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Background: The recently published 4-level Pulmonary Embolism Clinical Probability Score (4PEPS) integrates different aspects from currently available diagnostic strategies to further reduce imaging testing in patients with clinically suspected pulmonary embolism (PE)., Aim: To externally validate the performance of 4PEPS in an independent cohort., Methods: In this post-hoc analysis of the prospective diagnostic management YEARS study, the primary outcome measures were discrimination, calibration, efficiency (proportion of imaging tests potentially avoided), and failure rate (venous thromboembolism (VTE) diagnosis at baseline or follow-up in patients with a negative 4PEPS algorithm). Multiple imputation was used for missing 4PEPS items. Based on 4PEPS, PE was considered ruled out in patients with a very low clinical pre-test probability (CPTP) without D-dimer testing, in patients with a low CPTP and D-dimer <1000 μg/L, and in patients with a moderate CPP and D-dimer below the age-adjusted threshold., Results: Of the 3465 patients, 474 (14 %) were diagnosed with VTE at baseline or during 3-month follow-up. Discriminatory performance of the 4PEPS items was good (area under ROC-curve, 0.82; 95%CI, 0.80-0.84) as was calibration. Based on 4PEPS, PE could be considered ruled out without imaging in 58 % (95%CI 57-60) of patients (efficiency), for an overall failure rate of 1.3 % (95%CI 0.86-1.9)., Conclusion: In this retrospective external validation, 4PEPS appeared to safely rule out PE with a high efficiency. Nevertheless, although not exceeding the failure rate margin by ISTH standards, the observed failure rate in our analysis appeared to be higher than in the original 4PEPS derivation and validation study. This highlights the importance of a prospective outcome study., Competing Interests: Declaration of competing interest MJHA Kruip received research support from Sobi, The Netherlands Organisation for Health Research and Development and The Dutch Thrombosis Association for research outside this study and speakers fee from BMS, Roche and Sobi, payment to institution. FA Klok has received research support from Bayer, BMS, BSCI, MSD, Leo Pharma, Actelion, The Netherlands Organisation for Health Research and Development, The Dutch Thrombosis Association, The Dutch Heart Foundation and the Horizon Europe Program. The other authors have nothing to declare., (Copyright © 2023 The Authors. Published by Elsevier Ltd.. All rights reserved.)

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

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

Intracranial hemorrhage (ICH) is the most feared complication of anticoagulation with a high mortality and morbidity. Before registration of a specific reversal agent for factor Xa inhibitors (FXa-I), international guidelines recommended prothrombin complex concentrate (PCC), which also is the specific reversal agent for vitamin K antagonists (VKA). In two contemporary cohorts, we compared clinical outcomes between patients with FXa-I and VKA related ICH treated with PCC between 2014 and 2018. Primary outcome was effective hemostasis after 24 h, according to the International Society of Thrombosis and Hemostasis definition. Safety outcomes were defined as venous and arterial thromboembolic complications and death within 30 days. Thirty-six patients with FXa-I-ICH and 39 patients with VKA-ICH were available for analysis. Baseline characteristics were comparable between both groups, except for time from start of symptoms to presentation at the hospital. In the FXa-I-ICH cohort, 24 (73%) patients achieved effective hemostasis compared to 23 (62%) patients in the VKA-ICH cohort (crude odds ratio [OR] 1.62 [95%CI 0.59-4.48], adjusted OR 1.45 [95%CI 0.44-4.83]). Eight (24%) patients with FXa-I-ICH deceased compared to 17 (45%) patients with VKA-ICH (crude OR 0.38 [95%CI 0.14-1.24], adjusted OR 0.41 [95%CI 0.12-1.24]). In this observational cohort study, the outcome of ICH managed with PCC was similar in patients with FXa-I-ICH and in patients with VKA-ICH., (Copyright © 2020 The Authors. Published by Elsevier Ltd.. All rights reserved.)

