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REVIEW ARTICLE

Aspirin, Platelets,and Thrombosis: Theoryand Practice


By Gerald J. Roth and David C. Calverley

OES ASPIRIN PREVENT heart attacks? The question is asked by both patients and physicians who wonder how a pill for headaches could influence a lethal vascular event. Today, a wealth of evidence shows that aspirin does, indeed, prevent heartattacks and related thrombotic disorders such as strokes. Performed over more than two decades, the pertinent studies range from clinical epidemiology to molecular biology and include the observation that aspirin exerts its antithrombotic effect through a single specific reaction with an enzyme of blood platelet^.'^^ This review traces the connection between aspirin, the platelet enzyme (cyclo-oxygenase), andthe clinical dataon thrombosis, notingissues such as the indications, doses, and risks of this unique medication.
THE MECHANISM OF THE ANTITHROMBOTIC EFFECTOF ASPIRIN

Prostaglandins (PGs)

PGs were discovered as unique biologic activities in human erne en,'^^'^ leading to thesubsequent definition of PG structures16 and substrates. Biosynthesis of PGs depends on exogenous stimuli that release the substrate, arachidonate, from membrane phospholipid stores.L8 Throughthe 196Os, however, the general roles of PGs in physiology, the specific role of PGs in hemostasis, and the mode of action of the aspirin-like drugs all remained to be clarified. A Watershed: The PG Hypothesis In 197 1, Vane published his observation that aspirin inhibits PG synthesis. The work brought together two separate areasof inquiry (PGs andNSAIDs) and stimulated intense study of the agonist (PG)-inhibitor (NSAID) relationship. Over the ensuing two decades, the basic tenets of the PGhypothesis were confirmed. (1) PGs mediate responses, such as inflammation, that are blocked by NSAIDs. (2) NSAIDs act by blocking PG synthesis. When used in high doses, such as greater than 4 g/d for rheumatoid arthritis, aspirin may affect pathways of inflammation that do not involve PGs; but in most clinical settings, the drug works through its effect on PGS.~, PG Structure and Function PG synthesis involves four steps (Fig 2): (1) release of substrate (arachidonate, 20:4) from lipid stores by phospholipase; (2) formation of the common PG intermediate, PGHz, by PGH synthase; (3) rearrangement of PGH2 by cell-specific, branch pathways to give active endproducts (PGD2/E2/F2,, thromboxane, prostacyclin); and (4) breakdown of the active compounds to inactive metabolite^.^^-^^ All prostanoid-forming cells synthesize the common intermediate, PGH2, but they differ dramatically in their production of cell-specific PG products, which are categorized as either stable or unstable. Stable products such as PGD2/E2/FZa resist hydrolysis in water solution and mediate a number of physiologic processes (inflammatory, reproductive, renal, neurologic) in a variety of tissues and organs.23 However, the prostanoids of greatest interest in thrombosisareunstable compounds (platelet thromFrom the Hematology Section, Medical and Research Services, Seattle Veterans Hospital, and the University Washington, Seatof tle, WA. Submitted June 7, 1993; accepted November l l , 1993. Supported by a Merit Review grant from the Veterans Administration, by Grant No. HL 39947from the National Institutes o f Health, by Grant No. 90-904 from theAmerican Heart Association, and byfellowship awardsfrom the Royal College ofPhysicians and Surgeons o Canada/Sandoz Canada and the Medical Research f Council of Canada. Address reprint requests to Gerald J. Roth, MD. Seattle VAMC (111-Med), 1660SColumbian Way, Seattle, WA 98108. 0 1994 by The American Society of Hematology.
0006-4971/94/8304-0033$3.00/0
885

Earlier insights into Aspirin-Like Drugs and Prostaglandins


History, Structure, and Usage

From antiquity tothe 1800s, salicylates from plant sources (white willow, Salix alba) provided a folk remedy for pain and fever. In the mid 1800s, salicylic acid was synthesized in Europe, followed shortly thereafter by the synthesis of acetyl-salicyclic acid.5 The Bayer company developed acetyl-salicylic acid (ASA) as a commercial pharmaceutical product and trade-marked the compound as aspirim6 Aspirin is now widely accepted as a treatment for headache and musculo-skeletal pain as implied a doctors in well-worn suggestion: Take two aspirin and call me in the morning. For example, average yearly consumption of aspirin indeveloped countries in 1985 approximated 100 tablets per person. A variety of aspirin-like agents are available, referred to as nonsteroidal anti-inflammatory drugs (NSAIDS).~ Several forms of NSAIDs, including aspirin, are shown in Fig 1.
Antihemostatic Effects

As an acetylated salicylate, aspirin was initially considered to be a prodrug or precursor of salicylic acid itself, implying that all salicylates (acetylated and nonacetylated) might have identical effect^.^ However, investigators in the 1940s reported that aspirin is a more potent antihemostatic than salicylic acid. A decade later, observing that aspirin can induce clinically significant bleeding, Craven suggested that thedrug might be useful as an antithromboticagent, and several investigators in the 1960s affirmed this suggestion by describing the ability of aspirin to suppress platelet function.-12Other aspirin-like drugs vary in their effects on the hemostatic system. Usual doses of acetaminophen do not alterhemostasis, whereas agents such as ibuprofenexert a short-lived effect on platelets that resembles that of aspiriq8 but blocks the active site of prostaglandin cyclooxygenase in a reversible rather than a permanent manner.I3
Blood, Vol83, No 4 (February 15). 1994: pp 885-898

