Pathology
Atherogenesis is a decades-long process in which the lumen of a blood vessel becomes narrowed
by cellular and extracellular substances to the point of obstruction [Breslow JL. Science.
1996;272:685.] An autopsy study of coronary arteries and aortas in 1,160 people who died
between full-term birth and age 29 years found that the earliest lesion of atherosclerosis is the
fatty streak [Stary HC. Atherosclerosis. 1989;9 (suppl 1): 119]. Approximately 65% of children
between ages 12 and 14 years had such lesions. Fatty streaks, which are grossly visible as areas
of yellowish discoloration of the surface of the intimal layer of the vessel wall, are widely
distributed throughout the coronary arterial vasculature. On microscopy, the lesions primarily
consist of lipid-filled macrophages (foam cells).
The autopsy study revealed that an additional 8% of children in late childhood or early
adolescence had progressed beyond the fatty-streak stage and had developed more advanced,
focal lesions. These lesions, which occur only in areas of eccentric thickening (ie, at branch points
of the arterial vessel), are characterized by the addition of massive extra-cellular lipids that
displaced normal cells and matrix.
In the third decade of life, some atheromatous lesions evolve into complicated fibrous plaques,
consisting of a central acellular area of lipid covered by a cap of smooth muscle cells and collagen.
Caps tend to form slowly at first, but with deposition of platelets and fibrin on the surface -- which
appears to be the result of endothelial injury -- the caps thicken quickly, possibly as a result of
thrombosis-dependent fibrotic organization.
Type II injury is characterized by denuding of the endothelium and superficial intimal injury.
These changes, which appear to be the result of toxic products released by accumulating
macrophages in the intima, are accompanied by platelet deposition with or without thrombus
formation. Repetitive Type II injury of soft plaques, with thrombus formation. Repetitive Type II
injury of soft plaques, with thrombus incorporation, is thought to be a major mechanism for the
progression of atherosclerosis.
Type III injury is typified by deep intimal and medial damage, accompanied by marked platelet
aggregation and mural thrombosis. Vascular injury of this magnitude is seen following plaque
rupture.
Role of Monocytes and T-Lymphocytes in the Transformation to Foam Cells
The mechanisms by which macrophages accumulate lipids within the intima and the possible role
of T-lymphocytes in this process are major areas of research.
Oxidation of LDL-Cholesterol
Role of Platelets
Acute episodes of transient ischemia and ischemic stroke (as well as myocardial infarction,
unstable angina, as sudden death) may be precipitated by thrombosis on atherosclerotic plaques.
In these episodes, the size of the thrombus in an order of magnitude greater than the microscopic
thrombi that contribute to plaque growth [Davies MJ. In: Colman RW, et al (eds). Hemostasis and
Thrombosis: Basic Principles and Clinical Practice, Third Edition. Philadelphia, J.B. Lipincott
Company, 1994:1225].
In this figure, initial plaque fissure may lead to one of two immediate outcomes (1) The fissure is
sealed and the incorporated thrombus undergoes fibrotic organization; or (2) the fissure leads to
mural intraintimal and intraluminal thrombosis, resulting in partial or transient reduction in blood
flow. Some transient ischemic attacks (TIAs) could be caused by this mechanism, but other
factors such as increased viscosity, reduced vessel wall compliance, or other unknown factors also
appear to be important.
Following intraintimal and intraluminal thrombosis, (3) the fissure may result in occlusive
thrombosis which, if persistent, can lead to ischemic stroke or myocardial infarction, particularly in
the absence of collateral flow.
Platelet aggregation requires the platelet membrane glycoprotein integrin receptor (GP IIb-IIIa),
which -- at least under low fluid shear stress conditions -- is involved in calcium-dependent
interplatelet bridging by bound fibrinogen.
When platelets are activated, they acquire enhanced capacity to catalyze interaction between
activated coagulation on factors [Hirsh J, et al, 1994]. These factors circulated in the form of
inactive precursors (zymogens). Rupture of the atherosclerotic plaque leads to activation of the
coagulation cascade: Each zymogen in converted into an activated coagulation factor, which in
turn activates the next zymogen in the sequence. This process culminated in the generation of
thrombin, an enzyme that converts the soluble protein fibrinogen to the insoluble one, fibrin,
forming a blood clot.
The clotting cascade consists of two separate initial pathways ("intrinsic" and "extrinsic") that
ultimately converge on the "common" pathway [Colman RW, et al, 1994; Rapaport SI. Western J
Med. 1993;158:153]. The intrinsic and extrinsic pathways essentially serve to activate the
precursor protein prothrombin to the active enzyme thrombin. The intrinsic pathway includes the
"contact" activation system (see below).
