Publications by authors named "Beverley J Hunt"

181 Publications

A Comparison of Thrombosis and Hemorrhage Rates in Patients With Severe Respiratory Failure Due to Coronavirus Disease 2019 and Influenza Requiring Extracorporeal Membrane Oxygenation.

Crit Care Med 2021 Apr 5. Epub 2021 Apr 5.

1 Centre for Thrombosis and Haemostasis, Department of Haematology, Guy's & St Thomas' NHS Foundation Trust, London, United Kingdom. 2 Department of Critical Care, Guy's & St Thomas' NHS Foundation Trust, London, United Kingdom. 3 Department of Radiology, Guy's & St Thomas' NHS Foundation Trust, London, United Kingdom. 4 Centre from Human & Applied Physiological Sciences, King's College London, London, United Kingdom.

Objectives: Extracorporeal membrane oxygenation is a lifesaving therapy for patients with severe acute respiratory distress syndrome refractory to conventional mechanical ventilation. It is frequently complicated by both thrombosis and hemorrhage. A markedly prothrombotic state associated with high rates of venous thromboembolism has been described in patients with severe acute respiratory syndrome coronavirus 2 (coronavirus disease 2019) infection. These rates have currently not been described during extracorporeal membrane oxygenation in comparison to other viral pneumonias.

Design: Retrospective observational study.

Setting: Single high-volume tertiary critical care department at a university hospital.

Patients: Patients 16 years old or greater receiving venovenous extracorporeal membrane oxygenation between March 1, 2020, and May 31, 2020, with coronavirus disease 2019 were compared with a cohort of patients with influenza pneumonia between June 1, 2012, and May 31, 2020.

Interventions: None.

Measurements And Main Results: The rates of venous thromboembolism and hemorrhage were compared in patients with coronavirus disease 2019 against a historic population of patients with influenza pneumonia who required extracorporeal membrane oxygenation. There were 51 patients who received extracorporeal membrane oxygenation due to coronavirus disease 2019 and 80 patients with influenza. At cannulation for extracorporeal membrane oxygenation, 37% of patients with coronavirus disease 2019 compared with 8% of patients with influenza had filling defects on CT pulmonary angiography (p = 0.0001). Catheter-associated deep vein thrombosis shown on ultrasound Doppler after decannulation was present in 53% with coronavirus disease 2019 versus 25% with influenza (p = 0.01). The rates of intracranial hemorrhage at the time of cannulation were 16% with coronavirus disease 2019 and 14% with influenza (p = 0.8). Elevated D-dimer levels were seen in both conditions and were significantly higher in those with pulmonary thromboembolism than those without in coronavirus disease 2019 (p = 0.02). Fibrinogen and C-reactive protein levels were significantly higher in those with coronavirus disease 2019 than influenza (p < 0.01).

Conclusions: Significant rates of pulmonary thromboembolism and of catheter-associated deep vein thrombosis were seen in both viral infections but were greater in those requiring the use of extracorporeal membrane oxygenation in coronavirus disease 2019 than for influenza.
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http://dx.doi.org/10.1097/CCM.0000000000004971DOI Listing
April 2021

Compression hosiery to avoid post-thrombotic syndrome (CHAPS) protocol for a randomised controlled trial (ISRCTN73041168).

BMJ Open 2021 Apr 12;11(4):e044285. Epub 2021 Apr 12.

Academic Section of Vascular Surgery, Imperial College London, London, UK.

Introduction: Up to 50% of patients develop post-thrombotic syndrome (PTS) after an above knee deep vein thrombosis (DVT). The aim of the study was to determine the effect of graduated compression stockings in preventing PTS after DVT.

Methods And Analysis: Pragmatic, UK multicentre randomised trial in adults with first above knee DVT. The standard of care arm is anticoagulation. The intervention arm will receive anticoagulation plus stockings (European class II, 23-32 mm Hg compression) worn for a median of 18 months. The primary endpoint is PTS using the Villalta score. Analysis of this will be through a time to event approach and cumulative incidence at median 6, 12 and 18 months. An ongoing process evaluation will examine factors contributing to adherence to stockings to understand if and how the behavioural interventions were effective.

Ethics And Dissemination: UK research ethics committee approval (reference 19/LO/1585). Dissemination though the charity Thrombosis UK, the Imperial College London website, peer-reviewed publications and international conferences.

Trial Registration Number: ISRCTN registration number 73041168.
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http://dx.doi.org/10.1136/bmjopen-2020-044285DOI Listing
April 2021

Recent Randomized Trials of Antithrombotic Therapy for Patients With COVID-19: JACC State-of-the-Art Review.

J Am Coll Cardiol 2021 04 16;77(15):1903-1921. Epub 2021 Mar 16.

