rivaroxaban and Inflammation

Rivaroxaban is a direct, oral factor Xa inhibitor that is used for the prevention and treatment of various thromboembolic disorders. Several preclinical and clinical studies have utilized specific molecules as biomarkers to investigate the potential role of rivaroxaban beyond its anticoagulant activity and across a range of biological processes. The aim of this review is to summarize the existing evidence regarding the use of blood-based biomarkers to characterize the effects of rivaroxaban on coagulation and other pathways, including platelet activation, inflammation and endothelial effects. After a literature search using PubMed, almost 100 preclinical and clinical studies were identified that investigated the effects of rivaroxaban using molecular biomarkers. In agreement with the preclinical data, clinical studies reported a trend for reduction in the blood concentrations of D-dimers, thrombin-antithrombin complex and prothrombin fragment 1 + 2 following treatment with rivaroxaban in both healthy individuals and those with various chronic conditions. Preclinical and also some clinical studies have also reported a potential impact of rivaroxaban on the concentrations of platelet activation biomarkers (von Willebrand factor, P-selectin and thrombomodulin), endothelial activation biomarkers (matrix metalloproteinase-9, intercellular adhesion molecule-1 and vascular cell adhesion molecule-1) and inflammation biomarkers (interleukin-6, tumor necrosis factor-α and monocyte chemoattractant protein-1). Based on the results of biomarker studies, molecular biomarkers can be used in addition to traditional coagulation assays to increase the understanding of the anticoagulation effects of rivaroxaban. Moreover, there is preliminary evidence to suggest that rivaroxaban may have an impact on the biological pathways of platelet activation, endothelial activation and inflammation; however, owing to paucity of clinical data to investigate the trends reported in preclinical studies, further investigation is required to clarify these observations.

Topics: Anticoagulants; Biomarkers; Blood Coagulation; Factor Xa Inhibitors; Humans; Inflammation; Rivaroxaban

COVID-19 is also manifested with hypercoagulability, pulmonary intravascular coagulation, microangiopathy, and venous thromboembolism (VTE) or arterial thrombosis. Predisposing risk factors to severe COVID-19 are male sex, underlying cardiovascular disease, or cardiovascular risk factors including noncontrolled diabetes mellitus or arterial hypertension, obesity, and advanced age. The VAS-European Independent Foundation in Angiology/Vascular Medicine draws attention to patients with vascular disease (VD) and presents an integral strategy for the management of patients with VD or cardiovascular risk factors (VD-CVR) and COVID-19. VAS recommends (1) a COVID-19-oriented primary health care network for patients with VD-CVR for identification of patients with VD-CVR in the community and patients' education for disease symptoms, use of eHealth technology, adherence to the antithrombotic and vascular regulating treatments, and (2) close medical follow-up for efficacious control of VD progression and prompt application of physical and social distancing measures in case of new epidemic waves. For patients with VD-CVR who receive home treatment for COVID-19, VAS recommends assessment for (1) disease worsening risk and prioritized hospitalization of those at high risk and (2) VTE risk assessment and thromboprophylaxis with rivaroxaban, betrixaban, or low-molecular-weight heparin (LMWH) for those at high risk. For hospitalized patients with VD-CVR and COVID-19, VAS recommends (1) routine thromboprophylaxis with weight-adjusted intermediate doses of LMWH (unless contraindication); (2) LMWH as the drug of choice over unfractionated heparin or direct oral anticoagulants for the treatment of VTE or hypercoagulability; (3) careful evaluation of the risk for disease worsening and prompt application of targeted antiviral or convalescence treatments; (4) monitoring of D-dimer for optimization of the antithrombotic treatment; and (5) evaluation of the risk of VTE before hospital discharge using the IMPROVE-D-dimer score and prolonged post-discharge thromboprophylaxis with rivaroxaban, betrixaban, or LMWH.

