BreakthroughPharmacology Antiplatelet Therapy

with Glycoprotein IlbIliaReceptor Inhibitors andOther Novel Agents

Andrew 1. Schafer, MD

Key words: Amino acidsequence; antibodies,monoclonal; fibrinogen;peptides/therapeutic use;platelet activation/drugeffects; platelet aggregationinhibitors/therapeutic use;platelet glycoprotein GPllb-Illa complex/antagonists& inhibitors; plateletmembrane glycoproteinslantagonists & inhibitors;receptors, cell surface;thrombosis/prevention &control

From: The Department ofMedicine, Baylor College ofMedicine, Houston, Texas77030

Sources of support: NIHRO1 HL36045-10, and aVA Merit Review grant

Presented at the TexasHeart Institute's symposium,"Breakthrough Pharma-cology: llb/llla-TargetedTherapy, " held on 9November 1996, at the ITTSheraton New OrleansHotel, New Orleans,Louisiana

Address for reprints:Andrew I. Schafer, MD,The WA. and DeborahMoncrief, Jr. Professor ofMedicine, Department ofMedicine, Baylor Collegeof Medicine, 6550 Fannin,Smith Tower #1425,Houston, TX 77030

Aspirin has stood the test of time over decades as the gold standard for relatively effec-tive, safe, and inexpensive antiplatelet therapy. However, aspirin is only modestly effec-tive in preventing arterial thrombosis in certain settings, and it is virtually ineffective inothers (for example, preventing coronary restenosis after angioplasty). These observa-tions have been the impetus for the development of more effective antiplatelet strate-gies, the rational basis of which is largely our understanding of normal platelet function.The most clinically effective platelet inhibitors yet developed produce broad inhibitionof platelet function by blockade of the final common pathway of aggregation, in whichfibrinogen binds to its platelet membrane receptor localized in the glycoprotein (Gp) llbiIlla complex. The Gp llb/llla complex is a member of the family of integrins, which arecell membrane receptors for adhesive proteins. The binding of fibrinogen to platelet Gpllb/llla occurs via a specific amino acid sequence, arginine-glycine-aspartic acid. Effec-tive antagonists of platelet Gp llb/llla function have included monoclonal antibodiesagainst Gp llb/llla, peptide (peptidomimetic) antagonists of Gp llb/lila, and nonpeptide(nonpeptide mimetic) antagonists of Gp llb/llla. The major risk of any antiplatelet strat-egy is the potential for bleeding complications, since currently we do not understandthe molecular distinction between protective hemostasis and pathologic thrombosis.(Tex Heart Inst J 1997;24:90-6)

A rterial thrombosis in the coronary, cerebrovascular, and peripheral circu-lations can have devastating clinical consequences, often causing deathor permanent disability. Therefore, there is considerable motivation to

develop effective and safe antithrombotic agents that prevent these events. Sinceplatelets are predominant participants in the pathogenesis of arterial thrombosis,particularly in regions of high fluid shear stress, most research has been directedat the use of antiplatelet agents in the prophylaxis of arterial thrombosis, includ-ing coronary artery disease. (In contrast, venous thrombosis, which involves morefibrin than platelet deposition, has been treated primarily with anticoagulants.)

For more than 40 years, aspirin has stood the test of time as the gold standardfor relatively effective, safe, and inexpensive antiplatelet therapy. Its clinicalefficacy has been rigorously demonstrated in the prevention of thrombosis in avariety of coronary, cerebrovascular, and peripheral arterial disorders (Table I).Nevertheless, aspirin is only modestly effective in many of these thrombotic set-tings, and it is virtually ineffective in others (for example, the prevention of coro-nary restenosis after angioplasty). These observations have necessitated theexploration of more effective antiplatelet strategies. The rational basis for thedevelopment of these newer agents, in contrast to the empirical discovery of as-pirin as an antithrombotic drug, has been largely our understanding of normalplatelet function.

