Добавил:
Sekretar
kiopkiopkiop18@yandex.ru
t.me/Prokururor I Вовсе не секретарь, но почту проверяю
Опубликованный материал нарушает ваши авторские права? Сообщите нам.
Вуз:
Предмет:
Файл:Ординатура / Хирургия / Библиотека им академика М.И. Перельмана / Книга_3720_Библиотеки_им_академика_М_И_Перельмана
.pdf
56 Cardiovascular Thrombus
https://t.me/med1917
The association between an increased CD14
high
CD16þphenotype and the presence of atherosclerosis may be partly
explained by the presence of the CCR2 receptor on the surface of this particular monotype subset, which regulates the
migration and infiltration of monocytes [62]. Passacquale et al. have shown that in the context of acute inflammation, the
circulating CD14
endothelium [63].
A multitude of clinical studies have highlighted the association between raised levels of CD16
coronary disease. CD16
control subjects with stable coronary artery disease. Among the unstable angina patients, those with intermediateehigh
risk of myocardial infarction had significantly higher counts of the CD14
correlation between CD14
high
CD14
CD16þcounts and left-ventricular ejection fraction post-STEMI [65]. A study by Rogacev et al. in 20 12 using
951 patients referred for elective coronary angiography showed that a higher CD14
cardiovascular events, including myocardial infarction, ischemic stroke, and death from cardiovascular causes [66].
Conversely, Jaipersad et al. showed that the CD14
high
CD16þnumbers expand, and that this cell subset exhibits increased adhesiveness to the vascular
þ
þ
monocyte counts were elevated in patients with unstable angina compared with matched
high
high
CD16þcounts and peak troponin-T levels post-STEMI, as well as a correlation between
high
CD16, rather than CD14
CD16þsubset [64]. Tapp et al. found a
high
CD16þcount was predictive of
high
CD16þor CD14
monocytes and
low
CD16þ, subset
was predictive of carotid and systemic atherosclerosis severity and intraplaque neovascularization [48]. These differences
may be partially explained by the heterogeneity of subject groups recruited to the studies, as well as differences in
monocyte gating strategies during flow cytometry. Certainly, the majority of studies suggest that the CD14
subset is highly proinflammatory compared with its CD14
is strongly associated with the presence of cardiovascular disease. Whether CD14
high
CD16and CD14
low
CD16þcounterparts, and that this subset
high
CD16þlevels represent a more
high
CD16
þ
specific biomarker of cardiovascular risk than hs-CRP remains to be determined.
MonocyteePlatelet Interactions
Platelets move from a resting state to an activated state in response to endothelial-derived activating factors, such as ADP
and thrombin. Activated platelets adhere to damaged endothelium and locally mediate both inflammatory and thrombotic
events via the secretion of cytokines and interactions with leukocytes, which result in chemotaxis and development of an
inflammatory milieu within the arterial wall. Activated platelets form complexes with leukocytes, particularly monocytes,
as P-selectin, a platelet surface adhesion molecule expressed on the platelet plasmalemma upon activation, binds to its
ligand, P-selectin glycoprotein ligand-1 (PSGL-1) [67,68], which is constitutively expressed by circulating monocytes.
These monocyteeplatelet aggregates (MPAs) are measurable in the peripheral blood and serve as an easily quantifiable
marker of platelet activation and appear to predict cardiovascular events, such as myocardial infarction and ischemic stroke
[69,70]. Functionally, MPAs formed at the site of a vascular injury recruit circulating monocytes and facilitate their
adhesion to the endothelium where, following adhesion and migration into the subintima, they differentiate to macrophages
and contribute further to atherogenesis [71]. Platelet activation and subsequent MPA formation are increased in the
presence of high shear stress within blood vessels, such as occurs around the site of atherosclerotic lesions [72],and
circulating MPA levels in humans correlate with coronary plaque size [73] . P-selectin levels are independently associated
with carotid atherosclerotic lesions in humans [74].
Influenza immunization, which is a model of mild systemic inflammation used in otherwise healthy subjects, has been
used to demonstrate that acute inflammation leads to higher circulating levels of activated platelets and MPA formation,
which promotes expansion of the CD14
degree of circulating MPAs reported in patients with cardiovascular risk factors or established atherosclerotic disease
could represent a key event in the expansion of circulating CD16
cardiovascular disease. Targeting platelet activation could therefore counteract the development of the more proatherogenic
high
CD14
CD16þphenotype with a subsequent beneficial effect on ather osclerosis progression. Consistent with this
hypothesis, experiments conducted in ApoE
aspirin or clopidogrel administration, counteracts the blood monocytosis that accompanies disease progression in this
animal model of atherosclerosis, thus reducing inflammation [63].
Although they have no effect on circulating lipid levels, antiplatelet drugs act to disrupt pathways in which platelets
contribute to atherogenesis, including MPA-driven endothelial recruitment of monocytes and thrombus formation in areas
of endothelial damage [75,76]. The pharmacolo gical efficacy of the multiple classes of antiplatelet agents in counteracting
antiatherogenic mechanisms is variable. Administration of aspirin does not affect circulating levels of MPAs, whereas
clopidogrel appears to impair MPA formation [77,78]. Their distinct mechanisms of action may have differing effects on
the intracellular pathways that finally lead to P-selectin expression on acti vated platelets [79]. The possible role of
antiplatelet therapy in countering atherogenesis will be explored further later in this chapter.
high
CD16þsubset [63]. This evidence supports the hypothesis that the increased
þ
monocytes, which also occurs in the presence of
/
mice have demonstrated that platelet inhibition, as achieved by either
The Role of Platelets in the Pathophysiology of Atherosclerosis and Its Complications Chapter | 4 57
https://t.me/med1917
POLYMORPHePLATELET INTERACTIONS
Other than with monocytes, activated platelets also physically interact with circulating polymorphonuclear neutrophils
(PMNs) to form heterotypic aggregates. However, platelets display a reduced binding affinity for PMNs compared with
monocytes, for reasons that remain to be precisely identified. Monocytes express a greater level of PSGL-1 than do PMNs,
and this has been proposed as a potential explanation for the differential binding of platelets to these cell types [80,81].
Moreover, while the PSGL-1/P-selectin interaction constitutes the main effector in MPA formation, which is therefore
secondary to platelet activation, PMNeplatelet aggregation can also occur in the absence of platelet activation [81,82].
