Thrombin

P Thiagarajan, Baylor College of Medicine, Houston, Texas, USA
A S Narayanan, University of Washington School of Medicine, Seattle, Washington, USA

Published online: September 2009

DOI: 10.1002/9780470015902.a0001410.pub2

Thrombin is a serine protease that converts fibrinogen to fibrin in blood coagulation. The precursor of thrombin, prothrombin (inactive zymogen), is one of the several coagulation proteins containing -carboxyglutamic acid. Prothrombin is synthesized in the liver and secreted into blood circulation, and it 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, and 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 bivaliruidin), 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 to fibrin and plays a crucial role in hemostasis and thrombosis.

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

Figure 1. Complete amino acid sequence of human prothrombin showing the organization of the various domains and disulfide structure. The -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, 2006; Davie et al., 1991).
Figure 2. Various active species of thrombin derived from prothrombin. Coagulation factor Xa cleaves two peptide bonds in prothrombin, Arg271Thr272 and Arg320-Ile321, giving rise to mature thrombin. In physiological activation by the prothrombinase complex, first the cleavage at Arg320Thr321 occurs; this is 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 stabilize 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, 2006).
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.
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 References
    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(2006): 122–130.
    book Clark RAF (ed.) (1996) The Molecular Biology of Wound Repair. New York: Plenum Press.
    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 SJF and Davie EW (1987) Nucleotide sequence of the gene for human prothrombin. Biochemistry 26: 6165–6177.
    Irwin DM, Ahern KG, Pearson GD and MacGillivray RTA (1985) Characterization of the bovine prothrombin gene. Biochemistry 24: 6854–6861.
    Kalafatis M, Egan JO, van't Veer C and Mann KG (1996) Regulation and regulatory role of -carboxyglutamic acid containing clotting factors. Critical Reviews in Eukaryotic Gene Expression 6: 87–101.
    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.
    book Magnusson S (1971) "Thrombin and prothrombin". In: Boyer PD (ed.) The Enzymes, vol. III, pp. 277–321. New York: 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 -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 hirudin-thrombin complex. Journal of Molecular Biology 221: 583–601.
    Stouffer GA and Smyth SS (2003) Effects of thrombin on interactions between 3-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.
    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.
    Waltz DA, Anderson GF and Fenton JW II (1986) Responses of aortic smooth muscle to thrombin. 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.
    book Berliner LJ (ed.) (1992) Thrombin: Structure and Function. New York: Plenum Press.
    Broze GJ Jr (1998) Thrombin-dependent inhibition of fibrinolysis. Current Opinion in Hematology 5: 390–394.
    Crawley JTB, Zanardelli S, Chion CKNK 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.
    Harker LA (1998) Therapeutic inhibition of thrombin activities, receptors and production. Hematology/Oncology Clinics of North America 6: 1211–1230.
    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: 4–10.
    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 Hemostasis 22: 117–124.

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Protein Structure | Proteins: Structure, Function, Metabolism
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Article Title: Thrombin
 
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Thiagarajan, P, and Narayanan, A S(Sep 2009) Thrombin. In: eLS. John Wiley & Sons Ltd, Chichester. http://www.els.net [doi: 10.1002/9780470015902.a0001410.pub2]