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Infections and the role of plasma
proteins and platelets
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Theme Issue Editorial
Infections and the role of plasma proteins and platelets
Christine Mannhalter
Department of Laboratory Medicine, Medical University Vienna, Vienna, Austria
In this Theme Issue of Thrombosis and
Haemostasis, six contributions by experts
in the field of coagulation and immune defence were collected. The articles address
the role of the plasmatic coagulation system, fibrinogen and factor XIII at the intersection of coagulation and inflammation,
the immune function of platelets, the role
of platelets in infection and the formation
of neutrophil extracellular traps, platelets
in sepsis and platelet immunology in fungal infections.
Recently, it has been shown that platelet-rich plasma (PRP) and platelet-poor
plasma (PPP) provide early protection
against bacterial infections during surgical
interventions. The effect of PRP was higher
than that of PPP which presumably was
due to the larger quantity of platelets. Platelets are the most abundant cells with immune functions present in the circulation,
and they apparently make PRP particularly
valueable for tissue healing and microbicidal activity (1). Platelets are small anucleate
cells circulating in the blood. They adhere
and aggregate at the site of vascular injury
which is critical for efficient haemostasis
and initiation of clot formation to seal injured vessels and prevent major blood loss.
Activation of the haemostatic system has to
occur locally, any systemic activation can
cause severe problems including thromboembolism and disseminated intravascular coagulation (DIC) resulting in morbidity and even mortality. The haemostatic
system comprises a cascade of enzymatic
events of the plasmatic coagulation proteins which has been extensively studied
Correspondence to:
Prof. Christine Mannhalter
Department of Laboratory Medicine
Medical University Vienna, Vienna, Austria
E-mail: [email protected]
Received: September 2, 2014
Accepted: September 2, 2014
Epub ahead of print: September 11, 2014
http://dx.doi.org/10.1160/TH14-09-0721
Thromb Haemost 2014; 112: 630-631.
since the early 1960. Yet, the contribution
of coagulation proteins to immune defence
at a very early stage of microbial invasion
has only recently received intensive attention. In their contribution van der Poll and
Herwald (2) review the reaction of plasma
proteins to an invading pathogen leading
to an activation of the extrinsic (specifically
tissue factor and tissue factor pathway inhibitor 1) and the intrinsic coagulation system (particularly the contact factors) and
the potential elimination of the pathogen.
They discuss the generation and function
of bradykinin as potent inflammatory
mediator and contributor to early defence
against microorganisms which had been
shown previously by Monteiro (3). They
also outline modes of action of protease activated receptors (PAR), and they give
examples of peptide sequences in the carboxyterminal region of several coagulation
proteins that develop antimicrobial activity
when proteolytically liberated. A connection between the coagulation system and
the innate immune system is discussed on
the basis of the shared ancestry of vertebrate coagulation factors with complement
proteins. Previously, phylogenetic studies
have shown that a simple coagulation system comprising proteins that are structurally related to fibrinogen, and factor XIII
existed already in primitive anthropods.
Together with the precursors of platelets,
the so called haemocytes, these proteins
had also anti-microbial features (4, 5).
Today we know that during fibrin
formation active peptides are released from
fibrinogen which influence cellular processes. Sequence regions in the fibrinogen
α, β and γ chain and in factor XIII contribute to inflammatory processes. Some of
these regions have been identified and their
function and the interaction partners, e.g.
the complement system, are addressed by
B. Hoppe in this theme issue (6). He describes the regulation of fibrinogen synthesis as well as it‘s variation during acute
phase reaction, and he discusses the fibrin
matrix as inflammation mediator. Fur-
thermore, he presents interesting effects of
FXIII, such as the regulation of locomotion
and phagocytosis.
In the contribution on the immune
function of platelets Duerschmied et al.
present important clinical and experimental evidence (7). They outline that cessation
of antiplatelet therapy could theoretically
improve infectious disease outcome, but
any evidence for that is currently missing.
