Aspirin or Low-Molecular-Weight Heparin for Thromboprophylaxis after a Fracture.

BACKGROUND: Clinical guidelines recommend low-molecular-weight heparin for thromboprophylaxis in patients with fractures, but trials of its effectiveness as compared with aspirin are lacking. METHODS: In this pragmatic, multicenter, randomized, noninferiority trial, we enrolled patients 18 years of age or older who had a fracture of an extremity (anywhere from hip to midfoot or shoulder to wrist) that had been treated operatively or who had any pelvic or acetabular fracture. Patients were randomly assigned to receive low-molecular-weight heparin (enoxaparin) at a dose of 30 mg twice daily or aspirin at a dose of 81 mg twice daily while they were in the hospital. After hospital discharge, the patients continued to receive thromboprophylaxis according to the clinical protocols of each hospital. The primary outcome was death from any cause at 90 days. Secondary outcomes were nonfatal pulmonary embolism, deep-vein thrombosis, and bleeding complications. RESULTS: A total of 12,211 patients were randomly assigned to receive aspirin (6101 patients) or low-molecular-weight heparin (6110 patients). Patients had a mean (±SD) age of 44.6±17.8 years, 0.7% had a history of venous thromboembolism, and 2.5% had a history of cancer. Patients received a mean of 8.8±10.6 in-hospital thromboprophylaxis doses and were prescribed a median 21-day supply of thromboprophylaxis at discharge. Death occurred in 47 patients (0.78%) in the aspirin group and in 45 patients (0.73%) in the low-molecular-weight-heparin group (difference, 0.05 percentage points; 96.2% confidence interval, -0.27 to 0.38; P<0.001 for a noninferiority margin of 0.75 percentage points). Deep-vein thrombosis occurred in 2.51% of patients in the aspirin group and 1.71% in the low-molecular-weight-heparin group (difference, 0.80 percentage points; 95% CI, 0.28 to 1.31). The incidence of pulmonary embolism (1.49% in each group), bleeding complications, and other serious adverse events were similar in the two groups. CONCLUSIONS: In patients with extremity fractures that had been treated operatively or with any pelvic or acetabular fracture, thromboprophylaxis with aspirin was noninferior to low-molecular-weight heparin in preventing death and was associated with low incidences of deep-vein thrombosis and pulmonary embolism and low 90-day mortality. (Funded by the Patient-Centered Outcomes Research Institute; PREVENT CLOT ClinicalTrials.gov number, NCT02984384.).

How I treat pediatric venous thromboembolism in the DOAC era.

ABSTRACT: The direct oral anticoagulants (DOACs) rivaroxaban and dabigatran are newly licensed for the treatment and prevention of venous thromboembolism (VTE) in children and mark a renaissance in pediatric anticoagulation management. They provide a convenient option over standard-of-care anticoagulants (heparins, fondaparinux, and vitamin K antagonists) because of their oral route of administration, child-friendly formulations, and significant reduction in monitoring. However, limitations related to therapeutic monitoring when needed and the lack of approved reversal agents for DOACs in children raise some safety concerns. There is accumulating experience of safety and efficacy of DOACs in adults for a broad scope of indications; however, the cumulative experience of using DOACs in pediatrics, specifically for those with coexisting chronic illnesses, is sparse. Consequently, clinicians must often rely on their experience for treating VTE and extrapolate from data in adults while using DOACs in children. In this article, the authors share their experience of managing 4 scenarios that hematologists are likely to encounter in their day-to-day practice. Topics addressed include (1) appropriateness of indication; (2) use for special populations of children; (3) considerations for laboratory monitoring; (4) transition between anticoagulants; (5) major drug interactions; (6) perioperative management; and (7) anticoagulation reversal.

Longitudinal profile of estrogen-related thrombotic biomarkers after cessation of combined hormonal contraceptives.

