ATVB in Focus

New Targets of Antiplatelet Drug Development

Series Editor: Xiaoping Du

Current State and Novel Approaches of Antiplatelet Therapy

Pat Metharom, Michael C. Berndt, Ross I. Baker, Robert K. Andrews

Abstract—An unresolved problem with clinical use of antiplatelet therapy is that a significant number of individuals either
still get thrombosis or run the risk of life-threatening bleeding. Antiplatelet drugs are widely used clinically, either
chronically for people at risk of athero/thrombotic disease or to prevent thrombus formation during surgery. However, a
subpopulation may be resistant to standard doses, while the platelet targets of these drugs are also critical for the normal
hemostatic function of platelets. In this review, we will briefly examine current antiplatelet therapy and existing targets
while focusing on new potential approaches for antiplatelet therapy and improved monitoring of effects on platelet
reactivity in individuals, ultimately to improve antithrombosis with minimal bleeding. Primary platelet adhesion-signaling
receptors, glycoprotein (GP)Ib-IX-V and GPVI, that bind von Willebrand factor/collagen and other prothrombotic factors
are not targeted by drugs in clinical use, but they are of particular interest because of their key role in thrombus formation
at pathological shear.   (Arterioscler Thromb Vasc Biol. 2015;35:1327-1338. DOI: 10.1161/ATVBAHA.114.303413.)
Key Words: anticoagulants ◼ blood coagulation ◼ blood platelets ◼ drug therapy ◼ platelet adhesion inhibitor

A ntiplatelet and anticoagulant drugs, used alone or in com-

bination, are a cornerstone of clinical treatment for human
diseases associated with increased athero/thrombotic risks, such
as heart attack and stroke, and in preventing thrombosis during
surgery or other medical procedures involving vascular disrup-
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exist for the foreseeable future, emphasizing the clear need for
improved approaches for therapy and monitoring.
There are several classes of antiplatelet drugs, either cur-
rently in clinical use (Table 1) or in preclinical or early clini-
cal stages of development (Table 2), which act at a variety

tion or perturbed blood flow.1–6 The confounding issue is that
rapid platelet activation and aggregation leading to thrombus
formation in response to vascular injury is also a critical physi-
ological mechanism,7 and blocking platelet function can there-
fore elevate bleeding risk. Individuals within a population or a
disease cohort will also vary in their relative platelet reactivity
and thrombotic propensity because of variations in platelet phe-
notype or genotype coincident with other thrombotic risk fac-
tors, thereby complicating the development of practical clinical
guidelines for antiplatelet drugs, as well as dosing requirements
and monitoring. For the latter, there is currently a lack of reli-
able platelet analytic, genotyping or functional testing that con-
fidently predicts either thrombotic/bleeding risk or efficacy of
antiplatelet treatment in individuals. Of further importance, the
availability of drugs (oral or intravenous) and their pharmaco-
logical half-life in blood can potentially affect user compliance
or reversibility, respectively. Thus, the problem of controlling
bleeding versus thrombosis by antiplatelet therapy is likely to
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in this series.
of targets. These include platelet receptors, their binding
partners, signaling proteins, or soluble mediators of plate-
let function (Figure 1). In this review, we will discuss these
therapeutic targets and their known pathological and physi-
ological roles in healthy or diseased vasculature, the scientific
basis for their selection and inhibition by existing agents, and
new approaches for modulating their pathological function.
Importantly, mechanisms of platelet activation and thrombus
formation at the vessel wall need to be considered in the con-
text of shear stress and normal or abnormal blood flow.
Platelet Activation and Thrombus Formation at
the Vessel Wall
The capacity for human platelets circulating in the blood-
stream to attach to a specific region of the vasculature and
activate and aggregate within seconds to minutes is a sophis-
ticated biological accomplishment, in particular at arterial
flow rates where fluid shear forces act powerfully against
cell adhesion. Adherent activated platelets promote localized
coagulation, release proinflammatory mediators, and recruit
leukocytes to initiate wound healing.7 At arterial shear rates,
this is enabled principally by a specialized platelet-specific

Received on: November 10, 2014; final version accepted on: March 19, 2015.
From the Faculty of Health Sciences, Curtin University, Perth, Western Australia, Australia (P.M., M.C.B); Western Australian Centre for Thrombosis
and Haemostasis, Murdoch University, Perth, Western Australia, Australia (R.I.B.); and Australian Centre for Blood Diseases, Department of Clinical
Haematology, Monash University, Melbourne, Victoria, Australia (R.K.A.).
Correspondence to Michael C. Berndt, PhD, Curtin University, PVC Health Sciences Suite, Bldg 400, Level 4, Room 408, Kent St, Bentley, Western
Australia 6102, Australia. E-mail michael.berndt@curtin.edu.au
© 2015 American Heart Association, Inc.
Arterioscler Thromb Vasc Biol is available at http://atvb.ahajournals.org DOI: 10.1161/ATVBAHA.114.303413

