Antithrombotic Strategies Research Articles

The temptation of anticoagulant therapy after transcatheter aortic valve implantation.

The choice of the best antithrombotic strategy after transcatheter aortic valve implantation (TAVI) must be based on the careful balance between the ischaemic risk and the bleeding risk and on the evaluation of some concomitant conditions, such as atrial fibrillation or coronary artery disease which may lead to the choice of anticoagulant treatment or antiplatelet therapy. Another element to consider is the possibility, albeit remote in post-TAVI patients, of thrombosis of the valve leaflets, an event whose clinical impact has yet to be fully clarified and which however appears to present a lower incidence in patients treated with anticoagulants. Recent evidence has shown that in patients who do not require anticoagulant therapy, single therapy with aspirin represents the best treatment compared to dual antiplatelet or to the addition of anticoagulant which in post-TAVI patients should be reserved only for those with a clear indication such as atrial fibrillation. It is still much debated whether in this case the choice should fall on vitamin K antagonists or on the new direct-acting anticoagulants, as the comparison studies have produced inconclusive results.

A network meta-analysis of the antithrombotic strategies in patients with atrial fibrillation and percutaneous coronary interventions: Focus on bleeding

BackgroundWe performed a network meta-analysis of randomized controlled trials comparing non-vitamin K antagonist oral anticoagulant (NOAC)-based versus vitamin K antagonists (VKA)-based regimens in patients with atrial fibrillation (AF) and acute coronary syndromes or PCI, aiming to examine the precise impact of recently established antithrombotic strategies on major bleeding as primary end-point and other safety and efficacy as secondary end-points. MethodsA literature search was conducted for randomized controlled trials. Our search took place in three major databases. The primary endpoint of our study was bleeding. To combine direct and indirect evidence across trials, a frequentist network meta-analysis with a random-effects model was used. ResultsFive studies were found eligible for the meta-analysis enrolling a total of 11,542 patients. Five studies (N = 4903 patients) contributed to the network. Compared to the triple antithrombotic therapy (TAT)-based VKA, only the dual antithrombotic therapy (DAT) based NOAC reduced the bleeding (RR 0.57, 95%CI 0.40–0.82). There was no statistically significant difference between DAT-based VKA (RR = 0.66, 95%CI = 0.40–1.09) or TAT-based NOAC (RR = 0.80, 95%CI = 0.43–1.49). DAT-based NOAC ranked best (P-score = 0.91), followed by DAT-based VKA (P-score = 0.67), TAT-based NOAC (P-score = 0.40), and TAT-based VKA (P-score = 0.03). ConclusionThe network meta-analysis of four antithrombotic strategies, demonstrated that in patients with AF undergoing PCI the combination of DAT-based NOAC is associated with a significantly lower risk of major bleeding events. This strategy does not seem to be less effective in terms of prevention of ischemic events compared to the other regimens.

Treatment of Persistent Left Atrial Appendage Thrombus in Patients with Atrial Fibrillation on Adequate Oral Anticoagulation: Pathways of Care for All-comers and Heart Failure Patients.

In patients with AF, the presence of left atrial/left atrial appendage (LA/LAA) thrombus is related to an increased risk of thromboembolic events. Anticoagulation therapy, either with vitamin K antagonists or novel oral anticoagulants (NOACs) is therefore mandatory in AF with LA/LAA thrombus in order to lower the risk of stroke or other systemic embolic events. Despite the efficacy of these treatments, some patients will have persistent LAA thrombus remaining or may have contraindications to oral anticoagulation. Currently, little is known about the occurrence, risk factors and resolution rate of LA/LAA thrombus in patients who are already under optimal chronic oral anticoagulation, including vitamin K antagonists or NOACs. The common action in clinical practice in this scenario is switching from one to another anticoagulant drug exhibiting a different mechanism of action. Repeated cardiac imaging is then advised within several weeks to visually verify thrombus dissolution. Finally, there is a substantial scarcity of data on the role and optimal use of NOACs after LAA occlusion. The aim of this review is to critically evaluate data and provide up-to-date information on the best antithrombotic strategies in this challenging clinical scenario.

Antithrombotic Therapy in Peripheral Artery Disease: Current Evidence and Future Directions.

