69 results on '"Abshire TC"'
Search Results
2. Prophylaxis versus episodic treatment to prevent joint disease in boys with severe hemophilia.
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Manco-Johnson MJ, Abshire TC, Shapiro AD, Riske B, Hacker MR, Kilcoyne R, Ingram JD, Manco-Johnson ML, Funk S, Jacobson L, Valentino LA, Hoots WK, Buchanan GR, DiMichele D, Recht M, Brown D, Leissinger C, Bleak S, Cohen A, and Mathew P
- Abstract
Background: Effective ways to prevent arthropathy in severe hemophilia are unknown.Methods: We randomly assigned young boys with severe hemophilia A to regular infusions of recombinant factor VIII (prophylaxis) or to an enhanced episodic infusion schedule of at least three doses totaling a minimum of 80 IU of factor VIII per kilogram of body weight at the time of a joint hemorrhage. The primary outcome was the incidence of bone or cartilage damage as detected in index joints (ankles, knees, and elbows) by radiography or magnetic resonance imaging (MRI).Results: Sixty-five boys younger than 30 months of age were randomly assigned to prophylaxis (32 boys) or enhanced episodic therapy (33 boys). When the boys reached 6 years of age, 93% of those in the prophylaxis group and 55% of those in the episodic-therapy group were considered to have normal index-joint structure on MRI (P=0.006). The relative risk of MRI-detected joint damage with episodic therapy as compared with prophylaxis was 6.1 (95% confidence interval, 1.5 to 24.4). The mean annual numbers of joint and total hemorrhages were higher at study exit in the episodic-therapy group than in the prophylaxis group (P<0.001 for both comparisons). High titers of inhibitors of factor VIII developed in two boys who received prophylaxis; three boys in the episodic-therapy group had a life-threatening hemorrhage. Hospitalizations and infections associated with central-catheter placement did not differ significantly between the two groups.Conclusions: Prophylaxis with recombinant factor VIII can prevent joint damage and decrease the frequency of joint and other hemorrhages in young boys with severe hemophilia A. (ClinicalTrials.gov number, NCT00207597 [ClinicalTrials.gov].). [ABSTRACT FROM AUTHOR]- Published
- 2007
3. Sense and sensibility: approaching anemia in children.
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Abshire TC
- Abstract
To determine the cause of a child's anemia, focus on aspects of the history and physical examination and on a few laboratory tests, the author advocates. Generally, the hemoglobin concentration, reticulocyte count, mean corpuscular volume, and peripheral blood smear tell you what you need to know. [ABSTRACT FROM AUTHOR]
- Published
- 2001
4. A treatment bridge for infants with hemophilia.
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Abshire TC
- Subjects
- Infant, Humans, Antibodies, Monoclonal, Humanized, Hemophilia A therapy, Antibodies, Bispecific
- Published
- 2024
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5. Von Willebrand Factor (VWF) multiplex activity assay differentiation of type 1 von Willebrand Disease (VWD) and variant VWD.
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Roberts JC, Christopherson PA, Tarantino MD, Gonzales SE, Morateck PA, Perry CL, Flood VH, Abshire TC, and Montgomery RR
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- Humans, von Willebrand Factor analysis, Hemorrhage, Canada, von Willebrand Disease, Type 1 diagnosis, von Willebrand Diseases diagnosis, von Willebrand Disease, Type 2 diagnosis
- Abstract
Introduction: VWD diagnosis is challenging requiring multiple VWF activity tests using many individual assays. We have developed an ELISA-based VWF Multiplex Activity Assay (VWF-MAA) to address this concern; however, the ability of the VWF-MAA to discriminate between type 1 VWD, variant VWD, and normal subjects has not been evaluated., Aim: To evaluate the VWF-MAA and its ability to differentiate between type 1 VWD, variant VWD and normal subjects in individuals undergoing an initial laboratory evaluation for bleeding., Methods: A total of 177 plasma samples from the Zimmerman Program: Comparative Effectiveness in the Diagnosis of VWD were evaluated from 11 centres across the US and Canada. The VWF-MAA was compared to Versiti Blood Research Institute (VBRI) and Local Center (LC) assigned VWD diagnosis., Results: Overall, 129/177 (72.9%) were correctly assigned as normal (non-VWD), type 1, or variant VWD compared to the VBRI assigned diagnosis. VWF-MAA assigned non-VWD accurately in 29/57 (50.9%) samples, and type 1 VWD accurately in 93/110 (84.6%) samples. Considering LC diagnosis where there was agreement with VWF-MAA and not VBRI diagnosis, type 1 VWD was accurate in 105/110 (95.5%) samples. Bland-Altman analysis demonstrated good correlation between laboratory methods. VWD, types 2A, 2B, 1C VWD were also assigned by the VWF-MAA., Conclusions: We demonstrate that the VWF-MAA has utility in differentiating type 1 VWD, variant VWD and normal subjects in individuals undergoing an initial laboratory evaluation for bleeding., (© 2023 The Authors. Haemophilia published by John Wiley & Sons Ltd.)
- Published
- 2024
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6. Ristocetin dependent cofactor activity in von Willebrand disease diagnosis: Limitations of relying on a single measure.
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Christopherson PA, Haberichter SL, Flood VH, Sicking UO, Abshire TC, and Montgomery RR
- Abstract
Background: Von Willebrand disease (VWD) is a common inherited bleeding disorder, however the diagnosis can be complicated by a subjective bleeding history and issues with some current von Willebrand factor (VWF) laboratory assays., Objectives: In the Zimmerman Program, we sought to determine how often a type 1 diagnosis was based on a single low VWF ristocetin cofactor (VWF:RCo) level resulting from the common genetic variant p.D1472H or an isolated assay issue, if that low value was corroborated by the VWF glycoprotein-IbM (VWF:GPIbM) assay, and if retesting confirmed original levels., Methods: New patients being evaluated for bleeding were consented. Analysis included VWF sequencing, bleeding scores, and comparisons of local VWF antigen (VWF:Ag) and VWF:RCo to central VWF:Ag and VWF:GPIbM., Results: A total of 18% of VWD subjects had a low local VWF:RCo, but normal VWF:Ag and normal central testing including VWF:GPIbM. Seventy percent of the low VWF:RCo cohort had no pathogenic VWF variants; however, 33% carried p.D1472H. Low VWF:RCo subjects with follow-up local testing within 2 years showed those with p.D1472H continued to have low VWF:RCo and VWF:RCo/VWF:Ag ratio with normal VWF:GPIbM. Subjects without p.D1472H had an increase mean VWF:RCo, resulting in 59% with normal levels on repeat testing., Conclusions: The diagnosis of VWD based on a single low VWF:RCo but normal VWF:Ag, was often attributed to p.D1472H or variability in VWF:RCo that was eliminated with VWF:GPIbM. Our study suggests that using VWF:RCo alone for diagnostic purposes may be insufficient while repeat VWF:RCo or VWF:GPIbM testing can be valuable in establishing a VWD diagnosis., (© 2022 The Authors. Research and Practice in Thrombosis and Haemostasis published by Wiley Periodicals LLC on behalf of International Society on Thrombosis and Haemostasis (ISTH).)
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- 2022
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7. Evaluation for Bleeding Disorders in Suspected Child Abuse.
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Anderst J, Carpenter SL, Abshire TC, Killough E, Mendonca EA, Downs SM, Wetmore C, Allen C, Dickens D, Harper J, Rogers ZR, Jain J, Warwick A, Yates A, Hord J, Lipton J, Wilson H, Kirkwood S, Haney SB, Asnes AG, Gavril AR, Girardet RG, Heavilin N, Gilmartin ABH, Laskey A, Messner SA, Mohr BA, Nienow SM, Rosado N, Idzerda SM, Legano LA, Raj A, Sirotnak AP, Forkey HC, Keeshin B, Matjasko J, Edward H, Chavdar M, Di Paola J, Leavey P, Graham D, Hastings C, Hijiya N, Hord J, Matthews D, Pace B, Velez MC, Wechsler D, Billett A, Stork L, and Hooker R
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- Child, Hemorrhage diagnosis, Hemorrhage etiology, Humans, Prevalence, Blood Coagulation Disorders, Child Abuse diagnosis, Contusions diagnosis, Contusions etiology
- Abstract
Bruising or bleeding in a child can raise the concern for child abuse. Assessing whether the findings are the result of trauma and/or whether the child has a bleeding disorder is critical. Many bleeding disorders are rare, and not every child with bruising/bleeding that may raise a concern for abuse requires an evaluation for bleeding disorders. However, in some instances, bleeding disorders can present in a manner similar to child abuse. Bleeding disorders cannot be ruled out solely on the basis of patient and family history, no matter how extensive. The history and clinical evaluation can be used to determine the necessity of an evaluation for a possible bleeding disorder, and prevalence and known clinical presentations of individual bleeding disorders can be used to guide the extent of laboratory testing. This clinical report provides guidance to pediatricians and other clinicians regarding the evaluation for bleeding disorders when child abuse is suspected., (Copyright © 2022 by the American Academy of Pediatrics.)
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- 2022
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8. Evaluating for Suspected Child Abuse: Conditions That Predispose to Bleeding.
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Carpenter SL, Abshire TC, Killough E, and Anderst JD
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- Child, Diagnosis, Differential, Hemorrhage diagnosis, Humans, Blood Coagulation Disorders diagnosis, Child Abuse diagnosis, Contusions diagnosis, Contusions etiology
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Child abuse might be suspected when children present with cutaneous bruising, intracranial hemorrhage, or other manifestations of bleeding. In these cases, it is necessary to consider medical conditions that predispose to easy bleeding or bruising. When evaluating for the possibility of bleeding disorders and other conditions that predispose to hemorrhage, it is important for pediatricians to consider the child's presenting history, medical history, and physical examination findings before initiating a laboratory investigation. Many medical conditions can predispose to easy bleeding. Before ordering laboratory tests for a disease, it is useful to understand the biochemical basis and clinical presentation of the disorder, condition prevalence, and test characteristics. This technical report reviews the major medical conditions that predispose to bruising or bleeding and should be considered when evaluating for abusive injury., (Copyright © 2022 by the American Academy of Pediatrics.)
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- 2022
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9. Effect of Anticoagulant Therapy for 6 Weeks vs 3 Months on Recurrence and Bleeding Events in Patients Younger Than 21 Years of Age With Provoked Venous Thromboembolism: The Kids-DOTT Randomized Clinical Trial.
