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Deep vein thrombosis (DVT) is a cause of considerable morbidity worldwide. It is a common clinical disease in the daily practice of several medical disciplines including general medicine, angiology, and internal medicine, as well as of interest to public health because of its preventability and its sensitivity to secular changes in the distribution of population risk factors. In this review we present a comprehensive overview of the epidemiological features of DVT, including incidence and risk factors. Additionally, we give an overview of the burden that DVT poses on modern health care systems.

Background: Due to the rarity of cerebral venous thrombosis (CVT), performing high-quality scientific research in this field is challenging. Providing answers to unresolved research questions will improve prevention, diagnosis, and treatment, and ultimately translate to a better outcome of patients with CVT. We present an international research agenda, in which the most important research questions in the field of CVT are prioritized., Aims: This research agenda has three distinct goals: (1) to provide inspiration and focus to research on CVT for the coming years, (2) to reinforce international collaboration, and (3) to facilitate the acquisition of research funding., Summary of Review: This international research agenda is the result of a research summit organized by the International Cerebral Venous Thrombosis Consortium in Amsterdam, the Netherlands, in June 2023. The summit brought together 45 participants from 15 countries including clinical researchers from various disciplines, patients who previously suffered from CVT, and delegates from industry and non-profit funding organizations. The research agenda is categorized into six pre-specified themes: (1) epidemiology and clinical features, (2) life after CVT, (3) neuroimaging and diagnosis, (4) pathophysiology, (5) medical treatment, and (6) endovascular treatment. For each theme, we present two to four research questions, followed by a brief substantiation per question. The research questions were prioritized by the participants of the summit through consensus discussion., Conclusions: This international research agenda provides an overview of the most burning research questions on CVT. Answering these questions will advance our understanding and management of CVT, which will ultimately lead to improved outcomes for CVT patients worldwide., Competing Interests: Declaration of conflicting interestsThe author(s) declared the following potential conflicts of interest with respect to the research, authorship, and/or publication of this article: J.M.C. has received research support paid to his institution from Boehringer Ingelheim, Bayer, and Astra Zeneca. J.M.C. is co-founder and shareholder of TrianecT; D.A.d.S. reported personal fees for Astra Zeneca, Organon, Daiichi Sankyo and Johnson & Johnson advisory board participation, DSMB participation for the SECRET trial (University of British Columbia), and speaking fees from Bayer and Bial; S.P. has received research support from BMS/Pfizer, Boehringer Ingelheim, Daiichi Sankyo, European Union, German Federal Joint Committee Innovation Fund, German Federal Ministry of Education and Research, Helena Laboratories, and Werfen as well as speakers’ honoraria/consulting fees from Alexion, Astra Zeneca, Bayer, Boehringer Ingelheim, BMS/Pfizer, Daiichi Sankyo, Portola, and Werfen; A.A. has received research support paid to his Institution from Astra Zeneca; M.S.v.K. has received research support from the Amstol foundation; R.v.d.B. has received research support paid to his institution from CERENOVUS; T.S.F. has received in-kind study medication from Bayer Canada and has received personal fees from Bayer Canada and Roche for advosiry board participation; M.R.H. has received grants from the Swiss National Science Foundation, the SITEM Research Funds, and the Swiss Heart Foundation, all outside the submitted work; M.H.-P. has received compensation for scientific research by AptaTargets; F.A.K. has received research support from Bayer, BMS, BSCI, Astra Zeneca, MSD, Leo Pharma, Actelion, Farm-X, The Netherlands Organization for Health Research and Development, The Dutch Thrombosis Foundation, The Dutch Heart Foundation, and the Horizon Europe Program; R.R.L. has received speaker honoraria from IscemaView, Boehringer Ingelheim, Pfizer, Jansen, Biogen, Medtronic, and Abott and advisory board honoraria from Jansen, Bayer, and Filterlex; T.N.N. has disclosed advisory board for Idorsia and Brainomix; G.S. has received a stipend as the Editor-in-Chief of the World Stroke Academy for the World Stroke Organization; V.T. has received speaker honoraria from Boehringer Ingelheim and Bayer & Astra Zeneca and is on the steering committee of the Librexia Stroke trial, sponsored by Johnson & Johnson; D.J.W. has received grant funding from the Stroke Association and British Heart Foundation, speaking honoraria from Bayer, speaking and chairing honoraria from Alexion and NovoNordisk, and consultancy fees from Alnylam, Bayer, and NovoNordisk; T.T. has served/serves on scientific advisory boards for Astra Zeneca, Argenx, Bayer, Boehringer Ingelheim, Bristol Myers Squibb, Inventiva, and Portola Pharm and has received academic funding from University of Gothenburg, Sahlgrenska University Hospital, European Union, Sigrid Juselius Foundation, and Wennerström’s Foundation. The other authors have nothing to disclose.

Background:  The diagnosis of recurrent ipsilateral deep vein thrombosis (DVT) with compression ultrasonography (CUS) may be hindered by residual intravascular obstruction after previous DVT. A reference CUS, an additional ultrasound performed at anticoagulant discontinuation, may improve the diagnostic work-up of suspected recurrent ipsilateral DVT by providing baseline images for future comparison., Objectives:  To evaluate the cost-effectiveness of routinely performing reference CUS in DVT patients., Methods:  Patient-level data ( n  = 96) from a prospective management study (Theia study; NCT02262052) and claims data were used in a decision analytic model to compare 12 scenarios for diagnostic management of suspected recurrent ipsilateral DVT. Estimated health care costs and mortality due to misdiagnosis, recurrent venous thromboembolism, and bleeding during the first year of follow-up after presentation with suspected recurrence were compared., Results:  All six scenarios including reference CUS had higher estimated 1-year costs (€1,763-€1,913) than the six without reference CUS (€1,192-€1,474). Costs were higher because reference CUS results often remained unused, as 20% of patients (according to claims data) would return with suspected recurrent DVT. Estimated mortality was comparable in scenarios with (14.8-17.9 per 10,000 patients) and without reference CUS (14.0-18.5 per 10,000). None of the four potentially most desirable scenarios included reference CUS., Conclusion:  One-year health care costs of diagnostic strategies for suspected recurrent ipsilateral DVT including reference CUS are higher compared to strategies without reference CUS, without mortality benefit. These results can inform policy-makers regarding use of health care resources during follow-up after DVT. From a cost-effectiveness perspective, the findings do not support the routine application of reference CUS., Competing Interests: F.A.K. reports grants or contracts from Bayer, BMS, BSCI, MSD, Leo Pharma, Actelion, VarmX, The Netherlands Organisation for Health Research and Development, The Dutch Thrombosis Association, The Dutch Heart Foundation, and The Horizon Europe Program, all unrelated to this work and paid to his institution. All other authors report no conflict of interest., (Thieme. All rights reserved.)

Background: Treatment guidelines for splanchnic vein thrombosis in necrotizing pancreatitis are lacking due to insufficient data on the full clinical spectrum., Methods: We performed a post-hoc analysis of a nationwide prospective necrotizing pancreatitis cohort. Multivariable analyses were used to identify risk factors and compare the clinical course of patients with and without SVT., Results: SVT was detected in 97 of the 432 included patients (22%) (median onset: 4 days). Risk factors were left, central, or subtotal necrosis (OR 28.52; 95% CI 20.11-40.45), right or diffuse necrosis (OR 5.76; 95% CI 3.89-8.51), and younger age (OR 0.94; 95% CI 0.90-0.97). Patients with SVT had higher rates of bleeding (n = 10,11%) and bowel ischemia (n = 4,4%) compared to patients without SVT (n = 14,4% and n = 2,0.6%; OR 3.24; 95% CI 1.27-8.23 and OR 7.29; 95% CI 1.31-40.4, respectively), and were independently associated with ICU admission (adjusted OR 2.53; 95% CI 1.37-4.68). Spontaneous recanalization occurred in 62% of patients (n = 40/71). Radiological and clinical outcomes did not differ between patients treated with and without anticoagulants., Discussion: SVT is a common and early complication of necrotizing pancreatitis, associated with parenchymal necrosis and younger age. SVT is associated with increased complications and a worse clinical course, whereas anticoagulant use does not appear to affect outcomes., (Copyright © 2024 The Author(s). Published by Elsevier Ltd.. All rights reserved.)

