PATHOLOGY 5.

01
ATHEROSCLEROSIS AND VENOUS DISASES
Lecturer: Doc Debbie Dela Fuente | November 28, 2018
Transcriber group: 3B
VASCULAR ABNORMALITIES CAUSE CLINICAL ARTERIOVENOUS FISTULA
DISEASE BY: • Abnormal connection between arteries and veins
Review your normal anatomy of the arteries and which may consist of:
veins, or not lol* o Blood vessel
o A vascular channel formed by canalization of a
Whatever the disease is, it may cause the following thrombus
1. Narrowing of vessel lumina - ischemia o Aneurysmal sac
2. Provoking intravascular thrombosis - vessel • May arise:
obstruction, embolism o As a developmental defect
3. Weakening of the vessel wall - dilatation (aneurysm), o From rupture of an arterial aneurysm into an
rupture (in rare cases) adjacent vein
o As penetrating injuries that pierce the walls of
CONGENITAL ANOMALIES arteries and veins and later form an artificial
BERRY/ SACCULAR ANEURYSM connection
• Arises due to weakness of arterial vessels o Inflammatory necrosis of adjacent veins
• Causes: congenital defect in the media (causing it to • Clinical significance
be weak); other predisposing conditions such as age, o Since blood pressure in the arterial side is higher,
HPN, collagen disease it pushes the blood to the venous side.
• Commonly seen in: o Increased blood flow to venous circulation
o Medium sized vessels → Circle of Willis (most (increases the volume of blood pumped out by the
common: bifurcation of Anterior Communicating heart → high output cardiac failure)
and Anterior Cerebral Arteries) *see photo o May rupture and cause hemorrhage
o At areas of blood vessel bifurcation
▪ Due to the gap in development of the circular VASCULAR RESPONSE TO INJURY
muscular layer in areas of bifurcation • Essence of everything
▪ The high pressure of blood in this area can • Two elements of blood vessels
weaken this area → blood vessels expand and o Endothelium: endothelial activation, endothelial
dilate → aneurysms dysfunction
▪ Clinical significance: Rupture leads to o Smooth Muscle: intimal thickening
subarachnoid hemorrhage ▪ In response to injury they are activated →
migration to intima → proliferation

ENDOTHELIUM
PROPERTIES OF ENDOTHELIAL CELLS
1. Semi-permeable - controls transfer of small and large
molecules
2. Maintain non-thrombogenic interface between blood
and tissue
3. Modulate vascular tone and blood flow
4. Metabolize hormones
5. Controls leukocyte interaction with vessel wall
6. Modifies lipoproteins (LDL) in the artery wall
Figure 1. Left: Common sites of Berry Aneurysms (Circle 7. Regulates growth of other cells
of Willis); Right: Gross 8. Produces extracellular matrix

Figure 3. Healthy Endothelium function (summary).

Figure 2. Left: Berry aneurysm at vessel bifurcation;
Right: Types of aneurysms

Topic (Lecturer): ATHEROSCLEROSIS 1 AND ANEURYSM (Dr. Debbie dela Fuente)

