Thrombosis Research 133 (2014) 131–138

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Thrombosis Research
journal homepage: www.elsevier.com/locate/thromres

Mini Review

Use of antiplatelet agents in sepsis: A glimpse into the future

Karolina Akinosoglou a,⁎, Dimitrios Alexopoulos b
a
Department of Internal Medicine, University General Hospital of Patras, 26504, Rio, Greece
b
Department of Cardiology, University General Hospital of Patras, 26504, Rio, Greece

a r t i c l e i n f o a b s t r a c t

Article history: As mechanisms of sepsis pathophysiology have been elucidated with time, sepsis may be considered nowadays,
Received 7 June 2013 as an uncontrolled inflammatory and pro-coagulant response to a pathogen. In this cascade of events, platelets
Received in revised form 4 July 2013 play a key role, via interaction with endothelial cells and modulation of both innate and adaptive immune
Accepted 8 July 2013
system. In that manner, inhibition of platelet function could represent a useful tool for attenuating inflammatory
Available online 6 October 2013
response and improving outcomes. Data on current antiplatelet agents, including acetylsalicylic acid, P2Y12
Keywords:
inhibitors and GPIIb/IIIa antagonists, in animal models are promising. Clinical data in patients hospitalized for
Antiplatelet agents pneumonia, at risk for acute lung injury, and/or critically ill revealed an association between antiplatelet therapy
Platelets and reduction in both short-term mortality and prevalence of acute lung injury, as well as, the need for intensive
P2Y12 inhibitors care unit admission, without a concomitant increased bleeding risk. In need of innovative approach in the treat-
Sepsis ment of sepsis, further prospective, interventional, randomized trials are pivotal to establish potential use of
GPIIb/IIIa antagonists antiplatelet agents in this context.
© 2013 Elsevier Ltd. All rights reserved.

Contents

Introduction . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 131
Role of Platelets in Sepsis . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 132
Antiplatelet Agents in Sepsis . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 132
Acetylsalicylic Acid (ASA) . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 132
P2Y12 Inhibitors . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 133
GPIIb/IIIa Antagonists . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 136
Issues to be Considered . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 136
Conclusions . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 136
Conflict of Interest Statement . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 136
References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 136

Introduction mortality rate [1,2]. As a result, an estimated economic burden of

nearly 17 billion dollars annually in the USA, has currently been at-
Sepsis is a prevalent syndrome that carries significant morbidity tributed to sepsis [1].
and mortality. Almost 24% of patients with an admission diagnosis Activation of blood platelets is a typical finding in patients with sys-
of sepsis will progress to severe sepsis with an associated 35–50% temic inflammation and sepsis, while thrombocytopenia in critically ill

Abbreviations: ADAMTS-13, A Disintegrin And Metalloproteinase with a ThromboSpondin type 1 motif, member 13; ADP, Adenosine Diphosphate; ATP, Adenosine Triphosphate; ALI,
Acute Lung Injury; ARDS, Acute Respiratory Distress Syndrome; ASA, AcetylSaliculic Acid; ATL, 15-epi-lipoxin A4; CABG, Coronary Artery Bypass Grafting; CAP, Community Acquired
Pneumonia; COX, CyclOXygenase; CRP, C-Reactive Protein; C4b, complement component 4b; DIC, Disseminated Intravascular Coagulation; eNOs, endogenous nitric oxide synthase;
Erk1, extra cellular signal kinase 1; GP, GlycoProtein; ICU, Intensive Care Unit; IL-#, InterLeukine #; IL-10r, InterLeukine 10 receptor; iNOs, inducible nitric oxide synthase; LPS,
LipoPolySacccharide; Ltb4r, LeukoTriene b4 Receptor; MIP-1a, Macrophage inflammatory protein-1alpha; MOF, Multiple Organ Failure; NFκB, nuclear factor kappa-light-chain-enhancer
of activated B cells; NET, Neutrophil Extracellular Trap; NO, Nitrogen Oxide; PAF, Platelet Activating Factor; PLATO, PLATelet inhibition and clinical Outcomes; PMN, PolyMorphoNuclear
cells; PSGL-1, P-Selectin Glycoprotein Ligand-1; RANTES, Regulated on Activation, Normal T cell Expressed and Secreted; ROS, Reactive Oxygen Species; SIRS, Systemic Inflammatory Re-
sponse Syndrome; TCR, T-Cell Receptor; TF, Tissue Factor; TLR, Toll-Like Receptor; TNF alpha, Tumor Necrosis Factor alpha; vWF, von Willebrand Factor.
⁎ Corresponding author at: Dept of Internal Medicine, University Hospital of Patras, 26504, Rio, Greece. Tel.: +30 2610999583.
E-mail address: akin@upatras.gr (K. Akinosoglou).