1327
 1328   Arterioscler Thromb Vasc Biol   June 2015
Nonstandard Abbreviations and Acronyms
GP glycoprotein
ITAM immunoreceptor tyrosine–based activation motif
PCI percutaneous coronary intervention
ROS reactive oxygen species
TxA2 thromboxane A2
vWF von Willebrand factor
adhesion-signaling system, made up of glycoprotein (GP)
Ib-IX-V that binds von Willebrand factor (vWF; via the GPIbα
subunit)8 and collagen (via GPV)9 and GPVI that binds colla-
gen and the collagen-associated matrix protein, laminin.10–14
Thus, on exposure of collagenous subendothelial matrix in
the vasculature, platelet GPIb-IX-V/GPVI can rapidly induce
platelet adhesion and activation. Furthermore, in human
platelets, these receptor–ligand systems are highly evolved to
mediate thrombus formation as the shear rate increases to high
physiological or pathological,15 as found in occluded coronary
arteries with atherosclerotic plaque or where normal blood
flows are disrupted, for example, in ventricular assist devices.
GPIbα, disulfide-linked to GPIbβ, GPIX, and GPV are all
members of the transmembrane leucine-rich repeat family.8
Analogous leucine-rich repeat proteins are involved in innate
immunity in premammalian species.16 GPVI is a member of
the immunoreceptor family, with 2 extracellular immuno-
globulin domains, and forms a noncovalent complex with
the Fc receptor γ-chain required for GPVI surface expres-
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sion and ligand-induced signaling on human platelets.10–14
Signaling immediately downstream of GPIb-IX-V/GPVI
involves activation of Src and Syk kinase–dependent tyrosine
phosphorylation pathways and Src/Syk-dependent and Src/
Syk-independent generation of intracellular reactive oxygen
species (ROS).17–20 The cytoplasmic domains of GPIb-IX-V
and GPVI directly bind to signaling or adaptor proteins, includ-
ing phosphatidylinositol 3-kinase (via the p85 subunit)21,22 and
constitutively phosphorylated Lyn (via a proline-rich sequence
of GPVI),23 respectively. In the case of GPVI, ligand-induced
receptor cross-linking enables active Lyn to phosphorylate
Syk associated with the immunoreceptor tyrosine–based acti-
vation motif (ITAM) in the cytoplasmic domain of Fc receptor
γ-chain, initiating canonical Syk–dependent signaling path-
ways. Other ITAM-bearing receptors in platelets include the
low-affinity IgG receptor, FcγRIIa, and the C-type lectin fam-
ily receptor-2.24 Positively charged conserved sequences of
both GPIbβ and GPVI also directly bind to tumor necrosis fac-
tor receptor–associated factor 4,18 a receptor-localizing subunit
of the nicotinamide adenine dinucleotide phosphate-oxidase
oxidase complex (Nox-1/2), which generates intracellular
ROS in platelets.17,19,20 Rapid elevation of intracellular ROS
promotes platelet activation and supports platelet adhesion to
collagen, by a mechanism that may involve ROS-dependent
inactivation of protein tyrosine phosphatases that inhibit sig-
naling involving Lyn and associated phosphorylated proteins.
Engagement of GPIb-IX-V/GPVI by vWF/collagen or
other ligands leads to rapid platelet activation, morphological
changes, in platelet shape and rearrangement of the cytoskel-
etal actin filaments, and changes in platelet plasma membrane
phosphatidylserine expression that accelerate coagulation
leading to activation of factor Xa and thrombin. GPIbα binds
coagulation factors, XII, XI, high-molecular weight kininogen
(of the intrinsic coagulation pathway), and thrombin, local-
izing coagulation at the platelet surface, whereas increased
phosphatidylserine facilitates formation of procoagulant com-
plexes of factor Xa to increase thrombin generation. Active
thrombin bound to GPIbα activates platelets and facilitates
stimulation of the G-protein–coupled 7-transmembrane recep-
tor, protease-activated receptor-1; thrombin also activates
human platelets via protease-activated receptor-4.25,26 In acti-
vated platelets, secretion of the agonist, ADP, and activation
of the cyclooxygenase pathway leading to synthesis and secre-
tion of thromboxane A2 (TxA2) reinforce platelet activation
by autocrine stimulation of G-protein–coupled receptors for
ADP (P2Y1 and P2Y12)27 or TxA2, respectively (Figure 1).
In this way, activation via primary platelet receptors, GPIb-
IX-V/GPVI, or secondary receptors for ADP, TxA2 or, throm-
bin leads to activation of the platelet integrin, αIIbβ3 (GPIIb/
IIIa) that binds fibrinogen or vWF and mediates platelet aggre-
gation. This receptor is expressed in a low-affinity form that
does not bind ligand, but after intracellular signaling, it forms
a high-affinity ligand-binding site, enabling platelet aggrega-
tion and outside-in-signaling to reinforce platelet activation.28
In addition to αIIbβ3, other platelet integrins, α2β1, α5β1, and
α6β1 that bind collagen, fibronectin, or laminin, respectively,
also become functional on activated platelets and promote firm
platelet adhesion to collagenous subendothelial matrix.29,30
This amplification of platelet activation through release of sec-
ondary agonists is critical in stabilizing the thrombus and aug-
menting the thrombus volume. In cases of unrestrained growth,
which can result in occlusion and ischemia, inhibition of sec-
ondary messengers, such as TxA2, by aspirin or platelet adhe-
sion integrins assists in controlling thrombus size on the vessel
wall. Figure 2 demonstrates how targeting of specific steps,
using αIIbβ3 as an example, modulates thrombus formation.
In addition to activation pathways, there are at least 2
inhibitory pathways that can control platelet reactivity. First,
inhibitory receptors bearing an immunoreceptor tyrosine–
based inhibitory motif domain, such as platelet/endothelial
cell adhesion molecule 1 or carcinoembryonic antigen-related
cell adhesion molecule-1/2,31 can attenuate ITAM-mediated
signaling by GPVI/Fc receptor γ-chain or other ITAM-
bearing receptors, via recruitment of phosphatases or other
mechanisms, although how immunoreceptor tyrosine–based
inhibitory motif–containing receptors on circulating human
platelets are activated under physiological or pathological con-
ditions is uncertain. Second, elevation of intracellular cAMP/
cGMP inhibits platelet activation by activating cAMP/cGMP-
dependent protein kinases, protein kinase A/protein kinase
G,32 although the role of cGMP effects on platelet function
remains controversial with several studies demonstrating that
cGMP is stimulatory.33,34 Protein kinase A substrates include
cytoplasmic serine residues within conserved sequences of
GPIbβ, regulating the interaction with intracellular bind-
ing partners and attenuating vWF-dependent platelet activa-
tion.35 Inhibitory prostacyclin (also known as prostaglandin)
leads to activation of adenylyl or guanylyl cyclases to increase
 Metharom et al   Current State of Antiplatelet Therapy   1329

