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Abstract Background The peak of the global COVID-19 pandemic has not yet been reached, and many countries face the prospect of a second wave of infections before effective vaccinations will be available. After an initial phase of viral replication, some patients develop a second illness phase in which the host thrombotic and inflammatory responses seem to drive complications. Severe COVID-19 disease is linked to high mortality, hyperinflammation, and a remarkably high incidence of thrombotic events. We hypothesize a crucial pathophysiological role for the contact pathway of coagulation and the kallikrein-bradykinin pathway. Therefore, drugs that modulate this excessive thromboinflammatory response should be investigated in severe COVID-19. Methods In this adaptive, open-label multicenter randomized clinical trial, we compare low molecular weight heparins at 50 IU anti-Xa/kg twice daily—or 75 IU anti-Xa twice daily for intensive care (ICU) patients—in combination with aprotinin to standard thromboprophylaxis in hospitalized COVID-19 patients. In the case of hyperinflammation, the interleukin-1 receptor antagonist anakinra will be added on top of the drugs in the interventional arm. In a pilot phase, the effect of the intervention on thrombotic markers (D-dimer) will be assessed. In the full trial, the primary outcome is defined as the effect of the interventional drugs on clinical status as defined by the WHO ordinal scale for clinical improvement. Discussion In this trial, we target the thromboinflammatory response at multiple levels. We intensify the dose of low molecular weight heparins to reduce thrombotic complications. Aprotinin is a potent kallikrein pathway inhibitor that reduces fibrinolysis, activation of the contact pathway of coagulation, and local inflammatory response. Additionally, aprotinin has shown in vitro inhibitory effects on SARS-CoV-2 cellular entry. Because the excessive thromboinflammatory response is one of the most adverse prognostic factors in COVID-19, we will add anakinra, a recombinant interleukin-1 receptor antagonist, to the regimen in case of severely increased inflammatory parameters. This way, we hope to modulate the systemic response to SARS-CoV-2 and avoid disease progressions with a potentially fatal outcome. Trial registration The EU Clinical Trials Register 2020-001739-28 . Registered on April 10, 2020.

An amendment to this paper has been published and can be accessed via the original article.

Evaluation of treatment outcomes in patients supported by temporary mechanical circulatory support (tMCS) currently relies mainly on mortality, which may not sufficiently address other patient benefits or harms. Bleeding and thrombosis are major contributors to mortality. Still, current bleeding scores are not designed for critically ill patients undergoing tMCS, only consider selected populations, and do not account for the high heterogeneity among bleeding and thrombotic adverse events. To improve clinical management, a group of European experts has proposed a revised scoring system based on the MOMENTUM 3 Hemocompatibility Score and the Society of Cardiac Angiography and Interventions (SCAI)classification of cardiogenic shock. The new system termed the Scoring Haemostasis Events and Assessment for Risk (SHEAR) score, is divided into a baseline characterization stage and four escalating scoring stages encompassing all aspects of clinical relevance. This report summarizes the literature on hemocompatibility-related adverse events associated with tMCS, including bleeding, stroke, vascular access complications, hemolysis, thrombosis, and device failure. The SHEAR score provides a simple and rapid bedside scoring system aiming to provide a univocal tool to increase physician awareness of hemocompatibility complications at baseline and beyond, improve clinical research, and enable the capture of device-related complications that will inform relevant outcomes beyond mortality., Competing Interests: Declaration of competing interest The authors declare the following financial interests and/or personal relationships that may be considered potential competing interests: All authors received honoraria from Abiomed., (Copyright © 2024 Elsevier Inc. All rights reserved.)

Aims: Bleeding and thrombotic complications compromise outcomes in patients undergoing percutaneous mechanical circulatory support (pMCS) with veno-arterial extracorporeal membrane oxygenation (V-A ECMO) and/or microaxial flow pumps like Impella™. Antithrombotic practices are an important determinant of the coagulopathic risk, but standardization in the antithrombotic management during pMCS is lacking. This survey outlines European practices in antithrombotic management in adults on pMCS, making an initial effort to standardize practices, inform future trials, and enhance outcomes., Methods and Results: This online cross-sectional survey was distributed through digital newsletters and social media platforms by the Association of Acute Cardiovascular Care and the European branch of the Extracorporeal Life Support Organization. The survey was available from 17 April 2023 to 23 May 2023. The target population were European clinicians involved in care for adults on pMCS. We included 105 responses from 26 European countries. Notably, 72.4% of the respondents adhered to locally established anticoagulation protocols, with unfractionated heparin (UFH) being the predominant anticoagulant (Impella™: 97.0% and V-A ECMO: 96.1%). A minority of the respondents, 10.8 and 14.5%, respectively, utilized the anti-factor-Xa assay in parallel with activated partial thromboplastin time for UFH monitoring during Impella™ and V-A ECMO support. Anticoagulant targets varied across institutions. Following acute coronary syndrome without percutaneous coronary intervention (PCI), 54.0 and 42.7% were administered dual antiplatelet therapy during Impella™ and V-A ECMO support, increasing to 93.7 and 84.0% after PCI., Conclusion: Substantial heterogeneity in antithrombotic practices emerged from participants' responses, potentially contributing to variable device-associated bleeding and thrombotic complications., Competing Interests: Conflict of interest: None declared., (© The Author(s) 2024. Published by Oxford University Press on behalf of the European Society of Cardiology. All rights reserved. For commercial re-use, please contact reprints@oup.com for reprints and translation rights for reprints. All other permissions can be obtained through our RightsLink service via the Permissions link on the article page on our site—for further information please contact journals.permissions@oup.com.)

Rationale: The influence of the lung bacterial microbiome, including potential pathogens, in patients with influenza- or COVID-19-associated pulmonary aspergillosis (IAPA or CAPA) is yet to be explored., Objectives: To explore the composition of the lung bacterial microbiome and its association with viral and fungal infection, immunity and outcome in severe influenza versus COVID-19 with or without aspergillosis., Methods: We performed a retrospective study in mechanically ventilated influenza and COVID-19 patients with or without invasive aspergillosis in whom bronchoalveolar lavage (BAL) for bacterial culture (with or without PCR) was obtained within two weeks after ICU admission. Additionally, 16S rRNA gene sequencing data and viral and bacterial load of BAL samples from a subset of these patients, and of patients requiring non-invasive ventilation, were analyzed. We integrated 16S rRNA gene sequencing data with existing immune parameter datasets., Measurements and Main Results: Potential bacterial pathogens were detected in 20% (28/142) of influenza and 37% (104/281) of COVID-19 patients, while aspergillosis was detected in 38% (54/142) of influenza and 31% (86/281) of COVID-19 patients. A significant association between bacterial pathogens in BAL and 90-day mortality was found only in influenza patients, particularly IAPA patients. COVID-19 but not influenza patients showed increased pro-inflammatory pulmonary cytokine responses to bacterial pathogens., Conclusions: Aspergillosis is more frequently detected in lungs of severe influenza patients than bacterial pathogens. Detection of bacterial pathogens associates with worse outcome in influenza patients, particularly in those with IAPA, but not in COVID-19 patients. The immunological dynamics of tripartite viral-fungal-bacterial interactions deserve further investigation. This article is open access and distributed under the terms of the Creative Commons Attribution Non-Commercial No Derivatives License 4.0 (http://creativecommons.org/licenses/by-nc-nd/4.0/).

