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Sample records for hemophilia

  1. Hemophilia

    MedlinePlus

    Hemophilia A; Classic hemophilia; Factor VIII deficiency; Hemophilia B; Christmas disease; Factor IX deficiency ... missing or aren't functioning like they should. Hemophilia is caused by the lack of clotting factor ...

  2. Hemophilia

    MedlinePlus

    Hemophilia is a rare disorder in which the blood does not clot normally. It is usually inherited. ... Clotting factor is a protein needed for normal blood clotting. Without it, you may bleed for a ...

  3. Hemophilia

    MedlinePlus

    ... Clotting factor is a protein needed for normal blood clotting. Without it, you may bleed for a long ... of hemophilia are excessive bleeding and easy bruising. Blood tests can tell if you have it. The main treatment is injecting the missing clotting factor into the bloodstream. You may need it ...

  4. Hemophilia - resources

    MedlinePlus

    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/ ...

  5. Hemophilia A

    MedlinePlus

    Factor VIII deficiency; Classic hemophilia; Bleeding disorder - hemophilia A ... When you bleed, a series of reactions take place in the body that helps blood clots form. This process is called the coagulation ...

  6. Hemophilia A

    MedlinePlus

    Genetic counseling may be recommended. Testing can identify women and girls who carry the hemophilia gene. Identify women and girls who carry the hemophilia gene. Testing can be done during pregnancy on a baby in the mother's womb.

  7. Hemophilia Diagnosis

    MedlinePlus

    ... Community Counts Blood Safety Inhibitors Articles & Key Findings Free Materials Videos Starting the Conversation Playing it Safe A Look at Hemophilia Joint Range of Motion My Story Links to Other Websites ...

  8. Hemophilia Facts

    MedlinePlus

    ... Community Counts Blood Safety Inhibitors Articles & Key Findings Free Materials Videos Starting the Conversation Playing it Safe A Look at Hemophilia Joint Range of Motion My Story Links to Other Websites ...

  9. [Hemophilia camps.

    PubMed

    Juárez-Sierra, Julieta; Del Pilar Torres-Arreola, Laura; Marín-Palomares, Teresa; Dueñas-González, María Teresa; Monteros-Rincón, Martha Patricia; Osorio-Guzmán, Maricela

    2013-01-01

    We reported the experience of hemophilia camps which was accomplished with patients from hospitals of the Instituto Mexicano del Seguro Social. The aim was to prepare the families and patients regarding the disease treatment, in order to promote the self sufficiency and to know the impact of the program on the course of the disease. Surveys were applied about treatment items and personal opinions were collected. The results of the national hemophilia camp were: group of 56 patients, average 14 years, 2 % women, 51 % severe hemophilia and 43 % had hemophilic brothers. Benefits: patients increased their knowledge about earlier bleeding identification and the self-infusion method; they became aware on their responsibility in self care, timely treatment and duties at home. Hemophilia camps with patients are an option for attitude change before disease complications. Social network creation and the increase in self-sufficiency are other benefits. PMID:24290020

  10. Genetics Home Reference: hemophilia

    MedlinePlus

    ... Help Me Understand Genetics Home Health Conditions hemophilia hemophilia Enable Javascript to view the expand/collapse boxes. Print All Open All Close All Description Hemophilia is a bleeding disorder that slows the blood ...

  11. What Causes Hemophilia?

    MedlinePlus

    ... chromosomes, while males have one X and one Y chromosome. Only the X chromosome carries the genes related ... have hemophilia (that is, he has two normal chromosomes—X and Y). The mother is a carrier of hemophilia (that ...

  12. Hemophilia (For Teens)

    MedlinePlus

    ... very common, mostly affects guys. In rare cases, girls can have the disease and get bleeding problems ... have a 50% chance of having hemophilia. Although girls rarely develop the symptoms of hemophilia itself, they ...

  13. Frequently Asked Questions: Hemophilia

    MedlinePlus

    ... clotting factor deficiencies , and inherited platelet disorders . How serious is hemophilia? The severity of hemophilia depends on ... Pictures Young Voices Compendium of Assessment Tools Educational Games Video Library Find a Treatment Centre Haemophilia Journal ...

  14. How Is Hemophilia Diagnosed?

    MedlinePlus

    ... page from the NHLBI on Twitter. How Is Hemophilia Diagnosed? If you or your child appears to ... have bleeding problems. However, some people who have hemophilia have no recent family history of the disease. ...

  15. What is Hemophilia?

    MedlinePlus

    ... page from the NHLBI on Twitter. What Is Hemophilia? Español Hemophilia (heem-o-FILL-ee-ah) is a rare ... blood doesn't clot normally. If you have hemophilia, you may bleed for a longer time than ...

  16. How to Deal with Hemophilia

    MedlinePlus

    ... Hemophilia is considered a good test for gene therapy because it is caused by only one defective gene. It could ... Kids With Hemophilia Can Stay Healthy Life for a kid with hemophilia is much like ...

  17. Comprehensive care in hemophilia.

    PubMed

    Ruiz-Sáez, Arlette

    2012-04-01

    Hemophilia is a chronic and inherited X-linked bleeding disorder that requires life-long medical care. Hemophilia treatment is costly and complex partly because of the cost of the factor concentrates used in replacement therapy. However, the management of hemophilia is not based solely on achieving access to better treatment with safe factor concentrates; it also includes accurately diagnosing the disorder and providing specialized comprehensive care by a multidisciplinary team of specialists trained in hemophilia management. Comprehensive care for the person with hemophilia is defined as the continuous supervision of all medical and psychological aspects affecting the patient and his family and it demands the establishment of specialized centers, called Hemophilia Treatment Centers. The services that should be offered by a comprehensive hemophilia healthcare center are diverse and the multidisciplinary team should be coordinated preferably by a hematologist with the participation of other health professionals. It has been demonstrated that the benefits of establishing hemophilia centers are observed even in developing countries and that changes can be achieved when resources are re-organized, especially when education and training are provided at all levels. To reach these objectives, it is essential to have the participation of the patient and family members, and to strive to obtain the financial and legislative support from the State or Government in order to achieve a national comprehensive care program contemplating all the aspects needed for improving the quality of life for the community of patients with hemophilia and other bleeding disorders. PMID:22507803

  18. Animal Models of Hemophilia

    PubMed Central

    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

  19. How Is Hemophilia Treated?

    MedlinePlus

    ... Intramural Research Research Resources Research Meeting Summaries Technology Transfer Clinical Trials What Are Clinical Trials? Children & Clinical ... Treating donated blood products with a detergent and heat to destroy viruses Vaccinating people who have hemophilia ...

  20. Hemophilia Data and Statistics

    MedlinePlus

    ... Community Counts Blood Safety Inhibitors Articles & Key Findings Free Materials Videos Starting the Conversation Playing it Safe A Look at Hemophilia Joint Range of Motion My Story Links to Other Websites ...

  1. Hemophilia (For Parents)

    MedlinePlus

    ... to treat. There is also a medicine called recombinant factor VII that can help prevent the body ... treating children with hemophilia. For example, when giving immunization shots that are normally given in the muscle, ...

  2. Hemophilia during pregnancy.

    PubMed Central

    Goldman, Ran D.; Blanchette, Victor; Koren, Gideon

    2003-01-01

    QUESTION: A patient in my clinic, who is 10 weeks into her first pregnancy and is a known carrier of hemophilia B, is considering the advantages and disadvantages of antenatal tests and is especially worried about a vaginal delivery thatmight cause bleeding. How should I manage her pregnancy? ANSWER: Many female carriers of hemophilia were found to have lower-than-expected levels of plasma factors, which are thought to be due to X chromosome inactivation. Chorionic villous sampling is the preferred test to determine the sex of the fetus and whether a male infant is affected with hemophilia. Vaginal delivery is not contraindicated and has been proven during the last two decades to be as safe as cesarean section. Vacuum extraction should be avoided to minimize risk of intracranial hemolysis and severe cephalhematoma. PMID:14708924

  3. Understanding Hemophilia. Implications for the Physical Educator.

    ERIC Educational Resources Information Center

    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)

  4. [Hemophilia B replacement therapy drugs].

    PubMed

    Yan, Hong; Zeng, Fanyi

    2016-02-01

    Hemophilia B is an X chromosome linked hereditary hemorrhagic disease, which is caused by the lose function mutation of factor IX (FIX), and significantly affects the patients' lifespan and life quality. The severity of hemophilia B depends on the FIX level in the plasma. By referring to the relevant literatures, we reviewed and summarized hemophilia B replacement therapies. Specifically, we focus on recombinant factor IX products on the market and those in the pipeline, especially on the long-acting factor IX drugs, to provide the basis for researches of new hemophilia B drugs. PMID:27382766

  5. Muscle Gene Therapy for Hemophilia

    PubMed Central

    Sabatino, Denise E.; Arruda, Valder R.

    2013-01-01

    Muscle-directed gene therapy for hemophilia is an attractive strategy for expression of therapeutic levels of clotting factor as evident from preclinical studies and an early phase clinical trial. Notably, local FIX expression by AAV-mediated direct intramuscular injection to skeletal muscle persists for years. Development of intravascular delivery of AAV vector approaches to skeletal muscle resulted in vector in widespread areas of the limb and increased expression of FIX in hemophilia B dogs. The use of FIX variants with improved biological activity may provide the opportunity to increase the efficacy of these approaches. Studies for hemophilia A are less developed at this point, but utilizing transgenes that improve hemostasis independent of FIX and FVIII has potential therapeutic application for both hemophilia A and B. Continuous monitoring of humoral and T cell responses to the transgene and AAV capsid in human trials will be critical for the translation of these promising approaches for muscle gene therapy for hemophilia. PMID:24883231

  6. Myositis ossificans in hemophilia

    SciTech Connect

    Vas, W.; Cockshott, W.P.; Martin, R.F.; Pai, M.K.; Walker, I.

    1981-10-01

    A review of the radiographs of 60 hemophilia patients showed nine (15%) with ectopic new bone formation. Three of these patients had multiple sites of involvement. The high frequency discovered in this series contrasts with the paucity of descriptions to be found in the literature. This process of myositis ossificans affects the lower half of the body and probably represents dysplastic metaplasia developing at the site of an intramuscular hematoma when remote from bone, as well as ossification of hemorrhagic lesions related to the periosteum. In conventional radiographs anatomic localization of bone foci is difficult, but use of computed tomography permits precise identification of the affected muscle. There is negligible disability associated with this condition.

  7. Iron studies in hemophilia

    SciTech Connect

    Lottenberg, R.; Kitchens, C.S.; Roessler, G.S.; Noyes, W.D.

    1981-12-01

    Although iron deficiency is not recognized as a usual complication of hemophilia, we questioned whether intermittent occult loss of blood in urine or stool might predispose hemophiliacs to chronic iron deficiency. Seven men with factor VII and one with factor IX deficiency were studied. Blood studied, bone marrow aspirates, urine and stool samples, and ferrokinetics with total-body counting up to five months were examined. These data showed no excessive loss of blood during the study period; however, marrow iron stores were decidedly decreased, being absent in four subjects. We suggest that in some hemophiliacs, iron deposits in tissues such as synovial membranes may form a high proportion of the body's total iron stores.

  8. Adenoviral Vectors for Hemophilia Gene Therapy

    PubMed Central

    Brunetti-Pierri, N; Ng, Philip

    2013-01-01

    Hemophilia is an inherited blood clotting disorder resulting from deficiency of blood coagulation factors. Current standard of care for hemophilia patients is frequent intravenous infusions of the missing coagulation factor. Gene therapy for hemophilia involves the introduction of a normal copy of the deficient coagulation factor gene thereby potentially offering a definitive cure for the bleeding disorder. A variety of approaches have been pursued for hemophilia gene therapy and this review article focuses on those that use adenoviral vectors. PMID:24883229

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

    PubMed Central

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

    2016-01-01

    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 (<10, 10–50, >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 (P<0.001 and P=0.03, respectively), while that with less than 10 hemarthrosis was higher in hemophilia B (P<0.0001). World Federation of Hemophilia (36.6 vs. 20.2; P<0.0001) and ultrasound (10.9 vs. 4.3; P<0.0001) score mean values were significantly higher in hemophilia A patients. Serum osteoprotegerin and soluble RANK ligand were decreased in hemophilia A versus hemophilia B (P<0.0001 and P=0.006, respectively). Osteoprotegerin expression was markedly reduced in synovial tissue from hemophilia 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. PMID:26494839

  10. Acquired hemophilia masked by warfarin therapy.

    PubMed

    Kantor, R; Mayan, H; Puritz, L; Varon, D; Farfel, Z

    2000-03-01

    People without hemophilia but with autoantibodies specifically directed against the procoagulant activity of factor VIII are known to have acquired hemophilia. The bleeding diathesis in these patients is often severe and life-threatening. The definite laboratory diagnosis of this disorder includes demonstration of low factor VIII levels in plasma with a high titer of factor VIII inhibitors, but the initial suspicion for its presence should rise in view of a prolonged partial thromboblastin time (PTT) and a normal prothrombin time associated with an acquired bleeding disorder. Oral anticoagulant treatment is known to prolong PTT as well, and the merger of these 2 situations may cause delayed diagnosis of acquired hemophilia with devastating consequences. We describe here the first reported case of acquired hemophilia diagnosed in a patient treated with warfarin. In such patients prolonged PTT may be ascribed to warfarin therapy rather than to acquired hemophilia, thus causing a dangerous delay in diagnosis. PMID:10746834

  11. Hemophilia B: Molecular Pathogenesis and Mutation Analysis

    PubMed Central

    Goodeve, Anne C.

    2015-01-01

    Summary Hemophilia B is an X-chromosome-linked inherited bleeding disorder primarily affecting males, while those carrier females having reduced factor IX:C levels may also experience some bleeding issues. Genetic analysis has been undertaken for hemophilia B since the mid-1980s, both through linkage analysis to track inheritance of an affected allele and to enable determination of the familial mutation. Mutation analysis using PCR and Sanger sequencing along with dosage analysis for detection of large deletions/duplications enables mutation detection in more than 97% of hemophila B patients. Risk of inhibitory antibodies, reported in ~2% of hemophilia B patients can be predicted, especially in patients with large deletions and these individuals are also at risk of anaphylaxis, and nephrotic syndrome if they receive immune tolerance induction. Inhibitors also occur in patients with nonsense mutations, occasionally with small insertions/deletions, splice mutations and rarely with missense mutations (p.Gln237Lys and p.Gln241His). Hemophilia B results from several different mechanisms and those associated with hemophilia B Leyden, ribosome readthrough of nonsense mutations and apparently "silent" changes that do not alter amino acid coding are explored. Large databases of genetic variants in healthy individuals and patients with a range of disorders including hemophilia B are yielding useful information on sequence variant frequency to help establish possible variant pathogenicity whilst a growing range of algorithms is available to help predict pathogenicity for previously unreported variants. PMID:25851415

  12. Treatment of hemophilia in the near future.

    PubMed

    Peyvandi, Flora; Garagiola, Isabella

    2015-11-01

    Advancements and debacles have characterized hemophilia treatment over the past 50 years. The 1970s saw the availability of plasma-derived concentrates making prophylaxis and home therapy possible. This optimistic perception changed extremely in the early 1980s, when most people with hemophilia were infected with HIV and hepatitis viruses. Then, also in the 1980s, the rapid progress in molecular biology led to the development of recombinant therapeutic products. This important advancement was a huge technological leap fresh off from the earlier 1980s disaster. Now in the 21st century, the newer bioengineering drugs open a new hopeful phase for the management of hemophilia. The current efforts are concentrated on producing novel coagulation factors with prolonged bioavailability, increased potency, and resistance to inactivation and potentially reduced immunogenicity; this phase of evolution is improving very quickly. 2014 is the year of marketing approval by the Food and Drug Administration of the first bioengineered FVIII and FIX long-acting drugs, using Fc-fusion strategy. This represents the first significant advance in the hemophilia therapy that dramatically transforms patient management by substantially reducing the frequency of injections, improving compliance, and simplifying prophylaxis and, in turn, refining the quality of life of hemophilia patients, offering them a nearly normal life expectancy, particularly to newborns with hemophilia B. PMID:25703518

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

    ERIC Educational Resources Information Center

    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…

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

    ERIC Educational Resources Information Center

    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…

  15. What Are the Signs and Symptoms of Hemophilia?

    MedlinePlus

    ... from the NHLBI on Twitter. What Are the Signs and Symptoms of Hemophilia? The major signs and symptoms of hemophilia are excessive bleeding and ... Children who have mild hemophilia may not have signs unless they have excessive bleeding from a dental ...

  16. Hemophilia A: Dental considerations and management

    PubMed Central

    Shastry, Shilpa Padar; Kaul, Rachna; Baroudi, Kusai; Umar, Dilshad

    2014-01-01

    Aim: To review hemophilia A with emphasis on its oral manifestations, investigations, and dental management. Materials and Methods: Search was conducted using internet-based search engines, scholarly bibliographic databases, PubMed, and Medline with key words such as “Hemophilia A,” “factor VIII,” “bleeding and clotting disorders,” and “dental management.” Results: Hemophilia comprises a group of hereditary disorders caused due to the deficiency of one or more clotting factors leading to prolonged clotting time and excessive bleeding tendencies. It is broadly divided into hemophilia A, B, and C, which occur due to deficiency of factor VIII, IX, and XI, respectively. Hemophilia A is an X-linked recessive hereditary disorder and is the most common of the three, accounting for 80–85% of the cases. Conclusion: Understanding this complex entity is very important for a dentist to provide appropriate dental treatment and avoid undesirable consequences. PMID:25625071

  17. Oral pyogenic granuloma in hemophilia: a report of 2 cases.

    PubMed

    Lindsay, Holly; Srivaths, Lakshmi V

    2014-07-01

    Pyogenic granulomas (PGs) are benign vascular lesions occurring in skin and mucous membranes, often secondary to trauma or chronic inflammation. Oral PGs have never been described previously in hemophilia. We describe 2 pediatric patients with hemophilia A, who developed PGs with inadequate factor therapy for bleeding. PG pathophysiology suggests an association with hemophilia given chronic vascular damage and low-grade inflammation at sites of bleeding in hemophilia patients. Knowledge about the occurrence of PGs in hemophilia patients is essential for prompt diagnosis and early institution of factor therapy, which in turn allows more rapid cessation of bleeding and lesion involution. PMID:24663071

  18. Sports and hemophilia: antagonist or protagonist.

    PubMed

    Buzzard, B M

    1996-07-01

    Until recent years the life for the person with hemophilia was dictated by the severity and frequency of bleeding episodes. Those with hemophilia tended to be overprotected and not allowed to participate in sporting activities normal to their peer group. The past 2 decades has seen a dramatic change in attitudes, mainly due to the introduction of factor replacement, home therapy, and comprehensive care programs. Those involved in the care of people with hemophilia now recognize that sport and exercise can reduce or prevent intraarticular hemorrhages. The arguments for and against sport as described in the literature from 1960 to 1990 are reviewed. Swimming, golf, and table tennis were recommended by doctors, whereas most contact sports, including football, were discouraged. The move toward more active pursuits brings with it an increase in sporting injuries, which is addressed in this article, but more importantly the prevention of injuries is highlighted. PMID:8653965

  19. Clinical and Laboratory Approaches to Hemophilia A

    PubMed Central

    Mansouritorghabeh, Hassan

    2015-01-01

    Hemophilia A is a worldwide disorder of coagulation system. It is a male disorder, yet females with hemophilia are rarely seen in communities with high rate of consanguineous marriages. The abnormalities in factor VIII gene transfer as an X-linked pattern in the family, affects as many as one-third of patients who had no family history of abnormality and thus the occurrence of a sporadic mutation could be documented. Hemorrhagic symptoms usually correlate with the plasma level of factor VIII and comprise a wide range of hemorrhagic pictures, including from fatal spontaneous bleeding in the brain to ecchymosis of the skin. The coagulation study needs to differentiate between the two types of hemophilia A and B as well as the categorization of the disease severity. In the developing countries, due to limitations in diagnostic hemostasis facilities and a scant number of experts in the field, it is estimated that noticeable numbers of undiagnosed patients with hemophilia A exist. Occasionally, we encounter undiagnosed cases by general physicians while having hemorrhagic symptoms. The purpose of this review is to recap clinical and diagnostic parameters, pitfalls, and interpretation of coagulation assay in hemophilia A. A literature review was done in PubMed and Scopus medical search engines using the keywords “Hemophilia” and “Haemophilia”. A time limitation for the publication beyond 1995 and publication in the English language were considered. A total of 94 original articles and chapters of books was selected for the current review. Additionally, a comprehensive and up-to-date information on the clinical and laboratory features for the diagnosis of hemophilia is also presented. PMID:25999618

  20. Chronic immune thrombocytopenic purpura in hemophilia A.

    PubMed Central

    Reen, B. S.; Card, R. T.; McSheffrey, J. B.; Skinnider, L. F.

    1983-01-01

    Chronic immune thrombocytopenic purpura resistant to steroid therapy occurred in a 30-year-old patient with severe hemophilia A. This association has recently been reported in other patients, and a possible relation to the acquired immune deficiency syndrome (AIDS) has been suggested. Although this patient had been treated with factor VIII concentrate for 4 years, the proportions of helper and suppressor T cells were normal, and there was no evidence of AIDS. An uncomplicated splenectomy gave excellent results. All patients with hemophilia should have their platelet counts monitored closely and should report any unusual pattern of bleeding. PMID:6686949

  1. A natural choice for hemophilia B.

    PubMed

    Koeberl, Dwight D

    2015-03-01

    In this issue of Blood, Crudele et al describe a novel study of adeno-associated virus (AAV) vector-mediated gene therapy that induced immune tolerance to factor IX (FIX) in a hemophilia B (HB) dog with previously formed anti-FIX inhibitor antibodies (IAs). PMID:25745178

  2. Bruising and Hemophilia: Accident or Child Abuse?

    ERIC Educational Resources Information Center

    Johnson, Charles F.; Coury, Daniel L.

    1988-01-01

    Two case histories illustrate the difficulty in evaluating abuse/neglect in children with bleeding problems such as hemophilia. Discussed are guidelines for diagnosis and prevention of abuse, including: screening techniques, the need for protection from environmental trauma, parental stress, evaluation of parents' disciplinary methods, and the…

  3. Hemophilia: The Role of the School Nurse.

    ERIC Educational Resources Information Center

    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)

  4. Emerging and future therapies for hemophilia

    PubMed Central

    Carr, Marcus E; Tortella, Bartholomew J

    2015-01-01

    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. PMID:26366108

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

    ERIC Educational Resources Information Center

    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…

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

    ERIC Educational Resources Information Center

    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.…

  7. Molecular approaches for improved clotting factors for hemophilia

    PubMed Central

    Powell, Jerry S.

    2013-01-01

    Hemophilia is caused by a functional deficiency of one of the coagulation proteins. Therapy for no other group of genetic diseases has seen the progress that has been made for hemophilia over the past 40 years, from a life expectancy in 1970 of ∼20 years for a boy born with severe hemophilia to essentially a normal life expectancy in 2013 with current prophylaxis therapy. However, these therapies are expensive and require IV infusions 3 to 4 times each week. These are exciting times for hemophilia because several new technologies that promise extended half-lives for factor products, with potential for improvements in quality of life for persons with hemophilia, are in late-phase clinical development. PMID:24065241

  8. FEIBA versus NovoSeven in hemophilia patients with inhibitors.

    PubMed

    Franchini, Massimo; Coppola, Antonio; Tagliaferri, Annarita; Lippi, Giuseppe

    2013-10-01

    The management of patients with congenital hemophilia who develop alloantibodies that neutralize coagulation factor activity is the most important challenge for hemophilia care providers because this complication renders replacement treatment with factor concentrates partially or completely ineffective, exposing the patients to an increased risk of morbidity and mortality. Development of inhibitors complicates the clinical course of severe hemophilia in up to 30% of patients with hemophilia A and up to 5% of those with hemophilia B. Although the ultimate goal of treatment of patients with alloantibodies against factors VIII and IX is eradication of the inhibitor, the control of bleeding through high doses of factor concentrates (low titer inhibitors) or bypassing agents (high titer inhibitors) is the mainstay of management of these patients. In this review, we summarize the main characteristics of the bypassing agents FEIBA and NovoSeven, briefly discussing available literature data, and in particular, focusing on comparative studies. PMID:24014071

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

    PubMed

    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. PMID:26805907

  10. Utilization Patterns of Coagulation Factor Consumption for Patients with Hemophilia.

    PubMed

    Lee, Soo Ok; Yu, Su-Yeon

    2016-01-01

    Hemophilia is a serious rare disease that requires continuous management and treatment for which the medicine is costly at the annual average of 100 million KRW for an individual. The aim of this study was to investigate trends in the utilization of coagulation factor (CF) used for hemophilia treatment using the National Health Insurance database from 2010 to 2013 in Korea and compare the utilization of CF with other countries. The consumption of CF per capita (IU) in Korea was not more than other countries with similar income to Korea. However, CF usage per patient IU was higher because the prevalence rate of hemophilia in Korea was lower than in other countries while the number of serious patients was much more. Therefore, it is difficult to say that the consumption of hemophilia medicine in Korea is higher than that in other countries. The consumption and cost of hemophilia medicine in Korea is likely to increase due to the increased utilization of expensive bypassing agents and the widespread use of prophylaxis for severe hemophilia. Even during the research period, it increased slightly and other countries show a similar trend. Thus, hemophilia patient management should accompany active monitoring on the health and cost outcomes of pharmaceutical treatment in the future. This study is expected to contribute to further insight into drug policies for other countries that face similar challenges with high price pharmaceuticals. PMID:26770035

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

    PubMed Central

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

    PubMed

    Monahan, P E

    2015-06-01

    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

  13. 2 New Findings Offer Hope for Those with Severe Hemophilia

    MedlinePlus

    ... nih.gov/medlineplus/news/fullstory_159027.html 2 New Findings Offer Hope for Those With Severe Hemophilia ... while the other uncovers the promise of a new drug To use the sharing features on this ...

  14. 2 New Findings Offer Hope for Those with Severe Hemophilia

    MedlinePlus

    ... https://medlineplus.gov/news/fullstory_159027.html 2 New Findings Offer Hope for Those With Severe Hemophilia ... while the other uncovers the promise of a new drug To use the sharing features on this ...

  15. Factor VIII/factor IX prophylaxis for severe hemophilia.

    PubMed

    Carcao, Manuel; Srivastava, Alok

    2016-01-01

    Experience with clotting factor concentrate (CFC) replacement products over several decades has shown that regular replacement (prophylaxis) is the only way to prevent musculoskeletal damage in hemophilia and impact the natural history of hemophilia. Yet there is a lack of data on the optimal age to start such replacement therapy and the regimens to be used. While very early administration of high doses is certainly more effective in preventing bleeding, cost and compliance are major constraints all over the world. Starting prophylaxis with even lower doses comparable to that used in episodic therapies leads to major reduction in bleeding. Recognition of the clinical heterogeneity of hemophilia even among patients with a label of severe hemophilia in terms of their spontaneous bleeding has led to efforts aimed at individualizing CFC replacement, based on clinical responses or pharmacokinetic data of the CFC. The importance of long-term outcome assessment being combined with CFC replacement therapy cannot be overemphasized. PMID:26805901

  16. Advancements in gene transfer-based therapy for hemophilia A

    PubMed Central

    Doering, Christopher B; Spencer, H Trent

    2010-01-01

    Gene therapy has promised clinical benefit to those suffering with hemophilia A, but this benefit has not yet been realized. However, during the past two decades, basic and applied gene therapy research has progressed and the goal of gene therapy for hemophilia A is once again in our sights. The hemophilia A patient population suffers from a disease that requires invasive, lifelong management, is exorbitantly expensive to treat, has geographically limited treatment access and can become untreatable due to immune reactions to the treatment product. Subsequent to the cloning of the factor VIII gene and cDNA in the early 1980s, academic and commercial research laboratories began to pursue gene transfer-based therapies to supplement or supplant the available protein replacement therapy. However, to date, clinical trials for gene therapy of hemophilia A have been unsuccessful. Three trials have been conducted with each having tested a different gene-transfer strategy and each demonstrating that there is a considerable barrier to achieving sustained expression of therapeutic amounts of factor VIII. Recent progress has been made in gene-transfer technology and, relevant to hemophilia A, towards increasing the biosynthetic efficiency of factor VIII. These advances are now being combined to develop novel strategies to treat and possibly cure hemophilia A. PMID:20577574

  17. Practice of Iranian Adolescents with Hemophilia in Prevention of Complications of Hemophilia

    PubMed Central

    Valizadeh, Leila; Hosseini, Fahimeh Alsadat; Zamanzadeh, Vahid; Heidarnezhad, Fatemeh; Jasemi, Madineh; Lankarani, Kamran Bagheri

    2015-01-01

    Background: Prerequisite for management of a chronic disease involves knowledge about its complications and their prevention. Hemophilia in adolescents influences all the aspects of their lives and thier performance. Objectives: The present study aimed to determine the performance of Iranian hemophilic adolescents in prevention of disease complications. Patients and Methods: In this descriptive-analytical study, 108 adolescents with hemophilia were selected through convenience sampling. Their performance in preventing the complications of hemophilia was evaluated by sending a semi-structured questionnaire to their addresses throughout Iran. Then, the data was analysed using the Statistical Package for Social Sciences (SPSS) software (v. 13) and descriptive and interferential statistics were used. Results: Overall, 32.1% of the participants controlled bleeding during the 1st hour. Inaccessibility of coagulation products was mainly responsible for inhibiting timely and proper bleeding control. In order to relieve bleeding associated pain, only 39.0% of the adolescents used analgesics. On the other hand, 19.8% of the subjects used nonpharmacological methods to relieve pain. The majority of the adolescents did not participate in sport activities (65.4%) others allocated less than 5 hours a week to physical activities (70.5%). In addition, the participants did not have favorable dietary patterns, exercise habits, and dental care. The results showed a significant relationship between the adolescents’ preventive practice with coagulation disorders and utilization of pharmacological pain relief methods. Also, significant relationships were found between severity of the disease; participating in physical activities, number of hours of physical activities; and disease complications. Conclusions: Iranian adolescents did not exhibit favorable practices towards complication prevention. PMID:26600702

  18. Treatment outcomes, quality of life, and impact of hemophilia on young adults (aged 18-30 years) with hemophilia.

    PubMed

    Witkop, Michelle; Guelcher, Christine; Forsyth, Angela; Hawk, Sarah; Curtis, Randall; Kelley, Laureen; Frick, Neil; Rice, Michelle; Rosu, Gabriela; Cooper, David L

    2015-12-01

    The Hemophilia Experiences, Results and Opportunities (HERO) initiative assessed psychosocial issues reported by people with moderate to severe hemophilia and was led by a multidisciplinary international advisory board. This analysis reports data from young adult respondents (aged 18-30 years), including both US and overall global (including US respondents) results, and investigates treatment outcomes, quality of life, and impacts of hemophilia on relationships. More young adults in HERO received prophylaxis than on-demand treatment, although a majority reported not using factor products exactly as prescribed, and 50% of global respondents and 26% of US respondents reported issues with access to factor replacement therapy in the previous 5 years. Many young adults with hemophilia reported comorbidities, including bone/skeletal arthritis, chronic pain, and viral infections, and nearly half of young adults reported anxiety/depression. Most reported pain interference with daily activities in the past 4 weeks, although a majority reported participating in lower-risk activities and approximately half in intermediate-risk activities. Most young adults were very or quite satisfied with the support of partners/spouses, family, and friends, although roughly one-third reported that hemophilia affected their ability to develop close relationships with a partner. A majority of young adults reported that hemophilia has had a negative impact on employment, and 62% of global respondents and 78% of US respondents were employed at least part-time. Together these data highlight the psychosocial issues experienced by young adults with hemophilia and suggest that increased focus on these issues may improve comprehensive care during the transition to adulthood. PMID:26619194

  19. Visuoperceptual sequelae in children with hemophilia and intracranial hemorrhage

    PubMed Central

    Matute, Esmeralda; O’Callaghan, Erin T.; Murray, Joan; Tlacuilo-Parra, Alberto

    2015-01-01

    Background The goal of this study was to examine the impact of focal brain injuries on the outcomes of visual perception and visuospatial abilities in Mexican children with hemophilia who have experienced intracranial hemorrhages. Methods We assessed ten boys who had hemophilia with intracranial hemorrhage (HIC), six boys who had hemophilia without intracranial hemorrhage (HH), and ten boys without hemophilia (CTL). The Verbal (VIQ), Performance IQs (PIQ), and Full Scale IQs (FSIQ) from the Wechsler Intelligence Scale for Children—Mexican Revision, Visual Perception, and Visuospatial Abilities domains, which are from a neuropsychological assessment battery for Spanish-speaking children (ENI), were employed for our analysis. Results The results showed that the HIC group performed in the low-average range on the PIQ and FSIQ, which was lower than the HH group. The HIC group showed low performance on visual perception tests, such as line orientation, fragmented objects, and overlapping figures, compared with their matched controls. Conclusions The results suggest that it is not the ability to recognize objects that is impaired in the HIC group, but the ability to identify objects under less favorable conditions. Our findings may have therapeutic and rehabilitative implications for the management of children with hemophilia and early focal brain lesions. PMID:26835360

  20. Longer-acting clotting factor concentrates for hemophilia.

    PubMed

    Powell, J S

    2015-06-01

    Hemophilia, when severe, leads to spontaneous life-threatening bleeding episodes. Current therapy requires frequent intravenous infusions. Most patients must limit their physical activities to avoid bleeding when the factor activity levels are below normal. In 2014, new therapeutic factor VIII and IX products were approved in Canada and the U.S. Over the next couple of years, other new factor products will likely be approved. These new factors have been engineered to have improved pharmacokinetic properties, including extended half-life in circulation, thus providing major therapeutic advances for patients with hemophilia. In the completed clinical trials, over 700 patients have successfully used these longer acting products regularly for more than one year. These promising new therapies should allow patients with hemophilia to use fewer infusions to prevent spontaneous bleeding or to treat bleeding episodes, and to provide appropriate clotting factor levels for different physical activities. PMID:26149018

  1. Acquired Hemophilia A Successfully Treated with Rituximab

    PubMed Central

    D’Arena, Giovanni; Grandone, Elvira; Di Minno, Matteo Nicola Dario; Musto, Pellegrino; Di Minno, Giovanni

    2015-01-01

    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. PMID:25745551

  2. Evolution of the Treatments for Hemophilia.

    PubMed

    Guelcher, Christine J

    2016-01-01

    Although hemophilia has been recognized for centuries as an inherited disorder primarily affecting males, advances in treatments have been very recent. Initial availability of plasma-derived therapies offered significant improvements in morbidity and mortality, but the transmission of viruses quickly negated the benefit of early factor replacement products. After developing successful viral inactivation methods and subsequently developing recombinant technology, the manufacturing of factor concentrates became much safer. Access to safer factor products allowed for a shift from the treatment of bleeds to prevention, called prophylaxis. Although dosing and interval vary, prevention of joint disease is now a realistic goal. Unfortunately, despite advances in the safety of therapy, some patients are unable to use factor replacement products because they develop antibodies, known as inhibitors. Eradication of inhibitors is possible in the majority of patients, but it is expensive and takes time. Management of acute bleeding may require significantly higher doses of factor replacement or the use of a bypassing agent. As a result, patients with inhibitors are at increased risk for sequelae, including joint disease, life-threatening bleeding, infectious complications with central vascular access devices, and thrombotic complications. PMID:27379680

  3. Surgery-associated acquired hemophilia A.

    PubMed

    Theodossiades, G; Tsevrenis, V; Nomikou, E; Dadiotis, L; Kontopoulou-Griva, I

    2001-11-01

    We present two patients who acquired factor VIII antibodies in the immediate postoperative period. One patient was receiving warfarin that was temporarily discontinued but reintroduced after the procedure. Preoperatively, none gave a history of bleeding, even with past surgeries, and both had normal coagulation tests. Within days of surgery, hemorrhage with prolonged activated partial thromboplastin time, low factor VIII levels, and demonstrable factor VIII antibodies were observed. For the patient who was receiving warfarin the severe bleeding was attributed, at the beginning, only to the high international normalized ratio (INR), which resulted in a fatal delay in diagnosis and appropriate treatment. We would like to raise awareness of surgery as a precipitating cause of acquired hemophilia, which is something to be considered with unusual postoperative bleeding. This syndrome is remarkable for its abrupt onset within days of surgery, severe bleeding but potential successful outcome with combined hemostatic control with recombinant activated FVII (rFVIIa) and elimination of the antibody by immunosuppression. PMID:11757731

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

    PubMed

    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. PMID:27131224

  5. Physical and psychosocial challenges in adult hemophilia patients with inhibitors

    PubMed Central

    duTreil, Sue

    2014-01-01

    Numerous challenges confront adult hemophilia patients with inhibitors, including difficulty in controlling bleeding episodes, deterioration of joints, arthritic pain, physical disability, emotional turmoil, and social issues. High-intensity treatment regimens often used in the treatment of patients with inhibitors also impose significant scheduling, economic, and emotional demands on patients and their families or primary caregivers. A comprehensive multidisciplinary assessment of the physical, emotional, and social status of adult hemophilia patients with inhibitors is essential for the development of treatment strategies that can be individualized to address the complex needs of these patients. PMID:25093002

  6. Acquired hemophilia A in a patient with systemic lupus erythematosus.

    PubMed

    Ishikawa, T; Tsukamoto, N; Suto, M; Uchiumi, H; Mitsuhashi, H; Yokohama, A; Maesawa, A; Nojima, Y; Naruse, T

    2001-06-01

    A patient with systemic lupus erythematosus (SLE) developed acquired hemophilia A. The patient, a 24-year-old Japanese woman, was referred to our hospital because of uncontrollable bleeding following a tooth extraction. Laboratory examination revealed prolonged APTT (116 seconds), reduced factor VIII activity (2.8 %) and the presence of factor VIII inhibitor at a titer of 46.5 Bethesda units/ml. Transfusion of prothrombin complex concentrate and activated prothrombin complex concentrate followed by administration of prednisolone and cyclophosphamide successfully arrested bleeding and reduced the factor VIII inhibitor level. Acquired hemophilia A is a rare but lethal condition. Rapid diagnosis and introduction of adequate therapies are critical. PMID:11446683

  7. Patient and parent preferences for characteristics of prophylactic treatment in hemophilia

    PubMed Central

    Furlan, Roberto; Krishnan, Sangeeta; Vietri, Jeffrey

    2015-01-01

    Introduction New longer-acting factor products will potentially allow for less frequent infusion in prophylactic treatment of hemophilia. However, the role of administration frequency relative to other treatment attributes in determining preferences for prophylactic hemophilia treatment regimens is not well understood. Aim To identify the relative importance of frequency of administration, efficacy, and other treatment characteristics among candidates for prophylactic treatment for hemophilia A and B. Method An Internet survey was conducted among hemophilia patients and the parents of pediatric hemophilia patients in Australia, Canada, and the US. A monadic conjoint task was included in the survey, which varied frequency of administration (three, two, or one time per week for hemophilia A; twice weekly, weekly, or biweekly for hemophilia B), efficacy (no bleeding or breakthrough bleeding once every 4 months, 6 months, or 12 months), diluent volume (3 mL vs 2.5 mL for hemophilia A; 5 mL vs 3 mL for hemophilia B), vials per infusion (2 vs 1), reconstitution device (assembly required vs not), and manufacturer (established in hemophilia vs not). Respondents were asked their likelihood to switch from their current regimen to the presented treatment. Respondents were told to assume that other aspects of treatment, such as risk of inhibitor development, cost, and method of distribution, would remain the same. Results A total of 89 patients and/or parents of children with hemophilia A participated; another 32 were included in the exercise for hemophilia B. Relative importance was 47%, 24%, and 18% for frequency of administration, efficacy, and manufacturer, respectively, in hemophilia A; analogous values were 48%, 26%, and 21% in hemophilia B. The remaining attributes had little impact on preferences. Conclusion Patients who are candidates for prophylaxis and their caregivers indicate a preference for reduced frequency of administration and high efficacy, but preferences

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

    PubMed

    High, Katherine A; Anguela, Xavier M

    2016-04-15

    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

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

    ERIC Educational Resources Information Center

    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…

  10. Desmopressin in mild hemophilia A: indications, limitations, efficacy, and safety.

    PubMed

    Lethagen, Stefan

    2003-02-01

    Replacement therapy with blood products has long been the only available therapeutic option for patients with bleeding disorders. Plasma-derived cryoprecipitate and factor (F) VIII concentrates, which have been used for hemophilia A patients, involve the risk of transmitting blood-borne diseases. Both plasma-derived and recombinant FVIII concentrates are expensive, and there is a global shortage. The synthetic vasopressin analogue desmopressin acetate (1-deamino-[8-D-arginine]-vasopressin, DDAVP) increases plasma concentrations of coagulation FVIII and von Willebrand factor (vWF) two fold to six fold through endogenous release. The drug is an attractive therapeutic alternative because it carries no risk of transmission of infectious diseases. Desmopressin is today a widely used hemostatic agent not only in patients with mild hemophilia A or von Willebrand disease (vWD) but also in those with congenital or acquired platelet dysfunction. There is a long clinical experience with the drug because it has been used for prevention of bleedings in connection with invasive procedures and for treatment of bleedings since the mid-1970s. Not all hemophilia A patients can be treated. The clinical usefulness depends on the postdesmopressin plasma concentration of FVIII, which in turn depends on the patient's basal FVIII level. Therefore, a test dose is recommended in candidate patients. In general, only the mildest hemophilia A patients respond sufficiently. Optimal hemostatic effect is achieved with a dosage of 0.3 microg/kg given intravenously. An intranasal desmopressin spray is suitable for the home treatment. PMID:12640572

  11. Medicine betrayed: hemophilia patients and HIV in the US.

    PubMed

    Keshavjee, S; Weiser, S; Kleinman, A

    2001-10-01

    The contamination of blood products by HIV in the early 1980s resulted in thousands of deaths among people with hemophilia in the United States and elsewhere. In the US, industry, government, physicians, and advocacy groups were implicated in this tragedy. In response to pleas from members of the US hemophilia community, the Institute of Medicine (IOM) of the National Academy of Science convened a public hearing to identify the institutional determinants of the HIV/AIDS epidemic among US hemophilia patients. The resulting IOM Report (1995) established a narrative of the crisis and indicated necessary improvements to the management of the US blood supply. The Report, however, failed to address the hemophilia community's demands for accountability and retribution. In this paper we explore the moral and social dimensions of this tragedy through narrative analysis of the original testimonies of hemophilia sufferers, interviews with some patients and their families, and a re-examination of the text of the IOM Report itself. We examine the process by which this crisis was addressed--through the discourses of science and law--and how it was ultimately framed as a failure of management and oversight rather than a moral failure of the for-profit health-care system. Thus, while the Report and its aftermath demonstrate powerfully how testimonials of suffering can influence public policy, by not addressing what is at stake for the victims--failure to protect patients in an era of increasingly commodified health care--it led to an exculpatory solution that obfuscated the moral dimensions of suffering. PMID:11556777

  12. Thoracoscopic lobectomy in a lung cancer patient with severe hemophilia: A case report

    PubMed Central

    LIN, XING-YU; YANG, ZHI-GUANG; ZHANG, PENG; LIU, YUN-PENG; WANG, CHENG-XIANG; SHAO, GUO-GUANG

    2015-01-01

    Hemophilia is a hereditary disease with impaired blood coagulation due to a genetic deficiency of blood coagulation factors. Hemophilia often causes spontaneous life-threatening bleeding, so patients with hemophilia are often not suitable for any surgery that may cause iatrogenic bleeding and threaten the life of the patient. Therefore, surgery in lung cancer patients with hemophilia is extremely rare. The present study reported the case of a lung cancer patient with hemophilia who presented with a persistent cough. A mass was revealed by computed tomography and the patient underwent a successful thoracoscopic right lower lobectomy. The study discusses the patient's diagnosis and treatment options for hemophilia A and lung cancer, including indications for thoracoscopic lobectomy, pre-operative preparation and post-operative care, and other treatment options are discussed. The literature is also reviewed on this subject. PMID:26722282

  13. Men with severe hemophilia in the United States: birth cohort analysis of a large national database.

    PubMed

    Mazepa, Marshall A; Monahan, Paul E; Baker, Judith R; Riske, Brenda K; Soucie, J Michael

    2016-06-16

    The availability of longitudinal data collected prospectively from 1998 to 2011 at federally funded US hemophilia treatment centers provided an opportunity to construct a descriptive analysis of how outcomes of men with severe hemophilia have been altered by the incremental advances and setbacks in hemophilia care in the last 50 years in the United States. This surveillance collaboration with the US Centers for Disease Control and Prevention assembled the largest uniformly examined population with severe hemophilia (n = 4899 men with severe factor VIII and IX deficiency). To address the heterogeneity of this population, 4 successive birth cohorts, differentially affected by eras of hemophilia care, were examined separately in regard to demographics, complications of hemophilia and its treatment, and mortality. Severely affected men in each birth cohort were compared also with the corresponding mild hemophilia birth cohorts (n = 2587 men total) to control for outcomes that might be attributable to aging and environment independent of severely defective hemostasis. The analysis demonstrates improving access to standard of care therapy, correlating the proportion of men on prophylactic factor replacement and reduced bleeding frequency for the youngest men. Frequent bleeding persisted in one third to one half of men across all ages, however, and the disability gap between severe and mild hemophilia did not narrow. The greatest cause of death was liver failure, but attempted anti-hepatitis C virus therapy and cure were low. The study suggests a continued need for national surveillance to monitor and inform hemophilia interventions and outcomes. PMID:26983851

  14. Men with severe hemophilia in the United States: birth cohort analysis of a large national database

    PubMed Central

    Mazepa, Marshall A.; Baker, Judith R.; Riske, Brenda K.; Soucie, J. Michael

    2016-01-01

    The availability of longitudinal data collected prospectively from 1998 to 2011 at federally funded US hemophilia treatment centers provided an opportunity to construct a descriptive analysis of how outcomes of men with severe hemophilia have been altered by the incremental advances and setbacks in hemophilia care in the last 50 years in the United States. This surveillance collaboration with the US Centers for Disease Control and Prevention assembled the largest uniformly examined population with severe hemophilia (n = 4899 men with severe factor VIII and IX deficiency). To address the heterogeneity of this population, 4 successive birth cohorts, differentially affected by eras of hemophilia care, were examined separately in regard to demographics, complications of hemophilia and its treatment, and mortality. Severely affected men in each birth cohort were compared also with the corresponding mild hemophilia birth cohorts (n = 2587 men total) to control for outcomes that might be attributable to aging and environment independent of severely defective hemostasis. The analysis demonstrates improving access to standard of care therapy, correlating the proportion of men on prophylactic factor replacement and reduced bleeding frequency for the youngest men. Frequent bleeding persisted in one third to one half of men across all ages, however, and the disability gap between severe and mild hemophilia did not narrow. The greatest cause of death was liver failure, but attempted anti–hepatitis C virus therapy and cure were low. The study suggests a continued need for national surveillance to monitor and inform hemophilia interventions and outcomes. PMID:26983851

  15. Rheumatological management of patients with hemophilia. Part 1: joint manifestations.

    PubMed

    Alcalay, Michel; Deplas, Adeline

    2002-10-01

    The advent of factor VIII and IX replacement therapy has radically changed the physiognomy of hemophilia. In patients with no inhibitors, early replacement therapy shortens the immobilization and decreases the structural and functional alterations related to recurrent hemarthrosis. Routine prophylactic replacement therapy before or after the first episode of hemarthrosis is still rarely used in France. Recurrent hemarthrosis in the same joint can cause synovitis and chronic arthropathy. Injection synovectomy is now the preferred treatment, as opposed to secondary prophylactic replacement therapy and to arthroscopic or open synovectomy. The palliative treatment of chronic arthropathy is difficult and rests on analgesics and rehabilitation therapy, with orthotic devices and/or surgery where appropriate. The treatment of hemophilia is far more difficult in patients with inhibitors and, consequently, considerable hope is being placed in gene therapy, whose first results are encouraging. PMID:12477227

  16. Acquired hemophilia complicated by cardiorenal syndrome type 3

    PubMed Central

    Sharma, Rakesh; Dash, Sananta Kumar; Chawla, Rajesh; Kansal, Sudha; Agrawal, Devender Kumar; Dua, Harsh

    2013-01-01

    Development of autoantibodies against coagulation factor VIII (FVIII) leads to a rare condition defined as acquired hemophilia (AH). If not diagnosed and treated early, AH may be associated with high mortality and morbidity. A 65-year-old woman presented with history of macrohematuria, acute renal failure, cardiogenic shock, and acute respiratory failure. Blood investigation revealed azotemia, prolonged activated partial thromboplastin time (aPTT), coagulation FVIII level of <1%, and presence of FVIII inhibitor. Echocardiography showed global hypokinesia and ultrasonography and computed tomography (CT) revealed bilateral hydroureteronephrosis. The final diagnosis was acquired hemophilia A, complicated by acute obstructive renal failure and cardiorenal syndrome (CRS) type 3. Patient was managed with mechanical ventilation, heparin-free hemodialysis, negative fluid balance, recombinant activated factor VII, and prednisolone. Hematuria was relieved, renal function improved, and cardiac function showed improvement on repeat echocardiography. Patient was discharged on prednisolone with subsequent follow ups. PMID:24501492

  17. Clinical profile of hemophilia patients in Jodhpur Region

    PubMed Central

    Payal, Vikas; Sharma, Pramod; Goyal, Vishnu; Jora, Rakesh; Parakh, Manish; Payal, Deepika

    2016-01-01

    Background: Hemophilia is widely distributed all over the world, but little is known about its clinical profile in resource-limited regions. An insight into its clinical spectrum will help in the formulation of policies to improve the situation in these areas. Aims: To study the clinical profile of hemophiliacs (age <18 years) in Jodhpur region and screen them for transfusion-transmitted infections. Materials and Methods: A cross-sectional study conducted in the Department of Pediatrics, Umaid Hospital, Dr. S. N. Medical College, Jodhpur, over a period of 12 months. Result: Out of a total of 56 cases enrolled, 51 (91%) cases were diagnosed as hemophilia A while 5 (9%) were diagnosed as hemophilia B. Positive family history was found in 26 (46%) cases. According to their factor levels, 25 (44%) cases had severe disease, 20 (36%) had moderate disease, and 11 (20%) had mild disease. The mean age of onset of symptoms and diagnosis was 1.73 ± 1.43 and 3.87 ± 3.84 years, respectively. First clinical presentation was posttraumatic bleed in 20 (36%), gum bleeds in 17 (30%), epistaxis in 4 (7%), joint bleeds in 4 (7%), skin bleeds in 4 (7%), and circumcision bleed in 3 (5%) cases. Knee joint was the predominant joint affected by hemarthrosis in 38 (68%), followed by ankle in 29 (52%), elbow in 20 (36%), and hip joint in 7 (13%) cases. All patients had a negative screening test for transfusion-transmitted infections. Conclusion: Occurrence of posttraumatic bleeds and gum bleeds in an otherwise normal child should warn the clinician for evaluation of hemophilia. PMID:27011682

  18. Acquired hemophilia A: A rare cause of gross hematuria

    PubMed Central

    Hosier, Gregory W.; Mason, Ross J.; Sue Robinson, K.; Bailly, Gregory G.

    2015-01-01

    Acquired hemophilia A is a rare condition caused by spontaneous development of factor VIII inhibitor. This condition most commonly presents with multiple hemorrhagic symptoms and isolated hematuria is exceedingly rare. Early diagnosis is important, as this condition carries a high mortality rate (13–22%). We present a case of an 82-year-old man with isolated hematuria caused by a factor VIII inhibitor who was successfully treated with recombinant activated factor VII concentrate, as well as prednisone and cyclophosphamide. PMID:26834904

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

    PubMed Central

    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

  20. Hemophilia A in Brazil – epidemiology and treatment developments

    PubMed Central

    Ferreira, Adriana Aparecida; Leite, Isabel Cristina Gonçalves; Bustamante-Teixeira, Maria Teresa; Guerra, Maximiliano Ribeiro

    2014-01-01

    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 inequalities, the Ministry of Health has made significant advances in the treatment of hemophilia A. The gradual increase in importation of factor VIII concentrate enabled the implementation of primary and secondary modalities of prophylaxis, in addition to the induction of immune tolerance. There are also plans to set up a factory in the

  1. Genome-editing technologies for gene correction of hemophilia.

    PubMed

    Park, Chul-Yong; Lee, Dongjin R; Sung, Jin Jea; Kim, Dong-Wook

    2016-09-01

    Hemophilia is caused by various mutations in blood coagulation factor genes, including factor VIII (FVIII) and factor IX (FIX), that encode key proteins in the blood clotting pathway. Although the addition of therapeutic genes or infusion of clotting factors may be used to remedy hemophilia's symptoms, no permanent cure for the disease exists. Moreover, patients often develop neutralizing antibodies or experience adverse effects that limit the therapy's benefits. However, targeted gene therapy involving the precise correction of these mutated genes at the genome level using programmable nucleases is a promising strategy. These nucleases can induce double-strand breaks (DSBs) on genomes, and repairs of such induced DSBs by the two cellular repair systems enable a targeted gene correction. Going beyond cultured cell systems, we are now entering the age of direct gene correction in vivo using various delivery tools. Here, we describe the current status of in vivo and ex vivo genome-editing technology related to potential hemophilia gene correction and the prominent issues surrounding its application in patients with monogenic diseases. PMID:27357631

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

    PubMed Central

    Chaugule, Shraddha S; Hay, Joel W; Young, Guy

    2015-01-01

    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 from thrice-weekly to once-weekly prophylaxis therapy. Conclusion Improvements in treatment effectiveness and dosing frequency, treatment side effects, and out-of-pocket costs per month were the greatest determinants of hemophilia treatment choice and WTP. The positive preferences and WTP for longer acting

  3. Understanding cardiovascular risk in hemophilia: A step towards prevention and management.

    PubMed

    Sousos, Nikolaos; Gavriilaki, Eleni; Vakalopoulou, Sofia; Garipidou, Vasileia

    2016-04-01

    Advances in hemophilia care have led to increased life expectancy and new challenges in the management of the aging hemophilia population, including cardiovascular risk. Despite the deep knowledge into cardiovascular disease in terms of pathophysiology, risk prediction, prevention, early detection and management gained over the last decades, studies in hemophiliacs are scarce and mainly descriptive. As a growing amount of evidence points towards a similar or increased prevalence of traditional cardiovascular risk factors in hemophilia compared to the general population, the role of non-traditional, disease-related and treatment-related cardiovascular risk factors remains under investigation. Better understanding of cardiovascular risk in hemophilia is mandatory for proper cardiovascular risk prevention and management. Therefore, this review aims to summarize current knowledge on cardiovascular risk in hemophilia patients focusing on a) cardiovascular risk factors (traditional, non-traditional, disease-related and treatment-related), b) cardiovascular morbidity and mortality and c) cardiovascular prevention and management. PMID:27046799

  4. Inhibitors in childhood hemophilia A: genetic and treatment-related risk factors for development and eradication.

    PubMed

    DiMichele, Donna M

    2013-01-01

    The development of neutralizing antibodies remains a serious complication of hemophilia replacement therapy. Factor VIII inhibiting antibodies (inhibitors) occur commonly following replacement therapy in hemophilia A, creating a significant burden of clinical disease. This article will review our current understanding of risk factors and their known impact on inhibitor development in previously untreated or minimally treated children with severe and mild hemophilia A. It will also explore how the most recently elucidated immunology of inhibitor development might hold important clues to more effective inhibitor eradication and prevention in this heavily impacted patient population. PMID:23109404

  5. Management of Pregnancy in a Patient with Severe Hemophilia Type A

    PubMed Central

    Sharma, Vipra; Khalid, Aysha; Cohen, Alice J.

