposure days to exogenous FVIII. Pharmacokinetic data was analysed according to one-stage and chromogenic assays. Efficacy and safety during home therapy and in surgical procedures were evaluated; inhibitor formation was carefully monitored. Safety and efficacy were evaluated in 33 European patients for 24 months. Patients received more than 13 million IU KOGENATE® Bayer. Over 75% of patients accrued more than 100 exposure days with the new product. Of 875 bleeding episodes, 90.7% were treated with 1 or 2 infusions and 75.8% of responses to treatment were rated as ,excellent' or ,good'. Prophylactic treatment was the most common mode of therapy (60.7% of infusions). The product was well-tolerated and FVIII recovery studies were consistent throughout the study period. Only 0.26% of adverse events were reported to be drug related. No evidence of de novo inhibitor formation was observed. Overall, KOGENATE® Bayer was efficacious, safe and well-tolerated for the treatment of haemophilia A in multitransfused patients. [source] Lack of evidence for increased inhibitor incidence in patients switched from plasma-derived to recombinant factor VIIIHAEMOPHILIA, Issue 4 2001I. Scharrer De novo inhibitor development is a rare event in PTPs switched from pdFVIII to rFVIII. Based on previously published data of clinical studies a change in FVIII product is unlikely to provoke inhibitor formation. [source] High-titre factor VIII inhibitor in two children with mild haemophilia AHAEMOPHILIA, Issue 2 2001J. J. Puetz A frequently encountered complication of therapy given to patients with severe haemophilia A is the development of antibodies to infused factor VIII. While much less common, inhibitors also occur in patients with mild or moderate severity haemophilia A. Often thought to be of low titre and transient, several cases of high-titre inhibitors have been described in patients with mild or moderate haemophilia A. Generally these occur in adults or adolescents following significant infused factor VIII exposure. A review of reported cases revealed only two cases of high-titre inhibitor formation in mild haemophilia A patients younger than 10 years of age. We wish to report our experience with an additional two children with mild haemophilia A and high titre inhibitors, and offer suggestions for the management of these children. [source] Efficacy and safety of secondary prophylactic vs. on-demand sucrose-formulated recombinant factor VIII treatment in adults with severe hemophilia A: results from a 13-month crossover studyJOURNAL OF THROMBOSIS AND HAEMOSTASIS, Issue 1 2010P. COLLINS Summary.,Background: Hemarthroses in severe hemophilia precipitate physical, psychosocial and financial difficulties. Objective: To compare the effects of secondary prophylaxis with on-demand sucrose-formulated recombinant factor VIII (rFVIII-FS) therapy in severe hemophilia A. Patients and methods: This open-label study included patients aged 30,45 years with factor VIII (FVIII) coagulant activity < 1 IU dL,1 who were using on-demand FVIII treatment. Patients were treated with rFVIII-FS on demand for 6 months, followed by 7 months prophylaxis (20,40 IU kg,1, three times per week, with the first month considered a run-in). The primary endpoint was the number of hemarthroses. Results: Twenty patients were enrolled (n = 19 completed); the mean age was 36.4 years, and 16 had target joints. The median (25,75%) number of joint bleeds decreased significantly with prophylaxis [0 (0,3)] vs. on-demand [15 (11,26); P < 0.001] therapy. The number of all bleeds was 0 (0,3) vs. 20.5 (14,37; P < 0.001), respectively. Median (range) total Gilbert scores improved after prophylaxis [18 (3,39)] compared with on-demand [25 (4,46)] therapy, predominantly reflecting the improved bleeding score. Median time from last prophylactic infusion to bleed was 2 days; 82.5% of bleeds occurred 2,3 days after the last infusion. Median 48-h and 72-h FVIII trough levels measured during months 10 and 13 were consistently > 6 and > 4 IU dL,1, respectively. Treatment was well tolerated, and no inhibitor formation was observed. Conclusion: Secondary prophylaxis