Thrombin generation and phenotypic correlation in haemophilia A

The clinical phenotype of patients with haemophilia A (HA) often differs between individuals with the same factor VIII (FVIII) gene defect (e.g. within the same family) or the same coagulant activity of FVIII (FVIII:C). We proposed that because the thrombin generation assay in platelet-poor plasma of HA patients provides more information [peak thrombin concentration, endogenous thrombin potential (ETP), rate of thrombin generation and lag-time] than a clot-based FVIII assay it might provide insight into these differences. We therefore investigated the relation between the results of the thrombin generation assay and the clinical severity in nine families with HA (23 patients with different phenotypes). We also examined the contribution of prothrombotic risk factors: (FV Leiden G1691A and prothrombin G20210A), the coagulant activity of FVIII and tissue factor (5?UTR) polymorphisms. Our data detect marked differences between individuals but these did not correlate with the reported clinical phenotype. These differences were also reflected in a marked difference in response to the therapeutic amounts of FVIII. This might account for differences in amounts of treatment consumption. Reduced peak and possibly rate of thrombin generation, rather than FVIII:C or ETP appear to represent the critical defects in FVIII-deficient plasma. We suggest that the analysis of parameters in thrombin generation is a useful tool to detect bleeding tendency in HA but not to predict the modulation of the haemorrhagic tendency in patients within families. However the presence of the other factors such as vessel wall components, protein C and platelets might need to be incorporated into this system. � 2005 Blackwell Publishing Ltd

von Willebrand disease: proposing definitions for future research

Thrombosis and Hemostasi

Clinical outcomes and the impact of oral anticoagulants prior to diagnosis of COVID-19 on clinical outcomes in patients admitted to hospitals in the UK – a multicentre observational study

Coagulation dysfunction and thrombosis are major complications in patients with coronavirus disease-19 (COVID-19). Patients on oral anticoagulants prior to diagnosis of COVID-19 may therefore have better outcomes. We aimed: To first document the frequency of thrombosis, major bleeding and multiorgan failure (MOF) in patients admitted with COVID-19 and the contribution of these complications to 90-day mortality. To then determine the effects of oral anticoagulation, use prior to admission on the same outcomes as well as the requirement for Intensive Care Unit (ICU) admission, when compared to a propensity matched cohort of patients not taking oral anticoagulants prior to admission. Methods: This was a multicentre observational cohort including adult patients (≥18 years) admitted to 26 UK hospitals between 1st of April 2020 and 31 July 2020. Findings: A total of 5883 patients were included in the study. Overall mortality was 29.2%. Incidences of thrombosis, major bleeding and MOF were 5.4%,1.7% and 3.3% respectively. The presence of thrombosis, major bleeding, or MOF were associated with a 1.8, 4.5 or 5.9-fold increased risk of dying, respectively. Of the 5883 patients studied, 83.6% (n= 4920) were not on oral anticoagulants (OAC) and 16.4% (n=963) were taking OAC at the time of admission. There was no difference in mortality between patients on OAC vs no OAC prior to admission when compared in an adjusted multivariate analysis (HR 1.05 (95%CI 0.93-1.19) P=0.15) or in an adjusted propensity score analysis (HR 0.92 (95%CI 0.58-1.450, P=0.18). In multivariate and adjusted propensity score analyses, the only significant association of no anticoagulants prior to admission was treatment in ICU (HR 1.98 [95%CI 1.37-2.85]). Interpretation: Thrombosis, major bleeding, and MOF were associated with higher mortality. Our results indicate that patients may continue to benefit from OAC after admission, especially reduced admission to ICU, without any increase in bleeding. Funding: Bayer plc supported the study by providing the investigator-initiated funding (P87339) to setup the multicentre database of the study. Declaration of Interest: DJA received funding from Bayer plc to setup the multicentre database of the study as an investigator-initiated funding and received research grant from Leo Pharma. ML received consultation and speaker fees from Astra-Zeneca, Sobi, Leo-Pharma, Takeda and Pfizer. PN received research grants from Novartis, Principia and Rigel, unrestricted grants from Sanofi, Chugai and Octapharma and honoraria from Bayer. RA received fees from Alexion, Bayer, BMS, Pfizer and Portola. SS has received meeting sponsorship, speaker fees and/or consultancy from Bayer, Pfizer, NovoNordisk, Sobi, Chugai/Roche and Shire/Takeda. SS receives funding support from the Medical Research Council (MR/T024054/1). The research was supported by the National Institute for Health Research (NIHR) Oxford Biomedical Research Centre (BRC). SL has received speaker fees from Bayer, BMS and Pfizer. Others have no conflict of interests to declare. Ethical Approval: The study was approved by the Health Research Authority (HRA), Health and Care Research Wales (HCRW) and received local Caldicott Guardian support in Scotland (reference number: 20/HRA/1785). Data was collected both retrospectively and prospectively from patient clinical records by the treating medical team with no breach of privacy or anonymity by allocating a unique study number with no direct patient identifiable data; therefore, consent was waived by the HRA

