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.

Thrombotic Thrombocytopenia after ChAdOx1 nCov-19 Vaccination.

BACKGROUND: Several cases of unusual thrombotic events and thrombocytopenia have developed after vaccination with the recombinant adenoviral vector encoding the spike protein antigen of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) (ChAdOx1 nCov-19, AstraZeneca). More data were needed on the pathogenesis of this unusual clotting disorder. METHODS: We assessed the clinical and laboratory features of 11 patients in Germany and Austria in whom thrombosis or thrombocytopenia had developed after vaccination with ChAdOx1 nCov-19. We used a standard enzyme-linked immunosorbent assay to detect platelet factor 4 (PF4)-heparin antibodies and a modified (PF4-enhanced) platelet-activation test to detect platelet-activating antibodies under various reaction conditions. Included in this testing were samples from patients who had blood samples referred for investigation of vaccine-associated thrombotic events, with 28 testing positive on a screening PF4-heparin immunoassay. RESULTS: Of the 11 original patients, 9 were women, with a median age of 36 years (range, 22 to 49). Beginning 5 to 16 days after vaccination, the patients presented with one or more thrombotic events, with the exception of 1 patient, who presented with fatal intracranial hemorrhage. Of the patients with one or more thrombotic events, 9 had cerebral venous thrombosis, 3 had splanchnic-vein thrombosis, 3 had pulmonary embolism, and 4 had other thromboses; of these patients, 6 died. Five patients had disseminated intravascular coagulation. None of the patients had received heparin before symptom onset. All 28 patients who tested positive for antibodies against PF4-heparin tested positive on the platelet-activation assay in the presence of PF4 independent of heparin. Platelet activation was inhibited by high levels of heparin, Fc receptor-blocking monoclonal antibody, and immune globulin (10 mg per milliliter). Additional studies with PF4 or PF4-heparin affinity purified antibodies in 2 patients confirmed PF4-dependent platelet activation. CONCLUSIONS: Vaccination with ChAdOx1 nCov-19 can result in the rare development of immune thrombotic thrombocytopenia mediated by platelet-activating antibodies against PF4, which clinically mimics autoimmune heparin-induced thrombocytopenia. (Funded by the German Research Foundation.).

How I manage cyclic thrombocytopenia.

Cyclic thrombocytopenia (CTP) is a rare disease, which is characterized by periodic fluctuation of the platelet count. The pathogenesis of CTP is unknown and most likely heterogeneous. Patients with CTP are almost always misdiagnosed as having primary immune thrombocytopenia (ITP). The interval between ITP and CTP diagnosis can be many years. CTP patients often receive ITP-specific therapies including corticosteroids, thrombopoietin receptor agonists, rituximab, and splenectomy, which are followed by a transient increase in platelet count that is wrongly attributed to treatment effect with inevitable "relapse." CTP can be diagnosed by frequent platelet count monitoring, which reveals a typical pattern of periodic platelet cycling. An early diagnosis of CTP will prevent these patients from being exposed to possibly harmful therapies. The bleeding phenotype is usually mild and consists of mucocutaneous bleeding at the time when the platelet count is at its nadir. Severe bleeding from other sites can occur but is rare. Some patients respond to cyclosporine A or to danazol, but most patients do not respond to any therapy. CTP can be associated with hematological malignancies or disorders of the thyroid gland. Nevertheless, spontaneous remissions can occur, even after many years.

Long-Term Risk for Major Bleeding During Extended Oral Anticoagulant Therapy for First Unprovoked Venous Thromboembolism : A Systematic Review and Meta-analysis.

