Kuliah Umum Patologi Anatomik Blok Hemodinamik

Arteriosklerosis,
Aterosklerosis & Kelainan
Vena

dr. Ukhti Jamil Rustiasari, SpPA

Departemen Patologi Anatomik
Universitas Islam Indonesia
2016
Arteriosclerosis
Arteriosclerosis is a general term used to
include all conditions with thickening
and hardening of the arterial walls.
Morphologic entities :
I. Senile arteriosclerosis
II. Hypertensive arteriolosclerosis
III. Mnckebergs arteriosclerosis (Medial
calcific sclerosis)
IV. Atherosclerosis
SENILE
ARTERIOSCLEROSIS
Def : the thickening of media and intima of the
arteries seen due to aging.
The changes are nonselective and affect most of the
arteries. These are possibly induced by stress and
strain on vessel wall during life.

MORPHOLOGIC FEATURES
1. Fibroelastosis: The intima and media are thickened
due to increase in elastic and collagen tissue.
2. Elastic reduplication: The internal elastic lamina is split
or reduplicated so that two wavy layers are seen. Eventually,
the fibrotic changes result in age-related elevation of systolic
blood pressure.
HYPERTENSIVE
ARTERIOLOSCLEROSIS
Hypertension : an elevation in blood
pressure.
Arteriolosclerosis : morphologic forms of
vascular disease affecting arterioles and
small muscular arteries. These are:
1. hyaline arteriolosclerosis
2. hyperplastic arteriolosclerosis
3. necrotising arteriolitis
All the three types are common in
hypertension but may occur due to other
causes as well.
1. Hyaline
Arteriolosclerosis
Common arteriolar lesion that may be seen
physiologically due to aging, or may occur
pathologically in benign nephrosclerosis in
hypertensives and as a part of microangiopathy
in diabetics
MORPHOLOGIC CHANGES
The visceral arterioles are particularly involved. The
vascular walls are thickened and the lumina narrowed
or even obliterated.
Microscopically
the thickened vessel wall shows structureless,
eosinophilic, hyaline material in the intima and media
 PATHOGENESIS
The exact pathogenesis is not known. Hypotheses :
i) The lesions result most probably from leakage of
components of plasma across the vascular endothelium.
This is substantiated by the demonstration of
immunoglobulins, complement, fibrin and lipids in the
lesions. The permeability of the vessel wall is
increased, due to haemodyanamic stress in hypertension
and metabolic stress in diabetes, so that these plasma
components leak out and get deposited in the vessel wall.
ii) The lesions may be due to immunologic reaction.
iii) Some have considered it to be normal aging process that
is exaggerated in hypertension and diabetes mellitus.
Hyperplastic
Arteriolosclerosis
A characteristic lesion of malignant hypertension
MORPHOLOGIC FEATURES
The morphologic changes affect mainly the intima,
especially of the interlobular arteries in the kidneys. Three
types of intimal thickening may occur.
i) Onion-skin lesion consists of loosely-placed concentric layers of
hyperplastic intimal smooth muscle cells like the bulb of an onion.
The basement membrane is also thickened and reduplicated
ii) Mucinous intimal thickening is the deposition of amorphous
ground substance, probably proteoglycans, with scanty cells.
iii) Fibrous intimal thickening is less common and consists of
bundles of collagen, elastic fibres and hyaline deposits in the
intima. Severe intimal sclerosis results in narrowed or obliterated
lumen. With time, the lesions become more and more fibrotic.
PATHOGENESIS
The pathogenesis is unclear. Probably, the
changes result following endothelial
injury from systemic hypertension,
hypoxia or immunologic damage leading
to increased permeability. A healing
reaction occurs in the form of proliferation
of smooth muscle cells with fibrosis.
Necrotising Arteriolitis
In severe hypertension and malignant
hypertension , parts of small arteries and arterioles
show changes of hyaline sclerosis and parts of these
show necrosis.
MORPHOLOGIC FEATURES
Besides the changes of hyaline sclerosis, the changes of
necrotising arteriolitis include fibrinoid necrosis of vessel
wall, acute inflammatory infiltrate of neutrophils in the
adventitia. Oedema and haemorrhages often surround
the affected vessels.