0049-3848/$ – see front matter © 2013 Elsevier Ltd. All rights reserved.
http://dx.doi.org/10.1016/j.thromres.2013.07.002
132 K. Akinosoglou, D. Alexopoulos / Thrombosis Research 133 (2014) 131–138
patients is associated with poor outcome [3–5]. It has been well
established that platelets significantly contribute to organ failure via
their haemostatic and thrombotic potential, resulting in thrombotic
microangiopathy and disseminated intravascular coagulation. What is
less known however, is their involvement in the adaptive immune
response [6] as well as, their interaction with microorganisms [7]. A
number of agents including corticosteroids, tumour necrosis factor
(TNF)-alpha antagonists and interleukin 1 (IL-1) receptor antagonists,
have been suggested to potentially block the inflammatory cascade,
prevent severe sepsis and ensure better outcomes, [8]. Although data
from phase II clinical trials showed promise, larger studies have not
demonstrated any significant improvement in clinical outcomes [8].
Antiplatelet drugs including acetylsalicylic acid (ASA), and P2Y12
inhibitors are widely used in patients with cardiovascular disease for
the secondary prevention of atherothrombotic events [9]. Several stud-
ies have shown that ASA and clopidogrel not only diminish the risk of
atherothrombotic events, but also reduce markers of systemic inflam-
mation, including C-reactive protein (CRP), soluble CD62P (P-selectin)
and CD54, pro-inflammatory cytokines, and platelet-leukocyte conju-
gates [10]. It is assumed that the anti-inflammatory effects of antiplatelet
drugs are mediated by an inhibition of platelet activation [10]. Thus,
derived by the need to extend current pharmacological treatment
options, the question arises, whether drugs that inhibit platelet activa-
tion, such as ASA or P2Y12 inhibitors, may have a benefit in critically
ill patients.
This review will highlight current data on potential use of antiplatelet
agents in managing sepsis.
Role of Platelets in Sepsis
There is substantial evidence that blood platelets play an important
role in the development of multiple organ failure (MOF) in septic
patients [4,5]. During infection and systemic inflammation, platelets
become activated, as reflected by an increase in the number of CD62P-
positive platelets and platelet-leukocyte conjugates [3,5]. Different mech-
anisms have been associated with platelet activation, including imbalance
between plasma level of high molecular weight von-Willebrand factor
and - its cleavage protease - a disintegrin and metalloproteinase with a
thrombospondin type 1 motif, member 13 (ADAMTS-13), and binding
of endotoxins to specific receptors at the platelet surface [5,11]. Once
activated, the platelet alters from its normal disc-like shape to a more
spherical appearance with arm-like extensions, that facilitate adhesion
to the endothelium and to other cells [11]. Platelet/endothelium interac-
tion plays a central role in inflammatory mechanisms within the vessel
wall [12]. It has been reported that activated platelets - as occurs in
endotoxemia - aggregate and can bind to endothelial cells, despite
the presence of intact endothelium [11,13,14]. Platelet adhesion to
endothelium enhances the procoagulatory activity of endothelial cells,
subsequently impairing microcirculation and, thus, leading to hypoper-
fusion and organ dysfunction [11,15].
Platelet activation also causes the expression of cell surface receptors
and release of molecules that can amplify the immune response [11].
Namely, the initial interactions are driven by P-selectin (CD62P) on
the surface of activated platelets, which is recognised by P-selectin gly-
coprotein ligand-1 (PSGL-1) on leukocytes [3,5,11,16]. Functional cross
talk between the P-selectin-PSGL-1 pair and the leukocyte integrin
αMβ2 (Mac-1) orchestrates the molecular events necessary for leuko-
cyte recruitment, via platelet activation and the subsequent vascular
response to injury [6,11,16]. Adhesion of platelets to monocytes results
in signalling dependent transcriptional regulation, which leads to
expression of important mediators of inflammation and pro-coagulant
tissue factor (TF) [11]. Platelet surface expression of CD40L (CD154)
and its subsequent binding to the CD40 receptor may also be involved
in immune cell recruitment, chemokine production, IgM to IgG isotype