The extrinsic system, the principal initiating pathway of in vivo blood coagulation, involves both
blood and vascular elements. The critical component is tissue factor (TF, sometimes referred to as
thromboplastin), a glycoprotein embedded in association with phospholipid (PL) in the surface
membrane of fibroblasts within and around blood vessels and in various other tissue cells. Under
physiologic conditions, tissue factor is not exposed to blood, but with vascular or endothelial cell
injury, this substance acts in concert with activated Factor VIIa and phospholipid to convert Factor
IX (from intrinsic system) to IXa and Factor X (from the extrinsic system) to Xa. The coagulant
activity of Factor VII, the major plasma component of the extrinsic pathway, is increased by Factor
IXa of Factor XIIa of the contact system. These events take only about 15 seconds.
The intrinsic pathway can be viewed as coagulation initiated by components entirely contained
within the vasculature. This pathway results in the activation of Factor IX by Factor XIa, providing
a pathway independent of Factor VII for blood coagulation. A major difference between the
intrinsic and extrinsic pathways is that whereas the activation of Factor IX by IXa requires only the
presence of ionized calcium, the activation of Factor IX by VIIa (in the extrinsic system) requires
both calcium and tissue factor. Importantly, Factor XIa converts Factor X (in the extrinsic system)
to Factor Xa in concert with the "tenase" complex (PL/VIIIa) [see below].
Included in the intrinsic pathway is the contact system, by which skin, muscle, connective tissue,
and a variety of other surfaces may act as activators. However, a number of other surfaces,
especially vascular endothelium, are ineffective as activators. Among the events associated with
the contact system are activation of Factor XI by the XIIIa/activated high molecular with kinogen
(HKa) complex. The role of contact system proteins in initiation of the intrinsic pathway of
coagulation in hemostasis is questionable, but these proteins do participate in a number of other
events (eg, inflammatory response, complement activation, fibrinolysis, and kinin formation) and
are also critical when blood interacts with a foreign surface as in cardiopulmonary bypass [Colman
RW, et al, 1994].
Factor Xa, regardless of how it is formed, is the active catalytic component of the
"prothrombinase" complex, which converts prothrombin to thrombin. Thrombin cleaves
fibrinopeptides (FPA, FPB) from fibrinogen, allowing the resultant fibrin monomers to polymerize,
and converts Factor XIII to XIIIa, which crosslinks (XL) the fibrin clot. Thrombin accelerates the
process (interrupted lines) by its potential to activate Factors V and VIII. A number of natural
plasma inhibitors retard clotting, including C1-inhibitor (C1 INH), tissue factor pathway inhibitor
(TFPI), and antithrombin II (ATIII).
The fibrin molecules aggregate together, trapping platelets, erythrocytes, and leukocytes to form
the clot. The clot then contracts, pulling together the edges of the injured surface.
An internal clot that remains in the area in which it is formed is called a thrombus, and the general
condition is called thrombosis. In an area where a small thrombus has formed, there is a tendency
for the clot to enlarge for the following reason: As blood flow slows around the clot, clot-forming
elements (e.g., platelets, red blood cells, and clotting factors) are deposited, producing an
enlarging, or propagating thrombus.
Thrombosis is a common link between three subtypes of ischemic stroke, each having a different
etiology.
Athero- thrombotic occlusion of larger arteries (eg, carotid, middle cerebral, basilar) is not only the
most common cause of primary large vessel occlusive cerebrovascular disease, but also is the
most common cause of stroke.
After primary large vessel occlusive disease, embolism is the most common cause of stroke. Most
embolic strokes are due to cerebral arterial atherothrombosis, in which a larger thrombus and is
carried to other places in the cerebrovasculature. Cerebral emboli may also arise from other
cardiogenic sources and deep vein thrombosis.
Primary small vessel cerebrovascular disease most prominently causing lacunar strokes arises
from microatheroma of an influx of fat-like materials (lipohyalinosis).
In an ischemic stroke, damage to the brain may not only result from infarction but also from
cerebral edema, an excessive accumulation of fluid in the brain. Cerebral edema peaks at
approximately 2 to 5 days after onset of the stroke. Then, accumulation of fluid usually stabilizes
and may lessen.
In addition to thrombotic occlusion at the site of cerebral artery atherosclerosis, ischemic infarction
can be produced by emboli arising from proximally situated atheromatus lesions to vessels located
more distal in the arterial tree [Mohr JP, Sacco RL. In: Barnett HJM, et al (eds). Stroke.
Pathophysiology, Diagnosis, and Management. New York: Churchill Livingstone, 1992:271].
A small clot may break off from a larger thrombus and be carried to other places in the
bloodstream. When the embolus reaches an artery too narrow to pass through and becomes
lodged, blood flow distal to the fragment ceases, resulting in infarction of distal brain tissue due to
lack of nutrients and oxygen.
