508 results on '"Severe haemophilia A"'
Search Results
2. Relationship between plasma tissue Factor Pathway Inhibitor (TFPI) levels, thrombin generation and clinical risk of bleeding in patients with severe haemophilia A or B.
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Tardy‐Poncet, Brigitte, Montmartin, Aurélie, Chambost, Hervé, Lienhart, Anne, Frotscher, Birgit, Morange, Pierre‐Emmanuel, Falaise, Céline, Collange, Fanny, Dargaud, Yesim, Toussaint‐Hacquard, Marie, Ardillon, Laurent, Wibaut, Bénédicte, Jeanpierre, Emmanuelle, Nguyen, Philippe, Volot, Fabienne, and Tardy, Bernard
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HEMOPHILIACS , *THROMBIN , *PLATELET-rich plasma , *HEMORRHAGE - Abstract
Introduction: Bleeding severity in severe haemophilic patients, with low thrombin generation (TG) capacity, can vary widely between patients, possibly reflecting differences in tissue factor pathway inhibitor (TFPI) level. Aim: To compare free TFPI (fTFPI) levels in patients with severe haemophilia A (sHA) and severe haemophilia B (sHB) and to investigate in these patients as a whole the relationships between bleeding and TG potential, between TG potential and fTFPI level and between fTFPI level and bleeding tendency. Methods: Data on bleeding episodes retrospectively recorded during follow‐up visits over 5–10 years were collected and used to calculate the annualised joint bleeding rate (AJBR). fTFPI levels and basal TG parameters were determined in platelet‐poor plasma (PPP) and platelet‐rich plasma (PRP) using calibrated automated tomography (CAT). Results: Mean fTFPI levels did not differ significantly between sHA (n = 34) and sHB (n = 19) patients. Mean values of endogenous thrombin potential (ETP) and thrombin peak (peak) in PPP and PRP were two‐fold higher when fTFPI levels < 9.4 versus > 14.3 ng/mL. In patients treated on demand, ETP and peak in PRP were doubled when AJBR was ≤4.9$ \le 4.9$, AJBR being halved in patients with a low fTFPI level (9.4 ng/mL). In patients on factor prophylaxis, no association was found between TG parameters and either fTFPI level or AJBR. Conclusion: In patients treated on demand, bleeding tendency was influenced by fTFPI levels, which in turn affected basal TG potential. In patients on prophylaxis, bleeding tendency is probably determined primarily by the intensity of this treatment. [ABSTRACT FROM AUTHOR]
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- 2024
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3. Analysis of the correlation between body weight, body composition, and factor VIII recovery in paediatric patients with severe haemophilia A – a single-centre study
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Katarzyna Koch, Anna Liber, Grzegorz Dobaczewski, and Paweł Łaguna
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severe haemophilia a ,fviii recovery ,overweight ,obesity. ,Pediatrics ,RJ1-570 - Published
- 2023
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4. Analysis of the correlation between body weight, body composition, and factor VIII recovery in paediatric patients with severe haemophilia A - a single-centre study.
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Koch, Katarzyna, Liber, Anna, Dobaczewski, Grzegorz, and Łaguna, Paweł
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BODY composition ,HEMOPHILIA ,BODY weight ,ANTHROPOMETRY ,CHILDHOOD obesity ,LEAN body mass ,CROSS-sectional method ,PEDIATRICS ,SEVERITY of illness index ,PHYSICAL activity ,LEANNESS ,BIOELECTRIC impedance ,QUESTIONNAIRES ,BLOOD coagulation factors ,BODY mass index - Abstract
Introduction: Haemophilia A (HA) is a rare bleeding disorder. Patients with severe HA have a factor VIII activity of < 1%. The clinical picture of severe HA consists of a propensity for spontaneous haemorrhages to the skin, muscles, joints, and internal organs. To prevent severe complications of bleeds, patients with severe HA receive prophylaxis with deficient clotting factor. Obese people have larger absolute fat free mass (FFM) as well as fat mass than non-obese individuals of the same age, gender and height. Factor VIII (FVIII) concentrates are typically confined to the vascular space. Although the pharmacokinetics (PK) based FVIII dosing is becoming a standard in tailoring the prophylaxis for HA patients, the majority of them are still dosed according to total body weight and this may result in an overdose of FVIII. This study aimed to evaluate the PK of FVIII considering patients' body weight and body composition using electrical bioimpedance. Material and methods: Twenty-one boys with severe HA undergoing plasma-derived factor VIII prophylaxis were enrolled in the study. Patients underwent physical examination, body weight and height measurements, had body composition assessed using electrical bioimpedance, FVIII concentration was measured before and 30 min after FVIII administration, and FVIII recovery was evaluated. Patients completed a questionnaire regarding treatment, physical activity, and bleeding. Results: Of the patients who underwent the study, 47.6% had a normal body mass index (BMI), 42.8% were overweight, and 9.5% of patients were underweight. There was a correlation between patients' BMI and FVIII recovery, FFM and FVIII recovery, and fat mass and FVIII recovery. No relationship was found between FVIII recovery and bleeding rate. Conclusions: Determining factor VIII dosage according to FFM requires further study. [ABSTRACT FROM AUTHOR]
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- 2023
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5. Hemofi lia A grave con inhibidor: manejo clínico.
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Benítez Hidalgo, O. and Juárez Giménez, J. C.
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The treatment of haemophilia is based on the administration of the defi cient clotting factor (FVIII for haemophilia A and FIX for haemophilia B). One of the main complications is that the administration of factor concentrates can trigger production of inhibitory antibodies targeting the exogenous FVIII or FIX; this response neutralises the activity of the factors which have been administered, and therefore represents the most important complication of replacement therapies for patients with haemophilia. In patients who develop inhibitors, it becomes more diffi cult to prevent and treat bleeding episodes, with an increased risk of severe bleeding, and a greater likelihood of developing severe arthropathy with musculoskeletal sequelae. This leads to a reduction in quality of life for sufferers of haemophilia. In recent years, we have seen unprecedented advances in the management of patients with haemophilia, particularly in patients with haemophilia presenting with inhibitors. However, production of inhibitors continues to be a serious complication that impacts on how these patients are managed. This paper presents a clinical case of a patient with severe haemophilia A with inhibitors who underwent treatment with emicizumab for both eliminating this inhibitor and for simultaneous prophylaxis of bleeding events. [ABSTRACT FROM AUTHOR]
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- 2023
6. Assess the Efficacy and Safety of Personalized Prophylaxis Human-cl rhFVIII in Patients With Severe Haemophilia A
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- 2021
7. Altered brain activity and functional networks in school‐age boys with severe haemophilia A: A resting‐state functional magnetic resonance imaging study.
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Hu, Di, Liu, Jingran, Liu, Guoqing, Hu, Shasha, Li, Zekun, Wei, Yunyun, Zhang, Ningning, Wu, Runhui, and Peng, Yun
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FUNCTIONAL magnetic resonance imaging , *DEFAULT mode network , *SALIENCE network , *HEMOPHILIA , *DIAGNOSTIC imaging , *SOCIAL anxiety - Abstract
Introduction: Microstructural alterations of brain structure in haemophilic boys were found in our previous study. Aim: We investigated alterations of brain function in school‐age boys with severe haemophilia A (HA) with resting‐state functional magnetic resonance imaging (rs‐fMRI). Methods: We obtained rs‐fMRI scans from 24 boys with HA and 25 demographically matched healthy children. Spontaneous brain activity parameters were calculated. Graph theoretical analyses on rs‐fMRI data at the global and regional levels were performed. Two‐sample t tests were used to analyze differences, and correlation analyses identified relationships between altered neural properties and psychological characteristics. Results: Children with severe HA showed small‐worldness organization but with an increased efficiency and compactness in functional segregation. The whole brain showed an overtight connection pattern. At the regional level, significantly increased nodal efficiency in the salience network (SN), default mode network (DMN) and executive control network was found. Social Anxiety Scale for Children (SASC) scores were positively correlated with these alterations. Spontaneous brain activity alterations in regions including the cerebellum, frontal gyrus (orbital part), temporal gyrus and thalamus were observed; some of these regions have been closely related to social anxiety and family or social support. Conclusion: Our study is the first to evaluate the neurological functional changes in school‐age boys with severe HA. Disruptions in topographic characteristics and abnormal activity were closely related to social conditions. These data could help us to understand early neurological alterations in haemophilic children, improve the traditional view of family support and strengthen normal school life at an early stage. [ABSTRACT FROM AUTHOR]
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- 2022
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8. Efficacy and Cost Effectiveness of Pharmacokinetic Dosing in Haemophilia A
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University of Wales Cardiff United Kingdom (UK) and Uppsala University
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- 2018
9. Assess the Safety and Efficacy of Individually Tailored Prophylaxis With Human-cl rhFVIII in Patients With Severe Haemophilia A
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- 2018
10. Immune tolerance induction in severe haemophilia A: A UKHCDO inhibitor and paediatric working party consensus update.
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Hart, Daniel P., Alamelu, Jayanthi, Bhatnagar, Neha, Biss, Tina, Collins, Peter W., Hall, Georgina, Hay, Charles, Liesner, Ri, Makris, Michael, Mathias, Mary, Motwani, Jayashree, Palmer, Ben, Payne, Jeanette, Percy, Charles, Richards, Michael, Riddell, Anne, Talks, Kate, Tunstall, Oliver, and Chalmers, Elizabeth
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IMMUNOLOGICAL tolerance , *PEDIATRICS , *HEMOPHILIA , *EMICIZUMAB , *MEDICAL protocols , *GUIDELINES - Abstract
Introduction: In good risk patients (historic inhibitor peak < 200BU), the International Immune Tolerance Study demonstrated equal efficacy to induce tolerance between high (200iu/kg/day) and low dose (50iu/kg ×3 times/week) immune tolerance induction (ITI) regimens. However, the trial stopped early on account of the excessive bleed rate in the low dose ITI arm. Methods: United Kingdom Haemophilia Centre Doctors' Organization (UKHCDO) Paediatric and Inhibitor working parties considered available ITI data alongside the bi‐phenotypic antibody emicizumab (Hemlibra®) efficacy and safety data to develop a consensus guideline for the future UK ITI guideline. Results: This revision of UKHCDO ITI guidance incorporates the recommendation to use emicizumab as a prophylaxis haemostatic agent to reduce bleeding rates and to facilitate low dose and reduced frequency of FVIII CFC for ITI in the majority of children. Conclusion: This consensus protocol will facilitate future evaluation of ITI outcomes in the evolving landscape of haemophilia therapeutics and ITI strategies. [ABSTRACT FROM AUTHOR]
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- 2021
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11. Long‐term joint outcomes of regular low‐dose prophylaxis in Chinese children with severe haemophilia A.
