55 results on '"DiMichele DM"'
Search Results
2. Clotting and bleeding: a new understanding.
- Author
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Bennett JS, DiMichele DM, and Haire WD
- Abstract
The results of disordered hemostasis can range from local, transient bruising to a fatal pulmonary embolism. Three experts offer guidance on dealing with these complex, incompletely understood diseases. [ABSTRACT FROM AUTHOR]
- Published
- 1998
3. End points for sickle cell disease clinical trials: renal and cardiopulmonary, cure, and low-resource settings.
- Author
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Farrell AT, Panepinto J, Desai AA, Kassim AA, Lebensburger J, Walters MC, Bauer DE, Blaylark RM, DiMichele DM, Gladwin MT, Green NS, Hassell K, Kato GJ, Klings ES, Kohn DB, Krishnamurti L, Little J, Makani J, Malik P, McGann PT, Minniti C, Morris CR, Odame I, Oneal PA, Setse R, Sharma P, and Shenoy S
- Subjects
- Heart Diseases pathology, Humans, Lung Diseases pathology, Renal Insufficiency, Chronic pathology, Anemia, Sickle Cell physiopathology, Heart Diseases etiology, Lung Diseases etiology, Renal Insufficiency, Chronic etiology
- Abstract
To address the global burden of sickle cell disease and the need for novel therapies, the American Society of Hematology partnered with the US Food and Drug Administration to engage the work of 7 panels of clinicians, investigators, and patients to develop consensus recommendations for clinical trial end points. The panels conducted their work through literature reviews, assessment of available evidence, and expert judgment focusing on end points related to patient-reported outcome, pain (non-patient-reported outcomes), the brain, end-organ considerations, biomarkers, measurement of cure, and low-resource settings. This article presents the findings and recommendations of the end-organ considerations, measurement of cure, and low-resource settings panels as well as relevant findings and recommendations from the biomarkers panel.
- Published
- 2019
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- View/download PDF
4. Origins and organization of the NHLBI State of the Science Workshop: Generating a national blueprint for future research on factor VIII inhibitors.
- Author
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Sabatino DE, Pipe SW, Nugent DJ, Soucie JM, Hooper WC, Hoots WK, and DiMichele DM
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- Clinical Trials as Topic, Hemophilia A drug therapy, Humans, United States, Education organization & administration, Factor VIII antagonists & inhibitors, National Institutes of Health (U.S.), Research education
- Abstract
Introduction: The major complication of protein replacement therapy for haemophilia A is the development of anti-FVIII antibodies or inhibitors that occur in 25%-30% of persons with severe haemophilia A. Alternative therapeutics such as bypassing agents or immune tolerance induction protocols have additional challenges and are not always effective., Aim: Assemble a National Heart, Lung and Blood Institute (NHLBI) State of the Science (SOS) Workshop to generate a national blueprint for research on inhibitors to solve the problem of FVIII immunogenicity., Methods: An Executive Steering Committee was formed in October 2017 to establish the scientific focus and Scientific Working Groups for the SOS Workshop in May 2018. Four working groups were assembled to address scientific priorities in basic, translational and clinical research on inhibitors., Results: Working Group 1 was charged with determining the scientific priorities for clinical trials to include the integration of non-intravenous, non-factor therapeutics including gene therapy into the standard of care for people with haemophilia A with inhibitors. Working Group 2 established the scientific priorities for 21st-century data science and biospecimen collection for observational inhibitor cohort studies. The scientific priorities for acquiring an actionable understanding of FVIII immunogenicity and the immunology of the host response and FVIII tolerance were developed by Working Group 3. Working Group 4 designed prospective pregnancy/birth cohorts to study FVIII immunogenicity, inhibitor development and eradication., Conclusion: The NHLBI SOS Workshop generated a focused summary of scientific priorities and implementation strategies to overcome the challenges of eradicating and preventing inhibitors in haemophilia A., (© 2019 John Wiley & Sons Ltd.)
- Published
- 2019
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5. Executive summary of the NHLBI State of the Science (SOS) Workshop: Overview and next steps in generating a national blueprint for future research on factor VIII inhibitors.
- Author
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Pipe SW, Sabatino DE, Nugent DJ, Hooper WC, Soucie JM, Keith Hoots W, and DiMichele DM
- Subjects
- Antibodies, Neutralizing immunology, Hemophilia A drug therapy, Hemophilia A immunology, Humans, United States, Biomedical Research, Factor VIII immunology, National Heart, Lung, and Blood Institute (U.S.)
- Published
- 2019
- Full Text
- View/download PDF
6. Navigating Speed Bumps on the Innovation Highway in Hemophilia Therapeutics.
- Author
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DiMichele DM
- Abstract
The unprecedented emergence of novel therapeutics for both hemophilia A and B during the last half decade has been accompanied by the promise of even more extraordinary progress in ameliorative and curative strategies for both disorders. Paradoxically, the speed of innovation has created new dilemmas for persons with hemophilia and their physicians with respect to optimizing individual choices from the expanding menu of standard and novel therapies and approaches to symptom or risk reduction, and ultimately, to normalizing the hemophilia phenotype. Among the most disruptive new approaches, challenges remain in the form of the adverse reactions that have been observed with nonfactor therapies, as well as in the uncertain long-term safety profile of potentially curative gene therapy. Together, these challenges have generated uncertainty as to how to adopt novel therapies and treatment strategies across a diverse patient population, creating speed bumps on the hemophilia innovation highway. It is from this perspective that this article discusses the current state of gene therapy and bleeding prophylaxis for hemophilia A and B, as well as prevention and treatment of the factor VIII inhibitor phenotype in hemophilia A. It further posits that these speed bumps may provide important clues to the mechanistic understanding of both symptom manifestation and resilience within the hemophilia phenotype, as well as opportunities to reconsider and reconfigure the current paradigms for symptom prediction and individualized therapeutic decision making.
- Published
- 2018
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7. Catalyzing innovation in clinical trial design and analysis at NHLBI: a funding opportunity for clinical trials in blood disorders.
- Author
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DiMichele DM
- Abstract
Competing Interests: Conflict-of-interest disclosure: The author declares no competing financial interests.Conflict-of-interest disclosure: The author declares no competing financial interests.
- Published
- 2017
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8. Hemophilia Therapy--Navigating Speed Bumps on the Innovation Highway.
- Author
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DiMichele DM
- Subjects
- Humans, Male, Antibodies, Bispecific therapeutic use, Antibodies, Monoclonal, Humanized therapeutic use, Antibodies, Neutralizing blood, Factor VIII antagonists & inhibitors, Factor VIII immunology, Hemophilia A drug therapy, Hemorrhage prevention & control, Isoantibodies analysis, von Willebrand Factor therapeutic use
- Published
- 2016
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9. Thrombin generation and bleeding in haemophilia inhibitor patients during immune tolerance induction.
- Author
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Ragni MV, DiMichele DM, Hay CM, Malec LM, Seaman CD, Li J, Yabes JG, Butenas S, and Brummel-Ziedins K
- Abstract
Background: Inhibitor formation complicates haemophilia treatment and requires immune tolerance induction to rid inhibitors over 5 BU. In the prospective, randomized International Immune Tolerance Study, immune tolerance induction was equally effective with high-dose (HD) (200 IU kg
-1 day-1 ) and low-dose (LD) (50 IU kg-1 3× per week) factor VIII, but haemorrhages were twofold higher in the LD arm. This finding was unexpected as inhibitors neutralize FVIII activity. We hypothesized that the thrombin generation assay (TGA), a global measure of clot formation, might predict bleeding better than FVIII levels., Methods: We evaluated TGA using relipidated tissue factor (TF) on 83 thawed, recalcified corn trypsin inhibitor/citrate plasma samples from 31 subjects (17 HD, 14 LD) who participated on the ITI study, and who had sufficient sample available and appropriate informed consent., Results: There were no significant differences in peak thrombin, estimated thrombin potential, maximum rate or lag time between HD and LD arms; between pre-, during and post-ITI time points, or after FVIII spiking. In 19 subjects (12 HD, 7 LD) with anti-FVIII<1.0 BU, the prevalence of non-neutralizing antibody (NNA) and neutralizing antibody (NA) was 89.5% (17/19), and the latter strongly correlated with anti-VIII titer, r = 0.73 [95% CI: 0.55, 0.88]., Conclusion: In haemophilia inhibitor patients, thrombin generation is present, but does not predict bleeding risk. Following tolerance induction, NNA remains detectable in the majority., (© 2015 John Wiley & Sons Ltd.)- Published
- 2016
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10. Central venous access device (CVAD) complications in Haemophilia with inhibitors undergoing immune tolerance induction: Lessons from the international immune tolerance study.