Topics: Anticoagulants; Cardiology; Cardiovascular Diseases; COVID-19; COVID-19 Drug Treatment; Europe; Heparin, Low-Molecular-Weight; Humans; Inflammation; Practice Guidelines as Topic; Risk Factors; Rivaroxaban; SARS-CoV-2; Societies, Medical; Thrombophilia; Thrombosis

COMPASS study demonstrated efficacy of dual pathway inhibition with 2.5 mg twice daily rivaroxaban and aspirin in patients with polyvascular disease (coronary artery disease, peripheral arterial disease or both), the underlying mechanism of which is not clearly understood. In this Phase IV, prospective, open-label and randomized study, we hypothesize that treatment with rivaroxaban is associated with a reduction in platelet activation and aggregation, inflammation and coagulation markers. 30 patients will be randomly treated with aspirin (81 mg q.d.) or aspirin plus rivaroxaban (2.5 mg b.i.d.) for 12 weeks. Platelet aggregation, platelet activation and inflammation markers, thrombin generation kinetics and tissue factor-induced platelet-fibrin clot strength will be measured at baseline, and 4 and 12 weeks after randomization.

Topics: Aged; Aspirin; Biomarkers; Blood Coagulation; Coronary Artery Disease; Drug Therapy, Combination; Factor Xa Inhibitors; Female; Humans; Inflammation; Male; Peripheral Arterial Disease; Platelet Activation; Platelet Aggregation Inhibitors; Prospective Studies; Rivaroxaban

Coronary artery diseases are principal sources of mortality and disability in global human population. Progressively, rivaroxaban is being evaluated for the prevention of atherosclerotic thrombi, particularly with anti-platelet agents. Hence, the current report aimed to investigate the cardioprotective effect of rivaroxaban on isoproterenol (ISO)-induced cardiac injury model in rats and the possible synergistic effect when combined with aspirin. Male Wistar rats were randomly assigned into five different groups. Cardiac injury was induced by subcutaneous injection of ISO (85 mg/kg) for 2 consecutive days. Rat tail bleeding time was performed prior to sacrifice. Cardiac enzymes, platelet activity, inflammatory, and oxidative stress biomarkers levels were measured using enzyme-linked immunoassay (ELISA). Pre-administration of rivaroxaban alone and on combination with aspirin prevented ISO-induced increase in cardiac thiobarbituric acid reactive substances (TBARS), interleukin 6 (IL-6), and thromboxane B2 (TXB2) levels. Moreover, a significant prolongation of bleeding time was demonstrated among aspirin, rivaroxaban, and aspirin plus rivaroxaban treated groups. On the other hand, the combination treatment of aspirin plus rivaroxaban showed no marked difference in these biomarkers and bleeding time relative to either drug administered separately. However, a prominent decrease of cardiac 6-keto prostaglandin F1α (6-Keto-PGF1α) level was displayed in the combination treatment when compared with ISO and rivaroxaban-treated groups, whereas no significant improvement was seen in cardiac glycoprotein V (GPV) levels except in aspirin-treated group. The study results demonstrated that rivaroxaban decreases cardiac oxidative stress, inflammation, and platelets reactivity. However, the addition of rivaroxaban to aspirin did not seem to show synergistic antioxidant, anti-inflammatory, or antiplatelet effect.

Topics: Animals; Aspirin; Biomarkers; Factor Xa Inhibitors; Heart Injuries; Inflammation; Isoproterenol; Male; Oxidative Stress; Platelet Aggregation Inhibitors; Rats; Rats, Wistar; Rivaroxaban