Cardiovascular Medicine Division, Brigham and Women's Hospital, Harvard Medical School, Boston, Massachusetts, USA; Clinical Trials Center, Cardiovascular Research Foundation, New York, New York, USA; Center for Outcomes Research and Evaluation (CORE), Yale School of Medicine, New Haven, Connecticut, USA. Electronic address:

Endothelial injury and microvascular/macrovascular thrombosis are common pathophysiological features of coronavirus disease-2019 (COVID-19). However, the optimal thromboprophylactic regimens remain unknown across the spectrum of illness severity of COVID-19. A variety of antithrombotic agents, doses, and durations of therapy are being assessed in ongoing randomized controlled trials (RCTs) that focus on outpatients, hospitalized patients in medical wards, and patients critically ill with COVID-19. This paper provides a perspective of the ongoing or completed RCTs related to antithrombotic strategies used in COVID-19, the opportunities and challenges for the clinical trial enterprise, and areas of existing knowledge, as well as data gaps that may motivate the design of future RCTs.
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http://dx.doi.org/10.1016/j.jacc.2021.02.035DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7963001PMC
April 2021

A living WHO guideline on drugs to prevent covid-19.

BMJ 2021 03 1;372:n526. Epub 2021 Mar 1.

Royal Free London NHS Foundation Trust, London, UK

Clinical Question: What is the role of drugs in preventing covid-19? WHY DOES THIS MATTER?: There is widespread interest in whether drug interventions can be used for the prevention of covid-19, but there is uncertainty about which drugs, if any, are effective. The first version of this living guideline focuses on the evidence for hydroxychloroquine. Subsequent updates will cover other drugs being investigated for their role in the prevention of covid-19.

Recommendation: The guideline development panel made a strong recommendation against the use of hydroxychloroquine for individuals who do not have covid-19 (high certainty).

How This Guideline Was Created: This living guideline is from the World Health Organization (WHO) and provides up to date covid-19 guidance to inform policy and practice worldwide. Magic Evidence Ecosystem Foundation (MAGIC) provided methodological support. A living systematic review with network analysis informed the recommendations. An international guideline development panel of content experts, clinicians, patients, an ethicist and methodologists produced recommendations following standards for trustworthy guideline development using the Grading of Recommendations Assessment, Development and Evaluation (GRADE) approach.

Understanding The New Recommendation: The linked systematic review and network meta-analysis (6 trials and 6059 participants) found that hydroxychloroquine had a small or no effect on mortality and admission to hospital (high certainty evidence). There was a small or no effect on laboratory confirmed SARS-CoV-2 infection (moderate certainty evidence) but probably increased adverse events leading to discontinuation (moderate certainty evidence). The panel judged that almost all people would not consider this drug worthwhile. In addition, the panel decided that contextual factors such as resources, feasibility, acceptability, and equity for countries and healthcare systems were unlikely to alter the recommendation. The panel considers that this drug is no longer a research priority and that resources should rather be oriented to evaluate other more promising drugs to prevent covid-19.

Updates: This is a living guideline. New recommendations will be published in this article and signposted by update notices to this guideline.

Readers Note: This is the first version of the living guideline for drugs to prevent covid-19. It complements the WHO living guideline on drugs to treat covid-19. When citing this article, please consider adding the update number and date of access for clarity.
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http://dx.doi.org/10.1136/bmj.n526DOI Listing
March 2021

Prophylactic anticoagulation for patients in hospital with covid-19.

BMJ 2021 02 19;372:n487. Epub 2021 Feb 19.

Department of Cardiovascular Surgery, School of Medicine, University of Uskudar, Istanbul, Turkey.

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http://dx.doi.org/10.1136/bmj.n487DOI Listing
February 2021

Thromboses and COVID-19: reducing inflammation in addition to thromboprophylaxis.

Lancet Rheumatol 2021 Mar 7;3(3):e171-e172. Epub 2021 Jan 7.

Thrombosis and Haemophilia Centre, Guys and St Thomas NHS Foundation Trust, London SE1 7EH, UK.

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http://dx.doi.org/10.1016/S2665-9913(21)00003-5DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7832098PMC
March 2021

Antiphospholipid Syndrome with Monoclonal Gammopathy-A Mechanism for Recurrent Thrombosis?

Thromb Haemost 2021 Jan 20. Epub 2021 Jan 20.

Centre for Thrombosis and Haemostasis, Guy's and St Thomas' NHS Foundation Trust, London, United Kingdom.

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http://dx.doi.org/10.1055/a-1366-9379DOI Listing
January 2021

Incidence of VTE and Bleeding Among Hospitalized Patients With Coronavirus Disease 2019: A Systematic Review and Meta-analysis.

Chest 2021 03 17;159(3):1182-1196. Epub 2020 Nov 17.

CIBER Enfermedades Respiratorias (CIBERES), Madrid, Spain; Department of Internal Medicine, Hospital Germans Trias i Pujol, Badalona, Barcelona, Universidad Católica de Murcia, Murcia, Spain.

Background: Individual studies have reported widely variable rates for VTE and bleeding among hospitalized patients with coronavirus disease 2019 (COVID-19).

Research Question: What is the incidence of VTE and bleeding among hospitalized patients with COVID-19?

Methods: In this systematic review and meta-analysis, 15 standard sources and COVID-19-specific sources were searched between January 1, 2020, and July 31, 2020, with no restriction according to language. Incidence estimates were pooled by using random effects meta-analyses. Heterogeneity was evaluated by using the I statistic, and publication bias was assessed by using the Begg and Egger tests.