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Goldenberg NA, Kittelson JM, Abshire TC, Bonaca M, Casella JF, Dale RA, Halperin JL, Hamblin F, Kessler CM, Manco-Johnson MJ, Sidonio RF, Spyropoulos AC, Steg PG, Turpie AGG, and Schulman S
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- Adolescent, Age Factors, Anticoagulants adverse effects, Child, Child, Preschool, Drug Administration Schedule, Female, Follow-Up Studies, Humans, Incidence, Infant, Infant, Newborn, Kaplan-Meier Estimate, Male, Recurrence, Therapeutics, Time Factors, Venous Thromboembolism etiology, Young Adult, Anticoagulants administration & dosage, Hemorrhage chemically induced, Venous Thromboembolism drug therapy
- Abstract
Importance: Among patients younger than 21 years of age, the optimal duration of anticoagulant therapy for venous thromboembolism is unknown., Objective: To test the hypothesis that a 6-week duration of anticoagulant therapy for provoked venous thromboembolism is noninferior to a conventional 3-month therapy duration in patients younger than 21 years of age., Design, Setting, and Participants: Randomized clinical trial involving 417 patients younger than 21 years of age with acute, provoked venous thromboembolism enrolled at 42 centers in 5 countries from 2008-2021. The main exclusions were severe anticoagulant deficiencies or prior venous thromboembolism. Patients without persistent antiphospholipid antibodies and whose thrombi were resolved or not completely occlusive upon repeat imaging at 6 weeks after diagnosis underwent randomization. The final visit for the primary end points occurred in January 2021., Interventions: Total duration for anticoagulant therapy of 6 weeks (n = 207) vs 3 months (n = 210) for provoked venous thromboembolism., Main Outcomes and Measures: The primary efficacy and safety end points were centrally adjudicated symptomatic recurrent venous thromboembolism and clinically relevant bleeding events within 1 year blinded to treatment group. The primary analysis was noninferiority in the per-protocol population. The noninferiority boundary incorporated a bivariate trade-off that included an absolute increase of 0% in symptomatic recurrent venous thromboembolism with an absolute risk reduction of 4% in clinically relevant bleeding events (1 of 3 points on the bivariate noninferiority boundary curve)., Results: Among 417 randomized patients, 297 (median age, 8.3 [range, 0.04-20.9] years; 49% female) met criteria for the primary per-protocol population analysis. The Kaplan-Meier estimate for the 1-year cumulative incidence of the primary efficacy outcome was 0.66% (95% CI, 0%-1.95%) in the 6-week anticoagulant therapy group and 0.70% (95% CI, 0%-2.07%) in the 3-month anticoagulant therapy group, and for the primary safety outcome, the incidence was 0.65% (95% CI, 0%-1.91%) and 0.70% (95% CI, 0%-2.06%). Based on absolute risk differences in recurrent venous thromboembolism and clinically relevant bleeding events between groups, noninferiority was demonstrated. Adverse events occurred in 26% of patients in the 6-week anticoagulant therapy group and in 32% of patients in the 3-month anticoagulant therapy group; the most common adverse event was fever (1.9% and 3.4%, respectively)., Conclusions and Relevance: Among patients younger than 21 years of age with provoked venous thromboembolism, anticoagulant therapy for 6 weeks compared with 3 months met noninferiority criteria based on the trade-off between recurrent venous thromboembolism risk and bleeding risk., Trial Registration: ClinicalTrials.gov Identifier: NCT00687882.
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- 2022
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10. Screening for von Willebrand disease does not impact posttonsillectomy bleeding in a low-risk population.
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Digiandomenico S, Conley SF, Johnson VP, Christopherson PA, Haberichter SL, Zhang J, Simpson P, Abshire TC, Montgomery RR, and Flood VH
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- Blood Coagulation Tests, Child, Hemorrhage diagnosis, Humans, Perioperative Period adverse effects, von Willebrand Factor, von Willebrand Diseases complications
- Abstract
Background: Bleeding is an important complication in children following tonsillectomy. Screening with coagulation tests prior to procedure is common to assess bleeding risk in the perioperative period, although ASH/ASPHO Choosing Wisely guidelines recommend against routine PT/PTT testing. Our aim was to compare von Willebrand factor antigen (VWF:Ag) and activity levels among patients with postoperative bleeding following tonsillectomy to evaluate for potential risk for bleeding., Procedure: Eligible subjects were aged 0-18 without significant personal or family history of major bleeding. Postoperative bleeding diaries were collected and symptoms measured using a postoperative bleeding score. Plasma VWF levels were drawn at time of anesthesia administration., Results: Postoperative bleeding occurred in 248 cases out of 1399 total subjects. Median VWF:Ag was 86 in patients with postoperative bleeding scores of 1-2, 86 for scores 3-4, 84 for scores 5-6, and 83 for scores >6, with no significant difference among groups (p = .98). Additionally, no difference was observed for subjects with multiple days of postoperative bleeding as compared to those with only 1 day of postoperative bleeding. Finally, no difference in VWF:Ag was observed for subjects whose first reported bleed occurred early in the postoperative course compared to those whose first reported bleed occurred later. VWF:Ag does not correlate with severity of bleeding, time of onset of first bleeding event, or recurrence of bleeding in healthy children with no personal or family history of bleeding who have postoperative bleeding following tonsillectomy., Conclusions: This data does not support routine von Willebrand disease screening prior to tonsillectomy., (© 2021 Wiley Periodicals LLC.)
- Published
- 2021
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11. Laboratory variability in the diagnosis of type 2 VWD variants.
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DiGiandomenico S, Christopherson PA, Haberichter SL, Abshire TC, Montgomery RR, and Flood VH
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- Humans, Prospective Studies, Retrospective Studies, von Willebrand Factor genetics, von Willebrand Disease, Type 2 diagnosis, von Willebrand Disease, Type 2 genetics, von Willebrand Diseases
- Abstract
Essentials Patients with von Willebrand disease were enrolled in our study. Type 2 VWD diagnoses were based on original test results. Repeat evaluation resulted in many patients receiving a different type 2 diagnosis. Some genetic variants were particularly likely to move type 2 subcategories. ABSTRACT: Introduction Type 2 von Willebrand disease (VWD) refers to patients with a qualitative defect in von Willebrand factor. Accurate diagnosis of type 2 VWD subtypes can be challenging. Aim of the study To compare the historical diagnosis of type 2 VWD with current laboratory testing. Methods Subjects were enrolled in the Zimmerman Program either because of a preexisting diagnosis of VWD (retrospective cohort) or from evaluation for bleeding symptoms or suspected VWD (prospective cohort). Original diagnosis was assigned by the local center and central diagnosis was based on central laboratory testing. Results Two hundred and seventeen index cases in the retrospective cohort and 35 subjects in the prospective cohort carried a local diagnosis of type 2 VWD (29% and 6% of enrolled index cases, respectively). In the retrospective cohort, the diagnosis was confirmed in 66% of cases with a preexisting diagnosis of 2A, 77% 2B, 54% 2M, and 72% 2N. In the prospective cohort, 31% were confirmed 2A, 60% 2B, 23% 2M, and 100% 2N. Several genetic variants were repeatedly implicated in subjects with changed diagnosis: p.M1304R, p.R1315C, p.R1374C, and p.R1374H. Conclusions Both the prospective and retrospective cohorts demonstrated consistent variation in subjects whose diagnosis changed between 2A, 2B, and 2M. The importance of accurately diagnosing type 2 VWD may be most significant in the 2B subtype given potential concerns with the use of desmopressin in type 2B VWD. Some genetic variants appear in multiple types of VWD, making specific diagnoses challenging., (© 2020 International Society on Thrombosis and Haemostasis.)
- Published
- 2021
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12. Low VWF levels in children and lack of association with bleeding in children undergoing tonsillectomy.
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Gill JC, Conley SF, Johnson VP, Christopherson PA, Haberichter SL, Diaz CD, Strong TC, Zhang J, Simpson P, Abshire TC, Montgomery RR, and Flood VH
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- Adolescent, Adult, Child, Child, Preschool, Hemorrhage diagnosis, Hemorrhage etiology, Humans, Infant, Infant, Newborn, Surveys and Questionnaires, von Willebrand Factor, Tonsillectomy, von Willebrand Diseases
- Abstract
von Willebrand disease is a common bleeding disorder, but diagnosis can be difficult in young children who have not had bleeding challenges. We sought to evaluate the correlation between bleeding and von Willebrand factor (VWF) levels in children undergoing surgical challenge with tonsillectomy. Children ages 0 to 18 undergoing tonsillectomy without a personal or family history of bleeding were enrolled prospectively following informed consent and institutional review board approval. VWF levels were obtained at the time of surgery. VWF antigen (VWF:Ag) and VWF activity (VWF:GPIbM) were tested via enzyme-linked immunosorbent assay. Bleeding score was calculated using the International Society of Hematology bleeding assessment tool (BAT). Surgical and postoperative bleeding were determined using questionnaires filled out by the surgeon and patient/family. A total of 1399 subjects were enrolled with evaluable data, with a median age of 5 years. The median VWF:Ag was 85 IU/dL and the median VWF:GPIbM was 100 U/dL. Median BAT for the entire population was 0, including those with postoperative bleeding. There was no difference in VWF level between those who experienced postoperative bleeding and those who did not, with median VWF:Ag 85 vs 85 (P = .89) and mean VWF:GPIbM 98 vs 100 (P = .5). Interestingly, there was a difference in VWF levels with age, with median VWF:Ag 81 for those younger than 3 years, 82 for those 3 to 6 years, 90 for those 7 to 10 years, and 100 for those 11 to 18 years. A similar trend was noted for VWF:GPIbM. Of the 2 to 6 year olds, 5% had VWF:Ag <50, which would meet criteria for low VWF, but only 1.8% had an abnormal BAT at study entry and only 2.5% bled after surgery. Only 1 subject with low VWF had an elevated postoperative BAT >2. These data suggest that low VWF levels do not correlate with bleeding in children undergoing tonsillectomy. In addition, VWF levels outside the adult normal range in young children may be more common than previously thought and do not necessarily predict surgical bleeding., (© 2020 by The American Society of Hematology.)
- Published
- 2020
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13. Factor VIII prophylaxis effects outweigh other hemostasis contributors in predicting severe haemophilia A joint outcomes.
