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22
Pharmacology of Hemostasis and
Thrombosis
April Wang Armstrong and David E. Golan
Introduction Anticoagulants
Case Warfarin
Physiology of Hemostasis Unfractionated and Low Molecular Weight
Vasoconstriction Heparins
Primary Hemostasis Selective Factor Xa Inhibitors
Platelet Adhesion Direct Thrombin Inhibitors
Platelet Granule Release Reaction Recombinant Activated Protein C (r-APC)
Platelet Aggregation and Consolidation Thrombolytic Agents
Secondary Hemostasis: The Coagulation Cascade Streptokinase
Regulation of Hemostasis
Recombinant Tissue Plasminogen Activator (t-
Pathogenesis of Thrombosis
Endothelial Injury PA)
Abnormal Blood Flow Tenecteplase
Hypercoagulability Reteplase
Pharmacologic Classes and Agents Inhibitors of Anticoagulation and Fibrinolysis
Antiplatelet Agents Protamine
Cyclooxygenase Inhibitors Serine-Protease Inhibitors
Phosphodiesterase Inhibitors Lysine Analogues
ADP Receptor Pathway Inhibitors Conclusion and Future Directions
GPIIbIIIa Antagonists Suggested Readings
387
LP-FPPP-92900 R1 CH22 01-15-07 10:08:23
pain persists. He is taken to the cardiac catheterization labo- The goal of the final two stages of hemostasis is to form
ratory, where he is found to have a 90% mid-LAD (left a stable, permanent plug. During secondary hemostasis,
anterior descending artery) thrombus with sluggish distal also known as the coagulation cascade, the activated endo-
flow. He undergoes successful angioplasty and stent place- thelium and other nearby cells (see below) express a mem-
ment. At the time of stent placement, an intravenous load- brane-bound procoagulant factor called tissue factor, which
ing dose of clopidogrel is administered. The heparin is complexes with coagulation factor VII to initiate the coagu-
stopped, the eptifibatide is continued for 18 more hours, lation cascade. The end result of this cascade is the activation
and he is transferred to the telemetry ward. Six hours later, of thrombin, a critical enzyme. Thrombin serves two pivotal
Mr. Soprano is noted to have an expanding hematoma (an functions in hemostasis: (1) it converts soluble fibrinogen
area of localized hemorrhage) in his right thigh below the to an insoluble fibrin polymer that forms the matrix of the
arterial access site. The eptifibatide is stopped and pressure clot; and (2) it induces more platelet recruitment and activa-
is applied to the access site, and the hematoma ceases to tion. Recent evidence indicates that fibrin clot formation
expand. He is discharged 2 days later with prescriptions for (secondary hemostasis) overlaps temporally with platelet
plug formation (primary hemostasis), and that each process
clopidogrel and aspirin, which are administered to prevent
reinforces the other. During the final stage, platelet aggrega-
subacute thrombosis of the stent.
tion and fibrin polymerization lead to the formation of a
stable, permanent plug. In addition, antithrombotic mech-
QUESTIONS anisms restrict the permanent plug to the site of vessel in-
jury, ensuring that the permanent plug does not inappro-
1. How did a blood clot arise in Mr. Sopranos coronary priately extend to occlude the vascular tree.
artery?
2. If low molecular weight heparin had been used
instead of unfractionated heparin, how would the VASOCONSTRICTION
monitoring of the patients coagulation status during
the procedure have been affected? Transient arteriolar vasoconstriction occurs immediately
3. What accounts for the efficacy of eptifibatide (a after vascular injury. This vasoconstriction is mediated by
platelet GPIIbIIIa antagonist) in inhibiting platelet a poorly understood reflex neurogenic mechanism. Local
aggregation? endothelial secretion of endothelin, a potent vasoconstric-
4. When the expanding hematoma was observed, tor, potentiates the reflex vasoconstriction. Because the
could any measure other than stopping the vasoconstriction is transient, bleeding would continue if pri-
mary hemostasis were not activated.
eptifibatide have been used to reverse the effect of
this agent?
5. How do aspirin, heparin, clopidogrel, and epti- PRIMARY HEMOSTASIS
fibatide act in the attempt to treat Mr. Sopranos
blood clot and to prevent recurrent thrombus
The goal of primary hemostasis is to form a platelet plug
formation?
that rapidly stabilizes vascular injury. Platelets play a pivotal
role in primary hemostasis. Platelets are cell fragments that
arise by budding from megakaryocytes in the bone marrow;
these small, membrane-bound discs contain cytoplasm but
PHYSIOLOGY OF HEMOSTASIS lack nuclei. Glycoprotein receptors in the platelet plasma
membrane are the primary mediators by which platelets are
activated. Primary hemostasis involves the transformation
An injured blood vessel must induce the formation of a blood of platelets into a hemostatic plug through three reactions:
clot to prevent blood loss and to allow healing. Clot forma- (1) adhesion; (2) the granule release reaction; and (3) aggre-
tion must also remain localized to prevent widespread clot- gation and consolidation.
ting within intact vessels. The formation of a localized clot
at the site of vessel injury is accomplished in four temporally
overlapping stages (Fig. 22-1). First, localized vasocon- Platelet Adhesion
striction occurs as a response to a reflex neurogenic mecha-
In the first reaction, platelets adhere to subendothelial colla-
nism and to the secretion of endothelium-derived vasocon-
gen that is exposed after vascular injury (Fig. 22-2). This
strictors such as endothelin. Immediately following adhesion is mediated by von Willebrand factor (vWF), a
vasoconstriction, primary hemostasis occurs. During this large multimeric protein that is secreted by both activated
stage, platelets are activated and adhere to the exposed sube- platelets and the injured endothelium. vWF binds both to
ndothelial matrix. Platelet activation involves both a change surface receptors (especially glycoprotein Ib [GPIb]) on the
in shape of the platelet and the release of secretory granule platelet membrane and to the exposed collagen; this bridg-
contents from the platelet. The secreted granule substances ing action mediates adhesion of platelets to the collagen.
recruit other platelets, causing more platelets to adhere to The GPIb:vWF:collagen interaction is critical for initiation
the subendothelial matrix and to aggregate with one another of primary hemostasis, because it is the only known molecu-
at the site of vascular injury. Primary hemostasis ultimately lar mechanism by which platelets can adhere to the injured
results in the formation of a primary hemostatic plug. vessel wall.
LP-FPPP-92900 R1 CH22 01-15-07 10:08:23
Endothelin release
by activated endothelium
Reflex
vasoconstriction
A E
Endothelial cells
1. Subendothelial matrix
exposure
2. Platelet adhesion 6. Platelet aggregation
and activation (hemostatic plug)
B
5. Platelet recruitment
ADP
4. Platelet shape change Figure 22-1. Sequence of events in hemostasis. The hemostatic
TxA2
process can be divided conceptually into four stagesvasoconstric-
3. Platelet granule release tion, primary hemostasis, secondary hemostasis, and resolution
although recent evidence suggests that these stages are temporally
Fibrin overlapping and may be nearly simultaneous. A. Vascular injury
1. Tissue factor expression causes endothelial denudation. Endothelin, released by activated en-
on activated dothelium, and neurohumoral factor(s) induce transient vasocon-
endothelium striction. B. Injury-induced exposure of the subendothelial matrix (1)
C
provides a substrate for platelet adhesion and activation (2). In the
granule release reaction, activated platelets secrete thromboxane A2
4. Fibrin polymerization
(TxA2 ) and ADP (3). TxA2 and ADP released by activated platelets
cause nearby platelets to become activated; these newly activated
platelets undergo shape change (4) and are recruited to the site of
3. Thrombin activation
injury (5). The aggregation of activated platelets at the site of injury
forms a primary hemostatic plug (6). C. Tissue factor expressed on
2. Phospholipid complex expression
activated endothelial cells (1) and leukocyte microparticles (not
shown), together with acidic phospholipids expressed on activated
platelets and activated endothelial cells (2), initiate the steps of the
coagulation cascade, culminating in the activation of thrombin (3).
Thrombin proteolytically activates fibrinogen to form fibrin, which
polymerizes around the site of injury, resulting in the formation of a
D t-PA definitive (secondary) hemostatic plug (4). D. Natural anticoagulant
and thrombolytic factors limit the hemostatic process to the site of
PGI2 vascular injury. These factors include tissue plasminogen activator
1. Release of t-PA
(t-PA), which activates the fibrinolytic system (1); thrombomodulin,
(fibrinolysis)
which activates inhibitors of the coagulation cascade (2); prosta-
2. Thrombomodulin cyclin, which inhibits both platelet activation and vasoconstriction
(blocks coagulation cascade)
(3); and surface heparin-like molecules, which catalyze the inactiva-
3. Release of prostacyclin (inhibits tion of coagulation factors (4). E. Scanning electron micrographs of
platelet aggregation and vasoconstriction) resting platelets (1), a platelet undergoing cell spreading shortly after
4. Surface heparin-like molecules cell activation (2), and a fully activated platelet after actin filament
(blocks coagulation cascade) bundling and crosslinking and myosin contraction (3).