Dual pathway inhibition (DPI) with low-dose rivaroxaban and aspirin in patients with coronary artery disease (CAD) and/or peripheral artery disease (PAD) reduces the occurrence of cardiovascular (CV) events; however, the underlying mechanisms explaining these latter CV benefits are not clearly understood. Our explorative observational study aimed to evaluate the effect of dual pathway inhibition on plasma inflammation and coagulation markers among real-world patients with CAD and/or PAD. We prospectively included all consecutive patients with an established diagnosis of CAD and/or PAD treated with aspirin 100 mg once daily (OD) and rivaroxaban 2.5 mg twice daily (TD). Clinical evaluation and laboratory analyses, including hemoglobin, renal function (creatinine, urea, and cystatin-C), coagulation markers (INR and aPTT), inflammation markers (IL-6, CRP, lipoprotein-associated phospholipase A2, and copeptin), and growth differentiation factor-15 (GDF-15), were conducted at baseline, before starting treatment, and at 4 and 24 weeks after study drug administration. Fifty-four consecutive patients (mean age 66 ± 7 years; male 83%) who completed the 6-month follow-up were included. At 24-week follow-up, a statistically significant reduction in IL-6 serum levels [4.6 (3.5-6.5) vs. 3.4 (2.4-4.3) pg/mL ; P = 0.0001] and fibrinogen [336 (290-390) vs. 310 (275-364) mg/dL; P = 0.04] was shown; moreover, a significant increase in GDF-15 serum level [1309 (974-1961) vs. 1538 (1286-2913) pg/mL; P = 0.002] was observed. Hemoglobin, renal function, and cardiovascular homeostasis biomarkers remain stable over the time. The anti-Xa activity at both [0.005 (0-0.02) vs. 0.2 (0.1-0.34); P < 0.0001) significantly increased. The dual pathway inhibitions with low-dose rivaroxaban and aspirin in patients with CAD and/or PAD were associated with the reduction of inflammation biomarkers.

Topics: Aged; Aspirin; Atherosclerosis; Biomarkers; Coronary Artery Disease; Drug Therapy, Combination; Factor Xa Inhibitors; Female; Growth Differentiation Factor 15; Humans; Inflammation; Interleukin-6; Male; Middle Aged; Peripheral Arterial Disease; Platelet Aggregation Inhibitors; Rivaroxaban

Topics: Anticoagulants; Atherosclerosis; Blood Coagulation; Factor Xa Inhibitors; Humans; Inflammation; Rivaroxaban

Cardiovascular disease (CVD) is the leading cause of death in various complications of type 2 diabetes mellitus (T2DM). Rivaroxaban (Xarelto; Bayer), an oral direct factor Xa (FXa) inhibitor, prevents the activation of the coagulation cascade in CVD. Considering its anticoagulant and anti-inflammatory effects, we assessed the hypothesis that rivaroxaban treatment may attenuate the vascular lesion and dysfunction in T2DM mice. C57BL/6, BKS-db/db, BKS-db/+, wild-type (WT), and NLRP3

Topics: Animals; Cardiovascular Diseases; Carotid Intima-Media Thickness; Diabetes Mellitus, Experimental; Diabetes Mellitus, Type 2; Endothelial Cells; Inflammasomes; Inflammation; Mice; Mice, Inbred C57BL; Mice, Knockout; NF-kappa B; NLR Family, Pyrin Domain-Containing 3 Protein; Rivaroxaban

Rivaroxaban is a direct inhibitor of activated Factor X (FXa), an anti-inflammatory protein exerting a protective effect on the cardiac valve and vascular endothelium. We compare the effect of Warfarin and Rivaroxaban on inflammation biomarkers and their contribution to heart valve calcification progression and renal preservation in a population of atrial fibrillation (AF) patients with chronic kidney disease (CKD) stage 3b - 4.. This was an observational, multicenter, prospective study enrolling 347 consecutive CKD stage 3b - 4 patients newly diagnosed with AF: 247 were treated with Rivaroxaban and 100 with Warfarin. Every 12 months, we measured creatinine levels and cardiac valve calcification via standard trans-thoracic echocardiogram, while plasma levels of inflammatory mediators were quantified by ELISA at baseline and after 24 months.. Over a follow-up of 24 months, long-term treatment with Rivaroxaban was associated with a significative reduction of cytokines. Patients treated with Rivaroxaban experienced a more frequent stabilization/regression of valve calcifications comparing with patients treated with Warfarin. Rivaroxaban use was related with an improvement in kidney function in 87.4% of patients, while in those treated with Warfarin was reported a worsening of renal clearance in 98% of cases. Patients taking Rivaroxaban experienced lower adverse events (3.2% vs 49%, p-value <0.001).. Our findings suggest that Rivaroxaban compared to Warfarin is associated with lower levels of serum markers of inflammation. The inhibition of FXa may exert an anti-inflammatory effect contributing to reduce the risk of cardiac valve calcification progression and worsening of renal function.

