Thrombin (factor IIa) is a serine protease that converts fibrinogen into fibrin in blood coagulation. The precursor of thrombin, prothrombin (inactive zymogen), is one of the several coagulation proteins containing γ‐carboxyglutamic acid. Prothrombin is synthesised in the liver and secreted into blood circulation, and is activated by vascular injury by limited proteolysis following upstream activation of the coagulation cascade. Thrombin activity is regulated by serum inhibitors and by its own action. With its procoagulant and anticoagulant functions, it plays a central role in thrombosis and haemostasis. It is an agonist for a number of cellular responses during inflammation and wound repair. Many diseases including stroke and myocardial infarction involve thrombosis; therefore, thrombin is a preferred target of antithrombotic drugs. Drugs available to block thrombin action include heparins, hirudins (lepirudin and bivalirudin), vitamin K antagonists and a new generation of direct thrombin inhibitors such as dabigatran and argatroban.

Key Concepts:

  • Thrombin is a serine protease that converts fibrinogen into fibrin and plays a crucial role in haemostasis and thrombosis.

  • During coagulation, factor Xa/Va complex formed on phospholipid or platelet membrane converts prothrombin to thrombin in the presence of Ca2+.

  • Thrombin also activates platelets and factors V, VIII and XI to enhance haemostasis.

  • In addition to haemostasis, thrombin plays a major role in inflammation and wound healing, and it is a potent mitogenic factor.

  • Thrombin has anticoagulant effects by activating the protein C pathway and by releasing plasminogen activators from endothelial cells, which promote fibrinolytic cascade.

  • Consequences of thrombosis include vascular diseases such as stroke, myocardial infarction and deep‐vein thrombosis and pulmonary embolism.

  • Both direct and indirect inhibitors are used clinically to treat thrombotic disorders.

Keywords: thrombin; prothrombin; coagulation; antithrombin; vitamin K; endothelial cells

Figure 1.

Complete amino acid sequence of human prothrombin showing the organisation of the various domains and disulphide structure. The γ‐carboxyglutamic acid residues are identified as ‘g’. Glycosylation sites are marked with solid circles. Factor Xa cleavage and thrombin cleavage sites are marked by arrows. The amino acid residues constituting the catalytic triads are identified as open diamonds (H363, D419, S525; H43, D99, S205 in thrombin) (Davie and Kulman, ; Davie et al., ).

Figure 2.

Various active species of thrombin derived from prothrombin. Coagulation factor Xa cleaves two peptide bonds in prothrombin, Arg271‐Thr272 and Arg320‐Ile321, giving rise to mature thrombin. In physiological activation by the prothrombinase complex, first the cleavage at Arg320Thr321 occurs; followed by cleavage at Arg271Thr272.

Figure 3.

Central role of thrombin in the coagulation pathway. Blood coagulation is initiated by the ‘initiating’ or ‘extrinsic’ pathway by tissue factor and activated factor VIIa, which together activate factor X to Xa. The factor X is also activated through the ‘intrinsic’ pathway when factor IX is activated to IXa. The factor IXa, along with activated factor VIIIa, then activates the factor X to Xa. The factor Xa in the presence of cofactor Va activates prothrombin to thrombin, which in turn converts fibrinogen to fibrin monomers. Thrombin also activates factor XIII to stabilise the fibrin clot formed by crosslinking. Thrombin, once generated, can amplify its own formation by activating factors XI, VIII and V. It can also regulate its own generation by activating protein C (Davie and Kulman, ).

Figure 4.

Multifunctional role of thrombin. The pro‐ and anticoagulant effects of thrombin are listed. The various agonist actions on inflammatory and mesenchymal cell types make thrombin an important participant in inflammation and wound healing.



Angiolillo DJ, Capodanno D and Goto S (2010) Platelet thrombin receptor antagonism and atherothrombosis. European Heart Journal 2010: 17–28.

Bauer KA (2008) New anticoagulants. Current Opinion in Hematology 15: 509–515.

Bode W (2006) Structure and interaction modes of thrombin. Blood Cells, Molecules & Diseases 36: 122–130.

Clark RAF (ed.) (1996) The Molecular Biology of Wound Repair. New York, NY: Plenum Press.

Coppens M, Eikelboom JW, Gustafsson D, Weitz JI and Hirsh J (2012) Translational success stories: development of direct thrombin inhibitors. Circulation Research 111: 920–929.

Davie EW, Fujikawa K and Kisiel W (1991) The coagulation cascade: initiation, maintenance, and regulation. Biochemistry 30: 10363–10370.

Davie EW and Kulman JD (2006) An overview of the structure and function of thrombin. Seminars in Thrombosis and Hemostasis 32(suppl. 1): 3–15.