PATHOGENESIS
occurs in vessels in which there is sudden and great
elevation of pressure, the changes are said to result from
direct physical injury to the vessel wall.
Vascular pathology in hypertension. A, Hyaline arteriolosclerosis. The arteriolar wall is
thickened with increased protein deposition (hyalinized), and the lumen is markedly narrowed.
B, Hyperplastic arteriolosclerosis (onion-skinning) causing luminal obliteration (periodic acid
Schiff [PAS] stain). (Courtesy
Helmut Rennke, MD, Brigham and Womens Hospital, Boston, Mass.)
MNCKEBERGS ARTERIOSCLEROSIS
(MEDIAL CALCIFIC SCLEROSIS)

Def : calcification of the media of large and

medium-sized muscular arteries
Especially of the extremities and of the genital
tract, in persons >50y age-related
degenerative process (distrophic calcification),
and has little or no clinical significance.
MORPHOLOGIC FEATURES
Often an incidental finding in X-rays of the affected
sites having muscular arteries. The deposition of
calcium salts in the media produces pipestem-like
rigid tubes without causing narrowing of the lumen.
 Microscopically
Characterised by deposits of calcium salts in
the media without associated inflammatory
reaction while the intima and the adventitia
are spared. Often, coexistent changes of
atherosclerosis are present altering the
histologic appearance.
PATHOGENESIS
Is not known, considered as an age-related
physiologic change due to prolonged effect of
vasoconstriction.
Figure Monckebergs arteriosclerosis (medial calcific sclerosis).
There is calcification exclusively in the tunica media unassociated
with any significant inflammation.
ATHEROSCLEROSIS
A specific form of arteriosclerosis affecting primarily the
intima of large and medium-sized muscular arteries
and is characterised by fibrofatty plaques or
atheromas.
The term atherosclerosis :
athero-(meaning porridge) referring to the soft lipid-rich material
in the centre of atheroma
sclerosis (scarring) referring to connective tissue in the plaques.
Atherosclerosis is the commonest and the most
important of the arterial diseases.
Though any large and medium-sized artery may be
involved, the most commonly affected are the aorta, the
coronary and the cerebral arterial systems.
Characteristics Plaque components

Arterial intimal focal Smooth muscle cells

lesions (plaques) Connective tissue matrix
Macrophages
Lipid intracellular
Lipid extracellular
T-lymphocytes
Basophils
Mechanisms of plaque
formation
Adhesion of circulating monocytes to the intact
endothelial surface followed by their migration
between endothelial cells to reach the intima. In the
intima the monocytes take up lipid and become foam
cells.
invoked by the induction of a number of adhesion molecules
and cytokines.
On the endothelial cells : intercellular adhesion molecule
(ICAM-1), endothelial adhesion molecule (ELAM.E-selectin) and
vascular cell adhesion molecule (VCAM) are all expressed.
The monocytes are acting under the chemoattractant MCP-1.
Within the intima, macrophage colony stimulating factor
(MCSF) is important in maintaining monocytes and allowing
mitotic division.
 Low-density lipoprotein (LDL) from the plasma freely moves in,
and out, of the intima and invokes no response.
Within the intima, or on the endothelial surface, however,
a small proportion of the LDL undergoes oxidative change.
The minimally modified LDL acts as an inflammatory stimulus
Invokes adhesion molecule expression by endothelial cells,
monocyte migration and cytokine production.
Once oxidized, the LDL is taken up by macrophage
scavenger receptors. Some of these receptors do not
downregulate and lipid uptake continues until the cytoplasm is
packed with lipid to form the foam cell.
Smooth muscle cells may also take up some lipid via the
conventional LDL receptor and by low levels of expression of a
scavenger receptor, but seldom form classic foam cells.
 Extracellular lipid in the core : derived in large part from
the cytoplasm of dying macrophages and directly from LDL,
which becomes bound to proteoglycans in the intima.
Central core necrosis follows macrophage death due to the
direct toxicity of hydroxylipids in the core, as well as
apoptosis. The trigger for this is not known but may be a
reduction in growth factors such as MCSF-1 or induced by
tumour necrosis factor alpha (TNF).
