LP-FPPP-92900 R1 CH22 01-15-07 10:08:23

22Pharmacology of Hemostasis andThrombosis

April Wang Armstrong and David E. Golan

IntroductionCasePhysiology of Hemostasis

VasoconstrictionPrimary Hemostasis

Platelet AdhesionPlatelet Granule Release ReactionPlatelet Aggregation and Consolidation

Secondary Hemostasis: The Coagulation CascadeRegulation of Hemostasis

Pathogenesis of ThrombosisEndothelial InjuryAbnormal Blood FlowHypercoagulability

Pharmacologic Classes and AgentsAntiplatelet Agents

Cyclooxygenase InhibitorsPhosphodiesterase InhibitorsADP Receptor Pathway InhibitorsGPIIb–IIIa Antagonists

INTRODUCTION

Blood carries oxygen and nutrients to tissues and takes meta-bolic waste products away from tissues. Humans have devel-oped a well-regulated system of hemostasis to keep theblood fluid and clot-free in normal vessels and to form alocalized plug rapidly in injured vessels. Thrombosis de-scribes a pathologic state in which normal hemostatic pro-cesses are activated inappropriately. For example, a bloodclot (thrombus) may form as the result of a relatively minorvessel injury and occlude a section of the vascular tree. Thischapter presents the normal physiology of hemostasis, thepathophysiology of thrombosis, and the pharmacology ofdrugs that can be used to prevent or reverse a thromboticstate. Drugs introduced in this chapter are used to treat a

387

AnticoagulantsWarfarinUnfractionated and Low Molecular Weight

HeparinsSelective Factor Xa InhibitorsDirect Thrombin InhibitorsRecombinant Activated Protein C (r-APC)

Thrombolytic AgentsStreptokinaseRecombinant Tissue Plasminogen Activator (t-

PA)TenecteplaseReteplase

Inhibitors of Anticoagulation and FibrinolysisProtamineSerine-Protease InhibitorsLysine Analogues

Conclusion and Future DirectionsSuggested Readings

variety of cardiovascular diseases, such as deep vein throm-bosis and myocardial infarction.

Case

Mr. Soprano, a 55-year-old man with a history of hyperten-sion and cigarette smoking, is awakened in the middle ofthe night with substernal chest pressure, sweating, andshortness of breath. He calls 911 and is taken to the emer-gency room. An EKG shows deep T-wave inversions inleads V2 to V5. A cardiac biomarker panel shows a creatinekinase level of 400 U/L (normal, �200 U/L) with 10% MBfraction (the heart-specific isoform), suggesting myocardialinfarction. He is treated with IV nitroglycerin, aspirin, un-fractionated heparin, and eptifibatide, but his chest

LP-FPPP-92900 R1 CH22 01-15-07 10:08:23

388 III Principles of Cardiovascular Pharmacology

pain persists. He is taken to the cardiac catheterization labo-ratory, where he is found to have a 90% mid-LAD (leftanterior descending artery) thrombus with sluggish distalflow. He undergoes successful angioplasty and stent place-ment. At the time of stent placement, an intravenous load-ing dose of clopidogrel is administered. The heparin isstopped, the eptifibatide is continued for 18 more hours,and he is transferred to the telemetry ward. Six hours later,Mr. Soprano is noted to have an expanding hematoma (anarea of localized hemorrhage) in his right thigh below thearterial access site. The eptifibatide is stopped and pressureis applied to the access site, and the hematoma ceases toexpand. He is discharged 2 days later with prescriptions forclopidogrel and aspirin, which are administered to preventsubacute thrombosis of the stent.

QUESTIONS

■ 1. How did a blood clot arise in Mr. Soprano’s coronaryartery?

■ 2. If low molecular weight heparin had been usedinstead of unfractionated heparin, how would themonitoring of the patient’s coagulation status duringthe procedure have been affected?

■ 3. What accounts for the efficacy of eptifibatide (aplatelet GPIIb–IIIa antagonist) in inhibiting plateletaggregation?

■ 4. When the expanding hematoma was observed,could any measure other than stopping theeptifibatide have been used to reverse the effect ofthis agent?

■ 5. How do aspirin, heparin, clopidogrel, and epti-fibatide act in the attempt to treat Mr. Soprano’sblood clot and to prevent recurrent thrombusformation?

PHYSIOLOGY OF HEMOSTASIS

An injured blood vessel must induce the formation of a bloodclot to prevent blood loss and to allow healing. Clot forma-tion must also remain localized to prevent widespread clot-ting within intact vessels. The formation of a localized clotat the site of vessel injury is accomplished in four temporallyoverlapping stages (Fig. 22-1). First, localized vasocon-striction occurs as a response to a reflex neurogenic mecha-nism and to the secretion of endothelium-derived vasocon-strictors such as endothelin. Immediately followingvasoconstriction, primary hemostasis occurs. During thisstage, platelets are activated and adhere to the exposed sube-ndothelial matrix. Platelet activation involves both a changein shape of the platelet and the release of secretory granulecontents from the platelet. The secreted granule substancesrecruit other platelets, causing more platelets to adhere tothe subendothelial matrix and to aggregate with one anotherat the site of vascular injury. Primary hemostasis ultimatelyresults in the formation of a primary hemostatic plug.

The goal of the final two stages of hemostasis is to forma stable, permanent plug. During secondary hemostasis,also known as the coagulation cascade, the activated endo-thelium and other nearby cells (see below) express a mem-brane-bound procoagulant factor called tissue factor, whichcomplexes with coagulation factor VII to initiate the coagu-lation cascade. The end result of this cascade is the activationof thrombin, a critical enzyme. Thrombin serves two pivotalfunctions in hemostasis: (1) it converts soluble fibrinogento an insoluble fibrin polymer that forms the matrix of theclot; and (2) it induces more platelet recruitment and activa-tion. Recent evidence indicates that fibrin clot formation(secondary hemostasis) overlaps temporally with plateletplug formation (primary hemostasis), and that each processreinforces the other. During the final stage, platelet aggrega-tion and fibrin polymerization lead to the formation of astable, permanent plug. In addition, antithrombotic mech-anisms restrict the permanent plug to the site of vessel in-jury, ensuring that the permanent plug does not inappro-priately extend to occlude the vascular tree.

VASOCONSTRICTION

Transient arteriolar vasoconstriction occurs immediatelyafter vascular injury. This vasoconstriction is mediated bya poorly understood reflex neurogenic mechanism. Localendothelial secretion of endothelin, a potent vasoconstric-tor, potentiates the reflex vasoconstriction. Because thevasoconstriction is transient, bleeding would continue if pri-mary hemostasis were not activated.

PRIMARY HEMOSTASIS

The goal of primary hemostasis is to form a platelet plugthat rapidly stabilizes vascular injury. Platelets play a pivotalrole in primary hemostasis. Platelets are cell fragments thatarise by budding from megakaryocytes in the bone marrow;these small, membrane-bound discs contain cytoplasm butlack nuclei. Glycoprotein receptors in the platelet plasmamembrane are the primary mediators by which platelets areactivated. Primary hemostasis involves the transformationof platelets into a hemostatic plug through three reactions:(1) adhesion; (2) the granule release reaction; and (3) aggre-gation and consolidation.

Platelet AdhesionIn the first reaction, platelets adhere to subendothelial colla-gen that is exposed after vascular injury (Fig. 22-2). Thisadhesion is mediated by von Willebrand factor (vWF), alarge multimeric protein that is secreted by both activatedplatelets and the injured endothelium. vWF binds both tosurface receptors (especially glycoprotein Ib [GPIb]) on theplatelet membrane and to the exposed collagen; this ‘‘bridg-ing’’ action mediates adhesion of platelets to the collagen.The GPIb:vWF:collagen interaction is critical for initiationof primary hemostasis, because it is the only known molecu-lar mechanism by which platelets can adhere to the injuredvessel wall.

LP-FPPP-92900 R1 CH22 01-15-07 10:08:23

Chapter 22 Pharmacology of Hemostasis and Thrombosis 389

E

Resting platelets Activated spreadplatelet

Activated contractedplatelet

2μm

Figure 22-1. Sequence of events in hemostasis. The hemostaticprocess can be divided conceptually into four stages—vasoconstric-tion, primary hemostasis, secondary hemostasis, and resolution—although recent evidence suggests that these stages are temporallyoverlapping and may be nearly simultaneous. A. Vascular injurycauses endothelial denudation. Endothelin, released by activated en-dothelium, and neurohumoral factor(s) induce transient vasocon-striction. B. Injury-induced exposure of the subendothelial matrix (1)provides a substrate for platelet adhesion and activation (2). In thegranule release reaction, activated platelets secrete thromboxane A2

(TxA2) and ADP (3). TxA2 and ADP released by activated plateletscause nearby platelets to become activated; these newly activatedplatelets undergo shape change (4) and are recruited to the site ofinjury (5). The aggregation of activated platelets at the site of injuryforms a primary hemostatic plug (6). C. Tissue factor expressed onactivated endothelial cells (1) and leukocyte microparticles (notshown), together with acidic phospholipids expressed on activatedplatelets and activated endothelial cells (2), initiate the steps of thecoagulation cascade, culminating in the activation of thrombin (3).Thrombin proteolytically activates fibrinogen to form fibrin, whichpolymerizes around the site of injury, resulting in the formation of adefinitive (secondary) hemostatic plug (4). D. Natural anticoagulantand thrombolytic factors limit the hemostatic process to the site ofvascular injury. These factors include tissue plasminogen activator(t-PA), which activates the fibrinolytic system (1); thrombomodulin,which activates inhibitors of the coagulation cascade (2); prosta-cyclin, which inhibits both platelet activation and vasoconstriction(3); and surface heparin-like molecules, which catalyze the inactiva-tion of coagulation factors (4). E. Scanning electron micrographs ofresting platelets (1), a platelet undergoing cell spreading shortly aftercell activation (2), and a fully activated platelet after actin filamentbundling and crosslinking and myosin contraction (3).

3. Platelet granule release

Fibrin

A

B

C

D

PGI2

t-PA

1. Tissue factor expression on activated endothelium

4. Fibrin polymerization

1. Release of t-PA (fibrinolysis)

2. Thrombomodulin (blocks coagulation cascade)

3. Release of prostacyclin (inhibits platelet aggregation and vasoconstriction)

4. Surface heparin-like molecules (blocks coagulation cascade)

3. Thrombin activation

2. Phospholipid complex expression

2. Platelet adhesion and activation

1. Subendothelial matrix exposure

4. Platelet shape changeTxA2

ADP5. Platelet recruitment

6. Platelet aggregation (hemostatic plug)

Endothelial cells

Site of vascular injury(denuded endothelium)

Reflexvasoconstriction

Basement membrane

Vascular smooth muscle

Endothelin releaseby activated endothelium

LP-FPPP-92900 R1 CH22 01-15-07 10:08:23

390 III Principles of Cardiovascular Pharmacology

Endothelium

Platelet Fibrinogen

von Willebrandfactor

GPIb

GPIIb-IIIa

Collagen (subendothelium)

Collagen

Figure 22-2. Platelet adhesion and aggregation. von Willebrandfactor mediates platelet adhesion to the subendothelium by bindingboth to the platelet membrane glycoprotein GPIb and to exposedsubendothelial collagen. During platelet aggregation, fibrinogencrosslinks platelets to one another by binding to GPIIb–IIIa receptorson platelet membranes.

Platelet Granule Release ReactionAdherent platelets undergo a process of activation (Fig. 22-3) during which the cells’ granule contents are released. Therelease reaction is initiated by agonist binding to cell surfacereceptors, which activates intracellular protein phosphoryla-tion cascades and ultimately causes release of granule con-tents. Specifically, stimulation by ADP, epinephrine, andcollagen leads to activation of platelet membrane phospholi-pase A2 (PLA2). PLA2 cleaves membrane phospholipids andliberates arachidonic acid, which is converted into a cyclicendoperoxide by platelet cyclooxygenase. Thromboxanesynthase subsequently converts the cyclic endoperoxide intothromboxane A2 (TxA2). TxA2, via a G protein-coupledreceptor, causes vasoconstriction at the site of vascular in-jury by inducing a decrease in cAMP levels within vascularsmooth muscle cells. TxA2 also stimulates the granule re-lease reaction within platelets, thereby propagating the cas-cade of platelet activation and vasoconstriction.

During the release reaction, large amounts of ADP, Ca2�,ATP, serotonin, vWF, and platelet factor 4 are actively se-

Resting platelet

Prothrombin

Thrombin

TXA2

ADP

Tissue factor

von Willebrandfactor

CollagenActivated endothelium

Endothelium

Collagen

Figure 22-3. Platelet activation. Platelet activation is initiated atthe site of vascular injury when circulating platelets adhere to ex-posed subendothelial collagen and are activated by locally generatedmediators. Activated platelets undergo shape change and granulerelease, and platelet aggregates are formed as additional plateletsare recruited and activated. Platelet recruitment is mediated by therelease of soluble platelet factors, including ADP and thromboxaneA2 (TxA2). Tissue factor, expressed on activated endothelium, is acritical initiating component in the coagulation cascade. The mem-branes of activated platelets provide a surface for a number of criticalreactions in the coagulation cascade, including the conversion of pro-thrombin to thrombin.

creted from platelet granules. ADP is particularly importantin mediating platelet aggregation, causing platelets to be-come ‘‘sticky’’ and adhere to one another (see below). Al-though strong agonists (such as thrombin and collagen) cantrigger granule secretion even when aggregation is pre-vented, ADP can trigger granule secretion only in the pres-ence of platelet aggregation. Presumably, this difference iscaused by the set of intracellular effectors that are coupledto the various agonist receptors. Release of Ca2� ions is alsoimportant for the coagulation cascade, as discussed below.

Platelet Aggregation and ConsolidationTxA2, ADP, and fibrous collagen are all potent mediatorsof platelet aggregation. TxA2 promotes platelet aggregationthrough stimulation of G protein-coupled TxA2 receptors inthe platelet membrane (Fig. 22-4). Binding of TxA2 to plate-let TxA2 receptors leads to activation of phospholipase C

LP-FPPP-92900 R1 CH22 01-15-07 10:08:23

Chapter 22 Pharmacology of Hemostasis and Thrombosis 391

PKC

PKC(active)

PIP2

PLA2

IP3

DAG

βγ

GTP

αq

GDP

αq

GPIIb-IIIa

PLC

Ca2+

Ca2+

TXA2

TXA2-R

Arachidonic acid

CyclooxygenaseGeneration ofthromboxane A2by activatedplatelets

1

Activation ofthromboxane A2receptor

2

G protein-mediatedactivation ofphospholipase C

3

PLC hydrolyzes PIP2to yield IP3 and DAG

4

Increase in cytosoliccalcium concentration

5

Activation of proteinkinase C

6

Activation ofphospholipase A2

Fibrinogen

7

Activation ofGPIIb-IIIa

8

Binding of fibrinogento GPIIb-IIIa

9

Platelet aggregation10

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 G�q 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 vesicularrelease of Ca2� into the cytosol. 6. DAG activates protein kinase C (PKC). 7. PKC activates phospholipase A2 (PLA2). 8. Through a poorlyunderstood mechanism, activation of PLA2 leads to the activation of GPIIb–IIIa. 9. Activated GPIIb–IIIa binds to fibrinogen. 10. Fibrinogencrosslinks platelets by binding to GPIIb–IIIa receptors on other platelets. This crosslinking leads to platelet aggregation and formation of aprimary hemostatic plug.

(PLC), which hydrolyzes phosphatidylinositol 4,5-bisphos-phate (PI[4,5]P2) to yield inositol 1,4,5-trisphosphate (IP3)and diacylglycerol (DAG). IP3 raises the cytosolic Ca2�

concentration and DAG activates protein kinase C (PKC),which in turn promotes the activation of PLA2. Through apoorly understood mechanism, PLA2 activation induces theexpression of functional GPIIb–IIIa, the membrane integrinthat mediates platelet aggregation. ADP triggers platelet acti-vation by binding to G protein-coupled ADP receptors on theplatelet surface (Fig. 22-5). The two subtypes of G protein-coupled platelet ADP receptors are termed P2Y1 receptorsand P2Y(ADP) receptors. P2Y1, a Gq-coupled receptor,releases intracellular calcium stores through activation ofphospholipase C. P2Y(ADP), a Gi-coupled receptor, inhibitsadenylyl cyclase. The P2Y(ADP) receptor is the target of theantiplatelet agents ticlopidine and clopidogrel (see below).

