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Sample records for hemophilia cohort hgds-3

  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. Hemophilia usually occurs in males. If you have hemophilia, you have little or no clotting factor. Clotting ...

  3. [Hemophilia.

    PubMed

    Amador-Medina, Lauro Fabián; Vargas-Ruiz, Angel Gabriel

    2013-01-01

    Hemophilia is a genetic disease in which the clinical manifestation is mainly the presence of hemorrhage. There are two known types of hemophilia: hemophilia A and B, which have a deficiency of factor VIII or IX clotting, respectively. The intensity of bleeding in hemophilia depends on the plasma levels of factor VIII or IX and has traditionally been classified as mild (> 5 % activity), moderate (1-5 % activity) and severe (< 1 % activity). In laboratory tests, isolated prolongation of activated partial thromboplastin time (aPTT) can be found, but it is necessary to determine the plasma levels of factor VIII or IX to establish the diagnosis of hemophilia A or B. The treating of this disease involves replacing exogenous factor VIII or IX concentrates. Gene therapy could be an option in the future to achieve the cure of the disease. Complications of hemophilia are the risk of transfusion-associated infections, pseudotumor hemophilic, hemophilic arthropathy and the presence of serum inhibitors.

  4. 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

  5. The polygenic nature of inhibitors in hemophilia A: results from the Hemophilia Inhibitor Genetics Study (HIGS) Combined Cohort

    PubMed Central

    Donfield, Sharyne M.; Gomperts, Edward D.; Schwarz, John; Menius, Erika D.; Pavlova, Anna; Oldenburg, Johannes; Kessing, Bailey; DiMichele, Donna M.; Shapiro, Amy D.; Winkler, Cheryl A.; Berntorp, Erik

    2013-01-01

    Studies of determinants of development of inhibitory Abs to factor VIII in people with hemophilia A indicate a complex process involving multiple factors. The Hemophilia Inhibitor Genetics Study (HIGS) Combined Cohort was formed to extend our understanding of the genetic background of risk. The study group contains 833 subjects from 3 independent cohorts: brother pairs and singletons with and without a history of inhibitors, as well as 104 brother pairs discordant for inhibitor status. Using an Illumina iSelect platform, 13 331 single-nucleotide polymorphisms from 1081 genes, primarily immune response and immune modifier genes, were typed. Each cohort was analyzed separately with results combined using a meta-analytic technique. After adjustment for potential confounders, 53 single-nucleotide polymorphisms were found to be significant predictors of inhibitor status using the criteria of odds ratios in the same direction in all cohorts or allowing for a 20% interval around an odds ratio = 1 in 1 of the 3 and significant in at least 2. Of the 53 markers, 13 had meta P < .001. Eight of the 53 were significant predictors among the discordant pairs. Results support the complexity of the immune response and encourage further research with the goal of understanding the pathways involved. PMID:23223434

  6. F8 haplotype and inhibitor risk: results from the Hemophilia Inhibitor Genetics Study (HIGS) Combined Cohort

    PubMed Central

    Schwarz, John; Astermark, Jan; Menius, Erika D.; Carrington, Mary; Donfield, Sharyne M.; Gomperts, Edward D.; Nelson, George W.; Oldenburg, Johannes; Pavlova, Anna; Shapiro, Amy D.; Winkler, Cheryl A.; Berntorp, Erik

    2012-01-01

    Background Ancestral background, specifically African descent, confers higher risk for development of inhibitory antibodies to factor VIII (FVIII) in hemophilia A. It has been suggested that differences in the distribution of factor VIII gene (F8) haplotypes, and mismatch between endogenous F8 haplotypes and those comprising products used for treatment could contribute to risk. Design and Methods Data from the HIGS Combined Cohort were used to determine the association between F8 haplotype 3 (H3) vs. haplotypes 1 and 2 (H1+H2) and inhibitor risk among individuals of genetically-determined African descent. Other variables known to affect inhibitor risk including type of F8 mutation and HLA were included in the analysis. A second research question regarding risk related to mismatch in endogenous F8 haplotype and recombinant FVIII products used for treatment was addressed. Results H3 was associated with higher inhibitor risk among those genetically-identified (N=49) as of African ancestry, but the association did not remain significant after adjustment for F8 mutation type and the HLA variables. Among subjects of all racial ancestries enrolled in HIGS who reported early use of recombinant products (N=223), mismatch in endogenous haplotype and the FVIII proteins constituting the products used did not confer greater risk for inhibitor development. Conclusion H3 was not an independent predictor of inhibitor risk. Further, our findings did not support a higher risk of inhibitors in the presence of a haplotype mismatch between the FVIII molecule infused and that of the individual. PMID:22958194

  7. 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/ ...

  8. 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 ...

  9. Hemophilia B

    MedlinePlus

    ... hemophilia B, and you plan to have children; genetic counseling is available ... Genetic counseling may be recommended. Testing can identify women and girls who carry the hemophilia gene. Testing can ...

  10. 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

  11. 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 ...

  12. 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 ...

  13. [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.

  14. [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

  15. 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 ...

  16. 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 ...

  17. 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

  18. 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.

  19. Gene therapy for hemophilia

    PubMed Central

    Rogers, Geoffrey L.; Herzog, Roland W.

    2015-01-01

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

  20. Bleeding diathesis and hemophilias.

    PubMed

    Amin, Chirag; Sharathkumar, Anjali; Griest, Anne

    2014-01-01

    Patients with hemophilia and other congenital bleeding disorders are at risk for development of central nervous system (CNS) hemorrhage and can present with acute or chronic neurologic symptoms. These disorders are generally caused by qualitative or quantitative deficiency of components of hemostasis such as coagulation proteins, von Willebrand factor, or platelets. Rapid diagnosis and specific medical management such as coagulation factor replacement therapy are mandatory to minimize the morbidity and mortality of CNS bleeding. Therefore, the objective of this chapter is to introduce neurologists to the physiology of hemostasis and to provide an overview of the clinical presentation, and management of inherited bleeding disorders that can potentially present with CNS bleeding. Since hemophilia is the most common bleeding disorder encountered in clinical practice, more emphasis is placed on management of hemophilia. Additionally, neurologic manifestations related to the bleeding diathesis in patients with hemophilia are elaborated. PMID:24365370

  1. 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 ...

  2. 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, ...

  3. 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 ...

  4. 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)

  5. Eloctate for hemophilia A.

    PubMed

    2015-10-12

    Eloctate, a recombinant factor VIII Fc fusion protein with an extended half-life, was effective in preventing and controlling bleeding in patients with severe hemophilia A. Compared to other currently available factor VIII products, Eloctate's extended half-life reduces the number of doses required for routine prophylaxis, which could improve adherence. Eloctate has not been associated with formation of neutralizing antibodies, but it was not studied in previously untreated patients with severe hemophilia A, who have a higher risk of this complication. Like other recombinant factor VIII products, Eloctate is very expensive.

  6. 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

  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. Neonatal Hemophilia: A Rare Presentation

    PubMed Central

    Proença, Elisa; Godinho, Cristina; Oliveira, Dulce; Guedes, Ana; Morais, Sara; Carvalho, Carmen

    2015-01-01

    Hemophilia A is a X-linked hereditary condition that lead to decreased factor VIII activity, occurs mainly in males. Decreased factor VIII activity leads to increased risk of bleeding events. During neonatal period, diagnosis is made after post-partum bleeding complication or unexpected bleeding after medical procedures. Subgaleal hemorrhage during neonatal period is a rare, severe extracranial bleeding with high mortality and usually related to traumatic labor or coagulation disorders. Subgaleal hemorrhage complications result from massive bleeding. We present a neonate with unremarkable family history and uneventful pregnancy with a vaginal delivery with no instrumentation, presenting with severe subgaleal bleeding at 52 hours of life. Aggressive support measures were implemented and bleeding managed. The unexpected bleeding lead to a coagulation study and the diagnosis of severe hemophilia A. There were no known sequelae. This case shows a rare hemophilia presentation reflecting the importance of coagulation studies when faced with unexplained severe bleeding. PMID:26734126

  9. Discrepant ratios of arterial versus venous thrombosis in hemophilia A as compared with hemophilia B.

    PubMed

    Girolami, Antonio; Bertozzi, Irene; de Marinis, Giulia Berti; Tasinato, Valentina; Sambado, Luisa

    2014-04-01

    The occurrence of thrombosis in patients with congenital bleeding disorders represents an exceptional event. Hemophilia A and hemophilia B patients have been showed to present both arterial and venous thrombosis (85 cases of arterial thrombosis and 34 cases of venous thrombosis). The great majority of arterial thrombosis are myocardial infarction or other acute coronary syndromes, whereas the majority of venous thrombosis are deep vein thrombosis and/or pulmonary embolisms. However there are discrepancies in the proportion of arterial and venous thrombosis seen in hemophilia A versus hemophilia B. The ratio of arterial versus venous thrombosis in hemophilia A is 3.72 whereas that for hemophilia B is 1.12. This indicates that arterial thrombosis is more frequent in hemophilia A as compared to hemophilia B and the opposite is true for venous thrombosis. The potential significance of this discrepancy is discussed.

  10. Epidemiology of hepatocellular carcinoma (HCC) in hemophilia.

    PubMed

    Shetty, Shrimati; Sharma, Nitika; Ghosh, Kanjaksha

    2016-03-01

    Hepatocellular carcinoma (HCC) is an important cause of increasing mortality in elderly hemophilia population. Majority of the patients treated with virus non-inactivated factor concentrates prepared from large plasma pools prior to 1985 have been found to be infected with hepatitis C virus (HCV), a major risk factor for HCC. A PubMed search of articles published until February 2015 was performed utilizing the keywords hemophilia, malignancy, neoplasm, cancer, mortality, ageing hemophilia, epidemiology, hepatocellular carcinoma and liver cancer and the relevant articles were included. Contradictory reports are available in literature on the incidence of cancers in general in hemophilia population. Almost all the studies where the incidence of HCC or mortality due to HCC have been analyzed in hemophilia population show that a vast majority of these patients are HCV infected. The incidence of HCC though higher in hemophilic population is related to the higher incidence of HCV infection and not due to the hemophilia phenotype.

  11. Hemophilia A in the third millennium.

    PubMed

    Franchini, Massimo; Mannucci, Pier Mannuccio

    2013-07-01

    Hemophilia A is an X-linked hereditary bleeding disorder due to the deficiency of coagulation factor VIII (FVIII). According to the degree of FVIII deficiency, mild, moderate or severe forms are recognized. Although patients with mild hemophilia A usually bleed excessively only after trauma or surgery, those with severe hemophilia experience frequent episodes of spontaneous or excessive bleeding after minor trauma, particularly into joints and muscles. The modern management of hemophilia began in the 1970s and is actually based upon several plasma-derived or recombinant FVIII products. In addition, the synthetic drug desmopressin can be used to prevent or treat bleeding episodes in patients with mild hemophilia A. Long-term and continuous substitution therapy (prophylaxis), the recommended treatment in severe hemophilia, prevents bleeding and the resultant joint damage. In the last twenty years the high standard of hemophilia care has greatly improved the quality of life of patients and their life expectancy has reached that of the non-hemophilic male population, at least in high-income countries. The most serious and challenging complication of treatment of hemophilia A is the development of inhibitors, which renders FVIII concentrate infusion ineffective and exposes patients to an increased risk of morbidity and mortality. In this narrative review, the actual knowledge on the clinical features and management of patients with hemophilia A is summarized.

  12. 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

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

    PubMed

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

    2016-02-01

    Recent evidence suggests that patients with severe hemophilia B may have a less severe disease compared to severe hemophilia A. To investigate clinical, radiological, laboratory and histological differences in the arthropathy of severe hemophilia A and hemophilia B, 70 patients with hemophilia A and 35 with hemophilia B with at least one joint bleeding were consecutively enrolled. Joint bleedings (<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.

  14. Impact of an individualized prophylaxis approach on young adults with severe hemophilia.

    PubMed

    Fernandes, Susana; Carvalho, Manuela; Lopes, Manuela; Araújo, Fernando

    2014-10-01

    It is now well established that the treatment of choice for children with severe hemophilia is prophylaxis started early in life. Although, there is no consensus among the hemophilia management community to either stop or maintain prophylactic treatment in adulthood, experts, and centers advise individualized prophylaxis according to clinical bleeding pattern, condition of joints, pharmacokinetic profile, physical activity, type of employment, and patients' personal preferences. The aim of this article is to describe the impact of an individualized prophylaxis approach on young adults with severe hemophilia, in the setting of a Portuguese Haemophilia Comprehensive Care Centre. We proposed a tailored prophylaxis approach on a young adult cohort with 10 patients with severe hemophilia (7× type A and 3× type B) on standard prophylactic regimens in childhood, based on clinical outcome. Patients were evaluated and prophylaxis was adjusted (dose and/or frequency) to daily life activity and bleeding pattern. After 12 months of follow-up, one patient returned to the previous regimen due to breakthrough bleeds and the remaining nine patients maintained their new prophylaxis approach, without increasing bleeding episodes. With an individualized approach, in this cohort of nine patients, we observed no negative impact on clinical outcome, with a proposed improvement in quality of life and a reduction of costs.

  15. Hemophilia in the managed care setting.

    PubMed

    Dalton, Dan R

    2015-03-01

    Hemophilia A and B are chronic inherited bleeding disorders that together rank as one of the most expensive chronic diseases in the United States. Factor replacement products, which are the mainstay of treatment, are among the most expensive therapies, with a total annual cost of more than $250,000 per adult patient in the United States. Indirect costs also contribute to the economic burden and include lost productivity, caregivers' unpaid costs, and hemophiliarelated disability. Advances in hemophilia care have resulted in longer survival and a growing patient population, greater complexity in management of the disorder, and rising treatment costs. The establishment of federally recognized Hemophilia Treatment Centers has decreased costs and improved patient outcomes and quality of life by promoting outpatient, preventive, and homebased care. Successful collaboration among providers and managed care programs can improve outcomes and decrease costs for the delivery of hemophilia services.

  16. The management of musculoskeletal problems in hemophilia. Part I. Principles of medical management of hemophilia.

    PubMed

    McMillan, C W; Greene, W B; Blatt, P M; White, G C; Roberts, H R

    1983-01-01

    Musculoskeletal bleeding in general and arthropathy in particular are the central problems among many in the two major forms of hemophilia: classic hemophilia, caused by factor VIII deficiency, and Christmas disease, caused by factor IX deficiency. Currently available replacement therapy, if properly used in a multidisciplinary setting, should provide significant benefit to hemophilic patients despite its cost and occasional complications.

  17. 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…

  18. 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…

  19. 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 ...

  20. 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

  1. Laparoscopic nephrectomy in a hemophilia B patient

    PubMed Central

    Szopiński, Tomasz; Szczepanik, Andrzej B.; Sosnowski, Roman; Szczepanik, Anna M.

    2016-01-01

    Surgery in patients with hemophilia is a serious challenge. It requires a comprehensive approach, as well as careful postoperative monitoring. We present here the first case of a transperitoneal laparoscopic radical nephrectomy (TLRN) for renal cell carcinoma, of the clear-cell type, performed in a hemophilia B patient. The level of factor IX clotting activity before surgery and on postoperative days 1–6 was maintained at 65–130% and at 30–40% on subsequent days until healing of the post-operative wound was achieved. The intraoperative and postoperative courses were uneventful. TLRN can therefore be considered safe and effective for renal cell carcinoma. In hemophilia patients, the TLRN procedure requires proper preparation, as well as adequate substitution therapy for the deficient coagulation factor provided by a multidisciplinary team in a comprehensive center. PMID:27729993

  2. [Molecular genetics of hemophilia A].

    PubMed

    De Brasi, C D; Slavutsky, I R; Larripa, I B

    1996-01-01

    Hemophilia A (HemA), an X linked genetic disease, is the most common coagulation disorder with an incidence of about 1-2 in 10,000 males and is caused by mutations in the factor VIII (FVIII) coagulation gene. Firstly, some clinical aspects of the HemA are presented: the current methods to assess both the amount and activity of FVIII, the severity range observed and the presence of inhibitor antibodies against the therapeutic FVIII. Follows a discussion of the relationship of the structural domains of the FVIII protein (Figure 1), the aminoacid sequence and their functions. An activation-inactivation model of the successive peptide bonds cleavages of the FVIII is also presented (Figure 2). After the cloning of the FVIII gene in 1984, almost all types of HemA causing mutations have been characterized. However, the size and complexity of this gene prevented a screening of the full range of mutations for an accurate molecular diagnosis. Moreover, most of the patients with moderate and mild disease have missense mutations whereas approximately half of severe patients have nonsense, frameshift, and some missense mutations. There are also less frequently mutations such as deletions and insertions leading to severe phenotype and mutations affecting mRNA splicing and duplications causing both severe and mild HemA. In order to give genetic counselling in HemA families, studies at the DNA level using intragenic and/ or extragenic polymorphism analysis have been used. But this approach is not entirely satisfactory because it fails in several situations. Most of the causing mutations described above are private, and they have been found in only a few unrelated families. Recently, a common molecular inversion of the FVIII gene was identified in 50% of unrelated patients with severe HemA. The copies of a particular DNA sequence (termed F8A gene). One copy is located within intron 22 of the FVIII gene and the other two, 500 kb upstream. An homologous recombination mechanism was

  3. AIDS and hemophilia: experience in the La Paz Hemophilia Center.

    PubMed

    Magallón Martínez, M; Ortega, F; Pinilla, J

    1992-01-01

    435 hemophiliacs are usually being attended in the La Paz hemophilia Center (Madrid, Spain). 257 (59%) of these patients have been infected by the human immunodeficiency virus (HIV-1) because of human plasma derivate substitution therapy. The infection has been more frequent among the severely affected patients and among the most treated patients. 82% of the infected patients are between 14 and 40 years old. By December 1991, 95 (37%) of 257 seropositive patients have developed full-blown AIDS. The most frequent opportunistic infection they had suffered was esophageal candidiasis. Looking for an evolution marker, we can point that the patients older than 35 years with CD4 levels below 200/mm3 had the worst prognosis. There was no difference in the evolution among the patients aged below 17 and those aged between 17 and 35 years. The amount of concentrate used between 1980 and 1984 did not hold any relation to the evolution. 49 patients (51%) of the 95 suffering from AIDS had died by December 1991. The evolution to the death was unrelated to the patient age, CD4 lymphocyte levels, and amount of substitution therapy. In our opinion, the most valuable marker could be the kind of opportunistic infection or tumor the patient suffers from. Finally, Retrovir has demonstrated to be useful in increasing the survival rate of the patients, but after 36 months of treatment, only 33% of those AIDS patients who began taking it remained alive. Retrovir was also used in asymptomatic patients, and during an average period of time of 15 months, a lesser bone marrow toxicity and a stabilization in CD4 lymphocyte levels could be observed, but this was unable to modify the disease progression in those patients who presented circulating p24 antigen.

  4. 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…

  5. 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)

  6. Replacing bad (F)actors: hemophilia.

    PubMed

    Doering, Christopher B; Spencer, H Trent

    2014-12-01

    Hemophilia A and B are bleeding disorders that result from functional deficiencies in specific circulating blood clotting factors termed factor VIII (FVIII) and factor IX (FIX), respectively, and collectively display an incidence of 1 in 4000 male births. Stem cell transplantation therapies hold the promise of providing a cure for hemophilia, but currently available transplantable stem cell products do not confer endogenous FIX or FVIII biosynthesis. For this reason, stem cell-based approaches for hemophilia have focused primarily on genetic engineering of pluripotent or multipotent stem cells. While pluripotent stem cells have been branded with high expectation and promise, they remain poorly characterized in terms of clinical utility and safety. In contrast, adult-lineage-restricted stem cells are established agents in the clinical armamentarium. Of the clinically established stem cell types, hematopoietic stem cells (HSCs) are the most utilized and represent the standard of care for several genetic and acquired diseases. Furthermore, HSCs are ideal cellular vehicles for gene therapy applications because they self-renew, repopulate the entire blood lineage while concurrently amplifying the transgene copy number >10(6) fold, and also have direct access to the bloodstream. Current research on HSC transplantation gene therapy approaches for hemophilia A and B is focused on the following: (1) identification of safe and efficient methods of nucleic acid transfer, (2) optimization of transgene product expression, (3) minimization of conditioning-regimen-related toxicity while maintaining HSC engraftment, and (4) overcoming preexisting immunity. Based on the existing data and current rate of progress, clinical trials of HSC transplantation gene therapy for hemophilia are predicted to begin in the coming years.

  7. 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

  8. Individualizing prophylaxis in hemophilia: a review.

    PubMed

    Petrini, Pia; Valentino, Leonard A; Gringeri, Alessandro; Re, Wendy M; Ewenstein, Bruce

    2015-04-01

    Prophylaxis is considered optimal care for patients with severe hemophilia to prevent bleeding, including hemarthroses, which may cause arthropathy with chronic pain, occupational impairment and progressive loss of mobility. Questions remain regarding the optimal delivery of prophylaxis including how to individualize prophylaxis and optimize outcomes for each patient. Designing a prophylactic regimen for severe hemophilia must account for each patient's unique disease course, bleeding pattern, presence/absence of joint damage, pharmacokinetic profile, level of physical activity and adherence to treatment. Standard weight-based prophylaxis regimens and regimens optimized by bleeding phenotype (i.e., patients are 'allowed' to bleed to dose optimization) fail to prevent complications in many patients. Pharmacokinetic-guided dosing enables precise adjustment of dosing level and frequency to maintain adequate hemostatic levels and prevent bleeding. Optimal outcomes, such as reducing or eliminating hemorrhages, preventing or minimizing joint damage, and improving quality of life, can be achieved through an individualized care approach.

  9. CO 2 laser surgery in hemophilia treatment.

    PubMed

    Santos-Dias, A

    1992-08-01

    The use of CO 2 laser surgery between 1985 and 1991 in South Africa and Portugal for treatment of disorders in patients with mild to moderate cases of hemophilia A is discussed. Six cases of oral procedures and excision of skin tumors performed during this period are reported. In most of the cases of mild hemophilia no pre- or postoperative infusion of Factor VIII or desmopressin (DDAVP) was required. In some cases of moderate hemophilia, patients were infused with desmopressin (0.3 mug/kg body weight) and were treated postoperatively with the use of nasal desmopressin spray (150 mug to each nostril for four weeks following surgery). Factor VIII levels were measured before surgery. Follow up of four weeks was uneventful. The mean average power of the CO 2 laser was 20 W continuous and the pulse duration was 0.1 s for ablational procedures. For dermatologic procedures, a flexible plastic CO 2 laser hollow fiber was used (Flexilase, Sharplan, Allandale, NJ). We concluded that CO 2 laser surgery for hemophiliacs has a confirmed place in modern laser technology provided the standard precautions are taken and facilities are available.

  10. 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.…

  11. 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…

  12. 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

  13. New challenges in hemophilia: long-term outcomes and complications.

    PubMed

    Young, Guy

    2012-01-01

    For the past 5 decades, the care for hemophilia patients has improved significantly to the point that a newborn with hemophilia living in a developed nation can expect to have a normal lifespan and a high quality of life. Despite this, there are several new challenges that the hemophilia community will face in the coming years. First, the hemophilia community will soon be challenged with adopting a variety of new agents into clinical practice. Second, the normalization of patients' lives as a result of improved treatment has led to new problem areas, including obese/overweight hemophiliacs and osteoporosis. In addition, although mortality rates are similar to those of the healthy population, morbidities such as hemophilic arthropathy still occur. Third, the cost of care continues to rise, both due to the development of expensive new therapies and to the costs of managing problems such as obesity and osteoporosis. Finally, most patients in the world with hemophilia receive little to no care and although this is an enormous challenge, it must be confronted. This review discusses some new challenges facing developing nations and their care for hemophilia patients. In summary, in hemophilia in the coming few years, several new challenges will need to be confronted.

  14. 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.

  15. 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.

  16. 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

  17. 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

  18. 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

  19. 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.

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

    PubMed

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

    2014-06-01

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

  1. Individualizing factor replacement therapy in severe hemophilia.

    PubMed

    Carcao, Manuel D; Iorio, Alfonso

    2015-11-01

    Prophylactic replacement of factor concentrate is the established optimal treatment to avoid or minimize joint disease in severe hemophilia patients, thus ultimately improving their life expectancy and quality of life toward values matching those in the normal population. Where uncertainty still exists is around the optimal regimen to be prescribed for prophylaxis, and more and more treaters and patients are showing interest in patient tailored approaches to prophylaxis, aiming at matching the prophylaxis regimen to the specific needs of the patient. The rationale behind tailoring the prophylaxis regimen to the individual patient is based on the significant variability that exists between patients (all with the same label of severe hemophilia) with respect to their bleeding phenotype, their pharmacokinetic handling of factor, their levels of physical activity, and a variety of other characteristics that contribute to differential prophylaxis needs of patients. Of course, any form of tailoring of prophylaxis needs to take into consideration the economic resources of the country; for many countries very intense prophylaxis regimens are just not possible. This article will review different concerns and strategies when tailoring prophylaxis, and will address how these issues will apply to the new longer acting factor concentrates in development.

  2. [Extracorporeal shockwave lithotripsy and hemophilia: apropos of a case].

    PubMed

    Brunet, P; Rigot, J M; Coupez, B; Mazeman, E

    1995-02-01

    We report pelvis calculi fragmentation through the use of extracorporeal shock wave lithotripsy in a patient with mild hemophilia B. The EDAP LT 01 lithotriptor was used without incident. We review other reported cases in the literature.

  3. Pregnancy and delivery in a woman with hemophilia B.

    PubMed

    Rust, L A; Goodnight, S H; Freeman, R K; Johnson, C S

    1975-10-01

    Hemophilia B (Factor IX deficiency, Christmas disease) may cause excessive bleeding in women. The obstetric and hematologic management of the pregnancy and delivery of a woman with a Factor IX level of 4% is presented and discussed.

  4. Hemophilia B and free tissue transfer: medical and surgical management.

    PubMed

    Knott, P Daniel; Khariwala, Samir S; Minarchek, Joseph

    2005-03-01

    Hemophilia B (Christmas disease) is a rare, X-linked bleeding diathesis, which may present with life-threatening hemorrhage. Management of the coagulopathy in the setting of free tissue transfer may be particularly challenging. The authors present the first case in the English literature of a male with hemophilia B undergoing microvascular free flap reconstruction, as well as a review of the current surgical and medical management of hemophilia B. Based upon this experience, perioperative specific factor replacement is recommended. Given physiologic trough levels of the replaced factor, routine antiplatelet therapy appears appropriate. Management of free tissue transfer in the setting of severe hemophilia is significantly more challenging and should benefit from multidisciplinary coordination.

  5. Exertional compartment syndrome in covert mild hemophilia. A case report.

    PubMed

    Tountas, C P; Ferris, F O; Cobb, S W

    1992-07-01

    A 37-year-old white male experienced unexpected postoperative bleeding after fasciotomy and decompression for left pronator and compartment syndromes of the forearm. He was subsequently diagnosed with a mild form of hemophilia A. One year later, surgery was required for right pronator and compartment syndromes. Pre- and postoperative cryoprecipitate infusions controlled bleeding following the second operation until the patient discontinued his infusions, resulting in a wound hematoma. Covert mild hemophilia is implicated in the pathogenesis of his compartment syndromes.

  6. Gastrectomy in siblings with Christmas disease (hemophilia B).

    PubMed

    Mizumoto, R; Kawarada, Y; Ogura, Y

    1980-12-01

    Gastrointestinal hemorrhage is regarded as one of the commonest clinical manifestations of classic hemophilia and Christmas disease. Although major surgery is usually avoided in such cases, recently we had 2 cases of Christmas disease in siblings who had undergone a successful gastrectomy and concomitant administration of a concentrated preparation of factor IX. In addition, findings in 7 other Japanese patients with hemophilia who underwent gastrectomy are discussed.

  7. Acquired hemophilia A in the United Kingdom: a 2-year national surveillance study by the United Kingdom Haemophilia Centre Doctors' Organisation.

    PubMed

    Collins, Peter W; Hirsch, Sybil; Baglin, Trevor P; Dolan, Gerard; Hanley, John; Makris, Michael; Keeling, David M; Liesner, Ri; Brown, Simon A; Hay, Charles R M

    2007-03-01

    Acquired hemophilia A is a severe bleeding disorder caused by an autoantibody to factor VIII. Previous reports have focused on referral center patients and it is unclear whether these findings are generally applicable. To improve understanding of the disease, a 2-year observational study was established to identify and characterize the presenting features and outcome of all patients with acquired hemophilia A in the United Kingdom. This allowed a consecutive cohort of patients, unbiased by referral or reporting practice, to be studied. A total of 172 patients with a median age of 78 years were identified, an incidence of 1.48/million/y. The cohort was significantly older than previously reported series, but bleeding manifestations and underlying diseases were similar. Bleeding was the cause of death in 9% of the cohort and remained a risk until the inhibitor had been eradicated. There was no difference in inhibitor eradication or mortality between patients treated with steroids alone and a combination of steroids and cytotoxic agents. Relapse of the inhibitor was observed in 20% of the patients who had attained first complete remission. The data provide the most complete description of acquired hemophilia A available and are applicable to patients presenting to all centers.

  8. 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.

  9. 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

  10. 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

  11. 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

  12. 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

  13. 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

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

    PubMed Central

    Rambod, Masoume; Sharif, Farkhondeh; Molazem, Zahra; Khair, Kate

    2016-01-01

    ABSTRACT Background: Pain, as a crucial subsequence of joint hemorrhages in hemophilia patients, is chronic, debilitating, and distracting. This study aimed to describe and interpret pain experiences of hemophilia patients in their lives. Methods: This qualitative study with hermeneutic phenomenological approach was conducted on fourteen hemophilia patients who had been referred to a hemophilia center affiliated to Shiraz University of Medical Sciences, Shiraz, Iran. The study question was “what is the meaning of pain in hemophilia patients’ lives? The data were collected through semi-structured interviews and field notes through purposeful sampling. Then, thematic analysis with van Manen’s six-step methodological framework was used. MAX.QDA qualitative software package, 2010, was used to analyze the data. Results: The three main themes that emerged in this study were “alteration in physical health”, “engagement in psychological problems”, and “impairment in social relationships”. Alteration in physical health consisted of three subthemes, namely “impairment of physical function”, “change in body physics”, and “disturbance in sleep quality”. In addition, two subthemes including “nostalgia of pain in adults with hemophilia” and “psychological distress” emerged from engagement in psychological problems. Finally, “loss of social activity” and “change in relationships” were related to impairment in social relationships. Conclusion: The present study highlighted alteration in physical health, engagement in psychological problems, and impairment in social relationship as a result of pain in hemophilia patients. Thus, healthcare providers and family members have to pay special attention to these problems. Besides, providing complementary therapy interventions is suggested for reducing these issues. PMID:27713894

  15. 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.

  16. 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

  17. Acquired hemophilia a successfully treated with rituximab.

    PubMed

    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

  18. Hemophilia A in a Belgian Shepherd Malinois dog: case report.

    PubMed

    Gavazza, A; Lubas, G; Trotta, M; Caldin, M

    2014-08-01

    This case report presents a Belgian Shepherd Malinois dog affected by hemophilia A recognized at the age of seven months. The clinical follow-up including all the diagnostic procedures leading to the final diagnosis and the course of this disorder are presented. This is a typical proband case demonstrating the appearance of this genetic disease in a breed never involved by this coagulation disorder so far documented that started an intensive and laborious plan to reduce the incidence of hemophilia A and the further appearance of new cases.

  19. 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

  20. 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

  1. An unusual presentation of hemophilia B: pseudotumor of proximal tibia.

    PubMed

    Mittal, Saurav; Arora, Sumit; Khanna, Shilpa; Maini, Lalit; Gautam, V K

    2011-07-01

    Hemophilia is one of the most common genetically inherited causes of bleeding disorders. The usual presentation is continuous bleeding from a wound. Very seldom, it presents as a pseudotumor of bone. When left untreated, it may induce compression and pressure necrosis of adjacent structures. Careful evaluation and a high index of suspicion are usually required to arrive at the correct diagnosis. In this article, we report the case of a 10-year-old boy with hemophilia B (Christmas disease) that presented as a pseudotumor producing a large defect in the proximal tibia.

  2. 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…

  3. [Prophylactic replacement therapy in hemophilia. A case report (author's transl)].

    PubMed

    Mitterstieler, G

    1976-01-01

    In a six year old boy with severe hemophilia prophylactic substitution of factor VIII was started in 1973 in order to prevent early invalidity due to series of bleeding in the right anklejoint. A substitution of factor VIII over 8 months with 21 resp. 30 U/kg body-weight did not lead to a significant improvement. But since the factor VIII in a dosage of 18 U/kg body-weight is given three times a week no bleeding occurred during the treatment time of 14 months and also the ability to walk improved to an excellent degree.--So far no signs of hepatitis or an factor-VIII-antibody could be detected.--Some results from the prophylactic treatment of severe hemophilia and Christmas disease are cited from the literature.

  4. 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

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

    PubMed

    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

  6. 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

  7. 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

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

    PubMed

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

    2015-01-01

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

  9. Hemophilia A and hemophilia B in a family of French bulldogs.

    PubMed

    Slappendel, R J

    1975-10-15

    A congenital coagulation defect was suspected in 10 male French bulldogs, independently referred to the Small Animal Clinic of the Utrecht State University by private pet owners from all over the country. The cases are described in this report. Coagulation studies, performed in 8 of these dogs, revealed a factor VIII (anti-hemophilic globulin) deficiency in 5, and a factor IX (Christmas factor) deficiency in 3 propositi. A pedigree analysis revealed that all of the 10 propositi were lineal descendants, in the female line, of one and the same female ancestor. An inquiry by letter among the owners of 210 male descendants, in the female line, of this common ancestor revealed hemorrhagic episodes in at least another 10 male offspirng. The presence of a large number of carriers can be expected among the French bulldog population in the Netherlands, since the officially registered female offspring in the female line of the ancestor bitch, comprised over 170 dogs as of January, 1971. The possible mechanisms responsible for the simultaneous occurrence of hemophilia A and B in one canine family are discussed.

  10. 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.

  11. Importance of immune response genes in hemophilia A

    PubMed Central

    de Alencar, Josiane Bazzo; Macedo, Luciana Conci; de Barros, Morgana Ferreira; Rodrigues, Camila; Cadide, Renata Campos; Sell, Ana Maria; Visentainer, Jeane Eliete Laguila

    2013-01-01

    Hemophilia A is a disease caused by a deficiency of coagulation factor VIII resulting from genetic inheritance linked to chromosome X. One treatment option is the administration of plasma or recombinant FVIII. However, some patients develop inhibitors or antibodies against this factor. Inhibitors are alloantibodies that bind to the epitope of factor VIII causing it to be recognized by the immune system as a foreign peptide. This is the most serious complication in hemophilia patients in respect to replacement therapy. Some studies have suggested that genetic factors influence the development of factor VIII inhibitors such as ethnicity, family history, mutations in the factor VIII gene and in genes of the immune system. The aim of this study was to conduct a literature review to assess the influence of genetic factors of immune response genes, especially genes of the major histocompatibility complex and cytokines, which may be related to the development of factor VIII inhibitors in hemophilia A patients. Understanding these risk factors will help to determine future differential treatment in the control and prevention of the development of inhibitors. PMID:24106448

  12. Female twins with severe Christmas disease (hemophilia B).

    PubMed

    Wollina, K; Bowen, D J; Syrbe, G; Zintl, F

    1993-11-15

    Hemophilia B is an X-linked bleeding disorder. We report on female twins, who were conspicious in prolonged bleeding after venipuncture as well as hematomas after intramuscular injections even in the first months of their life. Their father suffering from a severe hemophilia B deceased in 1992. Their mother, half-brother and grandmother from their father's side had no signs of bleeding disorders. Clotting analysis performed in both twins revealed a markedly prolonged partial thromboplastin time (> 100 s). The factor IX levels were below 2%. In order to detect mutations, a general screen using the polymerase chain reaction (PCR) followed by single strand conformation polymorphism (SSCP) analysis of the PCR products have been performed. PCR products have been cut into smaller fragments using restriction endonucleases (RE) for an in-depth SSCP screen. A general screen for gross abnormalities in the factor IX gene including deletions, insertions and rearrangements was performed by Southern blot analysis of RE-digests of genomic DNA using the factor IX cDNA as a hybridization probe. Furthermore, we screened for mutations in the CG dinucleotides comprising part of RE-recognition sequences (exon 1, 2, 3, 4, 5, and 8). By all methods applied herein, no mutations have been detected in these twins. On the basis of our results the hemophilia B of these twins might be explained by extreme non-random lyonization.

  13. 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

  14. Interpatient phenotypic inconsistency in severe congenital hemophilia: a systematic review of the role of inherited thrombophilia.

    PubMed

    Franchini, Massimo; Montagnana, Martina; Targher, Giovanni; Veneri, Dino; Zaffanello, Marco; Salvagno, Gian Luca; Manzato, Franco; Lippi, Giuseppe

    2009-04-01

    It is well known that the clinical phenotype of hemophilia may vary greatly among patients with the same apparent level of coagulation factor and the same genetic mutation. Thus, patients with severe hemophilia may experience a severe phenotype or only a milder bleeding tendency, suggesting some other moderating influence. To elucidate the mechanism of this heterogeneity, some investigators have recently suggested that inherited thrombophilic factors may play a role in the milder clinical presentation of severe hemophilia. In this review, we summarize current knowledge with respect to the modulation of the clinical phenotype of severe hemophilia by prothrombotic genetic risk factors. Although the published literature seems to indicate a protective effect for the coinheritance of factor V Leiden, the limited data available do not permit any firm conclusions. Further trials on a large population of patients are needed to establish the role of genetic thrombophilia in the phenotypic expression of severe hemophilia.

  15. Diagnosis and treatment of congenital hemophilia with inhibitors a Latin American perspective.

    PubMed

    Pérez Bianco, Raúl; Ozelo, Margareth Castro; Villaça, Paula Ribeiro; Solano, Maria Helena; Jimenez Cruze, Guillermo; Martinez Murillo, Carlos; Garcia Chavez, Jaime; Mendoza, Saul; Rodriguez Grecco, Ismael; Ruiz-Saez, Arlette

    2008-01-01

    The Committee of Latin America on the Therapeutics of Inhibitor Groups (CLOTTING) is composed of a number of hemophilia specialists from Latin America. The group aims to encourage the adoption of a good standard of care for Latin American patients with hemophilia. The occurrence of inhibitors in patients with hemophilia poses clinical challenges, and it is estimated that between 1000 and 3000 patients in Latin America are affected by hemophilia with inhibitors. There is an urgent need to establish a regional consensus and clinical guidelines for the diagnosis and treatment of these patients. We present an extensive review based on best current clinical practice and published literature, as seen from a Latin American perspective, taking into account the variable nature of hemophilia care available in the various countries in this Region.

  16. Adenovirus-Associated Virus Vector–Mediated Gene Transfer in Hemophilia B

    PubMed Central

    Nathwani, Amit C.; Tuddenham, Edward G.D.; Rangarajan, Savita; Rosales, Cecilia; McIntosh, Jenny; Linch, David C.; Chowdary, Pratima; Riddell, Anne; Pie, Arnulfo Jaquilmac; Harrington, Chris; O’Beirne, James; Smith, Keith; Pasi, John; Glader, Bertil; Rustagi, Pradip; Ng, Catherine Y.C.; Kay, Mark A.; Zhou, Junfang; Spence, Yunyu; Morton, Christopher L.; Allay, James; Coleman, John; Sleep, Susan; Cunningham, John M.; Srivastava, Deokumar; Basner-Tschakarjan, Etiena; Mingozzi, Federico; High, Katherine A.; Gray, John T.; Reiss, Ulrike M.; Nienhuis, Arthur W.; Davidoff, Andrew M.

    2012-01-01

    BACKGROUND Hemophilia B, an X-linked disorder, is ideally suited for gene therapy. We investigated the use of a new gene therapy in patients with the disorder. METHODS We infused a single dose of a serotype-8–pseudotyped, self-complementary adenovirus-associated virus (AAV) vector expressing a codon-optimized human factor IX (FIX) transgene (scAAV2/8-LP1-hFIXco) in a peripheral vein in six patients with severe hemophilia B (FIX activity, <1% of normal values). Study participants were enrolled sequentially in one of three cohorts (given a high, intermediate, or low dose of vector), with two participants in each group. Vector was administered without immunosuppressive therapy, and participants were followed for 6 to 16 months. RESULTS AAV-mediated expression of FIX at 2 to 11% of normal levels was observed in all participants. Four of the six discontinued FIX prophylaxis and remained free of spontaneous hemorrhage; in the other two, the interval between prophylactic injections was increased. Of the two participants who received the high dose of vector, one had a transient, asymptomatic elevation of serum aminotransferase levels, which was associated with the detection of AAV8-capsid–specific T cells in the peripheral blood; the other had a slight increase in liver-enzyme levels, the cause of which was less clear. Each of these two participants received a short course of glucocorticoid therapy, which rapidly normalized aminotransferase levels and maintained FIX levels in the range of 3 to 11% of normal values. CONCLUSIONS Peripheral-vein infusion of scAAV2/8-LP1-hFIXco resulted in FIX transgene expression at levels sufficient to improve the bleeding phenotype, with few side effects. Although immune-mediated clearance of AAV-transduced hepatocytes remains a concern, this process may be controlled with a short course of glucocorticoids without loss of transgene expression. (Funded by the Medical Research Council and others; ClinicalTrials.gov number, NCT00979238

  17. Health-related quality of life in hemophilia: results of the Hemophilia-Specific Quality of Life Index (Haem-a-Qol) at a Brazilian blood center

    PubMed Central

    Ferreira, Adriana Aparecida; Leite, Isabel Cristina Gonçalves; Bustamante-Teixeira, Maria Teresa; Corrêa, Camila Soares Lima; da Cruz, Danielle Teles; Rodrigues, Daniela de Oliveira Werneck; Ferreira, Monica Calil Borges

    2013-01-01

    Background Studies on health-related quality of life are based on the increasingly evident need for medical care not to be limited to preventing death, but to focus instead on the value of health. Objective This study aimed to measure the health-related quality of life in hemophilia, using the Hemophilia- Specific Quality of Life (Haem-A-QoL) questionnaire and describe the socioeconomic characteristics and health conditions of these patients. Methods The Brazilian version of the Hemophilia-Specific Quality of Life questionnaire was administered to hemophiliac adults, treated in an on-demand regime at the Juiz de Fora Regional Blood Center - HEMOMINAS Foundation. The patients were interviewed about demographic and socioeconomic data and their understanding of the questionnaire. Clinical data were collected from medical records. The Mann-Whitney U test was used for statistical analysis. The level of significance was set for p-values < 0.05. Statistical analysis was performed using the Statistical Package for the Social Sciences (SPSS, version 15.0). Results Thirty-nine patients were evaluated. The mean age was 36.8 years. 84.6% had hemophilia A; 20.5% of the patients had hemophilia classified as mild, 41% as moderate and 38.5% as severe. The records of 10.5% of the patients registered seropositivity for anti-HIV and 57.9% for anti-HCV. Target joints were detected in 69.2%. The mean total Hemophilia-Specific Quality of Life score was 35.55. 'Sports and leisure'and 'Physical health'were the most impaired dimensions and the dimension 'Relationship and partners'was the least impaired. The Hemophilia-Specific Quality of Life scores showed good discriminant validity for hemophilia severity (p-value = 0.001), HIV-infection (p-value = 0.02), HCV-infection (p-value = 0.01) and the presence of target joints (p-value < 0.001). Conclusion Health-related quality of life in hemophilia, measured by the Hemophilia-Specific Quality of Life questionnaire, was influenced by the

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

    PubMed

    Shetty, Shrimati; Bhave, Manali; Ghosh, Kanjaksha

    2011-04-01

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

  19. Factor IX molecular defects in diagnosing hemophilia B: a review.

    PubMed

    Tanimoto, M

    1989-07-01

    The past several years have seen an explosive growth in the application of recombinant DNA methods to study the molecular pathology of various inherited disorders. As a consequence, molecular defects responsible for the disease have been identified at the sequence level. In this review, I briefly describe the recent progress in the uses of factor IX gene probes in clinical diagnosis of hemophilia B (Christmas disease) carriers, as well as their use for analyzing the structural gene abnormalities that are responsible for the disease.