Table 1. Antiplatelet Therapy: Current Drugs98–100

Route of
Type/Name (Drug Name) Marketing Status Administration Indication References
Cyclooxygenase inhibitors
 ASA and aspirin Over-the-counter Oral To reduce the risk of nonfatal 41, 101–103
thrombotic events
 Triflusal Available in some Oral Prevention of cardiovascular 104–106
European countries events and acute treatment of
infarction
ADP P2Y12 inhibitor
 Clopidogrel (Plavix) Prescription Oral For ACS NSTEMI, STEMI, 107–109
and reduction and prevent of
ischemic events
 Prasugrel (Effient) Prescription Oral Use in combination with aspirin 107, 109–111
in patients with ACS undergoing
PCI, also NSTEMI and STEMI
patients undergoing PCI
 Ticagrelor (Brilinta) Prescription Oral For prevention of thrombotic 111–113
events. Recommend in addition
to ASA for ACS patients
αIIbβ3 (GPIIb/IIIa) inhibitors
 Abciximab (Reopro) Prescription Injection As an adjunct to PCI for 42, 114–116
prevention of ischemic
complications
 Eptifibatide (Integrilin) Prescription Injection Treatment of MI and ACS 115, 116
 Tirofiban (Aggrastat) Prescription Injection For reduction of thrombotic 42, 115–117
cardiovascular events in patients
with NSTEMI ACS
Prostacyclin and analogues
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 PGI2 (Epoprostenol) Prescription Injection Long-term intravenous 118, 119

treatment of primary pulmonary
hypertension
 Iloprost (Ventavis) Prescription Oral inhalation Treatment of PAH 118, 119
 Treprostinil (Remodulin) Prescription Oral Treatment of PAH 119–121
Direct thrombin inhibitors
 Bivalirudin (Angiomax) Prescription IV For use in prevention of 122, 123
thrombosis in patients with ACS
undergoing PCI
 Dabigatran (Pradaxa) Prescription Oral Prevention of thrombosis post 124, 125
joint replacement and atrial
fibrillation
Phosphodiesterase inhibitor
 Dipyridamole (Persantine) Prescription Oral Use in adjunct to coumarin 126, 127
anticoagulants in the prevention
of thrombotic complications post
cardiac valve replacement
 Cilostazol (Pletal) Prescription Oral Reduction of symptoms of 126, 128, 129
intermittent claudication
ACS indicates acute coronary syndrome; ASA, acetylsalicylic acid; MI, myocardial infarction; NSTEMI, non–ST-segment–
elevation myocardial infarction; PAH, pulmonary arterial hypertension; PCI, percutaneous coronary intervention; PGI2,
prostaglandin; and STEMI, ST-segment–elevation myocardial infarction.

intracellular levels of cAMP/cGMP. Stimulation of the ADP
receptor, P2Y1, leads to inhibition of adenylyl cyclase and
reduced production of cAMP to facilitate platelet activa-
tion.27,32 Alternatively, phosphodiesterases can directly reduce
the levels of cAMP to increase platelet reactivity, and phos-
phodiesterase inhibitors can thereby be used to inhibit platelet
activation.36 These types of inhibitors are among a range of
promising new antithrombotic strategies and may have advan-
tages compared with current modes of antiplatelet therapy.36
Platelet Targets of Current Antithrombotics
Current antiplatelet agents used clinically (Table 1) target sev-
eral key components of platelet activation and aggregation
(Figure 1). The 3 major targets are cyclooxygenase of the TxA2
 1330   Arterioscler Thromb Vasc Biol   June 2015