    2012-01-01

    Hemophilia type A is a rare inherited bleeding disorder with a diversity of clinical manifestations ranging from persistent bleeding after minor trauma, spontaneous deep muscle or joint hemorrhage, to intracranial hemorrhage. As an X-linked disorder, hemophilia is rare in females and therefore there is little experience with pregnancy and no standardized guidelines to prevent bleeding antepartum, at delivery, and postpartum. We report the clinical course and management of a woman with severe hemophilia A who on two occasions had uncomplicated pregnancies and vaginal deliveries at term utilizing bolus recombinant factor VIII concentrate. PMID:23943706

  6. Barriers and perceived limitations to early treatment of hemophilia

    PubMed Central

    Saxena, Kapil

    2013-01-01

    Early treatment of bleeds in hemophilia patients, both with and without inhibitors, has been shown to be of immense benefit in the overall clinical outcome. Despite the advantages of treating the bleeding episodes early, significant barriers and limitations remain. The aim of this review is to highlight the various barriers and perceived limitations to early therapy of bleeding episodes, especially in patients who have developed inhibitors to factor VIII. The peer-reviewed literature was searched for articles on hemophilia patients, with and without inhibitors, and early treatment, to identify the barriers to early treatment and potential impact on patient outcomes. The most important barrier is the educational barrier, which involves lack of awareness among patients regarding the signs of a bleed, as well as importance of early therapy. It is also common for parents or caregivers of school-age children to exhibit inconvenience and scheduling barriers. Distance to the treatment center can also play a role here. Some patients experience financial barriers related to cost of clotting factor products, insurance coverage, or insurance caps and out-of-pocket costs. Rarely, there can also be problems related to venous access or home infusion. Lastly, multiple psychosocial barriers can prevent adherence to treatment regimens. Identification and addressing these individual barriers will result in improved compliance rates, prevent joint damage, be more cost-effective, and lead to better overall health of these patients. PMID:23700376

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

    PubMed Central

    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. PMID:24741588

  8. Obstacles and future of gene therapy for hemophilia

    PubMed Central

    Arruda, Valder R; Samelson-Jones, Ben J

    2015-01-01

    Introduction The recent success of early-phase clinical trials for adeno-associated viral (AAV) liver-directed gene therapy for hemophilia B (HB) demonstrates the potential for gene therapy, in the future, to succeed protein-based prophylaxis therapy for HB. Significant obstacles, however, need to be overcome prior to widespread adoption. The largest obstacles include immune responses to the AAV capsid including preexisting neutralizing antibodies (NAbs) and a delayed cellular immune response. Emerging evidence suggests that the latter is vector-dose dependent. Furthermore, the development and eradication of inhibitors remains a significant safety concern. Similarly, biological differences between Factor VIII and Factor IX (FIX) impose challenges to direct adoption of the successes for HB to hemophilia A (HA). Areas covered The advantages and limitations of the current strategies addressing these obstacles for gene therapy for HB and HA are discussed, as well as vector manufacturing issues relevant to widespread adoption. Alternative strategies including both ex-vivo and in-vivo lentiviral-based methods are discussed, though we focus on AAV-based approaches because of their recent clinical success and potential. Expert opinion Our opinion is that these obstacles can be overcome with current approaches, and AAV-based gene therapy for HB will likely translate into future clinical care. Innovative approaches are, however, likely needed to solve the current problems obstructing HA gene therapy. PMID:26900534

  9. Brain abnormalities in male children and adolescents with hemophilia: detection with MR imaging. The Hemophilia Growth and Development Study Group.

    PubMed

    Wilson, D A; Nelson, M D; Fenstermacher, M J; Bohan, T P; Hopper, K D; Tilton, A; Mitchell, W G; Contant, C F; Maeder, M A; Donfield, S M

    1992-11-01

    Cranial magnetic resonance (MR) imaging was performed in 124 male patients (aged 7-19 years), from 14 institutions, in whom a diagnosis of moderate to severe hemophilia was made. Blood tests in all subjects were negative for human immunodeficiency virus. Findings in MR studies were abnormal in 25 (20.2%) subjects. Six lesions in five subjects were classified as congenital. The most commonly identified congenital lesion was a posterior fossa collection of cerebrospinal fluid (five cases). Twenty-two subjects had acquired lesions that were probably related to the hemophilia or its treatment. The most commonly acquired lesions were single- or multifocal areas of high signal intensity within the white matter on T2-weighted images noted in 14 (11.3%) subjects. Two subjects had large focal areas of brain atrophy, and six had some degree of diffuse cerebral cortical atrophy. Three subjects (2.4%) had hemorrhagic lesions. To the authors' knowledge, the unexpected finding of small, focal, nonhemorrhagic white matter lesions has not previously been reported. PMID:1410372

  10. Bilateral recurrent external obturator muscle hematoma: An unusual cause of pelvic pain in hemophilia

    PubMed Central

    ARPACI, TANER; SASMAZ, ILGEN; AKBAS, TUGANA; EKEN, ALPER; OZGUR, ANIL; ANTMEN, BULENT

    2016-01-01

    Following joint hemorrhages, intramuscular hemorrhages are the second most prevalent bleeding pattern in hemophiliac patients. Hematomas of the iliopsoas muscle are a well-known complication of hemophilia; however, obturator muscle hematomas are rare. We herein report a case of spontaneous bleeding of the bilateral external obturator muscles, which occured three times within a period of 9 months in a hemophilia patient with factor VIII inhibitors. To the best of our knowledge, this is the first published case of an obturator externus muscle hematoma in hemophilia. In addition to hip hemarthrosis, iliopsoas hematomas and acute appendicitis, obturator muscle hematoma should be considered as one of the diagnostic alternatives for pelvic pain in hemophiliaψ patients. Magnetic resonance imaging enables rapid diagnosis of obturator muscle hematoma. PMID:27073678

  11. Is executive function intact after pediatric intracranial hemorrhage? A sample of Mexican children with hemophilia.

    PubMed

    Morales, Guadalupe; Matute, Esmeralda; Murray, Joan; Hardy, David J; O'Callaghan, Erin T; Tlacuilo-Parra, Alberto

    2013-10-01

    The goal of this study was to examine executive functioning outcomes in children with hemophilia who have suffered intracranial hemorrhage. We assessed 10 boys with hemophilia with intracranial hemorrhage; 6 boys with hemophilia without intracranial hemorrhage; and 10 healthy boys as controls. Intellectual functioning was assessed with subscales from the Wechsler Intelligence Scale for Children-Mexican Revision. Concept formation and reasoning, cognitive flexibility, and planning and organization domains from a neuropsychological assessment battery for Spanish-speaking children were employed for our analysis. Results indicated that children with intracranial hemorrhage demonstrated significant impairment on some measures of executive function compared with the control groups. All differences reflected poorer performance by the intracranial hemorrhage group. These results may reflect the impact of disruption to immature brain circuits and the deficiency of functional specificity within the immature brain. This is the only known study examining neuropsychological functioning in Mexican youth with hemophilia. PMID:23872342

  12. Young adults with hemophilia in the U.S.: demographics, comorbidities, and health status.

    PubMed

    Curtis, Randall; Baker, Judith; Riske, Brenda; Ullman, Megan; Niu, Xiaoli; Norton, Kristi; Lou, Mimi; Nichol, Michael B

    2015-12-01

    Improvements in hemophilia care over the last several decades might lead to expectations of a near-normal quality of life for young adults with hemophilia. However, few published reports specifically examine health status indicators in this population. To remedy this knowledge gap, we examined the impact of hemophilia on physical and social functioning and quality of life among a national US cohort of 141 young men with hemophilia aged 18-34 years of age who received care at 10 geographically diverse, federally funded hemophilia treatment centers in 11 states between 2005 and 2013 and enrolled in the Hemophilia Utilization Group Studies. Indicators studied included educational achievement, employment status, insurance, health-related quality of life, and prevalence of the following comorbidities: pain, range of motion limitation, overweight/obesity, and viral status. The cohort was analyzed to compare those aged 18-24 to those aged 25-34 years. When compared to the general US adult population, this nationally representative cohort of young US adults with hemophilia experienced significant health and social burdens: more liver disease, joint damage, joint pain, and unemployment as well as lower high-school graduation rates. Nearly half were overweight or obese. Conversely, this cohort had higher levels of health insurance and equivalent mental health scores. While attention has typically focused on newborns, children, adolescents, and increasingly, on older persons with hemophilia, our findings suggest that a specific focus on young adults is warranted to determine the most effective interventions to improve health and functioning for this apparently vulnerable age group. PMID:26619192

  13. Unmet needs in the transition to adulthood: 18- to 30-year-old people with hemophilia.

    PubMed

    Quon, Doris; Reding, Mark; Guelcher, Chris; Peltier, Skye; Witkop, Michelle; Cutter, Susan; Buranahirun, Cathy; Molter, Don; Frey, Mary Jane; Forsyth, Angela; Tran, Duc Bobby; Curtis, Randall; Hiura, Grant; Levesque, Justin; de la Riva, Debbie; Compton, Matthew; Iyer, Neeraj N; Holot, Natalia; Cooper, David L

    2015-12-01

    Young adults with hemophilia face unique challenges during the transition to adulthood, including issues associated with switching from pediatric to adult hematology care, building mature interpersonal relationships, and establishing an independent career with an assurance of medical insurance coverage. A greater understanding of these challenges is essential for developing effective strategies to address the specific needs of this population. These challenges may be differentiated from those of older adults with hemophilia in large part because of more extensive childhood prophylaxis and safer factor products, resulting in fewer joint problems and lower rates of HIV and HCV infections. This analysis of the changing nature and unmet needs of today's young adults entering into adult hemophilia treatment centers, as well as potential strategies for optimally addressing these needs, was developed following roundtable discussions between patients, caregivers, hematologists, and other health care professionals participating in comprehensive care. Challenges identified among young adults with hemophilia include psychosocial issues related to maturity, personal responsibility, and increased independence, as well as concerns regarding when and with whom to share information about one's hemophilia, limited awareness of educational and financial resources, and a low perceived value of regular hematology care. The initiatives proposed herein highlight important opportunities for health care professionals at pediatric and adult hemophilia treatment centers, as well as national organizations, community groups, and career counselors, to address key unmet needs of this patient population. PMID:26619193

  14. Labeled factor IX kinetics in patients with hemophilia-B

    SciTech Connect

    Smith, K.J.; Thompson, A.R.

    1981-09-01

    Labeled factor IX was infused five time into four patients with hemophilia-B. Ten-minute plasma recovery average 35% (SD +/- 2) and the mean T 1/2 beta-phase elimination was 23 hr (+/- 5). No alteration in the postinfusion 125I-factor-IX could be detected by radioautography of plasma samples run on polyacrylamide gels or on crossed-immunoelectrophoresis. Label was excreted into the urine as free 125I-iodide. Kinetics were similar when the labeled preparation was infused alone or with a commercial concentrate containing unlabeled factor IX. Infusion of factor IX in man is best described by a two-compartment open pharmacokinetic model where factor IX is distributed in a space larger than the plasma volume.

  15. Joint Function and Arthropathy Severity in Patients with Hemophilia

    PubMed Central

    Goto, Miwa; Takedani, Hideyuki; Nitta, Osamu; Kawama, Kennosuke

    2015-01-01

    Background: The Arnold-Hilgartner classification is one of the most popular evaluation systems for the progression hemophilic arthropathy. A previous study reported an association between arthropathy severity and arc range of motion (ROM). However, associations between arthropathy severity and angular ROM and muscle strength remain unclear. AIM: The purpose of this study was to clarify the association between joint function and arthropathy severity in hemophilia. Methods: We studied the knee, ankle, and elbow joints of 31 patients with hemophilia (PWH). The condition of the affected joints was evaluated on the basis of the interview data, joint function measurements, and roentgenography of the affected joints. In assessment of joint function, we evaluated knee strength (flexor, extensor) and grip strength as well as the passive ROM of the elbow, knee, and ankle. During the interview, all patients were asked about the history of intra-articular bleeding over the past year and pain. Results: As arthropathy severity worsened, knee flexor strength, knee extensor strength, grip strength, and ROM (elbow flexion, elbow extension, knee flexion, knee extension, and ankle extension) significantly decreased. Even patients with mild arthropathies experienced knee extensor weakness and extension limitation. In addition, joint function of severe ankle arthropathy was significantly related to the history of intra-articular bleeding and pain. Conclusion: Our results suggest that physical therapy is necessary to improve joint function in PWH and mild or no arthropathy. Pain control and prophylactic hematological management are necessary for patients with severe arthropathy because intra-articular bleeding and pain significantly decrease joint function. PMID:26733762

  16. Protein Replacement Therapy and Gene Transfer in Canine Models of Hemophilia A, Hemophilia B, von Willebrand Disease, and Factor VII Deficiency

    PubMed Central

    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.

    2011-01-01

    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. PMID:19293459

  17. Economic costs of hemophilia and the impact of prophylactic treatment on patient management.

    PubMed

    Chen, Sheh-Li

    2016-04-01

    Hemophilia is a rare congenital bleeding disorder characterized by spontaneous and potentially life-threatening bleeding episodes. In addition to its clinical burden on the patient, the condition also places a significant economic burden on healthcare payers, patients/caregivers, and society. Hemophilia is associated with staggering direct costs from hospitalizations, outpatient visits, and drug treatments, as well as high indirect costs from diminished work productivity and absenteeism from work and school. Additionally, hemophilia incurs tremendous intangible costs, including reduced quality of life, pain and suffering, and the emotional and physical toll on the patient and caregivers. The evolution of treatment patterns in hemophilia has transformed the once-fatal disease into a chronic but potentially well-managed condition through the use of prophylaxis treatment. However, other complications, such as development of inhibitory antibodies, have added to the complexity of managing the disease and its costs. To ensure optimal treatment outcomes and disease management, there is a critical need to understand the utilization of healthcare resources in the treatment of hemophilia and to educate patients on the importance of treatment adherence and compliance to reduce long-term effects on musculoskeletal health. PMID:27266809

  18. The World Federation of Hemophilia: 40 years of improving haemophilia care worldwide.

    PubMed

    Jones, Peter; Robillard, Line

    2003-11-01

    In 2003, the World Federation of Hemophilia marks its 40th anniversary. Established in 1963 by Frank Schnabel, a person with hemophilia from Montreal, Canada, the WFH has grown into its role as an independent, not-for-profit representative of the global haemophilia community. Since then, its biannual world congresses have provided an opportunity to exchange information on research and treatment. Today, more than 3,000 delegates attend these congresses. Until the early 1990s, the WFH's other major function was the International Hemophilia Training Centre programme, offering training fellowships and workshops to medical and paramedical staff from developing countries. In 1982, AIDS was reported in people with haemophilia who had received tainted blood products. The WFH developed task forces and committees to monitor safety and supply issues and set up the Global Forum on the Safety and Supply of Treatment Products. In the mid-1990s, twinning programmes were established for treatment centres and national haemophilia organizations. Twinning facilitates the exchange of training, coaching, and expertise. In the late 1990s, the WFH expanded and began working with local organizations and health authorities in a number of countries to improve the diagnosis and care of persons with hemophilia. The federation currently has ongoing projects in 25 developing countries. On World Hemophilia Day, April 17, 2003, the WFH launched the Global Alliance for Progress (GAP) in haemophilia which aims to double the number of people with haemophilia diagnosed and receiving treatment in up to 40 developing countries over a 10-year period. PMID:14750930

  19. Treatment of hemophilia: a review of current advances and ongoing issues

    PubMed Central

    Coppola, Antonio; Di Capua, Mirko; Di Minno, Matteo Nicola Dario; Di Palo, Mariagiovanna; Marrone, Emiliana; Ieranò, Paola; Arturo, Claudia; Tufano, Antonella; Cerbone, Anna Maria

    2010-01-01

    Replacement of the congenitally deficient factor VIII or IX through plasma-derived or recombinant concentrates is the mainstay of treatment for hemophilia. Concentrate infusions when hemorrhages occur typically in joint and muscles (on-demand treatment) is able to resolve bleeding, but does not prevent the progressive joint deterioration leading to crippling hemophilic arthropathy. Therefore, primary prophylaxis, ie, regular infusion of concentrates started after the first joint bleed and/or before the age of two years, is now recognized as first-line treatment in children with severe hemophilia. Secondary prophylaxis, whenever started, aims to avoid (or delay) the progression of arthropathy and improve patient quality of life. Interestingly, recent data suggest a role for early prophylaxis also in preventing development of inhibitors, the most serious complication of treatment in hemophilia, in which multiple genetic and environmental factors may be involved. Treatment of bleeds in patients with inhibitors requires bypassing agents (activated prothrombin complex concentrates, recombinant factor VIIa). However, eradication of inhibitors by induction of immune tolerance should be the first choice for patients with recent onset inhibitors. The wide availability of safe factor concentrates and programs for comprehensive care has now resulted in highly satisfactory treatment of hemophilia patients in developed countries. Unfortunately, this is not true for more than two-thirds of persons with hemophilia, who live in developing countries. PMID:22282697

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

    PubMed Central

    Pollpeter, Molly J.

    2016-01-01

    Background 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. Objective To investigate the survival and lethal bleeding frequency in two strains of E-16 hemophilia A mice. Methods 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. Results and Conclusions 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. PMID:27144769

  1. Profile of efraloctocog alfa and its potential in the treatment of hemophilia A

    PubMed Central

    George, Lindsey A; Camire, Rodney M

    2015-01-01

    Hemophilia care has improved dramatically over the past 50 years, evolving from plasma concentrates, to purified plasma proteins, to recombinant clotting factors. These collective developments allowed for home delivery of on-demand and prophylactic treatment, resulting in the reduction of hemophilia morbidity and mortality and improved quality of life. Although efficacious in treating bleeding, conventional factor products’ half-lives require frequent venipuncture, which remains a significant burden to patients. Despite the remarkable advances in hemophilia care, no improvements have, until now, been made to the pharmacokinetic properties of factor products. Multiple strategies have more recently been employed to generate novel bioengineered products that, with great hope, represent the next wave of progress in hemophilia care. The use of these products will undoubtedly raise important discussion about choosing conventional factor over new long-acting factor products. Incorporation of these therapies into clinical care is accompanied by unanswered safety questions that will likely be evaluated only in postmarketing surveillance analysis. Further, these products may change current treatment paradigms with unclear cost repercussions and feasibility. This paper will review efraloctocog alfa (FVIII-Fc) and its role in the treatment of hemophilia A. PMID:25977610

  2. Acquired immunodeficiency syndrome among patients attending hemophilia treatment centers and mortality experience of hemophiliacs in the United States.

    PubMed

    Johnson, R E; Lawrence, D N; Evatt, B L; Bregman, D J; Zyla, L D; Curran, J W; Aledort, L M; Eyster, M E; Brownstein, A P; Carman, C J

    1985-06-01

    The acquired immunodeficiency syndrome (AIDS) was first recognized among hemophiliacs in 1982. The authors have conducted investigations to determine the onset and incidence of AIDS among hemophiliacs and to determine trends in hemophilia mortality since the introduction of clotting-factor concentrates in the late 1960s. A survey of United States hemophilia treatment centers, supported by the Centers for Disease Control and the National Hemophilia Foundation, defined a population of hemophiliacs which was monitored for AIDS cases through June 1984. Death reports from the United States Vital Statistics System and from the hemophilia treatment center survey provided mortality trends for 1968-1979 and for 1978-1982, respectively. The results of these investigations demonstrate the following points. 1) The AIDS epidemic is a new and important cause of illness and mortality among hemophiliacs, although a very low incidence of AIDS among hemophiliacs prior to 1982 cannot be ruled out. 2) The AIDS cases who attended the surveyed hemophilia treatment centers were distributed throughout the United States and were older than hemophilia treatment center patients without AIDS. AIDS cases also used more lyophilized clotting-factor concentrate, but only a small number of cases were reported with this information. 3) Improved care for hemophilia, including the use of clotting-factor concentrates, dramatically reduced hemophilia mortality rates during the 1970s. 4) In 1982, hemorrhage was the major cause of death among hemophiliacs. Deaths from non-alcoholic liver disease were also increased. AIDS incidence among hemophilia treatment center attendees was stable at 0.6 cases per 1,000 hemophilia treatment center attendees per year during 1982 and 1983 but increased sharply to 5.4 cases per 1,000 during the first quarter of 1984. PMID:4014173

  3. Estimates of utility weights in hemophilia: implications for cost-utility analysis of clotting factor prophylaxis

    PubMed Central

    Grosse, Scott D; Chaugule, Shraddha S; Hay, Joel W

    2015-01-01

    Estimates of preference-weighted health outcomes or health state utilities are needed to assess improvements in health in terms of quality-adjusted life-years. Gains in quality-adjusted life-years are used to assess the cost–effectiveness of prophylactic use of clotting factor compared with on-demand treatment among people with hemophilia, a congenital bleeding disorder. Published estimates of health utilities for people with hemophilia vary, contributing to uncertainty in the estimates of cost–effectiveness of prophylaxis. Challenges in estimating utility weights for the purpose of evaluating hemophilia treatment include selection bias in observational data, difficulty in adjusting for predictors of health-related quality of life and lack of preference-based data comparing adults with lifetime or primary prophylaxis versus no prophylaxis living within the same country and healthcare system. PMID:25585817

  4. In Vivo Gene Therapy of Hemophilia B: Sustained Partial Correction in Factor IX-Deficient Dogs

    NASA Astrophysics Data System (ADS)

    Kay, Mark A.; Rothenberg, Steven; Landen, Charles N.; Bellinger, Dwight A.; Leland, Frances; Toman, Carol; Finegold, Milton; Thompson, Arthur R.; Read, M. S.; Brinkhous, Kenneth M.; Woo, Savio L. C.

    1993-10-01

    The liver represents a model organ for gene therapy. A method has been developed for hepatic gene transfer in vivo by the direct infusion of recombinant retroviral vectors into the portal vasculature, which results in the persistent expression of exogenous genes. To determine if these technologies are applicable for the treatment of hemophilia B patients, preclinical efficacy studies were done in a hemophilia B dog model. When the canine factor IX complementary DNA was transduced directly into the hepatocytes of affected dogs in vivo, the animals constitutively expressed low levels of canine factor IX for more than 5 months. Persistent expression of the clotting. factor resulted in reductions of whole blood clotting and partial thromboplastin times of the treated animals. Thus, long-term treatment of hemophilia B patients may be feasible by direct hepatic gene therapy in vivo.

  5. Abnormal coagulation factor VIII transcript in a Tennessee Walking Horse colt with hemophilia A.

    PubMed

    Norton, Elaine M; Wooldridge, Anne A; Stewart, Allison J; Cusimano, Layla; Schwartz, Dean D; Johnson, Calvin M; Boudreaux, Mary K; Christopherson, Pete W

    2016-03-01

    Hemophilia A is an X-chromosome-linked disorder caused by a deficiency in factor VIII (FVIII). Although foals have been diagnosed with hemophilia A based on deficiency in FVIII activity, causative gene mutations have not been identified. The genomic DNA and cDNA encoding FVIII of a Tennesee Walking Horse colt affected with hemophilia A and the genomic DNA of his dam and a normal unrelated horse were analyzed with no splice site or coding sequence abnormalities identified in any of the horses. Polymerase chain reactions (PCR) were then performed on hepatic cDNA from the affected colt and an unrelated normal horse, and no product was obtained for the sequence between and including exon 1 and exon 2 in the affected colt. Based on these results, suspected mutations were identified in the noncoding region of FVIII (intron 1), and genomic sequencing of intron 1 in the dam and the affected colt suggested maternal inheritance. PMID:26765501

  6. Cognitive and psychological profiles in treatment compliance: a study in an elderly population with hemophilia

    PubMed Central

    Riva, Silvia; Nobili, Alessandro; Djade, Codjo D; Mancuso, Maria Elisa; Santagostino, Elena; Pravettoni, Gabriella

    2015-01-01

    Elderly patients with hemophilia have to face new challenges linked to concomitant pathologies and concurrent use of different treatments. In order to promote optimal care in the elderly hemophilia population, this study is aimed to analyze treatment compliance in relation to the presence of comorbidities and the role of potential determinants that can affect compliance (positively or negatively), including health-related quality of life, cognitive decline, and sociodemographic parameters (eg, living situation, partnership, presence of caregivers). This will be an observational study of elderly patients with hemophilia (aged >60 years). Patients will be interviewed during their routine medical visits. The data interview will pertaining to several dimension of treatment management. This study will detect more vulnerable patients with special care needs and will highlight psychological factors that should be considered for future psychosocial interventions. PMID:26185433

  7. Immune tolerance induction for patients with severe hemophilia A: a critical literature review.

    PubMed

    Franchini, Massimo; Lippi, Giuseppe

    2011-11-01

    The development of inhibitors that neutralize the function of clotting factor VIII (FVIII) is currently the most challenging complication associated with the treatment of hemophilia A as it increases the disease-related morbidity and mortality. Immune tolerance induction (ITI) is the only documented strategy to eradicate persistent inhibitors in severe hemophilia A patients. Several studies have been conducted so far to identify patient- and treatment-related factors associated with greater ITI success. The currently available literature on ITI in hemophilia A will be critically reviewed in this article. In particular, we will focus on the role of the type of FVIII product on ITI outcome by analyzing the clinical and experimental data. PMID:21818664

  8. Use of factor IX concentrates in active teenagers with hemophilia B.

    PubMed

    Tagariello, Giuseppe

    2004-06-01

    This paper addresses issues specific to the treatment of teenagers with hemophilia B. All teenagers, including those with hemophilia, are at high risk of being exposed to accident-related trauma because of activities inherent within normal adolescent development. To reduce the impact of recurrent joint bleeds, studies have shown that prophylaxis should be started at an early age, with treatment individualized due to variability in patient pharmacokinetics and product recoveries. A key factor in the acceptance and success of prophylaxis in teenagers is the training given at hemophilia treatment centers regarding self-treatment dosing and infusion schedules. Both plasma-derived and recombinant products are appropriate in this cohort, depending on the patient's and family's experiences and preferences. PMID:15322451

  9. [Hepatitis C virus infection in patients with hemophilia].

    PubMed

    Baptista González, Héctor A

    2002-10-01

    After the introduction of second generation ELISA and confirmatory tests clinically available, it was possible to determine that prevalence of infection with HCV was 98% among hemophiliacs exposed to factor VIII concentrates that weren't submitted to viral inactivation. Liver failure is 4.2 times more probable among patients also infected with HIV. The hepatocellular carcinoma studies show similar findings. They report a rate of 1.4 for every 1,000 hemophiliacs, and almost all patients have antibodies for hepatitis C virus. The studies with hemophiliacs exposed to unsafe blood products for HCV showed a significant increase in mortality from different liver diseases, as compared to control subjects. Mortality rate shows an important increase in the hemophiliacs also infected with human immunodeficiency virus. Combination therapy (ribavirin and interferon) doesn't seem to make a difference in the response rate as compared to patients without hemophilia. In spite of the best efforts to improve the safety of factor VIII concentrates, it has been impossible to eliminate the risk of transmission of other infective agents. That's why it seems that recombinant technology will be the answer in obtaining the concentrates. PMID:12712860

  10. A genetic analysis of 23 Chinese patients with hemophilia B

    PubMed Central

    Wang, Qing-Yun; Hu, Bei; Liu, Hui; Tang, Liang; Zeng, Wei; Wu, Ying-Ying; Cheng, Zhi-Peng; Hu, Yu

    2016-01-01

    Hemophilia B (HB) is an X-linked recessive bleeding disorder caused by mutations in the coagulation factor IX (FIX) gene. Genotyping patients with HB is essential for genetic counseling and provides useful information for patient management. In this study, the F9 gene from 23 patients with HB was analyzed by direct sequencing. Nineteen point mutations were identified, including a novel missense variant (c.520G > C, p.Val174Leu) in a patient with severe HB and a previously unreported homozygous missense mutation (c.571C > T, p.Arg191Cys) in a female patient with mild HB. Two large F9 gene deletions with defined breakpoints (g.10413_11363del, g.12163_23369del) were identified in two patients with severe HB using a primer walking strategy followed by sequencing. The flanking regions of the two breakpoints revealed recombination-associated elements (repetitive elements, non-B conformation forming motifs) with a 5-bp microhomology in the breakpoint junction of g.12163_23369del. These findings imply that non-homologous end joining and microhomology-mediated break-induced replication are the putative mechanisms for the deletions of the F9 gene. Because the g.12163_23369del deletion caused exons to be absent without a frameshift mutation occurring, a smaller FIX protein was observed in western blot analyses. PMID:27109384

  11. A genetic analysis of 23 Chinese patients with hemophilia B.

    PubMed

    Wang, Qing-Yun; Hu, Bei; Liu, Hui; Tang, Liang; Zeng, Wei; Wu, Ying-Ying; Cheng, Zhi-Peng; Hu, Yu

    2016-01-01

    Hemophilia B (HB) is an X-linked recessive bleeding disorder caused by mutations in the coagulation factor IX (FIX) gene. Genotyping patients with HB is essential for genetic counseling and provides useful information for patient management. In this study, the F9 gene from 23 patients with HB was analyzed by direct sequencing. Nineteen point mutations were identified, including a novel missense variant (c.520G > C, p.Val174Leu) in a patient with severe HB and a previously unreported homozygous missense mutation (c.571C > T, p.Arg191Cys) in a female patient with mild HB. Two large F9 gene deletions with defined breakpoints (g.10413_11363del, g.12163_23369del) were identified in two patients with severe HB using a primer walking strategy followed by sequencing. The flanking regions of the two breakpoints revealed recombination-associated elements (repetitive elements, non-B conformation forming motifs) with a 5-bp microhomology in the breakpoint junction of g.12163_23369del. These findings imply that non-homologous end joining and microhomology-mediated break-induced replication are the putative mechanisms for the deletions of the F9 gene. Because the g.12163_23369del deletion caused exons to be absent without a frameshift mutation occurring, a smaller FIX protein was observed in western blot analyses. PMID:27109384

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

    PubMed

    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. PMID:25510060

  13. Hemophilia A: an ideal disease to correct in utero

    PubMed Central

    Porada, Christopher D.; Rodman, Christopher; Ignacio, Glicerio; Atala, Anthony; Almeida-Porada, Graça

    2014-01-01

    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. PMID:25566073

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

    PubMed

    Nazeef, Moniba; Sheehan, John P

    2016-01-01

    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 expression by the liver. Both of these approaches are long acting and potentially involve subcutaneous administration of the drug. In this review, we will discuss the biology of FIX, the evolution of FIX replacement therapy, the

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

    PubMed Central

    Nazeef, Moniba; Sheehan, John P

    2016-01-01

    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 expression by the liver. Both of these approaches are long acting and potentially involve subcutaneous administration of the drug. In this review, we will discuss the biology of FIX, the evolution of FIX replacement therapy, the

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

    PubMed Central

    Cao, Dong-Hua; Liu, Xiao-Li; Mu, Kai; Ma, Xiang-Wei; Sun, Jing-Li; Bai, Xiao-Zhong; Lin, Chang-Kun; Jin, Chun-Lian

    2014-01-01

    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. Materials and 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. PMID:25330515

  17. Large hemorrhage due to venipuncture in the elbow of a patient with severe hemophilia: A case report and literature review

    PubMed Central

    LYU, JINGTONG; WU, WENJIE; XIANG, ZHOU; HUANG, FUGUO

    2016-01-01

    Hemophilia A, which is the most common form of hemophilia, is caused by a deficiency of clotting factor VIII. The incidence of hemophilia A is 1:10,000 people worldwide. The most common complication associated with hemophilia A is bleeding into joints, predominantly the knees, ankles, and elbows, which may lead to destruction or osteoarthritis of the specific joint. Various degrees of disability may follow these initial or recurrent hemorrhages. Subsequent to improvements in medical management, patients with hemophilia A currently have a life expectancy similar to that of the normal population. However, the management of patients with hemophilia A remains a clinical challenge for various reasons, including the lack of reliable and cost-effective treatment, and the high risk of intra- or post-operative hemorrhages. Large hemorrhages due to the phlebotomizing of young patients are very rare. To the best of our knowledge, the present case is the first report regarding the occurrence of a large hemorrhage due to venipuncture in the elbow of a patient with hemophilia A, and discusses the pathogenesis, clinical manifestation, and the medico-chirurgical treatment of this patient. PMID:26998031

  18. Immunoadsorption for pregnancy-associated severe acquired hemophilia.

    PubMed

    Zeitler, Heike; Ulrich-Merzenich, Gudrun; Marquardt, Natascha; Oldenburg, Johannes; Goldmann, Georg

    2014-02-01

    Postpartum hemorrhage is a common cause of maternal mortality. Acquired hemophilia (AH) is a rare, life-threatening bleeding disorder induced by autoantibodies against coagulation factors (inhibitors). We report about eight patients with postpartum AH (out of 82). Seven AH patients with severe bleeding complications were treated by the "Modified Bonn-Malmö Protocol (MBMP)" which consists of inhibitor elimination via immunoadsorption (IA) in combination with immunosuppression and high-dose Factor VIII substitution. One patient was treated only by immunosuppression. Seven out of eight patients with severe AH and mean inhibitor titers (IT) of 118 BU/mL were referred to our center. They were severe cases with a median delay of diagnosis of 30.5 days (range 7-278 days). After a median of 3 IA sessions (range 3-5 days), no inhibitor was detectable. The factor substitution was discontinued after a median of 13 IA sessions (range 8-24 days) and IA was terminated after a median of 15 sessions (range 9-27 days). One less severe affected patient (IT: 2.1 BU/mL) received prednisolone (1.5 mg/kg BW) for 120 days. Complete remission was achieved in all patients with a median follow-up of 100 months (range 56-126 m). The delayed diagnosis of pregnancy-associated AH leads to a high bleeding risk with bleeding associated complications. Immunoadsorption offers an important treatment option in severe AH, enabling a fast reconstitution of the blood coagulation with a reduced time for the Factor VIII substitution and for immunosuppressive treatment. In cases of postpartum bleeding the diagnosis of AH should be routinely considered. PMID:24499091

  19. Unusual Late Presentation of Hemophilia A in an Active Duty U.S. Marine Following Open Shoulder Surgery.

    PubMed

    Shapiro, Bennett H; Minter, Alex R; McDonald, Lucas S

    2015-12-01

    Hemophilia A is clotting disorder affecting 8:100,000 males in the United States. It is an X-linked recessive genetic disorder, although about one-third of cases occur spontaneously without known family history. Because of the risk of uncontrolled hemorrhage on the battlefield, hemophilia and other bleeding disorders exclude individuals from service in the U.S. military. We report a case of an active duty U.S. Marine whose underlying diagnosis of Hemophilia A was discovered and treated by a multidisciplinary team of orthopedic surgeons and hematologists following recurrent hematomas after open rotator cuff surgery. The patient gave informed consent for publication. PMID:26633674

  20. 78 FR 57868 - Prospective Grant of Exclusive Patent License: Oral Treatment of Hemophilia

    Federal Register 2010, 2011, 2012, 2013, 2014

    2013-09-20

    ... administering an effective amount of the appropriate clotting factor, sufficient to induce oral tolerance and supply exogenous clotting factor to the subject. Roughly 20,000 people in the U.S. have hemophilia with... generally involves intravenous infusion of missing clotting factors derived from concentrated...

  1. Uncomplicated abortion with mifepristone and misoprostol in a hemophilia A carrier.

    PubMed

    Hou, Melody Y

    2016-08-01

    Little evidence exists regarding medical abortion for women with inherited bleeding disorders. A 21-year-old primigravid hemophilia A carrier desired a medical abortion. After counseling, she chose medical abortion, which occurred without excess bleeding or surgical intervention. PMID:27085601

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

    PubMed

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

    2012-03-01

    Recombinant adeno-associated virus (rAAV) is a promising gene delivery vector and has recently been used in patients with hemophilia. One limitation of AAV application is that most humans have experienced wild-type AAV serotype 2 exposure, which frequently generates neutralizing antibodies (NAbs) that may inhibit rAAV2 vector transduction. Employing alternative serotypes of rAAV vectors may circumvent this problem. 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 (the Joint Outcome Study). Clinical applications in hemophilia therapy have been suggested for serotypes AAV2, AAV5 and AAV8, therefore NAbs against these serotypes were serially assayed over a median follow-up of 4 years. NAbs prevalence increased during early childhood for all serotypes. NAbs against AAV2 (43.5%) were observed more frequently and at higher titers compared with both AAV5 (25.8%) and AAV8 (22.6%). NAbs against AAV5 or AAV8 were rarely observed in the absence of co-prevalent and higher titer AAV2 NAbs, suggesting that NAbs to AAV5 and AAV8 were detected following AAV2 exposure due to partial cross-reactivity of AAV2-directed NAbs. The results may guide rational design of clinical trials using alternative AAV serotypes and suggest that younger patients who are given AAV gene therapy will benefit from the lower prevalence of NAbs. PMID:21697954

  3. A Cohort Pilot Study on HIV-Associated Neuropsychological Impairments in Hemophilia Patients

    PubMed Central

    Riva, Silvia; Cutica, Ilaria; Krampe, Caspar; Reinecke, Laura F.; Russell-Edu, William; Santoro, Cristina; Rocino, Angiola; Santagostino, Elena; Rusconi, Vega; Pravettoni, Gabriella

    2015-01-01

    Despite advances in the management of HIV infection with the introduction of combination antiretroviral therapy, it is well known that HIV can directly infect the central nervous system and, as a result of such infection, neuropsychological impairments can be manifested. In this study, we tried to determine whether seropositivity was associated with a poor neuropsychological performance in patients with hemophilia and HIV. Such a cohort of patients is very often underrepresented and understudied in the HIV literature. To amend such a gap, we carried out an extensive neuropsychological evaluation on these patients, and compared their performance with that of a group of seronegative hemophilia patients. The results revealed that HIV infection in HIV-seropositive (HIV+) hemophilia patients was associated with deficits in attention, short-term memory, abstraction, and visual recognition. Such results are still preliminary and explorative due to the small cohort of patients enrolled. However, the results do seem to have some important implications for day-to-day functioning, as the level of impairment detected may cause difficulties in completing common everyday tasks such as maintaining adherence to complex medication regimens or maintaining social life activities. Continued research into the mechanisms related to HIV and neurocognitive dysfunction may provide targets for interventions that could have meaningful consequences in the real world for HIV hemophilia patients. PMID:26082706

  4. Spinal Epidural Hematoma Following Cupping Glass Treatment in an Infant With Hemophilia A.

    PubMed

    Fruchtman, Yariv; Dardik, Rima; Barg, Assaf Arie; Livnat, Tami; Feldman, Zeev; Rubinstein, Marina; Grinberg, Gahl; Rosenberg, Nurit; Kenet, Gili

    2016-06-01

    A 6 months old infant, diagnosed with a rare mutation causing severe hemophilia A, presented with spinal epidural hematoma. Parents later admitted the infant had glass cupping therapy performed within 2 weeks of the onset of symptoms. The rare mutation, rare bleeding complication, and the eventual course of therapy applied in this case will be discussed in our case report. PMID:26844816

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

    PubMed

    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. PMID:27052253

  6. Knowledge of Oral Hygiene among Hemophilic Patients Referred to Iranian Hemophilia Society

    PubMed Central

    Abrisham, Mohammad; Tabrizizadeh, Mehdi; Ghateh, Alireza

    2009-01-01

    Background and aims Hemophilic patients are faced with poor oral hygiene due to concerns about their dental care. The present study assessed the knowledge of hemophilic patients about oral hygiene and the effect of oral hygiene instruction in patients referred to Iranian Hemophilia Society. Materials and methods This cross-sectional study was carried out on 30 hemophilic patients randomly selected from volunteer patients referred to Iran Hemophilia Center. The study was performed by means of a questionnaire submitted to subjects before and after the instructional brochure submission. The questionnaire included demographic data and items regarding hemophilia and oral hygiene. Data was analyzed with McNemar test and paired t-test. Results The mean age of the patients was 21 years; 27 (90%) were males and 3 ones (10%) were females. They were mostly A hemophilia infected. Most patients enjoyed fair knowledge of oral hygiene. Changes in knowledge after reading the bro-chure were significant regarding the appropriate time to replace the toothbrush (P < 0.01), necessary visits for tooth examina-tions (P < 0.04), adjunctive methods of caries prevention (P < 0.001) and factors related to bleeding (P < 0.01); other factors improved slightly without significant changes. Conclusion The knowledge of hemophilic patients was fair regarding oral hygiene while some relevant factors improved after instructions. However, more instruction is needed in order to attain more improvement in some behaviors. PMID:23230484

  7. Factor VIII gene (F8) mutation and risk of inhibitor development in nonsevere hemophilia A.

    PubMed

    Eckhardt, Corien L; van Velzen, Alice S; Peters, Marjolein; Astermark, Jan; Brons, Paul P; Castaman, Giancarlo; Cnossen, Marjon H; Dors, Natasja; Escuriola-Ettingshausen, Carmen; Hamulyak, Karly; Hart, Daniel P; Hay, Charles R M; Haya, Saturnino; van Heerde, Waander L; Hermans, Cedric; Holmström, Margareta; Jimenez-Yuste, Victor; Keenan, Russell D; Klamroth, Robert; Laros-van Gorkom, Britta A P; Leebeek, Frank W G; Liesner, Ri; Mäkipernaa, Anne; Male, Christoph; Mauser-Bunschoten, Evelien; Mazzucconi, Maria G; McRae, Simon; Meijer, Karina; Mitchell, Michael; Morfini, Massimo; Nijziel, Marten; Oldenburg, Johannes; Peerlinck, Kathelijne; Petrini, Pia; Platokouki, Helena; Reitter-Pfoertner, Sylvia E; Santagostino, Elena; Schinco, Piercarla; Smiers, Frans J; Siegmund, Berthold; Tagliaferri, Annarita; Yee, Thynn T; Kamphuisen, Pieter Willem; van der Bom, Johanna G; Fijnvandraat, Karin

    2013-09-12

    Neutralizing antibodies (inhibitors) toward factor VIII form a severe complication in nonsevere hemophilia A, profoundly aggravating the bleeding pattern. Identification of high-risk patients is hampered by lack of data that take exposure days to therapeutic factor VIII concentrates into account. In the INSIGHT study, we analyzed the association between F8 mutation and inhibitor development in patients with nonsevere hemophilia A (factor VIII 2-40 IU/dL). This analysis included 1112 nonsevere hemophilia A patients from 14 centers in Europe and Australia that had genotyped at least 70% of their patients. Inhibitor risk was calculated as Kaplan-Meier incidence with cumulative number of exposure days as the time variable. During 44 800 exposure days (median, 24 exposure days per patient; interquartile range [IQR], 7-90), 59 of the 1112 patients developed an inhibitor; cumulative incidence of 5.3% (95% confidence interval [CI], 4.0-6.6) after a median of 28 exposure days (IQR, 12-71). The inhibitor risk at 50 exposure days was 6.7% (95% CI, 4.5-8.9) and at 100 exposure days the risk further increased to 13.3% (95% CI, 9.6-17.0). Among a total of 214 different F8 missense mutations 19 were associated with inhibitor development. These results emphasize the importance of F8 genotyping in nonsevere hemophilia A. PMID:23926300

  8. Translational data from adeno-associated virus-mediated gene therapy of hemophilia B in dogs.

    PubMed

    Nichols, Timothy C; Whitford, Margaret H; Arruda, Valder R; Stedman, Hansell H; Kay, Mark A; High, Katherine A

    2015-03-01

    Preclinical testing of new therapeutic strategies in relevant animal models is an essential part of drug development. The choice of animal models of disease that are used in these studies is driven by the strength of the translational data for informing about safety, efficacy, and success or failure of human clinical trials. Hemophilia B is a monogenic, X-linked, inherited bleeding disorder that results from absent or dysfunctional coagulation factor IX (FIX). Regarding preclinical studies of adeno-associated virus (AAV)-mediated gene therapy for hemophilia B, dogs with severe hemophilia B (<1% FIX) provide well-characterized phenotypes and genotypes in which a species-specific transgene can be expressed in a mixed genetic background. Correction of the hemophilic coagulopathy by sustained expression of FIX, reduction of bleeding events, and a comprehensive assessment of the humoral and cell-mediated immune responses to the expressed transgene and recombinant AAV vector are all feasible end points in these dogs. This review compares the preclinical studies of AAV vectors used to treat dogs with hemophilia B with the results obtained in subsequent human clinical trials using muscle- and liver-based approaches. PMID:25675273

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

    PubMed Central

    Fomin, Marina E.; Togarrati, Padma Priya; Muench, Marcus O.

    2015-01-01

    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 (iPSCs) 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 iPSCs. PMID:25297648

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

    PubMed Central

    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

  11. [Diagnosis of mild hemophilia A made by massive intraabdominal bleeding in a 13-year-old boy].

    PubMed

    Terao, Yoko; Akiyama, Masaharu; Yokoi, Kentaro; Yamaoka, Masayoshi; Shimizu, Mika; Kato, Yoko; Tanaka, Keiichiro; Baba, Yuji; Kuwashima, Naruo; Ashizuka, Shuichi; Yoshizawa, Jyoji; Motoki, Takanori; Saito, Yoshihiro; Ida, Hiroyuki

    2012-08-01

    We report a 13-year-old boy who had massive intra-abdominal bleeding without a history of bleeding episodes or traumatic cause of bleeding. The patient underwent surgical treatment because bleeding was not controlled after treatment with tranexamic acid and transfusions including fresh-frozen plasma. Bleeding was traced to the lower left lobe of the liver. The mother's side of the family had a history of bleeding episodes in the boy's grandfather, great uncle, and son of a great aunt. A low level of plasma factor VIII coagulant activity (22%) led to a diagnosis of mild hemophilia A. Compared with severe hemophilia, mild hemophilia is more difficult to diagnose because bleeding episodes are less frequent. Most cases are found after incidental trauma or uncontrolled surgery-related bleeding, there is rarely a family history of hemophilia and activated partial thromboplastin time is normal or slightly prolonged. However, bleeding episodes in mild hemophilia may result in excessive, sometimes life-threatening hemorrhage and require early diagnosis and replacement treatment with adequate amounts of factor VIII, as in severe hemophilia. PMID:22975817

  12. Maternal low-level somatic mosaicism of Cys155Tyr of F9 in severe hemophilia B.

    PubMed

    Kim, Hee-Jung; Lee, Ki-O; Yoo, Ki-Young; Kim, Sun-Hee; Kim, Hee-Jin

    2015-12-01

    Hemophilia B is an X-linked bleeding disorder caused by deficient coagulation factor IX from a mutation in the F9 gene. Here, we report a family with two brothers having severe hemophilia B inherited from a mother with low-level somatic mosaicism of a F9 mutation. The proband was a 2-year-old boy with severe hemophilia B from a hemizygous mutation of F9, c.464G>A (p.Cys155Tyr). He was the first child and was considered a sporadic case based on the lack of family history of bleeding diathesis. His mother was tested for carrier status and was determined to be homozygous for wild-type genotypes (noncarrier). Subsequently, however, his brother was born and also had severe hemophilia B from Cys155Tyr. This prompted us to review the chromatogram of the mother, which revealed a small peak corresponding to the mutant genotype. On suspicion of somatic low-level mosaicism in the mother, we further performed allele-specific PCR and thymine and adenine cloning, and confirmed the presence of the mutant allele in the mother. To our knowledge, this is the first case of maternal somatic mosaicism for a cytosine-phosphate-guanine transition mutation in hemophilia B. The acknowledgment of somatic mosaicism and further molecular investigation are important in sporadic hemophilia B to deliver informative genetic counseling and risk assessment. PMID:25402191

  13. How I use bypassing therapy for prophylaxis in patients with hemophilia A and inhibitors.

    PubMed

    Leissinger, Cindy A; Singleton, Tammuella; Kruse-Jarres, Rebecca

    2015-07-01

    Inhibitor development poses a significant challenge in the management of hemophilia because once an inhibitor is present, bleeding episodes can no longer be treated with standard clotting factor replacement therapy. Consequently, patients with inhibitors are at increased risk for difficult-to-control bleeding and complications, particularly arthropathy and physical disability. Three clinical trials in patients with inhibitors have demonstrated that prophylaxis with a bypassing agent reduces joint and other types of bleeding and improves health-related quality of life compared with on-demand bypassing therapy. In hemophilia patients without inhibitors, the initiation of prophylaxis with factor (F) VIII or FIX prior to the onset of recurrent hemarthroses can prevent the development of joint disease. Whether this is also true for bypassing agent prophylaxis remains to be determined. PMID:25827834

  14. [Mutational Analysis of Hemophilia B in Russia: Molecular-Genetic Study].

    PubMed

    Surin, V L; Demidova, E Yu; Selivanova, D S; Luchinina, Yu A; Salomashkina, V V; Pshenichnikova, O S; Likhacheva, E A

    2016-04-01

    Hemophilia B is a hereditary X-linked coagulation disorder. This pathology is caused by various defects in the factor IX gene, which is, being about 34 kb long and consisting of eight exons, localized in the Xq27 locus of the. X-chromosome long arm. Mutations were revealed in 56 unrelated patients with hemophilia B in this study by using direct sequencing of factor IX gene functionally important fragments. Forty-six mutations were found with prevailing missense mutations (n = 30). The rest of the mutations were nonsense (n = 4) and splicing (n = 4) mutations, large deletions (n = 3), microdeletions (n = 2), microinsertions (n = 2), and promoter mutations (n = 1). Eleven of 46 mutations were previously unknown for human populations. PMID:27529981

  15. [Mild hemophilia A fortuitously discovered during Henoch-Schönlein purpura].

    PubMed

    Joly, B; d'Oiron, R; Desconclois, C; Bendelac, L; Rafowicz, A; Meyzer, C; Labrune, P; Veyradier, A

    2015-11-01

    Henoch-Schönlein purpura is a common form of immunological vasculitis in children. Hemophilia A is a genetic disorder, inherited in a X-linked recessive pattern, and characterized by spontaneous hemorrhage or prolonged bleeding due to factor VIII deficiency. The clinical signs depend on the severity of factor VIII deficiency. We herein report the case of a 4-year-old boy admitted to the emergency room for typical rheumatoid purpura, associated with a lengthening of aPTT, whose exploration had uncovered mild hemophilia A. Laboratory assays should explore lengthening of aPTT: firstly the presence of lupus anticoagulant without bleeding risk, in an inflammatory context; secondly a deficiency of VWF and one of the factors involved in the extrinsic coagulation pathway associated with bleeding risk. PMID:26412326

  16. Emerging issues on comprehensive hemophilia care: preventing, identifying, and monitoring age-related comorbidities.

    PubMed

    Coppola, Antonio; Santoro, Cristina; Franchini, Massimo; Mannucci, Caterina; Mogavero, Selene; Molinari, Angelo Claudio; Schinco, Piercarla; Tagliaferri, Annarita; Santoro, Rita Carlotta

    2013-10-01

    Life expectancy for persons with hemophilia (PWH) has considerably increased in the last decades as a direct result of the availability of modern therapies to control the clotting defect. Because their life expectancy now matches that of the general population, PWH are experiencing age-related comorbidities, such as, cardiovascular diseases, metabolic syndrome, renal diseases, sexuality issues, malignancies, and neurologic problems, that until recently have been rarely seen in this group of patients. In this article, we present a summary of the current knowledge on the aging PWH along with the clinical approaches that may be integrated into the routine comprehensive care of these patients for preventing, diagnosing, and monitoring age-related comorbidities. In general, patients with and without hemophilia should receive similar care, with close collaboration between the physician treating PWH and the specialty expert treating the comorbid disease. PMID:24014070

  17. Prevention of bleeding in hemophilia patients with high-titer inhibitors.

    PubMed

    Leissinger, Cindy A; Konkle, Barbara A; Antunes, Sandra V

    2015-06-01

    Inhibitor development is the most serious adverse event linked to the treatment of hemophilia, as it renders standard hemostatic therapy ineffective. Consequently, inhibitor patients are at increased risk for difficult-to-control bleeding and complications, particularly arthropathy and physical disability. Three randomized clinical trials in patients with inhibitors have demonstrated that compared with on-demand bypassing therapy, prophylaxis with a bypassing agent reduces joint and other types of bleeding and improves health-related quality of life. In hemophilia patients without inhibitors, the initiation of prophylaxis with factor (F) VIII or IX prior to the onset of recurrent hemarthroses can prevent the development of joint disease. Whether this is also true for bypassing agent prophylaxis remains to be determined. PMID:25937074

  18. An innovative outcome-based care and procurement model of hemophilia management.

    PubMed

    Gringeri, Alessandro; Doralt, Jennifer; Valentino, Leonard A; Crea, Roberto; Reininger, Armin J

    2016-06-01

    Hemophilia is a rare bleeding disorder associated with spontaneous and post-traumatic bleeding. Each hemophilia patient requires a personalized approach to episodic or prophylactic treatment, but self-management can be challenging for patients, and avoidable bleeding may occur. Patient-tailored care may provide more effective prevention of bleeding, which in turn, may decrease the likelihood of arthropathy and associated chronic pain, missed time from school or work, and progressive loss of mobility. A strategy is presented here aiming to reduce or eliminate bleeding altogether through a holistic approach based on individual patient characteristics. In an environment of budget constraints, this approach would link procurement to patient outcome, adding incentives for all stakeholders to strive for optimal care and, ultimately, a bleed-free world. PMID:27074697

  19. Cost–utility analysis of prophylaxis versus treatment on demand in severe hemophilia A

    PubMed Central

    Colombo, Giorgio L; Di Matteo, Sergio; Mancuso, Maria Elisa; Santagostino, Elena

    2011-01-01

    Background: Individuals with severe hemophilia A have reduced blood levels of clotting factor VIII (FVIII) leading to recurrent bleeding into joints and muscles. Primary prophylaxis with clotting factor concentrates started early in childhood prevents joint bleeds, thus avoiding joint damage and improving people’s quality of life. There remain significant differences in the implementation of primary prophylaxis worldwide mainly due to the cost of prophylaxis compared with treatment on demand. Objective: To evaluate the cost-effectiveness of primary prophylaxis with FVIII concentrates versus secondary prophylaxis, versus treatment on demand, and versus a “hybrid” (primary prophylaxis followed by on-demand treatment in adults) in individuals with severe hemophilia A. Methods: A Markov model was developed and run using different sources of clinical, cost, and utility data. The model was populated with a hypothetical cohort of 100 individuals with severe hemophilia A. The perspective of the Italian National Health System was used. Results: The baseline results showed that primary and secondary prophylaxis is cost-effective compared both with treatment on demand and with a hybrid strategy. The incremental costs per quality-adjusted life-year gained for individuals with hemophilia A receiving primary and secondary prophylaxis were €40,229 to €40,236 versus an on-demand strategy. However, the sensitivity analyses performed showed that the results were sensitive to the unit cost of clotting FVIII, bleeding frequency, and the discount rate. Conclusion: Although primary prophylaxis is a costly treatment, our results show that it is cost-effective compared with treatment on demand. PMID:21935333

  20. Clinical efficacy and determinants of response to treatment with desmopressin in mild hemophilia a.

    PubMed

    Di Perna, Caterina; Riccardi, Federica; Franchini, Massimo; Rivolta, Gianna Franca; Pattacini, Corrado; Tagliaferri, Annarita

    2013-10-01

    Although desmopressin (DDAVP) is considered as the treatment of choice for many patients with mild hemophilia A, several aspects of DDAVP therapy remain unclear, including the rate and type of response and the molecular determinants of its clinical efficacy. To investigate these issues, we retrospectively studied all patients with mild hemophilia A followed up at the Parma Hemophilia Center. A total of 75 patients were enrolled who underwent a DDAVP test, and out of whom, 76% (57/75) had a complete or partial response. Response to DDAVP was significantly correlated to the patients' age (median age of responders and nonresponders: 24 and 18 y, respectively; p = 0.04) and type of mutation (all the 10 patients with mutations in the promoter region were nonresponders). The median basal factor VIII (FVIII):C level was significantly lower in responders than in nonresponders (0.14 vs. 0.19 IU/mL, respectively; p = 0.01); this was mainly due to nonresponders with promoter region mutations who had higher basal FVIII:C levels. During the 12-year follow-up, 82 of 237 (35%) bleeding episodes occurring in 27 responder patients were treated with 246 DDAVP infusions with complete or partial efficacy in 92% (75/82). Overall, 142 events were managed with 253 prophylactic DDAVP infusions, which were hemostatically effective in 96% of cases. No severe adverse reactions to DDAVP administration were recorded during the study period. These results document the safety and efficacy of DDAVP as a treatment or prevention of bleeding in patients with mild hemophilia A, also in the context of home treatment, and encourage the more widespread use of this product. PMID:24030345

  1. LASER versus electromagnetic field in treatment of hemarthrosis in children with hemophilia.

    PubMed

    Eid, Mohamed A; Aly, Sobhy M

    2015-11-01

    Children with hemophilia usually have recurrent joint bleeding that leads to joint damage, loss of range of motion, and restriction of mobility, therefore affecting the quality of life in these children. The purpose of this study was to compare the effects of low-level laser therapy (LLLT) to that of pulsed electromagnetic field (PEMF) in treatment of hemarthrosis in children with hemophilia. Thirty boys with hemophilia A with ages ranging from 9 to 13 years were selected and assigned randomly, using sealed envelopes, into two equal intervention groups. The study group I received the traditional physical therapy program in addition to LLLT, whereas the study group II received the same physical therapy program given to the study group I in addition to PEMF. Both groups received the treatment sessions three times per week for three successive months. Pain, laboratory investigations, swelling, and range of motion (ROM) of the affected knee joint, in addition to physical fitness were evaluated before, at the end of the sixth week and at 12 weeks of the treatment program. Laser group showed significant improvement in all measured variables after the sixth week of treatment when compared with PEMF. By 12 weeks of treatment, there was a significant improvement in pain, ROM, ESR and leucocytes levels in laser group compared with PEMF, while there was no significant difference in knee circumferences and the 6-min walk test (6MWT) between both groups. Both groups showed significant improvement at 12 weeks of treatment compared with that at 6 weeks. Both LLLT and PEMF are effective modalities in reducing pain, swelling, increasing ROM and improving physical fitness. Twelve weeks of treatment of both modalities demonstrated significant improvement than 6 weeks of treatment. Laser therapy induced significant improvement than electromagnetic therapy in treatment of hemarthrosis-related problems in children with hemophilia. PMID:26306883

  2. US Hemophilia Treatment Center population trends 1990-2010: patient diagnoses, demographics, health services utilization.

