Cardiovascular & Haematological Disorders-Drug Targets, 2008, 8, 99-11799
1871-529X/08 $55.00+.00 © 2008 Bentham Science Publishers Ltd.
Beyond Hemostasis: The Role of Platelets in Inflammation, Malignancy
Archibald McNicol1,2 and Sara J. Israels3,4,*
1Departments of Oral Biology, 2Pharmacology & Therapeutics, 3Pediatrics & Child Healthand4the Manitoba Institute of
Cell Biology, University of Manitoba, Winnipeg, Manitoba
Abstract: Platelets play a complex role in hemostasis and thrombosis. The expression of multiple membrane receptors,
both constitutive and activation-dependent, mediates platelet adhesion and aggregation at sites of vascular lesion. Platelet
activation leads to exocytosis of granular constituents, release of newly synthesized mediators, and discharge of mem-
brane-bound transcellular signaling molecules. Many of the same mechanisms that play a role in hemostasis and thrombo-
sis facilitate platelet participation in other physiological or pathological processes including inflammation, malignancy
and the immune response. Platelet receptors such as GPIb/IX/V, P-selectin, P-selectin glycoprotein ligand 1, CD40 and
the ?IIbß3 integrin, crucial to hemostasis, have been implicated in the progression of such inflammatory conditions as
atherosclerosis, rheumatoid arthritis and inflammatory bowel disease, in the progression and metastatic spread of malig-
nancies, and in the immune response to bacterial challenge. The release of platelet granular contents, including adhesive
proteins, growth factors and chemokines/cytokines, that serve to facilitate hemostasis and wound repair, also function in
acute and chronic inflammatory disease and in tumor cell activation and growth. Platelets contribute to host defence as
they recognise bacteria, recruit traditional immune cells to the site of infection and secrete bactericidal mediators. The
primary focus of this review is the “non-haemostatic” functions of platelets in physiological and pathological states.
Key Words: Platelets, inflammation, metastasis, angiogenesis, immunity.
biconvex disc structure with an equatorial diameter of 2-3
?m, and are anucleate. They are derived from progenitor
megakaryocytes in the bone marrow. Following their normal
life-span of 8-10 days they are removed from the circulation
during passage through the spleen. The role of platelets in
hemostasis was recognised very early ; their role in
thrombosis sometime later . The consequences of platelet
dysfunction, and the potential of the platelet as a therapeutic
target, have been realized and exploited .
Platelets are the smallest cells in circulating blood, have a
stasis are shared by a single cell type. The best-characterized
examples of this are the nucleated amebocytes of the horse-
shoe crab--these aggregate and release their granule contents
in response to such stimuli as exposure to foreign surfaces or
bacterial endotoxin . Non-mammalian vertebrate throm-
bocytes and mammalian platelets have retained non-hemo-
static roles in host defence and inflammation. During the last
decade, advances in functional analyses, knock-out models,
microscopy and characterization of the platelet proteome
have dramatically expanded our understanding of the role of
platelets in a variety of patho-physiological states, including
inflammatory disorders, tumor progression and infection.
In invertebrates the functions of host defence and hemo-
PLATELETS IN HEMOSTASIS AND THROMBOSIS
lets are found primarily along the vessel wall, well posi-
The dynamics of blood flow dictate that circulating plate-
*Address correspondence to this author at the Manitoba Institute of Cell
Biology, Rm. ON2021A, 675 McDermot Ave. Winnipeg, Manitoba, Canada,
R3E 0V9; Tel: (204) 787-4141; Fax: (204) 786-0195;
tioned for rapid response at sites of endothelial lesions. The
platelet response to vessel wall injury with exposure of sub-
endothelial collagen is characterized by the phases of adhe-
sion, amplification and stabilization. This response is medi-
ated by a variety of cell surface receptors, some of which are
constitutively present in an active conformation, some of
which require structural rearrangement to gain functional
integrity, and others that translocate to the platelet surface
following platelet activation .
an initial adhesive receptor at the endothelial lesion by bind-
ing to collagen-associated von Willebrand Factor (vWF).