Patients with peripheral artery disease (PAD) are at an increased risk of major adverse cardiovascular events, and those with disease in the lower extremities are at risk of major adverse limb events primarily driven by atherothrombosis. Traditionally, PAD refers to diseases of the arteries outside of the coronary circulation, including carotid, visceral and lower extremity peripheral artery disease, and the heterogeneity of PAD patients is represented by different atherothrombotic pathophysiology, clinical features and related antithrombotic strategies. The risk in this diverse population includes systemic risk of cardiovascular events as well as risk related to the diseased territory (e.g., artery to artery embolic stroke for patients with carotid disease, lower extremity artery to artery embolism and atherothrombosis in patients with lower extremity disease). Moreover, until the last decade, clinical data on antithrombotic management of PAD patients have been drawn from subanalyses of randomized clinical trials addressing patients affected by coronary artery disease. The high prevalence and related poor prognosis in PAD patients highlight the pivotal role of tailored antithrombotic therapy in patients affected by cerebrovascular, aortic and lower extremity peripheral artery disease. Thus, the proper assessment of thrombotic and hemorrhagic risk in patients with PAD represents a key clinical challenge that must be met to permit the optimal antithrombotic prescription for the various clinical settings in daily practice. The aim of this updated review is to analyze different features of atherothrombotic disease as well as current evidence of antithrombotic management in asymptomatic and secondary prevention in PAD patients according to each arterial bed.

Role of antimicrobial peptide cathelicidin in thrombosis and thromboinflammation.

Thrombosis is a frequent cause of cardiovascular mortality and hospitalization. Current antithrombotic strategies, however, target both thrombosis and physiological hemostasis and thereby increase bleeding risk. In recent years the pathophysiological understanding of thrombus formation has significantly advanced and inflammation has become a crucial element. Neutrophils as most frequent immune cells in the blood and their released mediators play a key role herein. Neutrophil-derived cathelicidin next to its strong antimicrobial properties has also shown to modulates thrombosis and thus presents a potential therapeutic target. In this article we review direct and indirect (immune- and endothelial cell-mediated) effects of cathelicidin on platelets and the coagulation system. Further we discuss its implications for large vessel thrombosis and consecutive thromboinflammation as well as immunothrombosis in sepsis and COVID-19 and give an outlook for potential therapeutic prospects.

Advances in the Diagnosis and Treatment of Pediatric Arterial Ischemic Stroke.

Though rare, stroke in infants and children is an important cause of mortality and chronic morbidity in the pediatric population. Neuroimaging advances and implementation of pediatric stroke care protocols have led to the ability to rapidly diagnose stroke and in many cases determine the stroke etiology. Though data on efficacy of hyperacute therapies, such as intravenous thrombolysis and mechanical thrombectomy, in pediatric stroke are limited, feasibility and safety data are mounting and support careful consideration of these treatments for childhood stroke. Recent therapeutic advances allow for targeted stroke prevention efforts in high-risk conditions, such as moyamoya, sickle cell disease, cardiac disease, and genetic disorders. Despite these exciting advances, important knowledge gaps persist, including optimal dosing and type of thrombolytic agents, inclusion criteria for mechanical thrombectomy, the role of immunomodulatory therapies for focal cerebral arteriopathy, optimal long-term antithrombotic strategies, the role of patent foramen ovale closure in pediatric stroke, and optimal rehabilitation strategies after stroke of the developing brain.

Chinese guideline for the clincal application of transcatheter aortic valve replacement

Transcatheter aortic valve replacement (TAVR), as an important procedure for aortic valve diseases worldwide, features with a late start and rapid development in China. In the process of clinical application, the lack of standard guidelines and training system has brought challenges to the widespread use of this technique. In order to standardize the application of TAVR technique and improve the quality of medical care, the National Center for Cardiovascular Diseases and the National Center for Quality Control of Structural Heart Disease Intervention, together with the Chinese Society of Cardiology and the Chinese Society for Thoracic and Cardiovascular Surgery, jointly established an expert group on the guidelines for TAVR, combined with the recommendations of international guidelines and the current clinical practice in China, integrated the latest evidence in China and worldwide to develop the clinical guideline of TAVR with extensive consultation (Chinese Expert Consensus). The guideline mainly included 11 parts: methods, epidemiological feature, TAVR devices, requirements of cardiac teams, recommendations for TAVR indications, perioperative multimodality imaging evaluation, surgical procedures, anti-thrombotic strategies after TAVR, prevention and treatment of complications, postoperative rehabilitation and follow-up, limitations and prospects, aiming to provide reasonable recommendations for all-level clinicians in China.

