ISBT Science Series (2019) 0, 1–11

© 2019 International Society of Blood Transfusion

INVITED REVIEW DOI: 10.1111/voxs.12529

Anti-platelet agents: past, present and future

Dermot Cox
Molecular & Cellular Therapeutics, Royal College of Surgeons in Ireland, Dublin, Ireland

Received: 12 July 2019,
revised 22 August 2019,
accepted 27 August 2019
The discovery of the role of platelets in cardiovascular disease led to the intro-
duction of aspirin as a therapeutic agent for heart disease. Aspirin has proven to
be effective in preventing cardiovascular events but the fact that not all patients
benefit from aspirin has led to the search for more effective agents. Numerous
agents have been discovered including thromboxane synthase inhibitors, phos-
phodiesterase inhibitors, GPIIb/IIIa antagonists, P2Y12 antagonists and PAR-1
antagonists. However, all faced two challenges – their cost-benefit relationship in
comparison with aspirin and the risk of bleeding that is often associated with
greater efficacy. In this paper, I review the performances of these different classes
of anti-platelet agent and discuss the potential future for novel anti-thrombotics.
I also highlight the role of platelets in immunology and discuss the potential for
targeting the immune properties of platelets.
Key words: anti-platelet agents, aspirin, GPIIb/IIIa antagonists, P2Y12 inhibitors,
immunology, thrombosis, FcgammaRIIa, infection.

the latest technologies including genomics and pro-

Introduction
The discovery of the role of platelets in thrombosis and
the realization that this was a major factor in the patho-
genesis of a myocardial infarction clearly identified plate-
lets as a very significant drug target [1]. As
cardiovascular disease is the major cause of death in the
world this has led to major pharmaceutical industry
resources being committed to developing the ultimate
anti-platelet agent especially since it is a lifelong chronic
disease affecting a large number of people worldwide.
This search for the perfect anti-platelet agent has been
on-going for 50-years and has been affected by the major
changes in the drug discovery process. Anti-platelet
agents were initially discovered by anecdote – where
drugs known to cause bleeding as a side-effect were used.
Some agents were discovered using chemistry-led drug
discovery – where drugs were screened for in vivo anti-
thrombotic activity with no knowledge of how they
worked. More recently, drugs were discovered by target-
led discovery strategies where drugs were designed to tar-
get specific platelet receptors/enzymes. Currently, all of
Correspondence: Prof Dermot Cox, MCT, Royal College of Surgeons in
Ireland, 123 St Stephens Green, Dublin D2, Ireland
Email: dcox@rcsi.ie
teomics have been deployed to discover the ultimate anti-
platelet agents. Below I will review the mechanism of
action of the different anti-platelet agents and discuss
their clinical effectiveness. I will also discuss the proper-
ties of the ultimate anti-platelet agent and whether it is
worth pursuing this elusive goal.
Inhibition of COX pathway
Aspirin
The first successful anti-platelet agent was aspirin [2]
which was discovered based on anecdotal accounts of
bleeding being associated with its use [3]. The long path
to understanding the mechanism of action of aspirin also
provided great insight into platelet function. The key dis-
covery that aspirin inhibited prostaglandin synthesis [4]
allowed some of the key signalling pathway in platelets
to be characterised (Fig. 1)[5].
Platelet activation by most agonists leads to the activa-
tion of phospholipase A2 which cleaves arachidonic acid
from the inner platelet membrane [6]. This arachidonic
acid is a substrate for cyclooxygenase (COX) which con-
verts it into prostaglandin (PG) H2. PGH2 is in turn con-
verted into thromboxane (Tx) A2 – a powerful platelet

1
2 D. Cox
Fig. 1 Platelet activation pathways and the sites of action of anti-platelet agents.
agonist – by the enzyme thromboxane synthase. This cre-
ates a feedback loop where the secreted TXA2 activates
further platelets. Aspirin (acetylsalicylic acid) is an irre-
versible inhibitor of COX – it binds to Ser530 in the cat-
alytic site and acetylates it. As a result, arachidonic acid
cannot gain access to the catalytic site [7].