ABSTRACT: The persistence of risk of venous thromboembolism (VTE) due to combined hormonal contraceptives (CHCs), after their cessation, is unknown but important to guide clinical practice. The objective of this prospective cohort study was to define the time until normalization of estrogen-related thrombotic biomarkers after CHC cessation. We enrolled women aged 18 to 50 years who had decided to stop their CHC, excluding those with a personal history of VTE, anticoagulation, or pregnancy. The study started before cessation of CHC, with 6 visits afterwards (at 1, 2, 4, 6, and 12 weeks after cessation). Primary outcomes were normalized sensitivity ratios to activated protein C (nAPCsr) and to thrombomodulin (nTMsr), with sex hormone-binding globulin (SHBG) as a secondary end point. We also included control women without CHC. Among 66 CHC users, from baseline until 12 weeks, average levels of nAPCsr, nTMsr, and SHBG decreased from 4.11 (standard deviation [SD], 2.06), 2.53 (SD, 1.03), and 167 nmol/L (SD, 103) to 1.27 (SD, 0.82), 1.11 (SD, 0.58), and 55.4 nmol/L (SD, 26.7), respectively. On a relative scale, 85.8%, 81.3%, and 76.2% of the decrease from baseline until 12 weeks was achieved at 2 weeks and 86.7%, 85.5%, and 87.8% at 4 weeks after CHC cessation, respectively. Levels were not meaningfully modified throughout the study period among 28 control women. In conclusion, CHC cessation is followed by a rapid decrease in estrogen-related thrombotic biomarkers. Two to 4 weeks of cessation before planned major surgery or withdrawal of anticoagulants in patients with VTE appears sufficient for the majority of women. The trial is registered at www.clinicaltrials.gov as #NCT03949985.

High microRNA-145 plasma levels are associated with decreased risk of future incident venous thromboembolism: the HUNT study.

ABSTRACT: MicroRNA-145 (miR-145) has been reported to downregulate the expression of tissue factor and factor XI in vitro and decrease venous thrombus formation in animal models. However, the association between miR-145 and risk of future venous thromboembolism (VTE) in the general population remains unknown. We investigated the association between plasma levels of miR-145 and risk of future VTE in a case-cohort study. Incident VTE cases (n = 510) and a subcohort (n = 1890) were derived from the third survey of the Trøndelag Health Study (HUNT3), a population-based cohort. The expression levels of miR-145 were measured in plasma samples obtained at baseline. The study population was divided into quartiles based on miR-145 levels in participants in the subcohort, and weighted Cox regression was used to estimate hazard ratios (HRs) with 95% confidence intervals (CIs). Plasma levels of miR-145 were inversely associated with VTE risk. Participants with miR-145 levels in the highest quartile had a 49% lower risk of VTE (HR, 0.51; 95% CI, 0.38-0.68) than those with miR-145 in the lowest quartile in age- and sex-adjusted analysis, and the inverse association was most pronounced for unprovoked VTE (HR, 0.39; 95% CI, 0.25-0.61). Risk estimates remained virtually the same after further adjustment for body mass index, and cancer and arterial cardiovascular disease at baseline. In conclusion, elevated expression levels of miR-145 in plasma were associated with decreased risk of future incident VTE. The protective role of miR-145 against VTE is consistent with previous experimental data and suggests that miR-145 has the potential to be a target for VTE prevention.

Increased risk of venous thromboembolism in young and middle-aged individuals with hereditary angioedema: a family study.

