Clinical impact of assessing thrombus age using magnetic resonance venography prior to catheter-directed thrombolysis.

OBJECTIVES: Magnetic resonance venography (MRV) is underutilized in the evaluation of thrombus properties prior to endovascular treatment but may improve procedural outcomes. We therefore investigated the clinical impact of using a dedicated MRV scoring system to assess thrombus characteristics prior to endovascular intervention for iliofemoral deep vein thrombosis (DVT). METHODS: This is a post hoc analysis of data from the CAVA trial ( Clinicaltrials.gov :NCT00970619). MRV studies of patients receiving ultrasound-accelerated catheter-directed thrombolysis (CDT) for iliofemoral DVT were reviewed. Thrombus age-related imaging characteristics were scored and translated into an overall score (acute, subacute, or old). MRV scores were compared to patient-reported complaints. MRV-scored groups were compared for CDT duration and success rate. RESULTS: Fifty-six patients (29 men; age 50.8 ± 16.4 years) were included. Using MRV, 27 thrombi were classified acute, 17 subacute, and 12 old. Based on patient-reported complaints, 11 (91.7%) of these old thrombi would have been categorized acute or subacute, and one (3.7%) of the acute thrombi as old. Average duration of CDT to > 90% restored patency differed significantly between groups (p < 0.0001): average duration was 23 h for acute thromboses (range: 19-25), 43 h for subacute (range: 41-62), and 85 h for old thromboses (range: 74-96). CDT was almost eleven times more successful in thromboses characterized as acute and subacute compared to old thromboses (OR: 10.7; 95% CI 2.1-55.5). CONCLUSION: A dedicated MRV scoring system can safely discriminate between acute, subacute, and old thromboses. MRV-based selection is predictive of procedural duration and success rate and can help avoid unnecessary complications. KEY POINTS: • Thrombus age, characterized by MRV as acute, subacute, and old, can predict CDT duration and probability of success. • Accurate pre-interventional MRV-based thrombus aging has the potential to facilitate identification of eligible patients and may thus prevent CDT-related complications.

Long-Term Adherence to Direct Oral Anticoagulants in Patients with Atrial Fibrillation: A Comparative Cross-Sectional Study.

BACKGROUND: Long-term treatment with direct oral anticoagulants (DOAC) is required for the majority of patients with nonvalvular atrial fibrillation (AF) to prevent ischemic stroke and systemic embolism. Adherence to therapy may impact clinical outcomes. Therefore, the purpose of this study was to assess the potential impact of structured follow-up on long-term adherence to DOAC therapy compared to standard care. METHODS: This is a cross sectional study on the implementation phase of medication adherence to DOACs, comparing patients with AF following completion of structured follow-up of minimally 1 year with those who received standard care. All patients used DOACs for more than 2 years and completed a questionnaire on adherence. Adherence was measured with the Morisky Medication Adherence Scale-8 (MMAS-8) score and assessed via an online web portal. RESULTS: A total of 212 patients were included. The mean MMAS-8 score was 7.55 (SD 0.93) after structured follow-up and 7.25 (SD 1.01) for standard care; p = 0.045. Following structured follow-up 64.1% of patients had a high adherence (MMAS score of 8) compared to 50% receiving standard care; p = 0.05. Patients following structured follow-up on a once daily DOAC regime had higher MMAS-8 scores compared to those on a twice daily regime; 7.74 (SD 0.74) versus 7.00 (SD 1.22); p < 0.001. The rates of minor bleedings were 10.6% versus 21.4% respectively, p = 0.038. CONCLUSION: In patients on long-term DOAC treatment, adherence to therapy was significantly increased after receiving an initial period of structured follow-up compared to standard care. Additionally, adherence to DOAC therapy was higher with once-daily treatment regimen. Significant more minor bleedings were reported in the standard care group. These results indicate that implementation of structured follow-up of patients with AF using DOACs merits further evaluation.

Exploring the Feasibility of Comprehensive Uncertainty Assessment in Health Economic Modeling: A Case Study.

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.

Reduced incidence of vein occlusion and postthrombotic syndrome after immediate compression for deep vein thrombosis.

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 syndrome as 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).

Prevalence of venous obstructions in (recurrent) venous thromboembolism: a case-control study.

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.

Comparison of three generic quality-of-life metrics in peripheral arterial disease patients undergoing conservative and invasive treatments.

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.

The need for a timely diagnostic workup for patients with venous leg ulcers.

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.

Screen or not to screen for peripheral arterial disease: guidance from a decision model.

