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Over the last decade, the advent of direct oral anticoagulants (DOACs) has rapidly changed the landscape of anticoagulation. In the early 2010s, DOACs became widely available for stroke prevention in atrial fibrillation and the treatment of venous thromboembolism. About 10 years later, approximately two-thirds of patients requiring oral anticoagulant treatment were receiving a DOAC. The results of several post-marketing studies consistently confirmed the findings of phase 3 clinical trials, and research has focused on new areas of development, with heterogeneous results. A role for DOACs has emerged for patients with peripheral artery disease and other challenging conditions, such as cancer-associated thrombosis, unusual-site venous thromboembolism, and end-stage renal disease. Conversely, clinical trials showed that DOACs were not efficacious in patients with valvular atrial fibrillation, mechanical heart valves, embolic strokes of undetermined source, or antiphospholipid syndrome. In this Review, we discuss the impact of DOACs in clinical practice over the last decade, new areas under development, and practical issues in the management of these drugs., Competing Interests: Declaration of interests WA participated in advisory boards for AstraZeneca, BMS-Pfizer, LEO Pharma, Norgine, Sanofi, and Viatris. All other authors declare no competing interests., (Copyright © 2024 Elsevier Ltd. All rights reserved, including those for text and data mining, AI training, and similar technologies.)

Background: Optimal anticoagulation management in patients with myeloproliferative neoplasms (MPN) experiencing splanchnic vein thrombosis (SpVT) requires balancing risks of bleeding and recurrent thrombosis., Objectives: We conducted a systematic review and meta-analysis to assess the incidence of bleeding and thrombosis recurrence in patients with MPN-SpVT., Methods: We included retrospective or prospective studies in English with ≥10 adult patients with MPN-SpVT. Outcomes included recurrent venous thrombosis (SpVT and non-SpVT), arterial thrombosis, and major bleeding. Pooled rates per 100 patient years with 95% CIs were calculated by DerSimonian-Laird method using random-effects model., Results: Out of 4624 studies screened, 9 studies with a total of 443 patients were included in the meta-analysis with median follow-up of 3.5 years. In the 364 patients with MPN-SpVT treated with anticoagulation, pooled event rate for major bleeding was 2.8 (95% CI, 1.5-5.1; I 2  = 95%), for recurrent venous thrombosis was 1.4 (95% CI, 0.8-2.2; I 2  = 72%), and for arterial thrombosis was 1.4 (95% CI, 0.6-3.3; I 2  = 92%) per 100 patient years. Among 79 patients (n = 4 studies) who did not receive anticoagulation, pooled event rate for major bleeding was 3.2 (95% CI, 0.7-12.7; I 2  = 97%), for recurrent venous thrombosis 3.5 (95% CI, 1.8-6.4; I 2  = 88%), and for arterial thrombosis rate 1.6 (95% CI, 0.4-6.6; I 2  = 95%) per 100 patient years., Conclusion: Patients with MPN-SpVT treated with anticoagulation have significant risks for both major bleeding and thrombosis recurrence. Further studies are necessary to determine the optimal anticoagulation approach in patients with MPN-SpVT., Competing Interests: Declaration of competing interests P.C., K.B., G.M.G., T.C., A.N., M.M., N.R., G.S., S.A., M.L., and J.B. have no conflict of interest. B.S. received grant support from AstraZeneca and Eisai, speaker honoraria from Eisai, and travel support from AbbVie, AstraZeneca, Ipsen, and Gilead, all not related to this study. P.E.R. has received research funding from Terrafirma; acted as a consultant for Hemostod, Mursla, Genfit, Boehringer Ingelheim, and Abbelight; received speaker fees from Tillots Pharma and AbbVie; and is supported by the Fondation pour la Recherche Médicale (FRM EQU202303016287), “Institut National de la Santé et de la Recherche Médicale” (ATIP AVENIR), the “Agence Nationale pour la Recherche” (ANR-18-CE14-0006-01, RHU QUID-NASH, ANR-18-IDEX-0001, ANR-22-CE14-0002), the “Émergence, Ville de Paris,” the Fondation ARC, the European Union’s Horizon 2020 research and innovation program under grant agreement number 847949, and by France 2030 Recherche Hospitalo-Universitaire Liver-Track, all not related to this study. W.A. has received research support from Bayer and has participated in advisory boards for AstraZeneca, Bayer, BMS-Pfizer, Leo Pharma, Norgine, Sanofi, and Viatris, all not related to this study. J.I.Z. has received research funding from Incyte and Quercegen; consultancy services to Sanofi, CSL, and Parexel; and honoraria from/advisory board participation with Pfizer/Bristol Myers Squibb (BMS), all outside current work. R.P. has received consultancy services from Merck Research Laboratory-Consultant, all outside the current work., (Copyright © 2024 International Society on Thrombosis and Haemostasis. Published by Elsevier Inc. All rights reserved.)

Background: Systematic reviews (SRs) are time-consuming and labor-intensive to perform. With the growing number of scientific publications, the SR development process becomes even more laborious. This is problematic because timely SR evidence is essential for decision-making in evidence-based healthcare and policymaking. Numerous methods and tools that accelerate SR development have recently emerged. To date, no scoping review has been conducted to provide a comprehensive summary of methods and ready-to-use tools to improve efficiency in SR production., Objective: To present an overview of primary studies that evaluated the use of ready-to-use applications of tools or review methods to improve efficiency in the review process., Methods: We conducted a scoping review. An information specialist performed a systematic literature search in four databases, supplemented with citation-based and grey literature searching. We included studies reporting the performance of methods and ready-to-use tools for improving efficiency when producing or updating a SR in the health field. We performed dual, independent title and abstract screening, full-text selection, and data extraction. The results were analyzed descriptively and presented narratively., Results: We included 103 studies: 51 studies reported on methods, 54 studies on tools, and 2 studies reported on both methods and tools to make SR production more efficient. A total of 72 studies evaluated the validity (n = 69) or usability (n = 3) of one method (n = 33) or tool (n = 39), and 31 studies performed comparative analyses of different methods (n = 15) or tools (n = 16). 20 studies conducted prospective evaluations in real-time workflows. Most studies evaluated methods or tools that aimed at screening titles and abstracts (n = 42) and literature searching (n = 24), while for other steps of the SR process, only a few studies were found. Regarding the outcomes included, most studies reported on validity outcomes (n = 84), while outcomes such as impact on results (n = 23), time-saving (n = 24), usability (n = 13), and cost-saving (n = 3) were less often evaluated., Conclusion: For title and abstract screening and literature searching, various evaluated methods and tools are available that aim at improving the efficiency of SR production. However, only few studies have addressed the influence of these methods and tools in real-world workflows. Few studies exist that evaluate methods or tools supporting the remaining tasks. Additionally, while validity outcomes are frequently reported, there is a lack of evaluation regarding other outcomes., (© 2024. The Author(s).)

Splanchnic vein thrombosis (SVT) is a rare type of venous thromboembolism occurring within the splanchnic venous system. Portal vein thrombosis is the most common presentation, while Budd-Chiari syndrome is the least common. Liver cirrhosis and abdominal solid cancer are the main local risk factors for SVT, whereas myeloproliferative neoplasms are the predominant systemic risk factors. Signs and symptoms of SVT are nonspecific and include abdominal pain, gastrointestinal bleeding, and ascites. Asymptomatic SVT is not uncommon, and the majority would be detected incidentally on routine abdominal imaging performed for the follow-up of liver diseases and tumors. The management of SVT aims to prevent thrombus progression, promote vessel recanalization, and prevent recurrent venous thromboembolism. Anticoagulation should be started early in order to increase the chances of vessel recanalization and reduce the risk of portal hypertension-related complications. Direct oral anticoagulants have been included in recent guidelines, as alternatives to vitamin K antagonists, after clinical stability has been reached; however, caution is required in patients with liver or kidney dysfunction. Treatment duration is based on the presence (or absence) and type (transient vs. permanent) of risk factors. This narrative review aims to summarize the latest evidence on SVT, with a particular focus on the anticoagulant treatment in special categories of patients (e.g., liver cirrhosis, solid cancer, myeloproliferative neoplasms, pancreatitis, incidentally detected SVT, Budd-Chiari syndrome, and chronic SVT)., Competing Interests: The authors declare that they have no conflict of interest., (Thieme. All rights reserved.)

Introduction: There is unmet need in the treatment of ovarian and testicular germ cell tumors (GCTs). This study analyzed registered trials of interventions for GCTs., Materials and Methods: We included trials of interventions for GCTs registered on ClinicalTrials.gov by July 29, 2022. We analyzed their interventions, outcome measures and study design., Results: We included 142 trials registrations; 42 (30 %) for ovarian GCTs, 50 (35 %) for testicular GCTs, and 50 (35 %) trials for both. The majority of the trials were completed (56 %) and did not have results available (75 %). Most trials were in Phase 2. Information about the study design were not reported for many analyzed trials. Most trials had a single-group assignment (44 %) and were open-label (68 %). The median planned number of enrolled participants was 43. Most registrations used medicine(s) (87 %), either as a single type of intervention or in combination. The most commonly used type of medicine was chemotherapy (54 %). Primary outcome was not reported in 23 % of registrations, and secondary outcomes were not reported in 35 % of registrations. Overall survival was used in 6 % of registrations as a primary outcome and in 31 % of registrations as a secondary outcome., Conclusions: Few trials on GCTs were registered on ClinicalTrials.gov, and their number was declining in recent times. Most registrations did not report relevant information about the study design, or results if completed. More effort is needed to foster trials on GCTs, as well as to optimize the management of the registrations and foster the publication of research results., Competing Interests: Declaration of competing interest The authors declare they do not have any conflict of interest., (Copyright © 2024 Elsevier Ltd, BASO ~ The Association for Cancer Surgery, and the European Society of Surgical Oncology. All rights reserved.)

