DƯỢC LÍ Goodman & Gilman's The Pharmacological Basis of Therapeutics 12th, 2010

852 formation of a superimposed thrombus that can occlude the lumen
of the vessel.
When exposed to stimuli such as endotoxin, tumor necrosis
factor, or interleukin-1, monocytes also express TF on their surface.
Circulating TF-bearing monocytes and membrane fragments derived
from them, known as microparticles, contribute to thrombosis. In
response to inflammatory stimuli or products of coagulation, such as
thrombin, endothelial cells express adhesion molecules, which tether
these monocytes and microparticles onto their surface. This augments
coagulation by delivering more TF to sites of injury. TF-bearing
monocytes and microparticles also home to thrombi by binding to
P-selectin expressed on the surface of activated platelets. Additional
TF from these sources maintains coagulation and promotes thrombus
expansion.
Another plasma protein, high-molecular-weight kininogen, also
serves as a cofactor. Negatively charged surfaces, such as catheters,
stents, and other blood-contacting medical devices, activate factor XII
in a reaction enhanced by high-molecular-weight kininogen. Factor
XIIa then propagates coagulation by activating factor XI, a reaction
also enhanced by high-molecular-weight kininogen. In the presence of
activated platelets, thrombin also activates factor XI, thereby bypassing
factor XIIa.
SECTION III
MODULATION OF CARDIOVASCULAR FUNCTION
Activation of Prothrombin. By cleaving two peptide bonds on prothrombin,
factor Xa converts it to thrombin. In the presence of factor
Va, a negatively charged phospholipid surface, and Ca 2+ , factor
Xa activates prothrombin with 10 9 -fold greater efficiency. The maximal
rate of activation only occurs when prothrombin and factor Xa
contain Gla residues, which endow them with the capacity to bind to
phospholipids. Artificial mixtures of anionic phospholipids substitute
for activated platelets in laboratory tests of coagulation. However,
activated platelets not only provide a surface for coagulation factor
assembly but also release factor Va, which may be more important
than circulating factor Va for thrombin generation.
Initiation of Coagulation. Under most circumstances, TF
exposed at sites of vessel wall injury initiates coagulation
via the extrinsic pathway. The small amount of factor
VIIa circulating in plasma binds subendothelial TF
and the TF-factor VIIa complex, then activates factors
X and IX (Figure 30–2). In the absence of TF, factor
VIIa has minimal activity. When bound to TF in the
presence of anionic phospholipids and Ca 2+ , the activity
of factor VIIa increases about 30,000-fold.
The intrinsic pathway is initiated in vitro when factor
XII, prekallikrein, and high-molecular-weight kininogen
interact with kaolin, glass, or another surface to
generate small amounts of factor XIIa. Activation of factor
XI to factor XIa and factor IX to factor IXa follows.
Factor IXa then activates factor X in a reaction accelerated
by factor VIIIa, anionic phospholipids, and Ca 2+ .
Optimal thrombin generation depends on the formation
of this factor IXa complex because it activates factor X
more efficiently than the TF-factor VIIa complex. The
bleeding that occurs in hemophiliacs who are deficient in
factor IX or factor VIII highlights the importance of the
factor IXa–factor VIIIa complex in thrombin generation.
Activation of factor XII is not essential for hemostasis, as evidenced
by the fact that patients deficient in factor XII, prekallikrein,
or high-molecular-weight kininogen do not have excessive bleeding.
Factor XI deficiency is associated with a variable and usually mild
bleeding disorder. The mechanism responsible for factor XI activation
in vivo is unknown. Activation may occur through feedback activation
of factor XI by thrombin. Alternatively, factor XIIa may
activate factor XI after injury to the vessel wall because there is evidence
that RNA released from damaged cells activates factor XII
and administration of RNA-degrading enzymes to mice attenuates
thrombus formation after arterial injury.
Fibrinolysis. The fibrinolytic system dissolves intravascular
fibrin through the action of plasmin. To initiate fibrinolysis,
plasminogen activators first convert single-chain
plasminogen, an inactive precursor, into two-chain plasmin
by cleavage of a specific peptide bond. There are two
distinct plasminogen activators; tissue plasminogen activator
(t-PA) and urokinase plasminogen activator (u-PA),
or simply urokinase. Although both activators are synthesized
by endothelial cells, t-PA predominates under most
conditions and drives intravascular fibrinolysis. In contrast,
synthesis of u-PA mainly occurs in response to
inflammatory stimuli, and u-PA promotes extravascular
fibrinolysis.
The fibrinolytic system is regulated such that
unwanted fibrin thrombi are removed, while fibrin in
wounds is preserved to maintain hemostasis (Lijnen and
Collen, 2001). t-PA is released from endothelial cells in
response to various stimuli, including the stasis that occurs
when thrombi occlude vessels. Released t-PA is rapidly
cleared from blood or inhibited by plasminogen activator
inhibitor-1 (PAI-1) and, to a lesser extent, plasminogen
activator inhibitor-2 (PAI-2); t-PA thus exerts little effect
on circulating plasminogen in the absence of fibrin.
α 2
-antiplasmin rapidly inhibits any plasmin that is generated.
However, when fibrin is present, t-PA binds to it, as
does plasminogen. The catalytic efficiency of t-PA activation
of plasminogen increases over 300-fold in the presence
of fibrin, which promotes plasmin generation on its
surface. Plasmin then degrades the fibrin.
Plasminogen and plasmin bind to lysine residues
on fibrin via five loop-like regions near their amino termini,
which are known as kringle domains. To inactivate
plasmin, α 2
-antiplasmin binds to the first of these
kringle domains and then blocks the active site of
plasmin. Because the kringle domains are occupied
when plasmin binds to fibrin, plasmin on the fibrin surface
is protected from inhibition by α 2
-antiplasmin and
can digest the fibrin. Once the fibrin clot undergoes