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Aims Evidence regarding the health burden of chronic venous insufficiency (CVI), its clinical determinants, and impact on outcome is scarce. Methods and results Systematic phenotyping of CVI according to established CEAP (Clinical-Etiologic-Anatomic-Pathophysiologic) classification was performed in 12 423 participants (age range: 40–80 years) of the Gutenberg Health Study from April 2012 to April 2017. Prevalence was calculated age- and sex-specifically. Multivariable Poisson regression models were calculated to evaluate the relation of CVI with cardiovascular comorbidities. Survival analyses were carried out to assess the CVI-associated risk of death. Replication of findings was done in an independent cohort study (MyoVasc, NCT04064450). The prevalence of telangiectasia/reticular, varicose veins, and CVI was 36.5% [95% confidence interval (CI), 35.6–37.4%], 13.3% [12.6–13.9%], and 40.8% [39.9–41.7%], respectively. Age, female sex, arterial hypertension, obesity, smoking, and clinically overt cardiovascular disease were identified as clinical determinants of CVI. Higher CEAP classes were associated with a higher predicted 10-year risk for incident cardiovascular disease in individuals free of cardiovascular disease (n = 9923). During a mean follow-up of 6.4 ± 1.6 years, CVI was a strong predictor of all-cause death independent of the concomitant clinical profile and medication [hazard ratio (HR) 1.46 (95% CI 1.19–1.79), P = 0. 0003]. The association of CVI with an increased risk of all-cause death was externally validated in the MyoVasc cohort [HR 1.51 (95% CI 1.11–2.05), P = 0.009]. Conclusion Chronic venous insufficiency is highly prevalent in the population and is associated with the presence of cardiovascular risk factors and disease. Individuals with CVI experience an elevated risk of death, which is independent of age and sex, and present cardiovascular risk factors and comorbidities.

Venous stenting has become a common treatment option for central deep venous outflow obstructions and postthrombotic syndrome. Following successful recanalization and stenting, stent patency is endangered by in‐stent thrombosis and recurrent venous thromboembolism. Antithrombotic therapy might reduce patency loss. This systematic review summarizes the literature on antithrombotic therapy following (post)thrombotic venous stenting. A systematic PubMed, MEDLINE, EMBASE, and Cochrane search was performed for studies addressing antithrombotic therapy prescribed following venous stenting of the iliofemoral tract indicated by acute or chronic thrombotic pathology. A total of 277 articles was identified of which 64 (56 original studies) were selected. Overall, a mean primary patency rate of 82.3% was seen 1 year after the intervention, which decreased to 73.3% after 2 years. In the majority (43 of 56 studies, 77%), treatment was based on use of vitamin K antagonists, either with (18%) or without (59%) use of antiplatelet drugs. Only two studies (4%) directly assessed the effect of antithrombotic therapy on treatment outcomes. The impact of postinterventional antithrombotic therapy on stent patency remains unknown because of limited and insufficient data available in current literature. Further clinical research should more clearly address the role of antithrombotic therapy for preservation of long‐term patency following venous stenting.

European Society for Vascular Surgery (ESVS) 2021 Clinical Practice Guidelines on the Management of Venous Thrombosis

Contains fulltext : 232751.pdf (Publisher’s version ) (Closed access) Clinical research in venous thromboembolism (VTE) is hindered by variability in the collection and reporting of data and outcomes. A consistent data language facilitates efficiencies, leads to higher quality data, and permits between-study comparisons and evidence synthesis. The International Society on Thrombosis and Haemostasis (ISTH) launched an international task force of more than 50 researchers to develop common data elements for clinical research in venous thromboembolism. The project was organized in seven working groups, each focusing on a topic area: General Core Data Elements; Anticoagulation and Other Therapies; Chronic VTE and Functional Outcomes; Diagnosis of VTE; Malignancy; Perioperative; and Predictors of VTE. The groups met via teleconference to collaboratively identify key data elements and develop definitions and data standards that were structured in a project-specific taxonomy. A Steering Committee met by teleconference and in-person to determine the overall scope of the project and resolve questions arising from the working groups. ISTH held an open public comment period to enable broader stakeholder involvement and feedback. The common data elements were then refined by the working groups to create a set of 512 unique data elements that are publicly available at http://isth.breakthrough.healthcare. The ISTH VTE Common Data Elements are intended to be a living project with ongoing curation, future expansion, and adaptation to meet the needs of the thrombosis and hemostasis research community.

Background Dual pathway inhibition with 2.5 mg rivaroxaban twice daily plus 100 mg aspirin once daily may be a promising alternative to 100 mg aspirin antiplatelet therapy for the prevention of cardiovascular events in patients with coronary artery disease and/or peripheral arterial disease. However, treatment costs and bleeding risks are higher, and there is another treatment option for peripheral arterial disease, 75 mg clopidogrel. A comprehensive assessment of benefits, risks and costs of dual pathway inhibition versus standard of care is needed. Methods We used a state transition model including cardiovascular, ischaemic limb and bleeding events to compare dual pathway inhibition to aspirin antiplatelet therapy in coronary artery disease, and additionally to clopidogrel antiplatelet therapy in peripheral arterial disease patients. We calculated the incremental cost-effectiveness ratio from costs and quality-adjusted life-years of lifelong treatment, and the cost-effectiveness probability at a €50,000/quality-adjusted life-year threshold. Results Quality-adjusted life-years and costs of dual pathway inhibition were highest, the incremental cost-effectiveness ratios versus aspirin were €32,109 in coronary artery disease and €26,381 in peripheral arterial disease patients, with 92% and 56% cost-effectiveness probability, respectively (clopidogrel was extendedly dominated). Incremental cost-effectiveness ratios were below €20,000 in comorbid peripheral arterial disease patients and coronary artery disease patients younger than 65 years, incremental cost-effectiveness ratios were above €50,000 in carotid artery disease patients and coronary artery disease patients older than 75 years. Conclusion Lifelong preventive treatment of coronary artery disease and peripheral arterial disease patients at risk of cardiovascular events with dual pathway inhibition improves health outcomes and seems overall cost-effective relative to aspirin antiplatelet therapy and also to clopidogrel antiplatelet therapy for peripheral arterial disease, particularly in comorbid patients, but not in older patients and in carotid artery disease patients. These findings may warrant a targeted approach.

Background: A previous individual participant data (IPD) meta-analysis showed that the Wells rule and D-dimer testing cannot exclude suspected deep vein thrombosis (DVT) in cancer patients. Objectives: To explore reasons for this reduced diagnostic accuracy and to optimize the diagnostic pathway for cancer patients suspected of DVT. Patients and Methods: Using IPD from 13 studies in patients with suspected DVT, DVT prevalence and the predictive value of the Wells rule items and D-dimer testing were compared between patients with and without cancer. Next, we developed a prediction model with five variables selected from all available diagnostic predictors. Results: Among the 10 002 suspected DVT patients, there were 834 patients with cancer. The median prevalence of DVT in these patients with cancer was 37.5% (interquartile range [IQR], 30.8-45.5), whereas it was 15.1% (IQR, 11.5-16.7) in patients without cancer. Diagnostic performance of individual Wells rule items and D-dimer testing was similar across patients with and without cancer, except “immobility” and “history of DVT.” The newly developed rule showed a pooled c-statistic 0.80 (95% confidence interval [CI], 0.75-0.83) and good calibration. However, using this model, still only 4.3% (95% CI, 3.0-5.7) of the suspected patients with cancer could be identified with a predicted DVT posttest probability of

BACKGROUND/OBJECTIVES: Nursing home (NH) residents are a vulnerable population, susceptible to respiratory disease outbreaks such as coronavirus disease 2019 (COVID-19). Poor outcome in COVID-19 is at least partly attributed to hypercoagulability, resulting in a high incidence of thromboembolic complications. It is unknown whether commonly used antithrombotic therapies may protect the vulnerable NH population with COVID-19 against mortality. This study aimed to investigate whether the use of oral antithrombotic therapy (OAT) was associated with a lower mortality in NH residents with COVID-19. DESIGN: A retrospective case series. SETTING: Fourteen NH facilities from the NH organization Envida, Maastricht, the Netherlands PARTICIPANTS: A total of 101 NH residents with COVID-19 were enrolled. MEASUREMENTS: The primary outcome was all-cause mortality. The association between age, sex, comorbidity, OAT, and mortality was assessed using logistic regression analysis. RESULTS: Overall mortality was 47.5% in NH residents from 14 NH facilities. Age, comorbidity, and medication use were comparable among NH residents who survived and who died. OAT was associated with a lower mortality in NH residents with COVID-19 in the univariable analysis (odds ratio (OR) = 0.89; 95% confidence interval (CI) = 0.41-1.95). However, additional adjustments for sex, age, and comorbidity attenuated this difference. Mortality in males was higher compared with female residents (OR = 3.96; 95% CI = 1.62-9.65). Male residents who died were younger compared with female residents (82.2 (standard deviation (SD) = 6.3) vs 89.1 (SD = 6.8) years; P < .001). CONCLUSION: NH residents in the 14 facilities we studied were severely affected by the COVID-19 pandemic, with a mortality of 47.5%. Male NH residents with COVID-19 had worse outcomes than females. We did not find evidence for any protection against mortality by OAT, necessitating further research into strategies to mitigate poor outcome of COVID-19 in vulnerable NH populations. J Am Geriatr Soc 68:1647-1652, 2020.

