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11 Platelets inthePathogenesis ofVascular Disease andTheir Role asaTherapeutic…
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activation, the platelet undergoes shape change, in a process linked to re-organisation of the cytoskeleton, which facilitates the generation of multiple, stable adhesion
contacts. In concert with shape change, platelets generate TxA2 and degranulate,
thereby releasing important soluble agonists such as ADP, which act in an autocrine
and paracrine fashion to amplify GPIIb/IIIa activation and stabilise the platelet
thrombus, whilst granule-derived brinogen and vWF maintain a reactive surface
for further platelet recruitment to the growing thrombus [86]. The activated integrin
GPIIb/IIIa binds to its major ligand in the circulation, brinogen, which mediates
platelet-platelet interactions and therefore the formation of platelet aggregates [3]
(Fig.11.3). Together, these processes produce a platelet rich thrombus at sites of
vascular injury necessary for efcient haemostasis. Conversely, the formation of
platelet thrombi at sites of atherosclerotic plaque rupture, or exaggerated platelet
thrombus formation, can lead to pathological thrombosis such as acute myocardial
infarction and ischaemic stroke.
The generation of thrombin at sites of vascular injury plays a central role in the
stabilisation of the platelet thrombus. Thrombin generation at the site of plaque
rupture is initiated by the exposure of tissue factor, which then forms a catalytic
complex with Factor VIIa, initiating the ‘extrinsic’ pathway of blood coagulation
[87]. Activated platelets and endothelial cells, at sites of vascular injury, express the
negatively charged phospholipid, phosphatidylserine (PS), which is required to
allow the assembly of the tenase and prothrombinase complexes [88, 89]. The generated thrombin not only potently stimulates platelets, but also cleaves brinogen to
form a brin mesh that anchors, crosslinks and thus stabilises the platelet thrombus
[90]. Platelets bind to brin via GPIIb/IIIa and therefore contractile forces generated by the platelet cytoskeleton can be transmitted via the integrin to mediate clot
retraction as a means to consolidate and stabilise the thrombus [91, 92].
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11.4.3 Platelet Adhesion toInamed Endothelium
The early phases of atherosclerosis are associated with endothelial inammation,
which disrupts normal endothelial function and is associated with platelet and leucocyte adhesion. Whilst the endothelium serves as a barrier between platelets and
the highly reactive subendothelial matrix, under pathological conditions, the endothelium expresses a number of adhesive ligands and receptors for platelets, allowing
for platelet adhesion and activation on the endothelium [93, 94]. Indeed, the inamed
endothelium expresses the selectins, P-selectin and E-selectin, in addition to vWF
secreted from endothelial Weibel-Palade bodies. P-selectin and vWF are the receptors for platelet PSGL-1 and GPIb, respectively, with these interactions mediating
platelet tethering and rolling. Akin to thrombus formation, the stable adhesion of
platelets to the inamed endothelium is largely mediated by GPIIb/IIIa. Here, the
expression of intercellular adhesion molecule-1 (ICAM-1) is upregulated in the
context of inammation and can bind brinogen/brin which then acts as a bridge
to engage platelet GPIIb/IIIa [95, 96] (Fig.11.4).
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Fig. 11.4 The role of platelets in atherosclerosis. The healthy endothelium liberates ectoADPase,
NO and PGI
inammatory conditions, such as endothelial ischaemia or diabetes, the inamed endothelium
releases vWF, and upregulates the expression of pro-adhesive molecules such as P-selectin and
ICAM-1. This permits the tethering of platelets to the inamed endothelium via interactions
between platelet GPIbα and endothelial bound P-selectin and vWF. Stable platelet adhesion is
contingent upon GPIIb/IIIa, which binds to brinogen immobilized by endothelial ICAM-1 and
α
. The activation of endothelial bound platelets leads to the release of platelet derived proin-
vβ3
ammatory mediators such as IL-1β, which incites further endothelial inammation. These interactions ultimately lead to the enhanced recruitment, adhesion and transmigration of leukocytes to
areas of endothelial inammation—all important aspects of atherogenesis
which prevent unwanted platelet adhesion to the endothelium. However, under pro-
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11.5 The Proinammatory Role ofPlatelets
11.5.1 Platelets asImmune andInammatory Mediators
Fundamental to the inammatory role of platelets is the expression of immune
receptors and capacity to store and produce a large range of proinammatory molecules. Platelet granules contain over 300 different proteins, including a vast array
of chemokines and other proinammatory molecules [97]. Chemokines play an
important biological role in their ability to recruit and activate leucocytes [98].