Background: Venous thromboembolism (VTE) is a frequent complication in critically ill patients with coronavirus disease 2019 (COVID-19) and is associated with mortality. Early diagnosis and treatment of VTE is warranted., Objective: To develop a prediction model for VTE in critically ill COVID-19 patients., Patients and Methods: In this retrospective cohort study, 127 adult patients with confirmed COVID-19 infection admitted to the intensive care unit of two teaching hospitals were included. VTE was diagnosed with either ultrasound or computed tomography scan. Univariate receiver operating characteristic (ROC) curves were constructed for Positive End Expiratory Pressure, PaO 2 /FiO 2 ratio, platelet count, international normalized ratio, activated partial thromboplastin time as well as levels of fibrinogen, antithrombin, D-dimer and C-reactive protein (CRP). Multivariate analysis was done using binary linear regression., Results: Variables associated with VTE in both univariate and multivariate analysis were D-dimer and CRP with an area under the curve (AUC) of 0.64, P = 0.023 and 0.75, P = 0.045, respectively. Variables indicating hypoxemia were not predictive. The ROC curve of D-dimer and CRP combined had an AUC of 0.83, P < 0.05. Categorized values of D-dimer and CRP were used to compute a mean absolute risk for the combination of these variables with a high positive predictive value. The predicted probability of VTE with a D-dimer > 15 in combination with a CRP > 280 was 98%. The negative predictive value of D-dimer was low., Conclusion: Elevated CRP and D-dimer have a high positive predictive value for VTE in critically ill COVID-19 patients. We developed a prediction table with these biomarkers that can aid clinicians in the timing of imaging in patients with suspected VTE., (Copyright © 2020 The Authors. Published by Elsevier Ltd.. All rights reserved.)

Background: Studies have shown the safety of home treatment of patients with pulmonary embolism (PE) at low risk of adverse events. Management studies focusing on home treatment have suggested that 30% to 55% of acute PE patients could be treated at home, based on the HESTIA criteria, but data from day-to-day clinical practice are largely unavailable., Aim: To determine current practice patterns of home treatment of acute PE in the Netherlands., Method: We performed a post-hoc analysis of the YEARS study. The main outcomes were the proportion of patients who were discharged <24 h and reasons for admission if treated in hospital. Further, we compared the 3-month incidence of PE-related unscheduled readmissions between patients treated at home and in hospital., Results: Of the 404 outpatients with PE included in this post-hoc analysis of the YEARS study, 184 (46%) were treated at home. The median duration of admission of the hospitalized patients was 3.0 days. The rate of PE-related readmissions of patients treated at home was 9.7% versus 8.6% for hospitalized patients (crude hazard ratio 1.1 (95% CI 0.57-2.1)). The 3-month incidence of any adverse event was 3.8% in those treated at home (2 recurrent VTE, 3 major bleedings and two deaths) compared to 10% in the hospitalized patients (3 recurrent VTE, 6 major bleedings and fourteen deaths)., Conclusions: In the YEARS study, 46% of patients with PE were treated at home with low incidence of adverse events. PE-related readmission rates were not different between patients treated at home or in hospital., Competing Interests: Disclosures Frederikus Klok reports research grants from Bayer, Bristol-Myers Squibb, Boehringer-Ingelheim, Daiichi-Sankyo, MSD and Actelion, the Dutch Heart foundation and the Netherlands Thrombosis Foundation, outside the submitted work. Menno Huisman reports grants from ZonMW Dutch Healthcare Fund, grants and personal fees from Boehringer Ingelheim, grants and personal fees from Pfizer-BMS, grants and personal fees from Bayer Health Care, grants from Aspen, grants and personal fees from Daiichi-Sankyo, outside the submitted work. Marieke Kruip reports research grants from ZonMW Dutch Healthcare Fund, Bayer, Boehringer-Ingelheim, Daiichi-Sankyo, Pfizer and personal fees from Bayer, outside the submitted work. Dr. Middeldorp reports grants and personal fees from Aspen, grants and personal fees from Daiichi Sankyo, grants and personal fees from Bayer, personal fees from BMS-Pfizer, personal fees from Boehringer-Ingelheim, personal fees from Portola, personal fees from Sanofi, outside the submitted work. All other authors have no disclosures., (Copyright © 2020 The Authors. Published by Elsevier Ltd.. All rights reserved.)

