Role of Antiplatelet Therapies in Preventing Atherothrombosis
Mohamed Z Khalil*
Consultant Cardiologist, Saudi British Hospital, Riyadh, Saudi Arabia Mohamed Z Khalil*
- *Corresponding Author:
- Mohamed Z Khalil
Consultant Cardiologist, Saudi British Hospital
P. O. Box 285627, Riyadh, 11323, Saudi Arabia
Tel: 966 550055587
Fax: 966 12693760
E-mail: [email protected]
Received February 26, 2013; Accepted March 29, 2013; Published April 02, 2013
Citation: Khalil MZ (2013) Role of Antiplatelet Therapies in Preventing Atherothrombosis. J Hematol Thromb Dis 1:108. doi:10.4172/jhtd.1000108
Copyright: © 2013 Khalil MZ. This is an open-access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.
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Platelets exhibit a major role in development and progression of atherothrombosis. The normal function of platelets is to secure hemostasis at sites of vascular injuries. Abnormal endovascular structure may result in excessive platelet function with consequence of progressive or acute reduction in vascular lumen and cessation of blood flow. Despite succeeding in averting bleeding, total occlusion of a vessel leads to inevitable ischemia with eventual cell death upon lack of blood supply clinically manifesting as myocardial infarction in coronary vessels, cerebral infarction (stroke) in cerebral vessels, or peripheral gangrene in peripheral arterial disease. Antiplatelets long have been used to halt the process of atherothrombosis preventing further tissue damage at the expense of bleeding as well as other side effects. In this review, the role of antiplatelets in primary and secondary prevention of thrombotic events is explored in light of evidence based clinical practice.
Antiplatelets; Atherothrombosis; Myocardial infarction;
Stroke; Acute coronary syndrome
Acute coronary syndromes (ACS) are increasing in incidence
throughout the world with clear heavy burden on humanity. The
progressive and pervasive nature of ACS affecting younger and more
commonly older men as well as women, sparing only young children has
activated scientific research for proper understanding the magnitude of
In contrast to ACS, stroke in the young is unusual and most
probably a manifestation of structural abnormality, nonetheless, older
individuals with transient ischemic attack (TIA) and stroke show
evidence of pathophysiology similar to ACS with common denominator
being atherothrombosis in the vast majority of cases.
Generally, atherothrombotic manifestation of ischemia relies on the
presence or absence of collateral circulation. Lack of such collaterals, at
the cellular level, means only one outcome and that is death of cells
fed by the occluded vessel. Documentation of reversing pre-infarction
tissue is evident in coronary vessels and to a lesser extent in cerebral
as well as peripheral circulations [1-4]. It is imperative to understand
the nature of atherothrombotic development in order to initiate timely
Atherothrombosis is a simple term refers to thrombus formation
on top of atherosclerotic plaque disruption of diseased arterial
lumen. Fascinatingly, platelets are activated in response to disrupted
atheromatous plaque in an attempt of mending the vessel wall, however,
in the presence of atherosclerosis; thrombus formation narrows the
lumen resulting in ischemia that may extend to total vessel occlusion.
Moreover, studies have demonstrated that softer atherosclerotic
plaques are more vulnerable to atherothrombosis, irrespective to the
luminal diameter prior to platelet activation [5-9]. Vulnerable plaque
is characterized by similar cholesterol deposition and inflammatory
cellular infiltrates but thinner cap that is more likely to disrupt compared
to non-vulnerable plaque [10-20]. Additionally, vulnerable plaques are
asymptomatic as the luminal effects of these lesions are less likely to
cause ischemia, hence interventional stabilization is not recommended.
The role of antiplatelet therapies, shown in clinical trials, is well
established in the management of atherothrombosis [21-28]. Reduction
of atherothrombotic events is clearly gained at the expense of bleeding
from administration of antiplatelets, particularly in patients with
platelet dysfunction such as patients with chronic kidney disease
. The balance between platelet inhibition and evading bleeding remains to be a difficult task to physicians administering antiplatelet
therapies. Furthermore, combination of antiplatelet therapies is another
concern increasing the risk for bleeding while achieving modest platelet
inhibition as well as modest reduction of thrombotic events [30-35].
Platelets are discoid un-nucleated cells (thrombocytes), produced
from the bone marrow to circulate in the blood stream for a lifespan
of 10 days. Obviously, decrease in platelet count is accompanied by
reduction in platelet function that manifests clinically at low critical
count. It is important to emphasize that platelet dysfunction may
be present despite normal platelet count. Moreover, the concept of
selective inhibition of certain platelet function whereas other functions
of platelets are intact has ignited an era of scientific research targeting
development of antiplatelet agents that are selective in performance.
