171 results on '"William Collins"'
Search Results
2. Asthma phenotypes, associated comorbidities, and long‐term symptoms in COVID‐19
- Author
-
R. Sharon Chinthrajah, Kari C. Nadeau, Shu Cao, Sayantani B. Sindher, William Collins, Gopal Krishna R. Dhondalay, Benjamin A. Pinsky, Theo T Snow, Alexandra S. Lee, Andra L. Blomkalns, Shirley Y. Jiang, Neera Ahuja, Lauren E. Eggert, Ruth O'Hara, Maja Artandi, Jessica Fitzpatrick, Linda Barman, Ziyuan He, Rajan Puri, Manisha Desai, and Richard Wittman
- Subjects
0301 basic medicine ,Longitudinal study ,Allergy ,medicine.medical_specialty ,Multivariate analysis ,Coronavirus disease 2019 (COVID-19) ,Immunology ,Disease ,Asymptomatic ,SARS‐CoV‐2 ,03 medical and health sciences ,COVID-19 Testing ,0302 clinical medicine ,COVID‐19 ,Internal medicine ,medicine ,Humans ,Immunology and Allergy ,Risk factor ,Respiratory system ,Retrospective Studies ,Asthma ,SARS-CoV-2 ,business.industry ,COVID-19 ,Original Articles ,asthma ,Eosinophil ,medicine.disease ,Phenotype ,030104 developmental biology ,medicine.anatomical_structure ,030228 respiratory system ,Original Article ,eosinophils ,medicine.symptom ,business - Abstract
Background It is unclear whether asthma and its allergic phenotype are risk factors for hospitalization or severe disease from SARS‐CoV‐2. Methods All patients over 28 days old testing positive for SARS‐CoV‐2 between March 1 and September 30, 2020, were retrospectively identified and characterized through electronic analysis at Stanford. A sub‐cohort was followed prospectively to evaluate long‐term COVID‐19 symptoms. Results 168,190 patients underwent SARS‐CoV‐2 testing, and 6,976 (4.15%) tested positive. In a multivariate analysis, asthma was not an independent risk factor for hospitalization (OR 1.12 [95% CI 0.86, 1.45], p = .40). Among SARS‐CoV‐2‐positive asthmatics, allergic asthma lowered the risk of hospitalization and had a protective effect compared with non‐allergic asthma (OR 0.52 [0.28, 0.91], p = .026); there was no association between baseline medication use as characterized by GINA and hospitalization risk. Patients with severe COVID‐19 disease had lower eosinophil levels during hospitalization compared with patients with mild or asymptomatic disease, independent of asthma status (p = .0014). In a patient sub‐cohort followed longitudinally, asthmatics and non‐asthmatics had similar time to resolution of COVID‐19 symptoms, particularly lower respiratory symptoms. Conclusions Asthma is not a risk factor for more severe COVID‐19 disease. Allergic asthmatics were half as likely to be hospitalized with COVID‐19 compared with non‐allergic asthmatics. Lower levels of eosinophil counts (allergic biomarkers) were associated with a more severe COVID‐19 disease trajectory. Recovery was similar among asthmatics and non‐asthmatics with over 50% of patients reporting ongoing lower respiratory symptoms 3 months post‐infection., Asthma is not a risk factor for more severe COVID‐19 disease. Allergic asthmatics are half as likely to be hospitalized compared with non‐allergic asthmatics and lower levels of eosinophil counts (allergic biomarkers) are associated with a more severe COVID‐19 disease trajectory. Recovery is similar among asthmatics and non‐asthmatics.
- Published
- 2021
3. Vaccines and Allergic reactions: The past, the current COVID-19 pandemic, and future perspectives
- Author
-
Domingo Barber, Robyn E O'Hehir, Mihir Shah, Ronald L. Rabin, Markus Ollert, Wytske Fokkens, Oliver Pfaar, Menno C. van Zelm, Luo Zhang, Milena Sokolowska, Mübeccel Akdis, De Yun Wang, Cezmi A. Akdis, Thomas Eiwegger, Katharine Fast, Claudia Traidl-Hoffmann, Heimo Breiteneder, Zuzana Diamant, Ioana Agache, Kari C. Nadeau, Milos Jesenak, Mohamed H. Shamji, María José Torres, Vanitha Sampath, Stefan Vieths, Carmen Riggioni, Liam O'Mahony, Oscar Palomares, Grace Rabinowitz, Sharon Chinthrajah, William Collins, Surabhi Jain, and Tomas Chivato
- Subjects
0301 basic medicine ,Allergy ,CHILDREN ,Review Article ,HYPERSENSITIVITY REACTIONS ,SARS‐CoV‐2 ,0302 clinical medicine ,allergy ,vaccine ,Pandemic ,Immunology and Allergy ,PROTEIN-COUPLED RECEPTOR-X2 ,Review Articles ,anaphylaxis ,Vaccines ,SARS-CoV-2 ,Vaccination ,Safety profile ,VACCINATION ,COVID-19 ,Anaphylaxis ,medicine.medical_specialty ,COVID-19 Vaccines ,Coronavirus disease 2019 (COVID-19) ,Hypersensitivity/diagnosis ,Immunology ,03 medical and health sciences ,COVID‐19 ,medicine ,Hypersensitivity ,Vaccines/adverse effects ,Humans ,MAST-CELL ,Intensive care medicine ,Pandemics ,business.industry ,Public health ,GELATIN ,ANTI-PEG ANTIBODIES ,medicine.disease ,030104 developmental biology ,030228 respiratory system ,Infectious disease (medical specialty) ,ADVERSE-REACTIONS ,SAFETY DATA ,business - Abstract
Vaccines are essential public health tools with a favorable safety profile and prophylactic effectiveness that have historically played significant roles in reducing infectious disease burden in populations, when the majority of individuals are vaccinated. The COVID-19 vaccines are expected to have similar positive impacts on health across the globe. While serious allergic reactions to vaccines are rare, their underlying mechanisms and implications for clinical management should be considered to provide individuals with the safest care possible. In this review, we provide an overview of different types of allergic adverse reactions that can potentially occur after vaccination and individual vaccine components capable of causing the allergic adverse reactions. We present the incidence of allergic adverse reactions during clinical studies and through post-authorization and post-marketing surveillance and provide plausible causes of these reactions based on potential allergenic components present in several common vaccines. Additionally, we review implications for individual diagnosis and management and vaccine manufacturing overall. Finally, we suggest areas for future research.
- Published
- 2021
4. Reduction in massive postpartum haemorrhage and red blood cell transfusion during a national quality improvement project, Obstetric Bleeding Strategy for Wales, OBS Cymru: an observational study
- Author
-
Tracey Edey, Peter William Collins, Thomas Kitchen, Christopher Bailey, Ingrid Volikas, Sarah F. Bell, Cerys Scarr, Claire Francis, Adam Watkins, R. E. Collis, Kathryn James, Elinore Macgillivray, Philip Pallmann, Miriam John, James Tozer, Iolo Roberts, Niladri Sengupta, Kevin Kelly, and Kathryn Greaves
- Subjects
medicine.medical_specialty ,Blood transfusion ,medicine.medical_treatment ,Red Blood Cell Transfusion ,Reproductive medicine ,Viscoelastometry ,Risk Assessment ,Postpartum haemorrhage ,03 medical and health sciences ,0302 clinical medicine ,Pregnancy ,Coagulopathy ,Humans ,Medicine ,Visual estimation ,030212 general & internal medicine ,Quality improvement ,Wales ,030219 obstetrics & reproductive medicine ,business.industry ,Obstetrics ,Incidence (epidemiology) ,Postpartum Hemorrhage ,Postpartum Period ,Obstetrics and Gynecology ,Gynecology and obstetrics ,medicine.disease ,RG1-991 ,Female ,National database ,Observational study ,Fresh frozen plasma ,Erythrocyte Transfusion ,business ,Risk assessment ,Research Article - Abstract
Background Postpartum haemorrhage (PPH) is a major cause of maternal morbidity and mortality and its incidence is increasing in many countries despite management guidelines. A national quality improvement programme called the Obstetric Bleeding Strategy for Wales (OBS Cymru) was introduced in all obstetric units in Wales. The aim was to reduce moderate PPH (1000 mL) progressing to massive PPH (> 2500 mL) and the need for red cell transfusion. Methods A PPH care bundle was introduced into all 12 obstetric units in Wales included all women giving birth in 2017 and 2018 (n = 61,094). The care bundle prompted: universal risk assessment, quantitative measurement of blood loss after all deliveries (as opposed to visual estimation), structured escalation to senior clinicians and point-of-care viscoelastometric-guided early fibrinogen replacement. Data were submitted by each obstetric unit to a national database. Outcome measures were incidence of massive PPH (> 2500 mL) and red cell transfusion. Analysis was performed using linear regression of the all Wales monthly data. Results Uptake of the intervention was good: quantitative blood loss measurement and risk assessment increased to 98.1 and 64.5% of all PPH > 1000 mL, whilst ROTEM use for PPH > 1500 mL increased to 68.2%. Massive PPH decreased by 1.10 (95% CI 0.28 to 1.92) per 1000 maternities per year (P = 0.011). Fewer women progressed from moderate to massive PPH in the last 6 months, 74/1490 (5.0%), than in the first 6 months, 97/1386 (7.0%), (P = 0.021). Units of red cells transfused decreased by 7.4 (95% CI 1.6 to 13.2) per 1000 maternities per year (P = 0.015). Red cells were transfused to 350/15204 (2.3%) and 268/15150 (1.8%) (P = 0.001) in the first and last 6 months, respectively. There was no increase in the number of women with lowest haemoglobin below 80 g/L during this time period. Infusions of fresh frozen plasma fell and there was no increase in the number of women with haemostatic impairment. Conclusions The OBS Cymru care bundle was feasible to implement and associated with progressive, clinically significant improvements in outcomes for PPH across Wales. It is applicable across obstetric units of widely varying size, complexity and staff mixes.
- Published
- 2021
5. COVID-19 coagulopathy and thrombosis: Analysis of hospital protocols in response to the rapidly evolving pandemic
- Author
-
Vijay Duggirala, Eric R. Schumacher, Michael B. Streiff, Kevin J. O'Leary, Justin J Choi, Geraldine E. Ménard, Margaret C. Fang, David F. Hemsey, Michael Y. Lin, Daniel J. Brotman, Jeffrey L. Schnipper, David G. Sterken, S Ryan Greysen, James E. Anstey, Shoshana J. Herzig, Todd E.H. Hecht, Anna L. Parks, Kwame Dapaah-Afriyie, Anne S. Linker, Daniel P. Hunt, Neera Ahuja, Valerie M. Vaughn, Andrew Dunn, Andrew D. Auerbach, William Collins, Melissa L. P. Mattison, Matthew A. Pappas, and Sanjay Bhandari
- Subjects
Pulmonary embolism (PE) ,medicine.medical_specialty ,Consensus ,Deep vein thrombosis (DVT) ,Coronavirus disease 2019 (COVID-19) ,Letter to the Editors-in-Chief ,Risk Assessment ,Anticoagulation ,Clinical Protocols ,Risk Factors ,Coagulopathy ,Pandemic ,medicine ,Humans ,Thrombophilia ,Venous thromboembolism (VTE) ,cardiovascular diseases ,Dosing ,Healthcare Disparities ,Practice Patterns, Physicians' ,Intensive care medicine ,Blood Coagulation ,Venous Thrombosis ,Academic Medical Centers ,business.industry ,Anticoagulants ,COVID-19 ,Thrombosis ,Venous Thromboembolism ,Hematology ,Heparin ,medicine.disease ,United States ,COVID-19 Drug Treatment ,Coronavirus ,Treatment Outcome ,Pulmonary Embolism ,business ,Venous thromboembolism ,medicine.drug - Abstract
As the Coronavirus disease 2019 (COVID-19) pandemic spread to the US, so too did descriptions of an associated coagulopathy and thrombotic complications. Hospitals created institutional protocols for inpatient management of COVID-19 coagulopathy and thrombosis in response to this developing data. We collected and analyzed protocols from 21 US academic medical centers developed between January and May 2020. We found greatest consensus on recommendations for heparin-based pharmacologic venous thromboembolism (VTE) prophylaxis in COVID-19 patients without contraindications. Protocols differed regarding incorporation of D-dimer tests, dosing of VTE prophylaxis, indications for post-discharge pharmacologic VTE prophylaxis, how to evaluate for VTE, and the use of empiric therapeutic anticoagulation. These findings support ongoing efforts to establish international, evidence-based guidelines., Highlights • COVID-19 protocols agreed on heparin-based venous thromboembolism prophylaxis. • Disagreement on thrombosis risk and diagnosis, D-dimer, empiric anticoagulation • Cumulative incidence of COVID-19 did not correlate with specific recommendations. • Framework for frontline providers and hospitals to evaluate practices and outcomes
- Published
- 2020
6. Detailed characterization of hospitalized patients infected with the Omicron variant of SARS-CoV-2
- Author
-
Errol Ozdalga, Neera Ahuja, Niraj Sehgal, Jason Hom, Yingjie Weng, Benjamin Pinsky, Kevin A. Schulman, and William Collins
- Subjects
Hospitalization ,SARS-CoV-2 ,Internal Medicine ,COVID-19 ,Humans - Published
- 2022
7. Building a Learning Health System: Creating an Analytical Workflow for Evidence Generation to Inform Institutional Clinical Care Guidelines
- Author
-
Arjun Gokhale, Dev Dash, Birju S. Patel, Alison Callahan, Jose Posada, Gomathi Krishnan, William Collins, Ron Li, Kevin Schulman, Lily Ren, and Nigam H. Shah
- Subjects
Observational Studies as Topic ,Health Information Management ,Practice Guidelines as Topic ,COVID-19 ,Humans ,Health Informatics ,Learning Health System ,Pandemics ,Computer Science Applications ,Workflow - Abstract
Background One key aspect of a learning health system (LHS) is utilizing data generated during care delivery to inform clinical care. However, institutional guidelines that utilize observational data are rare and require months to create, making current processes impractical for more urgent scenarios such as those posed by the COVID-19 pandemic. There exists a need to rapidly analyze institutional data to drive guideline creation where evidence from randomized control trials are unavailable. Objectives This article provides a background on the current state of observational data generation in institutional guideline creation and details our institution's experience in creating a novel workflow to (1) demonstrate the value of such a workflow, (2) demonstrate a real-world example, and (3) discuss difficulties encountered and future directions. Methods Utilizing a multidisciplinary team of database specialists, clinicians, and informaticists, we created a workflow for identifying and translating a clinical need into a queryable format in our clinical data warehouse, creating data summaries and feeding this information back into clinical guideline creation. Results Clinical questions posed by the hospital medicine division were answered in a rapid time frame and informed creation of institutional guidelines for the care of patients with COVID-19. The cost of setting up a workflow, answering the questions, and producing data summaries required around 300 hours of effort and $300,000 USD. Conclusion A key component of an LHS is the ability to learn from data generated during care delivery. There are rare examples in the literature and we demonstrate one such example along with proposed thoughts of ideal multidisciplinary team formation and deployment.