Aspirin effectiveness
There are many ways of assessing effectiveness of anti-
platelet agents such as mortality (30 days or 90 days) and
further cardiovascular events. Often a combined triple
endpoint of death, myocardial infarction (MI) or urgent
revascularization (e.g. need for stenting) is used. There
have been many studies that have shown that aspirin is
clinically effective in cardiovascular disease. In particular,
a major meta-analysis by the Antithrombotic Trialists
Collaboration in 2002 clearly showed a reduction of
around 25% in the event rate [8]. The benefit was found
in both stroke and MI patients.
Aspirin resistance
The fact that the benefit of aspirin is only about 25% at
best led to the concept of aspirin resistance [9]. In other
words, some patients fail to respond to aspirin and these
© 2019 International Society of Blood Transfusion, ISBT Science Series (2019) 0, 1–11
patients do worse and would benefit from alternative
treatments. It is obvious that if a patient does not respond
to aspirin they will not get its benefit and as a result will
have a worse prognosis. This in fact has been well estab-
lished in a meta-analysis [10]. However, the big question
is what exactly is aspirin resistance and how should it be
detected?
There are a number of different types of aspirin resis-
tance: pharmacodynamic, pharmacokinetic and clinical
[11,12]. These are masked by factors such as non-compli-
ance and drug–drug interactions due to poly-pharmacy.
All of this is dependent on the assay that is used to detect
aspirin resistance.
Non-compliance. Like any other medication, aspirin
only works when patients take it. As aspirin is usually
used after an MI, it would be expected that patients
would be motivated to take it. However, there is a signifi-
cant level of non-compliance among cardiovascular
patients in general [13]. Non-compliance with anti-
thrombotics has been found to be around 18% [14]. There
are a number of reasons for this non-compliance. Patients
are usually on multiple medications with different dosing
regimens, and this can easily lead to confusion. This

problem can be resolved by using blister packaging where
all of the tablets for a specific time are in a single pack-
age [13]. Another problem is lack of knowledge. Patients
often think that aspirin is not important as it is available
in supermarkets! However, in our experience education is
helpful here. This involves a nurse, doctor or pharmacist
explaining to the patient what aspirin does and why it is
so important. Another reason for non-compliance is
adverse effects. A patient may stop taking aspirin as it
upsets their stomach. It is important to identify this and
provide appropriate treatment such as a co-administration
of a proton pump inhibitor or misoprostol [15].
Pharmacodynamic resistance occurs where there are
detectable levels of aspirin in the blood but no detectable
pharmacological response. A number of studies have
shown evidence of true resistance to aspirin often due to
polymorphisms in COX [16] or other platelet enzymes/re-
ceptors [17] and reviewed by Goodman et al. [18]. How-
ever, the incidence of this resistant phenotype seems to
be low. Studies where patients weight is taken in consid-
eration show that all patients respond suggesting that the
incidence of pharmacodynamic resistance is likely to be
less than 1% [19,20].
Pharmacokinetic resistance occurs when a patient takes
their aspirin and there is no detectable aspirin in the
blood. This appears to be the major cause of aspirin non-
response after non-compliance. Primarily, it is due to
under-dosing. Most patients are on low-dose enteric-
coated aspirin but this is not bioequivalent with plain
aspirin [21,22]. In fact, different preparations of enteric
coating are not even bioequivalent with each other [23].
This reduced bioavailability of enteric-coated aspirin is
particularly a problem in heavier patients where aspirin
dose (mg/kg) is likely to fall below the minimum effective
dose [19]. While it is know that evidence for aspirin non-
response is assay-dependent with very poor agreement
between different assays the association of weight with
poor response appears to be true with all assays [24]. A
further cause of pharmacokinetic resistance is drug–drug
interactions. Both non-steroidal anti-inflammatories
(NSAIDs) and aspirin bind to the same site on COX; how-
ever, NSAIDs are reversible inhibitors while aspirin is
irreversible. Aspirin has a very short half-life while
NSAIDs have much longer half-lives. If a patient takes an
NSAID before aspirin then the aspirin cannot bind to
COX and is cleared from the circulation [25]. This can be
resolved by taking aspirin an hour or two before NSAIDs.