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Warren BB, Jacobson L, Kempton C, Buchanan GR, Recht M, Brown D, Leissinger C, Shapiro AD, Abshire TC, and Manco-Johnson MJ
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- Factor VIII pharmacology, Female, Hemophilia A pathology, Hemostasis, Humans, Male, Factor VIII therapeutic use, Hemophilia A complications, Hemophilia A drug therapy, Joint Diseases etiology
- Abstract
Introduction: The Joint Outcome Study (JOS) demonstrated that previously untreated children with severe haemophilia A treated with prophylactic factor VIII (FVIII) concentrate had superior joint outcomes at age 6 years compared to those children treated episodically for bleeding. However, variation in joint outcome within each treatment arm was not well explained., Aim: In this study, we sought to better understand variation in joint outcomes at age 6 years in participants of the JOS., Methods: We evaluated the influence of FVIII half-life, treatment adherence, constitutional coagulant and anticoagulant proteins, and global assays on joint outcomes (number of joint bleeds, total number of bleeds, total MRI score and joint physical exam score). Logistic regression was used to evaluate the association of variables with joint failure status on MRI, defined as presence of subchondral cyst, surface erosion or joint-space narrowing. Each parameter was also correlated with each joint outcome using Spearman correlations., Results: Prophylaxis treatment arm and FVIII trough were each found to reduce risk of joint failure on univariate logistic regression analysis. When controlling for treatment arm, FVIII trough was no longer significant, likely because of the high level of covariation between these variables. We found no consistent correlation between any laboratory assay performed and any joint outcome parameter measured., Conclusion: In the JOS, the effect of prescribed prophylactic FVIII infusions on joint outcome overshadowed the contribution of treatment adherence, FVIII half-life, global assays of coagulation and constitutional coagulation proteins. (ClinicalTrials.gov number, NCT00207597)., (© 2019 John Wiley & Sons Ltd.)
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- 2019
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14. Bleeding-related hospitalization in patients with von Willebrand disease and the impact of prophylaxis: Results from national registers in Sweden compared with normal controls and participants in the von Willebrand Disease Prophylaxis Network.
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Holm E, Carlsson KS, Lövdahl S, Lail AE, Abshire TC, and Berntorp E
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- Case-Control Studies, Female, Humans, Male, Sweden, von Willebrand Diseases therapy, Hemorrhage complications, Hemorrhage prevention & control, Hospitalization statistics & numerical data, Registries, von Willebrand Diseases complications
- Abstract
Introduction: Patients suffering from von Willebrand disease (VWD) have a variety of bleeding symptoms and require both outpatient care for treatment and, in more severe cases, hospitalization., Aim: To investigate the impact of having VWD on frequency of hospitalization compared to a control group and to evaluate whether regular replacement therapy (prophylaxis) is associated with reduction in the number of hospitalizations., Methods: Linkage of national population-based registries was used in the Congenital Bleeding Disorders study in Sweden (CBDS). Data were from the von Willebrand Disease Prophylaxis Network (VWD PN)., Results: The national registries contained 2790 subjects with a diagnosis of VWD between 1987 and 2009. A total of 13 920 age- and gender-matched controls were identified. There were 2.0 times (range 1.5-2.5) as many inpatient hospitalizations among subjects with VWD compared to controls. The most common causes of hospitalization were gastrointestinal (GI) bleeding (n = 232 as primary diagnosis), menorrhagia (n = 198) and epistaxis (n = 192). Outpatient visits per year were also twice as common among those with VWD. From the VWD PN, 105 subjects were included (VWD type 3, 52.4%; type2A, 22.9%; type 1, 12.4% and other types, 3.9%). A total of 122 hospitalizations due to bleeding episodes, dominated by GI bleeds, were analysed. Significantly fewer hospitalizations occurred after initiation of prophylaxis (75 prior to and 45 after, P = .006)., Conclusion: Our study indicates that subjects with VWD have a considerably higher consumption of healthcare resources compared to controls and that initiation of prophylaxis may reduce the number of hospitalizations due to bleeding., (© 2018 John Wiley & Sons Ltd.)
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- 2018
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15. Von Willebrand disease in the United States: perspective from the Zimmerman program.
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Flood VH, Abshire TC, Christopherson PA, Friedman KD, Cox Gill J, Montgomery RR, and Haberichter SL
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This article will discuss the diagnosis and management of von Willebrand disease (VWD) in the United States and results from the Zimmerman Program, a national study of VWD. An algorithm is presented to show how we currently approach diagnostic testing for VWD, including the potential replacement of the ristocetin cofactor assay with a new von Willebrand factor (VWF)-GPIb binding assay. Results from the Zimmerman Program type 1 cohort are presented, including the findings that genetic defects in the VWF gene are most common with VWF levels <30 IU/dL, but bleeding symptoms were present across the entire cohort regardless of VWF level. Typical management of VWD patients is also discussed, including the use of desmopressin and VWF concentrates. Despite these advances, there remain several areas of VWD where more research is required to optimize treatment., Competing Interests: Conflicts of Interest: VHF has served as a consultant for CSL Behring and Shire. KDF has served as a consultant for Bayer, CSL Behring, Genentech, NovoNordisk, and Shire, and as a speaker for Alexion. RRM has a patent for a VWF:GPIbM assay that is used by the Blood Center of Wisconsin. The remaining authors have no conflicts of interest to declare.
- Published
- 2018
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16. Complications of haemophilia in babies (first two years of life): a report from the Centers for Disease Control and Prevention Universal Data Collection System.
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Kulkarni R, Presley RJ, Lusher JM, Shapiro AD, Gill JC, Manco-Johnson M, Koerper MA, Abshire TC, DiMichele D, Hoots WK, Mathew P, Nugent DJ, Geraghty S, Evatt BL, and Soucie JM
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- Centers for Disease Control and Prevention, U.S., Child, Preschool, Data Collection, Female, Hemophilia A epidemiology, Humans, Infant, Infant, Newborn, Male, United States, Hemophilia A complications
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Aim: To describe the prevalence and complications in babies ≤2 years with haemophilia., Methods: We used a standardized collection tool to obtain consented data on eligible babies aged ≤2 years with haemophilia enrolled in the Centers for Disease Control and Prevention Universal Data Collection System surveillance project at US Hemophilia Treatment Centers (HTCs)., Results: Of 547 babies, 82% had haemophilia A, and 70% were diagnosed within one month of birth. Diagnosis was prompted by known maternal carrier status (40%), positive family history (23%), bleeding (35%) and unknown 2%; 81% bled during the first two years. The most common events were bleeding (circumcision, soft tissue, oral bleeding) and head injury. There were 46 episodes of intracranial haemorrhage (ICH) in 37 babies (7%): 18 spontaneous, 14 delivery related, 11 traumatic, 2 procedure related and 1 unknown cause. Of the 176 central venous access devices (CVADs) in 148 (27%) babies, there were 137 ports, 22 surgically inserted central catheters and 20 peripherally inserted central catheters. Ports had the lowest complication rates. Inhibitors occurred in 109 (20%) babies who experienced higher rates of ICH (14% vs. 5%; P = 0.002), CVAD placement (61% vs. 19%; P < 0.001) and CVAD complications (44% vs. 26%; P < 0.001). The most common replacement therapy was recombinant clotting factor concentrates., Conclusion: Bleeding events in haemophilic babies ≤2 years were common; no detectable difference in the rates of ICH by the mode of delivery was noted. Neonatal factor exposure did not affect the inhibitor rates. Minor head trauma, soft tissue and oropharyngeal bleeding were the leading indications for treatment., (© 2016 John Wiley & Sons Ltd.)
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- 2017
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17. Clinical and laboratory variability in a cohort of patients diagnosed with type 1 VWD in the United States.
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Flood VH, Christopherson PA, Gill JC, Friedman KD, Haberichter SL, Bellissimo DB, Udani RA, Dasgupta M, Hoffmann RG, Ragni MV, Shapiro AD, Lusher JM, Lentz SR, Abshire TC, Leissinger C, Hoots WK, Manco-Johnson MJ, Gruppo RA, Boggio LN, Montgomery KT, Goodeve AC, James PD, Lillicrap D, Peake IR, and Montgomery RR
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- Adolescent, Blood Coagulation Tests, Comparative Genomic Hybridization, Female, Genetic Variation, Hemorrhage etiology, Humans, Male, Phenotype, Sequence Analysis, DNA, Surveys and Questionnaires, United States epidemiology, Young Adult, von Willebrand Disease, Type 1 diagnosis, von Willebrand Disease, Type 1 epidemiology, von Willebrand Factor analysis, von Willebrand Factor genetics, von Willebrand Disease, Type 1 blood
- Abstract
von Willebrand disease (VWD) is the most common inherited bleeding disorder, and type 1 VWD is the most common VWD variant. Despite its frequency, diagnosis of type 1 VWD remains the subject of debate. In order to study the spectrum of type 1 VWD in the United States, the Zimmerman Program enrolled 482 subjects with a previous diagnosis of type 1 VWD without stringent laboratory diagnostic criteria. von Willebrand factor (VWF) laboratory testing and full-length VWF gene sequencing was performed for all index cases and healthy control subjects in a central laboratory. Bleeding phenotype was characterized using the International Society on Thrombosis and Haemostasis bleeding assessment tool. At study entry, 64% of subjects had VWF antigen (VWF:Ag) or VWF ristocetin cofactor activity below the lower limit of normal, whereas 36% had normal VWF levels. VWF sequence variations were most frequent in subjects with VWF:Ag <30 IU/dL (82%), whereas subjects with type 1 VWD and VWF:Ag ≥30 IU/dL had an intermediate frequency of variants (44%). Subjects whose VWF testing was normal at study entry had a similar rate of sequence variations as the healthy controls (14%). All subjects with severe type 1 VWD and VWF:Ag ≤5 IU/dL had an abnormal bleeding score (BS), but otherwise BS did not correlate with VWF:Ag. Subjects with a historical diagnosis of type 1 VWD had similar rates of abnormal BS compared with subjects with low VWF levels at study entry. Type 1 VWD in the United States is highly variable, and bleeding symptoms are frequent in this population., (© 2016 by The American Society of Hematology.)
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- 2016
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18. Changes in bleeding patterns in von Willebrand disease after institution of long-term replacement therapy: results from the von Willebrand Disease Prophylaxis Network.
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Holm E, Abshire TC, Bowen J, Álvarez MT, Bolton-Maggs P, Carcao M, Federici AB, Gill JC, Halimeh S, Kempton C, Key NS, Kouides P, Lail A, Landorph A, Leebeek F, Makris M, Mannucci P, Mauser-Bunschoten EP, Nugent D, Valentino LA, Winikoff R, and Berntorp E
- Subjects
- Adolescent, Adult, Aged, Aged, 80 and over, Child, Child, Preschool, Epistaxis complications, Female, Hemarthrosis complications, Humans, Infant, Male, Menorrhagia complications, Middle Aged, Prospective Studies, Retrospective Studies, Young Adult, Epistaxis prevention & control, Gastrointestinal Hemorrhage prevention & control, Hemarthrosis prevention & control, Menorrhagia prevention & control, von Willebrand Diseases complications, von Willebrand Diseases therapy, von Willebrand Factor therapeutic use
- Abstract
Clinically, the leading symptom in von Willebrand disease (VWD) is bleeding, chiefly of mucosal type, for example, epistaxis, gingival, or gastrointestinal bleeding, and menorrhagia. In severe forms of VWD with secondary deficiency of factor VIII, spontaneous joint bleeding, resembling that observed in severe haemophilia A, may also be observed. The bleeding patterns of VWD can affect quality of life, and may be life-threatening. The von Willebrand Disease Prophylaxis Network is an international study group formed with the goal of investigating the role of prophylaxis in clinically severe VWD. The objective of the present study is to investigate the response to prophylaxis focusing primarily on epistaxis, joint bleeding, gastrointestinal bleeding, and heavy bleeding associated with menses. Data from 105 subjects, 10 enrolled in a prospective study and 95 in a retrospective study between 2008 and 2013, were available for analysis. The median annualized rate reductions in bleeding were significant for epistaxis (P < 0.0001), gastrointestinal bleeding (P = 0.0003), joint bleeding (P < 0.0001), and menorrhagia (P = 0.008). Doses on a group level were approximately the same prior to and during prophylaxis, but more patients with gastrointestinal bleeding had prophylaxis three or more times per week as well as higher dosages. Our study, which primarily used retrospective data, indicates that prospective studies are needed to better delineate the doses and dose intervals that should be used for prophylactic treatment of VWD.