ABSTRACT: Hereditary angioedema (HAE), caused by C1 inhibitor protein deficiency, was recently shown to be associated with an increased risk for venous thromboembolism (VTE). To our knowledge, this is the first national family study of HAE, which aimed to determine the familial risk of VTE. The Swedish Multi-Generation Register was linked to the Swedish National Patient Register for the period of 1964 to 2018. Only patients with HAE with a validated diagnosis were included in the study and were linked to their family members. Hazard ratios (HRs) and 95% confidence intervals (CIs) for VTE were calculated for patients with HAE in comparison with relatives without HAE. Among 2006 individuals (from 276 pedigrees of 365 patients with HAE), 103 individuals were affected by VTE. In total, 35 (9.6%) patients with HAE were affected by VTE, whereas 68 (4.1%) non-HAE relatives were affected (P < .001). The adjusted HR for VTE among patients with HAE was 2.51 (95% CI, 1.67-3.77). Patients with HAE were younger at the first VTE than their non-HAE relatives (mean age, 51 years vs 63 years; P < .001). Before the age of 70 years, the HR for VTE among patients with HAE was 3.62 (95% CI, 2.26-5.80). The HR for VTE for patients with HAE born after 1964 was 8.29 (95% CI, 2.90-23.71). The HR for VTE for patients with HAE who were born in 1964 or earlier was 1.82 (95% CI, 1.14-2.91). HAE is associated with VTE among young and middle-aged individuals in Swedish families with HAE. The effect size of the association is in the order of other thrombophilias. We suggest that HAE may be considered a new rare thrombophilia.

Thrombosis risk in single- and double-heterozygous carriers of factor V Leiden and prothrombin G20210A in FinnGen and the UK Biobank.

ABSTRACT: The factor V Leiden (FVL; rs6025) and prothrombin G20210A (PTGM; rs1799963) polymorphisms are 2 of the most well-studied genetic risk factors for venous thromboembolism (VTE). However, double heterozygosity (DH) for FVL and PTGM remains poorly understood, with previous studies showing marked disagreement regarding thrombosis risk conferred by the DH genotype. Using multidimensional data from the UK Biobank (UKB) and FinnGen biorepositories, we evaluated the clinical impact of DH carrier status across 937 939 individuals. We found that 662 participants (0.07%) were DH carriers. After adjustment for age, sex, and ancestry, DH individuals experienced a markedly elevated risk of VTE compared with wild-type individuals (odds ratio [OR] = 5.24; 95% confidence interval [CI], 4.01-6.84; P = 4.8 × 10-34), which approximated the risk conferred by FVL homozygosity. A secondary analysis restricted to UKB participants (N = 445 144) found that effect size estimates for the DH genotype remained largely unchanged (OR = 4.53; 95% CI, 3.42-5.90; P < 1 × 10-16) after adjustment for commonly cited VTE risk factors, such as body mass index, blood type, and markers of inflammation. In contrast, the DH genotype was not associated with a significantly higher risk of any arterial thrombosis phenotype, including stroke, myocardial infarction, and peripheral artery disease. In summary, we leveraged population-scale genomic data sets to conduct, to our knowledge, the largest study to date on the DH genotype and were able to establish far more precise effect size estimates than previously possible. Our findings indicate that the DH genotype may occur as frequently as FVL homozygosity and may confer a similarly increased risk of VTE.

How I treat the co-occurrence of venous and arterial thromboembolism: anticoagulation, antiplatelet therapy, or both?

ABSTRACT: Arterial and venous thromboses are classically considered distinct disease states, with arterial thrombosis mediated predominantly by platelets and therefore, treated with antiplatelet therapy, and venous thrombosis mediated by the plasmatic coagulation system and treated with anticoagulation. However, co-occurrence of arterial and venous events is common, and there is increasing evidence of shared risk factors and pathophysiologic overlap. This presents a management challenge: does the patient with venous and arterial thrombosis, require anticoagulation, antiplatelet therapy, or both? Herein, we present a structured approach to the evaluation and management of patients with venous thrombosis who are also at risk for or have a history of an arterial thromboembolic event. We emphasize the importance of defining the indications for antithrombotic therapy, as well as the evaluation of factors that influence both thrombotic and bleeding risk, including disorder-specific and patient-specific factors, as well as the inherent risk balance of antithrombotic therapy regimens. We illustrate this approach in 4 cases, discussing the unique considerations and recent updates in the management of venous thrombosis, acute noncardioembolic ischemic stroke, coronary artery disease and acute myocardial infarction, and peripheral artery disease after revascularization.