Degen SJ and Davie EW (1987) Nucleotide sequence of the gene for human prothrombin. Biochemistry 26: 6165–6177.

Irwin DM, Ahern KG, Pearson GD and MacGillivray RT (1985) Characterization of the bovine prothrombin gene. Biochemistry 24: 6854–6861.

Lai MT, Di Cera E and Shafer JA (1997) Kinetic pathway for the slow to fast transition of thrombin. Evidence of linked ligand binding at structurally distinct domains. Journal of Biological Chemistry 272: 30275–30282.

Lee CJ and Ansell JE (2011) Direct thrombin inhibitors. British Journal of Clinical Pharmacology 72: 581–592.

Magnusson S (1971) Thrombin and prothrombin. In: Boyer PD (ed.) The Enzymes, vol. 3, pp. 277–321. New York, NY: Academic Press.

Monroe DM and Hoffman M (2006) What does it take to make the perfect clot. Arteriosclerosis, Thrombosis, and Vascular Biology 26: 41–48.

Richardson JL, Kröger B, Hoeffken W et al. (2000) Crystal structure of the human α‐thrombin‐haemadin complex: an exocite‐II binding inhibitor. EMBO Journal 19: 5650–5660.

Rydel TJ, Tulinsky A, Bode W and Huber R (1991) Refined structure of the hirudin‐thrombin complex. Journal of Molecular Biology 221: 583–601.

Stouffer GA and Smyth SS (2003) Effects of thrombin on interactions between β3‐integrins and extracellular matrix in platelets and vascular cells. Arteriosclerosis, Thrombosis, and Vascular Biology 23: 1971–1978.

Stubbs MT and Bode W (1993) A player of many parts: the spotlight falls on thrombin's structure. Thrombosis Research 69: 1–58.

Showkathali R and Natarajan A (2012) Antiplatelet and antithrombin strategies in acute coronary syndrome: state‐of‐the‐art review. Current Cardiology Reviews 8: 239–249.

Tello‐Montoliu A, Tomasello SD, Ueno M and Angiolillo DJ (2011) Antiplatelet therapy: thrombin receptor antagonists. British Journal of Clinical Pharmacology 72: 658–671.

Trejo J (2003) Protease‐activated receptors: new concepts in regulation of G protein‐coupled receptor signaling and trafficking. Journal of Pharmacology and Experimental Therapeutics 307: 437–442.

Vadivel K and Bajaj SP (2012) Structural biology of factor VIIa/tissue factor initiated coagulation. Frontiers in Bioscience (Landmark edition) 17: 2476–2494. PMID: 22652793.

Walz DA, Anderson GF and Fenton JW II (1986) Responses of aortic smooth muscle to thrombin and thrombin analogs. Annals of the New York Academy of Sciences 485: 323–334.

Further Reading

Adams TE and Huntington JA (2006) Thrombin‐cofactor interactions. Structural insights into regulatory mechanisms. Arteriosclerosis, Thrombosis, and Vascular Biology 26: 1738–1745.

Angiolillo DJ, Ueno M and Goto S (2010) Basic principles of platelet biology and clinical implications. Circulation Journal 74: 597–607.

Berliner LJ (ed.) (1992) Thrombin: Structure and Function. New York, NY: Plenum Press.

Broze GJ Jr. (1996) Thrombin‐dependent inhibition of fibrinolysis. Current Opinion in Hematology 3: 390–394.

Crawley JT, Zanardelli S, Chion CK and Lane DA (2007) The central role of thrombin in hemostasis. Journal of Thrombosis and Haemostasis 5(suppl. 1): 95–101.

Fenton JW II, Ofosu FA, Brezniak DV and Hassouna HI (1998) Thrombin and antithrombotics. Seminars in Thrombosis and Hemostasis 24: 87–91.

Lundblad RL and White GC II (2005) The interaction of thrombin with blood platelets. Platelets 16: 373–385.

Mann KG (2003) Thrombin formation. Chest 124(suppl. 3): 4S–10S.

Stubbs MT and Bode W (1995) The clot thickens: clues provided by thrombin structure. Trends in Biochemical Sciences 20: 23–28.

Tulinsky A (1996) Molecular interactions of thrombin. Seminars in Thrombosis and Haemostasis 22: 117–124.

Contact Editor close
Submit a note to the editor about this article by filling in the form below.

* Required Field

How to Cite close
Thiagarajan, P, and Narayanan, AS(Jul 2014) Thrombin. In: eLS. John Wiley & Sons Ltd, Chichester. [doi: 10.1002/9780470015902.a0001410.pub3]