- Author
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Rodriguez V, Mancuso ME, Warad D, Hay CR, DiMichele DM, Valentino L, Kenet G, and Kulkarni R
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- Child, Child, Preschool, Humans, Infant, Infant, Newborn, Prosthesis-Related Infections etiology, Risk Factors, Time Factors, Antibodies immunology, Catheterization, Central Venous adverse effects, Hemophilia A immunology, Immune Tolerance, Internationality
- Abstract
Introduction: Central venous access devices (CVADs) are frequently required as stable long-lasting venous access in children with haemophilia, especially those requiring immune tolerance induction (ITI) for inhibitors. CVAD infection is one of the most frequently reported catheter-related complications in this patient population., Aim: Detailed review of CVAD complications from the International ITI (I-ITI) study and analysis of potential risk factors for such complications., Methods: Retrospective analysis of prospectively obtained data from the I-ITI study primarily focused on CVAD-related complications., Results: A total of 115 children were recruited and 183 CVADs were placed in 99 subjects resulting in 121,206 CVAD-days observed on-study. A total of 124 CVAD infections were reported in 41 of 99 (41%) subjects with an overall infection rate of 0.94 per 1000 CVAD-days (interquartile ranges 0-1.7). A similar number of infections were observed in the two treatment arms (median: 2 and 3 in high dose and low dose respectively). Infections occurred more frequently in the presence of external catheters than with fully implanted catheters (P = 0.026). Infected patients were significantly younger at the time of CVAD insertion (median age: 22 vs. 25 months, P = 0.020). Patients with Gram-positive infections were also significantly younger than those with Gram-negative infections (median age: 17 vs. 25 months, P < 0.0001)., Conclusion: CVAD infection was the most common complication observed in children with severe haemophilia and inhibitors in the frame of the I-ITI study. Younger age at CVAD insertion and external CVAD were associated with higher risk for infection. ITI outcome was unaffected by CVAD infections., (© 2015 John Wiley & Sons Ltd.)
- Published
- 2015
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11. Design of clinical trials for new products in hemophilia: communication from the SSC of the ISTH.
- Author
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Dimichele DM, Lacroix-Desmazes S, Peyvandi F, Srivastava A, and Rosendaal FR
- Subjects
- Humans, Clinical Trials as Topic, Hemophilia A drug therapy
- Published
- 2015
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12. Planning for the future workforce in hematology research.
- Author
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Hoots WK, Abkowitz JL, Coller BS, and DiMichele DM
- Subjects
- Awards and Prizes, Education organization & administration, Financial Support, Humans, National Heart, Lung, and Blood Institute (U.S.) organization & administration, Research organization & administration, United States, Biomedical Research economics, Biomedical Research organization & administration, Health Workforce organization & administration, Hematology economics, Hematology organization & administration
- Abstract
The medical research and training enterprise in the United States is complex in both its scope and implementation. Accordingly, adaptations to the associated workforce needs present particular challenges. This is particularly true for maintaining or expanding national needs for physician-scientists where training resource requirements and competitive transitional milestones are substantial. For the individual, these phenomena can produce financial burden, prolong the career trajectory, and significantly influence career pathways. Hence, when national data suggest that future medical research needs in a scientific area may be met in a less than optimal manner, strategies to expand research and training capacity must follow. This article defines such an exigency for research and training in nonneoplastic hematology and presents potential strategies for addressing these critical workforce needs. The considerations presented herein reflect a summary of the discussions presented at 2 workshops cosponsored by the National Heart, Lung, and Blood Institute and the American Society of Hematology.
- Published
- 2015
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13. Citation impact of NHLBI R01 grants funded through the American Recovery and Reinvestment Act as compared to R01 grants funded through a standard payline.
- Author
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Danthi NS, Wu CO, DiMichele DM, Hoots WK, and Lauer MS
- Subjects
- Budgets, Cost-Benefit Analysis, Databases, Bibliographic statistics & numerical data, Financing, Government legislation & jurisprudence, Financing, Government statistics & numerical data, Humans, Research Personnel statistics & numerical data, Research Support as Topic legislation & jurisprudence, Research Support as Topic statistics & numerical data, United States, American Recovery and Reinvestment Act, Bibliometrics, Financing, Government economics, National Heart, Lung, and Blood Institute (U.S.) economics, Research Support as Topic economics
- Abstract
Rationale: The American Recovery and Reinvestment Act (ARRA) allowed National Heart, Lung, and Blood Institute to fund R01 grants that fared less well on peer review than those funded by meeting a payline threshold. It is not clear whether the sudden availability of additional funding enabled research of similar or lesser citation impact than already funded work., Objective: To compare the citation impact of ARRA-funded de novo National Heart, Lung, and Blood Institute R01 grants with concurrent de novo National Heart, Lung, and Blood Institute R01 grants funded by standard payline mechanisms., Methods and Results: We identified de novo (type 1) R01 grants funded by National Heart, Lung, and Blood Institute in fiscal year 2009: these included 458 funded by meeting Institute's published payline and 165 funded only because of ARRA funding. Compared with payline grants, ARRA grants received fewer total funds (median values, $1.03 versus $1.87 million; P<0.001) for a shorter duration (median values including no-cost extensions, 3.0 versus 4.9 years; P<0.001). Through May 2014, the payline R01 grants generated 3895 publications, whereas the ARRA R01 grants generated 996. Using the InCites database from Thomson-Reuters, we calculated a normalized citation impact for each grant by weighting each article for the number of citations it received normalizing for subject, article type, and year of publication. The ARRA R01 grants had a similar normalized citation impact per $1 million spent as the payline grants (median values [interquartile range], 2.15 [0.73-4.68] versus 2.03 [0.75-4.10]; P=0.61). The similar impact of the ARRA grants persisted even after accounting for potential confounders., Conclusions: Despite shorter durations and lower budgets, ARRA R01 grants had comparable citation outcomes per $million spent to that of contemporaneously funded payline R01 grants., (© 2015 American Heart Association, Inc.)
- Published
- 2015
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14. Prior publication productivity, grant percentile ranking, and topic-normalized citation impact of NHLBI cardiovascular R01 grants.
- Author
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Kaltman JR, Evans FJ, Danthi NS, Wu CO, DiMichele DM, and Lauer MS
- Subjects
- Biomedical Research economics, Quality Control, Research Support as Topic, United States, Financing, Government standards, National Heart, Lung, and Blood Institute (U.S.) standards, Peer Review, Research standards
- Abstract
Rationale: We previously demonstrated absence of association between peer-review-derived percentile ranking and raw citation impact in a large cohort of National Heart, Lung, and Blood Institute cardiovascular R01 grants, but we did not consider pregrant investigator publication productivity. We also did not normalize citation counts for scientific field, type of article, and year of publication., Objective: To determine whether measures of investigator prior productivity predict a grant's subsequent scientific impact as measured by normalized citation metrics., Methods and Results: We identified 1492 investigator-initiated de novo National Heart, Lung, and Blood Institute R01 grant applications funded between 2001 and 2008 and linked the publications from these grants to their InCites (Thompson Reuters) citation record. InCites provides a normalized citation count for each publication stratifying by year of publication, type of publication, and field of science. The coprimary end points for this analysis were the normalized citation impact per million dollars allocated and the number of publications per grant that has normalized citation rate in the top decile per million dollars allocated (top 10% articles). Prior productivity measures included the number of National Heart, Lung, and Blood Institute-supported publications each principal investigator published in the 5 years before grant review and the corresponding prior normalized citation impact score. After accounting for potential confounders, there was no association between peer-review percentile ranking and bibliometric end points (all adjusted P>0.5). However, prior productivity was predictive (P<0.0001)., Conclusions: Even after normalizing citation counts, we confirmed a lack of association between peer-review grant percentile ranking and grant citation impact. However, prior investigator publication productivity was predictive of grant-specific citation impact., (© 2014 American Heart Association, Inc.)
- Published
- 2014
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15. Use of global assays to understand clinical phenotype in congenital factor VII deficiency.
- Author
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Greene LA, Goldenberg NA, Simpson ML, Villalobos-Menuey E, Bombardier C, Acharya SS, Santiago-Borrero PJ, Cambara A, and DiMichele DM
- Subjects
- Adolescent, Adult, Child, Child, Preschool, Cross-Sectional Studies, Factor VII Deficiency blood, Factor VII Deficiency genetics, Female, Fibrinolysis, Hemorrhage blood, Hemorrhage etiology, Hemorrhage genetics, Humans, Male, Phenotype, Prospective Studies, Young Adult, Factor VII Deficiency diagnosis, Hemorrhage diagnosis
- Abstract
Congenital factor VII (FVII) deficiency is characterized by genotypic variability and phenotypic heterogeneity. Traditional screening and factor assays are unable to reliably predict clinical bleeding phenotype and guide haemorrhage prevention strategy. Global assays of coagulation and fibrinolysis may better characterize overall haemostatic balance and aid in haemorrhagic risk assessment. We evaluated the ability of novel global assays to better understand clinical bleeding severity in congenital FVII deficiency. Subjects underwent central determination of factor VII activity (FVII:C) as well as clot formation and lysis (CloFAL) and simultaneous thrombin and plasmin generation (STP) global assay analysis. A bleeding score was assigned to each subject through medical chart review. Global assay parameters were analysed with respect to bleeding score and FVII:C. Subgroup analyses were performed on paediatric subjects and subjects with FVII ≥ 1 IU dL(-1). CloFAL fibrinolytic index (FI2 ) inversely correlated with FVII:C while CloFAL maximum amplitude (MA) and STP maximum velocity of thrombin generation (VT max) varied directly with FVII:C. CloFAL FI2 directly correlated with bleeding score among subjects in both the total cohort and paediatric subcohort, but not among subjects with FVII ≥ 1 IU dL(-1) . Among subjects with FVII ≥ 1 IU dL(-1), STP time to maximum velocity of thrombin generation and time to maximum velocity of plasmin generation inversely correlated with bleeding score. These preliminary findings suggest a novel potential link between a hyperfibrinolytic state in bleeding severity and congenital FVII deficiency, an observation that should be further explored., (© 2013 John Wiley & Sons Ltd.)
- Published
- 2013
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16. The polygenic nature of inhibitors in hemophilia A: results from the Hemophilia Inhibitor Genetics Study (HIGS) Combined Cohort.
