43 results on '"Bagot, Catherine"'
Search Results
2. Real-world use of thrombopoietin receptor agonists for the management of immune thrombocytopenia in adult patients in the United Kingdom: Results from the TRAIT study.
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Cooper N, Scully M, Percy C, Nicolson PLR, Lowe G, Bagot CN, Thachil J, Grech H, Nokes T, Hill QA, Bradbury C, Talks K, Dutt T, Evans G, Pavord S, Wexler S, Charania A, Collington SJ, Ervin A, Ramscar N, and Provan D
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- Humans, Middle Aged, Male, Female, Adult, United Kingdom, Retrospective Studies, Aged, Platelet Count, Treatment Outcome, Aged, 80 and over, Young Adult, Adolescent, Receptors, Thrombopoietin agonists, Recombinant Fusion Proteins therapeutic use, Recombinant Fusion Proteins adverse effects, Recombinant Fusion Proteins administration & dosage, Purpura, Thrombocytopenic, Idiopathic drug therapy, Benzoates therapeutic use, Benzoates adverse effects, Pyrazoles therapeutic use, Pyrazoles adverse effects, Thrombopoietin therapeutic use, Thrombopoietin adverse effects, Hydrazines therapeutic use, Hydrazines adverse effects, Receptors, Fc therapeutic use
- Abstract
Few studies have reported the real-world use of both romiplostim and eltrombopag in immune thrombocytopenia (ITP). TRAIT was a retrospective observational study aimed to evaluate the platelet responses and adverse effects associated with the use of these thrombopoietin receptor agonists (TPO-RAs) in adult patients with ITP in the United Kingdom. Of 267 patients (median age at diagnosis, 48 years) with ITP (primary ITP [n = 218], secondary ITP [n = 49]) included in the study, 112 (42%) received eltrombopag and 155 (58%) received romiplostim as the first prescribed TPO-RA. A platelet count ≥30 × 10
9 /L was achieved in 89% of patients with the first TPO-RA treatments, while 68% achieved a platelet count ≥100 × 109 /L. Treatment-free response (TFR; platelet count ≥30 × 109 /L, 3 months after discontinuing treatment) was achieved by 18% of the total patients. Overall, 61 patients (23%) switched TPO-RAs, most of whom achieved platelet counts ≥30 × 109 /L with the second TPO-RA (23/25 who switched from eltrombopag to romiplostim [92%]; 28/36 who switched from romiplostim to eltrombopag [78%]). TFR was associated with secondary ITP, early TPO-RA initiation after diagnosis, the presence of comorbidity and no prior splenectomy or treatment with steroids or mycophenolate mofetil. Both TPO-RAs had similar efficacy and safety profiles to those reported in clinical studies., (© 2024 The Authors. British Journal of Haematology published by British Society for Haematology and John Wiley & Sons Ltd.)- Published
- 2024
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3. Fitusiran prophylaxis in people with hemophilia A or B who switched from prior BPA/CFC prophylaxis: the ATLAS-PPX trial.
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Kenet G, Nolan B, Zulfikar B, Antmen B, Kampmann P, Matsushita T, You CW, Vilchevska K, Bagot CN, Sharif A, Peyvandi F, Young G, Negrier C, Chi J, Kittner B, Sussebach C, Shammas F, Mei B, Andersson S, and Kavakli K
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- Humans, Male, Adult, Middle Aged, Adolescent, Young Adult, Child, RNA, Small Interfering administration & dosage, RNA, Small Interfering therapeutic use, Blood Coagulation Factors therapeutic use, Blood Coagulation Factors administration & dosage, Aged, Hemophilia B drug therapy, Hemophilia B complications, Hemophilia A drug therapy, Hemophilia A complications, Hemorrhage chemically induced, Hemorrhage prevention & control
- Abstract
Abstract: Fitusiran, a subcutaneous investigational small interfering RNA therapeutic, targets antithrombin to rebalance hemostasis in people with hemophilia A or B (PwHA/B), irrespective of inhibitor status. This phase 3, open-label study evaluated the efficacy and safety of fitusiran prophylaxis in males aged ≥12 years with hemophilia A or B, with or without inhibitors, who received prior bypassing agent (BPA)/clotting factor concentrate (CFC) prophylaxis. Participants continued their prior BPA/CFC prophylaxis for 6 months before switching to once-monthly 80 mg fitusiran prophylaxis for 7 months (onset and efficacy periods). Primary end point was annualized bleeding rate (ABR) in the BPA/CFC prophylaxis and fitusiran efficacy period. Secondary end points included spontaneous ABR (AsBR) and joint ABR (AjBR). Safety and tolerability were assessed. Of 80 enrolled participants, 65 (inhibitor, n = 19; noninhibitor, n = 46) were eligible for ABR analyses. Observed median ABRs were 6.5 (interquartile range [IQR], 2.2-19.6)/4.4 (IQR, 2.2-8.7) with BPA/CFC prophylaxis vs 0.0 (IQR, 0.0-0.0)/0.0 (IQR, 0.0-2.7) in the corresponding fitusiran efficacy period. Estimated mean ABRs were substantially reduced with fitusiran by 79.7% (P = .0021) and 46.4% (P = .0598) vs BPA/CFC prophylaxis, respectively. Forty-one participants (63.1%) experienced 0 treated bleeds with fitusiran vs 11 (16.9%) with BPAs/CFCs. Median AsBR and AjBR were both 2.2 with BPA/CFC prophylaxis and 0.0 in the fitusiran efficacy period. Two participants (3.0%) experienced suspected or confirmed thromboembolic events with fitusiran. Once-monthly fitusiran prophylaxis significantly reduced bleeding events vs BPA/CFC prophylaxis in PwHA/B, with or without inhibitors, and reported adverse events were generally consistent with previously identified risks of fitusiran. This trial was registered at www.ClinicalTrials.gov as #NCT03549871., (© 2024 American Society of Hematology. Published by Elsevier Inc. Licensed under Creative Commons Attribution-NonCommercial-NoDerivatives 4.0 International (CC BY-NC-ND 4.0), permitting only noncommercial, nonderivative use with attribution. All other rights reserved.)
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- 2024
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4. Long COVID and cardiovascular disease: a prospective cohort study.
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Lawson CA, Moss AJ, Arnold JR, Bagot C, Banerjee A, Berry C, Greenwood J, Hughes AD, Khunti K, Mills NL, Neubauer S, Raman B, Sattar N, Leavy OC, Richardson M, Elneima O, McAuley HJ, Shikotra A, Singapuri A, Sereno M, Saunders R, Harris V, Houchen-Wolloff L, Greening NJ, Harrison E, Docherty AB, Lone NI, Quint JK, Chalmers J, Ho LP, Horsley A, Marks M, Poinasamy K, Evans R, Wain LV, Brightling C, and McCann GP
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- Humans, Male, Female, Prospective Studies, Middle Aged, Aged, Risk Factors, Hospitalization statistics & numerical data, Time Factors, SARS-CoV-2, Recovery of Function, COVID-19 epidemiology, COVID-19 complications, COVID-19 diagnosis, Cardiovascular Diseases epidemiology, Cardiovascular Diseases diagnosis
- Abstract
Background: Pre-existing cardiovascular disease (CVD) or cardiovascular risk factors have been associated with an increased risk of complications following hospitalisation with COVID-19, but their impact on the rate of recovery following discharge is not known., Objectives: To determine whether the rate of patient-perceived recovery following hospitalisation with COVID-19 was affected by the presence of CVD or cardiovascular risk factors., Methods: In a multicentre prospective cohort study, patients were recruited following discharge from the hospital with COVID-19 undertaking two comprehensive assessments at 5 months and 12 months. Patients were stratified by the presence of either CVD or cardiovascular risk factors prior to hospitalisation with COVID-19 and compared with controls with neither. Full recovery was determined by the response to a patient-perceived evaluation of full recovery from COVID-19 in the context of physical, physiological and cognitive determinants of health., Results: From a total population of 2545 patients (38.8% women), 472 (18.5%) and 1355 (53.2%) had CVD or cardiovascular risk factors, respectively. Compared with controls (n=718), patients with CVD and cardiovascular risk factors were older and more likely to have had severe COVID-19. Full recovery was significantly lower at 12 months in patients with CVD (adjusted OR (aOR) 0.62, 95% CI 0.43 to 0.89) and cardiovascular risk factors (aOR 0.66, 95% CI 0.50 to 0.86)., Conclusion: Patients with CVD or cardiovascular risk factors had a delayed recovery at 12 months following hospitalisation with COVID-19. Targeted interventions to reduce the impact of COVID-19 in patients with cardiovascular disease remain an unmet need., Trail Registration Number: ISRCTN10980107., Competing Interests: Competing interests: KK is chair of the ethnicity subgroup of the UK Scientific Advisory Group for Emergencies (SAGE) and is a member of SAGE. KK (Chair) and RE are members of the Long COVID Epidemiological Research Group that reports to the CMO. CB is an author of the COVID-19 rapid guideline: managing the long-term effects of COVID-19 NICE guideline (NG188) https://www.nice.org.uk/guidance/ng188/history. CB is a member of the NHS National Services Scotland Long COVID group and his employer, the University of Glasgow, holds a research agreement with AstraZeneca and Somalogic for research in COVID-19. AJM is an employee of AstraZeneca., (© Author(s) (or their employer(s)) 2024. Re-use permitted under CC BY. Published by BMJ.)
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- 2024
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5. Socioeconomic deprivation and illness trajectory in the Scottish population after COVID-19 hospitalization.
