Last data update: May 06, 2024. (Total: 46732 publications since 2009)
Records 1-8 (of 8 Records) |
Query Trace: Ellingsen D[original query] |
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Evaluation of pre-analytic heat treatment protocol used in the CDC Nijmegen-Bethesda assay for heat inactivation of extended half-life haemophilia treatment products
Payne AB , Ellingsen D , Driggers J , Bean CJ , Miller CH . Haemophilia 2019 26 (1) e28-e30 Detection of low-titer factor VIII (FVIII) or factor IX (FIX) inhibitors can be difficult in the presence of endogenous or therapeutic factor.1 Pre-analytic heat treatment (PHT) of patient plasma specimens at 56⁰C for 30 minutes followed by centrifugation prior to measurement of the inhibitor titer is important to eliminate interference caused by endogenous or therapeutic factor in the specimen and to avoid the need for a washout period.1 PHT has been previously shown to enable more accurate determination of the inhibitor titer without removing antibodies in the context of traditional factor replacement products.2 |
Reagent substitution in the chromogenic Bethesda assay for factor VIII inhibitors
Payne AB , Miller CH , Ellingsen D , Driggers J , Boylan B , Bean CJ . Haemophilia 2019 25 (5) e342-e344 The Nijmegen-Bethesda assay (NBA) is the gold standard for measurement of factor VIII (FVIII) inhibitors in haemophilia A patients.1 Modification of the traditional NBA2 to use a chromogenic measurement of FVIII as the endpoint is necessary for measurement of FVIII inhibitors in the presence of heparin, lupus anticoagulants, or by-passing agents such as emicizumab, due to their interference in clot-based assays.3–5 Parallel testing has shown this modification to produce similar results to the NBA in the absence of these interfering substances.6 In the clot-based NBA, substitution of imidazole-buffered bovine serum albumin (IB-BSA) for FVIII-deficient plasma (FVIIIDP) as diluent in control mixtures and specimen dilutions has been shown to produce equivalent results when the threshold for positivity was slightly adjusted.7 This study aims to evaluate a similar substitution in the chromogenic Bethesda assay (CBA) and to describe the performance characteristics of this modified assay. |
Reagent substitutions in the Centers for Disease Control and Prevention Nijmegen-Bethesda assay for factor VIII inhibitors
Miller CH , Payne AB , Driggers J , Ellingsen D , Boylan B , Bean CJ . Haemophilia 2018 24 (3) e116-e119 The Nijmegen-Bethesda assay (NBA), considered the “gold standard” for measurement of factor VIII (FVIII) inhibitors in haemophilia A,1 introduced two modifications to the traditional Bethesda assay (BA) for stabilization during the 2-hour incubation at 37°C: (i) buffering of normal pooled plasma (NPP) in the test and control mixtures with imidazole and (ii) substitution of FVIII-deficient plasma (FVIIIDP) for imidazole buffer (IB) in the control mixture and for specimen predilution.2 The NBA has not been widely adopted in the United States, because of the increased cost incurred by use of FVIIIDP rather than buffer and the lack of FDA-approved commercial reagents.3 Surveys of North American coagulation laboratories have shown that only 20% use the NBA, 70% use buffered NPP in a “hybrid” of the NBA and BA, and one-third use diluents other than those recommended in published methods.3 This lack of methodological uniformity may partially account for poor interlaboratory reproducibility, a well-known problem with FVIII inhibitor testing.3 |
Discordance between self-report and genetic confirmation of sickle cell disease status in African-American adults.
Bean CJ , Hooper WC , Ellingsen D , Debaun MR , Sonderman J , Blot WJ . Public Health Genomics 2014 17 (3) 169-72 BACKGROUND: Sickle cell disease (SCD) is an autosomal recessive genetic disorder, with persons heterozygous for the mutation said to have the sickle cell trait (SCT). Serious adverse effects are mainly limited to those with SCD, but the distinction between disease and trait is not always clear to the general population. We sought to determine the accuracy of self-reported SCD when compared to genetic confirmation. METHODS: From stratified random samples of Southern Community Cohort Study participants, we sequenced the beta- globin gene in 51 individuals reporting SCD and 75 individuals reporting no SCD. RESULTS: The median age of the group selected was 53 years (range 40-69) with 29% male. Only 5.9% of the 51 individuals reporting SCD were confirmed by sequencing, with the remaining 62.7% having SCT, 5.9% having hemoglobin C trait, and 25.5% having neither SCD nor trait. Sequencing results of the 75 individuals reporting no SCD by contrast were 100% concordant with self-report. CONCLUSIONS: Misreporting of SCD is common in an older adult population, with most persons reporting SCD in this study being carriers of the trait and a sizeable minority completely unaffected. The results from this pilot survey support the need for increased efforts to raise community awareness and knowledge of SCD. |
Mutation analysis of a cohort of US patients with hemophilia B.