    PubMed

    Baker, J R; Riske, B; Drake, J H; Forsberg, A D; Atwood, R; Voutsis, M; Shearer, R

    2013-01-01

    For several decades, US government agencies have partially supported regional networks of Hemophilia Treatment Centers (HTC). HTC multidisciplinary teams provide comprehensive and coordinated diagnosis, treatment, prevention, education, outreach and surveillance services to improve the health of people with genetic bleeding disorders. However, national data are scarce on HTC-patient population trends and services. The aim of the study was to examine national trends over the past 20 years in patient diagnoses, demographics and health services utilization among the Health Resources and Services Administration (HRSA) and Centers for Disease Control and Prevention (CDC)-supported HTC network. Diagnoses, demographics and health services utilization data from 1990 to 2010 were aggregated from all HTCs using the Hemophilia Data Set (HDS). From 1990 to 2010, the HTC population grew 90% from 17 177 to 32 612. HTC patients with von Willebrand's disease increased by 148%, females by 346%, Hispanic patients by 236% and African Americans by 104%. Four thousand and seventy-five deaths were reported. From 2002 to 2010, annual comprehensive evaluations grew 38%, and persons with severe haemophilia on a home intravenous therapy programme rose 37%. In 2010, 46% of patients were less than 18 years vs. 24% for the general US population. The Hemophilia Data Set documents the growth and diversity of the US Hemophilia Treatment Center Network's patient population and services. Despite disproportionate deaths due to HIV, the HTC patient base grew faster than the general US population. The HDS is a vital national public health registry for this rare-disorder population. PMID:22845803

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

    PubMed Central

    Goto, Miwa; Takedani, Hideyuki; Yokota, Kazuhiko; Haga, Nobuhiko

    2016-01-01

    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 PA, before initiating the exercise regimen. For those patients who find it difficult to participate in PA, it is necessary to plan individual-based behavior change approach and encourage self-efficacy. PMID:27274330

  4. Telehealth Videoconferencing for Children With Hemophilia and Their Families: A Clinical Project.

    PubMed

    Jacobson, Kimberly; Hooke, Mary C

    2016-07-01

    Telehealth is the use of electronic information and telecommunications technologies to support long-distance health care. It supports quality health care that is accessible, and time- and cost-effective. Telehealth videoconferencing may enhance the care for hemophilia patients who are experiencing a bleed by supporting real-time detailed assessment including appearance, range of motion, and ambulation in addition to the traditional phone methods of verbal description of appearance, pain, and function. The aim of this clinical project was to evaluate the feasibility of using telehealth videoconferencing in children with severe hemophilia in the home setting. Twelve patients with severe hemophilia ages 2to 18 years, who had more than 2 breakthrough bleeds in the past year, and had Internet access with a computer camera were included. The incidence of bleeding was low; however, videoconferencing was effective for 3 patients who completed 4 video appointments. Patients and staff reported that videoconferencing improved communication and satisfaction. Telehealth videoconferencing is a feasible tool for managing bleeding disorders in the home setting. PMID:26510644

  5. Hemophilia A due to mutations that create new N-glycosylation sites.

    PubMed Central

    Aly, A M; Higuchi, M; Kasper, C K; Kazazian, H H; Antonarakis, S E; Hoyer, L W

    1992-01-01

    In studying the molecular defects responsible for cross-reacting material-positive hemophilia A, we have identified two patients in whom the nonfunctional factor VIII-like protein has abnormal, slower-moving heavy or light chains on SDS/PAGE. Both patients have severe hemophilia A (less than 1% of normal factor VIII activity) with a normal plasma level of factor VIII antigen. The molecular defects were identified by denaturing gradient gel electrophoresis screening of PCR-amplified products of the factor VIII-coding DNA sequence followed by nucleotide sequencing of the abnormal PCR products. In patient ARC-21, a methionine-to-threonine substitution at position 1772 in the factor VIII light chain creates a potential new N-glycosylation site at asparagine-1770. In patient ARC-22, an isoleucine-to-threonine substitution at position 566 creates a potential new N-glycosylation site at asparagine-564 in the A2 domain of the factor VIII heavy chain. The mobility of these chains on SDS/PAGE was normal after N-Glycanase digestion and procoagulant activity was generated--to a maximum of 23% and 45% of control normal plasma. Abnormal N-glycosylation, blocking factor VIII procoagulant activity, represents a newly recognized mechanism for the pathogenesis of severe hemophilia A. Images PMID:1594597

  6. The CDC Hemophilia A Mutation Project (CHAMP) Mutation List: a New Online Resource

    PubMed Central

    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

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

    PubMed Central

    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 <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. PMID:27011017

  8. Expression of von Willebrand factor Normandy: An autosomal mutation that mimics hemophilia A

    SciTech Connect

    Tuley, E.A.; Worrall, N.K.; Sadler, J.E. ); Gaucher, C.; Jorieux, S.; Mazurier, C. )

    1991-07-15

    von Willebrand disease Normandy (vWD Normandy) is a recently described phenotype in which a mutant von Willebrand factor (VWF) appears structurally and functionally normal except that is does not bind to blood coagulation factor VIII. This interaction is required for normal survival of factor VIII in the circulation; consequently, vWD Normandy can present as apparent hemophilia A but with autosomal recessive rather than X chromosome-linked inheritance. AvWF missense mutation, Thr{sup 28} {r arrow} Met, was identified in the propositus in or near the factor VIII binding site. The corresponding mutant recombinant vWF(T28M) formed normal multimers and had normal ristocetin cofactor activity. However, vWF(T28M) exhibited the same defect in factor VIII binding as natural vWF Normandy, confirming that this mutation causes the vWD Normandy phenotype. The distinction between hemophilia A and vWD Normandy is clinically important and should be considered in families affected by apparent mild hemophilia A that fail to show strict X chromosome-linked inheritance and, particularly, in potential female carriers with low factor VIII levels attributed to extreme lyonization.

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

    PubMed

    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 <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. PMID:27011017

  10. Delays in maturation among adolescents with hemophilia and a history of inhibitors

    PubMed Central

    Lynn, Henry S.; Lail, Alice E.; Hoots, W. Keith; Berntorp, Erik; Gomperts, Edward D.

    2007-01-01

    Inhibitory antibodies to factors VIII or IX have the potential to affect a broad range of outcomes among people with hemophilia; however, their possible effect on growth and maturation has not been explored. We evaluated skeletal maturation (bone age), pubertal progression, serum testosterone levels, height velocity, and stature in the multicenter Hemophilia Growth and Development Study. A total of 333 children and adolescents (mean age, 12.4 years) were enrolled from 1989 to 1990 and followed for 7 years. Of these, 18% (n = 60) had a history of inhibitors. Bone age among HIV− adolescents with a history of inhibitors lagged 9 or more months behind those without inhibitors at every age from 12 to 15 years. Those with a history of inhibitors were older at every Tanner stage transition, attained a lower maximum growth velocity, and their serum testosterone levels were significantly lower compared with those without inhibitors. Delays were greater among HIV+ patients with a history of inhibitors compared with those without inhibitors; however, the differences were generally small and not statistically significant. The results of this investigation underscore the importance of monitoring the growth and maturation of children and adolescents with hemophilia, particularly those with inhibitors. PMID:17715388

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

    PubMed

    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. PMID:27609734

  12. Leopold: the "bleeder prince" and public knowledge about hemophilia in Victorian Britain.

    PubMed

    Rushton, Alan R

    2012-07-01

    Hemophilia is a rare bleeding disorder inherited by males born of unaffected female carriers of the trait. British physicians became knowledgeable about this hereditary disease early in the nineteenth century as they investigated families transmitting the character through several generations. Prince Leopold (b. 1853), the fourth son of Queen Victoria, experienced recurrent bleeding episodes and was diagnosed with hemophilia during childhood. His hemorrhagic attacks were first described in the medical journals during 1868, and subsequently in the London and provincial newspapers. The royal family carefully managed news about health matters, and many newspapers reported widespread public sympathy for the travails of the queen and her children. But the republican press argued that the disaffected working classes resented the hyperbole connecting the health of royal individuals with the political future of the entire nation. Public discussion of hemophilia transformed it from a rare medical phenomenon to a matter of national news. Practicing physicians, the royal family, and the general public all came to understand the clinical features and the hereditary nature of the problem. Members of the royal family subsequently utilized this information to guide the marriages of their own children to prevent the spread of this dreaded bleeding disorder. PMID:21764831

  13. The Association Between HLA Class II Alleles and the Occurrence of Factor VIII Inhibitor in Thai Patients with Hemophilia A

    PubMed Central

    Nathalang, Oytip; Sriwanitchrak, Pramote; Sasanakul, Werasak; Chuansumrit, Ampaiwan

    2012-01-01

    Objective: This study aimed to investigate the association between HLA class II alleles and the occurrence of FVIIIinhibitor in Thai hemophilia A patients. Material and Methods: The distribution of HLA-DRB1 alleles and DQB1 alleles in 57 Thai hemophilia A patientsand 36 blood donors as controls was determined using the PCR sequence-specific primer (PCR-SSP) method, and theassociation between the occurrence of factor VIII (FVIII) inhibitor and the presence of certain HLA class II alleles wasinvestigated. Results: The frequency of HLA-DRB1*15 was higher in the hemophilia A patients with and without FVIII inhibitor,whereas that of DRB1*14, DRB1*07, and DQB1*02 was lower in the hemophilia A patients with FVIII inhibitor, ascompared to controls. Interestingly, only the frequency of DRB1*15 was significantly higher in the patients with inhibitorthan in the controls (P = 0.021). Moreover, the frequency of DRB1*15 in the patients with inhibitor was higher than inthose without inhibitor (P = 0.198). Conclusion: The study’s findings show that the DRB1*15 allele might have contributed to the occurrence of inhibitorin the Thai hemophilia A patients; however, additional research using larger samples and high-resolution DRB1 typingis warranted. PMID:24744621

  14. Life-threatening bleeding in a patient with mild hemophilia A and heterozygosity for von Willebrand disease Type 2N.

    PubMed

    Allan, John N; Friedman, Kenneth D; DeSancho, Maria T

    2014-12-01

    Hemophilia A and von Willebrand disease (VWD) are distinct bleeding disorders with a spectrum of clinical phenotypes. They are characterized by mutations in either factor VIII (F8) or von Willebrand factor (VWF) genes, respectively. The pattern of inheritance and appropriate laboratory evaluation differentiates these diseases, and treatment strategies for both are different. Here, we report a male patient with hemophilia A and VWD Type 2 Normandy (N) mutations who presented with life-threatening bleeding. We document his medical history, clinical course, management, and diagnostic work up. PMID:25212677

  15. [Gene mutation analysis of coagulation factor VIII from a female patient with hemophilia A].

    PubMed

    Zhou, Jing; Yan, Nai-hong; Jia, Yong-qian; Lu, Yi-lu; Yu, Jiang; Cao, Gui-qun; Chen, Qing-ying; Wang, Ling; Zhang, Fa-qiang; Xia, Oing-jie

    2006-05-01

    Hemophilia A affects male, whereas females are carriers and generally spared from this disease. However, we here reported a 65-year-old female with Hemophilia A while screening the gene mutation of coagulation factor VIII. The female went to hospital because of tripping to lead her right chest to be injured with subcutaneous hematoma. She had historically a hemorrhagic diathesis. The physical examination discovered her hip limited to bend and move, but no discrepancy length between her two legs. The initial laboratory tests showed that the activated partial thromboplastin time (APTT) was 61. 3 seconds (20-40 seconds), and the APTT corrected by mixing with normal plasma was 41.3 s, but the levels of PT, FIB and TT were normal. The plain radiographs revealed the hip joints to suffer from the acetabular dysplasia and osteoarthritis. The level of FVIII:C was 2%, F IX:C 200%, vWF:Ag 120%, vWF:Rcof 100%, vWF:CBA 128%, and the F VIII binding assay to vWF was normal. The primers for exon 14 of F VIII gene were designed according to the NM - 000132 gene sequence. DNA was abstracted from the patient blood. PCR were carried out and the DNA sequence was followed. A new mutation of 4111A-->C was discovered, which caused the amino acid sequence changed (T 1314 P). The mutation of T 1314 P may be the cause of this female patient to get the hemophilia A. This mutation was a novel one which has never been reported before. PMID:16761442

  16. Characterization of genetic defects of hemophilia A in patients of Chinese origin

    SciTech Connect

    Lin, Shu-Wha; Lin, Shu-Rung; Shen, Ming-Ching )

    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.

  17. Safety and prolonged activity of recombinant factor VIII Fc fusion protein in hemophilia A patients

    PubMed Central

    Josephson, Neil C.; Quon, Doris; Ragni, Margaret V.; Cheng, Gregory; Li, Ella; Jiang, Haiyan; Li, Lian; Dumont, Jennifer A.; Goyal, Jaya; Zhang, Xin; Sommer, Jurg; McCue, Justin; Barbetti, Margaret; Luk, Alvin

    2012-01-01

    Current factor VIII (FVIII) products display a half-life (t1/2) of ∼ 8-12 hours, requiring frequent intravenous injections for prophylaxis and treatment of patients with hemophilia A. rFVIIIFc is a recombinant fusion protein composed of a single molecule of FVIII covalently linked to the Fc domain of human IgG1 to extend circulating rFVIII t1/2. This first-in-human study in previously treated subjects with severe hemophilia A investigated safety and pharmacokinetics of rFVIIIFc. Sixteen subjects received a single dose of rFVIII at 25 or 65 IU/kg followed by an equal dose of rFVIIIFc. Most adverse events were unrelated to study drug. None of the study subjects developed anti-rFVIIIFc antibodies or inhibitors. Across dose levels, compared with rFVIII, rFVIIIFc showed 1.54- to 1.70-fold longer elimination t1/2, 1.49- to 1.56-fold lower clearance, and 1.48- to 1.56-fold higher total systemic exposure. rFVIII and rFVIIIFc had comparable dose-dependent peak plasma concentrations and recoveries. Time to 1% FVIII activity above baseline was ∼ 1.53- to 1.68-fold longer than rFVIII across dose levels. Each subject showed prolonged exposure to rFVIIIFc relative to rFVIII. Thus, rFVIIIFc may offer a viable therapeutic approach to achieve prolonged hemostatic protection and less frequent dosing in patients with hemophilia A. This trial was registered at www.clinicaltrials.gov as NCT01027377. PMID:22223821

  18. Direct detection of common and rare inversion mutations in the genetic diagnosis of severe hemophilia A

    SciTech Connect

    Windsor, A.S.; Lillicrap, D.P.; Taylor, S.A.M.

    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.

  19. Potential role of a new PEGylated recombinant factor VIII for hemophilia A

    PubMed Central

    Wynn, Tung Thanh; Gumuscu, Burak

    2016-01-01

    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-life will become available in a very short time. With all the promise of these new agents, many questions still remain. PMID:27382347

  20. [Surgical aortic valve replacement for acute Streptococcus viridans endocarditis with simultaneous moderate hemophilia A].

    PubMed

    Krawietz, W; Loracher, C; Struck, E; Schlimok, G; Falk, H

    1988-07-01

    This is a report of a 25-year-old patient with known aortic valve stenosis since early youth and hemophilia A, showing recurrent joint bleeding. Acute Streptococcus endocarditis induced aortic valve insufficiency resulting in cardiac failure. Aortic valve replacement was performed after substitution of factor VIII, during which intra- and postoperative bleeding was prolonged by pericardial adhesions. Heparin was administered during cardiopulmonary-bypass as usual, but usual postoperative cumarin therapy was not initiated due to prolonged PTT time. One year postoperatively, the patient was in an excellent condition and fully rehabilitated. PMID:3145652

  1. Vitamin D levels in children with severe hemophilia A: an underappreciated deficiency.

    PubMed

    Albayrak, Canan; Albayrak, Davut

    2015-04-01

    Osteoporosis in hemophilic patients is a significant problem. The causes of osteoporosis in hemophilic patients are lack of adequate exercise, multiple hemorrhage and inflammation, and low vitamin D levels. The aim of this study was to retrospectively determine the frequency of vitamin D deficiency and insufficiency in children with severe hemophilia A. Forty-seven children with severe hemophilia were included in the study. None of the patients had previously received vitamin D supplementation. No patient had clinical or radiologic findings of rickets or seropositivity of hepatitis C virus or HIV. The mean age of the patients was 11.64 ± 5.70 (range, 2-18) years. The mean vitamin D level was 16.35 ± 7.49 ng/ml (range, 3.25-33.80). Vitamin D levels were below 10 ng/ml (severe vitamin D deficiency) in 9 cases (19%), between 10 and 19.99 ng/ml (vitamin D deficiency) in 23 cases (49%), between 20 and 29.99 ng/ml (vitamin D insufficiency) in 13 cases (28%), and above 30 ng/ml (normal vitamin D level) in 2 cases (4%). The mean serum levels of 25-hydroxy vitamin D in the children with hemophilia during winter and autumn were significantly lower than that during summer (P = 0.0028 and P = 0.0091, respectively). A majority of our hemophilic patients (96%) had low vitamin D levels. The study showed that the risk of vitamin D deficiency is the most highest during winter and autumn. Normal lifelong vitamin D levels are especially important in hemophilia because of the possible synergistic effect of vitamin D levels on periarticular and general osteoporosis, which is intrinsic to hemophilic conditions. We advise routine checking of vitamin D levels twice a year and vitamin D supplementation to maintain its level between 30 and 100 ng/ml. PMID:25485786

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

    PubMed Central

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

  3. Child-Rearing Practices toward Children with Hemophilia: The Relative Importance of Clinical Characteristics and Parental Emotional Reactions.

    ERIC Educational Resources Information Center

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

    1999-01-01

    Addresses the relative importance of clinical characteristics of the child and parental emotional reactions, to child-rearing practices towards children with hemophilia. Results indicate that mother's emotional reactions appear to have a stronger influence on child-rearing uncertainty and overprotection than clinical characteristics of the child.…

  4. AAV-based Neonatal Gene Therapy for Hemophilia A: Long-Term Correction and Avoidance of Immune Responses in Mice

    PubMed Central

    Hu, Chuhong; Lipshutz, Gerald S.

    2012-01-01

    Hemophilia A gene therapy has been hampered by immune responses to vector-associated antigens and by neutralizing antibodies or inhibitors to the factor VIII (FVIII) protein; these ‘inhibitors’ more commonly effect 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. Serotype rh10 AAV was developed splitting the FVIII coding sequence into heavy and light chains with the chicken β-actin promoter/CMV enhancer for dual recombinant AAV vector delivery. Coinjection of virions of each FVIII chain intravenously to mice on the second day of life was performed. Mice express sustained FVIII antigen levels of ≥5% to 22 months of life without the development of antibodies to 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 to FVIII in this disease model where AAV is administered shortly after birth. These studies support consideration of gene replacement therapy for diseases that are diagnosed in utero or in the early neonatal period. PMID:22241178

  5. CRISPR/Cas9-mediated somatic correction of a novel coagulator factor IX gene mutation ameliorates hemophilia in mouse.

    PubMed

    Guan, Yuting; Ma, Yanlin; Li, Qi; Sun, Zhenliang; Ma, Lie; Wu, Lijuan; Wang, Liren; Zeng, Li; Shao, Yanjiao; Chen, Yuting; Ma, Ning; Lu, Wenqing; Hu, Kewen; Han, Honghui; Yu, Yanhong; Huang, Yuanhua; Liu, Mingyao; Li, Dali

    2016-01-01

    The X-linked genetic bleeding disorder caused by deficiency of coagulator factor IX, hemophilia B, is a disease ideally suited for gene therapy with genome editing technology. Here, we identify a family with hemophilia B carrying a novel mutation, Y371D, in the human F9 gene. The CRISPR/Cas9 system was used to generate distinct genetically modified mouse models and confirmed that the novel Y371D mutation resulted in a more severe hemophilia B phenotype than the previously identified Y371S mutation. To develop therapeutic strategies targeting this mutation, we subsequently compared naked DNA constructs versus adenoviral vectors to deliver Cas9 components targeting the F9 Y371D mutation in adult mice. After treatment, hemophilia B mice receiving naked DNA constructs exhibited correction of over 0.56% of F9 alleles in hepatocytes, which was sufficient to restore hemostasis. In contrast, the adenoviral delivery system resulted in a higher corrective efficiency but no therapeutic effects due to severe hepatic toxicity. Our studies suggest that CRISPR/Cas-mediated in situ genome editing could be a feasible therapeutic strategy for human hereditary diseases, although an efficient and clinically relevant delivery system is required for further clinical studies. PMID:26964564

  6. The Future of Hemophilia Treatment: Longer-Acting Factor Concentrates versus Gene Therapy.

    PubMed

    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. PMID:27148842

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

    PubMed Central

    Sarkar, Debalina; Biswas, Moanaro; Liao, Gongxian; Seay, Howard R; Perrin, George Q; Markusic, David M; Hoffman, Brad E; Brusko, Todd M; Terhorst, Cox; Herzog, Roland W

    2014-01-01

    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. PMID:25364772

  8. Acquired hemophilia possibly induced by etanercept in a patient with rheumatoid arthritis.

    PubMed

    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,<13) due to an anti-factor VIII antibody in a titer of 45 Bethesda units. Her factor VIII level was less than 1% (normal range, 55-150). The 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. PMID:25617259

  9. IDO1 suppresses inhibitor development in hemophilia A treated with factor VIII

    PubMed Central

    Matino, Davide; Gargaro, Marco; Santagostino, Elena; Di Minno, Matteo N.D.; Castaman, Giancarlo; Morfini, Massimo; Rocino, Angiola; Mancuso, Maria E.; Di Minno, Giovanni; Coppola, Antonio; Talesa, Vincenzo N.; Volpi, Claudia; Vacca, Carmine; Orabona, Ciriana; Iannitti, Rossana; Mazzucconi, Maria G.; Santoro, Cristina; Tosti, Antonella; Chiappalupi, Sara; Sorci, Guglielmo; Tagariello, Giuseppe; Belvini, Donata; Radossi, Paolo; Landolfi, Raffaele; Fuchs, Dietmar; Boon, Louis; Pirro, Matteo; Marchesini, Emanuela; Grohmann, Ursula; Puccetti, Paolo; Iorio, Alfonso; Fallarino, Francesca

    2015-01-01

    The development of inhibitory antibodies to factor VIII (FVIII) is a major obstacle in using this clotting factor to treat individuals with hemophilia A. Patients with a congenital absence of FVIII do not develop central tolerance to FVIII, and therefore, any control of their FVIII-reactive lymphocytes relies upon peripheral tolerance mechanisms. Indoleamine 2,3-dioxygenase 1 (IDO1) is a key regulatory enzyme that supports Treg function and peripheral tolerance in adult life. Here, we investigated the association between IDO1 competence and inhibitor status by evaluating hemophilia A patients harboring F8-null mutations that were either inhibitor negative (n = 50) or positive (n = 50). We analyzed IDO1 induction, expression, and function for any relationship with inhibitor occurrence by multivariable logistic regression and determined that defective TLR9-mediated activation of IDO1 induction is associated with an inhibitor-positive status. Evaluation of experimental hemophilic mouse models with or without functional IDO1 revealed that tryptophan metabolites, which result from IDO1 activity, prevent generation of anti-FVIII antibodies. Moreover, treatment of hemophilic animals with a TLR9 agonist suppressed FVIII-specific B cells by a mechanism that involves IDO1-dependent induction of Tregs. Together, these findings indicate that strategies aimed at improving IDO1 function should be further explored for preventing or eradicating inhibitors to therapeutically administered FVIII protein. PMID:26426076

  10. Tailoring hemostatic therapies to lower inhibitor development in previously untreated patients with severe hemophilia A.

    PubMed

    Mannucci, P M; Mancuso, M E; Franchini, M

    2016-07-01

    After technological progress provided safer therapeutic products for patients with hemophilia A, the development of alloantibodies (inhibitors) neutralizing the coagulant activity of infused factor VIII (FVIII) remains the most serious complication of replacement therapy, predisposing patients to greater morbidity and causing higher treatment costs. The pathogenesis of inhibitors, which develop at a high rate in previously untreated children with severe hemophilia A, is multifactorial, resulting from complex interactions between genetic and environmental factors. Among non-genetic determinants, a key role is played by treatment-related factors, including the source of FVIII product (i.e., plasma derived or recombinant) and the mode of replacement therapy delivery (i.e., intensity, prophylaxis vs. on demand). We review the potential interventions on these modifiable factors that may help to lower the rate of inhibitor development. In addition, interest is currently directed toward the potential for lesser immunogenicity of novel hemostatic agents designed to decrease the dosing frequency or avoid/delay the need of FVIII replacement therapy. PMID:27155314

  11. Severe hemophilia in a girl infant with mosaic Turner syndrome and persistent hyperplastic primary vitreous.

    PubMed

    Shahriari, Mahdi; Bazrafshan, Asghar; Moghadam, Mohamad; Karimi, Mehran

    2016-04-01

    A 6-month-old girl was referred by an ophthalmologist because of postoperative bleeding. She was scheduled for operation because of persistent hyperplastic primary vitreous. Workups were done and prolonged partial thromboplastin time with normal platelet count, normal bleeding time, and prothrombin time were detected. There was negative family history of bleeding tendency in both maternal and paternal family, so at the first step, Factor XI assay was requested which was normal. Then, von Willebrand factor and factor VIII were assayed which was 127% and less than 1%, respectively. Severe factor VIII deficiency was not suspected in a girl unless in siblings of a hemophilic patient who gets married with her carrier cousin. Chromosomal study and genetic testing were requested and mosaic Turner syndrome (45 XO) with ring X (p22, 2q13) along with inversion 22 (hemizygote) was detected. Abdominal and pelvic sonography showed absence of both ovaries with presence of infantile uterus. Maternal genetic study was in favor of carrier of hemophilia (heterozygote inversion 22). To the best of our knowledge, this is the first case of association of Turner syndrome with severe hemophilia A and persistent hyperplastic primary vitreous. PMID:26484646

  12. IDO1 suppresses inhibitor development in hemophilia A treated with factor VIII.

    PubMed

    Matino, Davide; Gargaro, Marco; Santagostino, Elena; Di Minno, Matteo N D; Castaman, Giancarlo; Morfini, Massimo; Rocino, Angiola; Mancuso, Maria E; Di Minno, Giovanni; Coppola, Antonio; Talesa, Vincenzo N; Volpi, Claudia; Vacca, Carmine; Orabona, Ciriana; Iannitti, Rossana; Mazzucconi, Maria G; Santoro, Cristina; Tosti, Antonella; Chiappalupi, Sara; Sorci, Guglielmo; Tagariello, Giuseppe; Belvini, Donata; Radossi, Paolo; Landolfi, Raffaele; Fuchs, Dietmar; Boon, Louis; Pirro, Matteo; Marchesini, Emanuela; Grohmann, Ursula; Puccetti, Paolo; Iorio, Alfonso; Fallarino, Francesca

    2015-10-01

    The development of inhibitory antibodies to factor VIII (FVIII) is a major obstacle in using this clotting factor to treat individuals with hemophilia A. Patients with a congenital absence of FVIII do not develop central tolerance to FVIII, and therefore, any control of their FVIII-reactive lymphocytes relies upon peripheral tolerance mechanisms. Indoleamine 2,3-dioxygenase 1 (IDO1) is a key regulatory enzyme that supports Treg function and peripheral tolerance in adult life. Here, we investigated the association between IDO1 competence and inhibitor status by evaluating hemophilia A patients harboring F8-null mutations that were either inhibitor negative (n = 50) or positive (n = 50). We analyzed IDO1 induction, expression, and function for any relationship with inhibitor occurrence by multivariable logistic regression and determined that defective TLR9-mediated activation of IDO1 induction is associated with an inhibitor-positive status. Evaluation of experimental hemophilic mouse models with or without functional IDO1 revealed that tryptophan metabolites, which result from IDO1 activity, prevent generation of anti-FVIII antibodies. Moreover, treatment of hemophilic animals with a TLR9 agonist suppressed FVIII-specific B cells by a mechanism that involves IDO1-dependent induction of Tregs. Together, these findings indicate that strategies aimed at improving IDO1 function should be further explored for preventing or eradicating inhibitors to therapeutically administered FVIII protein. PMID:26426076

  13. Joining the patient on the path to customized prophylaxis: one hemophilia team explores the tools of engagement

    PubMed Central

    Gue, Deborah; Squire, Sandra; McIntosh, Kam; Bartholomew, Claude; Summers, Nicole; Sun, Haowei; Yang, Ming; Jackson, Shannon

    2015-01-01

    Background The relationship between hemophilia team interventions and achievement of optimal clinical outcomes remains to be elucidated. The British Columbia Hemophilia Adult Team has previously reported results of a comprehensive approach to individualize prophylaxis that has resulted in substantially reduced bleeding rates. In order to facilitate knowledge exchange and potential replication, it was important to gain a thorough understanding of the team’s approach. Methods A focus group of the British Columbia Hemophilia Adult Team was conducted to identify specific roles and processes that might be contributing to the prophylaxis regimen outcomes in this clinic. The focus group consisted of two workshops; one to describe the individual and collective roles of the clinic team in providing clinical care and guiding patients toward individualized prophylaxis; and the other to describe the patient journey from initial contact through reaching a successful engagement with the clinic. Results Analysis of the results revealed team roles and processes that underpinned a shared decision-making relationship with the patient with a particular focus on supporting the patient’s autonomy. Within this relationship, team focus shifts away from “adherence” toward the process whereby patients design and implement prophylaxis regimens resulting in reduction or elimination of bleeding episodes. Limitations Using the current methodology, it is not possible to demonstrate a causal link between specific team processes and improved bleeding rates in patients. Conclusion Through the active support of patient autonomy in all aspects of decisions related to hemophilia management, the British Columbia Hemophilia Adult Team approach de-emphasizes “adherence” as the primary goal, and focuses on a prophylaxis plan that is customized by the patient and aligned with his priorities. Adoption of this comprehensive team approach facilitates shared goals between the patient and the team

  14. Marker and real-time quantitative analyses to confirm hemophilia B carrier diagnosis of a complete deletion of the F9 gene.

    PubMed

    Venceslá, Adoración; Barceló, María Jesús; Baena, Manel; Quintana, Manuel; Baiget, Montserrat; Tizzano, Eduardo F

    2007-11-01

    Approximately 3% of hemophilia B patients have major deletions in the F9 gene, half of which are complete. Marker and quantitative PCR analyses were employed for carrier diagnosis in a family of a mentally retarded hemophilia B patient with a total deletion of the F9 gene and neighbor genes. Both methodologies allowed the confirmation of carrier or non-carrier status. PMID:18024414

  15. Analysis of factor VIII gene inversions in 164 unrelated hemophilia A families

    SciTech Connect

    Vnencak-Jones, L.; Phillips, J.A. III; Janco, R.L.

    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.

  16. Perceptions of Men With Moderate to Severe Hemophilia Regarding the Management of Their Chronic Disorder and Utilization of Community-Based Support.

    PubMed

    Rolstad, Erik B

    2015-11-01

    Hemophilia is a genetic bleeding disorder that almost exclusively affects men. There is a nationwide network of nonprofit organizations providing support to men with hemophilia, which are affiliated with localized agencies that serve affected individuals within specific regions of the country. This community-based study was implemented in response to a local Utah agency's concern that men with hemophilia may be disengaged from and underserved by their local support network. The goal of the study was to gain a better understanding of the (a) unique challenges, (b) adaptations, and (c) physical, financial, psychological, and social needs of adult men with moderate to severe hemophilia from the local community. Over a period of 9 months, verbal qualitative interviews were conducted with 10 affected individuals, and written interviews were obtained from 3 additional participants. Using a grounded-theory approach, six themes were identified, based on men's commentary from interviews, across a spectrum of physical, social, communal, personal, medical, and vocational dimensions. Resilience theory, which explores internal resources that assist in coping with adverse situations, was used as a framework for interpreting research results. Findings indicate that men value the array of educational, social, and medical services that are available to them but choose to manage their hemophilia independently from the community and access support according to their individual needs. Understanding this dynamic may be helpful in developing services that are more specifically tailored to the physical and psychosocial needs of adult men with hemophilia and, potentially, men with other chronic health disorders. PMID:25294868

  17. Anti-inflammatory/regulatory cytokine microenvironment mediated by IL-4 and IL-10 coordinates the immune response in hemophilia A patients infected chronically with hepatitis C virus.

    PubMed

    Pimentel, João Paulo; Chaves, Daniel Gonçalves; Araújo, Ana Ruth Silva; de Araújo, Erbênia Maria Martins; da Silva Fraporti, Liziara; Neves, Walter Luiz Lima; Tarragô, Andrea Monteiro; Torres, Katia Luz; Gentz, Solange Henschke Lima; Teixeira-Carvalho, Andréa; Martins-Filho, Olindo Assis; Malheiro, Adriana

    2013-06-01

    In the past decades patients with hemophilia were infected commonly by hepatitis C virus (HCV) and a significant number of patients are infected chronically. Focusing on the role of the immune system for controlling and or maintaining HCV infection, the leukocyte and cytokine profiles of peripheral blood from hemophilia A patients and other patients with and without HCV infection were studied. The results demonstrated that hemophilia A is characterized by a general state of circulating leukocytes activation along with an overall increase in the frequency of IL-6 and IL-10 with decrease of IL-8 and IL-12. HCV infection of patients with hemophilia A does not influence further the activation state of circulating leukocytes but is accompanied by lower levels of alanine transaminase (ALT) and a prominent anti-inflammatory/regulatory serum cytokine pattern, mediated by IL-4 and IL-10. Additionally, the results demonstrated that hemophilia A patients infected with HCV displaying No/Low antibody response to C33c and C22 have significant lower viral load and higher serum levels of IL-12 and IL-4. This finding suggests that the differential RIBA reactivity to C33c/C22 HCV core proteins may have a putative value as a prognostic biomarker for the infection in hemophilia A patients. PMID:23591975

  18. Half-life extended factor VIII for the treatment of hemophilia A.

    PubMed

    Tiede, A

    2015-06-01

    Prophylactic infusion of factor VIII (FVIII) prevents joint bleeding and other hemorrhages in patients with hemophilia A. Conventional FVIII concentrates have a short half-life, with an average of about 12 h in adults, ranging in individual patients between 6 and 24 h, and even shorter in younger children. Therefore, effective prophylaxis requires frequent intravenous injection, usually three times per week or every other day. Several technologies are currently under investigation to extend the half-life of FVIII, including Fc fusion (Eloctate, Elocta, efmoroctocog alfa), addition of polyethylene glycol (turoctocog alfa pegol [N8-GP], BAY 94-9027, BAX 855), and a single-chain construct (CSL627). This review summarizes characteristics of products in clinical development and discusses their potential benefits. PMID:26149020

  19. Intraosseous Delivery of Lentiviral Vectors Targeting Factor VIII Expression in Platelets Corrects Murine Hemophilia A

    PubMed Central

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

    2015-01-01

    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. PMID:25655313

  20. Prophylactic efficacy of BeneFIX vs Alprolix in hemophilia B mice.

    PubMed

    Cooley, Brian; Funkhouser, William; Monroe, Dougald; Ezzell, Ashley; Mann, David M; Lin, Feng-Chang; Monahan, Paul E; Stafford, Darrel W

    2016-07-14

    FIX binds tightly to collagen IV. Furthermore, a FIX mutant, FIXK5R, which binds better than wild-type FIX to collagen IV, provides better hemostasis than wild-type FIX, long after both are undetectable in the plasma. There is also credible evidence of extravascular FIX. Here, we use the saphenous vein bleeding model to compare the efficacy of recombinant FIXFc (Alprolix) and wild-type FIX (BeneFIX) in hemophilia B mice 7 days postinfusion. Although the terminal half-life of Alprolix is significantly longer than that of BeneFIX, at equal doses Alprolix is not better at controlling bleeding 7 days postinfusion, presumably because of the extravascular FIX. Both BeneFIX and Alprolix exhibit a linear response in clotting efficacy up to 150 IU/kg, where they appear to saturate an extravascular compartment, because there is no additional prophylactic benefit from higher doses. A robust pool of extravascular FIX is clearly observed surrounding blood vessels, localized to the same region as collagen IV, in 2 representative human tissues: liver and skeletal muscle. We see no increased risk for thrombosis at 250 IU/kg FIX at 6 hours postinfusion. In summary, 7 days postinfusion into hemophilia B mice, BeneFIX and Alprolix are hemostatically indistinguishable despite the latter's increased half-life. We predict that doses of FIX ∼3 times higher than the currently recommended 40 to 50 IU/kg will, because of FIX's large extravascular compartment, efficiently prolong prophylactic hemostasis without thrombotic risk. PMID:27106122

  1. MicroRNA-15b Modulates Molecular Mediators of Blood Induced Arthropathy in Hemophilia Mice

    PubMed Central

    Sen, Dwaipayan; Jayandharan, Giridhara R.

    2016-01-01

    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. PMID:27070581

  2. Analysis of inversions in the factor VIII gene in Spanish hemophilia A patients and families

    SciTech Connect

    Domenech, M.; Tizzano, E.; Baiget, M.; Altisent, C.

    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.

  3. Spectrum of mutations in CRM-positive and CRM-reduced hemophilia A

    SciTech Connect

    McGinniss, M.J.; Kazazian, H.H. Jr.; Bi, L.; Antonarakis, S.E. ); Hoyer, L.W. ); Inaba, H. )

    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.

  4. Sclerotherapy Of Esophageal Varices In Severe Hemophilia A Patient And High Titer Inhibitor--Case Report.

    PubMed

    Szczepanik, Andrzej B; Dąbrowski, Wojciech P; Szczepanik, Anna M; Pielaciński, Konrad; Jaśkowiak, Wojciech

    2015-09-01

    In cirrhotic hemophilia patients bleeding from esophageal varices is a serious clinical condition due to congenital deficiency of clotting factors VIII or IX, decreased prothrombin synthesis and hypersplenic thrombocytopenia. In hemophiliac with high-titer inhibitor bypassing therapy is required with activated prothrombin complex concentrates (aPCC) or recombinant activated coagulation factor VII (rFVIIa). Doses and duration treatment with these agents following endoscopic treatment of esophageal varices have not been yet established. Authors report the first case of a severe hemophilia A patient with high titer inhibitor (40 BU) treated with repeated injection sclerotherapy. The patient was admitted with symptoms of massive esophageal variceal hemorrhage ceased with emergency sclerotherapy. Bypassing therapy was administered with aPCC at initial dose of 72.5 U/kg and then with average daily dose of 162 U/kg through 5 days. To achieved a total eradication of esophageal varices the patient was then subjected to four elective sclerotherapy procedures. Two were covered by aPCC with daily dose of 120 U/kg and 145 U/kg for 4 and 3 days respectively and the following two procedures were covered by rFVIIa with the initial dose of 116 µg/kg and the next doses of 87 µg/kg administered every 3 hours in procedure day and every 4 hours on the next two days. During all procedures excellent hemostasis was achieved and no hemorrhagic or thromboembolic complications were observed. Bypassing regimen therapy with aPCC and rFVIIa we applied have been shown to be safe and effective in this patient subjected to sclerotherapy procedures. PMID:26812842

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

    PubMed

    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. PMID:25927594

  6. Recombinant Factor IX Fc Fusion Protein Maintains Full Procoagulant Properties and Exhibits Prolonged Efficacy in Hemophilia B Mice

    PubMed Central

    Toby, Garabet G.; Liu, Tongyao; Buyue, Yang; Zhang, Xin; Bitonti, Alan J.; Pierce, Glenn F.; Sommer, Jurg M.; Jiang, Haiyan; Peters, Robert T.

    2016-01-01

    Introduction Hemophilia B is an inherited X chromosome–linked disorder characterized by impaired blood clotting owing to the absence of functional coagulation factor IX. Due to the relatively short half-life of factor IX, patients with hemophilia B require frequent factor IX infusions to maintain prophylaxis. We have developed a recombinant factor IX (rFIX) fused to the Fc region of IgG (rFIXFc) with an extended half-life in animals and humans. Materials and Methods Procoagulant properties of rFIXFc and rFIX (BENEFIX®) were compared to determine the effect of the Fc region on rFIXFc hemostatic function. Specifically, we assessed rFIXFc activation, intermolecular interactions within the Xase complex, inactivation by antithrombin III (AT) and thrombin generation potential compared with rFIX. We also assessed the acute and prophylactic efficacy profiles of rFIXFc and rFIX in vivo in hemophilia B mouse bleeding models. Results and Conclusions The activation by factor XIa or factor VIIa/tissue factor, inhibition by AT, interaction profiles with phospholipids, affinities for factor VIIIa within the context of the Xase complex, and thrombin generation profiles were similar for rFIXFc and rFIX. Xase complexes formed with either molecule exhibited similar kinetic profiles for factor Xa generation. In acute efficacy models, mice infused with rFIXFc or rFIX were equally protected from bleeding. However, in prophylactic efficacy models, protection from bleeding was maintained approximately three times longer in rFIXFc-dosed mice than in those given rFIX; this prolonged efficacy correlates with the previously observed half-life extension. We conclude that rFIXFc retains critical FIX procoagulant attributes and that the extension in rFIXFc half-life translates into prolonged efficacy in hemophilia B mice. PMID:26840952

  7. Hemophilia B

    MedlinePlus

    ... PA: Elsevier Saunders; 2013:chap 137. Scott JP, Flood VH. Hereditary clotting factor deficiencies (bleeding disorders). In: ... writing by ADAM Health Solutions. About MedlinePlus Site Map FAQs Contact Us Get email updates Subscribe to ...

  8. Hemophilia B

    MedlinePlus

    ... tract bleeding Nosebleeds Prolonged bleeding from cuts, tooth extraction, and surgery Bleeding that starts without cause ... chap 476. Srivastava A, Brewer AK, Mauser-Bunschoten EP, et al. Treatment Guidelines Working Group on Behalf ...

  9. Acquired hemophilia A as a cause of recurrent bleeding into the pleural cavity - case report and literature review.

    PubMed

    Wojtyś, Małgorzata; Żuk, Ewa; Alchimowicz, Jacek; Grodzki, Tomasz

    2014-09-01

    Acquired hemophilia A is a coagulation disorder caused by autoantibodies against blood coagulation factor VIII. The first sign of this disease is often massive bleeding, which can affect patients after routine procedures. The parameter which indicates the presence of this condition is isolated prolonged activated partial thromboplastin time (APTT). The present article describes a case of a 32-year-old man with acute interstitial pneumonia and pleural effusion, in whom a massive hemothorax appeared after thoracocentesis; active bleeding was observed after the introduction of a chest tube. The patient was operated on, and no pinpoint bleeding was discovered during the procedure. Active bleeding was still taking place postoperatively. The patient underwent another operation after 6 days. Once more, no pinpoint bleeding was found. Prolonged APTT was observed. The activity of blood coagulation factor VIII was 3.04%. The presence of antibodies against factor VIII was confirmed, and acquired hemophilia was diagnosed. The article also includes an analysis of the literature on acquired hemophilia. PMID:26336444

  10. Perioperative management of hemophilia patients receiving total hip and knee arthroplasty: a complication report of two cases

    PubMed Central

    Tateiwa, Toshiyuki; Takahashi, Yasuhito; Ishida, Tsunehito; Kubo, Kosuke; Masaoka, Toshinori; Shishido, Takaaki; Sano, Keiji; Yamamoto, Kengo

    2015-01-01

    It has been recognized that perioperative hemostasis management after joint-replacement surgery for hemophilia patients is complicated and cumbersome, due to the necessity of rigorous monitoring for clotting-factor levels throughout the infusion. Between 2005 and 2014, we examined seven patients with hemophilia A (ten joints: six hips and four knees) receiving total hip or knee arthroplasty (THA or TKA) for hemophilic arthropathy. One male patient (31 years old) showed an intra-articular hematoma formation after THA (case 1). In another male patient (46 years old) receiving TKA, the postoperative trough factor VIII level became lower significantly than reference levels (80%–100% for the 5–10 postoperative days) recommended by the guidelines from the Japanese Society on Thrombosis and Hemostasis, despite sufficient coagulant based on the guidelines being administered (case 2). In the latter patient, deep infection and hematoma formation were observed postoperatively. In this article, we provide a detailed clinical report regarding these two complication cases at the early postoperative periods, and the management of bleeding control for hemophilia patients is discussed. PMID:26396523

  11. [A quick and efficient method to generate hemophilia B mouse models by the CRISPR/Cas system].

    PubMed

    Qihan, Wang; Cong, Huai; Ruilin, Sun; Hua, Zhuang; Hongyan, Chen; Jian, Fei; Daru, Lu

    2015-11-01

    Hemophilia B, or the Christmas disease, is a common human disease caused by coagulation factor Ⅸ (FⅨ) deficiency. It is an X-linked recessive hereditary disease. Here we obtained FⅨ-knockout mouse strains with phenotype of hemophilia B with the CRISPR/Cas system efficiently. We chose the 8th exon as the target locus, and co-injected codon-optimized Cas9 mRNA with sgRNA of FⅨ into C57BL/6 mice zygotes. We obtained 60 mice in total and genotyped them by high resolution melting (HRM) and sequencing. The results showed the mutation rate was 85.0% in total, and 79.5% and 95.2% in males and females, respectively. No off-targets were detected in the similar locus by HRM. We future measured the FⅨ activity of each mice. The FⅨ: C of mutant mice were significantly below the normal level and reduced to 6.82% of wild-type mice. The activity assay demonstrated that all the mutant mice were lack of FⅨ. In summary, we have generated hemophilia B model mice with extreme efficiency, using the RNA-guided Cas9 nuclease gene editing system. PMID:26582528

  12. Highly effective peginterferon α-2a plus ribavirin combination therapy for chronic hepatitis C in hemophilia in Korea

    PubMed Central

    Yang, Suh Yoon; Lee, Hyun Woong; Lee, Youn Jae; Park, Sung Jae; Yoo, Ki Young

    2015-01-01

    Background/Aims Chronic hepatitis C (CHC) is a major comorbidity in patients with hemophilia. However, there are no published data on the efficacy of antiviral therapy in Korea. We assessed the safety and efficacy of combination therapy with peginterferon α-2a plus ribavirin for CHC in hemophilia. Methods Patients (n=115) were enrolled between March 2007 and December 2008. Seventy-seven patients were genotype 1 or 6, and 38 patients were genotype 2 or 3. We evaluated rapid virologic responses (RVRs), early virologic response (EVRs), end-of-treatment response (ETRs), sustained virologic response (SVRs), and relapses. Safety evaluations included adverse events and laboratory tests. Results Eleven patients were excluded from the study because they had been treated previously. Among the remaining 104 treatment-naïve patients, RVR was achieved in 64 (60.6%), ETR was achieved in 95 (91.3%), and SVR was achieved in 89 (85.6%). Relapse occurred in eight patients (8.9%). Common adverse events were hair loss (56.7%) and headache (51.0%). Common hematologic adverse events were neutropenia (22.1%), anemia (27.9%), and thrombocytopenia (3.8%). However, there were no serious adverse events such as bleeding. RVR was the only predictor of SVR in multivariate analysis. Conclusions Peginterferon α-2a plus ribavirin combination treatment produced a favorable response rate in CHC patients with hemophilia without serious adverse events. PMID:26157749

  13. Issues in assessing products for the treatment of hemophilia – the intersection between efficacy, economics, and ethics

    PubMed Central

    Farrugia, Albert; Noone, Declan; Schlenkrich, Uwe; Schlenkrich, Steffen; O’Mahony, Brian; Cassar, Josephine

    2015-01-01

    Following the obviation of the pathogen safety threats posed by previous generations of clotting factor concentrates for the treatment of hemophilia, the principal issue facing the patient community is timely access to adequate supplies of continuously improving therapies. The application of evidence-based medicine has enhanced the basis of hemophilia therapy, while resulting in some challenges to patient care. Increasingly, the criteria used for the approval and payment of treatment products by regulatory and reimbursement agencies, respectively, are becoming inflexible and unrealistic. This is occurring particularly in the requirements for demonstrating product efficacy. Concurrently, emerging evidence of the interpatient variability in the clinical response to therapy has led to the proposed personalization of therapeutic regimens. Possible impediments to optimal care include competitive tensions among suppliers who seek to gain label claims for reimbursement purposes, which result in clinical trial designs of, arguably, unethical design, carried out in poor countries. We synthesize these converging developments to suggest some changes to the current hemophilia treatment paradigm, which should make it more patient-centric and enable speedier access to new therapies. PMID:26124687

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

    PubMed Central

    Lin, Shin-Yu; Su, Yi-Ning; Hung, Chia-Cheng; Tsay, Woei; Chiou, Shyh-Shin; Chang, Chieh-Ting; Ho, Hong-Nerng; Lee, Chien-Nan

    2008-01-01

    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. PMID:18565236

  15. Molecular characterization of severe hemophilia A suggests that about half the mutations are not within the coding regions and splice junctions of the factor VIII gene

    SciTech Connect

    Higuchi, Miyoko; Kazazian, H.H. Jr.; Kasch, L.; Warren, T.C.; McGinniss, M.J.; Antonarakis, S.E. ); Phillips, J.A. III; Janco, R. ); Kasper, C. )

    1991-08-15

    Hemophilia A is an X chromosome-linked disorder resulting from deficiency of factor VIII, an important protein in blood coagulation. A large number of disease-producing mutations have been reported in the factor VIII gene. However, a comprehensive analysis of the mutations has been difficult because of the larger gene size, its many scattered exons, and the high frequency of de novo mutations. Recently, the authors have shown that nearly all mutations resulting in mild-to-moderate hemophilia A can be detected by PCR and denaturing gradient gel electrophoresis (DGGE). In this study, they attempted to discover the mutations causing severe hemophilia A by analyzing 47 unselected patients, 30 of whom had severe hemophilia and 17 of whom had mild-to-moderate disease. Using DGGE as a screening method, they analyzed 99% of the coding region, 94% of the splice junctions, the promoter region, and the polyadenylylation site of the gene. They found the mutation in 16 of 17 (94%) patients with mild-to-moderate disease but in only 16 of 30 (53%) patients with severe hemophilia A.

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

    PubMed

    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. PMID:25828422

  17. Hemophilia A Pseudoaneurysm in a Patient with High Responding Inhibitors Complicating Total Knee Arthroplasty: Embolization: A Cost-Reducing Alternative to Medical Therapy

    SciTech Connect

    Kickuth, Ralph Anderson, Suzanne; Peter-Salonen, Kristiina; Laemmle, Bernhard; Eggli, Stefan; Triller, Juergen

    2006-12-15

    Joint hemorrhages are very common in patients with severe hemophilia. Inhibitors in patients with hemophilia are allo-antibodies that neutralize the activity of the clotting factor. After total knee replacement, rare intra-articular bleeding complications might occur that do not respond to clotting factor replacement. We report a 40-year-old male with severe hemophilia A and high responding inhibitors presenting with recurrent knee joint hemorrhage after bilateral knee prosthetic surgery despite adequate clotting factor treatment. There were two episodes of marked postoperative hemarthrosis requiring extensive use of subsititution therapy. Eleven days postoperatively, there was further hemorrhage into the right knee. Digital subtraction angiography diagnosed a complicating pseudoaneurysm of the inferior lateral geniculate artery and embolization was successfully performed. Because clotting factor replacement therapy has proved to be excessively expensive and prolonged, especially in patients with inhibitors, we recommend the use of cost-effective early angiographic embolization.

  18. Human von Willebrand factor/factor VIII concentrates in the management of pediatric patients with von Willebrand disease/hemophilia A

    PubMed Central

    Castaman, Giancarlo; Linari, Silvia

    2016-01-01

    Several plasma-derived intermediate and high-purity concentrates containing von Willebrand factor (VWF) and factor VIII (FVIII) are currently available. The main role of these products in the management of the pediatric population is represented by the replacement therapy in patients with severe or intermediate forms of von Willebrand disease, in whom other treatments are ineffective or contraindicated. Another important role of VWF/FVIII concentrates in children may be their use in immune tolerance induction (ITI) protocols. ITI is particularly recommended for hemophilia A children who have developed an inhibitor against FVIII, currently the most serious complication of substitutive treatment in hemophilia. Although recombinant concentrates may represent the preferred option in children with hemophilia A, VWF/FVIII concentrates may offer an advantage in rescuing patients who failed previous ITI. PMID:27445481

  19. Human von Willebrand factor/factor VIII concentrates in the management of pediatric patients with von Willebrand disease/hemophilia A.

    PubMed

    Castaman, Giancarlo; Linari, Silvia

    2016-01-01

    Several plasma-derived intermediate and high-purity concentrates containing von Willebrand factor (VWF) and factor VIII (FVIII) are currently available. The main role of these products in the management of the pediatric population is represented by the replacement therapy in patients with severe or intermediate forms of von Willebrand disease, in whom other treatments are ineffective or contraindicated. Another important role of VWF/FVIII concentrates in children may be their use in immune tolerance induction (ITI) protocols. ITI is particularly recommended for hemophilia A children who have developed an inhibitor against FVIII, currently the most serious complication of substitutive treatment in hemophilia. Although recombinant concentrates may represent the preferred option in children with hemophilia A, VWF/FVIII concentrates may offer an advantage in rescuing patients who failed previous ITI. PMID:27445481

  20. Orthopedic disorders of the knee in hemophilia: A current concept review

    PubMed Central

    Rodriguez-Merchan, E Carlos; Valentino, Leonard A

    2016-01-01

    The knee is frequently affected by severe orthopedic changes known as hemophilic arthropathy (HA) in patients with deficiency of coagulation factor VIII or IX and thus this manuscript seeks to present a current perspective of the role of the orthopedic surgeon in the management of these problems. Lifelong factor replacement therapy (FRT) is optimal to prevent HA, however adherence to this regerous treatment is challenging leading to breakthrough bleeding. In patients with chronic hemophilic synovitis, the prelude to HA, radiosynovectomy (RS) is the optimal to ameliorate bleeding. Surgery in people with hemophilia (PWH) is associated with a high risk of bleeding and infection, and must be performed with FRT. A coordinated effort including orthopedic surgeons, hematologists, physical medicine and rehabilitation physicians, physiotherapists and other team members is key to optimal outcomes. Ideally, orthopedic procedures should be performed in specialized hospitals with experienced teams. Until we are able to prevent orthopedic problems of the knee in PWH will have to continue performing orthopedic procedures (arthrocentesis, RS, arthroscopic synovectomy, hamstring release, arthroscopic debridement, alignment osteotomy, and total knee arthroplasty). By using the aforementioned procedures, the quality of life of PWH will be improved. PMID:27335812

  1. Phenotypic correction of hemophilia A in sheep by postnatal intraperitoneal transplantation of FVIII-expressing MSC.

    PubMed

    Porada, Christopher D; Sanada, Chad; Kuo, Chung-Jung; Colletti, Evan; Mandeville, Walter; Hasenau, John; Zanjani, Esmail D; Moot, Robert; Doering, Christopher; Spencer, H Trent; Almeida-Porada, Graça

    2011-12-01

    We recently re-established a line of sheep that accurately mimics the clinical symptoms and genetics of severe hemophilia A (HA). Here, we tested a novel, nonablative transplantation therapy in two pediatric HA animals. Paternal mesenchymal stem cells (MSC) were transduced with a porcine FVIII-encoding lentivector and transplanted via the intraperitoneal route without preconditioning. At the time of transplantation, these animals had received multiple human FVIII treatments for various spontaneous bleeds and had developed debilitating hemarthroses, which produced severe defects in posture and gait. Transplantation of transduced MSC resolved all existent hemarthroses, and spontaneous bleeds ceased. Damaged joints recovered fully; the animals regained normal posture and gait and resumed normal activity. Despite achieving factor-independence, a sharp rise in pre-existent Bethesda titers occurred following transplantation, decreasing the effectiveness and duration of therapy. Postmortem examination revealed widespread engraftment, with MSC present within the lung, liver, intestine, and thymus, but particularly within joints affected at the time of transplantation, suggesting MSC homed to sites of ongoing injury/inflammation to release FVIII, explaining the dramatic improvement in hemarthrotic joints. In summary, this novel, nonablative MSC transplantation was straightforward, safe, and converted life-threatening, debilitating HA to a moderate phenotype in a large animal model. PMID:21906573

  2. Principles of genetic variations and molecular diseases: applications in hemophilia A.

    PubMed

    Lannoy, N; Hermans, C

    2016-08-01

    DNA structure alterations are the ultimate source of genetic variations. Without them, evolution would be impossible. While they are essential for DNA diversity, defects in DNA synthesis can lead to numerous genetic diseases. Due to increasingly innovative technologies, our knowledge of the human genome and genetic diseases has grown considerably over the last few years, allowing us to detect another class of variants affecting the chromosomal structure. DNA sequence can be altered in multiple ways: DNA sequence changes by substitution, deletion, or duplication of some nucleotides; chromosomal structure alterations by deletion, duplication, translocation, and inversion, ranging in size from kilobases to mega bases; changes in the cell's genome size. If the alteration is located within a gene and sufficiently deleterious, it can cause genetic disorders. Due to the F8 gene's high rate of new small mutations and its location at the tip of X chromosome, containing high repetitive sequences, a wide variety of genetic variants has been described as the cause of hemophilia A (HA). In addition to the F8 intron 22 repeat inversion, HA can also result from point mutations, other inversions, complex rearrangements, such as duplications or deletions, and transposon insertions causing phenotypes of variable severity characterized by complete or partial deficiency of circulating FVIII. This review aims to present the origins, mechanisms, and consequences of F8 alterations. A sound understanding of the multiple genetic mechanisms responsible for HA is essential to determine the appropriate strategy for molecular diagnosis and detected each type of genetic variant. PMID:27296059

  3. Orthopedic disorders of the knee in hemophilia: A current concept review.

    PubMed

    Rodriguez-Merchan, E Carlos; Valentino, Leonard A

    2016-06-18

    The knee is frequently affected by severe orthopedic changes known as hemophilic arthropathy (HA) in patients with deficiency of coagulation factor VIII or IX and thus this manuscript seeks to present a current perspective of the role of the orthopedic surgeon in the management of these problems. Lifelong factor replacement therapy (FRT) is optimal to prevent HA, however adherence to this regerous treatment is challenging leading to breakthrough bleeding. In patients with chronic hemophilic synovitis, the prelude to HA, radiosynovectomy (RS) is the optimal to ameliorate bleeding. Surgery in people with hemophilia (PWH) is associated with a high risk of bleeding and infection, and must be performed with FRT. A coordinated effort including orthopedic surgeons, hematologists, physical medicine and rehabilitation physicians, physiotherapists and other team members is key to optimal outcomes. Ideally, orthopedic procedures should be performed in specialized hospitals with experienced teams. Until we are able to prevent orthopedic problems of the knee in PWH will have to continue performing orthopedic procedures (arthrocentesis, RS, arthroscopic synovectomy, hamstring release, arthroscopic debridement, alignment osteotomy, and total knee arthroplasty). By using the aforementioned procedures, the quality of life of PWH will be improved. PMID:27335812

  4. Engineering protein processing of the mammary gland to produce abundant hemophilia B therapy in milk

    PubMed Central

    Zhao, Jianguo; Xu, Weijie; Ross, Jason W.; Walters, Eric M.; Butler, Stephen P.; Whyte, Jeff J.; Kelso, Lindsey; Fatemi, Mostafa; Vanderslice, Nicholas C.; Giroux, Keith; Spate, Lee D.; Samuel, Melissa S.; Murphy, Cliff N.; Wells, Kevin D.; Masiello, Nick C.; Prather, Randall S.; Velander, William H.