- Author
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Astermark J, Donfield SM, Gomperts ED, Schwarz J, Menius ED, Pavlova A, Oldenburg J, Kessing B, DiMichele DM, Shapiro AD, Winkler CA, and Berntorp E
- Subjects
- Adolescent, Antibodies immunology, Child, Cohort Studies, Drug Resistance genetics, Drug Resistance immunology, Factor VIII genetics, Genetic Markers, Genetic Predisposition to Disease epidemiology, Genetic Predisposition to Disease genetics, Humans, Male, Polymorphism, Single Nucleotide genetics, Risk Factors, Siblings, Factor VIII immunology, Factor VIII therapeutic use, Hemophilia A drug therapy, Hemophilia A epidemiology, Hemophilia A genetics, Multifactorial Inheritance genetics, Transcriptome
- Abstract
Studies of determinants of development of inhibitory Abs to factor VIII in people with hemophilia A indicate a complex process involving multiple factors. The Hemophilia Inhibitor Genetics Study (HIGS) Combined Cohort was formed to extend our understanding of the genetic background of risk. The study group contains 833 subjects from 3 independent cohorts: brother pairs and singletons with and without a history of inhibitors, as well as 104 brother pairs discordant for inhibitor status. Using an Illumina iSelect platform, 13 331 single-nucleotide polymorphisms from 1081 genes, primarily immune response and immune modifier genes, were typed. Each cohort was analyzed separately with results combined using a meta-analytic technique. After adjustment for potential confounders, 53 single-nucleotide polymorphisms were found to be significant predictors of inhibitor status using the criteria of odds ratios in the same direction in all cohorts or allowing for a 20% interval around an odds ratio = 1 in 1 of the 3 and significant in at least 2. Of the 53 markers, 13 had meta P < .001. Eight of the 53 were significant predictors among the discordant pairs. Results support the complexity of the immune response and encourage further research with the goal of understanding the pathways involved.
- Published
- 2013
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17. Inhibitors in childhood hemophilia A: genetic and treatment-related risk factors for development and eradication.
- Author
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DiMichele DM
- Subjects
- Child, Hemophilia A genetics, Hemophilia A immunology, Humans, Risk Factors, Antibodies, Neutralizing immunology, Factor VIII antagonists & inhibitors, Factor VIII immunology, Factor VIII therapeutic use, Hemophilia A drug therapy
- Abstract
The development of neutralizing antibodies remains a serious complication of hemophilia replacement therapy. Factor VIII inhibiting antibodies (inhibitors) occur commonly following replacement therapy in hemophilia A, creating a significant burden of clinical disease. This article will review our current understanding of risk factors and their known impact on inhibitor development in previously untreated or minimally treated children with severe and mild hemophilia A. It will also explore how the most recently elucidated immunology of inhibitor development might hold important clues to more effective inhibitor eradication and prevention in this heavily impacted patient population., (Copyright © 2012 Wiley Periodicals, Inc.)
- Published
- 2013
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18. Immune tolerance in haemophilia: the long journey to the fork in the road.
- Author
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DiMichele DM
- Subjects
- Antibody Formation, Factor IX antagonists & inhibitors, Hemophilia A therapy, Hemophilia B therapy, Humans, Autoantibodies immunology, Blood Coagulation Factor Inhibitors immunology, Factor IX immunology, Hemophilia A immunology, Hemophilia B immunology, Immune Tolerance
- Abstract
Antibody eradication is the ultimate goal of inhibitor management. The only clinically proven strategy for achieving antigen-specific tolerance to factor VIII is immune tolerance induction (ITI). Our knowledge about ITI in haemophilia A and B was, historically, derived from small cohort studies and retrospective national and international ITI registries. Practice is now further influenced by prospective cohort data, and the results of a single prospective randomized international ITI trial. However, due to the low incidence of inhibitors in haemophilia B, there are few comparable data from which to develop a useful evidence-based approach to the prevention and eradication of factor IX inhibitors. The lack of an effective strategy is particularly problematic given the morbidity associated with the unique occurrence of allergic and anaphylactic reactions that often herald factor IX antibody development and preclude effective eradication. This paper will discuss our current understanding of immune tolerance outcome and outcome predictors for haemophilia A and B; review the current consensus practice recommendations for ITI; and summarize the emerging body of immunological science relating to antibody formation and tolerance. It will conclude by suggesting how our knowledge might inform the future investigative priorities impacting the therapeutic and preventative tolerance strategies of tomorrow., (© 2012 Blackwell Publishing Ltd.)
- Published
- 2012
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19. Clinical trial design in haemophilia.
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Dimichele DM, Blanchette V, and Berntorp E
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- Humans, International Cooperation, Outcome Assessment, Health Care standards, Clinical Trials as Topic methods, Coagulants therapeutic use, Factor IX therapeutic use, Factor VIII therapeutic use, Hemophilia A drug therapy, Hemophilia B drug therapy
- Abstract
Progress in the evidence-based care of haemophilia A and B worldwide has been historically challenged by the dearth of evaluable outcome data, including but not limited to the safety and effectiveness of therapeutic interventions. These challenges are partially rooted in the inherent difficulty of conducting prospective clinical trials and observational studies with statistically meaningful endpoints in a rare disease such as haemophilia. Despite the logistical barriers, the need for outcome data has never been more critical than in this time of expansive therapeutic advance tempered by the shrinking economic capacity to fund the rapidly increasing cost of treatment. Given that systematic analyses of published literature have been largely unsuccessful in compensating for the lack of rigorous and purposeful data collection, new approaches to clinical study design and statistical modelling are urgently needed. However, even as these are considered, the lack of broadly accepted and well-defined clinical outcome endpoints poses an additional barrier to progress. The three presentations encompassed by this paper highlight the timely need for quality data from the perspectives of the clinicians, regulatory agencies and health care funders, and describe the ongoing coordinated efforts by the international haemophilia community to further understand and dismantle the barriers to harmonized and standardized data collection on a global scale using well-defined clinical outcome endpoints., (© 2012 Blackwell Publishing Ltd.)
- Published
- 2012
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20. Haemostasis prophylaxis using single dose desmopressin acetate and extended use epsilon aminocaproic acid for adenotonsillectomy in patients with type 1 von Willebrand disease.
- Author
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Santoro C, Hsu F, and Dimichele DM
- Subjects
- Adolescent, Child, Child, Preschool, Delayed-Action Preparations administration & dosage, Female, Humans, Infant, Infusions, Intravenous, Male, Retrospective Studies, Adenoidectomy, Aminocaproic Acid administration & dosage, Antifibrinolytic Agents administration & dosage, Deamino Arginine Vasopressin administration & dosage, Hemostatics administration & dosage, Postoperative Hemorrhage prevention & control, Tonsillectomy, von Willebrand Disease, Type 1 drug therapy
- Abstract
In patients with confirmed or suspected type 1 von Willebrand disease (VWD), adenotonsillectomy has been reported to be associated with a rate of peri-operative hemorrhage between 8 and 23%. Desmopressin acetate (DDAVP, 1-deamino 8-D arginine- vasopressin) is the treatment of choice for type 1 patients with baseline von Willebrand factor levels of 10 IU/dL or greater. DDAVP is generally well tolerated; however, severe hyponatremia and seizures have been reported in young children less than 2 years of age, limiting its use in this age group. Antifibrinolytic therapy plays an important adjunctive role in the effective treatment of mucocutaneous bleeding, particularly in the oropharynx where the salivary concentration of fibrinolytic enzymes is high. During the past 10 years, we treated 6 pediatric patients with mild/moderate type 1 VWD undergoing an adenotonsillar procedure at our institution with the same hemostatic regimen consisting of one single dose of DDAVP and an extended use of EACA. In this small case series, the above mentioned prophylactic treatment regimen was both well tolerated and efficacious in controlling hemorrhage. Furthermore, DDAVP-related complications were avoided in a pediatric population with a higher risk of developing them., (© 2011 Blackwell Publishing Ltd.)
- Published
- 2012
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21. The principal results of the International Immune Tolerance Study: a randomized dose comparison.
- Author
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Hay CR and DiMichele DM
- Subjects
- Catheter-Related Infections chemically induced, Child, Preschool, Dose-Response Relationship, Drug, Drug Administration Schedule, Factor VIII administration & dosage, Factor VIII adverse effects, Factor VIII immunology, Hemophilia A immunology, Hemorrhage chemically induced, Humans, Immune Tolerance, Infant, Logistic Models, Multivariate Analysis, Prospective Studies, Treatment Outcome, Factor VIII therapeutic use, Hemophilia A drug therapy
- Abstract
The International Immune Tolerance Study was a multicenter, prospective, randomized comparison of high-dose (HD; 200 IU/kg/d) and low-dose (LD; 50 IU/kg 3 times/week) factor VIII regimens in 115 "good-risk," severe high-titer inhibitor hemophilia A subjects. Sixty-six of 115 subjects reached the defined study end points: success, n = 46 (69.7%); partial response, n = 3 (4.5%); and failure, n = 17 (25.8%). Successes did not differ between treatment arms (24 of 58 LD vs 22/57 HD, P = .909). The times taken to achieve a negative titer (P = .027), a normal recovery (P = .002), and tolerance (P = .116, nonsignificant) were shorter with the HD immune tolerance induction (ITI). Peak historical (P = .026) and on-ITI (P = .002) titers were correlated inversely with success, but only peak titer on ITI predicted outcome in a multivariate analysis (P = .002). LD subjects bled more often (odds ratio, 2.2; P = .0019). The early bleed rate/month was 0.62 (LD) and 0.28 (HD; P = .000 24), decreasing by 90% once negative titers were achieved. Bleeding was absent in 8 of 58 LD versus 21 of 57 HD subjects (P = .0085). One hundred twenty-four central catheter infections were reported in 41 subjects (19 LD); infection frequency did not differ between the treatment arms. Neither bleeding nor infection influenced outcome. Although it was stopped early for futility and safety considerations, this trial contributed valuable data toward evidence-based ITI practice.