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Morrow AJ, Sykes R, Saleh M, Zahra B, MacIntosh A, Kamdar A, Bagot C, Bayes HK, Blyth KG, Bulluck H, Carrick D, Church C, Corcoran D, Findlay I, Gibson VB, Gillespie L, Grieve D, Barrientos PH, Ho A, Lang NN, Lowe DJ, Lennie V, Macfarlane PW, Mayne KJ, Mark PB, McConnachie A, McGeoch R, Nordin S, Payne A, Rankin AJ, Robertson K, Ryan N, Roditi G, Sattar N, Stobo D, Allwood-Spiers S, Touyz RM, Veldtman G, Weeden S, Weir R, Watkins S, Welsh P, Mangion K, and Berry C
- Abstract
Background: The associations between deprivation and illness trajectory after hospitalisation for coronavirus disease-19 (COVID-19) are uncertain., Methods: A prospective, multicentre cohort study was conducted on post-COVID-19 patients, enrolled either in-hospital or shortly post-discharge. Two evaluations were carried out: an initial assessment and a follow-up at 28-60 days post-discharge. The study encompassed research blood tests, patient-reported outcome measures, and multisystem imaging (including chest computed tomography (CT) with pulmonary and coronary angiography, cardiovascular and renal magnetic resonance imaging). Primary and secondary outcomes were analysed in relation to socioeconomic status, using the Scottish Index of Multiple Deprivation (SIMD). The EQ-5D-5L, Brief Illness Perception Questionnaire (BIPQ), Patient Health Questionnaire-4 (PHQ-4) for Anxiety and Depression, and the Duke Activity Status Index (DASI) were used to assess health status., Results: Of the 252 enrolled patients (mean age 55.0 ± 12.0 years; 40% female; 23% with diabetes), deprivation status was linked with increased BMI and diabetes prevalence. 186 (74%) returned for the follow-up. Within this group, findings indicated associations between deprivation and lung abnormalities (p = 0.0085), coronary artery disease (p = 0.0128), and renal inflammation (p = 0.0421). Furthermore, patients with higher deprivation exhibited worse scores in health-related quality of life (EQ-5D-5L, p = 0.0084), illness perception (BIPQ, p = 0.0004), anxiety and depression levels (PHQ-4, p = 0.0038), and diminished physical activity (DASI, p = 0.002). At the 3-month mark, those with greater deprivation showed a higher frequency of referrals to secondary care due to ongoing COVID-19 symptoms (p = 0.0438). However, clinical outcomes were not influenced by deprivation., Conclusions: In a post-hospital COVID-19 population, socioeconomic deprivation was associated with impaired health status and secondary care episodes. Deprivation influences illness trajectory after COVID-19., (© 2024. The Author(s).)
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- 2024
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6. Thrombopoietin mimetic-induced bone marrow fibrosis.
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Harper K, Bagot C, Leach M, and Bain BJ
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- Humans, Thrombopoietin adverse effects, Megakaryocytes, Bone Marrow Cells, Primary Myelofibrosis drug therapy, Primary Myelofibrosis chemically induced
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- 2024
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7. Outcomes of total hip and knee arthroplasty in patients with haemophilia: A meta-analysis of comparative studies and clinical practice recommendations.
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Challoumas D, Munn D, Jeyakumar G, Bagot C, Rodgers R, Kearns R, and Jones B
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- Humans, Retrospective Studies, Knee Joint, Risk Factors, Arthroplasty, Replacement, Knee adverse effects, Arthroplasty, Replacement, Hip adverse effects, Hemophilia A complications
- Abstract
Aim: We aimed to compare the outcomes of total hip and knee arthroplasty (THA, TKA) in haemophilic patients compared to matched controls., Methods: Through a literature search we identified all cohort studies comparing perioperative complications and other outcomes of THA and TKA in haemophilic patients and matched controls without haemophilia. Results of the same outcome measure assessed by two or more studies were pooled in meta-analyses; odds ratios (ORs) with 95% confidence intervals (CI) were calculated. The risk of bias in included studies and certainty of evidence of each result were assessed using the Newcastle-Ottawa scale and the GRADE tool respectively., Results: A total of five retrospective studies with matched controls were included; four of them were of good and one of fair quality. Based on moderate certainty evidence, compared to matched controls, patients with haemophilia had a significantly higher incidence of the following complications after a) TKA: periprosthetic joint infection [PJI; OR 1.6 CI (1.3, 1.9)], 1-year revision/re-operation [OR 1.4 CI (1.2, 1.8)] and b) THA: major and minor 90-day complications [major OR 2.2 CI (1.7, 2.9); minor OR 1.4 CI (1.1, 1.8)], venous thromboembolism [OR 3.1 CI (2.1, 4.6)]. PJI incidence in THA was not different in haemophilia compared to controls [OR 1.5 CI (.9, 2.6)]., Conclusion: Our results can be used by healthcare professionals counselling patients with haemophilia considering a THA or TKA as part of the informed consent process. We provide detailed clinical recommendations for the perioperative management of THA and TKA in haemophilic patients., (© 2023 John Wiley & Sons Ltd.)
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- 2024
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8. A new population pharmacokinetic model for recombinant factor IX-Fc fusion concentrate including young children with haemophilia B.
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Koopman SF, Goedhart TMHJ, Bukkems LH, Mulders TM, Leebeek FWG, Fijnvandraat K, Coppens M, Mathias M, Collins PW, Tait RC, Bagot CN, Curry N, Payne J, Chowdary P, Cnossen MH, and Mathôt RAA
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- Child, Humans, Child, Preschool, Adolescent, Young Adult, Adult, Middle Aged, Aged, Retrospective Studies, Prospective Studies, Recombinant Fusion Proteins therapeutic use, Recombinant Fusion Proteins pharmacokinetics, Half-Life, Factor IX therapeutic use, Factor IX pharmacokinetics, Hemophilia B drug therapy
- Abstract
Aims: Recombinant factor IX Fc fusion protein (rFIX-Fc) is an extended half-life factor concentrate administered to haemophilia B patients. So far, a population pharmacokinetic (PK) model has only been published for patients aged ≥12 years. The aim was to externally evaluate the predictive performance of the published rFIX-Fc population PK model for patients of all ages and develop a model that describes rFIX-Fc PK using real-world data., Methods: We collected prospective and retrospective data from patients with haemophilia B treated with rFIX-Fc and included in the OPTI-CLOT TARGET study (NTR7523) or United Kindom (UK)-EHL Outcomes Registry (NCT02938156). Predictive performance was assessed by comparing predicted with observed FIX activity levels. A new population PK model was constructed using nonlinear mixed-effects modelling., Results: Real-world data were obtained from 37 patients (median age: 16 years, range 2-71) of whom 14 were aged <12 years. Observed FIX activity levels were significantly higher than levels predicted using the published model, with a median prediction error of -48.8%. The new model showed a lower median prediction error (3.4%) and better described rFIX-Fc PK, especially for children aged <12 years. In the new model, an increase in age was correlated with a decrease in clearance (P < .01)., Conclusions: The published population PK model significantly underpredicted FIX activity levels. The new model better describes rFIX-Fc PK, especially for children aged <12 years. This study underlines the necessity to strive for representative population PK models, thereby avoiding extrapolation outside the studied population., (© 2023 The Authors. British Journal of Clinical Pharmacology published by John Wiley & Sons Ltd on behalf of British Pharmacological Society.)
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- 2024
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9. Fibrinogenolysis and fibrinolysis in vaccine-induced immune thrombocytopenia and thrombosis.
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Simpson M, Narwal A, West E, Martin J, Bagot CN, Page AR, Watson HG, Whyte CS, and Mutch NJ
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- Humans, Fibrinolysis, Fibrinolysin, COVID-19 Vaccines adverse effects, Fibrinogen, Purpura, Thrombocytopenic, Idiopathic, Disseminated Intravascular Coagulation chemically induced, Disseminated Intravascular Coagulation diagnosis, Thrombocytopenia chemically induced, Thrombocytopenia diagnosis, Thrombosis etiology, Vaccines
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Background: Vaccine-induced immune thrombocytopenia and thrombosis (VITT) is a rare syndrome associated with adenoviral vector vaccines for COVID-19. The syndrome is characterized by thrombosis, anti-platelet factor 4 (PF4) antibodies, thrombocytopenia, high D-dimer, and hypofibrinogenemia., Objectives: To investigate abnormalities in fibrinolysis that contribute to the clinical features of VITT., Methods: Plasma samples from 18 suspected VITT cases were tested for anti-PF4 by ELISA and characterized as meeting criteria for VITT (11/18) or deemed unlikely (7/18; non-VITT). Antigen levels of PAI-1, factor XIII (FXIII), plasmin-α
2 antiplasmin (PAP), and inflammatory markers were quantified. Plasmin generation was quantified by chromogenic substrate. Western blotting was performed with antibodies to fibrinogen, FXIII-A, and plasminogen., Results: VITT patients 10/11 had scores indicative of overt disseminated intravascular coagulation, while 0/7 non-VITT patients met the criteria. VITT patients had significantly higher levels of inflammatory markers, IL-1β, IL-6, IL-8, TNFα, and C-reactive protein. In VITT patients, both fibrinogen and FXIII levels were significantly lower, while PAP and tPA-mediated plasmin generation were higher compared to non-VITT patients. Evidence of fibrinogenolysis was observed in 9/11 VITT patients but not in non-VITT patients or healthy controls. Fibrinogen degradation products were apparent, with obvious cleavage of the fibrinogen α-chain. PAP complex was evident in those VITT patients with fibrinogenolysis, but not in non-VITT patients or healthy donors., Conclusion: VITT patients show evidence of overt disseminated intravascular coagulation and fibrinogenolysis, mediated by dysregulated plasmin generation, as evidenced by increased PAP and plasmin generation. These observations are consistent with the clinical presentation of both thrombosis and bleeding in VITT., Competing Interests: Declaration of competing interests The authors have no relevant conflict of interests to declare., (Copyright © 2023 The Author(s). Published by Elsevier Inc. All rights reserved.)- Published
- 2023
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10. Post-COVID-19 illness and associations with sex and gender.
