Batty P.,The Royal London Hospital Haemophilia Center |
Austin S.K.,Haemophilia Center |
Austin S.K.,St Thomas Hospital |
Khair K.,Great Ormond Street Haemophilia Center |
And 7 more authors.
British Journal of Haematology | Year: 2017
Inhibitor formation in non-severe haemophilia A is a life-long risk and associated with morbidity and mortality. There is a paucity of data to understand real-world inhibitor screening practice. We evaluated the treatment burden, haemostatic strategies, F8 genotyping and inhibitor screening practices in non-severe haemophilia A in seven London haemophilia centres. In the 2-year study period, 44% (377/853) patients received at least one haemostatic treatment. Seventy-nine percent of those treated (296/377) received factor VIII (FVIII) concentrate. F8 genotype was known in 88% (331/377) of individuals. Eighteen per cent (58/331) had ‘high-risk’ F8 genotypes. In patients with ‘standard-risk’ F8 genotypes treated on-demand with FVIII concentrate, 51·3% episodes (243/474) were screened within 1 year. However, poor screening compliance was observed after ‘high-risk’ treatment episodes. In patients with ‘standard-risk’ F8 genotypes, 12·3% (28/227) of treatment episodes were screened in the subsequent 6 weeks after surgery or a bleed requiring ≥5 exposure days. Similarly, in the context of ‘high-risk’ F8 genotypes after any FVIII exposure, only 13·6% (12/88) of episodes were screened within 6 weeks. Further study is required to assess optimal practice of inhibitor screening in non-severe haemophilia A to inform subsequent clinical decisions and provide more robust prevalence data to further understand the underlying immunological mechanism. © 2017 John Wiley & Sons Ltd
PubMed | Galliera Hospital, anchi Bonomi Hemophilia and Thrombosis Center, Policlinico Universitario Of Palermo And Uoc Ematologia Con Utmo, McMaster University and 6 more.
Type: Journal Article | Journal: The Lancet. Haematology | Year: 2016
Little information is available about the clinical history of patients with incidentally detected splanchnic vein thrombosis and its therapeutic management remains controversial. The aim of this study was to assess the risk factors, therapeutic strategies, and long-term outcomes of incidentally detected splanchnic vein thrombosis.We analysed data from patients with incidentally detected splanchnic vein thrombosis who were enrolled in an international, multicentre, prospective cohort study of splanchnic vein thrombosis between 2008 and 2012. The study was done at 31 centres in 11 countries (Italy, South Korea, Germany, Canada, Belgium, the Netherlands, Brazil, USA, France, Israel, UK). Information about demographic characteristics, risk factors, and treatment was collected. The study outcomes during the 2-year follow-up were major bleeding (International Society on Thrombosis and Haemostasis definition plus the need for hospital admission), thrombotic events (venous or arterial thromboses), and mortality. The primary analysis period was from the diagnosis of incidentally detected splanchnic vein thrombosis until the first adjudicated clinical outcome or the end of follow-up.Between May 2, 2008, and Jan 30, 2012, we enrolled 177 patients with incidentally detected splanchnic vein thrombosis (median age 57 years [IQR 49-66], 118 [67%] men, 138 [78%] patients with portal vein thrombosis). The most common underlying diseases were liver cirrhosis (82 [46%] patients) and solid cancer (62 [35%] patients). Anticoagulant treatment was prescribed to 109 (62%) patients. Median duration of anticoagulation was 6 months (IQR 5-12) for patients who received parenteral anticoagulants alone and 24 months (IQR 12-24) for patients treated with vitamin K antagonists. During a median follow-up of 2 years (IQR 1-2), the incidence of major bleeding was 33 events (95% CI 17-63) per 100 patient-years and the incidence of thrombotic events was 80 events (95% CI 52-121) per 100 patient-years. On-treatment incidence was 32 events (95% CI 12-84) per 100 patient-years for major bleeding and 39 events (95% CI 16-95) per 100 patient-years for thrombotic events. In multivariate analysis, anticoagulant treatment as a time-dependent variable reduced the incidence of thrombotic events (hazard ratio 085, 95% CI 076-096) without increasing the risk of major bleeding (p>005). In patients with clinically suspected splanchnic vein thrombosis, the incidence of major bleeding was 39 events (95% CI 26-57) per 100 patient-years and the incidence of thrombotic events was 70 events (95% CI 52-93) per 100 patient-years.Our results show that the prognosis of incidentally detected splanchnic vein thrombosis is similar to that of clinically suspected splanchnic vein thrombosis and suggest that similar treatment strategies should be applied.Pfizer Canada research grant.
