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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 The role of platelets in the pathogenesis of venous thromboembolism (VTE) is receiving increasing attention; however, limited information is available on platelet function in the acute phase of the disease. Objective To characterize platelet function according to VTE phenotypes. Patients/Methods In total, 154 subjects (isolated pulmonary embolism [iPE], n = 28; isolated deep vein thrombosis [iDVT], n = 35; DVT+PE, n = 91) were included. In this study platelet function analyzer (PFA)-200, light transmission aggregometry (LTA), thrombin generation (TG) in presence (PRP) and absence (PFP) of platelets and platelet flow cytometry were investigated. LASSO regression was used to select clinical and platelet biomarkers that distinguish between VTE phenotypes. Results PFA-200 results did not differ between VTE phenotypes. LTA from DVT+PE subjects showed lowest maximum aggregation after epinephrine and adenosine diphosphate compared to iPE and iDVT. Lower % of PAC-1-positive platelets after in-vitro trigger were present in DVT+PE and iPE compared to iDVT. TG in PRP had lower peak height and velocity in DVT+PE and iPE against iDVT. The results of LASSO regression for the distinction between DVT+PE vs iDVT identified 18 variables (AUC =0.93) of which 72% were platelet biomarkers. For distinction between iPE and iDVT, 10 variables were selected (AUC = 0.96) of which 50% were platelet-related. Obesity was the only variable weakly discriminating between DVT+PE vs iPE (AUC = 0.66). Conclusion This explorative study suggests an important distinction between PE-related phenotypes and iDVT when considering clinical and platelet function data. Lower platelet-dependent TG along with reduced platelet reactivity suggest higher platelet degranulation in PE-dependent phenotypes compared to iDVT.

INTRODUCTION: There is evidence that plasma protein profiles differ in the two subtypes of pulmonary embolism (PE), isolated PE (iPE) and deep vein thrombosis (DVT)-associated PE (DVT-PE), in the acute phase. The aim of this study was to determine specific plasma signatures for proteins related to platelets in acute iPE and DVT-PE compared to isolated DVT (iDVT).METHODS: Within the Genotyping and Molecular Phenotyping of Venous ThromboEmbolism (GMP-VTE) Project, a multicenter prospective cohort study of 693 confirmed VTE cases, a highly sensitive targeted proteomics approach based on dual-antibody proximity extension assay was applied. LASSO-regularized logistic regression analysis selected 33 and 30 of 135 platelet-related candidate proteins in iPE and DVT-PE vs. iDVT, respectively.RESULTS: All regulated proteins were well associated with six prominently released platelet proteins and the majority showed specificity for iPE and DVT-PE compared to iDVT. While iPE-specific proteins were assigned to be predominantly released via shedding mechanisms and extracellular vesicles, granule secretion was identified as a major release mechanism assigned to DVT-associated PE-specific proteins. Network analysis demonstrated three interconnected clusters of specifically regulated proteins in iPE linked to immunoreceptor signaling, pathogen clearance and chemotaxis, whereas for DVT-associated PE one cluster linked to tissue remodeling and leukocyte trafficking. Machine learning-based analysis reveals specific plasma signatures and differential release mechanisms of proteins related to platelets in acute iPE and DVT-associated PE.CONCLUSION: These data suggest that the platelet protein releasate contributes to the differential regulation of plasma proteins in acute PE compared to iDVT, which may be associated with different platelet activation patterns.