LP-FPPP-92900 R1 CH22 01-15-07 10:08:23
Endothelium
Collagen
Endothelium
Collagen
Resting platelet
Tissue factor
TXA2
Prothrombin
Platelet
Fibrinogen ADP Thrombin
GPIIb-IIIa
GPIb
von Willebrand
factor
Arachidonic acid
1
Generation of Cyclooxygenase
thromboxane A2
by activated
platelets
3
TXA2 G protein-mediated 4
activation of PLC hydrolyzes PIP2
PLC
phospholipase C to yield IP3 and DAG
PIP2 DAG
TXA2-R q PKC
q GTP
(active)
GDP
6
2 Activation of protein
PKC
Activation of kinase C
IP3
thromboxane A2
receptor
Ca2+
Ca2+ 7
5 Activation of
Increase in cytosolic PLA2 phospholipase A2
calcium concentration
8 GP
Activation of IIb
-III
GPIIb-IIIa a
9
Binding of fibrinogen
to GPIIb-IIIa
Fibrinogen
10
Platelet aggregation
Figure 22-4. Platelet activation by thromboxane A2 . 1. Thromboxane A2 (TxA2 ) is generated from arachidonic acid in activated platelets;
cyclooxygenase catalyzes the committed step in this process. 2. Secreted TxA2 binds to the cell surface TxA2 receptor (TxA2-R), a G protein-
coupled receptor. 3. The G isoform Gq activates phospholipase C (PLC). 4. PLC hydrolyzes phosphatidylinositol 4,5-bisphosphate (PIP2 )
to yield inositol 1,4,5-trisphosphate (IP3 ) and diacylglycerol (DAG). 5. IP3 raises the cytosolic Ca2 concentration by promoting vesicular
release of Ca2 into the cytosol. 6. DAG activates protein kinase C (PKC). 7. PKC activates phospholipase A2 (PLA2 ). 8. Through a poorly
understood mechanism, activation of PLA2 leads to the activation of GPIIbIIIa. 9. Activated GPIIbIIIa binds to fibrinogen. 10. Fibrinogen
crosslinks platelets by binding to GPIIbIIIa receptors on other platelets. This crosslinking leads to platelet aggregation and formation of a
primary hemostatic plug.
(PLC), which hydrolyzes phosphatidylinositol 4,5-bisphos- Activation of ADP receptors mediates platelet shape change
phate (PI[4,5]P2 ) to yield inositol 1,4,5-trisphosphate (IP3 ) and expression of functional GPIIbIIIa. Fibrous collagen
and diacylglycerol (DAG). IP3 raises the cytosolic Ca2 activates platelets by binding directly to platelet glycoprotein
concentration and DAG activates protein kinase C (PKC), VI (GPVI). Ligation of GPVI by collagen leads to phospholi-
which in turn promotes the activation of PLA2 . Through a pase C activation and platelet activation, as described above.
poorly understood mechanism, PLA2 activation induces the Platelets aggregate with one another through a bridging
expression of functional GPIIbIIIa, the membrane integrin molecule, fibrinogen, which has multiple binding sites for
that mediates platelet aggregation. ADP triggers platelet acti- functional GPIIbIIIa (Fig. 22-2). Just as the vWF:GPIb
interaction is important for platelet adhesion to exposed su-
vation by binding to G protein-coupled ADP receptors on the
bendothelial collagen, the fibrinogen:GPIIbIIIa interac-
platelet surface (Fig. 22-5). The two subtypes of G protein- tion is critical for platelet aggregation. Platelet aggregation
coupled platelet ADP receptors are termed P2Y1 receptors ultimately leads to the formation of a reversible clot, or a
and P2Y(ADP) receptors. P2Y1, a Gq-coupled receptor, primary hemostatic plug.
releases intracellular calcium stores through activation of Activation of the coagulation cascade proceeds nearly
phospholipase C. P2Y(ADP), a Gi-coupled receptor, inhibits simultaneously with the formation of the primary hemostatic
adenylyl cyclase. The P2Y(ADP) receptor is the target of the plug, as described below. Activation of the coagulation cas-
antiplatelet agents ticlopidine and clopidogrel (see below). cade leads to the generation of fibrin, initially at the periph-
LP-FPPP-92900 R1 CH22 01-15-07 10:08:23
Thrombin
4 ADP
ADP Adenylyl cyclase Thrombin
receptor PLC 5
1
i P2Y1 receptor
q q
P2Y(ADP) receptor i GTP
GDP 6 GTP
GDP ATP q
cAMP
2 GDP
PDE
PKA 7
AMP Increased PLC activity
leads to platelet activation
3
Decreased PKA activity
leads to platelet activation
Figure 22-5. Platelet activation by ADP and thrombin. Left panel: 1. Binding of ADP to the P2Y(ADP) receptor activates a Gi protein,
which inhibits adenylyl cyclase. 2. Inhibition of adenylyl cyclase decreases the synthesis of cAMP, and hence decreases protein kinase A (PKA)
activation (dashed arrow). cAMP is metabolized to AMP by phosphodiesterase (PDE). 3. PKA inhibits platelet activation through a series of
poorly understood steps. Therefore, the decreased PKA activation that results from ADP binding to the P2Y(ADP) receptor causes platelet
activation. Right panel: 4. Thrombin proteolytically cleaves the extracellular domain of its receptor. This cleavage creates a new N-terminus,
which binds to an activation site on the thrombin receptor to activate a Gq protein. 5. ADP also activates Gq by binding to the P2Y1 receptor.
6. Gq activation (by either thrombin or ADP) activates phospholipase C (PLC). 7. PLC activity leads to platelet activation, as shown in Figure
22-4. Note that ADP can activate platelets by binding to either the P2Y(ADP) receptor or the P2Y1 receptor, although recent evidence suggests
that full platelet activation requires the participation of both receptors.
ery of the primary hemostatic plug. Platelet pseudopods at- The activation reaction is catalytic and not stoichiometric.
tach to the fibrin strands at the periphery of the plug and For example, one unit of activated factor X can poten-
contract. Platelet contraction yields a compact, solid, irrever- tially generate 40 units of thrombin. This robust amplifi-
sible clot, or a secondary hemostatic plug. cation process rapidly generates large amounts of fibrin at
a site of vascular injury.
Second, the major activation reactions in the cascade
SECONDARY HEMOSTASIS: THE occur at sites where a phospholipid-based proteinprotein
COAGULATION CASCADE complex has formed (Fig. 22-7). This complex is composed
of a membrane surface (provided by activated platelets, acti-
vated endothelial cells, and possibly activated leukocyte mi-
Secondary hemostasis is also termed the coagulation cas- croparticles [see below]), an enzyme (an activated coagula-
cade. The goal of this cascade is to form a stable fibrin tion factor), a substrate (the proenzyme form of the
clot at the site of vascular injury. Details of the coagulation downstream coagulation factor), and a cofactor. The pres-
cascade are presented schematically in Figure 22-6. Several ence of negatively charged phospholipids, especially phos-
general principles should be noted. phatidylserine, is critical for assembly of the complex. Phos-
First, the coagulation cascade is a sequence of enzymatic phatidylserine, which is normally sequestered in the inner
events. Most plasma coagulation factors circulate as inactive leaflet of the plasma membrane, translocates to the outer
proenzymes, which are synthesized by the liver. These pro- leaflet of the membrane in response to agonist stimulation
enzymes are proteolytically cleaved, and thereby activated, of platelets, endothelial cells, or leukocytes. Calcium is re-
by the activated factors that precede them in the cascade. quired for the enzyme, substrate, and cofactor to adopt the
LP-FPPP-92900 R1 CH22 01-15-07 10:08:23
Proteolytic cleavage
Intrinsic pathway Extrinsic pathway
(activation) of factor X
XII Tissue injury
Kallikrein
VII Proteolytic cleavage
Prekallikrein IXa X (activation) of prothrombin
XIIa 2+
VIIIa Ca Xa IXa
HMWK IX Thrombin (IIa)
2+
VIIa VIIIa Ca
XI XIa
Xa
Ca2+ Prothrombin (II)
Thrombin (IIa) Xa 2+
Va Ca Thrombin (IIa)
Tissue
factor Va Ca2+
VIII VIIIa X VIIa
2+ IXa Ca2+
Ca
Common pathway
Xa Figure 22-7. Coagulation factor activation on phospholipid
surfaces. Surface catalysis is critical for a number of the activation
Thrombin (IIa) reactions in the coagulation cascade. Each activation reaction con-
sists of an enzyme (e.g., factor IXa), a substrate (e.g., factor X), and
V a cofactor or reaction accelerator (e.g., factor VIIIa), all of which are
Va
assembled on the phospholipid surface of activated platelets, endo-
2+ Xa
Ca thelial cells, and leukocytes. Ca2 allows the enzyme and substrate
to adopt the proper conformation in each activation reaction. In the
XIII example shown, factor VIIIa and Ca2 act as cofactors in the factor
2+ IXa-mediated cleavage of factor X to factor Xa. Factor Va and Ca2
Prothrombin (II) Thrombin (IIa) Ca
then act as cofactors in the factor Xa-mediated cleavage of prothrom-
XIIIa bin to thrombin.
Ca2+
ATIII
+ Heparin
ATIII
Endogenous heparin-like
molecules or
exogenous Heparin
Antithrombin III unfractionated heparin
B
Active Inactive
coagulation factors coagulation factors
Heparin
Xa
Xa Xa
+ ATIII ATIII ATIII + Heparin
IXa
Heparin Heparin
Heparin
XIIa
Figure 22-9. Antithrombin III action. Antithrombin III (ATIII) inactivates thrombin and factors IXa, Xa, XIa, and XIIa by forming a stoichiomet-
ric complex with these coagulation factors. These reactions are catalyzed physiologically by heparin-like molecules expressed on healthy
endothelial cells; sites of vascular injury do not express heparin-like molecules because the endothelium is denuded or damaged. Pharmacolog-
ically, these reactions are catalyzed by exogenously administered heparin. In more detail, the binding of heparin to ATIII induces a conforma-
tional change in ATIII (A) that allows the ATIII to bind thrombin or coagulation factors IXa, Xa, XIa or XIIa. The stoichiometric complex between
ATIII and the coagulation factor is highly stable, allowing heparin to dissociate without breaking up the complex (B).
