Edoxaban, a direct oral factor Xa inhibitor, ameliorates coagulation, microvascular thrombus formation, and acute liver injury in a lipopolysaccharide-induced coagulopathy model in rats
Tóm tắt
Infection increases the risk of thrombosis through the activation of inflammation and coagulation. Edoxaban, a direct oral factor Xa inhibitor, is used for the prevention and treatment of thrombotic diseases. The aim of this study was to determine the effects of edoxaban on microvascular thrombus formation in a rat model of lipopolysaccharide (LPS)-induced coagulopathy. Rats were intravenously injected with 7.5 mg/kg of LPS (Escherichia coli 055:B5). Immediately after LPS injection, the rats were treated with subcutaneous injection of edoxaban. At 2 and 6 h after the injection of LPS, biomarkers of coagulation and organ damages and inflammatory cytokines were measured. Microvascular thrombus formation in organs was evaluated using 125I-fibrinogen (human) or by the pathological analysis. Mortality was examined 24 h after LPS injection. After the injection of LPS, D-dimer and thrombin-antithrombin complex increased and platelet numbers decreased, indicating the activation of coagulation. Microvascular thrombi were found in the liver. Markers of liver injury (aspartate aminotransferase and alanine aminotransferase) also increased. Treatment with edoxaban attenuated the changes in the coagulation markers and microvascular thrombus formation in the liver. Edoxaban suppressed the increase in the liver injury markers and reduced the mortality. Edoxaban did not affect the levels of inflammatory cytokines. In conclusions, edoxaban significantly inhibited the activation of coagulation, the formation of microvascular thrombus in the liver and the liver damage, and reduced mortality in rats injected with LPS. These results suggest that the FXa inhibition by edoxaban might be a beneficial therapy for the management of infection-associated thrombosis.
Tài liệu tham khảo
Smeeth L, Cook C, Thomas S, Hall AJ, Hubbard R, Vallance P (2006) Risk of deep vein thrombosis and pulmonary embolism after acute infection in a community setting. Lancet 367:1075–1079
Dalager-Pedersen M, Sogaard M, Schonheyder HC, Nielsen H, Thomsen RW (2014) Risk for myocardial infarction and stroke after community-acquired bacteremia: a 20-year population-based cohort study. Circulation 129:1387–1396
Beristain-Covarrubias N, Perez-Toledo M, Thomas MR, Henderson IR, Watson SP, Cunningham AF (2019) Understanding infection-induced thrombosis: lessons learned from animal models. Front Immunol 10:2569. https://doi.org/10.3389/fimmu.2019.02569
Antoniak S (2018) The coagulation system in host defense. Res Pract Thromb Haemost 2:549–557
Cohen J (2002) The immunopathogenesis of sepsis. Nature 420:885–891
Pawlinski R, Pedersen B, Schabbauer G, Tencati M, Holscher T, Boisvert W, Andrade-Gordon P, Frank RD, Mackman N (2004) Role of tissue factor and protease-activated receptors in a mouse model of endotoxemia. Blood 103:1342–1347
Jesmin S, Gando S, Zaedi S, Prodhan SH, Sawamura A, Miyauchi T, Hiroe M, Yamaguchi N (2009) Protease-activated receptor 2 blocking peptide counteracts endotoxin-induced inflammation and coagulation and ameliorates renal fibrin deposition in a rat model of acute renal failure. Shock 32:626–632
Asakura H, Sano Y, Yoshida T, Omote M, Ontachi Y, Mizutani T, Yamazaki M, Morishita E, Takami A, Miyamoto K, Nakao S (2004) Beneficial effect of low-molecular-weight heparin against lipopolysaccharide-induced disseminated intravascular coagulation in rats is abolished by coadministration of tranexamic acid. Intensive Care Med 30:1950–1955
Elsayed YA, Nakagawa K, Kamikubo YI, Enjyoji KI, Kato H, Sueishi K (1996) Effects of recombinant human tissue factor pathway inhibitor on thrombus formation and its in vivo distribution in a rat DIC model. Am J Clin Pathol 106:574–583
Furugohri T, Isobe K, Honda Y, Kamisato-Matsumoto C, Sugiyama N, Nagahara T, Morishima Y, Shibano T (2008) DU-176b, a potent and orally active factor Xa inhibitor: in vitro and in vivo pharmacological profiles. J Thromb Haemost 6:1542–1549
Perzborn E, Strassburger J, Wilmen A, Pohlmann J, Roehrig S, Schlemmer K-H, Straub A (2005) In vitro and in vivo studies of the novel antithrombotic agent BAY 59–7939–an oral, direct Factor Xa inhibitor. J Thromb Haemost 3:514–521
Wong PC, Crain EJ, Xin B, Wexler RR, Lam PYS, Pinto DJ, Luettgen JM, Knabb RM (2008) Apixaban, an oral, direct and highly selective factor Xa inhibitor: in vitro, antithrombotic and antihemostatic studies. J Thromb Haemost 6:820–829
Wienen W, Stassen JM, Priepke H, Ries UJ, Hauel N (2007) Effects of the direct thrombin inhibitor dabigatran and its orally active prodrug, dabigatran etexilate, on thrombus formation and bleeding time in rats. Thromb Haemost 98:333–338
Schneider J (1993) Fibrin-specific lysis of microthrombosis in endotoxemic rats by saruplase. Thromb Res 72:71–82
Heuberger DM, Schuepbach RA (2019) Protease-activated receptors (PARs): mechanisms of action and potential therapeutic modulators in PAR-driven inflammatory diseases. Thromb J 17:4. https://doi.org/10.1186/s12959-019-0194-8
Klok FA, Kruip MJHA, van der Meer NJM, Arbous MS, Gommers DAMPJ, Kant KM, Kaptein FHJ, van Paassen J, Stals MAM, Huisman MV, Endeman H (2020) Incidence of thrombotic complications in critically ill ICU patients with COVID-19. Thromb Res 191:145–147
Oxley TJ, Mocco J, Majidi S, Kellner CP, Shoirah H, Singh IP, De Leacy RA, Shigematsu T, Ladner TR, Yaeger KA, Skliut M, Weinberger J, Dangayach NS, Bederson JB, Tuhrim S, Fifi JT (2020) Large-vessel stroke as a presenting feature of Covid-19 in the young. N Engl J Med 382:e60. https://doi.org/10.1056/NEJMc2009787
Zhang L, Yan X, Fan Q, Liu H, Liu X, Liu Z, Zhang Z (2020) D-dimer levels on admission to predict in-hospital mortality in patients with Covid-19. J Thromb Haemost 18:1324–1329
Paranjpe I, Fuster V, Lala A, Russak AJ, Glicksberg BS, Levin MA, Charney AW, Narula J, Fayad ZA, Bagiella E, Zhao S, Nadkarni GN (2020) Association of treatment dose anticoagulation with in-hospital survival among hospitalized patients with COVID-19. J Am Coll Cardiol 76:122–124
Marongiu F, Grandone E, Barcellona D (2020) Pulmonary thrombosis in 2019-nCoV pneumonia? J Thromb Haemost 18:1511–1513