Patient-reported outcome measures (PROMs) are patient-completed instruments that capture patient-perceived health status and well-being. PROMs measure disease impact and outcomes of care as reported by those who experience the disease. After pulmonary embolism or deep vein thrombosis, patients may face a broad spectrum of complications and long-term sequelae beyond the usual quality-of-care indicators of recurrent venous thromboembolism (VTE), bleeding complications, and survival. The full impact of VTE on individual patients can only be captured by assessing all relevant health outcomes from the patient's perspective in addition to the traditionally recognized complications. Defining and measuring all important outcomes will help facilitate treatment tailored to the needs and preferences of patients and may improve health outcomes. The International Society on Thrombosis and Haemostasis Scientific and Standardization Committee Subcommittee on Predictive and Diagnostic Variables in Thrombotic Disease endorsed the International Consortium for Health Outcomes Measurement (ICHOM) VTE project on development of a standardized set of patient-centered outcome measures for patients with VTE. In this communication, the course and result of the project are summarized, and based on these findings, we propose recommendations for the use of PROMs during clinical follow-up of patients with VTE. We describe challenges to implementation of PROMs and explore barriers and enablers., Competing Interests: Declaration of competing interests A.L.P. reports a grant from the National Institute on Aging (R03AG074074). S.C.W. reports funding for research from Bristol-Myers Squibb paid to his institution and support (expenses only) for attending Anticoagulation Forum, San Francisco, as an invited guest lecturer. F.A.K. reports grants or contracts from Bayer, BMS, BSCI, MSD, Leo Pharma, Actelion, VarmX, the Netherlands Organisation for Health Research and Development, the Dutch Thrombosis Association, the Dutch Heart Foundation, the Netherlands, and the Horizon Europe Program, all unrelated to this work and paid to his institution. C.M.M.d.J., K.d.W., S.A.B., A.M.G., C.M., H.R.-E., and R.T. have no competing interests to disclose., (Copyright © 2023 The Author(s). Published by Elsevier Inc. All rights reserved.)

Background: Splanchnic vein thrombosis (SVT) is a major complication of moderate and severe acute pancreatitis. There is no consensus on whether therapeutic anticoagulation should be started in patients with acute pancreatitis and SVT., Aim: To gain insight into current opinions and clinical decision making of pancreatologists regarding SVT in acute pancreatitis., Methods: A total of 139 pancreatologists of the Dutch Pancreatitis Study Group and Dutch Pancreatic Cancer Group were approached to complete an online survey and case vignette survey. The threshold to assume group agreement was set at 75%., Results: The response rate was 67% ( n = 93). Seventy-one pancreatologists (77%) regularly prescribed therapeutic anticoagulation in case of SVT, and 12 pancreatologists (13%) for narrowing of splanchnic vein lumen. The most common reason to treat SVT was to avoid complications (87%). Acute thrombosis was the most important factor to prescribe therapeutic anticoagulation (90%). Portal vein thrombosis was chosen as the most preferred location to initiate therapeutic anticoagulation (76%) and splenic vein thrombosis as the least preferred location (86%). The preferred initial agent was low molecular weight heparin (LMWH; 87%). In the case vignettes, therapeutic anticoagulation was prescribed for acute portal vein thrombosis, with or without suspected infected necrosis (82% and 90%), and thrombus progression (88%). Agreement was lacking regarding the selection and duration of long-term anticoagulation, the indication for thrombophilia testing and upper endoscopy, and about whether risk of bleeding is a major barrier for therapeutic anticoagulation., Conclusion: In this national survey, the pancreatologists seemed to agree on the use of therapeutic anticoagulation, using LMWH in the acute phase, for acute portal thrombosis and in the case of thrombus progression, irrespective of the presence of infected necrosis., Competing Interests: Conflict-of-interest statement: All authors declare no conflict of interest., (©The Author(s) 2023. Published by Baishideng Publishing Group Inc. All rights reserved.)

Background: Few studies evaluated the performance of noninvasive diagnostic strategies for suspected acute pulmonary embolism (PE) in pregnant women., Objectives: The aim of this study was to establish the safety and efficiency of the Wells rule with fixed and adapted D-dimer threshold, and the YEARS algorithm, combined with compression ultrasonography (CUS), in pregnant women with suspected PE in an individual patient data meta-analysis., Methods: We performed a systematic review to identify prospective diagnostic management studies in pregnant women with suspected PE. Primary outcomes were safety, defined as the failure rate, ie, the 3-month venous thromboembolism (VTE) incidence after excluding PE without chest imaging, and efficiency, defined as the proportion of patients in whom chest imaging could be avoided., Results: We identified 2 relevant studies, of which individual patient-level data were analyzed in a fixed-effect meta-analysis, totaling 893 pregnant women. The Wells rule with fixed and adapted D-dimer threshold as well as the YEARS algorithm could safely rule out acute PE (failure rate, 0·37%-1·4%), but efficiency improved considerably when applying pretest probability-adapted D-dimer thresholds. The efficiency of bilateral CUS was limited (2·3% overall; number needed to test 43), especially in patients without symptoms of deep-vein thrombosis (efficiency 0·79%; number needed to test 127)., Conclusion: This study supports the latest guideline recommendations (European Society of Cardiology 2019) to apply pretest probability assessment and D-dimer tests to rule out PE in pregnant women. From an efficiency perspective, the use of a strategy with pretest probability-adapted D-dimer threshold is preferred. The yield of CUS was very limited in patients without concomitant symptoms of deep-vein thrombosis., (Copyright © 2022 International Society on Thrombosis and Haemostasis. Published by Elsevier Inc. All rights reserved.)

Patients with acute venous thromboembolism (VTE) require anticoagulant therapy to prevent recurrent VTE and death, which exposes them to an inherent increased risk of bleeding. Identification of patients at high risk of bleeding, and mitigating this risk, is an essential component of the immediate and long-term therapeutic management of VTE. The bleeding risk can be estimated by either implicit judgment, weighing individual predictors (clinical variables or biomarkers), or by risk prediction tools developed for this purpose. Management of bleeding risk in clinical practice is, however, far from standardized. International guidelines are contradictory and lack clear and consistent guidance on the optimal management of bleeding risk. This report of the ISTH subcommittee on Predictive and Diagnostic Variables in Thrombotic Disease summarizes the evidence on the prediction of bleeding in VTE patients. We systematically searched the literature and identified 34 original studies evaluating either predictors or risk prediction models for prediction of bleeding risk on anticoagulation in VTE patients. Based on this evidence, we provide recommendations for the standardized management of bleeding risk in VTE patients., (© 2022 The Authors. Journal of Thrombosis and Haemostasis published by Wiley Periodicals LLC on behalf of International Society on Thrombosis and Haemostasis.)

Background: Splanchnic vein thrombosis (SVT) is an uncommon manifestation of venous thromboembolism. Epidemiological data on SVT-related mortality rate is not available to date., Methods: We investigated time trends in SVT-related mortality rate, 2008-2019, in Veneto, an Italian high-income region of approximatively 5,000,000 inhabitants. SVT-related deaths were identified by the following ICD-10 codes: I81 (portal vein thrombosis), K75.1 (phlebitis of portal vein), K76.3 (liver infarction), K76.5 (hepatic veno-occlusive disease) or I82.0 (Budd-Chiari syndrome)., Results: During the study period, a total of 557,932 deaths were recorded. SVT was reported in 823 cases; 776 (94%) consisted of portal vein thrombosis. The age-standardized SVT-related mortality rate varied from 1.47 (year 2008) to 1.52 (year 2019) per 100,000 person-years. An increase in the cause-specific annual mortality rate was observed in women (0.56 in 2008 to 1.04 per 100,000 person-years in 2019; average annual percent change +5.7%, 95%CI +3.1; +8.3%). In men, the cause-specific mortality rate moved from 2.53 in 2008 to 2.03 per 100,000 person-years in 2019 (average annual percent change -1.2%, 95%CI -4.0; +1.6%). After conditioning for age and sex, the odds of having a concomitant liver disease were higher for SVT-related deaths (OR 31.6; 95%CI 17.1-37.0) compared with non-SVT-related deaths. This also applies to gastrointestinal cancers (OR 1.28; 95%CI 1.07-1.55), although to a lesser extent., Conclusions: We report first epidemiological estimates of SVT-related mortality in a Western country. These values will serve as a reference to weight novel potential factors associated with SVT-related death and interpret them from an epidemiological perspective., (Copyright © 2021 Elsevier Ltd. All rights reserved.)