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Mangion K, Morrow AJ, Sykes R, Kamdar A, Bagot C, Bruce G, Connelly P, Delles C, Gibson VB, Gillespie L, Barrientos PH, Lennie V, Roditi G, Sattar N, Stobo D, Allwood-Spiers S, McConnachie A, and Berry C
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- Female, Humans, Male, SARS-CoV-2, Prospective Studies, Aftercare, Patient Discharge, Inflammation, COVID-19 diagnosis, COVID-19 epidemiology, Myocarditis
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Background: Post-COVID-19 syndromes have associated with female sex, but the pathophysiological basis is uncertain., Aim: There are sex differences in myocardial inflammation identified using cardiac magnetic resonance (CMR) in post-COVID-19 patients, and in patient reported health outcomes following COVID-19 infection., Design: This prospective study investigated the time-course of multiorgan injury in survivors of COVID-19 during convalescence., Methods: Clinical information, blood biomarkers, and patient reported outcome measures were prospectively acquired at enrolment (visit 1) and 28-60 days post-discharge (visit 2). Chest computed tomography (CT) and CMR were performed at visit 2. Follow-up was carried out for serious adverse events, including death and rehospitalization., Results: Sixty-nine (43%) of 159 patients recruited were female. During the index admission, females had a lower peak C-reactive protein (74 mg/l (21,163) versus 123 mg/l (70, 192) p = 0.008) and peak ferritin (229 μg/l (103, 551) versus 514 μg/l (228, 1122) p < 0.001). Using the Modified Lake-Louise criteria, females were more likely to have definite evidence of myocardial inflammation (54% (37/68) versus 33% (30/90) p = 0.003). At enrolment and 28-60 days post-discharge, enhanced illness perception, higher levels of anxiety and depression and lower predicted maximal oxygen utilization occurred more commonly in women. The mean (SD, range) duration of follow-up after hospital discharge was 450 (88) days (range 290, 627 days). Compared to men, women had lower rates of cardiovascular hospitalization (0% versus 8% (7/90); p = 0.018)., Conclusions: Women demonstrated worse patient reported outcome measures at index admission and 28-60 days follow-up though cardiovascular hospitalization was lower., (© 2023. BioMed Central Ltd., part of Springer Nature.)
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- 2023
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11. Fitusiran prophylaxis in people with severe haemophilia A or haemophilia B without inhibitors (ATLAS-A/B): a multicentre, open-label, randomised, phase 3 trial.
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Srivastava A, Rangarajan S, Kavakli K, Klamroth R, Kenet G, Khoo L, You CW, Xu W, Malan N, Frenzel L, Bagot CN, Stasyshyn O, Chang CY, Poloskey S, Qiu Z, Andersson S, Mei B, and Pipe SW
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- Male, Humans, Hemorrhage etiology, Hemorrhage prevention & control, Hemorrhage drug therapy, Blood Coagulation Factors therapeutic use, RNA, Small Interfering therapeutic use, Hemophilia A complications, Hemophilia A drug therapy, Hemophilia B complications, Hemophilia B drug therapy
- Abstract
Background: Fitusiran, a subcutaneous investigational siRNA therapeutic, targets antithrombin with the goal of rebalancing haemostasis in people with haemophilia A or haemophilia B, regardless of inhibitor status. We aimed to evaluate the efficacy and safety of fitusiran prophylaxis in people with severe haemophilia without inhibitors., Methods: This multicentre, open-label, randomised phase 3 study was conducted at 45 sites in 17 countries. Male participants aged at least 12 years with severe haemophilia A or B without inhibitors, who had previously been treated on-demand with clotting factor concentrates, were randomly assigned in a 2:1 ratio to receive 80 mg subcutaneous fitusiran prophylaxis once per month or to continue on-demand clotting factor concentrates for a total of 9 months. Randomisation was stratified by the number of bleeding events in the 6 months before screening (≤10 bleeds and >10 bleeds) and by haemophilia type (haemophilia A or B). The primary endpoint was annualised bleeding rate, analysed in the intention-to-treat analysis set. Safety and tolerability were assessed in the safety analysis set. This trial is registered with ClinicalTrials.gov, NCT03417245, and is complete., Findings: Between March 1, 2018, and July 14, 2021, 177 male participants were screened for eligibility and 120 were randomly assigned to receive fitusiran prophylaxis (n=80) or on-demand clotting factor concentrates (n=40). Median follow-up was 7·8 months (IQR 7·8-7·8) in the fitusiran group and 7·8 months (7·8-7·8) in the on-demand clotting factor concentrates group. The median annualised bleeding rate was 0·0 (0·0-3·4) in the fitusiran group and 21·8 (8·4-41·0) in the on-demand clotting factor concentrates group. The estimated mean annualised bleeding rate was significantly lower in the fitusiran prophylaxis group (3·1 [95% CI 2·3-4·3]) than in the on-demand clotting factor concentrates group (31·0 [21·1-45·5]; rate ratio 0·101 [95% CI 0·064-0·159]; p<0·0001). In the fitusiran group, 40 (51%) of 79 treated participants had no treated bleeds compared with two (5%) of 40 participants in the on-demand clotting factor concentrates group. Increased alanine aminotransferase concentration (18 [23%] of 79 participants in the safety analysis set) was the most common treatment-emergent adverse event in the fitusiran group and hypertension (four (10%) of 40 participants) was the most common in the on-demand clotting factor concentrates group. Treatment-emergent serious adverse events were reported in five (6%) participants in the fitusiran group (cholelithiasis [n=2, 3%], cholecystitis [n=1, 1%], lower respiratory tract infection [n=1, 1%], and asthma [n=1, 1%]) and five (13%) participants in the on-demand clotting factor concentrates group (gastroenteritis, pneumonia, suicidal ideation, diplopia, osteoarthritis, epidural haemorrhage, humerus fracture, subdural haemorrhage, and tibia fracture [all n=1, 3%]). No treatment-related thrombosis or deaths were reported., Interpretation: In participants with haemophilia A or B without inhibitors, fitusiran prophylaxis resulted in significant reductions in annualised bleeding rate compared with on-demand clotting factor concentrates and no bleeding events in approximately half of participants. Fitusiran prophylaxis shows haemostatic efficacy in both haemophilia A and haemophilia B, and therefore has the potential to be transformative in the management of all people with haemophilia., Funding: Sanofi., Competing Interests: Declaration of interests AS is a member of advisory boards and grant review committees for Sanofi, Takeda, Novo Nordisk, Roche, Pfizer, and Bayer Healthcare and has received research funding from Roche, Novo Nordisk, Sanofi, and Pfizer. SR has received honoraria for consulting from Reliance Life Sciences; participated in a speakers bureau for Takeda; and has been a member of advisory boards for Pfizer, Sanofi, and Sigilon Therapeutics. KK has received honoraria from and attended speakers bureaus for Pfizer, Bayer, Takeda, Roche, and Novo Nordisk and is on advisory committees for Pfizer, Bayer, Takeda, Roche, and Novo Nordisk. RK has received research funding from Bayer and LEO Pharma; received honoraria from Bayer, Biotest, BioMarin Pharmaceutical, Bristol Myers Squibb, CSL Behring, Daiichi Sankyo, LEO Pharma, Novo Nordisk, Octapharma, Pfizer, Roche, Sanofi, Sobi, and Takeda; and attended speakers bureaus for Bayer, Biotest, BioMarin Pharmaceutical, Bristol Myers Squibb, CSL Behring, Daiichi Sankyo, Novo Nordisk, Octapharma, Pfizer, Roche, Sanofi, Sobi, and Takeda. GK consults for Alnylam Pharmaceuticals, Bayer, BioMarin Pharmaceutical, CSL Behring, Novo Nordisk, OPKO Biologics, Pfizer, Takeda, Roche, Sanofi, and uniQure; has received research funding from Alnylam, Bayer, Bio Products Laboratory, OPKO Biologics, Pfizer, Roche, and Takeda; has attended speakers bureaus for Bayer, Pfizer, CSL Behring, Shire Pharmaceuticals, Novo Nordisk, and Roche; and is on advisory committees for Alnylam, Bayer, BioMarin Pharmaceutical, CSL Behring, Novo Nordisk, OPKO Biologics, Pfizer, Takeda, Roche, Sanofi, and uniQure. LK has received research funding from Roche and honoraria from Sanofi, Novo Nordisk, and Roche; has participated in speakers bureaus for Roche, Sanofi, Novo Nordisk, and Takeda; and is on advisory committees for Roche, Sanofi, and Novo Nordisk. C-YC has received research funding from Bayer and Sanofi and honoraria from Bayer, Sanofi, Novo Nordisk, Takeda, Chugai Pharmaceutical, and Pfizer; and has participated in advisory boards for Sanofi, Novo Nordisk, Bayer, and Chugai Pharmaceutical. NM has received research funding for clinical research yet to be conducted and is vice-chair of St Francis Hospice, South Africa. LF has received research funding from Pfizer, Roche, Sobi, and CSL Behring. OS has received research funding and honoraria from Novo Nordisk, Shire Pharmaceuticals, CSL Behring, Sanofi, Pfizer, and LFB and has participated in speaker bureaus for Novo Nordisk, Pfizer, Shire Pharmaceuticals, Octapharma and Roche. SP, ZQ, and SA are current employees of, and equity holders in, Sanofi. BM was an employee of and equity holder in Sanofi at the time of the study and has divested equity in Sanofi in the past 24 months; he is currently an employee of Editas Medicine. SWP has received consultancy fees from ApcinteX, ASC Therapeutics, Bayer, BioMarin Pharmaceutical, CSL Behring, GeneVentiv, HEMA Biologics, Freeline Therapeutics, Novo Nordisk, Pfizer, Regeneron/Intellia, Roche/Genentech, Sanofi, Takeda, Spark Therapeutics, and uniQure; has received research funding from Siemens; and is a member of a scientific advisory committee for GeneVentiv. C-WY, WX, and CNB declare no competing interests., (Copyright © 2023 Elsevier Ltd. All rights reserved.)
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- 2023
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12. Long-term risk of relapse in immune-mediated thrombotic thrombocytopenic purpura and the role of anti-CD20 therapy.
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Doyle AJ, Stubbs MJ, Dutt T, Lester W, Thomas W, van Veen J, Hermans J, Cranfield T, Hill QA, Clark A, Bagot C, Austin S, Westwood JP, Thomas M, and Scully M
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- Humans, Rituximab therapeutic use, ADAMTS13 Protein, Recurrence, United Kingdom epidemiology, Purpura, Thrombotic Thrombocytopenic therapy
- Abstract
Disease relapse is recognized as a risk in immune-mediated thrombotic thrombocytopenic purpura (iTTP) after treatment of the acute presenting episode. Identification of patients at risk of relapse and its patterns are yet to be clearly established. We reviewed patients with iTTP having had >3 years of follow-up over 10 years in the United Kingdom to identify patient characteristics for relapse, assess relapse rates and patterns, and response to anti-CD20 therapy in those with a disintegrin and metalloproteinase with a thrombospondin type 1 motif, member 13 (ADAMTS13) relapses (ADAMTS13 activity of <20% without thrombocytopenia). We identified 443 patients demonstrating relapse rates of 40% at 5-year follow-up. At 10-year follow-up, no difference in relapse was observed irrespective of whether rituximab was used at acute presentation (P = .39). Black Caribbean ethnicity increased the risk of disease relapse in the British population. There was a distinct population of patients (6%) that relapsed early with subsequent frequent relapses occurring on average within 2 years (average time to relapse in subgroup, 1.7 years). Overall, nearly 60% of relapses described were ADAMTS13 relapses, with subsequent treatment reducing the risk of progression to clinical relapses. We demonstrate that iTTP diagnosed in the latter part of the study period had lower rates of clinical relapses (22.6% vs 11.1%, P = .0004) with the advent of regular monitoring and preemptive rituximab. In ADAMTS13 relapses, 96% responded to anti-CD20 therapy, achieving ADAMTS13 activity of >20%. Anti-CD20 therapy was demonstrated to be an effective long-term treatment regardless of relapse pattern and there was no loss of this treatment response after subsequent treatment episodes., (© 2023 by The American Society of Hematology.)
