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BACKGROUND: Deep vein thrombosis (DVT) is a multifactorial disease with several outcomes, but current classifications solely stratify based on recurrence risk.OBJECTIVES: We aimed to identify DVT phenotypes and assess their relation to recurrent venous thromboembolism (VTE), post-thrombotic syndrome, arterial events, and cancer.PATIENTS/METHODS: Hierarchical clustering was performed on a DVT cohort with up to five years follow-up using 23 baseline characteristics. Phenotypes were summarized by discriminative characteristics. Hazard ratios (HR) were calculated using Cox regression; recurrence risk was adjusted for 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 four phenotypes: 1.women using estrogen therapy (n=112); 2.patients with a cardiovascular risk profile (n=268); 3.patients with previous VTE (n=128); 4.patients without discriminant characteristics (n=317). Overall, risks of recurrence, post-thrombotic 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 four distinct phenotypes among DVT patients that are not only associated with increasing recurrence risk, but also with outcomes beyond recurrence. Our results thereby highlight the limitations of current risk stratifications that stratify based on predictors of 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.

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

Item does not contain fulltext The results of this study suggest that CTEPH is not a more common long-term complication after COVID-19-associated PE than after PE in non-COVID-19 patients, and thrombus resolution did not seem to be different from non-COVID-19-associated PE https://bit.ly/3IjvWL3 01 april 2023

Post‑thrombotic 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 leukocyte‑endothelial 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.

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

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.

BACKGROUND: Postthrombotic syndrome (PTS) is a long-term complication after deep vein thrombosis (DVT) and can affect quality of life (QoL). Pathogenesis is not fully understood but inadequate anticoagulant therapy with vitamin K antagonists is a known risk factor for the development of PTS. OBJECTIVES: To compare the prevalence of PTS after acute DVT and the long-term QoL following DVT between patients treated with edoxaban or warfarin. METHODS: We performed a long-term follow-up study in a subset of patients with DVT who participated in the Hokusai-VTE trial between 2010 and 2012 (NCT00986154). Primary outcome was the prevalence of PTS, defined by the Villalta score. The secondary outcome was QoL, assessed by validated disease-specific (VEINES-QOL) and generic health-related (SF-36) questionnaires. RESULTS: Between 2017 and 2020, 316 patients were enrolled in 26 centers in eight countries, of which 168 (53%) patients had been assigned to edoxaban and 148 (47%) to warfarin during the Hokusai-VTE trial. Clinical, demographic, and thrombus-specific characteristics were comparable for both groups. Mean (SD) time since randomization in the Hokusai-VTE trial was 7.0 (1.0) years. PTS was diagnosed in 85 (51%) patients treated with edoxaban and 62 (42%) patients treated with warfarin (adjusted odds ratio 1.6, 95% CI 1.0-2.6). Mean differences in QoL scores between treatment groups were not clinically relevant. CONCLUSION: Contrary to our hypothesis, the prevalence of PTS tended to be higher in patients treated with edoxaban compared with warfarin. No differences in QoL were observed. Further research is warranted to unravel the role of anticoagulant therapy on development of PTS. ispartof: RESEARCH AND PRACTICE IN THROMBOSIS AND HAEMOSTASIS vol:6 issue:5 ispartof: location:United States status: published

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).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.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 to90% restored patency differed significantly between groups (p0.0001): 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).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.• 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.

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.

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 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.

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.

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.

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 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.

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.

Introduction Over the last years venous stent placement after deep venous thrombosis (DVT) in the iliofemoral veins has gained more attention. The majority of studies evaluating the safety and efficacy of this intervention are of poor methodological quality and the association with antithrombotic therapy has not been studied explicitly. We performed a systematic review to summarize the available literature on antithrombotic management in relation to the safety and efficacy of venous stenting. Methods We performed a Medline search to identify studies that addressed anticoagulation and/or antiplatelet treatment options after venous stenting in patients with a prior DVT in the iliofemoral area. We identified 192 articles and finally selected 14 articles for use in this review. Results In 86% (12/14) of the included studies anticoagulation was administered to all patients who underwent iliac venous stenting. In 33% of the studies patients received antiplatelet therapy consisting of aspirin and/or clopidogrel (4/12). The duration of antithrombotic treatment was not guided by the stenting procedure in 93% (13/14) of studies. The incidence of re-thrombosis in (sub) groups of only stented patients, ranged from 5% to 25%. Primary, assisted primary, and secondary patency rates 12 months after stent placement ranged from 54%, 72%, 83% respectively to 78%, 83%, 95% in (sub)groups of only stented patients. Rates of major bleedings during long term follow-up ranged from 0% to11%. Conclusion Antithrombotic therapy does not seem to influence any of the outcomes in patients with venous stenting after DVT: recurrent DVT, patency, post-thrombotic syndrome or restenosis and bleeding.