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Wu, Yuefang, Lu, Jingjing, Zhou, Yin, Li, Kuixing, Liu, Ying, Liu, Shufen, Li, Zhuo, zhao, Yongqiang, Poon, Man‐Chiu, and Xiao, Juan
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MAGNETIC resonance imaging , *CHINESE people , *HEMOPHILIA , *PREVENTIVE medicine , *JOINT infections - Abstract
Objectives: To explore the long‐term joint outcomes of low‐dose prophylaxis in Chinese children with severe haemophilia A and to analyse their related factors. Methods: We retrospectively analysed follow‐up data from 21 severe haemophilia A children on regular low‐dose prophylaxis for 6–10 years. We used International Prophylaxis Study Group magnetic resonance imaging score (IPSG MRI score), Hemophilia Joint Health Score (HJHS), number of target joints, and Hemophilia‐Specific Quality of Life Index (Haemo‐QoL) to evaluate joint outcomes. Factors associated with these outcomes were evaluated by statistical analysis. Results: (1) The children were 1.75 to 17 years age at prophylaxis initiation. Median prophylactic factor VIII dose was 22.9 IU/kg per week. (2) At the end of follow‐up: (a) The total IPSG MRI scores were 2–24 with 90.5% children exhibiting moderate to severe joint involvement (score 7–24); (b) The HJHS ranged 2–27, with 0–10 for 46.7% children and >10 for 53.3% children. There was a positive correlation between the MRI score and HJHS (p <.05); (c) Compared to their on‐demand treatment period before prophylaxis, target joints numbers decreased, and no child needed auxiliary devices to walk; (d) Joint outcomes were positively correlated with the age at initiation of low‐dose prophylaxis (p <.05) and negatively correlated with the treatment dose. Conclusion: Long‐term low‐dose prophylaxis had positive effect on joint outcomes compared with on‐demand treatment. However, a certain degree of joint damage remained in all children indicating the need for improving the current strategy of low‐dose prophylaxis. [ABSTRACT FROM AUTHOR]
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- 2021
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12. Subclinical Joint Bleeding in Irish Adults With Severe Haemophilia A on Personalised Prophylaxis Regimens (PERSONAL)
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Baxter BioScience and Dr. Niamh O'Connell, Consultant Haematologist
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- 2014
13. Tissue‐inhibitors of metalloproteinase‐1 and vascular‐endothelial growth‐factor in severe haemophilia A children on low dose prophylactic recombinant factor VIII: Relation to subclinical arthropathy.
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Andrawes, Nevine Gamal, Saker, Hossam Mousa, Salah El‐Din, Nouran Yousef, and Abd Elhakim Hussain, Mervat
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HEMOPHILIA , *VASCULAR endothelial growth factors , *RECEIVER operating characteristic curves , *MAGNETIC resonance imaging - Abstract
Background: Subclinical synovitis occur long before clinical haemophilic arthropathy (HA). New biomarkers are needed for early detection of HA. Aim: To compare the levels of tissue inhibitors of metalloproteinase‐1 (TIMP‐1) and vascular endothelial growth factor (VEGF)in severe haemophilia A boys on prophylaxis and on‐demand therapy to healthy boys and correlate them with the haemophilia joint health score (HJHS) & the Denver magnetic resonance imaging (MRI) scale; hence, determine their values in early detection of HA. Methods: Haemophilia joint health score, serum TIMP‐1, VEGF and Denver MRI score were assessed in 50 boys with severe haemophilia A (31 on prophylactic factor VIII therapy (62%) with a dose of 15 IU/kg/twice weekly) and 50 age‐matched healthy boys. Results: Boys with severe haemophilia A had significantly higher TIMP‐1 240 ng/mL, SD200‐350 (P <.001) and VEGF 600 pg/mL, SD400‐1100 (P <.001). Their mean HJHS was 4.5 ± 3.0 (0‐11) and their mean Denver MRI score was 5.55 ± 1.6 (2.00‐8.00). A significant positive correlation was found between TIMP‐1 and VEGF (P <.001), BMI Z‐score (P =.029), HJHS (P =.041)and total MRI score (<.001). Significant correlations were found between VEGF and age (P <.001), HJHS (P =.003) and total MRI score (P <.001). Boys with severe haemophilia A on prophylaxis therapy had significantly lower HJHS (P =.021), VEGF (P <.001), TIMP‐1 (P =.002) and total MRI score (P =.021) than those on on‐demand therapy. Receiver operating characteristic curve, defined a cut‐off value of 160 ng/mL for TIMP‐1 with a sensitivity of 90% and specificity of 60% and that of 350 pg/mL for VEGF with a sensitivity of 78% and specificity of 88% for discrimination between severe haemophilia A and healthy boys. Conclusion: Vascular endothelial growth factor and TIMP‐1 can be used for early detection of HA. Further prospective studies should include larger study populations. In addition, studies should address the role of various anti‐VEGFs as potential therapy for HA and their impact on prevention and treatment of HA. [ABSTRACT FROM AUTHOR]
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- 2020
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14. Effect of low‐dose factor VIII prophylaxis therapy on bone mineral density and 25(OH) vitamin D level in children with severe haemophilia A.
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Gamal Andrawes, Nevine, Hashem Fayek, Manal, Salah El‐Din, Nouran, and Atef Mostafa, Raguia
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BONE density , *HEMOPHILIA , *VITAMIN D , *DUAL-energy X-ray absorptiometry , *VITAMIN D deficiency - Abstract
Background: Decreased bone mineral density (BMD) is a significant morbidity in haemophilia. Vitamin D is important for the bone health of people with haemophilia. Regular factor VIII prophylaxis can prevent bleeding and arthropathy. Aim: To determine the 25(OH) vitamin D level in severe haemophilia A patients and correlate it to their Hemophilia Joint Health Score (HJHS) and dual‐energy X‐ray absorptiometry (DEXA). We also compared the 25(OH) vitamin D and DEXA in haemophilia A and healthy children and in haemophilia A children on prophylaxis versus on‐demand therapy. Methods: Fifty severe haemophilia A patients were compared to 50 age‐matched healthy boys. Patients were recruited from the Pediatric Hematology Clinic, Ain Shams University from May 2017 to April 2018. Full medical history was taken with emphasis on frequency of bleeding episodes, duration and amplitude of pain assessed by the pain score. Weight, height, body mass index and HJHS were assessed. 25(OH) vit‐D3, calcium, phosphorus and alkaline phosphatase were measured. BMD was assessed using Lunar DEXA, paediatric software. Results: People with haemophilia had significantly lower 25(OH) vit‐D3 (P <.001) and DEXA z‐score (P <.001) than controls. Seventy per cent of patients were on factor VIII prophylaxis twice weekly (15U/kg/dose). Significant difference was found regarding DEXA z‐score (P =.012), 25(OH) vit‐D3 (P =.033) and HJHS (P =.022) among patients on prophylaxis and on‐demand therapy. Conclusion: Severe haemophilia A patients showed significantly lower 25(OH) vit‐D3 and DEXA than controls. Hence, vitamin D deficiency should be tested in all people with haemophilia for early diagnosis and treatment. Low‐dose prophylaxis in severe haemophilia preserves BMD and increases vitamin D. Further studies are required to evaluate the effect of different prophylaxis protocols on BMD and haemophilic arthropathy. [ABSTRACT FROM AUTHOR]
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- 2020
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15. Measuring the impact of changing from standard half‐life (SHL) to extended half‐life (EHL) FVIII prophylaxis on health‐related quality of life (HRQoL) in boys with moderate/severe haemophilia A: Lessons learned with the CHO‐KLAT tool
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Carcao, Manuel, Zunino, Laura, Young, Nancy L., Dover, Saunya, Bouskill, Vanessa, Hilliard, Pamela, Price, Victoria E., and Blanchette, Victor S.
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HEMOPHILIA , *QUALITY of life , *PREVENTIVE medicine - Abstract
Introduction: In many countries, there is a shift from standard half‐life (SHL) to extended half‐life (EHL) clotting factor concentrates (CFCs). Aim: To describe the experience of switching from SHL to an EHL FVIII CFC and the impact of this on frequency of infusions, factor consumption, bleeding rates and HRQoL using the Canadian Hemophilia Kids' Life Assessment Tool (CHO‐KLAT). Methods: A retrospective chart review was conducted at a single haemophilia treatment centre in 2018 that included boys (ages: 4‐18 years) with moderate/severe haemophilia A, without inhibitors, who switched from a SHL to an EHL FVIII CFC in the previous 2 years and for whom HRQoL data were available. Results: The study cohort comprised 38 boys [mean (SD) age: 11.0 (3.4) years] with moderate (n = 5)/severe (n = 33) haemophilia A. The switch was associated with a 33% reduction in the number of weekly infusions from a median of 3.5 to 2.3 (P <.0001) and a 17% reduction in median FVIII consumption from 103 IU/kg/wk to 85.5 IU/kg/wk (P =.004). There was no significant change in annualized joint bleed rates or in CHO‐KLAT scores. Conclusions: Despite documenting several benefits of switching to EHL FVIII (less infusions, lower factor consumption with no increase in bleeding), our study did not demonstrate any improvement in HRQoL. We conclude that either the current CHO‐KLAT tool is not optimized to measure burden of treatment administration in boys with low bleed rates switching from SHL to EHL FVIII CFCs or that a reduction of 1.2 infusions/week does not result in a meaningful change in HRQoL. [ABSTRACT FROM AUTHOR]
- Published
- 2020
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16. Impact of intermediate‐dose prophylaxis on progression of haemarthropathy in patients with severe haemophilia A: A 10‐year, single‐centre experience in Korea.
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Kim, Ju Y., Lee, Da J., Chun, Tong J., and You, Chur W.
