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    d: Hemostasis and Thrombosis: Basic Principles and Clinical Practice http://gateway.ut.ovid.com/gw2/ovidweb.cgi

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    Copyright 2006 Lippincott Williams & Wilkins

    Colman, Robert W., Clowes, Alexander W., Goldhaber, Samuel

    Z., Marder, Victor J., George, James N.

    Hemostasis and Thrombosis: Basic Principles and Clinical

    Practice, 5th Edition

    Chapter 2

    Overview of Coagulation,Fibrinolysis, and their Regulation

    Robert W. Colman

    Victor J. MarderAlexander W. Clowes

    Blood coagulation is a series of steps in which plasma zymogens

    of serine proteases are transformed into active enzymes. These

    enzymes act to convert their procofactor substrates to

    cofactors, which assemble these proteases on cell surfaces. This

    assembly increases the local concentration of the reactants. The

    sequential nature of the reactions, in which the product serves

    as the next enzyme, amplifies the overall velocity of the

    reaction. The final event is the formation of thrombin, which

    converts a soluble protein, fibrinogen, into an insoluble

    polymer, fibrin, that forms the clot. Fibrinolysis is an analogous

    series of transformations of zymogens to proteolytic enzymes,

    which, in the presence of cofactors on cell surfaces, convert

    plasminogen to plasmin, which can hydrolyze the fibrin clot,

    thereby solubilizing it. At each step, a series of protease

    inhibitors limits the reaction. The occurrence of these reactions

    at cell surfaces allows regulation at the level of binding to

    receptors and the participation of the phospholipids of the cell

    membrane.

    It should be noted that the completion of the human genome

    project in 2003 has stimulated the addition of a new Chapter 4.

    An example of the importance of genomewide scans is the

    discovery of three new hemostasis-related genes. Combined

    factor VIII and V deficiency is due to mutations in an ERGogli

    protein coded for by the LMANIgene, also known as ERGIC-53

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    (1). Major breakthroughs are identification of the gene

    responsible for thrombotic thrombocytopenia purpura, ADAMTS

    13(2), and a gene related to warfarin resistance and action,

    vitamin K epoxide reductase (VKORC) (3).

    Normally, no coagulation takes place in the bloodstream

    because of the properties of the endothelium and the inactiveform of the proteins, which are either zymogens or

    procofactors. The initiation of the system depends on the

    exposure of the blood to components that are not present

    physiologically. These coagulation activators are revealed as a

    result of either mechanical injury, as is the case after a vessel

    is severed or after the endothelium is denuded during coronary

    angioplasty, or biochemical alteration, such as the release of

    cytokines, which in turn stimulate biosynthesis of induced

    receptors. Each of these events occurs in the initiation of blood

    coagulation and involves a single critical component, tissue

    factor (TF) (see Fig. 2-1). TF is a type I integral membrane

    receptor for coagulation factor VII (4). The extracellular portion

    is required for procoagulant activity, but the cytoplasmic

    domain is involved in signaling, important in angiogenesis and

    cell migration. TF is expressed constitutively on most cells

    (other than hepatocytes) that do not normally contact the

    blood, such as fibroblasts. After vascular injury, the blood

    contacts constitutive TF. Alternatively, endotoxin can stimulate

    monocytes and endothelial cells to biosynthesize the cytokines,

    tumor necrosis factor, and interleukin-1, which, in turn, induce

    the biosynthesis of TF (5,6). Factor VII binds to constitutive or

    induced TF on fibroblasts and monocytes, respectively. In all

    healthy individuals, trace levels of factor VIIa are present in the

    circulation, accounting for approximately 1% of the total factor

    VII concentration (7). Therefore, exposure of TF to plasmaresults in binding of both factor VII and factor VIIa; only the

    TFVIIa complexes are enzymatically active. Factor VII bound

    to TF is then activated by TFVIIa, termed autoactivation(8).

    This reaction may be insufficient to ignite the full capacity of

    the coagulation cascade. Other coagulation factor proteases,

    such as factor XIIa (9) and factor Xa (10), are much more

    effective.