Li T , Miller CH , Driggers J , Payne AB , Ellingsen D , Hooper WC . Am J Hematol 2013 89 (4) 375-9 Hemophilia B (HB) is a disorder resulting from genetic mutations in the Factor 9 gene (F9). Genotyping of HB patients is important for genetic counseling and patient management. Here we report a study of mutations identified in a large sample of HB patients in the US. Patients were enrolled through an inhibitor surveillance study at 17 hemophilia treatment centers (HTCs). A total of 87 unique mutations were identified from 225 of the 226 patients, including deletions, insertions, and point mutations. Point mutations were distributed throughout the F9 gene and were found in 86% of the patients. Of these mutations, 24 were recurrent in the population, and 3 of them (c.316G>A, c.1025C>T and c.1328T>A) accounted for 84 patients (37.1%). Haplotype analysis revealed that the high recurrence arose from a founder effect. The severity of HB was found to correlate with the type of mutation. Inhibitors developed only in severe cases with large deletions and nonsense mutations. None of the mild or moderate patients developed inhibitors. Our results provide a resource describing F9 mutations in US HB patients and confirm previous findings that patients bearing large deletions and nonsense mutations are at high risk of developing inhibitors. |
Heme oxygenase-1 gene promoter polymorphism is associated with reduced incidence of acute chest syndrome among children with sickle cell disease.
Bean CJ , Boulet SL , Ellingsen D , Pyle ME , Barron-Casella EA , Casella JF , Payne AB , Driggers J , Trau HA , Yang G , Jones K , Ofori-Acquah SF , Hooper WC , Debaun MR . Blood 2012 120 (18) 3822-8 Sickle cell disease (SCD) is a common hemolytic disorder with a broad range of complications, including vaso-occlusive episodes, acute chest syndrome (ACS), pain, and stroke. Heme oxygenase-1 (gene HMOX1; protein HO-1) is the inducible, rate-limiting enzyme in the catabolism of heme and might attenuate the severity of outcomes from vaso-occlusive and hemolytic crises. A (GT)(n) dinucleotide repeat located in the promoter region of the HMOX1 gene is highly polymorphic, with long repeat lengths linked to decreased activity and inducibility. We examined this polymorphism to test the hypothesis that short alleles are associated with a decreased risk of adverse outcomes (hospitalization for pain or ACS) among a cohort of 942 children with SCD. Allele lengths varied from 13 to 45 repeats and showed a trimodal distribution. Compared with children with longer allele lengths, children with two shorter alleles (4%; ≤25 repeats) had lower rates of hospitalization for ACS (incidence rate ratio 0.28, 95% confidence interval: 0.10-0.81), after adjusting for sex, age, asthma, percentage of fetal hemoglobin and alpha-globin gene deletion. No relationship was identified between allele lengths and pain rate. We provide evidence that genetic variation in HMOX1 is associated with decreased rates of hospitalization for ACS, but not pain. This study is registered at www.ClinicalTrails.gov (NCT00072761). |
Increased risk of venous thromboembolism is associated with genetic variation in heme oxygenase-1 in Blacks.
Bean CJ , Boulet SL , Ellingsen D , Trau H , Ghaji N , Hooper WC , Austin H . Thromb Res 2012 130 (6) 942-7 BACKGROUND: Venous thromboembolism (VTE) affects as many as 1 in 1000 individuals in the United States. Although Blacks are disproportionately affected by VTE, few genetic risk factors have been identified in this population. The inducible heme oxygenase-1 (HMOX1) gene encodes a key cytoprotective enzyme with anti-inflammatory, antioxidant and anticoagulant activity acting in the vascular system. A (GT)(n) microsatellite located in the promoter of the HMOX1 gene influences the level of response. METHODS AND RESULTS: Using the Genetic Attributes and Thrombosis Epidemiology (GATE) study, we examined the association between HMOX1 repeat length and VTE events in 883 Black and 927 White patients and matched controls. We found no association between HMOX1 genotypes and VTE in Whites. However, in Black patients, carrying two long (L) alleles (≥34 repeats) was significantly associated with provoked (odds ratio (OR) 1.86, 95% confidence interval (CI): 1.19-2.90) or recurrent (OR 3.13, 95% CI: 1.77-5.53) VTE events. CONCLUSIONS: We have demonstrated for the first time an association between genetic variation in HMOX1, and VTE in Blacks. Our results support a key role for the heme oxygenase system in protecting patients at increased risk for thrombosis and suggest a potential mechanism for targeted screening and intervention. |
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. |
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