Page 2319 - Williams Hematology ( PDFDrive )

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

restoration of hemostatic balance that promotes blood fluidity along As noted above in the section on “Pathobiology of Arterial Thrombi,”
healthy endothelial surfaces immediately adjacent to the site of injury. plaque rupture and the development of new intimal surface irregulari-
Thrombus propagation may occur, however, through a bloodborne pool ties also suddenly alter local rheologic characteristics, increasing local
of thrombogenic substances that originate at the site of vascular injury shear rates. Increased shear stress resulting from sudden changes in
and thrombosis. These substances can be in the form of platelets, leuko- degree of stenosis following rupture is compounded by increased focal
cytes, red cells, sloughed endothelial cells, other cellular microparticles, vasoconstriction induced by thrombin, thromboxane A , and other
2
and circulating active TF derived from leukocytes activated within the vasoactive substances released in the milieu of acute injury.
176
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thrombus. 174,175 In fact, cellular microparticles constitute the main res- At high shear rates (>1000 s ), platelets must be initially tethered
ervoir of bloodborne TF, the principal initiator of coagulation. to the vascular surface through a shear-activated interaction between
Thrombus persistence within an artery depends on the local bal- the platelet membrane GPIbα (of the GPIb–IX–V complex) and its
ance between prothrombotic, antithrombotic, and fibrinolytic factors. adhesive ligand, VWF. 187–189 Platelet adhesion also involves collagen
Ulcerated and thrombotic atherosclerotic plaques, particularly in the binding to platelet collagen receptors (integrin α β and GPVI). Other
2 1
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aorta, tend to persist or recur. Atherosclerotic plaques of the aortic matrix constituents that become exposed to platelets and serve as adhe-
arch have been detected in almost one-third of patients with crypto- sive ligands include fibronectin, laminin, fibrinogen, and fibrin. These
genic stroke. Although aortic arch atheroma are more frequent and initial adhesive interactions induce intracellular signaling pathways
more severe causes of cryptogenic stroke in individuals older than that activate platelets. High shear stress also activates platelets both
190
55 years of age, patent foramen ovale (and presumably paradoxical directly, as noted previously, and by lowering the threshold of platelet
embolism) are more strongly associated with cryptogenic stroke in activation by chemical agonists to which platelets are simultaneously
those younger than 55 years of age. 178 exposed in the microenvironment of the arterial thrombus. Thus, fol-
191
Advances in the development of coronary stents have created lowing adhesion, platelets are explosively activated by several interact-
a new form of arterial thrombosis that usually can only be prevented ing pathways: (1) intracellular signaling initiated by the adhesion event
by administration of two different platelet inhibitors (e.g., aspirin in itself, (2) direct action of locally increased shear stress, and (3) agonists
combination with a thienopyridine derivative, such as clopidogrel or released (e.g., ADP, thromboxane A ) and generated (e.g., thrombin) at
2
prasugrel). Although drug-eluting stents that deliver sirolimus or pacl- the site of vascular injury.
itaxel have been successful in reducing the problem of restenosis that Finally, the occlusive arterial platelet thrombus is created by the
is caused by smooth muscle cell proliferation and intimal hyperplasia aggregation of platelets. This process is mediated by several alterna-
following the coronary intervention, they have actually increased the tive ligands (VWF, fibrinogen, fibronectin) that bind to their activated
occurrence of “late stent thrombosis” compared to bare metal stents. receptors in the platelet integrin α β complex. Stability of the plate-
IIb 3
This form of arterial thrombosis, which typically occurs after discontin- let aggregate is conferred by additional ligand–receptor interactions,
192
uation of (dual) antiplatelet therapy, is probably caused by eluting drugs including CD40L binding to integrin α β . Platelet thrombus stabili-
IIb 3
interfering with endothelialization of the stent surface. 179 zation is designed to counteract shear forces that promote not only the
Thrombosis in Nonatherosclerotic Arteries Thrombosis may formation of arterial thrombi but also their embolization.
180
occur in arteries that are affected by vasculitis. As both SLE and The importance of the inflammatory component of arterial throm-
atherosclerosis are immune-driven processes, it is to be expected bosis, which is characterized by complex interactions among leuko-
164
that some patients with active SLE are more susceptible to acceler- cytes, endothelial cells, and platelets, is increasingly being recognized.
ated atherosclerosis (and related atherothrombosis) resulting from Activated platelets recruit leukocytes to the site of vascular damage,
autoantibody-mediated proatherogenic mechanisms. 181,182 However, promoting their adhesion to endothelium and their activation on endo-
even in the absence of underlying atherosclerosis, various types of thelium-bound chemokines. In fact, the presence of leukocytosis in
arterial thrombosis can complicate active vasculitis. For example, myeloproliferative neoplasms is a better predictor of pathologic throm-
patients with SLE may have MI with angiographically normal coronary bosis than the platelet count.
arteries. Giant cell arteritis, which characteristically targets the extracra-
nial carotid and vertebral arteries, leads to inflammation and necrosis Tissue Factor and Phospholipids
of the arterial wall and subsequent arterial occlusions in a distribution Tissue factor is a cell-surface–bound transmembrane protein that nor-
that is quite different from that of atherosclerosis. Takayasu arteritis has mally is not exposed to circulating blood. When expressed, TF initiates
an unusual predilection for the aortic arch and its branches, leading to coagulation by binding to factor VIIa and activates factors IX and X,
panarteritis, medial layer enlargement with luminal narrowing, and thereby triggering the common pathway of coagulation and the for-
sometimes thrombotic occlusion. Other types of vasculitis and autoim- mation of thrombin. Strong evidence indicates that TF is the principal
mune processes that may cause arterial thrombosis include polyarteritis thrombogenic factor in the lipid-rich core of atherosclerotic plaques.
nodosa, Behçet disease, and antiphospholipid antibody syndrome. While much of this TF is associated with monocytes/macrophages and
Arterial thrombosis in the absence of atherosclerosis is also seen vascular smooth muscle cells, more recent studies suggest that TF-
with immune- and nonimmune disorders of platelets and/or the vas- positive microparticles are the most abundant sources of TF in athero-
cular endothelium, such as heparin-induced thrombocytopenia (with sclerotic plaques. The main inhibitor of TF-mediated coagulation is
arterial thrombosis most commonly occurring in the aorta, iliofemoral TFPI. In atherosclerotic plaques TFPI colocalizes with TF and therefore
arteries, as well as in cerebral and coronary arteries), and in the mye- may play an atheroprotective role. 162,193
183
loproliferative neoplasms (e.g., essential thrombocythemia, polycythe- Upon rupture of the atherosclerotic plaque, exposure of vascular TF
mia vera; Chaps. 84 to 86). 184–186 to flowing blood initiates the coagulation cascade. Coagulation reactions
are accelerated on the surfaces of activated platelets, microparticles, and
Platelet Activation on other activated cells in the microenvironment of vascular injury. The
Disruption of an advanced atherosclerotic plaque results in abrupt surfaces of these activated cells express anionic phospholipids, particu-
exposure of highly thrombogenic material to flowing blood. This pro- larly phosphatidylserine. Apoptotic cells, with which advanced lesions
cess leads locally to both thrombin generation and platelet activation, are enriched, likewise translocate phospholipids from the inner to the
194
which operate simultaneously in a mutually self-amplifying process. outer leaflet of the cell membrane. Plasma lipoproteins can provide a

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