Patients with isolated pulmonary embolism (PE) have a distinct clinical profile from those with deep vein thrombosis (DVT)-associated PE, with more pulmonary conditions and atherosclerosis. These findings suggest a distinct molecular pathophysiology and the potential involvement of alternative pathways in isolated PE. To test this hypothesis, data from 532 individuals from the Genotyping and Molecular Phenotyping of Venous ThromboEmbolism Project, a multicenter prospective cohort study with extensive biobanking, were analyzed. Targeted, high-throughput proteomics, machine learning, and bioinformatic methods were applied to contrast the acute-phase plasma proteomes of isolated PE patients (n = 96) against those of patients with DVT-associated PE (n = 276) or isolated DVT (n = 160). This resulted in the identification of shared molecular processes between PE phenotypes, as well as an isolated PE-specific protein signature. Shared processes included upregulation of inflammation, response to oxidative stress, and the loss of pulmonary surfactant. The isolated PE-specific signature consisted of 5 proteins: interferon-γ, glial cell line–derived neurotrophic growth factor, polypeptide N-acetylgalactosaminyltransferase 3, peptidyl arginine deiminase type-2, and interleukin-15 receptor subunit α. These proteins were orthogonally validated using cis protein quantitative trait loci. External replication in an independent population-based cohort (n = 5778) further validated the proteomic results and showed that they were prognostic for incident primary isolated PE in individuals without history of VTE (median time to event: 2.9 years; interquartile range: 1.6-4.2 years), supporting their possible involvement in the early pathogenesis. This study has identified molecular overlaps and differences between VTE phenotypes. In particular, the results implicate noncanonical pathways more commonly associated with respiratory and atherosclerotic disease in the acute pathophysiology of isolated PE.

Background Isolated PE is associated with a higher burden of atherosclerotic disease than other manifestations of VTE. Research Question We hypothesized that the presence of isolated PE may signal a chronically elevated risk of arterial thrombotic disease. Study Design and Methods Data from the VTEval Study, a prospective cohort study enrolling individuals with clinical suspicion and imaging-based diagnosis or exclusion of VTE, were analyzed. Patients with PE received whole-leg ultrasonography to assess presence of DVT. Regularized logistic regression identified features that discriminate between isolated PE and other VTE phenotypes at clinical presentation. Survival analyses were performed to evaluate the crude and adjusted 3-year risks of arterial thrombotic disease, recurrent VTE, and death. Results The sample comprised 510 patients. Isolated PE patients (n = 63) had a distinct clinical profile from patients with other VTE phenotypes (n = 447). COPD, peripheral artery disease, atrial fibrillation, and coronary artery disease were significantly more prevalent among patients with isolated PE. Isolated PE patients had significantly higher risk (incidence rate ratio vs DVT-associated PE, 3.7 (95% CI, 1.3-10.8, P = .009); vs isolated DVT, 4.8 (1.7-14.3, P = .001) of arterial thrombotic events (ie, myocardial infarction, stroke/transient ischemic attack). After adjustment for clinical profile and medication intake, the risk of arterial thrombotic events for patients with isolated PE remained quadruple that of other VTE phenotypes (hazard ratio [HR], 3.8 [1.3-10.9], P = .01). Interpretation Patients with isolated PE are at higher risk for arterial thrombosis and may require screening for arterial disease and development of novel therapeutic strategies. Clinical Trial Registration NCT02156401

The obesity paradox, the controversial finding that obesity promotes disease development but protects against sequelae in patients, has been observed in venous thromboembolism (VTE). The aim of this investigation was to identify a body mass–related proteomic signature in VTE patients and to evaluate whether this signature mediates the obesity paradox in VTE patients. Data from the Genotyping and Molecular Phenotyping in Venous ThromboEmbolism Project, a prospective cohort study of 693 VTE patients, were analyzed. A combined end point of recurrent VTE or all-cause death was used. Relative quantification of 444 proteins was performed using high-throughput targeted proteomics technology. Measurements were performed in samples collected during the acute VTE event and at 12-month follow-up. An 11-protein signature (CLEC4C, FABP4, FLT3LG, IL-17C, LEP, LYVE1, MASP1, ST2, THBS2, THBS4, TSLP) for body mass in VTE patients was identified. The signature did not significantly mediate the obesity paradox (change in hazard ratio [HR]: 0.04; likelihood ratio test of nested models = 7.7; P = .74), but its main constituent protein, leptin, was inversely associated with recurrent VTE or death (adjusted HR [95% confidence interval] per standard deviation increase: 0.66 [0.46-0.94]). This relationship was significantly (P = .007) modified by markers of leptin resistance (ie, high body mass index and high circulating matrix metalloproteinase-2 levels). Although the signature did not substantially explain the obesity paradox, leptin appears to be protective against disease recurrence and death in VTE patients. This protective effect was abrogated under conditions of leptin resistance and hence was unrelated to the obesity paradox.