Antiplatelet therapy has not been linked to
an increase in infectious disease prevalence
or morbidity. There are no epidemiologic
data showing that platelet suppression affects infections. Furthermore, patients with
GPIb deficiency in Bernard-Soulier syndrome are not known to suffer from immune defects. Duerschmied et al. also refer
to the important property of platelets to
newly synthesise mediators such as interleukin (IL)-1β following signal-dependent
splicing of pre-mRNA which is present in
platelets (8). It is known that platelet activation is associated with the release of chemokines and proinflammatory lipids
which induce pleiotropic effects on many
tissues and cells, including leukocytes.
During thrombosis, the recruitment of leukocytes to activated platelets is considered
an important step which not only links
thrombosis to inflammatory responses but
may also enhance procoagulant state. Platelet-leukocyte interaction involves adhesion molecules, chemokines and chemoattractant molecules, various proinflammatory lipids and other materials (9).
Very recently data have been presented that
during systemic infections microvesselthrombosis can occur and mediate an intravascular innate immune response (immunothrombosis). This form of thrombosis is based on the generation of fibrin in
blood vessels and is triggered by neutrophils and their interactions with platelets
(10). Activated neutrophils then release
their granular contents including antimicrobial peptides and a number of serine
and metalloproteinases, and under certain
circumstances they form neutrophil extra-
Thrombosis and Haemostasis 112.4/2014
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Theme Issue Editorial
face expression of P-selectin and increased
platelet-neutrophil adhesion. The activation of platelet TLR-7 represents a link
between platelets and the response to RNA
viruses. Interestingly, platelet-TLR7 stimulation is independent of thrombosis. In
their article de Stoppelaar et al. (13) summarise that inappropriate accumulation
and activation of platelets are key events in
the development of sepsis-related complications. Along a number of examples it is
explained that platelet activation readouts,
e.g. of platelet secreted products (platelet
factor 4, soluble P-selectin), platelet P-selectin surface expression, platelet-leukocyte
complex formation or platelet function
(whole blood impedance aggregometry)
could serve as biomarkers for early sepsis
recognition. In their article the authors also
discuss the role of the complement system
and of FcγRIIa in bacterial sepsis. They
give details on acute kidney and lung injury
and show first experimental results and
data of clinical studies on the effects of
antiplatelet therapy in sepsis. The article by
Speth et al. (14) presents current knowledge on the role of platelets in fungal infections. It highlights aspects of the interaction between platelets and fungi, specifically candida, aspergillus, and cryptococcus, and the relevance of these processes
for the pathogenesis of the fungal infection
at different sites. Besides platelet microparticles, molecules present in the granules of
platelets e.g. serotonin and the complement
system are discussed in regard to the protective role of platelets and the reduction of
the fungal load. In addition, possible
negative effects of platelets are outlined
which could be due to endocytosis of
spores by platelets, followed by their transport through the body and protection of
the pathogen from immune attacks.
Finally, the article also addresses different
aspects of antimycotic therapy in context
with platelets.
There is general agreement that haemostatic proteins and blood platelets not
only modulate immune functions of leukocytes but also contribute directly to the
capture and in some cases even killing of
pathogens. Currently, however, it is still unclear if and how these mechanisms can be
exploited for patient treatment.
Conflicts of interest
None declared.
References
1. Mariani E, Filardo G, Canella V, et al. Platelet-rich
plasma affects bacterial growth in vitro. Cytotherapy 2014; 16: 1294-1304.
2. van der Poll T, Herwald H. The coagulation system
and its function in early immune defense. Thromb
Haemost 2014; 112: 640-648.
3. Monteiro AC, Schmitz V, Svensjo E, et al. Cooperative activation of TLR2 and bradykinin B2 receptor is required for induction of type 1 immunity in
a mouse model of subcutaneous infection by Trypanosoma cruzi. J Immunol 2006; 177: 6325-6335.
4. Zimmermann E. The evolution of the coagulation
system from primitive defense mechanisms. Behring Inst Mitt 1983; 73: 1-12.
5. Opal SM. Phylogenetic and functional relationships between coagulation and the innate immune
response. Crit Care Med 2000; 28 (9 Suppl):
S77-80.