Under normal circumstances, the intimal surface of the entire length of the cir-culatory tree is lined by a monolayer of endothelial cells. Endothelial cells main-tain blood fluidity in 2 ways. First, they act as a barrier to prevent exposure ofcirculating blood to thrombogenic subendothelial constituents of the vessel wall,such as collagen. Second, endothelial cells are themselves metabolically active insynthesizing and releasing potent substances that passivate platelets, includingprostacyclin (PGI2) and nitric oxide (NO). Both prostacyclin and NO are labilemolecules that act as autacoids to inhibit platelets only in the immediate vicinity

90 Antiplatelet Therapy Volume 24, Number 2, 1997

TABLE 1. Clinical Efficacy of Aspirin, Ticlopidine, and Dipyridamole

Clinical Setting Aspirin Ticlopidine Dipyridamole

Coronary artery diseasePrimary prevention of myocardial +/-

infarctionStable angina +Unstable angina + +Secondary prevention of myocardial +

infarctionCoronary artery bypass graft + +Acute occlusion after angioplasty + +Stent thrombosis + +Restenosis after angioplasty

Other cardiac diseaseMechanical or high-risk +W +W

tissue valvesAtrial fibrillation (nonrheumatic) +

Cerebrovascular diseasePrimary prevention of strokeStroke or recurrent TIA after + +TIA or minor stroke

Secondary prevention of stroke +(after major stroke)

Stroke or restenosis afterendarterectomy

Shunt thrombosis +

Peripheral vascular disease + + +A

Clinical efficacy designations represent generalizations based on weight of evidence in the literature. Table does not indicatenumber or powers of studies or specific doses or regimens of antiplatelet agents. Further information can be found in moredetailed reviews and original publications.+ = effective; - = ineffective; +/- = equivocal; +A = effective when used with aspirin; TIA = transient ischemic attack; +W =effective when used with warfarin

(Modified, with permission from Schafer.6)

of their sites of production. They inhibit plateletsby stimulating platelet adenylyl cyclase (in the caseof prostacyclin) and guanylyl cyclase (in the caseof NO), thereby raising intraplatelet levels of cyclicadenosine monophosphate (cyclic AMP) and cyclicguanosine monophosphate (cyclic GMP), respec-tively.

Attempts have been made to exploit the natural-ly occurring antiplatelet properties of prostacyclinand NO for therapy (Fig. lA). The clinical use ofprostacyclin and its analogs (for example, iloprost)has been limited by their relative chemical labilityand potent vasoactive (hypotensive) effects. Theseagents are particularly effective when administeredregionally in cardiopulmonary bypass, charcoal hemo-perfusion, and hemodialysis, where they preventplatelet consumption and activation in extracorpore-al circuits. Nitric oxide, which acts like prostacyclinto relax vascular smooth muscle as well as to inhibitplatelets, has similar potential limitations as a thera-peutic antiplatelet agent. In fact, the antiplatelet ef-

fects of organic nitrates and nitroprusside are medi-ated by their generation of NO. The platelet inhibi-tory actions of nitrovasodilators probably play a rolein the anti-ischemic benefits of these agents.The mechanism of antiplatelet action of dipyri-

damole is unclear. It may act by stimulating pros-tacyclin synthesis by the vessel wall, potentiatingthe platelet inhibitory effect of prostacyclin, raisingplatelet cyclic AMP levels by phosphodiesterase in-hibition, or enhancing local accumulation of vaso-dilatory and platelet inhibitory adenosine by pre-venting its uptake into endothelial and other cells.However, these effects of dipyridamole generallyoccur only at suprapharmacologic concentrations.Regardless of its mechanism of action, dipyridamole,when used alone, has yet to be shown to have anti-thrombotic efficacy in the prophylaxis of arterialthrombosis (Table I).

Platelets initially undergo the process of adhesionto sites of vascular injury. Platelet adhesion is me-diated primarily by plasma von Willebrand factor

Texas Heart InstituteJournal AAntiplatelet Therapy 91

N...

(vWF), which binds to specific receptors on theplatelet surface localized in membrane glycoproteinlb (Gp Ib) and thereby serves as a molecular 'glue"in this process. Antiplatelet agents have been de-signed to inhibit platelet adhesion by interferingwith the interaction of vWF and its platelet mem-brane Gp lb receptor (Fig. 1B). These agents includemonoclonal antibodies to Gp Ib; recombinant pep-tides to Gp Ib, which contain the binding site ofvWF; and aurintricarboxylic acid (ATA), which bindsto vWF and prevents its interaction with platelet GpIb. As yet, there is no clinical experience with theuse of this promising and potentially very potentantiplatelet strategy in human beings.