Background: The pathogenesis of arterial and venous thrombosis is in large part interlaced. How much platelet phenotype relates to acute venous thromboembolism (VTE) independent of the underlying cardiovascular profile is presently poorly investigated.Methods: Platelet count and mean platelet volume (MPV), platelet aggregation in whole blood and platelet rich plasma (PRP), platelet-dependent thrombin generation (TG) and platelet surface activation markers were measured under standardized conditions. Machine learning was applied to identify the most relevant characteristics associated with VTE from a large array (N = 58) of clinical and plateletrelated variables.Findings: VTE cases (N = 159) presented with lower platelet count and MPV vs controls (N = 140). Whole blood aggregation showed shorter collagen/Epinephrine closure times in cases, particularly within acetylsalicylic acid (ASA) users. Within ASA users, higher PRP aggregation after adenosine diphosphate (ADP), epinephrine, collagen and arachidonic acid was observed in cases vs controls. Within non-ASA and/or subjects on anticoagulants, cases presented with lower aggregation after ADP and collagen vs controls. Lower platelet-dependent TG, higher CD63 on resting and lower PAC-1 expression after collagen/ADP in-vitro stimulated platelets further characterized VTE cases vs controls, independent of therapy. Lasso regression analysis identified 26 variables associated with VTE of which 69% were platelet-related.Interpretation: Comprehensive phenotyping of platelet function identified a large proportion of low responders to ASA in VTE cases. Lower platelet-dependent TG and lower platelet reactivity after ex-vivo stimulation characterized the "platelet exhausted syndrome" in cases. Finally, from a large array of covariates including clinical risk factors, platelet biomarkers comprised 69% of all selected variables differentiating VTE cases vs controls.Funding: German Federal Ministry of Education and Research, CTH-Mainz and Bayer AG. (c) 2020 The Authors. Published by Elsevier B.V.

Venous thromboembolism (VTE) is a life-threatening disease with risk of recurrence. Oral anticoagulation (OAC) with vitamin K antagonists (VKA) is effective to prevent thromboembolic recurrence. We aimed to investigate the quality of OAC of VTE patients in regular medical care (RMC) compared to a telemedicine-based coagulation service (CS). The thrombEVAL study (NCT01809015) is a prospective, multi-center study to investigate OAC treatment (recruitment: January 2011&ndash, March 2013). Patients were evaluated using clinical visits, computer-assisted personal interviews, self-reported data and laboratory measurements according to standard operating procedures. Overall, 360 patients with VTE from RMC and 254 from CS were included. Time in therapeutic range (TTR) was higher in CS compared to RMC (76.9% (interquartile range [IQR] 63.2&ndash, 87.1%) vs. 69.5% (52.3&ndash, 85.6%), p &lt, 0.001). Crude rate of thromboembolic events (rate ratio [RR] 11.33 (95% confidence interval [CI] 1.85&ndash, 465.26), p = 0.0015), clinically relevant bleeding (RR 6.80 (2.52&ndash, 25.76), p &lt, 0.001), hospitalizations (RR 2.54 (1.94&ndash, 3.39), p &lt, 0.001) and mortality under OAC (RR 5.89 (2.40&ndash, 18.75), p &lt, 0.001) were consistently higher in RMC compared with CS. Patients in RMC had higher risk for primary outcome (clinically relevant bleedings, thromboembolic events and mortality, hazard ratio [HR] 5.39 (95%CI 2.81&ndash, 10.33), p &lt, 0.0001), mortality (HR 5.54 (2.22&ndash, 13.84), p = 0.00025), thromboembolic events (HR 6.41 (1.51&ndash, 27.24), p = 0.012), clinically relevant bleeding (HR 5.31 (1.89&ndash, 14.89), p = 0.0015) and hospitalization (HR 1.84 (1.34&ndash, 2.55), p = 0.0002). Benefits of CS care were still observed after adjusting for comorbidities and TTR. In conclusion, anticoagulation quality and outcome of VTE patients undergoing VKA treatment was significantly better in CS than in RMC. Patients treated in CS had lower rates of adverse events, hospitalizations and lower mortality. CS was prognostically relevant, beyond providing advantages of improved international ratio (INR) monitoring.

