Blood coagulation - Blood coagulation

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Blood coagulation

The haemostatic system maintains blood in a fluid state under normal conditions and responds to vessel injury by the rapid formation of a clot consisting of platelets and Fibrin. The traditional view of the regulation of blood coagulation is that the initiation phase is triggered by an extrinsic pathway, whereas amplification requires an intrinsic pathway. The extrinsic pathway begins with disruption of the endothelium, which exposes Coagulation factor III (Tissue factor) expressed in adventitial cells to the plasma, allowing it to bind circulating Coagulation factor VII [1]. The cell-surface complex of Tissue factor and activated Coagulation factor VII can be thought of as a two-subunit enzyme, with Coagulation factor VII as the catalytic subunit and Tissue factor as the regulatory subunit. The Tissue factor/Coagulation factor VII complex activates two serine protease zymogens Coagulation factor X and Coagulation factor IX by limited proteolysis [2]. Generated active Coagulation factor X activates Coagulation factor V, leading to formation of a prothrombinase complex [3]. Prothrombinase converts prothrombin to Thrombin. Thrombin feedback amplifies the system by activating not only Coagulation factor V, but also Coagulation factor VIII and Coagulation factor XI [4]. Coagulation factor VIII circulates while bound to von Willebrand factor, which is an adhesive protein important for the generation of the initial platelet plug. After activation, Coagulation factor VIII dissociates from von Willebrand factor and forms a so-called tenase complex with Coagulation factor IX [5]. Tenase complex converts Coagulation factor X into active Coagulation factor X and is regarded as a part of the intrinsic coagulation pathway.

The intrinsic pathway begins with contact activation of Coagulation factor XII. Coagulation factor XII cleaves prekallikrein, and the generated Plasma kallikrein catalyses Bradykinin formation and activates Coagulation factor XI [6]. The primary function of Coagulation factor XI is to activate Coagulation factor IX. Therefore the intrinsic and extrinsic pathways converge at the level of Coagulation factor X [7]. Thrombin generated during propagation of both cascades converts Fibrinogen to a fibrin network. Thrombin also activates Coagulation factor XIII, which is a transglutaminase that stabilizes the clot by covalent cross-linking of fibrin [8].

Fibrin clots are resorbed during fibrinolysis. Plasmin, generated from Pasminogen, is the major fibrinolytic protease. Plasminogen conversion to Plasmin could be triggered by both Tissue plasminogen activator (PLAT(TPA)) and by Plasminogen activator, urokinase (PLAU(UPA)). Under certain conditions, Coagulation factor XII and Plasma kallikrein could stimulate Plasmin generation as well [7].

Both blood coagulation and fibrinolysis are under fine control of various regulators. The major class of serine protease inhibitors regulating procoagulant and fibrinolytic enzymes is the serpin superfamily. Principal enzymes of the serpin family regulating coagulation/fybrinolytic pathways are Serpin peptidase inhibitor clade C memeber1 (Anthitrombin III), Serpin peptidase inhibitor, clade D member 1(HCII), Serpin peptidase inhibitor, clade E member 1 (PAI1), Serpin peptidase inhibitor, clade B member 2 (PAI2), Serpin peptidase inhibitor, clade A member 5 (Protein C inhibitor), Serpin peptidase inhibitor, clade E member 2 (SERPINE2), Serpin peptidase inhibitor, clade F member 2 (SERPINF2), Serpin peptidase inhibitor, clade A member 1 (SERPINA1). Antithrombin III binds and inhibits the principal procoagulant enzymes Thrombin and Coagulation factor X; HCII inhibits Thrombin enzymatic activity [9]. SERPINE2 may function as a non-circulating cell surface inhibitor of Thrombin, Coagulation factor X, PLAU(UPA) or Plasmin, resulting in protease-inhibitor complexes [7].

PAI1 is the most important and most rapidly acting physiological inhibitor of both PLAU(UPA) and PLAT(TPA) [7]. Of special interest is Protein C inhibitor, which inhibits activity of Thrombin (Thrombomodulin enhances this effect), Coagulation factor XI, Plasma kallikrein, PLAU(UPA), PLAT(TPA) and Protein C [9]. The Protein C system is activated on the surface of intact endothelial cells by Thrombin bound to Thrombomodulin. Protein S supports the anticoagulant activity of Protein C. Activated Protein C cleaves phospholipid-membrane bound Coagulation factor V and Coagulation factor VIII [4], [10].