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

    PubMed Central

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

    2013-01-01

    Hemophilia A is a hereditary disorder caused by various mutations in factor VIII gene resulting in either a severe deficit or total lack of the corresponding activity. Recent success in gene therapy of a related disease, hemophilia B, gives new hope that similar success can be achieved for hemophilia A as well. To develop a gene therapy strategy for the latter, a variety of model systems are needed to evaluate molecular engineering of the factor VIII gene, vector delivery efficacy and safety-related issues. Typically, a tissue culture cell line is the most convenient way to get a preliminary glimpse of the potential of a vector delivery strategy. It is then followed by extensive testing in hemophilia A mouse and dog models. Newly developed hemophilia A sheep may provide yet another tool for evaluation of factor VIII gene delivery vectors. Hemophilia models based on other species may also be developed since hemophiliac animals have been identified or generated in rat, pig, cattle and horse. Although a genetic nonhuman primate hemophilia A model has yet to be developed, the non-genetic hemophilia A model can also be used for special purposes when specific questions need to be addressed that cannot not be answered in other model systems. Hemophilia A is caused by a functional deficiency in the factor VIII gene. This X-linked, recessive bleeding disorder affects approximately 1 in 5000 males [1–3]. Clinically, it is characterized by frequent and spontaneous joint hemorrhages, easy bruising and prolonged bleeding time. The coagulation activity of FVIII dictates severity of the clinical symptoms. Approximately 50% of all cases are classified as severe with less than 1% of normal levels of factor VIII detected [4]. This deficiency may lead to spontaneous joint hemorrhages or life-threatening bleeding. In contrast, patients with 5–30% of normal factor VIII activity exhibit mild clinical manifestations. PMID:25401041

  1. 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

  2. Safety and efficacy of TIPS in patients with hemophilia and cirrhosis.

    PubMed

    Beirne, Joshua P; Bloom, Allan I; Bass, Nathan M; Kerlan, Robert K; Wilson, Mark W; Gordon, Roy L; Laberge, Jeanne M

    2007-02-01

    The prevalence of portal hypertension and its complications is increasing among patients with hemophilia and cirrhosis. The authors evaluated the safety and efficacy of transjugular intrahepatic postosystemic shunt (TIPS) placement in this population. A retrospective analysis was performed of adult patients who underwent TIPS placement at a single center. Four patients with hemophilia and cirrhosis were identified. Outcome measures included technical success and complications, recurrent gastrointestinal hemorrhage, shunt patency, hepatic encephalopathy, ascites control, and mortality. With periprocedural factor VIII supplementation, TIPS were placed in all patients without complications and with improvement in portal hypertension. Outcomes after TIPS placement appear to be comparable to those in patients without hemophilia. PMID:17327567

  3. 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

  4. Dallas, police surveillance and the NHF. National Hemophilia Foundation.

    PubMed

    Dubin, C S

    1995-04-01

    In 1995, the National Hemophilia Foundation (NHF) held its annual meeting in Dallas amid ongoing controversies over AIDS and viral contamination of the U.S. blood supply. Principal topics were the class action lawsuit, delivering justice to those infected with HIV, and the legislative campaign for government compensation. The Dallas meeting was marked by controversy: the NHF failed to endorse the class action suit against blood supply producers; the NHF Board elections produced a leadership dominated by people without hemophilia and ignored persons who represented change; and a large number of police were present, authorized by the NHF, and seen by many to be a result of the NHF members' concern about potentially unruly demonstrations or possibly as a way of squashing dissent and diversity. The NHF has also discouraged those infected with HIV from taking legal action, and they have openly obstructed the pursuit of legal justice by disseminating misinformation regarding individuals' legal rights. It is felt that the NHF cannot be characterized as a consumer advocacy group and that the Dallas meeting served only to reinforce the view of NHF's role in obstructing the real empowerment of the hemophiliac community.

  5. Recurrent bleeding following traumatic hyphema due to mild hemophilia B (Christmas disease).

    PubMed

    Wilker, Shawn C; Singh, Annapurna; Ellis, Forrest J

    2007-12-01

    Traumatic hyphemas generally resolve spontaneously. When recurrent bleeding occurs, a coagulopathy should be suspected. We present a unique case of a traumatic hyphema with recurrent bleeding in association with mild hemophilia B (factor IX deficiency).

  6. Nested Cohort

    Cancer.gov

    NestedCohort is an R software package for fitting Kaplan-Meier and Cox Models to estimate standardized survival and attributable risks for studies where covariates of interest are observed on only a sample of the cohort.

  7. 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

  8. 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.

  9. 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.

  10. Current and future prospects for hemophilia gene therapy.

    PubMed

    Ward, Peter; Walsh, Christopher E

    2016-07-01

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

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

    PubMed

    Ali, T; Schved, J F

    2012-11-01

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

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

    PubMed

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

    2014-12-01

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

  13. 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

  14. 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

  15. 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.

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

    PubMed

    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.

  17. 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

  18. Portal Vein Delivery of Viral Vectors for Gene Therapy for Hemophilia

    PubMed Central

    Sherman, Alexandra; Schlachterman, Alexander; Cooper, Mario; Merricks, Elizabeth P.; Raymer, Robin A.; Bellinger, Dwight A.; Herzog, Roland W.; Nichols, Timothy C.

    2014-01-01

    The liver is a very complex organ with a large variety of functions, making it an attractive organ for gene replacement therapy. Many genetic disorders can be corrected by delivering gene products directly into the liver using viral vectors. In this chapter, we will describe gene delivery via portal vein administration in mice and dogs to correct the blood coagulation disorder hemophilia B. Although there are multiple delivery routes for both viral and non-viral vectors in animals, portal vein administration delivers vectors directly and efficiently into the liver. Complete correction of murine hemophilia B and multi-year near-correction of canine hemophilia B have been achieved following portal vein delivery of adeno-associated viral (AAV) vectors expressing factor IX from hepatocyte-specific promoters. Peripheral vein injection can lead to increased vector dissemination to off-target organ such as the lung and spleen. Below, we will describe portal vein injection delivery route via laparotomy. PMID:24557919

  19. Transitioning issues in adolescent to young adult hemophilia patients with inhibitors: an approach for a growing population.

    PubMed

    Young, Guy

    2010-09-01

    The major adverse effect of factor replacement therapy in patients with hemophilia is the development of neutralizing antibodies termed inhibitors. This complication renders standard factor replacement therapy ineffective resulting in increased morbidity and mortality. Until recently, the population of adults with inhibitors was relatively small due to the death of many of the patients from HIV that they contracted from contaminated factor in the early 1980s. With the advent of factor products with reduced risks for deadly infections in the mid-1980s to early 1990s, a cohort of inhibitor patients is now beginning to enter adulthood thus raising the issues regarding the transition of these patients into adulthood. It is, therefore, expected that adult hematologists will be seeing more inhibitor patients and that pediatric hematologists will be faced with managing this transition process, which may not necessarily include transition to an adult facility or adult hematologist. This review will discuss the various issues ranging from choice of medical provider to a discussion of psychosocial and financial issues facing this specific patient population.

  20. 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

  1. Specific and global coagulation assays in the diagnosis of discrepant mild hemophilia A.

    PubMed

    Bowyer, Annette E; Van Veen, Joost J; Goodeve, Anne C; Kitchen, Steve; Makris, Michael

    2013-12-01

    The activity of the factor VIII coagulation protein can be measured by three methods: a one or two-stage clotting assay and a chromogenic assay. The factor VIII activity of most individuals with mild hemophilia A is the same regardless of which method is employed. However, approximately 30% of patients show marked discrepancies in factor VIII activity measured with the different methods. The objective of this study was to investigate the incidence of assay discrepancy in our center, assess the impact of alternative reagents on factor VIII activity assays and determine the usefulness of global assays of hemostasis in mild hemophilia A. Factor VIII activity was measured in 84 individuals with mild hemophilia A using different reagents. Assay discrepancy was defined as a two-fold or greater difference between the results of the one-stage and two-stage clotting assays. Rotational thromboelastometry and calibrated automated thrombography were performed. Assay discrepancy was observed in 31% of individuals; 12% with lower activity in the two-stage assay and 19% with lower activity in the one-stage assay. The phenotype could not always be predicted from the individual's genotype. Chromogenic assays were shown to be a suitable alternative to the two-stage clotting assay. Thromboelastometry was found to have poor sensitivity in hemophilia. Calibrated automated thrombography supported the results obtained by the two-stage and chromogenic assays. The current international guidelines do not define the type of assay to be used in the diagnosis of mild hemophilia A and some patients could be misclassified as normal. In our study, 4% of patients would not have been diagnosed on the basis of the one-stage factor VIII assay. Laboratories should use both one stage and chromogenic (or two-stage) assays in the diagnosis of patients with possible hemophilia A.

  2. 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

  3. 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

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

    PubMed

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

    2014-06-01

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

  5. 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

  6. Tailored versus standard dose prophylaxis in children with hemophilia A.

    PubMed

    Santoro, Cristina; Baldacci, Erminia; Mercanti, Caterina; Mazzucconi, Maria Gabriella

    2013-10-01

    Prophylaxis is universally recognized as the treatment of choice in people with hemophilia, and tailored prophylaxis is the consistent modification of the standard weight-based dosing regimen. A large number of factors guide the choice of a specific tailored regimen, and different regimens are under evaluation. Tailored low-dose frequent regimens are likely to be cost-effective, but they are less accepted by patients. Escalating dose regimens seem to be quite effective in preventing bleedings and, consequently, arthropathy, although data on long-term outcomes are still not available. Pharmacokinetic-driven approaches have been also proposed. Sensitive and validated tools able to reliably measure the different outcomes are necessary in this setting. With regard to the evaluation of arthropathy, magnetic resonance imaging and ultrasound are promising imaging techniques in detecting early joint damage. Factor VIII trough levels can be considered a measure of the efficacy of FVIII infused, although other factors influence the bleeding pattern. Global assays of coagulation could provide more complete information on the hemostatic potential of a sample and predict bleeding phenotype. These techniques are also promising for the individualization of prophylaxis regimens, potentially resulting in less frequent dosing, more comfortable and less expensive approaches.

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

    PubMed

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

    2015-03-01

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

  8. [Cohort studies].

    PubMed

    Mathis, Stefan; Gartlehner, Gerald

    2008-01-01

    This article about cohort studies is part of a methods series about study designs and their critical evaluation by the Ludwig Boltzmann Institute for Health Technology assessment. This article aims to describe the theoretical concept of cohort studies and their typical characteristics. Furthermore, it strives to highlight advantages and disadvantages of this study type and to make suggestions for the critical evaluation of the significance and validity of cohort studies. The article gives an account about characteristics due to the observational design and ways of acquiring control groups. Problems of blurring results by selection bias and confounding are also discussed. Cohort studies are applied in situations where the effects of environmental exposures are measured and rare side effects are identified but randomised controlled studies did not show significant results because of limitations. They are also used to assess the incidence of a disease or a condition.

  9. 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

  10. 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

  11. Efficacy and safety of recombinant factor VIII products in patients with hemophilia A.

    PubMed

    Musso, Robert

    2008-10-01

    The introduction of recombinant factor VIII (rFVIII) clotting factor concentrates nearly 20 years ago represented a significant advance in the treatment of hemophilia A. The major advantage of rFVIII products compared with plasma-derived FVIII products is related to product safety, with rFVIII products virtually eliminating bloodborne pathogen transmission. The most challenging aspect of hemophilia A management today is the development of FVIII inhibitors; previously untreated patients are at the highest risk for inhibitor formation. Presented in this article are results of clinical trials in previously treated and untreated patients and postmarketing surveillance studies for the four commercially available rFVIII products (Recombinate, ReFacto, Kogenate FS/Kogenate Bayer and Advate). Recombinant FVIII therapies are highly efficacious when used ondemand and prophylactically, and they have excellent safety profiles; there have been no reports of viral- or prion-based disease transmission associated with rFVIII administration. The incidence rate of inhibitors in previously untreated patients ranges from 15% to approximately 30%. Because rFVIII concentrates have proven efficacy and safety profiles, a number of hemophilia treatment groups recommend rFVIII products as first-line therapy in the management of hemophilia A.

  12. Hemophilia relief bill passes, but money won't arrive soon.

    PubMed

    1998-11-27

    The Ricky Ray Hemophilia Relief Act, signed by President Clinton, authorized up to $750 million in compensation to hemophiliacs infected with HIV through 1987 from contaminated blood products. That amount represents an estimated $100,000 per hemophiliac or survivor. The money will hopefully be available in fiscal 2000, subject to Congress passing a specific appropriations bill.

  13. Translational Data from Adeno-Associated Virus-Mediated Gene Therapy of Hemophilia B in Dogs

    PubMed Central

    Whitford, Margaret H.; Arruda, Valder R.; Stedman, Hansell H.; Kay, Mark A.; High, Katherine A.

    2015-01-01

    Abstract 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

  14. Advances in hemophilia and the role of current and emerging prophylaxis.

    PubMed

    Acharya, Suchitra S

    2016-04-01

    The primary goal of hemophilia treatment and management is the prevention of painful, disabling, and costly joint arthropathy that results from its characteristic bleeding into joints and muscles. Prophylactic treatment with clotting-factor concentrates has been shown to prevent hemophilic arthropathy and is, therefore, the standard of care for hemophilia A and B. Data has demonstrated the clinical efficacy and overall benefits of prophylaxis in young children, adolescents, and adults. Early initiation with prima-ry prophylaxis is ideal, but secondary prophylaxis in adolescents and adults has also demonstrated significant success. Because the standard of care includes prophylaxis with factor-concentrate replacement in order to prevent joint damage in patients with hemophilia, prophylaxis is now more common and needs to be addressed in all clinical settings, including managed care. However, further research is needed to help clinicians develop individualized factor-replacement protocols and under-stand the impact of long-term use into adulthood. World Federation of Hemophilia guidelines do not have definitive recommendations on continuation of prophylaxis into adulthood. The optimal regimen for initiating prophylaxis, duration of treatment, and dosing regimens continue to be studied.

  15. 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.

  16. 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

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

    PubMed Central

    Cancio, Maria I; Reiss, Ulrike M; Nathwani, Amit C; Davidoff, Andrew M; Gray, John T

    2013-01-01

    Hemophilia B is a genetic disorder that is characterized by a deficiency of clotting factor IX (FIX) and excessive bleeding. Advanced understanding of the pathophysiology of the disease has led to the development of improved treatment strategies that aim to minimize the acute and long-term complications of the disease. Patients with hemophilia B are ideal candidates for gene therapy, mostly because a small increase in protein production can lead to significantly decreased bleeding diathesis. Although human clotting FIX was cloned and sequenced over 30 years ago, progress toward achieving real success in human clinical trials has been slow, with long-term, therapeutically relevant gene expression only achieved in one trial published in 2011. The history of this extensive research effort has revealed the importance of the interactions between gene therapy vectors and multiple arms of the host immune system at multiple stages of the transduction process. Different viral vector systems each have unique properties that influence their ability to deliver genes to different tissues, and the data generated in several clinical trials testing different vectors for hemophilia have guided our understanding toward development of optimal configurations for treating hemophilia B. The recent clinical success implementing a novel adeno-associated virus vector demonstrated sufficient FIX expression in patients to convert a severe hemophilia phenotype to mild, an achievement which has the potential to profoundly alter the impact of this disease on human society. Continued research should lead to vector designs that result in higher FIX activity at lower vector doses and with reduced host immune responses to the vector and the transgene product. PMID:24159262

  18. The investigation of relationship between joint findings and serum angiogenic and inflammatory factor levels in severe hemophilia A patients.

    PubMed

    Karapnar, Tuba H; Karadaş, Nihal; Özek, Gülcihan; Tüfekçi, Özlem; Atabay, Berna; Türker, Meral; Yüksel, Faize; Karapınar, Deniz Y; Vergin, Canan; İrken, Gülersu; Ören, Hale

    2014-10-01

    Despite the use of primary prophylactic Factor VIII replacement in severe hemophilia A patients, bleeding into joints cannot be prevented completely and early diagnosis and treatment of the joint bleedings are important for prevention of permanent joint damage. Recent studies have shown that neoangiogenesis plays important role in development of synovitis after recurrent joint bleedings. This study aimed to investigate the relationship between joint findings and levels of serum angiogenic and inflammatory factors in severe hemophilia A patients.The patient groups consisted of 10 severe hemophilia A patients with acute joint bleeding and 25 severe hemophilia A patients without acute joint bleeding. They were all inhibitor negative. The control group consisted of 22 healthy male children. Complete blood cell count analysis, C-reactive protein (CRP), serum ferritin, lactic acid, and ELISA-based detection of vascular endothelial growth factor (VEGF), intercellular adhesion molecule-1, thrombomodulin, macrophage migration inhibitory factor (MIF), and endostatin were performed from peripheral blood of patient and the control groups. CRP and MIF levels were detected significantly higher in hemophilia patients with acute joint bleeding than patients without acute joint bleeding. There was a positive correlation between serum thrombomodulin, VEGF, and MIF levels. In this study, we demonstrated that serum CRP and MIF levels increases in acute bleeding period regardless of the presence of previous joint damage in children with severe hemophilia. CRP elevation may be a useful and rapid marker for acute bleeding in these patients.

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

    PubMed Central

    Yang, Yao-Hsu; Chang, Chia-Hao; Chen, Chih-Cheng; Chen, Pau-Chung

    2016-01-01

    Introduction Rehabilitation plays an important role in the physical health of patients with hemophilia. However, comprehensive information regarding the utilization of rehabilitation for such patients remains scarce. Aim This population-based study aimed to examine the characteristics, trends, and most important factors affecting rehabilitation usage in patients with hemophilia A using a nationwide database in Taiwan. Methods Data from 777 patients with hemophilia A who were registered in the National Health Insurance Research Database between 1998 and 2008 were analyzed using SAS 9.0. Results Musculoskeletal or nervous system-related surgical procedures and clotting factor VIII concentrate costs were identified as factors affecting rehabilitation usage; musculoskeletal or nervous system-related surgical procedures (odds ratio = 3.788; P < 0.001) were the most important predictor of whether a patient with hemophilia A would use rehabilitation services. Joint disorders, arthropathies, bone and cartilage disorders, intracranial hemorrhage, and brain trauma were common diagnoses during rehabilitation use. The costs of physical therapy (physiotherapy) comprised the majority (71.2%) of rehabilitation therapy categories. Increasingly, rehabilitation therapy was performed at physician clinics. The total rehabilitation costs were <0.1% of the total annual medical costs. Conclusion Musculoskeletal or nervous system-related surgical procedures and increased use of clotting factor VIII concentrate affect the rehabilitation utilization of patients with hemophilia A the most. The findings in this study could help clinicians comprehensively understand the rehabilitation utilization of patients with hemophilia A. PMID:27690229

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

    PubMed Central

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

    2009-01-01

    Liver sinusoidal endothelial cells are a major endogenous source of Factor VIII (FVIII), lack of which causes the human congenital bleeding disorder hemophilia A. Despite extensive efforts, gene therapy using viral vectors has shown little success in clinical hemophilia trials. Here we achieved cell type–specific gene targeting using hyaluronan- and asialoorosomucoid-coated nanocapsules, generated using dispersion atomization, to direct genes to liver sinusoidal endothelial cells and hepatocytes, respectively. To highlight the therapeutic potential of this approach, we encapsulated Sleeping Beauty transposon expressing the B domain–deleted canine FVIII in cis with Sleeping Beauty transposase in hyaluronan nanocapsules and injected them intravenously into hemophilia A mice. The treated mice exhibited activated partial thromboplastin times that were comparable to those of wild-type mice at 5 and 50 weeks and substantially shorter than those of untreated controls at the same time points. Further, plasma FVIII activity in the treated hemophilia A mice was nearly identical to that in wild-type mice through 50 weeks, while untreated hemophilia A mice exhibited no detectable FVIII activity. Thus, Sleeping Beauty transposon targeted to liver sinusoidal endothelial cells provided long-term expression of FVIII, without apparent antibody formation, and improved the phenotype of hemophilia A mice. PMID:19509468

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

    PubMed

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

    2015-10-01

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

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

    PubMed

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

    2015-06-01

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

  3. 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.

  4. Attitudes and practices of hemophilia care providers involved in HIV risk-reduction counseling.

    PubMed

    Meredith, K L; Hannan, J A; Green, T A; Wiley, S D

    1994-10-01

    Hemophilia physicians, nurses, and social workers attending a national conference were asked to complete a questionnaire assessing their attitudes and practices regarding HIV risk-reduction counseling. All of the 150 respondents reported recommending the use of condoms to their clients, but only two-thirds felt comfortable demonstrating a condom, while fewer could explain condom choices or how to make safe sex more pleasurable. Less than half questioned their clients about history of STDs, sexual practices, or level of sexual satisfaction. Those who devoted 50 percent or more time to HIV risk-reduction efforts reported being more complete in their assessment and more comfortable in their counseling role. Providers claimed it would help if they had more time (84%) and better skills (64%, especially nurses) for this practice. Because HIV prevention services in hemophilia are delivered by a team, further studies are required to determine the aggregate impact of their intervention on the client.

  5. Hemophilia And Von Willebrand Disease In Children: Emergency Department Evaluation And Management.

    PubMed

    Schwartz, Kevin R; Rubinstein, Max

    2015-09-01

    Hemophilia and von Willebrand disease are the most common inherited bleeding disorders encountered in the emergency department. Evidence suggests that the management of bleeding disorders in the emergency department is currently suboptimal, and literature to guide evaluation and management in this setting is limited, though some guidelines do exist. The emergency clinician must have a high index of suspicion for new diagnoses, particularly in young patients with unprovoked bleeding and children with multiple or severe bleeds. The foundation of hemophilia treatment is urgent clotting factor replacement, with replacement goals guided by the presenting complaint. Bleeding in von Willebrand disease may be treated with products containing von Willebrand factor or with desmopressin. This review focuses on the epidemiology, pathophysiology, common presentations, evaluation strategies, and emergency management of these bleeding disorders.

  6. Advances in the clinical management of inhibitors in hemophilia A and B.

    PubMed

    Leissinger, Cindy A

    2016-01-01

    Inhibitors to factor (F)VIII or FIX are the most serious and challenging complication of hemophilia treatment, increasing morbidity and mortality because bleeds no longer respond to standard clotting factor replacement therapy. For patients with high-titer inhibitors, immune tolerance induction achieved through regular factor exposure is the only proven therapy capable of Inhibitor eradication and is almost always indicated for inhibitors of recent onset. Bypassing therapy is used to treat and prevent bleeding, but neither of the two currently available bypassing agents has the predictable hemostatic efficacy of factor replacement in hemophilia patients without inhibitors. Major research efforts are focused on the development of new, more potent therapies for the management of patients with inhibitors.

  7. [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.

  8. Permanent phenotypic correction of hemophilia B in immunocompetent mice by prenatal gene therapy.

    PubMed

    Waddington, Simon N; Nivsarkar, Megha S; Mistry, Ajay R; Buckley, Suzanne M K; Kemball-Cook, Geoffrey; Mosley, Karen L; Mitrophanous, Kyriacos; Radcliffe, Pippa; Holder, Maxine V; Brittan, Mairi; Georgiadis, Anastasios; Al-Allaf, Faisal; Bigger, Brian W; Gregory, Lisa G; Cook, H Terence; Ali, Robin R; Thrasher, Adrian; Tuddenham, Edward G D; Themis, Mike; Coutelle, Charles

    2004-11-01

    Hemophilia B, also known as Christmas disease, arises from mutations in the factor IX (F9) gene. Its treatment in humans, by recombinant protein substitution, is expensive, thus limiting its application to intermittent treatment in bleeding episodes and prophylaxis during surgery; development of inhibitory antibodies is an associated hazard. This study demonstrates permanent therapeutic correction of his disease without development of immune reactions by introduction of an HIV-based lentiviral vector encoding the human factor IX protein into the fetal circulation of immunocompetent hemophiliac and normal outbred mice. Plasma factor IX antigen remained at around 9%, 13%, and 16% of normal in the 3 hemophilia B mice, respectively, until the last measurement at 14 months. Substantial improvement in blood coagulability as measured by coagulation assay was seen in all 3 mice and they rapidly stopped bleeding after venipuncture. No humoral or cellular immunity against the protein, elevation of serum liver enzymes, or vector spread to the germline or maternal circulation were detected.

  9. 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

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

    PubMed

    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

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

    PubMed Central

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

    PubMed

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

    2015-05-01

    The previously published mortality studies are limited in hemophilia populations but suggest that there is no increased risk of mortality in factor VIII inhibitor patients. This retrospective study analyzed surveillance data collected on 7,386 males with severe hemophilia A over a 13-year period to assess the association between a current inhibitor and death. During the study period, 432 participants died, among whom 48 were patients with an inhibitor. Clinical characteristics most strongly associated with death were increased number of reported bleeds, signs of liver disease, infection with either HIV or HCV, and the presence of inhibitor. Patients who underwent successful tolerization were not considered inhibitor patients in our analysis. In a multivariable analysis, the odds of death were 70% higher among patients with a current inhibitor compared to those without an inhibitor (P < 0.01). Deaths among patients with inhibitors were much more likely to be attributed to bleeding complications than those among patients without an inhibitor (42 vs. 12%, P < 0.0001). We conclude that males with severe hemophilia A and a current inhibitor are at increased risk of death.

  13. 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.

  14. 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

  15. Development of acquired hemophilia A during treatment of multiple myeloma with lenalidomide.

    PubMed

    Saburi, Masuho; Ohtsuka, Eiichi; Itani, Kazuhito; Nagamatsu, Kentarou; Ikebe, Taichi; Miyazaki, Yasuhiko; Ogata, Masao; Saburi, Yoshio

    2015-05-01

    We describe a 67-year-old female demonstrating symptomatic multiple myeloma (MM) with anemia and bone lesions initially diagnosed in 2009. Although a partial response was achieved after bortezomib and dexamethasone treatment, MM recurred in 2012. Therefore, treatment with lenalidomide, cyclophosphamide, and dexamethasone was commenced. Coagulation tests conducted prior to the chemotherapy were normal. Lenalidomide was discontinued after 10 days due to exacerbation of renal dysfunction. Simultaneously, activated partial thromboplastin time (APTT) was prolonged to 89.5 seconds. The mixing test showed an inhibitor pattern, with factor VIII at 2% and factor VIII inhibitor at 4.85 BU/ml. A diagnosis of acquired hemophilia A was made, and treatment with prednisolone was started, after which APTT improved to 36.4 seconds and factor VIII inhibitor decreased to 1.09 BU/ml. The factor VIII inhibitor level again increased concomitantly with restarting lenalidomide, which was, therefore, discontinued, while immunosuppressive therapy was administered with the addition of cyclophosphamide. Factor VIII inhibitor gradually disappeared from the patient's blood over the next four months. To the best of our knowledge, this is the first description of lenalidomide as a possible cause of acquired hemophilia A. Our experience indicates that we need to pay attention to acquired hemophilia A after initiating lenalidomide therapy in patients with hematologic malignancies.

  16. Targeting factor replacement therapy in severe hemophilia: which level is important?

    PubMed

    Fischer, Kathelijn; Berntorp, Erik

    2015-11-01

    The original aim of prophylactic replacement therapy was to convert the bleeding pattern of severe hemophilia to that of moderate hemophilia through regular infusions of clotting factor concentrates. However, targeting prophylaxis on minimum trough levels does not prevent all bleeding. At the group level, there is a clear association of factor levels with bleeding and outcome. But bleeding phenotype in individual patients shows large variation, independent of trough levels maintained. The association of peak levels with bleeding on prophylaxis is not established. Experience with surgery suggests that certain peak levels need to be achieved during other hemostatic challenges, such as playing sports. Individualization of prophylaxis should include timing of infusion according to special activities. The clinical relevance of factor levels is even more urgent since the recent introduction of long-acting clotting factor concentrates with their different pharmacokinetic profiles and the prospect of gene therapy resulting in constant factor levels. It should be considered that the success of any prophylactic regimen is also dependent on other factors, such as the age at initiation of prophylaxis, adherence, lifestyle, cartilage susceptibility, and the other components of the clotting system. Factor levels are thus an important but quite small piece in the total picture of treating hemophilia and we currently cannot identify a specific trough or peak level to use for monitoring. At the same time, knowledge of a patients' level during the infusion intervals may help to individualize and adjust treatment according to the clinical symptoms.

  17. 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.

  18. 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

  19. Danazol increases factor VIII and factor IX in classic hemophilia and Christmas disease.

    PubMed

    Gralnick, H R; Rick, M E

    1983-06-01

    We gave danazol (600 mg per day orally for 14 days), an attenuated androgen, to four adults with classic hemophilia and one adult with Christmas disease. The levels of factor VIII in the patients with classic hemophilia ranged from 1 to 3 per cent before treatment and rose to 3 to 8 per cent during the treatment period. The level of factor IX in the patient with Christmas disease rose from 5 to 14 per cent. The rise in clotting-factor activity was usually observed within five to six days after the initiation of therapy and peaked between 7 and 13 days. The drug had no untoward effects. During the 70 patient-days of therapy, only two patients required plasma products, each on one occasion. These data suggest that danazol therapy may decrease the hemorrhagic tendency and reduce the need for transfusions of plasma products in classic hemophilia and Christmas disease. Controlled clinical trials will be required to establish its value in these applications.

  20. Social Worker Perceptions and Observations Regarding Men's Management of Hemophilia and Use of Community-Based Support.

    PubMed

    Rolstad, Erik Bruce

    2015-08-01

    The study reported in this article was conducted in response to Utah service provider concerns that men with hemophilia may be disengaged from their local community-based support network. This study explored the challenges, adaptations, and needs of men with hemophilia from the perspective of Hemophilia Treatment Center (HTC) social workers. Utah's two active HTC social workers participated in face-to-face interviews. Fourteen HTC social workers from surrounding regions completed written interviews. The researcher used a qualitative, grounded theory approach to analyze the data. Resilience theory provided a lens for interpreting the results. Findings from these professionals indicate that men with hemophilia appear to be ambivalent toward services that are available to them for reasons that include work and insurance status, prior personal history with the bleeding disorders community, strength of relationship with local service providers, degree of customization of HTC services, and the desire to maintain personal independence. Understanding this dynamic may be helpful in developing services that are more specifically tailored to the needs of men with hemophilia, in addition to potentially providing stronger community-based support to men with other genetic disorders. PMID:26285364

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

    PubMed Central

    Porada, Christopher D.; Almeida-Porada, Graça

    2012-01-01

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

  2. Social Worker Perceptions and Observations Regarding Men's Management of Hemophilia and Use of Community-Based Support.

    PubMed

    Rolstad, Erik Bruce

    2015-08-01

    The study reported in this article was conducted in response to Utah service provider concerns that men with hemophilia may be disengaged from their local community-based support network. This study explored the challenges, adaptations, and needs of men with hemophilia from the perspective of Hemophilia Treatment Center (HTC) social workers. Utah's two active HTC social workers participated in face-to-face interviews. Fourteen HTC social workers from surrounding regions completed written interviews. The researcher used a qualitative, grounded theory approach to analyze the data. Resilience theory provided a lens for interpreting the results. Findings from these professionals indicate that men with hemophilia appear to be ambivalent toward services that are available to them for reasons that include work and insurance status, prior personal history with the bleeding disorders community, strength of relationship with local service providers, degree of customization of HTC services, and the desire to maintain personal independence. Understanding this dynamic may be helpful in developing services that are more specifically tailored to the needs of men with hemophilia, in addition to potentially providing stronger community-based support to men with other genetic disorders.

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

    PubMed

    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.

  4. 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

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

    PubMed

    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

  6. A population pharmacokinetic model for perioperative dosing of factor VIII in hemophilia A patients

    PubMed Central

    Hazendonk, Hendrika; Fijnvandraat, Karin; Lock, Janske; Driessens, Mariëtte; van der Meer, Felix; Meijer, Karina; Kruip, Marieke; Gorkom, Britta Laros-van; Peters, Marjolein; de Wildt, Saskia; Leebeek, Frank; Cnossen, Marjon; Mathôt, Ron

    2016-01-01

    The role of pharmacokinetic-guided dosing of factor concentrates in hemophilia is currently a subject of debate and focuses on long-term prophylactic treatment. Few data are available on its impact in the perioperative period. In this study, a population pharmacokinetic model for currently registered factor VIII concentrates was developed for severe and moderate adult and pediatric hemophilia A patients (FVIII levels <0.05 IUmL−1) undergoing elective, minor or major surgery. Retrospective data were collected on FVIII treatment, including timing and dosing, time point of FVIII sampling and all FVIII plasma concentrations achieved (trough, peak and steady state), brand of concentrate, as well as patients’ and surgical characteristics. Population pharmacokinetic modeling was performed using non-linear mixed-effects modeling. Population pharmacokinetic parameters were estimated in 75 adults undergoing 140 surgeries (median age: 48 years; median weight: 80 kg) and 44 children undergoing 58 surgeries (median age: 4.3 years; median weight: 18.5 kg). Pharmacokinetic profiles were best described by a two-compartment model. Typical values for clearance, intercompartment clearance, central and peripheral volume were 0.15 L/h/68 kg, 0.16 L/h/68 kg, 2.81 L/68 kg and 1.90 L/68 kg. Interpatient variability in clearance and central volume was 37% and 27%. Clearance decreased with increasing age (P<0.01) and increased in cases with blood group O (26%; P<0.01). In addition, a minor decrease in clearance was observed when a major surgical procedure was performed (7%; P<0.01). The developed population model describes the perioperative pharmacokinetics of various FVIII concentrates, allowing individualization of perioperative FVIII therapy for severe and moderate hemophilia A patients by Bayesian adaptive dosing. PMID:27390359

  7. 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.

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

    PubMed

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

    2016-07-01

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

  9. 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

  10. Use of recombinant activated factor VII for acute bleeding episodes in acquired hemophilia: final analysis from the Hemostasis and Thrombosis Research Society Registry acquired hemophilia study

    PubMed Central

    Ma, Alice D.; Kessler, Craig M.; Al-Mondhiry, Hamid A.B.; Gut, Robert Z.; Cooper, David L.

    2016-01-01

    The Hemostasis and Thrombosis Research Society Registry was used to monitor the postapproval use and safety of recombinant activated factor VII (rFVIIa). The objective of this article is to evaluate the data from the Hemostasis and Thrombosis Research Society Registry related to rFVIIa-treated bleeding episodes in patients with acquired hemophilia. For each rFVIIa-treated bleeding episode, the initial dose, total dose, average infused dose, number of doses, and treatment duration were calculated. Efficacy was assessed on a three-point scale. Out of the 166 registered patients with acquired hemophilia, 110 patients were treated for 237 bleeding episodes (139 rFVIIa treated); the majority (70%) were in patients older than 60 years. The most frequently reported bleeding locations were subcutaneous (40%) and mucosal (32%). Subcutaneous bleeding episodes were more commonly reported in women (55% vs. 40% men) and white patients (44 vs. 27% black). Of the 139 rFVIIa-treated bleeding episodes, rFVIIa was used as first-line treatment in 127 bleeding episodes. The median initial dose was 90 μg/kg; the median total dose per episode was 333.5 μg/kg. Physician-rated efficacy of rFVIIa for each bleeding episode was reported as ‘bleeding stopped’ in 85% of bleeding episodes, ‘bleeding slowed’ in 11% of bleeding episodes, ‘no improvement’ in 4% of bleeding episodes, and was not documented in 1 bleeding episode. One thromboembolic event was reported; transient neurologic symptoms were reported in a 31-year-old postpartum patient after 110 doses of rFVIIa. Adequate hemostasis was provided for most rFVIIa-treated bleeding episodes at doses largely conforming to the package insert. No major safety concerns were reported. PMID:26761583

  11. 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

  12. 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.…

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

    Technology Transfer Automated Retrieval System (TEKTRAN)

    The canine is the most important large animal model for testing novel hemophilia A(HA) treatment. It is often necessary to use canine factor VIII (cFIII) gene or protein for the evaluation of HA treatment in the canine model. However, the different biological properties between cFVIII and human FVII...

  14. [Prophylaxis in hemophilia: situation analysis and call-to-action in Latin America. A report from the GLAITH group].

    PubMed

    Mijares, Mercedes Elena; De Sánchez, Apsara Boadas

    2015-09-01

    Prophylactic treatment in the management of hemophilia has been a crucial factor in improving the prognosis and quality of life for people with hemophilia (PCH). However, it is not globally implemented. In Latin America it is difficult to assess the status of PCH and the its management does not conform to ideal standards. The GLAITH group discussed the problem in Latin America. A survey of its members and its findings were discussed at a meeting in Bogota in May 2013. Proportions of hemophilia A and B were 75-90% and 10-25% respectively. Severe hemophilia represents 26-55% of cases. A high percentage of PCH have hemophilic arthropathy. The general care and specific treatments of PCH vary by country, only 50-60% of the treatment is covered and in 85-95% of the cases are performed on an on- demand basis. Just 5-15% receives prophylaxis, most of them secondary. Few countries have a national program or homogeneous records. Finally the GLAITH group proceeded to develop a conclusion and call to action for the region where the following points are recommended: the establishment of a unified Latin American registry; prospective cost-effectiveness studies and evaluation criteria related to secondary prophylaxis; comparative studies of quality of life with and without prophylaxis in the region; promotion of individualization of treatment and, the increase of primary and secondary prophylaxis globally in Latin America.

  15. 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

  16. Hierarchical scaffold design for mesenchymal stem cell-based gene therapy of hemophilia B.

    PubMed

    Coutu, Daniel L; Cuerquis, Jessica; El Ayoubi, Rouwayda; Forner, Kathy-Ann; Roy, Ranjan; François, Moïra; Griffith, May; Lillicrap, David; Yousefi, Azizeh-Mitra; Blostein, Mark D; Galipeau, Jacques

    2011-01-01

    Gene therapy for hemophilia B and other hereditary plasma protein deficiencies showed great promise in pre-clinical and early clinical trials. However, safety concerns about in vivo delivery of viral vectors and poor post-transplant survival of ex vivo modified cells remain key hurdles for clinical translation of gene therapy. We here describe a 3D scaffold system based on porous hydroxyapatite-PLGA composites coated with biomineralized collagen 1. When combined with autologous gene-engineered factor IX (hFIX) positive mesenchymal stem cells (MSCs) and implanted in hemophilic mice, these scaffolds supported long-term engraftment and systemic protein delivery by MSCs in vivo. Optimization of the scaffolds at the macro-, micro- and nanoscales provided efficient cell delivery capacity, MSC self-renewal and osteogenesis respectively, concurrent with sustained delivery of hFIX. In conclusion, the use of gene-enhanced MSC-seeded scaffolds may be of practical use for treatment of hemophilia B and other plasma protein deficiencies. PMID:20864158

  17. The story of a unique molecule in hemophilia A: recombinant single-chain factor VIII.

    PubMed

    Pabinger-Fasching, Ingrid

    2016-05-01

    For patients with hemophilia A, replacement of deficient factor VIII (FVIII) using plasma-derived or recombinant FVIII (rFVIII) products to restore hemostatic control can reduce bleeding complications and preserve musculoskeletal function. Despite the clinical availability of several of these products, challenges remain in the treatment of hemophilia A, the most notable of which are the risk of inhibitor development and the limited half-life of existing FVIII concentrates, which can make prophylaxis burdensome for patients. The use of recombinant protein technology may lead to novel FVIII products with improved properties. This article describes the story of a unique recombinant FVIII protein, rVIII-SingleChain, which is currently in development. In contrast to native FVIII and other commercially available rFVIII preparations, rVIII-SingleChain uses a strong, covalent bond to connect the light and heavy chains, thereby creating a stable, single-chain rFVIII. It has enhanced intrinsic stability, better integrity after reconstitution, and a higher binding affinity to von Willebrand factor. The physicochemical profile of rVIII-SingleChain and preclinical data on its activity and phamacokinetics strengthened the rationale for its clinical investigation. Available data from the AFFINITY clinical trial program are promising; indicating that it has good hemostatic efficacy when used on demand, for prophylaxis, and in the surgical setting, and is also very well tolerated. A pediatric study and an extension study are ongoing as part of the AFFINITY program.

  18. 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.

  19. The story of a unique molecule in hemophilia A: recombinant single-chain factor VIII.

    PubMed

    Pabinger-Fasching, Ingrid

    2016-05-01

    For patients with hemophilia A, replacement of deficient factor VIII (FVIII) using plasma-derived or recombinant FVIII (rFVIII) products to restore hemostatic control can reduce bleeding complications and preserve musculoskeletal function. Despite the clinical availability of several of these products, challenges remain in the treatment of hemophilia A, the most notable of which are the risk of inhibitor development and the limited half-life of existing FVIII concentrates, which can make prophylaxis burdensome for patients. The use of recombinant protein technology may lead to novel FVIII products with improved properties. This article describes the story of a unique recombinant FVIII protein, rVIII-SingleChain, which is currently in development. In contrast to native FVIII and other commercially available rFVIII preparations, rVIII-SingleChain uses a strong, covalent bond to connect the light and heavy chains, thereby creating a stable, single-chain rFVIII. It has enhanced intrinsic stability, better integrity after reconstitution, and a higher binding affinity to von Willebrand factor. The physicochemical profile of rVIII-SingleChain and preclinical data on its activity and phamacokinetics strengthened the rationale for its clinical investigation. Available data from the AFFINITY clinical trial program are promising; indicating that it has good hemostatic efficacy when used on demand, for prophylaxis, and in the surgical setting, and is also very well tolerated. A pediatric study and an extension study are ongoing as part of the AFFINITY program. PMID:27288063

  20. 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

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

    PubMed

    Shetty, Shrimati D; Ghosh, Kanjaksha

    2015-03-01

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

  2. Mixing and administration times of bypassing agents: observations from the Dosing Observational Study in Hemophilia (DOSE)

    PubMed Central

    Maahs, Jennifer; Donkin, Jennifer; Recht, Michael; Cooper, David L

    2014-01-01

    DOSE (Dosing Observational Study in Hemophilia) was a prospective, observational diary study designed to evaluate the use of bypassing agents in patients prescribed recombinant activated factor VII (rFVIIa) as first-line treatment in the home setting. Patients with congenital hemophilia with inhibitors and caregivers participated, and as part of the study, the time spent preparing and administering product was recorded for bypassing agent (BPA) infusions. The aim of this manuscript is to present the results of the analysis of the time spent preparing and administering a single dose of either rFVIIa or plasma-derived activated prothrombin complex concentrate (pd-aPCC). Diaries were completed for 18 adult patients and 19 caregivers of 21 children with 176 BPA-treated bleeding episodes and 1,350 BPA infusions (1,270 rFVIIa, 80 pd-aPCC). The median preparation and administration times were 5.0 minutes and 5.0 minutes for rFVIIa and 29.0 minutes and 24.5 minutes for pd-aPCC, respectively. Preparation and administration times were significantly shorter with rFVIIa than pd-aPCC (P<0.0001). The significantly shorter combined preparation and administration time of rFVIIa, taking into consideration the faster-than-recommended aPCC infusion rates, suggests that rFVIIa permits a rapid and safe initiation of treatment once a bleeding episode is identified and a decision is made to treat at home. PMID:25187744

  3. 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.

  4. 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

  5. MANN: empowered and oppressed? Men's Advocacy Network of the National Hemophilia Foundation.

    PubMed

    Kuhn, D

    1995-04-01

    The author describes the purpose and the development of MANN (Men's Advocacy Network of the NHF), a complementary response for men to the women's advocacy group WONN (Women's Outreach Network of NHF), and discusses its potency as an advocacy group. MANN's initial platform demanded changes in the NHF that required more consumer input and leadership to the NHF Board. MANN had also demanded that forty percent of the NHF Board and Executive Board be comprised of persons with hemophilia and/or HIV, and that the NHF pursue conflict-of-interest guidelines, and a Congressional Investigation. The author states that these demands had never materialized because the leadership of the NHF refused to allow them to be implemented, and that MANN is being manipulated by the NHF old guard. Further, the author claims that COTT (The Committee of Ten Thousand) is not influenced by NHF, and has made significant impacts in educating the government, media, and public, regarding the history leading to the HIV infection of persons with hemophilia. COTT also has profound influence on the Food and Drug Administration (FDA), and on the safety of the nation's blood supply, including the progress of investigations and litigations.

  6. 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

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

    PubMed Central

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

    2012-01-01

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

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

    PubMed

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

    2016-01-01

    A rapidly growing evidence showed that regulatory T cells (Tregs) play a crucial role in tolerance to coagulation factors and may be involved in the pathogenesis of inhibitor formation in patients with hemophilia. We determined the percentage of Tregs (CD4CD25CD127) in 45 children with hemophilia A compared with 45 healthy controls, and assessed their relation to the clinical characteristics of patients and factor VIII (FVIII) inhibitors. Patients were studied stressing on frequency of bleeding attacks, joint pain, history of viral hepatitis, and the received therapy (FVIII precipitate/cryotherapy). FVIII activity and FVIII inhibitors were assessed with flow cytometric analysis of CD4CD25CD127 Tregs. According to residual FVIII activity levels, 30 patients (66.7%) had mild/moderate hemophilia A, whereas 15 (33.3%) patients had severe hemophilia A. The frequency of Tregs was significantly lower among all patients with hemophilia A compared with controls (2.59 ± 1.1 versus 3.73 ± 1.12%; P = 0.002). Tregs were significantly decreased among patients with FVIII inhibitors compared with the inhibitor-negative group (P < 0.001). Patients with hematuria or severe hemophilia A had lower Tregs levels than those without (P = 0.34 and P = 0.011, respectively). A significant positive correlation was found between the percentage of Tregs and FVIII among hemophilia A patients. ROC curve analysis revealed that the cut-off value of Tregs at 1.91% could differentiate patients with and without FVIII inhibitors, with a sensitivity of 100% and a specificity of 91.3%. We suggest that alteration in the frequency of Tregs in young patients with hemophilia A may contribute to inhibitor formation and disease severity.