- Published
- 2022
8. International recommendations on the diagnosis and treatment of acquired hemophilia A
- Author
-
Peter William Collins, Roseline d'Oiron, Giovanni Di Minno, Paul Giangrande, Midori Shima, Víctor Jiménez-Yuste, Craig M. Kessler, Andreas Tiede, Angela Huth-Kühne, Jerome M. Teitel, Paul Knoebl, and Peter Salaj
- Subjects
Male ,medicine.medical_specialty ,Cyclophosphamide ,Swine ,Hemorrhage ,Hemophilia A ,Guideline Article ,03 medical and health sciences ,0302 clinical medicine ,hemic and lymphatic diseases ,Internal medicine ,medicine ,Animals ,Humans ,Autoantibodies ,Blood coagulation test ,Factor VIII ,biology ,medicine.diagnostic_test ,business.industry ,Autoantibody ,Hematology ,Isotype ,Coagulation ,biology.protein ,Female ,Rituximab ,Blood Coagulation Tests ,Antibody ,business ,030215 immunology ,medicine.drug ,Partial thromboplastin time - Abstract
Acquired hemophilia A (AHA), a rare bleeding disorder caused by neutralizing autoantibodies against coagulation factor VIII (FVIII), occurs in both men and women without a previous history of bleeding. Patients typically present with an isolated prolonged activated partial thromboplastin time due to FVIII deficiency. Neutralizing antibodies (inhibitors) are detected using the Nijmegen-modified Bethesda assay. Approximately 10% of patients do not present with bleeding and, therefore, a prolonged activated partial thromboplastin time should never be ignored prior to invasive procedures. Control of acute bleeding and prevention of injuries that may provoke bleeding are top priorities in patients with AHA. We recommend treatment with bypassing agents, including recombinant activated factor VII, activated prothrombin complex concentrate, or recombinant porcine FVIII in bleeding patients. Autoantibody eradication can be achieved with immunosuppressive therapy, including corticosteroids, cyclophosphamide and rituximab, or combinations thereof. The median time to remission is 5 weeks, with considerable interindividual variation. FVIII activity at presentation, inhibitor titer and autoantibody isotype are prognostic markers for remission and survival. Comparative clinical studies to support treatment recommendations for AHA do not exist; therefore, we provide practical consensus guidance based on recent registry findings and the authors’ clinical experience in treating patients with AHA.
- Published
- 2020
9. SHP656, a polysialylated recombinant factor VIII (PSA‐rFVIII): First‐in‐human study evaluating safety, tolerability and pharmacokinetics in patients with severe haemophilia A
- Author
-
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
- Published
- 2019
10. Climate Change and Global Health: A Call to more Research and more Action
- Author
-
Ioana Agache, Vanitha Sampath, Juan Aguilera, Cezmi A. Akdis, Mubeccel Akdis, Michele Barry, Aude Bouagnon, Sharon Chinthrajah, William Collins, Coby Dulitzki, Barbara Erny, Jason Gomez, Anna Goshua, Marek Jutel, Kenneth W. Kizer, Olivia Kline, A. Desiree LaBeaud, Isabella Pali‐Schöll, Kirsten P. Perrett, Rachel L. Peters, Maria Pilar Plaza, Mary Prunicki, Todd Sack, Renee N. Salas, Sayantani B. Sindher, Susanne H. Sokolow, Cassandra Thiel, Erika Veidis, Brittany Delmoro Wray, Claudia Traidl‐Hoffmann, Christian Witt, and Kari C. Nadeau
- Subjects
Climate Change ,Immunology ,Immunology and Allergy ,Humans ,ddc:610 ,Environmental Pollution ,Global Health ,Greenhouse Gases ,Health ,Pollution - Abstract
There is increasing understanding, globally, that climate change and increased pollution will have a profound and mostly harmful effect on human health. This review brings together international experts to describe both the direct (such as heat waves) and indirect (such as vector-borne disease incidence) health impacts of climate change. These impacts vary depending on vulnerability (i.e., existing diseases) and the international, economic, political, and environmental context. This unique review also expands on these issues to address a third category of potential longer-term impacts on global health: famine, population dislocation, and environmental justice and education. This scholarly resource explores these issues fully, linking them to global health in urban and rural settings in developed and developing countries. The review finishes with a practical discussion of action that health professionals around the world in our field can yet take.
- Published
- 2021
11. Clotting factor concentrates for preventing bleeding and bleeding‐related complications in previously treated individuals with haemophilia A or B
- Author
-
Omotola O Olasupo, Alfonso Iorio, Peter William Collins, Megan S Lowe, Davide Matino, and Ashma Krishan
- Subjects
Clotting factor ,medicine.medical_specialty ,Factor VIII ,business.industry ,Haemophilia A ,medicine.disease ,Hemophilia A ,Hemophilia B ,Blood Coagulation Factors ,Regimen ,Quality of life ,Pharmaceutical Preparations ,Pain assessment ,Internal medicine ,Relative risk ,Hemarthrosis ,Medicine ,Humans ,Pharmacology (medical) ,Observational study ,business ,Adverse effect - Abstract
Background The hallmark of severe hemophilia (A or B) is recurrent bleeding into joints and soft tissues with progressive joint damage, despite on-demand treatment. Prophylaxis has long been used, but not universally adopted, because of medical, psychosocial, and cost controversies. Objectives To determine the effectiveness of clotting factor concentrate prophylaxis in managing previously-treated individuals with hemophilia A or B. Search methods We searched the Cochrane Cystic Fibrosis and Genetic Disorders Group's Coagulopathies Trials Register, compiled from electronic database searches and handsearching of journals and conference abstract books. In addition, we searched MEDLINE and Embase and online trial registries. Most recent search of Group's Coagulopathies Trials Register: 24 February 2021. Selection criteria Randomised controlled trials (RCTs) and quasi-RCTs evaluating people with hemophilia A or hemophilia B, who were previously treated with clotting factor concentrates to manage their hemophilia. Data collection and analysis Two authors independently reviewed trials for eligibility, assessed risk of bias and extracted data. The authors used the GRADE criteria to assess the certainty of the evidence. Main results Ten trials (including 608 participants) were eligible for inclusion. Eight of the trials (477 participants) had arms comparing two or more prophylactic regimens to one another and four of the trials (n = 258) compared prophylaxis to on-demand treatment (two trials had multiple arms and were included in both comparisons). Comparison of two or more prophylactic regimens For trials comparing one prophylaxis regimen to another, given the heterogeneity of the data, none of the data were pooled for this comparison. Considering the individual trials, three trials reported the primary outcome of joint bleeding, and none showed a dfference between dosing regimens (low-certainty evidence). For the secondary outcome of total bleeding events, prophylaxis with a twice-weekly regimen of FIX likely results in reduced total bleeds compared to a once-a-week regimen of the same dose, mean difference (MD) 11.2 (5.81 to 16.59) (one trial, 10 participants, low-certainty evidence). Transient low-titer anti-FVIII inhibitors were reported in one of the trials. Blood-transmitted infections were not identified. Other adverse events reported include hypersensitivity, oedema, and weight gain. These were, however, rare and unrelated to study drugs (very low-certainty evidence). Comparison of prophylactic and on-demand regimens Four of the trials (258 participants) had arms that compared prophylaxis to on-demand treatment. Prophylaxis may result in a large decrease in the number of joint bleeds compared to on-demand treatment, MD -30.34 (95% CI -46.95 to -13.73) (two trials, 164 participants, low-certainty evidence). One of these trials (84 participants) also reported the long-term effects of prophylaxis versus on-demand therapy showing improved joint function, quality of life, and pain; but no differences between groups in joint structure when assessed by magnetic resonance imaging (MRI). In one trial (84 participants) validated measures for joint health and pain assessment showed that prophylaxis likely improves joint health compared to an on-demand regimen with an estimated change difference of 0.94 points (95% CI 0.23 to 1.65) and improves total pain scores, MD -17.20 (95% CI -27.48 to -6.92 (moderate-certainty evidence). Two trials (131 participants) reported that prophylaxis likely results in a slight increase in adverse events, risk ratio 1.71 (1.24 to 2.37) (moderate-certainty evidence). No inhibitor development and blood-transmitted infections were identified. Overall, the certainty of the body of evidence was judged to be low because of different types of bias that could have altered the effect. AUTHORS' CONCLUSIONS: There is evidence from RCTs that prophylaxis, as compared to on-demand treatment, may reduce bleeding frequency in previously-treated people with hemophilia. Prophylaxis may also improve joint function, pain and quality of life, even though this does not translate into a detectable improvement of articular damage when assessed by MRI. When comparing two different prophylaxis regimens, no significant differences in terms of protection from bleeding were found. Dose optimization could, however, result in improved efficacy. Given the heterogeneity of the data, pooled estimates were not obtained for most comparisons. Well-designed RCTs and prospective observational controlled studies with standardised definitions and measurements are needed to establish the optimal and most cost-effective treatment regimens.
- Published
- 2021
12. Utility of viscoelastography with TEG 6s to direct management of haemostasis during obstetric haemorrhage: a prospective observational study
- Author
-
Sarah F. Bell, L. de Lloyd, V. Jenkins, R. E. Collis, D. James, L. Cohen, T. C. D. Roberts, V. Field, A. Ridgway, and Peter William Collins
- Subjects
Fibrinogen ,03 medical and health sciences ,0302 clinical medicine ,Blood loss ,Pregnancy ,030202 anesthesiology ,Humans ,Medicine ,Platelet ,Prospective Studies ,Hemostasis ,030219 obstetrics & reproductive medicine ,Receiver operating characteristic ,business.industry ,Postpartum Hemorrhage ,Obstetrics and Gynecology ,Postpartum haemorrhage ,Thrombelastography ,Anesthesiology and Pain Medicine ,Coagulation ,Anesthesia ,Female ,Observational study ,Blood Coagulation Tests ,business ,Cohort study ,medicine.drug - Abstract
Background\udThe TEG 6s is an automated cartridge-based device with limited description of use in obstetric haemorrhage. The aim of this analysis was to describe the utility of TEG 6s in identifying abnormal laboratory results of coagulation and platelet count, and inform an interventional treatment algorithm for postpartum haemorrhage.\udMethods\udA prospective observational cohort study of 521 women with moderate to severe obstetric haemorrhage (>1000 mL blood loss), including 372 women with at least one TEG 6s test. A non-pregnant control group was used for reference. TEG 6s test parameters Citrated Functional Fibrinogen (CFF), Citrated Kaolin TEG (CK) and Citrated Rapid TEG (CRT) were compared with paired laboratory tests of fibrinogen, PT/aPTT and platelet count, obtained during haemorrhage.\udResults\udAmong 456 TEG 6s tests, 389 were matched with laboratory coagulation results. The receiver operator characteristic area-under-the-curve (95% CI) for CFF amplitude by 10 min to detect Clauss fibrinogen ≤2 g/L was 0.95 (0.91 to 0.99) (P
- Published
- 2021
13. Monitoring methane emissions from oil and gas operations‡
- Author
-
William Collins, Raymond Orbach, Michelle Bailey, Sebastien Biraud, Ian Coddington, David DiCarlo, Jeff Peischl, Anuradha Radhakrishnan, and David Schimel
- Subjects
Air Pollutants ,Greenhouse Gases ,Humans ,Methane ,Atomic and Molecular Physics, and Optics - Abstract
The atmospheric concentration of methane has more than doubled since the start of the Industrial Revolution. Methane is the second-most-abundant greenhouse gas created by human activities and a major driver of climate change. This APS-Optica report provides a technical assessment of the current state of monitoring U.S. methane emissions from oil and gas operations, which accounts for roughly 30% of U.S. anthropogenic methane emissions. The report identifies current technological and policy gaps and makes recommendations for the federal government in three key areas: methane emissions detection, reliable and systematized data and models to support mitigation measures, and effective regulation.
- Published
- 2022
14. Rurioctocog alfa pegol PK-guided prophylaxis in hemophilia A: results from the phase 3 PROPEL study
- Author
-
Werner Engl, Oleksandra Stasyshyn, Hishamshah Ibrahim, Vlad C. Radulescu, Robert Klamroth, William J. Savage, Bruce Ewenstein, Peter William Collins, Jerzy Windyga, and Srilatha Tangada
- Subjects
Adult ,Male ,medicine.medical_specialty ,Adolescent ,Immunology ,Personalized treatment ,Severe disease ,Hemorrhage ,030204 cardiovascular system & hematology ,Hemophilia A ,Biochemistry ,Thrombosis and Hemostasis ,Young Adult ,03 medical and health sciences ,0302 clinical medicine ,Pharmacokinetics ,Internal medicine ,Clinical endpoint ,Medicine ,Humans ,Prospective Studies ,Adverse effect ,Factor VIII ,Coagulants ,business.industry ,Cell Biology ,Hematology ,Middle Aged ,Confidence interval ,Safety profile ,Treatment Outcome ,030220 oncology & carcinogenesis ,Female ,business ,Dosing Frequency - Abstract
Rurioctocog alfa pegol prophylaxis targeting factor VIII (FVIII) troughs ≥1% has shown to be efficacious with an acceptable safety profile in people with hemophilia A (PwHA). The PROPEL trial compared safety and efficacy of 2 target FVIII troughs in PwHA aged 12 to 65 years, with severe disease, annualized bleeding rate ≥2, and previous FVIII treatment. PwHA were randomized to 12 months’ pharmacokinetic (PK)-guided rurioctocog alfa pegol prophylaxis targeting FVIII troughs of 1% to 3% (reference arm) or 8% to 12% (elevated arm); first 6 months was treatment-adjustment period. The primary endpoint was absence of bleeds during the second 6 months, analyzed using multiple imputations (full analysis set [FAS]). In the 1% to 3% and 8% to 12% arms, respectively, point estimates (95% confidence interval) of proportions of PwHA with zero total bleeds were 42% (29% to 55%) and 62% (49% to 75%) in FAS (N = 115; P = .055) and 40% (27% to 55%) and 67% (52% to 81%) in per-protocol analysis set (N = 95; P = .015). Dosing frequency and consumption varied in each arm. Adverse events (AEs) occurred in 70/115 (60.9%) PwHA; serious AEs in 7/115 (6%) PwHA, including 1 treatment-related in 8% to 12% arm (transient anti–FVIII inhibitor). There were no deaths, serious thrombotic events, or AE-related discontinuations. PK-guided prophylaxis was achievable and efficacious in both arms. No new safety signals were observed in the 8% to 12% arm. These results demonstrate elevated FVIII troughs can increase the proportion of PwHA with zero bleeds and emphasize the importance of personalized treatment. This trial was registered at www.clinicaltrials.gov as #NCT02585960.