Topics: Anticoagulants; Atrial Fibrillation; Calcinosis; Factor Xa Inhibitors; Heart Valves; Humans; Inflammation; Kidney; Prospective Studies; Rivaroxaban; Stroke; Treatment Outcome; Warfarin

Activated factor X (FXa), which contributes to chronic inflammation via protease-activated receptor 2 (PAR2), might play an important role in atrial fibrillation (AF) arrhythmogenesis. This study aimed to assess whether PAR2 signaling contributes to AF arrhythmogenesis and whether rivaroxaban ameliorates atrial inflammation and prevents AF.Methods and Results:In Study 1, PAR2 deficient (PAR2-/-) and wild-type mice were infused with angiotensin II (Ang II) or a vehicle via an osmotic minipump for 2 weeks. In Study 2, spontaneously hypertensive rats (SHRs) were treated with rivaroxaban, warfarin, or vehicle for 2 weeks after 8 h of right atrial rapid pacing. The AF inducibility and atrial remodeling in both studies were examined. Ang II-treated PAR2-/- mice had a lower incidence of AF and less mRNA expression of collagen1 and collagen3 in the atrium compared to wild-type mice treated with Ang II. Rivaroxaban significantly reduced AF inducibility compared with warfarin or vehicle. In SHRs treated with a vehicle, rapid atrial pacing promoted gene expression of inflammatory and fibrosis-related biomarkers in the atrium. Rivaroxaban, but not warfarin, significantly reduced expression levels of these genes.. The FXa-PAR2 signaling pathway might contribute to AF arrhythmogenesis associated with atrial inflammation. A direct FXa inhibitor, rivaroxaban, could prevent atrial inflammation and reduce AF inducibility, probably by inhibiting the pro-inflammatory activation.

Topics: Angiotensin II; Animals; Atrial Fibrillation; Factor Xa; Inflammation; Mice; Rats; Receptor, PAR-2; Rivaroxaban; Signal Transduction; Warfarin

Background An enhanced renin-angiotensin system causes hypertensive renal damage. Factor Xa not only functions in the coagulation cascade but also activates intracellular signaling through protease-activated receptors ( PAR ). We investigated the effects of rivaroxaban, a factor Xa inhibitor, on hypertensive renal damage in hypertensive mice overexpressing renin (Ren-TG). Methods and Results The 12- to 16-week-old Ren-TG and wild-type mice were orally administered with or without 6 or 12 mg/kg of rivaroxaban for 1 or 4 months. Plasma factor Xa was significantly increased in the Ren-TG compared with the wild-type mice and was reduced by 12 mg/kg of rivaroxaban ( P<0.05). Urinary albumin excretion (UAE) was higher in the nontreated 8-month-old Ren-TG than in the wild-type mice (69.6±29 versus 20.1±8.2 μg/day; P<0.01). Treatment with 12 mg/kg of rivaroxaban for 4 months decreased the UAE to 38.1±13.2 μg/day ( P<0.01). Moreover, rivaroxaban treatment attenuated histologic changes of glomerular hypertrophy, mesangial matrix expansion, effacement of the podocyte foot process, and thickened glomerular basement membrane in the Ren-TG. The renal expression of PAR -2 was increased in the Ren-TG, but was inhibited with rivaroxaban treatment. In vitro study using the human podocytes showed that the expressions of PAR -2 and inflammatory genes and nuclear factor--κB activation were induced by angiotensin II stimulation, but were inhibited by rivaroxaban. PAR -2 knockdown by small interfering RNA also attenuated the PAR -2-related inflammatory gene expressions. Conclusions These findings indicate that rivaroxaban exerts protective effects against angiotensin II-induced renal damage, partly through inhibition of the PAR -2 signaling-mediated inflammatory response.