Lecture Date: December 21, 2017
 ENDOTHELIAL ACTIVATION
• As a response to various stimuli, endothelial cells
adjust their steady state-function and express newly
acquired properties
• The change in morphology and behavior of an
endothelial cell resulting from exposure to a cytokine,
chemokine, cellular ligand or soluble factor
• Inducers/stimuli: cytokines, bacterial products,
hemodynamic stress, lipid products, AGEs (advanced
glycation end-products), viruses, complement,
hypoxia, glycosylated products
o Activate endothelial cells, which activate
substances that will allow them to perform new
functions
• Activated endothelial cells express: adhesion
molecules, cytokines, chemokines, growth factors,
vasoactive molecules, coagulation proteins, MHC
molecules, nitric oxide, endothelin and other
biologically active products
o Endothelin – peptides that cause vasoconstriction
and increase blood pressure
ENDOTHELIAL DYSFUNCTION
• The endothelium Cannot resume its original function
→ Disturbance in the proper barrier function of the
endothelium.
• Change in endothelial properties and function → loss
of proper endothelial function
• Results to narrowing of the blood vessel lumen
• Alteration of endothelial phenotype that is often pro-
inflammatory and pro-thrombogenic
• May or may not involve new protein synthesis
• Causes:
o Endothelium dependent dilatation dysfunction →
vasoconstriction
o Inflammation
o Increased thrombotic and hemostatic factors,
decreased anti-thrombotic factors
o Increased vascular smooth muscle cells
proliferation, or atherosclerosis
Basically, the normal function of the endothelium is
reversed.
Figure 4. Endothelial Dysfunction Pathophysiology
ATHEROSCLEROSIS 1 AND ANEURYSM
DR. DEBBIE DELA FUENTE
Figure 5. Basal and activated endothelial cell states.
(Robbins p. 486)
SMOOTH MUSCLE CELLS
• Response of smooth muscle cells (SMCs)
o Vasoconstriction and vasodilation in response to
stimuli
o Synthesis of collagen and proteoglycans (ECM)
o Elaboration of growth factors and cytokines
o Migration and proliferation
• In normal healing of the damaged vascular wall,
neointima is formed:
o Caused by migration of endothelial cells and
smooth muscle cells
o Endothelial cells – migrate from adjacent,
unharmed areas and from into the intima, and they
multiply in the intima
▪ Effect – intimal thickening
o Smooth muscle cells also migrate to the intima.
o Once in the intima SMCs they lose the ability to
contract but they can divide, proliferate and
produce extracellular matrix
INTIMAL THICKENING
• In intimal thickening, there is exaggeration of the
physiological response
Figure 6. Intimal thickening is the stereotypical response
of the vessel wall to any insult.
• Migration of smooth muscle cells from media into
intima
• Proliferation of SMCs → increase in organelles
involved in protein synthesis
• Elaboration of extracellular matrix by SMCs
• Cellular changes in the neointimal SMCs:
o Loss of myosin containing elements
o Increase in organelles involved in protein
synthesis
o Increased mitotic activity
2
Can an endothelial cell be activated and dysfunctional at o Lipoproteins accumulate within the intima where
the same time? they aggregate or are oxidized by free radicals
They can perform their normal function when activated to become modified LDL
but can change their function based on the activated ▪ Modified LDL
substances. o Cannot be completely degraded
o Toxic to endothelial cells, smooth muscle
ARTERIOSCLEROSIS cells and macrophages
• Collective term o Their binding & uptake by the blood vessel
• Group of disorders characterized by thickening and wall stimulate the release of growth factors,
loss of elasticity of the arterial walls cytokines, and chemokines
• Patterns: o Evidence implicating hypercholesterolemia
o Atherosclerosis in atherogenesis includes:
o Monckeberg’s medial calcific sclerosis ❖ Dominant lipids in atheromatous
o Arteriolosclerosis plaques are cholesterol and cholesterol
esters
❖ Genetic defects in lipoprotein uptake
ATHEROSCLEROSIS
and metabolism that cause
• Disease of large and medium-sized arteries hyperlipoproteinemia are associated
• Results in progressive accumulation of SMCs, lipids & with accelerated atherosclerosis
connective tissue within the intima ❖ Other genetic or acquired disorders
• Main lesions: Atheroma or atheromatous plaque (e.g., DM, hypothyroidism) that cause
o Fibrous cap hypercholesterolemia lead to premature
o Necrotic core atherosclerosis
❖ Lowering serum cholesterol causes
PATHOGENESIS OF ATHEROSCLEROSIS regression of plaques and reduces risk
Response to Injury Hypothesis (Fig. 11-10, Robbins of cardiovascular events
p. 495) • Hypertension
• Lesions arise as a response to injury to the arterial • Smoking
endothelium and SMCs • Homocystine
• A chronic inflammatory and healing response of the • Viruses
arterial wall to endothelial injury
• According to this, atherosclerosis progresses in the 2. Endothelial dysfunction
following sequence: • Increased vascular permeability which allows more
o Endothelial injury and dysfunction lipids to enter the intima
o Accumulation of lipoproteins • Increased leukocyte, and platelet adhesion to
o Monocyte adhesion to the endothelium endothelium
o Platelet adhesion • Increased monocyte adhesion & migration
o Factor release • Thrombosis
o SMC proliferation, ECM production, recruitment of • Normally, WBCs do not bind with the endothelium
T cells • During endothelial dysfunction, endothelial cells
o Lipid accumulation express adhesion molecules, cytokines and
chemoattractants that bind various classes of WBC
1. Chronic or repetitive endothelial injury: two important • Macrophages also produce chemotactic factors
causes are hemodynamic factors and 3. Accumulation of LDL in the vessel wall
hypercholesterolemia 4. Monocytes adhere to the endothelium & enter the
• Mechanical denudation intima
• Immune complex deposition • Entry is mediated by chemotactic factors:
• Irradiation o Vascular cell adhesion molecule 1 (VCAM-1)
• Chemicals ▪ Binds monocytes & lymphocytes
• Hemodynamic factors ▪ Expressed by endothelial cells
o Hemodynamic turbulence • Monocytes are transformed into macrophages,
▪ Non-turbulent laminar flow induces which accumulate
endothelial genes to produce “athero- • Macrophages ingest lipid to form foam cells (have
protective products” (this is normal) scavenger receptors for oxidized LDL)
▪ Plaques tend to occur at ostia of exiting • Role of macrophages - they produce:
vessels, branch points, and along the o IL-1 and TNF: increase adhesion of leukocytes
posterior wall of the abdominal aorta, where o Chemokines (MCP-1, M-CSF): recruit leukocytes
there are disturbed flow patterns into plaque
• Hyperlipidemia o Growth factors (PDGF, FGF, TGF): SMC
o Hyperlipidemia causes endothelial dysfunction proliferation & ECM deposition
by: o Toxic oxygen species: oxidation of LDL
▪ Increasing local oxygen species that cause • Monocyte chemoattractant protein 1 (MCP-1)
membrane and mitochondrial damage o Produced by endothelial, smooth cells &
macrophages
• Potent mononuclear chemoattractant

ATHEROSCLEROSIS 1 AND ANEURYSM 3

DR. DEBBIE DELA FUENTE
 o Macrophage colony stimulating factor (MCSF)
o Tissue making proteins
o Oxidized LDL

Figure 7. Left: Attachment of monocyte; Right:

