How do we optimally utilize factor concentrates in persons with hemophilia?
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SUBMITTER: Lim MY
PROVIDER: S-EPMC8791116 | biostudies-literature |
REPOSITORIES: biostudies-literature
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Project description:BackgroundRecombinant factors VIII and IX Fc (rFVIIIFc/rFIXFc) were the only available extended half-life (EHL) products in Canada during 2016 to 2018.ObjectivesTo evaluate if patient-reported outcome measures (PROMs) improved in Canadian persons with hemophilia who switched from standard half-life (SHL) to EHL products (rFVIIIFc/rFIXFc).Patients/methodsThis prospective cohort study enrolled persons with moderate or severe hemophilia aged ≥6 years who switched to rFVIIIFc/rFIXFc (2016-2018) and those who remained on SHL. Health-related quality of life (HRQoL) was assessed using the Haemophilia-specific Quality of Life (Haem-A-QoL) and 36-item Short-Form Survey (SF-36) at baseline, 3-months, 12 months, and 24 months. Other PROMs included the Work Productivity and Impairment Questionnaire, chronic pain scale, partner/parent ratings of mood, International Physical Activity Questionnaire, and Treatment Satisfaction Questionnaire for Medication. We identified meaningful changes using minimally important difference for SF-36 and responder definition for Haem-A-QoL.ResultsWe enrolled 25 switchers (16 rFVIIIFc, 9 rFIXFc) and 33 nonswitchers. Those switched to rFVIIIFc/rFIXFc had improved overall HRQoL, and improved subscale physical activity, mental health, and social functioning at 3 months. The rFIXFc switchers had improved chronic pain and ability to engage in normal activities while the rFVIIIFc switchers had improved treatment satisfaction. There was no change in work impairment after the switch. Observed improvement disappeared by 24 months in most domains.ConclusionSwitching from SHL to rFVIIIFc/rFIXFc resulted in short-term meaningful improvement in overall HRQoL and other PROMs in a small proportion. Longitudinal changes on PROMs are affected by ceiling effects and response shift, warranting further studies in instrument optimization in the era of EHL and nonfactor products.
| S-EPMC8505988 | biostudies-literature
Project description:Hemophilia A and B are bleeding disorders caused by a deficiency of clotting factor VIII and IX, respectively. Patients with severe hemophilia (< 0.01 IU mL-1) and some patients with moderate hemophilia (0.01-0.05 IU mL-1) administer clotting factor concentrates prophylactically. Desmopressin (D-amino D-arginine vasopressin) can be applied in patients with non-severe hemophilia A. The aim of administration of factor concentrates or desmopressin is the prevention or cessation of bleeding. Despite weight-based dosing, it has been demonstrated that factor concentrates still exhibit considerable pharmacokinetic variability. Population pharmacokinetic analyses, in which this variability is quantified and explained, are increasingly performed in hemophilia research. These analyses can assist in the identification of important patient characteristics and can be applied to perform patient-tailored dosing. This review aims to present and discuss the population pharmacokinetic analyses that have been conducted to develop population pharmacokinetic models describing factor levels after administration of factor VIII or factor IX concentrates or D-amino D-arginine vasopressin. In total, 33 publications were retrieved from the literature. Two approaches were applied to perform population pharmacokinetic analyses, the standard two-stage approach and non-linear mixed-effect modeling. Using the standard two-stage approach, four population pharmacokinetic models were established describing factor VIII levels. In the remaining 29 analyses, the non-linear mixed-effect modeling approach was applied. NONMEM was the preferred software to establish population pharmacokinetic models. In total, 18 population pharmacokinetic analyses were conducted on the basis of data from a single product. From all available population pharmacokinetic analyses, 27 studies also included data from pediatric patients. In the majority of the population pharmacokinetic models, the population pharmacokinetic parameters were allometrically scaled using actual body weight. In this review, the available methods used for constructing the models, key features of these models, patient population characteristics, and established covariate relationships are described in detail.
| S-EPMC7808974 | biostudies-literature
Project description:Emicizumab, a bispecific monoclonal antibody, bridges activated factor IX (FIXa) and FX, replacing the function of missing FVIIIa to restore effective hemostasis in persons with hemophilia A (PwHA). Here we assess pharmacokinetic (PK) and pharmacodynamic (PD) biomarkers in PwHA with FVIII inhibitors in the Phase III HAVEN 1 study (NCT02622321). Blood samples from 112 PwHA receiving 1.5 mg/kg once-weekly subcutaneous emicizumab were analyzed at central laboratories. Emicizumab concentrations for PK analysis were measured via validated immunoassay. PD effects were assessed using FVIII chromogenic activity assay containing human factors (Hyphen Biophen FVIII:C), and by FXIa-triggered thrombin generation (TG). Activated partial thromboplastin time (aPTT), prothrombin time (PT), antigen levels of FIX and FX, fibrinogen, D-dimer, and prothrombin fragment 1.2 (PF1.2) levels were determined. Emicizumab trough concentrations ≥ 50 µg/mL were maintained throughout the study. FVIII-like activity and TG (peak height) correlated with emicizumab concentrations and remained above 20 U/dL and 100 nM, respectively, with a weekly maintenance dose, theoretically converting persons with severe hemophilia A to a mild disease phenotype. aPTT was normalized at subtherapeutic concentrations of emicizumab. Plasma concentrations of target antigens FIX and FX were not significantly affected by emicizumab treatment; nor were fibrinogen, PT (international normalized ratio), D-dimer, or PF1.2. The PK profile of once-weekly emicizumab in HAVEN 1 provides sustained therapeutic plasma levels, consistent with population PK models. Both the PK profile and the PD and safety biomarkers are consistent with the established efficacy of emicizumab prophylaxis in PwHA with FVIII inhibitors.