As platelets adhere to the intimal lining of thedamaged vessel, other platelet stimuli, including col-lagen, serotonin, epinephrine, and thrombin, bind to

Fig. 1 Sequence of events in platelet activation, with potentialtargets for antiplatelet therapy. A) Prostacyclin (PGI2) and nitricoxide (NO) (and their derivatives) are endothelium-derivedplatelet inhibitory autacoids. B) Platelet adhesion to the injuredvascular intimal surface is mediated by von Willebrand factor(vWF) binding to its receptor on platelet membrane Gp lb. C)Adherent platelets are also anchored to the damaged vesselwall by binding of subendothelial collagen (COL) to its plateletsurface COL receptors. Other platelet stimuli in blood,including thrombin (THR) and serotonin (SER), bind to theirrespective receptors. D) In response to these different stimuli,adherent platelets are activated and release thromboxane A2(TXA2) and adenosine diphosphate (ADP), which bind to theirown platelet receptors and amplify the activation process.(AA = arachidonic acid; FIB = fibrinogen; PGG2 and PGH2 =

labile prostaglandin endoperoxides) E) Platelet aggregationis mediated by fibrinogen (FIB) binding to its receptors onadjoining platelets, forming fibrinogen bridges. The FIBreceptor is formed by the complexing of Gp llb/llla in themembrane of activated platelets.

(Modified and reproduced with permission from Schafer. 7)

their specific platelet surface receptors. Antagonistsof specific platelet agonists or blockade of their re-ceptors on platelets has also received attention in thedesign of antiplatelet strategies. In particular, antago-nists of thrombin, the most potent platelet stimulus,serve not only to block fibrin formation but also tointerfere with platelet activation (Fig. IC). Thrombininduces both platelet activation and fibrin genera-tion in a mutually interdependent and synergisticmanner. Direct thrombin antagonists that interferewith this process include hirudin, hirulog, hirugen.

92tlolltm 24. Animnber2. 199792 Antiplatelet Therapy

argatroban, PPACK, and single-stranded DNA ap-tamers.

Receptor occupancy by vWF and these variousplatelet agonists initiates the activation of platelets.As shown in Figure 1D, thromboxane A2 (TXA2), apotent platelet aggregating and vasoconstrictingsubstance, is synthesized de novo after activatedplatelets release free arachidonic acid from theirmembrane phospholipid pools and convert it tothe labile prostaglandin endoperoxides, PGG2 andPGH2, by the enzyme cyclooxygenase. The endo-peroxides are then metabolized to TXA2 by throm-boxane synthase. Simultaneously, platelet granuleconstituents are discharged: this degranulation per-mits prepackaged platelet substances such as ad-enosine diphosphate (ADP) and fibrinogen to besecreted. Thromboxane A2 and ADP then bind totheir own platelet surface receptors, as well as thoseof other platelets being activated in the immediatevicinity, thereby amplifying the activation process.

Arachidonic acid metabolism, as well as TXA2 for-mation and binding to platelets, can be blockedpharmacologically at several steps (Fig. 1D). Theavailability of arachidonic acid for cyclooxygen-ase is competitively inhibited by the omega-3 fattyacid, eicosapentaenoic acid-a major constituentof cold-water fish oils. This inhibition contributesto the antiplatelet effects of "Eskimo diets." Aspirinand nonsteroidal anti-inflammatory drugs (NSAIDs)block cyclooxygenase activity; the inhibitory effectof aspirin is irreversible, while that of NSAIDs isreversible. Disappointing clinical experience withthromboxane synthase inhibitors may be due to thefact that prostaglandin endoperoxides, which accu-mulate with blockade of this enzyme, themselvesexert platelet agonist actions by binding to and acti-vating the same receptors as TXA2. Thromboxane A2receptor antagonists, dual thromboxane synthase in-hibitors, and TXA./endoperoxide receptor antago-nists have also been developed, but have not beenshown to be superior to aspirin in antiplatelet effi-cacy.Of drugs that are directed primarily at blocking

ADP-induced platelet activation, the thienopyridineclass of compounds has received the most atten-tion and includes ticlopidine and its analogs, oneof which is clopidogrel. The mechanism of action ofthese drugs is to modify the platelet membrane'saffinity for ADP, and possibly for fibrinogen (Fig.1D). In more limited clinical trials, ticlopidine gen-erally has been found to be at least as effectiveas aspirin in the prophylaxis of arterial thrombosis(Table I), although its side effects and higher costmay prove to offset any advantage it might have inefficacy compared with aspirin.