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- 2023
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13. The suboptimal fibrinolytic response in COVID-19 is dictated by high PAI-1.
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Whyte CS, Simpson M, Morrow GB, Wallace CA, Mentzer AJ, Knight JC, Shapiro S, Curry N, Bagot CN, Watson H, Cooper JG, and Mutch NJ
- Subjects
- Chromogenic Compounds, Fibrin, Fibrinolysin pharmacology, Fibrinolysis, Humans, Plasminogen Activator Inhibitor 1, Prospective Studies, Tenecteplase, Tissue Plasminogen Activator pharmacology, Vitronectin, Carboxypeptidase B2, Hemostatics pharmacology, Thrombosis drug therapy, COVID-19 Drug Treatment
- Abstract
Background: Severe COVID-19 disease is associated with thrombotic complications and extensive fibrin deposition. This study investigates whether the hemostatic complications in COVID-19 disease arise due to dysregulation of the fibrinolytic system., Methods: This prospective study analyzed fibrinolytic profiles of 113 patients hospitalized with COVID-19 disease with 24 patients with non-COVID-19 respiratory infection and healthy controls. Antigens were quantified by Ella system or ELISA, clot lysis by turbidimetric assay, and plasminogen activator inhibitor-1 (PAI-1)/plasmin activity using chromogenic substrates. Clot structure was visualized by confocal microscopy., Results: PAI-1 and its cofactor, vitronectin, are significantly elevated in patients with COVID-19 disease compared with those with non-COVID-19 respiratory infection and healthy control groups. Thrombin activatable fibrinolysis inhibitor and tissue plasminogen activator were elevated in patients with COVID-19 disease relative to healthy controls. PAI-1 and tissue plasminogen activator (tPA) were associated with more severe COVID-19 disease severity. Clots formed from COVID-19 plasma demonstrate an altered fibrin network, with attenuated fiber length and increased branching. Functional studies reveal that plasmin generation and clot lysis were markedly attenuated in COVID-19 disease, while PAI-1 activity was elevated. Clot lysis time significantly correlated with PAI-1 levels. Stratification of COVID-19 samples according to PAI-1 levels reveals significantly faster lysis when using the PAI-1 resistant (tPA) variant, tenecteplase, over alteplase lysis., Conclusion: This study shows that the suboptimal fibrinolytic response in COVID-19 disease is directly attributable to elevated levels of PAI-1, which attenuate plasmin generation. These data highlight the important prognostic potential of PAI-1 and the possibility of using pre-existing drugs, such as tenecteplase, to treat COVID-19 disease and potentially other respiratory diseases., (© 2022 The Authors. Journal of Thrombosis and Haemostasis published by Wiley Periodicals LLC on behalf of International Society on Thrombosis and Haemostasis.)
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- 2022
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14. Desmopressin for bleeding in non-severe hemophilia A: Suboptimal use in a real-world setting.
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Zwagemaker AF, Kloosterman FR, Coppens M, Gouw SC, Boyce S, Bagot CN, Beckers EAM, Brons P, Castaman G, Eikenboom J, Jackson S, Kruip MJHA, Leebeek FWG, Meijer K, Nieuwenhuizen L, Pabinger I, and Fijnvandraat K
- Abstract
Background: Desmopressin is an important treatment option in nonsevere hemophilia A because it has several benefits compared with factor (F) concentrates, including no inhibitor risk and much lower costs. Despite these advantages, data are limited on the real-world use of desmopressin in the treatment of bleeds., Objective: To describe the clinical use of desmopressin in relation to other therapeutic modalities in the treatment of bleeding episodes in patients with nonsevere hemophilia A., Methods: Patients with nonsevere hemophilia A aged 12-55 years were included from the DYNAMO cohort study. Data on the desmopressin test response and treated bleeding events in the period January 2009 to July 2020 were retrospectively collected from medical files. An adequate desmopressin test response was defined based on a peak FVIII level of ≥30 IU/dl., Results: A total of 248 patients with a median age of 38 years (interquartile range 25-49) were included. An adequate desmopressin test response was documented in 25% and 73% of patients with moderate and mild hemophilia, respectively. In adequate responders, 51% of bleeds were exclusively treated with FVIII concentrates, 24% exclusively with desmopressin, 21% with a combination of both and 4% with other treatments. In 54% of bleeds treated with a single dose of factor concentrates, the expected FVIII level after desmopressin exceeded the level targeted., Conclusion: Most bleeds in patients with an adequate response to desmopressin are treated with factor concentrates. These findings may indicate a suboptimal use of desmopressin and that barriers to the use of desmopressin should be explored., (© 2022 The Authors. Research and Practice in Thrombosis and Haemostasis published by Wiley Periodicals LLC on behalf of International Society on Thrombosis and Haemostasis (ISTH).)
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- 2022
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15. The bleeding phenotype in people with nonsevere hemophilia.
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Kloosterman FR, Zwagemaker AF, Bagot CN, Beckers EAM, Castaman G, Cnossen MH, Collins PW, Hay C, Hof M, Laros-van Gorkom B, Leebeek FWG, Male C, Meijer K, Pabinger I, Shapiro S, Coppens M, Fijnvandraat K, and Gouw SC
- Subjects
- Adolescent, Adult, Child, Factor IX, Hemarthrosis etiology, Hemorrhage etiology, Humans, Male, Middle Aged, Phenotype, Young Adult, Hemophilia A complications, Hemostatics
- Abstract
Detailed information on the onset, frequency, and severity of bleeding in nonsevere hemophilia is limited. We aimed to assess the bleeding phenotype of persons with nonsevere hemophilia and to analyze the association between baseline factor VIII/IX (FVIII/IX) levels and the joint bleeding rate. In the DYNAMO (Dynamic Interplay Between Bleeding Phenotype and Baseline Factor Level in Moderate and Mild Hemophilia A and B) study, an international multicenter cohort, we included males with nonsevere hemophilia (FVIII/IX, 0.02-0.35 IU/mL) aged 12 to 55 years. Information on age at first treated (joint) bleed, annual bleeding rates (ABRs), and annual joint bleeding rates (AJBRs) was collected from the medical files. The association between baseline FVIII/IX levels and the joint bleeding rate was assessed by using a frailty model for recurrent events. In total, 304 persons (70 with moderate hemophilia and 234 with mild hemophilia) were included. The median age was 38 years (interquartile range [IQR], 25-49 years), and the median baseline FVIII/IX level was 0.12 IU/mL (IQR, 0.05-0.21 IU/mL). In total, 245 (81%) persons had experienced at least 1 bleed, and 156 (51%) had experienced at least 1 joint bleed. The median age at first bleed and first joint bleed was 8 and 10 years, respectively. The median ABR and AJBR was 0.2 (IQR, 0.1-0.5) and 0.0 (IQR, 0.0-0.2). From baseline FVIII/IX levels 0.02 to 0.05 IU/mL to >0.25 IU/mL, the median ABR decreased from 0.6 (IQR, 0.2-1.4) to 0.1 (IQR, 0.0-0.2) and the AJBR from 0.2 (IQR, 0.0-0.4) to 0.0 (IQR, 0.0-0.0). Baseline FVIII/IX was inversely associated with the joint bleeding rate (P < .001). Low bleeding rates were observed in persons with nonsevere hemophilia. However, one-half of all adolescents and adults had experienced a joint bleed., (© 2022 by The American Society of Hematology. Licensed under Creative Commons Attribution-NonCommercial-NoDerivatives 4.0 International (CC BY-NC-ND 4.0), permitting only noncommercial, nonderivative use with attribution. All other rights reserved.)
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- 2022
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16. Seroprevalence to adeno-associated virus type 6 in people with hemophilia B from a UK adult cohort.
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Boyce S, James I, Rangarajan S, Curry N, Bagot C, Austin S, Laffan M, Mangles S, Chandrakumaran K, and Mundy C
- Abstract
Background: Gene therapy shows promise as a potential "cure" for hemophilia A and B. Adeno-associated virus (AAV) vectors are the leading platform to deliver modified genetic code of factor VIII or IX to the liver effecting endogenous production. Patient exposure to wild-type AAV leads to the formation of neutralizing factors, which can prevent successful transduction. It is thus important to establish the seroprevalence of the AAV serotypes in people with hemophilia to aid prediction of successful gene transfer. The seroprevalence of AAV6 in UK people with hemophilia B is not yet reported., Objectives: We studied the prevalence of anti-AAV6 neutralizing factors in UK people with hemophilia B ( n = 49). We collected data on people's hepatitis C exposure and treatment with plasma-derived factor IX (FIX) to identify if there was correlation with AAV6 exposure., Methods: Serum samples and patient data were collected from 49 people with hemophilia B registered at UK hemophilia comprehensive care centers. The samples were tested for neutralizing factors to AAV6 using a cell-based transduction inhibition assay., Results: Thirty-one percent of patients had serum neutralization against AAV6. There was no correlation between AAV6 seropositivity and previous treatment with plasma-derived FIX products or hepatitis C exposure., Conclusion: Based on limited data, there is no evidence of association between the presence of AAV6 neutralizing factors in people with hemophilia B and exposure to contaminated plasma derivatives. The frequency of AAV6 neutralizing factors in our hemophilia B cohort is similar to UK people with hemophilia A and non-hemophilia populations., (© 2022 The Authors. Research and Practice in Thrombosis and Haemostasis published by Wiley Periodicals LLC on behalf of International Society on Thrombosis and Haemostasis (ISTH).)
