Treatment of patients with von Willebrand disease

Von Willebrand disease (vWD) is the most common hereditary bleeding disorder. The aim of therapy is to correct the dual hemostatic defect, due to defective platelet adhesion-aggregation and abnormal coagulation due to Factor VIII (FVIII) deficiency. The choice of treatment depends on a number of factors, including the severity of the bleed, the procedure planned, the subtype and severity of the disease and the age and morbidity of the patient. Desmopressin (DDAVP) is the treatment of choice for type 1 vWD as it increases endogenous release of FVIII and von Willebrand factor (vWF) and is also used in some subtypes of type 2 vWD. In those patients in whom DDAVP is ineffective or contraindicated, levels can be restored by infusing vWF:FVIII concentrates. The role of antifibrinolytic treatment is an important adjunct to replacement therapy during minor or major surgery involving mucosal surfaces. The dosing and timing of vWF:FVIII concentrates is important depending on the nature of the surgical procedure. The role of secondary prophylaxis needs to be further defined

Impact of blood group on survival following critical illness: a single-centre retrospective observational study

Background Predicting patient outcomes following critical illness is challenging. Recent evidence has suggested that patients with blood group AB are more likely to survive following major cardiac surgery, and this is associated with a reduced number of blood transfusions. However, there are no current data to indicate whether a patient’s blood group affects general intensive care outcomes. Objective The objective of this study was to determine if ABO blood group affects survival in intensive care. The primary outcome measure was 90-day mortality with a secondary outcome measure of the percentage of patients receiving a blood transfusion. Design Retrospective analysis of electronically collected intensive care data, blood group and transfusion data. Setting General intensive care unit (ICU) of a major tertiary hospital with both medical and surgical patients. Patients All patients admitted to ICU between 2006 and 2016 who had blood group data available. Intervention None. Measurements and main results 7340 patients were included in the study, blood group AB accounted for 3% (221), A 41% (3008), B 10.6% (775) and O 45.4% (3336). These values are similar to UK averages. Baseline characteristics between the groups were similar. Blood group AB had the greatest survival benefit (blood group AB 90-day survival estimate 76.75, 95% CI 72.89 to 80.61 with the overall estimate 72.07, 95% CI 71.31 to 72.82) (log-rank χ2 16.128, p=0.001). Transfusion requirements were similar in all groups with no significant difference between the percentages of patients transfused (AB 23.1%, A 21.5%, B 18.7%, O 19.9%, Pearson χ2 5.060 p=0.167). Conclusion Although this is primarily a hypothesis generating study, intensive care patients with blood group AB appeared to have a higher 90-day survival compared with other blood groups. There was no correlation between blood group and percentage of patients receiving transfusion

Can we use biomarkers of coagulation to predict which patients with foot and ankle injury will develop vein thrombosis?

Background Our aim was to determine whether plasma levels of Tissue Factor (TF), Vascular Cell Adhesion Molecule 1 (VCAM-1), Interleukin 6 (IL-6) or D-dimer after foot and ankle injury could predict which patients would develop deep vein thrombosis (DVT). Methods Patients aged 18–60 years with acute foot and ankle injury had venous blood sample to measure TF, VCAM-1, IL-6 and D-dimer within 3 days of injury. Patients had bilateral lower limb venous ultrasound to assess for DVT on discharge from clinic. Results 21 of 77 patients were found to have DVT (27%). There was no statistically significant association between levels of TF, VCAM-1, IL-6 or D-dimer and subsequent development of DVT. Conclusion Tissue Factor (TF), Vascular Cell Adhesion Molecule-1 (VCAM-1), Interleukin-6 (IL-6) and D-dimer levels were not associated with development deep vein thrombosis in patients with acute foot and ankle injury

The effect of active toe movement (AToM) on calf pump function and deep vein thrombosis in patients with acute foot and ankle trauma treated with cast - a prospective randomized study