Table 2. Antiplatelet Therapy: Drugs in Clinical Trials and Clinical Development

Route of
Type/Name Developmental Status Administration Indication References
Prostacyclin analogue
 Beraprost Ongoing clinical trials Oral Treatment of PAH and diabetic 130, 131
nephropathy
GPIbα antagonist
 Anfibatide Phase I completed; phase II IV For treatment of thrombotic 71–73
listed but not yet active events MI
vWF-targeting (inhibit GPIbα binding)
 Anti-vWF aptamers (ARC1779 … IV For treatment of TTP, VWD 2b 132–134
and ARC15105)
 Anti-vWF nanobody (ALX- Phase I, phase II TITAN trial IV For treatment of TTP 132, 135, 136
0081, caplacizumab)
GPVI bivalent soluble form
 Revacept (PR-15), humanized Phase I completed; phase II IV For treatment of carotid artery 74, 75
Fc fusion of GPVI ectodomain recruiting stenosis, TIAs, and stroke
Thromboxane receptor antagonists
 Terutroban Clinical trials indicate no better Oral For secondary prevention 137–139
outcome than aspirin of thrombotic events in
cardiovascular disease
 Ifetroban Phase II Injection Treatment of hepatorenal 140
syndrome
PAR-1 inhibitors
 Vorapaxar (SCH530348) Recommended for approval Oral Reduction of atherothrombotic 141–143
by FDA’s Cardiovascular events in patients with history
and Renal Drugs Advisory of MI
Committee
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 Atopaxar (E5555) Phase II Oral CAD 141, 144, 145

ADP P2Y12 inhibitor
 Cangrelor FDA denied approval and IV For patients with ACS undergoing 146–148
requested further clinical data PCI; reduces MI and stent
thrombosis events compared
with other P2Y12 inhibitor drugs;
associates with bleeding risks
and lacks mortality benefit
ACS indicates acute coronary syndrome; CAD, coronary artery disease; FDA, Food and Drug Administration; IV, intravenous;
MI, myocardial infarction; PAH, pulmonary arterial hypertension; PAR-1, protease-activated receptor-1; PCI, percutaneous coronary
intervention; TIAs, transient ischemic attacks; TTP, thrombotic thrombocytopenic purpura; vWF, von Willebrand factor; and VWD 2b,
type 2b von Willebrand’s disease.

synthesis pathway (aspirin), the G-protein–coupled ADP recep-
tor P2Y12 (clopidogrel, prasugrel, or ticagrelor), and inhibitors
of αIIbβ3 (abciximab, eptifibatide, and tirofiban). Other targets
are the prostaglandin receptor that can be blocked by prosta-
cyclin mimetics and phosphodiesterase inhibitors that elevate
intracellular cAMP/cGMP (Figure 1). Anticoagulants that are
direct thrombin inhibitors3 can also suppress platelet activation
by inhibiting thrombin-dependent platelet activation via GPIbα
and protease-activated receptor-1/4. Notably, platelet adhesion
and aggregation induced at high shear stress are dependent on
ADP and αIIbβ3, and they are inhibited by elevated platelet
cAMP/cGMP.15,37 In contrast, cyclooxygenase inhibition by
aspirin has minimal effect.15,38 This may explain the relative
lack of efficacy of aspirin as treatment for arterial thrombosis
and the common use of aspirin in combination with other drugs.
Dual antiplatelet therapy typically refers to a combination
of aspirin and a P2Y12 inhibitor, targeting secondary platelet
activation via TxA2 and ADP, respectively. The αIIbβ3 inhibitors
block thrombus formation to all agonists because αIIbβ3 is essen-
tial for platelet aggregation. For these most widely used drugs, it
is interesting to consider the specific targets—cyclooxygenase,
P2Y12, and αIIbβ3—and the role of these targeted pathways in
thrombus formation, in terms of antithrombotic protection versus
bleeding risk, and resistance to dual antiplatelet therapy.
Bleeding Risk Associated With Current
Antiplatelet Therapeutics
Although antiplatelet drugs are effective in reducing vascular
deaths and nonfatal events by ≤50% in high-risk cardiovascu-
lar patients, the main safety concern is excess hemorrhage.39
Primary prevention of cardiovascular events with aspirin is
associated with a significant increased risk of extracranial
bleeding (relative risk, 1.55; 95% confidence interval, ­1.3–1.8;
P<0.001), which often negates the uncertain potential benefit
 Metharom et al   Current State of Antiplatelet Therapy   1331

Figure 1. Platelet targets of antiplatelet therapy. Schematic showing platelet surface receptors and signaling pathways leading to plate-
let activation and activation of the integrin, αIIbβ3, which binds fibrinogen or Von Willebrand factor and mediates platelet aggregation.
­Targets of currently available (shaded boxes) and novel drugs in development or in clinical trial (white boxes) are indicated. COX indicates
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cyclooxygenase; GP, glycoprotein; and TxA2, thromboxane A2.

