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Bleeding complications associated with oral anticoagulant (OAC) frequently lead to emergency department visits and hospitalization. Short-term all-cause mortality after severe bleeding is substantial ranging from about 10% for gastrointestinal bleeding (the most frequent single site) to about 50% for intracranial bleeding. A protocolized, multidisciplinary approach to bleeding ensures is needed to (i) rapidly identify of patients at risk of adverse outcomes, (ii) optimize delivery of supportive measures, (iii) treat the source of bleeding, and (iv) administer anticoagulant reversal or hemostatic therapies judiciously for patients most likely to benefit. We convened a multidisciplinary panel of experts (emergency medicine, gastroenterology, general internal medicine, hematology, neurology, pharmacy, thrombosis,) to review the literature and provide practical guidance including a corresponding algorithm for use at the point of care to assist clinicians in the management of patients with acute severe OAC-related bleeding., Competing Interests: All authors received an honorarium from Thrombosis Canada for participation in the development of this manuscript. In the last 36 months, Dr. Crowther has received Personal Funding, including but not limited to preparation of educational material, participation in Advisory Boards, or providing expert testimony for Bayer, Astra Zeneca, Pfizer, Hemostasis Reference Laboratories, Syneos Health, and Eversana. He has participated in various medicolegal activities relating to thrombosis, anticoagulant drugs, or other aspects of internal medicine and hematological practice. He has also worked with multiple for-profit and not-for-profit entities such as Up To Date and medical communication companies. He holds the Leo Pharma Chair in Thromboembolism, endowed at McMaster University. Dr. Siegal has received honoraria paid indirectly to her institution from Astra Zeneca, BMS-Pfizer, Roche and Servier. She is supported by a Tier 2 Canada Research Chair in Anticoagulant Management of Cardiovascular Disease and is the secretary of Thrombosis Canada. Dr Mithoowani receives authorship royalties from UpToDate. Dr Castellucci has received honoraria for speaking engagement from Bayer, Insara and Medscape, is the vice president of Thrombosis Canada and the chair of World Thrombosis Day. Dr Dowlatshahi has received a consulting fee from AstraZeneca and has a patent pending for CARL (Contrast leakage detection on CT). Dr de Wit is the Research Committee chair for Canadian Association of Emergency Physicians Research Committee, the vice-chair for Thrombosis Canada’s Patient and Family Committee, and a committee chair of the Predictive and Diagnostic Variables in Thrombotic Disease Scientific Standardization committee for the International Society of Thrombosis and Haemostasis. Dr Lin has nothing to disclose. Dr Forbes has received consulting fees and honoraria for speaker engagements for Boston Science and Pentax Medical, is a member Standards of Practice Committee for the American Society for Gastrointestinal Endoscopy and the Clinical Guidelines Committee for the Canadian Association of Gastroenterologists. Dr Bungard has received an honorarium for attending an advisory board meeting for Pfizer, and is chair of Thrombosis Canada’s Patient and Family Committee for Thrombosis Canada., (The Author(s). This is an open access article published by Thieme under the terms of the Creative Commons Attribution License, permitting unrestricted use, distribution, and reproduction so long as the original work is properly cited. (https://creativecommons.org/licenses/by/4.0/).)

Background:  Venous thromboembolism (VTE) is a chronic disorder with a significant health and economic burden. Several VTE-specific clinical prediction models (CPMs) have been used to assist physicians in decision-making but have several limitations. This systematic review explores if machine learning (ML) can enhance CPMs by analyzing extensive patient data derived from electronic health records. We aimed to explore ML-CPMs' applications in VTE for risk stratification, outcome prediction, diagnosis, and treatment., Methods:  Three databases were searched: PubMed, Google Scholar, and IEEE electronic library. Inclusion criteria focused on studies using structured data, excluding non-English publications, studies on non-humans, and certain data types such as natural language processing and image processing. Studies involving pregnant women, cancer patients, and children were also excluded. After excluding irrelevant studies, a total of 77 studies were included., Results:  Most studies report that ML-CPMs outperformed traditional CPMs in terms of receiver operating area under the curve in the four clinical domains that were explored. However, the majority of the studies were retrospective, monocentric, and lacked detailed model architecture description and external validation, which are essential for quality audit. This review identified research gaps and highlighted challenges related to standardized reporting, reproducibility, and model comparison., Conclusion:  ML-CPMs show promise in improving risk assessment and individualized treatment recommendations in VTE. Apparently, there is an urgent need for standardized reporting and methodology for ML models, external validation, prospective and real-world data studies, as well as interventional studies to evaluate the impact of artificial intelligence in VTE., Competing Interests: None declared., (Thieme. All rights reserved.)

Background:  Recent data on temporal trends in excess mortality for patients with pulmonary embolism (PE) and deep vein thrombosis (DVT) compared with the general population are scarce., Methods:  A nationwide Swedish register study conducted from 2006 to 2018 including 68,960 PE and 70,949 DVT cases matched with population controls. Poisson regression determined relative risk (RR) for 30-day and 1-year mortality trends while Cox regression determined adjusted hazard ratios (aHRs). A significance level of 0.001 was applied., Results:  In PE cases, both 30-day mortality (12.5% in 2006 to 7.8% in 2018, RR: 0.95 [95% CI: 0.95-0.96], p  < 0.0001) and 1-year mortality (26.5 to 22.1%, RR: 0.98 [0.97-0.98], p  < 0.0001) decreased during the study period. Compared with controls, no significant change was seen in 30-day (aHR: 33.08 [95% CI: 25.12-43.55] to 24.64 [95% CI: 18.81-32.27], p  = 0.0015 for interaction with calendar year) or 1-year (aHR: 5.85 [95% CI: 5.31-6.45] to 7.07 [95% CI: 6.43-7.78], p  = 0.038) excess mortality. The 30-day excess mortality decreased significantly (aHR: 39.93 [95% CI: 28.47-56.00) to 24.63 [95% CI: 17.94-33.83], p  = 0.0009) in patients with PE without known cancer before baseline, while the excess 1-year mortality increased (aHR: 3.55 [95% CI: 3.16-3.99] to 5.38 [95% CI: 4.85-5.98], p  < 0.0001) in PE cases surviving to fill a prescription of anticoagulation. In DVT cases, 30-day and 1-year mortality declined, while excess mortality compared with controls remained stable., Conclusion:  In general, the improved mortality following PE and DVT paralleled population trends. However, PE cases without cancer had decreasing excess 30-day mortality, whereas those surviving to fill a prescription for anticoagulant medication showed increasing excess 1-year mortality., Competing Interests: K.G.S. has received speaker's honoraria from Bristol-Myers Squibb, Pfizer, Bayer, and Leo Pharma. S.S. has received research grant from Octapharma and honoraria from Alexion, Bayer, Boehringer Ingelheim, Daiichi-Sankyo, Regeneron, Sanofi, Servier, Takeda, and Hemostasis Reference Laboratory. K.S. has received speaker's honoraria from Leo Pharma. J.P. has received speaker's honoraria from Pfizer. M.T. has received speaker's honoraria from Viatris. C.J.S. and A.P. report no conflict of interest., (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/).)

Background:  With the widespread use of direct oral anticoagulants (DOACs), there is an urgent need for a rapid assay to exclude clinically relevant plasma levels. Accurate and rapid determination of DOAC levels would guide medical decision-making to (1) determine the potential contribution of the DOAC to spontaneous or trauma-induced hemorrhage; (2) identify appropriate candidates for reversal, or (3) optimize the timing of urgent surgery or intervention., Methods and Results:  The DOAC Dipstick test uses a disposable strip to identify factor Xa- or thrombin inhibitors in a urine sample. Based on the results of a systematic literature search followed by an analysis of a simple pooling of five retrieved clinical studies, the test strip has a high sensitivity and an acceptably high negative predictive value when compared with levels measured with liquid chromatography tandem mass spectrometry or calibrated chromogenic assays to reliably exclude plasma DOAC concentrations ≥30 ng/mL., Conclusion:  Based on these data, a simple algorithm is proposed to enhance medical decision-making in acute care indications useful primarily in hospitals not having readily available quantitative tests and 24/7. This algorithm not only determines DOAC exposure but also differentiates between factor Xa and thrombin inhibitors to better guide clinical management., Competing Interests: J.H. is general manager and founder of DOASENSE GmbH, J.D. is CEO of Qualiblood SA. All other authors declare no conflicts of interest., (Thieme. All rights reserved.)

Background:  Patients with a mechanical heart valve (MHV) require oral anticoagulation. Poor anticoagulation control is thought to be associated with adverse outcomes, but data are limited., Objective:  To assess the risks of clinical outcomes in patients with a MHV and poor anticoagulation control on warfarin., Methods:  We conducted a retrospective study of consecutive patients undergoing MHV implantation at a tertiary care center (2010-2019). Primary outcome was a composite of ischemic stroke, systemic embolism, or prosthetic valve thrombosis. Major bleeding and death were key secondary outcomes. We constructed multivariable regression models to assess the association between time in therapeutic range (TTR) on warfarin beyond 90 days after surgery with outcomes., Results:  We included 671 patients with a MHV (80.6% in aortic, 14.6% in mitral position; mean age 61 years, 30.3% female). Median follow-up was 4.9 years, mean TTR was 62.5% (14.5% TTR <40%, 24.6% TTR 40-60%, and 61.0% TTR >60%). Overall rates of the primary outcome, major bleeding, and death were 0.73, 1.41, and 1.44 per 100 patient-years. Corresponding rates for patients with TTR <40% were 1.31, 2.77, and 3.22 per 100 patient-years. In adjusted analyses, every 10% decrement in TTR was associated with a 31% increase in hazard for the primary outcome (hazard ratio [HR]: 1.31, 95% confidence interval [CI]: 1.13-1.52), 34% increase in major bleeding (HR: 1.34, 95% CI: 1.17-1.52), and 32% increase in death (HR: 1.32, 95% CI: 1.11-1.57)., Conclusion:  In contemporary patients with a MHV, poor anticoagulation control on warfarin was associated with increased risks of thrombotic events, bleeding, and death., Competing Interests: I.J. has received consultancy fees from AstraZeneca, Novo Nordisk, and Boehringer Ingelheim and is supported by unrestricted research grants from Stockholm County Council, Swedish Heart-Lung Foundation, AstraZeneca, and Swedish Society of Cardiology. J.W.E. has received honoraria and/or research support from Anthos, AZ, Bayer, BI, BMS, DSI, Idorsia, Janssen, Merck, and Pfizer. M.R. has received honoraria support in the past from Bayer, BI, and Pfizer. S.S. has received research funding from Octapharma and honoraria from Alexion, Bayer, Boehringer Ingelheim, Bristol-Myers Squibb, Daiichi-Sankyo, Pfizer, and Sanofi. S.J.C. has received honoraria or research grants from Bayer, BMS, Pfizer, AstraZeneca, Javelin, Daiichi Sankyo. The remaining authors have no conflicting interests to report., (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/).)