- Published
- 2012
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22. Knowledge and therapeutic gaps: a public health problem in the rare coagulation disorders population.
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Shapiro AD, Soucie JM, Peyvandi F, Aschman DJ, and DiMichele DM
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- Cooperative Behavior, Databases, Factual, Humans, Internationality, Blood Coagulation Disorders drug therapy, Health Knowledge, Attitudes, Practice, Health Personnel education, Internet, Public Health Practice, Rare Diseases
- Abstract
Rare coagulation disorders (RCDs) present a considerable and multifaceted public health risk. Although inherited RCDs affect a minor segment of any local healthcare delivery system, their global impact is major and highlight the challenges of delivering healthcare services to any rare disease population. These include but are not limited to: (1) a general lack of knowledge about and familiarity with the genetic and clinical implications of the disorder among affected patients, and both urgent and specialty care providers; (2) the potential for preventable morbidity and mortality related to delayed diagnosis and treatment; (3) the lack of safe and effective therapies; and (4) minimal research activity to establish and improve standards of care. A multiagency national partnership has established an approach to address these problems through development of a clinical, genetic, and treatment-related web-based data-collection tool that will: (1) generate a reliable, sufficient knowledge base for these disorders; (2) facilitate new product licensure through subject identification and access to comparative historical treatment data; and (3) serve as an effective tool for outcomes research and post-licensure product surveillance. To maximize impact, this database is being harmonized with a European data-collection effort. Database development and harmonization is in progress. A resource library was completed and disseminated to major national and international bleeding disorder websites to provide state-of-the-art patient and provider education on each RCD. We believe that this model is effective and adaptable to other rare conditions., (Copyright © 2011 American Journal of Preventive Medicine. All rights reserved.)
- Published
- 2011
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23. Mutation in the factor VII hepatocyte nuclear factor 4α-binding site contributes to factor VII deficiency.
- Author
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Zheng XW, Kudaravalli R, Russell TT, DiMichele DM, Gibb C, Russell JE, Margaritis P, and Pollak ES
- Subjects
- Adult, Base Sequence, Binding Sites genetics, Child, Preschool, DNA Mutational Analysis, Factor VII chemistry, Factor VII metabolism, Factor VII Deficiency blood, HeLa Cells, Hep G2 Cells, Hepatocyte Nuclear Factor 4 genetics, Humans, Immunoprecipitation, Longitudinal Studies, Male, Plasmids, Protein Binding genetics, Transfection, Twins, Dizygotic, Factor VII genetics, Factor VII Deficiency genetics, Hepatocyte Nuclear Factor 4 metabolism, Point Mutation, Promoter Regions, Genetic
- Abstract
Severe coagulant factor VII (FVII) deficiency in postpubertal dizygotic twin males results from two point mutations in the FVII gene, a promoter region T→C transition at -60 and a His-to-Arg substitution at amino acid 348; both mutations prevent persistence of plasma functional FVII. This report documents longitudinal laboratory measurements from infancy to adulthood of FVII coagulant activity (FVII:C) in the twin FVII-deficient patients; it also details specific biochemical analyses of the -60 T→C mutation. The results revealed FVII:C levels of less than 1% in infancy that remain severely decreased through puberty and into adulthood. In-vitro analyses utilizing hepatocyte nuclear factor 4α (HNF4α) co-transfection and a chromatin immunoprecipitation assay indicate that the -60 T→C mutation severely diminishes functional interaction between the FVII promoter and transcription factor HNF4α. The importance of interaction between the FVII gene and HNF4α in normal FVII expression provides an in-vivo illustration of the regulated expression of an autosomal gene encoding a coagulation protein. The constancy of FVII:C and peripubertal patient symptomatology reported here illustrates androgen-independent expression in contrast to expression with an analogous mutation in the promoter region of the gene encoding coagulation FIX.
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- 2011
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24. Successful hip arthroplasty in an adult male with severe factor XI deficiency using Hemoleven®, a factor XI concentrate.
- Author
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Santoro C, Goldberg I, Bridey F, Figgie MP, Karila-Israel D, Haviland K, Mackenzie CR, and Dimichele DM
- Subjects
- Blood Loss, Surgical prevention & control, Hemostasis, Surgical methods, Humans, Male, Middle Aged, Treatment Outcome, Anticoagulants therapeutic use, Arthroplasty, Replacement, Hip methods, Factor XI therapeutic use, Factor XI Deficiency drug therapy
- Abstract
Severe factor XI (sFXI) deficiency is a rare bleeding disorder (RBD). FXI replacement is most often required for surgical hemostasis. Plasma, the sole US treatment option, is often complicated by life-threatening allergic reactions. In such circumstances, the FDA offers a mechanism for institution-industry collaboration to facilitate limited use of replacement products licensed abroad. A 58 years old man with sFXI deficiency, required hip replacement. In the past, he received prophylactic plasma for thyroidectomy and experienced a severe allergic reaction. A single use institutional IND FDA application was initiated in collaboration with LFB (Les Ulis, France) to access Hemoleven®, a plasma-derived FXI concentrate. The application required an investigator-initiated IRB-approved protocol for treatment and safety/efficacy monitoring that included: preoperative thrombophilia, FXI inhibitor and pharmacokinetic (PK) evaluations; peri- postoperative administration of ≤ 4 doses of 10-15 U/kg Hemoleven® ; DIC monitoring; postoperative thromboprophylaxis; observation for product efficacy and potential complications. PK study demonstrated the expected 1.8% FXI recovery per U/kg with half-life of 62 hours. Mild D-Dimer elevation was noted 6-9 hours post-infusion. The initial dose (15 U/kg) was administered 15 hours before surgery; subsequently, 3 doses (10 U/kg) were infused every 72 hours. Hemostasis was excellent. No complications were observed. Collaboration allowed for successful patient access to Hemoleven® with excellent PK, safety, and efficacy. This case underscores the need for additional efforts to ensure safe and effective licensed replacement therapies for RBD patients., (© 2011 Blackwell Publishing Ltd.)
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- 2011
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25. Successful cryoablation of atrioventricular nodal reentrant tachycardia in a child with hemophilia A.
- Author
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DeWitt ES, DiMichele DM, Larsen K, and Pass RH
- Subjects
- Child, Electrocardiography, Electrophysiology, Hemophilia A complications, Humans, Male, Prognosis, Tachycardia, Atrioventricular Nodal Reentry etiology, Cryosurgery, Hemophilia A therapy, Tachycardia, Atrioventricular Nodal Reentry therapy
- Abstract
We report the hematologic and invasive electrophysiologic management of a 12-year-old boy with mild hemophilia A (factor VIII deficiency) and atrioventricular nodal reentrant tachycardia. Thoughtful preparation with detailed input from the patient's comprehensive hemophilia center combined with vigilant pericatheterization hematologic management allowed for safe and successful cryoablation of this arrhythmia. Strategies for the management of patients with bleeding disorders who require invasive cardiac catheterization or surgery are reviewed.
- Published
- 2010
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26. Splenic infarction and subsequent splenic rupture in a patient with paroxysmal nocturnal hemoglobinuria and heparin-induced thrombocytopenia.
- Author
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Magnan H, Kayton ML, DiMichele DM, Araten DJ, Kernan NA, and Boulad F
- Subjects
- Adolescent, Female, Humans, Anticoagulants adverse effects, Hemoglobinuria, Paroxysmal complications, Heparin adverse effects, Splenic Infarction etiology, Splenic Rupture etiology, Thrombocytopenia complications
- Abstract
We describe a patient with paroxysmal nocturnal hemoglobinuria (PNH) and no previous history of thrombosis who presented with hepatic venous thromboses and subsequently developed splenic infarction and rupture requiring splenectomy while on anticoagulation therapy for the hepatic thromboses. The patient's anticoagulation was complicated by heparin-induced thrombocytopenia (HIT) highlighting the unique management challenge presented by PNH in combination with HIT., ((c) 2009 Wiley-Liss, Inc.)
- Published
- 2009
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27. Power Doppler sonography in the diagnosis of hemophilic synovitis--a promising tool.