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- 2022
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17. A multisystem, cardio-renal investigation of post-COVID-19 illness.
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Morrow AJ, Sykes R, McIntosh A, Kamdar A, Bagot C, Bayes HK, Blyth KG, Briscoe M, Bulluck H, Carrick D, Church C, Corcoran D, Findlay I, Gibson VB, Gillespie L, Grieve D, Hall Barrientos P, Ho A, Lang NN, Lennie V, Lowe DJ, Macfarlane PW, Mark PB, Mayne KJ, McConnachie A, McGeoch R, McGinley C, McKee C, Nordin S, Payne A, Rankin AJ, Robertson KE, Roditi G, Ryan N, Sattar N, Allwood-Spiers S, Stobo D, Touyz RM, Veldtman G, Watkins S, Weeden S, Weir RA, Welsh P, Wereski R, Mangion K, and Berry C
- Subjects
- Aftercare, Female, Humans, Male, Middle Aged, Patient Discharge, Prospective Studies, Quality of Life, SARS-CoV-2, COVID-19 complications
- Abstract
The pathophysiology and trajectory of post-Coronavirus Disease 2019 (COVID-19) syndrome is uncertain. To clarify multisystem involvement, we undertook a prospective cohort study including patients who had been hospitalized with COVID-19 (ClinicalTrials.gov ID NCT04403607 ). Serial blood biomarkers, digital electrocardiography and patient-reported outcome measures were obtained in-hospital and at 28-60 days post-discharge when multisystem imaging using chest computed tomography with pulmonary and coronary angiography and cardio-renal magnetic resonance imaging was also obtained. Longer-term clinical outcomes were assessed using electronic health records. Compared to controls (n = 29), at 28-60 days post-discharge, people with COVID-19 (n = 159; mean age, 55 years; 43% female) had persisting evidence of cardio-renal involvement and hemostasis pathway activation. The adjudicated likelihood of myocarditis was 'very likely' in 21 (13%) patients, 'probable' in 65 (41%) patients, 'unlikely' in 56 (35%) patients and 'not present' in 17 (11%) patients. At 28-60 days post-discharge, COVID-19 was associated with worse health-related quality of life (EQ-5D-5L score 0.77 (0.23) versus 0.87 (0.20)), anxiety and depression (PHQ-4 total score 3.59 (3.71) versus 1.28 (2.67)) and aerobic exercise capacity reflected by predicted maximal oxygen utilization (20.0 (7.6) versus 29.5 (8.0) ml/kg/min) (all P < 0.01). During follow-up (mean, 450 days), 24 (15%) patients and two (7%) controls died or were rehospitalized, and 108 (68%) patients and seven (26%) controls received outpatient secondary care (P = 0.017). The illness trajectory of patients after hospitalization with COVID-19 includes persisting multisystem abnormalities and health impairments that could lead to substantial demand on healthcare services in the future., (© 2022. The Author(s).)
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- 2022
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18. Clinical Features of Vaccine-Induced Immune Thrombocytopenia and Thrombosis.
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Pavord S, Scully M, Hunt BJ, Lester W, Bagot C, Craven B, Rampotas A, Ambler G, and Makris M
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- Adolescent, Adult, Aged, Anticoagulants, Autoantibodies blood, COVID-19 prevention & control, ChAdOx1 nCoV-19, Female, Humans, Immunoglobulins, Intravenous therapeutic use, Intracranial Hemorrhages etiology, Intracranial Hemorrhages mortality, Male, Middle Aged, Multivariate Analysis, Platelet Count, Platelet Factor 4 immunology, Prospective Studies, Purpura, Thrombocytopenic, Idiopathic mortality, Purpura, Thrombocytopenic, Idiopathic therapy, Risk Factors, Thrombosis drug therapy, Thrombosis mortality, United Kingdom epidemiology, Young Adult, COVID-19 Vaccines adverse effects, Purpura, Thrombocytopenic, Idiopathic etiology, Thrombosis etiology
- Abstract
Background: Vaccine-induced immune thrombocytopenia and thrombosis (VITT) is a new syndrome associated with the ChAdOx1 nCoV-19 adenoviral vector vaccine against severe acute respiratory syndrome coronavirus 2. Data are lacking on the clinical features of and the prognostic criteria for this disorder., Methods: We conducted a prospective cohort study involving patients with suspected VITT who presented to hospitals in the United Kingdom between March 22 and June 6, 2021. Data were collected with the use of an anonymized electronic form, and cases were identified as definite or probable VITT according to prespecified criteria. Baseline characteristics and clinicopathological features of the patients, risk factors, treatment, and markers of poor prognosis were determined., Results: Among 294 patients who were evaluated, we identified 170 definite and 50 probable cases of VITT. All the patients had received the first dose of ChAdOx1 nCoV-19 vaccine and presented 5 to 48 days (median, 14) after vaccination. The age range was 18 to 79 years (median, 48), with no sex preponderance and no identifiable medical risk factors. Overall mortality was 22%. The odds of death increased by a factor of 2.7 (95% confidence interval [CI], 1.4 to 5.2) among patients with cerebral venous sinus thrombosis, by a factor of 1.7 (95% CI, 1.3 to 2.3) for every 50% decrease in the baseline platelet count, by a factor of 1.2 (95% CI, 1.0 to 1.3) for every increase of 10,000 fibrinogen-equivalent units in the baseline d-dimer level, and by a factor of 1.7 (95% CI, 1.1 to 2.5) for every 50% decrease in the baseline fibrinogen level. Multivariate analysis identified the baseline platelet count and the presence of intracranial hemorrhage as being independently associated with death; the observed mortality was 73% among patients with platelet counts below 30,000 per cubic millimeter and intracranial hemorrhage., Conclusions: The high mortality associated with VITT was highest among patients with a low platelet count and intracranial hemorrhage. Treatment remains uncertain, but identification of prognostic markers may help guide effective management. (Funded by the Oxford University Hospitals NHS Foundation Trust.)., (Copyright © 2021 Massachusetts Medical Society.)
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- 2021
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19. Rapidly established guidelines for the diagnosis and management of vaccine-induced thrombocytopenia and thrombosis (VITT) - a double-edged sword?
- Author
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Bagot CN
- Subjects
- Humans, Thrombocytopenia chemically induced, Thrombocytopenia diagnosis, Thrombosis diagnosis, Thrombosis etiology, Thrombosis therapy, Vaccines
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- 2021
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20. Mycophenolate Mofetil for First-Line Treatment of Immune Thrombocytopenia.
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Bradbury CA, Pell J, Hill Q, Bagot C, Cooper N, Ingram J, Breheny K, Kandiyali R, Rayment R, Evans G, Talks K, Thomas I, and Greenwood R
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- Adolescent, Adult, Aged, Drug Therapy, Combination, Fatigue chemically induced, Female, Glucocorticoids adverse effects, Hemorrhage etiology, Hemorrhage prevention & control, Humans, Immunosuppressive Agents adverse effects, Male, Middle Aged, Mycophenolic Acid adverse effects, Platelet Count, Purpura, Thrombocytopenic, Idiopathic complications, Quality of Life, Young Adult, Glucocorticoids therapeutic use, Immunosuppressive Agents therapeutic use, Mycophenolic Acid therapeutic use, Purpura, Thrombocytopenic, Idiopathic drug therapy
- Abstract
Background: Immune thrombocytopenia is a rare autoimmune disorder with associated bleeding risk and fatigue. Recommended first-line treatment for immune thrombocytopenia is high-dose glucocorticoids, but side effects, variable responses, and high relapse rates are serious drawbacks., Methods: In this multicenter, open-label, randomized, controlled trial conducted in the United Kingdom, we assigned adult patients with immune thrombocytopenia, in a 1:1 ratio, to first-line treatment with a glucocorticoid only (standard care) or combined glucocorticoid and mycophenolate mofetil. The primary efficacy outcome was treatment failure, defined as a platelet count of less than 30×10
9 per liter and initiation of a second-line treatment, assessed in a time-to-event analysis. Secondary outcomes were response rates, side effects, occurrence of bleeding, patient-reported quality-of-life measures, and serious adverse events., Results: A total of 120 patients with immune thrombocytopenia underwent randomization (52.4% male; mean age, 54 years [range 17 to 87]; mean platelet level, 7×109 per liter) and were followed for up to 2 years after beginning trial treatment. The mycophenolate mofetil group had fewer treatment failures than the glucocorticoid-only group (22% [13 of 59 patients] vs. 44% [27 of 61 patients]; hazard ratio, 0.41; range, 0.21 to 0.80; P = 0.008) and greater response (91.5% of patients having platelet counts greater than 100×109 per liter vs. 63.9%; P<0.001). We found no evidence of a difference between the groups in the occurrence of bleeding, rescue treatments, or treatment side effects, including infection. However, patients in the mycophenolate mofetil group reported worse quality-of-life outcomes regarding physical function and fatigue than those in the glucocorticoid-only group., Conclusions: The addition of mycophenolate mofetil to a glucocorticoid for first-line treatment of immune thrombocytopenia resulted in greater response and a lower risk of refractory or relapsed immune thrombocytopenia, but with somewhat decreased quality of life. (Funded by the U.K. National Institute for Health Research; FLIGHT ClinicalTrials.gov number, NCT03156452; EudraCT number, 2017-001171-23.)., (Copyright © 2021 Massachusetts Medical Society.)- Published
- 2021
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21. European principles of care for women and girls with inherited bleeding disorders.