Associated with the macrophages surrounding the lipid core
are T-lymphocytes, a proportion of which are cytotoxic.
Within the plaque itself B-lymphocytes are absent, but a
heavy adventitial inflammatory cell infiltrate containing
numerous T- and B-lymphocytes and plasma cells is common.
In part this is an autoimmune response to oxidized LDL
released from within the plaque and circulating humoral
antibodies are generated. Such antibodies may bind to
lipid in the plaque, further enhancing macrophage uptake.
Lipid core formation in plaques. Plasma LDL enters the intima and
undergoes modification to become an inducer of adhesion molecules and
cytokines by endothelial cells. LDL is then further oxidized. Monocytes enter
the intima, take up oxidized LDL to become foam cells and then die by
apoptosis and necrosis to release oxidized lipid into the developing core.
Mekanisme Pembentukan Foam Cell
Smooth muscle proliferation
Stimulated by various cytokines : IL-1 and TNF- (from
monocyte-macrophages and by activated platelets at the site of
endothelial injury) lead to local synthesis of growth factors.
Smooth muscle cells also produce growth factors in an autocrine
stimulation system. Growth factors stimulating smooth muscle
cells :
Platelet-derived growth factor (PDGF) and fibroblast growth
factor (FGF) proliferation and migration
Transforming growth factor- (TGF-) and interferon-(IFN-)
derived from activated T lymphocytes regulate the synthesis of
collagen by smooth muscle cells. Transforming growth factor :
stimulatory or inhibitory depending on the level of other cytokines, but
along with interferon is usually regarded as the main inhibitory
mechanism.
Fibrinogen passes into the intima and within the plaque
converted to fibrin by thrombin produced by macrophages.
Thrombin/fibrin complexes are a potent stimulus to smooth
muscle cell growth.
Factors inducing smooth muscle cell proliferation. Many factors as shown potentially
drive smooth muscle proliferation and the production by smooth muscle cells of collagen and
other matrix proteins. Other factors inhibit these processes. [PDGF platelet derived growth
factor; bFGF basic fibroblast growth factor; EGF epidermal growth factor; TGF
transforming growth factor; TNF tumour necrosis factor alpha; IGF insulin-like growth
 Moreover, collagen turnover is controlled by
metalloproteinases (MMPs), enzymes elaborated
largely by macrophages and smooth muscle cells
within the atheromatous plaque; conversely,
tissue inhibitors of metalloproteinases (TIMPs)
produced by endothelial cells, smooth muscle
cells, and macrophages modulate MMP activity.
The plaque is therefore becoming increasingly
recognized as a site of intense activity in which
collagen deposition and collagen removal is
occurring. If collagenolysis is dominant, the core
increases in size and the cap thins; if deposition
predominates, the plaque becomes more fibrous.
Sequence of cellular interactions in atherosclerosis. Hyperlipidemia, hyperglycemia, hypertension, and other influences cause
endothelial dysfunction. This results in platelet adhesion and recruitment of circulating monocytes and T cells, with subsequent
cytokine and growth factor release from inflammatory cells leading to smooth muscle cell migration and proliferation as well as
further macrophage activation. Foam cells in atheromatous plaques derive from macrophages and smooth muscle cells that have
accumulated modified lipids (e.g., oxidized and aggregated low density lipoprotein [LDL]) via scavenger and LDL-receptor-related
proteins. Extracellular lipid is derived from insudation from the vessel lumen, particularly in the presence of hypercholesterolemia, as
well as from degenerating foam cells. Cholesterol accumulation in the plaque reflects an imbalance between influx and efflux; high-
density lipoprotein (HDL) likely helps clear cholesterol from these accumulations. In response to the elaborated cytokines and
chemokines, smooth muscle cells migrate to the intima, proliferate, and produce extracellular matrix, including collagen and
Evolution of arterial wall changes
in the response to injury
hypothesis.
1, Normal. 2, Endothelial injury with
monocyte and platelet adhesion. 3,
Monocyte and smooth muscle cell
migration into the intima, with
macrophage activation. 4,
Macrophage and smooth muscle cell
uptake of modified lipids, with further
activation and recruitment of T cells.
