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Background: Wells score comprises subjective elements, making physicians reluctant to use Wells score or cause them to use it incorrectly., Objectives: To develop and internally validate a prediction score that is objective and simple for evaluating suspected deep vein thrombosis (DVT), with a safety comparable with that of Wells score., Methods: We performed a post hoc analysis using data from the Ri-Schedule study (NCT02486445) involving suspected DVT patients at Østfold Hospital's Emergency Department, Norway (2015-2018). Candidate variables were identified through bootstrapping technique, with a confirmed DVT diagnosis as the outcome variable. Sensitivity, specificity, negative predictive value (NPV), and positive predictive values (PPV) were estimated and compared with the 2-tier Wells score., Results: Among 1312 patients (median age, 64 years [IQR, 52-73]; 55% women), 19.9% were diagnosed with DVT. Exploration of 30 variables identified tenderness along deep veins and previous venous thromboembolism as significant predictors (selection frequency >60% in 1000 bootstrapping samples). The derived score categorized 450 patients with 0 items as unlikely to have DVT, of whom 8.0% were diagnosed with DVT, compared with 8.2% in DVT unlikely category according to Wells score. Compared with Wells score, the derived score demonstrated sensitivity of 86.2 (95% CI, 81.4-90.2) vs 80.1 (95% CI, 74.7-84.8), specificity of 39.4 (95% CI, 36.4-42.4) vs 55.3 (95% CI, 52.2-58.3), NPV of 92.0 (95% CI, 89.4-94.0) vs 91.8 (95% CI, 89.7-93.5), and PPV of 26.1 (95% CI, 24.8-27.5) vs 30.8 (95% CI, 28.9-32.8). When incorporating D-dimer cutoff of <0.5 µg/mL, the derived score had sensitivity of 99.6 (95% CI, 97.9-99.9), specificity of 16.1 (95% CI, 13.1-18.4), NPV of 99.4 (95% CI, 96.0-99.9), and PPV of 22.8 (95% CI, 22.3-23.3)., Conclusion: The derived DVT score, with 2 objective variables, had a comparable safety with that of the Wells score. However, an external validation is mandated prior to clinical use., (© 2024 The Author(s).)

Background: Only 1 conventional score is available for assessing bleeding risk in patients with cancer-associated thrombosis (CAT): the CAT-BLEED score., Objectives: Our aim was to develop a machine learning-based risk assessment model for predicting bleeding in CAT and to evaluate its predictive performance in comparison to that of the CAT-BLEED score., Methods: We collected 488 attributes (clinical data, biochemistry, and International Classification of Diseases, 10th Revision, diagnosis) in 1080 unique patients with CAT. We compared CAT-BLEED score, Ridge and Lasso logistic regression, random forest, and Extreme Gradient Boosting (XGBoost) algorithms for predicting major bleeding or clinically relevant nonmajor bleeding occurring 1 to 90 days, 1 to 365 days, and 90 to 455 days after venous thromboembolism (VTE)., Results: The predictive performances of Lasso logistic regression, random forest, and XGBoost were higher than that of the CAT-BLEED score in the prediction of bleeding occurring 1 to 90 days and 1 to 365 days after VTE. For predicting major bleeding or clinically relevant nonmajor bleeding 1 to 90 days after VTE, the CAT-BLEED score achieved a mean area under the receiver operating characteristic curve (AUROC) of 0.48 ± 0.13, while Lasso logistic regression and XGBoost both achieved AUROCs of 0.64 ± 0.12. For predicting bleeding 1 to 365 days after VTE, the CAT-BLEED score achieved a mean AUROC of 0.47 ± 0.08, while Lasso logistic regression and XGBoost achieved AUROCs of 0.64 ± 0.08 and 0.59 ± 0.08, respectively., Conclusion: This is the first machine learning-based risk model for bleeding prediction in patients with CAT receiving anticoagulation therapy. Its predictive performance was higher than that of the conventional CAT-BLEED score. With further development, this novel algorithm might enable clinicians to perform personalized anticoagulation strategies with improved clinical outcomes., Competing Interests: Declaration of competing interests W.G. reports personal fees from Novartis, Amgen, Bayer, Pfizer/BMS, Sanofi, Principia, and MSD and grants from Bayer and Pfizer/BMS, outside the submitted work. The other authors declare no conflicts of interest related to this work., (Copyright © 2024 International Society on Thrombosis and Haemostasis. Published by Elsevier Inc. All rights reserved.)

Background: There is limited knowledge regarding physical activity and clinical correlates among people who have suffered a pulmonary embolism (PE)., Objectives: To assess physical activity levels after PE and potential clinical correlates., Methods: One hundred forty-five individuals free of major comorbidities were recruited at a mean of 23 months (range, 6-72) after PE diagnosis. Physical activity was assessed by steps/day on the Sensewear monitor for 7 consecutive days, exercise capacity with the incremental shuttle walk test, and cardiac function with left ventricular ejection fraction (LVEF). The association between physical activity and other variables was analyzed by a mixed-effects model., Results: Participants achieved a mean of 6494 (SD, 3294; range, 1147-18.486) steps/day. The mixed-effects model showed that physical activity was significantly associated with exercise capacity (β-coefficient, 0.04; 95% CI, 0.03-0.05) and LVEF (β-coefficient, -0.81; 95% CI, -1.42 to -0.21). The analysis further showed that men became less physically active with increasing age (β-coefficient, -0.14; 95% CI, -0.24 to -0.04), whereas no change with age could be detected for women., Conclusion: In selected post-PE patients, physical activity seems to be associated with exercise capacity and LVEF but not with quality of life, dyspnea, or characteristics of the initial PE. Men appear to become less physically active with increasing age., (© 2024 The Author(s).)

Background: There are limited data on the long-term risk of venous thromboembolism (VTE) after high-risk isolated superficial vein thrombosis (iSVT) treated with anticoagulants., Objectives: To determine the short- and long-term risk of VTE and iSVT recurrence after cessation of anticoagulant treatment and to calculate 45-day cumulative bleeding incidence in patients with iSVT., Methods: Between January 2014 and December 2021, 229 patients with high-risk iSVT (ie, thrombus length ≥5cm), without active cancer, with no history of VTE or iSVT, and who had received anticoagulant treatment for the iSVT were identified through the Venous Thrombosis Registry in Østfold Hospital (TROLL registry), Norway. Cumulative incidences of VTE and iSVT recurrence, as well as cumulative incidences of major and clinically relevant nonmajor bleeding events, were assessed., Results: Median age was 60 years (IQR, 48-71), and 125 (55%) were women. Most patients were treated with direct oral anticoagulants (74%), and of these, 79% received a dose of rivaroxaban 10 mg daily. Low-molecular-weight heparin was given to 26% of the patients. The 1- and 5-year cumulative incidences of VTE after iSVT were 4.6% (95% CI, 2.5-8.3) and 15.9% (95% CI, 10.8-22.9), respectively. Further, the 1- and 5-year cumulative incidences of iSVT recurrence were 6.5% (95% CI, 3.9-10.7) and 15.9% (95% CI, 10.8-23.1), respectively. The overall 45-day cumulative incidence of major and clinically relevant nonmajor bleeding events was 0.4% (95% CI, 0.06-3.06) and 1.8% (95% CI, 0.7-4.6), respectively. No major bleeding events were observed in patients treated with direct oral anticoagulants., Conclusion: Despite anticoagulant treatment, the risk of VTE after high-risk iSVT was substantial, while bleeding complications were low., Competing Interests: Declaration of competing interests C.T.J. reports lecture honoraria from Bayer. W.G. reports fees for participation on advisory boards from Amgen, Novartis, Pfizer, Principia Biopharma Inc (a Sanofi Company), Sanofi, SOBI, Griffols, UCB, and Argenx; lecture honoraria from Bayer, Amgen, Novartis, Pfizer, Bristol Myers Squibb, SOBI, Griffols, and Sanofi; and research grants from Bayer and BMS/Pfizer. E.T. reports fees from Novartis, SOBI, Alexion, Janssen, BiGene, AbbVie, Grifols, Jazz, Takeda, and Incyte. H.H.P. reports fees from Novartis and Sanofi. M.T., E.F., and S.K.B. have no competing interests to disclose., (Copyright © 2023 International Society on Thrombosis and Haemostasis. Published by Elsevier Inc. All rights reserved.)