Competing Interests: None declared.

Competing Interests: None declared.

Background:  There are limited data on anticoagulant management of acute venous thromboembolism (VTE) after spontaneous intracranial hemorrhage (ICH)., Methods:  We reviewed retrospectively all cases diagnosed with VTE during hospitalization for spontaneous ICH at our center during 15 years. Anticoagulation management outcomes were (1) timing after ICH of anticoagulant initiation for VTE treatment, (2) use of immediate therapeutic dosing or stepwise dose escalation, and (3) the proportion achieving therapeutic dose. Primary clinical effectiveness outcome was recurrent VTE. Primary safety outcome was expanding ICH., Results:  We analyzed 103 cases with VTE after 11 days (median; interquartile range [IQR]: 7-22) from the diagnosis of ICH. Forty patients (39%) achieved therapeutic anticoagulation 21.5 days (median; IQR: 14-34 days) from the ICH. Of those, 14 (35%; 14% of total) received immediately therapeutic dose and 26 (65%; 25% of total) had stepwise escalation. Anticoagulation was more aggressive in patients with VTE >14 days after admission versus those with earlier VTE diagnosis. Twenty-two patients (21%) experienced recurrent/progressive VTE-less frequently among patients with treatment escalation within 7 days or with no escalation than with escalation >7 days from the VTE. There were 19 deaths 6 days (median; IQR: 3.5-15) after the index VTE, with significantly higher in-hospital mortality rate among patients without escalation in anticoagulation., Conclusion:  Prompt therapeutic anticoagulation for acute VTE seems safe when occurring more than 14 days after spontaneous ICH. For VTE occurring earlier, it might also be safe with therapeutic anticoagulation, but stepwise dose escalation to therapeutic within a 7-day period might be preferable., Competing Interests: S.S. reports research funding from Octapharma and honoraria from Alexion, Bayer, Boehringer Ingelheim, Bristol-Myers Squibb, Daiichi-Sankyo, Pfizer, and Sanofi. All other authors report no conflict of interest., (Thieme. All rights reserved.)

Objective:  The SOX-PTS, Amin, and Méan models are three different clinical prediction scores stratifying the risk for postthrombotic syndrome (PTS) development in patients with acute deep vein thrombosis (DVT) of the lower limbs. Herein, we aimed to assess and compare these scores in the same cohort of patients., Methods:  We retrospectively applied the three scores in a cohort of 181 patients (196 limbs) who participated in the SAVER pilot trial for an acute DVT. Patients were stratified into PTS risk groups using positivity thresholds for high-risk patients as proposed in the derivation studies. All patients were assessed for PTS 6 months after index DVT using the Villalta scale. We calculated the predictive accuracy for PTS and area under receiver operating characteristic (AUROC) curve for each model., Results:  The Méan model was the most sensitive (sensitivity 87.7%; 95% confidence interval [CI]: 77.2-94.5) with the highest negative predictive value (87.5%; 95% CI: 76.8-94.4) for PTS. The SOX-PTS was the most specific score (specificity 97.5%; 95% CI: 92.7-99.5) with the highest positive predictive value (72.7%; 95% CI: 39.0-94.0). The SOX-PTS and Méan models performed well for PTS prediction (AUROC: 0.72; 95% CI: 0.65-0.80 and 0.74; 95% CI: 0.67-0.82), whereas the Amin model did not (AUROC: 0.58; 95% CI: 0.49-0.67)., Conclusion:  Our data support that the SOX-PTS and Méan models have good accuracy to stratify the risk for PTS., Competing Interests: None declared., (Thieme. All rights reserved.)

Competing Interests: None declared.

Competing Interests: None declared.

Importance:  Aortic stenosis is the most common valvular disease, and more than 90% of patients who undergo aortic valve replacement receive a bioprosthetic valve. Yet optimal antithrombotic therapy after bioprosthetic aortic valve replacement remains uncertain, and guidelines provide contradictory recommendations., Observations:  Randomized studies of antithrombotic therapy after bioprosthetic aortic valve replacement are small and underpowered. Observational data present opposing, and likely confounded, results. Historically, changes to guidelines have not been informed by high-quality new data. Current guidelines from different professional bodies provide contradictory recommendations despite citing the same evidence., Conclusion:  Insufficient antithrombotic therapy after bioprosthetic aortic valve replacement has serious implications: ischemic stroke, systemic arterial thromboembolism, and clinical and subclinical valve thromboses. Unnecessarily intense antithrombotic therapy, however, increases risk of bleeding and associated morbidity and mortality. Professional bodies have used the current low-quality evidence and generated incongruent recommendations. Researchers should prioritize generating high-quality, randomized evidence evaluating the risks and benefits of antiplatelet versus anticoagulant therapy after bioprosthetic aortic valve replacement., Competing Interests: None declared., (Thieme. All rights reserved.)

Introduction:  BAY 81-8973, a full-length recombinant factor VIII for hemophilia A treatment, has been extensively evaluated in previously treated patients in the LEOPOLD (Long-Term Efficacy Open-Label Program in Severe Hemophilia A Disease) clinical trials., Aim:  To assess BAY 81-8973 efficacy and safety when used for bleed prophylaxis and treatment in previously untreated/minimally treated patients (PUPs/MTPs)., Methods:  In this phase III, multicenter, open-label, uncontrolled study, PUPs/MTPs (<6 years old) with severe hemophilia A received BAY 81-8973 (15-50 IU/kg) at least once weekly as prophylaxis. Primary efficacy endpoint was the annualized bleeding rate (ABR) within 48 hours after prophylaxis infusion. Adverse events and immunogenicity were assessed. Patients who developed inhibitors were offered immune tolerance induction (ITI) treatment in an optional extension phase., Results:  Fifty-two patients were enrolled, with 43 patients (mean age: 13.6 months) treated. Median (interquartile range) ABR for all bleeds within 48 hours of prophylaxis infusion was 0.0 (0.0-1.8) among patients without inhibitors ( n  = 20) and 0.0 (0.0-2.2) among all patients. As expected, inhibitors were the most frequent treatment-related adverse event (high titer: 17 [39.5%] patients; low titer: 6 [13.9%] patients). Six of 12 patients who underwent ITI treatment in the extension phase (high titer [ n  = 5], low titer [ n  = 1]) achieved a negative inhibitor titer., Conclusion:  BAY 81-8973 was effective for bleed prevention and treatment in PUPs/MTPs. The observed inhibitor rate was strongly influenced by a cluster of inhibitor cases, and consequently, slightly higher than in other PUP/MTP studies. Overall, the BAY 81-8973 benefit-risk profile remains unchanged and supported by ongoing safety surveillance. Immune tolerance can be achieved with BAY 81-8973., Competing Interests: R.L. has received consultancy fee from Bayer, SOBI, Novo Nordisk, Baxter/Shire, Pfizer, and Sanofi. A.K.C.C. has received grants from Octapharma, Novo Nordisk, Bayer, Sanofi, Sobi, BMS, I-ACT, and AceAge, honoraria from Bayer, Novo Nordisk, Takeda, Roche, and CSL, jointly holds patent # 20180177924 (Application # 15/735,306) “Medical Devices, Systems, and Methods Utilizing Antithrombin-Heparin Composition,” and advisory fees from Bayer, Daiichi Sankyo, and CSL Behring. M.E.M. has received consultant, advisor, and speaker fees from Bayer, CSL Behring, BioMarin, Grifols, Kedrion, LFB, Novo Nordisk, Pfizer, Roche, Sobi, Sanofi, Spark Therapeutics, Uniqure, Takeda, and Octopharma. G.K. has received grants from Alnylam, Bayer, BPL, Opko Biologics, Pfizer, Roche, and Takeda, and consulting fees and honoraria from Alnylam, Bayer, BioMarin Pharmaceutical, CSL, NovoNordisk, Opko Biologics, Pfizer, Takeda, Roche, Sanofi, and Uniquore. O.A. is an employee of Bayer US LLC. B.B. is an employee and stockholder of Bayer AG. D.T.-S. is an employee of Bayer Pharma AG. S.S.-T. and H.G. have no conflicts of interest to declare., (The Author(s). This is an open access article published by Thieme under the terms of the Creative Commons Attribution License, permitting unrestricted use, distribution, and reproduction so long as the original work is properly cited. (https://creativecommons.org/licenses/by/4.0/).)

Introduction:  The Villalta scale is the endorsed tool to diagnose and grade the severity of postthrombotic syndrome (PTS); however, assessing presence and severity of PTS is time-consuming and relies on both the clinician and patient's assessments. The patient-reported Villalta scale version 2 (PRV2) is a visually assisted form that enables patients to self-assess presence and severity of PTS. Herein, we report on external validation of this tool., Methods:  We assessed the agreement and kappa values of PRV2 to diagnose and assess severity of PTS compared with the original Villalta score in a cohort of 181 patients (196 limbs) who participated in the SAVER pilot randomized control trial. Presence of PTS was defined as PRV2 ≥5 or a Villalta score ≥5., Results:  PTS prevalence was 42% using PRV2 and 33% using the Villalta scale. The corresponding kappa and percentage agreement were 0.60 (95% confidence interval [CI]: 0.49-0.71) and 81% (95% CI: 76-87), respectively. Kappa values and percentage agreements between PRV2 and Villalta scale increased with increasing severity of PTS. The sensitivity of PRV2 to detect PTS of any severity was 84% (95% CI: 73-92) with a specificity of 79% (95% CI: 71-86)., Conclusion:  We conclude that the PRV2 is an acceptable tool for diagnosing and grading the severity of PTS., Competing Interests: A.D. is the recipient of a University of Ottawa Department of Medicine Research Salary Award. S.R.K. holds a Tier 1 Canada Research Chair in Venous Thromboembolism. M.A.R. is the McGill University Harry Webster Thorp Professor of Medicine. A.D., M.J.K., S.S., S.R.K., C.K., and M.A.R. are investigators of the CanVECTOR network which received funding from the Canadian Institutes of Health Research (CDT-142654)., (Thieme. All rights reserved.)

