678 Theme Issue Article
Immune functions of platelets
Infections and the role of plasma
Daniel Duerschmied; Christoph Bode; Ingo Ahrens
proteins and platelets
Department of Cardiology and Angiology I, Heart Center, University of Freiburg, Freiburg, Germany
Summary
This review collects evidence about immune and inflammatory func-
tions of platelets from a clinician’s point of view. A focus on clinically
relevant immune functions aims at stimulating further research, be-
cause the complexity of platelet immunity is incompletely understood
and not yet translated into patient care. Platelets promote chronic in-
flammatory reactions (e.g. in atherosclerosis), modulate acute inflam-
matory disorders such as sepsis and other infections (participating in
Correspondence to:
Daniel Duerschmied, MD
Department of Cardiology and Angiology I
Heart Center, University of Freiburg
Hugstetter Str. 55, 79106 Freiburg, Germany
Tel.: +49 761 207 34410, Fax: +49 761 270 37855
E-mail: daniel.duerschmied@universitaets-herzzentrum.de
Introduction
The primary mission of platelets is haemostatic, because they me-
diate primary haemostasis and atherothrombotic events (reviewed
in [1]). Platelets also promote venous thromboembolism (2, 3).
But platelets not only build thrombi, they are also highly active in
the host defense against pathogens and have hence been recog-
nized as cells with immune functions. They are involved in sepsis
and other acute inflammatory responses to infection as well as in
chronic inflammatory diseases like atherosclerosis or arthritis (re-
viewed in [4–8]). Platelets circulate in large numbers through the
vasculature (several hundred thousand per microliter), patrolling
the endothelium and are able to rapidly release an array of immu-
nomodulatory cytokines, chemokines, and other mediators (9, re-
viewed in [10]). Platelets express several immune receptors on the
cell surface, such as Toll-like receptors, immunoglobulin receptors
or the co-stimulatory proteins CD40 and CD40L. Another feature
that platelets have in common with other immune cells is the pres-
ence of granules in the cytoplasm that can be exocytosed following
specific stimulation. This allows the targeted release of mediators
and the instantaneous upregulation of surface receptors at sites of
inflammation. Platelets are able to modulate leukocyte functions
such as phagocytosis or extravasation directly or in cooperation
with endothelial cells of inflamed vessels. Surprisingly, increasing
evidence shows that platelets are even able to capture and neutra-
lise pathogens directly. Here we summarise observations of im-
mune and inflammatory platelet components and functions.
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the host defense against pathogens), and contribute to exacerbations
of autoimmune conditions (like asthma or arthritis). It would hence be
obsolete to restrict a description of platelet functions to thrombosis
and haemostasis – platelets clearly are the most abundant cells with
immune functions in the circulation.
Keywords
Platelet immunology, sepsis, leukocyte function / activation
Received: February 17, 2014
Accepted after major revision: September 3, 2014
Epub ahead of print: September 11, 2014
http://dx.doi.org/10.1160/TH14-02-0146
Thromb Haemost 2014; 112: 678–691
Clinical and experimental evidence of
immune functions of platelets
Every clinician has experienced marked changes in platelet count
of patients with inflammatory diseases and many may have specu-
lated about the role that platelets play in immunity. Whether long-
term antiplatelet therapy, especially with the newer, more potent
agents, influences inflammatory or immune responses has not
been examined systematically. However, several studies have de-
ciphered relevant contributions of platelets to the pathophysiology
of inflammatory or immune disorders in animals or humans.
Infections
Thrombocytopenia is a common feature of severe bacterial or viral
infection and a marker of poor outcome (reviewed in [11]). This
suggests that platelets actively participate in the struggle against
pathogens. Interestingly, recovery is often associated with reactive
thrombocytosis (12). Platelet consumption in microthrombotic re-
sponses to infection is a possible complication, such as in dissemi-
nated intravascular coagulation (DIC), but does not explain these
frequent findings in milder clinical courses. Thrombocytopenia
and reactive thrombocytosis are hence not only collateral damage,
but most likely constitute an active part of the host defense against
infection. Curiously, direct antimicrobial activity of platelets has
been discovered in animal models. In murine malaria, platelets
were shown to eradicate intra-erythrocytic parasites and have
hence an impact on survival, an effect that could be reproduced in
ex vivo models with human blood cells (13). When platelet bind-
ing to hepatic Kupffer cells via glycoprotein (GP)Ibα was imaged
© Schattauer 2014

