A direct oral anticoagulant edoxaban accelerated fibrinolysis via enhancement of plasmin generation in human plasma: dependent on thrombin-activatable fibrinolysis inhibitor

  • Yoshiyuki MorishimaEmail author
  • Yuko Honda


A direct oral anticoagulant, edoxaban, is as effective as vitamin K antagonists for the treatment of venous thromboembolism (VTE). However, the mechanism underlying the treatment effect on VTE remains to be determined. The aims of this study were to evaluate the effect of edoxaban on tissue plasminogen activator (t-PA)-induced clot lysis in human plasma and to determine the roles of plasmin and thrombin-activatable fibrinolysis inhibitor (TAFI) in the profibrinolytic effect by edoxaban. Pooled human normal plasma or TAFI-deficient plasma (containing 180 ng/mL t-PA and 0.1 nM thrombomodulin) was mixed with edoxaban or an activated TAFI inhibitor, potato tuber carboxypeptidase inhibitor (PCI). Clot was induced by adding tissue factor and phospholipids. Clot lysis time and plasma plasmin-α2 antiplasmin complex (PAP) concentration were determined. Clot structure was imaged with a scanning electron microscope. In normal plasma, edoxaban at clinically relevant concentrations (75, 150, and 300 ng/mL) and PCI significantly shortened clot lysis time. PCI increased PAP concentration and a correlation between PAP concentration and percent of clot lysis was observed. Edoxaban also dose-dependently elevated PAP concentration. In TAFI-deficient plasma, the effects of edoxaban and PCI on clot lysis and PAP concentration were markedly diminished as compared with normal plasma. Fibrin fibers were thinner in clots formed in the presence of edoxaban. In conclusion, edoxaban at clinically relevant concentrations accelerates t-PA-induced fibrinolysis via increasing plasmin generation in human plasma. The effects of edoxaban is mainly dependent on TAFI. The profibrinolytic effect of edoxaban might contribute to the efficacy for the treatment of VTE.


Fibrinolysis Direct factor Xa inhibitor Plasmin Thrombin-activatable fibrinolysis inhibitor Edoxaban 



The authors would like to acknowledge the technical support from Ms. Toshie Yoshino.


This study was supported by Daiichi Sankyo Co., Ltd.

Compliance with ethical standards

Conflict of interest

The authors are the employees of Daiichi Sankyo Co., Ltd.

Ethical approval

This was an in vitro investigation and did not involve any living subjects.