BACKGROUND: The long-term risk for major bleeding in patients receiving extended (beyond the initial 3 to 6 months) anticoagulant therapy for a first unprovoked venous thromboembolism (VTE) is uncertain. PURPOSE: To determine the incidence of major bleeding during extended anticoagulation of up to 5 years among patients with a first unprovoked VTE, overall, and in clinically important subgroups. DATA SOURCES: MEDLINE, Embase, and the Cochrane Central Register of Controlled Trials from inception to 23 July 2021. STUDY SELECTION: Randomized controlled trials (RCTs) and prospective cohort studies reporting major bleeding among patients with a first unprovoked VTE who were to receive oral anticoagulation for a minimum of 6 additional months after completing at least 3 months of initial anticoagulant treatment. DATA EXTRACTION: Two reviewers independently abstracted data and assessed study quality. Unpublished data required for analyses were obtained from authors of included studies. DATA SYNTHESIS: Among the 14 RCTs and 13 cohort studies included in the analysis, 9982 patients received a vitamin K antagonist (VKA) and 7220 received a direct oral anticoagulant (DOAC). The incidence of major bleeding per 100 person-years was 1.74 events (95% CI, 1.34 to 2.20 events) with VKAs and 1.12 events (CI, 0.72 to 1.62 events) with DOACs. The 5-year cumulative incidence of major bleeding with VKAs was 6.3% (CI, 3.6% to 10.0%). Among patients receiving either a VKA or a DOAC, the incidence of major bleeding was statistically significantly higher among those who were older than 65 years or had creatinine clearance less than 50 mL/min, a history of bleeding, concomitant use of antiplatelet therapy, or a hemoglobin level less than 100 g/L. The case-fatality rate of major bleeding was 8.3% (CI, 5.1% to 12.2%) with VKAs and 9.7% (CI, 3.2% to 19.2%) with DOACs. LIMITATION: Data were insufficient to estimate incidence of major bleeding beyond 1 year of extended anticoagulation with DOACs. CONCLUSION: In patients with a first unprovoked VTE, the long-term risks and consequences of anticoagulant-related major bleeding are considerable. This information will help inform patient prognosis and guide decision making about treatment duration for unprovoked VTE. PRIMARY FUNDING SOURCE: Canadian Institutes of Health Research. (PROSPERO: CRD42019128597).

European position paper on the management of patients with patent foramen ovale. Part II - Decompression sickness, migraine, arterial deoxygenation syndromes and select high-risk clinical conditions.

Patent foramen ovale (PFO) is implicated in the pathogenesis of a number of medical conditions but to date only one official position paper related to left circulation thromboembolism has been published. This interdisciplinary paper, prepared with the involvement of eight European scientific societies, reviews the available evidence and proposes a rationale for decision making for other PFO-related clinical conditions. In order to guarantee a strict evidence-based process, we used a modified grading of recommendations, assessment, development, and evaluation (GRADE) methodology. A critical qualitative and quantitative evaluation of diagnostic and therapeutic procedures was performed, including assessment of the risk/benefit ratio. The level of evidence and the strength of the position statements were weighed and graded according to predefined scales. Despite being based on limited and observational or low-certainty randomised data, a number of position statements were made to frame PFO management in different clinical settings, along with suggestions for new research avenues. This interdisciplinary position paper, recognising the low or very low certainty of existing evidence, provides the first approach to several PFO-related clinical scenarios beyond left circulation thromboembolism and strongly stresses the need for fresh high-quality evidence on these topics.

Circumstances of provoked recurrent venous thromboembolism: the Austrian study on recurrent venous thromboembolism.

Patients with unprovoked deep-vein thrombosis (DVT) of the leg or pulmonary embolism (PE) have a high recurrence risk. How often these recurrences are provoked by a temporary risk condition is unknown. In a cohort of patients with unprovoked venous thromboembolism (VTE), we evaluated the clinical circumstances of recurrence. We studied patients with DVT of the leg and/or PE. End point was recurrence of objectively verified symptomatic VTE. Provoked recurrence was defined according to guidance criteria. 1188 patients were followed for a median of 8.9 years after withdrawal of oral anticoagulants. 312 patients had recurrent VTE, which was provoked in 42 (13%). Recurrence was related to a major risk factor in 19, to a minor risk factor in 22, and to a persistent risk factor in one patient(s). 14 recurrences occurred after major surgery and 5 during hospitalization. Ten recurrences occurred after minor surgery, eight after trauma and three during female hormone intake. Four recurrences occurred during heparin prophylaxis. The incidence of provoked VTE recurrence appears to be low. VTE can recur when prevention is stopped or even during thromboprophylaxis. Surgery and trauma are frequent risk factors.