Protein C and protein S are vitamin K-dependent pro- TFPI in a two-step reaction. First, TFPI binds to factor Xa
teins that slow the coagulation cascade by inactivating coag- and neutralizes its activity in a Ca2-independent reaction.
ulation factors Va and VIIIa. Protein C and protein S are part Subsequently, the TFPI:Xa complex interacts with the VIIa:
of a feedback control mechanism, in which excess thrombin TF complex via a second domain on TFPI, so that a quater-
generation leads to activation of protein C which, in turn, nary Xa:TFPI:VIIa:TF complex is formed. The molecular
helps to prevent the enlarging fibrin clot from occluding knots of the TFPI molecule hold the quaternary complex
the vascular lumen. Specifically, the endothelial cell surface tightly together and thereby inactivate the VIIa:TF complex.
protein thrombomodulin is a receptor for both thrombin In this manner, TFPI prevents excessive TF-mediated activa-
and protein C in the plasma. Thrombomodulin binds these tion of factors IX and X.
proteins in such a way that thrombomodulin-bound thrombin Plasmin exerts its anticoagulant effect by proteolytically
cleaves protein C to activated protein C (also known as pro- cleaving fibrin into fibrin degradation products. Because
tein Ca). In a reaction that requires the cofactor protein S, plasmin has powerful antithrombotic effects, the formation
activated protein C then inhibits clotting by cleaving (and of plasmin has intrigued researchers for many years, and a
thereby inactivating) factors Va and VIIIa. number of pharmacologic agents have been developed to
Tissue factor pathway inhibitor (TFPI), as its name target the plasmin formation pathway (Fig. 22-10). Plasmin
indicates, limits the action of tissue factor (TF). The coagula- is generated by the proteolytic cleavage of plasminogen, a
tion cascade is initiated when factor VIIa complexes with plasma protein that is synthesized in the liver. The proteoly-
TF at the site of vascular injury (Fig. 22-6). The resulting tic cleavage is catalyzed by tissue-type plasminogen acti-
VIIa:TF complex catalyzes the activation of factors IX and vator (t-PA), which is synthesized and secreted by the endo-
X. After limited quantities of factors IXa and Xa are gener- thelium. Plasmin activity is carefully modulated by three
ated, the VIIa:TF complex becomes feedback inhibited by regulatory mechanisms in order to restrict plasmin action to
LP-FPPP-92900 R1 CH22 01-15-07 10:08:23
Thrombosis
ENDOTHELIAL INJURY
Crosslinked
fibrin polymer Endothelial injury is the most dominant influence on throm-
Fibrin degradation
products bus formation in the heart and the arterial circulation. There
are many possible causes of endothelial injury, including
Figure 22-10. The Fibrinolytic System. Plasmin is formed by the
proteolytic cleavage of plasminogen by tissue-type or urokinase-type
changes in shear stress associated with hypertension or tur-
plasminogen activator. Plasmin formation can be inhibited by plas- bulent flow, hyperlipidemia, elevated blood glucose in dia-
minogen activator inhibitor 1 or 2, which binds to and inactivates betes mellitus, traumatic vascular injury, and some infec-
plasminogen activators. In the fibrinolytic reaction, plasmin cleaves tions. (Recall that Mr. Soprano developed coronary artery
crosslinked fibrin polymers into fibrin degradation products. 2-Anti- thrombosis, which was probably attributable to endothelial
plasmin, which circulates in the bloodstream, neutralizes free injury secondary to hypertension and cigarette smoking.)
plasmin in the circulation. Endothelial injury predisposes the vascular lumen to
thrombus formation through three mechanisms. First, plate-
let activators, such as exposed subendothelial collagen, pro-
mote platelet adhesion to the injured site. Second, exposure
the site of clot formation. First, t-PA is most effective when
of tissue factor on injured endothelium initiates the coagula-
it is bound to a fibrin meshwork. Second, t-PA activity can be
tion cascade. Third, natural antithrombotics, such as t-PA
inhibited by plasminogen activator inhibitor (PAI). When
and PGI2 , become depleted at the site of vascular injury
local concentrations of thrombin and inflammatory cyto- because these mechanisms rely on the functioning of an in-
kines (such as IL-1 and TNF-) are high, endothelial cells tact endothelial cell layer.
increase the release of PAI, preventing t-PA from activating
plasmin. This ensures that a stable fibrin clot forms at the
site of vascular injury. Third, 2-antiplasmin is a plasma ABNORMAL BLOOD FLOW
protein that neutralizes free plasmin in the circulation and
thereby prevents random degradation of plasma fibrinogen. Abnormal blood flow refers to a state of turbulence or stasis
Plasma fibrinogen is important for platelet aggregation in rather than laminar flow. Atherosclerotic plaques commonly
primary hemostasis (see above), and it is also the precursor predispose to turbulent blood flow in the vicinity of the
for the fibrin polymer that is required to form a stable clot. plaque. Bifurcations of blood vessels can also create areas
of turbulent flow. Turbulent blood flow causes endothelial
injury, forms countercurrents, and creates local pockets of
stasis. Local stasis can also result from formation of an aneu-
PATHOGENESIS OF THROMBOSIS rysm (a focal out-pouching of a vessel or a cardiac chamber)
and from myocardial infarction. In the latter condition, a
region of noncontractile (infarcted) myocardium serves as a
Thrombosis is the pathologic extension of hemostasis. In favored site for stasis. Cardiac arrhythmias, such as atrial
thrombosis, coagulation reactions are inappropriately regu- fibrillation, can also generate areas of local stasis. Stasis is
lated so that a clot uncontrollably enlarges and occludes the the major cause for the formation of venous thrombi.
lumen of a blood vessel. The pathologic clot is now termed Disruption of normal blood flow by turbulence or stasis
a thrombus. Three major factors predispose to thrombus promotes thrombosis by three major mechanisms. First, the
formationendothelial injury, abnormal blood flow, and absence of laminar blood flow allows platelets to come into
hypercoagulability. These three factors influence one an- close proximity to the vessel wall. Second, stasis inhibits
other, and are collectively known as Virchows triad (Fig. the flow of fresh blood into the vascular bed, so that activated
22-11). coagulation factors in the region are not removed or diluted.
LP-FPPP-92900 R1 CH22 01-15-07 10:08:23
Third, abnormal blood flow promotes endothelial cell activa- prothrombin gene. This mutation leads to a 30% increase in
tion, which leads to a prothrombotic state. plasma prothrombin levels. Both the factor V Leiden muta-
tion and the prothrombin G20210A mutation are associated
HYPERCOAGULABILITY with a significantly increased risk of venous thrombosis and
a modestly increased risk of arterial thrombosis. Other ge-
netic disorders that predispose some individuals to thrombo-
Hypercoagulability is generally less important than endothe- sis include mutations in the fibrinogen, protein C, protein
lial injury and abnormal blood flow in predisposing to throm- S, and antithrombin III genes. Although the latter disorders
bosis, but this condition can be an important factor in some
are relatively uncommon (less than 1% incidence), patients
patients. Hypercoagulability refers to an abnormally height-
with a genetic deficiency of protein C, protein S, or anti-
ened coagulation response to vascular injury, resulting from
thrombin III often present with spontaneous venous throm-
either: (1) primary (genetic) disorders; or (2) secondary
bosis.
(acquired) disorders (see Table 22-1). (Hypocoagulable
states, or hemorrhagic disorders, can also result from pri- Hypercoagulability can sometimes be acquired (second-
mary or secondary causes; see Box 22-1 for an example.) ary) rather than genetic. An example of acquired hypercoa-
Among the genetic causes of hypercoagulability, the most gulability is the heparin-induced thrombocytopenia syn-
prevalent known mutation resides in the gene for coagulation drome. In some patients, administration of the anticoagulant
factor V. It is estimated that 6% of the Caucasian population heparin stimulates the immune system to generate circulat-
in the U.S. carries mutations in the factor V gene. The most ing antibodies directed against a complex consisting of hepa-
common mutation is the Leiden mutation, in which gluta- rin and platelet factor 4. Because platelet factor 4 is present
mine is substituted for arginine at position 506. This position on platelet and endothelial cell surfaces, antibody binding
is important because it is part of a site in factor Va that is to the heparin:platelet factor 4 complex results in antibody-
marked for proteolytic cleavage by activated protein C. The mediated removal of platelets from the circulation; that is,
mutant factor V Leiden protein is resistant to proteolytic in thrombocytopenia. In some patients, however, antibody
cleavage by activated protein C. As a result of the Leiden binding also causes platelet activation, endothelial injury,
mutation, factor Va is allowed to accumulate and thereby to and a prothrombotic state. Although both unfractionated and
promote coagulation. low molecular weight heparin (see below) can cause throm-
A second common mutation (2% incidence) is the pro- bocytopenia, it appears that low molecular weight heparin
thrombin G20210A mutation, in which adenine (A) is sub- has a lower incidence of thrombocytopenia than unfraction-
stituted for guanine (G) in the 3-untranslated region of the ated heparin.
Primary (Genetic)
Factor V Leiden mutation (factor Resistance to activated protein C excess factor Va
V R506Q) (common)
Hyperhomocysteinemia Endothelial damage due to accumulation of homocysteine
(common)
Prothrombin G20210A mutation Increased prothrombin level and activity
(common)
Antithrombin III deficiency (less Decreased inactivation of factors IIa, IXa, and Xa
common)
Protein C or S deficiency (less Decreased proteolytic inactivation of factors VIIIa and Va
common)
Secondary (Acquired: Disease or Drug-Induced)
Antiphospholipid syndrome Autoantibodies to negatively charged phospholipids platelet adhesion
Heparin-induced Antibodies to platelet factor 4 platelet activation
thrombocytopenia
Malignancy Tumor cell induction of tissue factor expression
Myeloproliferative syndromes Elevated blood viscosity, altered platelets
Nephrotic syndrome Loss of antithrombin III in urine, fibrinogen, platelet activation
Oral contraceptive use, estrogen Hepatic synthesis of coagulation factors and/or effects of estrogen on endothelium (effect
replacement therapy may be more prominent in patients with underlying primary hypercoagulability)
Paroxysmal nocturnal Unknown, possibly leaky platelets
hemoglobinuria
Postpartum period Venous stasis, increased coagulation factors, tissue trauma
Surgery/trauma Venous stasis, immobilization, tissue injury
LP-FPPP-92900 R1 CH22 01-15-07 10:08:23
Membrane phospholipids
Phospholipase A2
NSAIDs
(aspirin, others)
COOH
O COOH OOH
O COOH
OOH
Prostaglandin G2 5-HPETE
Peroxidase Dehydrase
O
O COOH COOH
O
OH
Leukotriene A 4
Prostaglandin H2
Glutathione-
COOH S-transferase
PGI2 synthase Prostaglandin synthases OH
O
COOH
H H
Other
S
prostaglandins
H
OH OH N COOH
HN
Prostacyclin (PGI2) PGE2 synthase
H2N O
O
TxA2 synthase COOH
O
Leukotriene C 4
COOH COOH
O
O
HO OH
OH
Thromboxane A 2 Prostaglandin E2
Figure 22-12. Overview of Prostaglandin Synthesis. Membrane phospholipids are cleaved by phospholipase A2 to release free arachidonic
acid. Arachidonic acid can be metabolized through either of two major pathways, the cyclooxygenase pathway or the lipoxygenase pathway.