BackgroundDirect oral anticoagulants (DOACs) are administered in fixed doses without monitoring. There is still little published data on the impact of the absence of monitoring on adherence to medication and stability of DOAC plasma levels over time.ObjectivesTo explore adherence and stability of DOAC plasma levels over time in patients with atrial fibrillation (NVAF) recently started on DOAC therapy.Patients and methodsA prospective observational cohort study with structured follow up including assessment of adherence to medication, plasma levels at baseline, 3,6 and 12 months and adverse events.ResultsWe included 164 patients; 89% were previous users of a vitamin K antagonist (VKA). Oneyear adherence was reasonably good: Morisky adherence measurement scores of 6-8 in 92%. The majority of DOAC plasma levels were within reported on-therapy ranges; dabigatran (median 104.4 ng/ml, IQR 110.2), rivaroxaban (median 185.2 ng/ml, IQR 216.1) and on average levels were not different for full and adjusted doses. There was significant variation between patients, but no significant differences over time within individuals. A substantial proportion of patients starting in the upper-or lower 20th percentiles remained there during the entire follow up. Seventeen bleedings (16 minor, 1 major) were reported, no ischemic events and bleeding or thrombotic events were not associated with DOAC plasma levels.ConclusionsAdherence was reasonably good in the majority of patients. Our data confirm the stability of DOAC plasma levels over time. Knowledge of such data may, in the individual patient, contribute to optimal drug and dose selection.

Background: Surgical interventions in patients on long term vitamin K antagonist (VKA) treatment create a dilemma; periprocedural interruption of anticoagulation raises the risk of thrombosis, while continuation raises the risk of bleeding. The anticoagulation- free interval is minimized by “bridging” with parenteral anticoagulants. The efficacy and safety of bridging with low molecular weight heparins (LMWH) has however not been unequivocally established. Methods: We performed an EMBASE and MEDLINE search for studies that compared bridging anticoagulation with continuation or cessation of VKA without bridging; with thromboembolism (TE) and bleeding as outcomes. We identified 878 articles and finally selected 17. Results of individual studies were pooled. Results: None of the included studies reported significant differences in incidence of TEs between the bridging group and the comparator group; 4 out of 13 studies reported zero TEs. Heparin was identified as a risk factor for bleeding in multivariable adjusted analyses in 3 studies on pacemaker/implantable cardioverter defibrillator (PM/ICD) surgery. In 5 studies (different types of surgery) with unadjusted analyses, bridging was compared to warfarin cessation: 3 studies reported null results for bleeding; 2 studies identified bridging as a risk factor. We pooled a subset of 6 studies regarding postoperative bleeding after PM/ICD surgery and found a relative risk (RR) of 3.03 (95&#37 confidence interval (CI), 1.86-4.95) for bridging compared to continuation of VKA. Conclusions: While the antithrombotic efficacy of bridging with LMWH has not been demonstrated, increased bleeding risk is observed in different types of surgery. PM/ICD surgery can be safely performed on continued VKA.