BACKGROUND: Asymptomatic Peripheral Arterial Disease (PAD) is associated with greater risk of acute cardiovascular events. This study aims to determine the cost-effectiveness of one time only PAD screening using Ankle Brachial Index (ABI) test and subsequent anti platelet preventive treatment (low dose aspirin or clopidogrel) in individuals at high risk for acute cardiovascular events compared to no screening and no treatment using decision analytic modelling. METHODS: A probabilistic Markov model was developed to evaluate the life time cost-effectiveness of the strategy of selective PAD screening and consequent preventive treatment compared to no screening and no preventive treatment. The analysis was conducted from the Dutch societal perspective and to address decision uncertainty, probabilistic sensitivity analysis was performed. Results were based on average values of 1000 Monte Carlo simulations and using discount rates of 1.5% and 4% for effects and costs respectively. One way sensitivity analyses were performed to identify the two most influential model parameters affecting model outputs. Then, a two way sensitivity analysis was conducted for combinations of values tested for these two most influential parameters. RESULTS: For the PAD screening strategy, life years and quality adjusted life years gained were 21.79 and 15.66 respectively at a lifetime cost of 26,548 Euros. Compared to no screening and treatment (20.69 life years, 15.58 Quality Adjusted Life Years, 28,052 Euros), these results indicate that PAD screening and treatment is a dominant strategy. The cost effectiveness acceptability curves show 88% probability of PAD screening being cost effective at the Willingness To Pay (WTP) threshold of 40000 Euros. In a scenario analysis using clopidogrel as an alternative anti-platelet drug, PAD screening strategy remained dominant. CONCLUSION: This decision analysis suggests that targeted ABI screening and consequent secondary prevention of cardiovascular events using low dose aspirin or clopidogrel in the identified patients is a cost-effective strategy. Implementation of targeted PAD screening and subsequent treatment in primary care practices and in public health programs is likely to improve the societal health and to save health care costs by reducing catastrophic cardiovascular events.

Chronic inflammatory diseases increase the risk of post-thrombotic syndrome: A prospective cohort study.

BACKGROUND: Clinical management of patients with deep vein thrombosis (DVT) is centered around their risk of recurrent venous thromboembolism (VTE) and post-thrombotic syndrome (PTS). While chronic inflammatory disease (CID) has been established as a risk factor of (recurrent) VTE, research about its potential impact on PTS is lacking. OBJECTIVES: We aimed to assess the risk of PTS in patients with CID, stratifying for the use of anti-inflammatory treatment. PATIENTS/METHODS: Consecutive patients with proximal DVT and no active cancer between 2003 and 2018 received a two-year prospective follow-up. CID included inflammatory bowel disease, rheumatic diseases, and gout. Residual venous obstruction (RVO) was assessed by compressive ultrasound after 3-6 months. PTS was diagnosed using the Villalta score after 6-24 months. Hazard ratios (HR) and odds ratios (OR) were adjusted for patient characteristics. The medical ethics committee approved this study. RESULTS: In total 82 of 801 patients had CID (10.2 %). PTS more often developed in patients with CID (35.4% vs. 18.9 %, p < 0.001) than in those without CID (HR 1.72 [1.15-2.58]). The prevalence of RVO was similar in patients with and without CID (36.8% vs. 41.4 %), and RVO was strongly associated with PTS in patients with CID (OR 3.21 [1.14-9.03]). Moreover, patients with untreated CID (44 %, n = 36) more often had RVO than those with treated CID (51.6% vs. 26.7 %, p = 0.027), and accordingly had a higher risk of PTS (HR 2.18 [1.04-4.58]). CONCLUSIONS: Patients with CID had an increased risk of developing PTS, especially those without anti-inflammatory treatment, possibly due to an unfavorable impact on RVO-related venous pathology.

Fibrinogen levels and clot properties identify patients who benefit from catheter-directed thrombolysis after DVT.