Background: The role of anticoagulation in ovarian vein thrombosis (OVT) is uncertain., Objectives: We aimed to evaluate safety and efficacy of anticoagulant treatment in OVT patients., Methods: A systematic search was conducted in MEDLINE, EMBASE, and Cochrane Central Register of Controlled Trials databases up to April 2024. Eligible studies included randomized controlled trials and observational studies enrolling at least 10 adult patients with objectively diagnosed OVT and treated with any anticoagulants. The protocol was prospectively registered in the International Prospective Register of Systematic Reviews (CRD42021270883)., Results: We included 17 observational studies (621 anticoagulated and 376 nonanticoagulated OVT patients); 9 studies enrolled mainly pregnancy/puerperium-related OVT. Most patients received heparins alone (45.7%) or proceeded to vitamin K antagonists (39.2%). The average treatment duration was ≤3 months in 8 studies (47.1%), >3 to ≤6 months in 6 studies (35.3%), and >6 months in 3 studies (17.6%). In treated patients, mortality rate was 2.43% (95% CI, 0.54%-5.41%; I 2  = 53.8%; 12/406 patients; 13 studies), major bleeding was 1.27% (95% CI, 0.48%-2.38%; I 2  = 2.5%; 7/583 patients; 15 studies), recurrent venous thromboembolism (VTE) was 3.49% (95% CI, 1.12%-6.95%; I 2  = 63.5%; 22/482 patients; 15 studies), and vessel recanalization was 89.4% (95% CI, 74.6%-98.6%; I 2  = 80.6%; 163/184 patients; 8 studies). The rate of recurrent VTE in untreated patients was 8.65% (95% CI, 2.61%-17.35%); however, the difference compared with treated patients was not statistically significant (risk ratio, 0.70; 95% CI, 0.36-1.37). At subgroup analyses, the rates of major bleeding and recurrent VTE were 0.80% (95% CI, 0.0-2%.17%) and 3.81% (95% CI, 0.42%-9.63%) in pregnancy/puerperium-related OVT, respectively, and 1.12% (95% CI, 0.32%-2.34%) and 1.78% (95% CI, 0.62%-3.46%), respectively, when analyzing only full-text studies., Conclusion: There is paucity of literature regarding OVT. Our results suggest that anticoagulation is associated with low rates of major bleeding and recurrent VTE., (© 2024 The Authors.)

Background: Hemophilic arthropathy usually affects the knees bilaterally. In order to reduce costs and improve rehabilitation, bilateral simultaneous total knee arthroplasty (TKA) can be performed. However, pharmacological prophylaxis for deep venous thrombosis (DVT) remains controversial in patients with severe hemophilia. The purpose of this study was to establish the incidence of DVT in severe hemophilia A patients undergoing bilateral simultaneous TKA without pharmacological thromboprophylaxis., Methods: Consecutive patients with severe hemophilia A undergoing bilateral simultaneous TKA at a single center between January 2015 and December 2020 were retrospectively reviewed. All patients received a modified coagulation factor substitution regimen. Tranexamic acid (TXA) was used for hemostasis in all patients during surgery. All patients followed a standardized postoperative protocol with routine mechanical thromboprophylaxis, and none received anticoagulation. D-dimer was measured preoperatively, on the day of the operation and on postoperative days 1, 7 and 14. Ultrasound (US) of the lower extremities was performed before (within 3 days of hospitalization) and after surgery (days 3 and 14) to detect asymptomatic DVT. Patients were followed up until 2 years after surgery for the development of symptomatic DVT or pulmonary embolism (PE)., Results: 38 male patients with severe hemophilia A underwent 76 simultaneous TKAs. Mean (± standard deviation) age at the time of operation was 41.7 (± 17.1) years. Overall, 47.3% of patients had D-dimer concentrations above the threshold 10 µg/mL on day 7 and 39.5% on day 14. However, none of the patients had DVT detected on postoperative US, nor developed symptomatic DVT or PE during the 2-year follow-up., Conclusions: The risk of DVT in patients with severe hemophilia A after bilateral simultaneous TKA is relatively low, and routine pharmacological thromboprophylaxis may not be needed., (© 2024. The Author(s).)

The treatment of painful KOA in adult patients with ITP has not been well studied yet. We conducted a prospective, double-blind, randomized, placebo-controlled trial to evaluate the efficacy of intra-articular allogeneic PRP injections on symptoms and joint structure in patients with KOA and ITP. 80 participants were randomly allocated in a 1:1 ratio to allogeneic PRP group or saline group. The primary outcome was the WOMAC total score at 12 months post-injection. The number of patients in each group who achieved MCID of primary outcome showed a statistically significant difference only at 3-month (27/39 vs. 5/39, p  = 0.001) and 6-month (15/39 vs. 3/38, p  = 0.032). The difference in WOMAC total score exceeded the MCID only at 3 month (mean difference of -15.1 [95% CI -20.7 to -9.5], p  < 0.001). Results suggest that allogeneic PRP was superior to placebo only with respect to symptoms at 3-month of follow-up., Competing Interests: Each author certifies that he or she has no commercial associations (e.g., consultancies, stock ownership, equity interest, patent/licensing arrangements, and so forth) that might pose a conflict of interest in connection with the submitted article., (© 2024 The Authors.)

Background: Several generic formulations of rivaroxaban were recently marketed to be used interchangeably with their branded equivalent. However, there have been no previously published studies that directly compared the in vitro anticoagulant effect of branded vs. generic rivaroxaban. The aim of this in vitro study was to compare the effects of three raw rivaroxaban materials, obtained from the branded (Xarelto®) and two generic (Rivarolto® and Rivaroxaban Sandoz®) rivaroxaban formulations on an array of coagulation assays., Methods: A pool of normal plasma was spiked with several concentrations of the three rivaroxaban (range 50-750 ng/ml). The concentrations were assessed with a rivaroxaban calibrated anti-Xa assay and confirmed by ultra-high-performance liquid chromatography-mass spectrometry coupled with tandem mass spectrometry (UHPLC-MS/MS). The following assays were performed: Prothrombin time (PT), activated Partial Thromboplastin time (aPTT), Diluted Russell's Viper Venom Test (dRVVT), Thrombin time (TT), Clauss Fibrinogen, Factor VII, VIII and IX assays, and thromboelastography., Results: The results obtained by the three rivaroxaban at similar concentrations were comparable. Increasing concentrations of the three rivaroxaban showed a strong positive correlation with the PT, aPTT and dRVVT assays (r > 0.95, p < 0.01 for all), and a strong negative correlation with the Factors assays (r < -0.95, p < 0.01 for all). TT and Clauss Fibrinogen were not affected by rivaroxaban. No significant difference was identified in the mean assays' results obtained by the three rivaroxaban., Conclusion: This study showed that the branded and generic rivaroxaban exert an identical in vitro anticoagulant effect across a wide range of concentrations., Competing Interests: Declaration of competing interest The authors have no conflicts of interest to declare in relation to this study. This study was supported by grants from the University of Malta, Research Seed Fund, and from the Faculty of Health Sciences, University of Malta., (Copyright © 2024 The Authors. Published by Elsevier Ltd.. All rights reserved.)

Liver cirrhosis and splanchnic vein thrombosis (SVT) are strictly correlated. Portal vein thrombosis, the most common location of SVT, is frequently diagnosed in liver cirrhosis (pooled incidence 4.6 per 100 patient-years), and liver cirrhosis is a common risk factor for SVT (reported in 24%-28% of SVT patients). In cirrhosis-associated SVT, anticoagulant treatment reduces mortality rates, thrombosis extension, and major bleeding, and increases the rates of recanalization, compared to no treatment. Achieving vessel recanalization improves the prognosis of cirrhotic patients by reducing liver-related complications (such as variceal bleeding, ascites, hepatic encephalopathy). Anticoagulation should be therefore routinely prescribed to cirrhotic patients with acute SVT unless contraindicated by active bleeding associated with hemodynamic impairment or by excessively high bleeding risk. Of note, early treatment is associated with higher probability of achieving vessel recanalization. The standard treatment consists of low-molecular-weight heparin, followed by oral anticoagulants (eg, vitamin K antagonists or direct oral anticoagulants), if not contraindicated by severe liver dysfunction. Cirrhotic patients with SVT should be treated long-term (especially if candidate for liver transplantation) since liver cirrhosis is a persistent risk factor for recurrent thrombosis. In this review, we discuss the management of SVT in patients with liver cirrhosis, with a focus on the anticoagulant treatment in terms of indications, timing, drugs, duration, and particular scenarios, such as gastroesophageal varices and thrombocytopenia., (Copyright © 2023 by The American Society of Hematology.)