Alternative receptor-to-ligand interactions act as a bridging contact between PMNs and platelets in the absence of
P-selectin expression, such as those mediated by the Mac-1 receptor on PMNs, which engages platelet receptors through
fibrinogen or directly interacts with molecules expressed on the platelet plasmalemma such as glycoprotein Ib or ICAM
[83]. These molecular interactions are favored by specific conformational changes that Mac-1 undergoes upon cell
stimulation [84], which result in increased affinity of Mac-1 to the aforementioned platelet ligands. This difference in
mechanism of plateletePMN interaction compared with MPA formation means that it is the activation status of the PMNs,
rather than that of platelets, which is the decisive factor in promoting PMNeplatelet aggregation.
The role of PMNs in atherosclerosis development and progression is, however, less defined than the contribution made
by monocytes/macrophages. Experimental evidence from murine models of atherosclerosis [85e87], as well as from
atherosclerotic models in nonhuman primates [88], ha s revealed granulocyte infiltration of plaques, based on their positive
histological staining to myeloperoxidase (MPO) [89,90]. However, the cellular source of MPO could also be attributable to
the monocyte/macrophage component [91]. These experimental findings lack confirmation in human lesions, where failure
to detect PMNs can be attributable to the inappropriateness of available techniques or to fast turnover of PMNs within
those tissues [90]. However, a putative role of PMNs in atherosclerosis could be ascribed to their ability to favor monocyte
transmigration rather than their direct colonization of atherosclerotic plaques. Evidence has emerged that the release of
chemotactic substances such as azurocidin [92] and cathepsin G [93] by PMNs promotes monocyte chemotaxis and
adhesion to endothelial cells by inducing integrin activation. In keeping with this, neutrophil depletion in animal models
has been shown to effectively counteract monocyte recruitment into atherosclerotic lesions [90].
In this context, plateletePMN interaction, which is known to enhance PMN proinflammatory activity, can be regarded
as an inducer of PMN proatherogenic acti vity. For instance, PSGL-1, along with Mac-1 engagement, stimulates PMN
degranulation [94]. However, given the poor stability of PMNeplatelet complexes compared with MPA [69], their
measurement in the peripheral blood is highly problematic. This technical limitation makes it difficult to delineate the
clinical relevance of their formation to cardiovascular outcomes. MPA level increases with no change in the concentration
of PMNeplatelet complexes in patients with acute ischemic stroke, during either the acute or the convalescent phase
[95e97]. In the context of coronary disease, increased PMNeplatelet aggregation has been detected only during acute
myocardial infarction [98] and in unstable angina [99], whereas patients with stable angina had levels of PMNeplatelet
aggregates comparable to those of control subjects
in patients with both stable and unstable coronary disease, and has been also observed in subjects with underlying
cardiovascular risk factors but no cardiovascular symptoms and in the absence of thrombotic events. The level of
PMNeplatelet complexes appears to bear little if any relation to these clinical conditions [101,102].
To summarize, the poor stability of PMNeplatelet complexes may lead to underestimation of their level during the
subacute and chronic phases of atherosclerosis and, as a consequence, of their contribution to the progression of disease.
With regard to their possible proathe rogenic role, this may be attributed to their effect on the biologica l fun ction of
myeloid cells.
[98e100]. In contrast, enhanced MPA formation is a common finding
NETRIN-1
The netrin family are a class of laminin-like proteins, which are named from the Sanskrit word “netr,” which means “one
who guides” [103]. Netrin-1, the best-characterized member of this group as of this writing, is a secreted protein that was
initially identified as an embryonic axonal guidance cue [104] and acts via binding to the “deleted in colorectal cancer” and
neogenin receptors to mediate axonal chemoattractan t activity and via the uncoordinated-5 (UNC5) receptor to induce
chemorepulsion [105e107].
In recent years, netrin-1 has emerged as a key regulator in a wide range of pathological conditions, particularly within
the field of oncology, where it has been shown to be of both diagnostic and prognostic value in many cancer subtypes;
renal disease, where netrin-1 acts as a biomarker of kidney funct ion; and cardi ovascular disease, thus making it an
attractive potential therapeutic target (Fig. 4.4).
58 Cardiovascular Thrombus
https://t.me/med1917
Netrin-1 in Atherosclerosis
Netrin-1 has been identified as a fundamental modulator of atherosclerosis, although its precise role in this diseased
protective or deleteriousdhas been the subject of much debate. Animal models of hyperlipidemia using LDL
/
mice
have shown that deletion of netrin-1 in hematopoietic cells promotes macrophage migration from plaques and ultimately
results in reduced atheroma formation [108]. Macrophage-derived foam cells from human coronary artery plaques have
been shown to express both netrin-1 and its inhibitory receptor, UNC5, with the latter being responsible for the inhibitory
effect of netrin-1 on macrophage migration [108]. UNC5 activation results in macrophage retention within plaques, thus
promoting a cycle of chronic inflammation. Hypoxic conditions, which typically become increasingly present within the
FIGURE 4.4 Biological roles of netrin-1. The diverse actions of netrin-1 in cardiovascular and renal disease are presented. Netrin-1 directly modulates
survival and migration of different cell types, including cardiomyocytes, leukocytes, and endothelial and tubular renal cells, through engagement of cellspecific receptors, as indicated. These effects result in netrin-1-dependent cardioprotection and reduction of kidney damage in response to ischemia.
Netrin-1 also confers antiatherogenic protection, by repelling monocyte arterial infiltration. However, netrin-1-induced inhibition of resident macrophage
egress from atherosclerotic plaques could be detrimental. The effect of netrin-1 on neoangiogenesis may be beneficial in the context of cardiac ischemia
but detrimental for atherosclerotic plaque destabilization. The antiinflammatory action of netrin-1 is mediated by direct inhibition of leukocyte motility, as
well as by a protective effect on target organs that negatively feeds back on inflammatory cell trafficking within the tissue. *, Effect on neoangiogenesis
within plaques and ischemic myocardium needs to be explored. y, Beneficial effect on atherosclerosis onset and progression requires further investigation
since it can vary depending on disease stage. DCC, deleted in colorectal cancer receptor; EC, endothelial cell; UNC5B, uncoordinated-5 receptor B.
The Role of Platelets in the Pathophysiology of Atherosclerosis and Its Complications Chapter | 4 59
https://t.me/med1917
tunic intima as atherosclerosis develops, may also stimulate an upregulation in netrin-1 and UNC5 expression, potentiating
plaque formation [109]. Furthermore, netrin-1 upregulation protects macrophages from apoptosis in the presence of
hypoxia, thus promoting the survival of cells that will ultimately contribute to atherosclerosis progression [109].
