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Atherosclerosis and Thrombus Formation

Pathology

The pathogenic process leading from the


development of the cerebrovascular or
extracranial atherosclerosis of the occurrence of
acute ischemic stroke and consequent cell
damage is complex, and many of the
intermediary damage is complex, and many of
the intermediary steps are not completely
understood.

Ischemic stroke may arise from the


atherosclerotic large cerebral arteries (eg,
carotid, middle cerebral, and basilar arteries) or
atherosclerotic small cerebral arteries (eg,
lenticulostriate, basilar penetrating, and
medullary arteries); ischemic stroke may also be
cardioembolic in origin. Most investigations of
atherogenesis have focused on the coronary
arteries, but, with some possible exceptions,
similar processes occur in the cerebral
circulation. In the brain, the process is better
characterized in the larger arteries than in small
arteries supplying deep cerebral white matter.
Some evidence suggests that the underlying
pathogenetic process in small arteries may differ
from that described in larger arteries [DeGraba
TJ, et al. In: Barnett HJM, et al (eds). Stroke.
Pathophysiology, Diagnosis, and Management. New York, Churchill Livingstone, 1992:29].

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.

The progression of early atherosclerotic lesions to clinically relevant advanced atherosclerotic


lesions occurs with increased frequency in persons with risk factors for atherosclerotic disease (eg,
heypercholesterolemia, hypertension, cigarette smoking) [Ip JH, et al, 1994].
Arterial Wall Injury

Recent models of atherogenesis have been based,


in part, on the "response-to-injury" hypothesis
proposed by Ross and colleagues [Ross, R.
Nature. 1993;362:801]. The concept is that
atherosclerosis begins as a response to chronic
minimal injury to the endothelium (the continuous
monolayer of cells lining the arterial wall) and that
interactions among monocytes, lipoproteins,
platelets, lymphocytes, and smooth muscle cells
abet and continue the pathogenic process.

The main "battleground" of the atherosclerotic


process in the intima, which lies just below the
endothelium [Hajjar DP, Nicholson AC. American
Scientist. 1995;83:460]. While the media (middle
layer) appears to play some role -- and perhaps
the adventitia (outer layer) as well -- the
development of atherosclerosis is primarily
characterized by an accumulation of complex
lipids, proteins, and carbohydrates, as well as a
proliferation of cells, in the intimal layer of an
artery.

Ip and colleagues have proposed a


pathophysiologic classification of vascular injury
into three types [Ip JH, et al, 1990. Ip JH, et al,
1994]. Type I injury, a chronic minimal injury
characterized by functional alterations of
endothelial cells without significant morphologic
changes (i.e., epithelial denudation), is thought to
be caused primarily by the turbulence of blood
flow. However, other factors appear to potentiate endothelial injury, including hypertension,
hypercholesterolemia, circulating vasoactive amines, immunocomplexes, viral infections, and a
chemical irritant in tobacco smoke.

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

Adhesion of circulating monocytes


(white blood cells that become particle-
ingesting macrophages once they enter
another tissue) to the surface of intact
endothelial cells appears to be an early
event in the development of
atherosclerotic lesions [Hajjar DP and
Nicholson AC, 1995]. Investigators
have determined that monocyte binding
to the endothelium of animals fed a
high-cholesterol diet is preceded by
expression of the vascular cell adhesion
molecule (VCAM) and that a lipid is
ultimately responsible for activating the
gene for VCAM [Gimbrone MA, Jr.
Cybulsky MI, et al. Anne New York Acad
Sci. 1995:748:122].

The expression of VCAM on the


endothelium can be altered by abrupt
changes in the direction and force of
local blood flow at atherosclerotic
lesion-prone sites in the circulatory
system [Gimbrone MA and Cybulsky MI,
1995]. Specifically, a shear-stress
responsive element, identified in the regulatory region of several genes, has been show to promote
the expression of adhesion molecules as well as other molecular factors that participate in
atherogenesis. One mechanism by which abnormal shear forces on the surface of an endothelial
cell can induce the expression of genes that contribute to the development of atherosclerosis may
involve certain transcription factors (proteins that bind to regulatory regions of genes) that are
produced in response to shear stress [Davies PF, Tripathi SC. Circulation Research. 1993;72:239.
Hajjar DP and Nicholson AC, 1995].