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PREVENTIVE medicine , *HEMOPHILIA , *BLOOD coagulation disorders , *BLOOD diseases , *HEMORRHAGE - Abstract
Aim: To determine the impact of 10‐year intermediate‐dose prophylaxis on haemarthropathy progression in patients with severe haemophilia A (SHA). Methods: Prophylactic treatment with intermediate dose was given maximally for 10 years to 42 patients with SHA in a haemophilia treatment centre in Korea. Patients were divided into three groups based on prophylactic treatment started age: 1‐10 (group A'), 11‐20 (group B'), and ≥21 (group C'). Average annual increase of Pettersson score (P‐score) was compared between the treatment groups. Results: Average ages and P‐scores at initiation of prophylaxis were 4.65±3.43 years and 2.09±3.25, 16.13±1.73 years and 7.37±4.38, and 28.33±7.25 years and 12.33±6.50 for groups A', B', and C'. Average annual increase of P‐score in groups A', B', and C' was 0.039±0.11, 0.063±0.123, and 0.078±0.124. Assuming that intermediate‐dose prophylaxis started at the average age, P‐score and annual increase of P‐score would be the average values of each group; it would thus take 210 and 46.5 years to reach –2SD of the average critical level of haemarthropathy (The level of haemarthropathy (P‐score 13.0 ± 2.7) above which there is a significant impact on quality of life in Korean) in groups A' and B'. However, it would take 55 and 15.75 years if the annual P‐score increase were +2SD of the average value in groups A' and B'. Conclusion: Intermediate‐dose prophylaxis for patients with SHA in Korea would maintain arthropathy below the critical level for most of the patients' lifetime when started before adolescence. However, this would not be achieved in some adolescent patients with rapid progression of arthropathy and in most adult patients. [ABSTRACT FROM AUTHOR]
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- 2018
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17. Dental extractions on a patient with severe haemophilia A and inhibitors taking emicizumab prophylaxis. A case report and review
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Nigel Smithson and Aruche‐A‐Noor Hamid
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Emicizumab ,Pediatrics ,medicine.medical_specialty ,Dental extraction ,business.industry ,medicine.medical_treatment ,Medicine ,Surgery ,Severe haemophilia A ,Oral Surgery ,business ,Haemophilia ,medicine.disease - Published
- 2021
18. Real Life Population Pharmacokinetics Modelling of Eight Factors VIII in Patients with Severe Haemophilia A: Is It Always Relevant to Switch to an Extended Half-Life?
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Quentin Allard, Zoubir Djerada, Claire Pouplard, Yohann Repessé, Dominique Desprez, Hubert Galinat, Birgit Frotscher, Claire Berger, Annie Harroche, Anne Ryman, Claire Flaujac, Pierre Chamouni, Benoît Guillet, Fabienne Volot, Jean Szymezak, Philippe Nguyen, and Yoann Cazaubon
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factor VIII ,severe haemophilia A ,pharmacokinetics ,switch ,modelling ,dose tailoring ,Pharmacy and materia medica ,RS1-441 - Abstract
We retrospectively analysed the data files of 171 adults and 87 children/adolescents with severe haemophilia, except for 14 patients (moderate; minor) (1), to develop a global population pharmacokinetic (PK) model for eight factors VIII (FVIII) that could estimate individual PK parameters for targeting the desired level of FVIII activity (FVIII:C); and (2) to compare half-life (HL) in patients switching from a standard half-life (SHL) to an extended half-life (EHL) and evaluate the relevance of the switch. One-stage clotting assay for the measurement of FVIII activity (FVIII:C, IU/mL) was used for population PK modelling. The software, Monolix version 2019R1, was used for non-linear mixed-effects modelling. A linear two-compartment model best described FVIII:C. The estimated PK parameters (between-subject variability) were: 2640 mL (23.2%) for volume of central compartment (V1), 339 mL (46.8%) for volume of peripheral compartment (V2), 135 mL/h for Q (fixed random effect), and 204 mL/h (34.9%) for clearance (Cl). Weight, age, and categorical covariate EHL were found to influence Cl and only weight for V1. This model can be used for all of the FVIII cited in the study. Moreover, we demonstrated, in accordance with previous studies, that Elocta had longer half-life (EHL) than SHL (mean ratio: 1.48) as compared to Advate, Factane, Kogenate, Novoeight, and Refacto.
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- 2020
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19. Immune tolerance induction in severe haemophilia A: A UKHCDO inhibitor and paediatric working party consensus update
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Jayanthi Alamelu, Tina T. Biss, Mary Mathias, Georgina W. Hall, Oliver Tunstall, Neha Bhatnagar, Elizabeth Chalmers, Charles R. M. Hay, Jeanette Payne, Daniel P. Hart, Ben Palmer, Michael Makris, Charles Percy, Kate Talks, Peter William Collins, Anne Riddell, Michael Richards, Ri Liesner, and Jayashree Motwani
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Emicizumab ,medicine.medical_specialty ,Factor VIII ,business.industry ,Low dose ,Hemorrhage ,Hematology ,General Medicine ,Guideline ,Bleed ,Hemophilia A ,Haemophilia ,medicine.disease ,United Kingdom ,Immune tolerance ,Immune Tolerance ,medicine ,Humans ,Severe haemophilia A ,Child ,Intensive care medicine ,business ,Genetics (clinical) ,Consensus guideline - Abstract
INTRODUCTION In good risk patients (historic inhibitor peak
- Published
- 2021
20. Vaccinations are not associated with inhibitor development in boys with severe haemophilia A.
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Platokouki, H., van den Berg, H. M., Fischer, K., Gouw, S. C., Rafowicz, A., Carcao, M., Kenet, G., Liesner, R., Kurnik, K., and Rivard, G. E.
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VACCINATION , *HEMOPHILIA , *PATIENTS , *HEMORRHAGE , *MUSCLES - Abstract
Background: Inhibitor development in previously untreated patients (PUPs) with severe haemophilia A is a multifactorial event. It is unknown whether paediatric vaccinations given in close proximity to factor VIII (FVIII) are associated with inhibitor development. Objective: To assess whether paediatric vaccinations in close proximity to FVIII within the first 75 exposure days (EDs) are associated with inhibitor development in PUPs with severe haemophilia A. Methods: We included 375 PUPs with severe haemophilia A (<0.01 IU/mL) from the PedNet Registry who had received vaccinations between the first and 75th ED or inhibitor development. Inhibitor risk was compared between patients who did and who did not receive vaccinations within 24, 72 or 120 hours of FVIII infusion. Unadjusted and adjusted hazard ratios were calculated for any or repeated vaccinations in close proximity to FVIII, using Cox regression. Results: Inhibitor development occurred in 77 of 375 patients (20.5%). Overall inhibitor development appeared similar or lower in patients receiving vaccinations in close proximity to FVIII as compared to patients receiving vaccinations without FVIII: for 24 hours, this was 19.2% and 21.4% (
P = .186), for 72 hours, 16.4% and 27.3% (P = .023) and for 120 hours, 18.3% and 25.0% (P = .085), respectively. Conclusion: We found no association between vaccinations given in close proximity to FVIII exposure within the first 75 EDs and inhibitor development. Our data do not support avoiding administration of FVIII at time of routine vaccinations. [ABSTRACT FROM AUTHOR]- Published
- 2018
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21. The effect of emicizumab prophylaxis on long‐term, self‐reported physical health in persons with haemophilia A without factor VIII inhibitors in the HAVEN 3 and HAVEN 4 studies
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Amy D. Shapiro, Sylvia von Mackensen, Michael U. Callaghan, Ido Paz-Priel, Midori Shima, Steven W. Pipe, Víctor Jiménez-Yuste, Claude Negrier, Gallia G. Levy, Markus Niggli, Johnny Mahlangu, Sammy Chebon, Avrita Campinha-Bacote, Mark W. Skinner, Michaela Lehle, and Johannes Oldenburg
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Adult ,Change over time ,medicine.medical_specialty ,Haemophilia A ,haemophilia A ,030204 cardiovascular system & hematology ,Antibodies, Monoclonal, Humanized ,Hemophilia A ,03 medical and health sciences ,0302 clinical medicine ,work ,Quality of life ,Internal medicine ,Antibodies, Bispecific ,medicine ,Humans ,Genetics (clinical) ,Episodic treatment ,Emicizumab ,emicizumab ,health‐related quality of life ,Factor VIII ,business.industry ,Physical health ,Original Articles ,Hematology ,General Medicine ,medicine.disease ,therapeutic ,Pooled analysis ,Quality of Life ,Original Article ,Severe haemophilia A ,Muskuloskeletal ,prophylaxis ,Self Report ,business ,030215 immunology - Abstract
Introduction Severe haemophilia A (HA) has a major impact on health‐related quality of life (HRQoL). Aim Assess the impact of emicizumab on HRQoL in persons with severe HA (PwHA) without factor VIII (FVIII) inhibitors in the phase 3 HAVEN 3 and 4 studies. Methods This pooled analysis examines the HRQoL of PwHA aged ≥ 18 years treated with emicizumab prophylaxis via Haemophilia‐Specific Quality of Life Questionnaire for Adults (Haem‐A‐QoL) and EuroQoL 5‐Dimensions 5‐levels (EQ‐5D‐5L). In particular, changes from baseline in Haem‐A‐QoL ‘Physical Health’ (PH) domain and ‘Total Score’ (TS) are evaluated. Results Among 176 evaluable participants, 96 (55%) had received prior episodic treatment and 80 (45%) prophylaxis; 70% had ≥ 1 target joint and 51% had experienced ≥ 9 bleeds in the previous 24 weeks. Mean Haem‐A‐QoL PH and TS improved after emicizumab initiation. Mean (standard deviation) –12.0 (21.26)‐ and –8.6 (12.57)‐point improvements were observed in PH and TS from baseline to Week 73; Week 73 scores were 27.9 (24.54) and 22.0 (14.38), respectively. Fifty‐four percent of participants reported a clinically meaningful improvement in PH scores (≥ 10 points) by Week 73. Subgroups with poorer HRQoL prior to starting emicizumab (i.e. receiving episodic treatment, ≥ 9 bleeds, target joints) had the greatest improvements in PH scores, and corresponding reductions in missed workdays; change was not detected among those previously taking prophylaxis. No change over time was detected by the EQ‐5D‐5L questionnaire. Conclusions Emicizumab prophylaxis in PwHA without FVIII inhibitors resulted in persistent and meaningful improvements in Haem‐A‐QoL PH and less work disruption than previous treatment.