| S-EPMC7895541 | biostudies-literature
Project description:Background and objectivesTreatment availability and comprehensive care have resulted in improved clinical outcomes for persons with hemophilia. Recent data on socioeconomic participation in the Netherlands are lacking. This study assessed participation in education, in the labor market, and social participation for persons with hemophilia compared with the general male population.MethodsDutch adults and children (5-75 years) of all hemophilia severities (n = 1009) participated in a questionnaire study that included sociodemographic, occupational, and educational variables. Clinical characteristics were extracted from electronic medical records. General population data were extracted from Statistics Netherlands. Social participation was assessed with the PROMIS Ability to Participate in Social Roles and Activities short form, with a minimal important difference set at 1.0.ResultsData from 906 adults and children were analyzed. Participation in education of 20 to 24 year olds was 68% (general male population: 53%). Educational attainment was higher compared with Dutch males, especially for severe hemophilia. Absenteeism from school was more common than in the general population. The employment-to-population ratio and occupational disability were worse for severe hemophilia than in the general population (64.3% vs. 73.2% and 14.7% vs. 4.8%, respectively), but similar for nonsevere hemophilia. Unemployment was 5.4% (general male population: 3.4%). Absenteeism from work was less common (38% vs. 45.2%). Mean PROMIS score was similar to or higher than in the general population (54.2; SD 8.9 vs. 50; SD 10).ConclusionSocioeconomic participation of persons with nonsevere hemophilia was similar to the general male population. Some participation outcomes for persons with severe hemophilia were reduced.
| S-EPMC9414229 | biostudies-literature
Project description:Proteomic methods were used to identify the levels of impurities in three commercial plasma-derived clotting factor VIII-von Willebrand factor (FVIII/VWF) concentrates. In all three concentrates, significant amounts of other plasma proteins were found. In Octanate and Haemoctin, two concentrates developed in the 1990s, the major impurities identified were inter-alpha inhibitor proteins, fibrinogen and fibronectin. These two concentrates were also found to contain additional components such as clotting factor II (prothrombin) that are known activators of FVIII. In Wilate, a recently developed FVIII/VWF concentrate, the amount of these impurities was significantly reduced. Batch-to-batch variations and differences between three investigated products were detected using iTRAQ, an isotope labeling technique for comparative MS, demonstrating the potential value of this technique for quality control analysis. The importance of thorough proteomic investigations of therapeutic FVIII/VWF preparations from human plasma is also discussed.
| S-EPMC3030255 | biostudies-literature
Project description:Historically, people with hemophilia have been warned to avoid physical activities as a possible cause of bleeding; however, currently, sport is considered necessary, especially in the developmental age, for providing a good quality of life. A survey was proposed to a group of hematologists and sports physicians working in Puglia, Italy, to explore their approach to physical activities for their patients with hemophilia and to obtain suggestions about possible interventions to promote the access of patients to sports. The survey was answered by 6 hematologists and 15 sports physicians. In total, 71% (about six patients/year/physician) of patients with hemophilia seen by sports physicians asked for counseling about sports, and 67% (about five patients/year/physician) actually practiced sports. On the other hand, only 31% (about 16 patients/year/hematologist) of patients asked hematologists questions on sports, and only 16% (about seven patients/year/hematologist) of patients with hemophilia and that were followed-up by hematologists practiced sports. The sports most often recommended to patients with hemophilia by physicians included swimming, athletics, tennis, running and gymnastics. According to hematologists, physical activity was very efficient in improving the quality of life of patients; stability of joints; their psychological, social and musculoskeletal wellbeing; and in reducing the risk of bleedings. On the other hand, physical activity was considered less important in all these areas by sport physicians. In conclusion, answers to this survey suggested that sports could be promoted among hemophilic patients by increasing the sports physicians' knowledge about hemophilia and their special role in this area. In addition, interviewed clinicians were of the opinion that increased awareness of specific guidelines and clinical practice protocols among both hematologists and sports physicians could be beneficial. Finally, answers suggested that access to fitness certification should be facilitated.