Geersing G-J, Zuithoff P, Kearon C, Anderson D, Ten Cate-Hoek A, Elf J, et al. Uitsluiten van DVT met een klinische beslisregel. Huisarts Wet 2014;57(12):626-8. Huisartsen zien geregeld patienten die mogelijk een trombosebeen hebben. De symptomen van een trombosebeen zijn vaak weinig specifiek. Een groot deel van de patienten bij wie de huisarts aan trombose denkt heeft geen trombosebeen. Om die reden zijn er beslisregels ontwikkeld, die in combinatie met een D-dimeertest, bij een groot deel van de patienten een trombose kunnen uitsluiten. De veiligheid van deze strategie is bewezen voor de meeste patienten, maar er blijft onduidelijkheid bestaan over de veiligheid ervan in bijzondere patientengroepen. Daarom hebben we individuele patientengegevens uit 13 onderzoeken (n = 10.002) gecombineerd en de veiligheid van een beslisregel (in dit geval de Wells-beslisregel) en een D-dimeertest onderzocht om een trombosebeen uit te sluiten bij bijzondere patientengroepen. Ons onderzoek laat zien dat de huisarts bij de meeste patienten veilig en efficient een trombosebeen kan uitsluiten: in 29% van de gevallen (95%-BI 20 tot 40) scoort de patient laag op de beslisregel en is de D-dimeertest ook negatief; de kans op trombose is dan nog slechts 1,2% (95%-BI 0,7 tot 1,8). Bij patienten bij wie tijdens een oncologische behandeling het vermoeden bestaat dat ze een trombosebeen hebben komt deze combinatie van een lage score op de beslisregel en een negatieve D-dimeertest slechts voor in 9% van de gevallen. Ook is de kans op trombose in die groep bijna twee keer zo groot (2,2%). Voor patienten die eerder een trombose hebben doorgemaakt en bij wie sprake kan zijn van een recidief moet een punt worden opgeteld op de Wells-beslisregel om veilig een trombosebeen te kunnen uitsluiten. De huisarts kan met een beslisregel en een D-dimeertest veilig een trombosebeen uitsluiten. Alleen is extra aandacht nodig bij oncologische patienten met een verdenking op een trombosebeen en bij patienten die eerder een trombosebeen hebben doorgemaakt. De Wells-beslisregel is in die gevallen respectievelijk minder efficient en minder veilig.

Buller HR, Ten Cate-Hoek AJ, Hoes AW, Joore MA, Moons KGM, Oudega R, Prins MH, Stoffers HEJH, Toll DB, Van der Velde E-F, Van Weert HCPM. De huisarts kan zelf diepe veneuze trombose veilig uitsluiten. Huisarts Wet 2009;52(10):497-502. Achtergrond Tot 90% van de patienten die de huisarts instuurt voor compressie-echografie onder verdenking van diepe veneuze trombose (DVT) blijkt die aandoening niet te hebben. In het AMUSE-1-onderzoek (Amsterdam-Maastricht-Utrecht Study on thrombo-Embolism) is onderzocht of een eenvoudige klinische beslisregel in combinatie met een D-dimeertest in staat is om een trombosebeen al in de eerste lijn op veilige en efficiente wijze uit te sluiten. Methode Driehonderd huisartsen deden mee aan het onderzoek. Patienten bij wie de beslisregel op een lage klinische verdenking wees, stuurden zij niet in voor echografie en behandelden zij niet met antistolling. Patienten die positief scoorden op de beslisregel verwezen zij voor compressie-echografie. Alle patienten volgden wij drie maanden lang om eventuele trombo-embolische complicaties te kunnen vaststellen. Resultaten Uiteindelijk leverde de beslisregel bij 1002 patienten een geldige score op. Bij 500 patienten wees de beslisregel op een lage klinische verdenking (score ≤ 3). Zeven van hen (1,4%, 95%-BI 0,6-2,9%) kregen een trombo-embolische complicatie tijdens de drie maanden follow-up. De overige 502 patienten hadden een score ≥ 4 en werden verwezen voor echografie. Het echogram wees bij 125 (25%) patienten op een DVT. Van de 374 patienten met een normale echo kregen er 4 (1,1%, 95% BI 0,3-2,7%) een trombo-embolische complicatie tijdens de follow-upperiode. Bij 3 patienten werd geen echo verricht. Discussie Ons onderzoek bevestigt dat de diagnostische strategie die de NHG-Standaard Diepe veneuze trombose aanbeveelt, in de dagelijkse praktijk verantwoord is. Een werkwijze waarbij de huisarts een eenvoudige beslisregel combineert met een D-dimeertest is veilig om DVT uit te sluiten in de eigen praktijk of bij de patient thuis. Met deze strategie kan de helft van de verwijzingen voor compressie-echografie worden voorkomen.