Results: The pooled incidence was 17.0% (95% CI, 13.4-20.9) for VTE, 12.1% (95% CI, 8.4-16.4) for DVT, 7.1% (95% CI, 5.3-9.1) for pulmonary embolism (PE), 7.8% (95% CI, 2.6-15.3) for bleeding, and 3.9% (95% CI, 1.2-7.9) for major bleeding. In subgroup meta-analyses, the incidence of VTE was higher when assessed according to screening (33.1% vs 9.8% by clinical diagnosis), among patients in the ICU (27.9% vs 7.1% in the ward), in prospective studies (25.5% vs 12.4% in retrospective studies), and with the inclusion of catheter-associated thrombosis/isolated distal DVTs and isolated subsegmental PEs. The highest pooled incidence estimate of bleeding was reported for patients receiving intermediate- or full-dose anticoagulation (21.4%) and the lowest in the only prospective study that assessed bleeding events (2.7%).

Interpretation: Among hospitalized patients with COVID-19, the overall estimated pooled incidence of VTE was 17.0%, with higher rates with routine screening, inclusion of distal DVT, and subsegmental PE, in critically ill patients and in prospective studies. Bleeding events were observed in 7.8% of patients and were sensitive to use of escalated doses of anticoagulants and nature of data collection. Additional studies are required to ascertain the significance of various thrombotic events and to identify strategies to improve patient outcomes.

Trial Registry: PROSPERO; No.: CRD42020198864; URL: https://www.crd.york.ac.uk/prospero/.
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http://dx.doi.org/10.1016/j.chest.2020.11.005DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7670889PMC
March 2021

Individualized, Intraoperative Dosing of Fibrinogen Concentrate for the Prevention of Bleeding in Neonatal and Infant Cardiac Surgery Using Cardiopulmonary Bypass (FIBCON): A Phase 1b/2a Randomized Controlled Trial.

Circ Cardiovasc Interv 2020 Dec 20;13(12):e009465. Epub 2020 Nov 20.

Department of Paediatric Intensive Care, Evelina London Children's Hospital, United Kingdom (K.S., J.H., A.G.N., S.M.T.).

Background: Mediastinal bleeding is common following pediatric cardiopulmonary bypass surgery for congenital heart disease. Fibrinogen concentrate (FC) represents a potential therapy for preventing bleeding.

Methods: We performed a single-center, phase 1b/2a, randomized controlled trial on infants 2.5 to 12 kg undergoing cardiopulmonary bypass surgery, aimed at (1) demonstrating the feasibility of an intraoperative point-of-care test, rotational thromboelastometry, to screen out patients at low risk of postoperative bleeding and then guide individualized FC dosing in high-risk patients and (2) determining the dose, safety, and efficacy of intraoperative FC supplementation. Screening occurred intraoperatively 1-hour before bypass separation using the rotational thromboelastometry variable fibrinogen thromboelastometry maximum clot firmness (FibTEM-MCF; fibrinogen contribution to clot firmness). If FibTEM-MCF ≥7 mm, patients entered the monitoring cohort. If FibTEM-MCF ≤6 mm, patients were randomized to receive FC/placebo (2:1 ratio). Individualized FC dose calculation included weight, bypass circuit volume, hematocrit, and intraoperative measured and desired FibTEM-MCF. The coprimary outcomes, measured 5 minutes post-FC administration were FibTEM-MCF (desired range, 8-13 mm) and fibrinogen levels (desired range, 1.5-2.5 g/L). Secondary outcomes were thrombosis and thrombosis-related major complications and postoperative 24-hour mediastinal blood loss.

Results: We enrolled 111 patients (cohort, n=21; FC, n=60; placebo, n=30); mean (SD) age, 6.4 months (5.8); weight, 5.9 kg (2.0). Intraoperative rotational thromboelastometry screening effectively excluded low-risk patients, in that none in the cohort arm (FibTEM-MCF, ≥7 mm) demonstrated clinically significant early postoperative bleeding (>10 mL/kg per 4 hours). Among randomized patients, the median (range) FC administered dose was 114 mg/kg (51-218). Fibrinogen levels increased from a mean (SD) of 0.91 (0.22) to 1.7 g/L (0.41). The postdose fibrinogen range was 1.2 to 3.3 g/L (72% within the desired range). The corresponding FibTEM-MCF values were as follows: pre-dose, 5.3 mm (1.9); post-dose, 13 mm (3.2). Ten patients (8 FC and 2 placebo) exhibited 12 possible thromboses; none were clearly related to FC. There was an overall difference in mean (SD) 24-hour mediastinal drain loss: cohort, 12.6 mL/kg (6.4); FC, 11.6 mL/kg (5.2); placebo, 17.1 mL/kg (14.3; ANOVA =0.02).

Conclusions: Intraoperative, individualized dosing of FC appears feasible. The need for individualized dosing is supported by the finding that a 4-fold variation in FC dose is required to achieve therapeutic fibrinogen levels. Registration: URL: https://eudract.ema.europa.eu/; Unique identifier: 2013-003532-68. URL: https://www.isrctn.com/; Unique identifier: 50553029.
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http://dx.doi.org/10.1161/CIRCINTERVENTIONS.120.009465DOI Listing
December 2020

Personal tales of venous thromboembolism in the UK the last 60 years: from no interest to clinical excellence.