Topics: Albuminuria; Angiotensin II; Animals; Blood Coagulation; Factor Xa Inhibitors; Gene Knockdown Techniques; Glomerular Basement Membrane; Glomerular Mesangium; Humans; Hypertension; In Vitro Techniques; Inflammation; Kidney Glomerulus; Male; Mice; Mice, Transgenic; Podocytes; Receptor, PAR-2; Renal Insufficiency, Chronic; Renin; Reverse Transcriptase Polymerase Chain Reaction; Rivaroxaban; Vasoconstrictor Agents

Coagulation factor Xa (FXa) promotes thrombus formation and exacerbates inflammation via activation of protease-activated receptor (PAR)-2. We tested the hypothesis of whether administration of direct oral anticoagulant, rivaroxaban, would attenuate transverse aortic constriction (TAC)-induced atrial inflammatory fibrosis and vulnerability to atrial fibrillation (AF) in mice.. Ten-week-old male CL57/B6 mice were divided into a sham-operation (CNT) group and TAC-surgery group. These two groups were then subdivided into vehicle (VEH) and rivaroxaban (RVX) treatment (30μg/g/day) groups. We assessed PAR-2 expression in response to TAC-related stimulation using rat cultured cells.. TAC-induced left atrial thrombus formation was not observed in the TAC-RVX group. Cardiac PAR-2 upregulation was observed in both TAC groups. In the quantitative analysis of mRNA levels, cardiac PAR-2 upregulation was attenuated in the TAC-RVX group compared to TAC-VEH group. In histological evaluation, the TAC-VEH group showed cardiac inhomogeneous interstitial fibrosis and abundant infiltration of macrophages, which were attenuated by RVX administration. Electrophysiological examination revealed that AF duration in the TAC group was shortened by RVX administration. TAC-induced protein overexpression of monocyte chemoattractant protein-1, and mRNA overexpression of tumor necrosis factor-α, interleukin (IL)-1β and IL-6 in the left atrium was suppressed by RVX treatment. In cardiac fibroblasts, persistent intermittent stretch upregulated PAR-2, which was suppressed by RVX pre-incubation.. These observations demonstrate that coagulation FXa inhibitor probably has a cardioprotective effect against pressure-overload-induced atrial remodeling.

Topics: Administration, Oral; Animals; Atrial Fibrillation; Atrial Pressure; Atrial Remodeling; Factor Xa Inhibitors; Fibroblasts; Fibrosis; Heart Atria; Inflammation; Macrophages; Male; Mice; Mice, Inbred C57BL; Myocardium; Rats; Rivaroxaban; Tumor Necrosis Factor-alpha

Recent studies have implicated an important role for coagulation factors in neuroinflammatory disorders like multiple sclerosis (MS). Here, we investigate the role of factor X (FX) in neuroinflammation by using rivaroxaban the selective inhibitor of activated FX (FXa) in experimental autoimmune encephalomyelitis (EAE, an animal model of MS). Rivaroxaban-treated rats were less susceptible to EAE compared to the untreated control group. This finding was accompanied by reduced T-cell infiltration and microglia activation. Our study identifies FX as a possible target in neuroinflammatory diseases. As FXa inhibitors are approved for other disorders, FXa blockade could serve as a fast available medication.