Venous thromboembolism (VTE) and arterial thromboembolism (ATE) are linked by the common mechanism of thrombin generation. Historically these entities have been treated as separate pathophysiologic processes requiring different treatments: VTE, as the formation of fibrin-/coagulation-factor-derived thrombus in low-flow vasculature, requiring anticoagulants; versus ATE, as largely platelet-derived thrombus in high-flow vasculature, requiring antiplatelet agents. Observational studies have elucidated shared risk factors and comorbidities predisposing individuals with VTE to ATE, and vice versa, and have bolstered the strategy of dual-pathway inhibition (DPI)-the combination of low-dose anticoagulants with antiplatelet agents-to reduce thrombotic outcomes on both sides of the vasculature. Randomized clinical trials have evaluated the efficacy and safety of such regimens-mostly rivaroxaban and aspirin-in high-risk groups of patients, including those with recent acute or chronic coronary syndrome, as well as those with peripheral artery disease with or without revascularization. Studies of extended VTE prophylaxis in acutely ill medical patients have also contributed to the evidence evaluating DPI. The totality of available data supports the concept that DPI can reduce major and fatal thromboembolic outcomes, including stroke, myocardial infarction, VTE, and cardiovascular death in key patient cohorts, with acceptable risk of bleeding. Further data are needed to refine which patients derive the best net clinical benefit from such an approach. At the same time, other novel agents such as contact pathway inhibitors that reduce thrombin generation without affecting hemostasis-and thus maximize safety-should be assessed in appropriate populations., Competing Interests: J.I.W. has served as a consultant and has received honoraria from Alnylam, Anthos, Bayer, BMS, Boehringer Ingelheim, Ionis, Janssen, and Merck. A.C.S. has received research grants from Boehringer Ingelheim and consultation fees from Janssen, Bristol Meyers Squibb, Portola, Boehringer Ingelheim, Bayer, and the ATLAS group. M.G. has received research grant support and honoraria from Janssen. I.K. has no conflict of interest to declare., (Thieme. All rights reserved.)

The postthrombotic syndrome (PTS) is chronic venous insufficiency secondary to a prior deep vein thrombosis (DVT). It is the most common complication of venous thromboembolism (VTE) and, while not fatal, it can lead to chronic, unremitting symptoms as well as societal and economic consequences. The cornerstone of PTS treatment lies in its prevention after DVT. Specific PTS preventative measures include the use of elastic compression stockings and pharmacomechanical catheter-directed thrombolysis. However, the efficacy of these treatments has been questioned by large randomized controlled trials (RCTs). So far, anticoagulation, primarily prescribed to prevent DVT extension and recurrence, appears to be the only unquestionably effective treatment for the prevention of PTS. In this literature review we present pathophysiological, biological, radiological, and clinical data supporting the efficacy of anticoagulants to prevent PTS and the possible differential efficacy among available classes of anticoagulants (vitamin K antagonists [VKAs], low molecular weight heparins [LMWHs] and direct oral anticoagulants [DOACs]). Data suggest that LMWHs and DOACs are superior to VKAs, but no head-to-head comparison is available between DOACs and LMWHs. Owing to their potentially greater anti-inflammatory properties, LMWHs could be superior to DOACs. This finding may be of interest particularly in patients with extensive DVT at high risk of moderate to severe PTS, but needs to be confirmed by a dedicated RCT., Competing Interests: J.P.G. received consultant fees from Sanofi S.A. and Servier Laboratories; research grants from Leo Pharma, Bayer AG, and Bristol-Myers Squibb-Pfizer; and a travel grant from Innothéra. Other authors have no conflicts to declare., (Thieme. All rights reserved.)

Background:  The long-term risk of major bleeding after discontinuing anticoagulant therapy for a first unprovoked venous thromboembolism (VTE) is uncertain., Objectives:  To determine the incidence of major bleeding up to 5 years after discontinuing anticoagulation for a first unprovoked VTE., Methods:  We searched MEDLINE, EMBASE, and Cochrane CENTRAL (from inception to January 2021) to identify relevant randomized controlled trials (RCTs) and prospective cohort studies reporting major bleeding after discontinuing anticoagulation in patients with a first unprovoked or weakly provoked VTE who had completed (IMAGE&#95;)3 months of initial treatment. Unpublished data on major bleeding events and person-years were obtained from authors of included studies to calculate study-level incidence rates. Random-effects meta-analysis was used to pool results across studies., Results:  Of 1,123 records identified by the search, 20 studies (17 RCTs) and 8,740 patients were included in the analysis. During 13,011 person-years of follow-up after discontinuing anticoagulation, the pooled incidence of major bleeding ( n  = 41) and fatal bleeding ( n  = 7) per 100 person-years was 0.35 (95% confidence interval [CI]: 0.20-0.54) and 0.09 (95% CI: 0.05-0.15). The 5-year cumulative incidence of major bleeding was of 1.0% (95% CI: 0.4-2.4%). The case-fatality rate of major bleeding after discontinuing anticoagulation was 19.9% (95% CI: 10.6-31.1%)., Conclusion:  The risk of major bleeding once anticoagulants are discontinued in patients with a first unprovoked VTE is not zero. Estimates from this study can help clinicians counsel patients about the incremental risk of major bleeding with extended anticoagulation to guide decision making about treatment duration for unprovoked VTE., Competing Interests: M.C. reports receiving research support form Leo Pharma and BMS, and honoraria from Pfizer, Bayer, BMS, and Sanofi, outside the submitted work. S.S. reports receiving honoraria from Boehringer Ingelheim, Bayer HealthCare, Daiichi Sankyo, and Sanofi, and research support from Boehringer Ingelheim, Baxter, and Octapharma, outside the submitted work. J.I.W. reports receiving honoraria from Boehringer Ingelheim, Bayer, Daiichi Sankyo, Servier, Bristol-Myers Squibb, Janssen, Novartis, and Ionis Pharmaceuticals, and research support from Boehringer Ingelheim outside the scope of the submitted work. F.C. reports having received research grant support from Pfizer, honoraria for board memberships or symposia from Bayer and AstraZeneca, and travel support from Bayer, Daiichi Sankyo, Leo Pharma, Intermune, and Actelion, outside the submitted work. C.B. reports receiving lecture fees from Bayer HealthCare, Bristol Meyer Squibb, and Boehringer Ingelheim, outside the submitted work. G.A. reports personal fees from Bristol-Myers-Squibb, Pfizer, Bayer Healthcare, Boehringer Ingelheim, and Daiichi Sankyo, outside the submitted work. T.A.B. reports receiving personal fees from Bayer, Bayer Australia, Novo Nordisk, and GlaxoSmithKline, outside the submitted work. W.A.L. reports being an employee of Bayer HealthCare. G.P. reports advisory Board for Alfa-Wassermann, Daiichi-Sankyo, Pfizer, and Roche, and speaker fees from Werfen, outside the submitted work. B.H. reports receiving honoraria from Cornerstone Research Group for provision of methodologic advice related to systematic reviews and meta-analysis. P.P. reports receiving consultancy and lectures fees from Bayer Pharma, Sanofi, Daiichi-Sankyo, and Pfizer, outside the submitted work. H.R.B. reports receiving research support and consultancy fees from Sanofi-Aventis, Bayer HealthCare, Bristol-Myers Squibb, Daiichi-Sankyo, GlaxoSmithKline, Pfizer, Roche, Isis, Thrombogenics, and Boehringer Ingelheim, outside the submitted work. G.L.-G. holds the Chair on Diagnosis of Venous Thromboembolism at the Department of Medicine, University of Ottawa, and a Clinician-Scientist Award from the Heart and Stroke Foundation of Canada. M.R. is the McGill University Harry Webster Thorp Professor of Medicine. G.L.-G reports other support from Portola Pharmaceuticals, Boehringer Ingelheim, Pfizer, Bristol Myers Squibb, LEO Pharma, Daiichi Sankyo, Bayer, Sanofi, and bioMerieux, outside the submitted work. No other authors disclosed any competing interests., (Thieme. All rights reserved.)

Background:  Andexanet alfa (andexanet) is approved for specific anticoagulation reversal in patients with life-threatening or uncontrolled bleeding during treatment with rivaroxaban or apixaban. There is limited experience with andexanet in patients with acute bleeding on edoxaban., Methods:  Patients with acute major bleeding within 18 hours of edoxaban intake were prospectively enrolled. Patients received a bolus and 2-hour follow-on infusion of andexanet. The co-primary efficacy outcomes were change in antifactor Xa activity and the percentage of patients achieving excellent or good hemostasis, 12 hours after andexanet treatment. Efficacy was analyzed in patients with confirmed major bleeding and baseline antifactor Xa activity ≥40 ng/mL. Safety was analyzed in all patients., Results:  Thirty-six patients (mean age: 82 years, 61.1% male and 91.7% with atrial fibrillation) with acute major bleeding on edoxaban received andexanet. The primary site of bleeding was intracranial in 29 patients (80.6%). In the efficacy population ( n  = 28), median antifactor Xa activity decreased from 121.1 (interquartile range [IQR]: 70.3-202.4) ng/mL at baseline to 24.0 (IQR: 77.7-83.7) ng/mL at the end of andexanet bolus (median decrease: 68.9%, 95% confidence interval [CI]: 56.1-77.7%). Excellent or good hemostasis at 12 hours was achieved in 78.6% (95% CI: 59.0-91.7%) of patients. Within 30 days, four patients (11.1%) experienced a thrombotic event and four others (11.1%) died., Conclusion:  In patients with acute major bleeding on edoxaban, andexanet significantly decreased antifactor Xa activity. Hemostatic efficacy was similar to that observed in patients with bleeding on rivaroxaban or apixaban. Thrombotic events occurred at a rate expected in such patients., Competing Interests: A.P.B and L.X. have nothing to report. J.W.E. reports honoraria and/or research grants from AstraZeneca, Bayer, Boehringer Ingelheim, Bristol-Myers Squibb, Daiichi Sankyo Inc., Pfizer, and Servier. S.M. reports grant support from Daiichi Sankyo Inc., Bayer, and Aspen Pharma; serving on advisory boards for Bayer, Bristol-Myers Squibb/Pfizer, Boehringer Ingelheim, and Portola; receiving lecture fees from Portola; and serving on an adjudication committee for AbbVie. T.J.M. reports executive/steering committee payments for ANNEXA-I and ENRICH-AF studies from PHRI/McMaster University; consulting income from CSL Behring; and grants from NHLBI and Genentech. M.C. reports serving on a data and safety monitoring board for Bayer; receiving personal funding or serving on advisory boards for Bristol Myers Squibb Canada, CSL Behring, Servier Canada, Asahi Kasei, Precision Biologics, and Hemostasis Reference Laboratory; preparation of educational material and/or presentations and/or moderation of sessions for Pfizer, Alexion, CSL Behring, and Diagnostica Stago; and individual stock ownership for Alnylam. P.Y. reports former employment with Portola Pharmaceuticals Inc., now Alexion, AstraZeneca Rare Disease. P.C. reports former employment with Portola Pharmaceuticals Inc., now Alexion, AstraZeneca Rare Disease. G.L. reports employment with Portola Pharmaceuticals Inc., now Alexion, AstraZeneca Rare Disease. S.J.C. reports institutional research grants and honoraria from Boehringer Ingelheim, Portola/Alexion Pharmaceuticals, Bristol-Myers Squibb/Pfizer, Bayer, and Daiichi Sankyo Inc., (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/).)