ABSTRACT: Ultrasound-accelerated catheter-directed thrombolysis (UA-CDT) to improve patency after deep vein thrombosis (DVT) has not conclusively been shown to prevent postthrombotic syndrome (PTS) but might benefit patients who are unlikely to obtain patency with standard treatment. We hypothesized that these patients could be selected based on their fibrin clot properties. To study this, patients with acute iliofemoral DVT from the CAVA (Ultrasound-Accelerated Catheter-Directed Thrombolysis Versus Anticoagulation for the Prevention of Post-thrombotic Syndrome) trial had blood samples taken at inclusion. Fibrin clot properties in plasma were determined by turbidimetric clotting (lag time and maximal turbidity) and lysis assays (time to 50% lysis and lysis rate), permeation assay, and confocal microscopy (fiber density), as well as levels of fibrin clot modifiers fibrinogen and C-reactive protein (CRP). Patency was defined as >90% iliofemoral vein compressibility at 12-month ultrasound. PTS was defined as ≥5 Villalta score at 6 or 12 months. In total, 91 of 152 patients were included, including 43 with additional UA-CDT and 48 with standard treatment. Patients with additional UA-CDT more often obtained patency (55.8 vs 27.1%) Patients who obtained patency had longer lag times and lower maximal turbidity, fibrinogen, and CRP; only maximal turbidity and fibrinogen remained associated when adjusting for treatment, thrombus load, and body mass index. Fibrinogen levels had an optimal cutoff at 4.85 g/L. Low fibrinogen levels best predicted patency. Additional UA-CDT decreased the risk of PTS only in patients with high fibrinogen. Therefore, additional UA-CDT might prevent PTS in selected patients based on routinely measured fibrinogen levels. This study was registered at www.ClinicalTrials.gov as #NCT00970619.

Budget Impact of Three Improvement Targets for Compression Therapy for Patients with Deep Venous Thrombosis in The Netherlands.

BACKGROUND AND OBJECTIVE: Compression therapy following deep venous thrombosis in the Netherlands is suboptimal. We assessed the budget impact of targeted care improvements. METHODS: We calculated the per-patient and population healthcare resource use and costs concerning 26,500 new patients each year in the Netherlands for the current pathways in region North Holland (divided into two parts: NH-A and NH-B) and region Limburg. Next, we assessed the impact of three improvement targets: optimizing initial compression therapy, early consultation of an occupational therapist, and tailored duration of elastic compression stocking therapy. Inputs were based on interview (n = 30) and survey data (n = 114), literature, and standard prices. The robustness of the results was tested by sensitivity analyses. RESULTS: The current per-patient costs for a 2-year episode were €1046 (NH-A), €947 (NH-B), and €1256 (Limburg). The improvements led to direct savings for region Limburg (€4.7 million). Population costs increased in the first year for NH-A (+ €3.5 million) and NH-B (+ €6.4 million), and decreased in the second and third year resulting in a cost reduction for NH-A (- €2.2 million) but not for NH-B (+ €0.6 million). Workload for occupational therapists and internists in North Holland increased, and workload for home care nurses decreased in all regions. CONCLUSIONS: This study provides a detailed insight into current costs and healthcare resource use associated with compression therapy and the potential impact of implementing three improvement targets. We showed that the improvements resulted in considerable cost savings within 3 years after implementation for region NH-A and Limburg.

Exploring phenotypes of deep vein thrombosis in relation to clinical outcomes beyond recurrence.

BACKGROUND: Deep vein thrombosis (DVT) is a multifactorial disease with several outcomes, but current classifications solely stratify it based on recurrence risk. OBJECTIVES: We aimed to identify DVT phenotypes and assess their relation to recurrent venous thromboembolism (VTE), postthrombotic syndrome, arterial events, and cancer. PATIENTS/METHODS: Hierarchical clustering was performed on a DVT cohort with a follow-up of up to 5 years using 23 baseline characteristics. Phenotypes were summarized by discriminative characteristics. Hazard ratios (HRs) were calculated using Cox regression; the recurrence risk was adjusted for the anticoagulant therapy duration. The study was carried out in accordance with the Declaration of Helsinki and approved by the medical ethics committee. RESULTS: In total, 825 patients were clustered into 4 phenotypes: 1. women using estrogen therapy (n = 112); 2. patients with a cardiovascular risk profile (n = 268); 3. patients with previous VTE (n = 128); and 4. patients without discriminant characteristics (n = 317). Overall, the risks of recurrence, postthrombotic syndrome, arterial events, and cancer were low in phenotype 1 (reference), intermediate in phenotype 4 (HR: 4.6, 1.2, 2.2, 1.8), and high in phenotypes 2 (HR: 6.1, 1.6, 4.5, 2.9) and 3 (HR: 5.7, 2.5, 2.3, 3.7). CONCLUSIONS: This study identified 4 distinct phenotypes among patients with DVT that are not only associated with the increasing recurrence risk but also with outcomes beyond recurrence. Our results thereby highlight the limitations of current risk stratifications that stratify based on the predictors of the recurrence risk only. Overall, risks were lowest in women using estrogen therapy and highest in patients with a cardiovascular risk profile. These findings might inform a more personalized approach to clinical management.