with rFVIII-FS significantly reduced the frequency of hemarthroses compared with on-demand therapy in adult patients with severe hemophilia A. [source] Impact of polymorphisms of the major histocompatibility complex class II, interleukin-10, tumor necrosis factor-, and cytotoxic T-lymphocyte antigen-4 genes on inhibitor development in severe hemophilia AJOURNAL OF THROMBOSIS AND HAEMOSTASIS, Issue 12 2009A. PAVLOVA Summary.,Background: Approximately 25% of severe hemophilia A (HA) patients develop antibodies to factor VIII protein. Patients: In the present case-controlled cohort study, 260 severely affected, mutation-type-matched HA patients were studied for association of human leukocyte antigen (HLA) class II molecules and polymorphisms in the genes encoding interleukin-10 (IL-10), tumor necrosis factor-, (TNF-,) and cytotoxic T-lymphocyte antigen-4 (CTLA-4) and development of inhibitors. Results: Our results demonstrate a higher frequency of DRB1*15 and DQB1*0602 alleles as well as of the haplotype DRB1*15/DQB1*0602 in inhibitor patients [odds ratio (OR) 1.9; P < 0.05]. In TNF-,, the A allele of the ,308G>A polymorphism was found with higher frequency in the inhibitor cohort (0.22 vs. 0.13, OR 1.80). This finding was more pronounced for the homozygous A/A genotype (OR 4.7). For IL-10, the ,1082G allele was observed more frequently in patients with inhibitors (0.55 vs. 0.43; P = 0.008). The functional cytokine phenotype was determined for the first time, on the basis of the genetic background, and this showed that 12% of patients with inhibitors were high-TNF-,/high-IL-10 producers, as compared with 3% of non-inhibitor patients (OR 4.4). A trend for a lower frequency of the A allele of the CT60 polymorphism in CTLA-4 was found in inhibitor patients (0.42 vs. 0.50). Conclusions: In conclusion, the reported data clearly highlighted the participation of HLA molecules in inhibitor formation in a large cohort of patients. The higher frequencies of the ,308G>A polymorphism in TNF-, and ,1082A>G in IL-10 in inhibitor patients confirmed the earlier published data. The CT60 single-nucleotide polymorphism in CTLA-4 is of apparently less importance. [source] Incidence of inhibitors in a cohort of 838 males with hemophilia A previously treated with factor VIII concentratesJOURNAL OF THROMBOSIS AND HAEMOSTASIS, Issue 12 2006C. L. KEMPTON Summary.,Background:,Development of an inhibitory antibody to factor VIII is currently the most serious complication of hemophilia A treatment. The rate of inhibitor development in those that have been previously treated with factor concentrates is poorly defined. Understanding the baseline rate of inhibitor development in the population of previously treated patients (PTPs) is important when evaluating the effect of exposure to new factor replacement products on inhibitor formation. Objectives:,To determine the rate of inhibitor development in PTPs with hemophilia A. Methods:,A cohort of males with hemophilia A who had data collected on four or more occasions prior to 30 March 2003, as part of the Center for Disease Control and Prevention's Universal Data Collection Project, were eligible for inclusion in the cohort. Patients were included in the cohort if they had at least two Bethesda assay measurements and did not have an inhibitor prior to or at the start of the study period. The overall incidence rate was estimated as the number of verified incident inhibitor cases divided by the total follow-up time in years multiplied by 1000 (cases per 1000 person-years). Results:,A total of 838 patients were included in the study. The overall incidence rate was calculated to be 2.14 cases per 1000 person years. All incident cases had more than 50 exposure days prior to inhibitor development. Conclusions:,Given the low rate of inhibitor development in PTPs with hemophilia A, small, non-randomized studies are inadequate to determine the rate of inhibitor development after exposure to novel products. Ongoing, standardized, postmarketing surveillance is needed to determine if novel factor products pose an increased risk of inhibitor development. [source] | ||||||||||