Background The CAVA trial did not show the anticipated risk reduction for postthrombotic syndrome (PTS) after thrombus removal via additional ultrasound-accelerated catheter-directed thrombolysis (UACDT) in patients with acute iliofemoral deep vein thrombosis (IFDVT). Difficulties in achieving an effective degree of recanalization through thrombolysis may have influenced outcomes. We therefore assessed whether successful UACDT (restored patency ≥ 90%) did reduce the development of PTS. Methods This CAVA trial post hoc analysis compared the proportion of PTS at 1-year follow-up between patients with successful UACDT and patients that received standard treatment only. In addition, clinical impact as well as determinants of successful thrombolysis were explored. Results UACDT was initiated in 77 (50.7%) patients and considered successful in 41 (53.2%, interrater agreement κ = 0.7, 95% confidence interval 0.47–0.83). PTS developed in 15/41 (36.6%) patients in the successful UACDT group versus 33/75 (44.0%) controls (p = 0.44). In this comparison, successful UACDT was associated with lower Venous Clinical Severity Score (3.50 ± 2.57 vs. 4.82 ± 2.74, p = 0.02) and higher EuroQOL-5D (EQ-5D) scores (40.2 ± 36.4 vs. 23.4 ± 34.4, p = 0.01). Compared with unsuccessful UACDT, successful UACDT was associated with a shorter symptom duration at inclusion (p = 0.05), and higher rates of performed adjunctive procedures (p Conclusion Successful UACDT was not associated with a reduced proportion of PTS 1 year after acute IFDVT compared with patients receiving standard treatment alone. There was, however, a significant reduction in symptom severity and improvement of generic quality of life according to the EQ-5D. Better patient selection and optimization of treatment protocols are needed to assess the full potential of UACDT for the prevention of PTS. Trial Registration Number ClinicalTrials.gov number, NCT00970619.

Direct oral anticoagulants (DOACs) are recommended by several scientific societies as first-line therapy for the prevention of stroke and systemic embolism in patients with atrial fibrillation. However, there is uncertainty regarding the organisation of anticoagulation care, with various caregivers being involved. Patients and caregivers are often confronted by uncertainty about the coordination of treatment. With the functional resonance analysis method we visualised the process of anticoagulation care in daily practice in the Maastricht region. This resulted in recommendations on how to improve the organisation of anticoagulation care for DOAC patients.

Background: In patients with a venous outflow obstruction following iliofemoral deep vein thrombosis stenting of the venous tract to prevent or alleviate postthrombotic syndrome is applied with increasing frequency. The impact of the quality of anticoagulant therapy with vitamin K antagonists (VKAs) on the development of in-stent thrombosis is currently unknown.Objectives: To determine the association between the quality of postinterventional VKA treatment and the occurrence of in-stent thrombosis.Methods: Seventy-nine patients with iliofemoral and/or caval venous stent placement for obstruction of the venous outflow were included in this study. All patients received postinterventional VKA. The quality of VKA anticoagulant therapy was expressed as the time within therapeutic range (TTR) calculated using the linear interpolation method and as the proportion of International Normalized Ratio (INR) values Results: In-stent thrombosis developed in 16 patients (20.3%). The total population had a mean TTR of 64.0% (19.0) and a mean proportion of INR values Conclusions: We conclude that the quality of anticoagulant treatment reflected in the TTR following a venous stenting procedure is an important independent determinant for the risk of in-stent thrombosis. The role of anticoagulant treatment for the prevention of in-stent thrombosis following stenting procedures therefore merits further research.

ObjectivesElastic compression stocking (ECS) therapy is an important treatment for patients with deep venous thrombosis (DVT) and chronic venous insufficiency (CVI). This study aimed to provide insight into the structure and variability of the ECS therapy process, its effects on outcomes, and to elicit improvement themes from a multiple stakeholder perspective.DesignThirty semi-structured interviews with professionals and patients were performed. The essential functions for the process of ECS therapy were extracted to create two work-as-done models using the Functional Resonance Analysis Method (FRAM). These findings were used to guide discussion between stakeholders to identify improvement themes.SettingTwo regions in the Netherlands, region Limburg and region North-Holland, including an academic hospital and a general hospital and their catchment region.ParticipantsThe interviewees were purposely recruited and included 25 healthcare professionals (ie, general practitioners, internists, dermatologists, nurses, doctor’s assistants, occupational therapists, home care nurses and medical stocking suppliers) and 5 patients with DVT or CVI.ResultsTwo FRAM models were created (one for each region). The variability of the functions and their effect on outcomes, as well as interdependencies between functions, were identified. These were presented in stakeholder meetings to identify the structure of the process and designated variable and uniform parts of the process and its outcomes. Ultimately, six improvement themes were identified: dissemination of knowledge of the entire process; optimising and standardising initial compression therapy; optimising timing to contact the medical stocking supplier (when oedema has disappeared); improving the implementation of assistive devices; harmonising follow-up duration for patients with CVI; personalising follow-up and treatment duration in patients with DVT.ConclusionsThis study provided a detailed understanding of how ECS therapy is delivered in daily practice by describing major functions and variability in performances and elicited six improvement themes from a multistakeholder perspective.

Objectives: Decision makers adopt health technologies based on health economic models that are subject to uncertainty. In an ideal world, these models parameterize all uncertainties and reflect them in the cost-effectiveness probability and risk associated with the adoption. In practice, uncertainty assessment is often incomplete, potentially leading to suboptimal reimbursement recommendations and risk management. This study examines the feasibility of comprehensive uncertainty assessment in health economic models.Methods: A state transition model on peripheral arterial disease treatment was used as a case study. Uncertainties were identified and added to the probabilistic sensitivity analysis if possible. Parameter distributions were obtained by expert elicitation, and structural uncertainties were either parameterized or explored in scenario analyses, which were model averaged.Results: A truly comprehensive uncertainty assessment, parameterizing all uncertainty, could not be achieved. Expert elicitation informed 8 effectiveness, utility, and cost parameters. Uncertainties were parameterized or explored in scenario analyses and with model averaging. Barriers included time and resource constraints, also of clinical experts, and lacking guidance regarding some aspects of expert elicitation, evidence aggregation, and handling of structural uncertainty. The team's multidisciplinary expertise and existing literature and tools were facilitators.Conclusions: While comprehensive uncertainty assessment may not be attainable, improvements in uncertainty assessment in general are no doubt desirable. This requires the development of detailed guidance and hands-on tutorials for methods of uncertainty assessment, in particular aspects of expert elicitation, evidence aggregation, and handling of structural uncertainty. The issue of benefits of uncertainty assessment versus time and resources needed remains unclear.

Background: Previous prediction models for recurrent thromboembolism (VTE) are often complicated to apply and have not been implemented widely.Aim: To develop and internally validate a potential new prediction model for recurrent VTE that can be used without stopping anticoagulant treatment for D-dimer measurements in patients with provoked and unprovoked DVT.Methods: Cohort data of 479 patients treated in a clinical care pathway at Maastricht University Medical Center were used. Predictors for the Cox proportional hazards model (unprovoked DVT, male gender, factor VIII levels) were derived from literature and using forward selection procedure. The scoring rule was internally validated using bootstrapping techniques and the predictive ability was compared to existing prediction models.Results: Patients were followed for a median of 3.12 years after stopping anticoagulation treatment (IQR 0.78, 3.90). Sixty-four of 479 patients developed recurrent VTE (13%). The scoring rule consisted of unprovoked DVT (yes: 2 points), male sex (yes: 1 point), and factor VIII > 213 % (yes: 2 points) and was categorized into three groups [i.e., low risk (score 0), medium risk (scores 1, 2, or 3) and high risk (scores 4 and 5)]. The concordance statistic was 0.68 (95% CI: 0.61, 0.75).Conclusion: The discriminative ability of the new Continu-8 score was adequate. Future studies shall verify this score in an independent setting without stopping anticoagulation treatment.

Background: Thrombocytopenia in cancer patients with an indication for anticoagulation poses a unique clinical challenge. There are guidelines for the setting of venous thromboembolism but not atrial fibrillation (AF). Evidence is lacking and current practice is unclear.Objective: To identify patient and physician characteristics associated with anticoagulation management in hematological malignancy and thrombocytopenia.Methods: A clinical vignette-based experiment was designed. Eleven hematologists were interviewed, identifying 5 relevant variable categories with 2-5 options each. Thirty hypothetical vignettes were generated. Each physician received 5 vignettes and selected a management strategy (hold anticoagulation; no change; transfuse platelets; modify type/dose). The survey was distributed to hematologists and thrombosis specialists in 3 countries. Poisson regression models with cluster robust variance estimates were used to calculate relative risks for using one management option over the other, for each variable in comparison to a reference variable.Results: 168 physicians answered 774 cases and reported continuing anticoagulation for venous thromboembolism or AF in 607 (78%) cases, usually with dose reduction or platelet transfusion support. Overall, management was affected by platelet count, anticoagulation indication, time since indication, type of hematological disease and treatment, and prior major bleeding, as well as physician demographics and practice setting. The CHA(2)DS(2)-VASc score and time since AF diagnosis affected anticoagulation management in AF.Conclusion: This study indicates what the widely accepted management strategies are. These strategies, and possibly others, should be assessed prospectively to ascertain effectiveness. The decision process is intricate and compatible with current venous thromboembolism guidelines.