Sports medicine is generally associated with soft tissue injuries including muscle injuries, meniscus and ligament injuries, tendon ruptures, tendinopathy, rotator cuff tears, and tendon-bone healing during injuries. Tendon and ligament injuries are the most common sport injuries accounting for 30-40% of all injuries. Therapies for tendon injuries can be divided into surgical and non-surgical methods. Surgical methods mainly depend on the operative procedures, the surgeons and postoperative interventions. In non-surgical methods, cell therapy with stem cells and cell-free therapy with secretome of stem cell origin are current directions. Exosomes are the main paracrine factors of mesenchymal stem cells (MSCs) containing biological components such as proteins, nucleic acids and lipids. Compared with MSCs, MSC-exosomes (MSC-exos) possess the capacity to escape phagocytosis and achieve long-term circulation. In addition, the functions of exosomes from various cell sources in soft tissue injuries in sports medicine have been gradually revealed in recent years. Along with the biological and biomaterial advances in exosomes, exosomes can be designed as drug carriers with biomaterials and exosome research is providing promising contributions in cell biology. Exosomes with biomaterial have the potential of becoming one of the novel therapeutic modalities in regenerative researches. This review summarizes the derives of exosomes in soft tissue regeneration and focuses on the biological and biomaterial mechanism and advances in exosomal therapy in soft tissue injuries., Competing Interests: Declaration of Competing Interest We declare that we have no financial and personal relationships with other people or organizations that can inappropriately influence our work, and there is no professional or other personal interest of any nature or kind in any product, service and/or company that could be construed as influencing the position presented in, or the review of, the manuscript entitled., (Copyright © 2023 Elsevier B.V. All rights reserved.)

Cancer is associated with an increased risk of developing venous thromboembolism, due to its direct influence on the three pillars of Virchow's triad (e.g., compression on the blood vessels by the tumour, blood vessels invasion, and cytokine release), together with the effect of exogenous factors (such as chemotherapy, radiotherapy, surgery). In cancer patients, the risk of thrombosis at unusual sites, such as splanchnic, ovarian and renal vein thrombosis, is also increased. Abdominal vein thromboses are frequently incidental findings on abdominal imaging performed as part of the diagnostic/staging workup or the follow-up care of malignancies. There is little evidence on the management of unusual site venous thromboembolism in cancer patients since there are only a few specific recommendations; thus, the management follows the general principles of the treatment of cancer-associated deep vein thrombosis and pulmonary embolism. This narrative review summarises the latest evidence on cancer-associated abdominal vein thrombosis, i.e., thrombosis of the splanchnic, ovarian and renal veins.

Background: The clinical characteristics of splanchnic vein thrombosis (SVT) in pediatric patients and its optimal treatment strategies are unknown., Objectives: This study aimed to assess the effectiveness and safety of anticoagulant therapy for pediatric SVT., Methods: MEDLINE and EMBASE databases were searched up to December 2021. We included observational and interventional studies that enrolled pediatric patients with SVT and reported anticoagulant treatment and outcomes, including rates of vessel recanalization, SVT extension, venous thromboembolism (VTE) recurrence, major bleeding, and mortality. Pooled proportions of vessel recanalization were calculated with their 95% CI., Results: A total of 506 pediatric patients (aged 0-18 years) across 17 observational studies were included. The majority of patients had portal vein thrombosis (n = 308, 60.8%) or Budd-Chiari syndrome (n = 175, 34.6%). Most events were triggered by transient provoking factors. Anticoagulation (heparins and vitamin K antagonists) was prescribed in 217 (42.9%) patients, and 148 (29.2%) patients underwent vascular interventions. The overall pooled proportions of vessel recanalization were 55.3% (95% CI, 34.1%-74.7%; I 2  = 74.0%) among anticoagulated patients and 29.4% (95% CI, 2.6%-86.6%; I 2  = 49.0%) among non-anticoagulated patients. SVT extension, major bleeding, VTE recurrence, and mortality rates were 8.9%, 3.8%, 3.5%, and 10.0%, respectively, in anticoagulated patients and 2.8%, 1.4%, 0%, and 50.3%, respectively, in non-anticoagulated patients., Conclusion: In pediatric SVT, anticoagulation appears to be associated with moderate recanalization rates and a low risk of major bleeding. VTE recurrence is low and comparable to that reported in pediatric patients with other types of provoked VTE., Competing Interests: Declaration of competing interests O.C. reports IIS grants from Pfizer and personal fees from PlasFree, outside the submitted work. S.L.-M. reports grants from Pfizer and Novonordisk and personal fees from Pfizer, outside the submitted work. W.A. reports grants and personal fees from Bayer and personal fees from BMS/Pfizer, Sanofi, Viatris, and Norgine, outside the submitted work. G.K. reports grants from Pfizer and Roche; other receipts from ASC therapeutics, Bayer, Novonordisk, Pfizer, Roche, and Sanofi-Genzyme; and personal fees from Bayer, BioMarine, BPL, CSL, Pfizer, Novonordisk, Roche, Sanofi-Genzyme, Sobi, Spark, Takeda, and Uniquore, outside the submitted work. All other authors have no competing interests to disclose., (Copyright © 2023 International Society on Thrombosis and Haemostasis. Published by Elsevier Inc. All rights reserved.)

This is the protocol for a Campbell systematic review. The objectives are as follows: The main aim of this systematic review is to identify whether hospital leadership styles predict patient safety as measured through several indicators over time. The second aim is to assess the extent to which the prediction of hospital leadership styles on patient safety indicators varies as a function of the leader's hierarchy level in the organization., (© 2023 The Authors. Campbell Systematic Reviews published by John Wiley & Sons Ltd on behalf of The Campbell Collaboration.)

Background:  Computed tomography (CT) pulmonary angiography has simplified the diagnostic approach to patients with clinically suspected acute pulmonary embolism (PE), but alternative imaging tests are still advocated. We aimed to systematically assess the diagnostic accuracy of ventilation/perfusion (V/Q) and Q single-photon emission CT combined with low-dose CT (SPECT/CT) for PE diagnosis., Methods:  Studies evaluating the diagnostic accuracy of SPECT/CT for the diagnosis of acute PE were systematically searched in MEDLINE and EMBASE databases (up to August 2022). The QUADAS-2 tool was used for risk-of-bias assessment of the primary studies. A bivariate random-effects regression approach was used for summary estimates of both sensitivity and specificity. The PROSPERO registration number is CRD42021276538., Results:  Eight studies, for a total of 1,086 patients, were included. The risk of bias of all included studies was high. The weighted mean prevalence of PE was 27.1% at the random-effects model. The SPECT/CT bivariate weighted mean sensitivity was 96% (95% confidence interval [CI]: 93-98%), with a bivariate weighted mean specificity of 95% (95% CI: 90-97%). At subgroup analysis, for V/Q SPECT/CT bivariate weighted mean sensitivity and specificity were 96% (95% CI: 89-98%) and 96% (95% CI: 91-99%), while for Q SPECT/CT they were 96% (95% CI: 92-98%) and 84% (95% CI: 66-93%), respectively., Conclusion:  V/Q SPECT/CT has high sensitivity and specificity for the diagnosis of acute PE, meanwhile Q SPECT/CT has high sensitivity but limited specificity for the diagnosis of PE. Management studies will conclusively ascertain the actual role of SPECT/CT in the diagnostic workup of patients with suspected acute PE., Competing Interests: None declared., (Thieme. All rights reserved.)

Chronic kidney disease (CKD) affects around 9.1% of humankind globally resulting in a significant health burden. Some of these individuals will also require renal replacement therapy with dialysis due to complete kidney failure. Patients with CKD are known to be at increased risk of both bleeding and thrombosis. Often it is very difficult to manage these yin and yang since both risks tend to co-exist. Clinically, very few studies have looked at the effects of antiplatelet agents and anticoagulants in this highly vulnerable subgroup of medical patients and evidence is very limited. This review attempts to explain the current state-of-the-art regarding the basic science of haemostasis in patients with end-stage kidney disease. We also try to transfer this knowledge into the clinics by looking at some common haemostasis challenges that are encountered in this cohort of patients and what evidence and guidance there is for their optimal management., (© 2023 British Society for Haematology and John Wiley & Sons Ltd.)