in intravital microscopy of mice, challenging these mice with bac-
teria resulted in firm platelet immobilisation via GPIIb and encap-
sulating of bacteria (14).
Still, direct clinical evidence from human studies is required be-
fore preclinical data can be translated into therapeutic interven-
tions. It is possible that cessation of antiplatelet therapy improves
infectious disease outcome, but this assumption is far from evi-
dence-based and would likely be associated with thrombotic com-
plications. In fact, to our knowledge, antiplatelet therapy has not
been linked to an increase in infectious disease prevalence or mor-
bidity. Moreover, there are no epidemiologic data showing that
platelet suppression affects infections. In addition, patients with
GPIb deficiency in Bernard-Soulier syndrome are not known to
suffer from immune defects. Of note, however, a recent tragic case
report suggested an association between GPIIb/IIIa deficiency in
Glanzmann thrombasthenia and human immunodeficiency virus
(HIV) susceptibility (15).
The key to success in translational research is therefore further
mechanistic research. Targeted – positive – platelet modulation
(e.g. functional enhancement of GPIb or specific modulation of
intracellular signaling [16]) could theoretically complement anti-
infectious therapy, but this has not been addressed systematically.
More applicable however appears the prospect of platelet function
suppression in the context of inflammatory and (auto-) immune
disorders to attenuate pathological systemic inflammatory re-
sponses (e.g. in sepsis, asthma, or atherosclerosis).
Sepsis
In human sepsis, the number of circulating platelet-neutrophil
complexes (PNCs) and platelet-monocyte complexes (PMCs) in-
creases dramatically (17), correlating with the severity of multi-
organ failure (18). A differential release of growth factors from pla-
telets was observed in septic patients (19): The haemostatic func-
tions were attenuated in relation to the severity of sepsis but the re-
lease of vascular endothelial growth factor (VEGF) was enhanced.
Moreover, the transcriptome is altered in platelets from septic pa-
tients, facilitating differential release of proteins such as tissue fac-
tor (20). Microthrombotic complications are provoked by dissemi-
nated platelet activation and platelet-leukocyte interactions, mech-
anisms that may both be targeted in future therapeutic trials (17,
21, 22).
Autoimmune disease
Immune complex formation and complement activation by pla-
telets were found in patients with immune thrombocytopenia and
systemic lupus erythematosus [reviewed in (23)]. Platelets release
serotonin into acutely inflamed joints in murine rheumatoid ar-
thritis, increasing synovial permeability (24). Both mechanisms
may represent attractive targets for therapeutic intervention.
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Duerschmied et al. Platelet immunity 679
Asthma
Infections and the role of plasma
Platelet activation and granule secretion enhance bronchocon-
striction and –obstruction during asthmatic attacks in mice and
proteins and platelets
humans (25–29). ATP and serotonin are released from dense gran-
ules sustaining these attacks (30, 31). Bronchoalveolar lavage fluid
after segmental allergen challenge of asthmatic patients contains
high levels of platelet-derived serotonin, which enhances leukocyte
infiltration, Th2-priming capacity of dendritic cells (DCs), and ul-
timately all cardinal features of allergic airway inflammation (31).
Antiserotonergic and antipurinergic intervention consequently
represent promising strategies in the search for future therapies.
Metabolic syndrome
Data from the Framingham heart study suggest that inflammatory
platelet activation correlates with obesity and cardiovascular risk
(32, 33). Inflammatory gene transcripts derived from isolated pla-
telets such as tumour necrosis factor (TNF), toll-like receptor
(TLR)2, and TLR4 were associated with increased body mass
index (BMI) (33). It is hence conceivable, that platelets promote
the inflammatory phenotype of metabolic syndrome, which in
turn could be targeted in future applications (34).
Atherosclerosis
Platelets not only drive the atherothrombotic occlusion of a coron-
ary artery in acute myocardial infarction, but they also mediate the
chronic progression of vessel wall inflammation in atherosclerosis
(37) [reviewed in (35, 36)]. The various aspects ranging from cyto-
kine release to monocyte recruitment have been examined in sev-
eral in-depth animal studies and complemented by human ex vivo
data [reviewed in (7)]. Specific antiplatelet intervention to stop the
atherogenetic progression is as desirable as it is unavailable at pres-
ent. Several research projects, including clinical studies currently
address this topic.
Ischaemia / reperfusion injury
Ischaemia / reperfusion (IR) injury contributes to the final infarct
size in myocardial infarction and is still poorly controlled. PNC in-
filtration correlates with myocardial reperfusion damage (38) and
PMCs form rapidly after myocardial infarction in animal studies
[reviewed in (21)]. It has been reasoned that the adenosine diphos-
phate (ADP) receptor P2Y12 inhibitor ticagrelor may possess
pleiotropic effects and could limit IR injury (39, 40). IR injury of
the liver is also mediated by platelet-neutrophil interactions in
mice (41), while liver regeneration depends on platelet-derived se-
rotonin (42). Whether specific antiplatelet intervention could limit
IR injury in patients with myocardial infarction remains to be
shown. This is of particular interest, because although reperfusion
is often rapidly ensured by percutaneous coronary intervention,
the subsequent inflammatory sequelae still dictate the final extent
of the myocardial scar and we lack tools to limit them.
Thrombosis and Haemostasis 112.4/2014