Although the detrimental effect of netrin-1 on macrophage migration from atherosclerotic lesions is well established,
several studies have been published providing evidence that netrin-1 may additionally act in a protective capacity. Khan
et al. used a murine model of hyperlipidemia in which mice in the treatment group received intravenous netrin-1 copy DNA
and were subsequently shown to have lower levels of nitrotyrosine (a ROS marker) and several markers of macrophage and
monocyte activity, compa red with untreated control mice [110]. The netrin-1-treat ed mice demonstrated a reduction in
plaque formation, presumably through the prevention of monocytes migrating into atherosclerotic plaques [110,111]. Focal
application of netrin-1 in this situation highlights another potential pathway in atherogenesis in which modification of
netrin-1 expression may retard plaque formation. Of note, a reduction in the endothelial expression of netrin-1 under
proatherogenic conditions has been reported by van Gils et al., suggesting that suppression of netrin-1 within the
vasculature in response to proatherogenic factors could promote plaque development [108].
In 2012, Delloye-Bourgeois et al. identified that certain cancer cells produce a truncated intranuclear form of netrin-1,
as opposed to the well-characterized, full-length, secreted netrin-1 [112]. The majority of studies prior to this had not
differentiated between these isoforms, and it has since been postulated that measurement of different isoforms of netrin-1
may explain some of the conflicting data surrounding its role in atherosclerosis [79].
The Relationship Between Netrin-1 and Inflammation
Murine models of myocardial ischemiaereperfusion injury (IRI) have shown that elevated netrin-1 expression has a
cardioprotective effect, partly achieved by reducing the infiltration of neutrophils and recruitment of macrophages that
serve to further amplify the proapoptotic inflammatory response [113,114]. Similar results have been shown in models of
renal IRI as well as other proinflammatory states, including acute lung injury, peritonitis, and sepsis [115e117].
Both in vitro and in vivo studies have repeatedly demonstrated that netrin-1 and UNC5B modulate leukocyte migration
in proinflammatory states [117]. UNC5B is strongly expressed on leukocytes, and increased netrin-1 expression attenuates
leukocyte migration and leukocyte-driven inflammatory responses [117e 119]. These findings have generated interest in a
potential role for netrin-1 in the modification of inflammatory p rocesses.
Administration of netrin-1 suppresses cyclooxygenase-2 (COX-2) expression via regulation of nuclear factor
k-light-chain-enhancer of activated B cells (NF-kB). There is a subsequent reduction in COX-2 metabolites that mediate
neutrophil infiltration, interferon-g-induced macrophage activation, and TXA
production of Th1 helper cell cytokines, which generate interferon-g [118].
The degree to which suppression of the inflammatory response is desirable and whether this could have detrimental
effects in the context of infection remain unclear.
[120]. Netrin-1 additionally suppresses the
2
Antiplatelet Therapy and Netrin-1
As mentioned earlier, netrin-1 modulates macrophage migration into and out of plaque sites and thus represents a potential
target for modifying progression of atherosclerosis [108]. Passacquale et al. published a series of experiments in which the
relationship between endothelial netrin-1 expression and antiplatelet therapy was explored using both in vitro and in vivo
models. They found that aspirin, but not clopidogrel, reduced vascular endothelial permeability and increased netrin-1
production in the ApoE
atherosclerotic plaques [79]. These findings suggest that antiplatelet therapy with aspirin may have the potential to modify
circulating netrin-1 levels and thus modulate atherosclerosis generation. This, together with the previously mentioned
beneficial effect of platelet inhibition on blood monocytosis observed in ApoE
interaction between platelet activity, endothelial chemorepulsion against monocyte infiltration, and monocyte phenotype
that can be positively modulated by antiplatelet strategies.
ANTIPLATELET THERAPY AS A POSSIBLE NOVEL APPROACH TO INHIBITING
ATHEROSCLEROSIS
Given the role of platelet activation in modulating monocyte phenotype, and in turn the part played by monocyte
phenotype in determining their ability to infiltrate the vascular wall and contribute to atherogenesis, an obvious question
is whether antiplatelet thera py, in addition to its ability to prevent acute ischemic events by virtue of inhibiting
/
mouse model of atherosclerosis, which in turn led to reduced monocyte infiltration of
/
mice, points to the existence of a mutual
60 Cardiovascular Thrombus
https://t.me/med1917
thrombogenesis, may also retard the progression of atherosclerosis when administered long term. In recent years,
antiplatelet therapy has become well established in the secondary prevention of acute cardiovascular events in patients with
clinically evident preexisting atherosclerotic disease. It has also become increasingly apparent that, when used
nonselectively in the context of primary prevention, that is to say, in people with no personal history or clinical evidence of
cardiovascular disease, the relatively smaller benefit that accrues from antiplatelet therapy, although undoubtedly present,
is offset by the increase in bleeding that accompanies such therapy, so that, overall, the benefit of such therapy in the
primary prevention setting is small or nonexistent. However, it is equally clear that primary prevention represents a
spectrum: some individuals may have early atherosclerosis, whereas others may have advanced disease that simply has not
yet become manifest. Since we have no straightforward (and importantly, noninvasive) way to distinguish these, they
invariably are studied together, whereas they clearly do not represent a homogeneous population. It is likely that those with
more advanced disease will benefit from antiplatelet therapy to a much greater extent than those with mild atherosclerosis
and that any potential benefits in the former group are diluted by the relatively smaller effects seen in the latter. But even in
patients with mild disease, the question arises as to whether antiplatelet therapy might usefully be given, if those who are at
particular risk of bleeding complications are screened out.
In that respect, several studies have attempted to define predictors of major bleeding; these studies have mainly been
conducted in patients with acute coronary syndromes treated with aggressive antithrombotic therapy. Increased bleeding
has been found to associate with older age, female sex, renal impairment, anemia, prior history of bleeding, and low body
weight. Low body weight (<60 kg), age over 75 years, and a previous stroke or transient ischemic attack were predictors of
intracranial hemorrhage in the TRITON-TIMI 38 trial, conducted in patients with acute coronary syndrome scheduled for
percutaneous coronary intervention and undergoing dual antiplatelet treatment with aspirin and prasugrel [121]. A number
of risk stratification schemes for evaluation of bleeding risks in patients with acute coronary syndrome have been
developed from registry or trial cohorts. These include the CRUSADE and ACTION bleeding risk scores and a score
developed by Mehran et al. based on data from the ACUITY and HORIZONS trials; female sex, renal impairment, and
anemia are common to the three systems [122e124]. Both the CRUSADE and the ACTION bleeding risk scores predict
in-hospital major bleeding; scores of 20, 21e30, 31e40, 41e50, and >50 are indicative of very low, low, moderate,
high, and very high bleeding risks. The Mehran et al. bleeding risk score predicts 30-day non-coronary artery bypass
bleeding; patients with scores of <10, 10e14, 15e19, and 20 are classified as low, moderate, high, and very high risk of
bleeding. All of these scoring systems appear to be useful in research, though their clinical usefulness and their validity in
the clinical setting remain to be establis hed. The application of these or other algorithms, yet to be developed, for
identifying those individuals at low risk of bleeding may enable bett er identification of patients who would usefully benefit
from antiplatelet therapy in the primary prevention setting. In such patients, it is hypothesized that, not only will antiplatelet
therapy prevent acute thrombotic events, but also with long-term therapy it may retard atherosclerosis progression. The
question therefore arises: what is the evidence that antiplatelet therapy affects the pathophysiology of atherogenesis?