Individual net clinical outcome with oral anticoagulation in atrial fibrillation using the ABC‐AF risk scores

BackgroundDecisions on stroke prevention strategies in patients with atrial fibrillation (AF) depend on the perceived risks of stroke and bleeding with different antithrombotic treatment strategies. The study objectives were to evaluate net clinical outcome with oral anticoagulation (OAC) for the individual patient with AF and to identify clinically relevant thresholds for OAC treatment. MethodsPatients with AF receiving OAC treatment in the randomized ARISTOTLE and RE-LY trials, with available biomarkers for calculation of ABC-AF scores at baseline, were included (n = 23,121). Observed 1-year risk on OAC was compared with predicted 1-year risk if the same patients would not have received OAC using the ABC-AF scores calibrated for aspirin. Net clinical outcome was defined as the sum of stroke and major bleeding risks. ResultsThe ratio between the 1-year incidence of major bleeding and stroke/systemic embolism events ranged from 1.4 to 10.6 according to different ABC-AF risk profiles. Net clinical outcome analyses showed that in patients with an ABC-AF-stroke risk >1% per year on OAC (>3% without OAC), treatment with OAC consistently provides larger net clinical benefit than no-OAC treatment. In patients with an ABC-AF-stroke risk <1.0% per year on OAC (<3% without OAC) an individualized balancing of risks regarding OAC or no-OAC treatment is needed. ConclusionsIn patients with AF, the ABC-AF risk scores allow an individual and continuous estimate of the balance between benefits and risks with OAC treatment. This precision medicine tool therefore seems useful as decision support and visualizes the net clinical benefit or harm with OAC treatment (http://www.abc-score.com/abcaf/). Clinical Trial RegistrationClinicalTrials.gov identifier NCT00412984 (ARISTOTLE) and NCT00262600 (RE-LY).

Efficacy and safety of rivaroxaban plus clopidogrel versus aspirin plus clopidogrel in patients with coronary atherosclerotic heart disease and gastrointestinal disease undergoing percutaneous coronary intervention: study protocol for a non-inferiority randomized controlled trial

BackgroundDual antiplatelet therapy (DAPT) with aspirin and a P2Y12 inhibitor is recommended for patients with coronary heart disease (CHD) undergoing percutaneous coronary intervention (PCI) to antithrombosis, meanwhile, increasing the risks of gastrointestinal bleeding. Rivaroxaban, a novel oral anticoagulant, combined with a P2Y12 receptor inhibitor reduces adverse events in patients with CHD and atrial fibrillation who underwent PCI. The effect of rivaroxaban plus P2Y12 inhibitor on reducing bleeding events in patients with CHD and gastrointestinal disease (GID) undergoing PCI remains unclear.MethodThe study is a prospective, single-center, randomized controlled trial. A total of 1020 patients with CHD and GID undergoing PCI will be enrolled. Patients are randomized (1:1) to receive either rivaroxaban 10 mg plus clopidogrel 75 mg daily or aspirin 100 mg plus clopidogrel 75 mg daily; both treatments will last 6 months. The primary endpoint is Bleeding Academic Research Consortium (BARC) type 2–5 bleeding requiring medical intervention. The secondary endpoint is a composite of major adverse cardiovascular and cerebrovascular events (MACCE), including all-cause death, cardiac death, nonfatal myocardial infarction, stent thrombosis, ischemia-driven target vessel revascularization, and stroke.DiscussionThe objective of this study is to evaluate the efficacy and safety of rivaroxaban plus clopidogrel versus aspirin plus clopidogrel in patients with CHD and GID undergoing PCI. We aim to explore an optimized antithrombotic strategy, which achieves the same anti-ischemic effect as standard DAPT without increasing the risk of GIB, for patients with CHD and GID undergoing PCI.Trial registrationThis protocol is registered at the Chinese Clinical Trial Registry under the number ChiCTR2100044319. And this publication is based on version 1.4 of the trial protocol dated Sep 6, 2021.