Targeted prophylactic anticoagulation based on the TRiP(cast) score in patients with lower limb immobilisation: a multicentre, stepped wedge, randomised implementation trial.

BACKGROUND: Prophylactic anticoagulation in emergency department patients with lower limb trauma requiring immobilisation is controversial. The Thrombosis Risk Prediction for Patients with Cast Immobilisation-TRiP(cast)-score could identify a large subgroup of patients at low risk of venous thromboembolism for whom prophylactic anticoagulation can be safely withheld. We aimed to prospectively assess the safety of withholding anticoagulation for patients with lower limb trauma at low risk of venous thromboembolism, defined by a TRiP(cast) score of less than 7. METHODS: CASTING was a stepped-wedge, multicentre, cluster-randomised trial with blinded outcome assessment. 15 emergency departments in France and Belgium were selected and randomly assigned staggered start dates for switching from the control phase (ie, anticoagulation prescription according to the physician's usual practice) to the intervention phase (ie, targeted anticoagulation according to TRiP(cast) score: no prescription if score <7 and anticoagulation if score was ≥7). Patients were included if they presented to a participating emergency department with lower limb trauma requiring immobilisation for at least 7 days and were aged 18 years or older. The primary outcome was the 3-month cumulative rate of symptomatic venous thromboembolism during the intervention phase in patients with a TRiP(cast) score of less than 7. The targeted strategy was considered safe if this rate was less than 1% with an upper 95% CI of less than 2%. The primary analysis was performed in the intention-to-treat population. This study is registered at ClinicalTrials.gov (NCT04064489). FINDINGS: Between June 16, 2020, and Sept 15, 2021, 15 clusters and 2120 patients were included. Of the 1505 patients analysed in the intervention phase, 1159 (77·0%) had a TRiP(cast) score of less than 7 and did not receive anticoagulant treatment. The symptomatic venous thromboembolism rate was 0·7% (95% CI 0·3-1·4, n=8/1159). There was no difference between the control and the intervention phases in the cumulative rate of symptomatic venous thromboembolism or in bleeding rates. INTERPRETATION: Patients with a TRiP(cast) score of less than 7 who are not receiving anticoagulation have a very low risk of venous thromboembolism. A large proportion of patients with lower limb trauma and immobilisation could safely avoid thromboprophylaxis. FUNDING: French Ministry of Health.

How I approach the prevention and treatment of thrombotic complications in hospitalized patients.

This article uses case-based discussion to review prevention and management of thrombotic problems in hospitalized patients that involve a clinical hematologist. There is variation in the clinical hematologist's role in thrombosis practice throughout the world, and we discuss this where indicated. Hospital-associated venous thromboembolism (VTE), or hospital-associated thrombosis (HAT), is the term to cover VTE occurring during admission and for 90 days postdischarge and is a common patient safety problem. HATs are the most common cause of VTE accounting for 55% to 60% of all VTE, with an estimated 10 million occurring globally. VTE risk assessment alongside evidence-based thromboprophylaxis reduces this risk significantly. Many hospitalized patients, especially older patients, use direct oral anticoagulants (DOACs), mainly to prevent stroke in atrial fibrillation. DOACs require perioperative management and may need urgent reversal. Other complex interventions such as extracorporeal membrane oxygenation which require anticoagulation are also discussed. Lastly, those with uncommon high-risk thrombophilias, especially those with antithrombin deficiency, produce unique challenges when hospitalized.

Determining venous thromboembolism risk in patients with adult-type diffuse glioma.