The cyclooxygenase pathway, which is inhibited by aspirin and other nonsteroidal anti-inflammatory drugs (NSAIDs), converts arachidonic
acid into prostaglandins and thromboxanes. Platelets express TxA2 synthase and synthesize the pro-aggregatory mediator thromboxane A2 ;
endothelial cells express PGI2 synthase and synthesize the anti-aggregatory mediator prostacyclin. The lipoxygenase pathway converts arachi-
donic acid into leukotrienes, which are potent inflammatory mediators. (See Chapter 41, Pharmacology of Eicosanoids, for a detailed discussion
of the lipoxygenase and cyclooxygenase pathways.) Aspirin inhibits cyclooxygenase by covalent acetylation of the enzyme near its active site.
Because platelets lack the capability to synthesize new proteins, aspirin inhibits thromboxane synthesis for the life of the platelet.
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A
Arachidonic acid
NSAIDs Cyclooxygenase
(aspirin, others)
PIP2 DAG
TXA2-R q PKC
q GTP
(active)
GDP
PKC
IP3
Ca2+
Ca2+
PLA2
GP
IIb
-III
a
Abciximab
Fibrinogen
Thrombin
B
ADP Adenylyl cyclase ADP
Thrombin
Clopidogrel, receptor PLC
ticlopidine
i P2Y1 receptor
q q
P2Y(ADP) receptor i GTP
GDP
GTP
GDP ATP q
cAMP
Dipyridamole GDP
PDE
PKA
Platelet activation
AMP
Platelet activation
Figure 22-13. Mechanism of action of antiplatelet agents. A. NSAIDs and GPIIb-IIIa antagonists inhibit steps in thromboxane A2 (TxA2 )-
mediated platelet activation. Aspirin inhibits cyclooxygenase by covalent acetylation of the enzyme near its active site, leading to decreased
TxA2 production. The effect is profound because platelets lack the ability to synthesize new enzyme molecules. GPIIbIIIa antagonists, such
as the monoclonal antibody abciximab and the small-molecule antagonists eptifibatide and tirofiban (not shown), inhibit platelet aggregation
by preventing activation of GpIIbIIIa (dashed line), leading to decreased platelet crosslinking by fibrinogen. B. Clopidogrel, ticlopidine, and
dipyridamole inhibit steps in ADP-mediated platelet activation. Clopidogrel and ticlopidine are antagonists of the P2Y(ADP) receptor. Dipyrida-
mole inhibits phosphodiesterase (PDE), thereby preventing the breakdown of cAMP and increasing cytoplasmic cAMP concentration.
LP-FPPP-92900 R1 CH22 01-15-07 10:08:23
cyclin is relatively unaffected by aspirin at pharmacologi- steal phenomenon, which involves intense dilation of coro-
cally low doses (see below). nary arterioles (see Chapter 21, Pharmacology of Vascular
Aspirin is most often used as an antiplatelet agent to pre- Tone).
vent arterial thrombosis leading to stroke, transient ischemic
attack, and myocardial infarction. Because the action of aspi-
rin on platelets is permanent, it is most effective as a selective
ADP Receptor Pathway Inhibitors
antiplatelet agent when taken in low doses and/or at infre- Both ticlopidine and clopidogrel are derivatives of thieno-
quent intervals. For example, aspirin is often used as an pyridine. These agents, which irreversibly inhibit the ADP-
antiplatelet agent at a dose of 81 mg once daily, while a dependent pathway of platelet activation, have antiplatelet
typical anti-inflammatory dose of this agent could be 650 effects in vitro and in vivo. Ticlopidine and clopidogrel are
mg three to four times daily. Taken at high doses, aspirin thought to act by covalently modifying and inactivating the
can inhibit prostacyclin production without increasing the platelet P2Y(ADP) receptor (also called P2Y12 ), which is
effectiveness of the drug as an antiplatelet agent. A more physiologically coupled to the inhibition of adenylyl cyclase
extended discussion of the uses and toxicities of aspirin is (Fig. 22-13B). Ticlopidine is a prodrug that requires conver-
found in Chapter 41. Compared with aspirin, other nonsteroi- sion to active thiol metabolites in the liver. Maximal platelet
dal anti-inflammatory drugs (NSAIDs) are not as widely inhibition is observed 8 to 11 days after initiating therapy
used in the prevention of arterial thrombosis because the with the drug; used in combination with aspirin, 4 to 7 days
inhibitory action of these drugs on cyclooxygenase is not are needed to achieve maximal platelet inhibition. Adminis-
permanent. tration of a loading dose can produce a more rapid antiplate-
COX-1 is the predominant COX isoform in platelets, but let response. Ticlopidine is approved in the U.S. for two
endothelial cells appear to express both COX-1 and COX- indications: (1) secondary prevention of thrombotic strokes
2 under physiologic conditions. Because aspirin inhibits in patients intolerant of aspirin, and (2) in combination with
COX-1 and COX-2 nonselectively, this drug serves as an aspirin, prevention of stent thrombosis for up to 30 days after
effective antiplatelet agent. In contrast, the newer selective placement of coronary artery stents. In general, ticlopidine
COX-2 inhibitors cannot be used as antiplatelet agents be- is considered to be less safe than clopidogrel. The use of
cause they are poor inhibitors of COX-1. Furthermore, use ticlopidine has occasionally been associated with neutro-
of the selective COX-2 inhibitors appears to be associated penia, thrombocytopenia, and thrombotic thrombocytopenic
with increased cardiovascular risk, most likely because these purpura (TTP); for this reason, blood counts must be moni-
agents inhibit endothelial production of PGI2 without inhib- tored frequently when using ticlopidine.
iting platelet generation of TxA2 . The adverse impact of Clopidogrel, a thienopyridine closely related to ticlopi-
the selective COX-2 inhibitors on cardiovascular risk has dine, has been used widely in combination with aspirin for
resulted in the recent withdrawal of most of these agents improved platelet inhibition during and after elective percu-
from the market (see Chapter 41). taneous coronary intervention. Clopidogrel is a prodrug that
must undergo oxidation by hepatic P450 3A4 to the active
drug form; it may therefore interact with statins and other
Phosphodiesterase Inhibitors drugs metabolized by this P450 enzyme. Clopidogrel is ap-
proved for secondary prevention in patients with recent myo-
In platelets, an increase in the concentration of intracellular cardial infarction, stroke, or peripheral vascular disease. It
cAMP leads to a decrease in platelet aggregability. Platelet is also approved for use in acute coronary syndromes that
cAMP levels are regulated physiologically by TxA2 and are treated with either percutaneous coronary intervention
PGI2 , among other mediators (see above). The mechanism or coronary artery bypass grafting. Like ticlopidine, clopido-
by which increased intracellular cAMP concentration leads grel requires a loading dose to achieve a maximal antiplatelet
to decreased platelet aggregability is not well understood. effect rapidly. For this reason, Mr. Soprano was given an
cAMP activates protein kinase A, which, through incom- intravenous loading dose of clopidogrel in the context of his
pletely elucidated mechanisms, decreases availability of the myocardial infarction. The adverse effect profile of clopido-
intracellular Ca2 necessary for platelet aggregation (Fig. grel is more favorable than that of ticlopidine: the gastroin-
22-13B). Inhibitors of platelet phosphodiesterase decrease testinal side effects of clopidogrel are similar to those of
platelet aggregability by inhibiting cAMP degradation, while aspirin, and clopidogrel lacks the significant bone marrow
activators of platelet adenylyl cyclase decrease platelet ag- toxicity associated with ticlopidine.
gregability by increasing cAMP synthesis. (There are cur-
rently no direct adenylyl cyclase activators in clinical use.)
Dipyridamole is an inhibitor of platelet phosphodiester- GPIIbIIIa Antagonists
ase that decreases platelet aggregability (Fig. 22-13B). Dipy- As noted above, platelet membrane GPIIbIIIa receptors are
ridamole by itself has only weak antiplatelet effects, and is important because they constitute the final common pathway
therefore usually administered in combination with warfarin of platelet aggregation, serving to bind fibrinogen molecules
or aspirin. The combination of dipyridamole and warfarin that bridge platelets to one another. A variety of stimuli (e.g.,
can be used to inhibit embolization from prosthetic heart TxA2 , ADP, epinephrine, collagen, and thrombin), acting
valves, while the combination of dipyridamole and aspirin through diverse signaling molecules, are capable of inducing
can be used to reduce the likelihood of thrombosis in patients the expression of functional GPIIbIIIa on the platelet sur-
with a thrombotic diathesis. Dipyridamole also has vasodila- face. It could therefore be predicted that antagonists of
tory properties. It may paradoxically induce angina in pa- GPIIbIIIa would prevent fibrinogen binding to the
tients with coronary artery disease by causing the coronary GPIIbIIIa receptor and thus serve as powerful inhibitors of
LP-FPPP-92900 R1 CH22 01-15-07 10:08:23
platelet aggregation. Eptifibatide, the GPIIb IIIa receptor to the most selective agents (selective factor Xa inhibitors
antagonist used in the opening case, is a highly efficacious and direct thrombin inhibitors). Recombinant activated pro-
inhibitor of platelet aggregation. A synthetic peptide, eptifi- tein C also has anticoagulant activity, although its clinical
batide antagonizes the platelet GPIIbIIIa receptor with high indication is severe sepsis. Because of the mechanisms of
affinity. This drug has been used to reduce ischemic events action of these drugs, bleeding is an adverse effect common
in patients undergoing percutaneous coronary intervention to all anticoagulants.
and to treat unstable angina and non-ST elevation myocar-
dial infarction.
