Towards optimal use of antithrombotic therapy of people with cancer at the end of life: a research protocol for the development and implementation of the SERENITY shared decision support tool Thrombosis Research

Background: Even though antithrombotic therapy has probably little or even negative effects on the well-being of people with cancer during their last year of life, deprescribing antithrombotic therapy at the end of life is rare in practice. It is often continued until death, possibly resulting in excess bleeding, an increased disease burden and higher healthcare costs. Methods: The SERENITY consortium comprises researchers and clinicians from eight European countries with specialties in different clinical fields, epidemiology and psychology. SERENITY will use a comprehensive approach combining a realist review, flash mob research, epidemiological studies, and qualitative interviews. The results of these studies will be used in a Delphi process to reach a consensus on the optimal design of the shared decision support tool. Next, the shared decision support tool will be tested in a randomised controlled trial. A targeted implementation and dissemination plan will be developed to enable the use of the SERENITY tool across Europe, as well as its incorporation in clinical guidelines and policies. The entire project is funded by Horizon Europe.Results: SERENITY will develop an information-driven shared decision support tool that will facilitate treatment decisions regarding the appropriate use of antithrombotic therapy in people with cancer at the end of life. Conclusions: We aim to develop an intervention that guides the appropriate use of antithrombotic therapy, prevents bleeding complications, and saves healthcare costs. Hopefully, usage of the tool leads to enhanced empowerment and improved quality of life and treatment satisfaction of people with advanced cancer and their care givers

Evolutionary Adaptations inPseudonaja TextilisVenom Factor X Induce Zymogen Activity and Resistance to the Intrinsic Tenase Complex

The venom of the Australian snakePseudonaja textiliscomprises powerful prothrombin activators consisting of factor X (v-ptFX)- and factor V-like proteins. While all vertebrate liver-expressed factor X (FX) homologs, including that ofP. textilis, comprise an activation peptide of approximately 45 to 65 residues, the activation peptide of v-ptFX is significantly shortened to 27 residues. In this study, we demonstrate that exchanging the human FX activation peptide for the snake venom ortholog impedes proteolytic cleavage by the intrinsic factor VIIIa-factor IXa tenase complex. Furthermore, our findings indicate that the human FX activation peptide comprises an essential binding site for the intrinsic tenase complex. Conversely, incorporation of FX into the extrinsic tissue factor-factor VIIa tenase complex is completely dependent on exosite-mediated interactions. Remarkably, the shortened activation peptide allows for factor V-dependent prothrombin conversion while in the zymogen state. This indicates that the active site of FX molecules comprising the v-ptFX activation peptide partially matures upon assembly into a premature prothrombinase complex. Taken together, the shortened activation peptide is one of the remarkable characteristics of v-ptFX that has been modified from its original form, thereby transforming FX into a powerful procoagulant protein. Moreover, these results shed new light on the structural requirements for serine protease activation and indicate that catalytic activity can be obtained without formation of the characteristic Ile(16)-Asp(194)salt bridge via modification of the activation peptide.Thrombosis and Hemostasi

Cancer Associated Thrombosis:how many lung cancer patients seen in clinical practice would be eligible to a DOAC randomized controlled trial?

Background: Based on the results of randomized clinical trials (RCT) assessing direct oral anticoagulants (DOACs) for the treatment of patients with cancer-associated thrombosis, DOACs have been proposed as alternative to low molecular weight heparin by several international guidelines. However, the proportion of patients with VTE associated with lung cancer who would not have been eligible for such trials is currently unknownMethods: In a multicenter, observational study, all patients consecutively admitted from 01/2017 to 12/2019 for an acute VTE event were retrospectively analyzed. Patients were classified according to the presence or absence of non-inclusion criteria from the CARAVAGGIO study. Death, VTE recurrence and major bleeding during a 6-month follow-up were analyzed as secondary endpointsAims: The primary aim of this study was to assess the proportion of patients with lung cancer seen in clinical practice for acute VTE but ineligible for a RCT Secondary aims were to describe patients outcomes according to eligibility statusResults: Among the 302 patients included, 59 (19.5%) had lung cancer, in whom 39 (66.1%: 95%CI [54.02, 78.18]) were ineligible for the CARAVAGGIO study. Main exclusion criteria were: brain metastases (n=18, 46%), unusual deep vein thrombosis (n=10, 25.6%), ECOG PS>2 (n=10, 25.6%), risk of bleeding (n=8, 20.5%). At 6 months, the event-free survival rate was similar among groupsConclusion: Among patients with VTE associated with lung cancer, more than a half would have not been able to participate in a trial as CARAVAGGIO. Evaluation of DOACs safety and efficacy in these specific setting needs further researc

Cancer-associated thrombosis: how many patients seen in clinical practice would be eligible to a randomized controlled trial?