Competing Interests: Financial/Nonfinancial Disclosures None declared.

Background: Observational data suggest that the subset of patients with heart failure related CS (HF-CS) now predominate critical care admissions for CS. There are no dedicated HF-CS randomised control trials completed to date which reliably inform clinical practice or clinical guidelines. We sought to identify aspects of HF-CS care where both consensus and uncertainty may exist to guide clinical practice and future clinical trial design, with a specific focus on HF-CS due to acute decompensated chronic HF., Methods: A 16-person multi-disciplinary panel comprising of international experts was assembled. A modified RAND/University of California, Los Angeles, appropriateness methodology was used. A survey comprising of 34 statements was completed. Participants anonymously rated the appropriateness of each statement on a scale of 1 to 9 (1-3 as inappropriate, 4-6 as uncertain and as 7-9 appropriate)., Results: Of the 34 statements, 20 were rated as appropriate and 14 were rated as inappropriate. Uncertainty existed across all three domains: the initial assessment and management of HF-CS; escalation to temporary Mechanical Circulatory Support (tMCS); and weaning from tMCS in HF-CS. Significant disagreement between experts (deemed present when the disagreement index exceeded 1) was only identified when deliberating the utility of thoracic ultrasound in the immediate management of HF-CS., Conclusion: This study has highlighted several areas of practice where large-scale prospective registries and clinical trials in the HF-CS population are urgently needed to reliably inform clinical practice and the synthesis of future societal HF-CS guidelines., (© 2024. The Author(s).)

Background: Impella™ is increasingly used in cardiogenic shock. However, thromboembolic and bleeding events are frequent during percutaneous mechanical circulatory support (pMCS)., Objective: Therefore, we aimed to explore the optimal anticoagulation regime for pMCS to prevent thromboembolism and bleedings., Methods: This hypothesis-generating multi-center cohort study investigated 170 patients with left-Impella™ support. We (A) compared bleeding/thrombotic events in two centers with therapeutic range (TR-aPTT) activated partial thromboplastin time (60-80s) and (B) compared events of these centers with one center with intermediate range aPTT (40-60s)., Results: After matching, there were no differences in patients' characteristics. In centers aiming at TR-aPTT, major bleeding was numerically lower with aPTT <60s within 48 h of left-Impella™ support, versus patients that achieved the aimed aPTT of ≥60s [aPTT ≥60s: 22 (37.3%) vs. aPTT<60s 14 (23.7%); Hazard ratio [HR], 0.62 (95%) CI, 0.28-1.38; p = 0.234]. Major cardiovascular and cerebrovascular adverse events (MACCE) did not differ between groups. In comparison of centers, TR-aPTT strategy showed higher major bleeding rates [TR: 8 (47.1%) vs. intermediate range: 1 (5.9%); HR, 0.06 (95%) CI, 0.01-0.45; p = 0.006]. MACCE were lower in the intermediate range aPTT group as well [TR 12 (70.6%) vs. intermediate range 5 (29.4%) HR, 0.32 (95%) CI, 0.11-0.92; p = 0.034]., Conclusion: This pilot analysis showed that lowering UFH-targets in left-Impella™ supported CS patients seems to be a safe and promising strategy for reducing major bleedings without increasing MACCE. This needs to be validated in larger, randomized clinical trials., Competing Interests: Declaration of competing interest Christophe Vandenbriele, Tim Balthazar, Bart Meyns and Ralf Westenfeld received training and research grants from Abiomed (USA). The remaining authors have nothing to disclose., (Copyright © 2023 Elsevier B.V. All rights reserved.)

We present a protocol for the rapid postmortem bedside procurement of selected tissue samples using an endoscopic endonasal surgical technique that we adapted from skull base surgery. We describe steps for the postmortem collection of blood, cerebrospinal fluid, a nasopharyngeal swab, and tissue samples; the clean-up procedure; and the initial processing and storage of the samples. This protocol was validated with tissue samples procured postmortem from COVID-19 patients and can be applied in another emerging infectious disease. For complete details on the use and execution of this protocol, please refer to Khan et al. (2021) 1 and Khan et al. (2022). 2 ., Competing Interests: Declaration of interests The authors declare no competing interests., (Copyright © 2023 The Author(s). Published by Elsevier Inc. All rights reserved.)

Background: COVID-19-associated pulmonary aspergillosis (CAPA) is a severe superinfection with the fungus Aspergillus affecting patients who are critically ill with COVID-19. The pathophysiology and the role of neutrophil extracellular traps (NETs) in this infection are largely unknown. We aimed to characterise the immune profile, with a focus on neutrophils and NET concentrations, of critically ill patients with COVID-19, with or without CAPA., Methods: We conducted a single-centre, retrospective, observational study in two patient cohorts, both recruited at University Hospitals Leuven, Belgium. We included adults aged 18 years or older who were admitted to the intensive care unit because of COVID-19 between March 31, 2020, and May 18, 2021, and who were included in the previous Contagious trial (NCT04327570). We investigated the immune cellular landscape of CAPA versus COVID-19 only by performing single-cell RNA sequencing (scRNA-seq) on bronchoalveolar lavage fluid. Bronchoalveolar lavage immune cell fractions were compared between patients with CAPA and patients with COVID-19 only. Additionally, we determined lower respiratory tract NET concentrations using biochemical assays in patients aged 18 years and older who were admitted to the intensive care unit because of severe COVID-19 between March 15, 2020, and Dec 31, 2021, for whom bronchoalveolar lavage was available in the hospital biobank. Bronchoalveolar lavage NET concentrations were compared between patients with CAPA and patients with COVID-19 only and integrated with existing data on immune mediators in bronchoalveolar lavage and 90-day mortality., Findings: We performed scRNA-seq of bronchoalveolar lavage on 43 samples from 39 patients, of whom 36 patients (30 male and six female; 14 with CAPA) were included in downstream analyses. We performed bronchoalveolar lavage NET analyses in 59 patients (46 male and 13 female), of whom 26 had CAPA. By scRNA-seq, patients with CAPA had significantly lower neutrophil fractions than patients with COVID-19 only (16% vs 33%; p=0·0020). The remaining neutrophils in patients with CAPA preferentially followed a hybrid maturation trajectory characterised by expression of genes linked to antigen presentation, with enhanced transcription of antifungal effector pathways. Patients with CAPA also showed depletion of mucosal-associated invariant T cells, reduced T helper 1 and T helper 17 differentiation, and transcriptional defects in specific aspects of antifungal immunity in macrophages and monocytes. We observed increased formation of NETs in patients with CAPA compared with patients with COVID-19 only (DNA complexed with citrullinated histone H3 median 15 898 ng/mL [IQR 4588-86 419] vs 7062 ng/mL [775-14 088]; p=0·042), thereby explaining decreased neutrophil fractions by scRNA-seq. Low bronchoalveolar lavage NET concentrations were associated with increased 90-day mortality in patients with CAPA., Interpretation: Qualitative and quantitative disturbances in monocyte, macrophage, B-cell, and T-cell populations could predispose patients with severe COVID-19 to develop CAPA. Hybrid neutrophils form a specialised response to CAPA, and an adequate neutrophil response to CAPA is a major determinant for survival in these patients. Therefore, measuring bronchoalveolar lavage NETs could have diagnostic and prognostic value in patients with CAPA. Clinicians should be wary of aspergillosis when using immunomodulatory therapy that might inhibit NETosis to treat patients with severe COVID-19., Funding: Research Foundation Flanders, KU Leuven, UZ Leuven, VIB, the Fundação para a Ciência e a Tecnologia, the European Regional Development Fund, la Caixa Foundation, the Flemish Government, and Horizon 2020., Competing Interests: Declaration of interests SF received travel grants from Pfizer and Gilead and a speaker fee from The Healthbook Company. GH received travel fees from Eurosets. YD received travel grants from Pfizer and declares participation in advisory boards of Pfizer and MSD. KL received consultancy fees from MRM Health and Mundipharma, speaker fees and travel support from Pfizer and Gilead, and service fees from Thermo Fisher Scientific and TECOmedical. MP received travel fees from Pfizer. LV received travel fees from Gilead Sciences and Pfizer. KM received royalties to patent numbers US10617742B2, US11400139B2 in relation to the Children’s Hospital Corporation, reports fees for scientific advice to and stock options in Peel Therapeutics, and reports being an inventor on granted US patent numbers US9642822B2 (issued), US11400139B2 (issued), and US11426405B2 (issued). JW received an institutional research fund from Pfizer; received investigator-initiated grants from Pfizer, Gilead, and MSD; received speakers’ and travel fees from Pfizer, Gilead, and MSD; declares participation in advisory boards of Pfizer and Gilead; and declares receipt of study drugs from MSD. All other authors declare no competing interests., (Copyright © 2023 The Author(s). Published by Elsevier Ltd.. All rights reserved.)