Residual Venous Obstruction as an Indicator of Clinical Outcomes following Deep Vein Thrombosis: A Management Study.

BACKGROUND: Residual venous obstruction (RVO) is considered a risk factor of recurrence and possibly other clinical outcomes following deep vein thrombosis (DVT). Current guidelines do not support an RVO-tailored duration of anticoagulant therapy; contemporary data of such management strategies are scarce. We aimed to evaluate an RVO-based management strategy and to assess associations of RVO with recurrence, post-thrombotic syndrome (PTS), arterial events and cancer. To gain further insight, D-dimer levels were measured 1 month after stopping anticoagulant therapy. METHODS: Consecutive patients with symptomatic, proximal DVT were treated in a 2-year clinical care pathway (CCP) at Maastricht University Medical Center and were followed up to 5 years. RVO was assessed at the end of regular duration of anticoagulant therapy, which was extended once if RVO was detected. The study was approved by the medical ethics committee. RESULT: From a total of 825 patients, 804 patients (97.5%) completed the CCP and 755 (93.9%) were available for extended follow-up. Most patients (76.5%) stopped anticoagulant therapy. Incidence rates of recurrence, PTS, arterial events, and cancer were 4.4, 11.9, 1.7, and 1.8 per 100 patient-years, respectively. RVO was independently associated with PTS (hazard ratio [HR]: 1.66 [1.19-2.32]) and arterial events (HR: 2.07 [1.18-3.65]), but not with recurrence or cancer. High D-dimer was associated with recurrence (HR: 3.51 [2.24-5.48]). CONCLUSION: Our RVO-based management strategy might have attenuated the association of RVO with recurrence. In addition, RVO identified patients at increased risk of PTS and arterial events, which might be used to identify patients in need of alternative treatment strategies.

Predictive value for increased activated factor XI activity in acute venous thromboembolism.

BACKGROUND: Venous thromboembolism (VTE) is associated with excessive coagulation activity, which in part can be attributed to activation of contact system. However, the knowledge regarding the impact of contact activation in acute VTE is limited. OBJECTIVE: To unravel the involvement of contact activation in acute VTE. METHODS: Contact activation was investigated in patients with acute VTE (n = 321) and population controls without a history of VTE (n = 300). For comparison, Factor XI(a) levels, activity, and plasma kallikrein (PKa) activity were determined in plasma samples with an activated partial thromboplastin time- or thrombin generation-based assay (free FXI concentration [FXI:c] and calibrated automated thrombogram:FXIa, respectively) and with enzyme-linked immunosorbent assays for enzyme-inhibitor complexes (FXIa:alpha-1-antitrypsin [α1AT], FXIa:antithrombin [AT], FXIa:C1-inhibitor [C1Inh], and PKa:C1-inh). RESULTS: In patients with VTE, higher FXI:c levels (124 ± 37% vs 114 ± 28%), but lower calibrated automated thrombogram:FXIa levels were apparent. This was accompanied by increased FXIa:α1AT, FXIa:AT, and PKa:C1-inh levels in patients compared with controls (312pM [238-424] vs 203pM [144-288]; 29pM [23-38] vs 23pM [20-30]; 1.9nM [1.2-4.7] vs 1.4nM [0.7-3.5], respectively), whereas FXIa:C1-inh levels did not differ. Logistic regression models showed good discriminatory values for FXI:c and FXIa:α1AT (area under the curve = 0.64 [0.6/0.69] and 0.73 [0.69/0.77], respectively). After a 2-year follow-up, 81 recurrent VTE events or deaths occurred in the patient cohort, for which the baseline levels of FXIa:α1AT and FXIa:C1Inh had a significant prognostic value (Hazard ratios per SD [95% CI], 1.26 [1.10-1.45]; p =.0012 and 1.19 [1.05-1.36]; p =.0082, respectively). CONCLUSION: Our study revealed elevated FXIa levels and activity in acute VTE, which was also associated with recurrent VTE, suggesting an important risk contribution of FXI activation to VTE. The evidence provided by this study supports the utility of FXIa inhibition in the setting of acute VTE.

Blood Coagulation and Beyond: Position Paper from the Fourth Maastricht Consensus Conference on Thrombosis.