Platelet α granules contain the CXC chemokines PF4 (CXCL4), β-thromboglobulin
and epithelial-derived neutrophil-activating peptide 78 (ENA-78 or CXCL5) [99].
PF4 and β-thromboglobulin are amongst the most abundant proteins contained in α
granules and serve to enhance leucocyte chemotaxis and activation [99]. Nonchemokine, proinammatory molecules contained within platelet α granules include
CD40L, TREM-1 and TGF [97]. As a consequence, platelet activation has been
demonstrated to play a central role in the pathogenesis of a broad range of thromboinammatory and immune conditions including atherosclerosis [100–102].
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11.5.2 Platelets Induce Endothelial Activation
The binding of platelets to the endothelium facilitates endothelial cell activation and
thus aids the endothelium in taking on a proinammatory function [94] (Fig.11.4).
Endothelial bound platelets become activated and liberate numerous proinammatory
cytokines [94]. Foremost amongst these are IL-1β and PF4. IL-1β plays a central role
in facilitating the platelet dependent proinammatory endothelial phenotype by activating the NFκB pathway, upregulating ICAM-1 and α
release of IL-6, MCP-1 and GM-CSF [103]. PF4 serves to enhance E-selectin expression by activating the NFκB pathway [104]. CD40 ligand is a member of the tumour
necrosis factor (TNF) superfamily of molecules that binds to its specic receptor on
endothelial cells, CD40 [105]. Binding of CD40 ligand to endothelial CD40 results in
the production of inammatory cytokines such as IL-8 and MCP-1, the generation of
reactive oxygen species, enhanced expression of matrix metalloproteinases and
expression of adhesion molecules such as ICAM-1, VCAM-1 and E-selectin [105].
expression and inducing the
vβ3
11.5.3 The Role ofPlatelets inLeukocyte Recruitment
andActivation
In addition to promoting endothelial activation, activated platelets bound to the
endothelium serve to facilitate leucocyte recruitment and transmigration to sites of
endothelial injury [106]. Endothelial-adherent platelets enhance the recruitment of
leukocytes by expressing P-selectin, which serves as the ligand for the constitutively
expressed leukocyte receptor PSGL-1 and thereby enabling leukocyte tethering and
rolling even at high shear rates [107]. The interaction between P-selectin and PSGL-1
enhances the expression of the leucocyte integrin Mac-1 (αMβ2, CD11b/CD18),
which binds to platelet GPIb and junctional adhesion molecule (JAM-c) to mediate
stable adhesion [36, 108]. Furthermore, additional interactions between platelets and
leucocytes can occur to facilitate the stable platelet-leukocyte adhesion. Foremost
amongst these include the binding of brinogen to leucocyte Mac-1 which can serve
as a bridge to the platelet integrin GPIIb/IIIa and the binding of platelet CD40 ligand
to leucocyte CD40 [94]. Activated platelets release chemokines such as platelet factor 4 (PF4) and RANTES (regulated on activation, normal T cell expressed and
secreted), which serve to enhance the recruitment of leucocytes to areas with adherent platelets [109, 110]. Further, the release of platelet chemokines also stimulates
the production of the proinammatory cytokines such as TNFα, IL-1β, IL-8 and
monocyte chemoattractant protein-1 (MCP-1) from monocytes [111]. The importance of platelets in facilitating leukocyte recruitment is highlighted by numerous
studies, which demonstrate that either platelet depletion or inhibition signicantly
reduces the level of neutrophil recruitment to inamed organs [112]. In keeping with
the cross talk between platelets and endothelial cells, leukocyte binding to platelets
facilitates their adhesive capacity and proinammatory phenotype [113].
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11.6 The Contribution ofPlatelets toAtherosclerosis
Platelets contribute to the development and progression of atherosclerosis from the
early stages of endothelial inammation through to plaque rupture and subsequent
atherothrombosis [94]. Platelets inuence atherogenesis via multiple mechanisms,
by enhancing endothelial inammation, by facilitating leukocyte adhesion and
transmigration, and by the release of a plethora of inammatory factors (Fig.11.4).