- Published
- 2021
15. Clinical phenotype of severe and moderate haemophilia: who should receive prophylaxis and what is the target trough level?
- Author
-
Deepan Gorsani, Peter William Collins, Rachel Rayment, Samya Obaji, and Heledd Roberts
- Subjects
Pediatrics ,medicine.medical_specialty ,congenital, hereditary, and neonatal diseases and abnormalities ,Factor replacement ,Hemorrhage ,030204 cardiovascular system & hematology ,Baseline level ,Haemophilia ,Hemophilia A ,03 medical and health sciences ,0302 clinical medicine ,Breakthrough bleeding ,hemic and lymphatic diseases ,Arthropathy ,Hemarthrosis ,Medicine ,Humans ,Clinical phenotype ,Genetics (clinical) ,Factor VIII ,business.industry ,Hematology ,General Medicine ,medicine.disease ,Phenotype ,Trough level ,medicine.symptom ,business ,030215 immunology - Abstract
Introduction\ud One of the most often stated tenets of haemophilia care is that prophylaxis converts a person from a severe to a moderate phenotype. In this review, we argue that this is not an accurate assumption and that people on prophylaxis predominantly have factor VIII/IX levels in the mild range.\ud \ud Moderate haemophilia and prophylaxis\ud People with moderate haemophilia, who are treating with on‐demand regimens, experience joint bleeds and often develop significant arthropathy. This is especially true for people with a baseline level of 1‒3 IU/dl, as first reported 55 years ago, and confirmed in more recent studies. Evidence is emerging suggesting that people with severe haemophilia who are using prophylaxis have better musculoskeletal outcomes than people with moderate haemophilia treated episodically.\ud \ud Trough levels\ud The debate around the optimum trough level whilst on prophylaxis is ongoing. It is not appropriate to extrapolate information about baseline levels to recommendations about target trough levels on prophylaxis because these are different situations. Studies are emerging that support higher target trough levels than previously used, but in spite of this, the aim of achieving zero bleeds remains elusive with both factor replacement and non‐replacement therapies.\ud \ud Conclusions\ud We recommend that people with moderate haemophilia, especially those with a baseline of 1–3 IU/dl, should be offered prophylaxis based on the same criteria as people with severe haemophilia. Trough levels should be maintained above 3 IU/dl or higher if a level of 3 IU/dl does not control breakthrough bleeding and prophylaxis should be tailored to the bleeding phenotype. This advice is in line with recently published guidelines from the World Federation of Haemophilia and the UK Haemophilia Centre Doctors’ Organisation.
- Published
- 2021
16. The sensitivity and specificity of rotational thromboelastometry (ROTEM) to detect coagulopathy during moderate and severe postpartum haemorrhage: a prospective observational study
- Author
-
Sarah F. Bell, L. de Lloyd, D. James, Z. Amir, Peter William Collins, T. C. D. Roberts, J. Freyer Martins Pereira, P.V. Jenkins, and R. E. Collis
- Subjects
Prothrombin time ,medicine.diagnostic_test ,business.industry ,Postpartum Hemorrhage ,Fibrinogen ,Obstetrics and Gynecology ,Blood Coagulation Disorders ,medicine.disease ,Thrombelastography ,Thromboelastometry ,Anesthesiology and Pain Medicine ,Coagulation ,Anesthesia ,medicine ,Coagulopathy ,Humans ,Female ,Platelet ,Blood Coagulation Tests ,Prospective Studies ,Fresh frozen plasma ,business ,Partial thromboplastin time ,medicine.drug - Abstract
INTRODUCTION Point-of-care viscoelastic haemostatic assays such as rotational thromboelastometry (including ROTEM and TEG) have been used in the management of postpartum haemorrhage (PPH). This study compared results obtained from the automated ROTEM Sigma with laboratory tests of coagulation and platelet count during PPH. METHODS A prospective observational cohort study recruited women with PPH ≥1000 mL (or clinical concern of bleeding). The Fibtem A5, Extem CT and Pltem (Extem A5 - Fibtem A5) results were compared with laboratory tests of fibrinogen, prothrombin time (PT), activated partial thromboplastin time (APTT) and platelet count. RESULTS 521 women were recruited, including 274/277 (98.9%) of women with PPH ≥1500 mL. Fibtem A5 results were matched with laboratory fibrinogen in 552/644 (85.7%) samples. The incidence of abnormal laboratory results was low: fibrinogen ≤2 g/L 23/464 (5.0%), PT or APTT >1.5 × midpoint of reference range 4/464 (0.9%), and platelet count
- Published
- 2022
17. Incidence of postpartum haemorrhage defined by quantitative blood loss measurement: a national cohort
- Author
-
Peter William Collins, Jenna L. Stevens, Christopher Bailey, Elinore Macgillivray, Miriam John, Tracey Edey, Kathryn James, R. E. Collis, Cerys Scarr, Adam Watkins, Thomas Kitchen, Kevin Kelly, Donna James, and Sarah F. Bell
- Subjects
Adult ,medicine.medical_specialty ,Epidemiology ,Reproductive medicine ,lcsh:Gynecology and obstetrics ,Measured blood loss ,Cohort Studies ,03 medical and health sciences ,0302 clinical medicine ,Case mix index ,Blood loss ,Postpartum ,Pregnancy ,medicine ,Humans ,Childbirth ,Prospective Studies ,030212 general & internal medicine ,lcsh:RG1-991 ,Wales ,030219 obstetrics & reproductive medicine ,Obstetrics ,business.industry ,Incidence ,Incidence (epidemiology) ,Postpartum Hemorrhage ,Obstetrics and Gynecology ,Bleed ,Delivery, Obstetric ,Haemorrhage ,Cohort ,Female ,business ,Research Article - Abstract
Background Visual estimation of blood loss following delivery often under-reports actual bleed volume. To improve accuracy, quantitative blood loss measurement was introduced for all births in the 12 hospitals providing maternity care in Wales. This intervention was incorporated into a quality improvement programme (Obstetric Bleeding Strategy for Wales, OBS Cymru). We report the incidence of postpartum haemorrhage in Wales over a 1-year period using quantitative measurement. Methods This prospective, consecutive cohort included all 31,341 women giving birth in Wales in 2017. Standardised training was cascaded to maternity staff in all 12 hospitals in Wales. The training comprised mock-scenarios, a video and team drills. Uptake of quantitative blood loss measurement was audited at each centre. Data on postpartum haemorrhage of > 1000 mL were collected and analysed according to mode of delivery. Data on blood loss for all maternities was from the NHS Wales Informatics Service. Results Biannual audit data demonstrated an increase in quantitative measurement from 52.1 to 87.8% (P 1000 mL, > 1500 mL and > 2000 mL was 8.6% (8.3 to 8.9), 3.3% (3.1 to 3.5) and 1.3% (1.2 to 1.4), respectively compared to 5%, 2% and 0.8% in the year before OBS Cymru. The incidence (95% CI) of bleeds of > 1000 mL was similar across the 12 hospitals despite widely varied size, staffing levels and case mix, median (25th to 75th centile) 8.6% (7.8–9.6). The incidence of PPH varied with mode of delivery and was mean (95% CI) 4.9% (4.6–5.2) for unassisted vaginal deliveries, 18.4 (17.1–19.8) for instrumental vaginal deliveries, 8.5 (7.7–9.4) for elective caesarean section and 19.8 (18.6–21.0) for non-elective caesarean sections. Conclusions Quantitative measurement of blood loss is feasible in all hospitals providing maternity care and is associated with detection of higher rates of postpartum haemorrhage. These results have implications for the definition of abnormal blood loss after childbirth and for management and research of postpartum haemorrhage.
- Published
- 2020
18. Modeling to predict factor VIII levels associated with zero bleeds in patients with severe hemophilia A initiated on tertiary prophylaxis
- Author
-
Krista Fischer, Erik Berntorp, Steven W. Pipe, Barbara A. Konkle, Peter William Collins, Pratima Chowdary, Victor S. Blanchette, Gerald Spotts, Werner Engl, Martin J. Wolfsegger, and Amy Cotterill
- Subjects
0301 basic medicine ,Adult ,Pediatrics ,medicine.medical_specialty ,Canada ,Adolescent ,030204 cardiovascular system & hematology ,Severe hemophilia A ,Hemophilia A ,Models, Biological ,Severity of Illness Index ,Hemostatics ,03 medical and health sciences ,Young Adult ,0302 clinical medicine ,Risk Factors ,hemic and lymphatic diseases ,Post-hoc analysis ,Hemarthrosis ,Tertiary Prevention ,Medicine ,Humans ,In patient ,Child ,Hemostasis ,Factor VIII ,business.industry ,Hematology ,Bleed ,Middle Aged ,United States ,Europe ,030104 developmental biology ,Pharmacodynamics ,Trough level ,business - Abstract
Background Factor VIII (FVIII) trough levels > 1 IU/dL in patients with severe hemophilia A receiving regular prophylaxis may optimize bleed protection. Objectives In this post hoc analysis of patients receiving tertiary prophylaxis for approximately 1 year, the relationship between estimated FVIII levels and reported bleeds was investigated to predict the potential for zero bleeds. Methods Sixty-three patients (median [range] age, 28 [7–59] years) with severe hemophilia A (229 bleeds) were included. FVIII levels at time of each bleed were estimated from single-dose individual pharmacokinetics. The highest estimated FVIII level at which patients experienced a bleed was considered the “potentially effective trough level” for that bleed type. Kaplan–Meier estimates of proportions of patients with no bleeds above certain estimated FVIII levels were determined. Those not experiencing a bleed in the trial were assumed to have a bleed at 0 IU/dL (pragmatic approach) or at their median trough level (conservative approach). Results Kaplan–Meier estimates based on pragmatic approach predicted zero all bleeds, joint bleeds, and spontaneous joint bleeds in 1 year in 40, 43, and 63% of patients, respectively, when the potentially effective trough FVIII level was set at 1 IU/dL. Between 1 and 10 IU/dL, every 1 IU/dL rise in estimated FVIII level was associated with an additional 2% of patients having zero all bleeds. Conclusion This post hoc analysis confirms benefits with trough levels of approximately 1 to 3 IU/dL in most patients starting tertiary prophylaxis; prophylaxis with higher trough levels may help patients to achieve zero bleeds.
- Published
- 2020
19. The use of viscoelastic haemostatic assays in the management of major bleeding: A British Society for Haematology Guideline
- Author
-
Sue Pavord, Andrew A. Klein, Nicola Curry, Michael Laffan, Helena Maybury, Peter William Collins, Ross Davenport, Susan Mallett, and Dianne P. Kitchen
- Subjects
ROTATIONAL THROMBOELASTOMETRY ROTEM ,PEDIATRIC CARDIAC-SURGERY ,medicine.medical_specialty ,MASSIVE TRANSFUSION REQUIREMENTS ,Orthotopic liver transplantation ,Immunology ,Hemorrhage ,thromboelastometry ,Viscoelastic Substances ,030204 cardiovascular system & hematology ,CONVENTIONAL COAGULATION TESTS ,Acute traumatic coagulopathy ,03 medical and health sciences ,Sonoclot ,0302 clinical medicine ,030202 anesthesiology ,Internal medicine ,medicine ,RANDOMIZED-CLINICAL-TRIAL ,Humans ,Intensive care medicine ,1102 Cardiorespiratory Medicine and Haematology ,viscoelastic tests ,Hemostasis ,Science & Technology ,Hematology ,Hemostatic Techniques ,business.industry ,Disease Management ,thromboelastography ,Guideline ,Hemostatic technique ,ALLOGENEIC BLOOD-PRODUCTS ,United Kingdom ,ACUTE TRAUMATIC COAGULOPATHY ,SINGLE-CENTER EXPERIENCE ,Thrombelastography ,Thromboelastometry ,major bleeding ,ORTHOTOPIC LIVER-TRANSPLANTATION ,POSTPARTUM HEMORRHAGE OBS2 ,business ,Life Sciences & Biomedicine ,Major bleeding - Published
- 2020
20. Next-generation sequencing for the diagnosis of MYH9-RD: Predicting pathogenic variants
- Author
-
Daniel Duarte, Mariana Bonduel, Sri V V Deevi, Kathleen Stirrups, Paolo Gresele, David Allsup, Rutendo Mapeta, Jonathan Stephens, Tadbir K. Bariana, Kathleen Freson, Nihr BioResource, Ernest Turro, Kim Elliott, Nicola Curry, David Keeling, D. J. Perry, Kate Downes, Carolyn M. Millar, Luigi Grassi, Keith Gomez, Nora Butta, Ilenia Simeoni, Emanuela Falcinelli, Peter William Collins, Michele P. Lambert, Christopher J. Penkett, Loredana Bury, John K. Wu, Nick Gleadall, Karina Althaus, Daniel Greene, Bruce Furie, Willem H. Ouwehand, Rachel Linger, Sarah K Westbury, Karyn Megy, Sarah Mangles, Megy, Karyn [0000-0002-2826-3879], Stephens, Jonathan [0000-0003-2020-9330], Downes, Kate [0000-0003-0366-1579], Johnson, Kathleen [0000-0002-6823-3252], Turro Bassols, Ernest [0000-0002-1820-6563], Ouwehand, Willem [0000-0002-7744-1790], Simeoni, Ilenia [0000-0001-5039-2194], and Apollo - University of Cambridge Repository
- Subjects
Male ,Variable severity ,Fluorescent Antibody Technique ,Gene Expression ,high throughput next generation sequencing ,Child ,Genetics (clinical) ,Research Articles ,0303 health sciences ,Kidney ,030305 genetics & heredity ,Chromosome Mapping ,High-Throughput Nucleotide Sequencing ,Middle Aged ,Macrothrombocytes ,MYH9‐related disorders ,ACMG guidelines ,3. Good health ,Clinical Practice ,medicine.anatomical_structure ,Phenotype ,clinical diagnosis ,Child, Preschool ,Female ,ACMG Guidelines ,Research Article ,Adult ,medicine.medical_specialty ,Adolescent ,Genotype ,Platelet disorder ,genomics ,high throughput sequencing ,MYH9-related disorders ,variant classification ,Biology ,DNA sequencing ,Evolution, Molecular ,03 medical and health sciences ,Young Adult ,Internal medicine ,Genetics ,medicine ,Humans ,Genetic Predisposition to Disease ,Alleles ,Genetic Association Studies ,030304 developmental biology ,Aged ,Myosin Heavy Chains ,Genetic variants ,Genetic Variation ,Infant ,medicine.disease ,Bleeding diathesis ,Mutation - Abstract
The heterogeneous manifestations of MYH9‐related disorder (MYH9‐RD), characterized by macrothrombocytopenia, Döhle‐like inclusion bodies in leukocytes, bleeding of variable severity with, in some cases, ear, eye, kidney, and liver involvement, make the diagnosis for these patients still challenging in clinical practice. We collected phenotypic data and analyzed the genetic variants in more than 3,000 patients with a bleeding or platelet disorder. Patients were enrolled in the BRIDGE‐BPD and ThromboGenomics Projects and their samples processed by high throughput sequencing (HTS). We identified 50 patients with a rare variant in MYH9. All patients had macrothrombocytes and all except two had thrombocytopenia. Some degree of bleeding diathesis was reported in 41 of the 50 patients. Eleven patients presented hearing impairment, three renal failure and two elevated liver enzymes. Among the 28 rare variants identified in MYH9, 12 were novel. HTS was instrumental in diagnosing 23 patients (46%). Our results confirm the clinical heterogeneity of MYH9‐RD and show that, in the presence of an unclassified platelet disorder with macrothrombocytes, MYH9‐RD should always be considered. A HTS‐based strategy is a reliable method to reach a conclusive diagnosis of MYH9‐RD in clinical practice., MYH9‐related disorder diagnosis is still challenging in clinical practice. We analyzed the genetic variants in more than 3,000 patients with a bleeding or platelet disorder and identified 50 patients with a rare variant in MYH9. In the presence of an unclassified platelet disorder with macrothrombocytes, MYH9‐RD should always be considered.
