624 research outputs found
Coagulase activity by Staphylococcus aureus: a potential target for therapy?
No full textStaphylococcus aureus is a leading cause of skin and soft tissue infections, foreign body infections, and infective endocarditis. In case of endovascular infection with S. aureus, higher rates of cardiac valve destruction, embolic complications, severe sepsis, and death occur. The unique capacity of S. aureus to induce clotting has been known for over a century; however, its role in virulence has long been controversial. S. aureus secretes two coagulases, staphylocoagulase and von Willebrand factor binding protein that both activate prothrombin to generate fibrin. A better understanding of the molecular mechanisms as well as the new strategies to target the coagulases have highlighted their importance in S. aureus virulence. Coagulase activity is essential for the formation of S. aureus-fibrin-platelet microaggregates and for the homing of S. aureus to the vascular wall under flow. Absence or inhibition of S. aureus coagulase activity improved outcome in disease models of skin infection, sepsis, catheter infection, and endocarditis. Here, we review how the manipulation of the host's hemostatic system contributes to the disease-causing potential of S. aureus and discuss the S. aureus coagulases as promising targets for novel therapeutic strategies.sponsorship: This work was supported by grants of the Research Foundation Flanders (FWO-Vlaanderen, 11I0113N and G046610N). Marijke Peetermans and Thomas Vanassche are fellows of the FWO, Peter Verhamme is a senior clinical investigator of the FWO. (Research Foundation Flanders (FWO-Vlaanderen)|11I0113N, Research Foundation Flanders (FWO-Vlaanderen)|G046610N)status: Publishe
Bacterial pathogens activate plasminogen to breach tissue barriers and escape from innate immunity
No full textBoth coagulation and fibrinolysis are tightly connected with the innate immune system. Infection and inflammation cause profound alterations in the otherwise well-controlled balance between coagulation and fibrinolysis. Many pathogenic bacteria directly exploit the host's hemostatic system to increase their virulence. Here, we review the capacity of bacteria to activate plasminogen. The resulting proteolytic activity allows them to breach tissue barriers and evade innate immune defense, thus promoting bacterial spreading. Yersinia pestis, streptococci of group A, C and G and Staphylococcus aureus produce a specific bacterial plasminogen activator. Moreover, surface plasminogen receptors play an established role in pneumococcal, borrelial and group B streptococcal infections. This review summarizes the mechanisms of bacterial activation of host plasminogen and the role of the fibrinolytic system in infections caused by these pathogens.sponsorship: This work was supported by grants of the Research Foundation Flanders (FWO-Vlaanderen, 11I0113N and 11S5416N). Marijke Peetermans and Laurens Liesenborghs are fellows of the FWO, Peter Verhamme is a senior clinical investigator of the FWO. (Research Foundation Flanders (FWO-Vlaanderen)|11I0113N, Research Foundation Flanders (FWO-Vlaanderen)|11S5416N)status: Publishe
Association between reperfusion therapy and outcomes in patients with acute pulmonary embolism and right heart thrombi
No full textsponsorship: This work was supported by Bayer Pharma and Sanofi. Funding information for this article has been deposited with the Crossref Funder Registry. (Bayer Pharma, Sanofi)status: Publishe
Updated European Heart Rhythm Association practical guide on the use of non-vitamin-K antagonist anticoagulants in patients with non-valvular atrial fibrillation: Executive summary
No full textIn 2013, the European Heart Rhythm Association (EHRA) published a Practical Guide on the use of non-VKA oral anticoagulants (NOACs) in patients with atrial fibrillation (AF) (Heidbuchel H, Verhamme P, Alings M, Antz M, Hacke W, Oldgren J, Sinnaeve P, Camm AJ, Kirchhof P, European Heart Rhythm A. European Heart Rhythm Association Practical Guide on the use of new oral anticoagulants in patients with non-valvular atrial fibrillation. Europace 2013;15:625-651; Heidbuchel H, Verhamme P, Alings M, Antz M, Hacke W, Oldgren J, Sinnaeve P, Camm AJ, Kirchhof P. EHRA practical guide on the use of new oral anticoagulants in patients with non-valvular atrial fibrillation: executive summary. Eur Heart J 2013;34:2094-2106). The document received widespread interest, not only from cardiologists but also from neurologists, geriatricians, and general practitioners, as became evident from the distribution of > 350 000 copies of its pocket version (the EHRA Key Message Booklet) world-wide. Since 2013, numerous new studies have appeared on different