Background: The incidence of pulmonary embolism has been increasing, but its case-fatality rate is decreasing, suggesting a lesser severity of illness. The clinical importance of patients with pulmonary embolism isolated to the subsegmental vessels is unknown., Objective: To determine the rate of recurrent venous thromboembolism in patients with subsegmental pulmonary embolism managed without anticoagulation., Design: Multicenter prospective cohort study. (ClinicalTrials.gov: NCT01455818)., Setting: Eighteen sites between February 2011 and February 2021., Patients: Patients with isolated subsegmental pulmonary embolism., Intervention: At diagnosis, patients underwent bilateral lower-extremity venous ultrasonography, which was repeated 1 week later if results were negative. Patients without deep venous thrombosis did not receive anticoagulant therapy., Measurements: The primary outcome was recurrent venous thromboembolism during the 90-day follow-up period., Results: Recruitment was stopped prematurely because the predefined stopping rule was met after 292 of a projected 300 patients were enrolled. Of the 266 patients included in the primary analysis, the primary outcome occurred in 8 patients, for a cumulative incidence of 3.1% (95% CI, 1.6% to 6.1%) over the 90-day follow-up. The incidence of recurrent venous thromboembolism was 2.1% (CI, 0.8% to 5.5%) and 5.7% (CI, 2.2% to 14.4%) over the 90-day follow-up in patients with single and multiple isolated subsegmental pulmonary embolism, respectively. No patients had a fatal recurrent pulmonary embolism., Limitation: The study was restricted to patients with low-risk subsegmental pulmonary embolism., Conclusion: Overall, patients with subsegmental pulmonary embolism who did not have proximal deep venous thrombosis had a higher-than-expected rate of recurrent venous thromboembolism., Primary Funding Source: Heart and Stroke Foundation of Canada and French Ministry of Health Programme Hospitalier de Recherche Clinique.

Introduction: For exclusion of pulmonary embolism (PE) clinical decision rules in combination with a D-dimer assay are applied. Currently available D-dimer assays are not standardized and it is unknown whether these differences have an impact on diagnostic management of suspected PE. Therefore, the aim is to explore differences between D-dimer assays and their impact on diagnostic outcome., Methods: Data from all patients included in the YEARS study were collected. The YEARS study is a prospective, multicentre, cohort outcome study evaluating 3462 patients with suspected PE in which four different D-dimer assays were applied (Liatest, Innovance, Tinaquant, Vidas). Median D-dimer concentrations were calculated for each D-dimer assay. Sensitivity, specificity, PPV and NPV for detection of PE of all four assays were determined in patients without YEARS items and in those with ≥1 YEARS items (i.e. symptomatic deep vein thrombosis, haemoptysis, and whether PE is the most likely diagnosis)., Results: A total of 1323, 1100, 768 and 271 D-dimer concentrations were collected using the Liatest Innovance, Tinaquant and Vidas assay, respectively. Median D-dimer concentrations differed significantly between assays, with lowest values in the Tinaquant assay. In patients without YEARS items using a cutoff level of 1000 ng/mL, the NPV varied from 99,5 to 100%. In patients with ≥1 YEARS items using a 500 ng/mL cutoff, the NPV varied from 97,0 to 100% depending on the assay., Conclusions: The overall high NPV for all assays demonstrates the clinical value of the D-dimer assay. However, these results confirm differences between D-dimer assays, which have an impact on follow-up imaging. This emphasizes the need for standardization of D-dimer assays., (Copyright © 2021 The Authors. Published by Elsevier Ltd.. All rights reserved.)

The diagnostic workup of recurrent ipsilateral deep vein thrombosis (DVT) using compression ultrasonography (CUS) can be complicated by persistent intravascular abnormalities after a previous DVT. We showed that magnetic resonance direct thrombus imaging (MRDTI) can exclude recurrent ipsilateral DVT. However, it is unknown whether the application of MRDTI in daily clinical practice is cost effective. The aim of this study was to evaluate the cost effectiveness of MRDTI-based diagnosis for suspected recurrent ipsilateral DVT during first year of treatment and follow-up in the Dutch health care setting. Patient-level data of the Theia study (NCT02262052) were analyzed in 10 diagnostic scenarios, including a clinical decision rule and D-dimer test and imaging with CUS and/or MRDTI. The total costs of diagnostic tests and treatment during 1-year follow-up, including costs of false-positive and false-negative diagnoses, were compared and related to the associated mortality. The 1-year health care costs with MRDTI (range, €1219-1296) were generally lower than strategies without MRDTI (range, €1278-1529). This was because of superior specificity, despite higher initial diagnostic costs. Diagnostic strategies including CUS alone and CUS followed by MRDTI in case of an inconclusive CUS were potential optimal cost-effective strategies, with estimated average costs of €1529 and €1263 per patient and predicted mortality of 1 per 737 patients and 1 per 609 patients, respectively. Our model shows that diagnostic strategies with MRDTI for suspected recurrent ipsilateral DVT have generally lower 1-year health care costs than strategies without MRDTI. Therefore, compared with CUS alone, applying MRDTI did not increase health care costs., (© 2021 by The American Society of Hematology.)

Background: The diagnostic accuracy of clinical probability assessment and D-dimer testing for clinically suspected recurrent deep vein thrombosis (DVT) is largely unknown., Aim: To evaluate the safety of ruling out acute recurrent DVT based on an unlikely Wells score for DVT and a normal D-dimer test., Methods: This was a predefined endpoint of the Theia study in which the diagnostic accuracy of magnetic resonance direct thrombus imaging in acute recurrent ipsilateral DVT was validated. The Wells rule and D-dimer test, performed as part of the study protocol, were not used for management decisions. The primary outcome of this analysis was the incidence of recurrent DVT at baseline or during 3-month follow-up for patients with an unlikely Wells score and a normal D-dimer test., Results: Results of both Wells score and D-dimer tests were available in 231 patients without anticoagulant treatment. The recurrent DVT prevalence was 45% (103/231). Forty-nine patients had an unlikely Wells score and normal D-dimer test, of whom 3 (6.1%, 95% confidence interval [CI] 1.3%-18%) had recurrent DVT at baseline/follow-up, yielding a sensitivity of 97% (95% CI 92%-99%) and specificity of 36% (95% CI 28%-45%). Thus, if clinical probability scoring and D-dimer testing would have been applied, radiological imaging could have been omitted in 21% of patients with a diagnostic failure rate of 6.1%., Conclusion: By applying clinical probability scoring and D-dimer testing, radiological imaging could be spared in one fifth of patients with suspected recurrent ipsilateral DVT. However, the high failure rate does not support implementation of this strategy in daily practice., (© 2020 The Authors. Journal of Thrombosis and Haemostasis published by Wiley Periodicals LLC on behalf of International Society on Thrombosis and Haemostasis.)