Background: The clinical relevance and management of incidental splanchnic vein thrombosis (SVT) remain poorly defined., Objectives: The objectives of this study were to evaluate the clinical course of incidental SVT in comparison with symptomatic SVT and assess the safety and effectiveness of anticoagulant treatment in incidental SVT., Methods: Individual patient data meta-analysis of randomized controlled trials or prospective studies published up to June 2021. Efficacy outcomes were recurrent venous thromboembolism (VTE) and all-cause mortality. The safety outcome was major bleeding. Incidence rate ratios and 95% CIs for incidental vs symptomatic SVT were estimated before and after propensity-score matching. Multivariable Cox models were used considering anticoagulant treatment as a time-varying covariate., Results: In total, 493 patients with incidental SVT and 493 propensity-matched patients with symptomatic SVT were analyzed. Patients with incidental SVT were less likely to receive anticoagulant treatment (72.4% vs 83.6%). Incidence rate ratios (95% CI) for major bleeding, recurrent VTE, and all-cause mortality in patients with incidental SVT compared with symptomatic SVT were 1.3 (0.8, 2.2), 2.0 (1.2, 3.3), and 0.5 (0.4, 0.7), respectively. In patients with incidental SVT, anticoagulant therapy was associated with a lower risk of major bleeding (hazard ratio [HR] 0.41; 95% CI, 0.21 to 0.71), recurrent VTE (HR 0.33; 95% CI, 0.18 to 0.61), and all-cause mortality (HR 0.23; 95% CI, 0.15 to 0.35)., Conclusion: Patients with incidental SVT appeared to have a similar risk of major bleeding, a higher risk of recurrent thrombosis, but lower all-cause mortality than patients with symptomatic SVT. Anticoagulant therapy seemed safe and effective in patients with incidental SVT., Competing Interests: Declaration of competing interests E.V., M.C., N.R., S.M.B., M.M., J.A.D.P., J.M., A.M.D.B., V.P.C., M.S., and A.D.G. have nothing to disclose. M.D.N. received honoraria for participation at the advisory boards from Bayer, Daiichi Sankyo, Pfizer, Leo Pharma, Sanofi, and Viatris outside the submitted work. W.A. has received a research grant from Bayer to support a clinical study in patients with splanchnic vein thrombosis, received honoraria for participation at advisory boards from Bayer, BMS/Pfizer, Sanofi, Leo Pharma, and Portola, and reports grants and personal fees from Bayer, and personal fees from BMS/Pfizer, Daiichi Sankyo, Sanofi, Aspen, Janssen, Portola, and Werfen, outside the submitted work; M. Monreal received honoraria for participation at advisory boards from Bristol and Sanofi, outside the submitted work; S.S. has received research funding from Boehringer Ingelheim and Octapharma and honoraria from Bayer, Boehringer Ingelheim, Bristol-Myers Squibb, Daiichi Sankyo, Pfizer, and Sanofi; J.C.G.P. is a consulting for Cook Medical, Shionogi, WL Gore y Asociados, Vifor Pharma, and Boehringer Ingelheim and has received a research frant from Mallinckrodt and Noorik., (Copyright © 2023 International Society on Thrombosis and Haemostasis. All rights reserved.)

Background: Systematic reviews (SRs) are invaluable evidence syntheses, widely used in biomedicine and other scientific areas. Tremendous resources are being spent on the production and updating of SRs. There is a continuous need to automatize the process and use the workforce and resources to make it faster and more efficient., Methods: Information gathered by previous EVBRES research was used to construct a questionnaire for round 1 which was partly quantitative, partly qualitative. Fifty five experienced SR authors were invited to participate in a Delphi study (DS) designed to identify the most promising areas and methods to improve the efficient production and updating of SRs. Topic questions focused on which areas of SRs are most time/effort/resource intensive and should be prioritized in further research. Data were analysed using NVivo 12 plus, Microsoft Excel 2013 and SPSS. Thematic analysis findings were used on the topics on which agreement was not reached in round 1 in order to prepare the questionnaire for round 2., Results: Sixty percent (33/55) of the invited participants completed round 1; 44% (24/55) completed round 2. Participants reported average of 13.3 years of experience in conducting SRs (SD 6.8). More than two thirds of the respondents agreed/strongly agreed the following topics should be prioritized: extracting data, literature searching, screening abstracts, obtaining and screening full texts, updating SRs, finding previous SRs, translating non-English studies, synthesizing data, project management, writing the protocol, constructing the search strategy and critically appraising. Participants have not considered following areas as priority: snowballing, GRADE-ing, writing SR, deduplication, formulating SR question, performing meta-analysis., Conclusions: Data extraction was prioritized by the majority of participants as an area that needs more research/methods development. Quality of available language translating tools has dramatically increased over the years (Google translate, DeepL). The promising new tool for snowballing emerged (Citation Chaser). Automation cannot substitute human judgement where complex decisions are needed (GRADE-ing)., Trial Registration: Study protocol was registered at https://osf.io/bp2hu/ ., (© 2023. The Author(s).)

Introduction: Liver cirrhosis is accompanied by several hemostatic alterations, which contribute to the current theory of "rebalanced hemostasis." Splanchnic vein thrombosis (SVT) is a frequent complication of liver cirrhosis (17-26% of the cirrhotic patients), and liver cirrhosis is a common risk factor for SVT (24-28% of SVT cases)., Areas Covered: This narrative review aims to describe the current state of the art on the anticoagulant treatment of cirrhotic SVT, with a particular focus on the possible role of the direct oral anticoagulants (DOACs) and recent guidelines on this topic., Expert Opinion: Early anticoagulant therapy is recommended in cirrhotic patients with acute SVT, to obtain vessel recanalization and decrease the rates of portal hypertension-related complications. Gastroesophageal varices do not represent a contraindication to anticoagulation, if adequate prophylaxis of variceal bleeding is established, and varices band ligation can be safely performed without the need to stop the anticoagulant treatment. The conventional treatment of cirrhotic SVT consisted of low molecular weight heparin, as initial treatment of choice, eventually followed by vitamin K antagonists, but the DOACs can be considered as a reasonable alternative in patients with compensated liver cirrhosis.

Cancer is a major risk factor for venous thromboembolism (VTE), and cancer-associated thrombosis (CAT) constitutes approximately 15-25% of all VTE cases. For decades, the standard treatment for CAT used to be daily subcutaneous low molecular weight heparin (LMWH). Data on the safety and efficacy of the direct oral anticoagulants (DOACs) in this population emerged only in recent years and specific DOACs were included into recent guidelines recommendations. In this narrative review of the literature, we reported the results of the phase III randomized controlled trials that evaluated the DOACs for the prevention and the acute treatment of CAT. For the acute phase treatment, the anti-Xa inhibitors (apixaban, edoxaban, rivaroxaban) showed better efficacy than LMWH in preventing VTE recurrence; however, rivaroxaban and edoxaban were also associated with an increased risk of bleeding events. For primary prevention of CAT in ambulatory cancer patients starting chemotherapy, apixaban and rivaroxaban showed better efficacy than placebo but a trend towards higher bleeding rates. Recent guidelines suggest the DOACs for the treatment of CAT in selected cancer patients (eg, low bleeding risk, no luminal gastrointestinal or genitourinary malignancies, no interfering medications). The DOACs are also suggested for primary thromboprophylaxis in selected ambulatory cancer patients at high risk of VTE (eg, Khorana score ≥2 prior to starting new chemotherapy, low bleeding risk, no interfering medications)., Competing Interests: The authors have no relevant conflicts to declare in relation to this paper., (© 2022 Attard et al.)

Robust evidence on the optimal management of splanchnic vein thrombosis (SVT) is lacking. We conducted an individual-patient meta-analysis to evaluate the effectiveness and safety of anticoagulation for SVT. Medline, Embase, and clincaltrials.gov were searched up to June 2021 for prospective cohorts or randomized clinical trials including patients with SVT. Data from individual datasets were merged, and any discrepancy with published data was resolved by contacting study authors. Three studies of a total of 1635 patients were included. Eighty-five percent of patients received anticoagulation for a median duration of 316 days (range, 1-730 days). Overall, incidence rates for recurrent venous thromboembolism (VTE), major bleeding, and mortality were 5.3 per 100 patient-years (p-y; 95% confidence interval [CI], 5.1-5.5), 4.4 per 100 p-y (95% CI, 4.2-4.6), and 13.0 per 100 p-y (95% CI, 12.4-13.6), respectively. The incidence rates of all outcomes were lower during anticoagulation and higher after treatment discontinuation or when anticoagulation was not administered. In multivariable analysis, anticoagulant treatment appeared to be associated with a lower risk of recurrent VTE (hazard ratio [HR], 0.42; 95% CI, 0.27-0.64), major bleeding (HR, 0.47; 95% CI, 0.30-0.74), and mortality (HR, 0.23; 95% CI, 0.17-0.31). Results were consistent in patients with cirrhosis, solid cancers, myeloproliferative neoplasms, unprovoked SVT, and SVT associated with transient or persistent nonmalignant risk factors. In patients with SVT, the risk of recurrent VTE and major bleeding is substantial. Anticoagulant treatment is associated with reduced risk of both outcomes., (© 2022 by The American Society of Hematology. Licensed under Creative Commons Attribution-NonCommercial-NoDerivatives 4.0 International (CC BY-NC-ND 4.0), permitting only noncommercial, nonderivative use with attribution. All other rights reserved.)

Vitamin K antagonists (VKAs) are the standard oral anti-coagulant treatment for patients with cerebral venous thrombosis (CVT). However, the direct oral anti-coagulants (DOACs) started replacing VKAs also in this setting. We aimed to evaluate safety and efficacy of the DOACs for CVT treatment. We performed a systematic review and meta-analysis (PROSPERO protocol registration number CRD42020191472). The electronic databases MEDLINE, EMBASE and CENTRAL were searched from inception to January 2022. We included randomised controlled trials (RCTs) and observational studies, enrolling at least 10 adult patients with CVT treated with any DOACs. Twenty-three studies were included, for a total of 618 CVT patients treated with DOACs (treatment duration range 3-12 months). Mortality rate was 1.76% [95% confidence interval (CI) 0.70%-3.24%; I 2  = 0%; 5/428 patients, 18 studies]; major bleeding 2.41% (95% CI 1.26%-3.91%; I 2  = 1.5%; 12/534 patients, 21 studies); recurrent thrombosis 2.05% (95% CI 1.04%-3.37%; I 2  = 0%; 10/577 patients, 21 studies); excellent neurological outcome 85.9% (95% CI 79.0%-91.7%; I 2  = 63.7%; 289/340 patients, 13 studies); vessel recanalisation 89.0% (95% CI 82.9%-93.9%; I 2  = 62.7%; 316/359 patients, 16 studies). No significant differences emerged by study design (RCTs vs. observational studies) or by treatment (DOACs vs. VKAs). This systematic review showed that the DOACs might represent a reasonable oral anti-coagulant treatment option for CVT patients., (© 2022 British Society for Haematology and John Wiley & Sons Ltd.)