- Published
- 2021
22. Non-inhibitory antibodies inducing increased emicizumab clearance in a severe hemophilia A inhibitor patient
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Ivan Peyron, Delphine Borgel, Dominique Lasne, Thibaud Sefiane, Peter J. Lenting, Caterina Casari, Maximilien Desvages, Stéphanie Chhun, Cécile Bally, Laurent Frenzel, and Annie Harroche
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Emicizumab ,Factor VIII ,business.industry ,Hematology ,Case Reports ,Inhibitory antibodies ,Antibodies, Monoclonal, Humanized ,Hemophilia A ,Kinetics ,Immunology ,Antibodies, Bispecific ,Medicine ,Humans ,Severe haemophilia A ,business - Published
- 2021
23. Confirmed long-term safety and efficacy of prophylactic treatment with BAY 94-9027 in severe haemophilia A
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Pål Andre Holme, Karina Meijer, Claude Negrier, Shadan Lalezari, Ingrid Pabinger, Monika Maas Enriquez, Maria Wang, Lone Hvitfeldt Poulsen, Mark T. Reding, Pavani Chalasani, Maria Elisa Mancuso, and Real World Studies in PharmacoEpidemiology, -Genetics, -Economics and -Therapy (PEGET)
- Subjects
Male ,EXTENDED HALF-LIFE ,medicine.medical_specialty ,Haemophilia A ,haemophilia A ,030204 cardiovascular system & hematology ,Haemophilia ,Hemophilia A ,recombinant proteins ,Polyethylene Glycols ,03 medical and health sciences ,0302 clinical medicine ,Internal medicine ,PEGylated ,medicine ,Humans ,Genetics (clinical) ,Factor VIII ,business.industry ,Extension study ,Hematology ,General Medicine ,medicine.disease ,Regimen ,Treatment Outcome ,Severe haemophilia A ,Long term safety ,prophylaxis ,business ,Bay ,Extended half-life ,030215 immunology ,Prophylactic treatment - Abstract
Introduction: The phase 2/3 PROTECT VIII main study demonstrated efficacy and safety of BAY 94–9027 (damoctocog alfa pegol; Jivi®), a B-domain-deleted recombinant factor VIII (FVIII), site-specifically PEGylated to extend its half-life. Aim: To report the final efficacy and safety data for BAY 94–9027 from the PROTECT VIII extension. Methods: Previously treated males aged 12–65 years with severe haemophilia A (FVIII
- Published
- 2021
24. Correction of haemostasis can be reduced to four days for CVAD implantation in severe haemophilia A patients: Data from the PedNet study group
- Author
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Kobelt Rainer, Mäkipernaa Anne, Nolan Beatrice, Koskenvuo Minna, and Ranta Susanna
- Subjects
medicine.medical_specialty ,Intravenous treatment ,Haemophilia A ,030204 cardiovascular system & hematology ,Hemophilia A ,Hemostatics ,03 medical and health sciences ,0302 clinical medicine ,medicine ,Humans ,Child ,Infusions, Intravenous ,Genetics (clinical) ,Hemostasis ,business.industry ,Hematology ,General Medicine ,Perioperative ,Bleed ,medicine.disease ,3. Good health ,Venous access ,Surgery ,Single centre ,Cohort ,Severe haemophilia A ,business ,030215 immunology - Abstract
Introduction Central venous access devices (CVAD) are used to facilitate intravenous treatment with coagulation factor concentrates (CFCs) in haemophilia A (HA). Guidelines for perioperative CFC replacement therapy are based on single centre experiences, and the length of replacement therapy varies. Aim The aim of this study was to evaluate whether haemostasis coverage under four days is as effective and safe as a longer period of haemostatic coverage. Methods We identified patients with severe HA without inhibitors or major bleeds within one month of the surgery who received their first CVAD. We compared the CFC consumption and bleeds between children with ≤4 and those who received 5-7 perioperative treatment days including the day of surgery. Bleeds were recorded up to 4 days after the end of perioperative haemostatic coverage. Results In total, 144 children met the eligibility criteria and were included in the study cohort: 34 had received haemostatic coverage for ≤4 days, while 110 had received 5-7 days of haemostatic coverage. One bleed related to the surgery occurred in both groups. Conclusion Overall, the bleeding complications were rare. Haemostatic coverage with CFCs under ≤4 days with elective CVAD insertions was as effective as coverage for ≥5 days.
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- 2021
25. PROTECT VIII kids extension study: Long‐term safety and efficacy of BAY 94‐9027 (damoctocog alfa pegol) in children with severe haemophilia A
- Author
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Maria Elisa Mancuso, Monika Maas Enriquez, Tina T. Biss, Despina Tseneklidou-Stoeter, MacGregor Steele, Maria Wang, Krista Fischer, Gili Kenet, and Sanjay P Ahuja
- Subjects
Male ,FVIII ,damoctocog alfa pegol ,Pediatrics ,medicine.medical_specialty ,Haemophilia A ,haemophilia A ,030204 cardiovascular system & hematology ,Hemophilia A ,Haemophilia ,Recombinant factor viii ,Polyethylene Glycols ,03 medical and health sciences ,0302 clinical medicine ,children ,medicine ,Humans ,adolescents ,Child ,Clinical Haemophilia ,Genetics (clinical) ,Paediatric patients ,Factor VIII ,business.industry ,Extension study ,Infant, Newborn ,Original Articles ,Hematology ,General Medicine ,medicine.disease ,Treatment Outcome ,polyethylene glycol ,Original Article ,Severe haemophilia A ,prophylaxis ,Long term safety ,business ,Bay ,030215 immunology - Abstract
Introduction BAY 94‐9027 (damoctocog alfa pegol; an extended half‐life PEGylated recombinant factor VIII [FVIII]) demonstrated efficacy and safety in previously treated paediatric patients (PTPs) aged
- Published
- 2021
26. Evolution of clotting factor concentrates prescriptions and impact of recommendations of prophylaxis in children with haemophilia
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Florianne Bel, Alban Revy, Valérie Chamouard, Sandrine Meunier, and Anne Lienhart
- Subjects
Clotting factor ,Pediatrics ,medicine.medical_specialty ,Factor VIII ,business.industry ,Medical record ,Hemophilia A ,Haemophilia ,medicine.disease ,030226 pharmacology & pharmacy ,Blood Coagulation Factors ,03 medical and health sciences ,Regimen ,Prescriptions ,0302 clinical medicine ,Cohort ,Humans ,Medicine ,Pharmacology (medical) ,Severe haemophilia A ,Medical prescription ,Child ,business ,Birth Year ,Retrospective Studies - Abstract
Prophylaxis treatment is considered as the reference approach for children with severe haemophilia A or B. However, no consensus about the best prophylaxis protocol has yet been identified in term of dosage and timing of infusions. Guidelines were drawn up in France in the early 2000s by an expert group. The objective of this 16-year study (2001 to 2016) was to describe the clotting factor concentrates (CFCs) use in haemophiac outpatients. This is a retrospective monocentric study. Pharmaceutical and clinical data were captured using medical records. Main outcome measures are CFCs use and clinical data in paediatrics. Eighty haemophiliacs A or B under 12 years old with a factor level less than 2% were included (74% of HA), from pharmaceutical outpatient data. Global use of CFCs followed the evolution of the patients' number and regimen type introduced: increase of prophylaxis and decrease of on demand regimen. The average age at the prophylaxis introduction is significantly different according to the birth year. Prophylaxis introduction was made earlier with an increase of prophylactic regimen joined to an increase of CFCs use. The significant reduction of haemarthrosis in our cohort can be linked to a first infusion age and a prophylaxis introduction much earlier.
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- 2021
27. Case report of nasal pseudotumor – a rare presentation in severe haemophilia A with high titre inhibitors
- Author
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Utpal Jana, Malini Garg, Debasis Gantait, and Prakas Kumar Mandal
- Subjects
Pediatrics ,medicine.medical_specialty ,business.industry ,Pharmacy ,030204 cardiovascular system & hematology ,stomatognathic diseases ,03 medical and health sciences ,0302 clinical medicine ,hemic and lymphatic diseases ,medicine ,Severe haemophilia A ,030212 general & internal medicine ,Presentation (obstetrics) ,business ,High titre - Abstract
Haemophilia patients with inhibitors suffer from increased morbidity and mortality due to the ineffectiveness of factor VIII replacement. Pseudotumors are rare but dangerous complications in these patients, and nasal pseudotumors are even rarer. Here, we present the case of a young child with severe haemophilia A with high titre inhibitors who developed a nasal pseudotumor. When immune tolerance therapy was not possible due to financial constraints, he was treated with FEIBA prophylaxis and rituximab. The pseudotumor was managed with surgical excision. We conclude that epistaxis in haemophiliacs can be due to an underlying nasal pseudotumor, and highlight the use of rituximab for the eradication of inhibitors.
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- 2021
28. Bone mineral density in Canadian children with severe haemophilia A or B: a cross-sectional study
- Author
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Cecily Bos, Karen Strike, Anthony Kc Chan, John K. Wu, and Paul Tieu
- Subjects
musculoskeletal diseases ,Bone mineral ,Pediatrics ,medicine.medical_specialty ,Cross-sectional study ,business.industry ,Medicine ,Severe haemophilia A ,business - Abstract
Background Previous research has shown that bone mineral density (BMD), a measure of bone strength, may be lower among people with haemophilia. However, the majority of this research has been done in adults and in countries where the treatment for haemophilia differs from the standard of care in Canada, and there is a lack of paediatric data. Aims The primary objective of this study was to determine whether Canadian children and youth with severe haemophilia A and B have BMD similar to healthy controls matched for height, age and weight (HAW-score). Secondary objectives included the exploration of any association between BMD and the following variables: factor replacement regimen, Hemophilia Joint Health Score (HJHS), bleeding history, physical activity level, and dietary intake of calcium, vitamin D, vitamin K and protein. Methods A cross-sectional observational study was designed to determine the BMD of children with severe haemophilia A and B in Canada. Ethical approvals were obtained from participating institutions. Thirty-eight participants aged 3–18 with severe haemophilia A and B were recruited from two treatment centres in Canada. Subjects underwent dual-energy X-ray absorptiometry (DXA) scan, and data was collected from regular clinic visit to identify factor replacement regimen, HJHS, and number of joint bleeds over the lifespan. Physical activity level and dietary intake of calcium, vitamin D, vitamin K and protein were identified using self-report questionnaires. Results Participants showed a mean spine BMD Z-score and HAW-score higher than controls, with no participants showing a spine Z-score or HAW-score of Conclusion Canadian children with severe haemophilia A and B demonstrate differences in spine and total body BMD from height-, age-, and weight-matched controls, where spine BMD is higher than controls and total body BMD is lower than controls. Studies with a larger sample size are needed to clarify the status of BMD in children with haemophilia treated with primary prophylaxis.
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- 2021
29. Real‐world data of immune tolerance induction using recombinant factor VIII Fc fusion protein in patients with severe haemophilia A with inhibitors at high risk for immune tolerance induction failure: A follow‐up retrospective analysis
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Victoria Price, Haowei Linda Sun, Nisha Jain, Elisa Tsao, Jennifer A. Dumont, Janice M. Staber, Hilda Ding, Manuel Carcao, Zahra Al-Khateeb, Mark Belletrutti, Sanjay P Ahuja, MacGregor Steele, Steven W. Pipe, Amy D. Shapiro, Michael Wang, Jing Feng, Nina Hwang, and Kenneth Lieuw
- Subjects
Haemophilia A ,MEDLINE ,recombinant factor VIII Fc fusion protein ,haemophilia A ,Hemophilia A ,Recombinant factor viii ,Immune tolerance ,Retrospective analysis ,Immune Tolerance ,Medicine ,Humans ,In patient ,Letter to the Editor ,Genetics (clinical) ,Retrospective Studies ,immune tolerance induction ,Factor VIII ,business.industry ,Hematology ,General Medicine ,medicine.disease ,rescue therapy ,inhibitor ,Fc fusion ,Immunology ,retrospective chart review ,Severe haemophilia A ,business ,Follow-Up Studies - Published
- 2020
30. [Assessment of the budgetary impact of an emicizumab therapy introduction for patients with severe haemophilia A without inhibitor].