- Published
- 2015
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19. No increase in bleeding identified in type 1 VWD subjects with D1472H sequence variation.
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Flood VH, Friedman KD, Gill JC, Haberichter SL, Christopherson PA, Branchford BR, Hoffmann RG, Abshire TC, Dunn AL, Di Paola JA, Hoots WK, Brown DL, Leissinger C, Lusher JM, Ragni MV, Shapiro AD, and Montgomery RR
- Subjects
- Amino Acid Substitution genetics, Aspartic Acid genetics, Case-Control Studies, Hemorrhage diagnosis, Hemorrhage etiology, Histidine genetics, Humans, Incidence, Mutation, Missense, Research Design, Severity of Illness Index, von Willebrand Disease, Type 1 complications, von Willebrand Disease, Type 1 diagnosis, Hemorrhage epidemiology, Hemorrhage genetics, von Willebrand Disease, Type 1 epidemiology, von Willebrand Disease, Type 1 genetics, von Willebrand Factor genetics
- Abstract
The diagnosis of von Willebrand disease (VWD) is complicated by issues with current laboratory testing, particularly the ristocetin cofactor activity assay (VWF:RCo). We have recently reported a sequence variation in the von Willebrand factor (VWF) A1 domain, p.D1472H (D1472H), associated with a decrease in the VWF:RCo/VWF antigen (VWF:Ag) ratio but not associated with bleeding in healthy control subjects. This report expands the previous study to include subjects with symptoms leading to the diagnosis of type 1 VWD. Type 1 VWD subjects with D1472H had a significant decrease in the VWF:RCo/VWF:Ag ratio compared with those without D1472H, similar to the findings in the healthy control population. No increase in bleeding score was observed, however, for VWD subjects with D1472H compared with those without D1472H. These results suggest that the presence of the D1472H sequence variation is not associated with a significant increase in bleeding symptoms, even in type 1 VWD subjects.
- Published
- 2013
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20. Evaluation for bleeding disorders in suspected child abuse.
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Anderst JD, Carpenter SL, and Abshire TC
- Subjects
- Blood Coagulation Disorders blood, Blood Coagulation Disorders complications, Blood Coagulation Tests, Child, Child, Preschool, Contusions blood, Decision Support Techniques, Diagnosis, Differential, Hemorrhage blood, Hemorrhagic Disorders blood, Hemorrhagic Disorders complications, Humans, Infant, Infant, Newborn, Intracranial Hemorrhages blood, Intracranial Hemorrhages etiology, Vitamin K Deficiency Bleeding diagnosis, Blood Coagulation Disorders diagnosis, Child Abuse diagnosis, Contusions etiology, Hemorrhage etiology, Hemorrhagic Disorders diagnosis
- Abstract
Bruising or bleeding in a child can raise the concern for child abuse. Assessing whether the findings are the result of trauma and/or whether the child has a bleeding disorder is critical. Many bleeding disorders are rare, and not every child with bruising/bleeding concerning for abuse requires an evaluation for bleeding disorders. In some instances, however, bleeding disorders can present in a manner similar to child abuse. The history and clinical evaluation can be used to determine the necessity of an evaluation for a possible bleeding disorder, and prevalence and known clinical presentations of individual bleeding disorders can be used to guide the extent of the laboratory testing. This clinical report provides guidance to pediatricians and other clinicians regarding the evaluation for bleeding disorders when child abuse is suspected.
- Published
- 2013
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21. Evaluating for suspected child abuse: conditions that predispose to bleeding.
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Carpenter SL, Abshire TC, and Anderst JD
- Subjects
- Blood Coagulation Disorders blood, Blood Coagulation Disorders complications, Blood Coagulation Tests, Child, Contusions blood, Diagnosis, Differential, Hemorrhage blood, Hemorrhagic Disorders blood, Hemorrhagic Disorders complications, Humans, Intracranial Hemorrhages blood, Intracranial Hemorrhages etiology, Blood Coagulation Disorders diagnosis, Child Abuse diagnosis, Contusions etiology, Hemorrhage etiology, Hemorrhagic Disorders diagnosis
- Abstract
Child abuse might be suspected when children present with cutaneous bruising, intracranial hemorrhage, or other manifestations of bleeding. In these cases, it is necessary to consider medical conditions that predispose to easy bleeding/bruising. When evaluating for the possibility of bleeding disorders and other conditions that predispose to hemorrhage, the pediatrician must consider the child's presenting history, medical history, and physical examination findings before initiating a laboratory investigation. Many medical conditions can predispose to easy bleeding. Before ordering laboratory tests for a disease, it is useful to understand the biochemical basis and clinical presentation of the disorder, condition prevalence, and test characteristics. This technical report reviews the major medical conditions that predispose to bruising/bleeding and should be considered when evaluating for abusive injury.
- Published
- 2013
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22. Prophylaxis in severe forms of von Willebrand's disease: results from the von Willebrand Disease Prophylaxis Network (VWD PN).
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Abshire TC, Federici AB, Alvárez MT, Bowen J, Carcao MD, Cox Gill J, Key NS, Kouides PA, Kurnik K, Lail AE, Leebeek FW, Makris M, Mannucci PM, Winikoff R, and Berntorp E
- Subjects
- Adolescent, Adult, Aged, Child, Child, Preschool, Drug Administration Schedule, Female, Hemarthrosis etiology, Hemarthrosis prevention & control, Hemorrhage etiology, Humans, Male, Middle Aged, Retrospective Studies, Young Adult, von Willebrand Diseases complications, Coagulants therapeutic use, Hemorrhage prevention & control, von Willebrand Diseases drug therapy, von Willebrand Factor therapeutic use
- Abstract
The bleeding patterns of severe von Willebrand's disease (VWD) adversely affect quality of life, and may be life threatening. There is a presumed role for prophylaxis with VWF-containing concentrates, but data are scarce. The von Willebrand Disease Prophylaxis Network (VWD PN) was formed to investigate the role of prophylaxis in clinically severe VWD that is not responsive to other treatment(s).Using a retrospective design, the effect of prophylaxis was studied. Availability of records to document, or reliably assess, the type and frequency of bleeding episodes prior to, and after, the initiation of prophylaxis was required. Annualized bleeding rates were calculated for the period prior to prophylaxis, during prophylaxis and by primary bleeding indication defined as the site accounting for more than half of all bleeding symptoms. The Wilcoxon signed-rank test of differences in the medians was used. Sixty-one subjects from 20 centres in 10 countries were enrolled. Data for 59 were used in the analysis. The median age at onset of prophylaxis was 22.4 years. Type 3 VWD accounted for the largest number (N = 34, 57.6%). Differences in bleeding rates within individuals during compared with before prophylaxis were significant for the total group (P < 0.0001), and for those with primary bleeding indications of epistaxis (P = 0.0005), joint bleeding (P = 0.002) and GI bleeding (P = 0.001). The effect of prophylaxis was similar among those age < 18 years and those ≥ 18. One person developed an inhibitor during treatment. We conclude that prophylactic treatment of VWD is efficacious., (© 2012 Blackwell Publishing Ltd.)
- Published
- 2013
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23. Pharmacokinetics and safety of OBI-1, a recombinant B domain-deleted porcine factor VIII, in subjects with haemophilia A.
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Kempton CL, Abshire TC, Deveras RA, Hoots WK, Gill JC, Kessler CM, Key NS, Konkle BA, Kuriakose P, Macfarlane DE, and Bergman G
- Subjects
- Adolescent, Adult, Animals, Blood Coagulation Factor Inhibitors blood, Factor VIII adverse effects, Factor VIII antagonists & inhibitors, Hemophilia A blood, Humans, Infusions, Intravenous, Male, Middle Aged, Peptide Fragments administration & dosage, Peptide Fragments adverse effects, Peptide Fragments pharmacokinetics, Recombinant Proteins administration & dosage, Recombinant Proteins adverse effects, Recombinant Proteins pharmacokinetics, Swine, Young Adult, Factor VIII administration & dosage, Factor VIII pharmacokinetics, Hemophilia A therapy
- Abstract
OBI-1 is a recombinant B-domain deleted porcine factor VIII (FVIII). FVIII treatment in those with haemophilia A may be complicated by the development of anti-FVIII antibodies (inhibitors) leading to a failure to respond to treatment with human FVIII. To compare the pharmacokinetics and safety of a single dose of OBI-1 with Hyate:C in subjects with haemophilia A and inhibitors, subjects were randomized to receive either Hyate:C followed by placebo or placebo followed by OBI-1 in a double-blind fashion. FVIII levels were assayed using both a one-stage coagulation assay (OSCA) and chromogenic assay. Pharmacokinetic parameters for FVIII were calculated for 6/9 subjects randomized; in three subjects baseline anti-porcine FVIII inhibitors led to a lack of measurable FVIII activity. Mean C(max) appeared higher for OBI-1 (OSCA: 176.00 U dL(-1), standard deviation ± 88.00; chromogenic: 151.00 ± 31.51 U dL(-1)) than Hyate:C (OSCA: 82.3 ± 19.22 U dL(-1); chromogenic: 52.67 ± 13.8 U dL(-1)). Mean AUC also appeared higher for OBI-1 (OSCA: 2082.87 ± 1323.43 U h(-1) dL(-1) ; chromogenic: 1817.28 ± 625.14 U h(-1) dL(-1)) than Hyate:C (OSCA: 1177.8 ± 469.49 U h(-1) dL(-1); chromogenic: 707.61 ± 420.05 U h(-1) dL(-1)). Two infusion-related events occurred: one with Hyate:C, one with placebo. Four of five subjects without anti-porcine FVIII inhibitors at baseline remained porcine FVIII inhibitor negative 29 days after infusion. A single dose of OBI-1 appears to have higher bioavailability than Hyate:C in subjects with haemophilia A without measurable anti-porcine FVIII inhibitors, and is well tolerated. These results should be confirmed in a larger phase 2/3 study., (© 2012 Blackwell Publishing Ltd.)