Venous thromboembolism (VTE) is a life-threating condition that is common in patients with adult-type diffuse gliomas, yet thromboprophylaxis is controversial because of possible intracerebral hemorrhage. Effective VTE prediction models exist for other cancers, but not glioma. Our objective was to develop a VTE prediction tool to improve glioma patient care, incorporating clinical, blood-based, histologic, and molecular markers. We analyzed preoperative arterial blood, tumor tissue, and clinical-pathologic data (including next-generation sequencing data) from 258 patients with newly diagnosed World Health Organization (WHO) grade 2 to 4 adult-type diffuse gliomas. Forty-six (17.8%) experienced VTE. Tumor expression of tissue factor (TF) and podoplanin (PDPN) each positively correlated with VTE, although only circulating TF and D-dimers, not circulating PDPN, correlated with VTE risk. Gliomas with mutations in isocitrate dehydrogenase 1 (IDH1) or IDH2 (IDHmut) caused fewer VTEs; multivariable analysis suggested that this is due to IDHmut suppression of TF, not PDPN. In a predictive time-to-event model, the following predicted increased VTE risk in newly diagnosed patients with glioma: (1) history of VTE; (2) hypertension; (3) asthma; (4) white blood cell count; (5) WHO tumor grade; (6) patient age; and (7) body mass index. Conversely, IDHmut, hypothyroidism, and MGMT promoter methylation predicted reduced VTE risk. These 10 variables were used to create a web-based VTE prediction tool that was validated in 2 separate cohorts of patients with adult-type diffuse glioma from other institutions. This study extends our understanding of the VTE landscape in these tumors and provides evidence-based guidance for clinicians to mitigate VTE risk in patients with glioma.

Prediction of Venous Thromboembolism in Diverse Populations Using Machine Learning and Structured Electronic Health Records.

BACKGROUND: Venous thromboembolism (VTE) is a major cause of morbidity and mortality worldwide. Current risk assessment tools, such as the Caprini and Padua scores and Wells criteria, have limitations in their applicability and accuracy. This study aimed to develop machine learning models using structured electronic health record data to predict diagnosis and 1-year risk of VTE. METHODS: We trained and validated models on data from 159 001 participants in the Mount Sinai Data Warehouse. We then externally tested them on 401 723 participants in the UK Biobank and 123 039 participants in All of Us. All data sets contain populations of diverse ancestries and clinical histories. We used these data sets to develop small, medium, and large models with increasing features on a range of optimizing portability to maximizing performance. We make trained models publicly available in click-and-run format at https://doi.org/10.17632/tkwzysr4y6.6. RESULTS: In the holdout and external test sets, respectively, models achieved areas under the receiver operating characteristic curve of 0.80 to 0.83 and 0.72 to 0.82 for VTE diagnosis prediction and 0.76 to 0.78 and 0.64 to 0.69 for 1-year risk prediction, significantly outperforming the Padua score. Models also demonstrated robust performance across different VTE types and patient subsets, including ethnicity, age, and surgical and hospitalization status. Models identified both established and novel clinical features contributing to VTE risk, offering valuable insights into its underlying pathophysiology. CONCLUSIONS: Machine learning models using structured electronic health record data can significantly improve VTE diagnosis and 1-year risk prediction in diverse populations. Model probability scores exist on a continuum, affecting mortality risk in both healthy individuals and VTE cases. Integrating these models into electronic health record systems to generate real-time predictions may enhance VTE risk assessment, early detection, and preventative measures, ultimately reducing the morbidity and mortality associated with VTE.

Biomarker risk assessment model identified high-risk patients with cancer who benefit from thromboprophylaxis.

SOURCE CITATION: Alexander M, Harris S, Underhill C, et al. Risk-directed ambulatory thromboprophylaxis in lung and gastrointestinal cancers: the TARGET-TP randomized clinical trial. JAMA Oncol. 2023;9:1536-1545. 37733336.

The Vienna Prediction Model for identifying patients at low risk of recurrent venous thromboembolism: a prospective cohort study.