Management and prevention of venous thromboembolism (VTE) in cancer patients is challenging. Not only is the risk of VTE in cancer patients elevated compared to patients without malignancies, but also is standard treatment based on Vitamin K antagonists (VKAs) less effective and associated with an increased frequency of major bleeding. Therapy with Low Molecular Weight Heparin (LMWH) is less sensitive to drug interactions, not hindered by a narrow therapeutic window and needs no monitoring. LMWH therapy therefore seems more practical and may also be more effective in cancer patients. Moreover a possible survival benefit has been suggested, the underlying mechanism of which is not yet unraveled. A combination of cancer and thrombosis is a predictor of poor long-term survival. Anticoagulant drugs, especially LMWH, may be of influence on tumor progression. Hypercoagulability in cancer patients may indicate an aggressive change in the tumor and is associated with tumor progression. Hypercoagulability could on the other hand also be a risk factor for developing cancer. To assist clinicians in defining the role of LMWH in cancer patients, we categorized, summarized and critically weighed all available evidence on the subject. Based on available data derived from clinical trials recommendations on the application of heparin in oncological patients are made. However, many uncertainties remain regarding the subject of cancer related thrombosis in view of treatment and the possible effects on tumor biology by heparins.

SummaryThrombin generation measurement may be of value for assessing the risk of venous thromboembolism, but its long term profile has not been assessed in patients. We evaluated thrombin generation by Calibrated Automated Thrombogram (CAT) in plasma during follow up of 104 consecutive patients after an acute episode of deep venous thrombosis. Blood was drawn three times over the course of 24 months. Thrombin generation was measured in absence and presence of thrombomodulin and compared to a reference range derived from thrombin generation curves in 137 healthy volunteers. Thrombin generation of patients showed significantly higher endogenous thrombin potential (ETP) and peak height compared to the reference population. Differences were more pronounced in assays triggered with I pM TF. Inhibition by thrombomodulin was attenuated in patients off anticoagulants as compared to the reference population (21 % vs.42.2%, p

Background: Bridging with low molecular weight heparins (LMWH) is used in patients undergoing invasive procedures that require interruption of vitamin K antagonists (VKA). Little is known on the mechanisms underlying observed thrombotic and bleeding events. In this exploratory study we investigated the interactive effects of the co-administration of VKA, LMWH and surgery on coagulation. Materials and methods: Blood was sampled daily from day-3 to day+5 in 13 patients. In addition to measurement of INR, anti-Xa activity, thrombin generation (TG) testing and assessment of its protein determinants was performed. Results: At the time of intervention the mean INR was 1.0 (SD 0.1, range 0.9-1.2); the mean residual anti-Xa level was 0.19 units/ml (SD 0.20 units/ml, range

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.

SummaryPeripheral artery disease (PAD) is associated with an increased risk for cardiovascular events. D-dimers are a marker for hypercoagulability and are linked with thrombotic events in patients with venous as well as arterial thrombosis. The predictive value of plasma D-dimer levels in relation to cardiovascular events in patients with PAD is not unambiguously established. It was our objective to gather evidence evaluating the value of D-dimer as a predictor of arterial thrombotic events patients with PAD. The Pubmed, Embase, and Cochrane databases were searched (January 1980-November 2012), and 65 abstracts were found. The strategy was supplemented with manual review of reference lists. Case-control, cohort or prospective cohort studies that measured fibrin D-dimer in patients with PAD, were included. Studies were excluded if there was no follow-up for arterial thrombotic events or when no specific information on D-dimer was available. The search yielded 10 studies for our analysis, comprising 2,420 patients with PAD, with a total of 1,036 cardiovascular events in 10,599 patient-years. Two studies with a follow-up of one year showed that fibrin D-dimer predicts both deterioration of PAD and subsequent thrombotic events. Five out of six studies with a median follow-up of 2–4 years revealed that an increased D-dimer is predictive of various arterial thrombotic events including mortality. Two studies with a longer follow-up (over 6 years) did not show an independent association between increased D-dimer levels, arterial thrombotic events and CVD mortality. In conclusion, an increased D-dimer appeared to be independently associated with a two times increased risk of near-term cardiovascular events (relative risk 2.30, 95% confidence interval 1.43–3.68). However formal meta-analysis was only feasible for four out of 10 included studies. Due to the extended heterogeneity of the included studies cautious interpretation of these data is warranted.