- Author
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Acharya SS, Schloss R, Dyke JP, Mintz DN, Christos P, DiMichele DM, and Adler RS
- Subjects
- Adolescent, Adult, Child, Diagnostic Imaging methods, Diagnostic Imaging standards, Humans, Joints diagnostic imaging, Joints pathology, Magnetic Resonance Imaging, Synovitis diagnosis, Ultrasonography, Doppler economics, Ultrasonography, Doppler standards, Young Adult, Hemarthrosis complications, Hemophilia A complications, Synovitis diagnostic imaging, Ultrasonography, Doppler methods
- Abstract
Background: Recurrent hemarthroses in hemophilia results in synovitis and joint arthropathy. Primary prophylaxis when universally instituted at current doses can prevent joint deterioration but is expensive. Alternatively, the selective implementation of prophylaxis would require a more sensitive tool for detecting synovitis than possible with clinical surveillance or plain radiographs. Magnetic resonance imaging (MRI) is such a tool and is utilized for the evaluation of hemophilic joint disease (HJD). However, it is expensive, and requires sedation in younger children precluding its utility for monitoring of synovitis. Ultrasonography (USG) with power Doppler (USG-PDS) has been utilized to detect and quantitate synovial vascularity in other arthritides and could provide an equally effective but less costly tool for HJD, particularly in children who would not require sedation., Objectives: To determine whether USG-PDS is comparable to MRI in the evaluation of hemophilic synovitis., Patients: A prospective cohort of 31 subjects including 33 joints (knees, elbows, ankles) underwent dynamic contrast enhanced (DCE)-MRI and USG-PDS., Results: USG-PDS measurements of synovial thickness(r = 0.70, P < 0.0001) and synovial vascularity (r = 0.73, P < 0.0001) correlated strongly with those obtained with DCE-MRI. A cutoff of PDS intensity of 1.3 decibels (dB) per mm(2) was found to yield a sensitivity of 100% and a specificity of 94.1% in 17 joints with/without a history of hemarthroses. Pettersson radiographic scores correlated significantly with synovial thickness in adults but not children., Conclusions: Our data suggest that USG-PDS may be an inexpensive and easily implemented imaging tool for detecting hemophilic synovitis and could be useful in tailoring effective prophylaxis.
- Published
- 2008
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28. Rare inherited disorders of fibrinogen.
- Author
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Acharya SS and Dimichele DM
- Subjects
- Adult, Afibrinogenemia blood, Afibrinogenemia diagnosis, Afibrinogenemia drug therapy, Afibrinogenemia epidemiology, Blood Coagulation genetics, Coagulants administration & dosage, Factor VIII administration & dosage, Female, Fibrinogen administration & dosage, Fibrinogen chemistry, Fibrinogen metabolism, Genotype, Hemorrhage drug therapy, Hemorrhage genetics, Humans, Infant, Newborn, Iran epidemiology, Italy epidemiology, MEDLINE, Male, North America epidemiology, Phenotype, Pregnancy, Pregnancy Complications, Hematologic therapy, Prenatal Diagnosis, Rare Diseases genetics, Afibrinogenemia genetics, Fibrinogen genetics, Mutation, Pregnancy Complications, Hematologic genetics
- Abstract
Fibrinogen, a hexameric glycoprotein encoded by three genes - FGA, FGB, FGG - clustered on chromosome 4q is involved in the final steps of coagulation as a precursor of fibrin monomers required for the formation of the haemostatic plug. Inherited disorders of fibrinogen abnormalities are rare and not as well clinically characterized as some other inherited bleeding disorders. To characterize the clinical manifestations, molecular defects and treatment modalities of these rare disorders, a Medline search from January 1966 to September 2007 for these disorders reported in large studies and registries was undertaken. Inherited fibrinogen disorders can manifest as quantitative defects (afibrinogenemia and hypofibrinogenemia) or qualitative defects (dysfibrinogenemia). Quantitative fibrinogen deficiencies may result from mutations affecting fibrinogen synthesis, or processing while qualitative defects are caused by mutations causing abnormal polymerization, defective cross-linking or defective assembly of the fibrinolytic system. Clinical manifestations vary from being asymptomatic to developing catastrophic life-threatening bleeds or thromboembolic events. Management of bleeds includes use of purified plasma-derived concentrates, cryoprecipitate or fresh frozen plasma. Use of some of these products carries risks of viral transmission, antibody development and thromboembolic events. Establishment of registries in Iran, Italy and North America has fostered a better understanding of these disorders with an attempt to explore molecular defects. Rare Bleeding Disorder Registries developed through the United States and international efforts hopefully will encourage development and licensure of safer, effective products.
- Published
- 2008
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29. Ethical considerations in clinical investigation: exploring relevance in haemophilia research.
- Author
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DiMichele DM
- Subjects
- Bioethical Issues, Biomedical Research trends, Child, Evidence-Based Medicine, Gene Transfer Techniques trends, Genetic Therapy ethics, Hemophilia A complications, Humans, Informed Consent legislation & jurisprudence, Patient Selection ethics, Randomized Controlled Trials as Topic standards, Biomedical Research ethics, Gene Transfer Techniques ethics, Hemophilia A therapy, Human Experimentation ethics, Informed Consent ethics
- Abstract
Painful controversy has so far been largely absent from the history of haemophilia-related clinical research. However, the investigative methods now needed to realize evidence-based clinical practice, therapeutic advance, and a progressive standard of care for patients worldwide will be accompanied by the potential for ethical dilemma and transgression. From the current vantage point, three primary ethical issues merit special consideration: (i) the therapeutic misconception inherent to all clinical research and the randomized trial in particular; (ii) high risk and potentially non-beneficial novel technology research in children; and (iii) a collaborative partnership approach to research in the developing world. This study will focus on a discussion of each of these, drawing from the research ethics literature to offer a potential template for future deliberations in clinical trial design.
- Published
- 2008
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30. The use of factor VIII/von Willebrand factor concentrate for immune tolerance induction in haemophilia A patients with high-titre inhibitors: association of clinical outcome with inhibitor epitope profile.
- Author
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Greninger DA, Saint-Remy JM, Jacquemin M, Benhida A, and DiMichele DM
- Subjects
- Adolescent, Adult, B-Lymphocytes immunology, Child, Child, Preschool, Drug Combinations, Epitope Mapping, Epitopes analysis, Factor VIII therapeutic use, Genotype, Hemophilia A genetics, Humans, Immune Tolerance, Infant, Infant, Newborn, Retrospective Studies, Treatment Outcome, Autoantibodies blood, Factor VIII immunology, Hemophilia A drug therapy, Hemophilia A immunology, Hemostatics therapeutic use, von Willebrand Factor therapeutic use
- Abstract
A retrospective chart review of 11 subjects with severe haemophilia A and high-titre inhibitors who received a von Willebrand factor-containing FVIII concentrate (VWF/FVIII) for immune tolerance induction (ITI) was accompanied by B cell inhibitor epitope mapping during 10/11 treatment courses. ITI was successful or partially successful in all seven subjects who received VWF/FVIII for initial ITI, and failed in all four subjects whose ITI with this product was initiated following treatment failure using recombinant factor VIII. Variables including age at inhibitor development and age at ITI initiation, interval between inhibitor detection and ITI initiation, titre at start of ITI, and peak historical titres prior to and during ITI were not statistically significant outcome predictors in this cohort. However, the B cell epitope specificity in all four successful and in one of two partially successful ITI subjects for whom information was available included the C2 and excluded the A2 domains. Conversely, FVIII B cell epitopes in one partially successful ITI and in all three failed ITI subjects for whom data were available mapped to both the C2 and the A2 domains. The FVIII B cell epitope profile was associated with ITI outcome in this VWF/FVIII-treated cohort. Its role in predicting ITI outcome and guiding choice of FVIII product for ITI requires further study.
- Published
- 2008
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31. International workshop on immune tolerance induction: consensus recommendations.
- Author
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DiMichele DM, Hoots WK, Pipe SW, Rivard GE, and Santagostino E
- Subjects
- Catheters, Indwelling, Child, Preschool, Cost-Benefit Analysis, Equipment Failure, Factor IX administration & dosage, Factor IX immunology, Factor IX pharmacokinetics, Factor VIII administration & dosage, Factor VIII immunology, Factor VIII pharmacokinetics, Hemophilia A immunology, Humans, Infant, Infections complications, Infections immunology, Meta-Analysis as Topic, Randomized Controlled Trials as Topic, Risk Factors, Treatment Failure, Blood Coagulation Factor Inhibitors immunology, Factor IX antagonists & inhibitors, Factor VIII antagonists & inhibitors, Hemophilia A therapy, Immunosuppression Therapy methods
- Abstract
Although immune tolerance induction (ITI) has been used for 30 years to eliminate inhibitors and restore normal factor pharmacokinetics in patients with hemophilia, there is a paucity of scientific evidence to guide therapeutic decision-making. In an effort to provide direction for physicians and hemophilia treatment center staff members, an international panel of hemophilia opinion leaders met to develop consensus recommendations for ITI in patients with severe and mild hemophilia A and hemophilia B. These recommendations draw on the available published literature and the collective clinical experience of the group and are rated based on the level of supporting evidence.
- Published
- 2007
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32. A randomized comparison of bypassing agents in hemophilia complicated by an inhibitor: the FEIBA NovoSeven Comparative (FENOC) Study.
- Author
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Astermark J, Donfield SM, DiMichele DM, Gringeri A, Gilbert SA, Waters J, and Berntorp E
- Subjects
- Adolescent, Adult, Antibodies blood, Blood Coagulation Factors adverse effects, Child, Cohort Studies, Cross-Over Studies, Factor VII adverse effects, Factor VIII antagonists & inhibitors, Factor VIII immunology, Factor VIIa, Hemophilia A immunology, Humans, Middle Aged, Prospective Studies, Recombinant Proteins adverse effects, Recombinant Proteins therapeutic use, Treatment Outcome, Blood Coagulation Factors therapeutic use, Factor VII therapeutic use, Hemophilia A complications, Hemophilia A drug therapy
- Abstract
The development of inhibitory antibodies to factor VIII is a serious complication of hemophilia. FEIBA (factor VIII inhibitor-bypassing activity), an activated prothrombin complex concentrate (aPCC), and NovoSeven, recombinant factor VIIa (rFVIIa), are used as hemostatic bypassing agents in treating patients with inhibitors. The FENOC study was designed to test equivalence of the products in the treatment of ankle, knee, and elbow joint bleeding. A prospective, open-label, randomized, crossover, equivalency design was used. The parameters of interest were the percentage of patients who reported efficacy in response to FEIBA and the percentage that reported efficacy in response to NovoSeven. A difference in these percentages of no more than 15% was determined to be a clinically acceptable magnitude for equivalence of the 2 products. The primary outcome was evaluation 6 hours after treatment. Data for 96 bleeding episodes contributed by 48 participants were analyzed. The criterion for declaring the 2 products equivalent at 6 hours was not met; however, the confidence interval of the difference in percentages of efficacy reported for each product only slightly exceeded the 15% boundary (-11.4%-15.7%), P=.059. FEIBA and NovoSeven appear to exhibit a similar effect on joint bleeds, although the efficacy between products is rated differently by a substantial proportion of patients. This trial was registered at www.clinicaltrials.gov as #NCT00166309.