switching, and dendritic cell maturation [11].
Furthermore, platelets express toll-like receptors (TLRs), pathogen
recognition receptors involved in activation of innate immunity, in-
cluding TLR2 and TLR4 that recognize the common bacterial mole-
cules peptidoglycan and lipopolysaccharide (LPS), respectively [11].
Interactions between platelet TLR4 and LPS may contribute in throm-
bocytopenia in sepsis and pulmonary fibrin deposition [11]. Activated
platelets, particularly in the context of LPS stimulation, trigger the re-
lease of extracellular DNA traps (NETs) with proteolytic activity from
neutrophils, serving to capture and degrade microbes [11]. Thus,
immune-mediated effects of platelets may be important for the host
defence.
At the same time, platelet activation exacerbates the release of more
than 35 distinct, active compounds that are capable of modulating not
only their own function, but also that of cells around them [4,6,11].
Platelet alpha granules contain chemokines and other soluble media-
tors of inflammation such as IL-1b, regulated on activation normal T
cell expressed and secreted protein (RANTES), macrophage inflamma-
tory protein (MIP-1 alpha), monocyte chemo-attractant protein, thy-
mus and activation-regulated chemokine, and antimicrobial defensins
(thrombocidins) involved in coagulation pathways or stimulating
further platelet recruitment and attracting neutrophils and leukocytes,
which are key players in mediating ongoing inflammatory responses
such as sepsis [4,6,11]. Among them, the potent serine protease
granzyme B is expressed, resulting in cytotoxic platelets mediating
apoptosis in lung and spleen tissue [17]. Fig. 1 summarizes current
examples of activated platelets mediating immune responses.
However, the effects of certain bacterial products on platelet func-
tion have not been found to be consistent and may vary according to
species, timing of the study, location of platelets in the circulation, and
pathogenesis of sepsis [18–20]. For example, LPS has been shown to
increase platelet aggregation in various animal models [21–23], yet bac-
terial products seem to decrease human platelet aggregation in vitro
[24,25]. In a small group of 74 patients with sepsis and severe sepsis
Mavromattis et al. [26] showed that platelet aggregation increased
somewhat in patients with an uneventful course but decreased over
time in patients who developed severe sepsis. Similarly, in a series of
26 patients Boldt et al. noted decreased platelet aggregation in critically
ill patients, as later confirmed by others at a molecular level [18,27].
However, Gawaz et al. [19] described increased adhesion and activation
of platelets, even in patients in an intensive care unit (ICU).
Antiplatelet Agents in Sepsis
Acetylsalicylic Acid (ASA)
Endothelial dysfunction is one of the early signs of a systemic in-
flammatory reaction and is believed to be one of the triggers of organ
failure in sepsis [15]. ASA stimulates the synthesis of 15-epi-lipoxin
A4 (ATL), which in turn increases nitric oxide synthesis through endo-
thelial and inducible nitric oxide synthase [28]. Nitric oxide inhibits
the interactions between leucocytes and endothelial cells, resulting in
decreased polymorph neutrophil recruitment [28] (Fig. 2). Contrary to
findings in models of endotoxemia [29,30], low doses of aspirin seem
to inhibit platelet activation and have anti-inflammatory effects in
patients with coronary heart disease. The latter include decrease in
the expression of pro-inflammatory mediators including TNF, IL-6, TF,
or up-regulation of NFkB, a central transcription factor in inflammation
and cell death regulation.[10] (Fig. 2).
Several studies evaluating aspirin for the treatment of sepsis in
animal models, have suggested a potential benefit [31,32]. Recently,
Derhaschnig et al. [33] evaluated the effects of aspirin and a
nitroderivative of aspirin (NCX-4016) on platelet function in healthy
volunteers after infusion of endotoxin. NCX-4016 acts through COX in-
hibition and nitric oxide release, thus, reducing thrombin induced
platelet activation more effectively than ASA [34,35]. Interestingly,
while NCX-4016 had virtually no effect on platelet function, aspirin
 K. Akinosoglou, D. Alexopoulos / Thrombosis Research 133 (2014) 131–138 133