Functional neurological disorder is a feminist issue

Functional neurological disorder (FND) is a common and disabling disorder, often misunderstood by clinicians. Although viewed sceptically by some, FND is a diagnosis that can be made accurately, based on positive clinical signs, with clinical features that have remained stable for over 100 years. Despite some progress in the last decade, people with FND continue to suffer subtle and overt forms of discrimination by clinicians, researchers and the public. There is abundant evidence that disorders perceived as primarily affecting women are neglected in healthcare and medical research, and the course of FND mirrors this neglect. We outline the reasons why FND is a feminist issue, incorporating historical and contemporary clinical, research and social perspectives. We call for parity for FND in medical education, research and clinical service development so that people affected by FND can receive the care they need

An international survey to inform priorities for new guidelines on von Willebrand disease

Introduction: von Willebrand disease (VWD) is an inherited bleeding disorder caused by a quantitative or qualitative dysfunction of von Willebrand factor. Clinicians, patients and other stakeholders have many questions about the diagnosis and management of the disease. Aim: To identify topics of highest importance to stakeholders that could be addressed by guidelines to be developed by the American Society of Hematology (ASH), the International Society on Thrombosis and Haemostasis (ISTH), the National Hemophilia Foundation (NHF) and the World Federation of Hemophilia (WFH). Methods: A survey to determine and prioritize topics to be addressed in the collaborative development of guidelines for VWD was distributed to international stakeholders including patients, caregivers and healthcare providers (HCPs). Representatives of the four organizations coordinated the distribution strategy. The survey focused on both diagnosis and management of VWD, soliciting 7-point Likert-scale responses and open-ended comments, in English, French and Spanish. We conducted descriptive analysis with comparison of results by stakeholder type, gender and countries' income classification for the rating questions and qualitative conventional content data analysis for the open-ended responses. Results: A total of 601 participants responded to the survey (49% patients/caregivers and 51% healthcare providers). The highest priority topics identified were diagnostic criteria/classification, bleeding assessment tools and treatment options for women and surgical patients. In contrast, screening for anaemia and differentiating plasma-derived therapy versus recombinant therapies received lower ratings. Conclusion: This survey highlighted areas of importance to a diverse representation of stakeholders in the diagnosis and management of VWD, providing a framework for future guideline development and implementation. VWD Working Gr

Epigenome-wide association study of body mass index, and the adverse outcomes of adiposity

Approximately 1.5 billion people worldwide are overweight or affected by obesity, and are at risk of developing type 2 diabetes, cardiovascular disease and related metabolic and inflammatory disturbances. Although the mechanisms linking adiposity to associated clinical conditions are poorly understood, recent studies suggest that adiposity may influence DNA methylation, a key regulator of gene expression and molecular phenotype. Here we use epigenome-wide association to show that body mass index (BMI; a key measure of adiposity) is associated with widespread changes in DNA methylation (187 genetic loci with P < 1 × 10 -7, range P = 9.2 × 10 -8 to 6.0 × 10 -46; n = 10,261 samples). Genetic association analyses demonstrate that the alterations in DNA methylation are predominantly the consequence of adiposity, rather than the cause. We find that methylation loci are enriched for functional genomic features in multiple tissues (P < 0.05), and show that sentinel methylation markers identify gene expression signatures at 38 loci (P < 9.0 × 10 -6, range P = 5.5 × 10 -6 to 6.1 × 10 -35, n = 1,785 samples). The methylation loci identify genes involved in lipid and lipoprotein metabolism, substrate transport and inflammatory pathways. Finally, we show that the disturbances in DNA methylation predict future development of type 2 diabetes (relative risk per 1 standard deviation increase in methylation risk score: 2.3 (2.07-2.56); P = 1.1 × 10 -54). Our results provide new insights into the biologic pathways influen