- Published
- 2020
21. A Novel, Enriched Population Pharmacokinetic Model for Recombinant Factor VIII-Fc Fusion Protein Concentrate in Hemophilia A Patients
- Author
-
Charles R. M. Hay, Pratima Chowdary, Benjamin Bailiff, Mary Mathias, Jeanette Payne, Nicola Curry, Tine M. H. J. Goedhart, Marjon H. Cnossen, Jessica M. Heijdra, Sarah Mangles, Robert Campbell Tait, Karina Meijer, Frank W.G. Leebeek, Peter William Collins, Steve Austin, Ron A. A. Mathôt, Laura H. Bukkems, Karin Fijnvandraat, Bethan Myers, G. Evans, Pediatrics, Hematology, Graduate School, Pharmacy, Other Research, Paediatric Haematology, AGEM - Digestive immunity, AGEM - Endocrinology, metabolism and nutrition, ARD - Amsterdam Reproduction and Development, and Real World Studies in PharmacoEpidemiology, -Genetics, -Economics and -Therapy (PEGET)
- Subjects
0301 basic medicine ,Male ,SAMPLES ,population ,030204 cardiovascular system & hematology ,Hemostatics ,0302 clinical medicine ,STAGE ,Medicine ,Registries ,Child ,Factor IX ,Netherlands ,validation ,education.field_of_study ,PLASMA ,Age Factors ,Hematology ,Middle Aged ,Mean absolute percentage error ,recombinant factor VIII-Fc ,pharmacokinetics ,medicine.drug ,Adult ,medicine.medical_specialty ,Adolescent ,VON-WILLEBRAND-FACTOR ,Recombinant Fusion Proteins ,Population ,Hemophilia A ,Recombinant factor viii ,Models, Biological ,03 medical and health sciences ,Young Adult ,AGE ,Pharmacokinetics ,Internal medicine ,Humans ,Dosing ,education ,Aged ,Factor VIII ,business.industry ,Reproducibility of Results ,FACTOR-IX ,United Kingdom ,NONMEM ,Immunoglobulin Fc Fragments ,Clinical trial ,030104 developmental biology ,business - Abstract
Background The currently published population pharmacokinetic (PK) models used for PK-guided dosing in hemophilia patients are based on clinical trial data and usually not externally validated in clinical practice. The aim of this study was to validate a published model for recombinant factor VIII-Fc fusion protein (rFVIII-Fc) concentrate and to develop an enriched model using independently collected clinical data if required. Methods Clinical data from hemophilia A patients treated with rFVIII-Fc concentrate (Elocta) participating in the United Kingdom Extended Half-Life Outcomes Registry were collected. The predictive performance of the published model was assessed using mean percentage error (bias) and mean absolute percentage error (inaccuracy). An extended population PK model was developed using nonlinear mixed-effects modeling (NONMEM). Results A total of 43 hemophilia A patients (FVIII ≤ 2 IU/dL), aged 5 to 70 years, were included. The prior model was able to predict the collected 244 rFVIII-Fc levels without significant bias (–1.0%, 95% CI: –9.4 to 7.3%) and with acceptable accuracy (12.9%). However, clearance and central distribution volume were under predicted in patients Conclusion We concluded that the existing rFVIII-Fc population PK model is valid for patients ≥ 12 years. However, it is not reliable in younger patients. Our alternative model, constructed from real world patient data including children, allows for better description of patients ≥5 years.
- Published
- 2020
22. Platelet heterogeneity in activation-induced glycoprotein shedding
- Author
-
Tom G. Mastenbroek, Renhao Li, Paul E. Bock, Marjo M. P. C. Donners, Peter William Collins, Constance C.F.M.J. Baaten, Tomasz Misztal, Paola E. J. van der Meijden, Marion A.H. Feijge, Frauke Swieringa, Johan W. M. Heemskerk, Biochemie, RS: CARIM - R1.03 - Cell biochemistry of thrombosis and haemostasis, Pathologie, RS: CARIM - R3.06 - The vulnerable plaque: makers and markers, and RS: CARIM - R1.04 - Clinical thrombosis and haemostasis
- Subjects
0301 basic medicine ,Blood Platelets ,PHOSPHATIDYLSERINE EXPOSURE ,MECHANISM ,HEMOSTATIC FUNCTION ,ADAM10 ,Platelet Membrane Glycoproteins ,030204 cardiovascular system & hematology ,Thrombosis and Hemostasis ,03 medical and health sciences ,0302 clinical medicine ,Thrombin ,Scott syndrome ,medicine ,Disintegrin ,Humans ,Platelet ,Platelet activation ,Protein kinase C ,IN-VIVO ,Glycoproteins ,ADAM17 ,biology ,Chemistry ,CLEAVAGE ,Ionomycin ,SCOTT SYNDROME ,Thrombosis ,Hematology ,medicine.disease ,Flow Cytometry ,Platelet Activation ,Cell biology ,FIBRIN ,carbohydrates (lipids) ,THROMBUS FORMATION ,ADAM Proteins ,030104 developmental biology ,Platelet Glycoprotein GPIb-IX Complex ,Caspases ,biology.protein ,Calcium ,METALLOPROTEINASE ,GPVI ,Biomarkers ,medicine.drug ,Signal Transduction - Abstract
The platelet receptors glycoprotein Ibα (GPIbα) and GPVI are known to be cleaved by members of a disintegrin and metalloprotease (ADAM) family (ADAM10 and ADAM17), but the mechanisms and consequences of this shedding are not well understood. Our results revealed that (1) glycoprotein shedding is confined to distinct platelet populations showing near-complete shedding, (2) the heterogeneity between (non)shed platelets is independent of agonist type but coincides with exposure of phosphatidylserine (PS), and (3) distinct pathways of shedding are induced by elevated Ca2+, low Ca2+ protein kinase C (PKC), or apoptotic activation. Furthermore, we found that receptor shedding reduces binding of von Willebrand factor, enhances binding of coagulation factors, and augments fibrin formation. In response to Ca2+-increasing agents, shedding of GPIbα was abolished by ADAM10/17 inhibition but not by blockage of calpain. Stimulation of PKC induced shedding of only GPIbα, which was annulled by kinase inhibition. The proapoptotic agent ABT-737 induced shedding, which was caspase dependent. In Scott syndrome platelets that are deficient in Ca2+-dependent PS exposure, shedding occurred normally, indicating that PS exposure is not a prerequisite for ADAM activity. In whole-blood thrombus formation, ADAM-dependent glycoprotein shedding enhanced thrombin generation and fibrin formation. Together, these findings indicate that 2 major activation pathways can evoke ADAM-mediated glycoprotein shedding in distinct platelet populations and that shedding modulates platelet function from less adhesive to more procoagulant.
- Published
- 2018
23. The immunogenicity of ReFacto AF (moroctocog alfa AF-CC) in previously untreated patients with haemophilia A in the United Kingdom
- Author
-
Peter William Collins, Elizabeth Chalmers, M Richards, B. Palmer, Mary Mathias, Jayanthi Alamelu, Andrew M. Will, and Charles R. M. Hay
- Subjects
Male ,medicine.medical_specialty ,Time Factors ,Adolescent ,Genotype ,Haemophilia A ,Population ,030204 cardiovascular system & hematology ,Hemophilia A ,Haemophilia ,03 medical and health sciences ,0302 clinical medicine ,Interquartile range ,Internal medicine ,medicine ,Moroctocog alfa ,Humans ,Family history ,Child ,education ,Genetics (clinical) ,education.field_of_study ,Factor VIII ,business.industry ,Incidence (epidemiology) ,Immunogenicity ,Infant ,Hematology ,General Medicine ,medicine.disease ,United Kingdom ,Child, Preschool ,030220 oncology & carcinogenesis ,Female ,business - Abstract
Introduction\ud \ud Factor VIII inhibitor development is currently the most serious complication of the treatment of haemophilia A. Differences in manufacturing and the molecular structure of brands of recombinant factor VIII have led to speculation that concentrates may differ in immunogenicity. This has led to a regulatory focus on the immunogenicity of factor VIII concentrates both before and after licensure.\ud \ud \ud Aim\ud \ud To investigate the immunogenicity of ReFacto AF post licensure in a real‐world setting in previously untreated patients (PUPs) treated exclusively with this product until at least 50 exposure days (EDs).\ud \ud \ud Methods\ud \ud The United Kingdom Haemophilia Centre Doctors’ Organisation (UKHCDO) National Haemophilia Database (NHD) identified a consecutive cohort of patients with severe haemophilia A (
- Published
- 2018
24. Treatment of bleeding episodes in haemophilia A complicated by a factor VIII inhibitor in patients receiving Emicizumab. Interim guidance from UKHCDO Inhibitor Working Party and Executive Committee
- Author
-
Peter William Collins, Michael Makris, C. L. Percy, Charles R. M. Hay, Pratima Chowdary, Kate Talks, Elizabeth Chalmers, Daniel P. Hart, R. Liesner, Georgina W. Hall, and Anne Riddell
- Subjects
congenital, hereditary, and neonatal diseases and abnormalities ,medicine.medical_specialty ,Haemophilia A ,Guidelines as Topic ,Hemorrhage ,030204 cardiovascular system & hematology ,Antibodies, Monoclonal, Humanized ,Hemophilia A ,Haemophilia ,03 medical and health sciences ,0302 clinical medicine ,hemic and lymphatic diseases ,Interim ,Antibodies, Bispecific ,Humans ,Medicine ,Intensive care medicine ,Adverse effect ,Activated prothrombin complex concentrate ,Genetics (clinical) ,Emicizumab ,Bleeding episodes ,Factor VIII ,business.industry ,Hematology ,General Medicine ,medicine.disease ,Thrombosis ,030220 oncology & carcinogenesis ,business - Abstract
Emicizumab is a bispecific antibody that activates FX to FXa in the absence of FVIII. It has been shown to reduce bleeding episodes in people with haemophilia A complicated by a FVIII inhibitor. Despite the protection against bleeds, some breakthrough bleeds are inevitable and these may require additional haemostatic treatment. Emicizumab has been associated with severe adverse events when co-administered with activated prothrombin complex concentrate. To minimize the risk of adverse events, the UK Haemophilia Centre Doctors' Organisation issues the following updated interim guidance to its Inhibitor Guidelines for managing patients receiving Emicizumab based on the limit published information available in February 2018.
- Published
- 2018
25. Retrospective Review of a Prothrombin Complex Concentrate (Beriplex P/N) for the Management of Perioperative Bleeding Unrelated to Oral Anticoagulation
- Author
-
Ravi Gill, Peter William Collins, Margaret Rokicka, Hafiz Qureshi, Tim Nokes, Paul Diprose, Dale Watson, Augustine Tang, Martin Besser, Michael Desmond Creagh, and Pratima Chowdary
- Subjects
Male ,medicine.medical_specialty ,fresh frozen plasma ,030204 cardiovascular system & hematology ,Perioperative Care ,03 medical and health sciences ,0302 clinical medicine ,Internal medicine ,Coagulopathy ,medicine ,Humans ,Oral anticoagulation ,Aged ,Retrospective Studies ,Retrospective review ,cardiovascular surgery ,business.industry ,Anticoagulants ,030208 emergency & critical care medicine ,Original Articles ,Hematology ,General Medicine ,Perioperative ,Blood Coagulation Disorders ,Middle Aged ,bleeding ,medicine.disease ,Prothrombin complex concentrate ,Blood Coagulation Factors ,Confidence interval ,prothrombin complex concentrate ,Cohort ,bacteria ,Female ,prophylaxis ,Fresh frozen plasma ,business ,medicine.drug - Abstract
A multicenter, retrospective, observational study of 4-factor prothrombin complex concentrate (PCC) and/or fresh frozen\ud plasma (FFP) use within routine clinical care unrelated to vitamin K antagonists was conducted. The PCC was administered\ud preprocedure for correction of coagulopathy (prophylactic cohort) and treatment of bleeding postsurgery (treatment cohort). Of\ud the 445 patients included, 40 were in the prophylactic cohort (PCC alone [n ¼ 16], PCC and FFP [n ¼ 5], FFP alone [n ¼ 19]) and\ud 405 were in the treatment cohort (PCC alone [n ¼ 228], PCC and FFP [n ¼ 123], FFP alone [n ¼ 54]). Cardiovascular surgery was\ud the most common setting. PCC doses ranged between 500 and 5000 IU. Effectiveness (assessed retrospectively) was reported as\ud effective in 93.0% in the PCC-only group (95% confidence interval, 89.1% to 95.9%), 78.9% (70.8% to 85.6%) with PCC and FFP,\ud and 86.3% (76.2% to 93.2%) with FFP alone. In the treatment cohort, international normalized ratio was significantly reduced in all\ud 3 groups. In patients who received PCC, the rate of thromboembolic events (1.9%) was below rates in the literature for similar\ud procedures. PCCs offer a potential alternative to FFP in the management of perioperative bleeding unrelated to oral anticoagulant\ud therapy.