886

ROTH AND CALVERLEY A. Salicylates

COOH

0
COOH
\

B. Para-aminophenols
NHCOCH,

0 O C H 3
\

0
\

cyclizes arachidonate to PGG,) and peroxidase (reduces PGG2 toPGH,) a c t i v i t i e ~ . Aspirin~affects PG synthesis ~*~~ genase function PGHofby blocking only the cyclo-oxyin a highly specific way synthase3while leaving other PG elements unaffected (Fig 3). A novel and distinct PGH synthase was discovered recently in certain cells responding to exogenous stimuli, but this second form of the enzyme (PGH synthase-2) is not found in platelets and does not appear to relate to the antihemostatic and antithrombotic kffects ~ f a s p i r i n . ~ ~ At a molecular level, aspirin blocks cyclo-oxygenase by acetylating the protein, and the reaction depends on both the intrinsic chemical properties of the drug and theaffinity of the drug for the enzymes active The acetyl moiety of aspirin (COCH3,Figs l and 3) is labile and susceptible to being transferred to biologic substrates (acetylation). For example, aspirin nonspecifically acetylates a variety of proteins, lipids, and nucleic acids at millimolar concentrat i o n ~In~contrast, aspirin acetylates cyclo-oxygenase in a . ~ highly specific fashion with the reaction going to completion within minutes at micromolar concentrations under mild conditions.233 thousand-fold difference in aspirin The concentrations needed for nonspecific versus specific acetylations reflects the affinity of the drug for a single serine (residue 529, Fig 3) within the active site of cyclo-oxygena ~ eRecent work with enzyme mutants shows that serine . ~ ~ 529 is not itself required for catalysis, but that addition of the bulky acetyl moiety to the residue interferes with enzyme a ~ t i v i t y . ~ . ~ ~ Acetylation by aspirin of serine 529 within cyclo-oxygenase produces a covalent 0-acetyl bond that resists hydrolysis under intracellular conditions. The permanence of acetylation results in the irreversible inactivation of platelet cyclo-oxygenase by aspirin.233 a result, aspirin-modified As plateletsare affected for the rest oftheir circulatinglifespans. This accountsfor the cumulativeeffect of aspirin that one observes when the drug is first administered in low doses (5 to 75 mg/d) to patients, namely, a progressive daily increase in the aspirin-induced functional defect caused by the

cid

Acetyl-Salicylic Salicylic Acid Aspirin-ASA

OH Acetaminophen

C. Non-salicylate
Aspirin-like Agents

Ibuprofen Fig 1. Examples of compounds in three different classes of NSAIDs. A. Salicylates: Salicylic acid and acetyl-salicylic acid (ASA; trademarks: Aspirin, Bufferin, Alka-Seltzer). B. Para-amino phenols: acetaminophen(trademark Tylenol). C. Nonsalicylateaspirin-like drugs: ibuprofen (trademarks:Advil, Motrin, Nuprin).

boxane-TxA,, endothelial prostacyclin-PG12)that undergo rapid hydrolysis in water (seconds, minutes) and exert local, opposing hemostatic/antihemostatic effects.2ss26 Thromboxane promotes the formation of hemostatic plugs by aggregating platelets and constricting blood vessels,25whereas prostacyclin counteracts thromboxane by suppressing platelet aggregation and dilating vessels.26The implications for of the thromboxane/prostacyclin balan~e~ the use of aspirin as an antithrombotic agent are discussed in a later section.
The Mechanism Of the Aspirin Effect On PG Synthesis: Acetylation of an Active-Site Serine Within CycloOxygenase

The central enzyme of PG synthesis, PGH synthase, contains heme and possesses both cyclo-oxygenase(oxygenates/

Phospholipid substrate release Arachidonate 9 cyclo-oxygenase PGH synthase Common path

>

fOH PGH, Cell-specific paths

COOH

CO O H
\

OH Thromboxane (Tx) Gketo TxB,

A,

PGI, Prostacyclin

9PGF,,

Fig 2. Steps in PG biosynthesis. PG synthesis f involvesfour steps: (1) Releaseo the substrate, arachidonic acid (20:4),from membrane phospholipids by a phospholipase. (2) Formation of the common intermediate, PGH2, from arachidonate by PGH synthase through sequential cyclo-oxygenase and peroxidase activities, bothof which are present within the same enzyme.(3) Formation of cell-spe, cific PG products, either stable (D2. Et, )F or unstable (thromboxane, prostacyclin), by distinct enzymes found in different cells and tissues. (4)Breakdown of active compounds to inactive meTxB, and PGl, Gketo tabolites, using TxA, P , as examples. GF,

-.

-.

ASPIRIN, PLATELETS, AND THROMBOSIS

Prostaglandin Arachidonate oxyaenase

G2

Polypeptide A

f l
Methionine Fig 3. The mechanism of aspirins effect on platelets. The 599 amino acid polypeptide chain of PGH synthase (centerwavy line: NH2-terminalmethionine-l , COOH-terminal leucine-599) exerts cyclo-oxygenase activity as shown above (oxygenation/cyclization of arachidonate to PGG2) and interacts with aspirin as shown below. The serine residue located at position 529 of the polypeptide chain of cyclo-oxygenaseis acetylated through transfer of aspirins acetyl group, as indicated in boldface. Covalently modified, acetylated PGH synthase carries a single acetyl group in its active site and lacks cyclo-oxygenase activity. all

529 5993

I -COOH

Serine

steady accumulation of permanently modified platelets in the cir~ulation.~ Platelet and endothelial cyclo-oxygenase are equally sensitive to aspirin, as shown by direct experiments in intact cells.38 An earlier study compared the enzyme from blood vessel microsomes with that of platelets, and the result suggested that the platelet enzyme was more sensitive to aspirin.39 However, most observers consider the endothelial and platelet enzymes to be equivalent in their response to aspirin, particularly because they appear to be identical proteins that are encoded by the same gene.40 Relative Aspirin-Sensitivity of PG Synthesis in Different

Cells
Under in vivoconditions, platelet PG synthesis is approximately 10-fold more sensitive to orally administered aspirin than thatof other cells (Table 1). Consequently, effective analgesic/antipyreticdoses of aspirin are much higher than those needed to inhibit platelet^.^.^^ When used orally to treat headache or fever, aspirin is delivered to protein-syn-

thesizing tissues target by postportal and 600 mg doses are required for effective therapy.8Similar conditions apply to aspirin-inhibition of prostacyclin synthesis in vascular endothelial cells, because the vasculature consists of protein-synthesizing cellsand lies, in large part, outside the portal circulation. Direct studies of patients show that inhibition of PG12 synthesisrequires higher doses ofaspirin than does blockade of TxA2 formation,37343 although considerable overlap exists between the two effects, and no dose of aspirin will block TxA2 formation completely without affecting PG12production. The exact basisof the differential sensitivity of PGIz/TxA2 to oral aspirin remains somewhat unclear, but it does not lie in different aspirin susceptibilities of endothelial as opposed to platelet cyclo-oxyg e n a ~ eInstead, the important distinctions between PG12 .~~ and TxA2in regard to aspirin-dependent inhibition involve three distinct parameters: (1) the relative ability ofa target cell to replace an inactive enzyme by protein synthesis; (2) the exposure of target cellsto aspirin in portal versus postportal blood; and (3) the physiologic role ofthe prostanoid pathway inthe cell ofinterest.