Abciximab is a chimeric mousehuman monoclonal an-
Warfarin
tibody directed against the human GPIIbIIIa receptor. Ex- In the early 1900s, farmers in Canada and the North Dakota
periments in vitro have shown that occupation of 50% of plains adopted the practice of planting sweet clover instead
platelet GPIIbIIIa receptors by abciximab significantly re- of corn for fodder. In the winter months of 1921 to 1922, a
duces platelet aggregation. The binding of abciximab to fatal hemorrhagic disease was reported in cattle that had
GPIIbIIIa is essentially irreversible, with a dissociation foraged on the sweet clover. In almost every case, it was
half-time of 18 to 24 hours. In clinical trials, adding abcixi- found that the affected cattle had foraged on sweet clover
mab to conventional antithrombotic therapy reduces both that had been spoiled by the curing process. After an inten-
long-term and short-term ischemic events in patients sive investigation, scientist K. P. Link reported that the
undergoing high-risk percutaneous coronary intervention. spoiled clover contained the natural anticoagulant 3,3-meth-
Tirofiban is a nonpeptide tyrosine analogue that reversi- ylene-bis-(4-hydroxycoumarin) or dicumarol. Dicumarol
bly antagonizes fibrinogen binding to the platelet GPIIbIIIa and warfarin (a potent synthetic congener) were introduced
receptor. Both in vitro and in vivo studies have demonstrated during the 1940s as rodenticides and as oral anticoagulants.
the ability of tirofiban to inhibit platelet aggregation. Tirofi- Because the oral anticoagulants act by affecting vitamin
ban has been approved for use in patients with acute coro- K-dependent reactions, it is important to understand how
nary syndromes. vitamin K functions.
Because of their mechanism of action as antiplatelet
agents, all of the GPIIbIIIa antagonists can cause bleeding
Mechanism of Action of Vitamin K
as an adverse effect. In the opening case, Mr. Soprano devel-
oped a hematoma in his right thigh near the arterial access Vitamin K (K is derived from the German word Koagu-
site at which eptifibatide was being infused. The expanding lation) is required for the normal hepatic synthesis of four
hematoma was caused by the excessive antiplatelet effect of coagulation factors (II, VII, IX, and X), protein C, and pro-
a very high local concentration of eptifibatide at the infusion tein S. The coagulation factors, protein C, and protein S are
site. Importantly, the ability to reverse the effect of biologically inactive as unmodified polypeptides following
GPIIbIIIa receptor antagonists differs for the different protein synthesis on ribosomes. These proteins gain biologi-
agents. Because abciximab is an irreversible inhibitor of cal activity by post-translational carboxylation of their 9 to
platelet function, and all the abciximab previously infused 12 amino-terminal glutamic acid residues. The -carboxyl-
is already bound to platelets, infusion of fresh platelets after ated glutamate residues (but not the unmodified glutamate
the drug has been stopped can reverse the antiplatelet effect. residues) are capable of binding Ca2 ions. Ca2 binding
In contrast, because the two small-molecule antagonists (ep- induces a conformational change in these proteins that is
tifibatide and tirofiban) bind the receptor reversibly and are required for efficient binding of the proteins to phospholipid
infused in great stoichiometric excess of receptor number, surfaces. The ability of the -carboxylated molecules to bind
infusion of fresh platelets simply offers new sites to which Ca2 increases the enzymatic activity of coagulation factors
the drug can bind, and it is not practical to deliver a sufficient IIa, VIIa, IXa, Xa, and protein Ca by approximately 1,000-
number of platelets to overwhelm the vast excess of drug fold. Thus, vitamin K-dependent carboxylation is crucial for
present. Therefore, one must stop the drug infusion and wait the enzymatic activity of the four coagulation factors and
for platelet function to return to normal as the drug is cleared. protein C, and for the cofactor function of protein S.
In the case of Mr. Soprano, no other measure could have The carboxylation reaction requires (1) a precursor form
been taken to reverse the effect of eptifibatide at the time of the target protein with its 9 to 12 amino-terminal glutamic
his hematoma was recognized. acid residues, (2) carbon dioxide, (3) molecular oxygen, and
(4) reduced vitamin K. The carboxylation reaction is sche-
matically presented in Figure 22-14. During this reaction,
ANTICOAGULANTS vitamin K is oxidized to the inactive 2,3-epoxide. An en-
zyme, epoxide reductase, is then required to convert the inac-
As with antiplatelet agents, anticoagulants are used both to tive 2,3-epoxide into the active, reduced form of vitamin K.
prevent and treat thrombotic disease. There are four classes Thus, the regeneration of reduced vitamin K is essential
of anticoagulants: warfarin, unfractionated and low molecu- for the sustained synthesis of biologically functional clotting
lar weight heparins, selective factor Xa inhibitors, and direct factors II, VII, IX, and X, all of which are critical components
thrombin inhibitors. Anticoagulants target various factors in of the coagulation cascade.
the coagulation cascade, thereby interrupting the cascade and
preventing the formation of a stable fibrin meshwork (sec-
Mechanism of Action of Warfarin
ondary hemostatic plug). In this section, the four classes of
anticoagulants are discussed in order of selectivity, from the Warfarin acts on the carboxylation pathway, not by inhibit-
least selective agents (warfarin and unfractionated heparin) ing the carboxylase directly, but by blocking the epoxide
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O
H
O N
N
H H
N
N COOH
H
COOH
COOH
Glutamate residue in -Carboxy glutamate residue in
coagulation factor coagulation factor
CO2
Vitamin K-dependent
carboxylase
O2
OH O
R R
O
OH O
Vitamin K-reduced Vitamin K 2,3-epoxide
(active form) (inactive form)
Epoxide
reductase
reductase that mediates the regeneration of reduced vitamin Evidence from studies of long-term rodenticide use
K (Fig. 22-14). Because depletion of reduced vitamin K in supports the hypothesis that the epoxide reductase is the
the liver prevents the -carboxylation reaction that is re- molecular target of oral anticoagulant action. The use of
quired for the synthesis of biologically active coagulation oral anticoagulants as rodenticides has been a widespread
factors, the onset of action of the oral anticoagulants parallels practice in farming communities. In some areas of the
the half-life of these coagulation factors in the circulation. United States, heavy rodenticide use has selected for a
Of the four affected clotting factors (II, VII, IX, and X), population of wild rodents that is resistant to 4-hydrox-
factor VII has the shortest half-life (6 hours). Thus, the phar- ycoumarins. In vitro studies of tissues from these rodents
macologic effect of a single dose of warfarin is not mani- have demonstrated a mutation in the rodent epoxide re-
fested for approximately 18 to 24 hours (i.e., for 3 to 4 factor ductase that renders the enzyme resistant to inhibition by
VII half-lives). This delayed action is one pharmacologic the anticoagulant. Similarly, a small population of patients
property that distinguishes the warfarin class of anticoagu- is genetically resistant to warfarin because of mutations
lants from all the other classes of anticoagulants. in their epoxide reductase gene. These patients require 10
LP-FPPP-92900 R1 CH22 01-15-07 10:08:23
GI, gastrointestinal.
to 20 times the usual dose of warfarin to achieve the concentrations. For severe hemorrhage, patients should
desired anticoagulant effect. promptly receive fresh frozen plasma, which contains bio-
logically functional clotting factors II, VII, IX, and X. War-
farin should never be administered to pregnant women be-
Clinical Uses of Warfarin cause it can cross the placenta and cause a hemorrhagic
Warfarin is often administered to complete a course of anti- disorder in the fetus. In addition, newborns exposed to warfa-
coagulation that has been initiated with heparin (see below) rin in utero may have serious congenital defects character-
and to prevent thrombosis in predisposed patients. Orally ized by abnormal bone formation (certain bone matrix pro-
administered warfarin is nearly 100% bioavailable, and its teins are -carboxylated). Rarely, warfarin causes skin
levels in the blood peak at 0.5 to 4 hours after administration. necrosis as a result of widespread thrombosis in the micro-
In the plasma, 99% of racemic warfarin is bound to plasma vasculature. The fact that warfarin can cause thrombosis may
protein (albumin). Warfarin has a relatively long elimination seem paradoxical. Recall that, in addition to inhibiting the
half-life (approximately 36 hours). The drug is hydroxylated synthesis of biologically active coagulation factors II, VII,
by the cytochrome P450 system in the liver to inactive me- IX, and X, warfarin also prevents the synthesis of biologi-
tabolites that are subsequently eliminated in the urine. cally active proteins C and S, which are natural anticoagu-
Drugdrug interactions must be carefully considered in lants. In patients who are genetically deficient in protein C
patients taking warfarin. Because warfarin is highly albu- or protein S (most commonly, patients who are heterozygous
min-bound in the plasma, co-administration of warfarin with for protein C deficiency), an imbalance between warfarins
other albumin-bound drugs can increase the free (unbound) effects on coagulation factors and its effects on proteins C
plasma concentrations of both drugs. In addition, because and S may lead to microvascular thrombosis and skin ne-
warfarin is metabolized by P450 enzymes in the liver, co- crosis.
administration of warfarin with drugs that induce and/or Because warfarin has a narrow therapeutic index and par-
compete for P450 metabolism can affect the plasma concen- ticipates in numerous drugdrug interactions, the pharmaco-
trations of both drugs. Table 22-2 lists some of the major dynamic (functional) effect of chronic warfarin therapy must
interactions between warfarin and other drugs. be monitored regularly (on the order of every 2 to 4 weeks).
