Explore the vast range of titles available.

Thrombosis is the most feared complication of cardiovascular diseases and a main cause of death worldwide, making it a major health-care challenge. Platelets and the coagulation cascade are effectively targeted by antithrombotic approaches, which carry an inherent risk of bleeding. Moreover, antithrombotics cannot completely prevent thrombotic events, implicating a therapeutic gap due to a third, not yet adequately addressed mechanism, namely inflammation. In this Review, we discuss how the synergy between inflammation and thrombosis drives thrombotic diseases. We focus on the huge potential of anti-inflammatory strategies to target cardiovascular pathologies. Findings in the past decade have uncovered a sophisticated connection between innate immunity, platelet activation and coagulation, termed immunothrombosis. Immunothrombosis is an important host defence mechanism to limit systemic spreading of pathogens through the bloodstream. However, the aberrant activation of immunothrombosis in cardiovascular diseases causes myocardial infarction, stroke and venous thromboembolism. The clinical relevance of aberrant immunothrombosis, referred to as thromboinflammation, is supported by the increased risk of cardiovascular events in patients with inflammatory diseases but also during infections, including in COVID-19. Clinical trials in the past 4 years have confirmed the anti-ischaemic effects of anti-inflammatory strategies, backing the concept of a prothrombotic function of inflammation. Targeting inflammation to prevent thrombosis leaves haemostasis mainly unaffected, circumventing the risk of bleeding associated with current approaches. Considering the growing number of anti-inflammatory therapies, it is crucial to appreciate their potential in covering therapeutic gaps in cardiovascular diseases.In this Review, Stark and Massberg discuss how the interplay between innate immunity, platelet activation and coagulation, known as immunothrombosis, functions as a host defence mechanism to limit pathogen spreading, yet its aberrant activation, termed thromboinflammation, results in thrombotic complications, highlighting the therapeutic potential of anti-inflammatory strategies in cardiovascular pathologies.

Stroke thrombolysis with alteplase is currently recommended 0–4·5 h after stroke onset. We aimed to determine whether perfusion imaging can identify patients with salvageable brain tissue with symptoms 4·5 h or more from stroke onset or with symptoms on waking who might benefit from thrombolysis. In this systematic review and meta-analysis of individual patient data, we searched PubMed for randomised trials published in English between Jan 1, 2006, and March 1, 2019. We also reviewed the reference list of a previous systematic review of thrombolysis and searched ClinicalTrials.gov for interventional studies of ischaemic stroke. Studies of alteplase versus placebo in patients (aged ≥18 years) with ischaemic stroke treated more than 4·5 h after onset, or with wake-up stroke, who were imaged with perfusion-diffusion MRI or CT perfusion were eligible for inclusion. The primary outcome was excellent functional outcome (modified Rankin Scale [mRS] score 0–1) at 3 months, adjusted for baseline age and clinical severity. Safety outcomes were death and symptomatic intracerebral haemorrhage. We calculated odds ratios, adjusted for baseline age and National Institutes of Health Stroke Scale score, using mixed-effects logistic regression models. This study is registered with PROSPERO, number CRD42019128036. We identified three trials that met eligibility criteria: EXTEND, ECASS4-EXTEND, and EPITHET. Of the 414 patients included in the three trials, 213 (51%) were assigned to receive alteplase and 201 (49%) were assigned to receive placebo. Overall, 211 patients in the alteplase group and 199 patients in the placebo group had mRS assessment data at 3 months and thus were included in the analysis of the primary outcome. 76 (36%) of 211 patients in the alteplase group and 58 (29%) of 199 patients in the placebo group had achieved excellent functional outcome at 3 months (adjusted odds ratio [OR] 1·86, 95% CI 1·15–2·99, p=0·011). Symptomatic intracerebral haemorrhage was more common in the alteplase group than the placebo group (ten [5%] of 213 patients vs one [<1%] of 201 patients in the placebo group; adjusted OR 9·7, 95% CI 1·23–76·55, p=0·031). 29 (14%) of 213 patients in the alteplase group and 18 (9%) of 201 patients in the placebo group died (adjusted OR 1·55, 0·81–2·96, p=0·66). Patients with ischaemic stroke 4·5–9 h from stroke onset or wake-up stroke with salvageable brain tissue who were treated with alteplase achieved better functional outcomes than did patients given placebo. The rate of symptomatic intracerebral haemorrhage was higher with alteplase, but this increase did not negate the overall net benefit of thrombolysis. None.