After adhesion, monocytes insinuate


themselves between the tight junctions
of the endothelial cells and enter the
subendothelial space [Hajjar DP and
Nicholson AC, 1995].

Immune mechanisms also appear to


play a role in atherogenesis [Ip JH, et
al, 1994. Hajjar DP and Nicholson AC,
1995]. In particular, T-lymphocytes
(cells responsible for the cell-mediated
immune response) have been found to
be present, albeit in small numbers, in
both early fatty lesions and in advanced
fibrous lesions in humans. It has been
suggested that activation of T-
lymphocytes during atherogenesis may
be similar to other immune responses in
which T-cells help to mobilize
macrophages.

After monocytes have migrated beneath


the endothelial layer into the intima,
they are transformed into a phagocytic
state (macrophages) in which they ingest modified lipids (primarily oxidized lipids) [Hajjar DP and
Nicholson AC, 1995]. As atherogenesis progresses, these macrophages take on a "foamy"
appearance (thus their designation as "foam cells") and become one of the primary components of
the fatty streak.

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

It is clear that the accumulation of lipids


in macrophages and smooth-muscle
cells is a central aspect of atherogenesis
[Hajjar DP and Nicholson AC, 1995. Ip
JH, et al, 1994. DeGraba TJ, et al,
1991]. The interaction between lipids
and cellular contributions to
atherogenesis has been widely
investigated. In the late 1970s, Brown
and Goldstein showed that the hepatic
receptor for the low-density-lipoprotein
(LDL) particle removes cholesterol from
the bloodstream; however, this receptor
was not found to play a role in the
accumulation of lipids within the foam
cells of atherosclerotic lesions.
Subsequently, the two investigators
demonstrated that another type of LDL
receptor, called the "scavenger
receptor," was present on macrophages
[Brown MS, Goldstein JL. Science.
1986;232:34]. Later work by Steinberg
and colleagues showed that whereas
normal LDL is not readily taken up by
the scavenger receptor, this receptor
does recognize oxidized LDL particles
[Steinberg D, et al. N Engl J Med. 1989;320:915].

Oxidation of LDL-cholesterol is induced by free radicals produced by macrophages, endothelial


cells, or smooth-muscle cells [DeGraba TJ, et al, 1991]. In addition to its participation in the
formation of foam cells, oxidized LDL-cholesterol appears to contribute to atherogenesis in three
other ways: (1) It has cytotoxic properties that may promote endothelial injury; (2) it acts as a
chemoattractant for circulating monocytes, leading to their increased accumulation with plaques;
and (3) oxidized LDL-cholesterol inhibits egress of macrophages from plaques.
Smooth Muscle Cell Migration and
Proliferation

The smooth muscle cell is another major


component -- and progenitor -- of the
fatty streak [Hajjar DP and Nicholson
AC, 1995]. Along with macrophages,
smooth-muscle cells (which normally lie
in the medial layer and are responsible
for maintaining vascular tone)
proliferate in the intima during
atherogenesis.

Proliferation of smooth muscle cells


within the intima makes up a substantial
bulk of the atherosclerotic lesion, which
may rise several millimeters above the
surface of the surrounding intima. A
number of molecular factors may play a
role in the proliferation and migration of
smooth-muscle cells. They include
growth factors (eg, platelet-derived
growth factor, or PDGF, a polypeptide
released from blood platelets and
endothelial cells that may attract
smooth-muscle cells to the intima and
encourage them to divide), eicosanoids (which can stimulate the hydrolysis of cholesteryl ester,
producing free cholesterol), certain cytokines (eg, tumor necrosis factor, interleukin-1 and
interferon), and nitric oxide (which acts to dilate blood vessels) [Hajjar DP and Nicholson AC,
1995].

Role of Platelets

Platelet aggregation -- and thrombosis -- after Type II


injury are thought to play key roles in the progression
of atherosclerosis. Platelet adhesion may be promoted
by toxic products released by macrophages and by
moderate damage to the intimal surface with
denudation of the epithelium [Ip JH, et al, 1994].