Venous thromboembolism (VTE) is associated with significant morbidity and mortality. Accuracy of diagnosis is thus of vital importance. Failure to diagnose VTE increases the risk of progression and complications. Conversely, anticoagulation as a result of an incorrect diagnosis exposes patients to the associated hazards of bleeding. The diagnostic management of recurrent deep vein thrombosis (DVT) and postthrombotic syndrome (PTS) is especially challenging due to the lack of well-established diagnostic standards. Particularly, the differentiation between the two is notoriously difficult as symptoms, clinical signs, and diagnostic test findings largely overlap. This review highlights the current diagnostic and management strategies for recurrent DVT and PTS with a focus on clinical findings and imaging modalities. We also discuss current open questions for clinicians in the field, anticipating future directions and predictions for the year 2050., Competing Interests: Dr. Klok reports grants from Bayer, grants from Bristol-Myers Squibb, grants from Boehringer-Ingelheim, grants from MSD, grants from Daiichi-Sankyo, grants from Actelion, grants from The Dutch Thrombosis Association, grants from The Dutch Heart foundation, outside the submitted work. Dr. Klok reports grants from Bayer, grants from Bristol-Myers Squibb, grants from Boehringer-Ingelheim, grants from MSD, grants from Daiichi-Sankyo, grants from Actelion, grants from The Dutch Thrombosis Association, grants from The Dutch Heart foundation, outside the submitted work. Dr. Sebastian has nothing to disclose. Dr. Gautam has nothing to disclose., (Georg Thieme Verlag KG Stuttgart · New York.)

Guidelines suggest using empiric low-molecular-weight heparin if the diagnostic workup of deep vein thrombosis (DVT) is expected to be delayed. The role of direct oral anticoagulants for deferred compression ultrasound imaging (CUS) in patients with suspected DVT remains unexplored. The main objective of the study was to assess the safety of deferring CUS with therapeutic doses of rivaroxaban. We prospectively included consecutive outpatients referred to the Emergency Department at Østfold Hospital, Norway, with suspected first or recurrent lower-extremity DVT between February 2015 and November 2018. Patients were discharged with rivaroxaban 15 mg twice daily while awaiting CUS within 24 hours if D-dimer level was ≥0.5 mg/L fibrinogen-equivalent units. The primary outcome was the rate of major bleeding incidents from study inclusion until DVT was confirmed and anticoagulation therapy continued, or otherwise up to 48 hours following administration of the last tablet of rivaroxaban. The secondary outcome was the rate of progressive DVT symptoms or symptoms or signs of pulmonary embolism between hospital discharge until venous thromboembolism was diagnosed. Six hundred twenty-four of 1653 patients referred with suspected DVT were included (37.7%; 95% confidence interval [CI], 35.4-40.1). DVT was diagnosed in 119 patients (19.1%; 95% CI, 16.1-22.3). There were no major bleeding incidents, yielding an observed major bleeding rate of 0% (1-sided 95% CI <0.4). No patients experienced major complications in the interval that CUS was deferred (0%; 95% CI, 0.0-0.6). Deferring CUS for up to 24 hours in patients with suspected DVT with therapeutic doses of rivaroxaban is a safe strategy. This trial was registered at www.clinicaltrials.gov as #NCT02486445., (© 2020 by The American Society of Hematology.)

Cerebral vein thrombosis (CVT) is a rare presentation of venous thromboembolism. Prompt and accurate diagnosis is essential as delayed recognition and treatment may lead to permanent disability or even death. Since no validated diagnostic algorithms exist, the diagnosis of CVT mainly relies on neuroimaging. Digital subtraction angiography (DSA) is the historical diagnostic standard for CVT, but is rarely used nowadays and replaced by computed tomography (CT) and magnetic resonance imaging (MRI). High quality studies to evaluate the diagnostic test characteristics of state of the art imaging modalities are however unavailable to date. This review provides an overview of the best available evidence regarding the diagnostic performance of CT and MRI for the diagnosis of CVT. Notably, available studies are observational, mostly small, outdated, and with a high risk of bias. Therefore, direct comparison between studies is difficult due to large diversity in study design, imaging method, reference standard, patient selection and sample size. In general, contrast-enhanced techniques are more accurate for the diagnosis of CVT then non-contrast-enhanced techniques. CT venography and MRI have been both reported to be adequate for establishing a final diagnosis of CVT, but choice of modality as used in clinical practice depends on availability, local preference and experience, as well as patient characteristics. Our review underlines the need for high-quality diagnostic studies comparing CT venography and MRI in specific settings, to improve clinical care and standardize clinical trials., (Copyright © 2020 The Authors. Published by Elsevier Ltd.. All rights reserved.)

The diagnosis of recurrent ipsilateral deep vein thrombosis (DVT) is challenging, because persistent intravascular abnormalities after previous DVT often hinder a diagnosis by compression ultrasonography. Magnetic resonance direct thrombus imaging (MRDTI), a technique without intravenous contrast and with a 10-minute acquisition time, has been shown to accurately distinguish acute recurrent DVT from chronic thrombotic remains. We have evaluated the safety of MRDTI as the sole test for excluding recurrent ipsilateral DVT. The Theia Study was a prospective, international, multicenter, diagnostic management study involving patients with clinically suspected acute recurrent ipsilateral DVT. Treatment of the patients was managed according to the result of the MRDTI, performed within 24 hours of study inclusion. The primary outcome was the 3-month incidence of venous thromboembolism (VTE) after a MRDTI negative for DVT. The secondary outcome was the interobserver agreement on the MRDTI readings. An independent committee adjudicated all end points. Three hundred five patients were included. The baseline prevalence of recurrent DVT was 38%; superficial thrombophlebitis was diagnosed in 4.6%. The primary outcome occurred in 2 of 119 (1.7%; 95% confidence interval [CI], 0.20-5.9) patients with MRDTI negative for DVT and thrombophlebitis, who were not treated with any anticoagulant during follow-up; neither of these recurrences was fatal. The incidence of recurrent VTE in all patients with MRDTI negative for DVT was 1.1% (95% CI, 0.13%-3.8%). The agreement between initial local and post hoc central reading of the MRDTI images was excellent (κ statistic, 0.91). The incidence of VTE recurrence after negative MRDTI was low, and MRDTI proved to be a feasible and reproducible diagnostic test. This trial was registered at www.clinicaltrials.gov as #NCT02262052., (© 2020 by The American Society of Hematology.)

The main objectives of therapeutic trials in venous thromboembolism (VTE) are to prevent recurrent VTE, major bleeding and death. While these outcomes are indeed highly relevant, they are also rare and do not fully capture the overall functional outcome of VTE patients. Importantly, functional limitations after VTE are prevalent after both deep vein thrombosis and pulmonary embolism occurring in up to 50% of patients. These post-VTE syndromes are associated with a decreased quality of life, higher risk of depressive disorders, unemployment and increased utilization of healthcare resources. Because of the major impact of functional limitations on individual patients and society as a whole, development of tools able to capture functional outcomes in clinical trials are urgently needed. We anticipate that a standardized post-VTE functional status scale will aid in demarcating effective and ineffective VTE therapies on functional outcomes in trials with appropriately powered sample sizes, as well as pave the road for value-based healthcare. The scale that we have in mind covers the entire spectrum of functional outcomes ranging from no symptoms to death. Moreover, it focuses on both limitations in usual activity as well as changes in lifestyle. The scale is not meant to replace current diagnostic or prognostic scores for post-VTE syndromes, but to be used as an outcome measure to evaluate the overall consequences of VTE on functional status. This review is a call for action to the VTE community to join forces and support further development of the proposed scale, a process of which we summarize the necessary steps., (Copyright © 2019 Elsevier Ltd. All rights reserved.)

Background: The reported incidences of post-thrombotic syndrome (PTS) after deep vein thrombosis (DVT) vary. Further, PTS symptom development over time and its long-term incidence are unknown., Methods: Patients included in the MEGA study were interviewed at 1 year and completed a questionnaire at 8 years of follow-up regarding symptoms and signs of PTS based on the Villalta score after a first DVT diagnosis. The cumulative incidence of PTS at 0-1 and 1-8 year, changes in PTS classification and the effect of possible clinical and laboratory risk factors were determined., Results: After 1 year, 361 out of 1657 patients diagnosed with DVT were classified as having PTS, for a 0-1 year cumulative incidence of 21.8% (95%CI 19.9-23.8), out of whom 92 (5.6%) had severe PTS. After 8 years 633 patients without previous PTS completed the second questionnaire, of whom 44 were classified as having PTS, for a 1-8 year cumulative incidence of 7% (95%CI 5.2-9.2); of these 13 (2.1%) were classified as severe PTS. During follow-up PTS complaints improved in 69% and worsened in 7% of patients. At 1 year, risk factors were female sex (RR 1.5; 95%CI 1.2-1.9) and obesity (RR 1.5; 95%CI 1.2-7.9), with the same effect sizes at 8 years. Provoked/unprovoked DVT, thrombus location, pregnancy, hormone use and several laboratory parameters did not affect risk of PTS, either at 1 or 8 years., Conclusion: The incidence of PTS remained substantial up to 8 years after a first DVT. Symptoms improved in a large proportion of the cases. The short and long term risks were highest in women and obese patients., (Copyright © 2019 Elsevier Ltd. All rights reserved.)