    2015-01-01

    Both the low animal cell density of bioreactors and their ability to post-translationally process recombinant factor IX (rFIX) limit hemophilia B therapy to <20% of the world’s population. We used transgenic pigs to make rFIX in milk at about 3,000-fold higher output than provided by industrial bioreactors. However, this resulted in incomplete γ-carboxylation and propeptide cleavage where both processes are transmembrane mediated. We then bioengineered the co-expression of truncated, soluble human furin (rFurin) with pro-rFIX at a favorable enzyme to substrate ratio. This resulted in the complete conversion of pro-rFIX to rFIX while yielding a normal lactation. Importantly, these high levels of propeptide processing by soluble rFurin did not preempt γ-carboxylation in the ER and therefore was compartmentalized to the Trans-Golgi Network (TGN) and also to milk. The Golgi specific engineering demonstrated here segues the ER targeted enhancement of γ-carboxylation needed to biomanufacture coagulation proteins like rFIX using transgenic livestock. PMID:26387706

  5. Engineering protein processing of the mammary gland to produce abundant hemophilia B therapy in milk.

    PubMed

    Zhao, Jianguo; Xu, Weijie; Ross, Jason W; Walters, Eric M; Butler, Stephen P; Whyte, Jeff J; Kelso, Lindsey; Fatemi, Mostafa; Vanderslice, Nicholas C; Giroux, Keith; Spate, Lee D; Samuel, Melissa S; Murphy, Cliff N; Wells, Kevin D; Masiello, Nick C; Prather, Randall S; Velander, William H

    2015-01-01

    Both the low animal cell density of bioreactors and their ability to post-translationally process recombinant factor IX (rFIX) limit hemophilia B therapy to <20% of the world's population. We used transgenic pigs to make rFIX in milk at about 3,000-fold higher output than provided by industrial bioreactors. However, this resulted in incomplete γ-carboxylation and propeptide cleavage where both processes are transmembrane mediated. We then bioengineered the co-expression of truncated, soluble human furin (rFurin) with pro-rFIX at a favorable enzyme to substrate ratio. This resulted in the complete conversion of pro-rFIX to rFIX while yielding a normal lactation. Importantly, these high levels of propeptide processing by soluble rFurin did not preempt γ-carboxylation in the ER and therefore was compartmentalized to the Trans-Golgi Network (TGN) and also to milk. The Golgi specific engineering demonstrated here segues the ER targeted enhancement of γ-carboxylation needed to biomanufacture coagulation proteins like rFIX using transgenic livestock. PMID:26387706

  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

    PubMed Central

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

    2015-01-01

    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. Globally, nurse and social worker involvement increased with disability and pain; physiotherapist utilization was moderate regardless of the extent of disability or pain. Conclusion Increased disability and pain were associated with increased age, lower employment, higher reported bleed frequency, and lower HRQoL. PMID:26604708

  7. Coronary artery bypass grafting in a patient with hemophilia B: continuous recombinant factor IX infusion as per the Japanese guidelines for replacement therapy.

    PubMed

    Suzuki, Tomoyuki; Kawamoto, Shunsuke; Kumagai, Kiichiro; Adachi, Osamu; Kanda, Keisuke; Ishikawa, Masaaki; Okitsu, Yoko; Harigae, Hideo; Kurosawa, Shin; Saiki, Yoshikatsu

    2016-08-01

    We herein report our experience of successfully managing the hemostatic system by controlling serum factor IX levels throughout the perioperative period in a patient with hemophilia B. Coronary artery bypass grafting with cardiopulmonary bypass was planned for a 52-year-old man with moderate severity of hemophilia B. During surgery, recombinant factor IX (rFIX; BeneFIX(®) Pfizer Japan inc., Tokyo, Japan) was administered by bolus infusion followed by continuous infusion as per the guidelines of the Japanese Society on Thrombosis and Hemostasis. The operative course was uneventful without any considerable bleeding or complications. PMID:25523881

  8. A genome-wide association study of resistance to HIV infection in highly exposed uninfected individuals with hemophilia A

    PubMed Central

    Lane, Jérôme; McLaren, Paul J.; Dorrell, Lucy; Shianna, Kevin V.; Stemke, Amanda; Pelak, Kimberly; Moore, Stephen; Oldenburg, Johannes; Alvarez-Roman, Maria Teresa; Angelillo-Scherrer, Anne; Boehlen, Francoise; Bolton-Maggs, Paula H.B.; Brand, Brigit; Brown, Deborah; Chiang, Elaine; Cid-Haro, Ana Rosa; Clotet, Bonaventura; Collins, Peter; Colombo, Sara; Dalmau, Judith; Fogarty, Patrick; Giangrande, Paul; Gringeri, Alessandro; Iyer, Rathi; Katsarou, Olga; Kempton, Christine; Kuriakose, Philip; Lin, Judith; Makris, Mike; Manco-Johnson, Marilyn; Tsakiris, Dimitrios A.; Martinez-Picado, Javier; Mauser-Bunschoten, Evelien; Neff, Anne; Oka, Shinichi; Oyesiku, Lara; Parra, Rafael; Peter-Salonen, Kristiina; Powell, Jerry; Recht, Michael; Shapiro, Amy; Stine, Kimo; Talks, Katherine; Telenti, Amalio; Wilde, Jonathan; Yee, Thynn Thynn; Wolinsky, Steven M.; Martinson, Jeremy; Hussain, Shehnaz K.; Bream, Jay H.; Jacobson, Lisa P.; Carrington, Mary; Goedert, James J.; Haynes, Barton F.; McMichael, Andrew J.; Goldstein, David B.; Fellay, Jacques

    2013-01-01

    Human genetic variation contributes to differences in susceptibility to HIV-1 infection. To search for novel host resistance factors, we performed a genome-wide association study (GWAS) in hemophilia patients highly exposed to potentially contaminated factor VIII infusions. Individuals with hemophilia A and a documented history of factor VIII infusions before the introduction of viral inactivation procedures (1979–1984) were recruited from 36 hemophilia treatment centers (HTCs), and their genome-wide genetic variants were compared with those from matched HIV-infected individuals. Homozygous carriers of known CCR5 resistance mutations were excluded. Single nucleotide polymorphisms (SNPs) and inferred copy number variants (CNVs) were tested using logistic regression. In addition, we performed a pathway enrichment analysis, a heritability analysis, and a search for epistatic interactions with CCR5 Δ32 heterozygosity. A total of 560 HIV-uninfected cases were recruited: 36 (6.4%) were homozygous for CCR5 Δ32 or m303. After quality control and SNP imputation, we tested 1 081 435 SNPs and 3686 CNVs for association with HIV-1 serostatus in 431 cases and 765 HIV-infected controls. No SNP or CNV reached genome-wide significance. The additional analyses did not reveal any strong genetic effect. Highly exposed, yet uninfected hemophiliacs form an ideal study group to investigate host resistance factors. Using a genome-wide approach, we did not detect any significant associations between SNPs and HIV-1 susceptibility, indicating that common genetic variants of major effect are unlikely to explain the observed resistance phenotype in this population. PMID:23372042

  9. The value of usability testing for Internet-based adolescent self-management interventions: “Managing Hemophilia Online”

    PubMed Central

    2013-01-01

    Background 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. Methods 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. Results 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. Conclusions 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. PMID:24094082

  10. Long-term course of anti-factor VIII antibody in patients with hemophilia A at a single center

    PubMed Central

    Joo, Sang Chun; Choi, Yong Mook

    2016-01-01

    Background Immune tolerance induction (ITI) can reduce inhibitors against factor VIII concentrates by 70-80%. In this study, we elucidated the characteristics of inhibitors and attempted to determine the proper indications and timing for ITI. Methods Subjects included hemophilia A patients registered at the Korea Hemophilia Foundation from 1991 through 2014. Inhibitors were classified as persistent and transient. Patients were classified into groups according to peak inhibitor titer: low (<2 BU/mL), moderate (2 to <5 BU/mL), high (5 to <10 BU/mL), and very high titer (≥10 BU/mL). Results Overall, 350 (21.4%) of 1,634 hemophilia A patients developed inhibitors at least once. Of these, 100 (6.1%) and 250 (15.3%) patients developed persistent and transient inhibitors, respectively. For transient inhibitors, the median peak titer was 1.0 BU/mL, persistent for median of 11.0 months (10.0, 8.0, 13.0, and 19.0 months in the low, moderate, high, and very high titer transient inhibitor groups, respectively). Overall, 95.8% (215), 72.2% (17), 52.4% (21), and 21.7% (97) of patients in the low, moderate, high, and very high titer groups became inhibitor-negative spontaneously, without ITI. Conclusion Given the spontaneous disappearance of inhibitors and high cost of ITI, it is worthwhile to postpone ITI for 11 months unless the peak inhibitor titer is greater than 10 BU/mL. PMID:27104190

  11. Whole-exome sequencing to identify genetic risk variants underlying inhibitor development in severe hemophilia A patients.

    PubMed

    Gorski, Marcin M; Blighe, Kevin; Lotta, Luca A; Pappalardo, Emanuela; Garagiola, Isabella; Mancini, Ilaria; Mancuso, Maria Elisa; Fasulo, Maria Rosaria; Santagostino, Elena; Peyvandi, Flora

    2016-06-01

    The development of neutralizing antibodies (inhibitors) against coagulation factor VIII (FVIII) is the most problematic and costly complication of FVIII replacement therapy that affects up to 30% of previously untreated patients with severe hemophilia A. The development of inhibitors is a multifactorial complication involving environmental and genetic factors. Among the latter, F8 gene mutations, ethnicity, family history of inhibitors, and polymorphisms affecting genes involved in the immune response have been previously investigated. To identify novel genetic elements underling the risk of inhibitor development in patients with severe hemophilia A, we applied whole-exome sequencing (WES) and data analysis in a selected group of 26 Italian patients with (n = 17) and without (n = 9) inhibitors. WES revealed several rare, damaging variants in immunoregulatory genes as novel candidate mutations. A case-control association analysis using Cochran-Armitage and Fisher's exact statistical tests identified 1364 statistically significant variants. Hierarchical clustering of these genetic variants showed 2 distinct patterns of homozygous variants with a protective or harmful role in inhibitor development. When looking solely at coding variants, a total of 28 nonsynonymous variants were identified and replicated in 53 inhibitor-positive and 174 inhibitor-negative Italian severe hemophilia A patients using a TaqMan genotyping assay. The genotyping results revealed 10 variants showing estimated odds ratios in the same direction as in the discovery phase and confirmed the association of the rs3754689 missense variant (OR 0.58; 95% CI 0.36-0.94; P = .028) in a highly conserved haplotype region surrounding the LCT locus on chromosome 2q21 with inhibitor development. PMID:27060170

  12. Factor VIII (F8) inversions in severe hemophilia A: Male germ cell origin and diagnosis with RT-PCR

    SciTech Connect

    Antonarakis, S.E. |; Rossiter, J.P.; Young, M.

    1994-09-01

    The Factor VIII (F8) gene, which is defective in hemophilia A, is located in the most telomeric megabase of Xq. Inversions due to intrachromosomal homologous recombination between mispaired copies of gene A located within intron 22 of the gene and about 500 kb telomeric to it account for nearly half of the cases of severe hemophilia A. We hypothesized that pairing of Xq with its homolog inhibits the inversion process, and that therefore the event originates predominantly in male germ cells. In all 21 informative cases in which the inversion originated in a maternal grandparent, DNA polymorphism analysis using markers within or very closely linked to F8, determined that it occurred in the male germline. In addition, all but one of 56 mothers of sporadic cases due to inversions were carriers. The data indicate that the F8 gene inversions leading to severe hemophilia A occur almost exclusively in male germ cells. The mean age of maternal grandfathers at the birth of their carrier daughters was 29.9 years (13 cases), i.e. not different from the mean paternal age in the general population, supporting the hypothesis that the inversions occur in meiosis. The inversions can be diagnosed by Southern blot analysis. For more rapid diagnosis we have used RT-PCR of RNA ectopically expressed in blood. Oligonucleotides were used to PCR amplify, after the initial RT reaction of RNA samples using random hexamers, either the normal transcript (F8 exons 21 to 24;312 bp product) or the novel abnormal transcript that is generated after the inversion. Both type 1 and 2 inversions can be recognized in affecteds and carriers by the presence of the diagnostic PcR product of 248 bp. Correct diagnoses were made in samples from 6 patients and 2 carriers with type 1 inversions, 2 patients and 2 carriers with type 2 inversions and 5 normal controls.

  13. Consanguineous Marital Union Resulting in a Progeny of Whistling-face Syndrome and Hemophilia: A Case Report.

    PubMed

    Gurjar, Vivek; Gurjar, Minal

    2015-04-01

    Many different types of genetic disorders are noted to be prevalent among consanguineous progeny. Although the most common type of consanguineous union in all major societies is between first cousins, the importance of customary influences is apparent from variations in the specific types of first-cousin marriages contracted. Epidemiological data for the prevalence of whistling-face syndrome (WFS) are not available, but less than a hundred cases reported in the literature are noted. We are presenting a case where a consanguineous marriage resulted in two of their children presenting with WFS and one with hemophilia. PMID:25954077

  14. Concurrent influenza vaccination reduces anti-FVIII antibody responses in murine hemophilia A.

    PubMed

    Lai, Jesse D; Moorehead, Paul C; Sponagle, Kate; Steinitz, Katharina N; Reipert, Birgit M; Hough, Christine; Lillicrap, David

    2016-06-30

    Inflammatory signals such as pathogen- and danger-associated molecular patterns have been hypothesized as risk factors for the initiation of the anti-factor VIII (FVIII) immune response seen in 25% to 30% of patients with severe hemophilia A (HA). In these young patients, vaccines may be coincidentally administered in close proximity with initial exposure to FVIII, thereby providing a source of such stimuli. Here, we investigated the effects of 3 vaccines commonly used in pediatric patients on FVIII immunogenicity in a humanized HA murine model with variable tolerance to recombinant human FVIII (rhFVIII). Mice vaccinated intramuscularly against the influenza vaccine prior to multiple infusions of rhFVIII exhibited a decreased incidence of rhFVIII-specific neutralizing and nonneutralizing antibodies. Similar findings were observed with the addition of an adjuvant. Upon exposure to media from influenza- or FVIII-stimulated lymph node or splenic lymphocytes, naïve CD4(+) lymphocytes preferentially migrated toward media from influenza-stimulated cells, indicating that antigen competition, by means of lymphocyte recruitment to the immunization site, is a potential mechanism for the observed decrease in FVIII immunogenicity. We also observed no differences in incidence or titer of rhFVIII-specific antibodies and inhibitors in mice exposed to the live-attenuated measles-mumps-rubella vaccine regardless of route of administration. Together, our results suggest that concomitant FVIII exposure and vaccination against influenza does not increase the risk of inhibitor formation and may in fact decrease anti-FVIII immune responses. PMID:27034428

  15. Clinical and molecular characterization of a re-established line of sheep exhibiting hemophilia A

    PubMed Central

    PORADA, C. D.; SANADA, C.; LONG, C. R.; WOOD, J. A.; DESAI, J.; FREDERICK, N.; MILLSAP, L.; BORMANN, C.; MENGES, S. L.; HANNA, C.; FLORES-FOXWORTH, G.; SHIN, T.; WESTHUSIN, M. E.; LIU, W.; GLIMP, H.; ZANJANI, E. D.; LOZIER, J. N.; PLISKA, V.; STRANZINGER, G.; JOERG, H.; KRAEMER, D. C.; ALMEIDA-PORADA, G.

    2010-01-01

    Summary Background Large animal models that accurately mimic human hemophilia A (HA) are in great demand for developing and testing novel therapies to treat HA. Objectives To re-establish a line of sheep exhibiting a spontaneous bleeding disorder closely mimicking severe human HA, fully characterize their clinical presentation, and define the molecular basis for disease. Patients/methods Sequential reproductive manipulations were performed with cryopreserved semen from a deceased affected ram. The resultant animals were examined for hematologic parameters, clinical symptoms, and responsiveness to human FVIII (hFVIII). The full coding region of sheep FVIII mRNA was sequenced to identify the genetic lesion. Results and conclusions The combined reproductive technologies yielded 36 carriers and 8 affected animals. The latter had almost non-existent levels of FVIII:C and extremely prolonged aPTT, with otherwise normal hematologic parameters. These animals exhibited bleeding from the umbilical cord, prolonged tail and nail cuticle bleeding time, and multiple episodes of severe spontaneous bleeding, including hemarthroses, muscle hematomas and hematuria, all of which responded to hFVIII. Inhibitors of hFVIII were detected in four treated animals, further establishing the preclinical value of this model. Sequencing identified a premature stop codon and frame-shift in exon 14, providing a molecular explanation for HA. Given the decades of experience using sheep to study both normal physiology and a wide array of diseases and the high homology between human and sheep FVIII, this new model will enable a better understanding of HA and facilitate the development and testing of novel treatments that can directly translate to HA patients. PMID:19943872

  16. Fc-fusion technology and recombinant FVIII and FIX in the management of the hemophilias

    PubMed Central

    Mancuso, Maria Elisa; Mannucci, Pier Mannuccio

    2014-01-01

    Prophylaxis with regular infusions of factor VIII (FVIII)- or factor IX (FIX)- containing products is the mainstay of modern hemophilia care. However, this therapeutic regimen is inconvenient, requiring repeated intravenous injections from childhood. Approaches meant to prolong the half-life of FVIII and FIX in plasma have been developed in order to improve the feasibility and acceptability of replacement therapy, extending protection from bleeding, reducing infusion frequency and hence the need for venous access devices in young children. Several strategies have been implemented to enhance the pharmacokinetics of clotting factors, including conjugation with polyethylene glycol and the production by genetic engineering of fusion proteins containing the coagulation factors linked to a long-lived plasma protein such as albumin or the Fc fragment of immunoglobulin (Ig)G. The latter technology is one of the most promising, since the prolongation of FVIII and FIX half-life is obtained by exploiting the physiological binding of the Fc domain to the neonatal Fc receptor. Fc fusion monomers have been obtained with both recombinant FVIII (rFVIIIFc) and FIX (rFIXFc), and data from preclinical and clinical studies showed improved pharmacokinetics for both factors, which are produced in human embryonic kidney (HEK) 293 cells, thus ensuring full human post-translational modifications. In Phase I/IIa studies, rFVIIIFc and rFIXFc showed 1.5–1.7 fold and 3.0–4.0 fold longer elimination half-life, respectively. Similar data have been obtained in the Phase III clinical studies with rFVIIIFc and rFIX-Fc published recently. Both drugs were satisfactorily safe, particularly with respect to immunogenicity, and no serious adverse event was observed. PMID:24729686

  17. Early eradication of factor VIII inhibitor in patients with congenital hemophilia A by immune tolerance induction with a high dose of immunoglobulin.

    PubMed

    Mizoguchi, Yoko; Furue, Aya; Kagawa, Reiko; Chijimatsu, Ikue; Tomioka, Keita; Shimomura, Maiko; Imanaka, Yusuke; Nishimura, Shiho; Saito, Satoshi; Miki, Mizuka; Ono, Atsushi; Konishi, Nakao; Kawaguchi, Hiroshi; Kobayashi, Masao

    2016-04-01

    The production of factor VIII (FVIII) inhibitory antibodies is a serious problem in patients with hemophilia A. Immune tolerance induction (ITI) is the only strategy proven to eradicate persistent inhibitors and has been shown to be successful in 70 % of patients with hemophilia A. However, a minority of hemophilia patients present life-long inhibitors. To eliminate such inhibitors, we designed an intravenous immunoglobulin (IVIG) strategy in combination with high dose recombinant FVIII for ITI in hemophilia A children with inhibitors. Four previously untreated patients produced inhibitors within 16 exposures to FVIII. The peak inhibitor titers in these patients ranged from 3 to 14 BU/mL. The patients received ITI combined with IVIG within 1.5 months after the inhibitors were detected. All patients showed a negative titer for inhibitors by 28 days, with no anamnestic responses. The recovery of FVIII in the plasma concentration was normalized within three months after initiation of ITI. An additional course of IVIG administration led to induction of complete tolerance by 20 months after initiation of ITI therapy in all patients. ITI treatment with high-dose FVIII combined with IVIG may be effective for the early elimination of inhibitors. PMID:26830966

  18. Expression of human factor IX in rat capillary endothelial cells: Toward somatic gene therapy for hemophilia B

    SciTech Connect

    Shounan Yao; Wilson, J.M.; Nabel, E.G.; Kurachi, Sumiko; Hachiya, H.L.; Kurachi, Kotoku )

    1991-09-15

    In aiming to develop a gene therapy approach for hemophilia B, the authors expressed and characterized human factor IX in rat capillary endothelial cells (CECs). Moloney murine leukemia virus-derived retrovirus vectors that contain human factor IX cDNA linked to heterologous promoters and the neomycin-resistant gene were constructed and employed to prepare recombinant retroviruses. Rat CECs and NIH 3T3 cells infected with these viruses were selected with the neomycin analogue, G418 sulfate, and tested for expression of factor IX. A construct with the factor IX cDNA under direct control by long terminal repeat gave the highest level of expression as quantitated by immunoassays as well as clotting activity assays. A single RNA transcript of 4.4 kilobases predicted by the construct and a recombinant factor IX were found. The recombinant human factor IX produced showed full clotting activity, demonstrating that CECs have an efficient mechanism for posttranslational modifications, including {gamma}-carboxylation, essential for its biological activity. These results, in addition to other properties of the endothelium, including large number of cells, accessibility, and direct contact with the circulating blood, suggest that CECs can serve as an efficient drug delivery vehicle producing factor IX in a somatic gene therapy for hemophilia B.

  19. Phosphatidylserine containing liposomes reduce immunogenicity of recombinant human factor VIII (rFVIII) in a murine model of hemophilia A.

    PubMed

    Ramani, Karthik; Miclea, Razvan D; Purohit, Vivek S; Mager, Donald E; Straubinger, Robert M; Balu-Iyer, Sathy V

    2008-04-01

    Factor VIII (FVIII) is a multidomain protein that is deficient in hemophilia A, a clinically important bleeding disorder. Replacement therapy using recombinant human FVIII (rFVIII) is the main therapy. However, approximately 15-30% of patients develop inhibitory antibodies that neutralize rFVIII activity. Antibodies to epitopes in C2 domain, which is involved in FVIII binding to phospholipids, are highly prevalent. Here, we investigated the effect of phosphatidylserine (PS)-containing liposomes, which bind to C2 domain with high affinity and specificity, upon the immunogenicity of rFVIII. Circular dichroism studies showed that PS-containing liposomes interfered with aggregation of rFVIII. Immunogenicity of free- versus liposomal-rFVIII was evaluated in a murine model of hemophilia A. Animals treated with s.c. injections of liposomal-rFVIII had lower total- and inhibitory titers, compared to animals treated with rFVIII alone. Antigen processing by proteolytic enzymes was reduced in the presence of liposomes. Animals treated with s.c. injections of liposomal-rFVIII showed a significant increase in rFVIII plasma concentration compared to animals that received rFVIII alone. Based on these studies, we hypothesize that specific molecular interactions between PS-containing bilayers and rFVIII may provide a basis for designing lipidic complexes that improve the stability, reduce the immunogenicity of rFVIII formulations, and permit administration by s.c. route. PMID:17705286

  20. Recombinant factor VIII Fc (rFVIIIFc) fusion protein reduces immunogenicity and induces tolerance in hemophilia A mice.

    PubMed

    Krishnamoorthy, Sriram; Liu, Tongyao; Drager, Douglas; Patarroyo-White, Susannah; Chhabra, Ekta Seth; Peters, Robert; Josephson, Neil; Lillicrap, David; Blumberg, Richard S; Pierce, Glenn F; Jiang, Haiyan

    2016-03-01

    Anti-factor VIII (FVIII) antibodies is a major complication of FVIII replacement therapy for hemophilia A. We investigated the immune response to recombinant human factor VIII Fc (rFVIIIFc) in comparison to BDD-rFVIII and full-length rFVIII (FL-rFVIII) in hemophilia A mice. Repeated administration of therapeutically relevant doses of rFVIIIFc in these mice resulted in significantly lower antibody responses to rFVIII compared to BDD-rFVIII and FL-rFVIII and reduced antibody production upon subsequent challenge with high doses of rFVIIIFc. The induction of a tolerogenic response by rFVIIIFc was associated with higher percentage of regulatory T-cells, a lower percentage of pro-inflammatory splenic T-cells, and up-regulation of tolerogenic cytokines and markers. Disruption of Fc interactions with either FcRn or Fcγ receptors diminished tolerance induction, suggesting the involvement of these pathways. These results indicate that rFVIIIFc reduces immunogenicity and imparts tolerance to rFVIII demonstrating that recombinant therapeutic proteins may be modified to influence immunogenicity and facilitate tolerance. PMID:26775174

  1. An improved method for prenatal diagnosis of genetic diseases by analysis of amplified DNA sequences. Application to hemophilia A.

    PubMed

    Kogan, S C; Doherty, M; Gitschier, J

    1987-10-15

    We report the development of a rapid nonradioactive technique for the genetic prediction of human disease and its diagnostic application to hemophilia A. This method is based on enzymatic amplification of short segments of human genes associated with inherited disorders. A novel feature of the procedure is the use of a heat-stable DNA polymerase, which allows the repeated rounds of DNA synthesis to proceed at 63 degrees C. The high sequence specificity of the amplification reaction at this elevated temperature permits restriction-site polymorphisms, contained in the amplified samples, to be analyzed by visual inspection of their digestion products on polyacrylamide gels. By means of this method, we have performed carrier detection and prenatal diagnosis of hemophilia in two families with use of the factor VIII intragenic polymorphisms identified by the restriction enzymes BclI and XbaI. Predictions can be made directly from chorionic villi, without previous DNA extraction, and fetal sex can be determined by amplification of sequences specific for the Y chromosome. Specific amplification of genomic sequences with heat-stable DNA polymerase is applicable to the diagnosis of a wide variety of inherited disorders. These include diseases diagnosed by restriction-site variation, such as Duchenne's muscular dystrophy and sickle cell anemia, those due to a collection of known mutations, such as beta-thalassemia, and those due to gene deletion, such as alpha-thalassemia. PMID:3657865

  2. Risk Factors for High-Titer Inhibitor Development in Children with Hemophilia A: Results of a Cohort Study

    PubMed Central

    Heller, Christine; Gutsche, Sven; Holzhauer, Susanne; Kenet, Gili; Kurnik, Karin; Iorio, Alfonso; Nowak-Göttl, Ulrike

    2013-01-01

    Among the discussed risk factors for high-titre inhibitor (HRI) development in patients with hemophilia A (HA) are high dose FVIII replacement therapy and use of recombinant FVIII concentrates (rFVIII). The aim of this study was to evaluate the aforementioned risk factors for HRI development in children with hemophilia A ≤2%. About 288 ascertained PUPs (Israel and Germany) were followed after initial HA diagnosis over 200 exposure days. Inhibitor-free survival, hazard ratios (HR), and 95% confidence intervals (CIs) were calculated. Adjustment was performed for factor VIII concentrates, median single dose over the first three months of treatment, first FVIII administration before the age of three months, presence of risk HA gene mutations, “intensive treatment moments” and “year of birth” (proxy for different treatment periods). HRI occurred in 71/288 children (24.7%). In multivariate analysis adjusted for “year of birth”, underlying risk gene mutations (HR/CI: 2.37/1.40–3.99), FVIII dose, measured per one IU increase per kgbw (HR/CI: 1.05/1.04–1.07), and first FVIII administration before the age of three months showed a significant impact on HR development. The risk of HRI development was similar for recombinant or plasmatic FVIII products. Children at risk should be treated with carefully calculated lower dose regimens, adapted to individual bleeding situations. PMID:24199202

  3. Correction of the coagulation defect in hemophilia using a factor Xa variant with novel engineered protease function

    PubMed Central

    Ivanciu, Lacramioara; Toso, Raffaella; Margaritis, Paris; Pavani, Giulia; Kim, Haein; Schlachterman, Alexander; Liu, Jian-Hua; Clerin, Valerie; Pittman, Debra D.; Rose-Miranda, Rosalind; Shields, Kathleen M.; Erbe, David V.; Tobin, James F.; Arruda, Valder R.; Camire, Rodney M.

    2011-01-01

    Effective therapies are needed to control excessive bleeding in a range of clinical conditions. We describe a surprisingly useful approach to improve hemostasis in vivo using a variant of coagulation factor Xa (FXaI16L). This conformationally pliant derivative is partially inactive due to a defect in transitioning from zymogen to protease 1,2. Using mouse models of hemophilia, we show that FXaI16L has a prolonged half-life, relative to wild-type FXa and does not cause excessive activation of coagulation. Once clotting mechanisms are activated to produce its cofactor FVa, FXaI16L is driven to the protease state and restores hemostasis in hemophilic animals upon vascular injury. Moreover, using human or murine analogs, we show that FXaI16L is more efficacious than FVIIa which is used to treat bleeding in hemophilia inhibitor patients3. Because of its underlying mechanism of action, FXaI16L may provide an effective strategy to enhance blood clot formation and act as a rapid pan-hemostatic agent for the treatment of bleeding conditions. PMID:22020385

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

    SciTech Connect

    Young, M.; Antonarakis, S.E.; Inaba, Hiroshi

    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.

  5. Somatic mosaicism and female-to-female transmission in a kindred with hemophilia B (factor IX deficiency)

    SciTech Connect

    Taylor, S.A.M.; Deugau, K.V.; Lillicrap, D.P. )

    1991-01-01

    Studies have shown that hemophilia B (Christmas disease; factor IX deficiency) results from many different mutations in the factor IX gene, of which {gt}95% are single nulceotide substitutions. This study has identified a previously unreported form of hemophilia B in a patient who was a somatic mosaic for a guanine-to-cytosine transversion at nucleotide 31,170 in the factor IX gene. This point mutation changes the codon for residue 350 in the catalytic domain of factor IX from a cysteine to a serine. The authors used differential termination of primer extension to confirm and measure the degree of mosaicism. The study shows that a varying proportion of cells from hepatic, renal, smooth muscle, and hematopoietic populations possessed normal as well as mutant factor IX sequences. These results indicate that the mutation in this patient occurred either as an uncorrected half-chromatid mutation in the female gamete or as a replication or postreplication error in the initial mitotic divisions of the zygote preceding implantation. In addition, this kindred also contains two females in successive generations who have moderately severe factor IX deficiency. The molecular pathogenesis of this latter phenomenon has been studied and seems to relate to the unaccompanied expression of the mutant factor IX gene consequent upon a second, as yet undefined, genetic event that has prevented inactivation of sequences including the mutant factor IX gene on the X chromosome inherited from the affected male.

  6. Recombinant factor VIII Fc (rFVIIIFc) fusion protein reduces immunogenicity and induces tolerance in hemophilia A mice

    PubMed Central

    Krishnamoorthy, Sriram; Liu, Tongyao; Drager, Douglas; Patarroyo-White, Susannah; Chhabra, Ekta Seth; Peters, Robert; Josephson, Neil; Lillicrap, David; Blumberg, Richard S.; Pierce, Glenn F.; Jiang, Haiyan

    2016-01-01

    Anti-factor VIII (FVIII) antibodies is a major complication of FVIII replacement therapy for hemophilia A. We investigated the immune response to recombinant human factor VIII Fc (rFVIIIFc) in comparison to BDD-rFVIII and full-length rFVIII (FL-rFVIII) in hemophilia A mice. Repeated administration of therapeutically relevant doses of rFVIIIFc in these mice resulted in significantly lower antibody responses to rFVIII compared to BDD-rFVIII and FL-rFVIII and reduced antibody production upon subsequent challenge with high doses of rFVIIIFc. The induction of a tolerogenic response by rFVIIIFc was associated with higher percentage of regulatory T-cells, a lower percentage of pro-inflammatory splenic T-cells, and up-regulation of tolerogenic cytokines and markers. Disruption of Fc interactions with either FcRn or Fcγ receptors diminished tolerance induction, suggesting the involvement of these pathways. These results indicate that rFVIIIFc reduces immunogenicity and imparts tolerance to rFVIII demonstrating that recombinant therapeutic proteins may be modified to influence immunogenicity and facilitate tolerance. PMID:26775174

  7. Low cost industrial production of coagulation factor IX bioencapsulated in lettuce cells for oral tolerance induction in hemophilia B.

    PubMed

    Su, Jin; Zhu, Liqing; Sherman, Alexandra; Wang, Xiaomei; Lin, Shina; Kamesh, Aditya; Norikane, Joey H; Streatfield, Stephen J; Herzog, Roland W; Daniell, Henry

    2015-11-01

    Antibodies (inhibitors) developed by hemophilia B patients against coagulation factor IX (FIX) are challenging to eliminate because of anaphylaxis or nephrotic syndrome after continued infusion. To address this urgent unmet medical need, FIX fused with a transmucosal carrier (CTB) was produced in a commercial lettuce (Simpson Elite) cultivar using species specific chloroplast vectors regulated by endogenous psbA sequences. CTB-FIX (∼1 mg/g) in lyophilized cells was stable with proper folding, disulfide bonds and pentamer assembly when stored ∼2 years at ambient temperature. Feeding lettuce cells to hemophilia B mice delivered CTB-FIX efficiently to the gut immune system, induced LAP(+) regulatory T cells and suppressed inhibitor/IgE formation and anaphylaxis against FIX. Lyophilized cells enabled 10-fold dose escalation studies and successful induction of oral tolerance was observed in all tested doses. Induction of tolerance in such a broad dose range should enable oral delivery to patients of different age groups and diverse genetic background. Using Fraunhofer cGMP hydroponic system, ∼870 kg fresh or 43.5 kg dry weight can be harvested per 1000 ft(2) per annum yielding 24,000-36,000 doses for 20-kg pediatric patients, enabling first commercial development of an oral drug, addressing prohibitively expensive purification, cold storage/transportation and short shelf life of current protein drugs. PMID:26302233

  8. Neonatal helper-dependent adenoviral vector gene therapy mediates correction of hemophilia A and tolerance to human factor VIII

    PubMed Central

    Cela, Racel G.; Suzuki, Masataka; Lee, Brendan; Lipshutz, Gerald S.

    2011-01-01

    Neonatal gene therapy is a promising strategy for treating a number of congenital diseases diagnosed shortly after birth as expression of therapeutic proteins during postnatal life may limit the pathologic consequences and result in a potential “cure.” Hemophilia A is often complicated by the development of antibodies to recombinant protein resulting in treatment failure. Neonatal administration of vectors may avoid inhibitory antibody formation to factor VIII (FVIII) by taking advantage of immune immaturity. A helper-dependent adenoviral vector expressing human factor VIII was administered i.v. to neonatal hemophilia A knockout mice. Three days later, mice produced high levels of FVIII. Levels declined rapidly with animal growth to 5 wk of age with stable factor VIII expression thereafter to >1 y of age. Decline in factor VIII expression was not related to cell-mediated or humoral responses with lack of development of antibodies to capsid or human factor VIII proteins. Subsequent readministration and augmentation of expression was possible as operational tolerance was established to factor VIII without development of inhibitors; however, protective immunity to adenovirus remained. PMID:21245323

  9. The role of plasma-derived factor VIII/von Willebrand factor concentrates in the treatment of hemophilia A patients.

    PubMed

    Auerswald, Günter; Spranger, Torsten; Brackmann, Hans-Hermann

    2003-06-01

    Besides preventing bleeding episodes, common goals of the treatment of hemophilia include integrating of patients into a normal social life and optimizing their quality of life. Sufficient amounts of factor VIII (FVIII) concentrates, whether recombinant or plasma-derived, are continuously needed. Guidelines for quality assurance of treatment will be a cornerstone to maintain optimal clinical management of patients especially considering financial aspects. Advances in manufacturing technologies have made possible general availability of modern concentrates for the management of hemophilia A patients. Safety, cost and continuous supply of concentrates must be considered when deciding on a product for replacement therapy. As todays' products have reached an excellent margin of safety with regard to virus transmission, the development and treatment of inhibitors is currently the main concern for physicians and patients. The incidence of inhibitors is influenced by various patient-related factors such as mutation type or severity of the disease. Plasma-derived FVIII concentrates containing von Willebrand factor (VWF) may have clinical advantages over pure FVIII concentrates with regard to inhibitor development and inhibitor eradication. Clinical trials comparing FVIII/VWF concentrates with pure FVIII concentrates are lacking, thus a lower inhibitor incidence has not yet been proven. Data from Germany on immune tolerance induction with FVIII/VWF concentrates indicate higher success rates with these than with pure FVIII concentrates. In addition FVIII/VWF concentrates are the therapy of choice when immune tolerance therapy with pure FVIII products is not successful. PMID:12826531

  10. Prolonged activity of a recombinant factor VIII-Fc fusion protein in hemophilia A mice and dogs.

    PubMed

    Dumont, Jennifer A; Liu, Tongyao; Low, Susan C; Zhang, Xin; Kamphaus, George; Sakorafas, Paul; Fraley, Cara; Drager, Douglas; Reidy, Thomas; McCue, Justin; Franck, Helen W G; Merricks, Elizabeth P; Nichols, Timothy C; Bitonti, Alan J; Pierce, Glenn F; Jiang, Haiyan

    2012-03-29

    Despite proven benefits, prophylactic treatment for hemophilia A is hampered by the short half-life of factor VIII. A recombinant factor VIII-Fc fusion protein (rFVIIIFc) was constructed to determine the potential for reduced frequency of dosing. rFVIIIFc has an ∼ 2-fold longer half-life than rFVIII in hemophilia A (HemA) mice and dogs. The extension of rFVIIIFc half-life requires interaction of Fc with the neonatal Fc receptor (FcRn). In FcRn knockout mice, the extension of rFVIIIFc half-life is abrogated, and is restored in human FcRn transgenic mice. The Fc fusion has no impact on FVIII-specific activity. rFVIIIFc has comparable acute efficacy as rFVIII in treating tail clip injury in HemA mice, and fully corrects whole blood clotting time (WBCT) in HemA dogs immediately after dosing. Furthermore, consistent with prolonged half-life, rFVIIIFc shows 2-fold longer prophylactic efficacy in protecting HemA mice from tail vein transection bleeding induced 24-48 hours after dosing. In HemA dogs, rFVIIIFc also sustains partial correction of WBCT 1.5- to 2-fold longer than rFVIII. rFVIIIFc was well tolerated in both species. Thus, the rescue of FVIII by Fc fusion to provide prolonged protection presents a novel pathway for FVIII catabolism, and warrants further investigation. PMID:22246033

  11. Molecular characterization of severe hemophilia A suggests that about half the mutations are not within the coding regions and splice junctions of the factor VIII gene.

    PubMed Central

    Higuchi, M; Kazazian, H H; Kasch, L; Warren, T C; McGinniss, M J; Phillips, J A; Kasper, C; Janco, R; Antonarakis, S E

    1991-01-01

    Hemophilia A is an X chromosome-linked disorder resulting from deficiency of factor VIII, an important protein in blood coagulation. A large number of disease-producing mutations have been reported in the factor VIII gene. However, a comprehensive analysis of the mutations has been difficult because of the large gene size, its many scattered exons, and the high frequency of de novo mutations. Recently, we have shown that nearly all mutations resulting in mild-to-moderate hemophilia A can be detected by PCR and denaturing gradient gel electrophoresis (DGGE). In this study, we attempted to discover the mutations causing severe hemophilia A by analyzing 47 unselected patients, 30 of whom had severe hemophilia and 17 of whom had mild-to-moderate disease. Using DGGE as a screening method, we analyzed 99% of the coding region, 94% of the splice junctions, the promoter region, and the polyadenylylation site of the gene. We found the mutation in 16 of 17 (94%) patients with mild-to-moderate disease but in only 16 of 30 (53%) patients with severe hemophilia A. Since DGGE after computer analysis appears to detect all mutations in a given fragment, the lower-than-expected yield of mutations in patients with severe disease is likely not due to failure of the detection method; it is probably due to the presence of mutations in DNA sequences outside the regions studied. Such sequences may include locus-controlling regions, other sequences within introns or outside the gene that are important for its expression, or another gene involved in factor VIII expression that is very closely linked to the factor VIII gene. Images PMID:1908096

  12. Physical activity recommendations for children with specific chronic health conditions: Juvenile idiopathic arthritis, hemophilia, asthma and cystic fibrosis.

    PubMed

    Philpott, J; Houghton, K; Luke, A

    2010-04-01

    As a group, children with a chronic disease or disability are less active than their healthy peers. There are many reasons for suboptimal physical activity, including biological, psychological and social factors. Furthermore, the lack of specific guidelines for 'safe' physical activity participation poses a barrier to increasing activity. Physical activity provides significant general health benefits and may improve disease outcomes. Each child with a chronic illness should be evaluated by an experienced physician for activity counselling and for identifing any contraindications to participation. The present statement reviews the benefits and risks of participation in sport and exercise for children with juvenile arthritis, hemophilia, asthma and cystic fibrosis. Guidelines for participation are included. PMID:21455465

  13. Physical activity recommendations for children with specific chronic health conditions: juvenile idiopathic arthritis, hemophilia, asthma, and cystic fibrosis.

    PubMed

    Philpott, John F; Houghton, Kristin; Luke, Anthony

    2010-05-01

    As a group, children with a chronic disease or disability are less active than their healthy peers. There are many reasons for suboptimal physical activity, including biological, psychological, and social factors. Furthermore, the lack of specific guidelines for 'safe' physical activity participation poses a barrier to increasing activity. Physical activity provides significant general health benefits and may improve disease outcomes. Each child with a chronic illness should be evaluated by an experienced physician for activity counselling and for identifying any contraindications to participation. The present statement reviews the benefits and risks of participation in sport and exercise for children with juvenile arthritis, hemophilia, asthma, and cystic fibrosis. Guidelines for participation are included. PMID:20445355

  14. Severe hemophilia A in a female by cryptic translocation: Order and orientation of factor VIII within Xq28

    SciTech Connect

    Migeon, B.R.; McGinniss, M.J.; Antonarakis, S.E.; Axelman, J.; Stasiowski, B.A.; Youssoufian, H.; Kearns, W.G.; Chung, A.; Pearson, P.L.; Kazazian, H.H. Jr. ); Muneer, R.S. )

    1993-04-01

    The authors report studies of a female with severe hemophilia A resulting from a complex de novo translocation of chromosomes X and 17 (46,X,t(X; 17)). Somatic cell hybrids containing the normal X, the der(X), or the der(17) were analyzed for coagulation factor VIII (F8C) sequences using Southern blots and polymerase chain reaction. The normal X, always late replicating, contains a normal F8C gene, whereas the der(X) has no F8C sequences. The der(17) chromosome containing Xq24-Xq28 carries a functional G6PD locus and a deleted F8C allele that lacks exons 1--15. Also, it lacks the DXYS64-X locus, situated between the F8C locus and the Xq telomere. These results indicate that a cryptic breakpoint within Xq28 deleted the 5[prime] end of F8C, but left the more proximal G6PD locus intact on the der(17)chromosome. As the deleted segment includes the 5[prime] half of F8C as well as the subtelomeric DXYS64 locus, F8C must be oriented on the chromosome with its 5[prime] region closest to the telomere. Therefore, the order of these loci is Xcen-G6PD-3[prime]F8C-5[prime]F8C-DXYS64-Xqtel. The analysis of somatic cell hybrids has elucidated the true nature of the F8C mutation in the pro-band, revealing a more complex rearrangement (three chromosomes involved) than that expected from cytogenetic analysis, chromosome painting, and Southern blots. A 900-kb segment within Xq28 has been translocated to another autosome. Hemophilia A in this heterozygous female is due to the decapitation of the F8C gene on the der(17) and inactivation of the intact allele on the normal X. 27 refs., 5 figs., 1 tab.

  15. Extrahepatic sources of factor VIII potentially contribute to the coagulation cascade correcting the bleeding phenotype of mice with hemophilia A

    PubMed Central

    Zanolini, Diego; Merlin, Simone; Feola, Maria; Ranaldo, Gabriella; Amoruso, Angela; Gaidano, Gianluca; Zaffaroni, Mauro; Ferrero, Alessandro; Brunelleschi, Sandra; Valente, Guido; Gupta, Sanjeev; Prat, Maria; Follenzi, Antonia

    2015-01-01

    A large fraction of factor VIII in blood originates from liver sinusoidal endothelial cells although extrahepatic sources also contribute to plasma factor VIII levels. Identification of cell-types other than endothelial cells with the capacity to synthesize and release factor VIII will be helpful for therapeutic approaches in hemophilia A. Recent cell therapy and bone marrow transplantation studies indicated that Küpffer cells, monocytes and mesenchymal stromal cells could synthesize factor VIII in sufficient amount to ameliorate the bleeding phenotype in hemophilic mice. To further establish the role of blood cells in expressing factor VIII, we studied various types of mouse and human hematopoietic cells. We identified factor VIII in cells isolated from peripheral and cord blood, as well as bone marrow. Co-staining for cell type-specific markers verified that factor VIII was expressed in monocytes, macrophages and megakaryocytes. We additionally verified that factor VIII was expressed in liver sinusoidal endothelial cells and endothelial cells elsewhere, e.g., in the spleen, lungs and kidneys. Factor VIII was well expressed in sinusoidal endothelial cells and Küpffer cells isolated from human liver, whereas by comparison isolated human hepatocytes expressed factor VIII at very low levels. After transplantation of CD34+ human cord blood cells into NOD/SCIDγNull-hemophilia A mice, fluorescence activated cell sorting of peripheral blood showed >40% donor cells engrafted in the majority of mice. In these animals, plasma factor VIII activity 12 weeks after cell transplantation was up to 5% and nine of 12 mice survived after a tail clip-assay. In conclusion, hematopoietic cells, in addition to endothelial cells, express and secrete factor VIII: this information should offer further opportunities for understanding mechanisms of factor VIII synthesis and replenishment. PMID:25911555

  16. Expression and Characterization of Gly-317 Variants of Factor IX Causing Variable Bleeding in Hemophilia B Patients.

    PubMed

    Lu, Qiuya; Yang, Likui; Manithody, Chandrashekhara; Wang, Xuefeng; Rezaie, Alireza R

    2015-06-23

    We recently identified two hemophilia B patients who carried Gly-317 to Arg (FIX-G317R) or Gly-317 to Glu (FIX-G317E) substitutions in their FIX gene. The former mutation caused severe and the latter moderate bleeding in afflicted patients. To understand the molecular basis for the variable clinical manifestation of Gly-317 mutations, we prepared recombinant G317R and G317E derivatives of FIX and compared their kinetic properties to those of recombinant wild-type FIX in appropriate assay systems. Both physiological activators, factor XIa and extrinsic Tenase (factor VIIa-tissue factor), activated both zymogen variants with an ∼1.5-fold elevated K(m); however, extrinsic Tenase activated FIX-G317E with an ∼2-fold improved k(cat). By contrast to zymogen activation, the catalytic activities of both FIXa-G317R and FIXa-G317E enzymes toward the natural substrate, factor X, were dramatically (>4 orders of magnitude) impaired, but their apparent affinity for interaction with factor VIIIa was only slightly (<2-fold) decreased. Further studies revealed that the reactivity of FIXa-G317R and FIXa-G317E with antithrombin has been impaired 10- and 13-fold, respectively, in the absence and 166- and 500-fold, respectively, in the presence of pentasaccharide. As expected, the clotting activities of FIX variants could not be measured by the aPTT assay. These results implicate a critical role for Gly-317 in maintaining normal catalytic function for FIX/FIXa in the clotting cascade. The results further suggest that improved k(cat) of FIX-G317E activation in the extrinsic pathway together with dramatically impaired reactivity of FIXa-G317E with antithrombin may account for the less severe bleeding phenotype of a hemophilia B patient carrying the FIX-G317E mutation. PMID:26023895

  17. Minimizing the Risk of Perioperative Bleeding in a Child with Hemophilia A during Dental Rehabilitation under General Anesthesia: A Case Report

    PubMed Central

    Yehia El Batawi, Hisham

    2013-01-01

    ABSTRACT Hemophilia, among other bleeding disorders, raises concerns for dental service providers who routinely use sharp hand and rotary instruments, address highly vascular soft tissue and provide dental extractions. In pediatric dentistry, dealing with fearful or irritable children increases the possibility of trauma and subsequent bleeding risks in hemophilic pediatric dental patients. In the current report, we discuss how anesthetic, pediatric and dental management may contribute to the delivery of safe and complete dental treatment for such children. This report describes the safe performance of dental treatments, including multiple extractions under general anesthesia, in a hemophilic child. How to cite this article: El Batawi HY. Minimizing the Risk of Perioperative Bleeding in a Child with Hemophilia A during Dental Rehabilitation under General Anesthesia: A Case Report. Int J Clin Pediatr Dent 2013;6(3):217-222. PMID:25206227

  18. HLA Class I and KIR Genes Do Not Protect Against HIV Type 1 Infection in Highly Exposed Uninfected Individuals With Hemophilia A

    PubMed Central

    Vince, Nicolas; Bashirova, Arman A.; Lied, Alexandra; Gao, Xiaojiang; Dorrell, Lucy; McLaren, Paul J.; Fellay, Jacques; Carrington, Mary

    2014-01-01

    A recent genome-wide association study (GWAS) involving patients with hemophilia A who were exposed to but uninfected with human immunodeficiency virus type 1 (HIV-1) did not reveal genetic variants associated with resistance to HIV-1 infection, beyond homozygosity for CCR5-Δ32. Since variation in HLA class I and KIR genes is not well interrogated by standard GWAS techniques, we tested whether these 2 loci were involved in protection from HIV-1 infection in the same hemophilia cohort, using controls from the general population. Our data indicate that HLA class I alleles, presence or absence of KIR genes, and functionally relevant combinations of the HLA/KIR genotypes are not involved in resistance to parenterally transmitted HIV-1 infection. PMID:24719475

  19. Regional intravascular delivery of AAV-2-F.IX to skeletal muscle achieves long-term correction of hemophilia B in a large animal model.

    PubMed

    Arruda, Valder R; Stedman, Hansell H; Nichols, Timothy C; Haskins, Mark E; Nicholson, Matthew; Herzog, Roland W; Couto, Linda B; High, Katherine A

    2005-05-01

    In earlier work, we showed that adeno-associated virus-mediated delivery of a Factor IX gene to skeletal muscle by direct intramuscular injection resulted in therapeutic levels of circulating Factor IX in mice. However, achievement of target doses in humans proved impractical because of the large number of injections required. We used a novel intravascular delivery technique to achieve successful transduction of extensive areas of skeletal muscle in a large animal with hemophilia. We provide here the first report of long-term (> 3 years, with observation ongoing), robust Factor IX expression (circulating levels of 4%-14%) by muscle-directed gene transfer in a large animal, resulting in essentially complete correction of the bleeding disorder in hemophilic dogs. The results of this translational study establish an experimental basis for clinical studies of this delivery method in humans with hemophilia B. These findings also have immediate relevance for gene transfer in patients with muscular dystrophy. PMID:15479726

  20. Interprosthetic humeral fracture revision using a tibial allograft total elbow prosthetic composite in a patient with hemophilia A : a case report

    PubMed Central

    2012-01-01

    Introduction Interprosthetic fractures of the humerus are rare. Revisions of total elbow arthroplasty components in these cases are difficult. We report the first case of a patient with hemophilia who underwent a revision with a tibial allograft prosthetic composite without the need for hardware augmentation. Case presentation A 43-year-old Caucasian man with a history of hemophilia and transfusion-related human immunodeficiency virus and hepatitis B and C presented with an interprosthetic fracture of his humerus after months of pain between his total elbow and total shoulder arthroplasties. Because of the poor remaining bone stock available in his distal humerus, a revision using a barrel-staved tibial allograft prosthetic composite was performed. Our patients’ factor VIII level was optimized before the operation and he suffered no major long-term complications at 28 months. His only complication was an incomplete radial nerve palsy that ultimately recovered and left him with some numbness on the dorsum of his hand. Conclusion Careful use of an allograft prosthetic composite is a very reasonable option when a patient experiences an interprosthetic fracture. We have successfully performed revision total elbow arthroplasty for a patient with hemophilia with an interprosthetic fracture using a tibial allograft and no additional fixation, which resulted in his return to full activities of daily living, minimal pain and full incorporation of the allograft to host bone. PMID:23009283

  1. Factor eight inhibitor bypass activity (FEIBA) in the management of bleeds in hemophilia patients with high-titer inhibitors

    PubMed Central

    Tjønnfjord, Geir E; Andre Holme, Pål

    2007-01-01

    The development of high-titer inhibitors to FVIII and less often to other coagulation factors are the most serious complication of hemophilia therapy and makes treatment of bleeds very challenging. At present, bypassing agents, such as factor eight inhibitor bypass activity (FEIBA) and activated recombinant factor VII (rFVIIa) are the only coagulation factor concentrates available for the treatment of bleeds in inhibitor patients. Both products are effective and safe, and their efficacy has been found to be comparable (approximately 80%) in a recent prospective study. A significant number of patients report a better effect of one or the other of the products, and in a minority of the patients none of the products are particularly effective. The hemostatic efficacy of bypassing agents is not considered equal to that of coagulation factor replacement in patients without inhibitors by most physicians. An improvement in hemostatic efficacy may be achieved by optimizing the dosing of by passing agents. However, the lack of standardized and validated laboratory assays reflecting the hemostatic efficacy of the bypassing agents is an obstacle to this achievement. PMID:17969383

  2. In situ genetic correction of F8 intron 22 inversion in hemophilia A patient-specific iPSCs

    PubMed Central

    Wu, Yong; Hu, Zhiqing; Li, Zhuo; Pang, Jialun; Feng, Mai; Hu, Xuyun; Wang, Xiaolin; Lin-Peng, Siyuan; Liu, Bo; Chen, Fangping; Wu, Lingqian; Liang, Desheng

    2016-01-01

    Nearly half of severe Hemophilia A (HA) cases are caused by F8 intron 22 inversion (Inv22). This 0.6-Mb inversion splits the 186-kb F8 into two parts with opposite transcription directions. The inverted 5′ part (141 kb) preserves the first 22 exons that are driven by the intrinsic F8 promoter, leading to a truncated F8 transcript due to the lack of the last 627 bp coding sequence of exons 23–26. Here we describe an in situ genetic correction of Inv22 in patient-specific induced pluripotent stem cells (iPSCs). By using TALENs, the 627 bp sequence plus a polyA signal was precisely targeted at the junction of exon 22 and intron 22 via homologous recombination (HR) with high targeting efficiencies of 62.5% and 52.9%. The gene-corrected iPSCs retained a normal karyotype following removal of drug selection cassette using a Cre-LoxP system. Importantly, both F8 transcription and FVIII secretion were rescued in the candidate cell types for HA gene therapy including endothelial cells (ECs) and mesenchymal stem cells (MSCs) derived from the gene-corrected iPSCs. This is the first report of an efficient in situ genetic correction of the large inversion mutation using a strategy of targeted gene addition. PMID:26743572

  3. In situ genetic correction of F8 intron 22 inversion in hemophilia A patient-specific iPSCs.

    PubMed

    Wu, Yong; Hu, Zhiqing; Li, Zhuo; Pang, Jialun; Feng, Mai; Hu, Xuyun; Wang, Xiaolin; Lin-Peng, Siyuan; Liu, Bo; Chen, Fangping; Wu, Lingqian; Liang, Desheng

    2016-01-01

    Nearly half of severe Hemophilia A (HA) cases are caused by F8 intron 22 inversion (Inv22). This 0.6-Mb inversion splits the 186-kb F8 into two parts with opposite transcription directions. The inverted 5' part (141 kb) preserves the first 22 exons that are driven by the intrinsic F8 promoter, leading to a truncated F8 transcript due to the lack of the last 627 bp coding sequence of exons 23-26. Here we describe an in situ genetic correction of Inv22 in patient-specific induced pluripotent stem cells (iPSCs). By using TALENs, the 627 bp sequence plus a polyA signal was precisely targeted at the junction of exon 22 and intron 22 via homologous recombination (HR) with high targeting efficiencies of 62.5% and 52.9%. The gene-corrected iPSCs retained a normal karyotype following removal of drug selection cassette using a Cre-LoxP system. Importantly, both F8 transcription and FVIII secretion were rescued in the candidate cell types for HA gene therapy including endothelial cells (ECs) and mesenchymal stem cells (MSCs) derived from the gene-corrected iPSCs. This is the first report of an efficient in situ genetic correction of the large inversion mutation using a strategy of targeted gene addition. PMID:26743572

  4. New and Emerging Agents for the Treatment of Hemophilia: Focus on Extended Half-Life Recombinant Clotting Proteins.

    PubMed

    Ragni, Margaret V

    2015-09-01

    Hemophilia A and B are X-linked disorders caused by deficient or defective clotting factor VIII (FVIII) or IX factor (FIX) proteins, and characterized by spontaneous or traumatic bleeding into joints and muscles. Previous use of plasma and plasma-derived clotting factors that lacked appropriate viral inactivation steps in manufacturing led to significant morbidity associated with transfusion-transmitted HIV and hepatitis C virus (HCV). The development of recombinant proteins revolutionized their treatment, and, with no new HIV or HCV infection via clotting proteins for nearly 30 years, greatly improved their lifespan, which now approaches that of the general population, and with the same risks for aging complications. Novel long-acting factor proteins are being licensed to extend FVIII and FIX half-life, thereby reducing infusion frequency and potentially bleed frequency and associated morbidity. Further, novel therapeutics which take advantage of new technologies, including siRNA, monoclonal antibody, and small peptide inhibition technologies, have the potential to simplify treatment and improve outcomes for those with inhibitors. PMID:26310188

  5. Single nucleotide primer extension to detect genetic diseases: Experimental application to hemophilia B (factor IX) and cystic fibrosis genes

    SciTech Connect

    Kuppuswamy, M.N.; Hoffmann, J.W.; Spitzer, S.G.; Groce, S.L.; Bajaj, S.P. ); Kasper, C.K. )

    1991-02-15

    In this report, the authors describe an approach to detect the presence of abnormal alleles in those genetic diseases in which frequency of occurrence of the same mutation is high (e.g., hemophilia B). Initially, from each subject, the DNA fragment containing the putative mutation site is amplified by the polymerase chain reaction. For each fragment two reaction mixtures are then prepared. Each contains the amplified fragment, a primer (18-mer or longer) whose sequence is identical to the coding sequence of the normal gene immediately flanking the 5{prime} end of the mutation site, and either an {alpha}-{sup 32}P-labeled nucleotide corresponding to the normal coding sequence at the mutation site or an {alpha}-{sup 32}P-labeled nucleotide corresponding to the mutant sequence. An essential feature of the present methodology is that the base immediately 3{prime} to the template-bound primer is one of those altered in the mutant, since in this way an extension of the primer by a single base will give an extended molecule characteristic of either the mutant or the wild type. The method is rapid and should be useful in carrier detection and prenatal diagnosis of every genetic disease with a known sequence variation.