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van Galen K, Lavin M, Skouw-Rasmussen N, Fischer K, Noone D, Pollard D, Mauser-Bunschoten E, Khair K, Gomez K, van Loon E, Bagot CN, Elfvinge P, d'Oiron R, and Abdul-Kadir R
- Subjects
- Comprehensive Health Care, Delivery of Health Care, Europe, Female, Humans, Hemophilia A diagnosis, Hemophilia A therapy, Quality of Life
- Abstract
Introduction: Despite increasing awareness of issues faced by women and girls with inherited BDs (WGBD), standards of care are lacking, with disparities in diagnosis and treatment for WGBD across Europe. We aimed to develop practical principles of care (PoC) to promote standardization of care for WGBD within European Haemophilia Treatment and Comprehensive Care Centres (HTC/CCCs)., Methods: The co-creation process, supported by the European Association for Haemophilia and Allied Disorders, consisted of four multidisciplinary meetings with health care providers (HCPs) experienced in WGBD care, and European Haemophilia Consortium representatives, combined with broad patient and HCP consultations in the European haemophilia community. Relevant medical societies outside Europe were contacted for confirmation., Results: We developed ten PoC for WGBD, stressing the importance and benefits of a centralized, multidisciplinary, comprehensive, family-centred approach to support and manage WGBD during all life stages. These PoC emphasise the right to equitable access and quality of care for all people with BDs, irrespective of gender. Multiple medical societies outside Europe also confirmed their support for endorsement., Conclusions: Ten PoC for WGBD evolved from an iterative process among stakeholders, supported by relevant medical societies worldwide. These PoC can serve as a benchmark for diagnosis and comprehensive multidisciplinary management of WGBD, and improve awareness of their unique challenges. They offer a framework to guide HTC/CCCs in providing equitable care for all WGBD, both in their own services and in other healthcare settings. Implementation of these principles aims to positively impact the health, wellbeing and quality of life for WGBD., (© 2021 The Authors. Haemophilia published by John Wiley & Sons Ltd.)
- Published
- 2021
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22. Pulmonary thromboembolism in hospitalised patients with COVID-19: a retrospective national study of patients managed in critical care and ward environments in Scotland.
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McGettrick M, MacLellan A, McCaughey P, Bagot C, Brewis MJ, Lang NN, Johnson MK, and Church AC
- Subjects
- Critical Care, Hospitals, Humans, Retrospective Studies, SARS-CoV-2, COVID-19, Pulmonary Embolism diagnostic imaging, Pulmonary Embolism epidemiology
- Abstract
Objectives: To assess for increase in pulmonary thromboembolism (PTE) in hospitalised patients with COVID-19, in both critical care and ward environments., Setting: We reviewed all CT pulmonary angiograms (CTPA) performed in Scotland between 23 March 2020 and 31 May 2020 and identified those with COVID-19 using either classical radiological appearances or positive COVID-19 PCR swab., Participants: All hospitalised patients in Scotland with COVID-19 between 23 March 2020 and 31 May 2020 who underwent a CTPA., Primary Outcome Measure: To assess if the rate of PTE was increased in those with COVID-19 compared with previously published figures of hospitalised patients., Secondary Outcome Measures: To assess the effect of right heart strain or requirement for critical care on mortality., Results: 3401 CTPAs were reviewed. 192 were positive for PTE in patients with evidence of COVID-19 either real-time PCR swab positive for SARS-CoV-2 (n=104) or having radiological changes consistent with COVID-19 (n=88). The total number of hospital admissions in Scotland between 23rd March 2020 and 31st May 2020 with COVID-19 was 5195. The incidence of PTE during this time was 3.7% in all patients admitted to all hospitals in Scotland with COVID-19 during this period. 475 hospitalised patients were managed in critical care (both level 2 and level 3 care), in whom the incidence of PTE was 6% (n=29). 4720 patients did not require admission to critical care, in whom the incidence of PTE was 3.5% (n=163). There was increased risk of death with right heart strain (25/52 vs 128/140 (p<0.01)) and in critical care (15/29 vs 146/163 (p<0.01))., Conclusions: We have demonstrated an increased risk of PTE in critical care and ward-based environments. Further studies are required to establish effective prophylactic anticoagulation in this group., Competing Interests: Competing interests: None declared., (© Author(s) (or their employer(s)) 2021. Re-use permitted under CC BY-NC. No commercial re-use. See rights and permissions. Published by BMJ.)
- Published
- 2021
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23. Targeting of antithrombin in hemophilia A or B with investigational siRNA therapeutic fitusiran-Results of the phase 1 inhibitor cohort.
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Pasi KJ, Lissitchkov T, Mamonov V, Mant T, Timofeeva M, Bagot C, Chowdary P, Georgiev P, Gercheva-Kyuchukova L, Madigan K, Van Nguyen H, Yu Q, Mei B, Benson CC, and Ragni MV
- Subjects
- Acetylgalactosamine, Adult, Antithrombins adverse effects, Humans, Male, Quality of Life, RNA, Small Interfering, Hemophilia A diagnosis, Hemophilia A drug therapy, Hemophilia B diagnosis, Hemophilia B drug therapy, Hemophilia B genetics
- Abstract
Background: Fitusiran, an investigational small interfering RNA therapy, reduces antithrombin production to rebalance hemostasis in people with hemophilia A or B, with or without inhibitors., Objectives: To evaluate the safety and efficacy of fitusiran treatment for people with moderate/severe hemophilia A or B with inhibitors., Patients/methods: In this open-label phase 1, part D study, 17 males with hemophilia A or B with inhibitors received three once-monthly subcutaneous injections of fitusiran 50 mg (n = 6) or 80 mg (n = 11); followed for up to 112 days. Endpoints included safety (primary), pharmacokinetics/pharmacodynamics (secondary), annualized bleeding rate, and patient-reported outcomes (exploratory)., Results: The most common adverse event was injection site erythema (n = 8). No thrombotic events were reported. At nadir, mean (standard error of the mean [SEM]) antithrombin activity decreased from baseline by 82.0% (2.2) and 87.4% (0.7) in the 50 mg and 80 mg groups, respectively. Antithrombin reduction was associated with increased thrombin generation. 11/17 (64.7%) participants had no bleeds during the observation period (mean [standard deviation] 69.4 [16.3] days). Mean (SEM) changes from baseline in Haemophilia Quality of Life Questionnaire for Adults total (-9.2 [2.9]) and physical health (-12.3 [3.9]) domain scores suggested clinically meaningful improvement., Conclusions: Monthly fitusiran was generally well tolerated, lowered antithrombin levels from baseline, and resulted in improved thrombin generation. These preliminary results suggest that monthly fitusiran treatment may reduce bleeding episodes and improve quality of life in participants with hemophilia A or B with inhibitors., (© 2021 Sanofi. Journal of Thrombosis and Haemostasis published by Wiley Periodicals LLC on behalf of International Society on Thrombosis and Haemostasis.)
- Published
- 2021
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24. Correction to History of the West of Scotland Haemophilia Centre, Glasgow, 1950-2019.
- Author
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Lowe G, Walker I, Gibson B, Tait C, and Bagot C
- Abstract
Competing Interests: No conflict of interests declared
- Published
- 2020
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25. The Chief Scientist Office Cardiovascular and Pulmonary Imaging in SARS Coronavirus disease-19 (CISCO-19) study.
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Mangion K, Morrow A, Bagot C, Bayes H, Blyth KG, Church C, Corcoran D, Delles C, Gillespie L, Grieve D, Ho A, Kean S, Lang NN, Lennie V, Lowe DJ, Kellman P, Macfarlane PW, McConnachie A, Roditi G, Sykes R, Touyz RM, Sattar N, Wereski R, Wright S, and Berry C
- Subjects
- COVID-19 therapy, COVID-19 virology, Convalescence, Electrocardiography, Heart virology, Heart Diseases virology, Host-Pathogen Interactions, Humans, Kidney virology, Kidney Diseases virology, Longitudinal Studies, Lung virology, Predictive Value of Tests, Prospective Studies, Research Design, SARS-CoV-2 pathogenicity, Scotland, Time Factors, COVID-19 diagnostic imaging, Heart diagnostic imaging, Heart Diseases diagnostic imaging, Kidney diagnostic imaging, Kidney Diseases diagnostic imaging, Lung diagnostic imaging, Multimodal Imaging
- Abstract
Background: COVID-19 is typically a primary respiratory illness with multisystem involvement. The prevalence and clinical significance of cardiovascular and multisystem involvement in COVID-19 remain unclear., Methods: This is a prospective, observational, multicentre, longitudinal, cohort study with minimal selection criteria and a near-consecutive approach to screening. Patients who have received hospital care for COVID-19 will be enrolled within 28 days of discharge. Myocardial injury will be diagnosed according to the peak troponin I in relation to the upper reference limit (URL, 99th centile) (Abbott Architect troponin I assay; sex-specific URL, male: >34 ng/L; female: >16 ng/L). Multisystem, multimodality imaging will be undertaken during the convalescent phase at 28 days post-discharge (Visit 2). Imaging of the heart, lung, and kidneys will include multiparametric, stress perfusion, cardiovascular magnetic resonance imaging, and computed tomography coronary angiography. Health and well-being will be assessed in the longer term. The primary outcome is the proportion of patients with a diagnosis of myocardial inflammation., Conclusion: CISCO-19 will provide detailed insights into cardiovascular and multisystem involvement of COVID-19. Our study will inform the rationale and design of novel therapeutic and management strategies for affected patients., Clinical Trial Registration: ClinicalTrials.gov identifier NCT04403607., (© The Author(s) 2020. Published by Oxford University Press on behalf of the European Society of Cardiology.)
- Published
- 2020
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26. History of the West of Scotland Haemophilia Centre, Glasgow, 1950-2019.
- Author
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Lowe G, Walker I, Gibson B, Tait C, and Bagot C
- Subjects
- Blood Transfusion, Humans, Scotland, Hemophilia A drug therapy, Hemophilia A epidemiology, Medicine
- Abstract
Over 70 years, the West of Scotland Haemophilia Centre in the UK has played a leading role in research, education and training. Its staff studied the natural history of haemophilias, their complications, and their treatment complications, pioneered the use of fibrinolytic inhibitors to reduce the risk of receiving a blood transfusion and developed national audit. Collaborations across Scotland with other haemophilia centres and the Scottish National Blood Transfusion Service progressed self-suffi ciency in NHS-produced factor concentrates, heat treatments to prevent HIV and hepatitis transmission, and finally, replacement of human by recombinant factor concentrates., Competing Interests: No conflict of interests declared
- Published
- 2020
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27. Managing venous thromboembolic risk in women undergoing spontaneous or induced early pregnancy loss: a consensus statement from the British Society of Haematology Obstetric Haematology Special Interest Group.
