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  • 1
    In: Blood, American Society of Hematology, Vol. 104, No. 11 ( 2004-11-16), p. 3078-3078
    Abstract: Over 80% of adults with hemophilia are infected with hepatitis C (HCV) infection through exposure to clotting factor concentrates 20 or more years ago. Although liver biopsy is considered the gold standard to assess the severity of HCV liver disease, the majority of those with hemophilia do not undergo biopsy, even by the less invasive transjugular route. Little is known about the actual or perceived bleeding risks which may affect patient decisions about biopsy. Further, little is known about the minimal hemostatic dose of factor replacement which may affect physician decisions about biopsy. Of 161 hemophilic men enrolled in the multicenter HIV and HCV in Hemophilia (HHH) study which evaluates extent of and risks for HCV disease progression, 112 (69.6%) have decided against biopsy. Among the reasons, given by 75 of the latter, were fear of the procedure, in 23 (30.7%); lack of insurance, in 11 (14.7%); past biopsy, in 11 (14.7%); lack of time, in 10 (13.3%); lack of perceived indication, in 6 (8.0%); presence of an inhibitor, in 5 (6.7%); fear of bleeding, in 5 (6.7%); and other illness or uncertainty, in 4 (5.3%). The 49 (30.4%) agreeing to liver biopsy were more likely than those declining biopsy to be HIV+ (53.1% vs. 34.8%, p & lt; 0.05) and less likely to have an inhibitor (0% vs. 13.4%, p = 0.002), but were as likely to have hemophilia A, 81.6% vs. 83.0%; be over 35 years of age, 49.0% vs. 53.1%; Caucasian, 81.6% vs. 85.7%; and HCV genotype 1, 80.8% vs. 79.5%, all p & gt; 0.05. At the time of biopsy, the median platelet count was 185,000/ul (38,000–366,000/ul), the median PT was 12.0 seconds (9.4–15.4 sec), and the median INR was 1.0 (0.9–1.2). All patients received two doses of factor, and 25 (71.4%) received a third dose; three (8.6%) received a fourth dose for unrelated procedures. The median pre- and post-biopsy F.VIII doses were 49.5 U/kg, 26.6 U/kg at 1–4 hours and 45.0 U/kg at 24–48 hours; and the median F.IX doses were 74.0 U/kg, 44.3 U/kg, and 45.0 U/kg, respectively. No biopsy-related bleeding occurred. Minor adverse events included fever in two, liver function abnormality in one, and duodenal ulcer bleeding in one. The median Knodell, Ishak, and Metavir scores did not differ significantly by HIV status (+ vs.), type hemophilia (A vs. B), age ( & gt;35 vs ≤ 35 yr), HCV genotype (1 vs. non-1), or race (Caucasian vs. non-Caucasian). Although preliminary, these findings suggest that fear of the procedure is the most common deterrent to liver biopsy in patients with hemophilia. Yet, when performed by the transjugular route, liver biopsy appears to be safe, with excellent hemostasis achieved with a minimum of two doses of factor, including a 100% dose pre- and a 50% dose post-biopsy. These findings will require confirmation in larger numbers of subjects.
    Type of Medium: Online Resource
    ISSN: 0006-4971 , 1528-0020
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    Language: English
    Publisher: American Society of Hematology
    Publication Date: 2004
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  • 2
    In: Blood, American Society of Hematology, Vol. 110, No. 11 ( 2007-11-16), p. 1162-1162
    Abstract: Inhibitors are now considered to be the most important complication of clotting factor replacement therapy in hemophilia. In January 2005, the Universal Data Collection (UDC) project, which includes data on over 14,000 patients with hemophilia A or B, was amended to include prospective data collection on inhibitors. We report interim results of a pilot project involving 9 selected Hemophilia Treatment Centers in the U.S. Dedicated data managers collected risk factor and product exposure data from enrolled patients on a monthly basis. Tracked infusion log submissions were used to estimate patient adherence to infusion log completion. A blood specimen is collected at baseline, annually, at product switch, or for clinical indication and is tested centrally for inhibitor using the Nijmegen modification method. Results are reported and any above a threshold value are followed up with repeat testing and clinical correlation. As of August 2007, 514 male patients with hemophilia, ages 2–84 years (mean 23 yrs SD 17) had been enrolled. Of these, 415 (81%) had FVIII deficiency (64% severe, 20% moderate, 16% mild) and 99 (19%) had FIX deficiency (35%, 43%, and 22%, respectively). 85% of the patients were caucasian, 8% black, and 4% Hispanic. A previous history of inhibitor was present at enrollment in 71 (14%). Prophylactic treatment was used by 37% and 80% received product by home infusion. Historical exposure to product collected at enrollment was as follows: 14% had 0–20 exposure days (ED), 12% had 21–100 ED, 7% had 101–150 ED, and 64% 〉 150 ED. During follow-up, 6 patients have had inhibitor titer measurements over 0.4 BU. One of these was known to have an active inhibitor at enrollment. Confirmatory testing of remaining cases is underway. Mean adherence rate for patient infusion log completion in the 9 HTC’s was 45% (range 7% to 74%). Overall adherence increased with time on study from about 40% at one month to nearly 60% for those enrolled at least 10 months. In summary, enrolled participants represent a wide range of characteristics including age, race, disease severity and number of factor exposures. Interim findings indicate that prospective collection of factor infusion data from hemophilia patients necessary to appropriately monitor inhibitor formation, is feasible but labor intensive and requires patient adherence to completion and submission of accurate infusion logs. Because inhibitor formation is rare and the potential risk factors are many, large scale studies with long-term follow-up will be needed to fully assess risk factors for inhibitors.