  6. Correction of murine hemophilia A following nonmyeloablative transplantation of hematopoietic stem cells engineered to encode an enhanced human factor VIII variant using a safety-augmented retroviral vector

    PubMed Central

    Ramezani, Ali

    2009-01-01

    Insertional mutagenesis by retroviral vectors is a major impediment to the clinical application of hematopoietic stem cell gene transfer for the treatment of hematologic disorders. We recently developed an insulated self-inactivating gammaretroviral vector, RMSinOFB, which uses a novel enhancer-blocking element that significantly decreases genotoxicity of retroviral integration. In this study, we used the RMSinOFB vector to evaluate the efficacy of a newly bioengineered factor VIII (fVIII) variant (efVIII)—containing a combination of A1 domain point mutations (L303E/F309S) and an extended partial B domain for improved secretion plus A2 domain mutations (R484A/R489A/P492A) for reduced immunogenicity—toward successful treatment of murine hemophilia A. In cell lines, efVIII was secreted at up to 6-fold higher levels than an L303E/F309S A1 domain–only fVIII variant (sfVIIIΔB). Most important, when compared with a conventional gammaretroviral vector expressing sfVIIIΔB, lower doses of RMSin-efVIII-OFB–transduced hematopoietic stem cells were needed to generate comparable curative fVIII levels in hemophilia A BALB/c mice after reduced-intensity total body irradiation or nonmyeloablative chemotherapy conditioning regimens. These data suggest that the safety-augmented RMSin-efVIII-OFB platform represents an encouraging step in the development of a clinically appropriate gene addition therapy for hemophilia A. PMID:19470695

  7. Systematic review of the role of FVIII concentrates in inhibitor development in previously untreated patients with severe hemophilia a: a 2013 update.

    PubMed

    Franchini, Massimo; Coppola, Antonio; Rocino, Angiola; Santagostino, Elena; Tagliaferri, Annarita; Zanon, Ezio; Morfini, Massimo

    2013-10-01

    Nowadays, patients with hemophilia A receive a high standard of care; therefore, the most challenging complication of factor VIII (FVIII) replacement therapy has become the development of FVIII inhibitors, which render the concentrate infusion ineffective and expose patients to an increased risk of morbidity and mortality. Among environmental risk factors influencing inhibitor development, the type of FVIII products has always drawn the attention of investigators. Conflicting results are reported in the literature concerning rates of inhibitor development after either plasma-derived or recombinant FVIII concentrates. To help elucidate this controversial issue, we have performed a systematic review and meta-analysis of prospective studies evaluating the incidence of inhibitors in previously untreated patients with severe hemophilia A receiving plasma-derived or recombinant FVIII products. The quality of the studies was assessed using the Newcastle-Ottawa Scale (NOS), the STrenghtening the Reporting of OBservational studies in Epidemiology and an ad hoc quality score. Overall, 28 prospective studies, including 1,421 patients with hemophilia A, fulfilled our selection criteria and were included in the systematic review. No statistically significant differences were observed in the inhibitor incidence between plasma-derived and recombinant FVIII concentrates considering all (weighted means: 23%, 95% CI: 15-33% vs. 29%, 95% CI: 26-32%) and high titer (16%, 95% CI: 10-26% vs. 18%, 95% CI: 15-21%) inhibitors. Similarly, no significant differences were found in the inhibitor incidence among the different classes of recombinant products. In conclusion, the results of our meta-analysis show that the different types of FVIII products are not associated with different risks of inhibitor development. PMID:24022806

  8. Gene therapy for hemophilia B with liver-specific element mediated by Rep-RBE site-specific integration system.

    PubMed

    Xu, Zhengxin; Ye, Juan; Zhang, Amin; Xie, Linjun; Shen, Qi; Xue, Jinglun; Chen, Jinzhong

    2015-02-01

    Adeno-associated virus (AAV) is a nonpathogenic virus capable of targeting human chromosome 19 for integration at AAVS1 site, and a 16 bp Rep binding element (RBE) sequence of AAV was sufficient for mediating this specific integration in the presence of AAV regulation proteins (Rep). Previously, we cotransduced 2 plasmids, pRBE-CMV-hFIX and pRC, into the AAVS1 transgenic mice by hydrodynamic injection, and a long-term expression of human coagulation Factor IX (hFIX) was observed. The corresponding AAVS1 locus site-specific integrations were verified by nested polymerase chain reaction. In this study, we established a novel hFIX expression plasmid, pRBE-HCR-hAAT-hFIX, driven by a liver-specific promoter by replacing the CMV promoter of pRBE-CMV-hFIX with a humanized promoter consisting of HCR-hAAT. The expression of hFIX in vitro was almost the same in transient transfection of pRBE-CMV-hFIX or pRBE-HCR-hAAT-hFIX. AAVS1-specific integrations were identified both in mice transfected with pRC/pRBE-CMV-hFIX cocktail and pRC/pRBE-HCR-hAAT-hFIX cocktail. However, the expression of hFIX of pRBE-HCR-hAAT-hFIX mice was higher and persisted longer. It achieved more than 1% of normal plasma hFIX concentration and maintained for 240 days. The result suggested that RBE-HCR-hAAT element could improve the expression of hFIX and present potential usage of Rep-RBE site-specific integration in gene therapy for hemophilia B. PMID:25295466

  9. Evaluation of the biological differences of canine and human factor VIII in gene delivery: implications in human hemophilia treatment.

    PubMed

    Wang, Q; Dong, B; Firrman, J; Wu, W; Roberts, S; Moore, A R; Liu, L S; Chin, M P S; Diao, Y; Kost, J; Xiao, W

    2016-07-01

    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, different biological properties between cFVIII and human FVIII (hFVIII) indicated that the development of novel HA treatment may require careful characterization of non-human FVIII. To investigate whether the data obtained using cFVIII can translate to HA treatment in human, we analyzed the differential biological properties of canine heavy chain (cHC) and light chain (cLC) by comparing with human heavy chain (hHC) and light chain (hLC). The secretion of cHC was 5-30-fold higher than hHC, with or without light chains (LCs). cHC+hLC group exhibited ~18-fold increase in coagulation activity compared with hHC+hLC delivery by recombinant adeno-associated viral vectors. Unlike hHC, the secretion of cHC was independent of LCs. cLC improves the specific activity of FVIII by two- to threefold compared with hLC. Moreover, the cLC, but not cHC, contributes to the higher stability of cFVIII. Our results suggested that the cFVIII expression results in the canine model should be interpreted with caution as the cHC secreted more efficiently than hHC and cLC exhibited a more active and stable phenotype than hLC. PMID:27064790

  10. Extracorporeal Treatment for the Acute und Long-Term Outcome of Patients with Life-Threatening Acquired Hemophilia.

    PubMed

    Zeitler, Heike; Ulrich-Merzenich, Gudrun; Panek, Darius; Goldmann, Georg; Vidovic, Natascha; Brackmann, Hans-Hermann; Oldenburg, Johannes

    2012-08-01

    OBJECTIVES: In acquired hemophilia (AH), autoantibodies (inhibitors) impede blood coagulation factors leading to severe bleedings. Cornerstones of a successful treatment are the control of bleeding and an eradication of autoantibodies. The present study is an update of our previous documentation of the treatment of high-titer AH patients with severe life-threatening bleeding undergoing the modified Bonn-Malmö-Protocol (MBMP). METHODS: 64 AH patients were treated by a standard combination protocol (MBMP) consisting of antibody depletion through immunoadsorption, i.v. immunoglobulin, immunosuppression, and high-dose FVIII substitution. They underwent a long-term follow-up. RESULTS: Primary study endpoints loss of detection of the activity of the inhibitor and FVIII recovery ? 5% were reached in a median time of 3 days (95% CI: 2.6-3.4 days), the median time of FVIII substitution was 13 days (95% CI 10.6-15.3 days), and the median time of immunoadsorption was 16 days (95% CI 13-18.9 days). In 5 patients the AH occurred as paraneoplastic syndrome, and partial remission was achieved. Relapses without bleeding event occurred only in second-line MBMP. Those responded excellently to short time treatment. Overall patients remained in remission over a median follow-up time of 8 years. Conclusion: Except for paraneoplastic AH, MBMP-treated patients have a remarkable prognosis which is confirmed by long-term follow-up with a complete response rate of 93% (53/57) in the first year post MBMP and 100% during long-term follow-up. These outcome in life-threatening AH is unique and until now not achievable via other treatment schedules. In life-threatening bleedings physicians should take into account MBMP as a first line treatment. PMID:22969696

  11. Long term survival in persons with hemophilia and chronic hepatitis C: 40 year outcomes of a large single center cohort.

    PubMed

    Eyster, M Elaine; Kong, Lan; Li, Menghan; Schreibman, Ian R

    2016-09-01

    We studied the course of chronic HCV infections in a cohort of 222 persons with hemophilia (PWH) and von Willebrand disease followed at our center since 1973. Twenty two (10%) developed end stage liver disease (ESLD). Forty years after HCV infection, cumulative incidence of ESLD was 12.3% and overall survival was 45.5%. Those who were infected with HCV only (n = 100) had a survival of 75.2%, while those infected with HIV (n = 122) had a survival of 24% (P < 0.001). Survivals were significantly longer for those infected with HCV at younger age (< 15 years) compared to those infected over age 30 years (P = 0.014). Cause specific deaths for ESLD and bleeding were 8.8% and 8.3% respectively. For HIV negative subjects, the annual hazard of death from ESLD and bleeding was near zero for the first 10 years, and then rose slowly over the next 20 years to 0.4/100py for ESLD and 0.2/100py for bleeding. Sixty subjects completed 79 treatment episodes. Sustained viral response rates increased from 7/21 (33%) between 1990 and 2001, to 17/29 (58%) between 2002 and 2011, and to 27/29 (93%), since 2012 with the advent of the directly acting antiviral agents. These results confirm the very slow ESLD progression rate in HIV negative PWH. However, the risk of death from both ESLD and bleeding increases steadily with longer duration of HCV infection. More aggressive surveillance to detect those with early fibrosis is needed now that curative treatment is possible in >95% of individuals. Am. J. Hematol. 91:E335-E340, 2016. © 2016 Wiley Periodicals, Inc. PMID:27214557

  12. Incidence and survival of cancers among 1,054 hemophilia patients: A nationwide and 14-year cohort study.

    PubMed

    Huang, Yung-Chieh; Tsan, Yu-Tse; Chan, Wei-Cheng; Wang, Jiaan-Der; Chu, Wei-Min; Fu, Yun-Ching; Tong, Kwok-Man; Lin, Ching-Heng; Chang, Shin-Tsu; Hwang, Wen-Li

    2015-04-01

    As life expectancy increases in persons with hemophilia (PWH), more age-related diseases such as cancer emerge among this patient group. The aim of this study was to investigate incidence and survival of cancers among PWH in Taiwan. We analyzed data of 1,054 PWH retrieved from Taiwan's National Health Insurance Research Database between 1997 and 2010, by comparing variables to 10540 age- and gender-matched healthy individuals from the general population. There were 43 PWH and 178 individuals of general population with newly diagnosed cancer (RR 2.42, 95% CI 1.74-3.35). The cumulative incidences of cancer in PWH and the general population were 4.7 and 1.9%, respectively. Hepatocellular carcinoma (HCC) was the major type of cancer (17 cases) in PWH; cancer rate was still increased when HCC and HIV-related cancers were excluded (RR 1.66, 95% CI 1.06-2.59). There was no significant difference observed in lung, colorectal, or prostate cancer occurrence. Compared to the general population, PWH were younger at the time of cancer diagnosis (45.1 vs. 57.2 years old, P value < 0.001), and had fewer co-morbidities. Nineteen PWH with cancers died during the study period, and no bleeding-related death was recorded among these patients. The survival rate was not different between PWH and the general population, P = 0.86. In conclusion, the cumulative incidence of cancer among PWH was higher than the general population. PWH with cancer were younger and had fewer comorbidities, but the survival rates were similar in the two groups. PMID:25639564

  13. Advances in bypassing agent therapy for hemophilia patients with inhibitors to close care gaps and improve outcomes.

    PubMed

    Shapiro, Amy D; Hedner, Ulla

    2011-10-01

    In the past, patients with hemophilia and inhibitors have had less-than-optimal treatment and have experienced more orthopedic complications than patients without inhibitors. Bypassing agents offer the potential to close treatment gaps between inhibitor and noninhibitor patients by helping the former better attain key treatment goals, including: facilitating early initiation of treatment and hemostatic control in hemarthroses; providing effective treatment in serious hemorrhagic episodes; and performance of major surgery. Effective treatment with a bypassing agent minimizes joint and/or muscle damage and potentially can serve as an effective prophylactic agent to minimize the number of hemarthroses experienced per year, thereby mitigating the development of arthropathy. The reported efficacy of the currently available bypassing agents ranges from approximately 50-80% (50-64% in controlled studies) for plasma-derived activated prothrombin complex concentrate (pd-aPCC) and 81-91% (in controlled studies) for recombinant activated factor VII (rFVIIa), including use in major orthopedic surgery. Both bypassing agents have undergone key improvements in their formulation and/or properties in recent years. The nanofiltered, vapor-heated formulation of pd-aPCC has diminished the risk of acquiring blood-borne viral infections and the room temperature stable formulation of rFVIIa allows more convenient storage, increased ease to dissolve and inject, and smaller volumes, thereby increasing overall ease of administration. Use of recommended dosing has been demonstrated to provide effective hemostasis with a minimal number of injections for both agents. In this paper, we review the individual characteristics of pd-aPCC and rFVIIa and discuss clinical data from studies conducted in inhibitor patients that demonstrate the potential benefits of these bypassing agents in this difficult-to-treat population, and underscore the potential opportunities to close the gap in care between

  14. Evaluation of factor VIII polymorphic short tandem repeat markers in linkage analysis for carrier diagnosis of hemophilia A

    PubMed Central

    Shrestha, Sabina; Dong, Sufang; Li, Zuhua; Huang, Zhuliang; Zheng, Fang

    2016-01-01

    Hemophilia A (HA) is the most common inherited X-linked recessive bleeding disorder caused by heterogeneous mutations in the factor VIII gene (FVIII). Diagnosis of the carrier is critical for preventing the birth of children affected by this coagulation disorder, which ultimately facilitates its management. Due to the heterogeneous nature of mutations, the large inversions and the complexity of the FVIII gene, direct recognition of the disease-associated mutation in HA is complex. Indirect linkage analysis using highly informative heterozygous polymorphic markers is an alternative method for determining the co-segregation of the mutant gene within a family for carrier detection of HA. The aim of the present study was to perform carrier diagnosis in a family with HA. Rapid multifluorescent polymerase chain reaction (PCR) was performed with six extragenic short tandem repeats (STRs), DXS1073, DXS15, DXS8091, DXS1227, DXS991, DXS993 and one intragenic marker, STR22 for linkage analysis in the HA family. All the STR markers employed in the present study were informative for linkages of pathogenic and healthy haplotypes among family members, particularly STR22, DXS1073 and DXS15. The STR marker, STR22, is within the FVIII gene while the DXS1073 and DXS15 markers are very close to the FVIII gene, where the chances of recombination are comparatively low, and provided the most accurate interpretation analysis, indicating that the proband's sister may have been the HA carrier. Rapid multifluorescent PCR using STR markers and linkage analysis was identified to be a simple method for performing HA carrier diagnosis. PMID:27446547

  15. Somatic mosaicism in families with hemophilia B: 11% of germline mutations originate within a few cell divisions post-fertilization

    SciTech Connect

    Knoell, A.; Ketterling, R.P.; Vielhaber, E.

    1994-09-01

    Previous molecular estimates of mosaicism in the dystrophin and other genes generally have focused on the transmission of the mutated allele to two or more children by an individual without the mutation in leukocyte DNA. We have analyzed 414 families with hemophilia B by direct genomic sequencing and haplotype analysis, and have deduced the origin of mutation in 56 families. There was no origin individual who transmitted a mutant allele to more than one child. However, somatic mosaicism was detected by sequence analysis of four origin individuals (3{female} and 1{male}). The sensitivity of this analysis is typically one part in ten. In one additional female who had close to a 50:50 ratio of mutant to normal alleles, three of four noncarrier daughters inherited the haplotype associated with the mutant allele. This highlights a caveat in molecular analysis: a presumptive carrier in a family with sporadic disease does not necessarily have a 50% probability of transmitting the mutant allele to her offspring. After eliminating those families in which mosaicism could not be detected because of a total gene deletion or absence of DNA from a deduced origin individual, 5 of 43 origin individuals exhibited somatic mosaicism at a level that reflects a mutation within the first few cell divisions after fertilization. In one patient, analysis of cervical scrapings and buccal mucosa confirm the generalized distribution of somatic mutation. Are the first few cell divisions post-fertilization highly mutagenic, or do mutations at later divisions also give rise to somatic mosaicism? To address this question, DNA from origin individuals are being analyzed to detect somatic mosaicism at a sensitivity of 1:1000. Single nucleotide primer extension (SNuPE) has been utilized in eight families to date and no mosaicism has been detected. When the remaining 30 samples are analyzed, it will be possible to compare the frequency of somatic mosaicism at 0.1-10% with that of {ge}10%.

  16. Germ-line origins of mutation in families with hemophilia B: The sex ratio varies with the type of mutation

    SciTech Connect

    Ketterling, R.P.; Vielhaber, E.; Bottema, C.D.K.; Schaid, D.J.; Sommer, S.S. ); Cohen, M.P. ); Sexauer, C.L. )

    1993-01-01

    Previous epidemiological and biochemical studies have generated conflicting estimates of the sex ratio of mutation. Direct genomic sequencing in combination with haplotype analysis extends previous analyses by allowing the precise mutation to be determined in a given family. From analysis of the factor IX gene of 260 consecutive families with hemophilia B, the authors report the germ-line origin of mutation in 25 families. When combined with 14 origins of mutation reported by others and with 4 origins previously reported by them, a total of 25 occur in the female germ line, and 18 occur in the male germ line. The excess of germ-line origins in females does not imply an overall excess mutation rate per base pair in the female germ line. Bayesian analysis of the data indicates that the sex ratio varies with the type of mutation. The aggregate of single-base substitutions shows a male predominance of germ-line mutations (P < .002). The maximum-likelihood estimate of the male predominance is 3.5-fold. Of the single-base substitutions, deletions display a sex ratio of unity. Analysis of the parental age at transmission of a new mutation suggests that germ-line mutations are associated with a small increase in parental age in females but little, if any, increase in males. Although direct genomic sequencing offers a general method for defining the origin of mutation in specific families, accurate estimates of the sex ratios of different mutational classes require large sample sizes and careful correction for multiple biases of ascertainment. The biases in the present data result in an underestimate of the enhancement of mutation in males. 62 refs., 1 fig., 5 tabs.

  17. Expression of human factor IX in rabbit hepatocytes by retrovirus-mediated gene transfer: Potential for gene therapy of hemophilia B

    SciTech Connect

    Thompson, A.R. Puget Sound Blood Center, Seattle, WA ); Darlington, G. ); Armentano, D.; Woo, S.L.C.

    1990-08-01

    Hemophilia B (Christmas disease) is a chromosome X-linked blood clotting disorder which results when factor IX is deficient or functionally defective. The enzyme is synthesized in the liver, and the existence of animal models for this genetic disease will permit the development of somatic gene therapy protocols aimed at transfer of the functional gene into the liver. The authors report the construction of an N2-based recombinant retroviral vector, NCMVFIX, for efficient transfer and expression of human factor IX cDNA in primary rabbit hepatocytes. In this construct the human cytomegalovirus immediate early promoter directs the expression of factor IX. Hepatocytes were isolated from 3-week-old New Zealand White rabbits, infected with the recombinant virus, and analyzed for secretion of active factor IX. The infected rabbit hepatocytes produced human factor IX that is indistinguishable from enzyme derived from normal human plasma. The recombinant protein is sufficiently {gamma}-carboxylated and is functionally active in clotting assays. These results establish the feasibility of using infected hepatocytes for the expression of this protein and are a step toward the goal of correcting hemophilia B by hepatic gene transfer.

  18. Molecular characterization of mild-to-moderate hemophilia A: detection of the mutation in 25 of 29 patients by denaturing gradient gel electrophoresis.

    PubMed Central

    Higuchi, M; Antonarakis, S E; Kasch, L; Oldenburg, J; Economou-Petersen, E; Olek, K; Arai, M; Inaba, H; Kazazian, H H

    1991-01-01

    To date it has been difficult to characterize completely a genetic disorder, such as hemophilia A, in which the involved gene is large and unrelated affected individuals have different mutations, most of which are point mutations. Toward this end, we analyzed the DNA of 29 patients with mild-to-moderate hemophilia A in which the causative mutation is likely to be a missense mutation. Using computer analysis, we determined the melting properties of factor VIII gene sequences to design primer sets for PCR amplification and subsequent denaturing gradient gel electrophoresis (DGGE). A total of 45 primer sets was chosen to amplify 99% of the coding region of the gene and 41 of 50 splice junctions. To facilitate detection of point mutations, we mixed DNA from two male patients, and both homoduplexes and heteroduplexes were analyzed. With these 45 primer sets, 26 DNAs containing previously identified point mutations in the factor VIII gene were studied, and all 26 mutations were easily distinguishable from normal. After analyzing the 29 patients with unknown mutations, we identified the disease-producing mutation in 25 (86%). Two polymorphisms and two rare normal variants were also found. Therefore, DGGE after computer analysis is a powerful method for nearly complete characterization of disease-producing mutations and polymorphisms in large genes such as that for factor VIII. Images PMID:1924291

  19. Surgical Treatment of an Infected Nonunion of the Middle Third of the Femur Associated with Femoral Shortening in a Hemophilia Patient

    PubMed Central

    Salduz, Ahmet; Kaya, Özcan; Balci, Halil İbrahim; Akgul, Turgut; Dikici, Fatih; Zülfikar, Bülent; Kocaoğlu, Mehmet

    2016-01-01

    The management of nonunion and limb length discrepancy has remained a constant challenge in hemophilic patients. In this study, we aimed to present the treatment of femur infected nonunion and limb length discrepancy in a twenty-seven-year-old patient with hemophilia type A. A 27-year-old male patient with hemophilia type A referred to our institution for the treatment of right femur infected nonunion and 10 cm shortness of the femur. Resection of the nonunion site and bone-to-bone fixation with autologous bone grafting were performed. Compression to the pseudoarthrosis site and distraction from new osteotomy site were applied with the unilateral external fixator. Union was achieved, and 6 cm lengthening was obtained according to the initial length. Patient was followed up for 7 years. After this treatment, the patient is able to walk with full weight bearing on the affected extremity with 4 cm shortening which is compensated by the heel lift. The results of this case indicate that limb lengthening and treatment of nonunion with the external fixation could be reliable and effective method for hemophilic patients. PMID:27073706

  20. Functions of AAV-CMV-F.IX And AAV-EF1alpha-F.IX in gene therapy for hemophilia B.

    PubMed

    Wiwanitkit, Viroj

    2007-02-01

    There has been substantial progress in using gene therapy to treat animals with hemophilia. Adeno-associated viral (AAV) gene transfer of coagulation factor IX to skeletal muscle and liver of murine and canine models of hemophilia has resulted in sustained systemic expression and, in several studies, in complete cure of the bleeding disorder. Two AAV vectors widely used at present are AAV-CMV-F.IX and AAV-EF1alpha-F.IX. This work compares the predicted molecular functions of AAV-CMV-F.IX and AAV-EF1alpha -F.IX by sequence docking and gene ontology. It is shown that both AAV-CMV-F.IX and AAV-EF1alpha -F.IX induce coagulation factor IXa activity; however, AAV-CMV-F.IX administration also yields coagulation factor XIa activity and AAV-EF1alpha -F.IX treatment results in coagulation factor Xa activity. Therefore, AAV-CMV-F.IX might be useful for factor XI deficiency. AAV-CMV-F.IX has several additional molecular functions and processes compared with AAV-CMV-F.IX. PMID:17266422

  1. Integration-deficient Lentiviral Vectors Expressing Codon-optimized R338L Human FIX Restore Normal Hemostasis in Hemophilia B Mice

    PubMed Central

    Suwanmanee, Thipparat; Hu, Genlin; Gui, Tong; Bartholomae, Cynthia C; Kutschera, Ina; von Kalle, Christof; Schmidt, Manfred; Monahan, Paul E; Kafri, Tal

    2014-01-01

    Integration-deficient lentiviral vectors (IDLVs) have been shown to transduce a wide spectrum of target cells and organs in vitro and in vivo and to maintain long-term transgene expression in nondividing cells. However, epigenetic silencing of episomal vector genomes reduces IDLV transgene expression levels and renders these safe vectors less efficient. In this article, we describe for the first time a complete correction of factor IX (FIX) deficiency in hemophilia B mice by IDLVs carrying a novel, highly potent human FIX cDNA. A 50-fold increase in human FIX cDNA potency was achieved by combining two mechanistically independent yet synergistic strategies: (i) optimization of the human FIX cDNA codon usage to increase human FIX protein production per vector genome and (ii) generation of a highly catalytic mutant human FIX protein in which the arginine residue at position 338 was substituted with leucine. The enhanced human FIX activity was not associated with liver damage or with the formation of human FIX-directed inhibitory antibodies and rendered IDLV-treated FIX-knockout mice resistant to a challenging tail-clipping assay. A novel S1 nuclease-based B1-quantitative polymerase chain reaction assay showed low levels of IDLV integration in mouse liver. Overall, this study demonstrates that IDLVs carrying an improved human FIX cDNA safely and efficiently cure hemophilia B in a mouse model. PMID:23941813

  2. Molecular characterization of mild-to-moderate hemophilia A: Detection of the mutation in 25 of 29 patients by denaturing gradient gel electrophoresis

    SciTech Connect

    Higuchi, Miyoko; Antonarakis, S.E.; Kasch, L. Economou-Petersen, E.; Kazazian, H.H. Jr. ); Oldenburg, J.; Olek, K. ); Arai, Morio; Inaba, Hiroshi )

    1991-10-01

    To date it has been difficult to characterize completely a genetic disorder, such as hemophilia A, in which the involved gene is large and unrelated affected individuals have different mutations, most of which are point mutations. Toward this end, the authors analyzed the DNA of 29 patients with mild-to-moderate hemophilia A in which the causative mutation is likely to be a missense mutation. Using computer analysis, they determined the melting properties of factor VIII gene sequences to design primer sets for PCR amplification and subsequent denaturing gradient gel electrophoresis (DGGE). A total of 45 primer sets was chosen to amplify 99% of the coding region of the gene and 41 of 50 splice junctions. To facilitate detection of point mutations, they mixed DNA from two male patients, and both homoduplexes and heteroduplexes were analyzed. With these 45 primer sets, 26 DNAs containing previously identified point mutations were easily distinguishable from normal. After analyzing the 29 patient with unknown mutations, they identified the disease-producing mutation in 25 (86%). Two polymorphisms and two rare normal variants were also found. Therefore, DGGE after computer analysis is a powerful method for nearly complete characterization of disease-producing mutations and polymorphisms in large genes such as that for factor VIII.

  3. F8 gene mutation profile in Indian hemophilia A patients: Identification of 23 novel mutations and factor VIII inhibitor risk association.

    PubMed

    Pinto, Patricia; Ghosh, Kanjaksha; Shetty, Shrimati

    2016-04-01

    'FVIII inhibitors', especially in severe hemophilia A (HA) patients, is a serious adverse effect that complicates their clinical management. Many genetic and non-genetic risk factors have been proposed for FVIII inhibitor development, diverse in different population groups. This is the first study in Indian hemophiliacs that analyzes inhibitor risk in relation to the complete F8 mutation profile, in a case-control study that included 145 Indian severe HA patients, i.e. 69 inhibitor positive (with 18 inhibitor concordant/discordant family members), and 58 inhibitor negative patients, after informed consent. While 53.54% (68/127) index cases were positive for intron 22 or intron 1 inversions, 55 causative F8 mutations were detected in the 59 inversion negative patients, of which 23 were novel mutations (in 24 patients) and 32 were reported earlier (in 35 patients). A higher incidence of mutations, in the C1 and C2 domains in inhibitor positive patients, and in the A1 domain in inhibitor negative patients was observed, though not significantly different. The study suggests that large F8 rearrangements (significantly higher in the inhibitor positive patients) pose the highest risk, while missense mutations (significantly higher in the inhibitor negative patients) pose the lowest risk of inhibitor development in Indian hemophilia A patients. PMID:26897466

  4. Plant-based oral tolerance to hemophilia therapy employs a complex immune regulatory response including LAP+CD4+ T cells.

    PubMed

    Wang, Xiaomei; Su, Jin; Sherman, Alexandra; Rogers, Geoffrey L; Liao, Gongxian; Hoffman, Brad E; Leong, Kam W; Terhorst, Cox; Daniell, Henry; Herzog, Roland W

    2015-04-01

    Coagulation factor replacement therapy for the X-linked bleeding disorder hemophilia is severely complicated by antibody ("inhibitor") formation. We previously found that oral delivery to hemophilic mice of cholera toxin B subunit-coagulation factor fusion proteins expressed in chloroplasts of transgenic plants suppressed inhibitor formation directed against factors VIII and IX and anaphylaxis against factor IX (FIX). This observation and the relatively high concentration of antigen in the chloroplasts prompted us to evaluate the underlying tolerance mechanisms. The combination of oral delivery of bioencapsulated FIX and intravenous replacement therapy induced a complex, interleukin-10 (IL-10)-dependent, antigen-specific systemic immune suppression of pathogenic antibody formation (immunoglobulin [Ig] 1/inhibitors, IgE) in hemophilia B mice. Tolerance induction was also successful in preimmune mice but required prolonged oral delivery once replacement therapy was resumed. Orally delivered antigen, initially targeted to epithelial cells, was taken up by dendritic cells throughout the small intestine and additionally by F4/80(+) cells in the duodenum. Consistent with the immunomodulatory responses, frequencies of tolerogenic CD103(+) and plasmacytoid dendritic cells were increased. Ultimately, latency-associated peptide expressing CD4(+) regulatory T cells (CD4(+)CD25(-)LAP(+) cells with upregulated IL-10 and transforming growth factor-β (TGF-β) expression) as well as conventional CD4(+)CD25(+) regulatory T cells systemically suppressed anti-FIX responses. PMID:25700434

  5. Transforming the treatment for hemophilia B patients: update on the clinical development of recombinant fusion protein linking recombinant coagulation factor IX with recombinant albumin (rIX-FP).

    PubMed

    Santagostino, Elena

    2016-05-01

    Recombinant fusion protein linking recombinant coagulation factor IX with recombinant albumin (rIX-FP; Idelvion®(†)) is an innovative new treatment designed to extend the half-life of factor IX (FIX) and ease the burden of care for hemophilia B patients. The rIX-FP clinical development program - PROLONG-9FP - is in its advanced phases, with pivotal studies in previously treated adults, adolescents, and pediatrics now completed. Across all age groups studied, rIX-FP has demonstrated a markedly improved pharmacokinetic profile compared with plasma-derived and recombinant FIX treatments, with a 30-40% higher incremental recovery, an approximately 5-fold longer half-life, a lower clearance, and a greater area under the curve. rIX-FP has been very well tolerated with an excellent safety profile. In the pivotal studies, there have been no reports of FIX inhibitors or antidrug antibodies, and few treatment-related adverse events have been observed. Prophylactic regimens of rIX-FP administered once weekly to once every 14 days have been highly effective. When used for surgical prophylaxis, a single infusion of rIX-FP has been sufficient to maintain hemostasis, even during major orthopedic surgery. An ongoing study is now enrolling previously untreated patients and evaluating the possibility of extending the dosing interval to every 21 days. There is little doubt that rIX-FP will transform the treatment of hemophilia B. PMID:27288064

  6. Illustrated operative management of spontaneous bleeding and compartment syndrome of the lower extremity in a patient with acquired hemophilia A: a case report

    PubMed Central

    2014-01-01

    Introduction Spontaneous bleeding resulting in compartment syndrome at the lower adult leg due to acquired hemophilia A is rare. There are no reports on operative management of this entity. Case presentation We present a case of atraumatic compartment syndrome of the lower leg due to acquired factor VIII deficiency, in an 83-year-old Caucasian man of European descent. He was treated surgically with a long and complicated postoperative course after presenting to a community hospital with a 2-day history of increasing pain and swelling in his left lower leg without a previous history of trauma. Conclusions Awareness, prompt diagnosis and effective treatment of compartment syndrome caused by a rare bleeding disorder, which is usually acquired by the elderly, is essential and may spare a patient from surgery or even limb loss, if early administration of recombinant factor VIIa is effective. The course of disease in a patient with operative management of spontaneous bleeding, compartment syndrome and acquired hemophilia A may be prolonged. However, an interdisciplinary approach with meticulous surgical treatment and bleeding management with recombinant factor VIIa as well as inhibitor eradication by immunosuppressive treatment can be successful and expensive. PMID:24886030

  7. Successful immune tolerance induction with low-dose coagulation factor VIII in a patient with hemophilia A from a developing country.

    PubMed

    Ay, Yilmaz; Ersin, Toret; Yesim, Oymak; Hilkay, Karapinar Tuba; Dilek, Ince; Gulcihan, Ozek; Ahmet, Koc

    2016-09-01

    Inhibitor development is the most frequent and serious complication of the treatment in patients with hemophilia. Immune tolerance induction (ITI) is the only option of treatment for the eradication of factor VIII (FVIII) inhibitor. We would like to present our case with hemophilia whose FVIII inhibitor eradication was done by a low-dose ITI regimen. Our patient has been applied on-demand therapy until 8 years of age. Secondary prophylaxis was began because of having hemophilic arthropathy. A low titer of FVIII inhibitor (4.2 BU/ml) was detected in the fifth month of the prophylaxis. The peak inhibitor titer of patient was 4.6 BU/ml, and there was no decrease in inhibitor titer in the follow-up duration. The low-dose ITI (50 IU/kg, 3 days a week) was started. His inhibitor level was detected negative and the recovery test was ameliorated in the 15th of the ITI therapy. High-dose regimen ITI could not be given particularly in developing countries such as Turkey in view of the high cost of treatment. Patients who had good risk factors might be successfully treated by using low-dose ITI regimen as effective as high-dose ITI regimen. PMID:26484639

  8. Development of inhibitory antibodies to therapeutic factor VIII in severe hemophilia A is associated with microsatellite polymorphisms in the HMOX1 promoter

    PubMed Central

    Repessé, Yohann; Peyron, Ivan; Dimitrov, Jordan D; Dasgupta, Suryasarathi; Moshai, Elika Farrokhi; Costa, Catherine; Borel-Derlon, Annie; Guillet, Benoit; D’Oiron, Roseline; Aouba, Achille; Rothschild, Chantal; Oldenburg, Johannes; Pavlova, Anna; Kaveri, Srinivas V; Lacroix-Desmazes, Sébastien

    2013-01-01

    Induction of heme oxygenase-1, a stress-inducible enzyme with anti-inflammatory activity, reduces the immunogenicity of therapeutic factor VIII in experimental hemophilia A. In humans, heme oxygenase-1 expression is modulated by polymorphisms in the promoter of the heme oxygenase-1-encoding gene (HMOX1). We investigated the relationship between polymorphisms in the HMOX1 promoter and factor VIII inhibitor development in severe hemophilia A. We performed a case-control study on 99 inhibitor-positive patients and 263 patients who did not develop inhibitors within the first 150 cumulative days of exposure to therapeutic factor VIII. Direct sequencing and DNA fragment analysis were used to study (GT)n polymorphism and single nucleotide polymorphisms located at −1135 and −413 in the promoter of HMOX1. We assessed associations between the individual allele frequencies or genotypes, and inhibitor development. Our results demonstrate that inhibitor-positive patients had a higher frequency of alleles with large (GT)n repeats (L: n≥30), which are associated with lesser heme oxygenase-1 expression (odds ratio 2.31; 95% confidence interval 1.46–3.66; P<0.001]. Six genotypes (L/L, L/M, L/S, M/M, M/S and S/S) of (GT)n repeats were identified (S: n<21; M: 21≤n<30). The genotype group including L alleles (L/L, L/M and L/S) was statistically more frequent among inhibitor-positive than inhibitor-negative patients, as compared to the other genotypes (33.3% versus 17.1%) (odds ratio 2.21, 95% confidence interval 1.30–3.76; P<0.01). To our knowledge, this is the first association identified between HMOX1 promoter polymorphism and development of anti-drug antibodies. Our study paves the way towards modulation of the endogenous anti-inflammatory machinery of hemophilia patients to reduce the risk of inhibitor development PMID:23716558

  9. A DNA fragment from Xq21 replaces a deleted region containing the entire FVIII gene in a severe hemophilia A patient

    SciTech Connect

    Murru, S.; Casula, L.; Moi, P.

    1994-09-15

    In this paper the authors report the molecular characterization of a large deletion that removes the entire Factor VIII gene in a severe hemophilia A patient. Accurate DNA analysis of the breakpoint region revealed that a large DNA fragment replaced the 300-kb one, which was removed by the deletion. Pulsed-field gel electrophoresis analysis revealed that the size of the inserted fragment is about 550 kb. In situ hybridization demonstrated that part of the inserted region normally maps to Xq21 and to the tip of the short arm of the Y chromosome (Yp). In this patient this locus is present both in Xq21 and in Xq28, in addition to the Yp, being thus duplicated in the X chromosome. Sequence analysis of the 3` breakpoint suggested that an illegitimate recombination is probably the cause of this complex rearrangement. 52 refs., 7 figs.

  10. Mutation, detection, prenatal testing, and delineation of the germline origin in a family with sporadic hemophilia B and no living hemophiliacs

    SciTech Connect

    Vielhaber, E.; Sommer, S.S.

    1994-01-15

    Hemophilia B is an X-linked recessive disorder affecting 1 in 30,000 males. Determination of carrier status for at risk females can be done by utilizing indirect methods such as DNA sequencing. However, in most cases, reliable carrier testing is not possible without first analyzing the DNA from an affected male in the family to determine his haplotype/causative sequence change. In the case presented here, the only affected male in the family has been deceased for 25 years; no DNA was available from him. The sister (III-2) of the affected individual was a suspected carrier based on her factor IX coagulant (36%); she was pregnant with a male fetus, and requested prenatal testing. 6 refs., 2 figs.

  11. Current difficulties and recent advances in bypass therapy for the management of hemophilia with inhibitors: a new and practical formulation of recombinant factor VIIa.

    PubMed

    Butros, Linda; Boayue, Koh; Mathew, Prasad

    2011-01-01

    Bypassing agents are the mainstay of treatment for patients with hemophilia with high-titer inhibitors. Whereas the availability of these agents has greatly advanced the management of bleeding episodes in this population, timely administration of bypassing agents continues to be hampered by a number of practical limitations, including the need for refrigerated storage of the agent and its reconstitution at room temperature prior to administration, among others. In this review, the importance of early treatment of bleeds and factors that influence this more timely therapeutic approach are highlighted, together with the advantages offered by the use of a new formulation of recombinant activated factor VII that permits improved storage and portability, potentially optimizing timely bypassing agent administration. PMID:21625417

  12. Compound heterozygous hemophilia A in a female patient and the identification of a novel missense mutation, p.Met1093Ile.

    PubMed

    Qiao, Shu-Kai; Ren, Han-Yun; Ren, Jin-Hai; Guo, Xiao-Nan

    2014-02-01

    Hemophilia A (HA) in females is rare. Female HA cases are often misdiagnosed as acquired HA (AHA) or as von Willebrand disease type 2N (vWD-2N). Here, we report the case of a 37-year-old female HA patient with a moderate factor VIII (FVIII) deficiency. The patient had no personal or family history of bleeding disorders, but presented with heavy uterine bleeding following surgery to remove an intrauterine device. IgG inhibitory antibodies against FVIII were undetected. A compound heterozygote mutation of the FVIII gene (F8) was found in this patient. The p.Val502Asp mutation, which has been reported previously, affects A2 domain function. A novel missense point mutation, p.Met1093Ile, was identified in the B domain. The compound heterozygote mutations in F8, p.Val502Asp and p.Met1093Ile, caused HA in this female patient, with a moderate phenotype. PMID:24317041

  13. Compound heterozygous hemophilia A in a female patient and the identification of a novel missense mutation, p.Met1093Ile

    PubMed Central

    QIAO, SHU-KAI; REN, HAN-YUN; REN, JIN-HAI; GUO, XIAO-NAN

    2014-01-01

    Hemophilia A (HA) in females is rare. Female HA cases are often misdiagnosed as acquired HA (AHA) or as von Willebrand disease type 2N (vWD-2N). Here, we report the case of a 37-year-old female HA patient with a moderate factor VIII (FVIII) deficiency. The patient had no personal or family history of bleeding disorders, but presented with heavy uterine bleeding following surgery to remove an intrauterine device. IgG inhibitory antibodies against FVIII were undetected. A compound heterozygote mutation of the FVIII gene (F8) was found in this patient. The p.Val502Asp mutation, which has been reported previously, affects A2 domain function. A novel missense point mutation, p.Met1093Ile, was identified in the B domain. The compound heterozygote mutations in F8, p.Val502Asp and p.Met1093Ile, caused HA in this female patient, with a moderate phenotype. PMID:24317041

  14. Factor VIII A3 domain substitution N1922S results in hemophilia A due to domain-specific misfolding and hyposecretion of functional protein

    PubMed Central

    Summers, Ryan J.; Meeks, Shannon L.; Healey, John F.; Brown, Harrison C.; Parker, Ernest T.; Kempton, Christine L.; Doering, Christopher B.

    2011-01-01

    A point mutation leading to amino acid substitution N1922S in the A3 domain of factor VIII (fVIII) results in moderate to severe hemophilia A. A heterologous expression system comparing N1922S-fVIII and wild-type fVIII (wt-fVIII) demonstrated similar specific coagulant activities but poor secretion of N1922S-fVIII. Immunocytochemical analysis revealed that intracellular levels of N1922S-fVIII were similar to those of wt-fVIII. The specific activity of intracellular N1922S-fVIII was 10% of that of wt-fVIII, indicating the presence of large amounts of a nonfunctional N1922S-fVIII–folding intermediate. wt-fVIII colocalized with both endoplasmic reticulum (ER)– and Golgi-resident proteins. In contrast, N1922S-fVIII colocalized only with ER-resident proteins, indicating a block in transit from the ER to the Golgi. A panel of conformation-dependent monoclonal antibodies was used to determine native or nonnative folding of N1922S-fVIII. Intracellular N1922S-fVIII but not secreted N1922S-fVIII displayed abnormal folding in the A3 and C1 domains, indicating that the A1, A2, and C2 domains fold independently into antigenically intact tertiary structures, but that folding is stalled in the mutant A3 and its contiguous C1 domain. In summary, the N1922S substitution results in poor secretion of a functional protein, and the domain-specific defect in folding and intracellular trafficking of N1922S-fVIII is a novel mechanism for secretion defects leading to hemophilia A. PMID:21217077

  15. Remarkable Variation in the Informativeness of RFLP Markers Linked to Hemophilia B Locus in Indian Population Groups: Implication in the Strategy for Carrier Detection

    PubMed Central

    Mukherjee, S.; Saha, A.; Kumar P., Senthil; Chandak, G. R.; Majumder, P. P.; Ray, K.

    2006-01-01

    Hemophilia B, an X-linked recessive bleeding disorder, is caused by heterogeneous mutations in the factor IX (F9) gene. Hence, carriers of the disease are usually detected by F9 gene linked RFLP analysis. We aimed to test a set of RFLP markers (DdeI, XmnI, MnlI, TaqI & HhaI), used worldwide for carrier detection, to estimate its heterozygosity in different population groups of India, and identify additional single nucleotide polymorphisms (SNPs) if necessary. A total of 8 population groups encompassing different regions of India, consisting of 107 unrelated normal females without any history of hemophilia B in the family and 13 unrelated obligate carriers were recruited in the study. Regions of F9 gene were amplified by PCR from genomic DNA of the donors followed by restriction enzyme digestion and/or sequencing as appropriate. Combined informativeness for the markers varied between 52–86% among normal females belonging to different geographical locations of India. Haplotype analysis revealed that the most prevalent haplotype lacked the restriction sites for all five RFLP markers. Screening regions of F9 gene that harbor 10 SNPs reported in dbSNP yielded only two SNPs, which increased the overall informativeness in each population group and heterozygosity in the obligate carriers for the disease from 38% to 69%. Our data show that heterozygosity of commonly used RFLP markers is remarkably variable across different regions of India. Thus prudent selection of the markers based on specific population groups including usage of additional markers is recommended for efficient carrier detection. PMID:17264403

  16. Studies on hemophilia A in Sardinia bearing on the problems of multiple allelism, carrier detection, and differential mutation rate in the two sexes.

    PubMed Central

    Filippi, G; Mannucci, P M; Coppola, R; Farris, A; Rinaldi, A; Siniscalco, M

    1984-01-01

    A large survey of hemophilia A carried out with almost complete ascertainment on the island of Sardinia suggests that the variation of plasma levels of Factor VIII coagulant activity in normal individuals is largely controlled by a series of normal isoalleles or by closely linked modifiers. This variation is expected to affect the laboratory detection of the hemophilia A (HA) heterozygotes in addition to the X-inactivation-dependent mosaicism and the type of deficient mutant present in a given pedigree. The Sardinian pedigrees yielded 13 new cases of nonrecombinants between the loci for HA and glucose-6-phosphate dehydrogenase (G6PD), as well as four nonrecombinants between HA and Deutan color blindness. These findings bring to a total of 58 the number of scorable sibs and nonrecombinants thus far known for the linkage HA-G6PD. From such a figure it has been possible to infer that the 90% upper limit of meiotic recombination between the two loci is below 4%, thus justifying the application of the "linkage diagnostic test" for the detection of HA heterozygotes and the prenatal diagnosis of the hemophilic fetuses in families that segregate at both loci. In three out of the five HA pedigrees of our series that segregate also for G6PD or Deutan color blindness, the observed segregation of the combined phenotypes can be best explained by assuming the occurrence of a fresh mutation in the maternal grandfathers. Such a finding points out the opportunity to reevaluate Haldane's hypothesis of a possible higher incidence of X-linked mutations in the human male. It is anticipated that each of the issues addressed by the present study will be amenable to experimental verification as soon as suitable molecular probes become available to screen for common multiallelic DNA polymorphisms in the subtelomeric region of the X-chromosome long arm. PMID:6421151

  17. Long-acting recombinant coagulation factor IX albumin fusion protein (rIX-FP) in hemophilia B: results of a phase 3 trial

    PubMed Central

    Martinowitz, Uri; Lissitchkov, Toshko; Pan-Petesch, Brigitte; Hanabusa, Hideji; Oldenburg, Johannes; Boggio, Lisa; Negrier, Claude; Pabinger, Ingrid; von Depka Prondzinski, Mario; Altisent, Carmen; Castaman, Giancarlo; Yamamoto, Koji; Álvarez-Roman, Maria-Teresa; Voigt, Christine; Blackman, Nicole; Jacobs, Iris

    2016-01-01

    A global phase 3 study evaluated the pharmacokinetics, efficacy, and safety of recombinant fusion protein linking coagulation factor IX with albumin (rIX-FP) in 63 previously treated male patients (12-61 years) with severe hemophilia B (factor IX [FIX] activity ≤2%). The study included 2 groups: group 1 patients received routine prophylaxis once every 7 days for 26 weeks, followed by either 7-, 10-, or 14-day prophylaxis regimen for a mean of 50, 38, or 51 weeks, respectively; group 2 patients received on-demand treatment of bleeding episodes for 26 weeks and then switched to a 7-day prophylaxis regimen for a mean of 45 weeks. The mean terminal half-life of rIX-FP was 102 hours, 4.3-fold longer than previous FIX treatment. Patients maintained a mean trough of 20 and 12 IU/dL FIX activity on prophylaxis with rIX-FP 40 IU/kg weekly and 75 IU/kg every 2 weeks, respectively. There was 100% reduction in median annualized spontaneous bleeding rate (AsBR) and 100% resolution of target joints when subjects switched from on-demand to prophylaxis treatment with rIX-FP (P < .0001). The median AsBR was 0.00 for all prophylaxis regimens. Overall, 98.6% of bleeding episodes were treated successfully, including 93.6% that were treated with a single injection. No patient developed an inhibitor, and no safety concerns were identified. These results indicate rIX-FP is safe and effective for preventing and treating bleeding episodes in patients with hemophilia B at dosing regimens of 40 IU/kg weekly and 75 IU/kg every 2 weeks. This trial was registered at www.clinicaltrials.gov as #NCT0101496274. PMID:26755710

  18. Long-acting recombinant coagulation factor IX albumin fusion protein (rIX-FP) in hemophilia B: results of a phase 3 trial.

    PubMed

    Santagostino, Elena; Martinowitz, Uri; Lissitchkov, Toshko; Pan-Petesch, Brigitte; Hanabusa, Hideji; Oldenburg, Johannes; Boggio, Lisa; Negrier, Claude; Pabinger, Ingrid; von Depka Prondzinski, Mario; Altisent, Carmen; Castaman, Giancarlo; Yamamoto, Koji; Álvarez-Roman, Maria-Teresa; Voigt, Christine; Blackman, Nicole; Jacobs, Iris

    2016-04-01

    A global phase 3 study evaluated the pharmacokinetics, efficacy, and safety of recombinant fusion protein linking coagulation factor IX with albumin (rIX-FP) in 63 previously treated male patients (12-61 years) with severe hemophilia B (factor IX [FIX] activity ≤2%). The study included 2 groups: group 1 patients received routine prophylaxis once every 7 days for 26 weeks, followed by either 7-, 10-, or 14-day prophylaxis regimen for a mean of 50, 38, or 51 weeks, respectively; group 2 patients received on-demand treatment of bleeding episodes for 26 weeks and then switched to a 7-day prophylaxis regimen for a mean of 45 weeks. The mean terminal half-life of rIX-FP was 102 hours, 4.3-fold longer than previous FIX treatment. Patients maintained a mean trough of 20 and 12 IU/dL FIX activity on prophylaxis with rIX-FP 40 IU/kg weekly and 75 IU/kg every 2 weeks, respectively. There was 100% reduction in median annualized spontaneous bleeding rate (AsBR) and 100% resolution of target joints when subjects switched from on-demand to prophylaxis treatment with rIX-FP (P< .0001). The median AsBR was 0.00 for all prophylaxis regimens. Overall, 98.6% of bleeding episodes were treated successfully, including 93.6% that were treated with a single injection. No patient developed an inhibitor, and no safety concerns were identified. These results indicate rIX-FP is safe and effective for preventing and treating bleeding episodes in patients with hemophilia B at dosing regimens of 40 IU/kg weekly and 75 IU/kg every 2 weeks. This trial was registered atwww.clinicaltrials.govas #NCT0101496274. PMID:26755710

  19. Heat treatment of samples improve the performance of the Nijmegen-Bethesda assay in hemophilia A patients undergoing immune tolerance induction.

    PubMed

    de Lima Montalvão, Silmara Aparecida; Tucunduva, Alini Camargo; de Almeida Sambo, Andrea Luísa; De Paula, Erich Vinicius; de Souza Medina, Samuel; Ozelo, Margareth Castro

    2015-12-01

    Nijmegen-Bethesda assay is the gold standard to assess inhibitory antibodies against factor (F) VIII. This method has some limitations, including high coefficient of variation and possible interference of residual endogenous or exogenous factor VIII. Heat-treatment of samples at 56 °C for 30 min could be a strategy to improve the sensitivity of this test. The aim of this study was to compare inhibitor quantification in hemophilia patients with and without inhibitor performed in previously heated and non-heated samples. A total of 109 analyses from 46 patients with severe hemophilia A were performed. Patients were divided into three groups: 20 patients with no history of inhibitor, recently and not recently exposed to FVIII (group I), 21 patients with history of inhibitor not exposed to FVIII (group II), and 5 patients (68 samples) undergoing an immune tolerance induction (ITI) protocol (group III). For patients with no history of inhibitor, heat-treatment did not modify the results (p=0.24). However, differences in inhibitor levels between heated and non-heated samples were observed in patients with history of inhibitor (group II, p<0.05) and in patients in ITI (group III, p<0.001). In 11 samples, inhibitor quantification shifted from negative to positive. Additionally, a longitudinal evaluation of each ITI patient showed similar trend line for the results of heated and non-heated samples. In this study, we demonstrated that heating samples increase sensitivity of Nijmegen-Bethesda assay, with no shift from negative to positive results in patients with no history of inhibitor. Furthermore, this procedure has an important role to patients undergoing an ITI protocol. PMID:26344704

  20. Living with Hemophilia

    MedlinePlus

    ... are swimming, biking (wearing a helmet), walking, and golf. To prevent bleeding, you also may be able ... periods apply As children grow, it's important to learn about available options for insurance. Look into what ...

  1. Learning about Hemophilia

    MedlinePlus

    ... for Patient Care Education All About the Human Genome Project Fact Sheets Genetic Education Resources for Teachers ... Education Kit Online Genetics Education Resources Smithsonian NHGRI Genome Exhibition Talking Glossary: English Talking Glossary: Español Issues ...