Activation of ADP receptors mediates platelet shape changeand expression of functional GPIIb–IIIa. Fibrous collagenactivates platelets by binding directly to platelet glycoproteinVI (GPVI). Ligation of GPVI by collagen leads to phospholi-pase C activation and platelet activation, as described above.

Platelets aggregate with one another through a bridgingmolecule, fibrinogen, which has multiple binding sites forfunctional GPIIb–IIIa (Fig. 22-2). Just as the vWF:GPIbinteraction is important for platelet adhesion to exposed su-bendothelial collagen, the fibrinogen:GPIIb–IIIa interac-tion is critical for platelet aggregation. Platelet aggregationultimately leads to the formation of a reversible clot, or aprimary hemostatic plug.

Activation of the coagulation cascade proceeds nearlysimultaneously with the formation of the primary hemostaticplug, as described below. Activation of the coagulation cas-cade leads to the generation of fibrin, initially at the periph-

LP-FPPP-92900 R1 CH22 01-15-07 10:08:23

392 III Principles of Cardiovascular Pharmacology

βγ

GDP

αiGTP

αiβγ

βγ

GTP

αq

GDP

αq

GDP

αq

PKA

Adenylyl cyclase

P2Y(ADP) receptor

Thrombinreceptor

P2Y1 receptor

Thrombin

AMP

PLC

ADP ADP

1

Decreased PKA activityleads to platelet activation

3

Increased PLC activityleads to platelet activation

7

ATPcAMP

PDE2

4

5

6

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 ofpoorly understood steps. Therefore, the decreased PKA activation that results from ADP binding to the P2Y(ADP) receptor causes plateletactivation. 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 Figure22-4. Note that ADP can activate platelets by binding to either the P2Y(ADP) receptor or the P2Y1 receptor, although recent evidence suggeststhat full platelet activation requires the participation of both receptors.

ery of the primary hemostatic plug. Platelet pseudopods at-tach to the fibrin strands at the periphery of the plug andcontract. Platelet contraction yields a compact, solid, irrever-sible clot, or a secondary hemostatic plug.

SECONDARY HEMOSTASIS: THECOAGULATION CASCADE

Secondary hemostasis is also termed the coagulation cas-cade. The goal of this cascade is to form a stable fibrinclot at the site of vascular injury. Details of the coagulationcascade are presented schematically in Figure 22-6. Severalgeneral principles should be noted.

First, the coagulation cascade is a sequence of enzymaticevents. Most plasma coagulation factors circulate as inactiveproenzymes, which are synthesized by the liver. These pro-enzymes are proteolytically cleaved, and thereby activated,by the activated factors that precede them in the cascade.

The activation reaction is catalytic and not stoichiometric.For example, one ‘‘unit’’ of activated factor X can poten-tially generate 40 ‘‘units’’ of thrombin. This robust amplifi-cation process rapidly generates large amounts of fibrin ata site of vascular injury.

Second, the major activation reactions in the cascadeoccur at sites where a phospholipid-based protein–proteincomplex has formed (Fig. 22-7). This complex is composedof a membrane surface (provided by activated platelets, acti-vated endothelial cells, and possibly activated leukocyte mi-croparticles [see below]), an enzyme (an activated coagula-tion factor), a substrate (the proenzyme form of thedownstream coagulation factor), and a cofactor. The pres-ence of negatively charged phospholipids, especially phos-phatidylserine, is critical for assembly of the complex. Phos-phatidylserine, which is normally sequestered in the innerleaflet of the plasma membrane, translocates to the outerleaflet of the membrane in response to agonist stimulationof platelets, endothelial cells, or leukocytes. Calcium is re-quired for the enzyme, substrate, and cofactor to adopt the

LP-FPPP-92900 R1 CH22 01-15-07 10:08:23

Chapter 22 Pharmacology of Hemostasis and Thrombosis 393

Common pathway

Thrombin (IIa)

IXaVIIaVIIIa

XaVa

Intrinsic pathway

XII

XI

VIII

IX

X

Xa

V

XIII

Prothrombin (II)

XIIIa

Fibrinogen Fibrin Fibrinpolymer

Crosslinkedfibrin polymer

Thrombin (IIa)

XIa

Kallikrein

Ca2+

Ca2+

Ca2+

Tissue injury

Tissuefactor

Prekallikrein

Thrombin (IIa)

Thrombin (IIa)

VIIa

Xa

XIIa

HMWK

Extrinsic pathway

Ca2+

VII

Ca2+

Ca2+

Figure 22-6. Coagulation cascade. The coagulation cascade isarbitrarily divided into the intrinsic pathway, the extrinsic pathway,and the common pathway. The intrinsic and extrinsic pathways con-verge at the level of factor X activation. The intrinsic pathway is largelyan in vitro pathway, while the extrinsic pathway accounts for themajority of in vivo coagulation. The extrinsic pathway is initiated atsites of vascular injury by the expression of tissue factor on severaldifferent cell types, including activated endothelial cells, activatedleukocytes (and leukocyte microparticles), subendothelial vascularsmooth muscle cells, and subendothelial fibroblasts. Note that Ca2�

is a cofactor in many of the steps, and that a number of the stepsoccur on phospholipid surfaces provided by activated platelets, acti-vated endothelial cells, and activated leukocytes (and leukocyte mi-croparticles). Activated coagulation factors are shown in blue andindicated with a lower case ‘‘a.’’ HMWK, high-molecular–weight ki-ninogen.

proper conformation for the proteolytic cleavage of a coagu-lation factor proenzyme to its activated form.

Third, the coagulation cascade has been divided tradition-ally into the intrinsic and extrinsic pathways (Fig. 22-6).This division is a result of in vitro testing and is essentiallyarbitrary. The intrinsic pathway is activated in vitro by factorXII (Hageman factor), while the extrinsic pathway is initi-ated in vivo by tissue factor, a lipoprotein expressed byactivated leukocytes (and microparticles derived from acti-vated leukocytes; see below), activated endothelial cells, su-bendothelial smooth muscle cells, and subendothelial fibro-

VIIIaVIIIa

VaVa

XIXa

Xa

Xa

IXa

Proteolytic cleavage(activation) of factor X

Proteolytic cleavage(activation) of prothrombin

Ca2+

Ca2+

Ca2+

Ca2+

Prothrombin (II)

Thrombin (IIa)

Figure 22-7. Coagulation factor activation on phospholipidsurfaces. Surface catalysis is critical for a number of the activationreactions in the coagulation cascade. Each activation reaction con-sists of an enzyme (e.g., factor IXa), a substrate (e.g., factor X), anda cofactor or reaction accelerator (e.g., factor VIIIa), all of which areassembled on the phospholipid surface of activated platelets, endo-thelial cells, and leukocytes. Ca2� allows the enzyme and substrateto adopt the proper conformation in each activation reaction. In theexample shown, factor VIIIa and Ca2� act as cofactors in the factorIXa-mediated cleavage of factor X to factor Xa. Factor Va and Ca2�

then act as cofactors in the factor Xa-mediated cleavage of prothrom-bin to thrombin.

blasts at the site of vascular injury. Although these twopathways converge at the activation of factor X, there alsoexists much interconnection between the two pathways. Be-cause factor VII (activated by the extrinsic pathway) canproteolytically activate factor IX (a key factor in the intrinsicpathway), the extrinsic pathway is regarded as the primarypathway for the initiation of coagulation in vivo.

Fourth, both the intrinsic and extrinsic coagulation path-ways lead to the activation of factor X. In an important reac-tion that requires factor V, activated factor X proteolyticallycleaves prothrombin (factor II) to thrombin (factor IIa) (Fig.22-8). Thrombin is a multifunctional enzyme that acts in thecoagulation cascade in four important ways: (1) it convertsthe soluble plasma protein fibrinogen into fibrin, which thenforms long insoluble polymer fibers; (2) it activates factorXIII, which crosslinks the fibrin polymers into a highly sta-ble meshwork or clot; (3) it amplifies the clotting cascadeby catalyzing the feedback activation of factors VIII and V;and (4) it strongly activates platelets, causing granule re-lease, platelet aggregation, and platelet-derived microparti-cle generation. In addition to its procoagulant properties,thrombin acts to modulate the coagulation response. Throm-bin binds to thrombin receptors on the intact vascular endo-thelial cells adjacent to the area of vascular injury, and stimu-lates these cells to release the platelet inhibitors prostacyclin(PGI2) and nitric oxide (NO), the profibrinolytic protein tis-sue-type plasminogen activator (t-PA), and the endogenoust-PA modulator plasminogen activator inhibitor 1 (PAI-1)(see below).

The thrombin receptor, a protease-activated G protein-coupled receptor, is expressed in the plasma membrane of

LP-FPPP-92900 R1 CH22 01-15-07 10:08:23

394 III Principles of Cardiovascular Pharmacology

Prothrombin (II)

V

Ca2+

PL

Va

XaVa

VIII

Activatedendothelialcells

Restingendothelialcells

Restingplatelets

Fibrinogen

Fibrin

Fibrin polymer Crosslinkedfibrin polymer

Activatedplatelets

XIII XIIIa

VIIIaVII VIIaXI XIa

Thrombin (IIa)

Figure 22-8. Central role of thrombin in the coagulation cas-cade. In the coagulation cascade, prothrombin is cleaved to thrombinby factor Xa; factor Va and Ca2� act as cofactors in this reaction,and the reaction takes place on an activated (phosphatidylserine-expressing) phospholipid surface (PL). Thrombin converts the solu-ble plasma protein fibrinogen to fibrin, which spontaneously poly-merizes. Thrombin also activates factor XIII, a transglutaminase thatcrosslinks the fibrin polymers into a highly stable meshwork or clot.Thrombin also activates co-factors V and VIII, as well as coagulationfactors VII and XI. In addition, thrombin activates both platelets andendothelial cells. Finally, thrombin stimulates the release of severalantithrombotic factors—including PGI2, NO, and t-PA—from resting(intact) endothelial cells near the site of vascular injury; these factorslimit primary and secondary hemostasis to the injured site (notshown).

platelets, vascular endothelial cells, smooth muscle cells, andfibroblasts. Activation of the thrombin receptor involves pro-teolytic cleavage of an extracellular domain of the receptorby thrombin. The new NH2-terminal-tethered ligand bindsintramolecularly to a discrete site within the receptor andinitiates intracellular signaling. Activation of the thrombinreceptor results in G protein-mediated activation of PLC(Fig. 22-5) and inhibition of adenylyl cyclase.

Finally, recent evidence from intravital (in vivo) micros-copy experiments suggests that leukocyte-derived micropar-ticles have an important role in coupling platelet plug forma-tion (primary hemostasis) to fibrin clot formation (secondaryhemostasis). A subpopulation of these microparticles, re-leased from monocytes that are activated in the context oftissue injury and inflammation, appears to express both tis-sue factor and PSGL-1, a protein that binds to the P-selectinadhesion receptor expressed on activated platelets. By re-cruiting tissue factor-bearing microparticles throughout thedeveloping platelet plug (primary hemostasis), thrombingeneration and fibrin clot formation (secondary hemostasis)could be greatly accelerated within the plug itself. Indeed, itappears that vessel wall tissue factor (expressed by activatedendothelial cells and subendothelial fibroblasts and smoothmuscle cells) and microparticle tissue factor are both impor-tant for formation of a stable clot.

REGULATION OF HEMOSTASIS

Hemostasis is exquisitely regulated for two major reasons.First, hemostasis must be restricted to the local site of vascu-lar injury. That is, activation of platelets and coagulationfactors in the plasma should occur only at the site of endothe-lial damage, tissue factor expression, and procoagulant phos-pholipid exposure. Second, the size of the primary and sec-ondary hemostatic plugs must be restricted so that thevascular lumen remains patent. After vascular injury, intactendothelium in the immediate vicinity of the injury becomes‘‘activated.’’ This activated endothelium presents a set ofprocoagulant factors that promote hemostasis at the site ofinjury, and anticoagulant factors that restrict propagation ofthe clot beyond the site of injury. The procoagulant factors,such as tissue factor and phosphatidylserine, tend to be mem-brane-bound and localized to the site of injury — thesefactors provide a surface on which the coagulation cascadecan proceed. In contrast, the anticoagulant factors are gener-ally secreted by the endothelium and are soluble in the blood.Thus, the activated endothelium maintains a balance of pro-coagulant and anticoagulant factors to limit hemostasis tothe site of vascular injury.

After vascular injury, the endothelium surrounding theinjured area participates in five separate mechanisms thatlimit the initiation and propagation of the hemostatic processto the immediate vicinity of the injury. These mechanismsinvolve prostacyclin (PGI2), antithrombin III, proteins C andS, tissue factor pathway inhibitor (TFPI), and tissue-typeplasminogen activator (t-PA).

Prostacyclin (PGI2) is an eicosanoid (i.e., a metaboliteof arachidonic acid) that is synthesized and secreted by theendothelium. By acting through Gs protein-coupled plateletsurface PGI2 receptors, this metabolite increases cAMP lev-els within platelets and thereby inhibits platelet aggregationand platelet granule release. PGI2 also has potent vasodila-tory effects; this mediator induces vascular smooth musclerelaxation by increasing cAMP levels within the vascularsmooth muscle cells. (Note that these mechanisms are physi-ologically antagonistic to those of TxA2, which inducesplatelet activation and vasoconstriction by decreasing intra-cellular cAMP levels.) Therefore, PGI2 both prevents plate-lets from adhering to the intact endothelium that surroundsthe site of vascular injury and maintains vascular patencyaround the site of injury.

Antithrombin III inactivates thrombin and other coagu-lation factors (IXa, Xa, XIa, and XIIa, where ‘‘a’’ denotesan ‘‘activated’’ factor) by forming a stoichiometric complexwith the coagulation factor (Fig. 22-9). These interactionsare enhanced by a heparin-like molecule that is expressedat the surface of intact endothelial cells, ensuring that thismechanism is operative at all locations in the vascular treeexcept where endothelium is denuded at the site of vascularinjury. (These endothelial cell surface proteoglycans are re-ferred to as ‘‘heparin-like’’ because they are the physiologicequivalent of the pharmacologic agent heparin, discussedbelow.) Heparin-like molecules on the endothelial cells bindto and activate antithrombin III, which is then primed tocomplex with (and thereby inactivate) the activated coagula-tion factors.

LP-FPPP-92900 R1 CH22 01-15-07 10:08:23

Chapter 22 Pharmacology of Hemostasis and Thrombosis 395

+ +

Thrombin

Xa

IXa

XIa

XIIa

Activecoagulation factors

Inactivecoagulation factors

A

B

+ATIII ATIII

Antithrombin III

Endogenous heparin-likemolecules orexogenous

unfractionated heparin

Heparin

Heparin

ATIII

ATIII

ATIII

Thrombin

Xa

IXaXIaXIIa

Xa

IXaXIaXIIa

ATIII

ATIII

Thrombin

ATIII

Heparin Heparin

Heparin

Heparin

Heparin

ATIII

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 healthyendothelial 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 betweenATIII 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-teins that slow the coagulation cascade by inactivating coag-ulation factors Va and VIIIa. Protein C and protein S are partof a feedback control mechanism, in which excess thrombingeneration leads to activation of protein C which, in turn,helps to prevent the enlarging fibrin clot from occludingthe vascular lumen. Specifically, the endothelial cell surfaceprotein thrombomodulin is a receptor for both thrombinand protein C in the plasma. Thrombomodulin binds theseproteins in such a way that thrombomodulin-bound thrombincleaves protein C to activated protein C (also known as pro-tein Ca). In a reaction that requires the cofactor protein S,activated protein C then inhibits clotting by cleaving (andthereby inactivating) factors Va and VIIIa.