Platelet membrane changes occur after plateletactivation and degranulation. Most importantly, the

separate membrane glycoproteins IIb and Illa arecomplexed to form a heterodimer (Gp IIb/IlIa) thatserves as the functional receptor for fibrinogen. Fi-brinogen is the molecular glue that binds 1 activatedplatelet to another in the process of platelet aggre-gation (Fig. 1E). (In areas of the circulation charac-terized by higher levels of shear stress, includingdiseased coronary arteries, vWF actually replacesfibrinogen as the Gp IIb/IIIa-binding ligand.) In thisfinal event in the sequence of platelet activation,aggregation of platelets produces an occlusive plate-let thrombus at the site of vascular injury.The Gp IIb/IIIa complex is 1 member of the fam-

ily of integrins: cell membrane glycoproteins thatserve as receptors for adhesive proteins. Integrinsare heterodimeric molecules composed of a and fsubunits. Specific combinations of these 2 subunitsform functional receptors with unique specificitiesfor different ligands (adhesive proteins).The binding of fibrinogen to platelet Gp IIb/IIIa

(also referred to as a.P3 in the nomenclature ofintegrins) occurs via a specific amino acid sequence,RGD (arginine-glycine-aspartic acid). Fibrinogencontains 2 RGD sequences per half molecule; theyare located on the Aa chains of this dimeric protein.When 2 activated platelets with functional Gp IIb/Illa receptors each bind the same fibrinogen mol-ecule, a fibrinogen bridge is created between the 2platelets (Fig. 2). The surface of each platelet hasabout 50,000 widely distributed Gp IIb/Ilia fibrin-ogen binding sites. Therefore, numerous activated

Fig. 2 Linkage of 2 activated platelets by fibrinogen, whichbinds to its receptors in the platelet Gp llb/llla complex viatripeptide RGD (arginine-glycine-aspartic acid) sequenceslocated on the Aa chains of dimeric fibrinogen. The highdensity of Gp llb/llla complexes on the surfaces of activatedplatelets permits the rapid formation of a network of fibrino-gen bridges, leading to platelet aggregation at the site ofvascular injury. (In regions of high shear stress, such as indiseased coronary arteries, vWF may replace fibrinogen asthe primary aggregating ligand. Like fibrinogen, the vWFmolecule has RGD sequences that mediate this process.)The result of platelet aggregation is the formation of anocclusive platelet thrombus.

Texas Heart InstituteJournal Antiplatelet Therapy 93

platelets recruited to the site of vascular injury canrapidly form an occlusive aggregate via a dense net-work of intercellular fibrinogen bridges. The RGDsequence is present not only on fibrinogen mol-ecules but also on other adhesive ligands, includingvWF, which can substitute for fibrinogen as themolecular glue for platelet aggregation (as well asadhesion) in high-shear regions of the circulation.In addition to its RGD sequences, the y chains offibrinogen also contain a 12-amino acid residue(dodecapeptide HHLGGAKQAGDV) that also hasthe ability to bind to the platelet Gp IIb/IIIa recep-tor. Unlike the tripeptide RGD, however, this se-quence is found only on fibrinogen.

Adhesive proteins such as fibrinogen can use theirRGD sequences to bind not only to Gp IIb/Illa onplatelet membranes but also to other integrins ofsimilar structure on platelets and other cells. Forexample, fibrinogen RGD can also bind to oj30 fi-bronectin receptors and to ax P3 vitronectin recep-tors on vascular cells (Table II). Thus, the RGD se-quence on fibrinogen is promiscuous in its spectrumof binding to cell membrane integrins.A variety of strategies have been developed to

inhibit platelet aggregation by interfering with fi-brinogen binding to the platelet membrane integrinGp Ilb/Illa. The basic rationale for this approach isthat it is unlikely that inhibition of any single plate-let agonist or its receptor or any specific pathway ofplatelet activation alone will lead to substantial sup-pression of platelet thrombus formation. Therefore,broad inhibition of platelet function by blockade ofthe final common pathway of aggregation (that is,fibrinogen binding to Gp Ilb/Illa) should show thegreatest antiplatelet efficacy.To this end, several types of antagonists of plate-

let Gp IIb/IIIa function have been developed (TableIII). These include monoclonal antibodies againstGp IIb/IIIa and a variety of peptide and nonpeptideantagonists of Gp IIb/IIIa. The peptide antagonists