A similar problem can exist with statins [26].
Clinical resistance occurs when a patient has a cardio-
vascular event while on aspirin. If laboratory tests show
that the patient’s platelets are fully inhibited by aspirin
this is not aspirin resistance. It is evidence that the
patient had a cardiovascular event that is platelet-
© 2019 International Society of Blood Transfusion, ISBT Science Series (2019) 0, 1–11
Future of anti-platelet agents 3
independent or a platelet-mediated event that is COX-in-
dependent. Platelet agonists can be classed into weak
agonists which act through COX and strong agonists such
as thrombin which activate platelets through phospholi-
pase (PL)C-mediated cleavage of inositol triphosphate
(IP3) and diacylglycerol (DAG) from the membrane. IP3
binds to an intracellular Ca2+ channel increasing intracel-
lular Ca2+ levels through release from the endoplasmic
reticulum. DAG ultimately activates protein kinase C
which activates further downstream events [5]. Clearly,
activation through this pathway will not be affected by
aspirin. Furthermore, many agonists work through both
pathways – COX activation at low doses and PLC activa-
tion at high doses. The existence of this alternative path-
way has led to the search for the next-generation anti-
platelet agent.
Targeting thromboxane
One approach to dealing with aspirin resistance was to
target other parts of the PLA2 signalling pathway. Two
targets that were selected were the downstream enzyme
thromboxane synthase which like aspirin would totally
block the synthesis of thromboxane A2. The other target
was the thromboxane A2 receptor which could be blocked
with small molecule antagonists. Some agents were also
discovered that had activity on both the thromboxane
synthase enzyme and receptor [27].
Neither thromboxane receptor antagonists (e.g. seratro-
dast, terutroban) nor synthase inhibitors have shown ben-
efit over aspirin. So, while effective they could never
compete with aspirin on cost. This is not surprising. Once
issues of weight and aspirin bioavailability are taken into
consideration virtually all patients show complete inhibi-
tion (>97% inhibition) of thromboxane production [21].
Thus, blocking either the thromboxane synthase enzyme
or receptor is likely to achieve more than 97% inhibition
and unlikely that any further inhibition would be clini-
cally relevant.
GPIIb/IIIa antagonists
As the thrombi that precipitate an MI are platelet-rich
this led researchers to investigate how these thrombi are
formed. The discovery that the platelets in these thrombi
are bound together by fibrinogen binding to specific
receptors on platelets led to the prospect for a new class
of anti-thrombotic agent. As fibrinogen is a divalent
molecule, when it binds to its receptor on two different
platelets it cross-links them which is the basis of platelet
aggregation. In the mid-1980s, the platelet receptor for
fibrinogen was identified as a heterodimer of glycopro-
teins (GP) IIb and IIIa [28,29]. It soon became clear that
4 D. Cox
GPIIb/IIIa was a member of the expanding super-family
of integrin cell adhesion molecules (aIIbb3). GPIIb/IIIa
was a drug target with excellent potential as fibrinogen
binding to GPIIb/IIIa was considered to be the final step
in platelet aggregation. Thus, no matter how platelets
were activated, fibrinogen binding to GPIIb/IIIa was
always going to occur. As a result, these agents were
referred to as ‘super-aspirin’ in the media. Furthermore,
the fibrinogen sequence that supported binding was iden-
tified as Arg-Gly-Asp (RGD) [30] which provided a hit
compound for a drug discovery programme. In one of the
first examples of target-led drug discovery, multiple com-
panies set out to discover GPIIb/IIIa antagonists.
The first GPIIb/IIIa antagonist was abciximab, a mono-
clonal antibody directed against the GPIIIa subunit and
was one of the first monoclonal antibodies to be commer-
cialized [31]. A second approach used the fact that viper
venoms contain very potent RGD-containing GPIIb/IIIa
antagonists (disintegrins) [32] which are used to prevent
clot formation after a snake bite. Using these as the start-
ing point led to the discovery of the cyclic-peptide eptifi-
batide [33] and the non-peptide tirofiban [34]. These
agents all act by binding to GPIIb/III thereby preventing
fibrinogen from binding.