Background. Anticoagulant therapy, the cornerstone treatment in acute venous thromboembolism (VTE), strongly impacts thrombin generation (TG). Until now, the appearance of the TG curve in platelet rich plasma (PRP) from patients with acute VTE has not been investigated. Methods. We analyzed the shape of TG curves measured in PARP of 180 acute VTE patients. Results. Normal shape of TG curves was observed in 110 patients, 50 patients showed no TG and 20 patients showed biphasic TG curve. The linear regression analysis, adjusted for age, sex, VTE clinical phenotypes and therapy showed that the appearance of biphasic curves is significantly associated with female sex, presence of cancer and therapy with Factor Xa inhibitors. Conclusions. This study demonstrated that despite taking anticoagulants, TG in presence of platelets is still present in the majority of acute VTE patients. Appearance of unusual TG curves is strongly related to the intake of anti-Factor Xa inhibitors. The clinical relevance of biphasic TG curve appearance requires further investigation.

The Global Anticoagulant Registry in the Field-Atrial Fibrillation (GARFIELD-AF) examined real-world practice in a total of 57,149 (5069 retrospective, 52,080 prospective) patients with newly diagnosed AF at risk of stroke/systemic embolism, enrolled at over 1000 centers in 35 countries. It aimed to capture data on AF burden, patients’ clinical profile, patterns of clinical practice and antithrombotic management, focusing on stroke/systemic embolism prevention, uptake of new oral anticoagulants, impact on death and bleeding. GARFIELD-AF set new standards for quality of data collection and analysis. A total of 36 peer-reviewed articles were already published and 73 abstracts presented at international congresses, covering treatment strategies, geographical variations in baseline risk and therapies, adverse outcomes and common comorbidities such as heart failure. A risk prediction tool as well as innovative observational studies and artificial intelligence methodologies are currently being developed by GARFIELD-AF researchers. Clinical Trial Registration: NCT01090362 (ClinicalTrials.gov).

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

Background As an alternative to vitamin K antagonist and low-dose aspirin ( 2). Conclusion Non vitamin K oral anticoagulants are associated with a higher risk on all-cause mortality, particularly in men and in patients with higher stroke risk., International Journal of Clinical Pharmacy, 41 (6), ISSN:2210-7703, ISSN:0928-1231, ISSN:2210-7711

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.

Essentials Thrombosis experts still struggle to reach consensus regarding the optimal type, dosage and duration of treatment. We asked 13 leaders in the field to comment on the prevention of venous thromboembolism (VTE) in their respective countries. Universally relevant risk factors as well as area-specific barriers to adequate treatment are identified. Local guidelines may be beneficial to guide decision-making in areas where universal guidelines fall short. Objectives Secondary prevention of venous thromboembolism (VTE) remains a topical and contentious point of debate for thrombosis experts around the globe. This discussion centers around two aspects: optimum treatment duration and which type and dosage of thromboprophylaxis to prescribe. Collectives of thrombosis experts have tried to steer the debate by issuing periodical best-practice guidelines. However, the lack of adherence to said guidelines is such that there is a growing body of research devoted to this very problem. Most of the studies on the subject retrospectively observe a single setting, which leaves important questions as to the generalizability of their findings. As each setting appears to face its own unique challenges, the overarching question of why there is so much variance between physicians when it comes to the secondary prevention of VTE is never fully addressed. Methods For this study, we asked thirteen senior-level physicians representing equally as many countries about the current state of clinical practice regarding the secondary prevention of VTE. Results The discussion identifies several barriers to adequate VTE prevention, and hints at area-specific idiosyncrasies that may explain why physicians from different locales treat VTE patients differently. Conclusion Universal treatment guidelines may not fully translate to clinical practice in many areas, and that promoting local guidelines to supplement the universal guidelines may be beneficial.