- Published
- 2007
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33. Inhibitor treatment in haemophilias A and B: inhibitor diagnosis.
- Author
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DiMichele DM
- Subjects
- Blood Coagulation Factor Inhibitors analysis, Factor IX therapeutic use, Factor VIII therapeutic use, Hemagglutination Inhibition Tests, Hemophilia A drug therapy, Humans, Blood Coagulation Factor Inhibitors antagonists & inhibitors, Factor IX immunology, Factor VIII immunology, Hemophilia A immunology, Hemophilia B immunology, Immunoglobulin G immunology
- Abstract
The clinical diagnosis and quantitative measurement of polyclonal IgG inhibiting antibodies are the subjects of this review. Inhibitors in congenital haemophilia are usually diagnosed either as part of a routine surveillance schedule or following a bleeding episode that responds poorly to standard specific replacement therapy. Routine surveillance schedules for paediatric haemophilia A patients during high-risk incidence periods are variable and the subject of ongoing discussion. There have never been any published recommendations for following haemophilia B patients at high risk for inhibitor development. The Factor VIII/IX Subcommittee of the International Society on Thrombosis and Haemostasis scientifically endorsed the Nijmegen method for inhibitor measurement in 1996. However, there are many unresolved issues surrounding inhibitor diagnosis using these assays. These issues include: (i) questions of accuracy and inter-assay variability inherent to the one-stage clotting assay; (ii) lack of consensus regarding the assay cut-off for negative determination; (iii) lack of assay standardization and (iv) the clinical importance of capturing non-neutralizing antibodies currently not measured in the functional assays. Ongoing efforts to resolve these issues will be discussed.
- Published
- 2006
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34. Immune tolerance: critical issues of factor dose, purity and treatment complications.
- Author
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DiMichele DM
- Subjects
- Coagulants administration & dosage, Factor IX administration & dosage, Factor VIII administration & dosage, Hemophilia A complications, Hemophilia A immunology, Hemophilia B complications, Hemophilia B immunology, Humans, Coagulants therapeutic use, Factor IX therapeutic use, Factor VIII therapeutic use, Hemophilia A drug therapy, Hemophilia B drug therapy, Immune Tolerance drug effects
- Abstract
The current practice of immune tolerance induction (ITI) therapy has been largely influenced by the results of small institutional studies and three large registries. However, many questions remain. Successful outcome predictors for ITI in haemophilia A have been suggested by the analyses of two of these registries. Among these predictors, factor VIII (FVIII) dose/dosing regimen remains a controversial outcome parameter, demonstrating a strong direct relationship to ITI success in the international registry and a weaker inverse relationship in the North American registry. There is an international multicentre prospective randomized trial underway to further study the role of FVIII dose in successful ITI induction in a good risk haemophilia A inhibitor patient cohort. FVIII purity also remains an unproved ITI outcome predictor. Institutional experience with von-Willebrand-factor-containing products has suggested its therapeutic advantage in both inhibitor development and eradication. The International ITI Study, although not designed to answer this particular question, may be able to determine an impact on outcome depending on the final distribution of investigator choice of product among the study subjects. Much less is known about the influence of factor IX (FIX) dose and purity on ITI success in haemophilia B. Importantly, nephrotic syndrome has been a major determinant of ITI failure in FIX inhibitor patients, particularly those with the allergic phenotype. Unfortunately, large prospective randomized trials in this group will not be feasible. Rather, we will have to rely on prospectively collected registry data to build our knowledge base of inhibitors and ITI in haemophilia B.
- Published
- 2006
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35. The international immune tolerance study: a multicenter prospective randomized trial in progress.
- Author
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Dimichele DM and Hay CR
- Subjects
- Blood Coagulation Factor Inhibitors immunology, Child, Child, Preschool, Humans, Immune Tolerance, Infant, Prospective Studies, Time Factors, Factor VIII therapeutic use, Hemophilia A immunology, Hemophilia A therapy
- Published
- 2006
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- View/download PDF
36. Management of factor VIII inhibitors.
- Author
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Dimichele DM
- Subjects
- Disease Management, Factor VIII therapeutic use, Hemophilia A complications, Hemophilia A immunology, Hemorrhage prevention & control, Humans, Immune Tolerance, Factor VIII immunology, Hemophilia A drug therapy
- Abstract
The development of inhibitory alloantibodies to factor VIII (FVIII) is a major complication of clotting factor replacement therapy for hemophilia A. Inhibitor development compromises effective hemostasis management in affected individuals and results in higher morbidity and costs of care compared with hemophilic individuals without anti-FVIII antibodies. The therapeutic approach to the management of bleeding in the presence of low- and high-titer inhibitors is founded on the principles of either saturating antibody with excess FVIII or bypassing the FVIII requirement altogether. Although spontaneous antibody disappearance does occur, immune tolerance is often required for antibody eradication. Studies aimed at optimizing this treatment approach and developing newer strategies for inhibitor prevention are ongoing.
- Published
- 2006
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- View/download PDF
37. Management of factor VIII inhibitors.
- Author
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Acharya SS and DiMichele DM
- Subjects
- Autoantibodies pharmacology, Blood Coagulation Factor Inhibitors pharmacology, Blood Coagulation Factors therapeutic use, Factor VIII antagonists & inhibitors, Factor VIII therapeutic use, Hemophilia A drug therapy, Hemophilia A epidemiology, Hemorrhage epidemiology, Humans, Recombinant Proteins therapeutic use, Autoantibodies immunology, Blood Coagulation Factor Inhibitors immunology, Factor VIII immunology, Hemophilia A immunology, Hemorrhage immunology, Hemorrhage therapy
- Abstract
The development of inhibitory alloantibodies to factor VIII is arguably one of the most severe and important complications of clotting factor concentrate exposure in haemophilia A. The development of an inhibitor compromises the ability to effectively manage haemorrhage, resulting in a greater rate of disability, complications and costs of therapy. This chapter briefly reviews the epidemiology, immunobiology, and laboratory evaluation of inhibitors. It discusses the therapeutic approach and management of inhibitors in various clinical settings and also focuses on inhibitor eradication practices (immune tolerance) and newer experimental strategies with potential clinical application for inhibitor prevention.
- Published
- 2006
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- View/download PDF
38. Haemophilia Inhibitor Genetics Study - evaluation of a model for studies of complex diseases using linkage and association methods.
- Author
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Berntorp E, Astermark J, Donfield SM, Nelson GW, Oldenburg J, Shapiro AD, Dimichele DM, Ewenstein BM, Gomperts ED, and Winkler CA
- Subjects
- Alleles, Family Health, Genome, Human, Humans, Linkage Disequilibrium genetics, Hemophilia A genetics
- Published
- 2005
- Full Text
- View/download PDF
39. Rare Bleeding Disorder Registry: deficiencies of factors II, V, VII, X, XIII, fibrinogen and dysfibrinogenemias.
- Author
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Acharya SS, Coughlin A, and Dimichele DM
- Subjects
- Adolescent, Adult, Afibrinogenemia epidemiology, Afibrinogenemia genetics, Aged, Child, Child, Preschool, Coagulation Protein Disorders genetics, Coagulation Protein Disorders therapy, Factor V Deficiency epidemiology, Factor V Deficiency genetics, Factor VII Deficiency epidemiology, Factor VII Deficiency genetics, Factor X Deficiency epidemiology, Factor X Deficiency genetics, Factor XIII Deficiency epidemiology, Factor XIII Deficiency genetics, Fibrinogens, Abnormal, Heterozygote, Homozygote, Humans, Hypoprothrombinemias epidemiology, Hypoprothrombinemias genetics, Infant, Infant, Newborn, Middle Aged, Registries, Retrospective Studies, Blood Coagulation Factors genetics, Coagulation Protein Disorders epidemiology
- Abstract
A North American registry for rare bleeding disorders [factor (F)II, factor (F)VII, factor (F)X, factor (F)V, factor (F)XIII, fibrinogen deficiencies and dysfibrinogenemias] was established to gather information about disease prevalence, genotyping frequency, diagnostic events, clinical manifestations, treatment and prophylaxis strategies, as well as disease- and treatment-related complications. Questionnaires were sent to 225 hemophilia treatment centers in the USA and Canada. Among 26% of responding centers, 294 individuals [4.4% of the registered children (200/4583) and 2.4% of adults (94/3809)] were diagnosed with one or more of the rare bleeding disorders (RBDs) included in this survey. The ethnic distribution for each disorder paralleled that of the general US population with the exception of the disproportionately large number of Latinos with FII deficiency. Only 5.4% of affected individuals were genotyped. An abnormal preoperative bleeding screen most often led to diagnosis. The most common coagulopathy was FVII deficiency; however, 40% of homozygous patients were asymptomatic. FX and FXIII deficiencies caused the most severe bleeding manifestations. Among all RBDs, the most common sites of bleeding were skin and mucus membranes. Multiple products were used to treat hemorrhage; however, half of the bleeding episodes required no therapy. The majority of patients suffered no long-term complications from hemorrhage. Treatment-related complications included viral seroconversion, anemia, allergic reactions and venous access device-related events. This registry provides the most comprehensive information to date about North American individuals with RBDs and could serve as an important resource for both basic scientist and clinician.
