Efanesoctocog alfa provides high sustained factor VIII activity by overcoming the von Willebrand factor-imposed half-life ceiling. The efficacy, safety, and pharmacokinetics of efanesoctocog alfa for ...prophylaxis and treatment of bleeding episodes in previously treated patients with severe hemophilia A are unclear.
We conducted a phase 3 study involving patients 12 years of age or older with severe hemophilia A. In group A, patients received once-weekly prophylaxis with efanesoctocog alfa (50 IU per kilogram of body weight) for 52 weeks. In group B, patients received on-demand treatment with efanesoctocog alfa for 26 weeks, followed by once-weekly prophylaxis with efanesoctocog alfa for 26 weeks. The primary end point was the mean annualized bleeding rate in group A; the key secondary end point was an intrapatient comparison of the annualized bleeding rate during prophylaxis in group A with the rate during prestudy factor VIII prophylaxis. Additional end points included treatment of bleeding episodes, safety, pharmacokinetics, and changes in physical health, pain, and joint health.
In group A (133 patients), the median annualized bleeding rate was 0 (interquartile range, 0 to 1.04), and the estimated mean annualized bleeding rate was 0.71 (95% confidence interval CI, 0.52 to 0.97). The mean annualized bleeding rate decreased from 2.96 (95% CI, 2.00 to 4.37) to 0.69 (95% CI, 0.43 to 1.11), a finding that showed superiority over prestudy factor VIII prophylaxis (P<0.001). A total of 26 patients were enrolled in group B. In the overall population, nearly all bleeding episodes (97%) resolved with one injection of efanesoctocog alfa. Weekly prophylaxis with efanesoctocog alfa provided mean factor VIII activity of more than 40 IU per deciliter for the majority of the week and of 15 IU per deciliter at day 7. Prophylaxis with efanesoctocog alfa for 52 weeks (group A) improved physical health (P<0.001), pain intensity (P = 0.03), and joint health (P = 0.01). In the overall study population, efanesoctocog alfa had an acceptable side-effect profile, and the development of inhibitors to factor VIII was not detected.
In patients with severe hemophilia A, once-weekly efanesoctocog alfa provided superior bleeding prevention to prestudy prophylaxis, normal to near-normal factor VIII activity, and improvements in physical health, pain, and joint health. (Funded by Sanofi and Sobi; XTEND-1 ClinicalTrials.gov number, NCT04161495.).
Purpose
The purpose of this study was to investigate the feasibility of ultrashort echo time quantitative susceptibility mapping (UTE‐QSM) for assessment of hemosiderin deposition in the joints of ...hemophilic patients.
Methods
The UTE‐QSM technique was based on three sets of dual‐echo 3D UTE Cones data acquired with TEs of 0.032/2.8, 0.2/3.6, and 0.4/4.4 ms. The images were processed with iterative decomposition of water and fat with echo asymmetry and least‐squares estimation to estimate the B0 field map in the presence of fat. Then, the projection onto dipole field (PDF) algorithm was applied to acquire a local field map generated by tissues, followed by application of the morphology‐enabled dipole inversion (MEDI) algorithm to estimate a final susceptibility map. Three healthy volunteers and three hemophilic patients were recruited to evaluate the UTE‐QSM technique’s ability to assess hemosiderin in the knee or ankle joint at 3T. One patient subsequently underwent total knee arthroplasty after the MR scan. The synovial tissues harvested from the knee joint during surgery were processed for histological analysis to confirm iron deposition.
Results
UTE‐QSM successfully yielded tissue susceptibility maps of joints in both volunteers and patients. Multiple regions with high susceptibility over 1 ppm were detected in the affected joints of hemophilic patients, while no localized regions with high susceptibility were detected in asymptomatic healthy volunteers. Histology confirmed the presence of iron in regions where high susceptibility was detected by UTE‐QSM.
Conclusion
The UTE‐QSM technique can detect hemosiderin deposition in the joint, and provides a potential sensitive biomarker for the diagnosis and prognosis of hemophilic arthropathy.
