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To date, the actual prevalence of acute pulmonary embolism (PE) in patients with SARS-CoV-2 infection remains unknown, as systematic screening for PE is cumbersome. We performed a systematic review and meta-analysis on autoptic data to estimate the prevalence of histopathologic findings of acute PE and its relevance as a cause of death on patients with COVID-19. We searched MEDLINE-PubMed and Scopus to locate all articles published in the English language, up to August 10, 2021, reporting the autoptic prevalence of acute PE and evaluating PE as the underlying cause of death in patients with COVID-19. The pooled prevalence for both outcomes was calculated using a random-effects model and presenting the related 95% confidence interval (CI). Statistical heterogeneity was measured using the Higgins I

BACKGROUND: ECG abnormalities in COVID-19 have been widely reported, however data after discharge is limited. The aim was to describe ECG abnormalities on admission and following recovery of COVID-19, and their associated mortality. METHODS: All patients hospitalized in a tertiary care hospital between March 7th and July 1st 2020 with COVID-19 were included in a retrospective registry. The first ECG on admission was collected, together with an ECG after hospital discharge in the absence of acute pathology. Automated measures and clinical ECG interpretations were collected. Multivariate Cox regression analysis was performed to predict 1-year all-cause mortality. RESULTS: In total 420 patients were included, of which 83 patients (19.8%) died during the 1-year follow-up period. Repolarization abnormalities were present in 189 patients (45.0%). The extent of repolarization abnormalities was an independent predictor of 1-year all-cause mortality (HR per region 1.30, 95%CI 1.04-1.64) together with age (/year HR 1.06, 95%CI 1.04-1.08), heart rate (/bpm HR 1.02, 95%CI 1.01-1.03), neurological disorders (HR 2.41, 95%CI 1.47-3.93), active cancer (HR 2.75, 95%CI 1.57-4.82), CRP (per 10 mg/L HR 1.05, 95%CI 1.02-1.08) and eGFR (per 10 mg/L HR 0.90, 95%CI 0.83-0.98).In 245 patients (68.1%) an ECG post discharge was available. New repolarization abnormalities were more frequent in patients who died after discharge (4.7% versus 41.7%, p

Objectives We review the evidence for tranexamic acid (TXA) for the treatment and prevention of bleeding caused by surgery, trauma and bleeding disorders. We highlight therapeutic areas where evidence is lacking and discuss safety issues, particularly the concern regarding thrombotic complications. Methods An electronic search was performed in PubMed and the Cochrane Library to identify clinical trials, safety reports and review articles. Findings TXA reduces bleeding in patients with menorrhagia, and in patients undergoing caesarian section, myomectomy, hysterectomy, orthopedic surgery, cardiac surgery, orthognathic surgery, rhinoplasty, and prostate surgery. For dental extractions in patients with bleeding disorders or taking antithrombotic drugs, as well as in cases of idiopathic epistaxis, tonsillectomy, liver transplantation and resection, nephrolithotomy, skin cancer surgery, burn wounds and skin grafting, there is moderate evidence that TXA is effective for reducing bleeding. TXA was not effective in reducing bleeding in traumatic brain injury and upper and lower gastrointestinal bleeding. TXA reduces mortality in patients suffering from trauma and postpartum hemorrhage. For many of these indications, there is no consensus about the optimal TXA dose. With certain dosages and with certain indications TXA can cause harm, such as an increased risk of seizures after high TXA doses with brain injury and cardiac surgery, and an increased mortality after delayed administration of TXA for trauma events or postpartum hemorrhage. Whereas most trials did not signal an increased risk for thrombotic events, some trials reported an increased rate of thrombotic complications with the use of TXA for gastro-intestinal bleeding and trauma. Conclusions TXA has well-documented beneficial effects in many clinical indications. Identifying these indications and the optimal dose and timing to minimize risk of seizures or thromboembolic events is work in progress.

The antifungal drug itraconazole exerts in vitro activity against SARS-CoV-2 in Vero and human Caco-2 cells. Preclinical and clinical studies are required to investigate if itraconazole is effective for the treatment and/or prevention of COVID-19.Due to the initial absence of preclinical models, the effect of itraconazole was explored in a clinical, proof-of-concept, open-label, single-center study, in which hospitalized COVID-19 patients were randomly assigned to standard of care with or without itraconazole. Primary outcome was the cumulative score of the clinical status until day 15 based on the 7-point ordinal scale of the World Health Organization. In parallel, itraconazole was evaluated in a newly established hamster model of acute SARS-CoV-2 infection and transmission, as soon as the model was validated.In the hamster acute infection model, itraconazole did not reduce viral load in lungs, stools or ileum, despite adequate plasma and lung drug concentrations. In the transmission model, itraconazole failed to prevent viral transmission. The clinical trial was prematurely discontinued after evaluation of the preclinical studies and because an interim analysis showed no signal for a more favorable outcome with itraconazole: mean cumulative score of the clinical status 49 vs 47, ratio of geometric means 1.01 (95% CI 0.85 to 1.19) for itraconazole vs standard of care.Despite in vitro activity, itraconazole was not effective in a preclinical COVID-19 hamster model. This prompted the premature termination of the proof-of-concept clinical study.KU Leuven, Research Foundation - Flanders (FWO), Horizon 2020, Bill and Melinda Gates Foundation.