TCR

Platelets promote the activation of MHC

PAF
thrombin Gram (-) monocytes & dendritic cells through
T cell
bacteria CD40–CD154 interactions
DC
ADAMTS-13
vWF αiib/β3
DC activation increases antigen
presentation to T cells

Activated
LPS Platelets produce cytokines
platelet
& chemokines & promote
Circulating
neutrophil activation
platelets TLR4
PAF
RANTES
thrombocidins
CD154
IL-1b
TL4 expressing platelets PMN
present LPS to neutrophils
CD40
and promote their activation MIP-1a

P
Platelets mediate WBC rolling,
adhesion, arrest in the flowing
blood, & emigration
Platelets promote neutophil Platelet expressed
formation of NETs which selectins promote
trap free bacteria ROS
neutrophil tethering

Activated neutrophil PSGL-1

generate ROS that damage
the endothelium
Mac-1 Selectin
Sel

GPIba
Endothelial cell Damaged endothelium
Fibrin

Fig. 1. Activated platelets can mediate cell–cell interactions and affect innate immune responses. Platelet activation by thrombin, collagen, ADP, platelet-activating factor (PAF) and
other agonists including LPS leads to platelet–platelet aggregation. A variety of factors with inflammatory and adaptive immune functions, are released and/or surface displayed,
promoting among others heterotypic aggregates. Examples of how activated platelets can mediate cell–cell interactions and affect innate immune responses include a) Following
binding to LPS, platelets may directly kill the bacteria by producing thrombocidins or by aggregating around them and directing neutrophils to extrude their DNA. Neutrophil
extracellular traps (NETs) are formed, that stretch downstream and finally eliminate bacteria, b) activated platelets promote neutrophil tethering and activation through the
expression of selectins, CD154 (also known as CD40L), secretion of inflammatory cytokines and chemokines, c) platelets can also promote the activation of monocytes and dendritic
cells (DCs), particularly through CD40–CD154 interactions. This leads to increased antigen presentation to T cells and enhances adaptive immune responses. ADAMTS-13: A
Disintegrin And Metalloproteinase with a ThromboSpondin type 1 motif, member 13; PAF:Platelet Activating Factor; RANTES: Regulated on Activation, Normal T cell Expressed
and Secreted; MIP-1a: Macrophage inflammatory protein-1a; TCR:T-Cell Receptor; PMN:PolyMorphoNuclear cells; ROS:Reactive Oxygen Species; vWF:von Willebrand Factor;
PSGL-1: P-Selectin Glycoprotein Ligand-1; TLR: Toll-Like Receptor.

appeared to have a protective effect against the formation of endotoxin-
induced platelet plugs, as compared with placebo. Observational studies
evaluating the effects of chronic aspirin use on critically ill patients have
also reported encouraging results (Table 1). Favourable differences
were noted in patients treated with antiplatelet agents (aspirin or a
thienopyridine) prior to critical illness, including an apparent reduction
in organ dysfunction [36]. This finding comes in line with previous data
exhibiting that prior treatment with antiplatelet agents, including aspi-
rin, was associated with shorter length of stay and fewer ICU admissions
[37]. Even following ICU admission, it appears that patients who were
administered low-dose ASA at the time of the development of systemic
inflammatory response syndrome (SIRS) and sepsis, showed a signifi-
cant difference in mortality compared to those not using ASA in this
period [38–40]. Furthermore, in critically ill patients, antiplatelet thera-
py (95% with ASA) before hospitalization significantly reduced develop-
ment of acute lung injury (ALI) (12.7% vs 28.0%) [41,42] and need for
mechanical ventilation [42], as well as, mortality associated with septic
shock (by ~ 45%) [43]. This finding comes in agreement with preclinical
studies, suggesting that, platelet activation and sequestration play a
critical role in the pathogenesis of ALI/acute respiratory distress
syndrome (ARDS) [44–46] even though, in many studies no convincing
evidence has been reported regarding the impact of platelet inhibition
on ICU or hospital mortality or ICU- or hospital-free days [41,42,47]. In
other reports, aspirin use alone had no statistically significant associa-
tion with death, diagnosis of ALI/ARDS, or diagnosis of severe sepsis.
However, prehospital use of aspirin co-administered with statins was
associated with favourable outcomes [48]. Of note, ASA administration
was not associated with increased bleeding events or increased need
for transfusion even in patients with increased bleeding risk e.g. neuro-
surgery patients [36,38,42].
P2Y12 Inhibitors
The thienopyridines target the P2Y12 subclass of adenosine di-
phosphate (ADP) receptors and thereby blunt platelet activation and
aggregation stimulated by ADP [49]. Stimulation of P2Y12 receptors
promotes further release of the platelet agonist ADP from dense gran-
ules, is essential for ADP-mediated complete activation of glycoprotein
IIb/IIIa and Ia/IIa, and further stabilizes platelet aggregates[50]. The
134 K. Akinosoglou, D. Alexopoulos / Thrombosis Research 133 (2014) 131–138

prasugrel
clopidogrel
ticagrelor
cangrelor 2

P2Y12
receptor

1 IL13, IL10r, C4b,

Activated Ltb4r, Erk1genes
Abciximab ADP 5
Eptifibatide Platelet
Tirofiban δ-granules
cox
NFκB
αiib/β3 TxA2 gene
TxA2
receptor
7