Tissue factor pathway inhibitor (TFPI), as its nameindicates, limits the action of tissue factor (TF). The coagula-tion cascade is initiated when factor VIIa complexes withTF at the site of vascular injury (Fig. 22-6). The resultingVIIa:TF complex catalyzes the activation of factors IX andX. After limited quantities of factors IXa and Xa are gener-ated, the VIIa:TF complex becomes feedback inhibited by

TFPI in a two-step reaction. First, TFPI binds to factor Xaand neutralizes its activity in a Ca2�-independent reaction.Subsequently, the TFPI:Xa complex interacts with the VIIa:TF complex via a second domain on TFPI, so that a quater-nary Xa:TFPI:VIIa:TF complex is formed. The molecular‘‘knots’’ of the TFPI molecule hold the quaternary complextightly together and thereby inactivate the VIIa:TF complex.In this manner, TFPI prevents excessive TF-mediated activa-tion of factors IX and X.

Plasmin exerts its anticoagulant effect by proteolyticallycleaving fibrin into fibrin degradation products. Becauseplasmin has powerful antithrombotic effects, the formationof plasmin has intrigued researchers for many years, and anumber of pharmacologic agents have been developed totarget the plasmin formation pathway (Fig. 22-10). Plasminis generated by the proteolytic cleavage of plasminogen, aplasma protein that is synthesized in the liver. The proteoly-tic cleavage is catalyzed by tissue-type plasminogen acti-vator (t-PA), which is synthesized and secreted by the endo-thelium. Plasmin activity is carefully modulated by threeregulatory mechanisms in order to restrict plasmin action to

LP-FPPP-92900 R1 CH22 01-15-07 10:08:23

396 III Principles of Cardiovascular Pharmacology

+

Tissue-type orurokinase-typeplasminogen

activator(inactive)

Tissue-type orurokinase-typeplasminogen

activator

Plasminogenactivator

inhibitor 1 or 2

Plasmin

Inactivatedplasmin

α2-antiplasmin α2-antiplasmin

Plasminogenactivator

inhibitor 1 or 2

Plasminogen

Crosslinkedfibrin polymer

Fibrin degradationproducts

Figure 22-10. The Fibrinolytic System. Plasmin is formed by theproteolytic cleavage of plasminogen by tissue-type or urokinase-typeplasminogen activator. Plasmin formation can be inhibited by plas-minogen activator inhibitor 1 or 2, which binds to and inactivatesplasminogen activators. In the fibrinolytic reaction, plasmin cleavescrosslinked fibrin polymers into fibrin degradation products. �2-Anti-plasmin, which circulates in the bloodstream, neutralizes freeplasmin in the circulation.

the site of clot formation. First, t-PA is most effective whenit is bound to a fibrin meshwork. Second, t-PA activity can beinhibited by plasminogen activator inhibitor (PAI). Whenlocal concentrations of thrombin and inflammatory cyto-kines (such as IL-1 and TNF-�) are high, endothelial cellsincrease the release of PAI, preventing t-PA from activatingplasmin. This ensures that a stable fibrin clot forms at thesite of vascular injury. Third, �2-antiplasmin is a plasmaprotein that neutralizes free plasmin in the circulation andthereby prevents random degradation of plasma fibrinogen.Plasma fibrinogen is important for platelet aggregation inprimary hemostasis (see above), and it is also the precursorfor the fibrin polymer that is required to form a stable clot.

PATHOGENESIS OF THROMBOSIS

Thrombosis is the pathologic extension of hemostasis. Inthrombosis, coagulation reactions are inappropriately regu-lated so that a clot uncontrollably enlarges and occludes thelumen of a blood vessel. The pathologic clot is now termeda thrombus. Three major factors predispose to thrombusformation—endothelial injury, abnormal blood flow, andhypercoagulability. These three factors influence one an-other, and are collectively known as Virchow’s triad (Fig.22-11).

Thrombosis

Endothelialinjury

HypercoagulabilityAbnormalblood flow

Figure 22-11. Virchow’s triad. Endothelial injury, abnormal bloodflow, and hypercoagulability are three factors that predispose tothrombus formation. These three factors are interrelated; endothelialinjury predisposes to abnormal blood flow and hypercoagulability,while abnormal blood flow can cause both endothelial injury andhypercoagulability.

ENDOTHELIAL INJURY

Endothelial injury is the most dominant influence on throm-bus formation in the heart and the arterial circulation. Thereare many possible causes of endothelial injury, includingchanges in shear stress associated with hypertension or tur-bulent flow, hyperlipidemia, elevated blood glucose in dia-betes mellitus, traumatic vascular injury, and some infec-tions. (Recall that Mr. Soprano developed coronary arterythrombosis, which was probably attributable to endothelialinjury secondary to hypertension and cigarette smoking.)

Endothelial injury predisposes the vascular lumen tothrombus formation through three mechanisms. First, plate-let activators, such as exposed subendothelial collagen, pro-mote platelet adhesion to the injured site. Second, exposureof tissue factor on injured endothelium initiates the coagula-tion cascade. Third, natural antithrombotics, such as t-PAand PGI2, become depleted at the site of vascular injurybecause these mechanisms rely on the functioning of an in-tact endothelial cell layer.

ABNORMAL BLOOD FLOW

Abnormal blood flow refers to a state of turbulence or stasisrather than laminar flow. Atherosclerotic plaques commonlypredispose to turbulent blood flow in the vicinity of theplaque. Bifurcations of blood vessels can also create areasof turbulent flow. Turbulent blood flow causes endothelialinjury, forms countercurrents, and creates local pockets ofstasis. Local stasis can also result from formation of an aneu-rysm (a focal out-pouching of a vessel or a cardiac chamber)and from myocardial infarction. In the latter condition, aregion of noncontractile (infarcted) myocardium serves as afavored site for stasis. Cardiac arrhythmias, such as atrialfibrillation, can also generate areas of local stasis. Stasis isthe major cause for the formation of venous thrombi.

Disruption of normal blood flow by turbulence or stasispromotes thrombosis by three major mechanisms. First, theabsence of laminar blood flow allows platelets to come intoclose proximity to the vessel wall. Second, stasis inhibitsthe flow of fresh blood into the vascular bed, so that activatedcoagulation factors in the region are not removed or diluted.

LP-FPPP-92900 R1 CH22 01-15-07 10:08:23

Chapter 22 Pharmacology of Hemostasis and Thrombosis 397

Third, abnormal blood flow promotes endothelial cell activa-tion, which leads to a prothrombotic state.

HYPERCOAGULABILITY

Hypercoagulability is generally less important than endothe-lial injury and abnormal blood flow in predisposing to throm-bosis, but this condition can be an important factor in somepatients. Hypercoagulability refers to an abnormally height-ened coagulation response to vascular injury, resulting fromeither: (1) primary (genetic) disorders; or (2) secondary(acquired) disorders (see Table 22-1). (Hypocoagulablestates, or hemorrhagic disorders, can also result from pri-mary or secondary causes; see Box 22-1 for an example.)

Among the genetic causes of hypercoagulability, the mostprevalent known mutation resides in the gene for coagulationfactor V. It is estimated that 6% of the Caucasian populationin the U.S. carries mutations in the factor V gene. The mostcommon mutation is the Leiden mutation, in which gluta-mine is substituted for arginine at position 506. This positionis important because it is part of a site in factor Va that ismarked for proteolytic cleavage by activated protein C. Themutant factor V Leiden protein is resistant to proteolyticcleavage by activated protein C. As a result of the Leidenmutation, factor Va is allowed to accumulate and thereby topromote coagulation.

A second common mutation (2% incidence) is the pro-thrombin G20210A mutation, in which adenine (A) is sub-stituted for guanine (G) in the 3′-untranslated region of the

TABLE 22-1 Major Causes of Hypercoagulability

CONDITION MECHANISM OF HYPERCOAGULABILITY

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 adhesionHeparin-induced Antibodies to platelet factor 4 → platelet activation

thrombocytopeniaMalignancy Tumor cell induction of tissue factor expressionMyeloproliferative syndromes Elevated blood viscosity, altered plateletsNephrotic syndrome Loss of antithrombin III in urine, ↑ fibrinogen, ↑ platelet activationOral 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

hemoglobinuriaPostpartum period Venous stasis, increased coagulation factors, tissue traumaSurgery/trauma Venous stasis, immobilization, tissue injury

prothrombin gene. This mutation leads to a 30% increase inplasma prothrombin levels. Both the factor V Leiden muta-tion and the prothrombin G20210A mutation are associatedwith a significantly increased risk of venous thrombosis anda modestly increased risk of arterial thrombosis. Other ge-netic disorders that predispose some individuals to thrombo-sis include mutations in the fibrinogen, protein C, proteinS, and antithrombin III genes. Although the latter disordersare relatively uncommon (less than 1% incidence), patientswith a genetic deficiency of protein C, protein S, or anti-thrombin III often present with spontaneous venous throm-bosis.

Hypercoagulability can sometimes be acquired (second-ary) rather than genetic. An example of acquired hypercoa-gulability is the heparin-induced thrombocytopenia syn-drome. In some patients, administration of the anticoagulantheparin stimulates the immune system to generate circulat-ing antibodies directed against a complex consisting of hepa-rin and platelet factor 4. Because platelet factor 4 is presenton platelet and endothelial cell surfaces, antibody bindingto the heparin:platelet factor 4 complex results in antibody-mediated removal of platelets from the circulation; that is,in thrombocytopenia. In some patients, however, antibodybinding also causes platelet activation, endothelial injury,and a prothrombotic state. Although both unfractionated andlow molecular weight heparin (see below) can cause throm-bocytopenia, it appears that low molecular weight heparinhas a lower incidence of thrombocytopenia than unfraction-ated heparin.

LP-FPPP-92900 R1 CH22 01-15-07 10:08:23

398 III Principles of Cardiovascular Pharmacology

BOX 22-1. Hemorrhagic Disorders: The Caseof Hemophilia A

When the vascular endothelium is injured, the hemostaticprocess ensures localized, stable clot formation withoutobstruction of the vascular lumen. Just as thrombosisconstitutes a pathologic variation on this otherwiseorchestrated physiologic process, disorders involvinginsufficient levels of functional platelets or coagulationfactors can lead to a hypocoagulable state characterizedclinically by episodes of uncontrolled hemorrhage.Hemorrhagic disorders result from a multitude of causes,including disorders of the vasculature, vitamin Kdeficiency, and disorders or deficiencies of platelets,coagulation factors, and von Willebrand factor.Hemophilia A serves as an example of a hemorrhagicdisorder in which hypocoagulability is the underlyingpathology.

Hemophilia A is the most common genetic disorder ofserious bleeding. The hallmark of the disorder is areduction in the amount or activity of coagulation factorVIII. The syndrome has an X-linked mode oftransmission, and the majority of patients are males orhomozygous females. Thirty percent of patients have nofamily history of hemophilia A and presumably representspontaneous mutations. The severity of the diseasedepends on the type of mutation in the factor VIII gene.Patients with 6% to 50% of normal factor VIII activitymanifest a mild form of the disease; those with 2% to 5%activity manifest moderate disease; patients with less than1% activity develop severe disease. All symptomaticpatients demonstrate easy bruisability and can developmassive hemorrhage after trauma or surgery. Spontaneoushemorrhage can occur in body areas that are normallysubjected to minor trauma, including joint spaces, wherespontaneous hemorrhage leads to the formation ofhemarthroses. Petechiae (microhemorrhages involvingcapillaries and small vessels, especially in mucocutaneousareas), which are usually an indication of plateletdisorders, are absent in patients with hemophilia.

Patients with hemophilia A are currently treated withinfusions of factor VIII that is either recombinant orderived from human plasma. Factor VIII infusion therapyis sometimes complicated in patients who developantibodies against factor VIII. HIV infection was a seriouscomplication of infusion therapy in patients who receivedfactor VIII products before the institution of routinescreening of blood for HIV infection (before the mid-1980s). Some sources suggest that the entire cohort ofhemophilioes who received factor VIII concentrates(factor VIII concentrated from the blood of manyindividuals) between 1981 and 1985 has been infectedwith HIV. With current blood screening practices and thedevelopment of recombinant factor VIII, the risk ofcontracting HIV through factor VIII infusions is nowvirtually zero.

PHARMACOLOGIC CLASSES ANDAGENTS

Drugs have been developed to prevent and/or reverse throm-bus formation. These drugs fall into three classes: antiplate-let agents, anticoagulants, and thrombolytic agents. Hemo-static agents, discussed at the end of the chapter, areoccasionally used to reverse the effects of anticoagulants orto inhibit endogenous fibrinolysis.

ANTIPLATELET AGENTS

As described above, formation of a localized platelet plugin response to endothelial injury is the initial step in arterialthrombosis. Therefore, inhibition of platelet function is auseful prophylactic and therapeutic strategy against myocar-dial infarction and stroke caused by thrombosis in coronaryand cerebral arteries, respectively. The classes of antiplateletagents in current clinical use include cyclooxygenase (COX)inhibitors, phosphodiesterase inhibitors, ADP receptor path-way inhibitors, and GPIIb–IIIa antagonists.

Cyclooxygenase InhibitorsAspirin inhibits the synthesis of prostaglandins, thereby in-hibiting the platelet release reaction and interfering with nor-mal platelet aggregation.

The biochemistry of prostaglandin synthesis in plateletsand endothelial cells provides a basis for understanding themechanism of action of aspirin as an antiplatelet agent. Fig-ure 22-12 depicts the prostaglandin synthesis pathway,which is discussed in more detail in Chapter 41, Pharmacol-ogy of Eicosanoids. Briefly, activation of both platelets andendothelial cells induces phospholipase A2 (PLA2) to cleavemembrane phospholipids and release arachidonic acid. Ara-chidonic acid is then transformed into a cyclic endoperoxide(also known as prostaglandin G2 or PGG2) by the enzymeCOX. In platelets, the cyclic endoperoxide is converted intothromboxane A2 (TxA2). Acting through cell surface TxA2

receptors, TxA2 causes localized vasoconstriction and is apotent inducer of platelet aggregation and the platelet releasereaction. In endothelial cells, the cyclic endoperoxide is con-verted into prostacyclin (PGI2). PGI2, in turn, causes local-ized vasodilation and inhibits platelet aggregation and theplatelet release reaction.

Aspirin acts by covalently acetylating a serine residuenear the active site of the COX enzyme, thereby inhibitingthe synthesis of the cyclic endoperoxide and the various me-tabolites of the cyclic endoperoxide. In the absence of TxA2,there is a marked decrease in platelet aggregation and theplatelet release reaction (Fig. 22-13A). Because platelets donot contain DNA or RNA, these cells cannot regenerate newCOX enzyme once aspirin has permanently inactivated allof the available COX enzyme. That is, the platelets becomeirreversibly ‘‘poisoned’’ for the lifetime of these cells (7–10days). Although aspirin also inhibits the COX enzyme inendothelial cells, its action is not permanent in endothelialcells because these cells are able to synthesize new COXmolecules. Thus, the endothelial cell production of prosta-

LP-FPPP-92900 R1 CH22 01-15-07 10:08:23

Chapter 22 Pharmacology of Hemostasis and Thrombosis 399

OOH

COOH

COOHO

COOH

S

HN

O

HN COOH

OH2N

COOH

OH

COOH

O

O

OOH

COOH

O

O

OH

COOH

O

COOH

OHOH

HH

O

OCOOH

OH OHHO

O

COOH

NSAIDs(aspirin, others)

Phospholipase A2

Cyclooxygenase

Peroxidase

Lipoxygenase

5-HPETE

Leukotriene A4

Leukotriene C4

Arachidonic acid

Membrane phospholipids

Prostaglandin E2

Otherprostaglandins

Prostaglandin H2

Prostaglandin G2

Thromboxane A2

Prostacyclin (PGI )2

Dehydrase

PGE2 synthase

PGI2 synthase Prostaglandin synthases

TxA2 synthase

Glutathione-S-transferase

Figure 22-12. Overview of Prostaglandin Synthesis. Membrane phospholipids are cleaved by phospholipase A2 to release free arachidonicacid. 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 arachidonicacid 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 discussionof 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.