Background and Aims: Sex-specific differences exist for the initial presentation of acute venous thromboembolism (VTE): men are more likely to present with proximal deep vein thrombosis (DVT) in the lower limbs (versus pulmonary embolism [PE] or isolated distal DVT [IDDVT]) than women. We studied in detail the influence of sex, age, and VTE risk factors on the initial presentation of IDDVT versus proximal DVT., Methods: A total of 24,911 patients with a first episode of objectively diagnosed acute symptomatic lower-limb DVT (without symptomatic PE) were enrolled in RIETE (years 2000-2017) and included in the present analysis., Results: A total of 4266 (17.1%) patients had IDDVT. No trend for more IDDVT diagnoses was observed over time. Women aged 40-69 had a higher proportion of IDDVT, especially between 40 and 49 years (+6.7%; 95CI +3.7%; +9.9%), whereas men had more often proximal DVT. The presenting location of first acute DVT depended on sex, age, and the prevalence and type of VTE risk factors. Recent surgery was independently associated with a diagnosis of IDDVT in both women and men, whereas active cancer and pregnancy were associated with proximal DVT., Conclusions: The interaction between age and VTE risk factors influences the presenting location (distal versus proximal) of the first acute lower-limb DVT observed in women and men. Our observations extend to IDDVT the concept that different clinical manifestations of acute VTE may not fully share the same pathophysiological mechanisms: this contributes to explain sex-specific prognostic differences., (Copyright © 2018 Elsevier Ltd. All rights reserved.)

Pulmonary embolism (PE) is caused by emboli, which have originated from venous thrombi, travelling to and occluding the arteries of the lung. PE is the most dangerous form of venous thromboembolism, and undiagnosed or untreated PE can be fatal. Acute PE is associated with right ventricular dysfunction, which can lead to arrhythmia, haemodynamic collapse and shock. Furthermore, individuals who survive PE can develop post-PE syndrome, which is characterized by chronic thrombotic remains in the pulmonary arteries, persistent right ventricular dysfunction, decreased quality of life and/or chronic functional limitations. Several important improvements have been made in the diagnostic and therapeutic management of acute PE in recent years, such as the introduction of a simplified diagnostic algorithm for suspected PE as well as phase III trials demonstrating the value of direct oral anticoagulants in acute and extended treatment of venous thromboembolism. Future research should aim to address novel treatment options (for example, fibrinolysis enhancers) and improved methods for predicting long-term complications and defining optimal anticoagulant therapy parameters in individual patients, and to gain a greater understanding of post-PE syndrome.

A normal computed tomography pulmonary angiography (CTPA) remains a controversial criterion for ruling out acute pulmonary embolism (PE) in patients with a likely clinical probability. We set out to determine the risk of VTE and fatal PE after a normal CTPA in this patient category and compare these risk to those after a normal pulmonary angiogram of 1.7 % (95 %CI 1.0-2.7 %) and 0.3 % (95 %CI 0.02-0.7 %). A patient-level meta-analysis from 4 prospective diagnostic management studies that sequentially applied the Wells rule, D-dimer tests and CTPA to consecutive patients with clinically suspected acute PE. The primary outcome was the 3-month VTE incidence after a normal CTPA. A total of 6,148 patients were included with an overall PE prevalence of 24 %. The 3-month VTE incidence in all 4,421 patients in whom PE was excluded at baseline was 1.2 % (95 %CI 0.48-2.6) and the risk of fatal PE was 0.11 % (95 %CI 0.02-0.70). In patients with a likely clinical probability the 3-month incidences of VTE and fatal PE were 2.0 % (95 %CI 1.0-4.1 %) and 0.48 % (95 %CI 0.20-1.1 %) after a normal CTPA. The 3-month incidence of VTE was 6.3 % (95 %CI 3.0-12) in patients with a Wells rule >6 points. In conclusion, this study suggests that a normal CTPA may be considered as a valid diagnostic criterion to rule out PE in the majority of patients with a likely clinical probability, although the risk of VTE is higher in subgroups such as patients with a Wells rule >6 points for which a closer follow-up should be considered.

The pathomechanisms underlying the development of thrombofibrotic pulmonary artery occlusions in Chronic Thromboembolic Pulmonary Hypertension (CTEPH) are largely unknown. The aim of this study was to allocate distinct cellular processes playing a role in thrombus resolution, such as inflammation, hypoxia, proliferation, apoptosis and angiogenesis, to different stages of thrombofibrotic remodelling. A total of 182 pulmonary endarterectomy (PEA) specimens were collected from 31 CTEPH patients. To facilitate co-localisation, Tissue MicroArrays were prepared and processed for (immuno)-histochemistry and confocal fluorescence microscopy. Murine venous thrombus formation and resolution was examined after inferior vena cava ligation. PEA tissues exhibited five morphologically distinct regions predominantly consisting of either fibrin-, erythrocyte- or extracellular matrix-rich thrombus, myofibroblasts, vessels or fibrotic tissue, and were found to resemble chronological stages of thrombus resolution in mice. Cellularity was highest in vessel-rich regions, and numerous cells were strongly positive for HIF1α or HIF2α as well as markers of activated VEGF signalling, including endothelial nitric oxide synthase. On the other hand, negative regulators of angiogenic growth factor signalling and reactive oxygen species were also highly expressed. Immune cells, primarily macrophages of the M2 subtype and CD117 haematopoietic progenitors were detected and highest in vascularised regions. Our findings demonstrate the simultaneous presence of different stages of thrombus organisation and suggest that hypoxia-induced endothelial, mesenchymal and immune cell activation may contribute to thrombofibrosis in CTEPH. This systematic histological characterisation of the material obstructing pulmonary vessels in CTEPH may provide a valuable basis for further studies aimed at determining causal factors underlying this disease.

A pregnant woman aged 29 years, G1P0 at 21 weeks of gestation of a dichorionic diamniotic twin, presented with suspected deep vein thrombosis (DVT) of the left leg. Repeated (compression) ultrasonography was not diagnostic for DVT but showed reduced flow over the left external iliac vein, common femoral vein and superficial femoral vein. In pursue of a definite diagnosis, magnetic resonance direct thrombus imaging was performed showing a clear high signal in the left common iliac vein which is diagnostic for acute thrombosis in this venous segment. Phase contrast venography supported this diagnosis, showing no flow in the left common iliac vein. Treatment with anticoagulants was started. 6 months after the diagnosis, the patient is doing well and does not report signs of post-thrombotic syndrome., Competing Interests: Conflicts of Interest: None declared., (2016 BMJ Publishing Group Ltd.)