Investigator-initiated studies are invaluable, especially in fields that are not particularly of interest for the pharmaceutical industry because they are either less profitable or concern special patient groups such as pregnant women. However, designing, conducting, and completing an investigator-initiated randomised controlled trial is challenging. Patients and physicians' preferences, ethics requirements, (international) legislation and funding are all areas where such challenges are encountered. The Anticoagulants for LIving FEtuses (ALIFE)2 study (NTR3361) is an example of an investigator initiated international multicenter trial that progresses slowly, at least initially, as many challenges had to be overcome. Here, we discuss the challenges we faced during the course of the ALIFE2 study up till now and we explain how some of these challenges can be tackled or even avoided., (Copyright © 2020 The Authors. Published by Elsevier Ltd.. All rights reserved.)

Background: Evidence for guideline recommendations for the treatment of venous thromboembolism (VTE) during anticoagulant therapy is scarce. We aimed to observe and to describe the management of VTE occurring during anticoagulant therapy., Methods: This prospective multi-center, observational study included patients with objectively confirmed VTE during anticoagulant therapy (breakthrough event), with a follow-up of 3 months, after the breakthrough event., Results: We registered 121 patients with a breakthrough event, with a mean age of 56 years (range, 19 to 90); 61 were male (50%). Fifty-eight patients (48%) had an active malignancy. At the time of the breakthrough event, 57 patients (47%) were treated with a vitamin K antagonist (VKA), 53 patients (44%) with low-molecular-weight heparin (LMWH) and 11 patients (9%) with direct oral anticoagulants, unfractionated heparin, or VKA plus LMWH. A total of 21 patients (17%) were receiving a subtherapeutic dose of an anticoagulant. The main regimens to treat recurrence in patients on VKA were: switch to LMWH (33%), temporary double treatment with LMWH and VKA (23%), and VKA with a higher target INR (19%). In patients with a breakthrough on LMWH, the most frequently chosen regimen was a permanent dose increase (74%). During 3-month follow-up, 7% of patients had a second breakthrough event and 8% experienced major or clinically relevant non-major bleeding., Conclusion: There is wide variation in the management of VTE during anticoagulant treatment, reflecting a heterogeneous and complex clinical situation. Despite intensifying anticoagulation, the risk of a second breakthrough event in this population is 7%., (Copyright © 2020 The Authors. Published by Elsevier Ltd.. All rights reserved.)

Background: The safety and efficacy of edoxaban and dalteparin is unclear for several cancer groups., Methods: We evaluated the occurrence of the primary outcome in large cancer groups. The primary outcome was the composite of recurrent VTE or major bleeding over 12 months., Results: In patients with gastrointestinal cancer, the primary outcome occurred in 19.4% patients given edoxaban and in 15.0% given dalteparin (risk difference [RD], 4.4%; 95%-CI, -4.1% to 12.8%). The corresponding rates for edoxaban and dalteparin were 10.4% and 10.7% for lung cancer (RD, -0.3%; 95%-CI, -10.0% to 9.5%), 13.6% and 12.5% for urogenital cancer (RD, 1.1; 95%-CI, -10.1-12.4), 3.1% and 11.7% for breast cancer (RD, -8.6; 95%-CI, -19.3-2.2), 8.9% and 10.9% for hematological malignancies (RD, -2.0; 95%-CI, -13.1-9.1), and 10.4% and 17.4% for gynecological cancer (RD, -7.0; 95%-CI, -19.8-5.7). In the subgroup of gastrointestinal cancer, edoxaban was associated with a 3.5% lower absolute risk of recurrent VTE and a 7.9% higher risk of major bleeding., Conclusion: Edoxaban has a similar risk-benefit ratio to dalteparin in most cancer groups. In those with gastrointestinal cancer, the lower risk of recurrent VTE and the advantages of oral therapy need to be balanced against the increased risk of major bleeding., (Copyright © 2019. Published by Elsevier Ltd.)