Background: Persistent dyspnea, functional limitations, and reduced quality of life (QoL) are common following pulmonary embolism (PE). Rehabilitation is a potential treatment option, but the scientific evidence is limited., Research Question: Does an exercise-based rehabilitation program improve exercise capacity in PE survivors with persistent dyspnea?, Study Design and Methods: This randomized controlled trial was conducted at two hospitals. Patients with persistent dyspnea following PE diagnosed 6 to 72 months earlier, without cardiopulmonary comorbidities, were randomized 1:1 to either the rehabilitation or the control group. The rehabilitation program consisted of two weekly sessions of physical exercise for 8 weeks and one educational session. The control group received usual care. The primary end point was the difference in Incremental Shuttle Walk Test between groups at follow-up. Secondary end points included differences in the Endurance Shuttle Walk Test (ESWT), QoL (EQ-5D and Pulmonary Embolism-QoL questionnaires) and dyspnea (Shortness of Breath questionnaire)., Results: A total of 211 subjects were included: 108 (51%) were randomized to the rehabilitation group and 103 (49%) to the control group. At follow-up, participants allocated to the rehabilitation group performed better on the ISWT compared with the control group (mean difference, 53.0 m; 95% CI, 17.7-88.3; P = .0035). The rehabilitation group reported better scores on the Pulmonary Embolism-QoL questionnaire (mean difference, -4%; 95% CI, -0.09 to 0.00; P = .041) at follow-up, but there were no differences in generic QoL, dyspnea scores, or the ESWT. No adverse events occurred during the intervention., Interpretation: In patients with persistent dyspnea following PE, those who underwent rehabilitation had better exercise capacity at follow-up than those who received usual care. Rehabilitation should be considered in patients with persistent dyspnea following PE. Further research is needed, however, to assess the optimal patient selection, timing, mode, and duration of rehabilitation., Clinical Trial Registration: ClinicalTrials.gov; No.: NCT03405480; URL: www., Clinicaltrials: gov., (Copyright © 2023 The Author(s). Published by Elsevier Inc. All rights reserved.)

Background: Isolated distal deep vein thrombosis (IDDVT) is a common presentation of deep vein thrombosis. There are limited data on the long-term risk of recurrence after IDDVT., Objectives: We aimed to determine the short- and long-term incidence of venous thrombosis (VTE) recurrence after cessation of anticoagulation and the 3-month incidence of bleeding during anticoagulant treatment in patients with IDDVT., Methods: Between January 2005 and May 2020, 475 patients with IDDVT and without active cancer were identified from the Venous Thrombosis Registry in Østfold Hospital, which is an ongoing registry of consecutive patients with VTE at Østfold Hospital, Norway. Major and clinically relevant, nonmajor bleeding as well as recurrent VTE were registered, and the cumulative incidences of these events were assessed., Results: The median age of the patients was 59 years (IQR, 48-72 years), 243 (51%) patients were women, and 175 events (36.8%) were classified as unprovoked. The 1-, 5-, and 10-year cumulative incidences of recurrent VTE were 5.6% (95% CI, 3.7-8.4), 14.7% (95% CI, 11.1-19.4), and 27.2% (95% CI, 21.1-34.5), respectively. The recurrence rates were higher for unprovoked IDDVT than for provoked IDDVT. Among the recurrent events, 18 (29%) were pulmonary embolisms and 21 (33%) were proximal deep vein thromboses. The 3-month cumulative incidence of major bleeding was 1.5% (95% CI, 0.7-3.1) overall and 0.8% (95% CI, 0.2-3.1) when restricted to patients treated with direct oral anticoagulants., Conclusion: Despite initial treatment, the long-term risk of VTE recurrence after first-time IDDVT is high. The bleeding rates during anticoagulation, particularly with direct oral anticoagulants, were acceptably low., Competing Interests: Declaration Of Competing Interests C.T.J. reports lecture honoraria from Bayer. W.G. reports fees for participation in the advisory board of Amgen, Novartis, Pfizer, Principia Biopharma Inc (a Sanofi company), Sanofi, SOBI, Griffols, UCB, Argenx, and Cellphire and lecture honoraria from Bayer, Amgen, Novartis, Pfizer, Bristol Myers Squibb, SOBI, Griffols, and Sanofi. E.T. reports lecture honoraria from BMS, Pfizer, Bayer, Alexion, Novartis, AOP, Incyte, Grifols, SOBI, Takeda, and Janssen. H.H.P. reports fees from Novartis and Sanofi. M.T., E.F., and S.K.B. disclose no conflict of interest., (Copyright © 2023 International Society on Thrombosis and Haemostasis. Published by Elsevier Inc. All rights reserved.)

Background: Patients hospitalized with COVID-19 suffer thrombotic complications. Risk factors for poor outcomes are shared with coronary artery disease., Objectives: To investigate the efficacy of an acute coronary syndrome regimen in patients hospitalized with COVID-19 and coronary disease risk factors., Methods: A randomized controlled, open-label trial across acute hospitals (United Kingdom and Brazil) added aspirin, clopidogrel, low-dose rivaroxaban, atorvastatin, and omeprazole to standard care for 28 days. Primary efficacy and safety outcomes were 30-day mortality and bleeding. The key secondary outcome was a daily clinical status (at home, in hospital, on intensive therapy unit admission, or death)., Results: Three hundred twenty patients from 9 centers were randomized. The trial terminated early due to low recruitment. At 30 days, there was no significant difference in mortality (intervention vs control, 11.5% vs 15%; unadjusted odds ratio [OR], 0.73; 95% CI, 0.38-1.41; p = .355). Significant bleeds were infrequent and were not significantly different between the arms (intervention vs control, 1.9% vs 1.9%; p > .999). Using a Bayesian Markov longitudinal ordinal model, it was 93% probable that intervention arm participants were more likely to transition to a better clinical state each day (OR, 1.46; 95% credible interval [CrI], 0.88-2.37; Pr [beta > 0], 93%; adjusted OR, 1.50; 95% CrI, 0.91-2.45; Pr [beta > 0], 95%) and median time to discharge to home was 2 days shorter (95% CrI, -4 to 0; 2% probability that it was worse)., Conclusion: Acute coronary syndrome treatment regimen was associated with a reduction in the length of hospital stay without an excess in major bleeding. A larger trial is needed to evaluate mortality., Competing Interests: Declaration of competing interests P.K. receives research grants and consulting fees from Biosense-Webster, Abbott-Medical, Medtronic, and Boston Scientific. A patent for Ripple Mapping is licensed to Biosense-Webster, and royalties are paid to Imperial College. C.C. is the recipient of a British Heart Foundation Clinical Research Training Fellowship (number FS/20/14/34917). A.A. has had support to attend conferences from Bayer. A.N. received a research grant from the NIHR Academy. S.N. received payment or honoraria for speaker events/presentations from Bayer, Pfizer, and Philips and participates on an Advisory Board for Astra Zeneca. G.Y.H.L. is a consultant and speaker for BMS/Pfizer, Boehringer Ingelheim, and Daiichi Sankyo. No fees are received personally. N.M. is supported by a Chair Award, Program Grant, and Research Excellence Award (CH/F/21/90010, RG/20/10/34966, and RE/18/5/34216, respectively) from the British Heart Foundation. A.J.C. reports personal fees/consulting fees from Bayer, Pfizer, BMS, Daiichi Sankyo, and Boehringer Ingelheim; reports royalties and/or editorial fees from Oxford University Press, Wiley, and Springer Verlag; and participates on DSMBs/Advisory Boards at Biotronik, Johnson and Johnson, and Allergan. G.S.C. receives grants from the NIHR, participates on DSMBs, and is a nonexecutive director at the MHRA. W.G. reports fees for participation in Advisory Board from Amgen, Novartis, Pfizer, Principia Biopharma Inc—a Sanofi Company, Sanofi, SOBI, Grifols, UCB, Argenx, Cellphire, and Hutchmed; lecture honoraria from Amgen, Novartis, Pfizer, Bristol Myers Squibb, SOBI, Grifols, and Sanofi; and research grants from Bayer and BMS/Pfizer. M.T. reports Scientific Advisory Board personal fees from MorphogenIX and personal fees/honoraria from J&J/Actelion. R.A.-L. receives speaker’s honoraria from Philips Volcano, Medtronic, and Menarini. M.S.-S. has received honoraria from Pfizer (<£500). D.P.F., D.C., A.M., G.K., P.P., M.S., G.C., D.d.A.N., J.H., R.E., M.K., R.M., G.B., R.M.M., A.K., M.M., K.M., J.S., S.J.C., M.J.L., N.P., R.P., A.S.M.B., M.D., I.M., N.P., V.C. have no competing interests to disclose., (Copyright © 2023 The Authors. Published by Elsevier Inc. All rights reserved.)