Introduction: The Wells rule is the recommended first step in the work-up of suspected deep vein thrombosis (DVT). However, it is often incorrectly used leading to an excessive number of diagnostic tests used in daily practice and diagnostic failures. A simpler objective risk stratification tool may improve adherence to the guidelines. We evaluated the diagnostic performance of the I-DVT score, which consists of four easy assessable variables: Immobilization, >3cm Difference in calve circumferences, prior Venous thromboembolism (VTE) and active malignant Tumor., Methods: We performed an observational study in 617 consecutive patients with suspected DVT. All patients were managed according to the recommended algorithm starting with the Wells rule followed by D-dimer test and/or compression ultrasonography (CUS). The I-DVT score was prospectively calculated at baseline and evaluated post-hoc., Results: The DVT prevalence was 36%. DVT could be excluded in 13% of patients without CUS by the Wells rule and a normal D-dimer test, with a 3-month VTE incidence of 1.2% (95%CI 0.03-6.5%). Using the I-DVT score, DVT would have been excluded in 9.1% of patients without additional CUS, with a 3-month VTE incidence of 0% (95%CI 0.0-6.4%). The area under the ROC curve (AUC) was 0.70 (95%CI 0.66-0.74) and 0.65 (95%CI 0.61-0.70) for the Wells rule and I-DVT score respectively (difference 0.049, 95%CI -0.01-0.11; p=0.13)., Conclusions: The simple I-DVT score and Wells rule have comparable diagnostic accuracy. It's safety, efficiency and associated potential improvement of guideline adherence in clinical practice has to be further evaluated in a prospective management study., (Copyright © 2016 Elsevier Ltd. All rights reserved.)

Background: After diagnosis of cancer-associated VTE, guidelines recommend considering the continuation of anticoagulant treatment until the patient is cured of cancer, although the safety of stopping anticoagulant treatment after the patient is cured has never been evaluated., Methods: We conducted a cohort study in consecutive patients in whom cancer-associated VTE was diagnosed at the Leiden University Medical Center between January 2001 and January 2010 and monitored for the effect of cancer treatment, occurrence of recurrent VTE, major hemorrhage, and death., Results: Of the 358 patients with cancer-associated VTE, anticoagulant treatment was continued until the death of 207 patients. In another 12 patients anticoagulant treatment was continued because of an alternative indication despite their being cured of cancer. Anticoagulant treatment was stopped in 50 patients for reasons other than major hemorrhage despite active cancer, in 21 patients after major hemorrhage, and in 68 patients after they had been cured of cancer. Among these 68 patients, 10 patients received a diagnosis of symptomatic recurrent VTE during a cumulative follow-up of 311 years, resulting in an incidence rate of 3.2 per 100 patient-years (95% CI, 1.5-5.9). Seven of these 10 patients with recurrent VTE experienced a cancer relapse during follow-up. For the 50 patients who stopped anticoagulant treatment despite active cancer the recurrent VTE incidence rate was 19 per 100 patient-years (11 events during 59 years of follow-up; 95% CI, 9.3-33)., Conclusions: Our data support the recommendation to stop anticoagulant treatment of cancer-associated VTE in patients cured of cancer. A cancer relapse seems to be a strong risk factor for recurrent symptomatic VTE., (Copyright © 2016 American College of Chest Physicians. Published by Elsevier Inc. All rights reserved.)

Several studies have shown high incidence of atherothrombotic events (ATEs) in patients with unprovoked pulmonary embolism. This association remains understudied in patients presenting with deep-vein thrombosis (DVT). We evaluated the risk factors for and the incidence of ATEs in patients with unprovoked proximal DVT, and compared it to patients with provoked DVT and reference patients without DVT. Patients with compression ultrasonography (CUS)-proven unprovoked proximal DVT, provoked DVT, and symptomatic patients in whom DVT was excluded by CUS were followed and scored for the occurrence of ATEs. A total of 1235 patients were enrolled: 170 patients with provoked, 74 patients with unprovoked DVT, and 991 patients without DVT. During follow-up, 128 ATEs occurred (incidence 6.5/100 patient-years). Adjusted hazard ratio was not different between patients with DVT and without DVT [hazard ratio 1.4; 95% confidence interval (CI) 0.76-2.4]. In contrast, patients with unprovoked DVT suffered from ATEs more frequently than provoked DVT patients (hazard ratio 3.16; 95% CI 1.1-9.1) and reference patients (hazard ratio 2.8; 95% CI 1.3-5.7). Notably, when fully adjusted for the known ATE risk factors, the risk differences between references, provoked, and unprovoked DVT patients diminished: hazard ratio 1.1 (95% CI 0.47-2.5) and 1.7 (95% CI 0.80-3.6), respectively. Our study confirms that the risk of ATEs in patients with unprovoked DVT was higher than in those with provoked DVT or reference patients. Interestingly, our results raise the question whether the known risk factors for ATE and venous thromboembolism attribute equally in pulmonary embolism and DVT patients, and contradict a causal relation between ATE and proximal DVT.

Venous thromboembolism is commonly encountered both in the community and the in-patient setting. Despite major advances in diagnosis and treatment, there remain challenges in several clinical areas as a result of insufficient evidence to guide practice. This review covers six controversial topics, summarizes the best available evidence, and presents recommendations for practice. The clinical relevance of calf vein thrombosis and sub-segmental pulmonary embolism are often questioned; this has implications for both their diagnosis and management. The role of thrombolysis for the treatment of deep vein thrombosis (DVT) is discussed in consideration of the potential benefits and risks. Residual vein obstruction has been proposed as a predictor of recurrent thrombosis; we consider its relevance when determining the duration of anticoagulant treatment. The post-thrombotic syndrome (PTS) can be a disabling and costly consequence of DVT with limited options for prevention and treatment. We review the available evidence related to compression stockings for PTS prevention. Finally, the relationship between cancer and VTE is well recognized and this review considers the value of screening for occult cancer in patients with unprovoked VTE.

N-terminal pro-Brain Natriuretic Peptide (NT-pro-BNP) is primarily secreted by left ventricular (LV) stretch and wall tension. Notably, NT-pro-BNP is a prognostic marker in acute pulmonary embolism (PE), which primarily stresses the right ventricle (RV). We sought to evaluate the relative contribution of the RV to NT-pro-BNP levels during PE. A post-hoc analysis of an observational prospective outcome study in 113 consecutive patients with computed tomography (CT)-proven PE and 226 patients in whom PE was clinically suspected but ruled out by CT. In all patients RV and LV function was established by assessing ECG-triggered-CT measured ventricular end-diastolic-volumes and ejection fraction (EF). NT-pro-BNP was assessed in all patients. The correlation between RV and LV end-diastolic-volumes and systolic function was evaluated by multiple linear regression corrected for known confounders. In the PE cohort increased RVEF (β-coefficient (95% confidence interval [CI]) -0.044 (± -0.011); p<0.001) and higher RV end-diastolic-volume (β-coefficient 0.005 (± 0.001); p<0.001) were significantly correlated to NT-pro-BNP, while no correlation was found with LVEF (β-coefficient 0.005 (± 0.010); p=0.587) and LV end-diastolic-volume (β-coefficient -0.003 (± 0.002); p=0.074). In control patients without PE we found a strong correlation between NT-pro-BNP levels and LVEF (β-coefficient -0.027 (± -0.006); p<0.001) although not LV end-diastolic-volume (β-coefficient 0.001 (± 0.001); p=0.418). RVEF (β-coefficient -0.002 (± -0.006); p=0.802) and RV end-diastolic-volume (β-coefficient <0.001 (± 0.001); p=0.730) were not correlated in patients without PE. In PE patients, lower RVEF and higher RV end-diastolic-volume were significantly correlated to NT-pro-BNP levels as compared to control patients without PE. These observations provide pathophysiological ground for the well-known prognostic value of NT-pro-BNP in acute PE.

The potential role of the detection of residual thrombosis after deep vein thrombosis (DVT) in the differentiation of patients at risk for recurrent venous thromboembolism (VTE) has not yet been fully established and includes different definitions. We performed a systematic review in order to determine the role of residual thrombosis in predicting recurrent VTE after acute proximal DVT. Databases were searched until June 2010. Randomized, controlled trials or prospective cohort studies were eligible for inclusion if they included patients with objectively diagnosed proximal DVT, measured thrombus diameter after at least 3 months and reported recurrent VTE during follow-up. Two authors independently reviewed articles and extracted data. Data from 11 studies were used for the current analysis; in total 3203 patients were included. Residual thrombosis was positively correlated with recurrent VTE. Large heterogeneity was present, due to differences in study population, timing and the differences in method of measuring residual thrombosis. The effect was more pronounced in patients with malignancy or was dependent on the criteria used. This systematic review shows a positive relationship between residual thrombosis and recurrent VTE during follow-up. Assessing residual thrombosis could be useful in individual recurrence risk estimation., (© 2011 Blackwell Publishing Ltd.)