Fibrinogen IL-6
3 TNF-a
4 Selectin
Activated Platelet
Lung & Spleen Cells
6 Leukocyte CD40

CD154

8
ROS

NO 9
granzyme B
10
eNOs Endothelial cell
iNOs

Fig. 2. Different antiplatelet agents interfere with a variety of pathways mediating sepsis. (1,2) Amplification of platelet activation response is hampered by ASA and P2Y12 inhib-
itors through blockade of thromboxane (TxA2) production and ADP binding to P2Y12 receptors respectively. (3,4) Platelet aggregation, hence microcirculation impairment during
sepsis, is attenuated following blockade of ADP mediated GPIIb/IIIa (αiib/β3) receptor maturation by P2Y12 inhibitors and prevention of aggregate formation by GPIIb/IIIa antag-
onist administration. (5,6) ASA and clopidogrel down regulate expression of pro inflammatory mediators i.e. cytokines, complement factors, etc probably through modulation of
certain transcription factors e.g. NFκB. (7) ASA and P2Y12 inhibitors alter platelet-leukocyte interactions through decreased expression of cell ligands e.g. P-selectin, CD40,
CD154. (8) P2Y12 inhibitors attenuate endothelial damage caused by neutrophil ROS production. (9) ASA promotes anti-adhesive NO production preventing leukocyte tethering,
adhesion and emigration. (10) GPIIb/IIIa antagonists have been found to decrease platelet mediated cytotoxicity caused by granzyme-B secretion. ASA: acetylsalicylic acid; COX:
CyclOXygenase; IL-13: InterLeukine 13; IL-10r: InterLeukine 10 receptor; C4b: complement component 4b; Erk1: extra cellular signal kinase 1; NFκB: nuclear factor
kappa-light-chain-enhancer of activated B cells; ROS:Reactive Oxygen Species; NO: Nitrogen Oxide; IL-6: InterLeukine 6; TNF-a: Tumour Necrosis Factor a; iNOs: inducible nitric
oxide synthase; eNOs: endogenous nitric oxide synthase; Ltb4r: LeukoTriene b4 Receptor.

thienopyridines ticlopidine, clopidogrel and prasugrel irreversibly
inhibit the P2Y12 receptor and are rather specific for platelets [49].
Clopidogrel, the most widely used thienopyridine, may attenuate
platelet expression of inflammatory and immune markers, receptors
and the release of inflammatory cytokines including IL- 1a, 2, 6, 13,
10, TNF alpha, and TNF beta [10]. Recent evidence has come to show
that P2Y12 blockade may counteract platelet contribution to inflamma-
tion in vivo and in vitro [37,51–53]. Inhibition of thrombin-induced
P-selectin expression by P2Y12 blockade in human platelets in vitro, sig-
nificantly curbs platelet-leukocyte interaction and subsequent platelet-
induced reactive oxygen species (ROS) production in polymorphonu-
clear neutrophils and tissue factor production in monocytes [51]
(Fig. 2). Moreover, a reduction of LPS-mediated thrombocytopenia,
fibrin deposition in the lungs, and inflammatory mediator upregulation
occurs in mice pretreated with clopidogrel [37,53,54]. Clopidogrel
attenuated the fall in platelet count that was observed 6 hours follow-
ing LPS administration, with no effect on survival and haemodynamics
during the first 24–48 hours. Nonetheless, in a later phase of the
experiments, a tendency of a higher survival rate in the clopidogrel-
treated animals was noted [37]. Clopidogrel appears to modulate gene
expression in peripheral blood cells reflecting the transcriptional activity
of granulocytes, lymphocytes and monocytes [55]. In Winning’s model of
experimental endotoxinaemia, 25 annotated transcripts were found to
be down-regulated in mice pre-treated with clopidogrel, compared to
mice without such pre-treatment [52]. The gene products are involved
in various networks of inflammation and cellular stress response such
as cytokines and their receptors (IL13, IL10r), complement factors and
immune globulins (C4b), leukotriene system, growth factors and recep-
tors, protein kinases and others [52] (Fig. 2). Thus, one could speculate
that clopidogrel, similarly to ASA, suppresses some proinflammatory
pathways.
Recent studies investigating the effects of R-138727, prasugrel’s
active metabolite, showed that low-micromolar concentrations of
this P2Y12 antagonist inhibited ADP-induced platelet P-selectin ex-
pression, as well as, the formation of platelet-leukocyte conjugates
[56] (Fig. 2). Totani et al. [57] confirmed and extended these previous
 K. Akinosoglou, D. Alexopoulos / Thrombosis Research 133 (2014) 131–138 135

Table 1
Clinical data on the use of antiplatelet agents and sepsis.