Keeney S.,Royal Infirmary |
Collins P.,University of Cardiff |
Cumming A.,Royal Infirmary |
Goodeve A.,Sheffield Childrens NHS Foundation Trust |
Pasi J.,Haemophilia Center
Seminars in Thrombosis and Hemostasis | Year: 2011
The UK treatment strategy for von Willebrand disease (VWD) is based on consensus guidelines produced by the United Kingdom Haemophilia Centre Doctors' Organization (UKHCDO) relating to the diagnosis and management of VWD. Selection of therapeutic products suitable for treatment of this complex inherited bleeding disorder is based on the observed response. Desmopressin (DDAVP), an analog of vasopressin, is the recommended treatment in individuals who respond to this drug on trial infusion. DDAVP clearly has no effect in type 3 VWD but may have variable clinical effect in individuals with other subtypes or may be contraindicated in some cases. In patients where DDAVP treatment is unsuitable, replacement factor concentrate containing von Willebrand factor (VWF) is the recommended alternative. Relevant concentrates are available for all patients in the United Kingdom, and treatment is administered by a network of 67 hemophilia treatment centers that also provide specialist care for individuals diagnosed with VWD. Patients diagnosed with the condition are registered on a national inherited bleeding disorder database administered by the UKHCDO on behalf of the Department of Health to aid in service planning and commissioning. Genetic testing is employed in the United Kingdom in certain situations, which is also performed in accordance with current UKHCDO guidelines. © 2011 by Thieme Medical Publishers, Inc.
Wilde J.T.,University of Birmingham |
Mutimer D.,University of Birmingham |
Dolan G.,Haemophilia Center |
Millar C.,Hammersmith Hospital |
And 3 more authors.
Haemophilia | Year: 2011
Chronic HCV infection continues to be of significant clinical importance in patients with hereditary bleeding disorders. This guideline provides information on the recent advances in the investigation and treatment of HCV infection and gives GRADE system based recommendations on the management of the infection in this patient group. © 2011 Blackwell Publishing Ltd.
Chowdary P.,Royal Free Hospital |
Lethagen S.,Novo Nordisk AS |
Lethagen S.,Copenhagen University |
Friedrich U.,Novo Nordisk AS |
And 11 more authors.
Journal of Thrombosis and Haemostasis | Year: 2015
Background: Prophylaxis with either intravenous (i.v.) factor VIII (FVIII) or FIX is the gold standard of care for patients with severe hemophilia. A monoclonal antibody (concizumab) targeting tissue factor pathway inhibitor (TFPI) that can be administered subcutaneously (s.c.) has the potential to alter current concepts of prophylaxis in hemophilia. Objectives: To evaluate the safety and describe the pharmacokinetics and pharmacodynamics of single-dose concizumab in healthy volunteers and patients with hemophilia A or B. Methods: In this first human dose, phase 1, multicenter, randomized, double-blind, placebo-controlled trial escalating single i.v. (0.5-9000 μg kg-1) or s.c. (50-3000 μg kg-1) doses of concizumab were administered to healthy volunteers (n = 28) and hemophilia patients (n = 24). Results: Concizumab had a favorable safety profile after single i.v. or s.c. administration. There were no serious adverse events and no anti-concizumab antibodies. No clinically relevant changes in platelets, prothrombin time, activated partial thromboplastin time, fibrinogen, or antithrombin were found. A dose-dependent procoagulant effect of concizumab was seen as increased levels of D-dimers and prothrombin fragment 1 + 2. Nonlinear pharmacokinetics of concizumab was observed due to target-mediated clearance. A maximum mean AUC0-∞ of 33 960 h μg mL-1 and a maximum mean concentration of 247 μg mL-1 was measured at the highest dose. Conclusions: Concizumab showed a favorable safety profile after i.v. or s.c. administration and nonlinear pharmacokinetics was observed due to target-mediated clearance. A concentration-dependent procoagulant effect of concizumab was observed, supporting further study into the potential use of s.c. concizumab for hemophilia treatment. © 2015 The Authors. Journal of Thrombosis and Haemostasis published by Wiley Periodicals, Inc. on behalf of International Society on Thrombosis and Haemostasis.
