Objectives: We assessed possible myocardial involvement in previously cardiac healthy post-COVID patients referred for persisting symptoms with suspected myocarditis. Background: Prior studies suggested myocardial inflammation in patients with coronavirus-induced disease 2019 (COVID-19). However, the prevalence of cardiac involvement among COVID patients varied between 1.4 and 78%. Methods: A total of 56 post-COVID patients without previous heart diseases were included consecutively into this study. All patients had positive antibody titers against SARS-CoV-2. Patients were referred for persistent symptoms such as chest pain/discomfort, shortness of breath, or intolerance to activity. All patients underwent standardized cardiac assessment including electrocardiogram (ECG), cardiac biomarkers, echocardiography, and cardiac magnetic resonance (CMR). Results: 56 Patients (46 ± 12 years, 54% females) presented 71 ± 66 days after their COVID-19 disease. In most patients, the course of COVID-19 was mild, with hospital treatment being necessary in five (9%). At presentation, patients most often reported persistent fatigue (75%), chest pain (71%), and shortness of breath (66%). Acute myocarditis was confirmed by T1/T2-weighed CMR and elevated NTpro-BNP levels in a single patient (2%). Left ventricular ejection fraction was 56% in this patient. Additional eight patients (14%) showed suspicious CMR findings, including myocardial edema without fibrosis (n = 3), or non-ischemic myocardial injury suggesting previous inflammation (n = 5). However, myocarditis could ultimately not be confirmed according to 2018 Lake Louise criteria; ECG, echo and lab findings were inconspicuous in all eight patients. Conclusions: Among 56 post-COVID patients with persistent thoracic complaints final diagnosis of myocarditis could be confirmed in a single patient using CMR. Graphic

Background Direct oral anticoagulants (DOACs) are increasingly used worldwide. Little is known so far about their pharmacokinetics in emergency situations. Methods A prospective, observational registry was performed to determine the clinical course in consecutive patients with major bleeding or urgent surgery treated with DOACs. In samples collected as part of routine care DOAC drug concentrations were measured using ultraperformance liquid chromatography-tandem mass spectrometry. Anticoagulant intensity at first presentation and drug half-life (t _1/2), tested in repeat samples, were evaluated. Results A total of 140 patients were prospectively included. Pharmacokinetic data were available in 94% (132/140) of patients. Note that 67% (89/132) experienced life-threatening bleeding and 33% (43/132) needed an urgent surgery. For pharmacokinetic analysis a total of 605 blood samples was available. Median concentration on admission was 205 ng/mL for rivaroxaban and 108 ng/mL for apixaban. All treatment groups showed a high variation of drug concentrations at baseline. In rivaroxaban-treated patients t _½ was 17.3 hours (95% confidence interval [CI]: 15.4–19.7) without significant difference in both groups (major bleeding: t _½ 16.7 hours, 95% CI: 14.7–19.3; urgent surgery: t _½ 19.7 hours, 95% CI: 15.2–27.9; p = 0.292). In apixaban-treated patients t _½ was 25.0 hours (95% CI: 22.9–27.6) with a longer t _½ after urgent surgery (t _1/2: 30.8 hours; 95% CI: 26.9–36.4) compared with severe bleeding (t _1/2: 20.8 hours; 95% CI: 18.8–23.2; p < 0.001). Conclusion Emergency patients under DOAC treatment show a high variation of anticoagulant concentrations at baseline. Compared with rivaroxaban, apixaban showed a lower median concentration on admission and a longer t _½. E.L.-L. was responsible for the conceptualization and the methodology of the RADOA-registry, organized funding acquisition, and wrote the original draft preparation. I.B. performed the mass spectrometry analysis of the DOAC-levels and reviewed major parts of the manuscript. J.K. performed the mass spectrometry analysis of the DOAC-levels. S.L., S.K., O.G., U.N.-G., B.Z., C.v.H., I.B., A.S., J.B.-W., S.S., P.M., and A.G. recruited patients and supported the writing of the manuscript. J.L. and B.Z. were responsible for the project administration. E.H. performed the statistical analysis and was responsible for the validation and visualization of the results. All the authors have read and agreed to the published version of the manuscript. The study was conducted according to the guidelines of the Declaration of Helsinki, and approved by the Institutional Review Boards of all participating hospitals. For informed consent statements see Ethics as part of the Material and Methods section of the manuscript. ClinicalTrials.gov Identifier: NCT01722786 (URL: https://clinicaltrials.gov/ct2/show/NCT01722786?term=lindhoff-last&rank=9). ^* Both the authors contributed equally to the study. Received: 19 March 2021 Accepted: 25 June 2021 Accepted Manuscript online: 13 July 2021 Article published online: 29 September 2021 © 2021. The Author(s). This is an open access article published by Thieme under the terms of the Creative Commons Attribution-NonDerivative-NonCommercial License, permitting copying and reproduction so long as the original work is given appropriate credit. Contents may not be used for commercial purposes, or adapted, remixed, transformed or built upon. (https://creativecommons.org/licenses/by-nc-nd/4.0/) Georg Thieme Verlag KG Rüdigerstraße 14, 70469 Stuttgart, Germany