Background and Aims: Women present with pulmonary embolism (PE) more often than men, while the opposite is true for proximal deep vein thrombosis (DVT). We investigated whether sex-specific differences exist in the presenting location of acute symptomatic DVT among patients without concomitant PE., Methods: We tested our hypothesis in a meta-analysis of studies selected by systematically reviewing PubMed, Embase, and the grey literature. Thereafter, we analysed data of a single-center cohort including patients with first isolated acute DVT to assess the additional impact of age and provoking risk factors on the presenting location of DVT., Results: We identified 7 studies for a total of 20,534 patients. The weighed pooled absolute difference in the proportion of distal DVT between women and men was +5.4% (95%CI: +0.7%; +9.5%), which corresponds to a pooled odds ratio (OR) of 1.30 (95%CI: 1.07-1.58). This difference was +6.5% (95%CI: +2.1%; +10.9%) for first distal DVT (OR 1.38; 95%CI: 1.11-1.72) and +5.3% (95%CI: +0.5%; +10.0%) for either first or recurrent distal DVT (OR 1.29; 95%CI: 1.03-1.61). In the cohort study, the larger difference in the proportion of distal DVT between women and men was observed among patients aged 51-70 (+9.5%; 95CI: +2.8%; +16.0% compared to those aged 18-50) or with unprovoked events (+8.5%; 95CI: -0.9%; +17.9%)., Conclusions: Among patients with first symptomatic isolated acute DVT, women presented with distal DVT more often than men, whereas men had a higher proportion of proximal DVT events. This pattern appeared to depend on age and the absence of provoking risk factors for VTE., (Copyright © 2018 Elsevier Ltd. All rights reserved.)

Introduction: For treatment of deep vein thrombosis (DVT) and pulmonary embolism (PE), rivaroxaban is given in fixed doses without routine coagulation monitoring., Patients and Methods: To determine whether monitoring would enhance its benefit-risk profile, we examined whether peak and trough prothrombin time (PT) values measured in 3797 rivaroxaban-treated patients included in the EINSTEIN DVT and PE studies correlated with subsequent recurrent VTE and major bleeding. In addition, we examined the stability of PT values over time and the impact of clinical variables on PT values., Results: The mean peak PT values at months 3 and 6 or 12 were 21.9 ± 5 and 21.7 ± 6.0 s, respectively, while the mean trough PT values at months 2 and 6 were 15.1 ± 5.1 and 15.3 ± 2.9 s, respectively. Although peak and through PT values were higher in females, and with older age, frailty, active cancer, low body weight, impaired renal function and use of moderate to strong inhibitors of CYP3A4 and/or P-glycoprotein, and were lower in patients taking strong CYP 3A4 inducers, the differences were small and results were overlapping. Neither peak nor trough PT values correlated with recurrent VTE or major bleeding., Conclusions: PT monitoring is unlikely to improve the benefit-risk profile of rivaroxaban in patients with DVT or PE. The study was registered at www.clinicaltrials.gov as #NCT00440193 (EINSTEIN-DVT) and #NCT00439777 (EINSTEIN-PE)., (Copyright © 2018 Elsevier Ltd. All rights reserved.)