Background The CAVA (Ultrasound‐Accelerated Catheter‐Directed Thrombolysis Versus Anticoagulation for the Prevention of Post‐Thrombotic Syndrome) trial did not show a reduction of post‐thrombotic syndrome (PTS) after additional ultrasound‐accelerated catheter‐directed thrombolysis in patients with acute iliofemoral deep vein thrombosis at 1‐year follow‐up. This prespecified analysis of the CAVA trial aimed to determine the impact of additional thrombolysis on outcomes of PTS at long‐term follow‐up. Methods and Results Patients aged 18 to 85 years with a first‐time acute iliofemoral deep vein thrombosis were included and randomly assigned (1:1) to either standard treatment plus ultrasound‐accelerated catheter‐directed thrombolysis or standard treatment alone. The primary outcome was the proportion of PTS (Villalta score ≥5 on 2 occasions ≥3 months apart or venous ulceration) at the final follow‐up visit. Additionally, PTS according to the International Society on Thrombosis and Haemostasis (ISTH) consensus definition was assessed to allow external comparability. Major bleedings were the main safety outcome. At a median follow‐up of 39.0 months (interquartile range, 23.3–63.8), 120 patients (79.8%) participated in the final follow‐up visit: 62 from the intervention group and 58 from the standard treatment group. PTS developed in 19 (30.6%) versus 26 (44.8%) patients, respectively (odds ratio [OR], 0.54; 95% CI, 0.26 to 1.15 [ P =0.11]), with an absolute difference between groups of −14.2% (95% CI, −32.0% to 4.8%). Using the ISTH consensus definition, a significant reduction in PTS was observed (29 [46.8%] versus 40 [69.0%]) (OR, 0.40; 95% CI, 0.19–0.84 [ P =0.01]) with an absolute difference between groups of −22.2% (95% CI, −39.8% to −2.8%). No new major bleedings occurred following the 12‐month follow‐up. Conclusions The impact of additional ultrasound‐accelerated catheter‐directed thrombolysis on the prevention of PTS was found to increase with time. Although this study was limited by its sample size, the overall findings indicate a reduction of mild PTS without impact on quality of life. Registration URL: https://www.clinicaltrials.gov ; Unique identifier: NCT00970619.

Background The role of venous obstructions as a risk factor for recurrent venous thromboembolism has never been evaluated. This study aimed to determine whether there is a difference in prevalence of venous obstructions between patients with and without recurrent venous thromboembolism. Furthermore, its influence on the development of post-thrombotic syndrome and patient-reported quality of life was assessed. Methods This matched nested case-control study included 32 patients with recurrent venous thromboembolism (26 recurrent deep-vein thrombosis and 6 pulmonary embolism) from an existing prospective cohort of deep-vein thrombosis patients and compared them to 24 age and sex matched deep-vein thrombosis patients without recurrent venous thromboembolism. All participants received standard post-thrombotic management and underwent an additional extensive duplex ultrasonography. Post-thrombotic syndrome was assessed by the Villalta-scale and quality of life was measured using the SF36v2 and VEINES-QOL/Sym-questionnaires. Results Venous obstruction was found in 6 patients (18.8%) with recurrent venous thromboembolism compared to 5 patients (20.8%) without recurrent venous thromboembolism (Odds ratio 0.88, 95%CI 0.23–3.30, p = 1.000). After a median follow-up of 60.0 months (IQR 41.3–103.5) the mean Villalta-score was 5.55 ± 3.02 versus 5.26 ± 2.63 (p = 0.909) and post-thrombotic syndrome developed in 20 (62.5%) versus 14 (58.3%) patients, respectively (Odds ratio 1.19, 95%CI 0.40–3.51, p = 0.752). If venous obstruction was present, it was mainly located in the common iliac vein (n = 7, 63.6%). In patients with an objectified venous obstruction the mean Villalta-score was 5.11 ± 2.80 versus 5.49 ± 2.87 in patients without venous obstruction (p = 0.639). Post-thrombotic syndrome developed in 6 (54.5%) versus 28 (62.2%) patients, respectively (Odds ratio 1.37, 95%CI 0.36–5.20, p = 0.736). No significant differences were seen regarding patient-reported quality of life between either groups. Conclusions In this exploratory case-control study patients with recurrent venous thromboembolism did not have a higher prevalence of venous obstruction compared to patients without recurrent venous thromboembolism. The presence of recurrent venous thromboembolism or venous obstruction had no impact on the development of post-thrombotic syndrome or the patient-reported quality of life.

Supplemental Digital Content is available in the text., Objective: Patients with lower extremity peripheral artery disease (PAD) are at increased risk of major adverse cardiovascular events. Numerous plasma biomarkers have been investigated in lower extremity PAD, but none are used for clinical risk assessment. We aimed to provide a comprehensive overview of biomarker testing in PAD as a first step to improve risk stratification. Approach and Results: A systematic literature review in MEDLINE/PubMed, Cochrane, and Embase was performed, identifying all studies investigating plasma biomarkers in association with cardiovascular events and mortality in lower extremity PAD. Forty-seven studies comprising 21 473 PAD patients met our criteria and were included. Effect estimates were provided by the studies based on a minimum follow-up of 1 year. Meta-analyses were performed by pooling studies per biomarker for each end point. Patients with increased high-sensitivity CRP (C-reactive protein) levels had a relative risk of 1.86 (1.48–2.33) for major adverse cardiovascular events and a relative risk of 3.49 (2.35–5.19) for mortality. Increased fibrinogen and d-dimer levels were associated with an increased relative risk of mortality of 2.08 (1.46–2.97) and 2.22 (1.24–3.98), respectively. Additionally, patients with increased NT-proBNP (N-terminal pro-B-type natriuretic peptide) and high-sensitivity cTnT (cardiac troponin T) levels were at an even higher risk of mortality with relative risks of 4.50 (2.98–6.81) and 3.33 (2.70–4.10), respectively. Conclusions: This systematic review identifies promising biomarkers representing different pathophysiological processes implicated in lower extremity PAD, including high-sensitivity CRP, neutrophil-lymphocyte ratio, fibrinogen, d-dimer, NT-proBNP, and high-sensitivity cTnT. Clinical implementation should be preceded by a management study to test the utility of a combination of these markers for individual risk stratification. Ultimately, this may contribute to tailored treatment and increased effectiveness of current treatment strategies in PAD.

Thus far, the association between residual vein occlusion and immediate compression therapy and postthrombotic syndrome is undetermined. Therefore, we investigated whether compression therapy immediately after diagnosis of deep vein thrombosis affects the occurrence of residual vein obstruction (RVO), and whether the presence of RVO is associated with postthrombotic syndrome and recurrent venous thromboembolism. In a prespecified substudy within the IDEAL (individualized duration of elastic compression therapy against long-term duration of therapy for prevention of postthrombotic syndrome) deep vein thrombosis (DVT) study, 592 adult patients from 10 academic and nonacademic centers across The Netherlands, with objectively confirmed proximal DVT of the leg, received no compression or acute compression within 24 hours of diagnosis of DVT with either multilayer bandaging or compression hosiery (pressure, 35 mm Hg). Presence of RVO and recurrent venous thromboembolism was confirmed with compression ultrasonography and incidence of postthrombotic syndromeas a Villalta score of at least 5 at 6 and 24 months. The average time from diagnosis until assessment of RVO was 5.3 (standard deviation, 1.9) months. A significantly lower percentage of patients who did receive compression therapy immediately after DVT had RVO (46.3% vs 66.7%; odds ratio, 0.46; 95% confidence interval, 0.27-0.80; P = .005). Postthrombotic syndrome was less prevalent in patients without RVO (46.0% vs 54.0%; odds ratio, 0.65; 95% confidence interval, 0.46-0.92; P = .013). Recurrent venous thrombosis showed no significant association with RVO. Immediate compression should therefore be offered to all patients with acute DVT of the leg, irrespective of severity of complaints. This study was registered at ClinicalTrials.gov (NCT01429714) and the Dutch Trial registry in November 2010 (NTR2597).

Objective: To explore the need for an extended diagnostic workup in patients with venous leg ulcers (VLUs) and to establish the prevalence of the underlying causes of VLU. Method: This retrospective cohort study analysed data from patients with VLU. The visual analogue scale (VAS) was used for pain assessment. The ankle-brachial index (ABI) was measured to exclude patients with arterial pathology. A duplex was performed. All patients received a wound treatment plan and ambulatory compression therapy. Continuous variables were presented as mean±standard deviation (SD) or median and interquartile range (IQR). Mann-Whitney U test and Kruskal-Wallis were used. When normally distributed, an independent sample t-test was used. Results: A total of 70 patients were recruited. Of these, 18 (25.7%) experienced a VLU once and 52 (74.3%) had a recurrent VLU. Treatment of the underlying lesions was performed in almost 30% of patients. Patients who were treated showed almost two times slower healing rates compared with those who were not treated for an underlying pathology. The mean time in patient referral exceeded two years, and patients who did not see their GP were treated by nurses who did not provide regular feedback the GP; as a result, compression therapy was not always adequate. Conclusion: Patients with a VLU showing no signs of healing after 2 months should be referred to a dedicated wound care centre to avoid delays.

