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1Australian
Centre for Blood Diseases, Alfred Medical Research and Education Precinct, Monash University,
Melbourne, Australia
Platelets have evolved highly specialized adhesion mechanisms that enable cell-matrix and cell-cell interactions
throughout the entire vasculature irrespective of the prevailing hemodynamic conditions. This unique property of
platelets is critical for their ability to arrest bleeding and promote vessel repair. Platelet adhesion under conditions of
high shear stress, as occurs in stenotic atherosclerotic arteries, is central to the development of arterial thrombosis;
therefore, precise control of platelet adhesion must occur to maintain blood fluidity and to prevent thrombotic or
hemorrhagic complications. Whereas the central role of platelets in hemostasis and thrombosis has long been
recognized and well defined, there is now a major body of evidence supporting an important proinflammatory function
for platelets that is linked to host defense and a variety of autoimmune and inflammatory diseases. In the context of the
vasculature, experimental evidence indicates that the proinflammatory function of platelets can regulate various
aspects of the atherosclerotic process, including its initiation and propagation. The mechanisms underlying the
proatherogenic function of platelets are increasingly well defined and involve specific adhesive interactions between
platelets and endothelial cells at atherosclerotic-prone sites, leading to the enhanced recruitment and activation of
leukocytes. Through the release of chemokines, proinflammatory molecules, and other biological response modula-
tors, the interaction among platelets, endothelial cells, and leukocytes establishes a localized inflammatory response
that accelerates atherosclerosis. These inflammatory processes typically occur in regions of the vasculature
experiencing low shear and perturbed blood flow, a permissive environment for leukocyte-platelet and leukocyte-
endothelial interactions. Therefore, the concept has emerged that platelets are a central element of the atherothrom-
botic process and that future therapeutic strategies to combat this disease need to take into consideration both the
prothrombotic and proinflammatory function of platelets.
Hematology 2011 51
Figure 1. Hemostatic and prothrombotic function of platelets under flow. (A) Platelet adhesion mechanisms operating under arterial flow. After
disruption of the endothelium, platelets are rapidly recruited from flowing blood via a tethering mechanism dependent on the interaction of platelet
GPIb-V-IX and VWF. This adhesive bond has a rapid dissociation rate, resulting in platelet translocation on the vessel wall. (B) Platelet firm adhesion
and aggregation. Translocating platelets engage collagen in the vessel wall through their adhesion receptors GPVI and 21. GPVI is the major
collagen receptor inducing intracellular calcium flux necessary for stable platelet adhesion, cytoskeletal reorganization, IIb3 activation, and the release
of the soluble agonists (ADP and TxA2). These agonists act through specific G-protein coupled receptors to amplify the platelet activation response.
TxA2 is derived from the metabolism of arachidonic acid via the COX-1 pathway, whereas ADP is released from platelet-dense granules. Locally
generated thrombin also enhances platelet activation through proteolytic cleavage and activation of PARs. Activated platelets form stable aggregates
through IIb3 engagement of VWF and fibrinogen. These molecular pathways of amplification of platelet activation are the target of both clinically
available and experimental therapeutic interventions in the treatment of atherothrombotic disease. (C) Stabilization of the platelet thrombus. The primary
hemostatic plug is consolidated by fibrin generation at the site of injury and throughout the developing thrombus. -Thrombin generation at the injured
vessel wall is critically dependent on TF, whereas thrombin generation on the surface of activated platelets is likely to evolve both TF and contact
factor dependent activation of blood coagulation. UHF indicates unfractionated heparin; LMWH, low-molecular-weight heparin; VKA, vitamin K
antagonist; PGH2, prostaglandin H2; AA, arachidonic acid, PLA2, phospholipase A2; IP3R, inositol trisphosphate receptor; ITAM, immunoreceptor
tyrosine-based activation motif; FcR, Fc receptor gamma.
the prevailing blood-flow conditions. Under conditions of high component of the platelet GPIb-V-IX complex.6 Circulating plasma
shear stress, as encountered in arterioles and stenotic arteries, VWF VWF has limited binding potential for GPIb, however, once
plays a critical role in recruiting platelets from blood flow.5 This immobilized onto subendothelial collagen (type I, III, and VI), the
tethering function of subendothelial VWF is dependent on the unfolded VWF macromolecule provides a linear array of A1
interaction of its A1 domain with the glycoprotein Ib (GPIb) domains that facilitate binding to multiple GPIb receptors.7,8 The
Hematology 2011 53
Figure 2. Procoagulant function of platelets. (A) Plasma membrane phospholipids are asymmetrically distributed in resting platelets, with PS
confined to the inner leaflet. After platelet activation by potent agonists, high levels of sustained intracellular calcium triggers scramblase activity.