Background Patients with foot and ankle trauma treated with cast are advised to perform toe movements to prevent venous thromboembolism (VTE). Our aim was to determine the effect of active toe movement on asymptomatic deep vein thrombosis (DVT) and venous calf pump function. Methods Patients aged 18–60 years with acute foot and ankle trauma requiring below knee non weight bearing cast were randomized to intervention (regular active toe movement) or control groups (n = 100). Patients had bilateral lower limb venous ultrasound to assess for DVT on discharge from clinic. Patients requiring chemical thromboprophylaxis were excluded. Results 78 completed the study. 27% sustained asymptomatic DVT, with no statistically significant difference in calf pump function or DVT incidence between groups. All DVT's occurred in the injured lower limb. Conclusion Active toe movement is not a viable strategy for thromboprophylaxis in patients with acute foot and ankle trauma treated with cast

Impact of a dedicated cancer-associated thrombosis service on clinical outcomes: a mixed-methods evaluation of a clinical improvement exercise

Objectives Cancer-associated thrombosis (CAT) complex condition, which may present to any healthcare professional and at any point during the cancer journey. As such, patients may be managed by a number of specialties, resulting in inconsistent practice and suboptimal care. We describe the development of a dedicated CAT service and its evaluation. Setting Specialist cancer centre, district general hospital and primary care. Participants Patients with CAT and their referring clinicians. Intervention A cross specialty team developed a dedicated CAT service , including clear referral pathways, consistent access to medicines, patient's information and a specialist clinic. Primary and secondary outcome measures The service was evaluated using a mixed-methods evaluation , including audits of clinical practice, clinical outcomes, staff surveys and qualitative interviewing of patients and healthcare professionals. Results Data from 457 consecutive referrals over an 18-month period were evaluated. The CAT service has led to an 88% increase in safe and consistent community prescribing of low-molecular-weight heparin, with improved access to specialist advice and information. Patients reported improved understanding of their condition, enabling better self-management as well as better access to support and information. Referring clinicians reported better care standards for their patients with improved access to expertise and appropriate management. Conclusions A dedicated CAT service improves overall standards of care and is viewed positively by patients and clinicians alike. Further health economic evaluation would enhance the case for establishing this as the standard model of care

Does thromboprophylaxis reduce symptomatic venous thromboembolism in patients with below knee cast treatment for foot and ankle trauma? A systematic review and meta-analysis

Background Our aim was to determine the evidence for thromboprophylaxis for prevention of symptomatic venous thromboembolism (VTE) in adults with foot or ankle trauma treated with below knee cast or splint. Our secondary aim was to report major bleeding events. Methods MEDLINE and EMBASE databases were searched for randomized controlled trials from inception to 1st June 2015. Results Seven studies were included. All focused on low molecular weight heparin (LMWH). None found a statistically significant symptomatic DVT reduction individually. At meta-analysis LMWH was protective against symptomatic DVT (OR 0.29, 95% CI 0.09–0.95). Symptomatic pulmonary embolism affected 3/692 (0.43%). None were fatal. 86 patients required LMWH thromboprophylaxis to prevent one symptomatic DVT event. The overall incidence of major bleeding was 1 in 886 (0.11%). Conclusions Low molecular weight heparin reduces the incidence of symptomatic VTE in adult patients with foot or ankle trauma treated with below knee cast or splint

The acute management of haemorrhage, surgery and overdose in patients receiving dabigatran

Dabigatran is an oral direct thrombin inhibitor (DTI) licensed for stroke prevention in atrial fibrillation and likely to be soon approved in Europe for treatment of venous thrombosis. Predictable pharmacokinetics and a reduced risk of intracranial haemorrhage do not negate the potential risk of haemorrhage. Unlike warfarin, there is no reversal agent and measurement of the anticoagulant effect is not ‘routine’. The prothrombin time/international normalised ratio response to dabigatran is inconsistent and should not be measured when assessing a patient who is bleeding or needs emergency surgery. The activated partial thromboplastin time (APTT) provides a qualitative measurement of the anticoagulant effect of dabigatran. Knowledge of the time of last dose is important for interpretation of the APTT. Commercially available DTI assays provide a quantitative measurement of active dabigatran concentration in the plasma. If a patient receiving dabigatran presents with bleeding: omit/delay next dose of dabigatran; measure APTT and thrombin time (consider DTI assay if available); administer activated charcoal, with sorbitol, if within 2 h of dabigatran ingestion; give tranexamic acid (1 g intravenously if significant bleeding); maintain renal perfusion and urine output to aid dabigatran excretion. Dabigatran exhibits low protein binding and may be removed by dialysis. Supportive care should form the mainstay of treatment. If bleeding is life/limb threatening, consider an additional haemostatic agent. There is currently no evidence to support the choice of one haemostatic agent (FEIBA, recombinant factor VIIa, prothrombin complex concentrates) over another. Choice will depend on access to and experience with available haemostatic agent(s)

Evaluating the Effects of SARS-CoV-2 Spike Mutation D614G on Transmissibility and Pathogenicity.