Patients with heart failure (HF) in sinus rhythm (SR) experience an increased incidence of thromboembolic events including stroke. Among patients with HF, high-quality evidence supports the use of oral anticoagulation when atrial fibrillation is present, but the benefit of anticoagulation in SR in the absence of other known indications for anticoagulation is unclear. In four randomized controlled trials (RCTs), warfarin did not improve a composite of clinical outcomes compared with aspirin or placebo in patients with HF with reduced ejection fraction (HFrEF) and SR. A recent RCT assessed the efficacy of the direct oral anticoagulant rivaroxaban versus placebo in patients with HFrEF (including mildly reduced ejection fraction), SR, and coronary artery disease. While rivaroxaban had a neutral effect on the primary composite outcome of myocardial infarction, stroke, or all-cause mortality, exploratory analyses revealed a significant reduction in strokes. It is thus possible that a subgroup of patients with HFrEF who are at high risk of stroke may benefit from anticoagulation. The challenge is to adequately identify this subgroup and to balance the potential benefit of anticoagulation with the risk of major bleeding. There is also an unmet need for evidence around anticoagulation in HF with preserved ejection fraction and SR. This review explores the current evidence around anticoagulation in patients with HF and SR, identifies challenges regarding outcome definitions and patient selection, and offers suggestions for future research., Competing Interests: None declared., (Thieme. All rights reserved.)

Intermediate-high-risk pulmonary embolism (PE) is characterized by right ventricular (RV) dysfunction and elevated circulating cardiac troponin levels despite apparent hemodynamic stability at presentation. In these patients, full-dose systemic thrombolysis reduced the risk of hemodynamic decompensation or death but increased the risk of life-threatening bleeding. Reduced-dose thrombolysis may be capable of improving safety while maintaining reperfusion efficacy. The Pulmonary Embolism International THrOmbolysis (PEITHO)-3 study (ClinicalTrials.gov Identifier: NCT04430569) is a randomized, placebo-controlled, double-blind, multicenter, multinational trial with long-term follow-up. We will compare the efficacy and safety of a reduced-dose alteplase regimen with standard heparin anticoagulation. Patients with intermediate-high-risk PE will also fulfill at least one clinical criterion of severity: systolic blood pressure ≤110 mm Hg, respiratory rate >20 breaths/min, or history of heart failure. The primary efficacy outcome is the composite of all-cause death, hemodynamic decompensation, or PE recurrence within 30 days of randomization. Key secondary outcomes, to be included in hierarchical analysis, are fatal or GUSTO severe or life-threatening bleeding; net clinical benefit (primary efficacy outcome plus severe or life-threatening bleeding); and all-cause death, all within 30 days. All outcomes will be adjudicated by an independent committee. Further outcomes include PE-related death, hemodynamic decompensation, or stroke within 30 days; dyspnea, functional limitation, or RV dysfunction at 6 months and 2 years; and utilization of health care resources within 30 days and 2 years. The study is planned to enroll 650 patients. The results are expected to have a major impact on risk-adjusted treatment of acute PE and inform guideline recommendations., Competing Interests: O.S. has received institutional research grants from Bayer, Leo Pharma, Bristol-Myers Squibb, Merck Sharp and Dome, Daiichi-Sankyo, Boehringer Ingelheim, and Sanofi, and personal consultancy/speaker fees from Bayer, Bristol-Myers Squibb, Pfizer, Boston Scientific, Merck Sharp and Dome, Boehringer Ingelheim, Sanofi, and Chiesi. S.B. has received congress and travel payments from Daiichi-Sankyo and Bayer AG, honoraria from BTG Pharmaceuticals, Boston Scientific, Bayer HealthCare, and Leo Pharma, and institutional grants from Sanofi, outside the submitted work. W.A. reports research support from Bayer; activity in advisory boards for Bayer, Boehringer Ingelheim, Daiichi Sankyo, Portola, Janssen, Aspen, and Sanofi. D.D. has received speaker's honoraria from Bayer Vital, Daiichi-Sankyo, and Pfizer/Bristol-Myers Squibb, and consulting fees from Bayer Vital and Daiichi-Sankyo. In addition, D.D. is a member of SFB1425, funded by the Deutsche Forschungsgemeinschaft (DFG, German Research Foundation #422681845). K.E. reports lecture fees from AstraZeneca, Bayer Vital, Berlin Chemie, Boehringer Ingelheim, and Novartis, and consulting fees from Bayer Vital, Boehringer Ingelheim, Novartis, and Novo Nordisk. M.F. reports lecture fees and travel grants from Bayer, Bristol-Myers Squibb, and Pfizer, and travel grants from Daiichi-Sankyo and Leo Pharma. M.V.H. reports grants from ZonMW Dutch Healthcare Fund, and grants and personal fees to the hospital from Boehringer Ingelheim, Bristol-Myers Squibb/Pfizer, Bayer Health Care, Aspen, and Daiichi-Sankyo, all outside the submitted work. D.J. has served as an advisor or consultant for Bayer HealthCare Pharmaceuticals, Boehringer Ingelheim, Bristol-Myers Squibb, Daiichi-Sankyo, Leo Pharma, Pfizer, ROVI, and Sanofi; served as a speaker or a member of a speakers' bureau for Bayer HealthCare Pharmaceuticals, Boehringer Ingelheim, Bristol-Myers Squibb, Daiichi-Sankyo, Leo Pharma, ROVI, and Sanofi; received grants for clinical research from Daiichi-Sankyo, Sanofi, and ROVI. M.K. reports speaker fees from Pfizer, Boehringer Ingelheim, and Bayer AG, outside the submitted work. M.L. reports consultant and speaker fees from Actelion, Bayer, Thermo Fisher Scientific, Daiichi-Sankyo, MSD, and Bristol-Myers Squibb-Pfizer, and project funding from Thermo Fisher Scientific. N.M. reports consulting fees, speaker fees, and project funding from Bayer AG and Bristol-Myers Squibb/Pfizer; speaker fees from AstraZeneca and Boehringer Ingelheim; and consulting fees from Abbott and Terumo. A.P. reports speaker fees from S.C. Pfizer Romania SRL, Servier Pharma SRL, Novartis Pharma Services Romania SRL, Bayer SRL, and SC Sanience SRL.S.R. received honoraria for lectures and/or consultancy from Abbott, Acceleron, Actelion, Arena, Bayer, BMS, Ferrer, Janssen, MSD, Novartis, Pfizer, United Therapeutics, and Vifor, and institutional research grants from Actelion, AstraZeneca, Bayer, Janssen, and Novartis. S.S. has received consulting fees and speaker fees from Aspen and Boehringer Ingelheim, speaker fees from Bayer AG and Daiichi-Sankyo, and project funding and speaker fees from Pfizer/Bristol-Myers Squibb. P.V. received honoraria for lectures and/or consultancy from Anthos Therapeutics, Bayer, Boehringer, Daiichi-Sankyo, BMS, and Pfizer, and research support from Bayer, Daiichi-Sankyo, BMS, and Pfizer. S.K. reports institutional research grants and personal consultancy/speaker fees from Actelion/Janssen, Bayer AG, Daiichi-Sankyo, and Boston Scientific; institutional research grants from Boehringer Ingelheim and Servier; and personal consultancy/speaker fees from Bristol-Myers Squibb/Pfizer and Novartis. All other authors report no conflict of interest., (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/).)

Coronavirus disease-2019 (COVID-19) has been associated with significant risk of venous thromboembolism (VTE), arterial thromboembolism (ATE), and mortality particularly among hospitalized patients with critical illness and elevated D-dimer (Dd) levels. Conflicting data have yet to elucidate optimal thromboprophylaxis dosing. HEP-COVID (NCT04401293) is a phase 3, multicenter, pragmatic, prospective, randomized, pseudo-blinded, active control trial to evaluate efficacy and safety of therapeutic-dose low-molecular-weight heparin (LMWH) versus prophylactic-/intermediate-dose LMWH or unfractionated heparin (UFH) for prevention of a primary efficacy composite outcome of VTE, ATE, and all-cause mortality 30 ± 2 days post-enrollment. Eligible patients have COVID-19 diagnosis by nasal swab or serologic testing, requirement for supplemental oxygen per investigator judgment, and Dd >4 × upper limit of normal (ULN) or sepsis-induced coagulopathy score ≥4. Subjects are randomized to enoxaparin 1 mg/kg subcutaneous (SQ)/two times a day (BID) (creatinine clearance [CrCl] ≥ 30 mL/min) or 0.5 mg/kg (CrCl 15-30 mL/min) versus local institutional prophylactic regimens including (1) UFH up to 22,500 IU (international unit) daily (divided BID or three times a day), (2) enoxaparin 30 and 40 mg SQ QD (once daily) or BID, or (3) dalteparin 2,500 IU or 5,000 IU QD. The principal safety outcome is major bleeding. Events are adjudicated locally. Based on expected 40% relative risk reduction with treatment-dose compared with prophylactic-dose prophylaxis, 308 subjects will be enrolled (assuming 20% drop-out) to achieve 80% power. Distinguishing design features include an enriched population for the composite endpoint anchored on Dd >4 × ULN, stratification by intensive care unit (ICU) versus non-ICU, and the ability to capture asymptomatic proximal deep venous thrombosis via screening ultrasonography prior to discharge., Competing Interests: M.G.: research grant from Janssen; M.C.: speakers bureau Sanofi; A.T.: educational grant: Janssen, research grant: Janssen, Bristol Meyers Squibb, Idorsia, consultant: Recovery Force, J.M.K.: consultant for Bayer Healthcare, Jansen, the ATLAS Group, AMAG pharmaceuticals, Agile Therapeutics for advisory and steering committee activities. Data and safety monitoring committees for Cystic Fibrosis Foundation Therapeutics, Novo Nordisk, Pfizer, Genentech, and BioMarin pharmaceuticals. M.B.: research grant support to CPC Clinical Research from Amgen, AstraZeneca, Bayer, Janssen, Merck, NovoNordisk; J.L.H.: consultancies with the ATLAS Group, Bayer Healthcare, Boehringer Ingelheim, and Population Health Research Institute; J.I.W.: consultant for Anthos, ATLAS Group, Bayer, Boehringer Ingelheim, Bristol Myers Squibb, Daiichi Sankyo, Ionis, Janssen, Johnson and Johnson, Merck, Pfizer, PhaseBio, and Servier, institutional research grants from Bayer and Boehringer Ingelheim; A.C.S.: Janssen, Boehringer Ingelheim, Bayer, BMS, Portola, ATLAS Group: consultancy; Janssen, Boehringer Ingelheim: research funding. D.G., W.D., J.W., S.K., G.S., J.M.L., A.M., E.G., P.A.L., K.C., M.L., C.P.S., H.R., K.O., W.R.H., R.A.D., V.E.A.: no conflict of interest., (Thieme. All rights reserved.)