Venous thromboembolism (VTE) represents a major global burden of disease and requires collaborative efforts to conduct large, high-quality investigator-initiated and academically sponsored studies addressing the most relevant clinical questions. Owing to increasing regulatory requirements, the highly competitive nature of peer-reviewed funding and costs associated with conducting large, multinational clinical trials, completing practice-changing research constitutes a growing challenge for clinical investigators. As clinical trialists interested in VTE, we founded INVENT (International Network of Venous Thromboembolism Clinical Research Networks) in an effort to promote and accelerate patient-oriented, investigator-initiated, international collaborative research, to identify, prioritize and answer key clinical research questions for patients with VTE. We report on our activities to formalize the INVENT network and our accomplishments in our first year., (Copyright © 2018 Elsevier Ltd. All rights reserved.)

Background and Aims: Patients on parenteral nutrition for short bowel syndrome (SBS) have a high risk of thrombotic complications and are often treated with parenteral anticoagulation. Direct oral anticoagulants are absorbed proximally in the digestive tract and may represent alternative regimens in selected SBS patients. In our pilot study, we provided pharmacokinetics parameters of dabigatran etexilate and rivaroxaban in this setting and compared peak (Cmax), trough (Ctrough) concentrations, and areas-under-the-concentration-time-curve (AUC 0-t ) to reference values retrieved from phase I-III studies., Methods: We enrolled 6 adults with a remaining small bowel length≤200cm, normal renal/hepatic function, and intact stomach. In our crossover study, patients were exposed to twice-daily dabigatran etexilate 150mg and once-daily rivaroxaban 20mg., Results: After 5days of dabigatran dosing, Ctrough and Cmax geometric means were 39μg/L (90% CI: 23-66) and 88μg/L (90% CI: 56-137), respectively; AUC 0-12h was 958μg∗h/L (90% CI: 635-1445). After 5days of rivaroxaban dosing, Ctrough and Cmax geometric means were 9μg/L (90% CI: 1-71) and 167μg/L (90% CI: 102-276), respectively; AUC 0-24h was 1720μg∗h/L (90% CI: 899-3300). Absorption was negligible in one patient with ultra-short (~15cm) bowel. For dabigatran, Cmax ratio was 0.57 (SD 0.33) and Ctrough ratio was 0.35 (SD 0.44). For rivaroxaban, the mean observed-to-reference ratios AUC 0-24h and Cmax ratios were 0.73 (SD 0.32) and 0.76 (SD 0.34), respectively., Conclusions: While in SBS patients there is some absorption of the oral anticoagulants dabigatran etexilate and rivaroxaban, it appears to be lower than reference values. Plasma drug levels showed significant inter-individual variability., (Copyright © 2017 Elsevier Ltd. All rights reserved.)

Introduction: The optimal management of oral contraception and menstrual bleeding during treatment of venous thromboembolism (VTE) is largely unknown. We aimed to elicit expert opinion and compare that to current practice as assessed by a world-wide international web-based survey among physicians., Methods: 10 international thrombosis experts and 10 abnormal uterine bleeding experts independently completed a questionnaire containing three hypothetical patient cases each with four different scenarios, and additional queries covering different severities of VTE, patient circumstances, hormonal contraceptives and both thrombotic and bleeding complications. The consensus percentage was set a priori at ≥70%. The same questionnaire with randomized case scenarios was presented to international physicians via newsletters of the ISTH and national scientific communities. Differences between the expert groups and daily clinical care were assessed., Results: Expert recommendations were divergent and differed in several important points from clinical practice. In contrast to common practice in which contraceptives are discontinued at the moment of a VTE diagnosis, the thrombosis experts agreed to continue oral contraception (OC) during the anticoagulation treatment period. Also, experts reached consensus on treating patients with anticoagulation-associated abnormal uterine bleeding with tranexamic acid, although this is not supported by strong evidence from the literature. No consensus was reached on the optimal anticoagulant drug class., Conclusions: International experts' opinions on handling of contraceptives and management of anticoagulant-associated abnormal uterine bleeding in female VTE patients are divergent and management in clinical practice is heterogeneous. There is a great need of further studies on these topics., (Copyright © 2017 Elsevier Ltd. All rights reserved.)