  9. NCI Cohort Consortium Membership

    Cancer.gov

    The NCI Cohort Consortium membership is international and includes investigators responsible for more than 40 high-quality cohorts who are studying large and diverse populations in more than 15 different countries.

  10. 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.

  11. 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.

  12. Hemophilia B (Christmas disease) variants and carrier detection analyzed by DNA probes.

    PubMed

    Poon, M C; Chui, D H; Patterson, M; Starozik, D M; Dimnik, L S; Hoar, D I

    1987-04-01

    We have used two strategies to study 14 hemophilia B families from 11 kindreds for possible carrier detection and prenatal diagnosis. First, we sequentially used the Factor IX probes (sequentially with restriction enzymes Taq I, Xmn I, and Dde I), and the linked probes p45h (Taq I), p45d (Pst I), and 52a (Taq I) for restriction fragment length polymorphism (RFLP) analysis. Second, we searched for useful variant Taq I digestion fragments using the Factor IX complementary DNA. Two separate new Taq I variants in exon VIII were identified. Using both strategies, 11 of 14 families (from 9 of 11 kindreds) were informative for further studies. In five kindreds studied in detail, the carrier status of all 11 at risk females was determined and prenatal diagnosis could be offered to the offsprings of each of the six carriers identified. Thus, in this study, we have identified a higher proportion of informative families than has previously been reported.

  13. 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.

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

    PubMed

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

    2015-04-01

    Intraosseous (IO) infusion of lentiviral vectors (LVs) for in situ gene transfer into bone marrow may avoid specific challenges posed by ex vivo gene delivery, including, in particular, the requirement of preconditioning. We utilized IO delivery of LVs encoding a GFP or factor VIII (FVIII) transgene directed by ubiquitous promoters (a MND or EF-1α-short element; M-GFP-LV, E-F8-LV) or a platelet-specific, glycoprotein-1bα promoter (G-GFP-LV, G-F8-LV). A single IO infusion of M-GFP-LV or G-GFP-LV achieved long-term and efficient GFP expression in Lineage(-)Sca1(+)c-Kit(+) hematopoietic stem cells and platelets, respectively. While E-F8-LV produced initially high-level FVIII expression, robust anti-FVIII immune responses eliminated functional FVIII in circulation. In contrast, IO delivery of G-F8-LV achieved long-term platelet-specific expression of FVIII, resulting in partial correction of hemophilia A. Furthermore, similar clinical benefit with G-F8-LV was achieved in animals with pre-existing anti-FVIII inhibitors. These findings further support platelets as an ideal FVIII delivery vehicle, as FVIII, stored in α-granules, is protected from neutralizing antibodies and, during bleeding, activated platelets locally excrete FVIII to promote clot formation. Overall, a single IO infusion of G-F8-LV was sufficient to correct hemophilia phenotype for long term, indicating that this approach may provide an effective means to permanently treat FVIII deficiency. PMID:25655313

  15. 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

  16. 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.

  17. 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

  18. Alprolix (recombinant Factor IX Fc fusion protein): extended half-life product for the prophylaxis and treatment of hemophilia B.

    PubMed

    Ducore, Jonathan M; Miguelino, Maricel G; Powell, Jerry S

    2014-10-01

    Hemophilia B is a genetic disease caused by mutation of the gene for coagulation protein Factor IX. When severe, the disease leads to spontaneous life-threatening bleeding episodes. Current therapy requires frequent intravenous infusions of therapeutic recombinant or plasma-derived protein concentrates containing Factor IX. Alprolix™ (recombinant Factor IX Fc fusion protein), is a therapeutic Factor IX preparation that has been engineered for a prolonged half-life in circulation, has completed pivotal clinical trials and has been approved recently in the USA, Canada, Australia and Japan for use in the clinic for patients with hemophilia B. This promising therapy should allow patients to use fewer infusions to maintain appropriate Factor IX activity levels in all clinical settings, and its use may be indicated in both on demand and prophylactic treatments.

  19. High-affinity, noninhibitory pathogenic C1 domain antibodies are present in patients with hemophilia A and inhibitors

    PubMed Central

    Batsuli, Glaivy; Deng, Wei; Healey, John F.; Parker, Ernest T.; Baldwin, W. Hunter; Cox, Courtney; Nguyen, Brenda; Kahle, Joerg; Königs, Christoph; Li, Renhao; Lollar, Pete

    2016-01-01

    Inhibitor formation in hemophilia A is the most feared treatment-related complication of factor VIII (fVIII) therapy. Most inhibitor patients with hemophilia A develop antibodies against the fVIII A2 and C2 domains. Recent evidence demonstrates that the C1 domain contributes to the inhibitor response. Inhibitory anti-C1 monoclonal antibodies (mAbs) have been identified that bind to putative phospholipid and von Willebrand factor (VWF) binding epitopes and block endocytosis of fVIII by antigen presenting cells. We now demonstrate by competitive enzyme-linked immunosorbent assay and hydrogen-deuterium exchange mass spectrometry that 7 of 9 anti-human C1 mAbs tested recognize an epitope distinct from the C1 phospholipid binding site. These mAbs, designated group A, display high binding affinities for fVIII, weakly inhibit fVIII procoagulant activity, poorly inhibit fVIII binding to phospholipid, and exhibit heterogeneity with respect to blocking fVIII binding to VWF. Another mAb, designated group B, inhibits fVIII procoagulant activity, fVIII binding to VWF and phospholipid, fVIIIa incorporation into the intrinsic Xase complex, thrombin generation in plasma, and fVIII uptake by dendritic cells. Group A and B epitopes are distinct from the epitope recognized by the canonical, human-derived inhibitory anti-C1 mAb, KM33, whose epitope overlaps both groups A and B. Antibodies recognizing group A and B epitopes are present in inhibitor plasmas from patients with hemophilia A. Additionally, group A and B mAbs increase fVIII clearance and are pathogenic in a hemophilia A mouse tail snip bleeding model. Group A anti-C1 mAbs represent the first identification of pathogenic, weakly inhibitory antibodies that increase fVIII clearance. PMID:27381905

  20. 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

  1. Assessment of acquired hemophilia patient demographics in the United States: the Hemostasis and Thrombosis Research Society Registry

    PubMed Central

    Kessler, Craig M.; Ma, Alice D.; Al-Mondhiry, Hamid A.B.; Gut, Robert Z.; Cooper, David L.

    2016-01-01

    The Hemostasis and Thrombosis Research Society (HTRS) Registry was used to monitor the postapproval use of recombinant factor VIIa. The objective of this manuscript is to provide key insights on the demographics of patients with acquired hemophilia in the HTRS Registry. Acquired hemophilia patient registration in HTRS captured age; sex; comorbidities and predisposing conditions; first bleeding location; laboratory parameters; exposure to blood products, factor, and bypassing agents; and initiation of immune suppression/tolerance therapy. Overall, 166 patients with acquired hemophilia were registered in HTRS (83 women, 73 men, median age 70 years); the majority were non-Hispanic whites (61.4%). The most common comorbidities were autoimmune disease (28.4%) and malignancy (14.5%). The most common first site of bleeding was subcutaneous (27.1%); this was more common in whites (29.1%) than blacks (12.5%) and in non-Hispanics (26.4%) than Hispanics (11.8%). Blood product exposure was reported for 33.1% of patients; the most commonly reported product was packed red blood cells (28%). Of the 57 patients with outcome data available for immune tolerance therapy, 26 patients (46%) reported successful treatment, 13 reported unsuccessful treatment (23%), and 18 (32%) were receiving active treatment at the time of registration. The HTRS Registry final analysis provides the only current comprehensive look at acquired hemophilia in the US population, including details on underlying autoimmune diseases and malignancies. Pertinent to recognition and diagnosis of the disease, subcutaneous bleeding as a presenting bleeding symptom was more common in white and non-Hispanic individuals. PMID:27467981

  2. 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.

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

    PubMed Central

    Żuk, Ewa; Alchimowicz, Jacek; Grodzki, Tomasz

    2014-01-01

    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

  4. 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

  5. [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.

  6. Cohort Profile Update: The GAZEL Cohort Study.

    PubMed

    Goldberg, Marcel; Leclerc, Annette; Zins, Marie

    2015-02-01

    The original GAZEL cohort was composed of 20 625 employees of the French national gas and electricity companies (15 011 male employees then aged 40 to 50 years and 5614 women between 35 and 50 years old) at its inception in 1989. A Cohort Profile article was published in 2007. By the end of 2013, participants were aged 60-75, and almost all of them retired during follow-up. Accordingly, the main focus of research in the past decade was devoted to the study of the persistent, long-term effects of occupational exposures after retirement; of the transition between professionally active life and retirement; and on determinants of early ageing. Accordingly, in addition to the health, behavioural and social data collected yearly since the beginning of the follow-up, new data were thus collected on cognitive complaints, cognitive and physical functioning, limitations in daily activities, time use and social relationships of retirees. This update presents the main findings of research within the GAZEL Cohort Study during the past 7 years. Any research group, in France or elsewhere, can submit a research proposal to work on the GAZEL cohort. To do this, interested researchers should contact one of the principal investigators of the GAZEL Cohort Study. PMID:25422284

  7. 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.

  8. 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

  9. 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

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

    PubMed

    Collins, Peter; Baudo, Francesco; Knoebl, Paul; Lévesque, Hervé; Nemes, László; Pellegrini, Fabio; Marco, Pascual; Tengborn, Lilian; Huth-Kühne, Angela

    2012-07-01

    Acquired hemophilia A (AHA) is an autoimmune disease caused by an autoantibody to factor VIII. Patients are at risk of severe and fatal hemorrhage until the inhibitor is eradicated, and guidelines recommend immunosuppression as soon as the diagnosis has been made. The optimal immunosuppressive regimen is unclear; therefore, data from 331 patients entered into the prospective EACH2 registry were analyzed. Steroids combined with cyclophosphamide resulted in more stable complete remission (70%), defined as inhibitor undetectable, factor VIII more than 70 IU/dL and immunosuppression stopped, than steroids alone (48%) or rituximab-based regimens (59%). Propensity score-matched analysis controlling for age, sex, factor VIII level, inhibitor titer, and underlying etiology confirmed that stable remission was more likely with steroids and cyclophosphamide than steroids alone (odds ratio = 3.25; 95% CI, 1.51-6.96; P < .003). The median time to complete remission was approximately 5 weeks for steroids with or without cyclophosphamide; rituximab-based regimens required approximately twice as long. Immunoglobulin administration did not improve outcome. Second-line therapy was successful in approximately 60% of cases that failed first-line therapy. Outcome was not affected by the choice of first-line therapy. The likelihood of achieving stable remission was not affected by underlying etiology but was influenced by the presenting inhibitor titer and FVIII level.

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

    PubMed

    Baudo, Francesco; Collins, Peter; Huth-Kühne, Angela; Lévesque, Hervé; Marco, Pascual; Nemes, László; Pellegrini, Fabio; Tengborn, Lilian; Knoebl, Paul

    2012-07-01

    Acquired hemophilia A is a rare bleeding disorder caused by autoantibodies to coagulation FVIII. Bleeding episodes at presentation are spontaneous and severe in most cases. Optimal hemostatic therapy is controversial, and available data are from observational and retrospective studies only. The EACH2 registry, a multicenter, pan-European, Web-based database, reports current patient management. The aim was to assess the control of first bleeding episodes treated with a bypassing agent (rFVIIa or aPCC), FVIII, or DDAVP among 501 registered patients. Of 482 patients with one or more bleeding episodes, 144 (30%) received no treatment for bleeding; 31 were treated with symptomatic therapy only. Among 307 patients treated with a first-line hemostatic agent, 174 (56.7%) received rFVIIa, 63 (20.5%) aPCC, 56 (18.2%) FVIII, and 14 (4.6%) DDAVP. Bleeding was controlled in 269 of 338 (79.6%) patients treated with a first-line hemostatic agent or ancillary therapy alone. Propensity score matching was applied to allow unbiased comparison between treatment groups. Bleeding control was significantly higher in patients treated with bypassing agents versus FVIII/DDAVP (93.3% vs 68.3%; P = .003). Bleeding control was similar between rFVIIa and aPCC (93.0%; P = 1). Thrombotic events were reported in 3.6% of treated patients with a similar incidence between rFVIIa (2.9%) and aPCC (4.8%).

  12. Neonatal circumcision in severe haemophilia: a survey of paediatric haematologists at United States Hemophilia Treatment Centers.

    PubMed

    Kearney, S; Sharathkumar, A; Rodriguez, V; Chitlur, M; Valentino, L; Boggio, L; Gill, J

    2015-01-01

    Neonatal circumcision in patients with severe haemophilia has not been well studied. We performed a survey of paediatric haematologists from Hemophilia Treatment Centers (HTC) across the United States to better understand the attitudes toward and management of neonatal circumcision in haemophilia patients. Response rate to our survey was 40% (n = 64/159). Thirty-eight percent of respondents (n = 24) said that they would allow this procedure in the newborn period but in many cases this was against medical advice. The most reported concern regarding neonatal circumcision in haemophilia patients was the risk of development of an inhibitor (n = 25; 39%) followed by the concern for bleeding (n = 22; 34%) and issues related to vascular access in the neonate (n = 11; 17%). All respondents recommended at least one preprocedure dose of factor replacement. Twenty-two percent (n = 14) of respondents did not use more than one dose of factor replacement but 32% (n = 21) used 1-2 postoperative doses. The remainder of paediatric haematologists surveyed recommended between 3-5 (16%; n = 10) and 6-10 (3%, n = 2) additional days postoperatively. There was wide variation in both techniques of circumcision as well as adjuvant haemostatic agents used. Only 22% of respondents said that they had an established protocol for management of circumcision in the newborn haemophilia patient. These survey results highlight the need for evidence-based guidelines regarding the optimal management of circumcision in neonates with severe haemophilia.

  13. Minimal modification in the factor VIII B-domain sequence ameliorates the murine hemophilia A phenotype.

    PubMed

    Siner, Joshua I; Iacobelli, Nicholas P; Sabatino, Denise E; Ivanciu, Lacramiora; Zhou, Shangzhen; Poncz, Mortimer; Camire, Rodney M; Arruda, Valder R

    2013-05-23

    Recombinant canine B-domain deleted (BDD) factor VIII (FVIII) is predominantly expressed as a single-chain protein and exhibits greater stability after activation compared with human FVIII-BDD. We generated a novel BDD-FVIII variant (FVIII-RH) with an amino acid change at the furin cleavage site within the B domain (position R1645H) that mimics the canine sequence (HHQR vs human RHQR). Compared with human FVIII-BDD, expression of FVIII-RH protein revealed a 2.5-fold increase in the single-chain form. Notably, FVIII-RH exhibited a twofold increase in biological activity compared with FVIII-BDD, likely due to its slower dissociation of the A2-domain upon thrombin activation. Injection of FVIII-RH protein in hemophilia A (HA) mice resulted in more efficacious hemostasis following vascular injury in both the macro- and microcirculation. These findings were successfully translated to adeno-associated viral (AAV)-based liver gene transfer in HA mice. Expression of circulating FVIII-RH was approximately twofold higher compared with AAV-FVIII-BDD-injected mice. Moreover, FVIII-RH exhibits superior procoagulant effects compared with FVIII-BDD following a series of hemostatic challenges. Notably, the immunogenicity of FVIII-RH did not differ from FVIII-BDD. Thus, FVIII-RH is an attractive bioengineered molecule for improving efficacy without increased immunogenicity and may be suitable for both protein- and gene-based strategies for HA.

  14. Circumventing furin enhances factor VIII biological activity and ameliorates bleeding phenotypes in hemophilia models

    PubMed Central

    Siner, Joshua I.; Samelson-Jones, Benjamin J.; Crudele, Julie M.; French, Robert A.; Lee, Benjamin J.; Zhou, Shanzhen; Merricks, Elizabeth; Raymer, Robin; Camire, Rodney M.; Arruda, Valder R.

    2016-01-01

    Processing by the proprotein convertase furin is believed to be critical for the biological activity of multiple proteins involved in hemostasis, including coagulation factor VIII (FVIII). This belief prompted the retention of the furin recognition motif (amino acids 1645–1648) in the design of B-domain–deleted FVIII (FVIII-BDD) products in current clinical use and in the drug development pipeline, as well as in experimental FVIII gene therapy strategies. Here, we report that processing by furin is in fact deleterious to FVIII-BDD secretion and procoagulant activity. Inhibition of furin increases the secretion and decreases the intracellular retention of FVIII-BDD protein in mammalian cells. Our new variant (FVIII-ΔF), in which this recognition motif is removed, efficiently circumvents furin. FVIII-ΔF demonstrates increased recombinant protein yields, enhanced clotting activity, and higher circulating FVIII levels after adeno-associated viral vector–based liver gene therapy in a murine model of severe hemophilia A (HA) compared with FVIII-BDD. Moreover, we observed an amelioration of the bleeding phenotype in severe HA dogs with sustained therapeutic FVIII levels after FVIII-ΔF gene therapy at a lower vector dose than previously employed in this model. The immunogenicity of FVIII-ΔF did not differ from that of FVIII-BDD as a protein or a gene therapeutic. Thus, contrary to previous suppositions, FVIII variants that can avoid furin processing are likely to have enhanced translational potential for HA therapy. PMID:27734034

  15. Phase 3 study of recombinant factor VIII Fc fusion protein in severe hemophilia A.

    PubMed

    Mahlangu, Johnny; Powell, Jerry S; Ragni, Margaret V; Chowdary, Pratima; Josephson, Neil C; Pabinger, Ingrid; Hanabusa, Hideji; Gupta, Naresh; Kulkarni, Roshni; Fogarty, Patrick; Perry, David; Shapiro, Amy; Pasi, K John; Apte, Shashikant; Nestorov, Ivan; Jiang, Haiyan; Li, Shuanglian; Neelakantan, Srividya; Cristiano, Lynda M; Goyal, Jaya; Sommer, Jurg M; Dumont, Jennifer A; Dodd, Nigel; Nugent, Karen; Vigliani, Gloria; Luk, Alvin; Brennan, Aoife; Pierce, Glenn F

    2014-01-16

    This phase 3 pivotal study evaluated the safety, efficacy, and pharmacokinetics of a recombinant FVIII Fc fusion protein (rFVIIIFc) for prophylaxis, treatment of acute bleeding, and perioperative hemostatic control in 165 previously treated males aged ≥12 years with severe hemophilia A. The study had 3 treatment arms: arm 1, individualized prophylaxis (25-65 IU/kg every 3-5 days, n = 118); arm 2, weekly prophylaxis (65 IU/kg, n = 24); and arm 3, episodic treatment (10-50 IU/kg, n = 23). A subgroup compared recombinant FVIII (rFVIII) and rFVIIIFc pharmacokinetics. End points included annualized bleeding rate (ABR), inhibitor development, and adverse events. The terminal half-life of rFVIIIFc (19.0 hours) was extended 1.5-fold vs rFVIII (12.4 hours; P < .001). Median ABRs observed in arms 1, 2, and 3 were 1.6, 3.6, and 33.6, respectively. In arm 1, the median weekly dose was 77.9 IU/kg; approximately 30% of subjects achieved a 5-day dosing interval (last 3 months on study). Across arms, 87.3% of bleeding episodes resolved with 1 injection. Adverse events were consistent with those expected in this population; no subjects developed inhibitors. rFVIIIFc was well-tolerated, had a prolonged half-life compared with rFVIII, and resulted in low ABRs when dosed prophylactically 1 to 2 times per week.

  16. 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

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

    PubMed Central

    Baudo, Francesco; Knoebl, Paul; Lévesque, Hervé; Nemes, László; Pellegrini, Fabio; Marco, Pascual; Tengborn, Lilian; Huth-Kühne, Angela

    2012-01-01

    Acquired hemophilia A (AHA) is an autoimmune disease caused by an autoantibody to factor VIII. Patients are at risk of severe and fatal hemorrhage until the inhibitor is eradicated, and guidelines recommend immunosuppression as soon as the diagnosis has been made. The optimal immunosuppressive regimen is unclear; therefore, data from 331 patients entered into the prospective EACH2 registry were analyzed. Steroids combined with cyclophosphamide resulted in more stable complete remission (70%), defined as inhibitor undetectable, factor VIII more than 70 IU/dL and immunosuppression stopped, than steroids alone (48%) or rituximab-based regimens (59%). Propensity score-matched analysis controlling for age, sex, factor VIII level, inhibitor titer, and underlying etiology confirmed that stable remission was more likely with steroids and cyclophosphamide than steroids alone (odds ratio = 3.25; 95% CI, 1.51-6.96; P < .003). The median time to complete remission was approximately 5 weeks for steroids with or without cyclophosphamide; rituximab-based regimens required approximately twice as long. Immunoglobulin administration did not improve outcome. Second-line therapy was successful in approximately 60% of cases that failed first-line therapy. Outcome was not affected by the choice of first-line therapy. The likelihood of achieving stable remission was not affected by underlying etiology but was influenced by the presenting inhibitor titer and FVIII level. PMID:22517903

  18. 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

  19. Surgery in hemophilia and related disorders. A prospective study of 100 consecutive procedures.

    PubMed

    Kitchens, C S

    1986-01-01

    Surgery is safe in hemophiliacs. The current problem of blood product-transmitted AIDS has recently dampened an unqualified stance, but the dangers of not performing indicated nonelective surgery outweigh the possibility of inflicting AIDS. Successful surgery in hemophiliacs first requires determination of the type of hemophilia involved. If an inhibitor is present, the procedure needs careful re-evaluation, but in general, surgical indications should be those of the general population and routine procedures should be followed. We find it helpful to have nursing personnel aware from the onset that these patients and their medications require certain precautions, especially with respect to pain medication. Unfortunately, too few medical personnel realize how many pain compounds contain aspirin. In addition, we usually prescribe intramuscular injection of medication. Factor levels must be monitored. A less-than-expected yield of factor following infusion is an excellent screen for clinically significant inhibitors. Patients also vary with respect to factor replacement and the half-life of infused factors. Kasper et al found no difference in half-life of infused factor with respect to whether the patient was in a nonoperative or postoperative status; they did not find evidence that factor was consumed during the hemostatic stress of the surgery and that a given patient's response in a nonoperative setting was predictive of his response in the postoperative period. The internist should be available so that any hemostatic problems experienced by the surgeon can be promptly addressed.

  20. Strategies to target long-lived plasma cells for treating hemophilia A inhibitors.

    PubMed

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

    2016-03-01

    Long-lived plasma cells (LLPCs) can persistently produce anti-factor VIII (FVIII) antibodies which disrupt therapeutic effect of FVIII in hemophilia A patients with inhibitors. The migration of plasma cells to BM where they become LLPCs is largely controlled by an interaction between the chemokine ligand CXCL12 and its receptor CXCR4. AMD3100 combined with G-CSF inhibit their interactions, thus facilitating the mobilization of CD34(+) cells and blocking the homing of LLPCs. These reagents were combined with anti-CD20 to reduce B-cells and the specific IL-2/IL-2mAb (JES6-1) complexes to induce Treg expansion for targeting anti-FVIII immune responses. Groups of mice primed with FVIII plasmid and protein respectively were treated with the combined regimen for six weeks, and a significant reduction of anti-FVIII inhibitor titers was observed, associated with the dramatic decrease of circulating and bone marrow CXCR4(+) plasma cells. The combination regimens are highly promising in modulating pre-existing anti-FVIII antibodies in FVIII primed subjects.

  1. Innovative Pharmacological Therapies for the Hemophilias Not Based on Deficient Factor Replacement.

    PubMed

    Mannucci, Pier Mannuccio; Mancuso, Maria Elisa; Santagostino, Elena; Franchini, Massimo

    2016-07-01

    In recent years, advances in the pharmacological treatment of hemophilias A and B have mainly focused on the development of long-acting factor (F)VIII and FIX products. Alternative approaches not based on the replacement of the missing factor have also been explored, with the aim of producing therapeutic agents with reduced immunogenicity and yet equally effective in patients with or without inhibitors. These new classes of hemostatic agents act mainly by bypassing the need of FVIII and FIX in tenase formation, quenching anticoagulant pathways, enhancing the activity of some coagulation factors or stabilizing the fibrin clot. Current knowledge on the status of development of these novel molecules is summarized in this narrative review. We also surmise that the main interests for these products not based on the replacement of FVIII or FIX in deficient patients pertain to the potential for bleeding prevention in inhibitor patients, an earlier and easier prophylaxis implementation thanks to subcutaneous administration and prolonged half-life, and a low immunogenicity with the potential for prevention of inhibitor development in high-risk patients. PMID:27148843

  2. 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

  3. 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

  4. Cancer Epidemiology Cohorts

    Cancer.gov

    Cohort studies are fundamental for epidemiological research by helping researchers better understand the etiology of cancer and provide insights into the key determinants of this disease and its outcomes.

  5. Factor VIIa analog has marked effects on platelet function and clot kinetics in blood from patients with hemophilia A.

    PubMed

    Brophy, Donald F; Martin, Erika J; Nolte, Melinda E; Kuhn, Janice G; Barrett, J Christian; Ezban, Mirella

    2010-09-01

    To evaluate the hemostatic effects of NN1731 and rFVIIa, an ex-vivo study in hemophilia patients used the Hemodyne Hemostasis Analysis System (HAS) to measure platelet contractile force (PCF), clot elastic modulus (CEM), and force onset time (FOT), and the Haemoscope Thrombelastograph (TEG) to measure reaction time (R), kinetics time (K), and maximum amplitude (MA). Blood samples from 10 healthy volunteers and 10 Factor VIII-deficient patients of varying severity (mild, moderate, severe), were spiked with rFVIIa and NN1731 (both 0.64 and 1.28 microg/ml, respectively) and analyzed to characterize platelet function and clot kinetics. There was wide variability in the rFVIIa response. NN1731 had greater and more consistent effects on PCF, CEM, FOT, R, and K relative to rFVIIa, in all hemophilia groups. The lowest NN1731 concentration (0.64 microg/ml) shortened R and FOT, and increased CEM and PCF more than rFVIIa 1.28 microg/ml. NN1731 normalized clotting parameters equivalent to values obtained in healthy volunteers. FOT and R were highly correlated (r = 0.96). No correlation was observed between CEM and MA. NN1731 produced less variable, more pronounced and predictable ex-vivo hemostatic effects on PCF, CEM, FOT, R and K than rFVIIa in all hemophilia groups. HAS and TEG assays provided similar estimates of FOT and R, however CEM appeared to be more sensitive than MA to changes in clot firmness.

  6. 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.

  7. [Detection of alloantibodies against Factor VIII in plasma of patients with hemophilia A and its relationship with Factor VIIIC domain].

    PubMed

    Zhang, Lu-Lu; Yu, Zi-Qiang; Wan, Chu-Cheng; Zhang, Wei; Zhang, Zheng-Hua; Ruan, Chang-Geng

    2013-10-01

    This study was purposed to detect the alloantibodies against Factor VIII (FVIII) by ELISA for estimating the incidence of the alloantibodies against Factor VIII (FVIII) in patients with hemophilia A, and to investigate the relationship between factor VIIIC domain and alloantibodies. Total of 140 patients with hemophilia A and 80 normal controls were enrolled in this study, among them plasma FVIII level of 84 patients was less than 1%, plasma FVIII level of 34 patients was between 1% and 5%, and plasma FVIII level of 22 patients was more than 5%. All patients were treated with plasma-derived FVIII concentrate or plasma before. The ELISA plate was coated with McAb (SZ-132) against FVIII prepared in our laboratory, then human recombinant FVIII concentrates were applied. After incubation in room temperature for 2 hours, diluted plasma samples and HRP-conjugated goat anti-human IgG were added successively, finally A490 was recorded. The threshold of alloantibody of patient plasma was set as mean value>3 SD more than control. The plate was coated with antibody against His, then human recombinant FVIII-C1C2 prepared in our laboratory was added. After incubation in room temperature for 2 hours, diluted plasma samples and HRP-conjugated goat anti-human IgG were added successively, finally A490 were recorded. The threshold was set as the mean value>3 SD more than control. The results showed that the alloantibodies against FVIII were found in 56 patients (40%) by ELISA, and 82.1% (46/56) of this kind of alloantibody could interact with the C domain of FVIII. It is concluded that C domain of FVIII is one of the primary binding sites for the alloantibodies against FVIII in Chinese patients with hemophilia A.

  8. 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.

  9. 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

  10. Management of third molar removal with doses of native plasma-derived factor IX (Octanine) and local measures in a female patient with severe hemophilia B: a case report.

    PubMed

    Peisker, Andre; Kentouche, Karim; Raschke, Gregor Franziskus; Schultze-Mosgau, Stefan

    2014-03-01

    Patients with hemophilia are at high risk of bleeding following oral surgery. As an X-linked recessive chromosomal bleeding disorder it is very rare in female patients. This is the first described case of management of third molar removal in a female patient suffering from severe hemophilia B. Excellent hemostasis was achieved by following a protocol using defined pre- and postoperative doses of factor IX and local hemostatic measures of collagen fleece, fibrin glue, primary suture, and tranexamic acid solution. Following defined protocols is essential in the management of oral surgery in patients with hemophilia and helps to prevent postoperative hemorrhages.

  11. Inhibitor Recurrence Following Immune Tolerance Induction: A Multicenter Retrospective Cohort Study

    PubMed Central

    Antun, A.; Monahan, P.E.; Manco-Johnson, M.J.; Callaghan, M.U.; Kanin, M.; Knoll, C.; Carpenter, S.L.; Davis, J.A.; Guerrera, M.F.; Kruse-Jarres, R.; Ragni, M.V.; Witmer, C.; McCracken, C.E.; Kempton, C.L.

    2015-01-01

    Summary Background Immune tolerance induction (ITI) in patients with congenital hemophilia A is successful in up to 70%. Although there is growing understanding of predictors of response to ITI, the probability and predictors of inhibitor recurrence following successful ITI are not well understood. Objectives To determine the association of clinical characteristics, particularly adherence to FVIII prophylaxis following ITI, with inhibitor recurrence in patients with hemophilia A who were considered tolerant following ITI. Methods In this multicenter retrospective cohort study, 64 subjects with FVIII level <2% who were considered successfully tolerant following ITI were analyzed to estimate the cumulative probability of inhibitor recurrence using the Kaplan-Meier method. The association of clinical characteristics with inhibitor recurrence was assessed using logistic regression. Results A recurrent inhibitor titer ≥ 0.6 BU/ml occurred at least once in 19 (29.7%) and more than once in 12 (18.8%). The probability of any recurrent inhibitor at 1 and 5 years was 12.8% and 32.5% respectively. Having a recurrent inhibitor was associated with having received immune modulation during ITI (OR 3.8, 95% CI: 1.2-22.4) and FVIII recovery of <85% at the end of ITI (OR 2.6, 95% CI: 1.3-5.9), but was not associated with adherence to post-ITI prophylactic FVIII infusion (OR=0.5, 95% CI: 0.06-4.3). Conclusions The use of immune modulation therapy during ITI and lower FVIII recovery at the end of ITI appear to be associated with an increased risk of inhibitor recurrence following successful ITI. Adherence to post-ITI prophylactic FVIII infusions is not a major determinant of recurrence. PMID:26382916

  12. IMPACT OF HIV ON LIVER FIBROSIS IN MEN WITH HEPATITIS C INFECTION AND HEMOPHILIA

    PubMed Central

    Ragni, Margaret V.; Moore, Charity G.; Soadwa, Kakra; Nalesnik, Michael A.; Zajko, Albert B.; Cortese-Hassett, Andrea; Whiteside, Theresa L.; Hart, Suzanne; Zeevi, Adriana; Li, Jie; Shaikh, Obaid S.

    2010-01-01

    Introduction Hepatitis C virus (HCV) is the major cause of liver disease in hemophilia. Few data exist on the proportion with liver fibrosis in this group after long-term HCV and HIV co-infection. Aim We conducted a cross-sectional multi-center study to determine impact of HIV on the prevalence and risk factors for fibrosis in hemophilic men with chronic hepatitis C. Methods Biopsies were independently scored by Ishak, Metavir, and Knodell systems. Variables were tested for associations with fibrosis by logistic regression and receiver operating curves (ROC). Results Of 220 biopsied HCV(+) men, 23.6% had Metavir ≥F3 fibrosis, with higher mean Metavir fibrosis scores among HIV/HCV co-infected than HCV mono-infected, 1.6 vs. 1.3 (p=0.044). Variables significantly associated with fibrosis included AST, ALT, APRI score (AST/ULN×100/platelet ×109/L), alpha-fetoprotein (all p<0.0001), platelets (p=0.0003), and ferritin (p=0.0008). In multiple logistic regression of serum markers, alpha-fetoprotein, APRI, and ALT were significantly associated with ≥ F3 fibrosis, AUROC=0.77 (95%CI 0.69, 0.86). Alpha-fetoprotein, APRI, and ferritin were significant in HIV(−), (AUROC 0.82 (95%CI 0.72, 0.92), and alpha-fetoprotein and platelets in HIV(+) (AUROC=0.77 (95%CI 0.65, 0.88). In a multivariable model of demographic and clinical variables, transformed (natural logarithm) of alpha-fetoprotein (p=0.0003), age (p=0.006), and HCV treatment (p=0.027) were significantly associated with fibrosis. Conclusion Nearly one-fourth of hemophilic men have Metavir ≥ 3 fibrosis. The odds for developing fibrosis are increased in those with elevated alpha-fetoprotein, increasing age, and past HCV treatment. PMID:20722744

  13. 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

  14. Factor VIII gene variants and inhibitor risk in African American hemophilia A patients.

    PubMed

    Gunasekera, Devi; Ettinger, Ruth A; Nakaya Fletcher, Shelley; James, Eddie A; Liu, Maochang; Barrett, John C; Withycombe, Janice; Matthews, Dana C; Epstein, Melinda S; Hughes, Richard J; Pratt, Kathleen P

    2015-08-13

    African American hemophilia A (HA) patients experience a higher incidence of neutralizing anti-factor VIII (FVIII) antibodies ("inhibitors") vis-à-vis white patients. Nonsynonymous single-nucleotide polymorphisms (ns-SNPs) in the F8 gene encoding FVIII-H484, FVIII-E1241, and FVIII-V2238 are more prevalent in African Americans. This study tested the hypothesis that immune responses to these sites provoke inhibitors. Blood samples were obtained from 174 African American and 198 white HA subjects and their F8 gene sequences determined. Major histocompatibility complex class II binding and T-cell recognition of polymorphic sequences were evaluated using quantitative binding assays and HLA-DRB1 tetramers. Peptides corresponding to 4 common ns-SNPs showed limited binding to 11 HLA-DRB1 proteins. CD4 T cells from 22 subjects treated with FVIII products having sequences at residues FVIII-484, 1241, and 2238 differing from those of putative proteins encoded by their F8 genes did not show high-avidity tetramer binding, whereas positive-control staining of tetanus-specific CD4 T cells was routinely successful. African Americans with an intron-22 inversion mutation showed a 2-3 times-higher inhibitor incidence than whites with the same mutation (odds ratio = 2.3 [1.1-5.0, P = .04]), but this did not correlate with any of the ns-SNPs. We conclude that immune responses to "sequence-mismatched" FVIII products are unlikely to contribute appreciably to the inhibitor incidence in African Americans.

  15. Therapeutic efficacy in a hemophilia B model using a biosynthetic mRNA liver depot system

    PubMed Central

    DeRosa, F; Guild, B; Karve, S; Smith, L; Love, K; Dorkin, J R; Kauffman, K J; Zhang, J; Yahalom, B; Anderson, D G; Heartlein, M W

    2016-01-01

    DNA-based gene therapy has considerable therapeutic potential, but the challenges associated with delivery continue to limit progress. Messenger RNA (mRNA) has the potential to provide for transient production of therapeutic proteins, without the need for nuclear delivery and without the risk of insertional mutagenesis. Here we describe the sustained delivery of therapeutic proteins in vivo in both rodents and non-human primates via nanoparticle-formulated mRNA. Nanoparticles formulated with lipids and lipid-like materials were developed for delivery of two separate mRNA transcripts encoding either human erythropoietin (hEPO) or factor IX (hFIX) protein. Dose-dependent protein production was observed for each mRNA construct. Upon delivery of hEPO mRNA in mice, serum EPO protein levels reached several orders of magnitude (>125 000-fold) over normal physiological values. Further, an increase in hematocrit (Hct) was established, demonstrating that the exogenous mRNA-derived protein maintained normal activity. The capacity of producing EPO in non-human primates via delivery of formulated mRNA was also demonstrated as elevated EPO protein levels were observed over a 72-h time course. Exemplifying the possible broad utility of mRNA drugs, therapeutically relevant amounts of human FIX (hFIX) protein were achieved upon a single intravenous dose of hFIX mRNA-loaded lipid nanoparticles in mice. In addition, therapeutic value was established within a hemophilia B (FIX knockout (KO)) mouse model by demonstrating a marked reduction in Hct loss following injury (incision) to FIX KO mice. PMID:27356951

  16. Prevalence of IVS10nt-18G/A in Calabrian patients with moderate/mild hemophilia A and relation with Factor VIII inhibitor antibodies.

    PubMed

    Prejanò, Simona; Santoro, Rita C; Iannaccaro, Piergiorgio

    2015-10-01

    Hemophilia A is an X-linked bleeding disorder caused by widespread mutations in the factor VIII gene. In the course of a screening to research some hemophilia A mutations, our team has identified and posted a previously unreported nucleotide change in intron 10 in 20 patients with hemophilia A. We tried to identify a possible blood relationship between the people with this mutation, performing a backwards study of every family tree. First, we interviewed the patients and, if possible, parents and grandparents. When direct memory was no longer available, we consulted Registries of Births, Marriages and Deaths, and if these data were not sufficient, going backwards in time, we consulted registries of parish churches where newborns were baptized. The studied mutation was present in 33 hemophilic patients living in Calabria, 28 of them related. Three patients, carriers of this mutation, developed an FVIII inhibitor. In all the cases, the inhibitor development followed intensive treatments, after many days of exposure. Our study displayed the presence of a responsible moderate hemophilia A mutation, limited apparently to our country, probably because of a single ancestral event, and connected with FVIII inhibitor development.

  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. 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

  19. 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.

  20. 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.

  1. 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

  2. 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

  3. Carrier detection in classic hemophilia by combined measurement of immunologic (VIII AGN) and procoagulant (VIII AHF) activities.

    PubMed

    Eyster, M E; Jones, M B; Moore, T; Delli-Bovi, L

    1976-06-01

    Accurate carrier detection in classic hemophilia has been difficult because of (1) technical problems related to the performance of both immunologic (VIII AGN) and procoagulant (VIII AHF) determinations, and (2) statistical problems related to the analysis of these data. VIII AHF was determined by a one-stage assay based on the partial thromboplastin time (PTT). VIII AGN was measured by the method of quantitative immunoelectrophoresis. The discriminant function U. = 0.67 1n (AHF) -- 3.17 AGN X 10(-3) was calculated for a validation group of 20 normal persons and for seven obligate carriers, and tested for accuracy of prediction on a cross-validation group of seven additional normal women and ten additional obligate carriers. A U. score of greater than or equal to 2.54 correctly identified 25 of 27 normal persons. Sixteen of 17 obligate carriers had U. scores below 2.54. In addition, of seven possilbe carriers, four were identified as normal and three as carriers. Five normal women taking oral contraceptives had disproportionately high U. scores. It is concluded that detection of carriers of classic hemophilia should be possible in the clinical laboratory by calculation of a discriminant function from combined measurements of VIII AGN and VIII AHF.

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

    PubMed Central

    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.

    2012-01-01

    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

  5. Factor VIII delivered by hematopoietic stem cell-derived B cells corrects the phenotype of hemophilia A mice

    PubMed Central

    Ramezani, Ali; Zweier-Renn, Lynnsey A.; Hawley, Robert G.

    2011-01-01

    Summary The main impediments to clinical application of hematopoietic stem cell (HSC) gene therapy for treatment of hemophilia A are the bone marrow transplant-related risks and the potential for insertional mutagenesis caused by retroviral vectors. To circumvent these limitations, we have adapted a nonmyeloablative conditioning regimen and directed factor VIII (FVIII) protein synthesis to B lineage cells using an insulated lentiviral vector containing an immunoglobulin heavy chain enhancer-promoter. Transplantation of lentiviral vector-modified HSCs resulted in therapeutic levels of FVIII in the circulation of all transplanted mice for the duration of the study (6 months). Immunostaining of spleen cells showed that the majority of FVIII was synthesized by B220+ B cells and CD138+ plasma cells. Subsequent challenge with recombinant FVIII elicited at most a minor anti-FVIII antibody response, demonstrating induction of immune hyporesponsiveness. All transplant recipients exhibited clot formation and survived tail clipping, indicating correction of their hemophilic phenotype. Therapeutic levels of FVIII could be transferred to secondary recipients by bone marrow transplantation, confirming gene transfer into long-term repopulating HSCs. Moreover, short-term therapeutic FVIII levels could also be achieved in secondary recipients by adoptive transfer of HSC-derived splenic B cells. Our findings support pursuit of B cell-directed protein delivery as a potential clinical approach to treat hemophilia A and other disorders correctable by systemically distributed proteins. PMID:21264447

  6. Overexpression of factor VIII after AAV delivery is transiently associated with cellular stress in hemophilia A mice

    PubMed Central

    Lange, Amy M; Altynova, Ekaterina S; Nguyen, Giang N; Sabatino, Denise E

    2016-01-01

    Factor VIII (FVIII) is a large glycoprotein that is challenging to express both in vitro and in vivo. Several studies suggest that high levels of FVIII expression can lead to cellular stress. After gene transfer, transgene expression is restricted to a subset of cells and the increased FVIII load per cell may impact activation of the unfolded protein response. We sought to determine whether increased FVIII expression in mice after adeno-associated viral liver gene transfer would affect the unfolded protein response and/or immune response to the transgene. The FVIII gene was delivered as B-domain deleted single chain or two chain (light and heavy chains) at a range of doses in hemophilia A mice. A correlation between FVIII expression and anti-FVIII antibody titers was observed. Analysis of key components of the unfolded protein response, binding immunoglobulin protein (BiP), and C/EBP homologous protein (CHOP), showed transient unfolded protein response activation in the single chain treated group expressing >200% of FVIII but not after two chain delivery. These studies suggest that supraphysiological single chain FVIII expression may increase the likelihood of a cellular stress response but does not alter liver function. These data are in agreement with the observed long-term expression of FVIII at therapeutic levels after adeno-associated viral delivery in hemophilia A dogs without evidence of cellular toxicity. PMID:27738645

  7. 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.

  8. 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.

  9. 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

  10. Modification of an exposed loop in the C1 domain reduces immune responses to factor VIII in hemophilia A mice

    PubMed Central

    Wroblewska, Aleksandra; van Haren, Simon D.; Herczenik, Eszter; Kaijen, Paul; Ruminska, Aleksandra; Jin, Sheng-Yu; Zheng, X. Long; van den Biggelaar, Maartje; ten Brinke, Anja; Meijer, Alexander B.

    2012-01-01

    Development of neutralizing Abs to blood coagulation factor VIII (FVIII) provides a major complication in hemophilia care. In this study we explored whether modulation of the uptake of FVIII by APCs can reduce its intrinsic immunogenicity. Endocytosis of FVIII by professional APCs is significantly blocked by mAb KM33, directed toward the C1 domain of FVIII. We created a C1 domain variant (FVIII-R2090A/K2092A/F2093A), which showed only minimal binding to KM33 and retained its activity as measured by chromogenic assay. FVIII-R2090A/K2092A/F2093A displayed a strongly reduced internalization by human monocyte-derived dendritic cells and macrophages, as well as murine BM-derived dendritic cells. We subsequently investigated the ability of this variant to induce an immune response in FVIII-deficient mice. We show that mice treated with FVIII-R2090A/K2092A/F2093A have significantly lower anti-FVIII Ab titers and FVIII-specific CD4+ T-cell responses compared with mice treated with wild-type FVIII. These data show that alanine substitutions at positions 2090, 2092, and 2093 reduce the immunogenicity of FVIII. According to our findings we hypothesize that FVIII variants displaying a reduced uptake by APCs provide a novel therapeutic approach to reduce inhibitor development in hemophilia A. PMID:22498747

  11. Modification of an exposed loop in the C1 domain reduces immune responses to factor VIII in hemophilia A mice.

    PubMed

    Wroblewska, Aleksandra; van Haren, Simon D; Herczenik, Eszter; Kaijen, Paul; Ruminska, Aleksandra; Jin, Sheng-Yu; Zheng, X Long; van den Biggelaar, Maartje; ten Brinke, Anja; Meijer, Alexander B; Voorberg, Jan

    2012-05-31

    Development of neutralizing Abs to blood coagulation factor VIII (FVIII) provides a major complication in hemophilia care. In this study we explored whether modulation of the uptake of FVIII by APCs can reduce its intrinsic immunogenicity. Endocytosis of FVIII by professional APCs is significantly blocked by mAb KM33, directed toward the C1 domain of FVIII. We created a C1 domain variant (FVIII-R2090A/K2092A/F2093A), which showed only minimal binding to KM33 and retained its activity as measured by chromogenic assay. FVIII-R2090A/K2092A/F2093A displayed a strongly reduced internalization by human monocyte-derived dendritic cells and macrophages, as well as murine BM-derived dendritic cells. We subsequently investigated the ability of this variant to induce an immune response in FVIII-deficient mice. We show that mice treated with FVIII-R2090A/K2092A/F2093A have significantly lower anti-FVIII Ab titers and FVIII-specific CD4(+) T-cell responses compared with mice treated with wild-type FVIII. These data show that alanine substitutions at positions 2090, 2092, and 2093 reduce the immunogenicity of FVIII. According to our findings we hypothesize that FVIII variants displaying a reduced uptake by APCs provide a novel therapeutic approach to reduce inhibitor development in hemophilia A. PMID:22498747

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

    PubMed

    Taylor, S A; 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 greater than 95% are single nucleotide 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. We used differential termination of primer extension to confirm and measure the degree of mosaicism. Our 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.