Table 1. Three Levels of Aspirin Therapy: 10-Fold Dose Increments


Indication

Dosage

Comment

A n t i t h r o m b o t i ~ ~ ~ ,Platelet~ ~ Anucleate 60 mg Analgesic/ Headacheantipyretics Antirheumaticz

600 mg Salicylate6,000 mg

target, exquisite sensitivity, permanent/ limited effect Take two aspirinand call me in the morning Does not work through Drostaalandins alone

A Unique Relationship: Aspirin and Platelets Aspirin impairs platelet activation, implying that a prostanoid (PG) is involved in the activation p r o c e ~ s . l l . ~ , ~ ~ However, the effect of aspirin on platelet PGs is an exceptional example of the general aspirin-PG relationship. One small dose of oral aspirin permanently impairs the function of all available platelets, withthe effect lasting several days.2,37.43,45The gradual recovery of platelet function after a dose of aspirin is the converse of aspirins initial cumulative effect and reflects the appearance in the circulation of new, unaffected platelets that were formed in the marrow

ROTH AND CALVERLEY

platelets, lacking mRNA synthesis, cannot replace a blocked enzyme cytoplasmic

circulating platelets encounter absorbed aspirin

only one pathway


of activation is affected

aspirin acetylation inactivates Thromboxane

Stimulus protein ,noi,tols, kinase ResDonse

nucleated marrow megakaryocyte

anucleate blood platelet blood platelets

aggregate

A Anucleate target

B Exquisite sensitivity

C Permanent, limited effect

Fig 4. The features of the unique relationship between aspirin and platelets. (A) Anucleate target. Nucleatedmegakaryocytesin the bone marrow undergo cytoplasmic fragmentation and shed platelets into the circulating blood. Lackinga nucleus (anucleate)and being incapable of mRNA synthesis.blood platelets cannot synthesize new protein and are unableto replace an inactive enzyme such as aspirin-modified upper GI tract with about the same time course cyclo-oxygenase. (B) Exquisite sensitivity. After oral ingestion, aspirin is absorbed from the as that of platelet entry into the portal circulation from preportal blood. During the time aspirin absorption, the entire mass of platelets in of a patient ingesting 100 mg or more of the drug will be exposed a sufficient aspirin concentration to inhibit PG synthesis nearly completely. to After transit through the portal circulation, aspirin is partially deacetylated/inactivated in the liver. (C) Permanent, limited effect. Platelets activate and aggregate in response to exogenous stimuli such as thrombin or collagen. Severalintracellular pathways of activation mediate the responseof a platelet to a stimulus, but only one, TxA2synthesis, is blocked by aspirin. Other pathways. such as protein kinaseC, inositol release, andcalcium flux, are unaffected by aspirin and preselve a degree of platelet function despite aspirin inhibition of TxA2. Therefore, aspirins inhibitory effect on platelet function is partial because it is limited only one of several intracellularsignalling pathways. The aspirin to effect is permanent because it involves covalent acetylation of cyclo-oxygenase.

after the ingestion of the d r ~ g .The ~ ~ ~ , unique relationship between aspirin and platelets consists of three features: an anucleate target, exquisite sensitivity, and a permanent, limited effect (Fig 4).

Anucleate Target
As fragments of the cytoplasm of bone marrow megakaryocytes, blood platelets lack a nucleus and are unableto synthesize new mRNA. Although retaining/translating some megakaryocyte mRNA?6 platelets are generally incapable of protein synthesis,47and those exposed to aspirin do not appear to replace their complement of inactive cyclo-oxygenase (Fig 4A). The anucleate nature of platelets and the covalent nature of aspirin-dependent acetylation combine to produce the permanence of the aspirin effect on plate~ ~~,~~ ~ let PG ~ y n t h e s i s . ~ . ~ In .contrast, .nucleated cells such as endothelium can replenish their supply of cyclo-oxygenase after aspirin treatment by synthesizing new enzyme, and this ability to recover from aspirin treatment contributes to the reduced aspirin sensitivity of these cells as compared with platelet^.^^,^^

Esquisite Sensitivil>9 Small, infieqzwnt dosu. Platelet PG synthesis is almost completely inhibited by small, infrequent doses of oral aspirin. As gauged by several parameters (enzyme acetylation, urinary PG metabolites, ex vivo PG synthesis), oral aspirin inhibits platelet PG synthesis nearly completely when ad-

ministered either as large/single dose (> 100 mg) or as one daily small/cumulative doses (5 to 95 mg).37343,45 Small doses. The admixture of platelets and aspirin in the portal circulation accounts, in part, for the unique sensitivity of platelets to theoral drug. The evidence in this regard comes from a study that compared intravenous (systemic) to oral (presystemic/portal) aspirin and showed oral aspirin inhibiting TxA2 synthesis in blood platelets before the drugs passage through the liver.49Over about 30 minutestime after aspirin ingestion, the entire mass of platelets of a treated individual is exposed to active (acetylated) aspirin as it is being absorbed from the upper GI tract41-43.49 (Fig 4B). Apparently, aspirin enters portal blood at about the samerate as do platelets from the preportal circulation, and direct contact between platelets and newly absorbed aspirin facilitates the rapid and essentially complete inhibition of platelet cyclo-oxygenase. Therefore, access to platelets in portal rather than extraportal blood is an important aspect of aspirins antiplatelet effect because the drugis intact/active in this locale but partially deacylated/inactivated during its subsequent passage through the liver.41.42.49 However, hepatic deactivation of aspirin is not complete, and a portion ofaspirin portal blood passes intact through in the liver and affects prostanoid-forming cells in postportal blood, such as marrow megakaryocyte^.^' Infrequent doses. Daily oral administration of adequate doses of aspirin (> 100 mg) is sufficiently frequent to block platelet PGs to a maximal extent.37.43.45 S fact implies Thi that, in addition to platelets in the blood, a single dose (> 100