Platelets adhere to the perturbed endothelium early on in the development of atherosclerosis, which coincides with proinammatory gene expression in endothelial
cells. Interestingly, the presence of platelets occurs before leukocytes, suggesting
they play an important role in leukocyte recruitment in the context of atherosclerosis [100]. Accordingly, in experimental models, the inhibition or depletion of platelets attenuates atherosclerosis. Thus, it is interesting to speculate that some of the
protective effects of anti-platelet therapy in humans in secondary prevention of cardiovascular disease may be due in part to these effects, however this is yet to be
established. Moreover, subclinical plaque rupture is a frequent event with 9% of
autopsies on patients not dying from myocardial infarction demonstrating ruptured
brous caps (22% in patients with cardiovascular risk factors), suggesting that
rather than every plaque rupture precipitating an ischemic event, it is likely that the
thrombotic response to plaque disruption is dynamic with thrombosis and thrombolysis occurring simultaneously in patients with acute coronary syndrome [114].
Consequently, a rupture prone plaque may suffer periodic disruptions in its brous
cap resulting in ongoing interactions with activated platelets. Thus, in addition to
their role in acute plaque rupture, at any given time, activated platelets may be associated with unstable plaques presumably in a number and frequency proportional to
the degree of plaque instability. The detection of such activated platelets potentially
may allow identication of unstable plaques prior to rupture [115].
11.7 Current Anti-platelet Therapies
Anti-platelet drugs are the cornerstone of therapy in patients with acute coronary
syndromes (ACS), stable coronary artery disease, and those undergoing coronary,
carotid and peripheral artery revascularisation procedures [116–118].
11.7.1 Aspirin
Aspirin (salicylic acid) blocks the production of TxA2 via the irreversible inhibition
of cyclooxygenase-1 (COX-1), thereby inhibiting the generation of TxA2 and its
effect on platelet activation and aggregation (Fig. 11.1). Aspirin acetylates a key
serine residue at the COX-1 catalytic centre, irreversibly corrupting its enzymatic
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function. Platelets lack the machinery to resynthesize COX-1 and thus aspirin leads
to irreversible platelet inhibition for the lifespan of the platelet (7–10days), despite
aspirin’s relatively short plasma half-life of 15min.
Aspirin has a well-established clinical benet in vascular disease, particularly
myocardial infarction and stroke, in both the acute and chronic setting. Aspirin is
the rst-line anti-platelet therapy in ACS, reducing the relative risk of mortality by
23% after 5weeks of aspirin therapy [119, 120]. In addition, aspirin provides major
benets in secondary prevention, reducing the relative risk of MI by 25% [121].
However, the benets are less well established in primary prevention as the benets
of a reduced rate of myocardial infarction are tempered by an increased rate of
haemorrhagic stroke. Indeed, a recent, large scale clinical trial (ASPREE study) has
demonstrated that the use of aspirin for the primary prevention of cardiovascular
disease in elderly patients is not associated with clinical benet [122].
The optimal dose of aspirin had been established as 75–150mg daily, in order to
achieve its full platelet inhibitory effect. Higher doses (up to 325mg daily) demonstrate increased gastrointestinal side effects with no additional anti-platelet effect.
Signicantly, approximately one-third of patients receiving aspirin therapy demonstrate ‘treatment failure’ manifested by recurrent thrombosis. This has led to the
notion of aspirin resistance, which may be associated with evidence of biochemical
resistance or heightened platelet reactivity on platelet function testing. Clinical scenarios associated with a heightened inammatory response such as diabetes, post
cardiac surgery and acute coronary syndromes have all been associated with heightened platelet reactivity. Moreover, polymorphisms of the COX alleles and conditions associated with elevated platelet turnover (such as immune thrombocytopenia
and essential thrombocytosis) can also lead to the reduced anti-platelet effect of
aspirin. However, to date, a uniform denition of aspirin resistance and the management has yet to be clearly dened.