Heparins and vitamin K antagonists are the mainstay of treatment of splanchnic vein thrombosis (SVT). Rivaroxaban is a potential alternative, but data to support its use are limited. We aimed to evaluate the safety and efficacy of rivaroxaban for the treatment of acute SVT. In an international, single-arm clinical trial, adult patients with a first episode of noncirrhotic, symptomatic, objectively diagnosed SVT received rivaroxaban 15 mg twice daily for 3 weeks, followed by 20 mg daily for an intended duration of 3 months. Patients with Budd-Chiari syndrome and those receiving full-dose anticoagulation for >7 days prior to enrollment were excluded. Primary outcome was major bleeding; secondary outcomes included death, recurrent SVT, and complete vein recanalization within 3 months. Patients were followed for a total of 6 months. A total of 103 patients were enrolled; 100 were eligible for the analysis. Mean age was 54.4 years; 64% were men. SVT risk factors included abdominal inflammation/infection (28%), solid cancer (9%), myeloproliferative neoplasms (9%), and hormonal therapy (9%); 43% of cases were unprovoked. JAK2 V617F mutation was detected in 26% of 50 tested patients. At 3 months, 2 patients (2.1%; 95% confidence interval, 0.6-7.2) had major bleeding events (both gastrointestinal). One (1.0%) patient died due to a non-SVT-related cause, 2 had recurrent SVT (2.1%). Complete recanalization was documented in 47.3% of patients. One additional major bleeding event and 1 recurrent SVT occurred at 6 months. Rivaroxaban appears as a potential alternative to standard anticoagulation for the treatment of SVT in non-cirrhotic patients. This trial was registered at www.clinicaltrials.gov as #NCT02627053 and at eudract.ema.europa.eu as #2014-005162-29-36., (© 2022 by The American Society of Hematology. Licensed under Creative Commons Attribution-NonCommercial-NoDerivatives 4.0 International (CC BY-NC-ND 4.0), permitting only noncommercial, nonderivative use with attribution. All other rights reserved.)

Background : People resistant to vaccination against the coronavirus disease 2019 (COVID-19) pandemic have been counted in almost all countries worldwide. This anti-scientific subjectivity attitude could be explained by assuming as background the individual probability theory originally elaborated by the statistical school of de Finetti. Methods : This research method is based on a sample of 613 subjects from European countries who completed a questionnaire on attitudes towards COVID-19 vaccinations. On a six-value scale, a questionnaire investigated knowledge, assessments, degree of confidence, level of fear, anguish, and anger. Some items proposed an imaginary bet on the probability of not getting sick to deepen the possible presence of subjectivist assumptions about pandemics. Results : 50.4% were against vaccines and 52.5% against the so-called "Green Pass". Results of t-tests and correlations and stepwise regressions indicate that the sample's reasons for opposing vaccination are related to an ego centred vision of the values that assign minor, if any, confidence to authority. Conclusions : This result supports the conclusion that No Vax decisions are more based on subjectivist probabilistic assumptions, thus in line with the significant social trend called "individualism"., Competing Interests: No competing interests were disclosed., (Copyright: © 2022 Zatti A and Riva N.)

Background:  Bleeding risk is highly relevant for treatment decisions in cancer-associated thrombosis (CAT). Several risk scores exist, but have never been validated in patients with CAT and are not recommended for practice., Objectives:  To compare methods of estimating clinically relevant (major and clinically relevant nonmajor) bleeding risk in patients with CAT: (1) existing risk scores for bleeding in venous thromboembolism, (2) pragmatic classification based on cancer type, and (3) new prediction model., Methods:  In a posthoc analysis of the Hokusai VTE Cancer study, a randomized trial comparing edoxaban with dalteparin for treatment of CAT, seven bleeding risk scores were externally validated (ACCP-VTE, HAS-BLED, Hokusai, Kuijer, Martinez, RIETE, and VTE-BLEED). The predictive performance of these scores was compared with a pragmatic classification based on cancer type (gastrointestinal; genitourinary; other) and a newly derived competing risk-adjusted prediction model based on clinical predictors for clinically relevant bleeding within 6 months after CAT diagnosis with nonbleeding-related mortality as the competing event ("CAT-BLEED")., Results:  Data of 1,046 patients (149 events) were analyzed. Predictive performance of existing risk scores was poor to moderate (C-statistics: 0.50-0.57; poor calibration). Internal validation of the pragmatic classification and "CAT-BLEED" showed moderate performance (respective C-statistics: 0.61; 95% confidence interval [CI]: 0.56-0.66, and 0.63; 95% CI 0.58-0.68; good calibration)., Conclusion:  Existing risk scores for bleeding perform poorly after CAT. Pragmatic classification based on cancer type provides marginally better estimates of clinically relevant bleeding risk. Further improvement may be achieved with "CAT-BLEED," but this requires external validation in practice-based settings and with other DOACs and its clinical usefulness is yet to be demonstrated., Competing Interests: The Hokusai VTE Cancer study was sponsored and funded by Daiichi Sankyo, Inc. The authors are solely responsible for the content of this article. This study has been independently initiated by academic investigators. W.A. received research support from Bayer, and participated in advisory boards for Aspen, Bayer, Boehringer Ingelheim, Daiichi Sankyo, Janssen, Portola, and Sanofi. C.A. has received honoraria for lectures from Bayer, Daiichi Sankyo, BMS/Pfizer, and Sanofi; and participated in advisory boards for Bayer, Daiichi Sankyo, BMS/Pfizer, and Sanofi. M.C. reports research support or lecture and consultancy fees from Bayer, Boehringer Ingelheim, Pfizer, Daiichi Sankyo, Portola/Alexion, Sanquin Blood Supply Medcon International, and MEDtalks. F.A.K. reports research grants from Bayer, Bristol-Myers Squibb, Boehringer Ingelheim, Daiichi Sankyo, MSD, the Netherlands Organization for Health Research and Development, Actelion, the Dutch Heart Foundation, and the Dutch Thrombosis Association, all outside the submitted work. F.M. has served as a consultant for Bayer HealthCare Pharmaceuticals, Boehringer Ingelheim, and Sanofi, been a speaker for Bayer HealthCare Pharmaceuticals, Boehringer Ingelheim, Daiichi Sankyo, and Sanofi, and received grants from Sanofi, Bayer HealthCare, Roche Diagnosis, and LFB. P.C.R.A. reports personal fees from Bristol-Myers Squibb, Pfizer, Daiichi Sankyo, Leo Pharma, and ROVI, outside the submitted work. T.V. has received honoraria for acting as a speaker or participation in advisory boards from Bayer, Boehringer Ingelheim, Daiichi Sankyo, BMS/Pfizer, Sanofi Aventis, and Leo Pharma. M.N. reports a research grant from the Netherlands Organization for Health Research and Development. The other authors have no conflicts of interest to disclose., (Thieme. All rights reserved.)

Background: Overlapping systematic reviews (SRs) are increasingly frequent in the medical literature. They can easily generate discordant evidence, as estimates of effect sizes and their interpretation might differ from one source to another., Objective: To analyze how methodologists and clinicians make a decision when faced with discordant evidence formalized in structured tables., Methods: We conducted a 16-item survey exploring how methodologists and clinicians would react when presented with multiple Summary of Findings (SoF) tables (generated using the GRADE tool) derived from 4 overlapping and discordant SRs and meta-analyses on thrombolytic therapy for intermediate-risk pulmonary embolism. SoF tables reported 4 different magnitudes of effects and overall certainty. Participants were asked to provide their recommendations regarding the intervention and the reasons behind their conclusion., Results: Of the 80 invitees, 41 (51%) participated. The majority described themselves as "somewhat familiar" or experts with SoF tables. The majority recommended the therapy (pharmacological systemic thrombolysis), grading the recommendation as weak positive. Certainty of evidence and benefit-risk balance were the two criteria that prevailed in generating the recommendation. When faced with overlapping meta-analyses, the preferred approach was to use only high-quality SRs and exclude redundant SRs. Several participants suggested integrating the SoF tables with additional information, such as a more comprehensive evaluation of the risk of bias of systematic reviews (71%), heterogeneity/inconsistency (68%) and studies included within each SR (62%)., Conclusion: When faced with multiple controversial SR results, the type and completeness of reported information in SoF tables affect experts' ability to make recommendations. Developers of the SoF table should consider collating key information from overlapping and potentially discordant reviews., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2022 Puljak, Parmelli, Capobussi, Gonzalez-Lorenzo, Squizzato, Moja and Riva.)