LP-FPPP-92900 R1 CH22 01-15-07 10:08:23

400 III Principles of Cardiovascular Pharmacology

PKC

PKC(active)

PIP2

PLA2

IP3

DAG

βγ

GTP

αq

GDP

αq

GPIIb-IIIa

βγ

GDP

α i

α iβ

γ

βγ

GTP

αq

GDP

αq

GDP

αq

PKA

GTP

PLC

Ca2+

Ca2+

TXA2 (released by activated platelets)

NSAIDs(aspirin, others)

Abciximab

TXA2-R

Arachidonic acid

Cyclooxygenase

Fibrinogen

A

Clopidogrel,ticlopidine

Adenylyl cyclase

P2Y(ADP) receptor

Thrombinreceptor

P2Y1 receptor

Thrombin

AMP

PLC

ADP ADP

Platelet activation

Platelet activation

ATPcAMP

PDE

Dipyridamole

B

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 decreasedTxA2 production. The effect is profound because platelets lack the ability to synthesize new enzyme molecules. GPIIb–IIIa antagonists, suchas the monoclonal antibody abciximab and the small-molecule antagonists eptifibatide and tirofiban (not shown), inhibit platelet aggregationby preventing activation of GpIIb–IIIa (dashed line), leading to decreased platelet crosslinking by fibrinogen. B. Clopidogrel, ticlopidine, anddipyridamole 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

Chapter 22 Pharmacology of Hemostasis and Thrombosis 401

cyclin is relatively unaffected by aspirin at pharmacologi-cally low doses (see below).

Aspirin is most often used as an antiplatelet agent to pre-vent arterial thrombosis leading to stroke, transient ischemicattack, and myocardial infarction. Because the action of aspi-rin on platelets is permanent, it is most effective as a selectiveantiplatelet agent when taken in low doses and/or at infre-quent intervals. For example, aspirin is often used as anantiplatelet agent at a dose of 81 mg once daily, while atypical anti-inflammatory dose of this agent could be 650mg three to four times daily. Taken at high doses, aspirincan inhibit prostacyclin production without increasing theeffectiveness of the drug as an antiplatelet agent. A moreextended discussion of the uses and toxicities of aspirin isfound in Chapter 41. Compared with aspirin, other nonsteroi-dal anti-inflammatory drugs (NSAIDs) are not as widelyused in the prevention of arterial thrombosis because theinhibitory action of these drugs on cyclooxygenase is notpermanent.

COX-1 is the predominant COX isoform in platelets, butendothelial cells appear to express both COX-1 and COX-2 under physiologic conditions. Because aspirin inhibitsCOX-1 and COX-2 nonselectively, this drug serves as aneffective antiplatelet agent. In contrast, the newer selectiveCOX-2 inhibitors cannot be used as antiplatelet agents be-cause they are poor inhibitors of COX-1. Furthermore, useof the selective COX-2 inhibitors appears to be associatedwith increased cardiovascular risk, most likely because theseagents inhibit endothelial production of PGI2 without inhib-iting platelet generation of TxA2. The adverse impact ofthe selective COX-2 inhibitors on cardiovascular risk hasresulted in the recent withdrawal of most of these agentsfrom the market (see Chapter 41).

Phosphodiesterase InhibitorsIn platelets, an increase in the concentration of intracellularcAMP leads to a decrease in platelet aggregability. PlateletcAMP levels are regulated physiologically by TxA2 andPGI2, among other mediators (see above). The mechanismby which increased intracellular cAMP concentration leadsto decreased platelet aggregability is not well understood.cAMP activates protein kinase A, which, through incom-pletely elucidated mechanisms, decreases availability of theintracellular Ca2� necessary for platelet aggregation (Fig.22-13B). Inhibitors of platelet phosphodiesterase decreaseplatelet aggregability by inhibiting cAMP degradation, whileactivators of platelet adenylyl cyclase decrease platelet ag-gregability by increasing cAMP synthesis. (There are cur-rently no direct adenylyl cyclase activators in clinical use.)

Dipyridamole is an inhibitor of platelet phosphodiester-ase that decreases platelet aggregability (Fig. 22-13B). Dipy-ridamole by itself has only weak antiplatelet effects, and istherefore usually administered in combination with warfarinor aspirin. The combination of dipyridamole and warfarincan be used to inhibit embolization from prosthetic heartvalves, while the combination of dipyridamole and aspirincan be used to reduce the likelihood of thrombosis in patientswith a thrombotic diathesis. Dipyridamole also has vasodila-tory properties. It may paradoxically induce angina in pa-tients with coronary artery disease by causing the coronary

steal phenomenon, which involves intense dilation of coro-nary arterioles (see Chapter 21, Pharmacology of VascularTone).

ADP Receptor Pathway InhibitorsBoth ticlopidine and clopidogrel are derivatives of thieno-pyridine. These agents, which irreversibly inhibit the ADP-dependent pathway of platelet activation, have antiplateleteffects in vitro and in vivo. Ticlopidine and clopidogrel arethought to act by covalently modifying and inactivating theplatelet P2Y(ADP) receptor (also called P2Y12), which isphysiologically coupled to the inhibition of adenylyl cyclase(Fig. 22-13B). Ticlopidine is a prodrug that requires conver-sion to active thiol metabolites in the liver. Maximal plateletinhibition is observed 8 to 11 days after initiating therapywith the drug; used in combination with aspirin, 4 to 7 daysare needed to achieve maximal platelet inhibition. Adminis-tration of a loading dose can produce a more rapid antiplate-let response. Ticlopidine is approved in the U.S. for twoindications: (1) secondary prevention of thrombotic strokesin patients intolerant of aspirin, and (2) in combination withaspirin, prevention of stent thrombosis for up to 30 days afterplacement of coronary artery stents. In general, ticlopidineis considered to be less safe than clopidogrel. The use ofticlopidine has occasionally been associated with neutro-penia, thrombocytopenia, and thrombotic thrombocytopenicpurpura (TTP); for this reason, blood counts must be moni-tored frequently when using ticlopidine.

Clopidogrel, a thienopyridine closely related to ticlopi-dine, has been used widely in combination with aspirin forimproved platelet inhibition during and after elective percu-taneous coronary intervention. Clopidogrel is a prodrug thatmust undergo oxidation by hepatic P450 3A4 to the activedrug form; it may therefore interact with statins and otherdrugs metabolized by this P450 enzyme. Clopidogrel is ap-proved for secondary prevention in patients with recent myo-cardial infarction, stroke, or peripheral vascular disease. Itis also approved for use in acute coronary syndromes thatare treated with either percutaneous coronary interventionor coronary artery bypass grafting. Like ticlopidine, clopido-grel requires a loading dose to achieve a maximal antiplateleteffect rapidly. For this reason, Mr. Soprano was given anintravenous loading dose of clopidogrel in the context of hismyocardial infarction. The adverse effect profile of clopido-grel is more favorable than that of ticlopidine: the gastroin-testinal side effects of clopidogrel are similar to those ofaspirin, and clopidogrel lacks the significant bone marrowtoxicity associated with ticlopidine.

GPIIb–IIIa AntagonistsAs noted above, platelet membrane GPIIb–IIIa receptors areimportant because they constitute the final common pathwayof platelet aggregation, serving to bind fibrinogen moleculesthat bridge platelets to one another. A variety of stimuli (e.g.,TxA2, ADP, epinephrine, collagen, and thrombin), actingthrough diverse signaling molecules, are capable of inducingthe expression of functional GPIIb–IIIa on the platelet sur-face. It could therefore be predicted that antagonists ofGPIIb–IIIa would prevent fibrinogen binding to theGPIIb–IIIa receptor and thus serve as powerful inhibitors of

LP-FPPP-92900 R1 CH22 01-15-07 10:08:23

402 III Principles of Cardiovascular Pharmacology

platelet aggregation. Eptifibatide, the GPIIb– IIIa receptorantagonist used in the opening case, is a highly efficaciousinhibitor of platelet aggregation. A synthetic peptide, eptifi-batide antagonizes the platelet GPIIb–IIIa receptor with highaffinity. This drug has been used to reduce ischemic eventsin patients undergoing percutaneous coronary interventionand to treat unstable angina and non-ST elevation myocar-dial infarction.

Abciximab is a chimeric mouse–human monoclonal an-tibody directed against the human GPIIb–IIIa receptor. Ex-periments in vitro have shown that occupation of 50% ofplatelet GPIIb–IIIa receptors by abciximab significantly re-duces platelet aggregation. The binding of abciximab toGPIIb–IIIa is essentially irreversible, with a dissociationhalf-time of 18 to 24 hours. In clinical trials, adding abcixi-mab to conventional antithrombotic therapy reduces bothlong-term and short-term ischemic events in patientsundergoing high-risk percutaneous coronary intervention.

Tirofiban is a nonpeptide tyrosine analogue that reversi-bly antagonizes fibrinogen binding to the platelet GPIIb–IIIareceptor. Both in vitro and in vivo studies have demonstratedthe ability of tirofiban to inhibit platelet aggregation. Tirofi-ban has been approved for use in patients with acute coro-nary syndromes.

Because of their mechanism of action as antiplateletagents, all of the GPIIb–IIIa antagonists can cause bleedingas an adverse effect. In the opening case, Mr. Soprano devel-oped a hematoma in his right thigh near the arterial accesssite at which eptifibatide was being infused. The expandinghematoma was caused by the excessive antiplatelet effect ofa very high local concentration of eptifibatide at the infusionsite. Importantly, the ability to reverse the effect ofGPIIb–IIIa receptor antagonists differs for the differentagents. Because abciximab is an irreversible inhibitor ofplatelet function, and all the abciximab previously infusedis already bound to platelets, infusion of fresh platelets afterthe drug has been stopped can reverse the antiplatelet effect.In contrast, because the two small-molecule antagonists (ep-tifibatide and tirofiban) bind the receptor reversibly and areinfused in great stoichiometric excess of receptor number,infusion of fresh platelets simply offers new sites to whichthe drug can bind, and it is not practical to deliver a sufficientnumber of platelets to overwhelm the vast excess of drugpresent. Therefore, one must stop the drug infusion and waitfor platelet function to return to normal as the drug is cleared.In the case of Mr. Soprano, no other measure could havebeen taken to reverse the effect of eptifibatide at the timehis hematoma was recognized.

ANTICOAGULANTS

As with antiplatelet agents, anticoagulants are used both toprevent and treat thrombotic disease. There are four classesof anticoagulants: warfarin, unfractionated and low molecu-lar weight heparins, selective factor Xa inhibitors, and directthrombin inhibitors. Anticoagulants target various factors inthe coagulation cascade, thereby interrupting the cascade andpreventing the formation of a stable fibrin meshwork (sec-ondary hemostatic plug). In this section, the four classes ofanticoagulants are discussed in order of selectivity, from theleast selective agents (warfarin and unfractionated heparin)

to the most selective agents (selective factor Xa inhibitorsand direct thrombin inhibitors). Recombinant activated pro-tein C also has anticoagulant activity, although its clinicalindication is severe sepsis. Because of the mechanisms ofaction of these drugs, bleeding is an adverse effect commonto all anticoagulants.

WarfarinIn the early 1900s, farmers in Canada and the North Dakotaplains adopted the practice of planting sweet clover insteadof corn for fodder. In the winter months of 1921 to 1922, afatal hemorrhagic disease was reported in cattle that hadforaged on the sweet clover. In almost every case, it wasfound that the affected cattle had foraged on sweet cloverthat had been spoiled by the curing process. After an inten-sive investigation, scientist K. P. Link reported that thespoiled clover contained the natural anticoagulant 3,3′-meth-ylene-bis-(4-hydroxycoumarin) or ‘‘dicumarol.’’ Dicumaroland warfarin (a potent synthetic congener) were introducedduring the 1940s as rodenticides and as oral anticoagulants.Because the oral anticoagulants act by affecting vitaminK-dependent reactions, it is important to understand howvitamin K functions.

Mechanism of Action of Vitamin K

Vitamin K (‘‘K’’ is derived from the German word ‘‘Koagu-lation’’) is required for the normal hepatic synthesis of fourcoagulation factors (II, VII, IX, and X), protein C, and pro-tein S. The coagulation factors, protein C, and protein S arebiologically inactive as unmodified polypeptides followingprotein synthesis on ribosomes. These proteins gain biologi-cal activity by post-translational carboxylation of their 9 to12 amino-terminal glutamic acid residues. The �-carboxyl-ated glutamate residues (but not the unmodified glutamateresidues) are capable of binding Ca2� ions. Ca2� bindinginduces a conformational change in these proteins that isrequired for efficient binding of the proteins to phospholipidsurfaces. The ability of the �-carboxylated molecules to bindCa2� increases the enzymatic activity of coagulation factorsIIa, VIIa, IXa, Xa, and protein Ca by approximately 1,000-fold. Thus, vitamin K-dependent carboxylation is crucial forthe enzymatic activity of the four coagulation factors andprotein C, and for the cofactor function of protein S.

The carboxylation reaction requires (1) a precursor formof the target protein with its 9 to 12 amino-terminal glutamicacid 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,vitamin K is oxidized to the inactive 2,3-epoxide. An en-zyme, epoxide reductase, is then required to convert the inac-tive 2,3-epoxide into the active, reduced form of vitamin K.Thus, the regeneration of reduced vitamin K is essentialfor the sustained synthesis of biologically functional clottingfactors II, VII, IX, and X, all of which are critical componentsof the coagulation cascade.

Mechanism of Action of Warfarin

Warfarin acts on the carboxylation pathway, not by inhibit-ing the carboxylase directly, but by blocking the epoxide

LP-FPPP-92900 R1 CH22 01-15-07 10:08:23

Chapter 22 Pharmacology of Hemostasis and Thrombosis 403

Figure 22-14. Mechanism of action of warfarin.Vitamin K is a necessary cofactor in the post-transla-tional carboxylation of glutamate residues on factors II,VII, IX, and X. During the carboxylation reaction, vitaminK is oxidized to the inactive 2,3-epoxide. The enzymeepoxide reductase converts the inactive vitamin K 2,3-epoxide into the active, reduced form of vitamin K. Theregeneration of reduced vitamin K is essential for thesustained synthesis of biologically functional coagula-tion factors II, VII, IX, and X. Warfarin acts on the carbox-ylation pathway by inhibiting the epoxide reductasethat is required for the regeneration of reduced (active)vitamin K. Dicumarol is the natural anticoagulantformed in spoiled clover. Both warfarin and dicumarolare orally bioavailable, and are often termed ‘‘oral anti-coagulants.’’

O

OH

OO

OH

OO

OH

O O

R

OH

OH

R

O

O

O

HN

NH

O

COOH

COOH

HN

NH

O

COOH

Vitamin K-dependentcarboxylase

Epoxidereductase

WarfarinDicumarol

Oral anticoagulants

NADHNAD+

Vitamin K-reduced(active form)

Vitamin K 2,3-epoxide(inactive form)

Glutamate residue incoagulation factor

CO2

O2

γ-Carboxy glutamate residue incoagulation factor

reductase that mediates the regeneration of reduced vitaminK (Fig. 22-14). Because depletion of reduced vitamin K inthe liver prevents the �-carboxylation reaction that is re-quired for the synthesis of biologically active coagulationfactors, the onset of action of the oral anticoagulants parallelsthe half-life of these coagulation factors in the circulation.Of the four affected clotting factors (II, VII, IX, and X),factor VII has the shortest half-life (6 hours). Thus, the phar-macologic effect of a single dose of warfarin is not mani-fested for approximately 18 to 24 hours (i.e., for 3 to 4 factorVII half-lives). This delayed action is one pharmacologicproperty that distinguishes the warfarin class of anticoagu-lants from all the other classes of anticoagulants.

