Factor IIa inhibitors (compounds) binds IIa

Stable Identifier
Reaction [binding]
Homo sapiens
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In the blood coagulation process, prothrombin is proteolytically cleaved to form thrombin (factor IIa) which in turn, acts as a serine protease that converts soluble fibrinogen into insoluble strands of fibrin. Specifically, thrombin converts factor XI to XIa, factor VIII to VIIIa, factor V to Va, fibrinogen to fibrin, and factor XIII to XIIIa. The direct oral anticoagulant (DOAC) synthetic organic drugs dabigatran (brand name Pradaxa), argatroban (brand name Acova, Novastan; Exembol in the UK) and melagatran are potent, competitive direct thrombin inhibitors (DTIs). They reversibly and specifically bind both clot-bound and free thrombin (unlike warfarin or heparin), as well as inhibiting thrombin-induced platelet aggregation (Wienen et al. 2007, Stangier et al. 2007).

Commercially, dabigatran is formulated as a lipophilic prodrug, dabigatran etexilate, to promote gastrointestinal absorption before it is metabolised to the active drug. The kidneys excrete the majority (80%) of unchanged drug (Stangier et al. 2007). Argatroban is a synthetic inhibitor of thrombin derived from L-arginine, which has a relatively short period of binding only to thrombin’s active site (Hursting et al. 1997). It is given intravenously and is metabolised in the liver. Because of its hepatic metabolism, it may be used in patients with renal dysfunction. Melagatran is the active drug formed from the prodrug ximelagatran and is a competitive and rapid inhibitor of thrombin (Gustafsson et al. 1998). DuP 714 is a potent and specific thrombin inhibitor (Chiu et al. 1991).

A major downside of DOACs is that they don't have reversing antidotes if internal bleeding arises from their use. However, in the case of severe bleeding of patients on dabigatran, the antibody fragment idarucizumab reversed the anticoagulation effects of dabigatran within minutes (Pollack et al. 2015). This represents a novel anticoagulation reversing mechanism for a DOAC.

Literature References
PubMed ID Title Journal Year
1930190 Inhibition of the thrombin-platelet reactions by DuP 714

Chiu, AT, Bozarth, JM, Timmermans, PB, Reilly, TM, Roscoe, WA, Smith, RD, Mousa, SA, Pease, LJ

Biochem. Biophys. Res. Commun. 1991
9469622 Novastan (brand of argatroban): a small-molecule, direct thrombin inhibitor

McKinney, AA, Knappenberger, GD, Schwarz, RP, Alford, KL, Brooks, RL, Kogan, TP, Hursting, MJ, Kogan, PW, Joffrion, JL, Becker, JC

Semin. Thromb. Hemost. 1997
9459334 Effects of melagatran, a new low-molecular-weight thrombin inhibitor, on thrombin and fibrinolytic enzymes

Mattsson, C, Antonsson, T, Gustafsson, D, Sörensen, H, Nilsson, A, Pehrsson, S, Gyzander, E, Bylund, R, Elg, M, Karlsson, O, Deinum, J, Nilsson, I, Eriksson, U

Thromb. Haemost. 1998
17598008 In-vitro profile and ex-vivo anticoagulant activity of the direct thrombin inhibitor dabigatran and its orally active prodrug, dabigatran etexilate

Ries, UJ, Hauel, N, Priepke, H, Wienen, W, Stassen, JM

Thromb. Haemost. 2007
17506785 The pharmacokinetics, pharmacodynamics and tolerability of dabigatran etexilate, a new oral direct thrombin inhibitor, in healthy male subjects

Gansser, D, Roth, W, Stähle, H, Rathgen, K, Stangier, J

Br J Clin Pharmacol 2007
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