TABLE II. Gp llb/lila Recognition Sequences Involved inPlatelet Aggregation

Amino Acid Spectrum ofSequence Recognized Integrin Reactivity

RGD (arginine-glycine-aspartic acid) abf P3 (Gp Ilb/lila)

aV P3 (vitronectin receptor)

a5 PI (fibronectin receptor)

Others

KGD (lysine-glycine-aspartic acid) alb P3 (Gp llb/Ilila)

Dodecapeptide HPHLGGAKQAGDV abfn3 )Gp Ib/l la)

TABLE 111. Antagonists of Platelet Gp Ilb/IlIa Function

Monoclonal antibody against Gp llb/lIla

Peptide (peptidomimetic) antagonists of Gp Ilb/lIlaRGD-containing snake venoms (disintegrins)Synthetic linear RGD-containing peptidesCyclic RGD or KGD peptides

Nonpeptide (nonpeptide mimetic) antagonists of Gp Ilb/lila

KGD = lysine-glycine-aspartic acid; RGD = arginine-glycine-aspartic acid

include RGD-containing snake venoms (termed dis-integrins), synthetic linear RGD-containing peptides,and cyclic RGD or KGD (lysine-glycine-aspartic acid)peptides (peptidomimetics). More recently, nonpep-tide antagonists (nonpeptide mimetics) have beendeveloped with the potential for oral administra-tion.

Coller and colleagues initially showed that mousemonoclonal antibodies directed against platelet GpIlb/Illa blocked fibrinogen binding and consequentaggregation of platelets. To prevent immunogenic-ity, the Fc fragment of 1 such monoclonal antibody,7E3, was removed; the remaining Fab fragmentswere joined with the constant regions of human im-munoglobulin to create a chimeric compound, c7E3or abciximab (ReoProTM: Centocor, Inc. [Malvern,Penn]; and Eli Lilly and Company, Inc. [Indianapolis,Ind]). This antibody has now undergone extensiveclinical trials, particularly for coronary interventions,and has received approval for clinical use by theFood and Drug Administration. In the initial EPIC(Evaluation of c7E3 in Preventing Ischemic Compli-cations) trial and the subsequent EPILOG (Evalua-tion of PTCA to Improve Long-term Outcome byc7E3 Gp Ilb/Illa Receptor Blockade) trial, this mono-clonal antibody has been found to be effective inreducing early reocclusion (with attendant need forrevascularization, nonfatal myocardial infarction, ordeath). This effect is sustained and durable in pa-tients undergoing coronary angioplasty or direc-tional atherectomy, both at high risk (EPIC) and atany level of risk (EPILOG) of complications. Poten-tial problems that have been considered in the useof monoclonal antibody blockade of platelet Gp IJb/Illa include its bleeding risk due to the relativelyextended duration of antiplatelet effect (which mayalso prove advantageous in efficacy); its lack ofintegrin specificity, causing it to block vascular vit-ronectin receptors as well as platelet fibrinogen re-ceptors (which may likewise prove advantageous inpromoting vessel wall passivation and preventinglate restenosis); immunogenicity; and the rare occur-rence of thrombocytopenia.