Antithrombotic therapies in Canadian atrial fibrillation patients with concomitant coronary artery disease: Insights from the CONNECT AF + PCI-II program

BackgroundSelecting the appropriate antithrombotic regimen for patients with atrial fibrillation (AF) who have undergone percutaneous coronary intervention (PCI) or have had medically managed acute coronary syndrome (ACS) remains complex. This multi-centre observational study evaluated patterns of antithrombotic therapies utilized among Canadian patients with AF post-PCI or ACS. Methods and resultsBy retrospective chart audit, 611 non-valvular AF patients [median (interquartile range) age 76 (69–83) years, CHADS2 score 2 (1–3)] who underwent PCI or had medically managed ACS between August 2018 and December 2020 were identified by 68 cardiologists across eight provinces in Canada. Overall, triple antithrombotic therapy [TAT: combined oral anticoagulation (OAC) and dual antiplatelet therapy (DAPT)] was the most common initial antithrombotic strategy, with use in 53.8 % of patients, followed by dual pathway therapy (32.7 % received OAC and a P2Y12 inhibitor, and 4.1 % received OAC and aspirin) and DAPT (9.3 %). Median duration of TAT was 30 (7, 30) days. Compared to the previous CONNECT AF + PCI-I program, there was an increased use of dual pathway therapy relative to TAT over time (P-value <.0001). DOACs (direct oral anticoagulants) represented 90.3 % of all OACs used overall, with apixaban being the most utilized (50.5 %). Proton pump inhibitors were used in 57.0 % of all patients, and 70.1 % of patients on ASA. Planned antithrombotic therapies at 1 year were: 76.2 % OAC monotherapy, 8.3 % OAC + ASA, 7.9 % OAC + P2Y12 inhibitor, 4.3 % DAPT, 1.3 % ASA alone, and <1 % triple therapy. ConclusionIn accordance with recent Canadian Cardiovascular Society guideline recommendations, we observed an increased use of dual pathway therapy relative to TAT over time in both AF patients post-PCI (elective and emergent) and in those with medically managed ACS. Additionally, DOACs have become the prevailing form of anticoagulation across all antithrombotic regimens. Our findings suggest that Canadian physicians are integrating evidence-based approaches to optimally manage the bleeding and thrombotic risks of AF patients post-PCI and/or ACS.

Pharmacology and Clinical Development of Factor XI Inhibitors

Therapeutic anticoagulation is indicated for a variety of circumstances and conditions in several fields of medicine to prevent or treat venous and arterial thromboembolism. According to the different mechanisms of action, the available parenteral and oral anticoagulant drugs share the common principle of hampering or blocking key steps of the coagulation cascade, which unavoidably comes at the price of an increased propensity to bleed. Hemorrhagic complications affect patient prognosis both directly and indirectly (ie, by preventing the adoption of an effective antithrombotic strategy). Inhibition of factor XI (FXI) has emerged as a strategy with the potential to uncouple the pharmacological effect and the adverse events of anticoagulant therapy. This observation is based on the differential contribution of FXI to thrombus amplification, in which it plays a major role, and hemostasis, in which it plays an ancillary role in final clot consolidation. Several agents were developed to inhibit FXI at different stages (ie, suppressing biosynthesis, preventing zymogen activation, or impeding the biological action of the active form), including antisense oligonucleotides, monoclonal antibodies, small synthetic molecules, natural peptides, and aptamers. Phase 2 studies of different classes of FXI inhibitors in orthopedic surgery suggested that dose-dependent reductions in thrombotic complications are not paralleled by dose-dependent increases in bleeding compared with low-molecular-weight heparin. Likewise, the FXI inhibitor asundexian was associated with lower rates of bleeding compared with the activated factor X inhibitor apixaban in patients with atrial fibrillation, although no evidence of a therapeutic effect on stroke prevention is available so far. FXI inhibition could also be appealing for patients with other conditions, including end-stage renal disease, noncardioembolic stroke, or acute myocardial infarction, for which other phase 2 studies have been conducted. The balance between thromboprophylaxis and bleeding achieved by FXI inhibitors needs confirmation in large-scale phase 3 clinical trials powered for clinical end points. Several of such trials are ongoing or planned to define the role of FXI inhibitors in clinical practice and to clarify which FXI inhibitor may be most suited for each clinical indication. This article reviews the rationale, pharmacology, results of medium or small phase 2 studies, and future perspectives of drugs inhibiting FXI.