Topics: Analysis of Variance; Animals; Antigens, CD; Calcium-Binding Proteins; Disease Models, Animal; Factor Xa Inhibitors; Female; Forkhead Transcription Factors; Inflammation; Lymph Nodes; Microfilament Proteins; Multiple Sclerosis; Rats; Rats, Inbred Lew; Rivaroxaban; Spinal Cord

In addition to its central role in coagulation, thrombin is involved in non-hemostatic activities such as inflammation. Direct inhibition of thrombin activity (e.g. with dabigatran) or reducing its generation by inhibition of Factor Xa (e.g. with rivaroxaban) may therefore have anti-inflammatory effects.. Microarray experiments were performed to identify transcriptome-wide changes in mRNA expression levels induced by thrombin in the presence and absence of the PAR-1 antagonist vorapaxar in primary human umbilical vein endothelial cells (HUVECs). On this basis, HUVECs were incubated with recalcified plasma, with or without rivaroxaban (0.3-3000nM), dabigatran (0.3-10,000nM), or vorapaxar (0.3-10nM). Expression levels of preselected pro-inflammatory genes were quantified by real-time PCR.. Vorapaxar abolished 67 of the 69 transcripts altered by more than twofold on addition of thrombin to HUVECs. ELAM-1, VCAM-1, ICAM-1, MCP-1, IL-8, CXCL1, and CXCL2 were among the genes most strongly induced by thrombin. Inflammatory gene expression after stimulation of thrombin generation was concentration-dependently suppressed by vorapaxar, dabigatran, and rivaroxaban. However, dabigatran at low concentrations (3-300nM) increased significantly the expression levels of CXCL1, CXCL2, IL-8, ELAM-1, MCP-1, and tissue factor.. In HUVECs, plasma-induced transcriptional changes are mediated by thrombin-induced PAR-1 activation. Rivaroxaban downregulated the expression of pro-inflammatory markers and tissue factor to a similar extent to dabigatran.

Topics: Antithrombins; Dabigatran; Endothelial Cells; Factor Xa Inhibitors; Human Umbilical Vein Endothelial Cells; Humans; Inflammation; Lactones; Pyridines; Receptor, PAR-1; Rivaroxaban; Thrombin; Transcriptome

Dysfunction of indwelling central venous catheters (CVC) due to tissue ingrowth or clotting is common. The study objective was to determine if the oral anticoagulant rivaroxaban (RIVA) improved CVC patency and inflammation in mice.. Polyurethane catheters (0.5cm length) were placed unilaterally into the external jugular vein (EJV) of mice, which subsequently underwent daily gavage with either vehicle or RIVA (5mg/kg). CVC patency, as assessed by B-mode and Doppler ultrasound, and hematocrit were measured at 3, 7, 14 or 21days (n=8-11 mice/group/time-point). Plasma monocyte chemotactic protein-1 (MCP-1) levels were assessed by ELISA, EJV matrix metalloproteinase-9 (MMP-9) levels by western immunoblotting, and cell proliferation (anti-Ki67), macrophage infiltration (anti-MAC387) by immunostaining of EJV tissues.. CVC patency was significantly improved in RIVA-treated mice compared to vehicle-treated (93.8% vs. 62.9%) with the probability of patency in RIVA-treated mice being 1.5 times that in vehicle-treated (relative risk [RR], 1.50, 95% confidence interval [CI], 1.14-1.95, p=0.002). Plasma MCP-1 levels were lower in RIVA-treated mice vs. vehicle-treated at 21days (389±260 vs. 804±292ng/mL, p=0.005). Cell proliferation was less at day 7 in EJV from the RIVA-treated mice than vehicle-treated (5.0%±3.0 vs. 11.5%±3.6, p=0.0006), as were MMP-9 protein levels. There were no differences in hematocrit between vehicle and RIVA-treated groups at any time point. In conclusion, these data indicate RIVA lowers inflammation and improves CVC patency in a mouse model, supporting future studies to assess RIVA for improving CVC patency in patients.