Up to 90% of patients referred for ultrasonography with suspected deep venous thrombosis (DVT) of the leg do not have the disease.To evaluate the safety and efficiency of using a clinical decision rule that includes a point-of-care d-dimer assay at initial presentation in primary care to exclude DVT.A prospective management study.Approximately 300 primary care practices in 3 regions of the Netherlands (Amsterdam, Maastricht, and Utrecht).1028 consecutive patients with clinically suspected DVT.Patients were managed on the basis of the result of the clinical decision rule, which included a d-dimer result. Patients with a score of 3 or less were not referred for ultrasonography and received no anticoagulant treatment; patients with a score of 4 or more were referred for ultrasonography.The primary outcome was symptomatic, objectively confirmed, venous thromboembolism during 3-month follow-up.The mean age of the 1028 study patients was 58 years, and 37% of patients were men. A valid score was obtained in 1002 patients (98%). In 500 patients (49%), with a score of 3 or less, 7 developed venous thromboembolism within 3 months (incidence, 1.4% [95% CI, 0.6% to 2.9%]). A total of 502 patients (49%) had a score of 4 or more; 3 did not have ultrasonography. Ultrasonography showed DVT in 125 patients (25%), for an overall prevalence in evaluable patients of 13% (125 of 1002). Of the 374 patients who had normal ultrasonography results, 4 developed venous thromboembolism within 3 months (1.1% [CI, 0.3% to 2.7%]).The study lacked a randomized design and relied on clinical follow-up to detect missed thrombotic disease.A diagnostic management strategy in primary care by using a simple clinical decision rule and a point-of-care d-dimer assay reduces the need for referral to secondary care of patients with clinically suspected DVT by almost 50% and is associated with a low risk for subsequent venous thromboembolic events.The Netherlands Organization for Scientific Research.

Thrombin generation measurement may be of value for assessing the risk of venous thromboembolism, but its long term profile has not been assessed in patients. We evaluated thrombin generation by Calibrated Automated Thrombogram (CAT) in plasma during follow up of 104 consecutive patients after an acute episode of deep venous thrombosis. Blood was drawn three times over the course of 24 months. Thrombin generation was measured in absence and presence of thrombomodulin and compared to a reference range derived from thrombin generation curves in 137 healthy volunteers. Thrombin generation of patients showed significantly higher endogenous thrombin potential (ETP) and peak height compared to the reference population. Differences were more pronounced in assays triggered with 1 pM TF. Inhibition by thrombomodulin was attenuated in patients off anticoagulants as compared to the reference population (21% vs. 42.2%, p0.0001); inhibition in patients on anticoagulant treatment was less pronounced (9.7%, p0.0001). Protein C activity, protein S antigen as well as free protein S showed highly negative correlation with ETP in all patients. A significant negative relation was found between FVIII levels and thrombomodulin induced reduction of ETP and peak height. In conclusion, thrombin generation by CAT reflects changes in coagulation status in patients following a thromboembolic event and is most sensitive at CAT analysis triggered with 1 pM TF. A role for factor VIII as an important attributable cause of hypercoagulability is reflected by the reduced inhibitory effect of thrombomodulin at high factor VIII levels.

Management and prevention of venous thromboembolism (VTE) in cancer patients is challenging. Not only is the risk of VTE in cancer patients elevated compared to patients without malignancies, but also is standard treatment based on Vitamin K antagonists (VKAs) less effective and associated with an increased frequency of major bleeding. Therapy with Low Molecular Weight Heparin (LMWH) is less sensitive to drug interactions, not hindered by a narrow therapeutic window and needs no monitoring. LMWH therapy therefore seems more practical and may also be more effective in cancer patients. Moreover a possible survival benefit has been suggested, the underlying mechanism of which is not yet unraveled. A combination of cancer and thrombosis is a predictor of poor long-term survival. Anticoagulant drugs, especially LMWH, may be of influence on tumor progression. Hypercoagulability in cancer patients may indicate an aggressive change in the tumor and is associated with tumor progression. Hypercoagulability could on the other hand also be a risk factor for developing cancer. To assist clinicians in defining the role of LMWH in cancer patients, we categorized, summarized and critically weighed all available evidence on the subject. Based on available data derived from clinical trials recommendations on the application of heparin in oncological patients are made. However, many uncertainties remain regarding the subject of cancer related thrombosis in view of treatment and the possible effects on tumor biology by heparins.

Current treatment and secondary prophylaxis of venous thromboembolism has two major drawbacks. During vitamin K antagonist therapy, patients need to be monitored closely to maintain efficacy and minimize the bleeding risk due to fluctuations of the prothrombin time (international normalized ratio, INR), and after cessation of therapy there is the problem of recurrent thrombosis, ie, the catch-up phenomenon. Recent studies indicate that for most patients, vitamin K antagonist therapy aimed at an INR of 2.0 to 3.0 is optimal. For patients with thrombosis due to a temporary risk factor, extending treatment beyond 3 months is not needed, whereas for other patients a minimal duration of 1 year can be advocated. For patients with cancer, it is beneficial to postpone therapy with vitamin K antagonists and prolong initial low-molecular-weight therapy for 3 to 6 months. New developments are aimed at further individualization of the duration of treatment and at the introduction of agents that are suitable for long-term treatment and do not require monitoring.