5, Intimal smooth muscle cell
proliferation with extracellular matrix
production, forming a well-developed
plaque.
Plaqeu Nomenclature
(AHA)
Stage I : adhesion of monocytes to the intact endothelial
surface, subsequently move to enter the intima and become
the foam cells of the fatty streak.
Stage II : fatty streak consists of a focal collection of lipid-
filled macrophages over which there is an intact endothelial
surface.
Stage III : very like Stage II, apart from being larger.
Histologically : droplets of extracellular lipid and smooth
muscle cells just beneath the endothelium.
Stage IV : raised fibrolipid or advanced plaques may be
yellow or white. Histologically : plaque has a central core of
acellular lipid-containing cholesterol crystals, surrounded
by lipid-filled foam cells of macrophage origin and contained
within a capsule of collagen. The core is separated from the
lumen by collagenous capsule (plaque cap). The plaques have a
thin cap
Stage Va : the cap is much thicker. The external colour is yellow
(carotenoid pigment in the lipid core). If the plaque cap is thick,
Plaque evolution. The sequence of plaque evolution with the cellular
and lipid
Aortic fatty streaks. The aorta has been
opened and pinned out to display the
intimal/endothelial surface. There is a
series of yellow longitudinal streaks
which are barely raised above the
intimal surface. While some fatty
streaks are situated at the openings of
the intercostal arteries, many are not.
Aortic fatty dots. In the ascending
aorta in particular, but also in the rest
of the aorta, small yellow dots are
found. Their histology is identical to
that of fatty streaks.
Fatty streak, a collection of foamy macrophages in the intima.
Photomicrograph of fatty streak in an experimental
hypercholesterolemic rabbit, demonstrating intimal,
macrophage-derived foam cells (arrows).
Aortic atherosclerotic plaques. Two large fibrolipid plaques are shown
in the healing phase after plaque ulceration and thrombosis. The
plaques contain central craters with flat floors on which there is a
small amount of residual thrombus. The cholesterol of the original
core has been washed out and embolized into the lower limb
arteries.
Coronary advanced fibrolipid plaque. In this perfused fixed artery the lumen
is round and there is a large accentrically situated plaque. The core is very
large occupying most of the area of the plaque cross-section. The cap stains
a deeper pink in H&E stained sections due to its high content of collagen and
smooth muscle cells(H&E).
Fibroatheroma (stable plaque). More developed atheroma plaque, with a large necrotic
core focally calcified containing numerous cholesterol crystals and overlaid by a thick
fibrous cap. Lumen reduction is >75 %.
Atheroma Plaque
Complications
1. Thrombosis
2. Plaque calcification
3. Ulceration
4. Hemorrage
5. Aneurysm formation
1. Thrombosis
Erosion or rupture of the fibrous cap exposes
the atheromatous material to the flowing blood
components, initiating the process of platelet
aggregation and coagulation that will ultimately
lead to thrombus formation.
These thrombi may get dislodged to become
emboli and lodge elsewhere in the circulation,
or may get organised and incorporated into
the arterial wall as mural thrombi. Mural
thrombi may become occlusive thrombi
which may subsequently recanalise.
Atherosclerotic vulnerable plaque diagram showing ( a ) the thin-cap fibrous
atheroma ( arrow ) and necrotic core ( yellow ), rich in lipids ( black ). The cap consists
of smooth muscle cells with a variable number of macrophages and lymphocytes
( green ). Following plaque rupture, ( b ) thrombosis occurs, narrowing the lumen. In
cases of other plaque disease, ( c ) some lipid may be present deep in the lesion, but
the fibrous cap is rich in smooth muscle cells and proteoglycans. There may be some
macrophages, and lymphocytes may be present, but there is no necrotic fibrolipid core.
Erosion of the plaque surface ( d ) allows thrombosis and lumen narrowing
Thrombosis can be secondary to
three distinct processes
(a) Plaque erosion
Characterized by acute thrombosis in direct contact
with the intima.
Generally occurs :
in stenosis of less than 70 % of the lumen.
in 7075 % of Sudden Coronary Death due to coronary thrombosis.
in people aged 3050 years, with no gender preference.