As most MI patients would be given aspirin prior to
arriving at hospital it was clear that clinical trials with
aspirin na€ıve patients would be too difficult aspirin was
co-administered with the GPIIb/IIIa antagonist in all clin-
ical trials. As a result, they are clinically used with
aspirin.
The clinical trials with these agents were very successful
for MI, and a meta-analysis confirmed that they were more
effective than aspirin alone [35]. However, as none of these
agents were orally active their market was always going to
be restricted to the acute management of MI. In stroke,
these agents were found to have little clinical benefit with
increased bleeding risk [36]. At their peak, none of the
agents had annual sales of more than $300 million and by
2012 the combined sales for all three agents were less than
$250 million. Currently, they are only used in certain high-
risk situations [37] and thus far from being a commercial
blockbuster.
The solution to this problem was to develop orally
active agents. Using RGD as a hit compound led to the
discovery of xemilofiban and orbofiban [38]. Screening
small molecule libraries led to sibrafiban [39] and the dis-
covery that pentamidine had anti-GPIIb/IIIa activity
[40,41] led to the discovery of FK633 [42,43]. However,
there were surprising results in the clinical trials of all of
these agents. Rather than showing a benefit similar to the
IV compounds a meta-analysis showed that all of these
compounds led to an increase in cardiovascular mortality
[44].
© 2019 International Society of Blood Transfusion, ISBT Science Series (2019) 0, 1–11
The reason for the failure of the oral activity is multi-
factorial [45,46]. At the heart of the problem is the fact
that all of the agents trigger platelet activation by bind-
ing to GPIIb/IIIa [47,48]. Initially, GPIIb/IIIa appeared to
be a simple adhesion molecule but it was subsequently
shown that it is a true receptor and binding agonist (RGD
is the natural agonist, and most small molecules are ana-
logues) leads to platelet activation [49]. This was further
complicated by low bioavailability and poor pharmacoki-
netics which led to significant under-dosing. As a result,
all orally active GPIIb/IIIa antagonists were dropped.
P2Y12 antagonists
With the failure of GPIIb/IIIa antagonist, there was still a
need for a drug to take over from aspirin. One possibility
was ticlopidine [50]. This agent was discovered through a
chemistry-led drug discovery programme. Thus, it had
been discovered to be an anti-thrombotic in vivo although
it had no activity in vitro. It was not known how it
worked. While clinically effective, its side-effect profile
was a problem especially the neutropenia [51,52]. How-
ever, with the failure of oral GPIIb/IIIa antagonist it now
became the centre of attention.
Further studies on ticlopidine showed that it was a
pro-drug and that it was metabolized into an active agent
that bound irreversibly to an ADP receptor on platelets –
P2Y12. Retaining the active component, a new pro-drug
was developed. This was clopidogrel and is metabolized
to the active form by cytochrome P450 enzymes in the
liver. It has the advantage over ticlopidine of not causing
neutropenia [53].
There was initial scepticism about targeting P2Y12 as it
was only one receptor on platelets. While GPIIb/IIIa
antagonists had the potential to block aggregation due to
any agonist, clopidogrel was restricted to ADP activation
only – what about collagen, thrombin etc.? Furthermore,
P2Y12 was a weak agonist and not even the only ADP
receptor as there was also a P2Y1 receptor as well [54].
However, it turns out that once activated platelets secrete
ADP from their granules and this ADP activates other
platelets via P2Y12 thereby recruiting them into the
growing thrombus. Thus, P2Y12 is a critical receptor in
thrombosis [55].
The importance of P2Y12 in thrombosis has been sup-
ported by the many clinical trials that have shown that
clopidogrel is a very effective anti-platelet agent for acute
patients [56] and patients undergoing percutaneous coro-
nary intervention (e.g. angioplasty and stenting) [57],
although it is probably no better than aspirin for stable
disease [58]. Similar to GPIIb/IIIa antagonists, it is not a
replacement for aspirin and is normally used as part of
dual-therapy with aspirin. Clopidogrel became the 2nd

biggest selling drug with annual sales of $9 billion in
2010.