Introduction: During the last 50 years vitamin K antagonists (VKAs) have been widely used for the primary prevention of thromboembolism in patients with atrial fibrillation, or for the secondary prevention in patients with a history of venous thromboembolism. The most prevalent adverse effect of anticoagulant therapy is an increased risk of bleeding. Annually approximately 1-4% of patients treated with VKAs suffer from major bleeding episodes. In the past several attempts have been made to predict the bleeding risk for these patients. Among the methods used at this moment are clinical decision scores, of which the HAS-BLED score is the most common one. Up to this point there are no laboratory methods available to predict patients at risk for bleeding. Thrombin generation (TG) tests have been shown to provide an intermediate phenotype for thrombosis. Additionally, TG has the capacity to detect the anticoagulant effect of many, if not all, anticoagulants, including VKAs. This method was only applicable in plasma, but recently this TG test has been introduced in whole blood (WB). With this study we aimed to investigate whether TG, in plasma or WB, could detect bleeding in patients taking VKAs. Materials & methods: Blood samples were collected in citrate tubes from 129 patients taking VKAs for over 3 months, who were older than 18 years of age and followed over time for bleeding episodes. The patients signed informed consent forms and the study was approved by the local medical ethical committee. TG was determined in WB, platelet rich plasma (PRP) and platelet poor plasma (PPP) by means of calibrated automated thrombinography (CAT). Tissue factor was used as a trigger at a final concentration of 1 pM in WB and PRP and at both 1 pM and 5 pM with 4µM phospholipids in PPP. Hematocrit and the hemoglobin concentration were determined in WB. The PPP of the patients was used to define the International normalized ratio (INR). Results: In our study the average INR value of all patients was 2.95 (± 0.92 (SD)). Twenty six patients (20.2 %) suffered from 44 clinically relevant bleeding episodes during a mean follow-up of 15.5 months. Applying TG in PPP and PRP we found no differences in either endogenous thrombin potential (ETP), an indication for the total amount of thrombin that can be converted, nor peak height (the highest amount of active thrombin present during coagulation). Interestingly, when we applied TG in whole blood, so including the blood cells, we found a significantly lower ETP (p < 0.01) and peak (p < 0.05) in the patients that suffered from bleeding (median: 182.5 nM.min and 23.9 nM, respectively) compared to patients that did not bleed (median: 256.2 nM.min and 39.1 nM). When examining the INR, hematocrit and hemoglobin levels, no significant differences were detected. A receiver operating curve (ROC) was constructed for the ETP and peak (figure 1). By determining the area under the curve (AUC) of the ROC we found that the ETP and peak are significantly (p < 0.05) associated with the tendency to bleed (ETP, AUC: 0.700; peak, AUC: 0.642). This compares favorably with the AUC reported for the HAS-BLED score related to clinically relevant bleeding in patients on VKAs (0.60). Conclusions: The TG test in whole blood was only recently developed and this is the first study implementing it to test patients using VKAs. In our study TG measured in WB proved to be the first laboratory test that is able to detect patients at risk of bleeding when treated with VKAs. The INR and plasma TG (CAT-based method), on the other hand, did not discriminate between bleeding and non-bleeding patients. For WB TG, based on the AUC of the ROC, the ETP and peak in WB have a predictive value for bleeding in patients taking VKAs superior over the currently used HAS-BLED score. Figure 1: Analysis of patients with and without bleeding symptoms. Receiver operating curves (ROC) of the ETP and peak in WB TG. Figure 1:. Analysis of patients with and without bleeding symptoms. Receiver operating curves (ROC) of the ETP and peak in WB TG. Disclosures No relevant conflicts of interest to declare.