in otherwise healthy people.39 In patients with acute coronary therapy is associated with an annual incidence of 2% to 4%
syndromes, stable coronary artery disease, ischemic stroke or gastrointestinal bleeding and 0.5% rate of intracranial hemor-
peripheral vascular disease, single-agent aspirin, or clopidogrel rhage.40 A 2014 analysis of 8 trials involving 41 483 individuals

Figure 2. Antiplatelet therapy modulates thrombus formation on the vessel wall. The simplified flow chart indicates platelet activation
steps exploited in drug targeting to reduce platelet activation, aggregation, and ultimately thrombus formation. The figure focuses on
antiαIIbβ3 (GPIIb/IIIa) inhibition as an example illustrating reduction in thrombus volume as the result of blocking platelet aggregation
mediated by αIIbβ3 receptor. COX indicates cyclooxygenase; GP, glycoprotein; and TxA2, thromboxane A2.
 1332   Arterioscler Thromb Vasc Biol   June 2015
showed daily aspirin treatment (160 or 300 mg) within 48
hours post ischemic stroke reduced the risk of early recurrent
stroke, but it was connected with a small excess of intracra-
nial bleeding.41 With individuals undergoing percutaneous
coronary revascularization, administration of αIIbβ3 inhibitors
reduced the risk of death or myocardial infarction, however,
with an increased risk of severe bleeding. These meta-analyses
suggested the potential benefits of antiplatelet agents far out-
weighed the risk of bleeding complications. On the other hand,
a Cochrane review of αIIbβ3 inhibitors administered early after
an ischemic stroke showed a link with a significant risk of intra-
cranial hemorrhage with no reduction in mortality.42
The risk of bleeding has been shown to be dose related
for all antiplatelet drugs, including aspirin (100 versus >325
mg daily),40 clopidogrel (300- versus 600-mg loading),43 and
prasugrel (5 versus 10 mg daily).44,45 Combined antiplatelet
therapy, with dual targeted inhibition of the platelet cyclooxy-
enase-1 pathway (aspirin) and the P2Y12 unit of the platelet
ADP receptor (clopidogrel, prasugrel, and ticagrelor), is an
effective strategy for reducing cardiovascular events, but it
is associated with an increased relative risk of major bleed-
ing by ≤40%.46 Rates of bleeding increase with the prolonged
duration of dual antiplatelet therapy, percutaneous coronary
intervention (PCI), or urgent coronary artery bypass surgery.46
More rapid and consistent P2Y12 platelet ADP receptor
blockade by prasugrel and ticagrelor when compared with
clopidogrel generally produces better outcomes, particularly
in patients with acute coronary syndromes treated with PCI.46
However, this benefit comes at the cost of an increase in major
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life-threatening and fatal bleeding with prasugrel when com-
pared with clopidogrel (2.4% versus 1.8%; hazard ratio, 1.32;
P=0.03) as shown in the TRITON-TIMI 38 trial (TRial to
assess Improvement in Therapeutic Outcomes by optimizing
platelet InhibitioN with prasugrel Thrombolysis In Myocardial
Infarction 38).45 Patients with risk factors for bleeding were
elderly (>75 years) and with low body weight (<60 kg). Dose
reduction of prasugrel to 5 mg may improve the benefit/risk
ratio in this susceptible group as shown in a subsequent study
(TRILOGY ACS) where there was no difference in hemor-
rhage in a prespecified analysis of elderly patients (>75 years).44
Overall bleeding rates were similar with ticagrelor and clopido-
grel in the PLATelet inhibition and patient Outcomes (PLATO
trial); however, when bleeding from coronary artery bypass sur-
gery was removed from analysis, ticagrelor had a higher risk of
major nonprocedure-related bleeding (4.5% versus 3.8%; haz-
ard ratio, 1.19; P=0.03).47 Comparison between up-front and
delayed (after PCI) administration of either prasugrel or anti-
platelet αIIbβ3 receptor antagonists (tirofiban and eptifibatide)
showed little difference in efficacy, but early administration
significantly increased bleeding and red-cell transfusion rates.48
Definitions of bleeding are poorly standardized and
vary between different studies making direct comparison
between various combinations of antiplatelet drugs more
difficult. Dual oral antiplatelet therapy is now standard
practice for treatment of acute coronary syndromes with and
without PCI; however, the individual assessment of bleed-
ing risk over time and risk of later thrombotic complica-
tions often determines the duration of combined antiplatelet
therapy.46,49
Aspirin and Clopidogrel Resistance
It is accepted that there is a wide interindividual variation
in response to aspirin and clopidogrel, which can be defined
either through the patient experiencing recurrent platelet-
mediated clinical events (recurrent in stent thrombosis, acute
myocardial infarction, stroke, and death) or pharmacody-
namically with various ex vivo platelet inhibition measures
(agonist-induced platelet aggregation, serum and urinary
thromboxane measurement, electric impedance aggregome-
try, shear-induced platelet functional analysis [PFA100], flow
cytometry, and point of care agonist assessment [VerifyNow
and VASP-P assay]).50 Controversy still exists as to whether
any ex vivo test can simulate in vivo platelet response and
there is uncertainty as to which test to preferentially perform.