Background Venous thromboembolism (VTE) is a frequent complication of COVID-19, so that the importance of adequate in-hospital thromboprophylaxis in patients hospitalized with COVID-19 is well established. However, the incidence of VTE after discharge and whether postdischarge thromboprophylaxis is beneficial and safe are unclear. In this prospective observational single-center study, we report the incidence of VTE 6 weeks after hospitalization and the use of postdischarge thromboprophylaxis. Methods Patients hospitalized with confirmed COVID-19 were invited to a multidisciplinary follow-up clinic 6 weeks after discharge. D-dimer and C-reactive protein were measured, and all patients were screened for deep vein thrombosis with venous duplex-ultrasound. Additionally, selected high-risk patients received computed tomography pulmonary angiogram or ventilation–perfusion (V/Q) scan to screen for incidental pulmonary embolism. Results Of 485 consecutive patients hospitalized from March through June 2020, 146 patients were analyzed, of which 39% had been admitted to the intensive care unit (ICU). Postdischarge thromboprophylaxis was prescribed in 28% of patients, but was used more frequently after ICU stay (61%) and in patients with higher maximal D-dimer and C-reactive protein levels during hospitalization. Six weeks after discharge, elevated D-dimer values were present in 32% of ward and 42% of ICU patients. Only one asymptomatic deep vein thrombosis (0.7%) and one symptomatic pulmonary embolism (0.7%) were diagnosed with systematic screening. No bleedings were reported. Conclusion In patients who had been hospitalized with COVID-19, systematic screening for VTE 6 weeks after discharge revealed a low incidence of VTE. A strategy of selectively providing postdischarge thromboprophylaxis in high-risk patients seems safe and potentially effective.

Background: The antifungal drug itraconazole exerts in vitro activity against SARS-CoV-2 in Vero and human Caco-2 cells. Preclinical and clinical studies are required to investigate if itraconazole is effective for the treatment and/or prevention of COVID-19.Methods: Due to the initial absence of preclinical models, the effect of itraconazole was explored in a clinical, proof-of-concept, open-label, single-center study, in which hospitalized COVID-19 patients were randomly assigned to standard of care with or without itraconazole. Primary outcome was the cumulative score of the clinical status until day 15 based on the 7-point ordinal scale of the World Health Organization. In parallel, itraconazole was evaluated in a newly established hamster model of acute SARS-CoV-2 infection and transmission, as soon as the model was validated.Findings: In the hamster acute infection model, itraconazole did not reduce viral load in lungs, stools or ileum, despite adequate plasma and lung drug concentrations. In the transmission model, itraconazole failed to prevent viral transmission. The clinical trial was prematurely discontinued after evaluation of the preclinical studies and because an interim analysis showed no signal for a more favorable outcome with itraconazole: mean cumulative score of the clinical status 49 vs 47, ratio of geometric means 1.01 (95% CI 0.85 to 1.19) for itraconazole vs standard of care.Interpretation: Despite in vitro activity, itraconazole was not effective in a preclinical COVID-19 hamster model. This prompted the premature termination of the proof-of-concept clinical study. (C) 2021 The Authors. Published by Elsevier B.V. This project has received funding from the Covid-19-Fund KU Leuven / University Hospitals Leuven, the COVID-19 call of the Research Foundation - Flanders (FWO) (grant G0G4820N), the European Union's Horizon 2020 research and innovation program (Grant 101003627, Swift COronavirus therapeutics REsponse project) and the Bill and Melinda Gates Foundation (Grant INV-00636). LLi is member of the Institute of Tropical Medicine's Outbreak Research Team which is financially supported by the Department of Economy, Science and Innovation (EWI) of the Flemish government. BV is supported by a research grant of the Frans Van de Werf Fund for Clinical Cardiovascular Research. P. Verhamme, TV, P. Vermeersch are senior clinical investigators of the FWO. We thank Johnson & Johnson for determining drug concentrations in hamster samples and for providing guidance on the dosing. We thank Lindsey Bervoets, Carolien De Keyzer, Elke Maas and Jasper Rymentants for the technical support with the animal experiments.