Among the adverse effects of warfarin, bleeding is the Monitoring is most easily performed using the prothrombin
most serious and predictable toxicity. Withdrawal of the time (PT), which is a simple test of the extrinsic and com-
drug may be recommended for patients who suffer from mon pathways of coagulation. In this test, the patients
repeated bleeding episodes at otherwise therapeutic drug plasma is added to a crude preparation of tissue factor (called
GI, gastrointestinal.
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thromboplastin), and the time for formation of a fibrin clot of positive charge) on antithrombin III. Thus, the interaction
is measured. Warfarin prolongs the PT mainly because it between heparin and antithrombin III is partly electrostatic.
decreases the amount of biologically functional factor VII During the conjugation reaction between the protease and
in the plasma. (Recall that factor VII is the vitamin K-depen- the antithrombin, heparin may be released from antithrombin
dent coagulation factor with the shortest half-life.) Measure- III and become available to catalyze additional pro-
ment of the PT has been standardized worldwide, and is teaseantithrombin III interactions (i.e., heparin is not con-
expressed as the International Normalized Ratio (INR) of sumed by the conjugation reaction [Fig. 22-9]). In practice,
the prothrombin time in the patient sample to that in a control however, heparins high negative charge often causes this
sample, normalized for the international sensitivity index sticky molecule to remain electrostatically bound to pro-
(ISI) of the laboratorys thromboplastin preparation com- tease, antithrombin or another nearby molecule in the vicin-
pared to the World Health Organizations reference throm- ity of a thrombus.
boplastin preparation. The formula used to calculate the INR Interestingly, heparins of different molecular weights
is as follows: INR [PTpatient / PTcontrol ]ISI. have divergent anticoagulant activities. These divergent ac-
tivities derive from the differential requirements for heparin
Unfractionated and Low Molecular Weight binding exhibited by the inactivation of thrombin and factor
Heparins Xa by antithrombin III (Fig. 22-15). To catalyze most effi-
ciently the inactivation of thrombin by antithrombin III, a
Structure of Heparin single molecule of heparin must bind simultaneously to both
Heparin is a sulfated mucopolysaccharide stored in the se- thrombin and antithrombin. This scaffolding function is
cretory granules of mast cells. It is a highly sulfated polymer required in addition to the heparin-induced conformational
of alternating uronic acid and D-glucosamine. Heparin mole- change in antithrombin III that renders the antithrombin sus-
cules are highly negatively charged; indeed, endogenous ceptible to conjugation with thrombin. In contrast, to cata-
heparin is the strongest organic acid in the human body. lyze the inactivation of factor Xa by antithrombin III, the
Commercial preparations of heparin are quite heterogene- heparin molecule must bind only to the antithrombin, be-
ous, with molecular weights ranging from 1 to 30 kDa. Con- cause the conformational change in antithrombin III induced
ventionally, commercially prepared heparins have been cate- by heparin binding is sufficient by itself to render the anti-
gorized into unfractionated (standard) heparin and low thrombin susceptible to conjugation with factor Xa. Thus,
molecular weight (LMW) heparin. Unfractionated hepa- LMW heparins, which have an average molecular weight of
rin, which is often prepared from bovine lung and porcine 3 to 4 kDa and contain fewer than 18 monosaccharide units,
intestinal mucosa, ranges in molecular weight from 5 to 30 efficiently catalyze the inactivation of factor Xa by anti-
kDa. LMW heparins are prepared from standard heparin thrombin III but less efficiently catalyze the inactivation of
by gel filtration chromatography; their molecular weights thrombin by antithrombin III. In contrast, unfractionated
range from 1 to 5 kDa. heparin, which has an average molecular weight of 20 kDa
and contains more than 18 monosaccharide units, is of suffi-
cient length to bind simultaneously to thrombin and anti-
Mechanism of Action of Heparin
thrombin III, and therefore efficiently catalyzes the inactiva-
Heparins mechanism of action depends on the presence of tion of both thrombin and factor Xa by antithrombin III.
a specific plasma protease inhibitor, antithrombin III. Anti- Quantitatively, LMW heparin has a threefold higher ratio of
thrombin III is actually a misnomer because, in addition anti-Xa to anti-thrombin (anti-IIa) activity than does unfrac-
to inactivating thrombin, antithrombin III inactivates other tionated heparin. LMW heparin is therefore a more selective
serine proteases including factors IXa, Xa, XIa, and XIIa. therapeutic agent than unfractionated heparin. Both LMW
Antithrombin III can be considered as a stoichiometric sui- heparin and unfractionated heparin use a pentasaccharide
cide trap for these serine proteases. When one of the pro- structure of high negative charge to bind antithrombin III
teases encounters an antithrombin III molecule, the serine and to induce the conformational change in antithrombin
residue at the active site of the protease attacks a specific required for the conjugation reactions. This pentasaccharide
ArgSer peptide bond in the reactive site of the antithrom- has recently been approved for use as a highly selective
bin. The result of this nucleophilic attack is the formation inhibitor of factor Xa (fondaparinux; see below).
of a covalent ester bond between the serine residue on the
protease and the arginine residue on the antithrombin III.
Clinical Uses of Heparins
This results in a stable 1:1 complex between the protease
and antithrombin molecules, which prevents the protease Heparins are used for both prophylaxis and treatment of
from further participation in the coagulation cascade. thromboembolic diseases. Both unfractionated and LMW
In the absence of heparin, the binding reaction between heparins are used to prevent propagation of established
the proteases and antithrombin III proceeds slowly. Heparin, thromboembolic disease such as deep vein thrombosis and
acting as a cofactor, accelerates the reaction by 1,000-fold. pulmonary embolism. For prophylaxis against thrombosis,
Heparin has two important physiologic functions: (1) it heparins are used at much lower doses than those indicated
serves as a catalytic surface to which both antithrombin III for the treatment of established thromboembolic disease. Be-
and the serine proteases bind; and (2) it induces a conforma- cause the enzymatic coagulation cascade functions as an am-
tional change in antithrombin III that makes the reactive site plification system (e.g., 1 unit of factor Xa generates 40 units
of this molecule more accessible to the attacking protease. of thrombin), the administration of relatively small amounts
The first step of the reaction involves the binding of the of circulating heparin at the first generation of factor Xa is
negatively charged heparin to a lysine-rich region (a region highly effective. Heparins are highly negatively charged, and
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Unfractionated heparin
Heparin Heparin
LMWH LMWH
Xa
ATIII
Selective factor Xa inhibitors No effect on thrombin
Fondaparinux
Binds to antithrombin III (ATIII)
via pentasaccharide
(sufficient to inactivate Xa)
Lepirudin
Thrombin
Thrombin
Figure 22-15. Differential effects of unfractionated heparin and low molecular weight heparin on coagulation factor inactivation.
Effect on thrombin: To catalyze the inactivation of thrombin, heparin must bind both to antithrombin III via a high-affinity pentasaccharide
unit (5) and to thrombin via an additional 13 saccharide unit (here labeled Heparin). Low molecular weight heparin (LMWH) does not
contain a sufficient number of saccharide units to bind thrombin, and therefore is a poor catalyst for thrombin inactivation. Effect on factor
Xa: Inactivation of factor Xa requires only the binding of antithrombin III to the high-affinity pentasaccharide unit (5). Both unfractionated
heparin and low molecular weight heparin (and fondaparinux; not shown) are therefore able to catalyze the inactivation of factor Xa.
LP-FPPP-92900 R1 CH22 01-15-07 10:08:23
neither unfractionated heparin nor LMW heparin can cross sary for binding to antithrombin III and inducing the confor-
the epithelial cell layer of the gastrointestinal tract. Hence, mational change in antithrombin required for conjugation to
heparin must be administered parenterally, usually via intra- factor Xa (see above). This agent is therefore is a specific
venous or subcutaneous routes. inhibitor of Xa, with negligible anti-IIa (anti-thrombin) ac-
Unfractionated heparin is often used in combination tivity. Fondaparinux is approved for prevention and treat-
with antiplatelet agents in the treatment of acute coronary ment of deep vein thrombosis, and is available as a once-
syndromes. For example, Mr. Soprano was treated with the daily subcutaneous injection. It is excreted via the kidneys
antiplatelet agents aspirin and eptifibatide and with unfrac- and should not be administered to patients with renal insuffi-
tionated heparin in an attempt to limit the extent of his myo- ciency.
cardial infarction. Monitoring of unfractionated heparin ther-
apy is important for maintaining the anticoagulant effect
within the therapeutic range, because excessive heparin ad-
Direct Thrombin Inhibitors
ministration significantly increases the risk of bleeding. As discussed above, thrombin plays a number of critical
Monitoring is usually performed using the activated partial roles in the hemostatic process (Fig. 22-8). Among other
thromboplastin time (aPTT) assay. The aPTT is a simple effects, this clotting factor (1) proteolytically converts fibrin-
test of the intrinsic and common pathways of coagulation. ogen to fibrin, (2) activates factor XIII, which crosslinks
The patients plasma is added to an excess of phospholipid, fibrin polymers to form a stable clot, (3) activates platelets,
and fibrin forms at a normal rate only if the factors in the and (4) induces endothelial release of PGI2 , t-PA, and PAI-
intrinsic and common pathways are present at normal levels. 1. Thus, direct thrombin inhibitors would be expected to
Increasing amounts of unfractionated heparin in the plasma have profound effects on coagulation. The currently ap-
prolong the time required for the formation of a fibrin clot. proved direct thrombin inhibitors include lepirudin, desiru-
As is true of the other anticoagulants, the major adverse din, bivalirudin, and argatroban. These agents are specific
effect of heparin is bleeding. Thus, it is critical to maintain inhibitors of thrombin, with negligible anti-factor Xa ac-
the anticoagulant effect of unfractionated heparin within the tivity.