Authors:
Beverley J Hunt

Br J Haematol 2020 11;191(4):608-611

Thrombosis & Haemophilia centre, Guy's & St Thomas' NHS Foundation Trust, London, UK.

Sixty years ago there was little interest in venous thromboembolism (VTE) in global medical circles, and the British were no different in this respect. And yet, from nowhere the clinical field has developed: now prevention and management of VTE accounts for a large part of many consultant haematologists' working life, while some nursing staff and pharmacists spend the majority of their clinical time in this area. Indeed the 'Brits' have developed enormous VTE expertise and arguably lead the world in prevention of 60% of all VTE, which is hospital-associated venous thromboembolism (HAT).
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http://dx.doi.org/10.1111/bjh.17152DOI Listing
November 2020

Effect of thrombophilia on clinical outcomes of chronic post-thrombotic patients after iliofemoral stenting with nitinol venous stents.

J Vasc Surg Venous Lymphat Disord 2020 Nov 10. Epub 2020 Nov 10.

Cardiovascular Division, Academic Department of Vascular Surgery, School of Cardiovascular Medicine and Science, Guy's and St Thomas' NHS Trust, King's College London, London, United Kingdom. Electronic address:

Objective: Thrombophilia is a prothrombotic condition that increases the risk of venous thromboembolism. It is unclear whether the presence of thrombophilia alters the clinical outcomes after deep venous stenting. The aim of the present study was to examine the relationship between thrombophilia and outcomes after stenting for post-thrombotic syndrome.

Methods: Consecutive patients (2012-2017) receiving a nitinol venous stent for chronic post-thrombotic venous occlusive disease with a minimum of 18 months of follow-up in one center using the same anticoagulation protocol were included. The clinical history and thrombophilia testing results were reviewed. The outcomes were stent patency, which was assessed using duplex ultrasonography at 24 hours, 2 and 6 weeks, 3 months, 6 months, and annually thereafter; and reinterventions, which were performed when the stent diameter was <50% or occluded.

Results: Of the 136 patients who had undergone intervention, 55 (40%) had had a provoked deep vein thrombosis (DVT) and 81 (60%) had had an unprovoked DVT and had therefore undergone thrombophilia testing. Of the 81 patients, 38 (47%) had had either inherited (n = 19; 50%) or acquired (n = 19; 50%) thrombophilia. Of the 136 patients who had undergone stenting, 68 had required reintervention (50%) during follow-up to maintain stent patency. Of the 55 patients with a provoked DVT, 29 (53%) had required reintervention. Of the 81 patients with an unprovoked DVT, 39 (48%) had required reintervention (P = .420). Of the 38 patients with unprovoked DVT and thrombophilia, 17 (45%) had required reintervention. Of the 43 patients with unprovoked DVT and no thrombophilia, 22 (51%) had required reintervention (P = .766). The cumulative patency rate was 80% for patients with provoked DVT and 88% for those with unprovoked DVT (P = .193). The presence of thrombophilia was not associated with patency loss (92% cumulative patency for patients with thrombophilia and 84% for patients without thrombophilia; P = .307).

Conclusion: Using our anticoagulation protocol, patients with and without thrombophilia had similar clinical outcomes after deep venous stenting and should not be excluded from iliofemoral venous stenting. We found no significant differences in outcomes in conjunction with appropriate postoperative anticoagulation therapy.
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http://dx.doi.org/10.1016/j.jvsv.2020.09.013DOI Listing
November 2020

Intramuscular tranexamic acid: a real-world application of pharmacokinetics.

Br J Anaesth 2021 01 24;126(1):17-20. Epub 2020 Oct 24.

Kings Healthcare Partners, Thrombosis & Haemophilia Centre, Guy's & St Thomas' NHS Foundation Trust, London, UK.

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http://dx.doi.org/10.1016/j.bja.2020.10.003DOI Listing
January 2021

Age-sex specific pulmonary embolism-related mortality in the USA and Canada, 2000-18: an analysis of the WHO Mortality Database and of the CDC Multiple Cause of Death database.

Lancet Respir Med 2021 01 12;9(1):33-42. Epub 2020 Oct 12.

Center for Thrombosis and Hemostasis, University Medical Center Mainz, Mainz, Germany; Department of Cardiology, Democritus University of Thrace, Alexandroupolis, Greece.

Background: Pulmonary embolism (PE)-related mortality is decreasing in Europe. However, time trends in the USA and Canada remain uncertain because the most recent analyses of PE-related mortality were published in the early 2000s.

Methods: For this retrospective epidemiological study, we accessed medically certified vital registration data from the WHO Mortality Database (USA and Canada, 2000-17) and the Multiple Cause of Death database produced by the Division of Vital Statistics of the US Centers for Disease Control and Prevention (CDC; US, 2000-18). We investigated contemporary time trends in PE-related mortality in the USA and Canada and the prevalence of conditions contributing to PE-related mortality reported on the death certificates. We also estimated PE-related mortality by age group and sex. A subgroup analysis by race was performed for the USA.