Background: Venous thromboembolism (VTE) is a frequent disease with a high risk of recurrence. It has been suggested that the D-dimer level at the time of VTE diagnosis can be used to identify patients at a low risk of recurrence., Objectives: We aimed to investigate the impact of D-dimer levels measured at the time of VTE diagnosis on the risk of recurrence in a large cohort of patients with a first-time VTE., Methods: The study included 2585 patients with first symptomatic non-cancer-associated VTE from the Venous Thrombosis Registry in Østfold Hospital (TROLL) (2005-2020). All recurrent events during the follow-up were recorded, and cumulative incidences of recurrence were estimated according to D-dimer levels of ≤1900 ng/mL (≤25th percentile) and >1900 ng/mL., Results: During a median follow-up of 3.3 years, 395 patients experienced a recurrent VTE. The 1- and 5-year cumulative incidences of recurrence were 2.9% (95% CI: 1.8-4.6) and 11.4% (95% CI: 8.7-14.8), respectively, in those with a D-dimer concentration of ≤1900 ng/mL and 5.0% (95% CI, 4.0-6.1) and 18.3% (95% CI: 16.2-20.6), respectively, in those with a D-dimer concentration of >1900 ng/mL, respectively. In patients with unprovoked VTE, the 5-year cumulative incidence was 14.3% (95% CI: 10.3-19.7) in the ≤1900-ng/mL category, and 20.2% (95% CI: 17.3-23.5) in the >1900-ng/mL category., Conclusions: D-dimer levels within the lowest quartile, measured at the time of VTE diagnosis, were associated with lower recurrence risk. Our findings imply that D-dimer levels measured at the time of diagnosis may be used to identify patients with VTE at a low risk of recurrent VTE., Competing Interests: Declaration of competing interests C.T.J. reports lecture honoraria from Bayer. H.H.P. reports receiving fees from Sanofi and Novartis. W.G. reports receiving fees for participation in an advisory board from Amgen, Novartis, Pfizer, Principia Biopharma Inc—a Sanofi Company, Sanofi, SOBI, Grifols, UCB, Argenx, Cellphire; lecture honoraria from Amgen, Novartis, Pfizer, Bristol Myers Squibb, SOBI, Grifols, Sanofi, and Bayer; and research grants from Bayer, BMS/Pfizer, and UCB. The remaining authors F.B.R, S.K.B, and J.-B.H have no competing interests to disclose., (Copyright © 2023 The Author(s). Published by Elsevier Inc. All rights reserved.)

Background: SARS-CoV-2 adenoviral vector DNA vaccines have been linked to the rare but serious thrombotic postvaccine complication vaccine-induced immune thrombotic thrombocytopenia. This has raised concerns regarding the possibility of increased thrombotic risk after any SARS-CoV-2 vaccines., Objectives: To investigate whether SARS-CoV-2 vaccines cause coagulation activation leading to a hypercoagulable state., Methods: This observational study included 567 health care personnel; 521 were recruited after the first dose of adenoviral vector ChAdOx1-S (Vaxzevria, AstraZeneca) vaccine and 46 were recruited prospectively before vaccination with a messenger RNA (mRNA) vaccine, either Spikevax (Moderna, n = 38) or Comirnaty (Pfizer-BioNTech, n = 8). In the mRNA group, samples were acquired before and 1 to 2 weeks after vaccination. In addition to the prevaccination samples, 56 unvaccinated blood donors were recruited as controls (total n = 102). Thrombin generation, D-dimer levels, and free tissue factor pathway inhibitor (TFPI) levels were analyzed., Results: No participant experienced thrombosis, vaccine-induced immune thrombotic thrombocytopenia, or thrombocytopenia (platelet count <100 × 10 9 /L) 1 week to 1 month postvaccination. There was no increase in thrombin generation, D-dimer level, or TFPI level in the ChAdOx1-S vaccine group compared with controls or after the mRNA vaccines compared with baseline values. Eleven of 513 (2.1%) participants vaccinated with ChAdOx1-S had anti-PF4/polyanion antibodies without a concomitant increase in thrombin generation., Conclusion: In this study, SARS-CoV-2 vaccines were not associated with thrombosis, thrombocytopenia, increased thrombin generation, D-dimer levels, or TFPI levels compared with baseline or unvaccinated controls. These findings argue against the subclinical activation of coagulation post-COVID-19 vaccination., (© 2022 The Authors.)

Purpose: The incidence of venous thromboembolism (VTE) is expected to increase over the next decades, further increasing its substantial impact on patients and health care resources. Registries have the benefit of reporting real-world data without excluding clinically important subgroups. Our aim was to describe a Norwegian VTE registry and to provide descriptive data on the population and management., Registry Population: The Venous Thrombosis Registry in Østfold Hospital (TROLL) is an ongoing registry of consecutive patients diagnosed with, treated, and/or followed up for VTE at Østfold Hospital, Norway, since 2005. Baseline and follow-up data, including demographics, clinical features, risk factors, diagnostic procedures, classification of VTE, and treatment were collected during hospitalization, and at scheduled outpatient visits., Findings to Date: From January 2005 to June 2021, 5037 patients were eligible for research in TROLL. Median age was 67 years (interquartile range, 55-77), and 2622 (52.1%) were male. Of these, 2736 (54.3%) had pulmonary embolism (PE), 2034 (40.4%) had deep vein thrombosis (DVT), and 265 (5.3%) had upper-extremity DVT or splanchnic or cerebral sinus vein thrombosis. In total, 2330 (46.3%) were classified as unprovoked VTE, and 1131 (22.5%) had cancer. Direct oral anticoagulants were the most frequent therapeutic agents (39.3%) followed by low-molecular-weight heparins (30.4%) and vitamin K antagonists (30.3%). Outpatient treatment for PE increased from 4% in 2005 to 23% in 2019., Future Plans: TROLL is a population-based ongoing registry that represents a valuable source of real-world data that will be used for future research on the management and outcomes of VTE., (© 2022 The Authors. Research and Practice in Thrombosis and Haemostasis published by Wiley Periodicals LLC on behalf of International Society on Thrombosis and Haemostasis (ISTH).)