 680 Duerschmied et al. Platelet immunity
Soluble factor secretion
Infections and the role of plasma
Platelets have a number of immune and inflammatory features
ranging from secretable immunomodulatory factors to stably or
proteins and platelets
variably expressed surface receptors (summarised in ▶ Table 1).
Rapid secretion of a wide array of inflammatory mediators follow-
ing exocytosis of α granules, dense granules, and lysosomes upon
activation is a unique feature of platelets. This enables an almost
instantaneous response to stimuli in the affected vasculature. Of
note, platelets not only contain preformed secretable factors, but
are also capable of newly synthesizing mediators such as interleu-
kin (IL)-1β following signal-dependent splicing of pre-mRNA
(43).
α-granule factors
α-granules are the most abundant granules in platelets and contain
a variety of inflammatory mediators, including a number of adhes-
ive proteins (45). Platelet aggregation and (micro-)thrombus
formation are promoted by fibrinogen, von Willebrand factor
(VWF), fibronectin, vitronectin and serve as an immobilising ma-
trix for pathogen capture [reviewed in (21, 44, 45)]. Theoretically,
this limits pathogen growth and multiplication in the vasculature
and facilitates exposure of these captured pathogens to neutralis-
ing leukocytes. Although this pathophysiologic sequence has not
been deciphered directly in mechanistic studies, observations in
septic patients (and mice) suggest that platelet aggregation is not
only a complication but rather a feature of primary host defense
(17). Platelet factor 4 (PF4, CXCL4) and the β-thromboglobulin
neutrophil-activating protein 2 (NAP2, CXCL7) regulate neutro-
phil and monocyte functions and promote their recruitment (89).
PF4 furthermore suppresses neutrophil apoptosis, which was dem-
onstrated in a platelet depletion study of murine limb ischaemia
(140). Several α-granule-derived chemokines have been studied
extensively, especially in atherogenesis, and are considered impor-
tant messengers of immune functions [reviewed in (141)]. Che-
mokine functions include chemotaxis and modulation of different
leukocyte functions. Platelets are able to take up immunoglobulins
from plasma to store them in α-granules and to release this cargo
on-site following inflammatory stimulation (44, 142) [reviewed in
(44)]. This interesting observation may represent a contribution of
platelets to humoral immunity.
Dense granule factors
Dense granules store serotonin, calcium, magnesium, ATP, and
ADP (whether they also contain histamine is controversial [93,
143]) and secrete these factors upon activation (reviewed in [143,
144]). At the site of acute inflammation platelets release serotonin
at micromolar concentrations, boosting the recruitment of neutro-
phils into the inflamed tissue during murine pneumonia, peritoni-
tis, and skin wounds (91). In mice, this translates into improved
sepsis outcome when platelet serotonin stores were depleted. The
observation that antidepressants inhibiting the uptake of serotonin
modulate the release of several cytokines, suggests that platelet se-
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rotonin may also be important in human inflammation [reviewed
in (145)]. In fact numerous immunomodulatory functions of pe-
ripheral serotonin (which is mostly platelet-derived) have been
characterised, including differential effects on chemokine/cyto-
kine secretion by immune cells. ▶ Figure 1 summarises immune
effects of serotonin as one example of the complexity of platelet
immunomodulation (24, 31, 91, 146–165).
Lysosomes
Lysosomes release glycosidases, proteases, and bactericidal
enzymes such as β-glucuronidase, elastase, and collagenase [re-
viewed in (46)]. The lysosome releasate facilitates pathogen clear-
ance and breakdown of extracellular matrix but current studies are
rare and clinical implications have not been addressed systemati-
cally.
Defensins
Other secretable factors are not associated with any of the known
granules. They are either derived from cytoplasmic stores, are
newly synthesised proteins, or are components of a yet unknown
type of granule. β-defensin is an example of granule-independent
mediators with anti-bactericidal activity (107) and belongs to the
group of antimicrobial peptides. Human platelets express β-de-
fensins 1, 2, and 3 (107, 166, 167). Platelets release β-defensin 1
from cytoplasm in response to Staphylococcus aureus α-toxin to in-
duce neutrophil extracellular trap (NET) formation and limit bac-
terial growth (107).
Immune receptors
Different immune receptors operate on the platelet surface (and in
some cases intracellularly) [reviewed in (168)]. Toll-like receptors
recognise pathogen- and danger-associated molecular patterns
(PAMPs and DAMPS, respectively) [reviewed in (6)], complement
receptors mediate complement activation at sites of platelet ac-
cumulation (169), and Fc receptors recognising immunoglobulins
(FcR, notably the Fcγ receptor FcγRIIA, but also Fcα and Fcε re-
ceptors) provide a link to the adaptive immune system (79, 170).
In a murine model of Arthus reaction, platelets facilitate the im-
mune complex-induced recruitment of neutrophils in microvessels
(171). P-selectin on activated platelets appears to participate in
complement activation and platelet-associated immune complexes
mediate autoimmune diseases such as immune thrombocytopenia
or systemic lupus erythematosus (23, 79). C-type lectin-like recep-
tor 2 (CLEC-2) is involved in the regulation of vascular integrity in
acute inflammation (119, 172).
CD40 / CD40 ligand
With cell activation differentially regulating their surface presenta-
tion, CD40 and CD40L are not only expressed by platelets, but also
by endothelial cells, smooth muscle cells, and several leukocyte
© Schattauer 2014
 Duerschmied et al. Platelet immunity 681

