Page 2318 - Williams Hematology ( PDFDrive )

2292 Part XII: Hemostasis and Thrombosis Chapter 134: Atherothrombosis: Disease Initiation, Progression, and Treatment 2293

from endothelial cells, and promote the unfolding and binding of VWF to contribute to differences in thrombogenic substrates that are exposed
its receptors on platelet surface glycoprotein (GP) Ib-V-IX. This interac- upon arterial injury. For example, carotid and iliac arteries contain
tion, which does not occur in the normal circulation, mediates the adhe- relatively more elastic fibers and proportionately fewer smooth mus-
170
sion of platelets to the intimal surface and triggers GPIb-V-IX–dependent cle cells than coronary arteries. Furthermore, ACSs typically result
platelet thrombus formation. The mechanisms of arterial thrombogenesis from disruption of only modestly stenotic, lipid-rich plaques, whereas
are further elaborated below in the section on “Platelet Activation.” disruption-prone, high-risk plaques in the carotid arteries usually are
In contrast, wall shear rates are much lower in the venous circula- severely stenotic. Thus, a proposed more appropriate term is high-risk
tion where the hemodynamic forces are insufficient to directly activate plaque rather than vulnerable plaque (which connotes its composition)
166
platelets. Venous thrombi are almost always occlusive and may form to define a disruption-prone or thrombosis-prone plaque in different
virtual casts of the vessel in which they arise. Unlike the setting for arterial parts of the circulation. 171
thrombi, gross vascular damage generally is not found at sites of venous The pathophysiology of arterial thrombosis at different sites
thrombosis. Any ultrastructural abnormalities of adjacent endothelium in the circulation may also be determined in part by vascular bed-
likely are the consequences rather than the causes of thrombus forma- specific heterogeneity of endothelial and smooth muscle cells. Endothelial
tion. Therefore, in the low-flow and low-pressure venous system, reduced cell-derived anticoagulant and procoagulant activities are differentially
blood flow (stasis) and systemic activation of the coagulation cascade expressed throughout the vascular tree. Endothelial cell heteroge-
play the primary pathophysiologic roles. Venous thrombi are composed neity throughout the circulation is a function of varying organ- and
predominantly of red cells enmeshed in fibrin and contain relatively few tissue-specific microenvironments, hemodynamic forces, and site-
platelets; hence, they have been described pathologically as red thrombi. specific changes in epigenetic footprinting. The heterogeneity of endo-
The generalizations described are consistent with the following thelial cells and the vascular bed-specific signaling pathways that control
clinical observations: (1) hereditary hypercoagulable states (also called endothelial gene expression have been considered to play an important
“thrombophilias”), characterized by chronic hyperactivity of the coagu- role in the localization of arterial thrombosis. Heterogeneity of vascu-
172
lation system, are primarily associated with venous rather than arterial lar smooth muscle cells likewise exists throughout the arterial tree. They
thrombosis; and (2) anticoagulants that prevent fibrin formation (e.g., vary in embryonic origin, sources of progenitors, and lineage. With
heparin, warfarin) are generally used to prevent venous thrombosis, subsequent development, they acquire various phenotypes that can be
whereas antiplatelet agents (e.g., aspirin) are more effective in prevent- traced to preferential sites within vessel walls. 173
ing arterial thrombosis. The differences between arterial and venous Less is known about the pathophysiology of cerebrovascular
thrombosis are not, however, absolute because both types of thrombi thrombosis, and even less about peripheral arterial thrombosis, than
are composed of different amounts of platelets, fibrin, and leukocytes. about coronary artery thrombosis. Future research in these areas should
In addition, all thrombi continually undergo propagation, organization, permit the development of more rational antithrombotic strategies in
embolization, lysis, and rethrombosis, and this dynamic remodeling noncoronary artery thrombosis.
results in their constantly changing compositions.
Overview of Arterial Thrombotic Process
Site-Specific Arterial Thrombosis Arterial thrombosis typically occurs in the presence of underlying
The model of atherothrombosis described is best characterized in cor- atherosclerosis (hence the term “atherothrombosis”). Less frequently,
onary arteries. This pathophysiology may not be entirely applicable to however, it may also occur in nonatherosclerotic arteries, such as in the
arterial thrombosis at other sites. It cannot be assumed that the local setting of vasculitis.
determinants of thrombosis that are operative in the coronary arteries Atherothrombosis Disruption of an atherosclerotic plaque
are identical to those encountered in the cerebrovascular and peripheral triggers an explosive cascade of events that results in the formation
57
arterial circulations. Basic regional differences may involve (1) distribu- of a platelet-rich thrombus at the site of arterial injury. Focal loss of
tion and composition of atherosclerotic lesions, (2) variable local rheol- the antithrombotic and the vasodilatory properties of endothelium is
ogy, and (3) underlying vascular cell heterogeneity. compounded by plaque rupture or erosion. These events induce the
Atherosclerosis is highly localized within the systemic vasculature. local activation of platelets and the coagulation system by exposure of
Lesion formation particularly affects the carotid artery bifurcation, cor- blood to previously encrypted thrombogenic substances (e.g., suben-
onary arteries (especially the left coronary artery bifurcation), abdomi- dothelial cells, such as smooth muscle cells and fibroblasts; subendo-
nal aorta (especially its posterior wall downstream of the renal arteries, thelial structures, such as collagen; and subendothelial prothrombotic
but with little disease usually present in the upstream thoracic aorta), substances, such as TF, from all of which flowing blood is normally
and profunda femoral arteries. These lesion-prone sites in the arterial insulated by the barrier of a healthy endothelial monolayer). The local
circulation correspond to regions where wall shear stress is very low and milieu for thrombus formation is aggravated by focal vasoconstriction,
may even oscillate between positive and negative directions (i.e., rever- rapidly increased shear forces, and platelet-mediated recruitment of
sal of flow) during the cardiac cycle. A strong correlation exists between leukocytes. Platelet and coagulation activation are inseparable, recip-
local hemodynamic conditions of low shear stress and the development rocally self-amplifying processes. Activation of platelets generates
of atherosclerotic plaque formation and intimal thickening. 167–169 How- procoagulant properties on their cell surfaces. Combined with non–
ever, as arteries become progressively diseased and as stenoses develop platelet-dependent local activators of the coagulation cascade, platelet
at these sites, local hemodynamics change. Stenotic flows are char- activation culminates in the formation of thrombin, which itself is a
acterized by sharp increases in shear rate that achieve their peak just potent stimulus for further platelet activation. Superimposed on these
upstream of the stenosis throat, with development of intensive turbu- local determinants of arterial thrombosis, the thrombotic process may
lence downstream of the stenosis. The mechanisms of platelet activation be modulated by systemic, circulating factors. The factors include the
and accumulation that initiate arterial thrombosis at these high-shear systemic state of activation of platelets and coagulation, which may be
sites are further described in “Platelet Activation” below. governed by acquired or genetic factors and by hormonal influences
Striking heterogeneity is seen in the composition of atherothrom- (e.g., adrenergic state).
botic plaques, even within the same individual. In addition to plaque Arterial thrombi generally are localized to the site of acute vascu-
composition, the basic structural differences between specific arteries lar injury. They are prevented from extending beyond this site by the

Kaushansky_chapter 134_p2281-2302.indd 2292 17/09/15 3:49 pm