WorldWideScience

Sample records for hemophilia clinic directors

  1. Hemophilia

    Science.gov (United States)

    Hemophilia is a rare disorder in which the blood does not clot normally. It is usually inherited. Hemophilia usually occurs in males. If you have hemophilia, you have little or no clotting factor. Clotting ...

  2. Clinical, instrumental, serological and histological findings suggest that hemophilia B may be less severe than hemophilia A.

    Science.gov (United States)

    Melchiorre, Daniela; Linari, Silvia; Manetti, Mirko; Romano, Eloisa; Sofi, Francesco; Matucci-Cerinic, Marco; Carulli, Christian; Innocenti, Massimo; Ibba-Manneschi, Lidia; Castaman, Giancarlo

    2016-02-01

    Recent evidence suggests that patients with severe hemophilia B may have a less severe disease compared to severe hemophilia A. To investigate clinical, radiological, laboratory and histological differences in the arthropathy of severe hemophilia A and hemophilia B, 70 patients with hemophilia A and 35 with hemophilia B with at least one joint bleeding were consecutively enrolled. Joint bleedings (50), regimen of treatment (prophylaxis/on demand), World Federation of Hemophilia, Pettersson and ultrasound scores, serum soluble RANK ligand and osteoprotegerin were assessed in all patients. RANK, RANK ligand and osteoprotegerin expression was evaluated in synovial tissue from 18 hemophilia A and 4 hemophilia B patients. The percentage of patients with either 10-50 or more than 50 hemarthrosis was greater in hemophilia A than in hemophilia B (Phemophilia B (PHemophilia (36.6 vs. 20.2; Phemophilia A patients. Serum osteoprotegerin and soluble RANK ligand were decreased in hemophilia A versus hemophilia B (Phemophilia A patients. In conclusion, the reduced number of hemarthrosis, the lower World Federation of Hemophilia and ultrasound scores, and higher osteoprotegerin expression in serum and synovial tissue in hemophilia B suggest that hemophilia B is a less severe disease than hemophilia A. Osteoprotegerin reduction seems to play a pivotal role in the progression of arthropathy in hemophilia A. Copyright© Ferrata Storti Foundation.

  3. Molecular genetics of hemophilia A: Clinical perspectives

    African Journals Online (AJOL)

    Azza A.G. Tantawy

    Deep-muscle hematomas. Intracranial bleeding in the absence of major trauma .... major trauma or surgery. Often later in life. Clinical severity does not always correlate with the in vitro assay result. Molecular genetics of hemophilia A: Clinical perspectives. 107 .... treatment [55]. The cumulative risk of inhibitor development.

  4. Molecular genetics of hemophilia A: Clinical perspectives

    African Journals Online (AJOL)

    Azza A.G. Tantawy

    cian about progress in hemophilia treatment. Prenatal testing is generally indicated in families with severe or moderate forms of hemophilia. In families with the mild disease such indication is rare [27,80]. 10.1. Molecular genetic testing. Prenatal testing can be done for carrier women if the mutation is identified in a family ...

  5. Molecular genetics of hemophilia A: Clinical perspectives | Tantawy ...

    African Journals Online (AJOL)

    Since the publication of the sequence of the factor VIII (F8) gene in 1984, a large number of mutations that cause hemophilia A have been identified and a significant progress has been made in translating this knowledge for clinical diagnostic and therapeutic purposes. Molecular genetic testing is used to determine the ...

  6. [Clinical evaluation of three elderly cases with acquired hemophilia A].

    Science.gov (United States)

    Saito, Makoto; Wakasa, Kentaro; Mori, Akio; Irie, Tatsuro; Tanaka, Masanori; Morioka, Masanobu; Ieko, Masahiro

    2012-02-01

    In this paper we report our clinical investigation of three cases with acquired hemophilia A treated in our department. These patients were all elderly males (79, 77, and 68 years old), and presented with subcutaneous bleeding, a prolonged activated partial thromboplastin time (APTT), and anemia. On the basis of these findings as well as decreased factor VIII activities (0.9~3.1%) and the presence of factor VIII inhibitors (57.1~173 BU/ml), we made a diagnosis of acquired hemophilia A. In cases 1 and 2, a recombinant activated factor VII was used to achieve hemostasis. The factor VIII inhibitor disappeared with prednisolone (PSL) alone in case 1 and a combination of PSL and cyclophosphamide in case 2. In case 3, treatment involving five courses of weekly rituximab (RTX) reduced the activity of factor III inhibitor to 3.5 BU/ml (and subsequently to zero). During this time, the patient achieved hemostasis without using a specific hemostatic agent, and was again referred to the previous hospital for the treatment of hepatocellular carcinoma. Although PSL is often chosen as a first-line therapy to suppress the production of factor VIII inhibitor, which may cause acquired hemophilia A, RTX may be another therapeutic option in some patients.

  7. Acquired hemophilia a: diagnosis, aetiology, clinical spectrum and treatment options.

    Science.gov (United States)

    Shetty, Shrimati; Bhave, Manali; Ghosh, Kanjaksha

    2011-04-01

    Acquired hemophilia A (AHA) is a rare disorder with an incidence of approximately 1 per million/year with a high mortality rate of more than 20%. The disease occurs due to autoantibodies against coagulation factor VIII (FVIII) which neutralize its procoagulant function and result in severe, often life-threatening bleeding. The antibodies arise in individuals with no prior history of hemophilia A. AHA may be associated with pregnancy, autoimmune diseases, malignancy, infections or medication and occurs most commonly in the elderly. Approximately 50% of the patients remain idiopathic with no known underlying pathological condition. Clinical manifestations include spontaneous hemorrhages into the skin, muscles or soft tissues or excessive bleeding during surgery. Hemarthrosis which is the hallmark of congenital severe hemophilia A seldom occurs in AHA. The diagnosis of AHA is based on the isolated prolongation of activated partial thromboplastin time (APTT) which does not normalize after the addition of normal plasma along with reduced FVIII levels. The treatment involves two aspects-eradication of antibodies and maintaining effective hemostasis during a bleeding episode. The protocols for eradication of antibodies include immunoadsorption, immunosuppression or immune tolerance induction (ITI). The treatment of acute bleeding episodes involves use of different bypassing agents like recombinant activated factor VIIa (rFVIIa, NovoSeven®) and activated prothrombin complex concentrate (aPCC, (FEIBA®) in case of patients with high titer inhibitors or with antifibrinolytics,1-deamino-8-D-arginine vasopressin (DDAVP) or FVIII concentrates in low titer inhibitor patients. The anti CD20 monoclonal antibody, rituximab, has shown very good results either singly or in combination with immunosuppressive regimens in patients who do not respond to standard immunosuppressors. The present review summarizes the diagnostic, aetiological, clinical and treatment aspects of AHA focusing

  8. Child-rearing practices toward children with hemophilia: The relative importance of clinical characteristics and parental emotional reactions

    NARCIS (Netherlands)

    Banis, Hendrika; Suurmeijer, Th.P.B.M.; van Peer, D.R.

    This study addresses the relative importance of clinical characteristics of the child and parental emotional reactions, to child-rearing practices towards children who suffer from hemophilia. The variables were assessed in a Dutch sample of 108 zero-to-twelve-year-old boys with hemophilia and their

  9. A randomized clinical trial of prophylaxis in children with hemophilia A (the ESPRIT Study).

    Science.gov (United States)

    Gringeri, A; Lundin, B; von Mackensen, S; Mantovani, L; Mannucci, P M

    2011-04-01

    Prevention of arthropathy is a major goal of hemophilia treatment. While studies in adults have demonstrated an impact of prophylaxis on the incidence of joint bleeds and patients' well-being in terms of improved quality of life (QoL), it is unclear whether or not prophylaxis influences the outcome and perception of well- of children with hemophilia. This randomized controlled study compared the efficacy of prophylaxis with episodic therapy in preventing hemarthroses and image-proven joint damage in children with severe hemophilia A (factor VIII <1%) over a 10-year time period. Forty-five children with severe hemophilia A, aged 1-7 years (median 4), with negative clinical-radiologic joint score at entry and at least one bleed during the previous 6 months, were consecutively randomized to prophylaxis with recombinant factor VIII (25 IU kg(-1) 3 × week) or episodic therapy with ≥25 IU kg(-1) every 12-24 h until complete clinical bleeding resolution. Safety, feasibility, direct costs and QoL were also evaluated. Twenty-one children were assigned to prophylaxis, 19 to episodic treatment. Children on prophylaxis had fewer hemarthroses than children on episodic therapy: 0.20 vs. 0.52 events per patient per month (P < 0.02). Plain-film radiology showed signs of arthropathy in six patients on prophylaxis (29%) vs. 14 on episodic treatment (74%) (P < 0.05). Prophylaxis was more effective when started early (≤36 months), with patients having fewer joint bleeds (0.12 joint bleeds per patient per month) and no radiologic signs of arthropathy. This randomized trial confirms the efficacy of prophylaxis in preventing bleeds and arthropathy in children with hemophilia, particularly when it is initiated early in life. © 2011 International Society on Thrombosis and Haemostasis.

  10. Hemophilia Diagnosis

    Science.gov (United States)

    ... and the severity. Families With a History of Hemophilia Any family history of bleeding, such as following ... for hemophilia . Families With No Previous History of Hemophilia About one-third of babies who are diagnosed ...

  11. Hemophilia - resources

    Science.gov (United States)

    Resources - hemophilia ... The following organizations provide further information on hemophilia : Centers for Disease Control and Prevention -- www.cdc.gov/ncbddd/hemophilia/index.html National Heart, Lung, and Blood Institute -- www.nhlbi.nih.gov/ ...

  12. Hemophilia A

    Science.gov (United States)

    ... hemophilia may be treated with desmopressin (DDAVP). This medicine helps the body release factor VIII that is stored within the lining of blood vessels. To prevent a bleeding crisis, people with hemophilia and their families can be ...

  13. Animal Models of Hemophilia

    Science.gov (United States)

    Sabatino, Denise E.; Nichols, Timothy C.; Merricks, Elizabeth; Bellinger, Dwight A.; Herzog, Roland W.; Monahan, Paul E.

    2013-01-01

    The X-linked bleeding disorder hemophilia is caused by mutations in coagulation factor VIII (hemophilia A) or factor IX (hemophilia B). Unless prophylactic treatment is provided, patients with severe disease (less than 1% clotting activity) typically experience frequent spontaneous bleeds. Current treatment is largely based on intravenous infusion of recombinant or plasma-derived coagulation factor concentrate. More effective factor products are being developed. Moreover, gene therapies for sustained correction of hemophilia are showing much promise in pre-clinical studies and in clinical trials. These advances in molecular medicine heavily depend on availability of well-characterized small and large animal models of hemophilia, primarily hemophilia mice and dogs. Experiments in these animals represent important early and intermediate steps of translational research aimed at development of better and safer treatments for hemophilia, such a protein and gene therapies or immune tolerance protocols. While murine models are excellent for studies of large groups of animals using genetically defined strains, canine models are important for testing scale-up and for longer-term follow-up as well as for studies that require larger blood volumes. PMID:22137432

  14. Duodenal Tumor Presenting as Acquired Hemophilia in an 88-Year-Old Woman: A Clinical Case and Review of the Literature

    Science.gov (United States)

    Murray, Nigel P.; Moncada, Juan Carlos; Moran, Marcelo

    2012-01-01

    Acquired hemophilia is a rare disease, presenting with severe hemorrhage, we present a case caused by a duodenal tumor, the clinical management, ethical implications, treatment recommendations, and a review of the literature. PMID:22966469

  15. Duodenal Tumor Presenting as Acquired Hemophilia in an 88-Year-Old Woman: A Clinical Case and Review of the Literature

    Directory of Open Access Journals (Sweden)

    Nigel P. Murray

    2012-01-01

    Full Text Available Acquired hemophilia is a rare disease, presenting with severe hemorrhage, we present a case caused by a duodenal tumor, the clinical management, ethical implications, treatment recommendations, and a review of the literature.

  16. Acquired hemophilia A.

    Science.gov (United States)

    Webert, Kathryn E

    2012-10-01

    Acquired hemophilia A is a rare, autoimmune disorder that is caused by autoantibodies that act as inhibitors to factor VIII. It is characterized by severe, unexpected bleeding that may be life-threatening. The incidence of acquired hemophilia A is ~ 0.2 to 1.48 cases per 1 million individuals per year. Acquired hemophilia A has been associated with several clinical conditions including pregnancy, autoimmune or collagen vascular disorders, malignancies, drugs, respiratory disorders, and infections. However, in ~ 50% of cases, no disease association is determined. Acquired hemophilia A should be suspected when a patient with no previous personal or family history of bleeding, presents with bleeding and an unexplained prolonged activated partial thromboplastin time (APTT) and other common causes of a prolonged APTT are ruled out. The treatment of acquired hemophilia A has two main goals: (1) to treat and/or prevent bleeding complications and (2) to eradicate the inhibitor. The recommended agents to be used for the treatment or prevention of bleeding in patients with acquired hemophilia A are the bypassing agents. Patients should be treated initially with corticosteroids, either alone or in combination with cyclophosphamide, to eradicate the inhibitor. Thieme Medical Publishers 333 Seventh Avenue, New York, NY 10001, USA.

  17. Hemophilia (For Teens)

    Science.gov (United States)

    ... Personal Plan Hot Topics Flu Facts Arrhythmias Abuse Hemophilia KidsHealth > For Teens > Hemophilia Print A A A ... bruises can be a big deal. What Is Hemophilia? Hemophilia is a disease that prevents blood from ...

  18. The medical director in integrated clinical care models.

    Science.gov (United States)

    Parker, Thomas F; Aronoff, George R

    2015-07-07

    Integrated clinical care models, like Accountable Care Organizations and ESRD Seamless Care Organizations, present new opportunities for dialysis facility medical directors to affect changes in care that result in improved patient outcomes. Currently, there is little scholarly information on what role the medical director should play. In this opinion-based review, it is predicted that dialysis providers, the hospitals in which the medical director and staff physicians practice, and the payers with which they contract are going to insist that, as care becomes more integrated, dialysis facility medical directors participate in new ways to improve quality and decrease the costs of care. Six broad areas are proposed where dialysis unit medical directors can have the greatest effect on shifting the quality-care paradigm where integrated care models are used. The medical director will need to develop an awareness of the regional medical care delivery system, collect and analyze actionable data, determine patient outcomes to be targeted that are mutually agreed on by participating physicians and institutions, develop processes of care that result in improved patient outcomes, and lead and inform the medical staff. Three practical examples of patient-centered, quality-focused programs developed and implemented by dialysis unit medical directors and their practice partners that targeted dialysis access, modality choice, and fluid volume management are presented. Medical directors are encouraged to move beyond traditional roles and embrace responsibilities associated with integrated care. Copyright © 2015 by the American Society of Nephrology.

  19. Clinical characteristics and outcomes of acquired hemophilia A: experience at a single center in Japan.

    Science.gov (United States)

    Ogawa, Yoshiyuki; Yanagisawa, Kunio; Uchiumi, Hideki; Ishizaki, Takuma; Mitsui, Takeki; Gouda, Fumito; Ieko, Masahiro; Ichinose, Akitada; Nojima, Yoshihisa; Handa, Hiroshi

    2017-07-01

    Acquired hemophilia A (AHA), which is caused by autoantibodies against coagulation factor VIII (FVIII) is a rare, life-threatening bleeding disorder, the incidence of which appears to be increasing in Japan as the population ages. However, the clinical characteristics, treatment, and outcomes of AHA remain difficult to establish due to the rarity of this disease. We retrospectively analyzed data from 25 patients (median age 73 years; range 24-92 years; male n = 15) diagnosed with AHA between 1999 and 2015 at Gunma University Hospital. We identified autoimmune diseases and malignancy as underlying conditions in four and three patients, respectively. Factor VIII activity was significantly decreased in all patients (median 2.0%; range <1.0-8.0) by FVIII inhibitor (median 47.0 BU/mL; range 2.0-1010). Among 71 bleeding events, subcutaneous or intramuscular hemorrhage was the most prevalent. Seventeen patients required bypassing agents. Twenty-two (91.7%) of 24 patients treated with immunosuppressive agents achieved complete response (CR) during a median of 57.5 days (range 19-714 days). Although three patients (12%) relapsed and seven (28%) died of infection, none of the deaths were related to bleeding. Although most of our patients achieved CR after immunosuppressive therapy, the rate of infection-related mortality was unsatisfactorily high.

  20. Osteoporosis and Hemophilia

    Directory of Open Access Journals (Sweden)

    A.S. Kalis

    2013-01-01

    Full Text Available Hemophilia — an hereditary coagulopathy, in which the process of anticoagulation is due to genetic deficiency and decreased procoagulant activity of FVIII (IX. The most difficult manifestation of hemophilia is the development of chronic hemophilic arthropathy, the severity of which is directly dependent on the level of the scarce factor and the adequacy of replacement therapy. The clinical course of hemophilic arthropathy begins with acute hemarthrosis, is at the stage of chronic villous synovitis and ultimately leads to osteoarthritis deformans, fibrous ankylosis, and the development of secondary periarticular osteoporosis. The aim of our study was to identify risk factors for osteopenia and osteoporosis in metaepiphysis bones forming the joint, as well as trace the dependence of reduction in bone mineral density from the level of deficient FVIII (IX in patients with hemophilia.

  1. Research leadership: should clinical directors be distinguished researchers?

    Science.gov (United States)

    Allison, Stephen; Goodall, Amanda H; Bastiampillai, Tarun

    2016-06-01

    Clinical directors established research-led healthcare by combining research, teaching and clinical excellence within the teaching hospitals. This research culture created high clinical standards, which benefited patients, the workforce and healthcare organisations. The current paper explores this research leadership role for clinical directors. It reviews studies arising from the theory of expert leadership, which focuses on the relationship between a leader's core knowledge and organisational performance. More specifically, we examine the expert leader's research track record, the associations with their organisation's performance, and the influence of research activity on clinical excellence. Distinguished researchers still lead the most prestigious teaching hospitals and the most trusted departments of psychiatry in the United States where the clinical directorate structure originated. It is also known that good scholars can improve research output when appointed to leadership positions. This suggests that the clinical director's research track record should be a consideration at a time when research is being embedded in Australia's local health networks. A clinical director's leadership may influence the research performance of their department and contribute to the quality of mental healthcare. © The Royal Australian and New Zealand College of Psychiatrists 2015.

  2. Characteristics and Roles of Literacy Clinic Directors

    Science.gov (United States)

    Ortlieb, Evan; Pearce, Daniel L.

    2013-01-01

    A literacy clinic is an ideal setting where research and exploration often lead to breakthroughs in reading remediation; that information can then be transferred to classroom instruction (Morris, 2003). Although it is clear that literacy clinics should be structured around what works for their student populations, there remains ambiguity…

  3. How to Deal with Hemophilia

    Science.gov (United States)

    ... Your Teeth Bad Breath How to Deal With Hemophilia KidsHealth > For Kids > How to Deal With Hemophilia ... mild case of hemophilia. Why Do Kids Get Hemophilia? Hemophilia almost always affects boys. Why? Because the ...

  4. Hemophilia Data and Statistics

    Science.gov (United States)

    ... Search Form Controls Cancel Submit Search the CDC Hemophilia Note: Javascript is disabled or is not supported ... message, please visit this page: About CDC.gov . Hemophilia Homepage Facts Diagnosis How Hemophilia is Inherited Quiz ...

  5. Genetics Home Reference: hemophilia

    Science.gov (United States)

    ... Share: Email Facebook Twitter Home Health Conditions Hemophilia Hemophilia Printable PDF Open All Close All Enable Javascript to view the expand/collapse boxes. Description Hemophilia is a bleeding disorder that slows the blood ...

  6. Both Hemophilia Health Care Providers and Hemophilia A Carriers Report that Carriers have Excessive Bleeding

    Science.gov (United States)

    Paroskie, Allison; Oso, Olatunde; DeBaun, Michael R.; Sidonio, Robert F

    2014-01-01

    Introduction Hemophilia A, the result of reduced factor VIII (FVIII) activity, is an X-linked recessive bleeding disorder. Previous reports of Hemophilia A carriers suggest an increased bleeding tendency. Our objective was to determine the attitudes and understanding of the Hemophilia A carrier bleeding phenotype, and opinions regarding timing of carrier testing from the perspective of both medical providers and affected patients. Data from this survey was used as preliminary data for an ongoing prospective study. Material and Methods An electronic survey was distributed to physicians and nurses employed at Hemophilia Treatment Centers (HTC), and Hemophilia A carriers who were members of Hemophilia Federation of America. Questions focused on the clinical understanding of bleeding symptoms and management of Hemophilia A carriers, and the timing and intensity of carrier testing. Results Our survey indicates that 51% (36/51) of providers compared to 78% (36/46) of carriers believe that Hemophilia A carriers with normal FVIII activity have an increased bleeding tendency (pHemophilia A carriers report a high frequency of bleeding symptoms. Regarding carrier testing, 72% (50/69) of medical providers recommend testing after 14 years of age, conversely 65% (29/45) of Hemophilia A carriers prefer testing to be done prior to this age (pHemophilia A carriers self-report a higher frequency of bleeding than previously acknowledged, and have a preference for earlier testing to confirm carrier status. PMID:24309601

  7. Evaluation of a clinical governance training programme for non-executive directors of NHS organisations

    National Research Council Canada - National Science Library

    Greco M; Powell R; Jolliffe J; Sweeney K; Wyatt K

    2004-01-01

    Context Non-executive directors in the South West Region. Objectives To evaluate the effectiveness of a oneday training programme for non-executive directors in critically appraising board clinical governance reports...

  8. Demographic and clinical data in acquired hemophilia A: results from the European Acquired Haemophilia Registry (EACH2)

    National Research Council Canada - National Science Library

    ...; Knoebl, P; Marco, P; Baudo, F; Collins, P; Huth-Kuhne, A; Nemes, L; Pellegrini, F; Tengborn, L; Levesque, H; Aspoek, G; Heistinger, M; Knobl, P; Makipernaa, A; Ane, H; Aouba, A; Bellucci, Sylvia; Beurrier, P; Borg, J.Y; Darnige, L; Devignes, J; D'Oiron, R; Gautier, P; Gay, V; Girault, S; Gruel, Y; Guerin, V; Hezard, N; Khellaf, M; Koenig, M; Lifermann, F; Marlu, R; Ninet, Jacques; Peynet, J; Quemeneur, T; Rothschild, C; Schleinitz, N; Sigaud, M; Trouillier, S; Voisin, S; Giebl, A; Holstein, K; Loreth, R.M; Steigerwald, U; Tiede, A; Theodossiades, G; Radvanyi, G; Schlammadinger, A; Barillari, G; Pasca, S; Caimi, T; Contino, L; Di Minno, G; Cerbone, A.M; Di Minno, Matteo Nicola Dario; D'inca, M; Falanga, A; Maggioni, A; Lerede, T; Franchini, M; Gaidano, G; De Paoli, L; Gamba, G; Ghirardi, R; Girotto, M; Tasca, D; Grandone, E; Tiscia, G; Imberti, D; Iorio, A; Landolfi, R; Di Gennaro, L; Novarese, L; Mariani, G; Lapecorella, M; Marietta, M; Peazzi, P; Mazzucconi, M.G; Santoro, C; Morfini, M; Linari, S; Moratelli, S; Paolini, R; Piseddu, G; Poggio, R; Pogliani, E; Carpenedo, M; Remiddi, C; Santagostino, E; Mancuso, Maria Elisa; Santoro, R; Papaleo, G; Schinco, P; Borchiellini, A; Valeri, Federica; Scortechini, A.R; Siragusa, Sergio; Sottilotta, G; Squizzato, A; Sartori, R; Tagariello, G

    2012-01-01

    Background: Acquired hemophilia A (AHA) is a rare autoimmune disease caused by autoantibodies against coagulation factor VIII and characterized by spontaneous hemorrhage in patients with no previous family or personal history of bleeding...

  9. The management of hemophilia in elderly patients

    Directory of Open Access Journals (Sweden)

    Massimo Franchini

    2007-10-01

    Full Text Available Massimo Franchini1, Annarita Tagliaferri2, Pier Mannuccio Mannucci31Transfusion and Hemophilia Center, City Hospital of Verona, Italy; 2Regional Reference Center for Inherited Bleeding Disorders, University Hospital of Parma, Italy; 3Angelo Bianchi Bonomi Hemophilia and Thrombosis Center and Department of Medicine and Medical Specialties, IRCCS Maggiore Hospital, Mangiagalli and Regina Elena Foundation, University of Milan, ItalyAbstract: After the increasing rate of deaths observed during the 1980s due to human immunodeficiency virus (HIV infection, the health-related quality of life and life expectancy of persons with hemophilia have improved, mainly due to the progresses of replacement therapy and antiviral drugs and to the improvement of the global comprehensive care provided by specialized centers. As a consequence, an increasing number of hemophiliacs have reached an older age and nowadays physicians in hemophilia centers find that they must handle age-related clinical problems never previously observed in this population. The management of elderly persons with congenital hemophilia is discussed in the first part of this review. The second part describes the general aspects of acquired hemophilia due to anti-factor VIII autoantibodies, focusing on the clinical management of elderly patients, one of the groups most frequently affected by this acquired bleeding disorder.Keywords: hemophilia, factor VIII, elderly, aging, inhibitors, bleeding

  10. Sporting Activities and Quality of Life in Children With Hemophilia: An Observational Study.

    Science.gov (United States)

    Cuesta-Barriuso, Ruben; Torres-Ortuño, Ana; Pérez-Alenda, Sofía; José Carrasco, Juan; Querol, Felipe; Nieto-Munuera, Joaquín

    2016-01-01

    Sports activities are part of multidisciplinary treatments in people with hemophilia. The objective of this study was to assess the incidence of sports activities in the quality of life as perceived by children with hemophilia. A total of 53 children with hemophilia aged 7 to 13 years and 51 children without hemophilia were evaluated. The perception of quality of life, clinical variables, and the frequency of sports activities were registered. The joint condition of patients with hemophilia was measured with the Spanish version of the Haemophilia Joint Health Score. There were no significant differences in the perception of quality of life between children with hemophilia and children without hemophilia. Sports activities in people with hemophilia promoted a greater health satisfaction. Sports activity in children with hemophilia is associated with an improved quality of life and joint health. It is also associated with improved psychosocial wellness.

  11. Gene therapy in an era of emerging treatment options for hemophilia B

    Science.gov (United States)

    Monahan, P. E.

    2016-01-01

    Summary Factor IX deficiency (hemophilia B) is less common than factor VIII deficiency (hemophilia A) and innovations in therapy for hemophilia B have generally lagged behind those for hemophilia A. Recently the first sustained correction of the hemophilia bleeding phenotype by clotting factor gene therapy has been described using recombinant adeno-associated virus (AAV) to deliver factor IX. Despite this success, many individuals with hemophilia B, including children, men with active hepatitis, and individuals who have pre-existing natural immunity to AAV are not eligible for the current iteration of hemophilia B gene therapy. In addition, recent advances in recombinant factor IX protein engineering have led some hemophilia treaters to reconsider the urgency of genetic cure. Current clinical and preclinical approaches to advancing AAV-based and alternative approaches to factor IX gene therapy are considered in the context of current demographics and treatment of the hemophilia B population. PMID:26149016

  12. Neutralizing antibodies against adeno-associated virus examined prospectively in pediatric patients with hemophilia

    National Research Council Canada - National Science Library

    Li, C; Narkbunnam, N; Samulski, R J; Asokan, A; Hu, G; Jacobson, L J; Manco-Johnson, M J; Monahan, P E

    .... We investigated the development of NAbs in early childhood by examining sera gathered prospectively from 62 children with hemophilia A, participating in a multi-institutional hemophilia clinical trial...

  13. The management of hemophilia in elderly patients

    Science.gov (United States)

    Franchini, Massimo; Tagliaferri, Annarita; Mannucci, Pier Mannuccio

    2007-01-01

    After the increasing rate of deaths observed during the 1980s due to human immunodeficiency virus (HIV) infection, the health-related quality of life and life expectancy of persons with hemophilia have improved, mainly due to the progresses of replacement therapy and antiviral drugs and to the improvement of the global comprehensive care provided by specialized centers. As a consequence, an increasing number of hemophiliacs have reached an older age and nowadays physicians in hemophilia centers find that they must handle age-related clinical problems never previously observed in this population. The management of elderly persons with congenital hemophilia is discussed in the first part of this review. The second part describes the general aspects of acquired hemophilia due to anti-factor VIII autoantibodies, focusing on the clinical management of elderly patients, one of the groups most frequently affected by this acquired bleeding disorder. PMID:18044186

  14. Sense-making by clinical and non-clinical executive directors within new governance arrangements.

    Science.gov (United States)

    Storey, John; Holti, Richard

    2009-01-01

    The purpose of this paper is to explore the various ways in which clinical executive directors and non-clinical executive directors are interpreting and responding to the extensive reforms and restructuring in the UK health service. The paper draws upon detailed research in two very large teaching hospital organizations in order to understand how actors crucial to the delivery of this vision are responding. Schedule-structured interviews with executive directors were conducted, recorded, transcribed and coded. The clinical and non-clinical directors of these organizations engaged in a process of active sense-making are found, which is leading to significant changes to the service and also changes to identity. The clinical directors are revealing a willingness to assume accountability for devolved profit centres in their service lines. The non-clinical directors are supportive of this idea in broad terms but are cautious about releasing "too much" central control. The paper is based on just two case studies and the analyses are made through the perspectives of the executive teams in each case. Changes to healthcare environments of this kind are occurring in many countries, but such is the extent and intensity of these changes in the UK that the government's aspiration is high--it sees this set of reforms leading to a peerless world class health service. The way in which the actors make sense of and navigate their way through the cross cutting principles and the layered reforms is a critical issue. There have been few systematic studies of the practical reality involved in the enactment of profit centre and service line management initiatives in acute hospital settings and the ways these are understood and negotiated at executive team level.

  15. Animal Models of Hemophilia and Related Bleeding Disorders

    Science.gov (United States)

    Lozier, Jay N.; Nichols, Timothy C.

    2013-01-01

    Animal models of hemophilia and related diseases are important for development of novel treatments and to understand the pathophysiology of bleeding disorders in humans. Testing in animals with the equivalent human disorder provides informed estimates of doses and measures of efficacy, which aids in design of human trials. Many models of hemophilia A, hemophilia B, and von Willebrand disease have been developed from animals with spontaneous mutations (hemophilia A dogs, rats, sheep; hemophilia B dogs; and von Willebrand disease pigs and dogs), or by targeted gene disruption in mice to create hemophilia A, B, or VWD models. Animal models have been used to generate new insights into the pathophysiology of each bleeding disorder and also to perform pre-clinical assessments of standard protein replacement therapies as well as novel gene transfer technology. Both the differences between species and differences in underlying causative mutations must be considered in choosing the best animal for a specific scientific study PMID:23956467

  16. Clinical utility and patient perspectives on the use of extended half-life rFIXFc in the management of hemophilia B

    Directory of Open Access Journals (Sweden)

    Miguelino MG

    2014-08-01

    Full Text Available Maricel G Miguelino, Jerry S Powell Division of Hematology and Oncology, University of California Davis Medical Center, Sacramento, CA, USA Abstract: Hemophilia B is an X-linked genetic disease caused by mutation of the gene for coagulation protein factor IX (FIX, with an incidence of approximately once every 30,000 male births in all populations and ethnic groups. When severe, the disease leads to spontaneous life threatening bleeding episodes. When untreated, most patients die from bleeding complications before 25 years of age. Current therapy requires frequent intravenous infusions of therapeutic recombinant or plasma-derived protein concentrates containing FIX. Most patients administer the infusions at home every few days, and must limit their physical activities to avoid abnormal bleeding when the FIX activity levels are below normal. After completing the pivotal Phase III clinical trial, a new therapeutic FIX preparation that has been engineered for an extended half-life in circulation, received regulatory approval in March 2014 in Canada and the US. This new FIX represents a major therapeutic advance for patients with hemophilia B. The half-life is prolonged due to fusion of the native FIX molecule with the normal constant region of immunoglobulin G. This fusion molecule then follows the normal immunoglobulin recirculation pathways through endothelial cells, resulting in prolonged times in circulation. In the clinical trials, over 150 patients successfully used eftrenonacog alfa regularly for more than 1 year to prevent spontaneous bleeding, to successfully treat any bleeding episodes, and to provide effective coagulation for major surgery. All infusions were well tolerated and effective, with no inhibitors detected and no safety concerns. This promising therapy should allow patients to use fewer infusions to maintain appropriate FIX activity levels in all clinical settings. Keywords: factor IX, hemophilia B, prophylaxis, genetic

  17. Demographic and clinical data in acquired hemophilia A : results from the European Acquired Haemophilia Registry (EACH2)

    NARCIS (Netherlands)

    Knoebl, P.; Marco, P.; Baudo, F.; Collins, P.; Huth-Kuhne, A.; Nemes, L.; Pellegrini, F.; Tengborn, L.; Levesque, H.; Aspoek, G.; Heistinger, M.; Knobl, P.; Makipernaa, A; Andre, H.; Aouba, A.; Bellucci, Sylvia; Beurrier, P.; Borg, J.Y.; Darnige, L.; Devignes, J.; D'Oiron, R.; Gautier, P.; Gay, V.; Girault, S.; Gruel, Y.; Guerin, V.; Hezard, N.; Khellaf, M.; Koenig, M.; Levesque, H.; Lifermann, F.; Marlu, R.; Ninet, Jacques; Peynet, J.; Quemeneur, T.; Rothschild, C.; Schleinitz, N.; Sigaud, M.; Trouillier, S.; Voisin, S.; Giebl, A.; Holstein, K; Huth-Kuhne, A.; Loreth, R.M.; Steigerwald, U.; Tiede, A.; Theodossiades, G.; Nemes, L.; Radvanyi, G.; Schlammadinger, A.; Barillari, G.; Pasca, S.; Baudo, F.; Caimi, T.; Contino, L.; Di Minno, G.; Cerbone, A.M.; Di Minno, Matteo Nicola Dario; D'inca, M.; Falanga, A.; Maggioni, A.; Lerede, T.; Franchini, M.; Gaidano, G.; De Paoli, L.; Gamba, G.; Ghirardi, R.; Girotto, M; Tasca, D.; Grandone, E.; Tiscia, G.; Imberti, D.; Iorio, A.; Landolfi, R.; Di Gennaro, L.; Novarese, L.; Mariani, G.; Lapecorella, M.; Marietta, M.; Pedrazzi, P.; Mazzucconi, M.G.; Santoro, C.; Morfini, M.; Linari, S.; Moratelli, S.; Paolini, R.; Piseddu, G.; Poggio, R.; Pogliani, E; Carpenedo, M.; Remiddi, C; Santagostino, E; Mancuso, Maria Elisa; Santoro, R.; Papaleo, G.; Schinco, P.; Borchiellini, A.; Valeri, Federica; Scortechini, A.R.; Siragusa, Sergio; Sottilotta, G.; Squizzato, A.; Sartori, R.; Tagariello, G.; Tagliaferri, A.R.; Di Perna, C.; Rivolta, G.F.; Testa, S.; Paoletti, O.; Toschi, V.; Zanon, E; Brandolini, B.; Hamulyak, K.; Kamphuisen, P.; Laros-van Gorkom, B.; Leebeek, F.W.; Marten, N.; Novakova, I.; Schutgens, R.; van der Linden, P.W.; van Esser, J.; van der Meer, J.; Ypma, P.; Campos, M.; Aguilar, C.; Altisent, C.; Bermejo, N.; Del Campo, R.; Ferreiro Arguelles, M.; Gonzalez Boullosa, R.; Gutierrez Pimentel, M.J.; Jimenez-Yuste, V.; Jose-Felix, L.; Pascual, M; Mingot, M.E.; Garrido, R.P.; Perez Gonzale, Nz; Prieto Garcia, M.; Rodriguez-Huerta, A.M.; Sedano, C; Tolosa Munoz, A.; Baghaei, F; Tengborn, L.; Boehlen, F.; Korte, W.; Chowdary, P.; Collins, P.; Evans, G.; Pavord, S.; Rangarajan, S.; Wilde, J.

    Background: Acquired hemophilia A (AHA) is a rare autoimmune disease caused by autoantibodies against coagulation factor VIII and characterized by spontaneous hemorrhage in patients with no previous family or personal history of bleeding. Although data on several AHA cohorts have been collected,

  18. Risk stratification for inhibitor development at first treatment for severe hemophilia A : a tool for clinical practice

    NARCIS (Netherlands)

    Ter Avest, P. C.; Mancuso, M. E.; Santagostino, E.; Yuste, V. J.; van den Berg, H. M.; van der Bom, J. G.

    2008-01-01

    Background: Replacement therapy in severe hemophilia A patients is complicated by formation of inhibitory antibodies against factor VIII (inhibitors) in around 25% of children. Management of bleeds and eradicating inhibitors is complicated, costly and not always successful. Objective: To develop a

  19. Demographic and clinical data in acquired hemophilia A: results from the European Acquired Haemophilia Registry (EACH2)

    NARCIS (Netherlands)

    Knoebl, P.; Marco, P.; Baudo, F.; Collins, P.; Huth-Kühne, A.; Nemes, L.; Pellegrini, F.; Tengborn, L.; Lévesque, H.; Aspoeck, Gerold; Heistinger, Max; Knöbl, Paul; Makipernaa, Anne; André, Hélène; Aouba, Achille; Bellucci, Sylvia; Beurrier, Philippe; Borg, Jeanne Yvonne; Darnige, Luc; Devignes, Jean; d'Oiron, Roseline; Gautier, Philippe; Gay, Valérie; Girault, Stéphane; Gruel, Yves; Guerin, Viviane; Hézard, Nathalie; Khellaf, Mehdi; Koenig, Martial; Lévesque, Hervé; Lifermann, François; Marlu, Raphael; Peynet, Jocelyne; Quéméneur, Thomas; Rothschild, Chantal; Schleinitz, Nicolas; Sigaud, Marianne; Trouillier, Sébastien; Voisin, Sophie; Giebl, Andreas; Holstein, Katharina; Huth-Kühne, Angela; Loreth, Ralph M.; Steigerwald, Udo; Tiede, Andreas; Theodossiades, George; Nemes, László; Radvanyi, Gaspar; Schlammadinger, Agota; Barillari, Giovanni; Pasca, Samantha; Baudo, Francesco; Caimi, Teresa; Contino, Laura; Di Minno, Giovanni; Cerbone, Anna Maria; Di Minno, Dario; D'incà, Marco; Falanga, Anna; Maggioni, Anna; Lerede, Teresa; Franchini, Massimo; Gaidano, Gianluca; de Paoli, Lorenzo; Gamba, Gabriella; Ghirardi, Raffaele; Girotto, Mauro; Tasca, Delios; Grandone, Elvira; Tiscia, Giovanni; Imberti, Davide; Iorio, Alfonso; Landolfi, Raffaele; Di Gennaro, Leonardo; Novarese, Linda; Mariani, Guglielmo; Lapecorella, Mario; Marietta, Marco; Pedrazzi, Paola; Mazzucconi, Maria Gabriella; Santoro, Cristina; Morfini, Massimo; Linari, Silvia; Moratelli, Stefano; Paolini, Rossella; Piseddu, Gavino; Poggio, Renzo; Pogliani, Enrico; Carpenedo, Monica; Remiddi, Chiara; Santagostino, Elena; Santoro, Rita; Papaleo, Giuseppina; Schinco, Piercarla; Borchiellini, Alessandra; Scortechini, Anna Rita; Siragusa, Sergio; Sottilotta, Gianluca; Squizzato, Alessandro; Sartori, Roberto; Tagariello, Giuseppe; Tagliaferri, Anna Rita; Di Perna, Caterina; Rivolta, Gianna Franca; Testa, Sophie; Paoletti, Oriana; Toschi, Vincenzo; Zanon, Ezio; Brandolini, Barbara; Hamulyák, Karly; Kamphuisen, Pieter; Laros-van Gorkom, Britta; Leebeek, Frank W. G.; Marten, Nijziel; Novakova, Irena; Schutgens, Roger; van der Linden, P. W. G.; van Esser, Joost; van der Meer, J.; Ypma, Paula; Campos, Manuel; Aguilar, Carlos; Altisent, Carmen; Bermejo, Nuria; del Campo, Raquel; Ferreiro Argüelles, María; González Boullosa, Rosario; Gutiérrez Pimentel, María José; Jiménez-Yuste, Victor; Jose-Felix, Lucia; Pascual, Marco; Mingot, Maria Eva; Perez Garrido, Rosario; Perez Gonzale, Noelia z; Prieto Garcia, Manuel; Rodriguez-Huerta, Ana María; Sedano, Carmen; Tolosa Munoz, Alexandra; Baghaei, Fariba; Tengborn, Lilian; Boehlen, Françoise; Korte, Wolfgang; Chowdary, Pratima; Collins, Peter; Evans, Gillian; Pavord, Suzanne; Rangarajan, Savita; Wilde, Jonathan

    2012-01-01

    Background: Acquired hemophilia A (AHA) is a rare autoimmune disease caused by autoantibodies against coagulation factor VIII and characterized by spontaneous hemorrhage in patients with no previous family or personal history of bleeding. Although data on several AHA cohorts have been collected,

  20. Recent progress in gene therapy for hemophilia.

    Science.gov (United States)

    Chuah, Marinee K; Nair, Nisha; VandenDriessche, Thierry

    2012-06-01

    Hemophilia A and B are X-linked monogenic disorders caused by deficiencies in coagulation factor VIII (FVIII) and factor IX (FIX), respectively. Current treatment for hemophilia involves intravenous infusion of clotting factor concentrates. However, this does not constitute a cure, and the development of gene-based therapies for hemophilia to achieve prolonged high level expression of clotting factors to correct the bleeding diathesis are warranted. Different types of viral and nonviral gene delivery systems and a wide range of different target cells, including hepatocytes, skeletal muscle cells, hematopoietic stem cells (HSCs), and endothelial cells, have been explored for hemophilia gene therapy. Adeno-associated virus (AAV)-based and lentiviral vectors are among the most promising vectors for hemophilia gene therapy. Stable correction of the bleeding phenotypes in hemophilia A and B was achieved in murine and canine models, and these promising preclinical studies prompted clinical trials in patients suffering from severe hemophilia. These studies recently resulted in the first demonstration that long-term expression of therapeutic FIX levels could be achieved in patients undergoing gene therapy. Despite this progress, there are still a number of hurdles that need to be overcome. In particular, the FIX levels obtained were insufficient to prevent bleeding induced by trauma or injury. Moreover, the gene-modified cells in these patients can become potential targets for immune destruction by effector T cells, specific for the AAV vector antigens. Consequently, more efficacious approaches are needed to achieve full hemostatic correction and to ultimately establish a cure for hemophilia A and B.

  1. Measuring hemophilia caregiver burden: validation of the Hemophilia Caregiver Impact measure.

    Science.gov (United States)

    Schwartz, Carolyn E; Powell, Victoria E; Eldar-Lissai, Adi

    2017-09-01

    The purpose of this article is to describe the psychometric development of the Hemophilia Caregiver Impact measure. Qualitative interviews (n = 22) and a cross-sectional web-based study (n = 458) were implemented with caregivers of people with hemophilia. Classical test theory and item response theory analyses were implemented to evaluate the psychometric characteristics of the measure. The study sample had a mean age of 39 and a median level of college education. It was predominantly female (88%), and had an average of two children. 85% of this study sample had at least one child with hemophilia. The final 36-item Hemophilia Caregiver Impact measure is composed of seven subscales assessing relevant negative aspects of caregiver impact (Burden Summary) as well as one subscale reflecting a positive aspect of caregiver impact (Positive Emotions). These two summary scores are orthogonal and can be used together in analyses examining negative and positive aspects of caregiver impact. The items included within each subscale reflect a unidimensional construct, demonstrate good item information and trace lines, and lack of local dependence. The resulting subscales demonstrate high reliability, and good construct validity. They show moderate incremental and discriminant validity. The Hemophilia Caregiver Impact measure is a useful new tool for clinical research on hemophilia. In addition to having eight relevant subscales, the measure can also be summarized with two scores. This versatility can be useful in analyzing studies with very small samples, which is to be expected when dealing with a rare condition like hemophilia.

  2. Advances in Gene Therapy for Hemophilia.

    Science.gov (United States)

    Nathwani, Amit C; Davidoff, Andrew M; Tuddenham, Edward G D

    2017-11-01

    Gene therapy provides hope for a cure for patients with hemophilia by establishing continuous endogenous expression of factor VIII or factor IX following transfer of a functional gene copy to replace the hemophilic patient's own defective gene. Hemophilia may be considered a "low-hanging fruit" for gene therapy because a small increment in blood factor levels (≥2% of normal) significantly improves the bleeding tendency from severe to moderate, eliminating most spontaneous bleeds. After decades of research, the first trial to provide clear evidence of efficiency after gene transfer in patients with hemophilia B using adeno-associated virus vectors was reported by the authors' group in 2011. This has been followed by unprecedented activity in this area, with the commencement of seven new early-phase trials involving >55 patients with hemophilia A or hemophilia B. These studies have, in large part, generated promising clinical data that lay a strong foundation for gene therapy to move forward rapidly to market authorization. This review discusses the data from the authors' studies and emerging results from other gene therapy trials in both hemophilia A and B.

  3. Gene therapy for hemophilia

    Science.gov (United States)

    Rogers, Geoffrey L.; Herzog, Roland W.

    2015-01-01

    Hemophilia is an X-linked inherited bleeding disorder consisting of two classifications, hemophilia A and hemophilia B, depending on the underlying mutation. Although the disease is currently treatable with intravenous delivery of replacement recombinant clotting factor, this approach represents a significant cost both monetarily and in terms of quality of life. Gene therapy is an attractive alternative approach to the treatment of hemophilia that would ideally provide life-long correction of clotting activity with a single injection. In this review, we will discuss the multitude of approaches that have been explored for the treatment of both hemophilia A and B, including both in vivo and ex vivo approaches with viral and nonviral delivery vectors. PMID:25553466

  4. COMBINATION OF SEVERE GASTRODUODENAL ULCER AND HEMOPHILIA B IN A CHILD. CLINICAL CASE

    Directory of Open Access Journals (Sweden)

    E. Y. Dyakonova

    2015-01-01

    Full Text Available Gastroduodenal ulcer is less common and milder in children than in adults. Gastroduodenal ulcer complications, such as hemorrhage, penetration etc. are even less common. Recurrent ulcerous defect hemorrhage is a reason to expand diagnostic search and involve various specialists, primarily hematologists, into the diagnosis establishing process. The article presents a clinical case of a child with gastroduodenal ulcer complicated with recurrent hemorrhage not terminated with the standard therapy; thus, additional diagnostic testing was performed. This helped to detect a hematological disease and determine an optimal therapy amount.

  5. [Health care ethics committees in German university clinics. A survey of all medical directors and directors of nursing].

    Science.gov (United States)

    Vollmann, J; Burchardi, N; Weidtmann, A

    2004-05-28

    Health Care Ethics Committees (HEC) are new ways of implementing clinical ethics in hospitals and nursing homes. In the US all health care institutions must provide some structure to handle ethical conflicts in everyday patients' care. However, in Germany only a minority of hospitals, often members of the Protestant or Catholic Hospital Associations, have founded HEC. No studies exist in regard to the situation at German university hospitals. In November 2002 we posted a questionnaire with 13 items to all medical directors (M) and directors of nursing (N) of the 36 German university hospitals. The response rate was 82 %. Limitation of treatment, informed consent and the conflict between beneficience and autonomy are the most relevant ethical issues in everyday practice. N estimated the need for additional support of their staff in ethical issues higher than M. Improvement of interdisciplinary teamwork, further education in ethics and ethical guidelines have been identified in order to improve ethical professional performance. However, N mentioned the lack of time and the low priority of ethics more often than M as problems in implementing theses measures. Five German university hospitals are planning to establish a HEC and two hospitals want to employ a clinical ethicist. Our data show a high need for information about HEC in German university hospitals. The tasks, working methods and chances for further development of HEC are neither known nor used in the majority of German university hospitals.

  6. New approaches to gene and cell therapy for hemophilia.

    Science.gov (United States)

    Ohmori, T; Mizukami, H; Ozawa, K; Sakata, Y; Nishimura, S

    2015-06-01

    Hemophilia is considered suitable for gene therapy because it is caused by a single gene abnormality, and therapeutic coagulation factor levels may vary across a broad range. Recent success of hemophilia B gene therapy with an adeno-associated virus (AAV) vector in a clinical trial showed the real prospect that, through gene therapy, a cure for hemophilia may become a reality. However, AAV-mediated gene therapy is not applicable to patients with hemophilia A at present, and neutralizing antibodies against AAV reduce the efficacy of AAV-mediated strategies. Because patients that benefit from AAV treatment (hemophilia B without neutralizing antibodies) are estimated to represent only 15% of total patients with hemophilia, the development of basic technologies for hemophilia A and those that result in higher therapeutic effects are critical. In this review, we present an outline of gene therapy methods for hemophilia, including the transition of technical developments thus far and our novel techniques. © 2015 International Society on Thrombosis and Haemostasis.

  7. Frequently Asked Questions: Hemophilia

    Science.gov (United States)

    ... safe for most people with hemophilia, while American football, rugby, and boxing are usually not recommended. What ... issues in inhibitors Resources Prophylaxis Types of Prophylaxis Administration & Dosing Schedules Monitoring outcomes When to Start & Stop ...

  8. Learning about Hemophilia

    Science.gov (United States)

    Skip to main content Learning About Hemophilia Enter Search Term(s): Español Research Funding An Overview Bioinformatics Current Grants Education and Training Funding Extramural Research News Features Funding Divisions Funding ...

  9. Demographic and clinical data in acquired hemophilia A: results from the European Acquired Haemophilia Registry (EACH2).

    Science.gov (United States)

    Knoebl, P; Marco, P; Baudo, F; Collins, P; Huth-Kühne, A; Nemes, L; Pellegrini, F; Tengborn, L; Lévesque, H

    2012-04-01

    Acquired hemophilia A (AHA) is a rare autoimmune disease caused by autoantibodies against coagulation factor VIII and characterized by spontaneous hemorrhage in patients with no previous family or personal history of bleeding. Although data on several AHA cohorts have been collected, limited information is available on the optimal management of AHA. The European Acquired Hemophilia Registry (EACH2) was established to generate a prospective, large-scale, pan-European database on demographics, diagnosis, underlying disorders, bleeding characteristics, treatment and outcome of AHA patients. Five hundred and one (266 male, 235 female) patients from 117 centers and 13 European countries were included in the registry between 2003 and 2008. In 467 cases, hemostasis investigations and AHA diagnosis were triggered by a bleeding event. At diagnosis, patients were a median of 73.9 years. AHA was idiopathic in 51.9%; malignancy or autoimmune diseases were associated with 11.8% and 11.6% of cases. Fifty-seven per cent of the non-pregnancy-related cases were male. Four hundred and seventy-four bleeding episodes were reported at presentation, and hemostatic therapy initiated in 70.5% of patients. Delayed diagnosis significantly impacted treatment initiation in 33.5%. Four hundred and seventy-seven patients underwent immunosuppression, and 72.6% achieved complete remission. Representing the largest collection of consecutive AHA cases to date, EACH2 facilitates the analysis of a variety of open questions in AHA. © 2012 International Society on Thrombosis and Haemostasis.

  10. Gene therapy for hemophilia: past, present and future.

    Science.gov (United States)

    George, Lindsey A; Fogarty, Patrick F

    2016-01-01

    After numerous preclinical studies demonstrated consistent success in large and small animal models, gene therapy has finally seen initial signs of clinically meaningful success. In a landmark study, Nathwani and colleagues reported sustained factor (F)IX expression in individuals with severe hemophilia B following adeno-associated virus (AAV)-mediated in vivo FIX gene transfer. As the next possible treatment-changing paradigm in hemophilia care, gene therapy may provide patients with sufficient hemostatic improvement to achieve the World Federation of Hemophilia's aspirational goal of "integration of opportunities in all aspects of life… equivalent to someone without a bleeding disorder." Although promising momentum supports the potential of gene therapy to replace protein-based therapeutics for hemophilia, several obstacles remain. The largest challenges appear to be overcoming the cellular immune responses to the AAV capsid; preexisting AAV neutralizing antibodies, which immediately exclude approximately 50% of the target population; and the ability to scale-up vector manufacturing for widespread applicability. Additional obstacles specific to hemophilia A (HA) include designing a vector cassette to accommodate a larger cDNA; avoiding development of inhibitory antibodies; and, perhaps the greatest difficulty to overcome, ensuring adequate expression efficiency. This review discusses the relevance of gene therapy to the hemophilia disease state, previous research progress, the current landscape of clinical trials, and considerations for promoting the future availability of gene therapy for hemophilia. Copyright © 2016 Elsevier Inc. All rights reserved.

  11. Understanding Hemophilia. Implications for the Physical Educator.

    Science.gov (United States)

    Coelho, Jeffrey D.

    1998-01-01

    Describes hemophilia and ways to provide appropriate physical education experiences to children with hemophilia. The article focuses on what hemophilia is, how to treat hemophilia, benefits of physical activity, how to teach children with hemophilia, choosing and modifying sports and activities, and safety and emergency situations. (SM)

  12. Experience of Preimplantation Genetic Diagnosis for Hemophilia at the University Hospital Virgen Del Rocío in Spain: Technical and Clinical Overview

    Science.gov (United States)

    Fernández, Raquel M.; Peciña, Ana; Sánchez, Beatriz; Lozano-Arana, Maria Dolores; García-Lozano, Juan Carlos; Pérez-Garrido, Rosario; Núñez, Ramiro; Antiñolo, Guillermo

    2015-01-01

    Hemophilia A and B are the most common hereditary hemorrhagic disorders, with an X-linked mode of inheritance. Reproductive options for the families affected with hemophilia, aiming at the prevention of the birth of children with severe coagulation disorders, include preimplantation genetic diagnosis (PGD). Here we present the results of our PGD Program applied to hemophilia, at the Department of Genetics, Reproduction and Fetal Medicine of the University Hospital Virgen del Rocío in Seville. A total of 34 couples have been included in our program since 2005 (30 for hemophilia A and 4 for hemophilia B). Overall, 60 cycles were performed, providing a total of 508 embryos. The overall percentage of transfers per cycle was 81.7% and the live birth rate per cycle ranged from 10.3 to 24.1% depending on the methodological approach applied. Although PGD for hemophilia can be focused on gender selection of female embryos, our results demonstrate that methodological approaches that allow the diagnosis of the hemophilia status of every embryo have notorious advantages. Our PGD Program resulted in the birth of 12 healthy babies for 10 out of the 34 couples (29.4%), constituting a relevant achievement for the Spanish Public Health System within the field of haematological disorders. PMID:26258137

  13. Experience of Preimplantation Genetic Diagnosis for Hemophilia at the University Hospital Virgen Del Rocío in Spain: Technical and Clinical Overview

    Directory of Open Access Journals (Sweden)

    Raquel M. Fernández

    2015-01-01

    Full Text Available Hemophilia A and B are the most common hereditary hemorrhagic disorders, with an X-linked mode of inheritance. Reproductive options for the families affected with hemophilia, aiming at the prevention of the birth of children with severe coagulation disorders, include preimplantation genetic diagnosis (PGD. Here we present the results of our PGD Program applied to hemophilia, at the Department of Genetics, Reproduction and Fetal Medicine of the University Hospital Virgen del Rocío in Seville. A total of 34 couples have been included in our program since 2005 (30 for hemophilia A and 4 for hemophilia B. Overall, 60 cycles were performed, providing a total of 508 embryos. The overall percentage of transfers per cycle was 81.7% and the live birth rate per cycle ranged from 10.3 to 24.1% depending on the methodological approach applied. Although PGD for hemophilia can be focused on gender selection of female embryos, our results demonstrate that methodological approaches that allow the diagnosis of the hemophilia status of every embryo have notorious advantages. Our PGD Program resulted in the birth of 12 healthy babies for 10 out of the 34 couples (29.4%, constituting a relevant achievement for the Spanish Public Health System within the field of haematological disorders.

  14. Physician assistant program directors' attitudes, practices, and plans regarding financial compensation to clinical sites.

    Science.gov (United States)

    Glavaz, Gerald A; Alexander, Jeffrey L; Curtis, Denice; Eskes, Christy

    2014-01-01

    Some physician assistant (PA) program directors believe paying clinicians and administrators for clinical sites is fair and necessary, while others regard such practices as undermining traditional altruistic motivations for precepting. The purpose of this study was to assess PA program directors' attitudes on this topic and describe current practices and future plans regarding compensation to clinical sites. A cross-sectional descriptive survey was sent to directors of PA programs with continuing and provisional accreditation status in 2012. Seventy-eight (48%) of the 163 program directors surveyed participated in the study. Although most respondents indicated that paying for clinical sites was not an acceptable practice, almost half believed it would. be acceptable if there were standards and definitions for equitable and fair payments. Despite the finding that most respondents' programs do not pay for clinical sites, nearly half anticipate their programs will be paying for clinical sites in three years, and the cost of such payments will be passed on to students in the form of increased tuition or separate fees. Many indicated a concern that paying for clinical sites may result in monopolies and bidding wars. While paying clinical sites may be effective for recruitment and retention of clinical sites, most program directors are concerned about the expanded role economics will have for their program. Agreed-upon standards and definitions for fair and equitable payment practices may alleviate some of these concerns. However, the potential effects on students and programs identified in this study necessitate additional research to fully assess what implications this may have on PA education and the profession.

  15. Porcine model of hemophilia A.

    Science.gov (United States)

    Kashiwakura, Yuji; Mimuro, Jun; Onishi, Akira; Iwamoto, Masaki; Madoiwa, Seiji; Fuchimoto, Daiichiro; Suzuki, Shunichi; Suzuki, Misae; Sembon, Shoichiro; Ishiwata, Akira; Yasumoto, Atsushi; Sakata, Asuka; Ohmori, Tsukasa; Hashimoto, Michiko; Yazaki, Satoko; Sakata, Yoichi

    2012-01-01

    Hemophilia A is a common X chromosome-linked genetic bleeding disorder caused by abnormalities in the coagulation factor VIII gene (F8). Hemophilia A patients suffer from a bleeding diathesis, such as life-threatening bleeding in the brain and harmful bleeding in joints and muscles. Because it could potentially be cured by gene therapy, subhuman animal models have been sought. Current mouse hemophilia A models generated by gene targeting of the F8 have difficulties to extrapolate human disease due to differences in the coagulation and immune systems between mice and humans. Here, we generated a porcine model of hemophilia A by nuclear transfer cloning from F8-targeted fibroblasts. The hemophilia A pigs showed a severe bleeding tendency upon birth, similar to human severe hemophiliacs, but in contrast to hemophilia A mice which rarely bleed under standard breed conditions. Infusion of human factor VIII was effective in stopping bleeding and reducing the bleeding frequency of a hemophilia A piglet but was blocked by the inhibitor against human factor VIII. These data suggest that the hemophilia A pig is a severe hemophilia A animal model for studying not only hemophilia A gene therapy but also the next generation recombinant coagulation factors, such as recombinant factor VIII variants with a slower clearance rate.

  16. Porcine model of hemophilia A.

    Directory of Open Access Journals (Sweden)

    Yuji Kashiwakura

    Full Text Available Hemophilia A is a common X chromosome-linked genetic bleeding disorder caused by abnormalities in the coagulation factor VIII gene (F8. Hemophilia A patients suffer from a bleeding diathesis, such as life-threatening bleeding in the brain and harmful bleeding in joints and muscles. Because it could potentially be cured by gene therapy, subhuman animal models have been sought. Current mouse hemophilia A models generated by gene targeting of the F8 have difficulties to extrapolate human disease due to differences in the coagulation and immune systems between mice and humans. Here, we generated a porcine model of hemophilia A by nuclear transfer cloning from F8-targeted fibroblasts. The hemophilia A pigs showed a severe bleeding tendency upon birth, similar to human severe hemophiliacs, but in contrast to hemophilia A mice which rarely bleed under standard breed conditions. Infusion of human factor VIII was effective in stopping bleeding and reducing the bleeding frequency of a hemophilia A piglet but was blocked by the inhibitor against human factor VIII. These data suggest that the hemophilia A pig is a severe hemophilia A animal model for studying not only hemophilia A gene therapy but also the next generation recombinant coagulation factors, such as recombinant factor VIII variants with a slower clearance rate.

  17. Clinical skills assessment of procedural and advanced communication skills: performance expectations of residency program directors

    Directory of Open Access Journals (Sweden)

    Erik E. Langenau

    2012-07-01

    Full Text Available Background: High stakes medical licensing programs are planning to augment and adapt current examinations to be relevant for a two-decision point model for licensure: entry into supervised practice and entry into unsupervised practice. Therefore, identifying which skills should be assessed at each decision point is critical for informing examination development, and gathering input from residency program directors is important. Methods: Using data from previously developed surveys and expert panels, a web-delivered survey was distributed to 3,443 residency program directors. For each of the 28 procedural and 18 advanced communication skills, program directors were asked which clinical skills should be assessed, by whom, when, and how. Descriptive statistics were collected, and Intraclass Correlations (ICC were conducted to determine consistency across different specialties. Results: Among 347 respondents, program directors reported that all advanced communication and some procedural tasks are important to assess. The following procedures were considered ‘important’ or ‘extremely important’ to assess: sterile technique (93.8%, advanced cardiovascular life support (ACLS (91.1%, basic life support (BLS (90.0%, interpretation of electrocardiogram (89.4% and blood gas (88.7%. Program directors reported that most clinical skills should be assessed at the end of the first year of residency (or later and not before graduation from medical school. A minority were considered important to assess prior to the start of residency training: demonstration of respectfulness (64%, sterile technique (67.2%, BLS (68.9%, ACLS (65.9% and phlebotomy (63.5%. Discussion: Results from this study support that assessing procedural skills such as cardiac resuscitation, sterile technique, and phlebotomy would be amenable to assessment at the end of medical school, but most procedural and advanced communications skills would be amenable to assessment at the end of the

  18. Clinical skills assessment of procedural and advanced communication skills: performance expectations of residency program directors

    Science.gov (United States)

    Langenau, Erik E.; Zhang, Xiuyuan; Roberts, William L.; DeChamplain, Andre F.; Boulet, John R.

    2012-01-01

    Background High stakes medical licensing programs are planning to augment and adapt current examinations to be relevant for a two-decision point model for licensure: entry into supervised practice and entry into unsupervised practice. Therefore, identifying which skills should be assessed at each decision point is critical for informing examination development, and gathering input from residency program directors is important. Methods Using data from previously developed surveys and expert panels, a web-delivered survey was distributed to 3,443 residency program directors. For each of the 28 procedural and 18 advanced communication skills, program directors were asked which clinical skills should be assessed, by whom, when, and how. Descriptive statistics were collected, and Intraclass Correlations (ICC) were conducted to determine consistency across different specialties. Results Among 347 respondents, program directors reported that all advanced communication and some procedural tasks are important to assess. The following procedures were considered ‘important’ or ‘extremely important’ to assess: sterile technique (93.8%), advanced cardiovascular life support (ACLS) (91.1%), basic life support (BLS) (90.0%), interpretation of electrocardiogram (89.4%) and blood gas (88.7%). Program directors reported that most clinical skills should be assessed at the end of the first year of residency (or later) and not before graduation from medical school. A minority were considered important to assess prior to the start of residency training: demonstration of respectfulness (64%), sterile technique (67.2%), BLS (68.9%), ACLS (65.9%) and phlebotomy (63.5%). Discussion Results from this study support that assessing procedural skills such as cardiac resuscitation, sterile technique, and phlebotomy would be amenable to assessment at the end of medical school, but most procedural and advanced communications skills would be amenable to assessment at the end of the first

  19. Mutation spectrum of 122 hemophilia A families from Taiwanese population by LD-PCR, DHPLC, multiplex PCR and evaluating the clinical application of HRM

    Directory of Open Access Journals (Sweden)

    Chang Chieh-Ting

    2008-06-01

    Full Text Available Abstract Background Hemophilia A represents the most common and severe inherited hemorrhagic disorder. It is caused by mutations in the F8 gene, which leads to a deficiency or dysfunctional factor VIII protein, an essential cofactor in the factor X activation complex. Methods We used long-distance polymerase chain reaction and denaturing high performance liquid chromatography for mutation scanning of the F8 gene. We designed the competitive multiplex PCR to identify the carrier with exonal deletions. In order to facilitate throughput and minimize the cost of mutation scanning, we also evaluated a new mutation scanning technique, high resolution melting analysis (HRM, as an alternative screening method. Results We presented the results of detailed screening of 122 Taiwanese families with hemophilia A and reported twenty-nine novel mutations. There was one family identified with whole exons deletion, and the carriers were successfully recognized by multiplex PCR. By HRM, the different melting curve patterns were easily identified in 25 out of 28 cases (89% and 15 out of 15 (100% carriers. The sensitivity was 93 % (40/43. The overall mutation detection rate of hemophilia A was 100% in this study. Conclusion We proposed a diagnostic strategy for hemophilia A genetic diagnosis. We consider HRM as a powerful screening tool that would provide us with a more cost-effective protocol for hemophilia A mutation identification.

  20. Looking good or doing better? Patterns of decoupling in the implementation of clinical directorates.

    Science.gov (United States)

    Mascia, Daniele; Morandi, Federica; Cicchetti, Americo

    2014-01-01

    The interest toward hospital restructuring has risen significantly in recent years. In spite of its potential benefits, often organizational restructuring in health care produces unexpected consequences. Extant research suggests that institutional theory provides a powerful theoretical lens through which hospital restructuring can be described and explained. According to this perspective, the effectiveness of change is strongly related to the extent to which innovative arrangements, tools, or practices are adopted and implemented within hospitals. Whenever these new arrangements require a substantial modification of internal processes and practices, resistance to implementation emerges and organizational change is likely to become neutralized. This study analyzes how hospital organizations engage in decoupling by adopting but not implementing a new organizational model named clinical directorate. We collected primary data on the diffusion of the clinical directorate model, which was mandated by law in the Italian National Health Service to improve hospital services. We surveyed the adoption and implementation of the clinical directorate model by monitoring the presence of clinical governance tools (measures for the quality improvement of hospital services) within single directorates. In particular, we compared hospitals that adopted the model before (early adopters) or after (later adopters) the mandate was introduced. Hospitals were engaged in decoupling by adopting the new arrangement but not implementing internal practices and tools for quality improvement. The introduction of the law significantly affected the decoupling, with late-adopter hospitals being less likely to implement the adopted model. The present research shows that changes in quality improvement processes may vary in relation to policy makers' interventions aimed at boosting the adoption of new hospital arrangements. Hospital administrators need to be aware and identify the institutional changes

  1. Clinical Pharmacists as Educators in Family Medicine Residency Programs: A CERA Study of Program Directors.

    Science.gov (United States)

    Jarrett, Jennie B; Lounsbery, Jody L; D'Amico, Frank; Dickerson, Lori M; Franko, John; Nagle, John; Seehusen, Dean A; Wilson, Stephen A

    2016-03-01

    The clinical pharmacist's role within family medicine residency programs (FMRPs) is well established. However, there is limited information regarding perceptions of program directors (PDs) about clinical pharmacy educators. The study objectives were (1) to estimate the prevalence of clinical pharmacists within FMRPs and (2) to determine barriers and motivations for incorporation of clinical pharmacists as educators. The Council of Academic Family Medicine Educational Research Alliance (CERA) distributed an electronic survey to PDs. Questions addressed formalized pharmacotherapy education, clinical pharmacists in educator roles, and barriers and benefits of clinical pharmacists in FMRPs. The overall response rate was 50% (224/451). Seventy-six percent (170/224) of the responding PDs reported that clinical pharmacists provide pharmacotherapy education in their FMRPs, and 57% (97/170) consider clinical pharmacists as faculty members. In programs with clinical pharmacists, 72% (83/116) of PDs reported having a systematic approach for teaching pharmacotherapy versus 22% (21/95) in programs without. In programs without clinical pharmacists, the top barrier to incorporation was limited ability to bill for clinical services 48% (43/89) versus 29% (32/112) in programs with clinical pharmacists. In both programs with and without clinical pharmacists, the top benefit of having clinical pharmacists was providing a collaborative approach to pharmacotherapy education for residents (35% and 36%, respectively). Less than half of FMRPs incorporate clinical pharmacists as faculty members. Despite providing collaborative approaches to pharmacotherapy education, their limited ability to bill for services is a major barrier.

  2. Proteasome inhibitors enhance gene delivery by AAV virus vectors expressing large genomes in hemophilia mouse and dog models: a strategy for broad clinical application.

    Science.gov (United States)

    Monahan, Paul E; Lothrop, Clinton D; Sun, Junjiang; Hirsch, Matthew L; Kafri, Tal; Kantor, Boris; Sarkar, Rita; Tillson, D Michael; Elia, Joseph R; Samulski, R Jude

    2010-11-01

    Delivery of genes that are larger than the wild-type adeno-associated virus (AAV) 4,681 nucleotide genome is inefficient using AAV vectors. We previously demonstrated in vitro that concurrent proteasome inhibitor (PI) treatment improves transduction by AAV vectors encoding oversized transgenes. In this study, an AAV vector with a 5.6 kilobase (kb) factor VIII expression cassette was used to test the effect of an US Food and Drug Administration-approved PI (bortezomib) treatment concurrent with vector delivery in vivo. Intrahepatic vector delivery resulted in factor VIII expression that persisted for >1 year in hemophilia mice. Single-dose bortezomib given with AAV2 or AAV8 factor VIII vector enhanced expression on average ~600 and ~300%, respectively. Moreover, coadministration of AAV8.canineFVIII (1 × 10(13) vg/kg) and bortezomib in hemophilia A dogs (n = 4) resulted in normalization of the whole blood clotting time (WBCT) and 90% reduction in hemorrhages for >32 months compared to untreated hemophilia A dogs (n = 3) or dogs administered vector alone (n = 3). Demonstration of long-term phenotypic correction of hemophilia A dogs with combination adjuvant bortezomib and AAV vector expressing the oversized transgene establishes preclinical studies that support testing in humans and provides a working paradigm to facilitate a significant expansion of therapeutic targets for human gene therapy.

  3. Proteasome Inhibitors Enhance Gene Delivery by AAV Virus Vectors Expressing Large Genomes in Hemophilia Mouse and Dog Models: A Strategy for Broad Clinical Application

    Science.gov (United States)

    Monahan, Paul E; Lothrop, Clinton D; Sun, Junjiang; Hirsch, Matthew L; Kafri, Tal; Kantor, Boris; Sarkar, Rita; Tillson, D Michael; Elia, Joseph R; Samulski, R Jude

    2010-01-01

    Delivery of genes that are larger than the wild-type adeno-associated virus (AAV) 4,681 nucleotide genome is inefficient using AAV vectors. We previously demonstrated in vitro that concurrent proteasome inhibitor (PI) treatment improves transduction by AAV vectors encoding oversized transgenes. In this study, an AAV vector with a 5.6 kilobase (kb) factor VIII expression cassette was used to test the effect of an US Food and Drug Administration–approved PI (bortezomib) treatment concurrent with vector delivery in vivo. Intrahepatic vector delivery resulted in factor VIII expression that persisted for >1 year in hemophilia mice. Single-dose bortezomib given with AAV2 or AAV8 factor VIII vector enhanced expression on average ~600 and ~300%, respectively. Moreover, coadministration of AAV8.canineFVIII (1 × 1013 vg/kg) and bortezomib in hemophilia A dogs (n = 4) resulted in normalization of the whole blood clotting time (WBCT) and 90% reduction in hemorrhages for >32 months compared to untreated hemophilia A dogs (n = 3) or dogs administered vector alone (n = 3). Demonstration of long-term phenotypic correction of hemophilia A dogs with combination adjuvant bortezomib and AAV vector expressing the oversized transgene establishes preclinical studies that support testing in humans and provides a working paradigm to facilitate a significant expansion of therapeutic targets for human gene therapy. PMID:20700109

  4. Gene Therapy for Hemophilia.

    Science.gov (United States)

    Nathwani, Amit C; Davidoff, Andrew M; Tuddenham, Edward G D

    2017-10-01

    The best currently available treatments for hemophilia A and B (factor VIII or factor IX deficiency, respectively) require frequent intravenous infusion of highly expensive proteins that have short half-lives. Factor levels follow a saw-tooth pattern that is seldom in the normal range and falls so low that breakthrough bleeding occurs. Most hemophiliacs worldwide do not have access to even this level of care. In stark contrast, gene therapy holds out the hope of a cure by inducing continuous endogenous expression of factor VIII or factor IX following transfer of a functional gene to replace the hemophilic patient's own defective gene. Copyright © 2017 Elsevier Inc. All rights reserved.

  5. Emicizumab Prophylaxis in Hemophilia A with Inhibitors.

    Science.gov (United States)

    Oldenburg, Johannes; Mahlangu, Johnny N; Kim, Benjamin; Schmitt, Christophe; Callaghan, Michael U; Young, Guy; Santagostino, Elena; Kruse-Jarres, Rebecca; Negrier, Claude; Kessler, Craig; Valente, Nancy; Asikanius, Elina; Levy, Gallia G; Windyga, Jerzy; Shima, Midori

    2017-08-31

    Emicizumab (ACE910) bridges activated factor IX and factor X to restore the function of activated factor VIII, which is deficient in persons with hemophilia A. This phase 3, multicenter trial assessed once-weekly subcutaneous emicizumab prophylaxis in persons with hemophilia A with factor VIII inhibitors. We enrolled participants who were 12 years of age or older. Those who had previously received episodic treatment with bypassing agents were randomly assigned in a 2:1 ratio to emicizumab prophylaxis (group A) or no prophylaxis (group B). The primary end point was the difference in bleeding rates between group A and group B. Participants who had previously received prophylactic treatment with bypassing agents received emicizumab prophylaxis in group C. A total of 109 male participants with hemophilia A with inhibitors were enrolled. The annualized bleeding rate was 2.9 events (95% confidence interval [CI], 1.7 to 5.0) among participants who were randomly assigned to emicizumab prophylaxis (group A, 35 participants) versus 23.3 events (95% CI, 12.3 to 43.9) among those assigned to no prophylaxis (group B, 18 participants), representing a significant difference of 87% in favor of emicizumab prophylaxis (Phemophilia A with inhibitors. (Funded by F. Hoffmann-La Roche and Chugai Pharmaceutical; HAVEN 1 ClinicalTrials.gov number, NCT02622321 .).

  6. [Two cases of acquired hemophilia A in elderly patients].

    Science.gov (United States)

    Hayashi, Tomoe; Morishita, Eriko; Asakura, Hidesaku; Nakao, Shinji

    2010-01-01

    Acquired hemophilia A is a rare bleeding diathesis caused by autoantibodies against clotting factor VIII. The incidence of acquired hemophilia A increases with age. We report two cases of acquired hemophilia A in elderly patients and their clinical characteristics. Case 1: A 66-year-old man was referred to our hospital with massive subcutaneous and intramuscular hemorrhage. Prolonged APTT, low factor VIII activity and factor VIII inhibitor with high titer (42 BU/ml ) were observed, confirming the diagnosis of acquired hemophilia A. His hemorrhages disappeared soon after 50 mg/day oral prednisolone was administered. Although early steroid withdrawal lead to repeated prolongation of APTT, the addition of 20 mg/day oral prednisolone successfully decreased the inhibitor titer. The underlying disease was not identified. Case 2: An 85-year-old man with advanced gastric cancer was referred to our division because of severe bleeding. His factor VIII inhibitor titer was 64 BU/ml . Activated prothrombin complex concentrates were used to control the bleeding. Initially, he did not seem to respond to 20 mg/day oral prednisolone, but a further 12 weeks of 20 mg/day prednisolone finally achieved normalization of his hemostatic parameters. Subsequently, he successfully underwent surgery for cancer. The responses to immunosuppressive therapy were very different in the two cases, probably because of the difference in the underlying diseases. The immunosuppressive therapy of acquired hemophilia A should be strictly tailored to the patient's characteristics to minimize treatment-related adverse effects.

  7. Whats´New In Gene Therapy Of Hemophilia.

    Science.gov (United States)

    Rodriguez-Merchan, E Carlos

    2018-02-14

    Several methods have been investigated to effectively and safely transmit genes that stimulate cells to release therapeutic factor VIII (FVIII) and factor IX (FIX) into the circulation of people with hemophilia (PWH). To review the role of gene therapy (GT) in PWH. A Cochrane Library and PubMed (MEDLINE) search related to the role of GT in hemophilia was analyzed. The most promising vectors for hemophilia GT are adeno-associated virus (AAV) and lentivirus. Several gene methods are available to lessen risks related to random vector integration and insertional mutagenesis, based on designer nucleases or CRISPR/Cas9 (clustered regularly interspaced short palindromic repeats/CRISPR associated system). However, off-target issues need to be more meticulously and widely evaluated. Some clinical studies on hemophilia B based on AAV have obtained transitory or subtherapeutic levels of FIX expression. Another problem is possible transitory liver toxicity. Therefore, to reduce unintentional immune responses, transitory immunosuppression must be used, particularly when administering high-vector doses. Codon-optimized FVIII or FIX transgenes are able to promote clotting factor expression levels. The inclusion of a hyper-active gain-of-function R338L mutation in the FIX gene (FIX-R338L [FIX Padua]) makes the procedure more effective. Achieving a safe and efficient remedy for hemophilia A and B by means of GT vector engineering needs further improvement. No randomized or quasi-randomized clinical trials of GT for hemophilia have been found. Given it is in its incipient period, there is need for well-designed clinical trials to evaluate the long-term practicability, efficacy and risks of GT for PWH. Copyright© Bentham Science Publishers; For any queries, please email at epub@benthamscience.org.

