Last data update: May 06, 2024. (Total: 46732 publications since 2009)
Records 1-7 (of 7 Records) |
Query Trace: Kelly FM[original query] |
---|
Characteristics of hemophilia patients with factor VIII inhibitors detected by prospective screening
Miller CH , Rice AS , Boylan B , Payne AB , Kelly FM , Escobar MA , Gill J , Leissinger C , Soucie JM . Am J Hematol 2015 90 (10) 871-6 PURPOSE: To characterize patients with inhibitors identified by prospective screening. FINDINGS: In a prospective study at 17 hemophilia centers with central inhibitor measurement by Nijmegen-Bethesda assay, 23 (2.8%) of 824 hemophilia A patients had new inhibitors detected: 9 high-titer inhibitors (HTI: 7 ≥5.0 NBU plus 2 of 2.6 and 3.4 NBU at immune tolerance induction initiation) and 14 low-titer inhibitors (LTI: 0.5-1.9 NBU). HTI occurred at an earlier age (median 2 years, range 1-18, vs. median 11 years, range 2-61, p=0.016). Both HTI (22%) and LTI (43%) occurred in non-severe patients. All HTI, but only 64% of LTI, were found to be FVIII-specific by chromogenic Bethesda assay or fluorescence immunoassay (FLI), indicating a high rate of false-positive LTI. Repeat specimens confirmed all HTI, 7/9 LTI, and 7/7 FVIII-specific LTI. FLI results were similar between HTI and FVIII-specific LTI; all included IgG1 and IgG4 subclasses. A comparable prospective study conducted from 1975-9 at 13 U.S. centers found 31 (2.3%) new inhibitors among 1360 patients. In both studies, one-third of inhibitors occurred in non-severe patients and one-quarter after 150 exposure days (ED). Significant differences were seen in the age at which inhibitors occurred (median 16 years in the older study vs. 5 years in the current study, p=0.024) and in ED prior to inhibitor development, 10% in the older study and 43% in the current study occurring within 0-20 ED. CONCLUSIONS: Prospective screening detects Inhibitors in patients of all severities, ages, and ED. Some LTI, however, are false positives. |
A public health approach to the prevention of inhibitors in hemophilia
Soucie JM , Miller CH , Kelly FM , Oakley M , Brown DL , Kucab P . Am J Prev Med 2014 47 (5) 669-73 The development of an antibody in people with hemophilia to products used in the treatment and prevention of bleeding, also referred to as an inhibitor, is the most serious complication of hemophilia care today. The CDC, together with healthcare providers, consumer organizations, hemophilia organizations, and federal partners, has developed a public health agenda to prevent the development of inhibitors. This paper describes a public health approach that combines a national surveillance program with epidemiologic, laboratory, and prevention research to address knowledge gaps in rates and risk factors for inhibitor development, and in knowledge and behaviors of patients and providers, in addition to screening and treatment practices. |
National surveillance for haemophilia inhibitors in the United States: summary report of an expert meeting
Soucie JM , Miller CH , Kelly FM , Aschman D , Dimichele D , Konkle BA , Kulkarni R , Monahan PE . Am J Hematol 2014 89 (6) 621-5 On March 12, 2012, the Centers for Disease Control and Prevention (CDC) held a meeting of its partners in haemophilia treatment, community-based organizations, industry, and government to review data and discuss implementation issues relevant to planned United States (U.S.) national inhibitor surveillance. Issues discussed included the current status of inhibitor surveillance in the United Kingdom (U.K.) and the U.S., the results of a U.S. inhibitor surveillance feasibility study, proposed national surveillance schemes, laboratory testing and reporting issues and potential opportunities for future inhibitor-related research. It was concluded that implementation of a national program of inhibitor surveillance using standardized testing through an established public health registry along with patient and care provider education and targeted research provide the best opportunity to inform efforts to develop and evaluate effective prevention strategies. |
A study of prospective surveillance for inhibitors among persons with haemophilia in the United States
Soucie JM , Miller CH , Kelly FM , Payne AB , Creary M , Bockenstedt PL , Kempton CL , Manco-Johnson MJ , Neff AT . Haemophilia 2013 20 (2) 230-7 Inhibitors are a rare but serious complication of treatment of patients with haemophilia. Phase III clinical trials enrol too few patients to adequately assess new product inhibitor risk. This project explores the feasibility of using a public health surveillance system to conduct national surveillance for inhibitors. Staff at 17 U.S. haemophilia treatment centres (HTC) enrolled patients with haemophilia A and B into this prospective study. HTC staff provided detailed historic data on product use and inhibitors at baseline, and postenrolment patients provided monthly detailed infusion logs. A central laboratory performed inhibitor tests on blood specimens that were collected at baseline, annually, prior to any planned product switch or when clinically indicated. The central laboratory also performed genotyping of all enrolled patients. From January 2006 through June 2012, 1163 patients were enrolled and followed up for 3329 person-years. A total of 3048 inhibitor tests were performed and 23 new factor VIII inhibitors were identified, 61% of which were not clinically apparent. Infusion logs were submitted for 113 205 exposure days. Genotyping revealed 431 distinct mutations causing haemophilia, 151 of which had not previously been reported elsewhere in the world. This study provided critical information about the practical issues that must be addressed to successfully implement national inhibitor surveillance. Centralized testing with routine monitoring and confirmation of locally identified inhibitors will provide valid and representative data with which to evaluate inhibitor incidence and prevalence, monitor trends in occurrence rates and identify potential inhibitor outbreaks associated with products. |