Findings: In the USA, the age-standardised annual mortality rate (PE as the underlying cause) decreased from 6·0 deaths per 100 000 population (95% CI 5·9-6·1) in 2000 to 4·4 deaths per 100 000 population (4·3-4·5) in 2006. Thereafter, it continued to decrease to 4·1 deaths per 100 000 population (4·0-4·2) in women in 2017 and plateaued at 4·5 deaths per 100 000 population (4·4-4·7) in men in 2017. Among adults aged 25-64 years, it increased after 2006. The median age at death from PE decreased from 73 years to 68 years (2000-18). The prevalence of cancer, respiratory diseases, and infections as a contributing cause of PE-related death increased in all age categories from 2000 to 2018. The annual age-standardised PE-related mortality was consistently higher by up to 50% in Black individuals than in White individuals; these rates were approximately 50% higher in White individuals than in those of other races. In Canada, the annual age-standardised mortality rate from PE as the underlying cause of death decreased from 4·7 deaths per 100 000 population (4·4-5·0) in 2000 to 2·6 deaths per 100 000 population (2·4-2·8) in 2017; this decline slowed after 2006 across age groups and sexes.

Interpretation: After 2006, the initially decreasing PE-related mortality rates in North America progressively reached a plateau in Canada, while a rebound increase was observed among young and middle-aged adults in the USA. These findings parallel recent upward trends in mortality from other cardiovascular diseases and might reflect increasing inequalities in the exposure to risk factors and access to health care.

Funding: None.
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http://dx.doi.org/10.1016/S2213-2600(20)30417-3DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7550106PMC
January 2021

Validation of a liquid chromatography tandem mass spectrometry method for the simultaneous determination of hydroxychloroquine and metabolites in human whole blood.

Clin Chem Lab Med 2020 09 13;58(12):2047-2061. Epub 2020 Sep 13.

Biochemical Sciences, Viapath, Guys & St Thomas' NHSFT, London, UK.

Objectives Hydroxychloroquine (HCQ) is an anti-malarial and immunomodulatory drug reported to inhibit the Corona virus, SARS-CoV-2, in vitro. At present there is insufficient evidence from clinical trials to determine the safety and efficacy of HCQ as a treatment for COVID-19. However, since the World Health Organisation declared COVID-19 a pandemic in March 2020, the US Food and Drug Administration issued an Emergency Use Authorisation to allow HCQ and Chloroquine (CQ) to be distributed and used for certain hospitalised patients with COVID-19 and numerous clinical trials are underway around the world, including the UK based RECOVERY trial, with over 1000 volunteers. The validation of a liquid chromatography tandem mass spectrometry (LC-MS/MS) method for the simultaneous determination of HCQ and two of its major metabolites, desethylchloroquine (DCQ) and di-desethylchloroquine (DDCQ), in whole blood is described. Methods Blood samples were deproteinised using acetonitrile. HCQ, DCQ and DDCQ were chromatographically separated on a biphenyl column with gradient elution, at a flow rate of 500 μL/min. The analysis time was 8 min. Results For each analyte linear calibration curves were obtained over the concentration range 50-2000 μg/L, the lower limit of quantification (LLOQ) was 13 μg/L, the inter-assay relative standard deviation (RSD) was <10% at 25, 800 and 1750 μg/L and mean recoveries were 80, 81, 78 and 62% for HCQ, d4-HCQ, DCQ and DDCQ, respectively. Conclusion This method has acceptable analytical performance and is applicable to the therapeutic monitoring of HCQ, evaluating the pharmacokinetics of HCQ in COVID-19 patients and supporting clinical trials.
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http://dx.doi.org/10.1515/cclm-2020-0610DOI Listing
September 2020

Direct Oral Anticoagulant Concentrations in Obese and High Body Weight Patients: A Cohort Study.

Thromb Haemost 2021 Feb 30;121(2):224-233. Epub 2020 Aug 30.

Department of Haematology, Thrombosis & Haemophilia Centre, Guy's and St Thomas' Hospitals NHS Foundation Trust, London, United Kingdom.

Background:  Direct oral anticoagulants (DOACs) are prescribed for atrial fibrillation (AF) and venous thromboembolism (VTE) and both occur more frequently in obese patients. Outcomes from DOAC trials included few individuals ≥ 120 kg leading to uncertainty whether high body weight (BW) reduces DOAC concentrations.

Objectives:  This article investigates the relationship between factor Xa (FXa) inhibitor concentrations, BW, and renal function, and compares them in high BW patients with unselected populations.

Methods:  Consecutive patients in two United Kingdom centers, weighing ≥ 120 kg receiving 5 mg twice daily apixaban or 20 mg once daily rivaroxaban for AF or VTE were prospectively included. Peak or trough concentrations were measured using specific chromogenic assays, expressed in mean or median (5th-95th percentiles). On-therapy range was the interval from the 5th percentile trough concentration to the 95th percentile peak concentration.