BACKGROUND AND AIMS: Patients with unprovoked venous thromboembolism (VTE) have a high recurrence risk, and guidelines suggest extended-phase anticoagulation. Many patients never experience recurrence but are exposed to bleeding. The aim of this study was to assess the performance of the Vienna Prediction Model (VPM) and to evaluate if the VPM accurately identifies these patients. METHODS: In patients with unprovoked VTE, the VPM was performed 3 weeks after anticoagulation withdrawal. Those with a predicted 1-year recurrence risk of ≤5.5% were prospectively followed. Study endpoint was recurrent VTE over 2 years. RESULTS: A total of 818 patients received anticoagulation for a median of 3.9 months. 520 patients (65%) had a predicted annual recurrence risk of ≤5.5%. During a median time of 23.9 months, 52 patients had non-fatal recurrence. The recurrence risk was 5.2% [95% confidence interval (CI) 3.2-7.2] at 1 year and 11.2% (95% CI 8.3-14) at 2 years. Model calibration was adequate after 1 year. The VPM underestimated the recurrence risk of patients with a 2-year recurrence rate of >5%. In a post-hoc analysis, the VPM's baseline hazard was recalibrated. Bootstrap validation confirmed an ideal ratio of observed and expected recurrence events. The recurrence risk was highest in men with proximal deep-vein thrombosis or pulmonary embolism and lower in women regardless of the site of incident VTE. CONCLUSIONS: In this prospective evaluation of the performance of the VPM, the 1-year rate of recurrence in patients with unprovoked VTE was 5.2%. Recalibration improved identification of patients at low recurrence risk and stratification into distinct low-risk categories.

Venous thromboembolism: diagnostic advances and unaddressed challenges in management.

PURPOSE OF REVIEW: This review summarizes recent advances in developing targeted diagnostics for venous thromboembolism (VTE) and unaddressed knowledge gaps in patient management. Without addressing these critical data needs, the morbidity in VTE patients will persist. RECENT FINDINGS: Recent studies investigating plasma protein profiles in VTE patients have identified key diagnostic targets to address the currently unmet need for low-cost, confirmatory, point-of-care VTE diagnostics. These studies and a growing body of evidence from animal model studies have revealed the importance of inflammatory and vascular pathology in driving VTE, which are currently unaddressed targets for VTE therapy. To enhance the translation of preclinical animal studies, clinical quantification of thrombus burden and comparative component analyses between modeled VTE and clinical VTE are necessary. SUMMARY: Lead candidates from protein profiling of VTE patients' plasma offer a promising outlook in developing low cost, confirmatory, point-of-care testing for VTE. Additionally, addressing the critical knowledge gap of quantitatively measuring clinical thrombi will allow for an array of benefits in VTE management and informing the translatability of experimental therapeutics.

The plasma miRNome and venous thromboembolism in high-grade glioma: miRNA Sequencing of a nested case-control cohort.

Patients with high-grade gliomas are at high risk of venous thromboembolism (VTE). MicroRNAs (miRNAs) are small non-coding RNAs with multiple roles in tumour biology, haemostasis and platelet function. Their association with VTE risk in high-grade glioma has not been comprehensively mapped so far. We thus conducted a nested case-control study within 152 patients with WHO grade IV glioma that had been part of a prospective cohort study on VTE risk factors. At inclusion a single blood draw was taken, and patients were thereafter followed for a maximum of 2 years. During that time, 24 patients (16%) developed VTE. Of the other 128 patients, we randomly selected 24 age- and sex-matched controls. After quality control, the final group size was 21 patients with VTE during follow-up and 23 without VTE. Small RNA next-generation sequencing of plasma was performed. We observed that hsa-miR-451a was globally the most abundant miRNA. Notably, 51% of all miRNAs showed a correlation with platelet count. The analysis of miRNAs differentially regulated in VTE patients-with and without platelet adjustment-identified potential VTE biomarker candidates such as has-miR-221-3p. Therewith, we here provide one of the largest and deepest peripheral blood miRNA datasets of high-grade glioma patients so far, in which we identified first VTE biomarker candidates that can serve as the starting point for future research.

Contribution of FOS in neutrophils to venous thromboembolism via miR-144 based on bioinformatic prediction and validation.