Time course of ischemic and bleeding burden in consecutive patients undergoing transcatheter aortic valve replacement (FOCUS-ONE Registry)

Background and aimsIschemic or bleeding events might occur after transcatheter aortic valve replacement (TAVR), with the potential to hamper clinical outcomes. This study aimed to characterize the average daily ischemic risks (ADIRs) and the average daily bleeding risks (ADBRs) over 1-year in all consecutive patients undergoing TAVR. MethodsADBR included all bleeding events according to VARC-2 definition, and ADIR included cardiovascular deaths, myocardial infarction and ischemic stroke. ADIRs and ADBRs were assessed within different timeframes post TAVR: acute (0–30 days), late (31–180 days), and very late (>181 days). Generalized estimating equations were used to test the least squares mean differences for the pairwise comparison of ADIRs and ADBRs. Our analysis was performed in the overall cohort and according to antithrombotic strategy (LT-OAC vs No LT-OAC). ResultsIschemic burden was higher than bleeding burden, independently from the indication to LT-OAC, and in all timeframes examined. In the overall population, ADIRs were three-fold ADBRs (0.0467 [95% CI, 0.0431–0.0506] vs 0.0179 [95% CI, 0.0174–0.0185]; p < 0.001*). While ADIR was significantly higher in the acute phase, ADBR was relatively stable in all timeframes analysed. Of note, in LT-OAC population, OAC + SAPT group showed lower ischemic risk and higher bleeding events compared with OAC alone (ADIR: 0.0447 [95% CI: 0.0417–0.0477] vs 0.0642 [95% CI: 0.0557–0.0728]; p < 0.001*, ADBR 0.0395 [95% CI: 0.0381–0.0409] vs 0.0147 [95% CI: 0.0138–0.0156]; p < 0.001*). ConclusionsIn patients undergoing TAVR Average daily risk fluctuates over time. However, ADIRs overcome ADBRs in all timeframes, especially in the acute phase and regardless of antithrombotic strategy adopted.

COVID-19 and the Response to Antiplatelet Therapy

The coronavirus SARS-CoV2 disease (COVID-19) is connected with significant morbidity and mortality (3.4%), disorders in hemostasis, including coagulopathy, activation of platelets, vascular injury, and changes in fibrinolysis, which may be responsible for an increased risk of thromboembolism. Many studies demonstrated relatively high rates of venous and arterial thrombosis related to COVID-19. The incidence of arterial thrombosis in severe/critically ill intensive care unit-admitted COVID-19 patients appears to be around 1%. There are several ways for the activation of platelets and coagulation that may lead to the formation of thrombi, so it is challenging to make a decision about optimal antithrombotic strategy in patients with COVID-19. This article reviews the current knowledge about the role of antiplatelet therapy in patients with COVID-19.

Within and beyond 12-month efficacy and safety of antithrombotic strategies in patients with established coronary artery disease: two companion network meta-analyses of the 2022 joint clinical consensus statement of the European Association of Percutaneous Cardiovascular Interventions (EAPCI), European Association for Acute CardioVascular Care (ACVC), and European Association of Preventive Cardiology (EAPC).

To appraise all available antithrombotic treatments within or after 12 months following coronary revascularization and/or acute coronary syndrome in two network meta-analyses. Forty-three (N=189261 patients) trials within 12 months and 19 (N=139086 patients) trials beyond 12 months were included for efficacy/safety endpoints appraisal. Within 12 months, ticagrelor 90mg bis in die (b.i.d.) [hazard ratio (HR), 0.66; 95% confidence interval (CI), 0.49-0.88], aspirin and ticagrelor 90mg (HR, 0.85; 95% CI, 0.76-0.95), or aspirin, clopidogrel and rivaroxaban 2.5mg b.i.d. (HR, 0.66; 95% CI, 0.51-0.86) were the only treatments associated with lower cardiovascular mortality, compared with aspirin and clopidogrel, without or with greater bleeding risk for the first and the other treatment options, respectively. Beyond 12 months, no strategy lowered mortality; compared with aspirin; the greatest reductions of myocardial infarction (MI) were found with aspirin and clopidogrel (HR, 0.68; 95% CI, 0.55-0.85) or P2Y12 inhibitor monotherapy (HR, 0.76; 95% CI: 0.61-0.95), especially ticagrelor 90mg (HR, 0.54; 95% CI, 0.32-0.92), and of stroke with VKA (HR, 0.56; 95% CI, 0.44-0.76) or aspirin and rivaroxaban 2.5mg (HR, 0.58; 95% CI, 0.44-0.76). All treatments increased bleeding except P2Y12 monotherapy, compared with aspirin. Within 12 months, ticagrelor 90mg monotherapy was the only treatment associated with lower mortality, without bleeding risk trade-off compared with aspirin and clopidogrel. Beyond 12 months, P2Y12 monotherapy, especially ticagrelor 90mg, was associated with lower MI without bleeding trade-off; aspirin and rivaroxaban 2.5mg most effectively reduced stroke, with a more acceptable bleeding risk than VKA, compared with aspirin.Registration URL: https://www.crd.york.ac.uk/PROSPERO/; Unique identifiers: CRD42021243985 and CRD42021252398.

