414 Chapter 13
able to bind to the exposed collagen fibers. The force of blood
flow might pull the platelets off the collagen, however, were it
not for another protein produced by endothelial cells known as
von Willebrand’s factor ( fig. 13.7 b ), which binds to both col-
lagen and the platelets.
Platelets contain secretory granules; when platelets stick to
collagen, they degranulate as the secretory granules release their
products. These products include adenosine diphosphate (ADP),
serotonin, and a prostaglandin called thromboxane A 2 (chapter 11;
see fig. 11.34). This event is known as the platelet release
reaction. The ADP and thromboxane A 2 released from acti-
vated platelets recruits new platelets to the vicinity and makes
them “sticky,” so that they adhere to those stuck on the collagen
( fig. 13.7 b ). The second layer of platelets, in turn, undergoes a
platelet release reaction, and the ADP and thromboxane A 2 that
are secreted cause additional platelets to aggregate at the site of
the injury. This produces a platelet plug ( fig. 13.7 c ) in the dam-
aged vessel.
The activated platelets also help to activate plasma clotting
factors, leading to the conversion of a soluble plasma protein
known as fibrinogen into an insoluble fibrous protein, fibrin.
There are binding sites on the platelet’s plasma membrane for
fibrinogen and fibrin, so that these proteins help join platelets
together and strengthen the platelet plug ( fig. 13.7 c ). The clot-
ting sequence leading to fibrin formation is discussed in the
next topic.the pregnancy. At the time of birth, however, a variable degree
of exposure may occur, and the mother’s immune system may
become sensitized and produce antibodies against the Rh anti-
gen. This does not always occur, however, because the expo-
sure may be minimal and because Rh-negative women vary in
their sensitivity to the Rh factor. If the woman does produce
antibodies against the Rh factor, these antibodies could cross
the placenta in subsequent pregnancies and cause hemolysis of
the Rh-positive red blood cells of the fetus. Therefore, the baby
could be born anemic with a condition called erythroblastosis
fetalis, or hemolytic disease of the newborn.
Erythroblastosis fetalis can be prevented by injecting the Rh-
negative mother with an antibody preparation against the Rh fac-
tor (a trade name for this preparation is RhoGAM—the GAM is
short for gamma globulin, the class of plasma proteins in which
antibodies are found) within 72 hours after the birth of each Rh-
positive baby. This is a type of passive immunization in which the
injected antibodies inactivate the Rh antigens and thus prevent
the mother from becoming actively immunized to them. Some
physicians now give RhoGAM throughout the Rh-positive preg-
nancy of any Rh-negative woman.
Blood Clotting
When a blood vessel is injured, a number of physiological
mechanisms are activated that promote hemostasis, or the ces-
sation of bleeding ( hemo 5 blood; stasis 5 standing). Breakage
of the endothelial lining of a vessel exposes collagen proteins
from the subendothelial connective tissue to the blood. This ini-
tiates three separate, but overlapping, hemostatic mechanisms:
(1) vasoconstriction, (2) the formation of a platelet plug, and
(3) the production of a web of fibrin proteins that penetrates and
surrounds the platelet plug.
Platelets and Blood Vessel Walls
In the absence of blood vessel damage, platelets are repelled
from each other and from the endothelium of blood vessels.
The endothelium is a simple squamous epithelium that overlies
connective tissue collagen and other proteins that are capable of
activating platelets to begin clot formation. Thus, an intact endo-
thelium physically separates the blood from collagen and other
platelet activators in the vessel wall. In addition, the endothelial
cells secrete prostacyclin (or PGI 2 , a type of prostaglandin—see
chapter 11, fig. 11.34) and nitric oxide (NO), which (1) act as
vasodilators and (2) act on the platelets to inhibit platelet aggre-
gation. In addition, the plasma membrane of endothelial cells
contains an enzyme known as CD39, which has its active site
facing the blood. The CD39 enzyme breaks down ADP in the
blood to AMP and P i (ADP is released by activated platelets and
promotes platelet aggregation, as described shortly). These pro-
tective mechanisms are needed to ensure that platelets don’t stick
to the vessel wall and to each other, so that the flow of blood is
not impeded when the endothelium is intact ( fig. 13.7 a ).
When a blood vessel is injured and the endothelium is bro-
ken, glycoproteins in the platelet’s plasma membrane are now
CLINICAL APPLICATION
Platelet aggregation inhibitors are medically useful to pre-
vent clot formation and coronary thrombosis, a major cause
of myocardial infarction (“heart attack”; see section 13.7).
Aspirin irreversibly inhibits the enzyme cyclooxygenase,
which is required for prostaglandin formation (chapter 11; see
fig. 11.34). Aspirin thereby inhibits the ability of platelets to
produce the prostaglandin thromboxane A 2 , which is needed
for platelet aggregation. Since platelets are not complete cells,
they cannot regenerate new enzymes; aspirin thus inhibits
cyclooxygenase for the life of the platelets. Other drugs that
operate by different mechanisms to affect platelet function are
also available. For example, Clopidogrel ( Plavix ) inhibits the
ability of ADP to promote platelet aggregation, and dipyridam-
ole interferes with the ability of platelets to produce ADP. Gly-
coprotein IIb/IIIa drugs are monoclonal antibodies that block
the platelet plasma membrane receptors needed for platelets
to bind to collagen and to Von Willebrand factor ( fig. 13.7 ), pre-
venting platelets from sticking to the wound site.Clotting Factors: Formation of Fibrin
The platelet plug is strengthened by a meshwork of insoluble
protein fibers known as fibrin ( fig. 13.8 ). Blood clots there-
fore are composed of platelets and fibrin, and they usually
contain trapped red blood cells that give the clot a red color