94 Antiplatelet Therapy Voltime 24, Nzimber 2, 1997

In the development of peptide and nonpeptideantagonists of platelet Gp Ilb/IlIa, the potential an-tigenicity of naturally occurring disintegrins has ledto the synthesis of low-molecular-weight Gp IIb/IIIaantagonists based on competition for platelet bind-ing with RGD-containing fibrinogen. Conformation-ally constrained cyclic peptides have been producedto improve the stability and potency of linear RGD-containing peptides. One such inhibitor, IntegrilinTM(COR Therapeutics, Inc.; South San Francisco, Calif ),is a cyclic heptapeptide that contains a KGD ratherthan the RGD sequence. The rationale for Integrilinis that the substitution of a single lysine (K) for argi-nine (R) makes this agent specific for the Gp IIb/IIIaintegrin (see Table II). The IMPACT II (Integrilin toMinimize Platelet Aggregation and Prevent CoronaryThrombosis II) trial confirmed that different ap-proaches to interference with fibrinogen binding toplatelet Gp lIb/IlIa and the consequent inhibition ofplatelet aggregation are effective in the clinical set-ting of coronary intervention. However, the lowerlong-term efficacy of Integrilin compared with thatof abciximab in patients undergoing coronary an-gioplasty or atherectomy has raised the interestingpossibility that the promiscuity of monoclonal anti-bodies for platelet and vascular integrins may actu-ally be beneficial in maintaining coronary arterypatency. Alternatively, Integrilin may prove to be aseffective as abciximab with changes in dosing andscheduling protocols.More recently, a variety of nonpeptide mimetics

have been developed. In addition to the advantagesof peptidomimetics, these nonpeptide antagonists ofplatelet Gp IIb/IIIa have the potential to be orallybioavailable and thus to be effective for chronic anti-platelet therapy. In contrast to the RGD (or KGD)peptidomimetics, which bind competitively to theRGD recognition site of Gp IIb/IIIa, the nonpeptidesmimic the geometric, stereotactic, and charge char-acteristics of the RGD sequence and thereby inhibitplatelet aggregation. One such agent, tirofiban (MK-383 or Aggrastat, Merck and Company; West Point,Penn), a tyrosine derivative, has also undergonePhase 3 testing in human beings in the RESTORE(Randomized Efficacy Study of Tirofiban for Out-comes and Restenosis) trial. In this study, infusionof the drug for 36 hours after coronary interventionsignificantly reduced abrupt arterial closure at day2, but later benefit (up to 30 days) appears to havebeen masked by subsequent clinical events.

Thus each type of Gp IIb/Illa inhibitor listed inTable III (antibodies, peptides, and nonpeptide mi-metics) has now undergone initial clinical trials. Therelatively nonspecific receptor blockade achieved bymonoclonal antibodies may have the important ad-vantage of cross-reactivity with other integrin recep-tors, which may prevent restenosis. In support of

this concept, antagonism of the vitronectin receptorby relatively nonspecific RGD-peptide inhibitors hasbeen shown to reduce neointima proliferation afterangioplasty in experimental animals, presumablyby inhibiting the migration and proliferation of vit-ronectin receptor-bearing vascular smooth musclecells. At the same time, the shorter elimination half-life and lack of antigenicity of the peptides and non-peptide mimetics may be more advantageous withrespect to safety. Considerably more clinical experi-ence will be required to determine the therapeuticstrategy that provides optimal efficacy and safety indifferent clinical situations that demand potent anti-platelet therapy. Clinical trials are now under way tobroaden the application of anti-Gp IIb/IIIa therapyfrom coronary angioplasty to other coronary ische-mia syndromes, including unstable angina and, incombination with lytic therapy, acute myocardial in-farction. Future directions are likely to include theuse of anti-GP Ilb/IlIa therapy in cerebrovascularand peripheral arterial disease.The major risk of any antiplatelet strategy is the

potential for bleeding complications. In this regard,it is instructive to look at the risk of bleeding in thevarious inherited disorders of platelet function (Fig.3). Bleeding problems tend to be most prominent inplatelet defects that involve either the initial or thefinal steps in platelet activation. Therefore, patientswith platelet adhesion defects, such as von Wille-brand's disease and the Bernard-Soulier syndrome,or platelet aggregation defects, such as Glanzmann'sthrombasthenia, tend to be plagued throughout lifewith serious bleeding complications. In contrast, pa-tients with platelet release defects, including storagepool disease, tend to have minimal (if any) clinicalbleeding problems.

Likewise, there appears to be a correspondingrelationship between efficacy and bleeding risk ofantiplatelet agents directed at these specific steps ofplatelet activation (Fig. 4). Drugs like aspirin and

DISRUPTION OFENDOTHELIUM

4PLATELETADHESION

4PLATELETACTIVATION

PLATELETRELEASE

PLATELETAGGREGATION

von Willebrand's diseaseBernard-Soulier syndrome

Storage pool diseaseRelease defects

Thrombasthenia

Fig. 3 Inherited disorders of platelet function. Bleedingproblems tend to be most prominent in qualitative plateletabnormalities that involve either the initial (adhesion) or final(aggregation) steps in platelet activation.