11.7.2 P2Y12 Receptor Antagonists
The P2Y12 receptor has an important role in mediating sustained activation of the
major platelet adhesion receptor, GPIIb/IIIa, in response to ADP stimulation [123]
(Fig.11.1). P2Y12 receptor antagonists inhibit the amplication of platelet activation
induced by ADP, resulting in potent antithrombotic effects [123]. The P2Y12 inhibitors
comprise two classes of drugs: the thienopyridines (clopidogrel, prasugrel, and ticlopidine) and the nucleoside/nucleotide derivatives (cangrelor and ticagrelor).
11.7.2.1 Clopidogrel
Clopidogrel is a thienopyridine, and therefore is a prodrug that requires metabolism by the cytochrome P450 (CYP450) system into the active metabolite that
irreversibly inhibits the P2Y
receptor [116, 117]. Consequently, the concurrent
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use of other drugs that inhibit the CYP450 metabolism of clopidogrel may diminish its anti-platelet effects. This is typied by the proton pump inhibitors (PPIs),
which are also substrates of the CYP450 pathway, and have been associated with
heightened platelet reactivity in those taking clopidogrel concurrently. However,
to date, no randomised controlled trials have addressed the issue of whether there
is an increased rate of adverse cardiovascular outcomes in patients co-administered clopidogrel and a PPI.Notwithstanding, the FDA and European Medicines
Agency (EMA) currently recommend that PPIs, other than omeprazole and
esomeprazole, be used in patients prescribed clopidogrel. However, up to 10% of
patients experience recurrent ischaemic events despite receiving dual antiplatelet
therapy (DAPT) with aspirin and clopidogrel [124]. In addition, 30–40% of
patients receiving clopidogrel continue to exhibit elevated platelet reactivity.
These challenges led to the development of novel, potentially more potent P2Y12
antagonists [123].
11.7.2.2 Prasugrel
Prasugrel is a third generation thienopyridine that, similar to clopidogrel, is a prodrug that is converted into its active metabolite by the CYP450 system that irreversibly inhibits the P2Y12 receptor. However, prasugrel has greater in vivo
bioavailability, is associated with less inter-individual variability and thus is associated with more potent anti-platelet effects compared to clopidogrel [116, 117].
Moreover, no drug-drug interactions that inuence prasugrel metabolism have been
described.
11.7.2.3 Ticagrelor
In contrast to the thienopyridines, Ticagrelor is a nucleoside/nucleotide anatagonist
that is a reversible, direct acting antagonist of the P2Y12 receptor. Thus, unlike
clopidogrel and prasugrel, ticagrelor does not require metabolism by the CYP450
system to achieve its anti-platelet effects. As a consequence, ticagrelor is associated
with a faster, more potent and predictable anti-platelet effect compared to clopidogrel [116, 117]. Ticagrelor can cause dyspnoea more often than other P2Y12 inhibitors, which is often resolved by its replacement by either prasugrel or clopidogrel.
11.7.2.4 Cangrelor
Cangrelor is a direct, reversible P2Y
FDA and the European Medicines Agency (EMA) [125]. Cangrelor is given intravenously and has a rapid onset of action and ultra-short half-life (3–6min) thus
allowing the rapid recovery of platelet function [123]. Therefore, cangrelor is a
therapeutic option in clinical scenarios where P2Y12 inhibition with a rapid onset
antagonist that has been approved by the
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and offset of action is desired, such as for patients with ACS, who are P2Y12 antagonist naïve and need urgent PCI or those who require DAPT bridging before surgery [126].
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11.7.3 Dual Anti-platelet Therapy
With the high rates of recurrent ischaemic events, despite aspirin therapy, in addition to the widespread application of percutaenous coronary intervention (PCI), the
use of dual anti-platelet therapy (DAPT) has become one of the most widely and
intensively adopted therapies in cardiovascular medicine. DAPT generally comprises aspirin in addition to a P2Y12 antagonist. In this regard, there is strong evidence for the use of DAPT to prevent recurrent ischaemic events in patients with
ACS and/or post PCI where DAPT prevents stent thrombosis. Whilst the optimal
duration of DAPT remains a matter of much debate this is often based on the perceived risk of recurrent ischaemia versus the bleeding risk [116, 117].
