Cardiovascular Physiology
factor X. The importance of factor VIII in clotting is empha-
sized by the fact that the disease
characterized by
excessive bleeding, is usually due to a genetic absence of this
factor. (In a smaller number of cases, hemophilia is due to an
absence of factor IX.)
Now we turn to the extrinsic pathway for initiating the
clotting cascade (upper right of Figure 12–76). This path-
way begins with a protein called
tissue factor,
which is not a
plasma protein. It is located instead on the outer plasma mem-
brane of various tissue cells, including fi broblasts and other
cells in the walls of blood vessels below the endothelium. The
blood is exposed to these subendothelial cells when vessel
damage disrupts the endothelial lining. Tissue factor on these
cells then binds a plasma protein, factor VII, which becomes
activated to factor VIIa. The complex of tissue factor and fac-
tor VIIa on the plasma membrane of the tissue cell then cata-
lyzes the activation of factor X. In addition, it catalyzes the
activation of factor IX, which can then help activate even more
factor X by way of the intrinsic pathway.
In summary, clotting can theoretically be initiated either
by the activation of factor XII or by the generation of the tissue
factor-factor VIIa complex. The two paths merge at factor Xa,
which then catalyzes the conversion of prothrombin to throm-
bin, which catalyzes the formation of fi
brin. As shown in Figure
12–76, thrombin also contributes to the activation of: (1) fac-
tors XI and VIII in the intrinsic pathway; and (2) factor V, with
factor Va then serving as a cofactor for factor Xa. Not shown in
the fi
gure is the fact that thrombin also activates platelets.
As stated earlier, under physiological conditions, the two
pathways just described actually are activated sequentially. To
understand how this works, turn again to Figure 12–76; hold
your hand over the fi rst part of the intrinsic pathway so that
you can eliminate the contact activation of factor XII and then
begin the next paragraph’s description at the top of the extrin-
sic pathway in the fi
(1) The extrinsic pathway, with its tissue factor, is the
usual way of initiating clotting in the body, and factor XII—
the beginning of the full intrinsic pathway—normally plays
little if any role (in contrast to its initiation of clotting in test
tubes or within the body in several unusual situations). Thus,
thrombin is initially generated only by the extrinsic path-
way. The amount of thrombin is too small, however, to pro-
duce adequate, sustained coagulation. (2) It
large enough,
though, to trigger thrombin’s positive feedback effects on the
intrinsic pathway—activation of factors XI and VIII and of
platelets. (3) This is all that is needed to trigger the intrinsic
pathway independently of factor XII. This pathway then gen-
erates the large amounts of thrombin required for adequate
coagulation. Thus, the extrinsic pathway, via its initial gen-
eration of small amounts of thrombin, provides the means for
recruiting the more potent intrinsic pathway without the par-
ticipation of factor XII. In essence, thrombin eliminates the
need for factor XII. Moreover, thrombin not only recruits the
intrinsic pathway, but facilitates the prothrombin-thrombin
step itself by activating factor V and platelets.
Finally, note that the liver plays several important indi-
rect roles in clotting (
Figure 12–77
), and as a result persons
with liver disease often have serious bleeding problems. First,
the liver is the site of production for many of the plasma clot-
ting factors. Second, the liver produces bile salts (Chapter 15),
and these are important for normal intestinal absorption of the
lipid-soluble substance
vitamin K.
The liver requires this vita-
min to produce prothrombin and several other clotting factors.
Anticlotting Systems
Earlier we described how the release of prostacyclin and
nitric oxide by endothelial cells inhibits platelet aggregation.
Because this aggregation is an essential precursor for clotting,
these agents reduce the magnitude and extent of clotting. In
addition, however, the body has mechanisms for limiting clot
formation itself and for dissolving a clot after it has formed.
Factors That Oppose Clot Formation
There are at least three different mechanisms that oppose clot
formation, once underway, thereby helping to limit this pro-
cess and prevent it from spreading excessively. Defects in any
of these natural anticoagulant mechanisms are associated with
abnormally high risk of clotting, a condition called
(see Chapter 19 for a case discussion of a patient
with this condition).
The fi rst anticoagulant mechanism acts during the ini-
tiation phase of clotting and utilizes the plasma protein called
tissue factor pathway inhibitor (TFPI),
which is secreted
mainly by endothelial cells. This substance binds to tissue
factor-factor VIIa complexes and inhibits the ability of these
complexes to generate factor Xa. This anticoagulant mecha-
nism is the reason that the extrinsic pathway by itself can gen-
erate only small amounts of thrombin.
The second anticoagulant mechanism is triggered by
thrombin. As illustrated in
Figure 12–78
, thrombin can
bind to an endothelial cell receptor known as
This binding eliminates all of thrombin’s clot-producing
effects and causes the bound thrombin to bind a particular
Vitamin K
in blood
GI tract
Absorbs vitamin K
Bile salts
in bile
bile salts
clotting factors
Clotting factors
in blood
Figure 12–77
Roles of the liver in clotting.
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