Thrombocytopenia is a term used to describe reduction in the
number of platelets, nonetheless, platelet function may remain intact
in the presence of thrombocytopenia till reaching critical alarming
number beyond which bleeding is inevitable. The reserve function
of platelets is what maintains platelet function despite reduction
in platelet count. That is why we don’t have universal cutoff number
for platelets count that work correctly for all patients suffering from
It has been shown that platelets are not that simple in their response
towards endovascular injuries harboring many receptors upon activation
thrombus formation ensue [36-39]. The function of platelets may be
altered either by reduction in platelet count or decreased function in
the setting of normal platelet count in several disorders including
renal disease, hepatic disease, hematological malignancies, infectious
diseases, disseminated intravascular coagulopathy, pancreatitis,
immune-mediated thrombocytopenia, and certain medications.
Understanding of platelet function is mandatory prior to discussing antiplatelet therapies, hence; the term “antiplatelet” needs to be refined
in the near future, either to describe platelet receptor antagonists, or
more specifically to represent inhibition of platelet function; namely:
activation, degranulation (release), adhesion, or aggregation.
Activation of platelets in the blood flow is provoked by exposure
of adhesive molecules, including collagen and von Willebrand Factor
(vWF), at the site of vascular lumen injury. This step is integral in
securing hemostasis by circulating platelets adjacent to luminal wall at
the periphery of blood flow, and enforced by high sheer rates. Activation
of platelet occurs through surface receptors for collagen, thromboxane
A2, thrombin, and adenosine diphosphate (ADP). The exact size of
platelet plug required to patch up the area of vascular injury in an
attempt to prevent bleeding is governed by the release of natural platelet
inhibitors namely prostaglandin I2 and nitric oxide from activated
endothelial cells at the perimeter of vessel injury. Further control of
later thrombus formation is mediated by activation of protein C; a
natural anticoagulant inhibits thrombin formation by carving activated
factors V and VIII, as well as the natural fibrinolysis.
Platelets contain several different types of storage granules to be
released upon activation, a process often referred to as degranulation.
Dense granules contain small non-protein molecules such as; ADP,
adenosine triphosphate (ATP), serotonin and calcium, which are
released to recruit other platelets. Alpha granules are more abundant
and contain large adhesive polypeptides for instance vWF, protease
inhibitors, platelet derived growth factors, and fibrinogen that provide
essential aid to healing at the site of injury. The third type of platelet
storage granules are lysosomes whose enzymes are released to act on
platelets as well as vascular endothelial cells to eliminate the circulating
platelet aggregate and to form stable covalent cross-links between
Adhesion is a crucial function of platelets at the site of vascular
injury, which is activated in response to exposure to subendothelial
matrix triggering interactions between glycoprotein (GP) Ib and
vWF. Furthermore, exposed collagen type I, III, and VI are vessel wall
components prompting platelet adhesion to impede bleeding. Other
adhesive molecules corroborating in the process of platelet adhesion
are integrin α2β1, GP VI, fibronectin, thrombospondin, and laminin.
Thrombus propagation is dependent on the formation of platelet
aggregation. Platelets bind soluble adhesive proteins and form a
reactive surface for continuing platelet aggregation. Recruitment of
additional platelets for aggregation is mediated by platelet agonists
such as thromboxane A2 (TA2), platelet activating factor (PAF), ADP
and serotonin, which bind recruited platelets to the adhered platelets.
Additionally, platelet agonists signal morphological changes in the shape
of platelets resulting in long membrane projections, which allow the
platelets to interact with one another to form aggregates. GPIIb/IIIa is an
integrin receptor present at high density on platelets and is considered
the main adhesion molecule involved in platelet aggregation. The final
common pathway of platelet aggregation is induced by fibrinogen
acting as a bridge between two GPIIb/IIIa molecules on the membranes
of adjacent platelets under lower shear rates, while aggregation induced
by high shear conditions is induced by vWF substituting for fibrinogen.
Moreover, activated platelets not only recruit additional platelets to
the growing plug formed at the site of vascular injury, but also play a
principal role in secondary hemostasis by providing a valuable catalytic
surface for activation of the coagulation cascade.