Penetration of monocyte

Figure 8. Transformation of Monocyte to Macrophage

Foam Cell Figure 10. Formation of Cholesterol Crystals

CONSTITUTIONAL RISK FACTORS

5. Platelet adhesion • Age: 40-60 years old
6. Macrophages, platelets, & vascular wall cells release • Gender: estrogen confers protection against
other factors → recruit SMCs from media and atherosclerosis in premenopausal women
circulating precursors • Genetic abnormalities:
• PDGF, FGF, IL-1, TGF-a o Familial predisposition
• Stimulate smooth muscle cell migration o Genetic disease leading to atherosclerosis
7. SMC migration into the intima & proliferation
8. SMC synthesize ECM components (collagen and MODIFIABLE MAJOR RISK FACTORS
proteoglycans) • All lipids in the plasma circulate in combination with
• SMC may also give rise to foam cells proteins (lipoproteins)
9. Lipid accumulates both extracellularly and within • Transport and metabolism of lipids depend on:
macrophages & SMCs o Lipoprotein processing proteins (LCAT, lipoprotein
lipase, hepatic lipase, cholesterol ester transfer
protein)
o Lipoprotein receptors (LDL receptor, chylomicron
remnant receptor, scavenger receptor)

1. Hyperlipidemia - hypercholesterolemia
• Causes:
o Genetic defect in lipid metabolism
▪ Apoproteins
▪ LDL receptors
o Underlying disorder
▪ Nephrotic syndrome
Figure 9. SMCs becoming Foam Cells. ▪ Alcoholism
▪ Hypothyroidism
▪ DM
• Role of increased plasma lipid:
o Directly impairs endothelial function thru
production of superoxide & free radicals (ROS)
▪ Increased permeability
▪ Increased replication
▪ Increased monocyte adhesion

ATHEROSCLEROSIS 1 AND ANEURYSM 4

DR. DEBBIE DELA FUENTE
 o Increase the rate of lipid penetration into the
arterial wall where lipid is oxidized by free
radicals
▪ Lipoproteins accumulate at sites of increased
endothelial permeability
o Oxidized or modified LDL is readily ingested by
macrophages via scavenger receptors to form
foam cells (SMCs can also become foam cells)
o Oxidized LDL
▪ Readily ingested by macrophages
▪ Chemotactic for monocytes
▪ Increase monocyte adhesion
▪ Inhibits motility of monocytes in the lesion
▪ Stimulates release of growth factors,
chemokines & cytokines
▪ Cytotoxic to endothelial cells & SMC
2. Hypertension
• Induces endothelial damage
o Endothelial activation
o Endothelial dysfunction
3. Cigarette-smoking
• Lowers HDL levels
• Damages endothelium
• Elevates fibrinogen & plasminogen activator
inhibitor which contributes to thrombosis
o Growth factors (leads to SMC proliferation)
o Synthesis of ECM
• C-reactive protein
o Circulating marker of inflammation
o Induces prothrombotic state
o Increases adhesiveness of endothelium for
leukocytes
2. Hyperhomocystinemia
• Homocysteine is a toxic by-product of protein
metabolism
• Due to: low folate and Vitamin B intake,
homocystinuria
• Endothelial cells (aortic) lack the full capacity to
degrade homocysteine
• Effects:
o Endothelial cells become prothrombotic
o Auto-oxidation of homocysteine gives rise to
free radicals (hydrogen peroxide) that cause
endothelial dysfunction
3. Metabolic syndrome - a combination of medical
disorders
• Insulin resistance, hypertension, dyslipidemia,
hypercoagulability, pro-inflammatory state
(those in bold font – major contributors to
endothelial dysfunction)

4. Diabetes mellitus 4. Lipoprotein (a) - altered form of LDL

• Induces hypercholesterolemia • Reduced fibrinolysis
o Increases triglyceride, VLDL, thromboxane A2 • Thrombogenesis
o Decreases HDL • Transports proinflammatory oxidized phospholipids
• Increased production of AGE (Advanced Glycation which attract inflammatory cells and leads to SMC
End products); AGE-Receptors for AGE binding proliferation
results in:
o Release of cytokines & growth factors 5. Factors affecting hemostasis
o Proliferation of vascular SMC 6. Lack of physical activity
o Synthesis of ECM 7. Stressful lifestyle
o Generation of ROS in endothelial cells 8. Obesity
• AGE also crosslinks extracellular matrix proteins
leading to: MORPHOLOGY (ATHEROSCLEROSIS)
o Decreased vessel elasticity • Atherosclerotic plaque
o Decreased adhesion between endothelial cells o Parts:
o Increased resistance of proteins to proteolytic ▪ Fibrous cap - SMCs, macrophages, foam cells,
digestion lymphocytes, collagen, elastin
o Trapping of LDL in the vessel wall ▪ Necrotic center (or lipid center) - cell debris,
• Activates protein kinase C cholesterol crystals, foam cells,
o Protein Kinase C is involved in controlling the neovascularization, calcium
function of peptides ▪ Three components:
o Production of fibrogenic factors • Cells - SMC, macrophages, T cells
o Production of cytokines • Extracellular matrix - collagen, elastic fibers,
proteoglycans
ADDITIONAL RISK FACTORS • Intracellular & extracellular lipid
1. Inflammation (present in all stages of atherogenesis) ▪ Sites (ranked, most to least common):
• REMEMBER: Antherosclerosis is a chronic • Lower abdominal aorta & iliac arteries
inflammatory process • Proximal coronary arteries
• Cholesterol crystals & free fatty acids activate • Femoral & popliteal arteries
inflammasome → IL-1 production → (end effect) • Internal carotid arteries
recruit & activate leukocytes (monocytes & T-cells) • Circle of Willis
o Inflammsasome recognizes products of dead
cells
• Activated monocytes and leukocytes produce:
o Cytokines & chemokines (recruit and activate
more inflammatory cells)
o ROS (enhance LDL oxidation)
ATHEROSCLEROSIS 1 AND ANEURYSM 5
DR. DEBBIE DELA FUENTE
Figure 11. Components of an Atheromatous plaque.
(Robbins, p. 492)
Figure 15. Fatty streak gross