The available evidence for this is currently limited to animal models. In ApoE
over 10 weeks reduced the progression of atherosclerosis; by contrast, no such effect was seen with meloxicam, a COX-2
inhibitor [125]. In another study of ApoE
/
mice, the platelet-activating factor inhibitor ginkgolide B significantly
/
mice, low-dose aspirin administered
reduced atherosclerotic lesions, and at the same time suppressed P-selectin, platelet factor 4, RANTES, and CD40L
expression in aortic plaque in those mice; the efficacy of ginkgolide B in decreasing atherosclerosis was similar to that of
aspirin [126]. In ApoE/LDL receptor double-knockout mice, low-dose (4 mg/kg/day) aspirin decreased atherosclerosis, an
effect not seen with higher-dose (40 mg/kg/day) aspirin, which was found to possibly be explained by a greater suppressive
effect of the higher-dose aspirin on vascular generation of NO and prostacyclin [127]. Liu et al. reported that aspirin
improves plaque progression in ApoE
known to be important in atherosclerosis [128]) in murine aorta [129].
In a study by Cherdon et al., however, aspirin was ineffective in reducing atherosclerosis progression in ApoE
but these authors found that the dual thromboxane synthase inhibitor/thromboxane receptor antagonist BM-573 was
effective in this respect [130]. Most recently, it has been demonstrated, again in ApoE
/
mice through suppressing the expression of fractalkine (an NF-kB target gene
/
mice, that aspirin effectively
/
mice;
reduces plaque size as well as content of monocytes/macrophages, and that its antiatherogenic effect appears to be
mediated through its ability to increase vascular endothelial synthesis of netrin-1 [79]. The weight of evidence from this
widely used murine model of atherosclerosis is therefore that antiplatelet therapy (and most of the evidence in this respect
is with aspirin) retards the progression of atherosclerosis. This is backed up from evidence in cholesterol-fed rabbits
(another widely used animal model of atherosclerosis), in which aspirin has been found to retard aortic plaque formation,
an effect that was blocked by coadministration of the COX-2 inhibitor rofecoxib [131].
In humans, the evidence that antiplatelet therapy may inhibit atherogenesis is so far all indirect; and such evidence that
exists is with aspirin. Low-dose aspirin has been found to reduce secretion by adipocytes of chemerin, a peptide that acts as
The Role of Platelets in the Pathophysiology of Atherosclerosis and Its Complications Chapter | 4 61
https://t.me/med1917
a chemoattractant for macrophages, among other actions, through reducing proinflammatory cytokine secretion by
macrophages [132]. In another immunization model of mild inflammation, using Salmonella typhi vaccine, aspirin has
been shown to protect against inflammation-induced endothelial dysfunction [133]. In patients with stable angina, aspirin
decreases plasma levels of several inflammatory cytokines, including IL-6, CRP, and monocyte colony-stimulating factor
[134]. The case for aspirin in primary prevention is strengthened by the findings that aspirin use in hypertensive patients is
associated with increased arterial compliance over a relatively short time frame (2 weeks) [135], and that its ability to
prevent myocardial infarction in the context of primary prevention appears to be directly related to CRP levels, indicating
that its antiinflammatory effects may be at least as important as its antithrombotic actions [136]. An as-yet unanswered
question is whether any antiatherogenic effects of aspirin, separate from its antithrombotic properties, may differ between
patients with elevated or normal inflammatory markers.
CONCLUSIONS
Although the prothrombotic activity of platelets has been well established for many decades now, it has only recently been
recognized that platelets also play an important proinflammatory role through their modulation of leukocyte activity,
through both direct and indirect mechanisms. In this context, it is now clear that not only do platelets mediate arterial
thrombotic events in the short term, but they also participate in longer term buildup of plaque. This raises the possibility
that antiplatelet therapy, using either existing drugs (which largely act on homotypic aggregation) or future therapies,
which may exert a preferential effect on heterotypic aggregation (and hence formation of leukocyteeplatelet aggregates,
including MPAs), may prove to be a useful novel therapeutic approach to preventing atherosclerosis progression; the latter
type of therapy may also circumvent the problem of increased bleeding tendency, which is the main drawback of currently
available antiplatelet therapies and which is the main limitati on to their usefulness in primary prevention. The evidence for
such an approach is now well established in animal models of atherosclerosis, but the case in humans is yet to be proved.
REFERENCES
[1] Zucker MB, Nachmias VT. Platelet activation. Arteriosclerosis 1985;5(1):2e18.
[2] Patel SR, Hartwig JH, Italiano Jr JE. The biogenesis of platelets from megakaryocyte proplatelets. J Clin Invest 2005;115(12):3348e54.
[3] Geddis AE. The regulation of proplatelet production. Haematologica 2009;94(6):756e9.
[4] Cohen JA, Leeksma CH. Determination of the life span of human blood platelets using labelled diisopropylfluorophosphonate. J Clin Invest
1956;35(9):964e9.
[5] Flaumenhaft R, et al. The actin cytoskeleton differentially regulates platelet alpha-granule and dense-granule secretion. Blood
2005;105(10):3879e87.
[6] Escolar G, White JG. The platelet open canalicular system: a final common pathway. Blood Cell 1991;17(3):467e85. discussion 486e95.
[7] Blair P, Flaumenhaft R. Platelet alpha-granules: basic biology and clinical correlates. Blood Rev 2009;23(4):177e89.
[8] Rendu F, Brohard-Bohn B. The platelet release reaction: granules’ constituents, secretion and functions. Platelets 2001;12(5):261e73.
[9] Ciferri S, et al. Platelets release their lysosomal content in vivo in humans upon activation. Thromb Haemost 2000;83(1):157e64.
