856
c h a p t e r 36
Biochemistry of Hemostasis
F actor X -------- ►
A ctivated F actor X
+
АР (X]
1
1 4 3
1 9 5
4 4 8
T________ I
I________________
7
шшт
шяшяшяяш
Factor X
F IG U R E 3 6 -1 2
(Also see color figure.) Activation of factor X. Factor X is activated by
factor Vila through a single peptide bond cleavage, Arg51 -lie52 in the
heavy chain of the proenzyme. The activation peptide is highly
glycosylated as are many of the activation peptides of the procoagulant
proenzymes. Factor X is converted to factor Xa by factor IXa through
cleavage of the same peptide bond that is cleaved by factor Vila. In the
color version of this figure, motifs and domains are color coded as follows:
Gla domain (blue), EGF-like domain (magenta), activation peptide
(yellow), and proteinase domain (green). Light chains are indicated in dark
gray, heavy chains in light gray. Regions connecting the motifs are black.
and membrane surface are approximately 500,000 times.
The activation of factor X by factor Vila in the activation
complex thus follows the same general behavior of the
activation of prothrombin. A high rate of activation occurs
only in the complex, partly the result of a decrease in
Km,
and partly the result of an increase in
kc.
The activation of
factor X and the motifs present in the molecule are shown
in Figure 36-12. A unique inhibitor unlike the SERPINS
can modulate the activation of factor X by factor Vila and
tissue factor. The inhibitor, tissue factor pathway inhibitor
(TFPI), or extrinsic pathway inhibitor (EPI), is related to
the Kunitz-type pancreatic proteinase inhibitors.
36.7 The Intrinsic Pathway
Activation of Factor X
Factor IXa, factor Villa, and the phospholipid surface
compose the “intrinsic pathway” activator of factor X. Fac-
tor VIII, as described above, is activated prior to its becom-
ing functional in the activation of factor X by factor IXa.
Although the similarities in the activation of factor V and
factor VIII are extensive, factor VIII in the plasma differs
from factor V in a unique way. Whereas factor V circu-
lates as a single molecule, factor VIII is bound to the von
Willebrand factor that acts as a carrier and as a stabilizer
for factor VIII and may modulate its activity. Because of
the binding of vWF to collagen in the subendothelium
and to the platelet receptor Gplb, factor VIII is preferen-
tially associated with the hemostatic plug at the injury site.
This association provides an additional mechanism that is
distinct from factor VIII binding to the membrane lipids.
Some cases that appear to be factor VIII deficiency (classi-
cal hemophilia) can result from defective von Willebrand
factor and can be treated by increasing the quantity of vWF
rather than of factor VIII.
Factor X is converted to factor Xa by factor IXa by
cleavage of the same Arg
5
'-lie
5 2
peptide bond that is
cleaved by factor Vila and with the release of the same ac-
tivation peptide. The relative rates of activation are again
100,000-500,000 times greater in the complex than in so-
lution, i.e., with the proteinase and protein substrate alone
(Figure 36-12).
Activation of Factor IX by Factor Vila
and Tissue Factor
Factor IX can be activated by the complex containing fac-
tor Vila, tissue factor, phospholipid bilayer surface, and
Ca2+ ions. This “crossover” reaction for factor IX activa-
tion, although perhaps not strictly a reaction of the “intrin-
sic pathway,” contributes about half of the factor IXa that
is formed in situations in which tissue factor is present.
Factor IX is activated as the result of the cleavage of two
peptide bonds, Arg
145
and Argl
8 0
-Ile
181
(Figure 36-13).
Activation of Factor IX by Factor XIa
In the classical reaction of the “intrinsic pathway,” fac-
tor IXa is formed from factor IX by the action of factor
XIa (the proteinase). The “surface” for this reaction is
believed to be a glycosaminoglycan, a sugar polymer to
which factor IX and factor XIa can bind. In this situa-
tion, the “surface” is actually a two-dimensional polymer
that acts as a tether between the molecules and on which
they can migrate toward or away from each other. As gly-
cosaminoglycans are found on the surfaces of both en-
dothelial and subendothelial cells, such a two-dimensional
surface is a good candidate for promoting complex for-
mation at this stage of the procoagulant pathway. The
F a cto r IX ------► F a cto r IXa + P e p tid e
1
1 8 0
4 1 5
T________ I__________T
Factor IX
F I G U R E 3 6 - 1 3
(Also see color figure.) Activation of factor IX. Factor IX is activated by
cleavage of two peptide bonds, Arg145 and Arg180-Val181 The activation
peptide that is released is composed of 35 amino acid residues and is
highly glycosylated. The same peptide bonds are cleaved by factor Vila
and factor XIa. Glycosaminoglycans, particularly heparin, can increase the
rate of activation as the result of the binding of both factor XIa and factor
IX to the heparin molecule to form a ternary complex. Color coding is as
described in Figure 36-12.