Observational studies suggest that at standard doses of aspi-
rin (100 mg) or clopidogrel (75 mg), over a third of patients
have predefined ex vivo resistance.51 Reasons for antiplatelet
resistance include poor compliance, insufficient dose, slow
pharmacodynamic effect, related gene polymorphisms that
effect antiplatelet drug metabolism (eg, cytochrome P450
2C19 loss of function allele for clopidogrel biotransformation
to active metabolite and ABCB1 polymorphisms, particularly
3435C>T, affecting efflux of clopidogrel via P-glycoprotein),40
and PEAR1 variants in patients exposed to aspirin,52 increased
baseline platelet reactivity such as that found in diabetes mel-
litus and smoking, and increased platelet turnover.40 Whatever
the reason, predefined high on-treatment platelet reactivity
is consistently associated with 2- to 4-fold increased risk of
acute myocardial infarction, stent thrombosis, and stroke.50
Clopidogrel leads to a variable platelet inhibition and has a
delayed onset of action, mainly because of the need for bio-
transformation in the liver via CYP450 isoenzymes (particu-
larly the CYP2C19 isoenzyme) from the inactive parent drug
to the active metabolite. Prasugrel is also a prodrug requiring
CYP450-mediated metabolic activation, but it is less affected
by the CYP2C19 polymorphism and has a faster onset of
action. Ticagrelor is an orally active drug not requiring bio-
transformation and binds rapidly and reversibly to the P2Y12
receptor, making it an attractive direct P2Y12 inhibitor.46
Strategies for overcoming antiplatelet drug resistance
include increasing initial loading doses (eg, aspirin: 100–300
mg; clopidogrel: 75–600 mg; prasugrel: 10–60 mg; ticagre-
lor: 90–180 mg)43,45,47 and personalized dose adjustment (eg,
increase the maintenance dose of clopidogrel to 150 mg
daily53,54 or drug switching from clopidogrel to prasugrel53,55,56
or ticagrelor) that may include adjustment based on regular
testing platelet function monitoring.50
The lack of effect of individualized antiplatelet therapy by
platelet function testing in recent large randomized studies
in PCI and medically managed patients with coronary artery
disease is disappointing.54–57 Studies that have not shown a
change in outcomes include the TRILOGY-ACS (TaRgeted
platelet Inhibition to cLarify the Optimal strateGy to medi-
callY manage Acute Coronary Syndromes) trial (n=2564;
prasugrel versus clopidogrel),56 GRAVITAS (Gauging
Responsiveness With a VerifyNow P2Y12 Assay: Impact on
Thrombosis and Safety) increased dose (n=2214; clopidogrel
150 mg daily),54 and ARCTIC (Double Randomization of a
 Metharom et al   Current State of Antiplatelet Therapy   1333
Monitoring Adjusted Antiplatelet Treatment Versus a Common
Antiplatelet Treatment for DES Implantation, and Interruption
Versus Continuation of Double Antiplatelet Therapy) standard
versus monitoring antiplatelet drug/dose adjustment (n=2440
patients).55,57 Although ≈20% of patients did not achieve opti-
mal reduction in platelet reactivity, the event rates were low and
the studies were underpowered.50 However, a recent meta-anal-
ysis of 9 pooled studies consisting of 12 048 subjects showed
significant benefit for tailored versus standard antiplatelet ther-
apy with a risk reduction of ≈60% without an increase in bleed-
ing.51 Smaller studies that demonstrated a consistent reduction
in platelet reactivity in all patients below the threshold of high
on-treatment platelet reactivity also showed significant clinical
benefit of reduction in cardiovascular events.50
Observational studies have suggested that CYP2C19 poly-
morphisms associated with reduced activation of clopidogrel
increase the risk of thrombotic events by 2-fold in patients
treated with clopidogrel.58 However, analysis of 3 large ran-
domized control studies showed no effect of the CYP2C19 or
ABCB1 genotype on clinical outcomes in patients on clopido-
grel.59–62 In an ongoing prospective post-PCI study assessing
CYP2C19 genotype, antiplatelet therapy was changed from
clopidogrel to ticagrelor or prasugrel in those with a loss of
function polymorphism.63 These data will clarify the role of
CYP2C19 genotype in selecting the type of antiplatelet therapy
and will either confirm or refute the smaller studies suggesting
an improvement in cardiovascular outcome with this strategy.
Recent clinical guidelines suggest that platelet function test-
ing may have a limited role in selecting the choice of P2Y12
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inhibitors in high-risk patients treated with PCI (class IIb)
although routine testing is not recommended (class III).50 By
better personalizing the drug therapy, there is an opportunity
to better define high and low platelet reactivity to address the
balance for the individual between bleeding and thrombosis in
the context of antiplatelet therapy.
More Recent Targets for Antiplatelet Therapy
Interestingly, there are currently no inhibitors in routine clini-
cal use targeting the primary platelet receptors, GPIbα (or
GPIb-IX-V), GPVI, or their ligands (vWF/collagen), interac-
tions that initiate platelet adhesion and activation and which
become increasingly important as the shear rate increases.
The limited distribution of these receptors to megakaryocytes/
platelets should also offer advantages compared with targets