  8. A bispecific antibody mimicking factor VIII in hemophilia A therapy.

    Science.gov (United States)

    Nogami, Keiji

    2016-06-01

    Serious issues in current hemostatic treatment of hemophilia A are the requirement for frequent intravenous administrations of factor (F) VIII, FVIII inhibitor development, and hemostatic treatment for patients with this inhibitor. For the purpose of overcoming these challenges, the FVIIIa-substituting bispecific antibody against FIXa/FX (ACE910, INN emicizumab) was produced. Emicizumab demonstrated marked hemostatic effects on both ongoing and spontaneous joint bleeding in the acquired hemophilia A primate model. The clinical phase 1 study designed to assess the pharmacokinetics, pharmacodynamics and safety of emicizumab has been initiated. Severe emicizumab-related adverse events were minimal. The t1/2 was approximately 30 days, and bleeding events were significantly decreased by weekly subcutaneous administration in severe hemophilia A patients, independently of the presence of the inhibitor. Currently, the phase 1/2 extension study is ongoing. We anticipate that emicizumab will show the benefits of prophylactic efficacy with subcutaneous administration at a much lower frequency.

  9. Hemophilia Treatments Have Come a Long Way

    Science.gov (United States)

    ... Consumers Home For Consumers Consumer Updates Hemophilia Treatments Have Come a Long Way Share Tweet Linkedin Pin ... Research and Review. Hemophilia A occurs when people have low levels, or missing, clotting factor VIII (8). ...

  10. Unraveling the genetics of inhibitors in hemophilia

    NARCIS (Netherlands)

    Gouw, Samantha C.; Fijnvandraat, Karin

    2013-01-01

    In this issue of Blood, Astermark et al have identified novel genetic markers of inhibitory antibody formation in hemophilia patients that may ultimately lead to prediction and even prevention of this severe complication of hemophilia treatment.(1)

  11. Previously undiagnosed hemophilia patient with intracerebral hemorrhage

    Directory of Open Access Journals (Sweden)

    Eray Atalay

    2015-09-01

    Full Text Available Intracranial bleeding in hemophilia patients is a rare but a mortal complication. Diagnosis of hemophilia in adulthood is an uncommon occurrence. In this case report an adult patient with intracranial hemorrhage is presented.

  12. Inhibitor development and mortality in non-severe hemophilia A.

    Science.gov (United States)

    Eckhardt, C L; Loomans, J I; van Velzen, A S; Peters, M; Mauser-Bunschoten, E P; Schwaab, R; Mazzucconi, M G; Tagliaferri, A; Siegmund, B; Reitter-Pfoertner, S E; van der Bom, J G; Fijnvandraat, K

    2015-07-01

    The life expectancy of non-severe hemophilia A (HA) patients equals the life expectancy of the non-hemophilic population. However, data on the effect of inhibitor development on mortality and on hemophilia-related causes of death are scarce. The development of neutralizing factor VIII antibodies in non-severe HA patients may dramatically change their clinical outcome due to severe bleeding complications. We assessed the association between the occurrence of inhibitors and mortality in patients with non-severe HA. In this retrospective cohort study, clinical data and vital status were collected for 2709 non-severe HA patients (107 with inhibitors) who were treated between 1980 and 2011 in 34 European and Australian centers. Mortality rates for patients with and without inhibitors were compared. During 64,200 patient-years of follow-up, 148 patients died (mortality rate, 2.30 per 1000 person-years; 95% confidence interval (CI), 1.96-2.70) at a median age of 64 years (interquartile range [IQR], 49-76). In 62 patients (42%) the cause of death was hemophilia related. Sixteen inhibitor patients died at a median age of 71 years (IQR, 60-81). In ten patients the inhibitor was present at time of death; seven of them died of severe bleeding complications. The all-cause mortality rate in inhibitor patients was > 5 times increased compared with that for those without inhibitors (age-adjusted mortality rate ratio, 5.6). Inhibitor development in non-severe hemophilia is associated with increased mortality. High rates of hemophilia-related mortality in this study indicate that non-severe hemophilia is not mild at all and stress the importance of close follow-up for these patients. © 2015 International Society on Thrombosis and Haemostasis.

  13. In vitro and In vivo Model Systems for Hemophilia A Gene Therapy.

    Science.gov (United States)

    Mao, Jianhua; Xi, Xiaodong; Kapranov, Philipp; Dong, Biao; Firrman, Jenni; Xu, Ruian; Xiao, Weidong

    2013-01-17

    Hemophilia A is a hereditary disorder caused by various mutations in factor VIII gene resulting in either a severe deficit or total lack of the corresponding activity. Recent success in gene therapy of a related disease, hemophilia B, gives new hope that similar success can be achieved for hemophilia A as well. To develop a gene therapy strategy for the latter, a variety of model systems are needed to evaluate molecular engineering of the factor VIII gene, vector delivery efficacy and safety-related issues. Typically, a tissue culture cell line is the most convenient way to get a preliminary glimpse of the potential of a vector delivery strategy. It is then followed by extensive testing in hemophilia A mouse and dog models. Newly developed hemophilia A sheep may provide yet another tool for evaluation of factor VIII gene delivery vectors. Hemophilia models based on other species may also be developed since hemophiliac animals have been identified or generated in rat, pig, cattle and horse. Although a genetic nonhuman primate hemophilia A model has yet to be developed, the non-genetic hemophilia A model can also be used for special purposes when specific questions need to be addressed that cannot not be answered in other model systems. Hemophilia A is caused by a functional deficiency in the factor VIII gene. This X-linked, recessive bleeding disorder affects approximately 1 in 5000 males [1-3]. Clinically, it is characterized by frequent and spontaneous joint hemorrhages, easy bruising and prolonged bleeding time. The coagulation activity of FVIII dictates severity of the clinical symptoms. Approximately 50% of all cases are classified as severe with less than 1% of normal levels of factor VIII detected [4]. This deficiency may lead to spontaneous joint hemorrhages or life-threatening bleeding. In contrast, patients with 5-30% of normal factor VIII activity exhibit mild clinical manifestations.

  14. Adeno-associated viral vectors for the treatment of hemophilia

    Science.gov (United States)

    High, Katherine A.; Anguela, Xavier M.

    2016-01-01

    Gene transfer studies for the treatment of hemophilia began more than two decades ago. A large body of pre-clinical work evaluated a variety of vectors and target tissues, but by the start of the new millennium it became evident that adeno-associated viral (AAV)-mediated gene transfer to the liver held great promise as a therapeutic tool. The transition to the clinical arena uncovered a number of unforeseen challenges, mainly in the form of a human-specific immune response against the vector that poses a significant limitation in the application of this technology. While the full nature of this response has not been elucidated, long-term expression of therapeutic levels of factor IX is already a reality for a small number of patients. Extending this success to a greater number of hemophilia B patients remains a major goal of the field, as well as translating this strategy to clinical therapy for hemophilia A. This review summarizes the progress of AAV-mediated gene therapy for the hemophilias, along with its upcoming prospects and challenges. PMID:26614390

  15. Neonatal hemophilia: a rare presentation

    Directory of Open Access Journals (Sweden)

    Nuno Ferreira

    2015-12-01

    Full Text Available Hemophilia A is a X-linked hereditary condition that lead to decreased factor VIII activity, occurs mainly in males. Decreased factor VIII activity leads to increased risk of bleeding events. During neonatal period, diagnosis is made after post-partum bleeding complication or unexpected bleeding after medical procedures. Subgaleal hemorrhage during neonatal period is a rare, severe extracranial bleeding with high mortality and usually related to traumatic labor or coagulation disorders. Subgaleal hemorrhage complications result from massive bleeding. We present a neonate with unremarkable family history and uneventful pregnancy with a vaginal delivery with no instrumentation, presenting with severe subgaleal bleeding at 52 hours of life. Aggressive support measures were implemented and bleeding managed. The unexpected bleeding lead to a coagulation study and the diagnosis of severe hemophilia A. There were no known sequelae. This case shows a rare hemophilia presentation reflecting the importance of coagulation studies when faced with unexplained severe bleeding.

  16. The influence of prophylactic factor VIII in severe hemophilia A

    Science.gov (United States)

    Gissel, Matthew; Whelihan, Matthew F; Ferris, Lauren A; Mann, Kenneth G; Rivard, Georges E; Brummel-Ziedins, Kathleen E

    2013-01-01

    Introduction Hemophilia A individuals displaying a similar genetic defect have heterogeneous clinical phenotypes. Aim To evaluate the underlying effect of exogenous factor (f)VIII on tissue factor (Tf)-initiated blood coagulation in severe hemophilia utilizing both empirical and computational models. Methods We investigated twenty-five clinically severe hemophilia A patients. All individuals were on fVIII prophylaxis and had not received fVIII from 0.25 to 4 days prior to phlebotomy. Coagulation was initiated by the addition of Tf to contact-pathway inhibited whole blood ± an anti-fVIII antibody. Aliquots were quenched over 20 min and analyzed for thrombin generation and fibrin formation. Coagulation factor levels were obtained and used to computationally predict thrombin generation with fVIII set to either zero or its value at the time of the draw. Results Due to prophylactic fVIII, at the time of the blood draw, the individuals had fVIII levels that ranged from hemophilia A. The combination of each individual's coagulation factors (outside of fVIII) determine each individual's baseline thrombin potential and may affect bleeding risk. PMID:21899664

  17. THROMBIN GENERATION AND BLEEDING IN HEMOPHILIA A

    Science.gov (United States)

    Brummel-Ziedins, Kathleen E.; Whelihan, Matthew F.; Gissel, Matthew; Mann, Kenneth G.; Rivard, Georges E.

    2012-01-01

    Introduction Hemophilia A displays phenotypic heterogeneity with respect to clinical severity. Aim To determine if tissue factor (TF)-initiated thrombin generation profiles in whole blood in the presence of corn trypsin inhibitor (CTI) are predictive of bleeding risk in hemophilia A. Methods We studied factor(F) VIII deficient individuals (11 mild, 4 moderate and 12 severe) with a well-characterized five-year bleeding history that included hemarthrosis, soft tissue hematoma and annual FVIII concentrate usage. This clinical information was used to generate a bleeding score. The bleeding scores (range 0–32) were separated into three groups (bleeding score groupings: 0, 0 and ≤9.6, >9.6), with the higher bleeding tendency having a higher score. Whole blood collected by phlebotomy and contact pathway suppressed by 100μg/mL CTI was stimulated to react by the addition of 5pM TF. Reactions were quenched at 20min by inhibitors. Thrombin generation, determined by ELISA for thrombin – antithrombin was evaluated in terms of clot time (CT), maximum level (MaxL) and maximum rate (MaxR) and compared to the bleeding score. Results Data are shown as the mean±SD. MaxL was significantly different (phemophilia A. PMID:19563500

  18. Using the Hemophilia Joint Health Score for assessment of children: Reliability of the Spanish version.

    Science.gov (United States)

    R, Cuesta-Barriuso; A, Torres-Ortuño; S, Pérez-Alenda; J, Carrasco Juan; F, Querol; J, Nieto-Munuera; Ja, López-Pina

    2018-02-27

    Numerous measuring instruments for the evaluation of hemophilic arthropathy have been developed. One of the most used systems is the Hemophilia Joint Health Score (HJHS) given its sensitivity to clinical changes appearing in the joints because of recurrent hemarthrosis. Assessing the interrater reliability, using the Spanish version of the HJHS (version 2.1) in children with hemophilia. Reliability study to assess the interrater reliability of the Spanish version of HJHS. A sample of 36 children aged 7-13 years diagnosed with hemophilia A or B was used. Two physiotherapists performed physical assessments with the Spanish version of the HJHS. Descriptive statistics (range, mean, standard deviation) and the analysis of interrater reliability were calculated. The interrater reliability was heterogeneous since the Kappa coefficient range (ĸ), although significant (p reliability of the Spanish population version of the HJHS is high. This scale should be used generically in evaluating musculoskeletal pediatric patients with hemophilia.

  19. Clinical Reasoning Education at US Medical Schools: Results from a National Survey of Internal Medicine Clerkship Directors.

    Science.gov (United States)

    Rencic, Joseph; Trowbridge, Robert L; Fagan, Mark; Szauter, Karen; Durning, Steven

    2017-11-01

    Recent reports, including the Institute of Medicine's Improving Diagnosis in Health Care, highlight the pervasiveness and underappreciated harm of diagnostic error, and recommend enhancing health care professional education in diagnostic reasoning. However, little is known about clinical reasoning curricula at US medical schools. To describe clinical reasoning curricula at US medical schools and to determine the attitudes of internal medicine clerkship directors toward teaching of clinical reasoning. Cross-sectional multicenter study. US institutional members of the Clerkship Directors in Internal Medicine (CDIM). Examined responses to a survey that was emailed in May 2015 to CDIM institutional representatives, who reported on their medical school's clinical reasoning curriculum. The response rate was 74% (91/123). Most respondents reported that a structured curriculum in clinical reasoning should be taught in all phases of medical education, including the preclinical years (64/85; 75%), clinical clerkships (76/87; 87%), and the fourth year (75/88; 85%), and that more curricular time should be devoted to the topic. Respondents indicated that most students enter the clerkship with only poor (25/85; 29%) to fair (47/85; 55%) knowledge of key clinical reasoning concepts. Most institutions (52/91; 57%) surveyed lacked sessions dedicated to these topics. Lack of curricular time (59/67, 88%) and faculty expertise in teaching these concepts (53/76, 69%) were identified as barriers. Internal medicine clerkship directors believe that clinical reasoning should be taught throughout the 4 years of medical school, with the greatest emphasis in the clinical years. However, only a minority reported having teaching sessions devoted to clinical reasoning, citing a lack of curricular time and faculty expertise as the largest barriers. Our findings suggest that additional institutional and national resources should be dedicated to developing clinical reasoning curricula to improve

  20. Biodistribution of Liver-Derived Mesenchymal Stem Cells After Peripheral Injection in a Hemophilia A Patient.

    Science.gov (United States)

    Sokal, Etienne M; Lombard, Catherine Anne; Roelants, Véronique; Najimi, Mustapha; Varma, Sharat; Sargiacomo, Camillo; Ravau, Joachim; Mazza, Giuseppe; Jamar, François; Versavau, Julia; Jacobs, Vanessa; Jacquemin, Marc; Eeckhoudt, Stéphane; Lambert, Catherine; Stéphenne, Xavier; Smets, Françoise; Hermans, Cédric

    2017-08-01

    With the exception of liver transplantation, there is no cure for hemophilia, which is currently managed by preemptive replacement therapy. Liver-derived stem cells are in clinical development for inborn and acquired liver diseases and could represent a curative treatment for hemophilia A. The liver is a major factor VIII (FVIII) synthesis site, and mesenchymal stem cells have been shown to control joint bleeding in animal models of hemophilia. Adult-derived human liver stem cells (ADHLSCs) have mesenchymal characteristics and have been shown able to engraft in and repopulate both animal and human livers. Thus, the objectives were to evaluate the potency of ADHLSCs to control bleeding in a hemophilia A patient and assess the biodistribution of the cells after intravenous injection. A patient suffering from hemophilia A was injected with repeated doses of ADHLSCs via a peripheral vein (35 million In-oxine-labeled cells, followed by 125 million cells the next day, and 3 infusions of 250 million cells every 2 weeks thereafter; total infusion period, 50 days). After cell therapy, we found a temporary (15 weeks) decrease in the patient's FVIII requirements and severe bleeding complications, despite a lack of increase in circulating FVIII. The cells were safely administered to the patient via a peripheral vein. Biodistribution analysis revealed an initial temporary entrapment of the cells in the lungs, followed by homing to the liver and to a joint afflicted with hemarthrosis. These results suggest the potential use of ADHLSCs in the treatment of hemophilia A.

  1. Known-group validity of patient-reported outcome instruments and hemophilia joint health score v2.1 in US adults with hemophilia: results from the Pain, Functional Impairment, and Quality of life (P-FiQ) study.

    Science.gov (United States)

    Buckner, Tyler W; Wang, Michael; Cooper, David L; Iyer, Neeraj N; Kempton, Christine L

    2017-01-01

    The Pain, Functional Impairment, and Quality of Life (P-FiQ) study was an observational, cross-sectional assessment of the impact of pain on functional impairment and quality of life in adults with hemophilia in the United States who experience joint pain or bleeding. To describe known-groups validity of assessment tools used in the P-FiQ study. Participants completed 5 patient-reported outcome (PRO) instruments (5-level EuroQoL 5-dimensional questionnaire [EQ-5D-5L] with visual analog scale [VAS], Brief Pain Inventory v2 Short Form [BPI], International Physical Activity Questionnaire [IPAQ], Short-Form Health Survey [SF-36v2], and Hemophilia Activities List [HAL]) and underwent a musculoskeletal examination (Hemophilia Joint Health Score [HJHS]) during a routine clinical visit. P-FiQ enrolled 381 adults with hemophilia (median age, 34 years). Participants were predominantly white/non-Hispanic (69.2%), 75% had congenital hemophilia A, and 70.5% had severe hemophilia. Most (n=310) reported bleeding within the past 6 months (mean [SD] number of bleeds, 7.1 [13.00]). All instruments discriminated between relevant known (site- or self-reported) participant groups. Domains related to pain on EQ-5D-5L, BPI, and SF-36v2 discriminated self-reported pain (acute/chronic/both; Pvalidity and may have practical applicability in evaluating adults with hemophilia in clinical and research settings in the United States.

  2. Factoring nonviral gene therapy into a cure for hemophilia A.

    Science.gov (United States)

    Gabrovsky, Vanessa; Calos, Michele P

    2008-10-01

    Gene therapy for hemophilia A has fallen short of success despite several clinical trials conducted over the past decade. Challenges to its success include vector immunogenicity, insufficient transgene expression levels of Factor VIII, and inhibitor antibody formation. Gene therapy has been dominated by the use of viral vectors, as well as the immunogenic and oncogenic concerns that accompany these strategies. Because of the complexity of viral vectors, the development of nonviral DNA delivery methods may provide an efficient and safe alternative for the treatment of hemophilia A. New types of nonviral strategies, such as DNA integrating vectors, and the success of several nonviral animal studies, suggest that nonviral gene therapy has curative potential and justifies its clinical development.

  3. Understanding patient preferences and willingness to pay for hemophilia therapies

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    Chaugule SS

    2015-11-01

    Full Text Available Shraddha S Chaugule,1 Joel W Hay,1 Guy Young2 1Department of Clinical Pharmacy, Pharmaceutical Economics and Policy, University of Southern California, 2Hemostasis and Thrombosis Center, Children’s Hospital Los Angeles, University of Southern California, Keck School of Medicine, Los Angeles, CA, USA Background: Despite clearly improved clinical outcomes for prophylaxis compared to on-demand therapy, on average only 56% of patients diagnosed with severe hemophilia receive prophylactic factor replacement therapy in the US. Prophylaxis rates generally drop as patients transition from childhood to adulthood, partly due to patients becoming less adherent when they reach adulthood. Assessment of patient preferences is important because these are likely to translate into increased treatment satisfaction and adherence. In this study, we assessed preferences and willingness to pay (WTP for on-demand, prophylaxis, and longer acting prophylaxis therapies in a sample of US hemophilia patients.Methods: Adult US hemophilia patients and caregivers (N=79 completed a discrete-choice survey that presented a series of trade-off questions, each including a pair of hypothetical treatment profiles. Using a mixed logit model for analysis, we compared the relative importance of five treatment characteristics: 1 out-of-pocket treatment costs (paid by patients, 2 factor dose adjustment, 3 treatment side effects, 4 availability of premixed factor, and 5 treatment effectiveness and dosing frequency. Based on these attribute estimates, we calculated patients’ WTP.Results: Out-of-pocket treatment costs (P<0.001, side effects (P<0.001, and treatment effectiveness and dosing frequency (P<0.001 were found to be statistically significant in the model. Patients were willing to pay US $410 (95% confidence interval: $164–$656 out of pocket per month for thrice-weekly prophylaxis therapy compared to on-demand therapy and $360 (95% confidence interval: $145–$575 for a switch

  4. Cardiovascular risk in patients with hemophilia

    NARCIS (Netherlands)

    Kamphuisen, Pieter W.; ten Cate, Hugo

    2014-01-01

    Patients with hemophilia, who have a life-long hypocoagulability, seem to have a lower cardiovascular mortality than the general population. Nevertheless, the prevalence of cardiovascular risk factors in patients with hemophilia is as prevalent as in the general population, and hypertension is even

  5. A WOMAN WITH SPORADIC HEMOPHILIA-B DIE BECAUSE OF CEREBRAL BLEEDING: A Rare Case in Bali-Indonesia

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    K. Suega

    2015-08-01

    Full Text Available Background: Hemophilias are groups of blood clotting disorder caused by deficiency of blood clotting factors which is X-linked recessively inherited and explain why mostly man is the affected victim. But on an extremely rare condition a women can have hemophilia due to several reasons and sporadic hemophilia is used to describe when hemophilia appeared without ascent and decent history of hemophilia. A 38 years old women with a peripheral spontaneous bleeding for two days although an open flap and a cauterization to stop the bleeding has been applied. She was the third child of 7 children in the family, 3 of them were man with normal life and 4 women also have no history of bleeding. Her parent and grand-parent were all dead because of aging problems. She also has 2 sons with ages of 10 and 13 years, respectively, live normally. Results: factor VIII activity 192 seconds (control: 80 seconds, factor IX activity 2 seconds (control: 111 seconds, hence patient was considered suffered from sporadic haemophilia-B due to low level of factor IX 1.8% and bleeding episodes mimicking clinical presentation of classical hemophilia patients while no known history of having hemophiliac family. The different diagnose were Von Willebrand Diisease (VWD, symptomatic carriers, acquired hemophilia. After several admissions and repeatedly bleeding episodes patient died because of intra cerebral bleeding.

  6. Expanding the Ortholog Approach for Hemophilia Treatment Complicated by Factor VIII Inhibitors

    Science.gov (United States)

    Zakas, P.M.; Vanijcharoenkarn, K.; Markovitz, R.C.; Meeks, S.L.; Doering, C.B.

    2014-01-01

    Summary Background The formation of neutralizing antibodies (inhibitors) directed against human coagulation factor VIII (hFVIII) is a life-threatening pathogenic response that occurs in 20–30% of severe congenital hemophilia A patients and 0.00015% of remaining population (i.e. acquired hemophilia A). Interspecies amino acid sequence disparity among FVIII orthologs represents a promising strategy to mask FVIII from existing inhibitors while retaining procoagulant function. Evidence for the effectiveness of this approach exists in clinical data obtained for porcine FVIII products, which have demonstrated efficacy in the setting of congenital and acquired hemophilia. Objectives In the current study, recombinant (r) ovine FVIII (oFVIII), was evaluated for antigenicity and procoagulant activity in the context of human patient-derived and murine model-generated FVIII inhibitors. Methods The antigenicity of roFVIII was assessed using i) inhibitor patient plasma samples, ii) murine anti-FVIII MAbs, iii) immunized murine hemophilia A plasmas, and iv) an in vivo model of acquired hemophilia A Results Overall, roFVIII demonstrated reduced reactivity to, and inhibition by, anti-hFVIII immunoglobulin in patient plasmas. Additionally, several hFVIII epitopes were predicted and empirically shown not to exist within roFVIII. In a murine hemophilia A model designed to mimic clinical inhibitor formation, it was demonstrated that inhibitor titers to roFVIII were significantly reduced compared to the orthologous immunogens, rhFVIII or rpFVIII. Furthermore in a murine model of acquired hemophilia A, roFVIII administration conferred protection from bleeding following tail transection. Conclusion These data support the investigation of FVIII orthologs as treatment modalities in both the congenital and acquired FVIII inhibitor settings. PMID:25315236

  7. Gene therapy for immune tolerance induction in hemophilia with inhibitors.

    Science.gov (United States)

    Arruda, V R; Samelson-Jones, B J

    2016-06-01

    The development of inhibitors, i.e. neutralizing alloantibodies against factor (F) VIII or FIX, is the most significant complication of protein replacement therapy for patients with hemophilia, and is associated with both increased mortality and substantial physical, psychosocial and financial morbidity. Current management, including bypassing agents to treat and prevent bleeding, and immune tolerance induction for inhibitor eradication, is suboptimal for many patients. Fortunately, there are several emerging gene therapy approaches aimed at addressing these unmet clinical needs of patients with hemophilia and inhibitors. Herein, we review the mounting evidence from preclinical hemophilia models that the continuous uninterrupted expression of FVIII or FIX delivered as gene therapy can bias the immune system towards tolerance induction, and even promote the eradication of pre-existing inhibitors. We also discuss several gene transfer approaches that directly target immune cells in order to promote immune tolerance. These preclinical findings also shed light on the immunologic mechanisms that underlie tolerance induction. © 2016 International Society on Thrombosis and Haemostasis.

  8. Acquired hemophilia A in the HIV-infected patient: a case report and literature review.

    Science.gov (United States)

    Rattanathammethee, Thanawat; Norasetthada, Lalita; Tantiworawit, Adisak; Rattarittamrong, Ekarat; Hantrakool, Sasinee; Chai-Adisaksopha, Chatree

    2015-03-01

    Acquired hemophilia A is a rare bleeding disorder caused by autoantibodies against factor VIII (FVIII). Spontaneous bleeding in the various sites and severity is the most common clinical presentation. Here, we report a 74-year-old Thai woman with HIV infection who presented with spontaneous ecchymoses. The laboratory revealed isolated activated partial thromboplastin time prolongation with low FVIII activity and a presence of FVIII inhibitor. She was diagnosed with acquired hemophilia A. Corticosteroid monotherapy was the treatment regimen for inhibitor eradication. We demonstrate the clinical course of the rare condition and review the relevant literature.

  9. Acquired hemophilia: a rare but life-threatening potential cause of bleeding in the intensive care unit.

    Science.gov (United States)

    Shander, Aryeh; Walsh, Christopher E; Cromwell, Caroline

    2011-08-01

    There are a number of potential etiologies of severe bleeding encountered in the intensive care unit. Although rare, acquired hemophilia is one such etiology that often presents with major bleeding requiring intensive care. Despite the introduction of effective treatments, the reported mortality rate of patients with acquired hemophilia ranges from 6 to 8% and is in part attributable to sequential delays in diagnosis and appropriate treatment. The purpose of this review is to familiarize the intensive care specialist with this underrecognized cause of bleeding, with an emphasis on diagnosis and treatment. As the objective of this article was to provide a concise overview of the diagnosis and management of acquired hemophilia, a directed search of English-language literature was undertaken using the PubMed database, targeting such topics as the differential diagnosis of bleeding in the intensive care unit and the epidemiology, diagnosis, and treatment of acquired hemophilia. Clinical study findings pertaining to the efficacy of specific treatments for acquired hemophilia were summarized. Recognition of acquired hemophilia presents a clinical challenge, given the rarity of this condition, a general lack of familiarity with acquired hemophilia, and the potential for confusion with other more common causes of bleeding in the intensive care unit. Nevertheless, there are sentinel clinical and laboratory findings that should raise suspicion of this diagnosis. The treatment of acquired hemophilia is a multi-step, physiologically focused process aimed at controlling both active and recurrent bleeding. Therefore, prompt diagnosis is central to prognosis. Consultation with a hematologist may facilitate efficient diagnosis and management.

  10. Impact of inhibitors on hemophilia A mortality in the United States.

    Science.gov (United States)

    Walsh, Christopher E; Soucie, J Michael; Miller, Connie H

    2015-05-01

    The previously published mortality studies are limited in hemophilia populations but suggest that there is no increased risk of mortality in factor VIII inhibitor patients. This retrospective study analyzed surveillance data collected on 7,386 males with severe hemophilia A over a 13-year period to assess the association between a current inhibitor and death. During the study period, 432 participants died, among whom 48 were patients with an inhibitor. Clinical characteristics most strongly associated with death were increased number of reported bleeds, signs of liver disease, infection with either HIV or HCV, and the presence of inhibitor. Patients who underwent successful tolerization were not considered inhibitor patients in our analysis. In a multivariable analysis, the odds of death were 70% higher among patients with a current inhibitor compared to those without an inhibitor (P hemophilia A and a current inhibitor are at increased risk of death. © 2015 Wiley Periodicals, Inc.

  11. The treatment of hemophilia A: from protein replacement to AAV-mediated gene therapy.

    Science.gov (United States)

    Youjin, Shen; Jun, Yin

    2009-03-01

    Factor VIII (FVIII) is an essential component in blood coagulation, a deficiency of which causes the serious bleeding disorder hemophilia A. Recently, with the development of purification level and recombinant techniques, protein replacement treatment to hemophiliacs is relatively safe and can prolong their life expectancy. However, because of the possibility of unknown contaminants in plasma-derived FVIII and recombinant FVIII, and high cost for hemophiliacs to use these products, gene therapy for hemophilia A is an attractive alternative to protein replacement therapy. Thus far, the adeno-associated virus (AAV) is a promising vector for gene therapy. Further improvement of the virus for clinical application depends on better understanding of the molecular structure and fate of the vector genome. It is likely that hemophilia will be the first genetic disease to be cured by somatic cell gene therapy.

  12. The Use Of Feiba In Hemophilia A Patient With Inhibitory And Sign Of Severe Intraabdominal Hemorrhage

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    Murat Çelik

    2003-03-01

    Full Text Available The development of a factor VIII inhibitory is the most serious problem of Hemophilia A. High dose FVIII, recombinant FVIIa or FVIII inhibitor bypass activator (FEIBA only or combined may use in the treatment of hemophilia with inhibitory. We present here 42 year-old male was admitted to our clinic with sign of shock, abdominal tenderness and image of mass. In laboratory, Hemoglobin was found 5 gr/dl, aPTT: 106 sec, FVIII: %0 and inhibitory level was found 14 BU. Abdominal computerized tomography was shown hemorrhage in abdominal cavity and in psoas muscle. In treatment; We used blood transfusion and 100 U/kgx2/d FEIBA along 4 days. General symptoms and signs was healed after 2 days and hematologic parameters turned to normal. Immune tolerans treatment program was planned for patient, later. FEIBA treatment is very useful in hemophilia patients suffered from hemorrhage and inhibitors in addition to supportive treatment.

  13. Penny wise, pound foolish: an assessment of Canadian Hemophilia/inherited bleeding disorder comprehensive care program services and resources.

    Science.gov (United States)

    Page, D; Crymble, S; Lawday, K; Long, M; Stoffman, J; Waterhouse, L; Wilton, P

    2016-07-01

    A network of 25 haemophilia/inherited bleeding disorder comprehensive care centres was established in Canada in the 1970s and 1980s. In 2007, standards of care, focused on the structural and resource requirements necessary to effectively provide optimal care, were adopted. Assess how human and physical resources affect centres' capacity to attain standards of care. The Canadian Hemophilia Society (CHS), with the support of the Association of Hemophilia Clinic Directors of Canada (AHCDC), undertook the assessment. Health care providers were interviewed in person by lay CHS volunteers and staff. A comprehensive patient satisfaction survey was mailed to a representative cross-section of patients/caregivers. The CHS observed that, despite competent and dedicated staff, many of the programmes are experiencing serious resource deficiencies. Twenty-three of the 25 programmes lack resources in one or more of the following disciplines: haematology, nursing, physiotherapy, social work and clerical/data entry. In nine of the 25 programmes, no resources are allocated to certain core disciplines, notably physiotherapy and social work. Key standards of care, including regular health assessments and close monitoring of home infusion with factor concentrates, are not always respected. Nevertheless, a high level of satisfaction was observed among patients and their caregivers. The study also discovered that clotting factor concentrates constitute 90-95% of the total cost of care while all other aspects of care delivery represent only 5-10%. Under-funding of programmes and suboptimal monitoring of valuable clotting factor concentrate utilization and reporting are both 'penny-wise' and 'pound-foolish'. A formal accreditation process is needed. © 2016 John Wiley & Sons Ltd.

  14. A newborn with moderate hemophilia A with severe intracranial and extracranial hemorrhage: A case report

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    Şebnem Kader

    2017-09-01

    Full Text Available Intracranial hemorrhage among term newborns is a rare clinical condition with high morbidity and mortality. Although major bleeding is relatively uncommon, the incidence of intracranial hemorrhage in hemophilic children is higher during the first few days of life than at any other stage in childhood, which relates to the trauma of delive ry. Here, we reported a newborn case diagnosed with moderate hemophilia A, without the presence of a positive family history of hemophilia and presenting with intracranial and extracranial hemorrhage and we aimed to emphasize that the early diagnosis and replacement therapy carries an essential importance.

  15. Acquired Hemophilia A successfully treated with rituximab

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    Giovanni D'Arena

    2015-02-01

    Full Text Available Acquired hemophilia A (AHA is a rare bleeding disorder due to the development of specific autoantibodies against factor VIII. The anti-CD20 monoclonal antibody Rituximab has been proven to be effective in  obtaining a long-term suppression of inhibitors of AHA,  besides other immunosuppressive standard treatments. Here we describe a case of idiopathic AHA in a 60-year old man successfully treated with rituximab. He showed a complete clinical response with  a normalization of clotting  parameters after 5 weekly courses of rituximab given at a dose of 375 mg/sqm. , but after stopping rituximab, an initial worsening of coagulation  parameters  induced the addition of 3 further courses. At present, the patient is in complete clinical and hematological remission after 200 days.  This case confirms that Rituximab may be a safe and useful tool to treat AHA and, a prolonged administration can overcome the initial resistance. However, the precise position of this drug in the therapeutic strategy (first or second-line, alone or in combination with other drugs remains to be established and warrants further investigation.

  16. The Utilization of Rehabilitation in Patients with Hemophilia A in Taiwan: A Nationwide Population-Based Study.

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    Chien-Min Chen

    Full Text Available Rehabilitation plays an important role in the physical health of patients with hemophilia. However, comprehensive information regarding the utilization of rehabilitation for such patients remains scarce.This population-based study aimed to examine the characteristics, trends, and most important factors affecting rehabilitation usage in patients with hemophilia A using a nationwide database in Taiwan.Data from 777 patients with hemophilia A who were registered in the National Health Insurance Research Database between 1998 and 2008 were analyzed using SAS 9.0.Musculoskeletal or nervous system-related surgical procedures and clotting factor VIII concentrate costs were identified as factors affecting rehabilitation usage; musculoskeletal or nervous system-related surgical procedures (odds ratio = 3.788; P < 0.001 were the most important predictor of whether a patient with hemophilia A would use rehabilitation services. Joint disorders, arthropathies, bone and cartilage disorders, intracranial hemorrhage, and brain trauma were common diagnoses during rehabilitation use. The costs of physical therapy (physiotherapy comprised the majority (71.2% of rehabilitation therapy categories. Increasingly, rehabilitation therapy was performed at physician clinics. The total rehabilitation costs were <0.1% of the total annual medical costs.Musculoskeletal or nervous system-related surgical procedures and increased use of clotting factor VIII concentrate affect the rehabilitation utilization of patients with hemophilia A the most. The findings in this study could help clinicians comprehensively understand the rehabilitation utilization of patients with hemophilia A.

  17. Effects of FVIII immunity on hepatocyte and hematopoietic stem cell–directed gene therapy of murine hemophilia A

    Science.gov (United States)

    Lytle, Allison M; Brown, Harrison C; Paik, Na Yoon; Knight, Kristopher A; Wright, J Fraser; Spencer, H Trent; Doering, Christopher B

    2016-01-01

    Immune responses to coagulation factors VIII (FVIII) and IX (FIX) represent primary obstacles to hemophilia treatment. Previously, we showed that hematopoietic stem cell (HSC) retroviral gene therapy induces immune nonresponsiveness to FVIII in both naive and preimmunized murine hemophilia A settings. Liver-directed adeno-associated viral (AAV)-FIX vector gene transfer achieved similar results in preclinical hemophilia B models. However, as clinical immune responses to FVIII and FIX differ, we investigated the ability of liver-directed AAV-FVIII gene therapy to affect FVIII immunity in hemophilia A mice. Both FVIII naive and preimmunized mice were administered recombinant AAV8 encoding a liver-directed bioengineered FVIII expression cassette. Naive animals receiving high or mid-doses subsequently achieved near normal FVIII activity levels. However, challenge with adjuvant-free recombinant FVIII induced loss of FVIII activity and anti-FVIII antibodies in mid-dose, but not high-dose AAV or HSC lentiviral (LV) vector gene therapy cohorts. Furthermore, unlike what was shown previously for FIX gene transfer, AAV-FVIII administration to hemophilia A inhibitor mice conferred no effect on anti-FVIII antibody or inhibitory titers. These data suggest that functional differences exist in the immune modulation achieved to FVIII or FIX in hemophilia mice by gene therapy approaches incorporating liver-directed AAV vectors or HSC-directed LV. PMID:26909355

  18. Effects of FVIII immunity on hepatocyte and hematopoietic stem cell-directed gene therapy of murine hemophilia A.

    Science.gov (United States)

    Lytle, Allison M; Brown, Harrison C; Paik, Na Yoon; Knight, Kristopher A; Wright, J Fraser; Spencer, H Trent; Doering, Christopher B

    2016-01-01

    Immune responses to coagulation factors VIII (FVIII) and IX (FIX) represent primary obstacles to hemophilia treatment. Previously, we showed that hematopoietic stem cell (HSC) retroviral gene therapy induces immune nonresponsiveness to FVIII in both naive and preimmunized murine hemophilia A settings. Liver-directed adeno-associated viral (AAV)-FIX vector gene transfer achieved similar results in preclinical hemophilia B models. However, as clinical immune responses to FVIII and FIX differ, we investigated the ability of liver-directed AAV-FVIII gene therapy to affect FVIII immunity in hemophilia A mice. Both FVIII naive and preimmunized mice were administered recombinant AAV8 encoding a liver-directed bioengineered FVIII expression cassette. Naive animals receiving high or mid-doses subsequently achieved near normal FVIII activity levels. However, challenge with adjuvant-free recombinant FVIII induced loss of FVIII activity and anti-FVIII antibodies in mid-dose, but not high-dose AAV or HSC lentiviral (LV) vector gene therapy cohorts. Furthermore, unlike what was shown previously for FIX gene transfer, AAV-FVIII administration to hemophilia A inhibitor mice conferred no effect on anti-FVIII antibody or inhibitory titers. These data suggest that functional differences exist in the immune modulation achieved to FVIII or FIX in hemophilia mice by gene therapy approaches incorporating liver-directed AAV vectors or HSC-directed LV.

  19. Effects of FVIII immunity on hepatocyte and hematopoietic stem cell–directed gene therapy of murine hemophilia A

    Directory of Open Access Journals (Sweden)

    Allison M Lytle

    2016-01-01

    Full Text Available Immune responses to coagulation factors VIII (FVIII and IX (FIX represent primary obstacles to hemophilia treatment. Previously, we showed that hematopoietic stem cell (HSC retroviral gene therapy induces immune nonresponsiveness to FVIII in both naive and preimmunized murine hemophilia A settings. Liver-directed adeno-associated viral (AAV-FIX vector gene transfer achieved similar results in preclinical hemophilia B models. However, as clinical immune responses to FVIII and FIX differ, we investigated the ability of liver-directed AAV-FVIII gene therapy to affect FVIII immunity in hemophilia A mice. Both FVIII naive and preimmunized mice were administered recombinant AAV8 encoding a liver-directed bioengineered FVIII expression cassette. Naive animals receiving high or mid-doses subsequently achieved near normal FVIII activity levels. However, challenge with adjuvant-free recombinant FVIII induced loss of FVIII activity and anti-FVIII antibodies in mid-dose, but not high-dose AAV or HSC lentiviral (LV vector gene therapy cohorts. Furthermore, unlike what was shown previously for FIX gene transfer, AAV-FVIII administration to hemophilia A inhibitor mice conferred no effect on anti-FVIII antibody or inhibitory titers. These data suggest that functional differences exist in the immune modulation achieved to FVIII or FIX in hemophilia mice by gene therapy approaches incorporating liver-directed AAV vectors or HSC-directed LV.

  20. Nanocapsule-delivered Sleeping Beauty mediates therapeutic Factor VIII expression in liver sinusoidal endothelial cells of hemophilia A mice.

    Science.gov (United States)

    Kren, Betsy T; Unger, Gretchen M; Sjeklocha, Lucas; Trossen, Alycia A; Korman, Vicci; Diethelm-Okita, Brenda M; Reding, Mark T; Steer, Clifford J

    2009-07-01

    Liver sinusoidal endothelial cells are a major endogenous source of Factor VIII (FVIII), lack of which causes the human congenital bleeding disorder hemophilia A. Despite extensive efforts, gene therapy using viral vectors has shown little success in clinical hemophilia trials. Here we achieved cell type-specific gene targeting using hyaluronan- and asialoorosomucoid-coated nanocapsules, generated using dispersion atomization, to direct genes to liver sinusoidal endothelial cells and hepatocytes, respectively. To highlight the therapeutic potential of this approach, we encapsulated Sleeping Beauty transposon expressing the B domain-deleted canine FVIII in cis with Sleeping Beauty transposase in hyaluronan nanocapsules and injected them intravenously into hemophilia A mice. The treated mice exhibited activated partial thromboplastin times that were comparable to those of wild-type mice at 5 and 50 weeks and substantially shorter than those of untreated controls at the same time points. Further, plasma FVIII activity in the treated hemophilia A mice was nearly identical to that in wild-type mice through 50 weeks, while untreated hemophilia A mice exhibited no detectable FVIII activity. Thus, Sleeping Beauty transposon targeted to liver sinusoidal endothelial cells provided long-term expression of FVIII, without apparent antibody formation, and improved the phenotype of hemophilia A mice.

  1. The Hemophilia Games: An Experiment in Health Education Planning.

    Science.gov (United States)

    National Heart and Lung Inst. (DHEW/PHS), Bethesda, MD.

    The Hemophilia Health Education Planning Project was designed to (1) create a set of tools useful in hemophilia planning and education, and (2) create a planning model for other diseases with similar factors. The project used the game-simulations technique which was felt to be particularly applicable to hemophilia health problems, since as a…

  2. The Experience of Children with Hemophilia and HIV Infection.

    Science.gov (United States)

    Hall, Christopher S.

    1994-01-01

    Children with hemophilia and Human Immunodeficiency Virus (HIV) infection are not a transmission risk to other children, and they can help enact best practices for school attendance by other such children. The article examines the National Hemophilia Foundation's work to promote appropriate inclusion of students with hemophilia and HIV in all…

  3. The prognosis and treatment of acquired hemophilia: a systematic review and meta-analysis.

    Science.gov (United States)

    Bitting, Rhonda L; Bent, Stephen; Li, Yongmei; Kohlwes, Jeffrey

    2009-10-01

    The inhibition of factor VIII by autoantibody development, or acquired hemophilia, occurs in approximately one person per million each year and can cause life-threatening bleeding. Due to the disease rarity, there are no randomized studies addressing prognostic features and treatment. The goal of this study is to identify prognostic indictors in acquired hemophilia to guide treatment choices. MEDLINE and EMBASE search from 1985-2008 retrieved 32 studies with detailed clinical information on five or more patients with acquired hemophilia. Univariate and multivariate analysis of the effects of age, sex, underlying condition, inhibitor titer, and treatment regimen were evaluated with regards to complete remission and death. A total of 32 studies containing 359 patients with acquired hemophilia were included in the analysis. The all-cause mortality rate in this cohort was 21%. Multivariate analyses revealed that patients more likely to die are the elderly [odds ratio (OR) 2.4, 95% confidence interval (CI) 1.32-4.36] and those with underlying malignancy (OR 2.76, CI 1.38-5.50). Early achievement of complete remission resulted in improved survival. Complete remission occurred in 94% of patients receiving combination chemotherapy, 82% receiving dual therapy, and 68% receiving steroids alone. Patients receiving immunosuppression had reduced odds of persistent hemophilia, with combination chemotherapy being the most efficacious (OR 0.04, CI 0.01-0.23) and steroid therapy alone being the least (OR 0.38, CI 0.14-0.94). In acquired hemophilia, increased age, underlying malignancy, and lack of complete remission are risk factors for death. Although the included studies were not randomized, patients treated with combination chemotherapy had the greatest odds of remission and the lowest odds of death.

  4. Comparing thrombin generation in patients with hemophilia A and patients on vitamin K antagonists

    NARCIS (Netherlands)

    de Koning, M L Y; Fischer, K; de Laat, B; Huisman, A; Ninivaggi, M; Schutgens, R E G

    Essentials: It is unknown if hemophilia patients with atrial fibrillation need anticoagulation. Endogenous thrombin potentials (ETP) in hemophilia patients and patients on coumarins were compared. Severe hemophilia patients had comparable ETP to therapeutic international normalized ratio (INR). In

  5. Hemophilia A in Brazil – epidemiology and treatment developments

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    Ferreira AA

    2014-09-01

    Full Text Available Adriana Aparecida Ferreira,1 Isabel Cristina Gonçalves Leite,2 Maria Teresa Bustamante-Teixeira,2 Maximiliano Ribeiro Guerra2 1Foundation and Center for Hematology and Hemotherapy of Minas Gerais (Hemominas, 2Department of Collective Health, Federal University of Juiz de Fora, Juiz de Fora, Minas Gerais, BrazilAbstract: Hemophilia A is an inherited disorder characterized by deficiency of coagulation factor VIII, which predisposes patients to bleeding events. Treatment is based on replacement of the deficient factor, in a therapeutic or prophylactic manner. Brazil is the country with the third largest population of people with hemophilia, for which the public health system provides free comprehensive care. Maintaining an updated registry of patients, documenting the prevalence of complications, and assessing the effectiveness of resource use are indispensable elements in the design of a well-coordinated national program. According to sociodemographic, clinical, and laboratory data collected by the computerized Brazilian system on coagulopathies, in June 2013, there were 9,122 registered patients with hemophilia A in Brazil, of which 36.1% had a severe form of the disease. Clotting factor inhibitors were present in 7.5%, but 25.7% of records did not provide this type of data. Around 70% of the patients belonged to the economically active population, being between 15 and 59 years old. Infection by the human immunodeficiency virus was present in 23.4% of the patients tested and infection by hepatitis C virus antibodies in 59.3%. Infection by the hepatitis B virus and human T-lymphotropic virus was also reported. The high percentage of incomplete records regarding serological data shows the fragility of the information system to date. There was also no information available on the prevalence of permanent or disabling joint damage. Although few hemophiliacs receive adequate care in developing countries, and despite Brazil exhibiting great social

  6. AAV5-Factor VIII Gene Transfer in Severe Hemophilia A.

    Science.gov (United States)

    Rangarajan, Savita; Walsh, Liron; Lester, Will; Perry, David; Madan, Bella; Laffan, Michael; Yu, Hua; Vettermann, Christian; Pierce, Glenn F; Wong, Wing Y; Pasi, K John

    2017-12-28

    Patients with hemophilia A rely on exogenous factor VIII to prevent bleeding in joints, soft tissue, and the central nervous system. Although successful gene transfer has been reported in patients with hemophilia B, the large size of the factor VIII coding region has precluded improved outcomes with gene therapy in patients with hemophilia A. We infused a single intravenous dose of a codon-optimized adeno-associated virus serotype 5 (AAV5) vector encoding a B-domain-deleted human factor VIII (AAV5-hFVIII-SQ) in nine men with severe hemophilia A. Participants were enrolled sequentially into one of three dose cohorts (low dose [one participant], intermediate dose [one participant], and high dose [seven participants]) and were followed through 52 weeks. Factor VIII activity levels remained at 3 IU or less per deciliter in the recipients of the low or intermediate dose. In the high-dose cohort, the factor VIII activity level was more than 5 IU per deciliter between weeks 2 and 9 after gene transfer in all seven participants, and the level in six participants increased to a normal value (>50 IU per deciliter) that was maintained at 1 year after receipt of the dose. In the high-dose cohort, the median annualized bleeding rate among participants who had previously received prophylactic therapy decreased from 16 events before the study to 1 event after gene transfer, and factor VIII use for participant-reported bleeding ceased in all the participants in this cohort by week 22. The primary adverse event was an elevation in the serum alanine aminotransferase level to 1.5 times the upper limit of the normal range or less. Progression of preexisting chronic arthropathy in one participant was the only serious adverse event. No neutralizing antibodies to factor VIII were detected. The infusion of AAV5-hFVIII-SQ was associated with the sustained normalization of factor VIII activity level over a period of 1 year in six of seven participants who received a high dose, with

  7. Case Management Directors

    Science.gov (United States)

    Bankston White, Cheri; Birmingham, Jackie

    2015-01-01

    that include payer, provider, and regulatory agencies. At the same time, they must also develop the skills to positively influence the revenue cycle and financial health of both the organization for which they work and those to whom they transition patients. Implications for Case Management: A director of case management with responsibility for transitions of care has more power and influence over patient safety than is commonly known. Few of the directors who are drawn from clinical case management or other leadership positions and thrust into this role are prepared to navigate within the organization, much less across the whole spectrum of payer, provider, and monitoring organizations. Yet the external focus of the director's role continues to grow in importance as the health care industry evolves and more focus is placed on population management and relationships with payers and community providers. PMID:25700135

  8. Impact of mild to severe hemophilia on education and work by US men, women, and caregivers of children with hemophilia B: The Bridging Hemophilia B Experiences, Results and Opportunities into Solutions (B-HERO-S) study.

    Science.gov (United States)

    Cutter, Susan; Molter, Don; Dunn, Spencer; Hunter, Susan; Peltier, Skye; Haugstad, Kimberly; Frick, Neil; Holot, Natalia; Cooper, David L

    2017-04-01

    The psychosocial impact of hemophilia on work was recently investigated in the Hemophilia Experiences, Results and Opportunities (HERO) study. The findings revealed that hemophilia had an impact for adults with moderate/severe hemophilia and caregivers of children with hemophilia. HERO did not specifically evaluate impact on education in adults/children with mild/moderate hemophilia or the impact on employment of spouses/partners of caregivers of affected children. The Bridging Hemophilia B Experiences, Results and Opportunities into Solutions (B-HERO-S) study evaluated the impact of hemophilia on the lives of adult men/women with mild-severe hemophilia B and caregivers of boys/girls with hemophilia B and their spouses/partners. Many adults with hemophilia B (94%) reported that hemophilia had a negative effect on their ability to complete a formal education, often attributed to the inability to attend or concentrate in school as a result of hemophilia-related bleeding or pain. Most adults with hemophilia B (95%) and caregivers/partners (89%/84%) indicated that hemophilia had a negative impact on employment. Most adults with hemophilia were employed (81%), with construction/manufacturing (35%) as the most frequently reported industry; many worked in jobs requiring manual labor (39%). Of those unemployed, 62% never worked, and those who stopped working reported that they left the workforce due to financial issues (59%), including insurance coverage/co-pays, or hemophilia-related issues (55%). Nearly one-third of caregivers voluntarily left the workforce to care for children with hemophilia. These results suggest a need to focus more effort on career counseling for adults with hemophilia B and caregivers of affected children, especially around mild/moderate hemophilia, as this population may not be as well informed regarding potential impact in school and the workplace. © 2017 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd.

  9. The benefit of low dose prophylaxis in the treatment of hemophilia: a focus on China.

    Science.gov (United States)

    Wu, Runhui; Luke, Koon Hung

    2017-11-01

    Currently full dose prophylaxis is the standard of care in the treatment of hemophilia (World Federation of Hemophilia). However, the high costs prevent the use of standard or intermediate dose prophylaxis in China and other developing countries. Low dose prophylaxis would be a viable alternative treatment. At present global research data on the use of low dose prophylaxis is limited. Areas covered: Since 2007, China has been developing low dose prophylaxis as a high priority (90 % of moderate and severe hemophilia boys suffer joint disease by age 6 - 9). 11 studies were successfully conducted and published results showing evidence of the benefits of low dose prophylaxis to reduce joint bleeding. This new knowledge has been implemented into clinical practice in China. However the long-term outcome of arthropathy remains unclear and obstacles in execution exist. Expert commentary: In 2016, the first phenotype-based individualized prophylaxis study using four escalating low dose regimens on severe Chinese hemophilia A boys (China Individualized Prophylaxis Study (CHIP China)) launched. Using the previously published and imminent CHIP data, the goal for China is to establish an effective escalating low dose prophylaxis protocol for use in China as a standard of care.

  10. [Elderly patient with acquired hemophilia A with IX・XI and XII factor decline].

    Science.gov (United States)

    Hanyu, Naofumi; Aota, Yasuo; Gotoh, Akihiko; Sakurai, Michio

    2015-01-01

    Acquired hemophilia is a rare bleeding diathesis caused by autoantibodies against clotting factor VIII. Many cases are associated with autoimmune disease, malignancy and an elderly status. Acquired hemophilia is very rare, with a reported annual incidence of 1.48/million/y. However, it is necessary to consider this rare disease when encountering bleeding of unknown cause in elderly patients. An 84-year-old woman was referred to our hospital with subcutaneous bleeding and anemia. The patient had severe anemia and a prolonged activated partial prothrombin time (APTT). Despite the administration of red blood cell transfusions, the decline in hemoglobin continued. Since the activity of coagulation factor VIII was 5 BU/ml, the patient was diagnosed with acquired hemophilia. No underlying diseases were found, and we concluded that this case was idiopathic. Although she was treated with prednisolone at a dose of 40 mg per day, the bleeding tendency did not improve. Therefore, she was given activated prothrombin complex concentrates (APCC) for four days. The subcutaneous bleeding and Hb decline stopped, and the dose of prednisolone was gradually reduced. The patient's clotting function and clinical course were satisfactory, and she was discharged on the 64th day. An early diagnosis and optimal treatment are critical for treating acquired hemophilia. The development of a bleeding tendency related to the appearance of coagulation factor VIII inhibitor is serious in many patients. Therefore, recognizing this disease and providing prompt management are necessary.

  11. Understanding of genetic inheritance among Xhosa-speaking caretakers of children with hemophilia.

    Science.gov (United States)

    Solomon, Gabriele; Greenberg, Jacquie; Futter, Merle; Vivian, Lauraine; Penn, Claire

    2012-10-01

    Hemophilia A and B are X-linked recessive inherited bleeding disorders that have a profound impact on the family of affected individuals. Education is vital to enable women to appreciate the implications of being a carrier and the implications for a prospective child. Prior research has shown that cultural, socio-economic and linguistic issues in South Africa are major barriers to communication for first-language Xhosa-speakers. This exploratory study aimed to investigate the basic knowledge of genetic inheritance among this cultural group in order to promote culturally-sensitive, effective genetic counseling. Ten in-depth interviews were conducted with Xhosa-speaking mothers or caregivers of boys with hemophilia. Results suggest that the participants had a very limited understanding of the clinical management, genetic consequences and cause of hemophilia. While treatment and care by health care service providers was fully accepted, several participants believed that traditional methods would provide them with more satisfactory explanations. These findings suggest that there is a critical need for socio-culturally tailored, language-specific education for families with hemophilia.

  12. Recombinant factor VIII in the management of hemophilia A: current use and future promise

    Directory of Open Access Journals (Sweden)

    Jerry S Powell

    2009-05-01

    Full Text Available Jerry S PowellDivision of Hematology and Oncology, University of California Davis Cancer Center, Sacramento, CA, USAAbstract: Hemophilia A is a rare inherited bleeding disorder due to mutation of the gene that encodes the coagulation protein factor VIII. Historically, prior to the availability of treatment with factor VIII preparations, most boys died from uncontrolled bleeding, either spontaneous bleeding or after injury, before reaching 20 years of age. One of the most impressive triumphs of modern medicine is that with current recombinant factor VIII replacement therapy, a boy born in the 21st century with severe hemophilia A can anticipate a normal life expectancy with essentially no permanent complications from bleeding. For severe hemophilia A, current optimal treatment should have two goals: first, to provide sufficient factor VIII to prevent spontaneous bleeding, and second, to provide sufficient factor VIII to have normal coagulation function after any trauma. However, the replacement therapy requires tremendous resources for effective use, and remains extraordinarily expensive. Thus there are opportunities for further advances in therapy for hemophilia A. Two major concerns continue to trouble current optimal treatment approaches: some patients will develop neutralizing antibodies during the first 50 infusions of therapeutic factor VIII, and second, to administer therapeutic factor VIII every other day in young boys often requires placement of a central venous access device, and such use carries the life-threatening risks of infection and thrombosis. Because of the effectiveness of current therapy, any new developments in treatment will require significant concerns for safety, both immediate and in the long term. A number of research groups seek to prolong the biological efficacy of infused recombinant factor VIII. Currently, one such promising development is in the advanced stages of clinical trial. The goals will be to improve

  13. Interventions for treating acute bleeding episodes in people with acquired hemophilia A.

    Science.gov (United States)

    Zeng, Yan; Zhou, Ruiqing; Duan, Xin; Long, Dan; Yang, Songtao

    2014-08-28

    Acquired hemophilia A is a rare bleeding disorder caused by autoantibodies to coagulation factor VIII (FVIII). In most cases, bleeding episodes are spontaneous and severe at presentation. The optimal hemostatic therapy is controversial. To determine the efficacy of hemostatic therapies for acute bleeds in people with acquired hemophilia A; and to compare different forms of therapy for these bleeds. We searched the Cochrane Central Register of Controlled Trials (CENTRAL) (The Cochrane Library 2014, Issue 4) and MEDLINE (Ovid) (1948 to 30 April 2014). We searched the conference proceedings of the: American Society of Hematology; European Hematology Association; International Society on Thrombosis and Haemostasis (ISTH); and the European Association for Haemophilia and Allied Disorders (EAHAD) (from 2000 to 30 April 2014). In addition to this we searched clinical trials registers. All randomised controlled trials and quasi-randomised trials of hemostatic therapies for people with acquired hemophilia A, with no restrictions on gender, age or ethnicity. No trials matching the selection criteria were eligible for inclusion. No trials matching the selection criteria were eligible for inclusion. No randomised clinical trials of hemostatic therapies for acquired hemophilia A were found. Thus, we are not able to draw any conclusions or make any recommendations on the optimal hemostatic therapies for acquired hemophilia A based on the highest quality of evidence. GIven that carrying out randomized controlled trials in this field is a complex task, the authors suggest that, while planning randomised controlled trials in which patients can be enrolled, clinicians treating the disease continue to base their choices on alternative, lower quality sources of evidence, which hopefully, in the future, will also be appraised and incorporated in a Cochrane Review.

  14. Hemophilia: The Role of the School Nurse.

    Science.gov (United States)

    Damiano, Mary Lou; And Others

    1980-01-01

    Care of the school student with hemophilia requires a cooperative effort by the health care team. A multidisciplinary approach is suggested for the team, whose members include a hematologist, orthopedist, oral surgeon, geneticist, physical therapist, social worker, and school nurse. (JD)

  15. Inhibitor development in nonsevere hemophilia A

    NARCIS (Netherlands)

    Eckhardt, C.L.

    2014-01-01

    Hemophilia A is an X-linked inherited bleeding disorder that affects approximately 1 in 5000 male live births. It is caused by a deficient plasma level of clotting factor VIII and can be treated by the intravenous administration of factor VIII concentrates. A severe complication of the treatment

  16. Immunobiology of inhibitor development in hemophilia A

    NARCIS (Netherlands)

    Fijnvandraat, Karin; Bril, Wendy S.; Voorberg, Jan

    2003-01-01

    After treatment with factor (F) VIII concentrate a significant number of patients with hemophilia A develop inhibitory antibodies that neutralize FVIII. Epitope mapping revealed that antibodies bind to selected regions within the A2, A3, and C2 domains of FVIII. Anti-A2 and anti-A3 antibodies

  17. An extra X does not prevent acquired hemophilia - Pregnancy-associated acquired hemophilia A.

    Science.gov (United States)

    Barg, Assaf A; Livnat, Tami; Kenet, Gili

    2017-03-01

    Acquired hemophilia A (AHA) is a severe bleeding disorder caused by autoantibodies against clotting factor VIII (FVIII). With an estimated annual incidence of 1.3 to 1.5 per million, AHA is a rare disease. An extremely rare form of AHA has been described among women in the peripartum period, and may present with peripartum hemorrhage. Notably, although hemorrhagic symptoms commonly present 1-4 months around delivery, they may occur up to 1 year after parturition. When caring for a mother with AHA it is important to note that Factor VIII inhibitor may be transferred via the placenta from the mother to the fetus. Hence the newborn may also be affected. It is important to increase the awareness of Gynecologists for clinical symptoms and laboratory signs of AHA in order to avoid delayed diagnosis. Treatment may involve use of bypass agents to control hemorrhage, despite the risk of thrombosis, while immunomodulation (with increasing role for Rituximab) may be required to eradicate the inhibiting antibodies. Our review will evaluate the epidemiology, diagnosis, clinical course and treatment of peripartum AHA, focusing upon mother and infant care. © 2017 Elsevier Ltd. All rights reserved.

  18. Idiopathic Acquired Hemophilia A with Undetectable Factor VIII Inhibitor

    Directory of Open Access Journals (Sweden)

    Nicholas B. Abt

    2014-01-01

    Full Text Available Objective. We present the case of a 73-year-old female, with no family or personal history of a bleeding disorder, who had a classic presentation for acquired hemophilia A. Factor VIII activity was low but detectable and a factor VIII inhibitor was undetectable. Methods. The patient’s plasma was comprehensively studied to determine the cause of the acquired coagulopathy. Using the Nijmegen modification of the Bethesda assay, no factor VIII autoantibody was measureable despite varying the incubation time from 1 to 3 hours. Results. The aPTT was prolonged at 46.8 seconds, which did not correct in the 4 : 1 mix but did with 1 : 1 mix. Using a one stage factor VIII activity assay, the FVIII activity was 16% and chromogenic FVIII activity was also 16%. The patient was treated with recombinant FVII and transfusion, significantly reducing bleeding. Long-term therapy was initiated with cyclophosphamide and prednisone with normalization of FVIII activity. Conclusions. Physicians can be presented with the challenging clinical picture of an acquired factor VIII inhibitor without a detectable inhibitor by the Bethesda assay. Standard therapy for an acquired hemophilia A should be considered.

  19. Independent Directors

    DEFF Research Database (Denmark)

    Ringe, Wolf-Georg

    2013-01-01

    that they did not prevent firms' excessive risk taking; further, these directors sometimes showed serious deficits in understanding the business they were supposed to control, and remained passive in addressing structural problems. A closer look reveals that under the surface of seemingly unanimous consensus......This paper re-evaluates the corporate governance concept of ‘board independence’ against the disappointing experiences during the 2007-08 financial crisis. Independent or outside directors had long been seen as an essential tool to improve the monitoring role of the board. Yet the crisis revealed...... about board independence in Western jurisdictions, a surprising disharmony prevails about the justification, extent and purpose of independence requirements. These considerations lead me to question the benefits of the current system. Instead, this paper proposes a new, ‘functional’ concept of board...

  20. Relationships between high-stakes clinical skills exam scores and program director global competency ratings of first-year pediatric residents

    Science.gov (United States)

    Langenau, Erik E.; Pugliano, Gina; Roberts, William L.

    2011-01-01

    Background Responding to mandates from the Accreditation Council for Graduate Medical Education (ACGME) and American Osteopathic Association (AOA), residency programs have developed competency-based assessment tools. One such tool is the American College of Osteopathic Pediatricians (ACOP) program directors’ annual report. High-stakes clinical skills licensing examinations, such as the Comprehensive Osteopathic Medical Licensing Examination Level 2-Performance Evaluation (COMLEX-USA Level 2-PE), also assess competency in several clinical domains. Objective The purpose of this study is to investigate the relationships between program director competency ratings of first-year osteopathic residents in pediatrics and COMLEX-USA Level 2-PE scores from 2005 to 2009. Methods The sample included all 94 pediatric first-year residents who took COMLEX-USA Level 2-PE and whose training was reviewed by the ACOP for approval of training between 2005 and 2009. Program director competency ratings and COMLEX-USA Level 2-PE scores (domain and component) were merged and analyzed for relationships. Results Biomedical/biomechanical domain scores were positively correlated with overall program director competency ratings. Humanistic domain scores were not significantly correlated with overall program director competency ratings, but did show moderate correlation with ratings for interpersonal and communication skills. The six ACGME or seven AOA competencies assessed empirically by the ACOP program directors’ annual report could not be recovered by principal component analysis; instead, three factors were identified, accounting for 86% of the variance between competency ratings. Discussion A few significant correlations were noted between COMLEX-USA Level 2-PE scores and program director competency ratings. Exploring relationships between different clinical skills assessments is inherently difficult because of the heterogeneity of tools used and overlap of constructs within the AOA

  1. Relationships between high-stakes clinical skills exam scores and program director global competency ratings of first-year pediatric residents

    Directory of Open Access Journals (Sweden)

    Erik E. Langenau

    2011-09-01

    Full Text Available Responding to mandates from the Accreditation Council for Graduate Medical Education (ACGME and American Osteopathic Association (AOA, residency programs have developed competency-based assessment tools. One such tool is the American College of Osteopathic Pediatricians (ACOP program directors’ annual report. High-stakes clinical skills licensing examinations, such as the Comprehensive Osteopathic Medical Licensing Examination Level 2-Performance Evaluation (COMLEX-USA Level 2-PE, also assess competency in several clinical domains.The purpose of this study is to investigate the relationships between program director competency ratings of first-year osteopathic residents in pediatrics and COMLEX-USA Level 2-PE scores from 2005 to 2009.The sample included all 94 pediatric first-year residents who took COMLEX-USA Level 2-PE and whose training was reviewed by the ACOP for approval of training between 2005 and 2009. Program director competency ratings and COMLEX-USA Level 2-PE scores (domain and component were merged and analyzed for relationships.Biomedical/biomechanical domain scores were positively correlated with overall program director competency ratings. Humanistic domain scores were not significantly correlated with overall program director competency ratings, but did show moderate correlation with ratings for interpersonal and communication skills. The six ACGME or seven AOA competencies assessed empirically by the ACOP program directors’ annual report could not be recovered by principal component analysis; instead, three factors were identified, accounting for 86% of the variance between competency ratings.A few significant correlations were noted between COMLEX-USA Level 2-PE scores and program director competency ratings. Exploring relationships between different clinical skills assessments is inherently difficult because of the heterogeneity of tools used and overlap of constructs within the AOA and ACGME core competencies.

  2. Treatment of Hemophilia A in Utero and Postnatally using Sheep as a Model for Cell and Gene Delivery

    Science.gov (United States)

    Porada, Christopher D.; Almeida-Porada, Graça

    2012-01-01

    Hemophilia A represents the most common inheritable deficiency of the coagulation proteins. Current state-of- the-art treatment consists of frequent prophylactic infusions of plasma-derived or recombinant FVIII protein to maintain hemostasis, and has greatly increased life expectancy and quality of life for many hemophilia A patients. This treatment approach is, however, far from ideal, due to the need for lifelong intravenous infusions, the high treatment cost, and the fact that it is unavailable to a large percentage of the world’s hemophiliacs. There is thus a need for novel treatments that can promise long-term or permanent correction. In contrast to existing protein based therapeutics, gene therapy offers to provide a permanent cure following few, or even a single, treatment. In the present paper, we review ongoing work towards this end, focusing on studies we have performed in a large animal model. Some of the key topics covered in this review include the unique opportunities sheep offer as a model system, the re-establishment and clinical and molecular characterization of a line of sheep with severe hemophilia A, the advantages and feasibility of treating a disease like hemophilia A in utero, and the use of Mesenchymal Stem Cells (MSC) as cellular delivery vehicles for the FVIII gene. The review finishes with a brief discussion of our recent success correcting ovine hemophilia A with a postnatal transplant with gene-modified MSC, and the limitations of this approach that remain to be overcome. PMID:23264887

  3. New developments in the management of moderate-to-severe hemophilia B

    Directory of Open Access Journals (Sweden)

    Nazeef M

    2016-04-01

    Full Text Available Moniba Nazeef,1,2 John P Sheehan1,2 1Department of Medicine, Division of Hematology/Oncology, 2UW Carbone Cancer Center, University of Wisconsin School of Medicine and Public Health, Madison, WI, USA Abstract: Hemophilia B is an X-linked genetic deficiency of coagulation factor IX (FIX activity associated with recurrent deep tissue and joint bleeding that may lead to long-term disability. FIX replacement therapy using plasma-derived protein or recombinant protein has significantly reduced bleeding and disability from hemophilia B, particularly when used in a prophylactic fashion. Although modern factor replacement has excellent efficacy and safety, barriers to the broader use of prophylaxis remain, including the need for intravenous (IV access, frequent dosing, variability in individual pharmacokinetics, and cost. To overcome the requirement for frequent factor dosing, novel forms of recombinant FIX have been developed that possess extended terminal half-lives. Two of these products (FIXFc and rIX-FP represent fusion proteins with the immunoglobulin G1 (IgG1 Fc domain and albumin, respectively, resulting in proteins that are recycled in vivo by the neonatal Fc receptor. The third product has undergone site-specific PEGylation on the activation peptide of FIX, similarly resulting in a long-lived FIX form. Clinical trials in previously treated hemophilia B patients have demonstrated excellent efficacy and confirmed less-frequent dosing requirements for the extended half-life forms. However, gaps in knowledge remain with regard to the risk of inhibitor formation and allergic reactions in previously untreated patient populations, safety in elderly patients with hemophilia, effects on in vivo FIX distribution, and cost-effectiveness. Additional strategies designed to rebalance hemostasis in hemophilia patients include monoclonal-antibody-mediated inhibition of tissue factor pathway inhibitor activity and siRNA-mediated reduction in antithrombin

  4. Evaluation of transfusion-related complications along with estimation of inhibitors in patients with hemophilia: A pilot study from a single center

    Directory of Open Access Journals (Sweden)

    Anju Dubey

    2013-01-01

    Full Text Available Background: Apart from inhibitor development in patients with hemophilia (PWH the old problems of blood borne viral infections and red cell alloimmunization still persist in PWH from developing countries. This study was planned to detect the presence of inhibitors in our PWH and to determine the presence of transfusion transmitted infections (TTI markers and clinically significant red cell alloantibodies in these patients. Materials and Methods: One hundred fourteen PWH were screened for various laboratory tests. Screening for inhibitors was done by mixing study. Blood grouping, TTI testing and red cell alloantibody detection were done as per the departmental standard operating procedures. Results: Out of 114 patients evaluated 98(86% had hemophilia A and remaining 16(14% had hemophilia B. Five (5.1% patients of hemophilia A were positive on inhibitor screening. On Bethesda assay, one patient was high responder (14.4 BU/ml and rest 4 were low responders (<5 BU/ml. Overall, 19 PWH were positive for TTI markers and two had clinically significant red cell alloantibody (anti-E and anti-Jk b . Conclusion: This is probably first comprehensive study from our state on laboratory testing in PWH. The specialty of Transfusion Medicine can be a core part of hemophilia care. The overall prevalence of inhibitors in our hemophilia A patients was 5.1%, which is less as compared to majority of published studies.

  5. Progress and challenges in the development of a cell-based therapy for hemophilia A.

    Science.gov (United States)

    Fomin, M E; Togarrati, P P; Muench, M O

    2014-12-01

    Hemophilia A results from an insufficiency of factor VIII (FVIII). Although replacement therapy with plasma-derived or recombinant FVIII is a life-saving therapy for hemophilia A patients, such therapy is a life-long treatment rather than a cure for the disease. In this review, we discuss the possibilities, progress, and challenges that remain in the development of a cell-based cure for hemophilia A. The success of cell therapy depends on the type and availability of donor cells, the age of the host and method of transplantation, and the levels of engraftment and production of FVIII by the graft. Early therapy, possibly even prenatal transplantation, may yield the highest levels of engraftment by avoiding immunological rejection of the graft. Potential cell sources of FVIII include a specialized subset of endothelial cells known as liver sinusoidal endothelial cells (LSECs) present in the adult and fetal liver, or patient-specific endothelial cells derived from induced pluripotent stem cells that have undergone gene editing to produce FVIII. Achieving sufficient engraftment of transplanted LSECs is one of the obstacles to successful cell therapy for hemophilia A. We discuss recent results from transplants performed in animals that show production of functional and clinically relevant levels of FVIII obtained from donor LSECs. Hence, the possibility of treating hemophilia A can be envisioned through persistent production of FVIII from transplanted donor cells derived from a number of potential cell sources or through creation of donor endothelial cells from patient-specific induced pluripotent stem cells. © 2014 International Society on Thrombosis and Haemostasis.

  6. Hemofilia e anestesia Hemofilia y anestesia Hemophilia and anesthesia

    Directory of Open Access Journals (Sweden)

    Rafael Py Gonçalves Flores

    2004-12-01

    equipo multidisciplinar. CONTENIDO: Están definidas las características de la hemofilia en cuanto a la clínica y a los hallazgos laboratoriales, la terapia farmacológica actual y las atenciones con el manoseo del paciente hemofílico en el intra-operatorio. CONCLUSIONES: El manoseo del paciente hemofílico fue perfeccionado. Como consecuencia de ese avance, se percibe la importancia y la necesidad de que nuevos conocimientos, principalmente con relación a la terapia de reposición, sean dominados por hematologistas y por todo el cuerpo clínico-quirúrgico. Cuando pacientes hemofílicos se someten a procedimientos quirúrgicos, es necesario el envolvimiento de un equipo multidisciplinar de la cual el anestesiologista hace parte. A este profesional cabe la responsabilidad de tomar las conductas más adecuadas frente al paciente hemofílico, participando y comunicándose activamente con los miembros del equipo multidisciplinar.BACKGROUND AND OBJECTIVES: For more than 25 years, there has been no discussion in the Brazilian Journal of Anesthesiology about hemophiliac patients' perioperative management. Hemophilia has been described as a disease from the early 19th Century, but still today there are many hemophilia-related breakthroughs. This review aimed at pointing hemophilia patient-related perioperative care, focusing on hemophilia A management and the role of the anesthesiologist as part of the multidisciplinary team. CONTENTS: Hemophilia features are described in terms of clinical and laboratory findings, current pharmacological therapy and intraoperative care of hemophilia patients. CONCLUSIONS: Hemophiliac patients management has improved. As a consequence of this advance, it is important that new knowledge, especially related to replacement therapy, be mastered not only by hematologists but also by the whole clinical-surgical team. A multidisciplinary team of which the anesthesiologist is part has to be involved when hemophilia patients are submitted to surgical

  7. Acquired hemophilia A: Updated review of evidence and treatment guidance.

    Science.gov (United States)

    Kruse-Jarres, Rebecca; Kempton, Christine L; Baudo, Francesco; Collins, Peter W; Knoebl, Paul; Leissinger, Cindy A; Tiede, Andreas; Kessler, Craig M

    2017-07-01

    Acquired hemophilia A (AHA) is a rare disease resulting from autoantibodies (inhibitors) against endogenous factor VIII (FVIII) that leads to bleeding, which is often spontaneous and severe. AHA tends to occur in elderly patients with comorbidities and is associated with high mortality risk from underlying comorbidities, bleeding, or treatment complications. Treatment, which consists of hemostatic management and eradication of the inhibitors, can be challenging to manage. Few data are available to guide the management of AHA-related bleeding and eradication of the disease-causing antibodies. Endorsed by the Hemostasis and Thrombosis Research Society of North America, an international panel of experts in AHA analyzed key questions, reviewed the literature, weighed the evidence and formed a consensus to update existing guidelines. AHA is likely underdiagnosed and misdiagnosed in real-world clinical practice. Recommendations for the management of AHA are summarized here based on the available data, integrated with the clinical experience of panel participants. © 2017 Wiley Periodicals, Inc.

  8. Current and future prospects for hemophilia gene therapy.

    Science.gov (United States)

    Ward, Peter; Walsh, Christopher E

    2016-07-01

    Here we review the recent literature on Hemophilia gene transfer/therapy. Gene therapy is one of several new technologies being developed as a treatment for bleeding disorders. We will discuss current and pending clinical efforts and attempt to relate how the field is trending. In doing so, we will focus on the use of recombinant Adeno-associated viral (rAAV) vector-mediated gene transfer since all currently active trials are using this vector. Recent exciting results embody nearly 20 years of preclinical and translational research. After several early clinical attempts, therapeutic factor levels that can now be achieved reflect several modifications of the original vectors. Patterns of results are slowly starting to emerge as different AAV vectors are being tested. As with any new technology, there are drawbacks, and the potential for immune/inflammatory and oncogenic risks have emerged and will be discussed.

  9. Assessment of the frequency of regulatory T cells (CD4+CD25+CD127-) in children with hemophilia A: relation to factor VIII inhibitors and disease severity.

