s e c t io n 36.8
Anticoagulant Subsystem— Activation of Protein C and Inactivation of Factors Va and Villa
857
glycosaminoglycan is acting as a catalyst of a procoag-
ulant reaction. In contrast to the other stages of the pro-
coagulant subsystem, there is no known cofactor protein
involved in factor IX activation. The activation of factor
IX by factor XIa is not dependent on the presence of Ca2+,
although Ca2+ is certainly present in blood.
The Contact Phase of the
in V itro
Intrinsic Pathway of Coagulation
Figure 36-2 shows that two other reactions exist that are not
shown in Figure 36-3. These reactions, part of the “contact
phase” or “contact system,” are only important for
in vitro
clotting. Individuals with deficiencies in the components
of the “contact phase” do not suffer from bleeding.
The contact phase reactions are important for
in vitro
coagulation function testing using the activated partial
thromboplastin time test. This test is so named because it
was believed to involve nothing extrinsic to blood plasma.
Historically, the partial thromboplastin was considered to
be generated from plasma proteins alone and augmented
by phospholipid, a platelet substitute. Because the surface
of the glass test tube is a participant in the “contact re-
actions,” “intrinsic” is no longer an accurate distinction
between the two pathways.
The contact phase reactions involve two proteinase
precursors—factor XII and prekallikrein—and one co-
factor protein—plasma high-molecular-weight kininogen.
Activation of prekallikrein to form kallikrein occurs as a
consequence of proteolytic cleavage; however, activation
of factor XII does not obligatorily require proteolysis. Fac-
tor XII can be converted from an enzymatically inactive
molecule to an enzymatically active one through a con-
formation change that occurs when factor XII binds to the
surface of the glass test tube in which the plasma is con-
tained. In the commonly used laboratory test procedures,
the surface of fumed silica (very fine silica powder), kaolin
(an aluminosilicate clay), or ellagic acid (a dispersion of an
aromatic compound as fine droplets in aqueous solution)
is used (Figure 36-14).
36.8 Anticoagulant Subsystem— Activation
of Protein C and Inactivation of
Factors Va and Villa
The very large increases in the rates of activation of pro-
thrombin and factor X that occur in the presence of factors
Va and Villa, respectively, make the hemostatic response
both rapid and localized. However, if such rates were to
continue unabated, the extension of the hemostatic plug
F I G U R E 3 6 - 1 4
(Also see color figure.) Contact phase of
in vitro
coagulation. The contact
phase reactions involve two proteinase precursors—factor XII and
prekallikrein—and one cofactor protein—plasma high-molecular-weight
kininogen (HAWK). The structures, in bar diagrams, show the presence of
EGF-like fibronectin type I and type II, kringle, cystatin-like, and “apple”
motifs. The cleavage site for proteolytic activation of factor XII is Arg353
and for prekallikrein Arg371. The cofactor protein, HMWK, is cleaved by
kallikrein at Arg362 and Arg371 to release bradykinin (yellow). HMWK
contains a unique His-rich region that is associated with binding to the
contact surface (shown in light blue). Factor XI is a dimer of two identical
polypeptide chains that are linked by a single disulfide bridge. In the
circulating blood, factor Xlla cleaves the two Arg369-lie370 peptide bonds
in factor XI to form factor XIa. In the color version of this figure, other
motifs and domains are color coded as follows: apple domains (cyan),
EGF-like motifs (magenta), fibronectin motifs (yellow), kringle (orange),
and proteinase domain (green). Light chains are indicated in dark gray,
heavy chains in light gray. Regions connecting the motifs are black.
into the blood vessel would occlude the vessel and result in
ischemia and death to the adjacent cells and tissues. If the
pathologically extended hemostatic plug is in the venous
system, the separation of the occlusive plug (also desig-
nated clot, or red thrombus) can result in the clot being
sent to the lungs with consequent pulmonary embolism.
The proteinase activations of the procoagulant subsystem
are opposed by the cofactor protein inactivations of the
anticoagulant subsystem.
Protein C is activated by thrombin in the complex with
thrombomodulin to produce activated protein C, the pro-
teolytic inactivator of factors Va and Villa. The bind-
ing of thrombin to thrombomodulin changes thrombin
from a procoagulant proteinase to an anticoagulant pro-
teinase. Whereas the hemostatic reactions that prevent
blood loss at the injury site are associated with the ruptured
blood vessels, thrombomodulin is on the endothelium
(Figure 36-15).
Activation of protein C by thrombin occurs adjacent to
the injury site; inactivation of factors Va and Villa occurs
on the exposed surface at the injury site. Inactivation of
activated factors Va and Villa occurs by proteolysis of two
peptide bonds, both in each of the heavy chains (domains
A1 and A2, Figure 36-6) of factors Va and Villa. The con-
sequence of these cleavages is that the cofactor proteins