Scramblase activation results in the loss of phospholipid asymmetry and PS exposure on the outer leaflet of the platelet membrane, providing the
requisite surface for rapid thrombin generation. (B) PS exposure can be induced through two distinct cell-death pathways; apoptosis and necrosis.
Apoptosis results in assembly of the Bak/Bax mitochondrial membrane pore, causing release of cytochrome C (CytC), caspase activation, and
substrate proteolysis. Necrotic cell death can be initiated by elevated cytosolic Ca2, causing a loss in mitochondrial membrane potential and
subsequent formation of a mitochondrial permeability transition pore (mPTP). mPTP formation results in bioenergetic failure through ATP depletion with
consequent reactive oxygen species (ROS) generation, leading to loss of membrane integrity. (C) Platelets can also contribute to thrombin generation
via activation of FXII through the release of polyphosphate from dense granules. (D) Whether there are additional cell death pathways regulating PS
exposure and the procoagulant function of platelets remains unclear. PC indicates phosphatidylcholine.
termination of the protein has been demonstrated in a patient with instability and the release of intracellular contents into the extracel-
Scott syndrome.41 lular environment. Recently, evidence has emerged that platelet
stimulation by potent agonists initiates a tightly regulated cell death
Cell death and the procoagulant function of platelets pathway mediated by sustained high levels of cytosolic Ca2,
(Figure 2) culminating in distinct morphological and biochemical changes that
Procoagulant platelets expressing PS exhibit distinct morphologic are consistent with a necrotic cell death pathway.43 Direct induction
and biochemical features relative to fully activated platelets. Many of apoptosis can also induce PS expression and platelet procoagu-
of these changes are indicative of dead or dying cells, and include lant function,43 raising the possibility that multiple cell death
membrane blebbing, microvesiculation, activation of intracellular pathways may regulate thrombin generation on the surface of
proteases, and the cleavage of cytoskeletal proteins, PS surface platelets. In addition to promoting thrombin generation, procoagu-
exposure, and alterations in mitochondrial membrane potential.42 lant platelets may also contribute to the inflammatory response by
These results suggest that the pathways regulating cell death in generating high levels of the proinflammatory lipid platelet-
platelets may play an important role in regulating the platelet activating factor (PAF) and by enhancing leukocyte adhesion.44
procoagulant phenotype. Programmed cell death is orchestrated by
several pathways, including apoptosis, necrosis, and autophagy. Proinflammatory role of platelets
Apoptosis is an energy-dependent process contingent upon caspase Promiscuous platelets
activation and is critical for the removal of senescent cells. Necrosis The growing list of pathophysiological processes in which platelets
is typified by bioenergetic failure of the cell resulting in membrane have a proposed role is in part a reflection of the large number of
different cell types with which platelets can interact. These include for P-selectin include GPIb and P-selectin glycoprotein-1 (PSGL-
endothelial cells, neutrophils, monocytes, dendritic cells, cytotoxic 1),51,52 which support tethering and rolling, but not firm adhesion on
T-lymphocytes, malaria-infected red blood cells, and various tumor inflamed endothelium. Whereas there is some uncertainty as to the
cells. In the context of atherosclerosis, the interaction of platelets exact mechanism supporting stable platelet adhesion to activated
with endothelial cells and leukocytes appears to be important for the endothelium, in vitro and in vivo models suggest that binding of