aspects of NOAC therapy in AF patients. Therefore, EHRA updated the Practical Guide, including new information but also providing balanced guiding in the many areas where prospective data are still lacking. The outline of the original guide that addressed 15 clinical scenarios has been preserved, but all chapters have been rewritten. Main changes in the Update comprise a discussion on the definition of 'non-valvular AF' and eligibility for NOAC therapy, inclusion of finalized information on the recently approved edoxaban, tailored dosing information dependent on concomitant drugs, and/or clinical characteristics, an expanded chapter on neurologic scenarios (ischaemic stroke or intracranial haemorrhage under NOAC), an updated anticoagulation card and more specifics on start-up and follow-up issues. There are also many new flow charts, like on appropriate switching between anticoagulants (VKA to NOAC or vice versa), default scenarios for acute management of coronary interventions, step-down schemes for longterm combined antiplatelet-anticoagulant management in coronary heart disease, management of bleeding, and cardioversion under NOAC therapy. The Updated Guide is available in full in EP Europace (Heidbuchel H, Verhamme P, Alings M, Antz M, Diener HC, HackeW, Oldgren J, Sinnaeve P, Camm AJ, Kirchhof P, Advisors. Updated European Heart Rhythm Association Practical Guide on the use of non-vitamin K antagonist anticoagulants in patients with non-valvular atrial fibrillation. Europace 2015;17:1467-1507), while additional resources can be found at the related ESC/EHRA website (www.NOACforAF.eu)
Direct antivirals working against the novel coronavirus: azithromycin (DAWn-AZITHRO), a randomized, multicenter, open-label, adaptive, proof-of-concept clinical trial of new antivirals working against SARS-CoV-2-azithromycin (vol 22, 126, 2021)
No full textstatus: Publishe
Reversal of dabigatran by idarucizumab: when and how?
No full textINTRODUCTION: Anticoagulants are highly effective in reducing the risk of embolism in patients with atrial fibrillation and in the treatment of venous thromboembolism. However, interfering with the coagulation system increases the risk of bleeding. Non-vitamin K oral anticoagulants (NOACs) are associated with a reduced risk of major and life-threatening bleeding compared to warfarin, but the absence of a specific reversal agent has caused concern among clinicians. AREAS COVERED: This article describes the indications for and practical use of idarucizumab, a specific reversal agent for the direct thrombin inhibitor dabigatran. Expert commentary: Each year, 3-5% of anticoagulated patients will experience major bleeding and about 10% will require invasive interventions. While most of these situations can be managed without the need for a reversal agent, the ability to promptly switch off anticoagulant activity is likely beneficial in severe bleeding situations and can help to avoid delays and improve safety in the management of patients requiring urgent procedures. Idarucizumab rapidly and completely reverses the anticoagulant effect of dabigatran in vitro, in healthy volunteers, and in patients presenting with severe bleeding or requiring urgent procedures. Further clinical data will help to understand the clinical impact of rapid reversal on the outcome of bleeding patients.sponsorship: A Greinacher has received consultancy fees from Bayer, Boehringer, Astra-Zeneca and GSK. He has received payment for lectures from Aspen, Boehringer, NovoNordisk, Bayer Healthcare, BMS and GSK. Study support (third-party funding) has been provided by Bayer, Boehringer and Aspen. T Vanassche recieved speaker fees from Boehringer Ingelheim. P Verhamme received honoraria for lectures and consultancy from Boehringer Ingelheim, Bayer, Daiichi Sankyo, Pfizer and research support from Boehringer Ingelheim, Bayer, Sanofi and LeoPharma. The authors have no other relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript apart from those disclosed. (Bayer, Boehringer, Astra-Zeneca, GSK, Aspen, NovoNordisk, Bayer Healthcare, BMS, Boehringer Ingelheim, Daiichi Sankyo, Pfizer, LeoPharma, Sanofi)status: Publishe
Absence of Pear1 does not affect murine platelet function in vivo