- Published
- 2012
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24. VWF mutations and new sequence variations identified in healthy controls are more frequent in the African-American population.
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Bellissimo DB, Christopherson PA, Flood VH, Gill JC, Friedman KD, Haberichter SL, Shapiro AD, Abshire TC, Leissinger C, Hoots WK, Lusher JM, Ragni MV, and Montgomery RR
- Subjects
- Amino Acid Substitution, Exons, Gene Order, Humans, von Willebrand Factor metabolism, Black or African American genetics, Genetic Variation, Mutation, von Willebrand Diseases ethnology, von Willebrand Diseases genetics, von Willebrand Factor genetics
- Abstract
Diagnosis and classification of VWD is aided by molecular analysis of the VWF gene. Because VWF polymorphisms have not been fully characterized, we performed VWF laboratory testing and gene sequencing of 184 healthy controls with a negative bleeding history. The controls included 66 (35.9%) African Americans (AAs). We identified 21 new sequence variations, 13 (62%) of which occurred exclusively in AAs and 2 (G967D, T2666M) that were found in 10%-15% of the AA samples, suggesting they are polymorphisms. We identified 14 sequence variations reported previously as VWF mutations, the majority of which were type 1 mutations. These controls had VWF Ag levels within the normal range, suggesting that these sequence variations might not always reduce plasma VWF levels. Eleven mutations were found in AAs, and the frequency of M740I, H817Q, and R2185Q was 15%-18%. Ten AA controls had the 2N mutation H817Q; 1 was homozygous. The average factor VIII level in this group was 99 IU/dL, suggesting that this variation may confer little or no clinical symptoms. This study emphasizes the importance of sequencing healthy controls to understand ethnic-specific sequence variations so that asymptomatic sequence variations are not misidentified as mutations in other ethnic or racial groups.
- Published
- 2012
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25. A community-based partnership to promote information infrastructure for bleeding disorders.
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Aschman DJ, Abshire TC, Shapiro AD, Lusher JM, Forsberg AD, and Kulkarni R
- Subjects
- Ambulatory Care Facilities, Humans, Information Services economics, Public Health, Blood Coagulation Disorders, Community Networks organization & administration, Information Services organization & administration, Public-Private Sector Partnerships
- Abstract
Specialists in rare disorders often face challenges in collecting surveillance and research data. As movement toward more fully realizing the potential of electronic health information gains momentum, practitioners who treat individuals with rare disorders are in need of public-private support to tap into the advantages offered by the developing electronic information technologies and the interoperability standards promulgated by the USDHHS. The not-for-profit American Thrombosis and Hemostasis Network (ATHN) was created in 2006 to provide stewardship of a secure, national, web-based database to support federally funded hemophilia treatment centers (HTCs) across the country. In pursuit of its mission to support clinical outcomes analysis, research, advocacy, and public health reporting in the hemostasis and thrombosis community, ATHN has established a spectrum of community-based partnerships. This paper describes the process and public health benefits of creating formal relationships with 127 of the 134 HTCs from 12 regional networks across the U.S., government agencies such as the CDC, Health Resources and Services Administration, and NIH; consumer-based organizations; and industry leaders. This community-based partnership model can be applied to other rare disorders communities with high economic and public health impact., (Copyright © 2011 American Journal of Preventive Medicine. Published by Elsevier Inc. All rights reserved.)
- Published
- 2011
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26. Evaluation of factor VIII pharmacokinetics and anti-factor VIII antibodies in four boys with haemophilia A and a poor clinical response to factor VIII.
- Author
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Kempton CL, Meeks SL, Donald Harvey R 3rd, and Abshire TC
- Subjects
- Enzyme-Linked Immunosorbent Assay, Humans, Infant, Male, Partial Thromboplastin Time, Treatment Outcome, Antibodies analysis, Blood Coagulation Factor Inhibitors immunology, Factor VIII immunology, Factor VIII pharmacokinetics, Hemophilia A drug therapy
- Published
- 2011
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27. In non-severe hemophilia A the risk of inhibitor after intensive factor treatment is greater in older patients: a case-control study.
- Author
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Kempton CL, Soucie JM, Miller CH, Hooper C, Escobar MA, Cohen AJ, Key NS, Thompson AR, and Abshire TC
- Subjects
- Adult, Age Factors, Aged, Case-Control Studies, Factor VIII therapeutic use, Genotype, Humans, Male, Middle Aged, Multivariate Analysis, Mutation, Missense, Risk Factors, Factor VIII immunology, Hemophilia A blood, Hemophilia A drug therapy
- Abstract
Background: Twenty-five percent of new anti-factor VIII (FVIII) antibodies (inhibitors) that complicate hemophilia A occur in those with mild and moderate disease. Although intensive FVIII treatment has long been considered a risk factor for inhibitor development in those with non-severe disease, its strength of association and the influence of other factors have remained undefined., Objective: To evaluate risk factors for inhibitor development in patients with non-severe hemophilia A., Methods: Information on clinical and demographic variables and FVIII genotype was collected on 36 subjects with mild or moderate hemophilia A and an inhibitor and 62 controls also with mild or moderate hemophilia A but without an inhibitor., Results: Treatment with FVIII for six or more consecutive days during the prior year was more strongly associated with inhibitor development in those ≥30years of age compared with those <30years of age [adjusted odds ratio (OR) 12.62; 95% confidence interval (CI), 2.76-57.81 vs. OR 2.54; 95% CI, 0.61-10.68]. Having previously received <50days of FVIII was also not statistically associated with inhibitor development on univariate or multivariate analysis., Conclusions: These findings suggest that inhibitor development in mild and moderate hemophilia A varies with age, but does not vary significantly with lifetime FVIII exposure days: two features distinct from severe hemophilia A., (© 2010 International Society on Thrombosis and Haemostasis.)
- Published
- 2010
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28. Common VWF exon 28 polymorphisms in African Americans affecting the VWF activity assay by ristocetin cofactor.
- Author
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Flood VH, Gill JC, Morateck PA, Christopherson PA, Friedman KD, Haberichter SL, Branchford BR, Hoffmann RG, Abshire TC, Di Paola JA, Hoots WK, Leissinger C, Lusher JM, Ragni MV, Shapiro AD, and Montgomery RR
- Subjects
- Black or African American genetics, Crotalid Venoms, Exons, Humans, Polymerase Chain Reaction, Polymorphism, Single Nucleotide, Ristocetin metabolism, von Willebrand Diseases genetics, von Willebrand Diseases metabolism, von Willebrand Factor metabolism, Platelet Function Tests methods, von Willebrand Diseases diagnosis, von Willebrand Factor analysis, von Willebrand Factor genetics
- Abstract
The diagnosis of von Willebrand disease relies on abnormalities in specific tests of von Willebrand factor (VWF), including VWF antigen (VWF:Ag) and VWF ristocetin cofactor activity (VWF:RCo). When examining healthy controls enrolled in the T. S. Zimmerman Program for the Molecular and Clinical Biology of von Willebrand disease, we, like others, found a lower mean VWF:RCo compared with VWF:Ag in African American controls and therefore sought a genetic cause for these differences. For the African American controls, the presence of 3 exon 28 single nucleotide polymorphisms (SNPs), I1380V, N1435S, and D1472H, was associated with a significantly lower VWF:RCo/VWF:Ag ratio, whereas the presence of D1472H alone was associated with a decreased ratio in both African American and Caucasian controls. Multivariate analysis comparing race, SNP status, and VWF:RCo/VWF:Ag ratio confirmed that only the presence of D1472H was significant. No difference was seen in VWF binding to collagen, regardless of SNP status. Similarly, no difference in activity was seen using a GPIb complex-binding assay that is independent of ristocetin. Because the VWF:RCo assay depends on ristocetin binding to VWF, mutations (and polymorphisms) in VWF may affect the measurement of "VWF activity" by this assay and may not reflect a functional defect or true hemorrhagic risk.
- Published
- 2010
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29. The "parallel-cohort RCT": Novel design aspects and application in the Kids-DOTT trial of pediatric venous thromboembolism.
- Author
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Goldenberg NA, Tripputi M, Crowther M, Abshire TC, DiMichele D, Manco-Johnson MJ, and Hiatt WR
- Subjects
- Adolescent, Child, Child, Preschool, Cohort Studies, Drug Administration Schedule, Humans, Infant, Multicenter Studies as Topic, Secondary Prevention, Thrombophilia drug therapy, Anticoagulants administration & dosage, Antiphospholipid Syndrome drug therapy, Randomized Controlled Trials as Topic methods, Research Design, Venous Thromboembolism drug therapy
- Abstract
In traditional randomized controlled trial (RCT) designs, patients who are ineligible for randomization are excluded from study participation. However, these patients often constitute an important subgroup of the disease population. By extending existing RCT infrastructure, efforts to evaluate such patients in parallel cohort arms would provide an efficient means of generating multi-center prospective data on natural history, which would facilitate the development of future RCTs involving these subgroups of interest. This brief report discusses principles of the parallel-cohort RCT design, describes the few published trials in which it has been employed, and highlights novel aspects of its use in the Kids-DOTT trial-an ongoing multi-center randomized trial of the duration of anticoagulant therapy for venous thrombosis in children., (Copyright (c) 2009 Elsevier Inc. All rights reserved.)
- Published
- 2010
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30. Inhibitors of factor VIII in black patients with hemophilia.
- Author
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Viel KR, Ameri A, Abshire TC, Iyer RV, Watts RG, Lutcher C, Channell C, Cole SA, Fernstrom KM, Nakaya S, Kasper CK, Thompson AR, Almasy L, and Howard TE
- Subjects
- Adolescent, Adult, Amino Acid Sequence, Antibodies, Blood Coagulation Factor Inhibitors genetics, Child, Child, Preschool, Factor VIII therapeutic use, Haplotypes, Hemophilia A genetics, Hemophilia A therapy, Humans, Isoantibodies, Male, Mutation, Polymorphism, Single Nucleotide, Risk Factors, Young Adult, Black People genetics, Blood Coagulation Factor Inhibitors immunology, Factor VIII genetics, Factor VIII immunology, Hemophilia A ethnology, Hemophilia A immunology
- Abstract
Background: Black patients with hemophilia A (factor VIII deficiency) are twice as likely as white patients to produce inhibitors against factor VIII proteins given as replacement therapy. There are six wild-type factor VIII proteins, designated H1 through H6, but only two (H1 and H2) match the recombinant factor VIII products used clinically. H1 and H2 are found in all racial groups and are the only factor VIII proteins found in the white population to date. H3, H4, and H5 have been found only in blacks. We hypothesized that mismatched factor VIII transfusions contribute to the high incidence of inhibitors among black patients., Methods: We sequenced the factor VIII gene (F8) in black patients with hemophilia A to identify causative mutations and the background haplotypes on which they reside. Results from previous Bethesda assays and information on the baseline severity of hemophilia, age at enrollment, and biologic relationships among study patients were obtained from review of the patients' medical charts. We used multivariable logistic regression to control for these potential confounders while testing for associations between F8 haplotype and the development of inhibitors., Results: Of the 78 black patients with hemophilia enrolled, 24% had an H3 or H4 background haplotype. The prevalence of inhibitors was higher among patients with either of these haplotypes than among patients with haplotype H1 or H2 (odds ratio, 3.6; 95% confidence interval, 1.1 to 12.3; P=0.04), despite a similar spectrum of hemophilic mutations and degree of severity of illness in these two subgroups., Conclusions: These preliminary results suggest that mismatched factor VIII replacement therapy may be a risk factor for the development of anti-factor VIII alloantibodies., (2009 Massachusetts Medical Society)
- Published
- 2009
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31. One year follow-up of children and adolescents with chronic immune thrombocytopenic purpura (ITP) treated with rituximab.