Site of Action of Antiplatelet Therapies
Aspirin: Aspirin (acetylsalicylic acid) irreversibly inhibits cyclooxygenase-1 (COX-1) enzyme and blocks the production of TA2
from arachidonic acid of platelets. The detailed mechanism of action
is summarized to acetylation of the platelet COX-1 at the functionally
important amino acid serine529 preventing access of arachidonic
acid to the catalytic site of the enzyme at tyrosine385 and results in an
irreversible inhibition of platelet-dependent TA2 formation.
There are several limitations of the antiplatelet efficacy of Aspirin;
first: platelet activation caused by other factors, such as shear stress
and ADP, remains unchanged and might result in aspirin resistance.
Secondly: inhibition of COX-1 by aspirin will also reduce the amount
of precursors for vascular prostacyclin synthesis. Third: in the presence
of aspirin that blocks COX-1, platelets utilize COX-2 pathway to
The beneficial efficacy of aspirin for primary prevention of vascular
thrombosis is counterbalanced by hazards of excess bleeding, which has
resulted in critically selecting subjects at increased risk of thrombosis
for prevention after considerable evaluation for the existing risk of
bleeding [40,41]. Conversely, the benefits of aspirin for secondary
prevention clearly outweigh the risks of bleeding, thus aspirin continues
to be fundamental of antithrombotic therapy as secondary prevention
in coronary, cerebral as well as peripheral vascular thrombotic events.
Moreover, it has been shown that aspirin therapy for secondary
prevention reduces both fatal and nonfatal coronary events, while only
nonfatal thrombotic events were prevented by aspirin in the primary
prevention of ischemic heart disease .
Thienopyridines: The action of thienopyridines is mediated
through prevention of ADP-induced platelet activation and aggregation
by irreversibly inhibiting the platelet ADP receptor P2Y12. Indirectly
acting thienopyridines (ticlopidine, clopidogrel, and prasugrel) are
prodrugs that need to be converted by hepatic cytochrome P-450
(CYP) to active metabolites, which covalently and irreversibly bind
to the P2Y12 receptor. The antiplatelet activities of the indirectly
acting thienopyridines are delayed as a consequence of the need for
metabolism of the prodrug. Furthermore, there are considerable interindividual
discrepancies in the degree of metabolism of the prodrug
leading to unpredictability in platelet inhibition.
Direct P2Y12 inhibitors: The recent additions of antiplatelet
therapies are direct and reversible P2Y12 antagonists (cangrelor,
ticagrelor, and elinogrel), which have rapid onset and offset of platelet
inhibition in contrast to thienopyridines. Blocking the P2Y12 receptor
causes inhibition of stimulated adenylyl cyclase, ADP, TA2, and the
proteinase-activated receptor-1 (PAR1) selective peptide agonist [43-47]. Furthermore, blockade of the P2Y12 receptor has been shown
to decrease platelet aggregation under shear conditions as well as
subsequent thrombus formation [48-50].
Glycoprotein (GP) IIb/IIIa inhibitors: The final common pathway
of platelet aggregation is operational through Platelet membrane GPIIb/
IIIa receptors that allow binding of fibrinogen and vWF at multiple sites
present on each platelet, resulting in aggregation. Gp IIb/IIIa receptor
antagonists (abciximab, tirofiban, eptifibatide) inhibit fibrinogen from
effectively cross-linking platelets preventing aggregation and thrombus
probagation. The benefit of this mechanism of action is that inhibition
of platelet aggregation occurs independently of the specific platelet
activating agonist without inhibition of initial platelet adherence
to injured vascular surface. Moreover, GP IIb/IIIa blockade has the
ability to induce dethrombosis via dissolution of platelet-rich clot by
disrupting fibrinogen-platelet interaction [51-61].
PAR-1/thrombin receptor antagonists (TRAs): The ideal antiplatelet therapy is one that is easily administered, available in oral
format, promotes platelet activation contributing to thrombosis but
not essential for hemostasis. Currently, novel oral antiplatelet agents
targeting the PAR-1 pathway may provide more comprehensive
platelet inhibition without increased bleeding risk. Inhibition of PAR-1
represents a reasonable advance to development of novel antiplatelet
agents [62-71]. Two oral PAR-1 inhibitors are currently in clinical
research with promising efficacy but noticeable bleeding risk indicative
of further requirement for patients’ selection; vorapaxar is undergoing
evaluation in large phase 3 trials, whereas Atopaxar is currently being
evaluated in phase 2 trials [72-75].