- Published
- 2018
26. The incidence, aetiology, and coagulation management of massive postpartum haemorrhage: a two-year national prospective cohort study
- Author
-
Peter William Collins, Elinore Macgillivray, Christopher Bailey, Thomas Kitchen, Kathryn James, Miriam John, Kevin Kelly, R. E. Collis, Cerys Scarr, and Sarah F. Bell
- Subjects
medicine.medical_specialty ,medicine.medical_treatment ,Fibrinogen ,law.invention ,Blood product ,law ,Coagulopathy ,medicine ,Humans ,Blood Transfusion ,Prospective Studies ,Prospective cohort study ,Blood Coagulation ,Hysterectomy ,business.industry ,Obstetrics ,Incidence ,Incidence (epidemiology) ,Postpartum Hemorrhage ,Obstetrics and Gynecology ,medicine.disease ,Intensive care unit ,Anesthesiology and Pain Medicine ,Etiology ,Female ,business ,medicine.drug - Abstract
Introduction\udBetween 2017 and 2018 a national quality improvement initiative was introduced incorporating point-of-care viscoelastic haemostatic assays (VHA) to guide blood product transfusion. Laboratory coagulation profiles, use and results of VHA, and administration of blood products were investigated.\udMethods\udA two-year prospective cohort study of maternal outcomes of women experiencing massive postpartum haemorrhage (PPH) >1000 mL in Wales. In this study, cases of massive PPH (≥2500 mL and/or ≥5 units red blood cell (RBC) transfusion) were identified.\udResults\udMassive PPH occurred in 349 of 60 914 maternities (rate 5.7 per 1000). There were no deaths from PPH. Intensive care unit admission and/or hysterectomy occurred in 34/311 (10.9%) and 16/347 (4.6%), respectively. The leading cause of massive PPH was genital tract trauma (107/349, 30.6%). Two hundred and seventy-nine (80.6%) required RBC transfusion and 79/345 (22.9%) received at least one blood coagulation product. Results of VHA were recorded in 245/349 (70.2%), with 44/98 (44.9%) women tested in the first six months vs 63/77 (81.8%) in the final six months. Hypofibrinogenaemia (Clauss fibrinogen 1.5×reference range in 10/293 (3.4%).\udConclusion\udIn Wales, the use of VHA in cases of massive PPH increased over time, enabling clinicians to adopt a targeted, patient-specific approach to blood product administration, with only 22.9% of women receiving blood coagulation products and 17.1% having a documented clotting abnormality.
- Published
- 2021
27. The haemtrack home therapy reporting system: Design, implementation, strengths and weaknesses: A report from UK Haemophilia Centre Doctors Organisation
- Author
-
Gerry Dolan, R. Liesner, R. Hollingsworth, Hua Xiang, Peter William Collins, C. R. M. Hay, and Martin Scott
- Subjects
Adult ,medicine.medical_specialty ,Adolescent ,Databases, Factual ,Home therapy ,030204 cardiovascular system & hematology ,Haemophilia ,User-Computer Interface ,Young Adult ,03 medical and health sciences ,Blood Coagulation Disorders, Inherited ,0302 clinical medicine ,Treatment intensity ,Sql server ,Humans ,Telemetry ,Medicine ,Child ,Genetics (clinical) ,Aged ,Aged, 80 and over ,business.industry ,Infant, Newborn ,Disease Management ,Infant ,Hematology ,General Medicine ,Middle Aged ,Bleed ,medicine.disease ,Home Care Services ,Telemedicine ,United Kingdom ,Regimen ,Child, Preschool ,Physical therapy ,Medical emergency ,business ,Reporting system ,Strengths and weaknesses ,030215 immunology - Abstract
Introduction Haemtrack is an electronic home treatment diary for patients with inherited bleeding disorders, introduced in 2008. It aimed to improve the timeliness and completeness of patient-reported treatment records, to facilitate analysis of treatment and outcome trends. The system is easy to use, responsive and accessible. Methods The software uses Microsoft technologies with a SQL Server database and an ASP.net website front-end, running on personal computers, android and I-phones. Haemtrack interfaces with the UK Haemophilia Centre Information System and the National Haemophilia Database (NHD). Data are validated locally by Haemophilia Centres and centrally by NHD. Data collected include as follows: treatment brand, dose and batch number, time/date of bleed onset and drug administration, reasons for treatment (prophylaxis, bleed, follow-up), bleed site, severity, pain-score and outcome. Results Haemtrack was used by 90% of haemophilia treatment centres (HTCs) in 2015, registering 2683 patients using home therapy of whom 1923 used Haemtrack, entering >17 000 treatments per month. This included 68% of all UK patients with severe haemophilia A. Reporting compliance varied and 55% of patients reported ≥75% of potential usage. Centres had a median 78% compliance overall. A strategy for progressively improving compliance is in place. Age distribution and treatment intensity were similar in Haemtrack users/non-users with severe haemophilia treated prophylactically. Conclusion The Haemtrack system is a valuable tool that may improve treatment compliance and optimize treatment regimen. Analysis of national treatment trends and large-scale longitudinal, within-patient analysis of changes in regimen and/or product will provide valuable insights that will guide future clinical practice.
- Published
- 2017
28. First-line immune tolerance induction for children with severe haemophilia A: A protocol from the UK Haemophilia Centre Doctors' Organisation Inhibitor and Paediatric Working Parties
- Author
-
Oliver Tunstall, Elizabeth Chalmers, Jayanthi Alamelu, Kate Talks, C. R. M. Hay, Daniel P. Hart, Peter William Collins, Michael Williams, Savita Rangarajan, Michael Makris, M Richards, Jeanette Payne, Mary Mathias, and Raina Liesner
- Subjects
medicine.medical_specialty ,Pediatrics ,First line ,MEDLINE ,030204 cardiovascular system & hematology ,Hemophilia A ,Haemophilia ,Immune tolerance ,03 medical and health sciences ,0302 clinical medicine ,Immune Tolerance ,medicine ,Humans ,Child ,Genetics (clinical) ,Protocol (science) ,Factor VIII ,Dose-Response Relationship, Drug ,business.industry ,Hematology ,General Medicine ,medicine.disease ,United Kingdom ,Physical therapy ,Severe haemophilia A ,business ,030215 immunology - Published
- 2017
29. The top 10 research priorities in bleeding disorders: a James Lind Alliance Priority Setting Partnership
- Author
-
Laurence Woollard, Derek Elston, Michael Laffan, Patrick G. Gallagher, Susan Shapiro, Amanda Waterman, David Stephensen, Charlotte Camp, Peter William Collins, Liz Carroll, Jamie O'Hara, Kate Khair, Simon J. Stanworth, Sheela Upadhyaya, and William McKeown
- Subjects
Health Services Needs and Demand ,Priority setting ,Science & Technology ,Biomedical Research ,business.industry ,Research ,Immunology ,haemophilia ,Hematology ,Blood Coagulation Disorders ,Haemophilia ,medicine.disease ,bleeding ,priority setting ,Alliance ,Nursing ,General partnership ,Health Care Surveys ,obstetric ,Medicine ,ITP ,Humans ,business ,Life Sciences & Biomedicine ,1102 Cardiorespiratory Medicine and Haematology - Published
- 2019
30. Correction to: Outcome of kidney function after ischaemic and zero-ischaemic laparoscopic and open nephron-sparing surgery for renal cell cancer
- Author
-
Jan Ebbing, Felix Menzel, Paolo Frumento, Kurt Miller, Bernhard Ralla, Tom Florian Fuller, Jonas Busch, Justin William Collins, Christofer Adding, Hans Helge Seifert, Peter Ardelt, Christian Wetterauer, Timm Westhoff, and Carsten Kempkensteffen
- Subjects
Male ,Laparotomy ,Correction ,Nephrons ,Middle Aged ,lcsh:Diseases of the genitourinary system. Urology ,lcsh:RC870-923 ,Kidney ,Nephrectomy ,Kidney Neoplasms ,Ischemia ,Nephrology ,Humans ,Female ,Laparoscopy ,Warm Ischemia ,Carcinoma, Renal Cell ,Organ Sparing Treatments ,Aged ,Glomerular Filtration Rate ,Retrospective Studies - Abstract
Nephron-sparing surgery (NSS) remains gold standard for the treatment of localised renal cell cancer (RCC), even in case of a normal contralateral kidney. Compared to radical nephrectomy, kidney failure and cardiovascular events are less frequent with NSS. However, the effects of different surgical approaches and of zero ischaemia on the postoperative reduction in renal function remain controversial. We aimed to investigate the relative short- and long-term changes in estimated glomerular filtration rate (eGFR) after ischaemic or zero-ischaemic open (ONSS) and laparoscopic NSS (LNSS) for RCC, and to analyse prognostic factors for postoperative acute kidney injury (AKI) and chronic kidney disease (CKD) stage ≥3.Data of 444 patients (211 LNSS, 233 ONSS), including 57 zero-ischaemic cases, were retrospectively analysed. Multiple regression models were used to predict relative changes in renal function. Natural cubic splines were used to demonstrate the association between ischaemia time (IT) and relative changes in renal function.IT was identified as significant risk factor for short-term relative changes in eGFR (ß = - 0.27) and development of AKI (OR, 1.02), but no effect was found on long-term relative changes in eGFR. Natural cubic splines revealed that IT had a greater effect on patients with baseline eGFR categories ≥G3 concerning short-term decrease in renal function and development of AKI. Unlike LNSS, ONSS was significantly associated with short-term decrease in renal function (ß = - 13.48) and development of AKI (OR, 3.87). Tumour diameter was associated with long-term decrease in renal function (ß = - 1.76), whereas baseline eGFR was a prognostic factor for both short- (ß = - 0.20) and long-term (ß = - 0.29) relative changes in eGFR and the development of CKD stage ≥3 (OR, 0.89).IT is a significant risk factor for AKI. The short-term effect of IT is not always linear, and the impact also depends on baseline eGFR. Unlike LNSS, ONSS is associated with the development of AKI. Our findings are helpful for surgical planning, and suggest either the application of a clampless NSS technique or at least the shortest possible IT to reduce the risk of short-time impairment of the renal function, which might prevent AKI, particularly regarding patients with baseline eGFR category ≥G3.
- Published
- 2019
31. Treatment regimens and outcomes in severe and moderate haemophilia A in the UK: The THUNDER study
- Author
-
Peter William Collins, B. Palmer, Hua Xiang, Camelia S. Sima, Daniel P. Hart, Martin Scott, David Stephensen, and Charles R. M. Hay
- Subjects
Adult ,Male ,medicine.medical_specialty ,Adolescent ,Haemophilia A ,Pain ,Hemorrhage ,Moderate haemophilia A ,030204 cardiovascular system & hematology ,Haemophilia ,Hemophilia A ,Severity of Illness Index ,03 medical and health sciences ,Young Adult ,0302 clinical medicine ,stomatognathic system ,Isoantibodies ,Internal medicine ,medicine ,Humans ,Health score ,Child ,Genetics (clinical) ,Factor VIII ,business.industry ,Treatment regimen ,Coagulants ,Infant, Newborn ,Infant ,Hematology ,General Medicine ,Middle Aged ,medicine.disease ,United Kingdom ,Child, Preschool ,Joint Diseases ,business ,030215 immunology - Abstract
Introduction\ud \ud The THUNDER study provides an analysis of treatment patterns and outcomes in UK patients with severe or moderate haemophilia A (SHA/MHA) in 2015.\ud \ud \ud Methods\ud \ud Patients with SHA or MHA registered with the UK National Haemophilia Database (NHD) were segregated by severity, inhibitor status and age. Haemophilia joint health score (HJHS) was derived from NHD records and treatment regimen and annualized bleed/joint‐bleed rate (ABR/AJBR) from Haemtrack (HT) in HT‐compliant patients.\ud \ud \ud Results\ud \ud We report 1810 patients with SHA and 864 with MHA. Prophylaxis was used in 94.9% (n = 130/137) of HT‐compliant children
- Published
- 2019
32. Thrombomodulin enhances complement regulation through strong affinity interactions with factor H and C3b-Factor H complex
- Author
-
Valerie B. O'Donnell, Meike Heurich, Peter William Collins, Roger J. S. Preston, and B.P. Morgan
- Subjects
0301 basic medicine ,Chemistry ,Thrombomodulin ,Hematology ,Complement factor I ,Surface Plasmon Resonance ,R1 ,Complement factor B ,Complement system ,03 medical and health sciences ,Classical complement pathway ,030104 developmental biology ,Biochemistry ,Complement Factor H ,Lectin pathway ,Factor H ,Alternative complement pathway ,Humans ,Complement Activation ,Protein Binding ,circulatory and respiratory physiology - Abstract
Introduction Coagulation and complement systems are simultaneously activated at sites of tissue injury, leading to thrombin generation and opsonisation with C3b. Thrombomodulin (TM) is a cell-bound regulator of thrombin activation, but can also enhance the regulatory activity of complement factor H (FH), thus accelerating the degradation of C3b into inactive iC3b. Objectives This study sought to determine the biophysical interaction affinities of two recombinant TM analogs with thrombin, FH and C3b in order to analyze their ability to regulate serum complement activity. Methods Surface plasmon resonance (SPR) analysis was used to determine binding affinities of TM analogs with FH and C3b, and compared to thrombin as positive control. The capacity of the two recombinant TM analogs to regulate complement in serum was tested in standard complement hemolytic activity assays. Results SPR analysis showed that both TM analogs bind FH and C3b-Factor H with nanomolar and C3b with micromolar affinity; binding affinity for its natural ligand thrombin was several fold higher than for FH. At a physiological relevant concentration, TM inhibits complement hemolytic activity in serum via FH dependent and independent mechanisms. Conclusions TM exhibits significant binding affinity for complement protein FH and C3b-FH complex and its soluble form is capable at physiologically relevant concentrations of inhibiting complement activation in serum.