Cardiac Sources
A cerebral embolus can also originate in the internal carotid artery, where deposits of atheroma
cause stenosis of the artery. The site of this stenosis is most often at the bifurcation of the
common carotid artery into its internal and external branches.
Hemorrhagic Conversion
In this example there is a gross parenchymatous
hematoma with intraventricular extension,
midline shift, and herniation.
A relationship between hyperglycemia and hemorrhagic transformation has also been suggested
by he observation that occluding the middle cerebral artery of markedly hyperglycemia cats was
associated with 5-fold more frequent and 25-fold more extensive hemorrhage into infarcts than in
normoglycemic animals [de Courten-Myers GM, et al. 1992]. Compared with permanent occlusion,
temporary restoration of blood flow after 4 hours caused the most extensive hemorrhage into
infarcts. It was concluded that hyperglycemia and restoration of blood flow to ischemic territories
were strong risk factors for hemorrhagic infarct conversion. The evidence suggests that the
marked tissue energy depletion accompanied by acidosis damages brain vessels, causing leakage
of edema fluid and red blood cells [de Courten-Myers GM, et al, 1992]. Diffuse HI associated with
marked hyperglycemia has been reported in two patients [Broderick JP, et al, 1995].
In summary, HI occurs regularly in the natural evolution of acute embolic stroke and is usually
asymptomatic [Pessin MS, In: Hacke et al (eds), 1991]. PHs occur less frequently, but are often
symptomatic due to extension and mass effect beyond the original infarct territory. Interest in
these issues has been further generated by trials of thrombolytic therapy for acute ischemic
stroke.
Injury from ischemic stroke is the result of a complex series of cellular metabolic events that occur
rapidly after the interruption of nutrient blood flow to a region of the brain. The duration, severity,
and location of focal cerebral ischemia determine the extent of brain function and thus the severity
of stroke.
Injury from ischemic stroke is the result of a complex series of cellular metabolic events that occur
rapidly after the interruption of nutrient blood flow to a region of the brain. The duration, severity,
and location of focal cerebral ischemia determine the extent of brain function and thus the severity
of stroke.
A neuron consists of a cell body, which contains a nucleus, and one or more extensions protruding
from the cell body. Dendrites receive nerve impulses from other neurons or from sensory
receptors. The axon carries the nerve impulses (action potential) away from the cell body to
another neuron or to an effector organ such as a muscle.
With respect to the latter, anaerobic glycotic pathways are utilized in the affected region to
compensate for the loss of oxygen and provide a source of energy. However, this produces
damaging by-products, including lactic acid and hydrogen ions, which accumulate in tissue in
proportion to the carbohydrate stores present at the outset of ischemia. Toxicity of hydrogen ions,
especially their ability to facilitate ferrous-iron-mediated free-radical mechanisms, appears to
irreversibly affect neuronal integrity.
Brain cells within the penumbra, a rim of mild to moderately ischemic tissue lying between tissue
that is normally perfused and the area in which infarction is evolving, may remain viable for
several hours. That is because the penumbral zone is supplied with blood by collateral arteries
anastomosing with branches of the occluded vascular tree (see inset). However, even cells in this
region will die if reperfusion is not established
during the early hours since collateral
circulation is inadequate to maintain the
neuronal demand for oxygen and glucose
indefinitely.
Edema Formation
Cytotoxic edema is
characterized by swelling of all
the cellular elements of the
brain (shown). In the presence
of acute cerebral ischemia,
neurons, glia (indicated by
astrocytes), and endothelial cells swell within minutes of hypoxia due to failure of ATP-dependent
ion (sodium and calcium) transport. With the rapid accumulation of sodium within cells, water
follows to maintain osmotic equilibrium. Increased intracellular calcium activates phospholipases
and the release of arachidonic acid, leading to the release of oxygen-derived free radicals and
infarction.
Vasogenic edema (not shown) is characterized by an increase in extracellular fluid volume due to
increased permeability of brain capillary endothelial cells to macromolecular serum proteins (e.g.,
albumin). Normally, the entry of plasma protein-containing fluid into the extracellular space is
limited by tight endothelial cell junctions, but in the presence of massive injury there is increased
permeability of brain capillary endothelial cells to large molecules. Vasogenic edema can displace
the brain hemisphere and, when severe, lead to cerebral herniation.
Acute hypoxia initially causes cytotoxic edema, followed within the next hours to days by the
development of vasogenic edema as infarction develops (Fishman, 1992). The delayed onset of
vasogenic edema suggests that time is needed for the defects in endothelial cell function and
permeability to develop.