Competing Interests: Drs Dauwe and Vandenbriele have reported receiving research and travel funding and speaker fees from Abiomed outside of this article. The other authors report no conflicts.

Background: Coronavirus disease 2019 (COVID-19)-associated pulmonary aspergillosis (CAPA) is a frequent superinfection in critically ill patients with COVID-19 and is associated with increased mortality rates. The increasing proportion of severely immunocompromised patients with COVID-19 who require mechanical ventilation warrants research into the incidence and impact of CAPA during the vaccination era., Methods: We performed a retrospective, monocentric, observational study. We collected data from adult patients with severe COVID-19 requiring mechanical ventilation who were admitted to the intensive care unit (ICU) of University Hospitals Leuven, a tertiary referral center, between 1 March 2020 and 14 November 2022. Probable or proven CAPA was diagnosed according to the 2020 European Confederation for Medical Mycology/International Society for Human and Animal Mycology (ECMM/ISHAM) criteria., Results: We included 335 patients. Bronchoalveolar lavage sampling was performed in 300 (90%), and CAPA was diagnosed in 112 (33%). The incidence of CAPA was 62% (50 of 81 patients) in European Organisation for Research and Treatment of Cancer (EORTC)/Mycosis Study Group Education and Research Consortium (MSGERC) host factor-positive patients, compared with 24% (62 of 254) in host factor-negative patients. The incidence of CAPA was significantly higher in the vaccination era, increasing from 24% (57 of 241) in patients admitted to the ICU before October 2021 to 59% (55 of 94) in those admitted since then. Both EORTC/MSGERC host factors and ICU admission in the vaccination era were independently associated with CAPA development. CAPA remained an independent risk factor associated with mortality risk during the vaccination era., Conclusions: The presence of EORTC/MSGERC host factors for invasive mold disease is associated with increased CAPA incidence and worse outcome parameters, and it is the main driver for the significantly higher incidence of CAPA in the vaccination era. Our findings warrant investigation of antifungal prophylaxis in critically ill patients with COVID-19., Competing Interests: Potential conflicts of interest. S. F. and L. V. report PhD funding from the Research Foundation–Flanders (FWO; grants 11M6922N and 11E9819N). S. F. reports receipt of travel grants from Pfizer and Gilead and speaker fees from Healthbook. K. L. received consultancy fees from MRM Health, Merck Sharp and Dohme (MSD), and Mundipharma, speaker fees and travel support from Pfizer and Gilead, and a service fee from Thermo Fisher Scientific and TECOmedical and participated on an advisory board for MSD. Y. D. received travel grants from Pfizer (travel/congress attendance support) and declares participation on advisory boards for Pfizer and MSD. G. H. and R. V. are senior clinical research fellows of FWO. G. H. received travel fees from Eurosets for the 2023 Extracorporeal Life Support Organization meeting. M. H. received grants from Astellas, Gilead, MSD, Pfizer, Euroimmun, IMMY, Mundipharma, F2G, Pulmocide, and Scynexis and research funding from Gilead Sciences, Astellas, Mundipharma, Euroimmun, MSD, Pulmocide, IMMY, Scynexis, F2G, and Pfizer. J. M. received grants from Bio-Rad, Gilead Sciences, MSD, F2G, Mundipharma, and Pfizer; personal fees and nonfinancial support from Astellas, Basilea, Gilead Sciences, MSD, F2G, Mundipharma, and Pfizer; and personal fees from Bio-Rad. M. P. received travel fees from Pfizer (March 2023; registration for the 2023 International Symposium on Intensive Care & Emergency Medicine (ISICEM) in Brussels, Belgium). I. S. received funding from the Clinical Research Fund, University Hospitals Leuven, investigator-initiated grants from Pfizer, and speaker and travel fees from Pfizer, Gilead, and MSD, and reports participation on an advisory board for Pfizer and Gilead, and receipt of study drugs from MSD. L. V. received support for public doctoral defense from Pfizer and travel fees for conference attendance from Gilead Sciences and Pfizer and reports a PhD fellowship (grant 11E9819N) from FWO. R. V. reports an FWO fellowship and grant (grant G060322N). E. V. W. received travel fees from Gilead (for travel, hotel, and registration). J. W. received investigator-initiated grants from Pfizer, Gilead, and MSD and speaker and travel fees from Pfizer, Gilead, and MSD, and declares participation on advisory boards of Pfizer and Gilead and receipt of study drugs from MSD. J. W. also reports funding from the European Union's Horizon 2020 research and innovation program (grant 847507 HDM-FUN) and FWO project funding (grant G053121N). All other authors report no potential conflicts. All authors have submitted the ICMJE Form for Disclosure of Potential Conflicts of Interest. Conflicts that the editors consider relevant to the content of the manuscript have been disclosed., (© The Author(s) 2023. Published by Oxford University Press on behalf of Infectious Diseases Society of America.)