Introduction:  FVIII inhibitor development is the most serious contemporary treatment complication in haemophilia A, particularly in previously untreated patients (PUPs). No inhibitors developed in clinical trials in previously treated patients treated with simoctocog alfa (Nuwiq), a fourth-generation recombinant FVIII produced in a human cell line., Methods:  The NuProtect study investigated the immunogenicity of simoctocog alfa in PUPs. NuProtect was a prospective, multinational, open-label, non-controlled, phase III study. PUPs with severe haemophilia A (FVIII:C <1%) of any age and ethnicity were treated with simoctocog alfa for 100 exposure days or a maximum of 5 years. Patients were true PUPs without prior exposure to FVIII concentrates or blood components. Inhibitor titres were measured with the Nijmegen-modified Bethesda assay; cut-off for positivity was 0.6 BU mL -1 (≥0.6 to <5 low-titre, ≥5 high titre)., Results:  A total of 108 PUPs with a median age at first treatment of 12.0 months (interquartile range: 8.0-23.5) were treated with simoctocog alfa. F8 mutation type was known for 102 patients (94.4%) of whom 90 (88.2%) had null F8 mutations and 12 (11.8%) had non-null mutations. Of 105 PUPs evaluable for inhibitor development, 28 (26.7%) developed inhibitors; 17 high titre (16.2%) and 11 low titre (10.5%). No PUPs with non-null F8 mutations developed inhibitors., Conclusion:  In the NuProtect study, the rate of inhibitor development in PUPs with severe haemophilia A treated with simoctocog alfa was lower than the rate reported for hamster-cell-derived recombinant factor VIII products in other recent clinical trials. No inhibitors were reported in PUPs with non-null F8 mutations., Competing Interests: R. J. Liesner, A. Abraham, C. Altisent, M. J. Belletrutti, M. Carcao, M. Carvalho, H. Chambost, A. K. C. Chan, L. Dubey, J. Ducore, M. Gattens, P. Gresele, Y. Gruel, B. Guillet, V. J. Yuste, L. Kitanovski, A. Klukowska, S. Lohade, J. Oldenburg, A. Pavlova, B. Pollio, M. Sigaud, V. Vdovin, K. Vilchevska, J. K. M. Wu and E. J. Neufeld were clinical study investigators for the NuProtect Study (Octapharma-sponsored). R. J. Liesner has received grants/research support from Octapharma, Bayer, Baxalta, Novo Nordisk and Roche, has acted as a consultant for Bayer and Baxalta, and has participated in speaker bureaus for Novo Nordisk, Octapharma and SOBI. A. Abraham has received grants/research support from Novo Nordisk and Roche, and has received support for attending scientific meetings from Novo Nordisk. C. Altisent has been a member of advisory boards and/or speaker bureaus for Baxalta (Shire), Bayer, CSL Behring, Grifols, Octapharma, Novo Nordisk, Pfizer, Roche and SOBI. M. J. Belletrutti has received research support from Octapharma, has acted as a consultant for Roche Canada, Sanofi and Takeda Canada, and has participated in speaker bureaus for Octapharma Canada and Takeda Canada. M. Carcao received research support/grants from Bayer, Novo Nordisk, Pfizer, Sanofi and Takeda, and has participated in speaker bureaus for Bayer, CSL Behring, Grifols, LFB, Novo Nordisk, Octapharma, Pfizer, Roche, Sanofi and Takeda. M. Carvalho has been an investigator on clinical trials sponsored by CSL Behring, Novo Nordisk, Octapharma and Roche, and has received support for attending scientific meetings and honoraria (speaker fees/consultant in advisory boards) for Bayer, Baxalta (Shire), CSL Behring, Novo Nordisk, Octapharma, Pfizer, Siemens, SOBI and Stago. H. Chambost has received research support from CSL Behring, LFB, Novo Nordisk, Octapharma, Roche/Chugaï, Shire/Takeda, SOBI; honoraria from Bayer, LFB, Octapharma, Pfizer, Roche and SOBI. A. K. C. Chan has been an investigator on clinical trials sponsored by Bayer, Biogen, CSL, Novo Nordisk, Octapharma and Shire and has received grants/research support from Bayer and Pfizer, and has participated in advisory boards for Bayer, Biogen, BioMarin, Novo Nordisk and Octapharma. J. Ducore has been an investigator on clinical trials sponsored by Octapharma, CSL Behring, OPKO Biologics, Bayer, Baxalta (Shire), Sparks Therapeutics, Biogen, Pfizer, Genentech (Roche), LFB and RevBio, has provided consultancy services to Octapharma, Bayer, Baxalta (Shire), Biogen and LFB, and is a speaker for Bayer. Y. Gruel has received support for attending scientific meetings and honoraria (speaker fees/consultant in advisory boards) from Baxalta (Shire), Bayer Healthcare, CSL Behring, LFB, Novo Nordisk, Octapharma, Pfizer, Roche and SOBI, has been an investigator in studies sponsored by Biogen, LFB and SOBI, and has received research support from CSL Behring, LFB and Octapharma. B. Guillet has been an investigator on clinical trials, or has received honoraria for speaking/consulting or funds for research from Bayer, CSL Behring, LFB, Novo Nordisk, Octapharma, Roche, SOBI and Takeda/Shire. V. J. Yuste has received reimbursement for attending symposia/congresses and/or honoraria for speaking and/or honoraria for consulting, and/or funds for research from Shire, Bayer, CSL Behring, Grifols, Novo Nordisk, SOBI, Octapharma and Pfizer. A. Klukowska has received personal fees from CSL Behring, Novo Nordisk, Octapharma, Pfizer, Roche, Shire and SOBI. M. E. Mancuso has received speaker and/or consultancy fees from Bayer Healthcare, CSL Behring, Takeda, Octapharma, Roche, Pfizer, Kedrion, Grifols, Novo Nordisk and SOBI. J. Oldenburg has received reimbursement for attending symposia/congresses or honoraria for speaking or honoraria for consulting, or funds for research from Bayer, Biogen Idec, Biotest, Chugai, CSL Behring, Grifols, Novo Nordisk, Octapharma, Pfizer, Roche, Shire and SOBI. A. Pavlova has participated in studies sponsored by Octapharma AG. B. Pollio has received support for attending scientific meetings and honoraria (speaker fees/consultant in advisory boards) from Baxalta (Shire), Bayer Healthcare, CSL Behring, Kedrion, Novo Nordisk, Octapharma, Pfizer and SOBI. M. Sigaud has received reimbursement for attending symposia/congresses, honoraria for speaking or for consulting from Biomarin, CSL Behring, Novo Nordisk, Octapharma, Roche and Shire/Takeda. J. K. M. Wu received funding to attend meetings and has participated in Octapharma-funded clinical research. M. Jansen is a full-time employee of Octapharma GmbH, Vienna, Austria. L. Belyanskaya, O. Walter and S. Knaub are employees of Octapharma AG, Lachen, Switzerland. E. J. Neufeld has received honoraria and participated in advisory boards for Octapharma. He has been a consultant for Genentech and Pfizer, and has participated in advisory boards for Novo Nordisk, Kedrion, Genentech, Baxalta/Shire (now Takeda), Novartis and CSL-Behring during the course of the NuProtect study. He has served on data monitoring committees for Bayer, Acceleron Pharma and ApoPharma (now Chiesi), and received research funding from the American Thrombosis and Hemostasis Network (ATHN). L. Dubey, M. Gattens, P. Gresele, L. Kitanovski, S. Lohade, V. Vdovin and K. Vilchevska declare no competing financial interests., (The Author(s). This is an open access article published by Thieme under the terms of the Creative Commons Attribution License, permitting unrestricted use, distribution, and reproduction so long as the original work is properly cited. (https://creativecommons.org/licenses/by/4.0/).)

Background: Antiphospholipid syndrome is associated with recurrent pregnancy loss. Low-molecular-weight heparin (LMWH) and/or aspirin (ASA) prophylaxis during pregnancy to prevent future loss is based on limited trial data with mixed results., Objectives: Given the clinical equipoise, we sought to understand how patients and physicians navigate the decision-making process for use of LMWH and/or ASA in pregnancy., Methods: We interviewed 10 patients and 10 thrombosis physicians in Ottawa, Canada from January 2017 to March 2018. Patients who had ≥1 late pregnancy loss or ≥2 early losses and persistently positive antiphospholipid antibodies based on the revised Sapporo/Sydney criteria were identified in the a Thrombosis Clinic. Patients were also identified by the TIPPS Study screening logs of excluded patients. Data collection and analysis occurred iteratively, in keeping with constructivist grounded theory methodology., Results: Our analysis generated three themes, present across both patient and physician interviews, which captured a patient-led decision-making experience: (1) managing high stakes, (2) accepting uncertainty, and (3) focusing on safety. Patients and physicians acknowledged the high emotional burden and what was at stake: avoiding further pregnancy loss. Patients responded to their situation by taking action (i.e., using LMWH injections became a "ritual"), whereas physicians reacted by removing themselves from the final decision by "[leaving] it up to the patient.", Conclusion: Our findings should be considered when designing future research on studying the role for LMWH/ASA in this population, as it suggests that the perceived benefits of treatment go beyond improving pregnancy rates. Rather, patients described potential benefit from the process of taking action, even in the absence of a guaranteed good outcome., Competing Interests: L.S.: honoraria from LEO Pharma; Research funding from CSL Behring. M.A.R.: no conflicts of interest to report. S.M.B.: honoraria from LEO Pharma. C.G.: no conflicts of interests to report. A.K.: no conflicts of interest to report. T.S.T.: no conflicts of interest to report. S.M.B. holds the Eli Lilly Canada/May Cohen Chair in Women's Health. M.R. is the McGill Harry Webster Thorp Professor of Medicine., (Thieme. All rights reserved.)