No full textBACKGROUND: Platelet Endothelial Aggregation Receptor-1 (PEAR1) is a transmembrane platelet receptor that amplifies the activation of the platelet fibrinogen receptor (αIIbβ3) during platelet aggregation. In man, Pear1 polymorphisms are associated with changes in platelet aggregability. In this report, we characterized Pear1 expression and function in murine platelets. METHODS: Pear1 phosphorylation and signaling, platelet aggregation, α-degranulation and clot retraction were studied in WT and Pear1-/- platelets. The function of Pear1 in haemostasis and thrombosis was studied in a mouse tail vein bleeding and ferric chloride-induced mesenteric thrombosis model. RESULTS: Mature murine platelets express Pear1 on their membrane and clustering of Pear1 by anti-Pear1 antibodies triggered platelet aggregation. Pear1 was weakly phosphorylated during collagen-induced murine platelet aggregation and was translocated to the cytoskeleton. Absence of murine Pear1 impaired dextran sulfate-induced platelet aggregation, but did not impact collagen-, AYPGK and ADP-induced platelet aggregation, coupled to a lower Pear1 expression in murine than in human platelets and to weaker Pear1-mediated downstream signaling. Neither clot retraction nor α-degranulation was affected in Pear1-/- mice. Likewise, in vivo tests like the tail vein bleeding time and thrombus formation in mesenteric veins were similar in WT and Pear1-/- mice. CONCLUSION: Murine platelet Pear1 shares a number of characteristics with human platelet PEAR1. Nevertheless, murine Pear1 contributes less to platelet function as does human PEAR1 and does not overtly impact haemostasis and thrombosis in mice.sponsorship: This study received financial support from the "Fonds voor Wetenschappelijk Onderzoek (FWO) Vlaanderen" (G060112N and G0A6514N, Peter Verhamme: senior clinical investigatorship 1801414N, Benedetta Izzi: post-doctoral fellowship 12M2715N), "Programmafinanciering KU Leuven (PF/10/014)" and the Bayer Chair in Cardiovascular Medicine (appointed to Peter Verhamme). (Fonds voor Wetenschappelijk Onderzoek (FWO) Vlaanderen|G060112N, Fonds voor Wetenschappelijk Onderzoek (FWO) Vlaanderen|G0A6514N, Fonds voor Wetenschappelijk Onderzoek (FWO) Vlaanderen|1801414N, Fonds voor Wetenschappelijk Onderzoek (FWO) Vlaanderen|12M2715N, Programmafinanciering KU Leuven|PF/10/014, Bayer Chair in Cardiovascular Medicine)status: Publishe
Establishing diagnostic criteria and treatment of subsegmental pulmonary embolism: A Delphi analysis of experts
No full textBACKGROUND: Improved imaging techniques have increased the incidence of subsegmental pulmonary embolism (ssPE). Indirect evidence is suggesting that ssPE may represent a more benign presentation of venous thromboembolism not necessarily requiring anticoagulant treatment. However, correctly diagnosing ssPE is challenging with reported low interobserver agreement, partly due to the lack of widely accepted diagnostic criteria. OBJECTIVES: We sought to derive uniform diagnostic criteria for ssPE, guided by expert consensus. METHODS: Based on an extensive literature review and expert opinion of a Delphi steering committee, two surveys including statements regarding diagnostic criteria and management options for ssPE were established. These surveys were conducted electronically among two panels, respectively: expert thoracic radiologists and clinical venous thromboembolism specialists. The Delphi method was used to achieve consensus after multiple survey rounds. Consensus was defined as a level of agreement >70%. RESULTS: Twenty-nine of 40 invited radiologists (73%) and 40 of 51 clinicians (78%) participated. Following two survey rounds by the expert radiologists, consensus was achieved on 15 of 16 statements, including on the established diagnostic criteria for ssPE (96% agreement): a contrast defect in a subsegmental artery, that is, the first arterial branch division of any segmental artery independent of artery diameter, visible in at least two subsequent axial slices, using a computed tomography scanner with a desired maximum collimator width of ≤1 mm. These criteria were approved by 83% of the clinical venous thromboembolism (VTE) specialists. The clinical expert panel favored anticoagulant treatment in case of prior VTE, antiphospholipid syndrome, pregnancy, cancer, and proximal deep vein thrombosis. CONCLUSION: The results of this analysis provide standard radiological criteria for ssPE that may be applicable in both clinical trials and practice.sponsorship: G. Le Gal is the recipient of an Early Researcher Award from the Province of Ontario, a Heart and Stroke Foundation of Canada Ontario Mid-Career Investigator Award, and holds the Chair on Diagnosis of Venous Thromboembolism from the Department of Medicine, University of Ottawa. (Province of Ontario, Heart and Stroke Foundation of Canada Ontario Mid-Career Investigator Award, Chair on Diagnosis of Venous Thromboembolism from the Department of Medicine, University of Ottawa)status: Publishe
Pharmacotherapy with oral Xa inhibitors for venous thromboembolism