Table 1: Immune and inflammatory platelet components [reviewed in (4, 7, 21, 44–46)].

Infections and the role of plasma

Superfamily Molecule associated with Effector cell / ligand Ref.
α-granules Adhesion P-selectin cell-cell interactions (leukocytes, endothelium) PSGL-1 (on neutrophils, monocytes, (10, 45, 47)

proteins and platelets

molecules microparticles, Th1 cells), unknown
(on endothelium)
Fibrinogen cell-cell-interactions (platelets, leukocytes, en- GPIbα, GPIIb/IIIa (platelets), integrins (44, 48–55)
VWF dothelium), platelet aggregation around pa- (platelets, leukocytes), collagen
thogens, bacterial trapping (VWF)
Fibronectin
Vitronectin
Thrombospondin-1
PECAM-1
Coagulation Factor V promotion of coagulation n/a (56)
factors Protein S fibrinolysis n/a (57)
Factor XI promotion of coagulation n/a (58)
Factor XIII fibrin stabilization n/a (59)
Mitogenic PDGF wound healing monocytes, macrophages, T cells (60, 61)
factors TGF-β growth inhibition, immunosuppression monocytes, macrophages, T cells, (62, 63)
B cells
EGF pro-mitogenic action * (64)
Angiogenic VEGF pro-angiogenic action VEGF receptors (65)
factors
Protease C1 inhibitor modulation of complement and contact sys- n/a (66)
inhibitors tem
α2-plasmin inhibitor fibrinolysis plasmin, neutrophil elastase (67)
PAI-1 antifibrinolytic action tissue plasminogen activator (68, 69)
Antimicrobial Thrombocidin 1 and 2 antibacterial and antifungal action bacteria, candida (70)
peptides
Igs IgG immune haematologic disorders Fc receptors (71, 72)
IgA * * (73)
IgM * * (74)
Granule CD63 * integrins (75)
membrane-spec
ific proteins GMP33 * * (76)
Chemokines CCL3 (MIP-1α) leukocyte activation/recruitment monocytes/macrophages, eosinophils, (77, 78)
basophils, NK cells, DCs
CCL5 (RANTES) monocyte recruitment monocytes, eosinophils, basophils, NK (78–81)
cells, T cells, DCs, platelets
CXCL1 (GROα) monocyte recruitment neutrophils / CXCR2 (77, 82)
CXCL4 (PF4) monocyte recruitment and differentiation, monocytes, neutrophils, T cells, (83–86)
anti-angiogenic, T cell modulation platelets
CXCL5 (ENA78) modulation of chemokine scavenging, neutro- neutrophils (87, 88)
phil chemotaxis
CXCL7 (NAP2, (most abundant platelet chemokine, several neutrophils, EPCs / CXCR1,2 (89, 90)
β-thromboglobulin) variants) neutrophil recruitment and acti-
vation, EPC homing

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 682 Duerschmied et al. Platelet immunity

Table 1: Continued
Infections and the role of plasma

Superfamily Molecule associated with Effector cell / ligand Ref.

Dense Amines Serotonin (5-HT) neutrophil recruitment, leukocyte modulation neutrophils, monocytes, lymphocytes, (91, 92)
proteins and platelets