  13. Occupational Cohort Time Scales

    PubMed Central

    Roth, H. Daniel

    2015-01-01

    Purpose: This study explores how highly correlated time variables (occupational cohort time scales) contribute to confounding and ambiguity of interpretation. Methods: Occupational cohort time scales were identified and organized through simple equations of three time scales (relational triads) and the connections between these triads (time scale web). The behavior of the time scales was examined when constraints were imposed on variable ranges and interrelationships. Results: Constraints on a time scale in a triad create high correlations between the other two time scales. These correlations combine with the connections between relational triads to produce association paths. High correlation between time scales leads to ambiguity of interpretation. Conclusions: Understanding the properties of occupational cohort time scales, their relational triads, and the time scale web is helpful in understanding the origins of otherwise obscure confounding bias and ambiguity of interpretation. PMID:25647318

  14. NCI Cohort Consortium

    Cancer.gov

    The NCI Cohort Consortium is an extramural-intramural partnership formed by the National Cancer Institute to address the need for large-scale collaborations to pool the large quantity of data and biospecimens necessary to conduct a wide range of cancer studies.

  15. International Childhood Cancer Cohort Consortium

    Cancer.gov

    An alliance of several large-scale prospective cohort studies of children to pool data and biospecimens from individual cohorts to study various modifiable and genetic factors in relation to cancer risk

  16. Cohort Profile: Mysore Parthenon Birth Cohort

    PubMed Central

    Krishnaveni, Ghattu V; Veena, Sargoor R; Hill, Jacqueline C; Karat, Samuel C; Fall, Caroline HD

    2015-01-01

    The Mysore Parthenon Birth Cohort was established to examine the long-term effects of maternal glucose tolerance and nutritional status on cardiovascular disease risk factors in the offspring. During 1997–98, 830 of 1233 women recruited from the antenatal clinics of the Holdsworth Memorial Hospital (HMH), Mysore, India, underwent an oral glucose tolerance test. Of these, 667 women delivered live babies at HMH. Four babies with major congenital anomalies were excluded, and the remaining 663 were included for further follow-up. The babies had detailed anthropometry at birth and at 6–12-monthly intervals subsequently. Detailed cardiovascular investigations were done at ages 5, 9.5 and 13.5 years in the children, and in the parents at the 5-year and 9.5-year follow-ups. This ongoing study provides extensive data on serial anthropometry and body composition, physiological and biochemical measures, dietary intake, nutritional status, physical activity measures, stress reactivity measures and cognitive function, and socio-demographic parameters for the offspring. Data on anthropometry, cardiovascular risk factors and nutritional status are available for mothers during pregnancy. Anthropometry and risk factor measures are available for both parents at follow-up. PMID:24609067

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

    PubMed Central

    Philpott, J; Houghton, K; Luke, A

    2010-01-01

    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

  18. 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

  19. 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

  20. The old and new: PCCs, VIIa, and long-lasting clotting factors for hemophilia and other bleeding disorders.

    PubMed

    Ragni, Margaret V

    2013-01-01

    What is the correct use of established clotting factors, prothrombin complex concentrates (PCCs), and activated factor VII in bleeding complications of trauma, surgery, and old and new oral anticoagulants? How will new clotting factors, specifically the long-acting factors, change the hemostatic management of coagulation deficiency disorders? From bench to bedside, comparative coagulation studies and clinical trials of modified clotting factors are providing insights to help guide hemostatic management of congenital and acquired bleeding disorders. Comparative thrombin-generation studies and preclinical and clinical trials suggest that PCCs and fresh-frozen plasma are effective in reversing the anticoagulant effects of warfarin, yet there are few data to guide reversal of the new oral anticoagulants dabigatran and rivaroxaban. Although coagulation studies support the use of PCCs to reverse new oral anticoagulants, correlation with clinical response is variable and clinical trials in bleeding patients are needed. For congenital bleeding disorders, exciting new technologies are emerging from the bench. Data from clinical trials of molecularly modified coagulation factors with extended half-lives suggest the possibility of fewer infusions, reduced bleeds, and better quality of life in persons with hemophilia. Preclinical studies of other novel prohemostatic approaches for hemophilia and other congenital coagulation disorders include RNA interference silencing of antithrombin, monoclonal anti-tissue factor pathway inhibitor (anti-antibody, anti-tissue factor pathway inhibitor) aptamer, bispecific anti-IXa/X antibody, and fucoidans. Understanding the comparative coagulation studies of established prohemostatic agents, the pharmacokinetics of new long-acting clotting factors, and their correlation with bleeding outcomes will provide opportunities to optimize the hemostatic management of both congenital and acquired hemostatic disorders.

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

    PubMed

    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

    2015-07-01

    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.

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

    PubMed

    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

    2015-07-01

    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

  3. 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.

  4. 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.

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

    PubMed Central

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

    2015-01-01

    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 one 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 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 ~1.5-fold elevated Km, however, extrinsic Tenase activated FIX-G317E with ~2-fold improved kcat. By contrast to zymogen activation, the catalytic activities of both FIXa-G317R and FIXa-G317E enzymes toward the natural substrate, factor X, were dramatically (more than four 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 were not measurable 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 kcat 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 hemophilia B patient carrying the FIX-G317E mutation. PMID:26023895

  6. Intermediate-dose versus high-dose prophylaxis for severe hemophilia: comparing outcome and costs since the 1970s

    PubMed Central

    Steen Carlsson, Katarina; Petrini, Pia; Holmström, Margareta; Ljung, Rolf; van den Berg, H. Marijke; Berntorp, Erik

    2013-01-01

    Prophylactic treatment in severe hemophilia is very effective but is limited by cost issues. The implementation of 2 different prophylactic regimens in The Netherlands and Sweden since the 1970s may be considered a natural experiment. We compared the costs and outcomes of Dutch intermediate- and Swedish high-dose prophylactic regimens for patients with severe hemophilia (factor VIII/IX < 1 IU/dL) born between 1970 and 1994, using prospective standardized outcome assessment and retrospective collection of cost data. Seventy-eight Dutch and 50 Swedish patients, median age 24 years (range, 14-37 years), were included. Intermediate-dose prophylaxis used less factor concentrate (median: Netherlands, 2100 IU/kg per year [interquartile range (IQR), 1400-2900 IU/kg per year] vs Sweden, 4000 IU/kg per year [IQR, 3000-4900 IU/kg per year]); (P < .01). Clinical outcome was slightly inferior for the intermediate-dose regimen (P < .01) for 5-year bleeding (median, 1.3 [IQR, 0.8-2.7] vs 0 [IQR, 0.0-2.0] joint bleeds/y) and joint health (Haemophilia Joint Health Score >10 of 144 points in 46% vs 11% of participants), although social participation and quality of life were similar. Annual total costs were 66% higher for high-dose prophylaxis (mean, 180 [95% confidence interval, 163 - 196] × US$1000 for Dutch vs 298 [95% confidence interval, 271-325]) × US$1000 for Swedish patients; (P < .01). At group level, the incremental benefits of high-dose prophylaxis appear limited. At the patient level, prophylaxis should be tailored individually, and many patients may do well receiving lower doses of concentrate without compromising safety. PMID:23777770

  7. An Inventory of Healthy Weight Practices in Federally-Funded Hemophilia Treatment Centers in the United States

    PubMed Central

    Adams, Elizabeth; Deutsche, Joann; Okoroh, Ekwutosi; Owens-McAlister, Sally; Majumdar, Suvankar; Ullman, Megan; Damiano, Mary Lou; Recht, Michael

    2015-01-01

    In the hemophilia population, obesity has an adverse effect on health care cost, chronic complications, and joint disease. Although staffs of federally-funded Hemophilia Treatment Centers in the United States (HTCs) anecdotally recognize these outcomes, practices to promote healthy weights have not been reported. This evaluation identifies routine practices among HTCs in body mass index (BMI) assessment, perceptions about need to address obesity, and roles in offering evidence-based strategies to promote healthy weights. A telephone survey was developed to assess HTCs practices including patient BMI assessment and counseling, perceptions about the importance healthy patient weights, and HTCs roles in weight management. Ninety of the 130 federally-funded HTCs contacted elected to participate and completed the telephone survey. Of these, 67% routinely calculated BMI and 48% provided results to patients. Approximately one third classified obesity correctly for children (30%) and adults (32%), using the Centers for Disease Control and Prevention (CDC)’s BMI cutoffs. Most HTCs (87%) reported obesity as an issue of “big” or “moderate” concern and 98% indicated HTC responsibility to address this issue. Most centers (64%) address patient weight during comprehensive visits. One third (33%) of centers include a nutritionist; of those without, 61% offer nutrition referrals when needed. Most (89%) HTCs do not have a protocol in place to address healthy weights; 53% indicated guidelines are needed. HTCs offer services to help improve weight outcomes. Training programs for calculating and interpreting BMI as well as identification of appropriate guidelines to apply to the HTC patient population are needed. PMID:24629074

  8. Intermediate-dose versus high-dose prophylaxis for severe hemophilia: comparing outcome and costs since the 1970s.

    PubMed

    Fischer, Kathelijn; Steen Carlsson, Katarina; Petrini, Pia; Holmström, Margareta; Ljung, Rolf; van den Berg, H Marijke; Berntorp, Erik

    2013-08-15

    Prophylactic treatment in severe hemophilia is very effective but is limited by cost issues. The implementation of 2 different prophylactic regimens in The Netherlands and Sweden since the 1970s may be considered a natural experiment. We compared the costs and outcomes of Dutch intermediate- and Swedish high-dose prophylactic regimens for patients with severe hemophilia (factor VIII/IX < 1 IU/dL) born between 1970 and 1994, using prospective standardized outcome assessment and retrospective collection of cost data. Seventy-eight Dutch and 50 Swedish patients, median age 24 years (range, 14-37 years), were included. Intermediate-dose prophylaxis used less factor concentrate (median: Netherlands, 2100 IU/kg per year [interquartile range (IQR), 1400-2900 IU/kg per year] vs Sweden, 4000 IU/kg per year [IQR, 3000-4900 IU/kg per year]); (P < .01). Clinical outcome was slightly inferior for the intermediate-dose regimen (P < .01) for 5-year bleeding (median, 1.3 [IQR, 0.8-2.7] vs 0 [IQR, 0.0-2.0] joint bleeds/y) and joint health (Haemophilia Joint Health Score >10 of 144 points in 46% vs 11% of participants), although social participation and quality of life were similar. Annual total costs were 66% higher for high-dose prophylaxis (mean, 180 [95% confidence interval, 163 - 196] × US$1000 for Dutch vs 298 [95% confidence interval, 271-325]) × US$1000 for Swedish patients; (P < .01). At group level, the incremental benefits of high-dose prophylaxis appear limited. At the patient level, prophylaxis should be tailored individually, and many patients may do well receiving lower doses of concentrate without compromising safety.

  9. 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

  10. Anti-CD20 as the B-Cell Targeting Agent in a Combined Therapy to Modulate Anti-Factor VIII Immune Responses in Hemophilia a Inhibitor Mice.

    PubMed

    Liu, Chao Lien; Ye, Peiqing; Lin, Jacqueline; Butts, Chérie L; Miao, Carol H

    2014-01-01

    Neutralizing antibody formation against transgene products can represent a major complication following gene therapy with treatment of genetic diseases, such as hemophilia A. Although successful approaches have been developed to prevent the formation of anti-factor VIII (FVIII) antibodies, innovative strategies to overcome pre-existing anti-FVIII immune responses in FVIII-primed subjects are still lacking. Anti-FVIII neutralizing antibodies circulate for long periods in part due to persistence of memory B-cells. Anti-CD20 targets a variety of B-cells (pre-B-cells to mature/memory cells); therefore, we investigated the impact of B-cell depletion on anti-FVIII immune responses in hemophilia A mice using anti-CD20 combined with regulatory T (Treg) cell expansion using IL-2/IL-2mAb complexes plus rapamycin. We found that anti-CD20 alone can partially modulate anti-FVIII immune responses in both unprimed and FVIII-primed hemophilia A mice. Moreover, in mice treated with anti-CD20+IL-2/IL-2mAb complexes+rapamycin+FVIII, anti-FVIII antibody titers were significantly reduced in comparison to mice treated with regimens targeting only B or T cells. In addition, titers remained low after a second challenge with FVIII plasmid. Treg cells and activation markers were transiently and significantly increased in the groups treated with IL-2/IL-2mAb complexes; however, significant B-cell depletion was obtained in anti-CD20-treated groups. Importantly, both FVIII-specific antibody-secreting cells and memory B-cells were significantly reduced in mice treated with combination therapy. This study demonstrates that a combination regimen is highly promising as a treatment option for modulating anti-FVIII antibodies and facilitating induction of long-term tolerance to FVIII in hemophilia A mice.

  11. Births and cohort size.

    PubMed

    de Beer, J

    1991-01-01

    Ahlburg (1983, 1986) tested a simple version of Easterlin's relative-cohort-size model of fertility on the basis of U.S. and Canadian post-war data. His conclusion was that the Easterlin model fits the data very well and can therefore be used for calculating forecasts. However, the model he estimated is oversimplified. In this paper an alternative specification is presented. The model is applied to Dutch fertility data. The Easterlin effect is found to affect the movement of births in the Netherlands during the period 1950-85, but a declining long-term trend in average family size proves far more important in explaining post-war births. The model forecasts a rise of births until 2000.

  12. Cohort Size Effects and Migration.

    ERIC Educational Resources Information Center

    Wilson, Franklin D.

    1983-01-01

    Explores whether changes in the size of cohorts entering the labor force affected the propensity within the U.S. labor force to migrate and socioeconomic circumstances of migrants at destination within 1965-76. Suggests that a significant reduction in the volume of migration among members of the baby boom cohort was the primary adjustment…

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

    PubMed

    Doshi, Bhavya S; Gangadharan, Bagirath; Doering, Christopher B; Meeks, Shannon L

    2012-01-01

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

  14. Cohort profile: the Lothian Birth Cohorts of 1921 and 1936.

    PubMed

    Deary, Ian J; Gow, Alan J; Pattie, Alison; Starr, John M

    2012-12-01

    This cohort profile describes the origins, tracing, recruitment, testing and follow-up of the University of Edinburgh-based Lothian Birth Cohorts of 1921 (LBC1921; N = 550) and 1936 (LBC1936; N = 1091). The participants undertook a general intelligence test at age 11 years and were recruited for these cohorts at mean ages of 79 (LBC1921) and 70 (LBC1936). The LBC1921 have been examined at mean ages of 79, 83, 87 and 90 years. The LBC1936 have been examined at mean ages of 70 and 73 years, and are being seen at 76 years. Both samples have an emphasis on the ageing of cognitive functions as outcomes. As they have childhood intelligence test scores, the cohorts' data have been used to search for determinants of lifetime cognitive changes, and also cognitive change within old age. The cohorts' outcomes also include a range of physical and psycho-social aspects of well-being in old age. Both cohorts have a wide range of variables: genome-wide genotyping, demographics, psycho-social and lifestyle factors, cognitive functions, medical history and examination, and biomarkers (from blood and urine). The LBC1936 participants also have a detailed structural magnetic resonance imaging (MRI) brain scan. A range of scientific findings is described, to illustrate the possible uses of the cohorts.

  15. A Cohort, Is a Cohort, Is a Cohort...or Is It?

    ERIC Educational Resources Information Center

    Pemberton, Cynthia Lee A.; Akkary, Rima Karami

    2010-01-01

    This paper presents findings from a multi-year qualitative study based upon life-history narratives of women pursuing doctoral degrees in Educational Leadership. This paper focuses on findings specific to educational cohort models, and suggests that perhaps, at least for women, naturally emergent cohorts--born of relationships of choice--may be…

  16. 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.

  17. 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.

  18. Trends in human immunodeficiency virus type 1 (HIV-1) load among HIV-1-infected children with hemophilia.

    PubMed

    Engels, E A; Rosenberg, P S; Katki, H; Goedert, J J; Biggar, R J

    2001-08-01

    In human immunodeficiency virus type 1 (HIV-1)-infected persons, virus load (serum/plasma level of HIV) predicts outcome. Virus load trends have been characterized in adults and infants but not in children. Virus load trends in 22 male children with hemophilia who acquired HIV-1 postnatally (age 0.7-5.2 years at seroconversion) were studied. The mean HIV-1 load 2 years after seroconversion was 4.40 log10 copies/mL, and the mean change over time (slope) was 0.03 log10 copies/(mL x year). Significant among-children variation was apparent: a random effects model predicted that 95% of children had early virus loads 3.75-5.04 log10 copies/mL and slopes -0.07 to 0.12 log10 copies/(mL x year). Higher early virus loads and higher slopes were each associated with increased mortality (P=.006 and P=.03, respectively). In conclusion, those subjects had virus load trends similar to those in adults. Early virus loads were lower than those in vertically infected infants, which suggests that factors changing soon after birth affect viral replication.

  19. 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

  20. Acquired hemophilia A associated with IgG4-related lung disease in a patient with autoimmune pancreatitis.

    PubMed

    Sugino, Keishi; Gocho, Kyoko; Ishida, Fumiaki; Kikuchi, Naoshi; Hirota, Nao; Sato, Keita; Sano, Go; Isobe, Kazutoshi; Sakamoto, Susumu; Takai, Yujiro; Hata, Yoshinobu; Shibuya, Kazutoshi; Uekusa, Toshimasa; Kurosaki, Atsuko; Homma, Sakae

    2012-01-01

    Immunoglobulin G4 (IgG4)-related lung diseases can occur in patients with autoimmune pancreatitis (AIP). However, the causal relationship between AIP and acquired hemophilia A (AH) is unknown. We herein report the first case of AH associated with IgG4-related lung disease that developed in a patient with AIP. A 65-year-old asymptomatic man with a history of AIP and sclerosing cholangitis diagnosed at the age of 57 was admitted to our hospital due to an abnormal reticulonodular shadow on chest X-ray. An examination of lung biopsy specimens revealed IgG4-positive plasma cell infiltration in the interstitium. The serum IgG4 level was elevated. One year later, the patient developed a progressive severe hematoma in the left femoral muscle. On admission, laboratory examinations revealed severe anemia with a markedly prolonged activated partial prothrombin time, a decreased level of factor VIII (FVIII) activity, and the existence of anti-FVIII antibodies. These findings were consistent with a diagnosis of AH. No relapse has been observed over the past 25 months, during which time, corticosteroid therapy has been continuously administered.

  1. Cohort: critical science

    NASA Astrophysics Data System (ADS)

    Digney, Bruce L.

    2007-04-01

    Unmanned vehicle systems is an attractive technology for the military, but whose promises have remained largely undelivered. There currently exist fielded remote controlled UGVs and high altitude UAV whose benefits are based on standoff in low complexity environments with sufficiently low control reaction time requirements to allow for teleoperation. While effective within there limited operational niche such systems do not meet with the vision of future military UxV scenarios. Such scenarios envision unmanned vehicles operating effectively in complex environments and situations with high levels of independence and effective coordination with other machines and humans pursing high level, changing and sometimes conflicting goals. While these aims are clearly ambitious they do provide necessary targets and inspiration with hopes of fielding near term useful semi-autonomous unmanned systems. Autonomy involves many fields of research including machine vision, artificial intelligence, control theory, machine learning and distributed systems all of which are intertwined and have goals of creating more versatile broadly applicable algorithms. Cohort is a major Applied Research Program (ARP) led by Defence R&D Canada (DRDC) Suffield and its aim is to develop coordinated teams of unmanned vehicles (UxVs) for urban environments. This paper will discuss the critical science being addressed by DRDC developing semi-autonomous systems.

  2. Recombinant factor IX-Fc fusion protein (rFIXFc) demonstrates safety and prolonged activity in a phase 1/2a study in hemophilia B patients

    PubMed Central

    Ragni, Margaret V.; Valentino, Leonard A.; Key, Nigel S.; Josephson, Neil C.; Powell, Jerry S.; Cheng, Gregory; Thompson, Arthur R.; Goyal, Jaya; Tubridy, Karen L.; Peters, Robert T.; Dumont, Jennifer A.; Euwart, Donald; Li, Lian; Hallén, Bengt; Gozzi, Peter; Bitonti, Alan J.; Jiang, Haiyan; Luk, Alvin

    2012-01-01

    Current factor IX (FIX) products display a half-life (t1/2) of ∼ 18 hours, requiring frequent intravenous infusions for prophylaxis and treatment in patients with hemophilia B. This open-label, dose-escalation trial in previously treated adult subjects with hemophilia B examined the safety and pharmacokinetics of rFIXFc. rFIXFc is a recombinant fusion protein composed of FIX and the Fc domain of human IgG1, to extend circulating time. Fourteen subjects received a single dose of rFIXFc; 1 subject each received 1, 5, 12.5, or 25 IU/kg, and 5 subjects each received 50 or 100 IU/kg. rFIXFc was well tolerated, and most adverse events were mild or moderate in intensity. No inhibitors were detected in any subject. Dose-proportional increases in rFIXFc activity and Ag exposure were observed. With baseline subtraction, mean activity terminal t1/2 and mean residence time for rFIXFc were 56.7 and 71.8 hours, respectively. This is ∼ 3-fold longer than that reported for current rFIX products. The incremental recovery of rFIXFc was 0.93 IU/dL per IU/kg, similar to plasma-derived FIX. These results show that rFIXFc may offer a viable therapeutic approach to achieve prolonged hemostatic protection and less frequent dosing in patients with hemophilia B. The trial was registered at www.clinicaltrials.gov as NCT00716716. PMID:22110246

  3. Effects of Therapeutic Exercise and Hydrotherapy on Pain Severity and Knee Range of Motion in Patients with Hemophilia: A Randomized Controlled Trial

    PubMed Central

    Mazloum, Vahid; Rahnama, Nader; Khayambashi, Khalil

    2014-01-01

    Background: Pain and limited range of motion (ROM) are the crucial subsequent results of joint hemorrhages in individuals with bleeding disorders and hemophilia. Exercise interventions are particularly recommended in treatment of such patients. The purpose of this study was to detect the influences of conventional exercise therapy and hydrotherapy on the knee joint complications in patients with hemophilia. Methods: A total of 40 patients engaging hemophilia A were randomized into one of three groups: Therapeutic exercise (N = 13), hydrotherapy (N = 14) or control (N = 13). While the first two groups followed their specific programs for 4 weeks, routine life-style was maintained by subjects in the control group in this period. To evaluate the pain level and knee ROM the visual analog scale and standard goniometer were utilized, respectively. The outcome was measured at baseline and after completing the prescribed protocols. Data analysis was performed using one-way analysis of variance and Scheffe statistical tests (P < 0.05). Results: Both experimental groups experienced more significant decreasing in pain level (P < 0.001) and knee flexion and extension ROM (P < 0.001) in comparison to the control group. Although the pain was significantly (P < 0.01) more alleviated in participants treated through hydrotherapy in comparison to exercise therapy, the difference in ROM improvement was not statistically significant (P > 0.05). Conclusions: Using hydrotherapy in addition to usual rehabilitation training can result in beneficial effect in terms of pain and knee joint ROM. However, it appears that hydrotherapy is more effective in reducing pain. PMID:24554996

  4. Cohort Profile: Antiretroviral Therapy Cohort Collaboration (ART-CC)

    PubMed Central

    May, Margaret T; Ingle, Suzanne M; Costagliola, Dominique; Justice, Amy C; de Wolf, Frank; Cavassini, Matthias; D’Arminio Monforte, Antonella; Casabona, Jordi; Hogg, Robert S; Mocroft, Amanda; Lampe, Fiona C; Dabis, François; Fätkenheuer, Gerd; Sterling, Timothy R; del Amo, Julia; Gill, M John; Crane, Heidi M; Saag, Michael S; Guest, Jodie; Brodt, Hans-Reinhard; Sterne, Jonathan AC

    2014-01-01

    The advent of effective combination antiretroviral therapy (ART) in 1996 resulted in fewer patients experiencing clinical events, so that some prognostic analyses of individual cohort studies of human immunodeficiency virus-infected individuals had low statistical power. Because of this, the Antiretroviral Therapy Cohort Collaboration (ART-CC) of HIV cohort studies in Europe and North America was established in 2000, with the aim of studying the prognosis for clinical events in acquired immune deficiency syndrome (AIDS) and the mortality of adult patients treated for HIV-1 infection. In 2002, the ART-CC collected data on more than 12,000 patients in 13 cohorts who had begun combination ART between 1995 and 2001. Subsequent updates took place in 2004, 2006, 2008, and 2010. The ART-CC data base now includes data on more than 70 000 patients participating in 19 cohorts who began treatment before the end of 2009. Data are collected on patient demographics (e.g. sex, age, assumed transmission group, race/ethnicity, geographical origin), HIV biomarkers (e.g. CD4 cell count, plasma viral load of HIV-1), ART regimen, dates and types of AIDS events, and dates and causes of death. In recent years, additional data on co-infections such as hepatitis C; risk factors such as smoking, alcohol and drug use; non-HIV biomarkers such as haemoglobin and liver enzymes; and adherence to ART have been collected whenever available. The data remain the property of the contributing cohorts, whose representatives manage the ART-CC via the steering committee of the Collaboration. External collaboration is welcomed. Details of contacts are given on the ART-CC website (www.art-cohort-collaboration.org). PMID:23599235

  5. Cohort profile: Antiretroviral Therapy Cohort Collaboration (ART-CC).

    PubMed

    May, Margaret T; Ingle, Suzanne M; Costagliola, Dominique; Justice, Amy C; de Wolf, Frank; Cavassini, Matthias; D'Arminio Monforte, Antonella; Casabona, Jordi; Hogg, Robert S; Mocroft, Amanda; Lampe, Fiona C; Dabis, François; Fätkenheuer, Gerd; Sterling, Timothy R; del Amo, Julia; Gill, M John; Crane, Heidi M; Saag, Michael S; Guest, Jodie; Brodt, Hans-Reinhard; Sterne, Jonathan A C

    2014-06-01

    The advent of effective combination antiretroviral therapy (ART) in 1996 resulted in fewer patients experiencing clinical events, so that some prognostic analyses of individual cohort studies of human immunodeficiency virus-infected individuals had low statistical power. Because of this, the Antiretroviral Therapy Cohort Collaboration (ART-CC) of HIV cohort studies in Europe and North America was established in 2000, with the aim of studying the prognosis for clinical events in acquired immune deficiency syndrome (AIDS) and the mortality of adult patients treated for HIV-1 infection. In 2002, the ART-CC collected data on more than 12,000 patients in 13 cohorts who had begun combination ART between 1995 and 2001. Subsequent updates took place in 2004, 2006, 2008, and 2010. The ART-CC data base now includes data on more than 70,000 patients participating in 19 cohorts who began treatment before the end of 2009. Data are collected on patient demographics (e.g. sex, age, assumed transmission group, race/ethnicity, geographical origin), HIV biomarkers (e.g. CD4 cell count, plasma viral load of HIV-1), ART regimen, dates and types of AIDS events, and dates and causes of death. In recent years, additional data on co-infections such as hepatitis C; risk factors such as smoking, alcohol and drug use; non-HIV biomarkers such as haemoglobin and liver enzymes; and adherence to ART have been collected whenever available. The data remain the property of the contributing cohorts, whose representatives manage the ART-CC via the steering committee of the Collaboration. External collaboration is welcomed. Details of contacts are given on the ART-CC website (www.art-cohort-collaboration.org).

  6. Quality of life in haemophilia A: Hemophilia Utilization Group Study Va (HUGS-Va).

    PubMed

    Poon, J-L; Zhou, Z-Y; Doctor, J N; Wu, J; Ullman, M M; Ross, C; Riske, B; Parish, K L; Lou, M; Koerper, M A; Gwadry-Sridhar, F; Forsberg, A D; Curtis, R G; Johnson, K A

    2012-09-01

    This study describes health-related quality of life (HRQoL) of persons with haemophilia A in the United States (US) and determines associations between self-reported joint pain, motion limitation and clinically evaluated joint range of motion (ROM), and between HRQoL and ROM. As part of a 2-year cohort study, we collected baseline HRQoL using the SF-12 (adults) and PedsQL (children), along with self-ratings of joint pain and motion limitation, in persons with factor VIII deficiency recruited from six Haemophilia Treatment Centres (HTCs) in geographically diverse regions of the US. Clinically measured joint ROM measurements were collected from medical charts of a subset of participants. Adults (N = 156, mean age: 33.5 ± 12.6 years) had mean physical and mental component scores of 43.4 ± 10.7 and 50.9 ± 10.1, respectively. Children (N = 164, mean age: 9.7 ± 4.5 years) had mean total PedsQL, physical functioning, and psychosocial health scores of 85.9 ± 13.8, 89.5 ± 15.2, and 84.1 ± 15.3, respectively. Persons with more severe haemophilia and higher self-reported joint pain and motion limitation had poorer scores, particularly in the physical aspects of HRQoL. In adults, significant correlations (P < 0.01) were found between ROM measures and both self-reported measures. Except among those with severe disease, children and adults with haemophilia have HRQoL scores comparable with those of the healthy US population. The physical aspects of HRQoL in both adults and children with haemophilia A in the US decrease with increasing severity of illness. However, scores for mental aspects of HRQoL do not differ between severity groups. These findings are comparable with those from studies in European and Canadian haemophilia populations.

  7. Frequency of intron 1 and 22 inversions of Factor VIII gene in Mexican patients with severe hemophilia A.

    PubMed

    Mantilla-Capacho, Johanna Milena; Beltrán-Miranda, Claudia Patricia; Luna-Záizar, Hilda; Aguilar-López, Lilia; Esparza-Flores, María Amparo; López-Guido, Beatriz; Troyo-Sanromán, Rogelio; Jaloma-Cruz, Ana Rebeca

    2007-04-01

    Hemophilia A (HA) is one of the most common inherited bleeding disorders caused by FVIII gene mutations. Inversion of intron 22 (inv22) originates 50% of cases of severe HA and is a major risk factor for inhibitor development. Inversion of intron 1 (inv1) has been reported to occur in 2-3% of severe HA patients. We studied both inversions to determine their frequencies in Mexican patients with severe HA and to compare these data with other HA populations. The inv22 was evaluated as a risk factor for FVIII inhibitor development in severe HA patients. We studied 44 patients from 31 severe HA families for the detection of inv22 and 94 patients from 65 families to detect inv1. We used the subcycling long-distance PCR to detect inv22 and rapid PCR in duplex reactions to detect inv1. We found a frequency of 45% for the inv22 and no inv1-positive patients (0%). These frequencies were not statistically different from other populations, although haplotype analyses of FVIII gene and telomeric regions should be incorporated to explore population-specific variation of inv1 frequencies. Inv22-positive patients showed 1.88X higher risk for developing inhibitors with respect to patients carrying other severe mutations; however, this OR value was not significant. Our findings confirm inv22 as a hot-spot for severe HA and evidence the low frequency of inv1 in a Mexican population. The non-significant risk for developing inhibitors among inv22-positive patients agrees with the variety of genetic and non-genetic factors involved in such a complication.

  8. 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

  9. Therapeutic and routine prophylactic properties of rFactor VIII Fc (efraloctocog alfa, Eloctate®) in hemophilia A

    PubMed Central

    Chowdary, Pratima; Fosbury, Emma; Riddell, Anne; Mathias, Mary

    2016-01-01

    rFVIIIFc (efraloctocog alfa, Eloctate®) is an extended half-life (EHL) factor VIII licensed for use in patients with hemophilia A for prophylaxis and treatment of bleeding and surgical episodes. Pharmacokinetic studies in adults have shown a mean 1.5-fold increase in half-life compared to full-length factor VIII. When compared to adults, the half-life is decreased by 8% in adolescents between 12 and 17 years, by 18% in children 6 to <12 years, and by 33% in children between the ages of 2 and <6 years. There is a considerable interindividual variation in the prolongation of the half-life particularly in children and across the age groups, the range extending from no increase to a 2.5-fold increase. In addition to age, von willebrand factor (VWF) antigen level has demonstrated a significant impact on rFVIIIFc half-life, with higher VWF levels associated with greater prolongation of half-life. The pivotal and pediatric clinical trials have demonstrated the efficacy and safety of rFVIIIFc for use in regular prophylaxis and in management of bleeds and surgery. In these studies, just under half the participants showed a zero annualized bleed rate (ABR), and the median ABR (1.6 in the pivotal study for the individualized prophylaxis arm) showed a further decrease in the extension study. On average, the patients required fewer infusions (reduced by at least a third), and the mean weekly consumption seems to be in keeping with standard recombinant factor VIII. EHL rFVIIIFc has made decreased infusion frequency a possibility. However, the interindividual variability in dose and infusion frequency highlights the need for a personalized approach based on individual patient’s half-life and/or response to treatment.

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

    PubMed Central

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

    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, we 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 us, 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, transitions at the dinucleotide CpG show the largest male predominance (11-fold). In contrast to 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. PMID:8434583

  11. 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

  12. 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

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

    PubMed Central

    Wang, Qizhao; Dong, Biao; Firrman, Jenni; Wu, Wenman; Roberts, Sean; Moore, Andrea Rossi; Liu, LinShu; Chin, Mario P.S.; Diao, Yong; Kost, Joseph; Xiao, Weidong

    2016-01-01

    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, the 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 HC (hHC) and LC (hLC). The secretion of cHC was 5~30 fold higher than hHC, with or without 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 2~3-fold compared with hLC. Moreover, the cLC but not cHC, contributes the high 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

  14. Therapeutic and routine prophylactic properties of rFactor VIII Fc (efraloctocog alfa, Eloctate®) in hemophilia A

    PubMed Central

    Chowdary, Pratima; Fosbury, Emma; Riddell, Anne; Mathias, Mary

    2016-01-01

    rFVIIIFc (efraloctocog alfa, Eloctate®) is an extended half-life (EHL) factor VIII licensed for use in patients with hemophilia A for prophylaxis and treatment of bleeding and surgical episodes. Pharmacokinetic studies in adults have shown a mean 1.5-fold increase in half-life compared to full-length factor VIII. When compared to adults, the half-life is decreased by 8% in adolescents between 12 and 17 years, by 18% in children 6 to <12 years, and by 33% in children between the ages of 2 and <6 years. There is a considerable interindividual variation in the prolongation of the half-life particularly in children and across the age groups, the range extending from no increase to a 2.5-fold increase. In addition to age, von willebrand factor (VWF) antigen level has demonstrated a significant impact on rFVIIIFc half-life, with higher VWF levels associated with greater prolongation of half-life. The pivotal and pediatric clinical trials have demonstrated the efficacy and safety of rFVIIIFc for use in regular prophylaxis and in management of bleeds and surgery. In these studies, just under half the participants showed a zero annualized bleed rate (ABR), and the median ABR (1.6 in the pivotal study for the individualized prophylaxis arm) showed a further decrease in the extension study. On average, the patients required fewer infusions (reduced by at least a third), and the mean weekly consumption seems to be in keeping with standard recombinant factor VIII. EHL rFVIIIFc has made decreased infusion frequency a possibility. However, the interindividual variability in dose and infusion frequency highlights the need for a personalized approach based on individual patient’s half-life and/or response to treatment. PMID:27695377

  15. Recombinant long-acting glycoPEGylated factor IX in hemophilia B: a multinational randomized phase 3 trial

    PubMed Central

    Young, Guy; Knobe, Karin; Karim, Faraizah Abdul; Angchaisuksiri, Pantep; Banner, Claus; Gürsel, Türkiz; Mahlangu, Johnny; Matsushita, Tadashi; Mauser-Bunschoten, Eveline P.; Oldenburg, Johannes; Walsh, Christopher E.; Negrier, Claude

    2014-01-01

    This multinational, randomized, single-blind trial investigated the safety and efficacy of nonacog beta pegol, a recombinant glycoPEGylated factor IX (FIX) with extended half-life, in 74 previously treated patients with hemophilia B (FIX activity ≤2 IU/dL). Patients received prophylaxis for 52 weeks, randomized to either 10 IU/kg or 40 IU/kg once weekly or to on-demand treatment of 28 weeks. No patients developed inhibitors, and no safety concerns were identified. Three hundred forty-five bleeding episodes were treated, with an estimated success rate of 92.2%. The median annualized bleeding rates (ABRs) were 1.04 in the 40 IU/kg prophylaxis group, 2.93 in the 10 IU/kg prophylaxis group, and 15.58 in the on-demand treatment group. In the 40 IU/kg group, 10 (66.7%) of 15 patients experienced no bleeding episodes into target joints compared with 1 (7.7%) of 13 patients in the 10 IU/kg group. Health-related quality of life (HR-QoL) assessed with the EuroQoL-5 Dimensions visual analog scale score improved from a median of 75 to 90 in the 40 IU/kg prophylaxis group. Nonacog beta pegol was well tolerated and efficacious for the treatment of bleeding episodes and was associated with low ABRs in patients receiving prophylaxis. Once-weekly prophylaxis with 40 IU/kg resolved target joint bleeds in 66.7% of the affected patients and improved HR-QoL. This trial was registered at www.clinicaltrials.gov as #NCT01333111. PMID:25261199

  16. Cohort Profile Update: The 1982 Pelotas (Brazil) Birth Cohort Study

    PubMed Central

    Horta, Bernardo Lessa; Gigante, Denise P; Gonçalves, Helen; dos Santos Motta, JanainaVieira; Loret de Mola, Christian; Oliveira, Isabel O; Barros, Fernando C; Victora, Cesar G

    2015-01-01

    In this manuscript, we update the profile of the 1982 Pelotas Birth Cohort Study.In 1982, 5914 live births whose families lived in the urban are of Pelotas were enrolled in the cohort. In 2012–13, we tried to locate the whole original cohort; 3701 participants were interviewed who, added to the 325 known deaths, represented a follow-up rate of 68.1%. In contrast to the previous home interviews, in this wave all participants were invited to visit the research clinic to be interviewed and examined. The visit was carried out at a mean age of 30.2 years and mainly focused on four categories of outcomes: (i) mental health; (ii) body composition; (iii) precursors of complex chronic diseases; and (iv) human capital. Requests for collaboration by outside researchers are welcome. PMID:25733577

  17. First analysis of 10-year trends in national factor concentrates usage in haemophilia: data from CHARMS, the Canadian Hemophilia Assessment and Resource Management System.

    PubMed

    Traore, A N; Chan, A K C; Webert, K E; Heddle, N; Ritchie, B; St-Louis, J; Teitel, J; Lillicrap, D; Iorio, A; Walker, I

    2014-07-01

    The Canadian Hemophilia Assessment and Resource Management System (CHARMS) tracks factor concentrates (FC) from the sole suppliers, Canadian Blood Services (CBS) and Hema-Quebec (HQ), to hospitals and to patients' homes. Patients FC infusion data are entered into CHARMS at Canadian Hemophilia Treatment Centres (HTCs) then exported to the national database (CentrePoint). From 2000 to 2009, 2260 registered haemophilia A or B patients received FVIII (1,009,097,765 IU) and FIX (272,406,859 IU). Over 91% of FVIII and over 84% of FIX was infused at home. Utilization of FVIII progressively increased; this was accounted for by an increase in the number of patients treated (r = 0.97; P < 0.001), there being a linear relationship between the increase in utilization and the increase in number of patients treated (P < 0.001). There was also a correlation with the annual amount used per patient (r = 0.95; P < 0.001). Utilization of FIX did not increase over time. The highest proportional utilization of both FVIII and FIX was for prophylaxis, and this proportion progressively increased being, in year 10 (2009), 77% and 66% for FVIII and FIX respectively. The proportion used for bleeding remained steady; in year 10 that proportion was 14% for FVIII and 26% for FIX, the use per patient for bleeding decreasing. The HTC-based CHARMS tracking system is essential, in Canada, for analysing indications for infusion, for predicting utilization and planning for future needs.

  18. 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.

  19. 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

  20. 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

  1. 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.

  2. 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.

  3. 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

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

    PubMed

    Armentano, D; Thompson, A R; Darlington, G; Woo, S L

    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. We 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.

  5. Cohort Default Rates in Context

    ERIC Educational Resources Information Center

    Looney, Shannon M.

    2011-01-01

    Burgeoning student loan debt indicates problems not only for the country's borrowers but also for the postsecondary system. The rise in student loan defaults signifies a rise in institutional cohort default rates (CDRs)--a measure of accountability that informs the government and the general public how well an institution prepares its students for…

  6. Cohort Influences in Older Marriages.

    ERIC Educational Resources Information Center

    Eskew, Ron W.

    Cohort differentiation has been posited to crystallize around periods of social crises and to be most impactful on the young adults of a given socio-historical period. The two most prominent socio-historical events in the pasts of today's older married persons were the Great Depression of the 1930's and World War II. Older married couples were…

  7. A Study of Group Dynamics in Educational Leadership Cohort and Non-Cohort Groups

    ERIC Educational Resources Information Center

    Greenlee, Bobbie J.; Karanxha, Zorka

    2010-01-01

    The purpose of this study was to examine group dynamics of educational leadership students in cohorts and make comparisons with the group dynamics characteristics of non-cohort students. Cohorts have emerged as dynamic and adaptive entities with attendant group dynamic processes that shape collective learning and action. Cohort (n=42) and…

  8. Cohort Profile: The Themba Lethu Clinical Cohort, Johannesburg, South Africa

    PubMed Central

    Fox, Matthew P; Maskew, Mhairi; MacPhail, A Patrick; Long, Lawrence; Brennan, Alana T; Westreich, Daniel; MacLeod, William B; Majuba, Pappie; Sanne, Ian M

    2013-01-01

    The Themba Lethu Clinical Cohort was established in 2004 to allow large patient-level analyses from a single HIV treatment site to evaluate National Treatment Guidelines, answer questions of national and international policy relevance and to combine an economic and epidemiologic focus on HIV research. The current objectives of the Themba Lethu Clinical Cohort analyses are to: (i) provide cohort-level information on the outcomes of HIV treatment; (ii) evaluate aspects of HIV care and treatment that have policy relevance; (iii) evaluate the cost and cost-effectiveness of different approaches to HIV care and treatment; and (iv) provide a platform for studies on improving HIV care and treatment. Since 2004, Themba Lethu Clinic has enrolled approximately 30 000 HIV-positive patients into its HIV care and treatment programme, over 21 000 of whom have received anti-retroviral therapy since being enrolled. Patients on treatment are typically seen at least every 3 months with laboratory monitoring every 6 months to 1 year. The data collected include demographics, clinical visit data, laboratory data, medication history and clinical diagnoses. Requests for collaborations on analyses can be submitted to our data centre. PMID:22434860

  9. 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

    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.

  10. 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

  11. 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 at www.clinicaltrials.gov as #NCT0101496274.