Background Bleeding is a feared adverse event during anticoagulant treatment. In patients on vitamin K antagonists, most bleedings occur with the international normalized ratio (INR) in the therapeutic range. Currently, identification of high-risk patients via laboratory methods is not reliable. In this systematic review, we assessed the ability of calibrated automated thrombin generation (CAT-TG) to predict bleeding in patients on anticoagulant treatment. Methods A systematic search was executed in three databases: Medline, Embase, and Cochrane. Results Seven studies were included; two were of good methodological quality. One study showed that patients on warfarin with INRs in range (2–3) admitted for hemorrhage (n = 28), had lower CAT-TG levels (endogenous thrombin potential [ETP]: 333 ± 89 nM/min) than patients on warfarin admitted for other reasons (ETP: 436 ± 207 nM/min; p Conclusion Studies investigating the direct association between decreased CAT-TG values and hemorrhagic events are rare. Therefore, the clinical consequences of low CAT-TG values remain to be further investigated.

Background Post-thrombotic syndrome (PTS) is a common chronic consequence of deep vein thrombosis that affects the quality of life and is associated with substantial costs. In clinical practice, it is not possible to predict the individual patient risk. We develop and validate a practical two-step prediction tool for PTS in the acute and sub-acute phase of deep vein thrombosis. Methods Multivariable regression modelling with data from two prospective cohorts in which 479 (derivation) and 1,107 (validation) consecutive patients with objectively confirmed deep vein thrombosis of the leg, from thrombosis outpatient clinic of Maastricht University Medical Centre, the Netherlands (derivation) and Padua University hospital in Italy (validation), were included. PTS was defined as a Villalta score of ≥ 5 at least 6 months after acute thrombosis. Results Variables in the baseline model in the acute phase were: age, body mass index, sex, varicose veins, history of venous thrombosis, smoking status, provoked thrombosis and thrombus location. For the secondary model, the additional variable was residual vein obstruction. Optimism-corrected area under the receiver operating characteristic curves (AUCs) were 0.71 for the baseline model and 0.60 for the secondary model. Calibration plots showed well-calibrated predictions. External validation of the derived clinical risk scores was successful: AUC, 0.66 (95% confidence interval [CI], 0.63–0.70) and 0.64 (95% CI, 0.60–0.69). Conclusion Individual risk for PTS in the acute phase of deep vein thrombosis can be predicted based on readily accessible baseline clinical and demographic characteristics. The individual risk in the sub-acute phase can be predicted with limited additional clinical characteristics.

Essentials Post thrombotic syndrome (PTS) is a complication of deep vein thrombosis (DVT) with limited treatment options.Uniformity of the diagnostic strategy and the use of risk prediction models might improve treatment outcomes.Extending knowledge on the pathophysiology and improving therapeutic options is paramount for progress. PTS management should evolve to a multimodal approach with treatment tailored to individual patients' needs. Post thrombotic syndrome (PTS) is a common chronic complication of deep vein thrombosis of the leg (DVT). Treatment options are limited therefore emphasis is placed on its prevention. Several risk factors have been recognized, but were so far not used for risk stratification or translation into prediction models. Early interventions did not yet result in more successful preventive treatment strategies; for the acute phase of DVT there is equipoise on the value of elastic compression, as well as on catheter directed thrombolysis. There are no drugs specifically targeted at PTS prevention. The use of anticoagulant medication such as direct oral anticoagulants (DOACs) might decrease PTS incidence, but this needs to be corroborated. Both research into more effective treatment options as well as future PTS management may benefit from a uniform diagnostic strategy and the use of prediction rules to better allocate treatment and thereby increase treatment efficacy.

Background: Finding the optimal duration of anticoagulant treatment following an acute event of deep vein thrombosis (DVT) is challenging. Residual venous obstruction (RVO) has been identified as a risk factor for recurrence, but data on management strategies incorporating the presence of RVO and associated recurrence rates in defined clinical care pathways (CCP) are lacking.Objectives: We aimed to investigate the long-term clinical outcomes and predictors of venous thromboembolism (VTE) recurrence in a contemporary cohort of patients with proximal DVT and managed in a CCP incorporating the presence of RVO.Patients: All patients treated at the Maastricht University Medical Center within an established clinical care pathway from June 2003 through June 2013 were prospectively followed for up to 11 years in a prospective management study.Results: Of 479 patients diagnosed with proximal DVT, 474 completed the two-year CCP (99%), and 457 (94.7%) the extended follow-up (2231.2 patient-years; median follow-up 4.6 years). Overall VTE recurrence was 2.9 per 100 patient-years, 1.3 if provoked by surgery, 2.1 if a non-surgical transient risk factor was present and 4.0 if unprovoked. Predictors of recurrent events were unprovoked VTE (adjusted hazard ratio [HR] 4.6; 95% CI 1.7, 11.9), elevated D-dimer one month after treatment was stopped (HR 3.3; 1.8, 6.1), male sex (HR 2.8; 1.5, 5.1), high factor VIII (HR 2.2; 1.2, 4.0) and use of contraceptives (HR 0.1; 0.0, 0.9).Conclusions: Patients with DVT managed within an established clinical care pathway incorporating the presence of RVO had relatively low incidences of VTE recurrence.

Background Traditional coagulation tests are included in emergency guidelines for management of patients on direct oral anticoagulants (DOACs) who experience acute bleeding or require surgery. We determined the ability of traditional coagulation tests and fast whole blood thromboelastography (ROTEM®) to screen for anticoagulation activity of dabigatran and rivaroxaban as low as 30 ng/mL. Methods One hundred eighty-four citrated blood samples (75 dabigatran, 109 rivaroxaban) were collected from patients with non-valvular atrial fibrillation (NVAF), to perform screening tests from different manufacturers, (diluted, D) PT, aPTT, TT and ROTEM®. The activity of DOACs was quantitatively determined by clot detection assays: Hemoclot DTT and DiXaI test (Biophen), on CS2100 (Siemens). The clotting time (CT) of INTEM and EXTEM ROTEM® (Werfen) were used as test parameters. Results Dabigatran, ≥ 30 ng/mL, was accurately detected by five coagulation tests: APTT Actin FSL (93%), PT Neoplastin (93%), APTT Cephascreen, Thromboclotin, and Thrombin (all 100%), but not by PT Innovin (49%). CT-EXTEM (91%) was sufficiently sensitive, but not CT-INTEM (52%). APTT Cephascreen and Thrombin showed good linearity (R2 = 0.71,R2 = 0.72). For the other tests linearity was moderate to poor. Rivaroxaban was accurately detected by PT Neoplastin (98%) and less so by APTT Cephascreen (85%). In addition, rivaroxaban was also accurately detected by CT-INTEM (96%). PT Neoplastin showed good linearity (R2 = 0.81), all other tests had moderate to poor linearity. Conclusion In patients with NVAF, the ability of routine coagulation tests to detect the presence of significant levels of DOACs is test and reagent dependent. CT-INTEM and CT-EXTEM may be fast whole blood alternatives. Trial registration The Institutional Review Board of the MUMC approved this study (December 2011, project number 114069).

Venous thromboembolism (VTE) is associated with increased coagulation activity, which in part can be attributed to the contact pathway of coagulation. Evidence from pre-clinical and epidemiological studies suggests that deficiency in factors of contact activation (e.g. coagulation factors (F) XI and FXII) protects against VTE. However, limited information exists regarding the activation of the contact system in the setting of acute VTE. In the current study, patients with confirmed VTE events (n=321) from the VTEval study and controls (n=300) from the population-based PREVENT-it pilot study were included. Plasma samples were collected from patients after confirmed VTE events or controls upon inclusion in the study. FXI as well as FXIa and plasma kallikrein (PKa) levels were assessed in plasma samples from all subjects using an activated thromboplastin time-based assay (FXI:c), a thrombin generation-based assay (CAT:FXIa) and by measuring inhibitory complexes (FXIa:antithrombin (AT), FXIa:alpha-1-antitrypsin (α1AT), FXIa:C1 esterase inhibitor (C1Inh) and PKa:C1Inh) using enzyme-linked immunoassay (ELISA). After a 2-year follow up period, a composite endpoint of recurrent VTE or death was determined. Increased FXI:c levels were determined in VTE patients compared to control individuals (124.08 ± 37.48% vs. 113.55 ± 27.99%), whereas CAT:FXIa levels were reduced in VTE patients (0 pM [IQR, 0-0.56] vs 0.56 pM [IQR, 0-0.88]). Levels of FXIa:α1AT and FXIa:AT inhibitory complexes were increased in VTE patients compared to controls (median[IQR]; 311.8 pM [238.2-424.0] vs. 202.5 pM [143.7 - 287.5] and 29.1 pM [23.4-38.3] vs 23.2 pM [19.7-29.8], respectively). Considering that 86% of the VTE patients were already on anticoagulant treatment (Table 1), investigation of their possible effect on the biomarkers revealed that only the CAT:FXIa was influenced by the presence of anticoagulants. Logistic regression models revealed a good discriminatory value for FXI:c and FXIa:α1AT (AUC=0.64 [0.6/0.69] and AUC=0.67 [0.62/0.71], respectively) to distinguish VTE from controls, whereas the other biomarkers were not able to distinguish between groups. The outcome recurrent VTE or death could be predicted by the inhibitory complexes, but not by the FXI(a) levels (Figure 1). Only the FXIa:α1AT complexes were able to both detect the presence of VTE (OR per SD [95%CI]: 1.28 [1.01-1.63], p=0.04) and predict recurrent VTE or death (HR per SD [95%CI]: 1.40 [1.2-1.62], p In summary, acute VTE is associated with both elevated FXI:c levels and increased activation of FXI and plasma prekallikrein, the latter specifically indicating contact activation. The generation of FXIa during acute VTE and its association with recurrent VTE suggests an important risk contribution of FXI activation. This study has added evidence favouring the utility of FXIa inhibition in the setting of acute VTE. Figure 1 Figure 1. Disclosures Knoeck: Bayer AG: Consultancy. ten Cate: Bayer AG: Other; Pfizer: Other; LEO Pharma: Other; Gideon Pharmaceuticals: Other; Alveron Pharma: Other. Wild: Bayer AG: Other, Research Funding; Boehringer Ingelheim: Other, Research Funding; Novartis Pharma: Other, Research Funding; Sanofi-Aventis: Other, Research Funding; Astra Zeneca: Other, Research Funding; Daiichi Sankyo Europe: Other, Research Funding.