11th International Conference on Thrombosis and Hemostasis Issues in Cancer (ICTHIC), Bergamo, ITALY, MAY 27-29, 2022International audienc

Heart Rate and Mortality in Patients With Acute Symptomatic Pulmonary Embolism

Background: The association between heart rate (HR) and pulmonary embolism (PE) outcomes has not been well studied. Furthermore, optimal cutoffs to identify low-risk and intermediate- to high-risk patients are not well known. Research Question: Does an association exist between baseline HR and PE outcome across the continuum of HR values? Study Design and Methods: The current study included 44,331 consecutive nonhypotensive patients with symptomatic PE from the Registro Informatizado de la Enfermedad TromboEmbólica registry between 2001 and 2021. Outcomes included 30-day all-cause and PE-specific mortality. We used hierarchical logistic regression to assess the association between admission HR and outcomes. Results: A positive relationship was found between admission HR and 30-day all-cause and PE-related mortality. Considering an HR of 80 to 99 beats/min as a reference, patients in the higher HR strata showed higher rates of all-cause death (adjusted OR, 1.5 for HR of 100-109 beats/min; adjusted OR, 1.7 for HR of 110-119 beats/min; adjusted OR, 1.9 for HR of 120-139 beats/min; and adjusted OR, 2.4 for HR of ≥ 140 beats/min). Patients in the lower strata of HR showed significantly lower rates of 30-day all-cause mortality compared with the same reference group (adjusted OR, 0.6 for HR of 60-79 beats/min; and adjusted OR, 0.5 for HR of < 60 beats/min). The findings for 30-day PE-related mortality were similar. For identification of low-risk patients, a cutoff value of 80 beats/min (vs 110 beats/min) increased the sensitivity of the simplified Pulmonary Embolism Severity Index (sPESI) from 93.4% to 98.8%. For identification of intermediate- to high-risk patients, a cutoff value of 140 beats/min (vs 110 beats/min) increased the specificity of the Bova score from 93.2% to 98.0%. Interpretation: In nonhypotensive patients with acute symptomatic PE, a high HR portends an increased risk of all-cause and PE-related mortality. Modifying the HR cutoff in the sPESI and the Bova score improves prognostication of patients with PE

Liver status and outcomes in patients without previous known liver disease receiving anticoagulant therapy for venous thromboembolism

The association between elevated liver enzymes or FIB-4 (fibrosis index 4) and outcome in patients with venous thromboembolism (VTE) has not been evaluated. Data from patients in RIETE (Registro Informatizado Enfermedad TromboEmbólica) were used to assess the association between elevated liver enzymes or FIB-4 levels and the rates of major bleeding or death in apparent liver disease-free patients with acute VTE under anticoagulation therapy. A total of 6206 patients with acute VTE and without liver disease were included. Of them, 92 patients had major bleeding and 168 died under anticoagulation therapy. On multivariable analysis, patients with elevated liver enzymes were at increased mortality risk (HR: 1.58; 95% CI: 1.10–2.28), while those with FIB-4 levels > 2.67 points were at increased risk for major bleeding (HR: 1.69; 95% CI: 1.04–2.74). Evaluation of liver enzymes and FIB-4 index at baseline in liver disease-free patients with VTE may provide additional information on the risk for major bleeding or death during anticoagulation

Edoxaban for the Long-Term Therapy of Venous Thromboembolism: Should the Criteria for Dose Reduction be Revised?

Edoxaban is used for venous thromboembolism (VTE) treatment. Real-life data are lacking about its use in long-term therapy. We aimed to assess the efficacy and the safety of edoxaban for long-term VTE treatment in a real-life setting. Patients with VTE included in the Registro Informatizado Enfermedad TromboEmb\uf3lica (RIETE) registry, receiving edoxaban 60 or 30&nbsp;mg daily were prospectively followed up to validate the benefit of using different dosages. The main outcome was the composite of VTE recurrences or major bleeding in patients with or without criteria for dose reduction. Multivariable analysis to identify predictors for the composite outcome was performed. From October 2015 to November 2019, 562 patients received edoxaban for long-term therapy. Most (94%) of the 416 patients not meeting criteria for dose reduction received 60&nbsp;mg daily, and 92 patients meeting criteria (63%) received 30&nbsp;mg daily. During treatment, two patients developed recurrent VTE, six had major bleeding and nine died (2 from fatal bleeding). Among patients not meeting criteria for dose reduction, those receiving 30&nbsp;mg daily had a higher rate of the composite event (hazard ratio (HR) 8.37; 95% confidence interval (CI) 1.12\u201342.4) and a significant higher mortality rate (HR 31.1; 95% CI 4.63\u2013262) than those receiving 60&nbsp;mg. Among patients meeting criteria for dose reduction, those receiving 60&nbsp;mg daily had no events, and a nonsignificantly higher mortality rate (HR 5.04; 95% CI 0.54\u2013133) than those receiving 30&nbsp;mg daily. In conclusion, edoxaban seems to be effective and safe for long-term VTE treatment in real life. Criteria for dose reduction should be reformulated