The coagulation pathway

The process of blood coagulation is dependent upon a large number of blood clotting factors, which act in a sequential manner. At least 12 distinct factors participate in the coagulation cascade, along with several macromolecular cofactors. The clotting factors are all designated by Roman numerals (Table 12.1) and, with the exception of factor IV, all are proteins. Most factors are proteolytic zymogens, which become sequentially activated. An activated factor is indicated by inclusion of a subscript 'a' (e.g. factor Xlla is activated factor XII).

Although the final steps of the blood clotting cascade are identical, the initial steps can occur via two distinct pathways: extrinsic and intrinsic. Both pathways are initiated when specific clotting proteins make contact with specific surface molecules exposed only upon damage to a blood vessel. Clotting occurs much more rapidly when initiated via the extrinsic pathway.

Two coagulation factors function uniquely in the extrinsic pathway: factor III (tissue factor) and factor VII. Tissue factor is an integral membrane protein present in a wide variety of tissue types (particularly lung and brain). This protein is exposed to blood constituents only upon rupture of

Table 12.1 The coagulation factors that promote the blood clotting process. Note that the factor originally designated as VI was later shown to be factor Va

Factor

Pathway in which

number

Common name

it functions

Function

I

Fibrinogen

Both

Forms structural basis of clot after its conversion to fibrin

II

Prothrombin

Both

Precursor of thrombin, which activates factors I, V, VII,

VIII and XIII

III

Tissue factor

Extrinsic

Accessory tissue protein which initiates extrinsic

(thromboplastin)

pathway

IV

Calcium ions

Both

Required for activation of factor XIII and stabilizes some

factors

V

Proaccelerin

Both

Accessory protein, enhances rate of activation of X

VII

Proconvertin

Extrinsic

Precursor of convertin (VIIa) which activates X (extrinsic

system)

VIII

Antihaemophilic

Intrinsic

Accessory protein, enhances activation of X (intrinsic

factor

system)

IX

Christmas factor

Intrinsic

Activated IX directly activates X (intrinsic system)

X

Stuart factor

Both

Activated form (Xa) converts prothrombin to thrombin

XI

Plasma

Intrinsic

Activated form (XIa) serves to activate IX

thromboplastin

antecedent

XII

Hageman factor

Intrinsic

Activated by surface contact or the kallikrenin system.

XIIa helps initiate intrinsic system

XIII

Fibrin-stabilizing fa ptr*r

Both

Activated form cross-links fibrin, forming a hard clot

a blood vessel, and it initiates the extrinsic coagulation cascade at the site of damage as described below.

Factor VII contains a number of y-carboxyglutamate residues (as do factors II, IX and X), which play an essential role in facilitating their binding of Ca2+ ions. The initial events initiating the extrinsic pathway entail the interaction of factor VII with Ca2+ and tissue factor. In this associated form, factor VII becomes proteolytically active. It displays both binding affinity for, and catalytic activity against, factor X. It thus activates factor X by proteolytic processing, and factor Xa, which initiates the terminal stages of clot formation, remains attached to the tissue fac-tor-Ca2+ complex at the site of damage. This ensures that clot formation only occurs at the point where it is needed (Figure 12.1).

The initial steps of the intrinsic pathway are somewhat more complicated. This system requires the presence of clotting factors VIII, IX, XI and XII, all of which, except for factor VIII, are endo-acting proteases. As in the case of the extrinsic pathway, the intrinsic pathway is triggered upon exposure of the clotting factors to proteins present on the surface of body tissue exposed by vascular injury. These protein binding/activation sites probably include collagen.

Additional protein constituents of the intrinsic cascade include prekallikrein, an 88 kDa protein zymogen of the protease kallikrein, and high molecular mass kininogen, a 150 kDa plasma glyco-protein that serves as an accessory factor.

The intrinsic pathway appears to be initiated when factor XII is activated by contact with surface proteins exposed at the site of damage. High molecular mass kininogen also appears to form part of this initial activating complex (Figure 12.2).

Factor XIIa can proteolytically cleave and, hence, activate two substrates:

Figure 12.1 Schematic diagram of the initial steps of the extrinsic blood coagulation pathway. See text for details (TF: tissue factor)

Activating surface glycoprotein

Activating surface glycoprotein

Figure 12.2 The steps unique to the intrinsic coagulation pathway. Factor XIIa can also convert prekal-Likrein to kallikrein by proteolysis, but this is omitted for the sake of clarity. Full details are given in the main text. The final steps of the coagulation cascade, which are shared by both extrinsic and intrinsic pathways, are outlined in Figure 12.3

Figure 12.2 The steps unique to the intrinsic coagulation pathway. Factor XIIa can also convert prekal-Likrein to kallikrein by proteolysis, but this is omitted for the sake of clarity. Full details are given in the main text. The final steps of the coagulation cascade, which are shared by both extrinsic and intrinsic pathways, are outlined in Figure 12.3

• prekallikrein, yielding kallikrein (which, in turn, can directly activate more XII to XIIa).

Factor XIa, in turn, activates factor IX. Factor IXa then promotes the activation of factor X, but only when it (i.e. IXa) is associated with factor VIIIa. Factor VIIIa is formed by the direct action of thrombin on factor VIII. The thrombin will be present at this stage because of prior activation of the intrinsic pathway.

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