Associated with cigarette smoking thrombosis may be related to
a systemic, prothrombogenic pathway rather than a local,
atherothrombotic mechanism.
Histology :
thick, smooth muscle cellrich fibrous cap
reduced necrotic core area
low degree of inflammation.
Coronary thrombus over an endothelial erosion of fibrous
plaque (elastic van Gieson)
(b) Plaque rupture
Characterized by an interruption in the
fibrous cap with acute thrombosis in
continuity with the underlying lipid
core.
Occur :
Present in 2530 % of SD that occurs from
coronary thrombosis
More frequent in males than in females between
the ages of 3580 years.
It tends to be associated with dyslipidemia,
diabetes and tobacco.
 Plaques rupture :
unable to withstand mechanical stresses
generated by vascular shear forces.
The events include both intrinsic factors (e.g.,
plaque structure and composition) and extrinsic
elements (e.g., blood pressure, platelet reactivity,
vessel spasm).
The composition of plaques contribute
to risk of rupture.
vulnerable plaques : plaques contain large
areas of foam cells and extracellular lipid, and
those in which the fibrous caps are thin or
contain few smooth muscle cells or have clusters
of inflammatory cells
Vulnerable and stable atherosclerotic plaque. Vulnerable plaques have thin
fibrous caps, large lipid cores, and greater inflammation. Stable plaques have
thickened and densely collagenous fibrous caps with minimal inflammation
and underlying atheromatous core.
(c) Calcified nodule
Refers to a heavily calcified plaque in
which there is a rupture of the fibrous cap
and the thrombus is associated with a
protruding and calcified nodule.
Infrequent, in the elderly, more common
in men than in women, more frequent in
the carotid arteries.
Outcome of coronary thrombosis. Thrombus is labile and mural and occlusive
lesions pass from one to the other as a result of natural fibrinolytic activity. If
thrombus is not lysed it is ultimately replaced by collagen produced by incoming
smooth muscle cells. The end result can be anything from chronic total
occlusion, recanalization with multiple new smaller lumens or just a stenotic
2. Plaque calcification
Two distinct patterns :
nodular masses of calcium form within the lipid core
calcification develop in the connective tissue deep
in the intima close to the medial/intimal junction.
Recognized as a regulated process in which
osteopontin, osteonectin and osteocalcin
are involved. Both macrophages and smooth
muscle cells are involved in the production of
bone-promoting substances. Evidence of
osteoclast- and osteoblast-like differentiation
occurs in plaques and bone may be laid down.
3. Ulceration
Result of haemodynamic forces or
mechanical trauma discharge of
emboli composed of lipid material and
debris into the blood stream, leaving a
shallow, ragged ulcer with yellow lipid
debris in the base of the ulcer.
4. Haemorrhage
Intimal haemorrhage may occur in an
atheromatous plaque either from the blood
in the vascular lumen through an
ulcerated plaque, or from rupture of
thin-walled capillaries that vascularise
the atheroma from adventitial vasa
vasorum.
A common complication in coronary arteries.
The haematoma formed at the site contains
numerous haemosiderin-laden macrophages.
5. Aneurysm formation
Changes in media include atrophy,
thinning of the media and
fragmentation of internal elastic
lamina. The adventitia undergoes fibrosis
and some inflammatory changes. These
changes cause weakening in the arterial
wall resulting in aneurysmal dilatation.
The natural history, morphologic features, main pathogenic events, and
clinical complications of atherosclerosis.
Clinical Effects
Depend upon the size and type of
arteries affected:
1. Slow luminal narrowing causing ischaemia
and atrophy.
2. Sudden luminal occlusion causing infarction
necrosis.
3. Propagation of plaque by formation of
thrombi and emboli.
4. Formation of aneurysmal dilatation and
eventual rupture
 Accordingly, the symptomatic atherosclerotic
disease involves most often the heart, brain,
kidneys, small intestine and lower extremities .
The major effects :
i) AortaAneurysm formation, thrombosis and
embolisation to other organs.
ii) HeartMyocardial infarction, ischaemic heart disease.
iii) BrainChronic ischaemic brain damage, cerebral
infarction.
iv) Small intestineIschaemic bowel disease, infarction.
v) Lower extremitiesIntermittent claudication,
gangrene.