Topics: Animals; Catheterization, Central Venous; Central Venous Catheters; Chemokine CCL2; Factor Xa Inhibitors; Inflammation; Mice; Mice, Inbred C57BL; Rivaroxaban; Thrombosis; Vascular Patency

Essentials Complement activation has a pathogenic role in thrombotic antiphospholipid syndrome (APS). Coagulation proteases such as factor Xa can activate complement proteins. Complement activation markers were elevated in anticoagulated thrombotic APS patients. Complement activation decreased in APS patients switching from warfarin to rivaroxaban.. Background Complement activation may play a major role in the pathogenesis of thrombotic antiphospholipid syndrome (APS). Coagulation proteases such as factor Xa can activate complement proteins. Aims To establish whether rivaroxaban, a direct factor Xa inhibitor, limits complement activation compared with warfarin in APS patients with previous venous thromboembolism (VTE). Methods A total of 111 APS patients with previous VTE, on warfarin target INR 2.5, had blood samples taken at baseline and at day 42 after randomization in the RAPS (Rivaroxaban in Antiphospholipid Syndrome) trial. Fifty-six patients remained on warfarin and 55 switched to rivaroxaban. Fifty-five normal controls (NC) were also studied. Markers of complement activation (C3a, C5a, terminal complement complex [SC5b-9] and Bb fragment) were assessed. Results APS patients had significantly higher complement activation markers compared with NC at both time-points irrespective of the anticoagulant. There were no differences between the two patient groups at baseline, or patients remaining on warfarin at day 42. In 55 patients randomized to rivaroxaban, C3a, C5a and SC5b-9 were lower at day 42 (median (ng mL

Topics: Adult; Anticoagulants; Antiphospholipid Syndrome; Blood Coagulation; Complement Activation; Factor Xa; Factor Xa Inhibitors; Female; Humans; Inflammation; International Normalized Ratio; Male; Middle Aged; Rivaroxaban; Thrombosis; Venous Thromboembolism; Warfarin

Topics: Factor Xa Inhibitors; Glycation End Products, Advanced; Humans; Inflammation; Oxidative Stress; Receptor, PAR-2; Rivaroxaban; Thrombin

Activated factor X (FXa) plays a key role in the coagulation cascade, whereas accumulating evidence suggests that it also contributes to the pathophysiology of chronic inflammation on the vasculature. In this study, we assessed the hypothesis that rivaroxaban (Riv), a direct FXa inhibitor, inhibits atherogenesis by reducing macrophage activation.. Expression levels of PAR-1 and PAR-2, receptors for FXa, increased in the aorta of apolipoprotein E-deficient (ApoE(-/-)) mice compared with wild-type mice (P < 0.01, P < 0.05, respectively). Administration of Riv (5 mg/kg/day) for 20 weeks to 8-week-old ApoE(-/-) mice reduced atherosclerotic lesion progression in the aortic arch as determined by en-face Sudan IV staining compared with the non-treated group (P < 0.05) without alteration of plasma lipid levels and blood pressure. Histological analyses demonstrated that Riv significantly decreased lipid deposition, collagen loss, macrophage accumulation and matrix metallopeptidase-9 (MMP-9) expression in atherosclerotic plaques in the aortic root. Quantitative RT-PCR analyses using abdominal aorta revealed that Riv significantly reduced mRNA expression of inflammatory molecules, such as MMP-9, tumor necrosis factor-α (TNF-α). In vitro experiments using mouse peritoneal macrophages or murine macrophage cell line RAW264.7 demonstrated that FXa increased mRNA expression of inflammatory molecules (e.g., interleukin (IL)-1β and TNF-α), which was blocked in the presence of Riv.. Riv attenuates atherosclerotic plaque progression and destabilization in ApoE(-/-) mice, at least in part by inhibiting pro-inflammatory activation of macrophages. These results indicate that Riv may be particularly beneficial for the management of atherosclerotic diseases, in addition to its antithrombotic activity.