with expression profiles that include other cells. On one hand,
the rare congenital or acquired defects or deficiency of GPIb-
IX-V (Bernard-Soulier syndrome) or GPVI results in vari-
able bleeding risk, from relatively mild to more severe, which
could argue against directly targeting these receptors.64–67 On
the other hand, these cases often involve thrombocytopenia
or concurrent hemostatic disorders that complicate attributing
bleeding to receptor dysfunction alone. Experimental stud-
ies suggest that GPIbα has a far greater contribution to stable
arterial thrombosis than vWF,67 whereas the GPVI-binding
sites of collagen are not normally exposed to circulating plate-
lets. GPVI also regulates thrombus formation in experimen-
tal models of arterial thrombosis or stroke,68,69 whereas the
hemostatic consequences of GPVI deficiency on bleeding
times are generally minimal. Overall, these findings support
further development of antiplatelet therapies targeting either
GPIbα–vWF, GPVI–collagen, or both.
Currently used antiplatelet drugs are based on natural prod-
ucts (aspirin), toxins (snake venom–based inhibitory peptides
that blocked ligand binding to αIIbβ3), inhibitory antibodies
(derived from anti–αIIbβ3 monoclonal antibodies), or small
molecules (irreversible P2Y12 inhibitors developed as orally
available prodrugs). Inhibitory toxins and antibodies, ligand
mimetics, as well as nucleotide-based aptamers and soluble
recombinant forms of receptor, have already been substan-
tially developed as means of modulating GPIbα–vWF, GPVI–
collagen, or other platelet targets, including the prostaglandin
receptor, TxA2 receptor, and protease-activated receptor-1
(Table 2; Figure 1). The GPIbα–vWF axis has been targeted
using aptamers or antibody-based agents selective for the
GPIbα-binding A1 domain of vWF that prevent vWF-binding
platelet GPIbα. Snake venom proteins have been long known
to target human platelet GPIbα by metalloproteinase-medi-
ated proteolysis of the vWF/ligand-binding domain (mocar-
hagin, natural killer protease) or by binding of C-type lectin
family proteins to the leucine-rich repeat domain of GPIbα
(echicetin and alboaggregin-B).70 Anfibatide is a C-type lec-
tin-like protein that binds GPIbα and inhibits vWF-binding
GPIbα–dependent platelet adhesion and activation, impor-
tantly with potent activity at elevated shear rates.71–73
The GPVI–collagen axis has been targeted using a bivalent
recombinant soluble form of the GPVI ectodomain expressed
as a humanized Fc fusion protein.11,74,75 The ≈55-kDa soluble
ectodomain of GPVI is shed from the human platelet surface by
the membrane-expressed sheddase, ADAM-10.76,77 This process
is tightly regulated, with essentially all the GPVI on healthy cir-
culating platelets in an intact form, with shedding rapidly induced
by ligand binding to GPVI, by platelet activation, by platelet
exposure to high shear stress,78 by coagulation/factor Xa,79 or by
other triggers, releasing plasma soluble ectodomain of GPVI,
which is quantifiable by immunoassay as a platelet-specific
marker.80 Native soluble ectodomain of GPVI shed from plate-
lets is monovalent and binds collagen weakly compared with the
bivalent form, which shows promise as a novel antithrombotic.11
Indeed, these new agents against GPIbα–vWF, GPVI–
collagen, and other platelet targets have all shown merit as
potential antiplatelet drugs experimentally or in clinical settings
associated with pathological thrombosis (Table 2). The type and
properties of these agents, in terms of oral availability, revers-
ibility, bleeding risk, and antithrombotic or off-target effects,
will prove critical to their clinical application in different patient
groups and will require longer term trials to establish viability.
Future Targets for Antiplatelet Therapy
On the basis of recent research discoveries, there is far wider
scope for therapeutic regulation of platelet targets, including
αIIbβ3,28,81 integrin α6β1,82 GPIb-IX-V, and GPVI adhesive
function and signaling. In addition to vWF- and GPIbα-
targeting inhibitors in development (Table 2), alternative strat-
egies could have advantages, for example, small molecules
with increased scope for bioavailability. In this regard, alloste-
ric inhibitors can overcome the inherent difficulties of a small
 1334   Arterioscler Thromb Vasc Biol   June 2015
molecule inhibiting a protein–protein interaction in which a
large multisite interface occurs as for the interaction between
the ligand-binding domains of GPIbα and vWF. As proof of
this concept, a short cyclic peptide, CTERMALHNLC, which
binds GPIbα, potently inhibits vWF binding not through com-
petitive inhibition but by preventing formation of a ligand-
receptive structural conformation.83,84
An alternative strategy targeting the ADP-P2Y1/P2Y12 acti-
vation pathway is the use of a soluble form of CD39 (solCD39),
an ectonucleoside triphosphate diphosphohydrolase.85 This
approach uses the ability of CD39 to hydrolyze ADP, dissimi-
lar to the current ADP-P2Y12 drugs clopidogrel, prasugrel,
and ticagrelor that block ADP-mediated platelet activation by
binding to the receptor directly. An administration of a fusion
protein consisting of solCD39 and a single-chain Fv fragment
of an antibody specific for the αIIbβ3 active form showed
promising antithrombotic effects with no prolonged bleeding