The current challenges faced by people with hemophilia B Miesbach, Wolfgang; Drygalski, Annette; Smith, Clive ...
European journal of haematology,
March 2024, 2024-Mar, 2024-03-00, 20240301, Letnik:
112, Številka:
3
Journal Article
Recenzirano
Odprti dostop
Hemophilia B (HB) is a rare, hereditary disease caused by a defect in the gene encoding factor IX (FIX) and leads to varying degrees of coagulation deficiency. The prevailing treatment for people ...with HB (PWHB) is FIX replacement product. The advent of recombinant coagulation products ushered in a new era of safety, efficacy, and improved availability compared with plasma‐derived products. For people with severe HB, lifelong prophylaxis with a FIX replacement product is standard of care. Development of extended half‐life FIX replacement products has allowed for advancements in the care of these PWHB. Nonetheless, lifelong need for periodic dosing and complex surveillance protocols pose substantive challenges in terms of access, adherence, and healthcare resource utilization. Further, some PWHB on prophylactic regimens continue to experience breakthrough bleeds and joint damage, and subpopulations of PWHB, including women, those with mild‐to‐moderate HB, and those with inhibitors to FIX, experience additional unique difficulties. This review summarizes the current challenges faced by PWHB, including the unique subpopulations; identifying the need for improved awareness, personalized care strategies, and new therapeutic options for severe HB, which may provide future solutions for some of the remaining unmet needs of PWHB.
Background
Teleguidance on portable devices opens the possibility of joint self‐imaging in persons with hemophilia (PWH).
Aims
Determine the feasibility of patient self‐imaging with/without ...teleguidance.
Methods
Adult PWH received ultrasound teaching including 11 views for hemarthrosis detection in ankles, elbows, and knees. The patients acquired five randomly selected views with the Butterfly/IQ probe without assistance at 2, 6–8 weeks, and 3–4 months later, followed by teleguidance. Image acquisition was timed, patients identified anatomic landmarks, and image quality was graded. Questionnaires assessed the imaging experience. Hemophilia Joint Health Score (HJHS) indicated arthropathy status.
Results
Of 132 PWH, 10 (median age 52 years) opted for study inclusion. Most had severe Hemophilia A, were white/non‐Hispanic, with at least a high school degree and, overall, similar to the other 122 PWH.
At 2 and 6 weeks after training, ~80% images were acquired correctly compared with 53% at 12 weeks. Accuracy of landmark recognition was ~55%. With teleguidance, all images were acquired correctly, with near‐perfect image quality (P ≤ .01 compared with the 3–4 month time point). Median HJHS of scanned joints was 11.5 at each time point, demonstrating a similar spectrum of arthropathic changes. Median time of image acquisition was fast, and similar with or without teleguidance (median 01:04 mm:ss vs median 01:02), but differed slightly between arthropathic and non‐arthropathic joints. Study participants and the imaging facilitator rated that it was easy to navigate mobile technology and acquire images with teleguidance.
Conclusion
Mobile ultrasound with teleguidance for joint self‐imaging is feasible and warrants further exploration.
Introduction:
Acute respiratory illnesses from COVID19 infection are increasing globally. Reports from earlier in the pandemic suggested that patients hospitalized for COVID19 are at particularly ...high risk for pulmonary embolism (PE). To estimate the incidences of PE during hospitalization for COVID19, we performed a rigorous systematic review of published literature.
Methods:
We searched for case series, cohort studies and clinical trials from December 1, 2019 to July 13, 2020 that reported the incidence of PE among consecutive patients who were hospitalized for COVID19 in ICUs and in non-ICU hospital wards. To reflect the general population of hospitalized COVID19 patients, we excluded studies in which subject enrollment was linked to the clinical suspicion for venous thromboembolism (VTE).