  1. 1.
    Medved L, Nieuwenhuizen W (2003) Molecular mechanisms of initiation of fibrinolysis by fibrin. Thromb Haemost 89:409–419CrossRefGoogle Scholar
  2. 2.
    Huntington JA (2005) Molecular recognition mechanisms of thrombin. J Thromb Haemost 3:1861–1872CrossRefGoogle Scholar
  3. 3.
    Mosnier LO, Bouma BN (2006) Regulation of fibrinolysis by thrombin activatable fibrinolysis inhibitor, an unstable carboxypeptidase B that unites the pathways of coagulation and fibrinolysis. Arterioscler Thromb Vasc Biol 26:2445–2453CrossRefGoogle Scholar
  4. 4.
    Kearon C, Akl EA, Ornelas J, Blaivas A, Jimenez D, Bounameaux H, Huisman M, King CS, Morris TA, Sood N, Stevens SM, Vintch JRE, Wells P, Woller SC, Moores L (2016) Antithrombotic therapy for VTE disease: CHEST guideline and expert panel report. Chest 149:315–352CrossRefGoogle Scholar
  5. 5.
    Lip GY, Hammerstingl C, Marin F, Cappato R, Meng IL, Kirsch B, van Eickels M, Cohen A, X-TRA study and CLOT-AF registry investigators (2016) Left atrial thrombus resolution in atrial fibrillation or flutter: results of a prospective study with rivaroxaban (X-TRA) and a retrospective observational registry providing baseline data (CLOT-AF). Am Heart J 178:126–134CrossRefGoogle Scholar
  6. 6.
    Piazza G, Mani V, Goldhaber SZ, Grosso MA, Mercuri M, Lanz HJ, Schussler S, Hsu C, Chinigo A, Ritchie B, Nadar V, Cannon K, Pullman J, Concha M, Schul M, Fayad ZA, Edoxaban Thrombus Reduction Imaging Study (eTRIS) Investigators (2016) Magnetic resonance venography to assess thrombus resolution with edoxaban monotherapy versus parenteral anticoagulation/warfarin for symptomatic deep vein thrombosis: a multicenter feasibility study. Vasc Med 21:361–368CrossRefGoogle Scholar
  7. 7.
    Niku AD, Shiota T, Siegel RJ, Rader F (2019) Prevalence and resolution of left atrial thrombus in patients with nonvalvular atrial fibrillation and flutter with oral anticoagulation. Am J Cardiol 123:63–68CrossRefGoogle Scholar
  8. 8.
    Lee WC, Fang CY, Chen YL, Fang HY, Chen HC, Liu WH, Fu M, Chen MC (2019) Left atrial or left atrial appendage thrombus resolution after adjustment of oral anticoagulant treatment. J Stroke Cerebrovasc Dis 28:90–96CrossRefGoogle Scholar
  9. 9.
    Ammollo CT, Semeraro F, Incampo F, Semeraro N, Colucci M (2010) Dabigatran enhances clot susceptibility to fibrinolysis by mechanisms dependent on and independent of thrombin-activatable fibrinolysis inhibitor. J Thromb Haemost 8:790–798CrossRefGoogle Scholar
  10. 10.
    Carter RLR, Talbot K, Hur WS, Meixner SC, Van Der Gugten JG, Holmes DT, Côté HCF, Kastrup CJ, Smith TW, Lee AYY, Pryzdial ELG (2018) Rivaroxaban and apixaban induce clotting factor Xa fibrinolytic activity. J Thromb Haemost 16:2276–2288CrossRefGoogle Scholar
  11. 11.
    Königsbrügge O, Weigel G, Quehenberger P, Pabinger I, Ay C (2018) Plasma clot formation and clot lysis to compare effects of different anticoagulation treatments on hemostasis in patients with atrial fibrillation. Clin Exp Med 18:325–336CrossRefGoogle Scholar
  12. 12.
    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 6:1542–1549Google Scholar
  13. 13.
    Fuji T, Fujita S, Kawai Y, Nakamura M, Kimura T, Kiuchi Y, Abe K, Tachibana S (2014) Safety and efficacy of edoxaban in patients undergoing hip fracture surgery. Thromb Res 133:1016–1022CrossRefGoogle Scholar
  14. 14.
    Giugliano RP, Ruff CT, Braunwald E, Murphy SA, Wiviott SD, Halperin JL, Waldo AL, Ezekowitz MD, Weitz JI, Špinar J, Ruzyllo W, Ruda M, Koretsune Y, Betcher J, Shi M, Grip LT, Patel SP, Patel I, Hanyok JJ, Mercuri M, Antman EM, ENGAGE AF-TIMI 48 Investigators (2013) Edoxaban versus warfarin in patients with atrial fibrillation. N Engl J Med 369:2093–2104CrossRefGoogle Scholar
  15. 15.
    Investigators Hokusai-VTE, Büller HR, Décousus H, Grosso MA, Mercuri M, Middeldorp S, Prins MH, Raskob GE, Schellong SM, Schwocho L, Segers A, Shi M, Verhamme P, Wells P (2013) Edoxaban versus warfarin for the treatment of symptomatic venous thromboembolism. N Engl J Med 369:1406–1415CrossRefGoogle Scholar
  16. 16.
    Ogata K, Mendell-Harary J, Tachibana M, Masumoto H, Oguma T, Kojima M, Kunitada S (2010) Clinical safety, tolerability, pharmacokinetics, and pharmacodynamics of the novel factor Xa inhibitor edoxaban in healthy volunteers. J Clin Pharmacol 50:743–753CrossRefGoogle Scholar
  17. 17.
    Montes R, Páramo JA, Anglès-Cano E, Rocha E (1996) Development and clinical application of a new ELISA assay to determine plasmin-alpha2-antiplasmin complexes in plasma. Br J Haematol 92:979–985CrossRefGoogle Scholar
  18. 18.
    Schneider M, Nesheim M (2003) Reversible inhibitors of TAFIa can both promote and inhibit fibrinolysis. J Thromb Haemost 1:147–154CrossRefGoogle Scholar
  19. 19.
    Morishima Y, Kamisato C (2015) Laboratory measurements of the oral direct factor Xa inhibitor edoxaban: comparison of prothrombin time, activated partial thromboplastin time, and thrombin generation assay. Am J Clin Pathol 143:241–247CrossRefGoogle Scholar
  20. 20.
    Wolberg AS (2007) Thrombin generation and fibrin clot structure. Blood Rev 21:131–142CrossRefGoogle Scholar
  21. 21.
    Morishima Y, Kamisato C, Honda Y (2014) Treatment of venous thrombosis with an oral direct factor Xa inhibitor edoxaban by single and multiple administrations in rats. Eur J Pharmacol 742:15–21CrossRefGoogle Scholar
  22. 22.
    Esmon CT (2003) The protein C pathway. Chest 124:26S–32SCrossRefGoogle Scholar
  23. 23.
    Lorand L (2001) Factor XIII: structure, activation, and interactions with fibrinogen and fibrin. Ann NY Acad Sci 936:291–311CrossRefGoogle Scholar

Copyright information

© Springer Science+Business Media, LLC, part of Springer Nature 2019

Authors and Affiliations

  1. 1.Medical Science DepartmentDaiichi Sankyo Co., Ltd.TokyoJapan
  2. 2.End-Organ Disease LaboratoriesDaiichi Sankyo Co., Ltd.TokyoJapan

Personalised recommendations