Background: Postthrombotic syndrome (PTS) is a long-term complication after deep vein thrombosis (DVT) and can affect quality of life (QoL). Pathogenesis is not fully understood but inadequate anticoagulant therapy with vitamin K antagonists is a known risk factor for the development of PTS., Objectives: To compare the prevalence of PTS after acute DVT and the long-term QoL following DVT between patients treated with edoxaban or warfarin., Methods: We performed a long-term follow-up study in a subset of patients with DVT who participated in the Hokusai-VTE trial between 2010 and 2012 (NCT00986154). Primary outcome was the prevalence of PTS, defined by the Villalta score. The secondary outcome was QoL, assessed by validated disease-specific (VEINES-QOL) and generic health-related (SF-36) questionnaires., Results: Between 2017 and 2020, 316 patients were enrolled in 26 centers in eight countries, of which 168 (53%) patients had been assigned to edoxaban and 148 (47%) to warfarin during the Hokusai-VTE trial. Clinical, demographic, and thrombus-specific characteristics were comparable for both groups. Mean (SD) time since randomization in the Hokusai-VTE trial was 7.0 (1.0) years. PTS was diagnosed in 85 (51%) patients treated with edoxaban and 62 (42%) patients treated with warfarin (adjusted odds ratio 1.6, 95% CI 1.0-2.6). Mean differences in QoL scores between treatment groups were not clinically relevant., Conclusion: Contrary to our hypothesis, the prevalence of PTS tended to be higher in patients treated with edoxaban compared with warfarin. No differences in QoL were observed. Further research is warranted to unravel the role of anticoagulant therapy on development of PTS., Competing Interests: J.B.W. reports personal fees and other from Bayer HealthCare, personal fees and other from Boehringer. Ingelheim, personal fees and other from BMS/Pfizer, personal fees and other from CSL Behring, personal fees and other personal fees and other from Daiichi Sankyo, personal fees and other from LEO Pharma, outside the submitted work. F.C. reports grants from BMS/Pfizer, personal fees and other from Bayer HealthCare, personal fees and other from AstraZeneka, personal fees and other from MSD, personal fees and other from GSK, other from Janssen, personal fees and other from Novartis, outside the submitted work. M.C. reports personal fees from Bayer HealthCare, personal fees from Boehringer Ingelheim, personal fees from Bristol‐Myers Squib, personal fees from CSL Behring, personal fees from Daiichi Sankyo, personal fees from Pfizer, personal fees from Portola, personal fees from Sanquin Blood Supply, outside the submitted work. W.G. reports grants and other from Bayer HealthCare, grants and other from Pfizer, other from Novartis, other from Amgen, other from Principia, from Sanofi, other from MSD, other from Sobi, outside the submitted work. K. Meijer receives other from Bayer HealthCare, other from Uniqure, other from Alexion, other from Octapharma, outside the submitted work. S.M. reports grants from GSK, grants from BMS/Pfizer, grants from Aspen, grants from Daiichi Sankyo, grants from Bayer HealthCare, grants from Boehringer Ingelheim, grants from Sanofi, grants from Portola, outside the submitted work. M.A.S.P. reports honoraria from Bayer, Pfizer, and Leo Pharma. O.S. reports grants from Daiichi‐Sankyo, during the conduct of the study; grants, personal fees, and nonfinancial support from Bayer HealthCare, grants, personal fees and nonfinancial support from BMS, personal fees and non‐financial support from Pfizer, grants, personal fees and non‐financial support from Boehringer Ingelheim, grants and personal fees from MSD, personal fees from Chiesi, grants and personal fees from Boston Scientifics, outside the submitted work. S.M.S. reports receiving consulting fees from Bayer and Boehringer Ingelheim, and lecture fees from Bayer, Boehringer Ingelheim, and Bristol‐Myers Squibb–Pfizer. P.V. reports grants and personal fees from Bayer HealthCare, grants and personal fees from Boehringer Ingelheim, grants and personal fees from BMS/Pfizer, personal fees from Daiichi Sankyo, personal fees from LEO Pharma, personal fees from Anthos therapeutics, personal fees from Portola Pharmaceuticals/Alexion, outside the submitted work. M.G., M.S., and Y.L. report being an employee of Daiichi‐Sankyo. No other potential conflict of interest with relation to this study were reported., (© 2022 The Authors. Research and Practice in Thrombosis and Haemostasis published by Wiley Periodicals LLC on behalf of International Society on Thrombosis and Haemostasis (ISTH).)

Background: Statins may reduce the risk for recurrent venous thromboembolism (VTE); however, no randomized trials have explored this hypothesis. We performed a pilot randomized trial to determine feasibility of recruitment for a larger trial of secondary VTE prevention with rosuvastatin., Methods: Patients with a newly diagnosed symptomatic proximal deep vein thrombosis and/or pulmonary embolism, receiving standard anticoagulation, were randomly allocated to adjuvant rosuvastatin 20 mg once daily for 180 days or no rosuvastatin for 6 months., Results: Between November 2016 and December 2019, 3391 patients were assessed for eligibility in six centers. Of these patients, 1347 (39.7%) were eligible and approached for participation in the trial and 312 (23.1%) were randomized. The mean rate of randomization was 8.2 ± 4.3 patients per month. During follow-up, five recurrent VTE events were observed, three (1.9%) in the rosuvastatin group (two pulmonary embolism, one deep vein thrombosis), and two (1.3%) in the control group (two pulmonary embolism; P = 0.68). One major arterial event occurred in the rosuvastatin arm and none in the control arm (0.6% vs. 0%, P = 0.50)., Conclusion: This pilot trial supports the feasibility of a larger scale randomized controlled trial to determine the efficacy of adjuvant rosuvastatin for the secondary prevention of VTE., (© 2021 International Society on Thrombosis and Haemostasis.)

Background: Studies suggest that the direct factor Xa inhibitor rivaroxaban compared to warfarin reduces the risk of post-thrombotic syndrome (PTS) after deep vein thrombosis (DVT), but this has not been evaluated for oral direct thrombin inhibitors., Objectives: To compare the long-term prevalence of PTS, recurrent venous thromboembolism (VTE), and health-related quality of life (HRQoL) in patients with acute DVT and/or pulmonary embolism (PE), randomized to treatment with dabigatran or warfarin in the phase III RE-COVER studies., Methods: We conducted a cross-sectional follow-up study of patients randomized in Canada, Norway, and Sweden. PTS was assessed by the patient-reported Villalta scale (PRV) and HRQoL by EQ-5D and VEINES-QOL/Sym., Results: We included 349 patients between December 2015 and November 2018; 166 were treated with dabigatran and 183 with warfarin. DVT (+/- PE) was index event in 255 patients, whereas 94 patients had PE only. Mean time from index event was 8.7 (standard deviation 1.4) years. PTS was diagnosed in 63% of patients with DVT and in 46% of patients with PE only, and did not differ between the treatment groups; the crude odds ratio (OR) for PTS in patients treated with dabigatran compared with warfarin was 1.1 (95% confidence interval [CI] 0.6-1.8) after DVT and 1.2 (95% CI 0.5-2.6) after PE only. The prevalence of recurrent VTE was 21% in both treatment groups. HRQoL scores did not differ between groups., Conclusion: In this long-term cross-sectional study, the prevalence of PTS, recurrent VTE, and HRQoL were similar in patients treated with dabigatran and warfarin., (© 2021 The Authors. Journal of Thrombosis and Haemostasis published by Wiley Periodicals LLC on behalf of International Society on Thrombosis and Haemostasis.)