Under low shear conditions, collagen binds to platelets via
the ?2ß1 integrin (GPIa/IIa); GPVI and CD36 also bind to
collagen. Interestingly, both GPIb/IX/V and CD36 are plate-
let receptors for thrombospondin-1, an alternative to vWF in
mediating platelet adhesion under defined conditions. Sev-
eral other platelet surface integrins function as adhesive re-
ceptors, notably ?IIbß3 (immobilized fibrinogen), ?5ß1 (fi-
bronectin), ?Vß3 (vitronectin) and ?6ß1 (laminin) .
The platelet glycoprotein (GP) Ib/IX/V complex acts as
gage specific receptors that result in platelet activation and
amplification of the initial response as additional platelets are
attracted to the site. Thrombin, a product of the coagulation
cascade, is a powerful platelet agonist, mediated by the pro-
tease-activated receptors (PAR) 1 and 4, and by GPIb/ IX/V.
Activated platelets release ADP and thromboxane (Tx) A2,
both of which promote positive feedback stimuli via P2Y1
and P2Y12, and via TP? and TPß receptors, respectively. In
addition, platelets express receptors for epinephrine, platelet
activating factor (PAF), serotonin, vasopressin and immuno-
Following adhesion, a number of soluble mediators en-
100 Cardiovascular & Haematological Disorders-Drug Targets, 2008, Vol. 8, No. 2 McNicol and Israels
globulin G (IgG), each contributing to, and enhancing, plate-
let activation .
through two specific processes: First the release, by exocyto-
sis from platelet dense granules, of serotonin and of a non-
metabolic pool of ADP- the latter, in particular, is an impor-
tant secondary mediator of platelet activation . Second the
synthesis and release of TxA2 a pro-aggregatory mediator
critical to the full haemostatic function of the platelet .
TxA2 is generated by the sequential actions of phospholipase
A2, which liberates arachidonic acid from membrane phos-
pholipids, cyclooxygenase-1, which converts arachidonic
acid to prostaglandin endoperoxides (PGG2/PGH2), then
thromboxane synthetase for the final synthesis of TxA2. At-
tenuation of either of these amplification pathways inhibits
platelet function and significantly prolongs bleeding in
vivo. Therapeutic ADP receptor antagonists, such as clopi-
dogrel, and the cyclooxygenase inhibitor aspirin are effective
Additional platelets are recruited to the site of injury
mechanisms combine with the fragile layer of adherent plate-
lets at the site of injury to form a consolidated hemostatic
plug, or aggregate. This is facilitated by an activation-
mediated conformational change in the ?IIbß3 integrin, lead-
ing to the expression of its adhesive protein binding domain.
Fibrinogen is the major physiological ligand for this domain-
a bivalent molecule, fibrinogen binds to ?IIbß3 molecules on
adjacent platelets, establishing firm cross-linking to form a
stable plug .
Additional platelets recruited by ADP- or TxA2-mediated
two other exocytotic processes occur during platelet activa-
tion: the release of alpha granules and of lysosomal granules.
Alpha granules contain a large number of proteins of diverse
function, including adhesive proteins, chemokines, cytoki-
nes, coagulation factors and protease inhibitors (Table 1;
note that this table provides the definitions for all alpha
granule protein abbreviations that appear in the text) [7,8].
Lysosomal granules contain a variety of acid proteases, acid
glycosidases, acid phosphatases and aryl sulfatases .
In addition to the release of dense granule constituents,
with the plasma membrane, resulting in the translocation of
granular membrane proteins onto the platelet surface. In this
way, increased numbers of constitutively-expressed proteins,
and novel proteins, appear on the platelet surface. Proteins
up-regulated on the platelet surface in this manner include
the ?IIbß3 integrin, P-selectin (CD62P), CD63, and the
CD40 ligand (CD40L; CD154) .