[10] Warren BA. The platelet pseudopodium and its involvement in aggregation and adhesion to vessel walls. Br J Exp Pathol 1971;52(4):378e87.
[11] Davi G, Patrono C. Platelet activation and atherothrombosis. N Engl J Med 2007;357(24):2482e94.
[12] Nieswandt B, Pleines I, Bender M. Platelet adhesion and activation mechanisms in arterial thrombosis and ischaemic stroke. J Thromb Haemost
2011;9(Suppl. 1):92e104.
[13] Kehrel B, et al. Glycoprotein VI is a major collagen receptor for platelet activation: it recognizes the platelet-activating quaternary structure of
collagen, whereas CD36, glycoprotein IIb/IIIa, and von Willebrand factor do not. Blood 1998;91(2):491e9.
[14] Nieswandt B, Watson SP. Platelet-collagen interaction: is GPVI the central receptor? Blood 2003;102(2):449e61.
[15] Offermanns S. Activation of platelet function through G protein-coupled receptors. Circ Res 2006;99(12):1293e304.
[16] Hawiger J. Formation and regulation of platelet and fibrin hemostatic plug. Hum Pathol 1987;18(2):111e22.
[17] Ariens RA, et al. The factor XIII V34L polymorphism accelerates thrombin activation of factor XIII and affects cross-linked fibrin structure. Blood
2000;96(3):988e95.
[18] Coughlin SR. Thrombin signalling and protease-activated receptors. Nature 2000;407(6801):258e64.
[19] White RP, et al. Cerebral arterial contractions induced by human and bovine thrombin. Stroke 1980;11(4):363e8.
[20] Nakamura K, Hatano Y, Mori K. Thrombin-induced vasoconstriction in isolated cerebral arteries and the influence of a synthetic thrombin
inhibitor. Thromb Res 1985;40(5):715e20.
[21] Horgan MJ, Fenton 2nd JW, Malik AB. Alpha-thrombin-induced pulmonary vasoconstriction. J Appl Physiol 1987;63(5):1993e2000.
[22] Heller R, et al. Protein kinase C and cyclic AMP modulate thrombin-induced platelet-activating factor synthesis in human endothelial cells.
Biochim Biophys Acta 1991;1093(1):55e64.
[23] Kai Y, et al. Prevention of the hypercontractile response to thrombin by proteinase-activated receptor-1 antagonist in subarachnoid hemorrhage.
Stroke 2007;38(12):3259e65.
62 Cardiovascular Thrombus
https://t.me/med1917
[24] Daniel JL, et al. Molecular basis for ADP-induced platelet activation. I. Evidence for three distinct ADP receptors on human platelets. J Biol Chem
1998;273(4):2024e9.
[25] Jin J, et al. Adenosine diphosphate (ADP)-induced thromboxane A(2) generation in human platelets requires coordinated signaling through integrin
alpha(IIb)beta(3) and ADP receptors. Blood 2002;99(1):193e8.
[26] Jin J, Daniel JL, Kunapuli SP. Molecular basis for ADP-induced platelet activation. II. The P2Y1 receptor mediates ADP-induced intracellular
calcium mobilization and shape change in platelets. J Biol Chem 1998;273(4):2030e4.
[27] Wallentin L. P2Y(12) inhibitors: differences in properties and mechanisms of action and potential consequences for clinical use. Eur Heart J
2009;30(16):1964e77.
[28] Holmsen H, Weiss HJ. Hereditary defect in the platelet release reaction caused by a deficiency in the storage pool of platelet adenine nucleotides.
Br J Haematol 1970;19(5):643e9.
[29] Paul BZ, Jin J, Kunapuli SP. Molecular mechanism of thromboxane A(2)-induced platelet aggregation. Essential role for p2t(ac) and alpha(2a)
receptors. J Biol Chem 1999;274(41):29108e14.
[30] Ting HJ, et al. Thromboxane A2 receptor: biology and function of a peculiar receptor that remains resistant for therapeutic targeting. J Cardiovasc
Pharmacol Ther 2012;17(3):248e59.
[31] Dorn 2nd GW, DeJesus A. Human platelet aggregation and shape change are coupled to separate thromboxane A2-prostaglandin H2 receptors. Am
J Physiol 1991;260(2 Pt 2):H327e34.
[32] Gautier-Veyret E, et al. Could the thromboxane A2 pathway be a therapeutic target for the treatment of obstructive sleep apnea-induced
atherosclerosis? Prostaglandins Other Lipid Mediat 2015;121(Pt A):97e104.
[33] Nakahata N. Thromboxane A2: physiology/pathophysiology, cellular signal transduction and pharmacology. Pharmacol Ther 2008;118(1):18e35.
[34] Yamamoto K, et al. Thromboxane A2 receptor-mediated signal transduction in rabbit aortic smooth muscle cells. Gen Pharmacol
1995;26(7):1489e98.
[35] Zhao J, et al. Association of thromboxane A2 receptor gene polymorphisms with cerebral infarction in a Chinese population. Neurol Sci
2013;34(10):1791e6.
[36] Kamae T, et al. Bleeding tendency and impaired platelet function in a patient carrying a heterozygous mutation in the thromboxane A2 receptor.
J Thromb Haemost 2011;9(5):1040e8.
[37] Catella F, et al. 11-Dehydrothromboxane B2: a quantitative index of thromboxane A2 formation in the human circulation. Proc Natl Acad Sci USA
1986;83(16):5861e5.
[38] Ridker PM. High-sensitivity C-reactive protein and cardiovascular risk: rationale for screening and primary prevention. Am J Cardiol
2003;92(4B):17Ke22K.
[39] Ridker PM, JUPITER Study Group. Rosuvastatin in the primary prevention of cardiovascular disease among patients with low levels of
low-density lipoprotein cholesterol and elevated high-sensitivity C-reactive protein: rationale and design of the JUPITER trial. Circulation
2003;108(19):2292e7.
[40] Shah T, et al. Critical appraisal of CRP measurement for the prediction of coronary heart disease events: new data and systematic review of 31
prospective cohorts. Int J Epidemiol 2009;38(1):217e31.
[41] Vasan RS. Commentary: C-reactive protein and risk predictionemoving beyond associations to assessing predictive utility and clinical usefulness.
Int J Epidemiol 2009;38(1):231e4.
[42] Roifman I, et al. Chronic inflammatory diseases and cardiovascular risk: a systematic review. Can J Cardiol 2011;27(2):174e82.