In 2018, the International Council for Standardization in Haematology (ICSH) published a consensus document providing guidance for laboratories on measuring direct oral anticoagulants (DOACs). Since that publication, several significant changes related to DOACs have occurred, including the approval of a new DOAC by the Food and Drug Administration, betrixaban, and a specific DOAC reversal agent intended for use when the reversal of anticoagulation with apixaban or rivaroxaban is needed due to life-threatening or uncontrolled bleeding, andexanet alfa. In addition, this ICSH Working Party recognized areas where additional information was warranted, including patient population considerations and updates in point-of-care testing. The information in this manuscript supplements our previous ICSH DOAC laboratory guidance document. The recommendations provided are based on (1) information from peer-reviewed publications about laboratory measurement of DOACs, (2) contributing author's personal experience/expert opinion and (3) good laboratory practice., Competing Interests: Among the authors, J.D. is the CEO and founder of QUALIblood s.a., a contract research organization manufacturing the DP-Filter, is a co-inventor of the DP-Filter (patent application number: PCT/ET2019/052903) and reports personal fees from Daiichi Sankyo, Mithra Pharmaceuticals, Stago, Roche and Roche Diagnostics outside the submitted work. E.L.-L received lecture fees and consulting fees from Bayer, Boehringer Ingelheim, Bristol-Myers Squibb-Pfizer, Daiichi Sankyo, Portola, CSL Behring, Leo and Aspen. She received external funds for conducting a clinical contract study from Bayer and Daiichi Sankyo, for a research project that she initiated from Bayer AG, Bristol-Myers Squibb-Pfizer, Daiichi Sankyo and CSL Behring. E.J.F. and S.M.B. have no conflict of interest. I.G.T. received consulting fees from Bayer, Boehringer Ingelheim and Bristol-Myers Squibb-Pfizer. R.C.G. reports personal fees from Diagnostica Grifols, Siemens Healthcare Diagnostics and Diagnostica Stago, and has provided expert testimony on dabigatran and rivaroxaban testing., (Thieme. All rights reserved.)

Background: Lack of data on balancing bleeding and thrombosis risk causes uncertainty about restarting anticoagulants after major bleeding. Anticoagulant reversal trials offer prospectively gathered data after major bleeding with well-documented safety events and restarting behavior., Objectives: To examine the relationship of restarting anticoagulation with thrombosis, rebleeding, and death., Methods: This is a posthoc analysis of a prospective factor Xa inhibitor reversal study at 63 centers in North America and Europe. We compared outcomes of restarted patients with those not restarted using landmark and time-dependent Cox proportional hazards models. Outcomes included thrombotic and bleeding events and death and a composite of all three., Results: Of 352 patients enrolled, oral anticoagulation was restarted in 100 (28%) during 30-day follow-up. Thirty-four (9.7%) had thrombotic events, 15 (4.3%) had bleeding events (after day 3), and 49 (14%) died. In the landmark analysis comparing patients restarted within 14 days to those not, restarting was associated with decreased thrombotic events (hazard ratio [HR] = 0.112; 95% confidence interval [CI]: 0.001-0.944; p  = 0.043) and increased rebleeding (HR = 8.39; 95% CI: 1.13-62.29; p  = 0.037). The time-dependent Cox model showed evidence for a reduction in a composite (thrombotic events, bleeding, and death) attempting to capture net benefit (HR = 0.384; 95% CI: 0.161-0.915; p  = 0.031)., Conclusion: This analysis provides modest evidence that restarting anticoagulation in factor Xa inhibitor-associated major bleeding patients is correlated with reduced risk of thrombotic events and increased risk of rebleeding. There is low-level evidence of net benefit for restarting. A randomized trial of restarting would be appropriate., Competing Interests: T.J.M.: CSL Behring: consulting; Portola: grant support, steering committee; Octapharma: steering committee. B.K.: none. P.Y.: Portola: employee. S.M.: Daiichi Sankyo, Bayer, Aspen Pharma: grant support; Bristol Myers Squibb/Pfizer, Boehringer Ingelheim, Portola: advisory board; Portola: lecture fees; AbbVie: adjudication committee. J.B.-W.: Bayer, Daiichi Sankyo: grant support, lecture fees, advisory board fees; Pfizer: grant support; Portola: lecture fees, advisory board fees. J.W.E.: AstraZeneca, Bayer, Boehringer Ingelheim, Bristol Myers Squibb/Pfizer, Daiichi Sankyo, Eli Lilly, GlaxoSmithKline, Janssen, Sanofi-Aventis: grant support, honoraria. M.C.: Bristol Myers Squibb Canada, Asahi Kasei, Servier Canada, Precision Biologics, Hemostasis Reference Laboratory, CSL Behring: advisory board; Alexion, Pfizer, CSL Behring, Diagnostica Stago: educational funding; Bayer, Leo Pharma: grant support; Daiichi Sankyo, Bayer, Octapharma: data safety monitoring board. L.X.: None. P.V.: Bayer Healthcare, Boehringer Ingelheim, Daiichi Sankyo, Pfizer, Bristol Myers Squibb, Leo Pharma: grant support, consulting, lecture fees; Boehringer Ingelheim: adjudication committee; Anthos, Janssen, Portola: consulting. D.M.S.: Bayer, Bristol Myers Squibb/Pfizer, Servier Canada, Novartis, Leo Pharma, Aspen Pharma, Portola: consulting. S.J.C.: Portola, Bristol Myers Squibb, Bayer, Daiichi Sankyo: grant support, consulting; Javelin: consulting., (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/).)

Background: One year after the declaration of the coronavirus disease 2019 (COVID-19) pandemic by the World Health Organization (WHO) and despite the implementation of mandatory physical barriers and social distancing, humanity remains challenged by a long-lasting and devastating public health crisis., Management: Non-pharmacological interventions (NPIs) are efficient mitigation strategies. The success of these NPIs is dependent on the approval and commitment of the population. The launch of a mass vaccination program in many countries in late December 2020 with mRNA vaccines, adenovirus-based vaccines, and inactivated virus vaccines has generated hope for the end of the pandemic., Current Issues: The continuous appearance of new pathogenic viral strains and the ability of vaccines to prevent infection and transmission raise important concerns as we try to achieve community immunity against severe acute respiratory syndrome coronavirus type 2 (SARS-CoV-2) and its variants. The need of a second and even third generation of vaccines has already been acknowledged by the WHO and governments., Perspectives: There is a critical and urgent need for a balanced and integrated strategy for the management of the COVID-19 outbreaks organized on three axes: (1) P revention of the SARS-CoV-2 infection, (2) Detection and early diagnosis of patients at risk of disease worsening, and (3) Anticipation of medical care (PDA)., Conclusion: The "PDA strategy" integrated into state policy for the support and expansion of health systems and introduction of digital organizations (i.e., telemedicine, e-Health, artificial intelligence, and machine-learning technology) is of major importance for the preservation of citizens' health and life world-wide., Competing Interests: None declared., (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/).)

The coronavirus disease 2019 (COVID-19) is our latest pandemic, preceded by the H1N1 swine flu in 2009, which lasted approximately 19 months. One of the special characteristics of COVID-19 is the propensity to cause venous thromboembolism (VTE). Thromboinflammation seems to play a prominent role in the pathogenesis. We will here review some mechanisms in the pathogenesis and discuss some hematological biomarkers, and also whether they serve as useful risk factors for VTE. The role of general risk assessment models for medically ill patients specifically in COVID-19 is appraised. The type of prophylaxis and particularly whether standard or augmented doses of chemoprophylaxis should be used is reviewed based on available evidence. We are also comparing recommendations from 10 different guidance or position/consensus statements. Treatment recommendations for patients with COVID-19 and pulmonary embolism are discussed with current general treatment guidelines as reference. Specifics for patients with COVID-19 are pointed out and the potential role of thrombolytic treatment is explored., Competing Interests: S.S. reports grants from Boehringer-Ingelheim and Octapharma, personal fees from Boehringer-Ingelheim, Bayer, Daiichi, Alnylam, Sanofi, Bristol-Myers Squibb, and Pfizer, outside the submitted work. S.K. reports research grants from Bayer AG, Boehringer-Ingelheim, and Actelion Janssen; educational grants from Biocompatibles Group UK—Boston Scientific and Daiichi Sankyo; lecture fees from Bayer AG, Pfizer-Bristol-Myers Squibb, and MSD, all outside the submitted work. Y.H. has nothing to disclose., (Thieme. All rights reserved.)

Background:  Recent reports suggest an important contribution from frequent off-label use of apixaban 2.5 mg twice daily to the higher rates of thromboembolic events observed in observational studies (OSs) relative to in randomized controlled trials (RCTs), and consequently, advocate against such use in all patients., Objectives:  To examine factors contributing to the higher thromboembolic event rates, we estimated the prevalence of off-label use in contemporary practice, and compared patient characteristics and rates of stroke/systemic embolism, major bleeding, and mortality by apixaban dose and by study design in a systematic review and meta-analysis., Results and Discussion:  We identified 18 OSs and 2 RCTs that included 155,228 and 11,928 patients, respectively. Patients in OSs more often received apixaban 2.5 mg twice daily (31.3% vs. 5.1%), were older (mean age 73.8 vs. 69.8 years), and had higher CHA 2 DS 2 -VASc scores (mean 3.6 vs. 2.9) versus those in RCTs. We observed a consistent pattern of higher rates of thromboembolic events, bleeding, and mortality in patients treated with 2.5 versus 5 mg twice daily apixaban in both OSs and RCTs., Conclusion:  The higher risk profiles of patients in OSs versus RCTs, and higher rates of both bleeding and mortality not attributable to thromboembolism in patients treated with apixaban 2.5 versus 5 mg twice daily suggest that differences in patient characteristics are additional important contributors to the higher than expected thromboembolic event rates in clinical practice., Competing Interests: T.A.C.V. has received honoraria from Daiichi Sankyo. J.W.E. has received honoraria and research support from Astra-Zeneca, Bayer, Boehringer Ingelheim, Bristol-Myers Squibb, Daiichi Sankyo, Janssen, Pfizer, Portola, and Sanofi. V.C.B. has received grants from Pfizer, Canada and honoraria from Bayer. N.C.C. has received honoraria from Bayer. Other authors report no conflicts of interests., (Thieme. All rights reserved.)

