Nonhemostatic Activities of Factor Xa: Are There Pleiotropic Effects of Anti-FXa Direct Oral Anticoagulants?

Papadaki, Styliani

doi:10.1177/0003319719840861

Cited by 30 publications

(24 citation statements)

References 101 publications

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“…18 Our data appear to show that apixaban is associated with approximately the same decrease in OR and improvement in survival as prophylactic enoxaparin, whether this is because of a similar AC effect or a similar anti-inflammatory effect is unknown at this point. 19,20 The strengths of this article are its large size and mature adjusted determination of baseline risk, establishing relevant variables and therapeutic intent in the first 48 hours. In addition, specific attention to medication type and dose adjusted to patient weight and creatinine clearance allowed us to establish AC therapeutic intent (prophylaxis or full therapy) prior to evaluating the impact of that intent on downstream mortality.…”

Section: Discussionmentioning

confidence: 99%

Anticoagulation in COVID-19: Effect of Enoxaparin, Heparin, and Apixaban on Mortality

et al. 2020

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Background Mortality in coronavirus disease of 2019 (COVID-19) is associated with increases in prothrombotic parameters, particularly D-dimer levels. Anticoagulation has been proposed as therapy to decrease mortality, often adjusted for illness severity. Objective We wanted to investigate whether anticoagulation improves survival in COVID-19 and if this improvement in survival is associated with disease severity. Methods This is a cohort study simulating an intention-to-treat clinical trial, by analyzing the effect on mortality of anticoagulation therapy chosen in the first 48 hours of hospitalization. We analyzed 3,625 COVID-19+ inpatients, controlling for age, gender, glomerular filtration rate, oxygen saturation, ventilation requirement, intensive care unit admission, and time period, all determined during the first 48 hours. Results Adjusted logistic regression analyses demonstrated a significant decrease in mortality with prophylactic use of apixaban (odds ratio [OR] 0.46, p = 0.001) and enoxaparin (OR = 0.49, p = 0.001). Therapeutic apixaban was also associated with decreased mortality (OR 0.57, p = 0.006) but was not more beneficial than prophylactic use when analyzed over the entire cohort or within D-dimer stratified categories. Higher D-dimer levels were associated with increased mortality (p < 0.0001). When adjusted for these same comorbidities within D-dimer strata, patients with D-dimer levels < 1 µg/mL did not appear to benefit from anticoagulation while patients with D-dimer levels > 10 µg/mL derived the most benefit. There was no increase in transfusion requirement with any of the anticoagulants used. Conclusion We conclude that COVID-19+ patients with moderate or severe illness benefit from anticoagulation and that apixaban has similar efficacy to enoxaparin in decreasing mortality in this disease.

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Section: Discussionmentioning

confidence: 99%

Anticoagulation in COVID-19: Effect of Enoxaparin, Heparin, and Apixaban on Mortality

et al. 2020

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“…Most clinical studies demonstrated that targeting Factor Xa inhibition with NOAC including rivaroxaban prevented systemic thromboembolic disease, reduced cardiovascular events, and death [ 60 ]. Moreover, NOAC non-hemostatic cellular effects suggest a potential benefit in inflammation, arterial stiffness, neointima formation, atherosclerosis, and fibrosis [ 5 , 61 ].…”

Section: Discussionmentioning

confidence: 99%

“…Coagulation plays a key role in cardiovascular disorders [ 1 ] and interfering with coagulation factors represents one of the main pharmacological approaches in CVD [ 2 ]. Coagulation factors, not only participate to the activation of the coagulation cascade but also impact vascular function; this is the case for factor X (FXa), one of the main components in the coagulation process [ 3 ], which, through the activation of protease-activated receptors (PAR) [ 4 ], affects, vasomotor responses, inflammation, endothelial function, vascular proliferation, cellular hypertrophy, atherosclerosis, and thrombosis [ 5 , 6 ].…”

Section: Introductionmentioning

confidence: 99%

Rivaroxaban improves vascular response in LPS-induced acute inflammation in experimental models

