Improvement in pain-related quality of life in patients with hemophilia A treated with rFVIIIFc individualized prophylaxis: post hoc analysis from the A-LONG study

Background: Pain, a common symptom of hemophilia, begins early in life primarily due to joint bleeding. Recurrent bleeding adversely affects patients’ pain-related physical functioning, which can negatively impact their quality of life (QoL). Objective: Post hoc analysis of data from the A-LONG study (NCT01181128), to assess change over time in pain-related QoL in patients with severe hemophilia A treated prophylactically with recombinant factor VIII Fc fusion protein (rFVIIIFc). Methods: Patients who completed Haem-A-QoL (17–65 years) and EQ-5D-3L (⩾12–65 years) questionnaires at baseline (BL) and end of study (EoS). Individual-level changes were assessed using three pain-related items of the Haem-A-QoL ‘Physical Health’ domain and the pain/discomfort item of EQ-5D-3L. Distributions of responses (EoS versus BL) were compared using McNemar’s test. Results: A significantly greater proportion of patients reported they did not experience painful swellings (n = 87; 66% versus 46%, p < 0.01) or pain in their joints (n = 89; 42% versus 27%; p < 0.05) at EoS versus BL. The proportion of patients who did not find it painful to move numerically increased at EoS versus BL (n = 86; 47% versus 38%; p = NS). A significantly greater proportion of patients reported no pain/discomfort at EoS versus BL (n = 116; 45% versus 34%; p < 0.05). Conclusion: This study reports the effect of FVIII prophylaxis on patient-reported measures of pain over time in patients with severe hemophilia A. The results of this post hoc analysis showed improvements in pain from BL to EoS in patients receiving rFVIIIFc individualized prophylaxis indicating effective pain management, a key component of patient care

The role of physiotherapy in the new treatment landscape for haemophilia

The physiotherapist plays an essential role for people with haemophilia, an inherited bleeding disease responsible for musculoskeletal complications. Yet, with the advent of new and advanced therapies, the medical landscape is changing, and physiotherapy must adapt alongside. This paper considers whether there will still be a need for physiotherapy in the era of advanced therapies, and discusses ways in which services should evolve to complement emerging treatment paradigms for haemostasis in people with haemophilia. Ultimately, physiotherapy will remain an important element of care, even for people with little joint damage and low risks in the era of the new mild phenotype. However, competencies will need to evolve, and physiotherapists in both primary care and specialist treatment centres should work with haematology colleagues to develop more sensitive tools for detecting early joint changes. Physiotherapists will also play a crucial role in counselling and physically coaching, monitoring the musculoskeletal status of people with haemophilia who have transitioned to new treatments

Factor VIII: Long-established role in haemophilia A and emerging evidence beyond haemostasis

Abstract Factor VIII protein (FVIII) as a coagulation replacement factor has for decades been used as the standard of care for management of people with haemophilia A. It is effective for treatment of bleeding events, as prophylaxis to prevent bleeding events and preserve joint function, and to support surgery in people with haemophilia A. Despite long experience in treating haemophilia A, we are only beginning to understand the functions of FVIII beyond its established role as a coenzyme to factor IXa to expedite thrombin generation through the intrinsic pathway of coagulation. Here, we review the current role of FVIII coagulant (FVIII:C) in haemophilia A management and emerging evidence for the role of FVIII across multiple systems, including the cardiovascular system, angiogenesis and maintenance of bone health. For instance, supraphysiological FVIII levels are a risk factor for venous thromboembolism. von Willebrand factor (VWF), which forms a non-covalent complex with circulating FVIII, is an established marker and regulator of angiogenesis. In a mouse model of haemophilia, treatment with FVIII decreased expression of receptor activator of nuclear factor kappa-Β ligand (RANKL), a marker for bone turnover. Longitudinal follow-up data in people with haemophilia A are needed to confirm and extend these observations