initiation and propagation of inflammatory processes in the arterial IIb3 to fibrinogen bound to endothelial v3 or ICAM-1 facilitates
wall.45 firm platelet adhesion and activation.53,54
Hematology 2011 55
Table 1. Bioactive platelet mediators underlying atherothrombosis
Localization within the
platelet Released molecule Target cell Function
Dense granules ADP Platelet P2Y1 and P2Y12 Platelet activation
ATP Platelet P2X1 Platelet activation and sensitization to other
agonists
5HT Platelet 5HT2A Weak platelet agonist
Endothelium 5HT2B NO synthesis: vasodilation, platelet inhibitor
Vascular smooth muscle Vasoconstriction
Monocytes T-cell activation: proinflammatory
granules
Adhesion receptors IIb3 Platelet Platelet aggregation, platelet-endothelial, and
platelet-leukocyte adhesion
Coagulation factors FV Procoagulant
Adhesive ligands VWF Platelet Platelet-endothelium and platelet-vessel wall
tethering and platelet aggregation
Fibrinogen Platelet Platelet aggregation, fibrin clot formation, and
platelet-leukocyte adhesion
Fibronectin Platelet Platelet-endothelial and platelet-leukocyte
adhesion
P-selectin Platelets, endothelial cell and Adhesion of leukocytes to platelets and
leukocytesPSGL-1 endothelial cells
Chemokines CXCL4 (PF-4) Leukocytes Synergizes with other cytokines to promote
leukocyte adhesion and monocyte
differentiation
CXCL7 (PBP, -TG, CTAP-III, Leukocytes Enhances neutrophil and monocyte adhesion
and NAP-2) and neutrophil transendothelial migration
CCL5 (RANTES) Endothelium/leukocytes Promotes monocytes adhesion to the
endothelium and chemokine synthesis
Growth factors PDGF Vascular smooth muscle Stimulates vascular smooth muscle cell
cells migration and proliferation associated with
intimal hyperplasia
Synthesized cytokines IL-1 Endothelial cells Up-regulation of leukocyte adhesion molecules
and stimulation of endothelial release of
proinflammatory cytokines
granule and platelet
membrane
CD40 Ligand Endothelial cell CD40 Upregulation of leukocyte adhesion molecules
and stimulation of endothelial release of
proinflammatory cytokines
Proinflammatory lipids TxA2 Platelets Platelet activation
Leukotriene B4 Leukocytes (BLT-1 and Chemo-attractant and promotion of monocyte
BLT-2) differentiation into foam cells and neutrophil
activation
PAF Platelet/leukocytes Platelet agonist and promotes neutrophil
adhesion
(MCP-1).48,60,62 ICAM-1 and MCP-1 up-regulation by endothelial with its cognate receptor CD40 results in up-regulation of ICAM-1,
cells in response to IL-I is dependent on the activation of NF-B.63 VCAM-1, and E- and P-,selectin as well as the release of IL-6 and
Through this potential mechanism, platelets are able to significantly TF.69 CD40L inhibits endothelial NO production by destabilizing
enhance monocyte and neutrophil adhesion to the endothelium. NO synthase mRNA64,70; therefore, CD40L binding to endothelial
cells results in a proatherogenic and proinflammatory phenotype.64
CD40 ligand (CD40L-CD154; Figure 3). CD40 ligand is an
important platelet-derived bioactive mediator of endothelial cell Platelet-leukocyte cross-talk in atherogenesis
activation. CD40L is a transmembrane protein with structural The central role of leukocytes, especially monocytes and T lympho-
homology to TNF-.64 CD40L was initially identified on the surface cytes, in the development of atherosclerosis is well established.71
of activated CD4 T cells and is central to the function of the There is increasing evidence that activated platelets adherent to the
humoral immune system by supporting B-cell differentiation and inflamed endothelium may enhance leukocyte recruitment, activa-
immunoglobulin class switching.65 It was subsequently demon- tion, and transmigration, thereby enhancing the inflammatory
strated that platelets are a rich source of CD40L,66 with 95% of processes underlying atherosclerosis.