Menstrual-derived Stem Cells (MenSC) are a potential novel source of mesenchymal stem cells. There is an increased interest in investigating the therapeutic potential of MenSC due to the various advantages they exhibit, when compared to other types of stem cells. MenSC are obtained non-invasively from menstrual blood. Thus, collection of MenSC is simple, reproducible and can be carried out periodically, with minimal complications. MenSC are present in abundance, are highly proliferative, exhibit a low immunogenicity and lack ethical issues. MenSC have shown the ability to differentiate into several lineages. The therapeutic potential of MenSC in non-gynaecological applications has been investigated in wound healing, neurological, musculo-skeletal, cardiovascular, respiratory, and liver disorders, as well as in diabetes and cancer. Human clinical trials are limited. To date, therapeutic efficacy and safety have been reported in patients with Avian influenza A subtype H7N9, COVID-19, congestive heart failure, multiple sclerosis and Duchene muscular dystrophy. However, further clinical trials in humans should be conducted, to study the long-term therapeutic effects of these stem cells in various diseases and to further explore their mechanism of action. This systematic review focuses on the application of MenSC in non-gynaecological diseases., (Copyright© 2022 Avicenna Research Institute.)

Portal vein thrombosis (PVT) is the most frequent among the splanchnic vein thrombosis, accounting for 90% of cases. More than half of PVT are provoked by liver cirrhosis, solid cancer or myeloproliferative neoplasms. The remaining cases are non-malignant non-cirrhotic PVT and include either unprovoked events or thrombosis secondary to other less common risk factors (e.g. abdominal surgery, intrabdominal inflammations/infections, or hormonal stimuli). Anticoagulant therapy in patients with acute symptomatic PVT should be started early after diagnosis, if no active bleeding, to obtain greater vessel recanalization and reduce the occurrence of portal-hypertension related complications. Gastroesophageal varices do not represent a contraindication to anticoagulant treatment, as long as adequate measures have been undertaken for the prophylaxis of gastroesophageal bleeding. Different treatment options (unfractionated or low molecular weight heparin, vitamin K antagonists and direct oral anticoagulants [DOACs]) can be considered. In this narrative review we will discuss the treatment of PVT in the three most common scenarios (cirrhosis-associated, cancer-associated and non-malignant non-cirrhotic PVT). We will also discuss the role of the DOACs and summarize recent guidelines on this topic.

Background: D-dimer is included in the diagnostic algorithm for deep vein thrombosis and pulmonary embolism. However, its role in the diagnosis of splanchnic vein thrombosis (SVT) is still controversial. The aim of this study was to evaluate the diagnostic accuracy of D-dimer for SVT., Methods: We performed a systematic review of the literature with meta-analysis (PROSPERO protocol registration number: CRD42020184300). The electronic databases MEDLINE, EMBASE, and CENTRAL were searched from inception to March 2021 week 4. Studies which evaluated D-dimer accuracy for SVT in any category of patients were selected. The index test was any D-dimer assay; the reference standard was any radiological imaging. The QUADAS-2 checklist was used for the risk of bias assessment. A bivariate random-effects regression model was used to calculate summary estimates of sensitivity and specificity., Results: 12 studies (with a total of 1298 patients) evaluating the accuracy of D-dimer in patients at high risk of SVT (surgical patients, patients with liver cirrhosis or hepatocellular carcinoma) were included. None of the included studies was at low risk of bias. The weighted mean prevalence of SVT was 33.4% (95% CI, 22.5-45.2%, I 2  = 94.8%). D-dimer accuracy was expressed by sensitivity 96% (95% CI, 72-100%); specificity 25% (95% CI, 5-67%); positive likelihood ratio 1.3 (95% CI, 0.9-1.9); negative likelihood ratio 0.16 (95% CI, 0.03-0.84); area under the ROC curve 0.80 (95% CI, 0.76-0.83)., Conclusions: D-dimer seems to have high sensitivity in the diagnosis of patients at high-risk for SVT. However, there is a strong need for more robust evidence on this topic., (Copyright © 2021 Elsevier Ltd. All rights reserved.)

Objectives: The results of the RECOVERY trial identified dexamethasone as the first pharmacological therapy that reduces mortality in patients with COVID-19. The aim of this paper is to conduct a systematic literature review on safety and efficacy of pulse glucocorticoid therapy for Severe Acute Respiratory Syndrome (SARS)-CoronaVirus (CoV), Middle East Respiratory Syndrome (MERS)-CoV or SARS-CoV-2 infections and describe a case-series of COVID-19 patients treated with off-label pulse doses of methylprednisolone., Methods: We performed a systematic literature review on safety and efficacy of pulse therapy for betacoronaviridae infections as described in the protocol registered on PROSPERO (CRD42020190183). All consecutive patients admitted to Arcispedale Santa Maria Nuova di Reggio Emilia or Guastalla Hospital with COVID-19 between March 1st and April 30th, 2020 and treated with methylprednisolone 1 gram/day for at least three days were included in the case series. A retrospective review of available computed tomography (CT) scan and chest x-ray was performed independently by two radiologists blinded to clinical data, and discordances were resolved by consensus., Results: Twenty papers were included for SARS, but only two were comparative and were included in the primary endpoint analysis. Likewise, eleven papers were included for COVID-19, four of which were comparative and were considered for the primary outcome analysis. Included studies for both SARS and COVID-19 are mostly retrospective and highly heterogeneous, with lethality ranging from 0% to 100% and ICU admission rate ranging from 9% to 100%. Fourteen patients were included in our case series, 7 males and 7 females., Conclusions: No randomised controlled trial is available yet for corticosteroids pulse-therapy defined as at least ≥500mg/day methylprednisolone in patients with emerging coronavirus pneumonia. Lethality among our cohort is high (4/14), but this finding should be interpreted with caution due to the fact that in our setting pulse-steroids were used in patients not eligible for other treatments because of comorbidities or as rescue therapy. The incidence of steroid-related adverse events seems low in our cohort. The quality of the evidence on glucocorticoid pulse-therapy in SARS, MERS and COVID-19 is poor. Randomised controlled trials are greatly needed.

Ovarian vein thrombosis (OVT) is a rare type of venous thromboembolism. The most common risk factors for OVT include pregnancy, oral contraceptives, malignancies, recent surgery, and pelvic infections; however, in 4 to 16% of cases, it can be classified as idiopathic. Most of the available information regards pregnancy-related OVT, which has been reported to complicate 0.01 to 0.18% of pregnancies and to peak around 2 to 6 days after delivery or miscarriage/abortion. The right ovarian vein is more frequently involved (70-80% of cases). Clinical features of OVT include abdominal pain and tenderness, fever, and gastrointestinal symptoms. The most typical finding is the presence of a palpable abdominal mass, although reported in only 46% of cases. OVT can be the cause of puerperal fever in approximately a third of women. Ultrasound Doppler is the first-line imaging, because of its safety, low cost, and wide availability. However, the ovarian veins are difficult to visualize in the presence of bowel meteorism or obesity. Thus, computed tomography or magnetic resonance imaging is often required to confirm the presence and extension of the thrombosis. In oncological patients, OVT is often an incidental finding at abdominal imaging. Mortality related to OVT is nowadays low due to the combination treatment of parenteral broad-spectrum antibiotics (until at least 48 hours after fever resolution) and anticoagulation (low-molecular-weight heparin, vitamin K antagonists, or direct oral anticoagulants). Anticoagulant treatment duration of 3 to 6 months has been recommended for postpartum OVT, while no anticoagulation has been suggested for incidentally detected cancer-associated OVT., Competing Interests: The authors declare that they have no conflict of interest., (Thieme. All rights reserved.)

Background:  Splanchnic vein thrombosis (SVT) is a common complication in patients with liver cirrhosis. The aim of this study was to evaluate the efficacy and safety of anticoagulant therapy for SVT in cirrhotic patients., Methods:  In this systematic review and meta-analysis, studies reporting on SVT recanalization and progression, recurrent venous thromboembolism (VTE), major bleeding, and overall mortality were searched in MEDLINE, EMBASE, and ClinicalTrial.gov up to December 2019. Pooled proportions and risk ratios (RRs) with corresponding 95% confidence intervals (CIs) were calculated., Results:  A total of 1,475 patients were included in 26 studies (23 observational and 3 randomized controlled trials). In patients receiving anticoagulant therapy, SVT recanalization occurred in 68% (95% CI, 62-74; 571/842 patients; 22 studies), SVT progression in 6% (95% CI, 4-9; 25/748 patients; 22 studies), recurrent VTE in 10% (95% CI, 4-22; 48/399 patients; 7 studies), major bleeding in 6% (95% CI, 4-10; 58/785 patients; 18 studies), and overall mortality in 9% (95% CI, 6-14; 68/787 patients; 17 studies). Anticoagulant treatment was associated with higher SVT recanalization (RR 3.19; 95% CI, 1.42-7.17), lower thrombosis progression (RR 0.28; 95% CI, 0.15-0.52), major bleeding (RR 0.52; 95% CI, 0.28-0.97), and overall mortality (RR 0.42; 95% CI, 0.24-0.73) compared with no treatment., Conclusion:  Anticoagulant therapy seems to improve vein recanalization and to reduce SVT progression, major bleeding, and overall mortality in cirrhotic patients with SVT. The incidence of recurrent VTE during anticoagulation remains substantial., Competing Interests: E.V., N.R., O.C., E.P., M.S., A.D.G., and M.M. have nothing to disclose. M.D.N. reports personal fees from Bayer, Daiichi Sankyo, BMS-Pfizer, Leo Pharma, Sanofi, and Aspen, outside the submitted work; J.-C. G.-P. reports other (consulting) from W.L. Gore and Associates, Cook Medical, Shionogi, Vifor Pharma, grants from Conatus Pharmaceuticals, Theravance Biopharma, Novartis, Exalenz Bioscience, outside the submitted work; W.A. has received a research grant from Bayer to support a clinical study in patients with splanchnic vein thrombosis, received personal fees from Bayer, Boehringer Inghelheim, BMS/Pfizer, Daiichi Sankyo, Sanofi, Aspen, Janssen, and Portola, outside the submitted work., (Thieme. All rights reserved.)