Background: Compression ultrasonography (CUS) is the first-line imaging test for diagnosing upper extremity deep vein thrombosis (UEDVT), but often yields inconclusive test results. Contrast venography is still considered the diagnostic standard but is an invasive technique., Objectives: We aimed to determine the diagnostic accuracy of magnetic resonance noncontrast thrombus imaging (MR-NCTI) for the diagnosis of UEDVT., Methods: In this international multicenter diagnostic study, we prospectively included patients with clinically suspected UEDVT who were managed according to a diagnostic algorithm that included a clinical decision rule (CDR), D-dimer test, and diagnostic imaging. UEDVT was confirmed by CUS or (computed tomography [CT]) venography. UEDVT was excluded by (1) an unlikely CDR and normal D-dimer, (2) a normal serial CUS or (3) a normal (CT) venography. Within 48 h after the final diagnosis was established, patients underwent MR-NCTI. MR-NCTI images were assessed post hoc by two independent radiologists unaware of the presence or absence of UEDVT. The sensitivity, specificity, and interobserver agreement of MR-NCTI for UEDVT were determined., Results: Magnetic resonance noncontrast thrombus imaging demonstrated UEDVT in 28 of 30 patients with UEDVT and was normal in all 30 patients where UEDVT was ruled out, yielding a sensitivity of 93% (95% CI 78-99) and specificity of 100% (95% CI 88-100). The interobserver agreement of MR-NCTI had a kappa value of 0.83 (95% CI 0.69-0.97)., Conclusions: Magnetic resonance noncontrast thrombus imaging is an accurate and reproducible method for diagnosing UEDVT. Clinical outcome studies should determine whether MR-NCTI can replace venography as the second-line imaging test in case of inconclusive CUS., (© 2021 The Authors. Journal of Thrombosis and Haemostasis published by Wiley Periodicals LLC on behalf of International Society on Thrombosis and Haemostasis.)

Background: Long-term sequelae of acute pulmonary embolism (PE) include decreased quality of life (QoL). Evidence suggests that adequacy of initial anticoagulant treatment in the acute phase of venous thrombosis has a key impact on late postthrombotic complications. We hypothesize that patients with acute PE treated with edoxaban for acute PE experience have improved QoL compared to those treated with warfarin., Methods: Patients with PE who participated in the Hokusai-VTE trial were contacted between June 2017 and September 2020 for a single long-term follow-up visit. Main outcomes were the generic and disease-specific QoL measured by the 36-Item Short Form Health Survey (SF-36) and Pulmonary Embolism Quality of Life questionnaire., Results: We included 251 patients from 26 centers in eight countries, of which 129 (51%) had been assigned to edoxaban and 122 (49%) to warfarin. Patient- and thrombus-specific characteristics were similar in both groups. Mean time since randomization in the Hokusai-VTE trial was 7.0 years (standard deviation, 1.0). No relevant or statistical differences were observed in the QoL for patients treated with edoxaban compared to patients treated with warfarin. The mean difference between patients treated with edoxaban and patients with PE treated with warfarin was 0.8 (95% confidence interval [CI]. -1.6 to 3.2) for the SF-36 summary mental score and 1.6 (95% CI, -0.9 to 4.1) for summary physical score., Conclusion: Our findings indicate that patients with an index PE treated with edoxaban or warfarin have a similar long-term QoL. Since our study was a follow-up study from a well-controlled clinical trial setting, future studies should be designed in a daily clinical practice setting. We suggest a longitudinal design for investigation of changes in QoL over time., (© 2021 The Authors. Research and Practice in Thrombosis and Haemostasis published by Wiley Periodicals LLC on behalf of International Society on Thrombosis and Haemostasis (ISTH).)

To improve the quality and accuracy of the patient-reported outcome measures that assess health-related quality of life (HRQoL), guidelines have been developed to standardize the development and validation process. Considering the increasing importance of HRQoL questionnaires in research, we set out to review the literature and evaluate whether existing questionnaires developed for deep vein thrombosis (DVT) and pulmonary embolism (PE) fulfill state-of-the-art requirements. The literature search was conducted in March 2019 and updated in September 2020. Seven databases were searched. No time limit was set for the search to include all available questionnaires. The inclusion criteria were original publications describing the development of disease-specific HRQoL questionnaires specific to DVT or PE in adults and available in English. The questionnaires were assessed to determine whether they fulfill the requirements in the latest guidelines. A total of 3826 references were identified. After the exclusion process, 15 papers were reviewed in full, of which 7 were included. Four questionnaires were developed for chronic venous disease, two were specific to DVT, and one was specific to PE. Most questionnaires we found in this review, fulfilled some but none fulfilled all recommendations in existing guidelines. Because the development of current available HRQoL questionnaires specific to DVT or PE do not fulfil all recommendations of existing guidelines, there is room for improvements within this field. Such improvements could likely enhance the quality associated with the use of these end points in clinical trials and practice., (© 2021 The Authors. Research and Practice in Thrombosis and Haemostasis published by Wiley Periodicals LLC on behalf of International Society on Thrombosis and Haemostasis (ISTH).)

Background: The COVID-19 vaccine from AstraZeneca (AZD1222) is one of several vaccines introduced to provide immunity against SARS-CoV-2. Recently, more than 50 cases have been reported presenting a combination of thrombosis, thrombocytopenia, and remarkably high levels of anti-platelet factor 4 (PF4)/polyanion antibodies post-AZD1222 vaccination. Now linked to the vaccine, the condition is referred to as vaccine-induced immune thrombotic thrombocytopenia. The European Medicines Agency still recommends vaccination with AZD1222, but several European countries have temporally paused and/or restricted its use because of the perceived risk of this severe side effect. Because there is no description of PF4/polyanion antibody testing in the clinical trials, knowledge about the prevalence of such antibodies in a vaccinated cohort is needed., Objectives: To investigate prevalence of thrombocytopenia and anti-PF4/polyanion antibodies in a population recently vaccinated with AZD1222., Patients/methods: Four hundred and ninety-two health care workers recently vaccinated with the first dose of AZD1222 were recruited from two hospitals in Norway. Study individuals were screened for thrombocytopenia and the presence of anti-PF4/polyanion antibodies with a PF4/PVS immunoassay. Side effects after vaccination were registered., Results: The majority of study participants had normal platelet counts and negative immunoassay. Anti-PF4/polyanion antibodies without platelet activating properties were only detected in six individuals (optical density ≥0.4, range 0.58-1.16), all with normal platelet counts. No subjects had severe thrombocytopenia., Conclusions: We found low prevalence of both thrombocytopenia and antibodies to PF4/polyanion-complexes among Norwegian health care workers after vaccination with AZD1222., (© 2021 The Authors. Journal of Thrombosis and Haemostasis published by Wiley Periodicals LLC on behalf of International Society on Thrombosis and Haemostasis.)

Approximately 80% of adult patients with immune thrombocytopenia (ITP) have treatment failure with corticosteroids or become dependent on them and require second-line therapy. Several new and effective therapies have been introduced during the past decade and our understanding of disease burden and its effect on quality of life has expanded. It is now recommended that splenectomy, the standard second-line therapy for decades, be delayed for at least 12 to 24 months, allowing for more patients to achieve remission on medical therapies before considering surgery. It is highly recommended that medical therapies be used that have abundant clinical trial evidence, such as the thrombopoietin receptor agonists (TPO-RAs) rituximab and fostamatinib. Unfortunately, there are no reliable biomarkers that help in treatment selection. These therapeutic medical options have variable efficacy, safety profiles, mechanisms of action, and modes of administration. This enables and mandates an individualized approach to treatment, where patient involvement, preferences and values have become central to the process of choosing the appropriate therapy. Both TPO-RAs and fostamatinib are maintenance therapies, whereas rituximab is given for a limited number of doses. Although the response is usually maintained while receiving a TPO-RA or fostamatinib therapy, half of rituximab responders will no longer respond 1 to 2 years after administration and require retreatment or other therapy., (© 2021 by The American Society of Hematology.)