No full textIntroduction: Venous thromboembolism (VTE) causes substantial morbidity and mortality worldwide. The traditional treatment of VTE, with an initial therapy with (low molecular weight) heparin or fondaparinux and a continued treatment with vitamin K antagonists, is effective but has limitations. Areas covered: The current review summarizes the results of the Phase III trials with the new oral direct factor Xa inhibitors rivaroxaban, apixaban and edoxaban and provides a meta-analysis of these trials in the subgroups of elderly patients (> 75 years) and patients with impaired renal function. Expert opinion: The practical use of direct Xa inhibitors in the treatment of VTE in general and in specific subgroups is discussed. For elderly patients, patients with extremes of body weight, cancer patients or patients with moderate renal impairment, pooled data suggest that the direct oral Xa inhibitors are a reasonable alternative to standard therapy. For other indications, such as treatment of VTE in children, during pregnancy or in the context of heparin-induced thrombocytopenia, further data from clinical trials are needed.sponsorship: K Peerlinck received research support from Bayer, Baxter, CSL Behring and Pfizer. P Verhamme received honorarium for lectures or advisory boards from Boehringer-Ingelheim, Daiichi-Sankyo, Bayer and Pfizer, and research support from Boehringer-Ingelheim, Bayer and Sanofi. The authors have no other relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript apart from those disclosed. (Bayer, Baxter, CSL Behring, Pfizer, Boehringer-Ingelheim, Sanofi)status: Publishe
PROPOSAL FOR THE INCLUSION OF LOW MOLECULAR WEIGHT HEPARINS FOR THE PREVENTION OF VENOUS THROMBOEMBOLISM IN HOSPITALIZED PATIENTS IN THE WHO MODEL LIST OF ESSENTIAL MEDICINES
No full textVenous thromboembolism (VTE) is one of the leading causes of morbidity and mortality in hospitalized patients and pulmonary embolism is responsible for 10% of overall deaths. Because symptoms of deep vein thrombosis and pulmonary embolism are non-specific, a timely diagnosis remains difficult and screening tests for VTE are not cost-effective. Thus, careful selection of patients at increased risk and application of adequate prophylactic strategies is necessary to reduce the burden of disease. There is a large amount of evidence showing the efficacy of prophylactic strategies to prevent VTE in at-risk hospitalized patients. Pharmacologic prophylaxis with either low-dose unfractionated heparin (LDUH) or low molecular weight heparin (LMWH) has been shown to reduce the risk of pulmonary embolism in general surgical patients by 75%. Because of their greater ease of use (single daily dose) and their improved safety profile (the frequency of heparin induced thrombocytopenia is three-fold lower with LMWH than with unfractionated heparin), LMWH has widely become the management of choice for prophylaxis of VTE in this setting. In patients undergoing major orthopedic surgery, LMWH has been shown to be the most effective agent before the arrival of the direct oral anticoagulant drugs (DOACs) by producing an approximately 70% risk reduction in VTE and is currently recommended as the treatment of choice in this setting (see below). It was estimated that approximately two out of three patients undergoing surgical procedures should be deemed eligible to receive antithrombotic prophylaxis. Unfortunately, the results of a large observational study carried out in several countries throughout the world (ENDORSE) reported that only about 60% of at-risk surgical patients actually receive adequate prophylactic strategies. However, this rate widely varied among countries, being highest in western European countries and lowest in low and middle income Asian countries. In countries like Bangladesh, India, Pakistan, and Thailand, prescription rates ranged between 0.2% and 16.3%. These rates were higher in Northern African countries (Egypt, Tunisia, Algeria) while no information was available for Central African countries. Insufficient availability of drugs, but also insufficient awareness of post-surgical VTE as a major clinical issue remain the main drivers for this major gap between evidences and clinical practice. For example, the incidence of post-surgical venous thrombosis has traditionally been thought to be low in Asian ethnic populations. However, recent studies have challenged this common view showing that this incidence is similar to that reported in Western countries. For these reasons, we believe that improving access to drugs with the highest effectiveness in the prevention of VTE in surgical patients has the potential to reduce the burden of disease and thrombosis related costs also in low and middle income countries. However, this improvement can only be achieved in conjunction with an improved awareness of this life-threatening disease
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