Background: The results of the EINSTEIN-DVT/PE and AMPLIFY trials, which compared rivaroxaban and apixaban with conventional anticoagulation therapy for acute venous thromboembolism (VTE), respectively, are often compared. However, the trials differed in duration of therapy (3-12 and 6months, respectively) and in patient selection (few exclusion criteria and more stringent exclusion criteria, respectively)., Methods: To determine the effect of these methodological differences on outcomes, the patients enrolled in EINSTEIN-DVT/PE were divided into 2 cohorts; the 5253 patients that matched the exclusion criteria for AMPLIFY and were treated for at least 6months (cohort 1) and the 2368 patients who would have been ineligible for AMPLIFY (cohort 2)., Results: Compared with patients in cohort 2, those in cohort 1 were older and more often male and there were more with unprovoked VTE, prior VTE, cancer and known thrombophilia. In cohort 1, rivaroxaban would have significantly reduced recurrent VTE (relative risk [RR], 0.64; 95% confidence interval [CI], 0.43-0.95) and major bleeding (RR, 0.50; 95% CI, 0.30-0.82) compared with conventional therapy, whereas the two treatments would have had similar effects on recurrent VTE (RR, 1.08; 95% CI, 0.65-1.79) and major bleeding (RR, 1.03; 95% CI, 0.48-2.18) in cohort 2., Conclusions: This analysis illustrates the influence of patient selection and treatments duration on outcome results and highlights the limitations of cross-trial comparisons., (Copyright © 2016 Elsevier Ltd. All rights reserved.)

Background: Women with a history of venous thromboembolism (VTE) have a 2% to 10% absolute risk of VTE recurrence during subsequent pregnancies. Therefore, current guidelines recommend that all pregnant women with a history of VTE receive pharmacologic thromboprophylaxis. The optimal dose of low-molecular-weight heparin (LMWH) for thromboprophylaxis is unknown. In the Highlow study (NCT 01828697; www.highlowstudy.org), we compare a fixed low dose of LMWH with an intermediate dose of LMWH for the prevention of pregnancy-associated recurrent VTE. We present the rationale and design features of this study., Methods: The Highlow study is an investigator-initiated, multicentre, international, open-label, randomised trial. Pregnant women with a history of VTE and an indication for ante- and postpartum pharmacologic thromboprophylaxis are included before 14weeks of gestation. The primary efficacy outcome is symptomatic recurrent VTE during pregnancy and 6weeks postpartum. The primary safety outcomes are clinically relevant bleeding, blood transfusions before 6weeks postpartum and mortality. Patients are closely monitored to detect cutaneous reactions to LMWH and are followed for 3months after delivery. A central independent adjudication committee adjudicates all suspected outcome events., Conclusion: The Highlow study is the first large randomised controlled trial in pregnancy that will provide high-quality evidence on the optimal dose of LWMH thromboprophylaxis for the prevention of recurrent VTE in pregnant women with a history of VTE., (Copyright © 2016 Elsevier Ltd. All rights reserved.)

Introduction: Rivaroxaban is a convenient oral anticoagulant for patients with venous thromboembolism (VTE). The impact of rivaroxaban and vitamin K antagonists (VKAs) on abnormal uterine bleeding (AUB) in real life has not been previously explored., Materials and Methods: We performed a single-center retrospective study on AUB in female VTE patients of reproductive age who were treated with either rivaroxaban or VKAs., Results: Questionnaire results were available for 52 patients in each treatment group. Approximately two thirds of all women reported AUB after initiation of anticoagulant therapy. Patients using rivaroxaban were more likely to experience prolonged (>8days) menstrual bleeding (27 % vs. 8.3%, P=0.017). Rivaroxaban treatment increased the duration of menstrual bleeding from median 5 (IQR 3.5-6.0) days before start of treatment to 6 (IQR 4.1-8.9) days (P<0.001). VKA treatment did not lead to significant prolongation of the menstrual period. Patients on rivaroxaban more frequently reported an unscheduled contact with a physician for AUB than women using VKAs (41% vs. 25%, P=0.096). They also reported increased need for menorrhagia-related medical or surgical intervention (25% vs. 7.7%, P=0.032) and had more adaptations of anticoagulant therapy (15% vs. 1.9%, P=0.031)., Conclusion: AUB is frequent after initiation of anticoagulant therapy for acute symptomatic VTE. Compared to VKAs, rivaroxaban was associated with prolonged menstrual bleeding and more medical interventions and adaptation of anticoagulant treatment for AUB. These data can guide proactive discussion with patients starting anticoagulant therapy., (Copyright © 2015 Elsevier Ltd. All rights reserved.)

