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

851
Endothelial cells
PAI-1
PAI-2
t-PA
Plasminogen
Plasmin
α 2 -AP
Fibrin
Smooth muscle cells/macrophages
Figure 30–3. Fibrinolysis. Endothelial cells secrete tissue plasminogen activator (t-PA) at sites of injury. t-PA binds to fibrin and
converts plasminogen to plasmin, which digests fibrin. Plasminogen activator inhibitors-1 and -2 (PAI-1, PAI-2) inactivate t-PA;
α 2
-antiplasmin (α 2
-AP) inactivates plasmin
Coagulation involves a series of zymogen activation
reactions, as shown in Figure 30–2 (Mann et al.,
2003). At each stage, a precursor protein, or zymogen, is
converted to an active protease by cleavage of one or more
peptide bonds in the precursor molecule. The components
at each stage include a protease from the preceding stage,
a zymogen, a non-enzymatic protein cofactor, Ca 2+ , and
an organizing surface that is provided by a phospholipid
emulsion in vitro or by activated platelets in vivo. The
final protease generated is thrombin.
Conversion of Fibrinogen to Fibrin. Fibrinogen, a 340,000-Da protein,
is a dimer, each half of which consists of three pairs of polypeptide
chains (designated Aα, Bβ, and γ). Disulfide bonds covalently
link the chains and the two halves of the molecule together. Thrombin
converts fibrinogen to fibrin monomers by releasing fibrinopeptide A
(a 16–amino acid fragment) and fibrinopeptide B (a 14–amino acid
fragment) from the amino termini of the Aα and Bβ chains, respectively.
Removal of the fibrinopeptides creates new amino termini,
which fit into pre-formed holes on other fibrin monomers to form a
fibrin gel, which is the end point of in vitro tests of coagulation (see
“Coagulation in vitro”). Initially, the fibrin monomers are bound to
each other non-covalently. Subsequently, factor XIII, a transglutaminase
that is activated by thrombin, catalyzes interchain covalent
cross-links between adjacent fibrin monomers, which enhance the
strength of the clot.
Structure of Coagulation Factors. In addition to factor XIII, the
coagulation factors include factors II (prothrombin), VII, IX, X, XI,
XII, and prekallikrein. A stretch of about 200 amino acid residues at
the carboxyl-termini of each of these zymogens exhibits homology
to trypsin and contains the active site of the proteases. In addition,
9-12 glutamate residues near the amino termini of factors II, VII, IX,
and X are converted to γ-carboxyglutamate (Gla) residues during
their biosynthesis in the liver. The Gla residues bind Ca 2+ and are
necessary for the coagulant activities of these proteins.
Nonenzymatic Protein Cofactors. Factors V and VIII, which are
homologous 350,000-Da proteins, serve as cofactors. Factor VIII
circulates in plasma bound to von Willebrand factor, while factor V
not only circulates in plasma but also is stored in platelets in a partially
activated form. Platelets release this stored factor V when they
are activated. Thrombin cleaves factors V and VIII to yield activated
cofactors (factors Va and VIIIa) that have at least 50 times greater
procoagulant activity than their nonactivated counterparts.
Factors Va and VIIIa serve as cofactors by binding to the surface
of activated platelets, where they act as receptors for factors Xa
and IXa, respectively. The activated cofactors also help localize prothrombin
and factor X, the respective substrates for these enzymes,
on the activated platelet surface. Assembly of these coagulation factor
complexes increases the catalytic efficiency of factors Xa and
IXa by ~10 9 -fold.
TF is a non-enzymatic lipoprotein cofactor; it initiates coagulation
by enhancing the catalytic efficiency of VIIa. Not normally
present on blood-contacting cells, TF is constitutively expressed
on the surface of subendothlial smooth muscle cells and fibroblasts,
which are exposed when the vessel wall is damaged. Lipidrich
cores of atherosclerotic plaques also are rich in TF, which
explains why atherosclerotic plaque disruption often triggers the
CHAPTER 30
BLOOD COAGULATION AND ANTICOAGULANT, FIBRINOLYTIC, AND ANTIPLATELET DRUGS