How I treat recurrent deep-vein thrombosis.

Deep-vein thrombosis (DVT) is regarded a chronic disease as it often recurs. DVT affects most frequently the lower limbs and hence DVT of the leg will be the focus of this article. Whereas algorithms were developed and validated for the diagnosis of a first DVT, no such well-defined strategies exist in the case of recurrence of DVT. Likewise, the scientific evidence regarding the treatment of recurrent DVT is sparse, in particular when it comes to deciding on the duration of anticoagulation. Two typical cases of recurrent DVT, one with an unprovoked DVT and one with DVT during anticoagulation, will be presented. Based on these two clinical scenarios, algorithms for the diagnosis and treatment of recurrent DVT will be put forward. The purpose of this article is to discuss strategies that can be applied in daily clinical practice by physicians who do not have access to means and measures available in specialized thrombosis centers.

Medical therapy in venous thromboembolism.

Immediate intense anticoagulation with parenteral anticoagulants (heparin or fondaparinux) followed by vitamin K antagonists is the current standard therapy for deep vein thrombosis (DVT) or nonmassive pulmonary embolism. In the future, new oral anticoagulants may replace not only vitamin K antagonists but also initial parenteral anticoagulation. Duration of anticoagulation should be at least 3 months because shorter courses double the recurrence rates. More prolonged anticoagulation therapy may be warranted in the presence of specific clinical risk factors. Global markers of coagulation, particularly D-dimer, may discriminate low- and high-risk patients. Models that combine clinical characteristics and laboratory markers further improve prediction of the recurrence risk in individual patients, but these models await validation before they can be applied in routine care.

Duration of anticoagulation after venous thrombosis.

Venous thromboembolism (VTE) is a multicausal disease which tends to recur. Recurrence can be prevented by anticoagulant treatment albeit at the cost of bleeding. Deciding on the optimal duration of anticoagulation is based on balancing the risk of recurrence and of bleeding in case anticoagulation is continued. Patients with VTE provoked by a transient risk factor have a low risk of recurrence and stopping anticoagulation after 3 months is recommended because the risk of bleeding likely outweighs the risk of recurrence. In patients with unprovoked VTE recurrence is high and indefinite anticoagulation should be considered. However, the majority of these patients will not suffer recurrence but thus far safe identification of low or high patients risk is not possible. Despite considerable advances in the identification of new risk factors for (recurrent) VTE, predicting the risk of recurrence in an individual patient remains a challenge. Measuring D-Dimer as a global coagulation markers and the use of prediction models that integrate clinical characteristics and laboratory markers are the most promising approaches to improve risk assessment and to optimize the duration of anticoagulation. New oral anticoagulants have been studied for treatment of patients with VTE. However, more data on the bleeding risk during extended thromboprophylaxis are needed to decide which patients may indeed benefit from these novel agents.

Plasma levels of platelet-enriched microRNAs change during antiplatelet therapy in healthy subjects.

Platelets are the main effectors of primary hemostasis but also cause thrombosis in pathological conditions. Antiplatelet drugs are the cornerstone for the prevention of adverse cardiovascular events. Monitoring the extent of platelet inhibition is essential. Currently available platelet function tests come with constraints, limiting use in antiplatelet drug development as well as in clinical routine. With this study, we aim to investigate whether plasma miRNAs might be suitable biomarkers for monitoring antiplatelet treatment. Platelet-poor plasma was obtained from a trial including 87 healthy male volunteers that either received ticagrelor (n = 44) or clopidogrel (n = 43). Blood was collected before drug intake and after 2 h, 6 h, and 24 h. We measured a panel of 11 platelet-enriched miRNAs (thrombomiRs) by RT-qPCR and selected four biomarker candidates (i.e., miR-223-3p, miR-150-5p, miR-126-3p, miR-24-3p). To further characterize those miRNAs, we performed correlation analyses with the number of extracellular vesicles and clotting time dependent on procoagulant vesicles (PPL assay). We show that platelet-enriched miRNAs in the circulation are significantly reduced upon P2Y12-mediated platelet inhibition. This effect occurred fast, reaching its peak after 2 h. Additionally, we demonstrate that higher baseline levels of thrombomiRs are linked to a stronger reduction upon antiplatelet therapy. Finally, we show that miRNAs from our panel might be the cargo of platelet-derived and procoagulant vesicles. In conclusion, we provide evidence that thrombomiR levels change within 2 h after pharmacological platelet inhibition and circulate the body within platelet-derived and procoagulant extracellular vesicles, rendering them potential biomarker candidates for the assessment of in vivo platelet function.