Global dispersal and increasing frequency of the SARS-CoV-2 spike protein variant D614G are suggestive of a selective advantage but may also be due to a random founder effect. We investigate the hypothesis for positive selection of spike D614G in the United Kingdom using more than 25,000 whole genome SARS-CoV-2 sequences. Despite the availability of a large dataset, well represented by both spike 614 variants, not all approaches showed a conclusive signal of positive selection. Population genetic analysis indicates that 614G increases in frequency relative to 614D in a manner consistent with a selective advantage. We do not find any indication that patients infected with the spike 614G variant have higher COVID-19 mortality or clinical severity, but 614G is associated with higher viral load and younger age of patients. Significant differences in growth and size of 614G phylogenetic clusters indicate a need for continued study of this variant

The impact of viral mutations on recognition by SARS-CoV-2 specific T cells.

We identify amino acid variants within dominant SARS-CoV-2 T cell epitopes by interrogating global sequence data. Several variants within nucleocapsid and ORF3a epitopes have arisen independently in multiple lineages and result in loss of recognition by epitope-specific T cells assessed by IFN-γ and cytotoxic killing assays. Complete loss of T cell responsiveness was seen due to Q213K in the A∗01:01-restricted CD8+ ORF3a epitope FTSDYYQLY207-215; due to P13L, P13S, and P13T in the B∗27:05-restricted CD8+ nucleocapsid epitope QRNAPRITF9-17; and due to T362I and P365S in the A∗03:01/A∗11:01-restricted CD8+ nucleocapsid epitope KTFPPTEPK361-369. CD8+ T cell lines unable to recognize variant epitopes have diverse T cell receptor repertoires. These data demonstrate the potential for T cell evasion and highlight the need for ongoing surveillance for variants capable of escaping T cell as well as humoral immunity.This work is supported by the UK Medical Research Council (MRC); Chinese Academy of Medical Sciences(CAMS) Innovation Fund for Medical Sciences (CIFMS), China; National Institute for Health Research (NIHR)Oxford Biomedical Research Centre, and UK Researchand Innovation (UKRI)/NIHR through the UK Coro-navirus Immunology Consortium (UK-CIC). Sequencing of SARS-CoV-2 samples and collation of data wasundertaken by the COG-UK CONSORTIUM. COG-UK is supported by funding from the Medical ResearchCouncil (MRC) part of UK Research & Innovation (UKRI),the National Institute of Health Research (NIHR),and Genome Research Limited, operating as the Wellcome Sanger Institute. T.I.d.S. is supported by a Well-come Trust Intermediate Clinical Fellowship (110058/Z/15/Z). L.T. is supported by the Wellcome Trust(grant number 205228/Z/16/Z) and by theUniversity of Liverpool Centre for Excellence in Infectious DiseaseResearch (CEIDR). S.D. is funded by an NIHR GlobalResearch Professorship (NIHR300791). L.T. and S.C.M.are also supported by the U.S. Food and Drug Administration Medical Countermeasures Initiative contract75F40120C00085 and the National Institute for Health Research Health Protection Research Unit (HPRU) inEmerging and Zoonotic Infections (NIHR200907) at University of Liverpool inpartnership with Public HealthEngland (PHE), in collaboration with Liverpool School of Tropical Medicine and the University of Oxford.L.T. is based at the University of Liverpool. M.D.P. is funded by the NIHR Sheffield Biomedical ResearchCentre (BRC – IS-BRC-1215-20017). ISARIC4C is supported by the MRC (grant no MC_PC_19059). J.C.K.is a Wellcome Investigator (WT204969/Z/16/Z) and supported by NIHR Oxford Biomedical Research Centreand CIFMS. The views expressed are those of the authors and not necessarily those of the NIHR or MRC