11.7.4 PAR-1 (Protease Activated Receptor-1) Antagonists
Combining thrombin blockade with DAPT had been widely regarded as a potential
anti-thrombotic strategy [127, 128]. On the basis of the TRA 2P–TIMI 50 trial, the
PAR-1 antagonist vorapaxar was approved by the FDA for the reduction of ischaemic events in patients with a history of MI or peripheral vascular disease [129,
130]. However, the use of vorapaxar in addition to standard anti-platelet agents, has
not been demonstrated to be of benet in the context of ACS [131]. Importantly, in
two large randomized trials (TRA 2P–TIMI 50 and TRACER trials), the rates of
bleeding, in particular intracranial haemorrhage, were substantially increased by the
addition of vorapaxar to standard anti-platelet therapy. Consequently, the concerns
about safety have limited the use of vorapaxar in clinical practice.
11.7.5 GPIIb/IIIa Inhibitors
GPIIb/IIIa inhibitors are ligand-mimetic molecules that prevent brinogen from
binding to platelets, thereby directly inhibiting their aggregation (Fig.11.1). Three
agents are currently in use: abciximab, a humanized Fab fragment of a mouse
monoclonal antibody; eptibatide, a cyclic heptapeptide with a lysine-glycineaspartic acid (KGD) motif mimicking the brinogen binding sequence within
GPIIb/IIIa; and tiroban, a non-peptidic small molecule also mimicking the brinogen binding site [132]. First marketed in the mid-1990s, these drugs have been
widely used in patients with ACS and those undergoing PCI.However, the early
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clinical trials assessing GPIIb/IIIa inhibitors were conducted before the routine use
of P2Y12 antagonists. Therefore, the clinical benet derived from GPIIb/IIIa inhibitors seems to be restricted to certain high-risk subgroups, such as patients with MI
undergoing PCI without pretreatment with a P2Y12 antagonist [133]. Importantly,
whilst the GPIIb/IIIa inhibitors are potent anti-thrombotic drugs, they are associated
with bleeding complications in up to 50% of patients [134].
11.7.6 Phosphodiesterase Inhibitors
Cilostazol and dipyridamole are phosphodiesterase inhibitors that inhibit platelet
aggregation. Cilostazol is a phosphodiesterase III inhibitor that inhibits the degradation of cAMP, which in turn leads to an increase in Protein Kinase A (PKA) that acts
to impair platelet aggregation. Cilostazol also causes vasodilation since PKA
impairs smooth muscle contraction. In this regard, cilostazol has demonstrated benet in patients with peripheral arterial disease and intermittent claudication.
Dipyridamole inhibits the uptake of adenosine into platelets and endothelial cells,
thus resulting in the accumulation of cAMP, which mediates its platelet inhibitory
effects and vasodilatory properties. The use of dipyridamole has been most widely
studied for the prevention of ischaemic stroke in combination with aspirin.
11.7.7 Current Therapeutic Landscape
Whilst a detailed description of the current therapeutic guidelines regarding antiplatelet therapy are beyond the scope of this chapter, the current recommendations concerning anti-platelet therapy are summarized in Table 11.1. The
recommended duration of DAPT is often individualised and is particularly contingent upon the bleeding risk. In addition, we refer the reader to the most recent
guidelines published by the European Cardiac Society and American College of
Cardiology [116, 117].
Table 11.1 Recommended anti-platelet regimes in patients with cardiovascular disease (BMS
bare metal stent, DES drug-eluting stent)
Indication Treatment recommendation
Acute coronary syndrome PCI or non-PCI: lifelong ASA plus P2Y12 antagonist at least
Stable ischaemic heart
disease
Stroke Aspirin or clopidogrel
PAD Aspirin or clopidogrel
12months
BMS: Aspirin lifelong plus P2Y12 antagonist at least 1month
DES: Aspirin lifelong plus P2Y12 antagonist at least 6months
DAPT if history of previous lower extremity revascularisation
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11.8 Perioperative Management ofAnti-platelet Therapy
The continuation of DAPT peri-operatively is associated with a reduction in the rate
of thrombotic complications. However, importantly, the use of DAPT throughout
the peri-operative period is associated with a signicant increase in the risk of
bleeding complications and rate of blood transfusion. Therefore, the relative risks of
thrombotic complications and bleeding risk need to be assessed on a patient by
patient basis, taking into account the cardiovascular risk prole, bleeding risk of the
procedure, and the pharmacokinetic prole of the anti-platelet drug(s). The cessation of P2Y12 antagonists is often 7–10days (with a minimum of 5days) prior to
any planned procedure given this roughly equates to the lifespan of a platelet. For
patients who undergo surgery on anti-platelet therapy, bleeding is associated with
an increased morbidity and mortality. The management of anti-platelet associated
bleeding is complicated by the fact that no specic reversal agent exists for any of
the anti-platelet drugs. The management of major haemorrhage in this setting is
often managed empirically with the use of anti-brinolytics, such as tranexamic
acid, platelet transfusions or desmopressin. Interestingly, the role of platelet transfusions in the context of anti-platelet related bleeding has recently been called into
question with a randomized controlled trial demonstrating that patients with antiplatelet associated intracerebral bleeding administered platelets had adverse clinical
outcomes compared to standard care [135]. The use of pro-haemostatic agents such
as prothrombin complex concentrate or recombinant Factor VIIa have been
described, however the use of these agents can be associated with a risk of major
thrombotic complications.