Absorption of Direct Oral Anticoagulants in Cancer Patients after Gastrectomy.

Direct oral anticoagulants (DOACs) are safe and effective in cancer patients treated for venous thromboembolism (VTE) or atrial fibrillation (AF). Gastrectomy is the treatment of choice in patients with localized upper gastrointestinal cancer. DOACs are absorbed in the upper gastrointestinal tract, but to what extent is unclear. In a retrospective analysis, hospital data were searched for adult patients who underwent gastrectomy for gastroesophageal or pancreatic cancer, and DOAC therapy for VTE or AF after gastrectomy. DOAC blood levels were determined by chromogenic assays before and after administration, and thromboembolic and bleeding complications were recorded. Eleven patients (median age 76 years) received a factor Xa inhibitor (FXaI; apixaban (3), edoxaban (3), rivaroxaban (4)) or the factor IIa inhibitor dabigatran (1) for VTE (7) or AF (4) after gastrectomy. Eight patients on FXaI had anti-Xa (aXa) trough levels within the expected range (ER). In all of them, aXa levels increased upon DOAC administration. Two patients on 30 mg edoxaban had low aXa trough levels. Administration of 20 mg of rivaroxaban resulted in trough levels in the ER in one of them. None of the FXaI patients had thromboembolism, while two experienced bleeding (arterial puncture site, gastrointestinal). One dabigatran AF patient with trough and peak concentrations below the ER had strokes during 110 mg and 150 mg dabigatran administration. While on apixaban, aXa levels were in the ER, and no clinical complications occurred. DOACs, particularly FXaI, were adequately absorbed in cancer patients after gastrectomy. Our observation of recurrent thromboembolic events in a patient treated with dabigatran warrants cautious use in this specific patient population.

Extracellular Vesicles and Citrullinated Histone H3 in Coronavirus Disease 2019 Patients.

OBJECTIVES: Pulmonary thrombus formation is a hallmark of coronavirus disease 2019 (COVID-19). A dysregulated immune response culminating in thromboinflammation has been described, but the pathomechanisms remain unclear. METHODS: We studied 41 adult COVID-19 patients with positive results on reverse-transcriptase polymerase-chain-reaction assays and 37 sex- and age-matched healthy controls. Number and surface characteristics of extracellular vesicles (EVs) and citrullinated histone H3 levels were determined in plasma upon inclusion by flow cytometry and immunoassay. RESULTS: In total, 20 patients had severe and 21 nonsevere disease. The number of EV (median [25th, 75th percentile]) was significantly higher in patients compared with controls (658.8 [353.2, 876.6] vs. 435.5 [332.5, 585.3], geometric mean ratio [95% confidence intervals]: 2.6 [1.9, 3.6]; p < 0.001). Patients exhibited significantly higher numbers of EVs derived from platelets, endothelial cells, leukocytes, or neutrophils than controls. EVs from alveolar-macrophages and alveolar-epithelial cells were detectable in plasma and were significantly higher in patients. Intercellular adhesion molecule-1-positive EV levels were higher in patients, while no difference between tissue factor-positive and angiotensin-converting enzyme-positive EV was seen between both groups. Levels of EV did not differ between patients with severe and nonsevere COVID-19. Citrullinated histone H3 levels (ng/mL, median [25th, 75th percentile]) were higher in patients than in controls (1.42 [0.6, 3.4] vs. 0.31 [0.1, 0.6], geometric mean ratio: 4.44 [2.6, 7.7]; p < 0.001), and were significantly lower in patients with nonsevere disease compared with those with severe disease. CONCLUSION: EV and citrullinated histone H3 are associated with COVID-19 and could provide information regarding pathophysiology of the disease.