Results:  One hundred patients were included; age range: 23 to 78 years, 31% were women, 58% had AF, creatinine clearance range: 67 to 474 mL/min. Median BW was 139 kg, and 84% had body mass index (BMI) ≥ 40 kg/m. DOAC peak and trough concentrations varied from 44 to 727 and 14 to 299 ng/mL, respectively. There was no linear relationship between FXa inhibitor concentrations at peak or trough and BW or BMI, and creatinine clearance. Apixaban troughs in AF and rivaroxaban peaks in VTE were lower than in unselected populations. However, only two trough concentrations were below the expected range, and 109/116 were within the on-therapy range.

Conclusion:  These data indicated that obese or high BW patients generally achieve therapeutic FXa inhibitor concentrations. However, further investigations assessing clinical outcomes are required.
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http://dx.doi.org/10.1055/s-0040-1715834DOI Listing
February 2021

Anticoagulation Practice Patterns in COVID-19: A Global Survey.

Res Pract Thromb Haemost 2020 Jul 9. Epub 2020 Jul 9.

Blood Research Institute, Versiti, Department of Medicine Medical College of Wisconsin Milwaukee WI USA.

Background: Best practice for prevention, diagnosis, and management of venous thromboembolism (VTE) in patients with SARS-CoV-2 disease 2019 (COVID-19) is unknown due to limited published data in this population.

Objectives: We aimed to assess current global practice and experience in management of COVID-19 associated coagulopathy to identify information to guide prospective and randomized studies.

Methods: Physicians were queried about their current approach to prophylaxis, diagnosis, and treatment of VTE in patients with COVID-19 using an online survey tool distributed through multiple international organizations between April 10 and 14, 2020.

Results: 515 physicians responded from 41 countries. The majority of respondents (78%) recommended prophylactic anticoagulation for all hospitalized patients with COVID-19 with most recommending use of low-molecular-weight heparin or unfractionated heparin. Significant practice variation was found regarding need for dose escalation of anticoagulation outside the setting of confirmed or suspected VTE. Respondents reported the use of bedside testing when unable to perform standard diagnostic imaging for diagnosis of VTE. 291 respondents reported observing thrombotic complications in their patients with 64% noting that the complication was pulmonary embolism (PE). Of the 44% of respondents that estimated incidence of thrombosis in patients with COVID-19 in their hospital, estimates ranged widely from 1 to 50%. 174 respondents noted bleeding complications (34% minor bleeding, 14% clinically relevant non-major bleeding, and 12% major bleeding).

Conclusion: Well-designed epidemiologic studies are urgently needed to understand the incidence and risk factors of VTE and bleeding complications in COVID-19 patients. Randomized clinical trials addressing use of anticoagulation are also needed.
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http://dx.doi.org/10.1002/rth2.12414DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7361754PMC
July 2020

COVID-19 and haemoglobin oxygen affinity: some clarity?

Br J Haematol 2020 09 17;190(5):723-724. Epub 2020 Aug 17.

Inflammation Biology, King's College London, London, UK.

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http://dx.doi.org/10.1111/bjh.17053DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7460983PMC
September 2020

N-Methyl-3,4-methylendioxymethamphetamine (MDMA)-related coagulopathy and rhabdomyolysis: A case series and literature review.

Res Pract Thromb Haemost 2020 Jul 14;4(5):829-834. Epub 2020 Jun 14.

Centre for Thrombosis & Haemophilia St Thomas' Hospital London UK.

Coagulation changes, thrombosis, and hemorrhage have been described in patients following N-methyl-3,4-methylenedioxymethylamphetamine (MDMA) intoxication who subsequently developed serotonin syndrome and rhabdomyolysis. The clinical features and mechanism of this remain poorly described. We describe 5 sequential cases admitted to critical care due to severe recreational MDMA toxicity where coagulopathy occurred, and discuss key clinical issues. All patients presented with hyperpyrexia then developed subsequent rhabdomyolysis accompanied by a coagulopathy within 24 hours of presentation. This included a severe thrombocytopenia, prolonged coagulation times, grossly elevated D-dimer levels, and hypofibrogenemia. Multiorgan dysfunction was seen in all patients, including stroke in one patient and major hemorrhage in another. In 2 cases, low-dose low-molecular-weight heparin was used early after presentation, with no significant bleeding complications. Blood products usage was high but variable between the patients with lower use in those who received low-molecular-weight heparin early. Other treatments included intravascular therapeutic cooling, renal replacement therapy with large filter pores and cyprohepatidine. Current evidence suggests that in this group, rhabdomyolysis with subsequent myosin release may be a profound activator of coagulation leading to disseminated intravascular coagulation. Myosin-activated coagulation seems a potential cause of MDMA-related coagulopathy in the setting of rhabdomyolysis and serotonin syndrome. Further studies are needed to validate this and explore the use of low-molecular-weight heparin to reduce the clinical effects of this coagulopathy.
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http://dx.doi.org/10.1002/rth2.12360DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7354411PMC
July 2020

Thrombosis and coagulopathy in COVID-19: An illustrated review.

Res Pract Thromb Haemost 2020 Jul 11;4(5):744-751. Epub 2020 Jul 11.

Thrombosis & Haemophilia Centre Guys & St Thomas NHS Foundation Trust London UK.