Evidence from studies of long-term rodenticide usesupports the hypothesis that the epoxide reductase is themolecular target of oral anticoagulant action. The use oforal anticoagulants as rodenticides has been a widespreadpractice in farming communities. In some areas of theUnited States, heavy rodenticide use has selected for apopulation of wild rodents that is resistant to 4-hydrox-ycoumarins. In vitro studies of tissues from these rodentshave demonstrated a mutation in the rodent epoxide re-ductase that renders the enzyme resistant to inhibition bythe anticoagulant. Similarly, a small population of patientsis genetically resistant to warfarin because of mutationsin their epoxide reductase gene. These patients require 10

LP-FPPP-92900 R1 CH22 01-15-07 10:08:23

404 III Principles of Cardiovascular Pharmacology

TABLE 22-2A Examples of Drugs That Diminish Warfarin’s Anticoagulant Effect

DRUG OR DRUG CLASS MECHANISM

Cholestyramine Inhibits warfarin absorption in the GI tractBarbiturates, carbamazepine, Accelerate warfarin metabolism by inducing hepatic

phenytoin, rifampin P450 enzymes (especially P450 2C9)Vitamin K (reduced) Bypasses warfarin’s inhibition of epoxide reductase

GI, gastrointestinal.

to 20 times the usual dose of warfarin to achieve thedesired anticoagulant effect.

Clinical Uses of Warfarin

Warfarin is often administered to complete a course of anti-coagulation that has been initiated with heparin (see below)and to prevent thrombosis in predisposed patients. Orallyadministered warfarin is nearly 100% bioavailable, and itslevels in the blood peak at 0.5 to 4 hours after administration.In the plasma, 99% of racemic warfarin is bound to plasmaprotein (albumin). Warfarin has a relatively long eliminationhalf-life (approximately 36 hours). The drug is hydroxylatedby the cytochrome P450 system in the liver to inactive me-tabolites that are subsequently eliminated in the urine.

Drug–drug interactions must be carefully considered inpatients taking warfarin. Because warfarin is highly albu-min-bound in the plasma, co-administration of warfarin withother albumin-bound drugs can increase the free (unbound)plasma concentrations of both drugs. In addition, becausewarfarin is metabolized by P450 enzymes in the liver, co-administration of warfarin with drugs that induce and/orcompete for P450 metabolism can affect the plasma concen-trations of both drugs. Table 22-2 lists some of the majorinteractions between warfarin and other drugs.

Among the adverse effects of warfarin, bleeding is themost serious and predictable toxicity. Withdrawal of thedrug may be recommended for patients who suffer fromrepeated bleeding episodes at otherwise therapeutic drug

TABLE 22-2B Examples of Drugs That Enhance Warfarin’s Anticoagulant Effect

DRUG OR DRUG CLASS MECHANISM

Chloral hydrate Displaces warfarin from plasma albuminAmiodarone, clopidogrel, Decrease warfarin metabolism by inhibiting hepatic

ethanol (intoxicating dose), P450 enzymes (especially P450 2C9)fluconazole, fluoxetine,metronidazole,sulfamethoxazole

Broad-spectrum antibiotics Eliminate gut bacteria and thereby reduce availabilityof vitamin K in the GI tract

Anabolic steroids (testosterone) Inhibit synthesis and increase degradation ofcoagulation factors

GI, gastrointestinal.

concentrations. For severe hemorrhage, patients shouldpromptly 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-cause it can cross the placenta and cause a hemorrhagicdisorder in the fetus. In addition, newborns exposed to warfa-rin in utero may have serious congenital defects character-ized by abnormal bone formation (certain bone matrix pro-teins are �-carboxylated). Rarely, warfarin causes skinnecrosis as a result of widespread thrombosis in the micro-vasculature. The fact that warfarin can cause thrombosis mayseem paradoxical. Recall that, in addition to inhibiting thesynthesis of biologically active coagulation factors II, VII,IX, and X, warfarin also prevents the synthesis of biologi-cally active proteins C and S, which are natural anticoagu-lants. In patients who are genetically deficient in protein Cor protein S (most commonly, patients who are heterozygousfor protein C deficiency), an imbalance between warfarin’seffects on coagulation factors and its effects on proteins Cand S may lead to microvascular thrombosis and skin ne-crosis.

Because warfarin has a narrow therapeutic index and par-ticipates in numerous drug–drug interactions, the pharmaco-dynamic (functional) effect of chronic warfarin therapy mustbe monitored regularly (on the order of every 2 to 4 weeks).Monitoring is most easily performed using the prothrombintime (PT), which is a simple test of the extrinsic and com-mon pathways of coagulation. In this test, the patient’splasma is added to a crude preparation of tissue factor (called

LP-FPPP-92900 R1 CH22 01-15-07 10:08:23

Chapter 22 Pharmacology of Hemostasis and Thrombosis 405

thromboplastin), and the time for formation of a fibrin clotis measured. Warfarin prolongs the PT mainly because itdecreases the amount of biologically functional factor VIIin the plasma. (Recall that factor VII is the vitamin K-depen-dent coagulation factor with the shortest half-life.) Measure-ment of the PT has been standardized worldwide, and isexpressed as the International Normalized Ratio (INR) ofthe prothrombin time in the patient sample to that in a controlsample, normalized for the international sensitivity index(ISI) of the laboratory’s thromboplastin preparation com-pared to the World Health Organization’s reference throm-boplastin preparation. The formula used to calculate the INRis as follows: INR � [PTpatient / PTcontrol]ISI.

Unfractionated and Low Molecular WeightHeparinsStructure of Heparin

Heparin is a sulfated mucopolysaccharide stored in the se-cretory granules of mast cells. It is a highly sulfated polymerof alternating uronic acid and D-glucosamine. Heparin mole-cules are highly negatively charged; indeed, endogenousheparin is the strongest organic acid in the human body.Commercial preparations of heparin are quite heterogene-ous, with molecular weights ranging from 1 to 30 kDa. Con-ventionally, commercially prepared heparins have been cate-gorized into unfractionated (standard) heparin and lowmolecular weight (LMW) heparin. Unfractionated hepa-rin, which is often prepared from bovine lung and porcineintestinal mucosa, ranges in molecular weight from 5 to 30kDa. LMW heparins are prepared from standard heparinby gel filtration chromatography; their molecular weightsrange from 1 to 5 kDa.

Mechanism of Action of Heparin

Heparin’s mechanism of action depends on the presence ofa specific plasma protease inhibitor, antithrombin III. Anti-thrombin III is actually a misnomer because, in additionto inactivating thrombin, antithrombin III inactivates otherserine proteases including factors IXa, Xa, XIa, and XIIa.Antithrombin III can be considered as a stoichiometric ‘‘sui-cide trap’’ for these serine proteases. When one of the pro-teases encounters an antithrombin III molecule, the serineresidue at the active site of the protease attacks a specificArg–Ser peptide bond in the reactive site of the antithrom-bin. The result of this nucleophilic attack is the formationof a covalent ester bond between the serine residue on theprotease and the arginine residue on the antithrombin III.This results in a stable 1:1 complex between the proteaseand antithrombin molecules, which prevents the proteasefrom further participation in the coagulation cascade.

In the absence of heparin, the binding reaction betweenthe proteases and antithrombin III proceeds slowly. Heparin,acting as a cofactor, accelerates the reaction by 1,000-fold.Heparin has two important physiologic functions: (1) itserves as a catalytic surface to which both antithrombin IIIand the serine proteases bind; and (2) it induces a conforma-tional change in antithrombin III that makes the reactive siteof this molecule more accessible to the attacking protease.The first step of the reaction involves the binding of thenegatively charged heparin to a lysine-rich region (a region

of positive charge) on antithrombin III. Thus, the interactionbetween heparin and antithrombin III is partly electrostatic.During the conjugation reaction between the protease andthe antithrombin, heparin may be released from antithrombinIII and become available to catalyze additional pro-tease–antithrombin III interactions (i.e., heparin is not con-sumed by the conjugation reaction [Fig. 22-9]). In practice,however, heparin’s high negative charge often causes this‘‘sticky’’ molecule to remain electrostatically bound to pro-tease, antithrombin or another nearby molecule in the vicin-ity of a thrombus.

Interestingly, heparins of different molecular weightshave divergent anticoagulant activities. These divergent ac-tivities derive from the differential requirements for heparinbinding exhibited by the inactivation of thrombin and factorXa by antithrombin III (Fig. 22-15). To catalyze most effi-ciently the inactivation of thrombin by antithrombin III, asingle molecule of heparin must bind simultaneously to boththrombin and antithrombin. This ‘‘scaffolding’’ function isrequired in addition to the heparin-induced conformationalchange in antithrombin III that renders the antithrombin sus-ceptible to conjugation with thrombin. In contrast, to cata-lyze the inactivation of factor Xa by antithrombin III, theheparin molecule must bind only to the antithrombin, be-cause the conformational change in antithrombin III inducedby heparin binding is sufficient by itself to render the anti-thrombin susceptible to conjugation with factor Xa. Thus,LMW heparins, which have an average molecular weight of3 to 4 kDa and contain fewer than 18 monosaccharide units,efficiently catalyze the inactivation of factor Xa by anti-thrombin III but less efficiently catalyze the inactivation ofthrombin by antithrombin III. In contrast, unfractionatedheparin, which has an average molecular weight of 20 kDaand contains more than 18 monosaccharide units, is of suffi-cient length to bind simultaneously to thrombin and anti-thrombin III, and therefore efficiently catalyzes the inactiva-tion of both thrombin and factor Xa by antithrombin III.Quantitatively, LMW heparin has a threefold higher ratio ofanti-Xa to anti-thrombin (anti-IIa) activity than does unfrac-tionated heparin. LMW heparin is therefore a more selectivetherapeutic agent than unfractionated heparin. Both LMWheparin and unfractionated heparin use a pentasaccharidestructure of high negative charge to bind antithrombin IIIand to induce the conformational change in antithrombinrequired for the conjugation reactions. This pentasaccharidehas recently been approved for use as a highly selectiveinhibitor of factor Xa (fondaparinux; see below).

Clinical Uses of Heparins

Heparins are used for both prophylaxis and treatment ofthromboembolic diseases. Both unfractionated and LMWheparins are used to prevent propagation of establishedthromboembolic disease such as deep vein thrombosis andpulmonary embolism. For prophylaxis against thrombosis,heparins are used at much lower doses than those indicatedfor the treatment of established thromboembolic disease. Be-cause the enzymatic coagulation cascade functions as an am-plification system (e.g., 1 unit of factor Xa generates 40 unitsof thrombin), the administration of relatively small amountsof circulating heparin at the first generation of factor Xa ishighly effective. Heparins are highly negatively charged, and

LP-FPPP-92900 R1 CH22 01-15-07 10:08:23

406 III Principles of Cardiovascular Pharmacology

Unfractionated heparin

Binds to antithrombin III (ATIII)and thrombin(inactivates thrombin)

(about 45 saccharide units,MW ~ 13,500)

Low molecular weight (LMW) heparins

Selective factor Xa inhibitors

Direct thrombin inhibitors

No effect on thrombin

No effect on Xa

(about 15 saccharide units,MW ~ 4,500)

Effect on ThrombinAnticoagulant class Effect on Factor Xa

Binds to antithrombin III (ATIII)via pentasaccharide(sufficient to inactivate Xa)

Binds to antithrombin III (ATIII)but not to thrombin(poorly inactivates thrombin)

Selectively inactivate thrombin

Binds to antithrombin III (ATIII)via pentasaccharide(sufficient to inactivate Xa)

Binds to antithrombin III (ATIII)via pentasaccharide(sufficient to inactivate Xa)

Fondaparinux

Lepirudin

Argatroban

ATIII ATIII

LMWH LMWH

Thrombin

Thrombin

ATIIIATIII

Heparin

Xa

Xa

ATIII

Xa

Heparin

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 pentasaccharideunit (5) and to thrombin via an additional 13 saccharide unit (here labeled ‘‘Heparin’’). Low molecular weight heparin (LMWH) does notcontain a sufficient number of saccharide units to bind thrombin, and therefore is a poor catalyst for thrombin inactivation. Effect on factorXa: Inactivation of factor Xa requires only the binding of antithrombin III to the high-affinity pentasaccharide unit (5). Both unfractionatedheparin 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

Chapter 22 Pharmacology of Hemostasis and Thrombosis 407

neither unfractionated heparin nor LMW heparin can crossthe epithelial cell layer of the gastrointestinal tract. Hence,heparin must be administered parenterally, usually via intra-venous or subcutaneous routes.

Unfractionated heparin is often used in combinationwith antiplatelet agents in the treatment of acute coronarysyndromes. For example, Mr. Soprano was treated with theantiplatelet agents aspirin and eptifibatide and with unfrac-tionated heparin in an attempt to limit the extent of his myo-cardial infarction. Monitoring of unfractionated heparin ther-apy is important for maintaining the anticoagulant effectwithin the therapeutic range, because excessive heparin ad-ministration significantly increases the risk of bleeding.Monitoring is usually performed using the activated partialthromboplastin time (aPTT) assay. The aPTT is a simpletest of the intrinsic and common pathways of coagulation.The patient’s plasma is added to an excess of phospholipid,and fibrin forms at a normal rate only if the factors in theintrinsic and common pathways are present at normal levels.Increasing amounts of unfractionated heparin in the plasmaprolong the time required for the formation of a fibrin clot.

As is true of the other anticoagulants, the major adverseeffect of heparin is bleeding. Thus, it is critical to maintainthe anticoagulant effect of unfractionated heparin within thetherapeutic range in order to prevent the rare, devastatingadverse effect of intracranial hemorrhage. In addition, asmall fraction of patients taking heparin develop heparin-induced thrombocytopenia (HIT). In this syndrome, pa-tients develop antibodies to a hapten created when heparinmolecules bind to the platelet surface. In HIT type 1, theantibody-coated platelets are targeted for removal from thecirculation, and the platelet count decreases by 50% to 75%approximately 5 days into the course of heparin therapy.The thrombocytopenia in HIT type 1 is transient and rapidlyreversible upon heparin withdrawal. In HIT type 2, however,the heparin-induced antibodies not only target the plateletsfor destruction but also act as agonists to activate the plate-lets, leading to platelet aggregation, endothelial injury, andpotentially fatal thrombosis. There is a higher incidence ofHIT in patients receiving unfractionated heparin than inthose receiving LMW heparin.

The LMW heparins enoxaparin, dalteparin and tinza-parin are each fractionated heparins of low molecularweight. As discussed above, these agents are relatively selec-tive for anti-Xa compared to anti-IIa (anti-thrombin) activity.All LMW heparins are approved for use in the preventionand treatment of deep vein thrombosis. Additionally, enoxa-parin and dalteparin have been studied in the treatment ofacute myocardial infarction and as adjuncts to percutaneouscoronary intervention. LMW heparins have a higher thera-peutic index than unfractionated heparin, especially whenused for prophylaxis. For this reason, it is generally not nec-essary to monitor blood activity levels of LMW heparins.Accurate measurement of the anticoagulant effect of LMWheparins requires a specialized assay for anti-factor Xa activ-ity. Because LMW heparins are excreted via the kidneys,care should be taken to avoid excessive anticoagulation inpatients with renal insufficiency.

Selective Factor Xa InhibitorsFondaparinux is a synthetic pentasacharide molecule thatcontains the sequence of five essential carbohydrates neces-

sary for binding to antithrombin III and inducing the confor-mational change in antithrombin required for conjugation tofactor Xa (see above). This agent is therefore is a specificinhibitor of Xa, with negligible anti-IIa (anti-thrombin) ac-tivity. Fondaparinux is approved for prevention and treat-ment of deep vein thrombosis, and is available as a once-daily subcutaneous injection. It is excreted via the kidneysand should not be administered to patients with renal insuffi-ciency.

Direct Thrombin InhibitorsAs discussed above, thrombin plays a number of criticalroles in the hemostatic process (Fig. 22-8). Among othereffects, this clotting factor (1) proteolytically converts fibrin-ogen to fibrin, (2) activates factor XIII, which crosslinksfibrin polymers to form a stable clot, (3) activates platelets,and (4) induces endothelial release of PGI2, t-PA, and PAI-1. Thus, direct thrombin inhibitors would be expected tohave profound effects on coagulation. The currently ap-proved direct thrombin inhibitors include lepirudin, desiru-din, bivalirudin, and argatroban. These agents are specificinhibitors of thrombin, with negligible anti-factor Xa ac-tivity.