LITERATURE AIM STUDY DESIGN ANTIPLATELET AGENT PATIENTS-METHODS OUTCOME

Winning et al. Effect of antiplatelet agents
[36] on outcome of ICU patients
Winning et al. Effect of antiplatelet agents
[37] on outcome in patients at
risk for organ failure
Eisen et al. Association of ASA
[38] administration at the time of
development of SIRS with
reduced mortality.
Sossdorf et al. Impact of low-dose
[39] ASA/NSAIDs on hospital
mortality
Otto et al. [40] Benefit of ASA in critically ill
patients & possible interference
with atherosclerotic vascular
disease
Erlich et al. Association between
[41] pre-hospitalization antiplatelet
therapy & ALI/ARDS in ICU
patients at high risk for ALI.
Valerio-Rojas Outcome of critically ill patients
et al. [42] with/without antiplatelet
therapy before development of
severe sepsis/septic shock
Losche et al. Effect of ASA administration on
[43] outcome of ICU patients with
severe sepsis/septic shock
Kor et al. Association between
[47] pre-hospitalization ASA use & ALI of prospective
in a cohort of at-risk patients
O'Neal et al. Association of prehospital statin
[48] & combined ASA and statin use
with risk of sepsis, ALI/ARDS, and prospective cohort
mortality in critically ill patients.
Gross et al. Effects of clopidogrel on
[58] incidence & severity of CAP
Retrospective ASA, clopidogrel 615 admitted to an ICU Significant reduction in mortality
cohort within 24 hrs after in patients with normal or high
hospitalization; 25% received bleeding risk
antiplatelet drugs
Retrospective ASA, clopidogrel 224 patients admitted for Significant reduction in need of
cohort ticlopidin CAP; 20% received intensive care treatment and length
anti-platelet drugs of hospital stay
Retrospective ASA 5523 with SIRS; 2082 ASA administration was associated
cohort receiving ASA. with a lower mortality in patients
with SIRS/sepsis.
Retrospective ASA, clopidogrel 979 patients with severe Decreased mortality following ASA
sepsis/septic shock admitted administration; benefit of ASA abolished
to a surgical ICU when NSAIDs co administered; NSAIDs,
clopidogrel, statins without significant
effects;
Retrospective ASA,clopidogrel 886 patients admitted to Significantly lower mortality in
surgical ICU patients treated with ASA (100 mg/dl)
during ICU stay. Evidence that
clopidogrel may have similar effect.
Benefit abolished when combined
use of ASA and clopidogrel
Retrospective ASA-containing 161 patients admitted to a Reduced incidence of ALI/ARDS
cohort medication, clopidogrel medical ICU; 49% receiving
bisulfate, ticlopidine antiplatelet therapy
hydrochloride, cilostazol,
dipyramidole
Retrospective ASA, clopidogrel 651 patients admitted to No association of chronic antiplatelet
cohort ICU; 42.8% on antiplatelet therapy with decreased hospital/ICU
therapy (88.6% ASA,1.5% mortality. Potentially protective
clopidogrel, 9.9% against development of ALI/ARDS &
ASA + clopidogrel) reduces needs of mechanical
ventilation
Observational ASA 834 patients admitted to ICU Reduction in ICU mortality
with severe sepsis or septic
shock; 20% received
low-dose ASA
Secondary analysis ASA 3855 adult non-surgical Reduced incidence of ALI in those
patients at-risk for ALI; 25.3% receiving ASA in univariate analysis;
multicenter receiving ASA during not statistically significant following
international cohort hospitalization propensity adjustment.
investigation
Cross-sectional ASA 575 patients admitted to the No independent association of
analysis of medical or surgical ICU; 26% pre-hospital aspirin use with
on statin therapy prior to ALI/ARDS, sepsis, hospital mortality
hospitalization in multivariable analysis. Lower
rates of ALI/ARDS, severe sepsis &
hospital mortality in combined ASA
and statin use in univariable analysis
Retrospective clopidogrel 417,648 patients; 14,947 CAP more common among patients
cohort (3.6%) receiving N6 taking clopidogrel. Near-significant
consecutive clopidogrel trends in need for mechanical
prescriptions ventilation, risk of ARDS/ALI, &
mortality favouring clopidogrel