- Author
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Mueller BU, Bennett CM, Feldman HA, Bussel JB, Abshire TC, Moore TB, Sawaf H, Loh ML, Rogers ZR, Glader BE, McCarthy MC, Mahoney DH, Olson TA, Feig SA, Lorenzana AN, Mentzer WC, Buchanan GR, and Neufeld EJ
- Subjects
- Adolescent, Antibodies, Monoclonal, Murine-Derived, Child, Child, Preschool, Chronic Disease, Female, Follow-Up Studies, Hemorrhage, Humans, Infant, Male, Platelet Count, Recurrence, Remission Induction, Rituximab, Antibodies, Monoclonal administration & dosage, Purpura, Thrombocytopenic, Idiopathic drug therapy
- Abstract
Background: We previously showed in a prospective study that rituximab appears to be effective in some children and adolescents with severe chronic immune thrombocytopenia. Eleven of 36 patients achieved and maintained platelet counts over 50,000/mm(3) within the first 12 weeks. These patients were followed for the next year., Methods: Platelet counts were monitored monthly and all subsequent bleeding manifestations and need for further treatment was noted., Results: Eight of the 11 initial responders maintained a platelet count over 150,000/mm(3) without further treatment intervention. Three patients had a late relapse. One initial non-responder achieved a remission after 16 weeks, and two additional patients maintained platelet counts around 50,000/mm(3) without the need for further intervention., Conclusions: Rituximab resulted in sustained efficacy with platelet counts of 50,000/mm(3) or higher in 11 of 36 patients (31%)., ((c) 2008 Wiley-Liss, Inc.)
- Published
- 2009
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32. Diagnosis of type 1 VWD: can the clinical history trump laboratory findings?
- Author
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Abshire TC
- Subjects
- Child, Hemorrhage, Humans, Severity of Illness Index, von Willebrand Diseases diagnosis
- Published
- 2009
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- View/download PDF
33. Abnormalities of prothrombin: a review of the pathophysiology, diagnosis, and treatment.
- Author
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Meeks SL and Abshire TC
- Subjects
- Blood Coagulation physiology, Blood Coagulation Factors administration & dosage, Blood Coagulation Tests, Consanguinity, Female, Genotype, Hemorrhage drug therapy, Humans, Hypoprothrombinemias epidemiology, Hypoprothrombinemias physiopathology, Infant, Newborn, Iran epidemiology, Italy epidemiology, North America epidemiology, Plasma, Pregnancy, Prothrombin metabolism, Rare Diseases genetics, Thrombophilia genetics, Hemorrhage etiology, Hypoprothrombinemias genetics, Mutation, Prothrombin genetics, Registries
- Abstract
Prothrombin (factor II) deficiency is a rare autosomal recessive coagulation disorder that occurs in approximately 1 in 1-2 million people. Prothrombin is activated to thrombin, which in turn proteolytically cleaves fibrinogen to fibrin and contributes to forming a stable fibrin clot. The haemostatic level of prothrombin is thought to be between 20 and 40%, and the half-life is approximately 3 days. There are more than 40 known mutations in prothrombin. Both hypoprothrombinemia and dysprothrombinemia have been described. Low prothrombin activity typically prolongs both the activated partial thromboplastin time and prothrombin time. Clinical manifestations are predominantly mucosal or surgical- or trauma-associated bleeding, but joint bleeding and intracranial haemorrhages have been reported. No purified prothrombin products are available for replacement therapy. Both fresh frozen plasma and prothrombin complex concentrates contain prothrombin and may be used for treatment.
- Published
- 2008
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34. Recombinant tissue plasminogen activator may reduce frequency of central venous access device infection in hemophilia patients undergoing immune tolerance therapy.
- Author
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Dunn AL and Abshire TC
- Subjects
- Anti-Bacterial Agents therapeutic use, Bacterial Infections drug therapy, Bacterial Infections epidemiology, Bacterial Infections etiology, Child, Preschool, Disease Susceptibility, Drug Evaluation, Factor VIII immunology, Factor VIII therapeutic use, Fibrin biosynthesis, Fibrinolysis, Hemophilia A drug therapy, Humans, Isoantibodies immunology, Recombinant Proteins therapeutic use, Thrombophilia drug therapy, Thrombophilia etiology, Bacterial Infections prevention & control, Catheterization, Central Venous adverse effects, Desensitization, Immunologic, Hemophilia A complications, Tissue Plasminogen Activator therapeutic use
- Abstract
Many patients with hemophilia, particularly those with inhibitory antibodies, utilize central venous access devices (CVADs) to facilitate frequent infusions. Infection of these devices is a common complication of factor replacement therapy. This communication reports our center's experience with CVAD infection in three patients with severe hemophilia A undergoing immune tolerance therapy (ITT) in whom intermittent infusions of recombinant tissue plasminogen activator (rTPA, Cathflo Activase) were utilized. In this small experience, patients experienced a decreased frequency of gram-positive infections when receiving routine rTPA treatments. Larger randomized trial should be performed in this patient population at high risk of CVAD infection., ((c) 2007 Wiley-Liss, Inc.)
- Published
- 2008
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35. Incidence of inhibitors in a cohort of 838 males with hemophilia A previously treated with factor VIII concentrates.
- Author
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Kempton CL, Soucie JM, and Abshire TC
- Subjects
- Adolescent, Adult, Child, Child, Preschool, Coagulants therapeutic use, Factor VIII therapeutic use, Feasibility Studies, Follow-Up Studies, Hemophilia A drug therapy, Humans, Male, Population Surveillance, Product Surveillance, Postmarketing, Risk Factors, United States, Autoantibodies blood, Coagulants immunology, Factor VIII immunology, Hemophilia A immunology
- Abstract
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.
- Published
- 2006
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36. Prospective phase 1/2 study of rituximab in childhood and adolescent chronic immune thrombocytopenic purpura.
- Author
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Bennett CM, Rogers ZR, Kinnamon DD, Bussel JB, Mahoney DH, Abshire TC, Sawaf H, Moore TB, Loh ML, Glader BE, McCarthy MC, Mueller BU, Olson TA, Lorenzana AN, Mentzer WC, Buchanan GR, Feldman HA, and Neufeld EJ
- Subjects
- Adolescent, Antibodies, Monoclonal, Murine-Derived, Child, Child, Preschool, Humans, Hypotension chemically induced, Patient Selection, Prospective Studies, Rituximab, Serum Sickness chemically induced, Treatment Outcome, Antibodies, Monoclonal therapeutic use, Antibodies, Monoclonal toxicity, Immunologic Factors therapeutic use, Immunologic Factors toxicity, Purpura, Thrombocytopenic, Idiopathic drug therapy
- Abstract
We assessed safety and efficacy of rituximab in a prospective study of 36 patients, age 2.6 to 18.3 years, with severe chronic immune thrombocytopenic purpura (ITP). The primary outcome of sustained platelets above 50 x 10(9)/L (50,000/mm3) during 4 consecutive weeks, starting in weeks 9 to 12, was achieved by 11 of 36 patients (31%, confidence interval [CI], 16% to 48%). Median response time was 1 week (range, 1 to 7 weeks). Attainment of the primary outcome was not associated with age, prior pharmacologic responses, prior splenectomy, ITP duration, screening platelet count, refractoriness, or IgM reduction. First-dose, infusion-related toxicity was common (47%) despite premedication. Significant drug-related toxicities included third-dose hypotension (n = 1) and serum sickness (n = 2). Peripheral B cells were depleted in all subjects. IgM decreased 3.4% per week, but IgG did not significantly decrease. Rituximab was well tolerated, with manageable infusion-related side effects, but 6% of subjects developed serum sickness. Rituximab is beneficial for some pediatric patients with severe, chronic ITP.
- Published
- 2006
- Full Text
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37. Current issues in prophylactic therapy for persons with hemophilia.
- Author
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Dunn AL and Abshire TC
- Subjects
- Adolescent, Adult, Chemoprevention economics, Chemoprevention trends, Child, Child, Preschool, Coagulants economics, Factor IX economics, Factor IX therapeutic use, Factor VIII economics, Factor VIII therapeutic use, Female, Hemophilia A complications, Hemophilia A economics, Hemophilia B complications, Hemophilia B economics, Hemorrhage economics, Hemorrhage etiology, Humans, Male, Treatment Outcome, Coagulants therapeutic use, Hemophilia A drug therapy, Hemophilia B drug therapy, Hemorrhage prevention & control
- Abstract
Factor VIII or IX replacement in a prophylactic manner is utilized for many patients with moderate to severe hemophilia A or B. Studies have shown it to be effective in reducing or preventing degenerative joint disease in many but not all patients. However, many unanswered questions still exist and optimization of this expensive treatment regimen is needed. This paper recounts the current products that are available for use and explores the literature regarding different treatment regimens. It explores age at initiation, dose, interval between infusions, joint health outcomes, barriers to compliance and age at discontinuation of prophylaxis. Individualized treatment is recommended. Collaborative efforts are needed to improve outcomes for all persons with hemophilia., (Copyright 2006 S. Karger AG, Basel)
- Published
- 2006
- Full Text
- View/download PDF
38. Clinical uses of plasma and plasma fractions: plasma-derived products for hemophilias A and B, and for von Willebrand disease.