Risk assessment of recurrence in patients with unprovoked deep vein thrombosis or pulmonary embolism: the Vienna prediction model.

BACKGROUND: Predicting the risk of recurrent venous thromboembolism (VTE) in an individual patient is often not feasible. We aimed to develop a simple risk assessment model that improves prediction of the recurrence risk. METHODS AND RESULTS: In a prospective cohort study, 929 patients with a first unprovoked VTE were followed up for a median of 43.3 months after discontinuation of anticoagulation. We excluded patients with a strong thrombophilic defect such as a natural inhibitor deficiency, the lupus anticoagulant, and homozygous or combined defects. A total of 176 patients (18.9%) had recurrent VTE. Preselected clinical and laboratory variables (age, sex, location of VTE, body mass index, factor V Leiden, prothrombin G20210A mutation, D-dimer, and in vitro thrombin generation) were analyzed in a Cox proportional hazards model, and those variables that were significantly associated with recurrence were used to compute risk scores. Male sex (hazard ratio versus female sex 1.90, 95% confidence interval 1.31 to 2.75), proximal deep vein thrombosis (hazard ratio versus distal 2.08, 95% confidence interval 1.16 to 3.74), pulmonary embolism (hazard ratio versus distal thrombosis 2.60, 95% confidence interval 1.49 to 4.53), and elevated levels of D-dimer (hazard ratio per doubling 1.27, 95% confidence interval 1.08 to 1.51) were related to a higher recurrence risk. Using these variables, we developed a nomogram that can be used to calculate risk scores and to estimate the cumulative probability of recurrence in an individual patient. The model was cross validated, and patients were assigned to different risk categories based on their risk score. Recurrence rates corresponded well with the different risk categories. CONCLUSIONS: By use of a simple scoring system, the assessment of the recurrence risk in patients with a first unprovoked VTE and without strong thrombophilic defects can be improved.

D-dimer levels over time after anticoagulation and the association with recurrent venous thromboembolism.

INTRODUCTION: D-dimer measured shortly after discontinuation of anticoagulation by an immunoturbidimetric assay predicts the risk of recurrent venous thromboembolism (VTE). We assessed the performance of this assay over time and its association with recurrent VTE. MATERIALS AND METHODS: We followed 556 patients with a first VTE for a median of 9.6 years. The study end point was recurrent VTE. D-dimer was measured 3 weeks, and 3, 9, and 15 months after discontinuation of anticoagulation in plasma using an immunoturbidimetric assay (INNOVANCE D-Dimer). To estimate the effect of longitudinal D-dimer on the recurrence risk, we used a dynamic prediction Cox model with landmark times (3 weeks, and 3, 9, 15 months) as a stratification factor. RESULTS: 135 patients had recurrent VTE. D-dimer levels varied between patients but without a consistent pattern. Levels increased slightly over time [0.7% increase (95% CI: 0.5-0.9; p < 0.001)/month]. D-dimer levels were positively correlated with body mass index (BMI) [2% (95% CI: 1.1-2.9; p < 0.001) increase/1 unit BMI increase], and were 14.8% (95% CI: 5.1-25.3; p = 0.002) higher in women than in men. The recurrence risk with doubling D-dimer levels was higher after 3 weeks, 3, 9 and 15 months [hazard ratios 1.4 (1.06-1.84), 1.37 (1.06-1.77), 1.31 (1.04-1.65) and 1.26 (1.01-1.57), respectively]. CONCLUSIONS: In patients with a first VTE, immunoturbidimetric D-dimer levels are associated with the risk of recurrence at multiple times points from 3 weeks up to 15 months after discontinuation of oral anticoagulation.

MicroRNA Signatures in Plasma of Patients With Venous Thrombosis: A Preliminary Report.