Clopidogrel resistance
While highly successful it soon became clear that some
patients failed to respond to clopidogrel therapy. It was
subsequently found to be due to a failure to convert
clopidogrel into the active form. This is due to a poly-
morphism in the CYPP450 enzymes that metabolize clopi-
dogrel. Patients with the polymorphism are under-
expressers of the enzyme and thus fail to respond to
clopidogrel [59].
Prasugrel was one solution to this problem. It was the
same active agent as clopidogrel but a different pro-drug
that was not affected by the CYP450 polymorphisims
[60]. While a very effective agent with no evidence of
resistance it had one major drawback – price. Clopidogrel
is off-patent and as a result much cheaper than the newer
prasugrel. Because of the pressures of drug pricing health
authorities preferred to use clopidogrel as first line and
restrict prasugrel to confirmed cases of clopidogrel resis-
tance. As a result, by 2016 annual sales of prasugrel were
only $500 million, far below the expected sales.
Another approach to the problem of clopidogrel resis-
tance was to develop direct inhibitors of P2Y12. These
were not pro-drugs and were reversible. Reversibility had
a major advantage during intervention. Clopidogrel was
the drug of choice for use during stenting but sometimes
there are complications during stenting, and the patient
needs to go for by-pass surgery. However, surgeons are
often reluctant to operate on a clopidogrel-treated patient,
and as an irreversible inhibitor, it can take some time for
its effects to be reversed or require a platelet transfusion
[61]. A reversible antagonist would have the advantage of
rapid reversibility and thus ideal for use during interven-
tion. Ticagrelor and cangrelor are reversible antagonists
of P2Y12 [62]. Ticagrelor has proven to be more effective
than prasugrel in diabetes [63] and probably than clopi-
dogrel as well [64] and has achieved blockbuster status
with sales in excess of $1 billion annually. On the other
hand, the future of cangrelor is uncertain [65].
Phosphodiesterase inhibitors
As an MI is due to unwanted platelet activation, it is
important that the body has systems to prevent this
unwanted platelet activation. This is achieved through
another prostaglandin – prostacyclin (PGI2). It binds to
Gas receptor on platelets leading to an increase in cAMP
production by adenyl cyclase. This in turn leads to the
activation of Protein kinase A (PKA) which phosphory-
lates many downstream proteins. Protein phosphorylation
© 2019 International Society of Blood Transfusion, ISBT Science Series (2019) 0, 1–11
Future of anti-platelet agents 5
by PKA inhibits platelet activation [66]. While PGI2 and
its analogues are potent anti-platelet agents they are also
potent vasodilators and this vasodilatory activity is very
unpleasant for patients and thus they are not clinically
used as anti-platelet agents. Another natural anti-platelet
agent is nitric oxide (NO) produced by the endothelium. It
diffuses into the platelet where it activates a soluble gua-
nyl cyclase leading to an increase in cGMP. This in turn
activates PKG leading to downstream protein phosphory-
lation [67].
Both cAMP and cGMP are metabolized by phosphodi-
esterase (PDE). Cilostazol is a PDE3 inhibitor, and by
blocking PDE, it prolongs the activity of cAMP and thus
is an effective anti-platelet agent [68]. Clinical trials have
supported the effectiveness of cilostazol [69]. Another
agent with PDE inhibitory activity is dipyridamole which
is primarily used for the treatment of stroke [70].