Platelets release growth factors that stimulate migration


and proliferation of smooth muscle cells and also
contribute to the formation of subendothelial
"fibrointimal lesions" and possibly to formation of the
outside capsule of predominantly "fatty lesions".

Plaque Fissuring and Formation


The mechanisms of plaque
destabilization (fissuring and
rupture, followed by thrombus
formation) are not fully
understood. Study of plaques
in the coronary arteries that
have undergone fissuring
indicate that the majority are
composed of eccentrically
situated lipids (i.e., located in
an area where the vessel
bifurcates) that do not have an
internal lattice of collagen
supporting the cap of the
plaque.

The vulnerability of such a


structure to fissuring appears to
be related to circumferential
stress on the plaque cap in
systole, as well as infiltration of
the cap tissue with foam cells
(with reduction of total collagen
content and a concomitant fall in tensile strength) [Davis MJ, 1994]. It is unclear whether foam
cells weaken the tissue by passively distorting the spatial arrangement of the connective tissue
matrix or by actively destroying connective tissue matrix protein by lytic mechanisms.

Potential Outcomes of Plaque Fissuring

Most advanced plaques appear


to progress from the early
lesion very rapidly by means of
Type II injury with resulting
thrombus formation and its
incorporation into the plaque
[Ip JH, et al, 1994].

Thrombosis and incorporation of


the surrounding thrombus into
the plaque have been
demonstrated in various stages
of atherogenesis [Ip JH, et al,
1994]. In autopsy study of
coronary arteries in patients
with atherosclerotic syndromes,
for example, nearly 17% of
patients had fissures in
atherosclerotic plaques and
some cases overlying thrombi
[Davies MJ. In: Julian DG, et al
(eds). Thrombolysis in
Cardiovascular Disease. New
York, Marcel Dekker, 1989]. Moreover, studies have suggested that thrombus
formation/organization and acute or subacute progression of atherosclerotic plaque is probably
part of the same phenomenon [Wilcox JN, et al. J Clin Invest. 1988;82:1134].

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.

Thrombus Formation I -- Platelet Activation

Rupture of the atherosclerotic plaque


exposes the subendothelial collagen to
the bloodstream [Kumar V, et al. Basic
Pathology. 5th Edition. Philadelphia,
W.B. Saunders Co., 1992]. On contact
with collagen, platelets become
activated, with platelet adhesion,
secretion of platelet contents, and
platelet aggregation at the site of
injury. The activated platelet surface is
an essential catalytic surface for several
coagulation reactions that generate
thrombin, a key factor in the
coagulation sequence [D'Souza D, et al.
Lancet. 1994;344:991].

Platelets adhere to exposed


subendothelium through interaction with
a variety of platelet surface receptors,
the most important of which is GP-Ib-IX
[Hirsch J, et al. In: Colman RW, et al
(eds). Hemostasis and Thrombosis:
Basic Principles and Clinical Practice,
Third Edition. Philadelphia, J.B.
Lipincott Company, 1994:1151]. This glycoprotein is the main receptor for the subendothelial
protein ligand von Willebrand factor (vWF).

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.

Thrombus Formation II -- Platelet Activation and Blood Flow

Under high fluid shear-stress conditions,


there is evidence that platelet
aggregation depends on the binding of
vWF (indicated in blue) to platelet
GPIIb/IIIa [D'Souza E, et al, 1994;
Moake JL, et al. J Clin Invest.
1986;78:1456-61]. It has also been
shown that blockade of vWF-GPIIb/IIa
interaction inhibits platelet aggregation
and thrombus formation without
disturbing the initial platelet adhesion
[Aleviadou RB, et al. Blood.
1993;81:1263].
Thus, vWF appears to play a crucial role in both platelet adhesion and platelet aggregation under
high shear-stress conditions, such as turbulent blood flow in atherosclerotic vessels. The
importance of vWF is further supported by an association between elevated vWF concentrations
and arterial thrombosis [Jansson HH, et al. Br Heart J. 1991;66:351].

Thrombus Formation III -- Activation of Coagulation Cascade

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.

Physiologic Subtypes of Thrombosis-Related Ischemic Stroke

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).