  2. Comparison of Clot-based, Chromogenic, and Fluorescence Assays for Measurement of Factor VIII Inhibitors in the U.S. Hemophilia Inhibitor Research Study

    PubMed Central

    Miller, Connie H.; Rice, Anne S.; Boylan, Brian; Shapiro, Amy D.; Lentz, Steven R.; Wicklund, Brian M.; Kelly, Fiona M.; Soucie, J. Michael

    2015-01-01

    Summary Background Detection and validation of inhibitors (antibodies) to hemophilia treatment products are important for clinical care, evaluation of product safety, and assessment of population trends. Methods Centralized monitoring for factor VIII (FVIII) inhibitors was conducted for patients in the Hemophilia Inhibitor Research Study using a previously reported modified Nijmegen-Bethesda clotting assay (NBA), a chromogenic Bethesda assay (CBA), and a novel fluorescence immunoassay (FLI). Results NBA and CBA were performed on 1005 specimens and FLI on 272 specimens. CBA was negative on 880/883 specimens (99.7%) with Nijmegen-Bethesda units (NBU)<0.5 and positive on 42/42 specimens (100%) with NBU≥2.0 and 43/80 specimens (53.8%) with NBU 0.5–1.9. Among specimens with positive NBA and negative CBA, 58.1% were FLI-negative, 12.9% had evidence of lupus anticoagulant, and 35.5% had non-time-dependent inhibition. CBA and FLI were positive on 72.4% and 100% of 1.0–1.9 NBU specimens and 43.1% and 50.0% of 0.5–0.9 NBU specimens. FLI detected antibodies in 98.0% of CBA-positive and 81.6% of NBA-positive specimens (P=0.004). Among 21 new inhibitors detected by NBA, 5 (23.8%) with 0.7–1.3 NBU did not react in CBA or FLI. Among previously positive patients with 0.5–1.9 NBU, 7/25 (28%) were not CBA or FLI positive. FLI was positive on 36/169 NBU-negative specimens (21.3%). Conclusions FVIII specificity could not be demonstrated by CBA or FLI for 26% of inhibitors of 0.5–1.9 NBU; such results must be interpreted with caution. Low titer inhibitors detected in clot-based assays should always be repeated, with consideration given to evaluating their reactivity with FVIII using more specific assays. PMID:23601690

  3. 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.

    PubMed Central

    Becker, J.; Schwaab, R.; Möller-Taube, A.; Schwaab, U.; Schmidt, W.; Brackmann, H. H.; Grimm, T.; Olek, K.; Oldenburg, J.

    1996-01-01

    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 percent). Fifty-five patients (37.4 percent) showed a F8A-gene inversion, 47 (32.0 percent) a point mutation, 14 (9.5 percent) a small deletion, 8 (5.4 percent) a large deletion, and 2 (1.4 percent) a small insertion. Further, four (2.7 percent) mutations were localized but could not be sequenced yet. No mutation could be identified in 17 patients (11.6 percent). Sixteen (10.9 percent) of the 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 percent) 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 patients 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

  4. 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

    SciTech Connect

    Becker, J.; Schmidt, W.; Olek, K.

    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.

  5. The dataset from administration of single or combined immunomodulation agents to modulate anti-FVIII antibody responses in FVIII plasmid or protein primed hemophilia A mice.

    PubMed

    Liu, Chao Lien; Lyle, Meghan J; Shin, Simon C; Miao, Carol H

    2016-06-01

    Hemophilia A mice with pre-existing inhibitory antibodies against factor VIII (FVIII) were treated with single agents, AMD3100 and GCS-F, respectively. Inhibitor titers in treated mice and control HemA inhibitors mice were followed over time. Total B cells and plasma cells (PCs) were characterized by flow cytometry. HemA inhibitor mice were then treated with a combination regimen of IL-2/IL-2mAb complexes plus rapamycin and AMD3100. Finally, HemA inhibitor mice were treated with a new combination therapy using include IL-2/IL-2mAb complexes + Anti-CD20+AMD3100+G-CSF. The timeline of combination therapy was illustrated. Inhibitor titers following treatment in FVIII plasmid or protein induced inhibitor mice were evaluated overtime. A representative figure and gating strategies to characterize the subsets of Treg cells and B cells are presented. Please see http://dx.doi.org/10.1016/j.cellimm.2016.01.005 [1] for interpretation and discussion of these data and results. PMID:27081675

  6. Evolutionary pattern of mutation in the factor IX genes of great apes: How does it compare to the pattern of recent germline mutation in patients with hemophilia B?

    SciTech Connect

    Grouse, L.H.; Ketterling, R.P.; Sommer, S.S.

    1994-09-01

    Most mutations causing hemophilia B have arisen within the past 150 years. By correcting for multiple biases, the underlying rates of spontaneous germline mutation have been estimated in the factor IX gene. From these rates, an underlying pattern of mutation has emerged. To determine if this pattern compares to a underlying pattern found in the great apes, sequence changes were determined in intronic regions of the factor IX gene. The following species were studied: Gorilla gorilla, Pan troglodytes (chimpanzee), Pongo pygmacus (orangutan) and Homo sapiens. Intronic sequences at least 200 bp from a splice junction were randomly chosen, amplified by cross-species PCR, and sequenced. These regions are expected to be subject to little if any selective pressure. Early diverged species of Old World monkeys were also studied to help determine the direction of mutational changes. A total of 62 sequence changes were observed. Initial data suggest that the average pattern since evolution of the great apes has a paucity of transitions at CpG dinucleotides and an excess of microinsertions to microdeletions when compared to the pattern observed in humans during the past 150 years (p<.05). A larger study is in progress to confirm these results.

  7. Identification of 31 novel mutations in the F8 gene in Spanish hemophilia A patients: structural analysis of 20 missense mutations suggests new intermolecular binding sites.

    PubMed

    Venceslá, Adoración; Corral-Rodríguez, María Angeles; Baena, Manel; Cornet, Mónica; Domènech, Montserrat; Baiget, Montserrat; Fuentes-Prior, Pablo; Tizzano, Eduardo F

    2008-04-01

    Hemophilia A (HA) is an X-linked bleeding disorder caused by a wide variety of mutations in the factor 8 (F8) gene, leading to absent or deficient factor VIII (FVIII). We analyzed the F8 gene of 267 unrelated Spanish patients with HA. After excluding patients with the common intron-1 and intron-22 inversions and large deletions, we detected 137 individuals with small mutations, 31 of which had not been reported previously. Eleven of these were nonsense, frameshift, and splicing mutations, whereas 20 were missense changes. We assessed the impact of the 20 substitutions based on currently available information about FV and FVIII structure and function relationship, including previously reported results of replacements at these and topologically equivalent positions. Although most changes are likely to cause gross structural perturbations and concomitant cofactor instability, p.Ala375Ser is predicted to affect cofactor activation. Finally, 3 further mutations (p.Pro64Arg, p.Gly494Val, and p.Asp2267Gly) appear to affect cofactor interactions with its carrier protein, von Willebrand factor, with the scavenger receptor low-density lipoprotein receptor-related protein (LRP), and/or with the substrate of the FVIIIapi*FIXa (Xase) complex, factor X. Characterization of these novel mutations is important for adequate genetic counseling in HA families, but also contributes to a better understanding of FVIII structure-function relationship. PMID:18184865

  8. Identification of 31 novel mutations in the F8 gene in Spanish hemophilia A patients: structural analysis of 20 missense mutations suggests new intermolecular binding sites

    PubMed Central

    Venceslá, Adoración; Corral-Rodríguez, María Ángeles; Baena, Manel; Cornet, Mónica; Domènech, Montserrat; Baiget, Montserrat; Fuentes-Prior, Pablo

    2008-01-01

    Hemophilia A (HA) is an X-linked bleeding disorder caused by a wide variety of mutations in the factor 8 (F8) gene, leading to absent or deficient factor VIII (FVIII). We analyzed the F8 gene of 267 unrelated Spanish patients with HA. After excluding patients with the common intron-1 and intron-22 inversions and large deletions, we detected 137 individuals with small mutations, 31 of which had not been reported previously. Eleven of these were nonsense, frameshift, and splicing mutations, whereas 20 were missense changes. We assessed the impact of the 20 substitutions based on currently available information about FV and FVIII structure and function relationship, including previously reported results of replacements at these and topologically equivalent positions. Although most changes are likely to cause gross structural perturbations and concomitant cofactor instability, p.Ala375Ser is predicted to affect cofactor activation. Finally, 3 further mutations (p.Pro64Arg, p.Gly494Val, and p.Asp2267Gly) appear to affect cofactor interactions with its carrier protein, von Willebrand factor, with the scavenger receptor low-density lipoprotein receptor–related protein (LRP), and/or with the substrate of the FVIIIapi•FIXa (Xase) complex, factor X. Characterization of these novel mutations is important for adequate genetic counseling in HA families, but also contributes to a better understanding of FVIII structure-function relationship. PMID:18184865

  9. Hemophilia as a defect of the tissue factor pathway of blood coagulation: Effect of factors VIII and IX on factor X activation in a continuous-flow reactor

    SciTech Connect

    Repke, D.; Gemmell, C.H.; Guha, A.; Turitto, V.T.; Nemerson, Y. ); Broze, G.J. Jr. )

    1990-10-01

    The effect of factors VIII and IX on the ability of the tissue factor-factor VIIa complex to activate factor X was studied in a continuous-flow tubular enzyme reactor. Tissue factor immobilized in a phospholipid bilayer on the inner surface of the tube was exposed to a perfusate containing factors VIIa, VIII, IX, and X flowing at a wall shear rate of 57, 300, or 1130 sec{sup {minus}1}. The addition of factors VIII and IX at their respective plasma concentrations resulted in a further 2{endash}-to 3{endash}fold increase. The direct activation of factor X by tissue factor-factor VIIa could be virtually eliminated by the lipoprotein-associated coagulation inhibitor. These results suggest that the tissue factor pathway, mediated through factors VIII and IX, produces significant levels of factor Xa even in the presence of an inhibitor of the tissue factor-factor VIIa complex; moreover, the activation is dependent on local shear conditions. These findings are consistent both with a model of blood coagulation in which initiation of the system results from tissue factor and with the bleeding observed in hemophilia.

  10. Soy Phosphatidylinositol-Containing Lipid Nanoparticle Prolongs the Plasma Survival and Hemostatic Efficacy of B-domain-Deleted Recombinant Canine Factor VIII in Hemophilia A Dogs.

    PubMed

    Shetty, Krithika A; Merricks, Elizabeth P; Raymer, Robin; Rigsbee, Natalie; Nichols, Timothy C; Balu-Iyer, Sathy V

    2016-08-01

    Soy phosphatidylinositol (PI)-containing lipid nanoparticles prolong plasma survival, improve hemostatic efficacy, and decrease immunogenicity of human B-domain-deleted factor VIII (BDD FVIII) in hemophilia A (HA) mice. We hypothesize that PI-associated BDD FVIII is more potent than the free protein and, using mathematical modeling, have projected that PI-associated BDD FVIII could be used for once-weekly prophylactic dosing in patients. To facilitate translation to the clinic, comparative plasma survival and ex vivo efficacy of PI-associated recombinant canine FVIII (PI-rcFVIII) were evaluated in HA dogs. Two HA dogs were administered a 50-U/kg intravenous dose of free or PI-rcFVIII. rcFVIII activity measurements and ex vivo efficacy analyses such as whole blood clotting time and thromboelastography were conducted on recovered plasma and whole blood samples. PI association decreased clearance (∼25%) and increased plasma exposure (∼1.4-fold) of rcFVIII. PI-rcFVIII-treated animals had prolonged improvements in whole blood clotting time and thromboelastography parameters compared to free rcFVIII-treated animals. Because rcFVIII is a BDD form of FVIII, these studies provide proof of principle that observations with human BDD FVIII in mice translate to higher animal species. In addition, PI-rcFVIII has potential applications in canine HA management and as a bypass therapy in inhibitor-positive HA patients. PMID:27372547

  11. Targeting of the human F8 at the multicopy rDNA locus in Hemophilia A patient-derived iPSCs using TALENickases.

    PubMed

    Pang, Jialun; Wu, Yong; Li, Zhuo; Hu, Zhiqing; Wang, Xiaolin; Hu, Xuyun; Wang, Xiaoyan; Liu, Xionghao; Zhou, Miaojin; Liu, Bo; Wang, Yanchi; Feng, Mai; Liang, Desheng

    2016-03-25

    Hemophilia A (HA) is a monogenic disease due to lack of the clotting factor VIII (FVIII). This deficiency may lead to spontaneous joint hemorrhages or life-threatening bleeding but there is no cure for HA until very recently. In this study, we derived induced pluripotent stem cells (iPSCs) from patients with severe HA and used transcription activator-like effector nickases (TALENickases) to target the factor VIII gene (F8) at the multicopy ribosomal DNA (rDNA) locus in HA-iPSCs, aiming to rescue the shortage of FVIII protein. The results revealed that more than one copy of the exogenous F8 could be integrated into the rDNA locus. Importantly, we detected exogenous F8 mRNA and FVIII protein in targeted HA-iPSCs. After they were differentiated into endothelial cells (ECs), the exogenous FVIII protein was still detectable. Thus, it is showed that the multicopy rDNA locus could be utilized as an effective target site in patient-derived iPSCs for gene therapy. This strategy provides a novel iPSCs-based therapeutic option for HA and other monogenic diseases. PMID:26921444

  12. The dataset from administration of single or combined immunomodulation agents to modulate anti-FVIII antibody responses in FVIII plasmid or protein primed hemophilia A mice

    PubMed Central

    Liu, Chao Lien; Lyle, Meghan J.; Shin, Simon C.; Miao, Carol H.

    2016-01-01

    Hemophilia A mice with pre-existing inhibitory antibodies against factor VIII (FVIII) were treated with single agents, AMD3100 and GCS-F, respectively. Inhibitor titers in treated mice and control HemA inhibitors mice were followed over time. Total B cells and plasma cells (PCs) were characterized by flow cytometry. HemA inhibitor mice were then treated with a combination regimen of IL-2/IL-2mAb complexes plus rapamycin and AMD3100. Finally, HemA inhibitor mice were treated with a new combination therapy using include IL-2/IL-2mAb complexes + Anti-CD20+AMD3100+G-CSF. The timeline of combination therapy was illustrated. Inhibitor titers following treatment in FVIII plasmid or protein induced inhibitor mice were evaluated overtime. A representative figure and gating strategies to characterize the subsets of Treg cells and B cells are presented. Please see http://dx.doi.org/10.1016/j.cellimm.2016.01.005 [1] for interpretation and discussion of these data and results. PMID:27081675

  13. AAV liver expression of FIX-Padua prevents and eradicates FIX inhibitor without increasing thrombogenicity in hemophilia B dogs and mice.

    PubMed

    Crudele, Julie M; Finn, Jonathan D; Siner, Joshua I; Martin, Nicholas B; Niemeyer, Glenn P; Zhou, Shangzhen; Mingozzi, Federico; Lothrop, Clinton D; Arruda, Valder R

    2015-03-01

    Emerging successful clinical data on gene therapy using adeno-associated viral (AAV) vector for hemophilia B (HB) showed that the risk of cellular immune response to vector capsid is clearly dose dependent. To decrease the vector dose, we explored AAV-8 (1-3 × 10(12) vg/kg) encoding a hyperfunctional factor IX (FIX-Padua, arginine 338 to leucine) in FIX inhibitor-prone HB dogs. Two naïve HB dogs showed sustained expression of FIX-Padua with an 8- to 12-fold increased specific activity reaching 25% to 40% activity without antibody formation to FIX. A third dog with preexisting FIX inhibitors exhibited a transient anamnestic response (5 Bethesda units) at 2 weeks after vector delivery following by spontaneous eradication of the antibody to FIX by day 70. In this dog, sustained FIX expression reached ∼200% and 30% of activity and antigen levels, respectively. Immune tolerance was confirmed in all dogs after challenges with plasma-derived FIX concentrate. Shortening of the clotting times and lack of bleeding episodes support the phenotypic correction of the severe phenotype, with no clinical or laboratory evidence of risk of thrombosis. Provocative studies in mice showed that FIX-Padua exhibits similar immunogenicity and thrombogenicity compared with FIX wild type. Collectively, these data support the potential translation of gene-based strategies using FIX-Padua for HB. PMID:25568350

  14. AAV liver expression of FIX-Padua prevents and eradicates FIX inhibitor without increasing thrombogenicity in hemophilia B dogs and mice

    PubMed Central

    Crudele, Julie M.; Finn, Jonathan D.; Siner, Joshua I.; Martin, Nicholas B.; Niemeyer, Glenn P.; Zhou, Shangzhen; Mingozzi, Federico; Lothrop, Clinton D.

    2015-01-01

    Emerging successful clinical data on gene therapy using adeno-associated viral (AAV) vector for hemophilia B (HB) showed that the risk of cellular immune response to vector capsid is clearly dose dependent. To decrease the vector dose, we explored AAV-8 (1-3 × 1012 vg/kg) encoding a hyperfunctional factor IX (FIX-Padua, arginine 338 to leucine) in FIX inhibitor-prone HB dogs. Two naïve HB dogs showed sustained expression of FIX-Padua with an 8- to 12-fold increased specific activity reaching 25% to 40% activity without antibody formation to FIX. A third dog with preexisting FIX inhibitors exhibited a transient anamnestic response (5 Bethesda units) at 2 weeks after vector delivery following by spontaneous eradication of the antibody to FIX by day 70. In this dog, sustained FIX expression reached ∼200% and 30% of activity and antigen levels, respectively. Immune tolerance was confirmed in all dogs after challenges with plasma-derived FIX concentrate. Shortening of the clotting times and lack of bleeding episodes support the phenotypic correction of the severe phenotype, with no clinical or laboratory evidence of risk of thrombosis. Provocative studies in mice showed that FIX-Padua exhibits similar immunogenicity and thrombogenicity compared with FIX wild type. Collectively, these data support the potential translation of gene-based strategies using FIX-Padua for HB. PMID:25568350

  15. Anti-factor VIII IgA as a potential marker of poor prognosis in acquired hemophilia A: results from the GTH-AH 01/2010 study.

    PubMed

    Tiede, Andreas; Hofbauer, Christoph J; Werwitzke, Sonja; Knöbl, Paul; Gottstein, Saskia; Scharf, Rüdiger E; Heinz, Jürgen; Groß, Jürgen; Holstein, Katharina; Dobbelstein, Christiane; Scheiflinger, Fritz; Koch, Armin; Reipert, Birgit M

    2016-05-12

    Neutralizing autoantibodies against factor VIII (FVIII), also called FVIII inhibitors, are the cause of acquired hemophilia A (AHA). They are quantified in the Bethesda assay or Nijmegen-modified Bethesda assay by their ability to neutralize FVIII in normal human plasma. However, FVIII inhibitors do not represent the whole spectrum of anti-FVIII autoantibodies. Here, we studied isotypes, immunoglobulin G subclasses, and apparent affinities of anti-FVIII autoantibodies to assess their prognostic value for the outcome in AHA. We analyzed baseline samples from patients enrolled in the prospective GTH-AH 01/2010 study. Our data suggest that anti-FVIII immunoglobulin A (IgA) autoantibodies are predictors of poor outcome in AHA. Anti-FVIII IgA-positive patients achieved partial remission similar to anti-FVIII IgA-negative patients but had a higher risk of subsequent recurrence. Consequently, IgA-positive patients achieved complete remission less frequently (adjusted hazard ratio [aHR], 0.35; 95% confidence interval [CI], 0.18-0.68; P < .01) and had a higher risk of death (aHR, 2.62; 95% CI, 1.11-6.22; P < .05). Anti-FVIII IgA was the strongest negative predictor of recurrence-free survival after achieving partial remission and remained significant after adjustment for baseline demographic and clinical characteristics. In conclusion, anti-FVIII IgA represents a potential novel biomarker that could be useful to predict prognosis and tailor immunosuppressive treatment of AHA. PMID:26912467

  16. Efficacy and safety of rVIII-SingleChain: results of a phase 1/3 multicenter clinical trial in severe hemophilia A.

    PubMed

    Mahlangu, Johnny; Kuliczkowski, Kazimierz; Karim, Faraizah Abdul; Stasyshyn, Oleksandra; Kosinova, Marina V; Lepatan, Lynda Mae; Skotnicki, Aleksander; Boggio, Lisa N; Klamroth, Robert; Oldenburg, Johannes; Hellmann, Andrzej; Santagostino, Elena; Baker, Ross I; Fischer, Kathelijn; Gill, Joan C; P'Ng, Stephanie; Chowdary, Pratima; Escobar, Miguel A; Khayat, Claudia Djambas; Rusen, Luminita; Bensen-Kennedy, Debra; Blackman, Nicole; Limsakun, Tharin; Veldman, Alex; St Ledger, Katie; Pabinger, Ingrid

    2016-08-01

    Recombinant VIII (rVIII)-SingleChain is a novel B-domain-truncated recombinant factor VIII (rFVIII), comprised of covalently bonded factor VIII (FVIII) heavy and light chains. It was designed to have a higher binding affinity for von Willebrand factor (VWF). This phase 1/3 study investigated the efficacy and safety of rVIII-SingleChain in the treatment of bleeding episodes, routine prophylaxis, and surgical prophylaxis. Participants were ≥12 years of age, with severe hemophilia A (endogenous FVIII <1%). The participants were allocated by the investigator to receive rVIII-SingleChain in either an on-demand or prophylaxis regimen. Of the 175 patients meeting study eligibility criteria, 173 were treated with rVIII-SingleChain, prophylactically (N = 146) or on-demand (N = 27). The total cumulative exposure was 14 306 exposure days (EDs), with 120 participants reaching ≥50 EDs and 52 participants having ≥100 EDs. Hemostatic efficacy was rated by the investigator as excellent or good in 93.8% of the 835 bleeds treated and assessed. Across all prophylaxis regimens, the median annualized spontaneous bleeding rate was 0.00 (Q1, Q3: 0.0, 2.4) and the median overall annualized bleeding rate (ABR) was 1.14 (Q1, Q3: 0.0, 4.2). Surgical hemostasis was rated as excellent/good in 100% of major surgeries by the investigator. No participant developed FVIII inhibitors. In conclusion, rVIII-SingleChain is a novel rFVIII molecule showing excellent hemostatic efficacy in surgery and in the control of bleeding events, low ABR in patients on prophylaxis, and a favorable safety profile in this large clinical study. This trial was registered at www.clinicaltrials.gov as #NCT01486927. PMID:27330001

  17. Recombinant factor VIIa analog in the management of hemophilia with inhibitors: results from a multicenter, randomized, controlled trial of vatreptacog alfa

    PubMed Central

    Lentz, S R; Ehrenforth, S; Abdul Karim, F; Matsushita, T; Weldingh, K N; Windyga, J; Mahlangu, J N; For the Adept™2 Investigators

    2014-01-01

    Background Vatreptacog alfa, a recombinant factor VIIa (rFVIIa) analog with three amino acid substitutions and 99% identity to native FVIIa, was developed to improve the treatment of hemophilic patients with inhibitors. Objectives To confirm the safety and assess the efficacy of vatreptacog alfa in treating bleeding episodes in hemophilic patients with inhibitors. Patients and methods In this international, multicenter, randomized, double-blind, active-controlled, crossover, confirmatory phase III trial (adept™2) in patients with hemophilia A or B and inhibitors, bleeds were randomized 3 : 2 to treatment with vatreptacog alfa (one to three doses at 80 μg kg−1) or rFVIIa (one to three doses at 90 μg kg−1). Treatment failures after three doses of trial product (TP) were managed according to the local standard of care. Results In the 72 patients enrolled, 567 bleeds were treated with TP. Both vatreptacog alfa and rFVIIa gave 93% effective bleeding control at 12 h. Vatreptacog alfa was superior to rFVIIa in secondary efficacy outcomes, including the number of doses used to treat a bleed and sustained bleeding control 24–48 h after the first dose. Eight patients (11%) developed antibodies against vatreptacog alfa, including four with cross-reactivity against rFVIIa and one with an in vitro neutralizing effect to vatreptacog alfa. Conclusions This large randomized controlled trial confirmed the well-established efficacy and safety profile of rFVIIa, and showed that vatreptacog alfa had similar or better efficacy than rFVIIa. However, because of the development of anti-drug antibodies, a positive benefit–risk profile is unlikely to be achieved with vatreptacog alfa. PMID:24931322

  18. Efficacy and safety of rVIII-SingleChain: results of a phase 1/3 multicenter clinical trial in severe hemophilia A

    PubMed Central

    Mahlangu, Johnny; Kuliczkowski, Kazimierz; Karim, Faraizah Abdul; Stasyshyn, Oleksandra; Kosinova, Marina V.; Lepatan, Lynda Mae; Skotnicki, Aleksander; Boggio, Lisa N.; Klamroth, Robert; Oldenburg, Johannes; Hellmann, Andrzej; Santagostino, Elena; Baker, Ross I.; Fischer, Kathelijn; Gill, Joan C.; P’Ng, Stephanie; Chowdary, Pratima; Escobar, Miguel A.; Khayat, Claudia Djambas; Rusen, Luminita; Bensen-Kennedy, Debra; Blackman, Nicole; Limsakun, Tharin; Veldman, Alex; St. Ledger, Katie

    2016-01-01

    Recombinant VIII (rVIII)-SingleChain is a novel B-domain–truncated recombinant factor VIII (rFVIII), comprised of covalently bonded factor VIII (FVIII) heavy and light chains. It was designed to have a higher binding affinity for von Willebrand factor (VWF). This phase 1/3 study investigated the efficacy and safety of rVIII-SingleChain in the treatment of bleeding episodes, routine prophylaxis, and surgical prophylaxis. Participants were ≥12 years of age, with severe hemophilia A (endogenous FVIII <1%). The participants were allocated by the investigator to receive rVIII-SingleChain in either an on-demand or prophylaxis regimen. Of the 175 patients meeting study eligibility criteria, 173 were treated with rVIII-SingleChain, prophylactically (N = 146) or on-demand (N = 27). The total cumulative exposure was 14 306 exposure days (EDs), with 120 participants reaching ≥50 EDs and 52 participants having ≥100 EDs. Hemostatic efficacy was rated by the investigator as excellent or good in 93.8% of the 835 bleeds treated and assessed. Across all prophylaxis regimens, the median annualized spontaneous bleeding rate was 0.00 (Q1, Q3: 0.0, 2.4) and the median overall annualized bleeding rate (ABR) was 1.14 (Q1, Q3: 0.0, 4.2). Surgical hemostasis was rated as excellent/good in 100% of major surgeries by the investigator. No participant developed FVIII inhibitors. In conclusion, rVIII-SingleChain is a novel rFVIII molecule showing excellent hemostatic efficacy in surgery and in the control of bleeding events, low ABR in patients on prophylaxis, and a favorable safety profile in this large clinical study. This trial was registered at www.clinicaltrials.gov as #NCT01486927. PMID:27330001

  19. Factor VIII brand and the incidence of factor VIII inhibitors in previously untreated UK children with severe hemophilia A, 2000-2011

    PubMed Central

    Palmer, Benedict P.; Chalmers, Elizabeth A.; Hart, Daniel P.; Liesner, Ri; Rangarajan, Savita; Talks, Katherine; Williams, Michael; Hay, Charles R. M.

    2014-01-01

    The effect of recombinant factor VIII (rFVIII) brand on inhibitor development was investigated in all 407 severe hemophilia A previously untreated patients born in the United Kingdom (UK) between 1 January 2000 and 31 December 2011. Eighty-eight (22%) had been in the RODIN study. Information was extracted from the National Haemophilia Database. Because exposure days (EDs) were not known for some patients, time from first treatment was used as a surrogate for rFVIII exposure. An inhibitor developed in 118 (29%) patients, 60 high and 58 low titer, after a median (interquartile range) of 7.8 (3.3-13.5) months from first exposure and 16 (9-30) EDs. Of 128 patients treated with Kogenate Bayer/Helixate NexGen, 45 (35.2%, 95% confidence interval [CI] 27.4-43.8) developed an inhibitor compared with 42/172 (24.4%, 95% CI 18.6% to 31.4%) with Advate (P = .04). The adjusted hazard ratio (HR) (95% CI) for Kogenate Bayer/Helixate NexGen compared with Advate was 2.14 (1.12-4.10) (P = .02) for high titer and 1.75 (1.11-2.76) (P = .02) for all inhibitors. When excluding UK-RODIN patients, the adjusted HR (95% CI) for high-titer inhibitors was 2.00 (0.93-4.34) (P = .08). ReFacto AF was associated with a higher incidence of all, but not high-titer, inhibitors than Advate. These results will help inform debate around the relative immunogenicity and use of rFVIII brands. PMID:25339360

  20. Matching-adjusted indirect comparisons of efficacy of BAY 81-8973 vs two recombinant factor VIII for the prophylactic treatment of severe hemophilia A

    PubMed Central

    Pocoski, Jennifer; Li, Nanxin; Ayyagari, Rajeev; Church, Nikki; Maas Enriquez, Monika; Xiang, Quer; Kelkar, Sneha; Du, Ella X; Wu, Eric Q; Xie, Jipan

    2016-01-01

    Background No head-to-head trials comparing recombinant factor VIII (rFVIII) products currently exist. This was a matching-adjusted indirect comparison (MAIC) study of efficacy of BAY 81-8973 with antihemophilic factor (recombinant) plasma/albumin-free method (rAHF-PFM) and turoctocog alfa for the prophylaxis of severe hemophilia A. Methods A systematic literature review was conducted to identify trials of rAHF-PFM and turoctocog alfa. Comparisons were conducted using BAY 81-8973 individual patient data (IPD) from LEOPOLD trials and published data from rAHF-PFM and turoctocog alfa trials. Differences in outcome reporting were reconciled using transformation of BAY 81-8973 IPD. Patients in pooled LEOPOLD trials were weighted to match baseline characteristics for rAHF-PFM or turoctocog alfa trials using MAICs. After matching, annualized bleed rates (ABRs) were compared using weighted t-tests. Results Two rAHF-PFM trials and one turoctocog alfa trial were identified. In these trials, rFVIIIs were dosed thrice weekly or every other day; in LEOPOLD trials, BAY 81-8973 was dosed twice- or thrice weekly. Three MAICs were conducted because the two rAHF-PFM trials calculated ABRs differently, matching for age, race, and weight (turoctocog alfa only). BAY 81-8973 had similar ABR of all bleeds vs rAHF-PFM (two trials: 4.8 vs 6.3, 1.9 vs 1.8 [square root transform]) and lower ABR of spontaneous bleeds and trauma bleeds (2.6 vs 4.1, 2.1 vs 4.7; both P<0.05). BAY 81-8973 showed lower ABR of all bleeds and spontaneous bleeds vs turoctocog alfa (4.3 vs 6.5, 2.8 vs 4.3; both P<0.05) and similar ABR of trauma bleeds (1.5 vs 1.6). In subgroup analysis, twice-weekly BAY 81-8973 had similar ABRs of all bleeds, spontaneous bleeds, and trauma bleeds compared to rAHF-PFM and turoctocog alfa. Conclusion This indirect comparison found that prophylaxis with BAY 81-8973, even including the lower frequency of two times a week and lower factor VIII consumption, has efficacy comparable to r

  1. Survival of 125iodine-labeled Factor VIII in normals and patients with classic hemophilia. Observations on the heterogeneity of human Factor VIII.

    PubMed Central

    Over, J; Sixma, J J; Bruïne, M H; Trieschnigg, M C; Vlooswijk, R A; Beeser-Visser, N H; Bouma, B N

    1978-01-01

    Radiolabeled human Factor VIII was used to study its survival in normals and patients with classic hemophilia, and to study the heterogeneity of Factor VIII; Purified Factor VIII was radiolabeled with 125iodine (125I-VIII) without loss of its structural integrity. The survival of 125I-VIII was studied in six normals and six hemophiliacs of whom four of the hemophiliacs had received transfusions with normal cryoprecipitate before the 125I-VIII infusion. No significant difference was observed between the disappearance of Factor VIII coagulant activity and radioactivity in these hemophiliacs. 125I-VIII in plasma showed a biphasic disappearance with an average t1/2 of 2.9 +/- 0.4 h (SEM) for the first phase and 18.6 +/- 0.7 h (SEM) for the second phase, respectively. The survival of 125I-VIII was similar comparing normals and hemophiliacs. The highest molecular weight forms of Factor VIII disappear more rapidly than the lower molecular weight ones. This was established by analysis of the fractions obtained by gel chromatography of plasma collected at several times after infusion and by analysis of the in vivo disappearance of three subfractions of Factor VIII. The fraction of 125I-VIII binding to platelets in the presence of ristocetin (containing the highest molecular weight forms of Factor VIII including the ristocetin cofactor) represented about 50% of the radioactivity present in plasma after infusion and showed a t 1/2 of 11.7 +/- 0.9 h (SEM) for the second phase. The fraction, which was recovered in cryoprecipitate of the recipient's plasma, represented about 90% of the initial radioactivity and showed a t 1/2 of 16.3 +/- 0.8 h (SEM) for the second phase. The fraction of 125I-VIII remaining in the cryosupernatant plasma (containing low molecular weight forms of Factor (VIII) showed a t 1/2 of 27.2 +/- 1.1 h (SEM). The first phase of the disappearance of 125I-VIII is caused in part by the disappearance of the highest molecular weight forms, which are possibly

  2. Dose effect and efficacy of rFVIIa in the treatment of haemophilia patients with inhibitors: analysis from the Hemophilia and Thrombosis Research Society Registry.

    PubMed

    Parameswaran, R; Shapiro, A D; Gill, J C; Kessler, C M

    2005-03-01

    Recombinant activated factor VII (rFVIIa), licensed in 1999 for treatment of haemophilia patients with inhibitors (HI), represents an important advance in the therapeutic armamentarium. Standard bolus dosing ranges from 90 to 120 mcg kg(-1) every 2-3 h until arrest of bleeding. As licensure, clinical use of rFVIIa has increased and broadened. Clinicians now use a wide dose range, 90-300 mcg kg(-1). High-dose regimens may optimize thrombin generation or burst, and may allow for prolonged dose interval. The Hemophilia and Thrombosis Research Society (HTRS) maintains a registry database to study haemophilia treatment and related disorders, particularly treatment of acute bleeding in HI, acquired haemophilia, FVII deficiency and von Willebrand's disease (VWD). To assess the effect of rFVIIa dose on efficacy and safety in the treatment of acute bleeding in HI, data from the HTRS database from January 2000 through June 2002 were analysed. Bleeding episodes were grouped by bolus rFVIIa dose range: <100, 100-150, 150-200 and >200 mcg kg(-1). Investigator-reported efficacy for the first 72 h of treatment was evaluated. Thirty-eight congenital HI patients were treated for 555 bleeding episodes. Patient age range was 1-55 years (median: 14). Bleeding episodes were spontaneous (45%), caused by trauma (38%), or because of surgery, dental, diagnostic, or medical procedures (17%); bleeding occurred in joint, muscle, and intra/extracranial sites. Treatment location included: 80% at home, 12% at other facilities (treatment centres, ER, inpatient and OR), and 8% at both home/other facilities. Median total dose given over 72 h was 360 mcg kg(-1) (range: 40-4281, mean: 537). Bleeding stopped in 87% of the episodes. Bleeding cessation rate was 84% for the three lower dose groups, and 97% for the highest dose group (P < 0.001). Five patients experienced nine adverse events (AEs). AE rates were <1% for <100, 5% for 100-150, 0% for 150-200, <1% for >200 mcg kg(-1) dose group. Decreased

  3. Employing a Gain-of-Function Factor IX Variant R338L to Advance the Efficacy and Safety of Hemophilia B Human Gene Therapy: Preclinical Evaluation Supporting an Ongoing Adeno-Associated Virus Clinical Trial

    PubMed Central

    Sun, Junjiang; Gui, Tong; Hu, Genlin; Hannah, William B.; Wichlan, David G.; Wu, Zhijian; Grieger, Joshua C.; Li, Chengwen; Suwanmanee, Thipparat; Stafford, Darrel W.; Booth, Carmen J.; Samulski, Jade J.; Kafri, Tal; McPhee, Scott W.J.

    2015-01-01

    Abstract Vector capsid dose-dependent inflammation of transduced liver has limited the ability of adeno-associated virus (AAV) factor IX (FIX) gene therapy vectors to reliably convert severe to mild hemophilia B in human clinical trials. These trials also identified the need to understand AAV neutralizing antibodies and empty AAV capsids regarding their impact on clinical success. To address these safety concerns, we have used a scalable manufacturing process to produce GMP-grade AAV8 expressing the FIXR338L gain-of-function variant with minimal (<10%) empty capsid and have performed comprehensive dose–response, biodistribution, and safety evaluations in clinically relevant hemophilia models. The scAAV8.FIXR338L vector produced greater than 6-fold increased FIX specific activity compared with wild-type FIX and demonstrated linear dose responses from doses that produced 2–500% FIX activity, associated with dose-dependent hemostasis in a tail transection bleeding challenge. More importantly, using a bleeding model that closely mimics the clinical morbidity of hemophilic arthropathy, mice that received the scAAV8.FIXR338L vector developed minimal histopathological findings of synovitis after hemarthrosis, when compared with mice that received identical doses of wild-type FIX vector. Hemostatically normal mice (n=20) and hemophilic mice (n=88) developed no FIX antibodies after peripheral intravenous vector delivery. No CD8+ T cell liver infiltrates were observed, despite the marked tropism of scAAV8.FIXR338L for the liver in a comprehensive biodistribution evaluation (n=60 animals). With respect to the role of empty capsids, we demonstrated that in vivo FIXR338L expression was not influenced by the presence of empty AAV particles, either in the presence or absence of various titers of AAV8-neutralizing antibodies. Necropsy of FIX–/– mice 8–10 months after vector delivery revealed no microvascular or macrovascular thrombosis in mice expressing FIXR338L (plasma

  4. Employing a gain-of-function factor IX variant R338L to advance the efficacy and safety of hemophilia B human gene therapy: preclinical evaluation supporting an ongoing adeno-associated virus clinical trial.

    PubMed

    Monahan, Paul E; Sun, Junjiang; Gui, Tong; Hu, Genlin; Hannah, William B; Wichlan, David G; Wu, Zhijian; Grieger, Joshua C; Li, Chengwen; Suwanmanee, Thipparat; Stafford, Darrel W; Booth, Carmen J; Samulski, Jade J; Kafri, Tal; McPhee, Scott W J; Samulski, R Jude

    2015-02-01

    Vector capsid dose-dependent inflammation of transduced liver has limited the ability of adeno-associated virus (AAV) factor IX (FIX) gene therapy vectors to reliably convert severe to mild hemophilia B in human clinical trials. These trials also identified the need to understand AAV neutralizing antibodies and empty AAV capsids regarding their impact on clinical success. To address these safety concerns, we have used a scalable manufacturing process to produce GMP-grade AAV8 expressing the FIXR338L gain-of-function variant with minimal (<10%) empty capsid and have performed comprehensive dose-response, biodistribution, and safety evaluations in clinically relevant hemophilia models. The scAAV8.FIXR338L vector produced greater than 6-fold increased FIX specific activity compared with wild-type FIX and demonstrated linear dose responses from doses that produced 2-500% FIX activity, associated with dose-dependent hemostasis in a tail transection bleeding challenge. More importantly, using a bleeding model that closely mimics the clinical morbidity of hemophilic arthropathy, mice that received the scAAV8.FIXR338L vector developed minimal histopathological findings of synovitis after hemarthrosis, when compared with mice that received identical doses of wild-type FIX vector. Hemostatically normal mice (n=20) and hemophilic mice (n=88) developed no FIX antibodies after peripheral intravenous vector delivery. No CD8(+) T cell liver infiltrates were observed, despite the marked tropism of scAAV8.FIXR338L for the liver in a comprehensive biodistribution evaluation (n=60 animals). With respect to the role of empty capsids, we demonstrated that in vivo FIXR338L expression was not influenced by the presence of empty AAV particles, either in the presence or absence of various titers of AAV8-neutralizing antibodies. Necropsy of FIX(-/-) mice 8-10 months after vector delivery revealed no microvascular or macrovascular thrombosis in mice expressing FIXR338L (plasma FIX activity

  5. Challenges of the management of severe hemophilia A with inhibitors: two case reports emphasizing the potential interest of a high-purity human Factor VIII/von Willebrand factor concentrate and individually tailored prophylaxis guided by thrombin-generation test.

    PubMed

    Mathieu, Sophie; Crampe, Carine; Dargaud, Yesim; Lavigne-Lissalde, Géraldine; Escuriola-Ettingshausen, Carmen; Tardy, Brigitte; Meley, Roland; Thouvenin, Sandrine; Stephan, Jean L; Berger, Claire

    2015-12-01

    Severe hemophilia A is an X-linked bleeding disorder. Immune tolerance induction (ITI) is the best strategy of treatment when patients develop inhibitors. The objective is to illustrate the benefit of a high-purity human factor VIII/von Willebrand factor (VWF) concentrate (Octanate) in the management of ITI. We also wanted to raise the potential interest of laboratory assays such as thrombin-generation test (TGT) and epitope mapping. Two patients were treated during ITI, first with a recombinant FVIII and then with plasma-derived factor VIII without success, and, finally, with Octanate. Bypassing agents were used based on the results of TGT. Epitope mapping was performed during ITI therapy. These observations suggest the potential contribution of Octanate in the management of ITI in difficult cases. The use of bypassing agents can be necessary in prophylaxis or to treat bleedings, and may be guided by TGT results. Epitope mapping is used to describe the inhibitor. This article shows a decrease of the inhibitor directed against the C2 domain after initiation of Octanate. A high-purity human factor VIII/von Willebrand factor concentrate (Octanate) may be a valuable therapeutical option for ITI therapy. TGT and epitope mapping could be of help in the management of ITI. PMID:26517064

  6. Review Finds Mixed Success with Hemophilia Treatment

    MedlinePlus

    ... treatment of men with severe forms of the blood-clotting disorder To use the sharing features on this ... of standard of care multidisciplinary services and preventive blood clotting factor treatments to further normalize the lives of ...

  7. Hemophilia Treatments Have Come a Long Way

    MedlinePlus

    ... blood. Today, an increasing number are made using recombinant DNA technology (a form of artificial DNA), with ... Medical Devices Nutrition Radiation-Emitting Products Tobacco Products Vaccines, Blood & Biologics Articulos en Espanol Alimentos y Bebidas ...

  8. The growing number of hemophilia registries: Quantity vs. quality.

    PubMed

    Keipert, C; Hesse, J; Haschberger, B; Heiden, M; Seitz, R; van den Berg, H M; Hilger, A

    2015-05-01

    Registries for rare diseases provide a tool for obtaining an overview of the clinical situation and can be used to discover points of improvement and to monitor long-term safety. Registries could also become a powerful tool to provide supporting information for marketing authorization. There is an urgent need for a pan-European or global strategy that supports consistent data. Therefore, transparency in data collection, harmonization of the database structures, and the convergence of scientific approaches are required. PMID:25669198

  9. The Use of Tools by Children with Hemophilia.

    ERIC Educational Resources Information Center

    Markova, I.; And Others

    1984-01-01

    Eight mothers with their 3.1- to 5.7-year-old hemophiliac children and eight control mothers with their nonhemophiliac children were videotaped while playing two games without tools and three additional games involving use of a knife, a pair of scissors, and a wooden hammer. Mothers of hemophiliac children did not correct their children when they…

  10. Acquired hemophilia masked by warfarin therapy: report on two cases.

    PubMed

    Uggla, Bertil; Linder, Olle; Schulman, Sam

    2003-12-01

    Spontaneous appearance of acquired anticoagulants is a rare phenomenon. We present two cases, where such antibodies against factor VIII were masked by warfarin therapy. The two patients were anticoagulated with warfarin due to mechanical heart valve and recurrent thromboembolic events, respectively. Different therapies against the inhibitor of factor VIII were used in the two cases. One patient received corticosteroids and high-dose gammaglobulin with temporary effect and was then effectively treated with cyclophosphamide. The other patient was successfully treated with cyclosporine. The special problems of keeping the balance between thrombosis and bleeding in this group of patients with need of anticoagulation due to mechanical heart valves or other thrombogenic factors are discussed. PMID:14614359

  11. Spinal subdural hematoma revealing hemophilia A in a child: A case report

    PubMed Central

    Eftekhar, Behzad; Ghodsi, Mohammad; Ketabchi, Ebrahim; Bakhtiari, Abbas; Mostajabi, Pardis

    2003-01-01

    Background Intraspinal bleeding especially in the form of subdural hematoma is rare in hemophiliacs. In the present case, we report a neglected hemophilic A child with such a problem and discuss its management options. Case Presentation A 9-year old hemophilic A boy presented with quadriparesis, confusion and meningismus after a fall 4 days previously. There was no sign of direct trauma to his back. His CT Scan and MRI showed spinal extramedullary hematoma extended from C5 to L2. We corrected the factor VIII level, but two days later, the patient's lower limbs weakened to 1/5 proximally as well as distally. We performed a laminectomy from T11 to L2, according to the level of the maximal neurological deficit and recent deterioration course. The subdural hematoma was evacuated. The hematoma in other spinal levels was managed conservatively. In the week following the operation, the patient's neurological status approached normal. Conclusion This case calls attention to the clinical manifestation, radiological features and management options of the rarely reported intraspinal hematoma in hemophilic children. Although this case has been managed operatively for its hematoma in the thoracolumbar region, at the same time it can be considered a successful case of conservative management of intraspinal hematoma in the cervicothoracic region. Both conservative and surgical management could be an option in managing these patients considering their neurological course. PMID:12904268

  12. Spinal subdural hematoma revealing hemophilia A in a child: A case report.

    PubMed

    Eftekhar, Behzad; Ghodsi, Mohammad; Ketabchi, Ebrahim; Bakhtiari, Abbas; Mostajabi, Pardis

    2003-08-01

    BACKGROUND: Intraspinal bleeding especially in the form of subdural hematoma is rare in hemophiliacs. In the present case, we report a neglected hemophilic A child with such a problem and discuss its management options. CASE PRESENTATION: A 9-year old hemophilic A boy presented with quadriparesis, confusion and meningismus after a fall 4 days previously. There was no sign of direct trauma to his back. His CT Scan and MRI showed spinal extramedullary hematoma extended from C5 to L2. We corrected the factor VIII level, but two days later, the patient's lower limbs weakened to 1/5 proximally as well as distally. We performed a laminectomy from T11 to L2, according to the level of the maximal neurological deficit and recent deterioration course. The subdural hematoma was evacuated. The hematoma in other spinal levels was managed conservatively. In the week following the operation, the patient's neurological status approached normal. CONCLUSION: This case calls attention to the clinical manifestation, radiological features and management options of the rarely reported intraspinal hematoma in hemophilic children. Although this case has been managed operatively for its hematoma in the thoracolumbar region, at the same time it can be considered a successful case of conservative management of intraspinal hematoma in the cervicothoracic region. Both conservative and surgical management could be an option in managing these patients considering their neurological course. PMID:12904268

  13. Tissue Factor Activity in Lymphocyte Cultures from Normal Individuals and Patients with Hemophilia A

    PubMed Central

    Rickles, Frederick R.; Hardin, John A.; Pitlick, Frances A.; Hoyer, Leon W.; Conrad, Marcel E.

    1973-01-01

    The procoagulant material of lymphocytes has been characterized as tissue factor. Lymphocytes stimulated with phytohemagglutinin or the purified protein derivative of the tubercle bacillus developed procoagulant activity with incubation in tissue culture. While this material corrected the prolonged clotting time of factor VIII (AHF) deficient plasma, we have shown, utilizing a sensitive radioimmunoassay, that no AHF antigen was present in the cell cultures. Further, we have demonstrated this material to be tissue factor by coagulation techniques and immunological cross-reactivity. The published data regarding factor VIII synthesis is reviewed in light of these observations and comments are made regarding the role of the lymphocyte procoagulant. PMID:4634046

  14. [Molecular biologic study and the factor VIII gene in hemophilia A].

    PubMed

    Bock, I; Melegh, B; Nagy, A; Losonczy, H; Csete, B; Schröder, W; Kardos, M; István, L; Jager, R; Tóth, A M; Tóth, A; Falko, H; Mózsik, G

    1996-11-17

    Results of inversion in the intron 22 region of the VIII factor gene studied by Southern blot are presented. Inversion was found in 20 of 46 patients. In 14 cases (70%) distal and in 6 cases (30%) proximal type of inversion was detected. The significance of the positive result in genetic counseling and in presymptomatic diagnosis of Haemophilia A is emphasized. PMID:9005386

  15. Prevalence and incidence of intracranial haemorrhage in a population of children with haemophilia. The Hemophilia Growth and Development Study.

    PubMed

    Nelson, M D; Maeder, M A; Usner, D; Mitchell, W G; Fenstermacher, M J; Wilson, D A; Gomperts, E D

    1999-09-01

    The prevalence of intracranial haemorrhage (ICH) in our population of haemophiliacs was 12%. The incidence of ICH was approximately 2% per year. At entry, 7% (21/309) had clinical histories of ICH without MRI evidence of old haemorrhage, indicating that either the haemorrhages had completely resolved, that routine MRI sequences are not particularly sensitive for the detection of old blood products, or a combination of both of these factors. One half (4/8) of the ICHs documented by entry MRI were clinically silent, and three of the 11 incident cases documented by MRI were clinically silent. HIV infection did not increase the risk of ICH. PMID:10583511

  16. [Hemophilia B in a mixed breed male dog: treatment of a hemorrhagic crisis with fresh frozen plasma].

    PubMed

    Mischke, R; Hänies, R; Deniz, A; Hart, S

    1996-01-01

    A 6 months old male crossbred dog became conspicuous because of a considerable haematoma in the region of the left thigh without recognizable exterior trauma. The results of the screening tests of the haemostatic system (distinctly prolonged activated partial thromboplastin time [aPTT], normal thromboplastin time and platelet count as well as a shortening of thrombin time) yielded a tentative diagnosis of haemophilia. Haemophilia B could be diagnosed on the basis of a distinctly and isolated reduced factor IX activity (8%, reference range: 70-140%). Two infusions with 20 ml/kg BW fresh frozen plasma each caused a clear clinical recovery of the patient. In addition, the efficacy of plasma infusion was documented in vitro by a temporary increase of factor IX activity as well as repeated measurements with the resonance thrombograph and of the aPTT. PMID:8647012

  17. Evidence for a shift from a type I lymphocyte pattern with HIV disease progression. Hemophilia Growth and Development Study.

    PubMed

    Jason, J; Sleeper, L A; Donfield, S M; Murphy, J; Warrier, I; Arkin, S; Evatt, B

    1995-12-01

    Whether a shift from a type I (cell mediated) immune profile occurs with progressive HIV-related immune dysfunction is a matter of heated debate. We analyzed data for 333 HIV antibody-positive (HIV+) and -negative (HIV-) hemophilic children/adolescents, to examine whether the relationships among immunologic parameters and vaccine-related serology supported a shift with advancing HIV infection. In stepwise logistic regression analysis of HIV+ children's data, anergy to a panel of delayed hypersensitivity skin test antigens was positively associated with serum immunoglobulin A (IgA) levels (p = 0.012) and CD8+ cell counts (p = 0.021) and negatively associated with CD4+ cell counts (p = 0.002). Modeling supported anergy as a positive correlate of log IgA level (p = 0.046) and CD4+ lymphocyte count as a negative correlate, for HIV+ participants only (p < 0.0001). For mumps, the proportion of vaccinated HIV+ participants with protective IgG antibody titers was higher among those with CD4+ lymphocyte counts < 200 cells/mm3 (p = 0.058). For HIV+ participants < 14 years of age, this same trend was seen for measles and rubella, but was not seen in any age group for bacterial vaccine antigens. The intercorrelations among skin test anergy, CD4+ lymphocyte counts, serum IgA levels, and viral vaccine antigen-related serologic titers for HIV+ participants are consistent with an association between progressive HIV-related immune dysfunction and a predominance of type II (humoral immunity) or Type 0 (mixed immunity), relative to type I, lymphocyte profiles. PMID:7583444

  18. Patterns and predictors of high-risk sexual behavior in female partners of HIV-infected men with hemophilia.

    PubMed

    Dublin, S; Rosenberg, P S; Goedert, J J

    1992-05-01

    This study sought to characterize and quantify the high-risk heterosexual activity in HIV-discordant couples. An analysis of cross-sectional and longitudinal questionnaire data from 217 HIV-negative female sexual partners of HIV-infected hemophiliac men were included in this study. There was a comparison of prevalence rates of anal sex, oral sex, vaginal intercourse with or without condoms, and use of other contraceptives between 1985-91. Logistic regression analysis of demographic, sexual, and clinical variables was used to predict unprotected vaginal sex. Actuarial estimates of semiannual relapse rates to unsafe sex were used. The proportion of women at low risk increases from 7 to 69% between 1985-91, mainly because more women were using condoms during all acts of vaginal intercourse. Other contraceptive practices did not change during this time. The proportion who engaged in oral or anal sex decreased from 26 to 13% and from 13% to 4%, respectively. Unprotected vaginal sex was more common among women who enrolled earlier, had less education, engaged in oral or anal sex, and among those whose partners had not had AIDS. Unprotected vaginal sex before enrollment was the strongest predictor of this high-risk activity during followup. 2-year rates of relapse to high-risk behavior were significantly higher among women who enrolled at high risk compared with those who enrolled at low risk (39 vs 8%, p=0.005). Although high risk sexual behavior become much less prevalent in this population between 1985-91, many continued to have unprotected vaginal sex occasionally. Counseling efforts should target couples who have been the most sexually active or have less education, and should emphasize not only initial risk reduction but also maintenance of low-risk behavior. PMID:1616653

  19. Fibrinogen

    MedlinePlus

    ... or secondary Hemophilia A Hemophilia B Placenta abruption - definition Update Date 1/27/2015 Updated by: Yi- ... M. is also a founding member of Hi-Ethics and subscribes to the principles of the Health ...

  20. Bleeding Disorders

    MedlinePlus

    ... cause bleeding, such as endometriosis (EN-doh-MEE-tree-OH-suhss) Large bruises from a minor bump ... 8573 National Hemophilia Foundation Phone: 800-424-2634 World Federation of Hemophilia Phone: 514-875-7944 Return ...

  1. 76 FR 21753 - Noncompetitive Program Extension Supplemental Awards

    Federal Register 2010, 2011, 2012, 2013, 2014

    2011-04-18

    ... to the Maternal Child and Health Bureau's (MCHB) Comprehensive Hemophilia Diagnostic and Treatment... these grantees. SUPPLEMENTARY INFORMATION: Intended Recipient of the Award: Comprehensive Hemophilia... Projects of Regional and National Significance (SPRANS) (42 U.S.C. 701). Regional Comprehensive...

  2. Pharmaceutical Approval Update.

    PubMed

    Choy, Mary

    2016-05-01

    Coagulation factor IX (recombinant), albumin fusion protein (Idelvion) for hemophilia B; captisol-enabled melphalan hydrochloride (Evomela) for multiple myeloma; and antihemophilic factor (recombinant) (Kovaltry) for hemophilia A. PMID:27162467

  3. Genetics Home Reference: prothrombin deficiency

    MedlinePlus

    ... Patients and Caregivers: How Blood Clots Orphanet: Congenital factor II deficiency University of Iowa Health Care: Prothrombin Gene Mutation Patient Support and Advocacy Resources (2 links) Canadian Hemophilia Society National Hemophilia Foundation: Factor II ... Genetic Testing Registry (1 link) Prothrombin ...

  4. The diagnosis and management of von Willebrand disease in Canada.

    PubMed

    James, Paula D; Lillicrap, David P

    2011-07-01

    In Canada, care for individuals with inherited bleeding disorders, including Von Willebrand disease, is provided by 26 tertiary care multidisciplinary Inherited Bleeding Disorders clinics geographically spread across the country. The Association of Hemophilia Clinic Directors of Canada, the Canadian Association of Nurses in Hemophilia Care, the Canadian Physiotherapists in Hemophilia Care, the Canadian Social Workers in Hemophilia Care, and the Canadian Hemophilia Society all collaborate to provide optimal management for patients with inherited bleeding disorders. The standards of care for these patients were explicitly laid out in a 2007 document published by the Canadian Hemophilia Standards Group (with representation from all of the groups just mentioned) entitled Canadian Comprehensive Care Standards for Hemophilia and Other Inherited Bleeding Disorders. Separate Canadian guidelines for the management of patients with Hemophilia and Von Willebrand disease also exist, focused on diagnosis, comprehensive care, assessment, and treatment. PMID:22102195

  5. Increasing hepatitis C virus RNA levels in hemophiliacs: relationship to human immunodeficiency virus infection and liver disease. Multicenter Hemophilia Cohort Study.