  12. 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

  13. Riyadh Mother and Baby Multicenter Cohort Study: The Cohort Profile

    PubMed Central

    Esmaeil, Samia; Alzeidan, Rasmieh; Elawad, Mamoun; Tabassum, Rabeena; Hansoti, Shehnaz; Magzoup, Mohie Edein; Al-Kadri, Hanan; Elsherif, Elham; Al-Mandil, Hazim; Al-Shaikh, Ghadeer; Zakaria, Nasria

    2016-01-01

    Objectives To assess the effects of non-communicable diseases, such as diabetes, hypertension and obesity, on the mother and the infant. Methods A multicentre cohort study was conducted in three hospitals in the city of Riyadh in Saudi Arabia. All Saudi women and their babies who delivered in participating hospitals were eligible for recruitment. Data on socio-demographic characteristics in addition to the maternal and neonatal outcomes of pregnancy were collected. The cohort demographic profile was recorded and the prevalence of maternal conditions including gestational diabetes, pre-gestational diabetes, hypertensive disorders in pregnancy and obesity were estimated. Findings The total number of women who delivered in participating hospitals during the study period was 16,012 of which 14,568 women participated in the study. The mean age of the participants was 29 ± 5.9 years and over 40% were university graduates. Most of the participants were housewives, 70% were high or middle income and 22% were exposed to secondhand smoke. Of the total cohort, 24% were married to a first cousin. More than 68% of the participants were either overweight or obese. The preterm delivery rate was 9%, while 1.5% of the deliveries were postdate. The stillbirth rate was 13/1000 live birth. The prevalence of gestational diabetes was 24% and that of pre-gestational diabetes was 4.3%. The preeclampsia prevalence was 1.1%. The labour induction rate was 15.5% and the cesarean section rate was 25%. Conclusion Pregnant women in Saudi Arabia have a unique demographic profile. The prevalence of obesity and diabetes in pregnancy are among the highest in the world. PMID:26937965

  14. Cohort Profile: The Limache, Chile, birth cohort study

    PubMed Central

    Amigo, Hugo; Bustos, Patricia; Zumelzú, Elinor; Rona, Roberto J

    2014-01-01

    The Limache cohort was set up to assess the programming and life course events hypotheses in relation to cardiovascular risk factors and chronic respiratory conditions, especially asthma, in the context of an unprecedented economic growth in Chile. The cohort was a representative sample of 1232 participants born between 1974 and 1978 in the hospital of Limache. The study includes data collected at birth, during the 1st year of life, at 22 to 28 years (collected between 2000 and 2002) and at 32 to 38 years (collected between 2010 and 2012). The data collected include anthropometric measurements at birth, 1st year of life and in adulthood, socio-economic and demographic data, lifestyle information including smoking, alcohol consumption and food intake, respiratory symptoms, lung function, broncho-reactivity to methacholine and skin prick reaction to eight allergens, measurement of cardiovascular risk factors and information on common mental health, mainly in the most recent study. The principal researchers welcome collaborative projects, especially those that will compare similar data sets in other settings [E-mail: hamigo@med.uchile.cl]. PMID:24366489

  15. Cohort profile: The Limache, Chile, birth cohort study.

    PubMed

    Amigo, Hugo; Bustos, Patricia; Zumelzú, Elinor; Rona, Roberto J

    2014-08-01

    The Limache cohort was set up to assess the programming and life course events hypotheses in relation to cardiovascular risk factors and chronic respiratory conditions, especially asthma, in the context of an unprecedented economic growth in Chile. The cohort was a representative sample of 1232 participants born between 1974 and 1978 in the hospital of Limache. The study includes data collected at birth, during the 1st year of life, at 22 to 28 years (collected between 2000 and 2002) and at 32 to 38 years (collected between 2010 and 2012). The data collected include anthropometric measurements at birth, 1st year of life and in adulthood, socio-economic and demographic data, lifestyle information including smoking, alcohol consumption and food intake, respiratory symptoms, lung function, broncho-reactivity to methacholine and skin prick reaction to eight allergens, measurement of cardiovascular risk factors and information on common mental health, mainly in the most recent study. The principal researchers welcome collaborative projects, especially those that will compare similar data sets in other settings. PMID:24366489

  16. [Criminality in a birth cohort].

    PubMed

    Wolfgang, M E

    1975-01-01

    Beginning with a group of approximately 10,000 boys born in 1945 who lived in Philadelphia from at least ages ten through seventeen, the Center for Studies in Criminology and Criminal Law, University of Pennsylvania has engaged in a longitudinal analysis of the delinquency of the birth cohort. The first publication which examines the dynamic flow of delinquency committed by 3500 of the boys was published by the University of Chicago Press in 1972 and is entitled Delinquency in a Birth Cohort. This study is the first in the United States to establish a base line of delinquency probabilities and to analyze the types of delinquency committed over time, with the recording of the seriousness of each of the 10,000 acts committed by the 3500 boys. The seriousness scores were derived from the earlier work by Sellin and Wolfgang, entitle The Measurement of Delinquency. A stochastic model was used to analyze the delinquent patterns and one of the major conclusions, at least up to age eighteen, was that there was no specific delinquency specialization by type of offense. Moreover, after the third offense, the probabilities of desistence, or refraining from further delinquent acts, remained stable, thus indicating that the most propitious point for social intervention would be after the third offense rather than at some time prior to the onset of delinquency or even after the first or second offense-offenses which are usually of a very minor character. The Center for Studies in Criminology and Criminal Law has continued to follow up a ten per cent sample of the original birth cohort by interviewing them to obtain additional social psychological dynamic features of their background, of the situations involving their first and last delinquencies, and of their adult careers. The follow-up indicates thus far that approximately 12 per cent new cases of criminality appeared, thus adding to the original 35 per cent of the birth cohort who had a delinquency record. The study will

  17. A Cohort Model of Fertility Postponement

    PubMed Central

    Goldstein, Joshua R.; Cassidy, Thomas

    2015-01-01

    We introduce a new formal model in which demographic behavior such as fertility is postponed by differing amounts depending only on cohort membership. The cohort-based model shows the effects of cohort shifts on period fertility measures and provides an accompanying tempo adjustment to determine the period fertility that would have occurred without postponement. Cohort-based postponement spans multiple periods and produces “fertility momentum,” with implications for future fertility rates. We illustrate several methods for model estimation and apply the model to fertility in several countries. We also compare the fit of period-based and cohort-based shift models to the recent Dutch fertility surface, showing how cohort- and period-based postponement can occur simultaneously. PMID:25233957

  18. 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 ...

  19. 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 ...

  20. Age, Birth Cohorts, and Drinking: An Illustration of the Hazards of Inferring Effects from Cohort Data.

    ERIC Educational Resources Information Center

    Glenn, Norval D.

    1981-01-01

    Analyzes problems in the use of cohort data as illustrated by cohort data on drinking alcoholic beverages taken from American national surveys conducted during the late 1950s, late 1960s, and late 1970s. Researchers are cautioned that all available "side information" should be considered before statistical cohort models are tested. (Author/RC)

  1. 2011 Cohort Graduation and Dropout Rate Report

    ERIC Educational Resources Information Center

    Utah State Office of Education, 2011

    2011-01-01

    To align with new federal No Child Left Behind (NCLB) regulations for graduation rate calculations, the Utah State Office of Education (USOE) is reporting a new graduation rate beginning with the 2011 graduating class (also known as the 2011 cohort). The four-year cohort rate (includes all students who started 9th grade in 2007-2008 plus…

  2. Benefits of a Cohort Survival Projection Model

    ERIC Educational Resources Information Center

    Suslow, Sidney

    1977-01-01

    A cohort survival model of student attendance provides primary and secondary benefits in accurate student information not before available. At Berkeley the computerized Cohort Survival History File, in use for two years, has been successful in assessing various aspects of students' academic behavior and student flow problems. (Editor/LBH)

  3. FY 1993 Cohort Official Default Rate Guide.

    ERIC Educational Resources Information Center

    Office of Postsecondary Education (ED), Washington, DC.

    This document is intended to help institutions of postsecondary education understand their rights and responsibilities relating to school cohort default rates for the Federal Family Education Loan (FFEL)Program. Section 1 focuses on the calculation of FY 1993 official cohort default rates including how student loan activity is tracked and…

  4. Graduate Cohort Approach in Teacher Education

    ERIC Educational Resources Information Center

    Mattson-Gearhart, Jeanine

    2012-01-01

    The use of the cohorts in teacher education has steadily increased over the last decade. Research indicates both beneficial and negative aspects to this approach, with the field undecided. This study focuses on a Midwestern university's accelerated graduate program for special educators. The program uses a mixed cohort approach to model…

  5. Cohort Default Rate Guide. Revised August 2006

    ERIC Educational Resources Information Center

    US Department of Education, 2006

    2006-01-01

    This guide is designed to assist schools with their Federal Family Education Loan (FFEL) Program and William D. Ford Federal Direct Loan (Direct Loan) Program cohort default rate data. The guide is intended as a reference tool in understanding cohort default rates and processes. Material is organized into four parts: (1) Introduction; (2) General…

  6. A Chinese Birth Cohort: Theoretical Implications

    ERIC Educational Resources Information Center

    Friday, Paul C.; Ren, Xin; Weitekamp, Elmar; Kerner, Hans-Jurgen; Taylor, Terrance

    2005-01-01

    Research on delinquency has shown consistent results across Western industrialized countries. Few studies have been done in non-Western cultures. This study reports on the results of a birth cohort study in China, which was started by Marvin Wolfgang but never completed. The cohort, born in 1973, was traced through official and community files.…

  7. Cohort Crowding and Nonresident College Enrollment

    ERIC Educational Resources Information Center

    Winters, John V.

    2012-01-01

    This study uses a fixed effects panel data framework to examine the effects of cohort crowding and other variables on nonresident enrollment at four-year public colleges and universities. The results suggest that larger cohorts of resident students crowd out nonresident students at flagship universities, but there is inconsistent evidence of crowd…

  8. 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

  9. 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

  10. 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.

  11. Analysis of case-cohort designs.

    PubMed

    Barlow, W E; Ichikawa, L; Rosner, D; Izumi, S

    1999-12-01

    The case-cohort design is most useful in analyzing time to failure in a large cohort in which failure is rare. Covariate information is collected from all failures and a representative sample of censored observations. Sampling is done without respect to time or disease status, and, therefore, the design is more flexible than a nested case-control design. Despite the efficiency of the methods, case-cohort designs are not often used because of perceived analytic complexity. In this article, we illustrate computation of a simple variance estimator and discuss model fitting techniques in SAS. Three different weighting methods are considered. Model fitting is demonstrated in an occupational exposure study of nickel refinery workers. The design is compared to a nested case-control design with respect to analysis and efficiency in a small simulation. In this example, case-cohort sampling from the full cohort was more efficient than using a comparable nested case-control design. PMID:10580779

  12. Cohort profile: The Isle of Man Birth Cohort Study.

    PubMed

    Goodfellow, Stephanie A; Rolfe, Edna M; Golding, Jean

    2013-10-01

    The Isle of Man is a self-governing British Crown Dependency situated equidistantly from England, Scotland and Ireland. In 1991, its population of ∼75,000 comprised ∼50% indigenous Manx and 50% immigrants, mainly from the surrounding countries. It was invited to join the European Longitudinal Study of Pregnancy and Childhood. The aim of the study was to enrol all pregnant women resident on the Island with an expected date of delivery in the 18-month period of January 1991-June 1992. A total of 1314 livebirths formed the eligible cohort. Questionnaires were completed by mothers and their partners during pregnancy and subsequently at 6 weeks, 6 months, 18 months, 3, 5, 7 and 15/16 years. Hands-on examination of the children occurred at age 7 years, when biological samples were collected. Teachers completed questionnaires at 7 and 15 years; medical records were extracted for the obstetric and childhood periods. Response rates varied from >80% from teachers and children at 15 years to only 23% from partners when their children were aged 7 years. Selected data sets are available to collaborators, although many of the data need funds for further collaboration. PMID:23095165

  13. 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.

  14. Recommendations for authors of manuscripts reporting inhibitor cases developed in previously treated patients with hemophilia: communication from the SSC of the ISTH.

    PubMed

    Iorio, A; Barbara, A M; Bernardi, F; Lillicrap, D; Makris, M; Peyvandi, F; Rosendaal, F

    2016-08-01

    Aim The scope of this recommendation is to provide guidance for reporting of inhibitor cases in previously treated patients (PTPs) with hemophilia A. This guidance is intended to improve transparency and completeness of reporting of observed events; it does not cover planning, executing or analyzing original studies aimed at the assessment of inhibitor rates. Recommendation We recommend that for each case of inhibitor development reported in a published paper, a paragraph or a table is included in the main publication reporting as a minimum the underlined data fields in Table . We recommend transparent reporting when any of the suggested information is not available. We recommend that particular care is used in reporting the timeline of events by clearly identifying a reference time-point. We suggest that journals in the field adopt this guidance as instructions for the authors and as a guide for reviewers. Conclusion Development of inhibitors in PTPs is a very rare event. Standardized reporting of inhibitor characteristics will contribute to generating a body of evidence otherwise not available. Case by case reporting of the recommended data elements may shed light on the natural history and risk factors of inhibitor development in PTPs and be useful for tailoring care in similar future cases. PMID:27496160

  15. 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.

  16. Exposure of FVIII in the Presence of Phosphatidyl Serine Reduces Generation of Memory B-Cells and Induces Regulatory T-Cell-Mediated Hyporesponsiveness in Hemophilia A Mice.

    PubMed

    Ramakrishnan, Radha; Davidowitz, Andrew; Balu-Iyer, Sathy V

    2015-08-01

    A major complication of replacement therapy with Factor VIII (FVIII) for hemophilia A (HA) is the development of unwanted immune responses. Previous studies showed that administration of FVIII in the presence of phosphatidyl serine (PS) reduced the development of anti-FVIII antibodies in HA mice. However, the impact of PS-mediated effects on immunological memory, such as generation of memory B-cells, is not clear. The effect of PS on memory B-cells was therefore investigated using adoptive transfer approach in FVIII(-/-) HA mice. Adoptive transfer of memory B-cells from a PS-FVIII-treated group to naïve mice followed by challenge of the recipient mice with FVIII showed a significantly reduced anti-FVIII antibody response in the recipient mice, compared with animals that received memory B-cells from free FVIII and FVIII-charge matched phosphatidyl glycerol (PG) group. The decrease in memory B-cell response is accompanied by an increase in FoxP3 expressing regulatory T-cells (Tregs). Flow cytometry studies showed that the generation of Tregs is higher in PS-treated animals as compared with FVIII and FVIII-PG treated animals. The PS-mediated hyporesponsiveness was found to be antigen-specific. The PS-FVIII immunization showed hyporesponsiveness toward FVIII rechallenge but not against ovalbumin (OVA) rechallenge, an unrelated antigen. This demonstrates that PS reduces immunologic memory of FVIII and induces antigen-specific peripheral tolerance in HA mice.

  17. Acquired Hemophilia A May Be Associated with Ticagrelor Therapy in a 52-Year-Old Man After a Recent Percutaneous Transluminal Coronary Angioplasty

    PubMed Central

    Pasquino, Paola; Canaparo, Roberto; Capello, Tiziana; Deorsola, Barbara; Perazzolo, Laura; Marengo, Claudio; Serpe, Loredana

    2016-01-01

    We present a case report of a 52-year-old man who was hospitalized for right leg pain due to a relevant hemorrhagic effusion. He was on dual antiplatelet therapy (DAPT): acetylsalicylic acid and ticagrelor, a reversible P2Y12 receptor antagonist. Signs, symptoms, and laboratory blood tests led to the diagnosis of acquired hemophilia A (AHA). Ticagrelor therapy-associated AHA was hypothesized due to the fact that, before adding this drug, all laboratory and clinical examinations were repeatedly normal. Prednisone and cyclophosphamide treatment was started without DAPT interruption due to the high risk of stent thrombosis. After 10 days, prolonged activated partial thromboplastin time dropped from 107 to 49 seconds, the patient’s factor VIII (FVIII) levels gradually normalized over the following few weeks, and FVIII inhibitor titer was negative. Recently, some reports have established a link between the development of AHA and treatment with clopidogrel, an irreversible P2Y12 receptor antagonist. However, to the best of our knowledge, this is the first time that a link between AHA and ticagrelor has been reported.

  18. 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

  19. Acquired Hemophilia A May Be Associated with Ticagrelor Therapy in a 52-Year-Old Man After a Recent Percutaneous Transluminal Coronary Angioplasty

    PubMed Central

    Pasquino, Paola; Canaparo, Roberto; Capello, Tiziana; Deorsola, Barbara; Perazzolo, Laura; Marengo, Claudio; Serpe, Loredana

    2016-01-01

    We present a case report of a 52-year-old man who was hospitalized for right leg pain due to a relevant hemorrhagic effusion. He was on dual antiplatelet therapy (DAPT): acetylsalicylic acid and ticagrelor, a reversible P2Y12 receptor antagonist. Signs, symptoms, and laboratory blood tests led to the diagnosis of acquired hemophilia A (AHA). Ticagrelor therapy-associated AHA was hypothesized due to the fact that, before adding this drug, all laboratory and clinical examinations were repeatedly normal. Prednisone and cyclophosphamide treatment was started without DAPT interruption due to the high risk of stent thrombosis. After 10 days, prolonged activated partial thromboplastin time dropped from 107 to 49 seconds, the patient’s factor VIII (FVIII) levels gradually normalized over the following few weeks, and FVIII inhibitor titer was negative. Recently, some reports have established a link between the development of AHA and treatment with clopidogrel, an irreversible P2Y12 receptor antagonist. However, to the best of our knowledge, this is the first time that a link between AHA and ticagrelor has been reported. PMID:27660505

  20. 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

  1. Acquired Hemophilia A May Be Associated with Ticagrelor Therapy in a 52-Year-Old Man After a Recent Percutaneous Transluminal Coronary Angioplasty.

    PubMed

    Pasquino, Paola; Canaparo, Roberto; Capello, Tiziana; Deorsola, Barbara; Perazzolo, Laura; Marengo, Claudio; Serpe, Loredana

    2016-01-01

    We present a case report of a 52-year-old man who was hospitalized for right leg pain due to a relevant hemorrhagic effusion. He was on dual antiplatelet therapy (DAPT): acetylsalicylic acid and ticagrelor, a reversible P2Y12 receptor antagonist. Signs, symptoms, and laboratory blood tests led to the diagnosis of acquired hemophilia A (AHA). Ticagrelor therapy-associated AHA was hypothesized due to the fact that, before adding this drug, all laboratory and clinical examinations were repeatedly normal. Prednisone and cyclophosphamide treatment was started without DAPT interruption due to the high risk of stent thrombosis. After 10 days, prolonged activated partial thromboplastin time dropped from 107 to 49 seconds, the patient's factor VIII (FVIII) levels gradually normalized over the following few weeks, and FVIII inhibitor titer was negative. Recently, some reports have established a link between the development of AHA and treatment with clopidogrel, an irreversible P2Y12 receptor antagonist. However, to the best of our knowledge, this is the first time that a link between AHA and ticagrelor has been reported. PMID:27660505

  2. Reduced production of IFN-γ and LT-α is associated with successful prednisone therapy in patients with acquired hemophilia A: a pilot study.

    PubMed

    Kruse-Jarres, Rebecca; Fang, Jian; Leissinger, Cindy A; Ganapamo, Frédéric

    2011-11-01

    Glucocorticoids (GC) are a standard treatment for acquired hemophilia A (AH). Although the optimal treatment regimen and duration of GC's is unknown, measurement of sub-clinical immune responses may help direct therapeutic decision making. To study the helpfulness of this approach, three male patients diagnosed with AH were treated with prednisone. The therapy resulted in inhibitor elimination in two out of the three individuals. During the treatment, peripheral mononuclear cells were isolated at different time points and stimulated in vitro. The expression of IFN-γ and LT-α were monitored at both the protein and the mRNA levels. The amount of IFN-γ and LT-α were markedly reduced by the time of inhibitor disappearance in the patients responding to GC therapy but remained high in the non-responder until cyclophosphamide was added. This study suggests that the secretion level of IFN-γ and/or LT-α could be a predictive marker of prednisone responsiveness.

  3. 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.

  4. Detection of hemophilia a carriers in Azeri Turkish population of Iran: usefulness of HindIII and BclI markers.

    PubMed

    Moharrami, Tamouchin; Derakhshan, Sima Mansoori; Pourfeizi, Abbas Ali H; Khaniani, Mahmoud Shekari

    2015-11-01

    Hemophilia A (HA) is an inherited X-linked coagulation disorder caused by the deficiency of factor VIII (FVIII). Linkage analysis is a common indirect method for the detection of female carriers in families with HA. In the current study, 173 patients from 30 unrelated families with HA were recruited from the Azeri Turkish population of northwest Iran and analyzed for BclI and HindIII markers by polymerase chain reaction-restriction fragment length polymorphism. We investigated the potential of using these markers for the detection of mutation in carriers through linkage analysis, which would be of tremendous use in prenatal diagnosis. Among the tested women, 47% and 35% were found to be heterozygous for BclI and HindIII polymorphic markers, respectively. The BclI and HindIII markers were informative for the detection of 63% and 17% potential carriers, respectively, demonstrating the effectiveness of the BclI marker for the detection of HA carriers among the Azeri Turkish population.

  5. Factor IX levels in patients with hemophilia B (Christmas disease) following transfusion with concentrates of factor IX or fresh frozen plasma (FFP).

    PubMed

    Zauber, N P; Levin, J

    1977-05-01

    There has been no systematic re-examination of variables that may affect the level and duration of response of patients with hemophilia B (Christmas disease) to transfusion. Therefore, 49 of our transfusion episodes and 171 previously reported transfusions were evaluated. Mean calculated initial increase of Factor IX levels (delta %/unit (U) of procoagulant activity infused/kg) was 0.82 +/- 0.09% (mean +/-S.E.) in previously reported cases and 1.01 +/- 0.13% in our patients, after transfusion of concentrate; but only 0.05 +/- 0.11% after fresh frozen plasma (FFP). Response was not altered by acute hemorrhage, baseline Factor IX levels, or body weight. Proplex (Hyland) and Konyne (Cutter) produced similar responses. Following transfusion, the disappearance curve was biphasic. The mean T1/2 for the second component was 27.5 hrs, but the direct T1/2 was only 6.4 +/- 1.0 hr. Regardless of common clinical variables, increase of Factor IX following transfusion of American concentrates is 1.0% (or 0.01 U)/1 administered/kg. Appropriate frequency of transfusion depends upon an understanding of the biphasic disappearance of Factor IX. Importantly, the initial frequency of transfusion therapy should be based on a direct T1/2 of only 6 to 8 hrs.

  6. The cohort effect in childhood disease dynamics.

    PubMed

    He, Daihai; Earn, David J D

    2016-07-01

    The structure of school terms is well known to influence seasonality of transmission rates of childhood infectious diseases in industrialized countries. A less well-studied aspect of school calendars that influences disease dynamics is that all children enter school on the same day each year. Rather than a continuous inflow, there is a sudden increase in the number of susceptible individuals in schools at the start of the school year. Based on the standard susceptible-exposed-infectious-recovered (SEIR) model, we show that school cohort entry alone is sufficient to generate a biennial epidemic pattern, similar to many observed time series of measles incidence. In addition, cohort entry causes an annual decline in the effective transmission that is evident in observed time series, but not in models without the cohort effect. Including both cohort entry and school terms yields a model fit that is significantly closer to observed measles data than is obtained with either cohort entry or school terms alone (and just as good as that obtained with Schenzle's realistic age-structured model). Nevertheless, we find that the bifurcation structure of the periodically forced SEIR model is nearly identical, regardless of whether forcing arises from cohort entry, school terms and any combination of the two. Thus, while detailed time-series fits are substantially improved by including both cohort entry and school terms, the overall qualitative dynamic structure of the SEIR model appears to be insensitive to the origin of periodic forcing. PMID:27440254

  7. Cohort Profile: The Bissau HIV Cohort-a cohort of HIV-1, HIV-2 and co-infected patients.

    PubMed

    Jespersen, Sanne; Hønge, Bo Langhoff; Oliveira, Inés; Medina, Candida; da Silva Té, David; Correira, Faustino Gomes; Erikstrup, Christian; Laursen, Alex Lund; Østergaard, Lars; Wejse, Christian

    2015-06-01

    The West African country Guinea-Bissau is home to the world's highest prevalence of HIV-2, and its HIV-1 prevalence is rising. Other chronic viral infections like human T-lymphotropic virus type 1 (HTLV-1) and hepatitis B virus are common as well. The Bissau HIV Cohort was started in 2007 to gain new insights into the overall effect of introducing antiretroviral treatment in a treatment-naïve population with concomitant infection with three retroviruses (HIV-1, HIV-2 and HTLV-1) and tuberculosis. The cohort includes patients from the HIV clinic at Hospital Nacional Simão Mendes, the main hospital in Bissau, the capital of the country. From July 2007 to June 2013, 3762 HIV-infected patients (69% HIV-1, 18% HIV-2, 11% HIV-1/2 and 2% HIV type unknown) were included in the world's largest single-centre HIV-2 cohort. Demographic and clinical data are collected at baseline and every 6 months, together with CD4 cell count and routine biochemistry analyses. Plasma and cells are stored in a biobank in Denmark. The Bissau HIV Cohort is administered by the Bissau HIV Cohort study group. Potential collaborators are invited to contact the chair of the cohort study group, Christian Wejse, e-mail: [wejse@dadlnet.dk].

  8. Demographic cycles, cohort size, and earnings.

    PubMed

    Berger, M C

    1989-05-01

    This article examines whether position in the demographic cycle is an important factor in determining earnings and earnings growth. Earnings equations for white males are estimated by using March Current Population Survey data. Position in the demographic cycle is captured by including both measures of own cohort size and the size of surrounding cohorts in the estimated earnings equations. Position in the demographic cycle matters. Increases in own cohort size lead to flatter earnings profiles, whereas increases in the size of surrounding cohorts are associated with steeper earnings profiles. The net effect is that those who enter the labor market before or after the peak of the demographic cycle start out with lower earnings but experience faster earnings growth. This pattern is uniform across all schooling groups: high school dropouts, high school graduates, those with some college, and college graduates.

  9. Cohort Profile: Recruitment cohorts in the neuropsychological substudy of the Multicenter AIDS Cohort Study

    PubMed Central

    Becker, James T; Kingsley, Lawrence A; Molsberry, Samantha; Reynolds, Sandra; Aronow, Aaron; Levine, Andrew J; Martin, Eileen; Miller, Eric N; Munro, Cynthia A; Ragin, Ann; Sacktor, Ned; Selnes, Ola A

    2015-01-01

    The Multicenter AIDS Cohort Study (MACS) is one of the largest and longest running studies of the natural and treated history of HIV disease. The Neuropsychological (NP) substudy was begun in 1988 following reports of significant adverse neurological consequences of HIV disease, including dementia. The goal was to characterize the neuropsychological deficits among individuals with HIV disease, and track the natural history of the neurological complications over time. There were three distinct MACS recruitment stages that focused on different groups of HIV-infected men, or men at risk for infection. Initially, a subcohort was evaluated semi-annually with NP tests but, beginning in 2005, the entire group of MACS participants have had NP examinations biannually, unless closer follow-up was warranted. The participants complete a battery of NP tests, and are classified as either normal, mildly or severely impaired using the Antinori criteria for HIV-Associated Neurocognitive Disorder (HAND). Additional behavioural data, including mood state and psychoactive substance use, are recorded as part of the main MACS data collection. The MACS public data set (PDS) has been available since 1994 and includes baseline and 6-monthly follow-up data. Beginning in October 1995, the PDS has been released annually with new releases superseding previous versions. PMID:24771276

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

    PubMed

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

    2014-11-27

    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.

  11. Cost-Effectiveness Analysis of Biogeneric Recombinant Activated Factor VII (AryoSeven™) and Activated Prothrombin Complex Concentrates (FEIBA™) to Treat Hemophilia A Patients with Inhibitors in Iran

    PubMed Central

    Golestani, Mina; Eshghi, Peyman; Rasekh, Hamid Reza; Cheraghali, Abdoll Majid; Salamzadeh, Jamshid; Naderi, Majid; Managhchi, Mohammad Reza; Hoorfar, Hamid; Toogeh, Gholam Reza; Imani, Ali; Khodayari, Mohammad Taghi; Habibpanah, Behnaz; Hantooshzadeh, Razieh

    2016-01-01

    Nowadays, bypassing agents such as recombinant activated factor VII (rFVIIa) and activated prothrombin complex concentrates (aPCC) are used to treat bleeding episodes in the Hemophilia patients with inhibitors. AryoSeven® is an Iranian biogeneric rFVIIa with homogeneity of efficacy and the nature to NovoSeven in a comparative trial. The current clinical trial aimed to evaluate the cost-effectiveness of FEIBA and AryoSeven® by Decision Analytic Model according to the Iranian healthcare system. An open label, multi-center, cross-over clinical trial was designed. Patients were categorized into 3 groups based on their prior tendency to one or none of the products. To determine the premium therapeutic strategy, the Incremental cost-effectiveness ratio (ICER) was calculated. Protocol F led to more treatment success in group F than the other groups (P= 0.03). Also, there was a significant statistical difference between the mean of effectiveness scores in the groups using protocol F (P = 0.01). The effectiveness of protocol F and A were 89% and 72%, respectively. ICER cost US$ to manage an episode of bleeding to get one more unit of effectiveness using FEIBA VS. AryoSeven. Although the results showed that AryoSeven was more cost-effective compared to FEIBA, the two strategies were undominated. In other words, both medicines can be applied in the first line of the treatment if the cost of FEIBA was reduced. The present clinical trial was registered at IRCT website, under ID No.2013020612380N1. PMID:27642341

  12. Small ncRNA Expression-Profiling of Blood from Hemophilia A Patients Identifies miR-1246 as a Potential Regulator of Factor 8 Gene

    PubMed Central

    Sarachana, Tewarit; Dahiya, Neetu; Simhadri, Vijaya L.; Pandey, Gouri Shankar; Saini, Surbhi; Guelcher, Christine; Guerrera, Michael F.; Kimchi-Sarfaty, Chava; Sauna, Zuben E.; Atreya, Chintamani D.

    2015-01-01

    Hemophilia A (HA) is a bleeding disorder caused by deficiency of functional plasma clotting factor VIII (FVIII). Genetic mutations in the gene encoding FVIII (F8) have been extensively studied. Over a thousand different mutations have been reported in the F8 gene. These span a diverse range of mutation types, namely, missense, splice-site, deletions of single and multiple exons, inversions, etc. There is nonetheless evidence that other molecular mechanisms, in addition to mutations in the gene encoding the FVIII protein, may be involved in the pathobiology of HA. In this study, global small ncRNA expression profiling analysis of whole blood from HA patients, and controls, was performed using high-throughput ncRNA microarrays. Patients were further sub-divided into those that developed neutralizing-anti-FVIII antibodies (inhibitors) and those that did not. Selected differentially expressed ncRNAs were validated by quantitative reverse transcription-polymerase chain reaction (qRT-PCR) analysis. We identified several ncRNAs, and among them hsa-miR-1246 was significantly up-regulated in HA patients. In addition, miR-1246 showed a six-fold higher expression in HA patients without inhibitors. We have identified an miR-1246 target site in the noncoding region of F8 mRNA and were able to confirm the suppressory role of hsa-miR-1246 on F8 expression in a stable lymphoblastoid cell line expressing FVIII. These findings suggest several testable hypotheses vis-à-vis the role of nc-RNAs in the regulation of F8 expression. These hypotheses have not been exhaustively tested in this study as they require carefully curated clinical samples. PMID:26176629

  13. Good manufacturing practice production of self-complementary serotype 8 adeno-associated viral vector for a hemophilia B clinical trial.

    PubMed

    Allay, James A; Sleep, Susan; Long, Scott; Tillman, David M; Clark, Rob; Carney, Gael; Fagone, Paolo; McIntosh, Jenny H; Nienhuis, Arthur W; Davidoff, Andrew M; Nathwani, Amit C; Gray, John T

    2011-05-01

    To generate sufficient clinical-grade vector to support a phase I/II clinical trial of adeno-associated virus serotype 8 (AAV8)-mediated factor IX (FIX) gene transfer for hemophilia B, we have developed a large-scale, good manufacturing practice (GMP)-compatible method for vector production and purification. We used a 293T-based two-plasmid transient transfection system coupled with a three-column chromatography purification process to produce high-quality self-complementary AAV2/8 FIX clinical-grade vector. Two consecutive production campaigns using a total of 432 independent 10-stack culture chambers produced a total of ∼2 × 10(15) vector genomes (VG) by dot-blot hybridization. Benzonase-treated microfluidized lysates generated from pellets of transfected cells were purified by group separation on Sepharose beads followed by anion-exchange chromatography. The virus-containing fractions were further processed by gel filtration and ultrafiltration, using a 100-kDa membrane. The vector was formulated in phosphate-buffered saline plus 0.25% human serum albumin. Spectrophotometric analysis suggested ∼20% full particles, with only low quantities of nonviral proteins were visible on silver-stained sodium dodecyl sulfate-polyacrylamide gels. A sensitive assay for the detection of replication-competent AAV was developed, which did reveal trace quantities of such contaminants in the final product. Additional studies have confirmed the long-term stability of the vector at -80°C for at least 24 months and for at least 24 hr formulated in the clinical diluent and stored at room temperature within intravenous bags. This material has been approved for use in clinical trials in the United States and the United Kingdom.

  14. Genotyping of intron 22 inversion of factor VIII gene for diagnosis of hemophilia A by inverse-shifting polymerase chain reaction and capillary electrophoresis.

    PubMed

    Pan, Tzu-Yu; Wang, Chun-Chi; Shih, Chi-Jen; Wu, Hui-Fen; Chiou, Shyh-Shin; Wu, Shou-Mei

    2014-09-01

    This is the first capillary electrophoresis (CE) analysis for diagnosis of hemophilia A (HA). The intron 22 inversion of factor VIII gene (F8) causes 40-50 % of severe bleeding disorder of HA in all human populations. Consequently, identification of the disease-causing mutations is becoming increasingly important for accurate genetic counseling and prenatal diagnosis. In this study, the key steps of inverse-shifting polymerase chain reaction (IS-PCR) and of short-end injection capillary electrophoresis were used for more specific and rapid genotyping of intron 22 inversion of F8. In IS-PCR, three specific primers were used to amplify 512-bp amplicon for wild type and 584-bp amplicon for patients with intron 22 inversion. The capillary gel electrophoresis (CGE) system was performed using 1× Tris-borate-EDTA (TBE) buffer containing 0.3 % (w/v) polyethylene oxide (PEO). The PCR amplicons were electrokinetically injected at 10 kV for 10 s at a temperature of 25 °C. The optimal short-end injection CGE was applied to detect the F8 gene of HA patients and carriers within 5 min. Intron 22 inversion was indeed found on some HA patients (13/35, 37.1 %). All genotyping results showed good agreement with DNA sequencing method and long-distance polymerase chain reaction (LD-PCR). The IS-PCR combined with short-end injection CGE method was feasible and efficient for intron 22 inversion screening of F8 in the HA populations.

  15. 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

  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.

  17. Cost-Effectiveness Analysis of Biogeneric Recombinant Activated Factor VII (AryoSeven™) and Activated Prothrombin Complex Concentrates (FEIBA™) to Treat Hemophilia A Patients with Inhibitors in Iran.

    PubMed

    Golestani, Mina; Eshghi, Peyman; Rasekh, Hamid Reza; Cheraghali, Abdoll Majid; Salamzadeh, Jamshid; Naderi, Majid; Managhchi, Mohammad Reza; Hoorfar, Hamid; Toogeh, Gholam Reza; Imani, Ali; Khodayari, Mohammad Taghi; Habibpanah, Behnaz; Hantooshzadeh, Razieh

    2016-01-01

    Nowadays, bypassing agents such as recombinant activated factor VII (rFVIIa) and activated prothrombin complex concentrates (aPCC) are used to treat bleeding episodes in the Hemophilia patients with inhibitors. AryoSeven® is an Iranian biogeneric rFVIIa with homogeneity of efficacy and the nature to NovoSeven in a comparative trial. The current clinical trial aimed to evaluate the cost-effectiveness of FEIBA and AryoSeven® by Decision Analytic Model according to the Iranian healthcare system. An open label, multi-center, cross-over clinical trial was designed. Patients were categorized into 3 groups based on their prior tendency to one or none of the products. To determine the premium therapeutic strategy, the Incremental cost-effectiveness ratio (ICER) was calculated. Protocol F led to more treatment success in group F than the other groups (P= 0.03). Also, there was a significant statistical difference between the mean of effectiveness scores in the groups using protocol F (P = 0.01). The effectiveness of protocol F and A were 89% and 72%, respectively. ICER cost US$ to manage an episode of bleeding to get one more unit of effectiveness using FEIBA VS. AryoSeven. Although the results showed that AryoSeven was more cost-effective compared to FEIBA, the two strategies were undominated. In other words, both medicines can be applied in the first line of the treatment if the cost of FEIBA was reduced. The present clinical trial was registered at IRCT website, under ID No.2013020612380N1. PMID:27642341

  18. 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

  19. Cohort studies in health sciences librarianship

    PubMed Central

    Eldredge, Jonathan

    2002-01-01

    Question: What are the key characteristics of the cohort study design and its varied applications, and how can this research design be utilized in health sciences librarianship? Data Sources: The health, social, behavioral, biological, library, earth, and management sciences literatures were used as sources. Study Selection: All fields except for health sciences librarianship were scanned topically for either well-known or diverse applications of the cohort design. The health sciences library literature available to the author principally for the years 1990 to 2000, supplemented by papers or posters presented at annual meetings of the Medical Library Association. Data Extraction: A narrative review for the health, social, behavioral, biological, earth, and management sciences literatures and a systematic review for health sciences librarianship literature for the years 1990 to 2000, with three exceptions, were conducted. The author conducted principally a manual search of the health sciences librarianship literature for the years 1990 to 2000 as part of this systematic review. Main Results: The cohort design has been applied to answer a wide array of theoretical or practical research questions in the health, social, behavioral, biological, and management sciences. Health sciences librarianship also offers several major applications of the cohort design. Conclusion: The cohort design has great potential for answering research questions in the field of health sciences librarianship, particularly evidence-based librarianship (EBL), although that potential has not been fully explored. PMID:12398244

  20. Regulation of Viable and Optimal Cohorts

    SciTech Connect

    Aubin, Jean-Pierre

    2015-10-15

    This study deals with the evolution of (scalar) attributes (resources or income in evolutionary demography or economics, position in traffic management, etc.) of a population of “mobiles” (economic agents, vehicles, etc.). The set of mobiles sharing the same attributes is regarded as an instantaneous cohort described by the number of its elements. The union of instantaneous cohorts during a mobile window between two attributes is a cohort. Given a measure defining the number of instantaneous cohorts, the accumulation of the mobile attributes on a evolving mobile window is the measure of the cohort on this temporal mobile window. Imposing accumulation constraints and departure conditions, this study is devoted to the regulation of the evolutions of the attributes which are1.viable in the sense that the accumulations constraints are satisfied at each instant;2.and, among them, optimal, in the sense that both the duration of the temporal mobile window is maximum and that the accumulation on this temporal mobile window is the largest viable one. This value is the “accumulation valuation” function. Viable and optimal evolutions under accumulation constraints are regulated by an “implicit Volterra integro-differential inclusion” built from the accumulation valuation function, solution to an Hamilton–Jacobi–Bellman partial differential equation under constraints which is constructed for this purpose.

  1. Review of Cohort Studies for Mood Disorders

    PubMed Central

    Jeon, Hong Jin; Baek, Ji Hyun; Ahn, Yong-Min; Kim, Se Joo; Ha, Tae Hyun; Cha, Boseok; Moon, Eunsoo; Kang, Hee-Ju; Ryu, Vin; Cho, Chul-Hyun; Heo, Jung-Yoon; Kim, Kiwon

    2016-01-01

    This paper aimed to review currently available cohort studies of subjects with mood disorders such as major depressive disorder (MDD) and bipolar disorder (BD). Using the PubMed and KoreaMed databases, we reviewed eight major cohort studies. Most studies recruited participants with MDD and BD separately, so direct comparison of factors associated with diagnostic changes was difficult. Regular and frequent follow-up evaluations utilizing objective mood ratings and standardized evaluation methods in a naturalistic fashion are necessary to determine detailed clinical courses of mood disorders. Further, biological samples should also be collected to incorporate clinical findings in the development of new diagnostic and therapeutic approaches. An innovative cohort study that can serve as a platform for translational research for treatment and prevention of mood disorders is critical in determining clinical, psychosocial, neurobiological and genetic factors associated with long-term courses and consequences of mood disorders in Korean patients. PMID:27247592

  2. Cohort profile: The lidA Cohort Study—a German Cohort Study on Work, Age, Health and Work Participation

    PubMed Central

    Hasselhorn, Hans Martin; Peter, Richard; Rauch, Angela; Schröder, Helmut; Swart, Enno; Bender, Stefan; du Prel, Jean-Baptist; Ebener, Melanie; March, Stefanie; Trappmann, Mark; Steinwede, Jacob; Müller, Bernd Hans

    2014-01-01

    The lidA Cohort Study (German Cohort Study on Work, Age, Health and Work Participation) was set up to investigate and follow the effects of work and work context on the physical and psychological health of the ageing workforce in Germany and subsequently on work participation. Cohort participants are initially employed people subject to social security contributions and born in either 1959 (n = 2909) or 1965 (n = 3676). They were personally interviewed in their homes in 2011 and will be visited every 3 years. Data collection comprises socio-demographic data, work and private exposures, work ability, work and work participation attitudes, health, health-related behaviour, personality and attitudinal indicators. Employment biographies are assessed using register data. Subjective health reports and physical strength measures are complemented by health insurance claims data, where permission was given. A conceptual framework has been developed for the lidA Cohort Study within which three confirmatory sub-models assess the interdependencies of work and health considering age, gender and socioeconomic status. The first set of the data will be available to the scientific community by 2015. Access will be given by the Research Data Centre of the German Federal Employment Agency at the Institute for Employment Research (http://fdz.iab.de/en.aspx). PMID:24618186

  3. Cohort profile: the lidA Cohort Study-a German Cohort Study on Work, Age, Health and Work Participation.

    PubMed

    Hasselhorn, Hans Martin; Peter, Richard; Rauch, Angela; Schröder, Helmut; Swart, Enno; Bender, Stefan; du Prel, Jean-Baptist; Ebener, Melanie; March, Stefanie; Trappmann, Mark; Steinwede, Jacob; Müller, Bernd Hans

    2014-12-01

    The lidA Cohort Study (German Cohort Study on Work, Age, Health and Work Participation) was set up to investigate and follow the effects of work and work context on the physical and psychological health of the ageing workforce in Germany and subsequently on work participation. Cohort participants are initially employed people subject to social security contributions and born in either 1959 (n = 2909) or 1965 (n = 3676). They were personally interviewed in their homes in 2011 and will be visited every 3 years. Data collection comprises socio-demographic data, work and private exposures, work ability, work and work participation attitudes, health, health-related behaviour, personality and attitudinal indicators. Employment biographies are assessed using register data. Subjective health reports and physical strength measures are complemented by health insurance claims data, where permission was given. A conceptual framework has been developed for the lidA Cohort Study within which three confirmatory sub-models assess the interdependencies of work and health considering age, gender and socioeconomic status. The first set of the data will be available to the scientific community by 2015. Access will be given by the Research Data Centre of the German Federal Employment Agency at the Institute for Employment Research (http://fdz.iab.de/en.aspx).

  4. Cohort profile: the Spanish WORKing life Social Security (WORKss) cohort study

    PubMed Central

    López Gómez, María Andrée; Durán, Xavier; Zaballa, Elena; Sanchez-Niubo, Albert; Delclos, George L; Benavides, Fernando G

    2016-01-01

    Purpose The global economy is changing the labour market and social protection systems in Europe. The effect of both changes on health needs to be monitored in view of an ageing population and the resulting increase in prevalence of chronic health conditions. The Spanish WORKing life Social Security (WORKss) cohort study provides unique longitudinal data to study the impact of labour trajectories and employment conditions on health, in terms of sickness absence, permanent disability and death. Participants The WORKss cohort originated from the Continuous Working Life Sample (CWLS) generated by the General Directorate for the Organization of the Social Security in Spain. The CWLS contains a 4% representative sample of all individuals in contact with the Social Security system. The WORKss cohort exclusively includes individuals with a labour trajectory from 1981 or later. In 2004, the cohort was initiated with 1 022 779 Social Security members: 840 770 (82.2%) contributors and 182 009 (17.8%) beneficiaries aged 16 and older. Findings to date The WORKss cohort includes demographic characteristics, chronological data about employment history, retirement, permanent disability and death. These data make possible the measurement of incidence of permanent disability, the number of potential years of working life lost, and the number of contracts and inactive periods with the Social Security system. The WORKss cohort was linked to temporary sickness absence registries to study medical diagnoses that lead to permanent disability and consequently to an earlier exit from the labour market in unhealthy conditions. Future plans Thanks to its administrative source, the WORKss cohort study will continue follow-up in the coming years, keeping the representativeness of the Spanish population affiliated to the Social Security system. The linkage between the WORKss cohort and temporary sickness absence registries is envisioned to continue. Future plans include the linkage of

  5. Steep increase in best-practice cohort life expectancy.

    PubMed

    Shkolnikov, Vladimir M; Jdanov, Dmitri A; Andreev, Evgeny M; Vaupel, James W

    2011-01-01

    We analyze trends in best-practice life expectancy among female cohorts born from 1870 to 1950. Cohorts experience declining rather than constant death rates, and cohort life expectancy usually exceeds period life expectancy. Unobserved mortality rates in non-extinct cohorts are estimated using the Lee-Carter model for mortality in 1960–2008. Best-practice cohort and period life expectancies increased nearly linearly. Across cohorts born from 1870 to 1920 the annual increase in cohort length of life was 0.43 years. Across calendar years from 1870 to 2008, the annual increase was 0.28 years. Cohort life expectancy increased from 53.7 years in the 1870 cohort to 83.8 years in the 1950 cohort. The corresponding cohort/period longevity gap increased from 1.2 to 10.3 years. Among younger cohorts, survival to advanced ages is substantially higher than could have been anticipated by period mortality regimes when these cohorts were young or middle-aged. A large proportion of the additional expected years of life are being lived at ages 65 and older. This substantially changes the balance between the stages of the life cycle. PMID:22167810

  6. Quality of Life for the Camberwell Cohort

    ERIC Educational Resources Information Center

    Beadle-Brown, Julie; Murphy, Glynis; DiTerlizzi, Michele

    2009-01-01

    Background: Despite the acknowledged difficulties of measuring satisfaction for people with intellectual disabilities, the current study examined the quality of life (QoL) of the Camberwell Cohort, a total population sample of people with severe intellectual disability and/or autism [Wing & Gould, "Epidemiology and Classification," 9, 1979, 11].…

  7. Cohort Changes in Attitudes about Race Relations.

    ERIC Educational Resources Information Center

    Cutler, Stephen J.