Background Although combined oral contraceptives (COC) are considered a transient risk factor for venous thromboembolism (VTE), the risk of recurrence after discontinuation of anticoagulation is unclear. Few studies have focused on the risk of recurrence in this group; studies report variable results and are limited by small sample size. The risk of recurrence appears to be low, but this could relate to the young age of affected women. Deciphering the absolute VTE recurrence risk after a COC-associated VTE is crucial in helping clinicians and patients decide if anticoagulation could be discontinued after the initial treatment period. Objectives The objectives of this systematic review and meta-analysis are to estimate the incidence of recurrent VTE among women with COC-associated VTE, compared with women with unprovoked VTE. Methods We searched the following databases: Cochrane Central Register of Controlled Trial, Cochrane Database of Systematic Reviews, Embase Classic +Embase, and Medline ALL, all from the OvidSP platform, from the database's inception to July 2020. Additional studies were identified by screening citations from included studies. Prospective cohort studies, randomized controlled trials (RCTs), and meta-analyses of prospective cohort studies or RCTs were reviewed by two authors for study inclusion (Figure 1). Studies were included if women had objectively confirmed COC-associated VTE, received a minimum of three months of anticoagulation, discontinued COC prior to or at time of discontinuation of anticoagulation, time of follow-up began after anticoagulation was stopped, and recurrent VTE data was available. Studies were excluded if patients were systematically treated with an alternative pharmacologic agent intended to reduce the risk of recurrent VTE such as aspirin. Authors of identified papers were contacted for additional data on critical variables. If there were multiple publications from a cohort, the study with the longest follow up was included. Two authors extracted study data and assessed included studies for risk of bias using the Newcastle Ottawa Scale. Meta-analysis was done using a random effects Poisson regression model. Heterogeneity was assessed using the I-squared measure. Results Our systematic review included 19 studies with a total of 1,537 women (5,828 patient years of follow up) with an index COC-associated VTE, and 1,974 women (7,798 patient years of follow up) with an index unprovoked VTE. Authors contributed additional unpublished data in 16 of the 19 studies. Overall, studies were at low risk of bias, with a mean of 7 stars (out of a possible 9) in the Newcastle Ottawa Scale. Among the 19 studies, the incidence rate of VTE recurrence in women with COC-associated VTE was 1.22 per patient year (95% confidence interval (CI) 0.94 to 1.59, I 2 = 6.4%, 95% prediction interval (PI) 0.81 to 1.85) (Figure 2). The incidence rate of VTE recurrence in women with an index unprovoked VTE not associated with COC was 3.89 per patient year (95% CI 2.98 to 5.07, I 2 =74.2%, 95% PI 1.37 to 11.03). The unadjusted incidence rate ratio of recurrent VTE comparing women with COC-associated events to women with unprovoked events was 0.34 (95% CI 0.26 to 0.45, I 2 = 2.6%, 95% PI 0.26 to 0.46). Only three studies had age-adjusted comparisons, but each with a different effect measure so they could not be combined, with a relative risk ratio 0.4 (95% CI 0.2 to 0.8) (also adjusted for site of VTE and congenital thrombophilia) (Eischer 2014), a hazard ratio of 0.11 (95% CI 0.01 to 0.85) (Kearon 2019), and an incidence rate ratio of 1 (95% CI 0.3 to 3.2) (Le Moigne 2013). Conclusions The estimated risk of VTE recurrence after a COC-associated VTE is low, and is lower compared to women with unprovoked VTE, however this comparison may be confounded by age. With only a minority of studies providing age adjusted analyses, the true difference remains unknown. Our meta-analysis is strengthened by the substantial contribution of unpublished data from individual study authors. This can help to guide clinicians and patient shared decision-making on the duration of anticoagulation. Figure 1 Figure 1. Disclosures Le Gal: LEO Pharma: Honoraria; BMS: Honoraria; Pfizer: Honoraria; Bayer: Honoraria; Aspen: Honoraria; Sanofi: Honoraria. Schulman: Boehringer-Ingelheim: Research Funding; Octapharma: Research Funding. Skeith: CSL Behring: Research Funding; Leo Pharma: Honoraria; Sanofi: Honoraria.

Data on anti-platelet therapy (APT) for prevention of atherothrombotic events in thrombocytopaenic cancer patients is lacking. We aimed to identify patient and physician characteristics associated with APT management in thrombocytopaenic patients with haematological malignancy. A clinical vignette-based experiment was designed. Eleven haematologists were interviewed, identifying five variable categories. Next, 18 hypothetical vignettes were generated. Each physician received three vignettes and chose to: hold all APT; continue APT without platelet transfusion support; or continue APT with platelet transfusion support. The survey was distributed to haematologists and thrombosis specialists in three countries. Multivariate cluster robust Poisson regression models were used to calculate relative risks (RRs) of using one management option (over the other) for each variable in comparison to a reference variable. A total of 145 physicians answered 434 cases. Clinicians were more likely to hold APT in case of 20,000/µL platelets (vs. 40,000/µL; RR for continuing: 0.82 [95% confidence interval: 0.75–0.91]), recent major gastrointestinal bleeding (vs. none; RR 0.81 [0.72–0.92]) and when the physician worked at a university-affiliated community hospital (vs. non-academic community hospital; RR 0.84 [0.72–0.98]). Clinicians were more likely to continue APT in ST elevation myocardial infarction with dual APT (vs. unstable angina with single APT; RR 1.31 [1.18–1.45]) and when there were institutional protocols guiding management (vs. none; RR 1.15 [1.03–1.27]). When APT was continued, increased platelet transfusion targets were used in 34%. In summary, the decision process is complex and affected by multiple patient and physician characteristics. Platelet transfusions were frequently chosen to support APT, although no evidence supports this practice.

Background: Therapy with elastic compression stockings has been the cornerstone for prevention of post-thrombotic syndrome for decades in patients after acute deep venous thrombosis. It is uncertain who benefits most from therapy, and what the optimum duration of therapy should be. We therefore aimed to assess the safety and efficacy of individualised duration of compression therapy versus the standard duration of 24 months following an initial treatment period of 6 months. Methods: We did a multicentre, randomised, single-blind, allocation-concealed, non-inferiority trial at 12 hospitals in the Netherlands and two in Italy. We randomly assigned patients (1:1) with acute proximal deep vein thrombosis of the leg and without pre-existent venous insufficiency (Clinical Etiological Anatomical and Pathophysiological score

Aim Direct-acting oral anticoagulants (DOACs) have become available for the prevention of stroke in patients with atrial fibrillation (AF). Conflicting results have been published on the risk of acute myocardial infarction (AMI) with the use of DOACs in comparison with vitamin K antagonists (VKAs). The objective of the present study was to evaluate the risk of AMI in patients with AF who are exposed to either VKAs, DOACs or low-dose (< 325 mg) aspirin. Methods We conducted a population-based cohort study using data from the Clinical Practice Research Datalink (2008–2014). The study population (n = 30 146) consisted of all patients ≥18 years with a diagnosis of AF who were new users of VKAs, DOACs (rivaroxaban and dabigatran) or aspirin. Cox proportional hazards models were used to estimate the hazard ratio (HR) of AMI for users of DOACs or aspirin vs. VKA. Adjustments were made for age, gender, lifestyle, risk factors, comorbidity and other drugs. Results The risk of AMI was doubled when we compared current use of DOACs with current use of VKAs [adjusted HR 2.11; 95% confidence interval (CI) 1.08, 4.12] and for current users of aspirin vs. current VKA users (adjusted HR 1.91; 95% CI 1.45, 2.51). Conclusions There is a twofold increase in the risk of AMI for users of DOACs, in comparison with VKAs, in AF therapy. In addition, the results suggested that in patients with AF, the incidence of AMI is higher during aspirin monotherapy than during the use of VKAs.