Antiplatelet therapies in clinical practice: Atherosclerosis is a
continuum of multiple risk factors affecting the structure and function
of blood vessels throughout the body over long duration. The clinical
manifestations of atherothrombosis is obviously evident by either
chronic narrowing of the vascular lumen giving rise to reduced blood
supply to certain tissues, or mare dramatically abrupt and acute
occlusion of a feeding vessel with consequent catastrophic cellular
death if left untreated. Coronary artery disease (CAD), cerebro-vascular
disease, and peripheral artery disease (PAD) are of major importance
due to the ability of reversing a devastating clinical event upon timely
intervention. Therefore, the role of antiplatelet therapies is to halt the
natural thrombotic function of platelets at sites of atherothrombotic
Coronary atherothrombosis: Non ST segment elevation
myocardial infarction (NSTEMI), as well as unstable angina (UA), is
the outcome of incomplete occlusion of a particular coronary artery,
with evident chance for intervention to reverse the pathology. Patients
with NSTEMI are identified on vectorcardiography (ECG) by the
absence of ST segment elevation and further ECG evaluation do not
show Q waves, in contrast to patients with ST elevation and eventually
develop Q waves on ECG, while patients without elevated biomarker
values are designated with a diagnosis of unstable angina . Early
studies on antiplatelet therapy, were conducted mainly to study the
efficacy of aspirin in short-term as well as long-term treatment for
patients with CAD, have shown it to be effective in both primary i.e.
in patients without previous coronary events but are at increased risk
for developing CAD, as well as secondary prevention, and therefore
rendered as standard of care in clinical practice [77-94]. Nonetheless,
another antiplatelet has to be added to aspirin in the treatment of
patients with NSTEMI/UA, from the thienopyridines or more recently
from the P2Y12 inhibitors, for initial and maintenance treatment as
well as GPIIa/IIIb for the acute phase therapy [95-104].
The concept of dual antiplatelet therapy has been the standard of
care to patients with acute coronary events, particularly for those who
underwent percutanous coronary intervention (PCI) and following
coronary stenting [105-109]. Dual antiplatelet therapy (DAPT) is a
term used to describe additional antiplatelet therapy to aspirin. The
pathophysiologic motivation for DAPT is prompted by the presence
of two different pharmacodynamic mechanisms. The duration of
DAPT remains to be determined according to patient’s requirements,
nonetheless, recent analysis revealed no clinical benefit of prolonged
dual antiplatelet therapy for duration of 2 years compared to 6 months,
in patients with CAD and treated with PCI, irrespective of the type of
stent used, and resulted in increased risk of bleeding . Moreover, it
has been demonstrated that preoperative use of dual antiplatelet therapy
is associated with an increased risk of infection, blood transfusion, and
mortality after coronary artery bypass grafting (CABG) surgery .
The use of P2Y12 receptor inhibitors in the setting of ACS as well as PCI is associated with faster onset of action, greater potency
and reversibility of platelet inhibition compared to clopidogrel .
Clinical studies have shown evident reduction of rates of vascular death
and myocardial infarction (MI) comparing ticagrelor to clopidogrel
in patients with ACS at the expense of increased bleeding [113-123]. Additionally, shorter period of drug discontinuation before
CABG surgery was required in ticagrelor-treated patients compared
to clopidogrel-treated patients to limit the severity of post-surgical
bleeding [124-126]. Furthermore, prasugrel was significantly more
effective than clopidogrel in reducing ischemic events and stent
thrombosis of different types [127-128]. Current guidelines reflect the
superiority of newer P2Y12 inhibitors (ticagrelor, prasugrel) as both
agents are recommended in STEMI patients replacing clopidogrel [129-131]. The administration of ticagrelor is recommended in patients with
NSTEMI/UA, regardless of invasive or non-invasive treatment strategy
is opted [132,133].
In patients with ACS, the use of GP IIb/IIIa inhibitors is associated
with beneficial reduction of death and MI, and this benefit has been
demonstrated among patients with STEMI as well as high risk patients
with NSTEMI/UA. The beneficial use of these agents as part of tripleantiplatelet
therapy may not outweigh the risk, particularly, in patients
with a concern for increased risk of bleeding. An early invasive strategy
using GP IIb/IIIa inhibitor significantly reduced the incidence of major
cardiac events in patients with unstable angina who demonstrated
elevated levels of cardiac markers as well as patients with NSTEMI
. Antiplatelet therapy with the GP IIb/IIIa inhibitor abciximab in
patients with STEMI treated with PCI, improved outcome and reduced
major adverse coronary events (MACE). The INFUSE-AMI trial
demonstrated reduction in infarct size of intracoronary administration
of abciximab compared to thrombectomy in patients treated with PCI
for large anterior STEMI . Efficacy of small-molecule GP IIb/IIIa
inhibitors (tirofiban, eptifibatide) has been demonstrated in high-risk
patients with NSTEMI/UA treated with early invasive strategy, while
safety concerns, particularly, increased bleeding as well as transfusions
rates, lashed out their use in low risk NSTEMI/UA patients .