Clinical diagnosis of a venous thromboembolism (VTE) is often difficult because the symptoms of this disorder are diverse and unspecified. The combination of a low probability clinical decision rule and an unremarkable D-dimer test is a safe way to exclude the presence of a VTE. Clinical decision rules for the diagnosis of a deep-vein thrombosis are available for primary and secondary care and clinical decision rules for the diagnosis of a pulmonary embolism is available for secondary care. Various D-dimer tests are available that differ with regard to sensitivity, specificity and duration of the measurement. During pregnancy and puerperium using a clinical decision rule and a D-dimer test is inadequate: additional radiologic investigation is always indicated in this situation. The diagnostic value of the D-dimer test during suspected recurrence of a VTE is yet to be determined.

An accurate and prompt diagnosis of deep vein thrombosis and/or pulmonary embolism is important to prevent serious complications and mortality. Because the clinical presentation of venous thromboembolism (VTE) is often nonspecific, objective testing by means of radiological imaging is required to confirm the diagnosis. Historically, a diagnosis of VTE involved invasive imaging techniques like contrast venography or conventional pulmonary angiography. Technological developments toward more accurate and less invasive diagnostics have driven the implementation of a variety of newer technologies over the past decades, as well as the derivation and validation of clinical decision rules (CDRs) that can be used to rule out VTE in combination with D-dimer blood tests. In this narrative review, we provide a historical overview of the most notable developments in the imaging techniques and CDRs for VTE diagnosis. [ABSTRACT FROM AUTHOR]

The European Society of Cardiology (ESC) Working Group on Pulmonary Circulation and Right Ventricular Function focuses on the assessment and management of severe forms of pulmonary hypertension (PH) and acute pulmonary embolism (PE). The working group aims to improve patient outcomes through a multidisciplinary approach and active involvement of patients. They provide education through various platforms and support early-career researchers. The working group collaborates with other societies to publish guidelines and position papers. The COVID-19 pandemic has led to changes in their operations, with remote educational meetings becoming more prominent. They have also established a network called EXPERT-PE to improve outcomes for severe acute PE patients. [Extracted from the article]

Aims Risk stratification is used for decisions regarding need for imaging in patients with clinically suspected acute pulmonary embolism (PE). The aim was to develop a clinical prediction model that provides an individualized, accurate probability estimate for the presence of acute PE in patients with suspected disease based on readily available clinical items and D-dimer concentrations. Methods and results An individual patient data meta-analysis was performed based on sixteen cross-sectional or prospective studies with data from 28 305 adult patients with clinically suspected PE from various clinical settings, including primary care, emergency care, hospitalized and nursing home patients. A multilevel logistic regression model was built and validated including ten a priori defined objective candidate predictors to predict objectively confirmed PE at baseline or venous thromboembolism (VTE) during follow-up of 30 to 90 days. Multiple imputation was used for missing data. Backward elimination was performed with a P -value <0.10. Discrimination (c-statistic with 95% confidence intervals [CI] and prediction intervals [PI]) and calibration (outcome:expected [O:E] ratio and calibration plot) were evaluated based on internal-external cross-validation. The accuracy of the model was subsequently compared with algorithms based on the Wells score and D-dimer testing. The final model included age (in years), sex, previous VTE, recent surgery or immobilization, haemoptysis, cancer, clinical signs of deep vein thrombosis, inpatient status, D-dimer (in µg/L), and an interaction term between age and D-dimer. The pooled c-statistic was 0.87 (95% CI, 0.85–0.89; 95% PI, 0.77–0.93) and overall calibration was very good (pooled O:E ratio, 0.99; 95% CI, 0.87–1.14; 95% PI, 0.55–1.79). The model slightly overestimated VTE probability in the lower range of estimated probabilities. Discrimination of the current model in the validation data sets was better than that of the Wells score combined with a D-dimer threshold based on age (c-statistic 0.73; 95% CI, 0.70–0.75) or structured clinical pretest probability (c-statistic 0.79; 95% CI, 0.76–0.81). Conclusion The present model provides an absolute, individualized probability of PE presence in a broad population of patients with suspected PE, with very good discrimination and calibration. Its clinical utility needs to be evaluated in a prospective management or impact study. Registration PROSPERO ID 89366. [ABSTRACT FROM AUTHOR]

Background: Strong evidence indicates that venous thromboembolism is a presenting symptom of cancer. Cancer is a known cause of pulmonary hypertension; however, it remains unknown whether pulmonary hypertension is a marker of occult cancer. We examined the association between a pulmonary hypertension diagnosis and cancer risk in a cohort study using population-based data from the Danish health system. Patients and Methods: Using Danish nationwide registries, we identified 6335 patients with a pulmonary hypertension diagnosis and without a previous cancer diagnosis between 1995 and 2017. We computed the age-, sex-, and calendar year-standardized incidence ratio (SIR) as the ratio of observed to expected number of cancers using national incidence rates as the reference. We performed a subgroup analysis among patients with chronic thromboembolic pulmonary hypertension in the period in which a specific ICD-10 code was available (2006– 2017). Results: We identified 212 cancers within the first year of follow-up and 796 cancers thereafter. The one-year risk of cancer was 3.3% and the one-year SIR was 1.96 (95% confidence interval [CI]: 1.70– 2.23). In the second and subsequent years, the SIR remained elevated (SIR: 1.15 [95% CI: 1.08– 1.24]). In patients with chronic thromboembolic pulmonary hypertension, the one-year SIR was 1.41 (95% CI: 0.82– 2.25). Conclusion: Cancer risk was clearly higher in patients with pulmonary hypertension compared with the general population. The association was particularly strong in the first year of follow-up, but remained elevated thereafter. However, absolute risks were low, limiting the clinical relevance of pursuing early cancer detection in these patients. [ABSTRACT FROM AUTHOR]

European estimates of the burden imposed by pulmonary embolism are not available to this date. We aimed to assess pulmonary embolism-related mortality and time trends in the WHO European Region. We analysed vital registration data from the WHO Mortality Database (2000–15) covering subregions of the WHO European Region: Eastern Europe, Northern Europe, Southern Europe, Western Europe, and Central Asia. Deaths were considered pulmonary embolism-related if International Classification of Disease-10 code for acute pulmonary embolism (I26) or any code for deep or superficial vein thrombosis was listed as the primary cause of death. We used locally estimated scatterplot smoothing weighted by size of the Member State population to calculate proportionate mortality and time trends in age-standardised mortality. In the 3-year period between 2013 and 2015, an average of 38 929 pulmonary embolism-related deaths occurred annually in the 41 Member States with available data and a population of 650 950 921; among individuals aged 15–55 years, pulmonary embolism accounted for 8–13 per 1000 deaths in women and 2–7 per 1000 deaths in men. Between 2000 and 2015, age-standardised annual pulmonary embolism-related mortality rates decreased linearly from 12·8 (95% CI 11·4–14·2) to 6·5 (5·3–7·7) deaths per 100 000 population without substantial sex-specific differences. The observed decreasing trends in pulmonary embolism-related mortality might reflect improved management of the disease, in line with case fatality data from cohort studies. Additional, or alternative, explanations might include the absence of a uniform case definition and changes in coding practices and performing autopsy. Pulmonary embolism still imposes a relevant medical and societal burden. Continuing efforts are warranted to improve awareness and implement effective preventive and therapeutic measures. German Federal Ministry of Education and Research. [ABSTRACT FROM AUTHOR]