Cardiogenic shock (CS) is a life-threatening condition characterized by a state of inadequate systemic tissue perfusion caused by cardiac dysfunction. When to implement, change, or remove the use of a temporary mechanical circulatory support (tMCS) in patients with CS is dependent on the aetiology and severity. Here, patient scenarios underlying the need to escalate, de-escalate, wean, or bridge from tMCS devices are taken into consideration by interdisciplinary heart failure and CS teams. This includes a comprehensive review of and focus on the rationale for specific device escalation and de-escalation strategies, device selection, and general management., Competing Interests: Conflict of interest: A.M.B. has received consulting fees from Abbott, Abiomed, AstraZeneca, Berlin Heart, FineHeart, Medtronic, and Novartis. E.P. has received received manuscript support from Abiomed and Abbot; grant support and consulting fees from Abiomed, Abbott, Medtronic, and Recovery Therapeutics; has received honoraria and travel and speaker fees from Abiomed, Abbott, and Medtronic; and has attended the advisory board meetings of Abbott and Medtronic. C.V. has received manuscript support, honoraria, and travel support from Abiomed. C.S. has received payment or honoraria from Abiomed. L.F.B. has received honoraria from Abiomed. F.P. has received manuscript support, consulting fees, and honoraria from Abiomed and has attended the advisory board meetings of Abiomed., (© The Author(s) 2023. Published by Oxford University Press on behalf of the European Society of Cardiology.)

Monitoring of the patient supported with a temporary mechanical circulatory support (tMCS) is crucial in achieving the best possible outcome. Monitoring is a continuous and labour-intensive process, as cardiogenic shock (CS) patients can rapidly deteriorate and may require new interventions within a short time period. Echocardiography and invasive haemodynamic monitoring form the cornerstone of successful tMCS support. During monitoring, it is particularly important to ensure that adequate end-organ perfusion is achieved and maintained. Here, we provide a comprehensive overview of best practices for monitoring the CS patient supported by a micro-axial flow pump, veno-arterial extracorporeal membrane oxygenation, and both devices simultaneously (ECMELLA approach). It is a complex process that encompasses device control, haemodynamic control and stabilization, monitoring of interventions, and assessment of end-organ function. The combined, continuous, and preferably protocol-based approach of echocardiography, evaluation of biomarkers, end-organ assessment, and haemodynamic parameters is crucial in assessing this critically ill CS patient population., Competing Interests: Conflict of interest: C.V. received manuscript support from Abiomed, honoraria from Abiomed, and travel support from Abiomed. C.V. is supported by a research grant of the FWO-flanders (FKM 1803923N). J.B. is on a board for AstraZeneca and BoehringerIngelheim and received consulting fees from Abiomed, Getinge, Resuscitec, and Xenios. C.H. has received research grants from Novo Nordisk Foundation, Lundbeck Foundation, and Danish Heart Foundation and honoraria from Abiomed and is in an unpaid leadership role as Chair of the Danish Heart Foundation and board member of ESC. M.P. has received manuscript preparation support, consulting fees, and honoraria from Abiomed. A.P. has received manuscript preparation support from Abiomed, a research grant from the German Research Council, and honoraria from Abbott, Bayer, Bristol-Myers Squibb, Pfizer, Daiichi, and Medtronic. M.S. reports no disclosures or conflicts of interest. J.E.M. has received grants from Abiomed and Novo Nordic, honoraria from Abiomed, Boehringer Ingelheim, Abbott, and Orion, and travel support from Abiomed., (© The Author(s) 2023. Published by Oxford University Press on behalf of the European Society of Cardiology.)

COVID-19 is associated with an increased risk for thrombotic complications. The trials investigating the optimal thromboprophylactic dose are performed in challenging times and seemingly produce conflicting evidence. The burdensome circumstances, divergent endpoints, and different analytical approaches hamper comparison and extrapolation of available evidence. Most importantly, clinicians should provide thromboprophylaxis in hospitalized COVID-19 patients while (re)assessing bleeding and thrombotic risk frequently. The COVID-19 Thromboprophylaxis Working Group of the BSTH updated its guidance document. It aims to summarize the available evidence critically and to guide clinicians in providing the best possible thromboprophylaxis.

Conventional dual antiplatelet therapy (DAPT) for patients with acute coronary syndromes undergoing percutaneous coronary intervention comprises aspirin with a potent P2Y purinoceptor 12 (P2Y 12 ) inhibitor (prasugrel or ticagrelor) for 12 months. Although this approach reduces ischaemic risk, patients are exposed to a substantial risk of bleeding. Strategies to reduce bleeding include de-escalation of DAPT intensity (downgrading from potent P2Y 12 inhibitor at conventional doses to either clopidogrel or reduced-dose prasugrel) or abbreviation of DAPT duration. Either strategy requires assessment of the ischaemic and bleeding risks of each individual. De-escalation of DAPT intensity can reduce bleeding without increasing ischaemic events and can be guided by platelet function testing or genotyping. Abbreviation of DAPT duration after 1-6 months, followed by monotherapy with aspirin or a P2Y 12 inhibitor, reduces bleeding without an increase in ischaemic events in patients at high bleeding risk, particularly those without high ischaemic risk. However, these two strategies have not yet been compared in a head-to-head clinical trial. In this Consensus Statement, we summarize the evidence base for these treatment approaches, provide guidance on the assessment of ischaemic and bleeding risks, and provide consensus statements from an international panel of experts to help clinicians to optimize these DAPT approaches for individual patients to improve outcomes., (© 2023. Springer Nature Limited.)

Heart failure (HF) occurs predominantly in older adults. HF patients have an increased risk for an acute exacerbation, which commonly requires hospitalisation. Such a worsening HF (WHF) event has an impact on prognosis. Vericiguat is a novel agent which has been shown to reduce the HF hospitalisation risk in patients with a recent WHF event. It is not fully clear how to position this novel agent in geriatric HF inpatients., Competing Interests: Competing interests: LRVdL received payment from Bayer in 2021 to discuss the VICTORIA trial at the EAHP meeting. No other competing interests exist., (© European Association of Hospital Pharmacists 2023. No commercial re-use. See rights and permissions. Published by BMJ.)