Protease-activated receptor (PAR) inhibitors
Activation of the coagulation system generates thrombin
which is a very potent platelet activator. Thrombin is a
proteolytic enzyme and acts on a unique family of pro-
tease-activated receptors (PAR). Thrombin cleaves a ter-
minal peptide from the receptor, and the newly exposed
terminal becomes the agonist peptide and binds to the
binding site. There are four members of the family, and
two (PAR-1 and PAR-4) are expressed on human plate-
lets. PAR receptors are G-protein-coupled receptors, and
their activation leads to platelet activation via PLC and
thus is independent of aspirin [71]. This led to the devel-
opment of specific inhibitors of PAR-1 for use as anti-
platelet agents [72]. Vorapaxar [73] and atopaxar are two
such agents and have been shown to be effective in clini-
cal trials [74]. However, there is no evidence that they are
more effective than other agents and have a bleeding risk
associated with them. There is also interest in developing
PAR-4 antagonists as anti-platelet agents [75]. As PAR 1
and 4 are not restricted to platelets some of the potential
beneficial effects of these agents may be due to inhibition
of PAR on other cells.
Most effective anti-platelet agent
Recently network meta-analyses have been published that
compared multiple anti-platelet regimens for effective-
ness. In the case of stroke, both cilostazol and clopidogrel
were found to reduce stroke recurrence and composite
events compared to aspirin or dipyridamole. Dipyridamole
was found to have a good safety profile but had poor
efficacy. Combining clopidogrel with aspirin improved
efficacy but increased bleeding risk [76]. In the case of
MI, all of the agents and combinations of agents were
6 D. Cox
found to be more effective than placebo. However, when
compared to aspirin mono-therapy none of the agents
were more effective except for the addition of the factor
X inhibitor rivaroxaban to the clopidogrel/aspirin combi-
nation [77].
Improved anti-platelet agents
So, with the clear effectiveness of existing anti-platelet
agents and with at best incremental increases in efficacy
of newer agents the search for newer agents has focused
on developing agents that are effective without causing
bleeding [78–80]. Experience would suggest that this is a
difficult proposition. All of the studies have shown that
effectiveness of anti-platelet agents is directly associated
with increased bleeding risk. So, is it possible to discover
an agent that inhibits the thrombotic pathways but not
the haemostatic pathways?
In theory, this is possible. GPIb is the von Willebrand
factor (VWF) receptor on platelets. It plays an important
role in the adhesion of platelets to the damaged endothe-
lium as well as subsequent platelet activation [81]. This is
an important first step in thrombosis formation, and what
makes it an important drug target is that this interaction
only occurs under high shear conditions. Thus, it does
not play a significant role in the venous system or in a
healthy arterial system. It is particularly important in ste-
nosed arteries such as atherosclerotic coronary arteries.
Thus, a GPIb antagonist has the potential to block throm-
bosis in atherosclerotic vessels and not healthy vessels
and thus have little impact on bleeding [82,83] although
Bernard-Soulier disease (deficiency in GPIb) is associated
with a bleeding tendency [84]. However, over the last
30 years researchers have been trying to discover GPIb
antagonists and none progressed to the market. It is not
clear why all of these projects failed and whether it is
ever going to be possible to develop such an inhibitor.
However, the cost of developing new agents is very
high. Most of the agents have produced only modest ben-
efits over aspirin and thus hard to justify their cost. Cur-
rently, a combination of aspirin and clopidogrel is very
effective and inexpensive. Some of the other agents such
as prasugrel and ticagrelor while expensive can be used
for those patients that fail to respond in combination with
a CYP450 screening assay [85]. With the cost of a suc-
cessful drug discovery programme at approximately $1
billion, it is hard to see how a new anti-thrombotic dis-
covery programme is financially viable.
Novel anti-platelet agents
While platelets are critical components of haemostasis
that is not their only function. Recently, there is a
© 2019 International Society of Blood Transfusion, ISBT Science Series (2019) 0, 1–11
growing awareness that platelets are key components of
the immune system. This is clear in that they express
immune-associated receptors such as Toll-like receptors
(TLR), FccRIIa and CLEC-2 on their surface [86,87]. These
receptors have been shown to be functional on platelets
and engagement of these receptors leads to platelet acti-
vation. However, the activation pathways associated with
these receptors is different to that of the haemostasis-as-
sociated receptors. The nature of the activation is also dif-
ferent [88,89]. For instance, TLR-mediated activation of
platelets does not seem to trigger platelet aggregation
unlike that seen with ADP or thrombin. Instead TLR-me-
diated activation of platelets leads to platelet binding to
neutrophils which leads to the formation of neutrophil
extracellular traps (NET) [90].