Figure 12. Fibrous cap and underlying necrotic center

(blue arrow) w/ cholesterol clefts

Figure 16. Fatty Streak and Foam cells histology.

(Robbins p. 497)

Figure 13. Moderate to severe occlusion
COMPLICATIONS (ATHEROSCLEROSIS)
• Rupture, ulceration, or erosion → thrombosis
• Hemorrhage into plaque
• Atheroembolism
• Aneurysm formation
o Due to the ischemic atrophy of media and loss of
elastic tissue resulting from the atherosclerosis
• Calcification

CONSEQUENCES OF ATHEROSCLEROTIC DISEASE

• Large elastic arteries, and large & medium muscular
arteries are the major targets of atherosclerosis
• MI, cerebral infarction, aortic aneurysms, and
peripheral vascular disease (gangrene of legs) are the
major consequences

1. Stenosis → ischemia
• Critical stenosis: 70% occlusion →
o Sudden cardiac death
o Ischemic heart disease
Figure 14. “At the bottom, the mild atherosclerosis
o Mesenteric occlusion → bowel ischemia
shows only scattered lipid plaques. The aorta in the
o Ischemic encephalopathy
middle shows many more larger plaques. The severe
o Intermittent claudication (extremities): pain in
atherosclerosis in the aorta at the top shows extensive
foot and lower legs while walking
ulceration in the plaques.”
2. Acute plaque change
• Rupture/fissuring: exposes thrombogenic
• Fatty streak – made up of foam cells (lipid-filled
plaque constituents
macrophages); not all evolve into plaques
• Erosion/ulceration: exposes thrombogenic
o May be seen in children
subendothelial basement membrane to blood
o Not all become atheromas
• Hemorrhage into the atheroma: expands
o Lipid-filled foam cells
volume of atheroma
o Related to known risk factors of atherosclerosis
• Due to:
o Sometimes develop in areas where atheromas
o Extrinsic factors
don’t develop
▪ Mechanical stress of vascular shear forces
o Consist mainly of foam cells and nothing else
(hypertension)
o Pale streaks that are not elevated (see images
▪ Adrenergic stimulation
below)
o Intrinsic factors
o No SMC proliferation, lipid core, or fibrous cap
▪ Composition of plaques:

ATHEROSCLEROSIS 1 AND ANEURYSM 6

DR. DEBBIE DELA FUENTE
 o More likely to rupture (vulnerable
plaques) - large areas of foam cells &
extracellular lipid; thin fibrous caps; few
SMCs; many clusters of inflammatory
cells
▪ Remodeling of fibrous cap: increased
collagen degradation & decreased collagen
synthesis
3. Thrombosis and embolism
• Thrombosis superimposed on a disrupted plaque
can lead to total occlusion
4. Vasoconstriction
• Caused by circulating adrenergic agonists
• Compromises luminal diameter
• Can potentiate plaque disruption and weakening of
vessel wall giving rise to aneurysm
• Due to:
o Circulating adrenergic agonists
o Locally released platelet contents
o Impaired secretion of NO (endothelial relaxing
factor)
o Mediators released from perivascular
inflammatory cells
GENERAL CONSEQUENCES
• Circle of Willis & carotids
o Acute local ischemia → cerebral infarction (stroke)
o If occlusion is not so much: chronic ischemia of
brain → multi-infarct dementia
• Coronaries
o Acute infarction
o Chronic ischemia of myocardium w/ fibrosis
o Eventually leads to cardiac failure
• Abdominal aorta
o Aneurysm → embolism to legs
• Renal arteries
o Chronic ischemia of kidneys
• Visceral arteries
o Acute and chronic ischemia of bowels
• Lower limb arteries
o If severe, chronic ischemia with claudication and
gangrene
JUST REMEMBER THE PATHOGENESIS AND MAJOR RISK
FACTORS!!! (Daw sabi sa recordings)
MONCKEBERG’S MEDIAL CALCIFIC SCLEROSIS
• Age-related degenerative calcification of the media of
large- and medium-sized arteries
• Morphology: ring-like calcification in the media of
medium-sized to small muscular arteries
o Femoral artery
o Tibial artery
o Radial artery
o Ulnar artery
o Arterial supply of the genital tract
• Age-related degenerative process: of no clinical
significance (no luminal narrowing); no ischemia or
infarction
ATHEROSCLEROSIS 1 AND ANEURYSM
DR. DEBBIE DELA FUENTE
Figure 17. Monckeberg’s Medial Calcific Sclerosis
ARTERIOLOSCLEROSIS
• Affects small arteries and arterioles; most often
associated with hypertension & diabetes mellitus
HYALINE ARTERIOLOSCLEROSIS
• May or may not be associated with hypertension
• May be seen in:
o Hypertensive disease
o Patients with diabetes mellitus
o Aging (as a physiologic phenomenon)
• Pathogenesis:
o Caused by chronic hemodynamic stress (in
hypertension) and metabolic stress (in
hyperglycemia) lead to endothelial injury
o Leakage of plasma components and ↑ ECM
production by SMC
o Hyaline deposition
• Morphology:
o Homogenous pink thickening of the arteriolar walls
o Narrowing of the lumen
• Clinical significance:
o Narrowing of the lumen impairs blood supply
Figure 18. Hyaline Arteriosclerosis Histology
HYPERPLASTIC ARTERIOLOSCLEROSIS
• Seen in: severe or malignant hypertension
• Pathogenesis
o Endothelial injury due to increased pressure,
hypoxia or immunologic damage allow entry of
plasma proteins into the intima
o Followed by a healing reaction of the vessel wall:
▪ Migration and proliferation of SMC from media
▪ Fibrosis
• In contrast to hyaline arteriolosclerosis
• Morphologic patterns
o Onion-skin lesion: loosely disposed layers of SMC
creating a concentric laminated thickening
o Mucinous intimal thickening
o Fibrous intimal thickening
o Necrotizing arteriolitis: fibrinoid necrosis of
arteriolar wall
7
 o Pregnancy - compression of the iliac veins and
increased blood volume
o Obesity