During the process of exocytosis, granular membranes fuse
branes is significantly altered following activation. The in-
crease in expression of phosphatidylserine on the external
leaflet of the plasma membrane provides a larger surface
area for the assembly of coagulation factor complexes and
generation of thrombin. Two populations of small membrane
vesicles, microparticles and exosomes, are released from
activated platelets . Microparticles have a similar phos-
phatidylserine-enriched composition to that of the plasma
The phospholipid component of platelet plasma mem-
membrane of activated platelets and serve to significantly
increase the surface area available for thrombin generation.
Thrombin activates additional platelets and cleaves fibrino-
gen to fibrin; polymerized fibrin stabilizes the platelet plug.
Exosomes are smaller membrane vesicles released from acti-
vated platelets following fusion of multivesicular bodies and
alpha granules with the plasma membrane . Although
exosomes do not have procoagulant function, they do ex-
press CD63 and prion protein, and have been implicated in
the inter-cellular transfer of information.
PLATELETS AND INFLAMMATION
mation came, not surprisingly, from a pair of observations
related to atherosclerosis [10,11]: that atherosclerosis was an
inflammatory lesion, and that platelets were not merely pas-
sive constituents trapped in the atherosclerotic plaque. The
etiology of atherosclerosis is highly complex [12,13] and a
detailed description is beyond the scope of this review.
Briefly, increased levels of circulating low density lipoprotein
(LDL) diffuse through endothelial cell junctions into the sub-
endothelial matrix. The trapped LDL undergoes a variety of
structural modifications, including lipid oxidation, resulting
in the formation, and trapping, of minimally oxidized LDL.
The accumulation of minimally oxidized LDL triggers the
activation of the overlying endothelial cells. This activation
is characterized by a loss of vascular integrity, cytokine pro-
duction, and the expression and shedding of leukocyte adhe-
sive molecules , leading to the recruitment and binding
ofmonocytesandlymphocytes.These leukocytes “roll” along
the endothelium and pass through endothelial cell junctions
in a classic inflammatory response. The intensity of the re-
sponse is regulated by multiple factors, including genetic fac-
tors, elevated levels of free radicals generated by smoking,
hypertension or diabetes mellitus, elevated levels of homo-
cysteine, sex hormones and infections (e.g. herpes virus,
Chlamydophila pneumoniae). Sub-endothelial monocytes
proliferate and differentiate into macrophages that engulf
highly oxidized LDL to form foam cells - accumulation of
these cells appear as fatty streaks; they release extracellular
lipids to form a necrotic core. Under the influence of cytoki-
nes and growth factors a mature atherosclerotic fibrous
plaque is formed as the necrotic core enlarges, becomes cal-
cified and is infiltrated by smooth muscle cells [12,13].
The first suggestion that platelets have a role in inflam-
incorporated into the thrombus that forms at the site of ma-
ture plaque, their role in the early stages of atherosclerosis
has been recognised more recently [15; Fig. (1)]. The charac-
terization of the platelet releasate has identified a large num-
ber of proteins with significant pro-inflammatory properties,
including PF4, interleukin (IL)-1ß and RANTES . Studies
using a variety of murine knockout models established that
quiescent platelets adhere to, and roll on, stimulated endothe-
lial cells and demonstrated that there was a delay in the pro-
gression of the disease when certain adhesive proteins were
Although it has been long appreciated that platelets are
Beyond Hemostasis Cardiovascular & Haematological Disorders-Drug Targets, 2008, Vol. 8, No. 2 101
lets to activated endothelial cells has been the subject of con-
siderable study. In vitro studies using activated human um-
bilical cord endothelial cells (HUVECs) demonstrated that
antibodies to either vWF or ?IIbß3 attenuate platelet adhe-
sion, supporting the role of these proteins in the process .
Furthermore, blocking antibodies to the primary platelet
vWF receptor GPIb/IX/V inhibited atherosclerotic plaque
formation in an apoE-/- murine model, establishing vWF as a
mediator of platelet adhesion to dysfunctional (i.e. where
endothelial cell-dependent vasodilation is impaired ), and
to activated endothelial cells [16,18].