Several aspects of the diagnostic and therapeutic management of women with venous thrombosis are uncertain, because of the absence of adequately sized observational or intervention studies. Here, I will discuss the rationale and design of two currently ongoing investigator-initiated, international, randomized controlled trials of LMWHin pregnancy. The Highlow study (www.highlowstudy.org; NCT Clinicaltrials.gov) 01828697) investigates two doses of low-molecular-weight heparin to prevent recurrent venous thromboembolism (VTE) in pregnant women with a history of VTE. The ALIFE2 study (www.alife2study.org; www.trialregister.nl, NTR 3361) investigates the effect of LMWH on live birth in women with inherited thrombophilia and two or more miscarriages., (© 2015 Elsevier Ltd. All rights reserved.)

Introduction: Although quality of life (QoL) is recognized as an important indicator of the course of a disease, it has rarely been addressed in studies evaluating the outcome of care for patients with pulmonary embolism (PE). This study primarily aimed to evaluate the QoL of patients with acute PE in comparison to population norms and to patients with other cardiopulmonary diseases, using a generic QoL questionnaire. Secondary, the impact of time period from diagnosis and clinical patient characteristics on QoL was assessed, using a disease-specific questionnaire., Methods: QoL was assessed in 109 consecutive out-patients with a history of objectively confirmed acute PE (mean age 60.4 ± 15.0 years, 56 females), using the generic Short Form-36 (SF-36) and the disease specific Pulmonary Embolism Quality of Life questionnaire (PEmb-QoL). The score of the SF-36 were compared with scores of the general Dutch population and reference populations with chronic obstructive pulmonary disease (COPD), congestive heart failure (CHF), a history of acute myocardial infarction (AMI), derived from the literature. Scores on the SF-35 and PEmb-QoL were used to evaluate QoL in the short-term and long-term clinical course of patients with acute PE. In addition, we examined correlations between PEmb-QoL scores and clinical patient characteristics., Results: Compared to scores of the general Dutch population, scores of PE patients were worse on several subscales of the SF-36 (social functioning, role emotional, general health (P<0.001), role physical and vitality (P<0.05)). Compared to patients with COPD and CHF, patients with PE scored higher (=better) on all subscales of the SF-36 (P ≤ 0.004) and had scores comparable with patients with AMI the previous year. Comparing intermediately assessed QoL with QoL assessed in long-term follow-up, PE patients scored worse on SF-36 subscales: physical functioning, social functioning, vitality (P<0.05), and on the PEmb-QoL subscales: emotional complaints and limitations in ADL (P ≤ 0.03). Clinical characteristics did not correlate with QoL as measured by PEmb-QoL., Conclusion: Our study demonstrated an impaired QoL in patients after treatment of PE. The results of this study provided more knowledge about QoL in patients treated for PE., (Copyright © 2013 Elsevier Ltd. All rights reserved.)