Notes:
In severe cases of varicose veins, the valves no longer close so the
blood is dumped back into the more distal portion (tortuous
varicose diseases in the extremities).

Based on recording:
Normal valves would allow blood to flow unidirectionally. When
Figure 19. Onion skin thickening of arterioles causing valves are incompetent, blood under force of gravity distends the
narrowed lumen section of the vein below, causing further valves to fail.

MORPHOLOGY:
GROSS
• Dilated, tortuous, elongated veins (nodular)
• Variable wall thickness
o Dilated area wall is thinned out while there
may be hypertrophy in thin areas
• Intraluminal thrombosis
• Valvular deformities

HISTOLOGY
• Hypertrophy of smooth muscles
Figure 20. Fibrinoid necrosis undergone by this renal • Sub-intimal fibrosis (in thick areas of the veins)
arteriole • Degeneration of medial elastic fibers with spotty
calcification (phlebosclerosis)
VENOUS DISEASES • Thrombosis
SIGNIFICANCE OF VENOUS DISEASES
1. Predispose to intravascular thrombosis and potential
embolism → pulmonary embolism and infarction
2. Intravascular thrombosis, narrowing or abnormal
dilatation cause venous stasis → passive congestion
→ dusky cyanosis & edema

VARICOSE VEINS
• Dilated or tortuous veins in the lower extremities.
• Dilatation of the veins due to increased luminal
pressure and loss of vessel support.
• Varicose veins and thrombophlebitis account for 90%
of clinical venous diseases.
• REMEMBER (normally):
o Valves are closed when the person is not
ambulating.
o During movement, the skeletal muscle pumps,
squeezing the blood vessel → blood pumps
upward → valves open.
• The superficial veins of the upper and lower leg are Figure 21. Comparison of normal valve and
incompetent valve (one of the etiologies of varicose
commonly involved because venous pressures in
veins). Normal valve allows a unidirectional blood flow.
these sites can be markedly elevated (up to 10
Varicose veins are produced by prolonged, increased
times) by prolonged dependent posture.
intraluminal pressure leading to vessel dilatation and the
• When there is something wrong with the muscle that
incompetence of the venous valves.
are supposed to squeeze the veins, it causes varicose
veins.
• Involved: superficial veins CLINICAL COURSE
• Valves become incompetent → venous stasis (blood
remains in lower extremeties), causing: congestion,
Etiology and Pathogenetic Factors
• Weakness of venous walls and valves edema, thrombosis.
o Thromboembolism - more common in deeper
o Genetic - defective development of walls
veins because the contraction of surrounding
o Aging - atrophy of perivenous soft tissues
• Increased intraluminal venous pressure muscles can milk the contents of the veins
remove the attachment of thrombus from
o Posture - most important influence; when legs
venous wall.
are not ambulant for long period of time

ATHEROSCLEROSIS 1 AND ANEURYSM 8

DR. DEBBIE DELA FUENTE
• Stasis dermatitis (“brawny induration”; the brawny Notes:
color comes from the hemolysis of extravasated red
• In liver problems, blood can be shunted towards the
cells) and ulceration
esophageal plexus where varices will form
o Due to impairment of tissue nutrition
o Skin becomes thin, shiny, bluish brown • Blood flow in cirrhotic liver: portal vein → gastric vein →
o In severe cases, can give rise to varicose ulcers esophageal branches of the left gastric vein →
and poor wound healing esophageal plexus → azygous vein → vena cava
o Esophageal plexus becomes very prominent
o Blood can also go to phrenic vein → short
Notes:
gastric vein → esophageal plexus
• Thromboembolism is more common in the deeper veins in the
legs because contraction of the surrounding muscles results to
removal of the content of the veins from the attachment to the
venous walls.
• In stasis dermatitis and ulceration, skin becomes thinned out,
shiny, and bluish brown or irregularly pigmented. Varicose may
also occur because of impaired circulation leading to ulceration
and poor wound healing.