The Finkel-Biskis-Jinkins Osteosarcoma (c-Fos; encoded by FOS) plays an important role in several cardiovascular diseases, including atherosclerosis and stroke. However, the relationship between FOS and venous thromboembolism (VTE) remains unknown. We identified differentially expressed genes in Gene Expression Omnibus dataset, GSE48000, comprising VTE patients and healthy individuals, and analysed them using CIBERSORT and weighted co-expression network analysis (WGCNA). FOS and CD46 expressions were significantly downregulated (FOS p = 2.26E-05, CD64 p = 8.83E-05) and strongly linked to neutrophil activity in VTE. We used GSE19151 and performed PCR to confirm that FOS and CD46 had diagnostic potential for VTE; however, only FOS showed differential expression by PCR and ELISA in whole blood samples. Moreover, we found that hsa-miR-144 which regulates FOS expression was significantly upregulated in VTE. Furthermore, FOS expression was significantly downregulated in neutrophils of VTE patients (p = 0.03). RNA sequencing performed on whole blood samples of VTE patients showed that FOS exerted its effects in VTE via the leptin-mediated adipokine signalling pathway. Our results suggest that FOS and related genes or proteins can outperform traditional clinical markers and may be used as diagnostic biomarkers for VTE.

Edoxaban for 12 Months Versus 3 Months in Patients With Cancer With Isolated Distal Deep Vein Thrombosis (ONCO DVT Study): An Open-Label, Multicenter, Randomized Clinical Trial.

BACKGROUND: The optimal duration of anticoagulation therapy for isolated distal deep vein thrombosis in patients with cancer is clinically relevant, but the evidence is lacking. The prolonged anticoagulation therapy could have a potential benefit for prevention of thrombotic events; however, it could also increase the risk of bleeding. METHODS: In a multicenter, open-label, adjudicator-blinded, randomized clinical trial at 60 institutions in Japan, we randomly assigned patients with cancer with isolated distal deep vein thrombosis, in a 1-to-1 ratio, to receive either a 12-month or 3-month edoxaban treatment. The primary end point was a composite of a symptomatic recurrent venous thromboembolism (VTE) or VTE-related death at 12 months. The major secondary end point was major bleeding at 12 months, according to the criteria of the International Society on Thrombosis and Haemostasis. The primary hypothesis was that a 12-month edoxaban treatment was superior to a 3-month edoxaban treatment with respect to the primary end point. RESULTS: From April 2019 through June 2022, 604 patients were randomized, and after excluding 3 patients who withdrew consent, 601 patients were included in the intention-to-treat population: 296 patients in the 12-month edoxaban group and 305 patients in the 3-month edoxaban group. The mean age was 70.8 years, 28% of the patients were men, and 20% of the patients had symptoms of deep vein thrombosis at baseline. The primary end point of a symptomatic recurrent VTE event or VTE-related death occurred in 3 of the 296 patients (1.0%) in the 12-month edoxaban group and in 22 of the 305 patients (7.2%) in the 3-month edoxaban group (odds ratio, 0.13; 95% CI, 0.03-0.44). The major secondary end point of major bleeding occurred in 28 of the 296 patients (9.5%) in the 12-month edoxaban group and in 22 of the 305 patients (7.2%) in the 3-month edoxaban group (odds ratio, 1.34; 95% CI, 0.75-2.41). The prespecified subgroups did not affect the estimates on the primary end point. CONCLUSIONS: In patients with cancer with isolated distal deep vein thrombosis, 12 months was superior to 3 months for an edoxaban treatment with respect to the composite outcome of a symptomatic recurrent VTE or VTE-related death. REGISTRATION: URL: https://www.clinicaltrials.gov; Unique identifier: NCT03895502.

Pharmacology and Clinical Development of Factor XI Inhibitors.