A 46-year-old woman who died suddenly whilst sleeping.
( a ) Plaque with lipid appearance that causes luminal stenosis greater than 75
%.
( b ) Fibrolipid plaque with large necrotic core and thick fibrous cap (stable
plaque)
Recanalized thrombosis. A 59-year-old male, without known previous medical
history, who was found dead in bed. He presented with a recanalized
thrombosis in the posterior descending coronary artery and a healed postero-
septal myocardial infarction
Visual assessment of coronary stenosis. In this diagram the different
degrees of diameter stenosis are shown. The higher the grade of
stenosis the greater the degree of certainty that the figure would
reflect significant stenosis in life.
VARICOSITIES
Varicosities are abnormally dilated and
tortuous veins. The veins of lower
extremities most frequently, called
varicose veins.
The veins of other parts of the body
which are affected :
the lower oesophagus (oesophageal varices)
the anal region (haemorrhoids)
the spermatic cord (varicocele).
VARICOSE VEINS
Def : permanently dilated and tortuous
superficial veins of the lower extremities,
especially the long saphenous vein and its
tributaries.
10-12% of the general population develops
varicose veins of lower legs, with the peak
incidence in 4th and 5th decades of life.
Adult females > males, especially during
pregnancy venous stasis in the lower legs
because of compression on the iliac veins by
pregnant uterus.
ETIOPATHOGENESIS
i) Familial weakness of vein walls and valves is the
most common cause.
ii) Increased intraluminal pressure due to prolonged
upright posture e.g. in nurses, policemen, surgeons
etc.
iii) Compression of iliac veins e.g. during pregnancy,
intravascular thrombosis, growing tumour etc.
iv) Hormonal effects on smooth muscle.
v) Obesity.
vi) Chronic constipation.
MORPHOLOGIC FEATURES
The affected veins, especially of the lower
extremities, are dilated, tortuous, elongated
and nodular. Intraluminal thrombosis and
valvular deformities are often found.
Histologically :
Variable fibromuscular thickening of the wall of the
veins due to alternate dilatation and hypertrophy.
Degeneration of the medial elastic tissue may occur
which may be followed by calcific foci.
Mural thrombosis is commonly present which may get
organised and hyalinised leading to irregular intimal
thickening.
EFFECTS
Varicose veins of the legs result in venous stasis
which is followed by congestion, oedema,
thrombosis, stasis, dermatitis, cellulitis and
ulceration. Secondary infection results in chronic
varicose ulcers.
Varicose veins of the leg (arrow)
PHLEBOTHROMBOSIS
AND
THROMBOPHLEBITIS
phlebothrombosis or thrombus formation in veins.
thrombophlebitis or inflammatory changes within the vein wall.
currently used synonymously.

ETIOPATHOGENESIS
Venous thrombosis that precedes thrombophlebitis is initiated by
triad of changes:
Endothelial damage
Alteration in the composition of blood
Venous stasis.
The factors that predispose to these changes are cardiac failure,
malignancy, use of oestrogen-containing compounds,
postoperative state and immobility due to various reasons.
MORPHOLOGIC FEATURES
The most common locations for phlebothrombosis and
thrombophlebitis are the deep veins of legs accounting for
90% of cases; it is commonly termed as deep vein thrombosis
(DVT).
Grossly, the affected veins may appear normal or may be
distended and firm. Often, a mural or occlusive thrombus is
present.

Histologically
the thrombus that is attached to the vein wall induces
inflammatory-reparative response beginning from the intima
and infiltrating into the thrombi. The response consists of
mononuclear inflammatory cells and fibroblastic proliferation.
In late stage, thrombus is either organised or resolved leading
to a thick-walled fibrous vein.
EFFECTS
Local effects are oedema distal to
occlusion, heat, swelling,tenderness,
redness and pain.
Systemic effects are more severe and
occur due to embolic phenomena,
pulmonary thromboembolism being the
most common and most important. Other
systemic manifestations include
bacteraemia and septic embolisation to
brain, meninges, liver etc.
ALHAMDULILLA
H
DAN
TERIMA KASIH