Evolution of Cerebral Atherothrombosis

The complete occlusion of an


artery may lead to an ischemic
infarction, an area of necrotic
cells caused by the obstruction
of blood flow.

Thrombosis may take place in a


few minutes or take hours or
even days to fully evolve. A
stroke that is actively
progressing as a direct result of
increasing occlusion and
ischemia is termed stroke in
evolution of progressing stroke
[Aminoff MJ, et al. Clinical
Neurology. 3rd Edition.
Stamford, Conn., Appleton and
Lange, 1996]. A large blood
vessel (e.g., carotid, middle
cerebral, and basilar arteries)
can take longer to become
occluded than a smaller vessel
(e.g., lenticulostriate, basilar
penetrating, and medullary
arteries), and there may be
warning signs. One of the
most important is a transient ischemic attack (TIA).

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.

Cerebral Embolism Formation


Formation

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.

As a cause of stroke, embolism accounts for approximately 32% of cases.

Cardiac Sources

Identification of the sources of embolism has been


problematic [Mohr JP and Sacco RL, 1992].
Traditionally, the term "embolism" refers to arterial
thromboembolism stemming from a cardiac source.
The major source of cerebral emboli is the heart, and
for this to occur the abnormality, such as one resulting
in atrial fibrillation.

Cardiogenic emboli lodge in the middle cerebral artery


or its branches in 80% of cases, in the posterior
cerebral artery or its branches 10% of the time, and in
the vertebral artery or its branches in the remaining
10% of cases [Kistler JP, et al. In: Braunwald E, et al
(eds). Harrison's Principles of Internal Medicine. New
York, McGraw-Hill, 1994:2250]. Cardiac emboli rarely
reach the anterior cerebral artery. If an embolus is large enough to occlude the proximal stem of
the middle cerebral artery (3 to 4 mm), a major stroke results.

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.

Ischemic infarction can be divided into "bland"


infarction associated with secondary bleeding --
referred to as hemorrhagic conversion or
transformation (HT) -- in ischemically infarcted
areas [Mohr JP and Sacco RL, 1992; Teal PA and
Pessin MS, 1992; Pessin MS, In: Hacke et al
(eds), 1991]. Bland infarction is characterized
by bland widespread leukocyte infiltration and
macrophage invasion, with only scattered red
cells being found. Hemorrhagic conversion may
take the form of infarction (HI) or, less
commonly, parenchymatous infarction (PH).
The occurrence of hemorrhagic conversion is
"predominantly a natural tissue consequence of
embolism" [Teal PA and Pessin MS, 1992].

An autopsy, HI may vary from patchy petechial


bleeding to more confluent hemorrhages,
representing multifocal extravasation of blood
from capillaries or venules [Teal PA and Pessin
MS, 1992]. HI and PH have different incidences,
pathogenesis, and clinical outcome, but distinguishing HI and PH on CT may be difficult [Teal PA
and Pessin MS, 1992]. Although HI and PH have often been grouped together, there are certain
features on CT that help characterize these two types of hemorrhagic transformation. On CT, HI
appears as a discontinuous heterogeneous mixture of high and low densities occurring within the
vascular territory of the infarct. In contrast, PH appears as a discrete, homogeneous collection of
blood that often exerts mass effect and may extend beyond the original infarct boundaries or even
into the ventricles.

HI occurs regularly in the natural evolution of


acute embolic stroke [Pessin MS, In: Hacke et al
(eds), 1991]. In autopsy studies, the
occurrence of HI has ranged from 51% to 71%
of recent embolic strokes [Teal PA and Pessin
MS, 1992]. However, CT studies have shown a
lower incidence, with studies of con-coagulated
patients who have predominantly embolic
infarcts indicating an overall incidence of 26% to
43%. According to another estimate,
approximately 20% of patients with
cardioembolic stroke have hemorrhagic
transformation in the infarcted zone, usually
occurring within 48 hours [Leonard AD, Newburg
S. J Neurosci Nurs. 1992;24:69].
Transformation of a bland embolic infarct to HT
is rare in the first 6 hours. Most HIs are
asymptomatic, and it is not uncommon to detect
HI on CT patients who are stable or improving.
The pathogenesis of HT appears to relate to
reperfusion of bleeding from recanalized but
ischemically injured vessels by the natural,
dynamic dissolution of thrombi [Teal PA and
Pessin MS, 1992] -- i.e., an embolus that
represents all or part of a thrombus has a
spontaneous tendency to lyse and disperse.
Reperfusion into the ischemically injured vessels can therefore result in varying degrees of blood
extravasation through the damaged blood-brain barrier.
As noted by Mohr and Sacco (1992), HI has been often explained as a result of reperfusion of the
vascular bed of the infarct, such as would occur after fragmentation and distal migration of an
embolus or after early reopening of a large vessel occlusion in the setting of a large infarction; the
full pressure of arterial blood into hypoxic capillaries results in a diapedesis or red cells through
their hypoxic walls. The concept of restored lumen patency is consistent with greater frequency of
hemorrhagic infarction in patients with cardioembolic infarcts.