This illustrated review discusses the haemostatic changes seen in patients with severe coronavirus disease 2019 (COVID-19) infection and their possible causes. We discuss the crosstalk between inflammation and coagulation resulting in high levels of acute-phase proteins, very high levels of D-dimers, and absence of disseminated intravascular coagulation seen in patients with severe COVID-19. There appear to be high rates of venous thromboembolism and also, what has been poorly described before in acute lung injury, a high rate of pulmonary immunothrombosis (thrombosis secondary to inflammation).
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http://dx.doi.org/10.1002/rth2.12400DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7354416PMC
July 2020

A critical review of the pathophysiology of thrombotic complications and clinical practice recommendations for thromboprophylaxis in pregnant patients with COVID-19.

Acta Obstet Gynecol Scand 2020 09 5;99(9):1110-1120. Epub 2020 Aug 5.

Maternal-Fetal Medicine Service, National Women's Health, Auckland City Hospital, Auckland, New Zealand.

Those who are infected with Severe Acute Respiratory Syndrome-related CoronaVirus-2 are theoretically at increased risk of venous thromboembolism during self-isolation if they have reduced mobility or are dehydrated. Should patients develop coronavirus disease (COVID-19) pneumonia requiring hospital admission for treatment of hypoxia, the risk for thromboembolic complications increases greatly. These thromboembolic events are the result of at least two distinct mechanisms - microvascular thrombosis in the pulmonary system (immunothrombosis) and hospital-associated venous thromboembolism. Since pregnancy is a prothrombotic state, there is concern regarding the potentially increased risk of thrombotic complications among pregnant women with COVID-19. To date, however, pregnant women do not appear to have a substantially increased risk of thrombotic complications related to COVID-19. Nevertheless, several organizations have vigilantly issued pregnancy-specific guidelines for thromboprophylaxis in COVID-19. Discrepancies between these guidelines reflect the altruistic wish to protect patients and lack of high-quality evidence available to inform clinical practice. Low molecular weight heparin (LMWH) is the drug of choice for thromboprophylaxis in pregnant women with COVID-19. However, its utility in non-pregnant patients is only established against venous thromboembolism, as LMWH may have little or no effect on immunothrombosis. Decisions about initiation and duration of prophylactic anticoagulation in the context of pregnancy and COVID-19 must take into consideration disease severity, outpatient vs inpatient status, temporal relation between disease occurrence and timing of childbirth, and the underlying prothrombotic risk conferred by additional comorbidities. There is currently no evidence to recommend the use of intermediate or therapeutic doses of LMWH in thromboprophylaxis, which may increase bleeding risk without reducing thrombotic risk in pregnant patients with COVID-19. Likewise, there is no evidence to comment on the role of low-dose aspirin in thromboprophylaxis or of anti-cytokine and antiviral agents in preventing immunothrombosis. These unanswered questions are being studied within the context of clinical trials.
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http://dx.doi.org/10.1111/aogs.13962DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7404828PMC
September 2020

Image-proven thromboembolism in patients with severe COVID-19 in a tertiary critical care unit in the United Kingdom.

Thromb Res 2020 09 29;193:1-4. Epub 2020 May 29.

Haemostasis and Thrombosis Centre, St Thomas' Hospital, Westminster Bridge Road, London SE1 7EH, United Kingdom. Electronic address:

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http://dx.doi.org/10.1016/j.thromres.2020.05.049DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7256551PMC
September 2020

Re The source of elevated plasma D-dimer levels in COVID-19 infection.

Br J Haematol 2020 08 18;190(3):e133-e134. Epub 2020 Jun 18.

Department of Medicine and Cardiometabolic Programme-NIHR UCLH/UCL BRC, University College London Hospitals NHS Foundation Trust, London, UK.

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http://dx.doi.org/10.1111/bjh.16907DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7300986PMC
August 2020

A prospective observational study of acute traumatic coagulopathy in traumatic bleeding from the battlefield.

Transfusion 2020 Jun 1;60 Suppl 3:S52-S61. Epub 2020 Jun 1.

St Thomas' Hospital, Thrombosis & Haemophilia Centre & Thrombosis and Vascular Biology Group, London, UK.

Background: Acute trauma coagulopathy (ATC) after military trauma has not been comprehensively studied. ATC is defined as a prolonged prothrombin time ratio (PTr) or reduced clot amplitude (A5) in viscoelastic testing. Compared to civilian trauma, military trauma has more injuries from explosions and gunshot wounds (GSWs), potentially leading to a different pathophysiology for traumatic coagulopathy. This study aimed to characterize military ATC on admission to a military hospital in Afghanistan and to explore any differences due to the mechanism of injury.

Methods: Severely injured military casualties were enrolled in the study. Blood samples were taken on admission and after routine testing, waste plasma was prepared, frozen, and transported to the United Kingdom for in-depth hemostatic analysis.