Management of immune thrombocytopenia (ITP) during pregnancy can be challenging because treatment choices are limited. Thrombopoietin receptor agonists (Tpo-RAs), which likely cross the placenta, are not recommended during pregnancy. To better assess the safety and efficacy of off-label use of Tpo-RAs during pregnancy, a multicenter observational and retrospective study was conducted. Results from 15 pregnant women with ITP (pregnancies, n = 17; neonates, n = 18) treated with either eltrombopag (n = 8) or romiplostim (n = 7) during pregnancy, including 2 patients with secondary ITP, were analyzed. Median time of Tpo-RA exposure during pregnancy was 4.4 weeks (range, 1-39 weeks); the indication for starting Tpo-RAs was preparation for delivery in 10 (58%) of 17 pregnancies, whereas 4 had chronic refractory symptomatic ITP and 3 were receiving eltrombopag when pregnancy started. Regarding safety, neither thromboembolic events among mothers nor Tpo-RA-related fetal or neonatal complications were observed, except for 1 case of neonatal thrombocytosis. Response to Tpo-RAs was achieved in 77% of cases, mostly in combination with concomitant ITP therapy (70% of responders). On the basis of these preliminary findings, temporary off-label use of Tpo-RAs for severe and/or refractory ITP during pregnancy seems safe for both mother and neonate and is likely to be helpful, especially before delivery., (© 2020 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.)

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.)

Background: Rivaroxaban was the first new oral anticoagulant approved for treatment of venous thromboembolism (VTE). Clinical trials have shown that rivaroxaban is noninferior to conventional anticoagulation for VTE in efficacy and safety. Increased fatigue after the initiation of rivaroxaban has been observed in clinical practice, but data on this potential side effect are lacking., Objective: The study aimed to evaluate development of fatigue in patients treated for VTE, comparing rivaroxaban to other anticoagulants., Methods: Patients were prospectively recruited after a diagnosis of VTE. The Fatigue Questionnaire was used to determine the level of fatigue at baseline, at 3 weeks of treatment, and either at 1 month after the discontinuation of treatment if the treatment was discontinued after 3 months or at 6 months if treatment was continued beyond this time. Data was analyzed by a linear mixed model., Results: A total of 126 patients were included. Mean age was 59 years; 77 (61%) were males. Fifty-seven patients (45%) were diagnosed with deep vein thrombosis, 48 (38%) with pulmonary embolism, and 21 (17%) with both. Predicted changes in fatigue scores from baseline to the last measurement were -0.007 and -2.49 for the rivaroxaban and the other-anticoagulants groups, respectively, neither of which were statistically significant. No difference was detected between rivaroxaban and the other-anticoagulants group at any time point, including subgroup analysis comparing over and under 6 months of treatment duration., Conclusion: In this small study, our results suggest no increase in the level of fatigue after the initiation of treatment with rivaroxaban for VTE., (© 2020 The Authors. Research and Practice in Thrombosis and Haemostasis published by Wiley Periodicals, Inc on behalf of International Society on Thrombosis and Haemostasis.)

Background: Sleeve gastrectomy, with its short operating time, is possible to perform as same-day surgery, with the most common reason for requiring overnight hospital stay being postoperative nausea and vomiting., Objective: To demonstrate the feasibility and safety of sleeve gastrectomy as same-day surgery with regard to complication rate. Additionally, the study aimed to evaluate factors determining the duration of hospital stay, such as type of anesthesia, time of procedure, degree of postoperative nausea and pain, American Society of Anesthesiologists score, or previous abdominal surgery., Setting: Nonacademic primary referral center., Methods: A substudy of a single-center, double-blind, randomized controlled trial. Patients included in this study underwent sleeve gastrectomy and were randomized into 1 of the following 2 types of anesthesia: total intravenous anesthesia with propofol or desflurane. Primary endpoint was the number of patients discharged the same day as surgery. Secondary endpoints were unplanned telephone calls, readmission rate, and complication rate. Time of procedure was registered by the staff at the operation theatre. Visual analog scales score estimating patients' intensity of pain and nausea were completed at the postoperative unit, surgical ward, and 24 to 48 hours postoperatively., Results: Ninety-three patients were included in the study. Fifty-nine (63%) were discharged the same day as surgery (32 desflurane and 27 total intravenous anesthesia), 30 patients (32%) were discharged 1 day after surgery, and 4 patients (4%) were discharged after >2 days (15 desflurane and 19 total intravenous anesthesia). The most common reasons for prolonged stay were pain, nausea, and fatigue. Statistical analyses showed no association between day of discharge and the type of anesthesia, time of the procedure, degree of postoperative nausea and vomiting, pain intensity, American Society of Anesthesiologists score, or previous abdominal surgery., Conclusion: Same-day surgery is feasible and safe in terms of low complication rate. The type of anesthesia, time of procedure, degree of postoperative nausea and vomiting and pain, American Society of Anesthesiologists score and previous abdominal surgery does not appear to affect length of hospital stay., (Copyright © 2019 American Society for Bariatric Surgery. Published by Elsevier Inc. All rights reserved.)

Background: There is limited evidence-based knowledge regarding optimal anesthesia in obese patients., Objective: To evaluate optimal anesthetic approach for patients undergoing bariatric surgery by determining and comparing peri- and postoperative outcomes in patients receiving intravenous anesthesia with propofol versus desflurane anesthesia., Setting: Nonacademic primary referral center., Methods: Patients who underwent laparoscopic sleeve gastrectomy and Roux-en-Y gastric bypass between 2016 and 2017 were randomized into 1 of the following 2 types of anesthesia: intravenous anesthesia with propofol, or desflurane. Perioperative outcomes were registered by the operation staff. A form based on visual analog scale estimating the patient's intensity of pain and nausea was completed postoperatively at the postoperative unit, surgical ward, and 24 to 48 hours postsurgery. The primary outcome was postoperative nausea and vomiting or postoperative pain between treatment groups. The secondary outcome was to evaluate the "time of awakening," peritoneal stretch, and use of perioperative muscle relaxants., Results: One hundred eighty-three patients were randomized to receive intravenous anesthesia (n = 90) or desflurane anesthesia (n = 93). Mean time ± standard deviation of surgery for both procedures was 41 ± 17 minutes, whereas mean time of awakening was 2 ± 2 minutes for both the intravenous anesthesia and desflurane group. There was no significant difference in visual analog scale for pain or for nausea and vomiting postoperatively, nor in the number of patients receiving muscle relaxants for peritoneal stretch between the 2 groups., Conclusions: We found no significant differences between the 2 anesthetic regimens regarding postoperative nausea and pain, awakening time, peritoneal stretch, or the use of perioperative muscle relaxants., (Copyright © 2019 American Society for Bariatric Surgery. Published by Elsevier Inc. All rights reserved.)