et al. 2020

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Rivaroxaban (RVX) was suggested to possess anti-inflammatory and vascular tone modulatory effects. The goal of this study was to investigate whether RVX impacts lipopolysaccharide (LPS)-induced acute vascular inflammatory response. Male rats were treated with 5 mg/kg RVX (oral gavage) followed by 10 mg/kg LPS i.p injection. Circulating levels of IL-6, MCP-1, VCAM-1, and ICAM-1 were measured in plasma 6 and 24 hours after LPS injection, while isolated aorta was used for gene expression analysis, immunohistochemistry, and vascular tone evaluation. RVX pre-treatment significantly reduced LPS mediated increase after 6h and 24h for IL-6 (4.4±2.2 and 2.8±1.7 fold), MCP-1 (1.4±1.5 and 1.3±1.4 fold) VCAM-1 (1.8±2.0 and 1.7±2.1 fold). A similar trend was observed in the aorta for iNOS (5.5±3.3 and 3.3±1.9 folds reduction, P<0.01 and P<0.001, respectively), VCAM-1 (1.3±1.2 and 1.4±1.3 fold reduction, P<0.05), and MCP-1 (3.9±2.2 and 1.9±1.6 fold reduction, P<0.01). Moreover, RVX pre-treatment, improved LPS-induced PE contractile dysfunction in aortic rings (Control vs LPS, Emax reduction = 35.4 and 31.19%, P<0.001; Control vs LPS+RVX, Emax reduction = 10.83 and 11.48%, P>0.05, respectively), resulting in 24.5% and 19.7% change in maximal constriction in LPS and LPS+RVX respectively. These data indicate that RVX pre-treatment attenuates LPS-induced acute vascular inflammation and contractile dysfunction.

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“…pleio -множественный и tropos -действие) препарата называют множественность его эффектов. Наряду с влиянием на гемостаз обнаруживаются иные свойства антикоагулянтов, основными из которых при использовании прямых антикоагулянтов, в частности варфарина, являются воздействие на ангиогенез, противовоспалительное [8][9][10], антиатеросклеротическое [8,9], противоопухолевое [11,12] действия, угнетение процессов ремоделирования предсердий [8,9] и влияние на почки [13,14]. В настоящее время изучен далеко не весь спектр плейотропных эффектов антикоагулянтов.…”

Section: плейотропные эффекты антикоагу лянтов и пути их реализацииunclassified

“…После активации рецепторов FXa инициируется гидролиз фосфатидилинозитола, который приводит к изменению содержания внутриклеточного кальция. FXa также инициирует фосфорилирование митоген-активированных протеинкиназ [8], что приводит к запуску различных транскрипционных программ. Эти программы способствуют росту и дифференцировке клеток, а также индукции генов, кодирующих цитокины (интерлейкин (ИЛ)-6, ИЛ-8, моноцитарный хемотаксический фактор-1, тканевой фактор, молекулы межклеточной адгезии-1) и белки внеклеточного матрикса (фактор роста соединительной ткани, коллаген, фибронектин).…”

Section: плейотропные эффекты антикоагу лянтов и пути их реализацииunclassified

Pleiotropic Effects of Oral Anticoagulants

Галяутдинов

Фейсханова

Абдуллаев

2019

Gematologiâ i transfuziologiâ

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In this paper, we present a literature review with the purpose of elucidating the pleiotropic effects of oral anticoagulants. The literature search was performed using the PubMed and SCOPUS databases. Pleiotropic effects of direct anticoagulants are determined by the interaction of Xa and thrombin IIa factors with PAR-1 and PAR-2 receptors. The focus of this review is the connection between oral anticoagulants and their effects on atherosclerosis, angiogenesis, inflammation, cardiac remodelling, oncogenesis and glomerular diseases. Direct anticoagulants exhibit an anti-atherosclerotic effect manifested in a decreased progression and destabilization of atherosclerotic lesions. This effect is confirmed by a decreased binding activity of DNA with NF-kB and AP-1 transcription factors and reduced levels of some mediators. Such effects of new oral anticoagulants also relate to the processes of cardiac remodelling. FXa inhibitors contribute to the prevention of cardiac remodelling by reducing the processes of inflammation and fibrosis, which are associated with a decrease in the expression of PAR receptors in the heart. A number of studies also demonstrate an anti-inflammatory effect of oral anticoagulants, which is confirmed by reduced expression of mRNA inflammatory cytokines under the influence of direct anticoagulants and the production of IL-6 under the influence of warfarin. FXa inhibitors are shown to increase the expression of vascular growth factors, stimulate the migration of еndothelial рrogenitor сells and improve their function, thus manifesting their angiogenic pleiotropic effect. In addition, warfarin has an impact both on angiogenesis by means of reducing the activation of Axl tyrosine kinases and on glomerular pathologies by means of affecting the proliferation of mesangial cells through the Gas6/Axl pathway. The antitumour activity of warfarin is associated with inhibition of Gas6-mediated activation of Axl on tumour cells. Further investigations are required to fully understand the effect of oral anticoagulants on haemostasis.

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Nonhemostatic Activities of Factor Xa: Are There Pleiotropic Effects of Anti-FXa Direct Oral Anticoagulants?

Cited by 30 publications

References 101 publications

Anticoagulation in COVID-19: Effect of Enoxaparin, Heparin, and Apixaban on Mortality

Anticoagulation in COVID-19: Effect of Enoxaparin, Heparin, and Apixaban on Mortality

Rivaroxaban improves vascular response in LPS-induced acute inflammation in experimental models

Pleiotropic Effects of Oral Anticoagulants

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