- Published
- 2016
33. Combined Quantification of the Global Proteome, Phosphoproteome, and Proteolytic Cleavage to Characterize Altered Platelet Functions in the Human Scott Syndrome*
- Author
-
René P. Zahedi, Frauke Swieringa, Judith M.E.M. Cosemans, Johan W. M. Heemskerk, Julia M. Burkhart, Peter William Collins, Nadine J.A. Mattheij, Fiorella A. Solari, Albert Sickmann, Promovendi CD, Biochemie, and RS: CARIM - R1.03 - Cell biochemistry of thrombosis and haemostasis
- Subjects
0301 basic medicine ,Blood Platelets ,Proteomics ,Quantitative proteomics ,Integrin ,Biology ,Biochemistry ,Analytical Chemistry ,03 medical and health sciences ,Scott syndrome ,hemic and lymphatic diseases ,Crotalid Venoms ,medicine ,Humans ,Platelet ,Lectins, C-Type ,Molecular Biology ,Research ,Ionomycin ,fungi ,Thrombin ,Convulxin ,Blood Coagulation Disorders ,medicine.disease ,Phosphoproteins ,Cell biology ,030104 developmental biology ,Gene Expression Regulation ,Proteome ,Proteolysis ,biology.protein ,Phosphorylation ,Calcium ,Signal transduction ,Signal Transduction - Abstract
The Scott syndrome is a very rare and likely underdiagnosed bleeding disorder associated with mutations in the gene encoding anoctamin-6. Platelets from Scott patients are impaired in various Ca2+-dependent responses, including phosphatidylserine exposure, integrin closure, intracellular protein cleavage, and cytoskeleton-dependent morphological changes. Given the central role of anoctamin-6 in the platelet procoagulant response, we used quantitative proteomics to understand the underlying molecular mechanisms and the complex phenotypic changes in Scott platelets compared with control platelets. Therefore, we applied an iTRAQ-based multi-pronged strategy to quantify changes in (1) the global proteome, (2) the phosphoproteome, and (3) proteolytic events between resting and stimulated Scott and control platelets. Our data indicate a limited number of proteins with decreased (70) or increased (64) expression in Scott platelets, among those we confirmed the absence of anoctamin-6 and the strong up-regulation of aquaporin-1 by parallel reaction monitoring. The quantification of 1566 phosphopeptides revealed major differences between Scott and control platelets after stimulation with thrombin/convulxin or ionomycin. In Scott platelets, phosphorylation levels of proteins regulating cytoskeletal or signaling events were increased. Finally, we quantified 1596 N-terminal peptides in activated Scott and control platelets, 180 of which we identified as calpain-regulated, whereas a distinct set of 23 neo-N termini was caspase-regulated. In Scott platelets, calpain-induced cleavage of cytoskeleton-linked and signaling proteins was downregulated, in accordance with an increased phosphorylation state. Thus, multipronged proteomic profiling of Scott platelets provides detailed insight into their protection against detrimental Ca2+-dependent changes that are normally associated with phosphatidylserine exposure.
- Published
- 2016
34. The use of enhanced half-life coagulation factor concentrates in routine clinical practice: guidance from UKHCDO
- Author
-
Alun Thomas, Elizabeth Chalmers, Savita Rangarajan, Mary Mathias, James S. O’Donnell, K. J. Pasi, Peter William Collins, Pratima Chowdary, and David Keeling
- Subjects
medicine.medical_specialty ,Pediatrics ,Recombinant Fusion Proteins ,Hemorrhage ,030204 cardiovascular system & hematology ,Routine practice ,Hemophilia A ,Haemophilia ,Hemophilia B ,Polyethylene Glycols ,Factor IX ,03 medical and health sciences ,0302 clinical medicine ,medicine ,Humans ,Routine clinical practice ,Intensive care medicine ,Genetics (clinical) ,Factor VIII ,Coagulants ,business.industry ,Hematology ,General Medicine ,medicine.disease ,Antibodies, Neutralizing ,Past history ,Clinical trial ,business ,Half-Life ,030215 immunology - Abstract
Enhanced half-life factor VIII and IX products are being introduced into routine clinical practice. Published data report on clinical trials and there are limited data available on how to use these products in routine clinical practice. Many patients, for example, those with a past history of an inhibitor, have been excluded from clinical trials and there are limited data published on children. This guidance document is a consensus statement from the UK Haemophilia Centres Doctors' Organisation and aims to give pragmatic advice on the use of these products in routine practice.
- Published
- 2016
35. Association of peak factor <scp>VIII</scp> levels and area under the curve with bleeding in patients with haemophilia A on every third day pharmacokinetic‐guided prophylaxis
- Author
-
Erik Berntorp, Bruce M. Ewenstein, Leonard A. Valentino, Gerald Spotts, Krista Fischer, Peter William Collins, Victor S. Blanchette, Steven W. Pipe, and Myungshin Oh
- Subjects
Male ,030204 cardiovascular system & hematology ,Severity of Illness Index ,Gastroenterology ,0302 clinical medicine ,hemic and lymphatic diseases ,Breakthrough bleeding ,Medicine ,Genetics(clinical) ,Child ,joint bleeding ,Genetics (clinical) ,Medicine(all) ,Area under the curve ,Hematology ,General Medicine ,Middle Aged ,Area Under Curve ,prophylaxis ,medicine.symptom ,Adult ,Risk ,medicine.medical_specialty ,Adolescent ,Haemophilia A ,haemophilia ,Hemorrhage ,Hemophilia A ,Haemophilia ,Young Adult ,03 medical and health sciences ,haemarthrosis ,Pharmacokinetics ,Internal medicine ,Journal Article ,Humans ,rAHF-PFM ,In patient ,Dosing interval ,Factor VIII ,Coagulants ,business.industry ,bleeding ,medicine.disease ,Surgery ,ROC Curve ,Trough level ,Joints ,pharmacokinetic-guided treatment ,business ,030215 immunology - Abstract
Introduction: We previously showed that pharmacokinetic-guided prophylaxis (PKP) allows the dosing interval to be extended while maintaining a specific trough level. However, the associations of peak factor VIII (FVIII) levels and area under the curve (AUC) with breakthrough bleeding have not been investigated. Aim: The aim of this study was to analyse data from the PKP arm to determine whether peak FVIII levels, AUC and time with FVIII levels in a haemostatically effective range are independent predictors of bleeding during prophylaxis. Methods: Post hoc analysis of the association of FVIII levels and AUC with annualized bleeding rate in 34 patients on PKP. Results: During 1 year of PKP, 131 bleeding episodes occurred in 24/34 patients. Average peak FVIII levels ranged from 24 to 168 IU dL−1, with higher values associated with a decreased risk for all bleeding (joint and non-joint; P 20 IU dL−1 was 22%; median AUC was 1363. Both values were significantly associated with a lower ABR when targeting a 1% trough at 72 h. Conclusion: When PKP was administered every third day, higher peak FVIII levels, higher AUC and more time spent per week with FVIII levels >20 IU dL−1 provided increased protection from joint and non-joint bleeding. These data highlight the potential impact of variability in individual pharmacokinetic and bleeding risk and support the need for high peak levels and AUC in some patients treated every third day. The findings do not necessarily apply to alternate-day or other prophylactic dosing regimens.
- Published
- 2016
36. Survival protein anoctamin-6 controls multiple platelet responses including phospholipid scrambling, swelling, and protein cleavage
- Author
-
Marijke J.E. Kuijpers, Nadine J.A. Mattheij, Alastair W. Poole, Joachim Pircher, Peter William Collins, Roger van Kruchten, Constance C.F.M.J. Baaten, Johan W. M. Heemskerk, Rainer Schreiber, Judith M.E.M. Cosemans, Andrea Vortkamp, Elisabetta Castoldi, Attila Braun, Manuela Wülling, Ralf Köhler, Karl Kunzelmann, Bernhard Nieswandt, Promovendi CD, Biochemie, RS: CARIM - R1.01 - Blood proteins & engineering, RS: CARIM - R1.03 - Cell biochemistry of thrombosis and haemostasis, and MUMC+: DA CDL Analytisch cluster 1K (9)
- Subjects
Male ,0301 basic medicine ,Biochemistry ,Mice ,chemistry.chemical_compound ,Phospholipid scrambling ,Scott syndrome ,Phospholipid transfer protein ,Platelet ,Phospholipid Transfer Proteins ,Phospholipids ,Mice, Knockout ,biology ,medicine.diagnostic_test ,embryonic lethality ,Phosphatidylserine ,Blood Coagulation Disorders ,Intermediate-Conductance Calcium-Activated Potassium Channels ,Neoplasm Proteins ,Chloride channel ,Female ,Biologie ,Biotechnology ,Blood Platelets ,medicine.medical_specialty ,phosphatidylserine ,Anoctamins ,ANO1 ,03 medical and health sciences ,Chloride Channels ,Bleeding time ,Internal medicine ,Genetics ,medicine ,Animals ,Humans ,Molecular Biology ,Anoctamin-1 ,TMEM16F ,Cell Membrane ,medicine.disease ,bleeding ,030104 developmental biology ,Endocrinology ,chemistry ,Mutation ,Proteolysis ,biology.protein ,Calcium - Abstract
Scott syndrome is a rare bleeding disorder, characterized by altered Ca2+-dependent platelet signaling with defective phosphatidylserine (PS) exposure and microparticle formation, and is linked to mutations in the ANO6 gene, encoding anoctamin (Ano) 6. We investigated how the complex platelet phenotype of this syndrome is linked to defective expression of Anos or other ion channels. Mice were generated with heterozygous of homozygous deficiency in Ano6, Ano1, or Ca2+-dependent K(Ca)3.1Gardos channel. Platelets from these mice were extensively analyzed on molecular functions and compared with platelets from a patient with Scott syndrome. Deficiency in Ano1 or Gardos channel did not reduce platelet responses compared with control mice (P > 0.1). In 2 mouse strains, deficiency in Ano6 resulted in reduced viability with increased bleeding time to 28.6min (control 6.4min, P 0.05) with reduced PS exposure (265 to 90%); 2) lowered Ca2+-dependent swelling (280%) and membrane blebbing (-90%); 3) reduced calpain-dependent protein cleavage (-60%); and 4) moderately affected apoptosis-dependent PS exposure. In conclusion, mouse deficiency of Ano6 but not of other channels affects viability and phenocopies the complex changes in platelets from hemostatically impaired patients with Scott syndrome.
- Published
- 2016
37. Management of coagulopathy associated with postpartum hemorrhage: guidance from the SSC of the ISTH
- Author
-
Peter William Collins, Rezan Abdul-Kadir, and Jecko Thachil
- Subjects
medicine.medical_specialty ,Blood transfusion ,International Cooperation ,medicine.medical_treatment ,Cardiology ,Factor VIIa ,030204 cardiovascular system & hematology ,03 medical and health sciences ,0302 clinical medicine ,Blood loss ,Pregnancy ,030202 anesthesiology ,Activated factor VII ,Coagulopathy ,medicine ,Humans ,Blood Transfusion ,Intensive care medicine ,Blood Coagulation ,Societies, Medical ,Disseminated intravascular coagulation ,Hemostasis ,business.industry ,Postpartum Hemorrhage ,Postpartum Period ,Anticoagulants ,Fibrinogen ,Hematology ,Blood Coagulation Disorders ,medicine.disease ,Recombinant Proteins ,Obstetrics ,Tranexamic Acid ,Practice Guidelines as Topic ,Female ,Prothrombin ,Fresh frozen plasma ,business ,Postpartum period - Published
- 2016
38. The epidemiology and outcomes of women with postpartum haemorrhage requiring massive transfusion with eight or more units of red cells: a national cross-sectional study
- Author
-
Laura E. Green, R. E. Collis, Nigel Simpson, Marian Knight, S. S. Stanworth, Frances Seeney, Andrew Weeks, Cathy L Hopkinson, and Peter William Collins
- Subjects
Adult ,medicine.medical_specialty ,Blood transfusion ,Placenta accreta ,medicine.medical_treatment ,Population ,Placenta Accreta ,030204 cardiovascular system & hematology ,Hysterectomy ,03 medical and health sciences ,0302 clinical medicine ,Pregnancy ,Risk Factors ,Intensive care ,medicine ,Humans ,Blood Transfusion ,Caesarean section ,Prospective Studies ,education ,education.field_of_study ,030219 obstetrics & reproductive medicine ,Cesarean Section ,Obstetrics ,business.industry ,Incidence ,Incidence (epidemiology) ,Postpartum Hemorrhage ,Pregnancy Outcome ,Obstetrics and Gynecology ,medicine.disease ,United Kingdom ,Uterine atony ,Cross-Sectional Studies ,Female ,Uterine Inertia ,business - Abstract
Objective: To ascertain the incidence of massive transfusion (MT) in obstetrics in the UK, and describe its management and clinical outcomes. Design: A population‐based cross‐sectional study conducted through the UK Obstetric Surveillance System (UKOSS). Settings: All UK hospitals with consultant‐led maternity units. Population: Any pregnant woman at ≥20 weeks of gestation receiving ≥8 units of red blood cells within 24 hours of giving birth, from July 2012 to June 2013. Methods: Prospective case identification through the monthly mailing of UKOSS. Results: We identified 181 women who had undergone MT, making the estimated incidence of MT associated with postpartum haemorrhage (PPH) 23 per 100 000 maternities (95% confidence interval 19–26) per year. The median estimated blood loss was 6 l (interquartile range 4.5–8.0 l). The majority of women presented outside working hours (63%), 40% had had previous caesarean sections and 3% had normal vaginal births without risk factors. The main cause for MT was uterine atony (40%) and the main mode of birth was caesarean section (69%). Of the 181 women, 15 received >20 units of red blood cells. In total, 45% of women underwent hysterectomy, and among all causes of PPH, placenta accreta had the highest hysterectomy rate. Two women died, 82% were admitted to intensive care/high‐dependency units, and 28% developed major morbidities. Conclusion: Massive transfusion due to PPH is associated with high rates of morbidity and hysterectomy. Clinical and research efforts should focus on approaches to recognise and optimise timely resuscitation and management of these severe cases. Tweetable abstract: Massive transfusion due to postpartum haemorrhage is associated with high rates of morbidity and hysterectomy.