    Science.gov (United States)

    El-Asrar, Mohamed Abo; Hamed, Ahmed El-Saeed; Darwish, Yasser Wagih; Ismail, Eman Abdel Rahman; Ismail, Noha Ali

    2016-01-01

    A rapidly growing evidence showed that regulatory T cells (Tregs) play a crucial role in tolerance to coagulation factors and may be involved in the pathogenesis of inhibitor formation in patients with hemophilia. We determined the percentage of Tregs (CD4CD25CD127) in 45 children with hemophilia A compared with 45 healthy controls, and assessed their relation to the clinical characteristics of patients and factor VIII (FVIII) inhibitors. Patients were studied stressing on frequency of bleeding attacks, joint pain, history of viral hepatitis, and the received therapy (FVIII precipitate/cryotherapy). FVIII activity and FVIII inhibitors were assessed with flow cytometric analysis of CD4CD25CD127 Tregs. According to residual FVIII activity levels, 30 patients (66.7%) had mild/moderate hemophilia A, whereas 15 (33.3%) patients had severe hemophilia A. The frequency of Tregs was significantly lower among all patients with hemophilia A compared with controls (2.59 ± 1.1 versus 3.73 ± 1.12%; P = 0.002). Tregs were significantly decreased among patients with FVIII inhibitors compared with the inhibitor-negative group (P hemophilia A had lower Tregs levels than those without (P = 0.34 and P = 0.011, respectively). A significant positive correlation was found between the percentage of Tregs and FVIII among hemophilia A patients. ROC curve analysis revealed that the cut-off value of Tregs at 1.91% could differentiate patients with and without FVIII inhibitors, with a sensitivity of 100% and a specificity of 91.3%. We suggest that alteration in the frequency of Tregs in young patients with hemophilia A may contribute to inhibitor formation and disease severity.

  10. Effects of recombinant human prothrombin on thrombin generation in plasma from patients with hemophilia A and B.

    Science.gov (United States)

    Hansson, K M; Gustafsson, D; Skärby, T; Frison, L; Berntorp, E

    2015-07-01

    The present study was carried out to investigate the impact of FII levels, and their increase, on the hemostatic potential in plasma from hemophilia A and B patients with and without inhibitors. Recombinant human factor (F) II (rhFII) was added ex vivo to plasma from 68 patients with hemophilia A and B, with or without inhibitors. The hemostatic potential as measured by thrombin generation (calibrated automated thrombogram [CAT]) was focused on the endogenous thrombin potential (ETP) as it has been shown to correlate with the clinical phenotype of bleeding in hemophilia patients and has also been used to guide bypassing therapy in hemophilia patients with inhibitors before elective surgery. The factor eight inhibitor bypassing agent (FEIBA(®) ) was used as a reference to the clinical situation. The study shows that rhFII concentration-dependently increased ETP by a similar magnitude in hemophilia A and B, both with and without inhibitors. Compared with FEIBA, rhFII showed a shallower concentration-response curve. In both types of hemophilia 100 mg L(-1) of rhFII roughly doubled the ETP. A corresponding response was obtained by 0.5 U mL(-1) of FEIBA. These data support the theory that FII is one of the major components responsible for the efficacy of FEIBA. The data also indicate that rhFII may be useful, alone or in combination with other coagulation factors, in some of the conditions for which FEIBA is used today, although more data are needed to substantiate this. © 2015 International Society on Thrombosis and Haemostasis.

  11. In non-severe hemophilia A the risk of inhibitor after intensive factor treatment is greater in older patients: a case–control study

    Science.gov (United States)

    KEMPTON, C. L.; SOUCIE, J. M.; MILLER, C. H.; HOOPER, C.; ESCOBAR, M. A.; COHEN, A. J.; KEY, N. S.; THOMPSON, A. R.; ABSHIRE, T. C.

    2013-01-01

    Summary 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 ≥ 30 years of age compared with those hemophilia A varies with age, but does not vary significantly with lifetime FVIII exposure days: two features distinct from severe hemophilia A. PMID:20704648

  12. Developments in the treatment of hemophilia B: focus on emerging gene therapy

    Directory of Open Access Journals (Sweden)

    Cancio MI

    2013-10-01

    Full Text Available Maria I Cancio,1 Ulrike M Reiss,2 Amit C Nathwani,3 Andrew M Davidoff,4 John T Gray2 1Department of Hematology-Oncology, 2Department of Hematology, St Jude Children’s Research Hospital, Memphis, TN, USA; 3Department of Haematology, University College London Cancer Institute, London, UK; 4Department of Surgery, St Jude Children’s Research Hospital, Memphis, TN, USA Abstract: Hemophilia B is a genetic disorder that is characterized by a deficiency of clotting factor IX (FIX and excessive bleeding. Advanced understanding of the pathophysiology of the disease has led to the development of improved treatment strategies that aim to minimize the acute and long-term complications of the disease. Patients with hemophilia B are ideal candidates for gene therapy, mostly because a small increase in protein production can lead to significantly decreased bleeding diathesis. Although human clotting FIX was cloned and sequenced over 30 years ago, progress toward achieving real success in human clinical trials has been slow, with long-term, therapeutically relevant gene expression only achieved in one trial published in 2011. The history of this extensive research effort has revealed the importance of the interactions between gene therapy vectors and multiple arms of the host immune system at multiple stages of the transduction process. Different viral vector systems each have unique properties that influence their ability to deliver genes to different tissues, and the data generated in several clinical trials testing different vectors for hemophilia have guided our understanding toward development of optimal configurations for treating hemophilia B. The recent clinical success implementing a novel adeno-associated virus vector demonstrated sufficient FIX expression in patients to convert a severe hemophilia phenotype to mild, an achievement which has the potential to profoundly alter the impact of this disease on human society. Continued research should

  13. Mesenchymal stem cell treatment for hemophilia: a review of current knowledge.

    Science.gov (United States)

    Sokal, E M; Lombard, C; Mazza, G

    2015-06-01

    Hemophilia remains a non-curative disease, and patients are constrained to undergo repeated injections of clotting factors. In contrast, the sustained production of endogenous factors VIII (FVIII) or IX (FIX) by the patient's own cells could represent a curative treatment. Gene therapy has thus provided new hope for these patients. However, the issues surrounding the durability of expression and immune responses against gene transfer vectors remain. Cell therapy, involving stem cells expanded in vitro, can provide de novo protein synthesis and, if implanted successfully, could induce a steady-state production of low quantities of factors, which may keep the patient above the level required to prevent spontaneous bleeding. Liver-derived stem cells are already being assessed in clinical trials for inborn errors of metabolism and, in view of their capacity to produce FVIII and FIX in cell culture, they are now also being considered for clinical application in hemophilia patients. © 2015 International Society on Thrombosis and Haemostasis.

  14. Postpartum Acquired Hemophilia. A Case Report

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    María Antonia Cabezas Poblet

    2012-09-01

    Full Text Available Periparturient hemorrhages are the leading cause of extremely serious maternal morbidity and maternal death in Cuba and the world. Acquired Hemophilia A is a rare bleeding disorder characterized by the presence of antibodies against circulating factor VIII (FVIII. We present the case of a 36 years old pregnant woman with term pregnancy and vaginal delivery that suffers from hemorrhagic manifestations in the immediate postpartum secondary to raffia hematoma, requiring blood transfusion. Then she presents a bruise in the right upper limb secondary to stroke that requires surgical repair. The postpartum torpid evolution characterized by sustained bleeding raffia and the surgically treated arm, makes us suspect of the presence of a blood disorder. We observed a decrease in the FVIII factor, which involves the diagnosis of acquired hemophilia and requires treatment with recombinant VIIa factor (FVIIar concentrate and cyclophosphamide. Posterior evolution was favorable. The patient was discharged without sequelae.

  15. Emerging and future therapies for hemophilia

    OpenAIRE

    Carr, Marcus E; Tortella, Bartholomew J

    2015-01-01

    Marcus E Carr,1,2 Bartholomew J Tortella3,4 1Robert Wood Johnson Medical School, Rutgers University, New Brunswick, NJ, 2Worldwide Research and Development, Pfizer, Inc., Cambridge, MA, 3Drexel University College of Medicine, Philadelphia, PA, 4Global Innovative Pharma, Pfizer, Inc., Collegeville, PA, USA Abstract: The evolution of care in hemophilia is a remarkable story. Over the last 60 years, advances in protein purification, protein chemistry, donor screening, viral inactivation, gene s...

  16. Impact of mild to severe hemophilia on engagement in recreational activities by US men, women, and children with hemophilia B: The Bridging Hemophilia B Experiences, Results and Opportunities into Solutions (B-HERO-S) study.

    Science.gov (United States)

    Baumann, Kimberly; Hernandez, Grace; Witkop, Michelle; Peltier, Skye; Dunn, Spencer; Cutter, Susan; Frick, Neil; Haugstad, Kimberly; Guelcher, Christine; Frey, Mary Jane; Rotellini, Dawn; Clark, David B; Iyer, Neeraj N; Cooper, David L

    2017-04-01

    The psychosocial impact of hemophilia on activities was recently investigated in the Hemophilia Experiences, Results and Opportunities (HERO) study (675 people with hemophilia and 561 caregivers of children with hemophilia in 10 countries). The impact of hemophilia B may not be accurately reflected in the HERO results, as ~75% of respondents described issues affecting males with hemophilia A. To address the needs of this population, the Bridging Hemophilia B Experiences, Results and Opportunities Into Solutions (B-HERO-S) was developed as a pilot study in the United States in collaboration with the hemophilia community. The analysis reported here assessed engagement in recreational activities and changes to treatment regimens around activities as reported by 299 adults with hemophilia B and 150 caregivers of children with hemophilia B. Nearly all adults with hemophilia B (98%) experienced a negative impact on their participation in recreational activities due to hemophilia-related issues, and most caregivers (90%) reported that hemophilia B had a negative impact on their child's engagement in recreational activities. One of the main reasons identified for discontinuing past activities was the risk of bruising or bleeding (adults/children with hemophilia B, 49%/41%). In particular, adults with hemophilia B reported a history of activity-related bleeding, and most adults decreased their participation in high-risk activities as they aged. Substantial percentages of adults and children with hemophilia B (including mild/moderate severity) altered their treatment regimens to accommodate planned activities. These findings may help inform guidelines for individualizing treatment regimens around participation in recreational activities based on hemophilia severity, baseline factor level, and activity risk and intensity. © 2017 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd.

  17. Optimization of prophylaxis for hemophilia A.

    Directory of Open Access Journals (Sweden)

    Robert D Herbert

    Full Text Available Prophylactic injections of factor VIII reduce the incidence of bleeds and slow the development of joint damage in people with hemophilia. The aim of this study was to identify optimal person-specific prophylaxis regimens for children with hemophilia A.Analytic and numerical methods were used to identify prophylaxis regimens which maximize the time for which plasma factor VIII concentrations exceed a threshold, maximize the lowest plasma factor VIII concentrations, and minimize risk of bleeds.It was demonstrated analytically that, for any injection schedule, the regimen that maximizes the lowest factor VIII concentration involves sharing doses between injections so that all of the trough concentrations in a prophylaxis cycle are equal. Numerical methods were used to identify optimal prophylaxis schedules and explore the trade-offs between efficacy and acceptability of different prophylaxis regimens. The prophylaxis regimen which minimizes risk of bleeds depends on the person's pattern of physical activity and may differ greatly from prophylaxis regimens that optimize pharmacokinetic parameters. Prophylaxis regimens which minimize risk of bleeds also differ from prophylaxis regimens that are typically prescribed. Predictions about which regimen is optimal are sensitive to estimates of the effects on risk of bleeds of factor VIII concentration and physical activity.The methods described here can be used to identify optimal, person-specific prophylaxis regimens for children with hemophilia A.

  18. Optimization of prophylaxis for hemophilia A.

    Science.gov (United States)

    Herbert, Robert D; Broderick, Carolyn R; Barnes, Chris; Billot, Laurent; Zhou, Albert; Latimer, Jane

    2018-01-01

    Prophylactic injections of factor VIII reduce the incidence of bleeds and slow the development of joint damage in people with hemophilia. The aim of this study was to identify optimal person-specific prophylaxis regimens for children with hemophilia A. Analytic and numerical methods were used to identify prophylaxis regimens which maximize the time for which plasma factor VIII concentrations exceed a threshold, maximize the lowest plasma factor VIII concentrations, and minimize risk of bleeds. It was demonstrated analytically that, for any injection schedule, the regimen that maximizes the lowest factor VIII concentration involves sharing doses between injections so that all of the trough concentrations in a prophylaxis cycle are equal. Numerical methods were used to identify optimal prophylaxis schedules and explore the trade-offs between efficacy and acceptability of different prophylaxis regimens. The prophylaxis regimen which minimizes risk of bleeds depends on the person's pattern of physical activity and may differ greatly from prophylaxis regimens that optimize pharmacokinetic parameters. Prophylaxis regimens which minimize risk of bleeds also differ from prophylaxis regimens that are typically prescribed. Predictions about which regimen is optimal are sensitive to estimates of the effects on risk of bleeds of factor VIII concentration and physical activity. The methods described here can be used to identify optimal, person-specific prophylaxis regimens for children with hemophilia A.

  19. Acute Compartment Syndrome after an Olecranon Fracture in a Patient with Mild Hemophilia B

    OpenAIRE

    Reynolds, John M; Christophersen, Christy; Mulcahey, Mary K

    2017-01-01

    Introduction: Compartment syndrome is a serious condition characterized by compartmental pressures within 20 mmHg of diastolic blood pressure, or clinical signs of pain, paresthesia, pallor, and lack of pulses. Often a surgical intervention is necessary. Increased surveillance for compartment syndrome is important when a patient with a bleeding disorder sustains a traumatic injury. Case Report: We present a case of forearm compartment syndrome in a patient with mild hemophilia B who sustained...

  20. Rituximab as first-line treatment for the management of adult patients with non-severe hemophilia A and inhibitors.

    Science.gov (United States)

    Lim, M Y; Nielsen, B; Lee, K; Kasthuri, R S; Key, N S; Ma, A D

    2014-06-01

    The role of immunosuppression in the management of patients with congenital hemophilia and inhibitors is uncertain. The use of rituximab has been limited to case reports and case series. In most reports, rituximab was used as second-line or third-line treatment following failure of conventional immune tolerance induction therapy, and more commonly in pediatric patients. The objective of this study was to describe our experience with rituximab for the eradication of factor VIII inhibitors in adult patients with non-severe hemophilia A. We retrospectively reviewed the medical records of adult patients with non-severe hemophilia A and a diagnosis of FVIII inhibitor treated with rituximab (four weekly doses of 375 mg m(-2) ) as first-line treatment at our hemophilia center. We identified nine consecutive adult patients with hemophilia A (moderate, n = 5; mild, n = 4) at our institution between 2000 and 2013, with a median age of 54 years (range, 24-77 years) at the time of inhibitor diagnosis. No patient received concomitant immune tolerance induction therapy. All nine patients had successful eradication of FVIII inhibitors. The median time from the first dose of rituximab to a clinical response was 95 days (range, 12-278 days). The median follow-up was 56 months (range, 13-139 months). Following inhibitor eradication, eight patients were rechallenged with FVIII concentrates. Two patients developed inhibitor recurrence associated with surgery. This case series demonstrates that rituximab is a useful first-line treatment to achieve sustained inhibitor eradication in adult patients with non-severe hemophilia A. © 2014 International Society on Thrombosis and Haemostasis.

  1. The current state of adverse event reporting in hemophilia

    NARCIS (Netherlands)

    van Vulpen, Lize F D|info:eu-repo/dai/nl/413986330; Saccullo, Giorgia; Iorio, Alfonso; Makris, Michael

    INTRODUCTION: Replacement of the missing clotting factor is the mainstay of hemophilia treatment. Whilst historically many hemophilia patients were infected with blood-borne viruses transmitted via plasma-derived products, nowadays the formation of alloantibodies against the missing clotting factor

  2. Treatment of hemophilia: A qualitative study of mothers' perspectives.

    Science.gov (United States)

    von der Lippe, Charlotte; Frich, Jan C; Harris, Anna; Solbraekke, Kari Nyheim

    2017-01-01

    In Norway, boys with hemophilia usually begin treatment after their first bleeding episode. Boys with severe hemophilia usually start prophylactic treatment around 18-24 months. Health professionals administer factor concentrate initially, but when boys are around 4 years old most parents start treating their children at home. There is a lack of research on how parents, and especially how carrier mothers, experience the medical treatment for their sons' hemophilia. Our aim was to investigate how carrier mothers experience this treatment in the hospital setting and at home. In this qualitative study, we interviewed 16 mothers of boys or men with hemophilia A or B. Data were collected via semistructured interviews and analyzed using an inductive thematic analytical approach. Mothers experienced both practical and emotional challenges in relation to their sons' treatment, and repeated venipuncture was especially difficult emotionally. Parents preferred home treatment to hospital treatment because it was less time-consuming, less disruptive to family life, and provided a greater sense of control. Encountering healthcare professionals who were unfamiliar with hemophilia was a second major stress factor, especially when parents felt that health professionals lacked competence and were unwilling to seek advice. While home treatment for hemophilia enables freedom, flexibility, and autonomy for the boys as well as for the family, mothers may experience treatment of hemophilia as a burden. Health professionals should provide tailored practical and emotional support to parents by probing into their experiences with treating their sons' hemophilia. © 2016 Wiley Periodicals, Inc.

  3. Hemophilia and Sports: Guidelines for Participation. Case Report.

    Science.gov (United States)

    McLain, Larry G.; Heldrich, Fred T.

    1990-01-01

    Presents a case report of a 15-year-old boy with severe hemophilia who played soccer 1 school year but was denied continued participation following another screening examination. Before deciding about participation, physicians must assess the type and severity of hemophilia and risk factors for injury. Appropriate sports for hemophiliacs are…

  4. The Impact of HIV Infection on the Hemophilia Community.

    Science.gov (United States)

    Whitney, Christopher K.

    1989-01-01

    The hemophilia community has been deeply affected by the catastrophe of AIDS (Acquired Immune Deficiency Syndrome). The use of blood products that had first restored the potential for normal survival now bring the threat of AIDS infection and fear and discrimination from others. Strong leadership has come from the National Hemophilia Foundation.…

  5. Targeting anticoagulant protein S to improve hemostasis in hemophilia.

    Science.gov (United States)

    Prince, Raja; Bologna, Luca; Manetti, Mirko; Melchiorre, Daniela; Rosa, Irene; Dewarrat, Natacha; Suardi, Silvia; Amini, Poorya; Fernández, José A; Burnier, Laurent; Quarroz, Claudia; Reina Caro, Maria Desiré; Matsumura, Yasuhiro; Kremer Hovinga, Johanna A; Griffin, John H; Simon, Hans-Uwe; Ibba-Manneschi, Lidia; Saller, François; Calzavarini, Sara; Angelillo-Scherrer, Anne

    2018-01-09

    Improved treatments are needed for hemophilia A and B, bleeding disorders affecting 400,000 people worldwide. We investigated whether targeting protein S could promote hemostasis in hemophilia by re-balancing coagulation. Protein S is an anticoagulant acting as cofactor for activated protein C and tissue factor pathway inhibitor (TFPI). This dual role makes PS a key regulator of thrombin generation. Here, we report that targeting protein S rebalances coagulation in hemophilia. Protein S gene targeting in hemophilic mice protected them against bleeding, especially when intra-articular. Mechanistically, these mice displayed increased thrombin generation, resistance to activated protein C and TFPI, and improved fibrin network. Blocking protein S in plasma of hemophilia patients normalized in vitro thrombin generation. Both protein S and TFPIα were detected in hemophilic mice joints. Protein S and TFPI expression was stronger in joints of hemophilia A than hemophilia B patients when receiving on demand therapy, e.g., during a bleeding episode. In contrast, protein S and TFPI expression was decreased in hemophilia A patients receiving prophylaxis with coagulation factor concentrates, and comparable to osteoarthritis patients. These results establish protein S inhibition as both controller of coagulation and potential therapeutic target in hemophilia. The murine protein S silencing RNA approach that we successfully used in hemophilic mice might constitute a new therapeutic concept for hemophilic patients. Copyright © 2018 American Society of Hematology.

  6. Antihemophilic factor (recombinant plasma/albumin-free method for the management and prevention of bleeding episodes in patients with hemophilia A

    Directory of Open Access Journals (Sweden)

    Steven Pipe

    2009-02-01

    Full Text Available Steven PipeDepartment of Pediatrics and Communicable Diseases, University of Michigan, Ann Arbor, MI, USAAbstract: Hemophilia is a rare genetic bleeding disorder that, if not adequately controlled, is associated with life-threatening bleeding events and serious and costly complications, primarily from joint damage. The advent of effective clotting factor replacement therapy for patients with hemophilia is considered one of the foremost medical advances of the 20th century. The last 3 decades of experience in hemophilia care have witnessed the effectiveness of the care of patients with hemophilia within specialized comprehensive care centers, advances in factor replacement therapies, the benefits of prophylaxis over on-demand replacement therapy, and the role of aggressive management of joint disease to prevent dysfunction. Ongoing challenges, including the management of inhibitors to factor therapies and the consequences of thousands of patients with hemophilia becoming infected with human immunodeficiency virus and hepatitis C virus in the 1980s from contaminated plasma-derived factor concentrates, have highlighted the need for vigilance with respect to clotting factor product safety, access to care, and a full complement of choice of factor replacement therapies. Advate® (antihemophilic factor [recombinant] plasma/albumin-free method [rAHF-PFM] is the first recombinant factor VIII therapy manufactured without human or animal protein additives to eliminate the risk of pathogen transmission that could be carried by these additives. Preclinical studies established bioequivalence with recombinant antihemophilic factor (Recombinate®, a product with 16 years of clinical experience. Currently licensed in 44 countries worldwide, rAHF-PFM has over 7 years of clinical research within 5 global studies supporting its safety and efficacy in the treatment of patients with hemophilia A.Keywords: factor VIII, hemophilia A, recombinant proteins, clinical

  7. Myelofibrosis and acquired hemophilia A: a case report.

    Science.gov (United States)

    Wrobel, Marie; Comio, Emilie; Gay, Valerie; Baroudi, Noureddine; Meyer, Pascal; Chuniaud-Louche, Christine; Hacini, Maya; Pica, Gian Matteo

    2016-05-07

    Myelofibrosis and acquired hemophilia A is a rare association. To the best of our knowledge only one case of myelofibrosis and acquired hemophilia A has been previously described. A 66-year-old Caucasian man diagnosed with myelofibrosis evolving in acute myeloid leukemia was referred to us for postoperative bleeding. Hemostatic studies showed prolonged activated partial thromboplastin time, decreased factor VIII coagulation, and a high factor VIII inhibitor titer; these findings led to a diagnosis of acquired hemophilia A for which he was treated with methylprednisolone and recombinant activated factor VII on admission. Due to a lack of response he was subsequently treated with rituximab combined with activated prothrombin complex concentrates. Furthermore, he received azacytidine to treat the underlying hematological malignancies. Immunosuppressive rituximab therapy resolved acquired hemophilia A with marked efficacy. Rapid and accurate diagnosis, effective hemostatic therapy, and timely treatment for underlying disease are important in the management of acquired hemophilia A secondary to hematological malignancy.

  8. Innovative Approaches for Immune Tolerance to Factor VIII in the Treatment of Hemophilia A

    Directory of Open Access Journals (Sweden)

    Alexandra Sherman

    2017-11-01

    Full Text Available Hemophilia A (coagulation factor VIII deficiency is a debilitating genetic disorder that is primarily treated with intravenous replacement therapy. Despite a variety of factor VIII protein formulations available, the risk of developing anti-dug antibodies (“inhibitors” remains. Overall, 20–30% of patients with severe disease develop inhibitors. Current clinical immune tolerance induction protocols to eliminate inhibitors are not effective in all patients, and there are no prophylactic protocols to prevent the immune response. New experimental therapies, such as gene and cell therapies, show promising results in pre-clinical studies in animal models of hemophilia. Examples include hepatic gene transfer with viral vectors, genetically engineered regulatory T cells (Treg, in vivo Treg induction using immune modulatory drugs, and maternal antigen transfer. Furthermore, an oral tolerance protocol is being developed based on transgenic lettuce plants, which suppressed inhibitor formation in hemophilic mice and dogs. Hopefully, some of these innovative approaches will reduce the risk of and/or more effectively eliminate inhibitor formation in future treatment of hemophilia A.

  9. Innovative Approaches for Immune Tolerance to Factor VIII in the Treatment of Hemophilia A

    Science.gov (United States)

    Sherman, Alexandra; Biswas, Moanaro; Herzog, Roland W.

    2017-01-01

    Hemophilia A (coagulation factor VIII deficiency) is a debilitating genetic disorder that is primarily treated with intravenous replacement therapy. Despite a variety of factor VIII protein formulations available, the risk of developing anti-dug antibodies (“inhibitors”) remains. Overall, 20–30% of patients with severe disease develop inhibitors. Current clinical immune tolerance induction protocols to eliminate inhibitors are not effective in all patients, and there are no prophylactic protocols to prevent the immune response. New experimental therapies, such as gene and cell therapies, show promising results in pre-clinical studies in animal models of hemophilia. Examples include hepatic gene transfer with viral vectors, genetically engineered regulatory T cells (Treg), in vivo Treg induction using immune modulatory drugs, and maternal antigen transfer. Furthermore, an oral tolerance protocol is being developed based on transgenic lettuce plants, which suppressed inhibitor formation in hemophilic mice and dogs. Hopefully, some of these innovative approaches will reduce the risk of and/or more effectively eliminate inhibitor formation in future treatment of hemophilia A. PMID:29225598

  10. Gene therapy for hemophilia "A" and "B": efficacy, safety and immune consequences.

    Science.gov (United States)

    Chuah, M; Vandendriessche, T

    2007-01-01

    The first successful gene therapy trials for the treatment of hereditary disorders underscore the potential of gene therapy to combat disease and alleviate human suffering. The development of gene therapy for hemophilia is not only a research priority in its own right but also serves as an ideal trailblazer for many different diseases. Significant progress has recently been made in the development of gene therapy for the treatment of hemophilia A and B. Long-term therapeutic levels of factor VIII and IX could be expressed following gene therapy in hemophilic mice, stably correcting the bleeding diathesis. These advances parallel the development of improved gene delivery systems. The induction of neutralizing antibodies (inhibitors) to the clotting factors could potentially preclude stable phenotypic correction. The risk of inhibitor formation varied, depending at least in part on the type of vector used and its in vivo tropism. We also demonstrated that the risk of immune responses to the vector particles, the clotting factors and/or transduced cells can be reduced by using vectors that only minimally interact with antigen presenting cells. In hemophilic mice, robust and stable clotting factor expression levels were achieved using adeno-associated viral vectors based on the newly disovered serotypes AAV8 and AAV9 which can efficient deliver the clotting factor genes into hepatocytes without triggering any inflammatory responses or adverse events. Pre-clinical studies in large animal models will be initiated to further validate these improved AAV vectors to ultimately justify a clinical trial in patients with severe hemophilia.

  11. Bioengineered coagulation factor VIII enables long-term correction of murine hemophilia A following liver-directed adeno-associated viral vector delivery

    Directory of Open Access Journals (Sweden)

    Harrison C Brown

    2014-01-01

    Full Text Available Clinical data support the feasibility and safety of adeno-associated viral (AAV vectors in gene therapy applications. Despite several clinical trials of AAV-based gene transfer for hemophilia B, a unique set of obstacles impede the development of a similar approach for hemophilia A. These include (i the size of the factor VIII (fVIII transgene, (ii humoral immune responses to fVIII, (iii inefficient biosynthesis of human fVIII, and (iv AAV vector immunity. Through bioengineering approaches, a novel fVIII molecule, designated ET3, was developed and shown to improve biosynthetic efficiency 10- to 100-fold. In this study, the utility of ET3 was assessed in the context of liver-directed, AAV-mediated gene transfer into hemophilia A mice. Due to the large size of the expression cassette, AAV-ET3 genomes packaged into viral particles as partial genome fragments. Despite this potential limitation, a single peripheral vein administration of AAV-ET3 into immune-competent hemophilia A mice resulted in correction of the fVIII deficiency at lower vector doses than previously reported for similarly oversized AAV-fVIII vectors. Therefore, ET3 appears to improve vector potency and mitigate at least one of the critical barriers to AAV-based clinical gene therapy for hemophilia A.

  12. Acquired hemophilia a in a patient with lumbar disc herniation: a case report and review of the literature.

    Science.gov (United States)

    Li, Jingfeng; Shen, Hongxing; Hou, Tiesheng; Li, Ming; He, Shisheng; Zhang, Hailong

    2009-04-15

    To summarize the clinical manifestations and treatment of acquired hemophilia A in a patient with lumbar disc herniation. Acquired hemophilia A is a rare but potentially life-threatening hemorrhagic disorder. It is caused by the development of autoantibodies directed against coagulation factor VIII (F VIII) in adults or elderly patients, who do not have a personal or family history of bleeding episodes. The mortality is high if the diagnosis was missed or delays, especially after a surgery. A case was investigated retrospectively and the relevant literature was reviewed. A 59-year-old man with a 1-year history of lower back and leg pain was admitted to the hospital. He has no family medical history of hemophilia A and the routine laboratory examination did not find abnormality on blood coagulation function. He underwent decompression by laminectomy and discectomy. Seven hours after operation, it was found that the incision was oozing profusely and hemoglobin was reduced gradually, though platelet count was within the normal range. He was diagnosed with acquired factor VIII (FVIII) deficiency based on a prolonged activated partial-thromboplastin time (61.0 seconds), reduced FVIII activity (4.2%), and FVIII inhibitor (8 BU). After treatment with hemodynamic stabilization and immunosuppression therapies (including transfusion of packed red blood cells, fresh frozen plasma, and cryoprecipitate) and administration of human antihemophilic globulin, corticosteroid, and cyclophosphamide, bleeding was stopped gradually. The clinical and biologic condition of the patient improved, though neurological deficit was left. Surgical operation may be a factor contributing to acquired hemophilia A, which, to our knowledge, has not been reported in the literature. Diagnosis of acquired hemophilia requires clinical acumen and any patient who presents with bleeding and a prolonged activated partial-thromboplastin time should be considered. Initial hemodynamic stabilization followed by

  13. Knee and Ankle Arthroplasty in Hemophilia.

    Science.gov (United States)

    Solimeno, Luigi Piero; Pasta, Gianluigi

    2017-11-22

    Today, major surgical procedures can be safely performed in hemophilic patients with chronic arthropathy, using available factor concentrates. In this setting, total knee replacement is considered the "gold standard", while the use of total ankle replacement is still debated. Indeed, the unsatisfactory results obtained with the previous available design of implants did not raise enthusiasm as knee or hip replacement. Recently, the introduction of new implant designs and better reported outcomes have renewed the interest in total ankle replacement in people with hemophilia. In this review, the role of replacement surgery in the treatment of chronic hemophilic arthropathy will be described.

  14. Knee and Ankle Arthroplasty in Hemophilia

    Directory of Open Access Journals (Sweden)

    Luigi Piero Solimeno

    2017-11-01

    Full Text Available Today, major surgical procedures can be safely performed in hemophilic patients with chronic arthropathy, using available factor concentrates. In this setting, total knee replacement is considered the “gold standard”, while the use of total ankle replacement is still debated. Indeed, the unsatisfactory results obtained with the previous available design of implants did not raise enthusiasm as knee or hip replacement. Recently, the introduction of new implant designs and better reported outcomes have renewed the interest in total ankle replacement in people with hemophilia. In this review, the role of replacement surgery in the treatment of chronic hemophilic arthropathy will be described.

  15. Validation of a new pediatric joint scoring system from the International Hemophilia Prophylaxis Study Group: validity of the hemophilia joint health score

    NARCIS (Netherlands)

    Feldman, Brian M.; Funk, Sharon M.; Bergstrom, Britt-Marie; Zourikian, Nichan; Hilliard, Pamela; van der Net, Janjaap; Engelbert, Raoul; Petrini, Pia; van den Berg, H. Marijke; Manco-Johnson, Marilyn J.; Rivard, Georges E.; Abad, Audrey; Blanchette, Victor S.

    2011-01-01

    Repeated hemarthrosis in hemophilia causes arthropathy with pain and dysfunction. The Hemophilia Joint Health Score (HJHS) was developed to be more sensitive for detecting arthropathy than the World Federation of Hemophilia (WFH) physical examination scale, especially for children and those using

  16. Targeting of Antithrombin in Hemophilia A or B with RNAi Therapy.

    Science.gov (United States)

    Pasi, K John; Rangarajan, Savita; Georgiev, Pencho; Mant, Tim; Creagh, Michael D; Lissitchkov, Toshko; Bevan, David; Austin, Steve; Hay, Charles R; Hegemann, Inga; Kazmi, Rashid; Chowdary, Pratima; Gercheva-Kyuchukova, Liana; Mamonov, Vasily; Timofeeva, Margarita; Soh, Chang-Heok; Garg, Pushkal; Vaishnaw, Akshay; Akinc, Akin; Sørensen, Benny; Ragni, Margaret V

    2017-08-31

    Current hemophilia treatment involves frequent intravenous infusions of clotting factors, which is associated with variable hemostatic protection, a high treatment burden, and a risk of the development of inhibitory alloantibodies. Fitusiran, an investigational RNA interference (RNAi) therapy that targets antithrombin (encoded by SERPINC1), is in development to address these and other limitations. In this phase 1 dose-escalation study, we enrolled 4 healthy volunteers and 25 participants with moderate or severe hemophilia A or B who did not have inhibitory alloantibodies. Healthy volunteers received a single subcutaneous injection of fitusiran (at a dose of 0.03 mg per kilogram of body weight) or placebo. The participants with hemophilia received three injections of fitusiran administered either once weekly (at a dose of 0.015, 0.045, or 0.075 mg per kilogram) or once monthly (at a dose of 0.225, 0.45, 0.9, or 1.8 mg per kilogram or a fixed dose of 80 mg). The study objectives were to assess the pharmacokinetic and pharmacodynamic characteristics and safety of fitusiran. No thromboembolic events were observed during the study. The most common adverse events were mild injection-site reactions. Plasma levels of fitusiran increased in a dose-dependent manner and showed no accumulation with repeated administration. The monthly regimen induced a dose-dependent mean maximum antithrombin reduction of 70 to 89% from baseline. A reduction in the antithrombin level of more than 75% from baseline resulted in median peak thrombin values at the lower end of the range observed in healthy participants. Once-monthly subcutaneous administration of fitusiran resulted in dose-dependent lowering of the antithrombin level and increased thrombin generation in participants with hemophilia A or B who did not have inhibitory alloantibodies. (Funded by Alnylam Pharmaceuticals; ClinicalTrials.gov number, NCT02035605 .).

  17. Acute Compartment Syndrome after an Olecranon Fracture in a Patient with Mild Hemophilia B.

    Science.gov (United States)

    Reynolds, John M; Christophersen, Christy; Mulcahey, Mary K

    2017-01-01

    Compartment syndrome is a serious condition characterized by compartmental pressures within 20 mmHg of diastolic blood pressure, or clinical signs of pain, paresthesia, pallor, and lack of pulses. Often a surgical intervention is necessary. Increased surveillance for compartment syndrome is important when a patient with a bleeding disorder sustains a traumatic injury. We present a case of forearm compartment syndrome in a patient with mild hemophilia B who sustained an olecranon fracture. The patient received factor replacement and he underwent emergent forearm fasciotomies to avoid muscle necrosis. Over the subsequent week, the patient returned to the operating room 3 times for repeat irrigation and debridements, partial wound closure, open reduction internal fixation of his olecranon fracture and eventual skin grafting of the volar forearm wound. Failure to recognize compartment syndrome in even mild forms of hemophilia may result in loss of function, neurologic deficits, and limb amputations. The management of acute compartment syndrome in patients with hemophilia requires timely recognition, replacement of clotting factors, and emergent fasciotomies.

  18. Successful Phenotype Improvement following Gene Therapy for Severe Hemophilia A in Privately Owned Dogs.

    Directory of Open Access Journals (Sweden)

    Mary Beth Callan

    Full Text Available Severe hemophilia A (HA is an inherited bleeding disorder characterized by <1% of residual factor VIII (FVIII clotting activity. The disease affects several mammals including dogs, and, like humans, is associated with high morbidity and mortality. In gene therapy using adeno-associated viral (AAV vectors, the canine model has been one of the best predictors of the therapeutic dose tested in clinical trials for hemophilia B (factor IX deficiency and other genetic diseases, such as congenital blindness. Here we report our experience with liver gene therapy with AAV-FVIII in two outbred, privately owned dogs with severe HA that resulted in sustained expression of 1-2% of normal FVIII levels and prevented 90% of expected bleeding episodes. A Thr62Met mutation in the F8 gene was identified in one dog. These data recapitulate the improvement of the disease phenotype in research animals, and in humans, with AAV liver gene therapy for hemophilia B. Our experience is a novel example of the benefits of a relevant preclinical canine model to facilitate both translational studies in humans and improved welfare of privately owned dogs.

  19. Uptake of Genetic Counseling, Knowledge of Bleeding risks and Psychosocial Impact in a South African Cohort of Female Relatives of People with Hemophilia.

    Science.gov (United States)

    Gillham, Anne; Greyling, Brenda; Wessels, Tina-Marie; Mbele, Bongi; Schwyzer, Rosemarie; Krause, Amanda; Mahlangu, Johnny

    2015-12-01

    In excess of 200 people with hemophilia (PWH) and their families have received genetic counseling (GC) at the Hemophilia Comprehensive Care Centre at Charlotte Maxeke Johannesburg Academic Hospital. However, very few of their at-risk female relatives have attended GC to discuss their reproductive risks and options, or their potential bleeding risks. Limited research has been conducted internationally on factors influencing uptake of GC and testing amongst female relatives of PWH. This prospective study aimed to explore the factors that influence the uptake of GC and testing by female relatives of PWH. An open-ended semi-structured interview schedule was developed. Participants included female relatives of PWH who at least had a family member who had received GC. Seventeen participants were interviewed; 7 who had GC previously and 10 who had not. All participants who had previously received GC found the service helpful and were mothers referred because their sons had hemophilia. Of those who had not had GC, possible deterrents included: being unaware of GC service, focus in clinic on PWH and not potential carriers, misunderstood risks related to hemophilia and carrier status, fear of finding out carrier status, and non-disclosure in families. Most participants were unaware of potential bleeding risks for carriers. The information will be used to provide a better service to female relatives of PWH with a goal being to set up a dedicated hemophilia carrier clinic.

  20. Acquired hemophilia A: an underdiagnosed, severe bleeding disorder.

    Science.gov (United States)

    Zdziarska, Joanna; Musiał, Jacek

    2014-01-01

    Acquired hemophilia is a rare bleeding disorder caused by autoantibodies that inhibit coagulation factor VIII. In most cases, it manifests with severe, often life‑threatening bleeds. Acquired hemophilia may be idiopathic or secondary to another condition, most commonly other autoimmune disease or cancer. Treatment is directed to stop bleeding and eradicate inhibitory autoantibodies. Like in most life‑threatening conditions, early diagnosis and treatment are essential for good prognosis. Prompt diagnosis and treatment of acquired hemophilia are constantly improving owing to the increasing availability of laboratory diagnostic tests and growing awareness of physicians of various specialties.

  1. Surgical treatment of Perthes disease in child with hemophilia

    Directory of Open Access Journals (Sweden)

    Anisimov D.I.

    2011-03-01

    Full Text Available Hemophilia is a genetically mediated disease caused by recessive transmission of the gene. At present etiological orientation in treatment of the given pathology has just begun to develop. Replacement therapy by the concentrate of blood factors is the principal method of treatment. With great success in the sphere of medicine life quality of children suffering from hemophilia has improved significantly. However, the given category of patients refers to the high risk group to render surgical care as before. The example of the surgical intervention is an intertrochanteric osteotomy of the femur in a child with hemophilia

  2. Factor VIII therapy for hemophilia A: current and future issues.

    Science.gov (United States)

    Aledort, Louis; Ljung, Rolf; Mann, Kenneth; Pipe, Steven

    2014-06-01

    Hemophilia A is a congenital, recessive, X-linked bleeding disorder that is managed with infusions of plasma-derived or recombinant factor (F) VIII. The primary considerations in FVIII replacement therapy today are the: 1) immunogenicity of FVIII concentrates, 2) role of longer-acting FVIII products, 3) prophylactic use of FVIII in children and adults with severe hemophilia A, and 4) affordability and availability of FVIII products. Improving patient outcomes by increasing the use of FVIII prophylaxis, preventing or eliminating FVIII inhibitors, and expanding access to FVIII concentrates in developing countries are the major challenges confronting clinicians who care for patients with hemophilia A.

  3. Acquired hemophilia a: a current review of autoantibody disease.

    Science.gov (United States)

    Sborov, Douglas W; Rodgers, George M

    2012-01-01

    Acquired hemophilia A (AHA) is a rare, potentially life-threatening hemorrhagic disorder that presents a complex clinical challenge. The immune-mediated production of autoantibodies, known as factor VIII inhibitors, often results in clinically significant soft tissue or post-procedural bleeding episodes in patients without a previous diagnosis of a bleeding disorder. Acquired antibodies against factor VIII are associated with an extensive list of conditions, including pregnancy, autoimmune disease, and malignancy. There is great potential for morbidity and mortality resulting from autoantibody development. Death is more frequent within the first few weeks after symptomatic manifestation, making prompt recognition and treatment vitally important. Treatment focuses on stabilization of initial bleeding and long-term eradication of the acquired inhibitor. As no randomized clinical trials have been conducted regarding treatment in this patient population, clinical expertise and experience continue to guide treatment recommendations. This report provides an algorithm for the diagnosis of AHA and outlines potential treatment recommendations, most notably concomitant use of recombinant factor VIIa (rF7a) and factor VIII inhibitor bypassing agent to control bleeding in patients not responsive to single-agent therapy, and use of rituximab and prednisone for inhibitor eradication therapy.

  4. Emerging and future therapies for hemophilia

    Directory of Open Access Journals (Sweden)

    Carr ME

    2015-09-01

    Full Text Available Marcus E Carr,1,2 Bartholomew J Tortella3,4 1Robert Wood Johnson Medical School, Rutgers University, New Brunswick, NJ, 2Worldwide Research and Development, Pfizer, Inc., Cambridge, MA, 3Drexel University College of Medicine, Philadelphia, PA, 4Global Innovative Pharma, Pfizer, Inc., Collegeville, PA, USA Abstract: The evolution of care in hemophilia is a remarkable story. Over the last 60 years, advances in protein purification, protein chemistry, donor screening, viral inactivation, gene sequencing, gene cloning, and recombinant protein production have dramatically enhanced the treatment and lives of patients with hemophilia. Recent efforts have produced enhanced half-life (EHL clotting factors to better support prophylaxis and decrease the frequency of infusions. Medical needs remain in the areas of alternate modes of administration to decrease the need for venous access, better treatment, and prophylaxis for patients who form antibodies to clotting factors, and ultimately a cure of the underlying genetic defect. In this brief review, the authors summarize data on EHL clotting factors, introduce agents whose mode of action is not clotting factor replacement, and list current gene therapy efforts. Keywords: extended half-life clotting factors, gene therapy, anti-tissue factor pathway inhibitor antibodies, clotting factor analogs, nonfactor replacement therapy

  5. Strategies to encourage physical activity in patients with hemophilia to improve quality of life

    Directory of Open Access Journals (Sweden)

    Goto M

    2016-05-01

    Full Text Available Miwa Goto,1 Hideyuki Takedani,2 Kazuhiko Yokota,1 Nobuhiko Haga3 1Rehabilitation Center, The University of Tokyo Hospital, 2Department of Joint Surgery, Research Hospital of the Institute of Medical Science, The University of Tokyo, 3Department of Rehabilitation Medicine, Graduate School of Medicine, The University of Tokyo, Tokyo, Japan Abstract: Hemophilia is a bleeding disorder caused by a congenital abnormality of blood coagulation. Until the mid-1970s, patients with hemophilia (PWH were advised to refrain from physical activity (PA because of a perceived increased risk of bleeding. Since then, PA, which is recognized as being essential for health maintenance, is now recommended by the World Federation of Hemophilia. Moreover, a number of studies reported that PA can improve treatment efficacy and prevent bleeding in PWH. Physical assessment and intervention in PA are currently used in clinical practice. However, the necessity of PA is not emphasized, and many PWH generally have low- to- no PA. Therefore, a behavior change approach to encourage patient motivation is becoming ever more important. In this article, we review articles addressing PA in PWH and discuss strategies to encourage PA through a behavior change approach by focusing on factors relevant to hemophilia, such as benefits and bleeding risk of PA, risk management of bleeding, PA characteristics, and difficulty with exercise adherence. The trust relationship between clinicians and patients, a transtheoretical model of behavior change, and motivation theory as approaches to promote PA are introduced. Finally, we review a case report of the clinical success of a behavior change approach to promote PA. Many PWH find it difficult to continue PA because of aging, fear of bleeding, insufficient recognition of PA benefits, and psychological problems. Therefore, it is essential and important to perform prophylaxis with PWH and to heighten their understanding of the benefits and risks of

  6. An Open-label, Single-dose, Pharmacokinetic Study of Factor VIII Activity After Administration of Moroctocog Alfa (AF-CC) in Male Chinese Patients With Hemophilia A.

    Science.gov (United States)

    Liu, Hongzhong; Wu, Runhui; Hu, Pei; Sun, Feifei; Xu, Lihong; Liang, Yali; Nepal, Sunil; Qu, Peng Roger; Huard, Francois; Korth-Bradley, Joan M

    2017-07-01

    Hemophilia A represents up to 80% of all hemophilia cases in China. In patients with this condition, bleeding can be prevented and controlled by administering clotting factor VIII (FVIII). Since their initial availability, recombinant FVIII products have undergone several iterations to enhance their safety. Moroctocog alfa albumin-free cell culture (AF-CC) is among the third generation of recombinant FVIII products and received regulatory approval in China in August 2012. The present study characterizes the single-dose pharmacokinetic parameters of FVIII activity (FVIII:C) after administration of moroctocog alfa (AF-CC) in male Chinese patients with hemophilia A. This multicenter, open-label, single-dose study enrolled 13 male Chinese patients diagnosed with severe hemophilia A (FVIII:C hemophilia A. The pharmacokinetic profile in older patients was similar to that previously reported with recombinant FVIII products in studies with a predominantly white population; younger patients had reduced exposure to FVIII:C. The single doses of moroctocog alfa (AF-CC) were well tolerated; 2 cases of transient, low-titer FVIII inhibitor development were observed. ClinicalTrials.gov identifier: NCT02461992. Copyright © 2017 Elsevier HS Journals, Inc. All rights reserved.

  7. Acquired hemophilia: a case report and review of the literature.

    Science.gov (United States)

    Mulliez, S M N; Vantilborgh, A; Devreese, K M J

    2014-06-01

    Acquired hemophilia A (AHA) is a rare bleeding disorder caused by autoantibodies against clotting factor VIII (FVIII). FVIII autoantibody is characterized as polyclonal immunoglobulin G directed against the FVIII procoagulant activity. This disease occurs most commonly in the elderly population and with preponderance of men in nonpregnancy-related AHA. There are well-established clinical associations with AHA such as malignancy, other autoimmune diseases and pregnancy. However, up to 50% of reported cases remain idiopathic. The clinical manifestation of AHA includes mostly spontaneous hemorrhages into skin, muscles and soft tissues, or mucous membranes. AHA should be suspected when a patient with no previous history of bleeding presents with bleeding and an unexplained prolonged activated partial thromboplastin time. The diagnosis is confirmed in the laboratory by the subsequent identification of reduced FVIII levels and FVIII inhibitor titration. There is a high mortality, making prompt diagnosis and treatment vitally important. The principles of treatment consist in controlling the bleeding and eradicating the inhibitor. Because of the overall high relapse rate (15-33%), it is also recommended to follow up these patients. The review summarizes what is currently known about the epidemiology, pathogenesis, clinical features, diagnosis, treatment and prognosis of AHA and starts with a case report. © 2014 John Wiley & Sons Ltd.

  8. Development of a Web-Accessible Population Pharmacokinetic Service-Hemophilia (WAPPS-Hemo): Study Protocol.

    Science.gov (United States)

    Iorio, Alfonso; Keepanasseril, Arun; Foster, Gary; Navarro-Ruan, Tamara; McEneny-King, Alanna; Edginton, Andrea N; Thabane, Lehana

    2016-12-15

    2.4), with core functionalities allowing hemophilia treaters to obtain individual pharmacokinetic estimates on sparse data points after 1 or more infusions of a factor concentrate, was launched for use within the research network in July 2015. The WAPPS-Hemo project and research network aims to make it easier to perform individual pharmacokinetic assessments on a reduced number of plasma samples by adoption of a population pharmacokinetics approach. The project will also gather data to substantially enhance the current knowledge about factor concentrate pharmacokinetics and sources of its variability in target populations. ClinicalTrials.gov NCT02061072; https://clinicaltrials.gov/ct2/show/NCT02061072 (Archived by WebCite at http://www.webcitation.org/6mRK9bKP6).

  9. Linking quality-of-life measures using the International Classification of Functioning, Disability and Health and the International Classification of Functioning, Disability and Health-Children and Youth Version in chronic health conditions: the example of young people with hemophilia.

    Science.gov (United States)

    Krasuska, Marta; Riva, Silvia; Fava, Leonardo; von Mackensen, Sylvia; Bullinger, Monika

    2012-02-01

    This study aimed to measure the health and functioning of children with hemophilia in Europe using the International Classification of Functioning, Disability and Health (ICF) and the International Classification of Functioning, Disability and Health-Children and Youth Version (ICF-CY) as a frame of reference and items from health-related quality-of-life instruments as a measurement tool within a European data set. Based on the results of linkage of items from the hemophilia-specific health-related quality-of-life questionnaire for children and adolescents to ICF/ICF-CY, the categories most relevant for the description of health and functioning of children with hemophilia were identified for each domain of the ICF/ICF-CY. Using data from the European Study of Clinical, Health, Economic, and Quality-of-Life Outcomes of Hemophilia treatment on 446 children, the frequency of impairments in body structures and body functions, restrictions in activities and participation, and barriers in contextual factors were calculated. In general, the frequency of impairments, restrictions, and barriers was low in the studied population of children with hemophilia. However, the level of restriction as well as barriers was higher than the level of impairments. Older children, children receiving on-demand treatment, and children with severe hemophilia tended to have more problems compared with younger children, children receiving prophylaxis treatment, and children with mild to moderate hemophilia. Using items from quality-of-life instruments with the ICF-CY as a frame of reference proved to be a useful approach for the assessment of health and functioning in children with hemophilia.

  10. [Diagnosis and treatment of hemophilia A acquired during postpartum ].

    Science.gov (United States)

    Castillo-Cañadas, Ana María; Serrano-Diana, Carolina; López-Del Cerro, Esther; Gómez-García, María Teresa; González De Merlo, Gaspar

    2014-10-01

    Acquired hemophilia A is a truly exceptional hemorrhagic diathesis, that consists of the emergence of polyclonal autoantibodies (inhibitor) IgG-type (subclasses 1 and 4, in most cases) against the coagulant function of the circulating factor VIII, which acts in the domains C2, A2 and A3 of the molecule, thus interfering their interaction with the factor IXa, the phospholipids and the Von Willebrand factor. Its morbidity and mortality are high, but nevertheless its low incidence (1-1.5 cases per million population per year) is the most frequent autoimmune disorder. This paper reports the clinical case of two patients; the first one, 36 years old, who the tenth day of postpartum required re-entry due to a diagnosis of hematoma of the abdominal wall that was surgically drained twice. The patient of case 2 was 39 years old and at six days of postpartum went to the emergency room due to bleeding, she was underwent to curettage and therapeutic transfusion of 3 UCH. Because of the persistence of bleeding, which was not possible to control with medical treatment and conservative measures, therapeutic hysterectomy was performed, with blood transfusion later. Due to the hemorrhagic complications of this condition and the serious clinical consequences derived from them, it is important to establish an early diagnosis; it is therefore critical to know the existence of this very rare disease to be able to avoid its consequences.

  11. Costs and utilization of hemophilia A and B patients with and without inhibitors.

    Science.gov (United States)

    Armstrong, Edward P; Malone, Daniel C; Krishnan, Sangeeta; Wessler, Maj Jacob

    2014-11-01

    To evaluate the health system costs among patients with hemophilia A and B with and without inhibitors over 5 years. This was a retrospective, observational study utilizing medical and pharmacy electronic medical records and administrative encounters/claims data tracking US patients between 2006-2011. Patients with diagnosis codes for hemophilia A and B were identified. Patients with inhibitors were characterized by utilization of bypassing agents activated prothrombin complex concentrate or factor VIIa on two or more distinct dates. Severity was classified as mild, moderate, or severe based on laboratory tests of clotting factor. There were 160 hemophilia A patients and 54 hemophilia B patients identified. From this group, seven were designated as patients with inhibitors (five with hemophilia A and two with hemophilia B). Hemophilia A patients without inhibitors reported 65 (41.9%) as being severe, 19 (12.3%) as moderate, and 71 (45.8%) as mild. Hemophilia B patients without inhibitors reported nine (17.3%) had severe, 13 (25.0%) had moderate, and 30 (57.7%) had mild hemophilia. All patients with inhibitors had been hospitalized in the previous 5 years compared to 64 (41.3%) with hemophilia A without inhibitors and 22 (42.3%) with hemophilia B without inhibitors. The median aggregate cost per year (including factor and health resource use) was $325,780 for patients with inhibitors compared to $98,334 for hemophilia A patients without inhibitors and $23,265 for hemophilia B patients without inhibitors. The results suggest that, while the frequency of inhibitors within the hemophilia cohort was low, there was a higher frequency of hospitalizations, and the associated median aggregate costs per year were 3-fold higher than those patients without inhibitors. In contrast, hemophilia B patients experience less severe disease and account for lower aggregate yearly costs compared to either patients with hemophilia A or patients with inhibitors.

  12. Acquired hemophilia A: emerging treatment options

    Directory of Open Access Journals (Sweden)

    Janbain M

    2015-05-01

    Full Text Available Maissaa Janbain,1 Cindy A Leissinger,1 Rebecca Kruse-Jarres2 1Louisiana Center for Bleeding and Clotting Disorders, Tulane University Medical Center, New Orleans, LA, USA; 2Washington Center for Bleeding Disorders, Blood Works NW, Seattle, WA, USA Abstract: Acquired hemophilia A is a rare autoimmune disorder caused by an autoantibody (inhibitor to factor VIII (FVIII that interferes with its coagulant function and predisposes to severe, potentially life-threatening hemorrhage. Disease management focuses on controlling bleeding, primarily with the use of bypassing therapy and recombinant porcine FVIII, and permanently eradicating the autoantibody using various immunosuppressants. Treatment challenges include delayed diagnosis, difficulty achieving hemostasis and durable remissions, and complications associated with the use of hemostatic and immunosuppressive therapy in a primarily older patient population. Keywords: autoantibodies, factor VIII, hemostasis, inhibitors, inhibitor eradication

  13. 78 FR 57868 - Prospective Grant of Exclusive Patent License: Oral Treatment of Hemophilia

    Science.gov (United States)

    2013-09-20

    ... Treatment of Hemophilia AGENCY: National Institutes of Health, HHS. ACTION: Notice. SUMMARY: This is notice..., ``Oral Treatment of Hemophilia'' and ``Induction of Tolerance by Oral administration of Factor VIII and Treatment of Hemophilia''. The patent rights in these inventions have been assigned to or exclusively...

  14. Mortality caused by intracranial bleeding in non-severe hemophilia A patients

    NARCIS (Netherlands)

    Loomans, Janneke I.; Eckhardt, Corien L.; Reitter-Pfoertner, Sylvia E.; Holmstrom, Mats; Van Gorkom, B. Laros; Leebeek, F. W. G.; Santoro, C.; Haya, Saturnino; Meijer, K.; Nijziel, M. R.; Van Der Bom, J. G.; Fijnvandraat, K.

    Background: Non-severe hemophilia (factor VIII concentration [FVIII: C] of 2-40 IU dL(-1)) is characterized by a milder bleeding phenotype than severe hemophilia A. However, some patients with non-severe hemophilia A suffer from severe bleeding complications that may result in death. Data on

  15. Mortality caused by intracranial bleeding in non-severe hemophilia A patients

    NARCIS (Netherlands)

    Loomans, J. I.; Eckhardt, C. L.; Reitter-Pfoertner, S. E.; Holmström, M.; van Gorkom, B. Laros; Leebeek, F. W. G.; Santoro, C.; Haya, S.; Meijer, K.; Nijziel, M. R.; van der Bom, J. G.; Fijnvandraat, K.

    2017-01-01

    Background: Non-severe hemophilia (factor VIII concentration [FVIII: C] of 2-40 IU dL(-1)) is characterized by a milder bleeding phenotype than severe hemophilia A. However, some patients with non-severe hemophilia A suffer from severe bleeding complications that may result in death. Data on

  16. Recombinant B domain deleted porcine factor VIII for the treatment of bleeding episodes in adults with acquired hemophilia A.

    Science.gov (United States)

    Gomperts, Edward

    2015-08-01

    Hemophilia A is an inherited deficiency of clotting factor VIII (FVIII) often complicated by inhibitor development (CHAWI) in which neutralizing antibodies block the therapeutic benefit of replacement therapy. Inhibitors to FVIII can also be seen in an auto-immune disease known as acquired hemophilia A (AHA). 'Bypassing' therapies have been shown to provide hemostasis but dosing must be done empirically because current assays cannot measure objective markers of treatment efficacy and safety. A recombinant porcine sequence factor VIII (r-pFVIII) has been developed for the management of AHA. Preclinical, Phase I and Phase II clinical research studies in CHAWI subjects showed therapeutic potential and safety of this agent. A Phase II/III study in AHA with serious bleeding episodes shows a positive response in all subjects after administration. Based on current preclinical and clinical trial data, r-pFVIII should become the first line of treatment in the management of hemorrhage in patients with AHA.

  17. Hemophilia A: An Ideal Disease to Correct in Utero

    Directory of Open Access Journals (Sweden)

    Christopher D Porada

    2014-12-01

    Full Text Available Hemophilia A (HA is the most frequent inheritable defect of the coagulation proteins. The current standard of care for patients with HA is prophylactic factor infusion, which is comprised of regular (2-3 times per week intravenous infusions of recombinant or plasma-derived FVIII to maintain hemostasis. While this treatment has greatly increased the quality of life and lengthened the life expectancy for many HA patients, its high cost, the need for lifelong infusions, and the fact that it is unavailable to roughly 75% of the world’s HA patients make this type of treatment far from ideal. In addition, this lifesaving therapy suffers from a high risk of treatment failure due to immune response to the infused FVIII. There is thus a need for novel treatments, such as those using stem cells and/or gene therapy, which have the potential to mediate long-term correction or permanent cure following a single intervention. In the present review, we discuss the clinical feasibility and unique advantages that an in utero approach to treating HA could offer, placing special emphasis on a new sheep model of HA we have developed and on the use of mesenchymal stromal cells (MSC as cellular vehicles for delivering the FVIII gene.

  18. A novel supplemental approach to capturing post-marketing safety information on recombinant factor VIIa in acquired hemophilia: the Acquired Hemophilia Surveillance project

    Directory of Open Access Journals (Sweden)

    Lentz SR

    2014-01-01

    Full Text Available Steven R Lentz,1 Anand Tandra,2 Robert Z Gut,3 David L Cooper31Division of Hematology, Oncology and Blood and Marrow Transplantation, Department of Internal Medicine, University of Iowa, Iowa City, IA, USA; 2Hematology, Indiana Hemophilia and Thrombosis Center, Indianapolis, IN, USA; 3Clinical, Medical, and Regulatory Affairs, Novo Nordisk, Inc, Princeton, NJ, USAAcquired hemophilia (AH is a rare (incidence is 1 per 1.5 million but often severe bleeding disorder characterized by autoantibodies to coagulation factor VIII (FVIII. It is associated with life-threatening bleeding and ∼20% mortality.1,2 Recombinant factor VIIa (rFVIIa; NovoSeven® RT, Novo Nordisk A/S, Bagsværd, Denmark received an indication from the US Food and Drug Administration (FDA in October 2006 for the treatment of bleeding episodes and the prevention of bleeding in surgical interventions or invasive procedures in patients with AH.3View original paper by Collins and colleagues.

  19. [Analysis of individualized primary prophylactic treatment of 19 cases of children with severe hemophilia A].

    Science.gov (United States)

    Liu, G Q; Tang, L; Wu, X Y; Zhen, Y Z; Li, G; Chen, Z P; Wang, Y; Zhang, N N; Zhang, J S; Yu, G X; Wu, R H

    2016-12-02

    Objective: To study the current situation of primary prophylaxis in severe hemophilia A children and to explore rational regimen in order to provide evidence for the development of primary prophylaxis in China. Method: A retrospective clinical data collection and analysis was conducted for 19 severe hemophilia A children who received primary prophylaxis in Beijing Children's Hospital outpatient clinic between February 2011 and September 2015 and evaluated the regimen and efficacy. Result: (1) Primary prophylaxis regimen: the median beginning age 1.8 (range 0.5-2.9) years, the median FⅧ preparation using dosage 16.7 (8.0-23.5) U/(kg·time), the median using frequency was 1.0 (1.0-3.0) time/week. Eight cases among the patients received escalation of treatment intensity because of the poor bleeding control. (2) Efficacy: the median annual bleeding rate (ABR) was 1.9 (0-6.0) times/year, the median annual joint bleeding rate (AJBR) was 0 (0-3.3) times/year, without life threatening bleeding. All of them kept in 4th scale of Beijing Children Hospital daily activity level. The median annual factor consumption was 1 844 (840-5 040) U/kg. Conclusion: Low-dose primary prophylaxis regimen which were in low-dose /low frequencies and adjusted by bleeding frequency could decrease bleeding and joint bleeding frequency significantly, maintained the normal daily activity capacity and saved the factor consumption compared to standard regimen in severe hemophilia A children.

  20. Past, present and future of hemophilia: a narrative review.

    Science.gov (United States)

    Franchini, Massimo; Mannucci, Pier Mannuccio

    2012-05-02

    Over the past forty years the availability of coagulation factor replacement therapy has greatly contributed to the improved care of people with hemophilia. Following the blood-borne viral infections in the late 1970s and early 1980, caused by coagulation factor concentrates manufactured using non-virally inactivated pooled plasma, the need for safer treatment became crucial to the hemophilia community. The introduction of virus inactivated plasma-derived coagulation factors and then of recombinant products has revolutionized the care of these people. These therapeutic weapons have improved their quality of life and that of their families and permitted home treatment, i.e., factor replacement therapy at regular intervals in order to prevent both bleeding and the resultant joint damage (i.e. primary prophylaxis). Accordingly, a near normal lifestyle and life-expectancy have been achieved. The main current problem in hemophilia is the onset of alloantibodies inactivating the infused coagulation factor, even though immune tolerance regimens based on long-term daily injections of large dosages of coagulation factors are able to eradicate inhibitors in approximately two-thirds of affected patients. In addition availability of products that bypass the intrinsic coagulation defects have dramatically improved the management of this complication. The major challenges of current treatment regimens, such the short half life of hemophilia therapeutics with need for frequent intravenous injections, encourage the current efforts to produce coagulation factors with more prolonged bioavailability. Finally, intensive research is devoted to gene transfer therapy, the only way to ultimately obtain cure in hemophilia.

  1. Evaluating the psychosocial impact of hemophilia B: The Bridging Hemophilia B Experiences, Results and Opportunities into Solutions (B-HERO-S) study.

    Science.gov (United States)

    Sidonio, Robert; Holot, Natalia; Cooper, David L

    2017-04-01

    The needs of individuals living with hemophilia B, especially those with mild or moderate hemophilia and affected females, are not well understood. The Bridging Hemophilia B Experiences, Results and Opportunities into Solutions (B-HERO-S) initiative was developed in an effort to obtain greater insights into the unique issues and challenges faced by those with hemophilia B. This study explored the impact of hemophilia B on education, employment, engagement in physical activities and other psychosocial aspects of the lives of affected individuals and their families. The B-HERO-S findings reveal a number of unmet needs in the hemophilia B population, and these results may be leveraged to inform patient outreach and education initiatives. © 2017 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd.

  2. International recommendations on the diagnosis and treatment of patients with acquired hemophilia A

    Science.gov (United States)

    Huth-Kühne, Angela; Baudo, Francesco; Collins, Peter; Ingerslev, Jørgen; Kessler, Craig M.; Lévesque, Hervé; Castellano, Maria Eva Mingot; Shima, Midori; St-Louis, Jean

    2009-01-01

    Acquired hemophilia A (AHA) is a rare bleeding disorder characterized by autoantibodies directed against circulating coagulation factor (F) VIII. Typically, patients with no prior history of a bleeding disorder present with spontaneous bleeding and an isolated prolonged aPTT. AHA may, however, present without any bleeding symptoms, therefore an isolated prolonged aPTT should always be investigated further irrespective of the clinical findings. Control of acute bleeding is the first priority, and we recommend first-line therapy with bypassing agents such as recombinant activated FVII or activated prothrombin complex concentrate. Once the diagnosis has been achieved, immediate autoantibody eradication to reduce subsequent bleeding risk should be performed. We recommend initial treatment with corticosteroids or combination therapy with corticosteroids and cyclophosphamide and suggest second-line therapy with rituximab if first-line therapy fails or is contraindicated. In contrast to congenital hemophilia, no comparative studies exist to support treatment recommendations for patients with AHA, therefore treatment guidance must rely on the expertise and clinical experience of specialists in the field. The aim of this document is to provide a set of international practice guidelines based on our collective clinical experience in treating patients with AHA and contribute to improved care for this patient group. PMID:19336751

  3. Challenges and open issues in the management of acquired hemophilia A (AHA).

    Science.gov (United States)

    Shetty, Shrimati D; Ghosh, Kanjaksha

    2015-03-01

    Acquired hemophilia A (AHA) is a rare autoimmune bleeding disorder caused by antibodies which neutralize the function of factor VIII (FVIII). The disease presents a complex clinical challenge to the treating Physicians and Hematologists. As the disease is associated with high mortality, prompt management is necessary. Early recognition, quick diagnosis and timely referral to a specialized center are important for better management of these patients. The different clinical manifestations, underlying pathology, inhibitor kinetics and the associated age related comorbidities do not allow extrapolation of the treatment protocols of congenital hemophilia to AHA. The basic strategies of the management of AHA patients involve maintaining hemostasis, suppression or eradication of antibodies, diagnosis and treatment of underlying pathology and avoid treatment related complications like thrombosis. The efficiency of hemostatic agents which are generally used to treat AHA is unpredictable. Due to the rarity of the disease, there are no randomized clinical trials on the management of this disorder and thus the expertise and experience of the treating Physicians' guide treatment strategies. Copyright © 2014 Elsevier Inc. All rights reserved.

  4. Hemophilia A. Considerations for dental management of pediatric patients.

    Directory of Open Access Journals (Sweden)

    Sonia López-Villareal

    2016-12-01

    Full Text Available It comes to consulting the Faculty of Dentistry at the University of Nuevo León pediatric male patient of 9 years 10 months, who was admitted with a presumptive diagnosis of hemophilia due to a subsequent persistent bleeding to treatment with steel crowns made in an earlier appointment. Interconsultation is performed with the hematologist who by laboratory examinations notice decreased coagulation factor VIII confirming the diagnosis of hemophilia A. It plans and conducts comprehensive treatment dental team with the hematologist who said that patients in hospitals with the replacement of missing clotting factor is prepared by cryo precipitates or with concentrated factor VIII intravenously before and after his dental intervention. The aim of the article is to highlight that hemophilia can be a disease detected during dental surgery in some patients and for it to be successfully treated with multidisciplinary management protocol is required between hematologists and dentists.

  5. Burden of illness: direct and indirect costs among persons with hemophilia A in the United States.

    Science.gov (United States)

    Zhou, Zheng-Yi; Koerper, Marion A; Johnson, Kathleen A; Riske, Brenda; Baker, Judith R; Ullman, Megan; Curtis, Randall G; Poon, Jiat-Ling; Lou, Mimi; Nichol, Michael B

    2015-06-01

    To examine the direct and indirect costs of hemophilia care among persons with hemophilia A in the US. Observational data were obtained from HUGS-Va, a multi-center study from six federally supported hemophilia treatment centers (HTCs). Eligible individuals completed a standardized initial questionnaire and were followed regularly for 2 years to obtain information on work or school absenteeism, time spent arranging hemophilia care, and unpaid hemophilia-related support from caregivers. Data from 1-year healthcare utilization records and 2-year clotting factor dispensing records measured direct medical costs. Indirect costs were imputed using the human capital approach, which uses wages as a proxy measure of work time output. A total of 222 patients with complete data were included in the analysis. Two-thirds had severe hemophilia and the mean age was 21.1 years. The use of prophylaxis in severe hemophilia patients is associated with statistically significant reduction in the numbers of emergency department (ED) visits and bleeding episodes compared with those who were treated episodically. From the societal perspective, mild hemophilia costs $59,101 (median: $7519) annually per person, $84,363 (median: $61,837) for moderate hemophilia, $201,471 (median: $143,431) for severe hemophilia using episodic treatment, and $301,392 (median: $286,198) for severe hemophilia receiving prophylaxis. Clotting factor contributed from 54% of total costs in mild hemophilia to a maximum of 94% for patients with severe hemophilia receiving prophylaxis. Hemophilia is a costly disorder not only because of its high medical expenses, but also due to the high indirect costs incurred.

  6. Emerging Issues in Diagnosis, Biology, and Inhibitor Risk in Mild Hemophilia A.

    Science.gov (United States)

    Castaman, Giancarlo; Eckhardt, Corien; van Velzen, Alice; Linari, Silvia; Fijnvandraat, Karin

    2016-07-01

    Mild hemophilia A (MHA) is an X-linked bleeding disorder defined by factor VIII (FVIII) levels between 5 and 40 U/dL. Diagnosis occurs later in life compared with severe or moderate disease. Although bleeding episodes are especially posttraumatic, their unexpected occurrence may be potentially life threatening if diagnosis is missed or delayed. Desmopressin is the treatment of choice for MHA since it is cheap and safe, but a significant proportion of cases do not attain FVIII postinfusion greater than 50 U/dL, which is considered a safe level for major surgery. Thus, replacement therapy may be needed and is usually successful in MHA, but recent data indicate that this can be associated with the occurrence of inhibitors against FVIII, as for severe hemophilia A. However, in contrast to severe or moderate hemophilia A, patients with MHA have a lifelong risk of inhibitor formation. Inhibitors may change the clinical phenotype dramatically, as the inhibitor frequently cross-reacts with the patient's endogenous FVIII, reducing the endogenous FVIII plasma levels below 1 U/dL. Specific F8 missense mutations predispose to inhibitor development. Inhibitors are frequently provoked by intensive treatment with therapeutic FVIII concentrates (more than 5 consecutive exposure days). Bleeding in inhibitor patients may be treated with desmopressin, high doses of FVIII concentrate or FVIII bypassing agents. Many inhibitors disappear over time when no FVIII concentrate is administered. However, this does not imply that a patient is tolerant and an anamnestic reaction may occur when treatment with FVIII concentrate is again necessary. To eradicate, an inhibitor different strategies may be used: watchful waiting, immunosuppression, or immune tolerance induction regimen. Thieme Medical Publishers 333 Seventh Avenue, New York, NY 10001, USA.

  7. Therapeutic approaches for treating hemophilia A using embryonic stem cells.

    Science.gov (United States)

    Kasuda, Shogo; Tatsumi, Kohei; Sakurai, Yoshihiko; Shima, Midori; Hatake, Katsuhiko

    2016-06-01

    Hemophilia A is an X-linked rescessive bleeding disorder that results from F8 gene aberrations. Previously, we established embryonic stem (ES) cells (tet-226aa/N6-Ainv18) that secrete human factor VIII (hFVIII) by introducing the human F8 gene in mouse Ainv18 ES cells. Here, we explored the potential of cell transplantation therapy for hemophilia A using the ES cells. Transplant tet-226aa/N6-Ainv18 ES cells were injected into the spleens of severe combined immunodeficiency (SCID) mice, carbon tetrachloride (CCl4)-pretreated wild-type mice, and CCl4-pretreated hemophilia A mice. F8 expression was induced by doxycycline in drinking water, and hFVIII-antigen production was assessed in all cell transplantation experiments. Injecting the ES cells into SCID mice resulted in an enhanced expression of the hFVIII antigen; however, teratoma generation was confirmed in the spleen. Transplantation of ES cells into wild-type mice after CCl4-induced liver injury facilitated survival and engraftment of transplanted cells without teratoma formation, resulting in hFVIII production in the plasma. Although CCl4 was lethal to most hemophilia A mice, therapeutic levels of FVIII activity, as well as the hFVIII antigen, were detected in surviving hemophilia A mice after cell transplantation. Immunolocalization results for hFVIII suggested that transplanted ES cells might be engrafted at the periportal area in the liver. Although the development of a safer induction method for liver regeneration is required, our results suggested the potential for developing an effective ES-cell transplantation therapeutic model for treating hemophilia A in the future. Copyright © 2016 King Faisal Specialist Hospital & Research Centre. Published by Elsevier Ltd. All rights reserved.

  8. Qualidade de vida de pacientes hemofílicos acompanhados em ambulatório de hematologia Quality of life of patients with hemophilia treated in a hematology clinic

    Directory of Open Access Journals (Sweden)

    Altacílio A. Nunes

    2009-01-01

    education and 82.6% did not work. Of the 23 cases, 91.3% had hemophilia A. In respect to quality of life, 47.8% responded that their quality of life was good and 55% had a good level of satisfaction with their health. The psychological dominion presented the highest average score and the environment presented the lowest. This study highlights the magnitude of some problems of hemophilic patients.

  9. Prevention of the Musculoskeletal Complications of Hemophilia

    Directory of Open Access Journals (Sweden)

    E. C. Rodriguez-Merchan

    2012-01-01

    Full Text Available Hemophilia is an inherited disorder of clotting factor deficiencies resulting in musculoskeletal bleeding, including hemarthroses, leading to musculoskeletal complications. The articular problems of hemophiliac patients begin in infancy. These include: recurrent hemarthroses, chronic synovitis, flexion deformities, hypertrophy of the growth epiphyses, damage to the articular cartilage, and hemophilic arthropathy. The most commonly affected joints are the ankle, the knee, and the elbow. Hematologic prophylactic treatment from ages 2 to 18 years could avoid the development of hemophilic arthropathy if the concentration of the patient's deficient factor is prevented from falling below 1% of normal. Hemarthroses can be prevented by the administration of clotting factor concentrates (prophylaxis. However, high costs and the need for venous access devices in younger children continue to complicate recommendations for universal prophylaxis. Prevention of joint arthropathy needs to focus on prevention of hemarthroses through prophylaxis, identifying early joint disease through the optimal use of cost-effective imaging modalities and the validation of serological markers of joint arthropathy. Screening for effects on bone health and optimal management of pain to improve quality of life are, likewise, important issues. Major hemarthrosis and chronic hemophilic synovitis should be treated aggressively to prevent hemophilic arthropathy.

  10. Hemophilia Management via Data Collection and Reporting: Initial Findings from the Comprehensive Care Sustainability Collaborative.

    Science.gov (United States)

    Tarantino, Michael D; Pindolia, Vanita K

    2017-01-01

    Despite being a rare disorder, hemophilia represents a significant driver of health care resource utilization and requires expert hematologic and multidisciplinary services to achieve optimal outcomes. Since their inception nearly 40 years ago, hemophilia treatment centers (HTCs) have served as centers of excellence in providing the intensive care and ancillary services necessary for this unique patient base; however, the full capabilities of these centers may be underused in the current framework of managed care, largely because of a lack of communication and information shared between payers and HTC stakeholders. In an effort to enact tangible change toward improving the quality of care for bleeding disorders, the National Hemophilia Foundation developed an ongoing initiative among 18 leading clinicians and managed care decision makers called the Comprehensive Care Sustainability Collaborative (CCSC). The primary aim of the CCSC is to develop a framework for quality improvement pilot programs that can be replicated across the United States between payers and HTCs to facilitate cost-effective hemophilia management by integrating the HTC comprehensive care model. After CCSC committee members shared perspectives on care delivery, quality, and value, actionable data points were reviewed at length in order to develop meaningful metrics to facilitate information sharing between HTC and payer stakeholders. The following pragmatic measures will be reported by HTCs and payers via a series of pilot programs (reporting group is indicated in brackets): (a) patient classification by diagnosis (type, severity, and inhibitor status) [HTC]; (b) total cost of clotting factor [payer]; (c) prescribed factor dose/dispensed dose/patient weight (± range) [payer and HTC]; (d) emergency department visits/hospitalizations [payer and HTC]; (e) home infusion of clotting factor (%) [HTC]; (f) total cost per patient [payer]; and (g) patient contacts (e.g., clinic visits, follow

  11. Internal consistency and item-total correlation of patient-reported outcome instruments and hemophilia joint health score v2.1 in US adult people with hemophilia: results from the Pain, Functional Impairment, and Quality of life (P-FiQ) study.