VARIANTS OF VARICOSE VEINS

ESOPHAGEAL VAROCES • Or in simpler terms: liver cirrhosis → portal vein

• Coronary veins of the distal esophagus and cardia of
hypertension → opening of portosystemic shunts that
the stomach
increase blood flow into veins at the gastroesophageal
• Due to:
junction
o Presence of collaterals
o Obstruction of the portal venous flow
• Often seen in alcoholics with cirrhosis and esophageal
varices
▪ When there is a block, the blood draining
these areas cannot go through the normal o Alcoholic binge → vomits forcefully → can rupture
route. and cause fatal bleeding
▪ It will find another way, since this blood
vessel has many tributaries.
HEMORRHOIDS
Review of anatomy: • Primary varicose dilatation of the venous plexus at
Portal vein receives branches from: splenic vein (spleen), the anorectal junction
inferior mesenteric vein and superior mesenteric vein • Types:
(bowels), left gastric vein (stomach). o External hemorrhoids (below dentate line)
• When there is obstruction in the portal vein, it may ▪ Inferior hemorrhoidal venous plexus which
find collaterals in other places, like in the normally drains to the inferior iliac veins
esophagus. From left gastric vein → esophageal covered by squamous epithelium
plexus → esophageal branches of azygos vein → o Internal hemorrhoids (above dentate line)
inferior vena cava. ▪ Submucosal internal hemorrhoidal plexus
• These collaterals are small, when they receive too covered by transitional and columnar
much blood, they become dilated. epithelium
o From prominent branches, as seen below • Due to:
o Hereditary defect
o Erect posture
▪ Obstruction of venous return caused by
increased intra-abdominal pressure
(pregnancy, straining)
▪ Portal hypertension
• Complications:
Endoscopy: nodular appearance is due to the
o Thrombosis
prominence of the varicosities
o Ulceration
o Hemorrhage
• Most commonly found in chronic alcoholics
o Infection
o Cirrhotic liver
• Superior vena cava obstruction
o Portal vein thrombosis
o Hepatic vein thrombosis
o Pyelephlebitis and tumor compression of the
major portal trunk

ATHEROSCLEROSIS 1 AND ANEURYSM 9

DR. DEBBIE DELA FUENTE
 Notes: • Thrombosis may occur in:
o Malignancy
• Hemorrhoids can also be seen when you have portal
o Cardiac disease with congestive heart failure
hypertension
o Pregnancy
• Blood follows a collateral flow making hemorrhoidal plexus o Post-operative states
very prominent o Obesity
o Prolonged immobilization
• Thrombosis leads to inflammatory changes within
the vessel wall

Table 1. Causes of venous thrombosis

Vessel Hypercoagulability Venous Stasis
Wall
Injury
• Venous • Stress • Bed rest
• External hemorrhoids are usually painful because of the catheters • Trauma • Immobility
distention of the skin around the clot and thrombosis • Surgery • Pregnancy and • Spinal cord
• Internal hemorrhoids is not that painful because the area is • Trauma childbirth injury
not supplied by the somatic sensory nerves • Infection • Oral • Acute
contraceptive myocardial
• Complications:
use infarction
o Internal hemorrhoids: bleeding, prolapse, perianal
• Dehydration • Congestive
itching and irritation
• Cancer heart
o External hemorrhoids: thrombosis, pain, bleeding
failure
• Mixed hemorrhoids- involvement of both plexuses • Shock
• Venous
VARICOCELE obstruction
• Mass of varicose veins of the pampiniform plexus of
the spermatic cord MORPHOLOGY
• May appear normal or may be distended and firm to
palpation
Notes: • Thrombus is easily separated from vessel wall
• Pampiniform plexus drains the testes and epididymis → renal • inflammatory-reparative process is seen at point of
vein (left) and inferior vena cava (right) attachment
• Occurs more commonly on the left side because the left
spermatic vein is longer and therefore can be compressed SITES
between the superior mesenteric artery and the aorta • Deep leg vein in 90%
(congestion) • Periprostatic venous plexus in males
• Can cause infertility because of stasis of blood and can also be • Pelvic venous system in females
associated with epididymal conditions leading to • Large veins in the skull
hypospermatogenesis • Dural sinuses

CLINICAL MANIFESTATIONS
THROMBOPHLEBITIS • Edema
(Venous Thrombosis/ Phlebothrombosis) • Dusky cyanosis
• Thrombophlebitis and phlebothrombosis are • Pain and tenderness
interchangeable designations for venous • Heat, redness, swelling
thrombosis and inflammation. • Homan’s sign
• It involves an inflammatory process that causes a Notes:
blood clot to form and block one or more veins,
usually in the legs.
• Deep leg veins are involved in 90% of cases.
• The affected vein may be located near the surface
(superficial thrombophlebitis) or deep within a
muscle (deep vein thrombosis or DVT)