Thrombosis is a leading global cause of death, in part due to the low efficacy of thrombolytic therapy. Here, we describe a method for precise delivery and accurate dosing of tissue plasminogen activator (tPA) using an intelligent DNA nanodevice. We use DNA origami to integrate DNA nanosheets with predesigned tPA binding sites and thrombin-responsive DNA fasteners. The fastener is an interlocking DNA triplex structure that acts as a thrombin recognizer, threshold controller and opening switch. When loaded with tPA and intravenously administrated in vivo, these DNA nanodevices rapidly target the site of thrombosis, track the circulating microemboli and expose the active tPA only when the concentration of thrombin exceeds a threshold. We demonstrate their improved therapeutic efficacy in ischaemic stroke and pulmonary embolism models, supporting the potential of these nanodevices to provide accurate tPA dosing for the treatment of different thromboses. An intelligent DNA nanodevice, composed of DNA origami nanosheets and a thrombin-responsive DNA fastener, accurately delivers the appropriate dose of tissue plasminogen activator following activation by distinct thrombosis events.

This randomized comparison of low-dose and standard-dose alteplase in acute ischemic stroke did not establish noninferiority of low-dose alteplase for the primary outcome of death or disability at 90 days. Fewer patients had intracerebral hemorrhages in the low-dose group. Thrombolytic therapy with intravenous alteplase (recombinant tissue-type plasminogen activator) at a dose of 0.9 mg per kilogram of body weight is an effective treatment for acute ischemic stroke, despite increasing the risk of intracerebral hemorrhage. 1 – 3 However, the Japanese drug safety authority has approved the use of alteplase at a dose of 0.6 mg per kilogram after an uncontrolled, open-label study showed that this dose resulted in equivalent clinical outcomes and a lower risk of intracerebral hemorrhage than that reported in published studies in which the 0.9-mg-per-kilogram dose was used. 4 Other registry studies in Asia 5 – 11 have shown inconsistent results, . . .

Craniotomy, according to the results from trials, does not improve functional outcome after intracerebral haemorrhage. Whether minimally invasive catheter evacuation followed by thrombolysis for clot removal is safe and can achieve a good functional outcome is not known. We investigated the safety and efficacy of alteplase, a recombinant tissue plasminogen activator, in combination with minimally invasive surgery (MIS) in patients with intracerebral haemorrhage. MISTIE was an open-label, phase 2 trial that was done in 26 hospitals in the USA, Canada, the UK, and Germany. We used a computer-generated allocation sequence with a block size of four to centrally randomise patients aged 18–80 years with a non-traumatic (spontaneous) intracerebral haemorrhage of 20 mL or higher to standard medical care or image-guided MIS plus alteplase (0·3 mg or 1·0 mg every 8 h for up to nine doses) to remove clots using surgical aspiration followed by alteplase clot irrigation. Primary outcomes were all safety outcomes: 30 day mortality, 7 day procedure-related mortality, 72 h symptomatic bleeding, and 30 day brain infections. This trial is registered with ClinicalTrials.gov, number NCT00224770. Between Feb 2, 2006, and April 8, 2013, 96 patients were randomly allocated and completed follow-up: 54 (56%) in the MIS plus alteplase group and 42 (44%) in the standard medical care group. The primary outcomes did not differ between the standard medical care and MIS plus alteplase groups: 30 day mortality (four [9·5%, 95% CI 2·7–22.6] vs eight [14·8%, 6·6–27·1], p=0·542), 7 day mortality (zero [0%, 0–8·4] vs one [1·9%, 0·1–9·9], p=0·562), symptomatic bleeding (one [2·4%, 0·1–12·6] vs five [9·3%, 3·1–20·3], p=0·226), and brain bacterial infections (one [2·4%, 0·1–12·6] vs zero [0%, 0–6·6], p=0·438). Asymptomatic haemorrhages were more common in the MIS plus alteplase group than in the standard medical care group (12 [22·2%; 95% CI 12·0–35·6] vs three [7·1%; 1·5–19·5]; p=0·051). MIS plus alteplase seems to be safe in patients with intracerebral haemorrhage, but increased asymptomatic bleeding is a major cautionary finding. These results, if replicable, could lead to the addition of surgical management as a therapeutic strategy for intracerebral haemorrhage. National Institute of Neurological Disorders and Stroke, Genentech, and Codman.