    The TFVIIa complex has two substrates, factor IX (intrinsic

    pathway) and factor X (extrinsic pathway). Cleavage of either

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    protein results in a cell-bound serine protease, factor IXa or

    factor Xa. However, the reaction is tightly regulated by tissue

    factor pathway inhibitor (TFPI) (11), a protein produced by the

    endothelial cell and consisting of three Kunitz domains (12). The

    first domain binds to and inhibits TFVIIa, and the second,

    factor Xa. The direct activation of factor Xa is thereby rapidly

    downregulated. Ligation of factor Xa is required for TFPI to

    inhibit TFVIIa (11).

    In the presence of TFPI, the major pathway for the propagation

    of coagulation then becomes the intrinsic pathway, which is

    activated by factor IXa. The required cofactor for factor IXa to

    activate factor X is factor VIIIa. Factor VIII circulates in plasma

    bound to von Willebrand factor, which protects this vulnerable

    protein from unwanted proteolytic attack. For the procofactor,

    factor VIII, to be converted to the active cofactor, factor VIIIa,

    by thrombin or factor Xa, it must dissociate from von Willebrand

    factor. The factor IXaVIIIa complex is the most important

    activator of factor X, which helps explain the clinical severity of

    the deficiency of either factor IX or factor VIII and their

    identical clinical presentation in hemophilias B and A,

    respectively.

    Once formed, factor Xa can catalyze the conversion of

    prothrombin to thrombin, but the reaction is slow. The presence

    of the active cofactor, factor Va, bound to a cell surface

    (monocyte or platelet), results in a 300,000-fold acceleration

    (13). The procofactor, factor V, is converted to factor Va either

    by factor Xa or by thrombin (14). Factor Va functions as a

    cofactor by binding to a cell surface and in conjunction with

    phospholipid binding of factor Xa to form prothrombinase.

    Prothrombin binds with relatively low affinity to the cell surface,

    primarily by the -carboxyglutamic acid residues. This

    posttranslational modification is characteristic of all proteins

    that require vitamin K and is catalyzed by microsomal vitamin

    Kdependent carboxylase. These -carboxyglutamic acid

    residues are bridged by calcium to anionic phospholipid exposed

    on the surface of activated cells. Prothrombinase then cleaves

    prothrombin into fragment 1.2 (widely used as a marker of

    thrombin generation) and thrombin.

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    P.18

    FIGURE 2-1.Coagulation. Linesindicate binding; filled

    arrows, activation of zymogens to active enzymes; dashed

    arrows, inhibition of active enzymes. a, arterial enzyme; AT,

    antithrombin; EPR-1, monocyte effector protease

    receptor-1; Mac-1, monocyte integrin M2; PL,

    phospholipid; TF, tissue factor; TFPI, tissue factor pathway

    inhibitor.

    The older concept of the intrinsic system was that of

    coagulation initiated by components contained entirely in the

    vascular system so that the initiation would be independent of

    TF. One protein, factor XIa, is capable of activating factor IX

    and, therefore, provides a potential mechanism for initiating the

    intrinsic pathway. Factor XI deficiency, even when biochemicallysevere (

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    contrary, this system inhibits coagulation by blocking thrombin

    binding to platelets and is also profibrinolytic (17), which is

    discussed when fibrinolysis is considered (see Chapter 6).

    Factor XI also can autoactivate in the presence of a negatively

    charged surface such as dextran sulfate, but this is not a

    physiologic surface. In a purified system, factor XI is activated

    by thrombin (18), but HK and fibrinogen (19) both markedly

    decrease the rate of conversion in a plasma environment.

    However, both HK and prothrombin can serve as cofactors for

    the binding of factor XI to the surface of the activated platelet

    with a 5,000-fold increase in the rate of factor XI activation by

    thrombin (20). Therefore, positive feedback by thrombin is

    characteristic of the coagulation system because thrombin acts

    to convert both procofactors V and VIII to the active cofactors

    Va and VIIIa, which assemble the prothrombinase and tenasecomplexes, respectively.