    Science.gov (United States)

    Wang, Michael; Batt, Katharine; Kessler, Craig; Neff, Anne; Iyer, Neeraj N; Cooper, David L; Kempton, Christine L

    2017-01-01

    The Pain, Functional Impairment, and Quality of Life study was an observational, cross-sectional assessment of the impact of pain on functional impairment and quality of life in adult people with hemophilia (PWH) of any severity in the USA who experience joint pain and/or bleeding. To assess internal consistency (IC) and item-total correlation (ITC) of assessment tools used in the Pain, Functional Impairment, and Quality of Life study. Participants completed 5 patient-reported outcome instruments (EQ-5D-5L with visual analog scale, Brief Pain Inventory v2 Short Form [BPI], International Physical Activity Questionnaire [IPAQ], Short Form 36 Health Survey v2 [SF-36v2], and Hemophilia Activities List [HAL]) and underwent an optional physiotherapist-administered musculoskeletal exam (Hemophilia Joint Health Score v2.1) during routine visits. Reliability assessment included IC and ITC of each instrument. A total of 381 adult PWH (median age, 34 years) were enrolled. Participants were predominantly white/non-Hispanic (69.2%); 75% had congenital hemophilia A, and 70.5% had severe hemophilia. A total of 310 subjects reported bleeding within the past 6 months (mean [SD] number of bleeds, 7.1 [13.00]). IC was generally high across the instruments employed (Cronbach's alpha 0.79-0.98) with the exception of HAL use of transportation (0.58) and IPAQ total physical activity (0.51). ITC was high (Pearson's product-moment correlation coefficient >0.20) for all items except the "vigorous intensity activities" item of IPAQ, which was applicable to less than one-third of participants. The ITCs were generally highest in domains/scores that measured the functional consequences of hemophilic arthropathy on mobility and pain. The demonstrated reliability (IC/ITC) of the patient-reported outcome instruments and Hemophilia Joint Health Score v2.1 support a role for these instruments in evaluating adult PWH in US clinical and research settings.

  12. Identification of a novel mutation in HPS6 in a patient with hemophilia B and oculocutaneous albinism.

    Science.gov (United States)

    O'Brien, Kevin J; Lozier, Jay; Cullinane, Andrew R; Osorio, Brigitte; Nghiem, Khanh; Speransky, Vladislav; Zein, Wadih M; Mullikin, James C; Neff, Anne T; Simon, Karen L; Malicdan, May Christine V; Gahl, William A; Young, Lisa R; Gochuico, Bernadette R

    2016-11-01

    Hemophilia B, an X-linked disease, manifests with recurrent soft tissue bleeding episodes. Hermansky-Pudlak syndrome, a rare autosomal recessive disorder, is characterized by oculocutaneous albinism and an increased tendency to bleed due to a platelet storage pool defect. We report a novel mutation in HPS6 in a Caucasian man with hemophilia B and oculocutaneous albinism. The patient was diagnosed with hemophilia B at age 4months due to recurrent soft tissue bleeding episodes, and he was also diagnosed with Hermansky-Pudlak syndrome at 32years of age due to unexplained oculocutaneous albinism. His factor IX level was markedly reduced at 13%; whole exome and Sanger sequencing showed the Durham mutation in F9 (NM_000133.3). The diagnosis of Hermansky-Pudlak syndrome subtype 6 was established by demonstrating absence of platelet delta granules on whole mount electron microscopy, an abnormal secondary wave in platelet aggregation studies, and a novel homozygous c.1114 C>T (p.Arg372*) mutation in HPS6 (NM_024747.5) on exome analysis and Sanger sequencing. Clinical phenotyping revealed no evidence of recurrent or unusual infections, interstitial lung disease or pulmonary fibrosis, or neurological disorders. The patient was treated with fresh frozen plasma, recombinant factor IX, and aminocaproic acid. Treatment with desmopressin was added to his regimen after he was diagnosed with Hermansky-Pudlak syndrome. Treatment of bleeding episodes results in effective hemostasis, and the patient has not required platelet or blood product transfusions. This report highlights the need to consider Hermansky-Pudlak syndrome as an etiology of oculocutaneous albinism even in patients with known hematologic disorders associated with bleeding. Identification of a novel mutation in HPS6 in an individual with hemophilia B shows that, although quite rare, patients may be diagnosed with two independent inherited bleeding disorders. No evidence of lung disease was found in this adult patient

  13. Lentivirus-mediated platelet gene therapy of murine hemophilia A with pre-existing anti-FVIII immunity

    Science.gov (United States)

    Kuether, E. L.; Schroeder, J. A.; Fahs, S. A.; Cooley, B. C.; Chen, Y.; Montgomery, R. R.; Wilcox, D. A.; Shi, Q.

    2012-01-01

    Summary Background The development of inhibitory antibodies, referred to as inhibitors, against exogenous FVIII in a significant subset of patients with hemophilia A remains a persistent challenge to the efficacy of protein replacement therapy. Our previous studies using the transgenic approach provided proof-of-principle that platelet-specific expression could be successful for treating hemophilia A in the presence of inhibitory antibodies. Objective To investigate a clinically translatable approach for platelet gene therapy of hemophilia A with pre-existing inhibitors. Methods Platelet-FVIII expression in pre-immunized FVIIInull mice was introduced by transplantation of lentivirus-transduced bone marrow or enriched hematopoietic stem cells. FVIII expression was determined by a chromogenic assay. The transgene copy number per cell was quantitated by real time PCR. Inhibitor titer was measured by Bethesda assay. Phenotypic correction was assessed by the tail clipping assay and an electrolytic-induced venous injury model. Integration sites were analyzed by LAM-PCR. Results Therapeutic levels of platelet-FVIII expression were sustained long-term without evoking an anti-FVIII memory response in the transduced pre-immunized recipients. The tail clip survival test and the electrolytic injury model confirmed that hemostasis was improved in the treated animals. Sequential bone marrow transplants showed sustained platelet-FVIII expression resulting in phenotypic correction in pre-immunized secondary and tertiary recipients. Conclusions Lentivirus-mediated platelet-specific gene transfer improves hemostasis in hemophilic A mice with pre-existing inhibitors, indicating that this approach may be a promising strategy for gene therapy of hemophilia A even in the high-risk setting of pre-existing inhibitory antibodies. PMID:22632092

  14. Pharmacological modulation of humoral immunity in a nonhuman primate model of AAV gene transfer for hemophilia B.

    Science.gov (United States)

    Mingozzi, Federico; Chen, Yifeng; Murphy, Samuel L; Edmonson, Shyrie C; Tai, Alex; Price, Sandra D; Metzger, Mark E; Zhou, Shangzhen; Wright, J Fraser; Donahue, Robert E; Dunbar, Cynthia E; High, Katherine A

    2012-07-01

    Liver gene transfer for hemophilia B has shown very promising results in recent clinical studies. A potential complication of gene-based treatments for hemophilia and other inherited disorders, however, is the development of neutralizing antibodies (NAb) against the therapeutic transgene. The risk of developing NAb to the coagulation factor IX (F.IX) transgene product following adeno-associated virus (AAV)-mediated hepatic gene transfer for hemophilia is small but not absent, as formation of inhibitory antibodies to F.IX is observed in experimental animals following liver gene transfer. Thus, strategies to modulate antitransgene NAb responses are needed. Here, we used the anti-B cell monoclonal antibody rituximab (rtx) in combination with cyclosporine A (CsA) to eradicate anti-human F.IX NAb in rhesus macaques previously injected intravenously with AAV8 vectors expressing human F.IX. A short course of immunosuppression (IS) resulted in eradication of anti-F.IX NAb with restoration of plasma F.IX transgene product detection. In one animal, following IS anti-AAV6 antibodies also dropped below detection, allowing for successful AAV vector readministration and resulting in high levels (60% or normal) of F.IX transgene product in plasma. Though the number of animals is small, this study supports for the safety and efficacy of B cell-targeting therapies to eradicate NAb developed following AAV-mediated gene transfer.

  15. Role of B Cells in Breaking and Maintaining Tolerance to Clotting Factor VIII in Congenital and Acquired Hemophilia A

    Directory of Open Access Journals (Sweden)

    Amanda M. Actor

    2014-04-01

    Full Text Available Immune responses directed against clotting factor FVIII (FVIII seriously complicate treatments for patients with hemophilia A. This response can manifest in congenital hemophilia A patients who generate inhibitor antibodies that bind and inactivate “transplanted” replacement FVIII, as well as in acquired hemophiliacs, whose immune systems have lost tolerance to self-FVIII. Regardless of the mechanism by which production of anti-FVIII inhibitor antibody is triggered, the maintenance of this deleterious response in both congenital and acquired hemophiliacs likely relies upon FVIII specific memory B cells. In this review, the similarities and differences in the kinetics, specificities, and subclasses of antibodies produced in response to allo- and auto-FVIII is outlined. A brief description of the immune cell interactions that contribute to maintenance of antibody response, focusing on development of memory B cells and/or long lived plasma cells is also presented. As current treatments for inhibitor antibodies are not successful in all patients, a better understanding of the functions and persistence of memory B cells specific for FVIII is required. Herein, both clinical and experimental data regarding the effects of immune tolerance induction on memory B cell subpopulations is discussed. Finally, the outcomes of B cell-specific depletion via rituximab in hemophilia and other autoimmune diseases are discussed to highlight insights into the subpopulations of memory B cells that contribute to the development and maintenance of successful tolerance to FVIII.

  16. Directed engineering of a high-expression chimeric transgene as a strategy for gene therapy of hemophilia A.

    Science.gov (United States)

    Doering, Christopher B; Denning, Gabriela; Dooriss, Kerry; Gangadharan, Bagirath; Johnston, Jennifer M; Kerstann, Keith W; McCarty, David A; Spencer, H Trent

    2009-07-01

    Human coagulation factor VIII (fVIII) is inefficiently biosynthesized in vitro and has proven difficult to express at therapeutic levels using available clinical gene-transfer technologies. Recently, we showed that a porcine and certain hybrid human/porcine fVIII transgenes demonstrate up to 100-fold greater expression than human fVIII. In this study, we extend these results to describe the use of a humanized, high-expression, hybrid human/porcine fVIII transgene that is 89% identical to human fVIII and was delivered by lentiviral vectors (LVs) to hematopoietic stem cells for gene therapy of hemophilia A. Recombinant human immunodeficiency virus-based vectors encoding the fVIII chimera efficiently transduced human embryonic kidney (HEK)-293T cells. Cells transduced with hybrid human/porcine fVIII encoding vectors expressed fVIII at levels 6- to 100-fold greater than cells transduced with vectors encoding human fVIII. Transplantation of transduced hematopoietic stem and progenitor cells into hemophilia A mice resulted in long-term fVIII expression at therapeutic levels despite gene therapy applications for hemophilia A to significantly increase fVIII expression levels compared to what has been previously achieved.

  17. Hemoaction game: an educational step to improve hemophilia children and nurses self-efficacy

    Directory of Open Access Journals (Sweden)

    NOOASHIN BEHESHTIPOOR

    2016-10-01

    Full Text Available As hemophilia is a chronic bleeding disease and can interfere with daily performance of children, these children require continuous training to prevent bleeding and take timely action (1. Since children nurses play an important role in the education of involved children and their Selfefficacy and also due to today’s approach which is using educational computer games, the use of educational games in respect to teach hemophilia children how to have self-efficacy can be effective (2. Hemoaction game is a computerized educational game designed by the World Federation of Hemophilia to educate hemophilia disease and related procedures to the care of children with hemophilia. By the use of this game children with hemophilia (aged 8-12 and also nursing experts were educated how to increase self efficacy. Nursing School of Shiraz University of Medical Sciences has used this game for the first time after its publishing, in the world (3. The results of the mentioned study demonstrates that after the Hemophilia disease and its related procedures were instructed to children with hemophilia and nursing experts in order to know how to increase patients’ self efficacy by modern approaches, self efficacy of hemophilia children and nurses were both improved. This educational method is a novel way to enhance both Hemophilia children and nursing staff, as major participants in routine and lifelong education process, self-efficacy. Due to nurses’ important role in improving children with hemophilia self-efficacy by different instructions and world leading educational approaches towards use of modern technology in education, using Hemoaction educational game, published by World Federation of Hemophilia and used by Nursing and Midwifery College of Shiraz University of Medical Sciences for the first time, can fulfill hemophilia children needs of care.

  18. Director`s series on proliferation

    Energy Technology Data Exchange (ETDEWEB)

    Bailey, K.C.; Price, M.E. [eds.

    1994-12-27

    The Director`s Series on Proliferation is an occasional publication of essays on the topics of nuclear, chemical, biological, and missile proliferation. The seven papers presented in this issue cover the following topics: Should the Treaty on the Nonproliferation of Nuclear Weapons (NPT) be amended?; NPT extension - Legal and procedural issues; An Indonesian view of NPT review conference issues; The treaty of Tlatelolco and the NPT - Tools for peace and development; Perspectives on cut-off, weapons dismantlement, and security assurances; Belarus and NPT challenges; A perspective on the chemical weapons convention - Lessons learned from the preparatory commission.

  19. Anti-factor IXa/X bispecific antibody ACE910 prevents joint bleeds in a long-term primate model of acquired hemophilia A

    Science.gov (United States)

    Yoshihashi, Kazutaka; Takeda, Minako; Kitazawa, Takehisa; Soeda, Tetsuhiro; Igawa, Tomoyuki; Sampei, Zenjiro; Kuramochi, Taichi; Sakamoto, Akihisa; Haraya, Kenta; Adachi, Kenji; Kawabe, Yoshiki; Nogami, Keiji; Shima, Midori; Hattori, Kunihiro

    2014-01-01

    ACE910 is a humanized anti-factor IXa/X bispecific antibody mimicking the function of factor VIII (FVIII). We previously demonstrated in nonhuman primates that a single IV dose of ACE910 exerted hemostatic activity against hemophilic bleeds artificially induced in muscles and subcutis, and that a subcutaneous (SC) dose of ACE910 showed a 3-week half-life and nearly 100% bioavailability, offering support for effective prophylaxis for hemophilia A by user-friendly SC dosing. However, there was no direct evidence that such SC dosing of ACE910 would prevent spontaneous bleeds occurring in daily life. In this study, we newly established a long-term primate model of acquired hemophilia A by multiple IV injections of an anti-primate FVIII neutralizing antibody engineered in mouse-monkey chimeric form to reduce its antigenicity. The monkeys in the control group exhibited various spontaneous bleeding symptoms as well as continuous prolongation of activated partial thromboplastin time; notably, all exhibited joint bleeds, which are a hallmark of hemophilia. Weekly SC doses of ACE910 (initial 3.97 mg/kg followed by 1 mg/kg) significantly prevented these bleeding symptoms; notably, no joint bleeding symptoms were observed. ACE910 is expected to prevent spontaneous bleeds and joint damage in hemophilia A patients even with weekly SC dosing, although appropriate clinical investigation is required. PMID:25274508

  20. Transient blockade of the inducible costimulator pathway generates long-term tolerance to factor VIII after nonviral gene transfer into hemophilia A mice.

    Science.gov (United States)

    Peng, Baowei; Ye, Peiqing; Blazar, Bruce R; Freeman, Gordon J; Rawlings, David J; Ochs, Hans D; Miao, Carol H

    2008-09-01

    Formation of inhibitory antibodies is a common problem encountered in clinical treatment for hemophilia. Human factor VIII (hFVIII) plasmid gene therapy in hemophilia A mice also leads to strong humoral responses. We demonstrate that short-term therapy with an anti-ICOS monoclonal antibody to transiently block the inducible costimulator/inducible costimulator ligand (ICOS/ICOSL) signaling pathway led to sustained tolerance to hFVIII in hFVIII plasmid-treated hemophilia A mice and allowed persistent, high-level FVIII functional activity (100%-300% of normal). Anti-ICOS treatment resulted in depletion of ICOS(+)CD4(+) T cells and activation of CD25(+)Foxp3(+) Tregs in the peripheral blood, spleen, and lymph nodes. CD4(+) T cells from anti-ICOS-treated mice did not proliferate in response to hFVIII stimulation and produced high levels of regulatory cytokines, including interleukin-10 and transforming growth factor-beta. Moreover, CD4(+)CD25(+) Tregs from tolerized mice adoptively transferred dominant tolerance in syngeneic hFVIII plasmid-treated hemophilia A mice and reduced the production of antibodies against FVIII. Anti-ICOS-treated mice tolerized to hFVIII generated normal primary and secondary antibody responses after immunization with the T-dependent antigen, bacteriophage Phix 174, indicating maintenance of immune competency. Our data indicate that transient anti-ICOS monoclonal antibody treatment represents a novel single-agent immunomodulatory strategy to overcome the immune responses against transgene product after gene therapy.

  1. Anti-factor IXa/X bispecific antibody ACE910 prevents joint bleeds in a long-term primate model of acquired hemophilia A.

    Science.gov (United States)

    Muto, Atsushi; Yoshihashi, Kazutaka; Takeda, Minako; Kitazawa, Takehisa; Soeda, Tetsuhiro; Igawa, Tomoyuki; Sampei, Zenjiro; Kuramochi, Taichi; Sakamoto, Akihisa; Haraya, Kenta; Adachi, Kenji; Kawabe, Yoshiki; Nogami, Keiji; Shima, Midori; Hattori, Kunihiro

    2014-11-13

    ACE910 is a humanized anti-factor IXa/X bispecific antibody mimicking the function of factor VIII (FVIII). We previously demonstrated in nonhuman primates that a single IV dose of ACE910 exerted hemostatic activity against hemophilic bleeds artificially induced in muscles and subcutis, and that a subcutaneous (SC) dose of ACE910 showed a 3-week half-life and nearly 100% bioavailability, offering support for effective prophylaxis for hemophilia A by user-friendly SC dosing. However, there was no direct evidence that such SC dosing of ACE910 would prevent spontaneous bleeds occurring in daily life. In this study, we newly established a long-term primate model of acquired hemophilia A by multiple IV injections of an anti-primate FVIII neutralizing antibody engineered in mouse-monkey chimeric form to reduce its antigenicity. The monkeys in the control group exhibited various spontaneous bleeding symptoms as well as continuous prolongation of activated partial thromboplastin time; notably, all exhibited joint bleeds, which are a hallmark of hemophilia. Weekly SC doses of ACE910 (initial 3.97 mg/kg followed by 1 mg/kg) significantly prevented these bleeding symptoms; notably, no joint bleeding symptoms were observed. ACE910 is expected to prevent spontaneous bleeds and joint damage in hemophilia A patients even with weekly SC dosing, although appropriate clinical investigation is required. © 2014 by The American Society of Hematology.

  2. Emerging drugs for the treatment of hemophilia A and B.

    Science.gov (United States)

    Morfini, Massimo; Zanon, Ezio

    2016-09-01

    Replacement therapy with clotting factor concentrates is the most appropriate and effective way to treat bleedings of Hemophilia A&B to prevent chronic arthropathy. Unfortunately, the short half-life (HL) of FVIII/IX concentrates obliges the patients to receive frequent infusions, a big concern for children. The development of inhibitors in about 30-45% of hemophilia A and in 3-5% of hemophilia B patient is the major adverse event of replacement therapy. In the last few years, new rFIX have been developed with HL. New rFVIII concentrates are displaying small increase of PK characteristics. The new bio-engineering methods allowed the production of molecules fused with Fc fragment of IgG or Albumin or linked to PEG. A new approach to improve hemostasis is represented by Mab against TFPI and small RNA interfering with Antithrombin synthesis. Another innovative drug seems to be the new bi-specific antibody which mimics FVIII function in linking FXa and FX to tenase production. The emerging drugs for hemophilia treatment seem to be very promising. The extended half-life will improve the adherence of patients to therapy. Accurate post-marketing surveillance studies will be necessary to check the efficacy, safety and immunogenicity of these new molecules.

  3. HBV, HCV and HIV among patients with Hemophilia in Khartoum ...

    African Journals Online (AJOL)

    Objectives: The main objective is to determine the screening, vaccination, seroconversion of hepatitis B, C and HIV among Sudanese hemophilic patients registered in Hemophilia Center Khartoum Teaching Hospital. Methods: During the period from July to November 2008, sixty two hemophilic male patients were randomly ...

  4. Problems of Hemophilia and the Role of the Rehabilitation Counselor.

    Science.gov (United States)

    Carrai, Edward B.; Handford, H. Allen

    1983-01-01

    Because of the multiple problems associated with hemophilia, optimal treatment is usually provided in a comprehensive care setting by a team of medical and nonmedical professionals. The rehabilitation counselor contributes expertise to that of other team members in development and implementation of an individual rehabilitation plan for…

  5. Molecular genetic study of hemophilia B in an Algerian population

    African Journals Online (AJOL)

    DELL

    2016-12-21

    Dec 21, 2016 ... described with this disease in 1952. It is characterized by spontaneous or prolonged hemorrages due to factor IX deficiency. Factor IX mutations have not been previously reported in Algerian patients. To understand the molecular basis of hemophilia B in Algeria, polymerase chain reaction (PCR) and direct.

  6. Ex vivo expanded autologous polyclonal regulatory T cells suppress inhibitor formation in hemophilia

    Directory of Open Access Journals (Sweden)

    Debalina Sarkar

    2014-01-01

    Full Text Available Adoptive cell therapy utilizing ex vivo expanded polyclonal CD4+CD25+FOXP3+ regulatory T cells (Treg is in use in clinical trials for the treatment of type 1 diabetes and prevention of graft versus host disease in bone marrow transplantation. Here, we seek to evaluate this approach in the treatment of inherited protein deficiencies, i.e., hemophilia, which is often complicated by antibody formation against the therapeutic protein. Treg from mice that express green fluorescent protein–marked FoxP3 were highly purified by two-step magnetic/flow sorting and ex vivo expanded 50- to 100-fold over a 2-week culture period upon stimulation with antibody-coated microbeads. FoxP3 expression was maintained in >80% of expanded Treg, which also expressed high levels of CD62L and CTLA-4. Transplanted Treg suppressed inhibitory antibody formation against coagulation factors VIII and IX in protein and gene therapies in strain-matched hemophilia A and B mice, including in mice with pre-existing antibodies. Although transplanted Treg became undetectable within 2 weeks, suppression persisted for >2 months. Additional studies suggested that antigen-specific suppression emerged due to induction of endogenous Treg. The outcomes of these studies support the concept that cell therapy with ex vivo expanded autologous Treg can be used successfully to minimize immune responses in gene and protein replacement therapies.

  7. Management of US men, women, and children with hemophilia and methods and demographics of the Bridging Hemophilia B Experiences, Results and Opportunities into Solutions (B-HERO-S) study.

    Science.gov (United States)

    Buckner, Tyler W; Witkop, Michelle; Guelcher, Christine; Frey, Mary Jane; Hunter, Susan; Peltier, Skye; Recht, Michael; Walsh, Christopher; Kessler, Craig M; Owens, Wendy; Clark, David B; Frick, Neil; Rice, Michelle; Iyer, Neeraj N; Holot, Natalia; Cooper, David L; Sidonio, Robert

    2017-04-01

    The Bridging Hemophilia B Experiences, Results and Opportunities Into Solutions (B-HERO-S) initiative was launched in an effort to address specific gaps in the understanding of the psychosocial impact of mild-moderate-severe hemophilia B. The original Hemophilia Experiences, Results and Opportunities (HERO) qualitative study evaluated the needs of people with hemophilia A or B in multiple countries; however, a majority of participants had the more common moderate-severe hemophilia A. The B-HERO-S study was designed in collaboration with the hemophilia community to evaluate the needs of adults with hemophilia B and caregivers of children with hemophilia B, including affected women and caregivers of girls with hemophilia. The report presented here describes participant demographics and comorbidities, as well as treatment regimens and access to treatment. Bleeding symptoms were reported by 27% of mothers of children with hemophilia B who participated. Women were more likely than men to self-report arthritis and depression/anxiety as comorbidities associated with hemophilia B. More adults and children with hemophilia B were on routine treatment than on on-demand treatment, and a high percentage of adults with moderate hemophilia B received routine treatment (86%). Many adults with hemophilia B (78%) and caregivers (69%) expressed concern about access to factor in the next 5 years, and of adults with hemophilia B, women more commonly experienced issues with access to factor in the past than did men (72% vs 44%). The findings of the B-HERO-S study reveal potential unmet needs of some patients with mild-moderate hemophilia B, and the results may be leveraged to inform patient outreach by hemophilia treatment centers and education initiatives. © 2017 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd.

  8. Cross-cultural adaptation of the CHO-KLAT for boys with hemophilia in rural and urban china

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    Wu Runhui

    2012-09-01

    Full Text Available Abstract Background Quality of life (QoL is increasingly recognized as an important outcome measure in clinical trials. The Canadian Hemophilia Outcomes-Kids Life Assessment Tool (CHO-KLAT shows promise for use in China. Objective To adapt the CHO-KLAT version 2.0 for use in clinical trials in China. Methods Forward and back translations of the CHO-KLAT2.0 were completed in 2008. Between October 2009 and June 2010, a series of 3 focus groups were held with 20 boys and 31 parents in rural and urban China to elicit additional concepts, important to their QoL, for the Chinese CHO-KLAT2.0. All of the items identified by boys and parents were reviewed by a group of experts, resulting in a Chinese version of the CHO-KLAT2.0. This version underwent a detailed cognitive debriefing process between October 2010 and June 2011. Thirteen patient-parent pairs participated in this cognitive debriefing process until a stable and clearly understood Chinese version of the CHO-KLAT2.0 was obtained. Results The initial back translation of the Chinese CHO-KLAT2.0 was slightly discrepant from the original English version on 12 items. These were all successfully adjudicated. The focus groups identified 9 new items that formed an add-on Socio-Economic Context (SEC module for China. Linguistic improvements were made after the 2nd, 5th, 7th and 13th cognitive debriefings pairs and affected a total of 18 items. The result was a 35 item CHO-KLAT2.0 and a SEC module in Simplified Chinese, both of which have good content validity. Conclusion This detailed process proved to be extremely valuable in ensuring the items were accurately interpreted by Chinese boys with hemophilia ages ≤18 years. The need for the additional SEC module highlighted the different context that currently exists in China with regard to hemophilia care as compared to many Western countries, and will be important in tracking progress within both rural and urban China over time. Changes based on the

  9. Past, present and future of hemophilia: a narrative review

    Directory of Open Access Journals (Sweden)

    Franchini Massimo

    2012-05-01

    Full Text Available Abstract Over the past forty years the availability of coagulation factor replacement therapy has greatly contributed to the improved care of people with hemophilia. Following the blood-borne viral infections in the late 1970s and early 1980, caused by coagulation factor concentrates manufactured using non-virally inactivated pooled plasma, the need for safer treatment became crucial to the hemophilia community. The introduction of virus inactivated plasma-derived coagulation factors and then of recombinant products has revolutionized the care of these people. These therapeutic weapons have improved their quality of life and that of their families and permitted home treatment, i.e., factor replacement therapy at regular intervals in order to prevent both bleeding and the resultant joint damage (i.e. primary prophylaxis. Accordingly, a near normal lifestyle and life-expectancy have been achieved. The main current problem in hemophilia is the onset of alloantibodies inactivating the infused coagulation factor, even though immune tolerance regimens based on long-term daily injections of large dosages of coagulation factors are able to eradicate inhibitors in approximately two-thirds of affected patients. In addition availability of products that bypass the intrinsic coagulation defects have dramatically improved the management of this complication. The major challenges of current treatment regimens, such the short half life of hemophilia therapeutics with need for frequent intravenous injections, encourage the current efforts to produce coagulation factors with more prolonged bioavailability. Finally, intensive research is devoted to gene transfer therapy, the only way to ultimately obtain cure in hemophilia.

  10. Pain Experience in Hemophilia Patients: A Hermeneutic Phenomenological Study

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    Masoume Rambod

    2016-10-01

    Full Text Available Background: Pain, as a crucial subsequence of joint hemorrhages in hemophilia patients, is chronic, debilitating, and distracting. This study aimed to describe and interpret pain experiences of hemophilia patients in their lives. Methods: This qualitative study with hermeneutic phenomenological approach was conducted on fourteen hemophilia patients who had been referred to a hemophiliacenter affiliated to Shiraz University of Medical Sciences, Shiraz, Iran. The study question was “what is the meaning of pain in hemophilia patients’ lives? The data were collected through semi-structured interviews and field notes through purposeful sampling. Then, thematic analysis with van Manen’s six-step methodological framework was used. MAX.QDA qualitative software package, 2010, was used to analyze the data. Results: The three main themes that emerged in this study were “alteration in physical health”, “engagement in psychological problems”, and “impairment in social relationships”. Alteration in physical health consisted of three subthemes, namely “impairment of physical function”, “change in body physics”, and “disturbance in sleep quality”. In addition, two subthemes including “nostalgia of pain in adults with hemophilia” and “psychological distress” emerged from engagement in psychological problems. Finally, “loss of social activity” and “change in relationships” were related to impairment in social relationships. Conclusion: The present study highlighted alteration in physical health, engagement in psychological problems, and impairment in social relationship as a result of pain in hemophilia patients. Thus, healthcare providers and family members have to pay special attention to these problems. Besides, providing complementary therapy interventions is suggested for reducing these issues.

  11. A Case of Hemophilia A Associated with Spontaneous Hemorrhagic Pleural Effusion and Intracranial Hem

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    Nuri Tutar

    2014-03-01

    Full Text Available Hemophilia A is a sex-linked recessive coagulation disorder almost exclusively occurring in male subjects and caused by a deficiency of factor VIII. It  is a rare disorder characterized by spontaneous hemorrhages. Spontaneous bleeding in the pleural space is very rare in hemophilia both in children and adults. Here in, we present the case of a 56-year-old hemophilia A patient with hemorrhagic pleural effusion and intracranial hematoma.

  12. Lentivirus-mediated platelet gene therapy of murine hemophilia A with pre-existing anti-factor VIII immunity.

    Science.gov (United States)

    Kuether, E L; Schroeder, J A; Fahs, S A; Cooley, B C; Chen, Y; Montgomery, R R; Wilcox, D A; Shi, Q

    2012-08-01

    The development of inhibitory antibodies, referred to as inhibitors, against exogenous factor VIII in a significant subset of patients with hemophilia A remains a persistent challenge to the efficacy of protein replacement therapy. Our previous studies using the transgenic approach provided proof-of-principle that platelet-specific expression could be successful in treating hemophilia A in the presence of inhibitory antibodies. To investigate a clinically translatable approach for platelet gene therapy of hemophilia A with pre-existing inhibitors. Platelet FVIII expression in preimmunized FVIII(null) mice was introduced by transplantation of lentivirus-transduced bone marrow or enriched hematopoietic stem cells. FVIII expression was determined with a chromogenic assay. The transgene copy number per cell was quantitated with real-time PCR. Inhibitor titer was measured with the Bethesda assay. Phenotypic correction was assessed by the tail clipping assay and an electrolytically induced venous injury model. Integration sites were analyzed with linear amplification-mediated PCR. Therapeutic levels of platelet FVIII expression were sustained in the long term without evoking an anti-FVIII memory response in the transduced preimmunized recipients. The tail clip survival test and the electrolytic injury model confirmed that hemostasis was improved in the treated animals. Sequential bone marrow transplants showed sustained platelet FVIII expression resulting in phenotypic correction in preimmunized secondary and tertiary recipients. Lentivirus-mediated platelet-specific gene transfer improves hemostasis in mice with hemophilia A with pre-existing inhibitors, indicating that this approach may be a promising strategy for gene therapy of hemophilia A even in the high-risk setting of pre-existing inhibitory antibodies. © 2012 International Society on Thrombosis and Haemostasis.

  13. The relationship between the medical director and the executive director: guidelines for success.

    Science.gov (United States)

    Gabel, Stewart

    2011-03-01

    The positional leadership of mental health care organizations commonly is in the hands of an executive director who has had administrative experience, but who may or may not have had clinical experience. The medical director of the mental health organization is a psychiatrist who reports to the executive director despite their different backgrounds and areas of expertise. The relationship between these two leaders is the responsibility of both, and is crucial to the success of the organization. This paper is concerned specifically with approaches that can be taken by the medical director to foster a successful working alignment with the executive director. The situation has some similarities (and significant differences) with that described by Gabarro and Kotter in "Managing Your Boss" (1993). A series of guidelines to enhance the potential success of the medical director in this supervisor/supervisee relationship is presented.

  14. DESCRIPTIVE EPIDEMIOLOGY OF HEMOPHILIA AND OTHER COAGULATION DISORDERS IN MANSOURA , EGYPT

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    Rasha ElAshry

    2010-08-01

    Full Text Available

    Hemophilia represent the most severe inherited bleeding  disorder (INB , it’s thought to affect inviduals from all geographical areas in equal frequency. In Egypt which has a population of approximately (80million consanguineous marriage are frequent, therefore autosomal recessive coagulation disorders reach a higher prevalence than in many other countries.

    The primary aim of this study was to describe the epidemiological situation of hemophilia in Mansoura, Egypt ,as based on retrospective analysis of clinical records Mansoura University Children Hospital between years 2000 and 2008. The second aim was to assess the orthopedic complications and occurrence of hepatitis C in those patients and relate this status to the type of replacement therapy received prior to the study.

    The study included 72 children with hematological disorders registered from 2000 to 2008 in MUCH. The hemophilic patient was defined as a person with physician-diagnosed hemophilia A or B and a measured factor VIII or IX activity level of 30% or less. Persons with acquired inhibitors of FVIII or FIX excluded. Severity level was categorized as mild if the factor activity level was 6

  15. Identification of people with acquired hemophilia in a large electronic health record database

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    Wang M

    2017-07-01

    Full Text Available Michael Wang,1 Anissa Cyhaniuk,2 David L Cooper,3 Neeraj N Iyer3 1Hemophilia and Thrombosis Center, University of Colorado School of Medicine, Aurora, CO, 2AC Analytic Solutions, Barrington, IL, 3Clinical Development, Medical and Regulatory Affairs, Novo Nordisk Inc., Plainsboro, NJ, USA Background: Electronic health records (EHRs can provide insights into diagnoses, treatment patterns, and clinical outcomes. Acquired hemophilia (AH is an ultrarare bleeding disorder characterized by factor VIII inhibiting autoantibodies. Aim: To identify patients with AH using an EHR database.Methods: Records were accessed from a large EHR database (Humedica between January 1, 2007 and July 31, 2013. Broad selection criteria were applied using the International Classification of Diseases, Ninth Revision, clinical modification (ICD-9-CM code for intrinsic circulating anticoagulants (286.5 and all subcodes and confirmation of records 6 months before and 12 months after the first diagnosis. Additional selection criteria included mention of “bleeding” within physician notes identified via natural language processing output and a normal prothrombin time and prolonged activated partial thromboplastin time.Results: Of 6,348 patients with a diagnosis code of 286.5 or any subcodes, 16 males and 15 females met the selection criteria. The most common bleeding locations reported was gastrointestinal (23%, vaginal (16%, and endocrine (13%. A wide range of comorbidities was reported. Natural language processing identified chart note mention of “hemophilia” in 3 patients (10%, “bruise” in 15 patients (48%, and “pain” in all 31 patients. No patients received a prescription for approved/recommended AH treatments. Four patient cases were reviewed to validate whether the identified cohort had AH; each patient had bleeding symptoms and a normal prothrombin time and prolonged activated partial thromboplastin time, although none received hemostatic treatments

  16. Acquired Hemophilia A in an advanced age patient of hispanic origin: a case report.

    Science.gov (United States)

    Rivera Cora, Nalyssa I; Irizarry Delgado, Freddie; Merle Ramírez, Santa M; Vera Quiñones, Jorge

    2017-09-04

    Acquired Hemophilia A (AHA) is a rare hematological disorder that exhibits an incidence of approximately 1.5 cases per million patients a year. It is characterized by the development of autoantibodies against circulating Factor VIII coagulation proteins which, in turn, which in turn lead to potentially life-threatening hemorrhagic episodes. The incidence of AHA increases with age; with 80% of the affected patient population encompassing men and women that are 65 years or older. Some of the challenges that are highlighted in managing this disorder relate to the delayed diagnosis of this condition due to the rarity of the latter, the difficulty in establishing reliable hemostasis, and the secondary complications that are found when using immunosuppressive and hemostatic treatments in tandem with the elderly population afflicted with this disease. A 90-year-old female of Hispanic origin presented with a 2-week history of generalized weakness, dizziness, shortness of breath and extensive purpuric formations that involved the left arm towards the lateral aspect of the thorax with the inclusion of a small right lateral neck hematoma formation. Upon initial laboratory screening, a hemoglobin level of 7.9, a hematocrit level of 21.9 and a PTT value of 70.9 were discovered. Despite conventional hemostatic treatment approaches, the patient did not show marked improvement of the laboratory values. Ongoing specialized laboratory reports, combined with the clinical presentation of the patient, led to the diagnosis of Acquired Hemophilia A. Treatment with recombinant porcine Factor VIII was initiated, which led to rapid improvement of clinical symptoms and laboratory values. The patient was discharged with current treatment plan and emergent follow/up with a hematologist was scheduled. Acquired Hemophilia A is an elusive bleeding disorder that has been seldom encountered in the demographics of Puerto Rico. The prompt detection of this diagnosis based on the clinical

  17. Turoctocog alfa: an evidence-based review of its potential in the treatment of hemophilia A

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    Takedani H

    2015-03-01

    Full Text Available Hideyuki Takedani, Jun Hirose Department of Joint Surgery, Research Hospital of the Institute of Medical Science, The University of Tokyo, Tokyo, Japan Abstract: Turoctocog alfa is the first B-domain-truncated third generation recombinant coagulation factor VIII (FVIII product. Nonclinical in vitro and animal model studies have demonstrated that turoctocog alfa has similar functional potency and hemostatic efficacy as comparator FVIII products. With respect to discrepancies in the level of FVIII concentrate in plasma of current FVIII products on comparing measurement results between one-stage clot and chromogenic assays, there was no difference in the in vitro turoctocog alfa study; however, measured FVIII concentrate in field study was higher with the chromogenic assay (1.08 IU/mL than with one-stage assay (0.83 IU/mL. Two published clinical studies on previously treated patients (PTPs and clinical pharmacokinetics have described that the pharmacokinetic parameters are similar, and the safety and efficacy for prevention and treatment for bleeding are also similar to those of standard half-life FVIII products. Three clinical trials are ongoing to assess the long-term safety and efficacy of turoctocog alfa for PTPs and previously untreated patients. Those data will be published in the near future, and it will be possible to use turoctocog alfa for all hemophilia patients. However, studies will be needed to confirm the turoctocog alfa profile, such as the stability of dissolved turoctocog alfa over 24 hours at room temperature and post-marketing clinical research aimed at meeting Europe Medicines Agency post-marketing safety and efficacy requirements in PTPs. It is recommended to wait before using turoctocog alfa for previously untreated patients and major surgery until further data have been collected and published. Keywords: hemophilia A, B-domain-truncated, third generation factor VIII product, previous untreated patients, chromogenic assay

  18. Ideas for Directors.

    Science.gov (United States)

    Child Care Information Exchange, 1989

    1989-01-01

    Provides ideas for child care directors on such topics as: (1) increased productivity; (2) testimonial letters; (3) legal guidelines that prevent problems; (4) persuasion practices; (5) decision making; (6) common mistakes of nonprofit organizations; and (7) fundraising success stories. (RJC)

  19. Non-executive directors.

    Science.gov (United States)

    2010-03-31

    A new professional networking site has been created for the NHS Alliance's non-executive director network (NEDNET). The website uses OnMedica's professional networking platform to provide a secure online environment in which NEDNET members can share information and best practice. The network aims to help non-executive directors find theirpeers, learn from each other and learn about the latest developments. The website can be found at www.medefero.com/nednet.

  20. Anesthetic management of patient with hemophilia a undergoing emergency ventriculoperitoneal shunting: A case report and review of literature

    Directory of Open Access Journals (Sweden)

    Rashid Saeed Khokhar

    2016-01-01

    Full Text Available Hemophilia A is a hemorrhagic trend almost exclusively affecting males (X-related recessive disease. In 85% of cases, it is caused by factor VIII deficiency, called hemophilia A or classic hemophilia. Successful anesthetic management depends on the special care and a multidisciplinary team of health professionals informed about the disease, including qualified hematologist, surgeon, and anesthesiologist.

  1. Advanced therapies for the treatment of hemophilia: future perspectives

    Science.gov (United States)

    2012-01-01

    Monogenic diseases are ideal candidates for treatment by the emerging advanced therapies, which are capable of correcting alterations in protein expression that result from genetic mutation. In hemophilia A and B such alterations affect the activity of coagulation factors VIII and IX, respectively, and are responsible for the development of the disease. Advanced therapies may involve the replacement of a deficient gene by a healthy gene so that it generates a certain functional, structural or transport protein (gene therapy); the incorporation of a full array of healthy genes and proteins through perfusion or transplantation of healthy cells (cell therapy); or tissue transplantation and formation of healthy organs (tissue engineering). For their part, induced pluripotent stem cells have recently been shown to also play a significant role in the fields of cell therapy and tissue engineering. Hemophilia is optimally suited for advanced therapies owing to the fact that, as a monogenic condition, it does not require very high expression levels of a coagulation factor to reach moderate disease status. As a result, significant progress has been possible with respect to these kinds of strategies, especially in the fields of gene therapy (by using viral and non-viral vectors) and cell therapy (by means of several types of target cells). Thus, although still considered a rare disorder, hemophilia is now recognized as a condition amenable to gene therapy, which can be administered in the form of lentiviral and adeno-associated vectors applied to adult stem cells, autologous fibroblasts, platelets and hematopoietic stem cells; by means of non-viral vectors; or through the repair of mutations by chimeric oligonucleotides. In hemophilia, cell therapy approaches have been based mainly on transplantation of healthy cells (adult stem cells or induced pluripotent cell-derived progenitor cells) in order to restore alterations in coagulation factor expression. PMID:23237078

  2. Postpartum Acquired Hemophilia: A Rare Cause of Postpartum Hemorrhage

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    Srikanth Seethala

    2013-01-01

    Full Text Available A 36-year-old female started having postpartum vaginal bleeding after normal vaginal delivery. She underwent hysterectomy for persistent bleeding and was referred to our institution. An elevation of PTT and normal PT made us suspect postpartum acquired hemophilia (PAH, and it was confirmed by low factor VIII activity levels and an elevated factor VIII inhibitor. Hemostasis was achieved with recombinant factor VII concentrates and desmopressin, and factor eradication was achieved with cytoxan, methylprednisolone, and plasmapheresis.

  3. Advanced therapies for the treatment of hemophilia: future perspectives

    Directory of Open Access Journals (Sweden)

    Liras Antonio

    2012-12-01

    Full Text Available Abstract Monogenic diseases are ideal candidates for treatment by the emerging advanced therapies, which are capable of correcting alterations in protein expression that result from genetic mutation. In hemophilia A and B such alterations affect the activity of coagulation factors VIII and IX, respectively, and are responsible for the development of the disease. Advanced therapies may involve the replacement of a deficient gene by a healthy gene so that it generates a certain functional, structural or transport protein (gene therapy; the incorporation of a full array of healthy genes and proteins through perfusion or transplantation of healthy cells (cell therapy; or tissue transplantation and formation of healthy organs (tissue engineering. For their part, induced pluripotent stem cells have recently been shown to also play a significant role in the fields of cell therapy and tissue engineering. Hemophilia is optimally suited for advanced therapies owing to the fact that, as a monogenic condition, it does not require very high expression levels of a coagulation factor to reach moderate disease status. As a result, significant progress has been possible with respect to these kinds of strategies, especially in the fields of gene therapy (by using viral and non-viral vectors and cell therapy (by means of several types of target cells. Thus, although still considered a rare disorder, hemophilia is now recognized as a condition amenable to gene therapy, which can be administered in the form of lentiviral and adeno-associated vectors applied to adult stem cells, autologous fibroblasts, platelets and hematopoietic stem cells; by means of non-viral vectors; or through the repair of mutations by chimeric oligonucleotides. In hemophilia, cell therapy approaches have been based mainly on transplantation of healthy cells (adult stem cells or induced pluripotent cell-derived progenitor cells in order to restore alterations in coagulation factor expression.

  4. Acquired hemophilia a: retrospective analysis of 49 cases from a single Chinese hemophilia center.

    Science.gov (United States)

    Yang, Yanhui; Xue, Feng; Shi, Hao; Wang, Hongmei; Zhang, Lei; Ji, Linxiang; Yang, Renchi

    2015-01-01

    Acquired hemophilia A (AHA) is a rare bleeding disorder caused by the autoantibody directed against factor VIII in patients without previous history of a bleeding disorder. We retrospectively analyzed the characteristics and outcomes of 49 patients with AHA diagnosed in our center from February 1994 to October 2012. Twenty-four patients with acute bleeding episodes were treated with prothrombin complex concentrate (PCC) at a relative low dose of 30 to -50 U/kg/d and achieved good outcomes without any adverse reaction. Corticosteroids alone or in combination with cyclophosphamide were used as the first-line therapy to eradicate the inhibitors. In 39 evaluable patients, 35 (89.7%) achieved complete remission (CR). This study demonstrates that when bypassing agents such as recombinant activated factor VII and activated PCCs are not affordable or available, low dose PCC is effective and safe to control acute bleeding in patients with AHA. First-line therapy achieved good outcomes with a CR rate of 89.7%. © The Author(s) 2013.

  5. Importance of immune response genes in hemophilia A

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    Josiane Bazzo de Alencar

    2013-01-01

    Full Text Available Hemophilia A is a disease caused by a deficiency of coagulation factor VIII resulting from genetic inheritance linked to chromosome X. One treatment option is the administration of plasma or recombinant FVIII. However, some patients develop inhibitors or antibodies against this factor. Inhibitors are alloantibodies that bind to the epitope of factor VIII causing it to be recognized by the immune system as a foreign peptide. This is the most serious complication in hemophilia patients in respect to replacement therapy. Some studies have suggested that genetic factors influence the development of factor VIII inhibitors such as ethnicity, family history, mutations in the factor VIII gene and in genes of the immune system. The aim of this study was to conduct a literature review to assess the influence of genetic factors of immune response genes, especially genes of the major histocompatibility complex and cytokines, which may be related to the development of factor VIII inhibitors in hemophilia A patients. Understanding these risk factors will help to determine future differential treatment in the control and prevention of the development of inhibitors.

  6. Coexistence of acquired hemophilia A and epidermolysis bullosa acquisita: Two case reports and published work review.

    Science.gov (United States)

    Yan, Tian-Meng; He, Chun-Xia; Hua, Bao-Lai; Li, Li; Jin, Hong-Zhong; Liu, Yue-Hua; Zuo, Ya-Gang

    2017-01-01

    Epidermolysis bullosa acquisita (EBA) is a rare chronic subepidermal bullous autoimmune disease. The occurrence of acquired hemophilia A (AHA) is low and so the coexistence of EBA and AHA is extremely rare. We herein described a case of EBA coexisting with AHA and a case of EBA coexisting with AHA and hepatitis B. These EBA may be related to the pathogenesis of AHA. In this study, we analyzed the clinical features in the two Chinese cases of EBA coexisting with AHA, and found esophageal hemorrhage and hematemesis were the main symptoms of both patients. Cyclosporin, prednisone and lamivudine effectively control EBA with AHA and hepatitis B. The dose of cyclosporin should be more than 4 mg/kg per day and the period of treatment should be longer than 5 months to reduce the risk of EBA co-occurring with AHA. © 2016 Japanese Dermatological Association.

  7. Acquired hemophilia A caused by factor VIII inhibitors: report of a case.

    Science.gov (United States)

    Hosoya, Yoshinori; Matsumura, Miho; Madoiwa, Seiji; Zuiki, Toru; Matsumoto, Shiro; Nunomiya, Shin; Lefor, Alan; Sata, Naohiro; Yasuda, Yoshikazu

    2013-06-01

    We report a case of acquired hemophilia A (AHA) after esophageal resection. The patient was an 80-year-old woman whose preoperative activated partial-thromboplastin time (APTT) was well within the normal range, at 34.9 s. She underwent thoracic esophagectomy and gastric pull-up for superficial esophageal cancer (operative time, 315 min; intraoperative blood loss, 245 ml). Intrathoracic and subcutaneous bleeding occurred spontaneously on postoperative day (POD) 39. The APTT was prolonged, at 140 s, and factor VIII inhibitor was 36 Bethesda U/ml. Treatment with recombinant activated factor VII, prednisolone, and cyclophosphamide resulted in remission within 2 months. This case supports an association between surgery and the triggering of factor VIII inhibitors. The diagnosis of AHA requires clinical acumen and must be considered in any patient with bleeding and a prolonged APTT.

  8. Mortality caused by intracranial bleeding in non-severe hemophilia A patients: reply

    NARCIS (Netherlands)

    Loomans, J. I.; Fijnvandraat, K.

    2017-01-01

    With great interest we read the letter of Dr. Patil et al. (1) in which they present the number and percentage of hemophilia patients registered in the Mumbai hemophilia center who died from (intracranial) bleeding between 2002 and 2015. We thank Dr. Patil et al. for sharing their data and for

  9. INSIGHT in risk factors and treatment of inhibitors in nonsevere hemophilia A

    NARCIS (Netherlands)

    van Velzen, A.S.

    2016-01-01

    Hemophilia A is an inherited X-linked bleeding disorder that occurs in male offspring of carrier females. In these individuals a mutation in the F8 gene, located on the X-chromosome, causes a deficiency of the factor VIII protein, clotting factor VIII. The worldwide prevalence of hemophilia is 1 in

  10. Hypocoagulability does not protect against atherosclerosis in hemophilia A patients with obesity

    NARCIS (Netherlands)

    Biere-Rafi, S.; Tuinenburg, A.; Haak, B.; Peters, M.; De Groot, E.; Verhamme, P.; Peerlinck, K.; Visseren, F.; Kruip, M.; Gorkom, B.L.-V.; Buller, H.; Gerdes, V.; Schutgens, R.; Kamphuisen, P.

    Introduction: Hemophilia A patients have a 50% lower cardiovascular mortality than the general population. Whether this is caused by less atherosclerosis due to hypocoagulability is unclear. We assessed whether hemophilia A patients with obesity, a major atherosclerotic risk factor, have a lower

  11. Genetic Risk Factors for Inhibitor Development in Patients with Hemophilia and Rare Bleeding Disorders

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    Taregh Bamedi

    2017-01-01

    Full Text Available Inhibitor development is a lifelong challenge for patients with bleeding disorders who received replacement therapy. Most commonly, inhibitor formation was observed in hemophilia A patients but patients with rare bleeding disorders (RBD especially patients with deficiency of factor XIII (FXIII and factor V (FV can develop an inhibitor against exogenous factors. Several factors considered as risk factors for inhibitor formations in these patients. Genetic risk factors are the main accused that can cause inhibitor formation in hemophilia patients but are less important in RBDs.For this review study, we searched MEDLINE and Web of Science databases for English sources and the following key words: hemophilia, inhibitor, rare bleeding disorder, rare inherited disorder, acquired hemophilia, acquired rare bleeding disorders, treatment complication, genetic in hemophilia, polymorphism in rare bleeding disorder, mutation in hemophilia and other required keywords.Hemophilia A (HA patients who had large deletion, nonsense mutation or intron 22 inversion are more susceptible for inhibitor development. Gene polymorphisms in immune system are also considered as other risk factors in HA patients.Keywords:  Hemophilia, rare bleeding disorder, inhibitor

  12. Shortened Lifespan and Lethal Hemorrhage in a Hemophilia A Mouse Model.

    Science.gov (United States)

    Staber, Janice M; Pollpeter, Molly J

    2016-01-01

    Hemophilia A animal models have helped advance our understanding of factor VIII deficiency. Previously, factor VIII deficient mouse models were reported to have a normal life span without spontaneous bleeds. However, the bleeding frequency and survival in these animals has not been thoroughly evaluated. To investigate the survival and lethal bleeding frequency in two strains of E-16 hemophilia A mice. We prospectively studied factor VIII deficient hemizygous affected males (n = 83) and homozygous affected females (n = 55) for survival and bleeding frequency. Animals were evaluated for presence and location of bleeds as potential cause of death. Hemophilia A mice had a median survival of 254 days, which is significantly shortened compared to wild type controls (p hemophilia A mice experienced hemorrhage in several tissues. This previously-underappreciated shortened survival in the hemophilia A murine model provides new outcomes for investigation of therapeutics and also reflects the shortened lifespan of patients if left untreated.

  13. Hemodialysis in a patient with severe hemophilia A and factor VIII inhibitor.

    Science.gov (United States)

    Gopalakrishnan, Natarajan; Usha, Thiruvengadam; Thopalan, Balasubramaniyan; Dhanapriya, Jeyachandran; Dineshkumar, Thanigachalam; Thirumalvalavan, Kaliaperumal; Sakthirajan, Ramanathan

    2016-10-01

    Hemophilia A is a hereditary X-linked recessive disease caused by mutations in the gene encoding factor VIII (FVIII), occurring in 1 out of 10,000 persons. Life expectancy and quality of life have dramatically improved recently in patients with hemophilia. Chronic kidney disease and need for renal replacement therapy in these patients are rare. The development of inhibitors to FVIII is the most serious complication of hemophilia and makes treatment of bleeds very challenging. We describe here a 28-year-old male patient with severe hemophilia A with presence of factor VIII inhibitor, who had end stage renal disease. Central venous access device was inserted along with infusion of factor eight inhibitor bypass activity before and after the procedure. He is currently on thrice weekly hemodialysis and doing well for 6 months without bleeding episodes. To our knowledge, hemophilia A with factor VIII inhibitor managed with hemodialysis has not been reported so far. © 2016 International Society for Hemodialysis.

  14. Portal vein thrombosis in a patient with HCV cirrhosis and combined hemophilia A and thrombophilia V Leiden

    Directory of Open Access Journals (Sweden)

    Nikos Eleftheriadis

    2010-10-01

    Full Text Available Nikos Eleftheriadis, Pantelis MakrisHemostatic Unit of The First Propedeutic Department of Internal Medicine, AHEPA Hospital, Aristotles University of Thessaloniki, GreeceAbstract: The relation of hemophilia A with thrombophilia V Leiden is extremely rare in the literature. Furthermore, hemophiliac patients have an increased risk of severe life-threatening hemorrhage, blood transfusions, and therefore hepatitis transmission, mainly hepatitis C (HCV.Aims and methods: We present a 54-year-old male with a 5-year history of decompensated liver cirrhosis on the grounds of HCV hepatitis, hemophilia A, and thrombophilia V Leiden. He was admitted to our department because of severe abdominal distension, resembling ‘tense ascites’ despite the use of diuretics. Clinical examination showed shifting dullness and a protuberant abdomen, while hematological and blood chemistry results revealed thrombopenia (platelets: 77000/mL and hypoalbuminemia. Repeated abdominal paracentesis (under factor VIII administration failed to remove ascitic fluid, while abdominal echosonography and computed tomography revealed severe edema of mesenterium and intraabdominal viscus and the absence of free ascitic fluid, atrophic cirrhotic liver, and splenomegaly. Moreover, abdominal doppler echosonography revealed signs of portal hypertension, previous portal vein thrombosis, and revascularization of the portal vein. Gastroscopy showed esophageal varices grade II, without signs of bleeding. A-FP and all other laboratory examinations were normal.Results: Our patient was intravenously treated with albumine and diuretics (furosemide with mild improvement of his abdominal distension. During his hospitalization he presented an episode of spontaneous bacterial peritonitis and hepatic encephalopathy, which were successfully treated with lactulose clysmas and ciprofloxacine. He was discharged in a good general condition.Conclusion: According to our case we consider the false clinical

  15. Lessons learned hiring HMO medical directors.

    Science.gov (United States)

    Ottensmeyer, D J; Key, M K

    1991-01-01

    A medical director has enormous influence on medical cost and quality in managed care organizations. Little empirical work has been done on the attributes of an effective HMO medical director. The survey discussed in this article sought to examine those desirable traits from the perspective of medical directors who have risen in the ranks to become employers of medical directors. Mailed questionnaires asked 30 experts to rate skills and personality qualities based on what they would look for in a prospective hire. The factors that emerged as significant were communication and interpersonal skills, clinical credibility, ego strength, concern about quality, motivation, data orientation, and leadership qualities, along with organizational/systemic variables. Implications for hiring and physician education are drawn.

  16. Pla director de seguretat

    OpenAIRE

    Plarromaní Tarruella, Albert

    2015-01-01

    Realització d'un pla director de seguretat d'una organització, en aquest cas una botiga d'electrodomèstics. S'ha utilitzat la ISO/IEC 27001:2013 i la metodologia MAGERIT com a referència durant tot el treball. Realización de un plan director de seguridad de una organización, en este caso una tienda de electrodomésticos. Se ha utilizado la ISO/IEC 27001:2013 y la metodología MAGERIT como referencia durante todo el trabajo. The final project of the Master in Information and Communication ...

  17. Diagnostic and prognostic value of factor VIII binding antibodies in acquired hemophilia A: data from the GTH-AH 01/2010 study.

    Science.gov (United States)

    Werwitzke, S; Geisen, U; Nowak-Göttl, U; Eichler, H; Stephan, B; Scholz, U; Holstein, K; Klamroth, R; Knöbl, P; Huth-Kühne, A; Bomke, B; Tiede, A

    2016-05-01

    Essentials Factor VIII (FVIII) binding IgG detected by ELISA could be an alternative to the Bethesda assay. We studied the performance of anti-FVIII IgG ELISA in patients with acquired hemophilia and controls. Anti-FVIII IgG > 99th percentile of controls was highly sensitive and specific. Patients with high anti-FVIII IgG have a lower chance of achieving remission. Background Acquired hemophilia A is a severe bleeding disorder that requires fast and accurate diagnosis as it occurs often unexpectedly in previously healthy men and women of every age. The Nijmegen-modified Bethesda assay is the diagnostic reference standard for detecting neutralizing autoantibodies against factor VIII (FVIII), but is not widely available, not ideal for quantifying the complex type 2 inhibitors seen in acquired hemophilia, and suffers from high inter-laboratory variability. Objectives To assess the diagnostic and prognostic value of FVIII-binding antibodies as detected by ELISA compared with the Nijmegen Bethesda assay. Methods Samples from the time of first diagnosis and clinical data were available from 102 patients with acquired hemophilia enrolled in the prospective GTH-AH 01/2010 study. Controls (n = 102) were matched for gender and age. Diagnostic cut-offs were determined by receiver-operator curve analysis. The prognostic value was assessed in 92 of the 102 patients by Cox regression analysis of time to partial remission. Results Anti-FVIII IgG above the 99th percentile (> 15 arbitrary units per mL) revealed high sensitivity and specificity (both 0.99; 95% confidence interval, 0.95-1.0) for diagnosing acquired hemophilia. The likelihood of achieving partial remission was related to anti-FVIII IgG concentration ( 1050, 0.39). The Bethesda titer was only associated with the likelihood of partial remission when analyzed in the central laboratory, but not when data from local GTH study sites were used. Conclusion Although the Nijmegen-modified Bethesda assay is the reference

  18. Upper Limb Deep Vein Thrombosis in Patient with Hemophilia A and Heterozygosity for Prothrombin G20210A: A Case Report and Review of the Literature

    Directory of Open Access Journals (Sweden)

    Fares Darawshy

    2017-01-01

    Full Text Available Deep vein thrombosis (DVT is a rare disease in patients with hemophilia A. We report a case of 22-year-old male with severe hemophilia A who presented to the emergency room with 5-day history of right arm pain that was attributed initially to bleeding event. In the absence of external signs of bleeding or hematoma and normal hemoglobin level, we suspected an underlying DVT. Doppler ultrasonography of the right upper limb revealed thrombosis of the subclavian vein and this was confirmed by CT venography. The d-dimer level was normal and investigations for prothrombotic state revealed heterozygosity for prothrombin G20210A mutation. Treatment with factor VIII and low molecular weight heparin led to successful resolution and marked improvement of his clinical condition.

  19. Associations of quality of life, pain, and self-reported arthritis with age, employment, bleed rate, and utilization of hemophilia treatment center and health care provider services: results in adults with hemophilia in the HERO study.

    Science.gov (United States)

    Forsyth, Angela L; Witkop, Michelle; Lambing, Angela; Garrido, Cesar; Dunn, Spencer; Cooper, David L; Nugent, Diane J

    2015-01-01

    Severe hemophilia and subsequent hemophilic arthropathy result in joint pain and impaired health-related quality of life (HRQoL). Assessment of HRQoL in persons with hemophilia (PWH), including underlying factors that drive HRQoL differences, is important in determining health care resource allocation and in making individualized clinical decisions. To examine potential associations between HRQoL, pain interference, and self-reported arthritis and age, employment, activity, bleed frequency, and hemophilia treatment center and health care professional utilization. PWH (age ≥18 years) from ten countries completed a 5-point Likert scale on pain interference over the previous 4 weeks, the EQ-5D-3L scale (mobility, usual activities, self-care, pain/discomfort, anxiety/depression) including a health-related visual analog scale (0-100, coded as an 11-point categorical response). Pain interference (extreme/a lot) was higher in PWH aged >40 years (31%) compared to those aged 31-40 years (27%) or ≤30 years (21%). In an analysis of eight countries with home treatment, PWH who reported EQ-5D mobility issues were less likely to be employed (53% vs 79%, with no mobility issues). Median annual bleed frequency increased with worsening EQ-5D pain or discomfort. The percentage of PWH with inhibitors reporting visual analog scale scores of 80-90-100 was lower (20%) than those without inhibitors (34%). Median bleed frequency increased with pain. Globally, nurse and social worker involvement increased with disability and pain; physiotherapist utilization was moderate regardless of the extent of disability or pain. Increased disability and pain were associated with increased age, lower employment, higher reported bleed frequency, and lower HRQoL.

  20. Culham names new director

    CERN Multimedia

    2003-01-01

    "The United Kingdom Atomic Energy Authority (UKAEA) announced the appointment of Professor Sir Chris Llewellyn Smith FRS (Fellow of the Royal Society) as Director of Culham, responsible for developing and implementing the strategy for the UK's fusion research programme" (1 page).

  1. Comparison of factor VIII transgenes bioengineered for improved expression in gene therapy of hemophilia A.

    Science.gov (United States)

    Dooriss, Kerry L; Denning, Gabriela; Gangadharan, Bagirath; Javazon, Elisabeth H; McCarty, David A; Spencer, H Trent; Doering, Christopher B

    2009-05-01

    Successful gene therapy of hemophilia A depends on the sustained expression of therapeutic levels of factor VIII (fVIII). Because of mRNA instability, interactions with resident endoplasmic reticulum (ER) chaperones, and the requirement for carbohydrate-facilitated transport from the ER to the Golgi apparatus, fVIII is expressed at much lower levels from mammalian cells than other proteins of similar size and complexity. A number of bioengineered forms of B domain-deleted (BDD) human fVIII have been generated and shown to have enhanced expression. Previously, we demonstrated that recombinant BDD porcine fVIII exhibits high-level expression due to specific sequence elements that increase biosynthesis via enhanced posttranslational transit through the secretory pathway. In the current study, high-expression recombinant fVIII constructs were compared directly in order to determine the relative expression of the various bioengineered fVIII transgenes. The data demonstrate that BDD porcine fVIII expression is superior to that of any of the human fVIII variant constructs tested. Mean fVIII expression of 18 units/10(6) cells/24 hr was observed from HEK-293 cells expressing a single copy of the porcine fVIII transgene, which was 36- to 225-fold greater than that of any human fVIII transgene tested. Furthermore, greater than 10-fold higher expression was observed in human cells transduced with BDD porcine fVIII versus BDD human fVIII-encoding lentiviral vectors, even at low proviral copy numbers, supporting its use over other human fVIII variants in future hemophilia A gene therapy clinical trials.

  2. Intraosseous delivery of lentiviral vectors targeting factor VIII expression in platelets corrects murine hemophilia A.

    Science.gov (United States)

    Wang, Xuefeng; Shin, Simon C; Chiang, Andy F J; Khan, Iram; Pan, Dao; Rawlings, David J; Miao, Carol H

    2015-04-01

    Intraosseous (IO) infusion of lentiviral vectors (LVs) for in situ gene transfer into bone marrow may avoid specific challenges posed by ex vivo gene delivery, including, in particular, the requirement of preconditioning. We utilized IO delivery of LVs encoding a GFP or factor VIII (FVIII) transgene directed by ubiquitous promoters (a MND or EF-1α-short element; M-GFP-LV, E-F8-LV) or a platelet-specific, glycoprotein-1bα promoter (G-GFP-LV, G-F8-LV). A single IO infusion of M-GFP-LV or G-GFP-LV achieved long-term and efficient GFP expression in Lineage(-)Sca1(+)c-Kit(+) hematopoietic stem cells and platelets, respectively. While E-F8-LV produced initially high-level FVIII expression, robust anti-FVIII immune responses eliminated functional FVIII in circulation. In contrast, IO delivery of G-F8-LV achieved long-term platelet-specific expression of FVIII, resulting in partial correction of hemophilia A. Furthermore, similar clinical benefit with G-F8-LV was achieved in animals with pre-existing anti-FVIII inhibitors. These findings further support platelets as an ideal FVIII delivery vehicle, as FVIII, stored in α-granules, is protected from neutralizing antibodies and, during bleeding, activated platelets locally excrete FVIII to promote clot formation. Overall, a single IO infusion of G-F8-LV was sufficient to correct hemophilia phenotype for long term, indicating that this approach may provide an effective means to permanently treat FVIII deficiency.

  3. Consensus recommendations for the diagnosis and treatment of acquired hemophilia A

    Directory of Open Access Journals (Sweden)

    Shima Midori

    2010-06-01

    Full Text Available Abstract Background Acquired hemophilia A (AHA is a rare bleeding disorder caused by an autoantibody to coagulation factor (F VIII. It is characterized by soft tissue bleeding in patients without a personal or family history of bleeding. Bleeding is variable, ranging from acute, life-threatening hemorrhage, with 9-22% mortality, to mild bleeding that requires no treatment. AHA usually presents to clinicians without prior experience of the disease, therefore diagnosis is frequently delayed and bleeds under treated. Methods Structured literature searches were used to support expert opinion in the development of recommendations for the management of patients with AHA. Results Immediate consultation with a hemophilia center experienced in the management of inhibitors is essential to ensure accurate diagnosis and appropriate treatment. The laboratory finding of prolonged activated partial thromboplastin time with normal prothrombin time is typical of AHA, and the diagnosis should be considered even in the absence of bleeding. The FVIII level and autoantibody titer are not reliable predictors of bleeding risk or response to treatment. Most patients with AHA are elderly; comorbidities and underlying conditions found in 50% of patients often influence the clinical picture. Initial treatment involves the control of acute bleeding with bypassing agents. Immunosuppressive treatment to eradicate the FVIII inhibitor should be started as soon as the diagnosis is confirmed to reduce the time the patient is at risk of bleeding. Conclusions These recommendations aim to increase awareness of this disorder among clinicians in a wide range of specialties and provide practical advice on diagnosis and treatment.

  4. Reliability of patient-reported outcome instruments in US adults with hemophilia: the Pain, Functional Impairment and Quality of life (P-FiQ study

    Directory of Open Access Journals (Sweden)

    Kempton CL

    2017-09-01

    Full Text Available Christine L Kempton,1 Michael Wang,2 Michael Recht,3 Anne Neff,4 Amy D Shapiro,5 Amit Soni,6 Roshni Kulkarni,7 Tyler W Buckner,2 Katharine Batt,8 Neeraj N Iyer,9 David L Cooper9 1Departments of Pediatrics and Hematology and Medical Oncology, Emory University School of Medicine, Atlanta, GA, USA; 2Hemophilia and Thrombosis Center, University of Colorado School of Medicine, Aurora, CO, USA; 3The Hemophilia Center, Oregon Health & Science University, Portland, OR, USA; 4Hematology and Medical Oncology, Cleveland Clinic, Cleveland, OH, USA; 5Indiana Hemophilia & Thrombosis Center, Indianapolis, IN, USA; 6Center for Inherited Blood Disorders and CHOC Children’s Hospital/UC Irvine, Orange, CA, USA; 7MSU Center for Bleeding and Clotting Disorders, Michigan State University, East Lansing, MI, USA; 8Hematology and Oncology, Wake Forest School of Medicine, Winston-Salem, NC, USA; 9Clinical, Medical and Regulatory Affairs, Novo Nordisk Inc., Plainsboro, NJ, USA Background: Hemophilia is marked by frequent joint bleeding, resulting in pain and functional impairment.Objective: This study aimed to assess the reliability of five patient-reported outcome (PRO instruments in people with hemophilia (PWH in a non-bleeding state.Methods: Adult male PWH of any severity and inhibitor status, with a history of joint pain or bleeding, completed a pain history and five PRO instruments (EQ-5D-5L, Brief Pain Inventory v2 [BPI], International Physical Activity Questionnaire [IPAQ], Short Form 36 Health Survey v2 [SF-36v2], and Hemophilia Activities List [HAL] during their routine comprehensive care visit. Patients were approached to complete the PRO instruments again at the end of their visit while in a similar non-bleeding state. Concordance of individual questionnaire items and correlation between domain scores were assessed using intra-class correlation coefficient (ICC.Results: Participants completing the retest (n=164 had a median age of 33.9 years. Median time for

  5. Characterization of Adeno-Associated Viral Vector-Mediated Human Factor VIII Gene Therapy in Hemophilia A Mice.

    Science.gov (United States)

    Greig, Jenny A; Wang, Qiang; Reicherter, Amanda L; Chen, Shu-Jen; Hanlon, Alexandra L; Tipper, Christopher H; Clark, K Reed; Wadsworth, Samuel; Wang, Lili; Wilson, James M

    2017-05-01

    Adeno-associated viral (AAV) vectors are promising vehicles for hemophilia gene therapy, with favorable clinical trial data seen in the treatment of hemophilia B. In an effort to optimize the expression of human coagulation factor VIII (hFVIII) for the treatment of hemophilia A, an extensive study was performed with numerous combinations of liver-specific promoter and enhancer elements with a codon-optimized hFVIII transgene. After generating 42 variants of three reduced-size promoters and three small enhancers, transgene cassettes were packaged within a single AAV capsid, AAVrh10, to eliminate performance differences due to the capsid type. Each hFVIII vector was administered to FVIII knockout (KO) mice at a dose of 10(10) genome copies (GC) per mouse. Criteria for distinguishing the performance of the different enhancer/promoter combinations were established prior to the initiation of the studies. These criteria included prominently the level of hFVIII activity (0.12-2.12 IU/mL) and the pattern of development of anti-hFVIII antibodies. In order to evaluate the impact of capsid on hFVIII expression and antibody formation, one of the enhancer and promoter combinations that exhibited high hFVIII immunogenicity was evaluated using AAV8, AAV9, AAVrh10, AAVhu37, and AAVrh64R1 capsids. The capsids subdivided into two groups: those that generated anti-hFVIII antibodies in ≤20% of mice (AAV8 and AAV9), and those that generated anti-hFVIII antibodies in >20% of mice (AAVrh10, AAVhu37, and AAVrh64R1). The results of this study, which entailed extensive vector optimization and in vivo testing, demonstrate the significant impact that transcriptional control elements and capsid can have on vector performance.

  6. Associations of quality of life, pain, and self-reported arthritis with age, employment, bleed rate, and utilization of hemophilia treatment center and health care provider services: results in adults with hemophilia in the HERO study

    Directory of Open Access Journals (Sweden)

    Forsyth AL

    2015-10-01

    Full Text Available Angela L Forsyth,1 Michelle Witkop,2 Angela Lambing,3 Cesar Garrido,4 Spencer Dunn,5 David L Cooper,6 Diane J Nugent7 1BioRx, Cincinnati, OH, USA; 2Munson Medical Center, Traverse City, MI, USA; 3Henry Ford Hospital, Detroit, MI, USA; 4Asociacion Venezolana para la Hemofilia, Caracas, Venezuela; 5Center for Inherited Blood Disorders, Orange, CA, USA; 6Novo Nordisk Inc., Plainsboro, NJ, USA; 7Children’s Hospital of Orange County, Center for Inherited Blood Disorders, Orange, CA, USA Introduction: Severe hemophilia and subsequent hemophilic arthropathy result in joint pain and impaired health-related quality of life (HRQoL. Assessment of HRQoL in persons with hemophilia (PWH, including underlying factors that drive HRQoL differences, is important in determining health care resource allocation and in making individualized clinical decisions.Aim: To examine potential associations between HRQoL, pain interference, and self-reported arthritis and age, employment, activity, bleed frequency, and hemophilia treatment center and health care professional utilization.Methods: PWH (age ≥18 years from ten countries completed a 5-point Likert scale on pain interference over the previous 4 weeks, the EQ-5D-3L scale (mobility, usual activities, self-care, pain/discomfort, anxiety/depression including a health-related visual analog scale (0–100, coded as an 11-point categorical response.Results: Pain interference (extreme/a lot was higher in PWH aged >40 years (31% compared to those aged 31–40 years (27% or ≤30 years (21%. In an analysis of eight countries with home treatment, PWH who reported EQ-5D mobility issues were less likely to be employed (53% vs 79%, with no mobility issues. Median annual bleed frequency increased with worsening EQ-5D pain or discomfort. The percentage of PWH with inhibitors reporting visual analog scale scores of 80–90–100 was lower (20% than those without inhibitors (34%. Median bleed frequency increased with pain

  7. Role of bone marrow transplantation for correcting hemophilia A in mice

    Science.gov (United States)

    Follenzi, Antonia; Raut, Sanj; Merlin, Simone; Sarkar, Rita

    2012-01-01

    To better understand cellular basis of hemophilia, cell types capable of producing FVIII need to be identified. We determined whether bone marrow (BM)–derived cells would produce cells capable of synthesizing and releasing FVIII by transplanting healthy mouse BM into hemophilia A mice. To track donor-derived cells, we used genetic reporters. Use of multiple coagulation assays demonstrated whether FVIII produced by discrete cell populations would correct hemophilia A. We found that animals receiving healthy BM cells survived bleeding challenge with correction of hemophilia, although donor BM-derived hepatocytes or endothelial cells were extremely rare, and these cells did not account for therapeutic benefits. By contrast, donor BM-derived mononuclear and mesenchymal stromal cells were more abundant and expressed FVIII mRNA as well as FVIII protein. Moreover, injection of healthy mouse Kupffer cells (liver macrophage/mononuclear cells), which predominantly originate from BM, or of healthy BM-derived mesenchymal stromal cells, protected hemophilia A mice from bleeding challenge with appearance of FVIII in blood. Therefore, BM transplantation corrected hemophilia A through donor-derived mononuclear cells and mesenchymal stromal cells. These insights into FVIII synthesis and production in alternative cell types will advance studies of pathophysiological mechanisms and therapeutic development in hemophilia A. PMID:22368271

  8. Prevalent Inhibitors in Hemophilia B Subjects Enrolled in the Universal Data Collection Database

    Science.gov (United States)

    Puetz, John; Soucie, J. Michael; Kempton, Christine L.; Monahan, Paul E.

    2015-01-01

    Summary Background Several risk factors for inhibitors have recently been described for hemophilia A. It has been assumed that similar risk factors are also relevant for hemophilia B, but there is limited data to confirm this notion. Objectives To determine the prevalence of and risk factors associated with inhibitors in hemophilia B Methods The database of the Universal Data Collection (UDC) project of the Centers for Disease Control for the years 1998 – 2011 was queried to determine the prevalence of inhibitors in hemophilia B subjects. In addition, disease severity, race/ethnicity, age, factor exposure, and prophylaxis usage were evaluated to determine their impact on inhibitor prevalence. Results Of the 3800 male subjects with hemophilia B enrolled in the UDC database, 75 (2%) were determined to have an inhibitor at some point during the study period. Severe disease (OR 13.1, 95% CI 6.2-27.7), black race (OR 2.2, 95% CI 1.2-4.1), and age less than 11 (OR 2.5, 95% CI 1.5-4.0) were found to be significantly associated with having an inhibitor. There was insufficient data to determine if type of factor used and prophylaxis were associated with inhibitors. Conclusions Inhibitors in hemophilia B are much less prevalent than hemophilia A, especially in patients with mild disease. Similar factors associated with inhibitors in hemophilia A also seem to be present for hemophilia B. The information collected by this large surveillance project did not permit evaluation of potential risk factors related to treatment approaches and exposures, and additional studies will be required. PMID:23855900

  9. Christmas Disease (Hemophilia –B – A Case Report

    Directory of Open Access Journals (Sweden)

    Md Rafiqul Alam

    2010-04-01

    Full Text Available We report a 25 years old man developed Haemarthrosis of left hip joint with a history of recurrent swelling and pain in multiple joints and prolonged bleeding following minor trauma since childhood. Subsequent investigations revealed Christmas disease (Haemophilia B. Hemophilia B is an X-linked bleeding disorder. This case emphasises the importance of considering a diagnosis of haemophilia in a man with unexplained bleeding, even in the absence of a positive family history. DOI: 10.3329/bsmmuj.v2i2.4766 BSMMU J 2009; 2(2: 90-91

  10. Message from Fermilab Director

    CERN Document Server

    2009-01-01

    With this issue’s message, Fermilab Director Pier Oddone opens a new series of occasional exchanges between CERN and other laboratories world-wide. As part of this exchange, CERN Director-General Rolf Heuer, wrote a message in Tuesday’s edition of Fermilab TodayPerspectivesNothing is more important for our worldwide particle physics community than successfully turning on the LHC later this year. The promise for great discoveries is huge, and many of the plans for our future depend on LHC results. Those of us planning national programmes in anticipation of data from the LHC face formidable challenges to develop future facilities that are complementary to the LHC, whatever the physics discoveries may be. At Fermilab, this has led us to move forcefully with a programme at the intensity frontier, where experiments with neutrinos and rare decays open a complementary window into nature. Our ultimate goal for a unified picture of nat...