Collins P.W.,University of Cardiff |
Young G.,University of Southern California |
Knobe K.,Novo Nordisk AS |
Karim F.A.,Haemophilia Center |
And 9 more authors.
Blood | Year: 2014
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 episodeswere 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 associatedwith low ABRs in patients receiving prophylaxis.Once-weekly prophylaxiswith 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. © 2014 by The American Society of Hematology.
PubMed | Ogikubo Hospital, University Claude Bernard Lyon 1, Haemophilia Center, Novo Nordisk AS and 3 more.
Type: Journal Article | Journal: Haemophilia : the official journal of the World Federation of Hemophilia | Year: 2016
The paradigm() 2 and 4 phase 3 clinical trials investigated the safety and efficacy of nonacog beta pegol, a recombinant glycoPEGylated factor IX (FIX) with extended half-life, in previously treated haemophilia B patients.These post hoc analyses investigated the bleeding patterns in target joints.Patients randomized to 40 or 10 IU kg(-1) once weekly prophylaxis who had at least one target joint were included. Baseline demographics and disease-specific data were collected. Bleeding patterns were assessed, and an International Society on Thrombosis and Haemostasis (ISTH) definition of target joints was used.A total of 67% and 8% of patients in the 40 and 10 IU kg(-1) arm, respectively, did not experience target joint bleeds during the paradigm() 2 trial. Twenty-four target joints were recorded in each prophylaxis arm at baseline. During the paradigm() 2 trial, no bleeds were reported in 17 (71%) and 7 (29%) target joints in the 40 and 10 IU kg(-1) arms respectively. All target joint bleeds in the 40 IU kg(-1) once weekly prophylaxis arm were controlled with a single injection of 40 IU kg(-1) nonacog beta pegol. By the latest ISTH definition, 90% and 58% of target joints in the 40 and 10 IU kg(-1) arms, respectively, were no longer considered target joints at the end of the paradigm() 2 trial. At the end of the paradigm() 4 extension trial, all target joints in the 40 IU kg(-1) arm were no longer considered target joints.Routine prophylaxis with 40 IU kg(-1) once weekly nonacog beta pegol has the potential for effective management of target joint bleeds in haemophilia B patients.
Ljung R.,Skåne University Hospital |
Karim F.A.,Haemophilia Center |
Saxena K.,Harvard University |
Suzuki T.,Tokyo Medical University |
And 3 more authors.
Journal of Thrombosis and Haemostasis | Year: 2013
Summary: Background: A 40K glycoPEGylated, recombinant activated factor VII (rFVIIa) bypassing agent (N7-GP) with a prolonged half-life (15 h) compared with rFVIIa was developed as a potential candidate for bleed-preventive regimens in patients with hemophilia and inhibitors. Objectives: To evaluate the safety, pharmacokinetics and preliminary efficacy of multiple doses of N7-GP in congenital hemophilia A and B patients with high-titer inhibitors. Patients/Methods: In this global, prospective, randomized, double-blinded, phase 2 trial, 25, 100 or 200 μg kg-1 N7-GP was administered intravenously once every second day during a 3-month, bleed-preventive regimen and compared with a preceding 3-month observation period with on-demand treatment of bleeds with rFVIIa. The primary endpoint was adverse events; secondary endpoints were evaluation of immunogenicity, pharmacokinetics and efficacy. Results and Conclusions: Overall, 23 patients were randomized and dosed (n = 8/7/8 for 25/100/200 μg kg-1). N7-GP was well tolerated, with a low frequency of adverse events. No serious adverse events, immunogenic or thromboembolic events related to N7-GP were reported. The pharmacokinetic properties of N7-GP were similar to those reported in phase 1. The annualized bleeding rate (ABR) decreased in the treatment period vs. the observation period at all N7-GP dose levels. However, a dose-response relationship in the reduction could not be established in the N7-GP dose range evaluated. The ABR was also reduced at two dose levels during the last part of the observation period, and increased notably in the follow-up period irrespective of previous N7-GP dose. The trial was registered at ClinicalTrials.gov (Registration Number: NCT00951405). © 2013 International Society on Thrombosis and Haemostasis.