Lepirudin, a recombinant 65-amino acid polypeptide de-rived from the medicinal leech protein hirudin, is the proto-typical direct thrombin inhibitor. For years, surgeons haveused medicinal leeches to prevent thrombosis in the finevessels of reattached digits. Lepirudin binds with high affin-ity to two sites on the thrombin molecule — the enzymaticactive site and the ‘‘exosite,’’ a region of the thrombin pro-tein that orients substrate proteins. Lepirudin binding tothrombin prevents the thrombin-mediated activation of fi-brinogen and factor XIII. Lepirudin is a highly effectiveanticoagulant because it can inhibit both free and fibrin-bound thrombin in developing clots, and because lepirudinbinding to thrombin is essentially irreversible. It is approvedfor use in the treatment of heparin-induced thrombocyto-penia. Lepirudin has a short half-life, is available parenter-ally, and is renally excreted. It can be administered withrelative safety to patients with hepatic insufficiency. As withall direct thrombin inhibitors, bleeding is the major side ef-fect of lepirudin, and clotting times must be monitoredclosely. A small percentage of patients may develop anti-hirudin antibodies, limiting the long-term effectiveness ofthis agent as an anticoagulant. Another recombinant formu-lation of hirudin, desirudin, has been approved for prophy-laxis against deep vein thrombosis in patients undergoinghip replacement.

Bivalirudin is a synthetic 20-amino acid peptide that,like lepirudin and desirudin, binds to both the active site andexosite of thrombin and thereby inhibits thrombin activity.Thrombin slowly cleaves an arginine–proline bond in bivali-rudin, leading to reactivation of the thrombin. Bivalirudinis approved for anticoagulation in patients undergoing coro-nary angiography and angioplasty, and may have reducedrates of bleeding relative to heparin for this indication. Thedrug is excreted renally and has a short half-life (25 minutes).

Argatroban is a small-molecule inhibitor of thrombinthat is approved for the treatment of patients with heparin-induced thrombocytopenia. Unlike other direct thrombin in-hibitors, argatroban binds only to the active site of thrombin

LP-FPPP-92900 R1 CH22 01-15-07 10:08:23

408 III Principles of Cardiovascular Pharmacology

(i.e., it does not interact with the exosite). Also unlike otherdirect thrombin inhibitors, argatroban is excreted by biliarysecretion, and can therefore be administered with relativesafety to patients with renal insufficiency.

Recombinant Activated Protein C (r-APC)As described above, endogenously activated protein C(APC) exerts an anticoagulant effect by proteolyticallycleaving factors Va and VIIIa. APC also reduces the amountof circulating plasminogen activator inhibitor 1, thereby en-hancing fibrinolysis. Finally, APC reduces inflammation byinhibiting the release of tumor necrosis factor � (TNF-�) bymonocytes. Because enhanced coagulability and inflamma-tion are both hallmarks of septic shock, APC has been testedboth in animal models of this disorder and in humans. Re-combinant activated protein C (r-APC) has been foundto significantly reduce mortality in patients at high risk ofdeath from septic shock, and the U. S. Food and Drug Ad-ministration (FDA) has approved r-APC for the treatmentof patients with severe sepsis who demonstrate evidence ofacute organ dysfunction, shock, oliguria, acidosis, and hypo-xemia. r-APC is not indicated for the treatment of patientswith severe sepsis and a lower risk of death, however. Asis the case with other anticoagulants, r-APC increases therisk of bleeding. This agent is therefore contraindicated inpatients who have recently undergone a surgical procedureand in those with chronic liver failure, kidney failure, orthrombocytopenia.

THROMBOLYTIC AGENTS

Although warfarin, unfractionated and low molecular weightheparins, selective factor Xa inhibitors, and direct thrombininhibitors are effective in preventing the formation and prop-agation of thrombi, these agents are generally ineffectiveagainst pre-existing clots. Thrombolytic agents are used tolyse already-formed clots, and thereby to restore the patencyof an obstructed vessel before distal tissue necrosis occurs.Thrombolytic agents act by converting the inactive zymogenplasminogen to the active protease plasmin (Fig. 22-10). Asnoted above, plasmin is a relatively nonspecific protease thatdigests fibrin to fibrin degradation products. Unfortunately,thrombolytic therapy has the potential to dissolve not onlypathologic thrombi, but also physiologically appropriate fi-brin clots that have formed in response to vascular injury.Thus, the use of thrombolytic agents can lead to hemorrhageof varying severity.

StreptokinaseStreptokinase is a protein produced by �-hemolytic strepto-cocci as a component of that organism’s tissue-destroyingmachinery. The pharmacologic action of streptokinase in-volves two steps — complexation and cleavage. In the com-plexation reaction, streptokinase forms a stable, noncovalent1:1 complex with plasminogen. The complexation reactionproduces a conformational change in plasminogen that ex-poses this protein’s proteolytically active site. Streptokinase-complexed plasminogen, with its active site exposed andavailable, can then proteolytically cleave other plasminogen

molecules to plasmin. In fact, the thermodynamically stablestreptokinase:plasminogen complex is the most catalyticallyefficient plasminogen activator in vitro.

Although streptokinase exerts its most dramatic and po-tentially beneficial effects in fresh thrombi, its use has beenlimited by two factors. First, streptokinase is a foreign pro-tein that is capable of eliciting antigenic responses in humansupon repeated administration. Previous administration ofstreptokinase is a contraindication to its use, because of therisk of anaphylaxis. Second, the thrombolytic actions ofstreptokinase are relatively nonspecific and can result in sys-temic fibrinolysis. Currently, streptokinase is approved fortreatment of ST elevation myocardial infarction and for treat-ment of life-threatening pulmonary embolism.

Recombinant Tissue PlasminogenActivator (t-PA)An ideal thrombolytic agent would be nonantigenic andwould cause local fibrinolysis only at the site of a pathologicthrombus. Tissue plasminogen activator (t-PA) approxi-mates these goals. t-PA is a serine protease produced byhuman endothelial cells; therefore, t-PA is not antigenic.t-PA binds to newly formed (fresh) thrombi with high affin-ity, causing fibrinolysis at the site of a thrombus. Once boundto the fresh thrombus, t-PA undergoes a conformationalchange that renders it a potent activator of plasminogen. Incontrast, t-PA is a poor activator of plasminogen in the ab-sence of fibrin-binding.

Recombinant DNA technology has allowed the produc-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, andreducing mortality following an ST elevation myocardialinfarction. At pharmacologic doses, however, recombinantt-PA can generate a systemic lytic state and (as with otherthrombolytic agents) cause unwanted bleeding, including ce-rebral hemorrhage. Thus, its use is contraindicated in pa-tients who have had a recent hemorrhagic stroke. Like strep-tokinase, t-PA is approved for use in the treatment of patientswith ST elevation myocardial infarction or life-threateningpulmonary embolism. It is also approved for the treatmentof acute ischemic stroke.

TenecteplaseTenecteplase is a genetically engineered variant of t-PA.The molecular modifications in tenecteplase increase its fi-brin specificity relative to t-PA and make tenecteplase moreresistant to plasminogen activator inhibitor 1. Large trialshave shown that tenecteplase is identical in efficacy tot-PA, with similar (and possibly decreased) risk of bleeding.Additionally, tenecteplase has a longer half-life than t-PA.This pharmacokinetic property allows tenecteplase to be ad-ministered as a single weight-based bolus, thus simplifyingadministration.

ReteplaseSimilar to tenecteplase, reteplase is a genetically engineeredvariant of t-PA with longer half-life and increased specificity

LP-FPPP-92900 R1 CH22 01-15-07 10:08:23

Chapter 22 Pharmacology of Hemostasis and Thrombosis 409

for fibrin. Its efficacy and adverse effect profile are similarto those of streptokinase and t-PA. Because of its longerhalf-life, reteplase can be administered as a ‘‘double bolus’’(two boluses, 30 minutes apart).

INHIBITORS OF ANTICOAGULATION ANDFIBRINOLYSIS

ProtamineProtamine, a low molecular weight polycationic protein, isa chemical antagonist of heparin. This agent rapidly formsa stable complex with the negatively charged heparin mole-cule through multiple electrostatic interactions. Protamine isadministered intravenously to reverse the effects of heparinin situations of life-threatening hemorrhage or great heparinexcess (for example, at the conclusion of coronary arterybypass graft surgery). Protamine is most active against thelarge heparin molecules in unfractionated heparin and it canpartially reverse the anticoagulant effects of low molecularweight heparins, but it is inactive against fondaparinux.

Serine-Protease InhibitorsAprotinin, a naturally occurring polypeptide, is an inhibitorof the serine proteases plasmin, t-PA, and thrombin. By in-hibiting fibrinolysis, aprotinin promotes clot stabilization.Inhibition of thrombin may also promote platelet activity bypreventing platelet hyperstimulation. At higher doses, aprot-inin may also inhibit kallikrein and thereby (paradoxically)inhibit the coagulation cascade. Clinical trials have demon-strated decreased perioperative bleeding and erythrocytetransfusion requirement in patients treated with aprotininduring cardiac surgery. However, these positive findingshave been tempered by recent evidence suggesting that,compared to other antifibrinolytic agents, aprotinin may in-crease the risk of postoperative acute renal failure.

Lysine AnaloguesAminocaproic acid and tranexamic acid are analogues oflysine that bind to and inhibit plasminogen and plasmin.Like aprotinin, these agents are used to reduce perioperativebleeding during coronary artery bypass grafting. Unlikeaprotinin, these agents may not increase the risk of postoper-ative acute renal failure.

Conclusion and Future Directions

Hemostasis is a highly regulated process that maintains thefluidity of blood in normal vessels and initiates rapid forma-tion of a stable fibrin-based clot in response to vascular in-jury. Pathologic thrombosis results from endothelial injury,abnormal blood flow, and hypercoagulability. Antiplateletagents, anticoagulants, and thrombolytic agents target differ-ent stages of thrombosis and thrombolysis. Antiplateletagents interfere with platelet adhesion, the platelet releasereaction, and platelet aggregation; these agents can providepowerful prophylaxis against thrombosis in susceptible indi-

viduals. Anticoagulants primarily target plasma coagulationfactors and disrupt the coagulation cascade by inhibiting cru-cial intermediates. After a fibrin clot has been established,thrombolytic agents mediate dissolution of the clot by pro-moting the conversion of plasminogen to plasmin. Theseclasses of pharmacologic agents can be administered eitherindividually or in combination, to prevent or disrupt throm-bosis and to restore the patency of blood vessels occludedby thrombus.

Future development of new antiplatelet, anticoagulant,and thrombolytic agents will be forced to contend with twomajor constraints. First, for many clinical indications in thisfield, highly effective, orally bioavailable, and inexpensivetherapeutic agents are already available: these include theantiplatelet drug aspirin and the anticoagulant warfarin. Sec-ond, virtually every antithrombotic and thrombolytic agentis associated with the mechanism-based toxicity of bleeding,and this side effect is likely to plague new agents underdevelopment. Nonetheless, opportunities remain for the de-velopment of safer and more effective therapies. It is likelythat pharmacogenomic techniques (see Chapter 52, Pharma-cogenomics) will be capable of identifying individuals inthe population who carry an elevated genetic risk of throm-bosis, and such individuals may benefit from long-term anti-thrombotic treatment. Combinations of antiplatelet agents,low molecular weight heparins, orally bioavailable directthrombin inhibitors (such as the snake-venom–derived prod-rug ximelagatran, which is not approved for use in theU.S.), and new agents that target currently unexploited com-ponents of hemostasis (such as inhibitors of the factor VIIa/tissue factor pathway) could all be useful in these settings.At the other end of the spectrum, there remains a great needfor new agents that can achieve rapid, noninvasive, conven-ient, and selective lysis of acute thromboses associated withlife-threatening emergencies such as ST elevation myocar-dial infarction and stroke. Carefully designed clinical trialswill be critical to optimize the indications, dose, and durationof treatment for such drugs and drug combinations.

Suggested Readings

Baggish AL, Sabatine MS. Clopidogrel use in coronary artery dis-ease. Exp Rev Cardiovasc Ther 2006;4:7–15. (Reviews pharma-cology and expanding clinical applications for clopidogrel.)

Bates SM, Ginsberg JS. Treatment of deep-vein thrombosis. N EnglJ Med 2004;351:268–277. (Reviews treatment options for deepvein thrombosis.)

Bauer KA. New anticoagulants: anti IIa vs anti Xa—is one better?J Thromb Thrombolysis 2006;21:67–72. (Summarizes clinicaltrial data on selective factor Xa inhibitors and direct thrombininhibitors.)

Brass LF. The molecular basis for platelet activation. In: HoffmanR, Benz EJ, Shatill SJ, et al, eds. Hematology: basic principlesand practice. 4th ed. Philadelphia: Churchill Livingstone; 2004.(Detailed and mechanistic description of platelet activation.)

Di Nisio M, Middeldorp S, Buller HR. Direct thrombin inhibitors.N Engl J Med 2005;353:1028–1040. (Reviews mechanism ofaction and clinical indications for direct thrombin inhibitors.)

Franchini M, Veneri D, Salvagno GL, et al. Inherited thrombophi-lia. Crit Rev Clin Lab Sci 2006;43:249–290. (Reviews epidemiol-ogy, pathophysiology, and treatment of hypercoagulable states.)

LP-FPPP-92900 R1 CH22 01-15-07 10:08:23

410 III Principles of Cardiovascular Pharmacology

Furie B, Furie BC. Thrombus formation in vivo. J Clin Invest 2005;115:3355–3362. (Reviews molecular and cellular mechanismsof primary and secondary hemostasis in vivo.)

Grosser T, Fries S, FitzGerald GA. Biological basis for the cardio-vascular consequences of COX-2 inhibition: therapeutic chal-lenges and opportunities. J Clin Invest 2006;116:4–15. (Reviews

effects of COX-2 inhibition in cellular, animal, and humanstudies.)

Hirsh J, O’Donnell M, Weitz JI. New anticoagulants. Blood 2005;105:453–463. (Reviews anticoagulants in clinical development.)

Levy JH. Hemostatic agents. Transfusion 2004;44:58S–62S. (Re-views aprotinin, aminocaproic acid, and tranexamic acid.)