  11. Beam director design report

    Energy Technology Data Exchange (ETDEWEB)

    Younger, F.C.

    1986-08-01

    A design and fabrication effort for a beam director is documented. The conceptual design provides for the beam to pass first through a bending and focusing system (or ''achromat''), through a second achromat, through an air-to-vacuum interface (the ''beam window''), and finally through the vernier steering system. Following an initial concept study for a beam director, a prototype permanent magnet 30/sup 0/ beam-bending achromat and prototype vernier steering magnet were designed and built. In volume II, copies are included of the funding instruments, requests for quotations, purchase orders, a complete set of as-built drawings, magnetic measurement reports, the concept design report, and the final report on the design and fabrication project. (LEW)

  12. Discussion with CERN Directorate

    CERN Multimedia

    CERN. Geneva

    2017-01-01

    Please note that the Discussion with CERN Directorate will be transmitted also in the following rooms: Council Chamber - 503-1-001 IT Amphitheatre - 31-3-004 Prevessin 774-R-013 Simultaneous interpreting into French and English will be available in the Main Auditorium. Une interprétation simultanée en français et en anglais sera disponible dans l'amphithéâtre principal.

  13. Partial correction of a severe molecular defect in hemophilia A, because of errors during expression of the factor VIII gene

    Energy Technology Data Exchange (ETDEWEB)

    Young, M.; Antonarakis, S.E. [Univ. of Geneva (Switzerland); Inaba, Hiroshi [Tokyo Medical College (Japan)] [and others

    1997-03-01

    Although the molecular defect in patients in a Japanese family with mild to moderately severe hemophilia A was a deletion of a single nucleotide T within an A{sub 8}TA{sub 2} sequence of exon 14 of the factor VIII gene, the severity of the clinical phenotype did not correspond to that expected of a frameshift mutation. A small amount of functional factor VIII protein was detected in the patient`s plasma. Analysis of DNA and RNA molecules from normal and affected individuals and in vitro transcription/translation suggested a partial correction of the molecular defect, because of the following: (i) DNA replication/RNA transcription errors resulting in restoration of the reading frame and/or (ii) {open_quotes}ribosomal frameshifting{close_quotes} resulting in the production of normal factor VIII polypeptide and, thus, in a milder than expected hemophilia A. All of these mechanisms probably were promoted by the longer run of adenines, A{sub 10} instead of A{sub 8}TA{sub 2}, after the delT. Errors in the complex steps of gene expression therefore may partially correct a severe frameshift defect and ameliorate an expected severe phenotype. 36 refs., 6 figs.

  14. Acquired Hemophilia A: A Frequently Overlooked Autoimmune Hemorrhagic Disorder

    Directory of Open Access Journals (Sweden)

    Yoshihiko Sakurai

    2014-01-01

    Full Text Available Acquired hemophilia A (AHA is a rare hemorrhagic disease in which autoantibodies against coagulation factor VIII- (FVIII- neutralizing antibodies (inhibitors impair the intrinsic coagulation system. As the inhibitors developed in AHA are autoantibodies, the disease may have an autoimmune cause and is often associated with autoimmune disease. Although acute hemorrhage associated with AHA may be fatal and is costly to treat, AHA is often unrecognized or misdiagnosed. AHA should thus be considered in the differential diagnosis particularly in postpartum women and the elderly with bleeding tendency or prolonged activated partial thromboplastin time. Cross-mixing tests and measurement of FVIII-binding antibodies are useful to confirm AHA diagnosis. For treatment of acute hemorrhage, hemostatic therapy with bypassing agents should be provided. Unlike in congenital hemophilia A with inhibitors, in which immune tolerance induction therapy using repetitive infusions of high-dose FVIII concentrates is effective for inhibitor eradication, immune tolerance induction therapy has shown poor efficacy in treating AHA. Immunosuppressive treatment should thus be initiated to eradicate inhibitors as soon as the diagnosis of AHA is confirmed.

  15. Acquired hemophilia A: a frequently overlooked autoimmune hemorrhagic disorder.

    Science.gov (United States)

    Sakurai, Yoshihiko; Takeda, Tomohiro

    2014-01-01

    Acquired hemophilia A (AHA) is a rare hemorrhagic disease in which autoantibodies against coagulation factor VIII- (FVIII-) neutralizing antibodies (inhibitors) impair the intrinsic coagulation system. As the inhibitors developed in AHA are autoantibodies, the disease may have an autoimmune cause and is often associated with autoimmune disease. Although acute hemorrhage associated with AHA may be fatal and is costly to treat, AHA is often unrecognized or misdiagnosed. AHA should thus be considered in the differential diagnosis particularly in postpartum women and the elderly with bleeding tendency or prolonged activated partial thromboplastin time. Cross-mixing tests and measurement of FVIII-binding antibodies are useful to confirm AHA diagnosis. For treatment of acute hemorrhage, hemostatic therapy with bypassing agents should be provided. Unlike in congenital hemophilia A with inhibitors, in which immune tolerance induction therapy using repetitive infusions of high-dose FVIII concentrates is effective for inhibitor eradication, immune tolerance induction therapy has shown poor efficacy in treating AHA. Immunosuppressive treatment should thus be initiated to eradicate inhibitors as soon as the diagnosis of AHA is confirmed.

  16. Cerebellar hemorrhage as a first presentation of acquired Hemophilia A.

    Science.gov (United States)

    Micic, Dejan; Williams, Eliot C; Medow, Joshua E

    2011-08-01

    Acquired hemophilia A (AHA) is an uncommon coagulation disorder caused by the development of autoantibodies against coagulation factor VIII (FVIII). While intracranial hemorrhage is a known complication of AHA, intracranial hemorrhage as the presenting manifestation of AHA has only been described in three previous case reports. We report a case of an 86-year-old woman with no previously reported history of coagulopathy presenting with an acute intraparenchymal cerebellar hemorrhage and laboratory studies demonstrating an isolated prolonged activated partial thromboplastin time (aPTT). We discuss an approach to the prolonged aPTT, and review the literature concerning the diagnosis and treatment of AHA. Occipital decompressive craniectomy with evacuation of the hemorrhage was performed. Eight hours following the procedure, the patient's status acutely declined with demonstration of a reoccurrence of the cerebellar hemorrhage and new right frontal lobe hemorrhage. After discussion with the patient's family, life-sustaining support measures were withdrawn. Postmortem analysis revealed a low FVIII activity level and the presence of FVIII inhibitor. The presentation of intracranial hemorrhage with an isolated prolonged aPTT is concerning for an acquired hemophilia with FVIII deficiency. Other causes of isolated prolonged aPTT such as a lupus anticoagulant must also be considered. Preoperative identification and work-up of the coagulation abnormality is essential to guide initial treatment.

  17. Predictors of retention among HIV/hemophilia health care professionals.

    Science.gov (United States)

    Brown, Larry K; Schultz, Janet R; Forsberg, Ann D; King, Gary; Kocik, Susan M; Butler, Regina B

    2002-01-01

    Health care professionals working with individuals with chronic medical illness, especially those infected with the Human Immunodeficiency Virus (HIV), may be at risk for burnout and departure due to various job stresses such as the death of patients and social stigma. Factors that prevent burnout and employee attrition are seldom studied. Two hundred thirteen staff (doctors, nurses and mental health workers) at a representative sample of Hemophilia Treatment Centers (HTC) completed instruments to measure Burnout (Maslach Burnout Inventory), and perceived job stresses and satisfaction (job tasks, interactions with colleagues and patient care). The staff were surveyed again after two years and their job status determined after 4 years. After 4 years, 35% of the staff had left the field of Hemophilia/HIV care. Univariate tests found that retention was significantly associated with initial job satisfaction, being married and low levels of stress with colleagues. Burnout, as measured by the Maslach Burnout Inventory, at baseline, was unrelated to job retention over 4 years. An adjusted multiple logistic regression of all significant variables found that colleague support was most related to retention (OR=2.8, CI=1.49,5.1). We conclude that attrition of highly trained staff is a significant issue for patients and HTCs. These data suggest the important role that a well-functioning team can have in buffering the inevitable stresses associated with HIV care. Mental Health professionals have considerable expertise in addressing these issues.

  18. Bayesian approach to the assessment of the population-specific risk of inhibitors in hemophilia A patients: a case study

    Directory of Open Access Journals (Sweden)

    Cheng J

    2016-10-01

    Full Text Available Ji Cheng,1,2 Alfonso Iorio,2,3 Maura Marcucci,4 Vadim Romanov,5 Eleanor M Pullenayegum,6,7 John K Marshall,3,8 Lehana Thabane1,2 1Biostatistics Unit, St Joseph’s Healthcare Hamilton, 2Department of Clinical Epidemiology and Biostatistics, 3Department of Medicine, McMaster University, Hamilton, ON, Canada; 4Geriatrics, Fondazione Ca’ Granda Ospedale Maggiore Policlinico, Università degli Studi di Milano, Milan, Italy; 5Baxter HealthCare, Global Medical Affairs, Westlake Village, CA, USA; 6Child Health Evaluation Sciences, Hospital for Sick Children, 7Dalla Lana School of Public Health, University of Toronto, Toronto, 8Division of Gastroenterology, Hamilton Health Science, Hamilton, ON, Canada Background: Developing inhibitors is a rare event during the treatment of hemophilia A. The multifacets and uncertainty surrounding the development of inhibitors further complicate the process of estimating inhibitor rate from the limited data. Bayesian statistical modeling provides a useful tool in generating, enhancing, and exploring the evidence through incorporating all the available information.Methods: We built our Bayesian analysis using three study cases to estimate the inhibitor rates of patients with hemophilia A in three different scenarios: Case 1, a single cohort of previously treated patients (PTPs or previously untreated patients; Case 2, a meta-analysis of PTP cohorts; and Case 3, a previously unexplored patient population – patients with baseline low-titer inhibitor or history of inhibitor development. The data used in this study were extracted from three published ADVATE (antihemophilic factor [recombinant] is a product of Baxter for treating hemophilia A post-authorization surveillance studies. Noninformative and informative priors were applied to Bayesian standard (Case 1 or random-effects (Case 2 and Case 3 logistic models. Bayesian probabilities of satisfying three meaningful thresholds of the risk of developing a clinical

  19. Internal consistency and item-total correlation of patient-reported outcome instruments and hemophilia joint health score v2.1 in US adult people with hemophilia: results from the Pain, Functional Impairment, and Quality of life (P-FiQ study

    Directory of Open Access Journals (Sweden)

    Wang M

    2017-10-01

    Full Text Available  Michael Wang,1 Katharine Batt,2 Craig Kessler,3 Anne Neff,4 Neeraj N Iyer,5 David L Cooper,5 Christine L Kempton6 1Hemophilia and Thrombosis Center, University of Colorado School of Medicine, Aurora, CO, 2Hematology and Oncology, Wake Forest School of Medicine, Winston-Salem, NC, 3Department of Medicine and Pathology, Division of Hematology/Oncology, Georgetown University Hospital, Washington, DC, 4Hematology and Medical Oncology, Cleveland Clinic, Cleveland, OH, 5Novo Nordisk Inc., Clinical, Medical, and Regulatory Affairs, Plainsboro, NJ, 6Departments of Pediatrics and Hematology and Medical Oncology, Emory University School of Medicine, Atlanta, GA, USA Background: The Pain, Functional Impairment, and Quality of Life study was an observational, cross-sectional assessment of the impact of pain on functional impairment and quality of life in adult people with hemophilia (PWH of any severity in the USA who experience joint pain and/or bleeding.Objective: To assess internal consistency (IC and item-total correlation (ITC of assessment tools used in the Pain, Functional Impairment, and Quality of Life study.Methods: Participants completed 5 patient-reported outcome instruments (­EQ-5D-5L with visual analog scale, Brief Pain Inventory v2 Short Form [BPI], International Physical Activity Questionnaire [IPAQ], Short Form 36 Health Survey v2 [SF-36v2], and Hemophilia Activities List [HAL] and underwent an optional physiotherapist-administered musculoskeletal exam (Hemophilia Joint Health Score v2.1 during routine visits. Reliability assessment included IC and ITC of each instrument.Results: A total of 381 adult PWH (median age, 34 years were enrolled. Participants were predominantly white/non-Hispanic (69.2%; 75% had congenital hemophilia A, and 70.5% had severe hemophilia. A total of 310 subjects reported bleeding within the past 6 months (mean [SD] number of bleeds, 7.1 [13.00]. IC was generally high across the instruments employed (Cronbach

  20. Novel, high incidence exercise-induced muscle bleeding model in hemophilia B mice

    DEFF Research Database (Denmark)

    Tranholm, M.; Kristensen, Annemarie Thuri; Broberg, M. L.

    2015-01-01

    INTRODUCTION: Muscle hematomas are the second most common complication of hemophilia and insufficient treatment may result in serious and even life-threatening complications. Hemophilic dogs and rats do experience spontaneous muscle bleeding, but currently, no experimental animal model is available...... specifically investigating spontaneous muscle bleeds in a hemophilic setting. AIM: The objective of this study was to develop a model of spontaneous muscle bleeds in hemophilia B mice. We hypothesized that treadmill exercise would induce muscle bleeds in hemophilia B mice but not in normal non-hemophilic mice...... and that treatment with recombinant factor IX (rFIX) before treadmill exercise could prevent the occurrence of pathology. METHODS: A total of 203 mice (123 F9-KO and 80 C57BL/6NTac) were included in three separate studies: (i) the model implementation study investigating the bleeding pattern in hemophilia B mice...

  1. Prevention of inhibitor development in hemophilia A in 2016. A glimpse into the future?

    Science.gov (United States)

    Franchini, Massimo; Lippi, Giuseppe

    2016-12-01

    Thanks to considerable progresses made over the last 30years, hemophilia benefits from the most efficacious and safe treatment among the many monogenic inherited disorders. The most challenging complication of replacement therapy in hemophilia A is the occurrence of alloantibodies against infused factor VIII (FVIII), thus predisposing the patients to increased morbidity and disability. Extensive research in this field has definitively unraveled that development of inhibitors in hemophilia A is a complex and multifactorial process, in which inherited and environmental factors dynamically interact. This narrative review, after providing a concise overview about the main genetic and non-genetic risk factors, is aimed to focus on prediction risk models and preventive strategies for minimizing the risk of developing inhibitors in hemophilia A patients. Copyright © 2016 Elsevier Ltd. All rights reserved.

  2. Hemophilia in childhood: the impact of the disease on parent's participation in their child's education

    National Research Council Canada - National Science Library

    Fabiane de Amorim Almeida; Tássia de Oliveira Vidal

    2008-01-01

    Objectives: To identify the limitations faced by the hemophiliac child, according to his/her parents, and how they deal with these limitations, and to verify how parents approach the problem of hemophilia...

  3. Directors General appointed

    CERN Multimedia

    1975-01-01

    At a special session on 21 March, presided over by P. Levaux, the Council of the European Organization for Nuclear Research appointed J . B. Adams and L . Van Hove as Directors General of the Organization for a period of five years beginning 1 January 1976. Dr. Adams will be responsible for the administration of CERN, for the operation of the equipment and services and for the construction of buildings and major equipment. Professor Van Hove will be responsible for the research activities of the Organization.

  4. Growing up with hemophilia: Health related quality of life and psychosocial functioning

    OpenAIRE

    Limperg, P.F. (P. F.)

    2017-01-01

    In this thesis, three major elements in the research around growing up with hemophilia are presented: development and evaluation of instruments (Part I), HRQOL and psychosocial outcomes (Part II) and psychosocial care (Part III). This thesis is the first to describe what it is like to grow up with hemophilia, in terms of HRQOL and psychosocial functioning, for both patients and their mothers. The development and evaluation of several HRQOL and psychosocial instruments (Part I) showed us that ...

  5. Hemoaction Game: An educational Step to Improve Hemophilia Children and Nurses Self-Efficacy

    OpenAIRE

    NOOASHIN BEHESHTIPOOR; SHIRIN GHANAVATI; MITRA EDRAKI; MEHRAN KARIMI; SEZANEH HAGHPANAH

    2016-01-01

    As hemophilia is a chronic bleeding disease and can interfere with daily performance of children, these children require continuous training to prevent bleeding and take timely action (1). Since children nurses play an important role in the education of involved children and their Selfefficacy and also due to today’s approach which is using educational computer games, the use of educational games in respect to teach hemophilia children how to have self-efficacy can ...

  6. Heavy hematuria requiring cystectomy in a patient with hemophilia A: a case report and literature review.

    Science.gov (United States)

    Washino, Satoshi; Hirai, Masaru; Kobayashi, Yutaka; Saito, Kimitoshi; Miyagawa, Tomoaki

    2015-08-13

    Hemophilia A is an X-linked recessive disorder caused by a deficiency in factor VIII. Hemophilia A affects 1 in 5,000-10,000 males. Hematuria is frequent in hemophilia. Hematuria in hemophilia is generally considered benign and manageable with conservative therapy; however, severe hematuria requiring surgical therapy has rarely been reported. A 60-year-old male with hemophilia A presented with persistent gross hematuria of unknown cause. He was treated with recombinant factor VIII products, followed by several conservative therapies as follows: clot evacuation by vesicoclysis, continuous bladder irrigation with normal saline, and intravesical instillation of aluminum hydroxide/magnesium hydroxide (Maalox); however, these failed to resolve the hemorrhaging. The patient was offered and consented to cystectomy with an ileal conduit. Intraoperative clotting was normal with the infusion of adequate recombinant factor VIII products and transfusion of fresh-frozen plasma, and the procedure was performed safely. After surgery, the patient had blood in his stool several times. No bleeding site was demonstrated in the colon by colonoscopy and (99m)Technetium-human serum albumin-diethylenetriaminepenta-acetic acid scintigraphy demonstrated that the extravasation of radioactive isotope was detected at the anal side of terminal ileum but not at the oral side. These findings were suspected to be bleeding from the ileoileal anastomosis. However, the bleeding was managed with recombinant factor VIII products. Cystectomy in hemophilia may be safe, if monitored appropriately. Urinary diversion using the intestine may be avoided because anastomotic hemorrhage may become a problem.

  7. Acquired hemophilia A with sigmoid colon cancer: successful treatment with rituximab followed by sigmoidectomy.

    Science.gov (United States)

    Ichikawa, Satoshi; Kohata, Katsura; Okitsu, Yoko; Suzuki, Makiko; Nakajima, Shinji; Yamada, Minami F; Onishi, Yasushi; Yamamoto, Joji; Suzuki, Sozo; Ishizawa, Kenichi; Kameoka, Junichi; Harigae, Hideo

    2009-07-01

    Acquired hemophilia A is a rare and potentially fatal condition of coagulopathy caused by autoantibodies against clotting factor VIII (factor VIII inhibitor). We report a case of a 63-year-old woman, who presented with a sudden onset of severe hemorrhagic tendency with exclusively prolonged activated partial thromboplastin time (APTT). She was diagnosed with acquired hemophilia A due to a decrease in factor VIII activity and a high titer of factor VIII inhibitor. Hemorrhage was well controlled by recombinant activated factor VII. Although the level of factor VIII inhibitor did not decline with prednisolone and cyclophosphamide, it became undetectable with rituximab. In parallel with controlling hemorrhage, malignancy, which may cause acquired hemophilia A, was searched for and sigmoid colon cancer was found. After the eradication of factor VIII inhibitor, surgical resection was performed uneventfully. Thereafter, acquired hemophilia A has been in complete remission without any additional therapy. The present case suggests the efficacy of rituximab for refractory acquired hemophilia A and the importance of the identification of underlying diseases that can cause acquired hemophilia A.

  8. Changing Paradigm of Hemophilia Management: Extended Half-Life Factor Concentrates and Gene Therapy.

    Science.gov (United States)

    Kumar, Riten; Dunn, Amy; Carcao, Manuel

    2016-02-01

    Management of hemophilia has evolved significantly in the last century-from recognition of the causative mechanism in the 1950s to commercially available clotting factor concentrates in the 1960s. Availability of lyophilized concentrates in the 1970s set the stage for home-based therapy, followed by introduction of virally attenuated plasma-derived, and then recombinant factor concentrates in the 1980s and 1990s, respectively. The subsequent years saw a paradigm shift in treatment goals from on-demand therapy to prophylactic factor replacement starting at an early age, to prevent hemarthrosis becoming the standard of care for patients with severe hemophilia. In the developed world, the increasing use of home-based prophylactic regimens has significantly improved the quality of life, and life expectancy of patients with severe hemophilia. Seminal developments in the past 5 years, including the commercial availability of extended half-life factor concentrates and the publication of successful results of gene therapy for patients with hemophilia B, promise to further revolutionize hemophilia care over the next few decades. In this review, we summarize the evolution of management for hemophilia, with a focus on extended half-life factor concentrates and gene therapy. Thieme Medical Publishers 333 Seventh Avenue, New York, NY 10001, USA.

  9. Challenges and successes in the treatment of hemophilia: the story of a patient with severe hemophilia A and high-titer inhibitors

    Directory of Open Access Journals (Sweden)

    Saba HI

    2012-05-01

    Full Text Available Hussain I Saba, Duc Quang Tran, JrDepartment of Medicine, University of South Florida Medical Center, Tampa, FL, USAAbstract: In the past, patients with severe hemophilia have suffered a substantially reduced quality of life with frequent bleeding episodes, disabling arthropathy, and shorter life expectancy. In addition, methods of treatment and management have been costly and time-consuming, and have placed a considerable burden on patients' physical and psychological well-being. With the advent of the on-demand therapy and prophylactic treatment paradigm, patients have been able to receive care with less interruption of daily activities. Treatments may be more challenging for hemophiliacs with inhibitors to replacement factor; however, recent advances in the use of bypassing agents and immune tolerance therapy have enabled them to aggressively manage their disease while maintaining their independence. This review focuses on the challenges of treating such a severe hemophiliac through examination of the lifetime experience of a young adult male with a severe form of congenital hemophilia A. At this stage of his life, the patient has minimal disabilities and is inhibitor-free through optimal care and strong family support. His aspiration to pursue a productive life has led him to a career in medicine. After receiving his medical degree, he pursued a specialty in the treatment of hemophilia. By assisting other hemophilia patients, he exemplifies both the rewards of persevering through episodes of bleeding and other complications and the fact that disabilities can be minimized when managed meticulously and in a timely fashion to enable a productive and dignified life.Keywords: hemophilia, quality of life, factor VIII inhibitors, hemophilia treatment center, early treatment, bypassing agent

  10. Magnetic heat pump flow director

    Science.gov (United States)

    Howard, Frank S. (Inventor)

    1995-01-01

    A fluid flow director is disclosed. The director comprises a handle body and combed-teeth extending from one side of the body. The body can be formed of a clear plastic such as acrylic. The director can be used with heat exchangers such as a magnetic heat pump and can minimize the undesired mixing of fluid flows. The types of heat exchangers can encompass both heat pumps and refrigerators. The director can adjust the fluid flow of liquid or gas along desired flow directions. A method of applying the flow director within a magnetic heat pump application is also disclosed where the comb-teeth portions of the director are inserted into the fluid flow paths of the heat pump.

  11. Antoni Christian Bryk (1820-1881) - professor of forensic medicine at Jagiellonian University (1852-1860), and director of the surgical clinic of Jagiellonian University in Cracow (1860-1881).

    Science.gov (United States)

    Zajączkowski, Tadeusz

    2014-01-01

    scientific discipline. In the 19th century two milestones revolutionised surgery: the development of narcosis, which enabled painless surgery, and the introduction of antisepsis and asepsis. The author presents the beginnings of academic surgery in Cracow. Its pioneer surgeons are presented. Extensive research was undertaken to collect the literature and documents in Polish, Austrian and German archives and libraries in order to prepare this study. Biographical details of the director of the Surgical Clinic, Prof. Antoni Bryk, are provided. He was the first person in Poland to introduce antisepsis and galvanocautery as routine procedures in the Cracow Clinic. The introduction of antisepsis contributed to a reduction in infection during surgery, and a reduction in postoperative mortality in Cracow Surgical Clinic. In this way Professor Bryk became the first Polish surgeon to apply Lister's antiseptic method in the treatment of wounds. Thus enlarged, the scope of surgery for intracranial, bone and other procedures became routine. Surgery is the oldest discipline in medicine. Poland's first university chair of surgery was established in the 18th century. Surgery, which until then had been the domain of barbers and bath house attendants, became a clinical,

  12. Registry of hemophilia and other bleeding disorders in Syria.

    Science.gov (United States)

    Ali, T; Schved, J F

    2012-11-01

    Creating a national registry for bleeding disorders is a major step in establishing a National Hemophilia Care Program in all countries. Creating such a registry which would contain accurate and regularly updated data, including laboratory analysis confirmed by a reference laboratory established at the Syrian Hemophilia Society. Blood samples were drawn and analysed in the Society reference laboratory for the following screening tests: prothrombin time (PT), APTT and coagulation factor assays. Inhibitor detection and VWF RiCof were performed depending on the result of the screening tests. HBs Ag, anti-HCV, anti-HIV 1+2 and syphilis tests were also performed to detect transfusion transmitted agents (TTA). Diagnosis of the bleeding disorder type was confirmed for 760 of these cases. Among the 760 confirmed patients, 82.5% had haemophilia. Among these, 89.6%were haemophilia A; 10.4% were haemophilia B; 8.3% had VWD; 9.2% had other rare bleeding disorders as follows: 1.2% FVII deficiency, 0.7% FV deficiency, 1.8% F1 deficiency, 0.4% FX deficiency, 1.4% platelets dysfunctions (mainly Glanzmann Thrombasthenia) and 3.7% had combined FVIII and FV deficiency. Eighty (21.3%) cases of 375 screened for transfusion transmitted agents were positive for at least one infection: 0.5% were HBsAg positive, 19.7% were anti-HCV positive, 0.8% had combined HBsAg and anti-HCV positivity and 0.3% was anti-Syphilis positive. All patients were negative for HIV1 and HIV2. The preliminary data presented here follow known data on haemophilia A, haemophilia B and VWD disease. This registry will certainly help in improving haemophilia care in Syria. © 2012 Blackwell Publishing Ltd.

  13. Genética comunitária e hemofilia em uma população brasileira Community genetics and hemophilia in a Brazilian population

    Directory of Open Access Journals (Sweden)

    Vânia Maria Caio

    2001-06-01

    Full Text Available A hemofilia é uma doença hemorrágica importante no Brasil, afetando cerca de um em cada dez mil indivíduos do sexo masculino. A autopercepção do portador a respeito da hemofilia e a sua interação com a comunidade são relevantes na abordagem clínica dessa doença. Nós investigamos vários aspectos sociais, psicológicos e comunitários da hemofilia em uma população brasileira (Campinas, São Paulo. Entrevistamos trinta portadores adultos da hemofilia, uma amostra-controle composta por 73 de seus irmãos normais do sexo masculino e 641 indivíduos da comunidade. A integração comunitária dos portadores da hemofilia mostrou-se afetada apenas nos aspectos sócio-econômicos, sem alteração no que diz respeito ao casamento, à procriação e à aquisição de melhores níveis educacionais. Observaram-se entre os portadores da hemofilia altos níveis de auto-rotulação, acompanhados de depressão, ansiedade e insegurança. A comunidade apresentou uma alta freqüência de completo desconhecimento a respeito da hemofilia (49%, demonstrando contra os hemofílicos os preconceitos normalmente observados contra os portadores de doenças contagiosas, como a AIDS. O trabalho sugere a estruturação de programa comunitário, visando à melhor adequação psicossocial dos portadores da hemofilia.Hemophilia is an important hemorrhagic disease in Brazil, affecting about 1 out of every 10,000 males. Patient's self-perception of hemophilia and interaction with the community are relevant to the clinical management of this disease. We investigated several social, psychological, and community aspects of hemophilia in a Brazilian population (Campinas, São Paulo State, interviewing 30 hemophiliac males, a control sample comprised of 73 non-hemophiliac brothers, and 641 individuals from the community. According to our results, more severe social disability in the hemophiliac patient was related to economic factors, mainly unemployment; however, no

  14. Construct validity of patient-reported outcome instruments in US adults with hemophilia: results from the Pain, Functional Impairment, and Quality of life (P-FiQ study

    Directory of Open Access Journals (Sweden)

    Batt K

    2017-08-01

    Full Text Available Katharine Batt,1 Michael Recht,2 David L Cooper,3 Neeraj N Iyer,3 Christine L Kempton4 1Hematology and Oncology, Wake Forest School of Medicine, Winston-Salem, NC, 2The Hemophilia Center, Oregon Health & Science University, Portland, OR, 3Novo Nordisk Inc., Plainsboro, NJ, 4Departments of Pediatrics and Hematology and Medical Oncology, Emory University School of Medicine, Atlanta, GA, USA Background: People with hemophilia (PWH experience frequent joint bleeding, resulting in pain and functional impairment. Generic and disease-specific patient-reported outcome (PRO instruments have been used in clinical studies, but rarely in the comprehensive hemophilia care setting. Objective: The objective of this study was to assess construct validity of PRO instruments measuring pain, functional impairment, and health-related quality of life in US PWH with a history of joint pain/bleeding. Methods: Adult male PWH completed 4 PRO instruments (EQ-5D-5L with visual analog scale, Brief Pain Inventory v2 Short Form [BPI], SF-36v2, Hemophilia Activities List [HAL] and underwent a musculoskeletal examination (Hemophilia Joint Health Score v2.1 [HJHS]. Construct validity between index and domain scores was evaluated by Pearson product-moment correlation coefficient. Results: A total of 381 PWH were enrolled. EQ-5D-5L Mobility correlated with BPI, SF-36v2, and HAL domains related to pain, physical function, and activity of the lower extremities. EQ-5D-5L Self-Care correlated only with HAL Self-Care. EQ-5D-5L Usual Activities correlated with BPI Pain Interference and domains within SF-36v2 and HAL related to pain and physical function/activities (particularly those involving the lower extremities. EQ-5D-5L Pain/Discomfort correlated with Bodily Pain and Physical Summary on SF-36v2, HAL Overall Activity, and all BPI pain domains. EQ-5D-5L Anxiety/Depression correlated with social/emotional/mental aspects of SF-36v2. On BPI, most pain domains correlated with Bodily

  15. Cardiovascular disease risk factors: prevalence and management in adult hemophilia patients.

    Science.gov (United States)

    Lim, Ming Y; Pruthi, Rajiv K

    2011-07-01

    With increasing longevity, the prevalence of cardiovascular disease (CVD) risk factors in hemophilia patients is expected to increase; however, evidence-based guidelines on management are lacking. The aim of the study was to determine the prevalence and management of CVD risk factors in hemophilia patients. A retrospective study of 58 adult hemophilia patients (≥35 years) attending Mayo Comprehensive Hemophilia Center between 1 January 2006 and 15 October 2009 were reviewed. The prevalence of CVD risk factors was hypertension 65.5%, diabetes 10.3%, smoking 12.5% and obesity 19.6%. A total of 31% did not have a lipid profile on record. Management of risk factors included antihypertensive medications in 84.2% and lipid-lowering agents in 12.1%. During their medical evaluation, four of seven active smokers received smoking cessation counseling and four of 11 obese patients received lifestyle modification advice. Eight patients (13.8%) experienced a CVD event: myocardial infarction (MI) (n=3), coronary artery disease (n=2), both MI and ischemic stroke (n=1) and hemorrhagic strokes (n=2). Only five of eight patients were on low-dose aspirin, of which aspirin was discontinued in one patient after he was diagnosed with hemophilia following a bleeding work-up. Another patient on dual antiplatelet therapy post stent placement developed epistaxis resulting in clopidogrel cessation. Hemophilia patients are at risk for CVD, similar to the general age-matched male population. Screening for CVD risk factors, with preventive dietary and pharmacologic interventions, play a key role in the prevention and long-term management of CVD. Collaborative efforts between primary care providers, cardiologists and hemophilia center specialists remain essential in managing these complex patients.

  16. IT governance guidelines for directors

    CERN Document Server

    Calder, Alan

    2005-01-01

    This important new book – 'IT Governance: Guidelines for Directors' provides directors, executives, managers and professional advisers with clear, pragmatic guidelines for ensuring that IT and the business work together for the same strategic objectives. 

  17. Object Oriented Programming in Director

    Directory of Open Access Journals (Sweden)

    Marian DARDALA

    2006-01-01

    Full Text Available Director is one of the most popular authoring software. As software for developing multimedia applications, Director is an object oriented programming environment. A very important issue to develop multimedia applications is the designing of their own classes. This paper presents the particular aspects concerning the available facilities offered by Lingo to design classes and to generate objects.

  18. The Director's Work on Himself

    DEFF Research Database (Denmark)

    Kuhlmann, Annelis

    2008-01-01

    A reading of Stanislavsky's major works about the actor's work on himself from the viewpoint of the director's work on himself.......A reading of Stanislavsky's major works about the actor's work on himself from the viewpoint of the director's work on himself....

  19. A Budget Impact Model of Hemophilia Bypassing Agent Prophylaxis Relative to Recombinant Factor VIIa On-Demand.

    Science.gov (United States)

    Mehta, Darshan A; Oladapo, Abiola O; Epstein, Joshua D; Novack, Aaron R; Neufeld, Ellis J; Hay, Joel W

    2016-02-01

    Hemophilia patients use factor-clotting concentrates (factor VIII for hemophilia A and factor IX for hemophilia B) for improved blood clotting. These products are used to prevent or stop bleeding episodes. However, some hemophilia patients develop inhibitors (i.e., the patient's immune system develops antibodies against these factor concentrates). Hence, these patients do not respond well to the factor concentrates. A majority of hemophilia patients with inhibitors are managed on-demand with the following bypassing agents: recombinant factor VIIa (rFVIIa) and activated prothrombin complex concentrate (aPCC). The recently published U.S. registries Dosing Observational Study in Hemophilia (DOSE) and Hemostasis and Thrombosis Research Society (HTRS) reported higher rFVIIa on-demand use for bleed management than previously described. To estimate aPCC and rFVIIa prophylaxis costs relative to rFVIIa on-demand treatment cost based on rFVIIa doses reported in U.S. registries. A literature-based cost model was developed assuming a base case on-demand annual bleed rate (ABR) of 28.7 per inhibitor patient, which was taken from a randomized phase 3 clinical trial. The doses for rFVIIa on-demand were taken from the median dose per bleed reported by the DOSE and HTRS registries. Model inputs for aPCC and rFVIIa prophylaxis (i.e., dosing and efficacy) were derived from respective randomized clinical trials. Cost analysis was from the U.S. payer perspective, and only direct drug costs were considered. The drug cost was based on the Medicare Part B 2014 average sale price (ASP). Two-way sensitivity and threshold analyses were performed by simultaneously varying on-demand ABR, prophylaxis efficacy, and unit drug cost. In addition to studying relative costs associated with on-demand and prophylaxis treatments, relative cost per bleeding episode avoided were also calculated for aPCC and rFVIIa prophylaxis treatments. The prophylaxis efficacy reported in the trials were used to

  20. User-centered requirements engineering in health information systems: a study in the hemophilia field.

    Science.gov (United States)

    Teixeira, Leonor; Ferreira, Carlos; Santos, Beatriz Sousa

    2012-06-01

    The use of sophisticated information and communication technologies (ICTs) in the health care domain is a way to improve the quality of services. However, there are also hazards associated with the introduction of ICTs in this domain and a great number of projects have failed due to the lack of systematic consideration of human and other non-technology issues throughout the design or implementation process, particularly in the requirements engineering process. This paper presents the methodological approach followed in the design process of a web-based information system (WbIS) for managing the clinical information in hemophilia care, which integrates the values and practices of user-centered design (UCD) activities into the principles of software engineering, particularly in the phase of requirements engineering (RE). This process followed a paradigm that combines a grounded theory for data collection with an evolutionary design based on constant development and refinement of the generic domain model using three well-known methodological approaches: (a) object-oriented system analysis; (b) task analysis; and, (c) prototyping, in a triangulation work. This approach seems to be a good solution for the requirements engineering process in this particular case of the health care domain, since the inherent weaknesses of individual methods are reduced, and emergent requirements are easier to elicit. Moreover, the requirements triangulation matrix gives the opportunity to look across the results of all used methods and decide what requirements are critical for the system success. Copyright © 2010 Elsevier Ireland Ltd. All rights reserved.

  1. Coronary artery calcification in hemophilia A: No evidence for a protective effect of factor VIII deficiency on atherosclerosis

    NARCIS (Netherlands)

    Tuinenburg, A.; Rutten, A.; Kavousi, M.; Leebeek, F.W.G.; Ypma, P.F.; Laros-Van Gorkom, B.A.P.; Nijziel, M.R.; Kamphuisen, P.W.; Mauser-Bunschoten, E.P.; Roosendaal, G.; Biesma, D.H.; Van Der Lugt A., [No Value; Hofman, A.; Witteman, J.C.M.; Bots, M.L.; Schutgens, R.E.G.

    2011-01-01

    Mortality due to ischemic heart disease is lower in hemophilia patients when compared to the general male population. As coagulation plays a role in the inflammatory pathways involved in atherogenesis, we investigated whether the clotting factor deficiency protects hemophilia patients from

  2. A patient with hypereosinophilic syndrome that manifested with acquired hemophilia and elevated IgG4: a case report

    Directory of Open Access Journals (Sweden)

    Nagao Yoshiro

    2012-02-01

    Full Text Available Abstract Introduction Hypereosinophilic syndrome is defined as a prolonged state (more than six months of eosinophilia (greater than 1500 cells/μL, without an apparent etiology and with end-organ damage. Hypereosinophilic syndrome can cause coagulation abnormalities. Among hypereosinophilic syndrome types, the lymphocytic variant (lymphocytic hypereosinophilic syndrome is derived from a monoclonal proliferation of T lymphocytes. Here, we describe the case of a patient with lymphocytic hypereosinophilic syndrome who presented with a coagulation abnormality. To the best of our knowledge, this is the first such report including a detailed clinical picture and temporal cytokine profile. Case presentation A 77-year-old Japanese man presented to our facility with massive hematuria and hypereosinophilia (greater than 2600 cells/μl. His eosinophilia first appeared five years earlier when he developed femoral artery occlusion. He manifested with multiple hematomas and prolonged activated partial thromboplastin time. His IgG4 level was remarkably elevated (greater than 2000 mg/dL. Polymerase chain reaction tests of peripheral blood and bone marrow identified lymphocytic hypereosinophilic syndrome. His prolonged activated partial thromboplastin time was found to be due to acquired hemophilia. Glucocorticoids suppressed both the hypereosinophilia and coagulation abnormality. However, tapering of glucocorticoids led to a relapse of the coagulation abnormality alone, without eosinophilia. Tumor necrosis factor α, interleukin-5, and/or eotaxin-3 may have caused the hypereosinophilia, and interleukin-10 was correlated with the coagulation abnormality. Conclusions To the best of our knowledge, this is the first case in which lymphocytic hypereosinophilic syndrome and IgG4-related disease have overlapped. In addition, our patient is only the second case of hypereosinophilic disease that manifested with acquired hemophilia. Our patient relapsed with the

  3. Power in the role of the medical director: what it is and how to get more.

    Science.gov (United States)

    Gabel, Stewart

    2011-05-01

    The formal leadership of mental health care organizations commonly resides in an executive director, who may or may not have had clinical training. The medical director is a psychiatrist who reports to the executive director. For some, this arrangement suggests that the medical director lacks or has lost power in the organization. This paper examines more specifically the types of power available to the medical director using French & Raven (1959) and Raven (2008) bases of power framework. The executive director/medical director relationship can be thought of as a relationship between individuals holding formal and informal power, respectively. Although medical directors lack formal or positional power, they potentially have and can gain more informal power based on their recognized clinical/medical expertise, their personal presence and an assertive involvement and focus on the organizational mission.

  4. Consensus Review of the Treatment of Cardiovascular Disease in People With Hemophilia A and B

    Science.gov (United States)

    Boral, Leonard I.; Cohen, Alice J.; Smyth, Susan S.; White, Gilbert C.

    2015-01-01

    With advances in care, increasing numbers of people with hemophilia (PWH) achieve near-normal life expectancies and present with typical age-related cardiovascular conditions. Evidence-based guidelines for medical or surgical management of cardiovascular conditions in individuals with hemophilia are limited. Published recommendations exist for the management of some common cardiovascular conditions (eg, ischemic heart disease, atrial fibrillation), but identifying optimal strategies for anticoagulant or antithrombotic therapy constitutes the primary challenge of managing nonoperative cardiovascular disease (CVD) in PWH. In general, as long as factor concentrates or other hemostatic therapies maintain adequate hemostasis, the recommended medical and surgical management of CVD in PWH parallels that in individuals without hemophilia. The presence of factor inhibitors complicates hemophilia management. Published outcomes of CVD treatment in PWH are similar to those in the general population. Specific knowledge about factor replacement, factor inhibitors, and disease-specific treatment distinguishes the cardiovascular care of PWH from similar care of individuals without this rare bleeding disorder. Furthermore, a multidisciplinary approach incorporating a hematologist with an onsite coagulation laboratory, ideally associated with a hemophilia treatment center, is integral to the management of CVD in PWH. PMID:25436468

  5. Atherosclerotic Heart Disease: Prevalence and Risk Factors in Hospitalized Men with Hemophilia A

    Science.gov (United States)

    Ragni, Margaret V.; Moore, Charity G.

    2011-01-01

    Summary Background Atherosclerotic heart disease (ASHD) is a common cause of morbidity and mortality in Western society. Few studies have determined prevalence and predictors of ASHD in hemophilia (HA), a population whose survival is improving with safer blood products and effective treatments for AIDS and hepatitis C. Objectives The purpose of this study was to determine prevalence and factors associated with ASHD in hemophilia A patients in Pennsylvania. Methods The prevalence of ASHD (myocardial infarction, angina, coronary disease), cardiac catheterization, coronary angiography, co-morbidities, and in-hospital mortality were assessed on statewide ASHD discharge data, 2001–2006, from the Pennsylvania Health Care Cost Containment Council (PHC4). Results The prevalence of hemophilia ASHD admissions fluctuated between 6.5% and 10.5% for 2001 to 2006, p=0.62. Compared to HA without ASHD, HA with ASHD were older and more likely to be hypertensive, hyperlipidemic, and diabetic, all pHemophilia patients with ASHD have similar cardiovascular risk factors, admitting diagnoses, severity of illness, and in-hospital mortality as the general population. These findings suggest cardiovascular prevention measures should be promoted in hemophilia. PMID:21371197

  6. In vivo induction of regulatory T cells for immune tolerance in hemophilia.

    Science.gov (United States)

    Wang, Xiaomei; Terhorst, Cox; Herzog, Roland W

    2016-03-01

    Current therapy for the X-linked coagulation disorder hemophilia is based on intravenous infusion of the specifically deficient coagulation factor. However, 20-30% of hemophilia A patients (factor VIII, FVIII, deficiency) generate inhibitory antibodies against FVIII. While formation of inhibitors directed against factor IX, FIX, resulting from hemophilia B treatment is comparatively rare, a serious complication that is often associated with additional immunotoxicities, e.g. anaphylaxis, occurs. Current immune tolerance protocols to eradiate inhibitors are lengthy, expensive, not effective in all patients, and there are no prophylactic tolerance regimens to prevent inhibitor formation. The outcomes of recent experiments in animal models of hemophilia demonstrate that regulatory CD4(+) T cells (Treg) are of paramount importance in controlling B cell responses to FVIII and FIX. This article reviews several novel strategies designed to in vivo induce coagulation factor-specific Treg cells and discusses the subsets of Treg that may promote immune tolerance in hemophilia. Among others, drug- and gene transfer-based protocols, lymphocyte transplant, and oral tolerance are reviewed. Copyright © 2015 Elsevier Inc. All rights reserved.

  7. Shortened Lifespan and Lethal Hemorrhage in a Hemophilia A Mouse Model.

    Directory of Open Access Journals (Sweden)

    Janice M Staber

    Full Text Available Hemophilia A animal models have helped advance our understanding of factor VIII deficiency. Previously, factor VIII deficient mouse models were reported to have a normal life span without spontaneous bleeds. However, the bleeding frequency and survival in these animals has not been thoroughly evaluated.To investigate the survival and lethal bleeding frequency in two strains of E-16 hemophilia A mice.We prospectively studied factor VIII deficient hemizygous affected males (n = 83 and homozygous affected females (n = 55 for survival and bleeding frequency. Animals were evaluated for presence and location of bleeds as potential cause of death.Hemophilia A mice had a median survival of 254 days, which is significantly shortened compared to wild type controls (p < 0.0001. In addition, the hemophilia A mice experienced hemorrhage in several tissues. This previously-underappreciated shortened survival in the hemophilia A murine model provides new outcomes for investigation of therapeutics and also reflects the shortened lifespan of patients if left untreated.

  8. Protein replacement therapy and gene transfer in canine models of hemophilia A, hemophilia B, von willebrand disease, and factor VII deficiency.

    Science.gov (United States)

    Nichols, Timothy C; Dillow, Aaron M; Franck, Helen W G; Merricks, Elizabeth P; Raymer, Robin A; Bellinger, Dwight A; Arruda, Valder R; High, Katherine A

    2009-01-01

    Dogs with hemophilia A, hemophilia B, von Willebrand disease (VWD), and factor VII deficiency faithfully recapitulate the severe bleeding phenotype that occurs in humans with these disorders. The first rational approach to diagnosing these bleeding disorders became possible with the development of reliable assays in the 1940s through research that used these dogs. For the next 60 years, treatment consisted of replacement of the associated missing or dysfunctional protein, first with plasma-derived products and subsequently with recombinant products. Research has consistently shown that replacement products that are safe and efficacious in these dogs prove to be safe and efficacious in humans. But these highly effective products require repeated administration and are limited in supply and expensive; in addition, plasma-derived products have transmitted bloodborne pathogens. Recombinant proteins have all but eliminated inadvertent transmission of bloodborne pathogens, but the other limitations persist. Thus, gene therapy is an attractive alternative strategy in these monogenic disorders and has been actively pursued since the early 1990s. To date, several modalities of gene transfer in canine hemophilia have proven to be safe, produced easily detectable levels of transgene products in plasma that have persisted for years in association with reduced bleeding, and correctly predicted the vector dose required in a human hemophilia B liver-based trial. Very recently, however, researchers have identified an immune response to adeno-associated viral gene transfer vector capsid proteins in a human liver-based trial that was not present in preclinical testing in rodents, dogs, or nonhuman primates. This article provides a review of the strengths and limitations of canine hemophilia, VWD, and factor VII deficiency models and of their historical and current role in the development of improved therapy for humans with these inherited bleeding disorders.

  9. Another Phoenix VA director leaves

    Directory of Open Access Journals (Sweden)

    Robbins RA

    2016-08-01

    Full Text Available No abstract available. Article truncated after 150 words. The Arizona Republic reports that the director at the Phoenix VA Medical Center, Deborah Amdur, will retire after only 9 months for health reasons (1. Amdur will be replaced by Barbara Fallen, director of the VA Loma Linda Healthcare System. Fallen will be interim director until a permanent replacement for Amdur can be found. This is the fifth hospital director since former Director Sharon Helman was removed in mid-2014 amid the nationwide veterans health-care scandal that was first exposed at the Phoenix VA. The Veterans Integrated Service Network (VISN in Gilbert, which oversees the VA Medical Center in Arizona, New Mexico and West Texas has also been through a series of 4 directors since Susan Bowers retired under pressure in the wake of the VA scandal. Marie Weldon, current acting regional director, also oversees the Los Angeles-based VA Desert Pacific Healthcare System. Weldon described Fallen as “an experienced leader who ...

  10. Bayesian approach to the assessment of the population-specific risk of inhibitors in hemophilia A patients: a case study.

    Science.gov (United States)

    Cheng, Ji; Iorio, Alfonso; Marcucci, Maura; Romanov, Vadim; Pullenayegum, Eleanor M; Marshall, John K; Thabane, Lehana

    2016-01-01

    Developing inhibitors is a rare event during the treatment of hemophilia A. The multifacets and uncertainty surrounding the development of inhibitors further complicate the process of estimating inhibitor rate from the limited data. Bayesian statistical modeling provides a useful tool in generating, enhancing, and exploring the evidence through incorporating all the available information. We built our Bayesian analysis using three study cases to estimate the inhibitor rates of patients with hemophilia A in three different scenarios: Case 1, a single cohort of previously treated patients (PTPs) or previously untreated patients; Case 2, a meta-analysis of PTP cohorts; and Case 3, a previously unexplored patient population - patients with baseline low-titer inhibitor or history of inhibitor development. The data used in this study were extracted from three published ADVATE (antihemophilic factor [recombinant] is a product of Baxter for treating hemophilia A) post-authorization surveillance studies. Noninformative and informative priors were applied to Bayesian standard (Case 1) or random-effects (Case 2 and Case 3) logistic models. Bayesian probabilities of satisfying three meaningful thresholds of the risk of developing a clinical significant inhibitor (10/100, 5/100 [high rates], and 1/86 [the Food and Drug Administration mandated cutoff rate in PTPs]) were calculated. The effect of discounting prior information or scaling up the study data was evaluated. Results based on noninformative priors were similar to the classical approach. Using priors from PTPs lowered the point estimate and narrowed the 95% credible intervals (Case 1: from 1.3 [0.5, 2.7] to 0.8 [0.5, 1.1]; Case 2: from 1.9 [0.6, 6.0] to 0.8 [0.5, 1.1]; Case 3: 2.3 [0.5, 6.8] to 0.7 [0.5, 1.1]). All probabilities of satisfying a threshold of 1/86 were above 0.65. Increasing the number of patients by two and ten times substantially narrowed the credible intervals for the single cohort study (1.4 [0.7, 2

  11. Bullous pemphigoid associated with acquired hemophilia a: a rare association of autoimmune disease.

    Science.gov (United States)

    Aljasser, Mohammed I; Sladden, Chris; Crawford, Richard I; Au, Sheila

    2014-01-01

    Acquired hemophilia (AH) is a rare autoimmune disease with an annual incidence of one per million and has a mortality rate of up to 22%. It is caused by the development of autoantibodies against factor VIII. Approximately half of the reported cases are associated with autoimmune disorders, pregnancy, malignancies, and adverse drug reactions. Autoimmune diseases are the most frequently associated disorders and include rheumatoid arthritis, systemic lupus erythematosus, cryoglobulinemia, pemphigus vulgaris, and bullous pemphigoid. There are a few reports of acquired hemophilia and bullous pemphigoid in the literature. We report a 73-year-old male who presented with cutaneous blistering, upper gastrointestinal bleeding, and hemoptysis. He later developed right flank pain secondary to a retroperitoneal hematoma. He had a prolonged partial thromboplastin time, a low factor VIII level, and a high factor VIII inhibitor level, all consistent with acquired hemophilia. Skin biopsies were diagnostic for bullous pemphigoid. He was treated successfully with prednisone, cyclophosphamide, rituximab, and intravenous immunoglobulin.

  12. 7 CFR 29.17 - Director.

    Science.gov (United States)

    2010-01-01

    ... of the Department of Agriculture AGRICULTURAL MARKETING SERVICE (Standards, Inspections, Marketing... INSPECTION Regulations Definitions § 29.17 Director. Director or Acting Director, Tobacco Division, Agricultural Marketing Service, U.S. Department of Agriculture. ...

  13. Phenotypic correction of murine hemophilia A using an iPS cell-based therapy.

    Science.gov (United States)

    Xu, Dan; Alipio, Zaida; Fink, Louis M; Adcock, Dorothy M; Yang, Jianchang; Ward, David C; Ma, Yupo

    2009-01-20

    Hemophilia A is caused by mutations within the Factor VIII (FVIII) gene that lead to depleted protein production and inefficient blood clotting. Several attempts at gene therapy have failed for various reasons-including immune rejection. The recent generation of induced pluripotent stem (iPS) cells from somatic cells by the ectopic expression of 3 transcription factors, Oct4, Sox2, and Klf4, provides a means of circumventing the immune rejection barrier. To date, iPS cells appear to be indistinguishable from ES cells and thus provide tremendous therapeutic potential. Here we prepared murine iPS cells from tail-tip fibroblasts and differentiated them to both endothelial cells and endothelial progenitor cells by using the embryoid body differentiation method. These iPS cells express major ES cell markers such as Oct4, Nanog, SSEA-1, alkaline phosphatase, and SALL4. Endothelial/endothelial progenitor cells derived from iPS cells expressed cell-specific markers such as CD31, CD34, and Flk1 and secreted FVIII protein. These iPS-derived cells were injected directly into the liver of irradiated hemophilia A mice. At various times after transplantation (7-90 days) hemophilia A mice and their control mice counterparts were challenged by a tail-clip bleeding assay. Nontransplanted hemophilia A mice died within a few hours, whereas transplanted mice survived for more than 3 months. Plasma FVIII levels increased in transplanted hemophilia A mice during this period to 8% to 12% of wild type and corrected the hemophilia A phenotype. Our studies provide additional evidence that iPS cell therapy may be able to treat human monogenetic disorders in the future.

  14. Leadership development for program directors.

    Science.gov (United States)

    Bing-You, Robert; Wiltshire, Whitney; Skolfield, Jenny

    2010-12-01

    Residency program directors have increasingly challenging roles, but they may not be receiving adequate leadership development. To assess and facilitate program directors' leadership self-awareness and development at a workshop retreat. At our annual program director retreat, program directors and associate program directors from a variety of specialties completed the Thomas-Kilmann Conflict Mode Instrument (TKI), which evaluates an individual's behavior in conflict situations, and the Hersey-Blanchard Situational Leadership (HBSL) model, which measures individuals' preferred leadership style in working with followers. Participants received their results during the retreat and discussed their leadership style results in the context of conflict situations experienced in the past. An online survey was distributed 3 weeks after the retreat to assess participant satisfaction and to determine whether participants would make changes to their leadership styles. Seventeen program directors attended the retreat and completed the tools. On the TKI, 47% preferred the Compromising mode for handling conflict, while 18% preferred either the Avoiding or Accommodating modes. On the HBSL, 71% of program directors preferred a Coaching leadership style. Ninety-one percent of postretreat-survey respondents found the leadership tools helpful and also thought they had a better awareness of their conflict mode and leadership style preferences. Eighty-two percent committed to a change in their leadership behaviors in the 6 months following the retreat. Leadership tools may be beneficial for promoting the professional development of program directors. The TKI and HBSL can be used within a local retreat or workshop as we describe to facilitate positive leadership-behavior changes.

  15. Leadership Development for Program Directors

    Science.gov (United States)

    Bing-You, Robert; Wiltshire, Whitney; Skolfield, Jenny

    2010-01-01

    Background Residency program directors have increasingly challenging roles, but they may not be receiving adequate leadership development. Objective To assess and facilitate program directors' leadership self-awareness and development at a workshop retreat. Methods At our annual program director retreat, program directors and associate program directors from a variety of specialties completed the Thomas-Kilmann Conflict Mode Instrument (TKI), which evaluates an individual's behavior in conflict situations, and the Hersey-Blanchard Situational Leadership (HBSL) model, which measures individuals' preferred leadership style in working with followers. Participants received their results during the retreat and discussed their leadership style results in the context of conflict situations experienced in the past. An online survey was distributed 3 weeks after the retreat to assess participant satisfaction and to determine whether participants would make changes to their leadership styles. Results Seventeen program directors attended the retreat and completed the tools. On the TKI, 47% preferred the Compromising mode for handling conflict, while 18% preferred either the Avoiding or Accommodating modes. On the HBSL, 71% of program directors preferred a Coaching leadership style. Ninety-one percent of postretreat-survey respondents found the leadership tools helpful and also thought they had a better awareness of their conflict mode and leadership style preferences. Eighty-two percent committed to a change in their leadership behaviors in the 6 months following the retreat. Conclusions Leadership tools may be beneficial for promoting the professional development of program directors. The TKI and HBSL can be used within a local retreat or workshop as we describe to facilitate positive leadership-behavior changes. PMID:22132267

  16. Hemophilic pseudotumor of the mandible in a patient with hemophilia B.

    Science.gov (United States)

    Chattopadhyay, Probodh K; Nagori, Shakil Ahmed; Menon, Rahul P; Balasundaram, T

    2017-12-01

    Hemophilic pseudotumor is a rare complication occurring in patients with hemophilia, frequently seen in the femur, tibia, pelvic bones, iliac bones, or rarely in the maxillofacial region. A 7-year-old male reported with a spontaneous extra-oral swelling that was managed with pre-operative transfusion of factor IX along with curettage of the lesion. Our report presents only the fourth case in literature wherein this tumor presented in a patient with hemophilia B. Hemophilic pseudotumor is a rare entity in the maxillofacial region. High degree of suspicion is required for diagnosis, and close coordination between the medical and surgical teams aids in management.

  17. Bleeding due to acquired hemophilia A in acute pancreatitis: a case report.

    Science.gov (United States)

    Shimizu, Tomoki; Tsunoda, Yuya; Ito, Tsuyoshi; Imamura, Satoshi; Nagakubo, Shuichi; Morohoshi, Yuichi; Koike, Yuji; Fujita, Yuriko; Komatsu, Hirokazu

    2016-01-01

    Acquired hemophilia A leads to severe bleeding and is known to be related to many underlying diseases; however, it has not been reported to occur as a complication of pancreatitis. We present a case of acquired hemophilia A secondary to severe acute pancreatitis. A 76-year-old female developed a hematoma in the lower leg muscle while being treated for severe acute pancreatitis. Blood tests revealed prolonged activated partial thromboplastin time (APTT) and the presence of an autoantibody to factor VIII. The bleeding diathesis was successfully controlled by immunosuppressive therapy. This case highlights the need for careful differential diagnosis for successful management of bleeding disorders as complications of pancreatitis.

  18. Acquired factor VIII inhibitor (acquired hemophilia A) presenting as spontaneous blood-filled scrotum.

    Science.gov (United States)

    Verma, Rajanshu; Noack, Jill; Vemuri, Radhakrishna; Loehrke, Mark E

    2011-05-01

    Acquired hemophilia A, also known as acquired factor VIII deficiency, is an exceedingly rare bleeding diathesis that does not require any personal or family history of bleeding or clotting disorder. Because treatment is available, misdiagnosing or completely missing this diagnosis can be life threatening for patients. Clinicians should be aware that acquired forms of hemophilia do exist and are associated with high morbidity and mortality in elderly adults. We present a case of a 74-year-old man who was diagnosed with acquired factor VIII inhibitor during an admission for community-acquired pneumonia.

  19. [An elderly patient with senile dementia showing acquired hemophilia A].

    Science.gov (United States)

    Yano, Hiroyuki; Tsunoda, Misako; Onishi, Tetsuro; Mizuno, Shigeyoshi; Koibuchi, Hitoshi; Kigawa, Yoshiaki; Suzuki, Tastuya; Nakano, Hiroshi; Oba, Kenzo

    2011-01-01

    We report a case of an 82-year-old woman with senile dementia who was hospitalized at a specialist dementia hospital for 10 months. She had swelling of the left shoulder joint, subcutaneous hematoma in the left upper arm, and anemia was noted on blood examination. Her serum hemoglobin level was lower than normal at 4.6 g/dL, but there was no sign of gastrointestinal disease or gastrointestinal bleeding, and her stool specimens were negative for occult blood. Hematoma subsequently appeared on her chest and back. She had a low activation level of factor VIII (<1%), a high concentration of acquired inhibitors of factor VIII (18.5 BU/mL), and prolonged activated partial thromboplastin time (83.1 seconds). The possibility of drug-induced anemia or hematoma were ruled out. We diagnosed acquired hemophilia A (AHA), and suspected that this was the cause of her hematomas. We began treatment of her AHA with oral prednisolone and intravenous infusion of factor VIII. The bleeding improved, but she later died due to bacterial pneumonia. AHA is very rare, with a reported annual incidence of 0.1/100,000 in Japan. However, it is necessary to consider such a rare disease when we encounter bleeding in elderly patients.

  20. Laboratory diagnosis of acquired hemophilia A: limitations, consequences, and challenges.

    Science.gov (United States)

    Tiede, Andreas; Werwitzke, Sonja; Scharf, Rüdiger E

    2014-10-01

    Acquired hemophilia A (AHA) should be suspected in patients with a new onset of bleeding and an isolated prolongation of activated partial thromboplastin time. About 10% of patients do not bleed at the time of diagnosis, but are at risk of future bleeding, particularly during interventions or surgery. Diagnosis of AHA is confirmed by demonstrating markedly reduced factor VIII activity (FVIII:C) and neutralizing anti-FVIII antibodies, so-called inhibitors. Several limitations and pitfalls exist with the assays used to diagnose AHA. Interference can result from anticoagulants or lupus anticoagulant. The Bethesda assay used to measure inhibitor potency assumes a log-linear relationship between inhibitor concentration and effect on residual FVIII:C activity to allow exact quantification. However, this relationship is not present for the type 2 inhibitors typically seen in AHA. Therefore, this assay only provides a rough estimate of inhibitor potency. These limitations can explain, in part, why laboratory data, such as inhibitor potency, failed to predict bleeding or response to treatment in AHA. This article reviews the diagnostic approach to AHA, discusses assay-specific limitations and addresses some of the challenges for future research. Thieme Medical Publishers 333 Seventh Avenue, New York, NY 10001, USA.

  1. The first case of postpartum acquired hemophilia A in Korea.

    Science.gov (United States)

    Lee, Ji Hyun; Kim, Dong-Hwan; Yoo, Kiyoung; Choi, Yongmook; Kim, Sun-Hee; Kim, Hee-Jin

    2011-09-01

    Acquired hemophilia A (AHA) is a rare coagulopathy caused by autoantibodies to coagulation factor VIII (FVIII). Most patients with AHA have been previously healthy; however, a variety of morbidities have been associated with the condition including pregnancy. A 40-yr-old woman visited our institution with extensive hematoma on the right hip area. Her medical history revealed no personal or familial history of bleeding diathesis. Her coagulation tests showed markedly prolonged aPTT (117 sec), markedly decreased level of FVIII activity (0.4%) and high-titer FVIII inhibitor (77 BU). Collectively, she was diagnosed as having postpartum AHA and was treated with bypassing agents and corticosteroids. Her aPTT was normalized on the 174 th postpartum day and FVIII inhibitor showed negative conversion on the 224 th postpartum day. This is the first case of postpartum AHA with high-titer FVIII inhibitor in Korea. Timely diagnosis and management can reduce morbidity and mortality of this potentially life-threatening condition.

  2. Identification and Genetic Analysis of a Factor IX Gene Intron 3 Mutation in a Hemophilia B Pedigree in China

    Directory of Open Access Journals (Sweden)

    Dong Hua Cao

    2014-09-01

    Full Text Available OBJECTIVE: Hemophilia B is caused by coagulation defects in the factor IX gene located in Xq27.1 on the X chromosome. A wide range of mutations, showing extensive molecular heterogeneity, have been described in hemophilia B patients. Our study was aimed at genetic analysis and prenatal diagnosis of hemophilia B in order to further elucidate the pathogenesis of the hemophilia B pedigree in China. METHODS: Polymerase chain reaction amplification and direct sequencing of all the coding regions was conducted in hemophilia B patients and carriers. Prenatal diagnosis of the proband was conducted at 20 weeks. RESULTS: We identified the novel point mutation 10.389 A>G, located upstream of the intron 3 acceptor site in hemophilia B patients. The fetus of the proband’s cousin was identified as a carrier. CONCLUSION: Our identification of a novel mutation in the F9 gene associated with hemophilia B provides novel insight into the pathogenesis of this genetically inherited disorder and also represents the basis of prenatal diagnosis.

  3. Pharmacological concentrations of recombinant factor VIIa restore hemostasis independent of tissue factor in antibody-induced hemophilia mice.

    Science.gov (United States)

    Keshava, S; Sundaram, J; Rajulapati, A; Pendurthi, U R; Rao, L V M

    2016-03-01

    ESSENTIALS: The role of tissue factor (TF) in recombinant factor VIIa (rFVIIa) therapy in hemophilia is unclear. An acquired mouse hemophilia model with very low or normal levels of human TF was used in the study. rFVIIa is equally effective in correcting the bleeding in mice expressing low or normal levels of TF. Pharmacological doses of rFVIIa restore hemostasis in hemophilia independent of TF. Recombinant factor VIIa (rFVIIa) has been used widely for treating hemophilia patients with inhibitory autoantibodies against factor VIII or IX. Its mechanism of action is not entirely known. A majority of in vitro studies suggested that pharmacological concentrations of rFVIIa restore hemostasis in hemophilia in a phospholipid-dependent manner, independent of tissue factor (TF). However, a few studies suggested that a TF-dependent mechanism has a primary role in correction of bleeding by rFVIIa in hemophilia patients. Here, we investigated the potential contribution of TF in rFVIIa-induced hemostasis in hemophilia employing a model system of FVIII antibody-induced hemophilia in TF transgenic mice. Mice expressing low levels of human TF (LTF mice), mice expressing relatively high levels of human TF (HTF mice) and wild-type mice (WT mice) had neutralizing anti-FVIII antibodies administered in order to induce hemophilia in these mice. The mice were then treated with varying concentrations of rFVIIa. rFVIIa-induced hemostasis was evaluated with the saphenous vein bleeding model. Administration of FVIII inhibitory antibodies induced the hemophilic bleeding phenotype in all three genotypes. rFVIIa administration rescued the bleeding phenotype in all three genotypes. No significant differences were observed in rFVIIa-induced correction of bleeding between LTF and HTF mice that had FVIII antibodies administered. Our results provide strong evidence supporting the suggestion that the hemostatic effect of pharmacological doses of rFVIIa stems from a TF-independent mechanism. © 2016

  4. Long-term efficacy and safety of prophylaxis with recombinant factor VIII in Chinese pediatric patients with hemophilia A: a multi-center, retrospective, non-interventional, phase IV (ReCARE) study.

    Science.gov (United States)

    Li, Changgang; Zhang, Xinsheng; Zhao, Yongqiang; Wu, Runhui; Hu, Qun; Xu, Weiqun; Sun, Jing; Yang, Renchi; Li, Xiaojing; Zhou, Rongfu; Lian, Shinmei; Gu, Jian; Wu, Junde; Hou, Qingsong

    2017-07-01

    The first recombinant factor VIII (rFVIII) product was launched in China in 2007. However, until now, no study has been conducted to describe the efficacy and safety of prophylaxis with rFVIII in Chinese pediatric patients with hemophilia A (HA). To summarize the efficacy and safety data on prophylaxis with rFVIII in Chinese pediatric patients with HA. ReCARE (Retrospective study in Chinese pediatric hemophilia A patients with rFVIII contained regular prophylaxis) was a retrospective study conducted in 12 hemophilia treatment centers (HTCs) across China. The primary endpoints included reduction in annualized bleeding rate (ABR); the secondary endpoints included evaluation of joint function (number and sites of target joints) using Gilbert score and Hemophilia Joint Health Score (HJHS), quality of life (QoL) and factors affecting treatment choices. Safety assessment of rFVIII was also conducted. We analyzed a total of 183 male pediatric patients (mean age, 7.1 ± 4.23 years) who received prophylaxis between 1 November 2007 and 31 May 2013. Compared with baseline, prophylaxis with rFVIII significantly reduced overall annualized joint bleed rate (AJBR) (p < .001) and ABR (p < .001). Inhibitor formation was reported in 5 (2.7%) patients and hemarthrosis was reported in 1 patient. The mean number of target joints was positively related to age (p < .001) and weight (p = .003) at baseline. Responses from survey questionnaires reported that effective bleeding control, joint protection, improvement in quality of life, favorable medical insurance policies, and economic capability were reasons for choosing prophylaxis. Prophylaxis with rFVIII reduced bleeding and number of target joints, even with a low-dose regimen, in Chinese pediatric patients with HA. Other than the efficacy and safety, factors such as poor disease control, improved economic stability and stable financial support made prophylaxis as an attractive treatment option. ClinicalTrials.gov ID

  5. Recombinant factor VIII Fc fusion protein for the prevention and treatment of bleeding in children with severe hemophilia A.

    Science.gov (United States)

    Young, G; Mahlangu, J; Kulkarni, R; Nolan, B; Liesner, R; Pasi, J; Barnes, C; Neelakantan, S; Gambino, G; Cristiano, L M; Pierce, G F; Allen, G

    2015-06-01

    Prophylactic factor replacement, which prevents hemarthroses and thereby reduces the musculoskeletal disease burden in children with hemophilia A, requires frequent intravenous infusions (three to four times weekly). Kids A-LONG was a phase 3 open-label study evaluating the safety, efficacy and pharmacokinetics of a longer-acting factor, recombinant factor VIII Fc fusion protein (rFVIIIFc), in previously treated children with severe hemophilia A (endogenous FVIII level of hemophilia A. © 2015 The Authors. Journal of Thrombosis and Haemostasis published by Wiley Periodicals, Inc. on behalf of International Society on Thrombosis and Haemostasis.

  6. Growing up with hemophilia : Health related quality of life and psychosocial functioning

    NARCIS (Netherlands)

    Limperg, P.F.

    2017-01-01

    In this thesis, three major elements in the research around growing up with hemophilia are presented: development and evaluation of instruments (Part I), HRQOL and psychosocial outcomes (Part II) and psychosocial care (Part III). This thesis is the first to describe what it is like to grow up with

  7. Mortality and causes of death in patients with hemophilia, 1992-2001: a prospective cohort study

    NARCIS (Netherlands)

    Plug, I.; van der Bom, J. G.; Peters, M.; Mauser-Bunschoten, E. P.; de Goede-Bolder, A.; Heijnen, L.; Smit, C.; Willemse, J.; Rosendaal, F. R.

    2006-01-01

    Clotting factor products have been safe for HIV since 1985, and for hepatitis C since 1992. Few studies have reported on mortality in the total population of hemophilia patients after the period of risk of viral infection transmission. We studied the mortality, causes of death, and life expectancy

  8. A systematic review of the effects of hemophilia and von Willebrand disease on arterial trombosis

    NARCIS (Netherlands)

    Biere-Rafi, Sara; Zwiers, M.; Peters, Marjolein; Van Der Meer, Jan; Rosendaal, Frits R; Buller, Harry R; Kamphuisen, Pieter W

    Background: Patients with hemophilia and von Willebrand disease (VWD) may be protected against arterial thrombosis, through a hy-pocoagulable state or atherosclerosis. We performed a systematic review to assess the association between these clotting disorders, arterial thrombosis and the prevalence

  9. SVA retrotransposition in exon 6 of the coagulation factor IX gene causing severe hemophilia B.

    Science.gov (United States)

    Nakamura, Yuki; Murata, Moe; Takagi, Yuki; Kozuka, Toshihiro; Nakata, Yukiko; Hasebe, Ryo; Takagi, Akira; Kitazawa, Jun-ichi; Shima, Midori; Kojima, Tetsuhito

    2015-07-01

    Hemophilia B is an X-linked recessive bleeding disorder caused by abnormalities of the coagulation factor IX gene (F9). Insertion mutations in F9 ranging from a few to more than 100 base pairs account for only a few percent of all hemophilia B cases. We investigated F9 to elucidate genetic abnormalities causing severe hemophilia B in a Japanese subject. We performed PCR-mediated analysis of F9 and identified a large insertion in exon 6. Next, we carried out direct sequencing of a PCR clone of the whole insert using nested deletion by exonuclease III and S1 nuclease. We identified an approximately 2.5-kb SINE-VNTR-Alu (SVA)-F element flanked by 15-bp duplications in the antisense orientation in exon 6. Additionally, we carried out exontrap analysis to assess the effect of this retrotransposition on mRNA splicing. We observed that regular splicing at exons 5 and 6 of F9 was disturbed by the SVA retrotransposition, suggesting that abnormal FIX mRNA may be reduced by nonsense-mediated mRNA decay. In conclusion, this is the first report of SVA retrotransposition causing severe hemophilia B; only five cases of LINE-1 or Alu retrotranspositions in F9 have been reported previously.

  10. Assessment of Musculoskeletal Function and its Correlation with Radiological Joint Score in Children with Hemophilia A.

    Science.gov (United States)

    Gupta, Samriti; Garg, Kapil; Singh, Jagdish

    2015-12-01

    To evaluate the functional independence of children with hemophilia A and its correlation to radiological joint score. The present cross sectional study was conducted at SPMCHI, SMS Medical College, Jaipur, India. Children in the age group of 4-18 y affected with severe, moderate and mild hemophilia A and with a history of hemarthrosis who attended the OPD, emergency or got admitted in wards of SPMCHI, SMS Medical College were examined. Musculoskeletal function was measured in 98 patients using Functional Independence Score in Hemophilia (FISH) and index joints (joints most commonly affected with repeated bleeding) were assessed radiologically with plain X rays using Pettersson score. The mean FISH score was 28.07 ± 3.90 (range 17-32) with squatting, running and step climbing as most affected tasks. The mean Pettersson score was 3.8 ± 3.2. A significant correlation was found between mean Pettersson score and FISH (r = -0.875, P hemophilia A.

  11. Cost-effectiveness analysis of carrier and prenatal genetic testing for X-linked hemophilia

    Directory of Open Access Journals (Sweden)

    Meng-Che Tsai

    2015-08-01

    Conclusion: Carrier and prenatal genetic testing for hemophilia is a cost-effective investment in healthcare allocation. A case management system should be integrated in the current practice to facilitate patient care (e.g., collecting family pedigrees and providing genetic counseling.

  12. End-stage liver disease in persons with hemophilia and transfusion-associated infections

    NARCIS (Netherlands)

    Goedert, JJ; Eyster, ME; Lederman, MM; Mandalaki, T; de Moerloose, P; White, GC; Angiolillo, AL; Luban, NLC; Sherman, KE; Manco-Johnson, M; Preiss, L; Leissinger, C; Kessler, CM; Cohen, AR; DiMichele, D; Hilgartner, MW; Aledort, LM; Kroner, BL; Rosenberg, PS; Hatzakis, A

    2002-01-01

    Many persons with hemophilia were infected with hepatitis C and B viruses (HCV, HBV) and HIV, but the consequences of these transfusion-acquired infections are poorly defined. We estimated the risk of HCV-related end-stage liver disease (ESLD) and the associations of age, HBV, and HIV with that

  13. The etiology of inhibitor development in children with severe hemophilia A

    NARCIS (Netherlands)

    Gouw, S.C.

    2011-01-01

    Patients with severe hemophilia, a deficiency of functional clotting factor VIII, typically suffer from joint and muscle bleedings spontaneously or after minor trauma. The bleeding tendency can be effectively corrected by intravenous substitution of factor VIII products. However, about 25% of

  14. Management of bleeding in acquired hemophilia A : results from the European Acquired Haemophilia (EACH2) Registry

    NARCIS (Netherlands)

    Baudo, Francesco; Collins, Peter; Huth-Kuehne, Angela; Levesque, Herve; Marco, Pascual; Nemes, Laszlo; Pellegrini, Fabio; Tengborn, Lilian; Knoebl, Paul; Aspoeck, G.; Heistinger, M.; Knobl, P.; Makipernaa, A.; Andre, H; Aouba, A.; Bellucci, S.; Beurrier, P.; Borg, J.Y.; Darnige, L.; Devignes, J.; d'Oiron, R.; Gautier, P.; Gay, V.; Girault, S.; Gruel, Y.; Guerin, V.; Hezard, N.; Khellaf, M.; Koenig, M.; Levesque, H.; Lifermann, F; Marlu, R; Ninet, J.; Peynet, J.; Quemeneur, T.; Rothschild, C.; Schleinitz, N.; Sigaud, M.; Trouillier, S; Voisin, S.; Giebl, A.; Holstein, K.; Huth-Kuhne, A; Loreth, R.M.; Steigerwald, U.; Tiede, A.; Theodossiades, G.; Nemes, L.; Radvanyi, G.; Schlammadinger, A.; Barillari, G.; Pasca, S.; Baudo, F; Caimi, T.; Contino, L.; D'Angelo Armando, C.L.; Fattorini, A.; Di Minno, G.; Cerbone, A.M.; Di Minno, Matteo Nicola Dario; D'inca, M.; Falanga, A.; Maggioni, A.; Lerede, T.; Franchini, M.; Gaidano, G.; De Paoli, L.; Gamba, G.; Ghirardi, R; Girotto, M.; Tasca, D.; Grandone, E.; Tiscia, G.; Imberti, D.; Iorio, A.; Landolfi, R; Di Gennaro, L.; Novarese, L.; Mariani, G.; Lapecorella, M.; Marietta, M.; Pedrazzi, P.; Mazzucconi, M.G.; Santoro, C.; Morfini, M.; Linari, S.; Moratelli, S.; Paolini, R.; Piseddu, G.; Poggio, R.; Pogliani, E.; Carpenedo, M.; Remiddi, C.; Santagostino, E.; Mancuso, M.E.; Santoro, R.; Papaleo, G.; Schinco, P.; Borchiellini, A.; Valeri, F.; Scortechini, A.R.; Siragusa, S.; Sottilotta, G.; Squizzato, A.; Tagariello, G.; Sartori, R; Tagliaferri, A.R.; Di Perna, C.; Rivolta, G.F.; Testa, S.; Paoletti, O.; Toschi, V.; Zanon, E.; Brandolin, B.; Hamulyak, K.; Kamphuisen, P.; Laros-van Gorkom, B.; Leebeek, F.W.; Marten, N.; Novakova, I.; Schutgens, R.; van der Linden, P.W.; van Esser, J.; van der Meer, J.; Ypma, P.; Campos, M.; Aguilar, C.; Altisent, C.; Bermejo, N.; Del Campo, R.; Ferreiro Arguelles, M.; Gonzalez Bolos', R.; Gutierrez Pimentel, M.J.; Jimenez-Yuste, V.; Jose-Felix, L.; Marco, P.; Mingot, M.E.; Perez Garrido, R.; Perez Gonzale, N.Z.; Prieto Garcia, M.; Rodriguez-Huerta, A.M.; Sedano, C.; Tolosa Munoz, A.; Baghaei, F.; Tengborn, L.; Boehlen, F.; Korte, W.; Chowdary, P.; Collins, P.; Evans, G.; Pavord, S.; Rangarajan, S.; Wilde, J.