The occurrence of PH in areas of ischemic


infarction is less common that that of HI [Teal
PA and Pessin MS, 1992]. PH appears to be
associated with anticoagulation therapy, with a
low incidence of spontaneous PH in areas of
ischemic infarction (on the order of 2% to 9%)
in patients no receiving anticoagulation therapy.
In contrast to HI, clinical deterioration is often
associated with PH. It has been proposed that
the pathogenesis of PH may involve "ischemic
necrosis resulting in the rupture of small
penetrating vessels analogous to hypertensive
hemorrhage, leading to massive bleeding rather
that the multifocal diapedesis of blood through
capillary walls, as seen in HI" [Teal PA and
Pessin MS, 1992].

The observation that some hemorrhagic


infarctions develop distal to the site of a
persisting occlusion suggests that reperfusion is
not always a necessary condition. Investigators
from Japan examined the brains of 14 patients
who died from herniation of the brain after
cardioembolic stroke with persistent occlusion of
the internal carotid-middle arterial axis [Ogata J,
et al. Stroke. 1989;20:876-83]. The finding of
hemorrhagic infarct in 7 of the patients contradicts the concept that reopening a previously
occluded vessel is the only pathophysiologic mechanism for the development of hemorrhagic
infarct. Analysis of blood pressure after stroke has revealed on or more surges of arterial
hypertension or rapid rise of blood pressure in patients with hemorrhagic stroke without a
reopening of the occluded artery; it has been speculated that these blood pressure rises might
explain hemorrhagic infarction in many cases.

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.

Cellular Injury During Ischemia


Cellular Changes During Ischemia

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.

Shown is a summary of the cascade of cellular changes as ischemia progresses.

Neuronal Function: Importance of Oxygen and Glucose

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.

A stimulus affects the axon by changing the


permeability of the axon to positive ions. The influx
of positive ions reduces the electrical potential across
one segment of the membrane (depolarization). The
change in electrical potential in the first part of the
axon triggers a change in electrical potential in the
adjacent segment of the axon such that the impulse
travels along the axon as a self-generating chain
reaction.

At most synapses, arrival of the impulse at the


presynaptic terminal leads to release of
neurotransmitter, which crosses the synapse to
interact with receptors on the membrane of the
postsynaptic cell. This interaction opens ion-specific
channels in the postsynaptic membrane, changing
the membrane's permeability for positive ions.
The transient change in voltage induced by the action potential is determined by the concentration
of ions on either side of the cell membrane. Maintaining these ionic gradients is an energy-
consuming process that requires a constant supply of glucose and oxygen to the neuron

Inadequate Energy Supply

Lack of glucose and oxygen deplete the


cellular energy stores required to
maintain electrical potentials and ion
gradients.

In ischemic brain tissue, the membrane


that surrounds each affected neuron
becomes "leaky," and the cell loses
potassium and adenosine triphosphate
(ATP), the tissue's medium for energy
exchange.

Energy failure is not the immediate


cause of cell death; however, since all
brain cells tolerate loss of ATP for
several minutes. In humans, it
appears that 5 to 10 minutes of
complete occlusion is required for
irreversible brain damage. In actuality,
most strokes do not involve a complete
occlusion of blood flow, but even a
partial occlusion, if allowed to continue
for a sufficient time, may produce
irreversible brain damage.