    PubMed

    Eyster, M E; Fried, M W; Di Bisceglie, A M; Goedert, J J

    1994-08-15

    We have previously observed an increased frequency of liver failure in human immunodeficiency virus (HIV)-infected hemophiliacs. The purpose of this study was to quantitate hepatitis C virus (HCV) RNA levels in serial samples from HIV-seropositive (HIV+) and HIV-seronegative (HIV-) hemophiliacs before and after HIV seroconversion, and to examine the relationship of HCV RNA levels to CD4 cell counts and to hepatic dysfunction over time. HCV RNA levels were measured on serial samples of serum stored frozen from 17 HCV+/HIV+ and 17 HCV+/HIV- subjects matched within 5 years of their birth dates. All were HCV+ before study entry. HCV RNA levels were quantitated by a branched DNA-enhanced label amplification (bDNA) assay. For samples less than the cut off, HCV RNA was measured by the nested polymerase chain reaction. Individual changes over time, clinical groups, and mean values within predetermined time windows were compared with Wilcoxon rank sum tests. Mean HCV RNA levels increased from 2.76 (standard error [SE] 1.33) x 10(5) to 2.84 (SE 1.39) x 10(6) eq/mL during the first 2 years after HIV seroconversion (P = .006). Baseline HCV RNA levels in the pre-HIV seroconversion group were not significantly different from the baseline levels in those who remained HIV (P = .79). Over the entire period of study, HCV RNA levels increased nearly threefold in those who remained HIV- (mean 9.47 [SE 4.78] x 10(5) to 2.81 [SE 1.13] x 10(6)/mL; P = .02). Among those who became HIV+, HCV RNA levels increased 58-fold (mean 2.85 [SE 1.26] x 10(5) to 1.66 [SE 0.57] x 10(7) eq/mL; P = .0001). The rate of increase in HCV RNA levels was eightfold faster for HIV+ subjects than for subjects who remained HIV- (P = .009). HCV RNA levels increased twofold higher in 5 subjects who developed liver failure compared with the 12 who did not (P = .43). HCV RNA levels correlated significantly with CD4 counts (R = -.33, P = .01) and serum aspartate aminotransferase levels (AST) (R = .36, P = .007). We conclude that HCV RNA levels are significantly higher in HIV+ than in HIV- multitransfused hemophiliacs. HCV load increases over time, is enhanced by HIV, and further increases as immune deficiency progresses. HCV RNA levels are directly associated with high AST levels. These findings suggest that HIV-induced immune deficiency may promote increased HCV replication. PMID:8049420

  6. Efficacy of tranexamic acid mouthwash as an alternative for factor replacement in gingival bleeding during dental scaling in cases of hemophilia: A randomized clinical trial

    PubMed Central

    Nuvvula, Sivakumar; Gaddam, Kumar Raja; Kamatham, Rekhalakshmi

    2014-01-01

    Objective: The objective of the following study is to evaluate freshly prepared tranexamic acid mouth wash (FTAMW) as an alternative to factor replacement therapy (FRT) in controlling gingival bleeding in hemophiliacs during dental scaling. Materials and Methods: Experimental treatment regime (ETR) involved saline transfusion followed by FTAMW and the control treatment regime (CTR) involved FRT followed by placebo mouthwash. A total of 22 hemophiliacs randomly received dental scaling under either CTR or ETR at two different visits, following a split mouth design. They were instructed to use the rendered mouthwash 4 times a day for 5 days and record the mouthwash usage and bleeding episodes in a logbook. The difference in the bleeding episodes was analyzed using Chi-square test with the level of significance predetermined at 0.05. Results: Totally 19 patients completed the study. Seven patients reported no bleeding either in ETR or CTR; five patients noticed bleeding in CTR, but not in ETR. Three patients noticed bleeding in ETR, but not in CTR. Patients reported ease in usage and cost-effectiveness of ETR. Conclusion: FTAMW was found to be an effective alternative to FRT in controlling gingival hemorrhage in hemophiliacs during dental scaling. PMID:24808695

  7. The Hemophiliac and His World.

    ERIC Educational Resources Information Center

    Gourdeau, R., Ed.

    The document contains the papers presented at the 5th Congress of the World Federation of Hemophilia in Montreal in 1968. Seven papers concern specific therapy of hemophilia, five papers treat nonspecific forms of therapy, seven papers deal with prophylaxis and complications in hemophilia, seven others deal with orthopedic and other surgical…

  8. 77 FR 58849 - Prescription Drug User Fee Act Patient-Focused Drug Development; Public Meeting and Request for...

    Federal Register 2010, 2011, 2012, 2013, 2014

    2012-09-24

    ... hypertension. Heart failure. Primary glomerular diseases. Narcolepsy. Huntington's Disease. Depression. Autism... sexual dysfunction. Cancer and depression. Clotting disorders (e.g., hemophilia A (factor VIII...

  9. Spotlight on the human factor: building a foundation for the future of haemophilia A management: report from a symposium on human recombinant FVIII at the World Federation of Hemophilia World Congress, Melbourne, Australia on 12 May 2014.

    PubMed

    Kessler, C; Oldenburg, J; Ettingshausen, C Escuriola; Tiede, A; Khair, K; Négrier, C; Klamroth, R

    2015-01-01

    Inhibitor development is the most serious and challenging complication in the treatment of severe haemophilia A. Up to 38% of such patients develop inhibitors with current recombinant factor VIII (rFVIII) products produced in hamster cell lines. Human-cl rhFVIII is a new generation fully sulfated B-domain-deleted FVIII coagulant glycoprotein, which is generated from a human cell line. Thus, there are no non-human epitopes which would be potentially immunogenic. This molecule has significantly higher VWF-binding affinity compared with existing full-length rFVIII produced in hamster cell lines. The development aim of Human-cl rhFVIII is to address the challenges of FVIII inhibitors and frequent infusions during prophylaxis. Human-cl rhFVIII's mean half-life is very comparable to some of the newer products which involve modification of the FVIII molecule to extend the circulating half-life. There are promising data concerning the use of a personalized prophylaxis regimen with Human-cl rhFVIII. Preliminary data indicate a median dosing interval of 3.5 days with 66.7% of the patients on a twice per week or fewer infusions schedule combined with a low bleeding rate and no increased FVIII consumption when compared to standard prophylaxis. No product-specific laboratory assay is required to monitor the coagulation activity for Human-cl rhFVIII. The results of registration clinical trials with Human-cl rhFVIII as well as the ongoing studies in previously untreated patients (NuProtect) and personalized prophylaxis study in previously treated patients (NuPreviq), will be discussed. The manufacturer has received marketing authorization for Human-cl rhFVIII in Europe and Canada under the name Nuwiq(®) and plans to launch it in the USA and globally in 2015. PMID:25472812

  10. 42 CFR 130.2 - Definitions.

    Code of Federal Regulations, 2011 CFR

    2011-10-01

    ... 42 Public Health 1 2011-10-01 2011-10-01 false Definitions. 130.2 Section 130.2 Public Health PUBLIC HEALTH SERVICE, DEPARTMENT OF HEALTH AND HUMAN SERVICES COMPASSIONATE PAYMENTS RICKY RAY HEMOPHILIA RELIEF FUND PROGRAM General Provisions § 130.2 Definitions. As used in this part: (a) Act means the Ricky Ray Hemophilia Relief Fund Act of...

  11. 42 CFR 130.2 - Definitions.

    Code of Federal Regulations, 2010 CFR

    2010-10-01

    ... 42 Public Health 1 2010-10-01 2010-10-01 false Definitions. 130.2 Section 130.2 Public Health PUBLIC HEALTH SERVICE, DEPARTMENT OF HEALTH AND HUMAN SERVICES COMPASSIONATE PAYMENTS RICKY RAY HEMOPHILIA RELIEF FUND PROGRAM General Provisions § 130.2 Definitions. As used in this part: (a) Act means the Ricky Ray Hemophilia Relief Fund Act of...

  12. 42 CFR 130.2 - Definitions.

    Code of Federal Regulations, 2012 CFR

    2012-10-01

    ... 42 Public Health 1 2012-10-01 2012-10-01 false Definitions. 130.2 Section 130.2 Public Health PUBLIC HEALTH SERVICE, DEPARTMENT OF HEALTH AND HUMAN SERVICES COMPASSIONATE PAYMENTS RICKY RAY HEMOPHILIA RELIEF FUND PROGRAM General Provisions § 130.2 Definitions. As used in this part: (a) Act means the Ricky Ray Hemophilia Relief Fund Act of...

  13. 42 CFR 130.2 - Definitions.

    Code of Federal Regulations, 2013 CFR

    2013-10-01

    ... 42 Public Health 1 2013-10-01 2013-10-01 false Definitions. 130.2 Section 130.2 Public Health PUBLIC HEALTH SERVICE, DEPARTMENT OF HEALTH AND HUMAN SERVICES COMPASSIONATE PAYMENTS RICKY RAY HEMOPHILIA RELIEF FUND PROGRAM General Provisions § 130.2 Definitions. As used in this part: (a) Act means the Ricky Ray Hemophilia Relief Fund Act of...

  14. 42 CFR 130.2 - Definitions.

    Code of Federal Regulations, 2014 CFR

    2014-10-01

    ... 42 Public Health 1 2014-10-01 2014-10-01 false Definitions. 130.2 Section 130.2 Public Health PUBLIC HEALTH SERVICE, DEPARTMENT OF HEALTH AND HUMAN SERVICES COMPASSIONATE PAYMENTS RICKY RAY HEMOPHILIA RELIEF FUND PROGRAM General Provisions § 130.2 Definitions. As used in this part: (a) Act means the Ricky Ray Hemophilia Relief Fund Act of...

  15. Diagnosis and management of von Willebrand disease in The Netherlands.

    PubMed

    de Wee, Eva M; Leebeek, Frank W G; Eikenboom, Jeroen C J

    2011-07-01

    In the Netherlands, specialized care for patients with a bleeding disorder, including hemophilia, von Willebrand disease (VWD), and allied disorders, is concentrated in 13 Hemophilia Treatment Centers. The Dutch Hemophilia Treaters Society, the Dutch Hemophilia Nurses' Society, and the Netherlands Hemophilia Patients Society collaborate to optimize management of patients with a bleeding disorder. A recently updated consensus guideline of hemophilia and allied bleeding disorders provide guidance on the current optimal diagnostic strategy and treatment of VWD. Genetic testing is not routinely performed in the Netherlands. Desmopressin (DDAVP) is the choice of treatment in VWD patients responsive to DDAVP, as determined by a test infusion. Coagulation factor concentrates are used in nonresponsive individuals, in case of a contraindication for DDAVP, or in type 2B and type 3 VWD. These concentrates are available for all patients in the Netherlands; however, these may only be administered in a Hemophilia Treatment Center or under the care of a Hemophilia Treatment Center. Recently a study on moderate and severe VWD (the Willebrand in Netherlands study) was initiated to obtain more insight on VWD diagnosis, treatment, and the burden of the disease. PMID:22102190

  16. Prevalence, Incidence, and Factor Concentrate Usage Trends of Hemophiliacs in Taiwan

    PubMed Central

    Tu, Tsu-Chiang; Liou, Wen-Shyong; Chou, Tsui-Yun; Lin, Tsung-Kun; Lee, Chuan-Fang; Chen, Jye-Daa; Cham, Thau-Ming

    2013-01-01

    Purpose Hemophilia A and B (HA, HB) are the most common X-linked inherited bleeding disorders. The introduction of factor concentrates has allowed for control of the lifelong chronic disease. However, no studies have been published regarding the epidemiology of hemophilia in Taiwan. Our aim was to determine the prevalence, incidence, and mortality rate, as well as trends in the use of factor concentrates, in individuals with hemophilia in Taiwan. Materials and Methods A retrospective study was conducted using the National Health Insurance Research Database between 1997 and 2007. Results We identified 988 males with hemophilia (HA : HB ratio=5.4 : 1). The mean prevalence per 100000 males was 6.7±0.1 for HA and 1.2±0.1 for HB. The estimated mean annual incidence per live male birth was 1 in 10752 for HA and 1 in 47619 for HB. Standardized mortality ratios for males with hemophilia (all severities) or severe hemophilia were 1.3- and 2.1-fold higher than that of the general male population, respectively. Mean factor VIII (FVIII) and factor IX (FIX) usage was 1.5003±0.4029 and 0.3126±0.0904 international units (IUs) per capita, respectively. Mean FVIII and FIX usage per patient with hemophilia (all severities) or severe hemophilia was 44027±11532 and 72341±17298, respectively, and 49407±13015 and 74369±18411 IUs per person with HA or HB, respectively. Conclusion Our data revealed epidemiologic and factor concentrate usage trends in males with hemophilia in Taiwan, highlighting a need for improvements in the mandatory National Health Insurance registry. A better-designed, patient-centered registry system would enable more detailed patient information collection and analysis, improving subsequent care. PMID:23225801

  17. 42 CFR 412.521 - Basis of payment.

    Code of Federal Regulations, 2014 CFR

    2014-10-01

    ..., as provided in § 413.89 of this subchapter. (iii) A payment amount per unit for blood clotting factor... payments as provided in § 412.525 and payments for hemophilia clotting factor costs as provided...

  18. 42 CFR 412.521 - Basis of payment.

    Code of Federal Regulations, 2010 CFR

    2010-10-01

    ... subchapter. (iii) A payment amount per unit for blood clotting factor provided to Medicare inpatients who... hemophilia clotting factor costs as provided in paragraph (b)(2)(iii) of this section, are made to the...

  19. 42 CFR 412.521 - Basis of payment.

    Code of Federal Regulations, 2011 CFR

    2011-10-01

    ... subchapter. (iii) A payment amount per unit for blood clotting factor provided to Medicare inpatients who... hemophilia clotting factor costs as provided in paragraph (b)(2)(iii) of this section, are made to the...

  20. 42 CFR 412.521 - Basis of payment.

    Code of Federal Regulations, 2013 CFR

    2013-10-01

    ... subchapter. (iii) A payment amount per unit for blood clotting factor provided to Medicare inpatients who... hemophilia clotting factor costs as provided in paragraph (b)(2)(iii) of this section, are made to the...

  1. 42 CFR 412.521 - Basis of payment.

    Code of Federal Regulations, 2012 CFR

    2012-10-01

    ... subchapter. (iii) A payment amount per unit for blood clotting factor provided to Medicare inpatients who... hemophilia clotting factor costs as provided in paragraph (b)(2)(iii) of this section, are made to the...

  2. 42 CFR 130.40 - Reconsideration of denial of petitions.

    Code of Federal Regulations, 2012 CFR

    2012-10-01

    ... PAYMENTS RICKY RAY HEMOPHILIA RELIEF FUND PROGRAM Reconsideration Procedures § 130.40 Reconsideration of... individuals, who are independent of the Ricky Ray Program Office, to review the initial determination and...

  3. 42 CFR 130.40 - Reconsideration of denial of petitions.

    Code of Federal Regulations, 2013 CFR

    2013-10-01

    ... PAYMENTS RICKY RAY HEMOPHILIA RELIEF FUND PROGRAM Reconsideration Procedures § 130.40 Reconsideration of... individuals, who are independent of the Ricky Ray Program Office, to review the initial determination and...

  4. 42 CFR 130.40 - Reconsideration of denial of petitions.

    Code of Federal Regulations, 2010 CFR

    2010-10-01

    ... PAYMENTS RICKY RAY HEMOPHILIA RELIEF FUND PROGRAM Reconsideration Procedures § 130.40 Reconsideration of... individuals, who are independent of the Ricky Ray Program Office, to review the initial determination and...

  5. 42 CFR 130.40 - Reconsideration of denial of petitions.

    Code of Federal Regulations, 2014 CFR

    2014-10-01

    ... PAYMENTS RICKY RAY HEMOPHILIA RELIEF FUND PROGRAM Reconsideration Procedures § 130.40 Reconsideration of... individuals, who are independent of the Ricky Ray Program Office, to review the initial determination and...

  6. 42 CFR 130.40 - Reconsideration of denial of petitions.

    Code of Federal Regulations, 2011 CFR

    2011-10-01

    ... PAYMENTS RICKY RAY HEMOPHILIA RELIEF FUND PROGRAM Reconsideration Procedures § 130.40 Reconsideration of... individuals, who are independent of the Ricky Ray Program Office, to review the initial determination and...

  7. Study of an Intervention to Improve Problem List Accuracy and Use

    ClinicalTrials.gov

    2015-01-30

    Attention Deficit Disorder With Hyperactivity; Asthma; COPD; Breast Cancer; Coronary Artery Disease; Congestive Heart Failure; Diabetes; Glaucoma; Hemophilia; Hypertension; Hyperthyroidism; Hypothyroidism; Myasthenia Gravis; Osteoporosis; Osteopenia; Renal Failure; Renal Insufficiency; Sickle Cell Disease; Stroke

  8. Inhibitors

    MedlinePlus

    ... Community Counts Blood Safety Inhibitors Articles & Key Findings Free Materials Videos Starting the Conversation Playing it Safe A Look at Hemophilia Joint Range of Motion My Story Links to Other Websites ...

  9. 42 CFR 51a.2 - Definitions.

    Code of Federal Regulations, 2014 CFR

    2014-10-01

    ... CHILD HEALTH § 51a.2 Definitions. Act means the Social Security Act, as amended. Genetic diseases means.... Hemophilia means a genetically transmitted bleeding disorder resulting from a deficiency of a plasma...

  10. 42 CFR 51a.2 - Definitions.

    Code of Federal Regulations, 2011 CFR

    2011-10-01

    ... CHILD HEALTH § 51a.2 Definitions. Act means the Social Security Act, as amended. Genetic diseases means.... Hemophilia means a genetically transmitted bleeding disorder resulting from a deficiency of a plasma...

  11. 42 CFR 51a.2 - Definitions.

    Code of Federal Regulations, 2012 CFR

    2012-10-01

    ... CHILD HEALTH § 51a.2 Definitions. Act means the Social Security Act, as amended. Genetic diseases means.... Hemophilia means a genetically transmitted bleeding disorder resulting from a deficiency of a plasma...

  12. 42 CFR 51a.2 - Definitions.

    Code of Federal Regulations, 2013 CFR

    2013-10-01

    ... CHILD HEALTH § 51a.2 Definitions. Act means the Social Security Act, as amended. Genetic diseases means.... Hemophilia means a genetically transmitted bleeding disorder resulting from a deficiency of a plasma...

  13. What Should You Know about Blood Disorders in Women?

    MedlinePlus

    ... Although there are no cures for bleeding disorders, treatment is available to control symptoms and help women avoid complications and invasive procedures. Related Links Deep Vein Thrombosis Hemophilia Von Willebrand Disease Blood Disorders Home A- ...

  14. No more Doritos and lobster tails: a case report of life-threatening sublingual hematoma.

    PubMed

    Kausar, Huma; Gilani, Javed M; Khan, Omar A

    2009-07-01

    This case report highlights a life-threatening complication of mild hemophilia A. We report the onset of airway compromise through a massive sublingual hematoma in a 67-year-old male suffering from the mild form of hemophilia A. This case emphasizes the need for prompt medical attention and recognition of potentially serious complications of the disease in patients suffering with even mild form of this bleeding diathesis. PMID:19902776

  15. Assessment of Hemophilic Arthropathy by Ultrasound: Where Do We Stand?

    PubMed

    Di Minno, Matteo Nicola Dario; Ambrosino, Pasquale; Quintavalle, Gabriele; Coppola, Antonio; Tagliaferri, Annarita; Martinoli, Carlo; Rivolta, Gianna Franca

    2016-07-01

    Joint hemorrhages represent the most common type of bleeding episode in persons with hemophilia, and recurrent hemarthrosis triggers chronic arthropathy, which is the most frequent chronic complication in these patients. In recent years, in the frame of a comprehensive care approach, a growing attention has been given to the periodic assessment of the joint status in hemophilia patients with the aim to identify early arthropathic changes and to prevent the development of a clinically overt arthropathy. Besides clinical examination, X-ray and magnetic resonance imaging (MRI) are currently used to evaluate joint status and to monitor the disease progression in hemophilia. Considering the limitations of X-ray and MRI, growing interest has been given to ultrasound (US) as a possible tool to assess joint status and identify early arthropathic changes in hemophilia patients. In the present review, we summarize major literature evidence on the use of joint US for the evaluation of markers of disease activity (joint effusion and synovial hypertrophy) and of degenerative damages (osteochondral changes) in patients with hemophilia. On the whole, being able to identify the presence of intra- or extra-articular fluid, US examination is the fastest and most reliable technique to identify acute conditions, such as hemarthrosis. In addition, the information on joint involvement provided by US in the patient follow-up may influence treatment decisions on a personalized basis. The use of US as part of a routine clinical examination by hemophilia experts may optimize the diagnostic workflow, avoiding additional costs and long waiting lists for patients referred to imaging departments. In the frame of a comprehensive care approach, US might represent a strategy to early detect and monitor synovial hypertrophy and osteochondral changes in hemophilia, thus extending the clinical examination and helping identify joints to be studied with a second-level examination such as MRI. PMID

  16. The challenges of the homeless haemophilia patient.

    PubMed

    Lambing, A; Kuriakose, P; Kachalsky, E; Mueller, L

    2013-07-01

    The current economic hardships within the United States can increase the risk of persons becoming homeless. In 2001, it was estimated that between 0.1% and 2.1% of the population were homeless every night and that 2.3 - 3.5 million persons could become homeless every year [1]. Many issues can increase the risk of homelessness including: home foreclosure, declining work force due to declining wages, low-wage opportunities and less secure jobs, decline in public assistance, lack of affordable housing with limited housing assistance programs, poverty, lack of affordable health care, domestic violence, mental illness, and addiction disorders. Many on the streets may suffer from mental illness, developmental disabilities, and or chronic physical illness [6]. Given these issues, the Hemophilia Treatment Center (HTC) can expect to experience the issue of homelessness within their own population of persons with hemophilia. Currently, there are no studies that address the issue of the person with hemophilia who may become homeless. This presents unique challenges that this population may encounter to survive in addition to managing bleeding issues related to the diagnosis of hemophilia. This article will review the issues related to homelessness in the general population. Two case studies of persons with hemophilia who became homeless will be discussed outlining the strategies utilized to assist the patient during this crisis. PMID:23557394

  17. Optimal management of hemophilic arthropathy and hematomas

    PubMed Central

    Lobet, Sébastien; Hermans, Cedric; Lambert, Catherine

    2014-01-01

    Hemophilia is a hematological disorder characterized by a partial or complete deficiency of clotting factor VIII or IX. Its bleeding complications primarily affect the musculoskeletal system. Hemarthrosis is a major hemophilia-related complication, responsible for a particularly debilitating chronic arthropathy, in the long term. In addition to clotting factor concentrates, usually prescribed by the hematologist, managing acute hemarthrosis and chronic arthropathy requires a close collaboration between the orthopedic surgeon and physiotherapist. This collaboration, comprising a coagulation and musculoskeletal specialist, is key to effectively preventing hemarthrosis, managing acute joint bleeding episodes, assessing joint function, and actively treating chronic arthropathy. This paper reviews, from a practical point of view, the pathophysiology, clinical manifestations, and treatment of hemarthrosis and chronic hemophilia-induced arthropathy for hematologists, orthopedic surgeons, and physiotherapists. PMID:25378964

  18. Transfusion-transmitted infections in haemophilia patients.

    PubMed

    Zhubi, Bukurije; Mekaj, Ymer; Baruti, Zana; Bunjaku, Ilirijane; Belegu, Mazllum

    2009-11-01

    One of the largest therapeutic problem during the continuous treatment of the patients with Hemophilia A and B, are viral infections as Hepatitis B and C, and HIV, and the other infective diseases, which can be transmitted by the transfusion of blood products. The aim of this study is to analyze the complications of the hemophiliacs in Kosovo which have been treated with fresh frozen plasma, cryoprecipitate and concentrated products of FVIII and FIX. We have tested 75 patients with hemophilia A or B and there were used enzyme immunoassay test-Elisa method for the following: anti-HCV, HBsAg, HIV and TPHA.The serological data showed that HCV infection was positive in 29 cases or 38,7%, whereas infection with HBV and HIV were present in a smaller percentage of the patients (2,7% HBV and 1,4% for HIV). HCV infection was present only in 9,5% of the cases of the age group under 18 years. Infected hemophiliacs with one or two infective agents were found in 34,7%, respectively 4%. Infection with T. pallidum was present at none of the examined patients with hemophilia. HCV infection was higher in severe forms of hemophilia B (44,4%), compared with severe form of hemophilia A (30%).Based on our results, despite the infrequent application of FVIII and FIX concentrates, and other anti hemophilic preparations used in treating hemophilia patients, the number of infected hemophiliacs with blood-transmittable infectious agents was substantially high, especially with hepatitis C virus. PMID:20001991

  19. Reduction of Factor VIII Inhibitor Titers During Immune Tolerance Induction With Recombinant Factor VIII-Fc Fusion Protein.

    PubMed

    Groomes, Charles L; Gianferante, David M; Crouch, Gary D; Parekh, Dina S; Scott, David W; Lieuw, Kenneth

    2016-05-01

    The development of inhibitors toward factor VIII (FVIII) is a common and serious complication of hemophilia A (HA) therapy. Patients with hemophilia who develop inhibitors often undergo time- and resource-intensive immune tolerance induction (ITI) protocols. We report a 15-month-old male with severe HA and a high-titer inhibitor that occurred while receiving prophylactic treatment with recombinant FVIII (rFVIII), in whom significant inhibitor titer reduction was achieved with thrice weekly infusions of a new, prolonged half-life rFVIII-Fc fusion protein product (trade name Eloctate). Further studies are warranted to explore the potential of Eloctate in ITI protocols. PMID:26739399

  20. Hidden Disabilities: A Look at Alcohol and Other Drug Abuse Prevention.

    ERIC Educational Resources Information Center

    VSA Educational Services, Washington, DC. Resource Center on Substance Abuse Prevention and Disability.

    This leaflet discusses alcohol and other drug abuse prevention for individuals with hidden disabilities such as cancer, epilepsy, diabetes, kidney failure, hemophilia, hypertension, early stages of acquired immune deficiency syndrome (AIDS), or heart disease. Their increased risk for alcohol and other drug abuse and reasons for increased risk are…

  1. 32 CFR 634.37 - Voluntary breath and bodily fluid testing based on implied consent.

    Code of Federal Regulations, 2014 CFR

    2014-07-01

    ..., administrative actions, and civilian courts. (d) Special rules exist for persons who have hemophilia, other blood-clotting disorders, or any medical or surgical disorder being treated with an anticoagulant. These persons— (1) May refuse a blood extraction test without penalty. (2) Will not be administered a...

  2. 32 CFR 634.37 - Voluntary breath and bodily fluid testing based on implied consent.

    Code of Federal Regulations, 2010 CFR

    2010-07-01

    ..., administrative actions, and civilian courts. (d) Special rules exist for persons who have hemophilia, other blood-clotting disorders, or any medical or surgical disorder being treated with an anticoagulant. These persons— (1) May refuse a blood extraction test without penalty. (2) Will not be administered a...

  3. 32 CFR 199.14 - Provider reimbursement methods.

    Code of Federal Regulations, 2010 CFR

    2010-07-01

    ... occurring on or after October 1, 1997, the costs of blood clotting factor for hemophilia inpatients. An additional payment shall be made to a hospital for each unit of blood clotting factor furnished to a CHAMPUS... Payment System (42 CFR 412.115). (D) Hospitals subject to the CHAMPUS DRG-based payment system....

  4. 32 CFR 634.37 - Voluntary breath and bodily fluid testing based on implied consent.

    Code of Federal Regulations, 2013 CFR

    2013-07-01

    ..., administrative actions, and civilian courts. (d) Special rules exist for persons who have hemophilia, other blood-clotting disorders, or any medical or surgical disorder being treated with an anticoagulant. These persons— (1) May refuse a blood extraction test without penalty. (2) Will not be administered a...

  5. 32 CFR 634.37 - Voluntary breath and bodily fluid testing based on implied consent.

    Code of Federal Regulations, 2012 CFR

    2012-07-01

    ..., administrative actions, and civilian courts. (d) Special rules exist for persons who have hemophilia, other blood-clotting disorders, or any medical or surgical disorder being treated with an anticoagulant. These persons— (1) May refuse a blood extraction test without penalty. (2) Will not be administered a...

  6. 32 CFR 199.14 - Provider reimbursement methods.

    Code of Federal Regulations, 2012 CFR

    2012-07-01

    ... occurring on or after October 1, 1997, the costs of blood clotting factor for hemophilia inpatients. An additional payment shall be made to a hospital for each unit of blood clotting factor furnished to a CHAMPUS... Payment System (42 CFR 412.115). (D) Hospitals subject to the CHAMPUS DRG-based payment system....

  7. 42 CFR 130.21 - What documentation is required for petitions filed by living persons with HIV?

    Code of Federal Regulations, 2010 CFR

    2010-10-01

    ... individual described in § 130.10(a) has (or had) a blood-clotting disorder, such as hemophilia; (2) That the individual with a blood-clotting disorder and HIV was treated with antihemophilic factor at any time between July 1, 1982, to December 31, 1987; and (3) That the individual with a blood-clotting disorder and...

  8. 42 CFR 130.21 - What documentation is required for petitions filed by living persons with HIV?

    Code of Federal Regulations, 2013 CFR

    2013-10-01

    ... individual described in § 130.10(a) has (or had) a blood-clotting disorder, such as hemophilia; (2) That the individual with a blood-clotting disorder and HIV was treated with antihemophilic factor at any time between July 1, 1982, to December 31, 1987; and (3) That the individual with a blood-clotting disorder and...

  9. 42 CFR 130.21 - What documentation is required for petitions filed by living persons with HIV?

    Code of Federal Regulations, 2011 CFR

    2011-10-01

    ... individual described in § 130.10(a) has (or had) a blood-clotting disorder, such as hemophilia; (2) That the individual with a blood-clotting disorder and HIV was treated with antihemophilic factor at any time between July 1, 1982, to December 31, 1987; and (3) That the individual with a blood-clotting disorder and...

  10. 42 CFR 130.21 - What documentation is required for petitions filed by living persons with HIV?

    Code of Federal Regulations, 2012 CFR

    2012-10-01

    ... individual described in § 130.10(a) has (or had) a blood-clotting disorder, such as hemophilia; (2) That the individual with a blood-clotting disorder and HIV was treated with antihemophilic factor at any time between July 1, 1982, to December 31, 1987; and (3) That the individual with a blood-clotting disorder and...

  11. 32 CFR 199.14 - Provider reimbursement methods.

    Code of Federal Regulations, 2011 CFR

    2011-07-01

    ... occurring on or after October 1, 1997, the costs of blood clotting factor for hemophilia inpatients. An additional payment shall be made to a hospital for each unit of blood clotting factor furnished to a CHAMPUS... Payment System (42 CFR 412.115). (D) Hospitals subject to the CHAMPUS DRG-based payment system....

  12. 42 CFR 130.21 - What documentation is required for petitions filed by living persons with HIV?

    Code of Federal Regulations, 2014 CFR

    2014-10-01

    ... individual described in § 130.10(a) has (or had) a blood-clotting disorder, such as hemophilia; (2) That the individual with a blood-clotting disorder and HIV was treated with antihemophilic factor at any time between July 1, 1982, to December 31, 1987; and (3) That the individual with a blood-clotting disorder and...

  13. 32 CFR 634.37 - Voluntary breath and bodily fluid testing based on implied consent.

    Code of Federal Regulations, 2011 CFR

    2011-07-01

    ..., administrative actions, and civilian courts. (d) Special rules exist for persons who have hemophilia, other blood-clotting disorders, or any medical or surgical disorder being treated with an anticoagulant. These persons— (1) May refuse a blood extraction test without penalty. (2) Will not be administered a...

  14. Global Post-Authorization Safety Surveillance Study: real-world data on prophylaxis and on-demand treatment using FEIBA (an activated prothrombin complex concentrate)

    PubMed Central

    Negrier, Claude; Voisin, Sophie; Baghaei, Fariba; Numerof, Robert; Novack, Aaron; Doralt, Jennifer E.; Romanov, Vadim; Gringeri, Alessandro

    2016-01-01

    This prospective, Post-Authorization Safety Surveillance (PASS) study was carried out in patients with hemophilia A or B and inhibitors treated with FEIBA for 1 year to collect real-world data on safety and effectiveness of FEIBA. The study followed a cohort design and did not make stipulations on treatment or observation schedule, as it was designed to observe routine medical practices based on physicians’ treatment decisions, including whether patients received on-demand or prophylaxis with FEIBA. The attending physician maintained documentation, including medical records, laboratory reports, adverse event reports, and so on and a subject diary was used. Eighty-one patients were treated with FEIBA at 40 sites in 10 countries over a 4-year period. Sixty-nine patients (85.2%) had hemophilia A, two had (2.5%) hemophilia B, and ten (12.3%) had acquired hemophilia A. At baseline 45 patients (55.6%) were prescribed prophylaxis and 36 (44.6%) on-demand treatment. This study was novel in following safety and effectiveness in ‘real world’ on-demand and prophylactic use of FEIBA, and was able to collect data in these rare patients under routine clinical practice. PMID:26829366

  15. Home Care for Children with Chronic Illnesses and Severe Disabilities: A Bibliography and Resource Guide.

    ERIC Educational Resources Information Center

    Wells, Alice; And Others

    The bibliography and resource guide summarizes relevant research and information on home care for children with disabilities and chronic illnesses, including those with such diagnoses as spina bifida, cerebral palsy, severe mental retardation, acquired immune deficiency syndrome (AIDS), hemophilia, sickle cell anemia, autism, or failure-to-thrive…

  16. 75 FR 52533 - Agency Information Collection Activities: Proposed Collection: Comment Request

    Federal Register 2010, 2011, 2012, 2013, 2014

    2010-08-26

    ... hemophilia without regard to age, and for the screening of newborns for sickle cell anemia and other genetic...: Sickle Cell Disease and Other Hemoglobinopathies Program Evaluation-- Background: In response to the growing need for resources devoted to sickle cell disease and other hemoglobinopathies, Congress,...

  17. 42 CFR 130.35 - How and when will the Secretary pay a petition?

    Code of Federal Regulations, 2011 CFR

    2011-10-01

    ... 42 Public Health 1 2011-10-01 2011-10-01 false How and when will the Secretary pay a petition? 130.35 Section 130.35 Public Health PUBLIC HEALTH SERVICE, DEPARTMENT OF HEALTH AND HUMAN SERVICES COMPASSIONATE PAYMENTS RICKY RAY HEMOPHILIA RELIEF FUND PROGRAM Procedures for Filing and Paying...

  18. 42 CFR 130.33 - How will the Secretary determine whether a petition is complete?

    Code of Federal Regulations, 2014 CFR

    2014-10-01

    ... 42 Public Health 1 2014-10-01 2014-10-01 false How will the Secretary determine whether a petition is complete? 130.33 Section 130.33 Public Health PUBLIC HEALTH SERVICE, DEPARTMENT OF HEALTH AND HUMAN SERVICES COMPASSIONATE PAYMENTS RICKY RAY HEMOPHILIA RELIEF FUND PROGRAM Procedures for Filing...

  19. 42 CFR Appendix B to Part 130 - Confidential Physician or Nurse Practitioner Affidavit

    Code of Federal Regulations, 2014 CFR

    2014-10-01

    ... 42 Public Health 1 2014-10-01 2014-10-01 false Confidential Physician or Nurse Practitioner Affidavit B Appendix B to Part 130 Public Health PUBLIC HEALTH SERVICE, DEPARTMENT OF HEALTH AND HUMAN SERVICES COMPASSIONATE PAYMENTS RICKY RAY HEMOPHILIA RELIEF FUND PROGRAM Pt. 130, App. B Appendix B to...

  20. 42 CFR 130.33 - How will the Secretary determine whether a petition is complete?

    Code of Federal Regulations, 2013 CFR

    2013-10-01

    ... 42 Public Health 1 2013-10-01 2013-10-01 false How will the Secretary determine whether a petition is complete? 130.33 Section 130.33 Public Health PUBLIC HEALTH SERVICE, DEPARTMENT OF HEALTH AND HUMAN SERVICES COMPASSIONATE PAYMENTS RICKY RAY HEMOPHILIA RELIEF FUND PROGRAM Procedures for Filing...

  1. 42 CFR 130.35 - How and when will the Secretary pay a petition?

    Code of Federal Regulations, 2014 CFR

    2014-10-01

    ... 42 Public Health 1 2014-10-01 2014-10-01 false How and when will the Secretary pay a petition? 130.35 Section 130.35 Public Health PUBLIC HEALTH SERVICE, DEPARTMENT OF HEALTH AND HUMAN SERVICES COMPASSIONATE PAYMENTS RICKY RAY HEMOPHILIA RELIEF FUND PROGRAM Procedures for Filing and Paying...

  2. 42 CFR 130.32 - How and when will the Secretary determine the order of receipt of petitions?

    Code of Federal Regulations, 2010 CFR

    2010-10-01

    ... 42 Public Health 1 2010-10-01 2010-10-01 false How and when will the Secretary determine the order of receipt of petitions? 130.32 Section 130.32 Public Health PUBLIC HEALTH SERVICE, DEPARTMENT OF HEALTH AND HUMAN SERVICES COMPASSIONATE PAYMENTS RICKY RAY HEMOPHILIA RELIEF FUND PROGRAM Procedures...

  3. 42 CFR 130.33 - How will the Secretary determine whether a petition is complete?

    Code of Federal Regulations, 2010 CFR

    2010-10-01

    ... 42 Public Health 1 2010-10-01 2010-10-01 false How will the Secretary determine whether a petition is complete? 130.33 Section 130.33 Public Health PUBLIC HEALTH SERVICE, DEPARTMENT OF HEALTH AND HUMAN SERVICES COMPASSIONATE PAYMENTS RICKY RAY HEMOPHILIA RELIEF FUND PROGRAM Procedures for Filing...

  4. 42 CFR Appendix B to Part 130 - Confidential Physician or Nurse Practitioner Affidavit

    Code of Federal Regulations, 2010 CFR

    2010-10-01

    ... 42 Public Health 1 2010-10-01 2010-10-01 false Confidential Physician or Nurse Practitioner Affidavit B Appendix B to Part 130 Public Health PUBLIC HEALTH SERVICE, DEPARTMENT OF HEALTH AND HUMAN SERVICES COMPASSIONATE PAYMENTS RICKY RAY HEMOPHILIA RELIEF FUND PROGRAM Pt. 130, App. B Appendix B to...

  5. 42 CFR 130.20 - Form of medical documentation.

    Code of Federal Regulations, 2012 CFR

    2012-10-01

    ... 42 Public Health 1 2012-10-01 2012-10-01 false Form of medical documentation. 130.20 Section 130.20 Public Health PUBLIC HEALTH SERVICE, DEPARTMENT OF HEALTH AND HUMAN SERVICES COMPASSIONATE PAYMENTS RICKY RAY HEMOPHILIA RELIEF FUND PROGRAM Documentation Required for Complete Petitions §...

  6. 42 CFR 130.30 - Who may file a petition for payment or an amendment to a petition?

    Code of Federal Regulations, 2014 CFR

    2014-10-01

    ... 42 Public Health 1 2014-10-01 2014-10-01 false Who may file a petition for payment or an amendment to a petition? 130.30 Section 130.30 Public Health PUBLIC HEALTH SERVICE, DEPARTMENT OF HEALTH AND HUMAN SERVICES COMPASSIONATE PAYMENTS RICKY RAY HEMOPHILIA RELIEF FUND PROGRAM Procedures for Filing...

  7. 42 CFR 130.34 - How will the Secretary determine whether to pay a petition?

    Code of Federal Regulations, 2010 CFR

    2010-10-01

    ... 42 Public Health 1 2010-10-01 2010-10-01 false How will the Secretary determine whether to pay a petition? 130.34 Section 130.34 Public Health PUBLIC HEALTH SERVICE, DEPARTMENT OF HEALTH AND HUMAN SERVICES COMPASSIONATE PAYMENTS RICKY RAY HEMOPHILIA RELIEF FUND PROGRAM Procedures for Filing and...

  8. 42 CFR 130.50 - Limitation on agent and attorney fees.

    Code of Federal Regulations, 2012 CFR

    2012-10-01

    ... 42 Public Health 1 2012-10-01 2012-10-01 false Limitation on agent and attorney fees. 130.50 Section 130.50 Public Health PUBLIC HEALTH SERVICE, DEPARTMENT OF HEALTH AND HUMAN SERVICES COMPASSIONATE PAYMENTS RICKY RAY HEMOPHILIA RELIEF FUND PROGRAM Attorney Fees § 130.50 Limitation on agent and...

  9. 42 CFR 130.50 - Limitation on agent and attorney fees.

    Code of Federal Regulations, 2011 CFR

    2011-10-01

    ... 42 Public Health 1 2011-10-01 2011-10-01 false Limitation on agent and attorney fees. 130.50 Section 130.50 Public Health PUBLIC HEALTH SERVICE, DEPARTMENT OF HEALTH AND HUMAN SERVICES COMPASSIONATE PAYMENTS RICKY RAY HEMOPHILIA RELIEF FUND PROGRAM Attorney Fees § 130.50 Limitation on agent and...

  10. 42 CFR 130.24 - What additional documentation may the Secretary require to resolve eligibility or payment issues?

    Code of Federal Regulations, 2010 CFR

    2010-10-01

    ... 42 Public Health 1 2010-10-01 2010-10-01 false What additional documentation may the Secretary require to resolve eligibility or payment issues? 130.24 Section 130.24 Public Health PUBLIC HEALTH SERVICE, DEPARTMENT OF HEALTH AND HUMAN SERVICES COMPASSIONATE PAYMENTS RICKY RAY HEMOPHILIA RELIEF...

  11. 42 CFR 130.24 - What additional documentation may the Secretary require to resolve eligibility or payment issues?

    Code of Federal Regulations, 2014 CFR

    2014-10-01

    ... 42 Public Health 1 2014-10-01 2014-10-01 false What additional documentation may the Secretary require to resolve eligibility or payment issues? 130.24 Section 130.24 Public Health PUBLIC HEALTH SERVICE, DEPARTMENT OF HEALTH AND HUMAN SERVICES COMPASSIONATE PAYMENTS RICKY RAY HEMOPHILIA RELIEF...

  12. 42 CFR 130.32 - How and when will the Secretary determine the order of receipt of petitions?

    Code of Federal Regulations, 2012 CFR

    2012-10-01

    ... 42 Public Health 1 2012-10-01 2012-10-01 false How and when will the Secretary determine the order of receipt of petitions? 130.32 Section 130.32 Public Health PUBLIC HEALTH SERVICE, DEPARTMENT OF HEALTH AND HUMAN SERVICES COMPASSIONATE PAYMENTS RICKY RAY HEMOPHILIA RELIEF FUND PROGRAM Procedures...

  13. 42 CFR Appendix C to Part 130 - Petition Form, Petition Instructions, and Documentation Checklist

    Code of Federal Regulations, 2011 CFR

    2011-10-01

    ... 42 Public Health 1 2011-10-01 2011-10-01 false Petition Form, Petition Instructions, and Documentation Checklist C Appendix C to Part 130 Public Health PUBLIC HEALTH SERVICE, DEPARTMENT OF HEALTH AND HUMAN SERVICES COMPASSIONATE PAYMENTS RICKY RAY HEMOPHILIA RELIEF FUND PROGRAM Pt. 130, App. C...

  14. 42 CFR 130.3 - Amount of payments.

    Code of Federal Regulations, 2010 CFR

    2010-10-01

    ... 42 Public Health 1 2010-10-01 2010-10-01 false Amount of payments. 130.3 Section 130.3 Public Health PUBLIC HEALTH SERVICE, DEPARTMENT OF HEALTH AND HUMAN SERVICES COMPASSIONATE PAYMENTS RICKY RAY HEMOPHILIA RELIEF FUND PROGRAM General Provisions § 130.3 Amount of payments. If there are sufficient...

  15. 42 CFR 130.35 - How and when will the Secretary pay a petition?

    Code of Federal Regulations, 2012 CFR

    2012-10-01

    ... 42 Public Health 1 2012-10-01 2012-10-01 false How and when will the Secretary pay a petition? 130.35 Section 130.35 Public Health PUBLIC HEALTH SERVICE, DEPARTMENT OF HEALTH AND HUMAN SERVICES COMPASSIONATE PAYMENTS RICKY RAY HEMOPHILIA RELIEF FUND PROGRAM Procedures for Filing and Paying...

  16. 42 CFR 130.3 - Amount of payments.

    Code of Federal Regulations, 2011 CFR

    2011-10-01

    ... 42 Public Health 1 2011-10-01 2011-10-01 false Amount of payments. 130.3 Section 130.3 Public Health PUBLIC HEALTH SERVICE, DEPARTMENT OF HEALTH AND HUMAN SERVICES COMPASSIONATE PAYMENTS RICKY RAY HEMOPHILIA RELIEF FUND PROGRAM General Provisions § 130.3 Amount of payments. If there are sufficient...

  17. 42 CFR Appendix C to Part 130 - Petition Form, Petition Instructions, and Documentation Checklist

    Code of Federal Regulations, 2010 CFR

    2010-10-01

    ... 42 Public Health 1 2010-10-01 2010-10-01 false Petition Form, Petition Instructions, and Documentation Checklist C Appendix C to Part 130 Public Health PUBLIC HEALTH SERVICE, DEPARTMENT OF HEALTH AND HUMAN SERVICES COMPASSIONATE PAYMENTS RICKY RAY HEMOPHILIA RELIEF FUND PROGRAM Pt. 130, App. C...

  18. 42 CFR 130.20 - Form of medical documentation.

    Code of Federal Regulations, 2010 CFR

    2010-10-01

    ... 42 Public Health 1 2010-10-01 2010-10-01 false Form of medical documentation. 130.20 Section 130.20 Public Health PUBLIC HEALTH SERVICE, DEPARTMENT OF HEALTH AND HUMAN SERVICES COMPASSIONATE PAYMENTS RICKY RAY HEMOPHILIA RELIEF FUND PROGRAM Documentation Required for Complete Petitions §...

  19. 42 CFR 130.35 - How and when will the Secretary pay a petition?

    Code of Federal Regulations, 2013 CFR

    2013-10-01

    ... 42 Public Health 1 2013-10-01 2013-10-01 false How and when will the Secretary pay a petition? 130.35 Section 130.35 Public Health PUBLIC HEALTH SERVICE, DEPARTMENT OF HEALTH AND HUMAN SERVICES COMPASSIONATE PAYMENTS RICKY RAY HEMOPHILIA RELIEF FUND PROGRAM Procedures for Filing and Paying...

  20. 42 CFR 130.3 - Amount of payments.

    Code of Federal Regulations, 2012 CFR

    2012-10-01

    ... 42 Public Health 1 2012-10-01 2012-10-01 false Amount of payments. 130.3 Section 130.3 Public Health PUBLIC HEALTH SERVICE, DEPARTMENT OF HEALTH AND HUMAN SERVICES COMPASSIONATE PAYMENTS RICKY RAY HEMOPHILIA RELIEF FUND PROGRAM General Provisions § 130.3 Amount of payments. If there are sufficient...

  1. 42 CFR 130.30 - Who may file a petition for payment or an amendment to a petition?

    Code of Federal Regulations, 2010 CFR

    2010-10-01

    ... 42 Public Health 1 2010-10-01 2010-10-01 false Who may file a petition for payment or an amendment to a petition? 130.30 Section 130.30 Public Health PUBLIC HEALTH SERVICE, DEPARTMENT OF HEALTH AND HUMAN SERVICES COMPASSIONATE PAYMENTS RICKY RAY HEMOPHILIA RELIEF FUND PROGRAM Procedures for Filing...

  2. 42 CFR 130.3 - Amount of payments.

    Code of Federal Regulations, 2014 CFR

    2014-10-01

    ... 42 Public Health 1 2014-10-01 2014-10-01 false Amount of payments. 130.3 Section 130.3 Public Health PUBLIC HEALTH SERVICE, DEPARTMENT OF HEALTH AND HUMAN SERVICES COMPASSIONATE PAYMENTS RICKY RAY HEMOPHILIA RELIEF FUND PROGRAM General Provisions § 130.3 Amount of payments. If there are sufficient...

  3. 42 CFR 130.32 - How and when will the Secretary determine the order of receipt of petitions?

    Code of Federal Regulations, 2011 CFR

    2011-10-01

    ... 42 Public Health 1 2011-10-01 2011-10-01 false How and when will the Secretary determine the order of receipt of petitions? 130.32 Section 130.32 Public Health PUBLIC HEALTH SERVICE, DEPARTMENT OF HEALTH AND HUMAN SERVICES COMPASSIONATE PAYMENTS RICKY RAY HEMOPHILIA RELIEF FUND PROGRAM Procedures...

  4. 42 CFR 130.33 - How will the Secretary determine whether a petition is complete?

    Code of Federal Regulations, 2012 CFR

    2012-10-01

    ... 42 Public Health 1 2012-10-01 2012-10-01 false How will the Secretary determine whether a petition is complete? 130.33 Section 130.33 Public Health PUBLIC HEALTH SERVICE, DEPARTMENT OF HEALTH AND HUMAN SERVICES COMPASSIONATE PAYMENTS RICKY RAY HEMOPHILIA RELIEF FUND PROGRAM Procedures for Filing...

  5. 42 CFR Appendix B to Part 130 - Confidential Physician or Nurse Practitioner Affidavit

    Code of Federal Regulations, 2013 CFR

    2013-10-01

    ... 42 Public Health 1 2013-10-01 2013-10-01 false Confidential Physician or Nurse Practitioner Affidavit B Appendix B to Part 130 Public Health PUBLIC HEALTH SERVICE, DEPARTMENT OF HEALTH AND HUMAN SERVICES COMPASSIONATE PAYMENTS RICKY RAY HEMOPHILIA RELIEF FUND PROGRAM Pt. 130, App. B Appendix B to...

  6. 42 CFR Appendix C to Part 130 - Petition Form, Petition Instructions, and Documentation Checklist

    Code of Federal Regulations, 2012 CFR

    2012-10-01

    ... 42 Public Health 1 2012-10-01 2012-10-01 false Petition Form, Petition Instructions, and Documentation Checklist C Appendix C to Part 130 Public Health PUBLIC HEALTH SERVICE, DEPARTMENT OF HEALTH AND HUMAN SERVICES COMPASSIONATE PAYMENTS RICKY RAY HEMOPHILIA RELIEF FUND PROGRAM Pt. 130, App. C...

  7. 42 CFR 130.50 - Limitation on agent and attorney fees.

    Code of Federal Regulations, 2013 CFR

    2013-10-01

    ... 42 Public Health 1 2013-10-01 2013-10-01 false Limitation on agent and attorney fees. 130.50 Section 130.50 Public Health PUBLIC HEALTH SERVICE, DEPARTMENT OF HEALTH AND HUMAN SERVICES COMPASSIONATE PAYMENTS RICKY RAY HEMOPHILIA RELIEF FUND PROGRAM Attorney Fees § 130.50 Limitation on agent and...

  8. 42 CFR 130.30 - Who may file a petition for payment or an amendment to a petition?

    Code of Federal Regulations, 2012 CFR

    2012-10-01

    ... 42 Public Health 1 2012-10-01 2012-10-01 false Who may file a petition for payment or an amendment to a petition? 130.30 Section 130.30 Public Health PUBLIC HEALTH SERVICE, DEPARTMENT OF HEALTH AND HUMAN SERVICES COMPASSIONATE PAYMENTS RICKY RAY HEMOPHILIA RELIEF FUND PROGRAM Procedures for Filing...

  9. 42 CFR 130.34 - How will the Secretary determine whether to pay a petition?

    Code of Federal Regulations, 2014 CFR

    2014-10-01

    ... 42 Public Health 1 2014-10-01 2014-10-01 false How will the Secretary determine whether to pay a petition? 130.34 Section 130.34 Public Health PUBLIC HEALTH SERVICE, DEPARTMENT OF HEALTH AND HUMAN SERVICES COMPASSIONATE PAYMENTS RICKY RAY HEMOPHILIA RELIEF FUND PROGRAM Procedures for Filing and...

  10. 42 CFR Appendix B to Part 130 - Confidential Physician or Nurse Practitioner Affidavit

    Code of Federal Regulations, 2012 CFR

    2012-10-01

    ... 42 Public Health 1 2012-10-01 2012-10-01 false Confidential Physician or Nurse Practitioner Affidavit B Appendix B to Part 130 Public Health PUBLIC HEALTH SERVICE, DEPARTMENT OF HEALTH AND HUMAN SERVICES COMPASSIONATE PAYMENTS RICKY RAY HEMOPHILIA RELIEF FUND PROGRAM Pt. 130, App. B Appendix B to...

  11. 42 CFR 130.34 - How will the Secretary determine whether to pay a petition?

    Code of Federal Regulations, 2011 CFR

    2011-10-01

    ... 42 Public Health 1 2011-10-01 2011-10-01 false How will the Secretary determine whether to pay a petition? 130.34 Section 130.34 Public Health PUBLIC HEALTH SERVICE, DEPARTMENT OF HEALTH AND HUMAN SERVICES COMPASSIONATE PAYMENTS RICKY RAY HEMOPHILIA RELIEF FUND PROGRAM Procedures for Filing and...

  12. 42 CFR 130.24 - What additional documentation may the Secretary require to resolve eligibility or payment issues?

    Code of Federal Regulations, 2011 CFR

    2011-10-01

    ... 42 Public Health 1 2011-10-01 2011-10-01 false What additional documentation may the Secretary require to resolve eligibility or payment issues? 130.24 Section 130.24 Public Health PUBLIC HEALTH SERVICE, DEPARTMENT OF HEALTH AND HUMAN SERVICES COMPASSIONATE PAYMENTS RICKY RAY HEMOPHILIA RELIEF...

  13. 42 CFR 130.3 - Amount of payments.

    Code of Federal Regulations, 2013 CFR

    2013-10-01

    ... 42 Public Health 1 2013-10-01 2013-10-01 false Amount of payments. 130.3 Section 130.3 Public Health PUBLIC HEALTH SERVICE, DEPARTMENT OF HEALTH AND HUMAN SERVICES COMPASSIONATE PAYMENTS RICKY RAY HEMOPHILIA RELIEF FUND PROGRAM General Provisions § 130.3 Amount of payments. If there are sufficient...

  14. 42 CFR 130.33 - How will the Secretary determine whether a petition is complete?

    Code of Federal Regulations, 2011 CFR

    2011-10-01

    ... 42 Public Health 1 2011-10-01 2011-10-01 false How will the Secretary determine whether a petition is complete? 130.33 Section 130.33 Public Health PUBLIC HEALTH SERVICE, DEPARTMENT OF HEALTH AND HUMAN SERVICES COMPASSIONATE PAYMENTS RICKY RAY HEMOPHILIA RELIEF FUND PROGRAM Procedures for Filing...

  15. 42 CFR 130.30 - Who may file a petition for payment or an amendment to a petition?

    Code of Federal Regulations, 2011 CFR

    2011-10-01

    ... 42 Public Health 1 2011-10-01 2011-10-01 false Who may file a petition for payment or an amendment to a petition? 130.30 Section 130.30 Public Health PUBLIC HEALTH SERVICE, DEPARTMENT OF HEALTH AND HUMAN SERVICES COMPASSIONATE PAYMENTS RICKY RAY HEMOPHILIA RELIEF FUND PROGRAM Procedures for Filing...

  16. 42 CFR 130.30 - Who may file a petition for payment or an amendment to a petition?

    Code of Federal Regulations, 2013 CFR

    2013-10-01

    ... 42 Public Health 1 2013-10-01 2013-10-01 false Who may file a petition for payment or an amendment to a petition? 130.30 Section 130.30 Public Health PUBLIC HEALTH SERVICE, DEPARTMENT OF HEALTH AND HUMAN SERVICES COMPASSIONATE PAYMENTS RICKY RAY HEMOPHILIA RELIEF FUND PROGRAM Procedures for Filing...

  17. 42 CFR 130.32 - How and when will the Secretary determine the order of receipt of petitions?

    Code of Federal Regulations, 2014 CFR

    2014-10-01

    ... 42 Public Health 1 2014-10-01 2014-10-01 false How and when will the Secretary determine the order of receipt of petitions? 130.32 Section 130.32 Public Health PUBLIC HEALTH SERVICE, DEPARTMENT OF HEALTH AND HUMAN SERVICES COMPASSIONATE PAYMENTS RICKY RAY HEMOPHILIA RELIEF FUND PROGRAM Procedures...

  18. 42 CFR 130.35 - How and when will the Secretary pay a petition?

    Code of Federal Regulations, 2010 CFR

    2010-10-01

    ... 42 Public Health 1 2010-10-01 2010-10-01 false How and when will the Secretary pay a petition? 130.35 Section 130.35 Public Health PUBLIC HEALTH SERVICE, DEPARTMENT OF HEALTH AND HUMAN SERVICES COMPASSIONATE PAYMENTS RICKY RAY HEMOPHILIA RELIEF FUND PROGRAM Procedures for Filing and Paying...

  19. 42 CFR 130.34 - How will the Secretary determine whether to pay a petition?