Competing Interests: S.S. reports grants from Boehringer-Ingelheim and Octapharma, personal fees from Boehringer-Ingelheim, Bayer, Daiichi, Alnylam, Sanofi, Bristol-Myers Squibb, and Pfizer, outside the submitted work.S.K. reports grants and personal fees from Bayer AG, grants and personal fees from Daiichi Sankyo, personal fees from Pfizer-Bristol-Mayers Squibb, grants and personal fees from BTG - Boston Scientific Group, grants from Boehringer-Ingelheim, personal fees from MSD, grants and personal fees from Actelion - Janssen, grants from Servier, outside the submitted work.

Despite advances in secondary prevention strategies in patients with cardiovascular disease, the residual risk of recurrent atherothrombotic events remains high. Dual-antiplatelet therapy is the standard of care for secondary prevention in patients with acute coronary syndrome (ACS), whereas single antiplatelet therapy, generally with aspirin, is the standard of care for secondary prevention in stable patients with coronary artery disease (CAD), peripheral artery disease (PAD), or cerebrovascular disease. However, atherosclerotic plaque disruption not only triggers platelet activation but also results in thrombin generation because of tissue factor exposure. Therefore, blocking both pathways by combining antiplatelet therapy with an anticoagulant, or dual pathway inhibition (DPI), has the potential to be more effective than inhibiting either pathway alone. The benefit of DPI has been demonstrated in the ATLAS ACS 2-TIMI 51, COMPASS, and VOYAGER PAD trials, where the combination of rivaroxaban vascular dose (2.5 mg twice daily) plus aspirin significantly reduced the risk of atherothrombotic events compared with aspirin across a broad range of patients, including those with recent ACS, those with chronic CAD and/or PAD, and patients with PAD who have undergone peripheral revascularization. This article provides the rationale for this regimen in more detail, including why the DPI regimen with the rivaroxaban vascular dose was developed for vascular protection in a broad spectrum of patients with atherosclerotic disease., Competing Interests: J.I.W. received honoraria from Anthos, Bayer AG, Boehringer Ingelheim, Bristol-Myers Squibb, Daiichi Sankyo, Ionis, Janssen, Novartis, Pfizer, PhaseBio, Portola, Servier, and Tetherex Pharmaceuticals and institutional grants from Bayer AG and Boehringer Ingelheim. D.J.A. has received payment as an individual for: (a) consulting fee or honorarium from Amgen, Aralez Pharmaceuticals, AstraZeneca, Bayer AG, Biosensors, Boehringer Ingelheim, Bristol-Myers Squibb, Chiesi, Daiichi Sankyo, Eli Lilly, Haemonetics, Janssen, Merck, Pfizer, PhaseBio, PLx Pharma, Sanofi, and The Medicines Company; (b) participation in review activities from CeloNova BioSciences and St. Jude Medical; (c) institutional payments for grants from Amgen, AstraZeneca, Bayer AG, Biosensors, CeloNova BioSciences, CSL Behring, Daiichi Sankyo, Eisai, Eli Lilly, Gilead, Idorsia Pharmaceuticals, Janssen, Matsutani Chemical Industry Co., Merck, Novartis, Osprey Medical RenalGuard Solutions, and the Scott R. MacKenzie Foundation. T.G. received grants and personal fees from Bayer AG, Bristol-Myers Squibb, Daiichi Sankyo, and The Medicines Company, personal fees from AstraZeneca, Boehringer Ingelheim, Chiesi, Ferrer, MSD, and Pfizer, grants from Siemens Healthcare and Spartan Bioscience outside the submitted work. S.H. is an employee of Bayer AG. D.J.A. reports grants and personal fees from Amgen, grants and personal fees from Aralez, grants and personal fees from Bayer, grants and personal fees from Biosensors, grants and personal fees from Boehringer Ingelheim, grants and personal fees from Bristol-Myers Squibb, grants and personal fees from Chiesi, grants and personal fees from Daiichi-Sankyo, grants and personal fees from Eli Lilly, personal fees from Haemonetics, grants and personal fees from Janssen, grants and personal fees from Merck, personal fees from PhaseBio, personal fees from PLx Pharma, personal fees from Pfizer, grants and personal fees from Sanofi, personal fees from The Medicines company, grants and personal fees from CeloNova, personal fees from St Jude Medical, grants from CSL Behring, grants from Eisai, grants from Gilead, grants from Idorsia Pharmaceuticals Ltd, grants from Matsutani Chemical Industry Co., grants from Novartis, grants from Osprey Medical, grants from Renal Guard Solutions, grants from Scott R. MacKenzie Foundation, grants from NIH/NCATS Clinical and Translational Science Award to the University of Florida UL1 TR000064 and NIH/NHGRI U01 HG007269, grants and personal fees from Astra Zeneca, outside the submitted work. T.G. reports personal fees from Astra Zeneca, personal fees from Boehringer Ingelheim, personal fees from Pfizer, grants and personal fees from Bayer AG, grants and personal fees from Bristol Myers Squibb, grants and personal fees from Daiichi Sankyo, grants and personal fees from Eli Lilly, personal fees from Ferrer, outside the submitted work. J.I.W. reports personal fees from Bayer, personal fees from Boehringer Ingelheim, personal fees from Bristol-Myers Squibb, personal fees from Daiichi-Sankyo, personal fees from Ionis, personal fees from Janssen, personal fees from Merck, personal fees from Novartis, personal fees from Pfizer, personal fees from Portola, outside the submitted work., (Georg Thieme Verlag KG Stuttgart · New York.)

Coronavirus disease 2019 (COVID-19), currently a worldwide pandemic, is a viral illness caused by the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). The suspected contribution of thrombotic events to morbidity and mortality in COVID-19 patients has prompted a search for novel potential options for preventing COVID-19-associated thrombotic disease. In this article by the Global COVID-19 Thrombosis Collaborative Group, we describe novel dosing approaches for commonly used antithrombotic agents (especially heparin-based regimens) and the potential use of less widely used antithrombotic drugs in the absence of confirmed thrombosis. Although these therapies may have direct antithrombotic effects, other mechanisms of action, including anti-inflammatory or antiviral effects, have been postulated. Based on survey results from this group of authors, we suggest research priorities for specific agents and subgroups of patients with COVID-19. Further, we review other agents, including immunomodulators, that may have antithrombotic properties. It is our hope that the present document will encourage and stimulate future prospective studies and randomized trials to study the safety, efficacy, and optimal use of these agents for prevention or management of thrombosis in COVID-19., Competing Interests: No specific funding was sought or received for this manuscript. A list of Disclosures for co-authors is available online in the Supplementary Material (available in the online version)., (Georg Thieme Verlag KG Stuttgart · New York.)

Competing Interests: N.C.C. reports personal fees from Bayer outside the submitted work.

The association between blood levels of protein Z (PZ) and risk of ischemic stroke remains poorly understood. We aimed to assess this potential relationship through a meta-analysis of case-control studies. PubMed, Scopus, Web of Science Core Collection, and the Cochrane Library were searched from April 1984 to April 2019. We selected case-control studies comparing PZ levels in adult patients with ischemic stroke and controls without ischemic stroke. Six case-control studies, with a total of 1,011 ischemic stroke patients and 1,128 controls, were included. Patients in the acute phase of ischemic stroke showed significantly higher levels of PZ compared with patients in the convalescent phase (standardized mean difference [SMD]: 0.289 mg/L; 95% confidence interval [CI]: 0.010, 0.569; p  = 0.043). No significant differences in PZ levels were found between patients and controls in the acute phase (SMD: -0.059 mg/L; 95% CI: -0.570, 0.452; p  = 0.821) or in the convalescent phase of ischemic stroke (SMD: -0.341 mg/L; 95% CI: -0.736, 0.055; p  = 0.091). Subgroup analysis indicated that older patients (≥ 50 years old) had lower PZ levels than similarly aged controls. In contrast, when the study groups came from the United States and Australia or Europe no significant differences in PZ levels existed between patients and controls. No association between PZ and ischemic stroke was identified in this meta-analysis. The acute phase of ischemic stroke was associated with higher levels of PZ., Competing Interests: None declared., (Georg Thieme Verlag KG Stuttgart · New York.)

Background:  Venous thromboembolism (VTE) is a major cause of death in cancer patients. Although patients with cancer have numerous risk factors for VTE, the relative contribution of cancer treatments is unclear., Objective:  The objective of this study is to evaluate the association between cancer therapies and the risk of VTE., Methods:  From UK Clinical Practice Research Datalink, data on patients with first cancer diagnosis between 2008 and 2016 were extracted along with information on hospitalization, treatments, and cause of death. Primary outcome was active cancer-associated VTE. To establish the independent effects of risk factors, adjusted subhazard ratios (adj-SHR) were calculated using Fine and Gray regression analysis accounting for death as competing risk., Results:  Among 67,801 patients with a first cancer diagnosis, active cancer-associated VTE occurred in 1,473 (2.2%). During a median observation time of 1.2 years, chemotherapy, surgery, hormonal therapy, radiation therapy, and immunotherapy were given to 71.1, 37.2, 17.2, 17.5, and 1.4% of patients with VTE, respectively. The active cancers associated with the highest risk of VTE-as assessed by incidence rates-included pancreatic cancer, brain cancer, and metastatic cancer. Chemotherapy was associated with an increased risk of VTE (adj-SHR: 3.17, 95% confidence interval [CI]: 2.76-3.65) while immunotherapy with a not significant reduced risk (adj-SHR: 0.67, 95% CI: 0.30-1.52). There was no association between VTE and radiation therapy (adj-SHR: 0.91, 95% CI: 0.65-1.27) and hormonal therapies., Conclusion:  VTE risk varies with cancer type. Chemotherapy was associated with an increased VTE risk, whereas with radiation and immunotherapy therapy, an association was not confirmed., Competing Interests: A.T.C. reports receiving consulting fees and research funding from Bayer, Boehringer Ingelheim, BMS, Daiichi-Sankyo, Johnson and Johnson, Pfizer, Portola, Sanofi, and XO1. He is an advisor to the UK Government Health Select Committee, the all-party working group on thrombosis, the Department of Health and the NHS on the prevention of VTE. He is also an advisor to Lifeblood: the thrombosis charity and is the founder of the European educational charity, the Coalition to Prevent VTE. J.I.W. receives support from research grant (significant): Bayer AG, Daiichi-Sankyo, Bristol-Myers Squibb, Pfizer; Honoraria (significant): Bayer, Boehringer Ingelheim, Bristol-Myers Squibb, Daiichi-Sankyo, Ionis Pharmaceuticals, Janssen, Merck, Novartis, Portola, Pfizer. T.S.F. research supports from Bayer Canada (in-kind study medication); honoraria from Bayer Canada, Boehringer Ingelheim Canada, Pfizer-BMS, and Servier. A.K., C.M., and C.W. are employees of the Institute for Epidemiology, Statistics and Informatics GmbH. The Institute for Epidemiology, Statistics and Informatics GmbH has received grants from Bayer, Bristol-Myers Squibb, CSL Behring, and Merz Pharma outside the submitted work. M.G., A.C., S.S., and B.W. have nothing to disclose., (Georg Thieme Verlag KG Stuttgart · New York.)