Isolated PE is associated with a higher burden of atherosclerotic disease than other manifestations of VTE.We hypothesized that the presence of isolated PE may signal a chronically elevated risk of arterial thrombotic disease.Data from the VTEval Study, a prospective cohort study enrolling individuals with clinical suspicion and imaging-based diagnosis or exclusion of VTE, were analyzed. Patients with PE received whole-leg ultrasonography to assess presence of DVT. Regularized logistic regression identified features that discriminate between isolated PE and other VTE phenotypes at clinical presentation. Survival analyses were performed to evaluate the crude and adjusted 3-year risks of arterial thrombotic disease, recurrent VTE, and death.The sample comprised 510 patients. Isolated PE patients (n = 63) had a distinct clinical profile from patients with other VTE phenotypes (n = 447). COPD, peripheral artery disease, atrial fibrillation, and coronary artery disease were significantly more prevalent among patients with isolated PE. Isolated PE patients had significantly higher risk (incidence rate ratio vs DVT-associated PE, 3.7 (95% CI, 1.3-10.8, P = .009); vs isolated DVT, 4.8 (1.7-14.3, P = .001) of arterial thrombotic events (ie, myocardial infarction, stroke/transient ischemic attack). After adjustment for clinical profile and medication intake, the risk of arterial thrombotic events for patients with isolated PE remained quadruple that of other VTE phenotypes (hazard ratio [HR], 3.8 [1.3-10.9], P = .01).Patients with isolated PE are at higher risk for arterial thrombosis and may require screening for arterial disease and development of novel therapeutic strategies.NCT02156401.

Renal impairment, a source of chronic hypercoagulability[1][1] and inflammation,[2][2] is known to reduce the specificity of the D-dimer test in the diagnosis of venous thromboembolism (VTE).[3][3] This leads to many false positives in such patients and consequently to additional costs, as well as

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

Targeted proteomics utilizing antibody-based proximity extension assays provides sensitive and highly specific quantifications of plasma protein levels. Multivariate analysis of this data is hampered by frequent missing values (random or left censored), calling for imputation approaches. While appropriate missing-value imputation methods exist, benchmarks of their performance in targeted proteomics data are lacking. Here, we assessed the performance of two methods for imputation of values missing completely at random, the previously top-benchmarked ‘missForest’ and the recently published ‘GSimp’ method. Evaluation was accomplished by comparing imputed with remeasured relative concentrations of 91 inflammation related circulating proteins in 86 samples from a cohort of 645 patients with venous thromboembolism. The median Pearson correlation between imputed and remeasured protein expression values was 69.0% for missForest and 71.6% for GSimp (p = 5.8e-4). Imputation with missForest resulted in stronger reduction of variance compared to GSimp (median relative variance of 25.3% vs. 68.6%, p = 2.4e-16) and undesired larger bias in downstream analyses. Irrespective of the imputation method used, the 91 imputed proteins revealed large variations in imputation accuracy, driven by differences in signal to noise ratio and information overlap between proteins. In summary, GSimp outperformed missForest, while both methods show good overall imputation accuracy with large variations between proteins.

Oral anticoagulation (OAC) is effective at preventing and treating thromboses and thromboembolism in patients with normal renal function. We aimed to research the impact of severe renal failure (RF) on patient outcome and to determine the potential benefit of caring for these patients in a specialized coagulation service (CS). A total of 1516 usual medical care patients and 756 CS-managed patients of the thrombEVAL multicenter (21 centers), prospective, cohort study (NCT01809015) were analyzed in a 3-year follow-up. Patients with RF (serum creatinine &gt, 3 mg/dL, no renal replacement therapy) were compared to patients without RF in usual care and a CS. The fluctuations in the international normalized ratios were significantly lower in CS-managed patients, and regardless of treatment in usual care or a CS, the time in therapeutic range was significantly lower in RF patients. Cox regression-adjusted hazard ratios for long-term outcome (1.5, 95% CI: 1.22&ndash, 1.83, p &lt, 0.001), death (1.62, CI: 1.27&ndash, 2.08, p &lt, 0.001), and hospitalization (1.21, CI: 1.02&ndash, 1.44, p = 0.032) were significantly higher in RF patients in usual care. Furthermore, there was a trend of more bleeding events in RF patients. CS-treated patients had significantly lower adjusted hazard ratios for death (0.24, CI: 0.14&ndash, 0.39, p &lt, 0.001), hospitalizations (0.41, CI: 0.34&ndash, 0.5, p &lt, 0.001), clinically relevant bleeding (0.29, CI: 0.18&ndash, 0.47, p &lt, 0.001), and major bleeding (0.33, CI: 0.18&ndash, 0.59, p &lt, 0.001). Thus, patients who required oral anticoagulation therapy benefitted significantly from being managed in a specialized coagulation service, regardless of their renal function.