Gaps in evidence in recent cardiovascular guidelines: uncertainties in chronic coronary syndrome

The clinical guidelines, while representing an objective reference to perform correct therapeutic choices, contain grey zones, where the recommendations are not supported by solid evidence. In the fifth National Congress Grey Zones held in Bergamo in June 2022, an attempt was made to highlight some of the main grey zones in Cardiology and, through a comparison between experts, to draw shared conclusions that can illuminate our clinical practice. This manuscript contains the statements of the symposium concerning the controversies regarding ischemic cardiomyopathy. The manuscript represents the organization of the meeting, with an initial review of the current guidelines on this topic, followed by an expert presentation of pros (White) and cons (Black) related to the identified "gaps of evidence". For every issue is then reported the "response" derived from the votes of the experts and the public, the discussion and, finally, the highlights, which are intended as practical take home messages to be used in the everyday clinical practice. The first gap in evidence discussed regards the validity of the indication to search for ischemia in light of the data from the ISCHEMIA trial. The second examines the possibility of modifying the algorithm proposed by the European guidelines on anti-ischemic therapy in chronic coronary syndromes. The last gap in evidence evaluates the comparability of long-term antithrombotic strategies in chronic coronary syndromes.

Comparison of three antithrombotic strategies for emergent carotid stenting during stroke thrombectomy: a multicenter study

BackgroundPeriprocedural antithrombotic treatment is a key determinant for the risk–benefit balance of emergent carotid artery stenting (eCAS) during stroke thrombectomy. We aimed to assess the safety and efficacy of three...

Embolic Stroke of Undetermined Source: Current Perspectives on Diagnosis, Investigations, and Management.

In 2014, Hart etal. introduced the concept of "embolic stroke of undetermined source" (ESUS) to the clinical-research stroke community. The hypothesis underlying the development of the ESUS construct was that this potentially heterogenous group of stroke mechanisms were largely thromboembolic, and would thus benefit from anticoagulation over antiplatelet for secondary prevention. Since then, 2 large clinical trials have shown that, to date, there is not a clear uniform antithrombotic strategy for secondary prevention after ESUS as it was originally broadly defined. However, this work has yielded valuable information about the patient phenotypes that experience ESUS strokes, as well as hypothesis-generating substudies that have given rise to the next generation of secondary prevention trials aimed at more personalized approaches for different suspected mechanisms of embolic stroke. In parallel with the evolution of ESUS, several studies aimed at screening for atrial fibrillation in the secondary stroke prevention population have generated additional questions about the mechanistic relevance of atrial fibrillation detected after stroke, and how this should inform poststroke workup, and secondary prevention strategies. Herein, we provide a synthesis of the current understanding surrounding the patient phenotypes that experience ESUS strokes, and previous, ongoing, and anticipated clinical trials that will guide earlier and later secondary prevention strategies and poststroke cardiac investigations.