Background: Early thrombus removal might prevent post-thrombotic syndrome by preserving venous function and restoring flow. Previous trials comparing additional catheter-directed thrombolysis to standard treatment showed conflicting outcomes. We aimed to assess the benefit of additional ultrasound-accelerated catheter-directed thrombolysis for the prevention of post-thrombotic syndrome compared with standard therapy in patients with iliofemoral deep-vein thrombosis. Methods: We did a multicentre, randomised, single-blind, allocation-concealed, parallel group, superiority trial in 15 hospitals in the Netherlands. Patients aged 18–85 years with a first-time acute iliofemoral deep-vein thrombosis and symptoms for no more than 14 days were randomly assigned (1:1) to either standard treatment with additional ultrasound-accelerated catheter-directed thrombolysis or standard treatment alone. Randomisation was done with a web-based automatic programme and a random varying block size (2–12), stratified by age and centre. Standard treatment included anticoagulant therapy, compression therapy (knee-high elastic compression stockings; 30–40 mmHg), and early ambulation. Additional ultrasound-accelerated catheter-directed thrombolysis was done with urokinase with a starting bolus of 250 000 international units (IU) in 10 mL NaCl followed by a continuous dose of 100 000 IU/h for a maximum of 96 h through the Ekos Endowave-system. Adjunctive percutaneous transluminal angioplasty, thrombosuction, or stenting was performed at the discretion of the physician who performed the intervention. The primary outcome was the proportion of patients with post-thrombotic syndrome at 12 months diagnosed according to the original Villalta criteria—a Villalta-score of at least 5 on two consecutive occasions at least 3 months apart or the occurrence of venous ulceration—and was assessed in a modified intention-to-treat population of all randomly assigned patients who passed screening and started treatment. The safety analysis was assessed in the same modified intention-to-treat population. This study is complete and is registered at ClinicalTrials.gov, NCT00970619. Findings: Between May 28, 2010, and Sept 18, 2017, 184 patients were randomly assigned to either additional ultrasound-accelerated catheter-directed thrombolysis (n=91) or standard treatment alone (n=93). Exclusion because of screening failure or early withdrawal of informed consent resulted in 77 patients in the intervention group and 75 in the standard treatment group starting allocated treatment. Median follow-up was 12·0 months (IQR 6·0–12·0). 12-month post-thrombotic syndrome occurred in 22 (29%) patients allocated to additional treatment versus 26 (35%) patients receiving standard treatment alone (odds ratio 0·75 [95% CI 0·38 to 1·50]; p=0·42). Major bleeding occurred in four (5%) patients in the intervention group, with associated neuropraxia or the peroneal nerve in one patient, and no events in the standard treatment group. No serious adverse events occurred. None of the four deaths (one [1%] in the intervention group vs three [4%] in the standard treatment group) were treatment related. Interpretation: This study showed that additional ultrasound-accelerated catheter-directed thrombolysis does not change the risk of post-thrombotic syndrome 1 year after acute iliofemoral deep-vein thrombosis compared with standard therapy alone. Although this trial is inconclusive, the outcome suggests the possibility of a moderate beneficial effect with additional ultrasound-accelerated catheter-directed thrombolysis. Further research is therefore warranted to better understand this outcome in the context of previous trials, preferably by combining the available evidence in an individual patient data meta-analysis. Funding: The Netherlands Organisation for Health Research and Development (ZonMw), Maastricht University Medical Centre, BTG-Interventional Medicine.

Background The value of D-dimer testing for the diagnosis of thrombosis in unusual sites is not properly established and evidence is scarce. We performed a systematic review of the literature. Methods The search was conducted in MEDLINE and Cochrane Library for papers published in the last 10 years including different presentations of thrombosis in unusual sites. Twenty-three articles were included, from January 1, 2008, to December 31, 2018, comprising 3378 patients with thrombosis in unusual sites (upper extremity deep vein thrombosis, cerebral vein thrombosis and splanchnic vein thrombosis). The Newcastle-Ottawa scale was used to assess the quality of the studies. Results Two articles were related to upper extremity thrombosis, showing a high sensitivity and negative predictive value for D-dimer testing. Twelve articles concerned cerebral vein thrombosis, concluding that the timing of D-dimer testing was important, and that patients with a shorter duration of symptoms showed higher D-dimer levels. Sensitivity and specificity in these patients ranged from 58% to 97% and from 77% to 97.5%, respectively. Nine articles were related to splanchnic vein thrombosis. One described a population of patients with mesenteric venous thrombosis, and the rest included patients with portal vein thrombosis. The D-dimer testing methods and the proposed cut-off levels were remarkably different among the included studies. Conclusion D-dimer testing should not be currently recommended for the diagnosis of thrombosis in unusual sites as a first line diagnostic tool. The development of algorithms combining biomarkers such as D-dimer and clinical decision tools could improve the diagnosis.

Purpose To determine the effect of revascularisation for peripheral arterial disease (PAD) on QoL in the first and second year following diagnosis, to compare the effect depicted by Short Form Six Dimensions (SF-6D) and EuroQoL five Dimensions (EQ-5D) utilities, and Visual Analogue Scale (VAS) scores and to analyse heterogeneity in treatment response.Methods Longitudinal data from 229 PAD patients were obtained in an observational study in southern Netherlands. Utility scores were calculated with the international (SF-6D) and Dutch (EQ-5D) tariffs. We analysed treatment effect at years 1 and 2 through propensity score-matched ANCOVAs. Thereby, we estimated the marginal means (EMMs) of revascularisation and conservative treatment, and identified covariates of revascularisation effect.Results A year after diagnosis, 70 patients had been revascularised; the EMMs of revascularisation were 0.038, 0.077 and 0.019 for SF-6D, EQ-5D and VAS, respectively (always in this order). For conservative treatment these were -0.017, 0.038 and 0.021. At 2-year follow-up, the EMMs of revascularisation were 0.015, 0.077 and 0.027, for conservative treatment these were -0.020, 0.013 and -0.004. Baseline QoL (and rest pain in year 2) were covariates of treatment effect.Conclusions We measured positive effects of revascularisation and conservative treatment on QoL a year after diagnosis, the effect of revascularisation was sustained over 2 years. The magnitude of effect varied between the metrics and was largest for the EQ-5D, which may be most suitable for QoL measurement in PAD patients. Baseline QoL influenced revascularisation effect, in clinical practice this may inform expected QoL gain in individual patients.

Background: Inflammation and hypercoagulability play a pivotal role in venous thromboembolism and atherothrombosis. Since venous thrombosis increases the risk of atherothrombotic events and vice versa, common mechanisms may be involved.Objectives: To elucidate the role of neutrophils and coagulation in the occurrence of atherothrombotic events in patients with a history of deep vein thrombosis (DVT or peripheral artery disease (PAD).Materials and Methods: We studied 115 patients from two cohorts (75 DVT, 40 PAD). From those with PAD, 20 patients had progressive disease; from those with DVT, 25 patients had a recurrent DVT and 25 suffered from post thrombotic syndrome (PTS); patients were age and sex matched to DVT and PAD patients without events. Markers of neutrophil recruitment (p-selectin) and activation [nucleosomes, human neutrophil elastase- alpha 1anti-trypsin (HNE-AT)], an anti-inflammatory marker (Lipoxin A4) and a clotting activity marker (d-dimer), were measured with ELISA. Coagulation potential was analyzed by thrombin generation (CAT method).Results: Higher nucleosome levels were found in DVT patients [11.3 U/mL (7.4-17.7)] compared to PAD patients [7.1 U/mL (5.1-13.8)], lower HNE-AT levels were found in DVT patients [33.4 ng/mL (23.5-40.5)] in comparison to PAD patients [158 ng/mL (88.1-283)]. No difference in nucleosome levels was found between DVT patients with cardiovascular (CV) events [12.6 U/mL (8.2-16.1)], and PAD patients with CV events [6.9 U/mL (4.9-11.2)]. Lipoxin A4 levels appeared to be significantly lower in DVT [2.4 ng/mL (1.7-4.8)] vs. PAD [35.6 ng/mL (16.6-80.1)], with similar results in DVT patients with CV events vs. PAD patients with CV events. Thrombin generation showed higher ETP [160.4% (141.1-215.4)], and peak height [292.1% (177.9-330)] values in DVT patients. D-dimer levels were significantly lower in the DVT cohort [330 ng/mL (220-550)] compared to the PAD cohort [550 ng/mL (369-959)].Conclusion: In DVT patients, neutrophil activity does not appear to be an important driver of CV events. Although neutrophil activity is more pronounced in PAD, its effect is partly dampened by Lipoxin A4. Moreover, no associations were found between NET products and coagulation activity, suggesting that neutrophil activation does not play a pivotal role in the risk of thrombosis in either DVT or PAD.

Aims Therapeutic windows for residual platelet reactivity in patients with coronary artery disease on P2Y12 inhibitors were proposed in a consensus document. We aimed to explore the level of agreement between windows for different platelet function tests (PFTs) used to classify patients in low, optimal, and high on-treatment platelet reactivity categories, and to identify variables contributing to the level of agreement.Methods and results In this explorative clinical study, the VerifyNow P2Y12, Multiplate adenosine diphosphate (ADP), and light transmission aggregometry (LTA) 20 mu mol/L ADP were performed simultaneously in 145 consecutive vulnerable patients. Measurements were performed within 6 months of percutaneous intervention. Patients were considered vulnerable if they had >= 2 risk factors for bleeding or ischaemic events. Window-agreement between PFT pairs was slight to moderate. Multiplate-VerifyNow agreed in 72 patients (50%), kappa = 0.41; VerifyNow-LTA agreed in 76 patients (52%), kappa = 0.36; and LTA-Multiplate agreed in 64 patients (44%), kappa = 0.20. Several variables including the type of P2Y12 inhibitor, aspirin, haemoglobin level, platelet count, age, and previous stroke significantly influenced agreement between PFTs.Conclusions Our results suggest that the PFTs, with accompanying therapeutic windows, are not interchangeable when determining the response to antiplatelet therapy in vulnerable coronary artery disease patients on P2Y12 inhibitors. Hence, the type of PFT can directly affect the treatment strategy, which may be especially relevant for patients with multiple factors influencing individual PFTs and thereby test agreement.