ASPIRIN,PLATELETS,

AND THROMBOSIS

889

mg) of oral aspirin also affects nascent, preformed platelets in marrow megakaryocytes before they enter the circulating blood over the next day. If this were not the case, platelet PG synthesis would increase by 10% during the day after exposure to aspirin, reflecting the rate of normal production of platelets with their circulating life span of 10 days.5 Although the extent of transport of orally absorbed aspirin to the marrow andthe turnover/replenishment of cyclooxygenase in the platelet compartments of megakaryocyte cytoplasm are not defined, the available observations document theeffect of aspirin on theenzyme in megakaryo c y t e ~Consistent with the fact that megakaryocytes are .~~ inhibited by oral aspirin, higher doses of aspirin appear to affect an even earlier cohort of platelets that aredeveloping in the marrow, accounting for the effective every-other-day treatment schedules noted in a later section.

genase. The ability of low amounts (30 to 160 mg) of the drug to prevent thrombosis to the same extent as higher provides essentially irrefutamounts (300 to 1,500mg),65.66 able evidence that aspirin exerts its antithrombotic effect by acetylation of platelet cyclo-oxygenase. If additional mechanisms are involved, their contributions appearto be minimal.
The ClinicalImplication: Use Aspirin in Patients to Prevent Thrombosis

Permanent, Limited Efect In using aspirin as anantiplatelet agent,one seeks a balance between effectiveness and toxicity, treating thrombosis while avoiding bleeding. Aspirin has a limited effect on normal platelet function, causing a minimal prolongation of the bleeding time, amodest inhibition of in vitro aggregation, and only a slight decline in normal hemostatic function at a clinical level.,12The highly selective effect ofaspirin on platelet PGs underpins its limited effecton overall platelet function. Platelet TxAz synthesis is safely expandable in most patients because it is only one of several intraplatelet pathways that mediate activation (Fig 4C). For example, pathways involving protein kinase C activation and inositol release are not affected by a ~ p i r i n ,and , ~ ~ ~ ~ the retention of these pathways preserves platelet function to a significant degree. Therefore, platelet PG synthesis is an attractive therapeutic target because of its distinct but limited contribution to activationinthisparticular target (platelets). Selective elimination of the TxAz pathway by aspirin causes a clear-cut but modest decrease in platelet function and provides a limited but definite antithrombotic effect.
Correlating Platelet Cyclo-Oxygenase Inhibition With Prevention of Thrombosis: Molecular and Clinical Effects of Aspirin

The data reviewed above give a straight-forward rationale for the clinical use ofaspirin to prevent thrombosis, namely, aspirin inhibition ofplatelet function can exerta therapeutic effect in patients with thrombotic vascular disease by suppressing the contribution of platelets to thrombus formation. Trials of aspirin in patients also provide an opportunity to observe the role of platelet PGs in clinical thrombosis.
CURRENT EVIDENCE: PREVENTION OF CLINICAL THROMBOSIS BY ASPIRIN

The studies reviewed below show the effectiveness of aspirin in preventing certain thrombotic complicationsof vascular disease. In general, aspirin affects arterial rather than venous thrombosis, and most aspirin-responsive thrombi arise in the setting of atherosclerotic changes in an arterial vessel wall. The Federal Drug Administration has approved aspirin for unstable angina and after transient ischemic attacks and myocardial i n f a r ~ t i o n . ~ . ~ ~
Studies in Cardiovascular Disease

Direct examination of coronary arteries after myocardial infarction shows a pathophysiologic sequence that begins with the disruption of an atherosclerotic plaque and leads to platelet accumulation and thrombus f ~ r m a t i o n Such .~~ pathologic information suggests that aspirin has the potential to prevent myocardial infarction.

Secondary Prevention ofhfvocardial Infarction (MI) Eleven randomized, double-blindstudies of aspirin in the prevention of recurrent MI in nearly 40,000 patients are available, six using aspirin alone (Table 2), three with aspiTable 2. Aspirin in Patients AfterMI
Cardiac Events

Aspirins antithrombotic effect could arise from the drugs actions on systems that donot involve PGs, because aspirin can influence other aspects of hemostasis such as fibrinolysis and plasma coagulation.54355 However, these nonprostanoid effects ofaspirin proceed only at concentrations that are irrelevant to the antiplatelet and antithrombotic activity of the drug. Aclose correlation exists between the aspirin concentrations (micromolar) that acetylate platelet cyclo-oxygenase, block enzyme activity/PGsynthesis, and inhibit platelet function, with all three events occurring under the same conditions and with the same time course~2.3.11,12,37.43.45 The ability of low-dose aspirin (30 to 160 mg/d)56-64 prevent clinical thrombosis provides the in to vivo clinical correlate to thein vitro/ex vivo molecular data, because the only known effect of 30 to 160 mg of daily oral aspirin is the selective inhibition of platelet cyclo-oxy-

All Deaths (%)


Trial

(%I
Placebo Aspinn

No. of Patients

Months of Follow-Up

Placebo

ASDlrln

CDPA7 Elwood Breddin7* AMIS, adj* 74 PAIRS I t 7 5 Total Average

1,239 1,529 1,682 946 4,524 1,216 11.136

12 22 12 24 38 41

10.8 8.3 14.8 12.3 10.0 12.8

8.0 5.8 12.3 10.1 10.5 10.5

16.1 8.1 21.0

9.1 5.1 16.0

24

11.5

9.5

15.1

10.4

The data on cardiac events are graphed in Fig 5C. Only aspirin trials are included. *The AMIS trial resultsare adjusted t o balance entry parameters. t The portion of the PARIS trial usingaspirin alone is summarized.