[43] van Diepen S, et al. Prognostic relevance of baseline pro- and anti-inflammatory markers in STEMI: an APEX AMI substudy. Int J Cardiol
2013;168(3):2127e33.
[44] Deftereos S, et al. Anti-inflammatory treatment with colchicine in acute myocardial infarction: a pilot study. Circulation 2015;132(15):1395e403.
[45] Yang J, et al. Monocyte and macrophage differentiation: circulation inflammatory monocyte as biomarker for inflammatory diseases. Biomark Res
2014;2(1):1.
[46] Murray PJ, Wynn TA. Protective and pathogenic functions of macrophage subsets. Nat Rev Immunol 2011;11(11):723e37.
[47] Gao L, et al. The role of hypoxia-inducible factor 1 in atherosclerosis. J Clin Pathol 2012;65(10):872e6.
[48] Jaipersad AS, et al. Expression of monocyte subsets and angiogenic markers in relation to carotid plaque neovascularization in patients with
pre-existing coronary artery disease and carotid stenosis. Ann Med 2014;46(7):530e8.
[49] Lauener RP, Geha RS, Vercelli D. Engagement of the monocyte surface antigen CD14 induces lymphocyte function-associated antigen-1/
intercellular adhesion molecule-1-dependent homotypic adhesion. J Immunol 1990;145(5):1390e4.
[50] O’Brien KD, et al. Neovascular expression of E-selectin, intercellular adhesion molecule-1, and vascular cell adhesion molecule-1 in human
atherosclerosis and their relation to intimal leukocyte content. Circulation 1996;93(4):672e82.
[51] Pamukcu B, et al. The role of monocytes in atherosclerotic coronary artery disease. Ann Med 2010;42(6):394e403.
[52] Jaipersad AS, et al. The role of monocytes in angiogenesis and atherosclerosis. J Am Coll Cardiol 2014;63(1):1e11.
[53] Shantsila E, Watson T, Lip GY. Endothelial progenitor cells in cardiovascular disorders. J Am Coll Cardiol 2007;49(7):741e52.
[54] Michel JB, et al. From intraplaque haemorrhages to plaque vulnerability: biological consequences of intraplaque haemorrhages. J Cardiovasc Med
2012;13(10):628e34.
[55] Michel JB, et al. Pathology of human plaque vulnerability: mechanisms and consequences of intraplaque haemorrhages. Atherosclerosis
2014;234(2):311e9.
[56] Liaskou E, et al. Monocyte subsets in human liver disease show distinct phenotypic and functional characteristics. Hepatology 2013;57(1):385e98.
The Role of Platelets in the Pathophysiology of Atherosclerosis and Its Complications Chapter | 4 63
https://t.me/med1917
[57] Belge KU, et al. The proinflammatory CD14þCD16þDRþþmonocytes are a major source of TNF. J Immunol 2002;168(7):3536e42.
[58] Wong KL, et al. Gene expression profiling reveals the defining features of the classical, intermediate, and nonclassical human monocyte subsets.
Blood 2011;118(5):e16e31.
[59] Krasselt M, et al. CD56
immunosenescence. Arthritis Res Ther 2013;15(5):R139.
[60] Schlitt A, et al. CD14
2004;92(2):419e24.
[61] Poitou C, et al. CD14dimCD16
atherosclerosis. Arterioscler Thromb Vasc Biol 2011;31(10):2322e30.
[62] Naert G, Rivest S. A deficiency in CCR2
[63] Passacquale G, et al. Monocyte-platelet interaction induces a pro-inflammatory phenotype in circulating monocytes. PLoS One 2011;6(10):e25595.
[64] Zeng S, et al. Monocyte subsets and monocyte-platelet aggregates in patients with unstable angina. J Thromb Thrombolysis 2014;38(4):439e46.
[65] Tapp LD, et al. The CD14
J Thromb Haemost 2012;10(7):1231e41.
[66] Rogacev KS, et al. CD14
coronary angiography. J Am Coll Cardiol 2012;60(16):1512e20.
[67] Mickelson JK, et al. Leukocyte activation with platelet adhesion after coronary angioplasty: a mechanism for recurrent disease? J Am Coll Cardiol
1996;28(2):345e53.
[68] Harding SA, et al. Flow cytometric analysis of circulating platelet-monocyte aggregates in whole blood: methodological considerations. Thromb
Haemost 2007;98(2):451e6.
[69] Michelson AD, et al. Circulating monocyte-platelet aggregates are a more sensitive marker of in vivo platelet activation than platelet surface
P-selectin: studies in baboons, human coronary intervention, and human acute myocardial infarction. Circulation 2001;104(13):1533e7.
[70] Ishikawa T, et al. Appearance of WBC-platelet complex in acute ischemic stroke, predominantly in atherothrombotic infarction. J Atheroscler
Thromb 2012;19(5):494e501.
[71] Gawaz M, Stellos K, Langer HF. Platelets modulate atherogenesis and progression of atherosclerotic plaques via interaction with progenitor and
dendritic cells. J Thromb Haemost 2008;6(2):235e42.
[72] Kroll MH, et al. Platelets and shear stress. Blood 1996;88(5):1525e41.
[73] Yong AS, et al. Intracoronary shear-related up-regulation of platelet P-selectin and platelet-monocyte aggregation despite the use of aspirin and
clopidogrel. Blood 2011;117(1):11e20.
[74] Koyama H, et al. Platelet P-selectin expression is associated with atherosclerotic wall thickness in carotid artery in humans. Circulation
2003;108(5):524e9.
[75] Klinkhardt U, Harder S. Flow cytometric measurement of platelet-leukocyte aggregates: a possible target to monitor platelet function? Semin
Thromb Hemost 2005;31(4):400e3.
[76] Arazi HC, Badimon JJ. Anti-inflammatory effects of anti-platelet treatment in atherosclerosis. Curr Pharm Des 2012;18(28):4311e25.
[77] Li N, Hu H, Hjemdahl P. Aspirin treatment does not attenuate platelet or leukocyte activation as monitored by whole blood flow cytometry.
Thromb Res 2003;111(3):165e70.
[78] Klinkhardt U, et al. Clopidogrel but not aspirin reduces P-selectin expression and formation of platelet-leukocyte aggregates in patients with
atherosclerotic vascular disease. Clin Pharmacol Ther 2003;73(3):232e41.
[79] Passacquale G, et al. Aspirin-induced histone acetylation in endothelial cells enhances synthesis of the secreted isoform of netrin-1 thus inhibiting
monocyte vascular infiltration. Br J Pharmacol 2015;172(14):3548e64.