Therapeutic anticoagulation is indicated for a variety of circumstances and conditions in several fields of medicine to prevent or treat venous and arterial thromboembolism. According to the different mechanisms of action, the available parenteral and oral anticoagulant drugs share the common principle of hampering or blocking key steps of the coagulation cascade, which unavoidably comes at the price of an increased propensity to bleed. Hemorrhagic complications affect patient prognosis both directly and indirectly (ie, by preventing the adoption of an effective antithrombotic strategy). Inhibition of factor XI (FXI) has emerged as a strategy with the potential to uncouple the pharmacological effect and the adverse events of anticoagulant therapy. This observation is based on the differential contribution of FXI to thrombus amplification, in which it plays a major role, and hemostasis, in which it plays an ancillary role in final clot consolidation. Several agents were developed to inhibit FXI at different stages (ie, suppressing biosynthesis, preventing zymogen activation, or impeding the biological action of the active form), including antisense oligonucleotides, monoclonal antibodies, small synthetic molecules, natural peptides, and aptamers. Phase 2 studies of different classes of FXI inhibitors in orthopedic surgery suggested that dose-dependent reductions in thrombotic complications are not paralleled by dose-dependent increases in bleeding compared with low-molecular-weight heparin. Likewise, the FXI inhibitor asundexian was associated with lower rates of bleeding compared with the activated factor X inhibitor apixaban in patients with atrial fibrillation, although no evidence of a therapeutic effect on stroke prevention is available so far. FXI inhibition could also be appealing for patients with other conditions, including end-stage renal disease, noncardioembolic stroke, or acute myocardial infarction, for which other phase 2 studies have been conducted. The balance between thromboprophylaxis and bleeding achieved by FXI inhibitors needs confirmation in large-scale phase 3 clinical trials powered for clinical end points. Several of such trials are ongoing or planned to define the role of FXI inhibitors in clinical practice and to clarify which FXI inhibitor may be most suited for each clinical indication. This article reviews the rationale, pharmacology, results of medium or small phase 2 studies, and future perspectives of drugs inhibiting FXI.

RNA methylation patterns, immune characteristics, and autophagy-related mechanisms mediated by N6-methyladenosine (m6A) regulatory factors in venous thromboembolism.

Recent studies have found a link between deep vein thrombosis and inflammatory reactions. N6-methyladenosine (m6A), a crucial element in immunological regulation, is believed to contribute to the pathophysiology of venous thromboembolism (VTE). However, how the m6A-modified immune microenvironment is involved in VTE remains unclear. In the present study, we identified a relationship between VTE and the expression of several m6A regulatory elements by analyzing peripheral blood samples from 177 patients with VTE and 88 healthy controls from public GEO databases GSE19151 and GSE48000. We used machine learning to identify essential genes and constructed a diagnostic model for VTE using multivariate logistic regression. Unsupervised cluster analysis revealed a marked difference between m6A modification patterns in terms of immune cell infiltration, inflammatory reactivity, and autophagy. We identified two m6A-related autophagy genes (i.e., CHMP2B and SIRT1) and the crucial m6A regulator YTHDF3 using bioinformatics. We also examined two potential mechanisms through which YTHDF3 may affect VTE. m6A modification, immunity, and autophagy are closely linked in VTE, offering novel mechanistic and therapeutic insights.

Practical guidance for direct oral anticoagulant use in the treatment of venous thromboembolism in primary and metastatic brain tumor patients.

Management of venous thromboembolism (VTE) in patients with primary and metastatic brain tumors (BT) is challenging because of the risk of intracranial hemorrhage (ICH). There are no prospective clinical trials evaluating safety and efficacy of direct oral anticoagulants (DOACs), specifically in patients with BT, but they are widely used for VTE in this population. A group of neuro-oncology experts convened to provide practical clinical guidance for the off-label use of DOACs in treating VTE in patients with BT. We searched PubMed for the following terms: BTs, glioma, glioblastoma (GBM), brain metastasis, VTE, heparin, low-molecular-weight heparin (LWMH), DOACs, and ICH. Although prospective clinical trials are needed, the recommendations presented aim to assist clinicians in making informed decisions regarding DOACs for VTE in patients with BT.