890

ROTHANDCALVERLEY

Table 3. Aspirin in Patients With Unstable Angina rin and dipyridamole, one with aspirin and streptokinase, and one with aspirin, streptokinase, and heparin.58x62,70-78 All Deaths 1%) Cardiac Events (%) NP. of Months The recent follow-up trial to ISIS-2 involved 4 1,299 patients Trial Patents Follow-Up Placebo Asptrin Placebo Aspirm with MI receiving one of three thrombolyticregimens; all of Lewis 3 1.6 10.1 3.3 5.0 the patients in this ISIS-3 trial were treated with aspirin.79 1,338 11.7 17.0 Cairnsa6 555 18 3.0 8.6 The drug is now accepted as standard therapy for post-MI 0 12.0 479 0.2 1.7 3.0 TherouxE7 patients.79 796 0.17 0.25 0.25 RISC5 5.8 2.5 In 1988, the Antiplatelet Trialists Collaboration re13.4 1 2.0 4.3 0.5 viewed 25completed trials incorporating antiplateletagents 1.5 17.1 2.5 3 6.5 into secondary prophylaxis of vascular disease.65Nearly all 3,168 Total these trials documented a trend in favor of aspirin use, alAverages 5.0 12.6 1.1 4.2 3.6 though most lacked the statistical power to demonstrate reliably the modest true beneficial effect that aspirin has on thromboembolic endpoints. Among the MI-related trials, platelet inhibitors significantly reduced the vascular mortalreduces the incidence of early closure of saphenous vein byity rate by 13%, the rate of nonfatal recurrent MI by 3 I%, pass does not but influence the extent of and thenonfatal stroke rateby 42%. Nonvascular mortality chronic obliterative changes caused by atherosclerosis. Aswas unchanged. When all 25 trials were examined, antipirin is also effective in percutaneous, transluminal coroplatelet treatment led to a 15% reduction in vascular mornary angioplasty, as demonstrated in several randomized tality and a 30% reduction in nonfatal recurrent MI or trials, lowering the periprocedural complication rate comstroke in 29,000 patients. This report also examined compared with placebo but notaltering the incidence of late carpliance with treatment after 1 year. Among the MI-related diovascular sequelae such as r e s t e n o ~ i s ? ~ - ~ ~ trials, compliance ranged from 0.7 to 0.9. Another large meta-analysis of the results of 15 1 randomized antiplatelet Studies in Cerebrovascular Disease trials is now complete, ie, the second Antiplatelet Trialists In using aspirin to prevent cerebrovascular thrombosis, a Collaboration,66 and its results are similar to those of the distinction is made between transient or less severe events original such as transient ischemic attacks (TIAs)/minorstrokes and more severe, evolving or recently completed majorstrokes. Primary Prevention ofM1 Aspirin After TIAs and Minor Strokes Two large recent trials of aspirin in male physicians gave different, but not inconsistent, results. An American trial A series of trials shows that aspirin is effective in preventshowed significant benefit from the drug, whereas a smaller ing new or recurrent strokeand deathafter TIAs and minor British trial did not, perhaps because of its size.8038 raThe strokes. To date, there have been 12 randomized trials retionale behind the studies was to test the ability of aspirin ported in the English literature using aspirin as asecondary to prevent sequelae of vascular disease in generally healthy preventative measure in patients with previous cerebrovasindividuals. An overview analysis of the two studies indicular d i s e a ~ e . ~ The~Antiplatelet Trialists Collabora.~ ~~ cated a significant benefit due toaspirin in preventing both tion performed an analysis of 17 completed randomized trinonfatal MI and total vascular events8*Related informaals in patients with cerebrovascular disorders involving tion is available in women, although it is not as extensive aspirin, dipyridamole,sulfinpyrazone, and t i ~ l o p i d i n eIn- ~ .~ as that in men nor is it as well-controlled, being based on dividually, several of the larger TIA trials showed a statistiprospective cohorts ratherthan r a n d o m i ~ a t i o nIn a subset .~~ cally significant risk reduction in death, nonfatal stroke, or of male physicians with chronic stable angina, aspirin signonfatal MI, illustrating the important role of sufficient nificantly reduced the incidence of first MI,84and similar numbers of study patients in providing definitive results in results were obtained inan unrelated this disorder.

UnstableAngina
Based on four randomized, double-blind trials, aspirin is clearly effective in unstable angina, which provides one of the best examples of a thrombotic setting amenable to this form of antiplatelet therapy (Table 3).59.85-87 Either ~~.~~ a l ~ n e or.with h e ~ a r i n ,aspirin reduces the risk of MI ~ ~~ and cardiac death by 50% to 70% and is part of standard therapy for this condition.

Aspirin UsefbrEvolving or Completed Major Strokes


The efficacy of aspirin has not been subjected to a randomized trial inpatients with evolving major strokes. Hence, the data are unclear in terms of aspirin benefit in this setting. Whereas aspirin is recommended after a TIA or minor ischemic stroke, the same cannot be said after a completed major stroke because the data do not show a IO8 definite benefit being conferred in this circumstance. Studies in Peripheral Vascular Disease

CoronaryArtery Bypass Grafting and Angioplasty Randomized trials indicate that aspirin, aloneor with dipyridamole and administered within 48 hours of surgery,

Five studies show a clear-cut benefit from aspirin, with and without dipyridamole, in preventing prosthetic shunt occlusion caused by thrombus f o r m a t i ~ n . ~ ~ ~ ~ - ~ One study

ASPIRIN, PLATELETS, AND THROMBOSIS

89 1

indicated that low-dose aspirin reduces the incidence of MI and stroke but not shunt occlusion after saphenous vein femoral popliteal bypass.li3 Two aspirin trials in carotid end-arterectomy patients did not show a significant benefit from the d r ~ g . ~ Aspirin has not beenshown to be ~~ effective in distal arterial disease, whereasthe literature regarding the use of aspirin in microangiopathies, such as thrombotic thrombocytopenic purpura, has been controversial and inconclusive. Aspirin is not used in mostforms of deep venous thrombosis. After hip fracture or elective hip replacement, aspirin has been used to prevent venous thrombosis with variable success, and its routine use in these settings cannot be recommended, although a possiblebeneficialeffecthas not been ruled 0 ~ t . I ~
THERELATIONSHIPBETWEENTHEDOSE OF ASPIRIN AND ITS ANTITHROMBOTIC EFFECT

Table 4. Chronologyof Concern That Aspirin Decreases Endothelial PGll


Year

Observation

Conclusion, Aspirin Considered:

