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

degradation, α 2
-antiplasmin rapidly inhibits any plasmin
that escapes from this local milieu. To prevent premature
clot lysis, factor XIIIa mediates the covalent
cross-linking of small amounts of α 2
-antiplasmin onto
fibrin.
When thrombi occlude major arteries or veins,
therapeutic doses of plasminogen activators sometimes
are administered to degrade the fibrin and rapidly
restore blood flow. In high doses, these plasminogen
activators promote the generation of so much plasmin
that the inhibitory controls are overwhelmed. Plasmin
is a relatively nonspecific protease; it not only digests
fibrin but also degrades other plasma proteins, including
several coagulation factors. Reduction in the levels
of these coagulation proteins impairs the capacity for
thrombin generation, which can contribute to bleeding.
In addition, unopposed plasmin tends to dissolve fibrin
in hemostatic plugs as well as that in pathological
thrombi, a phenomenon that also increases the risk of
bleeding. Therefore, fibrinolytic drugs can be toxic,
producing hemorrhage as their major side effect. The
pathway of fibrinolysis and sites of pharmacological
perturbation are summarized in Figure 30–3.
Coagulation in vitro. Whole blood normally clots in 4-8 minutes
when placed in a glass tube. Clotting is prevented if a chelating agent
such as ethylenediaminetetraacetic acid (EDTA) or citrate is added
to bind Ca 2+ . Recalcified plasma normally clots in 2-4 minutes. The
clotting time after recalcification is shortened to 26-33 seconds by
the addition of negatively-charged phospholipids and a particulate
substance, such as kaolin (aluminum silicate) or celite (diatomaceous
earth), which activates factor XII; the measurement of this is termed
the activated partial thromboplastin time (aPTT). Alternatively,
recalcified plasma clots in 12-14 seconds after addition of “thromboplastin”
(a mixture of TF and phospholipids); the measurement of
this is termed the prothrombin time (PT).
Two pathways of coagulation are recognized. An individual
with a prolonged aPTT and a normal PT is considered to have a
defect in the intrinsic coagulation pathway because all of the components
of the aPTT test (except kaolin or celite) are intrinsic to the
plasma. A patient with a prolonged PT and a normal aPTT has a
defect in the extrinsic coagulation pathway because thromboplastin
is extrinsic to the plasma. Prolongation of both the aPTT and the PT
suggests a defect in a common pathway.
Natural Anticoagulant Mechanisms. Platelet activation and
coagulation do not normally occur within an intact blood
vessel (Edelberg et al., 2001). Thrombosis is prevented
by several regulatory mechanisms that require a healthy
vascular endothelium. Nitric oxide and prostacyclin
(PGI 2
) are synthesized by endothelial cells and released
into the blood (Chapter 33). These substances induce
vasodilation and inhibit platelet activation and subsequent
aggregation.
Antithrombin is a plasma protein that inhibits
coagulation enzymes of the intrinsic and common pathways
(see “Mechanism of Action”). Heparan sulfate
proteoglycans synthesized by endothelial cells enhance
the activity of antithrombin by ~1000-fold. Another
regulatory system involves protein C, a plasma zymogen
that is homologous to factors II, VII, IX, and X;
its activity depends on the binding of Ca 2+ to Gla
residues within its amino-terminal domain. Thrombin
activates protein C, but the efficiency of this reaction
increases by several orders of magnitude when thrombin
binds to thrombomodulin, its receptor on the
surface of endothelial cells (Esmon, 2003). Protein C
binds to another endothelial cell receptor, endothelial
protein C receptor (EPCR), which presents protein C
to the thrombin–thrombomodulin complex for activation.
Activated protein C then dissociates from EPCR
and, in combination with protein S, its non-enzymatic
Gla-containing cofactor, activated protein C degrades
factors Va and VIIIa. Without these activated cofactors,
the rates of activation of prothrombin and factor X are
greatly diminished. Therefore, activated protein C
downregulates thrombin generation (Esmon, 2006).
Deficiency of protein C or protein S is associated with
an increased risk of pathological thrombus formation
and tissue necrosis associated with the use of warfarin
(see the “Warfarin” section, later in the chapter).
With antithrombin requiring endogenous heparan
sulfate for its full activity and protein C requiring activation
by thrombomodulin-bound thrombin, the effects
of both of these natural anticoagulants are localized to
the vicinity of intact endothelial cells. Tissue factor
pathway inhibitor (TFPI), a natural anticoagulant found
in the lipoprotein fraction of plasma, also regulates
thrombin generation by inhibiting TF-bound factor VIIa
in a two-step fashion. TFPI first binds and inhibits factor
Xa, and this binary complex then inhibits factor
VIIa. Therefore, factor Xa regulates its own generation
through this mechanism. TFPI also can localize on the
endothelial cell surface by binding to heparan sulfate
proteoglycans.
PARENTERAL ANTICOAGULANTS
Heparin and Its Derivatives
Biochemistry. Heparin, a glycosaminoglycan found
in the secretory granules of mast cells, is synthesized
from UDP-sugar precursors as a polymer of alternating
D-glucuronic acid and N-acetyl-D-glucosamine residues
(Sugahara and Kitagawa, 2002).
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CHAPTER 30
BLOOD COAGULATION AND ANTICOAGULANT, FIBRINOLYTIC, AND ANTIPLATELET DRUGS