Introduction: For a long time, vitamin K antagonists (VKA) have been the preferred drugs for the anticoagulation management of both atrial fibrillation and venous thromboembolism. Hereby, the major purpose is to attenuate the onset of thrombosis without affecting hemostasis.Areas covered: Nowadays, non-vitamin K anticoagulants (NOAC), a new class of oral anticoagulants is available for the above-mentioned indications. NOAC are at least as effective and safer with regard to intracranial bleedings compared to VKA, but major bleedings still occur. For this reason, the search for safer anticoagulants is still ongoing.Expert commentary: There are several unmet needs in NOAC management, including selection of optimal drug and dose, uncertainty on specific conditions and lack of drug persistence. There remains to be an important need for safer anticoagulants; ‘upstream’ anticoagulants including inhibitors of factor XIa may provide additional benefit related to fewer bleeding complications.

Objective: In a prospective setting, we aimed to find associations between biomarkers of the hemostatic system and the occurrence of central venous catheter (CVC)-related thrombosis in patients with hematological malignancies undergoing intensive chemotherapy. Methods: The study was conducted between July 2006 and August 2010 at the University Hospital Maastricht, the Netherlands. Consecutive adult patients with hematological malignancies who were going to receive a CVC for intensive chemotherapy were included. The primary end points were (a) symptomatic CVC-related thrombosis and (b) CVC-related infections. Blood samples were taken directly after catheterization, and easy to determine biomarkers (platelet count, leukocyte count, and hemoglobin level) in combination with blood group, factor VIII (FVIII), plasminogen activator inhibitor 1 (PAI-1), activated protein C (APC) resistance, and free protein S antigen were determined. Results: Blood was collected and analyzed from 168 patients. The incidence of symptomatic CVC-related thrombosis was 9%. In univariate analysis, white blood cell count >10.6 × 109/L, mean FVIII activity, and PAI-1 >12.2 IU/mL were found to be associated with the development of symptomatic CVC-related thrombosis. Conclusion: Elevated leukocyte count, high PAI-1, and high FVIII were associated with an increased incidence of symptomatic CVC-related thrombosis. We hope in future that simple, easy to determine laboratory tests that reflect the hemostatic and fibrinolytic activity in combination with clinical parameters may help to identify hematological patients at highest risk of CVC-related thrombosis and help to tailor the management of thromboprophylaxis in hematological patients undergoing CVC placement.

Objective Animal models suggest that toll-like receptor 9 (TLR9) promotes thrombus resolution after acute deep venous thrombosis (DVT). We hypothesized that TLR9 expression is lower in patients with post-thrombotic syndrome (PTS) and investigated the role of TLR9 in residual thrombosis (RT) and recurrence. Methods Patients with a history of DVT with PTS (cases, n = 30) and without PTS after minimal 24 months follow-up (controls, n = 30) were selected. Healthy individuals (HI, n = 29) without DVT were included as reference. TLR9 mRNA expression in leukocytes was determined by qPCR and normalized to the housekeeping succinate dehydrogenase subunit A gene using the ΔCt method. Sub analyses were performed to explore the TLR9 expression in patients with and without RT and multiple DVT episodes. Results The median TLR9 expression was 0.45 (interquartile range 0.31 to 0.93), 0.39 (0.25 to 0.69) and 0.62 (0.32 to 0.75) in cases, controls and HI respectively (p = 0.61). The median TLR9 expression was 0.39 (0.26 to 0.51) in patients with RT compared to 0.55 (0.30 to 0.86, p = 0.13) in those without. The median TLR9 expression was significantly lower in patients who had one DVT compared to patients with recurrent DVT, 0.37 (0.23 to 0.63) versus 0.55 (0.43 to 0.96) respectively (p Conclusion No significant difference in TLR9 expression was found between cases, controls and HI. However TLR9 expression seems lower in individuals with DVT and RT, albeit not significant. Interestingly, TLR9 might play a role in recurrent DVT, as the TLR9 expression was significantly higher in patients with recurrent DVT.

Compression therapy, prescribed as elastic compression stockings, is the cornerstone in the management of post-thrombotic syndrome. The effectiveness of elastic compression stockings has recently been called into question in a large randomized placebo-controlled trial. The findings however may be less contradictory than assumed and presented. The mechanistic substrate for the effectiveness of compression therapy is based on its ability to counteract venous hypertension, which is a central aspect in the pathophysiology of post-thrombotic syndrome. Nevertheless, despite elastic compression stockings a significant percentage (20–50%) of patients develops post-thrombotic syndrome, suggesting that there are other factors to be considered next to compression. Every patient has an individual baseline risk value, constituted of non-modifiable and modifiable risk factors (i.e. age, sex, bodyweight etcetera). Straining patients at risk is therefore crucial. Exploring additional or alternative forms of therapy is desirable as well since these are in addition to the risk factors, costs aspects and quality of life, puzzle pieces in the management of post-thrombotic syndrome, which once pieced together enables multifactorial yet individualized therapy.

Post thrombotic syndrome (PTS) is a very common chronic complication of deep venous thrombosis (DVT), as three out of ten patients with lower extremity DVT will develop PTS. The possibility to identify patients at risk is limited. Diagnosis is challenging, because there is no gold standard diagnostic method. Progress in diagnostic options may therefore change future diagnostic strategies. The better understanding of pathophysiologic processes that underlie PTS may stimulate the development of treatment modalities and improve and diversify management options. The quest for adequate preventive strategies and treatment is important because PTS has a detrimental effect on patients' quality of life and is associated with increased healthcare as well as societal costs. [1,2]The problem of PTS prevention is therefore clearly relevant to patients, doctors as well as policy makers.

Immunoassays are essential in the workup of patients with suspected heparin-induced thrombocytopenia. However, the diagnostic accuracy is uncertain with regard to different classes of assays, antibody specificities, thresholds, test variations, and manufacturers. We aimed to assess diagnostic accuracy measures of available immunoassays and to explore sources of heterogeneity. We performed comprehensive literature searches and applied strict inclusion criteria. Finally, 49 publications comprising 128 test evaluations in 15 199 patients were included in the analysis. Methodological quality according to the revised tool for quality assessment of diagnostic accuracy studies was moderate. Diagnostic accuracy measures were calculated with the unified model (comprising a bivariate random-effects model and a hierarchical summary receiver operating characteristics model). Important differences were observed between classes of immunoassays, type of antibody specificity, thresholds, application of confirmation step, and manufacturers. Combination of high sensitivity (>95%) and high specificity (>90%) was found in 5 tests only: polyspecific enzyme-linked immunosorbent assay (ELISA) with intermediate threshold (Genetic Testing Institute, Asserachrom), particle gel immunoassay, lateral flow immunoassay, polyspecific chemiluminescent immunoassay (CLIA) with a high threshold, and immunoglobulin G (IgG)-specific CLIA with low threshold. Borderline results (sensitivity, 99.6%; specificity, 89.9%) were observed for IgG-specific Genetic Testing Institute-ELISA with low threshold. Diagnostic accuracy appears to be inadequate in tests with high thresholds (ELISA; IgG-specific CLIA), combination of IgG specificity and intermediate thresholds (ELISA, CLIA), high-dose heparin confirmation step (ELISA), and particle immunofiltration assay. When making treatment decisions, clinicians should be a aware of diagnostic characteristics of the tests used and it is recommended they estimate posttest probabilities according to likelihood ratios as well as pretest probabilities using clinical scoring tools.

BACKGROUND: Treatment with vitamin K antagonists (VKA) requires a high proportion of time in the therapeutic range (TTR) and a low international normalised ratio (INR) variability to be maximally safe and effective. Switching from short-acting acenocoumarol to long-acting phenprocoumon could improve VKA control.AIMS: We assessed whether switching from acenocoumarol to phenprocoumon improves the time in the therapeutic range (TTR) and INR variability.METHODS AND RESULTS: In a retrospective cohort with data on 236,957 patients-years of VKA management from two first-line anticoagulation clinics in the Netherlands, we identified 124 patients in target range 2-3, 269 patients in target range 2-3.5 and 98 patients in target range 2.5-3.5 who switched from acenocoumarol to phenprocoumon. They were matched in a 1:2 ratio to non-switching controls using propensity score matching. Over the first 180 days after a switch, switchers' TTR declined 5 (95% CI 1 to 10), 10 (95% CI 7 to 13) and 5 (95% CI 0 to 11) percentage points relative to non-switchers, in target ranges 2-3, 2-3.5 and 2.5-3.5. Anticoagulation was more often supra-therapeutic in switchers, and switchers had a higher INR variability. In the following 180 days, TTR in switchers became 1 (95% CI -4 to 6), 4 (95% CI 0 to 7) and 6 (95% CI 1 to 12) percentage points better than in non-switchers. Switchers' INRs were much more stable than non-switchers'.CONCLUSION: Eventually, a switch from acenocoumarol to phenprocoumon leads to a higher TTR and a lower INR variability. However, this is preceded by a transition period with opposite effects. An improved conversion algorithm could possibly shorten the transition period. Until then, physicians and patients should decide whether switching is worth the increased risk during the transition phase.