    The cellular localization of coagulation complexes is important.

    Activated monocytes localize the extrinsic system because they

    not only express TF after they are activated but also have

    receptors for factor X and the integrin Mac-1 (M2). After

    factor X is converted to factor Xa, it binds to a receptor on

    monocytes or to factor Va, which itself binds to cells (21).

    Platelets bind factor XI and XIa to separate binding sites (15).

    Platelets secrete factor Va, which serves as a locus for binding

    factor Xa. Once prothrombin is cleaved, thrombin binds to

    protease-activated receptors (PAR) 1 (22) and 4 on platelets.

    The principal substrate of thrombin is fibrinogen, which is a

    dimer composed of two identical heterotrimers. The A, B, and

    polypeptides, each under control of a separate gene, are

    arranged in a trinodular array linked by coiled-coil segments

    (23). The central domain consisting of N-terminals of each chain

    bound in a disulfide knot is the binding site for thrombin, which

    cleaves off 2 mol of each of the acidic fibrinopeptides A and B,

    resulting in fibrin monomer formation (24). These monomers

    then spontaneously polymerize by side-toside approximation to

    form the protofibrin and, finally, the fibrin array. The final step

    is cross-linking of fibrin to form -dimers and -polymers

    catalyzed by the transamidase, factor XIIIa (25). Factor XIIIa is

    derived from the precursor factor XIII by limited proteolysis by

    thrombin in the presence of Ca2+(26). The covalent

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    cross-linking isopeptide mechanically stabilizes the molecule.

    Regulation of blood coagulation is achieved by several

    mechanisms, including dilution and the rate of blood flow, and

    by the action of proteolytic inhibitors such as TFPI and

    antithrombin. Antithrombin is a serpin (SERine Protease

    INhibitor) that primarily inhibits thrombin, factor Xa, and, to alesser extent, factor IXa. However, thrombin binding to the

    fibrin clot is relatively protected from antithrombin (27). The

    rate of the inactivation of factor Xa increases by more than

    300-fold associated with a pentasaccharide derived from heparin

    (28). Serine proteases, such as kallikrein, factor XIIa, and

    factor IXa, also are inhibited, but not as potently as factor Xa or

    thrombin (29). Factor X is also inhibited by a 72-kDa serpin, Z

    protease inhibitor (ZPI), the activity of which is enhanced

    1,000-fold by a vitamin Kdependent protein, protein Z, in the

    presence of phospholipid and Ca2+(30). Another major

    mechanism is a negative feedback initiated by thrombin binding

    to thrombomodulin (31) on the endothelial surface. Thrombin

    changes its substrate specificity and loses its ability to cleave

    fibrinogen and activate factor V and VIII to the active cofactors,

    factors Va and VIIa. Instead, it cleaves and activates protein C,

    which, in the presence of protein S, can inactivate factors Va

    and VIIIa (31). Additionally, an endothelial cell protein C

    receptor has been identified and characterized (32) and shown

    to be expressed on the endothelial cell surface. In the presence

    of an endothelial cell protein C receptor, the activation of

    protein C is enhanced 10- to 20-fold, whereas the activity of

    activated protein C to hydrolyze factor V is inhibited by

    occupying the exosite (33).

    Fibrinolysis is the ultimate mechanism that counteracts the

    consequences of the coagulation process. The dissolution or

    solubilization of the fibrin clot at the correct time is crucial for

    the orderly process of wound healing. Fibrinolysis is required for

    angiogenesis as well as vessel recanalization after clot

    formation. Similar to coagulation, there are two activators with

    different localization and different cofactors (see Fig. 2-2).