Activated platelets also lead to secretion of antimicro-
bial peptides that kill bacteria [91]. When there is a
breach in the vasculature (a cut for instance), platelets are
the first responders binding to the exposed extracellular
matrix and forming platelet aggregates to prevent further
blood loss. They also secrete antimicrobial peptides to
sterilize the area and also secrete chemokines and cytoki-
nes that attract immune cells to the area and activate
them.
While this immune regulatory activity of platelets is
very important it can sometimes cause problems. When
bacteria gain access into the blood they start to grow
causing a bacteraemia. This leads to platelet activation
and secretion of antimicrobial peptides. However, some
strains of bacteria are resistant to platelet-derived antimi-
crobial peptides. In this case, the bacteria continue to
grow and platelets continue to become activated. These
activated platelets either get cleared in the spleen or form
aggregates. The result of the continued bacterial growth
and continued platelet activation leads to thrombocytope-
nia. Platelet aggregate formation can lead to clot forma-
tion in the microvasculature, a condition known as
disseminated intravascular coagulation (DIC). This can
lead to ischaemic damage which as it spreads causes
organ failure as the bacteraemia progresses to sepsis. Pla-
telet granules are full of serotonin, and the ongoing pla-
telet activation causes the release of large quantities of
serotonin which causes vasodilation ultimately leading to
septic shock [92].
The key role of platelets in the pathogenesis of sepsis is
clear from meta-analysis of anti-platelet agents in sepsis
although the conclusions are limited by the fact that the
studies are all retrospective. A network meta-analysis of
critically ill patients showed an odds ratio of 0
81 for in-
hospital mortality in patients on anti-platelet agents. The
OR for sepsis was 0
81 as well, and the mortality benefits
were associated with sepsis [93]. This is despite the fact
that the primary reason for being on an anti-platelet

agent is for secondary prevention of MI or stroke. Thus,
these patients did better despite being sicker. A study of
over 500 000 insurance patients showed that prior use of
aspirin was associated with between 2% and 12% reduc-
tion in mortality [94]. This is not far from the benefit of
aspirin in cardiovascular disease.
Platelets are also involved with the immune response
to viral infections. Viruses such as HIV bind to platelets
leading to thrombocytopenia. There are also the viral
haemorrhagic fevers (VHF), which are viral infections due
to four families of viruses – Arenaviridae, Bunyaviridae,
Filoviridae and Flaviviridae. These include viruses such as
Dengue, Ebola, Yellow fever and Lassa. These are all asso-
ciated with thrombocytopenia and can cause a coagu-
lopathy similar to DIC in sepsis [95,96].
In both sepsis and VHF, the DIC is a major contributor
to mortality and morbidity. Managing the coagulopathy
is an important strategy in treating patients. In the case
of sepsis, there can be a significant delay in identifying
the appropriate antibiotics especially with the growing
incidence of antibiotic resistant strains of bacteria. By
controlling the coagulopathy, an anti-platelet agent can
buy time to identify the best antibiotic to use. In the case
of VHF, there are no drugs but if patients survive the
coagulopathy their immune system can clear the infec-
tion. An anti-platelet agent may play a key role in
managing the VHF DIC.
The problem with using anti-platelet agents in sepsis/
VHF is that by their very nature they inhibit platelet
function and thereby increase the risk of bleeding. In a
patient with thrombocytopenia due to infection this
increased bleeding risk is much more significant. Thus,
anti-platelet agents preserve platelet number over platelet
function. However, as both viruses and bacteria activate
platelets using receptors entirely distinct from those that
mediate haemostasis it would be possible to discover
agents that inhibit pathogen-induced platelet activation
only.