Aim: We aimed to evaluate the feasibility and efficiency of a guidelines-compliant NAFLD assessment algorithm in patients with newly diagnosed type 2 diabetes (T2D)., Methods: Consecutive patients aged < 75 newly diagnosed with T2D without coexisting liver disease or excessive alcohol consumption were enrolled. Patients were stratified based on liver enzymes, fatty liver index, ultrasound, fibrosis scores and liver stiffness measurement. Referral rates and positive predictive values (PPVs) for histological non-alcoholic steatohepatitis (NASH) and significant fibrosis were evaluated., Results: Of the 171 enrolled patients (age 59 ± 10.2 years, 42.1% females), 115 (67.3%) were referred to a hepatologist due to abnormal liver enzymes (n = 60) or steatosis plus indeterminate (n = 37) or high NAFLD fibrosis score (n = 18). Liver biopsy was proposed to 30 patients (17.5%), but only 14 accepted, resulting in 12 NASH, one with significant fibrosis. The PPV of hepatological referral was 12/76 (15.8%) for NASH and 1/76 (1.3%) for NASH with significant fibrosis. The PPV of liver biopsy referral was 12/14 (85.7%) for NASH and 1/14 (7.1%) for NASH with significant fibrosis., Conclusions: By applying a guidelines-compliant algorithm, many patients with T2D were referred for hepatological assessment and liver biopsy. Further studies are necessary to refine non-invasive algorithms., Competing Interests: Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2021 Elsevier B.V. All rights reserved.)

Background: Cancer represents a risk factor for splanchnic vein thrombosis (SVT) and usual site venous thromboembolism (VTE)., Objectives: To compare characteristics and outcomes of patients with cancer-associated SVT and usual site VTE., Patients/methods: Patients with solid cancer and SVT were enrolled in an international, prospective registry between May 2008 and January 2012. The comparison cohort included (1:1 ratio) patients with solid cancer and usual site VTE treated at two thrombosis centers who had a minimum of 12 months follow-up at December 2019 or experienced one of the outcomes within 12 months follow-up. Recurrent VTE, major bleeding, and all-cause mortality were evaluated at 12-month follow-up., Results: A total of 264 patients (132 in each cohort) were enrolled. Patients with SVT were less likely to have metastatic disease (36.1% vs 72.5%) or receive cancer therapy at thrombosis diagnosis (29.6% vs 64.9%). The most frequent cancer types were hepatobiliary and pancreatic in the SVT cohort and gastrointestinal in the usual site VTE cohort. Fewer patients with SVT received anticoagulation (68.9% vs 99.2%), and treatment duration was shorter (6.0 vs 11.0 months). The cumulative incidence of major bleeding (2.3% vs 4.7%) was nonsignificantly lower in the SVT cohort, whereas recurrent thrombosis (4.7% vs 5.5%) and all-cause mortality (41.7% vs 39.4%) were comparable between the two cohorts., Conclusions: The risk of recurrent thrombosis and bleeding appears to be similar in cancer patients with SVT and cancer patients with usual site VTE, despite some differences in baseline characteristics and anticoagulant treatment. Further prospective studies are warranted to confirm these findings., (© 2020 International Society on Thrombosis and Haemostasis.)

Treatment of splanchnic vein thrombosis (SVT) is challenging, and evidence to guide therapeutic decisions remains scarce. The objective of this systematic review and meta-analysis was to determine the efficacy and safety of anticoagulant therapy for SVT. MEDLINE, EMBASE, and clinicaltrials.gov were searched from inception through December 2019, without language restrictions, to include observational studies and randomized controlled trials reporting radiological or clinical outcomes in patients with SVT. Pooled proportions and risk ratios (RRs) with 95% confidence intervals (CIs) were calculated in a random-effects model. Of 4312 records identified by the search, 97 studies including 7969 patients were analyzed. In patients receiving anticoagulation, the rates of SVT recanalization, SVT progression, recurrent venous thromboembolism (VTE), major bleeding, and overall mortality were 58% (95% CI, 51-64), 5% (95% CI, 3-7), 11% (95% CI, 8-15), 9% (95% CI, 7-12), and 11% (95% CI, 9-14), respectively. The corresponding values in patients without anticoagulation were 22% (95% CI, 15-31), 15% (95% CI, 8-27), 14% (95% CI, 9-21), 16% (95% CI, 13-20), and 25% (95% CI, 20-31). Compared with no treatment, anticoagulant therapy obtained higher recanalization (RR, 2.39; 95% CI, 1.66-3.44) and lower thrombosis progression (RR, 0.24; 95% CI, 0.13-0.42), major bleeding (RR, 0.73; 95% CI, 0.58-0.92), and overall mortality (RR, 0.45; 95% CI, 0.33-0.60). These results demonstrate that anticoagulant therapy improves SVT recanalization and reduces the risk of thrombosis progression without increasing major bleeding. The incidence of recurrent VTE remained substantial in patients receiving anticoagulation, as well. Effects were consistent across the different subgroups of patients. This trial was registered on the PROPERO database at (https://www.crd.york.ac.uk/prospero//display&#95;record.php?ID=CRD42019127870) as #CRD42019127870., (© 2021 by The American Society of Hematology.)

Background: Dyspnoea is the most common sign of heart failure (HF). Patients accessing the ED for HF-related symptoms require fast diagnosis and early treatment. Transthoracic echocardiography has a crucial role in HF diagnosis, but requires qualified staff and adequate time for execution. The measurement of inferior vena cava (IVC) diameter has been recently proposed as a rapid, simple and reliable marker of volume overload. The aim of this systematic review was to assess the accuracy of IVC-ultrasound as a stand-alone test for HF diagnosis in patients presenting to the ED with acute dyspnoea., Methods: Studies evaluating the diagnostic accuracy of the inferior vena cava collapsibility index (IVC-CIx) for HF diagnosis were systematically searched in the EMBASE and MEDLINE databases (up to January 2018). Quality Assessment of Diagnostic Accuracy Studies 2 tool was used for the quality assessment of the primary studies. A bivariate random-effects regression approach was used for summary estimates of both sensitivity and specificity., Results: Seven studies, for a total of 591 patients, were included. Three studies were at low-risk of bias. All studies used a proper reference test. Weighted mean prevalence of HF was 49.3% at random-effect model (I 2 index for heterogeneity=74.7%). IVC-CIx bivariate weighted mean sensitivity was 79.1% (95% CI 68.5% to 86.8%) and bivariate weighted mean specificity was 81.8% (95% CI 75.0% to 87.0%)., Conclusions: Our findings suggest that the sensitivity and specificity of IVC-CIx are suboptimal to rule in or rule out HF diagnosis in patients with acute dyspnoea in the ED setting. Therefore, IVC-CIx is not advisable as a stand-alone test, but may be useful when integrated in a specific diagnostic algorithm for the differential diagnosis of acute dyspnoea., Competing Interests: Competing interests: None declared., (© Author(s) (or their employer(s)) 2021. No commercial re-use. See rights and permissions. Published by BMJ.)

Direct oral anticoagulants (DOACs) are currently the preferred oral anticoagulant treatment for most of the patients with deep vein thrombosis of the lower extremities and/or pulmonary embolism. DOACs have several advantages over vitamin K antagonists, such as availability of fixed dosages, fewer drug interactions, faster onset of action, shorter half-life, and lower risk of major and intracranial bleeding. Although the evidence on the use of DOACs in patients with unusual-site venous thromboembolism (VTE) is limited to a few, small randomized controlled trials, these drugs are increasingly used in clinical practice, and several observational cohort studies have been published recently. This narrative review will describe the latest evidence for the use of the DOACs in patients with thrombosis in atypical locations (splanchnic, cerebral, upper extremity, ovarian, and renal vein thrombosis) and will provide some practical advice for their use in patients with unusual-site VTE., (© 2021 The Authors. Research and Practice in Thrombosis and Haemostasis published by Wiley Periodicals LLC on behalf of International Society on Thrombosis and Haemostasis (ISTH).)

Background: Abnormal clot structure has been identified in patients with thrombotic disorders. Anticoagulant therapy offers clear benefits for thrombosis prevention and treatment by reducing blood clot formation and size; nevertheless, there are limited data on the effects of different anticoagulants, where clotting is initiated with different triggers, on clot structure., Objectives: Our aim was to investigate the effects of vitamin K antagonists and factor Xa inhibitors on clot structure., Methods: Clots from pooled plasma spiked with rivaroxaban, apixaban, or enoxaparin, as well as plasma from patients on warfarin, were compared to plasma without anticoagulation. The kinetic profile of polymerizing clots was obtained by turbidity, fiber density was determined by confocal microscopy, clot pore size was investigated by permeation, and fiber size was analyzed using scanning electron microscopy. Clotting agonist was either tissue factor or thrombin., Results: Following clotting with tissue factor, all anticoagulated clots had a significantly increased lag time, with the exception of enoxaparin. Rivaroxaban additionally led to significantly less dense and more permeable clots, with thicker fibers. In contrast, turbidity analysis following initiation with thrombin showed few effects of anticoagulation, with only enoxaparin leading to a prolonged lag time. Enoxaparin clots made with thrombin were less dense and more permeable., Conclusion: Our results show that anticoagulants modulate clot structure particularly when induced by tissue factor, most likely due to reduction of thrombin generation. We propose that the effects of different anticoagulants could be assessed with a global clot structure measurement such as permeation or turbidity, providing information on clot phenotype., (© 2020 The Authors. Research and Practice in Thrombosis and Haemostasis published by Wiley Periodicals LLC on behalf of International Society on Thrombosis and Haemostasis (ISTH).)