Comparison of clot-based, chromogenic, and fluorescence assays for measurement of factor VIII inhibitors in the U.S. Hemophilia Inhibitor Research Study
Miller CH , Rice AS , Boylan B , Shapiro AD , Lentz SR , Wicklund BM , Kelly FM , Soucie JM . J Thromb Haemost 2013 11 (7) 1300-9 BACKGROUND: Detection and validation of inhibitors (antibodies) to hemophilia treatment products are important for clinical care, evaluation of product safety, and assessment of population trends. METHODS: Centralized monitoring for factor VIII (FVIII) inhibitors was conducted for patients in the Hemophilia Inhibitor Research Study using a previously reported modified Nijmegen-Bethesda clotting assay (NBA), a chromogenic Bethesda assay (CBA), and a novel fluorescence immunoassay (FLI). RESULTS: NBA and CBA were performed on 1005 specimens and FLI on 272 specimens. CBA was negative on 880/883 specimens (99.7%) with Nijmegen-Bethesda units (NBU)<0.5 and positive on 42/42 specimens (100%) with NBU≥2.0 and 43/80 specimens (53.8%) with NBU 0.5-1.9. Among specimens with positive NBA and negative CBA, 58.1% were FLI-negative, 12.9% had evidence of lupus anticoagulant, and 35.5% had non-time-dependent inhibition. CBA and FLI were positive on 72.4% and 100% of 1.0-1.9 NBU specimens and 43.1% and 50.0% of 0.5-0.9 NBU specimens. FLI detected antibodies in 98.0% of CBA-positive and 81.6% of NBA-positive specimens (P=0.004). Among 21 new inhibitors detected by NBA, 5 (23.8%) with 0.7-1.3 NBU did not react in CBA or FLI. Among previously positive patients with 0.5-1.9 NBU, 7/25 (28%) were not CBA or FLI positive. FLI was positive on 36/169 NBU-negative specimens (21.3%). CONCLUSIONS: FVIII specificity could not be demonstrated by CBA or FLI for 26% of inhibitors of 0.5-1.9 NBU; such results must be interpreted with caution. Low titer inhibitors detected in clot-based assays should always be repeated, with consideration given to evaluating their reactivity with FVIII using more specific assays. (This article is protected by copyright. All rights reserved.) |
The CDC Hemophilia A Mutation Project (CHAMP) mutation list: a new online resource.
Payne AB , Miller CH , Kelly FM , Soucie JM , Hooper WC . Hum Mutat 2012 34 (2) E2382-91 Genotyping efforts in hemophilia A (HA) populations in many countries have identified large numbers of unique mutations in the Factor VIII gene (F8). To assist HA researchers conducting genotyping analyses, we have developed a listing of F8 mutations including those listed in existing locus-specific databases as well as those identified in patient populations and reported in the literature. Each mutation was reviewed and uniquely identified using Human Genome Variation Society (HGVS) nomenclature standards for coding DNA and predicted protein changes as well as traditional nomenclature based on the mature, processed protein. Listings also include the associated hemophilia severity classified by International Society of Thrombosis and Haemostasis (ISTH) criteria, associations of the mutations with inhibitors, and reference information. The mutation list currently contains 2,537 unique mutations known to cause HA. HA severity caused by the mutation is available for 2,022 mutations (80%) and information on inhibitors is available for 1,816 mutations (72%). The CDC Hemophilia A Mutation Project (CHAMP) Mutation List is available at http://www.cdc.gov/hemophiliamutations for download and search and will be updated quarterly based on periodic literature reviews and submitted reports. |
F8 and F9 mutations in US haemophilia patients: correlation with history of inhibitor and race/ethnicity.
Miller CH , Benson J , Ellingsen D , Driggers J , Payne A , Kelly FM , Soucie JM , Hooper WC . Haemophilia 2011 18 (3) 375-82 Both genetic and treatment-related risk factors contribute to the development of inhibitors in haemophilia. An inhibitor surveillance system piloted at 12 US sites has the goal of assessing risk factors through prospective data collection. This report examines the relationship of genotype and race/ethnicity to history of inhibitor in a large cohort of US haemophilia patients. Mutation analysis was performed on 676 haemophilia A (HA) and 153 haemophilia B (HB) patients by sequencing, Multiplex Ligation-dependent Probe Amplification, and PCR for inversions in F8 introns 22 (inv22) and 1 (inv1). Two HB patients with deletions had history of inhibitor. In severe HA, frequency of history of inhibitor was: large deletion 57.1%, splice site 35.7%, inv22 26.8%, nonsense 24.5%, frameshift 12.9%, inv1 11.1% and missense 9.5%. In HA, 19.6% of 321 White non-Hispanics (Whites), 37.1% of 35 Black non-Hispanics (Blacks) and 46.9% of 32 Hispanics had history of inhibitor (P = 0.0003). Mutation types and novel mutation rates were similar across ethnicities. When F8 haplotypes were constructed, Whites and Hispanics showed only H1 and H2. Within H1, history of inhibitor was 12.4% in Whites, 40.0% in Blacks (P = 0.009) and 32.4% in Hispanics (P = 0.002). Inhibitor frequency is confirmed to vary by mutation type and race in a large US population. White patients with history of inhibitor did not exhibit rare F8 haplotypes. F8 gene analysis did not reveal a cause for the higher inhibitor frequencies in Black and Hispanic patients. |
- Page last reviewed:Feb 1, 2024
- Page last updated:May 06, 2024
- Content source:
- Powered by CDC PHGKB Infrastructure