Introduction Contact of blood with artificial surfaces such as mechanical support devices, catheters, and mechanical heart valves activates the contact activation (CA) pathway of coagulation. Furthermore, recent animal data and clinical studies suggest a more important contribution of CA in pathological thrombus formation in other cardiovascular diseases. Direct oral anticoagulants (DOACs) are recommended as first-line treatment in most patients who require long-term anticoagulation. However, because DOACs directly inhibit a single downstream coagulation factor (thrombin (fXIIa) or factor Xa (fXa)), it has been suggested that their efficacy could be reduced in the presence of strong activation of the CA pathway as compared to anticoagulants that target multiple, more upstream located coagulation factors. Purpose To compare the efficacy of a DOAC (apixaban) and heparin to suppress thrombin generation in the presence of strong CA pathway activation. Methods Pooled platelet-poor plasma was spiked with either apixaban (dissolved in DMSO and PBS) or unfractionated heparin to achieve therapeutic plasma levels. SynthASil, a commercially available mixture of phospholipids and silica, was used to stimulate the CA pathway in two different dilutions (1–80 and 5–80). Downstream coagulation was accessed by Thrombin Generation Test using Thrombinoscope by Stago and associated Thrombin Calibrator (activity 640 nM). The endogenous thrombin potential (area under the thrombin generation curve; ETP), peak thrombin generation (PTG), time to peak (ttPeak) and time to start (ttStart) were accessed. Results With decreasing concentrations of apixaban, stimulation with the lower dose SynthASil reveals an increasing ETP and PTG. As expected, ttPeak and ttStart decreased. Even supratherapeutic levels of apixaban (i.e. 1120 ng/mL) could not inhibit thrombin from being generated, in striking contrast with UFH where no thrombin was formed. Using a five times higher dose of SynthASil showed comparable ETP for all concentrations of apixaban, allocated around the control value. PTG, however, slightly increased with decreasing concentrations of apixaban. ttPeak and ttStart slightly decreased. Except for the subtherapeutic UFH concentration of 0,114 IU/mL, no thrombin was generated with UFH. Conclusion UFH is more effective in inhibiting downstream thrombin generation compared to apixaban as a response to activation of the CA pathway in vitro. These findings could help explain why direct inhibitors were not able to show non-inferiority in patients with mechanical heart valves and support the development of specific CA pathway inhibitors for patients with conditions that activate the CA pathway. Thrombin generation curves Funding Acknowledgement Type of funding source: None

Background Bleeding is a main cause of morbidity and mortality in critically ill cardiogenic shock patients, supported by short-term percutaneous mechanical circulatory support (pMCS) devices. Bleeding not only occurs because of obligatory heparin and antiplatelet therapy (both required in the prevention of pump and stent thrombosis) but possibly also results from device-related coagulopathy. Similar to long-term ventricular assist devices, mechanical shear-induced acquired von Willebrand syndrome (AVWS) might further increase the bleeding risk. Therefore, we aimed to investigate the effect of left Impella percutaneous continuous flow pumps on the development of AVWS due to shear-induced excessive cleavage of large vWF multimers by the metalloproteinase ADAMTS-13, resulting in loss of high-molecular-weight vWF multimers. Methods Between March 2019 and January 2020, all cardiogenic shock patients supported by a left Impella and referred to a single tertiary ICU were studied. Both vWF Antigen (vWF:Ag) and vWF:GPIbR (ristocetin-induced binding of vWF to a recombinant wildtype Glycoprotein Ib fragment) levels were measured by chemiluminescent immunoassays using an AcuStar (Werfen) assay to determine the vWF:GPIbR /vWF:Ag ratio (normal range ≥1.0). VWF multimer analysis was performed by electrophoresis. On-pump analyses were performed 12h after implantation and off-pump analyses 12h after Impella explantation. Patients who died on-pump were excluded because of lack of paired data after explantation. Results Eight left Impella patients (four Impella CP, four Impella 5.0) were analyzed for AVWS. The vWF:GPIbR /vWF:Ag ratio was Conclusions Our data highlight the rapid onset and reversal of AVWS in all studied cardiogenic shock patients, supported by a left Impella pump. The determination of the GPIbR /vWF:Ag ratio with the AcuStar appears a reliable and faster test to detect AVWS as compared to vWF multimers electrophoresis. Further research into innovative pharmacological interventions (e.g. ADAMTS-13 inhibitors) should target pMCS-induced AVWS in an effort to reduce hemostatic complications in this critically ill ICU population. AVWS in Impella supported patients Funding Acknowledgement Type of funding source: None