ETIOLOGIC AND PATHOGENETIC FACTORS:

• Pathogenetic factors in venous thrombosis:
o Changes in the vessel (e.g. Endothelial damage)
o Changes in the composition of the blood
▪ Hypercoagulability
o Disturbance in the blood flow
▪ Venous stasis → prolonged immobilization→
slowing of venous return (in congestive heart
failure, pregnancy, obesity)
ATHEROSCLEROSIS 1 AND ANEURYSM
DR. DEBBIE DELA FUENTE
• Homan’s sign: dorsiflexion of foot → pain (sign of DVT)
• Affected leg may appear normal or may be distended and
firm to palpation
• Inflammation usually seen initially in the point of
attachment the spreading to adjacent areas
10
TYPES: • If the bacteria are not contained within the lymph
1. Superficial thrombophlebitis nodes, they escape into the venous circulation
• Varicose veins in the legs causing bacteremia/sepsis.
• IV sites • Sometimes, there may be fibrosis and obstruction of
the lymphatic vessels which can result in chronic
2. Thrombophlebitis migrans lymphedema, since the obstruction prevents
• Recurrent episodes of venous thrombosis of the drainage of the lymph.
extremities and viscera • Chronic lymphangitis → permanent lymphatic
• Due to development of emboli fibrosis and obstruction
• Usually in malignancies where the
hypercoagulability occurs as a paraneoplastic LYMPHADEMA
syndrome • Swelling of soft tissue caused by localized
increase in the quantity of lymph
3. Phlegmasia alba dolens (“painful white leg”) • Often secondary if the lymphatic vessels are
• Iliofemoral venous thrombosis obstructed by tumors or if regional lymph nodes are
• In third trimester of pregnancy or in patients who surgically removed
had extensive pelvic surgery o e.g. In radical mastectomy with axillary
dissection, the axillary lymph nodes are
*Uterus becomes so large where it compresses the left removed thus there is nowhere for lymphatics in
common iliac vein against the pelvic rib therefore blocking the upper extremity of the involved side to flow,
the veins and the lymphatics resulting to massive swelling causing edema.
of the leg
1. PRIMARY LYMPHEDEMA
4. Phlegmasia cerulean dolens • Congenital Lymphedema or Milroy disease
• More severe o Autosomal dominant but can occasionally be
• Fulminant form of venous thrombosis autosomal recessive
characterized by pain, extraordinary edema and o Manifestations present at birth or develops
cyanosis of the affected leg during the first year of life
• Complete obstruction of venous blood flow, o FLT4 gene mutations → disrupts
including collaterals lymphangiogenesis causing lymphatic
• Most common etiology: malignancy agenesis or hypoplasia
• Thrombosis extends to the collateral veins with o Usually involves lower extremities
complete obstruction of venous outflow
• Lymphedema praecox or Meige disease
NOTE: May-Thurner syndrome (MTS), also known as o Most common form of primary lymphedema
the iliac vein compression syndrome, is a condition in o Develops at puberty or before 35 years
which compression of the common venous outflow tract o FOXC2 gene mutations → causes
of the left lower extremity may cause discomfort, incompetent valves of lymphatics
swelling, pain or blood clots (deep venous thrombosis) in o Usually unilateral lower extremity involvement
the iliofemoral veins. o Associated with a disease called districhiasis
syndrome
LYMPHANGITIS
• Lymphangitis is inflammation of the lymphatic
vessels.

ETIOLOGY
• Often due to beta-hemolytic Streptococcus sp. and
Staphylococcus sp., but can also be caused by any
microbe
Figure 22. Lymphedema districhiasis syndrome. In
MORPHOLOGY addition to the swelling of the limbs (lymphedema),
• Dilated lymphatic channels filled with exudates typically the legs and feet; another characteristic of this
• Usually associated with cellulitis and abscesses syndrome is the growth of extra eyelashes (districhiasis)
• Acute lymphadenitis causing eye problems such as the scarring of the cornea,
among others.
CLINICAL MANIFESTATIONS
• Painful subcutaneous red streaks along the course of • Lymphedema tarda
the lymphatics o Variant of Meige disease
• Painful enlargement of the lymph nodes draining the o Also involves a problem with FOXC2 gene
area o Presents after 35 years
o May be related to valvular defects in the
CLINICAL COURSE lymphatic vessels
• Most often, patients completely recover with
appropriate treatment.