circulating CD40L being of platelet origin.67 After release from
platelets, CD40L interacts which CD40 expressed on numerous cell Leukocyte recruitment to endothelial-bound platelets is a coordi-
types, including endothelial cells, smooth muscle cells, leukocytes, nated, multistep process involving selectin-mediated tethering and
fibroblasts, and platelets.64,68 In endothelial cells, CD40L binding rolling, followed by 2 integrinmediated stable adhesion (Figure
4). Platelet P-selectin has a central role in mediating the initial displayed on the platelet surface, where they exert numerous
capture and rolling of leukocytes through interactions with its key biological activities instrumental in atherosclerosis.77,78
counterreceptor P-selectin glycoprotein 1 (PSGL-1).51,72 Ligation of
PSGL-1 induces signaling events culminating in the activation of
the leukocyte 2 integrins, including macrophage antigen-1 (Mac-1, CXC chemokines NAP-2 and PF4 (Figure 4)
M2) and lymphocyte function-associated antigen-1 (LFA-1, L2), The two most abundant CXC chemokines stored in platelet
which are required to mediate stable leukocyte adhesion. Mac-1 is granules are CXCL7 and platelet factor 4 (PF4). CXCL7 has
the principal 2 integrin that facilitates firm adhesion onto the several molecular variants, including the inactive precursor, connec-
surface of platelets via its binding to multiple ligands, including tive tissue-activating peptide III (CTAP-III), which is enzymatically
GPIb,73 ICAM-2,74 and junctional adhesion molecule-3 (JAM- converted into active neutrophil activating protein-2 (NAP-2)
3),75 as well as through fibrinogen bound to IIb3.48,76 through proteolysis by the neutrophil membrane-associated serine-
protease cathepsin G.79 NAP-2 has been demonstrated to induce
Platelet activation with consequent degranulation results in the neutrophil and monocyte adhesion in vitro and neutrophil transendo-
liberation of numerous chemokines stored in platelet -granules. thelial migration.78,80 The chemotactic properties of PF4 on its own
These chemokines can either be released into the circulation or are controversial because it does not exert classical chemokine
Hematology 2011 57
functions at submicromolar concentrations.78,81 However, PF4 act- Shear effects on the endothelium
ing in concert with other chemokines such as the platelet-derived Endothelial cells in arteries are constantly exposed to dynamic
CC chemokine regulated upon activation normal T-cell expressed alterations in shear due to the pulsatile nature of blood flow.90
and secreted (RANTES) may enhance leukocyte adhesion and However, the rate of fluctuation in blood flow appears to be the
promote monocyte differentiation and atherosclerosis. These PF4- major parameter altering endothelial cell function. Endothelial cells
RANTES heterodimers have been proposed to represent potential respond to flow changes through a variety of mechanotransduction
therapeutic targets in the treatment of atherosclerosis.82 mechanisms, including mechanically gated ion channels and G pro-
teins, force-dependent alterations in membrane fluidity, nuclear
CC chemokine RANTES (Figure 4) deformation, cytoskeletal-dependent junctional signaling, and via
The proinflammatory CC chemokine RANTES is released from primary cilia and the glycocalyx.91 These mechanosensory signaling
activated platelets and deposited on activated endothelium, where it mechanisms are exquisitely sensitive to changes in wall shear stress,
is able to promote adhesion of monocytes.83 A prerequisite for the in leading to alterations in cell morphology, gene-expression profiles,
vivo activity of RANTES function is for it to bind to glycosamino- and increased adhesiveness.92
glycans and to form higher-order oligomers.84 Further, through its
interactions with other modulators, including MCP-4, PF4, and Atheromatous lesions in permissive flow environments for
P-selectin, RANTES has been implicated in inflammation, athero-
leukocyte adhesion
genesis, and vascular remodeling after injury. Interestingly, P-
The mechanisms by which disturbed blood flow influences leuko-
selectin engagement with PSGL-1 on monocytes is insufficient for
cyte adhesion mechanisms remain ill defined. In contrast to
the induction of MCP-1, requiring the cooperation of platelet-
platelets, leukocytes adhere preferentially at low shear regions in the
derived RANTES for chemokine synthesis by monocytes.85 Further,
vasculature, typically at wall shear rates 1000/s. Whereas a
monocytes costimulated by RANTES and P-selectin secrete a
minimum threshold shear is required for leukocyte adhesion,93 there
different cytokine profile, including MCP-1 and IL-8.85 Platelet
is typically an inverse correlation between wall shear and the
activation results in the release of microparticles that are able to
