s e c t io n 36.6
The Extrinsic Pathway
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
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,
5 1
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
5 2
residue subsequently forms the “salt bridge” with
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
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
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