Background: Drug repurposing is an attractive strategy to rapidly develop affordable therapy against COVID-19. The antifungal drug itraconazole exerts in vitro activity against SARS-CoV-2 comparable to that of hydroxychloroquine. Preclinical and clinical studies are required to investigate if itraconazole is effective for the treatment and/or prevention of COVID-19. Methods: Due to the initial absence of preclinical models the effect of itraconazole was explored in a clinical, proof-of-concept, open-label, single-center study, in which hospitalized patients with COVID-19 were randomly assigned to receive standard of care with or without itraconazole. The primary outcome was the cumulative score of the clinical status until day 15 based on the 7-point ordinal scale of the World Health Organization. Other outcomes included time to sustained clinical improvement, duration of supplemental oxygen and evolution of nasopharyngeal viral load. In parallel, itraconazole was evaluated in a newly established hamster model of acute SARS-CoV-2 infection and transmission, as soon as the model was validated. Findings: In the hamster acute infection model, itraconazole did not reduce viral load in lungs, stools or ileum, despite adequate plasma and lung drug concentrations. In the transmission model, itraconazole failed to prevent viral transmission. The clinical trial was prematurely discontinued after evaluation of the preclinical studies and interim analysis that showed no trends for a more favorable outcome with itraconazole: mean cumulative score of the clinical status 49 vs 47, ratio of geometric means 1.01 (95% CI 0.85 to 1.19), median time to clinical improvement 10 vs 9 days, hazard ratio 0.94 (95% CI 0.56 to 1.60) for itraconazole vs standard of care. Interpretation: Despite in vitro activity, itraconazole was not effective in a preclinical COVID-19 hamster model. A proof-of-concept clinical study was ended prematurely because of futility. Trial Registration: (EudraCT 2020-001243-15) Funding: Covid-19-Fund KU Leuven, Research Foundation - Flanders (FWO), Horizon 2020, Bill and Melinda Gates Foundation Declaration of Interests: Initial dug screening and discovery of the antiviral effect of itraconazole was done in collaboration with Johnson & Johnson and described in a separate manuscript. Scientists from Johnson & Johnson also performed drug measurements on hamster samples and provided guidance on the dosing regimens for the preclinical studies. The company had no role in the design, execution, analysis, publication or funding of the clinical trial. Author Conflict of Interests: None to declare. Ethics Approval Statement: The institutional Ethical Committee approved all animal experiments (license P065-2020). The study was conducted in accordance with the International Conference on Harmonization Guidelines for Good Clinical Practice and the Declaration of Helsinki. The protocol was approved by the institutional Ethics Committee and by the Belgian Federal Agency for Medicines and Health Products (EudraCT 2020-001243-15). The trial was part of the DAWn clinical studies.

Background Thrombolytic therapy is used as a lifesaving treatment for a broad range of acute thrombotic events. The role of thrombolysis for its various indications has rapidly evolved. Purpose To provide a contemporary overview of current indications and outcome of thrombolytic therapy in clinical practice. Methods This retrospective single-center study analyzed indications, complications and short-term mortality of systemic thrombolytic therapy between 2010 and 2016 in a university hospital, totaling 763 cases. Major bleedings were defined using criteria published by the International Society on Thrombosis and Haemostasis (ISTH). Results Thrombolytic drugs were mostly used for ischemic strokes (66.6%) and peripheral arterial disease (16.9%). Acute coronary syndrome only represented a minority of cases (in this PCI-center). Overall seven- and thirty-day-mortality were 7.3% and 12.0%, respectively. Major bleeding occurred in 8.3% of patients and was fatal in 0.9% of all patients. Both major bleeding and mortality differed by the indication for thrombolysis. Thrombolytic therapy for pulmonary embolism and peripheral arterial disease were associated with the highest rates of major bleeding, 28.6% and 23.3% respectively. Short-term mortality was highest in patients receiving thrombolysis for pulmonary embolism. Predictors for major bleeding included use of antiplatelet and anticoagulation drugs prior to thrombolysis. Major bleedings, age and concomitant anticoagulation were associated with lower survival rates. Indications in absolute numbers – 2010 – – 2011 – – 2012 – – 2013 – – 2014 – – 2015 – – 2016 – Ischemic Stroke 56 63 66 57 96 88 82 Peripheral Arterial Disease 21 23 21 28 14 16 6 Pulmonary Embolism 4 9 10 10 5 8 8 Deep Vein Thrombosis 2 1 2 0 2 3 3 Acute Coronary Syndrome 0 1 0 1 0 0 0 Mechanical Heart Valve Thrombosis 1 3 3 1 2 7 1 Other 5 8 3 10 2 5 6 TOTAL 89 108 105 107 121 127 106 Mortality and major bleeding in % Conclusion The use of thrombolytic therapy has evolved, with stroke now being the most frequent indication. Mortality and bleeding rates are significant and vary considerably per indication. Major bleedings, age and maintenance anticoagulant therapy were risk factors associated with lower survival rates, but the underlying disease and patient population seem to play a major role in survival as well.