BACKGROUND: Venous thromboembolism (VTE) is a frequent and potentially fatal disease, but its pathophysiology is incompletely understood. microRNAs (miR) dysregulate hemostatic proteins and influence thrombotic pathology by posttranscriptional regulation of gene expression. Consensus in defining VTE-related miR clusters and functionally relevant miR has not been reached. We aimed to generate a miR database in patients at high thrombotic risk of VTE and explored their biological functions by seeking information on their messenger RNA targets. METHODS: By high-throughput screening (Affymetrix miRNA Microarray), we identified 159 miR in venous blood of male patients who had two unprovoked VTE and in age-matched male controls. RESULTS: Of the 159 miR, 41 were significantly higher expressed in patients compared to controls. Six miR (hsa-miR-6798-3p, hsa-miR-6789-5p hsa-miR-4651, hsa-miR-6765-5p, hsa-miR-6816-5p, hsa-miR-4734) were modulated ≥ 5.0-fold higher. Higher expression levels of 4 of these miR (hsa-miR-6789-5p, hsa-miR-4651, hsa-miR-6765-5p, and hsa-miR-6816-5p; primers were unavailable for hsa-miR-6798-3p and hsa-miR-4734) were confirmed by quantitative real-time polymerase chain reaction in 10 independent patients and 10 control samples. Ingenuity Pathway Analysis identified 23 altered miR including hsa-miR-6789-5p, hsa-miR-4651, hsa-miR-6765-5p and hsa-miR-4734 as the main regulators of messenger RNAs involved in the pathology of VTE. Seven messenger RNA targets including thrombomodulin and four targets related to platelet function had a direct relationship to 4 identified miR. CONCLUSIONS: We provide evidence of distinct, independently validated miR signatures in patients with VTE and identified a subset of miR as main regulators of messenger RNA involved in disorders related to pathophysiologic processes in venous thrombosis development.

The EHA Research Roadmap: Blood Coagulation and Hemostatic Disorders.

In 2016, the European Hematology Association (EHA) published the EHA Roadmap for European Hematology Research1 aiming to highlight achievements in the diagnostics and treatment of blood disorders, and to better inform European policy makers and other stakeholders about the urgent clinical and scientific needs and priorities in the field of hematology. Each section was coordinated by 1-2 section editors who were leading international experts in the field. In the 5 years that have followed, advances in the field of hematology have been plentiful. As such, EHA is pleased to present an updated Research Roadmap, now including 11 sections, each of which will be published separately. The updated EHA Research Roadmap identifies the most urgent priorities in hematology research and clinical science, therefore supporting a more informed, focused, and ideally funded future for European hematology research. The 11 EHA Research Roadmap sections include Normal Hematopoiesis; Malignant Lymphoid Diseases; Malignant Myeloid Diseases; Anemias and Related Diseases; Platelet Disorders; Blood Coagulation and Hemostatic Disorders; Transfusion Medicine; Infections in Hematology; Hematopoietic Stem Cell Transplantation; CAR-T and Other Cell-based Immune Therapies; and Gene Therapy.

European position paper on the management of patients with patent foramen ovale. Part II - Decompression sickness, migraine, arterial deoxygenation syndromes and select high-risk clinical conditions.

Patent foramen ovale (PFO) is implicated in the pathogenesis of a number of medical conditions but to date only one official position paper related to left circulation thromboembolism has been published. This interdisciplinary paper, prepared with the involvement of eight European scientific societies, reviews the available evidence and proposes a rationale for decision making for other PFO-related clinical conditions. In order to guarantee a strict evidence-based process, we used a modified grading of recommendations, assessment, development, and evaluation (GRADE) methodology. A critical qualitative and quantitative evaluation of diagnostic and therapeutic procedures was performed, including assessment of the risk/benefit ratio. The level of evidence and the strength of the position statements were weighed and graded according to predefined scales. Despite being based on limited and observational or low-certainty randomised data, a number of position statements were made to frame PFO management in different clinical settings, along with suggestions for new research avenues. This interdisciplinary position paper, recognising the low or very low certainty of existing evidence, provides the first approach to several PFO-related clinical scenarios beyond left circulation thromboembolism and strongly stresses the need for fresh high-quality evidence on these topics.