granules NK cells, platelets / 5-HT receptors

Histamine (?) * endothelial cells, monocytes, (93)
neutrophils, NK cells, T cells, B cells,
eosinophils
Cations Calcium signal transduction effector proteins (94, 95)
Magnesium platelet-neutrophil interactions neutrophils (96)
Nucleotides ATP Th2 cell sensitisation following DC activation DCs / P2X, P2Y receptors (30)
ADP second-wave platelet activation platelets / P2Y receptors (97)
Lysosomes Proteases Carboxypeptidases A, eosinophil chemotaxis * (46, 98)
B
Cathepsin D, E chemokine cleavage * (99)
Acid phosphatase * * (100)
Collagenase facilitation of cell recruitment * (101)
Glyco-hydrolases Heparinase facilitation of cell recruitment endothelial glycocylix (102)
β-N-acetyl- facilitation of cell recruitment extracellular matrix (103)
glucosaminidase,
β-glucuronidase
β-glycerophosphatase
β-galactosidase
α-D-glucosidase
α-L-fucosidase
β-D-fucosidase
Granule- Cytoplasmic CCL7 (MCP3) monocyte chemotaxis monocytes, basophils, NK cells, DCs / (77)
independent or membrane CCR1–3
soluble components IL-1β T cell activation, atherosclerosis, obesity monocytes, macrophages, DCs, T cells (104)
mediators
HMGB1 systemic sclerosis * (105, 106)
β-defensin 1, 2, 3 bacteria clustering bacteria (107)
Thromboxane A2 vasoconstriction, leukocyte modulation platelets, macrophages, T cells (108)
PAF autoimmunity/anaphylaxis, inflammation, PAFR (109)
cancer
sCD40L acute coronary syndrome CD40 (110)
Surface Integrins α5β1 (VLA-5) adhesion fibrinogen, CD40L (111)
adhesion α6β1 (VLA-6) adhesion laminin (112)
molecules
α2β1 adhesion collagen (113)
α2bβ3 (GPIIb/IIIa) aggregation, bacterial trapping fibrinogen, fibronectin, vitronectin, (48)
VWF, thrombospondin
Adhesion GPIbα adhesion, “immunothrombosis”, bacterial in- VWF, P-selectin, Mac-1 (14,
receptors fections 114–116)
ICAM-2 leukocyte recruitment neutrophils, DCs, T cells, monocytes / (117, 118)
LFA-1, DC-SIGN
GPVI vascular integrity, rheumatoid arthritis, athero- collagen (119, 120)
genesis
CLEC2 vascular integrity podoplanin (119)

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 Duerschmied et al. Platelet immunity 683

Table 1: Continued

Infections and the role of plasma

Superfamily Molecule associated with Effector cell / ligand Ref.
Immune TLRs TLR1 * heterodimerizes with TLR2 (121)

proteins and platelets

receptors TLR2 antimicrobial gram-positive bacteria (122)
TLR4 sepsis lipopolysaccharide, gram-negative (122)
bacteria
TLR6 * heterodimerises with TLR2 (121)
TLR7 PNC formation viral genome (123)
TLR9 antiatherosclerotic action DNA rich in CpG motifs (124)
Co-stimulatory CD40 atherosclerosis, I/R injury T cells / CD40L (125)
proteins (TNF CD40L (CD154) atherosclerosis CD40 on monocytes and endothelial (126–129)
and TNFR cells / B cells, DCs, monocytes,
superfamily) macrophages, platelets
Ig superfamily TREM-1 ligand sepsis PMNs, DCs, macrophages, monocytes (130, 131)
Sheddase TACE (ADAM17) * GPIb, TNFá (132)
Ig receptors FcγRIIA (CD32) bactericidal action IgG (21, 133)
FcεRI allergy, parasite defense IgE (high affinity) (79)
FcεRII (CD23) allergy, parasite defense IgE (low affinity) (134)
FcαRI IL-1β production IgA (135)
Complement gC1qR antimocrobial bacterial protein A (136, 137)
compoments C5b-9 dense granule release anaphylatoxins (138, 139)
*: unknown or not applicable. Ref.: exemplary references, PSGL-1: P-selectin glycoprotein ligand 1, GP: glycoprotein, VWF: von Willebrand factor, PECAM-1:
platelet-endothelial cell adhesion molecule 1, n/a: not applicable, PDGF: platet-derived growth factor, TGF-β: transforming growth factor β, EGF: epidermal
growth factor, VEGF: vascular endothelial growth factor, NK cells: natural killer cells, DCs: dendritic cells, ENA78: epithelial-derived neutrophil-activating peptide
78, GROα: growth-related oncogene α, NAP-2: neutrophil-activating protein 2, PF4: platelet factor 4, PAI-1: plasminogen activator inhibitor 1, IgG: immunoglo-
bulin G, GMP: α-granule membrane protein, CCL: chemokine (C-C motif) ligand, RANTES: regulated on activation, normal T cell expressed and secreted, CXCL:
chemokine (C-X-C motif) ligand, MIP-1α: macrophage inflammatory protein-1α, EPC: endothelial progenitor cell, 5-HT: 5-hydroxytyptamine, ATP: adenosine trip-
hosphate, ADP: adenosine diphosphate, MCP: monocyte chemotactic protein, IL: interleukin: HMGB1: high mobility group protein 1, PAF: platelet-activating fac-
tor, CD40L: cluster of differentiation 40 ligand, sCD40L: soluble CD40L, Mac-1: macrophage-1 antigen (=αmβ2), LFA-1: lymphocyte function-associated antigen
1 (=αLβ2), DC-SIGN: dendritic cell-specific, ICAM-grabbing non-integrin, TLR: toll-like receptor, PNC: platelet-neutrophil complex, TNF: tumour necrosis factor,
TREM-1: triggering receptor expressed on myeloid cells 1, TACE: tumour necrosis factor α converting enzyme, ADAM17: a disintegrin and metalloproteinase 17,
FcR: Ig Fc region receptor, gC1qR: binding protein for the globular head domains of complement component C1q.