[80] Kappelmayer J, et al. Identification of P-selectin glycoprotein ligand-1 as a useful marker in acute myeloid leukaemias. Br J Haematol
2001;115(4):903e9.
[81] Bournazos S, et al. Monocyte functional responsiveness after PSGL-1-mediated platelet adhesion is dependent on platelet activation status.
Arterioscler Thromb Vasc Biol 2008;28(8):1491e8.
[82] Evangelista V, et al. Platelet/polymorphonuclear leukocyte interaction: P-selectin triggers protein-tyrosine phosphorylation-dependent CD11b/
CD18 adhesion: role of PSGL-1 as a signaling molecule. Blood 1999;93(3):876e85.
[83] Cerletti C, Evangelista V, de Gaetano G. P-selectin-beta 2-integrin cross-talk: a molecular mechanism for polymorphonuclear leukocyte
recruitment at the site of vascular damage. Thromb Haemost 1999;82(2):787e93.
[84] Spangenberg P, et al. The platelet glycoprotein IIb/IIIa complex is involved in the adhesion of activated platelets to leukocytes. Thromb Haemost
1993;70(3):514e21.
[85] Zernecke A, et al. Protective role of CXC receptor 4/CXC ligand 12 unveils the importance of neutrophils in atherosclerosis. Circ Res
2008;102(2):209e17.
[86] van Leeuwen M, et al. Accumulation of myeloperoxidase-positive neutrophils in atherosclerotic lesions in LDLR
Biol 2008;28(1):84e9.
[87] Rotzius P, et al. Distinct infiltration of neutrophils in lesion shoulders in ApoE
[88] Trillo AA. The cell population of aortic fatty streaks in African green monkeys with special reference to granulocytic cells. An ultrastructural study.
Atherosclerosis 1982;43(2e3):259e75.
[89] Weber C, Noels H. Atherosclerosis: current pathogenesis and therapeutic options. Nat Med 2011;17(11):1410e22.
þ
monocytes have a dysregulated cytokine response to lipopolysaccharide and accumulate in rheumatoid arthritis and
þ
CD16þmonocytes in coronary artery disease and their relationship to serum TNF-alpha levels. Thromb Haemost
þ
and CD14þCD16þmonocytes in obesity and during weight loss: relationships with fat mass and subclinical
þ
monocytes: the hidden side of Alzheimer’s disease. J Mol Cell Biol 2013;5(5):284e93.
þþ
CD16þmonocyte subset and monocyte-platelet interactions in patients with ST-elevation myocardial infarction.
þþ
CD16þmonocytes independently predict cardiovascular events: a cohort study of 951 patients referred for elective
-/-
mice. Arterioscler Thromb Vasc
-/-
mice. Am J Pathol 2010;177(1):493e500.
64 Cardiovascular Thrombus
https://t.me/med1917
[90] Drechsler M, et al. Neutrophilic granulocytesdpromiscuous accelerators of atherosclerosis. Thromb Haemost 2011;106(5):839e48.
[91] Daugherty A, et al. Myeloperoxidase, a catalyst for lipoprotein oxidation, is expressed in human atherosclerotic lesions. J Clin Invest
1994;94(1):437e44.
[92] Soehnlein O, et al. Neutrophil-derived heparin-binding protein (HBP/CAP37) deposited on endothelium enhances monocyte arrest under flow
conditions. J Immunol 2005;174(10):6399e405.
[93] Chertov O, et al. Identification of human neutrophil-derived cathepsin G and azurocidin/CAP37 as chemoattractants for mononuclear cells and
neutrophils. J Exp Med 1997;186(5):739e47.
[94] Hidari KI, et al. Engagement of P-selectin glycoprotein ligand-1 enhances tyrosine phosphorylation and activates mitogen-activated protein kinases
in human neutrophils. J Biol Chem 1997;272(45):28750e6.
[95] McCabe DJ, et al. Platelet degranulation and monocyte-platelet complex formation are increased in the acute and convalescent phases after
ischaemic stroke or transient ischaemic attack. Br J Haematol 2004;125(6):777e87.
[96] Tsai NW, et al. Levels and value of platelet activation markers in different subtypes of acute non-cardio-embolic ischemic stroke. Thromb Res
2009;124(2):213e8.
[97] Cao YJ, et al. The effects of antiplatelet agents on platelet-leukocyte aggregations in patients with acute cerebral infarction. J Thromb Thrombolysis
2009;27(2):233e8.
[98] Linden MD, et al. Indices of platelet activation and the stability of coronary artery disease. J Thromb Haemost 2007;5(4):761e5.
[99] Ott I, et al. Increased neutrophil-platelet adhesion in patients with unstable angina. Circulation 1996;94(6):1239e46.
[100] Furman MI, et al. Increased platelet reactivity and circulating monocyte-platelet aggregates in patients with stable coronary artery disease. J Am
Coll Cardiol 1998;31(2):352e8.
[101] Kaplar M, et al. The possible association of in vivo leukocyte-platelet heterophilic aggregate formation and the development of diabetic angiopathy.
Platelets 2001;12(7):419e22.
[102] Tuttle HA, et al. Platelet-neutrophil conjugate formation is increased in diabetic women with cardiovascular disease. Cardiovasc Diabetol
2003;2:12.
[103] Bongo JB, Peng DQ. The neuroimmune guidance cue netrin-1: a new therapeutic target in cardiovascular disease. J Cardiol 2014;63(2):95e8.
[104] Serafini T, et al. The netrins define a family of axon outgrowth-promoting proteins homologous to C. elegans UNC-6. Cell 1994;78(3):409e24.
[105] Culotti JG, Merz DC. DCC and netrins. Curr Opin Cell Biol 1998;10(5):609e13.
[106] Livesey FJ. Netrins and netrin receptors. Cell Mol Life Sci 1999;56(1e2):62e8.
[107] Bradford D, et al. Characterization of the netrin/RGMa receptor neogenin in neurogenic regions of the mouse and human adult forebrain. J Comp
Neurol 2010;518(16):3237e53.
[108] van Gils JM, et al. The neuroimmune guidance cue netrin-1 promotes atherosclerosis by inhibiting the emigration of macrophages from plaques.
Nat Immunol 2012;13(2):136e43.
[109] Ramkhelawon B, et al. Hypoxia induces netrin-1 and Unc5b in atherosclerotic plaques: mechanism for macrophage retention and survival.
Arterioscler Thromb Vasc Biol 2013;33(6):1180e8.