ASA:acetylsalicylic acid; CAP: community acquired pneumonia, ALI: acute lung injury, ARDS: acute respiratory distress syndrome; ICU:intensive care unit; NSAID: non-steroidal
anti-inflammatory drug.

observations in vitro, showing that treatment with prasugrel seems to
inhibit platelet activation and platelet-leukocyte interaction peptide
in whole blood from mice subjected to a systemic inflammatory reac-
tion. Moreover, analysis of plasma markers of platelet activation and
inflammation, namely TXB2, TNF-alpha revealed that treatment
with prasugrel curbed inflammatory reactions, in vivo [57].
Clinical studies also suggest that P2Y12 inhibitors may be associ-
ated with better outcomes in patients with pneumonia and critical
illness [36,37] (Table 1). Prior treatment with antiplatelet agents, in-
cluding P2Y12 inhibitors, was associated with favourable length of
stay and fewer ICU admissions even though, community acquired
pneumonia (CAP) appeared to be more common among patients taking
clopidogrel [37,58]. However, later clinical studies reported an association
of antiplatelet drug therapy including clopidogrel with favourable out-
come, [36,41,42] these results were mainly driven by the large number
of patients receiving ASA. Thus, due to the low number of patients receiv-
ing P2Y12 inhibitors in these studies no subgroup analysis is available.
No clinical data on the cyclopentyl-triazolo-pyrimidine ticagrelor
and the ATP analogue cangrelor currently exist. However, interest-
ingly the mortality reduction observed with ticagrelor versus clopidogrel
following coronary artery bypass grafting (CABG) in the PLATelet inhibi-
tion and patient Outcomes (PLATO) trial, was associated among others
with fewer deaths attributed to infection complication [59,60]. This find-
ing comes in line with recent data indicating that ticagrelor appears to
reduce neutrophil recruitment and lung damage in abdominal sepsis in
pre treated mice [61]. The latter may reflect one of ticagrelor’s many
136 K. Akinosoglou, D. Alexopoulos / Thrombosis Research 133 (2014) 131–138
off-target pleiotropic effects attributed to its adenosine mediated mode
of action [62], however, what the exact mechanism behind its apparently
strong anti-inflammatory action is, remains to be seen.
GPIIb/IIIa Antagonists
The platelet GPIIb/IIIa (αιιb/β3) receptor has been identified as the
pivotal mediator of platelet aggregation. GPIIb/IIIa antagonists block
fibrinogen binding to the GPIIb/IIIa receptor on activated platelets
and exert a strong antiplatelet effect by inhibiting the final common
step of platelet aggregation [63].
There are only few reports on GPIIb/IIIa inhibitors in animal model of
endotoxin-induced inflammatory responses and/or organ failure. In a
rabbit model of endotoxic shock, treatment with AZ-1, a murine mono-
clonal antibody against GPIIb/IIIa that inhibits platelet aggregation,
resulted in a decreased monocyte tissue factor expression and coagula-
tion changes, restoration of endothelium-derived vascular relaxation
and significant decrease in endothelial cell injury, as well as, decreased
mortality rate [64]. Moreover, in a previous study, Taylor et al. demon-
strated that a murine monoclonal antibody to the human platelet glyco-
protein (GP)-IIb/IIIa receptor protects against disseminated intravascular
coagulation and ischemic organ damage observed in baboons treated
with C4b binding protein and sublethal infusion of Escherichia coli [65].
In the same manner, GP IIb/IIIa inhibition, using abciximab, protects
against endothelial dysfunction and an increase in leukocyte adherence
to the vascular wall during experimental endotoxemia [66]. Of note, in-
hibition of platelet aggregation via GPIIb/IIIa blockade with eptifibatide,
attenuates platelet granzyme B-mediated apoptosis and results in less
severe sepsis and extended survival in a murine model of abdominal
sepsis [67] (Fig. 2). However, whether these results can be extrapolated
to humans remains unclear. In another study of human low grade
endotoxemia, GPIIb/IIIa blockade with eptifibatide or tirofiban did not
seem to influence TF-induced coagulation activation, hence sepsis path-
way [68]. It is possible that these compounds may not be effective on cir-
culating platelets, although, may exert a beneficial effect on platelets that
are aggregated in the microcirculation [64].
Issues to be Considered
Animal studies and observational clinical studies mentioned above
have provided some evidence that antiplatelet drugs may reduce
organ failure and mortality in critically ill patients. However, in absence
of interventional and prospective large randomized trials the results
presented here should be regarded as exploratory and hypothesis