1975

Thromboxane (TxA2) defined as prothrombotic Prostacyclin(PGI,) described as antithromboticZs Platelet enzymemore susceptible to ASA39 ASA effect equal on different enzymes3 Prostacyclinsynthesis in humans is miniscule2 Incremental ASA doses block TxA, > PG1243 All ASA doses block PGI, in veins/shed bloodg Low, slow-release doses of ASA spare P IlB G, Dutch TIA trial finds 3 0 mg ASA effect > 300 mg6

Beneficial! blocks damaging platelet PG HannfuPmay block protective PG Beneficial! if dose employed blocks platelet but not endothelial enzyme Harmful?sinceno dose would block either cells PG enzyme selectively Beneficial! prostacyclin amounts appear too low to be relevant in thrombosis Beneficial! careful choice of ASA dose may preserve PG12synthesis HarmfuPno evidence that any ASA dose works selectively in vivo Beneficial! the ASA formulation can selectively block TxA, in controls Beneficial! but the optimal ASA dose is elusive and differences are small

1976

1978

1979

1981

The ability of ever-decreasing doses aspirin (30 to I60 of mg/d) to prevent thrombosis strains the limits of credibility.56d6 The available information points out that aspirin doses below 300mg/dprovideeffective antithrombotic therapy.
A Rationale for Using Lower Doses of Aspirin: Minimize the Problem of Inhibition of Prostacyclin (PG12) Synthesis

1982-83

1980-87

1991

1991

Because aspirin can block endothelial prostacyclin synthesis, the drug is potentially harmful if a decrease in PGIz synthesis predisposes patients to t h r o m b ~ s i s .In ~ . ~field ~ the ~ of antiplatelet therapy, this issue has engendered a continuing debate about both the importance of aspirin-mediated inhibition of endothelial prostacyclin synthesis the dose and of aspirin that spares PG12.The controversy began with the description of PG12,26 both conflicting and confoundand ing data have since been added, as chronicled in Table 4. Initially, different results were obtained concerning the relative susceptibility platelet and endothelial cyclo-oxygenof ase to Subsequently, selected forms/doses of aspirin were found to spare the production of systemic prostacyclin as determined by the measurement of urinary metabolites, but not to spare the same parameter when asor sessed as PG12production in vascular tissue as PG12 levels in blood from bleeding time W O U ~ ~ S . Th~ extent of ~ ~ e ~ ~ prostacyclin biosynthesis in normal subjects appears to be miniscule, suggesting that normal PG12 levels might be below those that could influence hemostasis.12The clinical direct importance of PGI, sparing can only be resolved by patient studies with aspirin doses or formulations that are more efficacious because they block platelet TxA2 spare and endothelial PG12.An example of sucha study is the Dutch TIA trial comparing 30 and 283 mg aspirin in 3,131 patients. The lower dose, which would be expected to spare PGI2, was slightly more effective with fewer side effects than the dose of 283 mg, but the differenceswere not statistically significant.60 Therefore, the limited amount ofclinical data does not show an unequivocal role for PG12 sparing approaches in aspirin-basedprevention of thrombosis. The possibility remains that PG12inhibition limits the ben-

eficial effect of aspirin and that methods of aspirin administration that preserve PG12are useful.*Unfortunately, 17 years after the discovery of PG12, importance of aspirins the anti-PG12effect in antithrombotic therapy remains unclear. The advantage that may be gained by preserving PG12during aspirin therapy appears to be modest and difficult to measure, but still worthy of further pursuit.
Higher Aspirin Doses (900to 1,500 mg/d) Lack Increased Effectiveness

Clinicians seek to use the lowest amount of a drug that will givea maximal therapeutic effect. In case ofaspirins the ~ antithrombotic effect, the point was addressed in the Anti~ platelet Trialists Collaboration by the meta-analysis of 19 antiplatelet trials of aspirin inseveral thrombotic disorders.65An indirect comparison of trials using 900 to 1,500 mg/d of aspirin versus placebo withtrials using 300 to 325 mg/d versus placebo was reported, and higher doses were not more effective than lower doses whencompared in this way.65Patients treated with 900 to 1,500 mg experienced a 23% reduction in new vascular events, whereas those taking 320 mg showed a decrease of 24%. Therefore, a plateau appears to exist inthe dose-response relationship ofaspirins antithrombotic effect. Once an effective threshold dose of aspirin is reached, maximal benefit results. Clinicaland laboratory observations compliment each other in this regard, becauseaspirin inhibition of in vitro platelet PG synthesis shows a similar dose-response plateau with maxi-