therapeutic range in order to prevent the rare, devastating Lepirudin, a recombinant 65-amino acid polypeptide de-
adverse effect of intracranial hemorrhage. In addition, a rived from the medicinal leech protein hirudin, is the proto-
small fraction of patients taking heparin develop heparin- typical direct thrombin inhibitor. For years, surgeons have
induced thrombocytopenia (HIT). In this syndrome, pa- used medicinal leeches to prevent thrombosis in the fine
tients develop antibodies to a hapten created when heparin vessels of reattached digits. Lepirudin binds with high affin-
molecules bind to the platelet surface. In HIT type 1, the ity to two sites on the thrombin molecule the enzymatic
antibody-coated platelets are targeted for removal from the active site and the exosite, a region of the thrombin pro-
circulation, and the platelet count decreases by 50% to 75% tein that orients substrate proteins. Lepirudin binding to
approximately 5 days into the course of heparin therapy. thrombin prevents the thrombin-mediated activation of fi-
The thrombocytopenia in HIT type 1 is transient and rapidly brinogen and factor XIII. Lepirudin is a highly effective
reversible upon heparin withdrawal. In HIT type 2, however, anticoagulant because it can inhibit both free and fibrin-
the heparin-induced antibodies not only target the platelets bound thrombin in developing clots, and because lepirudin
for destruction but also act as agonists to activate the plate- binding to thrombin is essentially irreversible. It is approved
lets, leading to platelet aggregation, endothelial injury, and for use in the treatment of heparin-induced thrombocyto-
potentially fatal thrombosis. There is a higher incidence of penia. Lepirudin has a short half-life, is available parenter-
HIT in patients receiving unfractionated heparin than in ally, and is renally excreted. It can be administered with
those receiving LMW heparin. relative safety to patients with hepatic insufficiency. As with
The LMW heparins enoxaparin, dalteparin and tinza- all direct thrombin inhibitors, bleeding is the major side ef-
parin are each fractionated heparins of low molecular fect of lepirudin, and clotting times must be monitored
weight. As discussed above, these agents are relatively selec- closely. A small percentage of patients may develop anti-
tive for anti-Xa compared to anti-IIa (anti-thrombin) activity. hirudin antibodies, limiting the long-term effectiveness of
All LMW heparins are approved for use in the prevention this agent as an anticoagulant. Another recombinant formu-
and treatment of deep vein thrombosis. Additionally, enoxa- lation of hirudin, desirudin, has been approved for prophy-
parin and dalteparin have been studied in the treatment of laxis against deep vein thrombosis in patients undergoing
acute myocardial infarction and as adjuncts to percutaneous hip replacement.
coronary intervention. LMW heparins have a higher thera- Bivalirudin is a synthetic 20-amino acid peptide that,
peutic index than unfractionated heparin, especially when like lepirudin and desirudin, binds to both the active site and
used for prophylaxis. For this reason, it is generally not nec- exosite of thrombin and thereby inhibits thrombin activity.
essary to monitor blood activity levels of LMW heparins. Thrombin slowly cleaves an arginineproline bond in bivali-
Accurate measurement of the anticoagulant effect of LMW rudin, leading to reactivation of the thrombin. Bivalirudin
heparins requires a specialized assay for anti-factor Xa activ- is approved for anticoagulation in patients undergoing coro-
ity. Because LMW heparins are excreted via the kidneys, nary angiography and angioplasty, and may have reduced
care should be taken to avoid excessive anticoagulation in rates of bleeding relative to heparin for this indication. The
patients with renal insufficiency. drug is excreted renally and has a short half-life (25 minutes).
Argatroban is a small-molecule inhibitor of thrombin
Selective Factor Xa Inhibitors that is approved for the treatment of patients with heparin-
Fondaparinux is a synthetic pentasacharide molecule that induced thrombocytopenia. Unlike other direct thrombin in-
contains the sequence of five essential carbohydrates neces- hibitors, argatroban binds only to the active site of thrombin
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(i.e., it does not interact with the exosite). Also unlike other molecules to plasmin. In fact, the thermodynamically stable
direct thrombin inhibitors, argatroban is excreted by biliary streptokinase:plasminogen complex is the most catalytically
secretion, and can therefore be administered with relative efficient plasminogen activator in vitro.
safety to patients with renal insufficiency. Although streptokinase exerts its most dramatic and po-
tentially beneficial effects in fresh thrombi, its use has been
limited by two factors. First, streptokinase is a foreign pro-
Recombinant Activated Protein C (r-APC) tein that is capable of eliciting antigenic responses in humans
As described above, endogenously activated protein C upon repeated administration. Previous administration of
(APC) exerts an anticoagulant effect by proteolytically streptokinase is a contraindication to its use, because of the
cleaving factors Va and VIIIa. APC also reduces the amount risk of anaphylaxis. Second, the thrombolytic actions of
of circulating plasminogen activator inhibitor 1, thereby en- streptokinase are relatively nonspecific and can result in sys-
hancing fibrinolysis. Finally, APC reduces inflammation by temic fibrinolysis. Currently, streptokinase is approved for
inhibiting the release of tumor necrosis factor (TNF-) by treatment of ST elevation myocardial infarction and for treat-
monocytes. Because enhanced coagulability and inflamma- ment of life-threatening pulmonary embolism.
tion are both hallmarks of septic shock, APC has been tested
both in animal models of this disorder and in humans. Re-
combinant activated protein C (r-APC) has been found Recombinant Tissue Plasminogen
to significantly reduce mortality in patients at high risk of Activator (t-PA)
death from septic shock, and the U. S. Food and Drug Ad- An ideal thrombolytic agent would be nonantigenic and
ministration (FDA) has approved r-APC for the treatment would cause local fibrinolysis only at the site of a pathologic
of patients with severe sepsis who demonstrate evidence of thrombus. Tissue plasminogen activator (t-PA) approxi-
acute organ dysfunction, shock, oliguria, acidosis, and hypo- mates these goals. t-PA is a serine protease produced by
xemia. r-APC is not indicated for the treatment of patients human endothelial cells; therefore, t-PA is not antigenic.
with severe sepsis and a lower risk of death, however. As t-PA binds to newly formed (fresh) thrombi with high affin-
is the case with other anticoagulants, r-APC increases the ity, causing fibrinolysis at the site of a thrombus. Once bound
risk of bleeding. This agent is therefore contraindicated in to the fresh thrombus, t-PA undergoes a conformational
patients who have recently undergone a surgical procedure change that renders it a potent activator of plasminogen. In
and in those with chronic liver failure, kidney failure, or contrast, t-PA is a poor activator of plasminogen in the ab-
thrombocytopenia. sence of fibrin-binding.
Recombinant DNA technology has allowed the produc-
THROMBOLYTIC AGENTS tion of recombinant t-PA, generically referred to as al-
teplase. Recombinant t-PA is effective at recanalizing oc-
cluded coronary arteries, limiting cardiac dysfunction, and
Although warfarin, unfractionated and low molecular weight reducing mortality following an ST elevation myocardial
heparins, selective factor Xa inhibitors, and direct thrombin infarction. At pharmacologic doses, however, recombinant
inhibitors are effective in preventing the formation and prop- t-PA can generate a systemic lytic state and (as with other
agation of thrombi, these agents are generally ineffective thrombolytic agents) cause unwanted bleeding, including ce-
against pre-existing clots. Thrombolytic agents are used to rebral hemorrhage. Thus, its use is contraindicated in pa-
lyse already-formed clots, and thereby to restore the patency tients who have had a recent hemorrhagic stroke. Like strep-
of an obstructed vessel before distal tissue necrosis occurs. tokinase, t-PA is approved for use in the treatment of patients
Thrombolytic agents act by converting the inactive zymogen with ST elevation myocardial infarction or life-threatening
plasminogen to the active protease plasmin (Fig. 22-10). As pulmonary embolism. It is also approved for the treatment
noted above, plasmin is a relatively nonspecific protease that of acute ischemic stroke.
digests fibrin to fibrin degradation products. Unfortunately,
thrombolytic therapy has the potential to dissolve not only
pathologic thrombi, but also physiologically appropriate fi- Tenecteplase
brin clots that have formed in response to vascular injury.
Thus, the use of thrombolytic agents can lead to hemorrhage Tenecteplase is a genetically engineered variant of t-PA.
of varying severity. The molecular modifications in tenecteplase increase its fi-
brin specificity relative to t-PA and make tenecteplase more
resistant to plasminogen activator inhibitor 1. Large trials
Streptokinase have shown that tenecteplase is identical in efficacy to
Streptokinase is a protein produced by -hemolytic strepto- t-PA, with similar (and possibly decreased) risk of bleeding.
cocci as a component of that organisms tissue-destroying Additionally, tenecteplase has a longer half-life than t-PA.
machinery. The pharmacologic action of streptokinase in- This pharmacokinetic property allows tenecteplase to be ad-
volves two steps complexation and cleavage. In the com- ministered as a single weight-based bolus, thus simplifying
plexation reaction, streptokinase forms a stable, noncovalent administration.