Cerebral atherothrombosis: Secondary prevention of recurrent
cerebral Atherothrombosis (TIA, Stroke) using aspirin as initial
antiplatelet therapy remains the cornerstone of treatment in patients
without indication for anticoagulation [137,138]. Overall, prevention
for non cardio-embolic cerebral Atherothrombosis is attained by
administration of single antiplatelet agent and mostly, this is done using
aspirin, unless in patients who are intolerant to aspirin, alternative use
of clopidogrel, or to lesser extent, ticlopidine has been used [139,140].
It is important to emphasize that primary prevention of cerebral
atherothrombosis using aspirin is recommended only in selected
patients after establishing a clear cause for treatment that outweigh the
risk of bleeding .
Aspirin has been shown to result in approximately a quarter risk
reduction for recurrent nonfatal stroke compared to placebo .
The dose of aspirin has been debated in clinical trials for long time,
ultimately, evidence has documented lower doses, between 50 and 325
mg for prevention of recurrent non-cardioembolic TIA or stroke, as
efficacious as higher doses but with less bleeding risk, predominantly
gastrointestinal bleeding [143,144].
Primary as well as secondary prevention of cerebral
atherothrombosis research clinical trials were largely unsuccessful
in confirming superiority of clopidogrel over aspirin, nonetheless,
for patients intolerant to aspirin use, clopidogrel may be used as a
reasonable alternative . Moreover, combination of clopidogrel with aspirin for stroke prevention, have been shown to result in more
bleeding without marked benefit to balance the risk, over using either
aspirin or clopidogrel antiplatelet monotherapy .
For secondary prevention of non-cardioembolic stroke, aspirin
in combination with extended-release dipyridamole antiplatelet
therapy has been shown to be more effective than aspirin alone
. Fascinatingly, the combination of aspirin and extended-release
dipyridamole was twice as effective for stroke prevention as either
drug alone, with rates of bleeding of not exceeding those of aspirin
monotherapy [148-152]. Triflusal is a derivative of salicylic acid that
inhibits platelet-dependent TA2 formation by blocking COX while
preserving vascular prostacyclin, which provides safety of less bleeding
compared to aspirin particularly in secondary prevention .
Moreover, for secondary prevention of stroke, cilostazol; another
antiplatelet agent has been shown to provide similar efficacy to aspirin
with potentially less bleeding events .
Appropriate choices for therapy in patients with non-cardioembolic
stroke or TIA may consist of either aspirin as monotherapy, the
combination of aspirin and extended-release dipyridamole, or
clopidogrel alone. Furthermore, the combination of clopidogrel with
aspirin for stroke secondary prevention is inappropriate compared to
monotherapy due to increased bleeding risk without significant benefit.
Peripheral atherothrombosis: Peripheral artery disease (PAD)
is a clinical manifestation of reduced arterial blood supply to the
extremities (upper and lower limbs) secondary to pathological
mechanisms similar to CAD as well as cerebral atherothrombosis.
Patients with PAD present a spectrum of disease severity that may
be asymptomatic or symptomatic with intermittent claudication and
peripheral gangrene comparable to NSTEMI and STEMI or TIA and
stroke in CAD or cerebro-vascular disease respectively. It has been
found that combination antithrombotic therapy with an antiplatelet
agent and an oral anticoagulant was not more effective than antiplatelet
therapy alone in preventing major cardiovascular complications .
Antiplatelet monotherapy primarily by aspirin or by clopidogrel in
aspirin intolerant patients is beneficial for patients with asymptomatic
PAD, while combination therapy of aspirin and clopidogrel is reserved
for patients with symptomatic PAD.
The effect of aging on vascular patency is magnified by adopting
unhealthy lifestyle resulting in atherothrombosis presenting as ACS,
MI, TIA, or stroke either alone or in combination. Platelets play
pivotal role in the pathology of progressing atherothrombosis, hence,
antiplatelet therapy is recommended. The choice of antiplatelet therapy
for treatment decisions is largely related to patient’s clinical variables.
Bleeding is a major side effect of antiplatelet treatment that often can
be prevented by appropriate therapeutics initiation as well as patient’s
monitoring. The faultless antiplatelet agent is still to be developed
hopefully in the near future guided by more biochemical dissection of
platelet functions and pharmaceutical progress.
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