Essentials Immune thrombocytopenia (ITP) is an autoimmune disorder characterized by low platelet count. We conducted a cohort study of 3 584 chronic ITP patients from the Nordic countries. Cardiovascular events occurred across all platelet count levels. Cardiovascular or bleeding events were strong prognostic factors for all-cause mortality. Background Among patients with chronic immune thrombocytopenia (cITP), little is known regarding risk factors for cardiovascular and bleeding outcomes and how these events influence mortality. Objectives We examined the rate of cardiovascular events and bleeding requiring a hospital contact according to platelet count levels, as well as the prognostic impact of these events on all-cause mortality in adult patients with cITP. Methods We identified all cITP patients registered in the Nordic Country Patient Registry for Romiplostim during 1996 to 2015. Absolute risks and hazard ratios across platelet count levels based on Cox regression analysis were computed, adjusting for age, sex, prevalent/incident cITP, smoking, and comorbidities. We also compared all-cause mortality rates in cITP patients with and without cardiovascular and bleeding events. Results Among 3 584 cITP patients, 1-year risks were 1.9% for arterial cardiovascular events, 1.2% for venous thromboembolism, and 7.5% for bleeding. Rates of cardiovascular events were similar across platelet counts. Patients with platelet counts <50 × 10 9 /L had >2-fold higher rates of bleeding than patients with normal platelet counts. These associations were unchanged in time-varying analyses that considered changes in platelet counts during follow-up. Occurrences of cardiovascular and bleeding events were associated with 4-fold to 5-fold increases in 1-year mortality. Conclusions Among patients with cITP, the 1-year risks of cardiovascular events were 1% to 2%, while nearly 8% experienced a bleeding event within 1 year. Cardiovascular events occurred across all platelet levels, while low platelet counts were associated with increased hazards of bleeding. Cardiovascular and bleeding events were strong prognostic factors for mortality., (© 2019 International Society on Thrombosis and Haemostasis.)

Essentials The aim of deep vein thrombosis (DVT) diagnostic work-up is to maximize both safety and efficiency. We explored whether D-dimer is safe and efficient as a stand-alone test to exclude DVT. Our findings suggest it is a safe, efficient and simplified diagnostic strategy. The safety of age-adjusted D-dimer as a stand-alone test requires further investigation. SUMMARY: Background Several strategies for safely excluding deep vein thrombosis (DVT) while limiting the number of imaging tests have been explored. Objectives To determine whether D-dimer testing could safely and efficiently exclude DVT as a stand-alone test, and evaluate its performance as compared with strategies that incorporate the Wells score and age-adjusted D-dimer. Patients/Methods We included consecutive outpatients referred with suspected DVT to the Emergency Department at Østfold Hospital, Norway. STA-Liatest D-Di PLUS D-dimer was analyzed for all patients. Patients with a D-dimer level of ≥ 0.5 μg mL -1 were referred for compression ultrasonography (CUS). In patients with a D-dimer level of < 0.5 μg mL -1 , no further testing was performed and anticoagulation was withheld. Patients were followed for 3 months for venous thromboembolism (VTE). Results Of the 913 included patients, 298 (33%) had a negative D-dimer result. One hundred and seventy-three patients (18.9%) were diagnosed with DVT at baseline. One of 298 patients had DVT despite having a negative D-dimer result, resulting in a failure rate of 0.3% (95% confidence interval [CI] 0.1-1.9%). Adding the modified Wells score would have yielded a failure rate of 0.0% (95% CI 0.0-1.8%) while necessitating 87 more CUS examinations. Age-adjusted D-dimer as a stand-alone test would have necessitated 80 fewer CUS examinations than fixed D-dimer as a stand-alone test, at the cost of a failure rate of 1.6% (95% CI 0.7-3.4%). Conclusions This outcome study shows that a negative high-sensitivity D-dimer result safely excludes DVT in an outpatient population, and necessitates fewer CUS than if used in combination with Wells score. The safety of stand-alone age-adjusted D-dimer needs further assessment in prospective outcome studies., (© 2018 International Society on Thrombosis and Haemostasis.)

Background: Immune thrombocytopenia is characterised by immune-mediated destruction and suboptimum production of platelets. Despite the absence of supporting evidence, rituximab is frequently used off-label in patients with immune thrombocytopenia. We aimed to assess the efficacy of rituximab as compared with placebo as a splenectomy-sparing treatment in patients who were previously treated with corticosteroids., Methods: In this multicentre, randomised, double-masked, placebo-controlled trial, we enrolled corticosteroid unresponsive adult patients (aged ≥18 years) with primary immune thrombocytopenia and a platelet count of less than 30 × 10(9) platelets per L. Patients were randomly assigned (1:1) to four weekly infusions of 375 mg/m(2) rituximab or placebo. Concurrent treatment with corticosteroids only was allowed during the study. The primary endpoint was rate of treatment failure within 78 weeks--a composite of splenectomy or meeting criteria for splenectomy after week 12 if splenectomy was not done, assessed in all patients who received at least one dose of study treatment. Secondary endpoints were response rates, relapse rates, and duration of response. Efficacy endpoints were assessed with the Kaplan-Meier method. Safety endpoints were assessed in all patients who received at least one dose. This trial is registered with ClinicalTrials.gov, number NCT00344149., Findings: Between Aug 17, 2006, and June 30, 2011, we enrolled 112 patients. 32 (58%) of 55 patients in the rituximab group and 37 (69%) of 54 patients in the placebo group had treatment failure within 78 weeks (Kaplan-Meier cumulative incidence 46% for rituximab vs 52% for placebo (hazard ratio [HR] 0·89, 95% CI 0·55-1·45; p=0·65). The cumulative incidence of overall response was 81% in the rituximab group versus 73% in the placebo group (p=0·15) and complete response was 58% in the rituximab group versus 50% in the placebo group (p=0·12). Of those achieving an overall response, 68% relapsed in the rituximab group and 78% relapsed in the placebo group, and of those achieving complete response, 50% relapsed in the rituximab group and 62% relapsed in the placebo group. Time to relapse in the rituximab group was longer in patients who achieved overall response (36 vs 7 weeks; p=0·01) but not complete response (76 vs 49 weeks; p=0·19). Rates of bleeding were similar in the two groups (21 [38%] in the rituximab group vs 27 [50%] in the placebo group; p=0·08) as were rates of infection (22 [40%] vs 13 [24%]; p=0·09)., Interpretation: Despite no reduction in the rate of long-term treatment failure with rituximab, a small benefit cannot be ruled out, as suggested by an apparently longer duration of response and numerically higher response rates with rituximab., Funding: South-East Regional Health Authority and Østfold Hospital, Norway; Roche, France; and Roche, Norway., (Copyright © 2015 Elsevier Ltd. All rights reserved.)

The paradigm for managing primary immune thrombocytopenia (ITP) in adults has changed with the advent of rituximab and thrombopoietin receptor agonists (TPO-RAs) as options for second-line therapy. Splenectomy continues to provide the highest cure rate (60%-70% at 5+ years). Nonetheless, splenectomy is invasive, irreversible, associated with postoperative complications, and its outcome is currently unpredictable, leading some physicians and patients toward postponement and use of alternative approaches. An important predicament is the lack of studies comparing second-line options to splenectomy and to each other. Furthermore, some adults will improve spontaneously within 1-2 years. Rituximab has been given to more than 1 million patients worldwide, is generally well tolerated, and its short-term toxicity is acceptable. In adults with ITP, 40% of patients are complete responders at one year and 20% remain responders at 3-5 years. Newer approaches to using rituximab are under study. TPO-RAs induce platelet counts > 50 000/μL in 60%-90% of adults with ITP, are well-tolerated, and show relatively little short-term toxicity. The fraction of TPO-RA-treated patients who will be treatment-free after 12-24 months of therapy is unknown but likely to be low. As each approach has advantages and disadvantages, treatment needs to be individualized, and patient participation in decision-making is paramount.