Thrombo-inflammation describes the complex interplay between blood coagulation and inflammation that plays a critical role in cardiovascular diseases. The third Maastricht Consensus Conference on Thrombosis assembled basic, translational, and clinical scientists to discuss the origin and potential consequences of thrombo-inflammation in the etiology, diagnostics, and management of patients with cardiovascular disease, including myocardial infarction, stroke, and peripheral artery disease. This article presents a state-of-the-art reflection of expert opinions and consensus recommendations regarding the following topics: (1) challenges of the endothelial cell barrier; (2) circulating cells and thrombo-inflammation, focused on platelets, neutrophils, and neutrophil extracellular traps; (3) procoagulant mechanisms; (4) arterial vascular changes in atherogenesis; attenuating atherosclerosis and ischemia/reperfusion injury; (5) management of patients with arterial vascular disease; and (6) pathogenesis of venous thrombosis and late consequences of venous thromboembolism., Competing Interests: None declared., (Georg Thieme Verlag KG Stuttgart · New York.)

Patients with renal impairment are at higher risk of thrombosis and bleeding than those with normal renal function. The optimal rivaroxaban dose for thromboprophylaxis in acutely ill medical patients with renal impairment is unknown. MARINER and MAGELLAN were multicenter, randomized clinical trials of rivaroxaban in acutely ill medical patients. Efficacy and safety outcomes in patients with renal impairment in MARINER (7.5 mg once daily) were compared with those in patients with normal renal function in MARINER (10 mg once daily) and in a subpopulation of MAGELLAN that excluded patients at high risk for bleeding at baseline (10 mg once daily). Compared with enoxaparin/placebo in the MAGELLAN subpopulation, the relative risk (RR) of symptomatic venous thromboembolism (VTE) and VTE-related death with rivaroxaban 10 mg in patients with renal impairment (RR = 0.62; 95% confidence interval [CI] 0.27-1.44) was similar to that in those with normal renal function (RR = 0.78; 95% CI 0.44-1.40), while in MARINER, the 7.5 mg dose did not reduce the risk in patients with renal impairment (hazard ratio = 1.00; 95% CI 0.52-1.92). Major bleeding with rivaroxaban 10 mg once daily was higher in patients with renal impairment than in those with normal renal function in MAGELLAN (1.54% vs. 0.98%) and in the MAGELLAN subpopulation (0.94% vs. 0.61%). At a dose of 10 mg once daily, rivaroxaban is effective for thromboprophylaxis in acutely ill medical patients with impaired or normal renal function. The safety of this regimen is enhanced without loss of efficacy by excluding patients at high risk for bleeding, but not by using a reduced-dose strategy. TRIAL REGISTRATION:  ClinicalTrials.gov identifiers: NCT00571649 for the MAGELLAN trial, NCT02111564 for the MARINER trial., Competing Interests: J.I.W.: Bayer, Boehringer Ingelheim, Bristol-Meyers Squibb, Daiichi Sankyo, Ionis, Janssen, Merck, Novartis, Pfizer, Portola; A.C.S.: Janssen Research & Development LLC, Bayer, Portola, Boehringer Ingelheim, ATLAS group: Research Grants and Consulting; C.L., J.X., W.L., E.S., J.A., D.A., E.S.B.: Janssen Research & Development LLC: Employee/Stock; Y.D.S., T.E.S.: Bayer U.S. LLC: Employee; G.E.R.: Janssen Research & Development LLC & Bayer U.S. LLC, Daiichi Sankyo, Portola, Boehringer Ingelheim, PHRI Mc Master, Tetherex, Eli Lilly: Research Grants and Consulting., (Georg Thieme Verlag KG Stuttgart · New York.)

Traditionally, venous thromboembolism (VTE) resulting from major transient risk factors (e.g., surgery or trauma) or a major persistent risk factor such as cancer, has been defined as being provoked, whereas unprovoked VTE encompasses events without an identifiable cause. These categorizations influence anticoagulant treatment duration; unlike VTE provoked by major transient risk factors, extended anticoagulation beyond 3 months is advised for patients with cancer or unprovoked VTE due to risk persistence after treatment cessation. However, some patients with VTE provoked by minor transient or minor persistent risk factors may also be candidates for extended anticoagulation therapy due to the continuing risk of recurrence. In patients who require extended therapy, vitamin K antagonists (VKAs) are effective but are associated with an increased risk of bleeding and various treatment burdens (e.g., anticoagulation monitoring and dose adjustment). Evaluations of extended VTE treatment with the less-burdensome direct oral anticoagulants such as apixaban, dabigatran, edoxaban, and rivaroxaban show that they are at least as safe and effective as VKAs in a broad range of patients. In addition, apixaban and rivaroxaban offer more than one dosing option, allowing tailoring of treatment to the patient's specific risk factor profile. Analysis of more granular definitions for risk factor groupings has also yielded vital information on the most appropriate strategies for the treatment of patients with specific risk factors, highlighting that extended anticoagulation treatment may benefit those with minor transient and persistent environmental and nonenvironmental risk factors who commonly receive shorter-duration therapy., Competing Interests: M.S. has received speaker fees from Abbott, Aspen, Boston Scientific, Bristol-Myers Squibb, Daiichi Sankyo, GlaxoSmithKline, and Sanofi; travel grants from Bard, Bayer, Bristol-Myers Squibb, Medtronic, and Terumo; research grants from Cook, Daiichi Sankyo, and Terumo; and consulting fees from Bayer, Bristol-Myers Squibb, Daiichi Sankyo, and Sanofi. J.W. has received consultancy fees and honoraria from Bayer, Boehringer Ingelheim, Bristol-Myers Squibb, Daiichi Sankyo, Ionis, Janssen, Merck, Novartis, Pfizer, Portola, Anthos, and Tetherex., (Georg Thieme Verlag KG Stuttgart · New York.)

The rapid determination of the presence of direct oral anticoagulants (DOACs) in a patient remains a major challenge in emergency medicine and for rapid medical treatment decisions. All DOACs are excreted into urine. A sensitive and specific point-of-care test has been developed to determine whether they are present in patient urine samples. This prospective multicenter study aimed to demonstrate at least 95% correct positive and negative predictive results for factor Xa and thrombin inhibitors in urine samples using DOAC Dipstick pads compared with liquid chromatography-tandem mass spectrometry (LC-MS/MS) (NCT03182829). Nine hundred and fourteen subjects were included and 880 were evaluated per protocol (factor Xa inhibitors apixaban, edoxaban, and rivaroxaban: n  = 451, thrombin inhibitor dabigatran: n  = 429) at 18 centers. The sensitivity, specificity, accuracy, and predictive values and agreement between methods for determination of factor Xa inhibitors were at least noninferior to 95% with a 0.5% margin and of thrombin inhibitor superior to 97.5%. These results were compared with LC-MS/MS results in the intention-to-analyze cohort (all p  < 0.05). The receiver operating curve showed c -values of 0.989 (factor Xa inhibitors) and 0.995 (thrombin inhibitor). Visual evaluation of the factor Xa and thrombin inhibitor pads was not different between centers. Qualitative determination of both types of DOACs was accurate using the DOAC Dipstick compared with using LC-MS/MS. The high predictive values may impact laboratory and clinical decision-making processes., Competing Interests: J.H. is managing director and founder of DOASENSE and reports personal fees from Portola, outside the submitted work; a patent US 9,133,501 licensed, a patent EU 2643475 licensed, a patent US 9,944,971 licensed, and a patent EU 2723886 licensed. J.B.W. reports grants and personal fees from Bayer, grants and personal fees from Daiichi Sankyo, grants and personal fees from DOASENSE, grants and personal fees from Portola, grants from Pfizer, during the conduct of the study. P.V. reports grants and personal fees from Bayer, Boehringer Ingelheim, BMS, Pfizer, Daiichi-Sankyo and Portola, outside the submitted work. J.D. is the CEO and founder of QUALIblood and reports personal fees from Diagnostica Stago, Roche, Roche Diagnostics, Portola, and Daiichi-Sankyo, outside the submitted work. C.W. reports research grant and consultancy from DOASENSE during the conduct of the study. S.H. reports research grant from DOASENSE during the conduct of the study. M.C. reports grants and other from Bayer, personal fees from Shionogi, Alexion, Pfizer, Octapharma, BMS Canada, CSL Behring, Servier Canada, Diagnostica Stago, and Asahi Kasei, outside the submitted work; grants from Leo Pharma and Heart and Stroke Foundation, and other from Daiichi and Alnylam. I.E. reports grants and personal fees from Stago, Boehringer-Ingelheim, Bayer, Pfizer, Bristol Myers Squibb, during the conduct of the study; grants and personal fees from Stago, Boehringer Ingelheim, Pfizer, Bristol Myers Squibb, Bayer, outside the submitted work. R.B. reports personal fees from DOASENSE GmbH, during the conduct of the study; personal fees from Bayer AG, BMS, Daichii-Sankyo, Pfizer, outside the submitted work., (Georg Thieme Verlag KG Stuttgart · New York.)