The process underlying the adhesion of quiescent plate-
related development of atherosclerosis. P-selectin is expressed
only on the surface of activated platelets and, similarly, is ex-
pressed following activation of endothelial cells. Intravital
microscopy studies in mice have demonstrated that quiescent
platelets initially bind loosely to, and then roll on, endothe-
P-selectin has been implicated as a factor in the platelet-
lial cells; these processes are mediated by the expression of
P-selectin on endothelial cells, but not on the platelets
[16,17,19]. P-selectin glycoprotein ligand 1 (PSGL-1; CD15)
and GPIb/IX/V have both been implicated as P-selectin
counter-receptors on the platelet surface. Both PSGL-1 and
GPIb/IX/V are constitutively expressed on the surface of
quiescent platelets and probably function in tandem to medi-
ate the initial interaction of platelets with endothelial cell P-
selectin [16,17,19]. Regardless of the counter-receptor(s)
involved, the P-selectin-mediated adhesion is fragile and
reversible (Fig. (1b)).
ates a number of events with important pro-inflammatory
implications. Activated platelets express several integrins in
their “open” conformation, of which ?IIbß3 is the most im-
portant [16,17,19]. The ?IIbß3 binds adhesive proteins such
as fibrinogen, vWF and fibronectin which tether the platelets
to ICAM-1 and ?Vß2 on activated endothelial cells, thereby
consolidating platelet adhesion (Fig. (1c)). Studies in an
apoE/?IIb double-deficient murine model showed signifi-
During the adhesion process, activation of platelets initi-
Table 1. Platelet Alpha Granule Constituents
Adhesive Proteins Chemokines Other
Fibrinogen ? chain
Fibrinogen ? chain
Fibrinogen ? chain
Von Willebrand Factor (vWF)
Connective Tissue-Activating Peptide (CTAPIII; CXCL7)
Epithelial Neutrophil Activating Peptide (ENA-78; CXCL5)
Interleukin-8 (IL-8; CXCL8)
Macrophage Inflammatory Protein 1? (MIP-1?; CCL3)
Monocyte Chemoattractant Protein-1 (MCP-1; CCL2)
Monocyte Chemoattractant Protein-3 (MCP-3; CCL7)
Neutrophil-Activating Peptide-2 (NAP-2; CXCL7)
Platelet Basic Protein (CXCL7)
Platelet Factor (PF4; CXCL4)
Platelet Factor 4 variant 1 (PF4alt; CXCL4L1)
Regulated upon Activation, Normal T-cell Expressed, and Se-
creted (RANTES; CCL5)
Stromal Cell-Derived Factor (SDF-1; CXCL12)
Thymus and Activation-Regulated Chemokine (TARC; CCL17)
?-Thromboglobulin (?-TG; CXCL7)
Cytokines Growth Factors
High Mobility Group Box
Basic fibroblast growth factor (bFGF)
Epidermal growth factor (EGF)
Hepatocyte growth factor (HGF)
Insulin-like growth factor-1 (IGF-1)
Insulin-like growth factor-2 (IGF-2)
Platelet-derived endothelial cell growth factor (PD-ECGF)
Platelet-derived growth factor (PDGF)
Transforming growth factor (TGF-?)
Vascular endothelial growth factor A (VEGF-A)
Vascular endothelial growth factor C (VEGF-C)
Amyloid ?-A4 protein
High-molecular weight kininogen (HMWK)
Matrix metalloproteinase-2 (MMP-2)
Plasminogen activator inhibitor (PAI-1)
Protein C inhibitor
Secretory granule proteoglycan core protein
Tissue inhibitor of metalloproteinase (TIMP-4)
von Willebrand antigen-II
Protein and peptide contents of alpha granules that are released upon platelet activation, in response to a variety of stimuli. From Harrison and Cramer  and Coppinger et al. .
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Received: 14 July, 2007 Revised: 07 November, 2007 Accepted: 12 November, 2007