Lentz S.R.,University of Iowa |
Ehrenforth S.,Novo Nordisk AS |
Abdul Karim F.,Haemophilia Center |
Matsushita T.,Nagoya University |
And 3 more authors.
Journal of Thrombosis and Haemostasis | Year: 2014
Background: Vatreptacog alfa, a recombinant factor VIIa (rFVIIa) analog with three amino acid substitutions and 99% identity to native FVIIa, was developed to improve the treatment of hemophilic patients with inhibitors. Objectives: To confirm the safety and assess the efficacy of vatreptacog alfa in treating bleeding episodes in hemophilic patients with inhibitors. Patients and methods: In this international, multicenter, randomized, double-blind, active-controlled, crossover, confirmatory phase III trial (adept™2) in patients with hemophilia A or B and inhibitors, bleeds were randomized 3 2 to treatment with vatreptacog alfa (one to three doses at 80 μg kg-1) or rFVIIa (one to three doses at 90 μg kg-1). Treatment failures after three doses of trial product (TP) were managed according to the local standard of care. Results: In the 72 patients enrolled, 567 bleeds were treated with TP. Both vatreptacog alfa and rFVIIa gave 93% effective bleeding control at 12 h. Vatreptacog alfa was superior to rFVIIa in secondary efficacy outcomes, including the number of doses used to treat a bleed and sustained bleeding control 24-48 h after the first dose. Eight patients (11%) developed antibodies against vatreptacog alfa, including four with cross-reactivity against rFVIIa and one with an in vitro neutralizing effect to vatreptacog alfa. Conclusions: This large randomized controlled trial confirmed the well-established efficacy and safety profile of rFVIIa, and showed that vatreptacog alfa had similar or better efficacy than rFVIIa. However, because of the development of anti-drug antibodies, a positive benefit-risk profile is unlikely to be achieved with vatreptacog alfa. © 2014 The Authors. Journal of Thrombosis and Haemostasis.
Khair K.,Great Ormond Street Hospital for Children NHS Trust |
Littley A.,Haemophilia Center |
Will A.,Haemophilia Center |
von Mackensen S.,University of Hamburg
Haemophilia | Year: 2012
Sport is nowadays perceived as beneficial for children with haemophilia, as good muscle strength supports joints and may reduce bleed frequency; by contrast psychological benefits are less known. This study introduces the impact of sport on health-related quality of life (HRQoL) and physical performance in children with haemophilia. A cross-sectional, multi-site, study of boys aged 6-17 years with haemophilia A or B of any severity, current or past inhibitor, which assessed physical performance, sporting activity and HRQoL using age appropriate questionnaires including KINDL, Haemo-QoL and HEP-Test-Q. Eighty-four haemophilic boys (23 mild, 19 moderate, 42 severe) with a mean age of 11.52 years (SD = 3.4) were enrolled from two haemophilia centres in the United Kingdom. 28.4% were overweight/obese according to their BMI/age and had a good orthopaedic status (M = 1.55, SD = 3.3). Boys watching < 1-2 h of TV/PC/day had fewer days lost (M = 3, SD = 3.2) than those with a more sedentary lifestyle (M = 9.40, SD = 7.1) (P < 0.032). 90.5% participated in regular sporting activity; 79.9% at least twice a week. HRQoL in children was generally good, with highest impairments in boys aged 8-12 years. Boys aged 8-16 years reported good physical performance (M = 80.0, SD = 16.0) with highest impairments in the dimensions 'endurance' and 'mobility'. Boys doing sport had a significant better physical performance and HRQoL than boys not doing sport. Sedentary life styles had a negative impact on the subjective physical performance and number of days lost of children. Encouraging haemophilic boys to participate in sport will have a direct impact on their overall HRQoL. © 2012 Blackwell Publishing Ltd.