    2012-01-01

    Acquired hemophilia A is a rare bleeding disorder caused by autoantibodies to coagulation FVIII. Bleeding episodes at presentation are spontaneous and severe in most cases. Optimal hemostatic therapy is controversial, and available data are from observational and retrospective studies only. The

  15. Immunosuppression for acquired hemophilia A : results from the European Acquired Haemophilia Registry (EACH2)

    NARCIS (Netherlands)

    Collins, Peter; Baudo, Francesco; Knoebl, Paul; Levesque, Herve; Nemes, Laszlo; Pellegrini, Fabio; Marco, Pascual; Tengborn, Lilian; Huth-Kuehne, Angela; Aspoeck, Gerold; Heistinger, Max; Knobl, Paul; Makipernaa, Anne; Andre, Helene; Aouba, A; Bellucci, Sylvia; Beurrier, Philippe; Borg, Jeanne Yvonne; Darnige, Luc; Devignes, Jean; dOiron, Roseline; Gautier, Philippe; Gay, Valerie; Girault, Stephane; Gruel, Yves; Guerin, Viviane; Hezard, Nathalie; Khellaf, Mehdi; Koenig, Martial; Levesque, Herve; Lifermann, Francois; Marlu, Raphael; Ninet, J.; Peynet, Jocelyne; Quemeneur, Thomas; Rothschild, Chantal; Schleinitz, Nicolas; Sigaud, Marianne; Trouillier, Sebastien; Voisin, Sophie; Giebl, Andreas; Holstein, Katharina; Huth-Kuhne, Angela; Loreth, Ralph M.; Steigerwald, Udo; Tiede, Andreas; Theodossiades, George; Nemes, Laszlo; Radvanyi, Gaspar; Schlammadinger, Agota; Barillari, Giovanni; Pasca, Samantha; Baudo, Francesco; Caimi, T.; Contino, L.; D'Angelo, Armando; Crippa, Luciano; Fattorini, Annalisa; Di Minno, Giovanni; Cerbone, Anna Maria; Di Minno, Matteo Nicola Dario; D'inca, Marco; Falanga, Anna; Maggioni, Anna; Lerede, Teresa; Franchini, Massimo; Gaidano, Gianluca; De Paoli, Lorenzo; Gamba, Gabriella; Ghirardi, Raffaele; Girotto, Mauro; Tasca, Delios; Grandone, Elvira; Tiscia, Giovanni; Imberti, Davide; Iorio, Alfonso; Landolfi, Raffaele; Di Gennaro, Leonardo; Novarese, Linda; Mariani, Guglielmo; Lapecorella, Mario; Marietta, Marco; Pedrazzi, Paola; Mazzucconi, Maria Gabriella; Santoro, Cristina; Morfini, Massimo; Linari, Silvia; Moratelli, Stefano; Paolini, Rossella; Piseddu, Gavino; Poggio, Renzo; Pogliani, Enrico; Carpenedo, Monica; Remiddi, Chiara; Santagostino, Elena; Mancuso, Maria Elisa; Santoro, Rita; Papaleo, Giuseppina; Schinco, Piercarla; Borchiellini, Alessandra; Valeri, Federica; Scortechini, Anna Rita; Siragusa, Sergio; Sottilotta, Gianluca; Squizzato, Alessandro; Tagariello, Giuseppe; Sartori, Roberto; Tagliaferri, Anna Rita; Di Perna, Caterina; Rivolta, Gianna Franca; Testa, Sophie; Paoletti, Oriana; Toschi, Vincenzo; Zanon, Ezio; Brandolin, Barbara; Hamulyak, Karly; Kamphuisen, Pieter; Laros-van Gorkom, Britta; Leebeek, Frank W.G.; Marten, Nijziel; Novakova, Irena; Schutgens, Roger; van der Linden, P.W.G; van Esser, Joost; van der Meer, J.; Ypma, Paula; Campos, Manuel; Aguilar, Carlos; Altisent, Carmen; Bermejo, Nuria; Del Campo, Raquel; Ferreiro Arguelles, M.; Gonzalez Boullosa, Rosario; Gutierrez Pimentel, Maria Jose; Jimenez-Yuste, Victor [No Value; Jose-Felix, Lucia; Marco, Pascual; Mingot, Maria Eva; Perez Garrido, Rosario; Perez Gonzale, Noelia z; Prieto Garcia, Manuel; Rodriguez-Huerta, Ana Maria; Maranon, HGUG [No Value; Sedano, Carmen; Tolosa Munoz, Alexandra; Baghaei, Fariba; Tengborn, Lilian; Boehlen, Francoise; Korte, Wolfgang; Chowdary, Pratima; Collins, Peter; Evans, Gillian; Pavord, Suzanne; Rangarajan, Savita; Wilde, Jonathan

    2012-01-01

    Acquired hemophilia A (AHA) is an autoimmune disease caused by an autoantibody to factor VIII. Patients are at risk of severe and fatal hemorrhage until the inhibitor is eradicated, and guidelines recommend immunosuppression as soon as the diagnosis has been made. The optimal immunosuppressive

  16. Immunosuppression for acquired hemophilia A: results from the European Acquired Haemophilia Registry (EACH2)

    NARCIS (Netherlands)

    Collins, Peter; Baudo, Francesco; Knoebl, Paul; Lévesque, Hervé; Nemes, László; Pellegrini, Fabio; Marco, Pascual; Tengborn, Lilian; Huth-Kühne, Angela; Aspoeck, Gerold; Heistinger, Max; Knöbl, Paul; Makipernaa, Anne; André, Hélène; Aouba, Achille; Bellucci, Sylvia; Beurrier, Philippe; Borg, Jeanne Yvonne; Darnige, Luc; Devignes, Jean; d'Oiron, Roseline; Gautier, Philippe; Gay, Valérie; Girault, Stéphane; Gruel, Yves; Guerin, Viviane; Hézard, Nathalie; Khellaf, Mehdi; Koenig, Martial; Lifermann, François; Marlu, Raphael; Ninet, Jacques; Peynet, Jocelyne; Quéméneur, Thomas; Rothschild, Chantal; Schleinitz, Nicolas; Sigaud, Marianne; Trouillier, Sébastien; Voisin, Sophie; Giebl, Andreas; Holstein, Katharina; Loreth, Ralph M.; Steigerwald, Udo; Tiede, Andreas; Theodossiades, George; Radvanyi, Gaspar; Schlammadinger, Agota; Barillari, Giovanni; Pasca, Samantha; Caimi, Teresa; Contino, Laura; D'Angelo Armando, Crippa Luciano; Fattorini, Annalisa; Di Minno, Giovanni; Cerbone, Anna Maria; Di Minno, Dario; D'incà, Marco; Falanga, Anna; Maggioni, Anna; Lerede, Teresa; Franchini, Massimo; Gaidano, Gianluca; de Paoli, Lorenzo; Gamba, Gabriella; Ghirardi, Raffaele; Girotto, Mauro; Tasca, Delios; Grandone, Elvira; Tiscia, Giovanni; Imberti, Davide; Iorio, Alfonso; Landolfi, Raffaele; Di Gennaro, Leonardo; Novarese, Linda; Mariani, Guglielmo; Lapecorella, Mario; Marietta, Marco; Pedrazzi, Paola; Mazzucconi, Maria Gabriella; Santoro, Cristina; Morfini, Massimo; Linari, Silvia; Moratelli, Stefano; Paolini, Rossella; Piseddu, Gavino; Poggio, Renzo; Pogliani, Enrico; Carpenedo, Monica; Remiddi, Chiara; Santagostino, Elena; Mancuso, Maria Elisa; Santoro, Rita; Papaleo, Giuseppina; Schinco, Piercarla; Borchiellini, Alessandra; Valeri, Federica; Scortechini, Anna Rita; Siragusa, Sergio; Sottilotta, Gianluca; Squizzato, Alessandro; Tagariello, Giuseppe; Sartori, Roberto; Tagliaferri, Anna Rita; Di Perna, Caterina; Rivolta, Gianna Franca; Testa, Sophie; Paoletti, Oriana; Toschi, Vincenzo; Zanon, Ezio; Brandolin, Barbara; Hamulyák, Karly; Kamphuisen, Pieter; Laros-van Gorkom, Britta; Leebeek, Frank W. G.; Marten, Nijziel; Novakova, Irena; Schutgens, Roger; van der Linden, P. W. G.; van Esser, Joost; van der Meer, J.; Ypma, Paula; Campos, Manuel; Aguilar, Carlos; Altisent, Carmen; Bermejo, Nuria; del Campo, Raquel; Ferreiro Argüelles, María; González Boullosa, Rosario; Gutiérrez Pimentel, María José; Jiménez-Yuste, Victor; Jose-Felix, Lucia; Mingot, Maria Eva; Perez Garrido, Rosario; Perez Gonzale, Noelia Z.; Prieto Garcia, Manuel; Rodriguez-Huerta, Ana María; Sedano, Carmen; Tolosa Munoz, Alexandra; Baghaei, Fariba; Boehlen, Françoise; Korte, Wolfgang; Chowdary, Pratima; Evans, Gillian; Pavord, Suzanne; Rangarajan, Savita; Wilde, Jonathan

    2012-01-01

    Acquired hemophilia A (AHA) is an autoimmune disease caused by an autoantibody to factor VIII. Patients are at risk of severe and fatal hemorrhage until the inhibitor is eradicated, and guidelines recommend immunosuppression as soon as the diagnosis has been made. The optimal immunosuppressive

  17. Management of bleeding in acquired hemophilia A: results from the European Acquired Haemophilia (EACH2) Registry

    NARCIS (Netherlands)

    Baudo, Francesco; Collins, Peter; Huth-Kühne, Angela; Lévesque, Hervé; Marco, Pascual; Nemes, László; Pellegrini, Fabio; Tengborn, Lilian; Knoebl, Paul; Aspoeck, Gerold; Heistinger, Max; Knöbl, Paul; Makipernaa, Anne; André, Hélène; Aouba, Achille; Bellucci, Sylvia; Beurrier, Philippe; Borg, Jeanne Yvonne; Darnige, Luc; Devignes, Jean; d'Oiron, Roseline; Gautier, Philippe; Gay, Valérie; Girault, Stéphane; Gruel, Yves; Guerin, Viviane; Hézard, Nathalie; Khellaf, Mehdi; Koenig, Martial; Lifermann, François; Marlu, Raphael; Ninet, Jacques; Peynet, Jocelyne; Quéméneur, Thomas; Rothschild, Chantal; Schleinitz, Nicolas; Sigaud, Marianne; Trouillier, Sébastien; Voisin, Sophie; Giebl, Andreas; Holstein, Katharina; Loreth, Ralph M.; Steigerwald, Udo; Tiede, Andreas; Theodossiades, George; Radvanyi, Gaspar; Schlammadinger, Agota; Barillari, Giovanni; Pasca, Samantha; Caimi, Teresa; Contino, Laura; D'Angelo Armando, Crippa Luciano; Fattorini, Annalisa; Di Minno, Giovanni; Cerbone, Anna Maria; Di Minno, Dario; D'incà, Marco; Falanga, Anna; Maggioni, Anna; Lerede, Teresa; Franchini, Massimo; Gaidano, Gianluca; de Paoli, Lorenzo; Gamba, Gabriella; Ghirardi, Raffaele; Girotto, Mauro; Tasca, Delios; Grandone, Elvira; Tiscia, Giovanni; Imberti, Davide; Iorio, Alfonso; Landolfi, Raffaele; Di Gennaro, Leonardo; Novarese, Linda; Mariani, Guglielmo; Lapecorella, Mario; Marietta, Marco; Pedrazzi, Paola; Mazzucconi, Maria Gabriella; Santoro, Cristina; Morfini, Massimo; Linari, Silvia; Moratelli, Stefano; Paolini, Rossella; Piseddu, Gavino; Poggio, Renzo; Pogliani, Enrico; Carpenedo, Monica; Remiddi, Chiara; Santagostino, Elena; Mancuso, Maria Elisa; Santoro, Rita; Papaleo, Giuseppina; Schinco, Piercarla; Borchiellini, Alessandra; Valeri, Federica; Scortechini, Anna Rita; Siragusa, Sergio; Sottilotta, Gianluca; Squizzato, Alessandro; Tagariello, Giuseppe; Sartori, Roberto; Tagliaferri, Anna Rita; Di Perna, Caterina; Rivolta, Gianna Franca; Testa, Sophie; Paoletti, Oriana; Toschi, Vincenzo; Zanon, Ezio; Brandolin, Barbara; Hamulyák, Karly; Kamphuisen, Pieter; Laros-van Gorkom, Britta; Leebeek, Frank W. G.; Marten, Nijziel; Novakova, Irena; Schutgens, Roger; van der Linden, P. W. G.; van Esser, Joost; van der Meer, J.; Ypma, Paula; Campos, Manuel; Aguilar, Carlos; Altisent, Carmen; Bermejo, Nuria; del Campo, Raquel; Ferreiro Argüelles, María; González Boullosa, Rosario; Gutiérrez Pimentel, María José; Jiménez-Yuste, Victor; Jose-Felix, Lucia; Mingot, Maria Eva; Perez Garrido, Rosario; Perez Gonzale, Noelia Z.; Prieto Garcia, Manuel; Rodriguez-Huerta, Ana María; Sedano, Carmen; Tolosa Munoz, Alexandra; Baghaei, Fariba; Boehlen, Françoise; Korte, Wolfgang; Chowdary, Pratima; Evans, Gillian; Pavord, Suzanne; Rangarajan, Savita; Wilde, Jonathan

    2012-01-01

    Acquired hemophilia A is a rare bleeding disorder caused by autoantibodies to coagulation FVIII. Bleeding episodes at presentation are spontaneous and severe in most cases. Optimal hemostatic therapy is controversial, and available data are from observational and retrospective studies only. The

  18. Prevalence of Hypertension (HTN) and Cardiovascular Risk Factors in a Hospitalized Pediatric Hemophilia Population.

    Science.gov (United States)

    Alperstein, Warren; Corrales-Medina, Fernando F; Tamariz, Leonardo; Palacio, Ana M; Davis, Joanna A

    2017-12-12

    Improved life expectancy in hemophilia has led to a greater interest in age-related disorders. Hypertension (HTN) as well as cardiovascular disease have been increasingly reported in hemophilic adults but there is currently very limited data in the pediatric population. We conducted a cross-sectional study using data from the 2012 National Health Cost and Utilization Project database to determine the prevalence of HTN and associated cardiovascular risk factors in a hospitalized pediatric hemophilia population, between the ages of 0 to 21 years, in comparison with the general pediatric population. The prevalence of HTN was significantly higher in children with hemophilia (CWH) in comparison with the general pediatric population (1.71% vs. 1.02%, P-value=0.005). When adjusting the analysis for sex, the prevalence of HTN in the hemophilia cohort remained higher, although not statistically significant (1.52% vs. 1.22%, P-value=0.2568). When examining the concomitant presence of ≥1 cardiovascular risk factors in the hypertensive subgroups, CWH had a higher prevalence of obesity (2.64% vs. 1.32%, P-value <0.0001). Interestingly, diabetes mellitus was more prevalent in nonhemophilic children (1.47% vs. 0.56%, P-value=0.0015). These data suggest that cardiovascular risk factors need to be closely monitored in CWH, and a better preventive strategy is likely needed to identify those hemophilic patients at higher risk of developing cardiovascular disease in adulthood.

  19. Mortality caused by intracranial bleeding in non-severe hemophilia A patients

    NARCIS (Netherlands)

    Loomans, J.I.; Eckhardt, C.L.; Reitter-Pfoertner, S.E.; Holmstrom, M.; Laros-van Gorkom, B.A.; Leebeek, F.W.; Santoro, C.; Haya, S.; Meijer, K.; Nijziel, M.R.; Bom, J.G. Van Der; Fijnvandraat, K.

    2017-01-01

    Essentials Data on bleeding-related causes of death in non-severe hemophilia A (HA) patients are scarce. Such data may provide new insights into areas of care that can be improved. Non-severe HA patients have an increased risk of dying from intracranial bleeding. This demonstrates the need for

  20. Gene therapy for hemophilia B mice with scAAV8-LP1-hFIX.

    Science.gov (United States)

    Lu, Wei; Zhou, Qingzhang; Yang, Hao; Wang, Hao; Gu, Yexing; Shen, Qi; Xue, Jinglun; Dong, Xiaoyan; Chen, Jinzhong

    2016-06-01

    Hemophilia B is a hemorrhagic disease caused by the deficiency of clotting factor IX (FIX). Gene therapy might be the ultimate strategy for the disease. However, two main problems that should be solved in gene therapy for hemophilia B are immunity and safety. Self-complementary adeno-associated virus serotype 8 (scAAV8), a non-human primate AAV featuring low immunogenicity and high transfection efficiency in liver cells, might be a potential vector for hemophilia B gene therapy. A strong liver-specific promoter-1 (LP1) was inserted and mutant human FIX Arg338Ala was introduced into plasmid scAAV8-LP1 to develop an optimized AAV8 vector that expresses human clotting factor FIX (hFIX). The efficiency of scAAV8-LP1-hFIX administered through normal systemic injection or hydrodynamic injection was compared. A high expression was achieved using hydrodynamic injection, and the peak hFIX expression levels in the 5 × 10(11) and 1 × 10(11) virus genome (vg) cohorts were 31.94% and 25.02% of normal level, respectively, at 60 days post-injection. From the perspective of long-term (200 days) expression, both injection methods presented promising results with the concentration value maintained above 4% of normal plasma. The results were further verified by enzyme-linked immunosorbent assay and activated partial thromboplastin time. Our study provides a potential gene therapy method for hemophilia B.

  1. Validation of the VERITAS-Pro treatment adherence scale in a Spanish sample population with hemophilia

    Directory of Open Access Journals (Sweden)

    Cuesta-Barriuso R

    2017-03-01

    Full Text Available Rubén Cuesta-Barriuso,1–3 Ana Torres-Ortuño,4 Pilar Galindo-Piñana,4 Joaquín Nieto-Munuera,4 Natalie Duncan,5 José Antonio López-Pina6 1Department of Physiotherapy, School of Biomedical and Health Sciences, European University of Madrid, 2Fishemo, Centro Especial de Empleo, Spanish Federation of Hemophilia, 3Royal Foundation Victoria Eugenia, Madrid, 4Department of Psychiatry and Social Psychology, Faculty of Medicine, University of Murcia, Murcia, Spain; 5Indiana Hemophilia & Thrombosis Center, Indianapolis, IN, USA; 6Department of Basic Psychology and Methodology, Faculty of Psychology, University of Murcia, Murcia, Spain Purpose: We aimed to conduct a validation in Spanish of the Validated Hemophilia Regimen Treatment Adherence Scale – Prophylaxis (VERITAS-Pro questionnaire for use in patients with hemophilia under prophylactic treatment.Patients and methods: The VERITAS-Pro scale was adapted through a process of back translation from English to Spanish. A bilingual native Spanish translator translated the scale from English to Spanish. Subsequently, a bilingual native English translator translated the scale from Spanish to English. The disagreements were resolved by agreement between the research team and translators. Seventy-three patients with hemophilia, aged 13–62 years, were enrolled in the study. The scale was applied twice (2 months apart to evaluate the test–retest reliability.Results: Internal consistency reliability was lower on the Spanish VERITAS-Pro than on the English version. Test–retest reliability was high, ranging from 0.83 to 0.92. No significant differences (P>0.05 were found between test and retest scores in subscales of VERITAS-Pro. In general, Spanish patients showed higher rates of nonadherence than American patients in all subscales.Conclusion: The Spanish version of the VERITAS-Pro has high levels of consistency and empirical validity. This scale can be administered to assess the degree of

  2. Impact of the underlying mutation and the route of vector administration on immune responses to factor IX in gene therapy for hemophilia B.

    Science.gov (United States)

    Cao, Ou; Hoffman, Brad E; Moghimi, Babak; Nayak, Sushrusha; Cooper, Mario; Zhou, Shangzhen; Ertl, Hildegund C J; High, Katherine A; Herzog, Roland W

    2009-10-01

    Immune responses to factor IX (F.IX), a major concern in gene therapy for hemophilia, were analyzed for adeno-associated viral (AAV-2) gene transfer to skeletal muscle and liver as a function of the F9 underlying mutation. Vectors identical to those recently used in clinical trials were administered to four lines of hemophilia B mice on a defined genetic background [C3H/HeJ with deletion of endogenous F9 and transgenic for a range of nonfunctional human F.IX (hF.IX) variants]. The strength of the immune response to AAV-encoded F.IX inversely correlated with the degree of conservation of endogenous coding information and levels of endogenous antigen. Null mutation animals developed T- and B-cell responses in both protocols. However, inhibitor titers were considerably higher upon muscle gene transfer (or protein therapy). Transduced muscles of Null mice had strong infiltrates with CD8+ cells, which were much more limited in the liver and not seen for the other mutations. Sustained expression was achieved with liver transduction in mice with crm(-) nonsense and missense mutations, although they still formed antibodies upon muscle gene transfer. Therefore, endogenous expression prevented T-cell responses more effectively than antibody formation, and immune responses varied substantially depending on the protocol and the underlying mutation.

  3. Nonneutralizing antibodies against factor VIII and risk of inhibitor development in severe hemophilia A.

    Science.gov (United States)

    Cannavò, Antonino; Valsecchi, Carla; Garagiola, Isabella; Palla, Roberta; Mannucci, Pier Mannuccio; Rosendaal, Frits R; Peyvandi, Flora

    2017-03-09

    The development of anti-factor VIII (FVIII) neutralizing antibodies (inhibitors) is the major complication in hemophilia A. Nonneutralizing antibodies (NNAs) have been detected in hemophilia patients and also in unaffected individuals. The aim of this study was to assess the prevalence of NNAs and to evaluate whether their presence is associated with the development of inhibitors in a cohort of previously untreated or minimally treated patients with hemophilia A; plasma samples of 237 patients with severe hemophilia A enrolled in the SIPPET trial were collected before any exposure to FVIII concentrates and analyzed for the presence of anti-FVIII NNAs. Patients were observed for the development of neutralizing antibodies. NNAs were found in 18 (7.6%) of 237 patients at screening, and there was a clear age gradient. Of those with NNAs, 7 patients subsequently developed an inhibitor for a cumulative incidence of 45.4% (95% confidence interval [CI], 19.5% to 71.3%); among the 219 patients without NNAs, 64 (29%) developed an inhibitor (cumulative incidence, 34.0%; 95% CI, 27.1%-40.9%). In Cox regression analyses, patients with NNAs at screening had an 83% higher incidence of inhibitor development than patients without NNAs (hazard ratio [HR], 1.83; 95% CI, 0.84-3.99). For high-titer inhibitors, the incidence rate had an almost threefold increase (HR, 2.74; 95% CI, 1.23-6.12). These associations did not materially change after adjustment. The presence of anti-FVIII NNAs in patients with severe hemophilia A who were not previously exposed to FVIII concentrates is associated with an increased incidence of inhibitors. © 2017 by The American Society of Hematology.

  4. Hemophilia in childhood: the impact of the disease on parent's participation in their child's education

    Directory of Open Access Journals (Sweden)

    Fabiane de Amorim Almeida

    2008-09-01

    Full Text Available Objectives: To identify the limitations faced by the hemophiliac child, according to his/her parents, and how they deal with these limitations, and to verify how parents approach the problem of hemophilia with the child as well as their strategies for disciplining that child and their nonhemophiliac children. Methods: An exploratory descriptive research study with a quantitative approach carried out with 20 parents of hemophiliac children seen at the ambulatory of a medium size public hospital in the city of São Paulo. The data were collected by means of a structured interview, using a form with open-ended and closed questions. Rresults: All the parents (20; 100% reported talking to their children about hemophilia, especially as to the definition of the disease (19; 46,35% and the activities that should be avoided (eight; 19.50%. Most of them (17; 85% also reported talking about hemophilia with their other children. Eighteen parents (90% restricted participation in sports and physical activities for their hemophiliac child, including at school: 11 (55% prohibit participation in physical activities, and 12 (60% ban extracurricular activities. All the parents also reported raising the subject of their child’s hemophilia with the educational professionals at their child’s school. As to discipline, half of them (ten; 50% use different strategies for disciplining their hemophiliac and non-hemophiliac children. Cconclusions: All the parents are concerned with discussing the subject of hemophilia with the child, his/her siblings, and teachers at school, imposing limitations especially as to participation in sports and/or physical activities. Differences were noted as to the strategies used by the parents for the discipline of their hemophiliac and non-hemophiliac children.

  5. Tranexamic acid combined with recombinant factor VIII increases clot resistance to accelerated fibrinolysis in severe hemophilia A

    DEFF Research Database (Denmark)

    Hvas, Anne-Mette; Sørensen, Hanne Thykjær; Norengaard, Lisbeth

    2007-01-01

    BACKGROUND: Most patients with severe hemophilia A suffer from a profoundly compromised hemostatic response. In addition to both the delayed and slow development of a clot, previous studies have documented that severe hemophilia A is also associated with reduced clot stability. OBJECTIVES: We...... examined whether the clot stability in hemophiliacs could be improved by treatment with tranexamic acid (TXA) in combination with recombinant factor VIII (rFVIII). PATIENTS/METHODS: Baseline blood samples were obtained from eight males with severe hemophilia A. Thereafter, a bolus injection of r...... the elasticity curve increased 5-fold after rFVIII and 24-fold after addition of TXA. CONCLUSIONS: The study demonstrates that simultaneous treatment with TXA and rFVIII significantly improves the clot stability in patients with hemophilia A. Udgivelsesdato: December...

  6. [Detection of hemophilia A carriers by PCR analysis of hind III polymorphism in the factor VIII gene].

    Science.gov (United States)

    Wu, S; Li, Y; Cui, H; Xie, Y; Zheng, J; Pan, X; Zhang, H; Zhao, R; Zhang, Q

    1998-04-10

    To explore a scheme of using PCR analysis in the detection of carriers of Hind III polymorphism of factor VIII gene of hemophilia A. Implicating intron 19 of the factor VIII gene of 6 patients with the hemophilia A and 207 unrelated X-chromosomes were amplified by PCR and were analysed by means of Amp-RFLPs of Hind III. The incidence of the polymorphic Hind III sites in the given population was found to be 0.29. The frequence of the Hind III heterozygotes in women calculated according to Hardy-Weinberg equation was 0.41, which proved to be informative enough for carrier detection and prenatal diagnosis of hemophilia A. 2 out of 6 families (33%)examined in this study were informative. The new scheme proved to be effective for hemophilia A carrier detection and prenatal diagnosis.

  7. The effect of aquatic exercise therapy on muscle strength and joint′s range of motion in hemophilia patients

    Directory of Open Access Journals (Sweden)

    Mehdi Kargarfard

    2013-01-01

    Conclusion: The results showed that aquatic exercise therapy can be a useful method to improve joints′ strength and range of motion in hemophilia patients in order to improve their daily functioning and quality of life.

  8. The governance of director networks

    NARCIS (Netherlands)

    Renneboog, L.D.R.; Zhou, Y.; Wright, M.; Siegel, D.; Keasey, K.; Filatotchev, I.

    2013-01-01

    This chapter studies director networks, which have gained increasing attention from sociology, finance, and management. It considers the argument that these networks have an interesting role in corporate governance and then reviews their rules in major developed countries. The chapter goes on to

  9. Successful treatment of acquired hemophilia a with rituximab and steroids in a 5-year-old girl.

    Science.gov (United States)

    Fletcher, Matthew; Crombet, Ofelia; Morales-Arias, Jaime

    2014-03-01

    Acquired hemophilia A is a very rare, serious bleeding disorder. We describe a 5-year-old female who developed an acquired factor VIII inhibitor, and while under treatment with steroids, had an intestinal perforation with peritonitis and septic shock, making her a poor candidate for further immunosuppression. She was treated with rituximab with rapid, complete eradication of the inhibitor. She represents the first published case of a pediatric patient with acquired hemophilia A successfully treated with rituximab.

  10. First AGU Board of Directors

    Science.gov (United States)

    McPhaden, Michael J.

    2010-08-01

    On 1 July 2010, the first AGU Board of Directors took office. The board is composed of the president, president-elect, immediate past president, general secretary, international secretary, development board chair, six members elected by the Union membership, vice chair of the AGU Council, and the executive director. Two additional members may be nominated by the AGU president and approved by the board. The creation of the board is a result of the new governance structure approved by the AGU membership in November 2009. The board is responsible for the business aspects of the Union, while an expanded AGU Council will focus on science issues. Council members will be introduced in a future issue of Eos.

  11. Director of Office for Equal Opportunity named

    OpenAIRE

    Harris, Sally L.

    2005-01-01

    Kevin G. McDonald, of Baltimore, former associate director for Compliance and Conflict Resolution at The Johns Hopkins University, has been named director of Virginia Tech's Office for Equal Opportunity. He will begin work at Virginia Tech in July.

  12. Atraumatic Restorative Treatment (ART) in pediatric dentistry residency programs: a survey of program directors.

    Science.gov (United States)

    Kateeb, Elham; Warren, John; Damiano, Peter; Momany, Elizabeth; Kanellis, Michael; Weber-Gasparoni, Karin; Ansley, Tim

    2013-01-01

    The purpose of this study was to investigate the extent of clinical training on atraumatic restorative treatment (ART) among pediatric dentistry residency programs and assess program directors' attitudes toward ART. All U.S. Pediatric Dentistry residency programs' directors were asked to complete a web-based survey. Sixty-one of the 76 directors (80 percent) completed the survey, with no significant response bias. Eighty-nine percent of the responding programs provided clinical instruction on ART. Of these, 30 percent provided ART training often/very often. ART was used mostly in single-surface cavities (43 percent) and as an interim treatment in primary teeth (57 percent). Factors associated with ART clinical training included not placing amalgams in primary teeth (Ppediatric dentistry residency programs in the United States. Residency directors' attitudes were highly predictive of the amount of clinical training provided, suggesting that directors need to be better informed about the use of ART.

  13. 45 CFR 1700.5 - Executive Director.

    Science.gov (United States)

    2010-10-01

    ... 45 Public Welfare 4 2010-10-01 2010-10-01 false Executive Director. 1700.5 Section 1700.5 Public Welfare Regulations Relating to Public Welfare (Continued) NATIONAL COMMISSION ON LIBRARIES AND INFORMATION SCIENCE ORGANIZATION AND FUNCTIONS § 1700.5 Executive Director. (a) The Executive Director serves...

  14. Integration of Leadership Styles of School Director

    Science.gov (United States)

    Pavlovic, Nebojsa; Oljaca, Milka; Kostovic, Svetlana

    2012-01-01

    Management style can be defined as a special behavior of directors in the work process that affects the performance in an organization, in this case-school. Management style has two related meanings: first is behavior of directors to employees, second is directors' approach in school regarding management, participation of employees in decision…

  15. Academic, behavioral, and social adaptation of boys with hemophilia/HIV disease.

    Science.gov (United States)

    Colegrove, R W; Huntzinger, R M

    1994-08-01

    Examined the intelligence, academic achievement, behavior, and social competency of 37 school-aged boys with hemophilia, 56% with HIV infection. IQ scores fell in the average range, but total reading scores were almost 1 standard deviation below the mean. Parent and teacher ratings of social functioning and behavior fell in the normal range. Absenteeism, an average of 27 days for the previous school year, was inversely correlated with most teacher ratings, indicating that absenteeism may be a significant factor in the academic and social adaptation of children with hemophilia. Overall, boys infected with HIV demonstrated the same level of academic and behavioral adaptation as those uninfected. The need for special education programs and interventions to enhance competency in the school setting is discussed.

  16. Successful Phenotype Improvement following Gene Therapy for Severe Hemophilia A in Privately Owned Dogs.

    Science.gov (United States)

    Callan, Mary Beth; Haskins, Mark E; Wang, Ping; Zhou, Shangzhen; High, Katherine A; Arruda, Valder R

    2016-01-01

    Severe hemophilia A (HA) is an inherited bleeding disorder characterized by genetic diseases, such as congenital blindness. Here we report our experience with liver gene therapy with AAV-FVIII in two outbred, privately owned dogs with severe HA that resulted in sustained expression of 1-2% of normal FVIII levels and prevented 90% of expected bleeding episodes. A Thr62Met mutation in the F8 gene was identified in one dog. These data recapitulate the improvement of the disease phenotype in research animals, and in humans, with AAV liver gene therapy for hemophilia B. Our experience is a novel example of the benefits of a relevant preclinical canine model to facilitate both translational studies in humans and improved welfare of privately owned dogs.

  17. Risk Factors for Inhibitor Formation in Hemophilia: A Prevalent Case-Control Study

    Science.gov (United States)

    Ragni, Margaret V.; Ojeifo, Oluseyi; Feng, Jinong; Yan, Jin; Hill, Kathleen A.; Sommer, Steve S.; Trucco, Massimo N.; Brambilla, Donald J.

    2009-01-01

    Background Inhibitor formation is a major complication of hemophilia treatment. Aim In a prevalent case-control study, we evaluated blood product exposure, genotype, and HLA type on hemophilia A inhibitor formation. Methods Product exposure was extracted from medical records. Genotype was determined on stored DNA samples by detection of virtually all mutations-SSCP (DOVAM-S) and subcycling PCR. HLA typing was performed by PCR amplification and exonuclease-released fluorescence. Results Cases experienced higher intensity factor, 455 vs. 200 U per exposure, p0.100. Genotype was not associated with race. Time to immune tolerance was shorter for titers 0.50. Conclusions Inhibitor formation is associated with high intensity product exposure, CNS bleeding, African-American race, and low frequency of missense mutations. The ideal time to initiate prophylaxis to reduce CNS bleeding and inhibitor formation will require prospective studies. PMID:19563499

  18. A case of acquired hemophilia A diagnosed after percutaneous endoscopic gastrostomy.

    Science.gov (United States)

    Okamura, Takuma; Komatsu, Michiharu; Ito, Akihiro; Ito, Tetsuya; Suga, Tomoaki; Arakura, Norikazu; Sakai, Hitoshi; Tanaka, Eiji

    2015-10-01

    A 65-year-old male with no personal or familial history of bleeding disorders underwent percutaneous endoscopic gastrostomy (PEG) for neurogenic dysphagia due to subarachnoid hemorrhage. On postoperative day 6, continuous oozing of venous blood was observed at the stoma. Prothrombin time was within normal range, but activated partial thromboplastin time was prolonged. Cross-mixing test results indicated the existence of an inhibitor, and laboratory findings revealed decreased factor VIII activity and high levels of factor VIII inhibitor. The patient was diagnosed as having acquired hemophilia A, for which steroid monotherapy was effective. Acquired hemophilia A is a rare but potentially fatal disease. Clinicians should be aware of this condition in patients presenting with sudden hemorrhage after PEG or other endoscopic treatments, even in those with no apparent history of bleeding.

  19. Successful medical management of a neonate with spontaneous splenic rupture and severe hemophilia A.

    Science.gov (United States)

    Badawy, Sherif M; Rossoff, Jenna; Yallapragada, Sushmita; Liem, Robert I; Sharathkumar, Anjali A

    2017-03-01

    Splenic rupture in neonates is a rare event, usually occurring in the setting of underlying predisposing conditions. Here, we present the case of a term neonate who presented with worsening anemia in the setting of known hemolytic disease during the newborn period and was later found to have a spontaneous splenic rupture. He was subsequently diagnosed with severe hemophilia A, and was managed medically with recombinant factor VIII replacement therapy without any surgical intervention. This is the first reported case of a neonate who had spontaneous splenic rupture and severe hemophilia A, and underwent successful medical treatment without any surgical intervention. Copyright © 2016 King Faisal Specialist Hospital & Research Centre. Published by Elsevier Ltd. All rights reserved.

  20. Immunomodulation for inhibitors in hemophilia A: the important role of Treg cells

    Science.gov (United States)

    Miao, Carol H

    2010-01-01

    Approximately 25–30% of the hemophilia A patients develop inhibitory antibodies against Factor VIII (FVIII) following protein-replacement therapy. This problem is also thought to occur following gene-replacement therapy. Recently, many approaches have been investigated to modulate FVIII-specific immune responses in either protein-replacement or gene therapy hemophilia A mouse models. Several promising protocols have been demonstrated to successfully prevent or modulate the formation of anti-FVIII antibodies, including methods to manipulate antigen presentation, development of less immunogenic FVIII proteins, or formulations or gene therapy protocols to evade immune responses, as well as immunomodulation strategies to target either T- and/or B-cell responses. Most of these successful protocols involve the induction of activated Treg cells to create a regulatory immune environment during tolerance induction. Innovative strategies to overcome pre-existing anti-FVIII immune responses and induce long-term tolerance in primed subjects still need to be developed. PMID:20976115

  1. Acquired hemophilia A as a cause of acute upper gastrointestinal hemorrhage.

    Science.gov (United States)

    McCain, Stephen; Gull, Sadaf; Ahmad, Jawad; Carey, Declan

    2014-02-05

    A 71-year-old man presented to the emergency department with his first episode of hematemesis. He was anemic and coagulopathic on admission, and became hemodynamically unstable requiring surgical intervention to control the bleeding. Prior to surgery, he required 100% plasma exchange with human plasma derived prothrombin complex concentrate (Octaplex) as the exchange fluid. At induction of anesthesia, he received tranexamic acid, prothrombin complex concentrate, and platelets. At the time of knife to skin, he was given coagulation factor VIIa intravenously as a bolus. This treatment was on the recommendation of the hematology team who suspected a diagnosis of acquired hemophilia on the basis of his history and coagulation screen. His bleeding was controlled and a diagnosis of acquired hemophilia A was confirmed in the postoperative period. This was managed with immunosuppressive therapy, and at the 2 year follow-up he remains well and is off all treatment.

  2. Immunomodulation for inhibitors in hemophilia A: the important role of Treg cells.

    Science.gov (United States)

    Miao, Carol H

    2010-08-01

    Approximately 25-30% of the hemophilia A patients develop inhibitory antibodies against Factor VIII (FVIII) following protein-replacement therapy. This problem is also thought to occur following gene-replacement therapy. Recently, many approaches have been investigated to modulate FVIII-specific immune responses in either protein-replacement or gene therapy hemophilia A mouse models. Several promising protocols have been demonstrated to successfully prevent or modulate the formation of anti-FVIII antibodies, including methods to manipulate antigen presentation, development of less immunogenic FVIII proteins, or formulations or gene therapy protocols to evade immune responses, as well as immunomodulation strategies to target either T- and/or B-cell responses. Most of these successful protocols involve the induction of activated Treg cells to create a regulatory immune environment during tolerance induction. Innovative strategies to overcome pre-existing anti-FVIII immune responses and induce long-term tolerance in primed subjects still need to be developed.

  3. Potentiation of thrombin generation in hemophilia A plasma by coagulation factor VIII and characterization of antibody-specific inhibition.

    Directory of Open Access Journals (Sweden)

    Bhavya S Doshi

    Full Text Available Development of inhibitory antibodies to coagulation factor VIII (fVIII is the primary obstacle to the treatment of hemophilia A in the developed world. This adverse reaction occurs in 20-30% of persons with severe hemophilia A treated with fVIII-replacement products and is characterized by the development of a humoral and neutralizing immune response to fVIII. Patients with inhibitory anti-fVIII antibodies are treated with bypassing agents including recombinant factor VIIa (rfVIIa. However, some patients display poor hemostatic response to bypass therapy and improved treatment options are needed. Recently, we demonstrated that fVIII inhibitors display widely variable kinetics of inhibition that correlate with their respective target epitopes. Thus, it was hypothesized that for antibodies that display slow rates of inhibition, supplementation of rfVIIa with fVIII would result in improved thrombin generation and be predictive of clinical responses to this novel treatment regimen. In order to test this hypothesis, 10 murine monoclonal antibodies (MAbs with non-overlapping epitopes spanning fVIII, differential inhibition titers, and inhibition kinetics were studied using a thrombin generation assay. Of the 3 MAbs with high inhibitory titers, only the one with fast and complete (classically defined as "type I" kinetics displayed significant inhibition of thrombin generation with no improvement upon supplementation of rfVIIa with fVIII. The other two MAbs that displayed incomplete (classically defined as "type II" inhibition did not suppress the potentiation of thrombin generation by fVIII. All antibodies that did not completely inhibit fVIII activity demonstrated potentiation of thrombin generation by the addition of fVIII as compared to rfVIIa alone. In conclusion, fVIII alone or in combination with rfVIIa corrects the thrombin generation defect produced by the majority of anti-fVIII MAbs better than single agent rfVIIa. Therefore, combined f

  4. Most Factor VIII B Domain Missense Mutations Are Unlikely to Be Causative Mutations for Severe Hemophilia A: Implications for Genotyping

    Science.gov (United States)

    Ogata, Kyoichi; Selvaraj, Sundar R; Miao, Hongzhi Z; Pipe, Steven W

    2011-01-01

    Summary Background & Objective The factor VIII (FVIII) B domain shares very little amino acid homology to other known proteins and is not directly necessary for procoagulant activity. Despite this, missense mutations within the B domain have been reported in patients with hemophilia A. Given that the B domain is dispensable for secretion and function of FVIII, we hypothesized that these mutations should not be causative of hemophilia A in these patients. Methods Plasmid vectors containing B domain missense mutations that were reported to be associated with moderate/severe hemophilia A (T751S, D826E, V993L, H1047Y, T1353A, N1441K, L1462P, E1579D, A1591S, P1641L and S1669L) were analyzed for their effect on synthesis and secretion compared to FVIII wild-type (WT) following transient transfection into COS-1 and CHO cells in vitro. Further, H1047Y, N1441K and E1579D mutants were expressed in vivo in a hemophilia A mouse model by hydrodynamic tail-vein injection. Results FVIII activity and antigen levels for all mutants expressed into the conditioned media of COS-1 and CHO cells were similar to FVIII WT. Also, plasma expression of these mutants was similar to FVIII WT in hemophilia A mice. An in vivo tail clip bleeding assay also demonstrated that blood loss from hemophilia A mice expressing FVIII WT, H1047Y, N1441K and E1579D were similar. Conclusion We conclude that most missense mutations within the FVIII B domain would be unlikely to lead to severe hemophilia A and that the majority of such missense mutations represent polymorphisms or non-pathologic mutations. PMID:21645226

  5. Neonatal Gene Therapy for Hemophilia B by a Novel Adenovirus Vector Showing Reduced Leaky Expression of Viral Genes.

    Science.gov (United States)

    Iizuka, Shunsuke; Sakurai, Fuminori; Tachibana, Masashi; Ohashi, Kazuo; Mizuguchi, Hiroyuki

    2017-09-15

    Gene therapy during neonatal and infant stages is a promising approach for hemophilia B, a congenital disorder caused by deficiency of blood coagulation factor IX (FIX). An adenovirus (Ad) vector has high potential for use in neonatal or infant gene therapy for hemophilia B due to its superior transduction properties; however, leaky expression of Ad genes often reduces the transduction efficiencies by Ad protein-mediated tissue damage. Here, we used a novel Ad vector, Ad-E4-122aT, which exhibits a reduction in the leaky expression of Ad genes in liver, in gene therapy studies for neonatal hemophilia B mice. Ad-E4-122aT exhibited significantly higher transduction efficiencies than a conventional Ad vector in neonatal mice. In neonatal hemophilia B mice, a single neonatal injection of Ad-E4-122aT expressing human FIX (hFIX) (Ad-E4-122aT-AHAFIX) maintained more than 6% of the normal plasma hFIX activity levels for approximately 100 days. Sequential administration of Ad-E4-122aT-AHAFIX resulted in more than 100% of the plasma hFIX activity levels for more than 100 days and rescued the bleeding phenotypes of hemophilia B mice. In addition, immunotolerance to hFIX was induced by Ad-E4-122aT-AHAFIX administration in neonatal hemophilia B mice. These results indicated that Ad-E4-122aT is a promising gene delivery vector for neonatal or infant gene therapy for hemophilia B.

  6. Neonatal Gene Therapy for Hemophilia B by a Novel Adenovirus Vector Showing Reduced Leaky Expression of Viral Genes

    Directory of Open Access Journals (Sweden)

    Shunsuke Iizuka

    2017-09-01

    Full Text Available Gene therapy during neonatal and infant stages is a promising approach for hemophilia B, a congenital disorder caused by deficiency of blood coagulation factor IX (FIX. An adenovirus (Ad vector has high potential for use in neonatal or infant gene therapy for hemophilia B due to its superior transduction properties; however, leaky expression of Ad genes often reduces the transduction efficiencies by Ad protein-mediated tissue damage. Here, we used a novel Ad vector, Ad-E4-122aT, which exhibits a reduction in the leaky expression of Ad genes in liver, in gene therapy studies for neonatal hemophilia B mice. Ad-E4-122aT exhibited significantly higher transduction efficiencies than a conventional Ad vector in neonatal mice. In neonatal hemophilia B mice, a single neonatal injection of Ad-E4-122aT expressing human FIX (hFIX (Ad-E4-122aT-AHAFIX maintained more than 6% of the normal plasma hFIX activity levels for approximately 100 days. Sequential administration of Ad-E4-122aT-AHAFIX resulted in more than 100% of the plasma hFIX activity levels for more than 100 days and rescued the bleeding phenotypes of hemophilia B mice. In addition, immunotolerance to hFIX was induced by Ad-E4-122aT-AHAFIX administration in neonatal hemophilia B mice. These results indicated that Ad-E4-122aT is a promising gene delivery vector for neonatal or infant gene therapy for hemophilia B.

  7. Localised prostate cancer and hemophilia A (AHA: Case report and management of the disease

    Directory of Open Access Journals (Sweden)

    Francesco Celestino

    2014-09-01

    Full Text Available Acquired Hemophilia A (AHA is a rare bleeding diathesis characterized by the development of autoantibodies against factor VIII (FVIII. About half of the cases are idiopathic and the other half are associated with autoimmune diseases, postpartum problems, infections, inflammatory bowel disease, drugs, lymphoproliferative disorders or solid tumors . AHA is associated with malignancies in 7-15% of cases. We report a case of AHA in a 65 year old patient with prostatic carcinoma, who underwent retropubic radical prostatectomy (RP.

  8. DESCRIPTIVE EPIDEMIOLOGY OF HEMOPHILIA AND OTHER COAGULATION DISORDERS IN MANSOURA , EGYPT

    Directory of Open Access Journals (Sweden)

    Youssef Al Tonbary

    2010-08-01

    The study included 72 children with hematological disorders registered from 2000 to 2008 in MUCH. The hemophilic patient was defined as a person with physician-diagnosed hemophilia A or B and a measured factor VIII or IX activity level of 30% or less. Persons with acquired inhibitors of FVIII or FIX excluded. Severity level was categorized as mild if the factor activity level was 6–30%, moderate if 1–5% and severe if

  9. Oral Tolerance Induction in Hemophilia B Dogs Fed with Transplastomic Lettuce.

    Science.gov (United States)

    Herzog, Roland W; Nichols, Timothy C; Su, Jin; Zhang, Bei; Sherman, Alexandra; Merricks, Elizabeth P; Raymer, Robin; Perrin, George Q; Häger, Mattias; Wiinberg, Bo; Daniell, Henry

    2017-02-01

    Anti-drug antibodies in hemophilia patients substantially complicate treatment. Their elimination through immune tolerance induction (ITI) protocols poses enormous costs, and ITI is often ineffective for factor IX (FIX) inhibitors. Moreover, there is no prophylactic ITI protocol to prevent anti-drug antibody (ADA) formation. Using general immune suppression is problematic. To address this urgent unmet medical need, we delivered antigen bioencapsulated in plant cells to hemophilia B dogs. Commercial-scale production of CTB-FIX fusion expressed in lettuce chloroplasts was done in a hydroponic facility. CTB-FIX (∼1 mg/g) in lyophilized cells was stable with proper folding, disulfide bonds, and pentamer assembly after 30-month storage at ambient temperature. Robust suppression of immunoglobulin G (IgG)/inhibitor and IgE formation against intravenous FIX was observed in three of four hemophilia B dogs fed with lyophilized lettuce cells expressing CTB-FIX. No side effects were detected after feeding CTB-FIX-lyophilized plant cells for >300 days. Coagulation times were markedly shortened by intravenous FIX in orally tolerized treated dogs, in contrast to control dogs that formed high-titer antibodies to FIX. Commercial-scale production, stability, prolonged storage of lyophilized cells, and efficacy in tolerance induction in a large, non-rodent model of human disease offer a novel concept for oral tolerance and low-cost production and delivery of biopharmaceuticals. Copyright © 2017 The Authors. Published by Elsevier Inc. All rights reserved.

  10. Pharmacokinetics and pharmacodynamics of SCT800, a new recombinant FVIII, in hemophilia A mice

    Science.gov (United States)

    Gu, Ruo-lan; Liu, Liang; Xie, Liang-zhi; Gai, Wen-lin; Cao, Si-shuo; Meng, Zhi-yun; Gan, Hui; Wu, Zhuo-na; Li, Jian; Zheng, Ying; Zhu, Xiao-xia; Dou, Gui-fang

    2016-01-01

    Aim: SCT800 is a new third-generation recombinant FVIII agent that is undergoing promising preclinical study. This study aimed to investigate the pharmacokinetic and pharmacodynamic profiles of SCT800 in hemophilia A mice. Methods: After hemophilia A mice were intravenously injected with single dose of SCT800 (80, 180, and 280 IU/kg) or the commercially available product Xyntha (280 IU/kg), pharmacokinetics profiles were evaluated based on measuring plasma FVIII: C. For pharmacodynamics study, dose-response curves of SCT800 and Xyntha (1–200 IU/kg) were constructed using a tail bleeding model monitoring both bleeding time and blood loss. Results: Pharmacokinetics profile analysis showed a dose independency of SCT800 ranging from 80 to 280 IU/kg and comparable pharmacokinetic profiles between SCT800 and Xyntha at the doses tested. Pharmacodynamics study revealed comparable ED50 values of SCT800 and Xyntha in the tail bleeding model: 14.78 and 15.81 IU/kg for bleeding time, respectively; 13.50 and 13.58 IU/kg for blood loss, respectively. Moreover, at the doses tested, the accompanying dose-related safety evaluation in the tail bleeding model showed lower hypercoagulable tendency and wider dosage range potential for SCT800 than Xyntha. Conclusion: In hemophilia A mice, SCT800 shows comparable pharmacokinetics and pharmacodynamics to Xyntha at the doses tested, and possibly with better safety properties. PMID:26806305

  11. Life-threatening hemorrhage from acquired hemophilia A as a presenting manifestation of prostate cancer

    Directory of Open Access Journals (Sweden)

    Chirag Sheth

    2016-09-01

    Full Text Available Acquired factor VIII deficiency (acquired hemophilia A is a rare condition characterized by the acquisition of autoantibodies that affect the clotting activity of factor VIII (fVIII. The most common manifestation in affected patients is a hemorrhagic diathesis. This disorder is associated with autoimmune diseases, pregnancy, postpartum period, drugs, and malignancy. Management of this condition begins with attempts to arrest an acute bleed based on the site and severity of bleeding and inhibitor titer. The next priority is eradication of the fVIII antibodies using immunosuppressive therapies. We report the case of a 66-year-old male who presented with spontaneous right thigh hematoma with prolonged activated partial prothrombin time and normal prothrombin time. Mixing studies confirmed the presence of an inhibitor. Further investigation for the underlying etiology of acquired hemophilia A leads to diagnosis of prostate cancer. Treatment consisted of bypassing agents including activated factor VII and activated prothrombin plasma concentrate to arrest the bleeding. Steroids and cyclophosphamide were added to suppress the fVIII inhibitors. Concomitant treatment of locally advanced prostate cancer with chemotherapy confirmed the eradication of the inhibitors. To our knowledge, this is the first reported case of prostate cancer diagnosed and treated simultaneously with acquired hemophilia A resulting in favorable patient outcome.

  12. The CDC Hemophilia A Mutation Project (CHAMP) mutation list: a new online resource.

    Science.gov (United States)

    Payne, Amanda B; Miller, Connie H; Kelly, Fiona M; Michael Soucie, J; Craig Hooper, W

    2013-02-01

    Genotyping efforts in hemophilia A (HA) populations in many countries have identified large numbers of unique mutations in the Factor VIII gene (F8). To assist HA researchers conducting genotyping analyses, we have developed a listing of F8 mutations including those listed in existing locus-specific databases as well as those identified in patient populations and reported in the literature. Each mutation was reviewed and uniquely identified using Human Genome Variation Society (HGVS) nomenclature standards for coding DNA and predicted protein changes as well as traditional nomenclature based on the mature, processed protein. Listings also include the associated hemophilia severity classified by International Society of Thrombosis and Haemostasis (ISTH) criteria, associations of the mutations with inhibitors, and reference information. The mutation list currently contains 2,537 unique mutations known to cause HA. HA severity caused by the mutation is available for 2,022 mutations (80%) and information on inhibitors is available for 1,816 mutations (72%). The CDC Hemophilia A Mutation Project (CHAMP) Mutation List is available at http://www.cdc.gov/hemophiliamutations for download and search and will be updated quarterly based on periodic literature reviews and submitted reports. Published 2012. This Article is a US Government work and is in the public domain in the USA.

  13. Life-threatening hemorrhage from acquired hemophilia A as a presenting manifestation of prostate cancer.

    Science.gov (United States)

    Sheth, Chirag; Gill, Amandeep; Sekhon, Sumeet

    2016-01-01

    Acquired factor VIII deficiency (acquired hemophilia A) is a rare condition characterized by the acquisition of autoantibodies that affect the clotting activity of factor VIII (fVIII). The most common manifestation in affected patients is a hemorrhagic diathesis. This disorder is associated with autoimmune diseases, pregnancy, postpartum period, drugs, and malignancy. Management of this condition begins with attempts to arrest an acute bleed based on the site and severity of bleeding and inhibitor titer. The next priority is eradication of the fVIII antibodies using immunosuppressive therapies. We report the case of a 66-year-old male who presented with spontaneous right thigh hematoma with prolonged activated partial prothrombin time and normal prothrombin time. Mixing studies confirmed the presence of an inhibitor. Further investigation for the underlying etiology of acquired hemophilia A leads to diagnosis of prostate cancer. Treatment consisted of bypassing agents including activated factor VII and activated prothrombin plasma concentrate to arrest the bleeding. Steroids and cyclophosphamide were added to suppress the fVIII inhibitors. Concomitant treatment of locally advanced prostate cancer with chemotherapy confirmed the eradication of the inhibitors. To our knowledge, this is the first reported case of prostate cancer diagnosed and treated simultaneously with acquired hemophilia A resulting in favorable patient outcome.

  14. Development of acquired hemophilia A during treatment of multiple myeloma with lenalidomide.

    Science.gov (United States)

    Saburi, Masuho; Ohtsuka, Eiichi; Itani, Kazuhito; Nagamatsu, Kentarou; Ikebe, Taichi; Miyazaki, Yasuhiko; Ogata, Masao; Saburi, Yoshio

    2015-05-01

    We describe a 67-year-old female demonstrating symptomatic multiple myeloma (MM) with anemia and bone lesions initially diagnosed in 2009. Although a partial response was achieved after bortezomib and dexamethasone treatment, MM recurred in 2012. Therefore, treatment with lenalidomide, cyclophosphamide, and dexamethasone was commenced. Coagulation tests conducted prior to the chemotherapy were normal. Lenalidomide was discontinued after 10 days due to exacerbation of renal dysfunction. Simultaneously, activated partial thromboplastin time (APTT) was prolonged to 89.5 seconds. The mixing test showed an inhibitor pattern, with factor VIII at 2% and factor VIII inhibitor at 4.85 BU/ml. A diagnosis of acquired hemophilia A was made, and treatment with prednisolone was started, after which APTT improved to 36.4 seconds and factor VIII inhibitor decreased to 1.09 BU/ml. The factor VIII inhibitor level again increased concomitantly with restarting lenalidomide, which was, therefore, discontinued, while immunosuppressive therapy was administered with the addition of cyclophosphamide. Factor VIII inhibitor gradually disappeared from the patient's blood over the next four months. To the best of our knowledge, this is the first description of lenalidomide as a possible cause of acquired hemophilia A. Our experience indicates that we need to pay attention to acquired hemophilia A after initiating lenalidomide therapy in patients with hematologic malignancies.

  15. Eradication of neutralizing antibodies to factor VIII in canine hemophilia A after liver gene therapy.

    Science.gov (United States)

    Finn, Jonathan D; Ozelo, Margareth C; Sabatino, Denise E; Franck, Helen W G; Merricks, Elizabeth P; Crudele, Julie M; Zhou, Shangzhen; Kazazian, Haig H; Lillicrap, David; Nichols, Timothy C; Arruda, Valder R

    2010-12-23

    Inhibitory antibodies to factor VIII (FVIII) are a major complication in the treatment of hemophilia A, affecting approximately 20% to 30% of patients. Current treatment for inhibitors is based on long-term, daily injections of large amounts of FVIII protein. Liver-directed gene therapy has been used to induce antigen-specific tolerance, but there are no data in hemophilic animals with pre-existing inhibitors. To determine whether sustained endogenous expression of FVIII could eradicate inhibitors, we injected adeno-associated viral vectors encoding canine FVIII (cFVIII) in 2 strains of inhibitor hemophilia A dogs. In 3 dogs, a transient increase in inhibitor titers (up to 7 Bethesda Units [BU]) at 2 weeks was followed by continuous decline to complete disappearance within 4-5 weeks. Subsequently, an increase in cFVIII levels (1.5%-8%), a shortening of clotting times, and a reduction (> 90%) of bleeding episodes were observed. Immune tolerance was confirmed by lack of antibody formation after repeated challenges with cFVIII protein and normal protein half-life. A fourth dog exhibited a strong early anamnestic response (216 BU), with slow decline to 0.8 BU and cFVIII antigen detection by 18 months after vector delivery. These data suggest that liver gene therapy has the potential to eradicate inhibitors and could improve the outcomes of hemophilia A patients.

  16. The CDC Hemophilia A Mutation Project (CHAMP) Mutation List: a New Online Resource

    Science.gov (United States)

    Payne, Amanda B.; Miller, Connie H.; Kelly, Fiona M.; Soucie, J. Michael; Hooper, W. Craig

    2015-01-01

    Genotyping efforts in hemophilia A (HA) populations in many countries have identified large numbers of unique mutations in the Factor VIII gene (F8). To assist HA researchers conducting genotyping analyses, we have developed a listing of F8 mutations including those listed in existing locus-specific databases as well as those identified in patient populations and reported in the literature. Each mutation was reviewed and uniquely identified using Human Genome Variation Society (HGVS) nomenclature standards for coding DNA and predicted protein changes as well as traditional nomenclature based on the mature, processed protein. Listings also include the associated hemophilia severity classified by International Society of Thrombosis and Haemostasis (ISTH) criteria, associations of the mutations with inhibitors, and reference information. The mutation list currently contains 2,537 unique mutations known to cause HA. HA severity caused by the mutation is available for 2,022 mutations (80%) and information on inhibitors is available for 1,816 mutations (72%). The CDC Hemophilia A Mutation Project (CHAMP) Mutation List is available at http://www.cdc.gov/hemophiliamutations for download and search and will be updated quarterly based on periodic literature reviews and submitted reports. PMID:23280990

  17. The pharmacokinetics of a B-domain truncated recombinant factor VIII, turoctocog alfa (NovoEight®), in patients with hemophilia A.

    Science.gov (United States)

    Jiménez-Yuste, V; Lejniece, S; Klamroth, R; Suzuki, T; Santagostino, E; Karim, F A; Saugstrup, T; Møss, J

    2015-03-01

    Turoctocog alfa (NovoEight(®)) is a human recombinant coagulation factor VIII (rFVIII) for the treatment of patients with hemophilia A. To evaluate the pharmacokinetics of turoctocog alfa in all age groups across clinical trials. Data from previously treated patients with severe hemophilia A (FVIII activity level of ≤ 1%) with no history of FVIII inhibitors, in a non-bleeding state, were included. The pharmacokinetics were assessed following a wash-out period and a subsequent single intravenous 50 IU kg(-1) dose of turoctocog alfa. Blood was sampled during a 48-h period postdose. Standard pharmacokinetic (PK) parameters were estimated on the basis of plasma FVIII activity vs. time (PK profiles) with non-compartmental methods. Furthermore, a population PK analysis was conducted. Data from 76 patients (aged 1-60 years) enrolled globally across six clinical trials were included, totaling 105 turoctocog alfa PK profiles. Single-dose PK results 3-6 months after the first dose of turoctocog alfa were comparable with the results obtained after the first dose. Similar PK characteristics were shown for different lots and strengths of the drug product. Overall, area under the plasma concentration (activity) curve from administration to infinity (AUC) and t1(/2) tended to increase with increasing age, with lower AUC and shorter t(1/2) being seen in children than in adolescents and adults. The PK profiles of turoctocog alfa and other commercially available plasma-derived FVIII and rFVIII products were similar in all age groups. The PK characteristics of turoctocog alfa have been thoroughly studied, and shown to be consistent over time, reproducible between different lots and strengths of drug product, and similar to those observed for other FVIII products. © 2014 International Society on Thrombosis and Haemostasis.

  18. Leadership Changes Announced At Equine Medical Center Fregin To Retire, White Interim Director

    OpenAIRE

    Douglas, Jeffrey S.

    2003-01-01

    Nathaniel White has been named Interim Director of the Marion duPont Scott Equine Medical Center in Leesburg. White, who assumed leadership responsibilities for the equine clinical and research center on April 1, succeeds G. Frederick Fregin, the center's founding director.

  19. Rationale for a randomized controlled trial comparing two prophylaxis regimens in adults with severe hemophilia A: the Hemophilia Adult Prophylaxis Trial

    Science.gov (United States)

    Ragni, Margaret V

    2011-01-01

    A major goal of comprehensive hemophilia care is to prevent occurrence of bleeds by prophylaxis or regular preventive factor, one or more times weekly. Although prophylaxis is effective in reducing bleeding and joint damage in children, whether it is necessary to continue into adulthood is not known. The purpose of this article is to describe a Phase III randomized controlled trial to evaluate prophylaxis comparing two dose regimens in adults with severe hemophilia A. I hypothesize that adults with mature cartilage and joints are less susceptible to joint bleeds and joint damage, and that once-weekly recombinant factor VIII prophylaxis, with up to two rescue doses per week, is as effective as thrice-weekly prophylaxis in reducing bleeding frequency, but less costly and more acceptable, with higher quality of life. The ultimate goal of this project is to determine whether once-weekly prophylaxis is any worse than thrice-weekly prophylaxis in reducing joint bleeding frequency, while potentially utilizing less factor, at lower cost, leading to a better quality of life. This is an innovative concept, as it challenges the current paradigm of thrice-weekly prophylaxis in adults, which is based on dosing in children. Furthermore, this trial will assess interdose thrombin generation, a novel tissue factor-based assay of hemostasis, to determine if individualized thrombin generation can predict more individualized prophylaxis dosing, which would be practice changing. PMID:21939418

  20. Declining trends in invasive orthopedic interventions for people with hemophilia enrolled in the Universal Data Collection program (2000–2010)

    Science.gov (United States)

    TOBASE, P.; LANE, H.; SIDDIQI, A.-E-A.; INGRAM-RICH, R.; WARD, R. S.

    2016-01-01

    Introduction Recurrent joint hemarthroses due to hemophilia (Factor VIII and Factor IX deficiency) often lead to invasive orthopedic interventions to decrease frequency of bleeding and/or to alleviate pain associated with end-stage hemophilic arthropathy. Aim Identify trends in invasive orthopedic interventions among people with hemophilia who were enrolled in the Universal Data Collection (UDC) program during the period 2000–2010. Methods Data were collected from 130 hemophilia treatment centers in the United States annually during the period 2000–2010, in collaboration with the Centers for Disease Control and Prevention (CDC). The number of visits in which an invasive orthopedic intervention was reported was expressed as a proportion of the total visits in each year of the program. Invasive orthopedic interventions consisted of arthroplasty, arthrodesis, and synovectomy. Joints included in this study were the shoulder, elbow, hip, knee, and ankle. Results A 5.6% decrease in all invasive orthopedic interventions in all joints of people with hemophilia enrolled in the UDC program over the 11-year study period was observed. Conclusions These data reflect a declining trend in invasive orthopedic interventions in people with hemophilia. Further research is needed to understand the characteristics that may influence invasive orthopedic interventions. PMID:27030396

  1. Omental implantation of BOECs in hemophilia dogs results in circulating FVIII antigen and a complex immune response.

    Science.gov (United States)

    Ozelo, Margareth C; Vidal, Barbara; Brown, Christine; Notley, Colleen; Hegadorn, Carol; Webster, Sandra; Harpell, Lori; Ahlin, James; Winterborn, Andrew; Handforth, Janine; Arruda, Valder R; Hough, Christine; Lillicrap, David

    2014-06-26

    Ex vivo gene therapy strategies avoid systemic delivery of viruses thereby mitigating the risk of vector-associated immunogenicity. Previously, we delivered autologous factor VIII (FVIII)-expressing blood outgrowth endothelial cells (BOECs) to hemophilia A mice and showed that these cells remained sequestered within the implanted matrix and provided therapeutic levels of FVIII. Prior to translating this strategy into the canine (c) model of hemophilia A, we increased cFVIII transgene expression by at least 100-fold with the use of the elongation factor 1 alpha (EF1α) promoter and a strong endothelial enhancer element. BOECs isolated from hemophilia A dogs transduced with this lentiviral vector express levels of cFVIII ranging between 1.0 and 1.5 U/mL per 10(6) cells over 24 hours. Autologous BOECs have been implanted into the omentum of 2 normal and 3 hemophilia A dogs. These implanted cells formed new vessels in the omentum. All 3 hemophilia A dogs treated with FVIII-expressing autologous BOECs developed anti-FVIII immunoglobulin G2 antibodies, but in only 2 of the dogs were these antibodies inhibitory. FVIII antigen levels >40% in the absence of FVIII coagulant function were detected in the circulation for up to a year after a single gene therapy treatment, indicating prolonged cellular viability and synthesis of FVIII. © 2014 by The American Society of Hematology.

  2. Francisco Miranda, Director de Colciencias.

    Directory of Open Access Journals (Sweden)

    Efraím Otero Ruiz

    2006-09-01

    De su desempeño en Sussex (universidad distinguida mundialmente por sus estudios sobre desarrollo tecnológico, transferencia de tecnología y administración de proyectos se recibieron siempre los mejores informes, que lo colocaron en el alto nivel de los latinoamericanos ilustres que han pasado larga o brevemente por dicho claustro, como Máximo Halty-Carrere del Uruguay, Francisco Sagasti del Perú o Fernando Chaparro de Colombia. Con ese bagaje regresó al país donde fue designado como Director Administrativo del Centro Internacional de Entrenamiento e Investigación Médica (CIDEIM de Cali, cargo que ocupó de 1992 a 2002; y al terminar ese decenio fue nombrado por la Junta Directiva como Director Ejecutivo, cargo que ocupó hasta su designación en COLCIENCIAS. En Cali ha ocupado también distinguidas posiciones, tales como Miembro del Consejo Directivo de la Fundación Planeta Valle y del Consejo de Internacionalización de la Universidad Javeriana en esa ciudad...

  3. Computation Directorate Annual Report 2003

    Energy Technology Data Exchange (ETDEWEB)

    Crawford, D L; McGraw, J R; Ashby, S F; McCoy, M G; Michels, T C; Eltgroth, P G

    2004-03-12

    Big computers are icons: symbols of the culture, and of the larger computing infrastructure that exists at Lawrence Livermore. Through the collective effort of Laboratory personnel, they enable scientific discovery and engineering development on an unprecedented scale. For more than three decades, the Computation Directorate has supplied the big computers that enable the science necessary for Laboratory missions and programs. Livermore supercomputing is uniquely mission driven. The high-fidelity weapon simulation capabilities essential to the Stockpile Stewardship Program compel major advances in weapons codes and science, compute power, and computational infrastructure. Computation's activities align with this vital mission of the Department of Energy. Increasingly, non-weapons Laboratory programs also rely on computer simulation. World-class achievements have been accomplished by LLNL specialists working in multi-disciplinary research and development teams. In these teams, Computation personnel employ a wide array of skills, from desktop support expertise, to complex applications development, to advanced research. Computation's skilled professionals make the Directorate the success that it has become. These individuals know the importance of the work they do and the many ways it contributes to Laboratory missions. They make appropriate and timely decisions that move the entire organization forward. They make Computation a leader in helping LLNL achieve its programmatic milestones. I dedicate this inaugural Annual Report to the people of Computation in recognition of their continuing contributions. I am proud that we perform our work securely and safely. Despite increased cyber attacks on our computing infrastructure from the Internet, advanced cyber security practices ensure that our computing environment remains secure. Through Integrated Safety Management (ISM) and diligent oversight, we address safety issues promptly and aggressively. The safety of

  4. [Immune tolerance induction in a case of hemophilia B with inhibitor with prothrombin complex concentrate and rituximab].

    Science.gov (United States)

    Xue, F; Liu, W; Cheng, Y F; Liu, X F; Huang, Y T; Fu, R F; Zhang, L; Yang, R C

    2017-09-14

    Objective: To explore the immune tolerance induction (ITI) in a case of severe hemophilia B patient with inhibitor. Methods: The F Ⅸ∶C was detected using a one-stage method and FIX inhibitor was assayed using Bethesda method. ITI was performed with prothrombin complex concentrates (PCC) in combination with rituximab. Results: His past exposure days (ED) with PCC were 20 ED and his peak FⅨ inhibitor titer was 56 BU/ml. When his FIX inhibitor titer decreased to 10.4 BU/ml in Nov. 2015 and after receiving the informed consent from his parents, ITI was started. PCC with low dose rituximab successfully eradicated the high titer inhibitor within 17 months. There was no anaphylaxis, thrombotic event and infection. Conclusion: This is the first case report for successful immune tolerance induction therapy in Chinese hemophilia B patient. ITI using PCC combined with rituximab is an effective choice to induce immune tolerance of hemophilia B with inhibitor.

  5. Director general presentation to personnel

    CERN Multimedia

    2016-01-01

    Dear Colleagues, Many important discussions are scheduled for the upcoming Council Week (13-17 June) on topics including the Medium-Term Plan, the Pension Fund and other matters of great relevance to us.   I would therefore like to share the main outcome of the week with you and I invite you to join me and the Directors in the Main Auditorium at 10 a.m. on Thursday 23 June. The meeting will last about one hour and a webcast will also be available. Best regards, Fabiola Gianotti DG presentation to personnel Thursday 23 June at 10 am Main Auditorium Retransmission in Council Chamber, IT Auditorium, Kjell Jonhsen Auditorium, Prevessin 864-1-C02 Webcast on cern.ch/webcast More information on the event page.

  6. Institutional directors and board compensation: Spanish evidence

    Directory of Open Access Journals (Sweden)

    Felix López-Iturriaga

    2015-07-01

    Full Text Available We address the influence of directors who represent institutional investors in three aspects of board compensation policies: level of compensation, composition, and performance sensitivity. We differentiate pressure-sensitive directors (i.e., with business links and pressure-resistant directors (i.e., without business links. Our results show that pressure-resistant directors decrease total board compensation and its fixed proportion, whereas they increase the variable proportion of total remuneration and the pay-for-performance sensitivity. By contrast, pressure-sensitive directors offer the opposite results. These findings are consistent with the view that institutional investors are not a homogeneous group and that pressure-resistant directors fulfill a more thorough monitoring role.

  7. Emergency medicine resident moonlighting: a survey of program directors. CORD Task Force on Resident Moonlighting.

    Science.gov (United States)

    Langdorf, M I; Bearie, B; Ritter, M S; Ferkich, A

    1995-04-01

    1) To systematically describe emergency medicine (EM) program directors' perceptions of the benefits and risks of resident moonlighting. 2) To assess moonlighting policies of EM residencies, the degree of compliance with these policies, and the methods of dealing with residents who are out of compliance. A written survey was mailed or hand-delivered to all allopathic and osteopathic EM residency directors in the United States in 1992-93. Incomplete and ambiguous surveys were completed by phone. There was a 96% response rate (113/118). The average EM resident clinical workweek ranged from 38 to 50 hours while the resident was assigned to ED rotations. Most (90%) of the program directors believe moonlighting interferes with residency duties to some degree. Few (10%) programs prohibit moonlighting altogether, although 44% limit moonlighting to an average of 41.5 hours per month. Program directors believe residents moonlight primarily for financial reasons. Most (60%) of the program directors believe moonlighting offers experience not available in the residency, primarily related to autonomous practice. Fifteen programs reported residents who had been sued for malpractice while moonlighting, with one program director named along with the resident. One third of program directors have penalized residents for abuse of moonlighting privileges. EM residency directors are concerned about the effect of moonlighting on resident education. The directors' concerns regarding litigation, excessive work hours, and interference with residency duties are balanced by a general acceptance of the financial need to supplement residency income.

  8. Acquired hemophilia as first manifestation of breast carcinoma in a man under long-term spironolactone therapy.

    Science.gov (United States)

    Lamy, Olivier; Elmiger, Hubert; Fiche, Maryse; Bauer, Jean; Livio, FranCoise

    2004-04-01

    A 69-year-old man under long-term spironolactone therapy (16 years) was hospitalized with spontaneous hematoma on the trunk and extremities. Coagulation studies disclosed an acquired hemophilia that was successfully treated with human factor VIII for a few days and immunosuppressive agents for several months. Physical examination revealed bilateral gynecomastia and an upper left quadrant breast nodule. Complete staging was unremarkable. Complete left mastectomy was performed. Histopathology showed invasive ductal carcinoma, expressing positivity for estrogen and progesterone receptors. The acquired hemophilia was considered to be a paraneoplasic syndrome. The question of a linkage between long-term spironolactone therapy and breast carcinoma is discussed.

  9. Gene therapy with adeno-associated virus vector 5-human factor IX in adults with hemophilia B

    DEFF Research Database (Denmark)

    Miesbach, Wolfgang; Meijer, Karina; Coppens, Michiel

    2018-01-01

    Hemophilia B gene therapy aims to ameliorate bleeding risk and provide endogenous factor IX (FIX) activity/synthesis through a single treatment, eliminating the requirement for FIX concentrate. AMT-060 combines an adeno-associated virus-5 (AAV5) vector with a liver-specific promoter driving...... expression of a codon-optimized wild-type human FIX gene. This multi-national, open-label study included ten adults with hemophilia B (FIX ≤2% of normal) and severe-bleeding phenotype. No participants tested positive for AAV5-neutralizing antibodies using a green-fluorescent protein-based assay and all 10...

  10. Direct detection of common and rare inversion mutations in the genetic diagnosis of severe hemophilia A

    Energy Technology Data Exchange (ETDEWEB)

    Windsor, A.S.; Lillicrap, D.P.; Taylor, S.A.M. [Queen`s Univ., Ontario (Canada)

    1994-09-01

    Approximately 50% of the cases of severe hemophilia A (factor VIII:C < 0.01 units/ml) may be due to gross rearrangements of the factor VIII gene. The mutation involves homologous sequences upstream of the factor VIII locus and within intron 22 in an intrachromosomal recombination, inversion, event. The rearrangements can readily be detected on a Southern blot using a probe that is complementary to sequences from within intron 22. We describe here the analysis of this mutation in 71 severe hemophilia A patients. Thirty two of the patients (45%) showed evidence of a rearrangement. Five different patterns of rearrangements were seen, two of which have previously been described and account for the majority of cases (pattern 1, 70% and pattern 2, 16%). Three other abnormal patterns were observed. The inversion mechanism does not usually result in the loss or gain of any genetic material, but in one patient, in whom a unique rearrangement pattern was observed (pattern 3), we have previously documented a gross deletion which removes exons 1-22 of the factor VII gene as well as sequences 5{prime} to the gene. In another individual a fourth pattern in which an extra 19.0 kb band is present was detected. In this case it is unclear as to whether the rearrangement is responsible for the disease or is simply coincident normal variation. A fifth pattern, in which an extra 16.0 kb band was detected, was observed in a family with a new mutation causing hemophilia A. The affected individual and his mother inherited a de novo rearrangement of the factor VIII gene from his unaffected grandfather, implicating it as the cause of the disease. In conclusion, testing for the factor VIII inversion mutation was positive in approximately 45% of severe hemophiliacs, 72% of whom were isolated cases, and as such should constitute the initial stage in the genetic testing protocol for these patients` families.