Venous thromboembolism (VTE) is a leading cause of maternal mortality and morbidity during pregnancy in developed countries. The incidence of VTE per pregnancy-year increases about 4-fold during pregnancy and at least 14-fold during the puerperium. Risk factors include a personal history of VTE, presence of inherited or acquired thrombophilia, a family history of VTE and general medical conditions, such as immobilisation, overweight, varicose veins, some haematological diseases and inflammatory disorders. VTE is considered potentially preventable with the prophylactic administration of anticoagulants, but there are no high quality randomized clinical trials that compared different strategies of thromboprophylaxis in pregnant women. Balancing the absolute risk of VTE against the risks of exposure to anticoagulants, this review provides advice regarding which women may benefit from thromboprophylaxis during and after pregnancy., (Copyright © 2012 Elsevier Ltd. All rights reserved.)

Introduction: Whether high factor (F)VIII and low free protein S levels are risk factors for arterial thrombosis is unclarified., Material and Methods: In a post-hoc analysis of a single-centre retrospective family cohort, we determined if these two proteins could increase the risk of arterial thrombosis. In total, 1399 relatives were analysed., Results: Annual incidence in relatives with high FVIII levels was 0.29% (95%CI, 0.22-0.38) compared to 0.13% (95%CI, 0.09-0.19) in relatives with normal FVIII levels. In relatives with low free protein S levels, this risk was 0.26% (95%CI, 0.16-0.40), compared to 0.14% (95%CI, 0.10-0.20) in relatives with normal free protein S levels. Mean FVIII levels adjusted for age and sex were 11 IU/dL, 18 IU/dL, and 21 IU/dL higher in relatives with hypertension, diabetes mellitus, and obesity as compared to relatives without these arterial thrombotic risk factors. Moreover, a dose response relation between increasing FVIII and body mass index was found. None of these associations were shown for free protein S., Conclusions: High FVIII and low free protein S levels seemed to be mild risk factors for arterial thrombosis. High FVIII levels were particularly observed in relatives with traditional arterial thrombotic risk factors. Free protein S levels were not influenced by these thrombotic risk factors. This assumes that low free protein S levels were genetically determined., (Copyright © 2010 Elsevier Ltd. All rights reserved.)

Anticoagulant therapy with heparin has been the cornerstone of treatment and prevention of thrombosis for many decades. The properties and indications of heparin, as well as the development of its derivates, the low-molecular-weight heparins, and ultimately the synthetically designed pentasaccharides, are reviewed from a clinical perspective. Unfractionated heparin is a heterogeneous mixture of polysaccharides and glycosaminoglycuronsulfate which for commercial preparations is generally extracted from bovine and sheep lungs and porcine intestinal mucosa. Low-molecular-weight heparins are fragments of unfractionated heparin produced by controlled enzymatic or chemical depolymerization processes with the main difference being in their relative inhibitory activity against factor Xa and thrombin. Pentasaccharides are synthetic drugs that accelerate the interaction between factor Xa and antithrombin but selectively inhibit factor Xa activity. Many clinical studies in the prevention and treatment of venous thromboembolism in several patient groups, as well as for arterial indications have been performed over the last decades. Low-molecular-weight heparins have proved to be more efficacious and safer than unfractionated heparin. Phase 3 trials have demonstrated similar or superior efficacy combined with superior safety for the short-acting pentasaccharide fondaparinux, as compared to low-molecular-weight heparin. Results of phase 3 trials of the long-acting pentasaccharide idraparinux which is being compared to vitamin K antagonists for long-term treatment are much awaited.

To explore social aspects of asymptomatic carriership of factor V Leiden mutation (FVL) and how carriers have experienced procedure of screening for FVL, we have performed a qualitative study using semi-structured interviews. Seventeen carriers of FVL without history of venous thromboembolism (VTE) were interviewed. Carriership of FVL has the potential to influence daily life by inducing concerns, stigmatisation and problems with insurances. Furthermore, proper procedure of screening is important because carriers have many questions concerning progeny, risk factors for VTE and preventive measures. Both health worker and the individual to be screened for FVL need to be fully aware of the possible consequences of screening and the fact that proper screening comprises more than only the collection of a blood sample or explaining the amount of risk for VTE induced by a genetic defect. Any guideline to be developed for the screening for FVL should take this into account too.