As stated earlier, the coagulation system is normally in a state of dynamic equilibrium in which fibrin clots are constantly being laid down and dissolved. This latter process is termed fibrinolysis. Plasmin, the serine protease mainly responsible for degrading fibrin and fibrinogen, circulates in the form of its inactive zymogen, plasminogen (90 kDa), and any small amounts of plasmin that are formed in the fluid phase under physiologic conditions are rapidly inactivated by the fast-acting plasmin inhibitor, α2-antiplasmin. Plasminogen binds to fibrin and thus becomes incorporated in clots as they are produced; since plasmin that is formed when bound to fibrin is protected from α2-antiplasmin, it remains active. Activators of plasminogen of various types are found in most body tissues, and all cleave the same Arg-Val bond in plasminogen to produce the disulfide bridge-linked two-chain serine protease, plasmin (Figure 1). The specificity of plasmin for fibrin is another mechanism to regulate fibrinolysis. Via one of its kringle domains, plasmin(ogen) specifically binds lysine residues on fibrin and so is increasingly incorporated into the fibrin mesh as it cleaves it. (Kringle domains [see Figure 2] are common protein motifs of about 100 amino acid residues in length; they have a characteristic covalent structure defined by a pat tern of three disulfide bonds.) Thus, the carboxypeptidase activated thrombin-activatable fibrinolysis inhibitor (TAFIa) (see Figure 1), which removes terminal lysines from fibrin, also inhibits fibrinolysis. Thrombin activates TAFI to TAFIa, thereby inhibiting fibrinolysis during clot formation.

Fig1. Initiation of fibrinolysis by the activation of plasminogen to plasmin. Scheme of sites and modes of action of tissue plasminogen activator (t-PA), urokinase, plasminogen activator inhibitor, α2-antiplasmin, and thrombin-activatable fibrinolysis inhibitor (TAFIa).

Fig2. The structural domains of selected proteins involved in coagulation and fibrinolysis. Shared domains are a result of gene duplication and exon shuffling that contributed to the molecular evolution of the coagulation system. The domains are as identified at the bottom of the figure and include signal peptide, propeptide, Gla (γ-carboxyglutamate) domain, epidermal growth factor (EGF) domain, apple domain, kringle domain, fibronectin (types I and II) domain, the zymogen activation region, aromatic amino acid stack, and the catalytic domain. Interdomain disulfide bonds are indicated, but numerous intradomain disulfide bonds are not. Sites of proteolytic cleavage in synthesis or activation are indicated by arrows (dashed and solid, respectively). (FVII, factor VII; FIX, factor IX; FX, factor X, FXI; factor XI; FXII, factor XII; t-PA, tissue plasminogen activator.)

Tissue plasminogen activator (t-PA) (see Figures 2 and 1) is a serine protease that is released into the circulation from vascular endothelium under conditions of injury or stress and is catalytically inactive unless bound to fibrin. On binding to fibrin, t-PA cleaves plasminogen within the clot to generate plasmin, which in turn digests the fibrin to form soluble degradation products and thus dissolves the clot. Neither plasmin nor the plasminogen activator can remain bound to these degradation products, and so they are released into the fluid phase where they are inactivated by their natural inhibitors. Prourokinase is the precursor of a second activator of plasminogen, urokinase. Originally isolated from urine, it is now known that urokinase is synthesized by various cell types including monocytes and macrophages, fibroblasts, and epithelial cells. The main action of urokinase appears to be the degradation of extracellular matrix. Figure 2 indicates the sites of action of five proteins that influence the formation and action of plasmin.

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مواضيع ذات صلة

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Interaction with Water Influences the Structure of Biomolecules

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Conversion of Fibrinogen to Fibrin Is Catalyzed by Thrombin

Factor Xa Leads to Activation of Prothrombin to Thrombin

Most Transmembrane Proteins Have Membrane Spanning α Helices

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Lipid Composition Influences the Physical Properties of Membranes

The Intrinsic Pathway Also Leads to Activation of Factor X

The Extrinsic Pathway Leads to Activation of Factor X

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Most Lipids and Many Proteins Are Laterally Mobile in Biomembranes