  11. Characterization of genetic defects of hemophilia A in patients of Chinese origin

    Energy Technology Data Exchange (ETDEWEB)

    Lin, Shu-Wha; Lin, Shu-Rung; Shen, Ming-Ching (National Taiwan Univ., Taipei (Taiwan, Province of China))

    1993-12-01

    The molecular characterization of hemophilia A of Chinese origin was carried out by the polymerase chain reaction (PCR) and direct sequencing of patient's factor VIII genes. Single-strand conformation polymorphism (SSCP) and dideoxy fingerprinting (ddF) were used as screening methods to detect mutated DNAs. A total of 102 individuals from 87 different families, including 10 patients (10 families) with mild-to-moderate and 92 patients (77 families) with severe hemophilia A, were analyzed by PCR-SSCP and PCR-ddF. Of the 87 independent cases, 40 revealed a single mutation in the coding regions of their factor VIII genes. These mutations include 21 with single base changes resulting in 8 nonsense and 13 missense codons, 16 with deletion or insertion of 1-11 nucleotides, and 3 with deletion of large DNA fragments. The frequency of 8 of the identified factor VIII polymorphisms or silent mutations was also determined among Chinese. The frequencies for codons 1241, 1269, and 2223 (the numbering system follows J. Gitschier et al., 1984, Nature 312: 326-330) were found to be different from those reported for other populations. As for the 47 severe cases whose mutational events were not readily detected by PCR-SSCP and PCR-ddF, the reverse transcriptase PCR method was applied. In 24 such cases analyzed, 17 were found to be of the [open quotes]intron 22 mutations[close quotes] as described by Naylor et al. (1992, The Lancet, 342: 1066-1067), accounting for 39% of Chinese patients with hemophilia A. 31 refs., 2 figs., 6 tabs.

  12. Mutagenesis in sequence encoding of human factor VII for gene therapy of hemophilia

    Directory of Open Access Journals (Sweden)

    B Kazemi

    2009-12-01

    Full Text Available "nBackground: Current treatment of hemophilia which is one of the most common bleeding disorders, involves replacement therapy using concentrates of FVIII and FIX .However, these concentrates have been associated with viral infections and thromboembolic complications and development of antibodies. "nThe use of recombinant human factor VII (rhFVII is effective  for the treatment of patients with  hemophilia A or B, who develop antibodies ( referred as inhibitors against  replacement therapy , because it induces coagulation independent of FVIII and FIX. However, its short half-life and high cost have limited its use. One potential solution to this problem may be the use of FVIIa gene transfer, which would attain continuing therapeutic levels of expression from a single injection. The aim of this study was to engineer a novel hFVII (human FVII gene containing a cleavage site for the intracellular protease and furin, by PCR mutagenesis "nMethods: The sequence encoding light and heavy chains of hFVII, were amplified by using hFVII/pTZ57R and specific primers, separately. The PCR products were cloned in pTZ57R vector. "nResults and discussion: Cloning was confirmed by restriction analysis or PCR amplification using specific primers and plasmid universal primers. Mutagenesis of sequence encoding light and heavy chain was confirmed by restriction enzyme. "nConclusion: In the present study, it was provided recombinant plasmids based on mutant form of DNA encoding light and heavy chains.  Joining mutant form of DNA encoding light chain with mutant heavy chain led to a new variant of hFVII. This variant can be activated by furin and an increase in the proportion of activated form of FVII. This mutant form of hFVII may be used for gene therapy of hemophilia.

  13. Low intensity laser therapy speeds wound healing in hemophilia by enhancing platelet procoagulant activity.

    Science.gov (United States)

    Hoffman, Maureane; Monroe, Dougald M

    2012-01-01

    Our group has previously shown that cutaneous wound healing is delayed and histologically abnormal in a mouse model of hemophilia. Hemostasis is not only required to stop bleeding at the time of wounding, but also produces bioactive substances that promote appropriate inflammatory and proliferative responses during healing. Low intensity laser therapy (LILT) has been reported to enhance impaired wound healing in a variety of animal and human studies. The current studies were conducted to test the hypothesis that LILT can improve healing in a hemophilia B mouse model. Three daily treatments with 12 J/sq cm of 650 nm laser illumination reduced the time to closure of a 3-mm cutaneous punch biopsy wound in the hemophilic mice. All wounds were closed at 13 days in the sham-treated hemophilic mice, compared with 10 days in the LILT-treated hemophilic mice, and 9 days in wild-type mice. While LILT can speed healing by enhancing proliferation of cutaneous cells, we found that an additional mechanism likely contributes to the efficacy of LILT in the hemophilic mice. LILT enhanced the mechanical rigidity and platelet activity of clots formed from human platelet-rich plasma. Illumination of isolated platelets increased the mitochondrial membrane potential and enhanced binding of coagulation factors to the surface of activated platelets. Thus, while LILT can directly promote proliferative responses during healing, it also appears to enhance hemostasis in an animal model with impaired coagulation. These data suggest that trials of LILT as an adjunct to the usual hemostatic therapies in hemophilia are warranted. © 2012 by the Wound Healing Society.

  14. Termination of pregnancy due to Thalassemia major, Hemophilia, and Down's Syndrome: the views of Iranian physicians

    Directory of Open Access Journals (Sweden)

    Zareifar Soheila

    2008-12-01

    Full Text Available Abstract Background Genetic disorders due to kindred marriages are common medical conditions in Iran; however, the legal aspects of abortion remain controversial. This study was undertaken to determine physicians' opinions regarding the termination of pregnancy for three genetic diseases: thalassemia major, hemophilia, and Down's syndrome. Methods A questionnaire was administered to selected physicians by stratified random sampling to determine the following: age, gender, knowledge about prenatal diagnosis of diseases in high risk pregnancies, agreement with abortion, recommended gestational age for abortion, and, if opposed to abortion, the reason. Results Of 323 physicians, who participated in the study, 91.3(295, 40.6(131, and 78.6%(254 were in agreement and 8.7(28, 59.4(192, and 21.4%(69 were opposed to abortion for thalassemia major, hemophilia, and Down's syndrome, respectively. Among 289 physicians opposed to abortion in respect of each of all three conditions, the following reasons were cited: religion, 18; emotional, 10; quality of care, 23; hope to find a new treatment option in the future, 103; miscellaneous reasons, 6; and a combination of these reasons, 129. Among 680 physicians in agreement with abortion in relation to all of the diseases, 4.6%(31 were agreed with abortion in less than 12 weeks gestation, 79.2%(538 in less than 16 weeks gestation, 5.6%(38 in less than 20 weeks gestation, 2.2%(15 in less than 24 weeks gestation, and 8.4%(58 were agreed with beyond the 24 weeks of gestational age. Conclusion The majority of physicians were in agreement with abortion for thalassemia major and Down's syndrome because of the overall prognosis, but opposed to abortion for hemophilia.

  15. Program Director Survey: Attitudes Regarding Child Neurology Training and Testing.

    Science.gov (United States)

    Valencia, Ignacio; Feist, Terri B; Gilbert, Donald L

    2016-04-01

    As a result of major clinical and scientific advances and changes in clinical practice, the role of adult neurology training for Child Neurology and Neurodevelopmental Disability (NDD) certification has become controversial. The most recently approved requirements for board eligibility for child neurology and neurodevelopmental disability residents still include 12 months in adult neurology rotations. The objective of this study was to assess United States child neurology and neurodevelopmental disability residency program directors' opinions regarding optimal residency training. The authors developed an 18-item questionnaire and contacted all 80 child neurology and neurodevelopmental disability program directors via e-mail, using SurveyMonkey. A total of 44 program directors responded (55%), representing programs that train 78 categorical and 94 total resident positions, approximately 70% of those filled in the match. Respondents identified multiple areas where child neurology residents need more training, including genetics and neuromuscular disease. A substantial majority (73%) believed child neurology and neurodevelopmental disability residents need less than 12 adult neurology training months; however, most (75%) also believed adult hospital service and man-power needs (55%) and finances (34%) would pose barriers to reducing adult neurology. Most (70%) believed reductions in adult neurology training should be program flexible. A majority believed the written initial certification examination should be modified with more child neurology and fewer basic neuroscience questions. Nearly all (91%) felt the views of child neurology and neurodevelopmental disability program directors are under-represented within the Accreditation Council for Graduate Medical Education Residency Review Committee. The requirement for 12 adult neurology months for Child Neurology and Neurodevelopmental Disability certification is not consistent with the views of the majority of program

  16. Acquired hemophilia A: a review of recent data and new therapeutic options.

    Science.gov (United States)

    Franchini, Massimo; Vaglio, Stefania; Marano, Giuseppe; Mengoli, Carlo; Gentili, Sara; Pupella, Simonetta; Liumbruno, Giancarlo Maria

    2017-10-01

    Acquired hemophilia A (AHA) is a rare, but potentially life-threatening, bleeding disorder caused by an autoantibody against factor VIII that interferes with its coagulant function. We performed a narrative review focusing on the diagnostic aspects of AHA and on the current treatment strategies with particular regard to new data and therapeutic developments. The management of this severe hemorrhagic disorder is based on the control of bleeding with the use of bypassing agents and on the utilization of a variety of immunosuppressant agents with the goal of eliminating the autoantibody permanently. The optimal management of AHA should be multidisciplinary and requires a close collaboration between physicians from various specialties.

  17. Acquired Hemophilia A with a Rare Presentation of Acute Subdural Hematoma

    Directory of Open Access Journals (Sweden)

    Yoshihide Sehara

    2015-01-01

    Full Text Available An 80-year-old man was admitted for acute subdural hematoma caused by a mild brain injury. His coagulation test showed an isolated prolongation of activated partial thromboplastin time (aPTT. Though the subdural hematoma did not progress, oozing bleed from the wound of tracheostomy continued. Failure of correction on aPTT mixing test supported the presence of an inhibitor to a coagulation factor. Once the diagnosis of acquired hemophilia A (AHA was made, steroid therapy was performed, which leads him to complete remission of AHA. Isolated prolongation of aPTT can be the key to diagnose a rare coagulopathy, such as AHA.

  18. Potential role of a new PEGylated recombinant factor VIII for hemophilia A

    Directory of Open Access Journals (Sweden)

    Wynn TT

    2016-06-01

    Full Text Available Tung Thanh Wynn,1 Burak Gumuscu,2,3 1Department of Pediatrics, Division of Pediatric Hematology/Oncology, University of Florida, Gainesville, FL, 2Pediatric Hematology-Oncology, Bon Secours Health System, St. Mary’s Hospital, Richmond, VA, 3Department of Pediatrics, Division of Pediatric Hematology/Oncology, University of Virginia, Charlottesville, VA, USA Abstract: Hemophilia A, a deficiency in the activity of coagulation factor (F VIII, is an X-linked bleeding disorder with an approximate incidence of one in 5,000 male infants. Bleeding-related complications often result in greater severity of disease, poor quality of life, surgical interventions for severe joint destruction, and shortened life span. With the availability of plasma-derived and recombinant FVIII products, the benefits of primary prophylaxis were demonstrated and is now the standard of care for patients with severe factor deficiencies. Current hemophilia research is focusing on the creation of new factor replacement therapies with longer half-lives; accessing alternative mechanisms to achieve desired hemostasis and enhance bypassing ­activity; and limiting the immunogenicity of the protein. PEGylation involves the covalent attachment of polyethylene glycol (PEG to a protein, peptide, or a small molecule drug. PEG effectively increases the molecular weight and size of the protein by creating a hydrophilic cloud around the molecule. This molecular change may reduce susceptibility of the molecule to proteolytic activity and degradation. It is also believed that PEGylation changes the surface charge of the protein that ultimately interferes with some receptor-mediated clearance processes. The half-life of PEGylated factor is more prolonged when compared to non-PEGylated full-length recombinant FVIII. The dawn of a new era in the care of hemophilia patients is upon us with the release of recombinant FVIII products with extended half-lives, and products with even more extended half

  19. Predictors of Choral Directors' Voice Handicap

    Science.gov (United States)

    Schwartz, Sandra

    2013-01-01

    Vocal demands of teaching are considerable and these challenges are greater for choral directors who depend on the voice as a musical and instructive instrument. The purpose of this study was to (1) examine choral directors' vocal condition using a modified Voice Handicap Index (VHI), and (2) determine the extent to which the major variables…

  20. Guidance for the Directors of Banks

    OpenAIRE

    Westlake, Richard

    2013-01-01

    The need for sound governance of banks worldwide has never been stronger. After the global financial crisis of 2007-2009, spectacular bank failures, whether caused by greed, incompetence, or indifference, are still occurring. This guide is intended mainly for three groups of readers: (i) new directors with experience in banking; (ii) directors who understand governance, but have no experie...

  1. PLAY DIRECTING AND DIRECTORS: AN EVOLUTIONARY ...

    African Journals Online (AJOL)

    ... seen as a priest and a carrier who must coordinate human and material resources a master and a messenger. Drawing from the above, this paper traces the evolution of play directing and the theatre director in different theatres of the world. It also critically evaluates the art of play directing and the Nigerian theatre director.

  2. J. B. Adams Acting Director-General

    CERN Multimedia

    1960-01-01

    After the tragic death of Prof. C. J. Bakker, the Council of CERN held an emergency meeting on May 3, 1960. Following this session, Mr. F. de Rose, President of the Council of the European Organization for Nuclear Research, announced the appointment of Mr. J. B. Adams, Director of the PS division to the post of acting Director-General.

  3. Robert Aymar, Director-General of CERN

    CERN Multimedia

    Patrice Loïez

    2003-01-01

    Robert Aymar, photographed in 2003 before taking his position as Director-General at CERN, succeeding Luciano Maiani in 2004. At this time, Aymar was director of the International Thermonuclear Experimental Reactor (ITER) although he had already been involved with developments at CERN, chairing the External Review Committee, set up in 2001 in response to the increased cost of the LHC.

  4. CERN loses two former Directors-General

    CERN Multimedia

    2002-01-01

    Victor Weisskopf, a giant of modern physics and Director General of CERN from 1961-65, died on 21 April. The previous month, Willibald Jentschke, Director General from 1971-75 and founder of the DESY Laboratory in Hamburg, passed away.

  5. 75 FR 56667 - Facilitating Shareholder Director Nominations

    Science.gov (United States)

    2010-09-16

    ... shareholders' traditional State law rights to nominate and elect directors to company boards of directors. The... Affiliates of the Company E. Application of the Liability Provisions in the Federal Securities Laws to... law or imposing a ``one size fits all'' rule for all companies and expressed concerns about ``special...

  6. Quality Improvement in Otolaryngology Residency: Survey of Program Directors.

    Science.gov (United States)

    Bowe, Sarah N

    2016-02-01

    The Clinical Learning Environment Review focuses on the responsibility of the sponsoring institution for quality and patient safety. Very little information is known regarding the status of quality improvement (QI) education during otolaryngology training. The purpose of this survey is to evaluate the extent of resident and faculty participation in QI and identify opportunities for both resident curriculum and faculty development. Cross-sectional survey A 15-item survey was distributed to all 106 otolaryngology program directors. The survey was developed after an informal review of the literature regarding education in QI and patient safety. Questions were directed at the format and content of the QI curriculum, as well as barriers to implementation. There was a 39% response rate. Ninety percent of responding program directors considered education in QI important or very important to a resident's future success. Only 23% of responding programs contained an educational curriculum in QI, and only 33% monitored residents' individual outcome measures. Barriers to implementation of a QI program included inadequate number of faculty with expertise in QI (75%) and competing resident educational demands (90%). Every program director considered morbidity and mortality conferences as an integral component in QI education. Program directors recognize the importance of QI in otolaryngology practice. Unfortunately, this survey identifies a distinct lack of resources in support of these educational goals. The results highlight the need to generate a comprehensive and stepwise approach to QI for faculty development and resident instruction. © American Academy of Otolaryngology—Head and Neck Surgery Foundation 2015.

  7. Comparing the Effects of Therapeutic Exercise and Hydrotherapy on Pain Severity and Knee Range of Motion in Patients with Hemophilia: A Randomized Controlled Trial

    Directory of Open Access Journals (Sweden)

    V Mazloum

    2013-10-01

    . Results: Both experimental groups exhibited significant reduction of pain along with improved knee flexion and extension compared with the control group (P<0.001. Pain reduction in subjects treated in water treatment was significantly higher than exercise group in drought (P0.05. Conclusion: The use of therapeutic exercise in water with regular exercise rehabilitation for patients with hemophilia can be helpful to reduce pain and improve range of motion in hemophilia patients. The effect of exercise therapy on pain reduction is more effective compared to traditional pain therapy. Key words: Hydrotherapy, Exercise Therapy, Hemophilia, Knee Range of Motion

  8. INCIDENCE OF LYMPHOMAS AND OTHER CANCERS IN HIV-INFECTED AND HIV-UNINFECTED PATIENTS WITH HEMOPHILIA

    NARCIS (Netherlands)

    RABKIN, CS; HILGARTNER, MW; HEDBERG, KW; ALEDORT, LM; HATZAKIS, A; EICHINGER, S; EYSTER, ME; WHITE, GC; KESSLER, CM; LEDERMAN, MM; DEMOERLOOSE, P; BRAY, GL; COHEN, AR; ANDES, WA; MANCOJOHNSON, M; SCHRAMM, W; KRONER, BL; BLATTNER, WA; GOEDERT, JJ

    1992-01-01

    Objective. - To determine the types and rates of cancers occurring in excess in the presence of infection with the human immunodeficiency virus type 1 (HIV-1). Design. - Cohort analytic study of HIV-infected and HIV-uninfected subjects followed for up to 12 years. Setting. - Fifteen hemophilia

  9. Evaluation of the biological differences of canine and human factor VIII in gene delivery: Implications in human hemophilia treatment

    Science.gov (United States)

    The canine is the most important large animal model for testing novel hemophilia A(HA) treatment. It is often necessary to use canine factor VIII (cFIII) gene or protein for the evaluation of HA treatment in the canine model. However, the different biological properties between cFVIII and human FVII...

  10. Antibody response to recombinant human coagulation factor VIII in a new rat model of severe hemophilia A

    DEFF Research Database (Denmark)

    Löfgren, Karin Maria; Sondergaard, H.; Skov, Søren

    2016-01-01

    Background: Neutralizing antibodies towardFVIII replacement therapy (inhibitors) are the most seri-ous treatment-related complication in hemophilia A(HA). A rat model of severe HA (F8/) has recentlybeen developed, but an immunological characterization isneeded to determine the value of using...

  11. Serum HIV-1 RNA levels and time to development of AIDS in the multicenter hemophilia cohort study

    NARCIS (Netherlands)

    OBrien, TR; Blattner, WA; Waters, D; Eyster, ME; Hilgartner, MW; Cohen, AR; Luban, N; Hatzakis, A; Aledort, LM; Rosenberg, PS; Miley, WJ; Kroner, BL; Goedert, JJ

    1996-01-01

    Objective.-To determine if the long-term incidence of the acquired immunodeficiency syndrome (AIDS) is related to human immunodeficiency virus type 1 (HIV-1) RNA levels measured early in HIV-1 infection. Design.-Epidemiologic cohort study. Setting.-Five hemophilia treatment centers in the United

  12. AAV-based neonatal gene therapy for hemophilia A: long-term correction and avoidance of immune responses in mice.

    Science.gov (United States)

    Hu, C; Lipshutz, G S

    2012-12-01

    Hemophilia A gene therapy has been hampered by immune responses to vector-associated antigens and by neutralizing antibodies or inhibitors against the factor VIII (FVIII) protein; these 'inhibitors' more commonly affect hemophilia A patients than those with hemophilia B. A gene replacement strategy beginning in the neonatal period may avoid the development of these immune responses and lead to prolonged expression with correction of phenotype, thereby avoiding long-term consequences. A serotype rh10 adeno-associated virus (AAV) was developed splitting the FVIII coding sequence into heavy and light chains with the chicken β-actin promoter/CMV enhancer for dual recombinant adeno-associated viral vector delivery. Virions of each FVIII chain were co-injected intravenously into mice on the second day of life. Mice express sustained levels of FVIII antigen ≥5% up to 22 months of life without development of antibodies against FVIII. Phenotypic correction was manifest in all AAV-FVIII-treated mice as demonstrated by functional assay and reduction in bleeding time. This study demonstrates the use of AAV in a gene replacement strategy in neonatal mice that establishes both long-term phenotypic correction of hemophilia A and lack of antibody development against FVIII in this disease model where AAV is administered shortly after birth. These studies support the consideration of gene replacement therapy for diseases that are diagnosed in utero or in the early neonatal period.

  13. Phenotypic correction and stable expression of factor VIII in hemophilia A mice by embryonic stem cell therapy.

    Science.gov (United States)

    Wang, J J; Kuang, Y; Zhang, L L; Shen, C L; Wang, L; Lu, S Y; Lu, X B; Fei, J; Gu, M M; Wang, Z G

    2013-05-13

    Hereditary deficiency of factor VIII (FVIII) leads to hemophilia A, a severe X-linked bleeding disorder. Current therapies include fixed-dose FVIII prophylaxis, factor replacement therapy, and most recently, gene therapy. Prophylaxis and FVIII replacement therapies are limited by incomplete efficacy, high cost, restricted availability, and development of neutralizing antibodies in chronically treated individuals. Limited success has been obtained in preclinical trials using gene therapy for the treatment of hemophilia. Therefore, new options for therapy for hemophilia A are needed. We evaluated the potential of embryonic stem cells for correcting hemophilia A in mice. FVIII-deficient mouse blastocysts were collected and injected with mouse embryonic stem cells stably expressing green-fluorescent protein (GFP) and transferred to pseudopregnant recipient mice. Expression of FVIII was measured in the liver and plasma of the 5 chimeric mice that were produced. Three of these mice were GFP-positive at the age of 6 months. The plasma FVIII activity levels were equal to those of wild-type mice. These data demonstrate that embryonic stem cell transplantation at an early embryonic stage has potential as therapy for this progressively debilitating, life-threatening bleeding disorder.

  14. Optimal monitoring of bypass therapy in hemophilia A patients with inhibitors by the use of clot waveform analysis.

    Science.gov (United States)

    Haku, J; Nogami, K; Matsumoto, T; Ogiwara, K; Shima, M

    2014-01-01

    Assays to determine the optimal hemostatic effects of bypass therapy in hemophilia A (HA) patients with inhibitors are difficult to compare. Clot waveform analysis (CWA), based on the continuous monitoring of routine coagulation parameters (prothrombin time/activated partial thromboplastin time), offers a useful method for assessing global clotting function. To investigate the technique of CWA for the hemostatic monitoring of bypass therapy in HA patients with inhibitors. Ellagic acid (Elg), tissue factor (TF) or both (Elg/TF) were used as trigger reagents in CWA. The standard parameters - clot time (CT), maximum coagulation velocity (|min1|), and acceleration (|min2|) - were recorded. Optimal monitoring was defined as: (i) a significant difference in these parameters between plasma from HA patients with inhibitors and normal plasmas; and (ii) a significant improvement in these indices in HA patients with inhibitors after bypass therapy. Experiments in vitro demonstrated that there were significant differences between plasma from HA patients with inhibitors and normal plasma with various triggers, in the order Elg > Elg/TF > TF. Addition of therapeutically achievable concentrations of bypassing agents, however, showed significant improvements in the different parameters only with Elg/TF, suggesting that this reagent provided the most appropriate assay. A total of 20 plasmas from HA patients with inhibitors in which bypassing agents were infused were evaluated ex vivo by Elg/TF CWA. The postinfusion parameters CT and |min2| reflected clinical effects, and were close to normal levels. Furthermore, Elg/TF CWA facilitated quantitative evaluation of perioperative hemostatic management of bypass therapy in HA patients with inhibitors. CWA is a promising method for the quantitative monitoring of bypass therapy during routine automated clotting assays with a modified trigger reagent comprising a well-balanced mixture of Elg and TF. © 2013 International Society on

  15. Characterization of a genetically engineered mouse model of hemophilia A with complete deletion of the F8 gene.

    Science.gov (United States)

    Chao, B N; Baldwin, W H; Healey, J F; Parker, E T; Shafer-Weaver, K; Cox, C; Jiang, P; Kanellopoulou, C; Lollar, P; Meeks, S L; Lenardo, M J

    2016-02-01

    ESSENTIALS: Anti-factor VIII (FVIII) inhibitory antibody formation is a severe complication in hemophilia A therapy. We genetically engineered and characterized a mouse model with complete deletion of the F8 coding region. F8(TKO) mice exhibit severe hemophilia, express no detectable F8 mRNA, and produce FVIII inhibitors. The defined background and lack of FVIII in F8(TKO) mice will aid in studying FVIII inhibitor formation. The most important complication in hemophilia A treatment is the development of inhibitory anti-Factor VIII (FVIII) antibodies in patients after FVIII therapy. Patients with severe hemophilia who express no endogenous FVIII (i.e. cross-reacting material, CRM) have the greatest incidence of inhibitor formation. However, current mouse models of severe hemophilia A produce low levels of truncated FVIII. The lack of a corresponding mouse model hampers the study of inhibitor formation in the complete absence of FVIII protein. We aimed to generate and characterize a novel mouse model of severe hemophilia A (designated the F8(TKO) strain) lacking the complete coding sequence of F8 and any FVIII CRM. Mice were created on a C57BL/6 background using Cre-Lox recombination and characterized using in vivo bleeding assays, measurement of FVIII activity by coagulation and chromogenic assays, and anti-FVIII antibody production using ELISA. All F8 exonic coding regions were deleted from the genome and no F8 mRNA was detected in F8(TKO) mice. The bleeding phenotype of F8(TKO) mice was comparable to E16 mice by measurements of factor activity and tail snip assay. Similar levels of anti-FVIII antibody titers after recombinant FVIII injections were observed between F8(TKO) and E16 mice. We describe a new C57BL/6 mouse model for severe hemophilia A patients lacking CRM. These mice can be directly bred to the many C57BL/6 strains of genetically engineered mice, which is valuable for studying the impact of a wide variety of genes on FVIII inhibitor formation on a

  16. Solulin increases clot stability in whole blood from humans and dogs with hemophilia

    Science.gov (United States)

    Petersen, Karl-Uwe; Rea, Catherine J.; Harpell, Lori; Powell, Sandra; Lillicrap, David; Nesheim, Michael E.; Sørensen, Benny

    2012-01-01

    Solulin is a soluble form of thrombomodulin that is resistant to proteolysis and oxidation. It has been shown to increase the clot lysis time in factor VIII (fVIII)–deficient plasma by an activated thrombin-activatable fibrinolysis inhibitor (TAFIa)–dependent mechanism. In the present study, blood was drawn from humans and dogs with hemophilia, and thromboelastography was used to measure tissue factor–initiated fibrin formation and tissue-plasminogen activator–induced fibrinolysis. The kinetics of TAFI and protein C activation by the thrombin-Solulin complex were determined to describe the relative extent of anticoagulation and antifibrinolysis. In severe hemophilia A, clot stability increased by > 4-fold in the presence of Solulin while minimally affecting clot lysis time. Patients receiving fVIII/fIX prophylaxis showed a similar trend of increased clot stability in the presence of Solulin. The catalytic efficiencies of TAFI and protein C activation by the thrombin-Solulin complex were determined to be 1.53 and 0.02/μM/s, respectively, explaining its preference for antifibrinolysis over anticoagulation at low concentrations. Finally, hemophilic dogs given Solulin had improved clot strength in thromboelastography assays. In conclusion, the antifibrinolytic properties of Solulin are exhibited in hemophilic human (in vitro) and dog (in vivo/ex vivo) blood at low concentrations. Our findings suggest the therapeutic utility of Solulin at a range of very low doses. PMID:22234684

  17. A close insight to factor VIII inhibitor in the congenital hemophilia A.

    Science.gov (United States)

    Tabriznia-Tabrizi, Shamsoreza; Gholampour, Marzie; Mansouritorghabeh, Hassan

    2016-09-01

    Hemophilia A (HA) has an X-linked pattern of inheritance and is the most common of the hemorrhagic disorders. HA is caused by a decreased or deficiency of the functional clotting factor VIII (FVIII) and effects 1 in 5000-10,000 male births. The common treatment for hemophilia is replacement therapy by plasma-derived or recombinant FVIII. Approximately 20-30% of people with a severe type of HA develop an inhibitor and this phenomenon is the main challenge in the management of these patients. Genetic factors and environmental determinants contribute to inhibitor development. Here, the roles of various genetic and environmental factors such as the type of FVIII concentrate used, the number of exposure days, and peak treatment time will be discussed in detail. It seems this information is helpful for hematologists. A literature review was done in January 2016 on PubMed and Scopus using the following keywords:' h(a)emophilia A & factor VIII inhibitor', 'h(a)emophilia A & factor VIII alloantibody', 'h(a)emophilia A & inhibitor'. There was no time limitation; however, there was an English language limitation placed on the articles selected. Expert commentary: Influential genetic and environmental factors in developing inhibitors have been discussed. Most of the risk factors are related to previously untreated patients with hemophili.

  18. Knee Fat Pad Volumes in Patients with Hemophilia and Their Relationship with Osteoarthritis

    Directory of Open Access Journals (Sweden)

    Annette von Drygalski

    2017-01-01

    Full Text Available Hemophilic arthropathy is a progressive, disabling condition with poorly understood pathobiology. Since there is an emerging interest to study the role of intra-articular fat pad size and biology in arthritic conditions, we explored fat pad volume changes in hemophilic arthropathy and to what extent they differed from osteoarthritis. We matched a cohort of 13 adult patients with hemophilic arthropathy of the knee with age- and gender-matched cohorts without osteoarthritis (“control cohort” and with the same degree of radiographic osteoarthritis (“OA cohort” in 1 : 2 fashion. Infrapatellar fat pad (IPFP and suprapatellar fat pad (SPFP volumes were calculated based on magnetic resonance imaging and differences in fat pad volumes, demographics, height, weight, and osteoarthritis scores were evaluated. Fat pad volumes were positively associated with body size parameters in all three cohorts but were unaffected by the degree of osteoarthritis. While IPFP volumes did not differ between cohorts, SPFP volumes expanded disproportionally with weight in hemophilia patients. Our observations indicate that IPFPs and SPFPs behave biologically differently in response to different arthritic stimuli. The exaggerated expansion of the SPFP in hemophilia patients highlights the importance of further studying the implications of fat pad biology for progression of hemophilic arthropathy.

  19. Acquired inhibitors of coagulation factors: part I-acquired hemophilia A.

    Science.gov (United States)

    Coppola, Antonio; Favaloro, Emmanuel J; Tufano, Antonella; Di Minno, Matteo N D; Cerbone, Anna Maria; Franchini, Massimo

    2012-07-01

    Acquired hemophilia A (AHA) is a rare, but often severe, bleeding disorder caused by autoantibodies against clotting factor VIII (FVIII). AHA occurs more frequently in the elderly and in association with several conditions, such as malignancies, autoimmune diseases, postpartum, or drug exposure; however, about half of the cases remain idiopathic. At variance with congenital hemophilia, where hemarthroses are the most common bleeding symptoms, hemorrhages in AHA involving soft tissues (muscle, skin) are more frequently reported. AHA is diagnosed in patients: with negative personal or family bleeding history; in which prolonged activated partial thromboplastin time is not corrected after mixing and incubating equal volumes of patient and normal plasma for ~2 hours at 37°C; FVIII levels are reduced; and a specific FVIII-inhibiting activity is detected. Prompt recognition and treatment of AHA are mandatory, as inadequate management and complications of the disease are associated with high mortality rates. Therapeutic approaches should aim to control acute bleeds, eradicate FVIII-autoantibody production, treat associated diseases, and when possible, eliminate them. Present knowledge about this often overlooked and challenging condition has significantly increased following establishment of recent national and international studies, as will also be reviewed in this article. Thieme Medical Publishers 333 Seventh Avenue, New York, NY 10001, USA.

  20. Acquired hemophilia possibly induced by etanercept in a patient with rheumatoid arthritis.

    Science.gov (United States)

    Banse, Christopher; Benhamou, Ygal; Lequerré, Thierry; Le Cam-Duchez, Véronique; Lévesque, Hervé; Vittecoq, Olivier

    2015-05-01

    A 47-year-old woman with rheumatoid arthritis (RA) treated successively with infliximab, abatacept, and etanercept spontaneously developed subcutaneous bruises and a noncompressive hematoma 11 months after starting etanercept therapy (50mg/week). Her prothrombin time was normal but her activated partial thromboplastin time was increased to 2.48 (normal range, 0.85-1.17). She had a circulating anticoagulant (Rosner index, 45; normal,etanercept and leflunomide were stopped and prednisone was given in a daily dosage of 1mg/kg, in combination with rituximab, two 1-g doses at an interval of 2 weeks. After 5 months, persistence of the anti-factor VIII antibody prompted the initiation of azathioprine therapy, 2mg/kg/d. A remission was achieved 9 months after the diagnosis of acquired hemophilia and was sustained at last follow-up after 3 years. This new case of acquired hemophilia in a patient with RA may reflect a simple association or an inducing role of etanercept. Copyright © 2015 Société française de rhumatologie. Published by Elsevier SAS. All rights reserved.

  1. Tolerance induction in hemophilia A animal models: battling inhibitors with antigen-specific immunotherapies.

    Science.gov (United States)

    Adair, Patrick; Su, Yan; Scott, David W

    2013-05-01

    Hemophilia A is an X-linked recessive bleeding disorder due to either a lack of or greatly reduced activity in the blood coagulation protein factor VIII (FVIII), due to mutations in the F8 gene. This poses significant challenges for FVIII replacement therapy since hemophilic patients are not immunologically tolerant to the protein. Thus, a proportion of patients who receive plasma-derived or recombinant FVIII replacement therapy develop anti FVIII neutralizing antibodies, known as "inhibitors." These patients require long-term regimens of high dose FVIII administration, which has varying success rates and prohibitive costs. Therefore, therapeutics for tolerance induction in such patients with inhibitors are desired. In this review, we address the current progress of immunotherapies for inducing FVIII specific tolerance in animal models of hemophilia A. Specifically we discuss the beneficial effects of B-cell depletion on immune tolerance induction (ITI), B-cell mediated gene therapy, antigen-coupled lymphocyte therapy, and regulatory T-cell epitopes (Tregitopes).

  2. Hemophilia A inhibitor treatment: the promise of engineered T-cell therapy.

    Science.gov (United States)

    Parvathaneni, Kalpana; Abdeladhim, Maha; Pratt, Kathleen P; Scott, David W

    2017-09-01

    Hemophilia A is a bleeding disorder caused by mutations in the gene encoding factor VIII (FVIII), a cofactor protein that is essential for normal blood clotting. Approximately, 1 in 3 patients with severe hemophilia A produce neutralizing antibodies (inhibitors) that block its biologic function in the clotting cascade. Current efforts to eliminate inhibitors consist of repeated FVIII injections under what is termed an "ITI" protocol (Immune Tolerance Induction). However, this method is extremely costly and approximately 30% of patients undergoing ITI do not achieve peripheral tolerance. Human T regulatory cells (Tregs) have been proposed as a new strategy to treat this antidrug antibody response, as well as other diseases. Polyclonal Tregs are nonspecific and could potentially cause general immunosuppression. Novel approaches to induce tolerance to FVIII include the use of engineered human and mouse antigen-specific Tregs, or alternatively antigen-specific cytotoxic cells, to delete, anergize, or kill FVIII-specific lymphocytes. In this review, we discuss the current state of engineered T-cell therapies, and we describe the recent progress in applying these therapies to induce FVIII-specific tolerance. Published by Elsevier Inc.

  3. The Future of Hemophilia Treatment: Longer-Acting Factor Concentrates versus Gene Therapy.

    Science.gov (United States)

    Giangrande, Paul

    2016-07-01

    Gene therapy is the only novel technology that currently offers the prospect of a lasting cure for hemophilia and freedom from the burden of repeated injections. Recent data from a handful of patients who have undergone gene therapy for hemophilia B are very encouraging with a sustained factor IX (FIX) level of 0.05 IU/mL maintained for over 4 years. While this level is above the current usual target trough levels, it falls well short of the level that patients on prophylaxis with longer-acting products can expect. Prophylaxis is also associated with high peak levels, which permits patients to maintain an active lifestyle. A major barrier to widespread adoption of gene therapy is a high seroprevalence of antibodies to adeno-associated virus (AAV) vectors in the general population. Young children would be the best candidates for gene therapy in view of much lower seroprevalence to AAV in infants. A stable level of FIX early in life would prevent the onset of joint bleeds and the development of arthropathy. The recent experience with apolipoprotein tiparvovec (Glybera; uniQure, Amsterdam, the Netherlands) indicates that gene therapy is unlikely to prove to be a cheap therapeutic option. It is also quite possible that other new technologies that do not require viral vectors (such as stem cell therapy) may overtake gene therapy during development and make it redundant. Thieme Medical Publishers 333 Seventh Avenue, New York, NY 10001, USA.

  4. Indoleamine 2,3-dioxygenase attenuates inhibitor development in gene-therapy-treated hemophilia A mice.

    Science.gov (United States)

    Liu, L; Liu, H; Mah, C; Fletcher, B S

    2009-06-01

    A serious impediment to gene and protein replacement therapy in hemophilia A is the development of inhibitors. Mechanisms responsible for inhibitor development include T-cell-dependent adaptive immune responses and the CD28-B7 signaling pathway that eventually leads to the formation of antibodies directed against factor VIII (FVIII). Indoleamine 2,3-dioxygenase (IDO) is a potent immunosuppressive enzyme that can inhibit T-cell responses and induce T-cell apoptosis by regulation of tryptophan metabolism. Kynurenine, one of the metabolites of tryptophan, has been implicated as an immune modulator. Here we hypothesize that co-delivery of the genes for FVIII and IDO can attenuate inhibitor formation. Using transposon-based gene delivery, we observed long-term therapeutic FVIII expression and significantly reduced inhibitor titers when the genes were co-delivered. Co-expression of FVIII and IDO in the liver was associated with increased plasma kynurenine levels, an inhibition of T-cell infiltration and increased apoptosis of T cells within the liver. These experiments suggest that modulation of tryptophan catabolism through IDO expression provides a novel strategy to reduce inhibitor development in hemophilia gene/protein therapy.

  5. Emergency Medicine Clerkship Directors: Current Workforce

    Directory of Open Access Journals (Sweden)

    David A. Wald

    2014-07-01

    Full Text Available Introduction: The emergency medicine clerkship director serves an important role in the education of medical students. The authors sought to update the demographic and academic profile of the emergency medicine clerkship director. Methods: We developed and implemented a comprehensive questionnaire, and used it to survey all emergency medicine clerkship directors at United States allopathic medical schools accredited by the Liaison Committee on Medical Education. We analyzed and interpreted data using descriptive statistics. Results: One hundred seven of 133 (80.4% emergency medicine clerkship directors completed the survey. Clerkship Director’s mean age was 39.7 years (SD-7.2, they were more commonly male 68.2%, of Caucasian racial backgrounds and at the instructor or assistant professor (71.3% level. The mean number of years of experience as clerkship director was 5.5 (SD-4.5. The mean amount of protected time for clerkship administration reported by respondents was 7.3 hours weekly (SD-5.1, with the majority (53.8% reporting 6 or more hours of protected time per week. However, 32.7% of emergency medicine clerkship directors reported not having any protected time for clerkship administration. Most clerkship directors (91.6% held additional teaching responsibilities beyond their clerkship and many were involved in educational research (49.5%. The majority (79.8%, reported being somewhat or very satisfied with their job as clerkship director. Conclusion: Most clerkship directors were junior faculty at the instructor or assistant professor rank and were involved with a variety of educational endeavors beyond the clerkship. [West J Emerg Med. 2014;15(4:398–403.

  6. Frequency and epitope specificity of anti-factor VIII C1 domain antibodies in acquired and congenital hemophilia A.

    Science.gov (United States)

    Kahle, Joerg; Orlowski, Aleksander; Stichel, Diana; Healey, John F; Parker, Ernest T; Jacquemin, Marc; Krause, Manuela; Tiede, Andreas; Schwabe, Dirk; Lollar, Pete; Königs, Christoph

    2017-08-10

    Several studies showed that neutralizing anti-factor VIII (anti-fVIII) antibodies (inhibitors) in patients with acquired hemophilia A (AHA) and congenital hemophilia A (HA) are primarily directed to the A2 and C2 domains. In this study, the frequency and epitope specificity of anti-C1 antibodies were analyzed in acquired and congenital hemophilia inhibitor patients (n = 178). The domain specificity of antibodies was studied by homolog-scanning mutagenesis (HSM) with single human domain human/porcine fVIII proteins and antibody binding to human A2, C1, and C2 domains presented as human serum albumin (HSA) fusion proteins. The analysis with HSA-fVIII domain proteins confirmed the results of the HSM approach but resulted in higher detection levels. The higher detection levels with HSA-fVIII domain proteins are a result of antibody cross-reactivity with human and porcine fVIII leading to false-negative HSM results. Overall, A2-, C1-, and C2-specific antibodies were detected in 23%, 78%, and 68% of patients with AHA (n = 115) and in 52%, 57%, and 81% of HA inhibitor patients (n = 63). Competitive binding of the human monoclonal antibody (mAb) LE2E9 revealed overlapping epitopes with murine C1-specific group A mAbs including 2A9. Mutational analyses identified distinct crucial binding residues for LE2E9 (E2066) and 2A9 (F2068) that are also recognized by anti-C1 antibodies present in patients with hemophilia. A strong contribution of LE2E9- and 2A9-like antibodies was particularly observed in patients with AHA. Overall, our study demonstrates that the C1 domain, in addition to the A2 and C2 domains, contributes significantly to the humoral anti-fVIII immune response in acquired and congenital hemophilia inhibitor patients. © 2017 by The American Society of Hematology.

  7. The Effect of Aquatic Exercise Therapy on Muscle Strength and Joint's Range of Motion in Hemophilia Patients.

    Science.gov (United States)

    Kargarfard, Mehdi; Dehghadani, Mehdi; Ghias, Reza

    2013-01-01

    This study was to evaluate the effect of a period of aquatic exercise therapy on muscle strength and joints range of motion in hemophilia patients. This was a semiexperimental, pretest, post-test study with a control group. This semi-experimental study comprised twenty men suffering moderate hemophilia were selected by convenience sampling method from patients of a referral hospital. They were randomly assigned to intervention and control groups of equal number. The hemophilia patients who were referred to Sayedo-Shohada Hospital enrolled in this study. Twenty men suffering moderate hemophilia were selected using convenience sampling method and then divided randomly into intervention and control groups (10 patients in each group). Subjects of aquatic exercise therapy group underwent activity in water in three sessions (45-60 minutes) per week for 8 weeks, while the control group was only under follow-up and during this period did not experience any effective physical activity. The patients' muscle strength and joint range of motion were evaluated through standard laboratory tools, using an isokinetic dynamometer (Biodex, Systems III) and a standard goniometer in the beginning and at end of the study. Finally, data was analyzed using analysis of covariance (ANCOVA). The strength of the muscles around the knee joint (to perform extension and flexion movements) increased significantly in the case group while the control group experienced a significant reduction of strength in left leg, but in right leg remarkable change was observed. Range of motion in all joints was improved in the case group, while the control group did not improve significantly. The results showed that aquatic exercise therapy can be a useful method to improve joints' strength and range of motion in hemophilia patients in order to improve their daily functioning and quality of life.

  8. Gender Quotas on Board of Directors

    DEFF Research Database (Denmark)

    Smith, Nina

    2013-01-01

    Beside arguments of fairness and equal opportunities, it is often argued that gender diversity on boards of directors may improve firm performance, but the empirical results are mixed and often negative. Based on the available research, gender quotas on boards of directors cannot be justified...... on the grounds of economic efficiency. Furthermore, in most countries a limited number of women are qualified to join boards of directors, and it is not clear from the evidence to date on the operation of quotas whether they will lead to a better pool of female candidates in the medium and long term....

  9. What every library director should know

    CERN Document Server

    Curzon, Susan Carol

    2014-01-01

    What Every Library Director Should Know is the insider's view of vital actions, behaviors and strategies to succeed in every type of library. The content is based both on the author's direct experience after a long career in several types of libraries but also on the direct observation of other managers. Inset into the book are pearls of wisdom from other directors, managers and observers who are answering the question, "what is the one piece of management wisdom that you would give to anyone who wishes to become a library director?" This book will help to get you there by explaining and illus

  10. Computation Directorate 2007 Annual Report

    Energy Technology Data Exchange (ETDEWEB)

    Henson, V E; Guse, J A

    2008-03-06

    If there is a single word that both characterized 2007 and dominated the thoughts and actions of many Laboratory employees throughout the year, it is transition. Transition refers to the major shift that took place on October 1, when the University of California relinquished management responsibility for Lawrence Livermore National Laboratory (LLNL), and Lawrence Livermore National Security, LLC (LLNS), became the new Laboratory management contractor for the Department of Energy's (DOE's) National Nuclear Security Administration (NNSA). In the 55 years under the University of California, LLNL amassed an extraordinary record of significant accomplishments, clever inventions, and momentous contributions in the service of protecting the nation. This legacy provides the new organization with a built-in history, a tradition of excellence, and a solid set of core competencies from which to build the future. I am proud to note that in the nearly seven years I have had the privilege of leading the Computation Directorate, our talented and dedicated staff has made far-reaching contributions to the legacy and tradition we passed on to LLNS. Our place among the world's leaders in high-performance computing, algorithmic research and development, applications, and information technology (IT) services and support is solid. I am especially gratified to report that through all the transition turmoil, and it has been considerable, the Computation Directorate continues to produce remarkable achievements. Our most important asset--the talented, skilled, and creative people who work in Computation--has continued a long-standing Laboratory tradition of delivering cutting-edge science even in the face of adversity. The scope of those achievements is breathtaking, and in 2007, our accomplishments span an amazing range of topics. From making an important contribution to a Nobel Prize-winning effort to creating tools that can detect malicious codes embedded in commercial

  11. Wanted: Fermilab director who can build consensus

    CERN Multimedia

    Pierce, G M

    2004-01-01

    "With current Fermilab Director Michael Witherell stepping down in July 2005, an appointed committee has vowed to find a new leader who will keep the Batavia lab at the forefront of the high-energy physics field" (1 page).

  12. The Director As Mentor: Bringing Up Teachers.

    Science.gov (United States)

    Miller, Janice P.

    1987-01-01

    Acknowledges that child care teachers work in a climate of low pay, over work, and poor working conditions and suggests several ways a director can support and nurture teachers, for example, by serving as a mentor. (BB)

  13. 45 beacon: Keith Seitter, Deputy Executive Director

    National Research Council Canada - National Science Library

    Rachel Thomas-Medwid

    2003-01-01

    ... should be open to exploring them. Such an opportunity presented itself to Seitter a little over a decade ago when Richard Hallgren, then executive director of the AMS, asked Seitter to take a leave of absence from his faculty...

  14. Dr. Francis Collins Is New NIH Director

    Science.gov (United States)

    Skip Navigation Bar Home Current Issue Past Issues Dr. Francis Collins Is New NIH Director Past Issues / ... for NIH and for science in this country." "Dr. Collins is one of our generation's great scientific ...

  15. VMware vCloud director cookbook

    CERN Document Server

    Langenhan, Daniel

    2013-01-01

    VMware vCloud Director Cookbook will adopt a Cookbook-based approach. Packed with illustrations and programming examples, this book explains the simple as well as the complex recipes in an easy-to-understand language.""VMware vCloud Director Cookbook"" is aimed at system administrators and technical architects moving from a virtualized environment to cloud environments. Familiarity with cloud computing platforms and some knowledge of virtualization and managing cloud environments is expected.

  16. Perioperative treatment of hemophilia A patients: blood group O patients are at risk of bleeding complications.

    Science.gov (United States)

    Hazendonk, H C A M; Lock, J; Mathôt, R A A; Meijer, K; Peters, M; Laros-van Gorkom, B A P; van der Meer, F J M; Driessens, M H E; Leebeek, F W G; Fijnvandraat, K; Cnossen, M H

    2016-03-01

    ESSENTIALS: Targeting of factor VIII values is a challenge during perioperative replacement therapy in hemophilia. This study aims to identify the extent and predictors of factor VIII underdosing and overdosing. Blood group O predicts underdosing and is associated with perioperative bleeding. To increase quality of care and cost-effectiveness of treatment, refining of dosing is obligatory. Perioperative administration of factor VIII (FVIII) concentrate in hemophilia A may result in both underdosing and overdosing, leading to respectively a risk of bleeding complications and unnecessary costs. This retrospective observational study aims to identify the extent and predictors of underdosing and overdosing in perioperative hemophilia A patients (FVIII levels < 0.05 IU mL(-1)). One hundred nineteen patients undergoing 198 elective, minor, or major surgical procedures were included (median age 40 years, median body weight 75 kg). Perioperative management was evaluated by quantification of perioperative infusion of FVIII concentrate and achieved FVIII levels. Predictors of underdosing and (excessive) overdosing were analyzed by logistic regression analysis. Excessive overdosing was defined as upper target level plus ≥ 0.20 IU mL(-1). Depending on postoperative day, 7-45% of achieved FVIII levels were under and 33-75% were above predefined target ranges as stated by national guidelines. A potential reduction of FVIII consumption of 44% would have been attained if FVIII levels had been maintained within target ranges. Blood group O and major surgery were predictive of underdosing (odds ratio [OR] 6.3, 95% confidence interval [CI] 2.7-14.9; OR 3.3, 95% CI 1.4-7.9). Blood group O patients had more bleeding complications in comparison to patients with blood group non-O (OR 2.02, 95% CI 1.00-4.09). Patients with blood group non-O were at higher risk of overdosing (OR 1.5, 95% CI 1.1-1.9). Additionally, patients treated with bolus infusions were at higher risk of excessive

  17. Analysis of factor VIII gene inversions in 164 unrelated hemophilia A families

    Energy Technology Data Exchange (ETDEWEB)

    Vnencak-Jones, L.; Phillips, J.A. III; Janco, R.L. [Vanderbilt Univ. School of Medicine, Nashville, TN (United States)] [and others

    1994-09-01

    Hemophilia A is an X-linked recessive disease with variable phenotype and both heterogeneous and wide spread mutations in the factor VIII (F8) gene. As a result, diagnostic carrier or prenatal testing often relies upon laborious DNA linkage analysis. Recently, inversion mutations resulting from an intrachromosomal recombination between DNA sequences in one of two A genes {approximately}500 kb upstream from the F8 gene and a homologous A gene in intron 22 of the F8 gene were identified and found in 45% of severe hemophiliacs. We have analyzed banked DNA collected since 1986 from affected males or obligate carrier females representing 164 unrelated hemophilia A families. The disease was sporadic in 37%, familial in 54% and in 10% of families incomplete information was given. A unique deletion was identified in 1/164, a normal pattern was observed in 110/164 (67%), and 53/164 (32%) families had inversion mutations with 43/53 (81%) involving the distal A gene (R3 pattern) and 10/53 (19%) involving the proximal A gene (R2 pattern). While 19% of all rearrangements were R2, in 35 families with severe disease (< 1% VIII:C activity) all 16 rearrangements seen were R3. In 18 families with the R3 pattern and known activities, 16 (89%) had levels < 1%, with the remaining 2 families having {le} 2.4% activity. Further, 18 referrals specifically noted the production of inhibitors and 8/18 (45%) had the R3 pattern. Our findings demonstrate that the R3 inversion mutation patterns is (1) only seen with VIII:C activity levels of {le} 2.4%, (2) seen in 46% of families with severe hemophilia, (3) seen in 45% of hemophiliacs known to have inhibitors, (4) not correlated with sporadic or familial disease and (5) not in disequilibrium with the Bcl I or Taq I intron 18 or ST14 polymorphisms. Finally, in families positive for an inversion mutation, direct testing offers a highly accurate and less expensive alternative to DNA linkage analysis.

  18. Hemophilia A gene therapy via intraosseous delivery of factor VIII-lentiviral vectors.

    Science.gov (United States)

    Miao, Carol H

    2016-01-01

    Current treatment of hemophilia A (HemA) patients with repeated infusions of factor VIII (FVIII; abbreviated as F8 in constructs) is costly, inconvenient, and incompletely effective. In addition, approximately 25 % of treated patients develop anti-factor VIII immune responses. Gene therapy that can achieve long-term phenotypic correction without the complication of anti-factor VIII antibody formation is highly desired. Lentiviral vector (LV)-mediated gene transfer into hematopoietic stem cells (HSCs) results in stable integration of FVIII gene into the host genome, leading to persistent therapeutic effect. However, ex vivo HSC gene therapy requires pre-conditioning which is highly undesirable for hemophilia patients. The recently developed novel methodology of direct intraosseous (IO) delivery of LVs can efficiently transduce bone marrow cells, generating high levels of transgene expression in HSCs. IO delivery of E-F8-LV utilizing a ubiquitous EF1α promoter generated initially therapeutic levels of FVIII, however, robust anti-FVIII antibody responses ensued neutralized functional FVIII activity in the circulation. In contrast, a single IO delivery of G-FVIII-LV utilizing a megakaryocytic-specific GP1bα promoter achieved platelet-specific FVIII expression, leading to persistent, partial correction of HemA in treated animals. Most interestingly, comparable therapeutic benefit with G-F8-LV was obtained in HemA mice with pre-existing anti-FVIII inhibitors. Platelets is an ideal IO delivery vehicle since FVIII stored in α-granules of platelets is protected from high-titer anti-FVIII antibodies; and that even relatively small numbers of activated platelets that locally excrete FVIII may be sufficient to promote efficient clot formation during bleeding. Additionally, combination of pharmacological agents improved transduction of LVs and persistence of transduced cells and transgene expression. Overall, a single IO infusion of G-F8-LV can generate long-term stable

  19. 2011 Computation Directorate Annual Report

    Energy Technology Data Exchange (ETDEWEB)

    Crawford, D L

    2012-04-11

    From its founding in 1952 until today, Lawrence Livermore National Laboratory (LLNL) has made significant strategic investments to develop high performance computing (HPC) and its application to national security and basic science. Now, 60 years later, the Computation Directorate and its myriad resources and capabilities have become a key enabler for LLNL programs and an integral part of the effort to support our nation's nuclear deterrent and, more broadly, national security. In addition, the technological innovation HPC makes possible is seen as vital to the nation's economic vitality. LLNL, along with other national laboratories, is working to make supercomputing capabilities and expertise available to industry to boost the nation's global competitiveness. LLNL is on the brink of an exciting milestone with the 2012 deployment of Sequoia, the National Nuclear Security Administration's (NNSA's) 20-petaFLOP/s resource that will apply uncertainty quantification to weapons science. Sequoia will bring LLNL's total computing power to more than 23 petaFLOP/s-all brought to bear on basic science and national security needs. The computing systems at LLNL provide game-changing capabilities. Sequoia and other next-generation platforms will enable predictive simulation in the coming decade and leverage industry trends, such as massively parallel and multicore processors, to run petascale applications. Efficient petascale computing necessitates refining accuracy in materials property data, improving models for known physical processes, identifying and then modeling for missing physics, quantifying uncertainty, and enhancing the performance of complex models and algorithms in macroscale simulation codes. Nearly 15 years ago, NNSA's Accelerated Strategic Computing Initiative (ASCI), now called the Advanced Simulation and Computing (ASC) Program, was the critical element needed to shift from test-based confidence to science-based confidence

  20. Magnetic resonance imaging of myocardial infarction during prothrombin complex concentrate therapy of hemophilia A

    Energy Technology Data Exchange (ETDEWEB)

    Gruen, D.R. [Dept. of Radiology, The New York Hospital-Cornell Medical Center, New York, NY (United States); Winchester, P.H. [Dept. of Radiology, The New York Hospital-Cornell Medical Center, New York, NY (United States); Brill, P.W. [Dept. of Radiology, The New York Hospital-Cornell Medical Center, New York, NY (United States); Ramirez, E. [Dept. of Radiology, The New York Hospital-Cornell Medical Center, New York, NY (United States)

    1997-03-01

    In patients with hemophilia, prothrombin complex concentrates (PCCs) have been successfully used to bypass inhibitors to fctor VIII during bleeding episodes. The use of PCCS, including FEIBA (factor eight inhibitor bypassing activity), has been associated with thromboembolic complications. Myocardial infarction (MI) is a rare but serious complication, reported in 13 previous cases, six in the pediatric age group. In all four patients who died during the acute MI, autopsy revealed extensive myocardial hemorrhage. The hearts of three other patients examined at least 5 months after the acute MI showed no evidence of prior hemorrhage. Magnetic resonance (MR) imaging has been shown to be able to evaluate the sequelae of myocardial infarction in adults with coronary artery disease and in children with Kawasaki syndrome. We report the first case of the used of MR imaging in the evaluation of myocardial damage during the acute stage of a FEIBA-associated MI in a 10-year-old boy. (orig.)

  1. Autoimmune bullous disease and Hashimoto's disease complicated by acquired hemophilia A.

    Science.gov (United States)

    Nishiura, Nobuko; Ujimoto, Daisuke; Fujita, Jiro; Maeda, Tetsuo; Nakagawa, Yukinobu; Kashiwagi, Hirokazu; Oritani, Kenji; Tomiyama, Yoshiaki; Kanakura, Yuzuru

    2017-01-01

    A 67-year-old man was admitted with a 1-month history of spontaneous hematoma in his right back and severe anemia. He had suffered from rashes with blisters involving both legs for 10 years, which had shown worsening and extended to his entire body concurrently with the hematoma. APTT was markedly prolonged to 119 seconds, and Factor VIII:C and FVIII inhibitor levels were less than 1% and 153.1 BU/ml, respectively, confirming the diagnosis of acquired hemophilia A (AHA). Skin biopsy revealed his rashes to be caused by autoimmune bullous disease (ABD), and laboratory and physical findings showed that he also had autoimmune hypothyroidism (Hashimoto's disease). Recombinant FVIIa was effective for management of his bleeding; in addition, FVIII inhibitor reduction and FVIII:C recovery, in parallel with improvement of the skin lesions, were achieved by administering prednisolone and cyclophosphamide. To our knowledge, this is the first report of AHA associated with ABD and Hashimoto's disease.

  2. [Primary myelofibrosis complicated by acquired hemophilia A and subsequent development of acute myeloid leukemia].

    Science.gov (United States)

    Kuroda, Hiroyuki; Ishikawa, Kazuma; Jomen, Wataru; Yoshida, Masahiro; Yamada, Michiko; Abe, Tomoyuki; Sakurai, Tamaki; Fujii, Shigeyuki; Maeda, Masahiro; Matsuno, Teppei; Sato, Masanori; Fujita, Miri; Nagashima, Kazuo; Ieko, Masahiro; Kato, Junji

    2013-12-01

    A 77-year-old man diagnosed with primary myelofibrosis (PMF), successfully controlled by thalidomide and prednisolone, was referred to us for massive subcutaneous bleeding involving the face, body, and all four limbs. Hemostatic studies showed prolonged activated partial thromboplastin time, decreased factor VIII coagulation, and a high factor VIII inhibitor titer, resulting in a diagnosis of acquired hemophilia A (AHA) for which he was treated with prednisolone and cyclophosphamide on admission. He developed right femoral intramuscular hemorrhage soon after immunosuppressive therapy and was treated with rituximab combined with activated prothrombin complex concentrates. Furthermore, he suffered complications of respiratory failure with increasing throat hemorrhaging. Recombinant activated factor VII (rFVIIa) was administered combined with methylprednisolone pulse therapy. Bleeding, including respiratory failure, was ameliorated with rFVIIa. Immunosuppressive rituximab therapy resolved AHA with marked efficacy. He died of Pneumocystis jiroveci pneumonitis. Autopsy showed transformation from PMF to acute myeloid leukemia.

  3. Multifocal subdural hematomas as the presenting sign of acquired hemophilia A: a case report.

    Science.gov (United States)

    Burish, Mark J; Aysenne, Aimee; Singh, Vineeta

    2014-03-08

    Acquired hemophilia A (AHA) is a rare coagulopathy linked to a variety of etiologies including autoimmune diseases, neoplasms, diabetes, respiratory diseases, and the post-partum state. While bleeding in AHA is often seen in mucocutaneous or intramuscular locations, intracranial and intraspinal bleeds are exceedingly rare. We report an unusual case of spontaneous multifocal subdural hematomas in a 25 year old Asian woman with lupus who presented with headache and backache, and was found to have an elevated partial thromboplastin time (PTT) level and new diagnosis of AHA. Subdural hematomas as the initial sign of AHA are all but unknown in the medical literature. We bring this entity to the attention of the neurology community because lumbar puncture and/or conventional angiogram are often indicated in the work-up of idiopathic multifocal subdural hematomas, but may be dangerous in patients with AHA.

  4. Coexistence of pemphigus foliaceus and acquired hemophilia A: A case report.

    Science.gov (United States)

    Filipczak, Aleksandra; Michalska-Jakubus, Małgorzata; Górska-Kosicka, Magdalena; Woźniak, Katarzyna; Kowalewski, Cezary; Krupski, Witold; Pietrzak, Aldona; Wallner, Grzegorz; Mosiewicz, Jerzy; Lotti, Torello; Krasowska, Dorota

    2015-06-01

    Pemphigus foliaceus (PF) is an autoimmune bullous dermatosis with anti-desmoglein-1 autoantibodies. Acquired hemophilia A (AHA) is a rare coagulation disorder with a high mortality rate, caused by anti-factor VIII immunoglobulin G antibodies leading to spontaneous severe hemorrhages into skin, muscles or soft tissues. This coagulopathy may be associated with malignancies, drug reactions and autoimmune disorders including bullous dermatoses. Herein, we demonstrate a first report of AHA in the course of pemphigus foliaceus. A 55-year-old woman presenting with extensive, erosive, crusted, scaly skin lesions was diagnosed with PF based on histopathological and immunofluorescent examination, confirmed by the presence of anti-desmoglein-1 antibodies on enzyme-linked immunoassay. She developed extensive internal hemorrhages and prolonged external bleeding after laparotomy. Based on coagulation tests, AHA was diagnosed. Simultaneous remission of pemphigus and coagulopathy occurred with immunosuppressants and recombinant activated factor VII. © 2015 Japanese Dermatological Association.

  5. School directors and management in education

    Directory of Open Access Journals (Sweden)

    Srdić Vesna M.

    2015-01-01

    Full Text Available The main features of school management and organization comprise planning, decision making, management, leadership and communication. Research suggests that successful school management requires not only advanced managerial but also leadership skills, with highly developed social skills as the main competence. In a complex social system, good leadership becomes a fundamental component of a successful organization or institution. Although leadership has for a long time been of interest for theoreticians and practitioners alike, there are still numerous questions waiting to be answered in the area of management and leadership in education. According to the Law on the Basis of Educational System, the person who can be named a school director must posses appropriate education, competences, license and experience in education. Legal requirements allow the provision of effective training, but the fact that personal disposition can be both an advantage and an obstacle for acquiring necessary items of knowledge and skills, points to the necessity of including selection into the standard procedure for the election of a director. Democratization and decentralization of the educational system presupposes a series of structural, systemic and functional changes which reflect on school management and the role played by the director. This paper considers responsibilities and competences of directors, both in legislation and in school practice and addresses the question whether a school director is a manager or a leader, and what are the possibilities for the provision of professional resources for school management.

  6. Analysis of inversions in the factor VIII gene in Spanish hemophilia A patients and families

    Energy Technology Data Exchange (ETDEWEB)

    Domenech, M.; Tizzano, E.; Baiget, M. [Hospital de Sant Pau, Barcelona (Spain); Altisent, C. [Hospital Vall d`Hebron, Barcelona (Spain)

    1994-09-01

    Intron 22 is the largest intron of the factor VIII gene and contains a CpG island from which two additional transcripts originate. One of these transcripts corresponds to the F8A gene which have telomeric extragenic copies in the X chromosome. An inversion involving homologous recombination between the intragenic and the distal or proximal copies of the F8A gene has been recently described as a common cause of severe hemophilia A (HA). We analyzed intron 22 rearrangements in 195 HA patients (123 familial and 72 sporadic cases). According to factor VIII levels, our sample was classified as severe in 114 cases, moderate in 29 cases and mild in 52 cases. An intron 22 (F8A) probe was hybridized to Southern blots of BcII digested DNA obtained from peripheral blood. A clear pattern of altered bands identifies distal or proximal inversions. We detected an abnormal pattern identifying an inversion in 49 (25%) of the analyzed cases. 43% of severe HA patients (49 cases) showed an inversion. As expected, no inversion was found in the moderate and mild group of patients. We found a high proportion (78%) of the distal rearrangement. From 49 identified inversions, 33 were found in familial cases (27%), while the remaining 15 were detected in sporadic patients (22%) in support that this mutational event occurs with a similar frequency in familial or sporadic cases. In addition, we detected a significant tendency of distal inversion to occur more frequently in familial cases than in sporadic cases. Inhibitor development to factor VIII was documented in approximately 1/3 of the patients with inversion. The identification of such a frequent molecular event in severe hemophilia A patients has been applied in our families to carrier and prenatal diagnosis, to determine the origin of the mutation in the sporadic cases and to detect the presence of germinal mosaicism.

  7. Spectrum of mutations in CRM-positive and CRM-reduced hemophilia A

    Energy Technology Data Exchange (ETDEWEB)

    McGinniss, M.J.; Kazazian, H.H. Jr.; Bi, L.; Antonarakis, S.E. (John Hopkins Univ., Baltimore, MD (United States)); Hoyer, L.W. (American Red Cross Blood Services, Rockville, MD (United States)); Inaba, H. (Tokyo Medical College (Japan))

    1993-02-01

    Hemophilia A is due to the functional deficiency of factor VIII (FVIII, gene locus F8C). Although half the patients have no detectable FVIII protein in their plasma, the more rare patients ([approximately]5%) have normal levels of a dysfunctional FVIII and are termed cross-reacting material (CRM)-positive. More commonly ([approximately]45%), patients have plasma FVIII protein reduced to an extent roughly comparable to the level of FVIII activity and are designated CRM-reduced. We used denaturing gradient gel electrophoresis to screen for mutations within the F8C gene of 11 patients (6CRM-positive, 5 CRM-reduced) and identified 9 different mutations in 9 patients after analyses of all 26 exons, the promoter region, and the polyadenylation site. Six mutations have not been described previously. Five weree missense (Ser289Leu, Ser558Phe, Val634Ala, Val634Met, Asn1441Lys), and the sixth was a 3-bp deletion ([Delta]Phe652). A review of the literature and the assay of FVIII antigen in 5 hemophilia A patients with previously identified missense mutations from this laboratory yielded a total of 20 other unique CRM-reduced and CRM-positive mutations. Almost all CRM-positive/reduced mutations (24/26) were missense, and many (12/26) occurred at CpG dinucleotides. We examined 19 missense mutation for evolutionary conservation using the portions of the porcine and murine F8C sequences that are known, and 18/19 amino acid residue altered by mutation in these patients wer conserved. Almost 50% of mutations (11/26) clustered in the A2 domain, suggesting that this region is critical for the function of FVIII. The results indicate a nonrandom distribution of mutations and suggest that mutations in a limited number of FVIII regions may cause CRM-positive and CRM-reduced heomphilia A. 48 refs., 1 fig., 1 tab.

  8. MicroRNA-15b Modulates Molecular Mediators of Blood Induced Arthropathy in Hemophilia Mice

    Directory of Open Access Journals (Sweden)

    Dwaipayan Sen

    2016-04-01

    Full Text Available The development of arthropathy is a major co-morbidity in patients with hemophilia. The present study was designed to study the role of a microRNA biomarker (miR-15b in the development of joint disease. To investigate the expression profile of miR-15b during the development of arthropathy, we first isolated and studied small RNA from the acute and chronic hemarthrosis model of hemophilia A mice. We observed that miR-15b was consistently repressed (~1- to 4-fold from the onset of joint bleeding (1, 3, 7 and 24 h until six bleeding episodes (up to 90 days. To test if reconstitution of miR-15b modulates biomarkers of joint damage in a chronic hemarthrosis model, we administered an adeno-associated virus (AAV 5-miR-15b vector intra-articularly alone or in combination with systemic administration of AAV2-factor VIII. miR-15b overexpression downregulated markers of angiogenesis and hypoxia (vascular epithelial growth factor α (VEGF-α and hypoxia inducing factor 2α (HIF-2α, ~70% and ~34%, respectively in the affected joints. In addition, the co-administration of miR-15b and factor VIII vectors reduced the levels of the chondrodegenerative matrix-metalloproteinases (MMPs 1, 3, 9 and 14 (~14% to 60% in the injured joints. These data demonstrate for the first time the role of a miR-15b in the development of hemophilic arthropathy and has implications in development of miR based therapies for joint disease.

  9. Prevention and Reversal of Antibody Responses Against Factor IX in Gene Therapy for Hemophilia B

    Directory of Open Access Journals (Sweden)

    Sushrusha eNayak

    2011-12-01

    Full Text Available Intramuscular (IM administration of an adeno-associated viral (AAV vector represents a simple and safe method of gene transfer for treatment of the X-linked bleeding disorder hemophilia B (factor IX, F.IX, deficiency. However, the approach is hampered by an increased risk of immune responses against F.IX. Previously, we demonstrated that the drug cocktail of immune suppressants rapamycin, IL-10, and a specific peptide (encoding a dominant CD4+ T cell epitope caused an induction of regulatory T cells (Treg with a concomitant apoptosis of antigen-specific effector T cells (J. Thromb. Haemost. 7:1523, 2009. This protocol was effective in preventing inhibitory antibody formation against human F.IX (hF.IX in muscle gene transfer to C3H/HeJ hemophilia B mice (with targeted F9 gene deletion. Here, we show that this protocol can also be used to reverse inhibitor formation. IM injection of AAV1-hF.IX vector resulted in inhibitors of on average 8-10 BU within 1 month. Subsequent treatment with the tolerogenic cocktail accomplished a rapid reduction of hF.IX-specific antibodies to <2 BU, which lasted for >4.5 months. Systemic hF.IX expression increased from undetectable to >200 ng/ml, and coagulation times improved. In addition, we developed an alternative prophylactic protocol against inhibitor formation that did not require knowledge of T cell epitopes, consisting of daily oral administration of rapamycin for 1-month combined with frequent, low-dose intravenous injection of hF.IX protein. Experiments in T cell receptor transgenic mice showed that the route and dosing schedule of drug administration substantially affected Treg induction. When combined with intravenous antigen administration, oral delivery of rapamycin had to be performed daily in order to induce Treg, which were suppressive and phenotypically comparable to natural Treg.

  10. Muscle-directed gene therapy for hemophilia B with more efficient and less immunogenic AAV vectors.

    Science.gov (United States)

    Wang, L; Louboutin, J-P; Bell, P; Greig, J A; Li, Y; Wu, D; Wilson, J M

    2011-10-01

    Adeno-associated viral vector (AAV)-mediated and muscle-directed gene therapy is a safe and non-invasive approach to treatment of hemophilia B and other genetic diseases. However, low efficiency of transduction, inhibitor formation and high prevalence of pre-existing immunity to the AAV capsid in humans remain as main challenges for AAV2-based vectors using this strategy. Vectors packaged with AAV7, 8 and 9 serotypes have improved gene transfer efficiencies and may provide potential alternatives to overcome these problems. To compare the long-term expression of canine factor IX (cFIX) levels and anti-cFIX antibody responses following intramuscular injection of vectors packaged with AAV1, 2, 5, 7, 8 and 9 capsid in immunocompetent hemophilia B mice. Highest expression was detected in mice injected with AAV2/8 vector (28% of normal), followed by AAV2/9 (15%) and AAV2/7 (10%). cFIX expression by AAV2/1 only ranged from 0 to 5% of normal levels. High incidences of anti-cFIX inhibitor (IgG) were detected in mice injected with AAV2 and 2/5 vectors, followed by AAV2/1. None of the mice treated with AAV2/7, 2/8 and 2/9 developed inhibitors or capsid T cells. AAV7, 8 and 9 are more efficient and safer vectors for muscle-directed gene therapy with high levels of transgene expression and absence of inhibitor formation. The absence of antibody response to transgene by AAV7, 8 and 9 is independent of vector dose but may be due to the fact that these three serotypes are associated with high level distribution to, and transduction of, hepatocytes following i.m. injection. © 2011 International Society on Thrombosis and Haemostasis.

  11. TREATMENT OF BLEEDING AND FACTOR VIII INHIBITORS IN ACQUIRED HEMOPHILIA A PATIENTS

    Directory of Open Access Journals (Sweden)

    Peter Černelč

    2004-12-01

    Full Text Available Background. Bleeding in acquired hemophilia A patients with FVIII autoantibodies is often severe. The authors describe a successfuly acquired hemophilia A treatment with Feiba, glucocorticoids and cyclophosphamide in three patients.Results. In a 66-year patient with chest hematoma and m. iliopsoas hematoma, APTT 50.1 s, FVIII 0.05 IU/mL and inhibitors FVIII (anti-FVIII 22 BU/ml were found. After treatment of hemorrhages with Feiba, dexamethasone and cyclophosphamide, FVIII increased to 0.54 IU/mL and no inhibitors were found on day seventeen. In a 46-year patient with advanced AIDS, multiple hematomas and liver cirrhosis after HCV infection, the platelet count was 92 × 109/L, APTT 48.2 s, FVIII 0.05 IU/mL and anti-FVIII 1.7 BU/mL. The hemorrhages were treated with FEIBA and methylprednisolone therapy was started after 14 months. After 42 days FVIII increased to 0.56 IU/mL and no inhibitors were found. In a 69-year patient suffering from thyroiditis and idiopathic thrombocytopenic purpura, extensive gluteal and chest hematomas were detected during the maintenance therapy with methylprednisolone 16 mg/day. The thrombocyte count was normal but APTT 48.8 s, FVIII 0.01 IU/mL and anti-FVIII 7.0 BU/mL was found. FVIII activity were 1.72 IU/mL and no inhibitors was noted after 330-days of treatment with cyclophosphamide.Conclusions. The treatment with FEIBA was effective in stopping the hemorrhages. The glucocorticoids were efficient in prompt decreasing of the inhibitor titer whereas the effect of cyclophosphamide was retarded.

  12. Modeling of hemophilia A using patient-specific induced pluripotent stem cells derived from urine cells.

    Science.gov (United States)

    Jia, Bei; Chen, Shen; Zhao, Zhiju; Liu, Pengfei; Cai, Jinglei; Qin, Dajiang; Du, Juan; Wu, Changwei; Chen, Qianyu; Cai, Xiujuan; Zhang, Hui; Yu, Yanhong; Pei, Duanqing; Zhong, Mei; Pan, Guangjin

    2014-07-11

    Hemophilia A (HA) is a severe, congenital bleeding disorder caused by the deficiency of clotting factor VIII (FVIII). For years, traditional laboratory animals have been used to study HA and its therapies, although animal models may not entirely mirror the human pathophysiology. Human induced pluripotent stem cells (iPSCs) can undergo unlimited self-renewal and differentiate into all cell types. This study aims to generate hemophilia A (HA) patient-specific iPSCs that differentiate into disease-affected hepatocyte cells. These hepatocytes are potentially useful for in vitro disease modeling and provide an applicable cell source for autologous cell therapy after genetic correction. In this study, we mainly generated iPSCs from urine collected from HA patients with integration-free episomal vectors PEP4-EO2S-ET2K containing human genes OCT4, SOX2, SV40LT and KLF4, and differentiated these iPSCs into hepatocyte-like cells. We further identified the genetic phenotype of the FVIII genes and the FVIII activity in the patient-specific iPSC derived hepatic cells. HA patient-specific iPSCs (HA-iPSCs) exhibited typical pluripotent properties evident by immunostaining, in vitro assays and in vivo assays. Importantly, we showed that HA-iPSCs could differentiate into functional hepatocyte-like cells and the HA-iPSC-derived hepatocytes failed to produce FVIII, but otherwise functioned normally, recapitulating the phenotype of HA disease in vitro. HA-iPSCs, particular those generated from the urine using a non-viral approach, provide an efficient way for modeling HA in vitro. Furthermore, HA-iPSCs and their derivatives serve as an invaluable cell source that can be used for gene and cell therapy in regenerative medicine. Copyright © 2014 Elsevier Inc. All rights reserved.

