Rivaroxaban Reduces Arterial Thrombosis by Inhibition of FXa-Driven Platelet Activation via Protease Activated Receptor-1.

RATIONALE: A reduced rate of myocardial infarction has been reported in patients with atrial fibrillation treated with FXa (factor Xa) inhibitors including rivaroxaban compared with vitamin K antagonists. At the same time, low-dose rivaroxaban has been shown to reduce mortality and atherothrombotic events in patients with coronary artery disease. Yet, the mechanisms underlying this reduction remain unknown. OBJECTIVE: In this study, we hypothesized that rivaroxaban's antithrombotic potential is linked to a hitherto unknown rivaroxaban effect that impacts on platelet reactivity and arterial thrombosis. METHODS AND RESULTS: In this study, we identified FXa as potent, direct agonist of the PAR-1 (protease-activated receptor 1), leading to platelet activation and thrombus formation, which can be inhibited by rivaroxaban. We found that rivaroxaban reduced arterial thrombus stability in a mouse model of arterial thrombosis using intravital microscopy. For in vitro studies, atrial fibrillation patients on permanent rivaroxaban treatment for stroke prevention, respective controls, and patients with new-onset atrial fibrillation before and after first intake of rivaroxaban (time series analysis) were recruited. Platelet aggregation responses, as well as thrombus formation under arterial flow conditions on collagen and atherosclerotic plaque material, were attenuated by rivaroxaban. We show that rivaroxaban's antiplatelet effect is plasma dependent but independent of thrombin and rivaroxaban's anticoagulatory capacity. CONCLUSIONS: Here, we identified FXa as potent platelet agonist that acts through PAR-1. Therefore, rivaroxaban exerts an antiplatelet effect that together with its well-known potent anticoagulatory capacity might lead to reduced frequency of atherothrombotic events and improved outcome in patients.

Value of Rotational Thromboelastometry and Impedance Aggregometry for Evaluating Coagulation Disorders in Patients With Cyanotic and Nongenetic Congenital Heart Disease.

Adults with cyanotic congenital heart diseases (CCHD) have a higher risk for bleeding, but also for thrombosis. Rotational thromboelastometry (RT), using tissue factor (EXTEM), a contact activator (INTEM) or cytochalasin (FIBTEM), assesses coagulation by determining the time to initiation of clotting (CT) and clot firmness (MCF) including platelet-fibrin-interaction. The aim of this study was to evaluate RT and whole blood impedance aggregometry (IA) in CCHD compared with a control group without chronic cyanosis (NCCHD). These were used to establish normal reference ranges. We prospectively included 124 patients (76 CCHD, 48 NCCHD). Mean oxygen saturation in CCHD was 81.5%, and 98% in NCCHD (p <0.001). Fifty-five CCHD and 1 NCCHD had pulmonary hypertension. Eisenmenger syndrome was present in 39 CCHD (51.3%). Hemoglobin, hematocrit, and reticulocyte levels were significantly higher in CCHD, and they also showed more thrombocytopenia. Platelet aggregation was under normal range in 89.5% of CCHD after triggering with ADP, in 85.5% after triggering with arachidonic acid (ASPI) and in 73.7% after TRAP-6. RT showed significantly longer clotting times and reduced clot firmness in both EXTEM and INTEM tests. FIBTEM-MCF was also significantly reduced. Moderate inverse correlation was found between platelet count and erythrocytes (r = -0.608, p <0.001). Significant correlations were found between platelet number and RT-parameters as well as with all IA parameters. In conclusion, according to RT and IA, CCHD present hypocoagulable disorders. No signs of hypercoagulability were found.

Hemostatic abnormalities in adult patients with Marfan syndrome.

BACKGROUND: Aortic root ectasia might induce hemostatic disorders in patients with Marfan syndrome (MFS) via altered blood flow and rheology. The aim of this study was to explore the hemostasis in patients with MFS compared with healthy controls. METHODS: In this cross-sectional case-control study we included patients with verified MFS (n=51) and sex- and age-matched healthy controls (n=50). Main criteria were the aortic root in echocardiography and cardiac magnetic resonance imaging (MRI), and the coagulation status. RESULTS: When compared with healthy controls, patients with MFS showed significantly increased diameters of the aortic roots (43.0±7.72 vs. 28.8±3.74 mm, P<0.001) and aortic Z-scores (4.36±2.77 vs. 0.948±1.09, P<0.001), considerably higher values of Multiplate® tests (e.g., MP-ADP: 878.4±201.7 vs. 660.4±243.6 AU*min, P<0.001) and PFA-100® tests (PFA Col/ADP: 102.5±45.5 vs. 91.1±46.2 s, P<0.05), PTT (30.0±3.91 vs. 28.7±2.50 s, P<0.05) and D-dimers (0.488±0.665 vs. 0.254±0.099 mg/L, P<0.001). In MFS von Willebrand factor (VWF) activity (81.9%±41.8% vs. 106.3%±41.5%, P<0.05) and antigen (93.8%±43.9% vs. 118.8%±47.8%, P<0.05) and factor VIII activity (108.9%±29.6% vs. 126.7%±28.4%, P<0.05) were reduced. Significant positive correlations were found between aortic diameters and D-dimers (all P<0.05), as well as PFA Col/ADP (all P<0.01) in MFS patients. Factor VIII activity correlated significantly negatively with the diameter of the aortic root in MFS (r=-0.55, P<0.05). CONCLUSIONS: In conclusion, our study reveals hemostatic deviations in patients with MFS. Further studies are necessary to understand the causal relationship and the exact pathomechanism.