| S-EPMC8625842 | biostudies-literature
Project description:Background and objectiveEmicizumab is a monoclonal antibody that bridges activated coagulation factor IX and factor X to restore effective hemostasis in persons with hemophilia A. It is indicated for routine prophylaxis of bleeding episodes in persons with hemophilia A. The aim of the present study is to describe the exposure-response relationship between emicizumab concentrations and bleeding frequency, and to confirm adequate bleeding control of the investigated dosing regimens 1.5 mg/kg once weekly, 3 mg/kg every 2 weeks, and 6 mg/kg every 4 weeks.MethodsTreated bleeding events were pooled from 445 persons with hemophilia A with and without inhibitors against factor VIII, participating in six clinical studies. Emicizumab concentrations were predicted using a previously developed population pharmacokinetic model. A count model was used to quantify the exposure-response relationship. These models were used to illustrate the relationship between emicizumab concentrations and cumulative count of bleeding over 1 year (annualized bleeding rate).ResultsThe final exposure-response model, based on a generalized Poisson distribution and an inhibitory Emax relationship, adequately describes the relationship between daily emicizumab concentrations and daily bleed frequency. A significant effect of factor VIII prophylaxis among persons with hemophilia A without inhibitors was found. Annualized bleeding rate simulations show that the three emicizumab dosing regimens maintain the concentrations close to the plateau of the effect. At the average steady-state concentration across all regimens (53.5 µg/mL), the predicted mean annualized bleeding rate is 1.28, corresponding to a 94.0% reduction from baseline.ConclusionsThese results confirm that average emicizumab concentrations achieved with all three emicizumab dosing regimens provide adequate bleeding control.
| S-EPMC8249270 | biostudies-literature
Project description:Although persons with nonsevere hemophilia A (NSHA) account for about one-half of the hemophilia A population, epidemiological data in this subset of individuals are scarce. We set out to describe the clinical characteristics of persons with NSHA with inhibitors, and to determine mortality rates, predictors of mortality, and primary causes of death in persons with NSHA in the United States over a 9-year period (2010-2018). We queried the American Thrombosis and Hemostasis Network dataset (ATHNdataset) for information on demographics, inhibitor status, and date and cause of death. A total of 6624 persons with NSHA (86.0% men; 14.0% women) were observed for an average of 8.5 years; total 56 119 person-years . The prevalence of inhibitors was 2.6% (n = 171), occurring at a median age of 13 years. At the end of follow-up, 136 persons died at a median age of 63 years; an age-adjusted mortality rate of 3.3 deaths per 1000 person-years. Three deaths occurred in inhibitor participants. Presence of inhibitors was not associated with increased mortality risk (hazard ratio [HR], 0.7, 95% confidence interval [CI], 0.2-2.3). Factors independently associated with increased risk of death (HR, 95% CI) were the following: age (10-year increase) (2.1, 2.0-2.4); male (2.6, 1.0-6.4); hepatitis C (2.2, 1.5-3.1); and HIV (3.6, 2.2-6.0). The most common primary cause of death was malignancy (n = 27, 20.0%). In persons with NSHA, the development of inhibitors occurred at an early age and was not associated with increased mortality.
| S-EPMC7556148 | biostudies-literature
Project description:Hemophilia A (factor VIII [FVIII] deficiency) and hemophilia B (factor IX [FIX] deficiency) are the X-linked recessive bleeding disorders that clinically manifest with recurrent bleeding, predominantly into muscles and joints. In its severe presentation, when factor activity is less than 1% of normal, hemophilia presents with spontaneous musculoskeletal bleeds and may progress to debilitating chronic arthropathy. Management of hemophilia has changed profoundly in the past decades. From on-demand to prophylactic factor concentrate replacement, the treatment goal shifted from controlling bleeds to preventing bleeds and improving quality of life. In this new scenario, gene therapy has arisen as a paradigm-changing therapeutic option, a one-time treatment with the potential to achieve sustained coagulation FVIII or FIX expression even within the normal range. This review discusses the critical impact of adeno-associated virus (AAV) gene transfer in hemophilia care, including the recent clinical outcomes, changes in disease perceptions, and its treatment burden. We also discuss the challenging scenario of the AAV-directed immune response in the clinical setting and potential strategies to improve the long-lasting efficacy of hemophilia gene therapy efficacy.
| S-EPMC9899988 | biostudies-literature
Project description:In everyday life, many people believe that two heads are better than one. Our ability to solve problems together appears to be fundamental to the current dominance and future survival of the human species. But are two heads really better than one? We addressed this question in the context of a collective low-level perceptual decision-making task. For two observers of nearly equal visual sensitivity, two heads were definitely better than one, provided they were given the opportunity to communicate freely, even in the absence of any feedback about decision outcomes. But for observers with very different visual sensitivities, two heads were actually worse than the better one. These seemingly discrepant patterns of group behavior can be explained by a model in which two heads are Bayes optimal under the assumption that individuals accurately communicate their level of confidence on every trial.
| S-EPMC3371582 | biostudies-literature