Introduction We tested whether the recently introduced measurement of thrombin generation (TG) in whole blood can be used to evaluate the clotting status of patients on vitamin K antagonist (VKA) prophylaxis. The prothrombin time, and hence the International Normalized Ratio (INR), only evaluates the vitamin K dependent factors II, VII and X but not the anticoagulant factors, protein C and S as well as factor IX. In TG all factors play their role and when thrombomodulin (TM) is added the function of proteins C and S is stressed. The thrombotic tendency in congenital protein C resistance proves the importance of this protein C pathway. Aim To compare the INR in samples from patients under VKA prophylaxis to TG in whole blood and in platelet rich and platelet poor plasma (PRP, PPP) both in the presence and in the absence of TM. Materials & Methods Blood samples were collected from 123 consenting patients on VKA. In two thirds (67%) the indication for prophylaxis was atrial fibrillation. Other indications included prosthetic valves, lung embolisms or thrombosis. The INR was determined in the PPP of the samples and the patients were stratified into 5 groups: INR of 1.0 to 1.5, 1.5 to 2.5, 2.5 to 3.5, 3.5 to 4.5 and higher than 4.5. Thrombin generation (TG) was measured via Calibrated Automated Thrombinography (CAT) in whole blood and in PRP and PPP, with and without 20 nM added TM. From the TG curve lag time and time to peak were obtained as well as the maximal thrombin concentration (peak) and the area under the curve (endogenous thrombin potential: ETP). Also red and white blood cells and platelets were counted. Results With increasing INR values, the ETP and peak height decrease and lag time and time to peak prolong. All TG parameters measured in whole blood were significantly correlated (p-values< 0.01) with the values determined in both PRP and PPP. INR was linearly correlated with lag time and time to peak (p-value< 0.01), whereas for the concentration dependent parameters (ETP and peak height) the correlation with the INR was hyperbolical (p-value< 0.01). In plasma, 20 nM TM causes a diminution of ETP and peak of 50-60 % in normals and in patients in the INR 1 – 1.5 group. At higher INR values inhibition is between 25 and 40%, independent of the INR value. In whole blood, on the contrary, the same concentration of TM causes around 30 % of inhibition in normals and in all patients alike. Conclusions Whole blood TG data correlate well with INR and reflect more of the coagulation mechanism than the INR does. Like the INR it does not reflect the function of the VKAs on the natural anticoagulant factors, however. In PPP and PRP addition of TM shows that VKA treatment induces TM resistance in patients with an INR value higher than 1.5. Disclosures: No relevant conflicts of interest to declare.

Prior studies have evaluated the safety and effectiveness of a diagnostic work up based on combined use of a clinical decision rule and a D-dimer laboratory test in patients with suspected deep vein thrombosis in secondary care facilities. The overall outcome of these studies show that approximately 30% of additional objective evaluation can be avoided without compromising the safety, resulting in failure rates of less than 1%. The objective of our study was to assess the effectiveness of a modified algorithm using a dichotomized clinical decision rule including a point of care D-dimer test in patients suspected of deep vein thrombosis in primary care. The AMUSE study is a prospective cohort study of consecutive patients with clinically suspected acute deep vein thrombosis conducted in 400 general practices coordinated by 3 university affiliated centers in the Netherlands from March 2004 through January 2007. The study population of 1029 patients included 63% women. Patients were categorized as “deep vein thrombosis unlikely” or “deep vein thrombosis likely” using a dichotomized version of a for general practice adapted clinical decision rule based on the Wells rule. Patients classified as unlikely were excluded from further testing. All other patients underwent ultrasonography. Anticoagulants were withheld from patients classified as unlikely. All patients were followed up for 3 months. The main outcome measure was symptomatic or fatal venous thromboembolism (VTE) during 3 months follow-up. Deep vein thrombosis was classified as unlikely in 500 patients (48.6%), all of whom were not treated with anticoagulants; subsequent non fatal VTE occurred in 8 patients (1.6% [95 CI 0.7–3.1%]). In 500 patients categorized as likely, deep vein thrombosis was confirmed in 124 patients (24.8%), 3 patients did not receive objective testing (0.6%) and 373 patients were tested negative (74.6%). Two out of 4 patients not receiving objective testing had confirmed deep vein thrombosis in the 3 month follow-up period. In patients that tested negative 4 non fatal events occurred during the 3 month follow-up (1.1%). The algorithm was completed and allowed a management decision in 97.2% of patients. We conclude that this management strategy is both safe and highly effective in patients with suspected deep vein thrombosis in general practice. Its use is associated with low risk for subsequent fatal and nonfatal VTE and a further increase in the yield of objective diagnostic tests.