892

ROTH AND CALVERLEY

mal blockade at micromolar concentration^.^.^^.^^ The a ~ p i r i n . In ~ ~ . of ~ ~ information, the least amount ~ view ~ this clinical data reinforce the pointthat aspirin inhibits thromof aspirin that blocks platelet PG synthesis to a maximal bosis by blocking platelet PG synthesis. Currently, no solid extent is likely to be the most effective and least toxic dose. evidence is available that demonstrates an increased antiDoses of 80 to 160 mg/d satisfy that requirement, administhrombotic benefit of aspirin doses greater than 320 mg/d, tered daily for reasons of simplicity, maximal effect, and and a significant amount of data points to the opposite, ie, compensation for missed doses.A higher loading dose (320 that maximal benefit accrues from aspirin doses less than mg) is valuable for achieving an immediateeffect whenther320 mg/d.56h apy is initiated in the face ofactive t h r o m b o ~ i s . ~ ~ , ~ ~ Most aspirin trials in cerebrovascular disease have used THE RELATIONSHIP BETWEEN THE DOSE OF ASPIRIN higher doses of aspirin, in the range of 900 to 1,500 mg/d; AND ITS ADVERSE EFFECTS and concern persists, basedon ananalysis of available data, that higher doses may be needed in subsets of patients with Urticaria and related idiosyncratic reactions will exclude cerebrovascular thrombosis.108.12 However, a British study rare patients from the use ofaspirin.lZ8Gastric irritation and of TIA and minor stroke directly compared 300 mg with decreased renal and hemostatic function are more common 1,200 mg doses of aspirin and found nostatistically signifiadverse effects. cant difference in efficacy.Io6The evidence that higher doses of aspirin are needed in TIA and minor stroke is not comDose-Dependent Gastrointestinal and Renal Side pelling60*61.106 stands in contrast to prevailing informaand Effects tion about aspirin in related forms of vascular d i ~ e a s e . ~ ~ . ~ ~ Aspirin induces gastrointestinal (GI) irritation and bleeding by a mechanism that may involve both inhibition of PG Lower Aspirin Doses (30to 160 mg/d) MayBe More synthesis and direct damage to gastric and intestinal mucosa Effective Than Standard Doses of 320 mg through contact with ingested drug tablet^.''^,^^^ Clinical The success of the trials using relatively low doses of aspiand endoscopic data show the dose-dependency of aspirins rin suggest that only a portion of one adult320 mg tablet per GI t ~ x i c i t y , ~ and~ ~ l - l antithrombotic trials with aspirin corday is sufficient to prevent t h r o m b ~ s i s .The-only direct ~~ ~~ roborate this fact. For example, GI complaints and noncomparison was the DutchTIA trial comparing 30 and 283 compliance increase with aspirin doses of 900 to 1,500 commg doses.60 slight but statistically insignificant increase in A or ~ ~ ~ ~ the pared with 300 mg106 with p l a c e b ~ . However, ~ ~ ~ therapeutic effect and decrease in toxicity was seen withthe gastric mucosa appears to adapt to aspirin, and various lower dose.By comparing the benefits achieved in different preparations of aspirin (enteric coating, buffered preparatrials using different doses of aspirin, the observed effects tions) and two therapeutic modalities (misoprostol, ranitiappear to be roughly equivalent in patients with angina, bydine) may moderate the GI toxicity of the drug.129,134*35 pass grafts, and after M1.57,58,62,63,x4data do not resolve The Studies of the GI toxicity of aspirin doses less than 320 mg/ the question of the importance of prostacyclin sparing by d have given inconsistent results, with some trials indicating low-dose aspirin. However, the results of the Second Antilow levels of toxicity and others recording essentially no platelet Trialist overview support (nonsignificant trend, P = such adverse effect^.^^.^^.'^ Therefore, the available informa.06) the use oflower doses of aspirin because trials using less tion on GItoxicity provides another reason to use lower asthan 160 mg/d showed a 28% odds reduction in vascular pirin doses to prevent thrombosis, namely, with 80 to 160 events, compared with 26% and 20% odds reductions in trimg/d doses, one minimizes GI toxicity. als using 160 to 325 mg and 500 to 1,500 mg/d, respecSuppression of renal PG synthesis with attendant vasostitively.66 mulation is unlikely to occur with 80 to 160 mg doses of a~pirin,~ reiterating the argumentto use lower doses of the drug in thrombosis. An Elusive Fact: The Optimal Dose of Daily Oral
Aspirin to Prevent Thrombosis

The optimal antithrombotic dose lies somewhere between 30 and 320 mg of oral aspirin per day. Some lower limit of aspirin is required to accomplish the basic mission of the drug. Doses of less than 30 mg/d are unlikely to inhibit platelet PG synthesis completely and have not been subjected to clinical trials. All observers do not agree on any single effective lower dose, nor do all observers agree that the same dose of aspirin will work for every indication. However, the parameters of aspirins antithrombotic effect are remarkably consistent: (1) The intrinsic structural and functional properties of blood platelets do not vary in the thrombotic conditions of interest although platelet activation may be present.325 (2) The drug blocks platelet PG synthesis in every thrombotic disorder in which it is (3) Platelets in different thrombotic disorders do not differ from normal platelets in their susceptibility to

The Dose-Independent Decrease in Hemostatic Function Caused by Aspirin

The bleeding disorder induced by aspirin is usually subtle and goes unrecognized in hemostatically normal individuals as a mild increase in bruising or mucosal bleeding.32,37,138 antihemostatic and antithrombotic The effects of aspirin are inseparable because both result from platelet inhibition. Any aspirin dose that exceeds a low threshold level will block platelet PG synthesis and produce bothbleeding risks and potential antithrombotic benefits. The potential clinical importance of the hemostatic defect resulting from aspirin was suggested by the recent primary prevention trials in which an increase in life-threatening intracerebral hemorrhage was observed in men taking aspirin.80,8 Among 22,000 men, 10 severe hemorrhagic strokes