subtypes (4, 110, 125–129, 173–177) [reviewed in (4, 128, 129, 173,
174)]. This inflammatory axis mediates complex cell-cell interac-
tions. CD40/CD40L-mediated interactions have been well charac-
terised in atherosclerosis, but are likely also involved in several
other immune reactions. Platelets release CD40L and RANTES
upon stimulation with IgG complexes without showing signs of
general activation (80). Platelet CD40L triggers inflammatory acti-
vation of endothelium: it induces upregulation of E-selectin,
ICAM-1, and VCAM-1 and provokes chemokine secretion by en-
dothelial cells (178).
Toll-like receptors
Platelets express functional TLRs and respond to ligand binding
and activation (179–181) [reviewed in (122)]. TLR2 and TLR4 and
the predominately intracellular TLR9 (182) are the most exten-
sively studied platelet TLRs (121, 182–184). Platelets also contain
the adapter molecules MYD88 and TRIF required for specific
downstream signalling (185, 186). The TLR2/1-specific agonist
Pam3CSK4 has been utilised by different groups to stimulate pla-
telets. It induces a dose-dependent response involving different in-
tracellular signalling pathways, which may be part of defense
mechanisms against gram-positive bacteria (187, 188). Stimu-
lation of platelet TLR4 has been linked to NET formation and sub-
sequent capture of gram-negative bacteria in the blood stream
(189). Platelet TLR7 binds viral RNA triggering PNC formation in
mice, improving the animals’ survival (123). Platelet TLR9 recog-
nises viral and bacterial DNA and promotes platelet reactivity
(182, 190). Finally, TLR9 mediated protection from atherosclerosis
in mice by suppressing the influx of CD4+ T cells into plaques
(124). Platelet TLRs are an interesting target for future therapeutic
studies because pharmacological manipulation is uncomplicated.

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 684 Duerschmied et al. Platelet immunity

Membrane receptor shedding Overview of immune and inflammatory

Infections and the role of plasma

Soluble CD40 ligand platelet functions

Platelets are an important source of soluble CD40 ligand (sCD40L) The different immune and inflammatory functions of platelets
proteins and platelets

[reviewed in (173, 174)]. Platelet-derived sCD40L induces reactive
oxygen species (ROS) production, neutrophil adhesion receptor
upregulation, macrophage activation, and cytotoxic T cell and B
cell stimulation [reviewed in (21)]. CD40L can also be carried by
platelet microparticles, regulating antigen-specific IgG production
[reviewed in (21, 173)]. Whether platelet-derived sCD40L is ac-
cessible to pharmacological intervention remains to be shown.
TACE
TNFα converting enzyme (TACE, ADAM17) is a sheddase ex-
pressed not only by neutrophils (where it regulates shedding of
L-selectin and pro-TNFα), but also by platelets (191, 192). Numer-
ous signals can activate TACE, including atherosclerotic plaque
components (193, 194). Although specific immune functions of
platelet surface TACE have not yet been deciphered, it is intriguing
to note that oxidative stress and serotonin receptor activation in-
duce GPIbα and GPV shedding by TACE (132, 191, 195–197).
have been divided into four major functional classes: leukocyte
modulation, leukocyte recruitment, pathogen capture, and pa-
thogen killing [reviewd in (44)]. ▶ Table 2 allocates mechanisms
to these four classes.
Interactions with endothelium and
leukocytes
An early response to acute inflammation is the activation of en-
dothelium in affected vessels. This induces platelet and leukocyte
interactions with the vessel wall resulting in rolling, adhesion, and
transmigration into the inflamed organ [reviewed in (10, 208)].
During inflammatory cell recruitment, platelets and leukocytes
also closely interact with each other and form platelet-leukocyte
complexes, predominantly PNCs and PMCs (▶ Figure 2) (17, 209,
210) [reviewed in (21)]. A key mediator is P-selectin, which is ex-
posed on the platelet surface after α granule exocytosis and then
binds leukocyte PSGL-1 [reviewed in (45)].

Figure 1: An exemplary illustration of the complexity of platelet immunity. Inflammatory secretion of platelet (or in some cases neuronal) seroto-
nin provokes a wide array of differential effects on immune cells.