Heart failure is a prevalent syndrome among older adults, with a major impact on morbidity and mortality. Higher age is correlated with underuse of guideline-directed medical therapies which, in turn, has been linked to worse clinical outcomes. Importantly, most evidence so far has been collected in adults who were younger, less multi-morbid and polymedicated compared with those who are commonly treated in daily clinical practice. Hence, we aimed to assess and describe the evidence base for pharmacotherapy in older adults with heart failure with a reduced ejection. First, a narrative review was undertaken using Medline, from inception to January 2023. Four foundational therapies were selected based on the latest European Society of Cardiology clinical practice guideline: angiotensin-converting enzyme inhibitors/angiotensin receptor neprilysin inhibitors, beta blockers, mineralocorticoid receptor antagonists and sodium-glucose cotransporter-2 inhibitors. Post hoc analyses from landmark heart failure drug trials were searched and included if they contained data on the impact of age on efficacy, safety and/or timeliness of therapies in the management of heart failure with a reduced ejection fraction. Second, a proposal was developed to support and promote the use of evidence-based heart failure pharmacotherapy in complex, older adults. In total, 11 articles were selected: 4 meta-analyses, 6 post hoc analyses and 1 review paper. No attenuation of efficacy for any of the foundational agents was found in older adults. Regarding safety, dedicated analyses showed that beta blockers, mineraloid receptor antagonists, sacubitril-valsartan, dapagliflozin and empagliflozin retained their overall benefit-risk profile regardless of age. Time to benefit was short and occurred generally within 1 month. Consensus was achieved on a five-step proposal to manage complex medication regimens in older adults suffering from heart failure. In conclusion, older adults suffering from heart failure with a reduced ejection fraction should not be denied treatment based on their age., (© 2023. The Author(s), under exclusive licence to Springer Nature Switzerland AG.)

Purpose of Review: There is emerging evidence on the role of the multimodality imaging in the setting of cardiogenic shock. The utility of different imaging modalities, along with their pitfalls and limitations, and their integration in a multiparametric approach are discussed in the current review., Recent Findings: The evaluation of congestion and perfusion in patients with shock has allowed a better understanding of the underlying physiopathological mechanisms. Integration of echocardiography, using more physiological parameters, with lung ultrasound, as well as the Doppler evaluation of abdominal blood flow dynamics, has led to a better stratification in patinas with hemodynamic instability., Summary: Although validation of the integrated approaches and single parameters are needed, the physiopathological-driven approach using ultrasound in patients with cardiogenic shock on top of the clinical and biochemical evaluation, may aid to a quicker and more detailed evaluation of patient's phenotype., (Copyright © 2023 Wolters Kluwer Health, Inc. All rights reserved.)

Purpose of Review: Cardiogenic shock (CS) remains a very challenging condition with high mortality, despite the advances in therapeutic options. Haematological complications, including coagulopathy and haemolysis, frequently arise in these critically ill patients in CS, especially if they need percutaneous mechanical circulatory support (pMCS), and impair the outcome. This stresses the urgent need for further advancement of this field., Recent Findings: Here, we discuss the different haematological challenges during CS and additional pMCS. Furthermore, we propose a management strategy aiming for restabilization of this precarious haemostatic balance., Summary: In this review, pathophysiology and management of coagulopathies during CS and pMCS are discussed, as well as the need for further studies in this field., (Copyright © 2023 Wolters Kluwer Health, Inc. All rights reserved.)

Percutaneous ventricular assist devices (pVADs) are increasingly being used because of improved experience and availability. The Impella (Abiomed), a percutaneous microaxial, continuous-flow, short-term ventricular assist device, requires meticulous postimplantation management to avoid the 2 most frequent complications, namely, bleeding and hemolysis. A standardized approach to the prevention, detection, and treatment of these complications is mandatory to improve outcomes. The risk for hemolysis is mostly influenced by pump instability, resulting from patient- or device-related factors. Upfront echocardiographic assessment, frequent monitoring, and prompt intervention are essential. The precarious hemostatic balance during pVAD support results from the combination of a procoagulant state, due to critical illness and contact pathway activation, together with a variety of factors aggravating bleeding risk. Preventive strategies and appropriate management, adapted to the impact of the bleeding, are crucial. This review offers a guide to physicians to tackle these device-related complications in this critically ill pVAD-supported patient population., Competing Interests: Funding Support and Author Disclosures Drs Vandenbriele, Baldetti, Chieffo, Dauwe, Meyns, Panoulas, Pappalardo, Rosenberg, Scandroglio, Schaubroeck, Schrage, Stone, Vlasselaers, and Westermann have received research and/or travel funding and speaker fees from Abiomed outside this work. Drs Vandenbriele and Dauwe are supported by a grant from University Hospitals Leuven (Klinische Onderzoeks-en Opleidingsraad). Dr Beneduce has received speaker fees from Boston Scientific. Dr Chieffo has received consultant and speaker fees from Biosensor, Boston Scientific, Medtronic, Menarini, and Shockwave Medical. Dr Gorog has received speaker honoraria from AstraZeneca; and has received institutional research grants from Bayer, Medtronic, AstraZeneca, Werfen and Alpha MD. Dr Huber has received honoraria for consulting and lecturing from Amgen, AstraZeneca, Bayer, Boehringer Ingelheim, Bristol Myers Squibb, Chiesi, Daiichi Sankyo, Novartis, Pfizer, and Sanofi. Dr Pöss has received research funding from the German Cardiac Society, the German Foundation of Heart Research, and the Dr Rolf M. Schwiete Foundation. Dr Schrage has received speaker fees from AstraZeneca. Dr Stone has received speaker honoraria from Medtronic, Pulnovo, Infraredx, and Abbott; has served as a consultant to Daiichi Sankyo, Valfix, TherOx, Robocath, HeartFlow, Ablative Solutions, Vectorious, Miracor, Neovasc, Ancora, Elucid Bio, Occlutech, CorFlow, Apollo Therapeutics, Impulse Dynamics, Cardiomech, Gore, Amgen, Adona Medical, Millennia Biopharma; and has equity or options in Ancora, Cagent, Applied Therapeutics, the Biostar family of funds, SpectraWave, Orchestra Biomed, Aria, Cardiac Success, Valfix, and Xenter. Dr Stone’s daughter is an employee of IQVIA. Dr Stone’s employer, Mount Sinai Hospital, has received research support from Abbott, Abiomed, Bioventrix, Cardiovascular Systems, Philips, Biosense Webster, Shockwave, Vascular Dynamics, Pulnovo, and V-Wave. Dr Vranckx has received personal fees from Bayer, Daiichi Sankyo, CLS Behring, Pfizer–Bristol Myers Squibb, and Novartis. All other authors have reported that they have no relationships relevant to the contents of this paper to disclose., (Copyright © 2023 The Authors. Published by Elsevier Inc. All rights reserved.)

Background and Aims: Acute infections cause relevant activation of innate immunity and inflammatory cascade. An excessive response against pathogens has been proved to trigger the pathophysiological process of thrombo-inflammation. Nevertheless, an association between the use of antithrombotic agents and the outcome of critically ill patients with infectious diseases is lacking. The aim of this meta-analysis is to determine the impact of antithrombotic treatment on survival of patients with acute infective disease., Methods: MEDLINE, Embase, Cinahl, Web of Science and Cochrane Central Register of Controlled Trials (CENTRAL) databases were systematically searched from inception to March 2021. We included randomized controlled trials (RCTs) that evaluated any antithrombotic agent in patients with infectious diseases other than COVID-19. Two authors independently performed study selection, data extraction and risk of bias evaluation. The primary outcome was all-cause mortality. Summary estimates for mortality were calculated using the inverse-variance random-effects method., Results: A total of 16,588 patients participating in 18 RCTs were included, of whom 2141 died. Four trials evaluated therapeutic-dose anticoagulation, 1 trial prophylactic-dose anticoagulation, 4 trials aspirin, and 9 trials other antithrombotic agents. Overall, the use of antithrombotic agents was not associated with all-cause mortality (relative risk 0.96; 95% confidence interval, 0.90-1.03)., Conclusions: The use of antithrombotics is not associated with all-cause mortality in patients with infectious disease other than COVID-19. Complex pathophysiological interplays between inflammatory and thrombotic pathways may explain these results and need further investigation., Registration: PROSPERO, CRD42021241182., Competing Interests: Declaration of Competing Interest None declared., (Copyright © 2023 Elsevier B.V. All rights reserved.)

