γT-S195A thrombin reduces the anticoagulant effects of dabigatran in vitro and in vivo

Journal of Thrombosis and Haemostasis

Volumn 12, Issue 7, 2014, Pages 1110-1115

  Sheffield, W P ^a,b   Lambourne, M D ^a   Eltringham Smith, L J ^b   Bhakta, V ^a   Arnold, D M ^a,b   Crowther, M A ^b  

^a CANADIAN BLOOD SERVICES   (Canada)

^b MCMASTER UNIVERSITY   (Canada)

Author keywords

Antidotes; Antithrombins; Blood coagulation; Dabigatran; Thrombin

Indexed keywords

ANTIDOTE; DABIGATRAN; DABIGATRAN ETEXILATE; GAMMA T S195A IIA; S195A IIA; THROMBIN; UNCLASSIFIED DRUG; ANTICOAGULANT AGENT; BENZIMIDAZOLE DERIVATIVE; BETA ALANINE; RECOMBINANT PROTEIN;

ANIMAL EXPERIMENT; ANIMAL MODEL; ANTICOAGULATION; ARTICLE; BLEEDING TIME; CAROTID ARTERY THROMBOSIS; CONTROLLED STUDY; IN VITRO STUDY; IN VIVO STUDY; MOUSE; NONHUMAN; PRIORITY JOURNAL; THROMBIN TIME; TREATMENT OUTCOME; ANALOGS AND DERIVATIVES; ANIMAL; ANTAGONISTS AND INHIBITORS; ARTERIAL OCCLUSIVE DISEASES; BLOOD CLOTTING; CAROTID ARTERY; CELL LINE; CHEMISTRY; DRUG EFFECTS; ENZYME ACTIVE SITE; HAMSTER; HUMAN; MUTATION; PATHOLOGY;

ANIMALS; ANTICOAGULANTS; ARTERIAL OCCLUSIVE DISEASES; BENZIMIDAZOLES; BETA-ALANINE; BLEEDING TIME; BLOOD COAGULATION; CAROTID ARTERIES; CATALYTIC DOMAIN; CELL LINE; CRICETINAE; HUMANS; MICE; MUTATION; RECOMBINANT PROTEINS; THROMBIN; THROMBIN TIME;

EID: 84904318453     PISSN: 15387933     EISSN: 15387836     Source Type: Journal    
DOI: 10.1111/jth.12601     Document Type: Article

References (18)

1. Connolly SJ, Ezekowitz MD, Yusuf S, Eikelboom J, Oldgren J, Parekh A, Pogue J, Reilly PA, Themeles E, Varrone J, Wang S, Alings M, Xavier D, Zhu J, Diaz R, Lewis BS, Darius H, Diener HC, Joyner CD, Wallentin L. Dabigatran versus warfarin in patients with atrial fibrillation. N Engl J Med 2009; 361: 1139-51.
2. Schiele F, van Ryn J, Canada K, Newsome C, Sepulveda E, Park J, Nar H, Litzenburger T. A specific antidote for dabigatran: functional and structural characterization. Blood 2013; 121: 3554-62.
3. Grottke O, van Ryn J, Spronk HM, Rossaint R. Prothrombin complex concentrates and a specific antidote to dabigatran are effective ex-vivo in reversing the effects of dabigatran in an anticoagulation/liver trauma experimental model. Crit Care 2014; 18: R27.
4. Lambourne MD, Eltringham-Smith LJ, Gataiance S, Arnold DM, Crowther MA, Sheffield WP. Prothrombin complex concentrates reduce blood loss in murine coagulopathy induced by warfarin, but not in that induced by dabigatran etexilate. J Thromb Haemost 2012; 10: 1830-40.
5. Zhou W, Schwarting S, Illanes S, Liesz A, Middelhoff M, Zorn M, Bendszus M, Heiland S, van Ryn J, Veltkamp R. Hemostatic therapy in experimental intracerebral hemorrhage associated with the direct thrombin inhibitor dabigatran. Stroke 2011; 42: 3594-9.
6. Pragst I, Kaspereit F, Dorr B, Dickneite G. Prothrombin complex concentrate (Beriplex P/N) for control of bleeding after kidney trauma in a rabbit dilutional coagulopathy model. Thromb Res 2010; 125: 272-7.
7. Hauel NH, Nar H, Priepke H, Ries U, Stassen JM, Wienen W. Structure-based design of novel potent nonpeptide thrombin inhibitors. J Med Chem 2002; 45: 1757-66.
8. Lu G, DeGuzman FR, Hollenbach SJ, Karbarz MJ, Abe K, Lee G, Luan P, Hutchaleelaha A, Inagaki M, Conley PB, Phillips DR, Sinha U. A specific antidote for reversal of anticoagulation by direct and indirect inhibitors of coagulation factor Xa. Nat Med 2013; 19: 446-51.
9. Baglin TP, Carrell RW, Church FC, Esmon CT, Huntington JA. Crystal structures of native and thrombin-complexed heparin cofactor II reveal a multistep allosteric mechanism. Proc Natl Acad Sci USA 2002; 99: 11079-84.
10. Boyle AJ, Roddick LA, Bhakta V, Lambourne MD, Junop MS, Liaw PC, Weitz JI, Sheffield WP. The complete N-terminal extension of heparin cofactor II is required for maximal effectiveness as a thrombin exosite 1 ligand. BMC Biochem 2013; 14: 6.
11. Sheffield WP, Eltringham-Smith LJ, Bhakta V, Gataiance S. Reduction of thrombus size in murine models of thrombosis following administration of recombinant alpha1-proteinase inhibitor mutant proteins. Thromb Haemost 2012; 107: 972-84.
12. Sheffield WP, Eltringham-Smith LJ, Gataiance S, Bhakta V. A long-lasting, plasmin-activatable thrombin inhibitor aids clot lysis in vitro and does not promote bleeding in vivo. Thromb Haemost 2009; 101: 867-77.
13. Bode W, Turk D, Karshikov A. The refined 1.9-A X-ray crystal structure of D-Phe-Pro-Arg chloromethylketone-inhibited human alpha-thrombin: structure analysis, overall structure, electrostatic properties, detailed active-site geometry, and structure-function relationships. Protein Sci 1992; 1: 426-71.
14. Stone SR, Le Bonniec BF. Inhibitory mechanism of serpins. Identification of steps involving the active-site serine residue of the protease. J Mol Biol 1997; 265: 344-62.
15. Rogers SJ, Pratt CW, Whinna HC, Church FC. Role of thrombin exosites in inhibition by heparin cofactor II. J Biol Chem 1992; 267: 3613-7.
16. Myles T, Church FC, Whinna HC, Monard D, Stone SR. Role of thrombin anion-binding exosite-I in the formation of thrombin-serpin complexes. J Biol Chem 1998; 273: 31203-8.
17. Chang JY. The structures and proteolytic properties of autolysed human thrombin. Biochem J 1986; 240: 797-802.
18. Hofsteenge J, Braun PJ, Stone SR. Enzymatic properties of proteolytic derivatives of human alpha-thrombin. Biochemistry 1988; 27: 2144-51.