Aim: To compare health-related quality of life (HRQoL) descriptions and utility scores in newly diagnosed peripheral arterial disease (PAD) patients, using two most widely used instruments, EuroQol 5D (EQ-5D) and Medical Outcome Study 36-item Short-Form Health Status Survey (SF-36). Methods: Patients’ self-assessment of HRQoL was measured by the Dutch versions of the EQ-5D and SF-36 in the 204 patients. Results: Mean utility scores ranged from 0.675 for Short-Form Six-Dimension, 0.648 for the EQ-5D UK tariff and 0.715 for the Dutch EQ-5D tariff. A moderate correlation between the utility scores was found due to different valuation techniques of these instruments. Conclusion: Both instruments have clinical validity for use in the PAD and can be used alongside each other to provide a holistic assessment of the HRQoL. Before using these two instruments interchangeably for utility score calculations and healthcare resource allocation, a thorough sensitivity analysis is necessary to explore the robustness of the value argument based on these utility scores.

Introduction: Direct oral anticoagulants (DOACs) are increasingly prescribed for prevention of thromboembolic stroke, as well as for prevention and treatment of venous thromboembolism. Dose adjustment based on laboratory testing is not required; however, there are several potential situations that deserve insight into a DOAC plasma activity level. Methods: Based on a series of real-life case descriptions, we discuss indications for dedicated DOAC testing, as well as the interpretation and consequences. Results: Testing of DOACs in selected patients may help to better interpret acute situations such as bleeding or thrombosis while on anticoagulation, but also suspected drug failure, drug accumulation, or lack of adherence. Conclusion: The 24/7 availability of target-specific tests with adequate calibration is recommended to support the clinician in the interpretation and where needed adjustment of the management of patients on DOACs. The relevance of laboratory-guided DOAC management, particularly in the elderly, merits further study.

Atherothrombosis is a leading cause of cardiovascular mortality and long-term morbidity. Platelets and coagulation proteases, interacting with circulating cells and in different vascular beds, modify several complex pathologies including atherosclerosis. In the second Maastricht Consensus Conference on Thrombosis, this theme was addressed by diverse scientists from bench to bedside. All presentations were discussed with audience members and the results of these discussions were incorporated in the final document that presents a state-of-the-art reflection of expert opinions and consensus recommendations regarding the following five topics: 1. Risk factors, biomarkers and plaque instability: In atherothrombosis research, more focus on the contribution of specific risk factors like ectopic fat needs to be considered; definitions of atherothrombosis are important distinguishing different phases of disease, including plaque (in)stability; proteomic and metabolomics data are to be added to genetic information. 2. Circulating cells including platelets and atherothrombosis: Mechanisms of leukocyte and macrophage plasticity, migration, and transformation in murine atherosclerosis need to be considered; disease mechanism-based biomarkers need to be identified; experimental systems are needed that incorporate whole-blood flow to understand how red blood cells influence thrombus formation and stability; knowledge on platelet heterogeneity and priming conditions needs to be translated toward the in vivo situation. 3. Coagulation proteases, fibrin(ogen) and thrombus formation: The role of factor (F) XI in thrombosis including the lower margins of this factor related to safe and effective antithrombotic therapy needs to be established; FXI is a key regulator in linking platelets, thrombin generation, and inflammatory mechanisms in a renin–angiotensin dependent manner; however, the impact on thrombin-dependent PAR signaling needs further study; the fundamental mechanisms in FXIII biology and biochemistry and its impact on thrombus biophysical characteristics need to be explored; the interactions of red cells and fibrin formation and its consequences for thrombus formation and lysis need to be addressed. Platelet–fibrin interactions are pivotal determinants of clot formation and stability with potential therapeutic consequences. 4. Preventive and acute treatment of atherothrombosis and arterial embolism; novel ways and tailoring? The role of protease-activated receptor (PAR)-4 vis à vis PAR-1 as target for antithrombotic therapy merits study; ongoing trials on platelet function test-based antiplatelet therapy adjustment support development of practically feasible tests; risk scores for patients with atrial fibrillation need refinement, taking new biomarkers including coagulation into account; risk scores that consider organ system differences in bleeding may have added value; all forms of oral anticoagulant treatment require better organization, including education and emergency access; laboratory testing still needs rapidly available sensitive tests with short turnaround time. 5. Pleiotropy of coagulation proteases, thrombus resolution and ischaemia–reperfusion: Biobanks specifically for thrombus storage and analysis are needed; further studies on novel modified activated protein C–based agents are required including its cytoprotective properties; new avenues for optimizing treatment of patients with ischaemic stroke are needed, also including novel agents that modify fibrinolytic activity (aimed at plasminogen activator inhibitor-1 and thrombin activatable fibrinolysis inhibitor.

SummaryPost-thrombotic syndrome (PTS) is a common complication of deepvein thrombosis (DVT). Poor quality treatment with vitamin K antagonists (VKA) is a risk factor for PTS. We hypothesised that treatment with the direct oral anticoagulant (DOAC) rivaroxaban may lower PTS incidence as compared to enoxaparin/VKA, as DOACs have a more stable pharmacologic profile than VKA. We performed a post-hoc subgroup analysis of the Einstein DVT trial (n=3449). Kaplan-Meier survival analysis was performed to compare the cumulative incidence of PTS between the rivaroxaban and enoxaparin/VKA groups. Hazard ratios (HR) and 95 % confidence intervals (CI) were calculated using Cox proportional hazards models. We included 336 patients with a mean age of 58 ± 16 years and a median follow-up after index DVT of 57 months (interquartile range 48–64). Of these, 162 (48 %) had been treated with rivaroxaban and 174 (52 %) with enoxaparin/VKA. The cumulative PTS incidence at 60 months follow-up was 29 % in the rivaroxaban group and 40 % in the enoxaparin/VKA group. After adjusting for age, gender, body mass index, previous VTE, ipsilateral recurrent DVT, extent of DVT, idiopathic DVT, duration of anticoagulant treatment, compliance to assigned study medication, elastic compression stocking use and active malignancy, the HR of PTS development for rivaroxaban was 0.76 (95 % CI: 0.51–1.13). In conclusion, treatment of acute DVT with rivaroxaban was associated with a numerically lower but statistically non-significant risk of PTS compared to enoxaparin/VKA treatment. The potential effect on reducing PTS deserves evaluation in a large randomised trial.Supplementary Material to this article is available online at www.thrombosis-online.com.

SummaryPatients with coronary artery disease are usually treated with dual antiplatelet therapy (DAPT) after percutaneous coronary intervention. Patients on DAPT are at risk of both ischaemic and bleeding events. Although side-lined for a long time, real-life studies have shown that both the incidence and the associated morbidity and mortality of outof-hospital bleeding are high. This indicates that prevention of (postinterventional) bleeding is as important as prevention of ischaemia. For this purpose it is crucial to reliably identify patients with a high bleeding risk. In order to postulate an algorithm, which could help identifying these patients, we performed a systematic review to determine the value of previously proposed prognostic modalities for bleeding. We searched and appraised the following tools: platelet function tests, genetic tests, bleeding scores and questionnaires and haemostatic tests. Most studies indicated that low on-treatment platelet reactivity (LTPR), as measured by several platelet function tests, and the carriage of CYP2C19*17 allele were independent risk factors for bleeding. A bleeding score also proved to be helpful in identifying patients at risk. No studies on haemostatic tests were retrieved. Several patient characteristics were also identified as independent predictors of bleeding, such as older age, female sex and renal failure. Combining these risk factors we propose an algorithm that would hypothetically facilitate identification of those patients at highest risk, warranting prevention measures for bleeding. This could be a starting point for further research concerning the topic.

Objective/Background Stent placement in the venous system is an increasingly used treatment modality in chronic venous obstruction and as additional treatment after thrombolytic therapy in ilio-femoral deep vein thrombosis (DVT). Experience in treating in-stent thrombosis with ultrasound accelerated catheter directed thrombolysis (UACDT) is reported. Methods A retrospective analysis of patients treated for venous stent occlusion, after percutaneous transluminal angioplasty (PTA) and stent placement for either chronic venous occlusive disease or persistent vein compression in patients with acute DVT was performed. Duration of occlusion and suspected clot age were assessed using patient complaints and typical findings on duplex ultrasonography (DUS). DUS and venography were used to assess patency and to determine the cause of re-occlusion. Acute treatment of occlusion was by UACDT. Additional procedures included PTA, stent placement, and creation of an arteriovenous (AV) fistula. Results Eighteen patients (median age 43 years; 67% male), treated for occluded stent tracts with UACDT between January 2009 and July 2014, were identified. Indications for initial stenting were treatment of chronic venous obstructive disease (12 patients) and treatment of underlying obstruction after initial thrombolysis in acute DVT (six patients). Technical success was achieved in 11/18 (61%) patients. Primary patency in 8/11 patients was 73% at last follow up (median follow up 14 months [range 0–41 months]). Additional treatments after successful lysis were re-stenting (seven patients) and creation of an AV fistula (six patients). Conclusion Treatment with UACDT of recently occluded stent tracts is feasible and effective. Recanalization of the stent tract can be achieved in most cases. Additional interventions were frequently used after successful UACDT treatment. Suboptimal stent positioning caused the majority of the stent occlusions.