    Recent studies suggest that in times of growing liberalism in public opinion, social and political attitudes in all age cohorts become more tolerant. Such studies have challenged the long standing assumptions that social and political attitudes become more conservative as people age. To extend the research on this subject, a study was conducted to…

  8. Knowledge Building in an Online Cohort

    ERIC Educational Resources Information Center

    Engstrom, Mary E.; Santo, Susan A.; Yost, Rosanne M.

    2008-01-01

    This study sought to understand how an online cohort in a master's program, comprised of teachers from the same school district, constructed knowledge about instructional theories and practices. Participants in this descriptive study included 10 teachers from the same rural school district. Data collection consisted of a focus group and written…

  9. The Cohort Leadership Development Model: Student Perspectives

    ERIC Educational Resources Information Center

    McPhail, Christine Johnson; Robinson, Mary; Scott, Harriette

    2008-01-01

    This study examined how graduate students enrolled in a university-based cohort community college leadership doctoral program perceived their leadership development experiences. A total of 50 doctoral students enrolled in the Morgan State University (MSU) doctoral program were surveyed. A separate group of students (20) participated in a focus…

  10. Brain-Science Based Cohort Studies

    ERIC Educational Resources Information Center

    Koizumi, Hideaki

    2011-01-01

    This article describes a number of human cohort studies based on the concept of brain-science and education. These studies assess the potential effects of new technologies on babies, children and adolescents, and test hypotheses drawn from animal and genetic case studies to see if they apply to people. A flood of information, virtual media,…

  11. Teacher Education in an Interdisciplinary Cohort Model

    ERIC Educational Resources Information Center

    Smith, Douglas

    2007-01-01

    In this article, the author describes the Interdisciplinary Cohort Model of Teacher Preparation at the University of Kentucky. It has been successful in preparing business and marketing teachers in a one-year period, has made educational foundations an integral part of classroom practice, and fostered collaboration between business and marketing…

  12. Cohort Survival and Withdrawal Study District Report.

    ERIC Educational Resources Information Center

    Shainline, Michael

    At the completion of the 1986-87 school year, the Albuquerque (New Mexico) Public Schools (APS) conducted a cohort survival and withdrawal study to follow-up 5,976 students who had begun the ninth grade within the district in 1983-84. Current records were matched with those from the 1983-84 school year to determine whether members of the…

  13. 4-Year Cohort Graduation Rate: Overview

    ERIC Educational Resources Information Center

    Pennsylvania Department of Education, 2010

    2010-01-01

    Federal law requires Pennsylvania, and all other states, to transition to a new calculation method for determining high school graduation rates. Beginning in 2012, using graduation data from the Classes of 2010 and 2011, the "4-Year Cohort Graduation Rate" calculation will replace the "4-Year Leaver Graduation Rate" calculation. The new…

  14. Separation of intron 22 inversion type 1 and 2 of hemophilia A by modified inverse-shifting polymerase chain reaction and capillary gel electrophoresis.

    PubMed

    Pan, Tzu-Yu; Chiou, Shyh-Shin; Wang, Chun-Chi; Wu, Shou-Mei

    2014-12-01

    An inverse-shifting polymerase chain reaction (IS-PCR) combined with short-end capillary gel electrophoresis (CGE) was developed for genotyping of intron 22 inversion Type 1 (Inv22-1) and Type 2 (Inv22-2) of hemophilia A (HA). Severe HA cases are affected by intron 22 inversion around 45-50%. Inv22-1 has higher frequency than Inv22-2. The aim of this study is to distinguish them by genotyping. In order to improve Inv22 genotyping efficiency, five primers were designed and applied to differentiate the wild type, Inv22-1, Inv22-2 and carrier. Three amplicons of 405, 457 and 512 bp were recognized for wild type; 333, 457 and 584 bp for Inv22-1; 385, 405 and 584 bp for Inv22-2. The Inv22-1 carrier has 5 amplicons including 333, 405, 457, 512, 584 bp and Inv22-2 carrier is differentiated by 385, 405, 457, 512 and 584 bp. The amplicons between Inv22-1 and Inv22-2 carriers are only different in 333 bp for Inv22-1 carrier and 385 bp for Inv22-2 carrier. Capillary gel electrophoresis (CGE) was used for separation within 5 min. The separation voltage was set at 8 kV (cathode at detector), and the temperature was kept at 25°C. The sieving matrix was 89 mM Tris, 89 mM boric acid, 2mM EDTA containing 0.4% (w/v) HPMC and 1 μM of YO-PRO(®)-1 Iodide. Total of 50 HA patients (including 35 non-Inv22, 14 Inv22-1, and one Inv22-2 patients) and 7 HA carriers were diagnosed in the application. Seven random samples (5 patients and 2 carriers) were subjected to comparison and gave identical results of DNA sequencing and this modified IS-PCR.

  15. 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

  16. [Application of cohort study in cancer prevention and control].

    PubMed

    Dai, Min; Bai, Yana; Pu, Hongquan; Cheng, Ning; Li, Haiyan; He, Jie

    2016-03-01

    Cancer control is a long-term work. Cancer research and intervention really need the support of cohort study. In the recent years, more and more cohort studies on cancer control were conducted in China along with the increased ability of scientific research in China. Since 2010, Cancer Hospital, Chinese Academy of Medical Sciences, collaborated with Lanzhou University and the Worker' s Hospital of Jinchuan Group Company Limited, have carried out a large-scale cohort study on cancer, which covered a population of more than 50 000 called " Jinchang cohort". Since 2012, a National Key Public Health Project, "cancer screening in urban China" , has been conducted in Jinchang, which strengthened the Jinchang cohort study. Based on the Jinchang cohort study, historical cohort study, cross-sectional study and prospective cohort study have been conducted, which would provide a lot of evidence for the cancer control in China.

  17. Cohort profile: cerebral palsy in the Norwegian and Danish birth cohorts (MOBAND-CP)

    PubMed Central

    Tollånes, Mette C; Strandberg-Larsen, Katrine; Forthun, Ingeborg; Petersen, Tanja Gram; Moster, Dag; Andersen, Anne-Marie Nybo; Stoltenberg, Camilla; Olsen, Jørn; Wilcox, Allen J

    2016-01-01

    Purpose The purpose of MOthers and BAbies in Norway and Denmark cerebral palsy (MOBAND-CP) was to study CP aetiology in a prospective design. Participants MOBAND-CP is a cohort of more than 210 000 children, created as a collaboration between the world's two largest pregnancy cohorts—the Norwegian Mother and Child Cohort study (MoBa) and the Danish National Birth Cohort. MOBAND-CP includes maternal interview/questionnaire data collected during pregnancy and follow-up, plus linked information from national health registries. Findings to date Initial harmonisation of data from the 2 cohorts has created 140 variables for children and their mothers. In the MOBAND-CP cohort, 438 children with CP have been identified through record linkage with validated national registries, providing by far the largest such sample with prospectively collected detailed pregnancy data. Several studies investigating various hypotheses regarding CP aetiology are currently on-going. Future plans Additional data can be harmonised as necessary to meet requirements of new projects. Biological specimens collected during pregnancy and at delivery are potentially available for assay, as are results from assays conducted on these specimens for other projects. The study size allows consideration of CP subtypes, which is rare in aetiological studies of CP. In addition, MOBAND-CP provides a platform within the context of a merged birth cohort of exceptional size that could, after appropriate permissions have been sought, be used for cohort and case-cohort studies of other relatively rare health conditions of infants and children. PMID:27591025

  18. Adult Learning in Cohort Groups. Practice Application Brief No. 24.

    ERIC Educational Resources Information Center

    Imel, Susan

    A form of group learning, cohorts, has become increasingly attractive to administrators, instructors, and participants in adult education. Basic academic skills cohort learning supports three types of knowing: instrumental, socializing, and self-authoring; whereas, in higher and adult education cohort learning, the development of critical…

  19. The Doctoral Cohort Model: Increasing Opportunities for Success

    ERIC Educational Resources Information Center

    Nimer, Mary

    2009-01-01

    Participation in a doctoral program cohort significantly increases the chances for the successful completion of the course of studies for all members of the cohort. After examining the concept of the cohort and the current research literature, the author shares her experiences in the Ed. D., Instructional Leadership program at Western Connecticut…

  20. A case of successful hepatitis C virus eradication by 24 weeks of telaprevir-based triple therapy for a hemophilia patient with hepatitis C virus/human immunodeficiency virus co-infection who previously failed pegylated interferon-α and ribavirin therapy.

    PubMed

    Murata, Masayuki; Furusyo, Norihiro; Ogawa, Eiichi; Mitsumoto, Fujiko; Hiramine, Satoshi; Ikezaki, Hiroaki; Takayama, Koji; Shimizu, Motohiro; Toyoda, Kazuhiro; Kainuma, Mosaburo; Hayashi, Jun

    2014-05-01

    In Japan, the human immunodeficiency virus (HIV) and hepatitis C virus (HCV) coinfection of some patients with hemophilia was caused by the transfusion of imported blood products, such as unheated coagulation factor. With the development of antiretroviral therapy (ART) for HIV, chronic HCV infection has become a major cause of liver disease and mortality for hemophiliac patients coinfected with HCV/HIV. Data is limited regarding the efficacy and safety of antiviral therapy with the HCV protease inhibitor telaprevir (TVR) in combination with pegylated interferon-α (PegIFN-α) and ribavirin (RBV) for hemophilia patients coinfected with HCV/HIV. We report a case of a Japanese patient with hemophilia and HCV/HIV coinfection who had partial response to prior to PegIFN-α and RBV therapy. This is the first published report of 24-week TVR-based triple therapy for a hemophilia patient coinfected with HCV/HIV. The patient had HCV genotype 1a infection with a high viral load. His single-nucleotide polymorphism of the interleukin 28B (rs8099917) gene was the TT major allele. He presented with undetectable HIV RNA and a high CD4(+) T cell counts by taking ART including tenofovir, emtricitabine and raltegravir. He was again treated for HCV with TVR plus PegIFN-α2b and RBV for the first 12 weeks, followed by the continuation of PegIFN-α2b and RBV for 12 additional weeks while continuing ART. He had rapid virological response and achieved sustained virological response with the 24-week treatment. No serious adverse events such as skin rash, severe anemia or exacerbated bleeding tendency were observed, only a mild headache. No dose adjustment was necessary when tenofovir and raltegravir were used in combined with TVR, and no HIV breakthrough was observed. TVR-based triple therapy with ART could can an effective treatment for hemophilia patients coinfected with HCV (genotype 1)/HIV regardless of prior response. TVR can be used in combination with tenofovir, emtricitabine and

  1. The CONSTANCES cohort: an open epidemiological laboratory

    PubMed Central

    2010-01-01

    Background Prospective cohorts represent an essential design for epidemiological studies and allow for the study of the combined effects of lifestyle, environment, genetic predisposition, and other risk factors on a large variety of disease endpoints. The CONSTANCES cohort is intended to provide public health information and to serve as an "open epidemiologic laboratory" accessible to the epidemiologic research community. Although designed as a "general-purpose" cohort with very broad coverage, it will particularly focus on occupational and social determinants of health, and on aging. Methods/Design The CONSTANCES cohort is designed as a randomly selected representative sample of French adults aged 18-69 years at inception; 200,000 subjects will be included over a five-year period. At inclusion, the selected subjects will be invited to fill a questionnaire and to attend a Health Screening Center (HSC) for a comprehensive health examination: weight, height, blood pressure, electrocardiogram, vision, auditory, spirometry, and biological parameters; for those aged 45 years and older, a specific work-up of functional, physical, and cognitive capacities will be performed. A biobank will be set up. The follow-up includes a yearly self-administered questionnaire, and a periodic visit to an HSC. Social and work-related events and health data will be collected from the French national retirement, health and death databases. The data that will be collected include social and demographic characteristics, socioeconomic status, life events, behaviors, and occupational factors. The health data will cover a wide spectrum: self-reported health scales, reported prevalent and incident diseases, long-term chronic diseases and hospitalizations, sick-leaves, handicaps, limitations, disabilities and injuries, healthcare utilization and services provided, and causes of death. To take into account non-participation at inclusion and attrition throughout the longitudinal follow-up, a cohort

  2. Cohort size and female labour supply.

    PubMed

    Gustafsson, S

    1992-01-01

    Cohort size and female labor supply is examined through the literature available in the field. The impetus for this examination is the expected young male labor shortage in Europe. Although raising educational levels, or encouraging immigration of young well trained workers are policy alternatives, the emphasis in this article is on exploring the option of increasing the female labor supply to offset the shortage. After a brief introduction to the nature of the problem, Easterlin's theory of women's work is presented: relative income is a determinant of labor force participation. Wright's experience with European fertility shows that relative income is not the dominant influence on fertility when relative cohort size is taken as a measure of relative income. A model is presented and distinctions made between educated labor and experienced labor and uneducated labor. Several studies are discussed with equate or complement labor inputs with capital, and tentative findings are presented that women may indeed substitute for men in the work place. Cohort size effects on relative earnings studies are also presented. The conclusion is that the cohort size effects in the US labor market are small over the life cycle. In Europe, however, because of the smaller size of baby boom cohorts, the relative income of baby boom cohorts has not been upset, and quantity adjustments may have taken place rather than income injustments. Discussion of husbands income and women's labor supply indicated weaknesses in labor supply estimation, and an example of a frequently used model for estimating female labor force participation. Evidence points to own wage as a more important predictor of female labor force participation than husband's income. This lends support to the opportunity cost hypothesis or new home economics hypothesis rather than the Easterlin relative income hypothesis. Attention is given to the example of Sweden and its family policy which enables women the best opportunity

  3. Childhood cancer survivor cohorts in Europe.

    PubMed

    Winther, Jeanette F; Kenborg, Line; Byrne, Julianne; Hjorth, Lars; Kaatsch, Peter; Kremer, Leontien C M; Kuehni, Claudia E; Auquier, Pascal; Michel, Gérard; de Vathaire, Florent; Haupt, Riccardo; Skinner, Roderick; Madanat-Harjuoja, Laura M; Tryggvadottir, Laufey; Wesenberg, Finn; Reulen, Raoul C; Grabow, Desiree; Ronckers, Cecile M; van Dulmen-den Broeder, Eline; van den Heuvel-Eibrink, Marry M; Schindler, Matthias; Berbis, Julie; Holmqvist, Anna S; Gudmundsdottir, Thorgerdur; de Fine Licht, Sofie; Bonnesen, Trine G; Asdahl, Peter H; Bautz, Andrea; Kristoffersen, Anja K; Himmerslev, Liselotte; Hasle, Henrik; Olsen, Jørgen H; Hawkins, Mike M

    2015-05-01

    With the advent of multimodality therapy, the overall five-year survival rate from childhood cancer has improved considerably now exceeding 80% in developed European countries. This growing cohort of survivors, with many years of life ahead of them, has raised the necessity for knowledge concerning the risks of adverse long-term sequelae of the life-saving treatments in order to provide optimal screening and care and to identify and provide adequate interventions. Childhood cancer survivor cohorts in Europe. Considerable advantages exist to study late effects in individuals treated for childhood cancer in a European context, including the complementary advantages of large population-based cancer registries and the unrivalled opportunities to study lifetime risks, together with rich and detailed hospital-based cohorts which fill many of the gaps left by the large-scale population-based studies, such as sparse treatment information. Several large national cohorts have been established within Europe to study late effects in individuals treated for childhood cancer including the Nordic Adult Life after Childhood Cancer in Scandinavia study (ALiCCS), the British Childhood Cancer Survivor Study (BCCSS), the Dutch Childhood Oncology Group (DCOG) LATER study, and the Swiss Childhood Cancer Survivor Study (SCCSS). Furthermore, there are other large cohorts, which may eventually become national in scope including the French Childhood Cancer Survivor Study (FCCSS), the French Childhood Cancer Survivor Study for Leukaemia (LEA), and the Italian Study on off-therapy Childhood Cancer Survivors (OTR). In recent years significant steps have been taken to extend these national studies into a larger pan-European context through the establishment of two large consortia - PanCareSurFup and PanCareLIFE. The purpose of this paper is to present an overview of the current large, national and pan-European studies of late effects after childhood cancer. This overview will highlight the

  4. Cohort fertility in Western Europe: comparing fertility trends in recent birth cohorts.

    PubMed

    Hopflinger, F

    1984-01-01

    A comparative study of fertility levels among cohorts of women born in 1940, 1945, 1950, 1955, and 1960 in 16 European countries was undertaken using vital statistics data. The average number of live birth/woman for each of the 5 cohorts by age 20, 25, 30, and 35 was computed by cumulating age-specific fertility rates of women born in specific years. Median age at childbirth and completed fertility were estimated for the 3 oldest cohorts (1940, 1945, and 1950). 2 estimations of completed fertility were made. 1 was based on the assumption of a constant age-specific fertility rate, and the other was based on a relational Gompertz model. Where possible cohort fertility was disaggregated by birth order. Since the data for the countries was not fully comparable, it was not possible to use sophisticated analytical techniques. Other limits of the study were that fertility, especially for the more recent cohorts was incomplete, parity specific data was not available for all the countries, and open cohorts rather than closed cohorts were used. The analysis indicated that completed cohort fertility was lower for the 1950 cohort than for the 1940 cohort in all 16 countries. For the 1940 cohort, only Germany's estimated completed fertility was less than 2.00. For the other 15 countries, estimated completed fertility ranged from 2.04 (Finland) to 3.36 (Ireland). For the 1950 cohort, estimated completed fertility was less than 2.00 in 8 of the countries. Estimated completed fertility was lowest in Finland and Switzerland (1.82) and highest in Ireland (3.33). No marked increase in childlessness was observed, and for the 1940 and 1950 cohorts, childlessness did not exceed 20% in any of the countries and was considerably less than 20% in most of the countries. There was a trend toward delayed childbearing in most of the countries. An examination of available parity data for the 1940 and 1950 cohorts lead to the conclusion that the major factor contributing toward the decline in

  5. Parvenus and conflict in elite cohorts.

    PubMed

    Michael Lindsay, D; Schachter, Ariela; Porter, Jeremy R; Sorge, David C

    2014-09-01

    Previous studies find that greater workplace diversity leads to higher degrees of conflict in low and medium-status workgroups. This paper examines whether similar dynamics operate in elite cohorts. We use data from a survey of White House Fellows (N=475) to look at how the presence of parvenus-individuals from underrepresented groups in elite environments-change the rate at which fellows reported conflict with each other and with the director of the program. We find that there is no unified "parvenu experience." Analysis of the interaction between race and cohort diversity reveals inflection points consistent with Kanter's (1977) theory of tokenism, but the effects of increasing diversity diverge: for Hispanics, conflict with the director increases with diversity, while for Asians, conflict falls with diversity. While other groups' level of conflict with their peers stays roughly constant, Asians' reported level of conflict with their peers increases with diversity. PMID:24913951

  6. The genomic psychiatry cohort: partners in discovery.

    PubMed

    Pato, Michele T; Sobell, Janet L; Medeiros, Helena; Abbott, Colony; Sklar, Brooke M; Buckley, Peter F; Bromet, Evelyn J; Escamilla, Michael A; Fanous, Ayman H; Lehrer, Douglas S; Macciardi, Fabio; Malaspina, Dolores; McCarroll, Steve A; Marder, Stephen R; Moran, Jennifer; Morley, Christopher P; Nicolini, Humberto; Perkins, Diana O; Purcell, Shaun M; Rapaport, Mark H; Sklar, Pamela; Smoller, Jordan W; Knowles, James A; Pato, Carlos N

    2013-06-01

    The Genomic Psychiatry Cohort (GPC) is a longitudinal resource designed to provide the necessary population-based sample for large-scale genomic studies, studies focusing on Research Domain Criteria (RDoC) and/or other alternate phenotype constructs, clinical and interventional studies, nested case-control studies, long-term disease course studies, and genomic variant-to-phenotype studies. We provide and will continue to encourage access to the GPC as an international resource. DNA and other biological samples and diagnostic data are available through the National Institute of Mental Health (NIMH) Repository. After appropriate review and approval by an advisory board, investigators are able to collaborate in, propose, and co-lead studies involving cohort participants.

  7. Parvenus and conflict in elite cohorts.

    PubMed

    Michael Lindsay, D; Schachter, Ariela; Porter, Jeremy R; Sorge, David C

    2014-09-01

    Previous studies find that greater workplace diversity leads to higher degrees of conflict in low and medium-status workgroups. This paper examines whether similar dynamics operate in elite cohorts. We use data from a survey of White House Fellows (N=475) to look at how the presence of parvenus-individuals from underrepresented groups in elite environments-change the rate at which fellows reported conflict with each other and with the director of the program. We find that there is no unified "parvenu experience." Analysis of the interaction between race and cohort diversity reveals inflection points consistent with Kanter's (1977) theory of tokenism, but the effects of increasing diversity diverge: for Hispanics, conflict with the director increases with diversity, while for Asians, conflict falls with diversity. While other groups' level of conflict with their peers stays roughly constant, Asians' reported level of conflict with their peers increases with diversity.

  8. Bootstrap for the case-cohort design.

    PubMed

    Huang, Yijian

    2014-06-01

    The case-cohort design facilitates economical investigation of risk factors in a large survival study, with covariate data collected only from the cases and a simple random subset of the full cohort. Methods that accommodate the design have been developed for various semiparametric models, but most inference procedures are based on asymptotic distribution theory. Such inference can be cumbersome to derive and implement, and does not permit confidence band construction. While bootstrap is an obvious alternative, how to resample is unclear because of complications from the two-stage sampling design. We establish an equivalent sampling scheme, and propose a novel and versatile nonparametric bootstrap for robust inference with an appealingly simple single-stage resampling. Theoretical justification and numerical assessment are provided for a number of procedures under the proportional hazards model.

  9. Aging in the Context of Cohort Evolution and Mortality Selection

    PubMed Central

    Zheng, Hui

    2014-01-01

    This study examines historical patterns of aging through the perspectives of cohort evolution and mortality selection, where the former emphasizes the correlation across cohorts in the age dependence of mortality rates, and the latter emphasizes cohort change in the acceleration of mortality over the life course. In the analysis of historical cohort mortality data, I find support for both perspectives. The rate of demographic aging, or the rate at which mortality accelerates past age 70, is not fixed across cohorts; rather, it is affected by the extent of mortality selection at young and late ages. This causes later cohorts to have higher rates of demographic aging than earlier cohorts. The rate of biological aging, approximating the rate of the senescence process, significantly declined between the mid- and late-nineteenth century birth cohorts and stabilized afterward. Unlike the rate of demographic aging, the rate of biological aging is not affected by mortality selection earlier in the life course but rather by cross-cohort changes in young-age mortality, which cause lower rates of biological aging in old age among later cohorts. These findings enrich theories of cohort evolution and have implications for the study of limits on the human lifespan and evolution of aging. PMID:24889261

  10. Period Effects, Cohort Effects, and the Narrowing Gender Wage Gap

    PubMed Central

    Campbell, Colin; Pearlman, Jessica

    2015-01-01

    Despite the abundance of sociological research on the gender wage gap, questions remain. In particular, the role of cohorts is under investigated. Using data from the Current Population Survey, we use Age-Period-Cohort analysis to uniquely estimate age, period, and cohort effects on the gender wage gap. The narrowing of the gender wage gap that occurred between 1975 and 2009 is largely due to cohort effects. Since the mid-1990s, the gender wage gap has continued to close absent of period effects. While gains in female wages contributed to declines in the gender wage gap for cohorts born before 1950, for later cohorts the narrowing of the gender wage gap is primarily a result of declines in male wages. PMID:24090861

  11. Estimation of Error Components in Cohort Studies: A Cross-Cohort Analysis of Dutch Mathematics Achievement

    ERIC Educational Resources Information Center

    Keuning, Jos; Hemker, Bas

    2014-01-01

    The data collection of a cohort study requires making many decisions. Each decision may introduce error in the statistical analyses conducted later on. In the present study, a procedure was developed for estimation of the error made due to the composition of the sample, the item selection procedure, and the test equating process. The math results…

  12. Cohort study of atypical pressure ulcers development.

    PubMed

    Jaul, Efraim

    2014-12-01

    Atypical pressure ulcers (APU) are distinguished from common pressure ulcers (PU) with both unusual location and different aetiology. The occurrence and attempts to characterise APU remain unrecognised. The purpose of this cohort study was to analyse the occurrence of atypical location and the circumstances of the causation, and draw attention to the prevention and treatment by a multidisciplinary team. The cohort study spanned three and a half years totalling 174 patients. The unit incorporates two weekly combined staff meetings. One concentrates on wound assessment with treatment decisions made by the physician and nurse, and the other, a multidisciplinary team reviewing all patients and coordinating treatment. The main finding of this study identified APU occurrence rate of 21% within acquired PU over a three and a half year period. Severe spasticity constituted the largest group in this study and the most difficult to cure wounds, located in medial aspects of knees, elbows and palms. Medical devices caused the second largest occurrence of atypical wounds, located in the nape of the neck, penis and nostrils. Bony deformities were the third recognisable atypical wound group located in shoulder blades and upper spine. These three categories are definable and time observable. APU are important to be recognisable, and can be healed as well as being prevented. The prominent role of the multidisciplinary team is primary in identification, prevention and treatment. PMID:23374746

  13. AGRICOH: A Consortium of Agricultural Cohorts

    PubMed Central

    Leon, Maria E.; Beane Freeman, Laura E.; Douwes, Jeroen; Hoppin, Jane A.; Kromhout, Hans; Lebailly, Pierre; Nordby, Karl-Christian; Schenker, Marc; Schüz, Joachim; Waring, Stephen C.; Alavanja, Michael C.R.; Annesi-Maesano, Isabella; Baldi, Isabelle; Dalvie, Mohamed Aqiel; Ferro, Giles; Fervers, Béatrice; Langseth, Hilde; London, Leslie; Lynch, Charles F.; McLaughlin, John; Merchant, James A.; Pahwa, Punam; Sigsgaard, Torben; Stayner, Leslie; Wesseling, Catharina; Yoo, Keun-Young; Zahm, Shelia H.; Straif, Kurt; Blair, Aaron

    2011-01-01

    AGRICOH is a recently formed consortium of agricultural cohort studies involving 22 cohorts from nine countries in five continents: South Africa (1), Canada (3), Costa Rica (2), USA (6), Republic of Korea (1), New Zealand (2), Denmark (1), France (3) and Norway (3). The aim of AGRICOH, initiated by the US National Cancer Institute (NCI) and coordinated by the International Agency for Research on Cancer (IARC), is to promote and sustain collaboration and pooling of data to investigate the association between a wide range of agricultural exposures and a wide range of health outcomes, with a particular focus on associations that cannot easily be addressed in individual studies because of rare exposures (e.g., use of infrequently applied chemicals) or relatively rare outcomes (e.g., certain types of cancer, neurologic and auto-immune diseases). To facilitate future projects the need for data harmonization of selected variables is required and is underway. Altogether, AGRICOH provides excellent opportunities for studying cancer, respiratory, neurologic, and auto-immune diseases as well as reproductive and allergic disorders, injuries and overall mortality in association with a wide array of exposures, prominent among these the application of pesticides. PMID:21655123

  14. Cohort study of atypical pressure ulcers development.

    PubMed

    Jaul, Efraim

    2014-12-01

    Atypical pressure ulcers (APU) are distinguished from common pressure ulcers (PU) with both unusual location and different aetiology. The occurrence and attempts to characterise APU remain unrecognised. The purpose of this cohort study was to analyse the occurrence of atypical location and the circumstances of the causation, and draw attention to the prevention and treatment by a multidisciplinary team. The cohort study spanned three and a half years totalling 174 patients. The unit incorporates two weekly combined staff meetings. One concentrates on wound assessment with treatment decisions made by the physician and nurse, and the other, a multidisciplinary team reviewing all patients and coordinating treatment. The main finding of this study identified APU occurrence rate of 21% within acquired PU over a three and a half year period. Severe spasticity constituted the largest group in this study and the most difficult to cure wounds, located in medial aspects of knees, elbows and palms. Medical devices caused the second largest occurrence of atypical wounds, located in the nape of the neck, penis and nostrils. Bony deformities were the third recognisable atypical wound group located in shoulder blades and upper spine. These three categories are definable and time observable. APU are important to be recognisable, and can be healed as well as being prevented. The prominent role of the multidisciplinary team is primary in identification, prevention and treatment.

  15. [Lessons from the Hokkaido COPD cohort study].

    PubMed

    Nishimura, Masaharu; Makita, Hironi

    2016-05-01

    Hokkaido COPD cohort study is a carefully-designed, well-conducted, prospective observational 10 year-long study, which ended early in 2015. We have obtained a number of clinically-relevant novel findings, some of which are as follows. Severity of emphysema was highly varied even in those individuals whose airflow limitation is comparable. The annual change in forced expiratory volume in 1 second (FEV1) over 5 years was also widely varied with normal distribution among the subjects under appropriate treatment. Some patients maintained their pulmonary function for a long time, and others showed a rapid decline. Emphysema severity, but not pulmonary function, was independently associated with such an inter-subject variation in the annual decline in FEV1. When we explored any biomarkers for predicting the FEV1 decline, a lower leptin/adiponectin ratio alone emerged as an explanatory parameter for the rapid decline, and this was also confirmed in an independent Danish cohort study of different ethnicity. Monitoring of quality of life (QOL), using SGRQ scores, also provided interesting observations. The annual change in total score reflected that of FEV1 decline during the follow-up period. However, activity component in QOL deteriorated in almost all the subjects, while symptom component rather improved in many of the patients under appropriate treatment. PMID:27254960

  16. CHECK (Cohort Hip and Cohort Knee): similarities and differences with the Osteoarthritis Initiative

    PubMed Central

    Wesseling, J; Dekker, J; van den Berg, W B; Bierma-Zeinstra, S M A; Boers, M; Cats, H A; Deckers, P; Gorter, K J; Heuts, P H T G; Hilberdink, W K H A; Kloppenburg, M; Nelissen, R G H H; Oosterveld, F G J; Oostveen, J C M; Roorda, L D; Viergever, M A; Wolde, S ten; Lafeber, F P J G; Bijlsma, J W J

    2011-01-01

    Objective To describe the osteoarthritis study population of CHECK (Cohort Hip and Cohort Knee) in comparison with relevant selections of the study population of the Osteoarthritis Initiative (OAI) based on clinical status and radiographic parameters. Methods In The Netherlands a prospective 10-year follow-up study was initiated by the Dutch Arthritis Association on participants with early osteoarthritis-related complaints of hip and/or knee: CHECK. In parallel in the USA an observational 4-year follow-up study, the OAI, was started by the National Institutes of Health, on patients with or at risk of symptomatic knee osteoarthritis. For comparison with CHECK, the entire cohort and a subgroup of individuals excluding those with exclusively hip pain were compared with relevant subpopulations of the OAI. Results At baseline, CHECK included 1002 participants with in general similar characteristics as described for the OAI. However, significantly fewer individuals in CHECK had radiographic knee osteoarthritis at baseline when compared with the OAI (p<0.001). In contrast, at baseline, the CHECK cohort reported higher scores on pain, stiffness and functional disability (Western Ontario and McMaster osteoarthritis index) when compared with the OAI (all p<0.001). These differences were supported by physical health status in contrast to mental health (Short Form 36/12) was at baseline significantly worse for the CHECK participants (p<0.001). Conclusion Although both cohorts focus on the early phase of osteoarthritis, they differ significantly with respect to structural (radiographic) and clinical (health status) characteristics, CHECK expectedly representing participants in an even earlier phase of disease. PMID:18772189

  17. Global teaching and training initiatives for emerging cohort studies.

    PubMed

    Paulus, Jessica K; Santoyo-Vistrain, Rocío; Havelick, David; Cohen, Amy; Kalyesubula, Robert; Ajayi, Ikeoluwapo O; Mattsson, Jens G; Adami, Hans-Olov; Dalal, Shona

    2012-09-01

    A striking disparity exists across the globe, with essentially no large-scale longitudinal studies ongoing in regions that will be significantly affected by the oncoming non-communicable disease epidemic. The successful implementation of cohort studies in most low-resource research environments presents unique challenges that may be aided by coordinated training programs. Leaders of emerging cohort studies attending the First World Cohort Integration Workshop were surveyed about training priorities, unmet needs and potential cross-cohort solutions to these barriers through an electronic pre-workshop questionnaire and focus groups. Cohort studies representing India, Mexico, Nigeria, South Africa, Sweden, Tanzania and Uganda described similar training needs, including on-the-job training, data analysis software instruction, and database and bio-bank management. A lack of funding and protected time for training activities were commonly identified constraints. Proposed solutions include a collaborative cross-cohort teaching platform with web-based content and interactive teaching methods for a range of research personnel. An international network for research mentorship and idea exchange, and modifying the graduate thesis structure were also identified as key initiatives. Cross-cohort integrated educational initiatives will efficiently meet shared needs, catalyze the development of emerging cohorts, speed closure of the global disparity in cohort research, and may fortify scientific capacity development in low-resource settings.

  18. Global teaching and training initiatives for emerging cohort studies.

    PubMed

    Paulus, Jessica K; Santoyo-Vistrain, Rocío; Havelick, David; Cohen, Amy; Kalyesubula, Robert; Ajayi, Ikeoluwapo O; Mattsson, Jens G; Adami, Hans-Olov; Dalal, Shona

    2012-09-01

    A striking disparity exists across the globe, with essentially no large-scale longitudinal studies ongoing in regions that will be significantly affected by the oncoming non-communicable disease epidemic. The successful implementation of cohort studies in most low-resource research environments presents unique challenges that may be aided by coordinated training programs. Leaders of emerging cohort studies attending the First World Cohort Integration Workshop were surveyed about training priorities, unmet needs and potential cross-cohort solutions to these barriers through an electronic pre-workshop questionnaire and focus groups. Cohort studies representing India, Mexico, Nigeria, South Africa, Sweden, Tanzania and Uganda described similar training needs, including on-the-job training, data analysis software instruction, and database and bio-bank management. A lack of funding and protected time for training activities were commonly identified constraints. Proposed solutions include a collaborative cross-cohort teaching platform with web-based content and interactive teaching methods for a range of research personnel. An international network for research mentorship and idea exchange, and modifying the graduate thesis structure were also identified as key initiatives. Cross-cohort integrated educational initiatives will efficiently meet shared needs, catalyze the development of emerging cohorts, speed closure of the global disparity in cohort research, and may fortify scientific capacity development in low-resource settings. PMID:23856451

  19. A mortality cohort study of seamen in Italy.

    PubMed

    Rapiti, E; Turi, E; Forastiere, F; Borgia, P; Comba, P; Perucci, C A; Axelson, O

    1992-01-01

    A total of 2,208 male subjects, enrolled as merchant marine seamen at the Civitavecchia (Italy) harbor from 1936 to 1975 were followed up through 1989 in order to evaluate their mortality experience. Available information about the number of sailings made it possible to divide subjects into two subgroups: 948 workers with at least one sailing (cohort A) and 1,260 with no reported sailing (cohort B). Fewer than expected overall deaths were observed in both cohorts (cohort A: SMR = 0.83; cohort B: SMR = 0.81), mainly due to a lower mortality from circulatory, respiratory, and digestive diseases. Lung cancer deaths were significantly increased in cohort A (O = 30, SMR = 1.71, 95% CI = 1.15-2.44), whereas no excess was observed in cohort B (O = 6, SMR = 0.57, 95% CI = 0.21-1.26). Among subjects employed aboard ship, a trend in SMRs for lung cancer increasing with duration of employment was observed. Furthermore, three neoplasms of other parts of the respiratory system (including one mesothelioma) were detected in cohort A (SMR = 5.87), and one in cohort B. The study substantiates an increased risk of respiratory cancer among subjects with an occupational history of sailing; past exposure to asbestos and to other environmental carcinogens aboard could be implicated.

  20. A mortality cohort study of seamen in Italy.

    PubMed

    Rapiti, E; Turi, E; Forastiere, F; Borgia, P; Comba, P; Perucci, C A; Axelson, O

    1992-01-01

    A total of 2,208 male subjects, enrolled as merchant marine seamen at the Civitavecchia (Italy) harbor from 1936 to 1975 were followed up through 1989 in order to evaluate their mortality experience. Available information about the number of sailings made it possible to divide subjects into two subgroups: 948 workers with at least one sailing (cohort A) and 1,260 with no reported sailing (cohort B). Fewer than expected overall deaths were observed in both cohorts (cohort A: SMR = 0.83; cohort B: SMR = 0.81), mainly due to a lower mortality from circulatory, respiratory, and digestive diseases. Lung cancer deaths were significantly increased in cohort A (O = 30, SMR = 1.71, 95% CI = 1.15-2.44), whereas no excess was observed in cohort B (O = 6, SMR = 0.57, 95% CI = 0.21-1.26). Among subjects employed aboard ship, a trend in SMRs for lung cancer increasing with duration of employment was observed. Furthermore, three neoplasms of other parts of the respiratory system (including one mesothelioma) were detected in cohort A (SMR = 5.87), and one in cohort B. The study substantiates an increased risk of respiratory cancer among subjects with an occupational history of sailing; past exposure to asbestos and to other environmental carcinogens aboard could be implicated. PMID:1621694

  1. Neuroimaging of the Philadelphia Neurodevelopmental Cohort

    PubMed Central

    Satterthwaite, Theodore D.; Elliott, Mark A.; Ruparel, Kosha; Loughead, James; Prabhakaran, Karthik; Calkins, Monica E.; Hopson, Ryan; Jackson, Chad; Keefe, Jack; Riley, Marisa; Mensh, Frank D.; Sleiman, Patrick; Verma, Ragini; Davatzikos, Christos; Hakonarson, Hakon; Gur, Ruben C.; Gur, Raquel E.

    2013-01-01

    The Philadelphia Neurodevelopmental Cohort (PNC) is a large-scale, NIMH funded initiative to understand how brain maturation mediates cognitive development and vulnerability to psychiatric illness, and understand how genetics impacts this process. As part of this study, 1,445 adolescents ages 8–21 at enrollment underwent multimodal neuroimaging. Here, we highlight the conceptual basis for the effort, the study design, and measures available in the dataset. We focus on neuroimaging measures obtained, including T1-weighted structural neuroimaging, diffusion tensor imaging, perfusion neuroimaging using arterial spin labeling, functional imaging tasks of working memory and emotion identification, and resting state imaging of functional connectivity. Furthermore, we provide characteristics regarding the final sample acquired. Finally, we describe mechanisms in place for data sharing that will allow the PNC to become a freely available public resource to advance our understanding of normal and pathological brain development. PMID:23921101

  2. 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

  3. Cohort Change in Images of Older Adults, 1974-1981.

    ERIC Educational Resources Information Center

    Ferraro, Kenneth F.

    1992-01-01

    Examined images of older people held by adults of all ages in 1974 (n=4,254) and 1981 (n=3,427). Cohort changes in such perceptions over time were examined. Multivariate analysis indicated that social class and health status evaluations of older adults declined between the two surveys, principally because of the assessment by more recent cohorts.…

  4. The Cohort Model: Lessons Learned When Principals Collaborate

    ERIC Educational Resources Information Center

    Umekubo, Lisa A.; Chrispeels, Janet H.; Daly, Alan J.

    2015-01-01

    This study explored a formal structure, the cohort model that a decentralized district put in place over a decade ago. Schools were clustered into cohorts to facilitate professional development for leadership teams for all 44 schools within the district. Drawing upon Senge's components of organizational learning, we used a single case study design…

  5. Draft Cohort Default Rate Review Guide, FY 1996.

    ERIC Educational Resources Information Center

    Department of Education, Washington, DC. Default Management Div.

    This guide provides information to help postsecondary schools and guaranty agencies (GAs) understand how a cohort default rate is calculated, review backup data, submit challenges to GAs and/or Direct Loan Servicing Centers (DLSC), and understand the response from the GA and/or DLSC. A cohort default rate includes Federal Family Education Loan…

  6. Age, Period and Cohort Effects on Social Capital

    ERIC Educational Resources Information Center

    Schwadel, Philip; Stout, Michael

    2012-01-01

    Researchers hypothesize that social capital in the United States is not just declining, but that it is declining across "generations" or birth cohorts. Testing this proposition, we examine changes in social capital using age-period-cohort intrinsic estimator models. Results from analyses of 1972-2010 General Social Survey data show (1) that…

  7. Building the Future with Cohorts: Communities of Inquiry

    ERIC Educational Resources Information Center

    Rausch, David W.; Crawford, Elizabeth

    2012-01-01

    With recent interest in communities of practice, learning communities, and critical inquiry theory, the University of Tennessee at Chattanooga (UTC) developed, implemented, and studied the relationship of community and the cohort model. This paper shares information about successes and opportunities for improvement. Cohort-based learners across a…

  8. Matriculation Evaluation Using the New Student Cohort, Fall 1992.

    ERIC Educational Resources Information Center

    Birdsall, Les

    An analysis of student matriculation was conducted at Diablo Valley College, in California, using the cohort of 4,251 students identified as new in fall 1992. Data indicate that 22.3% of this cohort did not enroll in any courses after applying, being tested, and completing orientation and advising; 8.4% continued on in the semester, but dropped…

  9. Sex Differences in Faculty Salaries: A Cohort Analysis.

    ERIC Educational Resources Information Center

    Perna, Laura Walter

    This study examined sex differences in faculty salaries, exploring how lower salaries for women varied across different rank/experience cohorts. Data came from the 1993 National Study of Postsecondary Faculty. Six cohorts were defined: assistant professors with 1-2 years experience, 3-6 years experience, 7-12 years experience, or 13-20 years…

  10. What Drives Teacher Engagement: A Study of Different Age Cohorts

    ERIC Educational Resources Information Center

    Guglielmi, Dina; Bruni, Ilaria; Simbula, Silvia; Fraccaroli, Franco; Depolo, Marco

    2016-01-01

    Despite the growing body of research on work engagement, little is known about what drives work engagement among different age cohorts. This study aims to investigate whether engagement varies across age cohorts and examines the job resources that foster teacher engagement. A questionnaire was distributed to 537 teachers who were employed in…

  11. Issues Related to the Effects of Cohorts on Learners.

    ERIC Educational Resources Information Center

    Browne-Ferrigno, Tricia; Muth, Rodney

    Over the past decade, many university-based administrator-preparation programs have evolved into curricula delivered through cohorts of about 20 to 25 students. However, little evidence exists about the long-term effect of cohort experience on aspiring principals' future professional practice. Anecdotal evidence suggests that students in cohorts…

  12. Revisiting the Dedifferentiation Hypothesis with Longitudinal Multi-Cohort Data

    ERIC Educational Resources Information Center

    de Frias, Cindy M.; Lovden, Martin; Lindenberger, Ulman; Nilsson, Lars-Goran

    2007-01-01

    The present longitudinal multi-cohort study examines whether interindividual variability in cognitive performance and change increases in old age, and whether associations among developments of different cognitive functions increase with adult age. Multivariate multiple-group latent growth modeling was applied to data from narrow cohorts separated…

  13. Cohort Profile update: The 1993 Pelotas (Brazil) Birth Cohort follow-up visits in adolescence

    PubMed Central

    Gonçalves, Helen; Assunção, Maria CF; Wehrmeister, Fernando C; Oliveira, Isabel O; Barros, Fernando C; Victora, Cesar G; Hallal, Pedro C; Menezes, Ana MB

    2014-01-01

    In this paper we update the profile of the 1993 Pelotas (Brazil) Birth Cohort Study, with emphasis on a shift of priority from maternal and child health research topics to four main categories of outcome variables, collected throughout adolescence: (i) mental health; (ii) body composition; (iii) risk factors for non-communicable diseases (NCDs); (iv) human capital. We were able to trace 81.3% (n = 4106) of the original cohort at 18 years of age. For the first time, the 18-years visit took place entirely on the university premises, in a clinic equipped with state-of-the-art equipment for the assessment of body composition. We welcome requests for data analyses from outside scientists. For more information, refer to our website (http://www.epidemio-ufpel.org.projetos_de_pesquisas/estudos/coorte_1993) or e-mail the corresponding author. PMID:24729426

  14. Achieving Synergy: Linking an Internet-Based Inflammatory Bowel Disease Cohort to a Community-Based Inception Cohort and Multicentered Cohort in Inflammatory Bowel Disease

    PubMed Central

    Aldridge, Molly; Cook, Suzanne Follan; Bright, Renee; Mallette, Meaghan; Moniz, Heather; Shah, Samir A; LeLeiko, Neal S; Shapiro, Jason; Sands, Bruce E; Chen, Wenli; Jaeger, Elizabeth; Galanko, Joseph; Long, Millie D; Martin, Christopher F; Sandler, Robert S; Kappelman, Michael D

    2016-01-01

    Background Traditional cohort studies are important contributors to our understanding of inflammatory bowel diseases, but they are labor intensive and often do not focus on patient-reported outcomes. Internet-based studies provide new opportunities to study patient-reported outcomes and can be efficiently implemented and scaled. If a traditional cohort study was linked to an Internet-based study, both studies could benefit from added synergy. Existing cohort studies provide an opportunity to develop and test processes for cohort linkage. The Crohn’s and Colitis Foundation of America’s (CCFA) Partners study is an Internet-based cohort of more than 14,000 participants. The Ocean State Crohn’s and Colitis Area Registry (OSCCAR) is an inception cohort. The Sinai-Helmsley Alliance for Research Excellence (SHARE) is a multicentered cohort of inflammatory bowel disease patients. Both the later cohorts include medical record abstraction, patient surveys, and biospecimen collection. Objective Given the complementary nature of these existing cohorts, we sought to corecruit and link data. Methods Eligible OSCCAR and SHARE participants were invited to join the CCFA Partners study and provide consent for data sharing between the 2 cohorts. After informed consent, participants were directed to the CCFA Partners website to complete enrollment and a baseline Web-based survey. Participants were linked across the 2 cohorts by the matching of an email address. We compared demographic and clinical characteristics between OSCCAR and SHARE participants who did and did not enroll in CCFA Partners and the data linkage. Results Of 408 participants in the OSCCAR cohort, 320 were eligible for participation in the CCFA Partners cohort. Of these participants, 243 consented to participation; however, only 44 enrolled in CCFA Partners and completed the linkage. OSCCAR participants who enrolled in CCFA Partners were better educated (17% with doctoral degrees) than those who did not (3% with

  15. The millennium Cohort Study: a 21-year prospective cohort study of 140,000 military personnel.

    PubMed

    Gray, Gregory C; Chesbrough, Karen B; Ryan, Margaret A K; Amoroso, Paul; Boyko, Edward J; Gackstetter, Gary D; Hooper, Tomoko I; Riddle, James R

    2002-06-01

    Does military service, in particular operational deployment, result in a higher risk of chronic illness among military personnel and veterans? The Millennium Cohort Study, the largest Department of Defense prospective cohort study ever conducted, will attempt to answer this question. The probability-based sample of 140,000 military personnel will be surveyed every 3 years during a 21-year period. The first questionnaire, scheduled for release in summer 2001, will be sent to 30,000 veterans who have been deployed to southwest Asia, Bosnia, or Kosovo since August 1997 and 70,000 veterans who have not been deployed to these conflict areas. Twenty thousand new participants will be added to the group in each of the years 2004 and 2007 to complete the study population of 140,000. The participants will have the option of completing the study questionnaire either on the paper copy received in the mail or through the World Wide Web-based version, which is available at www.MillenniumCohort.org. This will be one of the first prospective studies ever to offer such an option. The initial survey instrument will collect data regarding demographic characteristics, self-reported medical conditions and symptoms, and health-related behaviors. Validated instruments will be incorporated to capture self-assessed physical and mental functional status (Short Form for Veterans), psychosocial assessment (Patient Health Questionnaire), and post-traumatic stress disorder (Patient Checklist-17). Information obtained from the survey responses will be linked with other military databases, including data on deployment, occupation, vaccinations, health care utilization, and disability. In addition to revealing changes in veterans' health status over time, the Millennium Cohort Study will serve as a data repository, providing a solid foundation upon which additional epidemiological studies may be constructed.