efficiency of leukocyte recruitment, with optimal adhesion around
facilitate the deposition of RANTES on the inflamed and atheroscle-
150/s.93 The site density of P- and E-selectin molecules also plays a
rotic endothelium, thus promoting monocyte adhesion.86
major role in regulating the efficiency of leukocyte adhesion;
therefore, the prevailing flow conditions and the degree of P-selectin
Proinflammatory lipids (Figure 4) expression on the surface of activated endothelial cells and endothe-
In addition to being storage houses for cytokines and chemokines, lial-bound platelets are likely to be major determinants regulating
platelets also generate lipid-derived inflammatory mediators. The leukocyte recruitment to atherogenesis-prone sites.94 Experimental
adhesion of platelets to leukocytes and the endothelium results in models of disturbed blood flow lead to enhanced leukocyte accumu-
transcellular metabolism of eicosanoids, leading to the local synthe- lation in low shear recirculation zones,95 supporting the concept that
sis of proinflammatory lipids such as PAF, leukotrienes, and flow disturbances may facilitate leukocyte recruitment to atheroscle-
TxA2.87 The imbalance of inflammatory mediators is further exacer- rotic sites.
bated by monocyte up-regulation of COX-2 expression via interac-
tions involving P-selectin derived from activated platelets and
IL-I. This up-regulation of COX-2 enables further synthesis of Impact of high shear and disturbed blood flow on platelet
proinflammatory eicosanoids.88 PAF is a potent platelet agonist and adhesive function
inflammatory mediator and has also been shown to regulate firm The importance of shear forces in regulating platelet adhesive
neutrophil adhesion on the surface of immobilized spread platelets.44 function has long been recognized. At normal wall shear rates
(20-2000/s), shear does not stimulate the activation of platelets in
Atherothrombosis and disturbed blood flow suspension. However at high stress rates ( 5000/s) as occurs in
An important determinant influencing platelet-endothelial and plate- stenosed atherosclerotic arteries, shear can directly induce platelet
let-leukocyte interactions at atherosclerotic-prone sites is the local activation.5 Based on in vitro findings, shear-induced platelet
blood flow conditions. It is well established that atherosclerotic activation is critically dependent upon the sequential binding of
lesions develop at arterial branch points, which are typically areas of VWF to GPIb and integrin IIb3, as well as on the release of
low shear and disturbed flow. Altered flow has a significant effect on ADP.96 Shear-induced platelet activation is insensitive to COX
the adhesive properties of platelets and leukocytes, as well on the inhibitors, a finding that may partly explain the relative weak
morphology and function of endothelial cells. Rheological factors antithrombotic effect of aspirin.97 In a complex shear environment
also contribute to the deposition of lipids and other modulators of characterized by rapid phases of shear acceleration and deceleration,
atherosclerosis. platelet aggregation can occur independently of ADP and TxA2,98
raising the possibility that shear gradients can promote platelet
Throughout much of the vasculature, blood flow is laminar, with deposition and initial thrombus growth even in the presence of
adjacent fluid layers traveling parallel to each other but at different aspirin and a P2Y12 inhibitor.
velocities because of the fluid drag exerted by the vessel wall. This
phenomenon leads to the generation of shear forces between Conclusion
adjacent fluid planes. These flow profiles apply to straight, healthy It has long been recognized that arterial thrombosis primarily
vesselsat arterial branch points, curvatures, and areas of stenosis, represents an exaggerated physiological hemostatic response at sites
flow profiles become significantly more complex. These alterations of atherosclerotic plaque disruption. A similar concept can be
in flow produce shear gradients, turbulence, flow separation, and developed for the role of platelets in the initiation and propagation
eddy formation, each of which can affect the atherogenic process. of atherosclerosis. Platelets normally interact with endothelial cells
Progression of the atherosclerotic lesion exacerbates flow distur- to preserve their physiological function and to enhance leukocyte
bances, thus inducing a potential hazardous cycle of shear- recruitment to sites of inflammation. An exaggeration of these
dependent acceleration of atherosclerosis.89 physiological responses at atherosclerosis-prone sites appears to
Hematology 2011 59
intrinsic coagulation pathway factor XI by antisense oligonucle- 56. Dav G, Patrono C. Platelet activation and atherothrombosis.