Texas Heart InstituteJournal Antiplatelet Therapy 95

ticlopidine, which affect single pathways of plateletactivation, have relatively low bleeding risks but alsorelatively low efficacy. In contrast, both the efficacyand the bleeding risk of platelet Gp IIb/IIIa antago-nists, which inhibit aggregation, are relatively high,consistent with clinical observations in patients withthrombasthenia. It might also be expected that effi-cacy and bleeding risk would be correspondinglyhigh with adhesion inhibitors, consistent with clini-cal observations in von Willebrand's disease andBernard-Soulier syndrome.The holy grail of antithrombotic therapy is to de-

velop an agent that is highly effective in treatingthrombosis without causing bleeding. To this end, itis important to remember that hemostasis is a pro-tective, physiologic process of clot formation thatstops blood loss at sites of vascular injury. In con-trast, thrombosis is a pathologic process of clot for-mation that causes vascular occlusion and stopsblood flow. It has been considered by many thatthrombosis is simply "hemostasis in the wrongplace" or hemostasis in an exaggerated form. Thisimplies that the mechanism of thrombosis is thesame as that of hemostasis. The corollary of this con-cept is that the potency of any antithrombotic agentwill inevitably correlate with its bleeding risk.

There are 2 possible responses to this apparentdilemma. First, it is indeed possible that the humancoagulation system will prove to be incapable of dis-tinguishing between protective, physiologic hemo-stasis and pathologic thrombosis. Alternatively, ourcurrent understanding of coagulation may be inad-equate to distinguish basic differences between theprocesses of hemostasis and thrombosis. If the latteris correct, we shall eagerly await the potential magicbullet of antithrombotic therapeutic agents that arehighly effective in treating thrombosis and cause nobleeding complications. Until then, further progressin the development of adhesion inhibitors or the

Efficacy

(+)

DISRUPTION OFENDOTHELIUM

PLATELETADHESION

PLATELETACTIVATION

PLATELETRELEASE

PLATELETAGGREGATION

careful use ofGp IIb/IIIa antagonists holds the great-est promise for highly effective antiplatelet interven-tion.

Suggested Reading1. Coutre S, Leung L. Novel antithrombotic therapeutics tar-

geted against platelet glycoprotein IIb/lIla. Annu Rev Med1995;46:257-65.

2. Frishman WH, Burns B, Atac B, Alturk N, Altajar B, LerrickK. Novel antiplatelet therapies for treatment of patients withischemic heart disease: inhibitors of the platelet glycopro-tein IIb/IIIa integrin receptor. Am Heart J 1995;130:877-92.

3. Lefkovits J, Plow EF, Topol EJ. Platelet glycoprotein IIb/IIIareceptors in cardiovascular medicine. N Engl J Med 1995;332:1553-9.

4. Matsuno H, Stassen JM, Vermylen J, Deckmyn H. Inhibitionof integrin function by a cyclic RGD-containing peptide pre-vents neointima formation. Circulation 1994;90:2203-6.

5. Phillips DR, Charo IF, Scarborough RM. GPIIb-IIIa: the re-sponsive integrin. Cell 1991;65:359-62.

6. Schafer AI. Antiplatelet therapy. AmJ Med 1996;101:199-209.7. Schafer AI. Aspirin and antiplatelet agents in cardiovascular

disease. In: Smith TW, editor. Cardiovascular therapeutics.Philadelphia: WB Saunders Co., 1996:427-42.

8. Tcheng JE. Glycoprotein 1Ib/III receptor inhibitors: puttingthe EPIC, IMPACT II, RESTORE, and EPILOG trials into per-spective. Am J Cardiol 1996;78(3A):35-40.

9. Willerson JT. Inhibitors of platelet glycoprotein IIb/IIIa re-ceptors. Will they be useful when given chronically? [edito-rial] Circulation 1996;94:866-8.

Bleeding Risk

(t')

Fig. 4 Correlation between efficacy and bleeding risk ofantiplatelet agents. Antiplatelet agents that disrupt the initial(adhesion) and final (aggregation) phases of the sequence ofplatelet activation are likely to have the greatest antithrom-botic efficacy but also the greatest bleeding risk.

96 Antiplatelet Therapy Volume 24, Number 2, 1997