Abstract WP212: Association Of Thrombin Generation With Leukocyte Inflammatory Profile In Patients With Acute Ischemic Stroke

Thrombosis is central to the pathogenesis of acute ischemic stroke, with higher thrombin generation being associated with increased stroke risk. The immune system may contribute to thrombin generation in stroke and thus may offer novel strategies for stroke prevention. This study addresses the research question regarding the relationship of thrombin generation to leukocyte gene expression in patients with acute ischemic stroke. We isolated RNA from whole blood and examined the relationship to thrombin generation capacity in patients with acute ischemic stroke. Due to its effects on thrombin generation, patients on anticoagulants were excluded from the study. The relationship of gene expression with peak thrombin was evaluated by analysis of covariance across peak thrombin quartiles adjusted for sex and age. In 97 patients with acute ischemic stroke, peak thrombin was variable, ranging from 252.0 to 752.4 nM. Increased thrombin generation was associated with differences in thromboinflammatory leukocyte gene expression, including a decrease in ADAM metallopeptidase with thrombospondin type 1 motif 13 and an increase in nuclear factor B (NF-kB)-activating protein, protein disulfde isomerase family A member 5, and tissue factor pathway inhibitor 2. Pathways associated with peak thrombin included interleukin 6 signaling, thrombin signaling, and NF-kB signaling. A linear discriminant analysis model summarizing the immune activation associated with peak thrombin in a first cohort of stroke could distinguish patients with low peak thrombin from high peak thrombin in a second cohort of 112 patients with acute ischemic stroke.The identified genes and pathways support a role of the immune system contributing to thrombus formation in patients with stroke. These may have relevance to antithrombotic strategies for stroke prevention.

Reduced- or Half-Dose Rivaroxaban Following Left Atrial Appendage Closure: A Feasible Antithrombotic Therapy in Patients at High Risk of Bleeding?

The optimal antithrombotic strategy after percutaneous left atrial appendage closure (LAAC) has not yet been established. The advisability of administering low-dose direct oral anticoagulation after LAAC to patients at high risk of bleeding is uncertain. Thus, in the present study, we evaluated the safety and effectiveness of reduced-(15 mg) or half-dose rivaroxaban (10 mg) versus warfarin regarding real-world risks of thromboembolism, bleeding, and device-related thrombosis (DRT) after LAAC. Patients with non-valvular atrial fibrillation and HASBLED ≥ 3 who had undergone successful LAAC device implantation from October 2014 to April 2020 were screened and those who had received 10 mg or 15 mg rivaroxaban or warfarin therapy were enrolled. The patients were followed up 45 days and 6 months after LAAC to evaluate outcomes, including death, thromboembolism, major bleeding, and DRT. Of 457 patients with HASBLED ≥ 3 who had undergone LAAC, 115 had received warfarin and 342 rivaroxaban (15 mg: N = 164; 10 mg: N = 178). There were no significant differences in the incidence of thromboembolism or DRT between the warfarin and both doses of rivaroxaban groups (all p > 0.05). The incidence of major bleeding was significantly higher in the warfarin group than in either the reduced- or half-dose rivaroxaban groups (warfarin vs. rivaroxaban 15 mg: 2.6% vs. 0%, p = 0.030; warfarin vs. rivaroxaban 10 mg: 2.6% vs. 0%, p = 0.038). Either reduced- or half-dose rivaroxaban may be an effective and safe alternative to warfarin therapy in patients with LAAC and who are at high risk of bleeding, the risk of thromboembolism being similar and of major bleeding lower for both doses of rivaroxaban.

Location, location, location: Fibrin, cells, and fibrinolytic factors in thrombi.

Thrombi are heterogenous in nature with composition and structure being dictated by the site of formation, initiating stimuli, shear stress, and cellular influences. Arterial thrombi are historically associated with high platelet content and more tightly packed fibrin, reflecting the shear stress in these vessels. In contrast, venous thrombi are generally erythrocyte and fibrin-rich with reduced platelet contribution. However, these conventional views on the composition of thrombi in divergent vascular beds have shifted in recent years, largely due to recent advances in thromboectomy and high-resolution imaging. Interestingly, the distribution of fibrinolytic proteins within thrombi is directly influenced by the cellular composition and vascular bed. This in turn influences the susceptibility of thrombi to proteolytic degradation. Our current knowledge of thrombus composition and its impact on resistance to thrombolytic therapy and success of thrombectomy is advancing, but nonetheless in its infancy. We require a deeper understanding of thrombus architecture and the downstream influence on fibrinolytic susceptibility. Ultimately, this will aid in a stratified and targeted approach to tailored antithrombotic strategies in patients with various thromboembolic diseases.