Critical illness in COVID-19 is an extreme and clinically homogeneous disease phenotype that we have previously shown1 to be highly efficient for discovery of genetic associations2. Despite the advanced stage of illness at presentation, we have shown that host genetics in patients who are critically ill with COVID-19 can identify immunomodulatory therapies with strong beneficial effects in this group3. Here we analyse 24,202 cases of COVID-19 with critical illness comprising a combination of microarray genotype and whole-genome sequencing data from cases of critical illness in the international GenOMICC (11,440 cases) study, combined with other studies recruiting hospitalized patients with a strong focus on severe and critical disease: ISARIC4C (676 cases) and the SCOURGE consortium (5,934 cases). To put these results in the context of existing work, we conduct a meta-analysis of the new GenOMICC genome-wide association study (GWAS) results with previously published data. We find 49 genome-wide significant associations, of which 16 have not been reported previously. To investigate the therapeutic implications of these findings, we infer the structural consequences of protein-coding variants, and combine our GWAS results with gene expression data using a monocyte transcriptome-wide association study (TWAS) model, as well as gene and protein expression using Mendelian randomization. We identify potentially druggable targets in multiple systems, including inflammatory signalling (JAK1), monocyte–macrophage activation and endothelial permeability (PDE4A), immunometabolism (SLC2A5 and AK5), and host factors required for viral entry and replication (TMPRSS2 and RAB2A).

Anticoagulant therapy is a cornerstone treatment for coronavirus disease 2019 (COVID-19) due to the high rates of thromboembolic complications associated with this disease. We hypothesized that chronic antithrombotic therapy could play a protective role in patients hospitalized for COVID-19. Retrospective, observational study of all patients admitted to our hospital for ≥ 24 h from March 1 to May 31, 2020 with SARS-CoV-2. The objective was to evaluate clinical outcomes and mortality in COVID-19 patients receiving chronic anticoagulation (AC) or antiplatelet therapy (AP) prior to hospital admission. A total of 1612 patients were evaluated. The mean (standard deviation; SD) age was 66.5 (17.1) years. Patients were divided into three groups according to the use of antithrombotic therapy prior to admission (AP, AC, or no-antithrombotic treatment). At admission, 9.6% of the patients were taking anticoagulants and 19.1% antiplatelet therapy. The overall mortality rate was 19.3%. On the multivariate analysis there were no significant differences in mortality between the antithrombotic groups (AC or AP) and the no-antithrombotic group (control group). Patients on AC had lower ICU admission rates than the control group (OR: 0.41, 95% CI, 0.18–0.93). Anticoagulation therapy prior to hospitalization for COVID-19 was associated with lower ICU admission rates. However, there were no significant differences in mortality between the patients receiving chronic antithrombotic therapy and patients not taking antithrombotic medications. These findings suggest that chronic anticoagulation therapy at the time of COVID-19 infection may reduce disease severity and thus the need for ICU admission.

In the version of this article initially published, the name of Ana Margarita Baldión-Elorza, of the SCOURGE Consortium, appeared incorrectly (as Ana María Baldion) and has now been amended in the HTML and PDF versions of the article.

Aims Direct oral anticoagulants (DOAC) are progressively replacing vitamin K antagonists in the prevention of thromboembolism in patients with atrial fibrillation. However, their real-world clinical outcomes appear to be contradictory, with some studies reporting fewer and others reporting higher complications than the pivotal randomized controlled trials. We present the results of a clinical model for the management of DOACs in real clinical practice and provide a review of the literature. Methods The MACACOD project is an ongoing, observational, prospective, single-center study with unselected patients that focuses on rigorous DOAC selection, an educational visit, laboratory measurements, and strict follow-up. Results A total of 1,259 patients were included. The composite incidence of major complications was 4.93% py in the whole cohort vs 4.49% py in the edoxaban cohort. The rate of all-cause mortality was 6.11% py for all DOACs vs 5.12% py for edoxaban. There weren’t differences across sex or between Edoxaban reduced or standard doses. However, there were differences across ages, with a higher incidence of major bleeding complications in patients >85 years (5.13% py vs 1.69% py in <75 years). Conclusions We observed an incidence of serious complications of 4.93% py, in which severe bleeding predominated (3.65% py). Considering our results, more specialized attention seems necessary to reduce the incidence of severe complications and also a more critical view of the literature. Considering our results, and our indirect comparison with many real-world studies, more specialized attention seems necessary to reduce the incidence of severe complications in AF patients receiving DOACs.

Background and purpose Renal excretion of direct oral anticoagulants (DOACs) varies depending on the drug. Hypothetically, an increased glomerular filtration rate (GFR) may lead to suboptimal dosing and a higher thromboembolic events incidence. However, real-world patient data do not support the theoretical risk. The aim is to analyse DOAC outcomes in patients with normal and high (≥90 mL/min) GFR, focusing on biological parameters and thrombotic/haemorrhagic events. Methods Observational prospective single-centre study and registry of patients on DOACs. Follow-up was 1,343 patient-years. A bivariate analysis was performed of baseline variables according to GFR (<90 mL/min vs ≥90 mL/min). Anti-Xa activity before and after drug intake (HemosIL, Liquid Anti-Xa, Werfen) was measured for edoxaban, apixaban, and rivaroxaban; diluted thrombin time for dabigatran (HEMOCLOT); and additionally, plasma concentrations in edoxaban (HemosIl, Liquid Anti-Xa suitably calibrated). Results 1,135 patients anticoagulated with DOACs were included and 152 patients with GFR ≥90 mL/min. Of 18 serious thrombotic complications during follow-up, 17 occurred in patients with GFR <90 mL/min, and 1 in a patient with GFR ≥90 mL/min. A higher incidence of complications was observed in patients with normal GFR, but the difference was not statistically significant (p>0.05). No statistically significant differences with clinical relevance were observed between the normal or supranormal groups in anti-Xa activity or in edoxaban plasma concentrations. Conclusions There was no increased incidence of thrombotic/haemorrhagic complications in our patients treated with DOACs, including 66% treated with edoxaban, and patients with GFR ≥90 mL/min. Likewise, drug anti-Xa activity and edoxaban plasma concentration did not seem to be influenced by GFR.