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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. Marder
Alexander 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 LMANI gene, 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 inactive
form 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 plasma
results 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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FIGURE 2-1. Coagulation. Lines indicate 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 M 2 ; PL,
phospholipid; TF, tissue factor; TFPI, tissue factor pathway
inhibitor.

P.18
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 biochemically
severe (<1% of normal), is clinically mild. The major
manifestation is posttraumatic bleeding (15), and only one half
of the patients have some excessive bleeding. Factor XII can be
activated by three plasma proteasesfactor XIIa, factor XIa,
and thrombin. Factor XIIa can activate factor XI in the presence
of the contact system cofactor, high-molecular-weight kininogen
(HK), and in the presence of a foreign surface (16), such as in
cardiopulmonary bypass or hemodialysis. However, deficiency of
factor XII, HK, or prekallikrein (which plays a role in activation
of factor XII) does not lead to a hemorrhagic state. On the

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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 tenase
complexes, 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 ( M 2 ). 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 Ca 2+ (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 a
lesser 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 Ca 2+ (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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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
P.19
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 the
HKprekallikrein (or kallikrein) interaction prevent the
formation of plasmin on the endothelial cell surface (41).

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FIGURE 2-2. Fibrinolysis. Lines indicate binding; thin

arrows, transformation or stimulation; filled arrows,
transformation of zymogens to active enzymes; dashed
arrows, inhibition of active enzymes. 2 AP, 2 antiplasmin;
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 fibrin matrix renders it much

more resistant to plasmin action.

FIGURE 2-3. Contact system and fibrinolysis. Horizontal

arrows indicate transformation from zymogen to active
enzyme. Vertical or diagonal arrows indicate 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 and
disseminated intravascular coagulation.

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