In patients with large-vessel ischemic stroke and no access to thrombectomy, tenecteplase given 4.5 to 24 hours after stroke resulted in less disability at 90 days than standard care but also a higher risk of intracranial hemorrhage.

When used for extended treatment after 6 to 12 months of anticoagulation therapy for venous thromboembolism, the factor Xa inhibitor apixaban reduced the risk of recurrent venous thromboembolism without increasing the risk of serious bleeding. Venous thromboembolism, which includes deep-vein thrombosis and pulmonary embolism, is the third most common cause of vascular disease–related deaths. 1 The mainstay of treatment is anticoagulation, and guidelines recommend therapy for 3 months or longer. 2 , 3 Decisions about extending treatment are challenging. Although warfarin is effective for the prevention of recurrent venous thromboembolism, the inconvenience of laboratory monitoring and the dietary restrictions, coupled with concerns about bleeding, often lead to a reluctance to continue warfarin therapy beyond 6 to 12 months. Attempts to reduce the risk of bleeding by lowering the intensity of warfarin therapy have resulted in decreased efficacy without . . .

In a randomized trial, 1006 patients with intermediate-risk pulmonary embolism were assigned to tenecteplase or placebo in addition to standard heparin therapy. The tenecteplase group had a lower rate of hemodynamic decompensation but more frequent major hemorrhage and stroke. Acute pulmonary embolism occurs frequently and may cause death or serious disability. 1 Case fatality rates vary widely, 2 , 3 but approximately 10% of all patients with acute pulmonary embolism die within 3 months after the diagnosis. 4 , 5 Acute right ventricular pressure overload at diagnosis is an important determinant of the severity and early clinical outcome of pulmonary embolism. 6 High-risk pulmonary embolism 7 is characterized by overt hemodynamic instability and warrants immediate advanced therapy, including consideration of fibrinolysis. In contrast, for patients presenting without systemic hypotension or hemodynamic compromise, standard anticoagulation is generally considered adequate treatment. 8 However, patients who have acute right ventricular . . .

In a trial conducted in China, patients with large cerebral infarctions as determined by imaging criteria within 24 hours after onset had better outcomes with endovascular therapy than with medical therapy alone.

This Guideline is a joint official statement of the Asian Pacific Association of Gastroenterology (APAGE) and the Asian Pacific Society for Digestive Endoscopy (APSDE). It was developed in response to the increasing use of antithrombotic agents (antiplatelet agents and anticoagulants) in patients undergoing gastrointestinal (GI) endoscopy in Asia. After reviewing current practice guidelines in Europe and the USA, the joint committee identified unmet needs, noticed inconsistencies, raised doubts about certain recommendations and recognised significant discrepancies in clinical practice between different regions. We developed this joint official statement based on a systematic review of the literature, critical appraisal of existing guidelines and expert consensus using a two-stage modified Delphi process. This joint APAGE-APSDE Practice Guideline is intended to be an educational tool that assists clinicians in improving care for patients on antithrombotics who require emergency or elective GI endoscopy in the Asian Pacific region.