  13. Enhanced factor VIII heavy chain for gene therapy of hemophilia A.

    Science.gov (United States)

    Chen, Lingxia; Lu, Hui; Wang, Jinhui; Sarkar, Rita; Yang, Xiao; Wang, Hongli; High, Katherine A; Xiao, Weidong

    2009-03-01

    Hemophilia A gene therapy using recombinant adenovirus-associated virus (AAV) vectors has been hampered by the size of the factor VIII (FVIII) cDNA. Previously, splitting the FVIII coding sequence into a heavy-chain (HC) fragment and a light-chain (LC) fragment for dual recombinant AAV vector delivery has been successfully explored. However, the main disadvantage of this approach is a "chain imbalance" problem in which LC secretion is approximately 1-2 logs higher than that of HC, and therefore, the majority of protein synthesized is nonfunctional. To improve HC secretion, we constructed alternate FVIII HCs based on our observation that LC facilitates HC secretion. To our surprise, most of the new HC molecules exhibited enhanced expression over the traditional HC molecule (HC(745)). The optimized HC mutein, HC(HL), including additional acidic-region-3 (ar3) sequences, exhibited three- to fivefold higher activity in both enzyme-linked immunosorbent assay (ELISA) and activated partial thromboplastin time (aPTT) assay in in vitro testing. Further characterization suggested ar3 sequences increased HC secretion, rather than promoting HC synthesis. Intravenous delivery of AAV8-HC(HL)+AAV8-LC or AAV8-HC(745)+AAV8-LC achieved phenotypic correction in hemophilia A mice. Mice receiving AAV8-HC(HL)+AAV8-LC achieved three- to fourfold higher HC expression than AAV8-HC(745)+AAV8-LC, consistent with the FVIII functional assays. HC(HL) should be substituted for HC(745) in a dual AAV vector strategy due to its enhanced expression.

  14. 16 CFR 1000.26 - Directorate for Epidemiology.

    Science.gov (United States)

    2010-01-01

    ... 16 Commercial Practices 2 2010-01-01 2010-01-01 false Directorate for Epidemiology. 1000.26... AND FUNCTIONS § 1000.26 Directorate for Epidemiology. The Directorate for Epidemiology, managed by the Associate Executive Director for Epidemiology, is responsible for the collection and analysis of data on...

  15. Prediction of Intraoperative Blood Loss during Total Knee Arthroplasty in HCV+ and HCV- Patients with Hemophilia A.

    Science.gov (United States)

    Shurkhina, E S; Polyanskaya, T Yu; Zorenko, V Yu; Nesterenko, V M

    2017-03-01

    We examined HCV+ and HCV- hemophilia A patients with knee arthropathy and hematocrit above 38.5%. The mean density of erythrocytes was studied by the phthalate method, intraoperative blood loss was assessed gravimetrically. The volume of blood loss in HCV+ patients with manifest adhesive process and chronic synovitis varied from 300 to 1900 ml, in patients with moderate adhesive process from 400 to 1500 ml. The volume of blood loss in HCV- patients was 300-800 ml. A positive correlation between the blood loss volume and mean density of erythrocytes was detected. Blood loss >1000 ml during total knee arthroplasty can be expected in patients with hemophilia A with HCV and high mean density of erythrocytes. Blood loss >1000 ml is unlikely in HCV- and HCV+ patients with the mean density of erythrocytes not surpassing the normal values.

  16. Unusual Initial Manifestation of Acquired Hemophilia A: A Normal Activated Partial Thromboplastin Time, Intramuscular Hematoma and Cerebral Hemorrhage.

    Science.gov (United States)

    Tsuyama, Nobuaki; Ichiba, Toshihisa; Naito, Hiroshi

    We herein present a case of acquired hemophilia A with a normal activated partial thromboplastin (aPTT), intramuscular hematoma and cerebral hemorrhage occurring in a 73-year-old man. The patient visited our emergency department with gait disturbance, pain and swelling in his right leg. Computed tomography (CT) and magnetic resonance imaging (MRI) revealed intramuscular hematoma and intracranial hemorrhage. The results of initial coagulation studies were normal, but repeated coagulation studies revealed an isolated prolongation of the aPTT. Additional laboratory tests confirmed the diagnosis of acquired hemophilia A. If the initial aPTT is normal, we should therefore repeat the aPTT and also perform other coagulation studies including a mixing study, factor VIII level and inhibitor, to investigate the underlying diseases in elderly patients with spontaneous hemorrhaging of unknown etiology.

  17. Treatment of bleeding in acquired hemophilia A with the proper administration of recombinant activated factor VII: single-center study of 7 cases

    Directory of Open Access Journals (Sweden)

    Saito M

    2016-11-01

    Full Text Available Makoto Saito,1 Minoru Kanaya,1 Koh Izumiyama,1 Akio Mori,1 Tatsuro Irie,1 Masanori Tanaka,1 Masanobu Morioka,1 Masahiro Ieko2 1Department of Internal Medicine and Hematology, Aiiku Hospital, Japan; 2Department of Internal Medicine, Health Sciences University of Hokkaido, Japan Abstract: Recombinant activated factor VII (rFVIIa is the bypassing agent used in the first-line hemostatic therapy for acquired hemophilia A (AHA; however, the occurrence of thrombotic complications in rFVIIa-treated AHA patients was recently reported to be 2.9–6.5%. Therefore, the investigation of the proper administration of rFVIIa for AHA is needed. In the present study, we retrospectively investigated the clinical features of AHA with regards to the use of rFVIIa (presence or absence of use and total amount in 7 AHA patients encountered in our department for 7 years between January 2008 and December 2014. Ages were 63–89 years old (median: 79 years old, and there were 5 male and 2 female patients. The coexistence of cardiovascular risk factors and arteriosclerotic diseases, such as hypertension, diabetes mellitus, and cerebral infarction were present in 6 patients. Anemia progressed to less than 7 g/dL of hemoglobin and required red blood cell transfusion in 5 patients, showing “severe” hemorrhage. Factor VIII inhibitors were removed by immunological treatments in 6 patients. As a hemostatic therapy, rFVIIa was used in 4 patients. rFVIIa was not administered or was administered at a very low dose (20 mg to 3 and 1 patient, respectively, and bleeding stopped as inhibitor titers decreased and disappeared in these patients. Inhibitors did not disappear in 1 patient and the control of hemostasis became poor and was accompanied by intestinal hemorrhage. Although a large amount of rFVIIa (265 mg in total was administered, the patient bled to death. Therefore, bleeding may be stopped without the administration of rFVIIa in some AHA cases, while the dose of rFVIIa is

  18. Characterization of the factor VIII defect in 147 patients with sporadic hemophilia A: Family studies indicate a mutation type-dependent sex ratio of mutation frequencies

    Energy Technology Data Exchange (ETDEWEB)

    Becker, J.; Schmidt, W.; Olek, K. [Univ. of Bonn (Germany)] [and others

    1996-04-01

    The clinical manifestation of hemophilia A is caused by a wide range of different mutations. In this study the factor VIII genes of 147 severe hemophilia A patients-all exclusively from sporadic families-were screened for mutations by use of the complete panel of modern DNA techniques. The pathogenous defect could be characterized in 126 patients (85.7%). Fifty-five patients (37.4%) showed a F8A-gene inversion, 47 (32.0%) a point mutation, 14 (9.5%) a small deletion, 8 (5.4%) a large deletion, and 2 (1.4%) a small insertion. Further, four (2.7%) mutations were localized but could not be sequenced yet. No mutation could be identified in 17 patients (11.6%). Sixteen (10.9%) of the P identified mutations occurred in the B domain. Four of these were located in an adenosine nucleotide stretch at codon 1192, indicating a mutation hotspot. Somatic mosaicisms were detected in 3 (3.9%) of 76 patients` mothers, comprising 3 of 16 de novo mutations in the patients` mothers. Investigation of family relatives allowed detection of a de novo mutation in 16 of 76 two-generation and 28 of 34 three-generation families. On the basis of these data, the male:female ratio of mutation frequencies (k) was estimated as k = 3.6. By use of the quotients of mutation origin in maternal grandfather to patient`s mother or to maternal grandmother, k was directly estimated as k = 15 and k = 7.5, respectively. Considering each mutation type separately, we revealed a mutation type-specific sex ratio of mutation frequencies. Point mutations showed a 5-to-10-fold-higher and inversions a >10-fold- higher mutation rate in male germ cells, whereas deletions showed a >5-fold-higher mutation rate in female germ cells. Consequently, and in accordance with the data of other diseases like Duchenne muscular dystrophy, our results indicate that at least for X-chromosomal disorders the male:female mutation rate of a disease is determined by its proportion of the different mutation types. 68 refs., 1 fig., 5 tabs.

  19. Adherence to treatment regimen and bleeding rates in a prospective cohort of youth and young adults on low-dose daily prophylaxis for severe hemophilia A.

    Science.gov (United States)

    Mizrahi, Terry; St-Louis, Jean; Young, Nancy L; Ménard, Francine; Zourikian, Nichan; Dubé, Evemie; Rivard, Georges E

    2016-01-01

    When availability and/or affordability of anti-hemophilic factor concentrates are limited, optimal prophylaxis regimens in severe hemophilia A (HA) remain to be determined. In selected situations, low-dose daily prophylaxis (LDDP) may be an effective and economical option. The goal of our study was to evaluate if subjects on a LDDP regimen could achieve adherence and good clinical outcome. Seventeen subjects (age between 15.2 and 28.4) on LDDP suffering from severe/moderate HA were followed prospectively for 2 to 3 years as part of a health-related quality of life (HRQoL) study. Bleeding and treatments data were collected using electronic diaries and validated every three months. The SF-36 questionnaire was administered at the beginning of the study and then every 6 months until the end of the study. The subjects (mean age 22.0, median 21.9, standard deviation 4.06), were all from a single centre and on LDDP for at least 12 months as part of their routine care before entering the study. Fifteen subjects were prescribed a daily dose of 500 IU factor VIII (FVIII) and 2 subjects received 1000 IU FVIII per day, resulting into a median dose of 7.1 IU/kg/day (ranging from 4 to 13 IU/kg/day) and of 2591 IU/kg/year. Median adherence (the percentage of the prescribed daily dose received) was 84 % (mean 80 %, range 57 % to 94 %) throughout the study. Seventy-six bleeds in the 6 index joints and 51 other types of bleeds were observed throughout the study. The median annualized bleeding rate in joints (ABRjoints) was 0.7 and the median annualized bleeding rate for all bleeds (ABRall) was 1.6. The Physical Component and Mental Component Summary scores of SF-36, and the Hemophilia Joint Health Score were not significantly different over the course of the study (respective medians of 49.8, 52.4 and 16.0 at entry; vs. 52.5, 51.5 and 16.0 upon exit). This prospective longitudinal study in youth and young adults shows that LDDP may be associated with low ABRs, adequate

  20. Severe Hemophilia A in a Male Old English Sheep Dog with a C→T Transition that Created a Premature Stop Codon in Factor VIII

    Science.gov (United States)

    Lozier, Jay N; Kloos, Mark T; Merricks, Elizabeth P; Lemoine, Nathaly; Whitford, Margaret H; Raymer, Robin A; Bellinger, Dwight A; Nichols, Timothy C

    2016-01-01

    Animals with hemophilia are models for gene therapy, factor replacement, and inhibitor development in humans. We have actively sought dogs with severe hemophilia A that have novel factor VIII mutations unlike the previously described factor VIII intron 22 inversion. A male Old English Sheepdog with recurrent soft-tissue hemorrhage and hemarthrosis was diagnosed with severe hemophilia A (factor VIII activity less than 1% of normal). We purified genomic DNA from this dog and ruled out the common intron 22 inversion; we then sequenced all 26 exons. Comparing the results with the normal canine factor VIII sequence revealed a C→T transition in exon 12 of the factor VIII gene that created a premature stop codon at amino acid 577 in the A2 domain of the protein. In addition, 2 previously described polymorphisms that do not cause hemophilia were present at amino acids 909 and 1184. The hemophilia mutation creates a new TaqI site that facilitates rapid genotyping of affected offspring by PCR and restriction endonuclease analyses. This mutation is analogous to the previously described human factor VIII mutation at Arg583, which likewise is a CpG dinucleotide transition causing a premature stop codon in exon 12. Thus far, despite extensive treatment with factor VIII, this dog has not developed neutralizing antibodies (‘inhibitors’) to the protein. This novel mutation in a dog gives rise to severe hemophilia A analogous to a mutation seen in humans. This model will be useful for studies of the treatment of hemophilia. PMID:27780008

  1. Phenotype correction of hemophilia A mice with adeno-associated virus vectors carrying the B domain-deleted canine factor VIII gene.

    Science.gov (United States)

    Ishiwata, Akira; Mimuro, Jun; Kashiwakura, Yuji; Niimura, Masanori; Takano, Katsuhiro; Ohmori, Tsukasa; Madoiwa, Seiji; Mizukami, Hiroaki; Okada, Takashi; Naka, Hiroyuki; Yoshioka, Akira; Ozawa, Keiya; Sakata, Yoichi

    2006-01-01

    Adeno-associated virus (AAV) vectors carrying the B domain-deleted canine FVIII (BDD cFVIII) gene utilizing the beta-actin minimum promoter (167b) pseudotyped with serotype 1 (AAV1-beta-actin-cFVIII) and serotype 8 (AAV8-beta-actin-cFVIII) were developed to express cFVIII in hemophilia A mice. FVIII clotting activities measured by the APTT method increased in hemophilia A mice with intramuscular injection of AAV1-beta-actin-cFVIII in a dose-dependent manner. Therapeutic FVIII levels (2.9+/-1.0%) in hemophilia A mice with the AAV1-beta-actin-cFVIII dose of 1 x 10(12) gc/body were achieved, suggesting partial correction of the phenotype with AAV1-beta-actin-cFVIII vectors. FVIII clotting activity levels in hemophilia A mice with intravenous injection of AAV8-beta-actin-cFVIII also were increased dose-dependently, achieving therapeutic FVIII levels (5-90%) in hemophilia A mice with the AAV8-beta-actin-cFVIII doses of 1-3 x 10(11) gc/body and supernormal FVIII levels (180-670%) in hemophilia A mice with the AAV8-beta-actin-cFVIII dose of 1 x 10(12) gc/body. Transduction of the liver with AAV8-beta-actin-cFVIII is superior to transduction of skeletal muscles with AAV1cFVIII regarding the FVIII production and antibody formation. These data suggested that both AAV1 and AAV8 vectors carrying the FVIII gene utilizing a minimum promoter have a potential for hemophilia A gene therapy.

  2. Budget Impact Analysis of Prolonged Half-Life Recombinant FVIII Therapy for Hemophilia in the United States.

    Science.gov (United States)

    McMullen, Suzanne; Buckley, Brieana; Hall, Eric; Kendter, Jon; Johnston, Karissa

    2017-01-01

    Hemophilia A is a factor VIII deficiency, associated with spontaneous, recurrent bleeding episodes. This may lead to comorbidities such as arthropathy and joint replacement, which contribute to morbidity and increased health care expenditure. Recombinant factor VIII Fc fusion protein (rFVIIIFc), a prolonged half-life factor therapy, requires fewer infusions, resulting in reduced treatment burden. Use a budget impact analysis to assess the potential economic impact of introducing rFVIIIFc to a formulary from the perspective of a private payer in the United States. The budget impact model was developed to estimate the potential economic impact of adding rFVIIIFc to a private payer formulary across a 2-year time period. The eligible patient population consisted of inhibitor-free adults with severe hemophilia A, receiving recombinant-based episodic or prophylaxis treatment regimens. Patients were assumed to switch from conventional recombinant factor treatment to rFVIIIFc. Only medication costs were included in the model. The introduction of rFVIIIFc is estimated to have a budget impact of 1.4% ($0.12 per member per month) across 2 years for a private payer population of 1,000,000 (estimated 19.7 individuals receiving treatment for hemophilia A). The introduction of rFVIIIFc is estimated to prevent 124 bleeds across 2 years at a cost of $1891 per bleed avoided. Hemophilia A is a rare disease with a low prevalence; therefore, the overall cost to society of introducing rFVIIIFc is small. Considerations for comprehensively assessing the budget impact of introducing rFVIIIFc should include episodic and prophylaxis regimens, bleed avoidance, and annual factor consumption required under alternative scenarios. Copyright © 2017 International Society for Pharmacoeconomics and Outcomes Research (ISPOR). Published by Elsevier Inc. All rights reserved.

  3. High-affinity, noninhibitory pathogenic C1 domain antibodies are present in patients with hemophilia A and inhibitors.

    Science.gov (United States)

    Batsuli, Glaivy; Deng, Wei; Healey, John F; Parker, Ernest T; Baldwin, W Hunter; Cox, Courtney; Nguyen, Brenda; Kahle, Joerg; Königs, Christoph; Li, Renhao; Lollar, Pete; Meeks, Shannon L

    2016-10-20

    Inhibitor formation in hemophilia A is the most feared treatment-related complication of factor VIII (fVIII) therapy. Most inhibitor patients with hemophilia A develop antibodies against the fVIII A2 and C2 domains. Recent evidence demonstrates that the C1 domain contributes to the inhibitor response. Inhibitory anti-C1 monoclonal antibodies (mAbs) have been identified that bind to putative phospholipid and von Willebrand factor (VWF) binding epitopes and block endocytosis of fVIII by antigen presenting cells. We now demonstrate by competitive enzyme-linked immunosorbent assay and hydrogen-deuterium exchange mass spectrometry that 7 of 9 anti-human C1 mAbs tested recognize an epitope distinct from the C1 phospholipid binding site. These mAbs, designated group A, display high binding affinities for fVIII, weakly inhibit fVIII procoagulant activity, poorly inhibit fVIII binding to phospholipid, and exhibit heterogeneity with respect to blocking fVIII binding to VWF. Another mAb, designated group B, inhibits fVIII procoagulant activity, fVIII binding to VWF and phospholipid, fVIIIa incorporation into the intrinsic Xase complex, thrombin generation in plasma, and fVIII uptake by dendritic cells. Group A and B epitopes are distinct from the epitope recognized by the canonical, human-derived inhibitory anti-C1 mAb, KM33, whose epitope overlaps both groups A and B. Antibodies recognizing group A and B epitopes are present in inhibitor plasmas from patients with hemophilia A. Additionally, group A and B mAbs increase fVIII clearance and are pathogenic in a hemophilia A mouse tail snip bleeding model. Group A anti-C1 mAbs represent the first identification of pathogenic, weakly inhibitory antibodies that increase fVIII clearance. © 2016 by The American Society of Hematology.

  4. The Fc gamma receptor IIa R131H polymorphism is associated with inhibitor development in severe hemophilia A.

    Science.gov (United States)

    Eckhardt, C L; Astermark, J; Nagelkerke, S Q; Geissler, J; Tanck, M W T; Peters, M; Fijnvandraat, K; Kuijpers, T W

    2014-08-01

    The development of factor (F) VIII neutralizing alloantibodies (inhibitors) is a major complication of treatment with FVIII concentrates in hemophilia A and the etiology is still poorly understood. The low-affinity Fc gamma receptors (FcγR), which are expressed on immune cells, provide an important link between cellular and humoral immunity by interacting with IgG subtypes. Genetic variations of the genes encoding FcγRs (FCGR genes) have been associated with susceptibility to infectious and autoimmune diseases. The aim of this study was to investigate the association between genetic variation of FCGR and inhibitor development in severe hemophilia A. In this case-control study samples of 85 severe hemophilia A patients (siblings from 44 families) were included. Single nucleotide polymorphisms and copy number variation of the FCGR2 and FCGR3 gene cluster were studied in an FCGR-specific multiplex ligation-dependent probe amplification assay. Frequencies were compared in a generalized estimating equation regression model. Thirty-six patients (42%) had a positive history of inhibitor development. The polymorphism 131R > H in the FCGR2A gene was associated with an increased risk of inhibitor development (odds ratio [OR] per H-allele, 1.8; 95% confidence interval [CI], 1.1-2.9). This association persisted in 29 patients with high titer inhibitors (OR per H-allele, 1.9; 95% CI, 1.2-3.2) and in 44 patients with the F8 intron 22 inversion (OR per H-allele, 2.6; 95% CI, 1.1-6.6). Hemophilia A patients with the HH genotype of the FCGR2A polymorphism 131R > H have a more than 3-fold increased risk of inhibitor development compared with patients with the RR genotype. © 2014 International Society on Thrombosis and Haemostasis.

  5. Treatment of chronic lymphocytic leukemia/small lymphocytic lymphoma presenting simultaneously with acquired hemophilia and warm autoimmune hemolytic anemia

    OpenAIRE

    Williams, Chelsea; Cable, Christian; Choi, Julia

    2017-01-01

    Since both acquired factor VIII inhibitor in non-hemophiliac patients and warm autoimmune hemolytic anemia are uncommon disorders with no case-controlled trials, managing these diseases can be challenging. We present a case of a 75-year-old man in whom both diseases were present simultaneously with life-threatening bleeding. This case is an example of the successful initial management and long-term treatment of acquired hemophilia A, warm autoimmune hemolytic anemia, and chronic lymphocytic l...

  6. A DUAL NETWORK MODEL OF INTERLOCKING DIRECTORATES

    Directory of Open Access Journals (Sweden)

    Humphry Hung

    2003-01-01

    Full Text Available The article proposes an integrative framework for the study of interlocking directorates by using an approach that encompasses the concepts of multiple networks and resource endowment. This serves to integrate the traditional views of interorganizational linkages and intra-class cohesion. Through appropriate strategic analysis of relevant resource endowment of internal environment and external networks of organizations and corporate elites, this article argues that the selection of directors, if used effectively, can be adopted as a strategic device to enhance the corporation's overall performance.

  7. Rolf-Dieter Heuer, next Director General

    CERN Multimedia

    CERN Council appointed Professor Rolf-Dieter Heuer to succeed Dr Robert Aymar as CERN’s Director General. Professor Heuer will serve a five-year term, taking office on 1 January 2009. Rolf-Dieter Heuer is currently Research Director for particle and astroparticle physics at Germany’s DESY laboratory in Hamburg. He was a staff member at CERN from 1984 to 1998, working for the OPAL collaboration at LEP, and from 1994 to 1998 he was the collaboration’s spokesman. See the Press Release.

  8. The value of usability testing for Internet-based adolescent self-management interventions: "Managing Hemophilia Online".

    Science.gov (United States)

    Breakey, Vicky R; Warias, Ashley V; Ignas, Danial M; White, Meghan; Blanchette, Victor S; Stinson, Jennifer N

    2013-10-04

    As adolescents with hemophilia approach adulthood, they are expected to assume responsibility for their disease management. A bilingual (English and French) Internet-based self-management program, "Teens Taking Charge: Managing Hemophilia Online," was developed to support adolescents with hemophilia in this transition. This study explored the usability of the website and resulted in refinement of the prototype. A purposive sample (n=18; age 13-18; mean age 15.5 years) was recruited from two tertiary care centers to assess the usability of the program in English and French. Qualitative observations using a "think aloud" usability testing method and semi-structured interviews were conducted in four iterative cycles, with changes to the prototype made as necessary following each cycle. This study was approved by research ethics boards at each site. Teens responded positively to the content and appearance of the website and felt that it was easy to navigate and understand. The multimedia components (videos, animations, quizzes) were felt to enrich the experience. Changes to the presentation of content and the website user-interface were made after the first, second and third cycles of testing in English. Cycle four did not result in any further changes. Overall, teens found the website to be easy to use. Usability testing identified end-user concerns that informed improvements to the program. Usability testing is a crucial step in the development of Internet-based self-management programs to ensure information is delivered in a manner that is accessible and understood by users.

  9. A novel cell-sheet technology that achieves durable factor VIII delivery in a mouse model of hemophilia A.

    Directory of Open Access Journals (Sweden)

    Kohei Tatsumi

    Full Text Available Gene- or cell-based therapies aimed at creating delivery systems for coagulation factor VIII (FVIII protein have emerged as promising options for hemophilia A treatment. However, several issues remain to be addressed regarding the efficacies and adverse events of these new classes of therapies. To improve an existing cell-based therapy involving the subcutaneous transplantation of FVIII-transduced blood outgrowth endothelial cells (BOECs, we employed a novel cell-sheet technology that allows individual dispersed cells to form a thin and contiguous monolayer without traditional bioabsorbable scaffold matrices. Compared to the traditional methodology, our cell-sheet approach resulted in longer-term and 3-5-fold higher expression of FVIII (up to 11% of normal in recipient hemophilia A mice that lacked a FVIII humoral immune response due to transient immunosuppression with cyclophosphamide. Histological studies revealed that the transplanted BOEC sheets were structured as flat clusters, supporting the long-term expression of therapeutic FVIII in plasma from an ectopic subcutaneous space. Our novel tissue-engineering approach using genetically modified BOEC sheets could aid in development of cell-based therapy that will allow safe and effective in vivo delivery of functional FVIII protein in patients with hemophilia A.

  10. A novel cell-sheet technology that achieves durable factor VIII delivery in a mouse model of hemophilia A.

    Science.gov (United States)

    Tatsumi, Kohei; Sugimoto, Mitsuhiko; Lillicrap, David; Shima, Midori; Ohashi, Kazuo; Okano, Teruo; Matsui, Hideto

    2013-01-01

    Gene- or cell-based therapies aimed at creating delivery systems for coagulation factor VIII (FVIII) protein have emerged as promising options for hemophilia A treatment. However, several issues remain to be addressed regarding the efficacies and adverse events of these new classes of therapies. To improve an existing cell-based therapy involving the subcutaneous transplantation of FVIII-transduced blood outgrowth endothelial cells (BOECs), we employed a novel cell-sheet technology that allows individual dispersed cells to form a thin and contiguous monolayer without traditional bioabsorbable scaffold matrices. Compared to the traditional methodology, our cell-sheet approach resulted in longer-term and 3-5-fold higher expression of FVIII (up to 11% of normal) in recipient hemophilia A mice that lacked a FVIII humoral immune response due to transient immunosuppression with cyclophosphamide. Histological studies revealed that the transplanted BOEC sheets were structured as flat clusters, supporting the long-term expression of therapeutic FVIII in plasma from an ectopic subcutaneous space. Our novel tissue-engineering approach using genetically modified BOEC sheets could aid in development of cell-based therapy that will allow safe and effective in vivo delivery of functional FVIII protein in patients with hemophilia A.

  11. Attitudes of Family Medicine Program Directors Toward Osteopathic Residents Under the Single Accreditation System.

    Science.gov (United States)

    Hempstead, Laura K; Shaffer, Todd D; Williams, Karen B; Arnold, Lt Col James

    2017-04-01

    Between 2015 and 2020, residency programs accredited through the American Osteopathic Association (AOA) are preparing the single graduate medical education (GME) system through the Accreditation Council for Graduate Medical Education (ACGME). (1) To assess the attitudes of family medicine program directors in programs accredited dually by the AOA and ACGME (AOA/ACGME) or ACGME only toward the clinical and academic preparedness of osteopathic residency candidates and (2) to determine program director attitudes toward the perceived value of osteopathic-focused education, including osteopathic manipulative treatment (OMT) curricula. A survey was sent to program directors of AOA/ACGME and ACGME-only accredited family medicine residency programs. Items concerned program directors' perception of the academic and clinical strength of osteopathic residents at the onset of residency, the presence of osteopathic faculty and residents currently in the program, and the presence of formal curricula for teaching OMT. The perceived value of osteopathic focus was obtained through a composite score of 5 items. A total of 38 AOA/ACGME family medicine residency program directors (17%) and 211 ACGME family medicine residency program directors (45.6%) completed the survey (N=249). No difference was found in the ranking of the perceived clinical preparation of osteopathic residents vs allopathic residents in programs with and without OMT curricula (P=.054). Directors of programs with OMT curricula perceived the academic preparation of their osteopathic residents vs allopathic residents more highly than those without OMT curricula (P=.039). Directors of AOA/ACGME programs perceived both the academic preparation and clinical preparation of their osteopathic residents more highly than those at ACGME-only programs (P=.004 and P=.002, respectively). Directors of AOA/ACGME programs, as well as those whose programs have an osteopathic focus in curricular offerings, were more likely to rank the

  12. Reduced production of IFN-γ and LT-α is associated with successful prednisone therapy in patients with acquired hemophilia A: a pilot study.

    Science.gov (United States)

    Kruse-Jarres, Rebecca; Fang, Jian; Leissinger, Cindy A; Ganapamo, Frédéric

    2011-11-01

    Glucocorticoids (GC) are a standard treatment for acquired hemophilia A (AH). Although the optimal treatment regimen and duration of GC's is unknown, measurement of sub-clinical immune responses may help direct therapeutic decision making. To study the helpfulness of this approach, three male patients diagnosed with AH were treated with prednisone. The therapy resulted in inhibitor elimination in two out of the three individuals. During the treatment, peripheral mononuclear cells were isolated at different time points and stimulated in vitro. The expression of IFN-γ and LT-α were monitored at both the protein and the mRNA levels. The amount of IFN-γ and LT-α were markedly reduced by the time of inhibitor disappearance in the patients responding to GC therapy but remained high in the non-responder until cyclophosphamide was added. This study suggests that the secretion level of IFN-γ and/or LT-α could be a predictive marker of prednisone responsiveness. Copyright © 2011 Elsevier Ltd. All rights reserved.

  13. Derivatives and the non-executive director

    NARCIS (Netherlands)

    van der Nat, M.; Buckley, A.A.

    2003-01-01

    Do non-executive directors have the wherewithal to overview a corporation's integrity, quality of performance and management in the area of derivatives policy? In a survey of the understanding and monitoring of derivatives in a small sample of quoted companies, we found disturbing levels of

  14. VMware vCloud Director essentials

    CERN Document Server

    Pal, Lipika

    2014-01-01

    If you are a technical professional with system administration knowledge, then this book is for you. The book also covers areas of importance if you are a virtualization engineer, consultant, architect, senior system engineer, or senior system analyst. You should possess core vSphere platform knowledge necessary to serve as a base to learn vCloud Director and its associated components.

  15. Director of Program Area | IDRC - International Development ...

    International Development Research Centre (IDRC) Digital Library (Canada)

    Job Summary The Director of a Program Area is accountable to the Vice President of the Program and Partnership Branch for providing strategic intelligence, intellectual leadership and the overall management of the Program Areas personnel (20-35 staff per Program Area).

  16. Leadership Attributes of Physician Assistant Program Directors

    Science.gov (United States)

    Eifel, Raymond Leo

    2014-01-01

    Physician assistant (PA) program directors perform an essential role in the initiation, continuation, and development of PA education programs in the rapidly changing environments of both health care and higher education. However, only limited research exists on this academic leader. This study examined the leadership roles of PA program directors…

  17. Dr Tedros Adhanom: New WHO Director General

    African Journals Online (AJOL)

    2017-08-03

    Aug 3, 2017 ... five other candidates to the post. His accomplishments both in Ethiopia and the global stage catapult him to this remarkable success. ... Dr Tedros is a change agent, and a reformist in the health sector. His election as the Director General of WHO brings along a lot of expectations for a better health agenda ...

  18. Director, Information Management and Technology Division (IMTD ...

    International Development Research Centre (IDRC) Digital Library (Canada)

    ... especially those related to the dissemination of research results. The Director manages a team of over 45 specialists and is an active member of the Resources Branch management team. He or she leads the Change Control Boards and advises senior managers on a broad range of matters related to the management of ...

  19. Authority and Responsibilities of a Network Director.

    Science.gov (United States)

    Reynolds, Maryan E.

    A network director is an individual who: is visionary yet practical; possesses understanding of the human animal; has good interpersonal relationships; is committed to the user not the institution; is knowledgeable in regard to the various types of participating institutions; recognizes the network must be built strength on strength; is a skillful…

  20. Measuring Burnout Among Psychiatry Clerkship Directors.

    Science.gov (United States)

    Rakofsky, Jeffrey J; Dallaghan, Gary Beck; Balon, Richard

    2017-09-22

    The primary purpose of this study was to determine the prevalence of burnout among Psychiatry clerkship directors. Psychiatry clerkship directors were solicited via email to complete an electronic version of the Maslach Burnout Inventory-General Survey and the Respondent Information Form. Fifty-four out of 110 surveys (49%) were completed. Fourteen percent of respondents scored in the "high exhaustion" category, 21.6% scored in the "low professional efficacy" category, 20.4% scored in the "high cynicism" category, and 15.1% of respondents met threshold for at least two of the three categories. Those who scored in the "low professional efficacy" category reported higher levels of salary support for research, while those who scored in the "high cynicism" category reported lower levels of salary support at a trend level. Those who scored in the "high cynicism" category were younger. Approximately 14-22 percent of psychiatry clerkship directors reported some level of burnout depending on the subscale used. Future studies should aim to better identify those clerkship directors who are at greatest risk for becoming burned out by their educational role and to clarify the link between salary support for research, age, and burnout.

  1. Leader in Digital Transformation: Director, Information Management ...

    International Development Research Centre (IDRC) Digital Library (Canada)

    ... Centre's information infrastructure — the mission-critical business platform for achieving the Centre's strategic and operational goals, especially those related to the dissemination of research results. The Director manages a team of over 40 specialists and is an active member of the Resources Branch management team.

  2. Board of directors and risk management

    NARCIS (Netherlands)

    van der Elst, C.F.; Birkmose, H.; Neville, M.; Sorensen, K.

    2013-01-01

    The board of directors is responsible for an appropriate business risk management environment. The paper studies in a comparative way how legislators and courts fill this duty. We question whether the legislative and regulatory framework will improve the equilibrium between entrepreneurship and risk

  3. Scenario-based Training: Director's Cut

    NARCIS (Netherlands)

    Peeters, M.M.M.; Van den Bosch, K.; Meyer, J-J.Ch.; Neerincx, M.A.

    2011-01-01

    Research regarding autonomous learning shows that freeplay does not result in optimal learning. Combining scenario-based training with intelligent agent technology off ers the possibility to create autonomous training enriched with automated adaptive support delivered by a director agent. We

  4. Director, Grant Administration | IDRC - International Development ...

    International Development Research Centre (IDRC) Digital Library (Canada)

    Job Summary Reporting to the Vice-President, Resources, and Chief Financial Officer (VPR & CFO), the Director, Grant Administration leads and manages the development and implementation of effective grant administration framework that ensures the stewardship of IDRC resources and provides a service that brings ...

  5. Hemophilia Facts

    Science.gov (United States)

    ... cause long term problems, such as seizures and paralysis Death can occur if the bleeding cannot be stopped or if it occurs in a vital organ such as the brain. "Do the 5" Key prevention messages from the ...

  6. Status and trend analysis of prophylactic usage of recombinant factor VIII in Chinese pediatric patients with hemophilia A: ReCare - a retrospective, phase IV, non-interventional study.

    Science.gov (United States)

    Li, Changgang; Zhang, Xinsheng; Zhao, Yongqiang; Wu, Runhui; Hu, Qun; Xu, Vicky; Sun, Jing; Yang, Renchi; Li, Xiaojing; Zhou, Rongfu; Lian, Shinmei; Gu, Jian; Wu, Junde; Hou, Qingsong

    2017-09-01

    No study has reported the status and chronological trend of prophylactic recombinant factor VIII (rFVIII) use in Chinese pediatric patients with hemophilia A (HA). We aimed to analyze the status and trend of rFVIII-containing prophylaxis in Chinese pediatric patients with HA. ReCARE (Retrospective study in Chinese pediatric hemophilia A patients with rFVIII contained REgular prophylaxis) was a retrospective study conducted in 12 hemophilia treatment centers across China. The trend of prophylaxis was evaluated by determining the mean duration of prophylaxis, mean injection frequency (per week), mean dose of each injection (IU/kg), mean total dose injected/week (IU) and proportion of rFVIII consumption relative to factor VIII (FVIII) consumption over the study period. We analyzed 183 male pediatric patients with HA (mean age, 7.1 ± 4.23 years), who received intermittent prophylaxis between 1 November 2007 and 31 May 2013. The mean duration of prophylaxis with rFVIII increased from 16.72 weeks in 2008 to 32.77 in 2012. Per injection dose of rFVIII increased significantly from 2008 to 2013 (25.89 to 28.31 IU/kg, p < .001). An increase was also reported in the mean total FVIII consumed (699.97 ± 173.25 IU in 2008 and 891.30 ± 730.341 in 2013) and mean proportion of rFVIII used (33.33 ± 57.73% in 2008 to 85.50 ± 29.077% in 2013). Our data revealed an overall improvement in treatment dosage and duration with an increase in the number of patients receiving prophylaxis. The total proportion of rFVIII also increased gradually indicating the development of economy and safety awareness. The trial is registered at ClinicalTrials.gov (CT.gov identifier: NCT02263066).

  7. Critical Care Pharmacist Market Perceptions: Comparison of Critical Care Program Directors and Directors of Pharmacy.

    Science.gov (United States)

    Hager, David R; Persaud, Rosemary A; Naseman, Ryan W; Choudhary, Kavish; Carter, Kristen E; Hansen, Amanda

    2017-05-01

    Background: While hospital beds continue to decline as patients previously treated as inpatients are stabilized in ambulatory settings, the number of critical care beds available in the United States continues to rise. Growth in pharmacy student graduation, postgraduate year 2 critical care (PGY2 CC) residency programs, and positions has also increased. There is a perception that the critical care trained pharmacist market is saturated, yet this has not been evaluated since the rise in pharmacy graduates and residency programs. Purpose: To describe the current perception of critical care residency program directors (CC RPDs) and directors of pharmacy (DOPs) on the critical care pharmacist job market and to evaluate critical care postresidency placement and anticipated changes in PGY2 CC programs. Methods: Two electronic surveys were distributed from October 2015 to November 2015 through Vizient/University HealthSystem Consortium, American Society of Health-System Pharmacists (ASHP), Society of Critical Care Medicine, and American College of Clinical Pharmacy listservs to target 2 groups of respondents: CC RPDs and DOPs. Questions were based on the ASHP Pharmacy Forecast and the Pharmacy Workforce Center's Aggregate Demand Index and were intended to identify perceptions of the critical care market of the 2 groups. Results: Of 116 CC RPDs, there were 66 respondents (56.9% response rate). Respondents have observed an increase in applicants; however, they do not anticipate increasing the number of positions in the next 5 years. The overall perception is that there is a balance in supply and demand in the critical care trained pharmacist market. A total of 82 DOPs responded to the survey. Turnover of critical care pharmacists within respondent organizations is expected to be low. Although a majority of DOPs plan to expand residency training positions, only 9% expect to increase positions in critical care PGY2 training. Overall, DOP respondents indicated a balance of

  8. Drug-drug interaction of the anti-TFPI aptamer BAX499 and factor VIII: studies of spatial dynamics of fibrin clot formation in hemophilia A.

    Science.gov (United States)

    Parunov, Leonid A; Soshitova, Natalia P; Fadeeva, Olga A; Balandina, Anna N; Kopylov, Konstantin G; Kumskova, Maria A; Gilbert, James C; Schaub, Robert G; McGinness, Kathleen E; Ataullakhanov, Fazoil I; Panteleev, Mikhail A

    2014-01-01

    In recent years, a number of tissue factor pathway inhibitor (TFPI) antagonists have been developed to serve as bypassing agents to improve hemostasis in hemophilia A. Since TFPI antagonists and FVIII concentrates are procoagulants, their combined effect on spatial clot formation could be potentially pro-thrombotic. To investigate the cooperative effect of TFPI inhibition and supplementation of FVIII in hemophilia A in a spatial, reaction-diffusion experiment in vitro. Plasma was collected at different time points from hemophilia A patients undergoing prophylaxis and was supplemented in vitro with TFPI inhibitor BAX499 (formerly ARC19499) at concentrations from 0 up to 600nM. Clotting propagation in recalcified plasma activated by a surface with immobilized tissue factor (TF) was monitored by videomicroscopy. Increasing concentration of BAX499 improved coagulation for all hemophilia A plasma samples activated with TF at 1.6pmole/m(2) by shortening lag time and increasing initial clot growth velocity and clot size. In contrast, plasma concentration of FVIII had little effect on lag time, but increased spatial clot growth velocity. There was a decrease in the BAX499 efficiency as FVIII concentration increased (lag time shortened by 50% if FVIII:C30%). The results indicate that BAX499 has an effect on clotting in hemophilia A plasma at low FVIII concentrations, however has little effect at high FVIII concentrations. © 2013.

  9. Training internal medicine residents in outpatient HIV care: a survey of program Directors.

    Science.gov (United States)

    Adams, Jennifer; Chacko, Karen; Guiton, Gretchen; Aagaard, Eva

    2010-09-01

    The care of patients with HIV is increasingly focused on outpatient chronic disease management. It is not known to what extent internal medicine residents in the US are currently being trained in or encouraged to provide primary care for this population of patients. To survey internal medicine residency program directors about their attitudes regarding training in outpatient HIV care and current program practices. Program directors were surveyed first by email. Non-responding programs were mailed up to two copies of the survey. All internal medicine residency program directors in the US. Program director attitudes and residency descriptions. Of the 372 program directors surveyed, 230 responded (61.8 %). Forty-two percent of program directors agreed that it is important to train residents to be primary care providers for patients with HIV. Teaching outpatient-based HIV curricula was a priority for 45.1%, and 56.5% reported that exposing residents to outpatient HIV clinical care was a high priority. Only 46.5% of programs offer a dedicated rotation in outpatient HIV care, and 50.5% of programs have curricula in place to teach about outpatient HIV care. Only 18.8% of program directors believed their graduates had the skills to be primary providers for patients with HIV, and 70.6% reported that residents interested in providing care for patients with HIV pursued ID fellowships. The strongest reasons cited for limited HIV training during residency were beliefs that patients with HIV prefer to be seen and receive better care in ID clinics compared to general medicine clinics. With a looming HIV workforce shortage, we believe that internal medicine programs should create educational experiences that will provide their residents with the skills and knowledge necessary to meet the healthcare needs of this population.

  10. A new recombinant factor VIII: from genetics to clinical use

    Directory of Open Access Journals (Sweden)

    Santagostino E

    2014-12-01

    Full Text Available Elena Santagostino Angelo Bianchi Bonomi Hemophilia and Thrombosis Center, Fondazione IRCCS Ca’ Granda, Ospedale Maggiore Policlinico, Milan, Italy Abstract: Advances in recombinant technology and knowledge about coagulation factor VIII (FVIII are building a platform for new therapeutic options in patients with hemophilia A. The development of turoctocog alfa, a novel, high-purity, third-generation, B-domain truncated recombinant FVIII, has been produced and formulated without the use of animal-derived or human serum-derived components, in the wake of understanding of the new biochemical characteristics of FVIII, namely its protein structure, and glycosylation and sulfating patterns. Culture conditions and a five-step purification process have been developed to optimize the safety of turoctocog alfa. The results of two pilot clinical trials using turoctocog alfa confirmed high safety levels, with no patient developing inhibitors during the period of observation. The purpose of this review is to describe briefly the molecular and biological properties of turoctocog alfa, together with details of its clinical development, with emphasis on the needs of patients with hemophilia A. Keywords: hemophilia A, recombinant factor VIII, turoctocog alfa, purification, inhibitor, safety

  11. Advanced general dentistry program directors' attitudes and behaviors regarding pediatric dental training for residents.

    Science.gov (United States)

    Massey, Christi Sporl; Raybould, Ted P; Skelton, Judith; Wrightson, A Stevens; Smith, Tim A

    2008-03-01

    The oral health of children became a more prominent concern with the U.S. surgeon general's report on oral health in America in 2000. The purpose of our study was 1) to assess General Practice Residency (GPR) and Advanced Education in General Dentistry (AEGD) (here jointly referred to as advanced general dentistry [AGD] programs) directors' current behaviors with regard to pediatric training of residents and 2) to assess their attitudes about which components of pediatric oral health training should be included in AGD programs. A twenty-one item survey was mailed to all GPR and AEGD programs accessed through the American Dental Association website. Seventy percent of directors (N=187) completed and returned the survey. Responses indicated that AGD residents receive adequate clinical exposure to pediatric patients and provide much-needed services to uninsured, underinsured, and underserved people. Although clinical training in pediatric treatment was high, didactic hours focused on pediatric treatment did not seem commensurate with clinical activity. Program directors indicated strong attitudinal support for teaching residents many components of pediatric oral health care, although most directors have concerns over increasing didactic hours spent on pediatric oral health due to already crowded curricula. Approximately 88 percent of directors said that they would implement a pediatric oral health module in their curricula if they had access to one.

  12. Acquired hemophilia A associated with internal border-zone infarction triggered by major hemorrhage of thigh and leg: a case report.

    Science.gov (United States)

    Miyazaki, Masayuki; Nagami, Shuuhei; Shimizu, Hisao; Takahashi, Nobuyuki

    2015-02-01

    It is unusual to be complicated with cerebral infarction for bleeding disorders. We describe a first case of internal border-zone infarction (I-BZI) complicated with acquired hemophilia A. A 79-year-old man was introduced from other hospital by cerebral infarction and severe anemia. His left thigh and leg were swollen with subcutaneous bleeding. Activated partial thromboplastin time was 99.4 seconds. Factor VIII activity was less than 1% and Factor VIII inhibitor concentration was 85 BU, respectively. The platelet count and prothrombin time were normal. These results were consistent with the diagnosis of acquired hemophilia A. Magnetic resonance imaging of the brain showed multiple small infarction in bilateral internal border zone. To our knowledge, this is the first case of I-BZI complicated with acquired hemophilia A. This case suggested that major hemorrhage is one of the sole causes of I-BZI. Copyright © 2015 National Stroke Association. Published by Elsevier Inc. All rights reserved.

  13. Identifying influential directors in the United States corporate governance network.

    Science.gov (United States)

    Huang, Xuqing; Vodenska, Irena; Wang, Fengzhong; Havlin, Shlomo; Stanley, H Eugene

    2011-10-01

    The influence of directors has been one of the most engaging topics recently, but surprisingly little research has been done to quantitatively evaluate the influence and power of directors. We analyze the structure of the US corporate governance network for the 11-year period 1996-2006 based on director data from the Investor Responsibility Research Center director database, and we develop a centrality measure named the influence factor to estimate the influence of directors quantitatively. The US corporate governance network is a network of directors with nodes representing directors and links between two directors representing their service on common company boards. We assume that information flows in the network through information-sharing processes among linked directors. The influence factor assigned to a director is based on the level of information that a director obtains from the entire network. We find that, contrary to commonly accepted belief that directors of large companies, measured by market capitalization, are the most powerful, in some instances, the directors who are influential do not necessarily serve on boards of large companies. By applying our influence factor method to identify the influential people contained in the lists created by popular magazines such as Fortune, Networking World, and Treasury and Risk Management, we find that the influence factor method is consistently either the best or one of the two best methods in identifying powerful people compared to other general centrality measures that are used to denote the significance of a node in complex network theory.

  14. UNC Cancer Center Director to Lead NCI.

    Science.gov (United States)

    2017-08-01

    President Donald Trump has selected Norman "Ned" Sharpless, MD, director of the University of North Carolina Lineberger Comprehensive Cancer Center, to lead the NCI. The news was met with widespread approval among cancer researchers, who view Sharpless as a strong communicator who can ably represent the needs of the cancer community in the face of proposed funding cuts. ©2017 American Association for Cancer Research.

  15. OSG Director reports on grid progress

    CERN Multimedia

    Pordes, Ruth

    2006-01-01

    "In this Q&A from the Open Science Grid (OSG), executive director Ruth Prodes provides a brief history of the OSG, an overview of current projects and partners, and a glimpse at future plans, including how the recent $30 million award from the ODE's office of Science and the NSF will be employed. She also shares her thoughts of SC, saying the personal contacts are the best part."(4,5 pages)

  16. Systems Analysis Directorate Activities Summary, May 1976

    Science.gov (United States)

    1976-06-01

    counselling and advice from members of your War Gaming Directorate. Therefore, I take this opportunity to express our gratitude to Messrs Van Albert...M 1-1 f? r- rr ii-1 -V ,,,.-■■ r XTTTl f I. *u»»j , ♦/A j Lewis i Li.rnxT7-:—r KRAI) .... -.... „.,. ; jjvj^ jj it BLir .5 p~rrr

  17. Two-incision laparoscopic appendectomy for a severe hemophilia A child patient with coagulation factor VII deficiency: Case report and review of literature.

    Science.gov (United States)

    He, Jin Peng; Feng, Jie Xiong

    2017-10-01

    The main complication of patients with severe hemophilia is recurrent bleeding events that usually affected musculoskeletal contractures. And replacement therapy methods were continuously improved to minimize adverse impacts brought by those complications. However, only several cases reported about the appendectomy for hemophilia A. We report a case of acute appendicitis treated by two-incision laparoscopy in a boy with hemophilia A and coagulation factor VII deficiency for the first time. An 8y7m-old Chinese boy presented with half a day of right sided abdominal pain, fever, nausea, and vomiting. He received a computed tomography (CT) scan which revealed an enlarged appendix, thickened wall and appendiceal fecalith, and had received a conservative anti-bacterial treatment for his acute appendicitis but failed. He was diagnosed with hemophilia A and coagulation factor VII deficiency. Two-incision laparoscopic appendectomy was made in success with a careful management of perioperative period. We monitored the clotting factor FVIII level and gave him a replacement therapy. The patient had an uneventful recovery. It is important to exclude intraabdominal or retroperitoneal hemorrhage in patients suffering from hemophilia and acute abdominal pain. Pre-operative evaluation of validity of the FVIII replacement therapy is another effective strategy to assess the safety and feasibility of applying an operation procedure. The two-incision laparoscopic appendectomy is an effective treatment for this kind of patients for its minimal trauma and fast recovery characteristics. Our report shows that laparoscopic appendectomy is feasible in a child suffering from hemophilia after adequate blood clotting factor replacement treatment.

  18. Survey of international regional anesthesia fellowship directors

    Directory of Open Access Journals (Sweden)

    Lansdown AK

    2013-07-01

    Full Text Available Andrew K Lansdown,1,2 Paul G McHardy,1 Sanjiv C Patel,1,3 Catherine M Nix,1 Colin JL McCartney1 1Department of Anesthesia, Sunnybrook Health Sciences Centre, University of Toronto, Toronto, ON, Canada; 2University of Sydney, Sydney, NSW, Australia; 3University College Hospital, London, UK Background: The scope of regional anesthesia fellowship programs has not been analyzed but may provide insights that could improve fellowship training and standards. Methods: Regional anesthesia fellowship directors across the world were asked to complete a comprehensive survey that detailed the range of educational and practical experience and attitudes as well as assessment procedures offered in their programs. Results: The survey response rate was 66% (45/68. Overall, the range of activities and the time and resources committed to education during fellowships is encouraging. A wide range of nerve block experience is reported with most programs also offering acute pain management, research, and teaching opportunities. Only two-thirds of fellowships provide formal feedback. This feedback is typically a formative assessment. Conclusion: This is the first survey of regional anesthesia fellowship directors, and it illustrates the international scope and continuing expansion of education and training in the field. The results should be of interest to program directors seeking to benchmark and improve their educational programs and to faculty involved in further curriculum development. Keywords: anesthesia, regional, fellowship, education

  19. Emotional intelligence model for directors of research centers in mexico

    Directory of Open Access Journals (Sweden)

    Mara Maricela Trujillo Flores

    2008-01-01

    H5 Social skills exhibited by directors, that are also part of interpersonal intelligence, allow a director to exert a greater influence on the working group, facilitating communication, conflict management, leadership, collaboration, cooperation and development of team skills.

  20. Dr. William C. Harris, Director-General, Science Foundation Ireland

    CERN Multimedia

    Maximilien Brice

    2002-01-01

    Photo 01: Dr William C. Harris, Director-General, Science Foundation Ireland (left) with R. Cashmore. Photos 02, 03: Dr William C. Harris, Director-General, Science Foundation Ireland signing the CERN guest book with R. Cashmore.

  1. Investigation of the phenotype heterogeneity in severe hemophilia A using thromboelastography, thrombin generation, and thrombodynamics.

    Science.gov (United States)

    Tarandovskiy, Ivan D; Balandina, Anna N; Kopylov, Konstantine G; Konyashina, Nadezhda I; Kumskova, Maria A; Panteleev, Mikhail A; Ataullakhanov, Fazoil I

    2013-06-01

    Hemophilia A (HA) patients with similar factor VIII levels can demonstrate varying bleeding tendencies. In particular, 10-15% of all severe HA patients (FVIII:Cinvestigated the coagulation status of different bleeding phenotypes using various types of global coagulation assays. Ten HA patients with severe phenotype and eleven patients with mild phenotypes were included in the study. For each patient, thromboelastography (TE), thrombodynamics (TD), and kaolin- or tissue factor-induced thrombin generation (TG) were measured. TG in platelet-rich plasma (PRP) was investigated using our original modification when the thrombin generation curve showed two peaks, previously shown to depend on platelet activity. We also utilized TG and TD with the addition of thrombomodulin. The second peak amplitude and ETP of PRP TG were the only parameters that were significantly higher in mild bleeders (peak 41.6 ± 3.5 nM, ETP 1966 ± 169 nM*min) than in patients with severe bleeding (peak 28.3 ± 3.3 nM, ETP 1359 ± 130 nM*min). Our results suggest that severe and mild HA phenotypes could be distiguished by TG assay in PRP suggesting that difference in platelet activity can be involved in the phenotype formation. According to our previous results we can suppose that the mechanism of the phenotypic heterogeneity is linked with TG mediated by PS-expressing platelets. Copyright © 2013 Elsevier Ltd. All rights reserved.

  2. The tipping point: The critical role of therapeutic apheresis in a case of refractory acquired hemophilia.

    Science.gov (United States)

    Losos, Michael; Scrape, Scott; Joshi, Sarita; Shmookler, Aaron; Chen, Jian

    2017-12-01

    Acquired hemophilia A (AHA) is a rare autoimmune disorder that leads to factor VIII (FVIII) deficiency via autoantibody formation. Standard treatment options include FVIII bypassing factors and immunosuppression. However, the role of therapeutic plasma exchange (TPE) is not clear in the treatment of AHA. We present a case of idiopathic AHA in a 66 year old female with severe bleeding and a FVIII inhibitor of 17.6 Bethesda units (BU). She failed to respond to standard treatment including maximum dose of recombinant FVIIa (rFVIIa), rituximab, and other immunosuppressive agents. Her FVIII inhibitor rapidly increased to 140 BU and FVIII was below 5%. TPE was initiated 3 weeks after admission and her bleeding stabilized after the first treatment and completely stopped after three treatments. Repeat testing revealed increased FVIII to 15% and FVIII inhibitor decreased to 2.0 BU. After an additional TPE treatment, her FVIII increased to 27% and FVIII inhibitor decreased to 0.6 BU and she was discharged without bleeding 40 days after admission. In this case, TPE played a critical role in reducing FVIII inhibitor, which resulted in a recovery of FVIII activity and hemostasis. Therefore, TPE should be initiated early in AHA patients with bleeding and high titer of FVIII inhibitor. © 2016 Wiley Periodicals, Inc.

  3. Immunosuppression for acquired hemophilia A: results from the European Acquired Haemophilia Registry (EACH2).

    Science.gov (United States)

    Collins, Peter; Baudo, Francesco; Knoebl, Paul; Lévesque, Hervé; Nemes, László; Pellegrini, Fabio; Marco, Pascual; Tengborn, Lilian; Huth-Kühne, Angela

    2012-07-05

    Acquired hemophilia A (AHA) is an autoimmune disease caused by an autoantibody to factor VIII. Patients are at risk of severe and fatal hemorrhage until the inhibitor is eradicated, and guidelines recommend immunosuppression as soon as the diagnosis has been made. The optimal immunosuppressive regimen is unclear; therefore, data from 331 patients entered into the prospective EACH2 registry were analyzed. Steroids combined with cyclophosphamide resulted in more stable complete remission (70%), defined as inhibitor undetectable, factor VIII more than 70 IU/dL and immunosuppression stopped, than steroids alone (48%) or rituximab-based regimens (59%). Propensity score-matched analysis controlling for age, sex, factor VIII level, inhibitor titer, and underlying etiology confirmed that stable remission was more likely with steroids and cyclophosphamide than steroids alone (odds ratio = 3.25; 95% CI, 1.51-6.96; P < .003). The median time to complete remission was approximately 5 weeks for steroids with or without cyclophosphamide; rituximab-based regimens required approximately twice as long. Immunoglobulin administration did not improve outcome. Second-line therapy was successful in approximately 60% of cases that failed first-line therapy. Outcome was not affected by the choice of first-line therapy. The likelihood of achieving stable remission was not affected by underlying etiology but was influenced by the presenting inhibitor titer and FVIII level.

  4. Neonatal circumcision in severe haemophilia: a survey of paediatric haematologists at United States Hemophilia Treatment Centers.

    Science.gov (United States)

    Kearney, S; Sharathkumar, A; Rodriguez, V; Chitlur, M; Valentino, L; Boggio, L; Gill, J

    2015-01-01

    Neonatal circumcision in patients with severe haemophilia has not been well studied. We performed a survey of paediatric haematologists from Hemophilia Treatment Centers (HTC) across the United States to better understand the attitudes toward and management of neonatal circumcision in haemophilia patients. Response rate to our survey was 40% (n = 64/159). Thirty-eight percent of respondents (n = 24) said that they would allow this procedure in the newborn period but in many cases this was against medical advice. The most reported concern regarding neonatal circumcision in haemophilia patients was the risk of development of an inhibitor (n = 25; 39%) followed by the concern for bleeding (n = 22; 34%) and issues related to vascular access in the neonate (n = 11; 17%). All respondents recommended at least one preprocedure dose of factor replacement. Twenty-two percent (n = 14) of respondents did not use more than one dose of factor replacement but 32% (n = 21) used 1-2 postoperative doses. The remainder of paediatric haematologists surveyed recommended between 3-5 (16%; n = 10) and 6-10 (3%, n = 2) additional days postoperatively. There was wide variation in both techniques of circumcision as well as adjuvant haemostatic agents used. Only 22% of respondents said that they had an established protocol for management of circumcision in the newborn haemophilia patient. These survey results highlight the need for evidence-based guidelines regarding the optimal management of circumcision in neonates with severe haemophilia. © 2014 John Wiley & Sons Ltd.

  5. Management of bleeding in acquired hemophilia A: results from the European Acquired Haemophilia (EACH2) Registry.

    Science.gov (United States)

    Baudo, Francesco; Collins, Peter; Huth-Kühne, Angela; Lévesque, Hervé; Marco, Pascual; Nemes, László; Pellegrini, Fabio; Tengborn, Lilian; Knoebl, Paul

    2012-07-05

    Acquired hemophilia A is a rare bleeding disorder caused by autoantibodies to coagulation FVIII. Bleeding episodes at presentation are spontaneous and severe in most cases. Optimal hemostatic therapy is controversial, and available data are from observational and retrospective studies only. The EACH2 registry, a multicenter, pan-European, Web-based database, reports current patient management. The aim was to assess the control of first bleeding episodes treated with a bypassing agent (rFVIIa or aPCC), FVIII, or DDAVP among 501 registered patients. Of 482 patients with one or more bleeding episodes, 144 (30%) received no treatment for bleeding; 31 were treated with symptomatic therapy only. Among 307 patients treated with a first-line hemostatic agent, 174 (56.7%) received rFVIIa, 63 (20.5%) aPCC, 56 (18.2%) FVIII, and 14 (4.6%) DDAVP. Bleeding was controlled in 269 of 338 (79.6%) patients treated with a first-line hemostatic agent or ancillary therapy alone. Propensity score matching was applied to allow unbiased comparison between treatment groups. Bleeding control was significantly higher in patients treated with bypassing agents versus FVIII/DDAVP (93.3% vs 68.3%; P = .003). Bleeding control was similar between rFVIIa and aPCC (93.0%; P = 1). Thrombotic events were reported in 3.6% of treated patients with a similar incidence between rFVIIa (2.9%) and aPCC (4.8%).

  6. Safety of AAV factor IX peripheral transvenular gene delivery to muscle in hemophilia B dogs.

    Science.gov (United States)

    Haurigot, Virginia; Mingozzi, Federico; Buchlis, George; Hui, Daniel J; Chen, Yifeng; Basner-Tschakarjan, Etiena; Arruda, Valder R; Radu, Antoneta; Franck, Helen G; Wright, J Fraser; Zhou, Shangzhen; Stedman, Hansell H; Bellinger, Dwight A; Nichols, Timothy C; High, Katherine A

    2010-07-01

    Muscle represents an attractive target tissue for adeno-associated virus (AAV) vector-mediated gene transfer for hemophilia B (HB). Experience with direct intramuscular (i.m.) administration of AAV vectors in humans showed that the approach is safe but fails to achieve therapeutic efficacy. Here, we present a careful evaluation of the safety profile (vector, transgene, and administration procedure) of peripheral transvenular administration of AAV-canine factor IX (cFIX) vectors to the muscle of HB dogs. Vector administration resulted in sustained therapeutic levels of cFIX expression. Although all animals developed a robust antibody response to the AAV capsid, no T-cell responses to the capsid antigen were detected by interferon (IFN)-gamma enzyme-linked immunosorbent spot (ELISpot). Interleukin (IL)-10 ELISpot screening of lymphocytes showed reactivity to cFIX-derived peptides, and restimulation of T cells in vitro in the presence of the identified cFIX epitopes resulted in the expansion of CD4(+)FoxP3(+)IL-10(+) T-cells. Vector administration was not associated with systemic inflammation, and vector spread to nontarget tissues was minimal. At the local level, limited levels of cell infiltrates were detected when the vector was administered intravascularly. In summary, this study in a large animal model of HB demonstrates that therapeutic levels of gene transfer can be safely achieved using a novel route of intravascular gene transfer to muscle.

  7. Immunomodulation of transgene responses following naked DNA transfer of human factor VIII into hemophilia A mice.

    Science.gov (United States)

    Miao, Carol H; Ye, Peiqing; Thompson, Arthur R; Rawlings, David J; Ochs, Hans D

    2006-07-01

    A robust humoral immune response against human factor VIII (hFVIII) following naked DNA transfer into immunocompetent hemophilia A mice completely inhibits circulating FVIII activity despite initial high-level hFVIII gene expression. To prevent this undesirable response, we compared transient immunomodulation strategies. Eight groups of mice (n = 4-9 per group) were treated with naked DNA transfer of pBS-HCRHPI-hFVIIIA simultaneously with immunosuppressive reagents that included cyclosporine A (CSA), rapamycin (RAP), mycophenylate mofetil (MMF), a combination of CSA and MMF, a combination of RAP and MMF, a monoclonal antibody against murine CD40 ligand (MR1), recombinant murine Ctla4Ig, and a combination of MR1 and Ctla4Ig. All animals except those receiving only CSA exhibited delayed or absent immune responses against hFVIII. The most effective immunosuppressive regimen, the combination of Ctla4Ig and MR1, prevented inhibitor formation in 8 of 9 animals; the ninth had transient low-titer antibodies. All 9 mice of this group produced persistent, therapeutic levels of hFVIII for more than 6 months. When challenged with the T-dependent antigen bacteriophage Phix174, tolerized mice exhibited normal primary and secondary antibody responses, suggesting that transient immunomodulation to disrupt B/T-cell interaction at the time of plasmid injection effectively promoted long-term immune tolerance specific for hFVIII.

  8. Acquired hemophilia A in a patient associated with community-acquired pneumonia.

    Science.gov (United States)

    Cheng, Qiansong; Yu, Guohui; Ye, Yongqing

    2013-10-01

    Acquired hemophilia A (AHA) is a rare disease induced by autoantibodies to factor VIII (FVIII) and may be correlated with pregnancy, underlying malignancies, autoimmune diseases or drug administration. An 81-year-old man who presented with cough, expectoration, hemoptysis and multiple ecchymoses was diagnosed with community-acquired pneumonia by computed tomography scan. Respiratory symptoms were ameliorated after the application of antibiotics. Despite repeated infusion of fresh frozen plasma and cryoprecipitate, his prolonged activated partial thromboplastin time (APTT) maintained in the 75-110-s range and ecchymoses were not ameliorated. Then, he was transferred to the department of hematology. Based on a prolonged APTT, decreased level of FVIII and presence of antibodies against FVIII, the patient was diagnosed with AHA. Then the patient was treated with activated prothrombin complex concentrates, prednisone and intravenous immunoglobulin, resulting in a complete remission of the bleeding, recovering the FVIII level and negativity for FVIII antibody titers. Here, we investigate this novel case retrospectively and review the relevant literature.

  9. [Development of acquired hemophilia A during maintenance therapy for immune thrombocytopenia].

    Science.gov (United States)

    Ogawa, Yoshiyuki; Yanagisawa, Kunio; Ishizaki, Takuma; Naito, Chiaki; Mihara, Masahiro; Handa, Hiroshi; Shizuka, Reiko; Inoue, Madoka; Naito, Sumiyoshi; Ieko, Masahiro; Ichinose, Akitada; Nojima, Yoshihisa

    2016-04-01

    Acquired hemophilia A (AHA) is a rare coagulation disorder caused by autoantibodies against coagulation factor VIII (FVIII). We report herein a very rare case of AHA complicated by immune thrombocytopenia (ITP). A 30-year-old woman was hospitalized with severe thrombocytopenia. Her platelet count was 5,000/μl on admission, at which time APTT was normal. ITP was diagnosed and she was treated with γ-globulin, platelet transfusion, and prednisolone at 1 mg/kg/day. She was discharged after platelet count normalization and prednisolone was tapered to 5 mg/day. During the prednisolone tapering, purpura appeared on both thighs and in the left inguinal region, and APTT was found to be prolonged. She was referred to our hospital for examination of APTT prolongation. FVIII activity was markedly decreased to 7.7% and the FVIII inhibitor was positive (1.5 BU/ml), based on which AHA was diagnosed. We carefully followed this patient without intensification of immunosuppressive therapy for 7 weeks, but her platelet count decreased from 150,000/μl to 70,000/μl and the FVIII inhibitor increased to 4 BU/ml. We therefore increased prednisolone to 30 mg/day, after which her platelet count increased and complete remission of AHA was achieved by day 42. In addition, we examined the relationship of the FVIII inhibitor and FVIII binding antibody in this case.

  10. [Remission of acquired hemophilia A following radiation therapy for esophageal cancer].

    Science.gov (United States)

    Yanagisawa, Kunio; Ogawa, Yoshiyuki; Mitsui, Takeki; Noguchi, Hiroyuki; Shimizu, Hiroaki; Ishizaki, Takuma; Handa, Hiroshi; Ieko, Masahiro; Ichinose, Akitada; Nojima, Yoshihisa

    2016-04-01

    Although acquired hemophilia A (AHA) often develops in patients with neoplasms, there are few reports on the efficacy of radiation therapy during the bleeding phase of AHA in the prior literature. We herein present a case of AHA experiencing remission soon after radiation therapy for esophageal cancer. A man in his seventies, who had a history of radical nephrectomy for left renal cell carcinoma, received a diagnosis of esophageal cancer. Three months later, he noticed a right thigh hematoma, and was transferred to our hospital. Laboratory data revealed a marked reduction of coagulation factor VIII (FVIII) activity at 0.9% and the inhibitor to FVIII was detected in his serum at 21.8 BU/ml. Under a diagnosis of AHA, the patient received high-dose oral prednisolone, which failed to achieve disease remission. He then underwent radiation therapy to eradicate the underlying esophageal cancer. Despite tapering of the prednisolone dosage, FVIII inhibitor declined to undetectable levels. In this case, radiation therapy for the underlying cancer was associated with achieving complete remission of AHA.

  11. [Successful treatment with rituximab of a patient with coincident acquired hemophilia A and thrombotic thrombocytopenic purpura].

    Science.gov (United States)

    Yamamoto, Kazuhiko; Sandou, Yasuhisa; Niiya, Masami; Osada, Yuuki; Ikeuchi, Kazuhiro; Yamamoto, Yoshikazu; Shiote, Yasuhiro; Makita, Masanori; Imajo, Kenji

    2015-11-01

    A 66-year-old man was admitted for oral hemorrhage, purpura, and APTT prolongation. Factor VIII (FVIII) activity was decreased, due to the presence of FVIII inhibitor. He was diagnosed with acquired hemophilia A (AHA) and treated with prednisolone. Eight months later, the FVIII inhibitor titer again increased. Upon readmission, thrombocytopenia and autoimmune hemolytic anemia were found. We suspected Evans syndrome accompanied by AHA, and we treated the patient with IVIG. However, his platelet count did not increase. Speech disturbance and delirium were observed from the 12th day of hospitalization. He was subsequently diagnosed with thrombotic thrombocytopenic purpura (TTP) because ADAMTS13 inhibitor was detected, causing a decrease in ADAMTS13 activity. We initiated plasma exchange (PE) and steroid-pulse therapy. After PE for 3 days, laboratory test results and psychiatric symptoms showed dramatic improvement. However, after a 2-day period without PE, the patient's platelet count decreased markedly. Therefore, we administered rituximab to eliminate these inhibitors. His platelet count recovered rapidly, and we were able to gradually wean the patient from PE. After two additional administrations of rituximab, neither inhibitor was detected. To date, the patient has remained in complete remission for approximately 3 years.

  12. Reversible acylation of factor Xa as a potential therapy for hemophilia.

    Science.gov (United States)

    Lin, P H; Laibelman, A M; Sinha, U

    1997-11-15

    Current therapies for treatment of hemophilia A involve infusion of factor VIII, but are ineffective for patients who develop inhibitory antibodies. We have previously proposed that bypassing the intrinsic pathway (VIIIa/IXa) with reversibly acylated factor Xa offers an improvement on existing therapies as it provides a time-dependent release of procoagulant activity without the addition of factors VIII or IX. The present study was designed to determine the effect of substituted 4-amidinophenyl benzoates on the acylation of factor Xa, as well as the subsequent deacylation rates of the resulting acyl Xa. A subset of this series of acyl Xa's were incorporated into the prothrombinase complex and recovery of catalytic activity was measured by activation of prothrombin to thrombin. Similarly, some acyl Xa's were also evaluated for their capacity to enhance clotting times of human plasma. Our study indicates that by choosing the appropriate acyl Xa, the time course of factor Xa regeneration can be modulated extensively. Animal studies will be required to show that the use of acyl Xa as a procoagulant agent is feasible in an in vivo system.

  13. [Establishment of hemophilia A patient-specific inducible pluripotent stem cells with urine cells].

    Science.gov (United States)

    Hu, Zhiqing; Hu, Xuyun; Pang, Jialun; Wang, Xiaolin; Lin Peng, Siyuan; Li, Zhuo; Wu, Yong; Wu, Lingqian; Liang, Desheng

    2015-10-01

    OBJECTIVE To generate hemophilia A (HA) patient-specific inducible pluripotent stem cells (iPSCs) and induce endothelial differentiation. METHODS Tubular epithelial cells were isolated and cultured from the urine of HA patients. The iPSCs were generated by forced expression of Yamanaka factors (Oct4, Sox2, c-Myc and Klf4) using retroviruses and characterized by cell morphology, pluripotent marker staining and in vivo differentiation through teratoma formation. Induced endothelial differentiation of the iPSCs was achieved with the OP9 cell co-culture method. RESULTS Patient-specific iPSCs were generated from urine cells of the HA patients, which could be identified by cell morphology, pluripotent stem cell surface marker staining and in vivo differentiation of three germ layers. The teratoma experiment has confirmed that such cells could differentiate into endothelial cells expressing the endothelial-specific markers CD144, CD31 and vWF. CONCLUSION HA patient-specific iPSCs could be generated from urine cells and can differentiate into endothelial cells. This has provided a new HA disease modeling approach and may serve as an applicable autologous cell source for gene correction and cell therapy studies for HA.

  14. Bypassing agent prophylaxis in people with hemophilia A or B with inhibitors.

    Science.gov (United States)

    Chai-Adisaksopha, Chatree; Nevitt, Sarah J; Simpson, Mindy L; Janbain, Maissaa; Konkle, Barbara A

    2017-09-25

    People with hemophilia A or B with inhibitors are at high risk of bleeding complications. Infusion of bypassing agents, such as recombinant activated FVII (rFVIIa) and plasma-derived activated prothrombin complex concentrate, are suggested as alternative therapies to factor VIII (haemophilia A) or IX (haemophilia B) for individuals who no longer respond to these treatments because they develop inhibitory antibodies. The ultimate goal of treatment is to preserve the individual's joints, otherwise destroyed by recurrent bleeds. To assess the effects of bypassing agent prophylaxis to prevent bleeding in people with hemophilia A or B and inhibitors. We searched for relevant studies from the Cystic Fibrosis and Genetic Disorders Group's Coagulopathies Trials Register, comprising of references identified from comprehensive electronic database searches and handsearches of relevant journals and abstract books of conference proceedings. We also searched trial registries (16 February 2017) and bibliographic references of retrieved studies were reviewed for potential articles to be included in the review.Date of the last search of the Cochrane Cystic Fibrosis and Genetic Disorders Coagulopathies Trials Register: 12 December 2016. We included randomized and quasi-randomized controlled studies (cross-over or parallel design) evaluating the effect of prophylaxis treatment with bypassing agents compared with on-demand treatment, or studies evaluating the effects of high-dose compared with low-dose prophylaxis in males of any age with hemophilia with inhibitors. Two authors independently selected studies and extracted data and assessed the risk of bias according to standard Cochrane criteria. They assessed the quality of the evidence using the GRADE criteria. We included four randomized studies (duration 7 to 15 months) involving 116 males. Risk of bias was judged to be high in two studies due to the open-label study design and in one study due to attrition bias.Two studies

  15. The loop antenna with director arrays of loops and rods

    DEFF Research Database (Denmark)

    Appel-Hansen, Jørgen

    1972-01-01

    Experiments indicate that the gain of a Yagi-Uda antenna arrangement depends only upon the phase velocity of the surface wave traveling along the director array and not to any significant extent upon the particular forms of the director elements.......Experiments indicate that the gain of a Yagi-Uda antenna arrangement depends only upon the phase velocity of the surface wave traveling along the director array and not to any significant extent upon the particular forms of the director elements....

  16. Nursing home director of nursing leadership style and director of nursing-sensitive survey deficiencies.

    Science.gov (United States)

    McKinney, Selina H; Corazzini, Kirsten; Anderson, Ruth A; Sloane, Richard; Castle, Nicholas G

    2016-01-01

    Nursing homes are becoming increasingly complex clinical environments because of rising resident acuity and expansion of postacute services within a context of historically poor quality performance. Discrete quality markers have been linked to director of nursing (DON) leadership behaviors. However, the impact of DON leadership across all measured areas of DON jurisdiction has not been tested using comprehensive domains of quality deficiencies. The aim of this study was to examine the effects of DON leadership style including behaviors that facilitate the exchange of information between diverse people on care quality domains through the lens of complexity science. Three thousand six hundred nine DONs completed leadership and intent-to-quit surveys. Quality markers that were deemed DON sensitive included all facility survey deficiencies in the domains of resident behaviors/facility practices, quality of life, nursing services, and quality of care. Logistic regression procedures estimated associations between variables. The odds of deficiencies for all DON sensitive survey domains were lower in facilities where DONs practiced complexity leadership including more staff input and shared decisional authority. DON quit intentions were aligned with higher odds of facility deficiencies across all domains. Results supported the hypotheses that DONs using complexity leadership approaches by interacting more freely with staff, discussing resident issues, and sharing decision making produced better care outcomes from every DON sensitive metric assessed by Centers for Medicare and Medicaid Services. The mechanism linking poor quality with high DON quit intentions is an area for future research. Encouraging DON use of complexity leadership approaches has the potential to improve a broad swath of quality outcomes.

  17. 22 CFR 67.2 - Board of Directors.

    Science.gov (United States)

    2010-04-01

    ... 22 Foreign Relations 1 2010-04-01 2010-04-01 false Board of Directors. 67.2 Section 67.2 Foreign... DEMOCRACY § 67.2 Board of Directors. (a) NED is governed by a bipartisan board of Directors of not fewer than thirteen and not more than twenty-five members reflecting the diversity of American society. The...

  18. 7 CFR 2.95 - Director, Office of Ethics.

    Science.gov (United States)

    2010-01-01

    ... 7 Agriculture 1 2010-01-01 2010-01-01 false Director, Office of Ethics. 2.95 Section 2.95... Administration § 2.95 Director, Office of Ethics. The Director, Office of Ethics, shall be the USDA Alternate Agency Ethics Official, pursuant to 5 CFR 2638.202, and shall exercise the authority reserved to the...

  19. Evaluating the Child Care Director: The Collaborative Professional Assessment Process.

    Science.gov (United States)

    Freeman, Nancy K.; Brown, Mac H.

    2000-01-01

    Describes the Collaborative Professional Assessment Process (CPAP) to guide the evaluation of the director of early childhood programs. Examines the assumptions upon which the CPAP is based. Lists the management skills and leadership abilities of successful child care directors. Includes the Director Self-Evaluation form and a program evaluation…

  20. 14 CFR 23.1335 - Flight director systems.

    Science.gov (United States)

    2010-01-01

    ... 14 Aeronautics and Space 1 2010-01-01 2010-01-01 false Flight director systems. 23.1335 Section 23...: Installation § 23.1335 Flight director systems. If a flight director system is installed, means must be provided to indicate to the flight crew its current mode of operation. Selector switch position is not...