Inhibitor development in non-severe haemophilia across Europe

Evidence about inhibitor formation in non-severe haemophilia and the potential role for clotting factor concentrate type is scant. It was the aim of this study to report inhibitor development in non-severe haemophilia patients enrolled in the European Haemophilia Safety Surveillance (EUHASS) study. Inhibitors are reported quarterly and total treated patients annually. Incidence rates and 95 % confidence intervals (95 % CI) were calculated according to diagnosis and concentrate used. Between 1–10–2008 and 31–12–2012, 68 centres reported on 7,969 patients with non-severe haemophilia A and 1,863 patients with non-severe haemophilia B. For haemophilia A, 37 inhibitors occurred in 8,622 treatment years, resulting in an inhibitor rate of 0.43/100 treatment years (95 % CI 0.30–0.59). Inhibitors occurred at a median age of 35 years, after a median of 38 exposure days (EDs; P25-P75: 20–80); with 72 % occurring within the first 50 EDs. In haemophilia B, one inhibitor was detected in 2,149 treatment years, resulting in an inhibitor rate of 0.05/100 years (95% CI 0.001–0.26). This inhibitor developed at the age of six years, after six EDs. The rate of inhibitors appeared similar across recombinant and plasma derived factor VIII (FVIII) concentrates. Rates for individual concentrates could not be calculated at this stage due to low number of events. In conclusion, inhibitors in non-severe haemophilia occur three times more frequently than in previously treated patients with severe haemophilia at a rate of 0.43/100 patient years (haemophilia A) and 0.05/100 years (haemophilia B). Although the majority of inhibitors developed in the first 50 EDs, inhibitor development continued with increasing exposure to FVIII

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

Background: Individual pharmacokinetic assessment is a critical component of tailored prophylaxis for hemophilia patients. Population pharmacokinetics allows using individual sparse data, thus simplifying individual pharmacokinetic studies. Implementing population pharmacokinetics capacity for the hemophilia community is beyond individual reach and requires a system effort. Objective: The Web-Accessible Population Pharmacokinetic Service-Hemophilia (WAPPS-Hemo) project aims to assemble a database of patient pharmacokinetic data for all existing factor concentrates, develop and validate population pharmacokinetics models, and integrate these models within a Web-based calculator for individualized pharmacokinetic estimation in patients at participating treatment centers. Methods: Individual pharmacokinetic studies on factor VIII and IX concentrates will be sourced from pharmaceutical companies and independent investigators. All factor concentrate manufacturers, hemophilia treatment centers (HTCs), and independent investigators (identified via a systematic review of the literature) having on file pharmacokinetic data and willing to contribute full or sparse pharmacokinetic data will be eligible for participation. Multicompartmental modeling will be performed using a mixed-model approach for derivation and Bayesian forecasting for estimation of individual sparse data. NONMEM (ICON Development Solutions) will be used as modeling software. Results: The WAPPS-Hemo research network has been launched and is currently joined by 30 HTCs from across the world. We have gathered dense individual pharmacokinetic data on 878 subjects, including several replicates, on 21 different molecules from 17 different sources. We have collected sparse individual pharmacokinetic data on 289 subjects from the participating centers through the testing phase of the WAPPS-Hemo Web interface. We have developed prototypal population pharmacokinetics models for 11 molecules. The WAPPS-Hemo website (available at www.wapps-hemo.org, version 2.4), with core functionalities allowing hemophilia treaters to obtain individual pharmacokinetic estimates on sparse data points after 1 or more infusions of a factor concentrate, was launched for use within the research network in July 2015. Conclusions: The WAPPS-Hemo project and research network aims to make it easier to perform individual pharmacokinetic assessments on a reduced number of plasma samples by adoption of a population pharmacokinetics approach. The project will also gather data to substantially enhance the current knowledge about factor concentrate pharmacokinetics and sources of its variability in target populations.All funds were granted to McMaster University and no funds were received for this manuscrip

European retrospective study of real-life haemophilia treatment

IntroductionHaemophilia treatment varies significantly between individuals, countries and regions and details of bleed rates, factor consumption and injection frequency are often not available.AimTo provide an overview of the FVIII/FIX treatment practice and outcome for patients with haemophilia A (HA) or haemophilia B (HB) across Europe.MethodsNon‐interventional, 12‐month retrospective study where anonymized data were retrieved from haemophilia centres/registers in Belgium, France, Germany, Italy, Spain, Sweden and the United Kingdom. Male patients (all ages) receiving coagulation factor treatment 24 months prior to the study, with basal FVIII/FIX levels ≤5 IU dL−1, without inhibitors, were included. Data were summarized descriptively.ResultsIn total, 1346 patients with HA and 312 with HB were included in the analysis; 75% and 57% had severe disease (FVIII/FIX < 1 IU dL−1) respectively. Prophylaxis was most common for severe haemophilia, especially for children, whereas on‐demand treatment was more common for moderate haemophilia in most countries. The mean (SD) prescribed prophylactic treatment ranged from 67.9 (30.4) to 108.4 (78.1) (HA) and 32.3 (10.2) to 97.7 (32.1) (HB) IU kg−1 per week, across countries. Most patients on prophylaxis were treated ≥3 times/week (HA) or two times/week (HB). The median annual bleeding rate (ABR) for patients on prophylaxis ranged from 1.0 to 4.0 for severe HA, and from 1.0 to 6.0 for severe HB, while those with moderate haemophilia generally had slightly higher ABRs. Median ABRs for on‐demand‐treated severe HA ranged from 4.5 to 18.0, and for HB, 1.5 to 14.0.ConclusionTreatment practice varied greatly between centres and countries and patients treated on‐demand and prophylactically both experienced bleeds, emphasizing the need for further optimization of care