LP-FPPP-92900 R1 CH22 01-15-07 10:08:23

Chapter 22 Pharmacology of Hemostasis and Thrombosis 411

Dru

gSu

mm

ary

Tabl

eCh

apte

r22

Ph

arm

acol

ogy

ofH

emos

tasi

san

dTh

rom

bos

is

Seri

ous

and

Com

mon

Dru

gCl

inic

alA

pplic

atio

nsA

dver

seEf

fect

sCo

ntra

indi

cati

ons

Ther

apeu

tic

Cons

ider

atio

nsA

NTI

PLA

TELE

TA

GEN

TSCy

cloo

xyge

nase

Inhi

bito

rsM

echa

nism

—In

hibi

tpl

atel

etcy

cloo

xyge

nase

,th

ereb

ybl

ocki

ngth

rom

boxa

neA

2ge

nera

tion

and

inhi

bitin

gpl

atel

etre

leas

ere

actio

nan

dpl

atel

etag

greg

atio

n

Asp

irin

Prop

hyla

xis

agai

nst

tran

sien

tG

Ibl

eedi

ng,

acut

ere

nal

insu

ffic

ienc

y,N

SAID

-ind

uced

sens

itivi

tyIn

hibi

tsC

OX

-1an

dC

OX

-2no

nsel

ectiv

ely

isch

emic

atta

ck,

myo

card

ial

thro

mbo

cyto

peni

a,he

pati

tis,

angi

oede

ma,

reac

tions

Use

caut

ious

lyin

patie

nts

with

GI

lesi

ons,

infa

rctio

n,an

das

thm

a,R

eye’

ssy

ndro

me

Chi

ldre

nw

ithch

icke

npox

orfl

u-im

pair

edre

nal

func

tion,

hypo

thro

mbi

nem

ia,

thro

mbo

embo

licdi

sord

ers

Tin

nitu

s,dy

spep

sia,

occu

ltbl

eedi

ng,

like

synd

rom

esvi

tam

inK

defi

cien

cy,

thro

mbo

ticT

reat

men

tof

acut

eco

rona

rypr

olon

ged

blee

ding

time,

rash

G6P

Dde

fici

ency

thro

mbo

cyto

peni

cpu

rpur

a,or

hepa

ticim

pair

men

tsy

ndro

mes

Ble

edin

gdi

sord

ers

such

asC

o-ad

min

istr

atio

nw

itham

inog

lyco

side

s,Pr

even

tion

ofre

occl

usio

nin

hem

ophi

lia,

von

Will

ebra

nd’s

bum

etan

ide,

capr

eom

ycin

,ci

spla

tin,

coro

nary

reva

scul

ariz

atio

ndi

seas

e,or

imm

une

eryt

hrom

ycin

,et

hacr

ynic

acid

,fu

rose

mid

e,or

proc

edur

esan

dst

ent

thro

mbo

cyto

peni

ava

ncom

ycin

may

pote

ntia

teot

otox

icef

fect

sim

plan

tatio

nC

o-ad

min

istr

atio

nw

itham

mon

ium

chlo

ride

orA

rthr

itis,

juve

nile

arth

ritis

,ot

her

urin

eac

idif

iers

may

lead

toas

piri

nto

xici

tyrh

eum

atic

feve

rA

spir

inan

tago

nize

sur

icos

uric

effe

cts

ofM

ildpa

inor

feve

rph

enyl

buta

zone

,pr

oben

ecid

,an

dsu

lfin

pyra

zone

;av

oid

co-a

dmin

istr

atio

nw

ithth

ese

agen

ts

Phos

phod

iest

eras

eIn

hibi

tors

Mec

hani

sm—

Inhi

bit

plat

elet

cAM

Pde

grad

atio

nan

dth

ereb

yde

crea

sepl

atel

etag

greg

abili

ty

Dip

yrid

amol

ePr

ophy

laxi

sag

ains

tE

xace

rbat

ion

ofan

gina

(IV

rout

e),

rare

Hyp

erse

nsiti

vity

todi

pyri

dam

ole

Wea

kan

tipla

tele

tef

fect

thro

mbo

embo

licdi

sord

ers;

myo

card

ial

infa

rcti

on,

rare

vent

ricu

lar

Usu

ally

adm

inis

tere

din

com

bina

tion

with

war

fari

nA

ltern

ativ

eto

exer

cise

inar

rhyt

hmia

,ra

rebr

onch

ospa

smor

aspi

rin

thal

lium

myo

card

ial

perf

usio

nA

bnor

mal

EC

G,

hypo

tens

ion

(IV

rout

e),

Has

vaso

dila

tory

prop

ertie

s;m

aypa

rado

xica

llyim

agin

gab

dom

inal

disc

omfo

rt(o

ral

rout

e),

indu

cean

gina

byca

usin

gth

eco

rona

ryst

eal

dizz

ines

s,he

adac

heph

enom

enon

AD

PR

ecep

tor

Path

way

Inhi

bito

rsM

echa

nism

—C

oval

ently

mod

ify

plat

elet

AD

Pre

cept

or,

ther

eby

prev

entin

gre

cept

orsi

gnal

ing

and

irre

vers

ibly

inhi

bitin

gA

DP

-dep

ende

ntpl

atel

etac

tivat

ion

path

way

Tic

lopi

dine

Seco

ndar

ypr

even

tion

ofA

plas

tic

anem

ia,

neut

rope

nia,

thro

mbo

tic

Act

ive

blee

ding

diso

rder

Use

islim

ited

byas

soci

ated

mye

loto

xici

tyth

rom

botic

stro

kes

inpa

tient

sth

rom

bocy

tope

nic

purp

ura

Neu

trop

enia

,th

rom

bocy

tope

nia

Req

uire

sa

load

ing

dose

toac

hiev

eim

med

iate

anti-

into

lera

ntof

aspi

rin

Prur

itus,

rash

,dy

spep

sia,

abno

rmal

liver

Seve

reliv

erdy

sfun

ctio

npl

atel

etef

fect

Prev

entio

nof

sten

tth

rom

bosi

sfu

nctio

nte

sts,

dizz

ines

s(i

nco

mbi

natio

nw

ithas

piri

n)

Clo

pido

grel

Seco

ndar

ypr

even

tion

ofA

tria

lfi

bril

lati

on,

hear

tfa

ilur

e,er

ythe

ma

Act

ive

blee

ding

diso

rder

Mor

efa

vora

ble

adve

rse

effe

ctpr

ofile

than

athe

rosc

lero

ticev

ents

inm

ulti

form

e,G

Ihe

mor

rhag

e(i

ntic

lopi

dine

;si

gnif

ican

tlyle

ssm

yelo

toxi

city

than

patie

nts

with

rece

ntco

mbi

nati

onw

ith

aspi

rin)

,ve

ryra

retic

lopi

dine

myo

card

ial

infa

rctio

n,st

roke

,an

emia

orne

utro

peni

a,ra

rein

trac

rani

alR

equi

res

alo

adin

gdo

seto

achi

eve

imm

edia

tean

ti-or

peri

pher

alva

scul

ardi

seas

ehe

mor

rhag

e,ab

norm

alre

nal

func

tion

plat

elet

effe

ctA

cute

coro

nary

synd

rom

esC

hest

pain

,ed

ema,

hype

rten

sion

,pu

rpur

a,Pr

even

tion

ofst

ent

thro

mbo

sis

rare

abno

rmal

liver

func

tion

test

s,G

I(i

nco

mbi

natio

nw

ithas

piri

n)di

scom

fort

,ar

thra

lgia

,di

zzin

ess

(Con

tinue

d)

LP-FPPP-92900 R1 CH22 01-15-07 10:08:23

412 III Principles of Cardiovascular Pharmacology

Dru

gSu

mm

ary

Tabl

eCh

apte

r22

Ph

arm

acol

ogy

ofH

emos

tasi

san

dTh

rom

bos

is(C

ontin

ued

)

Seri

ous

and

Com

mon

Dru

gCl

inic

alA

pplic

atio

nsA

dver

seEf

fect

sCo

ntra

indi

cati

ons

Ther

apeu

tic

Cons

ider

atio

nsG

PIIb

–II

IaA

ntag

onis

tsM

echa

nism

—B

ind

topl

atel

etre

cept

orG

PII

b–II

Iaan

dth

ereb

ypr

even

tbi

ndin

gof

fibr

inog

enan

dot

her

adhe

sive

ligan

ds

Ept

ifib

atid

eA

cute

coro

nary

synd

rom

esM

ajor

blee

ding

,in

trac

ereb

ral

hem

orrh

age,

His

tory

ofbl

eedi

ngdi

athe

sis

orA

void

co-a

dmin

istr

atio

nw

itha

seco

ndG

PIIb

-III

aPe

rcut

aneo

usco

rona

ryth

rom

bocy

tope

nia

rece

ntab

norm

albl

eedi

ngan

tago

nist

inte

rven

tion

Hyp

oten

sion

,bl

eedi

ngC

onco

mita

ntad

min

istr

atio

nof

aM

inim

ize

use

ofar

teri

alan

dve

nous

punc

ture

s,se

cond

glyc

opro

tein

IIb–

IIIa

urin

ary

cath

eter

s,an

dna

sotr

ache

alan

dan

tago

nist

naso

gast

ric

tube

sR

ecen

tm

ajor

surg

ery

Ept

ifib

atid

eis

asy

nthe

ticpe

ptid

ede

liver

edvi

aR

ecen

tst

roke

orhi

stor

yof

pare

nter

alad

min

istr

atio

nhe

mor

rhag

icst

roke

Intr

acra

nial

hem

orrh

age,

mas

s,or

arte

riov

enou

sm

alfo

rmat

ion

Seve

reun

cont

rolle

dhy

pert

ensi

on

Abc

ixim

abA

djun

ctto

perc

utan

eous

Sam

eas

epti

fiba

tide

Sam

eas

eptif

ibat

ide

Sam

eth

erap

eutic

cons

ider

atio

nsas

epiti

fiba

tide,

coro

nary

inte

rven

tion

orex

cept

abci

xim

abis

ach

imer

icm

ouse

–hum

anat

here

ctom

yto

prev

ent

acut

em

onoc

lona

lan

tibod

yca

rdia

cis

chem

icco

mpl

icat

ions

Add

ing

abci

xim

abto

conv

entio

nal

antit

hrom

botic

Uns

tabl

ean

gina

not

resp

ondi

ngth

erap

yre

duce

sbo

thlo

ng-t

erm

and

shor

t-te

rmto

conv

entio

nal

ther

apy

inis

chem

icev

ents

inpa

tient

sun

derg

oing

high

-ris

kpa

tient

ssc

hedu

led

for

coro

nary

angi

opla

sty

perc

utan

eous

coro

nary

inte

rven

tion

Tir

ofib

anA

cute

coro

nary

synd

rom

esin

Sam

eas

epti

fiba

tide

;A

ddit

iona

lly,

Sam

eas

eptif

ibat

ide

Sam

eth

erap

eutic

cons

ider

atio

nsas

eptif

ibat

ide,

patie

ntun

derg

oing

angi

opla

sty

coro

nary

arte

rydi

ssec

tion

isra

rely

exce

pttir

ofib

anis

ano

npep

tide

tyro

sine

anal

ogue

orat

here

ctom

yor

man

aged

obse

rved

med

ical

ly

AN

TICO

AG

ULA

NTS

War

fari

nM

echa

nism

—In

hibi

the

patic

epox

ide

redu

ctas

eth

atca

taly

zes

the

rege

nera

tion

ofre

duce

dvi

tam

inK

,w

hich

isre

quir

edfo

rsy

nthe

sis

ofbi

olog

ical

lyac

tive

coag

ulat

ion

fact

ors

II,

VII

,IX

,an

dX

and

antic

oagu

lant

prot

eins

Can

dS

War

fari

nPr

ophy

laxi

san

dtr

eatm

ent

ofC

hole

ster

olem

boli

zati

onsy

ndro

me,

skin

Preg

nanc

yM

onito

ring

isre

quir

edby

usin

gth

epr

othr

ombi

npu

lmon

ary

embo

lism

and

othe

rti

ssue

necr

osis

,he

mor

rhag

e,H

emor

rhag

icte

nden

cyor

bloo

dtim

e(P

T),

expr

esse

das

the

inte

rnat

iona

lPr

ophy

laxi

san

dtr

eatm

ent

ofhe

pati

tis,

hype

rsen

siti

vity

reac

tion

dysc

rasi

ano

rmal

ized

ratio

(IN

R)

deep

vein

thro

mbo

sis

Ble

edin

gte

nden

cyas

soci

ated

with

Dru

g–dr

ugin

tera

ctio

nsm

ust

beca

refu

llyPr

ophy

laxi

san

dtr

eatm

ent

ofac

tive

ulce

ratio

nor

blee

ding

due

cons

ider

edw

ithw

arfa

rin

(ref

erto

Tab

le22

-2fo

rsy

stem

icem

bolis

maf

ter

tom

ucos

alle

sion

s,ex

ampl

esof

impo

rtan

tin

tera

ctio

ns);

Co-

myo

card

ial

infa

rctio

nce

rebr

ovas

cula

rhe

mor

rhag

e,ad

min

istr

atio

nof

war

fari

nw

ithot

her

albu

min

-Pr

ophy

laxi

san

dtr

eatm

ent

ofce

rebr

alor

aort

ican

eury

sm,

boun

ddr

ugs

can

incr

ease

the

free

(unb

ound

)sy

stem

icem

bolis

mas

soci

ated

peri

card

itis

and

peri

card

ial

plas

ma

conc

entr

atio

nsof

both

drug

s;C

o-w

ithat

rial

fibr

illat

ion,

effu

sion

,ba

cter

ial

endo

card

itis

adm

inis

trat

ion

ofdr

ugs

that

indu

cean

d/or

rheu

mat

iche

art

dise

ase

with

Rec

ent

eye,

brai

n,or

spin

alsu

rger

yco

mpe

tefo

rP4

50m

etab

olis

mca

naf

fect

the

hear

tva

lve

dam

age,

orSe

vere

unco

ntro

lled

hype

rten

sion

plas

ma

conc

entr

atio

nsof

both

drug

spr

osth

etic

mec

hani

cal

hear

tva

lve

LP-FPPP-92900 R1 CH22 01-15-07 10:08:23

Chapter 22 Pharmacology of Hemostasis and Thrombosis 413

Thr

eate

ned

abor

tion,

ecla

mps

ia,

War

fari

nsh

ould

neve

rbe

give

nto

preg

nant

pree

clam

psia

wom

enbe

caus

eit

can

caus

ea

hem

orrh

agic

Reg

iona

lor

lum

bar

bloc

kdi

sord

eran

d/or

cong

enita

lde

fect

sin

the

fetu

san

esth

esia

War

fari

nca

nca

use

skin

necr

osis

asa

resu

ltof

His

tory

ofw

arfa

rin-

indu

ced

wid

espr

ead

thro

mbo

sis

inth

em

icro

vasc

ulat

ure

necr

osis

For

seve

rehe

mor

rhag

edu

eto

war

fari

n,pa

tient

sU

nsup

ervi

sed

patie

nts

with

shou

ldpr

ompt

lyre

ceiv

efr

esh

froz

enpl

asm

aps

ycho

sis,

seni

lity,

alco

holis

m,

orla

ckof

coop

erat

ion,

and

espe

cial

lyth

ose

with

risk

offa

lling

Unf

ract

iona

ted

Hep

arin

and

Low

Mol

ecul

arW

eigh

tH

epar

ins

Mec

hani

sm—

Unf

ract

iona

ted

hepa

rin:

com

bine

sw

ithan

tithr

ombi

nII

Ian

din

hibi

tsse

cond

ary

hem

osta

sis

via

nons

elec

tive

inac

tivat

ion

ofth

rom

bin

(fac

tor

IIa)

,fa

ctor

Xa,

fact

orIX

a,fa

ctor

XIa

,an

dfa

ctor

XII

a.L

MW

hepa

rins

:co

mbi

new

ithan

tithr

ombi

nII

Ian

din

hibi

tse

cond

ary

hem

osta

sis

via

rela

tivel

y(3

-fol

d)se

lect

ive

inac

tivat

ion

offa

ctor

Xa.