    Endothelial cells liberate tissue-type plasminogen activator

    (tPA) after stimulation by thrombin (34), which binds tightly to

    fibrin (35); fibrin serves as a cofactor enabling efficient

    activation of plasminogen to plasmin by tPA. Plasminogen also

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    P.19

    binds to fibrin (35). Therefore, the substrate, fibrin, localizes

    both the activator and the zymogen. Plasmin cleaves fibrinogen

    or fibrin, or both, to produce degradation products, which

    inhibit thrombin action and fibrin polymerization, serving as

    natural anticoagulants, especially in disseminated intravascular

    coagulation. Plasmin exerts a positive feedback by cleavage of

    an N-terminal peptide from the native glu-plasminogen,

    converting it to lys-plasminogen, which undergoes a large

    conformational change (36), rendering it much more susceptible

    to activation.

    A second plasminogen activator, urokinase plasminogen

    activator (uPA), is synthesized by endothelial cells, but on

    endothelial perturbation, prourokinase is expressed on the

    surface by binding to urokinase plasminogen activator receptor

    (uPAR), a glycerol-phosphate inositol-anchored receptor.

    Prourokinase can autoactivate, a process enhanced by binding

    to uPAR (37). Plasmin also can catalyze a positive feedback by

    converting prourokinase to urokinase. A potent initiating

    mechanism involving the contact system has been described

    that may account for the enhanced fibrinolysis that occurs with

    activation of this system (see Fig. 2-3). HK, after being cleaved,

    liberates bradykinin, which enhances release of tPA. The

    kinin-free kininogen (HKa) binds to endothelial uPAR (38) at

    domains 2 and/or 3 in close proximity to prourokinase. HK

    circulates in complex with prekallikrein (16), which is converted

    to kallikrein by an endothelial cell membraneassociated serine

    protease, prolylcarboxypeptidase (39). Kallikrein is known to

    activate prourokinase to urokinase (40). That this mechanism

    contributes to the initiation of the uPA pathway is supported by

    a study demonstrating that peptides that inhibit theHKprekallikrein (or kallikrein) interaction prevent the

    formation of plasmin on the endothelial ce ll surface (41).

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    FIGURE 2-2.Fibrinolysis. Linesindicate binding; thin

    arrows, transformation or stimulation; filled arrows,

    transformation of zymogens to active enzymes; dashed

    arrows, inhibition of active enzymes. 2AP, 2antiplasmin;

    FDP, fibrinogen deposition products; HK,

    high-molecularweight kininogen; HKa, kinin-free kininogen;Kal, kallikrein; PAI-1, plasminogen activator inhibitor 1; PK,

    prekallikrein; sc-tPA, single-chain tissue-type plasminogen

    activator; tc-tPA, two-chain tissue-type plasminogen

    activator; uPAR, urokinase plasminogen activator receptor.

    This system also is subject to multiple regulatory mechanisms.

    Lipoprotein A contains multiple kringles (42) that can compete

    with plasminogen. 2-Antiplasmin, a serpin, inhibits plasmin

    directly and with a rapid rate of association (43). Plasminogen

    activator inhibitor-1 is another serpin that inhibits both uPA and

    tPA. Thrombin-activated fibrinolytic inhibitor (TAFI) is a

    procarboxypeptidase that is activated by

    thrombinthrombomodulin complex (44). The active

    carboxypeptidase impairs fibrinolysis by removing lysine

    residues on fibrin critical to plasminogen binding (45). TAFI also

    inactivates two vasoactive peptides, C5a and bradykinin, and

    thereby downregulates vascular inflammation (46). Factor

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    XIIIainduced cross-linking of the f ibrin matrix renders it much

    more resistant to plasmin action.

    FIGURE 2-3.Contact system and fibrinolysis. Horizontal

    arrowsindicate transformation from zymogen to active

    enzyme. Vertical or diagonalarrowsindicate action of

    enzyme on substrate. HKa, kinin-free kininogen; BK,

    bradykinin.

    Coagulation and fibrinolysis are responses to vessel or cell

    injury. The reactions are mostly confined to the cell

    membranes, which increases their effective concentration by

    proximity on approximated receptors and by limiting their

    diffusion (47). The protease inhibitors exist in the plasma to

    prevent their propagation into the systemic circulation, and it is

    this process that may malfunction in thrombosis anddisseminated intravascular coagulation.

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