ATHEROSCLEROSIS 1 AND ANEURYSM 11

DR. DEBBIE DELA FUENTE
2. SECONDARY LYMPHEDEMA Not discussed but included in 2020 trans
• Obstruction by tumors; blockage of a previously SUPERIOR VENA CAVA SYNDROME
normal lymphatic • Caused by compression or invasion of the superior
• Removal of regional lymph nodes in surgery vena cava by neoplasms or aneurysms such as
• Post-irradiation bronchogenic carcinoma or mediastinal lymphoma.
• Filariasis • It may be caused by other space-occupying lesions
• Post-inflammatory fibrosis and scarring of in the mediastinum such as aortic aneurysms.
lymphatic channels (chronic lymphangitis) • The obstruction causes marked dilation of the veins
of the head, neck, and arms with cyanosis.
Summary: Pulmonary vessels can also be compressed causing
Primary Lymphedema – congenital respiratory distress.
• Congenital/Milroy disease • Complications:
o Autosomal dominant/recessive o Dyspnea
o At birth or up to the first year of life o Headache
o FLT4 gene mutation o Facial edema
o Venous distention in the neck and distended
• Lymphedema praecox/Meige disease
veins in the upper chest and arms
o Most common
o Upper limb edema
o Puberty to before 35 years of age
o Lightheadedness
o FOXC2 gene mutation
o Cough
• Lymphedema tarda
o Edema of the neck
o Variant of Meige disease
o After 35 years
INFERIOR VENA CAVA SYNDROME
o FOXC2 gene mutation
• Due to:
Secondary Lymphedema - obstructive
o Neoplasms that compress or invade the IVC
o Thrombosis of the hepatic, renal or lower
MORPHOLOGY extremity veins that progress Cephalad (toward
• Dilatation of the lymphatic up to the point of head of anterior end)
obstruction • Edema of the lower extremities (peripheral edema
• Increased interstitial fluid due to increase in the venous blood pressure)
• Other skin changes • Tachycardia
o Increased subcutaneous interstitial fibrosis o Due to decreased preload, causing the heart to
(“orange-peel appearance”) increase its frequency
o Verrucoid epidermal hyperplasia with • In pregnant women
hyperkeratosis o Signs of fetal hypoxia and distress
o Tuberous chronic lymphedema - papules and o Due to decreased perfusion of the uterus
nodules resulting in hypoxemia of the fetus
o Skin ulcers • Supine hypotensive syndrome
o Pallor, bradycardia, sweating, nausea,
COMPLICATIONS hypotension and dizziness
• Recurrent cellulitis (most common complication) o Occurs when a pregnant woman lies on her back
• Rupture → chylous ascites, chylothorax,
chyloperitoneum --END—
• Some chronic cases progress to malignancies
(lymphangiosarcoma)

Notes (from Robbins):

• Regardless of the cause, lymphedema increases the
hydrostatic pressure in the lymphatics distal to the obstruction
and causes increased interstitial fluid accumulation.
• Persistent edema and subsequent deposition of interstitial
connective tissue leads to peau d’orange or orange peel
appearance of the overlying skin, seen typically in skin overlying
breast cancers after the draining lymphatics are clogged with
tumor cells; ulcers may develop due to inadequate tissue
perfusion.
• Rupture of dilated lymphatics (e.g. secondary to obstruction by
a tumor) leads to milky accumulations of lymph (chylothorax,
chylopericardium, ascites).

ATHEROSCLEROSIS 1 AND ANEURYSM 12

DR. DEBBIE DELA FUENTE
 b. FALSE

10. Regarding the role of chronic hyperlipidemia in

atherogenesis, lipoproteins accumulate in the intima
where they oxidized to modified LDL:
Select one:
a. FALSE
b. TRUE

11. Regarding the role of chronic hyperlipidemia in

atherogenesis, modified LDL are toxic to endothelial cells,
smooth muscle cells and macrophages. Select one:
a. FALSE
b. TRUE

12. Regarding the role of chronic hyperlipidemia in

atherogenesis, modified LDL stimulate release of growth
factors, cytokines and chemokines. Select one:
Kapit lang doc! Isang linggo nalang 😊 a. FALSE
b. TRUE
REFERENCES: TRANSCRIBED BY:
13. Regarding the role of inflammation in atherosclerosis,
• Recordings • GROUP 3B
activated leukocytes in the vascular wall release growth
• Robbins • SUBTRANSHEAD: LCM
factors that promote smooth muscle cell proliferation and
• 2020 trans • TRANSHEAD: LFM
production of extracellular matrix. Select one:
• Lecture notes
a. FALSE
b. TRUE
PAST E
(1-5) Matching Type. Arrange the following events in 14. Regarding the role of inflammation in atherosclerosis,
atherogenesis chronologically. activation of inflammasomes trigger macrophage and T
A. First event cell activation. Select one:
B. Second event a. FALSE
C. Third event b. TRUE
D. Fourth event
E. Last event 15. Regarding the role of inflammation in atherosclerosis,
1. synthesis of extracellular matrix in the intima by inflammation is triggered by accumulation of cholesterol
smooth muscle cells – last event crystals and free fatty acids in cells. Select one:
2. accumulation of lipoproteins in the blood vessel wall – a. FALSE
second event b. TRUE
3. endothelial injury – first event
4. adhesion of monocytes and platelets onto the intima –
third event
5. smooth muscle cell migration and proliferation –
fourth event

6. Regarding atheromas and fatty streaks, both are

composed of a lipid core and a fibrous cap. Select one:
a. TRUE
b. FALSE

7. Regarding atheromas and fatty streaks, both contain

foam cells. Select one:
a. TRUE
b. FALSE

8. Regarding atheromas and fatty streaks, fatty streaks

always give rise to atheromas:
Select one:
a. FALSE
b. TRUE

9. Regarding the role of chronic hyperlipidemia in

atherogenesis, lipoproteins increase production of local
reactive oxygen species which directly impairs endothelial
cell function. Select one:
a. TRUE
ATHEROSCLEROSIS 1 AND ANEURYSM 13
DR. DEBBIE DELA FUENTE