Warfarin, but not rivaroxaban, promotes the calcification of the aortic valve in ApoE-/- mice.

INTRODUCTION: Vitamin K antagonists, such as warfarin, are known to promote arterial calcification through blockade of gamma-carboxylation of Matrix-Gla-Protein. It is currently unknown whether other oral anticoagulants such as direct inhibitors of Factor Xa can have protective effects on the progression of aortic valve calcification. AIMS: To compare the effect of warfarin and rivaroxaban on the progression of aortic valve calcification in atherosclerotic mice. RESULTS: 42 ApoE-/- mice fed with Western-type Diet (WTD) were randomized to treatment with warfarin (n = 14), rivaroxaban (n = 14) or control (n = 14) for 8 weeks. Histological analyses were performed to quantify the calcification of aortic valve leaflets and the development of atherosclerosis. The analyses showed a significant increase in valve calcification in mice treated with warfarin as compared to WTD alone (P = .025) or rivaroxaban (P = .005), whereas no significant differences were found between rivaroxaban and WTD (P = .35). Quantification of atherosclerosis and intimal calcification was performed on the innominate artery of the mice and no differences were found between the 3 treatments as far as atherogenesis and calcium deposition is concerned. In vitro experiments performed using bovine interstitial valve cells (VIC) showed that treatment with rivaroxaban did not prevent the osteogenic conversion of the cells but reduce the over-expression of COX-2 induced by inflammatory mediators. CONCLUSION: We showed that warfarin, but not rivaroxaban, could induce calcific valve degeneration in a mouse model of atherosclerosis. Both the treatments did not significantly affect the progression of atherosclerosis. Overall, these data suggest a safer profile of rivaroxaban on the risk of cardiovascular disease progression.

Evaluation of activated charcoal and lipid emulsion treatment in model of acute rivaroxaban toxicity.

AIM: Reducing or reversing the toxicity effects of new oral anticoagulants is an important question.The purpose of the present study is to evaluate the effect of lipid emulsion (LE) and Activated Charcoal (AC) therapy on the intoxication of rivaroxaban, on mice. METHODS: Adult male Balb/c mice weighing approximately 30g were used in the study. Seven groups were assigned, with six mice in each group. Groups were defined; given only rivaroxaban, given only LE, given only AC, after the administration of rivaroxaban LE applied group in the 1st hour, after the administration of rivaroxaban LE applied group in the 3rd hour, after the administration of rivaroxaban AC applied group in the1st hour, after the administration of rivaroxaban AC applied group in the 1st hour and LE applied group in the 3rd hour. PT and Anti-Factor Xa activity were measured in all blood samples from subjects. RESULTS: A statistically significant difference was found when all groups were compared in terms of mean PT values and Anti-FactorXa values. However, no statistically significant difference was found in the mean PT and Anti-FactorXa values when only rivaroxaban administrated group and after the administration of rivaroxaban LE and/or AC applied groups were compared one to one. No deaths occurred in groups during the observation. CONCLUSION: Although the administration of either AC or LE alone or in combination resulted in a decrease in the mean values of PT and anti-Factor Xa, in case of rivaroxaban toxicity, but one-to-one comparison of the groups was not statistically significant.

A new C-type lectin (RVsnaclec) purified from venom of Daboia russelii russelii shows anticoagulant activity via inhibition of FXa and concentration-dependent differential response to platelets in a Ca²âº-independent manner.

This is the first report on the characterization of a snaclec (RVsnaclec) purified from Daboia russelii russelii venom. The RVsnaclec is a heterodimer of two subunits, α (15.1 kDa) and ß (9 kDa). These subunits are covalently linked to form multimeric (αß)2 and (αß)4 structures. Peptide mass fingerprinting analysis of RVsnaclec via LC-MS/MS demonstrated its similarity to snaclecs purified from other viperid snake venoms. Two tryptic peptide sequences of RVsnaclec revealed the putative conserved domains of C-type lectin (CTL). RVsnaclec dose-dependently increased the Ca-clotting time and prothrombin time of platelet-poor plasma (PPP); however, it did not affect the partial thromboplastin time (APTT) or thrombin time of PPP. The in vitro and in vivo anticoagulant activity of RVsnaclec is correlated to its binding and subsequent uncompetitive inhibition of FXa (Ki = 0.52 µmole) in a Ca(2+)-independent manner; however, supplementation with 0.25 mM Ca(2+) enhanced the Xa binding potency of RVsnaclec. Monovalent or polyvalent antivenom failed to neutralize its anticoagulant potency, and RVsnaclec did not inhibit trypsin, chymotrypsin, thrombin or plasmin. RVsnaclec was devoid of hemolytic activity or cytotoxicity against several human cancer cell lines, demonstrated concentration-dependent aggregation and deaggregation of human platelets, and inhibited the ADP-induced aggregation of platelet. RVsnaclec (5.0 mg/kg body weight) was non-lethal to mice and showed no adverse pharmacological effects, suggesting that it has potential as a lead compound for future therapeutic applications in cardiovascular disorders.