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 Duerschmied et al. Platelet immunity 685

Table 2: Immune and inflammatory functions of platelets [reviewed in (4, 7, 21, 44)].

Infections and the role of plasma

Function Mechanism Effector cells, Pathophysiological relevance
targeted pathogen

proteins and platelets

Modulation PNC formation enhances phagocytosis (157, 198) neutrophils, bacteria periodontitis, staphylococcal infections
of leukocyte PNC formation promotes neutrophil degranulation (189) neutrophils sepsis
function
platelet sCD40L release activates endothelial cells and leukocytes (173, endothelial cells, atherosclerosis
174) lymphocytes,
macrophages
platelet sCD40L release advances the production of reactive oxygen Neutrophils acute inflammation
species (173, 174)
Leukocyte PMC formation facilitates monocyte recruitment (199–202) monocytes thrombosis, atherosclerosis, autoimmunity
recruitment platelet sCD40L induces endothelial ICAM-1, VCAM-1, E-selectin endothelial cells inflammation
expression (178)
platelet serotonin induces endothelial P-selectin, E-selectin expression (91, endothelial cells sepsis, wound healing, infections
203)
platelet GPIb-IX-V binding to VWF (48) subendothelium inflammation, thrombosis
platelet GPIIb/IIIa binding to ICAM (10) endothelial cells inflammation, thrombosis
cytokines and chemokines activate leukocytes neutrophils, monocytes, inflammation
macrophages,
lymphocyes
platelet GPVI binding to collagen (48) subendothelium inflammation, thrombosis
platelet P-selectin binding to neutrophil PSGL-1 (45) neutrophils sepsis
platelet GPIb and IIb/IIIa binding neutrophil Mac-1 (204, 205) neutrophils atherothrombosis
Pathogen platelet-triggered NET release by neutrophils (189) neutrophils sepsis
capture platelet aggregation limiting pathogen multiplication or spreading (206) bacteria bacterial infections
internalization of certain viruses and bacteria by platelets (207) viruses, bacteria HIV, S. aureus
complement C3-mediated binding and presentation to leukocytes (116) gram-positive bacteria bacterial infections
Neutralising recognition and eradication of plasmodia-infected red blood cells (13) red blood cells, plasmo- malaria
of dia
pathogens microbicidal activity of á-granule-derived â-defensins (107) bacteria S. aureus
entrapping of bacteria in cooperation with liver macrophages (14) bacteria Bacillus cereus, (methicillin-resistant)
S. aureus
PNC: platelet-neutrophil complex, sCD40L: soluble CD40 ligand, PMC: platelet-monocyte complex ICAM-1: intercellular adhesion molecule 1, VCAM-1: vascular cell
adhesion molecule, GP: glycoprotein, PSGL-1: P-selectin glycoprotein ligand 1, VWF: von Willebrand factor, NET: neutrophil extracellular trap, HIV: human immu-
nodeficiency virus.

Other important adhesion molecules mediating cell-cell inter-
actions are integrins and surface glycoproteins. Platelets express
several β1 and β3 integrins, including integrins α5β1 and α2bβ3
(GPIIb/IIIa) [reviewed in (168, 211)]. Integrin ligands on leuko-
cytes are intercellular adhesion molecule (ICAM) and junctional
adhesion molecules (JAMs) [reviewed in (45, 48, 212)]. Fur-
thermore, GPIbα of the GPIb/IX/V receptor complex interacts di-
rectly with Mac-1 on monocytes and neutrophils (205) and GPVI
mediates platelet recruitment and activation after collagen expo-
sure facilitating secondary leukocyte capture [reviewed in (45)].
Increased PNC and PMC circulation was observed in patients
with sepsis, atherosclerosis, inflammatory bowel disease, and
cystic fibrosis (17, 44, 213) [reviewed in (44, 214)]. Finally, pla-
telet-monocyte interactions are mediated and controlled by the co-
stimulatory CD40/CD40L axis (126, 129) [reviewed in (129)].
During endotoxaemia, platelets tether and roll on endothelium
and subendothelium via GPIbα and P-selectin, followed by GPIIb/
IIIa-mediated firm adhesion [reviewed in (10, 48, 212)]. This sub-
sequently induces PSGL-1-mediated rolling of neutrophils on the
P-selectin-expressing platelet layer. Neutrophil Mac-1 captures fi-
brinogen, which is presented by platelet GPIIb/IIIa and GPIbα, re-
sulting in neutrophil adhesion, a sequence of neutrophil recruit-
ment that was recently deciphered in a murine model of encepha-
lomyelitis (215). Accordingly, the infusion of lipopolysaccharide
into humans induces PNC and PMC formation (216, 217). In
summary, platelets closely interact with monocytes (218–220) and