Results: Seventy-seven percent of casualties had ATC defined by a PTr greater than 1.2 and 19% when defined by rotational thromboelastometry (ROTEM) A5 less than 36 mm. Coagulation factor depletion correlated with degree of shock, particularly factor V (p < 0.01), factor X (p < 0.01), and fibrinogen levels (p < 0.01). Thrombin generation was well preserved. Fibrinolytic biomarkers were raised correlating with the degree of shock (p < 0.01), and 8% of casualties had hyperfibrinolysis on ROTEM analysis. Plasmin-antiplasmin complexes (p < 0.01) and d-dimer levels (p = 0.01) were higher and clot firmness lower (p = 0.02) in those injured by explosion compared to GSW's.

Conclusions: ATC was present and correlated with shock, similar to civilian trauma. Thrombin generation remained adequate. Fibrinogen and factor V levels were disproportionately low but still sufficient to allow clot formation. Fibrinolysis is a key feature, probably due to a tissue plasminogen activator surge at the time of injury. Blast injuries are associated with a greater activation of fibrinolysis than GSWs.
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http://dx.doi.org/10.1111/trf.15658DOI Listing
June 2020

Pharmacological Agents Targeting Thromboinflammation in COVID-19: Review and Implications for Future Research.

Thromb Haemost 2020 Jul 30;120(7):1004-1024. Epub 2020 May 30.

Liverpool Centre for Cardiovascular Science, University of Liverpool and Liverpool Heart and Chest Hospital, Liverpool, United Kingdom.

Coronavirus disease 2019 (COVID-19), currently a worldwide pandemic, is a viral illness caused by the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). The suspected contribution of thrombotic events to morbidity and mortality in COVID-19 patients has prompted a search for novel potential options for preventing COVID-19-associated thrombotic disease. In this article by the Global COVID-19 Thrombosis Collaborative Group, we describe novel dosing approaches for commonly used antithrombotic agents (especially heparin-based regimens) and the potential use of less widely used antithrombotic drugs in the absence of confirmed thrombosis. Although these therapies may have direct antithrombotic effects, other mechanisms of action, including anti-inflammatory or antiviral effects, have been postulated. Based on survey results from this group of authors, we suggest research priorities for specific agents and subgroups of patients with COVID-19. Further, we review other agents, including immunomodulators, that may have antithrombotic properties. It is our hope that the present document will encourage and stimulate future prospective studies and randomized trials to study the safety, efficacy, and optimal use of these agents for prevention or management of thrombosis in COVID-19.
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http://dx.doi.org/10.1055/s-0040-1713152DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7516364PMC
July 2020

Haemoglobin oxygen affinity in patients with severe COVID-19 infection.

Br J Haematol 2020 08 28;190(3):e126-e127. Epub 2020 Jun 28.

School of Cardiovascular Medicine and Sciences, King's College London, London, UK.

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http://dx.doi.org/10.1111/bjh.16888DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7283631PMC
August 2020

Graduated compression stockings as adjuvant to pharmaco-thromboprophylaxis in elective surgical patients (GAPS study): randomised controlled trial.

BMJ 2020 May 13;369:m1309. Epub 2020 May 13.

Department of Surgery and Cancer, Imperial College London & Imperial Vascular Unit, Imperial College Healthcare NHS Trust, London W6 8RF, UK

Objectives: To investigate whether the use of graduated compression stockings (GCS) offers any adjuvant benefit when pharmaco-thromboprophylaxis is used for venous thromboembolism prophylaxis in patients undergoing elective surgery.

Design: Open, multicentre, randomised, controlled, non-inferiority trial.

Setting: Seven National Health Service tertiary hospitals in the United Kingdom.

Participants: 1905 elective surgical inpatients (≥18 years) assessed as being at moderate or high risk of venous thromboembolism were eligible and consented to participate.

Intervention: Participants were randomly assigned (1:1) to receive low molecular weight heparin (LMWH) pharmaco-thromboprophylaxis alone or LMWH pharmaco-thromboprophylaxis and GCS.

Outcome Measures: The primary outcome was imaging confirmed lower limb deep vein thrombosis with or without symptoms, or pulmonary embolism with symptoms within 90 days of surgery. Secondary outcome measures were quality of life, compliance with stockings and LMWH, lower limb complications related to GCS, bleeding complications, adverse reactions to LMWH, and all cause mortality.

Results: Between May 2016 and January 2019, 1905 participants were randomised. 1858 were included in the intention to treat analysis (17 were identified as ineligible after randomisation and 30 did not undergo surgery). A primary outcome event occurred in 16 of 937 (1.7%) patients in the LMWH alone group compared with 13 of 921 (1.4%) in the LMWH and GCS group. The risk difference between the two groups was 0.30% (95% confidence interval -0.65% to 1.26%). Because the 95% confidence interval did not cross the non-inferiority margin of 3.5% (P<0.001 for non-inferiority), LMWH alone was confirmed to be non-inferior.

Conclusions: For patients who have elective surgery and are at moderate or high risk of venous thromboembolism, administration of pharmaco-thromboprophylaxis alone is non-inferior to a combination of pharmaco-thromboprophylaxis and GCS. These findings indicate that GCS might be unnecessary in most patients undergoing elective surgery.

Trial Registration: ISRCTN13911492.
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http://dx.doi.org/10.1136/bmj.m1309DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7219517PMC
May 2020