Tissue factor pathway inhibitor (TFPI) is the only physiological inhibitor of the F3/Coagulation factor VII complex. TFPI binds to the Coagulation factor VII active site and to Coagulation factor X, forming a totally inactive complex [11], [12].

References:

  1. Mackman N, Tilley RE, Key NS
    Role of the extrinsic pathway of blood coagulation in hemostasis and thrombosis. Arteriosclerosis, thrombosis, and vascular biology 2007 Aug;27(8):1687-93
  2. Morrissey JH
    Tissue factor: a key molecule in hemostatic and nonhemostatic systems. International journal of hematology 2004 Feb;79(2):103-8
  3. Mann KG
    Biochemistry and physiology of blood coagulation. Thrombosis and haemostasis 1999 Aug;82(2):165-74
  4. Dahlbäck B
    Blood coagulation. Lancet 2000 May 6;355(9215):1627-32
  5. Saenko EL, Shima M, Sarafanov AG
    Role of activation of the coagulation factor VIII in interaction with vWf, phospholipid, and functioning within the factor Xase complex. Trends in cardiovascular medicine 1999 Oct;9(7):185-92
  6. Kaplan AP, Joseph K, Shibayama Y, Reddigari S, Ghebrehiwet B, Silverberg M
    The intrinsic coagulation/kinin-forming cascade: assembly in plasma and cell surfaces in inflammation. Advances in immunology 1997;66:225-72
  7. Cesarman-Maus G, Hajjar KA
    Molecular mechanisms of fibrinolysis. British journal of haematology 2005 May;129(3):307-21
  8. Weisel JW
    Fibrinogen and fibrin. Advances in protein chemistry 2005;70:247-99
  9. Pike RN, Buckle AM, le Bonniec BF, Church FC
    Control of the coagulation system by serpins. Getting by with a little help from glycosaminoglycans. The FEBS journal 2005 Oct;272(19):4842-51
  10. Esmon CT
    The protein C pathway. Chest 2003 Sep;124(3 Suppl):26S-32S
  11. Huang ZF, Wun TC, Broze GJ Jr
    Kinetics of factor Xa inhibition by tissue factor pathway inhibitor. The Journal of biological chemistry 1993 Dec 25;268(36):26950-5
  12. Golino P
    The inhibitors of the tissue factor:factor VII pathway. Thrombosis research 2002 May 1;106(3):V257-65

  1. Mackman N, Tilley RE, Key NS
    Role of the extrinsic pathway of blood coagulation in hemostasis and thrombosis. Arteriosclerosis, thrombosis, and vascular biology 2007 Aug;27(8):1687-93
  2. Morrissey JH
    Tissue factor: a key molecule in hemostatic and nonhemostatic systems. International journal of hematology 2004 Feb;79(2):103-8
  3. Mann KG
    Biochemistry and physiology of blood coagulation. Thrombosis and haemostasis 1999 Aug;82(2):165-74
  4. Dahlbäck B
    Blood coagulation. Lancet 2000 May 6;355(9215):1627-32
  5. Saenko EL, Shima M, Sarafanov AG
    Role of activation of the coagulation factor VIII in interaction with vWf, phospholipid, and functioning within the factor Xase complex. Trends in cardiovascular medicine 1999 Oct;9(7):185-92
  6. Kaplan AP, Joseph K, Shibayama Y, Reddigari S, Ghebrehiwet B, Silverberg M
    The intrinsic coagulation/kinin-forming cascade: assembly in plasma and cell surfaces in inflammation. Advances in immunology 1997;66:225-72
  7. Cesarman-Maus G, Hajjar KA
    Molecular mechanisms of fibrinolysis. British journal of haematology 2005 May;129(3):307-21
  8. Weisel JW
    Fibrinogen and fibrin. Advances in protein chemistry 2005;70:247-99
  9. Pike RN, Buckle AM, le Bonniec BF, Church FC
    Control of the coagulation system by serpins. Getting by with a little help from glycosaminoglycans. The FEBS journal 2005 Oct;272(19):4842-51
  10. Esmon CT
    The protein C pathway. Chest 2003 Sep;124(3 Suppl):26S-32S
  11. Huang ZF, Wun TC, Broze GJ Jr
    Kinetics of factor Xa inhibition by tissue factor pathway inhibitor. The Journal of biological chemistry 1993 Dec 25;268(36):26950-5
  12. Golino P
    The inhibitors of the tissue factor:factor VII pathway. Thrombosis research 2002 May 1;106(3):V257-65

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