C h a p t e r 1 2
Disorders of Hemostasis
263
Blood coagulation is regulated by several natural antico-
agulants, such as antithrombin III and proteins C and S,
which work by inactivating some of the clotting factors.
The plasma also contains a plasma protein called
plas-
minogen
that gets activated and converted to plasmin,
an enzyme capable of digesting the fibrin strands of the
clot. In addition to removing clots that are no longer
needed, plasmin scavenges continually to prevent clots
from forming inappropriately.
Endothelium
The blood vessels themselves play an important role
in preventing and controlling the formation of blood
clots. Blood vessels are lined with endothelial cells that
modulate several, frequently opposing stages of normal
hemostasis. Under most circumstances endothelial cells
maintain an environment that promotes blood flow by
blocking platelet adhesion and activation, inhibiting the
coagulation process, and lysing blood clots. It should be
noted, however, that the endothelium can be activated
by infectious agents, hemodynamic factors, plasma
mediators, and cytokines that are liberated during an
inflammatory reaction.
An intact endothelial surface prevents platelets and
plasma coagulation factors from interacting with the
underlying thrombogenic subendothelial extracellular
matrix. Moreover, if platelets are activated, they are
inhibited from adhering to the surrounding uninjured
endothelium by endothelial prostacyclin (prostaglan-
din I
2
[PGI
2
]) and nitric oxide (see Chapter 18). Both of
these mediators are potent vasodilators and inhibitors
of platelet aggregation. Endothelial cells also elaborate
an enzyme called
adenosine diphosphatase
(ADP) that
degrades and further inhibits platelet aggregation. The
anticoagulant effects of endothelial cells are mediated by
membrane-bound heparin and thrombomodulin, both
of which inactivate thrombin (factor IIa). In addition,
endothelial cells synthesize tissue plasminogen activator,
promoting fibrinolytic activity that clears fibrin deposits
from endothelial cell surfaces.
Although endothelial cells exhibit properties that
inhibit blood clotting, they are also capable of exhibit-
ing numerous procoagulant properties in response to
injury and activation. An important function of activated
endothelial cells is the synthesis of von Willebrand factor,
which participates in platelet adhesion and blood clotting.
Clot Formation and Dissolution
Hemostasis is divided into five stages: (1) vessel spasm,
(2) formation of the platelet plug, (3) blood coagula-
tion or development of an insoluble fibrin clot, (4) clot
retraction, and (5) clot dissolution.
1
During the process
of hemostasis, hairlike fibrin strands glue the aggregated
platelets together and intertwine to form the structural
basis of the blood clot. In the presence of fibrin, plasma
becomes gel-like and traps red blood cells and other
formed elements in the blood (see Fig. 12-1). Hemostasis
is complete when fibrous tissue grows into the clot and
seals the hole in the vessel.
Vessel Spasm
Vessel spasm is initiated by endothelial injury and caused
by local and humoral mechanisms. It is a transient event,
usually lasting less than one minute, that results from
neural reflexes and humoral factors released from plate-
lets and traumatized tissue.
1
For smaller vessels, release
of the vasoconstrictor TXA
2
is responsible for much of
the vessel spasm.
Platelet Plug Formation
The platelet plug, the second line of defense, is initi-
ated as platelets come in contact with the vessel wall.
Small breaks in the vessel wall are often sealed with
the platelet plug rather than with a blood clot. Platelet
plug formation involves adhesion, granule release, and
aggregation of platelets.
3
Platelets are attracted to a
damaged vessel wall, become activated, and change
from smooth disks to spiny spheres, exposing glyco-
protein receptors on their surfaces. Platelet adhesion
requires a protein molecule called
von Willebrand
factor
(vWF). This factor is produced by both mega-
karyocytes and endothelial cells and circulates in the
blood as a carrier protein for coagulation factor VIII.
Adhesion to the vessel subendothelial layer occurs
when the platelet membrane receptor binds to vWF at
the injury site, linking the platelet to exposed collagen
fibers.
Degranulation and release of the contents of both
the
α
- and
δ
-granules occur soon after platelet adhe-
sion. The
δ
-granule contents’, including calcium, is
required for the coagulation component of hemostasis.
3
The binding of ADP to the platelet membrane induces
a conformation change of the gpIIb/IIIa receptors,
allowing them to bind fibrinogen and form aggregates.
Besides ADP, platelets secrete the prostaglandin TXA
2
,
which is an important stimulus for platelet aggrega-
tion. The combined actions of ADP and TXA
2
lead
to the expansion of the enlarging platelet aggregate,
which is called the
primary hemostatic platelet plug
.
Conversion of the primary platelet plug into a definitive
clot (known as a
secondary hemostatic plug
) occurs as
the coagulation pathway is activated on the surface of
the aggregated platelets and fibrinogen is converted to
fibrin (factor Ia), thereby creating a fibrin meshwork
that cements the platelets and other blood components
together.
Platelet aggregation inhibitors, including aspirin,
clopidogrel (Plavix), and ticlopidine (Ticlid), can be
used to prevent platelet aggregation and clot forma-
tion in persons who are at risk for myocardial infarc-
tion, stroke, or peripheral artery disease.
6,7
Low-dose
aspirin therapy inhibits prostaglandin synthesis,
including TXA
2
. Clopidogrel and ticlopidine achieve
their antiplatelet effects by inhibiting the ADP path-
way in platelets. Unlike aspirin, these drugs have no
effect on prostaglandin synthesis. Drugs that act as
gpIIb/IIIa receptor inhibitors (abciximab, eptifibatide,
tirofiban) have been developed for use in the treat-
ment of persons with acute coronary syndromes (see
Chapter 19).
7
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