s e c t io n 36.6

The Extrinsic Pathway

855

F IG U R E 3 6 -1 1

(Also see color figure.) Tissue factor-factor Vila complex. The three-dimensional structure of the complex of factor

Vila and tissue factor (minus the transmembrane polypeptide domain of the tissue factor) in the absence of membrane

surface. It is approximately 115 A in length and has a diameter of 40-50 A. Factor Vila shows its four distinct domains:

the Gla domain, two EGF-like domains, and the proteinase domain. Tissue factor contacts factor Vila via the interface

between the two “fibronectin type Ill-like” domains. All four domains of factor Vila appear to be involved in the

interaction between tissue factor and factor Vila. The Gla domain of factor Vila is folded very similarly to the Gla

domain of prothrombin (Gla domain of prothrombin fragment 1

). Activation of factor VII can be catalyzed by thrombin,

factor Xa, factor Vila, and factor Xlla—all by cleavage at Arg152-Ile153. Secondary structures are shown in the center

diagram; two views of the close interactions between TF and factor Vila are shown in the two diagrams at each side.

produce factor Vila. Factor Vila is detectable in extremely

low concentration in the circulating blood of normal indi-

viduals. Low levels of factor Vila can be measured in an

assay that employs recombinant tissue factor that is miss-

ing the transmembrane and inner membrane domains. The

trace amounts of factor Vila that are present are proba-

bly sufficient to initiate the clotting process upon injury-

related exposure of tissue factor and membrane lipids.

The complex of tissue factor and factor Vila is shown in

Figure 36-11.

In vitro

other activators of factor VII exist, e.g., factor

Xlla, kallikrein, and factor XIa. The physiological signifi-

cance, i.e.,

in vivo

significance of these activators of factor

VII is unknown, although the presence of factor Xlla may

create risk of thrombosis.

In vitro,

factor VII becomes fac-

tor Vila upon storage in the cold, a process that involves

factor Xlla. Factor Xlla presumably is generated from fac-

tor XII through binding of the components of the

contact

phase

of

in vitro

clotting to the containers in which the

blood or plasma is being stored. Activation of factor VII by

factor Xlla does not require the presence of Ca2+ ions, and

therefore this activation occurs in anticoagulated blood or

plasma. Higher concentrations of factor Vila have been

shown by epidemiological studies to increase the risk of

thrombosis, whereas individuals with factor VII deficiency

appear to have a lower thrombotic risk.

Activation of Factor X by Factor VH(VIIa)

Factor X is activated by a single peptide bond cleavage,

Arg

5 1

-Ile

5 2

in the heavy chain of the proenzyme. The ac-

tivation peptide is highly glycosylated, as are many of the

activation peptides of the procoagulant proenzymes. The

lie

5 2

residue subsequently forms the “salt bridge” with

Asp

1 9 4

(chymotrypsin numbering) in the heavy chain, thus

enabling formation of the catalytic apparatus of factor Xa.

In the absence of tissue factor, factor Vila cleaves the

Arg

51

peptide bond in factor X at a rate so low that it is not

readily detectable

in vitro.

In the presence of tissue factor

and membrane surface phospholipids, factor Vila rapidly

activates factor X. The estimates for the magnitude of the

increase in activation rates in the presence of tissue factor