- Author
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Oka G, Pieragostini R, Roussel-Robert V, Paubel P, Degrassat-Theas A, and Lopez I
- Subjects
- Adolescent, Humans, Antibodies, Monoclonal, Humanized therapeutic use, Retrospective Studies, Antibodies, Bispecific therapeutic use, Antibodies, Bispecific pharmacology, Hemophilia A drug therapy
- Abstract
Since March 2019, émicizumab is indicated for the treatment of patients with severe haemophilia A without inhibitor. This therapy's price amounts approximately to €33 600 per 4 weeks for a 70kg patient which represents about two times more than a factor VIII concentrates treatment's price. This study aims to assess the budgetary impact for the French Health Insurance of an émicizumab therapy introduction for patients with severe haemophilia A without inhibitor. It was an observational, retrospective, and monocentric study. Every severe haemophilia A without inhibitor patient over 18 years old followed at the Cochin Hospital haemophilia treatment centre who received émicizumab from June 2020 and for at least one year have been included. The budgetary impact was estimated by comparing the total costs of patient care the year before versus the year after émicizumab initiation. Total costs of patient care included prices of i) treatments consumed, ii) consultations with specialist physicians, iii) hospitalizations and iv) imaging procedures. Thirty-eight patients were included. The total cost of patient care increased significantly the year after émicizumab introduction (P < 0.0001). On average, this cost was estimated at €537 887 ± €137 139 per patient whereas it was at €151 442 ± €94 708 the year before. While costs of physician consultations increased, no significant difference has been reported about hospitalizations and imaging costs. Over a one-year period, émicizumab therapy significantly increased the total costs of patient care. It is mostly caused by the drug price itself., (Copyright © 2022 Académie Nationale de Pharmacie. Published by Elsevier Masson SAS. All rights reserved.)
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- 2023
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31. HL-A*11:01, -B*51:01, -DQB1*02:02 and -DRB1*07:01 are associated with inhibitor development in boys with severe haemophilia A receiving rFVIII prophylaxis in Poland
- Author
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You-Qiang Song, Maciej Borowiec, Katarzyna Babol-Pokora, Bogusław Tymoniuk, Szymon Janczar, Wojciech Młynarski, and Ming Yue
- Subjects
Male ,Pediatrics ,medicine.medical_specialty ,Factor VIII ,business.industry ,Hematology ,Human leukocyte antigen ,Hemophilia A ,Haemophilia ,medicine.disease ,Humans ,Medicine ,Severe haemophilia A ,Poland ,business - Published
- 2021
32. Inhibitor development in previously untreated patients with severe haemophilia: A comparison of included patients and outcomes between a clinical study and a registry‐based study
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H. Marijke van den Berg, Peter G. M. Mol, Arno W. Hoes, Carla J. Jonker, Katrien Oude Rengerink, and Real World Studies in PharmacoEpidemiology, -Genetics, -Economics and -Therapy (PEGET)
- Subjects
Male ,previously untreated patients ,medicine.medical_specialty ,PREDICTION ,Haemophilia A ,haemophilia A ,registry ,030204 cardiovascular system & hematology ,Gene mutation ,Hemophilia A ,Orphan drug ,03 medical and health sciences ,0302 clinical medicine ,Disease registry ,Risk Factors ,FACTOR-VIII INHIBITORS ,Internal medicine ,SUPPORT ,Genotype ,medicine ,Humans ,Registries ,Family history ,Child ,Clinical Haemophilia ,Genetics (clinical) ,business.industry ,Original Articles ,Hematology ,General Medicine ,medicine.disease ,inhibitor development ,PRODUCTS ,Treatment Outcome ,TRIALS ,factor VIII ,Sample size determination ,Child, Preschool ,Female ,Original Article ,Severe haemophilia A ,RARE DISEASES ,business ,030215 immunology - Abstract
Aim The aim of this study was to investigate whether a disease registry could serve as a suitable alternative to clinical studies to investigate safety of orphan drugs in children. Methods We used individual patient data from previously untreated patients (PUPs) with severe haemophilia A from the factor VIII (rAHF‐PFM)‐clinical study and the PedNet registry. The primary outcome was the patient characteristics at entry and the difference in inhibitor development between the clinical study and the registry‐based study at 50 exposure days. Results Clinical study patients more often had a positive family history of inhibitors (31% vs 10%) and a high‐risk F8 genotype (82% vs 63%). In the clinical study 41/55 (75%) and in the registry‐based study 162/168 (96%) patients reached 50 exposure days. Inhibitors developed in 16 of the 41 patients in the clinical study (39%) vs 44 of the 162 patients in the registry‐based study (27%); seven patients (7%) vs 28 patients (17%) had high‐titre inhibitors. The risk of developing an inhibitor during the first 50 exposure days was similar (HR 1.04; 95% CI 0.56‐1.94), when adjusted for family history of inhibitors, F8 gene mutation and intensive treatment at first exposure. Conclusion In the registry‐based study, patient numbers and completeness of follow‐up were higher. The risk of developing an inhibitor to a single product was comparable. Although the sample size of this study was too small to conclude on differences in high‐ or low‐titre inhibitors, this suggests that a registry could serve as a more suitable source for evaluation of high‐titre inhibitors in the setting of factor VIII deficiency.
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- 2020
33. Influence of blood group, von Willebrand factor levels, and age on factor VIII levels in non‐severe haemophilia A
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Cornelia Gabler, Judit Rejtő, Peter Quehenberger, Gerhard Schuster, Ella Grilz, Cihan Ay, Ingrid Pabinger, Johanna Gebhart, Raute Sunder-Plaßmann, Stefanie Hofer, Oliver Königsbrügge, Lisa-Marie Mauracher, and Clemens Feistritzer
- Subjects
congenital, hereditary, and neonatal diseases and abnormalities ,medicine.medical_specialty ,animal diseases ,Haemophilia A ,haemophilia A ,030204 cardiovascular system & hematology ,Hemophilia A ,ABO Blood-Group System ,diagnostic techniques and procedures ,03 medical and health sciences ,0302 clinical medicine ,Von Willebrand factor ,Antigen ,Interquartile range ,hemic and lymphatic diseases ,ABO blood group system ,Internal medicine ,von Willebrand Factor ,medicine ,Humans ,Factor VIII ,biology ,business.industry ,Brief Report ,HAEMOSTASIS ,Background data ,Chromogenic substrate assay ,Hematology ,medicine.disease ,von Willebrand Diseases ,Endocrinology ,Blood Grouping and Crossmatching ,ABO blood‐group system ,biology.protein ,Brief Reports ,Severe haemophilia A ,business - Abstract
Background Data on the effect of ABO blood group (ABO), von Willebrand factor (VWF) levels, and age on factor VIII (FVIII) in non-severe haemophilia A (HA) is scarce. Objective To investigate if ABO, VWF levels, and age have an influence on the variability of FVIII levels and consequently on the assessment of severity in non-severe HA. Patients/methods Eighty-nine patients with non-severe HA and 82 healthy controls were included. Data on ABO was collected and FVIII clotting activity (FVIII:C) with one-stage clotting assay (FVIII:C OSA) and chromogenic substrate assay (FVIII:C CSA), FVIII antigen (FVIII:Ag) and VWF antigen (VWF:Ag) and activity (VWF:Act) were determined. Results In HA, FVIII:C OSA and CSA and FVIII:Ag were not different between non-O (n = 42, median 15.5, interquartile range 10.4-24.0; 10.0, 6.8-26.0 and 15.2, 10.7-24.9) and O (n = 47, 14.1, 9.0-23.0; 10.0, 5.0-23.0 and 15.2, 9.3-35.5), whereas in healthy controls, non-O individuals had significantly higher FVIII levels. Fviii C showed no relevant correlation with VWF levels in HA, but we observed strong correlations in healthy controls. Age had only a minor influence in HA, but had a considerable impact on FVIII:C in healthy controls. In multivariable regression analysis ABO, VWF:Ag and age were not associated with FVIII:C in HA, whereas this model explained 61.3% of the FVIII:C variance in healthy controls. Conclusions We conclude that in non-severe HA ABO and VWF levels do not substantially influence the variability of FVIII levels and age has only minor effects on it, which is important information for diagnostic procedures.
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- 2020
34. Turoctocog alfa pegol provides effective management for major and minor surgical procedures in patients across all age groups with severe haemophilia A: Full data set from the pathfinder 3 and 5 phase III trials
- Author
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Kingsley Hampton, Steven R. Lentz, Chunduo Shen, Elena Santagostino, Karina Meijer, Anne T. Neff, Jameela Sathar, Alberto Tosetto, Andrea Landorph, László Nemes, Pratima Chowdary, and Real World Studies in PharmacoEpidemiology, -Genetics, -Economics and -Therapy (PEGET)
- Subjects
Male ,PHARMACOKINETICS ,SURGERY ,030204 cardiovascular system & hematology ,FACTORVIII ,0302 clinical medicine ,hemic and lymphatic diseases ,Clinical endpoint ,Medicine ,extended half-life ,CLINICAL-EVALUATION ,Genetics (clinical) ,Not evaluated ,extended half‐life ,FACTOR-VIII ,Hematology ,General Medicine ,Middle Aged ,Recombinant Proteins ,REPLACEMENT ,factor VIII ,SAFETY ,Original Article ,Female ,Severe haemophilia A ,PLASMA/ALBUMIN-FREE METHOD ,Adult ,medicine.medical_specialty ,Adolescent ,Haemophilia A ,turoctocog alfa pegol ,haemophilia A ,Hemophilia A ,Haemophilia ,GLYCOPEGYLATED RECOMBINANT FVIII ,Young Adult ,03 medical and health sciences ,Humans ,In patient ,Clinical Haemophilia ,Aged ,business.industry ,Original Articles ,Perioperative ,Turoctocog alfa ,EFFICACY ,medicine.disease ,Surgery ,haemostasis ,Minor Surgical Procedures ,business ,030215 immunology - Abstract
Introduction Turoctocog alfa pegol is a glycoPEGylated recombinant factor VIII (FVIII) with an extended half‐life developed for prophylaxis, treatment of bleeds and perioperative management in patients with haemophilia A. Aim Evaluate the efficacy and safety of turoctocog alfa pegol treatment for major and minor surgeries in the pathfinder 3 and 5 phase III trials. Methods Adults/adolescents aged ≥12 years with severe haemophilia A (FVIII 80% during major surgery (pathfinder 3). The primary end point was haemostatic efficacy during surgery; secondary end points were blood loss, haemostatic effect postsurgery, consumption, transfusions, safety and health economics. Children (0‐11 years) undergoing minor surgeries received 20‐75 IU/kg turoctocog alfa pegol at Investigator's discretion (pathfinder 5). Results pathfinder 3 included 35 patients undergoing 49 major surgeries. Haemostasis was successful in 47/49 (95.9%) surgeries; two had moderate haemostatic responses. Median (mean) blood loss during major surgery was 75 (322.6) mL. Four bleeds were reported postsurgery; three were successfully treated with turoctocog alfa pegol (one was not evaluated). On the day of surgery, overall mean (median) dose was 75.5 (74.5) IU/kg and mean (median) number of doses was 1.7 (2.0). Five procedures required 11 transfusions on the day of surgery or days 1‐6. No safety concerns or inhibitors were identified. Forty‐five minor surgeries in 23 children were performed without complications. Conclusion Turoctocog alfa pegol was effective for perioperative haemostatic management of major and minor surgeries in patients across age groups with severe haemophilia A.