Topics: Animals; Anticoagulants; Aorta; Aorta, Thoracic; Apolipoproteins E; Atherosclerosis; Blood Pressure; Cell Line; Disease Progression; Factor Xa Inhibitors; Human Umbilical Vein Endothelial Cells; Humans; Immunohistochemistry; Inflammation; Macrophages; Male; Matrix Metalloproteinase 9; Mice; Mice, Inbred C57BL; Mice, Knockout; Plaque, Atherosclerotic; Platelet Membrane Glycoproteins; Receptor, PAR-1; Receptor, PAR-2; Rivaroxaban; RNA, Messenger

Activation of coagulation and vascular inflammation are prominent features of sickle cell disease (SCD). Previously, we have shown that inhibition of tissue factor (TF) attenuates activation of coagulation and vascular inflammation in mouse models of SCD. In this study, we examined the mechanism by which coagulation proteases enhance vascular inflammation in sickle BERK mice. To specifically investigate the contribution of FXa and thrombin, mice were fed chow containing either rivaroxaban or dabigatran, respectively. In addition, we used bone marrow transplantation to generate sickle mice deficient in either protease activated receptor-1 (PAR-1) or protease activated receptor-2 (PAR-2) on nonhematopoietic cells. FXa inhibition and PAR-2 deficiency in nonhematopoietic cells attenuated systemic inflammation, measured by plasma levels of interleukin-6 (IL-6). In contrast, neither thrombin inhibition nor PAR-1 deficiency in nonhematopoietic cells affected plasma levels of IL-6 in sickle mice. However, thrombin did contribute to neutrophil infiltration in the lung, independently of PAR-1 expressed by nonhematopoietic cells. Furthermore, the TF-dependent increase in plasma levels of soluble vascular cell adhesion molecule-1 in sickle mice was not mediated by FXa or thrombin. Our data indicate that TF, FXa, and thrombin differentially contribute to vascular inflammation in a mouse model of SCD.

Topics: Anemia, Sickle Cell; Animals; Anticoagulants; Antithrombins; Benzimidazoles; beta-Alanine; Bone Marrow Transplantation; Dabigatran; Disease Models, Animal; Factor Xa; Factor Xa Inhibitors; Female; Immunoenzyme Techniques; Inflammation; Male; Mice; Mice, Inbred C57BL; Mice, Knockout; Morpholines; Receptor, PAR-1; Receptor, PAR-2; Rivaroxaban; Thiophenes; Thrombin; Vascular Diseases

The aim of this study was to evaluate the effects of the antithrombotic agents enoxaparin and rivaroxaban on tissue survival following skin degloving injury in an experimental rat tail model.. The study included 24 rats divided into three equal groups of 8; the enoxaparin group (Group 1), the rivaroxaban group (Group 2) and the saline control group (Group 3). A degloving injury was created by making a circular incision 5 cm distal to the base of the tail; manual traction was applied to the tail skin distal to the incision. After 15 minutes, the ends of the incision were sutured back in place. Antithrombotic agents were administered immediately after suturing and repeated once a day for 15 days. At the end of Day 15, the experiment was terminated. Gross morphological tissue survival and histopathology were evaluated.. Histopathological examination of the enoxaparin and rivaroxaban groups revealed that the skin was mostly normal or intact with minimal inflammation. The mean length of necrotic area was significantly higher in the saline group compared to the enoxaparin and rivaroxaban groups (p<0.05). No statistically significant differences were noted between the rivaroxaban and enoxaparin groups (p=0.451). The mean extent of skin necrosis was significantly higher in the control group than the study groups (p<0.05), while there was no significant difference in the length of necrotic area between Group 1 and 2 (p=0.722).. Rivaroxaban and enoxaparin improved tissue survival in skin degloving injuries in terms of gross morphological and histopathological findings in a rat tail model.

Topics: Animals; Disease Models, Animal; Enoxaparin; Fibrinolytic Agents; Inflammation; Male; Morpholines; Necrosis; Rats; Rats, Sprague-Dawley; Rivaroxaban; Skin; Soft Tissue Injuries; Thiophenes; Tissue Survival; Trauma Severity Indices; Treatment Outcome