generating, considered with vigilance while conclusions are being ex-
trapolated with an uncertain degree of bias regarding the wide use of
antiplatelet agents in septic patients.
A number of issues that have to be considered further have been
identified. First, in the clinical studies described, mostly or exclusively
aspirin was used as the antiplatelet drug, whereas clopidogrel or
GPIIb/IIIa inhibitors as rather specific antiplatelet drugs were pre-
dominantly used in animal models [43]. Following pooled analysis
of studies reporting the favourable association of antiplatelet therapy
and outcomes in patients hospitalized for pneumonia, at risk for ALI,
and/or critically ill, [58], the reduction in mortality was mainly driven
by the large study of Eisen et al., which may hamper the ability to
generalize the results since only ASA was utilized in the respective
study [38].
Moreover, it has previously been reported that sepsis, at least in its
early state, is associated with hypercoagulability, indicated in partic-
ular by an increase in clot formation rate and maximum clot firmness
[69,70]. However, the increase in hemostatic efficacy in these models
seems to be in contrast to data obtained in other studies, exhibiting a
significant prolongation of clotting time and clot formation rate as
well as a decrease in clot formation rate and maximum clot firmness
[71,72]. These findings could reflect respective aggregometry data
described above, indicating similar contradictory results.[18,19] Thus,
the question arises of whether hypercoagulability observed in mice
and rat models during endotoxinemia and/or sepsis is not actual, or
whether hypercoagulability quickly turns to hypocoagulability, owing
to consumption of hemostatic factors depending on the stage of sepsis.
And if so, could sepsis trigger adaptive high platelet reactivity, hence
inadequate response to commonly used antiplatelet regimens, by pro-
voking increased platelet aggregation at least in its initial stages? Inter-
estingly, prasugrel’s inhibitory effects on a broad spectrum of platelet
aggregation pathways was blunted in a recent model of systemic inflam-
mation, in otherwise healthy volunteers following endotoxin infusion
compared to placebo [73]. This is particularly important, as use of anti-
platelet drugs is associated with increased bleeding events resulting in
their discontinuation in critically ill patients, even though, recent data
showed clear benefit even in patients with an increased bleeding risk
[36].
In similar sense, there is conflicting evidence to support prophylactic
antiplatelet administration in patients at risk for infection. In contrast to
pre-clinical results, suggesting a potential benefit of antiplatelet treat-
ment in infection [71], a retrospective study has suggested an increased
risk of infection in clopidogrel-treated patients undergoing CABG com-
pared with those treated with aspirin alone [74]. The mechanisms by
which clopidogrel may increase the risk of infection-related mortality
are not known, even though, clopidogrel treatment has been associated
with neutropenia [75]. Findings that use of clopidogrel may be associat-
ed with increased risk of CAP and hospitalization, as well as, a trend to-
wards reduced severity indices in hospitalized patients, [37] would be
consistent with a biphasic role for platelets in lung infection and its se-
quelae. Platelets may be important in the initial clearance of pathogens.
This is supported by the increased risk of sepsis seen among clopidogrel-
treated patients. Once the infection progresses systemically, inhibition of
platelet function may have beneficial consequences, especially with
regards to mechanical ventilation, ALI, ARDS or even DIC according to a
previous report [76]. Further investigations may determine the magni-
tude of this effect.
Conclusions
In the light of the above data, the current practice to discontinue
antiplatelet drugs in patients with sepsis should be tested in a prospec-
tive trial. Since no specific therapy for sepsis, beyond source control and
antimicrobial therapy currently exists, prevention or innovative treat-
ment approach is of utmost importance, especially in an era of stringent
budget. Given the compelling observational and scientific data in this
debilitating syndrome, patients at high risk for the development of
sepsis and a low risk for the development of side effects should be
considered as candidates of being prescribed, or at least not being
discontinued antiplatelet agents until clinical trials or further evidence
dictates otherwise.
Conflict of Interest Statement
Dr Alexopoulos reports receiving honoraria for lecturing by Astra
Zeneca.
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