BACKGROUND Although polypharmacy is associated with a negative clinical outcome in various settings and commonly observed in patients receiving oral anticoagulation therapy, evidence on the relevance for the clinical outcome of anticoagulated patients is currently limited. The aim of the study was to investigate the effect of polypharmacy on the clinical outcomes among patients taking phenprocoumon. DESIGN Prospective cohort study. SETTING Regular medical care. PARTICIPANTS Information on 2011 individuals receiving vitamin K antagonists was available for analysis from the prospective multicenter thrombEVAL study. MEASUREMENTS Data were obtained from clinical visits, computer-assisted interviews, and laboratory measurements. Information on clinical outcome was obtained during a 3-year follow-up period and subsequently validated via medical records. RESULTS The prevalence of polypharmacy (five drugs or more) was 84.1% (n = 1691). Quality of anticoagulation therapy assessed by time in therapeutic range was lower in individuals on five to eight drugs and nine drugs or more (70.7% and 64.7%, respectively) compared with subjects without polypharmacy (73.4%). In addition, a significantly higher variability of international normalized ratio measurements was found in the presence of polypharmacy. The cumulative incidence of bleeding, hospitalization, and all-cause mortality, but not for thromboembolic events, increased across groups of medication. In adjusted Cox regression analysis, polypharmacy is an independent risk factor for bleeding (hazard ratio [HR]≥ 9 drugs vs 1-4 drugs = 1.62; 95% confidence interval [CI] = 1.04-2.52; p = .033); hospitalization (HR≥ 9 drugs vs 1-4 drugs = 1.60; 95% CI = 1.26-2.03; p < .001; and all-cause mortality (HR≥ 9 drugs vs 1-4 drugs = 2.16; 95% CI = 1.43-3.27; p < .001) in a dose-dependent relationship. Per additional drug, bleeding risk was increased by 4%. CONCLUSIONS Polypharmacy influences the quality of anticoagulation therapy and translates into an elevated risk of adverse events in anticoagulated patients. This suggests that additional medication intake in such patients should be critically reviewed by physicians, and it highlights the importance of initiating investigations aimed at reducing multiple medication intake. J Am Geriatr Soc 67:463-470, 2019.

Introduction Venous thromboembolism (VTE) is a condition that annually occurs in approximately 1% of the world's population. Patients who have already had a VTE are at elevated risk for a recurrent VTE. Recurrent events increase the risk of long-term sequelae and can be fatal. Adequate secondary prophylaxis is thus needed to prevent such events. Patients with VTE are often prone to bleeding, and pharmacological prophylaxis exacerbates bleeding risk. Expert opinions on the optimum duration of secondary prophylaxis in VTE still vary substantially. The existence of treatment guidelines has not led to uniformity of VTE secondary prophylaxis strategies, which means that physicians still adhere to individual risk calculi in determining treatment duration.Methods and analysis The aim of this study is to establish what factors lie at the root of this variance in VTE secondary prophylactic treatment strategies, and what risk factors are deemed of particular importance in determining the perceived risks and benefits of variable treatment durations. To do this, we created a survey based on a D-efficient and G-efficient balanced experimental vignette design. This protocol covers all aspects of how this survey was set up and how it was implemented. The analysis of the experimental data will be carried out using mixed-effects methods, which are beneficial in scenarios with high interindividual variance and correlated (eg, repeated-measures) responses. We propose the use of maximal random effects structures insofar as possible.Ethics and dissemination All data are de-identified, and any identifying characteristics of the respondents will not be reported in a final manuscript or elsewhere. A paper describing the expert interviews is currently under peer review. A manuscript that contains the analysis of the results of the experiment described in this protocol is being drafted, and will also be submitted to a peer-reviewed journal.