- Author
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Josephson CD and Abshire TC
- Subjects
- Blood Coagulation Factors adverse effects, Blood Coagulation Factors supply & distribution, Humans, Plasma virology, Blood Coagulation Factors therapeutic use, Hemophilia A drug therapy, Hemophilia B drug therapy, Plasma chemistry, von Willebrand Diseases drug therapy
- Abstract
The use of plasma-derived factor products to treat hemophilia A, hemophilia B, and von Willebrand disease (vWD) has changed since the start of the human immunodeficiency virus (HIV) epidemic. The use of plasma-derived factor concentrates for hemophilias A and B has decreased in developed countries because of the availability of recombinant products. However, in developing countries, which encompass most of the world's hemophilia community, plasma-product-based therapy remains the backbone of treatment because of economic constraints. Viral attenuation strategies have resulted in a much safer product profile. vWD product selection is less complicated than for hemophilas A and B because plasma-derived products are the only choice for patients who are unresponsive or who cannot receive pharmacologic therapy. As the majority of patients in the world with hemophilias A, B and vWD are treated with plasma-derived clotting factors, the need for these safe and efficacious therapies will continue in the future. This chapter discusses safety strategies for plasma-derived clotting factor, its availability, economics, efficacy, and inhibitor formation.
- Published
- 2006
- Full Text
- View/download PDF
39. Prophylaxis and von Willebrand's disease (vWD).
- Author
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Abshire TC
- Subjects
- Hemorrhage etiology, Hemorrhage prevention & control, Humans, Joint Diseases etiology, Joint Diseases prevention & control, von Willebrand Diseases complications, Premedication, von Willebrand Diseases therapy
- Abstract
Von Willebrand disease (vWD) is an inherited bleeding disorder with a prevalence of approximately 1% in the general population. The bleeding occurs in this disorder primarily because of abnormalities in platelet adhesion, due to a primary deficiency or defect in the von Willebrand factor (vWF) often with a concomitant decrease in factor VIII (FVIII) levels. The mainstay of treatment for the majority of patients with vWD is desmopressin, which releases vWF from endothelial cells. For patients in which desmopressin is neither suitable or recommended, coagulation factor concentrates containing both vWF with FVIII are the alternative therapeutic option for controlling bleeding. Joint disease is an uncommon but disabling complication of vWD. The arthropathy results from recurrent bleeding into a joint, with the ankle and hip being the joints most often affected, particularly in patients with type 3 vWD. Without adequate treatment, persistent bleeding into joints can result in pain, joint degeneration, swelling and loss of range of motion (ROM). There is some evidence to suggest that joint bleeding and subsequent joint damage might be prevented by early prophylaxis. A soon to open clinical trial by the Von Willebrand Disease Prophylaxis Network (vWD PN) aims to further explore this treatment concept. This article addresses the prophylaxis of vWD, with a particular focus on joint disease.
- Published
- 2006
- Full Text
- View/download PDF
40. Leukemia and P32 radionuclide synovectomy for hemophilic arthropathy.
- Author
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Dunn AL, Manco-Johnson M, Busch MT, Balark KL, and Abshire TC
- Subjects
- Adolescent, Autoimmune Diseases complications, Child, Hemophilia A complications, Humans, Inflammation, Leukemia etiology, Male, Osteoarthritis complications, Hemarthrosis complications, Hemarthrosis radiotherapy, Leukemia complications, Phosphorus Radioisotopes adverse effects, Phosphorus Radioisotopes pharmacology, Radiopharmaceuticals therapeutic use, Synovial Membrane radiation effects
- Published
- 2005
- Full Text
- View/download PDF
41. The safety and efficacy of recombinant human blood coagulation factor IX in previously untreated patients with severe or moderately severe hemophilia B.
- Author
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Shapiro AD, Di Paola J, Cohen A, Pasi KJ, Heisel MA, Blanchette VS, Abshire TC, Hoots WK, Lusher JM, Negrier C, Rothschild C, and Roth DA
- Subjects
- Adolescent, Blood Loss, Surgical prevention & control, Child, Child, Preschool, Factor IX adverse effects, Female, HIV Infections diagnosis, Hepatitis A diagnosis, Humans, Infant, Infant, Newborn, Male, Recombinant Proteins administration & dosage, Recombinant Proteins adverse effects, Severity of Illness Index, Treatment Outcome, Factor IX administration & dosage, Hemophilia B drug therapy, Hemorrhage prevention & control
- Abstract
This international clinical trial evaluated the safety and efficacy of recombinant factor IX (rFIX) in previously untreated patients (PUPs) with severe or moderately severe hemophilia B (FIX activity, < or = 3 IU/dL). Sixty-three PUPs aged younger than 1 month to 14 years received rFIX (median treatment duration, 37 months; range, 4-64 months). Mean rFIX recovery (0.68 +/- 0.27 IU/dL per IU/kg) remained constant over 5 years and was similar in infants (1 month to < 2 years) and children (2 to < 12 years). Fifty-four PUPs used rFIX (median dose, 62.7 IU/kg per infusion; range, 8.2-292 IU/kg) to treat 997 hemorrhages. Bleeding was well controlled, with 75% of hemorrhages requiring only one rFIX infusion. Response to rFIX was "excellent" or "good" in 94% of cases. Effective hemostasis was achieved in 32 PUPs receiving rFIX for routine prophylaxis, with 91% of prophylaxis responses rated "excellent." rFIX administered for 30 surgical procedures in 23 PUPs achieved hemostasis for all rated procedures. Five patients experienced allergic-type manifestations, including 2 (3%) patients who developed FIX inhibitors (both > 5 BU/dL). rFIX was well tolerated, with no associated thrombotic events or evidence of viral transmission. These data indicate that rFIX is a safe and effective treatment for PUPs with hemophilia B.
- Published
- 2005
- Full Text
- View/download PDF
42. Recent advances in the management of the child who has hemophilia.
- Author
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Dunn AL and Abshire TC
- Subjects
- Child, Factor IX genetics, Factor VIII genetics, Genetic Carrier Screening, Hemophilia A genetics, Humans, Infant, Newborn, Neonatal Screening methods, Hemophilia A therapy, Hemophilia B therapy
- Abstract
This article discusses recent advances in the management of the child who has hemophilia.
- Published
- 2004
- Full Text
- View/download PDF
43. Arthroscopic synovectomy for hemophilic joint disease in a pediatric population.
- Author
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Dunn AL, Busch MT, Wyly JB, Sullivan KM, and Abshire TC
- Subjects
- Adolescent, Ankle Joint diagnostic imaging, Ankle Joint physiopathology, Ankle Joint surgery, Cartilage, Articular pathology, Child, Child, Preschool, Clinical Protocols, Elbow Joint diagnostic imaging, Elbow Joint surgery, Hemarthrosis etiology, Hemarthrosis pathology, Hemarthrosis physiopathology, Hemophilia A complications, Humans, Knee Joint diagnostic imaging, Knee Joint physiopathology, Knee Joint surgery, Radiography, Range of Motion, Articular, Retrospective Studies, Synovectomy, Arthroscopy, Hemarthrosis surgery
- Abstract
Children with hemophilia can develop progressive arthropathy. Arthroscopic synovectomy has been used to reduce hemarthroses, but few long-term results have been published. In this article the authors review their first 12 years of experience. Data are reported on 44 pediatric patients (69 joints: 39 ankles, 21 elbows, 7 knees, 2 shoulders). The median age at surgery was 10 years Median follow-up was 79 months. Joints with sufficient follow-up data showed a median bleeding frequency decline of 84% (P < 0.001). Median arc of motion was stable or improved in the year after surgery in ankles, elbows, and shoulders. Complications were rare. Radiographic scores worsened slightly. In this largest analysis of arthroscopic synovectomy for children with hemophilia, rehabilitation was not problematic., (Copyright 2004 Lippincott Williams and Wilkins)
- Published
- 2004
- Full Text
- View/download PDF
44. IGIV-C, a novel intravenous immunoglobulin: evaluation of safety, efficacy, mechanisms of action, and impact on quality of life.
- Author
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Bussel JB, Eldor A, Kelton JG, Varon D, Brenner B, Gillis S, Angiolillo A, Kulkarni R, Abshire TC, and Kelleher J
- Subjects
- Adolescent, Adult, Aged, Aged, 80 and over, Caprylates administration & dosage, Caprylates therapeutic use, Caprylates toxicity, Child, Child, Preschool, Double-Blind Method, Female, Humans, Immunoglobulins, Intravenous therapeutic use, Immunoglobulins, Intravenous toxicity, Incidence, Infant, Male, Middle Aged, Platelet Count, Sterilization, Treatment Outcome, Virus Diseases transmission, Immunoglobulins, Intravenous administration & dosage, Purpura, Thrombocytopenic, Idiopathic drug therapy, Quality of Life
- Abstract
The general safety and efficacy of intravenous immunoglobulin (IGIV) as treatment for idiopathic thrombocytopenic purpura (ITP) has been well-studied. The current study compares the safety and efficacy of a novel IGIV (IGIV-C; Gamunex, 10%) with a licensed solvent/detergent-treated product (IGIV-S/D; GamimuneN, 10%) in treatment of ITP. Ninety-seven pediatric and adult patients with acute and chronic ITP were treated in a multi-center, prospective, randomized, double-blind parallel group, non-inferiority trial at 26 international sites. Baseline data (age, duration of ITP, platelet counts, previous treatment) were comparable between groups. Patients were treated with 1 g/kg/day of IGIV-C or IGIV-S/D for 2 days. The primary end-point, proportion of patients whose platelet counts increased from >/=20 x 10(9)/L to >/=50 x 10(9)/L within 7 days after dosing, was achieved by 35/39 (90%) and 35/42 (83%) of patients treated with IGIV-C and IGIV-S/D, respectively. A secondary endpoint, maintaining platelet counts >/=50 x 10(9)/L for >/=7 days, was achieved by 29/39 (74%) of IGIV-C and 25/42 (60%) IGIV-S/D treated patients. Compared with IGIV-S/D, fewer patients treated with IGIV-C received corticosteroids beyond day 7 (p = 0.02). Efficacy was independent of the presence of isoantibodies or blood type, supporting mechanisms of effect different from anti-D treatments. Adverse events were generally mild and occurred with similar frequency in each group. Viral safety monitoring for HIV, HCV, HBV and Parvovirus B19 showed no seroconversions on study. In conclusion, IGIV-C is as safe and efficacious as IGIV-S/D in treatment of ITP.
- Published
- 2004
- Full Text
- View/download PDF
45. Dose optimization of recombinant factor VIIa for control of mild to moderate bleeds in inhibitor patients: Improved efficacy with higher dosing.