6. Hoppe B. Fibrinogen and factor XIII at the intersection of coagulation, fibrinolysis and inflammation. Thromb Haemost 2014; 112: 649-658.
7. Duerschmied D, Bode C, Ahrens I. Immune functions of platelets. Thromb Haemost 2014; 112:
678-691.
8. Denis MM, Tolley ND, Bunting M, et al. Escaping
the nuclear confines: signal dependent pre-mRNA
splicing in anucleate platelets. Cell 2005; 122:
379-391.
9. Ghasemzadeh M, Hosseini E. Platelet-leukocyte
crosstalk: Linking proinflammatory responses to
procoagulant state. Thromb Res 2013; 131:
191-197.
10. Engelmann B, Massberg S. Thrombosis as an intravascular effector of innate immunity. Nat Rev
Immunol 2013; 13: 34-45.
11. Brinkmann V, Reichard U, Goosmann C, et al.
Neutrophil extracellular traps kill bacteria. Science
2004; 303: 1532-1535.
12. Andrews RK, Arthur JF, Gardiner E. Neutrophil
extracellular traps (NETs) and the role of platelets
in infection. Thromb Haemost 2014; 112: 659-665.
13. de Stoppelaar SF, van 't Veer C, van der Poll T. The
role of platelets in sepsis. Thromb Haemost 2014;
112: 666-677.
14. Speth C, Rambach G, Lass-Flörl C. Platelet immunology in fungal infections. Thromb Haemost
2014; 112: 632-639.
15. Frenette PS, Johnson RC, Hynes RO, et al. Platelets
roll on stimulated endothelium in vivo: an interaction mediated by endothelial P-selectin. Proc Natl
Acad Sci USA 1995; 92: 7450-7454.
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© Schattauer 2014
Thrombosis and Haemostasis 112.4/2014
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Infections and the role of plasma
proteins and platelets
cellular traps (NETS) (11). Immunothrombosis is mediated by neutrophil elastase,
tissue factor and coagulation factor XII.
While the plasma contact system comprising factor XII, prekallikrein and high-molecular-weight kininogen, triggers the kallikrein-kinin system, the intrinsic pathway
of coagulation, the classical complement
cascade and the fibrinolytic system, the
main route by which infections initiate coagulation seems to be via tissue factor. Also
in this Theme Issue, Andrews et al. review
NETs and the role of platelets in infection
(12). They summarise how platelets orchestrate the involvement of neutrophils at
sites of injury and inflammation, how
NETs influence platelet function, and how
they modulate platelet-driven coagulation.
The electroststatically charged NETs limit
dispersion of pathogens by entrapping
them, but they also trigger intrinsic coagulation. The authors refer to recent studies
showing that bacterial DNA may substitute
for heparin in the formation of antigenic
complexes similar to those known in heparin-induced thrombocytopenia (HIT).
This could imply that the rapid immune response observed in HIT may in part be an
unfortunate consequence of a misdirected
platelet-immune response to bacterial infection. The articles by de Stoppelaar et al.
(13) and Speth et al. (14) review the role of
platelets in sepsis and discuss platelet immunology in fungal infections. Both contributions make it very clear that platelets
are important immune cells and contribute
to innate and adaptive immunity. Once
again examples are presented that they
have relevant functions in inflammation
and in immune response (15). Their proinflammatory molecules and cytokines
(e.g. P-selectin, CD40L, IL-1β, etc.), can
support leukocyte trafficking, modulate
immunoglobulin class switch, and germinal centre formation. Indeed, an intact platelet-fibrinogen plug can form a surface
that allows the recruitment of phagocyting
cells. Platelets express several functional
Toll-like receptors (TLRs), such as TLR-2,
TLR-4, TLR-9 and the most recently investigated TLR-7 (15). It had been shown that
platelet TLR-7 stimulates formation of platelet-neutrophil aggregates which results in
internalisation of platelet fragments by
neutrophils, platelet-granule release, sur-
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