The Fourth Maastricht Consensus Conference on Thrombosis included the following themes. Theme 1: The "coagulome" as a critical driver of cardiovascular disease. Blood coagulation proteins also play divergent roles in biology and pathophysiology, related to specific organs, including brain, heart, bone marrow, and kidney. Four investigators shared their views on these organ-specific topics. Theme 2: Novel mechanisms of thrombosis. Mechanisms linking factor XII to fibrin, including their structural and physical properties, contribute to thrombosis, which is also affected by variation in microbiome status. Virus infection-associated coagulopathies perturb the hemostatic balance resulting in thrombosis and/or bleeding. Theme 3: How to limit bleeding risks: insights from translational studies. This theme included state-of-the-art methodology for exploring the contribution of genetic determinants of a bleeding diathesis; determination of polymorphisms in genes that control the rate of metabolism by the liver of P2Y12 inhibitors, to improve safety of antithrombotic therapy. Novel reversal agents for direct oral anticoagulants are discussed. Theme 4: Hemostasis in extracorporeal systems: the value and limitations of ex vivo models. Perfusion flow chamber and nanotechnology developments are developed for studying bleeding and thrombosis tendencies. Vascularized organoids are utilized for disease modeling and drug development studies. Strategies for tackling extracorporeal membrane oxygenation-associated coagulopathy are discussed. Theme 5: Clinical dilemmas in thrombosis and antithrombotic management. Plenary presentations addressed controversial areas, i.e., thrombophilia testing, thrombosis risk assessment in hemophilia, novel antiplatelet strategies, and clinically tested factor XI(a) inhibitors, both possibly with reduced bleeding risk. Finally, COVID-19-associated coagulopathy is revisited.

Postoperative thromboembolic prophylaxis in joint replacement surgery: Guidelines and daily practice.

This is a commentary discussing the article published in Thrombosis Journal by Subramanian et al. [Thrombosis Journal 2012, 10:15].

How to optimize the prevention of post­thrombotic syndrome: recent advances.

Post­thrombotic syndrome (PTS) is the most frequent complication of deep vein thrombosis, and it can be detrimental to the quality of life of the affected patients. Once affected by this chronic condition, the patient's treatment options are very limited, so preventive therapies are crucial. Currently, the prevention of PTS is hampered by the lack of unequivocally effective therapies. However, improved insight into pathogenesis of this condition acquired in recent years, including the central role of residual venous obstruction, could lead to a better application of existing therapies and identification of novel therapeutic targets. Plausible therapeutic agents include flavonoids and statins, while promising future agents include those that target leukocyte­endothelial interaction. Moreover, differences in PTS risk were found to be partly explained by a tendency of patients to form clots that are less susceptible to lysis. Finally, identifying patients that are expected to benefit most from certain therapies is equally valuable for the success of future preventive strategies. This requires exploration of better risk stratification through machine learning techniques.

Development of a Consensus-Based Cross-Domain Protocol for the Management of Elastic Compression Stocking Therapy in Patients With Deep Venous Thrombosis and Chronic Venous Disease: A Modified Delphi Study.

Objective: Elastic compression stocking (ECS) therapy is commonly used in patients with deep venous thrombosis (DVT) and chronic venous disease (CVD). The provision of ECS therapy is complex, and studies indicate a lack of practical guidance and suboptimal collaboration among health care professionals. We aimed to reach consensus on critical issues of ECS therapy among the involved health care professionals and patients. Methods: A three-round modified Delphi analysis was performed in the Netherlands in which 56 health care professionals (internists, dermatologists, general practitioners, emergency room nurses, home care nurses, medical stocking suppliers, and occupational therapists) and seven patients were invited. The 21 statements included in this analysis were based on information collected from a previously conducted Functional Resonance Analysis Method and Realist Evaluation. We used 7-point Likert scale questions and a 75% threshold for consensus. Results: Of the 63 persons invited for this study, 59 (94%) agreed to participate and responded in the first questionnaire round; of whom 52 were health care professionals and seven were patients (five DVT and two CVD). The overall response rate for the three questionnaire rounds was 91%. After completion of the rounds, full consensus was achieved on 19 out of 21 statements. No consensus was reached on the need for a follow-up appointment for CVD patients and who should be responsible to determine the ECS type (custom-made or standard). Conclusion: We identified 19 consensus-driven recommendations on treatment decisions and collaboration in ECS therapy among an interdisciplinary panel of health care professionals and patients. These recommendations form a basis for consensus-driven optimization of ECS therapy and should ideally be incorporated in a general cross-domain protocol for ECS therapy in patients with DVT and CVD.