- Author
-
Abshire TC
- Subjects
- Blood Coagulation drug effects, Blood Coagulation Factor Inhibitors blood, Blood Coagulation Factor Inhibitors immunology, Blood Coagulation Factors metabolism, Blood Platelets enzymology, Dose-Response Relationship, Drug, Drug Administration Schedule, Factor VII immunology, Factor VII therapeutic use, Factor VIIa, Hemophilia A blood, Hemophilia A drug therapy, Hemophilia B blood, Hemophilia B drug therapy, Hemorrhage blood, Hemorrhage etiology, Humans, Infusions, Parenteral, Injections, Recombinant Proteins blood, Recombinant Proteins immunology, Recombinant Proteins therapeutic use, Treatment Outcome, Factor VII administration & dosage, Hemophilia A complications, Hemophilia B complications, Hemorrhage drug therapy, Recombinant Proteins administration & dosage
- Abstract
Optimal dosing schedules of recombinant factor VIIa (rFVIIa) for the treatment of mild to moderate bleeding episodes in hemophilia patients with inhibitors are currently the subject of much debate. Standard doses of 90 to 110 microg/kg have provided hemostatic efficacy in many cases in the current literature. However, recent studies using doses greater than 200 microg/kg suggest that high-dose regimens may not only be more effective, but may also reduce the number of doses required. Work using in vitro models has indicated that the increased efficacy of high-dose rFVIIa may be attributed to accelerated clot formation and a stronger, more rapid thrombin burst on the surface of activated platelets. Before higher dosing schedules become more widely used, however, a number of unanswered questions remain to be resolved. It is expected that ongoing and future trials will help to clarify some of these issues. Until such information is available, it is recommended that children and adolescents may be treated with a single bolus dose of 300 microg/kg rFVIIa within 1 to 2 hours of bleed onset. Due to a current lack of information regarding high-dose rFVIIa therapy in adults, however, it would be prudent to use standard doses (90 microg/kg every 2 to 3 hours for two or three doses) in this patient population.
- Published
- 2004
- Full Text
- View/download PDF
46. Hepatitis C in adults and adolescents with hemophilia: a randomized, controlled trial of interferon alfa-2b and ribavirin.
- Author
-
Fried MW, Peter J, Hoots K, Gaglio PJ, Talbut D, Davis PC, Key NS, White GC, Lindblad L, Rickles FR, and Abshire TC
- Subjects
- Adolescent, Adult, Aged, Antiviral Agents adverse effects, Drug Therapy, Combination, Hepacivirus genetics, Hepatitis C complications, Humans, Interferon alpha-2, Interferon-alpha adverse effects, Middle Aged, RNA, Viral analysis, Recombinant Proteins, Ribavirin adverse effects, Treatment Outcome, Antiviral Agents administration & dosage, Hemophilia A complications, Hepacivirus isolation & purification, Hepatitis C drug therapy, Interferon-alpha administration & dosage, Ribavirin administration & dosage
- Abstract
Adolescents and adults with inherited disorders of coagulation have one of the highest prevalence rates of hepatitis C among known risk groups. Few data are available on the use of combination therapy with interferon and ribavirin in this population. Patients 13 years of age and older who were positive for hepatitis C virus (HCV) RNA by polymerase chain reaction and negative for human immunodeficiency virus were randomized to receive interferon alfa-2b (3 million units 3 times a week) plus ribavirin (1,000 mg/day) or interferon alfa-2b alone for 48 weeks with 24 weeks of posttreatment follow-up. Patients started on interferon alone who remained positive for HCV RNA at week 12 crossed over to treatment with interferon plus ribavirin. A total of 113 patients were treated. Thirty-seven patients were younger than 18 years. At the end of treatment, 18 of 56 (32%) treated with interferon plus ribavirin and 6 of 57 (11%) treated with interferon alone were negative for HCV RNA (P =.005). Sustained virologic response in the combination arm was 29% (16 of 56) compared with 7% (4 of 57) for those started on interferon alone (P =.027). Among adolescents younger than 18 years who were treated with combination therapy, 10 of 17 (59%) had sustained response compared with 6 of 39 (15%) of adult patients on the same regimen (P =.001). In conclusion, in this U.S. multicenter, randomized trial of therapy for HCV in patients with inherited bleeding disorders, sustained virologic response rate was significantly improved for patients treated with interferon and ribavirin compared with those started on interferon alone. Adolescents treated with combination therapy had a significantly higher sustained response than adults did on the same regimen.
- Published
- 2002
- Full Text
- View/download PDF
47. An approach to the diagnosis and treatment of bleeding disorders in infants.
- Author
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Abshire TC
- Subjects
- Clinical Laboratory Techniques, Diagnosis, Differential, Hemorrhage etiology, Hemorrhage therapy, Humans, Infant, Infant, Newborn, Hemorrhage diagnosis
- Abstract
The approach to a newborn or infant who is bleeding can be troublesome for the physician. This lecture will focus upon utilizing the history and screening laboratory to narrow the differential diagnosis in order to provide the most appropriate treatment for this potentially challenging patient population. First, a new approach to understanding the mechanism of coagulation and fibrin deposition will be presented followed by a discussion of the unique aspects of the coagulation system in the infant as well the importance of properly interpreting these laboratory values within the context of the medical history will be reviewed. Next, an overview of possible diagnoses for the bleeding infant will be surveyed with focus upon five specific bleeding conditions commonly encountered in infancy. Finally, general treatment considerations will be explored, followed by a brief offering of case studies when diagnosed based upon the screening laboratory.
- Published
- 2002
- Full Text
- View/download PDF
48. Radionuclide synovectomy for hemophilic arthropathy: a comprehensive review of safety and efficacy and recommendation for a standardized treatment protocol.
- Author
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Dunn AL, Busch MT, Wyly JB, and Abshire TC
- Subjects
- Clinical Protocols, Hemarthrosis complications, Hemophilia A complications, Humans, Radioisotopes therapeutic use, Radioisotopes toxicity, Radiopharmaceuticals toxicity, Hemarthrosis radiotherapy, Radiopharmaceuticals therapeutic use, Synovial Membrane radiation effects
- Published
- 2002
49. Weekly polyethylene glycol conjugated L-asparaginase compared with biweekly dosing produces superior induction remission rates in childhood relapsed acute lymphoblastic leukemia: a Pediatric Oncology Group Study.
- Author
-
Abshire TC, Pollock BH, Billett AL, Bradley P, and Buchanan GR
- Subjects
- Adolescent, Adult, Antineoplastic Combined Chemotherapy Protocols adverse effects, Asparaginase administration & dosage, Asparaginase adverse effects, Asparaginase pharmacokinetics, Bone Marrow Cells drug effects, Bone Marrow Cells pathology, Cerebral Hemorrhage chemically induced, Child, Child, Preschool, Dose-Response Relationship, Drug, Doxorubicin administration & dosage, Drug Administration Schedule, Female, Humans, Infant, Male, Neoplasm Recurrence, Local, Polyethylene Glycols administration & dosage, Polyethylene Glycols adverse effects, Precursor Cell Lymphoblastic Leukemia-Lymphoma blood, Prednisone administration & dosage, Remission Induction, Venous Thrombosis chemically induced, Antineoplastic Combined Chemotherapy Protocols therapeutic use, Precursor Cell Lymphoblastic Leukemia-Lymphoma drug therapy, Vincristine administration & dosage
- Abstract
The relapse rate in childhood acute lymphoblastic leukemia (ALL) is approximately 30% but few reinduction regimens have investigated the intensive use of polyethylene glycol Escherichia coli asparaginase (PEG-Asp). Therefore, we assessed the pharmocokinetics and efficacy of PEG-Asp in this setting. Children with B-precursor ALL, in first marrow and/or extramedullary relapse were eligible. Reinduction included doxorubicin on day 1, prednisone for 28 days, vincristine weekly for 4 weeks, and PEG-Asp either weekly or biweekly by randomization. Asparaginase levels and antibody to both E coli asparaginase and PEG-asp were measured weekly just before each PEG-asp dose. Overall, 129 of 144 patients (pts) (90%) achieved a complete remission (CR). There was a highly significant difference in CR rates between weekly (69 of 71; 97%) and biweekly (60 of 73; 82%) PEG-Asp dosing (P =.003). Grade 3 or 4 infectious toxicity was common (50%), but only 4 pts died of sepsis during induction. Other toxicities were infrequent and hypersensitivity was rare (6 of 144; 4%). Low asparaginase levels were associated with high antibody titers to either native (P =.024) or PEG asp (P =.0013). The CR rate was significantly associated with higher levels of asparaginase (P =. 012). Patients with ALL in first relapse receiving weekly PEG-Asp had a higher rate of second remission compared with biweekly dosing. Low levels of asparaginase were associated with high antibody titers. Increased asparaginase levels may correlate with an improved CR rate. The use of intensive PEG-Asp should be explored further in the treatment of ALL. (Blood. 2000;96:1709-1715)
- Published
- 2000
50. Sucrose formulated recombinant human antihemophilic factor VIII is safe and efficacious for treatment of hemophilia A in home therapy--International Kogenate-FS Study Group.
- Author
-
Abshire TC, Brackmann HH, Scharrer I, Hoots K, Gazengel C, Powell JS, Gorina E, Kellermann E, and Vosburgh E
- Subjects
- Adolescent, Adult, Antibodies blood, Child, Cross-Over Studies, Drug Compounding, Drug Evaluation, Factor VIII administration & dosage, Factor VIII adverse effects, Factor VIII pharmacokinetics, Hemophilia A complications, Hemophilia A drug therapy, Hemorrhage drug therapy, Hemorrhage prevention & control, Home Infusion Therapy, Humans, Male, Middle Aged, Partial Thromboplastin Time, Patient Satisfaction, Recombinant Proteins administration & dosage, Recombinant Proteins adverse effects, Recombinant Proteins pharmacokinetics, Time Factors, Treatment Outcome, Sucrose
- Abstract
To add an increased level of safety to antihemophilic factor replacement therapy, a full-length, recombinant Factor VIII (rFVIII) product has been developed without human-derived plasma proteins during purification and formulation and using an additional solvent/detergent viral inactivation step. This first clinical trial of a sucrose-formulated full-length rFVIII (rFVIII-FS) was conducted in previously treated patients (> or = 100 prior exposure days) with severe (<2% FVIII) hemophilia A in North America (NA) and Europe (EU). Pharmacokinetic profiles for rFVIII-FS were compared with those of currently licensed rFVIII product (Kogenate) in 35 patients. Safety and efficacy during home therapy were evaluated in 71 patients. The new formulation displayed a pharmacokinetic profile similar to that of rFVIII. Patients on home therapy received a cumulative total of 11,867 exposure days, 12,546 infusions, and 22,443,694 IU of rFVIII-FS. Of 2585 bleeds, 93.5% were treated with 1-2 infusions and 80.5% of responses were rated as excellent or good. No evidence of de novo inhibitor formation was observed. Only 0.27% of infusions were associated with any drug-related adverse event. Except for an episode of intermittent chest pain with palpitations which ceased after treatment with analgesics, associated adverse events were mild or moderate. Overall, rFVIII-FS provided excellent hemostatic control, was well-tolerated, and caused no significant adverse effects, thus demonstrating safety and efficacy for treatment of bleeds in patients with hemophilia A.
- Published
- 2000
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