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- 2020
35. BAY 81‐8973 demonstrated efficacy, safety and joint status improvement in patients with severe haemophilia A in the LEOPOLD I extension for ≤2 years
- Author
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Nikki Church, Despina Tseneklidou-Stoeter, Elena Santagostino, Shadan Lalezari, Johnny Mahlangu, Maria Fernanda Lopez Fernandez, and Horst Beckmann
- Subjects
Adult ,Male ,medicine.medical_specialty ,Adolescent ,Haemophilia A ,haemophilia A ,Hemophilia A ,recombinant proteins ,Severity of Illness Index ,Young Adult ,03 medical and health sciences ,0302 clinical medicine ,Internal medicine ,Hemarthrosis ,medicine ,Humans ,In patient ,Myocardial infarction ,Child ,Adverse effect ,Aged ,recombinant factor VIII ,Factor VIII ,business.industry ,clinical trial ,Original Articles ,Hematology ,General Medicine ,Middle Aged ,medicine.disease ,Clinical trial ,Treatment Outcome ,Tolerability ,030220 oncology & carcinogenesis ,Quality of Life ,Original Article ,intravenous infusions ,Severe haemophilia A ,business ,Bay ,030215 immunology - Abstract
Objectives BAY 81‐8973 (Kovaltry®), a full‐length, unmodified, recombinant human factor VIII, provided excellent bleeding control for patients with haemophilia A in the pivotal 1‐year LEOPOLD I trial. The LEOPOLD I extension evaluated long‐term efficacy and safety of BAY 81‐8973 prophylaxis. Methods After completing LEOPOLD I, patients continued receiving 20‒50 IU/kg BAY 81‐8973 two‐ or three‐times weekly in the extension. Outcomes included annualised bleeding rate (ABR) and haemostasis during surgery. Results Fifty‐five patients aged 12‐65 years participated in the extension. Median (range) exposure days during the 2‐year total study period was 309 (115‐355). No patient switched regimens. Median (Q1; Q3) ABR for all bleeds was 2.0 (1.0; 6.1) during the pivotal study, 2.0 (0.0; 5.2) during the extension, and 2.0 (0.5; 5.5) combined. The proportion of joint bleeds affecting target joints decreased (pivotal study: 90.9%, extension: 60.0%). Haemostasis was assessed as excellent/good in all five major surgeries. One serious adverse event (myocardial infarction) occurred in a patient with cardiovascular risk factors. No patients developed inhibitors. Conclusions BAY 81‐8973 prophylaxis efficacy outcomes in the pivotal study were maintained or, in the case of joint protection, improved during the extension, with a safety and tolerability profile consistent with previous experience.
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- 2020
36. Recombinant factor VIII Fc fusion protein for the treatment of severe haemophilia A: Final results from the ASPIRE extension study
- Author
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Bent Winding, Keiji Nogami, Guy Young, Chris Barnes, Huixing Yuan, Johannes Oldenburg, Elena Santagostino, Liane Khoo, Beatrice Nolan, Barbara A. Konkle, Joachim Fruebis, K. John Pasi, Ingrid Pabinger, Dan Rudin, and Johnny Mahlangu
- Subjects
Adult ,Male ,medicine.medical_specialty ,Adolescent ,Recombinant Fusion Proteins ,030204 cardiovascular system & hematology ,Haemophilia ,Hemophilia A ,Recombinant factor viii ,bleed rate ,03 medical and health sciences ,Young Adult ,0302 clinical medicine ,Internal medicine ,medicine ,Clinical endpoint ,Humans ,Clinical Haemophilia ,Child ,Genetics (clinical) ,rFVIIIFc ,Aged ,extended half‐life ,Factor VIII ,business.industry ,Hematology ,General Medicine ,Original Articles ,Bleed ,Middle Aged ,medicine.disease ,Confidence interval ,Immunoglobulin Fc Fragments ,Regimen ,Fc fusion ,Treatment Outcome ,individualized prophylaxis ,Child, Preschool ,Severe haemophilia A ,Original Article ,Female ,business ,perioperative haemostasis ,030215 immunology - Abstract
Introduction The efficacy and safety of recombinant factor VIII Fc fusion protein (rFVIIIFc) as an extended half‐life treatment for severe haemophilia A were demonstrated in the Phase 3 A‐LONG and Kids A‐LONG studies. Eligible subjects who completed A‐LONG and Kids A‐LONG could enrol in ASPIRE (NCT01454739), an open‐label extension study. Aim To report the long‐term safety and efficacy of rFVIIIFc in subjects with severe haemophilia A who enrolled in ASPIRE. Methods Previously treated subjects received one or more of the following regimens: individualized prophylaxis (IP), weekly prophylaxis, modified prophylaxis or episodic treatment. Subjects could switch treatment regimen at any time. The primary endpoint was inhibitor development. Results A total of 150 subjects from A‐LONG and 61 subjects from Kids A‐LONG enrolled in ASPIRE. Most subjects received the IP regimen (A‐LONG: n = 110; Kids A‐LONG: n = 59). Median (range) treatment duration in ASPIRE for subjects from A‐LONG and Kids A‐LONG was 3.9 (0.1‐5.3) years and 3.2 (0.3‐3.9) years, respectively. No inhibitors were observed (0 per 1000 subject‐years; 95% confidence interval, 0‐5.2) and the overall rFVIIIFc safety profile was consistent with prior studies. For subjects on the IP regimen, annualized bleed rates (ABR) remained low (median overall ABR for adults and adolescents was
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- 2020
37. A new paradigm for personalized prophylaxis for patients with severe haemophilia A
- Author
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Edouard Ollier, Anne Lienhart, Xavier Delavenne, and Yesim Dargaud
- Subjects
Adult ,Male ,Adolescent ,business.operation ,Post hoc ,Haemophilia A ,haemophilia A ,030204 cardiovascular system & hematology ,Hemophilia A ,Octapharma ,Young Adult ,03 medical and health sciences ,0302 clinical medicine ,thrombin generation assay ,Pharmacokinetics ,hemic and lymphatic diseases ,Humans ,Medicine ,Dosing ,Clinical Haemophilia ,Genetics (clinical) ,Aged ,business.industry ,Original Articles ,Hematology ,General Medicine ,Middle Aged ,bleeding ,medicine.disease ,Treatment Outcome ,factor VIII ,Anesthesia ,Pharmacodynamics ,Trough level ,Female ,Original Article ,Severe haemophilia A ,prophylaxis ,business ,pharmacokinetics ,030215 immunology - Abstract
Aim For patients with severe haemophilia A, guidelines recommend prophylactic treatment with FVIII, with dose calculations targeting a predetermined FVIII trough level. However, this pharmacokinetic (PK) approach is suboptimal, with some patients experiencing breakthrough bleeds. We aimed to improve FVIII dosing by incorporating the thrombin generation assay, a global haemostasis assay whose main pharmacodynamic (PD) parameter, endogenous thrombin potential (ETP), predicts spontaneous bleeding risk. Methods We performed post hoc combined PK‐PD modelling using data from 66 adults who received human‐cl rhFVIII (Nuwiq®, Octapharma AG) in a phase IIIb study. Time‐to‐event analyses simulated the probability of spontaneous bleeding for different FVIII exposures and baseline ETPs. Results Ninety‐one spontaneous bleeds occurred in 20/66 patients. The relationship between FVIII:C and ETP was non‐linear, and the sigmoid Emax model adequately described the data. Individual PK‐PD Bayesian estimation significantly improved predictive performance. Simulations showed that the mean spontaneous annual bleeding rate decreased with increasing baseline ETP or dosing: with ETP values of 200, 400 and 600 (nmol/L)·min annual bleeding rates were 2.36, 1.25 and 0.66, respectively, on 40 IU/kg human‐cl rhFVIII every 3 days; and annual bleeding rates were 2.09, 1.10, and 0.60, respectively, on 60 IU/kg every 3 days. Conclusion Prophylactic FVIII dosing is more clinically meaningful when incorporating ETP alongside FVIII level. For the first time, FVIII dosing can be personalized with the aim of eliminating spontaneous breakthrough bleeds.
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- 2020
38. Adherence to prophylaxis in adolescents and young adults with severe haemophilia: a qualitative study with healthcare professionals
- Author
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Nicholas A. Troop, S. van Os, Nuala Ryder, and Daniel P. Hart
- Subjects
medicine.medical_specialty ,Health (social science) ,haemophilia ,Haemophilia ,03 medical and health sciences ,Behavioral Neuroscience ,0302 clinical medicine ,hemic and lymphatic diseases ,medicine ,Psychology ,030212 general & internal medicine ,adherence ,Young adult ,License ,General Psychology ,030505 public health ,Health professionals ,Creative commons ,Articles ,medicine.disease ,personalised treatment ,BF1-990 ,Family medicine ,Medicine ,Severe haemophilia A ,prophylaxis ,0305 other medical science ,Attribution ,adolescents and young adults ,Qualitative research ,Research Article - Abstract
Aim: to examine healthcare professionals’ (HP) perceptions and experiences in relation to adherence to prophylactic treatment among young people living with haemophilia (YPH). Methods: All HPs in four haemophilia centres across England and Wales were invited to participate, and all HPs who agreed to take part (n = 6) were interviewed. Interviews were audio-recorded, transcribed and then analysed using Interpretative Phenomenological Analysis (IPA). Results: HPs estimate that generally young people with haemophilia keep to their treatment regimen well, although they also recognise that adherence may fluctuate with many patients going through shorter periods of non-adherence. The increasingly personalised or flexible approach to prophylaxis makes it harder to assess adherence. The main themes identified through IPA included (1) HPs’ suggest that adherence fluctuates (2) Non-adherence is mainly driven by lifestyle and developmental, social and family factors, and (3) Education, HPs’ sensitivity to individual needs, and psychological and peer support are key facilitators of good adherence. Conclusion: The increasingly flexible approach to prophylaxis requires a new way of thinking about, and assessment of, adherence. More personalised treatment regimen can be more complicated and may, therefore, lead to accidental non-adherence. The results of this study with HPs complement those of a previous qualitative study with patients but place greater emphasis on a broader perspective on understanding drivers of non-adherence as well as understanding strategies to improve adherence in the minority of patients who appear to struggle.