Competing Interests: Conflict of interest: C.L.A.: Consulting fees Abbott. C.V.: Research grant and speaking fees from Abiomed. No other COI.

Data regarding the occurrence of venous thromboembolic events (VTE), including acute pulmonary embolism (PE) and deep vein thrombosis (DVT) in recovered COVID-19 patients are scant. We performed a systematic review and meta-analysis to assess the risk of acute PE and DVT in COVID-19 recovered subject. Following the PRIMSA guidelines, we searched Medline and Scopus to locate all articles published up to September 1st, 2022, reporting the risk of acute PE and/or DVT in patients recovered from COVID-19 infection compared to non-infected patients who developed VTE over the same follow-up period. PE and DVT risk were evaluated using the Mantel-Haenszel random effects models with Hazard ratio (HR) as the effect measure with 95% confidence interval (CI) while heterogeneity was assessed using Higgins I 2 statistic. Overall, 29.078.950 patients (mean age 50.2 years, 63.9% males), of which 2.060.496 had COVID-19 infection, were included. Over a mean follow-up of 8.5 months, the cumulative incidence of PE and DVT in COVID-19 recovered patients were 1.2% (95% CI:0.9-1.4, I2: 99.8%) and 2.3% (95% CI:1.7-3.0, I2: 99.7%), respectively. Recovered COVID-19 patients presented a higher risk of incident PE (HR: 3.16, 95% CI: 2.63-3.79, I 2  = 90.1%) and DVT (HR: 2.55, 95% CI: 2.09-3.11, I 2 : 92.6%) compared to non-infected patients from the general population over the same follow-up period. Meta-regression showed a higher risk of PE and DVT with age and with female gender, and lower risk with longer follow-up. Recovered COVID-19 patients have a higher risk of VTE events, which increase with aging and among females., (© 2023. The Author(s), under exclusive licence to Springer Science+Business Media, LLC, part of Springer Nature.)

Acute venous thromboembolism represents a spectrum of clinical syndromes of which high-risk pulmonary embolism (PE) with consecutive right ventricular failure and cardiogenic shock (CS) is the most severe presentation. First-line treatment options are surgical pulmonary embolectomy, systemic thrombolysis or catheter-based therapies. The role of mechanical circulatory support with veno-arterial extracorporeal membrane oxygenation (V-A-ECMO) is multifarious in this setting and can be considered as either a bridge to pulmonary artery reperfusion by any of the aforementioned options or as salvage bridge intervention for patients in refractory CS after failure of another treatment. In the subpopulation of patients that are placed on V-A-ECMO after failed thrombolysis, the mortality rates are among the highest, partially due to the high rates of bleeding events. The challenges in the interpretation of anticoagulant monitoring and, consequently, the titration of anticoagulation at least contribute to this high mortality. Here, we discuss the strengths and limitations of different anticoagulant parameters in this setting and propose an approach based on monitoring of Heparin anti-factor Xa (anti-Xa) assay and activated partial thromboplastin time (APTT) in parallel to drive unfractionated heparin (UFH) titration in patients with high-risk PE after fibrinolysis during the first 24 h on V-A-ECMO., Competing Interests: Declaration of Competing Interest The authors declare no conflict of interest. The research received no specific grant from any funding agency in the public, commercial, or not-for-profit sectors., (Copyright © 2022 Elsevier B.V. All rights reserved.)

Competing Interests: Conflict of interest: None declared.

Interest in the use of percutaneous left ventricular assist devices (p-LVADs) for patients undergoing high-risk percutaneous coronary intervention (PCI) is growing rapidly. The Impella ™ (Abiomed Inc.) is a catheter-based continuous micro-axial flow pump that preserves haemodynamic support during high-risk PCI. Anticoagulation is required to counteract the activation of the coagulation system by the patient's procoagulant state and the foreign-body surface of the pump. Excessive anticoagulation and the effect of dual antiplatelet therapy (DAPT) increase the risk of bleeding. Inadequate anticoagulation leads to thrombus formation and device dysfunction. The precarious balance between bleeding and thrombosis in patients with p-LVAD support is often the primary reason that patients' outcomes are jeopardized. In this chapter, we will discuss anticoagulation strategies and anticoagulant management in the setting of protected PCI. This includes anticoagulant therapy with unfractionated heparin, direct thrombin inhibitors, DAPT, purge blockage prevention by bicarbonate-based purge solution, and monitoring by activated clotting time, partial thromboplastin time, as well as anti-factor Xa levels. Here, we provide a standardized approach to the management of peri-interventional anticoagulation in patients undergoing protected PCI., Competing Interests: Conflict of interest: JL has received research funds paid to the institution from Shockwave Medical Inc, and payment or honoraria from AstraZeneca and Boston Scientific, NM has received personal fees from Abiomed, B. Braun, Biotronik, Boston Scientific, Pfizer, and Sanofi Genzyme, payment and honoraria from Abott, Abiomed, AstraZeneca, Bayer, B. Braun, Biotronik, Boston Scientific, Edwards Lifescience, Medtronic, Novartis, Pfizer, and Sanofi Genzyme and National PI for the PROTECT IV trial from Abiomed. OG has received consulting fees from Baxalta, Bayer AG, Boehringer Ingelheim, CSL Behring, Octapharma, Pfizer, Takeda, Portola, and Sanofi, payment or honoraria from Baxalta, Boehringer Ingelheim, Ferring, CSL Behring, Octapharma, Pfizer, Takeda, Portola, and Sanofi, participated on a data safety monitoring board or advisory board at Bayer AG, Boehringer Ingelheim, CSL Behring, Octapharma, Pfizer, Takeda, Portola, and Sanofi, and had a leadership role as chair of European guideline DOAC revesal (ESAIC). F.A. received payment or honoraria from Abiomed and Fresenius. M.O. received grants or contracts, consulting fees, payment or honoraria, support for attending meetings and/or travel, and participated on a data safety monitoring board or advisory board from Abiomed Europe., (© The Author(s) 2022. Published by Oxford University Press on behalf of the European Society of Cardiology.)