otides: a novel antithrombotic strategy with lowered bleeding N Engl J Med. 2007;357(24):2482-2494.
risk. Blood. 2010;116(22):4684-4692. 57. Massberg S, Brand K, Gruner S, et al. A critical role of platelet
35. Caen J, Wu Q. Hageman factor, platelets and polyphosphates: adhesion in the initiation of atherosclerotic lesion formation. J
early history and recent connection. J Thromb Haemost. Exp Med. 2002;196(7):887-896.
2010;8(8):1670-1674. 58. Belton OA, Duffy A, Toomey S, Fitzgerald DJ. Cyclooxygen-
36. Muller F, Mutch NJ, Schenk WA, et al. Platelet polyphosphates ase isoforms and platelet vessel wall interactions in the
are proinflammatory and procoagulant mediators in vivo. Cell. apolipoprotein E knockout mouse model of atherosclerosis.
2009;139(6):1143-1156. Circulation. 2003;108(24):3017-3023.
37. Daleke DL. Regulation of transbilayer plasma membrane 59. Hawrylowicz CM, Howells GL, Feldmann M. Platelet-derived
phospholipid asymmetry. J Lipid Res. 2003;44(2):233-242. interleukin 1 induces human endothelial adhesion molecule
38. Leventis PA, Grinstein S. The distribution and function of expression and cytokine production. J Exp Med. 1991;174(4):
phosphatidylserine in cellular membranes. Annu Rev Biophys. 785-790.
2010;39:407-427. 60. Kaplanski G, Farnarier C, Kaplanski S, et al. Interleukin-1
39. Bevers EM, Williamson PL. Phospholipid scramblase: an induces interleukin-8 secretion from endothelial cells by a
update. FEBS Lett. 2010;584(13):2724-2730. juxtacrine mechanism. Blood. 1994;84(12):4242-4248.
40. Weiss HJ, Vicic WJ, Lages BA, Rogers J. Isolated deficiency of 61. Lindemann S, Tolley ND, Dixon DA, et al. Activated platelets
platelet procoagulant activity. Am J Med. 1979;67(2):206-213. mediate inflammatory signaling by regulated interleukin 1beta
41. Suzuki J, Umeda M, Sims PJ, Nagata S. Calcium-dependent synthesis. J Cell Biol. 2001;154(3):485-490.
phospholipid scrambling by TMEM16F. Nature. 2010; 62. Gawaz M, Brand K, Dickfeld T, et al. Platelets induce
468(7325):834-838. alterations of chemotactic and adhesive properties of endothe-
42. Jackson SP, Schoenwaelder SM. Procoagulant platelets: are lial cells mediated through an interleukin-1-dependent mecha-
they necrotic? Blood. 2010;116(12):2011-2018. nism. Implications for atherogenesis. Atherosclerosis. 2000;
43. Schoenwaelder SM, Yuan Y, Josefsson EC, et al. Two distinct 148(1):75-85.
pathways regulate platelet phosphatidylserine exposure and 63. Gawaz M, Neumann FJ, Dickfeld T, et al. Activated platelets
procoagulant function. Blood. 2009;114(3):663-666. induce monocyte chemotactic protein-1 secretion and surface
44. Kulkarni S, Woollard KJ, Thomas S, Oxley D, Jackson SP. expression of intercellular adhesion molecule-1 on endothelial
Conversion of platelets from a proaggregatory to a proinflamma- cells. Circulation. 1998;98(12):1164-1171.