- Published
- 2004
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40. Transjugular liver biopsy is safe and diagnostic for patients with congenital bleeding disorders and hepatitis C infection.
- Author
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DiMichele DM, Mirani G, Wilfredo Canchis P, Trost DW, and Talal AH
- Subjects
- Adolescent, Adult, Biopsy, Needle adverse effects, Biopsy, Needle methods, Female, Hemostatic Techniques, Hepatitis C, Chronic complications, Humans, Jugular Veins, Male, Middle Aged, Retrospective Studies, Blood Coagulation Disorders, Inherited complications, Hepatitis C, Chronic diagnosis, Liver pathology
- Abstract
The prevalence of chronic hepatitis C virus (HCV) infection among patients with severe congenital bleeding disorders is as high as 98%. Advances in HCV treatment currently result in sustained virological response rates of > or =50%. Recent recommendations have reaffirmed that liver biopsy, which provides a direct histological assessment of liver inflammation and fibrosis, is still important for accurate diagnosis and therapeutic decision making. Percutaneous liver biopsy is a simple, standardized procedure that can be performed rapidly and relatively inexpensively, and has been safely performed in patients with congenital coagulopathies. However, the safety and efficacy of the transjugular approach (transjugular liver biopsy, TJLB), recommended for patients with acquired coagulopathies, has only been minimally studied in the congenital bleeding diathesis population. We now report our institutional experience with TJLB in 13 such adult patients (mean age 33 years) with severe/mild haemophilia A/B (10); von Willebrand disease (1); factor V deficiency (1) and factor XIII deficiency (1). Data were collected by retrospective chart review and the TJLB was performed according to institutional protocol as described. Haemostasis prophylaxis was given for 1-5 days. Patients were hospitalized for < or =48 h and all tolerated the procedure without bleeding. Three patients experienced self-limited abdominal discomfort; one episode was accompanied by transient transaminaemia. Diagnostic specimens were obtained from all patients and were instrumental in the therapeutic decision-making process. We suggest that with a co-ordinated multidisciplinary approach to care, TJLB is a safe, effective and potentially cost-effective alternative to the percutaneous approach in the congenital bleeding disorders population.
- Published
- 2003
- Full Text
- View/download PDF
41. Long-term FEIBA prophylaxis does not prevent progression of existing joint disease.
- Author
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Hilgartner MW, Makipernaa A, and Dimichele DM
- Subjects
- Child, Child, Preschool, Drug Administration Schedule, Factor VIII antagonists & inhibitors, Follow-Up Studies, Hemarthrosis etiology, Hemarthrosis physiopathology, Hemophilia A blood, Hemophilia A complications, Humans, Male, Retrospective Studies, Severity of Illness Index, Blood Coagulation Factors therapeutic use, Hemarthrosis prevention & control, Hemophilia A drug therapy
- Abstract
Activated prothrombin complex concentrates have been used to treat bleeding episodes for patients who have developed an inhibitor to factor VIII (FVIII). FEIBA-Vh (FVIII bypassing activity, FEIBA) has been used since 1970 for this purpose and with FVIII for immune tolerance programmes. Studies have not been presented to show the safety and efficacy of FEIBA when given over a long period of time to prevent haemophilic arthropathy with bleeding into the joints of these patients. This study was undertaken to ascertain the outcome of haemophilic arthropathy with FEIBA prophylaxis. Data were collected on seven patients with known long-standing high-titre FVIII inhibitors given FEIBA prophylaxis for 3-6(1/2) years. Patients were given 50-100 units of FEIBA three to four times weekly. A functional joint evaluation revealed some degree of arthropathy already present in all patients at time of prophylaxis initiation. Safety was measured by medical status, evidence of thrombosis, life-threatening bleeding and inhibitor titre. Efficacy was measured for joint outcome by a functional physical therapeutic scale. At the conclusion of the study, efficacy was mixed as all of the joints for which the patients were placed on prophylaxis had progressed and developed synovitis. Two patients had a functional improvement in their arthropathy, and all were functional enough to attend regular school. The product was deemed safe for long-term use, as there were no complications of therapy with no thrombosis, no life-threatening bleeding episodes and no anamnesis caused by FEIBA alone. Inhibitor titres fell in all patients over the course of the study. Total product usage ranged from approximately 9373-15,571 U kg(-1) year(-1). FEIBA is safe for long-term prophylaxis when given in the recommended dosage for an extended period of time. Efficacy to prevent arthropathy could not be seen as all patients had some degree of arthropathy at time of prophylaxis initiation. An additional study needs to be performed using FEIBA before arthropathy has developed.
- Published
- 2003
- Full Text
- View/download PDF
42. Clinical manifestations of the prothrombin G20210A mutation in children: a pediatric coagulation consortium study.
- Author
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Young G, Manco-Johnson M, Gill JC, Dimichele DM, Tarantino MD, Abshire T, and Nugent DJ
- Subjects
- Adolescent, Age Distribution, Arterial Occlusive Diseases epidemiology, Arterial Occlusive Diseases genetics, Child, Child, Preschool, Female, Genetic Predisposition to Disease, Heterozygote, Homozygote, Humans, Incidence, Infant, Infant, Newborn, Male, Retrospective Studies, Surveys and Questionnaires, Thrombosis epidemiology, Venous Thrombosis epidemiology, Venous Thrombosis genetics, Point Mutation, Prothrombin genetics, Thrombosis genetics
- Abstract
The prothrombin G20210A mutation is a common risk factor for thrombosis which increases the risk of deep vein thrombosis, stroke, and fetal loss. There are few publications of its clinical manifestations in children. Our objective was to determine the clinical manifestations of the prothrombin mutation in children. Via survey of pediatric hematologists, we collected data on children with thrombosis and the prothrombin mutation. Thirty-eight patients with a thrombotic event were identified as having the prothrombin mutation. Children with arterial thrombosis were younger, less than half had additional risk factors present at the time of the event, and had a high frequency of central nervous system thrombosis. Children with venous thrombosis were older, almost always had additional risk factors present, and had thrombosis occur most often in the extremities, although there were also a significant number of events in the central venous and cerebral circulation. There was a striking predilection for central nervous system events as 30% of all the events and 67% of the arterial events occurred there. In all, 14/38 children (37%) had central nervous system thrombosis. Unlike factor V Leiden and deficiencies of proteins C and S which cause venous thromboembolism, the prothrombin mutation in children is often associated with arterial thrombosis and with central nervous system events. In children with the prothrombin mutation and venous thrombosis, other risk factors are usually present. Therefore, children with arterial or venous thrombosis of any location should be evaluated for the presence of the prothrombin mutation.
- Published
- 2003
- Full Text
- View/download PDF
43. The upward spiral of drug costs: a time series analysis of drugs used in the treatment of hemophilia.
- Author
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Rogoff EG, Guirguis HS, Lipton RA, Seremetis SV, DiMichele DM, Agnew GM, Karpatkin M, Barish RJ, Jones RL, Bianco C, Knothe BD, and Lee MS
- Subjects
- Blood Coagulation Factors therapeutic use, Costs and Cost Analysis trends, Government Regulation, Health Expenditures, Hemophilia A drug therapy, Hemophilia A therapy, Humans, Marketing, Blood Coagulation Factors economics, Drug Costs trends, Hemophilia A economics
- Abstract
Background: Hemophilia is an expensive disease because its treatment is heavily dependent on costly clotting factor drugs. Over the last nine years,a consortium of three Comprehensive Hemophilia Treatment Centers and other hospitals, which purchased clotting factors for their patients, has seen treatment costs escalate on average 17% annually. Currently, new, even more expensive drugs are entering the market., Methods: This study analyzes 3,244 purchases that were made over a nine-year period totaling nearly 500 million units of clotting factor, representing every product on the market. Purchases were made both apart from and under the Federal Public Health Service (PHS)discount pricing rules., Findings: The main cause of the increases was the move to newer, more expensive products. The average price of existing products increased less than 2%per year, but new products were priced, on average, 47% higher than existing products. Overall consumption increased by an average of 5% per year, likely reflecting prophylactic treatment modalities that require greater amounts of clotting factor. Government pricing programs, such as the PHS program, were ineffective or counterproductive at reducing costs. There is a notable absence of competition in this market, with a few dominant companies having a functional monopoly in the largest segments of the market. Prices of older products are not lowered, even when new products are brought to market. A few products that serve small patient groups have had their prices increased substantially., Interpretation: This escalation is likely to continue as new, more expensive clotting factor drugs are developed. Since these new products are not proven to be any safer or more effective than the current products, this situation creates a risk of intervention by government and insurers to address both treatment costs and exhaustion of patients' insurance caps. Drug companies are not serving the patients by pricing new, but often very similar, products so aggressively. The trends seen in this patient group will likely be seen in other patient groups in the future. Ultimately, doctors and patients will lose treatment options and health care availability unless collaborative strategies are developed to reduce costs.