- Author
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Bagot CN, Pavord S, and Hunt BJ
- Subjects
- Adult, Consensus, Female, Humans, Pregnancy, Risk Factors, United Kingdom, Abortion, Spontaneous physiopathology, Venous Thrombosis etiology, Venous Thrombosis therapy
- Abstract
The level of venous thrombosis risk in women who experience spontaneous or induced pregnancy loss has previously been uncertain. However, recent data indicate that the risk of venous thrombosis in women undergoing pregnancy termination in the first trimester is increased two-fold compared to non-pregnant women but reduced five-fold compared to women in the 6 weeks following a term birth. The termination procedure itself appears not to influence thrombosis risk. In light of this data, this consensus statement provides recommendations for reducing the risk of venous thrombosis in women undergoing spontaneous or induced pregnancy loss based on Royal College of Obstetricians and Gynaecologists risk stratification guidelines., (© 2020 British Society for Haematology and John Wiley & Sons Ltd.)
- Published
- 2020
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28. Hereditary phytosterolaemia.
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Harper K, Bagot CN, and Leach M
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- Adult, Genetic Diseases, Inborn diagnosis, Genetic Diseases, Inborn pathology, Humans, Hypercholesterolemia diagnosis, Intestinal Diseases diagnosis, Lipid Metabolism, Inborn Errors diagnosis, Male, Phytosterols genetics, Phytosterols physiology, ATP Binding Cassette Transporter, Subfamily G, Member 5 genetics, Genetic Diseases, Inborn genetics, Heterozygote, Hypercholesterolemia genetics, Intestinal Diseases genetics, Lipid Metabolism, Inborn Errors genetics, Lipoproteins genetics, Mutation, Phytosterols adverse effects
- Published
- 2019
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29. The prevention of glucocorticoid-induced osteoporosis in patients with immune thrombocytopenia receiving steroids: a British Society for Haematology Good Practice Paper.
- Author
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Hill QA, Grainger JD, Thachil J, Provan D, Evans G, Garg M, Bradbury C, Bagot C, Kanis JA, and Compston JE
- Subjects
- Female, Hematology, Humans, Male, Societies, Medical, United Kingdom, Glucocorticoids adverse effects, Glucocorticoids therapeutic use, Osteoporosis chemically induced, Osteoporosis prevention & control, Purpura, Thrombocytopenic, Idiopathic drug therapy
- Published
- 2019
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30. Autologous 111 In-labelled platelet scan as a predictor of splenectomy outcome in ITP.
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Kazi S, Mckiddie F, Anderson J, Bagot C, Duncan C, Drummond M, Kerr R, Khan M, McColl M, Roddie H, Priddee N, Staff R, Thomas R, and Watson HG
- Subjects
- Adolescent, Adult, Aged, Female, Humans, Male, Middle Aged, Purpura, Thrombocytopenic, Idiopathic pathology, Young Adult, Blood Platelets physiology, Purpura, Thrombocytopenic, Idiopathic blood, Purpura, Thrombocytopenic, Idiopathic surgery, Radionuclide Imaging methods, Splenectomy methods
- Published
- 2019
- Full Text
- View/download PDF
31. Severe antithrombin deficiency in pregnancy: Achieving adequate anticoagulation.
- Author
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Pearson-Stuttard B, Bagot C, Ciantar E, Myers B, Davies R, Rayment R, Clark A, McKernan A, and Pavord S
- Abstract
Antithrombin deficiency is identified as one of the most potent risk factors for venous thromboembolism during pregnancy. Therapeutic low molecular weight heparin is recommended, but it can be difficult to attain sufficient anticoagulation since low molecular weight heparin requires antithrombin to exert its anticoagulant effect. We carried out a multicentre case-series assessing the dose of low molecular weight heparin required to achieve therapeutic anti-activated factor X levels in pregnant women with antithrombin deficiency. We assessed 27 pregnancies in 18 women with severe antithrombin deficiency, which we defined as an antithrombin level of <0.55 IU/ml (with or without prior venous thromboembolism) or an antithrombin level < 0.8 IU/ml and a personal history of venous thromboembolism. Our data illustrate the need for high doses of low molecular weight heparin to achieve therapeutic anti-activated factor X levels (average 20,220 IU/day). All pregnancies ended in live birth (excluding one elective termination), although intrauterine growth restriction occurred in five (18%).
- Published
- 2019
- Full Text
- View/download PDF
32. Trial protocol: a multicentre randomised trial of first-line treatment pathways for newly diagnosed immune thrombocytopenia: standard steroid treatment versus combined steroid and mycophenolate. The FLIGHT trial.
- Author
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Pell J, Greenwood R, Ingram J, Wale K, Thomas I, Kandiyali R, Mumford A, Dick A, Bagot C, Cooper N, Hill Q, and Bradbury CA
- Subjects
- Adrenal Cortex Hormones therapeutic use, Adult, Drug Therapy, Combination, Female, Humans, Male, Research Design, Clinical Trial Protocols as Topic, Immunosuppressive Agents therapeutic use, Multicenter Studies as Topic standards, Mycophenolic Acid therapeutic use, Purpura, Thrombocytopenic, Idiopathic drug therapy, Randomized Controlled Trials as Topic standards
- Abstract
Introduction: Immune thrombocytopenia (ITP) is an autoimmune condition that may cause thrombocytopenia-related bleeding. Current first-line ITP treatment is with high-dose corticosteroids but frequent side effects, heterogeneous responses and high relapse rates are significant problems with only 20% remaining in sustained remission with this approach. Mycophenolate mofetil (MMF) is often used as the next treatment with efficacy in 50%-80% of patients and good tolerability but can take up to 2 months to work., Objective: To test the hypothesis that MMF combined with corticosteroid is a more effective first-line treatment for immune thrombocytopenia (ITP) than current standard of corticosteroid alone., Methods and Analysis: DesignMulticentre, UK-based, open-label, randomised controlled trial., Setting: Haematology departments in secondary care., Participants: We plan to recruit 120 patients >16 years old with a diagnosis of ITP and a platelet count <30x10
9 /L who require first-line treatment. Patients will be followed up for a minimum of 12 months following randomisation., Primary Outcome: Time from randomisation to treatment failure defined as platelets <30x109 /L and a need for second-line treatment., Secondary Outcomes: Side effects, bleeding events, remission rates, time to relapse, time to next therapy, cumulative corticosteroid dose, rescue therapy, splenectomy, socioeconomic costs, patient-reported outcomes (quality of life, fatigue, impact of bleeding, care costs)., Analysis: The sample size of 120 achieves a 91.5% power to detect a doubling of the median time to treatment failure from 5 to 10 months. This will be expressed as an HR with 95% CI, median time to event if more than 50% have had an event and illustrated with Kaplan-Meier curves. Cost-effectiveness will be based on the first 12 months from diagnosis., Ethics and Dissemination: Ethical approval from NRES Committee South West (IRAS number 225959). EudraCT Number: 2017-001171-23. Results will be submitted for publication in peer-reviewed journals., Trial Registration Number: NCT03156452., Competing Interests: Competing interests: None declared., (© Author(s) (or their employer(s)) 2018. Re-use permitted under CC BY. Published by BMJ.)- Published
- 2018
- Full Text
- View/download PDF
33. A United Kingdom Immune Thrombocytopenia (ITP) Forum review of practice: thrombopoietin receptor agonists.
- Author
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Thachil J, Bagot C, Bradbury C, Cooper N, Lester W, Grainger JD, Lowe G, Evans G, Talks K, Sibson K, Garg M, Murphy MF, Watson HG, Bolton-Maggs PHB, Watson S, Scully M, Provan D, Newland A, and Hill QA
- Subjects
- Disease Management, Health Care Surveys, Humans, Practice Patterns, Physicians', Receptors, Thrombopoietin agonists, Receptors, Thrombopoietin antagonists & inhibitors, United Kingdom, Purpura, Thrombocytopenic, Idiopathic diagnosis, Purpura, Thrombocytopenic, Idiopathic drug therapy
- Published
- 2018
- Full Text
- View/download PDF
34. Women with unexplained recurrent pregnancy loss do not have evidence of an underlying prothrombotic state: experience with calibrated automated thrombography and rotational thromboelastometry.
- Author
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Bennett SA, Bagot CN, Appiah A, Johns J, Ross J, Roberts LN, Patel RK, and Arya R
- Subjects
- Adolescent, Adult, Blood Coagulation physiology, Calibration, Case-Control Studies, Female, Humans, Middle Aged, Pregnancy, Prospective Studies, Thrombin analysis, Young Adult, Abortion, Habitual blood, Pregnancy Complications, Hematologic blood, Thrombelastography methods, Thrombin metabolism, Thrombophilia blood
- Abstract
Introduction: Where unexplained recurrent pregnancy loss (RPL) is attributed to an underlying maternal prothrombotic state, empirical prophylactic anticoagulation may be recommended., Materials and Methods: In the present study we used calibrated automated thrombography and rotational thromboelastometry to determine the procoagulant potential of these women as a rationale for anticoagulation. Fifty women with ≥three consecutive unexplained losses prior to 14 weeks' gestation or one loss after this time were compared with forty-one parous women with no miscarriages. Exclusion criteria included antiphospholipid syndrome, inherited thrombophilia and prior venous thromboembolism. Thrombin generation in platelet poor plasma and whole blood thromboelastometry was performed outside pregnancy to determine the presence or not of an underlying prothrombotic state., Results: Peak thrombin and endogenous thrombin potential were not significantly increased in subjects relative to controls. The use of low tissue factor (1 pM) to better reflect physiological conditions and assay modification to better assess the protein C pathway (5 pM in the presence of thrombomodulin) provided no additional discrimination. Consistent results were shown with thromboelastometry; mean parameters were equivalent between subjects and controls., Conclusions: These data demonstrate that global coagulation assays provide no evidence of an underlying hypercoagulable state in women with unexplained RPL; this is in keeping with the results of recent randomised controlled trials and strengthens the evidence base against use of anticoagulants in this setting., (Copyright © 2014 Elsevier Ltd. All rights reserved.)