11.9 Novel Anti-platelet Drugs inDevelopment
The major limitation of all currently used anti-thrombotic approaches is the inherent
risk of bleeding associated with their use. This is particularly the case in elderly
patients and those with co-morbid conditions, such as renal failure. Given these
patients are usually at high risk of recurrent ischaemic events, they often do not
receive optimal anti-thrombotic therapy due to the risks of bleeding. These issues,
coupled with recent progress in our understanding of potentially important differences between the haemostatic and thrombotic response have led to the development of several new classes of drugs in early phase development that potentially
hold the promise to differentially target pathological thrombosis without impeding
haemostasis [118].
Inhibitors of GPVI, PAR-4 and protein disulde isomerase (PDI) are currently
being evaluated in early phase clinical trials on the basis that these targets display
marked anti-thrombotic effects with no signicant impact on bleeding in animal models [118]. Likewise, conformation specic inhibitors of GPIIb/IIIa, and PI3Kβ inhibitors also display signicant anti-thrombotic effects in pre-clinical models. However,
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how these agents ultimately translate in human studies and where their utility in the
context of our existing anti-platelet drugs remains to be established [136].
11.10 Platelet Function Testing
The widespread use of anti-platelet drugs for the treatment and prevention of arterial thrombosis has led to great interest in the potential of ‘tailored’ anti-platelet
therapy. As such, a multitude of platelet function tests have been utilised as a potential means of monitoring anti-platelet therapy. However, to date, no studies have
convincingly demonstrated that the tailoring of anti-platelet therapy, in patients taking aspirin and clopidogrel, in response to platelet function testing is associated
with clinical benet. Despite this, platelet function testing remains widely performed. Table 11.2 summarises the currently employed platelet function tests.
Table 11.2 Summary of common platelet function tests
Platelet function test Method Limitations
Light transmission
aggregometry
VerifyNow assay Point of care test detecting changes in
PFA-100 Measures time to aperture closure by
VASP phosphorylation
assay
Thromboelastography
(TEG)/rotational
thromboelastography
(ROTEM)
Flow cytometry Measures the binding of uorescence
Platelet agonists added to platelet rich
plasma with changes in the optical
transmission of light measured as a read
out of platelet aggregation
light transmission, after the addition of a
platelet agonist, as a marker of platelet
aggregation. Different assays available for
the evaluation of platelet inhibition in
response to aspirin, P2Y12 inhibitors and
GPIIb/IIIa inhibitors
platelet aggregates formed under shear
Flow cytometry based assay that
indirectly measures the degree of P2Y12
receptor inhibition
Measures viscoelastic properties of whole
blood clot formation
labelled activation-specic antibodies to
platelets. Allows the simultaneous
assessment of GPIIb/IIIa activation,
platelet degranulation and plateletleukocyte aggregate formation
Lack of standardisation
results in signicant
inter-laboratory variability
No normal values
Time consuming
Expensive
Lack of clinical data
demonstrating improved
clinical outcomes
Not sensitive to the effects
of aspirin or P2Y12
inhibitors
Insensitive to low levels of
P2Y12 inhibition
Requires specialised
equipment and skilled
personnel
Questionable specicity
and sensitivity to the
effects of aspirin and
P2Y12 inhibitors
Expensive
Requires expertise
Access mainly limited to
research settings
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