- Published
- 2015
39. The procoagulant activity of tissue factor expressed on fibroblasts is increased by tissue factor-negative extracellular vesicles
- Author
-
Peter V. Jenkins, Samya Obaji, Christopher P. Thomas, Marcela Rosas, Jason P. Webber, Jorge Alvarez-Jarreta, Peter William Collins, Valerie B. O'Donnell, David A. Slatter, Maceler Aldrovandi, and Victoria J. Tyrrell
- Subjects
0301 basic medicine ,Physiology ,Cell Membranes ,Cell ,030204 cardiovascular system & hematology ,Biochemistry ,chemistry.chemical_compound ,Spectrum Analysis Techniques ,0302 clinical medicine ,Animal Cells ,Annexin ,Medicine and Health Sciences ,Platelet ,Phospholipids ,Connective Tissue Cells ,Multidisciplinary ,medicine.diagnostic_test ,Chemistry ,Phosphatidylserine ,Flow Cytometry ,Lipids ,Body Fluids ,Cell biology ,Blood ,medicine.anatomical_structure ,Connective Tissue ,Spectrophotometry ,Medicine ,Cytophotometry ,Cellular Types ,Anatomy ,Cellular Structures and Organelles ,Research Article ,Blood Platelets ,Platelets ,Science ,Phosphatidylserines ,Research and Analysis Methods ,Cell Line ,Thromboplastin ,Flow cytometry ,Extracellular Vesicles ,03 medical and health sciences ,Tissue factor ,medicine ,Humans ,Vesicles ,Fibroblast ,Blood Coagulation ,Phosphatidylethanolamine ,Blood Cells ,Phosphatidylethanolamines ,Biology and Life Sciences ,Cell Biology ,Fibroblasts ,Biological Tissue ,030104 developmental biology ,Liposomes - Abstract
Tissue factor (TF) is critical for the activation of blood coagulation. TF function is regulated by the amount of externalised phosphatidylserine (PS) and phosphatidylethanolamine (PE) on the surface of the cell in which it is expressed. We investigated the role PS and PE in fibroblast TF function. Fibroblasts expressed 6–9 x 104 TF molecules/cell but had low specific activity for FXa generation. We confirmed that this was associated with minimal externalized PS and PE and characterised for the first time the molecular species of PS/PE demonstrating that these differed from those found in platelets. Mechanical damage of fibroblasts, used to simulate vascular injury, increased externalized PS/PE and led to a 7-fold increase in FXa generation that was inhibited by annexin V and an anti-TF antibody. Platelet-derived extracellular vesicles (EVs), that did not express TF, supported minimal FVIIa-dependent FXa generation but substantially increased fibroblast TF activity. This enhancement in fibroblast TF activity could also be achieved using synthetic liposomes comprising 10% PS without TF. In conclusion, despite high levels of surface TF expression, healthy fibroblasts express low levels of external-facing PS and PE limiting their ability to generate FXa. Addition of platelet-derived TF-negative EVs or artificial liposomes enhanced fibroblast TF activity in a PS dependent manner. These findings contribute information about the mechanisms that control TF function in the fibroblast membrane.
- Published
- 2020
40. Designing and implementing an all Wales postpartum haemorrhage quality improvement project: OBS Cymru (the Obstetric Bleeding Strategy for Wales)
- Author
-
Thomas Kitchen, Peter William Collins, Miriam John, James Tozer, Cerys Scarr, Tracey Edey, Claire Francis, Ingrid Volikas, Kathryn James, Elinore Macgillivray, Kathryn Greaves, R. E. Collis, Niladril Sengupta, Christopher Bailey, Kevin Kelly, Adam Watkins, and Sarah F. Bell
- Subjects
medicine.medical_specialty ,Quality management ,Quality Improvement Report ,Leadership and Management ,Psychological intervention ,Audit ,03 medical and health sciences ,0302 clinical medicine ,Obstetrics and gynaecology ,Surveys and Questionnaires ,Interim ,Humans ,Medicine ,030212 general & internal medicine ,Blood Coagulation ,obstetrics and gynecology ,lcsh:R5-920 ,Wales ,030219 obstetrics & reproductive medicine ,Information Dissemination ,business.industry ,Incidence ,Health Policy ,Incidence (epidemiology) ,Postpartum Hemorrhage ,Public Health, Environmental and Occupational Health ,Guideline ,Quality Improvement ,Point-of-Care Testing ,Emergency medicine ,teamwork ,healthcare quality improvement ,Erythrocyte Transfusion ,lcsh:Medicine (General) ,business ,Risk assessment - Abstract
BackgroundPostpartum haemorrhage (PPH) contributes to substantial maternal morbidity. Research into PPH has led to improvements in care which have been incorporated into the Obstetric Bleeding Strategy for Wales.InterventionA national quality improvement team supported local teams in implementing multiple interventions including risk assessment, objective measurement of blood loss, multiprofessional assessment (at the bedside at 1000 mL blood loss) and point-of-care (POC) testing of coagulation to guide blood product resuscitation during PPH. The project was rolled out to all 12 obstetric units in 2017. The interventions were reinforced by an All Wales Guideline, PPH proforma and standardised training. A national database, biannual audits, and patient and staff surveys reported process and outcome measures.ResultsProcess measures: during 2017, there was an increase in the percentage of maternities with documented risk assessment (0%–76%), objective measurement of blood loss (52%–88%) and POC testing for coagulation for PPH ≥1500 mL (38%–59%). Maternity staff survey indicated that 94% were aware of the project and 87% stated that it had changed their unit’s management of PPH. Interim outcome measures: the incidence (95% CI) of PPH ≥2500 mL per 1000 maternities in 2017 was 6.03 (5.23–6.95). The annual number of women receiving any red blood cell transfusion, level 3 intensive care admission and hysterectomy for PPH was 19.7 (18.2 to 21.3), 0.702 (0.464 to 1.06) and 0.255 (0.129 to 0.504) per 1000 maternities, respectively.ConclusionsA high level of project awareness across Welsh maternity units has been achieved. Measurement of blood loss was reported to be the most important early change in practice, while PPH documentation and POC testing continue to be embedded. Combining qualitative and quantitative measures to inform implementation has improved project delivery and allowed teams to adapt to local contexts.
- Published
- 2020
41. Mycophenolate mofetil as adjunctive therapy in acquired haemophilia A
- Author
-
Peter William Collins, Rachel Rayment, and Samya Obaji
- Subjects
Aged, 80 and over ,Male ,Pediatrics ,medicine.medical_specialty ,business.industry ,Treatment outcome ,MEDLINE ,Hematology ,General Medicine ,Middle Aged ,Mycophenolic Acid ,Mycophenolate ,Hemophilia A ,03 medical and health sciences ,0302 clinical medicine ,Treatment Outcome ,030220 oncology & carcinogenesis ,Acquired haemophilia ,Medicine ,Humans ,Female ,business ,Genetics (clinical) ,030215 immunology ,Aged - Published
- 2018
42. Recombinant factor VIII products and inhibitor development in previously untreated patients with severe haemophilia A: Combined analysis of three studies
- Author
-
Elena Santagostino, Jenny Goudemand, Kay Martin Hanschmann, Peter William Collins, Thierry Calvez, Daniel P. Hart, Ben Palmer, Peter Volkers, Ella M. van Hardeveld, Hervé Chambost, Charles R. M. Hay, Brigitte Keller-Stanislawski, Rolf Ljung, Virginie Demiguel, and Marijke van den Berg
- Subjects
medicine.medical_specialty ,Haemophilia A ,030204 cardiovascular system & hematology ,Haemophilia ,Lower risk ,Hemophilia A ,Gastroenterology ,law.invention ,03 medical and health sciences ,0302 clinical medicine ,law ,Risk Factors ,Internal medicine ,medicine ,Humans ,Genetics (clinical) ,Hematology ,Factor VIII ,business.industry ,Standard treatment ,Hazard ratio ,General Medicine ,medicine.disease ,Recombinant Proteins ,Coagulation ,Recombinant DNA ,business ,030215 immunology - Abstract
INTRODUCTION: Standard treatment of congenital haemophilia A is based on replacement therapy with coagulation factor VIII (FVIII) products. A major complication of FVIII therapy is the occurrence of IgG alloantibodies (inhibitors) that neutralize FVIII activity.AIM: The aim of the analysis was estimating the risk of high-titre inhibitor associated with the second-generation full-length product compared to third-generation full-length product and other recombinant FVIII (rFVIII).METHODS: We conducted a combined analysis of individual patient data from three large studies in previously untreated patients (PUPs) with severe haemophilia A.RESULTS: A total of 1109 PUPs were treated from 1993 to 2013 including 787 PUPs treated from 2004 onwards (primary analysis cohort). A total of 322 patients (29.0%) developed an inhibitor, of which 192 (17.3%) a high-titre inhibitor. In the primary analysis set, 29.9% of patients developed an inhibitor and 17.2% a high-titre inhibitor. The combined analysis indicated a lower risk of high-titre inhibitor development for the third-generation rFVIII product compared to the second-generation rFVIII product (primary analysis: adjusted hazard ratio (HR) = 0.72, 95% CI: 0.49 to 1.06). Adjusted HR for all inhibitor development was significantly lower for the third-generation product compared to the second-generation product.CONCLUSION: The trend of an increased risk of inhibitor development in PUPs for one recombinant product illustrates that extrapolation from one recombinant factor VIII product to other products might not be justified. (Less)
- Published
- 2018
43. Intracranial haemorrhage in children with inherited bleeding disorders in the UK 2003-2015: a national cohort study
- Author
-
Andrew D Mumford, M Richards, Peter William Collins, Jeanette Payne, Michael D. Williams, Oliver Tunstall, Jayanthi Alamelu, Elizabeth Chalmers, B. Palmer, and Mary Mathias
- Subjects
Male ,Pediatrics ,medicine.medical_specialty ,Intracranial haemorrhage ,Haemophilia A ,030204 cardiovascular system & hematology ,Hemophilia A ,Haemophilia ,Hemophilia B ,National cohort ,Cohort Studies ,03 medical and health sciences ,0302 clinical medicine ,Recurrence ,Risk Factors ,Retrospective analysis ,Humans ,Medicine ,Genetics (clinical) ,business.industry ,Infant, Newborn ,Infant ,Hematology ,General Medicine ,Delivery, Obstetric ,medicine.disease ,United Kingdom ,Phenotype ,Severe phenotype ,Female ,business ,Complication ,Intracranial Hemorrhages ,030215 immunology ,Cohort study - Abstract
Intracranial haemorrhage in children with inherited bleeding disorders is a potentially life‐threatening complication and presents a significant therapeutic challenge. \ud \ud \ud Aim\ud \ud To define the characteristics, management and outcomes of intracranial haemorrhage presenting in UK children ≤16 years of age with inherited bleeding disorders from 2003 to 2015. \ud \ud \ud Method\ud \ud Retrospective analysis of children treated at UK haemophilia centres.\ud \ud \ud Results\ud \ud Of 66 children presenting with Intracranial haemorrhage (ICH), 82% had haemophilia A or B, 3% VWD and 15% a rare IBD. The IBD was a severe phenotype in 91%. The rates of ICH were 6.4 and 4.2 per 1000 patient years for haemophilia A and B, respectively. Median age at presentation was 4 months (33% neonates; 91% children 2 years (67%) than in children 1 month to 2 years (18%; P = .027). Prior to ICH, only 4.5% of children were on prophylaxis. 6% of haemophiliacs had an inhibitor. The median duration of initial replacement therapy was 15 days. Mortality was 13.5%. Neurological sequelae occurred in 39% of survivors, being more common following intracerebral bleeding. In haemophilia survivors, 52% subsequently developed a FVIII inhibitor. \ud \ud \ud Conclusion\ud \ud Intracranial haemorrhage occurs most frequently in children with severe IBDs, during the first 2 years of life and in children not receiving prophylaxis. Intracranial haemorrhage often occurs without documented trauma.
- Published
- 2018
44. Core outcome sets for prevention and treatment of postpartum haemorrhage: an international Delphi consensus study
- Author
-
Ahmet Metin Gülmezoglu, G. Gyte, K. Gutteridge, Peter William Collins, A. S. Ducloy-Bouthors, Jennifer Blum, Shuba Mallaiah, Anna Cuthbert, Nasreen Aflaifel, Shireen Meher, Paula R Williamson, Declan Devane, Zulfiqar A Bhutta, Andrew Weeks, J. M. Smith, Jamie J Kirkham, Caroline S.E. Homer, Zarko Alfirevic, A. Bishop, Edgardo Abalos, and Bukola Fawole
- Subjects
medicine.medical_specialty ,Blood transfusion ,Consensus ,Delphi Technique ,medicine.medical_treatment ,International Cooperation ,Population ,Breastfeeding ,Delphi method ,Outcome Assessment (Health Care) ,03 medical and health sciences ,0302 clinical medicine ,Patient satisfaction ,Pregnancy ,Outcome Assessment, Health Care ,Medicine ,Humans ,Obstetrics & Reproductive Medicine ,Adverse effect ,education ,education.field_of_study ,030219 obstetrics & reproductive medicine ,business.industry ,Postpartum Hemorrhage ,Obstetrics and Gynecology ,medicine.disease ,Systematic review ,Patient Satisfaction ,Family medicine ,Maternal death ,Female ,business - Abstract
© 2018 Royal College of Obstetricians and Gynaecologists Objective: To develop core outcome sets (COS) for studies evaluating interventions for (1) prevention and (2) treatment of postpartum haemorrhage (PPH), and recommendations on how to report the COS. Design: A two-round Delphi survey and face-to-face meeting. Population: Healthcare professionals and women's representatives. Methods: Outcomes were identified from systematic reviews of PPH studies and stakeholder consultation. Participants scored each outcome in the Delphi on a Likert scale between 1 (not important) and 9 (critically important). Results were discussed at the face-to-face meeting to agree the final COS. Consensus at the meeting was defined as ≥ 70% of participants scoring the outcome as critically important (7–9). Lectures, discussion and voting were used to agree how to report COS outcomes. Main outcome measures: Outcomes from systematic reviews and consultations. Results: Both Delphi rounds were completed by 152/205 (74%) participants for prevention and 143/197 (73%) for treatment. For prevention of PPH, nine core outcomes were selected: blood loss, shock, maternal death, use of additional uterotonics, blood transfusion, transfer for higher level of care, women's sense of wellbeing, acceptability and satisfaction with the intervention, breastfeeding, and adverse effects. For treatment of PPH, 12 core outcomes were selected: blood loss, shock, coagulopathy, hysterectomy, organ dysfunction, maternal death, blood transfusion, use of additional haemostatic intervention, transfer for higher level of care, women's sense of wellbeing, acceptability and satisfaction with the intervention, breastfeeding, and adverse effects. Recommendations were developed on how to report these outcomes where possible. Conclusions: These COS will help standardise outcome reporting in PPH trials. Tweetable abstract: Core outcome sets for PPH: nine core outcomes for PPH prevention and 12 core outcomes for PPH treatment.