  16. Investing in Prospective Cohorts for Etiologic Study of Occupational Exposures

    PubMed Central

    Blair, A.; Hines, C.J.; Thomas, K.W.; Alavanja, M.C.R.; Beane Freeman, L.E.; Hoppin, J.A.; Kamel, F.; Lynch, C.F.; Lubin, J.H.; Silverman, D.T.; Whelan, E.; Zahm, S. H.; Sandler, D. P.

    2015-01-01

    Prospective cohorts have played a major role in understanding the contribution of diet, physical activity, medical conditions, and genes to the development of many diseases, but have not been widely used for occupational exposures. Studies in agriculture are an exception. We draw upon our experience using this design to study agricultural workers to identify conditions that might foster use of prospective cohorts to study other occupational settings. Prospective cohort studies are perceived by many as the strongest epidemiologic design. It allows updating of information on exposure and other factors, collection of biologic samples before disease diagnosis for biomarker studies, assessment of effect modification by genes, lifestyle, and other occupational exposures, and evaluation of a wide range of health outcomes. Increased use of prospective cohorts would be beneficial in identifying hazardous exposures in the workplace. Occupational epidemiologists should seek opportunities to initiate prospective cohorts to investigate high priority, occupational exposures. PMID:25603935

  17. Cohort Profile Update: The Norwegian Mother and Child Cohort Study (MoBa).

    PubMed

    Magnus, Per; Birke, Charlotte; Vejrup, Kristine; Haugan, Anita; Alsaker, Elin; Daltveit, Anne Kjersti; Handal, Marte; Haugen, Margaretha; Høiseth, Gudrun; Knudsen, Gun Peggy; Paltiel, Liv; Schreuder, Patricia; Tambs, Kristian; Vold, Line; Stoltenberg, Camilla

    2016-04-01

    This is an update of the Norwegian Mother and Child Cohort Study (MoBa) cohort profile which was published in 2006. Pregnant women attending a routine ultrasound examination were initially invited. The first child was born in October 1999 and the last in July 2009. The participation rate was 41%. The cohort includes more than 114 000 children, 95 000 mothers and 75 000 fathers. About 1900 pairs of twins have been born. There are approximately 16 400 women who participate with more than one pregnancy. Blood samples were obtained from both parents during pregnancy and from mothers and children (umbilical cord) after birth. Samples of DNA, RNA, whole blood, plasma and urine are stored in a biobank. During pregnancy, the mother responded to three questionnaires and the father to one. After birth, questionnaires were sent out when the child was 6 months, 18 months and 3 years old. Several sub-projects have selected participants for in-depth clinical assessment and exposure measures. The purpose of this update is to explain and describe new additions to the data collection, including questionnaires at 5, 7, 8 and 13 years as well as linkages to health registries, and to point to some findings and new areas of research. Further information can be found at [www.fhi.no/moba-en]. Researchers interested in collaboration and access to the data can complete an electronic application available on the MoBa website above.

  18. Cohort Profile: Sympathetic activity and Ambulatory Blood Pressure in Africans (SABPA) prospective cohort study

    PubMed Central

    Malan, Leoné; Hamer, Mark; Frasure-Smith, Nancy; Steyn, Hendrik S; Malan, Nicolaas T

    2015-01-01

    Adapting to an over-demanding stressful urban environment may exhaust the psychophysiological resources to cope with these demands, and lead to sympathetic nervous system dysfunction. The evidence that an urban-dwelling lifestyle may be detrimental to the cardiometabolic health of Africans motivated the design of the Sympathetic activity and Ambulatory Blood Pressure in African Prospective cohort study. We aimed to determine neural mechanistic pathways involved in emotional distress and vascular remodelling. The baseline sample included 409 teachers representing a bi-ethnic sex cohort from South Africa. The study was conducted in 2008–09 and repeated after 3-year follow-up in 2011–12, with an 87.8% successful follow-up rate. Seasonal changes were avoided and extensive clinical assessments were performed in a well-controlled setting. Data collection included sociodemographics, lifestyle habits, psychosocial battery and genetic analysis, mental stress responses mimicking daily life stress (blood pressure and haemostatic, cardiometabolic, endothelial and stress hormones). Target organ damage was assessed in the brain, heart, kidney, blood vessels and retina. A unique highly phenotyped cohort is presented that can address the role of a hyperactive sympathetic nervous system and neural response pathways contributing to the burden of cardiometabolic diseases in Africans. PMID:25344943

  19. Leukemia incidence in the Russian cohort of Chernobyl emergency workers.

    PubMed

    Ivanov, V K; Tsyb, A F; Khait, S E; Kashcheev, V V; Chekin, S Yu; Maksioutov, M A; Tumanov, K A

    2012-05-01

    Of all potentially radiogenic cancers, leukemia, a type of cancer of the blood, has the highest risk attributable to ionizing radiation. Despite this, the quantitative estimation of radiation risk of a leukemia demands studying very large exposed cohorts, because of the very low level of this disease in unexposed populations and because of the tendency for its radiation risk to decrease with time. At present, the Japanese cohort of atomic bomb survivors is still the primary source of data that allows analysis of radiation-induced leukemia and the underlying dose-response relationship. The second large cohort that would allow to study radiation-induced leukemia is comprised of individuals who were exposed due to the accident of the Chernobyl nuclear power plant in 1986. The objective of the present study was to estimate radiation risks of leukemia incidence among the Russian cohort of Chernobyl emergency workers, for different time periods after the accident. Twenty-five years after the Chernobyl accident and based on the results of the present study, one can conclude that the radiation risk of leukemia incidence derived from the Russian cohort of Chernobyl emergency workers is similar to that derived from the cohort of atomic bomb survivors: The time-averaged excess relative risk per Gray (ERR Gy(-1)) equals 4.98 for the Russian cohort and 3.9 for the life span study (LSS) cohort; excess absolute risk decreases with time after exposure at an annual rate of 9% for the Russian cohort, and of 6.5% for the LSS cohort. Thus, the excess in risk of leukemia incidence in a population due to a single exposure is restricted in time after exposure by the period of about 15 years.

  20. Testing Persistence of Cohort Effects in the Epidemiology of Suicide: an Age-Period-Cohort Hysteresis Model

    PubMed Central

    Chauvel, Louis; Leist, Anja K.; Ponomarenko, Valentina

    2016-01-01

    Birth cohort effects in suicide rates are well established, but to date there is no methodological approach or framework to test the temporal stability of these effects. We use the APC-Detrended (APCD) model to robustly estimate intensity of cohort effects identifying non-linear trends (or ‘detrended’ fluctuations) in suicide rates. The new APC-Hysteresis (APCH) model tests temporal stability of cohort effects. Analysing suicide rates in 25 WHO countries (periods 1970–74 to 2005–09; ages 20–24 to 70–79) with the APCD method, we find that country-specific birth cohort membership plays an important role in suicide rates. Among 25 countries, we detect 12 nations that show deep contrasts among cohort-specific suicide rates including Italy, Australia and the United States. The APCH method shows that cohort fluctuations are not stable across the life course but decline in Spain, France and Australia, whereas they remain stable in Italy, the United Kingdom and the Netherlands. We discuss the Spanish case with elevated suicide mortality of cohorts born 1965–1975 which declines with age, and the opposite case of the United States, where the identified cohort effects of those born around 1960 increase smoothly, but statistically significant across the life course. PMID:27442027

  1. Cohort Profile: The International Collaboration of Incident HIV and Hepatitis C in Injecting Cohorts (InC3) Study

    PubMed Central

    Grebely, Jason; Morris, Meghan D; Rice, Thomas M; Bruneau, Julie; Cox, Andrea L; Kim, Arthur Y; McGovern, Barbara H; Shoukry, Naglaa H; Lauer, Georg; Maher, Lisa; Lloyd, Andrew R; Hellard, Margaret; Prins, Maria; Dore, Gregory J; Page, Kimberly

    2013-01-01

    The International Collaboration of Incident HIV and Hepatitis C in Injecting Cohorts (InC3) Study is an international multi-cohort project of pooled biological and behavioural data from nine prospective cohorts of people who inject drugs (PWID). InC3 brings together researchers from Australia, Canada, USA and the Netherlands with expertise in epidemiology, biostatistics, clinical and behavioural sciences, virology and immunology to investigate research questions relevant to hepatitis C virus (HCV) and HIV outcomes. InC3 was established to: (i) create a merged multi-cohort study of pooled data from well-characterized cohorts of PWID with prospective data on HIV and HCV infections, with a particular focus on HCV; (ii) facilitate new studies not possible within individual cohorts; and (iii) bring together researchers across disciplines to answer a broad range of research questions. Study cohorts identify acute HCV cases through follow-up of high-risk HCV antibody–negative PWID or through clinical referral networks. To date, data from 1986 to 2010 have been received from all contributing cohorts, with 821 HCV-infected and 1216 HCV-uninfected participants (overall, n = 2037). Data collected include demographics, host genetics, HCV ribonucleic acid testing, alanine aminotransferase testing, HIV/hepatitis B virus testing, HCV therapy, loss to follow-up and mortality. Potential collaborators should contact the InC3 PI Dr Kimberley Page (kPage@psg.ucsf.edu) for further information. PMID:23203695

  2. PanScan, the Pancreatic Cancer Cohort Consortium, and the Pancreatic Cancer Case-Control Consortium

    Cancer.gov

    The Pancreatic Cancer Cohort Consortium consists of more than a dozen prospective epidemiologic cohort studies within the NCI Cohort Consortium, whose leaders work together to investigate the etiology and natural history of pancreatic cancer.

  3. In Vivo Expansion of Regulatory T cells With IL-2/IL-2 mAb Complexes Prevents Anti-factor VIII Immune Responses in Hemophilia A Mice Treated With Factor VIII Plasmid-mediated Gene Therapy

    PubMed Central

    Liu, Chao-Lien; Ye, Peiqing; Yen, Benjamin C; Miao, Carol H

    2011-01-01

    Generation of transgene-specific immune responses can constitute a major complication following gene therapy treatment. An in vivo approach to inducing selective expansion of Regulatory T (Treg) cells by injecting interleukin-2 (IL-2) mixed with a specific IL-2 monoclonal antibody (JES6-1) was adopted to modulate anti-factor VIII (anti-FVIII) immune responses. Three consecutive IL-2 complexes treatments combined with FVIII plasmid injection prevented anti-FVIII formation and achieved persistent, therapeutic-level of FVIII expression in hemophilia A (HemA) mice. The IL-2 complexes treatment expanded CD4+CD25+Foxp3+ Treg cells five- to sevenfold on peak day, and they gradually returned to normal levels within 7–14 days without changing other lymphocyte populations. The transiently expanded Treg cells are highly activated and display suppressive function in vitro. Adoptive transfer of the expanded Treg cells protected recipient mice from generation of high-titer antibodies following FVIII plasmid challenge. Repeated plasmid transfer is applicable in tolerized mice without eliciting immune responses. Mice treated with IL-2 complexes mounted immune responses against both T-dependent and T-independent neoantigens, indicating that IL-2 complexes did not hamper the immune system for long. These results demonstrate the important role of Treg cells in suppressing anti-FVIII immune responses and the potential of developing Treg cell expansion therapies that induce long-term tolerance to FVIII. PMID:21468007

  4. 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.

  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. Growing up together: cohort composition and child investment.

    PubMed

    Jones, Kelly M

    2014-02-01

    In sub-Saharan Africa, 60 % of child deaths are preventable by investments in child health as simple as immunizations, bed nets, or water purification. This article investigates how a household's decisions regarding such investments are affected by the size and gender composition of a child's cohort. I focus on a previously overlooked type of investment: nonrival, child-specific goods (club goods). I empirically estimate the response of immunization status to cohort characteristics. I carefully address the problem of endogenous fertility, which is common in cohort studies. Because most rural Senegalese households are composed of multiple nuclear families, a child's cohort is composed of both siblings and nonsibling children. Estimating within households, I instrument cohort characteristics with those of the nonsibling (exogenous) portion. I find that children with larger (or more predominantly male) cohorts of vaccine-eligible age are significantly more likely to receive immunization. These findings suggest that children with larger cohorts may be better off in terms of club investments; this is a significant finding for child health given that many illness prevention methods are of a club good nature. PMID:24072608

  7. Global climate change and phenotypic variation among red deer cohorts.

    PubMed Central

    Post, E; Stenseth, N C; Langvatn, R; Fromentin, J M

    1997-01-01

    The variability of two fitness-related phenotypic traits (body weight and a mandibular skeletal ratio) was analysed among cohorts and age-classes of red deer in Norway. Phenotypic variation among cohorts was pronounced for calves, yearlings and reproductively mature adults. Fluctuations in cohort-specific mean body weights and skeletal ratios of adults correlated with global climatic variation in winter conditions influenced by the North Atlantic Oscillation while cohorts were in utero. Red deer born following warm winters were smaller than those born after cold winters, and this inter-cohort variability persisted into adulthood. Phenotypic variation among cohorts of red deer influenced by climate change may pose consequences for fitness of cohorts since body size and condition contribute to reproductive success and survival in male and female red deer. In particular, the recent trend of increasingly warm winters in northern Europe and Scandinavia may lead to reduced body size and fecundity of red deer, and perhaps other ungulates, in those areas. PMID:9332016

  8. Thiazolidinediones and Parkinson Disease: A Cohort Study.

    PubMed

    Connolly, John G; Bykov, Katsiaryna; Gagne, Joshua J

    2015-12-01

    Thiazolidinediones, a class of medications indicated for the treatment of type 2 diabetes mellitus, reduce inflammation and have been shown to provide a therapeutic benefit in animal models of Parkinson disease. We examined the association between treatment with thiazolidinediones and the onset of Parkinson disease in older individuals. We performed a cohort study of 29,397 Medicare patients enrolled in state pharmaceutical benefits programs who initiated treatment with thiazolidinediones or sulfonylureas during the years 1997 through 2005 and had no prior diagnosis of Parkinson disease. New users of thiazolidinediones were propensity score matched to new users of sulfonylureas and followed to determine whether they were diagnosed with Parkinson disease. We used Cox proportional hazards models to compare time to diagnosis of Parkinson disease in the propensity score-matched populations. To assess the association with duration of use, we performed several analyses that required longer continuous use of medications. In the primary analysis, thiazolidinedione users had a hazard ratio for a diagnosis of Parkinson disease of 1.09 (95% confidence interval: 0.71, 1.66) when compared with sulfonylurea users. Increasing the duration-of-use requirements to 10 months did not substantially change the association; the hazard ratios ranged from 1.00 (95% confidence interval: 0.49, 2.05) to 1.17 (95% confidence interval: 0.60, 2.25). Thiazolidinedione use was not associated with a longer time to diagnosis of Parkinson disease than was sulfonylurea use, regardless of duration of exposure.

  9. Cohort study of silicon carbide production workers.

    PubMed

    Infante-Rivard, C; Dufresne, A; Armstrong, B; Bouchard, P; Thériault, G

    1994-12-01

    Silicon carbide is produced by a chemical reaction at high temperature between free crystalline silica and petroleum coke. The process generates airborne fibers and fibrogenic dusts such as alpha-quartz and cristobalite, which are also potentially carcinogenic. The authors report that this is the first cohort study in this industry. The study was carried out among 585 Québec silicon carbide production workers who had worked at any time from 1950 to 1980. Follow-up was to December 31, 1989, and 167 deaths were observed. The standardized mortality ratio (SMR) for all causes of death was 1.05 (95% confidence interval (CI) 0.90-1.23); for nonmalignant respiratory diseases it was 2.03 (95% CI 1.21-3.22); and for lung cancer it was 1.69 (95% CI 1.09-2.52). Controlling for smoking status using a Cox regression analysis, the risk for nonmalignant respiratory diseases and for lung cancer increased with exposure to total dust; in the highest exposure category, rate ratios (RR) were 4.08 (95% CI 1.11-14.96) for nonmalignant respiratory diseases and 1.67 (95% CI 0.57-4.83) for lung cancer. Results were in the expected direction, but the power of the study was low, because of small sample size and use of cumulative total dust as the exposure variable, which may be a poor indicator of lung irritants and other potential carcinogens in this industry, notably silicon carbide ceramic fibers.

  10. Observations of a large Dent disease cohort.

    PubMed

    Blanchard, Anne; Curis, Emmanuel; Guyon-Roger, Tiphaine; Kahila, Diana; Treard, Cyrielle; Baudouin, Véronique; Bérard, Etienne; Champion, Gérard; Cochat, Pierre; Dubourg, Julie; de la Faille, Renaud; Devuyst, Olivier; Deschenes, Georges; Fischbach, Michel; Harambat, Jérôme; Houillier, Pascal; Karras, Alexandre; Knebelmann, Bertrand; Lavocat, Marie-Pierre; Loirat, Chantal; Merieau, Elodie; Niaudet, Patrick; Nobili, François; Novo, Robert; Salomon, Rémi; Ulinski, Tim; Jeunemaître, Xavier; Vargas-Poussou, Rosa

    2016-08-01

    Dent disease classically combines low-molecular-weight proteinuria, hypercalciuria with nephrocalcinosis, and renal failure. Nephrotic range proteinuria, normal calciuria, and hypokalemia have been rarely reported. It is unknown whether the changes in phenotype observed over time are explained by a decrease in glomerular filtration rate (GFR) or whether there is any phenotype-genotype relationship. To answer this we retrospectively analyzed data from 109 male patients with CLCN5 mutations (Dent-1) and 9 patients with mutation of the OCRL gene (Dent-2). In Dent-1 disease, the estimated GFR decreased with age, by 1.0 to 1.6 ml/min per 1.73 m(2)/yr in the absence and presence of nephrocalcinosis, respectively, with no significant difference. Median values of low-molecular-weight proteinuria were in the nephrotic range and remained at the same level even in late renal disease. End-stage renal disease occurred in 12 patients, at a median age of 40 years. Hypercalciuria decreased with glomerular filtration and was absent in 40% of the patients under 30 and 85% of those over the age of 30. Hypophosphatemia did not resolve with age and calcitriol concentrations were in the upper normal range. Kalemia decreased with age, with half of the patients over the age of 18 presenting with hypokalemia. Thus, no phenotype/genotype correlation was observed in this cohort of patients with Dent disease.

  11. Design, methods and demographics from phase I of Alberta's Tomorrow Project cohort: a prospective cohort profile

    PubMed Central

    Robson, Paula J.; Solbak, Nathan M.; Haig, Tiffany R.; Whelan, Heather K.; Vena, Jennifer E.; Akawung, Alianu K.; Rosner, William K.; Brenner, Darren R.; Cook, Linda S.; Csizmadi, Ilona; Kopciuk, Karen A.; McGregor, S. Elizabeth; Friedenreich, Christine M.

    2016-01-01

    Background: Prospective cohorts have the potential to support multifactorial, health-related research, particularly if they are drawn from the general population, incorporate active and passive follow-up and permission is obtained to allow access by researchers to data repositories. This paper describes Phase I of the Alberta's Tomorrow Project cohort, a broad-based research platform designed to support investigations into factors that influence cancer and chronic disease risk. Methods: Adults aged 35-69 years living in Alberta, Canada, with no previous cancer diagnosis other than nonmelanoma skin cancer were recruited to the project by telephone-based random digit dialling. Participants were enrolled if they returned a Health and Lifestyle Questionnaire. Past year diet and physical activity questionnaires were mailed 3 months after enrolment. Consent was sought for active follow-up and linkage with administrative databases. Depending on enrolment date, participants were invited to complete up to 2 follow-up questionnaires (2004 and 2008). Results: Between 2001 and 2009, 31 072 (39% men) participants (mean age 50.2 [± 9.2] yr) were enrolled and 99% consented to linkage with administrative databases. Participants reported a wide range of educational attainment and household income. Compared with provincial surveillance data from the Canadian Community Health Survey, Alberta's Tomorrow Project participants had higher body mass index, lower prevalence of smoking and similar distribution of chronic health conditions. Follow-up questionnaires were completed by 83% and 72% of participants in 2004 and 2008, respectively. Robust quality control measures resulted in low frequencies of missing data. Interpretation: Alberta's Tomorrow Project provides a robust platform, based on a prospective cohort design, to support research into risk factors for cancer and chronic disease. PMID:27730115

  12. Sex differential for suicide among Austrian age cohorts.

    PubMed

    Etzersdorfer, E; Piribauer, F; Sonneck, G

    1996-04-01

    The suicide mortality data in Austria were studied over a period of four decades of continuous reporting. The data were studied for age, period and cohort effects. For the period 1951 to 1990 suicides among eight birth cohorts, born between 1932 and 1975, show a marked sex differential in time trends. Up to 1985, the rates increase in a constant manner for males in all age groups, in contrast to females. Results obtained using the Poisson regression models demonstrate a 35% (incidence rate ratio (IRR), 1.35%; 95% CI, 1.27-1.45) increased risk for male cohorts born later compared with those born earlier. The risk for later-born females was not increased (IRR, 1.03; 95% CI, 0.91-1.17). Explanations such as improved living conditions for Austrian women remain tentative, however, as age, period and cohort effects cannot be separated as independent variables in the suicide mortality data available in Austria. PMID:8712021

  13. Breast and Prostate Cancer Cohort Consortium (BPC3)

    Cancer.gov

    Breast and Prostate Cancer Cohort Consortium collaborates with three genomic facilities, epidemiologists, population geneticists, and biostatisticians from multiple institutions to study hormone-related gene variants and environmental factors in breast and prostate cancers.

  14. Childhood cancer incidence in a cohort of twin babies

    PubMed Central

    Murphy, M F G; Whiteman, D; Hey, K; Griffith, M; Gill, L; Goldacre, M J; Vincent, T J; Bunch, K

    2001-01-01

    We studied childhood cancer incidence in a population-based twin cohort using record linkage to the National Registry of Childhood Tumours. After correcting for mortality, an incidence deficit was observed (Standardized Incidence Ratio (SIR) 79; 95% Confidence Interval (CI) 39–120). Pooled analysis with data from published cohort studies indicates a similar significant incidence reduction (SIR 81, 95% CI 67–96). Further studies are warranted. © 2001 Cancer Research Campaign http://www.bjcancer.com PMID:11384093

  15. Cohort size and migration in a West Indian population.

    PubMed

    Brittain, A W

    1990-01-01

    The author examines the relationship between cohort size and migration patterns among the population of the French West Indies island of St. Barthelemy. Data show that "for people born from 1878 to 1967, neither cohort size nor fluctuations in external demands for labor had a lasting effect on the probability of eventual migration. Emigration rates only slowed after the development of the local tourist industry brought prosperity to the island." PMID:12283449

  16. Cohort profile of the Japan Collaborative Cohort Study at final follow-up.

    PubMed

    Tamakoshi, Akiko; Ozasa, Kotaro; Fujino, Yoshihisa; Suzuki, Koji; Sakata, Kiyomi; Mori, Mitsuru; Kikuchi, Shogo; Iso, Hiroyasu; Sakauchi, Fumio; Motohashi, Yutaka; Tsuji, Ichiro; Nakamura, Yosikazu; Mikami, Haruo; Kurosawa, Michiko; Hoshiyama, Yoshiharu; Tanabe, Naohito; Tamakoshi, Koji; Wakai, Kenji; Tokudome, Shinkan; Hashimoto, Shuji; Wada, Yasuhiko; Kawamura, Takashi; Watanabe, Yoshiyuki; Miki, Tsuneharu; Date, Chigusa; Kurozawa, Yoichi; Yoshimura, Takesumi; Shibata, Akira; Okamoto, Naoyuki; Shio, Hideo

    2013-01-01

    The Japan Collaborative Cohort Study for Evaluation of Cancer Risk (JACC Study) was established in the late 1980s to evaluate the risk impact of lifestyle factors and levels of serum components on human health. During the 20-year follow-up period, the results of the study have been published in almost 200 original articles in peer-reviewed English-language journals. However, continued follow-up of the study subjects became difficult because of the retirements of principal researchers, city mergers throughout Japan in the year 2000, and reduced funding. Thus, we decided to terminate the JACC Study follow-up at the end of 2009. As a final point of interest, we reviewed the population registry information of survivors. A total of 207 (0.19%) subjects were ineligible, leaving 110 585 eligible participants (46 395 men and 64 190 women). Moreover, errors in coding date of birth and sex were found in 356 (0.32%) and 59 (0.05%) cases, respectively, during routine follow-up and final review. Although such errors were unexpected, their impact is believed to be negligible because of the small numbers relative to the large total study population. Here, we describe the final cohort profile at the end of the JACC Study along with selected characteristics of the participants and their status at the final follow-up. Although follow-up of the JACC Study participants is finished, we will continue to analyze and publish study results.

  17. Cohort Profile: LifeLines, a three-generation cohort study and biobank.

    PubMed

    Scholtens, Salome; Smidt, Nynke; Swertz, Morris A; Bakker, Stephan J L; Dotinga, Aafje; Vonk, Judith M; van Dijk, Freerk; van Zon, Sander K R; Wijmenga, Cisca; Wolffenbuttel, Bruce H R; Stolk, Ronald P

    2015-08-01

    The LifeLines Cohort Study is a large population-based cohort study and biobank that was established as a resource for research on complex interactions between environmental, phenotypic and genomic factors in the development of chronic diseases and healthy ageing. Between 2006 and 2013, inhabitants of the northern part of The Netherlands and their families were invited to participate, thereby contributing to a three-generation design. Participants visited one of the LifeLines research sites for a physical examination, including lung function, ECG and cognition tests, and completed extensive questionnaires. Baseline data were collected for 167 729 participants, aged from 6 months to 93 years. Follow-up visits are scheduled every 5 years, and in between participants receive follow-up questionnaires. Linkage is being established with medical registries and environmental data. LifeLines contains information on biochemistry, medical history, psychosocial characteristics, lifestyle and more. Genomic data are available including genome-wide genetic data of 15 638 participants. Fasting blood and 24-h urine samples are processed on the day of collection and stored at -80 °C in a fully automated storage facility. The aim of LifeLines is to be a resource for the national and international scientific community. Requests for data and biomaterials can be submitted to the LifeLines Research Office [LLscience@umcg.nl].

  18. Draft Cohort Default Rate Guide for FFEL Program and Direct Loan Program Loans, FY 1998.

    ERIC Educational Resources Information Center

    Department of Education, Washington, DC. Default Management Div.

    This publication is intended to help postsecondary schools understand draft cohort default rate data. It explains how the Department of Education calculates cohort default rates, the effect of cohort default rates, and how to read cohort default rate loan record detail reports. Also, it reviews electronic reports available from the Department of…

  19. Draft Cohort Default Rate Guide for FFEL Program and Direct Loan Program Loans, FY 1999.

    ERIC Educational Resources Information Center

    Department of Education, Washington, DC. Default Management Div.

    This publication is intended to help postsecondary schools understand FY 1999 draft cohort default rate data. It explains how the Department of Education calculates cohort default rates, the effect of cohort default rates, and how to read the cohort default rate loan record detail reports. Also, it reviews electronic reports available from the…

  20. Comparing Three South African Student Cohorts on Their Attitudes to the Rights of Working Women

    ERIC Educational Resources Information Center

    Patel, Cynthia Joan

    2016-01-01

    This study compares three cohorts (1998-1999, 2005-2006 and 2010) of undergraduate psychology students at a South African university on the level of support for working women (women in paid employment) on various issues considered to be feminist. Cohort 1 (n?=?244), cohort 2 (n?=?311) and cohort 3 (n?=?266) completed an adapted version of a…

  1. Cohort shifts in the timing of births in Ghana.

    PubMed

    Oheneba-sakyi, Y

    1989-01-01

    A comparison of cohorts of ever-married Chanaian women suggests evidence of a fertility transition beginning among younger women and select subgroups. Ghana's crude birth rate declined from a high of 50/1000 population in 1970 to 38.8/1000 in 1985. To ascertain whether marital fertility is now being controlled through conscious attempts to lengthen birth intervals, World Fertility Survey data from 1979-80 on the timing of births among different birth cohorts were analyzed. It was hypothesized that, as a result of the influence of Western values that stress independence from parents and the introduction of compulsory education, cohorts of the mid-1950s and 1960s would be more likely to postpone childbearing, more active in the modern sector of the economy, and more accepting of modern contraceptive usage for birth spacing than women in the 1930-39, 1940-49, and 1950-59 cohorts. For the 1940-49 cohort, it took 10.8 months for 25% to have a birth following 1st marriage, 18.7 months for 50% to have a 1st birth, and 27.4 months for 75% to complete this step. By comparison, these figures for the 1955-64 birth cohort were 9.9, 16.7, and 20.5 months, respectively. The significantly shorter (p 0.01) interval between marriage and 1st birth found among younger women in part reflects rising age at marriage; mean age at 1st marriage was 17.9 years for the 1940 cohort and 21.6 years for the most recent cohort. After the birth of the 1st child, recent cohorts were more likely to wait longer for the 2nd birth. For women born in 1950-64, it took 21.8, 36.7, and 44.6 months for 25%, 50%, and 75%, respectively, to reach parity 2. This pattern of lengthened birth interval beyond the 1st birth was apparent at all parities in the youngest cohort and indicates increasing acceptance of contraception among those who have come of age during a period of rapid social change.

  2. A cohort study of bacteremic pneumonia

    PubMed Central

    Guillamet, Cristina Vazquez; Vazquez, Rodrigo; Noe, Jonas; Micek, Scott T.; Kollef, Marin H.

    2016-01-01

    Abstract Bacteremic pneumonia is usually associated with greater mortality. However, risk factors associated with hospital mortality in bacteremic pneumonia are inadequately described. The study was a retrospective cohort study, conducted in Barnes-Jewish Hospital (2008–2015). For purposes of this investigation, antibiotic susceptibility was determined according to ceftriaxone susceptibility, as ceftriaxone represents the antimicrobial agent most frequently recommended for hospitalized patients with community-acquired pneumonia as opposed to nosocomial pneumonia. Two multivariable analyses were planned: the first model included resistance to ceftriaxone as a variable, whereas the second model included the various antibiotic-resistant species (methicillin-resistant Staphylococcus aureus, Pseudomonas aeruginosa, and Enterobacteriaceae). In all, 1031 consecutive patients with bacteremic pneumonia (mortality 37.1%) were included. The most common pathogens associated with infection were S aureus (34.1%; methicillin resistance 54.0%), Enterobacteriaceae (28.0%), P aeruginosa (10.6%), anaerobic bacteria (7.3%), and Streptococcus pneumoniae (5.6%). Compared with ceftriaxone-susceptible pathogens (46.8%), ceftriaxone-resistant pathogens (53.2%) were significantly more likely to receive inappropriate initial antibiotic treatment (IIAT) (27.9% vs 7.1%; P < 0.001) and to die during hospitalization (41.5% vs 32.0%; P = 0.001). The first logistic regression analysis identified IIAT with the greatest odds ratio (OR) for mortality (OR 2.2, 95% confidence interval [CI] 1.5–3.2, P < 0.001). Other independent predictors of mortality included age, mechanical ventilation, immune suppression, prior hospitalization, prior antibiotic administration, septic shock, comorbid conditions, and severity of illness. In the second multivariable analysis that included the antibiotic-resistant species, IIAT was still associated with excess mortality, and P aeruginosa infection was

  3. Assessment of individual dose utilization vs. physician prescribing recommendations for recombinant activated factor VII (rFVIIa) in paediatric and adult patients with congenital haemophilia and alloantibody inhibitors (CHwI): the Dosing Observational Study in Hemophilia (DOSE).

    PubMed

    Gruppo, R A; Kessler, C M; Neufeld, E J; Cooper, D L

    2013-07-01

    Recent data from the Dosing Observational Study in Hemophilia diary study has described home treatment with recombinant activated factor VII (rFVIIa) in congenital haemophilia with inhibitors (CHwI). The current analysis compares prescribed and patient/caregiver-reported rFVIIa administration in paediatric and adult CHwI patients in this study. Patients with ≥ 4 bleeding episodes within a 3-month period prescribed rFVIIa as first-line therapy for bleeding episodes were eligible. Patients/caregivers completed a diary for ≥ 90 days or until the patient experienced four bleeds. Initial, total and mean rFVIIa doses reported for each bleeding episode were calculated and compared with the physician-prescribed doses. Of 52 enrolled patients (25 children; 27 adults), 39 (75%) completed the study. Children and adults had similar mean durations of bleeding episodes. Both patient groups were administered higher initial rFVIIa doses for joint bleeds than prescribed: median (range) 215.2 (74.1-400.0) mcg kg(-1) vs. 200.0 (61.0-270.0) mcg kg(-1) for children, and 231.3 (59.3-379.7) mcg kg(-1) vs. 123.0 (81.0-289.0) mcg kg(-1) for adults. The median infused dose for joint bleeds was higher in adults than children (175.2 vs. 148.0 mcg kg(-1) ), but children received significantly more doses per joint bleed than adults (median 6.5 vs. 3.0). The median total dose per joint bleed was higher in children than adults (1248.7 vs. 441.6). For children and adults, both initial and additional doses administered for bleeds were higher than prescribed. Children received higher total doses per bleed due to an increased number of infusions per bleed.

  4. Cohort estimates of nonmarital fertility for U.S. women.

    PubMed

    Wu, Lawrence L

    2008-02-01

    Historical trends in U.S. nonmarital fertility have been compiled almost exclusively from vital statistics on births. This paper complements this historical record by providing cohort estimates of nonmarital fertility for cohorts of U.S. women spanning approximately 50 years of cohort experience. Life table estimates using retrospective marital and fertility histories in the June 1980, 1985, 1990, and 1995 Current Population Surveys reveal nonnegligible levels of nonmarital fertility historically. For women born between 1925 and 1929, nearly 1 in 10 had at least one nonmarital birth by age 30. For women born between 1965 and 1969, more than 1 of 4 had one or more nonmarital births by age 30, with roughly 1 of5 white, 3 of 5 black, and 1 in 3 Hispanic women having at least one nonmarital birth by age 30. Life table estimates reveal a twofold increase between ages 20 and 30 in the percentage of women with at least one child outside of formal marriage for all cohorts of white and Hispanic women, and an increase of roughly two-thirds for all cohorts of black women. I also document qualitative differences in nonmarital fertility by race/ethnicity, with the percentage of nonmarital births following a divorce or marital separation for white women approximately twice that for black or Hispanic women. Finally, I introduce a new measure, the cohort nonmarital fertility ratio (CNMFR), which provides a cohort complement to the standard period nonmarital fertility ratio. Conservative estimates reveal a roughly threefold increase in the CNMFR for women born from 1925-1929 to 1950-1954 for both whites and blacks, despite substantially higher levels of nonmarital fertility among black women. Overall, these findings reveal surprisingly high levels of nonmarital fertility for women born since the 1920s and confirm that nonmarital fertility has become an increasingly substantial component of overall U.S. fertility.

  5. South Yorkshire Cohort: a 'cohort trials facility' study of health and weight - Protocol for the recruitment phase

    PubMed Central

    2011-01-01

    Background Growing levels of both obesity and chronic disease in the general population pose a major public health problem. In the UK, an innovative 'health and weight' cohort trials facility, the 'South Yorkshire Cohort', is being built in order to provide robust evidence to inform policy, commissioning and clinical decisions in this field. This protocol reports the design of the facility and outlines the recruitment phase methods. Method/Design The South Yorkshire Cohort health and weight study uses the cohort multiple randomised controlled trial design. This design recruits a large observational cohort of patients with the condition(s) of interest which then provides a facility for multiple randomised controlled trials (with large representative samples of participants, long term outcomes as standard, increased comparability between each trial conducted within the cohort and increased efficiency particularly for trials of expensive interventions) as well as ongoing information as to the natural history of the condition and treatment as usual. This study aims to recruit 20,000 participants to the population based South Yorkshire Cohort health and weight research trials facility. Participants are recruited by invitation letters from their General Practitioners. Data is collected using postal and/or online patient self completed Health Questionnaires. NHS numbers will be used to facilitate record linkage and access to routine data. Participants are eligible if they are: aged 16 - 85 years, registered with one of 40 practices in South Yorkshire, provide consent for further contact from the researchers and to have their information used to look at the benefit of health treatments. The first wave of data is being collected during 2010/12 and further waves are planned at 2 - 5 year intervals for the planned 20 year duration of the facility. Discussion The South Yorkshire Cohort combines the strengths of the standard observational, longitudinal cohort study design with

  6. Cohort Profile Update: The TRacking Adolescents’ Individual Lives Survey (TRAILS)

    PubMed Central

    Oldehinkel, Albertine J; Rosmalen, Judith GM; Buitelaar, Jan K; Hoek, Hans W; Ormel, Johan; Raven, Dennis; Reijneveld, Sijmen A; Veenstra, René; Verhulst, Frank C; Vollebergh, Wilma AM; Hartman, Catharina A

    2015-01-01

    TRAILS consists of a population cohort (N = 2230) and a clinical cohort (N = 543), both of which were followed from about age 11 years onwards. To date, the population cohort has been assessed five times over a period of 11 years, with retention rates ranging between 80% and 96%. The clinical cohort has been assessed four times over a period of 8 years, with retention rates ranging between 77% and 85%. Since the IJE published a cohort profile on the TRAILS in 2008, the participants have matured from adolescents into young adults. The focus shifted from parents and school to entry into the labour market and family formation, including offspring. Furthermore, psychiatric diagnostic interviews were administered, the database was linked to a Psychiatric Case Registry, and the availability of genome-wide SNP variations opened the door to genome-wide association studies regarding a wide range of (endo)phenotypes. With some delay, TRAILS data are available to researchers outside the TRAILS consortium without costs; access can be obtained by submitting a publication proposal (see www.trails.nl). PMID:25431468

  7. Inflammatory Bowel Disease Cohort Studies in Korea: Present and Future

    PubMed Central

    Lee, Jung Won; Cheon, Jae Hee; Kim, You Sun; Kim, Joo Sung; Han, Dong Soo

    2015-01-01

    Inflammatory bowel disease (IBD) is defined as a chronic and relapsing inflammatory disorder of the intestine. Intestinal inflammation in IBD has been proposed to be attributable to the interplay between microbial, genetic, environmental, and immunological factors. The incidence and prevalence rates of IBD are rapidly increasing apparently in other parts of the world, with dramatic increases especially in East Asia. Generally, cohort studies are useful for estimating the incidence, prevalence, natural course, prognosis, and risk factors of diseases. In particular, cohort studies performed in Western countries have well described the prevalence, risk factors, and natural course of IBD and investigated its genetic pathophysiology. However, the outcomes of IBD cohort studies performed in Korea are not as persuasive as those of Western studies because of the relatively low prevalence of IBD and short follow-up periods of the cohorts in Korea. Despite this critical limitation, members of the Korean Association for the Study of Intestinal Diseases have demonstrated outstanding results. Some unique features of IBD patients in Korea are well demonstrated, such as thiopurine-induced leukopenia or risks of opportunistic tuberculosis infection in patients receiving tumor necrosis factor-α inhibitors. In this review, the present authors summarized the key points of the results of the cohort studies performed in Korea and explored future perspectives. PMID:26130995

  8. Premarital sexual standards and sociosexuality: gender, ethnicity, and cohort differences.

    PubMed

    Sprecher, Susan; Treger, Stanislav; Sakaluk, John K

    2013-11-01

    In this article, we present results from a "cohort-longitudinal" analysis of sexual attitudes and behaviors based on a large sample of young adults (N = 7,777) obtained from a university setting over a 23-year period. We investigated gender, ethnicity, and cohort differences in sexual permissiveness, endorsement of the double standard, and sociosexuality. Compared to women, men had more permissive attitudes, particularly about sex in casual relationships, endorsed the double standard to a greater degree, and had a more unrestricted sociosexuality. Black men were generally more permissive than White, Hispanic, and Asian men, whereas ethnic differences were not found among women. Participants from the 1995-1999 cohort were slightly less permissive than those from the 1990-1994 and 2005-2012 cohorts. Although prior meta-analytic studies (e.g., Petersen & Hyde, 2010) found reduced gender differences in sexuality over time, our cohort analyses suggest that gender differences in sexual permissiveness have not changed over the past two decades among college students. PMID:23842785

  9. Monte Carlo estimation of stage structured development from cohort data.

    PubMed

    Knape, Jonas; De Valpine, Perry

    2016-04-01

    Cohort data are frequently collected to study stage-structured development and mortalities of many organisms, particularly arthropods. Such data can provide information on mean stage durations, among-individual variation in stage durations, and on mortality rates. Current statistical methods for cohort data lack flexibility in the specification of stage duration distributions and mortality rates. In this paper, we present a new method for fitting models of stage-duration distributions and mortality to cohort data. The method is based on a Monte Carlo within MCMC algorithm and provides Bayesian estimates of parameters of stage-structured cohort models. The algorithm is computationally demanding but allows for flexible specifications of stage-duration distributions and mortality rates. We illustrate the algorithm with an application to data from a previously published experiment on the development of brine shrimp from Mono Lake, California, through nine successive stages. In the experiment, three different food supply and temperature combination treatments were studied. We compare the mean duration of the stages among the treatments while simultaneously estimating mortality rates and among-individual variance of stage durations. The method promises to enable more detailed studies of development of both natural and experimental cohorts. An R package implementing the method and which allows flexible specification of stage duration distributions is provided. PMID:27220215

  10. Asbestos and cancer: a cohort followed up to death.

    PubMed Central

    Enterline, P E; Hartley, J; Henderson, V

    1987-01-01

    The mortality experience of 1074 white men who retired from a United States asbestos company during the period 1941-67 and who were exposed to asbestos working as production and maintenance employees for the company is reported to the end of 1980 when 88% of this cohort was known to be dead. As noted in earlier reports the mortality for respiratory and gastrointestinal cancer was raised. A more detailed examination of causes of death shows that the excess in gastrointestinal cancer was largely due to a statistically significant excess in stomach cancer. A statistically significant excess was also noted for kidney cancer, cancer of the eye, and non-malignant respiratory disease. Eight deaths from malignant mesothelioma were observed, two of which were peritoneal. Asbestos exposures for these mesothelioma cases were low relative to other members of the cohort. Continuing follow up of this cohort shows a dose response relation for respiratory cancer that has become increasingly linear. Standardised mortality ratios peaked 10 to 15 years after retirement and were relatively constant at around 250 in each five year interval starting in 1950. This excess might have been detected as early as 1960 but certainly by 1965. The mortality experience of this cohort reflects the ultimate effects of asbestos since nearly all of the cohort has now died. PMID:3606968

  11. Cohort study analysis with a FORTRAN computer program.

    PubMed

    Coleman, M; Douglas, A; Hermon, C; Peto, J

    1986-03-01

    We describe the analysis of cohort study data with a standard FORTRAN program which should run on most computers. It provides a summary measure of the mortality (or incidence) rate ratio between the study cohort and some standard population, based either on person-years at risk or on proportional mortality, and adjusted for age, sex and calendar period; a test of the statistical significance of the ratio; and a set of observed death rates in the study cohort. Results may also be produced in a form suitable for use with GLIM. The analysis may be subdivided into a range of time intervals since each subject was first exposed to risk. The program provides for movement of subjects between different 'level-of-exposure' subgroups within the cohort, and for various methods of censoring. It allows considerable flexibility in data management, and is available with complete documentation and a worked example. The program should enable epidemiologists with little computing experience to carry out formal analysis of cohort studies.

