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2284 Part XII: Hemostasis and Thrombosis Chapter 134: Atherothrombosis: Disease Initiation, Progression, and Treatment 2285

The NR4A nuclear receptors are also expressed in vein segments platelet adhesion and aggregation by stimulating platelet soluble guany-
exposed to arterial pressure and it is postulated that they are responsible lyl cyclase and raising intraplatelet levels of cyclic guanosine monophos-
for an inhibitory feedback mechanism that occurs in activated vascular phate (see Fig. 134–2). Physiologic flow and shear forces maintain the
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cells. Drug-eluting vascular stents that release agents such as sirolimus activity of endothelial (endothelium-derived) NO synthase (eNOS)
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and paclitaxel interfere with the cell cycle and inhibit restenosis in part under normal circumstances. Vascular cell-derived carbon monoxide, a
via decreased smooth muscle cell proliferation. 62 product of heme catabolism by heme oxygenase, may have similar anti-
platelet activity. 68,69 Prostacyclin (prostaglandin I ) likewise is released
2
Abnormal Endothelial Control of Blood Fluidity basally by normal endothelial cells and inhibits platelet aggregation
Endothelial cells normally elaborate a number of antithrombotic sub- by inducing platelet adenylyl cyclase and raising intraplatelet levels of
stances. Some of these substances are released into blood whereas cyclic adenosine monophosphate. 70
others are properties of the unactivated endothelial cell surface. These NO, carbon monoxide, and prostaglandin I are labile autacoids,
2
antiplatelet, anticoagulant, and profibrinolytic activities of endothe- acting only in the immediate vicinity of their release into blood from
lium, some of which also possess vasodilatory properties (e.g., pros- endothelial cells. An endothelial surface ecto-adenosine diphosphatase
tacyclin, NO), act in concert to promote blood fluidity under normal (CD39) also blocks platelet activity by metabolizing and disposing of
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circumstances. Acute activation or chronic dysfunction of endothelial platelet agonist adenosine diphosphate (ADP). In endothelial dysfunc-
cells alters the hemostatic balance, transforming them from predomi- tion, these various antiplatelet activities are lost, and endothelial release
nantly antithrombotic to prothrombotic cells. 63 of von Willebrand factor (VWF) is increased, which promotes platelet
To this end, endothelial cells modulate the activities of thrombin adhesion. In the case of NO, oxidative stress in the microenvironment
in health and disease. In the presence of intact and normally function- of endothelial dysfunction actually “uncouples” eNOS activity 68,72 to
ing endothelium, the prothrombotic actions of thrombin are quenched preferentially generate superoxide over NO. Oxygen free radicals bind
and the antithrombotic actions of the enzyme predominate. Thrombin any remaining available NO to produce the toxic product peroxynitrite.
binds to thrombomodulin, an integral membrane protein expressed Bioactive NO is further reduced in endothelial dysfunction by the pres-
by endothelial cells, and activates protein C (accelerated in the pres- ence of asymmetric dimethylarginine, which competes to block eNOS
ence of endothelial protein C receptor, another endothelial cell protein) and limit NO production. 67,73
(Chap. 116). Activated protein C, in concert with its cofactor, protein S,
has anticoagulant and profibrinolytic actions. It degrades by proteolytic Progenitor Cells and Atherosclerosis
digestion factors Va and VIIIa, and inactivates plasminogen-activator Endothelial progenitor cells (EPCs) are heterogenous in origin and par-
inhibitor (PAI)-1. Simultaneously, by binding to thrombomodulin, ticipate in endothelial cell regeneration and neovascularization of ische-
enzymatically active procoagulant thrombin is removed from the cir- mic tissue. The mobilization of EPCs from the marrow is stimulated
culation, thereby limiting its availability to catalyze fibrin formation. by hypoxia, cytokines such as vascular endothelial growth factor, hor-
Endothelial dysfunction causes loss of thrombomodulin activity from mones such as erythropoietin, and statin drugs, whereas mobilization
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the vascular surface. In fact, increased circulating plasma levels of free is inhibited in the diabetic state. The role of EPCs in atherosclerosis is
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(truncated) thrombomodulin represent a marker of endothelial damage. unclear as there are conflicting data. A study in apolipoprotein (apo)
In addition to the role of thrombomodulin in clearance of circulating E–/– mice showed that there is rapid turnover of endothelial cells in
thrombin, the procoagulant activity of thrombin is normally blocked atherosclerosis-prone areas and marrow derived EPCs are recruited to
by endothelial cells through the action of antithrombin, which binds sites of atheroprogression. 75
to heparin-like glycosaminoglycans on their luminal surface, thereby
catalyzing the inactivation of thrombin by antithrombin. Like throm- INFLAMMATION AND ATHEROSCLEROSIS
bomodulin, this thrombin-neutralizing action of endothelial heparan
sulfate glycosaminoglycans is lost with endothelial dysfunction. Innate Immunity and Atherosclerosis
Endothelial cells do not normally express TF, but they do so upon The endothelial response to injury manifests as a chronic inflammatory
activation by inflammatory cytokines or exposure to endothelium- response that involves both innate and adaptive immunity. Innate
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activating levels of homocysteine or free thrombin. The procoagu- immunity provides the first line of defense for the host and involves
lant effects of expression of TF by dysfunctional endothelial cells are several cell types, most importantly macrophages and dendritic cells,
potentially compounded by the loss of TF pathway inhibitor (TFPI), which express a limited number of highly conserved sensing molecules
which normally is synthesized by endothelial cells. Studies show that such as scavenger receptors and toll-like receptors. 76,77 Microbial infec-
monocyte- derived EVs (or microparticles) express TF and platelet- tion can be detected by pathogen-associated molecular patterns, which
derived EVs express phosphatidylserine and thus support coagulation are present in bacteria, viruses, and yeasts, but not in mammalian cells,
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complex formation. There is also evidence that P-selectin on platelets and are recognized by the toll-like receptors. Ligation of a pathogen
binds to P-selection protein ligand-1 on EVs. 65 or other substances containing pathogen-associated molecular patterns
Normal endothelium is profibrinolytic. It synthesizes and releases (such as lipopolysaccharides, aldehyde-derivatized proteins, mannans,
tissue-type plasminogen activator (t-PA); it possesses binding sites teichoic acids) elicits endocytosis or activation of endothelial cells (e.g.,
for t-PA and plasminogen to provide a surface for the concentrated through nuclear factor-κB) that results in an inflammatory response
assembly of the fibrinolytic complex and thereby enhance local plas- (Chaps. 17 and 18). 77,79 Proinflammatory cytokines, such as tumor
min generation; and it fails to produce significant amounts of PAI-1. necrosis factor, nuclear factor-κB and interleukin (IL)-1, magnify the
This profibrinolytic state is converted to an antifibrinolytic state in innate inflammatory response.
the presence of endothelial dysfunction. In activated or dysfunctional Innate defense involves soluble factors, such as complement,
endothelium, PAI-1 gene expression and PAI-1 secretion are induced; which is involved in atherosclerotic lesion formation. hsCRP has been
simultaneously, the profibrinolytic properties of normal endothelium found to be an important and independent predictor for cardiovascular
are lost (Chap. 135). events. Natural antibodies that are generated in the absence of known
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The antithrombotic profile of normal endothelium also manifests antigen stimulation, mainly immunoglobulin (Ig) M, provide an imme-
through the elaboration of several antiplatelet substances. NO is con- diate response against bacteria and viruses but also may be involved
stitutively released into blood by normal endothelial cells and inhibits in atherosclerosis. For example, innate B lymphocytes, the so-called

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