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- 2020
39. The one-stage assay or chromogenic assay to monitor baseline factor VIII levels and desmopressin effect in non-severe haemophilia A: Superiority or non-inferiority?
- Author
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Marieke J. H. A. Kruip, Luca S Hodes, Iris van Moort, Moniek P.M. de Maat, Sara C. M. Stoof, Lisette M. Schütte, Frank W.G. Leebeek, Marjon H. Cnossen, Hematology, and Pediatrics
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Adult ,Male ,desmopressin ,congenital, hereditary, and neonatal diseases and abnormalities ,medicine.medical_specialty ,Adolescent ,Haemophilia A ,haemophilia A ,030204 cardiovascular system & hematology ,Hemophilia A ,Gastroenterology ,Young Adult ,03 medical and health sciences ,chromogenic assay ,0302 clinical medicine ,Non inferiority ,hemic and lymphatic diseases ,Internal medicine ,medicine ,Humans ,Outpatient clinic ,Deamino Arginine Vasopressin ,one‐stage assay ,Desmopressin ,Genetics (clinical) ,Aged ,Retrospective Studies ,Aged, 80 and over ,Factor VIII ,business.industry ,Chromogenic ,One stage ,Original Articles ,Hematology ,General Medicine ,Factor VIII Activity ,Middle Aged ,medicine.disease ,Laboratory Science ,bleeding phenotype ,Original Article ,Severe haemophilia A ,business ,030215 immunology ,medicine.drug - Abstract
Introduction Diagnosis, treatment monitoring and assessment of desmopressin effect in haemophilia A patients are performed by measurement of factor VIII activity (FVIII). The two assays commonly applied are the one‐stage assay and the chromogenic assay. Especially in non‐severe haemophilia A, discrepancies between these assays are common. It is still unestablished which assay corresponds best with bleeding phenotype and desmopressin effect. Aim To correlate FVIII levels measured by the one‐stage assay and by the chromogenic assay with bleeding phenotype and, additionally, to compare FVIII assay discrepancies before and after desmopressin administration. Method Factor VIII was measured in 130 non‐severe haemophilia A patients during routine visits to the outpatient clinic and/or during desmopressin testing. FVIII was measured by both the one‐stage assay and the chromogenic assay. Discrepancies between assays were defined as at least a twofold difference of FVIII or an absolute FVIII difference between measurements of ≥0.10 IU/mL. Bleeding phenotype was defined as annual number of treated bleedings (adjusted ABR). Results Hundred and thirty non‐severe haemophilia A patients were included. In 31/130 patients, assay results were discrepant. However, FVIII measurements with both assays correlated adequately with adjusted ABR. In addition, in 27/130 patients FVIII measurements at baseline and after desmopressin administration were analysed. In 13/27 patients, all measurements were either equivalent or discrepant when results were compared. In 14/27 patients, this was not the case as both equivalent measurements and discrepant measurements at different time points within one patient were observed. Conclusion Neither the one‐stage assay nor the chromogenic assay is superior in predicting bleeding phenotype. In addition, equivalent or discrepant FVIII results measured before desmopressin do not always predict FVIII assay results after desmopressin administration.
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- 2020
40. Measuring the impact of changing from standard half‐life (SHL) to extended half‐life (EHL) FVIII prophylaxis on health‐related quality of life (HRQoL) in boys with moderate/severe haemophilia A: Lessons learned with the CHO‐KLAT tool
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Vanessa Bouskill, Manuel Carcao, Victoria E. Price, Victor S. Blanchette, Saunya Dover, Laura Zunino, P. Hilliard, and Nancy L. Young
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Male ,Pediatrics ,medicine.medical_specialty ,Adolescent ,030204 cardiovascular system & hematology ,Hemophilia A ,Haemophilia ,03 medical and health sciences ,0302 clinical medicine ,hemic and lymphatic diseases ,Chart review ,medicine ,Humans ,Child ,Genetics (clinical) ,Retrospective Studies ,Clotting factor ,Health related quality of life ,Factor VIII ,business.industry ,Half-life ,Hematology ,General Medicine ,Bleed ,medicine.disease ,Child, Preschool ,Cohort ,Quality of Life ,Severe haemophilia A ,business ,Half-Life ,030215 immunology - Abstract
INTRODUCTION In many countries, there is a shift from standard half-life (SHL) to extended half-life (EHL) clotting factor concentrates (CFCs). AIM To describe the experience of switching from SHL to an EHL FVIII CFC and the impact of this on frequency of infusions, factor consumption, bleeding rates and HRQoL using the Canadian Hemophilia Kids' Life Assessment Tool (CHO-KLAT). METHODS A retrospective chart review was conducted at a single haemophilia treatment centre in 2018 that included boys (ages: 4-18 years) with moderate/severe haemophilia A, without inhibitors, who switched from a SHL to an EHL FVIII CFC in the previous 2 years and for whom HRQoL data were available. RESULTS The study cohort comprised 38 boys [mean (SD) age: 11.0 (3.4) years] with moderate (n = 5)/severe (n = 33) haemophilia A. The switch was associated with a 33% reduction in the number of weekly infusions from a median of 3.5 to 2.3 (P
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- 2019
41. SHP656, a polysialylated recombinant factor VIII (PSA‐rFVIII): First‐in‐human study evaluating safety, tolerability and pharmacokinetics in patients with severe haemophilia A
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Andreas Tiede, Pratima Chowdary, Margarita Timofeeva, Geoffrey Allen, Kathleen Kӧck, Martin J. Wolfsegger, Alexander Bauer, Hongyu Jeanne Jiang, Peter William Collins, Brahm Goldstein, István Takács, and Shouryadeep Srivastava
- Subjects
safety ,Adult ,medicine.medical_specialty ,polysialic acid ,haemophilia A ,030204 cardiovascular system & hematology ,Hemophilia A ,Recombinant factor viii ,Gastroenterology ,03 medical and health sciences ,recombinant FVIII ,0302 clinical medicine ,Pharmacokinetics ,Internal medicine ,medicine ,Humans ,In patient ,tolerability ,Clinical Haemophilia ,Adverse effect ,Genetics (clinical) ,Factor VIII ,biology ,business.industry ,Immunogenicity ,Original Articles ,Hematology ,General Medicine ,Recombinant Proteins ,Cohort ,Sialic Acids ,biology.protein ,Original Article ,Severe haemophilia A ,Antibody ,business ,pharmacokinetics ,030215 immunology - Abstract
Introduction SHP656 is the first factor VIII (FVIII) product developed using polysialylation (PSA) technology, in which full‐length recombinant (r) FVIII (anti‐haemophilic factor [recombinant]) is conjugated with a 20 kDa PSA polymer. Aim To compare the safety, immunogenicity and pharmacokinetics of SHP656 vs the parent rFVIII (octocog alfa) after single infusions of 25‐75 IU/kg in patients with severe haemophilia A (FVIII activity
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- 2019
42. Low-dose immune tolerance induction therapy in children of Arab descent with severe haemophilia A, high inhibitor titres and poor prognostic factors for immune tolerance induction treatment success
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Hoda Hassab, Nevine G. Andrawes, Omar Elalfy, Mohsen Saleh Elalfy, Islam Elghamry, and Magdy El-Ekiaby
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medicine.medical_specialty ,Haemophilia A ,Hemophilia A ,Gastroenterology ,Immune tolerance ,Von Willebrand factor ,hemic and lymphatic diseases ,Internal medicine ,Immune Tolerance ,Medicine ,Humans ,Prospective Studies ,Child ,Genetics (clinical) ,Response rate (survey) ,Factor VIII ,biology ,business.industry ,Hematology ,General Medicine ,medicine.disease ,Prognosis ,Arabs ,Titer ,Regimen ,biology.protein ,Severe haemophilia A ,Antibody ,business - Abstract
INTRODUCTION Immune Tolerance Induction (ITI) is the first-choice therapy to eradicate Factor VIII (FVIII) neutralizing antibodies in patients with haemophilia A (HA). There is limited published data on ITI from East Mediterranean countries. AIM To assess the effectiveness of a low-dose ITI regimen to eradicate FVIII neutralizing antibodies in children with severe HA and high-titre inhibitors. METHODS A prospective, single-arm study was conducted in children with HA (FVIII
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- 2021
43. Predictors of inhibitor eradication by primary immune tolerance induction in severe haemophilia A with high responding inhibitors
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Elena Santagostino, Annarita Tagliaferri, Maria Elisa Mancuso, Giancarlo Castaman, Maurizio Margaglione, Pier Mannuccio Mannucci, Silvia Linari, Ezio Zanon, Giovanni Di Minno, Chiara Biasoli, Antonio Coppola, Angiola Rocino, and Cristina Santoro
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medicine.medical_specialty ,Poor prognosis ,Factor VIII ,business.industry ,Haemophilia A ,Hemorrhage ,Hematology ,General Medicine ,medicine.disease ,Hemophilia A ,Immune tolerance ,Homogeneous ,Internal medicine ,Immune Tolerance ,Medicine ,Humans ,In patient ,Severe haemophilia A ,Prospective Studies ,business ,Adverse effect ,Genetics (clinical) ,Complete response - Abstract
BACKGROUND Immune tolerance induction (ITI) is the only proven strategy to eradicate factor VIII inhibitors in patients with haemophilia A (HA). AIM To identify patients and treatment options with the highest chance of inhibitor eradication by primary ITI. PATIENTS AND METHODS In the frame of the Italian ITI Registry, carried out from 1995 to 2015 (last follow-up 2018), 137 primary ITI courses in severe HA patients (90/137 with poor prognosis) were analysed for predictors of outcome (complete/partial response or failure). Sixty-six of them (48%) were prospectively evaluated. RESULTS ITI was successful in 91/137 patients (66.4%) and 70 (51.1%) achieved complete response within 11 months (median). Historical peak titres ≤200 BU/ml (P = .033), inhibitor titres ≤5 BU/ml at ITI start (P = .001), peak titres ≤100 BU/ml during ITI (P
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- 2021
44. Performance of a clinical risk prediction model for inhibitor formation in severe haemophilia A
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Flora Peyvandi, Mohsen Saleh Elalfy, Roberta Palla, Carla Valsecchi, Vijay Ramanan, Samantha C. Gouw, Frits R. Rosendaal, Shermarke Hassan, Isabella Garagiola, Mehran Karimi, Amal El-Beshlawy, Pier Mannuccio Mannucci, Peyman Eshghi, Paediatric Haematology, and Amsterdam Reproduction & Development (AR&D)
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Oncology ,Risk ,medicine.medical_specialty ,Calibration (statistics) ,Haemophilia A ,Population ,haemophilia A ,030204 cardiovascular system & hematology ,Gene mutation ,immunogenicity ,Haemophilia ,Hemophilia A ,03 medical and health sciences ,0302 clinical medicine ,Predictive Value of Tests ,Internal medicine ,inhibitors ,medicine ,Humans ,Family history ,education ,Clinical Haemophilia ,Genetics (clinical) ,education.field_of_study ,business.industry ,Hematology ,General Medicine ,Original Articles ,prediction ,medicine.disease ,factor VIII ,Calibration ,Mutation ,Severe haemophilia A ,Original Article ,business ,Predictive modelling ,030215 immunology - Abstract
Background There is a need to identify patients with haemophilia who have a very low or high risk of developing inhibitors. These patients could be candidates for personalized treatment strategies. Aims The aim of this study was to externally validate a previously published prediction model for inhibitor development and to develop a new prediction model that incorporates novel predictors. Methods The population consisted of 251 previously untreated or minimally treated patients with severe haemophilia A enrolled in the SIPPET study. The outcome was inhibitor formation. Model discrimination was measured using the C-statistic, and model calibration was assessed with a calibration plot. The new model was internally validated using bootstrap resampling. Results Firstly, the previously published prediction model was validated. It consisted of three variables: family history of inhibitor development, F8 gene mutation and intensity of first treatment with factor VIII (FVIII). The C-statistic was 0.53 (95% CI: 0.46-0.60), and calibration was limited. Furthermore, a new prediction model was developed that consisted of four predictors: F8 gene mutation, intensity of first treatment with FVIII, the presence of factor VIII non-neutralizing antibodies before treatment initiation and lastly FVIII product type (recombinant vs. plasma-derived). The C-statistic was 0.66 (95 CI: 0.57-0.75), and calibration was moderate. Using a model cut-off point of 10%, positive- and negative predictive values were 0.22 and 0.95, respectively. Conclusion Performance of all prediction models was limited. However, the new model with all predictors may be useful for identifying a small number of patients with a low risk of inhibitor formation.