- Published
- 2018
45. Management of postpartum haemorrhage: from research into practice, a narrative review of the literature and the Cardiff experience
- Author
-
R. E. Collis, Sarah F. Bell, Peter William Collins, and L. de Lloyd
- Subjects
medicine.medical_specialty ,Blood transfusion ,Biomedical Research ,medicine.medical_treatment ,Point-of-Care Systems ,Platelet Transfusion ,Fibrinogen ,03 medical and health sciences ,0302 clinical medicine ,030202 anesthesiology ,Pregnancy ,medicine ,Coagulopathy ,Humans ,Platelet ,Intensive care medicine ,030219 obstetrics & reproductive medicine ,Placental abruption ,business.industry ,Postpartum Hemorrhage ,Obstetrics and Gynecology ,Bleed ,medicine.disease ,Postpartum haemorrhage ,Quality Improvement ,Thrombelastography ,Anesthesiology and Pain Medicine ,Coagulation ,Female ,business ,medicine.drug - Abstract
Postpartum haemorrhage (PPH) is caused by obstetric complications but may be exacerbated by haemostatic impairment. In a ten year programme of research we have established that haemostatic impairment is uncommon in moderate PPH and that fibrinogen falls earlier than other coagulation factors. Laboratory Clauss fibrinogen and the point of care surrogate measure of fibrinogen (Fibtem® A5 measured on the ROTEM® machine) are predictive biomarkers for progression from early to severe PPH, the need for blood transfusion and invasive procedures to control haemorrhage. Fibrinogen replacement is not required in PPH unless the plasma level falls below 2 g/L or the Fibtem A5 is below 12mm. Deficiencies of coagulation factors other than fibrinogen are uncommon even during severe PPH, and ROTEM monitoring can inform withholding FFP safely in most women. In the absence of placental abruption, clinically significant thrombocytopenia is uncommon unless the platelet count is low before the bleed started, or very large bleeds (>5000 mL) occur. Measuring blood loss is feasible in routine practice during PPH and is more accurate than estimation. These research findings have been collated to design an ongoing quality improvement programme for all maternity units in Wales called OBS Cymru (Wales) (The Obstetric Bleeding Strategy for Wales) .
- Published
- 2018
46. Real life experiences of a PK dosing study-Challenges and lessons learned
- Author
-
Savita Rangarajan, S. Mangles, C. Rea, J. Needham, Bella Madan, Siv Jönsson, Elisabet I. Nielsen, and Peter William Collins
- Subjects
Adult ,medicine.medical_specialty ,MEDLINE ,Medication adherence ,030204 cardiovascular system & hematology ,Hemophilia A ,Medication Adherence ,03 medical and health sciences ,Bayes' theorem ,0302 clinical medicine ,Isoantibodies ,Medicine ,Humans ,Drug Dosage Calculations ,Dosing ,Precision Medicine ,Intensive care medicine ,Antibodies, Blocking ,Genetics (clinical) ,Factor VIII ,business.industry ,Bayes Theorem ,Hematology ,General Medicine ,Middle Aged ,Precision medicine ,Drug Dosage Calculation ,Patient Outcome Assessment ,030220 oncology & carcinogenesis ,business - Published
- 2018
47. High Levels of Avenanthramides in Oat-Based Diet Further Suppress High Fat Diet-Induced Atherosclerosis in Ldlr
- Author
-
Weimin Guo, Mohsen Meydani, F. William Collins, Sharon Kim, Mitchell L. Wise, and Michael Thomas
- Subjects
0301 basic medicine ,Aortic valve ,Dietary Fiber ,Male ,medicine.medical_specialty ,animal structures ,Avena ,Diet, High-Fat ,Proinflammatory cytokine ,03 medical and health sciences ,chemistry.chemical_compound ,Mice ,Internal medicine ,otorhinolaryngologic diseases ,medicine ,Animals ,Humans ,ortho-Aminobenzoates ,VCAM-1 ,030109 nutrition & dietetics ,Chemistry ,Cell adhesion molecule ,Cholesterol ,Plant Extracts ,fungi ,food and beverages ,General Chemistry ,medicine.disease ,Atherosclerosis ,030104 developmental biology ,Atheroma ,medicine.anatomical_structure ,Endocrinology ,Receptors, LDL ,Avenanthramide ,LDL receptor ,Dietary Supplements ,General Agricultural and Biological Sciences - Abstract
Oats, in addition to cholesterol-lowering properties, contain unique antioxidants called avenanthramides (Avns), which inhibit both inflammatory cytokines and adhesion molecules in endothelial cells in culture. This study evaluated the effects of Avns of oats on atherosclerosis in Ldlr–/– mice, one of the most commonly used atherosclerosis mouse models with their similar cholesterol distributions to humans. The Ldlr–/– mice were fed a low fat, high fat, high fat containing regular oat brans with low levels of Avns (HFLA), or high fat containing regular oat brans with high levels of Avns (HFHA) diet. After 16 weeks of intervention, blood cholesterol and extent of aortic lesions were evaluated. We found that both oat-based diets reduced high fat diet-induced atheroma lesions in the aortic valve (p < 0.01). Furthermore, the effects of oat-based diets are more profound in HFHA mice than mice fed HFLA. Total plasma cholesterol levels were similarly reduced in both oat-supplemented mice. We concluded that oat b...
- Published
- 2018
48. Networks of enzymatically oxidized membrane lipids support calcium-dependent coagulation factor binding to maintain hemostasis
- Author
-
Alastair W. Poole, Charles L. Percy, Andrea Brancale, David A. Slatter, Salvatore Ferla, Philip R. Taylor, Jessica E. Molhoek, Anne O’Connor, Peter William Collins, Valerie B. O'Donnell, Samya Obaji, Phillip G. de Groot, Keith Allen-Redpath, Simon Arnett Jones, P. Vince Jenkins, Maceler Aldrovandi, Stefan Uderhardt, Christopher P. Thomas, Jochen A. Ackermann, Sirpa Rannikko, Daniel Farewell, Ginger L. Milne, Rolf T. Urbanus, Victoria J. Tyrrell, Gerhard Krönke, Sarah Nicol Lauder, and Sohvi Hörkkö
- Subjects
Adult ,Male ,0301 basic medicine ,Membrane lipids ,030204 cardiovascular system & hematology ,Biology ,Biochemistry ,Article ,Cohort Studies ,Mice ,03 medical and health sciences ,chemistry.chemical_compound ,0302 clinical medicine ,Hydroxyeicosatetraenoic Acids ,Animals ,Humans ,Platelet ,Platelet activation ,Blood Coagulation ,Molecular Biology ,Phospholipids ,Aged ,Venous Thrombosis ,Calcium metabolism ,Hemostasis ,Innate immune system ,Cell Membrane ,Cell Biology ,Phosphatidylserine ,Lipoxygenases ,Middle Aged ,Models, Theoretical ,Antiphospholipid Syndrome ,Platelet Activation ,R1 ,Blood Coagulation Factors ,Cell biology ,Mice, Inbred C57BL ,Disease Models, Animal ,lnfectious Diseases and Global Health Radboud Institute for Health Sciences [Radboudumc 4] ,030104 developmental biology ,Coagulation ,chemistry ,beta 2-Glycoprotein I ,Calcium ,Female ,lipids (amino acids, peptides, and proteins) - Abstract
Item does not contain fulltext Blood coagulation functions as part of the innate immune system by preventing bacterial invasion, and it is critical to stopping blood loss (hemostasis). Coagulation involves the external membrane surface of activated platelets and leukocytes. Using lipidomic, genetic, biochemical, and mathematical modeling approaches, we found that enzymatically oxidized phospholipids (eoxPLs) generated by the activity of leukocyte or platelet lipoxygenases (LOXs) were required for normal hemostasis and promoted coagulation factor activities in a Ca(2+)- and phosphatidylserine (PS)-dependent manner. In wild-type mice, hydroxyeicosatetraenoic acid-phospholipids (HETE-PLs) enhanced coagulation and restored normal hemostasis in clotting-deficient animals genetically lacking p12-LOX or 12/15-LOX activity. Murine platelets generated 22 eoxPL species, all of which were missing in the absence of p12-LOX. Humans with the thrombotic disorder antiphospholipid syndrome (APS) had statistically significantly increased HETE-PLs in platelets and leukocytes, as well as greater HETE-PL immunoreactivity, than healthy controls. HETE-PLs enhanced membrane binding of the serum protein beta2GP1 (beta2-glycoprotein 1), an event considered central to the autoimmune reactivity responsible for APS symptoms. Correlation network analysis of 47 platelet eoxPL species in platelets from APS and control subjects identified their enzymatic origin and revealed a complex network of regulation, with the abundance of 31 p12-LOX-derived eoxPL molecules substantially increased in APS. In summary, circulating blood cells generate networks of eoxPL molecules, including HETE-PLs, which change membrane properties to enhance blood coagulation and contribute to the excessive clotting and immunoreactivity of patients with APS.
- Published
- 2017
49. Correcting thrombin generation ex vivo using different haemostatic agents following cardiac surgery requiring the use of cardiopulmonary bypass
- Author
-
Dheeraj Mehta, Charles L. Percy, Peter William Collins, Judith Elizabeth Hall, Michael Dockal, Friedrich Scheiflinger, Subramaniam Balachandran, Rhidian M. Jones, Valerie B. O'Donnell, and Rudolf Hartmann
- Subjects
Adult ,Male ,Lipoproteins ,Factor VIIa ,Hemostatics ,Plasma ,Thrombin ,Tissue factor pathway inhibitor ,medicine ,Humans ,Cardiac Surgical Procedures ,Blood Coagulation ,Aged ,Blood coagulation test ,Aged, 80 and over ,Cardiopulmonary Bypass ,biology ,business.industry ,Anticoagulants ,Original Articles ,Hematology ,General Medicine ,Heparin ,Middle Aged ,blood coagulation factors ,Prothrombin complex concentrate ,Recombinant Proteins ,surgical procedures, operative ,Coagulation ,Recombinant factor VIIa ,Anesthesia ,biology.protein ,Female ,haemorrhage ,recombinant FVIIa ,Blood Coagulation Tests ,Fresh frozen plasma ,business ,circulatory and respiratory physiology ,medicine.drug - Abstract
Recently, lower thrombin generation has been associated with excess bleeding post-cardiopulmonary bypass (CPB). Therefore, treatment to correct thrombin generation is a potentially important aspect of management of bleeding in this group of patients. The objective of the present study was to investigate the effects of fresh frozen plasma (FFP), recombinant factor VIIa (rFVIIa), prothrombin complex concentrate (PCC) and tissue factor pathway inhibitor (TFPI) inhibition on thrombin generation when added ex vivo to the plasma of patients who had undergone cardiac surgery requiring CPB. Patients undergoing elective cardiac surgery were recruited. Blood samples were collected before administration of heparin and 30 min after its reversal. Thrombin generation was measured in the presence and absence of different concentrations of FFP, rFVIIa, PCC and an anti-TFPI antibody. A total of 102 patients were recruited. Thrombin generation following CPB was lower compared with pre-CPB (median endogenous thrombin potential pre-CPB 339 nmol/l per min, post-CPB 155 nmol/l per min, P < 0.0001; median peak thrombin pre-CPB 35 nmol/l, post-CPB 11 nmol/l, P < 0.0001). Coagulation factors and anticoagulants decreased, apart from total TFPI, which increased (55-111 ng/ml, P < 0.0001), and VWF (144-170 IU/dl, P < 0.0001). Thrombin generation was corrected to pre-CPB levels by the equivalent of 15 ml/kg FFP, 45 [mu]g/kg rFVIIa and 25 U/kg of PCC. Inhibition of TFPI resulted in an enhancement of thrombin generation significantly beyond pre-CPB levels. This study shows that FFP, rFVIIa, PCC and inhibition of TFPI correct thrombin generation in the plasma of patients who have undergone surgery requiring CPB. Inhibition of TFPI may be a further potential therapeutic strategy for managing bleeding in this group of patients.
- Published
- 2015
50. Role of enhanced half-life factor VIII and IX in the treatment of haemophilia
- Author
-
Samya Obaji, Peter William Collins, and Ali Jassem Mahdi
- Subjects
Pediatrics ,medicine.medical_specialty ,Factor VIII ,business.industry ,Cost effectiveness ,Haemophilia A ,Hematology ,Hemophilia A ,Haemophilia ,medicine.disease ,Hemophilia B ,Medication Adherence ,Factor IX ,Clinical trial ,Regimen ,Treatment Outcome ,Arthropathy ,medicine ,Humans ,Haemophilia B ,Drug Monitoring ,business ,Half-Life ,medicine.drug - Abstract
Treatment of congenital haemophilia with factor VIII and IX concentrates often requires frequent infusions. This has obvious implications in establishing effective administration strategies and, in turn, adherence. To overcome these issues, three main technologies – polyethylene-glycol, Fc-neonatal IgG1 and albumin fusion products – have emerged into various stages of clinical development. Published data indicates an approximately 1·5- and fivefold increase in half-life of factor VIII and IX, respectively, compared to standard recombinant concentrates. Studies into efficacy and safety are starting to be published. Monitoring and optimal use of these new concentrates remains unknown. Weekly factor IX prophylaxis appears to be a feasible prophylactic regimen in haemophilia B patients. Weekly longer-acting FVIII is unlikely to provide adequate prophylaxis in most patients with haemophilia A but may reduce the frequency of infusions. Ongoing clinical trials and real life experience will help shape how these products can be used in practice and their cost effectiveness. The drive for convenience however should not overshadow the ultimate goal of prophylaxis, namely, preventing bleeding and arthropathy.
- Published
- 2015
Catalog
Discovery Service for Jio Institute Digital Library
For full access to our library's resources, please sign in.