Virtually, all bacteria that have been shown to acti-
vate platelets do so in an FccRIIa-dependent manner and
blocking FccRIIa has been shown to prevent the platelet
activation [97]. This is true of both Gram-positive bacte-
ria such as Staphylococcus aureus [98], Streptococcus
sanguinis [99] and Streptococcus gordonii [100] and
Gram-negative such as Escherichia coli [101] and Heli-
cobacter pylori [102]. There are two approaches to
inhibiting FccRIIa – monoclonal antibodies and small
molecules. Currently, an anti-FccRIIa monoclonal anti-
body is entering phase I clinical trials [103]. Small mole-
cule antagonists have been discovered and while they
may not have sufficient potency to be used clinically it
shows that small molecules have the ability to block the
receptor [104].
© 2019 International Society of Blood Transfusion, ISBT Science Series (2019) 0, 1–11
Future of anti-platelet agents 7
With viruses, it is more complex as there are multiple
receptors involved [95]. FccRIIa certainly mediates some
virus-platelet interactions such as with Dengue [105].
Other key receptors are DC-SIGN [105], CLEC-2 and TLRs
[106]. Unlike bacteria-platelet interactions, there has been
little research into virus-platelet interactions partly
because some of the viruses such as VHF viruses require
BSL4 conditions and thus are very difficult to work with.
However, with future research in this area it should be
possible to better characterize virus-platelet interactions
and identify novel targets.
Conclusions
Anti-platelet drug discovery has been an area of mixed
results. Aspirin, a drug known for centuries proved to be
an effective agent for treatment of cardiovascular disease
and despite all of the money spent of drug discovery in
this area it is still the most important agent in clinical
use. Identified as a COX inhibitor, all attempts to generate
improved agents that target the COX pathway have failed
to produce an agent with an improved cost-benefit pro-
file. GPIIb/IIIa antagonists were the next category of anti-
platelet agent that promised that target-led drug discov-
ery could produce a new super-aspirin. However, while
showing a small clinical benefit over aspirin their lack of
oral activity and increase in bleeding has meant that they
are a niche class of drugs used for high-risk interventions
only. P2Y12 antagonists are the real success story in
thrombosis. Using a chemistry-led approach, ticlopidine
was discovered and further refined to improve its safety
profile leading to clopidogrel. At its peak, it was the 2nd
biggest selling drug in the world and now that it is off-
patent it is the drug of choice for prevention of events
post-stenting although usually used in conjunction with
aspirin. Further attempts to improve on clopidogrel failed
on the cost-benefit profile although ticagrelor as a rever-
sible P2Y12 antagonist has been a commercial success.
Thus, it is clear that the biggest hurdle for any new anti-
platelet agent is the cost-benefit profile in comparison to
aspirin/clopidogrel combination. While there maybe
agents that work better when this combination does not
work this will always be a minor market.
The other big challenge in anti-thrombotic therapy is
the safety profile. While some agents such as ticlopidine
have specific adverse effects the increased risk of bleeding
is common to all anti-platelet agents. Bleeding risk is a
problem with aspirin, especially cerebral bleeding, and as
a result, it is primarily used for secondary prevention
[107]. The ideal anti-platelet agent would be one that tar-
gets thrombosis over haemostasis and would thus mini-
mize the bleeding risk. However, while many agents have
promised to deliver in this area none have been
8 D. Cox
successful. While, theoretically possible it remains to be
seen if such an agent can be discovered that also has a
good cost-benefit profile compared with aspirin/clopido-
grel.
So, while the cost-benefit and safety profiles are the
two biggest challenges for a new anti-platelet agent there
remains one area where there is scope for drug discovery.
There is significant evidence that platelets are significant
players in the immune system where they play a major
role in the response to infection (DIC). Considering that
sepsis is the number one cause of in-hospital mortality
there is the potential for commercial success in this thera-
peutic area. As the receptors involved in the immune
functions of platelets are not involved in haemostasis any
agent targeting them would be unlikely to cause bleeding
problems. These novel agents would also be highly speci-
fic for pathogen-mediated platelet activation and thus
likely more effective than aspirin/clopidogrel. Thus, drugs
that target the immune function of platelets are most
likely to be cost-effective with a good safety profile.
Conflict of interests
The author declare no conflict of interests.
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