- Published
- 2014
- Full Text
- View/download PDF
35. Correlating prothrombin time with plasma rivaroxaban level.
- Author
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Rodgers R, Bagot CN, Lawrence C, Hickman G, McGurk M, and Tait RC
- Subjects
- Blood Coagulation drug effects, Calibration, Factor Xa Inhibitors, Humans, Morpholines pharmacokinetics, Morpholines pharmacology, Partial Thromboplastin Time, Patient Compliance, Rivaroxaban, Sensitivity and Specificity, Thiophenes pharmacokinetics, Thiophenes pharmacology, Morpholines blood, Prothrombin Time, Thiophenes blood
- Published
- 2013
- Full Text
- View/download PDF
36. Pregnancy loss and thrombophilia: the elusive link.
- Author
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Bennett SA, Bagot CN, and Arya R
- Subjects
- Abortion, Spontaneous diagnosis, Abortion, Spontaneous drug therapy, Anticoagulants therapeutic use, Female, Fetal Death diagnosis, Humans, Platelet Aggregation Inhibitors therapeutic use, Practice Guidelines as Topic, Pregnancy, Thrombophilia diagnosis, Thrombophilia drug therapy, Abortion, Spontaneous etiology, Fetal Death etiology, Thrombophilia complications
- Abstract
Recurrent pregnancy loss (RPL) affects 1% pregnancies and is multi-factorial in origin. The role of the acquired thrombophilia antiphospholipid syndrome (APS) as a common and potentially treatable cause of RPL is well established but this is less so for inherited thrombophilia. In obstetric APS the combination of aspirin and heparin has improved outcomes. By analogy, the use of low molecular weight heparin (LMWH) has become commonplace in women with inherited thrombophilia and also those with unexplained miscarriage to help safeguard the pregnancy. This review will examine the pathophysiological role of thrombophilia in pregnancy loss, and the evidence for anticoagulant-based intervention. The limited data supporting the use of heparin for women with RPL and inherited thrombophilia suggests adoption of a more cautious and judicious approach in this setting., (© 2012 Blackwell Publishing Ltd.)
- Published
- 2012
- Full Text
- View/download PDF
37. Late onset hypogonadism: an alternate cause for night sweats in the haematology clinic.
- Author
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Roberts LN, Bagot CN, Patel RK, Whitehead M, and Arya R
- Subjects
- Aged, Humans, Male, Thrombocythemia, Essential complications, Hyperhidrosis etiology, Hypogonadism complications
- Published
- 2009
- Full Text
- View/download PDF
38. Virchow and his triad: a question of attribution.
- Author
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Bagot CN and Arya R
- Subjects
- Germany, History, 19th Century, History, 20th Century, Humans, Venous Thrombosis history
- Abstract
Virchow's triad describes three factors that contribute to the development of venous thrombosis: hypercoagulability, stasis and endothelial injury. Yet, extensive review of the historical literature casts doubt on the existence of a triad described by Virchow in the form it is currently quoted throughout contemporary medical literature. Certainly his work involved extensive study of venous thrombosis and pulmonary embolism, with these two terms being coined by Virchow, but a triad of factors relating to the development of venous thrombosis is elusive. Interestingly, Virchow only began to be routinely credited with this triad one hundred years after publication of his work on venous thrombosis. This acknowledgement coincided with the accumulation of experimental evidence for the role these factors play in thrombogenesis. Controversial as the origins of Virchow's triad might be, it is apt given his substantial contribution to our knowledge of venous thromboembolism, and the fact that the triad continues to be clinically relevant today that a triad pertaining to Virchow should remain.
- Published
- 2008
- Full Text
- View/download PDF
39. Perioperative myocardial infarction in a patient receiving low-dose prothrombin complex concentrates.
- Author
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Bagot CN, Cregg R, Patel RK, Shariff A, and Arya R
- Subjects
- Blood Coagulation Factors therapeutic use, Fatal Outcome, Humans, Intraoperative Complications chemically induced, Male, Middle Aged, Myocardial Infarction etiology, Blood Coagulation Factors adverse effects, Myocardial Infarction chemically induced
- Published
- 2007
40. Extrinsic venous compression: a sufficient explanation for venous thromboembolism due to massive fibroids?
- Author
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Barsam S, Bagot C, Patel R, Sidhu PS, Davies A, and Arya R
- Subjects
- Adult, Female, Humans, Magnetic Resonance Imaging, Middle Aged, Thromboembolism etiology, Leiomyoma complications, Venous Thrombosis etiology
- Published
- 2006
41. Imatinib mesylate as a cause of acute liver failure.
- Author
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Cross TJ, Bagot C, Portmann B, Wendon J, and Gillett D
- Subjects
- Antineoplastic Agents administration & dosage, Benzamides, Female, Humans, Imatinib Mesylate, Leukemia, Myelogenous, Chronic, BCR-ABL Positive complications, Leukemia, Myelogenous, Chronic, BCR-ABL Positive pathology, Liver Failure, Acute pathology, Liver Failure, Acute therapy, Liver Transplantation, Middle Aged, Necrosis chemically induced, Necrosis pathology, Piperazines administration & dosage, Pyrimidines administration & dosage, Antineoplastic Agents adverse effects, Leukemia, Myelogenous, Chronic, BCR-ABL Positive drug therapy, Liver Failure, Acute chemically induced, Piperazines adverse effects, Pyrimidines adverse effects
- Abstract
A 46-year-old patient diagnosed with chronic myeloid leukemia in whom cytogenetic and molecular remission had never been achieved was commenced on Imatinib Mesylate (Gleevec, Novartis Pharmaceuticals Corp., East Hanover, NJ). After 18 months of treatment, she developed abnormal liver function tests and subsequently acute liver failure, requiring transfer to the regional liver unit. The patient proceeded to liver transplantation but later died. The explanted liver had histological features of severe hepatic necrosis. This is the first case described of fatal hepatic necrosis in a patient who has have been on long-term imatinib therapy. This may have implications for long-term use of the drug and emphasizes the need for regular monitoring of liver function.
- Published
- 2006
- Full Text
- View/download PDF
42. Transcriptional repression of peri-implantation EMX2 expression in mammalian reproduction by HOXA10.
- Author
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Troy PJ, Daftary GS, Bagot CN, and Taylor HS
- Subjects
- Animals, Binding Sites, Cells, Cultured, Endometrium cytology, Endometrium drug effects, Estradiol pharmacology, Female, Homeobox A10 Proteins, Homeodomain Proteins drug effects, Humans, Mammals physiology, Menstrual Cycle genetics, Mice, Mutation, Oligonucleotides, Antisense pharmacology, Pregnancy, Progesterone pharmacology, Recombinant Proteins genetics, Recombinant Proteins metabolism, Regulatory Sequences, Nucleic Acid, Repressor Proteins genetics, Repressor Proteins metabolism, Reproduction genetics, Transcription Factors, Embryonic Development genetics, Endometrium physiology, Homeodomain Proteins genetics, Homeodomain Proteins metabolism, Transcription, Genetic
- Abstract
HOXA10 is necessary for mammalian reproduction; however, its transcriptional targets are not completely defined. EMX2, a divergent homeobox gene, is necessary for urogenital tract development. In these studies we identify and characterize the regulation of EMX2 by HOXA10. By using Northern analysis and in situ hybridization, we found that EMX2 is expressed in the adult urogenital tract in an inverse temporal pattern from HOXA10, suggestive of a negative regulatory relationship. Constitutive expression of HOXA10 diminished EMX2 mRNA, whereas blocking HOXA10 through the use of antisense resulted in high EMX2 mRNA expression. Deletional analysis of the EMX2 5' regulatory region revealed that a 150-bp element mediated transcriptional repression when cotransfected with pcDNA3.1/HOXA10 in transient-transfection assays. Binding of HOXA10 protein to this element was demonstrated by electrophoretic mobility shift assay and further localized to a consensus HOXA10 binding site within this element by DNase I footprinting. Site-directed mutagenesis abolished binding, as well as the negative transcriptional regulation. Transcriptional activation of empty spiracles, the Drosophila ortholog of EMX2, by Abdominal-B (HOXA10 ortholog) has been previously demonstrated. These findings demonstrate conservation of the transcription factor-target gene relationship, although the direction of regulation is reversed with possible evolutionary implications.
- Published
- 2003
- Full Text
- View/download PDF
43. Direct regulation of beta3-integrin subunit gene expression by HOXA10 in endometrial cells.
- Author
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Daftary GS, Troy PJ, Bagot CN, Young SL, and Taylor HS
- Subjects
- Adenocarcinoma chemistry, Adenocarcinoma metabolism, Adult, Base Sequence, Binding Sites, Blotting, Northern, Consensus Sequence, DNA chemistry, DNA metabolism, Endometrial Neoplasms chemistry, Endometrial Neoplasms metabolism, Female, Genes, Reporter, Homeobox A10 Proteins, Homeodomain Proteins genetics, Homeodomain Proteins metabolism, Humans, Integrin beta3, Molecular Sequence Data, Promoter Regions, Genetic, RNA, Messenger analysis, Regulatory Sequences, Nucleic Acid, Transfection, Antigens, CD genetics, Endometrium metabolism, Gene Expression Regulation drug effects, Homeodomain Proteins physiology, Platelet Membrane Glycoproteins genetics
- Abstract
Estrogen and progesterone regulate HOXA10 expression in the endometrium, where HOXA10 is necessary for implantation. The integrins are also involved in early embryo-endometrial interactions. Here we show that HOXA10 directly regulates beta3-integrin subunit expression in the endometrium, likely mediating the effect of sex steroids on beta3-integrin expression. beta3-Integrin expression was decreased in endometrium shown to have low HOXA10 expression. beta3-Integrin mRNA levels were increased in endometrial adenocarcinoma cells (Ishikawa) transfected with pcDNA3.1/HOXA10, and decreased in cells treated with HOXA10 antisense. Seven consensus HOXA10 binding sites were identified 5' of the beta3-integrin gene. Direct binding of HOXA10 protein to four sites was demonstrated by EMSA. Reporter gene expression increased in BT-20 cells cotransfected with pcDNA3.1/ HOXA10 and pGL3-promoter vector containing region F (encompassing all seven HOXA10 consensus sites). A 41-bp segment (Region A) showed highest affinity binding to HOXA10 protein. Increased reporter expression, equal in magnitude to that obtained with Region F, was obtained with Region A. HOXA10 protein binding within Region A was localized by deoxyribonuclease I footprinting. beta3-Integrin expression was directly up-regulated by HOXA10 through a 41-bp 5'-regulatory element. Sex steroids regulate the expression of endometrial beta3-integrin through a pathway involving HOXA10.
- Published
- 2002
- Full Text
- View/download PDF
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