ASPIRIN, PLATELETS, AND THROMBOSIS

893

Clinical use of aspirin is changing (Fig 5). In the future, the drug may be used more asan antithrombotic and as less The Potential Role of Subclinical Bleeding Disorders in an analgesicfantipyretic because of concern over Reye synAspirin-Induced Hemorrhage drome in children' and because of the availability of other Aspirin is well-known to exacerbate the bleeding teneffective NSAIDs for pain and fever such as acetaminophen dency of hemophiliacs and patients with von Willebrand and ibuprofen.8 The major current controversy regarding disease ( V W D ) . ' ~ , 'However, not all individuals who are ~' aspirin as an antithrombotic its use as primaryprevention is predisposed to bleeding are fully aware of their di~abi1ity.l~~ in individuals who have not yet experienced a thrombotic event. Because the primary prevention studies are in not in Some may not have been evaluated or diagnosed accurately. The estimated incidence of mild forms of hemophilia, agreement and show rare but significant cerebrovascular vWD, congenital platelet defects, and unclassified bleeding bleeding complications,80 a current recommendation is to disorders varies widely and may range between 1% and reserve aspirin as a primary preventative for patients with 0.0 1% in various population^.'^^"^ Subclinical bleeding identified risk factors for atherosclerosis such as smoking, disorders are relevant to the bleeding problems seen with hypertension, hyperlipidemia, and diabete~.'.''~ Additional aspirin, particularly when the drug is administered to broad trials of aspirin for primary prevention are underway, with populations for primary prevention of thrombosis. In this one using warfarin in addition to aspirin in patients with instance, aspirin may exacerbate an underlying bleeding dirisk factors for atherosclerotic vascular disease.'57 Aspirin atheses in rare individuals, and severe bleeding may result.80 use in secondary prevention of thrombosis is noted above. Hemostatic evaluation of these individuals with aspirin-inFinal judgments on the optimal dose/form of aspirin duced bleeding might show cryptic hemostatic disorders. must come from direct study of individual disease states. Based on current data, 80 to I60 mg per day by mouth proCURRENT STATUS: CLINICAL USE OF ASPIRIN TO vides the maximal antithrombotic effect of the drug. This PREVENT THROMBOSIS dose corresponds to one or "babyfchild" tablets (80 mg two each) of aspirin taken orally, once each day. Status of Aspirin in Relation to Other Antiplatelet Agents Management of Toxicity Aspirin is insufficient antiplatelet therapy in some clinical To minimize the risk ofbleeding, a bleeding history is essettings. With impending or evolving thrombosis such as sential to aid in detecting the rare patient with a subclinical that found after coronary angioplasty or during thrombolybleeding diathesis. If an aspirin-treated patient must unsis for acute myocardial certain patients dergo surgery, the platelet defect induced by aspirin can be may benefit from more potent agents. For example, the mucircumvented by waiting 3 to 7 days for return of normal the rine monoclonal antibody 7E3 directed against platelet glyplatelets from the marrow. However, aspirin's antithromcoprotein IIb-IIIa can completely suppress platelet aggregabotic and antihemostatic effects cannot be separated, and ti01-1,'~~ and hirudincan effectively block the activity of the bleeding risk from aspirin can be minimized but not thrombin on platelets and plasma c ~ a g u l a t i o n . 'These ~~ eliminated. Similarly, GI irritation is an inescapable, alagents differ from aspirin in being intravenous therapy that though usually minor andmanageable, complication of ascan be applied in acute thrombotic settings and thatcan depirin therapy that can be minimized by using lower doses of press hemostatic function to a profounddegree. the drug. Other oral antiplatelet agents, such as sulfinpyrazone, suloctidil, dipyridamole, and ticlopidine, have not supplanted Risk-Benefit and Cost-Effectiveness Considerations aspirin. For example, aspirin is less expensive, associated with fewer side effects, and more effective than sulfinpyraPatient managementduring aspirin therapy is simple and zone.86,99,149-152 R epeated studies show that dipyridamole inexpensive. The workup before starting aspirin includes a generally provides no added benefit when combined with bleeding history and a platelet count. On rare occasions, adaspirin,'53 although it may have a limited role with aspirin ditional hemostatic tests are required. The follow-up evaluin coronary bypass g r a f t i ~ ~ g ,prosthetic arterial bypass ~~-~* ation during treatment generally consists only of inquires grafting,lo9-"*and with warfarin in patients with mechaniabout bleeding and GI upset. For the majority of patients

were observed in the aspirin group over 5 years, compared with 2 such events in the controls. The same toxicity has been observed in someprimarypreventiontrials'39 but not in others,83 and it is not seen in secondary trials in which an increase in intracerebral bleeding may be obscured by a concommitant decrease in thrombotic, occlusive stroke^.',^^*'^* In many secondary prevention trials, aspirin significantly reduces the riskof both fatal and nonfatal stroke.65 The incidence of serious bleeding caused by the dose-independent, antihemostatic effectof aspirin is not easily quantitated, but the potential threat of increased intracerebral bleeding should be a strong deterrent to the indiscriminant or uncritical use ofaspirin for the primary prevention of thrombosis.

cal mitral ~ a 1 v e s .Ticlopidine is an effective oral antiplatel~~ let agent whose active form appears to be a metabolite of the parent compound.'55It hasbeen directly compared with aspirin in a group of patients with cerebrovascular disease and shown to be more effective than aspirin in these individual~.'~' However, ticlopidine has significant reversible drug toxicity against the bonemarrow and GI tract, and the has not been studied in sufficient detail to warrant its widespread use. Currently, ticlopidine is recommended for patients who experience recurrent thrombosis during aspirin therapy or for those who are aspirin-intolerant.'

for Indications and Dosages Aspirin Therapy

894

ROTH AND CALVERLEY

daily aspirin

platelet cross-section

Incidence of recurrent myocardial infarction


6 secondary prevention trials

151

114 to 112

adult 320 mg tablet

placebo

aspirin

A Inexpensive,oraldrug

B Significantdrop in function, C Effective,chronictherapy known riskof bleeding

Fig 5. Aspects of the clinical use of aspirin as an antithrombotic agent, (A) The antithrombotic dose of daily oral aspirinis less than one adult 3 2 0 mg tablet. Doses of 80 or 1 6 0 mg give complete inhibition platelet PG synthesis and a of maximal therapeutic effect in published Aspirin exertsits antithrombotic effect by eliminating platelet PG synthesis, thereby blocking TxA2formation. The elimination of studies. (B) TxAz synthesis leadsto a moderate decrease in platelet function and a concomitant mild hemostatic defect. (C) Multiple studies showthe clinical benefit of aspirin. 6 secondary prevention trials The listed in Table 2 included11,l 6 patients studied over an average2 ofmonths. 3 4 with Aspirin treatment led to a 3 1 % risk reduction in cardiac events as compared placebo, an exampleof aspirin as effective chronic antithrombotic therapy defined patients with vascular disease. in

taking low doses of aspirin, both risks and costs are minimal. The future development of additional antiplatelet agents is an attractive goal; but, currently, no available drug compares favorably to aspirin as a long-term, oral antiplatelet agent.
CONCLUDING REMARKS

Aspirin has stood the test of time as an antithrombotic agent. Studies over several decades provide a solid base of information about the drug, starting with platelet cyclo-oxygenase inhibition and ending with the prevention of thrombosis. The links between these observations are sound, and actions, indications, doses, and risks of aspithe rin are well-defined. Questions remain concerning optithe mal dose and formulation ofaspirin and concerning itsuse in primary prevention and in cerebrovascular disease. However, as the field ofclinical thrombosis increases in complexity, the simplicity of aspirin stands out. It is a critically important antiplatelet component of many therapeutic regimens directed against arterial thrombosis. Properly used in appropriate patients, aspirin reduces the incidence of vascular deaths by about 15% and that of nonfatal vascular events by about 3070, a dramatic clinical benefit that results from the uniqueeffect ofaspirin on platelets.
ACKNOWLEDGMENT

We acknowledge and thank Philip W. Majerus for his insights into the mechanism ofaspirins effect.
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