- Published
- 2002
44. The North American Immune Tolerance Registry: practices, outcomes, outcome predictors.
- Author
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DiMichele DM and Kroner BL
- Subjects
- Canada epidemiology, Catheterization, Central Venous adverse effects, Cohort Studies, Comorbidity, Factor IX therapeutic use, Factor VIII therapeutic use, Female, HIV Infections epidemiology, HIV Infections immunology, Hemophilia A epidemiology, Hemophilia A therapy, Hemophilia B epidemiology, Hemophilia B therapy, Hemorrhage etiology, Humans, Immunization, Isoantibodies blood, Male, Outcome Assessment, Health Care, Recombinant Proteins immunology, Recombinant Proteins therapeutic use, Retrospective Studies, Surveys and Questionnaires, Treatment Outcome, United States epidemiology, Desensitization, Immunologic statistics & numerical data, Factor IX immunology, Factor VIII immunology, Hemophilia A immunology, Hemophilia B immunology, Immune Tolerance, Isoantibodies immunology, Registries statistics & numerical data
- Abstract
The North American Immune Tolerance Registry was initiated to study of immune tolerance (ITT) in Canada and the United States with respect to: 1) therapeutic regimens in use for haemophilia A (HA) and B (HB) inhibitor patients; 2) therapeutic outcomes; 3) potential predictors of successful outcome and 4) complications of therapy. Data on 188 ITT courses was collected by questionnaire from 60 haemophilia centers from 1993-99. Among the completed courses, the overall success rate was 70% (115/164) for all HA and 31% (5/16) for all HB. Outcome parameters noted to be predictive of ITT success for all HA were 1) pre-ITT induction (p = 0.003), 2) ITT peak (p = 0.007) and 3) historical pre ITT peak (p = 0.04) inhibitor titres. An inverse correlation between total daily dose (units/kg/day) and success: (80% with under 50; 71% with 50-99; 73% with 100-199; and 41% with > or = 200, p = 0.01) was found. Outcome predictors were not evaluable for HB, although adverse reactions to therapy, including nephrotic syndrome, and access complications were more common among failed courses. Infection most often complicated the use of access catheters. These results are discussed within the context of the international ITT registry and upcoming prospective ITT study.
- Published
- 2002
45. Continuous infusion of porcine factor VIII: stability, microbiological safety and clinical experience.
- Author
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DiMichele DM, Gorman PO, Kasper CK, Mannucci PM, Santagostino E, and Hay CR
- Subjects
- Adolescent, Adult, Animals, Bacteria growth & development, Child, Child, Preschool, Consumer Product Safety, Data Collection, Drug Stability, Factor VIII standards, Hemophilia A complications, Hemophilia A drug therapy, Humans, Infant, Infusions, Parenteral adverse effects, Infusions, Parenteral methods, Infusions, Parenteral standards, Swine, Therapeutic Equivalency, Factor VIII administration & dosage
- Abstract
Porcine factor VIII (pFVIII) is an effective haemostatic treatment for bleeding in selected patients with FVIII inhibitors. Its use is sometimes associated with a transient fall in platelet count and transfusion reactions, the risk of which may be related to the rate of administration. Theoretical considerations suggest that the administration of pFVIII by continuous infusion should be effective, and could have pharmacokinetic advantages that lead to an improvement in the side-effect profile. The results of a retrospective survey of continuous infusion of pFVIII with respect to clinical safety and efficacy are reported. Porcine FVIII stability and microbiological studies are included. It is concluded that pFVIII given by continuous infusion is safe and effective. The risk of transfusion reactions and fall in platelet count appears to be reduced, compared with bolus administration. Stability studies showed that pFVIII activity declined at room temperature, most rapidly in the dilute solution (5-10 U mL(-1)). More concentrated mixtures showed acceptable stability for up to 24 h using a variety of infusion devices. Various concentrations of pFVIII did not support the growth of Escherichia coli or Staphylococcus aureus. These observations suggest that the porcine factor is suitable for continuous infusion (CI).
- Published
- 2002
- Full Text
- View/download PDF
46. Continuous infusion of porcine factor VIII in patients with haemophilia A and high-responding inhibitors: stability and clinical experience.
- Author
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O'Gorman P, Dimichele DM, Kasper CK, Mannucci PM, Santagostini E, and Hay CR
- Subjects
- Adolescent, Adult, Animals, Child, Child, Preschool, Drug Evaluation, Factor VIII immunology, Factor VIII toxicity, Hemophilia A complications, Hemorrhage drug therapy, Hemorrhage etiology, Humans, Infant, Platelet Count, Retrospective Studies, Swine, Treatment Outcome, Factor VIII administration & dosage, Hemophilia A drug therapy, Infusions, Parenteral standards, Isoantibodies blood
- Abstract
A multicentre retrospective survey was conducted to assess the efficacy and side-effect profile of porcine factor VIII (pFVIII:C) given by continuous infusion (CI) to patients with congenital haemophilia A and inhibitors. Twenty-nine episodes in 18 patients were treated by CI of pFVIII:C. Efficacy was graded as good in 79% of infusions and fair in 17%. There was a failed response in only one episode. Fourteen percent of patients experienced transfusion reactions with bolus doses, but no reactions were observed in patients given CI. There were no severe reactions. All the reactions resolved following interruption of the infusion and administration of steroids. Premedication did not prevent reactions. In this series the median decrease in platelet count after bolus injection of pFVIII:C was -67 X 10(9) L(-1) compared with a median decrease of -2 x 109 L(-1) during the course of CI, thus, continuous infusion of pFVIII:C appears to have less effect on platelet count than bolus injection. An anamnestic response was associated with 77% of infusions. This high rate of anamnesis reflects patient selection, in that they were all known to have high-level high-responding FVIII inhibitors with cross-reactivity to pFVIII. After reconstitution, the pFVIII:C showed little loss in factor VIII activity in solution over a 24-h period. We conclude that pFVIII:C may be effectively administered by CI to patients with haemophilia A and high-responding FVIII inhibitors. CI is the probably the mode of administration of choice for intensive replacement therapy with pFVIII.
- Published
- 2001
- Full Text
- View/download PDF
47. Inhibitors in haemophilia: a primer.
- Author
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DiMichele DM
- Subjects
- Factor IX immunology, Factor IX therapeutic use, Factor VIII immunology, Factor VIII therapeutic use, Hemophilia A complications, Hemophilia A drug therapy, Humans, Immune Tolerance, Hemophilia A immunology, Isoantibodies blood
- Published
- 2000
- Full Text
- View/download PDF
48. Analysis of the North American Immune Tolerance Registry (NAITR) 1993-1997: current practice implications. ISTH Factor VIII/IX Subcommittee Members.
- Author
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DiMichele DM and Kroner BL
- Subjects
- Antibodies therapeutic use, Databases, Factual, Factor IX administration & dosage, Factor IX immunology, Factor VIII administration & dosage, Factor VIII immunology, Hemophilia A blood, Hemophilia A immunology, Humans, North America epidemiology, Time Factors, Treatment Outcome, Hemophilia A drug therapy, Immune Tolerance drug effects, Registries
- Published
- 1999
- Full Text
- View/download PDF
49. Inhibitors occur more frequently in African-American and Latino haemophiliacs.
- Author
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Aledort LM and Dimichele DM
- Subjects
- Factor VIII antagonists & inhibitors, Hemophilia A blood, Humans, Black or African American, Black People, Factor VIII therapeutic use, Hemophilia A drug therapy, Hispanic or Latino
- Published
- 1998
- Full Text
- View/download PDF
50. Heparin and the risk of intraventricular hemorrhage in premature infants.
- Author
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Chang GY, Lueder FL, DiMichele DM, Radkowski MA, McWilliams LJ, and Jansen RD
- Subjects
- Blood Coagulation Tests, Cerebral Hemorrhage diagnostic imaging, Female, Humans, Incidence, Infant, Newborn, Infant, Premature, Diseases diagnostic imaging, Infusions, Intravenous, Male, Risk Factors, Single-Blind Method, Ultrasonography, Doppler, Transcranial, Anticoagulants therapeutic use, Catheters, Indwelling, Cerebral Hemorrhage chemically induced, Cerebral Ventricles, Heparin therapeutic use, Infant, Premature, Diseases chemically induced, Umbilical Arteries
- Abstract
Objective: This study was carried out to determine whether the routine use of low-dose heparin in umbilical catheter infusates increases the risk of intraventricular hemorrhage or alters the coagulation profile in premature infants., Methods: In a randomized, blinded trial, 113 infants born at less than 31 weeks' gestation were assigned to receive, in their umbilical catheter infusate, either 1 unit of heparin per milliliter (n = 55) or no heparin (n = 58). Prothrombin time, activated partial thromboplastin time, fibrinogen concentration, and antithrombin III activity levels were determined at the start and the completion of the study. Cranial ultrasonography was performed during the first week of life., Results: There was no difference in the incidence of intraventricular hemorrhage between the heparin and no heparin groups, 35.8% and 31.5%, respectively (p = 0.6). Similarly, no difference was detected in the incidence of severe intraventricular hemorrhage (grades III/IV). Prothrombin time, activated partial thromboplastin time, and fibrinogen levels were not significantly different between the two groups. However, the use of heparin was associated with a lower antithrombin III activity level. Antenatal indomethacin use was associated with a 2.9 increased risk of intraventricular hemorrhage (95% confidence interval, 1.15 to 7.17)., Conclusion: A low dose of heparin added to umbilical catheter infusates does not increase the incidence or severity of intraventricular hemorrhage or significantly alter the coagulation profile in premature infants.
- Published
- 1997
- Full Text
- View/download PDF
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