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- 2021
45. The thrombin generation assay distinguishes inhibitor from non-inhibitor patients with severe haemophilia A.
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Mancuso, M. E., Chantarangkul, V., Clerici, M., Fasulo, M. R., Padovan, L., Scalambrino, E., Peyvandi, F., Tripodi, A., and Santagostino, E.
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THROMBIN , *BLOOD coagulation factor VIII antibodies , *GENETIC mutation , *HEMOPHILIACS , *TREATMENT effectiveness - Abstract
Introduction Patients with haemophilia A (HA) have impaired thrombin generation (TG) capacity and TG assay (TGA) values are linearly related to plasma factor VIII (FVIII) levels. Aim This study carried out in patients with unmeasurable FVIII (<1 IU dL−1) was aimed at unravelling any difference in TG capacity in patients with or without inhibitors. Methods Blood samples were collected from patients in a non-bleeding state, after a 5-day wash-out period from last treatment. Results TGA was performed in 102 patients with severe HA (15% with high-responding inhibitors; 51% with null F8 mutations, that as expected were more prevalent in inhibitor than in non-inhibitor patients). TG capacity was significantly lower in inhibitor than non-inhibitor patients and in those with null mutations than in those with non-null mutations. When the TG capacity was evaluated only in patients with null mutations with and without inhibitors it was lower in the presence of inhibitors. Conclusions This study shows a greater TG impairment in inhibitor patients irrespective of FVIII levels, inhibitor titre and F8 mutation type, suggesting a role for the TGA in unravelling functional interferences of anti-FVIII inhibitors on coagulation system activation. [ABSTRACT FROM AUTHOR]
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- 2016
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46. Effects of moderate-intensity physical exercise on pharmacokinetics of factor VIII and von Willebrand factor in young adults with severe haemophilia A: a pilot study.
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Zourikian, N., Merlen, C., Bonnefoy, A., St‐Louis, J., and Rivard, G. E.
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AEROBIC exercises , *PHARMACOKINETICS , *BLOOD coagulation factor VIII , *VON Willebrand disease , *HEMOPHILIA , *MUSCULOSKELETAL system - Abstract
Introduction In persons with severe haemophilia A (pwshA), infused factor VIII ( FVIII) half-life can vary according to such determinants as blood group, von Willebrand factor ( VWF) level or age; however, FVIII pharmacokinetics ( PK) has not been well studied in pwshA during exercise. Aim To investigate FVIII PK in pwshA performing moderate-intensity aerobic exercise. Methods Twelve young-adult pwshA with the intron-22 inversion mutation, on relatively low-dose FVIII prophylaxis regimens, and relatively good musculoskeletal status were recruited. Abbreviated PK of FVIII activity and von Willebrand factor antigen ( VWF:Ag) level were compared - during rest, and with 60-min exercise (2 × 15 min each of moderate-intensity stationary cycling and treadmill walking). During rest and exercise visits, a baseline blood specimen was drawn, routine prophylaxis FVIII infused; then six blood specimens were taken over the following 24 h. Results For all subjects, mean half-life of infused FVIII did not change significantly with exercise vs. at rest (577 ± 190 vs. 614 ± 163 min; P = 0.4131). VWF:Ag rose transiently by 40-50% for 6-8 h with exercise ( P < 0.01), particularly in non-O blood group subjects. No musculoskeletal bleeds occurred during the study. Conclusion Four × 15 min of moderate-intensity aerobic exercise increased VWF:Ag levels for 6-8 h, and showed no evidence of accelerated FVIII clearance or of musculoskeletal bleeding in these young-adult pwshA with relatively good musculoskeletal status, on relatively low-dose FVIII prophylaxis regimens. However, O blood group impact would merit larger studies, with longer durations of similar or more vigorous exercise intensities. [ABSTRACT FROM AUTHOR]
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- 2016
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47. Early prophylaxis in children with severe haemophilia A: clinical and ultrasound imaging outcomes.
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Altisent, C., Martorell, M., Crespo, A., Casas, L., Torrents, C., and Parra, R.
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HEMOPHILIA , *DENTAL prophylaxis , *HEALTH outcome assessment , *HEMOPHILIACS , *DRUG efficacy - Abstract
Aim This observational study was undertaken with the aim to describe the characteristics and evaluate the outcomes of prophylactic treatment in children with severe haemophilia A ( HA) treated at our centre. Methods Twenty-five patients aged 4-19 years with severe HA, no history of inhibitors and treated with at least two infusions of factor VIII (FVIII) per week were studied. Prophylactic doses and annual joint bleeding rate ( AJBR) were retrospectively evaluated over the last 5 years. Current joint status was assessed using the Haemophilia Joint Health Score ( HJHS) (136 joints of 23 patients) and the Haemophilia Early Arthropathy Detection with Ultrasound ( HEAD- US) procedure (124 joints of 21 patients). Results Median AJBR was 0.2 and median prophylaxis dose 65.4 IU−1 kg−1 week−1. Median total HJHS was 0 (range 0-13) and total HEAD- US 1 (0-8). At the joint level, 85.3% of joints were normal on HJHS and 79.0% on US. The ankle was the joint most commonly affected, considering bleeding and ultrasound results. Correlation was found between HEAD- US scores and bleeding scores but not between HEAD- US and HJHS scores. HJHS and HEAD- US scores were concordant in 91/124 (73.4%) joints (86 joints normal and five abnormal). Ultrasound detected minimal changes in 19.6% of joints with normal physical function, whereas 12.2% of joints considered normal on ultrasound showed changes at HJHS. Conclusion A well-preserved joint status was found in our cohort. High-resolution US detected a higher percentage of abnormalities than the physical evaluation, but the clinical implications of these findings still need to be ascertained. [ABSTRACT FROM AUTHOR]
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- 2016
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48. A matching‐adjusted indirect comparison in patients with severe haemophilia A: Comparing the efficacy and consumption of rVIII-SingleChain vs two recombinant FVIII
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S Santos, G Goldmann, B Vandewalle, V Andreozzi, R. Núñez, S. Bonanad, K Kurnik, and JL Poveda
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Consumption (economics) ,medicine.medical_specialty ,Matching (statistics) ,business.industry ,law ,Internal medicine ,medicine ,Recombinant DNA ,In patient ,Severe haemophilia A ,business ,Indirect comparison ,law.invention - Published
- 2021
49. Reappearance of inhibitor in a tolerized patient with severe haemophilia A during FVIII‐free emicizumab therapy
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Delphine Borgel, Cécile Bally, Sébastien Lacroix-Desmazes, Sandrine Delignat, Dominique Lasne, Maximilien Desvages, Annie Harroche, Ladislas Capdevila, and Laurent Frenzel
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Emicizumab ,business.industry ,Fviii inhibitor ,Immunology ,Haemophilia A ,Medicine ,Severe haemophilia A ,Hematology ,General Medicine ,business ,medicine.disease ,Genetics (clinical) - Published
- 2021
50. Emicizumab prophylaxis in infants with severe haemophilia A without inhibitors: Illustrative real-world cases to support shared decision-making
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Jane A. Mason and Guy Young
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Pediatrics ,medicine.medical_specialty ,Younger age ,Haemophilia A ,030204 cardiovascular system & hematology ,Haemophilia ,Antibodies, Monoclonal, Humanized ,Hemophilia A ,03 medical and health sciences ,0302 clinical medicine ,Antibodies, Bispecific ,medicine ,Humans ,In patient ,Adverse effect ,Child ,Genetics (clinical) ,Emicizumab ,business.industry ,Infant, Newborn ,Infant ,Hematology ,General Medicine ,medicine.disease ,Cohort ,Severe haemophilia A ,business ,030215 immunology ,Half-Life - Abstract
Introduction Emicizumab has been shown to be safe and effective for prevention of bleeds in patients with severe haemophilia A (SHA), both with and without inhibitors. The subcutaneous administration and long half-life make emicizumab an attractive option for prophylaxis in infants with SHA, however data to inform treatment decisions in this younger age group are almost absent. Aim The aim of this report is to share real world experience to illustrate how the availability of emicizumab has shifted the prophylaxis paradigm in the management of infants with SHA. Method We selected four cases from our own cohort of infants with SHA to outline the rationale for emicizumab prophylaxis in a range of scenarios familiar to paediatric haemophilia treaters. Results In Case 1 emicizumab was commenced at 7 days following initial treatment of neonatal ICH with a FVIII infusion. In Case 2 emicizumab was commenced at 5 weeks due to parental anxiety regarding the potential for ICH during infancy. Case 3 commenced emicizumab at 15 months in lieu of standard primary prophylaxis. Case 4 switched to emicizumab prophylaxis at 14 months after a period of primary prophylaxis with FVIII concentrates to alleviate parental anxiety regarding future inhibitor development. No patient had any bleeding events after commencement of emicizumab (median follow up 12 months), and no drug-related adverse effects were observed. Conclusion Despite the paucity of data in infants with SHA the potential role of emicizumab prophylaxis should be discussed with families when clinically relevant, with decisions tailored to individual need.
- Published
- 2021
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