in an experimental mouse model. The drug is designed to allow
a layer of platelets to firmly adhere to the wound and αIIbβ3 to
become activated before exerting its function, thus minimizing
the amplification phase of platelets in developing thrombus.
Innovative new approaches for targeting αIIbβ3 signaling
include the recent report of short myristoylated peptides based
on cytoplasmic sequences of β3 that selectively regulate the
dynamic interaction between the receptor and intracellular
binding partners, including the G protein Gα13.81 Notably,
it seems feasible to dissect out precise signaling functions of
αIIbβ3 involving Gα13 or talin associations, which control
platelet activation, adhesion, and aggregation/clot contrac-
Downloaded from http://ahajournals.org by on February 11, 2024
tion, and to inhibit thrombus formation in mice comparable
with current αIIbβ3 inhibitors, yet without adverse bleeding.81
Platelet integrin α6β1 also represents a novel antiplatelet tar-
get. Recently, using platelet-specific knockout of integrin α6,
the main vascular laminin receptor was indicated to play an
important part in platelet adhesion, activation, and in arterial
thrombosis without significant effect on bleeding risk.82 Future
research will need to address possible detrimental effects of
α6β1 blocking as the protein expression is not only limited
to platelets but it is also found on various cell types including
glial cells, neuronal stem cells, and endothelial cells.86–88
Signaling protein targets downstream of GPIb-IX-V/GPVI
may also be worthwhile considering. First, Syk inhibitors have
been tested clinically as selective, reversible anti-inflammatory/
cancer therapeutics, without inhibitory activity toward other
tyrosine kinases, such as Src, Lyn, or Btk.89 Syk inhibition
also blocks GPVI-dependent activation of human platelets.14
Second, Btk mediates signaling downstream of GPIb-IX-V
in platelets,90 and an irreversible Btk inhibitor (ibrutinib) is
approved for treatment of the lymphoproliferative diseases,
chronic lymphocytic leukemia, and mantle cell lymphoma.
Therapeutic concentrations of ibrutinib inhibit collagen/GPVI-
dependent platelet aggregation,91 and although it is associated
with clinical bleeding in patients with chronic lymphocytic leu-
kemia,91 this could be related to vulnerability resulting from
decreased GPVI expression in lymphoproliferative disease.92
Third, recent evidence that platelet Nox-1/2–dependent ROS
production is important for GPIb-IX-V/GPVI-dependent plate-
let function, including adhesion to collagen, and is inhibited
by Nox-1/2 inhibitors19,20 raises the possibility that such inhibi-
tors could be antithrombotic. An inhibitor targeting NOX1
and NOX4 (GKT137831) is in clinical trial as a treatment for
diabetic nephropathy,93 unrelated to any possible antiplatelet
effects. Evidence for the value of antioxidants in treating car-
diovascular disease seems limited and requires further atten-
tion. Although direct therapeutic targeting of Nox-1/294 is
viable as a general inhibitor of ROS and inflammation, it is
not selective for platelet ROS pathways.95 However, an attrac-
tive possibility exists for these ROS inhibitors, as well as
nonplatelet-specific targets mentioned above, in drug-eluting
stents where their actions will likely be more localized. Other
intracellular binding partners for G ­ PIb-IX-V in addition to the
p85 subunit of phosphatidylinositol 3-kinase21,22 include the
regulatory protein, 14-3-3ζ, and the phosphorylation depen-
dence, functional role, and potential for future targeting of this
interaction have been previously reviewed in detail.35
Finally, antiplatelet strategies could focus on the expression
and function of platelet-specific GPVI. In addition to block-
ing ligand binding or inhibiting signaling, either the require-
ment for GPVI to dimerize to elicit signaling (by cross-linking
FcRγ ITAM) or the controlled ectodomain shedding mediated
by ADAM10 could also potentially be targeted.10–12,96 Further
understanding of how shear stress and membrane proper-
ties control dimer formation and ADAM10 accessibility and
cleavage could enable alternative therapeutic control of plate-
let reactivity toward collagen.
Conclusions
Current antiplatelet therapy has no doubt prevented incalcu-
lable death and disability in people at risk of athero/throm-
botic/cardiovascular disease by preventing thrombotic events
and quelling the proinflammatory role of activated platelets.
Nevertheless, the lack of efficacy/resistance, reliable clini-
cal guidelines, and increased bleeding risk in individuals
remains an ongoing problem. New experimental evidence
and increased understanding of platelet function and regula-
tion are revealing new antiplatelet approaches to potentially
improve clinical outcomes and monitoring.
The readers may also find additional information on anti-
platelet and antithrombosis therapy from other reviews
in the ATVB series New Targets of Antiplatelet Drug
Development.14,28,36,97
Acknowledgments
We thank all our colleagues and collaborators for helpful discussions.
Sources of Funding
This work was supported by Curtin University, Murdoch University,
Monash University, and the National Health and Medical Research
Council of Australia.
Disclosures
None.
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