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 686 Duerschmied et al. Platelet immunity
Infections and the role of plasma
proteins and platelets
Figure 2: During lipopolysaccharide-induced peritonitis platelets
form complexes with leukocytes, which interact with the venous
vessel wall (own unpublished observations).
neutrophils (221) to regulate their recruitment to sites of inflam-
mation. In addition, PMC formation regulates the release of sev-
eral inflammatory mediators such as MDP-1, IL-8, TNF-α, IL-1β,
or MIP-1 [reviewed in (21)].
NET formation
Lipopolysaccharide (LPS)-activated platelets provoke the degranu-
lation of neutrophils (189). Plasma from septic patients activates
TLR4 on the platelet surface, inducing PNC formation, which cul-
minates in the release of NETs. Septic NET formation in mice oc-
curs primarily in liver and lung and supports pathogen clearance
by trapping (189) and finally neutralising of bacteria (222). Pla-
telet-neutrophil interactions ultimately further enhance phagocy-
tosis of pathogens (198). Triggering of NET formation by platelets
was found in murine models of bacterial and viral infection (223,
224). NETs have recently also been found in atherosclerotic
lesions, suggesting that NET formation may also be involved in
chronic inflammation (225). Indeed, the level of circulating NET
components is associated with advanced atherosclerosis in pa-
tients with coronary artery disease (226). Finally, NETs and func-
tional leukocytes are an integral part of venous thrombosis, coin-
ing the expression “immunothrombosis” (2, 227). Patients with
thrombotic microangiopathies accordingly show increased levels
of circulating DNA and myeloperoxidase (228). NETs hence ap-
pear to be beneficial in severe bacterial infections, but may be an
attractive target for limiting immunothrombotic complications,
e.g. by degradation of extracellular chromatin.
Pathogen capture and killing
In addition to NET-mediated pathogen capture, platelets are also
able to bind and sequester bacteria directly in experimental mod-
els (8, 206): In vitro, platelets aggregate around bacteria entirely
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“encapsulating” them to impede bacterial proliferation. HIV and S.
aureus were even documented to be internalised by activated pla-
telets (207). Both, HIV and S. aureus, were packed into engulfing
vacuoles that eventually fused with α-granules, possibly neutralis-
ing these pathogens. Platelets also aggregate around bacteria cap-
tured by Kupffer cells, facilitating pathogen neutralisation in a co-
operative effort between resident macrophages and recruited pla-
telets (14). Antimicrobial activity of platelets was also found in
murine malaria, where platelets bind P. falciparum-infected red
blood cells and release PF4 to kill the infected red blood cells to-
gether with the parasite (13). Similarly, platelet β-defensins directly
neutralise S. aureus (107). In mice, platelets bind Listeria monocy-
togenes (and other gram-positive bacteria) via GPIb and comple-
ment C3 to facilitate the directed transport of the bacteria to DCs
in the spleen for clearance (116). Therefore, platelets not only
modulate immune functions of leukocytes but also contribute di-
rectly to the capture and in some cases even killing of pathogens. It
is unclear if these mechanisms can be exploited for patient treat-
ment.
Potential future targets of platelet directed
anti-inflammatory therapies
Inhibitors of platelet adhesion receptors (e.g. GPIIb/IIIa inhibitors)
have been successfully developed in the past for the interference
with haemostatic/thrombotic platelet functions. Selectively target-
ing activated platelets with confirmation specific GPIIb/IIIa in-
hibitors was the next logical step (229). Advancement of this tech-
nology to produce inert (non-function blocking) activation-spe-
cific single-chain antibodies allows the targeting of activated pla-
telets and has successfully been used to enrich molecular contrast
agents at the site of inflammatory vascular injury and
(micro-)thrombosis (230–233) or to facilitate local fibrinolysis
(234, 235). The targeted inhibition – or enhancement – of immu-
nological platelet functions could be an attractive novel strategy
(236). Platelet TLRs are promising candidates for such a targeted
strategy. Of note, systemic targeting strategies (that bear the risk of
systemic adverse effects) are currently entering clinical phase II
trials with a TLR2 blocking antibody in IR injury (237).
Conclusion
Although the vast diversity of platelet immunity is well docu-
mented in animal or observational studies, it is surprising to note
that the pathophysiological relevance of platelet immune functions
is not well established in humans. Neither protection from autoim-
mune disorders nor an increase in infectious complications has yet
been noted in the millions of cardiologic patients treated with pla-
telet inhibitors in clinical or post-marketing studies. Pre-clinical as
well as clinical trials are therefore needed to make a “clinical mean-
ing” of the diverse data summarized here, before patients can
benefit from this knowledge.
© Schattauer 2014

Conflicts of interest
None declared.
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