Can SARS-CoV-2 hitchhike on the olfactory projection and take a direct and short route from the nose into the brain? We reasoned that the neurotropic or neuroinvasive capacity of the virus, if it exists, should be most easily detectable in individuals who died in an acute phase of the infection. Here, we applied a postmortem bedside surgical procedure for the rapid procurement of tissue, blood, and cerebrospinal fluid samples from deceased COVID-19 patients infected with the Delta, Omicron BA.1, or Omicron BA.2 variants. Confocal imaging of sections stained with fluorescence RNAscope and immunohistochemistry afforded the light-microscopic visualization of extracellular SARS-CoV-2 virions in tissues. We failed to find evidence for viral invasion of the parenchyma of the olfactory bulb and the frontal lobe of the brain. Instead, we identified anatomical barriers at vulnerable interfaces, exemplified by perineurial olfactory nerve fibroblasts enwrapping olfactory axon fascicles in the lamina propria of the olfactory mucosa., Competing Interests: Declaration of interests The authors declare no competing interests., (Copyright © 2022 The Author(s). Published by Elsevier Inc. All rights reserved.)

Purpose: Cardiovascular agents commonly used in geriatric patients, are linked to potentially avoidable harm and might hence be a suitable substrate for medication review practices. Therefore, we sought to update and validate the content of the cardiovascular segment of the previously published Rationalization of Home Medication by an Adjusted STOPP list in Older Patients (RASP) List., Methods: A three-step study was conducted by the pharmacy department in collaboration with the geriatric medicine and cardiology department at the University Hospitals Leuven, Belgium. First, the cardiovascular segment of the RASP list version 2014 was updated taking into account published research, other screening tools and the input of end-users. Secondly, this draft was reviewed during three panel discussions with five expert cardiologists and three clinical pharmacists, all of whom had relevant expertise in geriatric pharmacotherapy. Thirdly, the content was validated using a modified Delphi Technique by a panel of European hospital pharmacists, cardiologists, geriatricians and an internal medicine physician., Results: After the first and second step, the RASP&#95;CARDIO list comprised 94 statements. Consensus (≥ 80% agreement) of all statements and one new statement about gliflozins in heart failure was achieved by a panel of seventeen experts across four European countries after two validation rounds. The final construct comprised a list of 95 statements related to potentially inappropriate prescribing of cardiovascular agents., Conclusion: The RASP&#95;CARDIO list is an updated and validated explicit screening tool to optimize cardiovascular pharmacotherapy in geriatric patients., (© 2022. The Author(s), under exclusive licence to European Geriatric Medicine Society.)

Background: Influenza-associated pulmonary aspergillosis (IAPA) and COVID-19-associated pulmonary aspergillosis (CAPA) affect about 15% of critically ill patients with influenza or COVID-19, respectively. These viral-fungal coinfections are difficult to diagnose and are associated with increased mortality, but data on their pathophysiology are scarce. We aimed to explore the role of lung epithelial and myeloid innate immunity in patients with IAPA or CAPA., Methods: In this observational study, we retrospectively recruited patients who had been admitted to the intensive care unit (ICU) of University Hospitals Leuven, Belgium, requiring non-invasive or invasive ventilation because of severe influenza or COVID-19, with or without aspergillosis, between Jan 1, 2011, and March 31, 2021, whose bronchoalveolar lavage samples were available at the hospital biobank. Additionally, biobanked in vivo tracheobronchial biopsy samples from patients with IAPA or CAPA and invasive Aspergillus tracheobronchitis admitted to ICUs requiring invasive ventilation between the same dates were collected from University Hospitals Leuven, Hospital Network Antwerp (Belgium), and Amiens-Picardie University Hospital (France). We did nCounter gene expression analysis of 755 genes linked to myeloid innate immunity and protein analysis of 47 cytokines, chemokines, and growth factors on the bronchoalveolar lavage samples. Gene expression data were used to infer cell fractions by use of CIBERSORTx, to perform hypergeometric enrichment pathway analysis and gene set enrichment analysis, and to calculate pathway module scores for the IL-1β, TNF-α, type I IFN, and type II IFN (IFNγ) pathways. We did RNAScope targeting influenza virus or SARS-CoV-2 RNA and GeoMx spatial transcriptomics on the tracheobronchial biopsy samples., Findings: Biobanked bronchoalveolar lavage samples were retrieved from 166 eligible patients, of whom 40 had IAPA, 52 had influenza without aspergillosis, 33 had CAPA, and 41 had COVID-19 without aspergillosis. We did nCounter gene expression analysis on bronchoalveolar lavage samples from 134 patients, protein analysis on samples from 162 patients, and both types of analysis on samples from 130 patients. We performed RNAScope and spatial transcriptomics on the tracheobronchial biopsy samples from two patients with IAPA plus invasive Aspergillus tracheobronchitis and two patients with CAPA plus invasive Aspergillus tracheobronchitis. We observed a downregulation of genes associated with antifungal effector functions in patients with IAPA and, to a lesser extent, in patients with CAPA. We found a downregulated expression of several genes encoding proteins with functions in the opsonisation, recognition, and killing of conidia in patients with IAPA versus influenza only and in patients with CAPA versus COVID-19 only. Several genes related to LC3-associated phagocytosis, autophagy, or both were differentially expressed. Patients with CAPA had significantly lower neutrophil cell fractions than did patients with COVID-19 only. Patients with IAPA or CAPA had downregulated IFNγ signalling compared with patients with influenza only or COVID-19 only, respectively. The concentrations of several fibrosis-related growth factors were significantly elevated in the bronchoalveolar lavage fluid from patients with IAPA versus influenza only and from patients with CAPA versus COVID-19 only. In one patient with CAPA, we visualised an active or very recent SARS-CoV-2 infection disrupting the epithelial barrier, facilitating tissue-invasive aspergillosis., Interpretation: Our results reveal a three-level breach in antifungal immunity in IAPA and CAPA, affecting the integrity of the epithelial barrier, the capacity to phagocytise and kill Aspergillus spores, and the ability to destroy Aspergillus hyphae, which is mainly mediated by neutrophils. The potential of adjuvant IFNγ in the treatment of IAPA and CAPA should be investigated., Funding: Research Foundation Flanders, Coronafonds, the Max Planck Society, the Fundação para a Ciência e a Tecnologia, the European Regional Development Fund, "la Caixa" Foundation, and Horizon 2020., Competing Interests: Declaration of interests SF received travel grants from Pfizer. KL received consultancy fees from MRM Health, MSD, and Gilead; speaker fees from FUJIFILM WAKO, Pfizer, and Gilead; and a service fee from Thermo Fisher Scientific. LV received travel grants from Pfizer and Gilead. JW received investigator-initiated grants, speaker's fees, and travel fees from Pfizer, Gilead, and MSD and declares participation in advisory boards for Pfizer and Gilead and the receipt of study drugs from MSD. All other authors declare no competing interests., (Copyright © 2022 Elsevier Ltd. All rights reserved.)