We analyzed data for women who received fondaparinux for ≥7 days during pregnancy. The study retrospectively included women who received fondaparinux pre-, peri- and/or postpartum for ≥7 days for prophylaxis/venous thromboembolism (VTE) treatment at German specialist centers (2004-2010). Data on pregnancy, VTE risk factors, anticoagulant treatment, pregnancy outcome and adverse events were extracted from medical records. 120 women (mean age 31.5 years) were included. Among 84 women with prior pregnancies, 41.0% had ≥1 abortion. Anticoagulation was indicated for prophylaxis in 92.5% cases, including 82.5% women with an elevated VTE risk (82.8% thrombophilia, 34.2% VTE history). All women received low-molecular-weight heparin (LMWH) as first-line therapy; 3 also unfractionated heparin. Treatment changed to fondaparinux, due to heparin allergy (41.7%) or heparin-induced thrombocytopenia (10.0%). Fondaparinux was generally well tolerated. Adverse events included bleeding events (n = 5), abortion (n = 2), premature births (n = 2), stillbirth (n = 1), arrested labors (n = 2), injection site erythema (n = 4) and unspecified drug hypersensitivity (n = 6). No VTE events or increased liver enzymes occurred during treatment. In this retrospective study, fondaparinux was effective and well tolerated. Trial registration: ClinicalTrials.gov NCT01004939.

Summary: The worldwide increase in the aging population and the associated increase in the prevalence of atrial fibrillation and venous thromboembolism as well as the widespread use of direct oral anticoagulants (DOAC) have resulted in an increase of the need for the management of bleeding complications and emergency operations in frail, elderly patients, in clinical practice. When severe bleeding occurs, general assessment should include evaluation of the bleeding site, onset and severity of bleeding, renal function, and concurrent medications with focus on anti-platelet drugs and nonsteroidal anti-inflammatory drugs (NSAID). The last intake of the DOAC and its residual concentration are also relevant. The site of bleeding should be immediately localized, anticoagulation should be interrupted, and local measures to stop bleeding should be taken. In life-threatening bleeding or emergency operations immediate reversal of the antithrombotic effect may be indicated. If relevant residual DOAC-concentrations are expected and surgery cannot be postponed, prothrombin complex concentrate (PCC) and/or a specific antidote should be given. While idarucizumab, the specific antidote for dabigatran, has been recently approved for clinical use, the recombinant factor X protein andexanet alfa, an antidote for the reversal of inhibitors of coagulation factor Xa, and ciraparantag, a universal antidote, are not available. Future cohort studies are necessary to assess the efficacy and safety of specific and unspecific reversal agents in “real-life” conditions. This was the rationale for introducing the RADOA-registry (RADOA: Reversal Agent use in patients treated with Direct Oral Anticoagulants or vitamin K antagonists), a prospective non-interventional registry, which will evaluate the effects of specific and unspecific reversal agents in patients with life-threatening bleeding or emergency operations either treated with DOACs or vitamin K antagonists.