Unf

ract

iona

ted

Prev

entio

nan

dtr

eatm

ent

of:

Hem

orrh

age,

hepa

rin-

indu

ced

Hep

arin

-ind

uced

thro

mbo

cyto

peni

aT

here

isa

high

erin

cide

nce

ofhe

pari

n-in

duce

dhe

pari

n—

Pulm

onar

yem

bolis

mth

rom

bocy

tope

nia,

hype

rsen

siti

vity

Act

ive

maj

orbl

eedi

ngth

rom

bocy

tope

nia

inpa

tient

sre

ceiv

ing

—D

eep

vein

thro

mbo

sis

reac

tion

sin

clud

ing

anap

hyla

ctoi

dB

leed

ing

tend

enci

essu

chas

unfr

actio

nate

dhe

pari

nth

anin

thos

ere

ceiv

ing

—C

ereb

ral

thro

mbo

sis

reac

tion

she

mop

hilia

,th

rom

bocy

tope

nia,

orL

MW

hepa

rin

—L

eft

vent

ricu

lar

thro

mbu

sO

verl

ypr

olon

ged

clot

ting

time,

muc

osal

hepa

ticdi

seas

ew

ithA

ntih

ista

min

es,

card

iac

glyc

osid

es,

nico

tine,

and

Prev

entio

nof

syst

emic

ulce

ratio

n,he

mat

oma

hypo

prot

hrom

bine

mia

tetr

acyc

lines

may

part

ially

coun

tera

ctem

bolis

mas

soci

ated

with

Susp

ecte

din

trac

rani

alhe

mor

rhag

ean

ticoa

gula

ntef

fect

myo

card

ial

infa

rctio

nO

pen

ulce

rativ

ew

ound

s,ex

tens

ive

Cep

halo

spor

ins,

peni

cilli

ns,

oral

antic

oagu

lant

s,U

nsta

ble

angi

nade

nuda

tion

ofsk

inan

dpl

atel

etin

hibi

tors

may

incr

ease

antic

oagu

lant

Ope

n-he

art

surg

ery

Con

ditio

nsth

atca

use

incr

ease

def

fect

Dis

sem

inat

edin

trav

ascu

lar

capi

llary

perm

eabi

lity

Dis

cour

age

conc

omita

ntus

eof

herb

ssu

chas

dong

coag

ulat

ion

Bac

teri

alen

doca

rditi

squ

ai,

garl

ic,

ging

er,

gink

go,

mot

herw

ort,

and

red

Mai

ntai

npa

tenc

yof

IVSe

vere

hype

rten

sion

clov

erdu

eto

incr

ease

dri

skof

blee

ding

cath

eter

s

LM

Whe

pari

ns:

Prev

entio

nan

dtr

eatm

ent

ofH

emor

rhag

e,th

rom

bocy

tope

nia,

abno

rmal

Act

ive

maj

orbl

eedi

ngA

dmin

iste

red

asw

eigh

t-ba

sed

subc

utan

eous

Eno

xapa

rin

deep

vein

thro

mbo

sis

(all

live

rfu

ncti

onte

sts,

anap

hyla

ctoi

dH

epar

in-i

nduc

edth

rom

bocy

tope

nia

inje

ctio

nD

alte

pari

nL

MW

hepa

rins

)re

acti

on,

spin

alhe

mat

oma

Hyp

erse

nsiti

vity

tohe

pari

nor

pork

Avo

idex

cess

ive

antic

oagu

latio

nin

patie

nts

with

Tin

zapa

rin

Tre

atm

ent

ofac

ute

coro

nary

Ede

ma,

diar

rhea

,na

usea

,he

mat

oma,

prod

ucts

rena

lin

suff

icie

ncy

synd

rom

esan

dad

junc

tto

norm

ocyt

ichy

poch

rom

ican

emia

,R

enal

insu

ffic

ienc

y(r

elat

ive

perc

utan

eous

coro

nary

conf

usio

n,pa

in,

dysp

nea,

feve

r,lo

cal

cont

rain

dica

tion)

inte

rven

tion

(eno

xapa

rin

and

irri

tatio

nda

ltepa

rin)

Sele

ctiv

eFa

ctor

XaIn

hibi

tors

Mec

hani

sm—

Com

bine

with

antit

hrom

bin

III

and

inhi

bits

seco

ndar

yhe

mos

tasi

svi

ahi

ghly

sele

ctiv

ein

activ

atio

nof

fact

orX

a

Fon

dapa

rinu

xPr

ophy

laxi

san

dtr

eatm

ent

ofH

emor

rhag

e,th

rom

bocy

tope

nia,

abno

rmal

Act

ive

maj

orbl

eedi

ngFo

ndap

arin

uxis

ape

ntas

acha

ride

com

pose

dof

the

deep

vein

thro

mbo

sis

live

rfu

ncti

onte

sts,

anap

hyla

ctoi

dSe

vere

rena

lim

pair

men

tes

sent

ial

five

carb

ohyd

rate

sne

cess

ary

for

bind

ing

Prop

hyla

xis

and

trea

tmen

tof

reac

tion

,sp

inal

hem

atom

aB

acte

rial

endo

card

itis

antit

hrom

bin

III;

Itis

asp

ecif

icin

dire

ctin

hibi

tor

pulm

onar

yem

bolis

mE

dem

a,di

arrh

ea,

naus

ea,

hem

atom

a,of

fact

orX

a,w

ithne

glig

ible

anti-

thro

mbi

n(a

nti-

norm

ocyt

ichy

poch

rom

ican

emia

,II

a)ac

tivity

conf

usio

n,pa

in,

dysp

nea,

feve

r,lo

cal

Avo

idex

cess

ive

antic

oagu

latio

nin

patie

nts

with

irri

tatio

nre

nal

insu

ffic

ienc

yFo

ndap

arin

uxus

eha

sno

tbe

enas

soci

ated

with

hepa

rin-

indu

ced

thro

mbo

cyto

peni

a

(Con

tinue

d)

LP-FPPP-92900 R1 CH22 01-15-07 10:08:23

414 III Principles of Cardiovascular Pharmacology

Dru

gSu

mm

ary

Tabl

eCh

apte

r22

Ph

arm

acol

ogy

ofH

emos

tasi

san

dTh

rom

bos

is(C

ontin

ued

)

Seri

ous

and

Com

mon

Dru

gCl

inic

alA

pplic

atio

nsA

dver

seEf

fect

sCo

ntra

indi

cati

ons

Ther

apeu

tic

Cons

ider

atio

nsD

irec

tTh

rom

bin

Inhi

bito

rsM

echa

nism

—B

ind

dire

ctly

toth

rom

bin

and

ther

eby

inhi

bit

seco

ndar

yhe

mos

tasi

s

Hir

udin

-rel

ated

Hep

arin

-ind

uced

Hea

rtfa

ilur

e,ga

stro

inte

stin

alhe

mor

rhag

e,A

ctiv

em

ajor

blee

ding

Rec

ombi

nant

poly

pept

ides

base

don

the

med

icin

alag

ents

:th

rom

bocy

tope

nia

(lep

irud

in)

blee

ding

,ab

norm

alli

ver

func

tion

test

s,Pr

egna

ncy

leec

hpr

otei

nhi

rudi

n;bi

ndto

both

activ

esi

tean

dL

epir

udin

Prop

hyla

xis

agai

nst

deep

vein

anap

hyla

xis,

hype

rten

sion

,hy

pote

nsio

n,Se

vere

unco

ntro

lled

hype

rten

sion

exos

iteof

thro

mbi

nD

esir

udin

thro

mbo

sis

(des

irud

in)

cere

bral

isch

emia

,in

trac

rani

alSe

vere

rena

lim

pair

men

tL

epir

udin

inhi

bits

both

free

and

fibr

in-b

ound

Biv

alir

udin

Ant

icoa

gula

tion

inpa

tient

she

mor

rhag

e,pe

riph

eral

nerv

epa

raly

sis,

thro

mbi

nun

derg

oing

coro

nary

faci

alne

rve

para

lysi

s,he

mat

uria

,re

nal

Aft

erbi

valir

udin

bind

sto

thro

mbi

n,th

eth

rom

bin

angi

ogra

phy

and

angi

opla

sty

fail

ure,

extr

insi

cal

lerg

icre

spir

ator

ysl

owly

clea

ves

anar

gini

ne–p

rolin

ebo

ndin

(biv

alir

udin

)di

seas

e,pn

eum

onia

,se

psis

biva

lirud

in,

lead

ing

tore

activ

atio

nof

thro

mbi

nC

utan

eous

hype

rsen

sitiv

ity,

anem

ia,

feve

rD

ose

adju

stm

ent

isre

quir

edin

patie

nts

with

rena

lin

suff

icie

ncy

beca

use

thes

eag

ents

are

excr

eted

via

the

kidn

eys

Arg

atro

ban

Cor

onar

yar

tery

thro

mbo

sis

Car

diac

arre

st,

cere

brov

ascu

lar

diso

rder

,A

ctiv

em

ajor

blee

ding

Bin

dsto

activ

esi

tebu

tno

tex

osite

ofth

rom

bin

Prop

hyla

xis

inpe

rcut

aneo

usve

ntri

cula

rta

chyc

ardi

a,se

psis

,Se

vere

liver

impa

irm

ent

Dos

ead

just

men

tis

requ

ired

inpa

tient

sw

ithliv

erco

rona

ryin

terv

entio

nhy

pote

nsio

ndi

seas

ebe

caus

ear

gatr

oban

isex

cret

edin

the

bile

Hep

arin

-ind

uced

thro

mbo

cyto

peni

a

Rec

ombi

nant

Act

ivat

edPr

otei

nC

(r-A

PC)

Mec

hani

sm—

Pro

teol

ytic

ally

inac

tivat

esfa

ctor

sV

aan

dV

IIIa

;m

ayal

soex

ert

anti-

infl

amm

ator

yef

fect

byin

hibi

ting

tum

orne

cros

isfa

ctor

prod

uctio

nan

dbl

ocki

ngle

ukoc

yte

adhe

sion

tose

lect

ins

Rec

ombi

nant

Seve

rese

psis

with

orga

nH

emor

rhag

eA

ctiv

ein

tern

albl

eedi

ngPr

olon

gsac

tivat

edpa

rtia

lth

rom

bopl

astin

time

acti

vate

dpr

otei

ndy

sfun

ctio

nan

dhi

ghri

skof

Intr

acra

nial

mas

s(a

PTT

)bu

tha

slit

tleef

fect

onpr

othr

ombi

ntim

eC

(r-A

PC

)de

ath

Hem

orrh

agic

stro

kew

ithin

3(P

T)

mon

ths

Rec

ent

intr

acra

nial

orin

tras

pina

lsu

rger

yor

seve

rehe

adtr

aum

aw

ithin

2m

onth

sPr

esen

ceof

anep

idur

alca

thet

erM

ajor

trau

ma

with

anin

crea

sed

risk

oflif

e-th

reat

enin

gbl

eedi

ng

THR

OM

BO

LYTI

CA

GEN

TSM

echa

nism

—P

rote

olyt

ical

lyac

tivat

epl

asm

inog

ento

form

plas

min

,w

hich

dige

sts

fibr

into

fibr

inde

grad

atio

npr

oduc

ts

Stre

ptok

inas

eST

elev

atio

nm

yoca

rdia

lC

ardi

acar

rhyt

hmia

,ch

oles

tero

lem

bolu

sA

ctiv

ein

tern

albl

eedi

ngor

know

nSt

rept

okin

ase

isa

fore

ign

bact

eria

lpr

otei

nth

atca

nin

farc

tion

synd

rom

e,m

ajor

blee

ding

,an

aphy

lact

oid

blee

ding

diat

hesi

sel

icit

antig

enic

resp

onse

sin

hum

ans

upon

Art

eria

lth

rom

bosi

sre

acti

on,

poly

neur

opat

hy,

non-

card

ioge

nic

Intr

acra

nial

orin

tras

pina

lsu

rger

yre

peat

edad

min

istr

atio

n;pr

ior

adm

inis

trat

ion

ofD

eep

vein

thro

mbo

sis

pulm

onar

yed

ema,

hypo

tens

ion

ortr

aum

aw

ithin

2m

onth

sst

rept

okin

ase

isa

cont

rain

dica

tion

tous

edu

eto

Pulm

onar

yem

bolis

mFe

ver,

shiv

erin

gC

ereb

rova

scul

arac

cide

ntw

ithin

2th

eri

skof

anap

hyla

xis

Intr

a-ar

teri

alor

intr

aven

ous

mon

ths

Thr

ombo

lytic

actio

nsof

stre

ptok

inas

ear

eca

thet

eroc

clus

ion

Intr

acra

nial

mas

sre

lativ

ely

nons

peci

fic

and

can

resu

ltin

syst

emic

Seve

reun

cont

rolle

dhy

pert

ensi

onfi

brin

olys

is

LP-FPPP-92900 R1 CH22 01-15-07 10:08:23

Chapter 22 Pharmacology of Hemostasis and Thrombosis 415

Rec

ombi

nant

tiss

ueA

cute

myo

card

ial

infa

rctio

nC

ardi

acar

rhyt

hmia

,ch

oles

tero

lem

bolu

sSa

me

asst

rept

okin

ase

Bin

dsto

new

lyfo

rmed

(fre

sh)

thro

mbi

with

high

plas

min

ogen

Acu

tece

rebr

ovas

cula

rsy

ndro

me,

gast

roin

test

inal

hem

orrh

age,

affi

nity

,ca

usin

gfi

brin

olys

isat

the

site

ofa

acti

vato

r(t

-PA

)th

rom

bosi

sra

real

lerg

icre

acti

on,

intr

acra

nial

thro

mbu

s(A

ltep

lase

)Pu

lmon

ary

embo

lism

hem

orrh

age,

seps

isA

sw

ithot

her

thro

mbo

lytic

agen

ts,

t-PA

can

Cen

tral

veno

usca

thet

erge

nera

tea

syst

emic

lytic

stat

ean

dca

use

occl

usio

nun

wan

ted

blee

ding

Ten

ecte

plas

eA

cute

myo

card

ial

infa

rctio

nC

ardi

acar

rhyt

hmia

,ch

oles

tero

lem

bolu

sSa

me

asst

rept

okin

ase

Gen

etic

ally

engi

neer

edva

rian

tsof

t-PA

with

Ret

epla

sesy

ndro

me,

maj

orbl

eedi

ng,

alle

rgic

incr

ease

dsp

ecif

icity

for

fibr

inre

acti

on,

anap

hyla

xis,

cere

brov

ascu

lar

Lon

ger

half

-lif

eth

ant-

PA;

Ten

ecte

plas

eis

acci

dent

,in

trac

rani

alhe

mor

rhag

ead

min

iste

red

asa

sing

lew

eigh

t-ba

sed

bolu

s;re

tepl

ase

isad

min

iste

red

asa

doub

lebo

lus

INH

IBIT

OR

SO

FA

NTI

COA

GU

LATI

ON

AN

DFI

BR

INO

LYSI

SPr

otam

ine

Mec

hani

sm—

Inac

tivat

eshe

pari

nby

form

ing

ast

able

1:1

prot

amin

e:he

pari

nco

mpl

ex

Pro

tam

ine

Hep

arin

over

dose

Bra

dyar

rhyt

hmia

,hy

pote

nsio

n,H

yper

sens

itivi

tyto

prot

amin

ePr

otam

ine

can

also

part

ially

reve

rse

the

anap

hyla

ctoi

dre

acti

on,

circ

ulat

ory

antic

oagu

lant

effe

ctof

low

mol

ecul

arw

eigh

tco

llap

se,

capi

llar

yle

ak,

nonc

ardi

ogen

iche

pari

n,bu

tit

cann

otre

vers

eth

ean

ticoa

gula

ntpu

lmon

ary

edem

aef

fect

offo

ndap

arin

uxFl

ushi

ng,

naus

ea,

vom

iting

,dy

spep

sia

Seri

ne-P

rote

ase

Inhi

bito

rM

echa

nism

—In

hibi

tsse

rine

prot

ease

s,in

clud

ing

plas

min

,t-

PA

,an

dth

rom

bin

Apr

otin

inR

educ

epe

riop

erat

ive

blee

ding

Hea

rtfa

ilur

e,m

yoca

rdia

lin

farc

tion

,sh

ock,

Hyp

erse

nsiti

vity

toap

rotin

inA

thi

gher

dose

s,ap

rotin

inm

ayal

soin

hibi

tdu

ring

coro

nary

arte

ryby

pass

thro

mbo

tic

diso

rder

,an

aphy

laxi

sw

ith

kalli

krei

nan

dth

ereb

ypa

rado

xica

llyin

hibi

tth

egr

aft

surg

ery

reex

posu

re,

cere

bral

arte

ryoc

clus

ion,

coag

ulat

ion

casc

ade

rena

lfa

ilur

eA

prot

inin

may

incr

ease

the

risk

ofpo

stop

erat

ive

acut

ere

nal

failu

rere

lativ

eto

othe

ran

tifib

rino

lytic

agen

ts

Lysi

neA

nalo

gues

Mec

hani

sm—

Ana

logu

esof

lysi

neth

atbi

ndto

and

inhi

bit

plas

min

ogen

and

plas

min

Am

inoc

apro

icac

idD

isor

der

invo

lvin

gth

eB

rady

arrh

ythm

ia,

hypo

tens

ion,

thro

mbo

tic

Dis

sem

inat

edin

trav

ascu

lar

May

caus

ele

ssac

ute

rena

lfa

ilure

rela

tive

toT

rane

xam

icac

idfi

brin

olyt

icsy

stem

diso

rder

,dr

ug-i

nduc

edm

yopa

thy

coag

ulat

ion

apro

tinin

Hem

orrh

age

from

incr

ease

d(a

min

ocap

roic

acid

),ra

rere

nal

fail

ure

Hyp

erse

nsiti

vity

toam

inoc

apro

icfi

brin

olys

isac

id

LP-FPPP-92900 R1 CH22 01-15-07 10:08:23

Page 416 Blank