Background: We previously found plasma levels of CD40 ligand (CD40L), chemokine (C-X-C motif) ligand 5 (CXCL5), chemokine (C-C motif) ligand 5 (CCL5) and epidermal growth factor (EGF) to be low in aplastic anemia (AA) patients and to be correlated with platelet count., Objectives: To study the association of CD40L, CXCL5, CCL5 and EGF with platelets., Methods: We measured cytokines in the plasma of immune thrombocytopenic purpura (ITP) and AA patients using the Luminex assay and confirmed the results in a mouse model and in vitro experiments., Results: Both ITP and AA showed similarly low levels of CD40L, CXCL5, CCL5 and EGF, compared with healthy controls. In ITP, levels of these proteins were significantly greater in patients with higher platelet counts than in those with lower platelet counts. In a murine thrombocytopenia model, levels of CD40L, CXCL5, CCL5 and EGF decreased with platelet count after immune-mediated destruction, while the cytokine levels increased when the platelet count recovered. In vitro, concentrations of these cytokines in the supernatants of platelet suspensions were proportional to platelet numbers, and levels in sera prepared by simple blood coagulation were equivalent to those in platelet-rich plasma-converted sera. mRNA expression for CXCL5, CCL5 and EGF was higher in platelets than in megakaryocytes, peripheral blood mononuclear cells, granulocytes and non-megakaryocytic bone marrow cells., Conclusions: Plasma CD40L, CXCL5, CCL5 and EGF are mainly platelet-derived, suggesting a role of platelets in immune responses and inflammation. Measurement of CD40L, CXCL5, CCL5 and EGF in human blood allowed testable inferences concerning physiology and pathophysiology in quantitative platelet disorders., (© 2012 International Society on Thrombosis and Haemostasis.)

Background: Conventional anticoagulant treatment for acute deep vein thrombosis (DVT) effectively prevents thrombus extension and recurrence, but does not dissolve the clot, and many patients develop post-thrombotic syndrome (PTS). We aimed to examine whether additional treatment with catheter-directed thrombolysis (CDT) using alteplase reduced development of PTS., Methods: Participants in this open-label, randomised controlled trial were recruited from 20 hospitals in the Norwegian southeastern health region. Patients aged 18-75 years with a first-time iliofemoral DVT were included within 21 days from symptom onset. Patients were randomly assigned (1:1) by picking lowest number of sealed envelopes to conventional treatment alone or additional CDT. Randomisation was stratified for involvement of the pelvic veins with blocks of six. We assessed two co-primary outcomes: frequency of PTS as assessed by Villalta score at 24 months, and iliofemoral patency after 6 months. Analyses were by intention to treat. This trial is registered at ClinicalTrials.gov, NCT00251771., Findings: 209 patients were randomly assigned to treatment groups (108 control, 101 CDT). At completion of 24 months' follow-up, data for clinical status were available for 189 patients (90%; 99 control, 90 CDT). At 24 months, 37 (41·1%, 95% CI 31·5-51·4) patients allocated additional CDT presented with PTS compared with 55 (55·6%, 95% CI 45·7-65·0) in the control group (p=0·047). The difference in PTS corresponds to an absolute risk reduction of 14·4% (95% CI 0·2-27·9), and the number needed to treat was 7 (95% CI 4-502). Iliofemoral patency after 6 months was reported in 58 patients (65·9%, 95% CI 55·5-75·0) on CDT versus 45 (47·4%, 37·6-57·3) on control (p=0·012). 20 bleeding complications related to CDT included three major and five clinically relevant bleeds., Interpretation: Additional CDT should be considered in patients with a high proximal DVT and low risk of bleeding., Funding: South-Eastern Norway Regional Health Authority; Research Council of Norway; University of Oslo; Oslo University Hospital., (Copyright © 2012 Elsevier Ltd. All rights reserved.)

Background: Approximately one in four patients with acute proximal deep vein thrombosis (DVT) given anticoagulation and compression therapy develop post-thrombotic syndrome (PTS). Accelerated removal of thrombus by thrombolytic agents may increase patency and prevent PTS., Objectives: To assess short-term efficacy of additional catheter-directed thrombolysis (CDT) compared with standard treatment alone., Patients and Methods: Open, multicenter, randomized, controlled trial. Patients (18-75 years) with iliofemoral DVT and symptoms < 21 days were randomized to receive additional CDT or standard treatment alone. After 6 months, iliofemoral patency was investigated using duplex ultrasound and air-plethysmography assessed by an investigator blinded to previous treatment., Results: One hundred and three patients (64 men, mean age 52 years) were allocated additional CDT (n = 50) or standard treatment alone (n = 53). After CDT, grade III (complete) lysis was achieved in 24 and grade II (50%-90%) lysis in 20 patients. One patient suffered major bleeding and two had clinically relevant bleeding related to the CDT procedure. After 6 months, iliofemoral patency was found in 32 (64.0%) in the CDT group vs. 19 (35.8%) controls, corresponding to an absolute risk reduction (RR) of 28.2% (95% CI: 9.7%-46.7%; P = 0.004). Venous obstruction was found in 10 (20.0%) in the CDT group vs. 26 (49.1%) controls; absolute RR 29.1% (95% CI: 20.0%-38.0%; P = 0.004). Femoral venous insufficiency did not differ between the two groups., Conclusions: After 6 months, additional CDT increased iliofemoral patency from 36% to 64%. The ongoing long-term follow-up of this study will document whether patency is related to improved functional outcome.

Objectives: A prospective outcome study designed to evaluate a simple strategy for the management of outpatients with suspected pulmonary embolism (PE), based on clinical probability, D-dimer, and multi-slice computed tomography (MSCT)., Methods: A cohort of 432 consecutive patients admitted to the emergency department with suspected PE was managed by sequential non-invasive testing. Patients in whom PE was ruled out were not given anticoagulants, but were followed-up for 3 months., Results: Normal D-dimer and low-intermediate clinical probability ruled out PE in 103 patients [24% (95% CI 20-28)]. Seventeen patients had normal D-dimer, but high clinical probability and proceeded to MSCT. All patients proved negative for PE. A total of 329 (76%) patients underwent MSCT examination. Pulmonary embolism was diagnosed in 93 patients [21.5% (95% CI 18-26)] and was ruled out by negative MSCT in 221 patients [51% (95% CI 46-56)]. MSCT scans were determined as inconclusive in 15 (4.5%) patients. No patient developed objectively verified venous thromboembolism (VTE) during the 3-month follow-up period. However, the cause of death was adjudicated as possibly related to PE in two patients, resulting in an overall 3-month VTE risk of 0.6% (95% CI 0-2.2%). The diagnostic algorithm yielded a definite diagnosis in 96.5% of the patients., Conclusions: This simple and non-invasive strategy combining clinical probability, D-dimer, and MSCT for the management of outpatients with suspected PE appears to be safe and effective.

Conventional therapies for primary chronic cold agglutinin disease (CAD) are ineffective, but remissions after treatment with the anti-CD20 antibody rituximab have been described in a small, prospective trial and in some case reports. In this study we report on 37 courses of rituximab administered prospectively to 27 patients. Fourteen of 27 patients responded to their first course of rituximab, and 6 of 10 responded to re-treatment. In both groups combined, responses were achieved after 20 of 37 courses, giving an overall response rate of 54%. We observed 1 complete and 19 partial responses. Two nonresponders and 3 patients who experienced relapse received second-line therapy with interferon-alpha combined with a new course of rituximab, and 1 nonresponder and 2 patients who experienced relapse achieved partial responses. Responders achieved a median increase in hemoglobin levels of 40 g/L (4 g/dL). Median time to response was 1.5 months, and median observed response duration was 11 months. We conclude that rituximab is an effective and well-tolerated therapy for CAD. Histologic and flow cytometric findings suggest that some of the effect may be mediated by mechanisms other than the elimination of clonal lymphocytes. We were unable to predict responses from the hematologic, immunologic, or histologic parameters before therapy.