Once blood flow to cerebral neurons


diminishes, one or more branching
mechanisms may independently lead to brain cell death. These mechanisms may involve
deterioration of ion gradients or the effects of anaerobic metabolism.

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.

Deterioration of Ion Gradients


Inadequate energy supply leads to
deterioration of ion gradients. Anoxic
depolarization (equilibration of
intracellular and extracellular ions)
causes potassium to leave the cell and
sodium, chloride, and calcium ions to
enter. It also stimulates the massive
release of the amino acids glutamate
and aspartate, excitatory
neurotransmitters in the brain.

Glutamate further activates sodium


and calcium ion channels in the neuron
membrane.

As sodium and calcium ions rapidly


accumulate within the cells,
accompanied by an inflow of water,
cytotoxic edema causes rapid swelling
of neurons and glia.

Activation of calcium channels results


in further influx of calcium into the
cell. One of the most intensely studied
calcium channels is the N-methyl-D
aspartate (NMDA) channel.

Consequences of Calcium Overload

Entry of calcium through the NMDA


(and similar channels) can be
devastating. First, attempts to get rid
of the excess calcium use up already
scarce supplies of ATP. Second,
excessive calcium influx causes the
disordered activation of a wide range
of enzyme systems (proteases, lipases,
and nucleases). These enzymes and
their metabolic products, such as
oxygen free radicals, damage cell
membranes, genetic material, and
structural proteins in the neurons,
ultimately leading to cell death. This
sequence of events has been termed
excitotoxicity because of the pivotal
role of excitatory amino acids such as
glutamate.

Several agents are under investigation


to block these steps.

The Ischemic Penumbra


Within the ischemic cerebrovascular
bed, there are two major zones of
injury: the core ischemic zone and the
"ischemic penumbra" (the term
generally used to define ischemic but
still viable cerebral tissue).

In the core zone, which is an area of


severe ischemia (blood flow below 10%
to 25%), the loss of inadequate supply
of oxygen and glucose results in rapid
depletion of energy stores. Severe
ischemia can result in necrosis of
neurons and also of supporting cellular
elements (glial cells) within the severely
ischemic area.

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.

In this example, the ischemic penumbra is


shown as a rim of tissue surrounding the
severely ischemic core lying within the vascular
territory of the pre-Rolandic branch of the left
middle cerebral artery. The Rolandic artery is
occluded by a thromboembolus. The extent of
the penumbra varies directly with the number
and patency of collateral arteries.

The penumbra is where pharmacologic


interventions are most likely to be effective.
However, it may also be possible to salvage
cells within the severely ischemic core zone.
Although severe ischemia kills selectively
vulnerable neurons, glial cells may be spared if blood flow is restored early. Therefore, timely
recanalization of the occluded vessel should theoretically restore perfusion in both the penumbra
and in the severely ischemic core. Partial recanalization should markedly reduce the size of the
penumbra as well.

Cerebral Infarction / Effects of


Edema

Shown is a brain slice viewed from the


back following a stroke. Blood flow to
the region on the left was interrupted
due to a thrombus or embolus. The lack
of blood flow resulted in severe damage
(infarct) to some of the brain tissue.
The infarcted tissue caused fluids to
accumulate (edema) and result in
swelling. The center of the brain is
shifted to the right due to swelling from
the left.
The rigid container of the cranium allows limited room for expansion, and any condition that
causes an increase in volume of one or more structures within this vault will cause an increase in
intracranial pressure (ICP) or will shift one compartment of the brain, thereby compressing
others. As the pressure increases, the brain shifts or is distorted, compressing neurons, nerve
tracts, and cerebral arteries. A sustained increase in pressure causes persistent ischemia,
irreversible damage to brain cells, and potentially death.

Edema Formation

Ischemic brain edema is a


combination of two major types
of edema: cytotoxic (cellular)
and vasogenic [Fishman RA.
Cerebrospinal Fluid in Diseases
in the Nervous System. 2nd Ed.
Philadelphia, PA: W.B. Saunders
Co; 1992:103-155]. Cytotoxic
edema evolves over minutes to
hours and may be reversible,
while the vasogenic phase
occurs over hours to days, and
is considered an irreversibly
damaging process.

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.