[110] Khan JA, et al. Systemic human Netrin-1 gene delivery by adeno-associated virus type 8 alters leukocyte accumulation and atherogenesis in vivo.
Gene Ther 2011;18(5):437e44.
[111] Gerszten RE, Tager AM. The monocyte in atherosclerosis e should I stay or should I go now? N Engl J Med 2012;366(18):1734e6.
[112] Delloye-Bourgeois C, et al. Nucleolar localization of a netrin-1 isoform enhances tumor cell proliferation. Sci Signal 2012;5(236):ra57.
[113] Ranganathan P, et al. Guidance cue netrin-1 and the regulation of in
2014;2014:525891.
[114] Mao X, et al. Netrin-1 attenuates cardiac ischemia reperfusion injury and generates alternatively activated macrophages. Inflammation
2014;37(2):573e80.
[115] Liu L, et al. Netrin-1 pretreatment protects rat kidney against ischemia/reperfusion injury via suppression of oxidative stress and neuropeptide Y
expression. J Biochem Mol Toxicol 2013;27(4):231e6.
[116] Mirakaj V, et al. Netrin-1 dampens pulmonary infl ammation during acute lung injury. Am J Respir Crit Care Med 2010;181(8):815e24.
[117] Ly NP, et al. Netrin-1 inhibits leukocyte migration in vitro and in vivo. Proc Natl Acad Sci USA 2005;102(41):14729e34.
[118] Tadagavadi RK, Wang W, Ramesh G. Netrin-1 regulates Th1/Th2/Th17 cytokine production and inflammation through UNC5B receptor and
protects kidney against ischemia-reperfusion injury. J Immunol 2010;185(6):3750e8.
[119] Mussap M, et al. Urine neutrophil gelatinase-associated lipocalin (uNGAL) and netrin-1: are they effectively improving the clinical management of
sepsis-induced acute kidney injury (AKI)? J Matern Fetal Neonatal Med 2011;24(Suppl. 2):15e7.
[120] Ranganathan PV, et al. Netrin-1 regulates the inflammatory response of neutrophils and macrophages, and suppresses ischemic acute kidney injury
by inhibiting COX-2-mediated PGE2 production. Kidney Int 2013;83(6):1087e98.
[121] Wiviott SD, et al. Prasugrel versus clopidogrel in patients with acute coronary syndromes. N Engl J Med 2007;357(20):2001e15.
[122] Subherwal S, et al. Baseline risk of major bleeding in non-ST-segment-elevation myocardial infarction: the CRUSADE (Can Rapid risk
stratification of Unstable angina patients Suppress ADverse outcomes with Early implementation of the ACC/AHA Guidelines) bleeding score.
Circulation 2009;119(14):1873e82.
[123] Mathews R, et al. In-hospital major bleeding during ST-elevation and non-ST-elevation myocardial infarction care: derivation and validationofa
model from the ACTION Registry(R)-GWTG. Am J Cardiol 2011;107(8):1136e43.
[124] Mehran R, et al. A risk score to predict bleeding in patients with acute coronary syndromes. J Am Coll Cardiol 2010;55(23):2556e66.
flammation in acute and chronic kidney disease. Mediat Inflamm
The Role of Platelets in the Pathophysiology of Atherosclerosis and Its Complications Chapter | 4 65
https://t.me/med1917
[125] Kraus S, et al. Aspirin but not meloxicam attenuates early atherosclerosis in apolipoprotein E knockout mice. Isr Med Assoc J 2014;16(4):233e8.
[126] Liu X, et al. Ginkgolide B reduces atherogenesis and vascular inflammation in ApoE(-/-) mice. PLoS One 2012;7(5):e36237.
[127] Yamamoto Y, et al. The effect of the long term aspirin administration on the progress of atherosclerosis in apoE
Thromb Res 2010;125(3):246e52.
[128] Teupser D, et al. Major reduction of atherosclerosis in fractalkine (CX3CL1)-deficient mice is at the brachiocephalic artery, not the aortic root. Proc
Natl Acad Sci USA 2004;101(51):17795e800.
[129] Liu H, et al. Aspirin inhibits fractalkine expression in atherosclerotic plaques and reduces atherosclerosis in ApoE gene knockout mice. Cardiovasc
Drugs Ther 2010;24(1):17e24.
[130] Cherdon C, et al. BM-573 inhibits the development of early atherosclerotic lesions in Apo E deficient mice by blocking TP receptors and
thromboxane synthase. Prostaglandins Other Lipid Mediat 2011;94(3e4):124e32.
[131] Kaber G, et al. Antagonism of the antithrombotic and anti-atherosclerotic actions of aspirin by rofecoxib in the cholesterol-fed rabbit. Br J
Pharmacol 2011;164(2b):561e9.
[132] Herova M, et al. Low dose aspirin is associated with plasma chemerin levels and may reduce adipose tissue inflammation. Atherosclerosis
2014;235(2):256e62.
[133] Kharbanda RK, et al. Prevention of inflammation-induced endothelial dysfunction: a novel vasculo-protective action of aspirin. Circulation
2002;105(22):2600e4.
[134] Ikonomidis I, et al. Increased proinflammatory cytokines in patients with chronic stable angina and their reduction by aspirin. Circulation
1999;100(8):793e8.
[135] Pietri P, et al. Beneficial effects of low-dose aspirin on aortic stiffness in hypertensive patients. Vasc Med 2014;19(6):452e7.
[136] Ridker PM, et al. Inflammation, aspirin, and the risk of cardiovascular disease in apparently healthy men. N Engl J Med 1997;336(14):973e9.
[137] Jaipersad AS, et al. The role of monocytes in angiogenesis and atherosclerosis. J Am Coll Cardiol 2014;63(1):1e11.
[138] Wong KL, et al. Gene expression profiling reveals the defining features of the classical, intermediate, and nonclassical human monocyte subsets.
Blood 2011;118(5):e16e31.
[139] Shantsila E, et al. Immunophenotypic characterization of human monocyte subsets: possible implications for cardiovascular disease
pathophysiology. J Thromb Haemost 2011;9(5):1056e66.
[140] Cros J, et al. Human CD14dim monocytes patrol and sense nucleic acids and viruses via TLR7 and TLR8 receptors. Immunity 2010;33(3):375e86.
[141] Tapp LD, et al. The CD14++CD16+ monocyte subset and monocyte-platelet interactions in patients with ST-elevation myocardial infarction. J
Thromb Haemost 2012;10(7):1231e41.
-/-
-/-
LDLR
double knockout mouse.
Соседние файлы в папке Библиотека им академика М.И. Перельмана