    Type of Medium: Online Resource
    ISSN: 0006-4971 , 1528-0020
    RVK:
    RVK:
    Language: English
    Publisher: American Society of Hematology
    Publication Date: 2007
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    detail.hit.zdb_id: 80069-7
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  • 3
    In: Blood, American Society of Hematology, Vol. 112, No. 11 ( 2008-11-16), p. 1017-1017
    Abstract: More than 600 U.S. hemophilia patients have been genotyped as part of the pilot study for a prospective surveillance system for factor inhibitors conducted at 12 U.S. Hemophilia Treatment Centers. 80% of enrolled subjects had hemophilia A, 58% with severe disease, 24% moderate, and 18% mild. Age ranged from & lt;1 to 84 years. 83% were white, 8% black, and 4% Hispanic. In hemophilia A patients, all exons, all intron-exon junction regions, and the 3′ untranslated region of the factor VIII (F8) gene were resequenced in both directions by automated sequencer. The VariantSEQr™ protocol was used for resequencing on a 3730 DNA Analyzer from Applied Biosystems. The PCR primers and M13 sequencing primers are described at http://www.ncbi.nlm.nih.gov/sites/entrez?db=probe with a few modifications to the PCR primers to enhance throughput and reproducibility. Data were analyzed with SeqScape®. Inversions of intron 22 and intron 1 in the F8 gene were examined by PCR. Among 477 hemophilia A patients, missense mutations were found in 196 (41%), intron 22 inversions in 139 (29%), frameshifts in 50 (10%), nonsense mutations in 41 (9%), large deletions in 18 (4%), intron 1 inversions in 9 (2%), splice site changes in 5 (0.6%), and insertion in 1 (0.2%). Two mutations were identified in 4 (0.8%). No mutation was identified in 18 (4%). 124/139 of int22 inversions were reported to result in severe hemophilia, as well as 18/18 large deletions, 44/50 frameshifts, 37/41 nonsense mutations, and 8/9 int1 inversions. Of 196 missense mutations, 56 resulted in severe disease, 55 in moderate, and 80 in mild. History of inhibitor was reported in 79 patients, 22.4% of those with severe, 11.8% of those with moderate, and 2.4% of those with mild disease. Inhibitors occurred in 61% of those with large deletions, 26% of intron 22 inversions, 22% of nonsense mutations, 14% of frameshifts, 11% of intron 1 inversions, 6% of missense mutations, 20% of splice site changes, and 11% of those with no mutation identified. 173 distinct mutations were observed, 81 of which have not been reported previously in the Hemophilia A Mutation Database (HAMSTeRS). Among the patients enrolled in the study, black patients with hemophilia A were more likely to have a history of inhibitor than white patients (p=0.02). In hemophilia B patients, the promoter, coding regions, and intron-exon junctions of the factor IX (F9) gene were resequenced as above. Among 123 hemophilia B patients, 90 (73%) had missense mutations, 9 (7%) had frameshift mutations, 8 (7%) had nonsense mutations, and 3 (2%) had deletions. Two enrolled patients had history of FIX inhibitor, one with a large deletion and one a missense mutation. Centralized testing with high-throughput systems allows genotype to be used as a variable in ongoing studies of inhibitor risk. This project is supported by the CDC Foundation through a grant from Wyeth Pharmaceuticals, which had no role in data analysis or abstract preparation.
    Type of Medium: Online Resource
    ISSN: 0006-4971 , 1528-0020
    RVK:
    RVK:
    Language: English
    Publisher: American Society of Hematology
    Publication Date: 2008
    detail.hit.zdb_id: 1468538-3
    detail.hit.zdb_id: 80069-7
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