Sphingosine 1-phosphate (S1P) is a highly active lysophospholipid implicated in various cardiocerebrovascular events such as coagulation, myocardial infarction and stroke. However, as the functional S1P receptor antagonist, whether the S1P mimetic FTY720 can modulate coagulation and/or thrombotic formation remains largely unknown. We investigated the effects of FTY720 on adenosine diphosphate (ADP)-induced platelet aggregation, coagulation parameters and thrombus formation in rats. Pretreatment with FTY720 (2.5 mg/kg) inhibited platelet aggregation induced by ADP, elongated the thrombin time and decreased the fibrinogen levels. However, FTY720 produced no significant effects on the arteriovenous bypass thrombus formation or the FeCl3-induced thrombus formation in the inferior vena cava and the common carotid artery. Our data suggest that FTY720 can exert an inhibitory effect on platelet aggregation and coagulation-related parameters. These characteristics of FTY720 could be useful as an adjunct in the treatment of ischemic diseases such as ischemic stroke and myocardial infarction.

Knapp M: Cardioprotective role of sphingosine-1-phosphate. J Physiol Pharmacol 2011;62:601-607.
Rauch BH: Sphingosine 1-phosphate as a link between blood coagulation and inflammation. Cell Physiol Biochem 2014;34:185-196.
Shea BS, Brooks SF, Fontaine BA, Chun J, Luster AD, Tager AM: Prolonged exposure to sphingosine 1-phosphate receptor-1 agonists exacerbates vascular leak, fibrosis, and mortality after lung injury. Am J Respir Cell Mol Biol 2010;43:662-673.
Hofmann U, Burkard N, Vogt C, Thoma A, Frantz S, Ertl G, Ritter O, Bonz A: Protective effects of sphingosine-1-phosphate receptor agonist treatment after myocardial ischaemia-reperfusion. Cardiovasc Res 2009;83:285-293.
Hofmann U, Hu K, Walter F, Burkard N, Ertl G, Bauersachs J, Ritter O, Frantz S, Bonz A: Pharmacological pre- and post-conditioning with the sphingosine-1-phosphate receptor modulator fty720 after myocardial ischaemia-reperfusion. Br J Pharmacol 2010;160:1243-1251.
Rolland WB, Lekic T, Krafft PR, Hasegawa Y, Altay O, Hartman R, Ostrowski R, Manaenko A, Tang J, Zhang JH: Fingolimod reduces cerebral lymphocyte infiltration in experimental models of rodent intracerebral hemorrhage. Exp Neurol 2013;241:45-55.
Wei Y, Yemisci M, Kim HH, Yung LM, Shin HK, Hwang SK, Guo S, Qin T, Alsharif N, Brinkmann V, Liao JK, Lo EH, Waeber C: Fingolimod provides long-term protection in rodent models of cerebral ischemia. Ann Neurol 2011;69:119-129.
Brinkmann V, Davis MD, Heise CE, Albert R, Cottens S, Hof R, Bruns C, Prieschl E, Baumruker T, Hiestand P, Foster CA, Zollinger M, Lynch KR: The immune modulator FTY720 targets sphingosine 1-phosphate receptors. J Biol Chem 2002;277:21453-21457.
Mandala S, Hajdu R, Bergstrom J, Quackenbush E, Xie J, Milligan J, Thornton R, Shei GJ, Card D, Keohane C, Rosenbach M, Hale J, Lynch CL, Rupprecht K, Parsons W, Rosen H: Alteration of lymphocyte trafficking by sphingosine-1-phosphate receptor agonists. Science 2002;296:346-349.
Rosen H, Goetzl EJ: Sphingosine 1-phosphate and its receptors: an autocrine and paracrine network. Nat Rev Immun 2005;5:560-570.
Takeya H, Gabazza EC, Aoki S, Ueno H, Suzuki K: Synergistic effect of sphingosine 1- phosphate on thrombin-induced tissue factor expression in endothelial cells. Blood 2003;102:1693-1700.
Urtz N, Gaertner F, von Bruehl ML, Chandraratne S, Rahimi F, Zhang L, Orban M, Barocke V, Beil J, Schubert I, Lorenz M, Legate KR, Huwiler A, Pfeilschifter JM, Beerli C, Ledieu D, Persohn E, Billich A, Baumruker T, Mederosy Schnitzler M, Massberg S: Sphingosine 1-phosphate produced by sphingosine kinase 2 intrinsically controls platelet aggregation in vitro and in vivo. Circ Res 2015;117:376-387.
Isoyama N, Takai K, Tsuchida M, Matsumura M, Naito K: Evidence that FTY720 induces rat thymocyte apoptosis. Transpl Immunol 2006;15:265-271.
Wallington-Beddoe CT, Don AS, Qiao Q, Papa RA, Lock RB, Bradstock KF, Bendall LJ: Disparate in vivo efficacy of FTY720 in xenograft models of Philadelphia positive and negative B-lineage acute lymphoblastic leukemia. PLoS One 2012;7:e36429.
Sperzel M, Huetter J: Evaluation of aprotinin and tranexamic acid in different in vitro and in vivo models of fibrinolysis, coagulation and thrombus formation. J Thromb Haemost 2007;5:2113-2118.
Fukuda T, Kamisato C, Honda Y, Matsushita T, Kojima T, Furugohri T, Morishima Y, Shibano T: Impact of antithrombin deficiency on efficacy of edoxaban and antithrombin-dependent anticoagulants, fondaparinux, enoxaparin, and heparin. Thromb Res 2013;131:540-546.
Allende ML, Dreier JL, Mandala S, Proia RL: Expression of the sphingosine 1-phosphate receptor, S1P1, on T-cells controls thymic emigration. J Biol Chem 2004;279:15396-15401.
Graler MH, Goetzl EJ: The immunosuppressant FTY720 down-regulates sphingosine 1-phosphate G-protein-coupled receptors. FASEB J 2004;18:551-553.
Matloubian M, Lo CG, Cinamon G, Lesneski MJ, Xu Y, Brinkmann V, Allende ML, Proia RL, Cyster JG: Lymphocyte egress from thymus and peripheral lymphoid organs is dependent on S1P receptor 1. Nature 2004;427:355-360.
Oo ML, Thangada S, Wu MT, Liu CH, Macdonald TL, Lynch KR, Lin CY, Hla T: Immunosuppressive and anti-angiogenic sphingosine 1-phosphate receptor-1 agonists induce ubiquitinylation and proteasomal degradation of the receptor. J Biol Chem 2007;282:9082-9089.
Mahajan-Thakur S, Bohm A, Jedlitschky G, Schror K, Rauch BH: Sphingosine-1-phosphate and its receptors: a mutual link between blood coagulation and inflammation. Mediators Inflamm 2015;2015:831059.
Obinata H, Hla T: Sphingosine 1-phosphate in coagulation and inflammation. Semin Immunopathol 2012;34:73-91.
Yatomi Y, Ruan F, Hakomori S, Igarashi Y: Sphingosine-1-phosphate: a platelet-activating sphingolipid released from agonist-stimulated human platelets. Blood 1995;86:193-202.
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