Background: Anticoagulant treatment of splanchnic (SVT) and cerebral vein thrombosis (CVT) can be challenging due to the rarity of these conditions, the concomitantly high thrombotic and bleeding risks, and the available low-quality evidence., Objectives: To explore the current therapeutic approaches to SVT and CVT, and the rationale behind the anticoagulant treatment choice., Methods: A cross-sectional survey was conducted (October 2018-April 2019) among members of three thrombosis and hemostasis societies. The survey consisted of four vignette cases: (i) SVT secondary to transient risk factor; (ii) cirrhotic SVT with esophageal varices; (iii) CVT secondary to transient risk factor; and (iv) unprovoked CVT with intracranial hemorrhage., Results: A total of 397 physicians responded to the survey. There was wide variability in anticoagulant treatment options, starting time, and duration. Vitamin K antagonists were the commonest choice across the four vignette cases (44.2%-63.0%). The direct oral anticoagulants (DOACs) were the second commonest choice in low-bleeding-risk scenarios (27.7% in case 1, 22.9% in case 3), while parenteral anticoagulation alone was the second commonest choice in high-bleeding-risk scenarios (39.9% in case 2, 39.8% in case 4). The most frequent reasons for selecting DOACs were oral route of administration (50.6%), lack of need for laboratory monitoring (48.1%), and favorable safety profile of these drugs (43.4%)., Conclusions: The results of our study showed that, despite being off-label, the DOACs were considered for the treatment of unusual-site venous thromboembolism. The wide variability among different physicians reflected the clinical difficulties and raised the need for more collaborative trials on these disorders., (© 2020 The Authors. Research and Practice in Thrombosis and Haemostasis published by Wiley Periodicals LLC on behalf of International Society on Thrombosis and Haemostasis (ISTH).)

Background: The use of point-of-care (POC) coagulometers for monitoring patients on vitamin K antagonist (VKA) treatment makes international normalised ratio (INR) results immediately available. The aim of this study was to compare patients' satisfaction with VKA treatment in two settings characterised by distinct ways of monitoring: POC INR versus laboratory INR., Materials and Methods: We recruited adult patients on long-term warfarin treatment (July 2017-February 2018) from the Anticoagulation Clinics at five district health centres (namely Cospicua, Floriana, Mosta, Qormi, Rabat-POC INR) and at Mater Dei Hospital (Msida - Laboratory INR) in Malta. We administered two psychometric questionnaires: the Duke Anticoagulation Satisfaction Scale (DASS) (range 25-175, lower scores corresponding to higher satisfaction) and the Perception of Anticoagulation Treatment Questionnaire (PACT-Q2) (range 0-100, higher scores corresponding to higher satisfaction)., Results: We analysed 313 questionnaires (POC INR n=159, laboratory INR n=154). In the POC INR cohort, median age was 72 years and 59.1% were males; in the laboratory INR cohort, median age was 70.5 years and 46.1% were males. The POC INR cohort obtained significantly lower overall DASS score (p<0.001) and significantly higher PACT-Q2 scores (p<0.001 for the subscale "convenience"; p=0.039 for the subscale "anticoagulant treatment satisfaction") than the laboratory INR cohort. In multiple regression analysis, the use of POC coagulometers was significantly associated with the overall DASS score (p=0.013) and the PACT-Q2 convenience score (p=0.012)., Discussion: Patients on warfarin treatment were generally satisfied. Patients monitored with the POC INR with a dedicated time slot reported less inconvenience and burdens and better psychological impact than patients monitored with the traditional laboratory INR.

Septic thrombophlebitis (STP) is a complex, cross-disciplinary clinical condition that combines a localized infection with a neighboring venous thrombosis. STP can occur at several possible anatomic sites, such as dural sinuses, jugular vein (Lemierre syndrome), portal vein (pylephlebitis), and pelvic veins. Its high mortality in the preantibiotic era improved considerably with the introduction of modern antibiotics. However, little evidence exists to date to guide its clinical management. The incidence of STP or its risk factors may be increasing, and its mortality may still be considerable. These trends would have far-reaching implications, especially in the setting of increasing resistance to antimicrobial agents. No clinical assessment tools exist to support patient screening or guide treatment in STP. Few interventional studies exist on the efficacy and safety of anticoagulation. Recommendations on its indications, duration, and the agents of choice are mostly based on evidence derived from small observational studies. While all forms of STP pose similar challenges, future research may benefit from the distinction between bacteria-associated, virus-associated, and mycosis-associated thrombophlebitis. Addressing these gaps in evidence would enhance our ability to diagnose this condition and treat patients effectively., Competing Interests: The authors declare, that they have no conflict of interest., (Georg Thieme Verlag KG Stuttgart · New York.)

A high incidence of thrombotic events has been reported in patients with coronavirus disease (COVID-19), which is caused by severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2) infection. We report 3 clinical cases of patients in Italy with COVID-19 who developed abdominal viscera infarction, demonstrated by computed tomography.

The 2020 Congress of the International Society of Thrombosis and Haemostasis (ISTH) was held virtually July 12-15, 2019, due to the coronavirus disease 2019 pandemic. The congress convenes annually to discuss clinical and basic topics in hemostasis and thrombosis. Each year, the program includes State of Art (SOA) lectures given by prominent scientists. Presenters are asked to create Illustrated Capsules of their talks, which are concise illustrations with minimal explanatory text. Capsules cover major themes of the presentation, and these undergo formal peer review for inclusion in this article. Owing to the shift to a virtual congress this year, organizers reduced the program size. There were 39 SOA lectures virtually presented, and 29 capsules (9 from talks omitted from the virtual congress) were both submitted and successful in peer review, and are included in this article. Topics include the roles of the hemostatic system in inflammation, infection, immunity, and cancer, platelet function and signaling, platelet function disorders, megakaryocyte biology, hemophilia including gene therapy, phenotype tests in hemostasis, von Willebrand factor, anticoagulant factor V, computational driven discovery, endothelium, clinical and basic aspects of thrombotic microangiopathies, fibrinolysis and thrombolysis, antithrombotics in pediatrics, direct oral anticoagulant management, and thrombosis and hemostasis in pregnancy. Capsule authors invite virtual congress attendees to refer to these capsules during the live presentations and participate on Twitter in discussion. Research and Practice in Haemostasis and Thrombosis will release 2 tweets from @RPTHJournal during each presentation, using #IllustratedReview, #CoagCapsule and #ISTH2020. Readers are also welcome to utilize capsules for teaching and ongoing education., (© 2020 The Authors. Research and Practice in Thrombosis and Haemostasis published by Wiley Periodicals LLC on behalf of International Society on Thrombosis and Haemostasis.)

Cerebral vein thrombosis (CVT) and splanchnic vein thrombosis (SVT) are two manifestations of venous thromboembolism (VTE) at unusual sites. They have an incidence at least 25-50 times lower than usual site VTE, but represent true clinical challenges. Recent evidence on the epidemiology, risk factors, prognosis, and treatment of CVT and SVT has been published in the last two decades, thus contributing to a better understanding of these diseases. The improvement in imaging techniques and a higher degree of clinical suspicion may have led to the observed increased frequency, whereas a better knowledge of provoking mechanisms could have contributed to reducing the proportion of events classified as unprovoked or idiopathic (13%-21% of CVT, 15%-27% of SVT). Few small randomized clinical trials and a number of observational studies, although hampered by heterogeneous therapeutic approaches, shed light on the safety and effectiveness of anticoagulant therapy in these populations. However, there are still some grey areas that warrant future research. In this narrative review, we discuss recent advances and therapeutic challenges in CVT and SVT.

Background: Data extraction from reports about experimental or observational studies is a crucial methodological step informing evidence syntheses, such as systematic reviews (SRs) and overviews of SRs. Reporting discrepancies were defined as pairs of statements that could not both be true. Authors of SRs and overviews of SRs can encounter reporting discrepancies among multiple sources when extracting data-a manuscript and a conference abstract, and a manuscript and a clinical trial registry. However, these discrepancies can also be found within a single manuscript published in a scientific journal., Objectives: Hereby, we describe examples of internal reporting discrepancies that can be found in a single source, with the aim of raising awareness among authors of SRs and overviews of SRs about such potential methodological issues., Conclusions: Authors of SRs and overviews of SRs should check whether the same information is reported in multiple places within a study and compare that information. Independent data extraction by two reviewers increases the chance of finding discrepancies, if they exist. We provide advice on how to deal with different types of discordances and how to report such discordances when conducting SRs and overviews of SRs., (Copyright © 2019 Elsevier Inc. All rights reserved.)