Metrology on-board PROBA-3: The shadow position sensors subsystem

PROBA-3 is an ESA mission aimed at the demonstration of formation flying performance of two satellites that will form a giant coronagraph in space. The first spacecraft will host a telescope imaging the solar corona in visible light, while the second, the external occulter, will produce an artificial eclipse. This instrument is named ASPIICS (Association of Spacecraft for Polarimetric and Imaging Investigation of the Corona of the Sun). To accomplish the payload's scientific tasks, PROBA-3 will ensure sub-millimeter reciprocal positioning of its two satellites using closed-loop on-board metrology. Several metrology systems will be used and the Shadow Position Sensor (SPS) subsystem senses the penumbra around the instrument aperture and returns the 3-D displacement of the coronagraph satellite, with respect to its nominal position, by running a dedicated algorithm. In this paper, we describe how the SPS works and the choices made to accomplish the mission objectives

Management of COVID‐19‐associated coagulopathy in persons with haemophilia

Introduction The SARS‐CoV‐2 coronavirus‐induced infection (COVID‐19) can be associated with a coagulopathy mainly responsible for pulmonary microvasculature thrombosis and systemic thromboembolic manifestations. The pathophysiology and management of the COVID‐19 coagulopathy are likely more complex in patients with inherited bleeding diseases such as haemophilia. These individuals might indeed present with both bleeding and thrombotic complications and require simultaneous antithrombotic and haemostatic treatments. Objective We propose practical guidance for the diagnosis and management of COVID‐19 coagulopathy in persons with haemophilia. Results Continuation of regular haemostatic treatment is recommended for ambulatory patients. For patients requiring hospital admission and on replacement therapy with factors VIII or IX concentrates, prophylaxis with concentrates should be intensified according to the risk of bleeding complications and associated with prophylactic doses of LMWH. For patients on nonreplacement therapy, emicizumab should be continued and possibly combined with factor VIII and prophylactic doses of LMWH depending on the risk of bleeding and thrombosis. Dose escalation of LMWH tailored to the risk of thrombosis can be employed but not supported by evidence. Conclusions These practical recommendations are based on the current literature on COVID‐19 with its impact on haemostasis, indications and modalities for thromboprophylaxis mainly in nonhaemophilic patients and how that is likely to affect persons with haemophilia in different circumstances. They will need to be tailored to each patient's clinical status and validated in future studies

Design status of ASPIICS, an externally occulted coronagraph for PROBA-3

The "sonic region" of the Sun corona remains extremely difficult to observe with spatial resolution and sensitivity sufficient to understand the fine scale phenomena that govern the quiescent solar corona, as well as phenomena that lead to coronal mass ejections (CMEs), which influence space weather. Improvement on this front requires eclipse-like conditions over long observation times. The space-borne coronagraphs flown so far provided a continuous coverage of the external parts of the corona but their over-occulting system did not permit to analyse the part of the white-light corona where the main coronal mass is concentrated. The proposed PROBA-3 Coronagraph System, also known as ASPIICS (Association of Spacecraft for Polarimetric and Imaging Investigation of the Corona of the Sun), with its novel design, will be the first space coronagraph to cover the range of radial distances between ~1.08 and 3 solar radii where the magnetic field plays a crucial role in the coronal dynamics, thus providing continuous observational conditions very close to those during a total solar eclipse. PROBA-3 is first a mission devoted to the in-orbit demonstration of precise formation flying techniques and technologies for future European missions, which will fly ASPIICS as primary payload. The instrument is distributed over two satellites flying in formation (approx. 150m apart) to form a giant coronagraph capable of producing a nearly perfect eclipse allowing observing the sun corona closer to the rim than ever before. The coronagraph instrument is developed by a large European consortium including about 20 partners from 7 countries under the auspices of the European Space Agency. This paper is reviewing the recent improvements and design updates of the ASPIICS instrument as it is stepping into the detailed design phase

Le pharmacien face aux agents hémostatiques et anti-thrombotiques d'aujourd'hui et de demain

Le pharmacien face aux agents hémostatiques et anti-thrombotiques d'aujourd'hui et de demai