Results:
Fifty-seven studies were included in the analysis. The combined random effects estimate of PE incidence among all hospitalized COVID19 patients was 7.1% (95% CI: 5.2%, 9.1%). Studies with larger sample sizes reported significantly lower PE incidences than smaller studies (r2 = 0.161, p = 0.036). The PE incidence among studies that included 400 or more patients was 3.0% (95% CI: 1.7%, 4.6%). Among COVID19 patients admitted to ICUs, the combined estimated PE incidence was 13.7% (95% CI: 8.0%, 20.6%). The incidence of ICU-related PE also decreased as the study sample sizes increased. The single largest COVID19 ICU study (n = 2215) disclosed a PE incidence of 2.3% (95% CI: 1.7%, 3.0%).
Conclusion:
PE incidences among hospitalized COVID19 patients are much lower than has been previously postulated based on smaller, often biased study reports. The incidence of “microthrombosis,” leading to occlusion of microscopic blood vessels, remains unknown.
Etranacogene dezaparvovec (AMT-061) is a recombinant AAV5 vector including a gene cassette containing the factor IX (FIX) Padua variant under the control of a liver-specific promoter. A phase 2b ...study was conducted to confirm that a single dose of 2 × 1013 genome copies per kilogram of etranacogene dezaparvovec will result in FIX activity ≥5% 6 weeks after dosing. Secondary end points included FIX activity at other time points, bleed frequency, FIX replacement, and safety. Etranacogene dezaparvovec was administered as a single IV infusion to 3 adults with severe to moderately severe hemophilia B. Before treatment, participants had low levels of preexisting neutralizing antibodies to AAV5. This article reports a planned 26-week interim assessment. At week 6, mean FIX activity was 31% (23.9%-37.8%), increasing to 47% (33.2%-57.0%) at 26 weeks, with 2 subjects exhibiting sustained activity >40%. Consistent with the FIX activity, etranacogene dezaparvovec was associated with a complete bleed cessation with no need for FIX replacement therapy up to 26 weeks. Etranacogene dezaparvovec was generally well tolerated. No clinically significant elevations in levels of liver enzymes or inflammatory markers were observed, and no use of corticosteroids related to treatment was required. In individuals with severe to moderately severe hemophilia B, etranacogene dezaparvovec resulted in clinically relevant increases in FIX activity, cessation of bleeds, and abrogation of the need for FIX replacement, despite the presence of preexisting anti-AAV5 neutralizing antibodies detected by using a highly sensitive luciferase assay. Consistency of results in the 3 participants supported an expanded evaluation of the safety/efficacy of etranacogene dezaparvovec in the HOPE-B (Health Outcomes With Padua Gene; Evaluation in Hemophilia-B) phase 3 trial. The current trial was registered at www.clinicaltrials.gov as #NCT03489291.
•Etranacogene dezaparvovec resulted in clinically relevant increases in FIX activity in severe/moderately severe hemophilia B over 6 months.•Etranacogene dezaparvovec eliminated bleeding and need for FIX replacement in patients with preexisting anti-AAV5 neutralizing antibodies.
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Ultrasound and patient self‐imaging in hemophilia Drygalski, Annette; Pasta, Gianluigi; Corte‐Rodriguez, Hortensia
Haemophilia : the official journal of the World Federation of Hemophilia,
March 2021, Letnik:
27, Številka:
2
Journal Article
Iron Metabolism in Man von Drygalski, Annette; Adamson, John W.
JPEN. Journal of parenteral and enteral nutrition,
September 2013, Letnik:
37, Številka:
5
Journal Article
Recenzirano
Iron metabolism in man is a highly regulated process designed to provide iron for erythropoiesis, mitochondrial energy production, electron transport, and cell proliferation. The mechanisms of iron ...handling also protect cells from the deleterious effects of free iron, which can produce oxidative damage of membranes, proteins, and lipids. Over the past decade, several important molecules involved in iron homeostasis have been discovered, and their function has expanded our understanding of iron trafficking under normal and pathological conditions. Physiologic iron metabolism is strongly influenced by inflammation, which clinically leads to anemia. Although hepcidin, a small circulating peptide produced by the liver, has been found to be the key regulator of iron trafficking, molecular pathways of iron sensing that control iron metabolism and hepcidin production are still incompletely understood. With this review, we provide an overview of the current understanding of iron metabolism, the recently discovered regulators of iron trafficking, and a focus on the effects of inflammation on the process.
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