1:1 complex with plasminogen. The complexation reaction
produces a conformational change in plasminogen that ex-
poses this proteins proteolytically active site. Streptokinase-
Reteplase
complexed plasminogen, with its active site exposed and Similar to tenecteplase, reteplase is a genetically engineered
available, can then proteolytically cleave other plasminogen variant of t-PA with longer half-life and increased specificity
LP-FPPP-92900 R1 CH22 01-15-07 10:08:23
for fibrin. Its efficacy and adverse effect profile are similar viduals. Anticoagulants primarily target plasma coagulation
to those of streptokinase and t-PA. Because of its longer factors and disrupt the coagulation cascade by inhibiting cru-
half-life, reteplase can be administered as a double bolus cial intermediates. After a fibrin clot has been established,
(two boluses, 30 minutes apart). thrombolytic agents mediate dissolution of the clot by pro-
moting the conversion of plasminogen to plasmin. These
classes of pharmacologic agents can be administered either
INHIBITORS OF ANTICOAGULATION AND individually or in combination, to prevent or disrupt throm-
FIBRINOLYSIS bosis and to restore the patency of blood vessels occluded
by thrombus.
Protamine Future development of new antiplatelet, anticoagulant,
Protamine, a low molecular weight polycationic protein, is and thrombolytic agents will be forced to contend with two
a chemical antagonist of heparin. This agent rapidly forms major constraints. First, for many clinical indications in this
a stable complex with the negatively charged heparin mole- field, highly effective, orally bioavailable, and inexpensive
cule through multiple electrostatic interactions. Protamine is therapeutic agents are already available: these include the
administered intravenously to reverse the effects of heparin antiplatelet drug aspirin and the anticoagulant warfarin. Sec-
in situations of life-threatening hemorrhage or great heparin ond, virtually every antithrombotic and thrombolytic agent
excess (for example, at the conclusion of coronary artery is associated with the mechanism-based toxicity of bleeding,
bypass graft surgery). Protamine is most active against the and this side effect is likely to plague new agents under
large heparin molecules in unfractionated heparin and it can development. Nonetheless, opportunities remain for the de-
partially reverse the anticoagulant effects of low molecular velopment of safer and more effective therapies. It is likely
weight heparins, but it is inactive against fondaparinux. that pharmacogenomic techniques (see Chapter 52, Pharma-
cogenomics) will be capable of identifying individuals in
the population who carry an elevated genetic risk of throm-
Serine-Protease Inhibitors bosis, and such individuals may benefit from long-term anti-
thrombotic treatment. Combinations of antiplatelet agents,
Aprotinin, a naturally occurring polypeptide, is an inhibitor low molecular weight heparins, orally bioavailable direct
of the serine proteases plasmin, t-PA, and thrombin. By in- thrombin inhibitors (such as the snake-venomderived prod-
hibiting fibrinolysis, aprotinin promotes clot stabilization. rug ximelagatran, which is not approved for use in the
Inhibition of thrombin may also promote platelet activity by U.S.), and new agents that target currently unexploited com-
preventing platelet hyperstimulation. At higher doses, aprot- ponents of hemostasis (such as inhibitors of the factor VIIa/
inin may also inhibit kallikrein and thereby (paradoxically)
tissue factor pathway) could all be useful in these settings.
inhibit the coagulation cascade. Clinical trials have demon-
At the other end of the spectrum, there remains a great need
strated decreased perioperative bleeding and erythrocyte
for new agents that can achieve rapid, noninvasive, conven-
transfusion requirement in patients treated with aprotinin
ient, and selective lysis of acute thromboses associated with
during cardiac surgery. However, these positive findings
have been tempered by recent evidence suggesting that, life-threatening emergencies such as ST elevation myocar-
compared to other antifibrinolytic agents, aprotinin may in- dial infarction and stroke. Carefully designed clinical trials
crease the risk of postoperative acute renal failure. will be critical to optimize the indications, dose, and duration
of treatment for such drugs and drug combinations.
Furie B, Furie BC. Thrombus formation in vivo. J Clin Invest 2005; effects of COX-2 inhibition in cellular, animal, and human
115:33553362. (Reviews molecular and cellular mechanisms studies.)
of primary and secondary hemostasis in vivo.) Hirsh J, ODonnell M, Weitz JI. New anticoagulants. Blood 2005;
Grosser T, Fries S, FitzGerald GA. Biological basis for the cardio- 105:453463. (Reviews anticoagulants in clinical development.)
vascular consequences of COX-2 inhibition: therapeutic chal- Levy JH. Hemostatic agents. Transfusion 2004;44:58S62S. (Re-
lenges and opportunities. J Clin Invest 2006;116:415. (Reviews views aprotinin, aminocaproic acid, and tranexamic acid.)
Drug Summary Table Chapter 22 Pharmacology of Hemostasis and Thrombosis
Phosphodiesterase Inhibitors
MechanismInhibit platelet cAMP degradation and thereby decrease platelet aggregability
Dipyridamole Prophylaxis against Exacerbation of angina (IV route), rare Hypersensitivity to dipyridamole Weak antiplatelet effect
thromboembolic disorders; myocardial infarction, rare ventricular Usually administered in combination with warfarin
Alternative to exercise in arrhythmia, rare bronchospasm or aspirin
thallium myocardial perfusion Abnormal ECG, hypotension (IV route), Has vasodilatory properties; may paradoxically
imaging abdominal discomfort (oral route), induce angina by causing the coronary steal
dizziness, headache phenomenon
thrombotic strokes in patients thrombocytopenic purpura Neutropenia, thrombocytopenia Requires a loading dose to achieve immediate anti-
intolerant of aspirin Pruritus, rash, dyspepsia, abnormal liver Severe liver dysfunction platelet effect
Prevention of stent thrombosis function tests, dizziness
(in combination with aspirin)
Clopidogrel Secondary prevention of Atrial fibrillation, heart failure, erythema Active bleeding disorder More favorable adverse effect profile than
atherosclerotic events in multiforme, GI hemorrhage (in ticlopidine; significantly less myelotoxicity than
patients with recent combination with aspirin), very rare ticlopidine
myocardial infarction, stroke, anemia or neutropenia, rare intracranial Requires a loading dose to achieve immediate anti-
or peripheral vascular disease hemorrhage, abnormal renal function platelet effect
Acute coronary syndromes Chest pain, edema, hypertension, purpura,
Prevention of stent thrombosis rare abnormal liver function tests, GI
(in combination with aspirin) discomfort, arthralgia, dizziness
(Continued)
Chapter 22 Pharmacology of Hemostasis and Thrombosis 411
Drug Summary Table Chapter 22 Pharmacology of Hemostasis and Thrombosis (Continued)
ANTICOAGULANTS
Warfarin
MechanismInhibit hepatic epoxide reductase that catalyzes the regeneration of reduced vitamin K, which is required for synthesis of biologically active coagulation factors II, VII, IX, and X and
LP-FPPP-92900 R1 CH22 01-15-07 10:08:23
(Continued)
Chapter 22 Pharmacology of Hemostasis and Thrombosis 413
Drug Summary Table Chapter 22 Pharmacology of Hemostasis and Thrombosis (Continued)
within 2 months
Presence of an epidural catheter
Major trauma with an increased
risk of life-threatening bleeding
THROMBOLYTIC AGENTS
MechanismProteolytically activate plasminogen to form plasmin, which digests fibrin to fibrin degradation products
Streptokinase ST elevation myocardial Cardiac arrhythmia, cholesterol embolus Active internal bleeding or known Streptokinase is a foreign bacterial protein that can
infarction syndrome, major bleeding, anaphylactoid bleeding diathesis elicit antigenic responses in humans upon
Arterial thrombosis reaction, polyneuropathy, non-cardiogenic Intracranial or intraspinal surgery repeated administration; prior administration of
Deep vein thrombosis pulmonary edema, hypotension or trauma within 2 months streptokinase is a contraindication to use due to
Pulmonary embolism Fever, shivering Cerebrovascular accident within 2 the risk of anaphylaxis
Intra-arterial or intravenous months Thrombolytic actions of streptokinase are
catheter occlusion Intracranial mass relatively nonspecific and can result in systemic
Severe uncontrolled hypertension fibrinolysis
Recombinant tissue Acute myocardial infarction Cardiac arrhythmia, cholesterol embolus Same as streptokinase Binds to newly formed (fresh) thrombi with high
plasminogen Acute cerebrovascular syndrome, gastrointestinal hemorrhage, affinity, causing fibrinolysis at the site of a
activator (t-PA) thrombosis rare allergic reaction, intracranial thrombus
(Alteplase) Pulmonary embolism hemorrhage, sepsis As with other thrombolytic agents, t-PA can
Central venous catheter generate a systemic lytic state and cause
occlusion unwanted bleeding
Tenecteplase Acute myocardial infarction Cardiac arrhythmia, cholesterol embolus Same as streptokinase Genetically engineered variants of t-PA with
Reteplase syndrome, major bleeding, allergic increased specificity for fibrin
reaction, anaphylaxis, cerebrovascular Longer half-life than t-PA; Tenecteplase is
accident, intracranial hemorrhage administered as a single weight-based bolus;
reteplase is administered as a double bolus
Serine-Protease Inhibitor
MechanismInhibits serine proteases, including plasmin, t-PA, and thrombin
Aprotinin Reduce perioperative bleeding Heart failure, myocardial infarction, shock, Hypersensitivity to aprotinin At higher doses, aprotinin may also inhibit
during coronary artery bypass thrombotic disorder, anaphylaxis with kallikrein and thereby paradoxically inhibit the
graft surgery reexposure, cerebral artery occlusion, coagulation cascade
renal failure Aprotinin may increase the risk of postoperative
acute renal failure relative to other
antifibrinolytic agents
Lysine Analogues
MechanismAnalogues of lysine that bind to and inhibit plasminogen and plasmin
Aminocaproic acid Disorder involving the Bradyarrhythmia, hypotension, thrombotic Disseminated intravascular May cause less acute renal failure relative to
Tranexamic acid fibrinolytic system disorder, drug-induced myopathy coagulation aprotinin
Hemorrhage from increased (aminocaproic acid), rare renal failure Hypersensitivity to aminocaproic
fibrinolysis acid
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