Abstract: Background: Acute pulmonary embolism may be ruled out by combining nonhigh clinical probability and a normal D‐dimer level. Both antiplatelet drugs and HMG‐CoA reductase inhibitors (statins) have been associated with effects on thrombus formation, potentially influencing D‐dimer levels in this setting, leading to a higher rate of false‐negative tests. Therefore, we determined whether D‐dimer levels in patients with suspected pulmonary embolism are affected by concomitant use of antiplatelet drugs and/or statins and evaluated whether the effect of antiplatelet drugs or statins might affect diagnostic accuracy. Materials and methods: We performed a posthoc analysis in the YEARS diagnostic study, comparing age‐ and sex‐adjusted D‐dimer levels among users of antiplatelet drugs, statins and nonusers. We then reclassified patients within the YEARS algorithm by developing a model in which we adjusted D‐dimer cut‐offs for statin use and evaluated diagnostic accuracy. Results: We included 156 statins users, 147 antiplatelet drugs users and 726 nonusers of either drugs, all with suspected pulmonary embolism. Use of antiplatelet drugs did not have a significant effect, whereas statin use was associated with 15% decrease in D‐dimer levels (95% CI, −28% to −0.6%). An algorithm with lower D‐dimer thresholds in statin users yielded lower specificity (0.42 compared to 0.33) with no difference in false‐negative tests. Conclusions: We conclude that use of statins but not of antiplatelet agents is associated with a modest decrease in D‐dimer levels. Adjusting D‐dimer cut‐offs for statin use did, however, not result in a safer diagnostic strategy in our cohort. [ABSTRACT FROM AUTHOR]

Anticoagulant therapy is the cornerstone of therapeutic management in acute venous thromboembolism (VTE), consisting of pulmonary embolism and deep vein thrombosis. Direct oral anticoagulants (DOACs) have become the standard of care because of their good safety profile and ease of use in clinical practice. Indeed, phase 3 randomized trials (AMPLIFY, EINSTEIN, RECOVER, and HOKUSAI studies) showed that DOACs provided a similar efficacy and a better safety than conventional treatment with parenteral heparin with overlapping loading dose of vitamin K antagonists in acute VTE therapeutic management. The results of published data from real-world registries confirm the safety and efficacy of DOACs demonstrated in the phase 3 trials. [ABSTRACT FROM AUTHOR]

• 1155 patients with cancer-associated VTE receiving dalteparin or apixaban from the randomized Caravaggio study. • Recurrent VTE occurred in 78 patients (6.8%) and major bleeding in 45 (3.9%). • Pancreatic or hepatobiliary cancer, increase in creatinine clearance, ECOG status of at least 1, index DVT and anti-cancer treatment were independent predictors for recurrent VTE. • ECOG status of 2, genitourinary cancer, upper and non-resected luminal gastrointestinal cancer were independent predictors of major bleeding. Risks of recurrence and treatment-emergent bleeding are high in patients with cancer-associated venous thromboembolism (VTE) but factors associated with these risks remain substantially undefined. The aim of this analysis in patients with cancer-associated VTE included in the Caravaggio study was to identify risk factors for recurrent VTE and major bleeding. Variables potentially predictive for recurrent VTE or major bleeding were evaluated in a Cox proportional hazard multivariable analysis with backward variable selection. Recurrent VTE occurred in 78 patients (6.8%) and major bleeding in 45 (3.9%). Independent risk factors for recurrent VTE were deep vein thrombosis (DVT) as index event (Hazard ratio (HR) 1.84, 95% CI 1.17–2.88), ECOG status of 1 or more (HR 1.95, 95% CI 1.11–3.43), pancreatic or hepatobiliary cancer site (HR 2.20, 95% CI 1.19–4.06), concomitant anti-cancer treatment (HR 1.98, 95% CI 1.03–3.81) and creatinine clearance (HR 1.10, 95% CI 1.00–1.20 for every 10 ml/min absolute increase). Independent risk factors for major bleeding were ECOG status of 2 (HR 2.31, 95% CI 1.24–4.29), genitourinary cancer site (HR 2.72, 95% CI 1.28–5.77), upper gastrointestinal cancer site (HR 3.17, 95% CI 1.22–8.23), and non-resected luminal gastrointestinal cancer (HR 2.77, 95% CI 1.38–5.56). This analysis of the Caravaggio study in patients with cancer-associated VTE who were on standardized anticoagulant treatment identified five independent predictors for recurrent VTE and four independent predictors of treatment-emergent major bleeding. Considering these risks could help clinicians to optimize the anticoagulant treatment in patients with cancer-associated VTE. [ABSTRACT FROM AUTHOR]

• Women and men have different prevalence of risk factors for venous thromboembolism. • Understanding these differences may help to predict sex-related risk of recurrence. • Women and men had similar rates of one year recurrent venous thromboembolism (VTE). • Women had lower quality of life and treatment satisfaction after the first VTE. Sex and the presence of specific provoking risk factors, along with age, influence the presentation and prognosis of venous thromboembolism (VTE). We investigated the presentation, course and quality of life in women and men with acute VTE classified according to their VTE provoking factors. PREFER in VTE is an international, non-interventional registry of patients with a first episode of acute symptomatic VTE. Baseline provoking factors were classified as follows: major transient, minor transient, active cancer, and none identifiable. The primary outcome was recurrent VTE. Quality of life and treatment satisfaction were secondary outcomes. Of 3,455 patients with acute VTE, 1,623 (47%) were women. The mean age at the time of VTE was 61 (SD 18) in women, 60 (SD 15) in men. The distribution of provoking risk factors was similar between sexes, despite a tendency for higher frequency of minor and major transient risk factors in women, and cancer or unprovoked VTE in men. At 12-month follow-up, VTE recurrence was reported in 74 (6.5%) women and 80 (6.4%) men (absolute risk difference -0.1%, 95% CI -1.9%; +2.1%). In patients with unprovoked VTE, the VTE recurrence rate was 38/612 (6.2%) in women and 53/798 (6.6%) in men (absolute risk difference -0.4, 95% CI -3.0; +2.1%). Multivariable Cox regressions confirmed the absence of sex differences. Quality of life and treatment satisfaction scores one year after VTE were lower in women than in men irrespective of the provoking risk factors (p <0.001 for both scores). Despite differences in the provoking risk factors for VTE, women and men had a similar rate VTE recurrence at one year. After acute VTE, women had lower quality of life and treatment satisfaction scores. [ABSTRACT FROM AUTHOR]

• This is a multicenter case-control study conducted at four intensive care units • COVID-19 was highly associated with catheter-related thrombosis • The strong association seems to confirm the suggestion of an overall hypercoagulable state [ABSTRACT FROM AUTHOR]

Home treatment of cancer-associated venous thromboembolism (VTE) is challenging due to the high risk of adverse events. While home treatment is quite agreeable to cancer patients, studies evaluating the safety of VTE home treatment in this setting are largely unavailable. This was an observational study in patients with cancer-associated VTE. The main outcomes were the proportion of patients treated at home (hospital discharge <24 h after diagnosis) and the 3-month incidence of VTE-related adverse events (major bleeding, recurrent VTE and/or suspected VTE-related mortality) in patients managed in hospital versus at home. A total of 183 outpatients were diagnosed with cancer-associated VTE: 69 had deep vein thrombosis (DVT) and 114 had pulmonary embolism (PE ± DVT). Of those, 120 (66%) were treated at home; this was 83% for patients with DVT and 55% for patients with PE (±DVT). The 3-month incidence of any VTE-related adverse event was 13% in those treated at home versus 19% in the hospitalized patients (HR 0.48; 95%CI 0.22–1.1), independent of initial presentation as PE or DVT. All-cause 3-month mortality occurred in 33 patients treated as inpatient (54%) compared to 29 patients treated at home (24%; crude HR 3.1 95%CI 1.9–5.0). Two-third of patients with cancer-associated VTE - including PE - were selected to start anticoagulant treatment at home. Cancer-associated VTE is associated with high rates of VTE-related adverse events independent of initial in hospital or home treatment. However, home treatment may be a good option for selected patients with cancer-associated DVT or PE. • Guidelines recommend hospitalization of patients with cancer-associated pulmonary embolism (PE). • More than half of our patients with cancer-associated PE were selected to start home treatment. • Cancer-associated thrombosis has a poor prognosis, independent of initial home or in-hospital treatment • Home treatment may be a good option for selected patients with cancer-associated DVT and/or PE. [ABSTRACT FROM AUTHOR]