  12. Incidence of cancer in a cohort of magnesium production workers.

    PubMed Central

    Heldaas, S S; Langård, S; Andersen, A

    1989-01-01

    The results from a cohort study on the incidence of cancer and the mortality in a cohort of 2391 male workers producing magnesium metal are presented. The study population was restricted to employees with more than one year of work experience in the study plant between 1951 and 1974 and the cohort was observed from 1953 to 1984. Altogether 152 new cases of cancer were observed versus 132.6 expected. Six cases of cancer of the lip were found against 2.3 expected, 21 of stomach cancer against 12.8 expected, and 32 of lung cancer against 18.2 expected. A possible causal relation between exposure to factors in the work environment and the development of cancer is discussed. PMID:2789964

  13. The Effects of Multiple Reformed Courses on Freshman Cohorts

    NASA Astrophysics Data System (ADS)

    Lynch, Robert B.; West, Emily A.; Potter, Wendell H.

    2010-02-01

    Beginning fall 2007 successive 48-student cohorts of entering freshmen bio-science majors have been enrolled in reformed course sections to test the proposition that students who were exposed simultaneously to both math and science courses, which explicitly stress sense-making rather than memorization, would more quickly develop habits of mind and approaches to learning that are more productive and useful than the memorization mindset that is so typical of entering freshmen. Preliminary results show positive performance gains of the cohort students in subsequent courses. Variations in the sequence of course offerings has allowed the separate analysis of the impact of taking a radically reformed physics course even on immediately following science courses in the freshman year. Longitudinal performance data through fall-quarter 2009 for cohorts entering in 2007 and 2008 will be presented as well as qualitative interview and survey data. )

  14. Mortality among three refinery/petrochemical plant cohorts. II. Retirees.

    PubMed

    Gamble, J F; Lewis, R J; Jorgensen, G

    2000-07-01

    This study updates mortality data for 6238 retirees from three refinery/petrochemical plants. Almost 90% of the cohort was deceased. Deaths from all causes (standardized mortality ratio, 104; 95% confidence interval, 102 to 107) and all cancers (standardized mortality ratio, 109; 95% confidence interval, 102 to 116) were elevated. Increased deaths due to kidney cancer, mesothelioma, and the category of other lymphohemopoietic cancers also were observed. The rate of leukemia was not increased. There was little internal or external consistency to support an occupational relationship for kidney cancer, but findings for mesothelioma and other lymphohemopoietic cancers are consistent with reports for other petroleum cohorts. Analyses by age indicated significantly higher all-cause mortality rates among persons retiring before age 65. The results suggest that continued surveillance of mesothelioma and lymphohemopoietic cancer malignancies in younger workers with more contemporary exposures may be warranted. Furthermore, age at retirement should be considered when analyzing occupational cohorts.

  15. Caring for an aging society: cohort values and eldercare services.

    PubMed

    Karner, T X

    2001-01-01

    Understanding the impact of cohort values is important in trying to project future aging service needs. The cultural characteristics of cohorts yet to reach the age of 65 are compared with those already "old," with specific focus on the Baby Boomers. Aging policies (and available services) reflect the cultural notions of age and aging held as normative during the historical era in which they are enacted. Previous research into lifestyle preferences, consumer practices, and key characteristics is drawn upon to investigate the values of Baby Boomers in light of their projected needs for eldercare services. Cohort research and generational marketing practices offer a promising foundation for exploring how best to develop, target, and deliver aging services that most effectively utilize our social resources.

  16. Methodological aspects of the 1993 Pelotas (Brazil) Birth Cohort Study

    PubMed Central

    Victora, Cesar Gomes; Araújo, Cora Luiza Pavin; Menezes, Ana Maria Batista; Hallal, Pedro Curi; Vieira, Maria de Fátima; Neutzling, Marilda Borges; Gonçalves, Helen; Valle, Neiva Cristina; Lima, Rosangela Costa; Anselmi, Luciana; Behague, Dominique; Gigante, Denise Petrucci; Barros, Fernando Celso

    2010-01-01

    This paper describes the main methodological aspects of a cohort study, with emphasis on its recent phases, which may be relevant to investigators planning to carry out similar studies. In 1993, a population based study was launched in Pelotas, Southern Brazil. All 5,249 newborns delivered in the city’s hospitals were enrolled, and sub-samples were visited at the ages of one, three and six months and of one and four years. In 2004-5 it was possible to trace 87.5% of the cohort at the age of 10-12 years. Sub-studies are addressing issues related to oral health, psychological development and mental health, body composition, and ethnography. Birth cohort studies are essential for investigating the early determinants of adult disease and nutritional status, yet few such studies are available from low and middle-income countries where these determinants may differ from those documented in more developed settings. PMID:16410981

  17. Smoking and psychopathology increasingly associated in recent birth cohorts*

    PubMed Central

    Talati, Ardesheer; Wickramaratne, Priya J; Keyes, Katherine M; Hasin, Deborah S; Levin, Frances R; Weissman, Myrna M.

    2013-01-01

    Background: In recent decades, smoking has become an increasingly non-normative behavior. Because deviant behaviors are associated with greater clinical and genetic risks, current-generation smokers may have greater concentrations of psychiatric comorbidity than previous generations. We examined this question empirically by testing whether associations between measures of smoking, psychiatric diagnoses, and riskassociated personality traits, increased across seven birth-cohorts of the 20th century. Method: 4,326 subjects from a cross-sectional NIMH control sample were categorized into one of seven groups based on birth (born before 1930, and 1930s-‘80s) and one of three smoking levels (lifetime dependent smoker, never dependent smoker, never smoker smoking and ND were assessed using the Fagerstrom Test for Nicotine Dependence; psychiatric diagnoses (drug and alcohol dependence, major depression, and generalized anxiety disorder) using the Composite International Diagnostic Interview-Short Form, and personality traits (neuroticism and extraversion) with the Eysenck Personality Questionnaire. Result: Lifetime prevalence of smoking decreased across the seven cohorts. Associations between smoking and drug dependence, generalized anxiety, and neuroticism, as well as total psychiatric comorbidity, were greater in more recent cohorts [smoking-by-cohort interaction: p<0.01], with greatest increases contributed by nicotine-dependent smokers. Smoking was also independently associated with alcohol dependence and depression, but these associations did not significantly vary across cohorts. Conclusions: More recent generations included fewer persons who smoked, but their smoking was associated with greater psychiatric morbidity. Failure to account for systematic variation in comorbidity across smoking cohorts may lead to unwanted heterogeneity in clinical, and possibly genetic, studies of nicotine dependence. PMID:24071570

  18. A clinical research analytics toolkit for cohort study.

    PubMed

    Yu, Yiqin; Zhu, Yu; Sun, Xingzhi; Tao, Ying; Zhang, Shuo; Xu, Linhao; Pan, Yue

    2012-01-01

    This paper presents a clinical informatics toolkit that can assist physicians to conduct cohort studies effectively and efficiently. The toolkit has three key features: 1) support of procedures defined in epidemiology, 2) recommendation of statistical methods in data analysis, and 3) automatic generation of research reports. On one hand, our system can help physicians control research quality by leveraging the integrated knowledge of epidemiology and medical statistics; on the other hand, it can improve productivity by reducing the complexities for physicians during their cohort studies.

  19. Data linkage in an established longitudinal cohort: the Western Australian Pregnancy Cohort (Raine) Study.

    PubMed

    Mountain, Jenny A; Nyaradi, Anett; Oddy, Wendy H; Glauert, Rebecca A; de Klerk, Nick H; Straker, Leon M; Stanley, Fiona J

    2016-01-01

    The Western Australian Data Linkage System is one of a few comprehensive, population-based data linkage systems worldwide, creating links between information from different sources relating to the same individual, family, place or event, while maintaining privacy. The Raine Study is an established cohort study with more than 2000 currently active participants. Individual consent was obtained from participants for information in publicly held databases to be linked to their study data. A waiver of consent was granted where it was impracticable to obtain consent. Approvals to link the datasets were obtained from relevant ethics committees and data custodians. The Raine Study dataset was subsequently linked to academic testing data collected by the Western Australian Department of Education. Examination of diet and academic performance showed that children who were predominantly breastfed for at least 6 months scored higher academically at age 10 than children who were breastfed for less than 6 months. A further study found that better diet quality at ages 1, 2 and 3 years was associated with higher academic scores at ages 10 and 12 years. Examination of nutritional intake at 14 years of age found that a better dietary pattern was associated with higher academic performance. The detailed longitudinal data collected in the Raine Study allowed for adjustment for multiple covariates and confounders. Data linkage reduces the burden on cohort participants by providing additional information without the need to contact participants. It can give information on participants who have been lost to follow-up; provide or complement missing data; give the opportunity for validation studies comparing recall of participants with administrative records; increase the population sample of studies by adding control participants from the general population; and allow for the adjustment of multiple covariates and confounders. The Raine Study dataset is extensive and detailed, and can be

  20. Cohort Profile: the Avon Longitudinal Study of Parents and Children: ALSPAC mothers cohort.

    PubMed

    Fraser, Abigail; Macdonald-Wallis, Corrie; Tilling, Kate; Boyd, Andy; Golding, Jean; Davey Smith, George; Henderson, John; Macleod, John; Molloy, Lynn; Ness, Andy; Ring, Susan; Nelson, Scott M; Lawlor, Debbie A

    2013-02-01

    Summary The Avon Longitudinal Study of Children and Parents (ALSPAC) was established to understand how genetic and environmental characteristics influence health and development in parents and children. All pregnant women resident in a defined area in the South West of England, with an expected date of delivery between 1st April 1991 and 31st December 1992, were eligible and 13761 women (contributing 13867 pregnancies) were recruited. These women have been followed over the last 19-22 years and have completed up to 20 questionnaires, have had detailed data abstracted from their medical records and have information on any cancer diagnoses and deaths through record linkage. A follow-up assessment was completed 17-18 years postnatal at which anthropometry, blood pressure, fat, lean and bone mass and carotid intima media thickness were assessed, and a fasting blood sample taken. The second follow-up clinic, which additionally measures cognitive function, physical capability, physical activity (with accelerometer) and wrist bone architecture, is underway and two further assessments with similar measurements will take place over the next 5 years. There is a detailed biobank that includes DNA, with genome-wide data available on >10000, stored serum and plasma taken repeatedly since pregnancy and other samples; a wide range of data on completed biospecimen assays are available. Details of how to access these data are provided in this cohort profile.

  1. Plasma lipid profiling in a large population-based cohort[S

    PubMed Central

    Weir, Jacquelyn M.; Wong, Gerard; Barlow, Christopher K.; Greeve, Melissa A.; Kowalczyk, Adam; Almasy, Laura; Comuzzie, Anthony G.; Mahaney, Michael C.; Jowett, Jeremy B. M.; Shaw, Jonathan; Curran, Joanne E.; Blangero, John; Meikle, Peter J.

    2013-01-01

    We have performed plasma lipid profiling using liquid chromatography electrospray ionization tandem mass spectrometry on a population cohort of more than 1,000 individuals. From 10 μl of plasma we were able to acquire comparative measures of 312 lipids across 23 lipid classes and subclasses including sphingolipids, phospholipids, glycerolipids, and cholesterol esters (CEs) in 20 min. Using linear and logistic regression, we identified statistically significant associations of lipid classes, subclasses, and individual lipid species with anthropometric and physiological measures. In addition to the expected associations of CEs and triacylglycerol with age, sex, and body mass index (BMI), ceramide was significantly higher in males and was independently associated with age and BMI. Associations were also observed for sphingomyelin with age but this lipid subclass was lower in males. Lysophospholipids were associated with age and higher in males, but showed a strong negative association with BMI. Many of these lipids have previously been associated with chronic diseases including cardiovascular disease and may mediate the interactions of age, sex, and obesity with disease risk. PMID:23868910

  2. DRINKING WATER ARSENIC IN UTAH: A COHORT MORTALITY STUDY

    EPA Science Inventory

    The association of drinking water arsenic and mortality outcome was investigated in a cohort of residents from Millard County, Utah. Median drinking water arsenic concentrations for selected study towns ranged from 14 to 166 ppb and were from public and private samples collected ...

  3. Cohort Size and Migration in a West Indian Population.

    ERIC Educational Resources Information Center

    Brittain, Ann W.

    1990-01-01

    Data from St. Barthelemy (French West Indies) show that, for people born from 1878 to 1967, neither cohort size nor fluctuations in external demands for labor had a lasting effect on the probability of eventual migration. Emigration slowed only after development of local tourism brought prosperity to the island. (AF)

  4. A Cohort-Driven Assessment Task for Scientific Report Writing

    ERIC Educational Resources Information Center

    Chuck, Jo-Anne; Young, Lauren

    2004-01-01

    A formative assessment task was developed to improve the scientific report writing skills of university students. Students undertaking this task typically possessed varying levels of scientific literacy and were drawn from a cohort of mixed abilities. The assessment task involved the construction of a scientific report that included feedback from…

  5. Using a Hybrid Approach for a Leadership Cohort Program

    ERIC Educational Resources Information Center

    Norman, Maxine A.

    2013-01-01

    Because information technology continues to change rapidly, Extension is challenged with learning and using technology appropriately. We assert Extension cannot shy away from the challenges but must embrace technology because audiences and external forces demand it. A hybrid, or blended, format of a leadership cohort program was offered to public…

  6. The Unique Governance Challenges of Graduate Contract-Cohort Programs.

    ERIC Educational Resources Information Center

    Dent, Eric B.

    2000-01-01

    The trend for a cohort of employees to participate in management education through their employer's contract with a university raises governance issues: equity between contract and open enrollment students; clash of university and corporate cultures; corporation as stakeholder; excellent employees with poor academic performance; grades used for…

  7. MMed cohort supervision: A path out of the swamp?

    PubMed

    Rout, C; Sommerville, T; Aldous, C

    2015-04-01

    The authors present the case for collaborative cohort supervision (CCM), including both master's students and novice supervisors, as a possible way to rapidly increase the number of supervisors needed to address the recent implementation of a compulsory research component to specialist registration with the Health Professions Council of South Africa. Different models of CCM are discussed and possible pitfalls highlighted.

  8. Spirituality among a College Student Cohort: A Quantitative Assessment

    ERIC Educational Resources Information Center

    Dennis, Dixie; Muller, Susan M.; Miller, Kim; Banerjee, Priya

    2004-01-01

    This study was designed to quantify indices of spirituality, the directing health dimension, which affects health and life satisfaction. Because college marks a time when life patterns are established, a college population was chosen. A cohort of 524 northeastern U.S. college students completed the 48-item Life Attitude Profile-Revised (LAP-R) in…

  9. Exposure Assessment in Cohort Studies of Childhood Asthma

    PubMed Central

    Arrandale, Victoria H.; Brauer, Michael; Brook, Jeffrey R.; Brunekreef, Bert; Gold, Diane R.; London, Stephanie J.; Miller, J. David; Özkaynak, Halûk; Ries, Nola M.; Sears, Malcolm R.; Silverman, Frances S.; Takaro, Tim K.

    2011-01-01

    Background The environment is suspected to play an important role in the development of childhood asthma. Cohort studies are a powerful observational design for studying exposure–response relationships, but their power depends in part upon the accuracy of the exposure assessment. Objective The purpose of this paper is to summarize and discuss issues that make accurate exposure assessment a challenge and to suggest strategies for improving exposure assessment in longitudinal cohort studies of childhood asthma and allergies. Data synthesis Exposures of interest need to be prioritized, because a single study cannot measure all potentially relevant exposures. Hypotheses need to be based on proposed mechanisms, critical time windows for effects, prior knowledge of physical, physiologic, and immunologic development, as well as genetic pathways potentially influenced by the exposures. Modifiable exposures are most important from the public health perspective. Given the interest in evaluating gene–environment interactions, large cohort sizes are required, and planning for data pooling across independent studies is critical. Collection of additional samples, possibly through subject participation, will permit secondary analyses. Models combining air quality, environmental, and dose data provide exposure estimates across large cohorts but can still be improved. Conclusions Exposure is best characterized through a combination of information sources. Improving exposure assessment is critical for reducing measurement error and increasing power, which increase confidence in characterization of children at risk, leading to improved health outcomes. PMID:21081299

  10. Constructing Alternate Assessment Cohorts: An Oregon Perspective. Research Brief 3

    ERIC Educational Resources Information Center

    Saven, Jessica L.; Farley, Dan; Tindal, Gerald

    2013-01-01

    Longitudinally modeling the growth of students with significant cognitive disabilities (SWSCDs) on alternate assessments based on alternate achievement standards (AA-AAS) presents many challenges for states. The number of students in Grades 3-8 who remain in a cohort group varies over time, depending on the methods used to construct the…

  11. FY 1995 Cohort Default Rates for Originating Lenders/Holders.

    ERIC Educational Resources Information Center

    Office of Postsecondary Education (ED), Washington, DC.

    This report provides data on fiscal year 1995 cohort default rates for lending institutions and loan holders with 30 or more borrowers in repayment, calculated from data reported to the National Student Loan Data System by guaranty agencies. Types of loans covered include subsidized Federal Stafford, unsubsidized Federal Stafford, Federal…

  12. Using the whole cohort in the analysis of countermatched samples.

    PubMed

    Rivera, C; Lumley, T

    2016-06-01

    We present a technique for using calibrated weights to incorporate whole-cohort information in the analysis of a countermatched sample. Following Samuelsen's approach for matched case-control sampling, we derive expressions for the marginal sampling probabilities, so that the data can be treated as an unequally-sampled case-cohort design. Pseudolikelihood estimating equations are used to find the estimates. The sampling weights can be calibrated, allowing all whole-cohort variables to be used in estimation; in contrast, the partial likelihood analysis makes use only of a single discrete surrogate for exposure. Using a survey-sampling approach rather than a martingale approach simplifies the theory; in particular, the sampling weights need not be a predictable process. Our simulation results show that pseudolikelihood estimation gives lower efficiency than partial likelihood estimation, but that the gain from calibration of weights can more than compensate for this loss. If there is a good surrogate for exposure, countermatched sampling still outperforms case-cohort and two-phase case-control sampling even when calibrated weights are used. Findings are illustrated with data from the National Wilms' Tumour Study and the Welsh nickel refinery workers study. PMID:26393818

  13. Socioeconomic Status and Injury in a Cohort of Saskatchewan Farmers

    ERIC Educational Resources Information Center

    Pickett, William; Day, Andrew G.; Hagel, Louise; Sun, Xiaoqun; Day, Lesley; Marlenga, Barbara; Brison, Robert J.; Pahwa, Punam; Crowe, Trever; Voaklander, Donald C.; Dosman, James

    2011-01-01

    Purpose: To estimate the strength of relationships between socioeconomic status and injury in a large Canadian farm population. Methods: We conducted a prospective cohort study of 4,769 people from 2,043 farms in Saskatchewan, Canada. Participants reported socioeconomic exposures in 2007 and were followed for the occurrence of injury through 2009…

  14. Cohort follow-up: the 21st century procedures.

    PubMed

    Bahr, Debra E; Hughes, Therese; Aldrich, Timothy E; Silver, Kenneth Z; Brion, Gall M

    2009-01-01

    The basic logic of designing an occupational cohort study has changed little since William R. Gaffey outlined the issues of follow-up, measurement of exposure, and analysis of data. However, many new avenues of tracking workers for epidemiological studies have been developed since Gaffey wrote his paper in 1973. Many disease registries also perform follow-up of subjects for vital status determination, so the procedures used with this process are common to the two applications. This article speaks to cohort construction for this occupational research as well as describes the 2007 methods for vital status follow-up. Rises in concern about work-related disease risks and the scientific resources for performing these studies coincided with the computer revolution. Government and private sources of data on vital status have changed in several ways over the 35 years since Gaffey's seminal paper. Some systems make the process of follow-up more rapid and productive, and some barriers have been imposed as societal concerns for privacy have risen. We describe the process of linking 5 sources of data to compile a roster of 6,820 workers employed at the Paducah Gaseous Diffusion Plant from 1953 to 2003. The record linkage processes achieved a final death cohort of 1672 deaths--the ascertainment of these deaths (by time period) was 1379 (1979-2003) and 293 (1953-1978); follow-up then was 100% for this cohort.

  15. Investing in Prospective Cohorts for Etiologic Study of Occupational Exposures

    EPA Science Inventory

    Prospective cohorts have played a major role in understanding the role of diet, physical activity, medical conditions, and genes in the development of many diseases, but have not been widely used in the study of occupational exposures. Studies in agriculture are an exception. W...

  16. Realising e-Learning Matters in a Bioscience Cohort

    ERIC Educational Resources Information Center

    Parry, Damian; Larsen, Carl; Marwood, Simon; Walsh, Cathy

    2007-01-01

    The use of blended learning, face-to-face contact alongside e-based activities, provides academic staff with an opportunity to match their teaching strategies with the changing student cohort. This study report students' perceptions of e-learning activities early in bioscience modules; students from all three levels of undergraduate study were…

  17. Working Adults in Accelerated Cohorts: More than a Learning Community

    ERIC Educational Resources Information Center

    Spaid, Robin; Duff, Evan D.

    2009-01-01

    There are 54 million working adults in the United States without bachelor's degrees (Pusser et al., 2007). Many would like to obtain a college degree but need an educational program that fits their needs. A viable alternative to a traditional college program is an accelerated program in a cohort format. This article highlights best practices for…

  18. Motor disability in children in three birth cohorts.

    PubMed

    Rumeau-Rouquette, C; du Mazaubrun, C; Mlika, A; Dequae, L

    1992-04-01

    A systematic registration was carried out in 1985-1986 and 1989 in 14 French 'departments' in order to assess whether the prevalence rates of different components of motor disability (MD) in three different birth cohorts (1972, 1976 and 1981) had changed at a time when the preterm birth rate and neonatal mortality were decreasing and there was evidence of changing perinatal practice. A total of 1355 MD were registered amongst resident children born in 1972, 1976 and 1981 with a prevalence of 3.34 per 1000. The prevalence of the MD types due to different causes did not differ significantly amongst the three birth cohorts with the exception of an excess of hereditary and degenerative disease of the central nervous system (CNS) among children born in 1981. The prevalence of cerebral palsy (CP) remained stable in the three birth cohorts: it was 1.30, 1.06 and 1.08 per 1000 respectively, for children born in 1972, 1976 and 1981. The prevalence of pre- or perinatal-origin of other motor disabilities (OMD) and of CNS malformations did not differ amongst the three birth cohorts. The method of registration is discussed and the results are related to those of the French perinatal surveys performed in 1972, 1976 and 1981, which showed a decrease in preterm birthrate, an increase in perinatal care and a decrease in the mortality rate of high-risk infants. PMID:1428493

  19. Survey of motivation to participate in a birth cohort.

    PubMed

    Yamamoto, Midori; Fujita, Misuzu; Mori, Chisato; Hata, Akira

    2016-09-01

    For a longitudinal prospective cohort study to be successful, participants' motivation to provide information must be maintained. Therefore, this study aimed to identify items that effectively promote participants' motivation. Questionnaires were mailed to 4541 mothers and expectant mothers in Chiba Prefecture, Japan who participated in a nationwide birth cohort. A total of 2387 (52.6%) responses were received. The following items were identified as primary motivating factors among our cohort: "benefits to the participants' children", "monetary compensation" and "contribution to a better future environment". More than 30% of the respondents expressed a lack of understanding regarding the study purpose and requirements for participation. About 14% were concerned about the leakage of personal information, and 13% felt burdened by having to make a long-term commitment to the study. Cluster analysis identified four groups, two of which, one with extremely low levels of motivation and the other motivated by only money or goods, lacked an understanding of the study and tended to be concerned about the associated risks and burdens. Participants in these groups were considered to be at a high risk of dropout. Therefore, implementing measures to provide participants with a better understanding of cohort studies could lead to more successful results.

  20. RISK FACTORS FOR ENDEMIC GASTROINTESTINAL ILLNESS AMONG A WASHINGTON COHORT

    EPA Science Inventory

    RISK FACTORS FOR ENDEMIC GASTROINTESTINAL ILLNESS AMONG A WASHINGTON COHORT

    *Christina A. Peterson 1,2,3 and Rebecca L. Calderon 2

    1 Department of Epidemiology
    School of Public Health (SPH)
    University of North Carolina at Chapel Hill (UNC-CH), 27516
    2 Nat...

  1. Tinned Fruit Consumption and Mortality in Three Prospective Cohorts

    PubMed Central

    Aasheim, Erlend T.; Sharp, Stephen J.; Appleby, Paul N.; Shipley, Martin J.; Lentjes, Marleen A. H.; Khaw, Kay-Tee; Brunner, Eric; Key, Tim J.; Wareham, Nicholas J.

    2015-01-01

    Dietary recommendations to promote health include fresh, frozen and tinned fruit, but few studies have examined the health benefits of tinned fruit. We therefore studied the association between tinned fruit consumption and mortality. We followed up participants from three prospective cohorts in the United Kingdom: 22,421 participants from the European Prospective Investigation into Cancer and Nutrition (EPIC)-Norfolk cohort (1993–2012), 52,625 participants from the EPIC-Oxford cohort (1993–2012), and 7440 participants from the Whitehall II cohort (1991–2012), all reporting no history of heart attack, stroke, or cancer when entering these studies. We estimated the association between frequency of tinned fruit consumption and all cause mortality (primary outcome measure) using Cox regression models within each cohort, and pooled hazard ratios across cohorts using random-effects meta-analysis. Tinned fruit consumption was assessed with validated food frequency questionnaires including specific questions about tinned fruit. During 1,305,330 person years of follow-up, 8857 deaths occurred. After adjustment for lifestyle factors and risk markers the pooled hazard ratios (95% confidence interval) of all cause mortality compared with the reference group of tinned fruit consumption less often than one serving per month were: 1.05 (0.99, 1.12) for one to three servings per month, 1.10 (1.03, 1.18) for one serving per week, and 1.13 (1.04, 1.23) for two or more servings per week. Analysis of cause-specific mortality showed that tinned fruit consumption was associated with mortality from cardiovascular causes and from non-cardiovascular, non-cancer causes. In a pooled analysis of three prospective cohorts from the United Kingdom self-reported tinned fruit consumption in the 1990s was weakly but positively associated with mortality during long-term follow-up. These findings raise questions about the evidence underlying dietary recommendations to promote tinned fruit

  2. Tinned fruit consumption and mortality in three prospective cohorts.

    PubMed

    Aasheim, Erlend T; Sharp, Stephen J; Appleby, Paul N; Shipley, Martin J; Lentjes, Marleen A H; Khaw, Kay-Tee; Brunner, Eric; Key, Tim J; Wareham, Nicholas J

    2015-01-01

    Dietary recommendations to promote health include fresh, frozen and tinned fruit, but few studies have examined the health benefits of tinned fruit. We therefore studied the association between tinned fruit consumption and mortality. We followed up participants from three prospective cohorts in the United Kingdom: 22,421 participants from the European Prospective Investigation into Cancer and Nutrition (EPIC)-Norfolk cohort (1993-2012), 52,625 participants from the EPIC-Oxford cohort (1993-2012), and 7440 participants from the Whitehall II cohort (1991-2012), all reporting no history of heart attack, stroke, or cancer when entering these studies. We estimated the association between frequency of tinned fruit consumption and all cause mortality (primary outcome measure) using Cox regression models within each cohort, and pooled hazard ratios across cohorts using random-effects meta-analysis. Tinned fruit consumption was assessed with validated food frequency questionnaires including specific questions about tinned fruit. During 1,305,330 person years of follow-up, 8857 deaths occurred. After adjustment for lifestyle factors and risk markers the pooled hazard ratios (95% confidence interval) of all cause mortality compared with the reference group of tinned fruit consumption less often than one serving per month were: 1.05 (0.99, 1.12) for one to three servings per month, 1.10 (1.03, 1.18) for one serving per week, and 1.13 (1.04, 1.23) for two or more servings per week. Analysis of cause-specific mortality showed that tinned fruit consumption was associated with mortality from cardiovascular causes and from non-cardiovascular, non-cancer causes. In a pooled analysis of three prospective cohorts from the United Kingdom self-reported tinned fruit consumption in the 1990s was weakly but positively associated with mortality during long-term follow-up. These findings raise questions about the evidence underlying dietary recommendations to promote tinned fruit consumption

  3. Environmental Variation and Cohort Effects in an Antarctic Predator

    NASA Technical Reports Server (NTRS)

    Garrott, Robert A.; Rotella, Jay J.; Siniff, Donald B.; Parkinson, Claire L.; Stauffer, Glenn E.

    2011-01-01

    Understanding the potential influence of environmental variation experienced by animals during early stages of development on their subsequent demographic performance can contribute to our understanding of population processes and aid in predicting impacts of global climate change on ecosystem functioning. Using data from 4,178 tagged female Weddell seal pups born into 20 different cohorts, and 30 years of observations of the tagged seals, we evaluated the hypothesis that environmental conditions experienced by young seals, either indirectly through maternal effects and/or directly during the initial period of juvenile nutritional independence, have long-term effects on individual demographic performance. We documented an approximately 3-fold difference in the proportion of each cohort that returned to the pupping colonies and produced a pup within the first 10 years after birth. We found only weak evidence for a correlation between annual environmental conditions during the juvenile-independence period and cohort recruitment probability. Instead, the data strongly supported an association between cohort recruitment probability and the regional extent of sea ice experienced by the mother during the winter the pup was in utero. We suggest that inter-annual variation in winter sea-ice extent influences the foraging success of pregnant seals by moderating the regional abundance of competing predators that cannot occupy areas of consolidated sea ice, and by directly influencing the abundance of mid-trophic prey species that are sea-ice obligates. We hypothesize that this environmentally-induced variation in maternal nutrition dictates the extent of maternal energetic investment in offspring, resulting in cohort variation in mean size of pups at weaning which, in turn, contributes to an individual?s phenotype and its ultimate fitness. These linkages between sea ice and trophic dynamics, combined with demonstrated and predicted changes in the duration and extent of sea

  4. Epilepsy in adults with mitochondrial disease: A cohort study

    PubMed Central

    Devine, Helen E.; Gorman, Grainne S.; Schaefer, Andrew M.; Horvath, Rita; Ng, Yi; Nesbitt, Victoria; Lax, Nichola Z.; McFarland, Robert; Cunningham, Mark O.; Taylor, Robert W.; Turnbull, Douglass M.

    2015-01-01

    Objective The aim of this work was to determine the prevalence and progression of epilepsy in adult patients with mitochondrial disease. Methods We prospectively recruited a cohort of 182 consecutive adult patients attending a specialized mitochondrial disease clinic in Newcastle upon Tyne between January 1, 2005 and January 1, 2008. We then followed this cohort over a 7‐year period, recording primary outcome measures of occurrence of first seizure, status epilepticus, stroke‐like episode, and death. Results Overall prevalence of epilepsy in the cohort was 23.1%. Mean age of epilepsy onset was 29.4 years. Prevalence varied widely between genotypes, with several genotypes having no cases of epilepsy, a prevalence of 34.9% in the most common genotype (m.3243A>G mutation), and 92.3% in the m.8344A>G mutation. Among the cohort as a whole, focal seizures, with or without progression to bilateral convulsive seizures, was the most common seizure type. Conversely, all of the patients with the m.8344A>G mutation and epilepsy experienced myoclonic seizures. Patients with the m.3243A>G mutation remain at high risk of developing stroke‐like episodes (1.16% per year). However, although the standardized mortality ratio for the entire cohort was high (2.86), this ratio did not differ significantly between patients with epilepsy (2.96) and those without (2.83). Interpretation Epilepsy is a common manifestation of mitochondrial disease. It develops early in the disease and, in the case of the m.3243A>G mutation, often presents in the context of a stroke‐like episode or status epilepticus. However, epilepsy does not itself appear to contribute to the increased mortality in mitochondrial disease. Ann Neurol 2015;78:949–957 PMID:26381753

  5. The Lisbon Cohort of men who have sex with men

    PubMed Central

    Meireles, Paula; Lucas, Raquel; Martins, Ana; Carvalho, Ana Cláudia; Fuertes, Ricardo; Brito, João; Campos, Maria José; Mendão, Luís; Barros, Henrique

    2015-01-01

    Purpose Newly diagnosed HIV infections among men who have sex with men (MSM) are rising in many European countries. Surveillance tools must be tailored to the current state of the epidemic, and include decentralised prospective monitoring of HIV incidence and behavioural changes in key populations. In this scenario, an open prospective cohort study was assembled—The Lisbon Cohort of MSM—aiming to dynamically monitor the frequency of disease and its predictors. Participants The Lisbon Cohort of MSM is an ongoing observational prospective study conducted at a community-based voluntary HIV counselling and testing centre in Lisbon, Portugal (CheckpointLX). Men testing negative for HIV, aged 18 or over and reporting having had sex with men are invited to follow-up visits every 6 months. At each evaluation, a face-to-face interview using a structured questionnaire is conducted, and HIV and syphilis rapid tests are performed by trained peer counsellors. From April 2011 to February 2014, 3106 MSM were eligible to the cohort of whom 923 (29.7%) did not participate. The remaining 2183 (70.3%) MSM were enrolled and 804 had at least one follow-up evaluation, for a total of 893 person-years of observation. Future plans The study findings will be disseminated in peer-reviewed journals and presented at national and international conferences. The follow-up of this cohort of HIV-negative MSM will be a valuable tool for monitoring HIV incidence in a setting where limited prospective information existed. Moreover, it will allow for a deeper analytical approach to the study of population time trends and individual changes in risk factors that currently shape the HIV epidemic among MSM. PMID:25967995

  6. Mysid Population Responses to Resource Limitation Differ from those Predicted by Cohort Studies

    EPA Science Inventory

    Effects of anthropogenic stressors on animal populations are often evaluated by assembling vital rate responses from isolated cohort studies into a single demographic model. However, models constructed from cohort studies are difficult to translate into ecological predictions be...

  7. Fragmentary Cohorts, Full Cohorts, and the Placement/Course Level Match in Remedial Mathematics Courses among Urban Community College Students

    ERIC Educational Resources Information Center

    Maxwell, William; Hagedorn, Linda Serra; Cypers, Scott; Lester, Jaime; Moon, Hye

    2004-01-01

    This paper is an exploratory description of remedial coursetaking over several semesters. In attempting to characterize the introductory course classrooms of urban community colleges, it proposes a distinction between fragmentary and full cohorts. Also proposed is a concept little examined in community colleges, the placement/course level match,…

  8. Ten years of progress in the Hokkaido birth cohort study on environment and children's health: cohort profile--updated 2013.

    PubMed

    Kishi, Reiko; Kobayashi, Sachiko; Ikeno, Tamiko; Araki, Atsuko; Miyashita, Chihiro; Itoh, Sachiko; Sasaki, Seiko; Okada, Emiko; Kobayashi, Sumitaka; Kashino, Ikuko; Itoh, Kumiko; Nakajima, Sonomi

    2013-11-01

    The Hokkaido Study on Environment and Children's Health is an ongoing cohort study that began in 2002. The study consists of two prospective birth cohorts, the Sapporo cohort (n = 514) and the Hokkaido large-scale cohort (n = 20,940). The primary goals of this study are to first examine the potential negative effects of perinatal environmental chemical exposures on birth outcomes, including congenital malformations and growth retardation; second, to evaluate the development of allergies, infectious diseases and neurodevelopmental disorders and perform longitudinal observations of the children's physical development to clarify the causal relationship between these outcomes and environmental chemicals; third, to identify individuals genetically susceptible to environmental chemicals; finally, to identify the additive effects of various environmental factors in our daily life, such as secondhand smoke exposure or low folate intake during early pregnancy. In this paper, we introduce our recent progress in the Hokkaido study with a cohort profile updated in 2013. For the last ten years, we followed pregnant women and their offspring, measuring various environmental chemicals, i.e., PCB, OH-PCB and dioxins, PFCs (Perfluorinated Compounds), Organochlorine pesticides, Phthalates, bisphenol A and mercury. We discovered that the concentration of toxic equivalents (TEQ) of dioxin and other specific congeners of PCDF or PCDD have effects on birth weight, infants' neurodevelopment and immune function. There were significant gender differences in these effects; our results suggest that male infants have more susceptibility to those chemical exposures than female infants. Interestingly, we found maternal genetic polymorphisms in AHR, CYP1A1 or GSTs that significantly modified the dioxin concentrations in maternal blood, suggesting different dioxin accumulations in the bodies of individuals with these genotypes, which would lead to different dioxin exposure levels. These genetic

  9. Pre-Service Teacher Cohorts: Characteristics and Issues--A Review of the Literature

    ERIC Educational Resources Information Center

    Knorr, Ron

    2012-01-01

    Since their introduction to teacher education programs in the 1980s, teacher education cohorts have become a standard scheme of organization in teacher preparation programs. This literature review notes some common characteristics and issues in cohort operations. Cohorts contain a standard academic core, class scheduling, and timeline to program…

  10. Counselors-in-Training Perceptions of Cohort Participation: A Q-Sort

    ERIC Educational Resources Information Center

    Glorfield, Cyndia K.

    2011-01-01

    This study explored master's level counselors-in-training perceptions of participation in a cohort model of education. Although the cohort model of education is widely used, research addressing its use in counselor education is scant. Literature regarding the cohort model of education from a variety of higher education programs was reviewed to…

  11. 34 CFR 668.183 - Calculating and applying cohort default rates.

    Code of Federal Regulations, 2010 CFR

    2010-07-01

    ... four steps that we follow to calculate and apply your cohort default rate for a fiscal year: (1) First, under paragraph (b) of this section, we identify the borrowers in your cohort for the fiscal year. If... cohorts for the 2 most recent prior fiscal years. (2) Second, under paragraph (c) of this section,...

  12. Comment: Distinguishing Cohort Effects from Age*Period Effects on Non-Marital Fertility

    ERIC Educational Resources Information Center

    Martin, Steve

    2009-01-01

    In the article "Cohort Effects on Non-marital Fertility," in this issue of "Social Forces," Jean Stockard employs a novel strategy for disentangling cohort, period, and age effects on the non-marital fertility ratio. In a model with fixed-effect controls for age and for time period, the author documents evidence for three cohort-specific factors…

  13. Developmental Models for Time of Testing x Cohort x Grade (Age) Research Designs.

    ERIC Educational Resources Information Center

    Williams, John Delane

    Missing data for a given cohort of students in a longitudinal study occurs for at least two reasons: either the student has moved or otherwise become unavailable for testing, or the cohort was not in the testing range at a given testing time. A developmental sampling for time of testing x cohort x grade research plan of testing is used to…

  14. When a College Class Becomes a Mob: Coping with Student Cohorts

    ERIC Educational Resources Information Center

    Hubbell, Larry; Hubbell, Kelly

    2010-01-01

    This article is a theoretical, experiential and reflective analysis of potential problems that may arise when teaching cohorts of students. Although more often than not teaching cohorts of students can be a fulfilling experience, the authors have, on occasion, taught cohort groups that were challenging. The authors speculate whether this…

  15. Cohort Differences in Cognitive Aging and Terminal Decline in the Seattle Longitudinal Study

    ERIC Educational Resources Information Center

    Gerstorf, Denis; Ram, Nilam; Hoppmann, Christiane; Willis, Sherry L.; Schaie, K. Warner

    2011-01-01

    Life span researchers have long been interested in how and why fundamental aspects of human ontogeny differ between cohorts of people who have lived through different historical epochs. When examined at the same age, later born cohorts are often cognitively and physically fitter than earlier born cohorts. Less is known, however, about cohort…

  16. Race Differences in Cohort Effects on Non-Marital Fertility in the United States

    ERIC Educational Resources Information Center

    Stockard, Jean; Gray, Jo Anna; O'Brien, Robert; Stone, Joe

    2009-01-01

    We employ newly developed methods to disentangle age, period and cohort effects on non-marital fertility ratios from 1972 through 2002 for black and white women ages 20-44 in the United States. We focus on three cohort factors: family structure, school enrollment and the sex ratio. For both blacks and whites, cohorts with less traditional family…

  17. 34 CFR 668.205 - Notice of your official cohort default rate.

    Code of Federal Regulations, 2010 CFR

    2010-07-01

    ... 34 Education 3 2010-07-01 2010-07-01 false Notice of your official cohort default rate. 668.205... § 668.205 Notice of your official cohort default rate. (a) We electronically notify you of your cohort... default rate calculated as an average rate, you will receive a loan record detail report as part of your...

  18. Cohorts based on Decade of Death: No Evidence for Secular Trends Favoring Later Cohorts in Cognitive Aging and Terminal Decline in the AHEAD Study

    PubMed Central

    Hülür, Gizem; Infurna, Frank J.; Ram, Nilam; Gerstorf, Denis

    2012-01-01

    Studies of birth-year cohorts examined over the same age range often report secular trends favoring later-born cohorts, who are cognitively fitter and show less steep cognitive declines than earlier-born cohorts. However, there is initial evidence that those advantages of later-born cohorts do not carry into the last years of life, suggesting that pervasive mortality-related processes minimize differences that were apparent earlier in life. Elaborating this work from an alternative perspective on cohort differences, we compared rates of cognitive aging and terminal decline in episodic memory between cohorts based on the year participants had died, earlier (between 1993 and 1999) or later in historical time (between 2000 and 2010). Specifically, we compared trajectories of cognitive decline in two death-year cohorts of participants in the Asset and Health Dynamics among the Oldest Old (AHEAD) Study that were matched on age at death and education and controlled for a variety of additional covariates. Results revealed little evidence of secular trends favoring later cohorts. To the contrary, the cohort that died in the 2000s showed a less favorable trajectory of age-related memory decline than the cohort who died in the 1990s. In examinations of change in relation to time-to-death, the cohort dying in the 2000s experienced even steeper terminal declines than the cohort dying in the 1990s. We suggest that secular increases in “manufacturing” survival may exacerbate age- and mortality-related cognitive declines among the oldest old. PMID:23046001

  19. “Antihemophilic factor is not the only answer for all factor VIII deficiencies.” Case report of odontogenic infection in a patient with hemophilia A, complicated by factor VIII inhibitors, and managed by transfusion of antihemophilic factor and factor VIII inhibitor bypass activity

    PubMed Central

    Sudheesh, K. M.; Bharani, K. S. N. Siva; Kiran, H. Y.; Hanagavadi, Suresh

    2016-01-01

    Dental extraction in hemophiliacs with acquired inhibitors is always a risky procedure, which often presents a lot of problems associated with bleeding. A known case of hemophilia A complicated with factor VIII inhibitors and having odontogenic infection was successfully managed by transfusion of factor VIII inhibitor bypass activity (FEIBA) and antihemophilic factor. Past medical history was significant for multiple factor VIII transfusions. Bethesda assay done to identify inhibitors revealed low titer factor VIII inhibitors. Extraction of the involved tooth was done after transfusion of FEIBA with low-dose protocols. Minimal bleeding was noted after extraction which was controlled by local measures. FEIBA was proven to be highly effective, and no side effects of the product were observed.

  20. A cohort study on the mortality of firefighters.

    PubMed Central

    Hansen, E S

    1990-01-01

    This study was set up to investigate the effect of exposure to combustion effluents on the chronic health of firefighters. A cohort of firefighters was followed up through 10 years with regard to cause specific mortality. Comparisons were made with another cohort of civil servants and salaried employees in physically demanding jobs. After a latency of five years, an excess mortality from cancer was seen for persons aged 30 to 74 (standardised mortality ratio (SMR) 173, 95% confidence interval (95% CI) 104-270). A significant increase in lung cancer was seen in the group aged 60 to 74 (SMR 317, 95% CI 117-691), whereas non-pulmonary cancer was significantly increased in the group aged 30 to 49 (SMR 575, 95% CI 187-1341). It is concluded that inhalation of carcinogenic and toxic compounds during firefighting may constitute an occupational cancer risk. An extended use of respiratory protective equipment is advocated. PMID:2271386