Background: Foundational therapies in heart failure improve clinical outcomes in heart failure with a reduced ejection fraction (HFrEF). Underuse of these life-prolonging heart failure therapies, such as sacubitril-valsartan, is common in older adults and has been associated with worse clinical outcomes. Characterizing the early benefits seen with these therapies might help increase their uptake in older adults., Objective: We applied several methods to estimate the time to benefit of an HFrEF therapy, using sacubitril-valsartan as a case study., Methods: PARADIGM-HF was a randomized controlled study on sacubitril-valsartan versus enalapril in stable, ambulatory HFrEF patients (n = 8399). The primary endpoint, a composite of death from cardiovascular causes or a first hospitalization for heart failure, was significantly reduced (sacubitril-valsartan (21.8%) versus enalapril (26.5%), hazard ratio (HR) 0.80 (95% confidence interval [CI] 0.73-0.87). We extracted and tabulated the Kaplan-Meier (KM) curves of the primary endpoint. An individual patient dataset was then reconstructed. The following methods were applied to explore the time to benefit of sacubitril-valsartan versus enalapril: visual estimation of the point of divergence of the KM curves, statistical process control (SPC), unadjusted landmark analyses using Cox proportional hazards analysis with 30-day increments until significance was persistently achieved, and comparing the survival probabilities of the extracted life tables., Results: Six raters visually estimated the time to benefit at a median of 60 days (interquartile range 38-10 days). Using SPC we found an early benefit from 28 days on, using the longest predefined control period of 28 days. An absolute risk reduction of 1 and 2% was found after 59 and 250 days, respectively. The reconstructed dataset provided a similar HR of 0.8004 (95% CI 0.7331-0.8739). Landmark analyses persistently showed statistical significance from 390 days and later. Survival probabilities differed from 35 days onward., Conclusion: Using multiple approaches, the earliest benefit of sacubitril-valsartan compared to enalapril in stable HFrEF was found at about 1 month after initiation., (© 2022. The Author(s), under exclusive licence to Springer Nature Switzerland AG.)

Background: Acquired von Willebrand syndrome (aVWS) is common in patients with mechanical circulatory support (MCS) devices. In these patients, the high shear stress in the device leads to increased shear-induced proteolysis of von Willebrand factor (VWF) by A Disintegrin And Metalloprotease with Thrombospondin type 1 repeats, number 13 (ADAMTS13). As a result, the high molecular weight (HMW) VWF multimers are lost, leading to a decreased VWF function and impaired hemostasis that could explain the bleeding complications that are frequently observed in these patients. To counteract this abnormal VWF degradation by ADAMTS13, we developed a novel targeted therapy, using an anti-ADAMTS13 monoclonal antibody (mAb) that inhibits the shear-induced proteolysis of VWF by ADAMTS13., Methods: Human or bovine blood was circulated through in vitro MCS device systems with either inhibitory anti-ADAMTS13 mAb 3H9 or 17C7 (20 μg/ml) or control anti-ADAMTS13 mAb 5C11 or phosphate buffered saline (PBS). VWF multimers and function (collagen binding activity) were determined at different time points. Next, Impella pumps were implanted in calves and the calves were injected with PBS and subsequently treated with mAb 17C7. VWF, ADAMTS13, and blood parameters were determined., Results: We demonstrated that blocking ADAMTS13 could prevent the loss of HMW VWF multimers in in vitro MCS device systems. Importantly, our antibody could reverse aVWS in a preclinical Impella-induced aVWS calf model., Conclusion: Hence, inhibition of ADAMTS13 could become a novel therapeutic strategy to manage aVWS in MCS device patients., (© 2022 International Society on Thrombosis and Haemostasis.)

Background: Thromboinflammation plays a central role in severe COVID-19. The kallikrein pathway activates both inflammatory pathways and contact-mediated coagulation. We investigated if modulation of the thromboinflammatory response improves outcomes in hospitalized COVID-19 patients., Methods: In this multicenter open-label randomized clinical trial (EudraCT 2020-001739-28), patients hospitalized with COVID-19 were 1:2 randomized to receive standard of care (SOC) or SOC plus study intervention. The intervention consisted of aprotinin (2,000,000 IE IV four times daily) combined with low molecular weight heparin (LMWH; SC 50 IU/kg twice daily on the ward, 75 IU/kg twice daily in intensive care). Additionally, patients with predefined hyperinflammation received the interleukin-1 receptor antagonist anakinra (100 mg IV four times daily). The primary outcome was time to a sustained 2-point improvement on the 7-point World Health Organization ordinal scale for clinical status, or discharge., Findings: Between 24 June 2020 and 1 February 2021, 105 patients were randomized, and 102 patients were included in the full analysis set (intervention N  = 67 vs. SOC N  = 35). Twenty-five patients from the intervention group (37%) received anakinra. The intervention did not affect the primary outcome (HR 0.77 [CI 0.50-1.19], p  = 0.24) or mortality (intervention n  = 3 [4.6%] vs. SOC n  = 2 [5.7%], HR 0.82 [CI 0.14-4.94], p  = 0.83). There was one treatment-related adverse event in the intervention group (hematuria, 1.49%). There was one thrombotic event in the intervention group (1.49%) and one in the SOC group (2.86%), but no major bleeding., Conclusions: In hospitalized COVID-19 patients, modulation of thromboinflammation with high-dose aprotinin and LMWH with or without anakinra did not improve outcome in patients with moderate to severe COVID-19., (© 2022 The Authors. Research and Practice in Thrombosis and Haemostasis published by Wiley Periodicals LLC on behalf of International Society on Thrombosis and Haemostasis (ISTH).)

In atrial and ventricular tachyarrhythmias, reduced time for ventricular filling and loss of atrial contribution lead to a significant reduction in cardiac output, resulting in cardiogenic shock. This may also occur during catheter ablation in 11% of overall procedures and is associated with increased mortality. Managing cardiogenic shock and (supra) ventricular arrhythmias is particularly challenging. Inotropic support may exacerbate tachyarrhythmias or accelerate heart rate; antiarrhythmic drugs often come with negative inotropic effects, and electrical reconversions may risk worsening circulatory failure or even cardiac arrest. The drop in native cardiac output during an arrhythmic storm can be partly covered by the insertion of percutaneous mechanical circulatory support (MCS) devices guaranteeing end-organ perfusion. This provides physicians a time window of stability to investigate the underlying cause of arrhythmia and allow proper therapeutic interventions (e.g., percutaneous coronary intervention and catheter ablation). Temporary MCS can be used in the case of overt hemodynamic decompensation or as a "preemptive strategy" to avoid circulatory instability during interventional cardiology procedures in high-risk patients. Despite the increasing use of MCS in cardiogenic shock and during catheter ablation procedures, the recommendation level is still low, considering the lack of large observational studies and randomized clinical trials. Therefore, the evidence on the timing and the kinds of MCS devices has also scarcely been investigated. In the current review, we discuss the available evidence in the literature and gaps in knowledge on the use of MCS devices in the setting of ventricular arrhythmias and arrhythmic storms, including a specific focus on pathophysiology and related therapies., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2022 Tavazzi, Dammassa, Colombo, Arbustini, Castelein, Balik and Vandenbriele.)