    Code of Federal Regulations, 2012 CFR

    2012-10-01

    ... 42 Public Health 1 2012-10-01 2012-10-01 false How will the Secretary determine whether to pay a petition? 130.34 Section 130.34 Public Health PUBLIC HEALTH SERVICE, DEPARTMENT OF HEALTH AND HUMAN SERVICES COMPASSIONATE PAYMENTS RICKY RAY HEMOPHILIA RELIEF FUND PROGRAM Procedures for Filing and...

  20. 42 CFR Appendix B to Part 130 - Confidential Physician or Nurse Practitioner Affidavit

    Code of Federal Regulations, 2011 CFR

    2011-10-01

    ... 42 Public Health 1 2011-10-01 2011-10-01 false Confidential Physician or Nurse Practitioner Affidavit B Appendix B to Part 130 Public Health PUBLIC HEALTH SERVICE, DEPARTMENT OF HEALTH AND HUMAN SERVICES COMPASSIONATE PAYMENTS RICKY RAY HEMOPHILIA RELIEF FUND PROGRAM Pt. 130, App. B Appendix B to...

  1. 42 CFR Appendix C to Part 130 - Petition Form, Petition Instructions, and Documentation Checklist

    Code of Federal Regulations, 2013 CFR

    2013-10-01

    ... 42 Public Health 1 2013-10-01 2013-10-01 false Petition Form, Petition Instructions, and Documentation Checklist C Appendix C to Part 130 Public Health PUBLIC HEALTH SERVICE, DEPARTMENT OF HEALTH AND HUMAN SERVICES COMPASSIONATE PAYMENTS RICKY RAY HEMOPHILIA RELIEF FUND PROGRAM Pt. 130, App. C...

  2. 42 CFR 130.34 - How will the Secretary determine whether to pay a petition?

    Code of Federal Regulations, 2013 CFR

    2013-10-01

    ... 42 Public Health 1 2013-10-01 2013-10-01 false How will the Secretary determine whether to pay a petition? 130.34 Section 130.34 Public Health PUBLIC HEALTH SERVICE, DEPARTMENT OF HEALTH AND HUMAN SERVICES COMPASSIONATE PAYMENTS RICKY RAY HEMOPHILIA RELIEF FUND PROGRAM Procedures for Filing and...

  3. 42 CFR 130.24 - What additional documentation may the Secretary require to resolve eligibility or payment issues?

    Code of Federal Regulations, 2013 CFR

    2013-10-01

    ... 42 Public Health 1 2013-10-01 2013-10-01 false What additional documentation may the Secretary require to resolve eligibility or payment issues? 130.24 Section 130.24 Public Health PUBLIC HEALTH SERVICE, DEPARTMENT OF HEALTH AND HUMAN SERVICES COMPASSIONATE PAYMENTS RICKY RAY HEMOPHILIA RELIEF...

  4. 42 CFR Appendix C to Part 130 - Petition Form, Petition Instructions, and Documentation Checklist

    Code of Federal Regulations, 2014 CFR

    2014-10-01

    ... 42 Public Health 1 2014-10-01 2014-10-01 false Petition Form, Petition Instructions, and Documentation Checklist C Appendix C to Part 130 Public Health PUBLIC HEALTH SERVICE, DEPARTMENT OF HEALTH AND HUMAN SERVICES COMPASSIONATE PAYMENTS RICKY RAY HEMOPHILIA RELIEF FUND PROGRAM Pt. 130, App. C...

  5. 42 CFR 130.32 - How and when will the Secretary determine the order of receipt of petitions?

    Code of Federal Regulations, 2013 CFR

    2013-10-01

    ... 42 Public Health 1 2013-10-01 2013-10-01 false How and when will the Secretary determine the order of receipt of petitions? 130.32 Section 130.32 Public Health PUBLIC HEALTH SERVICE, DEPARTMENT OF HEALTH AND HUMAN SERVICES COMPASSIONATE PAYMENTS RICKY RAY HEMOPHILIA RELIEF FUND PROGRAM Procedures...

  6. 42 CFR 130.20 - Form of medical documentation.

    Code of Federal Regulations, 2014 CFR

    2014-10-01

    ... 42 Public Health 1 2014-10-01 2014-10-01 false Form of medical documentation. 130.20 Section 130.20 Public Health PUBLIC HEALTH SERVICE, DEPARTMENT OF HEALTH AND HUMAN SERVICES COMPASSIONATE PAYMENTS RICKY RAY HEMOPHILIA RELIEF FUND PROGRAM Documentation Required for Complete Petitions §...

  7. 42 CFR 130.50 - Limitation on agent and attorney fees.

    Code of Federal Regulations, 2014 CFR

    2014-10-01

    ... 42 Public Health 1 2014-10-01 2014-10-01 false Limitation on agent and attorney fees. 130.50 Section 130.50 Public Health PUBLIC HEALTH SERVICE, DEPARTMENT OF HEALTH AND HUMAN SERVICES COMPASSIONATE PAYMENTS RICKY RAY HEMOPHILIA RELIEF FUND PROGRAM Attorney Fees § 130.50 Limitation on agent and...

  8. 42 CFR 130.24 - What additional documentation may the Secretary require to resolve eligibility or payment issues?

    Code of Federal Regulations, 2012 CFR

    2012-10-01

    ... 42 Public Health 1 2012-10-01 2012-10-01 false What additional documentation may the Secretary require to resolve eligibility or payment issues? 130.24 Section 130.24 Public Health PUBLIC HEALTH SERVICE, DEPARTMENT OF HEALTH AND HUMAN SERVICES COMPASSIONATE PAYMENTS RICKY RAY HEMOPHILIA RELIEF...

  9. 42 CFR 130.20 - Form of medical documentation.

    Code of Federal Regulations, 2013 CFR

    2013-10-01

    ... 42 Public Health 1 2013-10-01 2013-10-01 false Form of medical documentation. 130.20 Section 130.20 Public Health PUBLIC HEALTH SERVICE, DEPARTMENT OF HEALTH AND HUMAN SERVICES COMPASSIONATE PAYMENTS RICKY RAY HEMOPHILIA RELIEF FUND PROGRAM Documentation Required for Complete Petitions §...

  10. Handi Helps, 1984.

    ERIC Educational Resources Information Center

    Handi Helps, 1984

    1984-01-01

    The eight issues of Handi Helps presented in this document focus on specific issues of concern to the disabled, parents, and those working with the disabled. The two-page handi help fact sheets focus on the following topics: child abuse, leukemia, arthritis, Tourette Syndrome, hemophilia, the puppet program "Meet the New Kids on the Block" and dog…

  11. 32 CFR 80.3 - Definitions.

    Code of Federal Regulations, 2013 CFR

    2013-07-01

    ... special education and related services required by the student under this part in accordance with 32 CFR... institution not operated in accordance with 32 CFR part 345. This term includes Section 6 special contractual..., nephritis, asthma, sickle cell anemia, hemophilia, epilepsy, lead poisoning, leukemia, and diabetes....

  12. Program for the Chronically Ill.

    ERIC Educational Resources Information Center

    Schoenherr, Arline; Schnarr, Barbara

    The program for chronically ill students in the Detroit public schools is described. Forms are presented listing needed information and implications for teachers of the following conditions: diabetes, sickle cell anemia, chronic renal failure, congenital heart disease, hemophilia, rheumatoid arthritis, asthma, leukemia, and cystic fibrosis. The…

  13. 32 CFR 80.3 - Definitions.

    Code of Federal Regulations, 2014 CFR

    2014-07-01

    ... special education and related services required by the student under this part in accordance with 32 CFR... institution not operated in accordance with 32 CFR part 345. This term includes Section 6 special contractual..., nephritis, asthma, sickle cell anemia, hemophilia, epilepsy, lead poisoning, leukemia, and diabetes....

  14. 42 CFR 130.50 - Limitation on agent and attorney fees.

    Code of Federal Regulations, 2010 CFR

    2010-10-01

    ... 42 Public Health 1 2010-10-01 2010-10-01 false Limitation on agent and attorney fees. 130.50 Section 130.50 Public Health PUBLIC HEALTH SERVICE, DEPARTMENT OF HEALTH AND HUMAN SERVICES COMPASSIONATE PAYMENTS RICKY RAY HEMOPHILIA RELIEF FUND PROGRAM Attorney Fees § 130.50 Limitation on agent and...

  15. 42 CFR 51a.2 - Definitions.

    Code of Federal Regulations, 2010 CFR

    2010-10-01

    ... 42 Public Health 1 2010-10-01 2010-10-01 false Definitions. 51a.2 Section 51a.2 Public Health... CHILD HEALTH § 51a.2 Definitions. Act means the Social Security Act, as amended. Genetic diseases means.... Hemophilia means a genetically transmitted bleeding disorder resulting from a deficiency of a plasma...

  16. 42 CFR Appendix A to Part 130 - Definition of HIV Infection or HIV

    Code of Federal Regulations, 2011 CFR

    2011-10-01

    ... 42 Public Health 1 2011-10-01 2011-10-01 false Definition of HIV Infection or HIV A Appendix A to... PAYMENTS RICKY RAY HEMOPHILIA RELIEF FUND PROGRAM Pt. 130, App. A Appendix A to Part 130—Definition of HIV Infection or HIV ER31MY00.000 ER31MY00.001...

  17. 42 CFR Appendix A to Part 130 - Definition of HIV Infection or HIV

    Code of Federal Regulations, 2010 CFR

    2010-10-01

    ... 42 Public Health 1 2010-10-01 2010-10-01 false Definition of HIV Infection or HIV A Appendix A to... PAYMENTS RICKY RAY HEMOPHILIA RELIEF FUND PROGRAM Pt. 130, App. A Appendix A to Part 130—Definition of HIV Infection or HIV ER31MY00.000 ER31MY00.001...

  18. 42 CFR 414.900 - Basis and scope.

    Code of Federal Regulations, 2011 CFR

    2011-10-01

    ...) Influenza. (ii) Pneumococcal and Hepatitis B vaccines. (iii) Antigens. (iv) Hemophilia blood clotting factor...) MEDICARE PROGRAM PAYMENT FOR PART B MEDICAL AND OTHER HEALTH SERVICES Payment for Drugs and Biologicals Under Part B § 414.900 Basis and scope. (a) This subpart implements sections 1842(o), 1847A, and...

  19. 42 CFR 414.900 - Basis and scope.

    Code of Federal Regulations, 2012 CFR

    2012-10-01

    ...— (i) Influenza. (ii) Pneumococcal and Hepatitis B vaccines. (iii) Antigens. (iv) Hemophilia blood...) MEDICARE PROGRAM (CONTINUED) PAYMENT FOR PART B MEDICAL AND OTHER HEALTH SERVICES Payment for Drugs and Biologicals Under Part B § 414.900 Basis and scope. (a) This subpart implements sections 1842(o), 1847A,...

  20. 42 CFR 414.701 - Purpose.

    Code of Federal Regulations, 2011 CFR

    2011-10-01

    ... PROGRAM PAYMENT FOR PART B MEDICAL AND OTHER HEALTH SERVICES Payment for Drugs and Biologicals § 414.701... for determining the payment allowance limit for drugs and biologicals covered under Part B of Title... covered drugs, for example, influenza, pneumococcal and hepatitis vaccines, antigens, hemophilia...

  1. 42 CFR 414.900 - Basis and scope.

    Code of Federal Regulations, 2014 CFR

    2014-10-01

    ...— (i) Influenza. (ii) Pneumococcal and Hepatitis B vaccines. (iii) Antigens. (iv) Hemophilia blood...) MEDICARE PROGRAM (CONTINUED) PAYMENT FOR PART B MEDICAL AND OTHER HEALTH SERVICES Payment for Drugs and Biologicals Under Part B § 414.900 Basis and scope. (a) This subpart implements sections 1842(o), 1847A,...

  2. 21 CFR 864.7290 - Factor deficiency test.

    Code of Federal Regulations, 2010 CFR

    2010-04-01

    ... defects, to monitor certain types of therapy, to detect coagulation inhibitors, and to detect a carrier state (a person carrying both a recessive gene for a coagulation factor deficiency such as hemophilia and the corresponding normal gene). (b) Classification. Class II (performance standards)....

  3. 21 CFR 864.7290 - Factor deficiency test.

    Code of Federal Regulations, 2014 CFR

    2014-04-01

    ... defects, to monitor certain types of therapy, to detect coagulation inhibitors, and to detect a carrier state (a person carrying both a recessive gene for a coagulation factor deficiency such as hemophilia and the corresponding normal gene). (b) Classification. Class II (performance standards)....

  4. 21 CFR 864.7290 - Factor deficiency test.

    Code of Federal Regulations, 2011 CFR

    2011-04-01

    ... defects, to monitor certain types of therapy, to detect coagulation inhibitors, and to detect a carrier state (a person carrying both a recessive gene for a coagulation factor deficiency such as hemophilia and the corresponding normal gene). (b) Classification. Class II (performance standards)....

  5. 21 CFR 864.7290 - Factor deficiency test.

    Code of Federal Regulations, 2013 CFR

    2013-04-01

    ... defects, to monitor certain types of therapy, to detect coagulation inhibitors, and to detect a carrier state (a person carrying both a recessive gene for a coagulation factor deficiency such as hemophilia and the corresponding normal gene). (b) Classification. Class II (performance standards)....

  6. 21 CFR 864.7290 - Factor deficiency test.

    Code of Federal Regulations, 2012 CFR

    2012-04-01

    ... defects, to monitor certain types of therapy, to detect coagulation inhibitors, and to detect a carrier state (a person carrying both a recessive gene for a coagulation factor deficiency such as hemophilia and the corresponding normal gene). (b) Classification. Class II (performance standards)....

  7. School Absences and School Achievements in Children with Congenital Coagulation Disorders.

    ERIC Educational Resources Information Center

    Kvist, S. Beatrice M.

    1988-01-01

    Ten Finnish children (aged 7-15 years) suffering from hemophilia or von Willebrand's disease were compared with 20 healthy schoolmates with reference to scholastic achievement and school absences. It appears that despite a greater number of absences, the children affected by the disease were doing relatively well in school. (TJH)

  8. UNIVERSAL DATA COLLECTION PROJECT

    EPA Science Inventory

    CDC has created the UDC project to maintain a monitoring of the nation's blood supply for those receiving blood products as well as those experiencing hemophilia. CDC is to monitor the extent of the disease, the risk factors, and related complications in persons being treated wit...

  9. Reactions to Prenatal Testing: Reflection of Religiosity and Attitudes toward Abortion and People with Disabilities.

    ERIC Educational Resources Information Center

    Bell, Martie; Stoneman, Zolinda

    2000-01-01

    A study asked 166 undergraduates what they would do if through prenatal testing they discovered that they (or their partner) were carrying a fetus with disabilities. Respondents were more uncertain about whether to continue the pregnancy when the fetus was diagnosed with Down syndrome than with spina bifida or hemophilia. (Contains references.)…

  10. Fractional populations in sex-linked inheritance

    NASA Astrophysics Data System (ADS)

    Pyo Lee, Seung; Chung, Myung-Hoon; Koo Kim, Chul; Nahm, Kyun

    2001-03-01

    We study the fractional populations in chromosome inherited diseases. The governing equations for the fractional populations are found and solved in the presence of mutation and selection. The physical fixed points obtained are used to discuss the cases of color blindness and hemophilia.

  11. Coping Strategies of Patients with Haemophilia as a Risk Group for AIDS (Acquired Immune Deficiency Syndrome). Brief Research Report.

    ERIC Educational Resources Information Center

    Naji, Simon; And Others

    1986-01-01

    Plans are described for a 2-year project whose major focus is the identification of ways in which patients with hemophilia and their families assimilate, interpret, and act on information about Acquired Immune Deficiency Syndrome (AIDS). Findings will be related to perceived risk, anxiety levels, and the development of coping strategies.…

  12. The Role of Parental and Extrafamilial Social Support in the Psychosocial Adjustment of Children with a Chronically Ill Father.

    ERIC Educational Resources Information Center

    Kotchick, Beth A.; Summers, Peter; Forehand, Rex; Steele, Ric G.

    1997-01-01

    Examines the relation between social support and psychosocial adjustment in children of men with hemophilia. Results, based on 53 families, indicate that the impact of illness, not the severity of illness itself, related to children's psychosocial adjustment. Main effects were observed for parental support on child- and parent-reported…

  13. Strategies for Working with Culturally Diverse Communities and Clients.

    ERIC Educational Resources Information Center

    Randall-David, Elizabeth

    This guide, originally written to aid in the identification and education of ethnic minority patients with hemophilia, has been published to assist community groups in a range of educational, medical, and social service outreach efforts. It begins with two introductory chapters on ethnic identity and intergroup relations. Chapter 3 offers…

  14. School Behavior and Attendance during the First Year of Treatment for Childhood Cancer.

    ERIC Educational Resources Information Center

    Stehbens, James A.; And Others

    1983-01-01

    Investigated school behavior and attendance of children with cancer (N=36) and hemophilia (N=26). Teacher ratings of students' behavior showed no differences before and after treatment. Children with cancer were absent four times more than healthy children; absenteeism of hemophiliacs was twice the normal rate. Academic performance was negatively…

  15. 42 CFR 51a.1 - To which programs does this regulation apply?

    Code of Federal Regulations, 2010 CFR

    2010-10-01

    ... intervention training and services development); genetic disease testing, counseling and information programs; comprehensive hemophilia diagnostic and treatment centers; projects for screening and follow-up of newborns for sickle cell anemia and other genetic disorders; and special maternal and child health...

  16. 42 CFR 51a.1 - To which programs does this regulation apply?

    Code of Federal Regulations, 2011 CFR

    2011-10-01

    ... intervention training and services development); genetic disease testing, counseling and information programs; comprehensive hemophilia diagnostic and treatment centers; projects for screening and follow-up of newborns for sickle cell anemia and other genetic disorders; and special maternal and child health...

  17. 42 CFR 51a.1 - To which programs does this regulation apply?

    Code of Federal Regulations, 2012 CFR

    2012-10-01

    ... intervention training and services development); genetic disease testing, counseling and information programs; comprehensive hemophilia diagnostic and treatment centers; projects for screening and follow-up of newborns for sickle cell anemia and other genetic disorders; and special maternal and child health...

  18. 42 CFR 51a.1 - To which programs does this regulation apply?

    Code of Federal Regulations, 2014 CFR

    2014-10-01

    ... intervention training and services development); genetic disease testing, counseling and information programs; comprehensive hemophilia diagnostic and treatment centers; projects for screening and follow-up of newborns for sickle cell anemia and other genetic disorders; and special maternal and child health...

  19. 42 CFR 51a.1 - To which programs does this regulation apply?

    Code of Federal Regulations, 2013 CFR

    2013-10-01

    ... intervention training and services development); genetic disease testing, counseling and information programs; comprehensive hemophilia diagnostic and treatment centers; projects for screening and follow-up of newborns for sickle cell anemia and other genetic disorders; and special maternal and child health...

  20. 42 CFR Appendix A to Part 130 - Definition of HIV Infection or HIV

    Code of Federal Regulations, 2012 CFR

    2012-10-01

    ... 42 Public Health 1 2012-10-01 2012-10-01 false Definition of HIV Infection or HIV A Appendix A to... PAYMENTS RICKY RAY HEMOPHILIA RELIEF FUND PROGRAM Pt. 130, App. A Appendix A to Part 130—Definition of HIV Infection or HIV ER31MY00.000 ER31MY00.001...

  1. 42 CFR Appendix A to Part 130 - Definition of HIV Infection or HIV

    Code of Federal Regulations, 2014 CFR

    2014-10-01

    ... 42 Public Health 1 2014-10-01 2014-10-01 false Definition of HIV Infection or HIV A Appendix A to... PAYMENTS RICKY RAY HEMOPHILIA RELIEF FUND PROGRAM Pt. 130, App. A Appendix A to Part 130—Definition of HIV Infection or HIV ER31MY00.000 ER31MY00.001...

  2. 42 CFR Appendix A to Part 130 - Definition of HIV Infection or HIV

    Code of Federal Regulations, 2013 CFR

    2013-10-01

    ... 42 Public Health 1 2013-10-01 2013-10-01 false Definition of HIV Infection or HIV A Appendix A to... PAYMENTS RICKY RAY HEMOPHILIA RELIEF FUND PROGRAM Pt. 130, App. A Appendix A to Part 130—Definition of HIV Infection or HIV ER31MY00.000 ER31MY00.001...

  3. Challenges in the Evaluation for Possible Abuse: Presentations of Congenital Bleeding Disorders in Childhood

    ERIC Educational Resources Information Center

    Jackson, Jami; Carpenter, Shannon; Anderst, Jim

    2012-01-01

    Objectives: To describe children with congenital bleeding disorders that present in a manner that may be concerning for non-accidental trauma (NAT), and to evaluate associations with disease and demographic characteristics. Methods: Ten year retrospective charts of subjects were reviewed at a Hemophilia Treatment Center. Demographic, historical,…

  4. 34 CFR 369.4 - What definitions apply to these programs?

    Code of Federal Regulations, 2013 CFR

    2013-07-01

    ... PROJECTS General § 369.4 What definitions apply to these programs? (a) The following definitions in 34 CFR... disabilities resulting from amputation, arthritis, autism, blindness, burn injury, cancer, cerebral palsy, cystic fibrosis, deafness, head injury, heart disease, hemiplegia, hemophilia, respiratory or...

  5. 34 CFR 385.4 - What definitions apply to these programs?

    Code of Federal Regulations, 2012 CFR

    2012-07-01

    ... § 385.4 What definitions apply to these programs? (a) The following definitions in 34 CFR part 77 apply... resulting from amputation, arthritis, autism, blindness, burn injury, cancer, cerebral palsy, cystic fibrosis, deafness, head injury, heart disease, hemiplegia, hemophilia, respiratory or...

  6. 34 CFR 385.4 - What definitions apply to these programs?

    Code of Federal Regulations, 2011 CFR

    2011-07-01

    ... § 385.4 What definitions apply to these programs? (a) The following definitions in 34 CFR part 77 apply... resulting from amputation, arthritis, autism, blindness, burn injury, cancer, cerebral palsy, cystic fibrosis, deafness, head injury, heart disease, hemiplegia, hemophilia, respiratory or...

  7. 34 CFR 369.4 - What definitions apply to these programs?

    Code of Federal Regulations, 2010 CFR

    2010-07-01

    ... PROJECTS General § 369.4 What definitions apply to these programs? (a) The following definitions in 34 CFR... disabilities resulting from amputation, arthritis, autism, blindness, burn injury, cancer, cerebral palsy, cystic fibrosis, deafness, head injury, heart disease, hemiplegia, hemophilia, respiratory or...

  8. 34 CFR 369.4 - What definitions apply to these programs?

    Code of Federal Regulations, 2011 CFR

    2011-07-01

    ... PROJECTS General § 369.4 What definitions apply to these programs? (a) The following definitions in 34 CFR... disabilities resulting from amputation, arthritis, autism, blindness, burn injury, cancer, cerebral palsy, cystic fibrosis, deafness, head injury, heart disease, hemiplegia, hemophilia, respiratory or...

  9. 34 CFR 385.4 - What definitions apply to these programs?

    Code of Federal Regulations, 2014 CFR

    2014-07-01

    ... § 385.4 What definitions apply to these programs? (a) The following definitions in 34 CFR part 77 apply... resulting from amputation, arthritis, autism, blindness, burn injury, cancer, cerebral palsy, cystic fibrosis, deafness, head injury, heart disease, hemiplegia, hemophilia, respiratory or...

  10. 34 CFR 385.4 - What definitions apply to these programs?

    Code of Federal Regulations, 2010 CFR

    2010-07-01

    ... § 385.4 What definitions apply to these programs? (a) The following definitions in 34 CFR part 77 apply... resulting from amputation, arthritis, autism, blindness, burn injury, cancer, cerebral palsy, cystic fibrosis, deafness, head injury, heart disease, hemiplegia, hemophilia, respiratory or...

  11. 34 CFR 369.4 - What definitions apply to these programs?

    Code of Federal Regulations, 2014 CFR

    2014-07-01

    ... PROJECTS General § 369.4 What definitions apply to these programs? (a) The following definitions in 34 CFR... disabilities resulting from amputation, arthritis, autism, blindness, burn injury, cancer, cerebral palsy, cystic fibrosis, deafness, head injury, heart disease, hemiplegia, hemophilia, respiratory or...

  12. 34 CFR 369.4 - What definitions apply to these programs?

    Code of Federal Regulations, 2012 CFR

    2012-07-01

    ... PROJECTS General § 369.4 What definitions apply to these programs? (a) The following definitions in 34 CFR... disabilities resulting from amputation, arthritis, autism, blindness, burn injury, cancer, cerebral palsy, cystic fibrosis, deafness, head injury, heart disease, hemiplegia, hemophilia, respiratory or...

  13. 34 CFR 385.4 - What definitions apply to these programs?

    Code of Federal Regulations, 2013 CFR

    2013-07-01

    ... § 385.4 What definitions apply to these programs? (a) The following definitions in 34 CFR part 77 apply... resulting from amputation, arthritis, autism, blindness, burn injury, cancer, cerebral palsy, cystic fibrosis, deafness, head injury, heart disease, hemiplegia, hemophilia, respiratory or...

  14. Dental management of hemophiliac child under general anesthesia.

    PubMed

    Rayen, R; Hariharan, V S; Elavazhagan, N; Kamalendran, N; Varadarajan, R

    2011-01-01

    Hemophilia is the most common inherited bleeding disorder. Hemophilic patients should be cosidered as special patients. There is no contraindication to general dental treatment for hemophiliacs, as they generally do not involve bleeding. But caution must be used with any surgical procedures that involve the local and general anesthesia. Such patients should always be managed in the setting of specialized units with appropriate clinical expertise and laboratory support. Recent advances in the management of hemophilia have enabled many hemophiliac patients to receive surgical dental procedures in an outpatient dental care on a routine basis. The purpose of this case report is to provide a few management strategies when providing full mouth rehabilitation under anesthesia and replacement therapies that are available. In addition, overviews of possible complication that may be encountered when providing such treatment are discussed here. PMID:21521925

  15. SK-HEP cells and lentiviral vector for production of human recombinant factor VIII.

    PubMed

    da Rosa, Nathalia Gonsales; Swiech, Kamilla; Picanço-Castro, Virgínia; Russo-Carbolante, Elisa Maria de Sousa; Soares Neto, Mario Abreu; de Castilho-Fernandes, Andrielle; Faça, Vitor Marcel; Fontes, Aparecida Maria; Covas, Dimas Tadeu

    2012-08-01

    Hemophilia A is caused by a deficiency in coagulation factor VIII. Recombinant factor VIII can be used as an alternative although it is unavailable for most patients. Here, we describe the production of a human recombinant B-domain-deleted FVIII (rBDDFVIII) by the human cell line SK-HEP-1, modified by a lentiviral vector rBDDFVIII was produced by recombinant SK-HEP cells (rSK-HEP) at 1.5-2.1 IU/10(6) in 24 h. The recombinant factor had increased in vitro stability when compared to commercial pdFVIII. The functionality of rBDDFVIII was shown by its biological activity and by tail-clip challenge in hemophilia A mice. The rSK-HEP cells grew in a scalable system and produced active rBDDFVIII, indicating that this platform production can be optimized to meet the commercial production scale needs. PMID:22488441

  16. A consortium for purchase of blood products directed by physicians.

    PubMed

    Aledort, L M; Lipton, R A; Hilgartner, M

    1988-05-01

    Clotting-factor therapy is a costly part of comprehensive hemophilia treatment. Physicians treating patients with hemophilia in New York formed a consortium for the purchasing and regional distribution of clotting-factor concentrates. Concentrates are centrally purchased based on a bidding formula aimed at obtaining the lowest price for quality product while guaranteeing all suppliers continued involvement in a large market area. The consortium has successfully maintained, and, in instances, lowered prices each year. Estimated regional savings this year are more than $750,000 for an anticipated purchase of approximately 60,00,000 units of clotting-factors VIII and IX. Central distribution has additionally lowered costs to participating hospitals. The consortium is able to provide patients and third-party payers with some of the lowest prices for clotting-factor concentrates in the United States. A physician-directed regional approach to purchasing costly medical products might be applied to other areas of clinical medicine. PMID:3358574

  17. [Hemorrhagic congenital diseases: What can be the future of plasma-derived products against recombinants?].

    PubMed

    Schved, J-F

    2015-08-01

    Until 1990, congenital hemorrhagic disorders were treated by plasma-derived concentrates. The first recombinant drug, recombinant factor VIII was available after this date and few years later recombinant factor IX could also be proposed to patients. The evolution of market share in France was different between these two drugs: while recombinant factor VIII took a large place in hemophilia A treatment (85%), plasma-derived factor IX represent 50% of the French market. In the next years, the arrival of long-acting antihemophilic factors may lead to the dramatically reduce the amount of plasma-derived antihemophilic factors used to treat hemophilia. For rare bleeding coagulation disorders, plasma-derived concentrates are still widely used, while they are the only concentrates available in most diseases. This situation is unlikely to evolve significantly in the next years. PMID:25933512

  18. How I treat patients with inherited bleeding disorders who need anticoagulant therapy.

    PubMed

    Martin, Karlyn; Key, Nigel S

    2016-07-14

    Situations that ordinarily necessitate consideration of anticoagulation, such as arterial and venous thrombotic events and prevention of stroke in atrial fibrillation, become challenging in patients with inherited bleeding disorders such as hemophilia A, hemophilia B, and von Willebrand disease. There are no evidence-based guidelines to direct therapy in these patients, and management strategies that incorporate anticoagulation must weigh a treatment that carries a risk of hemorrhage in a patient who is already at heightened risk against the potential consequences of not treating the thrombotic event. In this paper, we review atherothrombotic disease, venous thrombotic disease, and atrial fibrillation in patients with inherited bleeding disorders, and discuss strategies for using anticoagulants in this population using cases to illustrate these considerations. PMID:27106121

  19. How I treat patients with inherited bleeding disorders who need anticoagulant therapy

    PubMed Central

    Martin, Karlyn

    2016-01-01

    Situations that ordinarily necessitate consideration of anticoagulation, such as arterial and venous thrombotic events and prevention of stroke in atrial fibrillation, become challenging in patients with inherited bleeding disorders such as hemophilia A, hemophilia B, and von Willebrand disease. There are no evidence-based guidelines to direct therapy in these patients, and management strategies that incorporate anticoagulation must weigh a treatment that carries a risk of hemorrhage in a patient who is already at heightened risk against the potential consequences of not treating the thrombotic event. In this paper, we review atherothrombotic disease, venous thrombotic disease, and atrial fibrillation in patients with inherited bleeding disorders, and discuss strategies for using anticoagulants in this population using cases to illustrate these considerations. PMID:27106121

  20. Hematology Expert System (HES) For Tonsillectomy/Adenoidectomy Patients

    NASA Astrophysics Data System (ADS)

    Pizzi, Nicolino J.; Kapoor, Sandhya; Gerrard, Jon M.

    1989-03-01

    The purpose of this expert system is to assess a predisposition to bleeding in a patient undergoing a tonsillectomy and/or adenoidectomy as may occur with patients who have certain blood conditions such as hemophilia and von Willebrand's disease. This goal is achieved by establishing a correlation between the patients' responses to a medical questionnaire and the relative quantities of blood lost during the operation.

  1. Advances in gene technology: Human genetic disorders

    SciTech Connect

    Scott, W.A.; Ahmad, F.; Black, S.; Schultz, J.; Whelan, W.J.

    1984-01-01

    This book discusses the papers presented at the conference on the subject of ''advances in Gene technology: Human genetic disorders''. Molecular biology of various carcinomas and inheritance of metabolic diseases is discussed and technology advancement in diagnosis of hereditary diseases is described. Some of the titles discussed are-Immunoglobulin genes translocation and diagnosis; hemophilia; oncogenes; oncogenic transformations; experimental data on mice, hamsters, birds carcinomas and sarcomas.

  2. Transfusion medicine

    SciTech Connect

    Murawski, K.; Peetoom, F.

    1986-01-01

    These proceedings contain 24 selections, including papers presented at the conference of American Red Cross held in May 1985, on the Subject of transfusion medicine. Some of the titles are: Fluosol/sup R/-DA in Radiation Therapy; Expression of Cloned Human Factor VIII and the Molecular Basis of Gene Defects that Cause Hemophilia; DNA-Probing Assay in the Detection of Hepatitis B Virus Genome in Human Peripheral Blood Cells; and Monoclonal Antibodies: Convergence of Technology and Application.

  3. The current clinical revolution. Applications of gene therapy in treatment of disease.

    PubMed

    Worden, M

    1994-05-01

    A major technological revolution is on the horizon that promises cures for inherited diseases such as cystic fibrosis, sickle cell anemia, muscular dystrophy, hemophilia, leukocyte-adhesion deficiency, and Gaucher's disease. This revolutionary technology also promises effective treatments for acquired diseases such as cancer and AIDS. The technique is gene therapy and it has already been used in humans. Some applications raise ethical considerations that not only affect the individual who is treated but have implications for future generations as well. PMID:10134065

  4. Balloon Catheter Delivery of Helper-dependent Adenoviral Vector Results in Sustained, Therapeutic hFIX Expression in Rhesus Macaques

    PubMed Central

    Brunetti-Pierri, Nicola; Liou, Aimee; Patel, Priti; Palmer, Donna; Grove, Nathan; Finegold, Milton; Piccolo, Pasquale; Donnachie, Elizabeth; Rice, Karen; Beaudet, Arthur; Mullins, Charles; Ng, Philip

    2012-01-01

    Hemophilia B is an excellent candidate for gene therapy because low levels of factor IX (FIX) (≥1%) result in clinically significant improvement of the bleeding diathesis. Helper-dependent adenoviral (HDAd) vectors can mediate long-term transgene expression without chronic toxicity. To determine the potential for HDAd-mediated liver-directed hemophilia B gene therapy, we administered an HDAd expressing hFIX into rhesus macaques through a novel and minimally invasive balloon occlusion catheter-based method that permits preferential, high-efficiency hepatocyte transduction with low, subtoxic vector doses. Animals given 1 × 1012 and 1 × 1011 virus particle (vp)/kg achieved therapeutic hFIX levels for the entire observation period (up to 1,029 days). At 3 × 1010 and 1 × 1010 vp/kg, only subtherapeutic hFIX levels were achieved which were not sustained long-term. Balloon occlusion administration of HDAd was well tolerated with negligible toxicity. Five of six animals developed inhibitors to hFIX. These results provide important information in assessing the clinical utility of HDAd for hemophilia B gene therapy. PMID:22828499

  5. Meeting the emerging public health needs of persons with blood disorders.

    PubMed

    Parker, Christopher S; Tsai, James; Siddiqi, Azfar-e-Alam; Atrash, Hani K; Richardson, Lisa C

    2014-11-01

    In its decades-long history, the Division of Blood Disorders (DBD) at CDC has evolved from a patient-focused, services-supporting entity at inception, to one of the world leaders in the practice of public health to improve the lives of people at risk for or affected by nonmalignant blood disorders. The DBD's earliest public health activities consisted of working with care providers in a network of hemophilia treatment centers to provide AIDS risk reduction services to people with hemophilia. Because this infectious disease threat has been reduced over time as a result of the development of safer treatment products, the DBD--under the auspices of congressional appropriations guidance--has expanded its core activities to encompass blood disorders other than hemophilia, including hemoglobinopathies such as thalassemia and sickle cell disease, and Diamond Blackfan anemia. Simultaneously, in transitioning to a greater public health role, the DBD has expanded its network of partners to new consumer and professional organizations, as well as state and other federal health agencies. The DBD has also developed and maintains many surveillance and registry activities beyond the Universal Data Collection system aimed at providing a better understanding of the health status, health needs, and health-related quality of life of people with nonmalignant blood disorders. The DBD has integrated applicable components of the Essential Services of Public Health successfully to promote and advance the agenda of blood disorders in public health. PMID:25245797

  6. Treatment of Hemophilic Ankle Arthropathy with One-Step Arthroscopic Bone Marrow–Derived Cells Transplantation

    PubMed Central

    Buda, Roberto; Cavallo, Marco; Cenacchi, Annarita; Natali, Simone; Vannini, Francesca; Giannini, Sandro

    2015-01-01

    Objective Ankle arthropathy is a frequent and invalidating manifestation of hemophilia. Arthrodesis is the gold standard surgical procedure in end-stage disease, with many drawbacks in young patients. Recent literature has shown increase interest in regenerative procedures in hemophilic arthropathy, which may be desirable to delay or even avoid arthrodesis. The aim of this article is to present five cases of osteochondral lesions in ankle hemophilic arthropathy treated with a regenerative procedure: bone marrow–derived cells transplantation (BMDCT). Design We report five hemophilic patients (four cases with hemophilia type A; one case with hemophilia type B) who have undergone BMDCT treatment, synovectomy, and arthroscopic debridement, with the use of autologous platelet-rich fibrin, to treat osteochondral lesions in hemophilic ankle arthropathy. The patients, included within this retrospective study, were clinically and radiologically evaluated with serial follow-ups, using the American Orthopaedic Foot and Ankle Society (AOFAS) scores, radiographs, and magnetic resonance imaging (MRI). Results The mean preoperative AOFAS score was 35. After a mean follow-up of 2 years, the mean postoperative AOFAS score was 81, which included three patients returning back to sporting activities. The MRI Mocart score demonstrated signs of regeneration of chondral and bony tissue. No progression of joint degeneration was shown radiographically. Conclusion BMDCT is a promising regenerative treatment for osteochondral lesions in mild ankle hemophilic arthropathy, which may be useful to delay or even avoid ankle arthrodesis. Nevertheless, longer follow-ups and a larger case series are required. PMID:26175860

  7. Engineered antigen-specific human regulatory T cells: immunosuppression of FVIII-specific T- and B-cell responses

    PubMed Central

    Kim, Yong Chan; Zhang, Ai-Hong; Su, Yan; Rieder, Sadiye Amcaoglu; Rossi, Robert J.; Ettinger, Ruth A.; Pratt, Kathleen P.; Shevach, Ethan M.

    2015-01-01

    Expansion of human regulatory T cells (Tregs) for clinical applications offers great promise for the treatment of undesirable immune responses in autoimmunity, transplantation, allergy, and antidrug antibody responses, including inhibitor responses in hemophilia A patients. However, polyclonal Tregs are nonspecific and therefore could potentially cause global immunosuppression. To avoid this undesirable outcome, the generation of antigen-specific Tregs would be advantageous. Herein, we report the production and properties of engineered antigen-specific Tregs, created by transduction of a recombinant T-cell receptor obtained from a hemophilia A subject’s T-cell clone, into expanded human FoxP3+ Tregs. Such engineered factor VIII (FVIII)-specific Tregs efficiently suppressed the proliferation and cytokine production of FVIII-specific T-effector cells. Moreover, studies with an HLA-transgenic, FVIII-deficient mouse model demonstrated that antibody production from FVIII-primed spleen cells in vitro were profoundly inhibited in the presence of these FVIII-specific Tregs, suggesting potential utility to treat anti-FVIII inhibitory antibody formation in hemophilia A patients. PMID:25498909

  8. Characterization of five partial deletions of the factor VIII gene

    SciTech Connect

    Youssoufian, H.; Antonarakis, S.E.; Aronis, S.; Tsiftis, G.; Phillips, D.G.; Kazazian, H.H. Jr.

    1987-06-01

    Hemophilia A is an X-linked disorder of coagulation caused by a deficiency of factor VIII. By using cloned DNA probes, the authors have characterized the following five different partial deletions of the factor VIII gene from a panel of 83 patients with hemophilia A: (i) a 7-kilobase (kb) deletion that eliminates exon 6; (ii) a 2.5-kb deletion that eliminates 5' sequences of exon 14; (iii) a deletion of at least 7 kb that eliminates exons 24 and 25; (iv) a deletion of at least 16 kb that eliminates exons 23-25; and (v) a 5.5-kb deletion that eliminates exon 22. The first four deletions are associated with severe hemophilia A. By contrast, the last deletion is associated with moderate disease, possibly because of in-frame splicing from adjacent exons. None of those patients with partial gene deletions had circulating inhibitors to factor VIII. One deletion occurred de novo in a germ cell of the maternal grandmother, while a second deletion occurred in a germ cell of the maternal grandfather. These observations demonstrate that de novo deletions of X-linked genes can occur in either male or female gametes.

  9. Mutations and a polymorphism in the factor VIII gene discovered by denaturing gradient gel electrophoresis

    SciTech Connect

    Kogan, S.; Gitschier, J. )

    1990-03-01

    Hemophilia A results from mutations in the gene coding for coagulation factor VIII. The authors gradient gel electrophoresis to screen for mutations in the region of the factor VIII gene coding for the first acidic domain. Amplification primers were designed employing the MELTMAP computer program to optimize the ability to detect mutations. Screening of amplified DNA from 228 unselected hemophilia A patients revealed two mutations and one polymorphism. Rescreening the same population by making heteroduplexes between amplified patient and control samples prior to electrophoresis revealed one additional mutation. The mutations include two missense and one 4-base-pair deletion, and each mutation was found in patients with severe hemophilia. The polymorphism, located adjacent to the adenine branch site in intron 7, is useful for genetic prediction in some cases where the Bcl I and Xba I polymorphisms are uninformative. These results suggest that DNA amplification and denaturing gradient gel electrophoresis should be an excellent strategy for identifying mutations and polymorphisms in defined regions of the factor VIII gene and other large genes.

  10. Intracerebellar haemorrage in a haemophilia child

    PubMed Central

    Senapati, Satya Bhusan; Mishra, Sudhansu Sekhar; Dhir, Manmath Kumar; Das, Srikanta

    2016-01-01

    Hemophilia A is an inherited, X-linked, recessive disorder caused by deficiency of clotting factor VIII. Intracranial hemorrhage is the leading cause of morbidity and mortality in these patients. Use of factor replacement products and medications had improved outcome in these patients. But in developing countries many such patients are not able to afford factor replacement products. We report a case of traumatic intracerebellar hemorrage in a hemophilia child. This child presented to us as a case of sub-acute intracerebellar hemorrage, he was managed conservatively with six units of fresh frozen plasma transfusion. He improved clinically and on follow-up investigation hematoma was found to have dissolved spontaneously. Through this report we want to emphasize that those cases of hemophilia presenting with acute or sub-acute intracranial bleed, conservative approach through procoagulant transfusion and intravenous fibrinolysis inhibitors should be tried as first line of management. Before daring for surgery sufficient amount of factor replacement should be kept available. PMID:27057240

  11. Prolonged activity of factor IX as a monomeric Fc fusion protein.

    PubMed

    Peters, Robert T; Low, Susan C; Kamphaus, George D; Dumont, Jennifer A; Amari, John V; Lu, Qi; Zarbis-Papastoitsis, Greg; Reidy, Thomas J; Merricks, Elizabeth P; Nichols, Timothy C; Bitonti, Alan J

    2010-03-11

    Treatment of hemophilia B requires frequent infusions of factor IX (FIX) to prophylax against bleeding episodes. Hemophilia B management would benefit from a FIX protein with an extended half-life. A recombinant fusion protein (rFIXFc) containing a single FIX molecule attached to the Fc region of immunoglobulin G was administered intravenously and found to have an extended half-life, compared with recombinant FIX (rFIX) in normal mice, rats, monkeys, and FIX-deficient mice and dogs. Recombinant FIXFc protein concentration was determined in all species, and rFIXFc activity was measured in FIX-deficient animals. The half-life of rFIXFc was approximately 3- to 4-fold longer than that of rFIX in all species. In contrast, in mice in which the neonatal Fc receptor (FcRn) was deleted, the half-life of rFIXFc was similar to rFIX, confirming the increased circulatory time was due to protection of the rFIXFc via the Fc/FcRn interaction. Whole blood clotting time in FIX-deficient mice was corrected through 144 hours for rFIXFc, compared with 72 hours for rFIX; similar results were observed in FIX-deficient dogs. Taken together, these studies show the enhanced pharmacodynamic and pharmacokinetic properties of the rFIXFc fusion protein and provide the basis for evaluating rFIXFc in patients with hemophilia B. PMID:20056791

  12. Hemophilic arthropathy of the elbow: prophylaxis, imaging, and the role of invasive management.

    PubMed

    Dale, Timothy M; Saucedo, James M; Rodríguez-Merchán, E Carlos

    2015-10-01

    Hemophilia is an X-linked recessive deficiency of clotting factor VIII (hemophilia A) or IX (hemophilia B) that can result in hemarthrosis of various joints, including the elbow. Left unchecked, this can lead to progressive joint destruction and significant morbidity. Appropriate management of the elbow joint through prophylactic measures, accurate imaging, and timely intervention is essential. Replacing or supplementing deficient factor with a plasma-derived or recombinant factor concentrate can minimize bleeding episodes. Joints should be routinely monitored for damage. Plain films offer an inexpensive window into bone disease and joint space changes but lack soft tissue detail and may not detect early changes. Magnetic resonance imaging provides a high level of detail but may be limited by its cost and need for sedation in younger patients. Ultrasound may not achieve the same level of resolution as magnetic resonance imaging, but it is increasingly used as a convenient, effective, and relatively inexpensive alternative. Patients who experience hemarthrosis of the elbow with joint damage often require more invasive treatment. Radiosynovectomy and arthroscopic synovectomy are effective at minimizing pain and preventing future bleeding episodes, whereas extensive joint damage may necessitate total elbow replacement. PMID:26385390

  13. Desensitization and immune tolerance induction in children with severe factor IX deficiency; inhibitors and adverse reactions to replacement therapy: a case-report and literature review.

    PubMed

    Bon, Andrea; Morfini, Massimo; Dini, Alessandro; Mori, Francesca; Barni, Simona; Gianluca, Sottilotta; de Martino, Maurizio; Novembre, Elio

    2015-01-01

    Hemophilia B is a rare X-linked recessive disorder with plasma factor IX (FIX) deficiency. 1-3% of patients treated with exogenous FIX-containing products develop inhibitors (i.e. polyclonal high affinity immunoglobulins) that neutralize the procoagulant activity of a specific coagulation factor. Although the incidence of inhibitors in hemophilia B patients is low, most are "high titer" and frequently associated with the development of severe allergic or anaphylactic reactions. Immune tolerance induction as a strategy for inhibitor eradication was first described in 1984. Unfortunately, the overall reported success of immune tolerance induction in FIX deficiency with inhibitors is approximately 25-40%.We report the case of a 2-year-old boy with hemophilia B severe FIX deficiency (<1%), inhibitor antibodies to FIX development, and a history of adverse reactions to FIX infusions, who underwent a successful desensitization and immune tolerance induction with a daily FIX infusion. With this regimen the inhibitor titer decreased with effective bleeding prevention. PMID:25887512

  14. Enhanced Pharmacokinetics of Factor VIIa as a Monomeric Fc Fusion.

    PubMed

    Salas, Joe; Liu, Tongyao; Lu, Qi; Kulman, John D; Ashworth, Tamera; Kistanova, Elena; Moore, Nancy; Pierce, Glenn F; Jiang, Haiyan; Peters, Robert

    2015-05-01

    Recombinant Factor VIIa (rFVIIa) is utilized for on-demand treatment of bleeding episodes in hemophilia patients with neutralizing antibodies (inhibitors) against Factor VIII or Factor IX, but a short half-life in the circulation (~2.5hrs) limits its use in a prophylactic setting. Recombinant FVIIa variants with improved pharmacokinetic properties may enable improved treatment and prevention of bleeding episodes in the inhibitor population. In this study we describe recombinant FVIIaFc (rFVIIaFc), a recombinant Fc-fusion protein generated to utilize the neonatal Fc receptor (FcRn)-mediated recycling pathway that protects immunoglobulin G from catabolism. On the basis of activity, rFVIIaFc exhibited a 5.5-fold extension in terminal half-life in hemophilia A mice compared to rFVIIa. The potency of rFVIIaFc was comparable to that of rFVIIa in thrombin generation assay and ROTEM. In agreement with these data, rFVIIaFc and rFVIIa showed similar acute efficacy at comparable molar doses in the tail clip bleeding model in hemophilia A mice. Taken together, these studies demonstrate enhanced pharmacokinetics and similar hemostatic properties for rFVIIaFc compared to rFVIIa. PMID:25721936

  15. Antigenic liposomes displaying CD22 ligands induce antigen-specific B cell apoptosis

    PubMed Central

    Macauley, Matthew S.; Pfrengle, Fabian; Rademacher, Christoph; Nycholat, Corwin M.; Gale, Andrew J.; von Drygalski, Annette; Paulson, James C.

    2013-01-01

    Antibodies confer humoral immunity but can also be harmful when they target an autoantigen, alloantigen, allergen, or biotherapeutic. New strategies are needed for antigen-specific suppression of undesired antibody responses, particularly to T cell–dependent protein antigens, because they elicit T cell help. Here we show that liposomal nanoparticles, displaying both antigen and glycan ligands of the inhibitory coreceptor CD22, induce a tolerogenic program that selectively causes apoptosis in mouse and human B cells. These SIGLEC-engaging tolerance-inducing antigenic liposomes (STALs, where SIGLEC is defined as sialic acid–binding Ig-like lectin) induced robust antigen-specific tolerance to protein antigens in mice, preventing subsequent immune response to challenge with the same antigen. Since development of inhibitory antibodies to FVIII is a serious problem in treatment of hemophilia A patients, we investigated the potential of this approach for inducing tolerance to FVIII in a hemophilia mouse model. STALs prevented formation of inhibitory FVIII antibodies, allowing for effective administration of FVIII to hemophilia mice to prevent bleeding. These findings suggest that STALs could be used to eliminate or prevent harmful B cell–mediated immune responses. PMID:23722906

  16. Stable and high-level production of recombinant Factor IX in human hepatic cell line.

    PubMed

    de Castilho Fernandes, Andrielle; Fontes, Aparecida; Gonsales, Nathalia; Swiech, Kamilla; Picanco-Castro, Virginia; Faca, Sandra; Covas, Dimas

    2011-01-01

    Hemophilia B is a genetic disease of the coagulation system that affects one in 30,000 males worldwide. Recombinant human Factor IX (rhFIX) has been used for hemophilia B treatment, but the amount of active protein generated by these systems is inefficient, resulting in a high-cost production of rhFIX. In this study, we developed an alternative for rhFIX production. We used a retrovirus system to obtain two recombinant cell lines. We first tested rhFIX production in the human embryonic kidney 293 cells (293). Next, we tested a hepatic cell line (HepG2) because FIX is primarily expressed in the liver. Our results reveal that intracellular rhFIX expression was more efficient in HepG2/rhFIX (46%) than in 293/rhFIX (21%). The activated partial thromboplastin time test showed that HepG2/rhFIX expressed biologically active rhFIX 1.5 times higher than 293/rhFIX (P = 0.016). Recovery of rhFIX from the HepG2 by reversed-phase chromatography was straightforward. We found that rhFIX has a pharmacokinetic profile similar to that of FIX purified from human plasma when tested in hemophilic B model. HepG2/rhFIX cell line produced the highest levels of rhFIX, representing an efficient in vitro expression system. This work opens up the possibility of significantly reducing the costs of rhFIX production, with implications for expanding hemophilia B treatment in developing countries. PMID:21838798

  17. Bispecific antibody mimicking factor VIII.

    PubMed

    Nogami, Keiji

    2016-05-01

    There are some issues in the current factor (F)VIII replacement therapy for severe hemophilia A. One is mental and physical burden for the multiple intravenous infusions, and the other is difficulty in the hemostatic treatment for the patients with FVIII inhibitor. The development of novel drug with fully hemostatic effect, simply procedure, and long-acting reaction has been expected. Recently, FVIIIa-mimicking humanized recombinant bispecific antibody (ACE910) against FIXa and FX was developed. In the non-human clinical study, primate model of acquired hemophilia A demonstrated that the ACE910 was effective on both on-going and spontaneous bleedings. A phase I clinical study was conducted in healthy adults by single subcutaneous infusion of ACE910, followed by the patients' part study, Japanese patients with severe hemophilia A without or with inhibitor were treated with once-weekly subcutaneous injection of ACE910 at three dose levels for 12 successive weeks. There was no significant adverse event related to ACE910 in the clinical and laboratorial findings, and t1/2 of ACE910 was ∼30 days. The median annual bleeding rates were reduced very markedly dose-dependently, independently of inhibitor. Furthermore, among the patients with dose escalation, bleeding rate was decreased as ACE910 dose was increased. In conclusion, ACE910 would have a number of promising features: its high subcutaneous bioavailability and long half-life make the patients possible to be injected subcutaneously with a once-a-week or less frequency. In addition, ACE910 would provide the bleeding prophylactic efficacy, independently of inhibitor. PMID:27207420

  18. [Attitude of hemophilic adult individuals towards their disease].

    PubMed

    Carruyo-Vizcaíno, Cecilia; Vizcaíno, Gilberto; Carrizo, Edgardo; Arteaga-Vizcaíno, Melvis; Sarmiento, Sandra; Vizcaíno-Carruyo, Jennifer

    2004-09-01

    The mental health of hemophilic individuals and their families play an important role on the integral treatment of the disease. The knowledge of the beliefs and attitudes perceived by the patients toward their disease will make possible a positive influence in their clinical improvement, their response to the treatment, as well as their quality of life. On the basis of the Azjen and Fishbein's Theory of Reasoned Action, a questionnaire was applied to 43 adult hemophilics to determine the salient beliefs about their disease. These beliefs permitted to elaborate a main structured questionnaire named Attitude Model in Patients with Hemophilia (Modelo de Actitud en Pacientes con Hemofilia, MAPACHE, in spanish), which was administered to the individuals and thus, the attitude toward their disease was obtained. Seventy two percent (72%) gave a major importance to the clinical aspects of the disease (hemorrhage, joint discomfort and trauma), 40% knew the general concepts of hemophilia (heredity, care and seriousness of the disease), 20% mentioned the implications of the psychosocial factors and only 18% had knowledge concerning the coagulation factors deficiency and the appropriate treatment. The MAPACHE showed a slightly positive score attitude (4.44 +/- 1.12 SEM) towards the disease in the majority of the groups (74.5%); with 26% of the hemophilics with a negative attitude. There were no significant differences between attitude and clinical parameters. It is recommended that a multidisciplinary team of caregivers should focus their efforts toward education and preventive measures in order to avoid the complications and consequences of the disease, to make possible a better quality of life in individuals with hemophilia. PMID:15469070

  19. Small Peptides Blocking Inhibition of Factor Xa and Tissue Factor-Factor VIIa by Tissue Factor Pathway Inhibitor (TFPI)*

    PubMed Central

    Dockal, Michael; Hartmann, Rudolf; Fries, Markus; Thomassen, M. Christella L. G. D.; Heinzmann, Alexandra; Ehrlich, Hartmut; Rosing, Jan; Osterkamp, Frank; Polakowski, Thomas; Reineke, Ulrich; Griessner, Andreas; Brandstetter, Hans; Scheiflinger, Friedrich

    2014-01-01

    Tissue factor pathway inhibitor (TFPI) is a Kunitz-type protease inhibitor that inhibits activated factor X (FXa) via a slow-tight binding mechanism and tissue factor-activated FVII (TF-FVIIa) via formation of a quaternary FXa-TFPI-TF-FVIIa complex. Inhibition of TFPI enhances coagulation in hemophilia models. Using a library approach, we selected and subsequently optimized peptides that bind TFPI and block its anticoagulant activity. One peptide (termed compound 3), bound with high affinity to the Kunitz-1 (K1) domain of TFPI (Kd ∼1 nm). We solved the crystal structure of this peptide in complex with the K1 of TFPI at 2.55-Å resolution. The structure of compound 3 can be segmented into a N-terminal anchor; an Ω-shaped loop; an intermediate segment; a tight glycine-loop; and a C-terminal α-helix that is anchored to K1 at its reactive center loop and two-stranded β-sheet. The contact surface has an overall hydrophobic character with some charged hot spots. In a model system, compound 3 blocked FXa inhibition by TFPI (EC50 = 11 nm) and inhibition of TF-FVIIa-catalyzed FX activation by TFPI (EC50 = 2 nm). The peptide prevented transition from the loose to the tight FXa-TFPI complex, but did not affect formation of the loose FXa-TFPI complex. The K1 domain of TFPI binds and inhibits FVIIa and the K2 domain similarly inhibits FXa. Because compound 3 binds to K1, our data show that K1 is not only important for FVIIa inhibition but also for FXa inhibition, i.e. for the transition of the loose to the tight FXa-TFPI complex. This mode of action translates into normalization of coagulation of hemophilia plasmas. Compound 3 thus bears potential to prevent bleeding in hemophilia patients. PMID:24275667

  20. Genome Editing of Structural Variations: Modeling and Gene Correction.

    PubMed

    Park, Chul-Yong; Sung, Jin Jea; Kim, Dong-Wook

    2016-07-01

    The analysis of chromosomal structural variations (SVs), such as inversions and translocations, was made possible by the completion of the human genome project and the development of genome-wide sequencing technologies. SVs contribute to genetic diversity and evolution, although some SVs can cause diseases such as hemophilia A in humans. Genome engineering technology using programmable nucleases (e.g., ZFNs, TALENs, and CRISPR/Cas9) has been rapidly developed, enabling precise and efficient genome editing for SV research. Here, we review advances in modeling and gene correction of SVs, focusing on inversion, translocation, and nucleotide repeat expansion. PMID:27016031