Cardiovascular Physiology
433
and permits the blood to contact the underlying tissue. This
contact initiates a locally occurring cascade of chemical activa-
tions. At each step of the cascade, an inactive plasma protein,
or “factor,” is converted (activated) to a proteolytic enzyme,
which then catalyzes the generation of the next enzyme in
the sequence. Each of these activations results from the split-
ting of a small peptide fragment from the inactive plasma pro-
tein precursor, thus exposing the active site of the enzyme.
However, several of the plasma protein factors, following their
activation, function not as enzymes but rather as cofactors for
the enzymes.
For simplicity, Figure 12–74 gives no specifi cs about the
cascade until the key point at which the plasma protein
pro-
thrombin
is converted to the enzyme
thrombin.
Thrombin
then catalyzes a reaction in which several polypeptides are
split from molecules of the large, rod-shaped plasma protein
fi brinogen. The fi
brinogen remnants then bind to each other
to form fi brin. The fi brin, initially a loose mesh of interlac-
ing strands, is rapidly stabilized and strengthened by the
enzymatically mediated formation of covalent cross-link-
ages. This chemical linking is catalyzed by an enzyme known
as factor XIIIa, which is formed from plasma protein factor
XIII in a reaction also catalyzed by thrombin.
Thus, thrombin catalyzes not only the formation of
loose fi brin but also the activation of factor XIII, which sta-
bilizes the fi brin network. But thrombin does even more than
this—it exerts a profound positive feedback effect on its own
formation. It does so by activating several proteins in the cas-
cade and also by activating platelets. Therefore, once thrombin
formation has begun, reactions leading to much more throm-
bin generation are activated by this initial thrombin. We will
make use of this crucial fact later when we describe the specif-
ics of the cascade leading to thrombin.
In the process of clotting, many erythrocytes and other
cells are trapped in the fi brin meshwork (
Figure 12–75
), but
the essential component of the clot is fi brin, and clotting can
occur in the absence of all cellular elements except platelets.
Activated platelets are essential because several of the cas-
cade reactions take place on the surface of the platelets. As
noted earlier, platelet activation occurs early in the hemo-
static response as a result of platelet adhesion to collagen, but
in addition, thrombin is an important stimulator of platelet
activation. The activation causes the platelets to display spe-
cifi c plasma membrane receptors that bind several of the clot-
ting factors, and this permits the reactions to take place on
the surface of the platelets. The activated platelets also display
particular phospholipids, called
platelet factor (PF),
which
function as a cofactor in the steps mediated by the bound clot-
ting factors.
In addition to protein factors, plasma calcium is required
at various steps in the clotting cascade. However, calcium
concentration in the plasma can never get low enough to
cause clotting defects because death would occur from muscle
paralysis or cardiac arrhythmias before such low concentrations
were reached.
Now we present the specifi cs of the early portions of the
clotting cascade—those leading from vessel damage to the
prothrombin-thrombin reaction. These early reactions consist
of two seemingly parallel pathways that merge at the step just
before the prothrombin-thrombin reaction. Under physiologi-
cal conditions, however, the two pathways are not parallel but
are actually activated sequentially, with thrombin serving as
the link between them. It will be clearer, however, if we fi rst
discuss the two pathways as though they were separate and
then deal with their actual interaction. The pathways are called
(1) the
intrinsic pathway,
so named because everything nec-
essary for it is in the blood; and (2) the
extrinsic pathway,
so
named because a cellular element outside the blood is needed.
Figure 12–76
will be an essential reference for this entire dis-
cussion. Also,
Table 12–13
is a reference list of the names of
and synonyms for the substances in these pathways.
The fi rst plasma protein in the intrinsic pathway (upper
left of Figure 12–76) is called factor XII. It can become acti-
vated to factor XIIa when it contacts certain types of surfaces,
Figure 12–75
Electron micrograph of erythrocytes enmeshed in fi brin.
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