Thrombin

Abstract

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.

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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.

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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.

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Thiagarajan, P, and Narayanan, AS(Jul 2014) Thrombin. In: eLS. John Wiley & Sons Ltd, Chichester. http://www.els.net [doi: 10.1002/9780470015902.a0001410.pub3]