tory adhesive phenotype: role of PAF in spatially regulating 64. Antoniades C, Bakogiannis C, Tousoulis D, Antonopoulos AS,
neutrophil adhesion and spreading. Blood. 2007;110(6):1879- Stefanadis C. The CD40/CD40 ligand system: linking inflam-
1886. mation with atherothrombosis. J Am Coll Cardiol. 2009;54(8):
45. Borissoff JI, Spronk HM, ten Cate H. The hemostatic system as 669-677.
a modulator of atherosclerosis. N Engl J Med. 2011;364(18): 65. Kroczek RA, Graf D, Brugnoni D, et al. Defective expression
1746-1760. of CD40 ligand on T cells causes X-linked immunodeficiency
46. Jin RC, Voetsch B, Loscalzo J. Endogenous mechanisms of with hyper-IgM (HIGM1). Immunol Rev. 1994;138:39-59.
inhibition of platelet function. Microcirculation. 2005;12(3):247- 66. Henn V, Slupsky JR, Grafe M, et al. CD40 ligand on activated
258. platelets triggers an inflammatory reaction of endothelial cells.
47. Gawaz M, Neumann FJ, Ott I, Schiessler A, Schomig A. Nature. 1998;391(6667):591-594.
Platelet function in acute myocardial infarction treated with 67. Heeschen C, Dimmeler S, Hamm CW, et al. Soluble CD40
direct angioplasty. Circulation. 1996;93(2):229-237. ligand in acute coronary syndromes. N Engl J Med. 2003;
48. Gawaz M, Langer H, May AE. Platelets in inflammation and 348(12):1104-1111.
atherogenesis. J Clin Invest. 2005;115(12):3378-3384. 68. Schonbeck U, Libby P. The CD40/CD154 receptor/ligand
49. Libby P, Ridker PM, Maseri A. Inflammation and atherosclero- dyad. Cell Mol Life Sci. 2001;58(1):4-43.
sis. Circulation. 2002;105(9):1135-1143. 69. Semple JW, Italiano JE, Freedman J. Platelets and the immune
50. Wagner DD, Frenette PS. The vessel wall and its interactions. continuum. Nat Rev Immunol. 2011;11(4):264-274.
Blood. 2008;111(11):5271-5281. 70. Schonbeck U, Libby P. CD40 signaling and plaque instability.
51. Frenette PS, Denis CV, Weiss L, et al. P-Selectin glycoprotein Circulation Research. 2001;89(12):1092-1103.
ligand 1 (PSGL-1) is expressed on platelets and can mediate 71. Ross R. Atherosclerosisan inflammatory disease. N Engl
platelet-endothelial interactions in vivo. J Exp Med. 2000;191(8): J Med. 1999;340(2):115-126.
1413-1422. 72. McEver RP, Cummings RD. Perspectives series: cell adhesion
52. Romo GM, Dong JF, Schade AJ, et al. The glycoprotein in vascular biology. Role of PSGL-1 binding to selectins in
Ib-IX-V complex is a platelet counterreceptor for P-selectin. leukocyte recruitment. J Clin Invest. 1997;100(3):485-491.
J Exp Med. 1999;190(6):803-814. 73. Simon DI, Chen Z, Xu H, et al. Platelet glycoprotein ibalpha is
53. Gawaz M, Neumann FJ, Dickfeld T, et al. Vitronectin receptor a counterreceptor for the leukocyte integrin Mac-1 (CD11b/
(alpha(v)beta3) mediates platelet adhesion to the luminal aspect CD18). J Exp Med. 2000;192(2):193-204.
of endothelial cells: implications for reperfusion in acute 74. Diacovo TG, deFougerolles AR, Bainton DF, Springer TA. A
myocardial infarction. Circulation. 1997;96(6):1809-1818. functional integrin ligand on the surface of platelets: intercellu-
54. Massberg S, Enders G, Matos FC, et al. Fibrinogen deposition lar adhesion molecule-2. J Clin Invest. 1994;94(3):1243-1251.
at the postischemic vessel wall promotes platelet adhesion 75. Santoso S, Sachs UJ, Kroll H, et al. The junctional adhesion
during ischemia-reperfusion in vivo. Blood. 1999;94(11):3829- molecule 3 (JAM-3) on human platelets is a counterreceptor for
3838. the leukocyte integrin Mac-1. J Exp Med. 2002;196(5):679-
55. Langer HF, Gawaz M. Platelet-vessel wall interactions in 691.
atherosclerotic disease. Thromb Haemost. 2008;99(3):480-486. 76. Weber C, Springer TA. Neutrophil accumulation on activated,
Hematology 2011 61